Pediatric

Respiratory Diseases
A Comprehensive Textbook
Pablo Bertrand
Ignacio Sánchez
Editors

123
Pediatric Respiratory Diseases
Pablo Bertrand  •  Ignacio Sánchez
Editors

Pediatric Respiratory
Diseases
A Comprehensive Textbook
Editors
Pablo Bertrand Ignacio Sánchez
Pontificia Universidad Católica de Chile Pontificia Universidad Católica de Chile
Santiago Santiago
Chile Chile

Translation from the Spanish language edition: “Enfermedades Respiratorias del

Niño  - Segunda edición” by Pablo Bertrand and Ignacio Sánchez. © Ediciones
Universidad Católica de Chile (Ediciones UC) Pontificia Universidad Católica de
Chile, 2016. Original Publication ISBN 978-956-14-1945-2. All rights reserved.

ISBN 978-3-030-26960-9    ISBN 978-3-030-26961-6 (eBook)

https://doi.org/10.1007/978-3-030-26961-6

© Springer Nature Switzerland AG 2020

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Contents

1 History of Specialist Training in Respiratory Diseases����������������   1

Ignacio Sánchez
Introduction��������������������������������������������������������������������������������������    1
The Situation in South America������������������������������������������������������    1
Sources��������������������������������������������������������������������������������������������    4
2 Development of the Respiratory System����������������������������������������   5
Fernando Iñiguez Osmer and Ignacio Sánchez
Introduction��������������������������������������������������������������������������������������    5
Stages in Lung Development ����������������������������������������������������������    5
Development of Bronchial Circulation��������������������������������������������    8
Respiratory Mechanics��������������������������������������������������������������������    9
Lung Weight/Body Weight and Lung Volume/Body
Weight Ratios����������������������������������������������������������������������������������    9
Genetic Control of Lung Development��������������������������������������������   10
Factors That Influence Lung Development��������������������������������������   11
Conclusion ��������������������������������������������������������������������������������������   14
Sources��������������������������������������������������������������������������������������������   15
3 Physiological Basis of the Respiratory System������������������������������  17
Pablo Bertrand and Ignacio Sánchez
Respiratory Mechanics��������������������������������������������������������������������   17
Airway Resistance ��������������������������������������������������������������������������   19
Pulmonary Ventilation����������������������������������������������������������������������   20
Alterations in Pulmonary Ventilation����������������������������������������������   21
Pulmonary Circulation ��������������������������������������������������������������������   22
The Ventilation/Perfusion Ratio������������������������������������������������������   23
Respiratory Gases in the Blood��������������������������������������������������������   24
Sources��������������������������������������������������������������������������������������������   27
4 Clinical History and Physical Examination of the Respiratory
System ����������������������������������������������������������������������������������������������  29
Pablo Bertrand
Anamnesis����������������������������������������������������������������������������������������   29
Physical Examination����������������������������������������������������������������������   31
Sources��������������������������������������������������������������������������������������������   36

vii
viii Contents

5 Physiological Evolution of Sleep ����������������������������������������������������  37

Mara Cvejic and Christian Guilleminault
Introduction��������������������������������������������������������������������������������������   37
History and Anamnesis��������������������������������������������������������������������   38
Age and Development����������������������������������������������������������������������   38
The Fetal Stage��������������������������������������������������������������������������������   38
Premature Newborns������������������������������������������������������������������������   39
Newborns ����������������������������������������������������������������������������������������   39
Infants����������������������������������������������������������������������������������������������   41
Preschool Children and Older Infants (1–3 Years of Age)��������������   42
Schoolchildren and Neuronal Plasticity������������������������������������������   42
Adolescents��������������������������������������������������������������������������������������   43
Risk Factors and Academic Performance����������������������������������������   44
Specific Sleep-Associated Symptoms����������������������������������������������   45
Sources��������������������������������������������������������������������������������������������   45
6 Immunological Defense Mechanisms
of the Respiratory System ��������������������������������������������������������������  47
Arturo Borzutzky Schachter and Pamela Morales Matamala
Organization of the Respiratory Immune System����������������������������   47
Immune Induction in the Lung��������������������������������������������������������   48
Innate Immunity������������������������������������������������������������������������������   48
Adaptive Immunity��������������������������������������������������������������������������   49
Immune Responses to Respiratory Infections����������������������������������   50
Immunology of Acute Alveolar Damage and Tissue Repair ����������   51
The Microbiome������������������������������������������������������������������������������   52
Sources��������������������������������������������������������������������������������������������   52
7 New Frontiers in Research on the Respiratory System����������������  55
Andrew Bush and Luis Enrique Vega-Briceño
Cystic Fibrosis as a Model for Dealing
with Chronic Lung Disease��������������������������������������������������������������   56
Chronic Lung Disease Crises or Attacks: Lessons for
a Long-Term Response��������������������������������������������������������������������   60
Genetically Associated Diseases and Their Close Systemic
Relationship: Ciliopathy������������������������������������������������������������������   62
Learning from Follow-Up Studies on Chronic Lung Diseases��������   65
The Microenvironment of the Airway and Development
of Respiratory Diseases: The Microbiome��������������������������������������   66
Sources��������������������������������������������������������������������������������������������   70
8 Evaluation of Pulmonary Function in Infants
and Preschool Children ������������������������������������������������������������������  73
Alejandro Teper, Carlos Kofman, and Alejandro Colom
Pulmonary Function in Infants��������������������������������������������������������   73
Measurement Conditions ����������������������������������������������������������������   74
Methods��������������������������������������������������������������������������������������������   74
Pulmonary Function in Preschool Children������������������������������������   80
Sources��������������������������������������������������������������������������������������������   82
Contents ix

9 Assessment of Pulmonary Function in Schoolchildren

and Adolescents��������������������������������������������������������������������������������  85
Marcela Linares Paserini and Solange Caussade Larraín
Introduction��������������������������������������������������������������������������������������   85
Spirometry and the Flow/Volume Curve������������������������������������������   86
Peak Expiratory Flow����������������������������������������������������������������������   89
Bronchial Provocation Tests������������������������������������������������������������   89
Provocation Test with Exercise��������������������������������������������������������   90
Methacholine-Induced Bronchial Test ��������������������������������������������   90
Static Lung Volume Measurement ��������������������������������������������������   91
Plethysmography������������������������������������������������������������������������������   91
Helium Dilution ������������������������������������������������������������������������������   92
Nitrogen Wash����������������������������������������������������������������������������������   93
Lung Carbon Monoxide Diffusion��������������������������������������������������   93
Airway Resistance ��������������������������������������������������������������������������   94
Exhaled Nitric Oxide Measurement������������������������������������������������   95
Evaluation of Respiratory Muscle Strength ������������������������������������   95
Sources��������������������������������������������������������������������������������������������   95
10 Assessment of Respiratory Muscular Function
in Patients with Neuromuscular Diseases��������������������������������������  97
Solange Caussade Larraín
Introduction��������������������������������������������������������������������������������������   97
General Respiratory Muscle Assessment����������������������������������������   98
Muscular Strength����������������������������������������������������������������������������  101
Muscular Fatigue ����������������������������������������������������������������������������  104
Conclusion ��������������������������������������������������������������������������������������  104
Sources��������������������������������������������������������������������������������������������  105
11 Study of Images in Respiratory Diseases �������������������������������������� 107
Cristián García Bruce and Rodrigo Parra Rojas
Introduction��������������������������������������������������������������������������������������  107
Methods of Study����������������������������������������������������������������������������  107
Evaluation of the Structures of the Chest����������������������������������������  110
Sources��������������������������������������������������������������������������������������������  125
12 Assessing Arterial Oxygen Saturation ������������������������������������������ 127
Christian Poets and Pablo Brockmann Veloso
Oxygen Transport in the Blood��������������������������������������������������������  127
Transcutaneous Measurement of Oxygen Saturation����������������������  128
Factors That Affect Oxygen Saturation Measurement��������������������  129
SpO2 Reference Values��������������������������������������������������������������������  131
Transcutaneous Oxygen Measurement��������������������������������������������  132
Sources��������������������������������������������������������������������������������������������  133
13 Assessment of Sleep in Newborns to Adolescents�������������������������� 135
Óscar Sans Capdevila and David Gozal
Introduction��������������������������������������������������������������������������������������  135
Diagnosis������������������������������������������������������������������������������������������  137
x Contents

Conclusion ��������������������������������������������������������������������������������������  143

Sources��������������������������������������������������������������������������������������������  144
14 Study of Infectious Agents in Respiratory Diseases���������������������� 145
Cecilia Perret Pérez
Virological Diagnosis����������������������������������������������������������������������  145
Bacterial Diagnosis��������������������������������������������������������������������������  148
Diagnosis of Fungi��������������������������������������������������������������������������  149
Sources��������������������������������������������������������������������������������������������  149
15 Assessment of the Airway with Flexible Endoscopy �������������������� 151
Pablo Bertrand, Nils Linus Holmgren Palmen,
and Francisco Prado Atlagic
Indications����������������������������������������������������������������������������������������  152
Contraindications ����������������������������������������������������������������������������  152
Technical Aspects����������������������������������������������������������������������������  152
Complications of Flexible Bronchoscopy����������������������������������������  155
Performance of Flexible Bronchoscopy������������������������������������������  156
Sources��������������������������������������������������������������������������������������������  160
16 Assessment of the Airway with Rigid Endoscopy ������������������������ 161
Harlan Muntz and Constanza Beltrán Morales
History����������������������������������������������������������������������������������������������  161
Assessment of the Patient����������������������������������������������������������������  162
Symptoms and Signs of Airway Obstruction����������������������������������  162
Indications for Airway Endoscopy��������������������������������������������������  163
When Is Rigid Endoscopy, Rather than Flexible Endoscopy,
Appropriate?������������������������������������������������������������������������������������  163
Rigid Instruments����������������������������������������������������������������������������  163
Complications of Airway Endoscopy����������������������������������������������  166
Sources��������������������������������������������������������������������������������������������  167
17 Children with Respiratory Failure ������������������������������������������������ 169
Juan Andrés Carrasco Orellana and Andrés Castillo Moya
Definition ����������������������������������������������������������������������������������������  169
Classification������������������������������������������������������������������������������������  169
Physiopathology������������������������������������������������������������������������������  170
Clinical Effects��������������������������������������������������������������������������������  172
Diagnosis������������������������������������������������������������������������������������������  173
Sources��������������������������������������������������������������������������������������������  176
18 Children with Persistent Cough������������������������������������������������������ 177
Katalina Bertrán Salinas, Ricardo Saranz, Alejandro Lozano,
and José Antonio Castro-Rodríguez
Definition and General Concepts ����������������������������������������������������  177
Cough Reflex Anatomy��������������������������������������������������������������������  178
Etiology��������������������������������������������������������������������������������������������  178
Diagnosis������������������������������������������������������������������������������������������  179
Treatment ����������������������������������������������������������������������������������������  181
Conclusion ��������������������������������������������������������������������������������������  185
Sources��������������������������������������������������������������������������������������������  186
Contents xi

19 Infants with Persistent Tachypnea�������������������������������������������������� 187

Pablo Bertrand and Ana Moya Olivares
Definition ����������������������������������������������������������������������������������������  187
Respiration Control Mechanisms����������������������������������������������������  188
Etiology��������������������������������������������������������������������������������������������  188
Diagnosis������������������������������������������������������������������������������������������  189
Sources��������������������������������������������������������������������������������������������  191
20 Children with Persistent Stridor���������������������������������������������������� 193
Solange Caussade Larraín and Carlos Flores Berríos
Definition ����������������������������������������������������������������������������������������  193
Epidemiology����������������������������������������������������������������������������������  193
Applied Physiopathology����������������������������������������������������������������  194
Clinical History��������������������������������������������������������������������������������  195
Assessment��������������������������������������������������������������������������������������  196
Sources��������������������������������������������������������������������������������������������  199
21 Children with Snoring �������������������������������������������������������������������� 201
Daniel Zenteno Araos, José Luis Pérez Sánchez,
and Pablo Brockmann Veloso
Introduction��������������������������������������������������������������������������������������  201
Diagnosis������������������������������������������������������������������������������������������  202
Sources��������������������������������������������������������������������������������������������  203
22 Children with Recurrent Wheezing ���������������������������������������������� 205
Luis Enrique Vega-Briceño, Ilse Contreras Estay,
and Ignacio Sánchez
Epidemiology����������������������������������������������������������������������������������  205
Etiology��������������������������������������������������������������������������������������������  206
Physiopathology������������������������������������������������������������������������������  206
Clinical Characteristics��������������������������������������������������������������������  207
Diagnosis������������������������������������������������������������������������������������������  209
Management������������������������������������������������������������������������������������  210
Sources��������������������������������������������������������������������������������������������  213
23 Hemoptysis in Children ������������������������������������������������������������������ 215
Julio Maggiolo Massone, Carlos Mendoza Fox,
and Ricardo Kogan Alterman
Epidemiology and Etiology ������������������������������������������������������������  216
Physiopathology������������������������������������������������������������������������������  216
Etiology��������������������������������������������������������������������������������������������  216
Diagnostic Approach to Hemoptysis in Children����������������������������  219
Treatment ����������������������������������������������������������������������������������������  222
Conclusion ��������������������������������������������������������������������������������������  224
Sources��������������������������������������������������������������������������������������������  224
24 Infants with an Apparent Life-­Threatening Event ���������������������� 227
Pablo Brockmann Veloso, Daniel Zenteno Araos, and José
Luis Pérez Sánchez
Diagnosis������������������������������������������������������������������������������������������  227
Management Algorithm ������������������������������������������������������������������  227
xii Contents

Indications for Cardiorespiratory Monitoring����������������������������������  230

Sources��������������������������������������������������������������������������������������������  230
25 Immunosuppressed Children with Lung Infection���������������������� 233
Alejandra Zamorano Wittwer and Marcela Ferrés Garrido
Epidemiology����������������������������������������������������������������������������������  233
Physiopathology������������������������������������������������������������������������������  234
Etiology��������������������������������������������������������������������������������������������  235
Diagnostic Studies ��������������������������������������������������������������������������  241
Sources��������������������������������������������������������������������������������������������  243
26 Respiratory Complications in Children
with Neurological Diseases�������������������������������������������������������������� 245
Raúl Escobar Henríquez and Bernardita Chateau Infante
Epidemiology����������������������������������������������������������������������������������  245
Etiology and Physiopathology ��������������������������������������������������������  246
Clinical Manifestations��������������������������������������������������������������������  247
Diagnostic Foci��������������������������������������������������������������������������������  248
Treatment ����������������������������������������������������������������������������������������  250
Prognosis������������������������������������������������������������������������������������������  252
Ethical Dilemmas����������������������������������������������������������������������������  252
Sources��������������������������������������������������������������������������������������������  253
27 A Children with an Airway Foreign Body ������������������������������������ 255
Jacques de Blic and Agustín León Cortés
Epidemiology����������������������������������������������������������������������������������  255
Clinical Presentation������������������������������������������������������������������������  256
Radiological Study��������������������������������������������������������������������������  256
Treatment ����������������������������������������������������������������������������������������  258
Prevention����������������������������������������������������������������������������������������  260
Sources��������������������������������������������������������������������������������������������  260
28 Epidemiology of Respiratory Infections���������������������������������������� 263
Luis Avendaño Carvajal and Cecilia Perret Pérez
Viral Respiratory Infections������������������������������������������������������������  264
Diagnosis������������������������������������������������������������������������������������������  266
Epidemiological Management: The Winter Plan ����������������������������  268
Epidemiology of the Most Frequent Bacterial Infections����������������  269
Sources��������������������������������������������������������������������������������������������  272
29 Laryngitis (Croup) �������������������������������������������������������������������������� 273
Ida Concha Murray and Cecilia Perret Pérez
Epidemiology����������������������������������������������������������������������������������  273
Etiology and Physiopathology ��������������������������������������������������������  274
Clinical Manifestations��������������������������������������������������������������������  275
Severity Scores��������������������������������������������������������������������������������  275
Diagnostic Focus������������������������������������������������������������������������������  276
Treatment ����������������������������������������������������������������������������������������  276
Hospitalization ��������������������������������������������������������������������������������  279
Indications for Hospitalization��������������������������������������������������������  279
Contents xiii

Criteria for Patient Release from an Emergency Service����������������  280

Complications����������������������������������������������������������������������������������  280
Specialist Follow-Up������������������������������������������������������������������������  280
Summary������������������������������������������������������������������������������������������  280
Sources��������������������������������������������������������������������������������������������  281
30 Bronchiolitis�������������������������������������������������������������������������������������� 283
Miriam Pérez and Giovanni Piedimonte
Historical Perspective����������������������������������������������������������������������  283
Epidemiology����������������������������������������������������������������������������������  284
Pathogenesis and Physiopathology��������������������������������������������������  285
Microbiology������������������������������������������������������������������������������������  285
Clinical Manifestations��������������������������������������������������������������������  290
Treatment ����������������������������������������������������������������������������������������  291
Prevention����������������������������������������������������������������������������������������  294
Sources��������������������������������������������������������������������������������������������  297
31 Community-Acquired Pneumonia������������������������������������������������� 299
María Lina Boza Costagliola
Definition ����������������������������������������������������������������������������������������  299
Epidemiology����������������������������������������������������������������������������������  299
Etiology��������������������������������������������������������������������������������������������  300
Physiopathology������������������������������������������������������������������������������  301
Clinical Manifestations��������������������������������������������������������������������  301
Diagnostic Approach������������������������������������������������������������������������  302
Differential Diagnosis����������������������������������������������������������������������  304
Treatment ����������������������������������������������������������������������������������������  305
Complications����������������������������������������������������������������������������������  306
Prevention����������������������������������������������������������������������������������������  306
Conclusion ��������������������������������������������������������������������������������������  307
Sources��������������������������������������������������������������������������������������������  307
32 Atypical Pneumonia������������������������������������������������������������������������ 309
Ricardo Kogan Alterman and Julio Maggiolo Massone
Definition ����������������������������������������������������������������������������������������  309
Pneumonia Caused by Mycoplasma pneumoniae����������������������������  310
Pneumonia Caused by Chlamydophila pneumoniae������������������������  317
Summary������������������������������������������������������������������������������������������  320
Sources��������������������������������������������������������������������������������������������  321
33 Complicated Pneumonia ���������������������������������������������������������������� 323
Francisco Prado Atlagic, Rodrigo Vásquez-De Kartzow,
Pamela Salinas Flores, and Pamela Navarrete Contreras
Definition ����������������������������������������������������������������������������������������  323
Epidemiology����������������������������������������������������������������������������������  324
Etiology��������������������������������������������������������������������������������������������  325
Empyema Physiopathology ������������������������������������������������������������  325
Pleural Effusion, Classification, and Progression Phases����������������  326
Sources��������������������������������������������������������������������������������������������  333
xiv Contents

34 Pneumonia Caused by Emerging Viral Agents ���������������������������� 335

Cecilia Perret Pérez and Marcela Ferrés Garrido
Middle East Respiratory Syndrome ������������������������������������������������  335
Severe Acute Respiratory Syndrome/Asian Pneumonia������������������  337
HCoV-NL 63 and HCoV-HKU1������������������������������������������������������  337
Avian Influenza��������������������������������������������������������������������������������  338
Hantavirus����������������������������������������������������������������������������������������  339
Enterovirus D68 ������������������������������������������������������������������������������  340
Polyomavirus ����������������������������������������������������������������������������������  341
Sources��������������������������������������������������������������������������������������������  341
35 Pulmonary Tuberculosis������������������������������������������������������������������ 343
Carlos Casar Collazo, María Elena Guarda Barros,
and Carolina Gvirtzman
Introduction��������������������������������������������������������������������������������������  343
Epidemiology����������������������������������������������������������������������������������  344
Etiology and Pathophysiology ��������������������������������������������������������  344
Treatment ����������������������������������������������������������������������������������������  350
Follow-Up and Control��������������������������������������������������������������������  352
Sources��������������������������������������������������������������������������������������������  353
36 Respiratory Diseases in the Newborn�������������������������������������������� 355
José Luis Tapia Illanes, Paulina Toso Milos,
and Javier Kattan Said
Respiratory Physiology��������������������������������������������������������������������  355
Approaching the Newborn with Respiratory Disease����������������������  356
Classification of the Respiratory Problems of the Newborn������������  359
Sources��������������������������������������������������������������������������������������������  370
37 Bronchopulmonary Dysplasia�������������������������������������������������������� 373
Alberto Toso Milos, Jorge Fabres Biggs,
and Pablo Bertrand
Introduction��������������������������������������������������������������������������������������  373
Epidemiology����������������������������������������������������������������������������������  374
Physiopathology������������������������������������������������������������������������������  374
Diagnosis������������������������������������������������������������������������������������������  375
Complications and Treatment����������������������������������������������������������  376
Sources��������������������������������������������������������������������������������������������  381
38 Allergic Diseases, from the Infant to the Adolescent�������������������� 383
Mario Calvo Gil and Fernando Iñiguez Osmer
Definition ����������������������������������������������������������������������������������������  383
Epidemiology����������������������������������������������������������������������������������  383
Etiology and Physiopathology ��������������������������������������������������������  384
Clinical Manifestations��������������������������������������������������������������������  385
Therapy��������������������������������������������������������������������������������������������  389
Summary������������������������������������������������������������������������������������������  391
Sources��������������������������������������������������������������������������������������������  391
Contents xv

39 Latin America Asthma Epidemiology and Related

Risk Factors�������������������������������������������������������������������������������������� 393
Viviana Aguirre Camposano, Manuel Soto Martínez, and
Manuel Soto Quirós
Introduction��������������������������������������������������������������������������������������  393
Asthma in Latin America: Phase I and Phase III ISAAC Studies ��  394
Risk Factors ������������������������������������������������������������������������������������  396
Asthma Epidemiology in Chile��������������������������������������������������������  398
Sources��������������������������������������������������������������������������������������������  399
40 Evaluation of Asthma Risk in Infants and Preschoolers�������������� 401
José Antonio Castro-Rodríguez
Wheezing Phenotypes and Their Risk Factors��������������������������������  402
Asthma Predictive Indexes��������������������������������������������������������������  404
Sources��������������������������������������������������������������������������������������������  406
41 Asthma: Clinical and Diagnosis Approach������������������������������������ 407
Guido Girardi Briere
Definition ����������������������������������������������������������������������������������������  407
Etiopathogenesis������������������������������������������������������������������������������  408
Physiopathology������������������������������������������������������������������������������  409
Clinical Aspects ������������������������������������������������������������������������������  409
Diagnosis������������������������������������������������������������������������������������������  411
Sources��������������������������������������������������������������������������������������������  413
42 Asthma: Treatment�������������������������������������������������������������������������� 415
Pablo Bertrand and Andrea Beckhaus Faccin
Introduction��������������������������������������������������������������������������������������  415
Treatment ����������������������������������������������������������������������������������������  416
Nonpharmacological Treatment������������������������������������������������������  416
Pharmacological Treatment ������������������������������������������������������������  417
Sources��������������������������������������������������������������������������������������������  427
43 Primary Ciliary Dyskinesia������������������������������������������������������������ 429
Nils Linus Holmgren Palmen, Ximena Fonseca Arrieta,
and Sergio González Bombardiere
Definition ����������������������������������������������������������������������������������������  429
Epidemiology����������������������������������������������������������������������������������  430
Etiology and Physiopathology ��������������������������������������������������������  430
Clinical Condition����������������������������������������������������������������������������  432
Diagnosis������������������������������������������������������������������������������������������  433
Diagnostic Approach������������������������������������������������������������������������  435
Evaluation and Treatment����������������������������������������������������������������  435
Prognosis������������������������������������������������������������������������������������������  437
Sources��������������������������������������������������������������������������������������������  438
44 Cystic Fibrosis: Clinical and Diagnosis Approach������������������������ 439
Claudio Castaños, Lilien Chertkoff, and Luis Gravina
Introduction��������������������������������������������������������������������������������������  439
Epidemiology����������������������������������������������������������������������������������  440
Pathophysiology������������������������������������������������������������������������������  440
xvi Contents

Diagnosis������������������������������������������������������������������������������������������  441
Clinical Manifestations��������������������������������������������������������������������  441
Laboratory Methods������������������������������������������������������������������������  445
Molecular Diagnosis������������������������������������������������������������������������  447
CF Neonatal Screening��������������������������������������������������������������������  448
Sources��������������������������������������������������������������������������������������������  450
45 Cystic Fibrosis: Treatment�������������������������������������������������������������� 453
Felix Ratjen and María Ester Pizarro Gamboa
General Considerations��������������������������������������������������������������������  453
Minimum Standard of a Cystic Fibrosis Center������������������������������  454
Nutritional Support and Enzyme Supplements��������������������������������  455
Treatment of Lung Disease��������������������������������������������������������������  456
Sources��������������������������������������������������������������������������������������������  465
46 Pulmonary Aspergillosis������������������������������������������������������������������ 467
Claudio Castaños, Verónica Aguerre, and Verónica Giubergia
Epidemiology����������������������������������������������������������������������������������  467
Etiology and Physiopathology ��������������������������������������������������������  467
Invasive Pulmonary Aspergillosis����������������������������������������������������  468
Chronic Necrotizing Pulmonary Aspergillosis��������������������������������  470
Aspergilloma������������������������������������������������������������������������������������  470
Allergic Bronchopulmonary Aspergillosis��������������������������������������  471
Allergic Bronchopulmonary Aspergillosis in Asthma ��������������������  471
Allergic Bronchopulmonary Aspergillosis in CF����������������������������  472
Sources��������������������������������������������������������������������������������������������  473
47 Post-Infectious Bronchiolitis Obliterans���������������������������������������� 475
Alejandro Colom, Gilberto Fischer, and Alejandro Teper
Prevalence����������������������������������������������������������������������������������������  475
Pathology ����������������������������������������������������������������������������������������  476
Etiology��������������������������������������������������������������������������������������������  476
Clinical Findings������������������������������������������������������������������������������  478
Diagnosis������������������������������������������������������������������������������������������  478
Evolution and Prognosis������������������������������������������������������������������  481
Treatment ����������������������������������������������������������������������������������������  482
Sources��������������������������������������������������������������������������������������������  482
48 Obstructive Sleep Apnea Syndrome in Children�������������������������� 485
Asher Tal, Pablo Brockmann Veloso, and Aviv Goldbart
Introduction��������������������������������������������������������������������������������������  486
Epidemiology����������������������������������������������������������������������������������  486
Physiopathology������������������������������������������������������������������������������  486
Clinical Presentation������������������������������������������������������������������������  488
Diagnosis������������������������������������������������������������������������������������������  492
Treatment ����������������������������������������������������������������������������������������  493
Sources��������������������������������������������������������������������������������������������  494
Contents xvii

49 Sudden Infant Death Syndrome ���������������������������������������������������� 495

María Angélica Oyarzún and Pablo Brockmann Veloso
Introduction��������������������������������������������������������������������������������������  495
Epidemiology����������������������������������������������������������������������������������  496
Etiology��������������������������������������������������������������������������������������������  496
Risk Factors and Clinical Presentation��������������������������������������������  496
Prevention and Approach ����������������������������������������������������������������  499
Conclusions��������������������������������������������������������������������������������������  500
Sources��������������������������������������������������������������������������������������������  500
50 Primary Immunodeficiencies and Immune Diseases�������������������� 501
Eduardo Talesnik Guendelman and Cecilia Méndez Rivera
Introduction��������������������������������������������������������������������������������������  502
Primary Immunodeficiencies (PID) ������������������������������������������������  503
Antibody Immunodeficiencies ��������������������������������������������������������  504
Cellular and Combined Immunodeficiency ������������������������������������  506
Phagocytes Immunodeficiencies������������������������������������������������������  508
Clinical Case������������������������������������������������������������������������������������  508
Complement Immunodeficiencies ��������������������������������������������������  509
Non-classified PID ��������������������������������������������������������������������������  509
Clinical Case������������������������������������������������������������������������������������  509
Immunological Diseases������������������������������������������������������������������  511
Connective Tissue Diseases and Lung ��������������������������������������������  513
Autoinflammatory Diseases of the Lung ����������������������������������������  515
Sources��������������������������������������������������������������������������������������������  516
51 Acquired Immune Deficiency Syndrome �������������������������������������� 517
Anamaría Peña Donati and Marcelo Laufer
Introduction��������������������������������������������������������������������������������������  517
Epidemiology����������������������������������������������������������������������������������  518
Physiopathology������������������������������������������������������������������������������  518
Clinical Aspects ������������������������������������������������������������������������������  519
Sources��������������������������������������������������������������������������������������������  528
52 Sickle Cell Disease���������������������������������������������������������������������������� 529
Ofelia Álvarez and María Angélica Wietstruck
Definition ����������������������������������������������������������������������������������������  529
Epidemiology����������������������������������������������������������������������������������  530
Etiology and Physiopathology ��������������������������������������������������������  530
Clinical Manifestation of Sickle Cell Disease ��������������������������������  532
Respiratory Clinical Manifestations, Diagnostic Approach
and Treatment����������������������������������������������������������������������������������  532
Sources��������������������������������������������������������������������������������������������  540
53 Congenital Malformations of the Airway�������������������������������������� 543
Ilse Contreras Estay, Luis Enrique Vega-Briceño,
and Ignacio Sánchez
Epidemiology����������������������������������������������������������������������������������  543
xviii Contents

Clinical Presentation������������������������������������������������������������������������  543

Sources��������������������������������������������������������������������������������������������  549
54 Congenital Lung Malformations���������������������������������������������������� 551
Juan Carlos Pattillo Silva, Sergio Zúñiga Rocha,
and José Vuletin Solís
Embryology��������������������������������������������������������������������������������������  551
Epidemiology����������������������������������������������������������������������������������  552
Congenital Malformations of the Lung��������������������������������������������  552
Diagnosis������������������������������������������������������������������������������������������  558
Treatment ����������������������������������������������������������������������������������������  558
Sources��������������������������������������������������������������������������������������������  559
55 Gastroesophageal Reflux and Respiratory Diseases�������������������� 561
María Francisca Jaime Méndez, José San Martín Prieto,
and Juan Cristóbal Gana Ansaldo
Introduction��������������������������������������������������������������������������������������  561
Proposed GER Damage Mechanisms in Respiratory Diseases ������  562
Asthma ��������������������������������������������������������������������������������������������  562
Chronic Cough ��������������������������������������������������������������������������������  563
Swallow Disorders ��������������������������������������������������������������������������  563
Obstructive Sleep Apnea������������������������������������������������������������������  564
Apnea and ALTE������������������������������������������������������������������������������  564
Subglottic Stenosis��������������������������������������������������������������������������  564
Laryngomalacia��������������������������������������������������������������������������������  565
Recurrent Laryngitis������������������������������������������������������������������������  565
Recurrent Laryngeal Papillomatosis������������������������������������������������  565
Diagnosis������������������������������������������������������������������������������������������  566
Treatment ����������������������������������������������������������������������������������������  566
Conclusions��������������������������������������������������������������������������������������  568
Sources��������������������������������������������������������������������������������������������  568
56 Pneumothorax and Thoracic Trauma�������������������������������������������� 571
Claudia Fuentes Sáez and Raúl Bustos Betanzo
Pneumothorax����������������������������������������������������������������������������������  571
Thorax Trauma��������������������������������������������������������������������������������  577
Summary������������������������������������������������������������������������������������������  577
Sources��������������������������������������������������������������������������������������������  578
57 Nutrition in Chronic Respiratory Disease ������������������������������������ 579
Salesa Barja Yáñez
Introduction��������������������������������������������������������������������������������������  579
Specific Diseases������������������������������������������������������������������������������  582
Nutritional Support In Chronic Respiratory Diseases ��������������������  584
Conclusion ��������������������������������������������������������������������������������������  589
Sources��������������������������������������������������������������������������������������������  589
58 Diseases Caused by Pollutants and Tobacco Exposure���������������� 591
Lidia Amarales Osorio, María José Prieto Correa, and
Gabriela Muñoz Gómez
Introduction��������������������������������������������������������������������������������������  591
Contents xix

Atmospheric Pollution (AP)������������������������������������������������������������  592

Indoor Pollution (IP)������������������������������������������������������������������������  595
Smoking, a Pediatric Disease����������������������������������������������������������  597
Sources��������������������������������������������������������������������������������������������  603
59 Nursing Care Education in Chronic Respiratory Diseases���������� 605
Ana Moya Isamitt
Introduction��������������������������������������������������������������������������������������  606
Nursing Care Management��������������������������������������������������������������  608
Self-Care in Asthma������������������������������������������������������������������������  610
Self-Care in Cystic Fibrosis ������������������������������������������������������������  612
Self-Care in Sleep Disorders������������������������������������������������������������  614
Self-Care in Allergies����������������������������������������������������������������������  617
Conclusions��������������������������������������������������������������������������������������  621
Sources��������������������������������������������������������������������������������������������  621
60 Evidence-Based Medicine for Respiratory Diseases �������������������� 623
Carlos Ubilla Pérez, María Angélica Palomino Montenegro,
and José Antonio Castro-Rodríguez
Introduction��������������������������������������������������������������������������������������  623
How to Practice Evidence-Based Medicine������������������������������������  623
Classification of Quality of Evidence and Strength of
Recommendations����������������������������������������������������������������������������  631
Sources��������������������������������������������������������������������������������������������  632
61 Inhalation Therapy�������������������������������������������������������������������������� 633
Fernando Iñiguez Osmer and Viviana Aguirre Camposano
Physical Characteristics of Aerosols������������������������������������������������  633
Aerosol Deposition Mechanisms ����������������������������������������������������  635
General Factors That Affect Airway Aerosol Deposition����������������  635
Advantages and Disadvantages of Aerosol Drug Therapy��������������  637
Aerosol Generating Systems������������������������������������������������������������  637
Sources��������������������������������������������������������������������������������������������  641
62 Pulmonary Anti-Inflammatory Effects of Macrolides������������������ 643
Luis Enrique Vega-Briceño and Ignacio Sánchez
Introduction��������������������������������������������������������������������������������������  643
Macrolides����������������������������������������������������������������������������������������  643
Physiopathology������������������������������������������������������������������������������  644
Sources��������������������������������������������������������������������������������������������  648
63 Chest Physiotherapy������������������������������������������������������������������������ 649
Homero Puppo Gallardo and Gonzalo Hidalgo Soler
Introduction��������������������������������������������������������������������������������������  649
Objectives����������������������������������������������������������������������������������������  650
Bases������������������������������������������������������������������������������������������������  650
Therapeutic Intervention������������������������������������������������������������������  652
Techniques of Respiratory Physical Therapy����������������������������������  653
Conclusions��������������������������������������������������������������������������������������  658
Sources��������������������������������������������������������������������������������������������  658
xx Contents

64 Pulmonary Rehabilitation in Children

with Chronic Respiratory Diseases������������������������������������������������ 661
Rodrigo Torres Castro, Homero Puppo Gallardo,
and Daniel Zenteno Araos
Definition ����������������������������������������������������������������������������������������  661
Goals of a Pulmonary Rehabilitation Program��������������������������������  661
Parts of a Pulmonary Rehabilitation Program ��������������������������������  662
Final Comments ������������������������������������������������������������������������������  667
Sources��������������������������������������������������������������������������������������������  667
65 Prolonged Hospitalization Due to Chronic
Respiratory Diseases������������������������������������������������������������������������ 669
Mireya Méndez Raggi and Claudia Astudillo Maggio
Introduction��������������������������������������������������������������������������������������  669
Definitions����������������������������������������������������������������������������������������  670
Chronic Hospitalization Outside the Intensive Care Unit����������������  670
Medical Team����������������������������������������������������������������������������������  671
Role of the Professional Team ��������������������������������������������������������  672
Infrastructure and Equipment����������������������������������������������������������  672
Monitoring of Chronic Respiratory Ill Patient
by Level of Complexity ������������������������������������������������������������������  672
Routine Monitoring to Avoid in-Hospital Infections ����������������������  673
Additional Activities������������������������������������������������������������������������  673
Progression��������������������������������������������������������������������������������������  674
Discharge Planning��������������������������������������������������������������������������  674
Sources��������������������������������������������������������������������������������������������  674
66 Oxygen Therapy������������������������������������������������������������������������������ 675
Alejandra Zamorano Wittwer and Claudia Astudillo Maggio
Introduction��������������������������������������������������������������������������������������  675
Physio Pathological Basis����������������������������������������������������������������  676
Conclusions��������������������������������������������������������������������������������������  681
Sources��������������������������������������������������������������������������������������������  681
67 Acute Mechanical Ventilation �������������������������������������������������������� 683
Andrés Castillo Moya
Historical Review of Mechanical Ventilation����������������������������������  683
Mechanical Ventilation Physiology��������������������������������������������������  684
Conclusion ��������������������������������������������������������������������������������������  694
Sources��������������������������������������������������������������������������������������������  694
68 Chronic Invasive Ventilation ���������������������������������������������������������� 697
Claudia Astudillo Maggio, Patricio Barañao Garcés,
and Mireya Méndez Raggi
Epidemiology����������������������������������������������������������������������������������  697
Chronic Mechanical Ventilation Indications������������������������������������  699
Weaning or Removal of Invasive Chronic
Mechanical Ventilation��������������������������������������������������������������������  702
Sources��������������������������������������������������������������������������������������������  704
Contents xxi

69 Long-Term Non-invasive Ventilation���������������������������������������������� 705

Francisco Prado Atlagic, Pamela Salinas Flores,
and Gerardo Ferrero
Physiological Bases ������������������������������������������������������������������������  705
Benefits of Non-invasive Ventilation in Chronic Patients����������������  706
Ethical Dilemmas����������������������������������������������������������������������������  711
Conclusions��������������������������������������������������������������������������������������  712
Sources��������������������������������������������������������������������������������������������  712
70 Tracheotomy ������������������������������������������������������������������������������������ 715
Bernardita Chateau Infante and Constanza Beltrán Morales
Introduction��������������������������������������������������������������������������������������  715
Anatomy������������������������������������������������������������������������������������������  716
Indications����������������������������������������������������������������������������������������  716
Tube Selection����������������������������������������������������������������������������������  717
Complications����������������������������������������������������������������������������������  718
Early Complications������������������������������������������������������������������������  718
Late Complications��������������������������������������������������������������������������  719
Care��������������������������������������������������������������������������������������������������  720
Decannulation����������������������������������������������������������������������������������  722
Sources��������������������������������������������������������������������������������������������  722
71 Airway Surgery and Endoscopic Procedures�������������������������������� 725
Patricio Varela Balbontín
Larynx Diseases ������������������������������������������������������������������������������  725
Congenital Laryngeal Anomalies����������������������������������������������������  725
Congenital Tracheal Anomalies ������������������������������������������������������  728
Technical Aspects����������������������������������������������������������������������������  731
Pediatric Airway Frequently Acquired Lesions ������������������������������  732
Summary������������������������������������������������������������������������������������������  735
Sources��������������������������������������������������������������������������������������������  735
72 Lung, Chest Cavity, and Dorsal Spine Surgery���������������������������� 737
Mauricio Campos Daziano, José Vuletin Solís, and Juan
Carlos Pattillo Silva
Introduction��������������������������������������������������������������������������������������  737
Surgery of Congenital Malformations of the Chest Cavity ������������  737
Lung Surgery�����������������������������������������������������������������������������������  741
Dorsal Spine Surgery ����������������������������������������������������������������������  743
Sources��������������������������������������������������������������������������������������������  747
73 Extracorporeal Circulation Membrane Oxygenation
Therapy for Acute Respiratory Diseases �������������������������������������� 749
Javier Kattan Said, Álvaro González Morandé,
and Andrés Castillo Moya
Introduction��������������������������������������������������������������������������������������  749
Selection Criteria for Applying ECMO ������������������������������������������  753
Managing ECMO����������������������������������������������������������������������������  754
Complications����������������������������������������������������������������������������������  756
Prognosis and ECMO Programs in Latin America��������������������������  756
xxii Contents

Conclusions and Future Considerations������������������������������������������  758

Sources��������������������������������������������������������������������������������������������  759
74 Pediatric Lung Transplantation������������������������������������������������������ 761
Anand Patel and Albert Faro
History����������������������������������������������������������������������������������������������  762
Indications����������������������������������������������������������������������������������������  762
Contraindications ����������������������������������������������������������������������������  763
Disease Specific Indications and Contraindications������������������������  763
Donor Evaluation ����������������������������������������������������������������������������  765
Surgical Technique��������������������������������������������������������������������������  766
Immunosuppression ������������������������������������������������������������������������  766
Post-operative Monitoring and Management����������������������������������  767
Post-transplantation Monitoring������������������������������������������������������  768
Post-transplantation Complications ������������������������������������������������  768
Rejection������������������������������������������������������������������������������������������  771
Outcomes ����������������������������������������������������������������������������������������  773
Future Considerations����������������������������������������������������������������������  773
Sources��������������������������������������������������������������������������������������������  774
Index���������������������������������������������������������������������������������������������������������� 777
Contributors

Verónica Aguerre  Hospital Garrahan, Buenos Aires, Argentina

Viviana  Aguirre Camposano Department of Pediatrics, School of
Medicine, University of Santiago, Santiago, Chile
Ofelia Álvarez  Clinical Pediatrics, University of Miami, Coral Gables, FL,
USA
Lidia Amarales Osorio  Ministry of Health, Santiago, Chile
Claudia  Astudillo Maggio Pediatrics, Respiratory Diseases, Hospital
Josefina Martínez, Puente Alto, Chile
Pontificia Universidad Católica de Chile, Santiago, Chile
Luis  Avendaño Carvajal Faculty of Medicine, Universidad de Chile,
Santiago, Chile
Patricio  Barañao Garces Respiratory Kinesiotherapy, Hospital Josefina
Martínez, Puente Alto, Chile
Pontificia Universidad Católica de Chile, Santiago, Chile
Salesa  Barja Yáñez Pontificia Universidad Católica de Chile, Santiago,
Chile
Andrea  Beckhaus Faccin  Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Constanza  Beltrán Morales  Department of Otorhinolaryngology, School
of Medicine, Universidad de los Andes, Santiago, Chile
Katalina  Bertrán Salinas Department of Pediatrics, Hospital Clínico
Universidad Católica de Chile, Santiago, Chile
Pablo  Bertrand  Department of Pediatrics, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Arturo Borzutzky Schachter  Department of Pediatrics School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
María Lina Boza Costagliola  Pediatrics, Respiratory diseases, University
of Chile, Santiago, Chile

xxiii
xxiv Contributors

Pablo  Brockmann  Veloso  Department of Pediatrics, School of Medicine,

Pontificia Universidad Católica de Chile, Santiago, Chile
Raúl  Bustos  Betanzo Pediatrics, Intensive Care at Clínica Sanatorio
Alemán, Concepción, Chile
Andrew  Bush Faculty of Medicine, Imperial College of London,
London, UK
Mario Calvo Gil  Department of Pediatrics, School of Medicine, Universidad
Austral, Valdivia, Chile
Mauricio  Campos Daziano Pontificia Universidad Católica de Chile,
Santiago, Chile
Juan  Andrés  Carrasco Orellana Department of Pediatrics, School of
Medicine, Universidad del Desarrollo, Santiago, Chile
Carlos Casar Collazo  Department of Pediatrics, Hospital Roberto del Río,
Santiago, Chile
Claudio Castaños  Hospital Garrahan, Buenos Aires, Argentina
Andrés  Castillo Moya Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
José  Antonio  Castro-Rodríguez Department of Pediatrics, School of
Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Solange Caussade Larraín  Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Bernardita Chateau Infante  Department of Pediatrics, Clínica Los Andes,
Santiago, Chile
Lilien Chertkoff  Hospital Garrahan, Buenos Aires, Argentina
Alejandro  Colom Pediatric Pulmonology, Hospital Ricardo Gutiérrez,
Buenos Aires, Argentina
Ida  Concha Murray Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Ilse  Contreras Estay Department of Pediatrics, Hospital Padre Hurtado,
Santiago, Chile
Mara  Cvejic Division of Sleep Medicine, School of Medicine, Stanford
University, Redwood City, CA, USA
Jacques  de Blic Université Paris Descartes, Hôpital Necker Enfants
Malades, Paris, France
Raúl  Escobar Henríquez  Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Jorge Fabres Biggs  Department of Pediatrics, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Contributors xxv

Albert  Faro Washington University in St. Louis School of Medicine,

St. Louis, MO, USA
Gerardo  Ferrero Respiratory Kinesiology and Physiatry, Hospital
Rehabilitación Respiratoria Maria Ferrer, Buenos Aires, Argentina
Marcela  Ferrés Garrido Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Gilberto  Fischer Pediatric Pulmonology, Federal University of Health
Sciences of Porto Alegre, Porto Alegre, Brazil
Carlos  Flores Berríos Department of Pediatrics, Hospital de Ovalle,
Ovalle, Chile
Ximena  Fonseca Arrieta Otorhinolaryngology, Pontificia Universidad
Católica de Chile, Santiago, Chile
Claudia Fuentes Saez  Pediatrics, Respiratory Diseases, Hospital Regional
de Concepción, Concepción, Chile
Juan  Cristóbal  Gana Ansaldo Pontificia Universidad Católica de Chile,
Santiago, Chile
Cristián García Bruce  Pediatric Radiology, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Guido Girardi Briere  Faculty of Medicine, Universidad de Chile, Santiago,
Chile
Verónica Giubergia  Hospital Garrahan, Buenos Aires, Argentina
Aviv Goldbart  Ben Gurion University of Negev, Beersheba, Israel
Sergio  González Bombardiere Pathological Anatomy, Pontificia
Universidad Católica de Chile, Santiago, Chile
Álvaro González Morandé  Pediatrics, Neonatology, Pontificia Universidad
Católica de Chile, Santiago, Chile
David Gozal  Department of Pediatrics, The University of Chicago, Chicago,
IL, USA
Luis Gravina  Hospital Garrahan, Buenos Aires, Argentina
María Elena Guarda Barros  Department of Pediatrics, Hospital Roberto
del Río, Santiago, Chile
Christian Guilleminault  Division of Sleep Medicine, School of Medicine,
Stanford University, Redwood City, CA, USA
Carolina Gvirtzman  Department of Pediatrics, Hospital Garrahan, Buenos
Aires, Argentina
Gonzalo  Hidalgo Soler Respiratory Kinesiology, Faculty of Medicine,
Universidad de Chile, Santiago, Chile
Nils Linus Holmgren Palmen  Department of Pediatrics, Clínica Alemana
and Universidad del Desarrollo, Santiago, Chile
xxvi Contributors

Fernando  Iñiguez Osmer Department of Pediatrics, Hospital de Puerto

Montt, Puerto Montt, Chile
María Francisca Jaime Méndez  Pontificia Universidad Católica de Chile,
Santiago, Chile
Javier Kattan Said  Department of Pediatrics, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Carlos  Kofman Department of Pediatric Pulmonology, Hospital Ricardo
Gutiérrez, Buenos Aires, Argentina
Ricardo Kogan Alterman  Department of Pediatrics, Faculty of Medicine,
Universidad de Chile, Santiago, Chile
Marcelo  Laufer Pediatrics, Infectious Diseases, Nicklaus Children’s
Hospital, Miami, FL, USA
Agustín León Cortés  Pediatrics, Respiratory Diseases, Clínica Santa María,
Providencia, Chile
Marcela  Linares  Paserini Department of Pediatrics, Clínica Indisa,
Santiago, Chile
Alejandro  Lozano Department of Allergy and Immunology, Faculty of
Medicine, Universidad Católica de Córdoba, Córdoba, Argentina
Julio  Maggiolo  Massone Department of Pediatrics, Hospital Exequiel
González Cortés, San Miguel, Chile
Mireya Mendez Raggi  Pediatrics, Respiratory Diseases, Hospital Josefina
Martínez, Puente Alto, Chile
Pontificia Universidad Católica de Chile, Santiago, Chile
Cecilia  Méndez Rivera Pediatrics, Immunology and Rheumatology,
Pontificia Universidad Católica de Chile, Santiago, Chile
Carlos Mendoza Fox  Department of Pediatrics, Hospital Nacional Hipólito
Unanue, Lima, Peru
Pamela Morales Matamala  Department of Pediatrics School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Ana Moya Isamitt  School of Health, Duoc UC, Santiago, Chile
Ana  Moya Olivares Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Gabriela  Muñoz Gómez Faculty of Medicine, Universidad de Chile,
Santiago, Chile
Harlan  Muntz Health Sciences Center, Universidad de Utah, Salt Lake
City, UT, USA
Pamela  Navarrete Contreras  Department of Pediatrics, Hospital de Los
Ángeles, Los Ángeles, Chile
Contributors xxvii

María  Angélica  Oyarzún Pontificia Universidad Católica de Chile,

Santiago, Chile
María Angélica Palomino Montenegro  Faculty of Medicine, Universidad
de Chile, Santiago, Chile
Rodrigo Parra Rojas  Pediatric Radiology, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Anand  Patel  Washington University in St. Louis School of Medicine, St.
Louis, MO, USA
Juan  Carlos  Pattillo Silva Pediatric Surgery, Pontificia Universidad
Católica de Chile, Santiago, Chile
Anamaría Peña Donati  Pontificia Universidad Católica de, Santiago, Chile
Miriam Pérez  Cleveland Clinic Children’s Hospital, Cleveland, OH, USA
José Luis Pérez Sánchez  Department of Pediatrics, Universidad Austral de
Chile, Osorno, Chile
Cecilia  Perret Pérez Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Giovanni Piedimonte  The Cleveland Clinic at Cleveland, Cleveland, OH,
USA
María Ester Pizarro Gamboa  Pediatrics, Respiratory Diseases, Associate
Asociado, School of Medicine, Pontificia Universidad Católica de Chile,
Santiago, Chile
Christian Poets  Department of Neonatology, University Children’s Hospital
Tübingen, Alemania, Tübingen, Germany
Francisco  Prado Atlagic  Department of Pediatrics, Hospital Clínico San
Borja Arriarán, Santiago, Chile
María José Prieto Correa  Respiratory Kinesiology, Academic at UMCE,
UNAB, Santiago, Chile
Homero  Puppo Gallardo Respiratory Kinesiology, Faculty of Medicine,
Universidad de Chile, Santiago, Chile
Felix Ratjen  The Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada
Pamela Salinas Flores  Pediatric Service, Clínica Las Lilas, Providencia, Chile
José San Martín Prieto  Pontificia Universidad Católica de Chile, Santiago,
Chile
Ignacio Sánchez  Department of Pediatrics, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile
Óscar Sans Capdevila  Departament of Pediatric Neurology, Hospital Sant
Joan de Déu, Barcelona, Spain
xxviii Contributors

Ricardo  Saranz Department of Allergy and Immunology, Faculty of

Medicine, Universidad Católica de Córdoba, Córdoba, Argentina
Manuel  Soto Martínez Department of Pediatrics, School of Medicine,
University of Costa Rica, San José, Costa Rica
Manuel Soto Quirós  Department of Pediatrics, Hospital San José, San José,
Costa Rica
Asher Tal  Ben Gurion University of Negev, Beersheba, Israel
Eduardo Talesnik Guendelman  Pediatrics, Immunology and Rheumatology,
Pontificia Universidad Católica de Chile, Santiago, Chile
José  Luis  Tapia Illanes Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile, Santiago, Chile
Alejandro  Teper  Faculty of Medicine, Universidad de Buenos Aires and
Division of Pediatric Pulmonology, Hospital Ricardo Gutiérrez, Buenos
Aires, Argentina
Rodrigo  Torres Castro Respiratory Kinesiology, Faculty of Medicine,
Universidad de Chile, Santiago, Chile
Alberto  Toso Milos Department of Pediatrics, Pontificia Universidad
Católica de Chile, Santiago, Chile
Paulina  Toso Milos Department of Pediatrics, Pontificia Universidad
Católica de Chile, Santiago, Chile
Carlos Ubilla Pérez  Faculty of Medicine, Universidad de Chile, Santiago,
Chile
Patricio  Varela Balbontín Pediatric Surgery, Hospital Luis Calvo
Mackenna, Universidad de Chile, Santiago, Chile
Rodrigo  Vásquez-De Kartzow Department of Pediatrics, Faculty of
Medicine, Universidad de Chile, Santiago, Chile
Luis  Enrique  Vega-Briceño Faculty of Medicine, Universidad del
Desarrollo, Santiago, Chile
José  Vuletin Solís Pediatric Surgery, Pontificia Universidad Católica de
Chile, Santiago, Chile
María  Angélica Wietstruck  Pediatrics, Oncology, Pontificia Universidad
Católica de Chile, Santiago, Chile
Alejandra  Zamorano  Wittwer Department of Pediatrics, School of
Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Daniel  Zenteno Araos Department of Pediatrics, Universidad de
Concepción, Concepción, Chile
Sergio Zúñiga Rocha  Pediatric Surgery, Pontificia Universidad Católica de
Chile, Santiago, Chile
 History of Specialist Training
in Respiratory Diseases
1
Ignacio Sánchez

Contents
Introduction......................................................................................................................  1
The Situation in South America......................................................................................  1
Sources...............................................................................................................................  4

Introduction develop standards and structures for formal train-

ing can learn from others practicing medicine in
Mortality caused by pediatric respiratory dis- places where the specialty has a long tradition.
eases continues to represent a challenge for doc- Because there has been a long-standing exchange
tors and health systems worldwide, although the of researchers and students between different
prevalence and incidence of different diseases countries, it is important to invite the interna-
vary greatly among countries and regions. While tional pediatric respiratory community to report
the specific requirements of suitable attention on the state of the specialty in different areas
vary, the aspiration is to have common standards around the world so that current training stan-
for clinical management, besides training spe- dards and potential future developments can be
cialists in pediatric respiratory diseases in order advanced.
to provide the best possible care to children with
these types of illnesses. It is desirable that future
specialists know of global issues, besides having The Situation in South America
a standpoint on respiratory health. An updated
and published plan of study describes the content Pediatric respiratory diseases are among the main
of specialist training, and advances are being causes of morbidity in South America. Viral and
made in updating the full curriculum. Efforts to bacterial infections of the upper respiratory air-
improve training in pediatric respiratory medi- way, pneumonia, and obstructive diseases of the
cine benefit from exchanges among those who lower airway are the major reasons for consulta-
work in this field. Considering this, those who tion with pediatricians and hospitalization of
children. The South American countries that have
I. Sánchez (*) facilitated access to data about training programs
Department of Pediatrics, School of Medicine, in pediatric respiratory diseases are Argentina,
Pontificia Universidad Católica de Chile, Brazil, Chile, and Peru. Training programs have
Santiago, Chile

© Springer Nature Switzerland AG 2020 1

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_1
2 I. Sánchez

existed in these countries since the late 1970s, usually offered in an optional rotation period that
with 2–10 programs per country, each of which allows students to participate in a wide range of
has trained between 10 and more than 100 spe- research projects and in the development of a
cialists. The main reason to start these programs research line---in particular, during the training
has been to create schools and achieve advances period. This is especially useful for those who
in medical training, as well as building on and voluntarily take a third year of training. This part
disseminating knowledge acquired by academics is crucial to define specific interests in the pediat-
overseas at medical schools in North America, ric respiratory specialty, knowing that the chosen
Europe, and Australia. After completing their project can be the basis of future academic activi-
studies, these academics have returned home to ties. Mixed-content programs have been devel-
work in public and university hospitals. In these oped in recent years, such as those that combine
settings, they have developed training programs intensive child care, neonatology, and specific
at a local level that have had clear objectives and research areas. More in-depth studies have also
university certification, which are officially rec- been strengthened in sleep medicine, invasive
ognized. To enter any of these programs in pedi- procedures, and diseases such as cystic fibrosis
atric respiratory medicine and to apply for studies and others.
in subspecialization, candidates must complete 3 The professors in these programs are full-time
years of training in the specialty of pediatrics. In university academics, most of whom have worked
most cases, these are 2-year programs with an overseas to perfect their knowledge and have
optional third year, which is mainly focused on experience in basic, clinical, and epidemiological
clinical and basic research. research. Several of them have taken academic
The objectives and content of all existing pro- positions and have received recognition of great
grams include a broad and detailed review of renown. They participate with residents in jour-
basic sciences: anatomy, physiology, physiopa- nal clubs in order to critically analyze the most
thology, biochemistry, and molecular genetics; a recent scientific publications and asses medical
complete review of the various respiratory dis- evidence for treatment.
eases that affect the upper and lower respiratory At the end of the program, scholarship recipi-
tract; restrictive pathologies; bronchial and pul- ents must complete a written exam and an oral
monary deformations; and obstructive and exam before an examination committee. The
genetic diseases. Students should also measure majority of schools require that as part of com-
and analyze pulmonary function in children of all pleting their program, students publish a scien-
ages and learn about their potential applications tific manuscript or article that may summarize a
in research. The programs have a wide range of research project that the student has participated
techniques and methods like: spirometry, pleth- in and that may have been presented previously at
ysmography, histamine bronchial challenge test, a scientific meeting.
exercise challenge test, measurement of exhaled Research conducted in South America and
nitric oxide, polygraphy, sweat test and assess- published in international scientific journals has
ment of ciliary function among others. At some approached themes such as asthma, pediatric
centers, pulmonary function tests include assess- lung function, cystic fibrosis, bronchopulmonary
ment of pulmonary mechanics and of the volume dysplasia, and infectious respiratory diseases---in
and function of airways through rapid thoracoab- particular, infection by the syncytial virus and
dominal compression. Rotations during training bronchiolitis obliterans caused by an adenovirus.
in the specialty include basic hospital admission Noninvasive ventilation for patients with chronic
services, intensive and intermediate units, neona- respiratory diseases has received considerable
tology, ambulatory attention, the lung function interest in recent years. While there have been
laboratory, the bronchoscopy unit, and rotational fewer publications at the regional level in relation
units such as pathological anatomy, immunology, to these subjects, in comparison with the num-
radiology, and otorhinolaryngology. Research is bers published in developed countries, these pub-
1  History of Specialist Training in Respiratory Diseases 3

lications have been the result of significant efforts increasing lack of new applicants in this training
at different South American centers and the work area, which threatens the future of this specialty in
of different universities. this region. Similarly, there is a longstanding train-
Specialists in South America have historically ing program in Canada, although there is a lack of
joined societies focused on respiratory diseases experts. Some of the training centers in Australia
with pediatric chapters. In recent years, pediatric do not regularly receive funding, which limits the
respiratory societies have been created at the future development of the specialty. However, the
local level, including the Latin American fact that there is only one body of national author-
Pediatric Respiratory Society. For 25 years, this ity for the USA and one for Canada can make it
organization has held meetings every 3 years, easier to deal with the deficiencies in their respec-
with the participation of 1000 pediatricians and tive programs and the needs of the society. In the
specialists in the region. These encounters have other regions of the world, although they present
encouraged discussion of clinical cases and their different situations, the principal challenge is to
treatment, besides the multicenter and multidisci- achieve a consensus to harmonize training and
plinary planning of clinical and basic research flexibility in different countries, both during and
protocols. after the training period. It may be easier to estab-
The development of pediatric respiratory lish research networks than to achieve a consensus
medicine in South America is based on interna- about the best and most appropriate training.
tional networks and agreements between Ongoing exchange among specialists is funda-
­academics and former students from training pro- mental to support the development of the specialty
grams in North America, Europe, and Australia. at regional and national levels. A successful initia-
These contacts and exchanges have been of great tive in one region can be expected to facilitate the
importance in achieving harmonic development. development of harmonized training in other
Ongoing training also keeps academics up to date regions. Consequently, the European pediatric
on research projects and medical issues. A per- project HERMES (Harmonised Education in
manent challenge is to strengthen collaborative Respiratory Medicine for European Specialists)
research and academic exchange to promote can serve as a positive example of how to develop
ongoing upgrading and training. South American the pediatric respiratory specialty in a region
centers can offer interesting areas for academic where national governments are responsible for
exchange and research with centers in North developing specialties.
America, Europe, and Australia because they Respiratory diseases are among the most
have highly trained specialists, excellent stu- important challenges for pediatricians, as well as
dents, and a wide range of patients with a variety for health systems and societies in general,
of pathological entities. An ongoing challenge for whether the focus is on infectious diseases, as it is
specialists in our region is to continue improving in developing countries, or on allergic respiratory
our programs to cover a wide variety of patholo- disorders and respiratory problems caused by
gies in pediatric respiratory medicine. The aim is increasing pollution, as is the case in developed
to involve current and future specialists in cre- countries. The respiratory pediatric community
ative and innovative basic and clinical research to continues to collaborate and exchange knowledge
transfer knowledge “from the laboratory to the in the interest of young patients and their families.
patient,” thus achieving ongoing improvement in Student exchange programs between low-,
patient care. medium-, and high-income countries can improve
The longest-standing programs in the world, training and the transfer of competencies, besides
with more than 40  years of experience, are in promoting greater global awareness of pediatric
Australia and the USA.  Despite this vast educa- respiratory diseases. The positive attitude of spe-
tional experience and the great reputations of cialists and their respective societies toward the
many centers in the USA in clinical experience goal of improving the care of pediatric respiratory
and research, there is major concern about the diseases is reflected in this book, which demon-
4 I. Sánchez

strates worldwide support to increase the harmo- Gappa M, Ferkot T, Kovesi T, Landau L, McColley S,
Sanchez I, Tal A, Wong GHGK, Zar H.  Paediatric
nization of content  in training and programs respiratory medicine: an international perspective.
related to this specialty. Pediatr Pulmonol. 2010;45:14–24.
Gappa M, Noel JL, Severin T, et al. Paediatric HERMES:
a European syllabus in paediatric respiratory medi-
cine. Breathe. 2009a;5:237–47.
Sources Gappa M, Paton J, Baraldi E, et al. Paediatric HERMES:
update of the European training syllabus for paedi-
Cockcroft DW, Wensley D.  Respirology manpower in atric respiratory medicine. Eur Respir J. 2009b;33:
Canada—a report for the Canadian Thoracic Society 464–5.
Education Committee. Can Respir J. 2000;7:451–5. Mellins RB, Zar HJ.  Training pediatric pulmonologists
Chernick V, Mellins RB. Pediatric pulmonology: a devel- for the future: academic is a state of mind not just a
opmental history in North America. Pediatr Res. location. Pediatr Pulmonol Suppl. 2004;26:9–11.
2004;55:514–20. Taussig L. Pediatric pulmonology. In: Pearson H, editor.
Fok AO, Wong GW.  What have we learnt from ISAAC History of the American Board of Pediatrics. Chapel
phase III in the Asia–Pacific rim? Curr Opin Allergy Hill: American Board of Pediatrics; 2008. p. 163–7.
Clin Immunol. 2009;9:116–22. Zach M.  Pediatric respiratory training in Europe: politi-
Freed GL, Dunham KM, Switalski KE, Jones MD Jr, cal, educational and historical perspective. Breathe.
McGuinness GA.  Pediatric fellows: perspectives 2009;5:374–83.
on training and future scope of practice. Pediatrics.
2009;123:S31–7.
 Development of the Respiratory
System
2
Fernando Iñiguez Osmer
and Ignacio Sánchez

Contents
Introduction......................................................................................................................  5
Stages in Lung Development...........................................................................................  5
Development of Bronchial Circulation...........................................................................  8
Respiratory Mechanics....................................................................................................  9
Lung Weight/Body Weight and Lung Volume/Body Weight Ratios.............................  9
Genetic Control of Lung Development.........................................................................  10
Factors That Influence Lung Development..................................................................  11
Conclusion.......................................................................................................................  14
Sources.............................................................................................................................  15

Introduction These therapies can save their lives, but they can
also cause lung damage.
Events in fetal and early postnatal life influence To have a better understanding of how the lung
the respiratory health of the child and even of the functions in newborns, it is necessary to explain
adult. Alveolar development occurs mainly post- the normal development of the fetal lung. Three
natally, and injuries that can affect the fetus or things must take place for the newborn to adapt to
newborn undoubtedly have an impact on this pro- the extrauterine environment: lung fluid must be
cess. Preterm newborns are often submitted to absorbed, the lungs must be filled with air, and an
artificial ventilation and oxygen administration. adequate gas exchange surface must be present.

F. Iñiguez Osmer
Department of Pediatrics, Hospital de Puerto Montt, Stages in Lung Development
Puerto Montt, Chile
I. Sánchez (*) Lung development is a series of closely interre-
Department of Pediatrics, School of Medicine, lated events. Several stages have been described
Pontificia Universidad Católica de Chile, in the development of the prenatal human lung on
Santiago, Chile

© Springer Nature Switzerland AG 2020 5

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_2
6 F. Iñiguez Osmer and I. Sánchez

Table 2.1  Stages of lung development

Postnatal or
Stage gestational age
Main events
Embryonic 3–7 weeks Development of main airway
Appearance of pulmonary circulation
Pseudoglandular 7–17 weeks Development of conduction airway until terminal bronchi (preacinar)
Differentiation of epithelial cells
Vascular growth in parallel with airway growth; appearance of lung arteries
and veins
Canalicular 17–27 weeks Acinus formation
Growth of the capillary bed (angiogenesis)
Epithelial differentiation; surfactant appears
Saccular 28–36 weeks Formation of transient air space
Gas exchange area increases
Elastic fiber accumulation in places where future secondary septa will be
Alveolar 36 weeks–3 years Appearance of secondary septa; formation of alveoli
Microvascular 0–3 years Thinning of the intra-alveolar wall; fusion of the capillary double layer into
maturation a single layer
Active 0–3 years Number of alveoli increases; discrete changes in size
hyperplasia
Hypertrophy 3–21 years Size of alveoli increases; cellular growth is greater than body growth

FETAL STAGE AIRWAY ARTERIAL DEVELOPMENT

Trachea (day 24) Extrapulmonary arteries

Vasculogenesis
Embrionary: Source bronchii (day 28) (day 34)
(3-7 weeks) Lobe bronchii (day 37) Lobe arteries (day 44)
Segmentary bronchii (day 42) Pre-acinar arteries (7-17
weeks): 11 to 23
generations
Bronchiolii (12-16 weeks)
Pseudoglandular: Terminal bronchiolii
(7-17 weeks) (16-17 weeks)
Intra-acinar arteries (18-25
Canalicular: Respiratory bronchiolii
weeks): 3 to 5 generations
Angiogenesis
(17-27 weeks) (18 -25 weeks)
Alveolar ducts arteries (25
weeks – 18 months): 2-3
Saccular: Alveolar ducts
generations
(28-36 weeks) (25 weeks to 1 year)
Capillary alveoli (30 weeks –
Alveolar: 18 years) 11 to 23
Alveoli (36 weeks to 3 years)
(36-40 weeks) generations

Fig. 2.1  Stages of lung development: airway and lung vessels

the basis of its morphology (Table 2.1). Figure 2.1 diverticula, which penetrates the surrounding
illustrates the relationship between the airway mesenchyme. After this, it grows by dichotomous
and lung vasculature development. division downward to form the proximal struc-
tures of the tracheobronchial tree. The epithelial
The Embryonic Stage (Weeks  3–7)  At days cells of the entire respiratory tree, from the cen-
24–26 of gestation, a lung bud emerges from the tral airway to the pneumocytes, derive from this
epithelial cells of the endoderm in the primitive bud, while the cartilage, smooth muscle, connec-
anterior intestine, taking the shape of a ventral tive, and vasculature lung tissue originate from
2  Development of the Respiratory System 7

the mesenchyme. Division into two main at which point all of the preauricular airways and
branches occurs around day  33, with the lung their respective veins and arteries have formed,
buds lying on either side of the future esophagus. with little undifferentiated mesenchyme remain-
The surrounding mesoderm regulates the branch- ing between these structures.
ing of the tracheobronchial tree. The lobular
bronchi begin their formation by day 37 and by The Canalicular Stage (Weeks 17–27)  The ter-
the end of this stage (day 42) the 19 pulmonary minal bronchioles split to form respiratory bron-
segments can be distinguished. The mesenchyme chioles and alveolar ducts in the form of sacs,
surrounding the lung buds has cells that stain which constitute acinar structures. The thinning
positively for epithelial cell marker (CD31), indi- of the epithelium progresses with the approxima-
cating the origin of future capillaries. By day 34, tion of the capillaries that lie just below it. The
a network of capillaries has formed around each cuboidal epithelium differentiates and the alveo-
future main bronchus. In the upper part, this lar ducts are lined with type  II alveolar cells
plexus communicates with the aortic sac via the (pneumocytes), from which type I pneumocytes
pulmonary arteries, and the lower part communi- come, which line the distal sacs, thinning out as
cates with the venous sinus (the future left atrium) they approach the capillaries. Toward week  24,
through the pulmonary veins. At this point, circu- the alveolar–capillary barrier has been formed,
lating blood cells are evident. The first pulmo- which has a similar thickness to that in adults
nary vessels form de  novo from the underlying (0.2 μm), and the area available for gas exchange
mesenchyme through the process of vasculogen- allows some extreme preterm newborns to sur-
esis—cellular differentiation forming unique epi- vive. The metabolic machinery of type II pneu-
thelial cells, which are organized into capillary mocytes increases in preparation for synthesis of
tubes. These capillaries coalesce, forming small surfactant, and toward week  24, surfactant pro-
blood vessels throughout the airway. teins can be observed in the form of lamellar bod-
ies in the cytoplasm. Toward the end of this stage
The Pseudoglandular Stage (Weeks 7–17)  The the periphery of the lung is composed of transi-
main airway develops during this period through tory saccules with fine walls, which have formed
successive dichotomous divisions. The name of as a result of the decrease in the number of mes-
this stage reflects the glandular histological enchyme cells.
aspect of bronchioles that end in the stroma as
glands. During this period the most rapid division At this stage, capillaries are formed by angiogen-
of the intersegmental airway can be seen. The esis (sprouting of blood vessels from pre-­existing
bronchial wall cells develop from the mesen- vessels) and the dividing cells are more com-
chyme, giving rise to cartilage, smooth bronchial monly found in the capillary tubes than in the
muscle, and submucosal glands. By the end of undifferentiated mesenchyme.
this stage the definitive number of terminal bron-
chioles has been established. The pseudostrati- The Saccular Stage (Weeks 28–36)  The divi-
fied columnar epithelium is replaced progressively sion of the peripheral airways continues in this
by tall columnar cells in the proximal airway and period. Each terminal bronchiole gives rise to
cuboidal cells toward the periphery. The latter, three generations of respiratory bronchioles, each
rich in glycogen, are immature type II epithelial of which gives rise to a generation of transitory
cells. ducts, which in turn generate three sacs that flow
into the terminal saccules. In this way, the size of
The vasculature branches out following the air- the peripheral airway increases and the surface
way. As each new bud penetrates the mesen- for gas exchange increases as the walls continue
chyme, a new capillary plexus surrounds it like a to thin out (the primary septa). In preparation for
halo, joining the pre-existing venous and arterial the alveolar stage, elastic fibers are deposited at
vessels. Vasculogenesis continues until week 17, the points where secondary septa will emerge.
8 F. Iñiguez Osmer and I. Sánchez

Type  II pneumocytes increase the number of maturation. This phenomenon begins at birth and
lamellar bodies and the differentiation into type I continues for approximately 3  years. Alveolar
pneumocytes continues. multiplication continues for at least 2–3  months
after birth, while the alveolar surface size contin-
The arteries that feed the alveolar ducts develop ues to increase even after adolescence. A study that
from week 25 to 18 months after birth. The alve- measured the caliber of the small airway and alve-
olus and small pre- and postcapillary vessels oli in maximum extension in 53 children and youth
appear at week 30. aged 6–22 years and in 59 adults aged 23–80 years
reported that the size of the small bronchioles and
The Alveolar Stage (Week 36 to 2–3 Years)  The alveoli increased significantly with age and size
onset of this stage is defined by the appearance of until the age of 22 years, at which point there were
small prominences on both sides of the saccular no differences.
walls where the elastic fibers are deposited. These
grow perpendicularly to the airspace, incom- It is estimated that at birth there are 20–50 mil-
pletely dividing the sacs into smaller units (alve- lion alveoli, while in the developed lung of an
oli), which form to a lesser extent in the adult there are 300–500  million, with approxi-
respiratory bronchioles and transitory ducts. mately 170 alveoli/mm3. The gas exchange sur-
These secondary septa consist of a double capil- face is estimated to be 2.8 m2 at birth, 32 m2 at
lary loop separated by a sheath of connective tis- 8  years of age, and 75  m2 in adulthood. Males
sue. At this point, there is a marked proliferation have larger lungs than do females, which results
of all cell types. The mesenchyme cells prolifer- in a larger number of alveoli and a larger alveolar
ate, depositing the necessary cellular matrix. surface in comparison with females of the same
Type I and II pneumocytes increase in number to age and stature. The dimensions of the alveoli
delineate the alveolar walls, where approximately and the number of alveoli per unit of area do not
85–90% of the surface will be coated with type I differ between the sexes.
pneumocytes.

As new alveoli form, new capillaries are also cre- Development of Bronchial
ated by angiogenesis and increase the size of the Circulation
proximal veins and arteries, thus accommodating
the increased flow and volume of blood to the The second circulatory system of the human lung
growing capillary bed. These processes imply an is the bronchial system, through which oxygen and
increase in the net gas exchange surface and nutrients are supplied to the walls of the airways
preparation of the cells of the airway that will and large pulmonary vessels. In adults, the bron-
respond to the extrauterine environment. chial arteries reach the peripheral alveolar ducts.
They do not appear at the same time as the pulmo-
Postnatal Growth  Most of the development of the nary circulation, given that it begins around week 8
pulmonary parenchyma occurs after birth. The with one or two vessels that emerge from the dorsal
alveolus forms rapidly in the first months of life, aorta and are directed to the lung, as the cartilagi-
with maturation of the transitional ducts and alveo- nous plaques of the bronchi extend to the periphery
lar sacs. The alveolar stage lasts for up to 2–3 years, as the airway grows and the components of their
with increases in the number and size of the alve- walls differentiate. These vessels, which are
oli. The epithelial cells in the secondary septa smaller than the nearby pulmonary vessels, form a
undergo massive growth, followed by apoptosis network through the airway wall under the epithe-
(programmed cell death without inflammation), lium and on the outer wall. Several small bronchial
which remodels the irrigation of the septa from a veins of the airway drain into the pulmonary veins,
double capillary loop to the definitive morphology while the larger bronchial veins in the hilum drain
of a single loop, in a process termed microvascular into the cardinal veins and right atrium.
2  Development of the Respiratory System 9

Respiratory Mechanics  ung Weight/Body Weight and Lung

L
Volume/Body Weight Ratios
It is estimated that the functional residual capac-
ity (FRC) of term newborns of either sex is The pulmonary development status can be veri-
around 21 ml/kg and the total distensibility (com- fied in a perinatal autopsy. One of the elements to
pliance) of the respiratory system (CRS) is 5 ml/ consider is the lung weight/body weight ratio
cm  H2O.  This is mainly provided by the lungs, (LW/BW). According to an autopsy study, the
given that the thoracic wall at this age is very LW/BW between 17 and 27 weeks is 2.98–3.15%
compliant, in contrast to a later stage in child- and then decreases to 2.55% between 28 and
hood when the distensibility decreases. The total 36 weeks, the average at 40 weeks being 1.79%.
resistance of the respiratory system can reach up The tenth percentile is 2.24% between 20 and
to 70 cm H2O/l/s, the major part of which is given 23  weeks, 2.59% between 24 and 27  weeks,
by the bronchial tree. It is estimated that the dis- 2.27% between 28 and 36  weeks, and 1.24%
tensibility of a newborn is one twelfth of that of beyond 37  weeks. These reference values (per-
an adult, while the resistance is 15 times that in centile 10) are useful for detecting milder degrees
an adult. In the first breath, a thoracic pressure of of pulmonary hypoplasia than the values that
−70 cm H2Oc can be generated. Wigglesworth proposed in 1981 of 1.2% as the
The current volume of a term newborn is lower limit of normality for premature newborns
6–8  ml/kg, and the minute volume is around >28 weeks and 1.5% for those under this gesta-
0.6 l. The anatomical dead space approximates tional age.
half the current volume, which translates into a The increase in pulmonary liquid can result in
level of alveolar ventilation of 0.3 l/min. Oxygen overestimation of lung growth on the basis of
consumption is within the range of 20–30  ml/ weight, while lung volume is not affected by
min. intra-alveolar pulmonary liquid. In 2013,
There are several anatomical and functional De Paepe reported reference values according to
differences between the infant and adult respira- gestational age for the lung volume/body weight
tory systems, which are summarized in index. The lungs were inflated to a standardized
Table 2.2. pressure and submerged in water to determine

Table 2.2  Anatomical and functional differences in babies

Anatomical differences Functional differences
Upper airway: Hering–Breuer deflation reflex present in newborns
 Proportionally larger tongue and babies
 Small nostrils Babies have greater chest wall distensibility than
 Nasal breathing during the first 3 months of life preschoolers
 Larynx shaped like a cone; the cricoid is the smaller area Lung distensibility increases with age
Central and inferior airway: Resistance decreases with growth (greater diameter of
 Scarce cartilage at birth, which will develop during the the airway)
following years Greater reactivity of the airway
 Airway poor in collagen and elastin at birth Weaker elastic retraction opposing contraction (less
 The thickness of the wall corresponds to 30% of the stable airway)
airway (15% in the adult)
 Poorer tracheal mucociliary clearance
 Smooth muscle is present during early stages
 Greater number of mucus glands per surface unit
 Inefficient collateral ventilation
 Compliant chest wall (newborn)
 Ribs oriented horizontally
 Sternal ossification starting in week 22
 Progressive development of muscle mass during childhood
10 F. Iñiguez Osmer and I. Sánchez

their volume, which increases by 11  times behavior of neighboring cells, forming gradi-
between weeks 16 and  41, while in the same ents in a structure under development. In the
period the body weight increases by 16  times. developing lungs, they define branching pat-
The index remains constant at around 33–34 ml/ terns and control the sizes of the airway and its
kg between week 16 and 31 weeks of gestational cells, among other functions. In general, growth
age and then decreases to 23.4 ml/kg at the end of factors, whose signals are mediated by tyrosine
gestation. According to the authors, this index kinase–type receptors, promote cell differentia-
can also serve to detect more subtle degrees of tion and multiplication (fibroblast, epidermal,
pulmonary hypoplasia (premature rupture of vascular endothelial, and platelet-derived
membranes, chromosomic anomalies), in which growth factors). There are growth factors that
this index can be normal. act through serine/threonine–type receptors
(transforming growth factor  1 and morphoge-
netic bone protein  4), which oppose the previ-
 enetic Control of Lung
G ously mentioned factors. These signals achieve
Development equilibrium when the lungs are developed in
such a way that they can preserve cellular activi-
Lung development is a highly organized process ties and lung structure and function. Table  2.3
in which the interactions between the mesen- shows growth factors and their functions at dif-
chyme and epithelia control and coordinate the ferent developmental stages.
temporal and spatial expression of multiple reg-
ulatory factors that are necessary for appropri-
ate formation and growth of the lung. Diverse
Table 2.3  Growth factors and their roles in growth and
endogenous and exogenous factors can alter this lung development
delicate balance, which can result in disorders
Transforming growth factor beta: lung healing after
related to growth, maturation, or function of the injuries and extracellular matrix production; cellular
tissues in formation. A series of controlling fac- proliferation inhibition; appearance of secondary septa
tors have been identified for each lung develop- Epidermal growth factor: ramification, differentiation,
ment stage, consisting mainly of transcription and proliferation of the airway epithelium
Keratinocyte growth factor: macrophage differentiation
and growth factors (and their respective recep-
Fibroblast growth factors (FGFs; a 23-subgroup fam-
tors), extracellular matrix molecules, integrin, ily): location of organs that originate at the primitive
intercellular adhesion molecules, and others. As intestine; budding and ramification (FGFs 9 and 10);
a whole, these factors interact throughout the alveolar development, type II cell differentiation, and
distal proximal axis of the respiratory system, surfactant protein C induction (FGFs 2 and 7); creation
of tracheal cartilage rings (FGFs 10 and 18)
locally influencing numerous genes that control Bone morphogenic protein: formation and control of
modeling of the endotherm and the morphogen- dorsal and ventral branches; angiogenesis and
esis of the lung branches, left–right asymmetry, vasculogenesis
vascularization, and the response to mechanical Platelet-derived growth factor: alveolar development
forces. Granulocyte–macrophage colony–stimulating factor:
macrophage differentiation
Growth factors are diffusible proteins that act Vascular endothelial growth factor: angiogenesis,
at a short distance from their production site, vasculogenesis, and lymphangiogenesis
inducing various cellular activities through bio- Insulin-like growth factor: Airway proliferation may
chemical signals, promoting cellular prolifera- facilitate the effect of other growth factors; Fetal
endothelial cell tropism
tion, and mediating tissue interactions during
Sonic hedgehog (SHH): suppression of FGF 10
embryogenesis and in postnatal life. In organo- expression, preventing ramification in unsuitable places
genesis, these molecules provide information Retinoic acid: FGF 10 induction and endoderm
for the appropriate feedback response among differentiation
the different germ layers. Growth factors define MicroRNA, noncodifying: development of epithelial
the cellular signaling centers that control the cells
2  Development of the Respiratory System 11

 actors That Influence Lung

F Fetal Respiration and Pulmonary Fluid  Pul­
Development monary fluid is produced by the epithelial cells of
the lung, especially in the distal airway. The pul-
For normal lung development to take place, monary fluid flows toward the amniotic fluid or
fetal respiratory movement (FRM) is funda- is  swallowed. The fluid is poor in proteins
mental, besides adequate intrathoracic space, (<0.03 g/100 ml) and bicarbonate, but it is rich in
sufficient intra- and extrapulmonary fluid, and chlorine (>150 mEq/l). The velocity of pulmonary
good irrigation. Aspects of maternal health such fluid production increases as gestation progresses.
as nutrition, smoking, endocrine factors, preg- Its presence in the airways exerts mild positive
nancy-related factors (e.g., gestational diabetes pressure in relation to amniotic fluid pressure and
and hypertensive syndrome), and unrelated prevents collapse. Toward the end of the gestation,
health factors also influence fetal development the fetal airway contains approximately 40 ml of
(Fig. 2.2). pulmonary fluid, which is rapidly exchanged. A
balance between production and drainage appears
Developmental Anomalies  Abnormalities can crucial for lung development.
occur at any of the stages of lung development,
caused by maternal–fetal factors (e.g., oligohy- FRM has been observed from as early as week 11.
dramnios), genetic factors (e.g., a deficit of pro- Toward the end of gestation, movements are pres-
tein  B in the surfactant), or developmental ent a third of the time and increase in periods of
anomalies (Table 2.4). Table 2.5 lists factors that fetal activity, and the diaphragm is the main mus-
adversely affect lung development in both the cle involved. There is a circadian rhythm to FRM,
pre- and postnatal periods. with movements decreasing in the hours prior to

Mother-fetus
wellbeing

Development
Genetic burden
anomalies

Respiratory Peristaltic contractions

movements in the airway POSTNATAL PRENATAL

Active tobacco use Hormonal

LUNG
Tobacco use GROWTH Nutritional

O2 toxicity Infection

Biotrauma by the Persistent arterious

airway ductus

Disease caused by
Prematurity
surfactant deficit

Fig. 2.2  Prenatal and postnatal factors that influence lung development. Nutritional and hormonal factors are active
during the prenatal and postnatal periods. Infections can also act during the prenatal period
12 F. Iñiguez Osmer and I. Sánchez

Table 2.4  Stages of lung development during which certain congenital malformations related to abnormal lung devel-
opment appear
Saccular and alveolar
Embryonic stage Pseudoglandular stage Canalicular stage stages
Lung, tracheal, or laryngeal Cystic adenomatoid Lung hypoplasia Lung hypoplasia
agenesis malformation Acinar dysplasia Acinar dysplasia
Laryngeal or tracheal stenosis Lung hypoplasia Alveolar capillary
Tracheomalacia and Congenital lung dysplasia
bronchomalacia lymphangiectasia
Bronchial malformations Congenital diaphragmatic
Ectopic lobes hernia
Horseshoe lung Pulmonary sequestration
Congenital lung cysts (including
bronchogenic cysts)
Tracheoesophageal fistula

Table 2.5  Factors that adversely affect lung development

Prenatal factors Postnatal factors
Intrathoracic space reduction Prematurity
 Diaphragm alterations Drugs: tobacco smoke, steroids
 ­  Diaphragmatic agenesis: poor development of septum transversum
   Posterolateral hernia (Bochdalek): failure of pleuroperitoneal canal to seal
  Anterior or Morgagni hernia: lack of development of the retrosternal septum
transversum
   Eventration: failure of primitive muscle cell migration
 Cystic adenomatoid malformation:
   Type 0: acinar dysplasia
   Type 1: multiple large cysts or a dominant one
   Type II: multiple small cysts
   Type III: solid mass
   Type IV: peripheral cysts
 Pulmonary sequestration:
  Intralobar
  Extralobar
 Congenital lobar emphysema
 Pleural effusion
  Idiopathic
  Chylothorax
   Immune or nonimmune generalized hydrops
  Chromosome abnormalities, congenital heart disease, diaphragmatic hernia
associated with the antenatal period
  Newborn transient tachypnea, persistent lung hypertension, meconium
aspiration syndrome, heart failure associated with the postnatal period
  Trauma: nasogastric tube injuring the hypopharynx, erosion of the inferior
vena cava toward the pleural space through a total parenteral feeding tube
 Bone disorders:
   Asphyxiating thoracic dystrophy (Jeune syndrome)
   Ellis–van Creveld syndrome
   Saldino–Noonan syndrome (short ribs syndrome type I)
   Majewski syndrome (short ribs syndrome type II)
  Diastrophic dysplasia
   Thanatophoric dwarfism
  Osteogenesis imperfecta
2  Development of the Respiratory System 13

Table 2.5 (continued)
Prenatal factors Postnatal factors
   Achondrogenesis
  Hypophosphatasia
  Campomelic dysplasia
  Jarcho–Levin syndrome
 Reduction of fetal respiratory movement
  Neurological anomalies: Werdnig–Hoffmann syndrome, congenital muscular
dystrophy
   Imperfections in the anterior abdominal wall: omphalocele, gastroschisis
  Drugs: tobacco
Amniotic fluid reduction (oligohydramnios)
 Reduced production: nephropathies (e.g., Potter)
 Amniotic fluid leak: premature rupture of membranes
 Invasive procedures: amniocentesis

midnight and increasing between 4  a.m. and d­ evelopment and epithelial differentiation.
6  a.m. FRM increases after maternal feeding Pulmonary subdistension occurs in cases of con-
(hyperglycemia) and also in situations of hyper- genital diaphragmatic hernia, drainage of pul-
capnia, acidosis, or temperature rise, and before monary fluid, or abolition of FRM (in the
administration of indomethacin, caffeine, or the- medullar or phrenic section), which causes the
ophylline. FRM is depressed in the context of lungs to be small (hypoplasia) and favors the
hypoxia (a global depressor of fetal activity), type II epithelial phenotype at the cost of type I,
hypoglycemia, administration of prostaglan- while pulmonary overdistension (tracheal liga-
din E2, intrauterine infection, maternal smoking, tion) promotes lung growth (hyperplasia) and
consumption of alcohol, or use of sedatives such favors the type  I epithelial phenotype at the
as diazepam or morphine. FRM is fundamental to expense of type II.
maintenance of adequate lung volume. In periods Toward the end of gestation, the volume of
of apnea, the pharynx collapses and the larynx pulmonary fluid and its rate of production
offers resistance to the escape of liquid, with decrease. The expression of sodium channels and
maintenance of the pressure gradient. The upper the sodium–potassium ATPase pump in the epi-
airway dilates and the diaphragm contracts in the thelium increase at this stage. These changes in
inspiration phase, allowing fluid to enter, which ion transport in the pulmonary epithelial cells in
contributes to lung expansion. late gestation reflect the change from a pattern of
The physical forces referred to as stretching or chlorosecretion to one of sodium absorption near
distension are in fact better described as a variety birth, thus preparing the lung for postnatal
of different mechanical forces, such as stress adaptation.
(force per unit of area), elongation (lengthening
of a structure), restoring force (when the struc- Peristaltic Contractions  Studies with animals
ture returns to its original length), surface tension have highlighted the importance of spontaneous
(differences between intracellular adhesion and peristaltic contractions that occur in the airway.
cytoskeletal contractility), and prestress (isomet- Peristaltic waves originate in the trachea, propa-
ric tension that balances intra- and extracellular gated by the bronchial tree, and pump lung fluid
elongation tension). These different mechanical distally. When the tubes relax, the flow reverses.
forces within and between cells, tissues, and The frequency is 2–3 per minute in the fetal pig
organs are as important as genes and chemical lung at the pseudoglandular and canalicular
signals in controlling lung development. stages, while it is 10–12 per minute in the rabbit
Several methods have been developed to lung at the saccular stage. The intraluminal pres-
study the role of physical forces in pulmonary sure measured in the trachea of fetal rabbits is
14 F. Iñiguez Osmer and I. Sánchez

2.3 cm H2O. It is highly probable that the expan- tive study compared the CRS of premature
sion of the most peripheral buds is favored by this newborns (32 weeks of gestation, <3 days of life,
phenomenon, which facilitates its growth toward prior to administration of surfactants, if required)
the surrounding mesenchyme. who had received steroids more than a week
before birth and that of infants who had received
Peristaltic waves of smooth muscle emanate from steroids 1–7 days before birth. CRS was measured
certain pacemaker areas in the proximal airway in 28 patients by use of the single-breath occlusion
before being transmitted to the distal area. Study technique. Infants born more than a week after
of peristaltic wave frequency in embryonic lung administration of steroids had significantly lower
cultures has shown that acceleration of the fre- CRS values, in terms of both the absolute value
quency with cholinergic agents or fibroblast and the value normalized for weight, than infants
growth factor (FGF)-10 stimulates pulmonary born between 1 and 7 days after steroid adminis-
growth, while inhibition of the frequency reduces tration (1.52 ml/cm H2O versus 2.12 ml/cm H2O,
growth. Other studies have shown that there are and 0.98 ml/cm H2O/kg versus 1.41 ml/cm H2O/
spontaneous intercellular calcium waves that are kg, respectively). A lower CRS value may reflect
propagated throughout the air just before the per- dissipation of the beneficial effects of antenatal
istaltic contractibility wave. These waves depend steroids on lung function when birth occurs more
on intra- and extracellular calcium and the integ- than 7 days after steroid administration.
rity of intercellular bonds. These oscillations
stimulate lung development by regulating growth Nutrition  Fetal malnourishment appears to
through muscular peristalsis. decrease lung volume but not airway maturation.
Studies with animals have shown that a decrease
Steroids  Prenatal administration of steroids in fetal nutrition alters the development of sec-
accelerates lung growth by several mechanisms; ondary septa, with a reduced exchange area, but
among them, steroids favor lung maturation, with without affecting alveolar size. It has been argued
an increase in the volumetric density of the air that less elastin is deposited in the saccular and
spaces and increased maturation of epithelial alveolar stages. In addition to the fact that mal-
cells. Early thinning of the double capillary loop nourished infants have less muscular mass, they
is promoted during the saccular and alveolar have a greater tendency to experience bronchial
stages, but the final number of secondary septa collapse during respiratory infections. Studies in
decreases and, with this, so does the final number adults who were the children of mothers who suf-
of alveoli. Type II pneumocytes increase in num- fered a famine in 1944–1945 have indicated the
ber and functionality with increased levels of importance of adequate intrauterine nutrition for
messenger RNA for the surfactant proteins. Other pulmonary development. Subjects exposed to
effects include increased transcription of the maternal malnutrition between the second and
genes responsible for growth and maturation, as third trimesters of gestation had a higher inci-
well as increased levels of antioxidant enzymes. dence of airway obstructive diseases in adu­
When administered postnatally, steroids acceler- lthood, without alterations in the level of
ate the maturation of developing lung tissue, immunoglobulin E or in lung function tests.
shortening the time in which the double loop is
present, which is vital for the development of
secondary septa. In this way, septation is short-
ened and the total number of alveoli that can Conclusion
develop is limited.
Lung development is a highly coordinated and
When premature birth is imminent, antenatal ste- complex process, about which much remains
roids can affect respiratory mechanics. A prospec- unknown. Future developments will provide use
2  Development of the Respiratory System 15

of concrete tools to help newborns afflicted with Iñiguez F, Sánchez I.  Desarrollo pulmonar. Neumología
bronchopulmonary dysplasia or other congenital Pediátrica. 2008;3:148–55.
Katz C, Bentur L, Elias N. Clinical implications of lung fluid
conditions in which normal lung development is balance in the perinatal period. J Perinatol. 2011;31:230–5.
altered. Lopuhaa C, Roseboom T, Osmond C, et  al. Atopy, lung
function, and obstructive airways disease after prena-
tal exposure to famine. Thorax. 2000;55:555–61.
McEvoy C, Schilling D, Spitale P, Peters D, O’Malley
Sources J, Durand M.  Decreased respiratory compliance in
infants less than or equal to 32 weeks’ gestation, deliv-
Baguma-Nibasheka M, Gugic D, Saraga-Babic M, Kablar ered more than 7 days after antenatal steroid therapy.
B.  Role of skeletal muscle in lung development. Pediatrics. 2008;121:e1032–8.
Histhol Histopathol. 2012;27:817–26. Roth-Kleiner M, Post M. Similarities and dissimilarities
Copland I, Post M.  Lung development and fetal lung of branching and septation during lung development.
growth. Pediatr Respir Rev. 2004;5(Suppl A):S259–64. Pediatr Pulmonol. 2005;40:113–34.
De Paepe M, Shapiro S, Hansen K, Gündogan F. Postmortem Schittny J, Miserocchi G, Sparrow M. Spontaneous peri-
lung volume/body weight standards for term and pre- staltic airway contractions propel lung liquid through
term infants. Pediatr Pulmonol. 2014;49(1):60–6. the bronchial tree of intact and fetal lung explants. Am
Gibson A.  Perinatal corticosteroids and the developing J Respir Cell Mol Biol. 2000;23:11–8.
lung. Pediatr Respir Rev. 2002;3:70–6. Waburton D, El-Hashash A, Carraro G, et al. Lung organ-
Greenough A.  Factors adversely affecting lung growth. ogenesis. Curr Top Dev Biol. 2010;90:73–158.
Pediatr Respir Rev. 2000;1:314–20. Wilson S, Olven R, Walters D. Developmental regulation
Hislop A. Developmental biology of the pulmonary circu- of lumenal lung fluid and electrolyte transport. Respir
lation. Pediatr Respir Rev. 2005;6:35–43. Physiol Neurobiol. 2007;159:247–55.
Hulskamp G, Pillow J, Dinger J, Stocks J. Lung function Zeman K, Bennet W.  Growth of the small airways and
tests in neonates and infants with chronic lung dis- alveoli from childhood to the adult lung measured by
ease of infancy: functional residual capacity. Pediatr aerosol-derived airway morphology. J Appl Physiol.
Pulmonol. 2006;41:1–22. 2006;100:956–71.
 Physiological Basis
of the Respiratory System
3
Pablo Bertrand and Ignacio Sánchez

Contents
Respiratory Mechanics..................................................................................................  17
Airway Resistance..........................................................................................................  19
Pulmonary Ventilation....................................................................................................  20
Alterations in Pulmonary Ventilation...........................................................................  21
 lveolar Hypoventilation.................................................................................................  22
A
Alveolar Hyperventilation................................................................................................  22
Pulmonary Circulation...................................................................................................  22
The Ventilation/Perfusion Ratio....................................................................................  23
Respiratory Gases in the Blood.....................................................................................  24
Sources.............................................................................................................................  27

Respiratory Mechanics The respiratory system contains the lungs

within the rib cage. The two structures adhere
Respiratory system mechanics analyzes the to each other through pleural surface contact.
forces and resistances that determine the move- The lungs have a natural tendency to reduce
ment of gases between the lungs and the exte- their volume and the rib cage has a natural ten-
rior. Airflows from the region of greater dency to increase its volume; thus, between
pressure to that of lesser pressure as a result of them, they create negative subatmospheric
the changes in the thorax, but it must overcome pressure at the level of the pleural space. The
the elastic resistance of the respiratory system lung behaves like elastic because of its struc-
(the lungs and rib cage) and frictional resis- ture and the presence of an extensive liquid
tance to airflow, which is known as airway interface that reduces the force of surface ten-
resistance. sion, which is very important for production of
the elastic recoil pressure of the lungs. Because
of this, all of the 300  million alveoli tend to
P. Bertrand (*) · I. Sánchez retract. The sum of this force exercised through-
Department of Pediatrics, School of Medicine, out the lung determines the resistance to dila-
Pontificia Universidad Católica de Chile, tion. Surface tension depends on lung volume.
Santiago, Chile Surface tension values are low at small ­volumes
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 17

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_3
18 P. Bertrand and I. Sánchez

Residual Functional Capacity

Pleural pressure (cm H2O)

–8.5
100

80
35 cm

60

Volume (%)
–1.5

40

20

0
–10 0 10 20 30 40
Transpulmonary pressure (cm H2O)

Fig. 3.1  Changes in distensibility (the change in volume divided by the change in pressure) (ΔV/ΔP) according to the
lung zone (standing position)

and high at large volumes. At the alveolar level, lung volumes in which it is measured, as well
the surfactant is responsible for reducing sur- as the area, considered with the patient in a
face tension and avoiding alveolar collapse at standing position. Compliance is lower if lung
small volumes. The respiratory system follows volume is greater, as occurs in the apex, and it
Hook’s law: “The greater the muscular force or is greater if lung volume is lower, as occurs in
pressure applied to the lungs, the greater the the base (Fig. 3.1). In other words, close to total
change in the volume obtained.” The relation lung volume, the elastic is more difficult to
between the volume that is reached and the extend, while the opposite is true at residual
pressure that is used is known as lung compli- volume. To determine if a lung has normal elas-
ance, which is defined as the change in volume tic properties, compliance must be corrected for
determined by the changes in pressure at zero the residual functional capacity (RFC), which
airflow. It is expressed as the coefficient ∅V/∅P, is called specific compliance, a value that
measured in milliliters per centimeter of changes little with age. The factors that decrease
H2O. The measurement that considers the flow pulmonary compliance are pulmonary edema,
and resistance of the airway to the change in alveolar collapse, inflammation, pulmonary
volume determined by changes in pressure is hyperflow, and pulmonary fibrosis. A factor that
termed dynamic pulmonary compliance. increases compliance is structural destruction
Compliance varies according to the different of the parenchyma.
3  Physiological Basis of the Respiratory System 19

Airway Resistance Under any condition that decreases pulmo-

nary compliance, optimal breathing occurs at low
According to pressure measurements done tidal volumes (TVs) to reduce the respiratory
throughout the intrathoracic airway, airway resis- work in distending rigid lungs. Compensation is
tance decreases as the airway gets smaller. achieved by increasing the respiration rate to
Therefore, the greatest airflow resistance is in the obtain adequate alveolar ventilation (VA). Under
trachea and large bronchi, and the smallest air- any condition that increases airway resistance,
flow resistance is in the small bronchioles. The the respiratory rate will optimally decrease to
small airway (<2  mm in diameter) represents obtain slower and less turbulent airflows and
only 20% of the total resistance because transver- reduced respiratory work. In this scenario, the
sal resistance in this area adds a significant diam- compensation to achieve adequate VA is an
eter in comparison with that of the central airway. increased TV, but the displacement of the equal
Moreover, the flow is laminar at the level of the pressure point to the proximal airway causes pul-
small airway; thus, diseases that affect this area monary hyperinflation, such that the lungs are at
theoretically increase the resistance very little. maximum volume. In this case, lung compliance
Consequently, this area is termed the “quiet is reduced and the TV therefore cannot increase.
zone.” Lung compliance and airway resistance can be
The causes of increased airway resistance are: determined only by invasive tests in specialized
laboratories, because of which simpler ­procedures
1. Constriction of the bronchial and bronchiolar have been developed to ascertain the mechanical
smooth muscles characteristics of the lungs and chest. To analyze
2. Inflammation or edema of the bronchial or ventilation function it is possible to measure the
bronchiolar wall volume of gas that can be moved with maximum
3. Obstruction of the lumen due to exudate,
respiratory force, which is expressed adequately
mucus, or foreign bodies with the vital capacity (VC) and the velocity with
4. Fibrosis of the bronchial wall which this volume is exhaled, known as spirome-
5. External compression of the airways try. This pulmonary function test depends on air-
6. The diameter of the airway, which is subject way resistance and the elastic resistance of the
to the lung volume lungs and chest. During much of the maneuver of
forced expiration, the maximum airflow is fixed,
The last factor has a significant influence on air- such that increased effort does not result in
way resistance, given that the tensor action of the increased flow, and it is only at very high lung vol-
tissue maintains the caliber of the airway and at umes of over 75% of the VC that the flow is effort
large lung volumes the diameter of the airway dependent. Forced respiratory flow is determined
tends to increase, while at low volumes the diam- by the alveolar pressure and dynamic compres-
eter decreases and resistance increases. At low sion of the intrathoracic airways. Alveolar pres-
lung volumes, where the airway does not have sure is determined by the elastic rebound pressure
structural rigidity and its permeability depends of the lung tissue and positive intrapleural pres-
on the elastic support of the surrounding tissue sure produced by the rib cage muscles, which can
(peripheral airway), the airway can collapse. be summarized in the following manner:

Alveolar pressure = Elastic rebound pressure + Intrapleural pressure

Intrathoracic airways are subjected to intrapleu- way, so the airway remains permeable. However,
ral pressure, which is transmitted through the in the forced expiration maneuver, the existing
parenchyma surrounding them. During normal positive pressure in the airway is less than or
respiration, the pressure in the lumen is greater equal to the pressure exerted from outside the air-
than the pressure in all of the intrathoracic air- way, which is termed the equal pressure point. At
20 P. Bertrand and I. Sánchez

0 0

+0,25 +3

-8 -8 +25 +5 +25 Contraction of

+10 internal and accesory
+0,5
intercostal exhalative
+15 muscles
-8 -8 +25 +25
+20

+25 Equal Pressure Point

-8 -8 +25 +25
+30
+1

+10 +10 +10 +10

+2 +35

+10 +10 +10 +10

Diaphragm is displaced by the

contraction of the abdominal muscles

Passive Exhalation Forced Exhalation

Fig. 3.2  Equal pressure point

this point the nonrigid airway collapses, provok- The conduction airway extends from the trachea
ing a valve effect that maintains critical lung vol- to the terminal bronchioles (generation 16), and
ume, which is termed the residual volume the transition and respiratory airway extends
(Fig. 3.2). At any lung volume below 75% of the from the respiratory bronchioles (generation 17)
VC, a pressure point equal to collapse appears in to the alveoli (generation  23). Of the total air
all of the airway, which determines a fixed air- inhaled, 70% is involved in gas exchange and the
flow that cannot increase beyond an equal remaining 30% remains in the anatomical dead
increase in pleural pressure. The location of this space of the airway.
point varies with the lung volume: at high vol- Inspiration is produced by active contraction
umes it is located at the second to third bronchial of the diaphragm and external intercostal mus-
generation, and with lower volumes it moves cles, which determines a tridimensional increase
toward the small distal airway. in the rib cage (Fig. 3.3), with a decrease in tho-
racic pressure to create a gradient that permits air
from the mouth and nose to reach the alveoli. The
Pulmonary Ventilation degree to which these muscles participate in
inspiration varies depending on the patient’s age
Pulmonary ventilation is a cyclical process of and physical position. Respiration with the dia-
inspiration and expiration through which alveolar phragm predominates in the first years of life,
air is renovated in each respiratory cycle through mainly because at this stage of life the child fre-
the airway. The airway is composed of a series of quently lies in a supine position, but also because
ramifications that are divided dichotomously, of the low level of resistance by the abdominal
resulting in 23 generations at the alveolar level. cavity to displace the diaphragm. As the child
3  Physiological Basis of the Respiratory System 21

Inhalation Intercostal muscles

External

Columna
Internal
Diaphragm Tubercle head
Exhalation Ribs

Abdominal
muscles
Rotation axis
Active
Passive

Fig. 3.3  Action mechanism of respiratory muscles

grows, the external intercostal muscles start to Alterations in Pulmonary Ventilation

become more important and are responsible for
equivalent breathing work during adolescence Pulmonary ventilation is altered by excess (hyper-
when the patient is in a standing position, and this ventilation) or by deficit (hypoventilation) and
set of muscles is predominant when the patient is can be understood as the result of the volume of
in a sitting position, when increased abdominal each respiratory cycle, or TV, and the number of
pressure reduces diaphragmatic displacement. In times it occurs in 1 minute, or the respiratory fre-
adolescence, respiration in a supine position con- quency (RF). In this way, the 1-minute exchange
tinues to be largely diaphragmatic and involves volume, or VA (which is summarized in the equa-
approximately 70% of the volume change in each tion below), provides the best clinical estimation
respiratory cycle. The supine position is slightly of hypoventilation or hyperventilation:
more advantageous in the context of respiratory VA = VC ´ RF
difficulty, especially in the case of newborns and
infants. The accessory inspirational muscles, Uniform and adequate chest movement in quiet
such as the scalene and sternocleidomastoid mus- breathing mobilizes about 5–6  ml/k of air in
cles, are used only in forced inspiration, and their every cycle. This is the TV, and in an adolescent
participation in upper airway obstruction is evi- male it is approximately 500 ml. This expansion
dent. With conditions that produce pulmonary is greater in a crisis of adolescent panic, but it is
hyperinflation, such as asthma or bronchiolitis, reduced by poor thoracic–abdominal dynamics
the inspiratory muscles are shortened, which due to diaphragmatic paralysis or muscular
reduces their efficiency when they are contracted. fatigue. There is inherent variability in a child’s
In this situation, the flattening of the diaphragm respiratory rate, and it is influenced by stress,
also conditions the retraction of the free costal pain, and other factors. Clinical integration of the
edge, which is considered a marker of respiratory chest expansion and RF is what matters from a
difficulty. physiological perspective. The compensation that
Expiration is passive under normal conditions occurs in the context of an increased breathing
of quiet respiration, and it is determined by the rate or an increased TV results in adequate, insuf-
elastic force of the lungs and rib cage, and by ficient, or excessive VA, which in every case
relaxation of the inspiratory muscle. In contrast, depends on the minute volume that fills the phys-
during exercise or in the context of airway iological dead space (PDS). The increased respi-
obstruction, expiration is active, using the mus- ratory rate in a subject compared with the same
culature of the abdominal wall and the internal proportional increase in TV in the same subject at
intercostal muscles to facilitate pulmonary another moment yields less VA in the former situ-
action. ation because there is more ventilation of the
22 P. Bertrand and I. Sánchez

PDS.  The diagnosis of hyperventilation or partial pressure of O2 increases marginally at the

hypoventilation is closely related to the measure- alveolar level in such a way that the hemoglobin
ment of the partial pressure of carbon dioxide saturation of the arterial blood does not increase,
(PaCO2), given that the level of this gas is one of given that this part of the hemoglobin disassocia-
the most important regulators of VA. A condition tion curve is flat. Hyperventilation is caused by
is defined as hyperventilation when the PaCO2 anxiety, pain, lesions in the central nervous sys-
falls below 40 mmHg (respiratory alkalosis) and tem, intoxication with medication, increased
as hypoventilation when the PaCO2 goes above metabolism, and a compensation mechanism in
40 mmHg (respiratory acidosis). the context of hypoxemia or metabolic acidosis.

Alveolar Hypoventilation Pulmonary Circulation

Hypoventilation is a condition in which the quan- The pulmonary circulation begins in the pulmo-
tity of air that is circulating does not meet the needs nary artery, which receives venous blood from the
of the organism. The quantity of oxygen that enters right ventricle and then successively branches,
the organism is smaller, which causes a decrease in together with the respiratory paths, until it reaches
the partial pressure of oxygen in arterial blood the terminal bronchioles, providing the capillary
(PaO2). At the same time, the smaller quantity of bed located in the alveolar walls. This network
air that is circulating does not succeed in removing contains 280  billion capillaries, which supply
all of the CO2 produced in the organism, which approximately 300 million alveoli, with a poten-
increases the partial pressure of CO2 in venous tial gaseous exchange of between 50 and 100 m2—
blood (PvCO2) and in the alveolus (PACO2), in an area comparable to half a tennis court.
turn causing a reduction in the blood pH. The com- The pulmonary blood circulation is at a much
bination of these two changes is termed respiratory lower pressure than that of the blood in the circu-
acidosis. A child who is hypoventilating and latory system and is very closely related to the
breathing environmental air will always suffer alveolar pressure.
from hypoxemia and hypercapnia; administration With a deep inhalation, the alveolar vessels tend
of oxygen will improve the hypoxemia but not the to collapse with the increase in alveolar pressure,
hypercapnia. The causes of hypoventilation are an while the extra-alveolar vessels tend to expand
alteration in the central nervous system (brain con- because of the radial traction of the surrounding
tusion, stroke, etc.), an alteration in nerve conduc- parenchyma. With a deep exhalation, the alveolar
tion (phrenic paralysis, Guillain–Barré syndrome, vessels do not collapse, because of alveolar pres-
etc.), muscular dysfunction (myopathy, myasthe- sure, while the extra-alveolar vessels do collapse
nia gravis), an alteration in the rib cage (costover- because of the lack of radial traction. Figure  3.4
tebral malformations, kyphoscoliosis), and airway shows that the optimal vascular pulmonary resis-
obstruction (severe laryngitis, foreign body inhala- tance is in the center of the curve, near the RFC.
tion, asthma crisis, etc.). It is important to consider that the pulmonary
circulation also has the capacity to maintain and
even reduce vascular pulmonary resistance when
Alveolar Hyperventilation the pulmonary circulation pressure increases,
which occurs through the recruitment mechanism,
Hyperventilation is a condition in which the quan- through which it is possible to circulate the blood
tity of air circulating is excessive for the require- through capillaries that are normally closed or
ments of the organism. Thus, the circulating air open, but without a flow of blood and distension,
removes more CO2, and so the PaCO2 in the arte- through which the capillary segments widen,
rial flow decreases, which raises the pH level in changing tridimensionally from flat to more circu-
the blood. This is termed respiratory alkalosis. The lar (Fig. 3.5).
3  Physiological Basis of the Respiratory System 23

Lung vascular resistance (mm Hg/mL/min)

Total

Alveolar

Extraalveolar

RV: RFC: TLC:

Residual volume Residual Functional Total lung
Capacity capacity

Fig. 3.4  Pulmonary vascular resistance according to the lung zone (in a standing individual)

Recruiting Distension

Fig. 3.5  Pulmonary circulation, recruitment, and vascular distention

The Ventilation/Perfusion Ratio ventilation at the bases because the apices are
more distended (more negative intrapleural pres-
The efficacy of pulmonary gas exchange depends sure at the apices) and also favoring more perfu-
on uniform distribution of the inhaled air and sion at the base because of the effect of gravity.
blood flow (Q) that circulates in the pulmonary However, the result in the bases is that the V/Q
vascular bed. The VA in a young adult is 4 l/min ratio is 0.6. In effect, there is ­proportionally more
and the blood flow is 5 l/min. The ventilation/per- perfusion acting as shunt areas (with shunting
fusion (V/Q) ratio of the entire pulmonary system from right to left). The result in the apices is a V/Q
is thus 4/5 = 0.8. Ventilation and perfusion are not ratio of 3, in which the ventilation acting as alveo-
homogeneously distributed throughout the lungs. lar dead space is proportionally greater (Fig. 3.6).
These values vary according to the areas estab- These phenomena, which occur in normal
lished in a standing individual, favoring better children because of gravity, can be accentuated
24 P. Bertrand and I. Sánchez

Fig. 3.6 Ventilation/
perfusion ratio ,15 3
according to the lung
zone (in a standing

Ventilation/Perfusion per volumen unit

individual)
Blood flow

10 2

VA/Q
VA/Q
Ventilation

,05 1

Base 5 4 3 2 Apex
Coastal Height

in cases of illness. An alteration in the V/Q ratio exhaled air (PeCO2), according to a simplified
is the most common physiopathological disor- Bohr equation:
der in pediatric respiratory diseases. The clini-
PDS = ( PaCO 2 * PeCO 2 ) / PaCO 2
cally significant aspect in this alteration is the
decrease in the PaO2, given that well-ventilated
areas do not improve the low blood PaO2 from
poorly ventilated areas, because the hemoglobin Respiratory Gases in the Blood
saturation in the former is almost 100%. In con-
trast, the well-­ventilated areas do improve the According to Dalton’s law of partial pressure, the
PaCO2 in poorly ventilated areas, easily com- pressure exerted by each gas in a mixture of gases
pensating for the decreased elimination of CO2 is independent of the other gases, and the total
in hypoventilated areas. For these reasons, alter- pressure of a mixture of gases is equal to the sum
ations in the V/Q ratio always lead to arterial of each gas separately. Atmospheric air contains
hypoxemia—whether it is due to irregular venti- 20.93% oxygen, 0.04% carbon dioxide, and
lation with uniform blood flow or irregular 79.03% nitrogen, with a pressure of 760 mmHg
blood flow with regular ventilation—and, in at sea level (barometric pressure). The partial
contrast, its influence on the PaCO2 is variable, pressure of O2 in inhaled air (PIO2) is conse-
given that this parameter depends more on the quently 20.93% of 760 mmHg, or 159.1 mmHg.
efficacy of the total VA. When air is inhaled, it is saturated with water
Alveolar areas that do have exchange because vapor, which evaporates from the surface of the
of nil or insufficient vascular perfusion are not nasal tissue and is diluted in the air occupying the
used in gaseous exchange and constitute dead airways and the lungs. The gaseous mixture that
alveolar space. The PDS is the sum of the ana- reaches the alveoli is termed alveolar air and now
tomical dead space in the airways and the alveo- contains the gases from inhaled air: O2, N2, and
lar dead space, which is normally 30% of the CO2, as well as water vapor. The partial water
total pulmonary volume. The PDS is calculated vapor pressure is a saturated mix in the function
on the basis of simultaneous measurements of the of temperature, such that at 37 °C it is 47 mmHg’.
partial pressure of CO2 in blood (PaCO2) and in The total pressure of the gases in alveolar air is
3  Physiological Basis of the Respiratory System 25

equal to the barometric pressure, and as 47 mmHg allows us to assess the degree of sufficiency of
of this pressure is necessarily water vapor, the the total respiratory function. These determina-
pressure of the other gases has to be equal to the tions are indispensable in pulmonary function
barometric pressure minus 47 mmHg. studies and are now routine examinations in the
In a normal male at rest and breathing nor- treatment of serious respiratory problems.
mally, the PACO2 is around 40  mmHg. In con- The oxygen hemoglobin saturation is related
trast, the partial pressure of O2 in alveolar air closely to the arterial oxygen content, given that
(PAO2) depends on the PACO2 (given that the the fraction of dissolved oxygen in the blood is
partial pressure of N2 and water vapor do not negligible because of the low solubility coeffi-
vary). This relationship is expressed in the alveo- cient. The oxygen saturation depends on the par-
lar air equation: tial pressure of oxygen and the characteristics of
the hemoglobin disassociation curve, which is
PAO 2 = ( FIO 2 * ( Patmos - PH 2 O ) ) - ( PaCO 2 /R ) influenced by factors such as the type of hemo-
globin (fetal, adult, abnormal), pH, PaCO2, tem-
where FIO2 is the inhaled O2 fraction, Patmos perature, and 2,3-diphosphoglycerate content.
is the local atmospheric pressure, PH2O is the The hemoglobin disassociation curve has an
water vapor pressure in the airway and its value is inflection point, below which small decreases in
47 mmHg, and R is the normal respiratory quo- the PaO2 correlate with substantial decreases in
tient and its value is 0.8. the hemoglobin saturation and consequently the
arterial O2 content. Above the inflection point, the
R : normal respiratory quotient = 0.8
slope is flattened and small increases in hemoglo-
The PACO2 can be estimated from the PaCO2 bin saturation correlate with a pronounced
at the arterial level, which can be measured. increase in the PaO2. The decrease in the PaO2
Resolving the alveolar air equation for a person from 100 mmHg to 70 mmHg has only a minimal
with a PaCO2 of 40 mmHg at sea level yields a effect on hemoglobin saturation. In contrast, an
PAO2 of 109 mmHg during breathing of an FIO2 increase in hemoglobin saturation above 93% is
of 21%. Oxygen in the lungs diffuses from alveo- associated with proportionally greater increases
lar air into the blood because venous blood arriv- in the PaO2 (Fig. 3.7).
ing in the lungs has a lower mixed venous oxygen Because of the characteristics of fetal Hb, the
tension than the PAO2. As the blood passes newborn dissociation curve shifts to the left. This
through the lung capillaries, it never reaches a means that at a determined hemoglobin satura-
complete equilibrium with the alveolar air, and so tion level, the PaO2 is lower than the O2 tension in
the PaO2 of the blood that leaves the lung capil- an older child. Hemoglobin saturation at 80% is
laries is slightly lower than the PAO2; in normal reached in a newborn at a PaO2 of 30 mmHg, and
circumstances, this difference is not greater than in an older child at a PaO2 of over 50 mmHg.
1 mmHg. However, before this arterialized blood The transport of CO2 is totally different from
reaches the arteries systematically, it mixes with that of oxygen because of the differences in their
a small quantity of venous blood that has not chemical properties. CO2 moves through the
passed through the lung capillaries, which comes bloodstream in a dissolved form, combining with
from anastomosis with the bronchial system, proteins and transformed into bicarbonate. CO2 is
from venoarterial shunts or hypoventilated alve- 20 times as soluble as O2; thus, up to 10% of the
oli. This mixture determines a decrease in the total CO2 is dissolved in the bloodstream.
PaO2 of 9  mmHg. In this way, a PAO2 of Moreover, CO2 combines easily with proteins in
109 mmHg, which is normal at sea level, deter- the plasma in an enzyme-independent reaction,
mines a PaO2 of 100 mmHg. Because the primary and so another 10% moves through the blood-
purpose of respiration is to maintain a normal stream bonded to proteins, the most abundant
PaO2 and a normal PaCO2, knowledge of the par- being carboxyhemoglobin. The most efficient CO2
tial pressures of these gases in arterial blood transport mechanism is conversion into bicarbon-
26 P. Bertrand and I. Sánchez

Fig. 3.7 Hemoglobin Total O2

dissociation curve
22
100

18
80 O2 combined with Hb

O2 concentration (mL/100 mL)

14
60
% saturaciòn Hb

10
40

20
Dissolved O2

20 40 60 80 100 600
PO2 (mm Hg)

Fig. 3.8 Comparative
concentration curves for
60
CO2 and O2

CO2
50
O2 or CO2 concentration

40
(mL/100 mL)

30

20
O2

10

0 20 40 60 80 100

O2 and CO2 partial pressure (mm HG)

3  Physiological Basis of the Respiratory System 27

ate, which involves 80% of the total. This reaction Levitzky MG. Pulmonary physiology. 8th ed. New York:
McGraw-Hill; 2013.
is highly efficient because of the presence of the Lumb A. Nunn’s applied respiratory physiology. 7th ed.
carbonic anhydrase enzyme found in erythrocytes. London: Elsevier; 2010.
The CO2 blood concentration curve is much more Moyle J.  Uses and abuses of pulse oximetry. Arch Dis
pronounced, which determines that the changes in Child. 1996;74:77–80.
Murray JF.  The normal lung. 2nd ed. Filadelfia, PA:
the partial pressure of CO2 are proportional to the Saunders; 1986. p. 108–17, 339–358.
changes in the CO2 blood content (Fig. 3.8). Sly P, Collins RA.  Applied clinical respiratory physiol-
ogy. In: Taussig L, Landau L, Le Souëf P, Martinez F,
Morgan W, Sly P, editors. Pediatric respiratory medi-
Sources cine. 2nd ed. St. Louis: Mosby; 2008. p. 73–88.
Sola A, Chow L, Rodrigo M. Oximetría de pulso en la asis-
Berger AJ.  Control of breathing. In: Murray JF, Nadel tencia neonatal en 2005. Revisión de los conocimien-
JA, editors. Textbook of respiratory medicine. 3rd ed. tos actuales. An Pediatr (Barc). 2005;62:266–81.
Filadelfia, PA: Saunders; 2000. p. 179–96. West JB. Ventilation/blood flow and gas exchange. 5th ed.
Decramer M.  The respiratory muscles. In: Fishman AP, Oxford: Blackwell; 1990. p. 25–9.
et al., editors. Pulmonary diseases and disorders. 3rd West JP.  Respiratory physiology: the essentials. 9th ed.
ed. New York: McGraw-Hill; 1998. p. 63–71. Philadelphia: Lippincott Williams & Wilkins; 2012.
Griese M.  Pulmonary surfactant in health and human West JP.  Pulmonary pathophysiology: the essentials. 8th
lung diseases: state of the art. Eur Respir J. ed. Philadelphia: Lippincott Williams & Wilkins; 2013.
1999;13:1455–76.
 Clinical History and Physical
Examination of the Respiratory
4
System

Pablo Bertrand

Contents
Anamnesis.......................................................................................................................  29
Physical Examination.....................................................................................................  31
I nspection.........................................................................................................................  31
Palpation...........................................................................................................................  34
Percussion.........................................................................................................................  34
Auscultation......................................................................................................................  34
Sources.............................................................................................................................  36

Anamnesis important to ask open-ended questions that allow

the parents to provide a broader description of the
The clinical diagnosis of a respiratory disease symptoms, which often reveal other hidden rea-
begins with an interview to gather information sons for the consultation. Likewise, the doctor
pertinent to the clinical situation, which is then must supplement the interview with closed-ended
supplemented with a physical examination. In and specific questions in relation to the symptoms,
this interaction with the family and the patient, it in order to precisely evaluate their relative impor-
is important, when appropriate, to develop a bond tance, as well as any other relevant information.
before proposing a deeper study plan and treat- The symptom or set of symptoms that have
ment that is realistic and in line with the family’s prompted the respiratory consultation are not
expectations. always those most relevant to the child’s health,
In the interview, the doctor must question all but they show quite well the main concerns of the
caregivers who can provide information, includ- family. Thus, if in the course of the interview,
ing the patient, if he or she is old enough. The doc- very relevant symptoms appear that require con-
tor should ask about the main reasons for the sideration of the reason for the consultation, it is
consultation and proceed to characterize the mani- advisable to address the doubts that led the fam-
festations and what repercussions they may have ily to seek medical help in the first place.
on the patient’s daily activities such as playing, Most respiratory symptoms are apparent in a
eating, or sleeping. During the interview it is regular patient interview, but it is always useful to
look for symptoms that are not mentioned and are
P. Bertrand (*) relevant to respiratory diseases. It is suggested to
Department of Pediatrics, School of Medicine, inquire about the following: cough, sneezing,
Pontificia Universidad Católica de Chile, coryza, fever, epistaxis, nasal pruritus, sputum,
Santiago, Chile odynophagia, dysphagia, gagging, snoring, noisy
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 29

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_4
30 P. Bertrand

breathing, dysphonia, wheezing, dyspnea, chest many patients with hyperreactivity, especially
pain, hemoptysis, tachypnea, apnea, and cyanosis. during exercise in cold areas. Besides this, exer-
The duration of the respiratory symptoms cise increases cough in those who have persistent
makes it possible to characterize, in a simple bronchorrhea and in those who have a running
way, those diseases that have less than a 4-week nose or sputum caused by a common respiratory
duration as an acute course, and those that exceed infection; however, in the former patients the
this period as a chronic course. This definition is symptoms appear during exercise, while in the
extended to consider an intermediate subacute latter patients they appear later. Exercise may be
period of between 4 weeks and 3 months in ado- good to quantify the importance of functional
lescent children and young adults. If the symp- compromise in advanced diseases. In this case,
toms are clearly discontinuous, with documented the doctor should ask about dyspnea during mini-
intervals of general well-being, the disease is mal or little effort. The characteristics of the
recurrent. It is important to clarify this distinction cough, as well as the strength of the voice, can
for the parents, who often perceive that their also be considered, which will directly reflect
child has a chronic disease, without realizing that inhalation and/or exhalation weakness. Playing,
the symptoms are actually intermittent. laughing, and crying in infants are considered the
When characterizing the symptoms, it is useful equivalent of exercise in older children. In new-
to describe the intensity with which they occur and borns and young infants, feeding is an exercise
the functional repercussion they involve. For that shows how tolerant the child is, considering
example, an episode of cyanosis in a breastfed how long he or she takes to finish feeding.
baby is just as serious for both the parents and the The child’s sleep provides information about
doctor because it implies an episode severe enough several symptoms. This happens mainly because
to completely compromise respiratory function. of the supine decubitus position, but also because
As a counterpart, parents can seek attention if the of the alternance between active and passive peri-
child has a persistent cough, which in the vast ods that every child has. Parents of newborns and
majority of cases will be attributable to a benign young infants, whose children sleep often, may
and self-limited cause. A set of symptoms and their seek urgent medical care if there is apnea or if
frequency over time will be very valuable to clas- there is irregular or rapid breathing. In contrast,
sify a disease from mild to severe and from con- the parents of schoolchildren or adolescents who
trolled to uncontrolled, as happens with asthma. snore and present apneas many times consider
Part of the symptom characterization is the this a normal finding, although it may reflect an
exploration of triggers and ways to alleviate the obstruction of the superior airway. If there is a
patient’s condition. This is useful information in cough when the child goes to bed, it is possible
relation to daily activities, which are very clear for that there are secretions in the posterior area of
the caregiver, such as feeding, exercise, sleep, etc. the pharynx or gastroesophageal reflux, but if
Feeding can be a triggering and/or worsening there is no cough it is still relevant if there is no
factor, from reporting of choking and cyanosis cough, it is still relevant to consider a possible
during swallowing of food to a persistent cough diagnosis of a habit cough or psychogenic cough.
that worsens during feeding. When the voice If an infant has tachypnea or difficulty during
acquires a wet tone it is suggestive of faulty swal- breathing in the supine position, it can suggest
lowing, but a hoarse voice can also suggest glot- diaphragmatic muscular weakness. This sign
tic inflammation caused by intermittent tracheal when the infant is sitting suggests chest muscular
aspiration. It is relevant to determine if the symp- weakness. For the parents, an increase in respira-
toms appear before, during, or after feeding, tory frequency may not be clear, but they will
besides determining if their appearance changes describe “agitated” and “different” breathing.
according to the consistency of the food. Clinical variations in symptoms between day and
Exercise is a common triggering factor for night may be evident in the clinical history, but
cough, shortness of breath, and wheezing in they are not always caused by the child’s position.
4  Clinical History and Physical Examination of the Respiratory System 31

Sometimes, the explanation will lie in the air that phy, chronic granulomatous disease, etc.), caused by
the child breathes in the room while sleeping a mutation (Prader–Willi syndrome or cri du chat) or
(e.g., the presence of contaminant heating, aller- that are multigenic (asthma). This forces us to inves-
gen exposure, etc.). Respiratory diseases tend to tigate the family history for at least two generations of
be related to environmental factors, and so a every origin, with special attention to blood relation-
detailed description of the place where the patient ships and information about any infant deaths in the
lives in is very important. Most of the symptoms family. It is advisable to document the health of the
may worsen or persist when there is exposure to direct family, including both parents and siblings.
allergens or irritating inhaled agents such as those
caused by industrial pollution or household pollu-
tion due to tobacco smoke, or contaminant heat- Physical Examination
ing involving burning of wood or paraffin. At the
same time, there must be careful identification of Inspection
seasonal and/or geographical changes that affect
the symptoms, in order to discover possible trig- Simple observation of the child during the inter-
gers such as those related to the weather, altitude, view and during the physical examination pro-
etc. Respiratory symptoms that can be caused by vides a lot of information. The first thing that
respiratory infections—such as cough, fever, a must be observed is the respiratory pattern; this
running nose, or sputum, among others—make it includes the respiratory frequency and rhythm,
necessary to ask about family members or people and the work of breathing. The respiratory fre-
in usual contact with the patient who may also be quency is a measurement taken routinely and
affected. At this stage it is very important to note must be interpreted as part of the physical exami-
the order in which the different symptoms have nation. Because of the inherent variability that
appeared in the different patients. the rhythm of the respiratory cycle presents—
The longer-term general history provides a which is heavily influenced by the state of alert-
good summary of the health condition of the ness, besides the presence of pain or crying—it is
child. Information from the pregnancy and the important to measure a full minute of it instead of
perinatal period is very important in relation to its estimating it on the basis of a 30-second mea-
consequences—for example, if the mother or the surement. This is more important in newborns, in
fetus suffered from infections or metabolic disor- whom the presence of periodic breathing is com-
ders, or if they were exposed to toxic agents such mon. There are reference tables for the respira-
as nicotine. A stridor appearing during the first tory frequency range and average at different
year of life may be caused by multiple factors, ages, and these are very useful for global approx-
and knowing about the sequence of the events, imation of the breathing of a child (Table  4.1).
and aggravating and alleviating circumstances, is Auscultation will corroborate the inspection or
the basis of a good diagnosis. The events that can be used to evaluate very superficial breath-
happened within this period—for example, neo- ing. An increase in the respiratory frequency or
natal asphyxia or recurrent seizures—may deter- tachypnea is nonspecific and appears in normal
mine the persistent respiratory problems that the conditions such as crying, pain, fear, or as
child may have afterward, such as a cough, spu- compensation for losses caused by anemia or
­
tum, choking, and wheezing. Growth during the hypoxemia, as well as conditions of reduced dis-
first months of life is a good indicator of the tensibility in the respiratory system and meta-
health of an infant. If there is a lack of growth bolic alterations. A reduction in the respiratory
related to respiratory symptoms, this points to frequency or bradypnea is less common and dif-
greater systemic compromise due to the disease. ficult to perceive. It happens as a manifestation of
There are many respiratory diseases that have a central neurological or metabolic alterations. The
Mendelian genetic component (cystic fibrosis, respiratory rhythm varies greatly during the first
alpha-1 antitrypsin deficiency, Duchenne’s dystro- months of life. In newborns, especially prema-
32 P. Bertrand

ture newborns, breathing is irregular, and they work, separated by absence of breathing) is
normally present a percentage of periodic breath- always an abnormal and infrequent finding in
ing (apneas lasting <6 seconds in three bursts or children with intracranial hypertension or heart
more with alternate breathings separated by failure. Biot’s respiration (irregular and variable
<20 seconds). After this period, the presence of work cycles with absence of breathing) is a com-
periodic breathing is abnormal. Cheyne–Stokes mon finding and is characteristic of severe brain
respiration (cycles of increasing and decreasing damage. Kussmaul’s breathing, or acidotic
breathing, is fast breathing along with an increase
in chest incursion, which is very characteristic of
Table 4.1  Respiratory rates in children by age
metabolic alterations (Fig.  4.1.). Absence of
Respiratory rate (percentile) breathing with flow stopping is called apnea and
Age 1 5 10 25 50 75 90 95 99
is always serious, no matter what context it
0 to <3 months 20 25 27 30 35 40 47 51 60
3 to <6 months 20 23 25 27 31 36 42 46 55
appears in. Normal breathing work is reflected in
6 to <9 months 20 22 24 26 29 33 38 42 51 synchronized chest and abdominal expansion, as
10 to <12 months 20 21 23 25 28 31 36 39 46 exhalation takes place as a passive phenomenon
12 to <18 months 20 20 22 24 26 29 33 36 42 at rest. Increased breathing work is reflected in
18 to <24 months 19 20 21 23 25 28 31 34 40 the use of accessory muscles and chest wall
2 to <3 years 18 20 20 22 24 27 30 32 38 retraction (Fig. 4.2). The infant may also present
3 to <4 years 18 20 20 21 24 25 28 30 34
nasal flaring and sometimes an increase in the
4 to <6 years 18 19 20 20 23 24 27 28 32
6 to <8 years 17 18 20 20 22 24 26 28 31
work when he or she goes to bed (orthopnea).
8 to <12 years 16 18 18 20 20 23 24 26 29 The presence of paradoxical movement (thora-
12 to <15 years 14 16 16 18 20 22 24 24 28 coabdominal asynchrony during inhalation) is a
15 to <16 years 13 16 16 18 20 20 23 24 28 sign of severe and imminent compromise in rela-
Modified from O’Leary et al. (2015) tion to muscular fatigue in a child with respira-
tory distress, but it may also appear during sleep
in schoolchildren or adolescents with obstructive
Normal Respiration sleep apnea, or sleep paralysis caused by medica-
tions used in surgery or endotracheal intubation.
Kussmaul Breathing Subcostal retraction is easily visible in newborns,
especially premature newborns, who have greater
chest lung compliance than older children.
Cheyne-Stokes Respiration Suprasternal retraction during inhalation is a sign
of upper airway obstruction and is usually accom-
Periodic Breathing panied by hoarseness and stridor.
Asymmetry in chest expansion is difficult to
Biot’s Respiration perceive in infants, but it can be noticeable in
older children who have pain and who manage
Fig. 4.1  Respiratory rhythm not to move the affected side with greater flexion

Normal breathing Paradoxical breathing

Fig. 4.2  Breathing synchronization

4  Clinical History and Physical Examination of the Respiratory System 33

of the trunk. Evidence of the use of abdominal are all findings that are suggestive of allergic rhi-
muscles at exhalation is a reflection of active nitis. It is extremely useful to observe the nasal
breathing secondary to respiratory distress. In mucosa in a routine examination, because it can
infants this mechanism may appear with glottic show purulent discharges, blood, polyps, and even
closure at the end of exhalation, which can be foreign bodies. In allergic children, the presence
heard and is called a breathing grunt. In an infant of serum fluid can be confirmed by observation of
with diaphragmatic paralysis, inhalation will the tympanum. With this technique the sequelae
cause a noticeable sinking of the abdomen when of recent infections can be controlled, such as
the infant is in the decubitus supine position, and when there is a perforation of the membrane or
there will also be asymmetry on the nonaffected when there are plaques of tympanosclerosis.
side, which will sink when the infant is in the lat- Inspection of the pharynx may show isolated mal-
eral decubitus position. formations such as a palatine fissure or findings
Chest dimensions may differ in different geo- that are part of a syndrome such as macroglossia
graphical zones and in different races. The chest in a child with Beckwith–Wiedemann syndrome.
undergoes a change from the newborn period, Opening of the oral cavity in a simple exami-
when it tends to be round, toward the school nation gives a hint if the airway is in a difficult
stage, when it acquires a flattened ovoid configu- condition (according to the Mallampati index),
ration when considered from the anteroposterior and it also reveals the proportion that the amyg-
angle. A barrel-shaped chest in a teenager is a dules occupy; they are frequently increased in
sign of chronic obstructive lung disease, which, size in children who snore at night. Skin altera-
in infants with severe bronchopulmonary dyspla- tions are extremely relevant in respiratory dis-
sia, manifests as a dove-shaped chest (Fig. 4.3). eases. For example, the presence of keratosis
A head and neck examination is useful to com- pilaris, pityriasis alba plaques, or eczema are all
plement the respiratory diagnosis. Extremely signs of atopic dermatitis. Pigmentation changes,
obvious and characteristic findings in the facies of light brown spots, and vascular tumors such as
a child may determine the presence of craniofacial hemangiomas are indicators of diseases that may
syndromes, as happens in Down syndrome, Apert compromise the respiratory system. The most
syndrome, Crouzon syndrome, and CHARGE relevant skin sign that reflects respiratory com-
syndrome, among others. Usually, medial facial promise is cyanosis. When cyanosis appears, it
dysplasia in these children causes respiratory dis- means that the hemoglobin level is reduced (>5 g/
tress in the upper airway. The presence of purple dl) in the skin capillaries (distal cyanosis) or in
skin under the lower eyelid, the finding of a fold in the tongue and mucosal capillaries (central cya-
the skin of this zone (the Dennie–Morgan line), a nosis). It tends to be an indicator of hypoxemia
transverse nasal crease under the bony section that because of the presence of reduced hemoglobin,
is visible to the naked eye, or edema of the nasal but it is clearly a poor indicator of hypoxemia
mucosa, dry secretions, or abundant and aqueous when there is anemia, because in this situation a
rhinorrhea that unites the nasal septum and the hemoglobin reduction large enough for cyanosis
turbinate (nasal bridges) on anterior rhinoscopy to become clinically evident rarely occurs.

Normal Emphysematous Kyphoscoliotic Pectus excavatum Pectus carinatum

Fig. 4.3  Thoracic configuration

34 P. Bertrand

Phalangeal Depth Ratio c Hyponychial angle

b c
b
0

ipd > dpd dpd > ipd abc < 180˚ abc > 195˚

Schamroth Sign

Fig. 4.4  Nail clubbing

The presence of digital clubbing is a nonspecific airway, but the perception of “wet” vibrations in
indicator of chronic lung disease, which is charac- chest palpation does not necessarily have a local-
teristic of cystic fibrosis, although it is also present ization. If air or fluid has entered the pleura, the
in heart and gastrointestinal disease. It appears as a transmission of these vibrations is reduced.
focal increase in the connective tissue in the distal
phalanges of the feet and hands (Fig. 4.4).
The rest of the examination may contribute to Percussion
the diagnosis of respiratory disease and is part of a
good evaluation. Findings in the heart, abdominal, The chest can be percussed because of its reso-
and limb examinations are especially important. nance, which is a consequence of its air capacity.
Percussion in this area maintains the vibration,
which is not softened, so the vibration resounds,
Palpation and this is called “tympanic.” When percussion is
done in solid tissue, the vibration propagates
Chest palpation is done at the same time as the quickly and is rapidly deafened, and this is called
inspection, and it follows a sequence that starts in “dull.” Percussion is done using the index finger
the cervical area and ends in the abdominal area. At over the distal phalange of the middle finger of the
the neck it is important to notice any increase in vol- other hand, making equal and symmetrical move-
ume or the presence of masses caused by adenopa- ments, and then making comparisons. This tech-
thies, growth of the thyroid gland, or hemangiomas nique shows the maximum lung excursion in the
and lymphangiomas. All of these structures may posterior wall of the chest, as well as the areas that
partially or totally occlude the upper airway and should have a tympanic sound but where—
cause noisy breathing, stridor, and tracheal cough. because of fluid in the pleural space, or because of
Anomalous positioning of the trachea may some peripheral consolidation in the lung paren-
indicate related intrachest malformations. chyma—a dull sound can be heard instead. When
Palpation and soft pressure in the cricoid area can the sound of the chest is not symmetrical and
be used to trigger a cough in order to evaluate it. increased, a pneumothorax must be considered.
Chest palpation helps to find deformities, asym-
metries of the costal structure, and areas where
there is pain. Besides this, it is possible to per- Auscultation
ceive vibrations created by the voice when the
child speaks out loud cries, in the case of infants. The auscultation technique yields variable results
This technique is instinctively used by mothers to depending on the conditions in which it is done.
describe the presence of secretions in the lower In order to improve sound perception, the child
4  Clinical History and Physical Examination of the Respiratory System 35

must be calm and the environment must be quiet. during inhalation, and in the trachea during
Therefore, it is not unwise to start the ausculta- exhalation; therefore, it is affected by the con-
tion when the baby is in the arms of the mother, vergence of the flow in the airway bifurcations.
before he or she starts crying out of fear. If the The lung sound of a child in the compared areas
patient cooperates, it is desirable to have the of the chest can be heard as being quite sym-
patient sitting with his or her back straight in metrical but not precisely symmetrical, as there
order to have the sound flowing normally. The may be differences in the auscultation of both
number of areas that are evaluated during auscul- hemithoraxes. Sound transmission is very use-
tation are variable, but at least three areas per ful in abnormal situations. When passing
side, anterior and posterior, should be considered. through the airway, respiratory sounds are usu-
The breathing that shows more sound is deep ally filtered, but in the presence of consolida-
breathing through the open mouth, with which tion, their transmission improves and it is
the airflow is increased. Among infants, distrac- possible to hear a tracheal sound in lung areas (a
tion and, in many situations, play can achieve this tubular breath sound) and transmission of vocal
objective, although sometimes this includes only sounds in a similar way (bronchophony), even
those sounds that are produced by sighing during during whispering (aphonic pectoriloquy). The
crying. It is advisable to avoid the appearance of terminology used to describe respiratory sounds
“artifact” sounds caused by forced breathing or has been reviewed recently, and an effort has
affected by the phonation of the child. been made to create universal terminology
The auscultation technique is based on bilat- (Table  4.2). Adventitious breath sounds are
eral comparison of sounds, but it also uses the extra sounds that occur besides the normal
intensity with which the patient may produce the sounds specified for the respiratory disease.
sounds in different situations. In this way, it is
possible to describe respiratory sounds as sym- Wheezing
metrical or asymmetrical and as increased or Wheezing is a musical and continuous sound
reduced, according to the situation. (lasting >250  milliseconds) that is produced
The respiratory sounds we hear during aus- when the airway vibrates in a narrowing area.
cultation in the respiratory examination are
caused by turbulence in the air in the central air- Table 4.2  Classification of breath sounds
way. The tracheal breathing sound is normally Sounds
heard symmetrically above the jugular notch Breath sounds
during the whole respiratory cycle. The tracheal  Normal breath sounds
sound has a wide spectrum (0–2000 Hz) and is   Laryngotracheal sounds
enriched by the resonance of the area. The tra-   Lung murmur
 Abnormal breath sounds
cheal sound increases in intensity proportion-
  Noisy breathing
ally to the circulating flow, especially at high    Tubular breathing
frequencies. In this way, when there is a narrow-    Decreased or absent lung murmur
ing at this level, the sound increases with the Transmitted voice sounds
speed, which even allows us to perceive it at dis-  Normal sounds
tance. Normal lung sounds can be heard on the  Bronchophony
surface of the chest and are well represented  Egophony
Adventitious breath sounds
during inhalation but cannot be heard during
 Continuous sounds
exhalation. The lung sound has a lower fre-   Rhonchi
quency than the tracheal sound (0–500  Hz)    Wheezing
because of the filtration—particularly in rela-   Stridor
tion to the higher frequencies—that happens  Discontinuous sounds
when air enters the lungs. The lung sound is   Crackles
produced in the primary and segmental bronchi   Pleural rubs
36 P. Bertrand

The frequency of this oscillation depends on the closed forcibly and abruptly. In a similar way,
vibrating mass around this airway but not on the snoring comes from vibration of the soft tissues
diameter of the airway. Diffuse narrowing of the in the pharynx, which causes a mixture of con-
airway causes different wheezes with different or tinuous and discontinuous low-tone sounds
polyphonic tones. In turn, narrowing of the cen- throughout the breathing cycle.
tral airway creates wheezing in a similar or
monophonic tone. Wheezing during exhalation  leural Friction Rub
P
shows narrowing of the airway and flow limita- A pleural friction rub is the only sound that is
tion, and these are the hallmarks of asthma and caused not by airflow but by the cuff of struc-
bronchiolitis. Wheezing shows frequencies close tures that are not smooth and are inflamed. It
to 600 Hz, and some authors use the term rhon- sounds like a discontinuous sound and it occurs
chus to refer to those frequencies close to 200 Hz, in a  symmetrical way during inhalation and
although they are also called low-tone wheezing. exhalation.

Crackles
Crackles are discontinuous cracking sounds (last- Sources
ing <20  milliseconds) due to the passage of air
Bohadana A, Izbicki G, Kraman S. Fundamentals of lung
through the secretions of the airway, caused by
auscultation. N Engl J Med. 2014;370:744.
sudden equalization of the gas pressure. Crackles Brown MA, Von Mutius E, Morgan WJ.  Clinical assess-
can be fine or thick, depending on how long the ment and diagnostic approach to common problems.
sound lasts and its frequency. Fine crackles dur- In: Taussig L, Landau L, editors. Pediatric respira-
tory medicine. 2nd ed. Philadelphia: Mosby; 2008.
ing the end of exhalation are common in active
p. 125–8.
lung diseases. Fine crackles cannot be heard in Finder JD, Noyes BE, Orenstein DM.  Pulmonary disor-
the mouth, whereas thick crackles are transmitted ders. In: Zitelli-Davis BJ, Davis HW, editors. Atlas of
through the airway and can be heard in the mouth. pediatric physical diagnosis. 3rd ed. St. Louis: Mosby;
1997. p. 467–86.
Fleming S, Thompson M, Stevens R, et al. Normal ranges
Stridor of heart rate and respiratory rate in children from birth
A stridor is a musical and continuous sound that to 18  years of age: a systematic review of observa-
is produced by vibration of the phonation system: tional studies. Lancet. 2011;377:1011–8.
Gagliardi L, Rusconi F. Respiratory rate and body mass
the larynx, vocal cords, and adjacent tissues, as
in the first three years of life. The Working Party on
well as narrowing of the tracheal extrathoracic Respiratory Rate. Arch Dis Child. 1997;76:15.
area. The sound can be heard with no instru- Gilmartin JJ, Gibson GJ.  Mechanisms of paradoxical
ments, mainly during inhalation, but as the rib cage motion in patients with chronic obstruc-
tive pulmonary disease. Am Rev Respir Dis.
obstruction continues, it may be audible through-
1986;134:683–8.
out the respiratory cycle. The resonance spec- O’Leary F, Hayen A, Lockie F, et  al. Defining normal
trum of a stridor is very wide (200–1000 Hz), and ranges and centiles for heart and respiratory rates
it has a high intensity. in infants and children: a cross-sectional study of
patients attending an Australian tertiary hospital
paediatric emergency department. Arch Dis Child.
Grunting 2015;100:733–7.
A grunt is a musical and continuous sound caused Yernault JC, Bohadana AB. Chest percussion. Eur Respir
by vibration of the vocal cords when they are J. 1995;8:1756–9.
 Physiological Evolution of Sleep
5
Mara Cvejic and Christian Guilleminault

Contents
Introduction....................................................................................................................  37
History and Anamnesis..................................................................................................  38
Age and Development.....................................................................................................  38
The Fetal Stage................................................................................................................  38
Premature Newborns......................................................................................................  39
Newborns.........................................................................................................................  39
Infants..............................................................................................................................  41
Preschool Children and Older Infants (1–3 Years of Age) ���������������������������������������  42
Schoolchildren and Neuronal Plasticity........................................................................  42
Adolescents......................................................................................................................  43
Risk Factors and Academic Performance....................................................................  44
Specific Sleep-Associated Symptoms............................................................................  45
Sources.............................................................................................................................  45

Introduction patients alike. A study of the prevalence of neuro-

logical problems in Europe ranked sleep disor-
Education on sleep has become a priority for ders third in terms of prevalence and impact, after
many communities, social services, medical headaches and anxiety disorders. The study esti-
institutions, and government and educational mated that the costs secondary to sleep disorders
bodies. Parallel to this, sleep disorders have were over US $35 billion in 2010—more than the
become an important problem for doctors and costs associated with epilepsy and multiple scle-
rosis put together.
M. Cvejic · C. Guilleminault (*) Children are particularly affected by respiratory
Division of Sleep Medicine, School of Medicine, disorders and alterations in normal sleep architec-
Stanford University, Redwood City, CA, USA ture. In itself, the total time spent sleeping does not
e-mail: [email protected]; correlate directly with academic p­ erformance. The
[email protected]

© Springer Nature Switzerland AG 2020 37

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_5
38 M. Cvejic and C. Guilleminault

physiological mechanisms underlying these asso- child, in contrast to what happens in adults.
ciations remain unclear. It is thought that intermit- Questions should be directed at academic perfor-
tent hypoxemia decreases brain blood flow to mance, daytime sleepiness, naps, sleep routines and
specific areas, and alterations in the architecture of hygiene, eating habits, attentional conflicts, and
sleep contribute significantly. hyperactivity. Children often present symptoms and
Given that there are no clear algorithms of problems of concentration, disruptive behavior, and
study, doctors should use clinical tools to diag- lack of concentration in school and at home, rather
nose and treat patients with sleep disorders. There than evident somnolence (unlike adults). There are
are few doctors specializing in sleep medicine or numerous questionnaires that investigate these
centers that can provide more in-depth studies. symptoms, such as the Pediatric Daytime Sleepiness
Consequently, there are long waiting lists for Scale (PDSS), which is a tool with broad support
sleep studies in several countries. Waiting lists in for application by parents who have noted drowsi-
the USA for polysomnography are 3–6  weeks ness and tiredness in their children.
long, while in Canada there are waiting lists of The investigation into sleep hygiene and
more than a year to get into a tertiary center capa- symptoms suggestive of insomnia should be pre-
ble of diagnosing sleep disorders with methods sented in a directed way in an anamnesis. The use
that are accepted as standard today. Consequently, of televisions, radios, cell phones, computers,
it is critical that the treating physician—whether and various portable devices is associated with
he or she is a neurologist, pediatrician, broncho- poor sleep and numerous sleep disorders. Special
pulmonary specialist, or child psychiatrist—is attention should be given to questions regarding
informed as to how to diagnose these very preva- the number of hours these devices are used for.
lent disorders, which leave many sequelae. In The family context should also be explored; the
current pediatric practice, we need to know where working routines of the parents and the family
patients with suspicion of sleep disorders should composition themselves imply an implicit adap-
be referred to. Education on healthy and safe tation of the children’s sleeping habits.
sleep should be an important theme in the train-
ing of pediatricians and doctors who work with
children. Despite this evident need, studies show Age and Development
that education on sleep occupies less than
4.4 hours in total in the average training of a pedi- Given that sleep disorders in children can manifest
atric resident in the USA. themselves in a number of ways, search and
There is a high prevalence of sleep disorders, screening tools should be adapted specifically to
comparable to that of bronchial asthma. It is esti- age groups and the type of sleep disorder being
mated that 12% of children experience daily considered. The first step in developing these
problems associated with sleep, while 76% have kinds of tools is to define what is normal at each
occasional problems. Certain populations have a age level. In the following sections, we summarize
greater risk of developing sleep-related problems, the main characteristics of sleep at different ages.
such as children with Down syndrome, neuro-
muscular diseases, craniofacial alterations, epi- The Fetal Stage
lepsy, intracranial tumors, and late development.
It has been possible to obtain information about
sleep at the early stages of life. Apart from what
History and Anamnesis can be observed in premature newborns, nonin-
vasive techniques have been used to study neuro-
The first step in diagnosing a possible sleep disorder physiological waves at the fetal stage to allow for
is to study and understand the child in wakefulness. the study of sleep in children before their birth.
An example of this is the low yield of the symptom Prechtl defined four stages of fetal sleep as
of snoring to predict obstructive sleep apnea in a measured by ultrasound:
5  Physiological Evolution of Sleep 39

1. Regular and slow heart rate, twitching,

gestation. This hormone reaches its maximum
absence of eye movements concentration at birth, whereupon it decreases
2. Irregular heart rate, eye movements, occa-
progressively until it reaches 15–30% of its ini-
sional body movement tial concentration in adulthood. However,
3. Regular and rapid heart rate, eye movements, because numerous neurotransmitters have been
absence of body movements identified in different species of mammals, it is
4. Irregular and rapid heart rate, eye movements, not clear which of these is responsible for the
continuous body movements development and differentiation of sleep in
humans. Among the neurotransmitters involved
in the sleep/wakefulness cycle are glutamate,
Premature Newborns glycine, and γ-aminobutyric acid (GABA).
An electroencephalography (EEG) study of
Premature newborns have more complex sleep- newborns should include at least 16 channels.
ing patterns in parallel with development. Active The reading is highly complex and distinctly dif-
and quiet sleep can be distinguished between ferent from one for an adult, in terms of both
33 and 34 weeks of gestational age, with greater voltage and EEG morphology. A premature
reactivity evident around 35–36 weeks. patient can demonstrate periods of bursts of delta
Movements, blinking, smiles, and nonspe- activity, followed by more than 25 μV of ampli-
cific facial movements can be observed during tude. This has classically been called an alternat-
active sleep. Jerking and twitching occur at the ing trace pattern.
onset of sleep, which should not be interpreted The tracé discontinue refers to a discontinu-
as pathological. This sleep is not equivalent to ous pattern of alternating bursts of activity and
REM in older children. While there are common intervals of apparent inactivity, which can be
phenomena, studies in newborn rats have found seen in premature newborns of less than 32 weeks
that lesions in the nuclei of the anterior raphe of gestational age. This pattern has an amplitude
result in either the absence of rapid eye move- of less than 25 μV and is transformed into quiet
ment (REM) at the adult stage or no alteration, sleep at 36 weeks. At around 36 weeks the pattern
depending on the gestational age when the termed “continuous slow-wave sleep” emerges,
lesions occur. Given the above, it is unclear if which predominates by 36 weeks (Table 5.1).
REM sleep emerges subsequently as an inde- Bilateral synchrony has bimodal develop-
pendent stage per  se. Non-REM (NREM) or ment; it is initially synchronic (until 30 weeks of
slow-wave sleep is not present in newborns. It gestational age), then becomes 25% asynchronic
develops between the second and sixth weeks at up to 35 weeks, and then becomes synchronic
after birth, parallel to the appearance of greater again at 40 weeks. The symmetry is considered
brain voltages. Quiet sleep in newborns is normal if the ratio of the interhemispheric ampli-
equivalent to NREM. tude is no greater than 2:1.
The development of the sleep/wakefulness
cycle in the brain includes the mesencephalic
reticular formation, the posterior hypothalamus, Newborns
and the medullary magnocellular nucleus. These
structures are present at birth and, over the course There are many sleep-related situations in the
of the first year of life, they mature concomitantly neonatal period that can be stressful for parents
with their myelination, which begins with the or caregivers. The normal sleep patterns at this
posterior structures and proceeds anteriorly age should be explained to them, with screening
through the cerebral cortex. to identify postpartum depression among moth-
There is evidence from animal models that ers. One of the most common questions relates to
somatostatin promotes the development of REM the impression of inversion of the sleep–wakeful-
sleep. It is detectable in human at 120  days of ness cycle between night and day.
40 M. Cvejic and C. Guilleminault

Table 5.1  Description of sleep patterns of newborns and premature newborns

Gestational
Type of pattern Description State age
Tracé alternant Interburst intervals >25 μV Alert 34–37 weeks
Tracé Interburst intervals < 25 μV Quiet 32–36 weeks
discontinue
Slow-wave High-amplitude delta and theta waves Quiet 36–45 weeks
sleep
Activité Low voltage, irregular, continuous Wakeful, >36 weeks
moyenne active
Sleep spindles 12–14 Hz, central Quiet 44–49 weeks
Delta bursts 0.3–1.5 Hz, high-amplitude waves (50–250 μV), occipitotemporal, Quiet 29–33 weeks
asynchronous

At birth, babies have a very basic and initial 7. Sleeping position: the baby should sleep on
circadian rhythm that is sensitive to changes in his or her back; recommendations followed to
light in relation to melatonin secretion. prevent sudden death of the baby
Although parents may not note a significant dif-
ference in the distribution of hours of sleep Newborns with apnea represent a special and
between day and night, it has been demon- unique population. There are several risk fac-
strated that there is a tendency from the first tors that facilitate the development of apnea,
days of life for the baby to sleep more during one of which is premature birth. The gestational
night hours. It is estimated that term newborns age marks the presence of “premature apnea,”
sleep on average for 16 hours a day. Newborns such that 7% have it at 34–35 weeks of gesta-
present a polycyclic pattern that ranges between tional age, 15% at 32–33  weeks, 54% at
1 and 4 hours, with the need for feeding between 30–31 weeks, and almost 100% of newborns at
the cycles. The alternation between the sleep less than 29 weeks. Although premature apnea
stages is shorter in newborns—on average, is considered a self-limiting condition, it is
50–60  minutes—in contrast to the 90-minute treated to avoid possible neurocognitive conse-
alternation in adults. quences associated with desaturations. The
It is estimated that 50% of newborn sleep is underlying physiological mechanism of this
REM and that REM sleep latency is shorter in phenomenon is not completely understood, and
newborns than in adults. it is supposed that it is based on the immaturity
A sleep anamnesis of a newborn should include: of the respiratory center. In all cases of persis-
tent apnea, the possibility of conditions such as
1 . Gestational age and neonatal complications hemorrhages, infections, intracranial lesions,
2. Complications of the birth gastroesophageal reflux, convulsions, and meta-
3. Admissions to neonatological care bolic and electrolytic alterations should be
4. Presence of apnea or family history of any considered.
apparent life-threatening events (ALTEs; events One theory is that premature babies are particu-
that put the infant’s life at risk, in the eyes of the larly sensitive to inhibitory neurotransmitters such
observer) or sudden death syndrome as GABA, adenosine, serotonin, and other prosta-
5. Environment for sleeping: where, how much, glandins. Adenosine is one of the key targets of
and how the baby sleeps; shared bed, expo- treatment with methylxanthine. There is evidence
sure to smoking that adenosine facilitates the release of GABA,
6. Safe environment for sleeping: separate and leading to respiratory depression in the newborn.
strong crib, absence of stuffed animals or pil- More recent studies have shown the presence of
lows, sleeping on her or his back, avoidance of prostaglandins that induce the formation of proin-
soft surfaces to avoid the risk of suffocation flammatory mediators such as interleukin beta 1.
5  Physiological Evolution of Sleep 41

The experience of newborn admissions to sleep problems. Parents respond in different

neonatological care raises questions about the ways to their infant’s crying and needs. Some
stressful effect that intensive services can have on actions can interrupt the infant’s sleep, such as
sleep. The overstimulation of arousals and awak- using a baby bottle as a pacifier, but can also
enings by sounds, and the attention related to help the baby go back to sleep once he or she
continuous monitoring, raise concerns. There has woken up.
have been few studies on this issue, but simple
interventions such as the use of music have been At 3–4 months of age, the infant develops more
shown to reduce parental stress and improve consistent sleeping blocks, which can be a source
newborn sleep stages. of relief to the parents, who will say the baby now
Long-term follow-up has shown that new- “sleeps the whole night through.” During the first
borns who have had efficient sleep are more 6  months of life, melatonin secretion matures
attentive between 4  and 18  months of age than concomitantly, with a strong correlation between
those who did not sleep efficiently at the newborn melatonin levels and sleep/wakefulness cycles.
stage. This correlation is not observed in children who
have lost their vision. The aberrant sleep patterns
of blind infants tend to improve with use of exog-
Infants enous melatonin.
Nap taking begins to decrease at 6 months of
Infancy is a period of significant changes for the age, and the majority of infants continue with two
normal sleep pattern, and questions should be naps in the second semester of life. Most infants
directed in particular to the following aspects: immediately begin with REM sleep or with sig-
nificantly shorter REM latency than adults. The
1. Number and duration of naps: In total, these REM cycles get longer with the passing months.
should not exceed 3–4 hours. The time passed in REM sleep decreases pro-
2. Total time spent sleeping: Nocturnal sleep
gressively from 50% of the total sleep time in
around 9–10 hours, total time 12–13 hours. small infants to less than 30% as they reach the
3. Sleep routine and rituals: Incipient routines age of 1 year.
and rituals generally already exist at this age. The response of infants to arousals matures
4. Presence of colic, diseases, and the use of rapidly in the first 9 months of life. The response
medications. to hypoxia with arousals decreases toward
5. Gastroesophageal reflux: This condition,
week  9, because of which responses to micro-
which is often physiological, has been associ- awakenings gradually shift from subcortical to
ated with an increase in arousals, although it is cortical responses.
sometimes associated with apnea. One theory for infant sudden death is a failure
6. Details of any ALTEs. to adapt an arousal response to particular stimuli
7. Psychomotor development: Nonacquisition of or a toxic substance. It is especially important
the different stages in psychomotor develop- with infants to prepare guidelines to prevent sud-
ment can involve concomitant problems related den death: the baby should sleep on his or her
to sleep. This should be investigated to deter- back, the bed should not be shared, and exposure
mine the presence of hypotony, which can to cigarette smoke should be avoided. A low
affect the occurrence of hypoventilation. socioeconomic level and prematurity have also
8. Use of pacifiers and bottles: The American been identified as risk factors for infant sudden
Academy of Pediatrics currently recommends death. The reticular formation of the brain stem is
the use of pacifiers to avoid sudden infant involved in balancing inhibitory and excitatory
death. impulses that collect sensorial, somatic, and
9. Parents’ attention and routines: In many cases, chemical/mechanical receptor–sourced informa-
parents sleep with their infant as a result of tion. The progression of microawakenings in
42 M. Cvejic and C. Guilleminault

response to stimuli, such as tactile stimuli and an Another aspect that implies complex interac-
increase in CO2, have demonstrated an ascending tion of several factors is the initiation of sleep. In
spinal, subcortical, and cortical pattern. Waking general, by 2–3 years of age, children are adapted
begins with small subtle movements, following to the routines and rituals of the family with
by swaying, and culminating in eye opening and respect to sleep. The use of audiovisual media,
full awakening, with the shift to wakefulness. extended working hours of parents, or bedroom
These microawakenings occur in both active and sharing with siblings can result in alteration of
quiet sleep. the time for going to sleep.
Nocturnal fears and nightmares are character-
istic of this age and can often disrupt sleep.
 reschool Children and Older
P A sleep anamnesis at this age should include
Infants (1–3 Years of Age) the following points:

The sleeping habits of small preschool children is 1. Sleep rituals and hygiene
biphasic, with sleep concentrated in the night and 2. Switching from a crib to a bed at around
two naps during the day. The sleep/wakefulness 2.5–3 years of age
cycle gradually consolidates, and by the age of 3. Naps: their number and duration
3 years the child usually has only one nap during 4. Symptoms of attention deficit, misbehavior,
the day. By the age of 6 years, naps have become hyperactivity, bad moods, changes in regular
abnormal and suggest a sleep-specific disorder. patterns in daycare or school
REM sleep decreases gradually at this stage, 5. Nightmares or nocturnal fears
reaching 30% after the age of 1  year. By 6. Shared bed, sleep space environment, use of
9–11 years of age, the REM/NREM ratio is simi- a pacifier
lar to that in adults. EEG spectral analysis can 7. Enuresis (which generally should not occur
show the changes over time during this period. beyond 6 years of age)
Parallel to the decrease in REM sleep, the total 8. Drowsiness and problems in waking up
sleeping time decreases from 16–18  hours to 9. Use of electronic devices (e.g., television,
≤9  hours at the postpuberty stage. The average radio, cell phone, computer, tablet, or elec-
number of hours of sleep at the preschool stage is tronic game)
10 hours. 10. Allergies, dermatitis, asthma
Between 20% and 30% of older infants and 11. Snoring
preschool children remain awake during the
night, which constitutes a common reason for Respiratory sleep disorders begin to increase at
medical consultation. It is considered that inter- this age.
vention is appropriate for awakenings when the
family routine is disrupted and the parents are
forced to take actions such as staying with the Schoolchildren and Neuronal
child or forcing the child to return to his or her Plasticity
room. However, as actigraphy studies have
shown, most preschool children wake up twice a Slow-sleep-wave activity can be mapped with
night without their parents realizing it. In most EEG spectral analysis, showing cortical develop-
cases, the children go back to sleep and do not ment. Slow-wave activity in preschool children is
alter the family’s sleep routine. The data from predominant in the occipital lobes and moves
EEG studies of children between 6 and 11 years progressively to the parietal and occipital regions
of age who experience 1–3 three small awaken- during adolescence. The role of naps in this mat-
ings per night suggest that the sleep of preschool uration process is not clear, but it appears that
children is more fragmented than we might they play an important role in consolidating
think. learning and memory. Naps remain important in
5  Physiological Evolution of Sleep 43

the schedules of many daycare centers and more effort is made to protect neuronal homeo-
schools. In this respect, a study indicated that the stasis and the consolidation of memory in the
use of naps resulted in a 10% improvement in hippocampus.
learning of visual–spatial tasks by preschool chil- Attention deficit–hyperactivity disorder
dren. The concomitant polysomnography record (ADHD) has been linked directly to sleep disor-
in this study showed the presence of a larger ders, especially at the preschool and school
number of sleep spindles among the children, stages, where it is also more evident to teachers.
which would improve their learning. Treatment of this syndrome can alter the normal
The impact of sleep on memory is one the sleep of the child. Changes have been evidenced
main concerns at this vulnerable stage of neuro- in slow-wave and REM sleep in children with
cognitive development. Memory development is ADHD in a manner similar to what was
influenced by a series of molecular factors and described above in relation to memory consoli-
signals. One of the processes of memory is con- dation. The frontal brain activity of children
solidation, which is favored by repairing sleep. It with ADHD is slow during wakefulness and
is assumed that there are regenerative processes presents an anteroposterior imbalance in slow-
during sleep, distributed into two stages, the first wave activity during sleep. In particular, altera-
occurring immediately at the beginning of sleep, tions have been found in the frontal circuits
characterized by signals and protein synthesis in associated with control of emotions and mem-
the hippocampus, and a second stage 4  hours ory regulation in children with ADHD.  These
later. The kinase that facilitates these processes is circuits change over time and cease to be as
altered when individuals lose sleep or change important in adulthood, which could explain the
their sleep schedule. lower prevalence of ADHD in adults than in
Adenosine inhibits the hippocampus, which children. This change with age could also
reduces neuronal plasticity. The oscillating theta explain why children show more hyperactive
rhythm in the hippocampus can be shown both in symptoms in response to poor sleep, while
REM sleep and in wakefulness during the execu- adults show more drowsiness.
tion of neurocognitive learning and memory
tasks. It was initially believed that REM sleep
was responsible for memory consolidation, but in Adolescents
the 1980s it was shown that slow-wave NREM
sleep affects memory consolidation. The increase The sleep patterns of adolescents are very simi-
in slow-wave NREM sleep and the density of lar to those of adults and, on average, adoles-
sleep spindles subsequent to training and learn- cents sleep for 8–9.5  hours per night, 25% of
ing has been demonstrated in studies with human which is REM sleep. Neuronal pruning contin-
and with animal models. A “dual hypothesis” is ues, and it is supposed that this is the main
currently proposed and assumes that NREM mechanism producing changes in the sleep
sleep is responsible for declarative memory con- architecture seen in this population. In particu-
solidation in the hippocampus, while REM sleep lar, there is a shift in the sleep phases at this age;
tends to regulate functional (procedural) and thus, adolescents go to sleep later and wake up
emotion-related memory. However, this vision is later. The normal phenomenon does not change
possibly too simplistic and cannot explain a the total number of hours of sleep. Distinct
series of much more complex interactions. chronotypes can be distinguished at this age,
Nevertheless, it has been clearly demonstrated and common complaints from parents and
that sleep deprivation affects memory and teachers are difficulty in waking up adolescents
changes the cytoarchitecture of the hippocampus. and their morning drowsiness. The idea of start-
Considering how both REM and NREM sleep ing school at a later hour for adolescents than
decrease over the course of one’s life, the pre- for preadolescents has been discussed in some
school and early school stages should be when parts of the USA and Canada.
44 M. Cvejic and C. Guilleminault

An anamnesis at this age should include:  isk Factors and Academic

R
Performance
1. School performance: drowsiness can change
performance and behavior in school It should be kept in mind that there is a series of
2. Depression and psychiatric illnesses risks in relation to adolescents; an examining
3. Hours slept physician should ask about these and should be
4. Daytime drowsiness: sleeping in classes or vigilant when dealing with an adolescent patient
while doing tasks with a sleep disorder. Risky sexual behavior, eat-
5. Dental history: bruxism or cavities ing habits, abrupt changes in mood, and use of
6. Consumption of coffee, cola, energy drinks, medications or other drugs should immediately
or sports supplements be associated with base diseases or mental health
7. Headaches, blows, or falls compromise. It is during adolescence that dis-
eases such as depression, bipolar disorder, and
The interaction between sleep, puberty, and (less commonly) Kleine–Levin syndrome appear.
hormones is complex. Even when adolescents are The latter is characterized by hypersomnia, hal-
not tired, they experience changes in melatonin lucinations, hyperphagia, and hypersexuality.
secretion that invariably lead to a shift in the The syndrome is episodic and tends to resolve
hours of the sleep phase. It is believed that this is 5–10 years after its appearance.
linked to sexual hormonal development in ado- Anxiety, mood, and depression disorders are
lescents. Endocrine changes during sleep follow often associated with sleep disorders. Adolescents
fixed patterns specific to each hormone. Growth who get less sleep (an average of 6.75 hours) than
hormone is secreted in the first hours of sleep, normal (an average of 8.25  hours) have
reaching its maximum exactly an hour after the been  reported to have more mood disorders.
rise in prolactin. Follicle-stimulating hormone Adolescents who are defined as “night persons”
(FSH) and luteinizing hormone (LH) also follow are more often reported as having symptoms of
fixed patterns, and their release is delayed in ado- anxiety than those defined as “daytime” persons.
lescence. In contrast, the time when cortisol is Mood disorders can result from even brief
released does not change during adolescence, and periods of sleep deprivation. It has been shown
its maximum release is always kept for dawn at that patients with anxiety disorders in adoles-
the end of sleep. cence often had early sleep problems in child-
The maturation of the cerebral cortex in ado- hood, including before the age of 4  years. One
lescents is not explained simply by an EEG phe- study found that adolescents with obsessive–
nomenon or change. One of the maturational compulsive disorder had shorter hours of sleep,
mechanisms of the cerebral cortex is sleep spin- reduced NREM sleep, and less REM latency than
dles, which change with age and increase in fre- control subjects. Another study found more sleep
quency toward the frontal area. A lower frequency fragmentation, microawakenings, and decreased
of spindles in children shows better neurocogni- slow-wave sleep among adolescents with anxiety
tive performance, while the reverse has been disorders than among control subjects. In
demonstrated in adults, with a higher frequency ­particular, adolescent males with depression have
of sleep spindles indicating better neurocognitive demonstrated decreased latency in REM sleep,
performance. an increase in the N1 sleep stage, a larger number
The cyclic alternating pattern (CAP) is an of microawakenings, and decreased short-wave
EEG and polysomnography pattern for assessing sleep.
sleep stability. CAP alterations are associated Academic performance correlates signifi-
with conditions such as Asperger syndrome and cantly in many studies with sleep-related prob-
poor cognitive performance. lems. Treatment of these problems has been
5  Physiological Evolution of Sleep 45

shown to improve poor academic performance. A distinguished among types of parasomnia by

study of first graders found that students who had the frequency of disorders of the “arousal” or
undergone surgical treatment had improved their awakening type. The latter tend to be benign
grades. Similar results from other studies suggest and are associated with premature birth and
that good school performance is associated with difficulties during pregnancy or birth.
regular long hours, while daytime drowsiness is 9. Confusional arousal, which can emerge from
associated with lower grades. deep NREM sleep and has an autonomic
component ranging from the very simple to
the complex.
Specific Sleep-Associated 10. Somnambulism or sleepwalking, which can
Symptoms occur at any age but is most common in ado-
lescents. Episodes occur during NREM sleep,
There is a long list of symptoms that are under- with general rhythmic activity of 2–7 Hz. An
stood as physiological and normal in sleep. autonomic component is generally absent.
Among the most common are the following: 11. Nocturnal terror, which is one of the most
common reasons for medical referral, owing
1. Benign childhood myoclonus, which refers to the dramatic nature of these episodes. The
to local or diffuse twitching in otherwise child awakens in an agitated state, screaming
healthy children (with normal EEG read- in terror, and parents often report an incon-
ings) that stops immediately upon the child solable cry. Diagnosis is generally possible
waking up. with polysomnography or a video
2. Movements at the beginning of sleep, related EEG.  Seizures, which are the differential
to small tremors in the transition between diagnosis, frequently occur during stages 1
wakefulness and sleep. and 2, while most parasomnias occur during
3. Somniloquy or sleep-talking, which occurs stage 3. Children do not remember nocturnal
particularly during NREM sleep. terrors from one day to another.
4. Nonepileptic nocturnal psychogenic con 12. Nightmares, which are disagreeable dreams,
­vulsions. typically in childhood. They occur in the
5. Sandifer syndrome, which is nocturnal wak- early hours of dawn during REM sleep, and
ing with rigidity and movement of extremi- a memory of this type of dream almost
ties, associated with the presence of always remains the following day.
gastroesophageal reflux. 13. Bruxism, which is the habit of moving and
6. Sleep paralysis, which generally occurs dur- grinding one’s teeth. It is most common
ing the transition from sleep to wakefulness. among children between 7  and 10  years of
Paralysis that occurs at the beginning of age. It rarely continues beyond adolescence,
sleep is termed hypnagogic, and that which except in association with stress or obstruc-
occurs upon waking is termed hypnopompic. tive sleep apnea.
While sleep paralysis is benign in most
cases, it is associated with epilepsy in a small
percentage of cases.
7. Jactatio capitis, which is rhythmic head
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by similar body movement. This is typically basis of sleep development. In: Loughlin GM, Caroll
found in patients with Down syndrome or JL, Marcus CL, editors. Sleep and breathing in chil-
neurocognitive disabilities. dren, a developmental approach. New  York: Marcel
Dekker; 2000. p. 3–37.
8. Parasomnias, which occur in up to 80% of Anders TF, Keener M. Developmental course of nighttime
children between 2 and 6 years of age. This sleep–wake patterns in full-term and premature infants
commonly occurs during NREM sleep and is during the first year of life. Sleep. 1985;8:173–92.
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Drake C, Nickel C, Burduvali E, Roth T, Jefferson C, Loewy J, Steart K, Dassler AM, Telsey A, Homel
Pietro B.  The pediatric daytime sleepiness scale P.  The effects of music therapy on vital signs, feed-
(PDSS): sleep habits and school outcomes in middle-­ ing, and sleep in premature infants. Pediatrics.
school children. Sleep. 2003;26(4):455–8. 2013;131:902–18.
Espezel H, Jan JE, O’Donnell ME, Milner R.  The use Martin RJ, Abu Shaweesh JM, Baird TM. Apnea of prema-
of melatonin to treat sleep wake–rhythm disorders turity. Paediatr Respir Rev. 2004;5(Suppl 1):S377–82.
in children who are visually impaired. J Vis Impair Mindell JA, Bartle A, Ahn Y, Ramamurthy MB, Huong
Blind. 1996;90:43–50. HT, Kohyama J, Li AM, Ruangdaraganon N, Sekartini
Fallone G, Owens JA, Deane J. Sleepiness in children and R, Teng A, Goh DY.  Sleep education in pediatric
adolescents: clinical implications. Sleep Med Rev. residency programs: a cross-cultural look. BMC Res
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Franco P, Kato I, Richardson HL, Yang JS, Montemitro E, Prechtl H. F. (1985). Ultrasound studies of human
Horne RS. Arousal from sleep mechanisms in infants. fetal behaviour. Early. Hum. Dev. 12 91–98
Sleep Med. 2010;11:603–14. 10.1016/0378–3782(85)90173–2.
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Mitschke A, Wiater A, Lehmkuhl G.  Prevalence hood through adolescence. In: Loughlin GM, Caroll
and course of sleep problems in childhood. Sleep. JL, Marcus CL, editors. Sleep and breathing in chil-
2007;30(10):1371–7. dren, a developmental approach. New  York: Marcel
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 Immunological Defense
Mechanisms of the Respiratory
6
System

Arturo Borzutzky Schachter
and Pamela Morales Matamala

Contents
Organization of the Respiratory Immune System.......................................................  47
Immune Induction in the Lung.....................................................................................  48
Innate Immunity.............................................................................................................  48
Adaptive Immunity.........................................................................................................  49
Immune Responses to Respiratory Infections.............................................................  50
Immunology of Acute Alveolar Damage and Tissue Repair.......................................  51
The Microbiome..............................................................................................................  52
Sources.............................................................................................................................  52

Organization of the Respiratory locally, provoke mucociliary elimination of

Immune System inhaled antigens. In the mucosa there are macro-
phages, dendritic cells, plasma cells, and T lym-
The lung can be divided into two functional phocytes, which are explained in more detail in
areas: the airways and the lung parenchyma. In later sections of this chapter. In the airway there
each of these areas there are different cellular are resident dendritic cells that specialize in
populations that take part in the immune immune monitoring similarly to what happens
response. in the gastrointestinal tract. Epithelial T  lym-
In the airway, which is the conduit area, the phocytes in the mucosa are mainly T  CD8+
epithelium is mainly composed of hair cells and lymphocytes, and the T lymphocytes in the lam-
secretory (goblet) cells, which, together with ina propria are T CD4+ lymphocytes. The pre-
secretory immunoglobulin  A (sIgA) produced dominant cellular population in the lamina
propria consists of mastocytes and plasma cells,
which secrete IgA. In the airway mucosa there
A. Borzutzky Schachter (*) · P. Morales Matamala are also areas of lymphoid tissue, associated
Department of Pediatrics School of Medicine, with the bronchus, which is similar to amygda-
Pontificia Universidad Católica de Chile, lar tissue and Peyer’s patches in the intestine.
Santiago, Chile This tissue is considered to play an important
e-mail: [email protected]
role during childhood, characterized by great
© Springer Nature Switzerland AG 2020 47
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_6
48 A. Borzutzky Schachter and P. Morales Matamala

immune activity, before reducing its function Innate Immunity

and devolving during adulthood. These zones of
lymphoid tissue associated with mucosa are As in other systems covered in epithelium, the
located mainly in the nasal mucosa (nasal-asso- first line of defense in the respiratory system is
ciated lymphoid tissue (NALT)) and in the bron- composed of epithelial cells of the airway.
chial mucosa (bronchus-­ associated lymphoid Innate immunity responds to two kinds of
tissue (BALT)). In contrast to the lymph nodes, stimuli: molecules derived from exogenous
this tissue is not encapsulated and does not have microorganisms and molecules produced as a
afferent lymph vessels. It is in direct contact result of tissue damage.
with the epithelial mucosa and reacts to antigens There are receptors that specifically recognize
that cross the epithelial barrier. Given its loca- a narrow variety of molecular patterns, called
tion, it can respond quickly to upper and lower pattern recognition receptors (PRRs). These are
respiratory tract infections. classified according to the types of molecule they
In the lung parenchyma, where gas exchange recognize.
occurs, 90% of the cellular population of the
alveoli corresponds to alveolar macrophages. Pathogen-Associated Molecular Patterns  We
There are also small populations of T lympho- know that pathogenic molecules derived from
cytes, B  lymphocytes, and dendritic cells, but viruses and bacteria are recognized by PRRs.
there are no plasma cells as there are in the air- Among these molecules are lipopeptides, liposac-
way. In the lung parenchyma vascular bed there charides, viral RNA, viral DNA, and flagellin.
is a large population of T lymphocytes, many of
which are anergic, and their contribution to the Damage-Associated Molecular Patterns 
defense and regulation of lung immunity is still Several molecules associated with tissue damage
unclear. This anergic cellular immunity might can activate PRRs. Among these are proteins,
contribute to a decrease in the local inflamma- transcription factors, RNA, DNA, matrix compo-
tory response, decreasing possible tissue dam- nents (hyaluronic acid and fibronectin), and
age in the event of activation caused by fibrinogen.
antigens.
Tissue Damage and Recognition of
Infection  Reco­gnition patterns are coded in the
Immune Induction in the Lung toll-like receptors (TLRs) expressed on the sur-
faces of cells and vesicles, and in intracytoplasmic
The respiratory mucosa, especially in the upper nucleotide-binding oligomerization domain
airway, is constantly exposed to nonpathogenic (NOD)–like receptors (NLRs). Also, retinoic acid
environmental antigens, including various veg- receptors induced by NRA helicase (retinoic acid–
etable and animal proteins. It is essential for the inducible gene  I (RIG-I)–like helicase (RLH))
respiratory system to be inert against nonpatho- have been described, among other receptors.
genic antigens, otherwise it would collapse in a
continuous inflammatory process. As a mucosal Each of these receptors can detect different mol-
protection mechanism, it constantly activates a ecules. There are 10 types of TLR, 20 types of
tolerogenic response, apart from a low-grade NLR, and one type of RLH.
type 2 helper T cell (Th2) response, to stop acti-
vation of the Th1 inflammatory response. This Toll-Like Receptors  These can be divided into
discrimination of cellular responses is perma- those that have an antibacterial response (TLR1,
nently regulated by the local dendritic cells. The TLR2, TLR4, TLR5, TLR6, and TLR9) and those
inhibitory response of the airway is reinforced that have an antiviral response (TLR3, TLR7, and
by the inhibitory activity of the alveolar TLR8), although some viral proteins activate
macrophages. TLR4. The most-studied receptors are TLR2 and
6  Immunological Defense Mechanisms of the Respiratory System 49

Table 6.1  Innate immune receptors and ligands in respi- The epithelial cells of the airway express
ratory system cells
TLR1–TLR10, and their stimulation increases
Receptor Ligands the production of various proinflammatory
TLR1 Bacterial lipoproteins cytokines.
TLR2 Lipopeptides, lipoteichoic acid
TLR3 Double-stranded RNA
TLR4 Lipopolysaccharides Neutrophils  Neutrophils are recruited rapidly
TLR5 Flagellin by the production of proinflammatory mediators
TLR6 Lipopeptides such as B4 leukotriene, C5a, and IL-8. Pathogens
TLR7/TLR8 Imidazoquinolines, single-stranded RNA are then phagocytized. Neutrophils have a short
TLR9 Unmethylated CpG DNA half-life; after their apoptosis, they trigger an
TLR10 Unknown anti-inflammatory response and restore the nor-
NOD-like Ligands
receptor
mal architecture of the epithelium.
NOD1, NOD2 Peptidoglycan derivatives
NOD  nucleotide-binding oligomerization domain, TLR Macrophages and Monocytes  There are macro-
toll-like receptor phages in the interstice and the alveolus. Alveolar
macrophages are located in the surfactant in the
air–lung tissue interface, and this location allows
TLR4, and it is widely known that they respond to them to be the first barrier of defense against
the molecules of the bacterial wall (lipopeptides inhaled pathogens and environmental toxins.
and lipopolysaccharides). TLR4 responds mainly They are involved in phagocytic activity, starting
to lipopolysaccharides present in Gram-negative an inflammatory cascade and participating as
bacteria, pathogen-associated molecular patterns antigen-presenting cells before being replaced by
(PAMPs) such as pneumolysin in Streptococcus monocytes.
pneumoniae, and the proteins of respiratory syncy-
tial virus (RSV). TLR2 is heterodimerized with Dendritic Cells  Dendritic cells play a funda-
TLR1 and TLR6, and recognizes lipoproteins and mental role in the interface between the innate
lipoteichoic acid in Gram-positive bacteria. TLR5 immune response and the adaptive immune
recognizes flagellin in Legionella pneumophila, response. They have the ability to capture anti-
Pseudomonas aeruginosa, and Klebsiella spp. gens and, through damage-associated molecular
TLRs can distinguish between human and bacte- pattern (DAMP) stimulation, they migrate toward
rial DNA (Table 6.1). the lymph node and present the antigens to acti-
vate T cells.
NOD-Like Receptors  Twenty types of these
receptors have been identified. They are involved
in detection of bacterial pathogens. Two NLR Adaptive Immunity
types—NOD1 and NOD2—recognize bacterial
peptidoglycan from Gram-positive bacteria and For many years, our understanding of cellular
activate nuclear factor (NF)-κΒ, which generates immunity in the lungs has been simplified,
an increase in interleukin (IL)-1. This is an divided only into Th1 and Th2 responses; how-
important way of controlling intracellular bacte- ever, it is now understood that there are other
ria such as L. pneumophila. kinds of cellular response, forming a system
that is more diverse and complex. Th1 immunity
Many types of cell participate in the innate (mediated by T  CD4+ lymphocytes, which
immune response of the respiratory system. secrete cytokines such as interferon (IFN)-γ,
IL-6, and IL-12) is fundamental in defense
Epithelial Cells  Type  2 alveolar cells express against environmental pathogens, both bacterial
TL2 and TL4, contributing to the response to lipo- and viral. In particular, it plays a fundamental
polysaccharides and bacterial peptidogly­cans. role in defense against intracellular bacteria
50 A. Borzutzky Schachter and P. Morales Matamala

such as Mycobacterium tuberculosis. The Th2 I mmune Responses to Respiratory

response is mediated by T  CD4 lymphocytes, Infections
which secrete mainly IL-4, IL-5, and IL-13. Its
main function is defense against helminths, but Infection of the respiratory system initiates a
it also takes part in defense against viral patho- cascade of events that end in activation of the
gens and in immune system regulation. Th2 cellular immune response in the lung (Fig. 6.1).
immunity is possibly better known for its patho- The initial respiratory infection provokes the
genic role; it is central to generation of allergic production of inflammatory mediators in the epi-
responses mediated by IgE, which can trigger thelial cells, which activate the innate immune
asthma and allergic rhinitis, as in excessive system. The dendritic cells of the upper airway
immune responses to some respiratory viruses detect the presence of pathogens via TLRs. The
such as RSV. combination of the presence of proinflammatory
Our understanding of the Th1–Th2 balance has mediators and the activation of dendritic cells
been modified since the discovery of the Th17 increases the expression of type  I and type  II
immune response, which is essential for defense major histocompatibility complex, initiating the
against extracellular bacteria and plays an impor- production of costimulatory molecules and cyto-
tant role in diverse inflammatory illnesses. kines required for induction of the response
Differentiation of T lymphocytes into Th17 lym- mediated by T cells. The dendritic cells migrate
phocytes is provoked by the combination of IL-6, to the lymph nodes and activate virgin or naïve
IL-1β, and IL-23. Once the response has been T cells, initiating the adaptive immune response.
activated, large amounts of IL-17 are produced. When the virgin T  CD4+ and CD8+ lympho-
This cytokine participates in the mobilization of cytes activate, these present clonal expansion
neutrophils and plays an essential role in the and differentiation from effector T lymphocytes
elimination of pathogens in the airway. It has into some helper T cell types (Th1, Th2, or Th17),
been observed that there is an inhibitory interac- depending on the cytokine environment at the
tion between the different responses: Th1 cyto- moment of activation. The T cells present three
kines inhibit Th2 and Th17 responses, and Th2 antiviral action mechanisms: (1)  lithic mecha-
cytokines inhibit Th1 and Th17 responses. The nisms associated with T  CD8+ lymphocytes,
inflammatory response provoked by Th17 can which provoke the lysis of infected cells;
participate in the pathogenesis of bronchial (2) induction by T cells of tumor necrosis factor
asthma. There is a relationship between the pro- (TNF) in the infected cells, causing their apopto-
duction of Th17 cells and regulator T cells; when sis; and (3) production of proinflammatory fac-
T cell production is inhibited by IL-6, the differ- tors by cells that attract other cells of the immune
entiation into Th17 increases. Once the levels of system.
proinflammatory cytokines increase, the regula- It has been observed that in influenza virus
tor T cell population starts to grow to re-establish infection, the cytolytic response of the T CD8+
the basal state. lymphocytes is very important, and they also
Regulatory T lymphocytes (Tregs) play a fun- contribute to viral elimination and recovery. In
damental role in the regulation of the peripheral viral infections, T  CD8+ lymphocytes produce
immune response of T lymphocytes; other medi- IL-10, which takes part in the regulation of the
ators also participate: IL-10, transforming growth immune response, and they also produce IFN-γ.
factor (TGF)-β, and nitrous oxide. Tregs have a The production of these two cytokines decreases
fundamental function in the regular postviral when viral clearance occurs. For production of
inflammatory response (helping to avoid sequelae IL-10 to occur in the lung tissue, IL-2 (produced
of postviral infections) and in modulation of by T CD4+ lymphocytes) and IL-27 (produced
tolerance of aeroallergens to avoid allergic
­ by mononuclear cells and neutrophils) must be
illnesses. present. Some viruses such as RSV trigger an
6  Immunological Defense Mechanisms of the Respiratory System 51

Alveolar macrophage
Virus
Airway

DC CD8
Alveolus Type I alveolar
+
epithelial cell
Proinflammatory cytokine
and chemokines Cytotoxic CD8+ T
CD8 lymphocytes eliminate
+ infected cells
Type II alveolar
epithelial cell
DC Dendritic cell presents viral
antigen to T lymphocytes
Macrophage
Th1/
Th2 B
Th
0 Antibodies
Antivirals
Th
0 T CD4+ lymphocytes activate
macrophages and B lymphocytes

Fig. 6.1  Activation of the cellular immune response in the airway

exacerbated Th2-type response, which can trig- rial growth. In the case of extracellular bacteria
ger bronchial hyperreactivity and eventually such as S. pneumoniae, an inflammatory response
lead to development of bronchial asthma. This is triggered, mediated mainly by massive infiltra-
Th2 response is mediated not only by T  CD4+ tion of neutrophils and, secondarily, by a late
lymphocytes but also by Th2 cytokines such as response of the adaptive immunity normally
IL-13, which can be secreted by innate type  2 orchestrated by Th1 and Th17 cells, in turn acti-
lymphoid cells and by natural killer T  cells vating macrophages and B  lymphocytes, which
(NKTs). In addition to the regulation mediated produce specific antibodies against the invading
by CD4+ and CD8+ T lymphocytes, the modula- microorganism.
tion of the immune response involves the partici-
pation of Tregs (which produce thousands of
regulatory interleukins such as IL-10 and TGF- I mmunology of Acute Alveolar
β1) and expression of inhibitory molecules such Damage and Tissue Repair
as c­ytotoxic T-lymphocyte-associated protein
(CTLA)-4. Acute alveolar damage can originate from multi-
Regarding bacterial infections, which nor- ple causes such as trauma, infections, allergies,
mally occur after viral infections as superinfec- cancer, and chemical injury. When there is dam-
tions, the first line of defense is generally age, an inflammatory cascade is generated in the
composed of alveolar macrophages, which are lung, and if there an imbalance in this cascade, an
capable of limiting the spread of the bacterial exacerbated inflammatory response occurs,
infection and orchestrating the recruitment and which provokes increased injury and exacerbates
activation of other immune cells to control bacte- the illness. This is mainly due to deregulation in
52 A. Borzutzky Schachter and P. Morales Matamala

the recruitment of leukocytes and to their exag- one found in the upper airways, where
gerated activation, with inappropriate expression Streptococcus, Prevotella, Fusobacterium, and
of proinflammatory cytokines and lipid media- Veillonella can be found, with small populations
tors, and uncontrolled activation of platelets and of Haemophilus and Neisseria. The presence of
the coagulation cascade. All of this is initiated these bacteria in small numbers in asymptomatic
and perpetuated by the presence of antigens, patients has no significant clinical implications.
which activate the innate immunity receptors in The microbiome is considered symbiotic and
the alveolar epithelium. The hypoxia that is gen- is associated with cell growth; tissue repair after
erated, which is secondary to the acute alveolar injury; maintenance of barrier function; and
damage, is also proinflammatory and contributes induction, development, and modulation of the
to the production of greater epithelial and endo- immune response. Quantitative alterations in the
thelial damage. microbiome of the airway have been described,
After episodes of acute injury comes tissue such as obstructive lung diseases, asthma, and
repair, in which immune elements also partici- cystic fibrosis. A potential therapeutic mecha-
pate. This process is essential for epithelial integ- nism is administration of probiotic supplements.
rity and lung homeostasis. After lung injury, However, more studies are necessary for us to
repairing factors are liberated, including epider- completely understand the role of the airway and
mal and fibroblast growth factors, cytokines, and lung parenchyma microbiomes in the immune
prostaglandins, which coordinate the repair pro- homeostasis of these organs.
cess through matrix proteins, metalloproteinases,
and integrins. An important role of Tregs is that
they decrease fibrosis in the repair; TNF-α Sources
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shown that a bacterial population is present, ulatory T  cells in children less than 2  years of age.
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Neish AS.  Mucosal immunity and the microbiome. Ann Suzuki T, Chow CW, Downey GP. Role of innate immune
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 New Frontiers in Research
on the Respiratory System
7
Andrew Bush and Luis Enrique Vega-Briceño

Contents
Cystic Fibrosis as a Model for Dealing with Chronic Lung Disease.......................... 56
 ovel Strategies for Current Objectives...........................................................................  57
N
Gene Therapy...................................................................................................................  57
Small Molecules...............................................................................................................  57
Introduction to Complex Mutations.................................................................................  58
The Challenge: How Can We Know It Works? ��������������������������������������������������������������  59
The Problem: Delicate Secondary Effects Associated with Longevity............................  59
Selection of Resistant Organisms.....................................................................................  59
Allergies to Antibiotics.....................................................................................................  59
Chronic Renal Insufficiency.............................................................................................  60
Chronic Lung Disease Crises or Attacks: Lessons for a Long-Term Response........ 60
 ulmonary Attacks in Cystic Fibrosis..............................................................................  60
P
Pulmonary Attacks in Asthma..........................................................................................  61
Genetically Associated Diseases and Their Close Systemic Relationship:
Ciliopathy........................................................................................................................ 62
Learning from Follow-Up Studies on Chronic Lung Diseases................................... 65
 eyond Tucson: Patterns of Wheezing in Preschool Children.........................................  65
B
Improved Phenotyping.....................................................................................................  66
The Microenvironment of the Airway and Development of Respiratory
Diseases: The Microbiome............................................................................................. 66
The Importance of the Microbiome in Healthy Children.................................................  67
The Microbiome in Early Wheezing Disorders................................................................  68
The Microbiome and Cystic Fibrosis...............................................................................  69
Is Clinical Pediatric Pneumology Dead? .........................................................................  69
Sources............................................................................................................................. 70

A. Bush (*)
Faculty of Medicine, Imperial College of London,
London, UK
e-mail: [email protected]
L. E. Vega-Briceño
Faculty of Medicine, Universidad del Desarrollo,
Santiago, Chile
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 55

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_7
56 A. Bush and L. E. Vega-Briceño

 ystic Fibrosis as a Model

C remained normal until subjects were 2 years old.
for Dealing with Chronic Lung The pulmonary clearance rate decreased through-
Disease out the study period, although most of the infants
had levels in the normal range. The structural
The old biomedical paradigm was the diagnosis changes detected by HRCT were so minor at 1
of cystic fibrosis in a child with chronic lung dis- year of age that they could not be assessed in a
ease (CLD) and malnutrition. Cystic fibrosis is reproducible manner using the Brodie score. As
increasingly being diagnosed by neonatal screen- in the AREST-CF study group, the nutritional
ing based on blood samples taken by heel punc- condition of the subjects remained normal
ture or from cord blood. There are different throughout the study.
protocols for this, which are dependent on com- There are consequences of early neonatal
binations of immunoreactive trypsin (IRT), pan- detection and favorable clinical evolution. Firstly,
creatic polypeptide, and polymerase chain it is important to consider the possibility that there
reaction (PCR) for several cystic fibrosis genes. are children with late-manifestation cystic fibrosis
All early detection programs for cystic fibrosis (without pancreatic disease) and other atypical
have the following characteristics in common: forms. Secondly, we are diagnosing a “new” gen-
they detect the majority of newborns with this eration of cystic fibrosis patients who have never
disease, but they also do not detect the disease in been sick and who increasingly see themselves as
a small minority of newborns who may even have persons with non-neonatal detection, which can
severe phenotypes. have implications for their subsequent treatment.
There is a guiding consensus on handling of It is increasingly necessary to adapt treatment and
cystic fibrosis that has been identified early protocols to attend to persons who are healthy, not
through neonatal screening. For example, in the sick, changing the therapeutic load without risk-
randomized, controlled Infant Study of Inhaled ing the loss of benefits provided by the aggressive
Saline (ISIS), preschool children with cystic therapy of the past. We need to explore innovative
fibrosis were treated with hypertonic saline solu- modes of attention, including telemedicine.
tion (HSS), the use of which improved the lung Finally, the good results reported by the LCFC
clearance index (LCI). While there are diverse group imply that the number of patients (small
opinions about the prophylactic role of antibiot- children) needed for randomized, controlled clini-
ics for newborns, there is universal concurrence cal trials would be prohibitively large, and such
that the use of prophylactic cephalosporin is con- trials would be virtually impossible. It is probable
traindicated owing to the greater risk of infection that clinical trial that evaluate new therapies have
by Pseudomonas aeruginosa, although the role to be postponed until after the patient is 2 years
of prophylactic flucloxacillin remains a matter of old, which is a critical time in terms of pulmonary
debate. The clinical evolution of these children development. The variables of clinical trials will
following diagnosis by screening is even more be increasingly more difficult to establish even
controversial. AREST-CF (the Australian with older children.
Respiratory Early Surveillance Team for Cystic The implications in terms of treatment indi-
Fibrosis) showed that while the nutritional state cate that the old paradigm was “reactive” and
of these children may be very good, the forced responded to the complications of cystic fibrosis.
expiratory volume in 0.5 seconds (FEV0.5) dimin- The new paradigm begins with novel treatment
ishes over 2 years. In fact, high-resolution com- strategies for the current objectives—manage-
puted tomography (HRCT) reveals the presence ment of infection, inflammation, and mucus
of bronchiectasis, trapped air, and other abnormal clearance—as well as “modern” prescriptions for
structures at 1 year of age. In contrast, the LCFC novel objectives (perhaps the most interesting of
(London Cystic Fibrosis Collaboration) showed all). A last aspect is the greater risk of toxicity or
that the FEV0.5 was decreased at the time of diag- the adverse effects of using medications in the
nosis but was normalized by the age of 1 year and context of increased longevity.
7  New Frontiers in Research on the Respiratory System 57

 ovel Strategies for Current

N patients. Two issues are the optimal vector and
Objectives variables to employ. A recent double-blind, ran-
domized trial included 130 patients who received
These include the development of new mucolytic 12 monthly doses of a nebulized gene–liposomal
agents, antibiotics, and delivery devices. Inhaled complex or a saline solution placebo at 0.9%.
mannitol is defined as auxiliary in mucus clear- The first response to evaluate is the relative
ance in patients with cystic fibrosis for whom change in the FEV1, with responses of secondary
suppression subtractive hybridization (SSH) and efficacy in the LCI, on HRCT, and on the Cystic
DNase are not effective, although the need to Fibrosis Questionnaire—Revised (CFQ-R).
inhale multiple capsules could limit adherence to Subgroups have been submitted to more detailed
its use. New nebulized antibiotics include liposo- molecular and physiological studies of the nose
mal amikacin and ciprofloxacin. The use of nebu- and lower airway. The results promise to be inter-
lized amikacin poses a dilemma. It is so useful esting. Another even more sophisticated strategy
for treating atopic infection by mycobacterium is repair of the abnormal CFTR gene. It should be
that there is a strong argument in favor of limiting remembered that gene repair is a normal physio-
its use to this indication. On the other hand, there logical process. At present, gene manipulation
are commercial considerations that argue for its with appropriate primers is still in the future.
availability for treating airway infections by
P. aeruginosa, arguing that its use once a day (or
perhaps once a week) would be beneficial for Small Molecules
many patients with cystic fibrosis. This dilemma
has not yet been resolved. Genetic mutations in cystic fibrosis can be
Nebulized therapy has historically not been divided into six classes (Table  7.1). Increasing
used that extensively. Although there are powder attention has been directed at specific therapies
forms of tobramycin and colomycin, it has been for small-molecule mutations. This has been
shown that they are not superior to traditional spurred by multimillion-dollar investments by
nebulized formulations. The technology of nebu- the US-based Cystic Fibrosis Foundation in high-­
lized medications has greatly reduced the time yield robotic detection to discover novel com-
required to administer drugs. The most interest- pounds. In fact, the first of these treatments
ing development in relation to cystic fibrosis has comes from the observation that aminoglycosides
been initiatives to treat the consequences of can inhibit premature detention codons (class  1
CFTR mutation, thus attacking the fundamental mutations) without interfering with natural deten-
disease instead of waiting for clinical manifesta- tion codons, leading to the formation of func-
tion of the problem. tional CFTR. This was followed by testing of the
orally active compound PTC124 (Ataluren™),
which has proved to be effective for other genetic
Gene Therapy conditions (for example, the rat model of
Duchenne muscular dystrophy). Phase 2 studies
This is the simplest of treatments in conceptual showed very diverse effects in different popula-
terms: a defective gene is replaced by a normal tions, attributed to the probability of different
gene and the cystic fibrosis is cured (or at least effects of messenger RNA decay, mediated by
decreased) independently of the mutation. There “nonsense” sequences or the position or nature of
have been numerous studies with single or mul- “early termination” codons. A phase  3 trial did
tiple doses and using a variety of vectors, includ- not meet the primary response for the group as a
ing an adenovirus, adeno-associated viruses, whole, but in an analysis of planned subgroups of
liposomes, and nanoparticles. These studies have patients who did not use nebulized tobramycin,
focused on determining whether gene transfer is the FEV1 was significantly higher than that of
feasible rather than on the clinical benefits for patients who received the placebo. The argument
58 A. Bush and L. E. Vega-Briceño

Table 7.1  Types of CFTR mutations, their consequences, very small children. Other proposed indications
and potential treatments
include the class 4 mutation R117H, the channel
Examples of Potential conductance of which decreases by 20%, with a
Type and consequences mutations therapies
75% reduction in the probability of channel
1. No CFTR synthesis G542X, PTC124
W1282X, opening. The high cost of this medication is ques-
R553X, tionable, given the slight mutation, never mind
3950delT the fact that patients effectively lose a significant
2. Abnormal CFTR ΔF508 VX-809 level of pulmonary function in adult life.
retained in the VX-700
endoplasmic reticulum Other Theoretically, VX-770 can also be used to
and damaged strengthen class  5 mutations and to “rescue”
3. CFTR reaches the cell G551D, 9 other VX-770 DF508, which has a residual gate defect.
membrane but does known gating VX-809 (lumacaftor) has been studied in
not open correctly mutations
class  2 mutations—in particular, DF508. These
4. CFTR reaches the R1117H, R334W VX-770
cell membrane but studies have shown small improvements in chlo-
the channel properties ride levels in sweat, but when lumacaftor is com-
are abnormal bined with ivacaftor, the changes are less notable
5. Decreased CFTR 3120+1G>A than those seen with VX-770, and it is improba-
synthesis
ble that VX-809, used by itself or in association
6. Unstable CFTR in N287Y,
the cell membrane 120del23, with VX-770, serves to undo the dysfunction of
(rapid replacement) 4326delTC, the residual damper of “recovered” CFTR DF508
4279insA and is sufficient to provide real clinical benefit.
This is because CFTR folding has multiple
phases. Formation of functional CFTR requires
is that those who used tobramycin could have contact between the domains and cotranslational
received the benefit of inhibition of “early stop” and post-translational folding. Consequently, it is
codons. New clinical trials of better compounds likely that more than one compound is required
will probably be developed in the future. to correct class  2 mutations. Small-molecule
The most dramatic molecular success has therapy for DF508 is currently being developed.
been observed with VX-770 (ivacaftor; Kalydeco)
for class 3 mutations. It was approved initially for
the mutation G551D, and its approval was then Introduction to Complex Mutations
broadened to include eight of another nine known
class  3 mutations. A large-scale, double-blind, The problem of correcting class 3 mutations has
randomized, placebo-controlled trial was con- been resolved easily, but a more sophisticated
ducted in children aged over 12 years and adults strategy could be required for other more com-
with at least one G551D mutation. The study plex anomalies. One model is that CFTR func-
showed an improvement of absolute FEV1 of tion can be described as an equation: CTFR
12% with concomitant improvements in weight function = (quantity of CFTR) × (probability of
and quality of life associated with cystic fibrosis, opening) × (protein conductance). Hypothetically,
as well as in the timing of the first pulmonary independently of the mutation, VX-770 can be
exacerbation. Surprisingly, the chloride level in used to improve the probability of opening and
sweat fell by close to 50% toward the doubtful possibly conductance, while specific strategies
diagnostic range (60–80  mEq/l). Other studies are required to raise the quantities of CFTR in the
have subsequently shown similar benefits in chil- epithelium. A new era of specific and multiple
dren 6–11 years old and in children with a normal molecular manipulations has begun. The effects
FEV1 (≥90% of the predicted value). There is of VX-770 on sweat chloride are notable,
currently a tendency to broaden the use of although it is not clear if this finding is signifi-
VX-770 to prevent pathological complications in cant. There is only a weak correlation between
7  New Frontiers in Research on the Respiratory System 59

sweat chloride and change in pulmonary func- changed. The study would have been more impor-
tion. We know that the sweat test provides one of tant if it had been considered ethical to recruit a
the best diagnoses in medicine, but this does not control group to establish the natural variability
mean that chloride transport is related to chronic among the events in these measurements.
lung disease. In fact, there are reasons to suppose
that it is not.
A major challenge for the community with cys-  he Problem: Delicate Secondary
T
tic fibrosis is control of the costs of these new mol- Effects Associated with Longevity
ecules. VX-770 currently costs US$330,000 per
patient per year. It is not clear how it has become Historically, cystic fibrosis was a childhood dis-
so expensive. It is calculated that use of VX-770 ease, with patients rarely surviving into adult-
raises the cost of treating cystic fibrosis in the UK hood. Consequently, the long-term toxicity of
by 50%, driven by the 5% of the population with medications did not need to be balanced against
this disease. If patients need to take two or more their short-term benefits. However, patients now
newly discovered molecules, the cost can be have life expectancies of several decades, and so
frightening. There are no easy answers. Without it is necessary to consider the question of long-­
public and private investment, these medications term accumulation of toxicity.
would not have been discovered, no country any-
where in the world—whatever its political system
is—has unlimited resources for health care. Selection of Resistant Organisms

The use of antibiotics has provided major benefits

 he Challenge: How Can We Know It
T for cystic fibrosis patients, but there has been a cost
Works? in terms of selecting new organisms and selecting
for antibiotic resistance in organisms that are
In the past, mortality was an inevitable outcome known and common in this disease. A study com-
of cystic fibrosis. Subsequently, improvements in pared a historical cohort of 520 patients with a
the FEV1 were accepted as a reasonable substitute comparable contemporary cohort and found an
for mortality, although the relationship between increase in P. aeruginosa resistant to tobramycin,
the FEV1 and mortality is increasingly uncertain. amikacin, and other drugs, and a higher percentage
However, the FEV1 is currently so good and the of isolation of methicillin-­resistant Staphylococcus
decline curves are so flat that measurement is aureus (MRSA), Stenotrophomonas maltophilia,
becoming less useful as a variable for clinical and Achromobacter. It is evident that we cannot
assessment. The US CF Gene Therapy Consortium stop using antibiotics, but this information empha-
has used an innovative strategy to address this sizes the need for responsible antibiotic manage-
problem on the basis of the observation that sub- ment and use.
stitute markers improved during an intervention
with demonstrated efficacy (intravenous antibiot-
ics) for pulmonary exacerbations in 44 cystic Allergies to Antibiotics
fibrosis patients. The improvements were evi-
denced by symptoms, the FEV1, the LCI, HRCT It is inevitable that the more antibiotics are used,
(showing thickening of the airway wall, air the more allergy to antibiotics becomes a factor.
entrapment, and large mucosal buffers) and mark- Allergy to antibiotics is common with cystic fibro-
ers of inflammation in serum (interleukin (IL)-6, sis and although desensitization is possible, it must
C-reactive protein (CRP), and calprotectin). be repeated with each application, which is time
However, what can be considered more direct consuming and poses potential risks. This is not an
measures of airway inflammation (sputum and argument against the use of antibiotics; rather, it is
mucus rheology, exhalation condensate) have not a reminder that they need to be used responsibly.
60 A. Bush and L. E. Vega-Briceño

Chronic Renal Insufficiency lar: “I know this is an exacerbation because I have

received treatment (prednisone for asthma, intra-
Chronic renal insufficiency (CRI) has been well venous antibiotics for cystic fibrosis), and I have
described and is usually the consequence of treat- received this treatment because it is an exacerba-
ment with aminoglycosides indicated at the same tion.” The term “exacerbation” implies something
time as other nephrotoxic drugs—in particular, relatively benign—a minor inconvenience that is
nonsteroidal anti-inflammatory drugs—and dehy- completely reversible. The purpose of the follow-
dration owing to excessive sweating or gastroen- ing section is to suggest that this is an error and
teritis. Nevertheless, CRI is a growing problem. that the term “pulmonary attack” is preferable. A
The cause is controversial. One study has pointed pulmonary attack is an emergency that could lead
to the glomerular filtration rate (GFR) with respect to irreparable harm and must therefore be
to the number of intravenous antibiotic treatments addressed, necessitating a response focused on
received (in some cases, >100). Another study determination of the cause and measures to pre-
identified nebulized aminoglycosides, and a third vent it from occurring again.
study found that the GFR is higher in persons who
require insulin. Whatever the explanation is, it is
clear that a medication that is administered for Pulmonary Attacks in Cystic Fibrosis
many decades needs to be carefully monitored.
Cystic fibrosis has set the pattern in this These are common (so-called pulmonary exacer-
changing paradigm, but other diseases will cer- bations—a term that will not be employed here)
tainly follow. For example, it is probable that pri- and have been used increasingly in randomized,
mary ciliary dyskinesia (PCD) is on the cusp of controlled therapeutic trials. In fact, in a study of
similar advances, considering the rapid expan- airway clearance in cystic fibrosis, positive pres-
sion of knowledge of multiple genetic mutations sure techniques were superior to external oscilla-
that cause diseases and their consequences, for tion of the thoracic wall in decreasing pulmonary
example, such as nonsense mutations that can be attacks, but there was no change in spirometry
sensitive to PTC124. It is clear that we need to findings. Pulmonary attacks in the context of cys-
expand our therapeutic horizons in the coming tic fibrosis are far from benign.
years. The challenge is to overlook therapies Several studies have concluded that these
without losing the benefits of the aggressive regi- patients cannot recover a basal spirometry level
mens that have accomplished so much to improve after completing adequate treatment in response
the prognosis of cystic fibrosis in the past. There to a pulmonary attack. Another study showed that
is a real danger of complacency; in the case of at 3  months after treatment, 24 of 104 cystic
children who have been diagnosed but have never fibrosis patients (23.1%) had not recovered even
been sick, it can be difficult to get them to adhere 95% of their maximum FEV1 from 6 months ear-
to treatment, which could be especially important lier. Pulmonary attacks in cystic fibrosis are asso-
if unexpected complications emerge. We need to ciated with a more rapid rate of FEV1 reduction.
maintain clarity between the double risk of A study of 8490 patients from the Cystic Fibrosis
imposing a large therapeutic load on persons who Foundation Patient Registry reported that 60%
are asymptomatic but have this disease and think- had no exacerbations, 23% had one per year, 10%
ing that the problem of cystic fibrosis is resolved. had two per year, and 7% had at least three per
year. Even one exacerbation per year in children
is associated with accelerated rates of FEV1
 hronic Lung Disease Crises or
C decline, while in adults, accelerated decline is
Attacks: Lessons for a Long-Term observed only in those with at least three exacer-
Response bations per year.
Pulmonary attacks with cystic fibrosis are
“Exacerbation” is a not-very-convincing term that associated with a higher rate of mortality. In a
describes acute deterioration in the symptoms of a three-year prospective cohort study involving
chronic lung disease. The definition is often circu- 446 adult patients, 140 subjects had one exac-
7  New Frontiers in Research on the Respiratory System 61

erbation per year at most, 160 had one or two There is a tacit supposition that pulmonary
exacerbations per year, and 146 had more than attacks in cystic fibrosis involve a general
two exacerbations per year. In this work, the change rather than a focused change. This
exacerbations were defined as an indication for notion has been challenged by a recent report
oral or intravenous antibiotics. There was a featuring fluorodeoxyglucose–positron emis-
higher probability of more frequent exacerba- sion tomography (FDG-PET), which detected
tions in women, individuals with low pulmo- inflammation and infection, and HRCT in 20
nary function, and diabetics. Individuals with cystic fibrosis patients 14–54  years of age.
more than two exacerbations per year had a FDG-PET showed active focal spots, which
higher probability of having a reduction of were more pronounced during pulmonary
more than 5% per year in the FEV1 and a higher attacks in cystic fibrosis and, in contrast to the
probability of death or of receiving a HRCT findings, the changes were sensitive to
transplant. intravenous antibiotics, at least in this study.
Not surprisingly, those with a high risk of not We may need biomarkers of local signals of the
achieving a complete recovery had a more pro- disease. Unfortunately, the level of exposure to
nounced decline in the FEV1, with respect to the radiation with the current technique is prohibi-
baseline value, during the exacerbation, which tively high.
provides more evidence of inflammation (a
higher CRP level at the time of hospitalization
and a higher white blood cell count at the end of Pulmonary Attacks in Asthma
treatment). However, the absence of these risk
factors should not be considered satisfactory. There is less evidence of long-term effects of
Given the evidence above, are we making opti- pulmonary attacks in children with asthma.
mal use of conventional treatments? For exam- Asthma attacks are significant causes of mor-
ple, would use of more antibiotics be more bidity and a reduction in the quality of life.
helpful than intensive use of anti-inflammatories? Observational studies suggest that exacerba-
In terms of the duration of treatment with antibi- tions are associated at some level with a more
otics, there is no evidence to guide the doctor. rapid decline in spirometry readings, but it is
However, in a study that was an extension of not clear if this is related to low adherence
work on antibiotics, which analyzed the evolu- associated with exacerbations independent of
tion of spirometry in 95 cystic fibrosis patients the accelerated decline in lung function, due
who had received antibiotics intravenously for at possibly to nonuse of medications. In an origi-
least 4  days (mean 12.6  days, median  13, stan- nal study based on a controlled trial, 7165
dard deviation 3.2), the average time to reach the adults and children with asthma were randomly
maximum FEV1 was 8.7  days and, in practice, assigned to receive either a low dose of
everyone reached a FEV1 peak within 13 days of budesonide or a placebo by inhalation. Despite
treatment. These data indicate that 2  weeks of the large size of the study, only a minority of
treatment with intravenous antibiotics does not patients experienced exacerbations (190 in the
result in an improved response to pulmonary placebo group and 115  in the budesonide
attacks in cystic fibrosis. group). There was an accelerated decline in spi-
There have been several studies on the use of rometry values among both children and adults
anti-inflammatory medication for short-term who were taking the placebo and experienced
treatment of pulmonary attacks in cystic fibrosis. an exacerbation, but not in the group that
Studies of steroids (prednisolone 2 mg/kg up to a received budesonide (−2.43% in placebo recip-
maximum of 60 mg for 5 days and methylpred- ients without exacerbations versus −6.44% in
nisolone in pulses) indicate that the benefits do placebo recipients with exacerbations,
not exceed the potential secondary effects. An p  <  0.001; and −1.72% in budesonide recipi-
initial trial of DNase (which has certain putative ents without exacerbations versus −2.48% in
anti-inflammatory effects) showed no benefits of budesonide recipients with exacerbations,
application during exacerbation. p  value not significant). This study did not
62 A. Bush and L. E. Vega-Briceño

establish whether the exacerbations caused the  enetically Associated Diseases

G
decline in spirometry values or whether the and Their Close Systemic
accelerated decline and the exacerbations were Relationship: Ciliopathy
part of an underlying phenotype, but subse-
quent analysis of the data suggested that Until now, ciliary bronchopulmonary disease has
budesonide lessened the effects of the exacer- been limited to PCD. It is now clear that aspects
bations. Inhaled steroids can have more long- of ciliary function extend to the systems of prac-
term benefits than has been thought. tically all organs, and pediatric bronchopulmo-
It is important to understand that pulmonary nary specialists need to be familiar with these
attacks in asthma and control of asthma at the manifestations. There are three types of cilia
basal level should not be treated in a similar (Table 7.2): primary (which, disconcertingly, are
manner, even though they can coexist in the not really abnormal in PCD), nodal, and mobile.
same subject; in fact, poor control of asthma is The cilium structure is very complex, with at
an important risk factor for the development of least 1000 polypeptides. The process of elabora-
acute attacks. The new antibiotics appear to be tion and assembly is also complex and involves
good, particularly for reducing acute infectious multiple stages coded by genes that do not by
attacks, but they have a much smaller effect on themselves have a role in ciliary structure.
basal control of asthma. This might be surpris- Functional genomic detection using RNA inter-
ing, considering that acute attacks are almost ference recently found 36 positive cilium
invariably due to viral infection. Although there assembly modulators and 13 negative ones.
are certainly interactions between viral infection Consequently, the genetics of ciliopathy is clearly
and inflammation of the airway by eosinophils, complex, which should be registered during
controlling basal eosinophilic inflammation assessment of diagnostic paths in PCD. It can be
reduces exacerbations, as can be clearly seen argued that there is at least one additional level of
with the use of omalizumab to prevent seasonal complexity. The cilia function not in isolation
outbreaks of acute asthma among children but, rather, in a complex extracellular environ-
returning to school. ment of periciliary mucus and fluid. At least in
Like a heart attack, a pulmonary attack
requires a focused response and a detailed assess-
Table 7.2  Different types of cilia
ment to prevent a reoccurrence. Protocols have
been recommended for asthma and cystic fibro- Type Description
Primary They have a 9+0 axoneme structure
sis. The general theme in the context of asthma (generally with no pair of central microtubule
has been To achieve what it is suggested by the singlets)
guidelines. We use a detailed protocol with a There is a primary cilium in every tubular
nursing guide indicating that in at least half of the epithelial cell and in many others
They participate in numerous chemosensory
patients with severe asthma, we need to consider and mechanosensory functions, linking with
adherence to medication (including use of the key metabolic pathways such as Hippo, Sonic
appropriate drug and correct use of the device Hedgehog, canonical and noncanonical wnt,
employed), the environment (allergens and expo- pdgf, and mtor
The structure varies along the axoneme (they
sure to cigarette smoke), and educational as well may have regions with central singles)
as psychological problems. We need to under- They play an important role in reabsorption
stand that pulmonary attacks are not benign, and of water in the kidney
we also need to focus on other diseases (PCD and Nodal They are structurally of the primary type and
are the only known primary mobile cilia
bronchiectasis) and work to prevent their recur-
Motile They have the classic 9+2 axoneme structure
rence. An important scientific focus is the mecha- (9 outer doublets, 2 central microtubule
nisms of pulmonary attacks in the different singlets)
diseases and factors for prediction and optimal They move mucus along epithelial surfaces or
management. drive unicellular organisms through liquids
7  New Frontiers in Research on the Respiratory System 63

theory, a PCD phenotype should be produced, essary. Obviously, more sophisticated tests are
even if the cilia are completely normal in cases not necessary if the child fulfills the classical
where the genes that regulate the extraciliary diagnostic criteria (Table 7.3),
environment mutate. Chronic rhinitis can make it impossible to har-
An important aspect of ciliary function is vest enough cells for a first measurement. In such
intraflagellar transport, which is evidenced by the cases, it may be possible to culture epithelial
movements of A  and B “cumulus” of different cells, with new growth of cultured cilia and deter-
sizes, ascending and descending, respectively, in mination of ciliary beat patterns and morphology.
the cilia. The physiological function of this pro- Immunofluorescence can be used in diagnosing
cess is not clear, but it is probably related to cili- PCD to show misplaced ciliary proteins. This test
ary growth and nutrition. Mutations in A and B has the advantage that it captures many mutations
genes result in thick and short cilia. This process that carry misplaced proteins. Moreover, the nec-
is related to the key cilium signaling paths and essary equipment is much simpler and less costly
clinical syndromes such as Jeune asphyxiating than that used for ciliary beat frequency testing. It
thoracic dystrophy and Sensenbrenner and other is likely to have broader applications in the
syndromes. future.
There is growing interest in the regulatory role PCD primary ciliary dyskinesia
of primary cilia. For example, a layer of primary A growing number of PCD genes have been
cilia can be detected in the smooth musculature discovered, and it is probable that in the future
of the airway by immunofluorescence and confo- there will be therapies for specific mutations,
cal microscopy and by transmission and scanning such as PTC124. The diagnosis is certain if two
electron microscopy. They are enriched by mutations known to produce disease in trans are
mechanical–chemical sensors, polycystins, and detected. However, as with cystic fibrosis, not
the epidermal growth factor receptor, and have finding two mutations does not exclude PCD. The
roles in healing injuries and in cellular genetics of PCD is also much more complex,
migration.
Research into this disease has experienced a Table 7.3  Diagnostic criteria for primary ciliary dyski-
resurgence, led by the European Respiratory nesia (PCD)
Society (ERS) task force and the North American Probable Improbable
group. The most important recent advances have Clear diagnosis diagnosis diagnosis
been in diagnostics and genetics, with the discov- Clinical phenotype Clinical Normal nNO +
ery of more PCD genes. Unfortunately, there + low nNOa + phenotype + abnormal CBF
CBF or pattern low nNO, or EM findings;
have not been comparable advances in therapies, anomaly + EMb regardless of it is necessary to
the management of which is not evidence based; anomalies EM and CBF exclude
rather, it is generally based on protocols for cys-  or findings; test secondary
tic fibrosis. Table 7.3 shows the current standard Two known repetition is changes
diseases that mandatory
diagnostic criteria for PCD. However, these crite- produce mutations
ria are currently under review by the ERS task in trans
force. In particular, novel techniques such as  or
immunofluorescence and electron microscopic A specific disease
that produces
tomography are available for challenging cases. abnormalities on
The first prerequisite in a contemporary EM (e.g., ODA
response to PCD is to establish the probability of abnormalities)
a diagnosis of PCD. In the case of a child with a CBF  ciliary beat frequency, EM  electron microscopy,
low-risk history, a nasal nitric oxide test and mea- nNO nasal nitric oxide, ODA outer dynein arm
a
nNO should be interpreted with caution unless the patient
surement of the ciliary beat frequency is all that is is old enough to use the breath hold technique
required to rule out PCD, whereas in a child with b
Functional structural abnormalities may appear in freshly
a high-risk history, broader examinations are nec- harvested epithelial cells or after in vitro ciliary culturing
64 A. Bush and L. E. Vega-Briceño

involving multiple loci in the karyotype and zle. As with cystic fibrosis, there are atypical
large, complex genes with multiple mutations. cases of PCD that resist a definitive diagnosis.
The general problem of genetics is evidently dis- These children should be kept under strict fol-
tinguishing causal mutations from harmless poly- low-­up, and any manifestation of the disease
morphisms. For example, of the close to 2000 should be dealt with aggressively. Diagnostic
described CFTR mutations, fewer than 150 are uncertainty should never lead to therapeutic
currently known to cause disease. Consequently, paralysis.
there is a real danger in PCD that genetic searches Table 7.4 summarizes the manifestations of
will aggravate existing diagnostic confusion. ciliopathy. The most obvious question is why the
Conventional electron microscopy is viewed bronchopulmonary system of children should be
by some as the reference standard. This is clearly linked to obscure genetic syndromes. There are
a mistake, given that many patients with PCD several reasons. Firstly, we need to encourage
have a normal ultrastructure. More sophisticated colleagues in other disciplines (especially cardi-
techniques will change this in the future. ology, neurology, and nephrology) to consider
Sophisticated tomography, which requires highly PCD. No place can be more dangerous than spe-
qualified personnel and is very time consuming, cialist care for a patient with a problem the spe-
can detect subtle anomalies that are overlooked cialist does not recognize. We should be aware of
by electron microscopy. Clearly, the range of the possibility of another pathology in the PCD
novel testing has allowed for confirmation of the patients, such as retinitis pigmentosa. There has
diagnosis of PCD in patients whose condition not been any recommendation for routine detec-
would otherwise have remained a diagnostic puz- tion of patients with PCD—for example, echo-

Table 7.4  Summary of pulmonary and systemic manifestations of ciliopathy

Manifestations of ciliopathy
Respiratory manifestations
 Upper airway (PCD) Rhinosinusitis, chronic secretory otitis media and impaired hearing, nasal polyps
(rarely in children)
 Lower airway (PCD) Recurrent lower respiratory infections, bronchiectasis, respiratory failure
 Chest wall (ciliopathy) Small thoracic cavity, anomalies of the ribs
 Sleep disorder (ciliopathy) Central apnea, obstructive sleep apnea, obesity
 Control of breathing Abnormal pattern of breathing
(ciliopathy)
Systemic manifestations
 Cardiovascular Complex congenital heart disease (especially with laterality disorders),
cardiomyopathy
 Renal Polycystic kidney, nephronophthisis, renal dysplasia, glomerulonephritis
 Hepatic Congenital fibrocystic disease
 Ocular Retinitis pigmentosa, photophobia, keratoconus, hyperopia, nystagmus, reduced
pupillary response, cone dystrophy, strabismus, cataracts, astigmatism, epicanthal
folds
 Neurological Hydrocephalus, development delay, ataxia, cerebellar disease, hypotonia or
hypertonia, oculomotor apraxia, diseases of the brain stem, sensorineural hearing
loss, hypoplasia of the corpus callosum, Dandy–Walker malformation, posterior
encephalocele
 Musculoskeletal Polydactyly, brachydactyly, syndactyly, facial abnormalities including midface
hypoplasia, short ribs, hypoplasic iliac crests, trident acetabulum, rhizomelic limb
shortening, nail dysplasia, brachycephaly
 Genitourinary Sperm without motility (only in 50% of men with PCD), ectopic pregnancy (PCD),
hypogonadism, instability of the urinary detrusor, hydrometrocolpos
 Others Anosmia, insulin resistance, diabetes, nasal abnormalities, frontal alopecia, large
ears, narrow nasolabial groove, alterations of teeth, intestinal malrotation
7  New Frontiers in Research on the Respiratory System 65

cardiography or ophthalmoscopy when PCD is specialty of bronchopulmonary medicine. The

diagnosed—but we should not require guidelines ciliopathies include asphyxiating thoracic dystro-
in order to be clinically alert. Finally, without phy (Jeune syndrome) and Mainzer–Saldino syn-
doubt, there are more associations with ciliopa- drome, in which genetic mutations can affect
thy to be discovered. This is another fruitful area intraflagellar transport. Retinitis pigmentosa is
for bronchopulmonary specialists. itself a ciliopathy and is also found in families in
Ciliopathies make up a spectrum of congeni- which PCD occurs. This area of research is at an
tal, hepatorenal, bronchial, and multisystem syn- early stage. There are many more discoveries to
dromes, in which renal compromise is common. be made about these complex and multisystem
Depending on whether the genetic defect leads to disorders. Pediatric bronchopulmonary special-
dysfunction or nonfunction, complete absence ists should advise their colleagues in other spe-
results in different syndromes, such as Meckel– cialties with respect to the manifestations of
Gruber syndrome, while there are aberrant results ciliopathy in their patients and keep in mind the
with late-onset adult polycystic kidney disease. possibility of manifestations of PCD in nonrespi-
There is a marked heterogeneity in these syn- ratory examinations.
dromes; overlap syndromes are common, and dif-
ferent manifestations of genetic mutations can
appear among members of the same family. The  earning from Follow-Up Studies
L
same phenotype can be caused by very disparate on Chronic Lung Diseases
genes. The bronchopulmonary specialist should
be alert to the possibility of ciliopathy among We have learned much about childhood wheez-
patients with heterotaxy syndromes. The disposi- ing and allergies from numerous neonatal cohort
tion of the organs is determined by nodal cilia studies. Recent scientific developments have
during embryogenesis. Classic Kartagener syn- made phenotyping more effective, using unsu-
drome is characterized by complete specular pervised mathematical techniques that overcome
imaging, but isolated abdominal and thoracic researcher bias and combining neonatal cohorts.
imaging has been described, as well as isomeric This has the effect of greatly increasing the power
sequences. These are associated with complex of studies. This has been Medall’s focus and
congenital heart disease. Specialists should undoubtedly will increase our knowledge of dis-
always keep PCD in mind during consultations eases that include childhood wheezing.
about these children. They normally present
defects in the outer dynein arm (DNAH1 and
DNAI5 mutations). Congenital heart defects  eyond Tucson: Patterns of Wheezing
B
without lateral disorders are part of other nonmo- in Preschool Children
bile ciliopathies.
The possibility of bronchiectasis should be con- The Tucson study did a great service by discover-
sidered in patients with renal disease, as well as in ing four wheezing patterns: absence of wheezing,
those with hepatic cysts, which can be the first early transitory wheezing (at 0–3  years of age),
manifestation of renal disease. Renal ciliopathies persistent wheezing (at 0–6  years of age), and
include juvenile and adult polycystic kidney dis- wheezing with late manifestations (at 3–6 years of
ease, nephronophthisis, and renal dysplasia syn- age). These were “self-fulfilling,” given that the
dromes. It is interesting to note that polycystin 1, children were assessed at the ages of 3 years and
the mutated gene in polycystic kidney disease, is 6 years and no other phenotypes could be detected.
expressed in the airway. Even patients with renal ALSPAC (the Avon Longitudinal Study of Parents
disease unassociated with ciliopathies have a and Children), which gathered information from
higher than expected prevalence of bronchiectasis. subjects at 6, 18, 30, 42, 54, 69, and 81 months of
The associated deformities of the thoracic age, employed mathematical analysis (to overcome
wall and pulmonary hypoplasia can be part of the researcher bias) to define six phenotypes: “early
66 A. Bush and L. E. Vega-Briceño

nontransitory,” “intermittent appearance,” “persis- allergic rhinitis and rhinoconjunctivitis. It was

tent,” “early prolonged,” “late,” and “never/infre- proposed that atopy be assessed by the sum of
quent”. These phenotypes were confirmed by diameters or IgE values for airborne and food-­
similar studies in Southampton and the Netherlands, based allergens. A classification strategy was
thus strengthening the evidence that they represent later employed to divide atopy into phenotypes
real entities. This further supported genetic studies. that employed wheezing phenotypes. Five types
Locus 17q21 (which contains, among other things, of atopy were defined: nonlatent atopic vulnera-
ORMDL3) was a novel and solid discovery in bility, atopic vulnerability not from household
recent asthma genome-wide association studies. dust mites, atopic vulnerability from household
When the six wheezing phenotypes were geno- dust mites, late multiple atopic vulnerability, and
typed, only “children with persistent wheezing” early multiple atopic vulnerability. Early multi-
had a persistent single-nucleotide polymorphism ple atopy was the only condition that predicted
(SNP) at this locus. Moreover, in follow-up studies, asthma, which is consistent with the results of
these wheezing phenotypes predicted abnormal other studies, effectively indicating the impor-
developments in spirometry. Children with persis- tance of the early appearance of atopy.
tent intermediate or late manifestations had a com-
paratively lower FEV1 in adolescence. Finally, a
study that combined the ALSPAC, KOALA (Child, Improved Phenotyping
Parents and Health: Lifestyle and Genetic
Constitution), and PIAMA (Prevention and We have reached a point where combination of
Incidence of Asthma and Mite Allergy) cohorts phenotypes is possible. The Manchester group
explored whether early transitory wheezing is asso- has taken the lead, combining its five “atopies”
ciated with genes of chronic obstructive pulmonary with four w‑heezing phenotypes (absence of
disease (COPD). The results were not completely wheezing, transitory wheezing, late-appearance
consistent for the three cohorts, but the data did wheezing, and persistent wheezing). They
indicate a genuine association for at least some showed that persistent wheezing combined with
genes, supporting the follow-up results of the 1964 early multiple atopy is the only combination that
Aberdeen neonatal cohort, in which children with predicts progressive worsening of airflow
what was termed “wheezing bronchitis” (but prob- obstruction in childhood. This type of work can
ably could be termed “early transitory wheezing”) make an important contribution to predictive
experienced an accelerated decline in spirometry in indices of asthma, which will be needed when we
middle age, predisposing them to finally discover therapeutic strategies to prevent
COPD.  Considered together, these novel pheno- the progression from episodic viral wheezing to
types are closely related to the clinical reality, and asthma. Current indices have good negative pre-
these correlations require further exploration. dictive values, but the positive predictive values
Atopy has traditionally been considered a are only a little better than a toss of the coin. This
“yes/no” condition on the basis of the presence or probably reflects the crude way in which we have
absence of a 3-mm burr with a skin prick test and assessed parameters such as atopy.
a blood IgE level of >0.34, but these limits are
arbitrary and reinforce the belief in grouping
children with a weak positive skin prick test for a The Microenvironment
milk allergy with children with strong positive of the Airway and Development
tests for multiple aeroallergens. The Manchester of Respiratory Diseases:
study reported that there was—as expected—a The Microbiome
broad range of sensitivities to airborne allergens,
determined by either the skin prick or IgE tests. It has long been believed that the airway below the
There were good dose–response relationships larynx is sterile, despite the large quantities of air
between the degree of allergic sensitization and that we inhale daily and the fact that the air is laden
7  New Frontiers in Research on the Respiratory System 67

with microorganisms, allergens, and contami- concluded that exposure to a mixture of bacterial
nants. One reason this myth persists over time has species can have a more powerful inhibiting
been the excessive confidence we have in conven- effect on the allergic response than exposure to
tional microbiology based on cultures, which is Bifidobacterium alone. It was also shown that
able to detect only about 1% of total bacteria. A germ-free rats had lower IgA levels in the bron-
battery of increasingly sophisticated molecular coalveolar lavage, larger numbers of basophils,
tools has been developed, resulting in the detection and smaller numbers of alveolar macrophages
of bacterial DNA, which has revealed that human and plasmacytoid dendritic cells, while the num-
beings have more than ten times as many bacterial ber of regulatory T lymphocytes (Tregs) was not
cells as eukaryote cells. An early bronchoscopy affected. It was concluded that commensal bacte-
study highlighted that there is an abundant lower ria are important for the normal maturation of
flora; it identified 5054 bacterial 16S ribosomal immune cells.
RNA (rRNA) sequences from 43 adults and chil- Another study using an ovalbumin model of
dren, which represented more than 70% of the spe- murine allergic airway disease showed that previ-
cies that were present. The bronchial tree is not ous exposure to Escherichia coli precluded the
sterile and contains on average 2100 bacterial possibility of airway eosinophilia, which proba-
genomes per square centimeter of the sampled sur- bly requires signaling through TLR4 but does not
face. The number of proteobacteria is significantly function via Th1 or Treg mechanisms. The authors
higher in children with asthma than in healthy concluded that the effect occurred via dendritic
children, while Bacteroidetes—in particular, and T  cells, although this was not confirmed.
Prevotella species—are more common in healthy Infection of murine models with Helicobacter
children than in asthmatic children. This and other provoked by ovalbumin or household dust mite
original works have highlighted the scientific allergens prevented eosinophilia and Th2 and
importance of the microbiome and have promoted Th17 infiltration. Neonatal infection altered the
a new vision of inflammatory diseases. Moreover, maturation of dendritic cells and induced inhibi-
it is clear that there is a high degree of interaction tory Tregs. The researchers showed that the
between the airway and the intestinal mechanism of the effects of Helicobacter func-
microbiome. tions via Tregs. Adoptive protector Tregs were
observed, and there was no depletion of Tregs in
a rat model. Finally, in another study that used
 he Importance of the Microbiome
T rats with ovalbumin provocation, allergic airway
in Healthy Children disease was inhibited by viable and dead
Streptococcus pneumoniae. The study demon-
A major part of the work on lung development strated inhibition of a Th2-specific antigen
has been done in animals, and significant insights response and pulmonary and peripheral
into early stages of human lung development ­eosinophils, hyperplasia of calciform cells, and
have been gained. One study investigated the hyperactivity of the airways. The probable mech-
development of allergic inflammation induced by anisms included Treg induction, less T cell pro-
intraperitoneal ovalbumin in three groups of rats: liferation, and release of Th2 cytokines. The
rats bred normally, germ-free rats, and germ-free effects were reversed by anti-CD25. In summary,
rats that had been reconstituted with bacterial there is clearly an important interaction between
flora from normal rats. The germ-free rats had airway infection and immune response, which we
more pronounced type  2 helper T  cell (Th2) have recently begun to understand. We also need
responses, evidenced by having more IL-4+ or to demonstrate the complexities of fungi and
IL-5+ CD4+ cells in the broncoalveolar lavage, viruses, which have been found in large quanti-
without differences in IL-10+ or in interferon ties with molecular techniques.
(IFN)-γ+ cells. They also had a more pronounced It should not be supposed that bacteria are
IgE response to intranasal provocation. It was benign in normal immune development. In
68 A. Bush and L. E. Vega-Briceño

COPSAC (the Copenhagen Prospective Study on antibiotic-associated diarrhea. The use of antibi-
Asthma in Childhood), early isolation of S. pneu- otics has the potential to alter the microbiome of
moniae, Moraxella catarrhalis, Haemophilus the airway and modulate the immune response
influenzae, or a combination of these organisms over the long term. This is obviously not an argu-
from the nasopharynx was closely associated ment against the use of antibiotics for life-­
with persistent wheezing, acute exacerbations of threatening diseases for children, but it is another
severe wheezing, and hospitalization due to potent argument against the use of antibiotics for
wheezing. The blood eosinophil and total IgE more trivial self-limiting problems.
counts at the age of 4 years were found to be sig-
nificantly higher in children colonized with these
organisms in the neonatal phase, but there was no  he Microbiome in Early Wheezing
T
effect on specific IgE.  The incidence of asthma Disorders
and acute bronchodilator response were signifi-
cantly higher in children colonized at the age of There is evidence that environmental microbial
5  years. Colonization was associated with an diversity has a positive effect on the risk of
inflammatory response in the nasal coating fluid, asthma. It has been known for many years that
of a mixed Th1/Th2/Th17 type. It remains to be the children of Friesen farmers in the Netherlands
determined whether this is a cause or a conse- have a very low prevalence of atopic diseases.
quence of colonization. GABRIELA (the Multidisciplinary Study to
There is increasingly convincing evidence that Identify the Genetic and Environmental Causes
early exposure to both good and bad microbes is of Asthma in the European Community
important for children. The place and mode of [GABRIEL] Advanced Study) and PARSIFAL
release have been demonstrated to affect the (the Prevention of Allergy-Risk Factors for
long-term results, and the probable mechanism Sensitization in Children Related to Farming and
functions through early bacterial exposure. Two Anthroposophic Lifestyle study) joined forces
meta-analyses have shown greater risk of atopic and showed that the diversity of bacteria and
disease, including food allergies, in newborns fungi in the environment was greater in children
delivered by cesarean section. Notably, the intes- living on farms and this was associated with bet-
tinal flora of newborns delivered by cesarean sec- ter responses to asthma and atopy. The presence
tion was different from that of other newborns. of Gram-negative environmental bacilli such as
Vaginal flora was reduced in newborns delivered Staphylococcus spp. and Listeria monocyto-
by cesarean section. Another research group col- genes, and fungi such as Eurotium and
lected fecal samples from 1167 participants when Penicillium, was protective. There are still many
they were 1  month old, took blood samples for unanswered questions. It is not clear if diversity
specific IgE when the participants were 2  years is causal of better responses or a marker of
old and again when they were 6–7 years old, and something else that is really responsible. The
­
gathered data through questionnaires repeatedly mechanism by which the environment affects the
applied from the birth of the participants until flora of the lower airway is not clear.
they were 7 years old. The study found that isola- Another group pyrosequenced amplifications
tion of Clostridium difficile at 1 month of age was of the polymorphic bacterial rRNA gene 16S from
associated with wheezing and eczema throughout oropharyngeal samples collected from 24 infants
the follow-up period. Children of atopic parents in tropical Ecuador with noninfectious early-
who were born vaginally at home had lower prev- appearance wheezing and 24 healthy controls
alence rates of eczema and asthma. (average age 10.2 months). The researchers found
There are major unknown areas. However, the pathogens much more often in the wheezing
data do have implications for the use of antibiot- infants than in the controls (for example, species
ics in preschool children. It is interesting to spec- of Haemophilus and Staphylococcus), while spe-
ulate whether there is an airway equivalent to cies of Veillonella were less common in subjects
7  New Frontiers in Research on the Respiratory System 69

with wheezing. The important things to note about not be established whether the lower level of
this study were that (1)  the results were con- diversity was caused by the treatment or was a
founded by treatment with antibiotics or inhaled function of the underlying pathology. There is
steroids, and (2)  the results implied that throat only limited information about early changes in
samples can be helpful in understanding the micro- the microbiome of patients with cystic fibrosis.
biota of the lower airway. As repeated bronchos- The best study included just seven infants, who
copy is never possible in children, whereas were studied over a 2-year period. Their intestinal
collection of repeated throat samples is possible, it and respiratory microbiota were investigated
will be an immense advance if this is confirmed. using fecal and oropharyngeal samples, respec-
These results are challenging, and it is interest- tively. Veillonella and Streptococcus were the
ing to speculate that asthma is an infectious dis- main species found and, in general, the trajecto-
ease or at least has a major contributing component ries of the microbiome in the intestine and respi-
of airway infection. Will we treat asthma with anti- ratory tract were comparable. Breastfeeding and
biotics someday? Before ruling out this idea as too the intestinal microbiome affected the respiratory
absurd, we should remember that we treat duode- tract. Diversity increased over time in the respira-
nal ulcers with antibiotics directed at Helicobacter tory and gastrointestinal tracts. Diversity in the
pylori. We should also remember that the first gastrointestinal tract was greater with breastfeed-
reports of findings of spirochetes in the duodenal ing than with formula feeding, while diversity in
mucosa were received with sarcasm. the respiratory tract increased more with formula
feeding. Finally, a solid food diet increased diver-
sity in the respiratory tract, whereas it had the
The Microbiome and Cystic Fibrosis opposite effect in the gastrointestinal tract.
Where do these complex data leave us in clinical
Life used to be simple. The pathogens involved in terms? It would be easy to reach therapeutic paraly-
cystic fibrosis were S.  aureus, H.  influenzae, sis as a result of this great mass of highly indigest-
P.  aeruginosa, Burkholderia cepacia, and occa- ible and undigested data. This new paradigm means
sionally Gram-negative bacteria. Recent studies that antibiotics can be beneficial, harmful, or neu-
have challenged this view. Conventional cultur- tral. John LiPuma has argued convincingly that
ing shows that there are large numbers and a high while we attempt to figure out the implications of
degree of diversity of obligate and facultative these new findings, we should not lose sight of strat-
anaerobes in cystic fibrosis sputum. Molecular egies that have clearly been beneficial in the past.
techniques have shown that there is a true fauna Current antibiotic policies should continue being
of bacteria in the cystic fibrosis airway, as well as implemented, and if the patient does not respond
a diversity of fungi and viruses. It is increasingly well, new molecular technologies can be applied to
clear that the relationships in this diverse com- try to detect microorganisms can be applied to try to
munity are complex. A microorganism can inhibit detect microorganisms not detected and not covered
the growth of a pathogen. Just because a microor- by current treatment. However, it should also be
ganism is present does not mean that it is doing kept in mind that we do not currently have a base of
harm; the opposite could be true. evidence to interpret the information we receive
A longitudinal study of adult patients with cys- from these new technologies.
tic fibrosis found that bacterial communities were
stable over time but, surprisingly, individuals with
similar clinical evolutions had very different com- I s Clinical Pediatric Pneumology
munities. The perturbations in the community in Dead?
response to administration of antibiotics was evi-
dent but transitory. Multiple courses of antibiotics Enormous scientific advances have been made
and a low level of pulmonary functioning were since the last edition of this book; does the
associated with less diversity. However, it could increasing sophistication of laboratory tech-
70 A. Bush and L. E. Vega-Briceño

niques therefore mean that we no longer need our Exposure to environmental microorganisms and child-
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in the range of normality and the manifestations ological, functional and structural markers of cystic
of disease are even more necessary. For example, fibrosis lung disease with treatment of a pulmonary
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Working Group. Guidelines on the early management 2012;67:289–95.
of infants diagnosed with cystic fibrosis following Vson Linstow ML, Schonning K, Hoegh AM, Sevelsted
newborn screening. J Cyst Fibros. 2010;9:323–9. A, Vissing NH, Bisgaard H. Neonatal airway coloniza-
Stressmann FA, Rogers GB, van der Gast CJ, et al. Long-­ tion is associated with troublesome lung symptoms in
term cultivation-independent microbial diversity anal- infants. Am J Respir Crit Care Med. 2013;188:1041–2.
ysis demonstrates that bacterial communities infecting Ware SM, Gubay-Aygun M, Hildebrandt F. Spectrum of
the adult cystic fibrosis lung show stability and resil- clinical diseases caused by disorders of primary cilia.
ience. Thorax. 2012;67:867–73. Proc Am Thorac Soc. 2011;8:444–502.
Thia LP, Calder A, Stocks J, Bush A et al., on behalf of
the London Cystic Fibrosis Collaboration (LCFC).
 Evaluation of Pulmonary Function
in Infants and Preschool Children
8
Alejandro Teper, Carlos Kofman,
and Alejandro Colom

Contents
Pulmonary Function in Infants.....................................................................................  73
Measurement Conditions...............................................................................................  74
Methods...........................................................................................................................  74
 easurement of Forced Expiratory Flow.........................................................................  74
M
Analysis of Breathing at Current Volume.........................................................................  76
Measurement of Respiratory Mechanics..........................................................................  77
Measurement of Lung Volume.........................................................................................  78
Lung Clearance Index.......................................................................................................  79
Study of the Diffusing Capacity of the Lung for Carbon Monoxide................................  79
Fraction of Exhaled Nitric Oxide.....................................................................................  80
 ulmonary Function in Preschool Children.................................................................  80
P
Spirometry........................................................................................................................  80
Forced Oscillation Technique...........................................................................................  81
Interrupter Resistance Technique.....................................................................................  81
Hyperactivity Studies in Preschool Children....................................................................  82

Sources.............................................................................................................................  82

Pulmonary Function in Infants first years of life was limited until the develop-
ment of sophisticated equipment to measure
The respiratory system undergoes extraordinary respiratory function that was adapted for use with
changes in the first 2 years of life, in terms of its small children. Since then, it has been possible to
growth and functional development. Knowledge understand the inherent aspects of normal respi-
of the mechanical properties of the lungs in the ratory function, as well as the effects of diverse
pre- and postnatal injuries, besides treatments. It
A. Teper has been possible to determine physiopathologi-
Faculty of Medicine, Universidad de Buenos Aires cal mechanisms, therapeutic mechanisms, and
and Department of Pediatric Pulmonology, Hospital certain prognostics in children with distinct
Ricardo Gutiérrez, Buenos Aires, Argentina pathologies.
C. Kofman · A. Colom (*) Although there are centers around the world
Department of Pediatric Pulmonology, Hospital that study pulmonary function, the application of
Ricardo Gutiérrez, Buenos Aires, Argentina

© Springer Nature Switzerland AG 2020 73

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_8
74 A. Teper et al.

Table 8.1  Indications to perform functional respiratory Methods

studies in small children
Cystic fibrosis  easurement of Forced Expiratory
M
Neonatal chronic lung disease
Flow
Postinfectious bronchiolitis obliterans
Recurrent bronchial obstruction that does not respond
to the usual treatments Understandably, small children cannot perform
Central airway obstruction maximum forced exhalations based on their total
Epidemiological and research studies lung capacity for evaluation of the caliber of the
peripheral airways. Different methods are used to
prompt infants and small children to exhale forc-
the results to medical care has not been ibly. Deflation techniques, rapid thoracic com-
­generalized for various reasons: (1) some of the pression at the tidal volume (RC-RTC), and rapid
physiological principles on which the methods thoracoabdominal compression: RTC with prein-
are based are still not sufficiently understood; sufflation are used to determine the magnitude of
(2) the instruments for measurement are complex bronchial obstruction and variations in obstruc-
and costly; (3)  the procedures are lengthy and tion after administration of a bronchodilator or a
require sedation of the patient; and (4) there is no bronchoconstrictor agent.
standardized form of these methods. However, in The deflation technique was the first to be
certain clinical situations it is appropriate to mea- developed, but it is no longer used, because it
sure pulmonary function in the first years of life requires heavy sedation and intubation of the
(Table 8.1). patient. Consequently, in this chapter, we discuss
the other two methods.

Measurement Conditions Rapid Thoracoabdominal Compression

Technique at Current Volume
Infants who are to be assessed through a func- Adler et  al. (1978) and Taussig et  al. (1982)
tional respiratory study should fast for the previ- described the rapid thoracoabdominal compres-
ous 4 hours and be examined to rule out certain sion technique for determining the bronchial cali-
conditions in which the procedure is not advised, ber in infants. It has been used to describe the
such as fever or the presence of secretions in the normal growth and development of the airways in
upper airway. The patient’s height and weight infancy, on the basis of which equations have
should be measured and the results should be been developed to establish the magnitude of
compared with theoretical values. Prior to the bronchial obstruction, using a standard deviation
procedure, 50–75  mg/kg of chloral hydrate is score as a function of the sex and size of the sub-
administered orally to induce a relaxed sleep, ject. With this, the observed alterations in the
which in most cases lasts for 90–120 minutes. It functional response to the treatments applied in
is considered high-risk to administer this medica- the respiratory clinic can be identified and
tion to patients with severe upper airway obstruc- evaluated.
tion or those with some degree of hepatic, renal, The technique employs an inflatable vest
or cardiac insufficiency. inside another inextensible vest around the
The patient should be in a supine position child’s chest and stomach, which goes from the
during the study, with his or her head held armpits to the pubis, with the child’s arms out-
straight in hyperextension. Small movements side both jackets. A reserve air tank connected to
and flexing of the neck can alter the results and the inflatable jacket transmits air at the end of the
thus should be avoided. Arterial oxygen satura- inhalation, with sufficient pressure to produce
tion and the heart rate are monitored continu- rapid thoracoabdominal compression (Fig. 8.1).
ously with an oximeter. Expiratory flows are registered during forced
8  Evaluation of Pulmonary Function in Infants and Preschool Children 75

Analizer

Pneumotachograph

Inflatable
vest Air pressure
reservoir

Fig. 8.1  Equipment used for rapid thoracoabdominal compression at tidal volume (calculation of the maximum flow
at the functional residual capacity (VmaxFRC))

Flow PEF
(mL/s)
Expiration

VmáxFRC

Volume (mL)

FRC FRC: Functional residual capacity

PEF: Peak expiratory flow
Inspiration V’max FRC: Maximal expiratory flow
at FRC

Fig. 8.2  Partial forced flow/volume curve

exhalation by a pneumotachograph equipped applying the pressure that yields the highest
with a facial mask, which hermetically covers the VFRC values (Fig. 8.2).
nose and mouth of the patient. The resulting While the highest pressures have no limit in
flow/volume curve is graphed in real time on a relation to airflow in healthy infants, this is not
computer screen. The curve characteristically the case in patients with bronchial obstruction,
presents a rapid rise in the expiratory flow until where much less pressure is required. Abrupt
the peak expiratory flow (PEF) is reached, and falls in airflow are attributed to glottic or pharyn-
then it gradually descends to a point below the geal closure, and they can be corrected according
one established as the functional residual capac- to the correct location in the neck. At least three
ity (FRC). The flow obtained at this point is acceptable and reproducible curves are obtained
termed VFRC. To determine the limitation in air- with maximum FRC values that do not vary by
flow, the maneuver is progressively repeated more than 10%, and VmaxFRC is the average of
with more pressure on the jacket, ranging the three values. The curves obtained with this
between +20 and +100 cm of water. The maxi- method are “partial,” given that they are based
mum flow at the FRC (VmaxFRC), which corre- not on the total pulmonary capacity but, rather, on
lates with the airway caliber, is determined by the end of the inspiration at the current volume.
76 A. Teper et al.

Fig. 8.3 Rapid Pressure release

thoracoabdominal valve
compression with
previous insufflation

Airflow Insp.
Exp.

Pneumotachometer

Pressure
tank
Vest

Rapid Thoracoabdominal Compression also disparate criteria in the ventilation pattern

Technique at a Volume with Previous before the forced expiration. The pulmonary
Insufflation insufflation rate depends on the lung volume and
A modification of the technique described above flow magnitude, while the volume reached for a
has recently been developed to obtain, in a nonin- standard pressure is directly proportional to the
vasive way, better forced expiratory curves. The infant’s level of respiratory compliance. Most
equipment used is similar to that used for the authors suggest 2–5 successive insufflations until
other technique, with the addition of an insuffla- pressure and volume plateaus are reached.
tion system to take the patient close to his or her The most relevant functional parameters are
total pulmonary capacity immediately before the obtained on the basis of the “maximum” forced
thoracoabdominal compression (Fig. 8.3). curve of volume/time and flow/volume
The insufflation system consists of an external (Fig.  8.4)—namely, the forced vital capacity
source of air, valves to automatically occlude the (FVC), forced expiratory volume (FEV) in
airway or a Y connector for manual insufflation, 0.5 seconds (FEV0.5), and forced expiratory flow
and a safety valve to control the insufflation pres- at 25–75% of FVC (FEF25–75). Other parameters
sure. The jacket reaches maximum pressure in that can be considered are the expiratory flows at
70–100 milliseconds. Given that there is a small 50%, 75%, and 85% of FVC, and FEV0.4 in small
delay between insufflation and compression, it is children. The parameters that are reported are
a common practice to activate the compression those that are obtained on the basis of the “best
10–100 milliseconds before releasing the occlu- curve,” and at least two values that do not differ
sion of the airway. One of the main discrepancies by more than 10% should be used, with the better
among users has been the application of different value reported. Similarly, the results refer to the-
insufflation pressures to reach higher volumes. oretical values.
However, there is a consensus in the application
of 30 cm of water pressure for older infants and
20 cm of water pressure for newborns and prema-  nalysis of Breathing at Current
A
ture babies. The inspiratory flow is established at Volume
1.5 times the current flow. The real pressure at the
level of the mouth is monitored in real time so Analysis of the curves obtained during current
that the operator can adjust the flows and opti- breathing is useful for functional respiratory
mize the pressure being administered. There are assessment of infants, given that they yield
8  Evaluation of Pulmonary Function in Infants and Preschool Children 77

Fig. 8.4 Maximum Flow (mL/s)

forced flow/volume 900
(F-V) loop obtained by
rapid thoracoabdominal Maximal forced
compression with expiration
previous insufflation

600

300

Passive
expiration

300
200 150 100 50 0 -50
Volume (mL)

greater variability and lower levels of specific- Some epidemiological studies have consid-
ity. However, there are different parameters that ered these measurements because of their techni-
can be obtained from observing the flow curves/ cal simplicity in comparison with other methods.
tidal volumes that allow for establishment
of  obstructive and low-compliance patterns
(Fig. 8.5). Measurement of Respiratory
Simply by the airtight mask being placed on Mechanics
the patient’s face and attached to the pneumo-
tachograph, the flow and volume signals are inte- Respiratory mechanics can be assessed by
grated to determine: dynamic or passive methods. The respiratory
cycle is not interrupted during measurements
(a) Parameters that are altered in pulmonary done with dynamic methods, whereas it is inter-
elastic retraction disorders: the rate between rupted with use of passive methods. Body pleth-
the peak expiratory flow and current volume ysmography and pressure/volume curves are
(PEF/Vc) dynamic methods. The main advantages of these
(b) Parameters that vary with obstructive pathol- methods are their greater sensitivity and specific-
ogies: the percentages of volume and time to ity. Pressure/volume curves are particularly useful
reach PEF to optimize mechanical respiratory assistance in
78 A. Teper et al.

Bronchial VA Extrathoracic
NORMAL
Obstruction Obstruction

Volume Volume Volume

Flow

Flow

Flow
VA Intrathoracic VA Fixed Low Compliance
Obstruction Obstruction Restriction

Volume Volume Volume

Flow

Flow

Flow
Fig. 8.5  Flow/volume loop patterns

ventilated patients. However, dynamic methods FRC is increased when air is trapped (obstructive
are not widely used, because they require sophis- pathologies), and it is lower in patients with
ticated personnel and intubation of the patient. restrictive pathologies. Consequently, determin-
Passive methods include single- and multiple-­ ing the FRC allows us to differentiate these pro-
occlusion techniques, which assess changes in cesses functionally. It also provides an objective
flow or volume in relation to changes in pressure parameter for following lung growth and devel-
at the level of the mouth during periods of relax- opment, although it does not provide information
ation of the respiratory muscles, triggered by the about the number or size of the alveoli.
Hering–Breuer reflex in the occlusion of the air- The FRC can be quantified by two methods,
way at the end of the inspiration. The time con- which are discussed in the following sections.
stant of the respiratory system is thus determined
on the basis of the slope of the flow/volume Body Plethysmography
curve. The compliance and resistance of the The principle of this technique is the same as that
respiratory system are then calculated. Passive of plethysmography in older children and adults.
methods are simple, rapid, and noninvasive, The child is placed in a supine position in a her-
although they assess the entire respiratory system metic box (plethysmograph) while breathing
and not just the lungs. through a facial mask connected to a pneumo-
tachograph. At the end of an inspiration current,
the circuit is closed for 6–10 seconds, making the
Measurement of Lung Volume child breathe against the closed system. As the
pressure in the lung decreases and its volume
FRC is defined as the volume of gas that remains increases, the opposite occurs in the plethysmo-
in the lungs after a passive exhalation. It is the graph. The FRC is determined by applying
result of the balance between the force of elastic Boyle’s law (the product of pressure (P) and vol-
lung retraction and the expansive capacity of the ume (V) are always constant in a closed system at
rib cage. It is also the easiest method for obtain- a constant temperature: P  ×  V  =  P’  x  V’). This
ing precise and reproducible lung volume values technique measures all of the gas in the thoracic
when the patient is incapable of cooperating. The cavity, which is the areas that communicate with
8  Evaluation of Pulmonary Function in Infants and Preschool Children 79

the airway and the areas that do not. As we saw cates obstruction of the small airways. This
before, the plethysmograph can also determine reflects a nonhomogeneous ventilator pattern,
the airway resistance. which slows the N2 (or marker gas) lavage at
those zones with air trapping. This index is calcu-
Multiple-Breath Washout lated by dividing the volume of exhaled volume
The multiple-breath washout (MBW) method is (until the marker gas has been washed out and
based on dilution of a marker gas to a known con- reaches a concentration of one fortieth of its ini-
centration in an unknown volume (the FRC) over tial concentration) by the FRC. A clearance index
multiple current breaths. This can be done in two under 7.8 is considered normal regardless of the
ways: patient’s sex, age, height, and weight. Its mea-
surement is simple and noninvasive, and it has
• MBW using gases that are not involved in the low variability and good reproducibility. The
gas exchange and are not absorbed into the measurements are done three times, the FRC is
blood flow or secreted by the tissues (helium noted, and the average lung clearance index of
or sulfur hexafluoride): The patient inhales a the three maneuvers is calculated. Because this
gas mixture with the gas marker until it method gives information about the peripheral
reaches an equilibrium concentration (the airway (also called the “silent zones”), its clinical
same concentration for inhaling and exhal- utility has been studied more extensively in
ing). From this moment on, the patient begins patients with cystic fibrosis. It has been shown
to breathe environmental air (the washout that this parameter is altered before the appear-
principal phase) and the gas marker is lowered ance of symptoms, making it possible to explore
until it reaches a concentration lower than different therapeutic choices at an early stage. In
2.5% of its initial concentration. the same way, the studies conducted in these
• Nitrogen MBW: The patient washes out the N2 patients have shown good correlation with the
in his or her lungs by inhaling 100% O2 in changes in high-resolution computerized tomog-
multiple breaths. raphy. Its usefulness in asthma and in chronic
newborn lung diseases has been discussed, and it
The child should be asleep (not necessarily is still under investigation.
sedated) in order to obtain a stable breathing pat-
tern. An airtight facial mask is placed on the
child’s face, covering the mouth and nose. The  tudy of the Diffusing Capacity
S
mask is connected to the pneumotachograph and of the Lung for Carbon Monoxide
a mass spectrometer (or an ultrasonic transducer),
which quantifies the concentration of the gases. Castillo et  al. (2006) described determination of
The FRC is reported in millimeters as the average the diffusing capacity of the lung for carbon mon-
of three technically acceptable maneuvers with oxide (DLCO), using the single-breath technique
values that do not differ by more than 10%. There adapted for infants and small children. The test
are different reference values for gas dilution consists of placing the child (after sedation) in a
methods using N2 or He, as well as for the pleth- supine position, breathing through a mask con-
ysmography method. nected to a pneumotachograph and a mass spec-
trometer. As in the rapid thoracoabdominal
compression technique at high volumes, the air-
Lung Clearance Index way is insufflated at 20 cm of water pressure with
a gaseous mixture (0.3% CO, 5% He, 21% O2,
The Lung Clearance Index (LCI) can be deter- and the rest N2). The lungs remain insufflated for
mined with the gas dilution technique, which 6  seconds to diffuse the carbon, after which the
evaluates the distribution or degree of homogene- child can exhale passively. The measurement prin-
ity of pulmonary ventilation. A high index indi- ciple is similar to that used to determine carbon
80 A. Teper et al.

monoxide diffusion in adults. The alveolar vol- bronchoalveolar lavage, and bronchial biopsy
ume (AV) is determined by the gas dilution tech- materials. Atopic and asthmatic adults and chil-
nique using He as the marker gas, and the diffusion dren present high levels, which drop after
capacity of the alveolar–capillary m ­ embrane is ­anti-­inflammatory treatment. Technically, deter-
determined by measuring the concentration of mination of the fractional exhaled nitric oxide is
exhaled carbon. The measurements are done three done using a chemiluminescent analyzer. In
times and the AV and CO diffusion are noted. The infants it can be performed through the “current
value considered is the average of three techni- breathing technique” and the measurement can
cally acceptable measurements with values that be done online (in real time) or offline (when the
do not differ from each other by more than 10%. air is kept in a hermetic bag and is measured
Because anemia or polycythemia alter CO diffu- afterward). When the child is asleep (it can also
sion values, Hb must be determined beforehand in be done during spontaneous sleep), the values for
order to correct for altered carbon monoxide dif- 1 minute are registered while the child breathes at
fusion. With this method, the physiological shape his or her current breathing volume through a
of the surface that is available for gas exchange facial mask connected to a pneumotachograph
can be evaluated; therefore, alveolar growth and and the fractional exhaled nitric oxide analyzer. It
development can be studied without use of anato- is reported as the average result of three techni-
mopathological studies. Studies conducted in pre- cally accepted maneuvers with results that do not
mature babies have shown a change in normal differ from each other by more than 10%. For this
alveolar development. These children present an technique, the normal values considered are
AV that is similar to that seen in term children, but between 2 and 8 particles per billion (ppb).
they have a smaller area for gas exchange because
the alveoli are larger and fewer in number. This
technique may be useful in extremely premature  ulmonary Function in Preschool
P
patients to evaluate alveolar growth and develop- Children
ment, as well as responses to different treatments.
Besides this, the technique may be used to valuate Spirometry
children with lung hypoplasia, for follow-up of
children treated with lung resections early in life, Children aged 2–5 years present particular chal-
or in patients with necrotized parenchymal areas. lenges for conducting pulmonary function tests,
Finally, this technique provides an objective including lack of attention and cooperation,
parameter to establish a diagnosis and follow-up besides fear of the equipment that is used.
of interstitial diseases during the first years of life. A variable to consider is the fact that pre-
However, commercial equipment to measure car- school children exhale lung volumes faster than
bon monoxide diffusion in infants has not been adults; therefore, evaluations of FEV0.4, FEV0.5,
developed yet, and its use is currently restricted to and FEV0.75 are more important. Besides this,
research practices. because of the smaller volumes that these sub-
jects move, the equipment should include mini-
mum dead space.
Fraction of Exhaled Nitric Oxide In the past, it was thought that children were
incapable of acceptably carrying out the FVC
Measurement of the fraction of exhaled nitric maneuver and achieving maximum inspiration
oxide (FeNO) has recently emerged as a tool for and expiration, because of lack of attention and
evaluating, managing, and diagnosing asthma. Its concentration, besides low tolerance of frustra-
determination is simple and it gives information tion. This is why spirometry reference tables
about eosinophilic inflammation in the airway such as the Polgar and Knudson tables do not
noninvasively. High nitric oxide levels are related include measurements for children under 110 cm
to the increase of eosinophils in induced sputum, in height or under 6 years of age. Consequently,
8  Evaluation of Pulmonary Function in Infants and Preschool Children 81

the reference values for small children have been procedure is readily accessible and easy to use,
extrapolated from those for older children. and it requires a minimum of cooperation on the
However, the first spirometry studies of part of the patient. The child puts on the mouth-
healthy 3- to 6-year-old children have been pub- piece and the nasal clip, and breathes at his or her
lished in recent years. The measurement of pul- current volume for 17 seconds while holding his
monary function takes into account the or her cheeks with both hands. The equipment
recommendations that (1) this should be done by creates a pulsating airflow at different oscillation
an experienced technician, and (2) time should be frequencies, which may be measured in one
taken prior to the procedure to explain what it maneuver, or each frequency can be studied in an
involves and to demonstrate the maneuver. individual maneuver. In this way, the resistance is
There is no consensus about the benefits of measured and then calculated using a mathemati-
using a nasal clip in open-circuit spirometry. It cal model of compliance. This technique mea-
can depend on the experience of the technician sures the resistance of the entire respiratory
who conducts the study, and its use can be system and provides information to ascertain if
decided for each individual patient to obtain the the resistance is increased in the central or periph-
best FVC reading. The maneuvers are repeated eral airway. The bronchodilator response can be
until three acceptable curves have been obtained. evaluated; if the resistance measured at 5 Hz falls
The study should be brief, lasting no more than by at least 30% of the basal value, the bronchodi-
15 minutes. Different interactive programs can be lator response is considered positive. The limita-
used with games on the spirometry screen to tion of the forced oscillation technique is the
facilitate acquisition of adequate curves. If the difficulty in distinguishing between an obstructive
patient cries during the study, there should be no pattern and a restrictive pattern. The main advan-
further attempt, and the test should instead be tage of the technique is that it requires a minimum
done at another opportunity. of cooperation from the patient; therefore, it can
The maneuvers that are considered unaccept- be used in patients while they sleep, with patients
able are the ones in which: under mechanical ventilatory assistance, and also
in children who are too young for acquisition of
• The maximum flow cannot be clearly an acceptable result using the forced capacity
identified. maneuver. In the same way, it is a valid method to
• The expiratory effort stops abruptly at a point study patients with a collapsed airway, as can hap-
where it is less than 25% of the maximum flow. pen in cystic fibrosis or emphysema. In these
• The expiratory flow lasts for less than 1 second. cases, it is the ideal method to assess the broncho-
• The child’s inspiration is not greater than his dilator response. In 2004, the European
or her current volume. Respiratory Society published a standardization
• There is a high degree of variability. of the methodology, with recommendations for its
clinical use, and stated that the diagnostic capac-
With these criteria, acceptable spirometry results ity of the method is equal to that of spirometry in
are obtained in more than 80% of studied 3- to patients with obstructive disorders.
6-year-old children, including both healthy children
and those affected by different pathologies.
Interrupter Resistance Technique

Forced Oscillation Technique The interrupter resistance (Rint) technique allows

noninvasive measurement of the resistance of the
Advances have been made in the clinical study of respiratory system while being normally breath-
pulmonary function using the forced oscillation ing. Its main advantages are its simplicity, the
technique (FOT), as described by Arthur DuBois need for minimal patient cooperation, and the fact
in 1956. The necessary equipment to conduct this that it requires only a small portable apparatus.
82 A. Teper et al.

Among its principles are concepts that were Adler SM, Wohl MEB 1978 Flow-volume relationships
at low lung volumes in healthy newborn infants.
first described in 1927, when it was proposed to Pediatrics 61:636–40.
estimate alveolar pressure by rapid occlusion of Aurora P, Gustafsson P, Bush A, Lindblad A, et  al.
the airway during the respiratory cycle at rest, Multiple breath inert gas washout as a measure of
supposing that alveolar pressure will be equal to ventilation distribution in children with cystic fibrosis.
Thorax. 2004;59(12):1068–73.
the pressure in the mouth. Balinotti J, Chakr V, Tiller C, Kimmel R, et al. Growth of
The respiratory cycle is interrupted briefly (for lung parenchyma in infants and toddlers with chronic
<100  milliseconds) in the occlusion technique. lung disease of infancy. Am J Respir Crit Care Med.
The resistance (Rint) and pressure/flow rate are 2010;181(10):1093–7.
Balinotti JE, Tiller CJ, Llapur CJ, Jones MH, et al. Growth
calculated from how the pressure rate changes in of the lung parenchyma early in life. Am J Respir Crit
comparison with the flow evaluated in the respi- Care Med. 2009;179(2):134–7.
ratory airway before or after the occlusion Castillo A, Llapur CJ, Martinez T, Kisling J, et  al.
(depending on the technique). While occlusion Measurement of single breath–hold carbon monox-
ide diffusing capacity in healthy infants and toddlers.
can be done during inspiration or expiration, both Pediatr Pulmonol. 2006;41(6):544–50.
the American Thoracic Society and the European Delacourt C, Lorino H, Fuhrman C, Herve-Guillot M,
Respiratory Society recommend measurement Reinert P, Harf A, Housset B.  Comparison of the
during expiration. forced oscillation technique and the interrupter
technique for assessing airway obstruction and its
Both entities have standardized norms to mea- reversibility in children. Am J Respir Crit Care Med.
sure the mechanical properties of the respiratory 2001;164(6):965–72.
system through occlusion techniques. Dubois AB, Botelho SY, Comroe JH Jr. A new method
for measuring airway resistance in man using a body
plethysmograph: values in normal subjects and in
patients with respiratory disease. J Clin Invest. 1956
 yperactivity Studies in Preschool
H Mar;35(3):327–335.
Children Dubois AB, Brody AW, Lewis DH, Burgess BF Jr.
Oscillation mechanics of lungs and chest in man. J
Appl Physiol. 1956 May;8(6):587–594.
Forced oscillation and multiple occlusion are Hellinckx J, Cauberghs M, De Boeck K, Demedts
alternatives to spirometry to assess bronchial M. Evaluation of impulse oscillation system: compari-
hyperactivity in preschool children. The two son with forced oscillation technique and body pleth-
techniques used with uncooperative children— ysmography. Eur Respir J. 2001;18(3):564–70.
Hoo AF, Dezateux C, Hanrahan JP, Cole TJ, Tepper
the transcutaneous oxygen pressure measure- RS, Stocks J.  Sex-specific prediction equations
ment and the tracheal auscultation method–merit for VmaxFRC in infancy: a multicenter col-
certain attention. In this last test, the parameter to laborative study. Am J Respir Crit Care Med.
be determined is called PCwheeze, and it is 2002;165:1084–92.
Horsley AR, Gustafsson PM, Macleod KA, Saunders C,
defined as the concentration of bronchoconstric- et  al. Lung clearance index is a sensitive, repeatable
tor substance with which wheezing is heard in the and practical measure of airways disease in adults with
trachea and lung fields. With the transcutaneous cystic fibrosis. Thorax. 2008;63:135–40.
oxygen measurement method, the value in ques- Jones MH, Castile R, Davis S, Kisling J, et  al. Forced
expiratory flows and volumes in infants: normative
tion is the concentration of methacholine that data and lung growth. Am J Respir Crit Care Med.
causes a 5% fall from the baseline value or an 2000;161:353–9.
increase of 50% in the baseline heart frequency. Morgan WJ, Geller DE, Tepper RS, et al. Partial expira-
tory flow–volume curves in infants and young chil-
dren. Pediatr Pulmonol. 1988;5:232–43.
Nystad W, Samuelsen S, Nafstad P, Edvardsen E, Stensrud
Sources T, Jaakkola J. Feasibility of measuring lung function
in preschool children. Thorax. 2002;57:1021–7.
Stam H, Van den Beek A, Grunberg K, Stijnen T, et  al.
American Thoracic Society, European Respiratory
Pulmonary diffusing capacity at reduced alveolar vol-
Society. ATS/ERS statement: raised volume forced
umes in children. Pediatr Pulmonol. 1996;21:84–9.
expirations in infants guidelines for current practice.
Am J Respir Crit Care Med. 2005;172:1463–71.
8  Evaluation of Pulmonary Function in Infants and Preschool Children 83

Taussig LM, Landau LI, Godfrey S, Arad I. Determinants Tepper RS, Morgan WJ, Cota K, et al. Physiologic growth
of forced expiratory flows in newborn infants. J Appl and development of the lung during the first year of
Physiol. 1982;53:1220–7. life. Am Rev Respir Dis. 1986b;134:513–9.
Tepper RS, Morgan WJ, Cota K, et  al. Expiratory flow Tepper RS, Reister T.  Forced expiratory flows and
limitation in infants with bronchopulmonary dyspla- lung volumes in normal infants. Pediatr Pulmonol.
sia. J Pediatr. 1986a;109:1040–6. 1993;15:357–61.
 Assessment of Pulmonary
Function in Schoolchildren
9
and Adolescents

Marcela Linares Paserini
and Solange Caussade Larraín

Contents
Introduction....................................................................................................................  85
Spirometry and the Flow/Volume Curve......................................................................  86
Peak Expiratory Flow....................................................................................................  89
Bronchial Provocation Tests..........................................................................................  89
Provocation Test with Exercise......................................................................................  90
Methacholine-Induced Bronchial Test..........................................................................  90
Static Lung Volume Measurement................................................................................  91
Plethysmography............................................................................................................  91
Helium Dilution..............................................................................................................  92
Nitrogen Wash.................................................................................................................  93
Lung Carbon Monoxide Diffusion................................................................................  93
Airway Resistance..........................................................................................................  94
Exhaled Nitric Oxide Measurement.............................................................................  95
Evaluation of Respiratory Muscle Strength.................................................................  95
Sources.............................................................................................................................  95

Introduction

Assessment of pulmonary function is impor-

M. Linares Paserini
Department of Pediatrics, Clínica Indisa, tant in schoolchildren and adolescents with
Santiago, Chile chronic or recurrent lung disease, especially in
e-mail: [email protected] those with progressive lung damage. Several
S. Caussade Larraín (*) tests may aid understanding of lung function in
Department of Pediatrics, School of Medicine, this age group (Table  9.1). To obtain valid
Pontificia Universidad Católica de Chile, results, it is important to apply strict quality
Santiago, Chile

© Springer Nature Switzerland AG 2020 85

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_9
86 M. Linares Paserini and S. Caussade Larrain

Table 9.1  Pulmonary function tests available in pediatrics

Test Measured variables Physiopathological diagnosis
Spirometry and flow/volume Forced flows and volumes: Obstructive ventilatory alteration
loop Expiratory: PEF, FVC, FEV0.5, FEV0.75, (with or without decreased FVC)
FEV1, FEV6, FEV1/FVC, FEF25, Restrictive ventilatory alteration
FEF50, FEF75, FEF25–50 Bronchodilator response
Inspiratory: FIF50, FEF50/FIF50 Fixed central airway obstruction
Variable intra- or extrathoracic
central airway obstruction
Measurement of static lung Volumes and capacities not measurable with Restrictive lung disease
volumes: spirometry: FRC, RV, TLC Air trapping
Plethysmography Hyperinflation
 Nitrogen washout
 Helium dilution
Bronchial challenge test PC20 Presence and degree of bronchial
Direct: methacholine,  or hyperreactivity
histamine Increased airway resistance
Indirect: exercise, mannitol,
adenosine
Airway resistance Specific resistance and airway conductance Increase in airway resistance
Plethysmography Airway resistance Increase or decrease in compliance
Rint Fres, Rrs5, Rrs20, Xrs5, Zrs, reactance area (IOS)
IOS Bronchodilator response
Bronchial hyperreactivity
Diffusing capacity of the lung DLCO Alteration of the diffusing capacity
for carbon monoxide of the alveolar–capillary membrane
Measurement of static MIP Strength of inspiratory muscles
pressures MEP Strength of expiratory muscles
Sniff nasal test Ability to mobilize secretions
Cough PEF
Maximal voluntary ventilation Maximum amount of air inhaled and exhaled Thoracopulmonary capacity
within 1 minute Resistance to fatigue, airway
resistance, respiratory drive
6-Minute walk test Distance traveled Functional capacity to exercise
Cardiac capacity, respiratory
capacity, muscular function capacity
CO carbon monoxide, DLCO diffusing capacity of the lung for carbon monoxide, FEF25, FEF50, FEF75 forced expira-
tory flow at 25%, 50%, or 75% of FVC, FEF25–75 forced expiratory flow at 25–75% of FVC, FEV0.5, FEV0.75, FEV1,
FEV6 forced expiratory volume in 0.5, 0.75, 1, or 6 seconds, FIF50 forced inspiratory flow at 50% of forced inspiratory
capacity (FVC), FRC functional residual capacity, Fres resonance frequency, FVC forced vital capacity, IOS impulse
oscillometry, MEP maximum expiratory pressure, MIP maximum inspiratory pressure, PC20 methacholine or histamine
concentration that causes a 20% drop in FEV1, PEF peak expiratory flow, Rint interrupter resistance, Rrs5 resistance at
5 Hz, Rrs20 resistance at 20 Hz, RV residual volume, TLC total lung capacity, Xrs5 reactance at 5 Hz, Zrs respiratory
impedance

control measures and i­nterpret the results on tests, managing emergency situations, and pro-
the basis of internationally accepted standards. viding reports.
Better results are obtained if tests are con-
ducted in an appropriate environment, without
interference or distraction, and by personnel Spirometry and the Flow/Volume
experienced in working with children. In some Curve
cases, training and use of incentive programs
help to improve the performance. The respira- Spirometry measures lung volume and flow on
tory laboratory should have a qualified doctor the basis of forced expiration following maxi-
available who is responsible for supervising mum inspiration to reach the total lung capacity
9  Assessment of Pulmonary Function in Schoolchildren and Adolescents 87

Table 9.2  Definitions of lung volumes, flows, and capacities

Tidal volume (TV): volume of inspired and expired air during normal breathing
Inspiratory reserve volume (IRV): volume of air that enters the lungs when a deep inspiration is performed, above
TV
Expiratory reserve volume (ERV): volume of air exhaled during a deep expiration after a normal expiration
Residual volume (RV): volume of air remaining in the lungs after a maximum expiration
Vital capacity (VC): sum of the maximum expired volume after a maximal inspiration
  SVC: slow vital capacity
  FVC: forced vital capacity
Inspiratory capacity (IC): maximum amount of air that can be inspired after normal expiration
Functional residual capacity (FRC): volume of air that remains in the lungs after normal expiration
Total lung capacity (TLC): maximum volume of air that the lungs can contain
RV/TLC ratio: percentage of RV in relation to TLC
Forced expiratory volume in a given time (FEVt): volume of air expired during the FVC maneuver from TLC in a
given time (e.g., 0.5, 0.75, 1, or 6 seconds)
FEV1/FVC ratio: percentage of exhaled volume in 1 second in relation to FVC
Forced expiratory flow at 25–75% of FVC (FEF25–75): slope of the spirometric volume/time curve between 25% and
75% of FVC
Forced expiratory flow at 25%, 50%, or 75% of FVC (FEF25, FEF50, FEF75): forced expiratory flow when 25%,
50%, or 75% of FVC has been exhaled
Forced inspiratory flow at 50% of forced vital capacity (FVC) (FIF50): forced inspiratory flow measured at the 50%
point of the inspiratory part of the flow/volume curve
Peak expiratory flow (PEF): maximum flow velocity observed during the forced expiratory maneuver

(TLC). Table  9.2 lists lung volumes, flows, and of the examination. The volume/time curve
capacities. (Fig. 9.1a) relates the volume of exhaled air to the
Spirometry is indicated to diagnose alterations time taken to exhale. It has an initial rapid increase
in lung function in patients with respiratory symp- and then reaches a plateau. The flow/volume curve
toms and signs (pathologies that can directly or (Fig.  9.1b) distinguishes between the inspiratory
indirectly affect lung function) or with exposure to and expiratory phases. The inspiratory phase goes
risk factors such as smoking, environmental con- from the residual volume (RV) to TLC, constitut-
tamination, radiotherapy, chemotherapy, or other ing the lower part of the graph and forming a semi-
drugs with known pulmonary toxicity. Spirometry circle in which it is possible to measure the
is also indicated to assess anesthetic and surgical maximum inspiratory flow at 50% of forced vital
risks and the prognosis of patients with respiratory capacity (FVC): (FIF50). The expiratory phase has
pathologies, to assess the response to different a triangular profile, with a rapid ascent from the
treatments (bronchodilators, inhaled corticoste- total pulmonary capacity to the peak expiratory
roids, kinesiotherapy), and to control the advance flow (PEF), and a slow descent with a constant
of progressive pathologies such as neuromuscular slope until RV is reached. In the first part of the
diseases and cystic fibrosis. expiratory phase, in which pulmonary volume is
The equipment used for spirometry should be high, the flow depends on effort, but after expira-
calibrated daily. tion of the first third of the vital capacity (VC), at
The maneuver is performed with a maximum the level of low pulmonary volumes, the flows are
and rapid inspiration to reach the total pulmonary independent of effort. The shape of the flow/vol-
capacity, followed by a maximum expiratory ume curve indicates the presence of fixed or vari-
effort 3–6 seconds in duration and/or a plateau of able obstruction of the central airway (Fig. 9.2). At
at least 1 second. least three curves that comply with international
The test yields two graphic registers—the vol- criteria for acceptability should be obtained, and at
ume/time curve and the flow/volume curve— least two of these should be repeatable—that is,
which should be analyzed to assess the acceptability with variability of less than 5% in the forced vital
88 M. Linares Paserini and S. Caussade Larrain

a b FEFmax

FEF 25%

Expiration
Volume (I) FEF 50%
FVC

Flow (L/sec)
FEV1 FEF 75%

Volume

Inspiration
FIF 50%

1 2 3 4 5 6
0 50 100
Time (s)

Fig. 9.1  Spirometric curves. a Volume/time curve show- (FEF50), and 75% (FEF75) of the forced vital capacity
ing the forced expiratory volume in 1 second (FEV1) and (FVC), and the forced inspiratory flow (FIF) at 50% of the
in 6  seconds (FEV6). b  Flow/volume loop showing the inspiratory loop. FEFmax  maximum instantaneous flow
forced expiratory flow (FEF) at 25% (FEF25), 50% achieved during a FVC maneuver

Bronchial VA Extrathoracic
NORMAL Obstruction
Obstruction

Volume Volume Volume

Flow
Flow

Flow

VA Intrathoracic VA Fixed Low Compliance

Obstruction Obstruction Restriction

Volume Volume Volume

Flow

Flow

Flow

Fig. 9.2  Alterations in the flow/volume loop: forms of the loop that display pathophysiological changes in the airway
and lungs. Airway: Extrathoracic airway Obstruction; Intrathoracic airway Obstruction; Fixed airway obstruction

capacity (FVC) and forced expiratory volume in aerosol form to assess the response to the
1  second (FEV1). A numerical report should be ­bronchodilator. Any increase of 12% in FEV1
produced for FVC, FEV1, FEV1/FVC, and forced and/or 30% in FEF25–75 is considered a significant
expiratory flow at 25–75% of FVC (FEF25–75). response (provided that the postbronchodilatory
The spirometry test is repeated 15 minutes after FVC does not vary more than 10% from the basal
administration of 400  μg of salbutamol in an value).
9  Assessment of Pulmonary Function in Schoolchildren and Adolescents 89

The reference values that are used should be Peak Expiratory Flow
registered in the report. Those most widely used
at present are Knudson, NHANES III (National The peak expiratory flow (PEF) documents lung
Health and Nutrition Examination Survey  III), function at different moments during the day and
and Gutierrez. The Global Lung Function in the regular environment of the patient. It is
Initiative (GLI) has recently developed reference used to determine bronchial ability, contributing
equations that address an age range from 3  to to the diagnosis and treatment of asthma.
90  years, with differences according to the eth- It can be used for self-control by the asthmatic
nicity of the population. A spirometry reading is patient for short periods—above all, when the
considered normal when the values are above P5 patient and family have a limited perception of
or within ±1.64 standard deviations (Z score) of the symptoms.
the reference values. What is termed the personal best value is rec-
Obstructive and restrictive alterations in venti- ommended for interpretation of the results. This is
lation, with or without a decrease in FVC, can be the maximum value obtained from two readings
distinguished (Table 9.3). per day during an asymptomatic 2-week period.
The degree of severity of obstructive altera- Although the major asthma guides advise the
tions is determined by FEV1, and the severity of use of peak expiratory flow (PEF) for self-­
restrictive alterations is determined by FVC management, no improvement in asthma has
(Table 9.4). been demonstrated in this case, and adherence is
generally low.

Table 9.3  Types of alterations observed in spirometry

Obstructive Bronchial Provocation Tests
With normal With decreased
Parameter Restrictive FVC FVC Bronchial provocation tests induce obstruction of
FVC ↓ Normal ↓
the airway by using different stimuli to determine
FEV1 Normal or Normal or ↓ ↓
↓ the presence and degree of bronchial reactivity.
FEV1/ Normal or ↓ ↓ They are classified as (1) direct techniques, which
FVC ↑ act on the bronchial smooth muscle to provoke
FEF25–75 Normal or Normal or ↓ ↓ bronchoconstriction, using stimuli such as metha-
↓
choline and histamine; and (2)  indirect tech-
↑ increased, ↓ decreased, FEF25–75 forced expiratory flow niques, which cause release of mediators by mast
at 25–75% of FVC, FEV1  forced expiratory volume in
1 second, FVC forced vital capacity cells, in turn triggering contraction of the bron-
chial smooth muscle, using stimuli such as exer-
cise, cold air, adenosine, and mannitol. The most
Table 9.4  Degrees of severity in spirometry commonly used tests employ exercise and
Restrictive alteration Obstructive alteration methacholine.
Mild: 65% < FVC < LLNa Minimum: FEF25–75 < LLNb Increased bronchial reactivity is a distinctive
Moderate: 50% < FVC < Mild: FEV1 > 65%c characteristic of asthma, but reactivity is also
65%
present in other conditions such as atopy, bron-
Advanced: FVC < 50% Moderate: 50% < FEV1 <
65% chopulmonary dysplasia, cystic fibrosis, and
Advanced: FEV1 < 50% exposure to pollen or contamination, because of
FEF25–75  forced expiratory flow at 25–75% of FVC, which the results of the examination should be
FEV1 forced expiratory volume in 1 second, FVC forced considered in the context of the individual patient.
vital capacity, LLN lower limit of normal The provocation test is contraindicated in
a
Percentage of the reference value
patients with a base FEV1 lower than 80% of the
b
Normal FVC, FEV1, and FEV1/FVC
c
The FEV1/FVC ratio must be less than LLN in cases with reference value. The methacholine test is contrain-
a normal FEV1 dicated in pregnant patients, and exercise cannot
90 M. Linares Paserini and S. Caussade Larrain

be used in patients with heart disease (arrhythmia, the last 4–6 minutes of the run. FEV1 is measured
hypertension, or aortic stenosis), physical inca- before the exercise and at 3,  5, 10, 15, and
pacity (neuromuscular disease, orthopedic dis- 30 minutes. The higher of two values is chosen
ease, or severe deformation), fever, chronic for each measurement.
respiratory insufficiency, insulin-­dependent dia- The exercise-induced test is considered posi-
betes, or uncontrolled epilepsy. tive when the maximum observed fall in FEV1 is
When the results of these examinations are ≥10% of the baseline value (FEV1 value at rest
being interpreted, it should be kept in mind that before the test). Inhaled salbutamol is adminis-
there are medications that reduce bronchial hyper- tered to children who have positive responses or
reactivity, such as short- and long-acting broncho- who present symptoms of bronchial obstruction.
dilators. Antihistamines and antileukotrienes have False positive results can be due to vocal cord
the same effect on the exercise test. Inhaled corti- dysfunction, tracheobronchomalacia, use of pro-
coids attenuate the response of the airway when pranolol, or suboptimal forced expiration. False
they are administered for more than 4  weeks. negative results can be due to failure to achieve
When the objective is to assess the degree of con- maximum ventilation, atmospheric conditions
trol over the disease and not to establish a diagno- beyond the specified range, and use of medica-
sis, the examinations can be conducted without tions that attenuate bronchial hyperreactivity.
these medications being stopped.

Methacholine-Induced Bronchial
Provocation Test with Exercise Test

This test measures the response of the airway to This test measures the response of the airway to
exercise with pre-established intensity and char- different concentrations of nebulized methacho-
acteristics. Hyperventilation experienced while line, a cholinergic agonist that binds muscarinic
exercising and breathing cold dry air causes receptors of the smooth muscles of the airways,
dehydration and increases the osmolality of bron- provoking dose-dependent contraction.
chial mucus, which triggers the release by mast The child should be free from acute respiratory
cells of histamine, leukotrienes, and prostaglan- infections for 3–4 weeks prior to the examination,
dins, in turn stimulating contraction of the bron- otherwise a false positive result could be obtained.
chial smooth muscle. An environment with an The most widely used method is a modified
absolute moisture content of less than 10 mg/l of version of the method described by Cockcroft
air is recommended to increase the yield of the et  al., in which the patient is nebulized every
test. The report should include the moisture level 5  minutes, first with the diluent and then with
and ambient temperature. increasing dilutions of methacholine. The con-
The exercise-induced provocation test is indi- centrations of the latter are doubled with each
cated to support the diagnosis of asthma in chil- successive nebulization, from 0.06 to 16 mg/ml.
dren with a compatible clinical picture and FEV1 is measured at 60 and 90 seconds after each
normal spirometry results. The test can be used to nebulization, with selection of the best determi-
assess the response to maintenance treatment of nation. At the end of the examination, ipratro-
asthmatic children and to assess bronchial hyper- pium bromide is administered together with
reactivity in athletes. It has a high degree of spec- fenoterol or inhaled salbutamol.
ificity (90%) and low sensitivity (50%) for The level of response of the airway to metha-
diagnosing asthma. choline is measured with the PC20 calculation,
The child runs for 6–8 minutes on a treadmill which is defined as the methacholine concentra-
or a track while wearing a nose clip, with a tion that causes a 20% decrease in FEV1 with
requirement to reach a submaximal heart rate in respect to the FEV1 value obtained with a diluent.
9  Assessment of Pulmonary Function in Schoolchildren and Adolescents 91

Table 9.5  Cutoff points used to establish the degree of

bronchial hyperreactivity (BHR) in children under
15 years old
IRV
BHR degree PC20
IC
Normal (no BHR) >8 mg/ml
Limited 4–8 mg/ml
VC TV
Mild 1–4 mg/ml
Moderate 0.25–1 mg/ml TLC
Severe <0.25 mg/ml

ERV
FRC
Arbitrary PC20 cutoff values have been estab-
lished to determine the severity of bronchial
RV
hyperreactivity (Table 9.5).
The sensitivity and specificity of the metha-
choline test to diagnose asthma varies according NORMAL
to the PC20 value obtained. A PC20 value of less Fig. 9.3  Lung volumes and capacities. ERV  expiratory
than 1  or  2 has high specificity for diagnosing reserve volume, FRC  functional residual capacity,
asthma, similar to that of indirect tests such as the IC  inspiratory capacity, IRV  inspiratory reserve volume,
exercise-induced test. When the PC20 value is RV  residual volume, TLC  total lung capacity, TV  tidal
voume, VC vital capacity
higher than 8 or 16, it is highly probable that the
child does not have asthma, although it cannot be
totally ruled out—above all, in athletes. The posi- pathologies. In the case of chronic obstructive
tive predictive value for diagnosing asthma diseases, increases in RV and the RV/TLC ratio
increases as the PC20 decreases from scores indicate air trapping. Moreover, an elevated
between 4 and 16. CPT  value confirms pulmonary hyperinflation
(Fig. 9.4). Table 9.6 shows the percentage values
used to interpret the results of the measurements.
Static Lung Volume Measurement The available techniques are a closed circuit
with helium dilution, an open circuit or nitro-
This technique is used to determine the total lung gen wash, and plethysmography. The latter
volume and capacity (Fig.  9.3), through which constitutes the gold standard in that it measures
the functional residual capacity can be measured, the total volume of thoracic gas, unlike other
which is the sum of the reserve expiratory vol- measures that only attempt to determine the
ume and RV. The latter is the volume that remains quantity of gas that communicates with the
in the lungs after a forced maximum expiration, airway.
because of which it cannot be assessed with a spi- There are national reference values for pulmo-
rometer. To calculate TLC, the functional resid- nary volumes measured by plethysmography and
ual capacity is added to IC, previously measured nitrogen washout.
by spirometry. PC20 methacholine or histamine concentration
Measurement of pulmonary volume is indi- that causes a 20% drop in the forced expiratory
cated for the study of restrictive pathologies, volume in 1 second (FEV1)
early assessment of airway obstruction in chronic
pulmonary diseases such as cystic fibrosis, deter-
mination of the degree of air entrapment and Plethysmography
hyperinflation, and determination of the existence
of a restrictive limitation in patients with obstruc- There are three types of plethysmography: flow,
tive spirometry with reduced vital strength. TLC volume, and pressure; the last is the one that is
characteristically decreases with restrictive most commonly used. Measurement of the func-
92 M. Linares Paserini and S. Caussade Larrain

TLC

TLC TLC

TLC
TLC
FRC

FRC
FRC
FRC
FRC

RV RV
RV RV
RV

NORMAL Pulmonary Air trapping Air trapping and Air trapping

restriction pulmonary and pulmonary
restriction hyperinflation

Fig. 9.4  Types of alterations in static lung volumes. FRC functional residual capacity, RV residual volume, TLC total
lung capacity

Table 9.6  Percentage limits for static lung volumes Variations at the level of the patient’s mouth are
Parameter Limit equivalent to alveolar pressure. The pressure sig-
TLC Normal: 80–130% nals read by the transductors in the box are used
Pulmonary restriction: <80% to calculate the functional residual capacity on
Pulmonary hyperinflation: >130% the basis of Boyle’s law.
RV Normal: ≤130%
Air trapping: >130%
As well as measuring the total volume of
RV/TLC Normal: ≤30% intrathoracic gas, this method has the advantage
Air trapping: >30% of being rapid and reproducible. Its disadvan-
RV residual volume, TLC total lung capacity tages are that it requires a high degree of coopera-
tion and it is costly.

tional residual capacity (FRC) is based on Boyle’s

law, which states that in an airtight system (in this Helium Dilution
case, the plethysmograph) at a constant tempera-
ture, the product of pressure multiplied by vol- A closed-circuit system is used for this measure-
ume remains constant: ment, employing a spirometer containing a
known concentration of inert helium in a known
P1 ´ V1 = P2 ´ V2 . volume (Fig. 9.6). The patient is connected to the

spirometer mouthpiece and breathes at the cur-
The patient sits in the plethysmograph box and is rent volume until the helium concentration in the
connected to a mouthpiece, which is blocked for system is in equilibrium. The formula to calcu-
2–3  seconds, during which the patient must late the functional residual capacity (FRC) is:
breathe at a high rate. This determines the com-
pression and decompression of air trapped in the
chest (FRC), which translates into pressure and
( %Hinitial - %H final )
CRF = ´ volume
volume in the plethysmograph box (Fig.  9.5). %H final

9  Assessment of Pulmonary Function in Schoolchildren and Adolescents 93

Nitrogen Wash ing oxygen at 100% of the current volume. In

this way, the intrapulmonary gas is “washed”
The patient is connected through an open cir- with the volume and concentration of nitrogen
cuit to the mouthpiece of the equipment, breath- being registered with each exhalation. The test
ends when the concentration of nitrogen
remains constant or falls below 5% in succes-
sive exhalations. To calculate the functional
residual capacity, the volume of total exhaled
P¯V gas and the final concentration of nitrogen are
related to the initial nitrogen concentration in
the intrapulmonary gas, which is assumed to be
Mouthpiece 80% (Fig. 9.7).

Lung Carbon Monoxide Diffusion

The test for the diffusing capacity of the lung for

carbon monoxide (DLCO) measures the capacity
PV¯ to transfer inhaled carbon monoxide to the eryth-
rocytes of the pulmonary capillary blood. This
phenomenon depends on the pulmonary volume,
ventilation/perfusion ratio, surface and thickness
of the alveolar membrane, capillary volume, con-
centration, properties of hemoglobin, and carbon
monoxide affinity for hemoglobin. Because of the
dependence on these multiple factors, it is termed
P: pressure. V: volume. a “transfer factor” in the European literature.
The main indications for this test in pediatrics
Fig. 9.5  Lung volumes: plethysmography. Boyle’s law are diseases that compromise the pulmonary
states that in a hermetically closed box, at a constant tem-
perature, the pressure/volume (PV) relation remains con-
interstitium, such as those secondary to immuno-
stant. Increasing the chest volume increases the cabin logical or rheumatic diseases, damage by drugs,
pressure and decreases the volume, and vice versa. The cal- radiotherapy, and checkups of patients who have
culation of the functional residual capacity (FRC) considers received lung and hematopoietic cell transplants.
pressure changes inside the cabin and in the patient’s mouth

Initial Final
concentration concentration
of the volume
of the system

FRC

Before equilibration After equilibration

Fig. 9.6  Helium dilution technique. FRC functional residual capacity

94 M. Linares Paserini and S. Caussade Larrain

Oxygen Oxygen
100% 100% Exhaled
air
volume

Exhaled air Exhaled air balance

80% Nitrogen 5% Nitrogen

Fig. 9.7  Nitrogen washout technique

Because hemoglobin has high affinity for car- Adjustments should also be made in the case of
bon, the partial pressure of this (carbon monox- patients with anemia or polycythemia, according
ide) in plasma can be considered zero when the to their hemoglobin values.
concentration of carboxyhemoglobin is low. The complexity of the process of measuring
Thus, the carbon transfer capacity is the volume carbon monoxide diffusion is reflected in dis-
of carbon monoxide transferred per minute per crepancies in results from different laboratories.
millimeter of mercury of the partial alveolar Consequently, if no baseline values are available,
pressure. the results obtained from each patient should be
Because high levels of understanding and compared with one another.
cooperation are required on the part of the
patient, the procedure is usually not applied to
children under 10  years of age. The single- Airway Resistance
breath method is the one most widely used. It
consists of the subject exhaling until RV is Spirometry is usually employed to find limita-
reached, and then inhaling rapidly until more tions to airflow in patients with chronic obstruc-
than 85% of FVC is reached, during which car- tive disease. Since resistance is a contributing
bon is inhaled at 0.03%. The patient should factor for obstruction, measurement of resistance
remain in apnea for 10  seconds, during which can contribute additional information and more
the carbon is diffused. Finally, the patient should sensitivity for assessment of the response to
exhale slowly until RV is reached, at which bronchodilatory and bronchoconstriction agents
point the final concentration of carbon is mea- such as methacholine. In pediatric practice the
sured (Fig.  9.8). At least two acceptable mea- study is indicated mainly in patients with bron-
surements should be made, with a difference chial asthma, cystic fibrosis, or postinfectious
between them of 10% or less. bronchiolitis obliterans.
An inert gas (helium or methane) is included The methods used for assessing airway resis-
in the mixture of diffusion gases for calculation tance are plethysmography (considered the gold
of the diffusing lung volume, which allows for standard), impulse oscillometry (IOS), and inter-
adjustment of the values that are obtained. rupter resistance (Rint). The latter two offer the
9  Assessment of Pulmonary Function in Schoolchildren and Adolescents 95

Fig. 9.8 Diffusing Breath-hold

capacity of the lung for
carbon monoxide
(DLCO). CO carbon
monoxide, N2 nitrogen, Gas mixture:
O2 oxygen -O2 21%
Inspiration -CO 0.3%
-Methane 0.3%
-N2 balanced

Tidal volume
Exhalation

1 5 10 Time (seconds)

advantage that they can be used in children as than what is observed in the lower respiratory air-
young as 3 years old. way. The diagnostic value of nitric oxide concen-
trations has been demonstrated only for primary
ciliary dyskinesia, in which the values are low.
Exhaled Nitric Oxide Measurement

Although the relationship between airway inflam-  valuation of Respiratory Muscle

E
mation and nitric oxide (NO) is not fully under- Strength
stood, there is evidence supporting the view that
the measurement of NO exhaled (FeNO) from The failure of the respiratory pump is one of the
the lower respiratory tract is an indicator of main causes of complications and death among
eosinophilic inflammation. The main indication patients with neuromuscular diseases. However,
is assessment of the response to inhaled corticoid the risk of respiratory insufficiency can be deter-
treatment for asthma. mined by assessing the strength of the respiratory
The patient should be in a sitting position for muscles. Muscular weakness is sometimes diffi-
the measurement, wearing nasal pincers to avoid cult to detect clinically, which indicates the
measurement of nitric oxide from the upper air- importance of objective measurements.
way. The mouthpiece is placed on the patient, and
he/she inhales until TLC is reached. The subject
should immediately exhale at a constant flow
against the pressure exercised by the system, until Sources
at least a 2-second plateau in the concentration of
Anderson SD, Kippelen P.  Assessment of EIB: what
nitric oxide is reached during an exhalation of at you need to know to optimize test results. Immunol
least 4  seconds. The results should be based on Allergy Clin North Am. 2013;33:363–80.
three repetitions of the procedure with no more American Thoracic Society, European Respiratory
than a 10% variation among them, or two repeti- Society. ATS/ERS recommendations for standardized
procedures for the online and offline measurement of
tions with no more than a 5% variation. exhaled lower respiratory nitric oxide and nasal nitric
There is also equipment to measure nasal oxide, 2005. Am J Respir Crit Care Med. 2005;171:
nitric oxide, the production of which is greater 912–30.
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Caussade S, Pulgar D, Vega-Briceño L, Viviani P, Díaz población chilena normal mayor de 5 años, a nivel del
C, Contreras I, Sánchez I.  Plethysmographic lung mar. Rev Med Chile. 1996;124:1295–306.
volumes in normal Chilean children and adolescents. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric ref-
Pediatr Pulmonol. 2008;43:866–73. erence values from a sample of the general US popula-
Criee CP, Sorichter S, Smith HJ, Kardos P, Merget R, tion. Am J Respir Crit Care Med. 1999;159:179–87.
Heise D, et al. Body plethysmography—its principles Kaminsky D.  What does airway resistance tell us about
and clinical use. Respir Med. 2011;105:959–71. lung function? Respir Care. 2012;57:85–96.
Cockcroft DW, Davis BE. The bronchoprotective effect Lebowitz M, Quanjer P.  ERS statement on peak expira-
of inhaling methacholine by using total lung capac- tory flow. Eur Respir J. 1997;10:1s–83s.
ity inspirations has a marked influence on the inter- Linares M, Sánchez I, Corrales R, Díaz A, Escobar
pretation of the test result. J Allergy Clin Immunol. A. Pruebas de función pulmonar en el niño. Rev Chil
2006;117:1244–8. Pediatr. 2000;71(3):228–44.
Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ. McIntyre N, Crapo RO, Viegi G, Johnson DC, van der
Methacholine challenge: comparison of two methods. Grinten CPM, Brusasco V, et  al. Standardization of
Chest. 2005;127:839–44. the single breath determination of carbon monoxide
Cockcroft DW, Hurst TS, Gore BP. Importance of evap- uptake in the lung. Eur Respir J. 2005;26:720–35.
orative water losses during standardized nebulized Miller M, Hankinson J, Brusasco V, Burgos F, Casaburi R,
inhalation provocation tests. Chest. 1989;96:505–8. Coates A et al; ATS/ERS Task Force. Standardisation
Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. of spirometry. Eur Respir J. 2005;26:319–338.
Bronchial reactivity to inhaled histamine: a method Parsons J, Hallstarnd T, Mastronarde J, Kaminsky
and clinical survey. Clin Allergy. 1977;7:235–43. D, Rundell K, Hull J, et  al. An official American
Davies B, Cockcroft D.  Past, present and future uses Thoracic Society practice guideline: exercise-induced
of methacholine testing. Expert Rev Respir Med. bronchoconstriction. Am J Respir Crit Care Med.
2012;6:321–9. 2013;187:1016–27.
Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS Pellegrino R, Viegi G, Brusasco V, Crapo R, Burgos F,
clinical practice guideline: interpretation of exhaled Casaburi R, et al. ATS/ERS task force: standardisation
nitric oxide levels (FeNO) for clinical applications. of lung function testing: interpretative Strategies for
Am J Respir Crit Care Med. 2011;184(5):602–15. lung function tests. Eur Respir J. 2005;26:948–68.
Gutiérrez M, Rioseco F, Rojas A, Casanova
D.  Determinación de valores espirométricos en una
 Assessment of Respiratory
Muscular Function in Patients
10
with Neuromuscular Diseases

Solange Caussade Larraín

Contents
Introduction....................................................................................................................  97
 eneral Respiratory Muscle Assessment.....................................................................  98
G
Spirometry Flow/Volume Loops.......................................................................................  98
Pulmonary Volume and Capacity.....................................................................................  98
Arterial Gases and Saturometry......................................................................................  100
Muscular Strength........................................................................................................  101
 tatic Pressures: Maximum Inspiratory and Expiratory Pressures.................................  102
S
Nasal Sniff Test...............................................................................................................  102
Peak Cough Flow............................................................................................................  103
Invasive Methods: Transdiaphragmatic Pressure............................................................  103
Muscular Fatigue..........................................................................................................  104
 entilometry...................................................................................................................  104
V
Tension/Time Index........................................................................................................  104
Conclusion.....................................................................................................................  104
Sources...........................................................................................................................  105

Introduction the speed of its progression. The cause of respi-

ratory alteration can originate in the lungs or in
The respiratory systems of patients with neuro- the respiratory pump (the rib cage and respira-
muscular diseases (NMDs) are often compro- tory muscles). The function of the latter is to
mised. The stage at which the compromise mobilize the air toward the alveoli, overcoming
emerges depends on the base disease, the degree the elastic and resistive force of the lungs. It can
of muscular and neurological compromise, and be altered by central or mechanical causes or
muscular fatigue. Its compromise is sometimes
difficult to detect early on, indicating the impor-
tance of objective measurements. This chapter
reviews the examinations that assess general
S. Caussade Larraín (*) respiratory function, force, and muscular fatigue.
Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile,
Santiago, Chile

© Springer Nature Switzerland AG 2020 97

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_10
98 S. Caussade Larraín

 eneral Respiratory Muscle

G promise through analysis of the shape of the
Assessment inspiratory and expiratory flow/volume loops
(described above) and their variables, the most
These examinations are not specific to assess- useful being the forced vital capacity (FVC) test,
ment of muscular function, although they provide which measures inspiratory and expiratory mus-
useful information about the severity, functional culature at the time. A normal score indicates the
consequences, and prognosis of NMDs. absence of significant muscular compromise.
However, it is not a sensitive indicator as it does
not decrease until muscular force is highly com-
Spirometry Flow/Volume Loops promised. It is mainly used to follow the evolu-
tion of patients as a marker of the risk of
A simple inspection of the flow/volume loops respiratory insufficiency and mortality. Thus,
makes evident the presence of respiratory muscu- FVC of <1  liter predicts an 8% probability of
lar weakness. In some cases, there is a decrease in 5-year survival in patients with Duchenne mus-
the slope of the ascending phase and a delay in cular dystrophy.
reaching the maximum expiratory flow (MEF). Another useful spirometry technique to iden-
MEF can also be poorly defined. These findings tify diaphragmatic compromise is performance of
reflect slow initial pulmonary emptying. At the the test with the patient first sitting or standing and
end of expiration, there can be an abrupt drop just then in the prone position. A 25% or greater
before the residual volume (RV) is reached, which decrease in FVC in the supine position indicates
is caused by expiratory muscular fatigue due to altered diaphragm functioning that is not able to
sustained effort (Fig. 10.1a). When there is greater overcome the gravitational force of the abdominal
muscular compromise, characteristically there is a content. On the other hand, if the patient has an
more pronounced reduction in flows that depend obstructive disease of the small intrathoracic air-
on effort in the expiration and inspiration phases way (asthma, postviral damage, or other disease),
of the flow/volume loop (Fig. 10.1b). measurements of forced expiratory flow (FEF)
An effective cough that efficiently removes (e.g., FEF at 25–75% of FVC (FEF25–75) and FEF
secretions from the airway requires sufficient at 50% of FVC (FEF50)) help to determine the
intrathoracic pressure to produce dynamic com- presence of this associated compromise.
pression of the airway and respiratory flow at a
high velocity. The expiratory flow/volume loop  easurement of Static Pulmonary
M
also serves to show the effect of coughing. In nor- Volume
mal subjects, coughing appears as transitory The gold-standard method for performing these
flows that exceed the maximum flow achieved by measurements is plethysmography. Measurement of
a forced expiration, with spikes that rise above the static pulmonary volume allows assessment of
the loop. The absence of these spikes indicates the balance between lung compliance, the rib cage,
respiratory muscular weakness and correlates and the respiratory musculature. A characteristically
very well with a maximum respiratory pressure restrictive pattern is observed in NMDs: diminished
of <40 cm H2O (Fig. 10.1c). vital capacity, diminished total lung capacity (TLC),
and RV proportional to this. The degree to which
TLC decreases varies depending on the muscular
Pulmonary Volume and Capacity impairment and is basically due to reduced inspira-
tory capacity (IC). Initially the RV remains in the
Spirometry Measurements: Volumes normal range and increases with the appearance of
and Flows of Forced Expirations significant compromise in the respiratory muscula-
The basic examination assesses respiratory ture at the cost of less expiratory reserve volume
mechanics and is used in patients with NMDs to (ERV). In these cases, a higher RV/TLC ratio does
establish the degree of respiratory muscular com- not indicate the presence of trapped air (Fig. 10.2).
10  Assessment of Respiratory Muscular Function in Patients with Neuromuscular Diseases 99

a Flow (1/sec) MEF not well defined

Decreased
slope

Abrupt end

Volume (I)
Flow (1/sec)

Flow (1/sec)

b c

Cough

Volume (I)

Volume (I)

Fig. 10.1  Flow/volume curves. (a) Patient with mild to of the initial phase of the expiratory phase and of the
moderate expiratory muscular compromise. The initial inspiratory phase of the flow/volume loop. (c) Transient
slope of a slow ascent is observed. The maximum expira- fluxes during the expiratory phase of the flow/volume
tory flow (MEF) does not show a defined peak. An abrupt curve, determined by coughing in a healthy subject. Its
end of the expiration is apparent. (b) Patient with moder- absence indicates expiratory muscle compromise
ate to severe muscular compromise. There is a flattening

 aximum Voluntary Ventilation

M obstructive bronchial diseases. In the case of
The maximum voluntary ventilation (MVV) is a obstructive bronchial disease, the MVV maneuver
measurement (using a spirometer) of the volume exaggerates air trapping and limitation of airflow,
of air that a subject can repeatedly move with max- and should be done with care. This maneuver relies
imum voluntary effort. It assesses the integration heavily on the effort and cooperation of the patient,
of several components of respiratory function: the who must breathe deeply and rapidly for 12 sec-
musculature, chest and lung compliance, ventila- onds at a volume that is more than normal but less
tion control mechanisms, and airway resistance. than the maximum capacity, the optimal volume
MVV can decrease as a result of a variety of neu- being 30%. The graph of the maneuver should
romuscular, restrictive pulmonary, rib cage, and show a continuous and rhythmic trace, keeping the
100 S. Caussade Larraín

Fig. 10.2 Lung
volumes. (a) Normal. IC
(b) Restrictive lung
disease, showing
proportional decreases
in all volumes. (c)
Restrictive lung disease
with air trapping,
showing a proportional
increase in the residual
volume, due to the lower
expiratory reserve
volume and the decrease TLC
in inspiratory capacity

RV RV RV

a b c

Fig. 10.3 Maximum
voluntary ventilation
measurement. The out-
line is homogeneous,
with the end of expira-
tion at a constant level
12 seconds

exhalation constant until the end (Fig.  10.3). At awake can underestimate the severity of the alter-
least two maneuvers should be obtained that do not ation of gaseous exchange.
differ by more than 10%. Because there is a good In patients who have moderate to severe muscu-
correlation between the forced expiratory volume lar compromise, continuous measurement of periph-
in 1 second (FEV1) and MVV in individuals with- eral oxygen saturation (SpO2) during sleep shows
out airway compromise, it is possible to assess frequent falls due to apnea and/or central and/or
whether the individual makes an adequate effort, obstructive hypopnea. This measurement correlates
using an indirect index: FEV1 × 35. very well with the vital capacity. More details can be
found in the chapter on pulse oximetry in this book.
Polysomnography is the test of choice for diagnos-
Arterial Gases and Saturometry ing sleep disorders, with the capacity to register
SpO2 and transcutaneous CO2 tension.
The main purpose of arterial gas measurement is
detection of hypercapnia secondary to hypoventi-  entilation Control: Measurement
V
lation. This appears initially in patients with slow of Occlusion Pressure
and progressive compromise during sleep; conse- Respiratory control depends on the partial pres-
quently, the sample should be taken upon awak- sures of carbon dioxide (pCO2), and of oxygen
ening. Samples taken when patents are fully (pO2), the pH chemoreceptors in the neural centers
10  Assessment of Respiratory Muscular Function in Patients with Neuromuscular Diseases 101

and paths, and the motor action of the respiratory pose of the test in patients with chronic pulmonary
muscles. A progressive increase in pCO2 is disease is a checkup for respiratory rehabilitation.
observed in patients with NMDs, which may be The test requires a 30  m walkway with a
caused by alveolar hypoventilation and/or failure smooth hard surface. A marker should be placed
to control respiration. The latter has been described every 3 m, and turning points should be marked
in myotonic dystrophy and other congenital with a cone. The heart rate and SpO2 are assessed
myopathies. Measurement of occlusion pressure before and after the exercise. When continuous
in the mouth in the first 100 ­milliseconds of inspi- monitoring is required, the patient should carry
ration (P0.1) allows estimation of the response to the equipment, which needs to be light enough
CO2 retention. This is the pressure generated in the not to hinder the patient’s performance. The
airway by contraction of the inspiratory muscles degree of basal and post-test dyspnea is measured
when the airway is occluded at the end of an expi- on the modified Borg scale. If the patient requires
ration at rest (the functional residual capacity continuous oxygen support, the system should
(FRC)). FRC is the pressure generated in the first not interfere with the walking circuit. Ongoing
100 milliseconds of inspiration, during which the encouragement by the technician is important,
conscious response does not interfere with the drawing on the chronology and standard phrases.
occlusion or the mechanical properties of the lung. It has been observed that longer walk distances
However, it depends on the contractile state of the are achieved with encouragement.
respiratory musculature and on the FRC variation There are several reasons for obtaining differ-
in the subject. FRC can be measured in infants ent results in the test performance. Factors that
while they are sleeping and in older children when reduce the distance walked are smaller body size,
they are capable of breathing peacefully with a obesity, failure to understand the technique, and a
nasal clamp and a mouthpiece for at least 5 min- walkway of <30 m, given that this implies more
utes, with occlusion occurring every minute until turning. The most important factor in increasing
five acceptable measurements have been obtained. the walk distance is the motivation of the patient.
The main purpose is assessment of respiratory The most reliable way to determine the clinical
control in stable patients with an increased respi- improvement of a patient on the basis of this test
ratory load due to bronchopulmonary dysplasia, after some form of intervention is to conduct two
cystic fibrosis, bronchiolitis obliterans, or another or three pre- and post-treatment tests (thus ensur-
cause. The normal value in adults is 1 cm H2O, ing the reproducibility of the test), using the same
and under normal conditions of stability, P0.1 technician to ensure the same methodology.
increases by approximately 3 cm H2O. In relation to Chilean reference values, we use
those described by Gatica et al. (2002), which are
 unctional Capacity: 6-Minute Walk Test
F described in greater detail in the chapter on respi-
There are several ways to objectively study func- ratory rehabilitation in this book.
tional exercise capacity. The 6-minute walk test
is considered the easiest to undertake, the easiest
for the patient to tolerate, and the test that most Muscular Strength
reflects tolerance of regular activities. The test
measures the distance the patient can cover when Muscular strength in the respiratory system is
walking as rapidly as possible for 6  minutes. It estimated as the pressure generated by muscular
assesses, in an integral manner, all of the systems contraction. However, this relationship is com-
involved in the exercise: pulmonary, cardiovascu- plex and depends on the mechanical characteris-
lar, circulatory, blood, neuromuscular, muscular, tics of the rib cage and the abdominal wall.
and metabolic. Consequently, it is preferable to interpret the
Because of their base condition, patients with results of these measurements as a global index
NMDs have difficulty doing the test. The main pur- of respiratory musculature performance.
102 S. Caussade Larraín

 tatic Pressures: Maximum

S results are obtained (with a maximum variation
Inspiratory and Expiratory Pressures of 10% between the two best values), and the bet-
ter one should be chosen. A MIP value under
Tests that measure the maximum inspiratory −80 cm H2O is of great value for ruling out dia-
pressure (MIP) and maximum expiratory pres- phragmatic compromise.
sure (MEP) are most commonly used to assess The disadvantages of these measurements are
muscular strength, given that the MIP test is their high degree of variability and the fact that
more sensitive than vital capacity measurements they reflect the effect of learning. Consequently,
at the initial stage of the disease. The MIP is the it is advisable to do more than five maneuvers in
maximum pressure generated during inhalation patients who do not achieve an adequate tech-
with the airway occluded and is based on RV. nique, until two repeatable results are obtained.
MEP is the maximum pressure generated during The analysis of the values obtained will be aided
exhalation with the airway occluded and is by inclusion of the FVC value, given that the
based on TLC.  Measurement of MIP assesses pressures the patient can generate depend signifi-
the functioning of the inspiratory musculature: cantly on this. A MIP value of less than
the diaphragm and the external intercostal and −25 cm H2O suggests a risk of respiratory fail-
accessory muscles (the scalenes and sternoclei- ure. This indicates the importance of serial mea-
domastoids). The abdominal and internal inter- surements of pulmonary volumes and static
costal expiratory muscles are assessed with pressure.
MEP. It is recommended to use the reference values
These techniques measure the pressure gen- provided by Szeinberg et al. with schoolchildren
erated by the respiratory muscles plus the pres- and adolescents. MIP and MEP values can be
sure of the elastic retraction of the rib cage and measured in infants when they cry, with the mask
the lungs. Consequently, it should be keep in placed over the infant’s mouth. The mouthpiece
mind that measurement of MIP on the basis of should have an escape to avoid glottic closure.
RV can increase the latter by up to The airway should be occluded at the end and at
−30 cm H2O. Similarly, to measure MEP on the the beginning of the crying effort to measure
basis of TLC, the contribution can be up to MEP and MIP, respectively.
+40 cm H2O. Some specialists argue that, realis-
tically, in MIP and MEP measurements in
chronic respiratory failure (CRF)—that is, with Nasal Sniff Test
elastic retraction at zero—the pressures mea-
sured in the mouth reflect only the pressure that Sniffing is a natural action, which many patients
is generated by muscular contraction. find easier than performing a maneuver for mea-
For the measurement, a nasal clamp should be suring static pressure. It is a reproducible
placed on the patient, and a cylindrical mouth method, validated in children, and used to
piece is recommended. Although some authors asse­ss  global inspiratory muscular function.
have used scuba diving–type masks to obtain ref- Measurement of MIP has the advantage of being
erence values, it is recommended that this be an easily applied technique that avoids the prob-
based on theoretical values for the same method lem of air loss through a mouthpiece, as often
used on the patient. The mouthpiece should have occurs in patients with neuromuscular illnesses.
an escape 1 mm in diameter to avoid glottic clo- It consists of a short, rapid, voluntary inhalation
sure and an artificially elevated MIP, and also to through the nose and with the mouth closed,
reduce the use of the mouth musculature during beginning after an exhalation at rest (FRC). One
the maneuver for MEP. of the patient’s nostrils is sealed with a rubber or
The force should be maintained for a mini- sponge mold, into which a catheter is inserted.
mum of 1.5  seconds; at least five maneuvers The patient breathes through the nostril that is
should be conducted until at least two repeatable not blocked. The catheter measures the nasopha-
10  Assessment of Respiratory Muscular Function in Patients with Neuromuscular Diseases 103

ryngeal pressure, which is a reasonable indicator Invasive Methods:

of the intra-­ alveolar pressure. The values are Transdiaphragmatic Pressure
generally lower than the MIP value because
there is less shortening of the inspiratory These techniques are used especially in small
musculature. children, in whom it is not possible to conduct the
As with measurement of static pressure, a lim- tests described above. The most commonly used
itation is the dependence on effort. Most children of these techniques is measurement of transdia-
over 4 years of age are capable of performing the phragmatic pressure (TDP), which specifically
maneuver adequately. There should be a assesses the contraction of the diaphragm, unlike
30-­second lapse between maneuvers. If it is dif- the aforementioned methods, which measure the
ficult to obtain reliable data in child subjects, it is synergetic action of several inspiratory and expi-
recommended to make more than ten attempts, ratory muscles. Transducers are placed on the
given the important effect of learning. The values stomach and esophagus to measure the gastric
tend to be underestimated in patients with intra- pressure (GP) and esophageal pressure (EP),
or extrathoracic airway obstruction. respectively. Infants and small children should be
Pressure values greater than −70 cm H2O and sedated, with continuous monitoring of SpO2.
−60 cm H2O are considered acceptable for males The most commonly used method is placement
and females, respectively. of a balloon catheter. The method used for calcu-
lating TDP is:

Peak Cough Flow TDP = Ppl - AP

Coughing is a basic defense mechanism to elimi- where:

nate secretions from the airway. One or more TDP = EP - GP
coughing phases are affected in patients with
NMDs: maximum inspiration, opening or clos- Ppl is the pleural pressure, which is measured
ing of the glottis, keeping the glottis open or in the esophagus, and AP is the abdominal pres-
closed while increasing intrathoracic pressure, sure, which is measured in the stomach.
and opening the glottis together with forced EP is generally negative. As the diaphragm is
expiration. Coughing can be assessed objec- the only muscle that simultaneously determines a
tively by measuring the peak cough flow (PCF) decrease in EP and an increase in GP when it
or MEF generated while the subject is coughing. contracts, its normal contraction results in
A nasal clamp is placed on the patient, who is increased TDP.
asked to take a deep breath and then cough into TDP has been measured by the nasal sniff test,
the flow meter. The maneuver should be done at with less variability observed than with the MIP
least five times, taking care to ensure that the technique. TPD is measured in infants in the
mouthpiece remains well sealed. The normal inspiratory phase of crying, with values of
MEF is above 300  l/min. A value of less than ±60 cm H2O being acceptable at 1 month of life,
160 l/min is associated with difficulty in elimi- which is lower than what is registered by mea-
nating secretions and a consequent risk of respi- surement of MIP during crying.
ratory complications such as pneumonia, Another method to assess diaphragm function
atelectasis, or respiratory insufficiency. If the is electrical stimulation, the great advantage of
reading is between 160 and 270 l/min, it is likely which is that it does not require the cooperation
it will fall below 160  l/min in the context of a of the patient. However, the stimulation is pain-
respiratory infection. ful, and it is not easy to place the electrodes.
104 S. Caussade Larraín

Muscular Fatigue the inhalation time, and Tot T is the total inhala-
tion time.
Muscular fatigue is defined as loss of capacity to The It/Tot  T ratio depends on the breathing
generate force and/or contraction velocity, rate and on the inhalation/exhalation relation-
accompanied by recovery during muscle repose. ship. The higher the It/Tot T ratio is, the greater
The method to demonstrate the presence of mus- the respiratory work is. The diaphragm does not
cular fatigue is serial measurements. Of the benefit from the rest periods provided by the
existing techniques, serial measurement of mus- expiratory phase.
cular tension, using an electrical or magnetic The calculation can use the maximum TDP or
stimulus, is the most precise one, although it is MIP.
technically complex and involves discomfort for
the patient.
Conclusion

Ventilometry There are now several methods used to precisely

assess respiratory muscle function. The most
Although it is not a specific marker of the pres- widely used measure of static pressures is the
ence of muscular fatigue, ventilometry has the maximum expiratory flow generated by cough-
advantage of being a simple and noninvasive ing, which is a relatively simple and well toler-
method. It consists of measuring the ventilated ated technique. Of the general examinations, we
volume in 1 minute, using a Wright respirometer. highlight the usefulness of the graphic spirome-
The total volume measured is related to the try flow/volume loop, although their alterations
breathing rate per minute. A breathing rate asso- appear late. In addition, the walk test contributes
ciated with low tidal volumes may predict respi- information about the functional capacity of the
ratory failure. patient related to his or her quality of life.
One of the limiting factors in obtaining reli-
able results is the age of the patient, given that the
Tension/Time Index techniques require a high level of cooperation.
Moreover, it should always be keep in mind that
Tension/time index (ITT) measurement contrib- these patients tire easily with performance of the
utes to determining the presence of diaphrag- tests, and sometimes they have problems coordi-
matic muscular fatigue. It is used in patients in nating movements or their muscular weakness is
the phase of suspension of ventilatory assistance such that they cannot hold the nozzles. This high-
and assessment prior to and after inspiratory lights the importance of the technician being well
muscular training. It measures the force gener- trained and able to determine if a poor maneuver
ated by the diaphragm in each inspiration, estab- is due to the factors noted above, and if it will be
lishing its relation to the maximum force that the acceptable for analysis.
same individual can reach, and the duration of New techniques of interest have been devel-
inspiratory time with respect to the total time of oped, such as inductance plethysmography—and,
the cycle. A value of <65% implies low resis- more recently, optoelectronic plethysmogra-
tance of the inspiratory musculature, even if MIP phy—to assess thoracoabdominal respiratory pat-
is normal. ITT is calculated as follows: terns. Furthermore, ultrasonographic methods
have emerged to assess diaphragmatic structure
ITT = AI / MP It / Tot T
and dynamics, along with new tomographic tech-
where AI is the average inhalation pressure at nologies to measure regional ventilatory changes
tidal volume, MP is the maximum pressure, It is in patients with ventilatory assistance.
10  Assessment of Respiratory Muscular Function in Patients with Neuromuscular Diseases 105

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Allen J. Pulmonary complications of neuromuscular dis-
flow and spirometry in Duchenne muscular dystrophy.
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Pediatr Pulmonol. 2005;39:457–60.
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Lofaso F, Nicot F, Lejaille M, Falaize L, Louis A, Clement
American Thoracic Society/European Respiratory Society.
A, Raphael J-C, Orlikowsky D, Fauroux B. Sniff nasal
ATS/ERS statement on respiratory muscle testing. Am
inspiratory pressure: what is the optimal number of
J Respir Crit Care Med. 2002;166:518–624.
sniffs? Eur Respir J. 2006;27:980–2.
Bach JR, Ishikawa Y, Kim H.  Prevention of pulmonary
Masdeu MJ, Ferrer A.  Función de los músculos respi-
morbidity for patients with Duchenne muscular dys-
ratorios en enfermedades neuromusculares. Arch
trophy. Chest. 1997;112:1024–8.
Bronconeumol. 2003;39:176–83.
Birnkrant DJ, Bushby K, Amin RS, Bach JR, Benditt JO,
Nicot F, Hart N, Forin V, Boule M, Clement A, Polket
Eagle M, Finder JD, Kalra MS, Kissel JT, Koumbourlis
I, Lofaso F, Fauroux B.  Respiratory muscle test-
AC, Kravitz RM.  The respiratory management of
ing: a valuable tool for children with neuromuscu-
patients with Duchenne muscular dystrophy: a DMD
lar disorder. Am J Respir Crit Care Med. 2006;174:
care considerations working group specialty article.
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Phillips MF, Quinlivan CM, Edwards RHT, Calverley
Dohna-Schwake C, Ragette R, Teschler H, Voit T, Mellies
PMA.  Changes in spirometry over time as a prog-
U.  Predictors of severe chest infections in pedi-
nostic marker in patients with Duchenne muscular
atric neuromuscular disorders. Neuromuscul Dis.
dystrophy. Am J Respir Crit Care Med. 2001;164:
2006;16:325–8.
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Fauroux B.  Respiratory muscle testing in children.
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cular dystrophy. Respir Med. 2001;95:898–903.
Gatica D, Puppo H, Villarroel G, San Martin I, Lagos R,
Montecino JJ, Lara C, Zenteno D. Valores de referen-
 Study of Images in Respiratory
Diseases
11
Cristián García Bruce and Rodrigo Parra Rojas

Contents
Introduction..................................................................................................................  107
Methods of Study..........................................................................................................  107
 hest X-Ray...................................................................................................................  107
C
Ultrasound......................................................................................................................  108
Computerized Tomography............................................................................................  108
Magnetic Resonance Imaging........................................................................................  109
Other Methods................................................................................................................  109
Evaluation of the Structures of the Chest..................................................................  110
 he Airways....................................................................................................................  110
T
The Lung Parenchyma....................................................................................................  110
Acute Lower Respiratory Tract Infections.....................................................................  117
Diffuse or Focal Diseases of the Pulmonary Parenchyma..............................................  122
Specific Pathologies of Importance................................................................................  124
Sources...........................................................................................................................  125

Introduction costly, which should be considered when a study

is requested. Imaging methods should not be mis-
The radiologist should work closely with the cli- used and should be requested only when a direct
nician, not only to choose the best imaging study benefit for the patient can be expected. Every
for every patient but also to meet one of our pri- time an examination is requested, it should be
mary objectives: providing better care for our based on a diagnostic hypothesis, considering
patients. We should not forget that the clinical that the findings of the examination could deter-
aspects of every patient are fundamental to reach- mine the course of therapy.
ing a correct diagnosis.
Imaging methods that use ionizing radiation
are not innocuous, and many of them are very Methods of Study

C. García Bruce (*) · R. Parra Rojas Chest X-Ray

Pediatric Radiology, School of Medicine, Pontificia
Universidad Católica de Chile, Santiago, Chile There are numerous indications for a conven-
e-mail: [email protected]; [email protected]
tional chest x-ray in assessment of the chest and
© Springer Nature Switzerland AG 2020 107
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_11
108 C. García Bruce and R. Parra Rojas

airway; among them are inflammatory diseases, Another common and important indication
tumors, deformations of the rib cage, heart dis- for ultrasound is assessment of diaphragm
ease, and trauma. If possible, anteroposterior mobility, particularly following heart surgery.
(AP) and lateral projections should always be This is usually done at the patient’s bedside in
obtained for adequate assessment of thoracic the intensive care unit. When there is unilateral
structures. A chest x-ray of the patient lying on diaphragm compromise, the affected side can be
his or her side has traditionally been used to compared with the healthy side. The M  mode
detect fluid in the pleural cavity, although it has also provides a spectral representation of dia-
progressively been replaced by ultrasound phragmatic movement. Moreover, ultrasound
because the latter has greater sensitivity and the can guide procedures such as pleural puncture
capacity to characterize the fluid. Fluoroscopy is or installation of central catheters. The main
useful to assess the dynamics of the chest, spe- disadvantage of this technique is that it requires
cifically in the study of diaphragm movement and adequate equipment, with color Doppler and
in cases when there is suspicion that a foreign high-resolution transductors, as well as a trained
body is present in the airway. operator.
We do not recommend this technique as an
initial study for suspected pneumonia, as some
Ultrasound authors have. A chest x-ray employs a very low
dose of radiation and continues to be the gold
Chest ultrasonography is a highly useful tech- standard in these cases. Doppler ultrasound can
nique, which complements x-rays. It was ini- be applied to cases of suspected necrotizing
tially applied to detect pleural effusion, but in pneumonia, but it is not used universally.
recent years its use in studying the chest has been
greatly extended to include the study of other
pleural lesions, juxtadiaphragmatic or juxtapari- Computerized Tomography
etal masses, neck masses, the mediastinum, peri-
cardial diseases, diaphragm pathologies, etc. The features of computerized tomography (CT)
Color Doppler ultrasound is used to assess cen- of the chest in children are quite different from
tral catheters, vascular anatomy, vessel permea- those in adults. The lower percentage of adipose
bility, and vascular flow in thoracic masses. tissue and spontaneous movement of the patient
Echocardiography also has great value but is reduce the quality of the image, making its
beyond the scope of this chapter. interpretation more difficult. The introduction
Some of the advantages of ultrasound are of helical and multislice or multidetector CT has
that it is harmless (as it does not involve ion- increased the utility of the technique and broad-
izing radiation), it does not require administra- ened the indications for its use in assessing
tion of a contrast medium or sedation, and it is pediatric patients, because these techniques
a portable methodology that can be used at the offer the possibility of optimizing intravenous
patient’s bedside. One of its main applications contrast while reducing the study time and the
is assessment of the pleural space, because of need for sedation. In addition, these techniques
its high sensitivity for detecting pleural effu- significantly reduce the exposure of the patient
sion and its capacity to characterize pleural flu- to radiation while yielding images with submil-
ids. While both the exudate and transudate can limeter definition, thus significantly improving
be anecogenic, findings of echoes, partitions, the quality of multiplane reconstructions and
and/or loculations generally indicate empy- even permitting virtual navigation of the
ema. In the case of complete opacity of a hemi- airway.
thorax, pleural effusion can be easily High-resolution CT assesses the lungs with
distinguished from other expansive lesions or excellent spatial resolution, providing precise
atelectasis. anatomical detail of the parenchymal and airway.
11  Study of Images in Respiratory Diseases 109

It has a high yield in the assessment of diffuse Magnetic Resonance Imaging

pulmonary diseases. To obtain good spatial reso-
lution, it requires a cut with a thickness of less The usefulness of magnetic resonance imagining
than 3  mm (ideally 1  mm) with an interval of (MRI) in chest pathologies lies basically in assess-
5–10 mm, depending on the size of the patient. ment of chest masses, given its excellent resolu-
Reconstruction algorithms are techniques used to tion for contrast and its multiplane capacity, as
optimize CT performance, such as expiratory well as the possibility it offers for characterizing
imaging while the patient is lying prone or tissue. Another more recent and less defined prac-
laterally. tice is the use of studies triggered by the heartbeat
Expiratory imaging is extremely useful in (using electrocardiography), which can assess
patients with suspected abnormalities in fine congenital heart disease and extracardiac vascular
airways and in patients with a history of repeated structures, with the great advantage of providing
pulmonary infections. This technique shows not just morphological information but also infor-
areas with trapped air that are often not evident mation on function and blood flow dynamics.
on conventional imaging. A practical method to Although MRI has been used for evaluation of
obtain expiratory imaging in uncooperative pulmonary the parenchyma, chest CT currently
children is to make axial cuts while they lie on continues to be superior in this area. Advances in
their left or right side. If there is air trapping, the fetal MRI have been made in recent years with
affected lung, lobe, or segment is hyperlucid the development of ultrarapid sequencing, which
when that side of the chest is in the dependent reduces the examination time and the number of
position. The same principle of gravity-­ artifacts resulting from fetal movement. There
dependent aeration can be used in prone cuts to are no known risks or harmful effects on either
obtain images with better expansion of the lower the mother or the fetus. It does not employ an
and inner lobes in their posterior or dependent intravenous contrast medium, nor does it require
aspect. maternal sedation.
Expiratory imaging can also be useful to The indications have increased at some medi-
assess suspected tracheobronchomalacia, both as cal centers, but the examination is sometimes
a primary condition and in association with other unnecessary and the findings do not contribute
diseases. In this respect, CT provides an excellent more than those of fetal ultrasound (which is the
anatomical demonstration of thorax structures gold-standard technique) and do not necessarily
and the airway. It often shows abnormalities that modify the clinical evolution of the fetus, nor
are poorly defined or not apparent on chest postnatal care.
x-rays. CT can distinguish differences in density Chest MRI should be limited to cases in which
with 100 times the sensitivity of conventional ultrasound findings are doubtful or inconclusive, or
radiography. where it is desirable to assess the upper airway in
CT is used to assess different structures of the the case of a fetal cervical mass. It is also used as
chest, including the chest wall, the mediastinum, an examination before an interventional procedure
the airway, vascular structures, and the pulmo- such as fetoscopy or fetal surgery. MRI provides
nary parenchyma. An intravenous contrast excellent definition of fetal anatomy and can clar-
medium is usually not necessary to assess the ify doubts arising from ultrasound examinations.
pulmonary parenchyma but is used to study the
mediastinum, vascular structures, masses, or con-
genital anomalies, or when looking for inflamma- Other Methods
tion. CT should be used with strict criteria and
caution, and only when it is strictly indicated, Other methods that are less often used but can
owing to the high dosage of radiation that its use nevertheless be useful include nuclear medical
entails. studies (scintigraphy), angiography, and contrast
110 C. García Bruce and R. Parra Rojas

studies of the upper digestive tract. This last test epiglottis and the aryepiglottic folds suggest
is particularly useful to detect extrinsic airway acute epiglottitis (Fig.  11.2), while increased
compression. thickness of the soft retropharyngeal and prever-
tebral tissue suggests inflammation at this level (a
retropharyngeal abscess).
Evaluation of the Structures The upper airway can be evaluated precisely
of the Chest by CT, including tridimensional and multiplane
reconstructions, especially in cases of acquired or
The Airways congenital stenosis (Fig. 11.3) or extrinsic com-
pression of the airway by vascular rings
There are currently only a few precise indications (Figs. 11.4 and 11.5). CT can characterize a cer-
for simple radiography to assess the upper air- vical mass and its relationship to other struc-
way, including evaluation of nasopharyngeal tures—for example, in situations where the mass
adenoid tissue and the paranasal sinuses. One is compressing the airway. It is also the most sen-
less common indication is acute obstruction of sitive method for detecting calcification.
the upper airway; an x-ray can be performed CT is usually a good complement to fibros-
when airway obstruction by a foreign body is copy in the study of a congenital stridor and sub-
suspected (Fig.  11.1). Radiography can also be glottic hemangioma (Fig.  11.6). MRI is also
useful in cases of suspected stenosis and/or tra- useful in assessing cervical masses because of its
cheal compression, particularly in the context of contrast resolution, especially when a vascular
suspected vascular rings, where a chest x-ray pro- component is suspected.
vides information about the position of the aortic
arch. Considering the greater resolution of other
methods, standard radiology has limited useful- The Lung Parenchyma
ness for studying the upper airway.
The standard radiography study should Congenital Anomalies
include anteroposterior and lateral projections. Congenital bronchopulmonary anomalies are
Lateral projections that show thickening of the common and are composed of a heterogeneous

a b

Fig. 11.1  Foreign bodies in the airway of a 14-month-old and displacement of the heart and mediastinum to the left.
patient with a history of penetration syndrome. Chest The air-trapping area excludes the right upper lobe, which
x-rays obtained on inspiration (a) and expiration (b) show is displaced cephalad (arrow). This is indicative of the
greater transparency in the right lung. On expiration, air presence of a foreign body in the right intermediate bron-
trapping in the right lung is evident and is due to the valve chus, which was confirmed by fiberoptic bronchoscopy.
mechanism, which determines a mass effect of that lung The foreign body (a peanut) was later extracted
11  Study of Images in Respiratory Diseases 111

a b

Fig. 11.2  Acute epiglottitis. (a) Lateral neck x-ray of a and thickness. (b) X-ray of a 2-year-old patient with an
3-year-old patient, showing the epiglottis (thin arrow) and acute stridor, showing significant thickening of the epiglot-
the aryepiglottic folds (thick arrow), both of normal size tis (thin arrow) and of the aryepiglottic folds (thick arrow)

group of anomalies that affect the pulmonary

parenchyma, its vascularization, and the lower
airway. More than one anomaly can coexist
(hybrid forms), and their clinical presentation is
variable. They have been classified in different
ways by different authors—in particular, accord-
ing to their anatomy and pathogeny.
A simple classification considers two types:
(1)  focal malformations (congenital pulmonary
hyperinsufflation, bronchial atresia, simple intra-
pulmonary cysts, congenital pulmonary airway
malformation (CPAM), pulmonary sequestra-
tion, and an irrigation system congenitally iso-
Fig. 11.3  Congenital tracheal stenosis in a 2-month-old
patient with a congenital stridor. A multislice CT scan
lated from a normal lung segment); and (2)  a
with three-dimensional reconstruction of the airway dysmorphic lung (pulmonary aplasia–hypoplasia
shows a long segment of tracheal stenosis (arrows) complex, lobar agenesis–hypoplasia).
112 C. García Bruce and R. Parra Rojas

a b

Fig. 11.4  Vascular ring in a 4-month-old patient with a arch; i: left arch). (b) An anteroposterior view of the tra-
congenital stridor, shown on multidetector helical CT chea shows compression and narrowing of its distal end,
scans with three-dimensional reconstruction. (a) An due to the vascular ring (arrows)
anteroposterior view shows a double aortic arch (d: right

Imaging studies are fundamental for diagno- or lobes, and differentiate between this lesion and
sis, and several methods can be used. other pathologies such as CPAM (Fig.  11.7).
Most patients become symptomatic in the neona-
 ongenital Pulmonary Hyperinflation
C tal period.
Previously called congenital lobar emphysema,
this condition is characterized by progressive Bronchial Atresia
overdistension of one (or sometimes two) pulmo- Bronchial atresia is characterized by proximal
nary lobes without destruction of the alveolar obliteration of a bronchial segment but with pres-
walls. Most often the upper lobes or the right ervation of distal structures. The air enters the
middle lobe are compromised. In the first days of affected lung through the collateral canals, pro-
life there is pulmonary fluid trapped in the com- ducing hyperinflation and air trapping. In turn,
promised lobe, so on a chest x-ray this appears bronchial mucus secretions accumulate at the site
opaque and enlarged, with a mass effect on the of obstruction, producing mucosal and mucocele
heart and mediastinum. As vascular and lym- impaction. In most cases, only one segment is
phatic reabsorption progresses, the compromised affected—usually the upper left lobe—and the
lobe is aerated. It presents a reticular pattern and condition may be associated with other anoma-
later a typical pattern of a hyperinflated lobe with lies. Segmental focal air trapping during exhala-
reduced density. The pulmonary vessels are tion can be observed on a chest x-ray, accompanied
markedly attenuated, but there is no alteration in by a central tubular or rounded appearance of the
their structure. These alterations are best demon- mucocele. CT shows segmental pulmonary
strated by CT, which can confirm the diagnosis, hyperinsufflation and mucosal impaction signs in
determine with certainty the compromised lobe much more detail (Fig. 11.8).
11  Study of Images in Respiratory Diseases 113

a b

Fig. 11.5  Vascular ring and double aortic arch in a 3-month- compression of the esophagus (posterior arrow) and com-
old patient with a congenital stridor. An esophagram in the pression of the airway (thin anterior arrow). An axial
anteroposterior view (a) shows posterior compression of the T2-weighted MRI of the chest  (c) shows the right aortic
esophagus (arrows); the lateral view  (b) shows posterior arch (D) and left aortic arch (I) with airway compression

I solated or Single Congenital Chest the airway (Figs.  11.9 and  11.10). The cysts
Cysts sometimes have calcified walls and can also be
This group includes isolated congenital cysts associated with other anomalies such as pulmo-
located in the mediastinum or the pulmonary nary sequestration or congenital pulmonary
parenchyma (bronchogenic cysts, duplication hyperinflation.
cysts, or pleuropericardial cysts). Around 85% of
such cysts are located in the mediastinum, and  ongenital Pulmonary Airway
C
the remaining 15% are located within the lung Malformation
parenchyma. Mediastinal cysts are most often Previously called a pulmonary cystic adenoma-
located in the subcarinal region, while pulmo- toid malformation, CPAM is a rare anomaly in
nary cysts are most often found in the lower development of the lower respiratory tract and
lobes. The cysts contain mucus fluid and may branching of the tracheobronchial tree, with
contain air when there is communication with hamartomatous formations of distal pulmonary
114 C. García Bruce and R. Parra Rojas

a b

Fig. 11.6  Subglottic hemangioma in a 5-day-old new- tion (b) of the neck, severe stenosis of the subglottic air-
born with a progressive stridor. Multidetector helical CT way (arrowhead) secondary to a lesion intensely
scans obtained after intravenous contrast administration impregnated with contrast, compatible with a hemangi-
show, in the axial section  (a) and coronal reconstruc- oma (thin arrows)

a b

Fig. 11.7  Congenital lobar overinflation in a 3-day-old right. (b) A CT scan of the chest shows localized hyperin-
newborn with progressive difficulty breathing. (a) A chest flation of the left upper lobe with displacement of the
x-ray shows hyperinflation of the left upper lobe with sec- mediastinal structures and compression of the left lower
ondary displacement of the heart and mediastinum to the lobe (arrow) and right lung (asterisk)

tissue. Histologically, it is characterized by ade- ferent types of CPAM arise from interruption of
nomatous proliferation of bronchial-type struc- development at different levels of the tracheo-
tures and formation of macro- and ­microcysts bronchial tree and at different stages of pulmo-
coated with columnar or cuboidal epithelium, nary development. These malformations have
with no cartilage or bronchial glands. The dif- been classified into five subtypes according to
11  Study of Images in Respiratory Diseases 115

Fig. 11.8  Bronchial atresia in a 12-year-old girl with a

history of recent right pneumonia. A CT scan of the chest b
below the carina shows a zone of greater transparency in
the right lung (thin arrows), associated with mucosal
impaction and a mucocele in the hilar region on the same
side (thick arrow). There are also two thin-walled cystic
masses inside, compatible with a congenital pulmonary
airway malformation (formerly known as a congenital
cystic adenomatoid malformation) (curved arrows)

their clinical, radiological, and histological

aspects. The most common (representing 70%
of cases) is type I CPAM, which is composed of
several cysts of variable size, with at least one
being dominant (>2 cm) (Fig. 11.11). Type II is
composed of smaller uniform cysts ≤2  cm in c
diameter and represents 15–20% of cases.
Around 10% of cases are type III, which is com-
posed of microcysts, all <0.5  cm in diameter,
generally with one lobe completely compro-
mised. Type IV is very rare and consists of one
or more very large cysts that are not coated by
epithelium and that compromise a pulmonary
lobe. Finally, type  0 is an extremely rare and
lethal form of CPAM in which lung develop-
ment fails completely. All types have arterial
irrigation and normal venous drainage, and the
Fig. 11.9  Bronchogenic cysts in a 2-month-old infant with
radiological aspect depends on the type of bronchial obstruction syndrome. Chest x-rays in the antero-
lesion, the age of the patient, and the presence posterior (a) and lateral (b) views show a mass in the poste-
or absence of complications such as infection. rior mediastinum that displaces the trachea to the right and
The clinical picture varies according to the anteriorly (arrows). (c) An axial CT scan with intravenous
enhancement at the carina level confirms a cystic mass that
patient’s age, the size of the lesion, and whether compresses and displaces the trachea anteriorly (arrow)
there are associated anomalies or complica-
tions. Patients may present respiratory distress
during the neonatal period or remain asymp- sometimes it appears as an incidental finding or
tomatic for variable periods of time. This condi- may be detected in routine prenatal ultrasound
tion may also appear as recurrent pneumonia; examinations.
116 C. García Bruce and R. Parra Rojas

a b c

d e

Fig. 11.10  Bronchogenic cysts in an 11-year-old boy interior of the right upper lobe (arrows). Axial CT scan-
with radiographic findings. Chest x-rays in the anteropos- ning of the chest (d, e) below the carina confirms a thin-
terior (a), AP localized (b), and lateral (c) views show a walled cystic lesion (arrows)
rounded radiolucent image of thin walls with air in the

a b

Fig. 11.11  Congenital pulmonary airway malformation ance, is in the posterior aspect of the lung on that side
in a 2-month-old infant with a cough and breathing diffi- (with upper and lower lobe involvement (arrows)), and
culty. (a) A chest x-ray shows a transparent cystic mass, causes a mass effect, with mediastinal displacement
with thin walls, in the right lung (arrows). (b) A CT scan toward the left
of the chest shows that this mass is multicystic in appear-
11  Study of Images in Respiratory Diseases 117

Types I and  II can grow progressively with nary hypoplasia, a horseshoe lung, CPAM, a
time, communicate with the airway, and fill with bronchogenic cyst, a diaphragmatic hernia, or
air. According to the type of CPAM, a chest x-ray cardiovascular anomalies such as an arterial
shows areas of greater or lesser lung transpar- trunk and total anomalous pulmonary venous
ency, with a mass effect on other chest structures, drainage.
which can be confused with congenital pulmo- The radiological aspect of intralobar seques-
nary hyperinflation or a diaphragmatic hernia. tration depends on the degree of aeration and on
Chest CT is fundamental in diagnosis because it the presence or absence of associated infection.
not only enables characterization of lesions and Nonaerated opacity is a common finding on a
shows their location and extension, but also allows chest x-ray (Fig. 11.12). Mixed opacity is evident
them to be differentiated from other diseases. after recurrent or chronic infections, with air and
Differential diagnosis for CPAM should include sometime fluid levels in their cavities. Newborns
pleuropulmonary blastoma, particularly for type IV. with extralobar sequestration typically show per-
sistently dense images in the posterolateral aspect
Pulmonary Sequestration of the thorax, normally on the left side.
Pulmonary sequestration is a congenital anomaly Chest CT is an indispensable tool in the diag-
characterized by an aberrant pulmonary tissue nosis of pulmonary sequestration and can confirm
mass that does not have a normal connection with the diagnosis through demonstration of aberrant
the tracheobronchial tree or pulmonary arteries. vessels, and also through its extension and venous
It is usually irrigated by an arterial anomaly that drainage (Fig. 11.12). If there is a lung infection,
originates directly from the aorta with venous the sequestration is commonly multicystic. Fetal
drainage through the azygos system, pulmonary MRI can be useful in intrauterine cases when
veins, or inferior vena cava. It normally appears ultrasound findings are inconclusive (Fig. 11.13).
as pneumonia, although (depending on its size) it
can also appear as a chest mass that causes respi-
ratory distress in newborns.  cute Lower Respiratory Tract
A
Pulmonary sequestration is most often found Infections
in the basal segments of the lower lobes, particu-
larly in the medial zone of the lower left lobe. It It is generally not possible to determine with cer-
has traditionally been divided into two types: tainty the etiology of an acute lower respiratory
intralobar and extralobar. In the former, seques- tract infection with just a radiological study and,
tration is contained within the adjacent lobe, with because of this, clinical correlation is fundamen-
which it shares its pleural covering and venous tal. However, there are radiographic characteris-
drainage, normally through the pulmonary veins. tics that can orient the clinician and that correlate
Extralobar sequestration is most often located with anatomopathological manifestations.
between the lower lobe and the diaphragm, and Viral infections produce superficial infection
has its own pleural covering. Around 90% of of the mucosa, and the bronchial and bronchiolar
cases are located on the left side, and the venous walls present edema and diffuse infiltration by
drainage is commonly via the azygos system. inflammatory cells. Often there is compromise of
The clinical picture is diverse. Most cases of the peribronchial tissues and interlobular septa,
intralobar sequestration involve a history of and this may also extend to the alveolar space.
recurrent focal pneumonia, but some of them These alterations are manifested in chest x-rays
appear as an incidental finding, particularly in as interstitial compromise, with thickening of the
newborns and infants. Extralobar sequestration peribronchial and perivascular interstitium, bilat-
is most often diagnosed during the first 6 months eral hyperinflation due to air trapping, and areas
of life with clinical manifestations such as dys- of atelectasis (Figs. 11.14 and 11.15). Less often,
pnea, cyanosis, and difficulty feeding. It can be there can be isolated confluent shadows, usually
associated with other anomalies such as pulmo- without pleural effusion. It is important to note
118 C. García Bruce and R. Parra Rojas

a b

c d

e f

Fig. 11.12  Intralobar pulmonary sequestration of the left much of the left lower lobe (arrows). Axial CT scans with
lower lobe in a 5-day-old infant who had a prenatal ultrasound intravenous contrast enhancement (c, d) and coronal recon-
suggestive of a congenital pulmonary malformation but was struction  (e,  f) confirm the presence of the left lung mass
born without respiratory distress. Chest x-rays in the antero- (asterisk), which receives a systemic arterial supply from at
posterior (a) and lateral (b) views show a mass that occupies least two aberrant arteries that arise from the thoracic aorta
11  Study of Images in Respiratory Diseases 119

a b

LL
S

LK
S

Fig. 11.13  Extralobar pulmonary sequestration in a sin- base of the left hemithorax in the posterior situation, adja-
gleton pregnancy of 34 weeks. Coronal (a) and axial (b) cent to the diaphragm (arrows). L  liver, LK  left kidney,
T2-weighted fetal MRIs show a hypointense mass at the LL left lung, S spine

a b

Fig. 11.14 Interstitial lung disease with bronchial lateral (b) views show marked bilateral pulmonary hyper-
obstruction in an 8-month-old infant with a fever, cough, inflation and interstitial shadowing in the central regions
and wheeze. Chest x-rays in the anteroposterior  (a) and of both lungs (arrows)

that with viral infections, radiological alterations Typically, with bacterial infection, there is an
can take 2–3  weeks to resolve completely, by exudate that occupies air space and progresses
which time there have been clinical improve- until it compromises a segment or lobe, and it can
ments and the child is asymptomatic. Most cases have multiple foci (Figs. 11.16 and 11.17).
of infection resolve without sequelae. However, Radiographically, alveolar condensation
some viruses, such as some strains of adenovirus, appears as a confluent opacity with generally lob-
can leave sequela such as bronchiolitis obliterans ular or segmentary distribution (Fig.  11.16) and
and bronchiectasis. When these predominantly can include an air bronchogram. “Hidden pneu-
affect one lung, this can manifest as a unilateral monia” is common in children and may go unno-
hyperlucent lung. ticed by an inexperienced observer. It is located in
120 C. García Bruce and R. Parra Rojas

a b

Fig. 11.15  Interstitial pneumonia in a 6-month-old infant with a cough and fever. Chest x-rays in the anteroposte-
rior (a) and lateral (b) views show interstitial shadowing in the central regions of both lungs (arrows)

a b

Fig. 11.16  Lobar pneumonia in a 14-month-old infant tion in the right upper lobe, with signs of volume loss and
with a cough and fever. Chest x-rays in the anteroposte- a shifted minor fissure (arrows)
rior (a) and lateral (b) views show pneumonic consolida-

a retrocardiac situation, in the region of the poste- not evident until 12–24  hours after the disease
rior costophrenic sinuses, or in a paramediastinal begins (Fig. 11.18). Pleural effusion, a pneumato-
situation. Because of its morphology, pneumonic cele, and a pulmonary abscess can occur as com-
condensation is always highly visible in the plications (Figs. 11.19 and 11.20). Pneumatoceles
anteroposterior and lateral planes, in contrast to are fine-­
walled air cavities, which commonly
atelectasis, which, in addition to being associated appear 10–14 days after the beginning of infec-
with volume loss, is generally much more evident tion during clinical improvement. A pulmonary
in one of the projections. The visualization of a abscess is a severe complication of a bacterial
central radiolucid area in the condensation can infection and tends to occur early in the course of
represent an aerated lung, excavation, or the for- the disease. Radiographically, it appears as a low-
mation of a pneumatocele. It appears initially as a density lesion, generally at the center of the con-
rounded opaque area (round pneumonia) and is densation of the thick walls, and sometimes with
11  Study of Images in Respiratory Diseases 121

a b

Fig. 11.17  Multifocal pneumonia in a 2-year-old infant dation in the right lung that compromise the upper  (1),
with a persistent fever. Chest x-rays in the anteroposte- middle (2), and lower (3) lobes
rior (a) and lateral (b) views show three spots of consoli-

a b

Fig. 11.18  Early pneumonia in a 6-year-old child with middle third of the left lung (arrows), corresponding to
an 18-hour fever. Chest x-rays in the anteroposterior (a) early pulmonary consolidation
and lateral  (b) views show a small nodular mass in the

a fluid level visible on the x-ray, depending on the ectatic component with a discrete pleural reac-
patient’s position during the study (vertical or tion (usually basal and marginal). A
horizontal). reticulonodular-type pattern can also be present.
Infection by Mycoplasma pneumoniae can Presentations of consolidation of the air space or
cause more than 30% of pneumonia cases in diffuse compromise of both lungs are much less
older children, and radiological alterations can common, are usually associated with greater
simulate other pulmonary diseases. The most clinical compromise, and can be associated with
common pattern consists of poorly defined infil- immunosuppression.
trates (which are predominantly interstitial), While chest CT can provide excellent anatom-
with small areas of alveolar compromise, espe- ical information in pneumonia, in most cases it
cially in one or both lower lobes, or in one of the does not change therapeutic decisions. We gener-
upper lobes. This can be accompanied by an atel- ally do not recommend this technique in the study
122 C. García Bruce and R. Parra Rojas

a b

c d

Fig. 11.19  Left basal pneumonia with uncomplicated sion (arrows). Pleural ultrasound shows the consolidated
pleural effusion in a 5-year-old child. Chest x-rays in the lung (asterisk) and the uncomplicated pleural effusion,
anteroposterior (a) and lateral (b) views show left lower echo-free and without partitions inside (arrows)
lobe pneumonia (asterisk) associated with pleural effu-

of acute lower respiratory infections in children, The examination should be done with imaging
except in certain specific situations such as com- before and after the use of intravenous contrast,
plicated pneumonia, a pulmonary abscess, com- and the finding of adenopathies with central
plicated empyema, or a refractory bronchopleural hyperdense areas is highly suggestive of TB. In
fistula. general, TB should be suspected in all cases of
Pulmonary tuberculosis (TB) merits a sepa- pneumonia with unusual progression, with a
rate mention. The chest x-ray continues to be poor response to antibiotics, or with hilar and/or
the fundamental pillar of TB diagnosis in chil- unilateral mediastinal adenopathies.
dren. In most cases, there is evident localized
lung disease, with partially confluent shadows
and hilar adenopathies, usually unilaterally  iffuse or Focal Diseases
D
(Fig.  11.21). Axial CT is indicated in unusual, of the Pulmonary Parenchyma
complicated, or disseminated cases of the dis-
ease. It provides better definition of the exten- Simple radiography can be useful in diagnosing
sion of lung disease and ganglion compromise. diffuse diseases of the pulmonary parenchyma,
11  Study of Images in Respiratory Diseases 123

a b

c d

Fig. 11.20  Right-sided pneumonia with parapneumonic Pleural ultrasounds  (b–d) show echoic, septate pleural
pleural effusions and empyema in a 10-month-old infant. effusion with fibrin inside (arrows), compatible with
A chest x-ray  (a) shows right pleural effusion (arrow). empyema. (d) The arrow shows the Doppler effect

with excellent spatial resolution and providing

precise anatomical details of the pulmonary
parenchyma. Some of the most common patterns
or alterations are:

Ground glass pattern  This consists of a slight

increase in lung density, with conservation of
normal vascular and bronchial margins. This is
sometimes associated with an air bronchogram
and can be heterogeneous, determining a mosaic
pattern. This pattern can be seen in many pediat-
ric diseases, and infectious pneumonia of any eti-
ology is the most common cause. The pattern can
Fig. 11.21  Pulmonary tuberculosis in a 14-year-old ado- also be seen following bronchoalveolar lavage
lescent with tuberculosis. An anteroposterior chest x-ray
shows an area of consolidation in the right upper lobe
and in pulmonary edema, pulmonary hemor-
(arrows), with volume loss and some areas of lower den- rhage, leukemic infiltrates, pulmonary contusion,
sity inside, compatible with excavation zones (asterisked) respiratory distress syndrome, collagen diseases,
extrinsic allergic alveolitis, drug toxicity,
but high-resolution CT undoubtedly yields the ­interstitial pneumonia, alveolar proteinosis, and
best results, allowing for assessment of the lungs idiomatic pulmonary fibrosis.
124 C. García Bruce and R. Parra Rojas

Consolidation pattern  This appears as a homo- takes the form of multiple cyst-like air spaces, with
geneous increase in the density of the paren- well-defined walls 1–3 mm thick, which are found
chyma, which erases the contours of vessels and mainly in peripheral and subpleural areas.
the walls of the airway, and can include an air
bronchogram. By definition, alveolar air is occu- Bronchiectasis  This is defined as irreversible
pied by liquid, cells, tissue, or other matter. The dilatation of the bronchial tree. The diagnostic
most common causes are pneumonia of any etiol- criteria for axial CT are a greater internal diame-
ogy, pulmonary edema, hemorrhage, and pulmo- ter of the bronchus in comparison with the diam-
nary contusion. eter of the adjacent pulmonary artery branch, loss
of the normal progressive thinning of the bron-
Bronchial disease pattern  This is suspected chus, thickening of the bronchial wall, and iden-
when there is thickening of the bronchial walls tification of bronchus in the periphery of the lung
or of the peribronchial interstitium, when the (1 cm apart from the pleural space). According to
bronchial walls in the peripheral third of the the morphology, this condition is classified as
lungs are clearly identified, or when the thick- cylindrical, varicose, or cystic. The cylindrical
ness of the wall of the proximal bronchial tree form is the only form without thinning of the
represents more than a third of the bronchial bronchus distally, with smooth or slightly irregu-
diameter. lar bronchial walls. The varicose form has a
pearl-necklace appearance, while the cystic form
Tree-in-bud pattern  This pattern represents has a saccular appearance.
severe bronchial impaction. The small airway
that is dilated and/or filled with mucus, pus, or Bronchiolitis obliterans  This is characterized by
inflammatory matter appears as small, well-­ thickening of the bronchiolar wall due to submu-
defined nodules associated with structures that cosal collagenation, with few changes in the distal
branch out. This is commonly seen in infectious parenchyma. Progressive narrowing of the bron-
bronchiolitis of any etiology, endobronchial dis- chioles is associated with lumen distortion, mucus
semination of TB, cystic fibrosis (CF), allergic plugs, and chronic inflammation. This condition is
bronchopulmonary aspergillosis, immobile cilia usually secondary to viral or bacterial infections,
syndrome, bronchiolitis obliterans, and asthma. lung or bone marrow transplantation, collagen dis-
eases, or inhalation of toxic substances. A chest
Air trapping  This is defined as retention or an x-ray can be normal, while CT shows a mosaic
excess of air in a lung, which is evident during pattern due to air trapping or oligemia, which can
expiration and is the result of complete or partial be visualized better in exhalation images.
obstruction of the airway, or local abnormalities
in lung compliance. It is particularly common in
bronchiolitis obliterans, CF, bronchiectasis, and Specific Pathologies of Importance
asthma. The mosaic pattern consists of the pres-
ence of multiple areas of trapped air, generally in Cystic fibrosis  The role of imaging in CF has
both lungs, with segmentary or subsegmentary changed. Care was historically based on clinical
distribution, appearing as areas with greater assessment, using chest x-rays to confirm the
transparency and a decrease in the vascular pat- clinical impression and in the event of suspicion
tern, alternating with normally ventilated areas of overinfection. While chest x-rays continue to
with normal vascularization. be the most commonly used images for study of
CF patients, CT is becoming increasingly
“Honeycomb” pattern  This is indicative of important.
destruction and pulmonary fibrosis involving com-
plete loss of the normal acinus and bronchial archi- Children with CF are born with normal lungs
tecture in the final stage of chronic lung disease. It but rapidly develop a cycle of infection and
11  Study of Images in Respiratory Diseases 125

a b

Fig. 11.22  Cystic fibrosis a 5-year-old child. A chest CT scan (a) shows multiple cylindrical bronchiectases in the right
lung. A coronal CT scan (b) shows maxillary sinuses and ethmoidal sinuses filled with fluid and mucosal edema

inflammation that causes airway disease and common finding. Nuclear medicine has been
eventually parenchymal damage. Thus, a chest used to assess the ventilation/perfusion ratio and
x-ray will be normal in these infants in their first mucus clearance in patients with CF.
year of life. Any alterations that do appear can be
nonspecific and similar to those observed in viral Immotile ciliary syndrome (ciliary dyskine-
or atypical infection, with swelling of the bron- sia)  This term includes diseases that occur as a
chial walls. High-resolution CT is the most accu- direct result of congenital defects of the airway
rate method for assessment of morphological cilia. The main findings are inflammatory sinus
changes in CF. It can detect bronchiectasis, peri- disease (sinusitis), recurring pulmonary infec-
bronchial thickening, mucus plugs, air trapping, tions, situs inversus, and infertility. An a­ ssociation
condensation zones, and lung destruction between chronic respiratory disease and immo-
(Fig. 11.22). tile ciliary is well known. Kartagener syndrome
Bronchiectases are usually diffuse, with com- is characterized by total situs inversus, bronchi-
promise of the upper lobes occurring in most ectasis, and sinusitis, and it affects 50% of
cases and central and peripheral bronchiectases patients with immotile ciliary syndrome. The
being present in two thirds of patients. While cys- radiological aspects and clinical manifestations
tic and varicose bronchiectases are not uncom- of immotile ciliary syndrome are similar to those
mon, the cylindrical form predominates, of CF but less severe. The most common altera-
particularly in small children. Mucosal impaction tions are hyperinflation, peribronchial thicken-
and a mosaic perfusion pattern secondary to air ing, bronchiectasis, mucus plugs, atelectasis, and
trapping are very common findings in CF. Mosaic areas of consolidation.
perfusion can be the only finding in the initial
course of the disease, and mucosal impaction can
manifest as large nodes or elonelongated central
shapes, or as a tree-in-bud pattern in the periph- Sources
ery of the lung. Mucus plugs can, in turn, lead to
segmentary or lobar atelectasis. Total or partial Andronikou S, Irving B, Hlabangana LT, Pillay T, et al.
Technical developments in postprocessing of paediat-
resolution of mucus plugs can reflect therapeutic ric airway imaging. Pediatr Radiol. 2013;43:269–84.
effectiveness and is useful for monitoring the dis- Arce JD.  Estudio radiológico de la vía aérea central.
ease. Hilar lymphadenopathy is another relatively Neumol Pediatr. 2012;7:72–83.
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Calder A, Owens CM. Imaging of parapneumonic pleural dren: evolution from axial to 4-D assessment. Pediatr
effusions and empyema in children. Pediatr Radiol. Radiol. 2013;43:285–97.
2009;39:527–37. Lucaya J, Strife JL. Pediatric chest imaging: chest imag-
Carsin A, Mely L, Chrestian MA, Devred P, De Lagausie ing in infants and children. Berlin: Springer; 2002.
P, Guys JM, et al. Association of three different con- Lyons K, Cassady C, Mehollin-Ray A, Krishnamurthy
genital malformations in a same pulmonary lobe in a R.  Current role of fetal magnetic resonance imag-
5-year-old girl. Pediatr Pulmonol. 2010;45:832–5. ing in body anomalies. Semin Ultrasound CT MR.
Deshmukh S, Rubesova E, Barth R.  MR assessment of 2015;36:310–23.
normal fetal lung volumes: a literature review. AJR Mong A, Epelman M, Darge K. Ultrasound of the pediat-
Am J Roentgenol. 2010;194:W212–7. ric chest. Pediatr Radiol. 2012;42:287–97.
Recio Rodríguez M, Martinez de Vega V, Cano Alonso R, Pedata R, Palermo M, Maiello M, Esposito N, Ermito
Carrasco Arranz J, Martinez Ten P, Perez Pedregosa S, Dinatale A, et  al. Fetal lung lesions diagnosis:
J. MR imaging of thoracic abnormalities in the fetus. the crucial role of ultrasonography. J Prenat Med.
Radiographics. 2012;32:E305–21. 2009;3:49–52.
Dillman JR, Attili AK, Agarwal PP, Dorfman AL, Ramos-Duran L, Nance JW Jr, Schoepf UJ, Henzler T,
Hernandez RJ, Strouse PJ. Common and uncommon Apfaltrer P, Anthony M, Hlavacek AM. Developmental
vascular rings and slings: a multi-modality review. aortic arch anomalies in infants and children assessed
Pediatr Radiol. 2011;41:1440–54. with CT angiography. AJR Am J Roentgenol.
Espinoza A.  Ultrasonido del tórax pediatrico. Neumol 2012;198:W466–74.
Pediatr. 2015;10:58–66. Raychaudhuri P, Pasupati A, James A, Whitehead B,
Irodi A, Prabhu SM, John RM, Leena RV.  Congenital Kumar R. Prospective study of antenatally diagnosed
bronchopulmonary vascular malformations, “seques- congenital cystic adenomatoid malformations. Pediatr
tration” and beyond. Indian J Radiol Imaging. Surg Int. 2011;27:1159–64.
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 Assessing Arterial Oxygen
Saturation
12
Christian Poets and Pablo Brockmann Veloso

Contents
Oxygen Transport in the Blood...................................................................................  127
Transcutaneous Measurement of Oxygen Saturation...............................................  128
 actors That Affect Oxygen Saturation Measurement.............................................  129
F
Type of Sensor and Its Placement...................................................................................  129
Peripheral Perfusion.......................................................................................................  129
Response Time................................................................................................................  130
Motion Artifacts..............................................................................................................  130
Influence of Changes in Hemoglobin and Skin Pigmentation........................................  130
Influence of Specific Algorithms....................................................................................  131
Precision in Detecting Hyperoxemia and Hypoxemia....................................................  131
SpO2 Reference Values.................................................................................................  131
Transcutaneous Oxygen Measurement.......................................................................  132
Sources...........................................................................................................................  133

Oxygen Transport in the Blood coefficient is only 0.003 ml of oxygen for every

100 ml of blood.
The dissolved oxygen transported in the blood Hemoglobin (Hb) is the main oxygen
constitutes a small fraction of the total oxygen transporter, which bonds with the Fe++ of the
content, which has a direct relation to the partial hemoglobin molecules. Each hemoglobin cell
oxygen pressure (Henry’s law). The solubility contains four Fe++ ions; thus, every Hb molecule
transports four oxygen molecules in the form of
a compound that easily delivers oxygen to tissue,
C. Poets (*) called oxyhemoglobin (HbO2). Under normal
Department of Neonatology, University Children’s
Hospital Tübingen, Alemania, Tübingen, Germany conditions, every gram of hemoglobin transports
e-mail: [email protected] 1.34  ml of oxygen. The oxygen content is the
P. Brockmann Veloso sum of dissolved oxygen plus the oxygen that
Department of Pediatrics, School of Medicine, is chemically bonded to the hemoglobin. The
Pontificia Universidad Católica de Chile, oxygen content is determined by both the partial
Santiago, Chile pressure of oxygen (PaO2) and the quantity of
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 127

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_12
128 C. Poets and P. Brockmann Veloso

hemoglobin and its degree of arterial saturation 600–750  nm), while unoxygenated hemoglobin
(SaO2), which is represented by the following absorbs more infrared light (at 850–1000  nm).
formula: The pulse oximeter emits light at two specific
CaO2 = Hb ´ 1.34 ´ SaO2 + PaO2 ´ 0.003
wavelengths (660 and 940 nm), which are trans-
mitted through tissue (a finger, for example) and
sensed by a photodetector. The light absorbance
radius of the two wavelengths correlates with the
Transcutaneous Measurement saturation of the oxygenated hemoglobin in the
of Oxygen Saturation tissue blood, in accordance with a pre-established
formula (Fig. 12.1). However, of all of the light
Pulse oximeters do not measure oxygen concen- that is absorbed, only the light absorbed by the
trations in the plasma; rather, they measure the pulsatile component of the arterial vasculature
proportion of hemoglobin that carries oxygen correlates with the arterial oxygen saturation.
molecules, which is termed oxygen saturation. Consequently, the pulse oximeter makes use of
This technique was first developed in 1975 but the fact that the expansion and contraction of
not introduced into clinical practice until 10 years the vasculature causes changes in the distance
later. The terms for the oxygen saturation values the light has to travel, which in turn changes the
are saturated and unsaturated. This technique is amount that is absorbed. The peaks and nadirs of
based on a simple physiological principle, which the amount of light absorbed are determined by
determines that oxygenated and unoxygenated measuring the light transmitted several hundred
hemoglobin absorb light rays differently. The times per second. The peak oximeter divides the
former absorbs more light from the red band (at absorbance in the peaks by that in the nadirs. This

Fig. 12.1 Absorption 1
mechanism used in pulse
oximetry
(Red) (Infrared)
660 nm 940 nm

0
Extinction 10x

O2Hb

-1
H Hb

-2
600 700 800 900 1000
Wavelength
12  Assessing Arterial Oxygen Saturation 129

absorbance ratio is different from that in nonpul- patient, proper placement of the sensor should be
satile tissue. The value obtained from the absor- ensured. The light emitter should be facing the
bance ratio in pulsatile tissue can be extrapolated receiver, with both correctly covered to avoid
to a pre-established scale of oxygen saturation contact with ambient light. The sensors should be
values. fastened to a fabric that does not let light pass
through. The sensors should not be fastened to
the skin with excessive force (over 50  mm Hg)
 actors That Affect Oxygen
F that could affect the signal-to-noise ratio and
Saturation Measurement severely disturb the operation of the SpO2 sensor.
Another less common problem with pulse
Pulse oximeters are relatively easy to use. They oximeters is skin lesions by burning. This usu-
do not require calibration or preheating of the ally occurs when a different type of sensor is used
patient’s skin, and they can be used immediately from that determined by the oximetry equipment
with all types of patients of any age. However, or when the surface of the sensor has been dam-
there are factors that can affect peripheral oxygen aged. The sensor should be checked to ensure
saturation (SpO2) measurement and interpreta- it is the correct one, and its position should be
tion, which are discussed below. changed every 8 hours.
It is worth noting that, to date, little atten-
tion has been given to the performance of differ-
Type of Sensor and Its Placement ent types of sensors in newborns and infants. In
fact, we know of no study that has systematically
The location of the sensor is the most important assessed the differences among sensors used in
factor in obtaining a real SpO2 value. Incorrect this age group. In the experience of the authors,
placement results in an optical shunt, which hap- more flexible sensors provide more reliable SpO2
pens when the light received by the photodiode measurements in young patients, given that these
does not pass correctly through the tissue to be sensors can be applied more easily, without the
analyzed. Incorrect placement can also result in need for a lot of pressure to fasten them. The
exposure to ambient light, which can affect the problem with flexible sensors is that they tend
measurement. In most cases where this occurs, to be more expensive than more fixed or rigid
ambient light accounts for 85% of SpO2 read- sensors.
ings, which is approximately the extrapolated
value that corresponds to a ratio of 1:0 between
red and infrared light. Overestimations occur as a Peripheral Perfusion
result of exposure to an excess of ambient light,
which can lead to a belief that a patient is prop- Pulse oximeters depend on peripheral perfusion,
erly saturated, while in reality the values are low. and most of the equipment currently available
Actual hypoxemia may pass undetected in these requires at least 20 mm Hg of pulse pressure or
patients. systolic pressure of over 30 mm Hg to operate
An optical shunt can also occur in the absence adequately and reliably. The efficiency of the
of ambient light. This is because in the major- pulse oximeter falls significantly if the pressure
ity of oximeter devices, the red light and infra- falls below these thresholds. The most reliable
red emission diodes are 2–3  mm apart. If the test of correct functioning is the signal-to-
sensor is detached and one of the diodes is left noise ratio, which can be appreciated through
out, it can produce falsely low (60–70%) or high the pulse curve, built into most new oximeters.
(95–100%) SpO2 values, depending whether it is There are significant variations among the dif-
the infrared diode or the red-light diode that is ferent pulse meter brands with respect to the
uncoupled, respectively. To avoid this situation, SpO2 reading in situations of hypotension—for
which can result in clinical complications for the example, shock.
130 C. Poets and P. Brockmann Veloso

Response Time detection of threatening situations on the basis of

determined limits.
In theory, the response time of the pulse oximeter
depends only on the time it takes the oxygen-
ated blood to reach the point where the sensor is Motion Artifacts
located, which is 4 seconds to the toe of a new-
born, 4.5 seconds to that of an infant, and 5.5 sec- The pulsatile (arterial) component contributes
onds to that of a child of around 5 years of age. only 1–5% of the total absorbance as measured
However, the pulse oximeters available nowadays by the pulse oximeter. Consequently, the instru-
average the values registered in a range from 2 to ment is very sensitive to signal changes—for
15  seconds (average time) or 4 to 32 beats per example, body movement. It is particularly
minute, to avoid errors and provide a more reli- important to identify the presence of movements
able reading of SpO2. in order to discount them. This can be done by
This procedure attempts to reduce the num- analyzing the plethysmograph curve from the
ber of false alarms. The longer the average time SpO2 reading. Ideally, the plethysmograph curve
of these values is, the more slowly the equip- should be complete. The SpO2 values are not reli-
ment reacts to changes. For example, fewer able and must be discarded if the curve is dis-
alarms sound with postural changes; however, rupted or incomplete. A less reliable alternative
this extends the time that the physician has to is to compare the pulse rate and the heart rate
react to real changes in SpO2 or it can lead to obtained with the electrocardiograph, because
false low SpO2 values if the patient is constantly the two rates should be identical. Without a sys-
moving, and this might falsely suggest the pres- tem for validating and excluding artifacts, SpO2
ence of hypoxemia. Erroneous readings can be values should not be interpreted.
indistinguishable from real hypoxemia, particu-
larly without pulse plethysmography curves. In
addition, the use of the average time can lead to I nfluence of Changes in Hemoglobin
erroneous conclusions in situations in which a and Skin Pigmentation
very precise measurement of SpO2 is required.
An example is the decision to use supple- Pulse oximeters only use two light wavelengths.
mentary oxygen in newborns and infants with Consequently, they cannot identify abnormal
bronchopulmonary dysplasia. The association hemoglobin or pigments that can interfere with
between oxygen desaturations and cardiorespi- the reading. Some of these pigments or distinct
ratory events such as apnea necessarily require forms of hemoglobin—among them fetal hemo-
a short average time. Finally, the different aver- globin—absorb light, which results in false
age SpO2 times make it impossible to define readings. Methemoglobinemia will give values
normal values in a population and extrapolate of around 85% of SpO2, and carbon monox-
them to oximeters with different average times. ide intoxication will result in falsely high SpO2
Therefore, all of the reference values obtained values. Bilirubin generally does not alter pulse
with a specific pulse oximeter can be extrapo- oximeter readings.
lated only to subjects in which the same equip- Reference studies of skin pigmentation and
ment is used. SpO2 have yielded variable results. A study
These problems can be overcome by using involving nine premature African American new-
the beat-to-beat mode, which provides an SpO2 borns concluded that a Nellcor N100® overesti-
value for every heartbeat. However, every clini- mated SpO2 by 5% in two cases, but the others
cal unit must decide to what extent it needs SpO2 were very precise. Another study showed falsely
measurements and whether oximetry is intended high SpO2 levels in black adults but only if the
for adequate diagnosis (for example, polysom- SpO2 was <90%. At higher levels, there are no
nography) or for more general monitoring and discrepancies between SpO2 and SaO2. This
12  Assessing Arterial Oxygen Saturation 131

­ atter is remains unclear, and more studies are

m  recision in Detecting Hyperoxemia
P
required, especially in relation to children. and Hypoxemia

Pulse oximeters derive their measurements from

Influence of Specific Algorithms algorithms based on empirical in  vitro data on
oxygen saturation values obtained from healthy
Pulse oximeters extrapolate their measures to a adult volunteers, in which SpO2 generally varies
table of predetermined values, which is based on within a normal range around 100%. Most sup-
empirical data obtained in adults. Consequently, pliers maintain that their equipment shows SpO2
these instruments should be revalidated to be values at close to ±4–6% of the real SaO2 val-
used in children. Studies that have compared ues. Normal SpO2 levels in infants and preschool
different types of pulse oximeters have found children are in the same range as those in adults.
statistically significant differences in their However, with SpO2 below 75–80%, the val-
results. Moreover, the same equipment can yield ues are simply extrapolated from the algorithm
significant differences when applied to different obtained with higher SpO2 values. This procedure
age groups. can result in underestimation of the real oxygen
These differences among devices can be partly saturation values. Given the above, we do not
explained by the ways in which the equipment know the real sensitivity of oximeters to screen
shows or calculates SpO2. Examples of this are for low SaO2 values in seriously ill children—for
the Nellcor® oximeter, which measures functional example, those in shock or with associated infec-
SpO ([HbO2/(HbO2 + RHb)] ∗ 100)—where RHb tious problems.
is reduced hemoglobin—as compared with the Given the shape of the hemoglobin disso-
Ohmeda® oximeter, which estimates the frac- ciation curve, pulse oximeters are not ideal for
tional SpO [HbO2/(HbO2 + RHb + MetHb + CO screening for hyperoxemia. The upper limit above
Hb) ∗ 100]—where MetHb is methemoglobin and which there is not sufficient sensitivity to screen
COHb is carboxyhemoglobin. The former equip- effectively varies depending on the equipment.
ment estimates SaO2 by simply subtracting 2%, There have been few studies involving children
which represents MetHb and COHb concentra- that have correlated high SpO levels with SaO2
tions, and displaying an SpO2 that is 2% less than and established a threat level (Fig. 12.2).
the fractional SpO2. However, in the clinical con-
text, functional SpO2 is preferred, and COHb and
MetHb are determined only in patients in whom SpO2 Reference Values
clinical suspicion requires them.
The differences in the values obtained in The correct clinical application of the nocturnal
studies using the same equipment could be saturometer requires adequate SpO2 reference
caused by the way in which motion artifacts values for every age, type of equipment, soft-
are discounted. For reasons that are explained ware, and clinical scenario for the patient. For
below, another important factor is the SpO2 evident reasons, these are very difficult to obtain,
values that are measured: the lower the SpO2 and reference values from healthy populations—
range is, the less precise the measurement is. mostly, young adult volunteers—have been used
The differences can likewise be explained by to interpret pulse oximeter algorithms.
different types of software. This can explain There have been a series of studies to establish
why in a 1990 study the same Ohmeda Biox values for pediatric ages, particularly for prema-
III/3700® underestimated real SaO2 values by ture and term newborns and small infants, where
2.9%, while in 1991 this same equipment over- the deviation from the reference values for adult
estimated SaO2 by only 0.4%. Reassessments populations are the greatest.
should be done when every new version of the Most studies that cite references have provided
software is installed. oxygen saturation averages and means, without
 132 C. Poets and P. Brockmann Veloso

100
PTc O2 (mm Hg) / SpO2(%)

80
SpO2 limit

60

PtcO2 limit
40

Masimo SET OXISMART N-200 Pulse Rate

250
Pulse/Pulse Rate (L/min)

200

150

100 Heart rate limit

50
341 342 343 344 345 346 347 348
Time (min)

Fig. 12.2  Comparison of different pulse oximetry equipment

fixing on the number and frequency of desaturation The desaturation index of 4 percent (ID4) of
events. The desaturation index (DI) is one of the SpO2 is within normal limits when the index is < 4
most important elements, especially in newborns points per hour (in children above 1 year of age).
and infants, to detect pathological conditions. ID We recommend using a saturation index below 80%
corresponds to the total count of times that SpO2 of SpO2, which is considered normal if it is less than
values fall 3–4 points during 1 hour. In a study that 1.5 events per hour in infants under 3 months of age.
involved more than 200 child volunteers, our team A consolidated SpO2 under a specific cutoff is
found a significant presence of desaturation among widely used in chronic lung disease, such as bron-
completely healthy babies less than 3  months of chopulmonary dysplasia. The cutoff depends on
age. This level of desaturation was consistent with the equipment. For example, when Massimo SET
those described in other works, emphasizing that equipment is used, it is considered normal if the
desaturation by 3 or 4 points in children in this age patient has an SpO2 of <90% for <3% of the time.
range may be physiological. In contrast, in school-
children and adolescents, desaturation by 3 or 4
points has a pathological connotation, suggesting Transcutaneous Oxygen
obstructive sleep apnea. Measurement
Unlike what happens with desaturation events,
SpO2 averages tend to be quite even and are simi- Transcutaneous oxygen (TCPO2) measurement
lar at different pediatric ages. SpO2 is normally is a noninvasive method to determine the partial
expected to be above 95%. oxygen pressure from the surface of the skin,
12  Assessing Arterial Oxygen Saturation 133

using an electrode that chemically senses the con- Sources

centration of oxygen molecules circulating in the
blood. The oxygen molecules that pass through Bohnhorst B, Geuting T, Peter CS, Dordelmann M,
Wilken B, Poets CF. Randomized, controlled trial of
the skin are illuminated by an optical fiber that oral creatine supplementation (not effective) for apnea
emits a specific light. The electrode consists of of prematurity. Pediatrics. 2004;113:e303–7.
a platinum cathode and a silver reference anode Brockmann PE, Poets A, Urschitz MS, Sokollik C,
separated by an electrolyte solution that is perme- Poets CF.  Reference values for pulse oximetry
recordings in healthy term neonates during their first
able to oxygen. The electrode is heated to 42 °C, 5  days of life. Arch Dis Child Fetal Neonatal Ed.
which diffuses the oxygen molecules from the 2011;96:F335–8.
skin to the electrode. Once they are in the elec- O’Brien LM, Stebbens VA, Poets CF, Heycock EG,
trode, the oxygen molecules are reduced, generat- Southall DP.  Oxygen saturation during the first
24  hours of life. Arch Dis Child Fetal Neonatal Ed.
ing an electrical current. The red reflection that is 2000;83:F35–8.
produced is interpreted by the probe as the partial Poets A, Urschitz MS, Poets CF. Intermittent hypoxia in
oxygen pressure according to an algorithm. supine versus side position in term neonates. Pediatr
Pulse oximeters and apparatuses that calculate Res. 2009;65:654–6.
Poets CF, Stebbens VA, Alexander JR, Arrowsmith
TCPO2 perform measurements in different but WA, Salfield SA, Southall DP.  Oxygen saturation
related ways. Because the relationship between and breathing patterns in infancy. 2:  Preterm infants
PaO2 and SaO2 is based on the hemoglobin dis- at discharge from special care. Arch Dis Child.
association curve, this is not linear or constant. 1991;66:574–8.
Poets CF, Stebbens VA, Samuels MP, Southall
Thus, the values obtained from measuring the DP. Oxygen saturation and breathing patterns in chil-
TCPO2 do not necessarily reflect the SpO2 in dren. Pediatrics. 1993;92:686–90.
the same patient. There are several factors that Poets CF, Urschitz MS, Bohnhorst B. Pulse oximetry in
should be taken into consideration when extrapo- the neonatal intensive care unit (NICU): detection
of hyperoxemia and false alarm rates. Anesth Analg.
lating one value to another: the measuring time, 2002;94:S41–3.
the number of measurements, and the peripheral Richard D, Poets CF, Neale S, Stebbens VA, Alexander
perfusion of the patient. The equipment for mea- JR, Southall DP.  Arterial oxygen saturation in pre-
suring TCPO2 also has a series of disadvantages, term neonates without respiratory failure. J Pediatr.
1993;123:963–8.
including the fact that it is difficult to use and Urschitz MS, Wolff J, Sokollik C, Eggebrecht E, Urschitz-
the sensors need to be changed often, because of Duprat PM, Schlaud M, et al. Nocturnal arterial oxygen
which it is recommended to use the equipment as saturation and academic performance in a community
a complement to the pulse oximeter. sample of children. Pediatrics. 2005;115:e204–9.
 Assessment of Sleep in Newborns
to Adolescents
13
Óscar Sans Capdevila and David Gozal

Contents
Introduction...................................................................................................................  135
Sleep in Childhood and Adolescence.............................................................................  136
Functions of Sleep..........................................................................................................  136
Diagnosis........................................................................................................................  137
 namnesis......................................................................................................................  137
A
Complete Physical Exploration......................................................................................  137
Useful Tools....................................................................................................................  138
Complementary Tests.....................................................................................................  141
Conclusion.....................................................................................................................  143
Sources...........................................................................................................................  144

Introduction nervous system, accompanied by variations in

intellectual function that constitute dreaming.
Sleep is a physiological state that is reversible, Historically, sleep has always been consid-
cyclical, and appears in opposition to the state of ered a passive state, although today it is seen as a
wakefulness. It presents characteristic behavioral paradoxically active one in which several neural
manifestations such as a relative absence of systems intervene that are mutually regulated:
mobility and a higher response threshold for the diencephalon, brain trunk, and cerebral cor-
external stimuli. At the organic level, sleep pro- tex. Humans spend approximately a third of their
duces a series of modifications of activity in the lives sleeping. It has been shown that sleep is
absolutely necessary, given that physiological
functions occur during sleep that are essential
for the physical and psychic balance of individu-
als, restoration of homeostasis of the central ner-
Ó. Sans Capdevila
Department of Pediatric Neurology, vous system and of other tissue, reestablishment
Hospital Sant Joan de Déu, Barcelona, Spain of cellular energy stores, and consolidation of
e-mail: [email protected] memory.
D. Gozal (*) The quantitative need for nocturnal sleep var-
Department of Pediatrics, The University of Chicago, ies as a function of age, the state of health, the
Chicago, IL, USA emotional state, and other factors. The ideal
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 135

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_13
136 Ó. Sans Capdevila and D. Gozal

d­ uration is one that allows us to undertake our slept in the first days of life. Newborns sleep
daily activities with normality. It has always been for more than 16 hours per day, distributed over
considered that sleep is related to behavior. several periods. The sleep is characterized by
However, the specific characteristics of the elec- irregular breathing and an irregular heart rate,
trical brain function registered by electroencepha- rapid eye movements, axial muscular atony,
lography (EEG) confirm that there is a relationship and brief muscular contractions accompanied
between base brain activity and the state of sleep. by facial motions such as smiles and sucking.
Polysomnography (PSG) was also developed for • Beginning at 2–3 months of age: Sleep spin-
this purpose and provides standardized and simul- dles (characteristic of phase  2) appear.
taneous reading of several biological signals dur- Differentiation of all sleep stages is now pos-
ing the wakeful and sleeping states, allowing for sible. The number of hours slept begins to
their clear differentiation. These bioelectrical sig- decrease at this age as part of changes relating
nals are processed digitally. to cerebral maturation, which is expressed
There are two well differentiated types of fundamentally by a reduction in REM sleep.
sleep: rapid-eye-movement (REM) sleep and non- • At 12 months: The mean duration of sleep is
REM (NREM) sleep. REM sleep is associated 12–13 hours per day, 30% of which is in the
with a high level of neuronal activity and dream- form of REM sleep.
ing, while NREM sleep is divided into three states • At 2  years: The child sleeps for an average
according to the new terminology recommended 13  hours, which falls to 10–12  hours at
by the American Academy of Sleep Medicine: 3–5 years and 11 hours at 5 years of age.
phase  1 is the shortest phase and represents a • Between 6 and 10 years: The central nervous
superficial level of sleep; phase 2 represents 50% system is almost completely mature, and the
of the total time slept; and phase 3 represents the child sleeps for an average of 10 hours per day.
deepest and most repairing level of sleep. • In adolescence: The number of hours needed
REM and NREM sleep alternate cyclically for sleep increases, and there is a physiologi-
(4–6 times) during nocturnal sleep. Deep sleep cal tendency for individuals to go to sleep at a
predominates during the initial phases of the later hour.
night. The duration of the REM sleep periods • In young adults: Young adults spends some
increases progressively in successive cycles. 8  hours per day sleeping, most of which is
NREM sleep (phase  1: approximately 5%;
phase 2: approximately 50%; phase 3: approx-
Sleep in Childhood and Adolescence imately 20%). At this age, REM sleep does
not represent more than 25% of the total time
Sleep behavior varies throughout life in the func- sleeping.
tioning of intrinsic and extrinsic biological cycles,
with changes related to development of the cen-
tral nervous system and to educational, work- Functions of Sleep
related, and social conditioning factors. These
determinants vary depending on the stage of life: Just as REM and NREM sleep differ physiologi-
cally, they also have different functions. NREM
• At the intrauterine stage: The human fetus sleep has a restorative capacity, favoring energy
presents wakefulness–sleep cycles (lasting processes and protein synthesis. It increases the
less than 24  hours) at 30–32  weeks of release of growth hormones, decreases the stress
gestation. response (cortisol synthesis), and favors cellular
• In newborns and 3-month-old infants: Active regeneration. REM sleep plays an important role
sleep, the precursor to REM sleep, lasts the in attention and memory processes and in con-
longest, representing 60% of the total time solidation of learning.
13  Assessment of Sleep in Newborns to Adolescents 137

Diagnosis Table 13.1  Indications to perform a polysomnography test

Indications
Anamnesis Excessive daytime sleepiness unrelated to chronic sleep
deprivation; for diagnosis of hypersomnia, a multiple
sleep latency test (MSLT) may be necessary
It is necessary to assess the following aspects: Alteration of the respiratory pattern during sleep;
suspicion of sleep apnea
• Age at onset: The presence of processes other Violent motor activity or abnormal behaviors related to
than the usual ones for a given age should sleep; differential diagnosis between parasomnias and
nocturnal frontal lobe seizures
raise suspicion of a problem; examples include
Periodic limb movement disorder (PLMD) during sleep
daytime naps beyond the age of 6  years,
Source: American Academy of Sleep Medicine
appearance of parasomnias in adolescence, or
persistence of nocturnal enuresis beyond the
age of 6 years.
• Incorrect habits: Aspects related to healthy • Use of pharmaceuticals and other drugs that
sleeping habits should always be valued: the can affect sleep: These include antihistamines,
type of response of the parents; bedtime antidepressants, antismoking drugs, or drugs
schedules; the types of leisure activities of used in adolescents.
children/adolescents; and the presence of tele- • The presence of other concomitant patholo-
vision, computers, mobile phones, and/or gies: These include organic disorders (gastro-
video games in the sleep routines or the room esophageal reflux, asthma, obesity, atopic
of the patient. dermatitis, blindness, etc.), neurological dis-
• Description of sleep over 24 hours: This refers orders (headaches, epilepsy, attention deficit
to how and how much the patient sleeps over disorder, hyperactivity, etc.), psychiatric dis-
the course of a day. orders (depression and anxiety), and social
• Family history of sleep disorders: There are disorders (family problems, mistreatment,
processes with a hereditary basis that should abuse, and certain types of parent–child rela-
be considered, such as insomnia, restless leg tionship or partner relationship).
syndrome (RLS), and phase delay. Sleep
apnea has an evident genetic component, In summary, what happens during the night and
because of which we should investigate other during the day should be assessed (see the indica-
cases of this pathology in the family. Likewise, tions suggested in Table 13.1).
it is advisable to consider unfavorable envi-
ronmental or socioeconomic situations—for
example, smokers in the family. Complete Physical Exploration
• Transitory alterations: These include the birth
of a sibling, a new school, or a change of home. Mouth breathing does not correlate with the pres-
• Disorders associated with chronic problems: ence of catarrh or adenoid–amygdala hypertrophy,
These include problems such as asthma, rhini- nor does it coincide with aspects of craniofacial
tis, and atopic dermatitis. anatomy, the upper respiratory tract, retrogna-
• Effects of other biological functions: Examples thism, the Mallampati score, and midfacial hypo-
include eating habits, nighttime or daytime plasia (Fig. 13.1).
behavior, the type of respiration during sleep, The degree of adenoid–amygdala hypertrophy
the appearance of snoring, the presence of does not correlate linearly with the presence of
apnea, and leisure habits. sleep apnea–hypopnea; small adenoids and a
• Typical sleep-specific sleep disorders: These small amygdala do not exclude the condition if
include sleep apnea–hypopnea and RLS. other symptoms are present.
138 Ó. Sans Capdevila and D. Gozal

practice time, because of which it is recom-

mended to have a practice time of about 15 days.
Figure 13.2 is an example of a real diary.
This time period provides a baseline that is
more reliable and representative of the character-
istics of sleep. Likewise, it makes it possible to
monitor the progress of the child, facilitating
self-assessment of the problem, and at the same
time it is reassuring for the parents, who can
observe improvements.
A sleep schedule is composed of a table with
Fig. 13.1  Tonsillar hypertrophy in a 15-year-old patient
vertical subdivisions for every day of the month
with obstructive sleep apnea (OSA) and horizontal subdivisions for every hour of
every day. It should indicate times for going to
bed and rising, highlighting the hours spent
Useful Tools sleeping. In this way, it provides a global view of
the subject’s sleep: total hours slept, latency, noc-
Some useful tools are available for general turnal awakenings, and bedtime and awakening
assessment of children and adolescents, and these routines. Using the diary, parents can provide rel-
are discussed below. evant information about the child’s sleep and his
or her social context.
 leep Duration Percentiles
S
Every child has his or her own sleep require- Actigraphy
ments, and there are no absolute data in this An actigraph assesses rest and active phases
respect. Iglowstein et al. (2003) studied 500 chil- according to measurement of motor activity,
dren and adolescents to establish reference values which can be determined in an ambulatory sub-
and to establish how naps are distributed accord- ject with an actigraph/actimeter. The sleep diary
ing to age. The percentiles help to determine the and the actigraph provide similar information,
evolution of sleep, inform doctors if changes but studies have pointed to interesting differ-
have occurred, and allow them to compare a ences in terms of information on the quality and
child’s habits with those of other children. continuity of sleep. The most notable difference
is that the sleep diary fails to register all noctur-
Sleep Diary nal awakenings, given that the parents are often
Knowledge about the number of hours a child not aware of many aspects of their child’s sleep
spends sleeping and awake over the 24 hours of a or are confused about times when reporting
day is fundamental and can be obtained and orga- them.
nized with the use of a sleep diary. The health
professional can suggest to the patient’s parents Actigraph/Actimeter
that they keep a register of when the child goes to An actimeter is the size of a watch and detects
bed, the time the child remains awake in bed bodily movements during activities. It provides
before going to sleep, the frequency with which information about the chronology and duration of
the child wakes up at night, the amount of time sleep phases and events related to them. Periods
the child remains awake during the night, what of inactivity are interpreted as periods of sleep. It
time the child wakes up in the morning, and how constitutes a very useful tool for diagnosing
the child feels in the morning (quality of sleep). A delayed sleep phase syndrome (which is more
diary with these characteristics can also be used common in adolescents and young adults). The
to assess the appropriateness of daily routines as transition time from wakefulness to sleep in this
they relate to sleeping habits. It requires some disorder is generally delayed by more than
13  Assessment of Sleep in Newborns to Adolescents 139

Morning Afternoon Evening

Wednesday 10.09.13 10.40-12.20 20.30-23.20 (100ml of milk) / 23:25-3.45

(diaper change) /5.10-7.45 (fell asleep
after milk)
Thursday 10.10.13 11.00-14.00 Did not sleep 20.30-23.15 (100ml of milk) / 23.15-1.30
(diaper change) /1.40-7.00 (milk on the
recommendation of the kinesiologist)

Friday 10.11.13 Did not sleep 13.30-16.00 21.00-23-15 (milk) / 23.15-00.30 / 00.35-
02.00 / 02.05-7.30
Saturday 10.12.13 20.00-22.00 (milk) / 22.00-3.00 / 3.00-4.00 /
Did not sleep 12.30-14.00
4.00-5.00 / 5.00 (milk)-8.00

Sunday 10.13.13 Did not sleep 12.50-14.40 20.10-22.20 (milk) / 22.20-5.30 (woke up
but went back to sleep right after) /
5.30-7.40

Monday 10.14.13 Did not sleep 12.55-16.10 20.30-22.20 (leche) / 22.20-1.30 / 1.35-4.00 /
4.45-6.50 (fell asleep only after milk)

Tuesday 10.15.13 Did not sleep 12.00-13.20 20.30-23.00 (milk) / 22.00-1.00 / 2.45-6.50
(restless between 1.00 and 2.45)

Wednesday 10.16.13 9.45-11.50 Did not sleep 20.10-22.35 (milk) / 22.45-1.00 / restless
between 1.00 and 3.00 / milk
6.30 / 6.30-7.45

Thursday 10.17.13 10.40-12.50 16.10-17.00 20.30-

Friday 10.18.13 Very bad night (coughing)

Saturday 10.19.13 Bad night

Sunday 10.20.13 11.50-13.15 17.30-18.00 20.30-1.00 (milk) / 1.00-6.00 (milk)

6.00-7.30
Monday 10.21.13 10.40-12.40 Did not sleep 20.00-00.00 (cried, did not drink milk) /
00.00-3.30 (did drink milk) / 3.30-7.30

Tuesday 10.22.13 11.00-12.00 17.30-18.15 20.30-2.00 / 3.00 / 7.30

Wednesday 10.13.13

Thursday 10.24.13 11.00-12.30 Did not sleep 20.00-00.00 / 00.00-2.45 / 5.15-8.00

Fig. 13.2  Sleep diary of a patient who snores

2  hours in relation to the conventional time of sleep is reduced as a result of the delay in
needed to fall asleep. Patients have difficulty beginning sleep.
going to sleep at the start, but once they are
asleep, the structure and quality of sleep are com- Domestic Video
pletely normal. They also have difficulty waking This can be a useful tool in diagnosing sleep dis-
up in the morning, because the number of hours orders. It is focused fundamentally on assessing
140 Ó. Sans Capdevila and D. Gozal

respiratory disorders during sleep (the Sivan There are broader and specific questionnaires
video score), parasomnia with rhythmic move- that require more time to complete and serve to
ments, and periodic movements of the focus on specific problems such as parasomnias,
extremities. respiratory disorders during sleep, etc. There are
With the Sivan video score, the parents are also questionnaires that are simpler and easier to
asked to record their child sleeping for 30 min- complete for screening for pediatric sleep disor-
utes. Specifically, the parents should be asked to ders. Some of these that can be useful in primary
ensure that the child sleeps with his or her chest health care are described below (for a more com-
and abdomen uncovered. The parents should plete and in-depth review of sleep questionnaires
record any sounds the child makes and not inter- and methodologies, see Spruyt and Gozal).
fere with any position the child assumes while
sleeping (hyperextension of the neck is common • Brief Infant Sleep Questionnaire (BISQ): This
among these patients to improve the caliber of screening tool is aimed at identifying risk fac-
the upper airway). It is advisable that a recording tors for sudden infant death, sleep routines, and
be obtained during the last hours of the night sleep problems in infants under 1 year of age,
(between 5:00  a.m. and 5:30  a.m.)—given that detected by the parents. The questionnaire can
obstructive respiratory events are more common be completed in 5–10  minutes. It has been
during REM sleep—or, failing that, when parents developed on the basis of a series of significant
observe that the child’s respiratory sounds are variables through a review of specialized litera-
more intense. The Sivan score assesses seven ture: the duration of nocturnal sleep, the dura-
parameters. Scores equal to or below 5 indicate tion of daytime sleep, the number of nighttime
normality, scores between 6 and 10 are doubtful awakenings, the duration of nocturnal awaken-
for a probable diagnosis of sleep apnea–hypop- ings, the time to go to sleep, the duration of
nea syndrome (SAHS); and scores over  10 are sleep latency, the method used for staying
highly suggestive of such a diagnosis (77–89%, asleep, where the child sleeps, the preferred
respectively). body position, the age and sex of the child, the
child’s numeric order among his or her siblings,
Sleep Scales/Questionnaires and the person who completed the question-
Studies generally suggest there is not sufficient naire. A significant correlation has been shown
screening for sleep problems among pediatric with objective data obtained using an actigraph
populations, which is confirmed by the signifi- in children 5–29  months of age in terms of
cant underdiagnosis of sleep disorders. awakenings and the duration of nocturnal sleep.
According to some surveys, more than 20% of However, this questionnaire has not been vali-
pediatricians who are consulted do not screen dated in a Spanish-speaking context.
schoolchildren for sleep problems during routine • BEARS Questionnaire [B  =  bedtime issues,
visits, and up to 40% of them do not ask adoles- E  =  excessive daytime sleepiness, A  =  night
cents directly about their sleeping habits. Taking awakenings, R  =  regularity and duration of
this into account, the American Association of sleep, S  =  snoring]: This questionnaire is
Sleep Medicine (AASM) recommends regular aimed at children from 2 to 18 years of age,
screening of all children in clinical practice to with questions directed at the children and the
detect sleep-related problems. parents. It establishes three age groups:
In primary care, structured questionnaires can 2–5 years old, 6–12 years old, and 13–18 years
facilitate screening for sleep disorders among old. It assesses five aspects of sleep: problems
children and adolescents. They are a basic tool to at bedtime, excessive daytime sleepiness, noc-
assess healthy children and to diagnose children turnal awakenings, sleep regularity and dura-
with behavioral disorders. They can be applied tion, and snoring. If there are positive answers
from the neonatal period onward. to any of the questions, the matter should be
13  Assessment of Sleep in Newborns to Adolescents 141

investigated further. However, this question- a literature review. FLEP has sensitivity of
naire has not been validated in a Spanish-­ 100%, specificity of 90%, a positive predictive
speaking context. value of 91%, and a negative predictive value
of 100% in diagnosing frontal lobe epilepsy.
Once the screening questionnaires described above Although it is basically used with adults, the
have been applied, more specific questionnaires can questionnaire can also be useful in children
be employed in the search for disorders: and adolescents.
• Screening Questionnaire for Snoring and
• Bruni Sleep Disturbance Scale for Children SAHS: This is a very brief and simple ques-
(SSSC): This scale has 27 items and is tionnaire that serves to identify children at risk
designed to detect sleep disorders, including and consequently reduces the need for more
respiratory disorders. It assesses events in the complicated and onerous tests.
prior 6 months. While its internal consistency
is greater in controls (0.79), it maintains a sat-
isfactory level of consistency in children with Complementary Tests
sleep disorders (0.71). The reliability of the
test/retest is satisfactory for the total (r = 0.71) Extensive complimentary examinations are usu-
and for scoring every individual item. ally unnecessary in the study of children with
However, this scale has not been validated in a sleep disturbances. However, in some situations,
Spanish-speaking context. on the basis of the medical history, laboratory
• Chervin Pediatric Sleep Questionnaire (PSQ): studies (such as blood counts and biochemical
This questionnaire is directed at children from screening), image studies, psychological studies,
2 to 18 years of age, and there are two versions and/or laboratory sleep studies (polysomnogra-
of the questionnaire. The reduced version has phy, respiratory polygraph, actigraphy, or oth-
22 items, and the original version has been vali- ers), the patient may be referred to a pediatric
dated. It addresses sleep-related respiratory dis- sleep unit or a sleep center.
orders. Its validity, reliability, and sensitivity
are all over 80%. It compares the symptoms of Analysis
attention deficit and hyperactivity, and corre- A basic biochemical examination, which includes
lates them with the polysomnography readings. cholesterol and high-sensitivity C-reactive pro-
More than eight positive responses suggest tein, is performed.
respiratory problems during sleep. The poly-
somnographic study is necessary to establish Respiratory Polygraph
the definitive diagnosis of respiratory disorders Portable or respiratory polygraph systems
during sleep. A determination based only on the (American Sleep Disorders Association (ASDA)
questionnaire is neither sensitive nor specific. levels III and IV) are available for initial use at
The complete version of the PSQ also explores home. Typically, they include measurement of
a wide range of other sleep disorders such as cardiorespiratory variables but not neurophysio-
parasomnias and excessive daytime somno- logical variables. Polygraphs can register orona-
lence. This questionnaire has been validated in sal flow (which is generally measured with a
a Spanish-­ speaking context, and there is a thermocouple/thermistor and/or a nasal cannula),
Chilean version of it. thoracic and/or abdominal respiratory effort,
• Frontal Lobe Epilepsy And Parasomnias Scale oxygen saturation by pulse oximetry, the body
(FLEP): This scale was developed to differen- position, snoring, and the heart rate. Another
tiate between frontal lobe epilepsy and para- variable that is often incorporated is a tibial elec-
somnias through a series of questions related tromyogram (two electrodes in the anterior tibial
to the clinical characteristics of the two condi- muscle) to evaluate periodic leg movements
tions. It was designed by an expert panel after (PLMs). This technique is not monitored directly
142 Ó. Sans Capdevila and D. Gozal

and does not allow for intervention while it is dren, and it is an appropriate screening technique
being carried out. Like polysomnography, the for use in children.
tibial electromyogram is carried out while the
subject is asleep at night. The criteria for analysis Nocturnal Polysomnography
of the records should be the same for all poly- Nocturnal polysomnography (PSG) is the refer-
graphs in terms of the variables they record, in ence test for diagnosing SAHS or motor or
accordance with the AASM criteria. behavioral sleep disorders (for example, the
The respiratory polygraph (PR) presents some Modified Pediatric Epworth Scale (MPES) score
limitations that should be noted: or rhythmic movements during sleep), allowing
for registration of physiological variables during
1. It does not detect electroencephalographic
sleep, among which are:
arousals, because of which it cannot diagnose
upper airway resistance syndrome. In this • Neurophysiological variables: An electroen-
context, some studies have related arousals to cephalogram, electro-oculogram, and tibial
other variables such as a decreased pulse tran- and submental electromyograms to assess
sit time, flattening of the inspiratory flow loop, sleep states and architecture.
or reduced amplitude of the bands following • Cardiorespiratory variables with registration of:
hyperventilation. –– Oronasal flow to assess respiratory events:
2. Instead of registering neurophysiological vari- apnea, hypopnea, and flow limitations,
ables to measure the time spent sleeping, it using thermosensors (a thermocouple/
uses the time spent in bed as a denominator of thermistor) and/or a nasal cannula.
indices such as apnea, hypopnea, and desatu- –– Respiratory effort: to classify respiratory
ration, which can yield false negatives because events as central, obstructive, or mixed,
more time is spent in bed than is spent using piezoelectric thoracic and abdomi-
sleeping. nal bands or impedance plethysmography.
–– Gas exchange: oxygen saturation by pul-
There have been few studies of application of sometry (blood oxygen saturation (SatO2))
a respiratory polygraph in children, and those and measurement of expired or transcuta-
that exist have been done in populations with neous CO2.
high probabilities of sleep apnea–hypopnea, • Heartbeat.
involving small numbers of patients. Moreover, • Snoring.
those studies did not involve comparison with • Bodily positions: Analysis of the occurrence
polysomnography, and the results were of respiratory events in relation to bodily
inconsistent. positions.
A recently published study involved 53 chil- • Electromyography of the anterior tibial mus-
dren with clinical suspicion of sleep apnea– cles: This allows for determination of the pres-
hypopnea, in which both polysomnography and a ence of myoclonic movement of the legs
respiratory polygraph were applied in the sleep during wakefulness and/or sleep associated
laboratory. Obstructive apnea–hypopnea index with respiratory events. From a logistical per-
(IAH) values of ≥1, ≥3, and ≥5 were considered spective, it is not reasonable to employ noctur-
for the diagnosis, with the receiver operating nal polysomnography in the context of
characteristic (ROC) curve being calculated for minimal suspicion of apnea–hypopnea syn-
each of these and being 4.6 the best respiratory drome or other sleep disorders. Consequently,
events index for obstructive AHI, with an area there is growing interest in improving screen-
under the curve (AUC) of diagnostic efficiency ing techniques or tests for this pediatric syn-
greater than 85% and specificity of up to 91.7%. drome, as well as development of simpler
Consequently, a respiratory polygraph is a valid tools that yield reliable diagnostic results,
alternative to diagnose apnea–hypopnea in chil- reserving more complex and/or costly tech-
13  Assessment of Sleep in Newborns to Adolescents 143

niques (polysomnography, respiratory poly- day) have been shown to reduce the effective
graphs) for cases in which simple tests do not sleeping time, increase nocturnal awakenings,
provide certain diagnoses or in which the and produce problems at bedtime. Moreover,
results of a complex technique can condition this type of habit continues into adolescence
therapy (for example, noninvasive ventilation and adulthood, with consequences for the
in the context of surgical treatment). patient’s social and working life. The easy
access that children now have to electronic
 ultiple Latency Sleep Test
M games and the internet should also be
The multiple latency sleep test (MLST) is a stan- considered.
dardized diagnostic method used to objectively With the beginning of puberty, there is a
measure daytime drowsiness. After nocturnal concurrent physiological shift to a later time to
polysomnography, the patient has the opportu- initiate sleep, which does not imply a reduction
nity to nap during the day (up to five naps between in the number of hours needed for nocturnal
20–30  minutes long). The naps occur at 2-hour sleep during adolescence. Schools demand spe-
intervals. Sleep latency in these naps is assessed cific wake-­up times that can result in lack of
with polysomnography, and it is determined sleep and affect learning. Healthy sleep habits
whether the child begins sleep with REM or at this stage of life include avoidance of televi-
NREM sleep (two or more initiations of a nap sion, video games, cell phones, and stimulating
with REM sleep is highly suggestive of drinks such as coffee, cola, and alcohol at deter-
narcolepsy). mined hours of the day. The sleeping schedule
for working days should be maintained during
the weekend, as should regular physical activi-
Conclusion ties. Exposure to natural morning light favors
correct sleep physiology at night. It is also nec-
Approximately 30% of children and adolescents essary to control other concomitant pathologies
experience some type of sleep disorder, from an that can affect sleep, such as asthma and
isolated difficulty in falling asleep or in remain- obesity.
ing asleep to more serious problems such as sleep The professionals involved in primary atten-
apnea–hypopnea syndrome. tion play a fundamental role in early detection,
Sleep disorders present clear clinical manifes- diagnosis, treatment, and follow-up of this type
tations during the night that are easily identifi- of patient, as well as in helping families. Good
able: snoring, noisy and difficult breathing, sleeping habits should be fostered and, when nec-
respiratory pauses, mouth breathing, abnormal essary, patients should be referred to sleep spe-
postures, profuse perspiration, or enuresis. cialists. Good communication with experts can
However, given their importance for the quality provide access to more complex complementary
of life of patients and their families, daytime tests such as polysomnography and specific treat-
symptoms such as motor restlessness, somno- ment for the disorder.
lence, poor school performance, altered behavior, In conclusion, sleep is a physiological neces-
aggressiveness, and predisposition to accidents sity, and an impoverishment in its quality or
should also be considered. Structured question- quantity can have significant repercussions for
naires that facilitate initial screening can be use- physical, cognitive, and psychosocial well-being,
ful for diagnosis, as can complementary tests both for the present and for the future of a child.
such as nocturnal polysomnography. Likewise, a sleep disorder generates stress and
The main cause of sleep disorders at pre- problems in the family environment. Many of
school and school ages lies in inappropriate these problems can be easily resolved in the first
habits—in particular, related to television. weeks of life with behavioral measures, whereas
Using television as a way to fall asleep and they could persist for years if not adequately
prolonged viewing (for more than 2 hours per addressed.
144 Ó. Sans Capdevila and D. Gozal

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from infancy to adolescence: reference values and
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Mindell JA, Owens JA.  Symptom-based algorithms. A
T, Meyer H, et  al. Changes in upper airway size
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Brietzke SE, Katz ES, Roberson DW.  Can history and
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Pijpers M, Poels PJ, Vaandrager JM, De H, Van D, Hoeve
Neck Surg. 2004;131(6):827–32.
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Pin Arboledas G, Cubel Alarcon M, Morell Salort M. Del
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Friberg D, Sundquist J, Li X, Hemminki K, Sundquist
Sueño. 2005;17(1):24–8.
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Rechtschaffen A, Kales A.  A manual of standardized
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 Study of Infectious Agents
in Respiratory Diseases
14
Cecilia Perret Pérez

Contents
Virological Diagnosis....................................................................................................  145
 iral Cultures..................................................................................................................  145
V
Accelerated Cultures......................................................................................................  146
Immunofluorescence.......................................................................................................  146
Immunochromatography................................................................................................  146
Molecular Biology..........................................................................................................  147
Bacterial Diagnosis.......................................................................................................  148
 raditional Bacteria........................................................................................................  148
T
Atypical Bacteria............................................................................................................  149
Mycobacteria..................................................................................................................  149
Diagnosis of Fungi........................................................................................................  149
Sources...........................................................................................................................  149

Virological Diagnosis agents and their clinical manifestations has been

possible only through techniques that allow iden-
A few years ago, it was possible to diagnose a tification of a particular virus.
viral infection only on the basis of clinical and There have been major advances in the last
epidemiological information about the patient, decade in this respect, and new techniques have
without going beyond that. Among the large emerged that have greater sensitivity to detect a
group of viral infections, there are many types of viral causal agent within a wider viral spectrum
viruses with distinct behavior, and they produce that we can identify.
distinct clinical scenarios, affect different age Today, the epidemiology of viral respiratory
groups in different ways, and require different infections is changing with the identification of
types of treatment. The capacity to establish a new agents that help us to better understand this
correlation between the different types of viral large group of “viral infections.”

C. Perret Pérez (*)

Department of Pediatrics, School of Medicine, Viral Cultures
Pontificia Universidad Católica de Chile,
Santiago, Chile The oldest method used to diagnose respiratory
e-mail: [email protected]
viruses is the viral culture—a cumbersome
© Springer Nature Switzerland AG 2020 145
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_14
146 C. Perret Pérez

method that requires laboratories with special

characteristics and highly trained staff. Added to
this is the cost of identification of each virus,
which greatly limits the possibility of more uni-
versal diagnosis. The method is used almost
exclusively for research.

Accelerated Cultures

An improvement on viral culture is the acceler-

ated culture or viral shell technique appeared,
which involves forcing the entry of a sample of a
respiratory virus into culture cell lines. However, Fig. 14.1  Use of direct immunofluorescence to show a
positive result for influenza  A virus, observed using
instead of having to wait for the appearance of immunofluorescence microscopy on a nasopharyngeal
cytopathic effects, the presence of the virus can swab at 400× magnification
be confirmed by marking of viral replication pro-
teins with fluorescence, which can be seen with adenovirus and is independent of the age of the
immunofluorescence microscopy. This technique patient. The sensitivity is higher for the influenza
allows study of the most common respiratory and RSV viruses. In the best scenario, only
viruses such as respiratory syncytial virus (RSV), around 30% of patients who consult a physician
influenza A and B, adenovirus, and parainfluenza because of respiratory symptoms remain without
1–3. The method still requires cultures in cell an etiological diagnosis after the application of
lines and therefore has the same disadvantages as this method.
viral culture. Moreover, this method cannot pro-
vide results in less than 48 hours.
Immunochromatography

Immunofluorescence Rapid immunochromatographic tests, which can

identify the presence of viral antigens directly
The technique of using antibodies marked with from patients’ samples, also represent an impor-
fluorescence, directed against different antigens tant tool for diagnosing respiratory viruses. They
of respiratory viruses, is known as direct or indi- have the advantage of providing results within
rect immunofluorescence (DIF or IIF) and does 2 hours, but their sensitivity to detect viruses is
not require culturing. It has vastly broadened the still lower than that of immunofluorescence, and
possibility of diagnosing viral agents in patients their performance depends on the age of the
with symptoms that suggest a viral infection patient and on the type of respiratory virus.
(Fig. 14.1). This technique provides a response in Another disadvantage is that they cover a smaller
less than 24 hours and can simultaneously iden- spectrum of viruses—basically just influenza A
tify several respiratory viruses. The identification and  B, RSV, and adenovirus. An immunochro-
of several respiratory viruses is called a viral matographic test is a blind test in which the qual-
panel, which is available in commercial kits that ity of the sample cannot be assessed, because of
include adenovirus, influenza A and B, parainflu- which it is not possible to determine whether a
enza 1–3, RSV, and metapneumovirus. The negative result is valid or due to a scarcity of
method has good sensitivity and specificity. The mucosal epithelial cells in the sample. Another
sensitivity varies between age groups (being best problem with this technique is that it can detect
in subjects under 5 years of age) and between dif- only the specified virus rather than a wide spec-
ferent viruses. The lowest sensitivity is related to trum of respiratory viruses. The ability to identify
14  Study of Infectious Agents in Respiratory Diseases 147

a spectrum of viruses is particularly important for than the others. Distinct sensitivity levels have
use in children under 5 years of age, in whom the been described for different respiratory viruses,
correlation between the clinical syndrome and and the sensitivity for RSV, influenza virus, and
the virological diagnosis is inadequate, especially metapneumovirus in the pediatric population is
with regard to flu symptoms and the influenza over 95%. The sensitivity is somewhat lower for
virus status. parainfluenza and influenza B, at 90%, while for
adenovirus it does not exceed 85% and in the
majority of studies is between 75% and 80%.
Molecular Biology These sensitivity rates are notably better than
those achieved by immunofluorescence for
In recent years, there have been significant viruses such as influenza B and adenovirus.
advances in the development of molecular bio- A study at the Infectology and Molecular
logical techniques in the field of virological diag- Virology Laboratory of the Pontificia Universidad
nosis—in particular, the use of polymerase chain Católica compared the performance of a DIF
reaction (PCR) (Fig. 14.2). This technique ampli- respiratory virus panel with that of a PCR molec-
fies the nucleic acids in respiratory viruses in a ular panel. The viral diagnostic yield of DIF was
sample from a patient with a respiratory infec- 35.1%, based on 6743 samples, versus 46.9% for
tion. Molecular panels have been developed that PCR, based on 1792 samples (Table 14.1). As it
are comparable to immunofluorescence panels can be seen in the table, the molecular technique
and can identify several respiratory viruses in a has better performance than DIF, and this is con-
single sample. Their advantage over immunoflu- sistent with the results of other laboratory stud-
orescence is that a wider spectrum of respiratory ies. The PCR technique also has higher sensitivity
viruses can be identified, including new viruses (88%) with 98% specificity, while the sensitivity
such as enterovirus, rhinovirus, coronavirus, and and specificity of the DIF technique are both
bocavirus. This technique is also more sensitive around 70%. Another important aspect that can

Fig. 14.2 Respiratory A B C
virus molecular panel

Table 14.1  Diagnostic performance of direct immunofluorescence (DIF) and polymerase chain reaction (PCR)
Patients, n (%)
Age groups
Technique Total population <5 years 5–15 years >15 years
DIF, n = 6743 samples 2368 (35.1) 1874 (46.9) 273 (35.5) 264 (13.3)
PCR, n = 1792 samples 841 (46.9) 508 (61.3) 78 (47.8) 255 (31.9)
148 C. Perret Pérez

be appreciated in the table is the performance and the most appropriate therapeutic strategies, par-
sensitivity of the methods in different age groups. ticularly for viruses that require specific therapy,
The sensitivity of both techniques clearly such as influenza.
decreases in persons over 15  years of age and
becomes progressively lower with age. This
could be due to factors such as later medical con- Bacterial Diagnosis
sultation and less viral excretion in adults, with
consequently lower viral loads in their samples. Traditional Bacteria
Given the wider spectrum of studied viruses,
PCR allows identification of respiratory viruses Diagnosis of bacterial infections of the respira-
that traditionally have not been diagnosed, such tory system has also made advances in recent
as rhinovirus, coronavirus, bocavirus, and entero- years with the incorporation of techniques to
virus. While these viruses are known as causal reach rapid and precise diagnoses. Until some
agents of respiratory infections, it was long years ago, microbiological diagnosis was based
thought that their pathogenic role was limited to mainly on phenotypical characteristics and appli-
infections of the upper respiratory tract and other cation of a battery of biochemical tests.
trivial infections. However, the known spectrum Automated methods for applying biochemical
of clinical manifestations that these viruses pro- tests were then developed, which provided more
duce has broadened with the appearance of tech- precision in the identification of bacteria. Now a
niques capable of diagnosing them, and it is now new method has been introduced that has been
possible to understand their frequency, their sea- used for many years in research laboratories—
sonality, and their pathogenic role in mild or namely, proteomic or mass spectrometry, in
severe infections. which bacterial protein profiles are identified by
Several clinical studies have shown that rhino- their distinct characteristics, on the basis of which
virus is prevalent in all age groups, and it has the genus and species can be determined rapidly.
been identified with greater frequency in some This microbiological technique has been devel-
series. The sensitivity and specificity of PCR to oped for a system called MALDI-TOF (matrix-
identify rhinovirus are 100% and 98%, respec- assisted laser desorption/ionization time-­ of-­
flight)
tively. This virus has been described as the most mass spectrometry, which basically consists of four
prevalent one in pediatric populations and as the stages: recovery of a colony under study previously
second most frequent cause of hospitalization of isolated from the culture, running of the mass spec-
children under 2 years of age with wheezing. trometry, comparison with databases, and presenta-
Another important comparative advantage of tion of the results. Once the sample has been
PCR over DIF is the possibility of diagnosing viral prepared, identification takes less than 2  minutes.
coinfections in the same patient with greater sensi- The results have been very promising for the identi-
tivity. DIF offers approximately a 2% possibility fication of Gram-negative bacilli such as enterobac-
of diagnosing coinfections, while the possibility teria and nonfermenting Gram-negative bacilli. The
can reach 20% with PCR. Coinfections are more incorporation of new protein profiles into the data-
common among children under 5 years of age, and bases has led to more than 94% correct identification
bocavirus commonly appears as a copathogen. of Stenotrophomonas and HACEK group bacteria.
Two problems with the molecular technique This technique is also highly sensitive for traditional
are its cost and the need for a specialized labora- Gram-positive coccaceae such as Staphylococcus,
tory. However, given its aforementioned charac- Enterococcus, and Streptococcus. The protein pro-
teristics, PCR should be the technique of choice file of Streptococcus pneumoniae is very similar to
for use in hospitalized patients, adults, and that of streptococci of the viridian group, because of
patients with immunodeficiency. Achievement of which this method is really only useful for identify-
a rapid and certain diagnosis with good sensitiv- ing Streptococcus species. The percentage of diag-
ity is fundamental in these patients to determine nosis of Gram-positive bacilli is only about 85%.
14  Study of Infectious Agents in Respiratory Diseases 149

Atypical Bacteria

Diagnosis of atypical bacteria (which are termed

“atypical” because of the difficulty in cultivating
them in commonly used media) such as
Legionella pneumophila, Chlamydia pneu-
moniae, and Mycoplasma pneumoniae is based
on determination of immunoglobulin M antibod-
ies for Mycoplasma and Chlamydia, and determi-
nation of urinary antigens in the case of Legionella
species. The PCR method is also used to search
for these agents and forms part of the expanded
panel of many laboratories. Fig. 14.3  Use of calcofluor-white stain to show fluores-
cence captured by the wall of Rhizopus sp. coenocytic
hyphae at 400× magnification

Mycobacteria
case of a suspected fungal infection, the most
Mycobacteria can be identified by different diag- useful option is calcofluor-white stain, which
nostic methods. Firstly, there is staining applied bonds with the chitin of the fungal walls and can
directly to a respiratory sample, using Ziehl– be observed by use of immunofluorescence
Neelsen stain, which gives bacilli an intense pink microscopy (Fig.  14.3). Fungal species grow in
color. Mycobacteria can grow in solid or liquid cul- special culture media and can be identified by the
ture media, and the characteristics of the colonies characteristics of the colony and the types of
and the growth velocity indicate whether or not hypha and conidia. There is no universal PCR
they are tubercular complex bacteria. The culture that allows diagnosis of all types of fungi with a
methods used to identify Mycobacterium tubercu- short diagnostic time and a high level of sensitiv-
losis can take up to 60  days. Molecular methods ity. There are indirect methods, such as identifi-
such as PCR have been of great help for identifying cation of antigens in the cell walls of Aspergillus
nontubercular mycobacterial species, allowing (galactomannan) in blood or respiratory samples,
rapid diagnosis of tubercular complex bacteria or polysaccharides from yeasts and fungi
with a high degree of sensitivity. The application of (β-D  glucan) in blood. These methods are not
mass spectrometry (MALDI-TOF) results in a high widely available, and they have not been well
percentage of identification, although an additional standardized for application in children, as in the
preparatory step for mycobacteria is to create the case of β-D glucan.
necessary conditions for the cellular wall. There is
a 97% identification rate when the mycobacteria
are grown in a solid medium and a 77% rate when Sources
they are grown in a liquid medium.
Bellau-Pujol S, Vabret A, Legrand L, Dina J, Gouarin
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Yeasts and filamentous fungi should be etiologi-
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cally suspected in gravely ill patients and patients tion of viral coinfection in children hospitalized
with immunosuppression. Like bacteria, fungi with acute respiratory tract infection using a real-­
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 Assessment of the Airway
with Flexible Endoscopy
15
Pablo Bertrand, Nils Linus Holmgren Palmen,
and Francisco Prado Atlagic

Contents
Indications.....................................................................................................................  152
Contraindications.........................................................................................................  152
Technical Aspects..........................................................................................................  152
Equipment.......................................................................................................................  152
Procedure........................................................................................................................  153
Sedation..........................................................................................................................  154
Bronchoalveolar Lavage.................................................................................................  155
Recovery.........................................................................................................................  155
Complications of Flexible Bronchoscopy...................................................................  155
 erformance of Flexible Bronchoscopy......................................................................  156
P
Congenital Stridor..........................................................................................................  156
Acute Stridor..................................................................................................................  156
Recurrent Laryngitis.......................................................................................................  156
Upper Airway Obstruction..............................................................................................  156
Atelectasis.......................................................................................................................  157
Pneumonia in Immunocompetent Patients.....................................................................  157
Pneumonia in Immunocompromised Patients................................................................  157
Recurrent Wheezing and Pneumonia..............................................................................  157
Hemoptysis.....................................................................................................................  158
Extubation Failure..........................................................................................................  158
Difficult Intubation.........................................................................................................  158
Foreign Bodies................................................................................................................  159
Miscellaneous Applications............................................................................................  159
Sources...........................................................................................................................  160

F. Prado Atlagic
P. Bertrand (*) Department of Pediatrics,
Department of Pediatrics, School of Medicine, Hospital Clínico San Borja Arriarán, Santiago, Chile
Pontificia Universidad Católica de Chile,
Santiago, Chile
e-mail: [email protected]
N. L. Holmgren Palmen
Department of Pediatrics, Clínica Alemana and
Universidad del Desarrollo, Santiago, Chile

© Springer Nature Switzerland AG 2020 151

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_15
152 P. Bertrand et al.

Indications Table 15.2 Therapeutic indications for flexible bron­

choscopy

The indications to employ flexible bronchos- Indication

Aspiration of a foreign body
copy can be diagnostic or therapeutic. The
 Assessment before and after extraction of a foreign
most common diagnostic indications include body
the assessment of persistent stridor and wheez-  Extraction of a distal foreign body
ing, atelectasis, recurrent pneumonia, and sus- Bronchoalveolar lavage
picion of malformation of the upper or lower  Expansion of persistent or massive atelectasis
airway (Table 15.1). The most common thera-  Inhalation of highly irritating matter (barium, soot,
blood, etc.)
peutic indications are bronchoalveolar lavage  Selective/massive cleaning of alveolar proteinosis
(BAL) for expansion of atelectasis and as a  Application of medication (DNase, surfactant, cold
complement to extraction of a foreign body serum, etc.)
(Table 15.2). Difficult intubation
 Monointubation for thoracic surgery
 Seldinger endoscopic intubation technique
Additional procedures (unusual indications)
Contraindications  Airway biopsy
 Distal airway laser surgery
The contraindications for flexible bronchoscopy  Dilatation of the airway with an inflatable balloon
 Sealing of a persistent tracheoesophageal fistula
are generally relative, because these situations
will be transitory; therefore, they do not involve
major risk. The only real contraindications are
scenarios in which the procedure will not be measures to recover the airway. The following
­useful diagnostically or the patient’s guardians conditions are relative contraindications that
do not give consent for its use. should be corrected before the procedure is
A relative contraindication is performance of undertaken:
a procedure without the necessary rigid bron-
choscopy support or in an unstable airway con- 1. Hemodynamic instability
dition in which predictable failure of the 2. Intracranial hypertension
procedure forces the physician to take invasive 3. Hemorrhagic diathesis
4. Pulmonary hypertension
5. Massive hemoptysis
Table 15.1  Diagnostic indications for flexible 6. Respiratory insufficiency
bronchoscopy
Indication
Assessment of the airway Technical Aspects
 Suspicion of a foreign body
 Malformation of the upper airway
 Obstructive sleep apnea syndrome Equipment
 Persistent/recurrent symptom (cough, stridor,
wheezing) There are two types of instruments currently
 Persistent/recurrent disease (atelectasis, pneumonia,
etc.)
available: the fiber bronchoscope, which has an
 Follow-up of some conditions (tracheostomy, optical fiber that sends images to a simple viewer
transplantation, surgery) or an external camera and then to an image pro-
Bronchoalveolar lavage cessor; and the more recently introduced video
 Pulmonary hemorrhage endoscope, featuring a camera at one end of the
 Interstitial lung disease
 Pneumonia in immunosuppressed patients instrument that sends images directly to a proces-
 Severe pneumonia in immunocompetent patients sor. The latter instrument has better optical reso-
 Suspicion of endobronchial tuberculosis lution, being termed “high definition”, when the
 Suspicion of pulmonary aspiration image is translated into a determined number of
15  Assessment of the Airway with Flexible Endoscopy 153

Table 15.3  Types and sizes of instruments, their applicability in different age groups, and their compatibility with
other equipment
External Working Laryngeal mask Endotracheal tube
diameter Channel (minimum size (minimum size
Patient age Instrument type (mm) (mm) BAL Biopsy (mm)) (mm))
Premature/ Fiberscope 2.2 No No No 1 ≥3
newborn
0–2 years Fiberscope/video 2.7–2.8 1.2 Yes Yesa 1.5 ≥3.5
endoscope
0–5 years Fiberscope/video 3.4–3.6 1.2 Yes Yesa 2 ≥4.5
endoscope
2–5 years Fiberscope 4 2 Yes Yes 2.5 ≥5.5
>5 years Fiberscope/video 4.9–5.1 2–2.2 Yes Yes 3 ≥6
endoscope
>15 years Fiberscope/video 5.9–6 2.2–2.8 Yes Yes 4 ≥7.5
endoscope
BAL bronchoalveolar lavage
Only with difficulty
a

pixels on a screen. Both types of equipment Procedure

should include a working channel for aspiration
of secretions, instrumentalization, and drug Flexible bronchoscopy is a clean procedure, but it
instillation. is not sterile, because the route of entry—nasal,
The equipment necessary to adequately view tracheostomy, laryngeal mask, etc.—is always
the airway depends on the fundamental charac- contaminated. The risk of intrahospital infection
teristics of the patient, such as his or her age and by flexible bronchoscopy is low if protocols for
the estimated diameter of the airway, but it also disinfection, storage, and handling of equipment
depends on the characteristics of the disease or are adequately followed. Sterilization can be
the proposed objectives of the procedure: done with ethylene oxide, ortho-phthalaldehyde,
biopsy, BAL, etc. (Table 15.3). Equipment with or glutaraldehyde for high-level disinfection. In
an external diameter of 3.6  mm is most often this scenario, disinfection with glutaraldehyde is
used, given that it can have a broad reach and is very practical, given that it takes only 60 minutes
useful for access via the nasal passage of to have the equipment available for reuse, but it
patients ranging from newborns to children does require a central unit with staff trained to
10 years of age. An instrument with an external ensure adherence to standards of efficacy, as well
diameter of around 2  mm is needed for small as the safety of the personnel who handle the dis-
children (weighing <3 kg) and children with air- infectant. There is now equipment that includes a
way stenosis or an artificial airway (an endotra- disposable outer jacket with a suction channel.
cheal tube or tracheostomy cannula), in order to The external jacket is sterile and is discarded
obtain a peripheral view of the airway. In con- after the procedure; thus, multiple procedures can
trast, in children over 6 years of age, it is essen- be conducted without the need for disinfection
tial that the instruments have an external intervals.
diameter of approximately 5 mm for improved First, the procedure is explained in detail to
illumination, particularly for management of the parents before it begins, and informed con-
excessive secretions and for BAL.  The equip- sent is obtained in accordance with the protocols
ment should ideally have an image processor for of the specific center, with the objective of clari-
real-time viewing, as well as partial or complete fying the procedure, its usefulness, and potential
documentation of the procedure with photogra- complications. The procedure room should be
phy or videography. equipped with oxygen, central aspiration, a resus-
154 P. Bertrand et al.

citation cart, a manual ventilator, a laryngoscope, foreign body or to perform BAL for culturing,
tracheal tubes, masks, aspiration cannulas, bronchial brushing, or bronchial biopsy. The idea
­monitors, drugs for sedation, and inputs. Other is to anticipate hypoxemia to avoid systemic con-
situations in which flexible bronchoscopy is sequences. The most useful medications for this
applied are the critical care unit and the operating sedation are those that, in combination, offer
room, which allows us to carry out the procedure sedation and analgesia for short periods, with
without any additional risk. The procedure is car- minimal effects on spontaneous respiration. The
ried out with noninvasive cardiovascular moni- most widely used medications are midazolam
toring (heartbeat and blood pressure) and with morphine, midazolam with ketamine, and
continuous registering of peripheral oxygen satu- propofol. To some degree, and depending on
ration (SpO2) until the patient recovers com- their doses, all of the medications that are used
pletely. The procedure should be carried out by a can have a depressive effect on the respiratory
doctor trained in endoscopy, accompanied by system and increase secretions in the airway;
another doctor trained in deep sedation and mon- thus, there are adverse effects that must be moni-
itoring. It is also necessary to have the help of a tored throughout the procedure. Topical sedation
nurse and a high-level technician trained in the is necessary from the nasal passage to the main
procedure, administration of drugs, and high-­ carina to avoid pain, reflexive spasms, and cough-
level disinfection. The members of the team have ing. Lidocaine in either a liquid or gel form is
specific responsibilities during the procedure, used to an obtain an adequate level of sedation.
which are coordinated prior to the procedure, Lidocaine is preferably administered at 2% in the
such as drug labeling, registration of vital signs, upper airway and 1% in the lower airway, and not
and positioning of the patient, nasal or oral aspi- exceeding a total dose of 7 mg/kg. The adminis-
ration of secretions, and assisting the operator in tration of lidocaine in the upper airway should be
other tasks. preceded by adequate visualization of the epi-
glottis and of the movement of the vocal cords, so
as to not attribute exaggerated collapse of these
Sedation structures to a pathological condition rather than
to the effect of anesthesia, especially in patients
The patient should have a clinical assessment for in whom paralysis of the vocal cords is
potential problems associated with the proce- suspected.
dure, including a consultation between an anes- Administration of atropine, which was a com-
thesiologist and the doctor in charge of sedation mon practice in instrumentation of the airway in
for the procedure. The patient should have a per- the past, is now reserved for patients who present
meable venous access inserted before the proce- an excessive vagal response or for infant under 6
dure begins. The sedation depends on the access months of age. Administration of oxygen is con-
and the characteristics of the patient, and can sidered in all procedures from the beginning
range from deep sedation with access through the because of the high risk of hypoxemia when the
nose (with spontaneous ventilation) to profound instrument is inserted into the airway, to which is
anesthesia and a muscular block (with assisted added an exaggerated spasm reflex, coughing,
manual ventilation with the airway maintained). and the excess of secretions produced by the
For patients at risk of respiratory insufficiency or introduction of the instruments. Oxygen is pro-
a minimal ventilatory reserve, the use of a laryn- vided by means of a nasal cannula with a flow of
geal mask, an endotracheal tube, or manual ven- ≥2 l/min, so as to obtain a reservoir of the inhaled
tilation should be considered before the procedure fraction of oxygen in the rhinopharyngeal space
is conducted. A laryngeal mask can be used in of a patient breathing spontaneously.
procedures in which the objective is not to view Another way to administer oxygen is by man-
the airway dynamics but, rather, to perform more ual ventilation with an inflatable bag, whether
invasive exploration, whether it is to search for a through an endotracheal tube or a laryngeal
15  Assessment of the Airway with Flexible Endoscopy 155

mask. Finally, oxygen can be administered for Recovery

bronchoscopy. However, this should be done
only in the central airway and intermittently, The patient recovers from flexible bronchoscopy
because of the high risk of increasing pressure in in the procedure room, the critical care unit, or
the airway and an associated pneumothorax. the anesthetic recovery room, under the same
Ideally, an SpO2 of >93% is maintained continu- noninvasive monitoring that is described above,
ously and the procedure is temporarily inter- and under the responsibility of the physician in
rupted if this level is not maintained. In this charge of sedation. Once the patient awakens
context, hypoxemia is always considered a late from sedation and his or her respiratory and car-
indicator of hypoventilation because oxygen is diovascular condition is stable, he or she is taken
administered concomitantly throughout the to the unit of origin. Depending on the sedation
procedure. that is used, and once the patient is fully awake,
he or she can be fed within 2  hours after the
­procedure. This safety interval also allows for
Bronchoalveolar Lavage full recovery of the protective reflexes of the air-
way following the use of local lidocaine. A rou-
Bronchoalveolar lavage consists of administra- tine chest x-ray is not necessary unless there is
tion of a physiological serum in a specific area respiratory deterioration with increased oxygen
for diagnostic or therapeutic purposes. The pro- requirements and breathing difficulty. Following
cedure involves positioning the point of the the application of flexible bronchoscopy with
instrument in a bronchus with a caliber similar to BAL, the patient can present a fever, which is
that of the device, such that it allows for a certain usually limited and is not associated with any
degree of bronchial sealing when the physiologi- intercurrent infection. This can be prevented with
cal serum is transferred, which is termed “inter- administration of paracetamol (15  mg/kg every
locking.” The procedure is done in the selected 6–8  hours, orally) within hours after the proce-
area either because it is a collapsed pulmonary dure or dexamethasone (0.3  mg/kg) during the
area (in the case of lobar atelectasis) or because it procedure.
presents infectious compromise, in which case
the procedure is expected to determine the etio-
logical agent (pneumonia in the case of immuno- Complications of Flexible
compromised patients). Upon reaching the Bronchoscopy
desired location, 1–2  ml/kg of physiological
serum is instilled in the working channel on at Complications of flexible bronchoscopy are
least three occasions (with a volume not greater common; most of them are transitory. The com-
than 25% of the functional residual capacity), to plications are directly related to the duration of
be subsequently aspirated through the same chan- the procedure, because of which it is vital to
nel, with recovery of approximately 30–50% of reduce the procedural time as much as possible.
the instilled volume. If a good seal is achieved The most common complications are the result
during the maneuver, the liquid that is obtained of the partial occlusion of the airway and the
contains cells from the respiratory bronchiole effects of sedation. The most frequent complica-
and the alveolar territory. tion is transitory hypoxemia, which occurs as a
The risk of contamination of equipment that result of hypoventilation while the equipment is
enters the upper airway can be reduced with the in the airway, and it is resolved by temporarily
use of a laryngeal mask and with bronchial brush- removing the equipment. An excessive cough
ing, using brushes with protected ends that are reflex is also common, which is generally con-
only exposed when they reach the area to obtain trolled with the application of local lidocaine.
a culture sample. The use of topical anesthesia in patients with
156 P. Bertrand et al.

excessive secretions (e.g., due to cystic fibrosis) treatment: surgery for patent ductus arteriosus
is decisive to prevent this complication. Less in the former case, and prolonged intubation in
common, but no less important, are complica- the latter case. More uncommon conditions that
tions arising from the sedation, such as hypoven- are nevertheless important to rule out are a tra-
tilation secondary to the use of depressor drugs cheal cleft, laryngeal membrane, tracheal steno-
and accumulation of secretions due to the lack sis, and tracheal hemangioma.
of a cough reflex. Rapid diagnosis allows for
immediate resolution with regard to the posi-
tioning of the upper airway, manual ventilation Acute Stridor
with a mask, and sometimes intubation of the
airway. In patients with respiratory difficulty In patients suffering from an episode of acute
prior to the procedure, endotracheal intubation obstructive laryngitis, flexible bronchoscopy is
and mechanical ventilation should be consid- justified only when the patient has not improved
ered. Epistaxis during or after the application of despite treatment or when intubation is needed
flexible bronchoscopy is common in infants, because of deterioration of the condition. The
where the narrow nasal passage is similar in size findings can be compatible with bacterial trache-
to the equipment. This condition often resolves itis, a foreign body, or unexpected congenital
spontaneously or after application of cold serum malformations, which is particularly relevant
at the end of the procedure. Other complications information for treating the patient.
are also common, such as postprocedural hem-
orrhaging of the distal airway, pneumothorax,
laryngospasms, and pneumonia. Recurrent Laryngitis

If there are more than three recurrent episodes of

Performance of Flexible acute obstructive laryngitis, especially when they
Bronchoscopy occur within a year, a flexible bronchoscopy study
is mandatory. There is evidence from such cases in
Congenital Stridor children under 3 years of age that a third of them
present some degree of alteration of the airway
Most patients who consult physicians because that explains the recurrence of this condition.
of a congenital stridor have laryngomalacia, a
condition that is suspected on the basis of a
characteristic medical history, which can be Upper Airway Obstruction
confirmed by nasal fibroscopy conducted with
topical anesthesia. However, flexible bronchos- Assessment of the upper airway of patients with
copy is necessary to confirm the causes of the upper airway obstruction (UAO) is facilitated by
condition in patients with a severe stridor, epi- directed viewing through a flexible bronchos-
sodes of cyanosis or apnea, or with eating diffi- copy, where the potential therapeutic value of
culties. Likewise, flexible bronchoscopy should medical or surgical solutions in specific situa-
be applied when the stridor has an uncommon tions can be evaluated. In patients with craniofa-
temporal profile, when a condition other than cial malformations or neuromuscular disease,
laryngomalacia is suspected, and, above all, repositioning of the tongue or collapse of the ton-
when there is a therapeutic possibility. The pro- sils can be very evident with the patient under
cedure is sometimes justified by parental anxi- sedation but not when the patient is awake. The
ety caused by the stridor. Common causes are procedure in this scenario tends to be highly risky
vocal cord paralysis and subglottic stenosis, because of the possibility of destabilizing the
both of which are generally related to a previous airway.
15  Assessment of the Airway with Flexible Endoscopy 157

Atelectasis because noninvasive tests have poorer results.

Bronchial lavage has a high negative predictive
In the context of lobar or massive atelectasis, value for some infectious agents, so therapeutic
flexible bronchoscopy has a mainly diagnostic decisions can be facilitated by reducing antibiotic
objective, whether this situation is the result of a coverage. However, the time available to perform
bronchial malformation, vascular compression, a the procedure may be limited by the presence of
foreign body, a mucosal plug, or an endobron- hypoxemic respiratory failure because of the high
chial lesion. In conditions in which bronchial risk, under these conditions, of the patient’s condi-
cleaning with physiological serum facilitates the tion worsening and the need to resort to ventilatory
expansion of the tributary area, bronchial lavage, support. Other complications are more common in
which expands the area in 70% of cases, can be immunocompromised patients; thus, the potential
attempted. It is useful to apply diluted adrenaline benefits must always be weighed against the risks.
(epinephrine) and/or DNase in this procedure to
facilitate the removal of mucus plugs. In other
situations, the treatment is done according to the Recurrent Wheezing and Pneumonia
endoscopic findings.
In patients with episodes of bronchial obstruction
or recurrent pneumonia that do not respond well
Pneumonia in Immunocompetent to treatment, it may be necessary to perform flex-
Patients ible bronchoscopy to rule out conditions that can
imitate this clinical presentation (tracheomalacia
The performance of BAL through a flexible bron- (Fig. 15.1), a foreign body, etc.). A cellular study
choscope in patients with an acute lower respira- of BAL fluid and a tissue study by means of a
tory infection is variable but does not achieve carinal biopsy (Fig. 15.2) can help in the diagno-
etiological identification in more than 50% of sis of other conditions.
cases. The performance is affected by prior use of
antibiotics, the timing of the disease, and the qual-
ity of the samples obtained. New techniques such
as polymerase chain reaction and quantitative bac-
terial culturing have improved etiological identifi-
cation. The procedure is thus justified in patients
who have a severe condition without a known
agent and who do not respond to treatment.

Pneumonia in Immunocompromised
Patients

In immunocompromised patients, pulmonary

infections by the usual and opportunistic agents
are a common cause of complications, and their
identification is usually difficult. The agents
involved vary according to when the disease
appears and its treatment: neutropenia, chemother-
Fig. 15.1  Tracheomalacia. Endoscopic visualization of
apy, antibiotics, etc. BAL is effective in more than
significant collapse of the posterior wall of the middle
50% of cases under these conditions, and it is even third of the trachea in a 15-month-old infant with persis-
more justified in immunocompromised patients tent wheezing
158 P. Bertrand et al.

not clarified the diagnosis. If the patient’s age

allows it, it is necessary to consider proceeding
with equipment that has a suction channel mea-
suring ≥2  mm for adequate aspiration in the
event of active bleeding. In cases of massive
hemoptysis, flexible bronchoscopy is indicated.

Extubation Failure

It is often necessary to assess the airway of an

infant after a severe and acute illness or when the
infant exhibits an abrupt deterioration after a long
period of connection to ventilatory support. Once
correctable conditions have been ruled out, it is
Fig. 15.2  Biopsy of the main carina. Endoscopic visual-
ization of biopsy forceps in the carina of a 6-year-old essential to assess the airway to rule out the pres-
child with suspected ciliary dyskinesia ence of vocal cord paralysis, subglottic stenosis
(Fig. 15.3), or other acquired or congenital lesions.

Difficult Intubation

Flexible bronchoscopy is used as an alternative in

patients who need an artificial airway, especially
in children with craniofacial anomalies or genetic
syndromes. In these cases, the instrument is used
as a guide for an endotracheal tube. The airway is
first accessed in a controlled manner, then the
tube is advanced for its final positioning or to
position semiflexible guides to help in the intuba-

Fig. 15.3  Subglottic stenosis. Endoscopic visualization

showing 60% lumen tightness in the subglottic region,
due to the presence of an eccentric membrane in a
15-month-old infant after mechanical ventilation for
30 days during recovery from a Glenn procedure

Hemoptysis

Hemoptysis is an uncommon situation in pediat-

rics in which fiberoptic bronchoscopy can iden-
tify a source of bleeding, rule out the presence of
a foreign body in the airway, and perform a bron-
choalveolar lavage to rule out bacterial, fungi,
and tuberculosis infections. Fiberoptic bronchos-
Fig. 15.4  Difficult intubation. Airway scoring with a
copy should be considered for all patients with semiflexible guide lead by means of bronchial video
repeated mild or moderate hemoptysis in whom endoscopy in a 20-day-old patient with Pierre Robin
medical evaluation and noninvasive tests have syndrome
15  Assessment of the Airway with Flexible Endoscopy 159

tion (Fig.  15.4). The flexible bronchoscope is about the location of the foreign body, especially
also useful for selective bronchial intubation, in the case of objects that are radiolucent or that
either to perform asymmetrical ventilation or to can fragment after extraction. In older children in
facilitate selective thoracic surgery. whom it is possible to use bronchoscopes with
working channels 2 mm in diameter, some low-­
risk foreign bodies can be extracted with twee-
Foreign Bodies zers or cryoprobes. The tip of the latter is frozen
to catch foreign bodies with a liquid content,
Extraction of a foreign body by means of a flexi- although this alternative should be considered
ble bronchoscope has become a routine proce- only at centers where flexible bronchoscopy and
dure. The advantages of the bronchoscope are emergency airway surgery can be performed in
that it provides diagnostic certainty and certainty case the procedure fails.

Miscellaneous Applications

Fiberoptic bronchoscopy has advanced rapidly as

new devices have become available that facilitate
the procedure and allow for assistance with other
diseases. It is used routinely in children with a
tracheostomy (Fig. 15.5) to determine the size of
the trachea, the position of the cannula, and the
presence of complications before decannulation
is performed. At our center, we have performed
permeabilization of a congenital tracheoesopha-
geal fistula (Fig. 15.6) as a way to ease the sur-
gery process during the fistula identification. This
Fig. 15.5  Tracheostomy. Endoscopic view of a tracheos- technique for tracheal intubation has also been
tomy cannula in its correct position in a 5-year-old patient used as part of the EXIT (Ex Utero Intrapartum
with nemaline myopathy who is dependent on long-term Treatment) technique. The objective of this is to
mechanical ventilation

a b

Fig. 15.6  Tracheoesophageal fistula. Endoscopic visualization of a congenital tracheoesophageal fistula (a) and scor-
ing with a semiflexible guide lead by means of bronchial video endoscopy (b) to facilitate surgical closure
160 P. Bertrand et al.

safeguard the airway of the newborn during a Hertzog H, Campbell J, Dalton H, Hauser G.  Propofol
anesthesia for invasive procedures in ambulatory
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2002;18:103–11. Medulla F, de Blic J, Bush A, Eber E, et  al. Flexible
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 Assessment of the Airway
with Rigid Endoscopy
16
Harlan Muntz and Constanza Beltrán Morales

Contents

History  161
Assessment of the Patient  162
Symptoms and Signs of Airway Obstruction  162
Indications for Airway Endoscopy  163
 hen Is Rigid Endoscopy, Rather than Flexible
W
Endoscopy, Appropriate?   163
Rigid Instruments 163
Laryngoscopy and Bronchoscopy  164
Documentation and Teaching  165
 omplications of Airway Endoscopy
C  166
Loss of Control of the Airway  166
Excessive Injury to the Subglottis and Edema During
Recovery from Anesthesia  166
Injury to the Teeth or Gums  166
Hemorrhaging  166
Pneumothorax  167
Failure to Recognize Abnormalities  167
Sources  167

History
H. Muntz
Health Sciences Center, Universidad de Utah, Historically, many attempts were made to exam-
Salt Lake City, UT, USA ine the human airway, and it was not until 1854
e-mail: [email protected] that Manuel García was able to do so with the use
C. Beltrán Morales (*) of a mirror. Before that, in 1828, Babington used
Department of Otorhinolaryngology, School of what he called a glotoscope—a mirror attached to
Medicine, Universidad de los Andes, Santiago, Chile a tongue depressor. In 1837, Liston tried to obtain
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 161

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_16
162 H. Muntz and C. Beltrán Morales

a better view of the airway with a dental mirror. (croup) or inhalation of a foreign body. If the
García reported his advance to the Royal Society latter is suspected, rigid endoscopy should be
in London in 1855, but it was not until 1858 that applied urgently for both diagnosis and treat-
Czemark (in Budapest, Hungary) ­popularized the ment. It should be noted that the presence of a
clinical use of García’s laryngeal mirror. foreign body in the airway cannot be ruled out
Direct examination of the larynx became pos- with an x-ray, which is useful only if the object
sible near the end of the nineteenth century is radiopaque. Thus, the need for airway
(1888) with the use of cocaine as a local anes- endoscopy is determined clinically and by the
thetic. Killian developed suspension laryngos- need for an adequately ventilated airway.
copy in 1912. Thanks to Kleinsasser, the surgical 2. Chronic airway symptoms: In children with
microscope was later developed, which allowed chronic airway symptoms where the pathology
for laryngeal microsurgery. Killian introduced is well known, periodic airway assessment
the bronchoscope in 1897, but it was Chevalier may be required—for example, to rule out ste-
Jackson (who is now considered the inventor of nosis or for therapeutic purposes, such as bron-
the rigid bronchoscope) who introduced instru- choalveolar lavage or resection of tracheal
ments with distal light. Jackson dedicated his life granulomas. In these cases, endoscopy is gen-
to clinical and technological developments for erally an elective procedure, where the child is
direct assessment of the human upper airway. assessed in good conditions if it is possible.
Together with Pilling, in the first two decades of 3. Severity of symptoms: The severity of the child’s
the twentieth century, Jackson developed the symptoms can determine the need for airway
angulated telescope and a bronchoscope with the endoscopy and its urgency. This is a rather
capacity for ventilation, which has made rigid dynamic determination, as it depends on the
endoscopy a safe procedure in most cases. severity of the symptoms, and that in turn
Toward the end of his life in 1937, Jackson stated, depends on the degree of obstruction in the
“A new era has dawned. The day of inferential child. This can be resolved only through fre-
diagnosis of the airway has ended. The larynx of quent observation and measurement of parame-
any human being, from newborn to century old ters such as the pulse rate, respiratory rates, and
can be examined in the entirety.” This is true saturation. Timely intervention is important
today and indicates the need to endoscopically because there is a direct relationship between the
and thoroughly assess any patient with upper air- magnitude and the severity of the obstruction.
way pathologies.

 ymptoms and Signs of Airway

S
Assessment of the Patient Obstruction

Rigid endoscopy of the airway can be used diag- It is important to determine the degree of airway
nostically, therapeutically, or both. The diagnosis obstruction, for which there are signs and symp-
is sometimes known, as in the case of laryngeal toms such as:
papillomatosis, while in other cases there may
not be a clear diagnosis or any diagnosis at all, 1. Oxygen saturation
but all of these cases can require assessment of 2. Respiratory frequency
the airway. 3. Use of accessory musculature
The patient’s medical history is very impor- 4. Costal retraction
tant, and particular attention should be given to 5. Level of awareness
the beginning of symptoms:
This clinical observation has been formalized
1. Rapid beginning: A rapid beginning of the in the croup score, which assigns points to the
symptoms suggests the cause is infection parameters (Table 16.1). This helps in d­ etermining
16  Assessment of the Airway with Rigid Endoscopy 163

Table 16.1  Severity score for obstructive laryngitis

Score
Parameter 0 1 2
Respiratory sounds None Rough Delayed
Stridor None Inspiratory Biphasic
Cough/voice None Dysphonic cry Canine cough
Retraction None Suprasternal 1 + intercostal
Cyanosis None With air With 40% O2
Level of consciousness Normal Lethargic Obtunded
A score of ≥30 minutes requires more airway support

when intervention should occur, which generally rior plaques do not provide sufficient resolution to
consists of controlling the airway with endotra- rule out a large number of common pathologies.
cheal intubation or a tracheotomy. Consequently, direct visual observation by flexi-
ble or rigid endoscopy is more useful than imag-
ery for assessing the airway in pediatrics.
Indications for Airway Endoscopy

A severe stridor generally goes hand in hand with  hen Is Rigid Endoscopy, Rather
W
significant airway obstruction. It is important to than Flexible Endoscopy,
know how much air the patient is moving. If there is Appropriate?
no movement of air through the airway, because of
a severe obstruction, the symptom of a stridor will Rigid and flexible endoscopy are complementary.
not be noticeable. Whenever possible, flexible Flexible endoscopy is used to examine the larynx
endoscopy should be considered as a first step in of a child who is awake, and it allows useful
assessing the larynx in any patient with a moderate information to be obtained about cordal mobility
to severe stridor. This test can provide the diagnosis, and laryngeal dynamics.
and a rigid endoscope can be used if necessary. Lesions in the pharynx and lower airway can
The best way to make a good assessment is with be viewed only with rigid endoscopy. If necessary,
laryngoscopy or with flexible or rigid bronchoscopy with general anesthesia after suspension of the lar-
prior to endotracheal intubation, because afterward ynx, the vocal cords can be viewed with a binocu-
the opportunity for a good diagnosis decreases. lar microscope, providing a stereoscopic view.
If the stridor and airway obstruction are pro- Rigid endoscopy allows for a good and detailed
gressive—and to this can be added a weight view, while control of the airway is maintained.
increase and difficulty in feeding—rigid endos- Flexible bronchoscopy does not allow for absolute
copy is generally indicated not only for diagnos- control of the airway and can obstruct it entirely in
ing the pathology but also with the aim of small children. The quality of the image with a
applying immediate treatment. For example, this rigid Hopkins rod-type telescope is superior to
can occur with laryngomalacia. that obtained with a flexible bronchoscope, and its
Endoscopy is often complemented with x-rays, documentation is undoubtedly much clearer.
while computerized axial tomography can also be
useful when the endoscopic study suggests the
presence of an abnormality, such as a vascular Rigid Instruments
ring. In children with symptoms of severe obstruc-
tion, radiographic or magnetic resonance tests Instruments can be considered under two
that require sedation should not be done before headings:
the diagnosis has been established by means of
rigid endoscopy. As with the diagnosis of a for- 1 . Laryngoscopy and bronchoscopy
eign object, upper airway lateral and anteroposte- 2. Documentation and teaching
164 H. Muntz and C. Beltrán Morales

Bronchoscopes

Telescopes
In 1966, Hopkins introduced the long telescope
with different lenses, which improved the resolu-
tion and the angle of viewing, and revolutionized
pediatric bronchoscopy, providing the potential
to see into very small spaces. For example, a
4.0 mm by 20 cm zero-degree telescope is ideal
for passing through a laryngoscope in the sub-
glottis or trachea.
Fig. 16.1  Laryngoscopes for intubation A Hopkins rod telescope alone (bare) or with a
ventilating bronchoscope can be used for rigid
Laryngoscopy and Bronchoscopy assessment of the upper airway. Both visualize the
larynx, trachea, and bronchi with magnification.
Laryngoscopes The advantage of using the telescope alone is that
There are a wide variety of laryngoscopy it minimizes the trauma to the airway walls, given
approaches and devices, and they can be divided that the diameter of the endoscope is less than that
into those that are designed for suspension and of the ventilating bronchoscope. The diameters of
those that are not. It is important to know how Hopkins rod telescopes (the most widely used)
to employ the different types, including those are 1.9, 2.7, and 4  mm, while the lengths vary.
for intubation. There are two types of nonsus- There are also lenses with 30- and 70-degree
pension laryngoscope: straight bladed and angles. When a bare telescope is used, the patient
curved bladed (Fig.  16.1). The straight blades cannot be actively ventilated, and so the endos-
are more compatible with rigid endoscopy. copy is usually conducted under spontaneous ven-
Among the straight blades are the Miller, Wis- tilation (see below for more information on this).
Hipple (or Wisconsin), and Philips; the Philips A ventilating bronchoscope is much wider and
provides the most space in the oropharynx to thicker than a bare telescope, given that the
pass the endoscope and facilitate intubation. An Hopkins rod is inserted inside the bronchoscope
important feature of suspension laryngoscopes light. The size of the telescope that is inserted
is that they have a xenon light source and con- depends on the size of the bronchoscope.
sequently provide more illumination than intu- Sometimes it is useful that the telescope is longer
bation laryngoscopes do. Suspension is also than the bronchoscope, because more peripheral
necessary for endolaryngeal surgery with a areas can be examined. Ventilating broncho-
microscope. The most commonly used suspen- scopes allow for ventilation of the patient while
sion laryngoscope in pediatrics is the Parsons therapeutic maneuvers are being conducted in the
type (Karl Storz), of which there are several trachea. These bronchoscopes are characterized
sizes for all ages, and it is partially open, allow- in the following manner:
ing for its use in suspension or intubation. It is
also useful to have small closed laryngoscopes 1. Connection of a closed gas system to the anes-
to view the anterior of the larynx, such as the thesia circuit so that the bronchoscope also
Hollinger anterior commissure laryngoscope. acts as an endotracheal tube, which can serve
Finally, the closed Benjamin–Lindholm laryn- to provide spontaneous ventilation and posi-
goscope, which is available in many sizes for tive ventilation
all ages, offers the possibility of a broad poste- 2. A rigid optical Hopkins rod inside its light, to
rior view. provide distal illumination
16  Assessment of the Airway with Rigid Endoscopy 165

latter in the case of suspension laryngoscopy—

and projects images to monitors; the images can
also be digitally recorded.

Anesthesia
It is important to maintain the patient’s spontane-
ous ventilation during the induction of anesthesia
and during laryngoscopy or bronchoscopy. If
there is significant stenosis in the airway, it causes
major resistance to ventilation with positive pres-
sure. However, it can be difficult to maintain
Fig. 16.2  Storz bronchoscopy with zero-degree optics spontaneous ventilation in newborns or very sick
Table 16.2  Bronchoscope size infants under deep anesthesia. In most cases the
patient can be anesthetized under spontaneous
Nominal size Internal
of optical External ventilation with a combination of inhaled and
bronchoscope telescope diameter intravenous agents (propofol, dexmedetomidine,
(mm) size (mm) (mm) Age range ketamine).
2.5 1.9; 2.7 4.0 Preterm, The following considerations are also critical:
newborn
3.0 1.9; 2.7 5.0 Newborn to
6 months 1. Work as a team with the anesthesiologist and
3.5 2.7; 4.0 5.7 6–18 months have a good working relationship with him/
3.7 2.7; 4.0 6.0 6–24 months; her.
a peanut clamp 2. Never start an endoscopy procedure without a
can be inserted
safe venous line, even if it means waiting.
4.0 4.0; 5.0 7.0 18–36 months
5.0 4.0; 5.0 7.8 3–8 years 3. Apply local anesthesia in the larynx and tra-
6.0 4.0; 5.0 8.2 >8 years chea, using 4 mg/kg of lidocaine at 2–4% to
minimize the risk of laryngospasm.
4. Conduct the laryngoscopy without the endo-
3. A lateral channel for passing a suction cathe- tracheal tube getting in the way.
ter or flexible forceps 5. If the larynx cannot be visualized directly

with the laryngoscope, because of a very ante-
Ventilating bronchoscopes in different sizes rior position, it can often be accessible to the
are fabricated by Karl Storz (Fig. 16.2). Table 16.2 rigid bronchoscope.
shows bronchoscope sizes for use in children of 6. If the upper airway is obstructed, it is better to
different ages. It should be kept in mind that the conduct a tracheotomy, even as an emergency
size of the optics depends on the size of the bron- (for which you should be prepared).
choscope. Small bronchoscopes cannot accom- 7. There should be mutual confidence between
modate a suction catheter. Optical forceps or a the anesthesiologist and the endoscopist to
clamp are highly useful for removing foreign bod- maintain control of the process.
ies and granulomas. Optical forceps, which are
available in a variety of sizes and shapes, can be Operative Techniques
introduced into the airway by use of a rubber cap.
Laryngoscopy
Documentation and Teaching In most cases the larynx can be visualized by tele-
scope or microscope. The patient lies face up in
Cameras have, without doubt, been of great help hyperextension, with his or her shoulders raised.
to endoscopy. The camera is connected to the The laryngoscope is inserted on the right side of
telescope in bronchoscopy or microscopy—the the mouth while the jaw is held in the physician’s
166 H. Muntz and C. Beltrán Morales

left hand. Care must be taken not to harm the lips ing physician must be familiar with the proce-
or teeth. The laryngoscope is inserted to the val- dure, the instruments, and the problems that can
lecula, following the tongue and moving the lead to loss of control. The factors that can pre-
tongue to the left. Then the tip of the laryngoscope cipitate this are:
should be hooked to the epiglottis, to observe the
vocal cords, arytenoid folds, arytenoid cartilage, 1 . An airway that is already compromised
and subglottis. The telescope is then passed into 2. Occurrence of laryngospasm when insertion
the trachea and advanced to the main bronchi. If a of the bronchoscope is attempted, especially
ventilating bronchoscope is used, the laryngo- when this occurs early in the procedure
scope must be removed because of its size. The 3. An undiscovered cardiovascular abnormality in
physician should withdraw it with his or her left which the positive ventilation pressure impedes
hand to advance the bronchoscope in the trachea. venous return
If it is planned to use suspension laryngos- 4. Unfamiliarity with the instruments
copy, the laryngoscope is placed in position and 5. Inexperience
suspended from an arm that is inserted into the
handle of the laryngoscope. Once in position, a
telescope or microscope is put in place with a  xcessive Injury to the Subglottis
E
400 mm lens. and Edema During Recovery
from Anesthesia
Bronchoscopy
Before the procedure, the instruments should be The use of a very large bronchoscope can result in
completely assembled, and their sizes should be injury to the subglottic mucosa, provoke postop-
appropriate for the patient. As noted above, after erative edema and major obstruction of the air-
exposure of the larynx, a bare telescope or a ven- way, and even precipitate the need for tracheal
tilating telescope is inserted into the airway. intubation or a tracheotomy. When the rigid endo-
When a bare telescope is used, it is important scope does not enter easily, it should be exchanged
that the patient ventilates spontaneously with the for a smaller gage or a bare telescope.
help of oxygen insufflation administered via the
nose or into the hypopharynx by a tube during
the bronchoscopy. If a ventilating bronchoscope Injury to the Teeth or Gums
is used, it is necessary to remove the laryngo-
scope as the bronchoscope advances. Once the Dental injury is more common with the laryngo-
bronchoscope is inserted, it reaches to the carina scope than with the bronchoscope. Children’s
to recognize structures and possible pathologies jaws, which are relatively small and mobile, can
in the trachea. To get the bronchoscope to enter also suffer injury and can be displaced when the
the main bronchi, it is often useful to move the laryngoscope is inserted.
patient’s head from side to side, allowing access
to the bronchi from right to left. Viewing should
continue until removal of the bronchoscope. Hemorrhaging

Hemorrhaging of the airway can become severe.

Complications of Airway Endoscopy The predisposing factors are:

Loss of Control of the Airway 1. Vascular lesions, such as laryngeal papillomas

2. Hemangiomas
Loss of control of the airway can result in the 3. Removal of a foreign body, particularly when
patient suffering hypoxia or respiratory/cardiac it has been there for a long time and is sur-
arrest. To avoid these complications, the attend- rounded by granulating tissue
16  Assessment of the Airway with Rigid Endoscopy 167

Pneumothorax Fidkowski CW, Zheng H, Firth PG. The anesthetic con-

siderations of tracheobronchial foreign bodies in
children: a literature review of 12,979 cases. Anesth
This occurs when there is a major respiratory Analg. 2010;111(4):1016–25. https://doi.org/10.1213/
obstruction or unnecessary positive pressure to ANE.0b013e3181ef3e9c.
ventilate. In such cases, pleural drainage should Muntz HR.  Therapeutic rigid bronchoscopy in the neo-
natal intensive care unit. Ann Otol Rhinol Laryngol.
be put in place. 1985;94(5 Pt 1):462–5.
Nicolai T. The role of rigid and flexible bronchoscopy in
children. Paediatr Respir Rev. 2011;12(3):190–5.
Failure to Recognize Abnormalities Niggemann B, Haack M, Machotta A.  How to enter
the pediatric airway for bronchoscopy. Pediatr Int.
2004;46(2):117–21.
Strictly speaking, this is not a complication, but it Reilly J, Thompson J, MacArthur C, Pransky S, Beste D,
can require other interventions, which is why it is Smith M, Gray S, Manning S, Walter M, Derkay C,
best to seek assistance from someone with more Muntz H, Friedman E, Myer CM, Seibert R, Riding K,
Cuyler J, Todd W, Smith R. Pediatric aerodigestive for-
experience if one is not familiar with the methods. eign body injuries are complications related to timeli-
ness of diagnosis. Laryngoscope. 1997;107(1):17–20.
Reilly BK, Holliday MA, Rock AN, Kang X, Shekhar
Sources R, Preciado DA.  Three-dimensional direct laryn-
goscopy and bronchoscopy: enhanced visualization
of the airway. JAMA Otolaryngol Head Neck Surg.
Cotton RT, O’Connor DM. Evaluation of the airway for
2013;139(4):367–70.
laryngotracheal reconstruction. Int Anesthesiol Clin.
Tucker JA, Reilly BK, Tucker ST, Reilly JS. Pediatric oto-
1992;30(4):93–8.
laryngology in the United States: Chevalier Jackson’s
Doherty JS, Froom SR, Gildersleve CD. Pediatric laryn-
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Anaesth. 2009;19 Suppl 1:30–7.
 Children with Respiratory Failure
17
Juan Andrés Carrasco Orellana
and Andrés Castillo Moya

Contents
Definition  169
Classification  169
Physiopathology  170
Ventilation/Perfusion Alterations  170
Hypoventilation  171
Shunting  172
Clinical Effects  172
Diagnosis  173
Airway  173
Respiration  175
Sources  176

Definition alveolar and capillary walls; and (3)  circulation,

through which O2 is distributed to the tissues and the
Respiration is the exchange of gases between the CO2 resulting from metabolism is removed.
organism and the external environment, providing According to this concept, respiratory insuffi-
the body with the oxygen (O2) necessary for aerobic ciency is defined as an alteration in the capacity
metabolism and removing carbon dioxide (CO2). of the respiratory system to maintain an adequate
This is done through three processes: (1) ventilation, exchange of oxygen and carbon dioxide,
which allows air to reach the alveoli in the areas expressed as hypoxemia, with or without hyper-
where there is blood exposed; (2) diffusion, which is capnia. This causes serious dysfunction of other
the movement of gases (O2 and CO2) between the organs, with a consequent risk to life.

J. A. Carrasco Orellana Classification

Department of Pediatrics, School of Medicine,
Universidad del Desarrollo, Santiago, Chile
While the respiratory system can be divided into
A. Castillo Moya (*) two major functional components (pump and gas
Department of Pediatrics, School of Medicine,
exchange components), anatomically it can be
Pontificia Universidad Católica de Chile,
Santiago, Chile divided into at least seven components: (1)  the
e-mail: [email protected] central nervous system; (2)  the spinal medulla;
© Springer Nature Switzerland AG 2020 169
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_17
170 J. A. Carrasco Orellana and A. Castillo Moya

(3) the neuromuscular system; (4) the rib cage and alveolar ventilation and pulmonary perfusion
pleura; (5) the upper airway; (6) the cardiovascu- ratio (V/Q ratio); (2)  a shunt (short circuit);
lar system (including hemoglobin); and (7)  the (3) hypoventilation; (4) an alteration in the diffu-
lower airway until the alveoli. Normal respiration sion of gases in the alveolocapillary membrane;
depends on proper interaction of all of these com- and (5) a decrease in the concentration of inhaled
ponents, because an alteration in any of them (see oxygen. The three most important are the V/Q
Table 17.1) can lead to respiratory insufficiency. ratio, hypoventilation, and a shunt, with a decrease
in inhaled O2 being considered a minor clinical
implication of acute respiratory insufficiency.
Physiopathology

There are five physiopathological mechanisms Ventilation/Perfusion Alterations

that can alter the homeostasis of gases and lead to
respiratory insufficiency: (1) an alteration in the An alteration in the V/Q ratio is the most com-
mon cause of arterial hypoxemia. The concentra-
Table 17.1  Anatomical classification of types and causes tion of O2 in the alveoli and capillary blood
of respiratory insufficiency
depends on the relative concentrations of inhaled
Type Cause O2 and unsaturated blood in the pulmonary artery,
Respiratory drive which is termed the ventilation/perfusion ratio.
 Pharmacological Drug overdose,
anesthesia
The same applies to CO2. While it could be
 Congenital Central hypoventilation expected that there is an adequate ratio for every
syndrome alveolar unit, the lung does not act as a multitude
 Acquired Cerebrovascular of identical gas exchange units; rather, it acts as a
accident multitude of parallel and serial perfusion and
Neuromuscular
ventilation units, which vary, even in healthy
 Cervical spinal cord injury Trauma
 Chronic inflammatory Guillain–Barré
individuals, because of age, physical activity,
demyelinating syndrome bodily posture, and other factors, with some
polyneuropathy poorly ventilated but well perfused areas, and
 Anterior horn disease Poliomyelitis other areas that are well ventilated but poorly
 Phrenic nerve injury Trauma, cardiac surgery perfused (Fig. 17.1).
Muscles of respiration
Alveolar oxygen pressure (PaO2) is determined
 Pharmacological Neuromuscular blocks
 Congenital Hypophosphatemia by the pressure of inhaled oxygen, the pressure of
 Acquired Kyphoscoliosis, trauma alveolar carbon dioxide (PaCO2), and the respira-
Rib cage tory quotient, while PaCO2 is determined by alve-
 Decreased mobility olar ventilation (VA) and the range of corporeal
Alt. Pleura CO2 production. When the pulmonary blood flow
 Extrapulmonary restriction Pneumothorax, pleural of the unit decreases (i.e., the V/Q ratio increases),
effusion
Airway
PaO2 and the capillary oxygen pressure approach
 Upper airway obstruction Epiglottitis, foreign the partial inhaled oxygen pressure. When the
body ventilation of the unit decreases (i.e., the V/Q
 Lower airway obstruction Asthma ratio decreases), PaO2 and PcO2 approximate the
Increase in dead space PaO2 of mixed venous blood. In the normal lung,
 Increased ventilation/ Emphysema the V/Q ratio ranges between 0/6 and 3.0, concen-
perfusion ratio
 Decreased ventilation/ Acute respiratory
trated mostly at 1.0. Hypoxemia occurs when per-
perfusion ratio distress syndrome fusion exceeds ventilation—that is, when the V/Q
 General pulmonary Hypovolemia, ratio is <1 (Fig. 17.2).
hypoperfusion cardiogenic shock In a person who is breathing spontaneously,
 Localized hypoperfusion Thromboembolism there are compensatory mechanisms to correct
17  Children with Respiratory Failure 171

Fig. 17.1 Ventilation
distribution, blood flow, ,15 3
and ventilation/perfusion
(V/Q) ratio

Ventilation/Perfusion per unit volume

Blood Flow

10 2

VA/Q
VA/Q
Ventilation

,05 1

5 4 3 2
Base Costal high Apex

Alveolus Alveolus Alveolus

Capillary Capillary Capillary

<V/Q Normal >V/Q

Fig. 17.2  Ventilation/perfusion alteration

hypoxia and/or hypercarbia. In the context of significantly, PaO2 decreases and PcO2 increases,
hypoxemia, pulmonary vascular vasoconstriction which are the fundamental characteristics of
consists of the alveolar units with better V/Q hypoventilation.
ratios an excluding those that are poorly venti- PcO2 is determined by VA and the production
lated, while the increase in VA as a response to of CO2 (VCO2), multiplied by the K constant, as
hypoxia prevents an increase in PcO2, including is seen in the formula PaCO2 = (VCO2/VA) × K,
lowering it to below normal levels. from which it can be deduced that increased CO2
production or a decrease in VA increases PaCO2.
As the compensatory renal response to hypercar-
Hypoventilation bia is slow (bicarbonate retention), there is an
acute fall in arterial pH.
PaO2 is determined by the balance between oxy- Given that minute ventilation includes both VA
gen provided by VA (which provides oxygen from and dead space, its reduction or increase implies
inhaled air) and the extraction of oxygen by cap- an increase or decrease in VA. The ratio between
illary blood. Consequently, when VA decreases the decrease in PaO2 and the increase in PcO2 that
172 J. A. Carrasco Orellana and A. Castillo Moya

Fig. 17.3 Relationship 80 Hypoventilation 140

between arterial PaO2 PaCO2 PaO2
(PaO2) and arterial PcO2 (mm Hg) (mm Hg)
(PaCO2) with changes in
ventilation. An
alveolar–arterial
difference of stable PaO2 Normal
and a respiratory change 40 90
ratio of 0.8 are assumed

Hyperventilation
0 40

occurs in hypoventilation can be calculated by O2, given that it no longer is in contact with the
the alveolar gas equation, (PaO2  =  PIo2  − blood. In contrast, PcO2 remains constant because
(PaCO2/R) + F, where PIo2 is the inhaled oxygen of the compensatory increase in minute ventila-
fraction multiplied by barometric pressure, minus tion caused by hypoxemia.
water vapor; R  is the gas exchange ratio (CO2
production/oxygen consumption), which is deter-
mined by the metabolic state of the tissue; and Clinical Effects
F is a minimal correction. This formula makes it
clear that hypoventilation responds to the contri- There is a series of anatomical and functional
bution of oxygen without necessarily decreasing considerations that explain why the incidence of
PcO2. The effects of the equation at the arterial respiratory insufficiency is higher in the pediatric
level can be seen in Fig. 17.3. age group, particularly among infants. The differ-
ence is found in the extrathoracic airway and the
respiratory pump (Table 17.2).
Shunting Mild hypoxemia produces few symptoms,
although it can be clinically perceptible in the
This is the extreme case in which the V/Q ratio presence of compensatory symptoms. In this
is zero; that is, there are unventilated but per- way, the patient will initially present tachypnea,
fused alveolar units, so the blood that drains tachycardia, arterial hypertension, and sensory
them does not participate in gas exchange, or the restlessness, which can progress from nasal flut-
blood circulates in an arteriovenous short circuit tering to use of accessory musculature and active
and does not participate in gas exchange (a car- respiration in exhaling, associated with wheez-
diac shunt). This can be calculated by compar- ing. Only when the level falls below 40–50 mmHg
ing the oxygen content in arterial, mixed venous, are any effects on different organs observed, with
and pulmonary capillary blood, according to the headaches, sleepiness, compromised awareness,
formula: convulsions, and subsequent permanent brain
damage. The cardiovascular system, which
Qs / Qt = CcO 2 - CaO 2 / CcO 2 - Cvo 2
initially reacts with tachycardia and arterial
­
Where Qs is blood flow through the shunt per hypertension, progresses to bradycardia and
minute, Qt is total cardiac output per minute, CcO2 hypotension, with pulmonary hypertension.
is pulmonary end-capillary O2 content, CaO2 is At the tissue level, anaerobic glycolysis begins,
arterial O2 content and Cvo2 venous O2 content. with formation of lactic acid and consequent met-
The percentage of a shunt in a healthy indi- abolic acidosis. The effects of hypercapnia over-
vidual is <10%. When it exceeds 30%, it pro- lap with those of hypoxia. Cerebral vasodilation
duces hypoxia refractory to the administration of produces headaches, increased cerebrospinal fluid
17  Children with Respiratory Failure 173

Table 17.2  Anatomical and functional considerations in have blood gas measurements to determine the
children
level of compromise and the evolution time (the
A. Extrathoracic airway presence or absence of renal compensation, based
 Neonates are absolute nasal respirators, so nasal
on bicarbonate levels). The diagnostic criteria for
congestion can precipitate significant respiratory
distress respiratory insufficiency are arbitrary. The most
 The airway is smaller in infants and young children widely accepted one is a partial arterial CO2 pres-
than in patients ≥ 8 years old sure (PaCO2)  of >50  mmHg or a partial arterial
 Infants and young children have larger tonsils in a
oxygen pressure (PaO2) of <60 mmHg in a person
smaller oropharynx
 The larynx of the infant is more anterior and more breathing ambient air at sea level, which can vary
cephalic (being positioned at the C3–C4 level) than according to the fraction of inspired oxygen
that of adults (which is positioned at the C6–C7 (FiO2), barometric pressure, and the patient’s age
level)
and prior gasometric condition.
 The epiglottis is longer and horizontal to the
pharyngeal wall In accordance with the recommendations of
 The subglottic area is smaller and cone shaped, with the American Heart Association (AHA) for deal-
the narrowest area being the cricoid cartilage ing with respiratory insufficiency (Fig.  17.4),
 Adenoid and tonsil tissue can grow considerably in
rapid assessment of the patient includes a general
preschool children and schoolchildren, contributing
to high airway obstruction cardiopulmonary assessment, characterized by
B. Intrathoracic airway an initial impression prior to physical contact
 Infants and young children have fewer alveoli and with the patient. This general assessment includes
thus a smaller gas exchange area three elements: the aspect (“looks well/poorly”,
 The alveoli are smaller
 Collateral ventilation is not very developed,
muscle tone, and interaction with the environ-
facilitating the formation of atelectasis (few pores of ment); respiration (respiratory work, effort, signs
Kohn and canals of Lambert) of respiratory difficulty); and skin color and tem-
 Smaller intrathoracic airway perature (which indicate oxygenation; thus, pal-
 Less cartilaginous support
lid cyanotic or cold skin indicates inadequate
C. Respiratory muscle pump
 Immature respiratory center, with irregular breathing oxygenation). If there are no signs of a life-­
and risk of apnea threatening risk, the team in direct contact with
 More horizontal ribs with a smaller displaced the patient should then carry out a primary
volume ABCDE (airway, breathing, circulation, disabil-
 Smaller area of interaction between the diaphragm
and the thorax ity (neurological state), and exposure) assess-
 Less developed musculature ment and a secondary SAMPLE (signs and
 More compliant thorax, with a greater tendency for symptoms, allergies, medications, past medical
deflation, with a decrease in residual capacity in history, last oral intake, and events) assessment,
comparison with adults
which includes the history of the patient.
pressure, and qualitative compromise of con-
sciousness, ranging from restlessness to Treatment  Management of respiratory insuffi-
obtundation. ciency begins with the early recognition proposed
by this guideline, followed by application of the
measures proposed. This chapter discusses the
Diagnosis first two steps.

Suspicion and early diagnosis are critical, given

that lack of treatment can result in respiratory Airway
failure, irreversible brain damage, and ultimately
cardiorespiratory failure, with all of the associ- The airway of the pediatric patient poses inherent
ated risks and prognoses. It is also important to anatomical difficulties. In comparison with
174 J. A. Carrasco Orellana and A. Castillo Moya

PATIENT
WITH
RESPIRATORY
DIFFICULTY
AND/OR
FAILURE

RAPID CARDIOPULMONARY
ASSESSMENT
Consciousness-breathing-color
PRIMARY ASSESSMENT
A-B-C-D-E

SECONDARY ASSESSMENT
• Focused history
• Focused physical examination
PROCEDURES AND
DIAGNOSTIC EXAMS
(according to clinical condition)
• Cardiorespiratory monitoring
• Pulse saturometry
• Chest x-ray
• Arterial gases/hto
• Others

• Bad overall appearance, polypnea, costal retraction, cyanosis, etc.

• Saturation <90%
• PaO2 <60 or PaCO2> 50

INTERVINE
• Handling a-b-c
• Administer oxygen: nasal cannula, mask, non-rebreather
mask, high-flow nasal cannula
• Reevaluate

Improvement No Improvement

Signs of moderate respiratory failure, persistent

Better overall appearance, saturations saturations <90%
> 90%, etc. Improvement • Use non-invasive ventilation according to
• Maintain cardiorespiratory pathology:CPAP, BIPAP, HFNC, etc.
monitoring and saturation • Start therapy addressing the cause
• Complete history and physical exam • Reevaluate
• Complementary examinations to
determine etiology No Improvement
• Start therapy addressing the cause

(Signs of severe respiratory failure, compromise

of conscience, unstable airway)
• Endotracheal intubation
• Use of invasive mechanical ventilation
• Therapy addressing the cause

Fig. 17.4  Algorithm for management of respiratory failure

17  Children with Respiratory Failure 175

adults, the infant tongue is larger in relation to Table 17.3  Respiratory frequency at different ages
the mouth, and the larynx is higher, more poste- Frequency (breaths per
rior, and smaller, which means it fills with secre- Age group minute)
tions, blood, or other elements more easily. All of Infants <1 year 30–60
1–2 years 25–35
this implies the need for greater care in aligning
Preschool children 25–30
the airway, without hyperextending it. This (2–5 years)
involves the technique of elevating the head and Schoolchildren 18–30
chin, leaving the head in a sniffing position. One >12 years 15–20
hand holds the child’s head, while the other hand Adolescents and adults 12–15
holds his or her chin. The chin is raised, while the
head is turned downward and back. This raises tion or use of accessory musculature, besides
the tongue and aligns the pharynx with the lar- grunting and nasal flaring.
ynx, allowing for the entrance of air. Once the With this information, we can determine how
airway is open, it is reviewed visually for secre- air enters, whether there is good thoracic expan-
tions and other elements. The airway can be cat- sion, and whether there are respiratory noises
egorized as permeable, sustainable, or such as a stridor or wheezing. Categorization of
unsustainable, provided that the necessary ele- the respiratory status and support with oxygen
ments are available. An endotracheal tube is the and ventilation equipment have now been imple-
element of choice for airway intervention, using mented. Respiratory compromise can be catego-
the orotracheal route when the patient is uncon- rized by the degree of severity in respiratory
scious. The correct tube diameter is of utmost difficulty and respiratory failure, which are part
importance to avoid damaging the airway. The of a single progression. Respiratory difficulty is
airway into which the endotracheal tube is characterized by an increased respiratory rate,
inserted should be examined clinically, with with signs of respiratory distress: nasal flaring,
observation of chest movements (which should increased effort, intercostal retraction, etc.
be symmetrical), bilateral auscultation over the Respiratory failure is characterized by an inap-
armpits (which should also be symmetrical), and propriate rate and effort for the condition of the
auscultation over the epigastrium (which can patient, with poor ventilatory mechanisms and
indicate whether or not the tube is in the trachea). signs of hypoxia: hypoventilation, cyanosis, and
Clinical examination is still the method used for gasping. At this level, the state of consciousness
confirmation, but this can also be done with is compromised. Oxygen support should be pro-
devices such as a colorimetric CO2 detector, a vided once it is available. There have been no
capnographic exhaled CO2 detector, and a self- comparative studies of different oxygen concen-
inflating esophageal bulb, which is used in chil- trations, because of which oxygen support is
dren who weigh ≥20 kg. maintained at 100% during resuscitation and is
adjusted afterward as necessary. If the patient has
a pulse with adequate perfusion, an oximeter can
Respiration be excellent for monitoring. Ventilatory support
is indicated for patients with poor ventilatory
In relation to respiration, it is important to assess mechanics or if there is no spontaneous respira-
how the patient ventilates and oxygenates; thus, tion. Among the ventilation methods, use of a
determination of the respiration rate is essential mask and bag is the method of choice. To achieve
in the assessment. It is important to know the adequate ventilation, it is important to choose the
ranges of normal respiratory rates at different right mask and bag for the child. The mask should
ages (Table 17.3). Very high or low and/or irregu- cover the patient’s face. If the right mask is not
lar rates constitute ominous signs. The state of used, it will not be possible to have a good seal
respiratory mechanics and effort also need to be that would provide good ventilation. The bags
assessed, including the presence of costal retrac- differ in size according to the volume that can be
176 J. A. Carrasco Orellana and A. Castillo Moya

infused with each breath: a bag that is too large such as a high-flow nasal cannula, noninvasive
puts the safety of the lung at risk, while one that mechanical ventilation, and, if necessary, inva-
is too small can result in part of the lung collaps- sive ventilation modalities.
ing, resulting in hypoventilation and thus not Treatments are as varied as the causal patholo-
meeting the primary objective. Good ventilation gies: bronchodilators, steroids, antibiotics, respi-
with a bag and a mask is as effective as ventila- ratory kinesiology, and others, alone or in
tion with a bag and an endotracheal tube; thus, if different combinations, depending on the trigger-
experience in intubation is lacking and the objec- ing pathology. Oxygen therapy is a fundamental
tive is achieved with a mask, the process should therapeutic pillar and, depending on the serious-
continue with it. It is common that in stressful ness of the clinical picture, there are different
situations such as resuscitation, there is a ten- methods for aiding patients without external ven-
dency to hyperventilate the patient. Observational tilatory support, ranging from a nasal cannula to
studies show that even personnel who are experi- a nonrebreather mask with a reservoir bag.
enced in resuscitation tend to do this. Therapy for support and correction of secondary
Hyperventilation leads to an increase in trans- alterations depends on the degree of compromise
thoracic pressure with a decrease in venous associated with the respiratory insufficiency.
return, which implies a decrease in cardiac output There are common base acid, electrolyte, and
and, consequently, decreases in coronary and hemodynamic alterations, each of which has spe-
cerebral blood flow, compromising the survival cific therapeutic requirements. Finally, another
rate. In the absence of cardiac arrest, or in its pillar in managing severe respiratory insuffi-
presence (but with an isolated airway), the objec- ciency is ventilatory support, the purpose of
tive must be to maintain ventilation of 8–10 which is to reduce or support the ventilatory
breaths per minute in children and adolescents function of the patient. As noted, this ranges from
and 12–20 breaths per minute in infants. During noninvasive mechanical support to invasive
ventilation with a bag and mask, it should be mechanical ventilation—therapies that are ana-
remembered that the airway is not isolated; thus, lyzed in other chapters of this book.
air can pass into the esophagus, with the risk of
gastric distension and possible regurgitation.
Finally, it should be remembered that the first Sources
action when evaluating respiration is to deter-
mine if the patient is breathing. This is done by Bateman S, Arnold J.  Acute respiratory failure in chil-
observing if the chest rises and falls, and if dren. Curr Opin Pediatr. 2000;12:233–7.
Mason RJ, Broaddus VC, Murray JF, Nadel JA. In: 4th,
breathing sounds can be heard. If the patient is editor. Murray and Nadel’s textbook of respiratory
not breathing, the physician should begin basic medicine. Philadelphia: Saunders; 2005.
and then advanced resuscitation. Chameides L, Ralston R; American Academy of Pediatrics,
Once the patient is stabilized, the process to American Heart Association. Pediatric advanced life
support: provider manual. Dallas: American Heart
determine the cause of the patient’s condition Association, 2011.
continues and specific treatment begins, concom- Prodhan P, Noviski N. Pediatric acute hypoxemic respira-
itantly with the introduction of therapies to tory failure: management of oxygenation. J Intensive
improve oxygenation, correction of secondary Care Med. 2004;19:140–53.
Rubenfeld GD.  Epidemiology of acute lung injury. Crit
alterations (metabolic, hemodynamic, etc.), and, Care Med. 2003;31(4 Suppl):S276–84.
depending on the severity, different degrees of Taussig LM, Landau LI.  Pediatric respiratory medicine.
ventilatory support to reduce respiratory work, St. Louis: Mosby; 1999.
 Children with Persistent Cough
18
Katalina Bertrán Salinas, Ricardo Saranz,
Alejandro Lozano, and
José Antonio Castro-Rodríguez

Contents
Definition and General Concepts   177
Cough Reflex Anatomy  178
Etiology  178
Diagnosis  179
Treatment  181
Treatment of Chronic Cough with an Identified Cause  183
Chronic Cough Without an Identified Cause: Is Symptomatic Treatment Useful?   183
Advantages of Managing Chronic Cough with Diagnostic–Therapeutic Algorithms  184
Conclusion  185
Sources  186

Definition and General Concepts with the objective of freeing the airway of secre-
tions and foreign material. Nevertheless, as a result
Cough is a complex physiological reflex that pro- of its chronic evolution or intensity, it can become
tects the airway from chemical, mechanical, and an annoying symptom that seriously affects the
thermal injury. It consists of violent expiration quality of life of the child, interrupting sleep, stud-
ies, and sports, and creating anxiety in the family.
It is of great clinical use to define cough according
K. Bertrán Salinas to its duration, its association with specific causes,
Department of Pediatrics, Hospital Clínico and its response to rationally indicated therapy.
Universidad Católica de Chile, Santiago, Chile
Cough is defined as acute when it lasts for at
R. Saranz · A. Lozano least 3  weeks and is defined as subacute when
Department of Allergy and Immunology, Faculty of
Medicine, Universidad Católica de Córdoba, it continues for 3–8  weeks. Cough is recurrent
Córdoba, Argentina when there are more than two episodes per year
e-mail: [email protected] that are not associated with the common cold
J. A. Castro-Rodríguez (*) and that last for more than 1–2 weeks. Cough is
Department of Pediatrics, School of Medicine, defined as chronic in pediatric patients when it
Pontificia Universidad Católica de Chile, persists for more than 8 weeks. It is not a disease
Santiago, Chile

© Springer Nature Switzerland AG 2020 177

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_18
178 K. Bertrán Salinas et al.

per se; rather, it is a cardinal symptom of numer- extrarespiratory locations: the outer ear,
ous respiratory and nonrespiratory pathologies, stomach, pericardium, and diaphragm.
and it is responsible for a large number of medical There are rapid-adaptation irritant recep-
consultations. Cough is the reason for 10% of pri- tors (mainly concentrated in the higher-
mary health care consultations for schoolchildren caliber airways on the luminal side of the
and 20% of consultations for preschool children. basal membrane, close to the cilia of the
Assessment and diagnosis of chronic cough pseudostratified epithelium), mechanical
in pediatrics require adequate knowledge of the receptors (which are sensitive to changes
possible causes. Consequently, correct identifica- in the caliber of the airway), and chemi-
tion of the cause is a priority for etiological treat- cal receptors (which are sensitive to
ment in order to avoid a symptomatic approach gases and smoke).
with antitussives or expectorants, which most (b) Afferent nerves: The afferent tracts reflect
often have disappointing results and pose risks of their origin in the different locations of
addiction and negative side effects. the aforementioned receptors. Laryngeal
impulses go through the homonymous
nerve, while tracheobronchial impulses
Cough Reflex Anatomy go through the vagus nerve—the high-­
velocity myelinated fibers being the most
Key Concepts important in mediating centripetal stimu-
1. Cough is an integral part of the defensive sys- lus. The phrenic nerve is responsible for
tem of the respiratory tree, together with passing a stimulus from the diaphragm
mucociliary clearance, alveolar macrophages, and pericardium, and the trigeminal
and the immune system. nerve passes a stimulus from the nose and
2. The reflexive mechanism of cough is very
paranasal sinuses to the cough center.
complex and consists of five components (c) Medullary center: The integrating center
(Fig. 18.1): is at the level of the medulla, although its
(a) Cough receptors: These are distributed existence is controversial.
throughout the respiratory tract and (d) Efferent nerves: The efferent–effector

response is transmitted to the expiratory
and diaphragmatic muscles by the spinal
Receptors
and phrenic motor nerves and to the lar-
Cough Center ynx by the recurring branches of the vagus
Epiglottis nerve. The ends of the parasympathetic
nerve system supply the trachea and bron-
VN Vagus Nerve chi, and through their effect of contracting
VN the smooth muscle, they contribute to the
effort of cough by narrowing the airway
Pharinx
and consequently increasing the velocity
VN of airflow.
Trachea
(e) Effector muscles.
VN
Main Bronchi

VN Etiology

VN Key Concepts
1. The causes of chronic cough in children and
adults are different, and within pediatrics they
can differ among infants, preschool children,
Fig. 18.1  Anatomy of cough and schoolchildren and adolescents.
18  Children with Persistent Cough 179

2. The etiological spectrum can include one or ized by chronic productive cough caused by
more coexisting causes. Moraxella catarrhalis, Haemophilus influen-
zae, or Streptococcus pneumoniae. It produces
There are numerous causes of chronic cough intense neutrophilic inflammation in the airways
as a consequence of the interaction of the mecha- and characteristically resolves within 2 weeks of
nisms summarized in Fig. 18.2. administration of amoxicillin and clavulanic acid
The cause of cough can vary according to or clarithromycin acid.
age. In infants, cough in early life suggests the In schoolchildren and adolescents, postna-
presence of congenital anomalies such as a tra- sal discharge rhinosinusitis (UACS) is the main
cheoesophageal fistula, vascular ring, innomi- cause. Cough-equivalent asthma, exacerbated by
nate artery, neuromuscular disorders, or other smoking, and eventually a psychogenic cough,
abnormalities or malformations of the airways. which characteristically calms during sleep, also
Viral infections such as Chlamydia, Bordetella acquire relevance and should be considered in
pertussis, mycobacteria (tuberculosis), and oth- the differential etiological diagnosis of this fre-
ers should not be ignored, nor should the pos- quent symptom. The diagnosis of bronchiectasis
sibility of gastroesophageal reflux (GER), should not be overlooked, especially in patients
cough-­equivalent asthma, or cystic fibrosis. who have suffered severe pneumonia during
In preschool children, upper airway cough childhood. Table 18.1 shows the main causes of
syndrome (UACS)—including rhinosinusitis, chronic cough according to pediatric age.
adenoiditis, infection, and inflammation of
Waldeyer’s lymphatic ring—and the effects of
cigarette smoke (passive smoking) are added Diagnosis
to the aforementioned range of causes. This
is one of the periods of life when the possibil- Key Concepts
ity of asthma (cough-variant asthma) is particu- 1. The clinical history (interview and physical
larly important. Cough caused by inhalation of examination) is the fundamental diagnostic
a foreign body is typically paroxysmal but can pillar.
be delayed and become chronic. Prolonged bac- 2. Confirmation of a cause does not necessarily
terial bronchitis, described above, is character- mean that it is responsible for the cough.

Fig. 18.2  Interaction of Bronchial

etiological factors in hyperreactivity
chronic cough

Airway
compression Infections

Anatomical CHRONIC
alterations Allergy
COUGH

Upper airway Psychogenic

pathology causes

Macro and micro

respiratory
aspiration
180 K. Bertrán Salinas et al.

Table 18.1  Causes of chronic cough by age

Infant Preschool School and adolescence
Congenital anomalies Infections Asthma
 Tracheoesophageal fistula  Bacterial Rhinosinusitis
 Vascular ring  Viral Psychogenic
 Airway malformation   Mycoplasma Gastroesophageal reflux
 Neuromuscular disorders  Tuberculosis Infections
Infections Rhinosinusitis  Tuberculosis
 Viral Asthma   Mycoplasma
 Bacterial Gastroesophageal reflux Bronchiectasis
 Tuberculosis Foreign body Irritative
 Chlamydia Irritative  Environmental pollution
Asthma  Passive smoking  Smoking
Gastroesophageal reflux Cystic fibrosis
Cystic fibrosis Bronchiectasis

3. The sensitivity, specificity, positive predictive Table 18.2  Symptoms and signs associated with specific
value, and negative predictive value of the dif- causes of chronic cough in childhood
ferent diagnostic methods should be ade- Symptom/sign Possible etiology
quately considered. Pulmonary Asthma, bronchitis, foreign
4. A diagnostic test is accurate only if the cough auscultatory findings body, aspiration, congenital
anomalies, cystic fibrosis
is resolved with the specific therapy for that
Heart murmur Heart disease
diagnosis. Chest pain Asthma, pleurisy
5. Complementary studies should always be
Thoracic deformity Severe chronic obstructive
supported by the clinical history. pulmonary disease
Productive cough Chronic bronchitis, suppurative
The anamnesis should detect and characterize lung disease, cystic fibrosis
Nail clubbing Suppurative lung disease, cystic
the time of onset and evolution, type of cough, fibrosis
hourly rhythm, aggravating and triggering fac- Dyspnea on exertion/ Airway or lung parenchymal
tors, production and quality of sputum, and pres- at rest disease, heart disease
ence of associated symptoms. Orienting signs Growth retardation Severe lung or heart disease,
and the growth and development of the child cystic fibrosis
Deglutition disorders Gastroesophageal reflux,
should be assessed in a detailed physical exami- primary aspiration
nation (Table 18.2). Immunodeficiency Suppurative lung disease,
In particular, consideration should be given to atypical infections
infants’ neonatal and feeding history, any habits Recurrent pneumonia Immunodeficiency, congenital
relating to putting foreign objects in the mouth, anomalies of the lung,
tracheoesophageal fistula
and the personal and family background in rela-
Fever Tuberculosis, suppurative lung
tion to allergies. The pediatrician should review disease, bacterial bronchitis,
the history of vaccinations, irritants, and aller- other infections
gies at home and the prescribed medications: the Hemoptysis Suppurative lung disease,
dosages, durations of treatment, adherence, and vascular anomalies, bronchitis
responses to medication. The use of angiotensin-­ This is only a partial list of associated symptoms and signs
converting enzyme (ACE) inhibitors should be
investigated. definitive diagnosis. Knowledge of the personal
Asthma-associated cough is typically noc- and family history of atopy can be orienting.
turnal and exacerbated by cold air, irritants, A chronic cough associated with purulent
allergens, and exercise. Cough can be the only expectoration indicates bronchiectasis, suppura-
manifestation for a long period and can delay a tive pulmonary, or cystic fibrosis. An associa-
18  Children with Persistent Cough 181

tion with chronic diarrhea, slow growth, nasal dromes associated with upper airway patholo-
polyposis, and/or nail clubbing provides strong gies (UACS). Computerized tomography is
evidence of cystic fibrosis. not generally recommended to assess sinus-
Postnasal discharge in children often indicates itis, although it can provide more diagnostic
nasal obstruction and mucopurulent rhinorrhea. precision.
Persistent headaches and eventually facial pain Rhinopharyngeal assessment can contribute
and pain around the eyes are symptoms sug- to detection of organic pathologies of the upper
gestive of sinusitis, while a history of recurrent airway and provide indirect signs of a laryngo-
febrile syndrome, with general malaise and gen- pharyngeal reflux that is responsible for cough.
erally productive cough, indicates the need to An esophagogastroduodenal transit study allows
inquire about contacts and raises suspicion of us to study GER, foreign bodies in the esopha-
tuberculosis. gus, tracheoesophageal fistulas, and exogenous
Cough can be linked in aspiration syndromes compressions of the esophagus. GER and/or
to regurgitation and choking, and can be exac- laryngopharyngeal reflux should be suspected in
erbated during or after eating. Occasionally, all cases of cough with an undetermined cause.
wheezing and basal crackling can be heard. In this respect, 24-hour esophageal pH monitor-
Finally, psychogenic cough is unproductive, ing may be useful, although a normal study does
relaxes while the subject is sleeping, and does not rule out nonacid reflux as a cause of associ-
not improve with antitussive drugs. It is usually ated cough, which can be detected by impedance
diagnosed by a process of elimination. measurement.
The pediatrician should carefully consider Allergological assessment (skin tests for
complementary studies, which will depend on immediate detection of allergens, immunoglobu-
the initial clinical assessment. A chest x-ray is lin dosages, etc.) should be reserved for specialist
the first indicated study and should be done in use for proper interpretation.
almost all cases. It can confirm the existence of A study of tuberculin sensitivity is absolutely
an organic pulmonary cause of cough, and it is necessary if epidemiological evidence of tuber-
the guide for an algorithm of subsequent com- cular contacts is found, including the entire fam-
plementary studies. If the chest x-ray is abnor- ily if necessary.
mal—for example, if it shows the presence of Figure 18.3 shows a diagnostic algorithm for
localized shadows or diffuse infiltrates—more chronic cough in pediatrics.
complex imaging techniques, cultures, sputum
cytology, and/or diagnostic bronchoscopy should
be employed. Treatment
In children under 3  years of age, spirometry
can contribute to detection of reversible bronchial Key Concepts
obstruction, which is compatible with a diagnosis 1. The treatment of chronic cough has a greater
of asthma. If the results are normal, with a strong possibility of success when the precise cause
suspicion of asthma, a bronchial provocation test has been identified and is specifically
with either exercise or methacholine, and an air- addressed.
way inflammation study measuring exhaled nitric 2. Before prescribing any symptomatic medica-
oxide or induced sputum, are indicated if they are tion, the pediatrician should perform an
available. The sensitivity and specificity of the exhaustive causal investigation of the
method that is employed should be considered in symptoms.
order to optimize the diagnostic utility. 3. Analysis of the evidence according to the

X-rays of the paranasal sinuses offer low Grading of Recommendations, Assessment,
diagnostic specificity, but it improves signifi- Development, and Evaluations (GRADE)
cantly when combined with clinical findings system supports more precise therapeutic
­
for etiological determination of cough syn- recommendations.
182 K. Bertrán Salinas et al.

ANAMNESIS
AND
PHYSICAL
EXAM
Chronic cough without apparent Chronic cough with apparent
pulmonary pathology pulmonary pathology

Chest x-ray

Abnormal or with high

Normal
clinical suspicion

Foreign body Bronchoscopy

Cystic fibrosis Sweat test

X ray, paranasal
ENT pathology sinuses CT,
rhinofibroscopy Ciliary Biopsy and ciliary
dyskinesia function studies

PFT (> 3 years);

allergy testing Bronchoscopy,
Normal

Congenital
Asthma BCT, FeNO, anomalies
CT, NMR,
induced sputum angiography
analysis

High risk Investigate

patients tuberculosis, HIV
Gastroesophageal EGD transit,
reflux esophageal 24-
hour pH/Impedance
Pertussis, chlamydia,
reflux monitoring Specific serology
cytomegalovirus, etc.

Sputum and BAL

culture, CT, sweat
Purulent infection
test , immunological
studies

PFTs, diffusion, CT,

Fibrosing alveolitis,
autoinmune disease
autoantibodies, lung
biopsy

Heart disease Echocardiogram

Fig. 18.3  Algorithm suggested for diagnosis of chronic phy, EGD esophagogastroduodenal transit, ENT ear, nose,
cough in pediatrics. BAL  bronchoalveolar lavage, and throat, FeNO fraction of exhaled nitic oxide, PFT pul-
BCT bronchial challenge test, CT computerized tomogra- monary function test

At the beginning of the twentieth century, often give us drugs that put the guard dog to sleep
Chevalier Jackson said, “The cough is the guard just when we need it most.” This author consid-
dog of the lungs that protects them from external ered that cough was a physiological defense
damage and internal enemies. However, doctors mechanism and that doctors of that time were,
18  Children with Persistent Cough 183

wrongly, more concerned with treating symp- 6. For any type of cough, smoking cessation by
toms than identifying the origins of them; the the parents (where applicable) carries the
same occurs today. strongest GRADE recommendation.
The objectives of treating chronic cough can
be summarized as follows:
 hronic Cough Without an Identified
C
1 . Remove the causal agent or irritant. Cause: Is Symptomatic Treatment
2. Mobilize and facilitate expectoration. Useful?
3. Suppress stimulation of peripheral receptors.
4. Depress the cough center. Key Concepts
1. The cause of cough can sometimes not be
determined, or it can present prejudicial
 reatment of Chronic Cough
T effects such as chest pains, fatigue, vomiting,
with an Identified Cause headaches, or disturbed sleep, making symp-
tomatic treatment necessary.
1. Chronic cough due to asthma requires treat- 2. Nonspecific therapy tends to provide relief

ment with a bronchodilator, antileukotrienes, from symptoms when the cough does not
and/or steroids via inhalers. These treatments serve any physiological reason (such as irrita-
should be accompanied by measures to avoid tive, dry, and prolonged postviral cough) or to
allergens and irritants, such as avoiding ciga- avoid these complications or pernicious
rette smoke (GRADE recommendation effects.
strength: strong). 3. Productive cough should not be suppressed,
2. For cough associated with allergic rhinitis,
given that retention of secretions can prolong
allergens should be avoided, and nasal antihis- the base disease and the consequent
tamines and steroids should be applied symptoms.
(GRADE recommendation strength: weak). If 4. Many therapeutic combinations used in

there is bacterial sinusitis, antibiotic therapy is symptomatic treatment of cough (antitus-
imperative. sives and mucolytics) do not make sense,
3. There is no specific GRADE recommendation given that their components have contradic-
for use of a proton pump inhibitor assay in tory effects, as well as toxic and addictive
children for 8–12 weeks. Laparoscopic fundo- side effects.
plication is not advised for relief from cough
caused by GER. The practice of “observe, wait, and review”
4. For cough produced by prolonged bacterial is strongly recommended to avoid unnecessary
bronchitis, antibiotic therapy with amoxicillin medication, given that the benefit of such medi-
and clavulanic acid or clarithromycin is useful cation generally does not exceed that of a pla-
for 2–6  weeks (GRADE recommendation cebo, and because in a high percentage of cases,
strength: strong). Antituberculosis therapy nonspecific cough resolves spontaneously.
should be given in response to a confirmed
diagnosis of tuberculosis. The most common 1. Antitussive drugs: There is a wide variety of
viral causes of respiratory infection are gener- commercial antitussive drugs, which are clas-
ally not self-limited. sified according to their site of action. Narcotic
5. Psychogenic cough requires detailed explora- and non-narcotic centrally acting agents
tion of the family situation and dynamics, and depress the integrating medullar reflex center,
of stressful aspects of the family and school while peripherally acting agents depress or
environments. This can require the involve- anesthetize the receptors where the cough
ment of a psychologist. reflex originates.
184 K. Bertrán Salinas et al.

2. Centrally acting antitussives are most widely interferes with disulfide bonds in the mucus,
used. Codeine, a narcotic antitussive par reducing its viscosity. However, these drugs
excellence, is one of the most potent cough can increase bronchial hyperresponsiveness.
suppressants and has addictive effects. It is GRADE strongly recommends minimizing the
usually well tolerated but can provoke drowsi- use of mucolytics and demulcents.
ness, dizziness, symptoms of digestive intol- Despite these warnings—and although symp-
erance, and a dry mouth. It is contraindicated tomatic cough medicines are not recommended
in all guidelines. by the American Academy of Pediatrics and the
3. Synthetic derivatives of codeine and mor-
US Food and Drug Administration (FDA) did
phine, such as oxycodone and hydrocodone, not approve their use in children under 4 years of
can be found in many preparations. They are age in 2008—they continue to be the drugs most
highly effective but can have the same side commonly prescribed by doctors and consumed
effects as their parent drugs. There are strong by patients.
GRADE recommendations against their use
in all cases.
4. Dextromethorphan is one of the most impor-  dvantages of Managing Chronic
A
tant non-narcotic antitussive agents. Acting at Cough with Diagnostic–Therapeutic
the central level, it appears to be as potent as Algorithms
codeine. It is better tolerated but can sometimes
have unwanted gastrointestinal effects, The clinical performance of chronic cough man-
although the recommended dose does not pro- agement is improved by incorporation of a stan-
duce the types of sedative and respiratory dardized diagnostic–therapeutic sequence. The
depressant effects that often accompany more rapidly an algorithm is applied, the sooner
codeine. Dextromethorphan is rarely addictive. the problem is resolved and the sooner the qual-
Noscapine, chlophedianol (clofedanol), clofe- ity of life of the patient is improved. Chang et al.
dianol, clobutinol, oxeladin, and butamirate (2013) conducted a multicenter study to test the
complete the list of non-narcotic antitussives hypothesis that management of chronic cough
recommended for children over 6 years of age. in children according to an evidence-based
5. Mucolytic and expectorant drugs: These liq- algorithm is feasible and improves clinical out-
uefy mucus, reduce retention of secretions, comes (Fig.  18.4). Two groups, with early use
and increase mucociliary clearance, because and late use, were compared with the aid of the
of which they are used in patients who have algorithm shown in the figure. The percentage
difficulties in expectorating abnormally vis- of cough-­free children at 6 weeks (the primary
cous secretions. outcome) was significantly higher (p < 0.0001)
in the early use group (54.3%) than in the late
Guaifenesin and iodine compounds are pres- use group (29.5%). The absolute reduction in
ent in several commercial preparations, but as risk among the intention-to-treat groups was
iodine-containing drugs they carry the risk of 24.7% (95% confidence interval (CI) 13–35),
causing hypothyroidism, skin rashes, and mouth with an NNT of 4 during a 6 week period (95%
infections. More modern drugs such as bromh- CI 3–8). In effect, 85% of the diagnoses were
exine and ambroxol are available in our pharma- made following this protocol, without the need
copoeia, but their effectiveness does not exceed for specialized investigation, showing that stan-
the mean range of the other drugs mentioned dardized management of chronic cough leads to
above. As a mucolytic agent, N-acetylcysteine improved results in practice.
18  Children with Persistent Cough 185

ASSESSMENT

Specific cause search for basic diagnosis: x-ray changes, altered spirometry,
neurodevelopmental alterations, deglutition alteration, malnutrition, drugs, wheezing or
LRTI, typical characteristics of cough, thoracic deformity, nail clubbing, altered
auscultation, error in previous treatments

Without characteristics Cough of specific cause

of the upper body
Characteristics of another specific
diagnosis such as asthma or CSLD

Wet cough Dry cough Investigate and treat

according to diagnosis

Specific cough Non-specific cough

Findings of prolonged No specific diagnosis
bacterial bronchitis findings

Use of antibiotics Expectant

management and
follow-up

If the cough continues

Consider trial therapy

Fig. 18.4  Algorithm for diagnostic and therapeutic management of chronic cough. CSLD chronic suppurative lung
disease. (Adapted from Chang et al. 2013)

2. A careful and exhaustive anamnesis and phys-

Conclusion ical examination are fundamental pillars of
the diagnosis.
1. Cough is a cardinal symptom of numerous 3. The etiological spectrum is different in chil-
respiratory and nonrespiratory diseases. In dren and adults, with consequent therapeutic
pediatrics, cough is defined as chronic when it implications.
persists for more than 8  weeks, and chronic 4. The causes of chronic cough in childhood

cough requires an ordered and precise vary with age. The most common causes are
diagnosis. cough syndrome related to upper airway
186 K. Bertrán Salinas et al.

pathologies, cough-variant asthma, and pro- lung disease and bronchiectasis. Pediatr Pulmonol.
2008;43:519–31.
longed bacterial bronchitis. Chang AB, Robertson CF, van Asperen PP, Glasgow NJ,
5. The exact etiological identification should be Masters IB, Teoh L, Mellis CM, Landau LI, Marchant
followed by specific treatment. If this does not JM, Morris PS. A cough algorithm for chronic cough
prove effective, the following should be in children: a multicenter, randomized controlled
study. Pediatrics. 2013;131:e1576–83.
considered: Chow PY.  Chronic cough in children. Singap Med  J.
(a) The cause is partially identified and 2004;45(10):462–8.
undertreated. de Jongste JC, Shields MD.  Cough  2: chronic cough in
(b) The diagnosis is incorrect. children. Thorax. 2003;58:998–1003.
Ali M.  Laryngopharyngeal reflux: diagnosis and treat-
(c) The treatment is not appropriate. ment of a controversial disease. Curr Opin Allergy
(d) The patient is not compliant with the
Clin Immunol. 2008;8:28–33.
treatment. Gibson PG, Chang AB, Glasgow NJ, Holmes PW,
6. Symptomatic therapy is necessary in rare
Katelaris P, Kemp AS, et al. CICADA: cough in chil-
dren and adults: diagnosis and assessment. Australian
instances if the cause is properly determined. cough guidelines summary statement. Med J Aust.
Treatment with antitussives, mucolytics, and 2010;192:265–71.
expectorants is often disappointing. It has Goldsobel AB, Chipps BE. Cough in the pediatric popula-
undesirable side effects and should be consid- tion. J Pediatr. 2010;156:352–8.
Irwin RS. Chronic cough due to gastroesophageal reflux
ered for use only as an adjuvant in the case of disease: ACCP evidence-based clinical practice guide-
an “irritating” cough that does not respond to lines. Chest. 2006;129:80S–94S.
a demonstrable cause, or used as a comple- Marchant JM, Masters IB, Taylor SM, Chang
ment to a specific therapy. AB. Utility of signs and symptoms of chronic cough
in predicting specific cause in children. Thorax.
7. New symptomatic therapies are being devel- 2006;61:694–8.
oped with specific effects on peripheral recep- Marchant JM, Newcombe PA, Juniper EF, Sheffield JK,
tors and channels involved in the cough reflex Stathis SL, Chang AB. What is the burden of chronic
and in the modulation of the sensorial pep- cough for families? Chest. 2008;134:303–9.
Pratter MR. Chronic upper airway cough syndrome sec-
tides of the respiratory tract. These therapies ondary to rhinosinus diseases (previously referred to
are opening promising new fields of treatment as postnasal drip syndrome). ACCP evidence-based
for cough. clinical practice guidelines. Chest. 2006;129:63S–71S.
Ramanuja S, Kelkar P. Habit cough. Ann Allergy Asthma
Immunol. 2009;102:91–5.
Rank MA, Kelkar P, Oppenheimer JJ.  Taming
chronic cough. Ann Allergy Asthma Immunol.
Sources 2007;98:305–13.
Saranz RJ, Lozano A, Lozano N, Castro Rodríguez
Asiloy S, Bayram E, Agin H, Apa H, Can D, et  al. JA.  Diagnóstico y tratamiento de la tos crónica en
Evaluation of chronic cough in children. Chest. pediatría. Arch Arg Pediatr. 2013;111(2):140–7.
2008;134:1122–8. Schaefer MK, Shehab N, Cohen AL, Budnitz DS. Adverse
Chang AB, Glomb WB. Guidelines for evaluating chronic events from cough and cold medications in children.
cough in pediatrics: ACCP evidence-based clinical Pediatrics. 2008;121:783–7.
practice guidelines. Chest. 2006;129:260–83. Schroeder K, Fahey T.  Over-the-counter medica-
Chang AB, Lasserson TJ, Kiljander TO, Connor FL, tions for acute cough in children and adults in
Gaffney JT, Garske LA. Systematic review and meta-­ ambulatory settings. Cochrane Database Syst Rev.
analysis of randomized controlled trials of gastro-­ 2008;1:CD001831.
oesophageal reflux interventions for chronic cough Shields MD, Bush A, Everard ML, McKenzie S,
associated with gastro-oesophageal reflux. BMJ. Primhak R, et  al. Recommendations for the assess-
2006;332:11–7. ment and management of cough in children. Thorax.
Chang AB, Redding GJ, Everard ML.  Chronic wet 2008;63(Suppl III):iii1–iii15.
cough: protracted bronchitis, chronic suppurative
 Infants with Persistent Tachypnea
19
Pablo Bertrand and Ana Moya Olivares

Contents
Definition.....................................................................................................................  187
Respiration Control Mechanisms  188
Etiology �����������������������������������������������������������������������������������������������������������������������  188
Diagnosis  189
Sources  191

Definition In newly emerging conditions, tachypnea is a

symptom in the course of a clinical picture with
Tachypnea is an increased respiratory rate above or without respiratory symptoms. It can result
the reference value for the patient’s age. This from physiological phenomena such as fear,
clinical sign is extremely useful and forms part anxiety, crying, and exercise, as well as being
of the basic vital signs necessary for good clini- influenced by organic causes such as pain, fever,
cal assessment of a child. The respiratory rate neurological alterations, or metabolic alterations.
changes over the course of childhood and, on the Above all, it is a good indicator of respiratory
basis of curves by age, it is possible to character- illness. Tachypnea is defined as persistent when
ize a physiological decrease and narrowing of the it continues for more than a month as the main
dispersion range as the child grows toward ado- symptom in an infant who has overcome the
lescence (O’Leary et al.). original cause of the condition. The respiratory
rate that qualifies as tachypnea depends on the
age of the patient, as defined by the World Health
Organization (Table 19.1).

Table 19.1  Tachypnea according to the World Health

Organization
Respiratory rate (respirations per
P. Bertrand (*) · A. Moya Olivares Patient age minute)
Department of Pediatrics, School of Medicine,
Newborn >60
Pontificia Universidad Católica de Chile,
2–12 months >50
Santiago, Chile
e-mail: [email protected] 1–5 years >40

© Springer Nature Switzerland AG 2020 187

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_19
 188 P. Bertrand and A. Moya Olivares

Respiration Control Mechanisms 20

PaO2 = 35 mm Hg
PaO2 = 50 mm Hg
Respiration begins in the nervous system by

Alveolar ventilation (L/min)

means of centers located in the brain stem (which 15
automatically command every inhalation–­
exhalation cycle) but is influenced by voluntary
10
cortical control.
Most of the time, respiration is under the con-
trol of the automatic respiratory center, which can
5
alter respiration to meet the metabolic demand,
activating the respiratory system in a highly sen- PaO2 = 100 mm Hg
sitive manner by a system of negative feedback 0
in response to the partial pressures of oxygen and 30 35 40 45 50
carbon dioxide (PaO2 and PaCO2) and the pH. The PaCO 2 (mm/Hg)
ventilatory response to hypoxemia emerges
when PaO2 values reach 50–60 mmHg, when the Fig. 19.2  Respiratory response to partial pressure of CO2
(PaCO2)
afferent influence of peripheral chemoreceptors
(especially carotid bodies) on the regulatory cen-
ter increases. The ventilatory response increases gen ions of between 20 and 60 nEq/L, whether
significantly when there is a slight concomitant they are of respiratory or metabolic origin. If the
increase in PaCO2 values (42–48 mmHg) and fol- respiratory system is in a condition to respond to
lows a logarithmic curve as PaO2 decreases. The the stimuli of hypoxemia and hypercarbia, the
ventilatory response to hypercapnia is determined increase in alveolar ventilation improves PaCO2
by a rapid response at the central level, where levels, which significantly decreases the afferent
the PaCO2 of the cerebrospinal liquid, which is influence of carotid chemoreceptors in the respi-
in balance with the blood because of its capacity ration process (Fig. 19.2).
to easily diffuse through the blood–brain barrier, The respiratory cycle is influenced by affer-
stimulates the central chemoreceptors linearly ent receptors of diverse voluntary and involun-
(Fig. 19.1). Parallel to this, ventilation increases tary respiratory control mechanisms, such as the
along with a rise in the concentration of hydro- reflexes of the lungs and respiratory tract, the car-
diovascular system, and the reflexes of stretched
muscles and articulations. Moreover, the respira-
50 tory cycle is influenced by higher centers such as
the hypothalamus and areas of the cerebral cortex
PaCO2 = 48 that take control over the automatic system when
Pulmonary ventilation (L\min)

40
we speak, cry, or laugh.

30
PaCO2 = 42
Etiology
20
Assessment of persistent tachypnea requires
adequate knowledge of the possible causes.
10
Identification of the probable etiology is nec-
No isocapnic
essary to appropriately deal with and manage
0 the condition. Once the influences of fever, cry-
20 40 60 80 100 120
PaO2 (mm/Hg)
ing, and pain on the respiratory rate have been
assessed, it is important to determine the respi-
Fig. 19.1  Respiratory response to partial pressure of O2 ratory and nonrespiratory causes of tachypnea
(PaO2) in infants (Table 19.2).
19  Infants with Persistent Tachypnea 189

Table 19.2  Organic causes of tachypnea signs of increased respiratory effort, which may
Nonrespiratory be indicative of the physiopathological situation.
Respiratory causes causes In this scenario, in which a small child is not able
Hypoxemia (persistent Psychogenic
to communicate his or her respiratory difficulty
pneumonia, bronchopulmonary (anxiety, irritability)
dysplasia, pulmonary aspiration, Metabolic (acidosis, or dyspnea, the examining physician should look
hemorrhage, alveolar proteinosis, liver failure) for nasal flaring, retraction of the thoracic wall,
interstitial pneumonitis) Poisoning use of accessory musculature, and/or paradoxi-
Trauma (pneumothorax, rib cage (salicylates,
cal movement, as well as determining if there is
fracture, interstitial emphysema) methylxanthines)
Pulmonary edema Central nervous asymmetry in the rib cage. Tachypnea is some-
Pulmonary hypertension system (tumors, times not associated with significant respiratory
Pulmonary embolism infections) symptoms or signs, and it constitutes a clinical
Pleural effusion Cardiovascular
challenge.
(cardiac
insufficiency) Requests for tests depend on the initial diag-
Miscellaneous nostic suspicion. When a disease of respiratory
(fever, pain, sepsis) origin is suspected, a chest x-ray is the first-line
examination to determine whether there is an
organic cause of the tachypnea, as occurs with
Diagnosis atypical pneumonia, pneumothorax, and x-ray
patterns for interstitial diseases. A chest x-ray is
The history of the course of tachypnea is essential also indicated to search for heart disease when
for a diagnostic approximation. It is necessary to there is cardiomegaly or pulmonary congestion
characterize the initial symptoms and the evolu- that suggests heart insufficiency. In this sce-
tion over time, the type of respiration, aggravating nario, it is recommended to perform an echo-
and triggering factors, and associated symptoms. cardiogram for a more complete assessment of
A rapid general assessment is recommended prior the cardiological situation. Immunofluorescence
to a physical examination, observing the appear- and polymerase chain reaction tests are very use-
ance, respiratory work, and circulation to deter- ful in identifying viral or bacterial etiology. An
mine whether the ­ phenomenon is potentially abnormal chest x-ray indicates that the study
serious or not. In the physical examination, it is must be complemented by axial computerized
imperative to observe respiratory patterns: the tomography (CT) of the helical thorax to better
rate, rhythm, efforts, and associated respiratory classify images suggesting chronic lung damage,
sounds. The respiratory rate should be determined interstitial disease, malformations, or a pulmo-
over a minute, ideally with the subject at rest and nary embolism. When tachypnea appears to be
in the most comfortable position for him or her. attributable to nonrespiratory causes, the x-ray
The breathing rate increases with fever by investigations are directed according to the sus-
5–7  rpm (respirations per minute) for every picion. Respiratory patterns such as acidotic or
degree over 37  °C, with metabolic acidosis. Kussmaul respiration provoke significant meta-
In the assessment of small children, consider- bolic acidosis, making it necessary to conduct
ation should be given to the significant changes arterial gas analysis and a biochemical profile that
that occur in the respiratory rhythm, includ- includes glycemia, creatinine, and hepatic tests.
ing periodic respiration, which can reach up When tachypnea of a central origin is suspected,
to 20% of the time in newborns, but in infants the investigations should be complemented with
over 3 months old, this is clearly abnormal and axial CT scanning of the brain to rule out brain
suggests neurological disease. Cheyne–Stokes or cerebellar tumors and malformations of the
breathing is not a common finding in children, central nervous system. In the case of suspicion
but it can appear with congestive cardiac insuf- of infection, it is important to perform a lumbar
ficiency or intracranial hypertension. Most often, puncture.
tachypnea is related to hypoxemia, because of Figure  19.3 shows a proposed algorithm for
which the examining physician should look for diagnostic study.
190 P. Bertrand and A. Moya Olivares

Anamnesis
and Physical
Examination

Tachypnea without Tachypnea with

apparent disease apparent disease

Pain
Fever Chest x-ray
Crying
Irritability

No study

Abnormal or normal with

Normal
high clinical suspicion

Respiratory Non respiratory

Persistent Bronchopulmonary CNS: tumor / Cerebral NMR /

pneumonia dysplasia infection LP

Pulmonary Heart failure Echocardiogram

aspiration

Pneumothorax,
interstitial Pulmonary Poisoning PL
emphysema fibrosis Chest
CT
Pulmonary Interstitial Metabolic: Glycemia
edema pneumonitis acidosis, liver Gases
failure Biochem profile

Pulmonary Infectious
Pleural effusion Miscellaneous:
hemorrhage parameters,
sepsis
cultures
Pulmonary Alveolar
hypertension proteinosis LB

Echocardiogram

Pulmonary Angiography CT,

Altitude hypoxia
embolism scintigraphy V/Q

Arterial gases

Fig. 19.3  Algorithm for study of persistent tachypnea. Biochem biochemical, CT computerized tomography, LB lung
biopsy, LP lumbar puncture, NMR nuclear magnetic resonance, PL plasma levels
19  Infants with Persistent Tachypnea 191

Sources Levitzky M.  Pulmonary physiology. 8th ed. New  York:

McGraw-Hill; 2013.
O’Leary F, Hayen A, Lockie F, Peat J.  Arch Dis Child.
Bloomfield D. Tachypnea. Ped Rev. 2002;23:294–5.
2015;100:733.
Chernick V, Boat T, Wilmott R, Bush A, Deterding R,
Palafox M, Guiscafré H, Reyes H, Muñoz O, Martínez
Ratjen F.  Kendig and Chernick’s disorders of the
H.  Diagnostic value of tachypnoea in pneumonia
respiratory tract in children. 8th ed. Filadelfia, PA:
defined radiologically. Arch Dis Child. 2000;82:41–5.
Elsevier; 2012.
Perpiñá M.  Síndrome de hiperventilación y asma. Arch
De Groot EP.  Review breathing abnormalities in chil-
Bronconeumol. 2004;40 Suppl 3:6–10.
dren with breathlessness. Paediatr Respir Rev.
Rothrock G, Green S, Fanelli JM, et  al. Do published
2011;12:83–7.
guidelines predict pneumonia in children presenting
Dijk F, Curtin J, Lord D, Fitzgerald DA. Pulmonary embo-
to an urban ED? Pediatr Emerg Care. 2001;17:240–3.
lism in children. Paediatr Resp Rev. 2012;13:112–22.
Taylor J, Beccaro M, Dune S, et al. Establishing clinically
Kossowsky J, Wilhelm F, Schneider S. Responses to vol-
relevant standards for tachypnea in febrile children
untary hyperventilation in children with separation
younger than two years. Arch Pediatr Adolesc Med.
anxiety disorder: implications for the link to panic dis-
1995;149:283–7.
order. J Anxiety Disord. 2013;27:627–34.
 Children with Persistent Stridor
20
Solange Caussade Larraín
and Carlos Flores Berríos

Contents
Definition   193
Epidemiology   193
Applied Physiopathology   194
Clinical History   195
Assessment   196
Images   196
Respiratory Function   196
Visualization of the Airway   198
Sources   199

Definition by a biphasic stridor. When airflow decreases

because of a severe obstruction of the airway,
Stridor is the main symptom or sign of obstruc- stridor can disappear.
tion of the upper airway. It can be congenital or
acquired, and acute or chronic. The latter is a
form that persists for more than 4 weeks. It is Epidemiology
defined as a high-pitched (>500  Hz) musical
respiratory sound and is predominantly inspira- Obstruction of the upper airway is more common
tory. Stridor that is solely inspiratory suggests in children than in adults because children have a
obstruction of the extrathoracic airway. Fixed greater risk of infections and their anatomical
lesions of the extrathoracic airway are manifested features differ from those of adults.
The incidence of stridor in the general pediatric
S. Caussade Larraín (*) population is unknown. Acute conditions are usu-
Department of Pediatrics, School of Medicine, ally the result of inflammation or infection, and
Pontificia Universidad Católica de Chile, chronic conditions are due to anatomical or patho-
Santiago, Chile logical alterations. The most common cause of
C. Flores Berríos acute stridor in preschool children is viral laryngo-
Department of Pediatrics, Hospital de Ovalle, Ovalle, tracheobronchitis (LTB), which has been identified
Chile

© Springer Nature Switzerland AG 2020 193

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_20
194 S. Caussade Larraín and C. Flores Berríos

Table 20.1  Causes of chronic stridor portional relationship between resistance (R),
Cause fluid viscosity (η), and the length of the tube (L),
Laryngomalacia and a proportional inverse relationship to the
Vocal cord paralysis fourth power of the radius (r4) of the tube:
Congenital or acquired congenital stenosis
Laryngeal cleft R = 8h L / p r 4
Laryngeal membrane
Subglottic hemangioma According to this formula, a 50% decrease in
Laryngeal papillomatosis
the radius increases airflow resistance by 16
Cysts and laryngoceles
Laryngeal condylomatosis times and consequently produces a notable
Proximal tracheomalacia decrease in airflow. When the lumen of the air-
Foreign body way is reduced, the velocity of the flow increases
and induces the Bernoulli effect, which estab-
in Chilean and international endoscopic studies as lishes that when the air velocity increases, the
the cause of 40–70% of stridors. With endoscopic pressure exerted by the airflow in the lumen
studies, it has been possible to determine the asso- decreases and, in this case, facilitates the col-
ciation of two or more airway anomalies in lapse of the airway. Finally, stridor is produced
10–50% of patients with congenital stridor. by distortions of the laminar flow and turbu-
Table 20.1 lists the causes of chronic stridor. lence, with a vibratory effect on the adjacent
tissue.
The diaphragm descends during inspiration;
Applied Physiopathology the ribs ascend and are in a horizontal position,
generating negative pressure within the chest
Stridor is related to the anatomy of the central cavity and the airway. The structures that sur-
airway and airflow dynamics. There is a natural round the extrathoracic airway are at atmospheric
anatomical division of the airway at the level of pressure, and so a pressure gradient is created
the glottis or vocal cords. However, from the that compresses this segment of the airway dur-
physiological point of view, the central airway is ing inspiration. Stridor is produced when the air-
composed of an extrathoracic part (the nose, way is collapsible or is partially obstructed (for
nasopharynx, larynx, and upper part of the tra- example, in patients with laryngomalacia or lar-
chea) and an intrathoracic part (the rest of the tra- yngitis, respectively).
chea and the bronchi). The thorax meets the neck The most common cause of chronic stridor in
at the level of the first dorsal vertebra, the first infants is laryngomalacia, located anatomically
ribs, and the sternal manubrium. in the extrathoracic and supraglottic region. This
The upper airway in children, and especially can include a tubular and collapsible epiglottis,
in infants, is funnel shaped and has a smaller with redundant supra-arytenoid and/or short ary-
diameter than that in adults; the tongue is propor- tenoepiglottic folds, which anatomically and/or
tionally larger, the location of the larynx is closer dynamically impede the passage of air (as a result
to the brain and to the anterior section, the tissues of collapse of the supraglottic structures during
are more lax, and there is greater cartilaginous inspiration) (Fig.  20.1). Viral laryngotracheal
flexibility of the support structures. The cricoid bronchitis fundamentally affects the subglottic
cartilage is the narrowest airway segment in space, and stridor can be solely inspiratory or
infants and preschool children, while the narrow- biphasic, according to the severity of the obstruc-
est segment in newborns is the nose. In school- tion (Fig. 20.2). The subglottic region is formed
children, the narrowest airway segment is the by cricoid cartilage, which is the only complete
vocal cords. cartilage in the airway and is the narrowest part
There are two physical principles that play a of the larynx in infants and preschoolers. Because
role in generating stridor. The first is Poiseuille’s it is a rigid area, it facilitates significant obstruc-
law of fluid dynamics, which shows a direct pro- tion of the airway.
20  Children with Persistent Stridor 195

a b

Fig. 20.1  Laryngomalacia. On expiration (a), redundant mucosa is visible. On inspiration (b), the arytenoids partially
obstruct the lumen and the epiglottis collapses in a cross direction

• Form of initiation: If stridor is acute and is

associated with a fever, the etiology probably
involves viral or bacterial infection. Abrupt
initiation with respiratory difficulty or
asphyxia suggests aspiration of a foreign
body  or an inflammatory cause (an allergic
reaction).
• Evolution timeline: A patient with stridor for
more than a week after viral laryngitis could
Fig. 20.2 Viral laryngotracheobronchitis. The larynx be suffering a complication such as bacterial
shows erythema and edema in the entire glottis, including tracheitis.
the cord and arytenoids
• Chronology: Stridor caused by laryngomala-
cia becomes notable at 1–2 weeks after birth
Clinical History and can increase until 3 months of age, after
which it decreases progressively, generally
The clinical history is very helpful for diagnosing disappearing by 1 year of age. A subglottic
stridor, assessing its severity, and deciding on the hemangioma often appears at 2 months of age
therapeutic approach, including referral to a and is progressive, following the same course
specialist. as hemangiomas of the skin.
The data to consider in the anamnesis are: • Conditions that modify stridor: In children
with laryngomalacia, stridor increases when
• Age at initiation: Congenital causes are most they eat, cry, or lie on their back; it decreases
common in newborns, and the most common when they lie face down or are asleep.
of these is laryngomalacia. The most common • History of cervical or thoracic trauma or sur-
cause among preschool children is LTB, gery: Lesions of the vagus nerve or its upper
although the possibility of foreign body aspi- laryngeal or recurrent laryngeal branches can
ration should always be considered. Croup decrease the mobility of the vocal cords,
usually presents in patients between 6 months including paralysis.
and 6 years of age. An infant under 6 months • Association with apnea and cyanosis: This
of age with repeated LTB could have a sub- can occur in cases of laryngomalacia, but it
glottic anatomical anomaly. can also appear in the presence of vascular
196 S. Caussade Larraín and C. Flores Berríos

rings and external causes not related to the branches, with a compromise of the vocal cords.
airway. A “potato voice” suggests abscessed tonsils.
• History of intubation: This indicates the pres-
ence of acquired subglottic stenosis. Figure 20.3 shows the clinical approach to dif-
• Association with feeding difficulty: This can indi- ferential diagnosis of acute-onset stridor.
cate the presence of acid reflux or an anatomical
anomaly, such as a laryngeal cleft or a tracheo-
esophageal fistula. It also constitutes a symptom Assessment
of the seriousness of the airway obstruction.
• Physical growth: Alterations can be due to Images
greater respiratory work that indicates the
seriousness of the obstruction. Radiology has been somewhat useful as a diag-
nostic tool. Traditionally, soft tissue cervical
The general aspects that should be taken into radiography has been used to look for reductions
consideration in the physical examination are: of the airway lumen in cases of LTB and congeni-
tal subglottic and tracheal lesions. When a patient
• Signs of respiratory failure: Intercostal and has aspirated a radiopaque foreign body, a radio-
subcostal retraction, use of accessory muscu- logical study is genuinely useful. Uroscopy is a
lature, state of awareness, cyanosis, decreased complementary method, which provides dynamic
arterial oxygen saturation. information on the airway from the nasopharynx
• Associated cough: A barking cough associated to the main bronchi, taking pictures in different
with stridor suggests LTB. phases of breathing. A contrast study of the
• Presence of craniofacial malformations, espe- esophagus is useful for diagnosing vascular rings.
cially those that compromise the middle third Computerized tomography (CT) with three-­
of the face and the base of the tongue. Stridor dimensional reconstruction helps to delimit and
and snoring can coexist because of their asso- characterize lesions, particularly when they are
ciation with diseases such as adenotonsillar complex and poorly defined anatomically, or
hypertrophy and laryngomalacia. when there is a severe stenosis of the airway that
• Presence of cutaneous hemangiomas: In 50% does not allow for an endoscope entering the air-
of subglottic hemangioma cases, there are way. In this way, CT can contribute to planning
similar lesions on the skin. Subglottic heman- for surgery, when it is appropriate. Nuclear mag-
giomas are observed in 1% of children who netic resonance imaging is useful for assessing
present cutaneous hemangiomas. aberrant cervical and vasculature masses (vascu-
• Presence of cervical malformations or a mass, lar rings).
which can compress the airway.

The characterization of the stridor should take Respiratory Function

into account the following:
In cooperative patients, the spirometric flow–vol-
• Phase of the respiratory cycle of stridor: The ume curve can be useful to distinguish between a
stridor is generally inspiratory if the compro- fixed obstruction of the central airway (in which
mise is extrathoracic. If the compromise is both the inspiratory and expiratory segments are
glottic, the stridor can be inspiratory or bipha- affected) and a variable obstruction (in which
sic. If the subglottic space is affected, the stri- only the inspiratory phase is compromised)
dor is usually biphasic. (Figs. 20.4 and 20.5). The inspiratory and expira-
• Accompanying signs: Chronic dysphony can tory phases of the flow/volume are affected (with
suggest the presence of a glottic mass (papil- flattening). It is not possible to determine if the
loma) or a lesion of the vagus nerve or of its obstruction is intra- or extrathoracic.
20  Children with Persistent Stridor 197

Acute
stridor

Yes Fever No

Severe respiratory
Foreign body
distress or increased
history or trauma
salivation

Yes No Yes No

Epiglottitis Croup Foreign body

Bacterial tracheitis Angioneurotic
Severe tonsillitis Thermal
Retropharyngeal abscess edema
Parapharyngeal epiglottitis
Croup Spasmodic croup
abscess Laryngeal trauma
Diphtheria

Fig. 20.3  Diagnostic approach to an acute-onset stridor

Inspiration Expiration Expiration

TLC RV

Inspiration

Fig. 20.4  Fixed obstruction of the intra- or extrathoracic central airway

The pressure of the airway is lower than the In more severe cases, gas exchange is
atmospheric pressure during inspiration, and if assessed by measurement of arterial or venous
this is unstable, its cross-sectional area decreases, gases, and measurement of arterial oxygen
decreasing the flow, which is manifested as a flat- saturation.
tening of the inspiratory phase of the flow/vol- If there is suspicion of obstructive apnea dur-
ume curve. ing sleep in patients with persistent stridor,
198 S. Caussade Larraín and C. Flores Berríos

Expiration

TLC RV

Pva < Patm Pva > Patm

Inspiration Expiration Inspiration

Fig. 20.5  Variable obstruction of the extrathoracic central airway

polygraph monitoring of ventilatory parameters The indications for comprehensive viewing of

during sleep is indicated. the airway are shown in Table 20.2. Figure 20.6
shows a proposed algorithm for endoscopic study
of stridor. The treating physician should make a
Visualization of the Airway decision on referral to a specialist for partial or
complete visualization of the airway.
Direct laryngoscopy and bronchoscopy currently If the stridor suggests laryngomalacia, there is
constitute the gold-standard treatments for etio- no need for invasive studies (Table 20.2), and if
logical diagnosis of chronic stridor. regression is observed, flexible bronchoscopy is
In diagnosing laryngomalacia, flexible bron- not absolutely indicated.
choscopy has 93% sensitivity and 92% specific-
ity, while laryngoscopy scores 100% for both Table 20.2  Indications for bronchoscopy
parameters. However, laryngoscopy is not opti- Indication
mal for searching for associated lesions in the Signs of respiratory distress
airway, as it does not allow for viewing below the Two-phase stridor
vocal cords. According to some authors, these Laryngomalacia with an unusual course
Stridor starting on the first day of life
lesions associated with the cause of stridor are Apnea and/or cyanosis
not clinically significant and only rarely require Feeding difficulty
specific treatment. If they implied any serious Failure to grow
condition, there would be clinical manifestations. Normal or inconclusive nasal fibroscopy
20  Children with Persistent Stridor 199

Chronic
stridor

Inspiratory without other

Expiratory or biphasic
associated sign. Clinical
Warning signs (Table 20.2)
suggestive of laryngomalacia

Flexible bronchoscopy or Nasal fibroscopy

rigid bronchoscopy

Definitive No diagnosis is
diagnosis required or
associated anomaly
is suspected

Flexible or rigid
bronchoscopy

Fig. 20.6  Algorithm for endoscopic study of chronic stridor

Ida J, Thompson D. Pediatric stridor. Otolaryngol Clin N

Sources Am. 2014;47:795–819.
Kubba H.  An infant with stridor. Clin Otolaryngol.
Bodahana A, Izbicki G, Kraman S. Fundamentals of lung 2007;32:283–4.
auscultation. N Engl J Med. 2014;370:744–51. Laya B, Lee E. Congenital causes of upper airway obstruc-
Boudewyns A, Claes J, Van de Heyning P. An approach tion in pediatric patients: updated imaging techniques
to stridor in infants and children. Eur J Pediatr. and review of imaging findings. Semin Roentgenol.
2010;169:135–41. 2012;47:147–58.
Carter E.  Evaluating noisy breathing in children: Petrocheilou A, Tanou K, Kalampouka E, Malakasioti
how far down the airway should one look? Chest. G, Giannios C, Katidis A.  Viral croup: diagno-
2004;125:1185–6. sis and a treatment algorithm. Pediatr Pulmonol.
Contreras I, Rosa G, Navarro H, Bertrand P, Cuevas M, 2014;49:421–9.
Sánchez I, Caussade S. Estridor en el paciente pediátrico: Pfleger A, Eber E.  Management of acute severe upper
estudio descriptivo. Rev Chil Pediatr. 2004;75:247–53. airway obstruction in children. Paediatr Respir Rev.
Doherty G. Acute and chronic airway obstruction in chil- 2013;14:70–7.
dren. Anaesth Int Care Med. 2012;13:220–5.
 Children with Snoring
21
Daniel Zenteno Araos, José Luis Pérez Sánchez,
and Pablo Brockmann Veloso

Contents
Introduction   201
Associated Risk Factors   202
Asthma   202
Rhinitis   202
Poor Dental Occlusion   202
Diagnosis   202
Sources   203

Introduction The prevalence of snoring in the general pediat-

ric population is 3–12%. Among individuals with
Habitual snoring is the cardinal symptom of obstructive sleep apnea (OSA) it is 0.7–2%, mainly
respiratory sleep disorders (RSDs) and arises associated with adenotonsillar hypertrophy.
from a series of causes that are classified into The notable increase in the prevalence of
three large groups: adenotonsillar hypertrophy child obesity has changed the demographic and
without obesity, adenotonsillar hypertrophy with anthropometric characteristics of children who
obesity, and a group that includes neuromuscular
diseases, Down syndrome, cerebral paralysis, Table 21.1  Classification of causes of sleep breathing
disorders (SBDs)
and craniofacial syndromes (Table 21.1).
Type I SBD Type II SBD Type III SBD
Adenotonsillar Obesity with Neuromuscular
D. Zenteno Araos (*) hypertrophy mild-to-­ diseases
Department of Pediatrics, Universidad de without obesity moderate Down syndrome
Concepción, Concepción, Chile adenotonsillar Arnold–Chiari
hypertrophy malformation
J. L. Pérez Sánchez Cerebral palsy
Department of Pediatrics, Universidad Austral de Craniofacial
Chile, Osorno, Chile syndromes: Pierre
P. Brockmann Veloso Robin syndrome,
Department of Pediatrics, School of Medicine, Apert syndrome,
Pontificia Universidad Católica de Chile, Goldenhar
Santiago, Chile syndrome, Crouzon
e-mail: [email protected] syndrome,
achondroplasia

© Springer Nature Switzerland AG 2020 201

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_21
202 D. Zenteno Araos et al.

Table 21.2  Differences between type I and type II sleep influence on the therapeutic focus. Some authors
breathing disorders (SBDs)
have even proposed these as specific phenotypes.
Type I Type II
Symptoms SBDs* SBDs*
Somnolence + ++++
Weight gain − ++ Asthma
Hyperactivity ++++ −/+
Attention deficit disorder ++++ +++ A recent meta-analysis, which included 17 stud-
Truncal/visceral obesity −/+ +++ ies, found that asthmatic children have SBDs
Increased cervical girth −/+ +++ more often than nonasthmatic children (24% ver-
Increased adenotonsillar size ++++ ++ sus 17%), which implies that just being asthmatic
Acute otitis media/tympanostomy +++ + increases the risk of having this disorder by
Depression and low self-esteem + +++
almost.
Shyness and social isolation + +++
Left ventricular hypertrophy ++ ++++
Hypertension + ++++
Insulin resistance − ++++ Rhinitis
Dyslipidemia + ++++
Elevated C-reactive protein ++ ++++ The coexistence between rhinitis and SBDs has
Elevated liver enzymes − ++ been reported and discretely studied, although the
+ to ++++ infrequent to very frequent, − absent
*
focus remains on treatment to control rhinitis. A
recent study confirmed this coexistence (in 43%
are referred to sleep units. In the USA, fewer of study participants with rhinitis) but without
than 15% of children were obese in the 1990s, considering the severity of sleep disorders in the
but in the last decade more than 50% were. pediatric population.
Several authors have argued that type I and II
SBDs should be considered specific phenotypes
with different characteristics and forms of pre- Poor Dental Occlusion
sentation (Table 21.2).
In children and adolescents with neuromuscu- Different anatomical alterations can affect respi-
lar diseases, obesity, or craniofacial malforma- ratory flows and resistance in the upper airway,
tions, the prevalence of SBDs with clinical and thus facilitate the appearance of SBD. These
significance can be as high as 50%. alterations sometimes coexist with other possible
While there are symptoms associated with causes. Therapeutic treatment of these children
SBDs, the clinical history and directed anamnesis should be considered.
have low sensitivity and/or specificity, because of
which complementary examinations are necessary
to obtain an early examination and timely interven- Diagnosis
tions, thus reducing the possibility of neurocogni-
tive alterations and deleterious biological effects on Habitual snoring is defined as the presence of snor-
the child’s metabolic, cardiovascular, and other ing on three or more nights per week. The anamne-
systems, with the possibility of affecting the quality sis should serve to determine if the snoring is
of life throughout his or her lifetime. independent from colds or respiratory infections,
the position the child is in when snoring occurs,
and whether the snoring is associated with buccal
Associated Risk Factors breathing or apnea that is evident to the observer.
The precise diagnosis to rule out OSA is based
There are factors that we can consider to be asso- on nocturnal polysomnography in a sleep labora-
ciated with snoring, which have not been well tory. This examination is the only one currently
studied despite their high prevalence and potential considered a gold standard. However, there are
21  Children with Snoring 203

No Habitual Yes
snoring

Follow-up
<2 years, RF, NMD, Down syndrome,
craniofacial malformations, obesity, asthma

No Yes

Pedriatric sleep questionnaire, polygraph, Ear nose PSG

and throat, drug treatment for 6 weeks should be
considered

Snoring improves Snoring persists

Follow-up PSG

Multidisciplinary
treatment and evaluation

Fig. 21.1  Diagnostic and therapeutic approaches

abbreviated studies that play a role in screening Clinical and physical examinations do not
for patients who snore. have sufficient sensitivity and specificity to rule
It is important to incorporate screening for out OSA, because of which a combination of dif-
habitual snoring into all care for children and ferent tools such as questionnaires, polygraph
adolescents, given its association with risk fac- tests, and an established system of referrals is
tors (type II SBDs, obesity, craniofacial malfor- proposed as an option for screening of the gen-
mations, Down syndrome, etc.). Sleep studies eral population.
should be conducted as early as possible and ide-
ally should involve polysomnography (Fig. 21.1).
In children between 2  and 8  years of age, Sources
when the main cause of OSA is adenotonsillar
hypertrophy, an abbreviated diagnosis and empir- Brockmann PE, Schaefer C, Poets A, Poets CF, Urschitz
MS.  Diagnosis of obstructive sleep apnea in chil-
ical treatment can be introduced, such as nasal dren: a systematic review. Sleep Med Rev. 2013;17:
corticoids for 6 weeks. The persistence of noctur- 331–40.
nal and diurnal symptoms at the end of this period Brockmann P, Bertrand P, Castro-Rodríguez JA. Influence
should be assessed, and it should be decided if of asthma on sleep disordered breathing in children:
a systematic review. Sleep Med Rev. 2014;18:393–7.
polysomnography and a multidisciplinary study Elso MJ, Brockmann P, Zenteno D.  Consecuencias del
are necessary. síndrome de apnea obstructiva del sueño. Rev Chil
Pediatr. 2013;84(2):128–37.
204 D. Zenteno Araos et al.

Gozal D, Simakajornboon N, Holbrook CR. Secular tends Mellies U, Dohna-Schwake C, Voit T. Respiratory func-
in obesity and parentally reported daytime sleepiness tion assessment and intervention in neuromuscular
among referred to a pediatrics center for snoring and sus- disorders. Curr Opin Neurol. 2005;18:543–7.
pected sleep-disorders breathing. Sleep. 2006;29:A74. Sans-Capdevila O, Gozal D.  Neurobiological conse-
Huseni S, Gutierrez MJ, Rodriguez CE, Nino CL, Perez quences of sleep apnea syndrome in children. Rev
GF, Pancham K, Nino G.  The link between rhinitis Neurol. 2008;47:659–64.
and rapid-eye-movement sleep breathing disturbances Urschitz MS, et al. Snoring in children: algorithm for diag-
in children with obstructive sleep apnea. Am J Rhinol nostic approach. Monatsch Kinder. 2013;161:347–50.
Allergy. 2014;28:56–61. Zenteno D, Salinas P, Vera R, Brockmann P, Prado
Kaditis A, Kheirandish-Gozal L, Gozal D.  Algorithm F.  Enfoque pediátrico para el estudio de los trastor-
for the diagnosis and treatment of pediatric OSA: a nos respiratorios del sueño. Rev Chil Pediatr.
proposal of two pediatric sleep centers. Sleep Med. 2010;81(5):445–55.
2012;13:217–27.
 Children with Recurrent Wheezing
22
Luis Enrique Vega-Briceño, Ilse Contreras Estay,
and Ignacio Sánchez

Contents
Epidemiology  205
Etiology  206
Physiopathology  206
Clinical Characteristics  207
Diagnosis  209
Management  210
Episodic Wheezing  210
Multitriggered Wheezing  212
Assessment of Severity  212
Evolution and Prognosis  213
Sources  213

Epidemiology up studies have shown that in approximately 30%

of cases, wheezing begins before the children are
Close to 50% of children experience wheezing 1  year old, with significantly poorer pulmonary
during the first 6 months of life, but not all of them function test results (before the first infection) than
experience bronchial asthma. Long-term follow- those of children who never experience wheezing.
Many researchers agree that many early-age epi-
sodes of wheezing are associated with infections
L. E. Vega-Briceño (*) of viral origin. Several studies have shown that
Faculty of Medicine, Universidad del Desarrollo,
Santiago, Chile these infections are associated with abnormal pul-
e-mail: [email protected] monary functioning during adolescence, even in
I. Contreras Estay the absence of respiratory symptoms.
Department of Pediatrics, Hospital Padre Hurtado, The observational Avon Longitudinal Study of
Santiago, Chile Parents and Children (ALSPAC) identified that
I. Sánchez 26% of a cohort of 6265 children experienced
Department of Pediatrics, School of Medicine, at least one episode of wheezing by the age of
Pontificia Universidad Católica de Chile, 18 months.
Santiago, Chile

© Springer Nature Switzerland AG 2020 205

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_22
206 L. E. Vega-Briceño et al.

Etiology Physiopathology

Recurrent wheezing in infants raises serious The term “wheezing” is often used imprecisely.
problems with regard to determining its etiol- It has been assessed in diverse epidemiological
ogy or nature, owing to the clinical similari- studies that have employed video questionnaires
ties of different conditions (Table 22.1). While and works that have quantified wheezing. In
viral respiratory infections represent the main some European languages, there is no appropri-
causal factor in many obstructive episodes, it is ate translation for the English word “wheezing.”
recognized that there are environmental factors Wheezing is the audible clinical manifestation of
that can result in wheezing episodes. There are the small airway obstruction. It consists of high-­
important anatomical differences between the pitched musical sounds generated by the flow
airway of an infant or a preschool child and the of air through the narrow intrathoracic airway.
airway of an adult—differences that can favor It usually is perceived during expiration, and it
the development of obstructive conditions in is associated with increased work of breathing,
small children. It is also recognized that a state although it can also occur during inspiration.
of bronchial hyperresponsiveness (BHR) is nor- Studies of pulmonary sounds have quantified
mal in the first years of life, but it decreases wheezing directly through the use of microphones
progressively with age, although it increases on the chest surface, which is ideal, but it is not
significantly after certain viral infections (respi- very useful in clinical situations. This method has
ratory syncytial virus (RSV), influenza, parain- shown that doctors do clearly identify this symp-
fluenza). This indicates that the causes of many tom, although parents and nurses often do not,
obstructive episodes in children are multifacto- as it is not easily reproducible. As noted earlier,
rial. It is estimated that in almost 80% of chil- wheezing is common among infants.
dren with wheezing, the condition is associated It is possible that more than one physiopath-
with a viral infection. ological mechanism is involved in generating

Table 22.1  Differential diagnosis of infants with recurrent wheezing

Etiology Clinical characteristics Tests and investigations
Bronchopulmonary Prematurity, respiratory distress of the newborn, Chest x-ray, nocturnal SpO2
dysplasia mechanical ventilation in the neonatal period, O2
needed for >28 days
Cystic fibrosis Malnutrition, malabsorption syndrome, Sweat electrolyte test, genetic testing
pneumopathy, or recurrent sinusitis
Congenital heart disease Heart murmur, heart failure X-ray, ECG, Doppler echocardiogram
Foreign body aspiration Acute episode of asphyxia, asymmetrical lung X-ray, flexible or rigid bronchoscopy
signs
Gastroesophageal reflux Recurrent vomiting X-ray, pH measurement
Dysphagia due to Recurrent or persistent pneumopathy Pulmonary aspiration scintigraphy
neurological damage
Lung malformations Radiological finding Prenatal ultrasound, chest x-ray, CT
scan, angiography, MRI
Vascular malformations Stridor X-ray, esophagogram, endoscopy,
Doppler echocardiogram,
angiography, MRI
Primary ciliary Sinus pathology, recurrent acute otitis media, X-ray, saccharin test, respiratory
dyskinesia bronchiectasis, situs inversus epithelium biopsy
CT computerized tomography scan, ECG electrocardiogram, MRI magnetic resonance imagining, SpO2 peripheral cap-
illary oxygen saturation
22  Children with Recurrent Wheezing 207

recurrent wheezing: intraluminal obstruction due lymph nodes, bronchogenic cysts, and pulmo-
to inflammation, edema, contraction of the smooth nary sequestration, among others.
muscle, or BHR; extraluminal obstruction due to Bronchial hyperresponsiveness: This is one
compression by vascular rings, adenopathy, or of the components of bronchial asthma. The
congenital pulmonary malformations; and struc- traditional model maintains that inflammation
tural defects that condition dynamic obstruction produces hyperresponsiveness and is respon-
of the airway: hemangiomas, polyps, broncho- sible for the symptoms. While there is a good
malacia, and tracheomalacia, among others. correlation between BHR and the severity of
Airway inflammation: While bronchial asthma asthma in preschool children, this is not cer-
has been considered an inflammatory disease tain when the response to medication is being
of the airway induced by eosinophils and medi- assessed at an individual level. BHR is a non-
ated by type 2 helper T (Th2) lymphocytes, stud- specific condition of asthma, often second-
ies of bronchial lavage fluid, bronchial biopsies, ary to other causes such as viral infections,
and induced sputum have identified noneosino- Mycoplasma Pneumoniae, exposure to ciga-
philic forms of recurrent wheezing in preschool rette smoke or other types of smoke, environ-
children that may be a form of nonallergic child mental contamination, and allergies, among
asthma. Other inflammatory diseases (such as others. For clinical effects, BHR and inflamma-
cystic fibrosis) present a neutrophilic cell pref- tion should be considered as independent and
erence, with an increase in interleukin-8 (IL- overlapping conditions. Children are born with
8), including before the presence of a bacterial a predisposition to develop BHR, which disap-
colony. The participation of inflammation in the pears with age. However, viral infections can
pathogeny of other respiratory diseases, such aggravate the condition and even make it per-
as bronchopulmonary dysplasia in premature manent. Figure  22.1 summarizes the possible
infants, is well recognized. mechanisms involved in the development of
Limitation of airflow: Limitation of airflow recurrent wheezing in preschool children.
can be secondary to pre- or postnatal anatomical
reduction of the airway caliber. Different alterna-
tions of the distensibility of the airway wall can Clinical Characteristics
occur (a primary defect in the structure of the
wall, or loss of the alveolar framework). Prenatal Once it has been determined that a child is suf-
factors include a mother who smokes, hyper- fering an acute episode of wheezing, an adequate
tension during the pregnancy, and atopy. While clinical history and a complete physical exami-
changes in the distensibility of the airway wall nation are required to place the child in one of
have been suggested as being important, this is the three categories mentioned in Table 22.2. The
difficult to establish without histological studies. medical history and the physical examination are
The most common causes at the postnatal stage essential to categorize a child and to decide if
are bronchopulmonary dysplasia, postinfectious further investigation is needed. The reasons for
bronchiolitis obliterans (generally caused by an referring a child to a specialist in respiratory dis-
adenovirus), gastroesophageal reflux, and aspi- eases are if there is doubt about the diagnosis, if
ration syndromes. There are also flow limita- the treatment that is applied does not work, or
tions secondary to aspiration of a foreign body, if the parents are not satisfied with the results.
congenital and acquired stenosis of the airway, Most preschool children with recurrent wheez-
cicatricial polyps in patients with bronchopul- ing do not require any further laboratory study.
monary dysplasia, hemangiomas, vascular rings, Diagnostic confusion increases with the use of
compression by vascular structures (the ligamen- terms such as “bronchiolitis,” “obstructive bron-
tum arteriosum or the pulmonary artery trunk), chitis,” and “asthmatic bronchitis,” which refer
208 L. E. Vega-Briceño et al.

Prenatal injury
Maternal smoking
Vascular ring Maternal atopy
Complete tracheal ring ¿Gestational hypertension?
Ligamentum arteriosum Airflow limitation
Lung malformations
Malacias, hemangiomas, Postnatal injury
polyps Bronchiolitis obliterans
Foreign body Foreign body
Mediastinal tumor
Lymph nodes

Intra-extraluminal
obstruction of non- Bronchial
Wheezing hyperresponsiveness
inflammatory
cause

Asthma
Eosinophilic infiltration
Post-viral
Asthma
Cystic fibrosis
ABPA
BPD, GERD
Parasitosis
Inflammation Aspiration syndrome
Bronchiolitis obliterans
Neutrophilic infiltration
Cystic fibrosis
BPD, severe asthma
HRSV infection

Fig. 22.1  Etiopathogenesis of recurrent wheezing. ABPA allergic bronchopulmonary aspergillosis, BPD bronchopul-

monary dysplasia, GERD gastroesophageal reflux disease, HRSV human respiratory syncytial virus

Table 22.2  Causes of recurrent wheezing

Frequent causes Infrequent causes Rare causes
Viral infections Cystic fibrosis Mediastinal masses (tumors, tuberculosis)
Asthma Bronchopulmonary dysplasia Immunodeficiencies
Congenital heart disease Primary ciliary dyskinesia
Foreign bodies Bronchiolitis obliterans
Bronchiectasis
Aspiration syndromes
Vascular and pulmonary malformations

to different clinical conditions. In UK, the first Many classifications that use different catego-
term refers to a condition characterized by respi- ries for children with recurrent wheezing have
ratory difficulty, with the presence of fine crepi- been published, and these are outlined below.
tant crackles (alveolar noises) in children under
1  year of age. While wheezing can be present, (a) Epidemiological phenotype: In this context,
UK authors consider that crepitant crackles the wheezing phenotypes are “transitory or
define the illness. No rigid definition based on early” (occurring only during the first 3 years
age should prevail, given that any generalization after birth) and persistent wheezing (continu-
is artificial. In the USA and elsewhere, for exam- ing until the age of 6 years). This study from
ple, bronchiolitis is synonymous with wheezing Tucson (AZ, USA) was focused on the evo-
diseases. lution of symptoms (wheezing) and long-­
22  Children with Recurrent Wheezing 209

term pulmonary function, but its categories nonspecific and do not point to a determined eti-
can be determined only retrospectively and ology, their absence does not rule out the possi-
are not clinically useful. bility that a process is under way. The presence
(b) Phenotype based on the presence/absence of of nail clubbing, a heart murmur, postbroncho-
atopy: Early sensitization to aeroallergens is dilator clinical deterioration, a stridor, lack of
the best predictor of development of symp- growth, craniofacial malformation, compromise
toms and loss of pulmonary function by of the branchial arches (CHARGE and velocar-
school age, such that assignment to an atopic diofacial syndromes), recurrent pneumonia, or
category or a nonatopic category can be use- other parenchymal infections are indications for
ful as a guide for treatment. ruling out conditions associated with a secondary
(c) Phenotype based on triggers for wheezing: cause.
The Task Force of the European Respiratory Infants with more intense respiratory symp-
Society recommends that preschool children toms or with a chronic base condition (neurologi-
with a recurrent sibilant wheeze should be cal, comorbid, digestive, cardiological, genetic,
put into one of two categories—episodic dysmorphic, or growth related) require further
wheezing or multitriggered wheezing— study to determine bronchial, inflammatory, or
which is also what we propose. infectious compromise. Any atypical clinical or
radiological presentation—such as the onset of
• Wheezing episodes: These children present symptoms during the neonatal period, asymmet-
wheezing solely in the context of upper respi- rical wheezing, localized hyperinflation, bronchi-
ratory tract infection of viral etiology but are ectasis, diaphragmatic asymmetry, radiological
free of symptoms between such episodes. patterns, or persistent or recurrent atelectasis—
• Multitriggered wheezing: These children have indicates the need to consider another disease.
wheezing in the context of upper respiratory
infections of viral etiology and also in the con-
text of other triggers such as exercise, expo- Diagnosis
sure to cigarette smoke, exposure to allergens,
and others. The assessment of a child with recurrent wheez-
ing begins with a good anamnesis and a com-
The ERS-recommended classification is now plete physical examination. To establish the
used in many publications to guide treatment. diagnosis of asthma in children under 2–3 years
Since its publication, it has been criticized for of age, certain chronic diseases need to be ruled
the fact that children can change between cat- out (particularly in children who do not present
egories over time; consequently, the drug treat- the aforementioned risk factors). A family his-
ment can also change. This is analogous to what tory of asthma or a personal or parental history
occurs in schoolchildren with asthma, in which of allergies can be very important. The diagno-
the treatment does not remain fixed over time; sis of asthma should always include anatomical
rather, dose increases or reductions are intro- or structural considerations. While asthma is a
duced (and are eventually suspended), depending chronic inflammatory disease of the small airway
on the presence of symptoms and their severity. and preferentially eosinophilic, with changes in
Unfortunately, few studies have adopted this clas- expiratory flows, these characteristics are not usu-
sification, because many epidemiological studies ally assessed in clinical practice, particularly in
and clinical assays have combined the two phe- infants and preschool children. Flow reversibility
notypes as being more relevant. with pulmonary studies and exhaled nitric oxide
Obstructive conditions in infants are mani- measurements do not yet have practical applica-
fested by the presence of coughing, wheezing, tion in differentiating the aforementioned clinical
audible or prolonged expiration, costal retrac- patterns. A chest x-ray can confirm the elements
tion, an increased anteroposterior diameter, and of air trapping and rule out associated anatomical
dullness to percussion. While these findings are conditions. The most common radiological find-
210 L. E. Vega-Briceño et al.

ings in relation to an obstructive ­bronchial crisis tal contamination increases the probability of
are hyperinsufflation, diaphragmatic flattening, developing wheezing in the preschool period, but
increased retrosternal space, increased intersti- currently there is no clear recommendation based
tial and peribronchovascular trauma, segmental on individual exposures—only recommendations
atelectasis, and subsegmentation. When there is at the population level.
clinical evidence suggesting a determined etiol- Medication should be considered in order to
ogy, complementary examinations can be useful, avoid complications such as remodeling of the
such as esophagography, bronchoscopy, chest airway and persistent obstruction of airflow, as
echography, and echocardiography. Axial com- well as for treatment of symptoms. In practice,
puterized tomography (CT) and nuclear magnetic we do not have a clear strategy to reduce the risk
resonance imaging allow diagnosis of vascular of developing asthma, even through continuous
malformations such as rings and vascular com- or intermittent use of inhaled corticosteroids.
pressions of the airway, as well as confirming When prescribing an inhaled medication, it is
pulmonary, airway, or digestive tract malforma- essential to be prepared to stop the inhalation
tions (tracheoesophageal fistulas or recurrence of technique and use of the spacer at any time if the
tracheoesophageal fistulas in patients with a his- prescribed aerosol does not appear to be work-
tory of esophageal atresia), aspiration of a foreign ing. Proper administration should be determined,
body, tracheomalacia, or bronchomalacia. Video rather than escalating the treatment.
deglutition is useful to establish the diagnosis of
aspiration syndromes and pharyngeal incoordina-
tion, particularly in children with cerebral paraly- Episodic Wheezing
sis or psychomotor retardation. During an acute
episode, some laboratory examinations should be Children with episodic wheezing are not at
considered that can point toward or confirm the greater risk of atopy or respiratory symptoms,
responsible etiological agent in some uncommon according to follow-up series that have studied
conditions. In such conditions, it can be neces- children up to 14 years old. The evidence is clear
sary to determine the esophageal pH, total immu- and comes from clinical studies showing that
noglobulin, and immunoglobulin subclasses, and early treatment, whether intermittent or continu-
to perform fiber bronchoscopy (with a mucosal ous, does not affect the progress of the disease.
biopsy, alveolar lavage, and eventually electron This means that we do not have treatments that
microscopy) or an echocardiogram. A sweat test modify the disease, and that treatment should be
should be always be requested for children with focused on controlling symptoms.
recurrent wheezing, given that this is a way to Intermittent symptoms should be treated with
diagnose cystic fibrosis, particularly if there is intermittent drug strategies, which in practice
nutritional compromise and suspicion of diges- is what parents do. It is important to determine
tive compromise. which patients require ongoing treatment. The
use of inhaled medication to treat mild respira-
tory sounds with minimal respiratory pressure
Management can be more problematic than the disease itself.
The treatment should start with intermittent use
Before any medication is prescribed to a child of bronchodilators (either short-acting agonists
with episodic or multitriggered wheezing, it or anticholinergics). If the treatment needs to be
is essential to ensure that the environment in staggered from bronchodilators because of lack of
which the child lives is controlled, particularly symptom control, the next option is intermittent
with regard to exposure to smoking: smoking use of antileukotrienes, corticosteroids, or both.
outside the house (not in front of the child) does There have been recent and important random-
not protect the child from harm. A follow-up ized, controlled clinical studies assessing inter-
study cohort from birth found that environmen- mittent therapy. One study compared i­ ntermittent
22  Children with Recurrent Wheezing 211

use of antileukotrienes with a placebo in children to support the use of inhaled corticosteroids at the
who received the treatment from the time of onset usual doses in children with episodic wheezing.
for a minimum of 7 days or until the symptoms of There are studies that have recommended more
respiratory tract infection disappeared. The study research into intermittent use of inhaled corti-
found that the children who received the treat- coids in response to virus-triggered wheezing to
ment required fewer unscheduled medical con- clarify the doses, the timing, and the benefits of
sultations because of asthma exacerbations (odds this intervention in this context. It appears inap-
ratio 0.65; 95% confidence interval 0.47–0.89) propriate and unsafe to use fluticasone twice a
and had fewer days away from school or kinder- day in doses above 150 μg in healthy preschool
garten, with fewer days being lost from work by children (without base conditions) with viral
the parents (37% versus 33%, p < 0.001). In a pre-­ colds, given the risk of adverse effects such as
established analysis of a subgroup of patients, the axis suppression and adrenal failure with high
benefits were greater among children 2–5  years doses. To date, no studies have combined inter-
of age (close to 80%). However, these findings mittent doses of inhaled corticoids with montelu-
have not been confirmed by subsequent studies. kast to treat episodic wheezing.
A comparative study of standard treatment for There is no evidence supporting regular use
children versus intermittent antileukotriene and of inhaled corticoids in preschool children who
intermittent budesonide, showed that the active wheeze between colds. However, if children
treatment and standard strategy provided similar experience severe episodic exacerbations that
benefits. On the basis of such studies, we recom- require frequent hospitalization, or if they have
mend a trial of antileukotrienes for preschool prolonged symptoms, with interruptions in the
children with virus-induced symptoms. We rec- quality of their home life, prophylactic doses of
ommend beginning the treatment when the first inhaled corticosteroids can be tested. In some
sign of a cold appears and stopping it when the cases, it may seem that fluctuations in symptom
child is well, rather than continuing it for a fixed control are not fully perceived by the parents.
number of days. A trial of an inhaled corticoid should always be
A Cochrane review identified that intermit- avoided in milder cases of episodic wheezing. The
tent use of inhaled corticoids is a partially effec- treatment should be reviewed and discontinued if
tive strategy in response to episodic wheezing in there is no benefit. There is no evidence estab-
preschool children. A study in children between lishing the optimal duration of the treatment, but
the ages of 1  and 6  years showed that use of 6–8 weeks appears to be a reasonable period. If
fluticasone for 10 days at the beginning of cold the episodic wheezing improves with treatment,
symptoms was responsible for reducing the use a brief interruption and reduced doses should be
of rescue prednisone in comparison with a pla- considered according to the clinical evolution of
cebo. However, this use of inhaled corticoids the condition. If it is suspected that the child has
is associated with adverse effects, because of symptoms between colds that are not perceived
which it is not recommended. Another study that by the parents, a trial of inhaled corticosteroids
compared continuous versus intermittent use of can reveal whether the child was really more
budesonide from the onset of a cold did not show symptomatic than previously believed. Whatever
differences in any parameter, but the absence of the context of a therapeutic trial in preschool
a placebo group meant that it could not be deter- children is, the treatment period must be prede-
mined which of the two strategies was more termined and the treatment must be suspended at
beneficial. What this study did show is that daily the end of the trial to determine if the symptoms
doses of inhaled budesonide do not prevent the reappear and if the treatment is indeed necessary.
development or onset of viral exacerbations with Recent evidence has called into question the
wheezing. Older small-scale studies that used use of oral prednisone in acute episodes of viral
beclomethasone also failed to demonstrate this wheezing in preschool children. There have been
preventive effect. There is currently no evidence at least two well-designed studies in children with
212 L. E. Vega-Briceño et al.

recurrent wheezing and at least one hospitaliza- sion rate and the duration of hospitalization were
tion, where the use of prednisone was compared measured, and were lower in the hypertonic saline
with use of a placebo. No differences were found group, but there were no significant differences
between the two groups in either study. This indi- in the severity score, probably because the study
cates that preschool children who have virus-trig- included only a small number of patients. Since
gered episodic wheezing and who are well enough hypertonic saline can produce bronchospasm, it
to not be hospitalized do not receive any benefit should be used only in the hospital. Palivizumab
from oral steroids. Moreover, many children who has been used to prevent RSV infections in high-
are hospitalized should not receive oral steroids risk children, such as extreme premature survi-
either. These studies considered children with vors. However, because of cost and inconvenience,
mild cases, since many were discharged in the first it is not the treatment of choice for all children.
24 hours, so this experience cannot be extrapolated In a recent study, 429 children born at gestational
to children with severe exacerbations triggered by ages from 33 to 35 weeks were randomly given
viruses. In the absence of evidence, it is probable palivizumab or a placebo. Palivizumab reduced
that prednisone continues to be prescribed for a the number of days with wheezing in the first year
small subgroup of hospitalized children. of life by 61% and reduced the percentage of chil-
dren with recurrent wheezing from 21% to 10%.
The most interesting question this study could
Multitriggered Wheezing resolve—provided that the children are followed
up from infancy to school age—is the controversy
In preschool children with wheezing or cough- as to whether early RSV infection causes asthma
ing who respond to bronchodilators with reduced or is simply a sign that a child has a predisposition
breathing difficulty even in the absence of viral to develop asthma. The current position is that this
infections, prophylactic treatment should be con- is a work in progress, rather than an indication of
sidered, whether it is inhaled corticoids or antileu- a change in public policy.
kotrienes. As inflammation of the airway cannot Treatment plans highlight the importance of
be ruled out in this age group, and many children self-management, depending on the severity of
are asymptomatic until school age, it is wrong symptoms and the measurement of peak flow at
to assume that the physiopathology of this dis- school age. A controlled trial involved 200 chil-
ease is the same as that of asthma. Furthermore, dren between 18 months and 5 years of age with a
eosinophilic inflammation is less likely in small history of unscheduled visits to a hospital or emer-
children, because of which the use of inhaled gency room because of wheezing. The children
corticoids is more problematic. The final objec- were divided into two groups; one group received
tive is to avoid incorrectly diagnosing children standard treatment, while the parents of the other
as having asthma and, as a consequence, pre- group received two education sessions and an
scribing inappropriate treatment, given that most instruction booklet with a plan of guided action
children begin treatment when there is a strong to manage the symptoms. No differences were
probability that they will improve spontaneously. found in any of the outcomes. Although there is
Long-­acting β-adrenoceptor antagonist (LABA) no evidence of their effectiveness, education ses-
treatment is not approved for this age group. sions and action plans are widely employed.
In a small, double-blind study, 451 children
between 1  and 6  years of age were randomly
assigned to receive hypertonic saline at 7% or Assessment of Severity
normal saline at 0.9%, both combined with sal-
butamol. The treatments were administered twice, In determining the seriousness of recurrent
20  minutes apart, in the emergency ward, and obstructive symptoms, consideration should be
four times, separated by 20-minute intervals, if given to the number of hospitalizations or emer-
the child was hospitalized. The hospital admis- gency visits, the presence of nocturnal respi-
22  Children with Recurrent Wheezing 213

ratory symptoms or associated conditions (for Blanken MO, Rovers MM, Molenaar JM, Winkler-­
Seinstra PL, Meijer A, Kimpen JL, Dutch RSV
example, gastroesophageal reflux), tolerance of Neonatal Network, et  al. Respiratory syncytial virus
exercise and eating, frequency of oral steroid and recurrent wheeze in healthy preterm infants. N
use, and other factors. Several clinical scores Engl J Med. 2013;368:1791–9.
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Rodriguez JA, Custovic A, et  al. Definition, assess-
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varies greatly, and so the sensitivity of scoring Bush A.  Practice imperfect—treatment for wheezing in
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MC, Pettersen M, Mowinckel P, et  al. Severity of
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The clinical score should be determined under asthma at 10 years of age. Thorax. 2008;63:8–13.
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Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT,
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McKean M, Ducharme F.  Inhaled steroids for episodic
are 6 years old. The influence of viral infections viral wheeze of childhood. Cochrane Database Syst
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 Hemoptysis in Children
23
Julio Maggiolo Massone, Carlos Mendoza Fox,
and Ricardo Kogan Alterman

Contents
Epidemiology and Etiology  216
Physiopathology  216
Etiology  216
Aspiration of a Foreign Body  216
Infections  217
Cystic Fibrosis  217
Trauma: Accidents, Surgery, and Other Causes  217
Cardiovascular Causes  217
Tumors and Vascular Malformations  217
Hemorrhagic Diathesis  217
Diffuse Alveolar Hemorrhage Syndrome  217
Diffuse Alveolar Hemorrhage Syndrome Associated with Capillaritis:
Pulmonary–Renal Syndrome  218
Other Causes of Diffuse Alveolar Hemorrhage Syndrome with Lung Capillaritis  218
Diffuse Alveolar Hemorrhage Syndrome Not Related to Idiopathic Pulmonary
Hemosiderosis Capillaritis   218
Acute Idiopathic Pulmonary Hemorrhage in Infancy: Epidemic in Cleveland  219
Other Causes of Diffuse Alveolar Hemorrhage Syndrome
Without Lung Capillaritis  219
Factitious Hemoptysis �������������������������������������������������������������������������������������������������  219
Diagnostic Approach to Hemoptysis in Children  219
Treatment  222
Conclusion  224
Sources  224

J. Maggiolo Massone (*)

Department of Pediatrics, Hospital Exequiel
González Cortés, San Miguel, Chile
C. Mendoza Fox
Department of Pediatrics, Hospital Nacional Hipólito
Unanue, Lima, Peru
e-mail: [email protected]
R. Kogan Alterman
Department of Pediatrics, Faculty of Medicine,
Universidad de Chile, Santiago, Chile
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 215

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_23
216 J. Maggiolo Massone et al.

Epidemiology and Etiology Infections in the respiratory tract produce

minor bleeds in the lower airway, which are of
Hemoptysis is an infrequent condition in children little clinical importance. Foreign bodies can
although some of the diseases that can cause it cause hemoptysis in the bronchial circulation by
are not uncommon—such as bronchiectasis in damaging the airway wall. Hyperplasia, tortu-
patients with cystic fibrosis (CF) or chronic lung osity, and dilation of bronchial arteries exist in
disease postadenovirus—or it may be caused by bronchiectasis, provoking anastomosis between
other conditions such as aspiration of a foreign both systems. As a result of chronic inflamma-
body or a respiratory infection. It can also occur tion, recurrent infections may cause erosion and
in much less frequent conditions such as diffuse tearing of abnormal bronchial arteries, which
alveolar hemorrhage syndrome (DAHS), the explains the hemorrhage. In DAHS, bleeding is
most important causes of which are pulmonary– produced by an injury in the lung microcircula-
renal syndrome (PRS) and idiopathic pulmonary tion, which later extends to the alveoli.
hemosiderosis (IPH).
The frequency varies between different cen-
ters. Coss-Bu and collaborators published a study Etiology
of 228 children and young adults over a period of
10 years, and they found that in 65% of cases, it Aspiration of a Foreign Body
was caused by CF. Among the remainder of the
cases, the main causes were congenital cardiopa- Aspiration of a foreign body is relatively com-
thies (16%), infections (16%), tumors (2.6%), mon, especially in children younger than 3 years.
and miscellaneous (14%). Hemorrhage is more frequent during extraction
Godfrey and collaborators evaluated indica-
tions for fibrobronchoscopy over a period of
6  years, during which 2148 procedures were
performed in children younger than 18 years of
Table 23.1  Conditions associated with hemoptysis
age. Hemoptysis was the indication in just 0.8%
Frequent conditions Infrequent conditions
of cases and, of this group, 29.4% of cases were
Aspiration of a foreign body Lung malformations
indicated for lower airway disease, 17.6% for tra- Infection Pulmonary
cheostomy bleeding, 17.6% for an unidentified  Tracheobronchitis sequestration
reason, and the rest for miscellaneous reasons.  Pneumonia Tumor
Table  23.1 lists conditions associated with  Influenza (e.g., H1N1)  Adenoma
 Lung abscess  Carcinoid
hemoptysis in children, differentiated by their  Bronchiectasis (cystic Diffuse alveolar
frequency. fibrosis and noncystic hemorrhage syndrome
fibrosis)  Pulmonary–renal
 Echinococcosis syndrome
 Tuberculosis  Goodpasture
Physiopathology  Aspergillosis (e.g., syndrome
aspergilloma)  Wegener
The lung receives blood from two systems: the Trauma granulomatosis
arterial lung circulation (an extensive vascular,  Accidental  Microscopic
 Lung puncture polyangiitis
complacent, low-pressure bed, which irrigates  Bronchoscopy  Systemic lupus
up to the alveoli) and the bronchial circulation (a  Tracheostomy-related erythematosus
minor system, which perfuses up to the terminal  Intentional (suffocation)  Henoch–Schonlein
bronchioles). Although bleeding can originate Cardiovascular purpura
 Congenital cardiopathies  Idiopathic
from any of these systems, massive hemoptysis  Lung hypertension pulmonary
usually originates from the bronchial circulation  Arteriovenous fistula hemosiderosis
because its pressure is systemic.  Lung thromboembolism  Factitious
hemoptysis
23  Hemoptysis in Children 217

of the foreign body if enough time has elapsed because of the availability of early correctional
for it to cause infection. surgery.

Infections Tumors and Vascular Malformations

Hemoptysis caused by an acute infection of the Adenoma and carcinoid tumors are the types of
lower airway, as in tracheobronchitis, is of little tumor that present hemoptysis more frequently,
clinical significance, although this is the most com- and they are more important in older patients.
mon cause, accounting for around 40% of cases. Hemoptysis with a tumor-related etiology is not
In Chile, cavitary lung tuberculosis is an infre- very prevalent, although it can result in a massive
quent cause, but in endemic zones it is not rare hemorrhage. The most common type of vascular
for it to cause hemoptysis, which may become malformation is multiple arteriovenous fistulas,
massive. Another cause is bronchiectasis after related to hereditary hemorrhagic telangiectasia
pneumonia due to an adenovirus. These two (Osler–Weber–Rendu syndrome).
causes can result in hemoptysis in older children.

Hemorrhagic Diathesis
Cystic Fibrosis
Occasionally, hemoptysis has been reported
Patients with advanced disease present exten- in patients with von  Willebrand disease and
sive bronchiectasis, which can cause massive hemophilia.
hemoptysis.

 iffuse Alveolar Hemorrhage

D
 rauma: Accidents, Surgery,
T Syndrome
and Other Causes
This occurs as a result of an injury in small ves-
Direct trauma to the thorax in a motor vehicle sels, mainly capillaries, as well as arterioles and
accident or other causes of lung contusion can venules from the lung microcirculation. The cur-
cause hemorrhage. Children with tracheostomies rent classification of DAHS subclassifies the dis-
can also bleed, especially during aspiration. A eases according to whether or not they present
significant number of children with suspected capillaritis on histopathological study.
sudden death present with bleeding in the mouth, Capillaritis can appear in isolation or as part
nose, or lungs at autopsy, suggesting accidental of a systemic compromise, as happens in PRS.
or intentional suffocation. Other cases occur in the absence of capillaritis,
not associated with vascular or systemic inflam-
matory disease (as in IPH), and are subclassified
Cardiovascular Causes according to whether or not they are associated
with cardiopathies.
Arterial or venous lung hypertension due to Clinically, DAHS can appear in a spectrum
congenital or acquired diseases was an impor- that ranges from life-threatening acute respira-
tant cause of hemoptysis in children without tory failure to a more insidious appearance with
CF in the series described by Coss-Bu and few symptoms. During the hemorrhage, hemop-
collaborators. Other relevant diseases are pul- tysis, coughing, paleness, dyspnea, respiratory
monary veno-­occlusive disease and congestive difficulties, crackles, and hypoxemia can be
heart failure, among others. Nowadays, con- observed; meanwhile, characteristic chest x-rays
genital cardiopathies are a less relevant cause
218 J. Maggiolo Massone et al.

show cottony, shifting, and usually bilateral inter- ease has improved because of early diagnosis and
stitial alveolar infiltrates. more effective treatments, with use of systemic
In entities that present capillaritis, alongside steroids and immunosuppressive drugs, besides
lung compromise, some signs of an associated inhaled steroids in high doses.
systemic disease can appear as a result of an Eighty percent of cases appear in the first
immune-mediated condition. decade of life. Clinical cases are characterized by
Patients with nonimmune lung hemorrhage can- recurrent hemoptysis (although this is not pres-
not be clinically differentiated. When there is sus- ent in up to 33% of cases) and anemia, which is
picion of vasculitis, a lung biopsy must be done. usually important. Severe episodes can put the
patient’s life at risk because of respiratory insuf-
ficiency and hemodynamic instability.
 iffuse Alveolar Hemorrhage
D During an acute episode, shifting interstitial
Syndrome Associated alveolar forms, usually symmetrical, are apparent
with Capillaritis: Pulmonary–Renal on chest x-rays, which predominate in the peri-
Syndrome hilar regions and the bases of the lungs, without
compromise of the apical zones and costophrenic
In Wegener granulomatosis or microscopic poly- angles (Fig.  23.1). Computerized tomography
angiitis, ANCAc and ANCAp (antineutrophil (CT) scans of the chest show cottony forms and
cytoplasmatic antibodies), which directly dam- a frosted glass effect (Fig. 23.2). The x-rays stud-
age the lung microvasculature, are usually pres- ies in both figures are from patients in our series.
ent. In Goodpasture syndrome or systemic lupus From the hematological standpoint, anemia with
erythematosus, lung hemorrhage is produced by reticulocytosis exists depending on the availabil-
vasculitis, while in Wegener granulomatosis and ity of spinal deposits of iron and can subsequently
microscopic polyangiitis it results from the pres- turn into microcytic, hypochronic anemia if recur-
ence of cavitary injuries. rences of the lung hemorrhage occur.
Similar findings have been reported in chil- Lung function can be normal or show a restric-
dren with Henoch–Schonlein purpura and other tive ventilatory pattern. The CO diffusion capac-
infrequent conditions such as antiphospho- ity can be diminished, although it increases during
lipid antibody syndrome or immunoglobulin  A
nephropathy.

 ther Causes of Diffuse Alveolar

O
Hemorrhage Syndrome with Lung
Capillaritis

Idiopathic lung capillaritis, polyarteritis nodosa,

cryoglobulinemia, and, lastly, medicines such as
propylthiouracil, amiodarone, or penicillamine can
provoke hemoptysis, even in therapeutic doses.

 iffuse Alveolar Hemorrhage

D
Syndrome Not Related to Idiopathic
Pulmonary Hemosiderosis Capillaritis
Fig. 23.1  Chest x-rays showing idiopathic pulmonary
hemosiderosis (IPH) in a 13-year-old girl with an active
Idiopathic pulmonary hemosiderosis is a rare dis- hemorrhage, showing cottony, bibasilar, symmetrical
ease, limited to the lungs; there is no kidney or forms without compromise of the lung apexes and costo-
systemic compromise. The prognosis of this dis- phrenic angles
23  Hemoptysis in Children 219

 ther Causes of Diffuse Alveolar

O
Hemorrhage Syndrome Without Lung
Capillaritis

Other causes of idiopathic pulmonary hemor-

rhage include Heiner syndrome or allergy to
cow’s milk protein, von Willebrand disease,
celiac disease, infanticide (suffocation), medi-
cations in therapeutic doses or overdoses (such
as acetylsalicylic acid), cocaine abuse, inha-
lation of trimethyl anhydride, or exposure to
Fig. 23.2  CT scanning of idiopathic pulmonary hemo- pesticides.
siderosis (IPH) in a 7-year-old boy with an active hemor-
rhage, showing cottony, bilateral shapes and a frosted
glass effect in the right lung area (arrow)
Factitious Hemoptysis

active bleeding, which indicates intra-­ alveolar Within this group is Munchausen syndrome,
hemoglobin, representing a useful and sensitive which presents especially in emotionally unsta-
indicator of hemorrhage during treatment. ble adolescents, who self-provoke injuries that
Tests to exclude other causes of lung hemor- simulate hemoptysis.
rhage, such as PRS or disease of a cardiac origin,
give negative results.
 iagnostic Approach to Hemoptysis
D
in Children
 cute Idiopathic Pulmonary
A
Hemorrhage in Infancy: Epidemic It is necessary to establish whether the ­presenting
in Cleveland problem is hemoptysis or a hemorrhage in the
upper airway (pseudohemoptysis) or in the upper
Dearborn and collaborators described a pul- digestive tract (hematemesis).
monary hemorrhage epidemic that affected 30 An upper airway hemorrhage—such as epi-
infants. All of them presented severe DAHS. In staxis or bleeding due to gingivitis, a pharyngeal
some of them, the bleeding stopped spontane- ulcer, or tonsillar or adenoidal bleeding—can
ously; in others, steroids had to be applied. The simulate hemoptysis. Hematemesis, which is
researchers found an association with environ- infrequent in children, can occasionally be hard
mental exposure to fungi, especially Stachybotrys to differentiate from hemoptysis (Table 23.2).
chartarum, which was present in the damp
houses of these patients, and the damaging mech-
Table 23.2  Differential diagnosis of hemoptysis and
anism acted through a mycotic angiotoxin. These hematemesis
children showed stunting and hemoglobinuria—
Hemoptysis Hematemesis
characteristics suggesting that this entity should Color Bright, foaming Dark red or brown
be differentiated from classical idiopathic pulmo- red
nary hemorrhage. pH Alkaline Acidic
Consistency May be mixed May contain food
with sputum particles
Background Lung disease Gastroesophageal or
hepatic disease
Symptoms Coughing may be May be preceded by
preceded by a nausea and vomiting
gurgling noise
Confirmation Bronchoscopy Endoscopy
220 J. Maggiolo Massone et al.

On the other hand, the fact that young children or if its origin is not identified through imag-
swallow blood that originates in the lung should ing procedures, since it allows visualization of
be kept in mind; this can rarely cause hemoptysis both the upper and lower airways, being able
(except when the hemorrhage is significant), hin- to determine the place of bleeding. However,
dering the diagnosis. Furthermore, children can when the hemorrhage is profuse, it is very hard
vomit blood without coughing, which forces us to pinpoint; on the other hand, if bronchoscopy
to consider a diagnosis of hemoptysis in children is done when the hemorrhage has stopped, the
with presumed hematemesis of unclear etiology origin may not be located. Likewise, through
in the presence of abnormalities on chest x-rays. fibrobronchoscopy, the esophagus can be
In many cases, the clinical history and physi- observed in order to dismiss a high digestive
cal tests do not considerably help to define the hemorrhage.
cause. Occasionally, the etiology is relatively Use of a flexible bronchoscope allows us to
obvious, such as in the case of patients with CF, obtain samples for microbiological, cytologi-
chronic lung disease, or systemic diseases associ- cal, and histopathological studies, and it can be
ated with lung hemorrhage, such as PRS. Other used to perform bronchoalveolar lavage (BAL).
scenarios require more investigation. A rigid bronchoscope is useful for extracting
Chest x-rays are mandatory, specifying foreign bodies and in cases of a massive hemor-
whether the hemorrhage is unilateral or bilat- rhage, for keeping the airway permeable while
eral, and additionally showing the extension. appropriate aspiration is conducted.
The most common findings are atelectasis, and When there is not an obvious cause, BAL must
alveolar and interstitial cottony infiltrates; never- be performed to search for hemosiderophages,
theless, up to a third of children with hemoptysis which can also be found in induced sputum and
have normal chest x-rays. gastric contents, with Prussian blue dye (Perl’s
CT scanning of the chest with contrast dye is reaction). In this regard, an experimental study in
necessary to define bronchiectasis, cavitary inju- a murine model by Epstein and collaborators dem-
ries, malformations, arteriovenous fistulas, or onstrated that hemosiderophages start appearing
tumors. within 3  days (2.8% cellularity) after the appear-
Computerized angiotomography and angiog- ance of blood in the lungs. The numbers peak
raphy—the latter being less used nowadays— between the sixth and tenth day (60%) and drop to
help to evaluate pulmonary sequestration, which 10% in the following 1–2 months. A hemosidero-
denotes the presence of an aberrant vessel, arte- phage count higher than 20% starting from the third
riovenous malformation, and other vasculature to the fourth day of hemorrhage indicates IPH.
anomalies or a pulmonary thromboembolism. Once the bleeding has stopped and the results
Despite scintigraphy ventilation/perfusion of imaging studies, bronchoscopy, and BAL are
being progressively less used, it is useful if a normal, it is reasonable to wait for another epi-
pulmonary thromboembolism is suspected. sode of hemorrhage before inquiring in further
Magnetic resonance imaging has better reso- investigation.
lution in soft tissues such as the mediastinum, If there is evidence of hemorrhage not due
hilum, and blood vessels, but it is less useful for to airway injury, a foreign body, or CF, and
the lung parenchyma. Finally, ultrasound scan- there is no bronchiectasis due to other disease,
ning contributes only limited information. a ­cardiological evaluation must be performed
Administration of red blood cells marked with (including an electrocardiogram, an echocardio-
technetium 99 is useful for identifying an active gram with color Doppler), with studies for PRS
hemorrhage with a flow rate as low as 0.1  ml/ and hemorrhagic diathesis. If these diseases are
min. The source of the hemorrhage is identified dismissed, the lung hemorrhage may be due to
in 50% of patients. IPH, the diagnosis of which is exclusionary.
Fibrobronchoscopy is prescribed if the hem- Figure 23.3 shows a diagnostic algorithm for
orrhage is persistent, significant, or recurrent, hemoptysis/lung hemorrhage.
23  Hemoptysis in Children 221

ANAMNESIS AND
PHYSICAL TEST

Suspicion of haemorrhage in Suspicion of haemoptysis /

upper or digestive airway lung haemorrhage

Present / Appropriate Chest x rays / CT

management

No evidence of lung disease Evidence of lung disease

Bronchoscopy searching for

injury in lower airway Study for CF, bronchiestasis,
pulmonary-renal syndrome,
etc.

Present / Appropriate
Absent
handling

BAL for searching of haemosiderophages

between days 3-14

Negative Positive

Monitoring and investigation

Echocardiography
if new bleeding appears

Normal Abnormal

Tests for pulmonary- Negative results = Tests for haemorrhagic Probable

renal syndrome IPH diathesis cardiopathy

Fig. 23.3  Algorithm for diagnosis of hemoptysis/lung hemorrhage in children. BAL bronchioalveolar lavage, CF cystic
fibrosis, IPH idiopathic pulmonary hemosiderosis
222 J. Maggiolo Massone et al.

A lung biopsy is needed to dismiss sys- frequency mechanical ventilation. If this ther-
temic diseases associated with vasculitis, apy is not effective, extracorporeal ventilatory
veno-­occlusive disease, or pulmonary capillary support must be considered. Death in patients
hemangiomatosis. It is rarely performed in IPH; with a massive hemorrhage results more from
its diagnosis is based on the clinical and radio- acute respiratory insufficiency than from the
logical findings, besides the finding of hemosid- extent of blood loss.
erophages, although it has been observed that this During the hemorrhage, BAL with cold
entity can evolve into a systemic autoimmune saline solution and instillation of adrenaline
disease. Histopathology in IPH during active (epinephrine) 1:10,000 must be performed for
bleeding shows a large number of intact red vasoconstriction, using a rigid bronchoscope;
blood cells in the alveoli and lung interstitium, furthermore, extraction of clots is performed
and after some days, hemosiderophages appear; during this procedure. Use of tranexamic acid
there is no evidence of vasculitis, granulomas, or must be considered in patients with CF, on
immune complexes. top of providing vitamin K, with avoidance of
physical therapy, medicines that alter coagula-
tion, and irritants such as DNase or nebulized
Treatment antibiotics.
Some alternative treatments in the case of
Hemoptysis can be slight and transient, depend- persistence of the hemorrhage are plugging
ing on its etiology and magnitude, or, con- with an inflatable Fogarty balloon catheter
versely, it can be a severe and even fatal event. installed for 24  hours a day, application of
In this last case, the management approach fibrinogen and thrombin, carbon dioxide, or
must be proactive in order to establish appro- laser treatment.
priate treatment. The next step is selective embolization of
In patients with hemoptysis with an acute the lung or bronchial vessels—a procedure
onset, the therapeutic objectives are, firstly, that is relatively frequent in patients with
stabilization (which includes a permeable air- advanced CF—and a satisfactory response
way), oxygen administration, and eventual use is observed in 80% of cases. At our hospital,
of noninvasive or invasive mechanical ven- we have used it successfully in two instances
tilation. Positive pressure at the end of expi- (Fig.  23.4). If the objective is not accom-
ration can produce compression of vessels, plished, re-embolization must be done, associ-
thereby limiting the hemorrhage, and this is ated with use of tranexamic acid. Lastly, if the
the reason why the patient must be kept in a hemorrhage still persists, surgical resection of
lateral decubitus position, with the bleeding the bleeding zone must be performed, such as
site downward. Furthermore, if hemodynamic a segmentectomy, lobectomy, or, exception-
instability exists, appropriate management for ally, pneumonectomy.
hypovolemic shock must be instituted through In cases of lung hemorrhage due to DAHS,
administration of a crystalloid bolus and/or a systemic steroids are accepted as first-line
blood transfusion. If respiratory insufficiency medicines. Aggressive therapy has been used
persists, the patient must be connected to high- successfully, such as intravenous pulses of
23  Hemoptysis in Children 223

a b

Fig. 23.4 Angiography and embolization of the left embolization, the left bronchial artery shows hyperplasia,
bronchial artery in an 18-year-old patient with advanced tortuosity, and dilation (arrow). (b)  Post-embolization
cystic fibrosis and a recurrent hemorrhage. (a)  Pre-­ with polyvinyl alcohol (arrow)

methylprednisolone 10–30  mg/kg (1  g maxi- (2  mg/day). Although there have been few
mum) per day for three consecutive days. publications describing such an approach, the
Then, daily administration of oral prednisone results have been successful.
(2  mg/kg/day) should be started, associated Finally, plasmapheresis is employed in
with an immunosuppressant such as azathio- Goodpasture syndrome. Lately, there have been
prine, hydroxychloroquine, mycophenolate, reports of its utility for refractory hemorrhage in
cyclophosphamide, or methotrexate, followed isolated lung vasculitis and for cases associated
by an inhaled steroid in long-term high doses, with connective tissue disease.
to induce remission and improve the prognosis. Figure 23.5 shows an algorithm for manage-
Recently, monthly intravenous immunoglobu- ment of hemoptysis.
lin has been used in immunomodulating doses
224 J. Maggiolo Massone et al.

HAEMOPTYSIS

Minor haemoptysis:
Massive haemoptysis
treat aetiology

Permeable airway/ Maintain haemo-

Treat etiology
O2 contribution dynamic stability

Bronchoscopy

Controlled Uncontrolled
haemorrhage haemorrhage

Treat etiology Arterial

embolisation

Surgery

Fig. 23.5  Algorithm for management of hemoptysis in children

Conclusion include serious pathologies that are a part of

DAHS, such as PRS or IPH.
Hemoptysis in children is infrequent but can
be caused by common diseases; generally, it is
of minor magnitude but occasionally can mani- Sources
fest because of a severe case of hemorrhage that
could be fatal if not appropriately managed. Batra PS, Holinger LD. Etiología y manejo de la hemop-
tisis pediátrica. Arch Otolaryngol Head Neck Surg.
The most likely causes are bronchiectasis 2001;127:137.
associated with CF, chronic lung disease, injuries Boat TF.  Pulmonary hemorrhage and hemoptysis. In:
located in the airway, foreign bodies, coagulopa- Chernick V, Boat TF, Wilmatt RW, Bush A, edi-
thies, or cardiopathies. Other less frequent causes tors. Kendig’s disorders of the respiratory tract
23  Hemoptysis in Children 225

in children. 7th ed. Philadelphia: Saunders; 2006. in the intensive care unit: severity, localization and eti-
p. 676–85. ology. Br J Radiol. 2007;80(949):21–5.
Coss-Bu JA, Sachdeva RC, Bricker JT, Harrison GM, Lara AR, Schwarz MI. Hemorragia alveolar difusa. Chest.
Jefferson LS. Hemoptysis: a 10-yr retrospective study. 2010;137:1164.
Pediatrics. 1997;100:E7. Le Clainche L, Le Bourgeois M, Fauroux B, Forenza N,
Dearborn DG, Smith PG, Dahms BB, Allan TM, et  al. Long-term outcome of idiopathic pulmonary
et  al. Clinical profile of 30 infants with acute pul- hemosiderosis in children. Medicine (Baltimore).
monary hemorrhage in Cleveland. Pediatrics. 2000;79:318–26.
2002;110:627–37. Maggiolo J, Farbinger F, Rubilar L.  Hemoptisis/­
Epstein CE, Elidemir O, Colasurdo GN, Fan LL. Time hemorragia pulmonar en pediatría. Neumol Pediatr.
course of hemosiderin production by alveolar mac- 2009;4(2):65–72.
rophages in a murine model. Chest. 2001;120: Pianosi P, Al-Sadoowh. Hemoptisis en niños. Pediatr Rev.
2013–20. 1997;18:16–9.
Fontenot AP, Schwarz MI.  Hemorragia alveolar difusa. Rubilar L, Maggiolo J, Girardi G, González
In: King Jr TE, Schwarz MI, editors. Enfermedad pul- R.  Hemosiderosis pulmonar idiopática: evolución de
monar intersticial. 4th ed. Hamilton: Decker; 2003. 5 niños. Neumol Pediatr. 2006;1:30–3.
p. 632. Shah MK, Hugghins SY. Characteristics and outcomes of
Gaude GS.  Hemoptysis in children. Indian Pediatr. patients with Goopasture’s syndrome. South Med J.
2010;47:245–54. 2002;95:1411–8.
Godfrey S.  Pulmonary hemorrhage/hemoptysis in chil- Susarla SC, Fan LL.  Diffuse alveolar hemor-
dren. Pediatr Pulmonol. 2004;37:476–84. rhage syndromes in children. Curr Opin Pediatr.
Ioachimescu OC, Sieber S, Kotch A.  Idiopathic pul- 2007;19:314–20.
monary haemosiderosis revisited. Eur Respir J. Von Vigier RO, Trummler SA, Laux-End R, et  al.
2004;24:162–70. Pulmonary renal syndrome in childhood: a report of
Khalil A, Soussan M, et al. Utility of high-resolution chest twenty-one cases and a review of the literature. Pediatr
CT scan in the emergency management of hemoptysis Pulmonol. 2000;29:3.
 Infants with an Apparent
Life-­Threatening Event
24
Pablo Brockmann Veloso, Daniel Zenteno Araos,
and José Luis Pérez Sánchez

Contents
Diagnosis  227
Management Algorithm  227
Indications for Cardiorespiratory Monitoring  230
Sources  230

Diagnosis severe ALTE are prematurity, gestational age,

symptoms of respiratory infection, and a history
Apparent life-threatening events (ALTEs) tend to of sudden death of a sibling. The cause is found, in
be difficult to assess, given that, by definition, they most cases, after an exhaustive review of the med-
present a subjective element based on the view of ical history (which is repeated in many cases), an
the observer. In this sense, it is expressly recom- extensive physical examination, and basic labora-
mended to avoid terms such as “apnea crisis” and tory examinations (with sampling for viral agents,
“aborted sudden death,” which suggest a physio- glycemia, and blood gases). ALTE cases generally
pathological process not necessarily related to have the following causes: a poor feeding tech-
ALTE. The risk factors for ALTE are exposure to nique associated with regurgitation, respiratory
cigarette smoke—in particular, intrauterine expo- infections, gastroesophageal reflux, or convul-
sure—and premature birth. The risk factors for sions. The causes in a minority of cases are meta-
bolic diseases, poisoning, arrhythmia,
Munchhausen syndrome, or others in a long list of
P. Brockmann Veloso associated diseases and syndromes.
Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile,
Santiago, Chile
e-mail: [email protected] Management Algorithm
D. Zenteno Araos (*)
Department of Pediatrics, Universidad de ALTE patients should be assessed comprehen-
Concepción, Concepción, Chile sively with all clinical examinations that appear
J. L. Pérez Sánchez necessary. However, the decision as to which steps
Department of Pediatrics, Universidad Austral de to follow and when to undertake a particular
Chile, Osorno, Chile

© Springer Nature Switzerland AG 2020 227

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_24
228 P. Brockmann Veloso et al.

examination is difficult and costly. As a general the event occurred, and other factors. Specific
recommendation, most ALTE cases should be examinations are recommended in the context of
hospitalized in a facility where monitoring is pro- symptoms indicating a particular disease
vided for at least 24–48 hours, because of which (Table 24.1). It is critically important to determine
the following factors should be considered as risk whether the event occurred while the child was
factors in making such a decision: premature birth, awake or asleep, as that information is helpful for
age <2  months, vigorous resuscitation, recurrent determining the cause. In most series in Chile and
condition, background disease, history of sudden other countries, even after an exhaustive evaluation,
death of a sibling, and social background. up to 30% of ALTE cases end up being diagnosed
The diagnosis should be made in stages, always as “idiopathic.” A sleep study (polysomnography)
considering details of the medical history and of is particularly important in these patients to deter-
physical examinations that may prove to be key in mine the presence of any sleep pathology. The
the final diagnosis: the family history, previous algorithm shown in Fig.  24.1 (adapted from the
events, respiratory symptoms, sickness in a family Chilean consensus statement) orients the stages of
member, history of epilepsy, the time of day when the study of an infant with ALTE.

Table 24.1  Possible causes, symptoms and findings, and suggested studies in infants with an apparent life-threatening
event
Possible causes Symptoms and findings Suggested studies
Gastrointestinal causes Vomiting pH metry
 GERD Blockage or coughing with food Video swallow study
 Aspiration Speech therapy assessment
Respiratory causes Cor yza, cough, wheezing, fever, hypothermia Viral panel, viral DIF
 Viral infection/pertussis History of foreign body ingestion PCR testing for Bordetella
 Aspiration/foreign body Stridor, feeding difficulties, dysmorphisms Endoscopic airway evaluation
 Anatomical airway (especially craniofacial dysmorphisms)
alteration
Trauma History of trauma, blood in the mouth or nose Radiological clinical evaluation
 Munchhausen syndrome Previous ALTE, SIDS in a sibling, discordant Rule out abuse
by proxy history Clinical suspicion
Neurological/convulsive Loss of consciousness EEG
causes Eye deviation Brain echocardiogram
Seizure, hypotonia/hypertonia CT scan/brain MRI
Microcephaly/macrocephaly Glycemia; Ca, P, Mg, PLD levels
Dysmorphia Metabolic study
Emotional apnea Suggestive clinical history without other Rule out associated anemia
findings (while awake)
Metabolic causes Family history Glycemia
Seizures Lactate, ammonium, pyruvate
Feeding difficulties Aminoacidemia, aminoaciduria, etc.
Consciousness compromise
Dysmorphia
Cardiovascular causes Feeding difficulties ECG (QTc)
 Congenital heart disease Diaphoresis 24-hour Holter monitoring
 Arrhythmia Central cyanosis, syncope Doppler echocardiography
Infectious causes Fever, hypothermia, lethargy, and/or shock Hemogram, blood culture PCR,
 Meningitis complete urine, urine culture
 Septicemia Lumbar puncture
 UTI
Medications or toxicity Consciousness compromise Toxicology screening of blood and/
Lethargy, previous history or urine
CT computerized tomography, DIF direct immunofluorescence, ECG electrocardiogram, EEG electroencephalogram,
GERD gastroesophageal reflux disease, MRI magnetic resonance imaging, PCR polymerase chain reaction, PLD phos-
pholipase D, QTc corrected QT interval, SIDS sudden infant death syndrome, UTI urinary tract infection
24  Infants with an Apparent Life-Threatening Event 229

History and
diligent physical
examination

Capillary blood glucose* and venous gases*

(*in case of severe ALTE. As an alternative, they can be rapid gas collection systems)

Episode was short

During feeding
Yes Did not require No
resuscitation
No recurrence

Hospitalize unit with possible

Send home if: monitoring and resuscitation:
• Normal physical examination • Observation monitoring for at least
No
• Controlled paternal anxiety 24 hours
• Pediatric control in 24-48 hours • Does history and physical
examination guide diagnosis?

History and physical examination History and physical

guide the diagnosis. examination do not guide
Study according to Table 24.1 diagnosis

Suggested study, adjust according to

each case:
• Initial: blood count, blood gases,
glycemia, plasma electrolytes,
blood urea nitrogen, calcium,
magnesium, ammonium, lactate,
urine test
• EEG
• EKG
• Chest x-ray
• Viral panel (virus season, winter,
suspicion), Bordetella test
• In case of suspicion: Echo or
cerebral NMR
• Toxicological examination

Multidisciplinary evaluation,
PSG test study
Neurology, cardiology,
Diagnosis not clarified
bronchopulmonary, specialist in
(idiopathic) and history of
metabolic diseases
severe ALTE
Discharge with
cardiorespiratory monitoring
should be considered

Fig. 24.1  Algorithm for study of an infant with an apparent life-threatening event (ALTE)
230 P. Brockmann Veloso et al.

The objectives of hospitalization are clinical Table 24.2  Recommended variables for cardiorespira-
tory monitoring in preterm and term infants with an appar-
observation and treatment of a recurrent event,
ent life-threatening event
general and specific studies according to indica-
Bradycardia Apnea duration
tive symptoms, and education of the parents in Infant age (beats/minute) (seconds)
cardiopulmonary resuscitation and safe sleeping Preterm infantsa
conditions. If the standard monitoring period of  <40 weeks 100 15
24–48  hours ends without occurrence of any  40–44 weeks 80 15
events of concern and the study results are in the  >44 weeks 70 15–20
expected ranges, the treating physician can plan Term infants
 <1 months 80 20
to release the patient to go home.
 1–3 months 70 20
 3–12 months 60 20
Corrected gestational age
a
Indications for Cardiorespiratory
Monitoring
toring is 3 months in patients without risk fac-
Monitoring has been used for 40 years in ALTE tors or 6 months in those with risk factors.
patients, although, as noted above, it has not been 2. In patients who depend on oxygen or assisted
possible to prevent incidents of sudden infant ventilation, monitoring should be continuous
death. Cardiorespiratory monitoring does not for as long as this type of support is required.
detect obstructive apnea nor episodes of oxygen 3. In the case of a patient with a history of sud-
saturation decline. It detects only central-type den death of a sibling, monitoring should con-
apnea and changes in the heart rate (tachycardia, tinue until the patient reaches the age at which
bradycardia). Apart from cardiorespiratory moni- the sibling died.
toring, we do not recommend other forms of
monitoring that measure infant movements on The variables for cardiorespiratory monitoring
the bed or that are superimposed. are flexible and can be adjusted for each patient.
The indications for comprehensive investiga- Monitoring of the variables listed in Table 24.2 is
tions in a child who has suffered ALTE are: recommended in patients with idiopathic ALTE.

1. ALTE without a specific diagnosis (i.e.,

idiopathic) Sources
2. Recurrent ALTE (≥2 episodes)
3. Severe ALTE without a clear cause, with formal Brockmann P, González X, Bertrand P, Sánchez I,
resuscitation, or with persistent cyanosis; history Holmgren NI. Perfil clínico de lactantes hospitalizados
of base disease (prematurity, bronchopulmonary por un episodio de ALTE (apparent life-­threatening
event). Rev Chil Pediatr. 2006;77(3):267–73.
dysplasia, Down syndrome, neuromuscular dis- Brockmann PE, et  al. Consenso sobre el manejo de
ease, craniofacial malformations, etc.) eventos de aparente amenaza a la vida del lactante
4. Requirement for domestic ventilation or
(ALTE) Comisión de Sueño, Sociedad Chilena de
oxygen Neumología Pediátrica 2013. Rev Chil Pediatr.
2014;85(3):378–87.
5. History of sudden death of a sibling Esani N, Hodhman JE, Ehsani N, Hoppenbrouwers
T. Apparent life-threatening events and sudden infant
Our recommendations regarding the duration death syndrome: comparison of risk factors. J Pediatr.
of monitoring are as follows: 2008;152(3):365–70.
Fu LY, Moon RY.  Apparent life-threatening events: an
update. Pediatr Rev. 2012;33(8):361–8.
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Kaji AH, Claudius I, Santillanes G, Mittal MK, Hayes
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24  Infants with an Apparent Life-Threatening Event 231

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 Immunosuppressed Children
with Lung Infection
25
Alejandra Zamorano Wittwer
and Marcela Ferrés Garrido

Contents
Epidemiology  233
Physiopathology  234
Etiology  235
Bacteria  237
Viruses  238
Fungi  238
Mycobacteria  240
Parasites  240
Diagnostic Studies  241
Clinical Presentation  241
Radiology  241
Microbiological Diagnosis  241
Treatment  241
Sources  243

Epidemiology this cause, and it is the cause of death in 1.38 of

every 1000 live births. Development of serious
Respiratory infections are the most common illnesses is more concerning in high-risk popula-
cause of morbidity in children. The World Health tions such as immunosuppressed patients.
Organization (WHO) calculates that there are Infectious agents that cause respiratory prob-
1.9  million cases of pneumonia that result in lems in immunocompetent and immunosup-
death each year. In Chile, half of all hospital pressed patients are also opportunistic, remaining
admissions in the early years of life are due to latent in the body and being reactivated in the
situation of immunosuppression. The immune
deficiencies in this patient group are diverse, and
the orientation of the etiological diagnosis will
A. Zamorano Wittwer ∙ M. Ferrés Garrido (*) depend on knowledge of the specific condition in
Department of Pediatrics, School of Medicine, every case.
Pontificia Universidad Católica de Chile, With the optimization of treatments for onco-
Santiago, Chile logical diseases (which have resulted in greater
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 233

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_25
234 A. Zamorano Wittwer and M. Ferrés Garrido

numbers of survivors) and increases in the numbers these noninfectious causes with early or late and
of solid organ transplant and hematopoietic precur- diffuse or local infiltrates are listed in Table 25.1.
sor recipients, patients with human immunodefi- An example of this is diffuse alveolar bleeding,
ciency virus (HIV) infection, and patients with which may compromise or even endanger life
primary immunodeficiency, well-informed man- and manifests as anemia, hemoptysis, diffuse
agement of respiratory infections—which are the respiratory infiltrates, and development of acute
main causes of morbidity and mortality in these lung insufficiency. In immunocompromised
groups—is becoming increasingly important. patients, drugs are the main cause of infections.

Table 25.1  Etiology of infection according to the radio-

Physiopathology logical pattern
Pattern Incidence Causal agent
Lung infection occurs generally through contact
Diffuse Common Pneumocystis
with droplets from people who are infected with, Cytomegalovirus
or who are carriers of, an infectious agent, or Mycobacterium
through exposure in a contaminated environment; Rare Cryptococcus
for example, filamentous fungal infections occur Aspergillus
Candida
this way. The infection is disseminated from the Nodular or Common Cryptococcus
higher airway through the descending broncho- cavitary Bacteria
genic airway, finding a host with altered natural Nocardia
barriers, a deficient systemic or local immune Aspergillus
Mycobacterium
response, alteration of the ciliary response, or
Rare Legionella
decreased phagocytosis, among other factors, Septic embolism
which in turn depend on the basic pathology of the Focal Common Bacteria
patient. This group of weakened elements creates Cryptococcus
an environment for the settling of a bacterial, viral, Aspergillus
Mucor
fungal, or parasitic infection. All of the infectious
Rare Tuberculosis
processes that are a result of reactivation of latent Viruses
infections acquired previously are added to the Legionella
acute episode—for example, Mycobacterium Local infiltrates Bronchiolitis obliterans with
tuberculosis, Pneumocystis jirovecii, Toxoplasma organizing pneumonia
Diffuse alveolar bleeding
gondii, or Cytomegalovirus (CMV). Metastasis
The clinical approach to a process that raises Pharmacological toxicity
suspicion of pneumonia in these patients is not Graft-versus-host disease
easy, since the symptomatology is not always Post-transplantation
lymphoproliferative disease
typical and depends on the type of immunodefi- Radiotherapy toxicity
ciency and the etiological agent involved. Thus, Pulmonary alveolar proteinosis
there are cases of febrile pneumonia with lung Diffuse Metastasis
condensation, pneumonia with torpid evolution infiltrates Pharmacological toxicity engraftment
syndrome
despite broad-spectrum antimicrobial treatment,
Early infiltrates Pulmonary edema
recurrent pneumonia, lung suppuration, or respi- Pulmonary embolism
ratory symptoms with or without fever. In many Atelectasis
cases, radiological images are not typical, Bleeding
Aspiration, acute respiratory distress
because it is impossible to focus on an infection.
syndrome
Some patients will develop respiratory insuffi- Chemotherapy
ciency, which is often fatal. Added to this diffi- Late infiltrates Radiation
culty are the noninfectious processes that Tumors
simulate or complicate pneumonia. Some of Chemotherapy
25  Immunosuppressed Children with Lung Infection 235

In patients with hematopoietic precursor trans- zoster; or mycotic pneumonia due to Aspergillus,
plants, the associated mortality exceeds 50% P.  jirovecii, Mucor, Rhizopus, or occasionally
within 3 weeks after diagnosis. Candida. The possibility of pneumonia associ-
ated with M.  tuberculosis—or, less often,
Toxoplasma or Cryptococcus neoformans—must
Etiology also be taken into account.
In patients who have undergone bone marrow
The spectrum of microorganisms is very wide, so or solid organ transplantation, lung complica-
it is very important to identify the causal agent. tions will depend on the period of immunosup-
For this, we must take the following parameters pression associated with the transplantation.
into account: In general terms, lung infections occurring
early after solid organ transplantation are linked
1. The type of immunosuppression that the
to the surgery and invasive procedures performed
patient has. in hospitalized patients. After the first month and
2. The medical history, physical examination,
up to 6 months afterward, the level of immuno-
epidemic status, clinical presentation, and suppression that is achieved favors infection by
speed at which the respiratory disorder has organisms that are dormant in the donor or the
developed: acute, subacute, or chronic. recipient, opportunistic infections, and infections
3. The timing of the appearance of the respira- acquired in the community. After 6  months the
tory disorder relative to that of the base ill- predominant infections are those contracted from
ness, transplantation, or immunosuppressive both viral and bacterial communities (Fig. 25.1).
drug administration. It is important to bear in mind that the risks are
4. The preliminary results of general and specific higher in lung transplantation when acquired
examinations to establish the etiology. agents have tropisms for the respiratory tract.
5. The type of radiological infiltrate (diffuse,
During the first 15 days after hemopoietic pre-
focal, nodular, cavitated) and the images cursor transplantation, neutropenia and severe
obtained from computerized tomography (CT damage of the mucosa, due to chemotherapy,
scanning), ultrasound scanning, or nuclear favor bacterial infections that can focus on the
magnetic resonance imaging. lung. At the following stage, after bone marrow
6. The drugs and treatments the patient has
grafting, CMV is one of the most common prob-
received, considering that some of them might lems that can affect the lung, together with oppor-
favor immunosuppression and/or lung dam- tunistic filamentous fungal infections. At the
age. The use of immunosuppressive treat- third stage, 3 months after the transplantation, the
ments needs to be noted in patients with cell response and humoral response remain weak,
transplants, such as cyclosporin, steroids, and infections due to encapsulated bacteria, fila-
mycophenolate, monoclonal antibodies, or mentous bacteria, and opportunistic bacteria are
antithymocyte globulins. frequent (Fig. 25.2).
7. Chemotherapy drugs such as bleomycin,
Patients with common variable immune defi-
cyclophosphamide, and methotrexate can ciency and agammaglobulinemia present recur-
cause lung damage, while radiotherapy can rent bacterial pneumonia, normally produced by
cause myelosuppression and lung fibrosis. encapsulated germs; they are rarely present in
pneumonia caused by P.  jirovecii. Children with
Because of their base condition and chemo- T  cell immunodeficiency, serious combined
therapy/radiotherapy, oncological patients have immunodeficiencies, etc., have a higher risk of
periods of neutropenia and secondary cell immu- contracting the same type of opportunistic
nodeficiency, with a higher risk of developing ­diseases as patients with acquired immunodefi-
viral pneumonia due to respiratory syncytial ciency syndrome (AIDS), as well as recurrent and
virus (RSV), adenovirus, enterovirus, or varicella persistent infections caused by Candida albicans
236 A. Zamorano Wittwer and M. Ferrés Garrido

Seasonal respiratory virus

CMV and Epstein–Barr

HSV Adenovirus VZV

Hepatitis B and C BK-JC

Site
surgical*

Aspergillus sp., Candida sp., Pneumocystis jirovecii

NAC, filamentous fungi, and Nocardia

TBC reactivation, toxoplasmosis, trypanosomiasis

0 30 60 90 120 150 180 365

Days after the transplant

*Bacterial infections associated with surgery

Fig. 25.1  Timing of infections in solid organ transplant recipients

Seasonal respiratory virus

CMV

HSV

EBV

VZV
Gram-negative
bacilli Encapsulated bacteria

Gram-positive cocci

Candida sp.

Aspergillus sp. Aspergillus sp.

Pneumocystis jirovecii

Days after the transplant

0 15 30 45 60 100 365

Neutropenia and
Bad quality period Slow improvement of the immune
toxicity of
cellular humoral response response
drugs

Fig. 25.2  Timing of infections in hematopoietic precursor transplant recipients

25  Immunosuppressed Children with Lung Infection 237

Table 25.2  Immunosuppression and infectious etiology

Type of
immunosuppression Mechanisms compromised Favored organisms Common causes
Phagocytosis Engulfment of bacteria and Staphylococcus aureus, bacilli, Neutropenia (leukemia,
fungi by mononuclear cells Gram-negative aerobes bone marrow suppression
(monocytes and macrophages) (Pseudomonas aeruginosa, due to chemotherapy)
and polymorphonuclear cells Klebsiella pneumoniae, Chronic granulomatous
(neutrophils) Escherichia coli), Candida diseases
Antigen presentation spp., Aspergillus spp. Corticotherapy
Hyper-IgE (Job syndrome)
Humoral immunity B lymphocytes Extracellular encapsulated Primary:
Neutralization bacteria: Streptococcus agammaglobulinemia,
Opsonization pneumoniae, Haemophilus IgA deficiency,
Complement activation influenzae, Staphylococcus IgM deficiency
aureus Secondary: myeloma,
Waldenström
macroglobulinemia,
lymphocyte leukemia
Complement Mediation of opsonization C3-C5: encapsulated bacteria C3–C5: encapsulated
Attraction of inflammatory C5–C9: Neisseria bacteria
cells gonorrhoeae, Neisseria C5–C9: Neisseria
Elimination of meningitidis gonorrhoeae, Neisseria
microorganisms through meningitidis
damage to their membranes
Cellular immunity T lymphocytes Mycobacterium tuberculosis, Primary
Killing of pathogen-infected Mycobacterium avium-c, Secondary: malnutrition,
cells by cytotoxic T (CD8) Nocardia asteroides, lymphoma, leukemia, old
cells Legionella spp., Cryptococcus age, drugs, AIDS
Macrophage activation by Th1 neoformans, Histoplasma Corticosteroids
(CD4) cells capsulatum, Coccidioides
B lymphocytes activation by immitis, varicella zoster, herpes
Th2 (CD4) cells to produce simplex, Cytomegalovirus,
antibodies Epstein–Barr virus,
Pneumocystis jirovecii,
Toxoplasma gondii
Hyposplenia/ Blood filtration Encapsulated bacteria Thrombotic
asplenia Production of bacteria-specific thrombocytopenic purpura,
antibodies Hodgkin lymphoma
Removal of bacteria covered
in antibodies
AIDS acquired immunodeficiency syndrome, IgA immunoglobulin A, IgE immunoglobulin E, IgM immunoglobulin M,
Th1 type 1 helper T cell, Th2 type 2 helper T cell

in the mucosa or the skin. Patients with chronic The most frequent etiologies for severe pneu-
granulomatous disease suffer lung infections monia according to the type of immunosuppres-
caused by Aspergillus or Staphylococcus aureus— sion are listed in Table 25.2.
agents that require effective phagocytosis for their
destruction. Children with primary immunodefi-
ciency always present severe lung complications: Bacteria
bronchiectasis, empyema, lung abscesses, etc.
In patients with AIDS, there is a long list of In addition to bacterial infection caused by com-
associated lung infections, including those mon pathogens such as Streptococcus pneu-
caused by P. jirovecii, CMV, Epstein–Barr virus, moniae or Haemophilus spp., we find agents
and mycobacteria, both typical and atypical. selected by broad-spectrum antimicrobial thera-
These are detailed in the corresponding chapter. pies or long stays in the hospital, such as S. aureus,
238 A. Zamorano Wittwer and M. Ferrés Garrido

Pseudomonas aeruginosa, and resistant Gram- The clinical picture is acute or subacute with
negative bacilli such as Stenotrophomonas malto- fever, tachypnea, a dry cough, and, in serious
philia and Burkholderia cepacia complex. cases, respiratory failure. The radiological pat-
tern is very varied, ranging from presentation of
slight interstitial infiltration to a diffuse alveolar
Viruses filling pattern.
An accurate disease diagnosis for CMV
Viral infections are the most frequent cause of respi- requires demonstration of tissue damage with the
ratory infection in immunosuppressed patients with characteristic cytopathic effect caused by the
pneumonia. The diseases have an atypical course, virus, with intranuclear or intracytoplasmic inclu-
which can be severe, and they can lead to respira- sion bodies, or positive immunohistochemistry.
tory failure with a high death rate. This is especially However, collection of tissue samples is an inva-
serious in patients with bone marrow transplants, in sive procedure, and so it is generally avoided in
whom RSV, adenovirus, and parainfluenza 3 result these patients. Nowadays, other methods for diag-
in death rates of 60–70%. A favorable prognosis in nosis are used, such as detection by quantification
these patients is determined by early suspicion, of viral genomes in the blood (using quantitative
diagnosis, and therapy, if available. polymerase chain reaction (PCR) for CMV or the
Infections can be due to seasonal viruses pres- CMV viral load), which provides the etiological
ent in the community, such as influenza A and B diagnosis and confirms pulmonary involvement.
viruses, parainfluenza  (1–4), RSV, adenovirus, A finding of inclusion bodies on cytological anal-
metapneumovirus, or rhinovirus. With advances ysis of bronchoalveolar lavage (BAL) fluid or
in molecular diagnostic techniques, it is PCR for CMV in BAL fluid is helpful. However,
increasingly common to find coinfections by
­ these findings must be interpreted cautiously
both respiratory viruses and latent bacteria or because such detection may signify contamina-
viruses that have reactivated, such as viruses in tion of the higher respiratory tract, where CMV
the Herpesviridae family, among which CMV can exist without causing disease.
can be highlighted. It is important to regularly monitor the pri-
Unfortunately, there are few antiviral drugs mary infectious condition or reactivation in
available as a therapeutic resource. Influenza vac- patients who have undergone solid organ or bone
cination must be targeted toward close contacts marrow transplantation, at least during the
of the patients, especially within the first 3 months higher-immunosuppression phase (correspond-
after transplantation. Beyond this period, it can ing roughly to the 3-month period after the trans-
be used in transplant recipients themselves, who plantation). Appropriate prophylaxis and early
can progressively mount an immune response. treatment can prevent severe infection.

 ytomegalovirus
C
Cytomegalovirus is a herpes virus and infects Fungi
40–100% of the general population in adulthood.
After the primary infection, it persists as a latent Fungal infections in immunosuppressed patients
infection for long periods and can reactivate in can be divided into opportunist infections caused
states of cellular immunosuppression, as in the by organisms that invade the lung primarily
case of patients treated with a lymphocyte immu- (Aspergillus or C.  neoformans), opportunistic
nosuppressant (OKT3). infections that reach the lung through hematoge-
The infection and disease caused by CMV are nous dissemination from another site, fungal
the main complications in patients who undergo overinfection of lung tissue previously damaged
bone marrow transplantation and in patients with by a viral or bacterial infection (Candida or
AIDS; the latter have a high risk of reaching CD4 Aspergillus), and reactivated secondary systemic
counts as low as <50 cells/mm3. mycosis (in the context of immunosuppression)
25  Immunosuppressed Children with Lung Infection 239

from previously acquired infections, as occurs in happen in patients with an alteration of the under-
cases of blastomycosis, coccidioidomycosis, and lying lung architecture.
histoplasmosis. Measurement of galactomannan antigen in
BAL fluid has 90% sensitivity and 94% specific-
Aspergillosis ity for invasive lung aspergillosis. Detection of
The genus Aspergillus (especially the species the fungus in significant amounts in BAL fluid or
A. fumigatus and A. flavum) is the most frequent in three repeat samples of sputum can be enough
cause of fungal pneumonia in neutropenic to establish the diagnosis.
patients and in bone marrow transplant recipients Molecular diagnosis of fungal infections is
(it can affect up to 20% of recipients). There is a not as advanced as molecular diagnosis of viral
lower incidence (between 1% and 8%) in solid or bacterial infections. Biopsy with histopatho-
organ transplant recipients. This invasive pulmo- logical analysis of the lung tissue is still the gold
nary infection is associated with prolonged neu- standard but is rarely done, because of the risks
tropenia, graft-versus-host disease, and use of associated with collection of samples.
steroids. The incidence depends on antifungal Lung angiography can be useful in the search
prophylaxis and the kind of immunosuppression. for an angioinvasive disease. Untreated infec-
The infection is acquired by inhalation, and tions can have a mortality rate as high as 90%.
the clinical picture consists of a high fever, cough, Voriconazole is the first-line treatment for
dyspnea and hemoptysis, with pleuritic chest invasive lung aspergillosis, and the duration of the
pain. It usually occurs after a previous bacterial treatment depends on clinical improvement, reso-
infection. lution of galactomannan antigenemia, and radio-
From a radiological point of view, many alve- logical confirmation of lesion improvement.
olar infiltrates, which can coalesce, may be Lobectomy has a limited role in neutropenic
observed. A thoracic CT scan presents typical patients and is reserved for patients with poten-
findings of nodules with central density and a tially lethal massive hemoptysis.
peripheral halo with intermediate density, and
sometimes these lesions can cavitate (Fig. 25.3). Mucormycosis
CT scanning is the preferred imaging test for Mucormycosis is the second most common type
diagnosis. Aspergilloma does not usually occur of invasive lung infection and is caused by
in immunosuppressed patients, although it can Rhizopus, Mucor, or Rhizomucor. It manifests as
lung nodules in patients with bone marrow trans-
plants. It evolves faster than aspergillosis in caus-
ing angioinvasion. A definitive diagnosis requires
histological evidence. The first-line treatment for
this etiology is liposomal amphotericin B.

 andida
C
Neutropenia, cell immunity alterations, diabetes
mellitus, and the use of immunosuppressants and
broad-spectrum antibiotics are predisposing fac-
tors for infection with Candida albicans, which
usually manifests as widespread pneumonia with
focal or diffuse alveolar infiltrates. Isolated lung
infections are uncommon.
In HIV-positive patients, C. neoformans is the
Fig. 25.3  Aspergillosis. “Half-moon” shaped, cavitated
nodular opacity in an axial section of a CT scan, due to
fungus that most frequently causes lung infil-
Aspergillus infection in a child with acute lymphoblastic trates. It usually produces a disseminated infec-
leukemia tion that affects the central nervous system,
240 A. Zamorano Wittwer and M. Ferrés Garrido

causing meningitis, which is the most common The treatment of choice is sulfamethoxazole/
manifestation; this can conceal the respiratory trimethoprim with added corticosteroids in
clinical condition, but in up to a 40% of cases, hypoxemic patients.
pulmonary impairment can also be present, with Prophylaxis for P. jirovecii is recommended for
interstitial reticulonodular opacities or well-­ at least 6 months after transplantation, or for longer
delimited nodules. if immunosuppression persists. A specific length of
time has not been defined for oncological patients.
 neumocystis jirovecii
P
Despite prophylaxis with sulfamethoxazole trim-
ethoprim, P.  jirovecii is a common infection in Mycobacteria
immunocompromised patients. Risk factors
include immunosuppressant therapies, both in Reactivation of latent tuberculosis is the most com-
transplant patients and in oncological patients, mon form of disease in patients from countries with
and systemic steroid use for long periods of time. a high tuberculosis prevalence. Chemoprophylaxis
Patients can have the following clinical mani- before immunosuppression reduces but does not
festations: a cough, progressive shortness of eliminate the risk of reactivation.
breath (especially during exercise), and hypoxia. The clinical picture is usually insidious, with
Chest x-rays can be normal or can present diffuse general discomfort, a low-grade fever, a wet
interstitial infiltrates, which can evolve to become cough, and dyspnea. The most common clinical
alveolar, bilateral, or perihilar (Fig.  25.4). The presentation is that 1  year after transplantation
changes are more evident on CT scans, and P. jir- the patient develops fever without respiratory
ovecii cysts can be identified in sputum or BAL symptoms but with nonspecific radiological
fluid. In patients with a compatible clinical pic- changes, including lymphadenopathy with pleu-
ture, a serum β-D-glucan test can be used to con- ral effusion and patchy pulmonary infiltrates.
firm the diagnosis in immunocompromised
patients with 94.8% sensitivity and 86.3% Nontubercular Mycobacteria
specificity. In patients with significant immunosuppression,
A death rate of up to 34% has been reported such as AIDS patients and recipients of solid
for this etiology in patients with oncological organ or bone marrow transplants, Mycobacterium
pathologies that require mechanical ventilation. can cause pulmonary bacterial infections and dis-
seminated disease, with M. avium and M. kansa-
sii being the most frequently causal species.
In patients with cystic fibrosis, colonization
by M.  avium and M.  abscessus complex are
­common, becoming worse in the state of post-­
transplantation immunosuppression.
Automatized culture methods such as molecu-
lar techniques allow for quick diagnosis.
Treatment is maintained for 12–18  months
with three or more drugs.

Parasites

The most common parasite is Toxoplasma, which

usually causes fever, a dry cough, and dyspnea.
Fig. 25.4  Pneumocystis jirovecii. Anteroposterior chest
x-ray showing bilateral pneumonia caused by P. jirovecii Its radiological presentation usually shows a dif-
in an infant with cellular immunodeficiency fuse interstitial pattern.
25  Immunosuppressed Children with Lung Infection 241

Diagnostic Studies Blood cultures are useful mainly in neutrope-

nic patients and for germs that invade the blood-
Early commencement of adequate therapy is cru- stream, such as S.  pneumoniae. Special culture
cial; thus, empirical therapy is initiated and then media are required if Nocardia or atypical
adjusted according to the evolution of the disease Mycobacterium are present.
and the results of investigations. BAL with bronchoscopy is the main diagnos-
tic procedure performed in an immunosuppressed
patient with pulmonary infiltrates. It enables iden-
Clinical Presentation tification of the causal agents, adjustment of treat-
ment according to the etiology, and exclusion of
It is important to know what the cause of the infections that are not present, allowing suspen-
immunosuppression is, whether it is primary or sion of any empirically initiated therapies that are
secondary, and what the relationship is between inappropriate and could be harmful to the patient.
the start of the symptoms or pulmonary infiltrates While a surgical pulmonary biopsy allows us
and the immunosuppression. to obtain an adequate amount of lung tissue for
complete microbiological and pathological diag-
nosis, in these patients it presents a high risk of
Radiology complications, and often the diagnostic capabil-
ity is low, so the decision to perform such a
Radiological findings are very useful, and even biopsy must be made on a case-by-case basis.
though no radiological pattern is pathognomonic The possibility of reaching a correct diagnosis
of an etiology, differentiation of diffuse, nodular, that might change the treatment must be evalu-
and focal patterns can provide an initial orienta- ated, along with the likelihood of tolerance and
tion (Table 25.1). surgical complications.
Early axial CT scanning is important for diag- Figure 25.5 shows an algorithm for microbio-
nosis, because in neutropenic patients with fever, logical diagnosis on the basis of pulmonary infil-
up to 50% of pulmonary lesions diagnosed with trates in immunosuppressed patients with fever.
CT may not be observable with simple
radiography.
Treatment

Microbiological Diagnosis Given the severity of the clinical picture and the
importance of early commencement of treatment,
Sampling the normal way of managing an immunosup-
Sampling of spontaneous sputum or sputum pressed patient with a respiratory infection is to
induced by nebulization of hypertonic serum can start empirical therapy while waiting for test
be performed before collection of BAL fluid by results.
bronchoscopy, which can be useful if germs that The initial empirical therapies that may be
do not belong to the oropharyngeal cavity grow instituted according to the clinical picture are
in the culture. listed in Table 25.3.
242 A. Zamorano Wittwer and M. Ferrés Garrido

Pulmonary
infiltrates

Localized Diffuse

LBA or
Early Refractory Late
pulmonary biopsy

Induced
sputum LBA or
pulmonary
biopsy

Add the following to what

• Gram staining • Gram staining has been mentioned for
• Calcofluor white staining • Calcofluor white staining localized infiltrates:
• Common culture • Ziehl-Neelsen staining
• IF, ELISA or RPC for VRS,
• Fungi culture • Common culture influenza A and B,
• Fungi culture parainfluenza 1-2-3, MPVH,
Serum aspergillus ADV, CMV
• Galactomannan • C. pneumoniae IgM, M.
• Mycobacterium culture pneumoniae IgM
• PCR for chlamydia and
• Gomori-Grocott/RPC P. jirovecii
M. pneumoniae
• Serum Mycoplasma IgM

Fig. 25.5  Microbiological diagnosis in immunosuppressed patients with fever

Table 25.3  Initial empirical therapeutic management

Indication Therapy
Febrile neutropenia Broad-spectrum β-lactam with antipseudomonal activity +
 (Gram-negative bacteria, Staphylococcus, fungi) quinolone or aminoglycoside
 No response Addition of glycopeptide
 Patchy/diffuse infiltrates
 If neutropenia is prolonged Addition of amphotericin B or voriconazole
Solid organ transplantation Cotrimoxazole + ganciclovir
 Interstitial pattern (pneumonia due to
Pneumocystis or Cytomegalovirus)
 Lobar infiltrates (pneumococcus, Haemophilus Broad-spectrum β-lactam with antipseudomonal activity +
influenzae, Staphylococcus) aminoglycoside
 Diffuse process (Pneumocystis, viruses, fungi) Cotrimoxazole + ganciclovir + amphotericin B
 Atypical agents Macrolide or quinolone
Hypogammaglobulinemia (bacterial process) Intravenous immunoglobulin + β-lactam with
antipseudomonal activity ± macrolide
HIV infection Cotrimoxazole
 Interstitial process (Pneumocystis, viruses) Cotrimoxazole
 Lobar infiltrates (bacteria) Third-generation cephalosporin + macrolide
 Nosocomial pneumonia (Gram-negative resistant Broad-spectrum β-lactam with antipseudomonal activity +
Staphylococcus) aminoglycoside
(continued)
25  Immunosuppressed Children with Lung Infection 243

Table 25.3 (continued)
Indication Therapy
Bone marrow transplantation Ganciclovir + immunoglobulin
 Allogenic Ganciclovir + immunoglobulin
  Interstitial process
  Patchy/diffuse Ganciclovir + immunoglobulin + amphotericin B + β-lactam
+ aminoglycoside
HIV human immunodeficiency virus

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imágenes, e inferencia Bayesiana. Rev Chil Infectol. AM, et  al. Consenso manejo racional del paciente
2014;31(2):139–52. con cáncer, neutropenia y fiebre. Rev Chil Infectol.
Doan TT, Phung TT, Pham HV, Pham SH, Nguyen 2005;22(Suppl 2):S80.
LT.  Effect of ganciclovir for the treatment of severe Silva RF.  Fungal infections in immunocompromised
Cytomegalovirus-associated pneumonia in children patients. J Bras Pneumol. 2010;36(1):142–7.
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Infect Dis. 2013;13:424. ido: un problema en aumento. Rev Patol Respir.
Eslamy H, Newman B. Pneumonia in normal and immu- 2005a;8(2):157–8.
nocompromised children: an overview and update. Steen B. Neumonía en el inmunodeprimido. In: García Satué
Radiol Clin N Am. 2011;49:895–920. JL, Aspa Marco J, editors. Monografías Neumomadrid,
Gambra MP, Bidart T.  Profilaxis de neumonía por vol. IX. Madrid: Neumomadrid; 2005b. p. 159–78.
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 Respiratory Complications
in Children with Neurological
26
Diseases

Raúl Escobar Henríquez
and Bernardita Chateau Infante

Contents
Epidemiology...............................................................................................................   245
Etiology and Physiopathology...................................................................................   246
Associated Conditions..................................................................................................  247
Clinical Manifestations..............................................................................................   247
Diagnostic Foci............................................................................................................   248
 eurological Focus.......................................................................................................  248
N
Respiratory Focus.........................................................................................................  248
Cardiological Focus......................................................................................................  250
Treatment....................................................................................................................   250
 utrition.......................................................................................................................  250
N
Respiratory Kinesiotherapy..........................................................................................  251
Scoliosis........................................................................................................................  251
Neurorehabilitation.......................................................................................................  251
Pharmacological Treatment..........................................................................................  252
Assisted Ventilation......................................................................................................  252
Oxygen Therapy...........................................................................................................  252
Prognosis......................................................................................................................   252
Ethical Dilemmas........................................................................................................   252
Sources.........................................................................................................................   253

R. Escobar Henríquez Epidemiology

Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile,
Santiago, Chile Respiratory disorders are one of the main causes
e-mail: [email protected] of morbidity and mortality among patients with
B. Chateau Infante (*) neurological diseases. They have multifactorial
Department of Pediatrics, Clínica Los Andes, causes, their prevalence is variable, and they
Santiago, Chile depend on the type of neurological disease.
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 245

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_26
246 R. Escobar Henríquez and B. Chateau Infante

The most common condition that affects the Etiology and Physiopathology

central nervous system is cerebral palsy, with
an estimated incidence of 1.5–2.5 cases per Respiratory disorders in patients with neurologi-
1000 live births. The prevalence and intensity cal diseases have multifactorial causes, the
of respiratory alterations within this disease importance of which depends fundamentally on
depend on the type of motor compromise. The the base neurological disease.
worst prognosis is quadriplegic cerebral palsy. Diseases of the central nervous system can
In highly disabling neurological diseases, of present alteration of respiratory control and
which spastic quadriplegic cerebral palsy is the muscular weakness of the upper airway.
most common, factors such as immobility, Alteration of respiratory control is manifested
feeding via a nasogastric tube and not by gas- by progressive hypoventilation. The process can
trostomy, and epilepsy have significant effects be slow and overlapping, with subtle clinical
in increasing mortality. Recurrent pneumonia signs, at first during sleep with hypopneas and/
appears in almost 70% of this patient popula- or hypercapnia, and finally with evident central
tion, and there is a 77% mortality rate among apnea. Muscular weakness of the upper airway
those who contract pneumonia. determines a higher risk of obstructive apnea
Diseases that compromise the peripheral ner- and alters the protection of the airway, with a
vous system, known as neuromuscular diseases greater risk of aspiration and consequent dam-
(NMDs), have an estimated prevalence of 63 age. Repeated and persistent aspiration causes
cases per 100,000 people under the age of repeated pneumonia, besides progressive dam-
16 years. The most common conditions are spi- age to the pulmonary parenchyma, with ventila-
nal muscular atrophy (SMA), with an incidence tion/perfusion (V/Q) mismatch in which dead
of 1  in every 6000 live births, and Duchenne space and hypoxemia increase, leading to a
muscular dystrophy (DMD), with an incidence restrictive respiratory pattern and increasing the
of 1  in every 3500 live male births. We do not load on the system.
have specific information about the prevalence The problem with NMDs is essentially the
rates of SMA and DMD in Chile. failure of the pump: there is an imbalance between
In NMDs, respiratory compromise can be the muscular force and the load on the respiratory
very rare, as happens in Charcot–Marie–Tooth system, and this finally causes hypoventilation
neuropathy, or it can affect 100% of patients, as and hypercapnia, which is characteristic.
in the case of children over 10 years of age with Respiratory muscular weakness translates into
DMD. By the time these children are 10 years incapacity to generate pressure and normal flows
old, they show a progressive decrease in respira- during inhalation and exhalation, increasing the
tory force, which is accentuated by loss of the mechanical load, thus altering the mechanics and
ability to walk. All of them require assisted ven- gaseous exchange. Inspiratory muscular compro-
tilation before they reach the age of 20 years. In mise decreases the corresponding reserve volume
patients with SMA, the level of respiratory com- and total lung capacity, causing a characteristi-
promise can vary depending on the type. In the cally restrictive respiratory pattern. There is also
case of SMA type 1, 100% of patients will die a decrease in the vital capacity (VC), which is not
from respiratory insufficiency within a year if linearly proportional to the reduction in the expi-
they do not receive ventilatory support. In ratory force, because of the mechanical effect of
patients with SMA types 2 or 3 (as in those with the elastic retraction of the system, which main-
DMD), a progressive decline in respiratory tains a higher VC than might be expected.
force begins around 8 years of age, which leads However, expiratory muscular compromise
to respiratory insufficiency that requires assisted reduces the expiratory reserve volume, increas-
ventilation. ing the residual volume and maintaining an
26  Respiratory Complications in Children with Neurological Diseases 247

almost constant functional reserve capacity. Table 26.1  Forms of clinical presentation of neurologi-
Alterations in inspiratory and expiratory muscles cal diseases
are manifested in weak coughing and inadequate Presentation
maneuvers in both phases, increasing the risks of Hypotonic infant
aspiration, atelectasis, and pneumonia. Delayed psychomotor development
Swallowing disorder
Gait alteration, frequent falls
Central neurological symptoms: epileptic seizures
Associated Conditions Lack of strength, fatigability
Muscular pain, cramps
Sleep disorders are common in patients with neu- Orthopedic alterations: clubfoot, equinus foot,
rological diseases, although they tend to be pes cavus, scoliosis
Recurrent pneumonia, recurrent or persistent atelectasis
underdiagnosed. The factors that determine these
with no clear respiratory cause
alterations are respiratory muscular weakness of Sleep disturbances, snoring, obstructive and central
the upper airway, deformities of the rib cage and apneas
spine, obesity, craniofacial alterations, and altera-
tions in respiratory control. It is important to sus- inspiratory muscles is related to nocturnal
pect and search for these conditions in a directed hypoventilation syndrome as an initial clinical
manner. Weakness of the respiratory pump—in presentation, which often goes unnoticed if it is
particular, during rapid-eye-movement (REM) not looked for directly. If there is preferential
sleep, or the active sleep stage—accentuates the involvement of the expiratory muscles, the symp-
normal situation of muscular atony, resulting in toms include a weak cough and more frequent
hypoventilation and apnea. atelectasis. If there is compromise of the muscu-
Orthopedic alterations are common and lature of the upper airway, the mechanisms of
should be diagnosed early so that appropriate swallowing and aspiration are affected. The
interventions can be instituted. They are caused physiopathological relationships are multiple and
by damage to the spinal extensor muscles, the complex, as shown in Fig. 26.1.
effect of gravity, nonharmonic movements, and The respiratory clinical picture depends on
axial rotation. Kyphoscoliosis, which is progres- the severity and timing of respiratory muscular
sive and difficult to control, contributes to the compromise. For example, in patients with SMA
alteration of respiratory mechanics. It has been type 1, who have an early and severe presenta-
shown that there is a directly proportional rela- tion, the infant’s chest is bell shaped, with tachy-
tionship between the degree of kyphoscoliosis, as pnea and paradoxical breathing, in a context of
defined by the Cobb angle, and respiratory generalized hypotonia. With diseases that prog-
insufficiency. ress more slowly, such as DMD, the respiratory
symptoms are insidious and often go unnoticed,
such as sleep alterations due to nocturnal
Clinical Manifestations hypoventilation, resulting in hypoxia and sleep
fragmentation, in turn leading to neurocognitive
There is a wide variety of neurological diseases and behavioral problems, hyperactivity or leth-
and consequently a wide variety of clinical mani- argy, morning headaches, and anorexia.
festations, which are summarized in Table 26.1. There are various signs and symptoms caused
Muscular weakness is a cardinal sign of neu- by compromise of the respiratory system in neu-
rological diseases with respiratory compromise. rological diseases. It is important for physicians
Depending on which respiratory muscle group is to know of these and seek them in a directed
compromised, a clinical examination may reveal manner in an anamnesis and a thorough physical
the condition. Preferential involvement of the examination (Table 26.2).
248 R. Escobar Henríquez and B. Chateau Infante

Inspiratory muscle Expiratory muscle

weakness weakness

Restrictive Chest wall Respiratory Weakness of upper Inefficient

pattern rigidity sleep disorders airway muscles cough

Microatelectasis Speech Deglutition

disorder disorder

Weight
Sialorrhea
Clearance loss

Work of
breathing Aspiration

Kyphoscoliosis
Pneumonia

Alveolar hypoventilation

Fig. 26.1  Pathophysiology and clinical signs in neurological disease

Diagnostic Foci enzyme levels, electromyography, and peripheral

nerve conduction velocity; muscular imaging
A complete initial assessment that includes the studies; muscle and/or nerve biopsies; and spe-
medical history is needed, besides a complete cific molecular and genetic studies.
physical examination that seeks the signs and
symptoms described above, with evaluation by
specialists in the relevant fields. Respiratory Focus

 valuation of Sleep Alterations

E
Neurological Focus Peripheral oxygen saturation: The peripheral
oxygen saturation (SpO2) can be assessed con-
To determine the prognosis, it is necessary to tinuously during sleep to determine the base and
have a topographical neurological diagnosis that average levels, besides the levels during desatu-
identifies the level of compromise of the nervous ration events or clusters in relation to snoring or
system. A complete neurological examination is sleep stages in particular. More sophisticated
essential, which includes nuclear magnetic reso- and sensitive equipment has been developed in
nance (NMR) imaging of the brain and/or bone recent years, using signal purification tech-
marrow; neurophysiological studies such electro- niques that better show periods of desaturation,
encephalography, evoked potentials, muscle although this test does not adequately identify
26  Respiratory Complications in Children with Neurological Diseases 249

Table 26.2  Symptoms and signs of alterations of the eases, including in the absence of significant
respiratory system in neurological disease clinical manifestations and in the absence of
System Symptoms and signs examinations of pulmonary function in normal
Constitutional Fatigue wakefulness. Active (REM) sleep inhibits mus-
Weakness
cular activity, and slow-wave non-REM
Retarded growth
Cardiopulmonary Cyanosis (NREM) sleep impedes nonchemical afferences
Tachycardia to the respiratory center, increasing the risk of
Dyspnea nocturnal hypoventilation, obstruction of the
Tachypnea upper airway, and apnea. Polygraph testing,
Diaphragmatic paradox
Use of accessory muscles which is derived from polysomnography, uses
Decreased diaphragmatic excursion other criteria besides electroencephalographic
Bell-shaped thorax waves to determine sleep stages. The polygraph
Weak cough has the advantage of being portable, and this
Recurrent or persistent atelectasis
Recurrent pneumonia type of test is relatively inexpensive. Respiratory
Central nervous Morning headache alterations during sleep should be assessed at
Hypersomnolence least once a year in patients presenting any of
Neurocognitive alterations the following criteria: VC <60% of the predicted
Hyperactivity
Speech disorder
value, loss of mobility, symptoms or signs of
Sleep Restless sleep obstructive apnea–hypoventilation, and dia-
Nightmares phragmatic weakness (level of recommenda-
Nocturnal enuresis tion: D). If rapid worsening, repeated infections,
Frequent awakenings
or sleep alteration symptoms occur, the studies
Snoring
Apneas should be repeated with the necessary frequency
Others Blockages for early diagnosis and intervention.
Sialorrhea
Speech disorder  ssessment of Pulmonary Force
A
and Function
respiratory sleep disorders (RSDs) in this type Spirometry: There is a characteristically restric-
of patient. tive pattern (reduced forced vital capacity (FVC)
Capnography: Expirated or transcutaneous and reduced forced expiratory volume in 1 sec-
carbon dioxide levels can be measured. This ond (FEV1)). The flow curve is useful to show a
parameter indicates alveolar ventilation. This reduction in force-dependent respiratory flows:
measurement is more useful as a complement to the maximum inspiratory flow (MIF) and maxi-
sleep study than in isolation. mum expiratory flow (MEF). VC should be mea-
Gases in arterial blood: The partial pressure sured as part of lung function studies in all
of carbon dioxide (PaCO2) shows the severity of patients diagnosed with NMDs who can perform
hypoventilation, while the pH, bicarbonate, and this maneuver (level of recommendation: C).
base excess indicate the repercussions in terms of Muscular strength assessment: Decreases in
the acid–base balance and the degree of meta- muscular strength and resistance in the context
bolic correction, adding specificity to the diagno- of fatigue are the first clinical elements that pres-
sis. Studies by Hukins (2000) and Mellies (2003) ent in NMDs. The assessment includes measure-
showed that PaCO2 values above 40 mmHg and ment of the maximum voluntary ventilation
45 mmHg, respectively, correlated with nocturnal (MVV), maximum inspiratory pressure (MaxIP),
hypoventilation, with sensitivity of more than and maximum expiratory pressure (MaxEP), and
90% and specificity of around 75%. it is more sensitive than VC measurement at the
Polysomnography: Polysomnography studies initial stages of the disease. MaxIP is the maxi-
play an important role in early detection of mum pressure generated during inspiration with
RSDs among patients with neurological dis- the airway occluded and is based on the residual
250 R. Escobar Henríquez and B. Chateau Infante

volume or the functional reserve capacity. atelectasis, fiber bronchoscopy can indicate
MaxEP is the maximum pressure generated dur- appropriate therapy.
ing expiration with the airway occluded and is
based on the total lung capacity. The effort
should be maintained for 1 second, and at least Cardiological Focus
five maneuvers of each type should be done until
at least two reproducible results are obtained. A Patients with neurological disease can have pri-
MaxIP value of >80 cm H2O is of great value in mary or secondary compromise of the cardiovas-
excluding muscular compromise of clinical cular system. Primary myocardial involvement
importance. A 75% decrease in the MaxIP value must be ruled out in myopathies such as DMD or
or a predicted value close to 30% is needed to Becker disease, some congenital myopathies,
observe a significant decrease in FVC. Thus, spi- mitochondrial diseases, and other conditions,
rometry and the volume/time relationship are not as determined by a specialist in NMDs.
very sensitive tests to evaluate muscular failure Cardiovascular compromise is secondary to
at the initial stages. muscle-­based diseases or to the development of
Maximum flow with cough: This is a tool to pulmonary hypertension due to chronic hypox-
assess the effectiveness of coughing and can be emia, which at the advanced stage constitutes
measured using a mask or mouthpiece. There is pulmonary heart disease. Hyperpulmonary flow,
evidence in adults that a minimum of 160 l/min is due to increased transpulmonary pressures, is
necessary to adequately mobilize secretions, and also a cause of pulmonary hypertension, as
that values above 270 l/min represent respiratory occurs in patients with obstructive sleep apnea.
indemnity (level of evidence:  3). Although no Other alterations of the airway, such as heart
specific values have been established in children, rhythm disorders, should be evaluated in patients
this test is recommended for respiratory evalua- with central hypoventilation syndromes and
tion in subjects over 12 years of age. patients with specific NMDs, such as Emery–
Dreyfus syndrome or certain congenital
Evaluation of Complications myopathies.
Imaging studies: A chest x-ray determines the
presence of associated pneumonia or atelectasis.
Radioscopy and echoscopy assess diaphragmatic Treatment
mobility.
The chest of a patient with NMDs is bell In neurological diseases, respiratory failure
shaped when there is thoracic muscle involve- accounts for most acute and chronic morbidity, as
ment. The esophagus–stomach–duodenum (ESD) well as mortality. Until curative therapies are
transit, assessed with a specific videodilution available for the underlying neurological disease,
study, evaluates the presence of gastroesophageal efforts must be made to slow the progressive
reflux (GER) and deglutition disorders as causes deterioration of musculoskeletal and respiratory
of pulmonary aspiration, recurrent pneumonia, or function, thus improving the quality of life. The
chronic interstitial lung compromise. treatment is multidisciplinary, including respira-
Assessment of the airway: Suspicion of bulbar tory medicine, neurology, nutrition, kinesiology,
or pharyngeal and suprahyoid musculature com- gastroenterology, orthopedics, and other
promise makes it necessary to evaluate the air- specialties.
way. Fiber bronchoscopy is useful to diagnose
hypotonic or pharyngeal incoordination and
vocal cord paralysis or paresis, which is related to Nutrition
a potentially unstable airway. In patients with a
tracheostomy, it is useful to anatomically evalu- Patients with neurological diseases often suffer
ate the intervened airway. In the case of persistent from malnutrition, due to both deficiency and
26  Respiratory Complications in Children with Neurological Diseases 251

excess. Situations of malnutrition occur more in a considering that the muscles of patients with
context of low nutritional intake (due to difficulty NMDs are diseased and their training capacity
in swallowing) or greater energy expenditure does not necessarily follow the same principles
(due to excessive respiratory work). Excesses that apply to healthy muscles.
occur in a context of assured nutrition, without
consideration of the fact that the patients have
lower basal energy expenditure, so their require- Scoliosis
ments are also lower.
Malnutrition affects the functioning of the The rapid progression of scoliosis in patients
respiratory musculature, and at the same time it with neurological diseases is directly related to
facilitates recurrent infections. Thus, when diag- the progression of the disease and to the sitting
nosed, the patient must be supported until an postures that patients maintain, which do not
acceptable nutritional status is reached, which always preserve correct alignment, making the
varies from one person to another. Slow growth is gravitational effect on the curvature of their spine
common, so it is advisable to adapt the height/ accelerate the progression of the kyphoscoliosis.
weight ratio to limit the diet in order to avoid Respiratory complications are an indication for
overfeeding. Enteral feeding via a nasogastric treatment with arthrodesis, because systems for
tube or gastrostomy is usually necessary. It is also support and maintenance with corsets in these
useful to consider specific nutritional gaps—in cases have not been shown to be useful, while
particular, those related to bone metabolism— hindering respiratory mechanics. Surgery should
because of a higher risk of multicausal osteope- be deferred for as long as possible; however, the
nia and related fractures. presence of a Cobb angle of >40° correlates with
respiratory failure.

Respiratory Kinesiotherapy
Neurorehabilitation
The main objectives of respiratory kinesiotherapy
are to prevent and treat atelectasis, permeabilize Neurorehabilitation aims to improve the general
the airway, and assist respiratory rehabilitation. functioning of the patient in relation to the activi-
Multiple maneuvers of successive inspirations ties that correspond to their age. Two types of
and forced expirations with assisted coughing add interventions are generally carried out: one
to the workload and to respiratory muscle fatigue involves techniques to stimulate the generation or
in children with ventilatory insufficiency, so this restoration of central or peripheral motor circuits
therapy should be conducted with caution. to improve motor functionality, while the other
There are now cough assist devices that can be employs external support for neuromuscular
used in patients with neurological disease. These functioning—for example, padding to keep the
devices are applied through interfaces such as head erect, chairs adapted for sitting require-
masks, mouthpieces, and tracheostomies as part ments, a tilting table to put patients without con-
of the management of respiratory exacerbations, trol over head movement in a standing position,
minimizing the risk of intubation and providing or a prone-position table for patients with partial
mechanical cough assistance for stable patients control over their heads.
who are too weak to cough. Standing systems are based on the extensive
Respiratory muscle training with adjustable published evidence of the benefits of patients
valves has allowed the development of training being in a standing position in several respects: it
plans for adult patients with chronic obstructive improves gastric and urinary emptying, and it
pulmonary disease. These have begun to be strengthens ossification, according to studies in
applied to children, with positive results, although quadriplegic patients, who stand for an hour five
long-term research will be needed, especially times a week. This evidence can be extrapolated
252 R. Escobar Henríquez and B. Chateau Infante

to patients with more serious NMDs, who com- Assisted Ventilation

monly experience fractures of long bones as a
result of low-impact trauma associated with Publications on the impact of noninvasive
movement and postural changes. assisted ventilation—especially in relation to
Evaluation and management of swallowing NMDs and thoracic deformities such as kypho-
are essential to avoid pulmonary complications. scoliosis—recommend its use in investigation of
Although oral feeding is not an objective, tech- nocturnal hypoventilation, a condition associated
niques of desensitization and intra- and perioral with disorders of pulmonary function and blood
management are essential for development of gases during wakefulness.
reflexes. Establishment of motor sequences and Thus, investigation of nocturnal hypoventila-
muscle strengthening through speech therapy tion and RSDs, involving sleep and pulmonary
intervention techniques must also be considered function studies, makes it possible to decide
early on. Swallowing rehabilitation is aimed at whether or not to employ noninvasive ventilatory
maintaining and/or recovering suction–swallow- assistance.
ing mechanisms. Long-term follow-up of this type of assistance
has shown improvements in the quality of life,
RSDs, nocturnal hypoventilation, and daytime
Pharmacological Treatment hypercapnia, with decreased health care costs. It
has also been recently verified that the frequency
The use of steroids is indicated in patients with and severity of respiratory infections are reduced,
DMD; prednisone and deflazacort have been with a decreased incidence of hospitalizations for
shown to be effective in increasing force and complications of infections.
delaying loss of force, prolonging autonomy for
around 2  years. The increase in strength, and
especially the increase in the time spent walk- Oxygen Therapy
ing, has a direct effect on the ventilatory capac-
ity of affected children, although side effects The cardinal disorder in NMDs is hypoventila-
must be monitored. Recent studies have shown tion. Treatment should aim to correct this situa-
that treatment with lower doses of corticoste- tion; thus, ventilation support is fundamental. In
roids in nondaily regimens has the same benefi- the case of chronic hypercapnic respiratory insuf-
cial effects as daily use of prednisone, but ficiency, oxygen therapy can accentuate hypoven-
without the traditional side effects. However, tilation by inhibiting the only other stimulus for
once the ability to walk is lost, this therapy ventilation that remains: hypoxemia. Therefore,
merely increases potential adverse effects such special care should be taken when considering
as osteoporosis. indications for oxygen therapy in these patients.
Creatine is a dietary supplement that has
been shown to improve strength in both healthy
individuals and carriers of disabling diseases. Prognosis
The beneficial effect is due to increased muscle
protein synthesis—in particular, heavy chain On the basis of their clinical progression, NMDs
myosin—and to increased intramuscular gly- can be classified as shown in Table 26.3.
cogen. However, it should be kept in mind that
this effect is beneficial only when it supple-
ments creatine associated with strength train- Ethical Dilemmas
ing and antiresistance techniques. Carnitine
may be useful in patients with myopathies sec- The survival of children with neurological dis-
ondary to metabolic syndromes with carnitine eases and dependence on medical technologies
deficiency. has improved because of specialized respiratory
26  Respiratory Complications in Children with Neurological Diseases 253

Table 26.3 Prognostic features of neuromuscular to do good and prevent evil. Participation in the
diseases decision-­making process for patients and their
Feature Disease families must honor the principle of autonomy.
Early appearance of acute Spinal muscular atrophy
respiratory failure type 1
Congenital myotonic
dystrophy Sources
Some congenital
myopathies Allen J. Pulmonary complications of neuromuscular dis-
Continuous slow Duchenne muscular ease: a respiratory mechanics perspective. Paediatr
progression dystrophy Respir Rev. 2010;11:18–23.
Some congenital Arens R, Muzumdar H.  Sleep, sleep disordered breath-
myopathies ing, and nocturnal hypoventilation in children
Myotonic dystrophy with neuromuscular diseases. Paediatr Respir Rev.
Spinal muscular atrophy 2010;11:24–30.
types 2 and 3 Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff
Some polyneuropathies E. Long term survival in Werdnig–Hoffmann disease.
Stable slow progression Some congenital muscular Am J Phys Med Rehabil. 2007;86:339–45.
dystrophies Benditt JO, Boitano LJ. Pulmonary issues in patients with
Some polyneuropathies chronic neuromuscular disease. Am J Respir Crit Care
Some congenital Med. 2013;187(10):1046–55.
myopathies Hukins CA, Hillman DR. Daytime predictors of sleep
Improvement with Congenital myotonic hypoventilation in Duchenne muscular dystrophy. Am
development dystrophy J Respir Crit Care Med. 2000;161(1):166–70.
Some congenital Hull J, Aniapravan R, Chan E.  British Thoracic Society
myopathies guideline for respiratory management of children with
neuromuscular weakness. Thorax. 2012;67:i1–i40.
Katz SL.  Assessment of sleep-disordered breathing
care, such as prolonged mechanical ventilation, in pediatric neuromuscular diseases. Pediatrics.
among other factors. 2009;123:S222–5.
Kennedy JD, Martin AJ.  Chronic respiratory failure
This has been related to improvements in the and neuromuscular disease. Pediatr Clin N Am.
quality of patients’ lives and their family envi- 2009;56:261–73.
ronment. However, the desired results are not Khirani S, Colella M, Caldarelli V, Aubertin G, Boulé M,
always obtained, and the psychological, social, Forin V, Ramirez A, Fauroux B. Longitudinal course
of lung function and respiratory muscle strength in
and financial burdens need to be evaluated in the spinal muscular atrophy type 2 and 3. Eur J Paediatr
framework of bioethics. The challenges and Neurol. 2013;17:552–60.
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in Duchenne muscular dystrophy. Pediatr Pulmonol.
ing to the pathologies and their prognoses. An 2014;49:473–81.
evident reduction in respiratory effort is Kwon YH, Lee HY. Differences of respiratory function in
achieved in some patients, improving the growth children with spastic diplegic and hemiplegic cerebral
and development of the pulmonary system, and palsy, compared with normally developed children. J
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tilation or making a transition to another more Outcome risk factors during respiratory infections in
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2012. PLoS One. 2013;8:1–9.
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siderations that rationally guide human actions lar disorders. Pediatrics. 2009;123:S219–21.
254 R. Escobar Henríquez and B. Chateau Infante

Vega-Briceño LE, Contreras I, Prado F. Evaluación respi- disorders—congenital myopathies, congenital mus-
ratoria de la enfermedad neuromuscular en niños. Rev cular dystrophies, congenital myotonic dystrophy and
Neumol Pediatr. 2007a;2(1):6–10. SMA (II). Neuromuscul Disord. 2004;14:56–69.
Vega-Briceño LE, Prado F, Bertrand P, Sánchez I. Soporte Yang ML, Finkel RS. Overview of paediatric neuromus-
ventilatorio no invasivo en enfermedades neuromuscu- cular disorders and related pulmonary issues: diag-
lares. Rev Neumol Pediatr. 2007b;2:15–20. nostic and therapeutic considerations. Paediatr Respir
Wallgren-Pettersson C, Bushbyb K, Melliesc U, Simonds Rev. 2010;11:9–17.
A.  Ventilatory support in congenital neuromuscular
 A Children with an Airway
Foreign Body
27
Jacques de Blic and Agustín León Cortés

Contents
Epidemiology...............................................................................................................   255
Clinical Presentation..................................................................................................   256
 enetration Syndrome..................................................................................................  256
P
The Acute Clinical Situation........................................................................................  256
Chronic Complications.................................................................................................  256
Radiological Study......................................................................................................   256
Treatment....................................................................................................................   258
Prevention....................................................................................................................   260
Sources.........................................................................................................................   260

Epidemiology obstruction by a foreign body, representing a rate

of 140 per 100,000 infants. A foreign body in the
Inhalation of a foreign body is a common cause airway is the most common cause of accidental
of morbidity and mortality among children. In death among children under 1  year of age.
2001, there were more 17,000 pediatric consulta- Although mortality has decreased with the devel-
tions in emergency rooms because of airway opment of bronchoscopy, it remains at 5–7%
according to a meta-analysis by Foltran et  al.
involving 174 multinational publications describ-
J. de Blic (*)
ing almost 40,000 cases.
Université Paris Descartes, Hôpital Necker Enfants While inhalation of a foreign body can occur
Malades, Paris, France at any age, the majority of cases (80%) occur
e-mail: [email protected] between the ages of 9  months and 3  years, and
A. León Cortés they are more common among males. At a
Pediatrics, Respiratory Diseases, Clínica Santa María, younger age, children are at greater risk because
Providencia, Chile
they explore their surroundings with their mouths,

© Springer Nature Switzerland AG 2020 255

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_27
256 J. de Blic and A. León Cortés

they lack molars to chew properly, their swallow- its importance may be minimized when an
ing–glottic function is still immature, and they asymptomatic period ensues following the acci-
often play, run, laugh, or cry with food in their dent. The most common reason for consultation
mouths. is coughing and, although the triad of a persistent
The diagnosis is delayed by more than cough, abolition of a lung murmur, and localized
24  hours in 50–60% of cases, typically in the wheezing has a good positive predictive value,
<3-year age group, because the penetration is not the absence of symptoms of penetration syn-
reported by the child and is not witnessed by an drome does not rule out the presence of a bron-
adult, and any accompanying respiratory sounds chial foreign body.
are attributed mainly to an infection. Thus, the
reason for consultation is coughing or wheezing
rather than a suffocation crisis. The Acute Clinical Situation
The nature of the foreign body varies accord-
ing to age and cultural habits. Organic foreign The clinical situation depends on the level of
bodies—usually dried fruit, but also nuts, beans, obstruction. Muscular retraction and/or cyanosis
rice, and popcorn—are most common in subjects indicate obstruction of the proximal airway.
at a younger age, representing up to 80% of cases. Laryngeal obstruction is manifested by a hoarse
Inorganic foreign bodies as varied as parts of cough, a muffled voice or dysphonia, hypersali-
toys, pen nibs, pins, stones, pearls, and others are vation, and a stridor with dyspnea. Tracheal
more common in children >3 years of age. The obstruction produces a stridor or wheezing on
high rate of inhalation of food as a foreign body both inspiration and expiration, sometimes with a
among infants and preschool children makes evi- thrill and bilateral diminution of a lung murmur.
dent the responsibility of adults in charge of chil- The most distal obstruction causes auscultatory
dren in relation to permitting access to potentially asymmetry, with a unilateral manifestation of
inspirable foods. hypersonority and wheezing, and a localized
Foreign bodies reach the bronchi in more than decrease in the lung murmur.
80% of cases, according to the different published
series, with a slightly higher preponderance of the
right bronchus after 2 years of age. While the less Chronic Complications
common larynx–trachea location can produce
potentially fatal asphyxia or severe respiratory Chronic complications occur if the foreign body
distress, bronchial foreign bodies can remain is not suspected and not removed, and remains at
asymptomatic for a variable duration, although if the bronchial level, which occurs especially
the foreign body is vegetal, the symptomatology when the penetration syndrome has gone unno-
usually does not last long, given the significant ticed or its importance has been minimized. The
inflammatory reaction that is triggered. manifestations are diverse, such as persistent
wheezing, asthma that does not respond to treat-
ment, chronic coughing (Fig. 27.1), atelectasis or
Clinical Presentation persistent or recurrent pneumonia (particularly in
the same area), a lung abscess, and hemoptysis.
Penetration Syndrome

Penetration syndrome refers to a coughing attack Radiological Study

with dyspnea, an inspiratory stridor, and cyanosis
in situations in which a child has put a solid In the case of a radiolucent foreign body, which is
object in its mouth. When penetration syndrome the most common type, localized hyperinflation
occurs, it does not always prompt immediate is the most evocative radiological sign (occurring
consultation with an emergency service, because in 30–60% of cases). This results from air trap-
27  A Children with an Airway Foreign Body 257

a b

Fig. 27.1  Bronchial sequelae of a foreign body. Anteroposterior chest x-ray of a 5-year-old child presenting with
chronic atelectasis in the left inferior lobe (a). Axial CT scan of the chest, showing bronchiectasis in the left lung (b)

a b

Fig. 27.2  Lung hyperinflation. Anteroposterior chest x-rays of a 4-year-old child during inhalation  (a) and during
exhalation, showing hyperinflation of the left hemithorax (b)

ping secondary to partial obstruction of the air-

way, where the foreign body represents a valve
that allows greater air passage on inspiration than
on expiration (Fig. 27.2). This sign is more evi-
dent on forced expiratory or lateral decubitus
radiography, which should be done systemati-
cally when there is suspicion of a foreign body.
Atelectasis is a product of complete bronchial
obstruction, particularly in the case of infants, in
whom reabsorption of distal air causes alveolar
collapse because of the absence of well-­developed
collateral ventilation. Other suggestive radiologi-
cal findings are mediastinal deviation, interrup-
Fig. 27.3 Radiotranslucent foreign body in the left
tion of an air bronchogram, and radiopaque source bronchi, with secondary left lung hyperinflation
foreign bodies, such as metal, bone, a tooth, or a
stone (Figs. 27.3 and 27.4). A normal chest x-ray why the clinical picture is the most important fac-
(which is present in up to 30% of cases) does not tor in deciding whether or not to perform
rule out the presence of a foreign body, which is bronchoscopy.
258 J. de Blic and A. León Cortés

The most universal therapeutic approach is

based on the degree of certainty about the pres-
ence of the foreign body.
Absolute certainty: There is absolute certainty
in the case of dyspnea or persistent coughing
after penetration syndrome, with asymmetry on
pulmonary auscultation, localized hyperinsuffla-
tion, or a radiopaque foreign body. In these cases,
the use of therapeutic bronchoscopy is indicated.
Most often, the clinical situation is stable because
the foreign body is located in the bronchi; thus,
removal can wait for the recommended fasting
Fig. 27.4  Radiopaque foreign body (a screw) in the right
time and to ensure the availability of the ideal
posterior basal bronchi equipment for extraction. On the other hand,
extraction is urgently required if there is severe
If the foreign body remains in the bronchi for respiratory distress, mediastinal diversion, mas-
an extended period, radiography may show atel- sive atelectasis, a pneumothorax, or, in the case
ectasis or bronchiectasis, the extent of which of a particularly harmful foreign body such as a
depends on the level of interlocking. battery, because it can cause tissue necrosis, or
The usefulness of computerized tomography spikes, that rapidly migrate distally.
(CT) and virtual endoscopy is debatable. It has Suspicion of a foreign body: In cases where
been suggested that these are indicated in cases there are few specific symptoms following pene-
of penetration syndrome with normal radiogra- tration syndrome (especially if the child was
phy, to avoid the anesthesia required for rigid symptomatic before the syndrome), or when the
bronchoscopy. However, in these cases, fiber chest x-ray is normal or there are chronic or
bronchoscopy evaluation under sedation is recurring radiological abnormalities, diagnostic
more advantageous than CT, which, in addition exploration by flexible bronchoscopy is per-
to involving a radiation dose and being less formed, which requires simple sedation
readily available, also does not show the nature (Fig. 27.5).
of the foreign body or the presence of granula- Most foreign bodies are extracted with use of
tion tissue, and thus has no therapeutic value. a rigid bronchoscope. This is the mandatory
method in an asphyxia crisis, where the foreign
body is in the larynx, subglottis, or trachea, and
Treatment where it is probably large or has an irregular sur-
face that anchors it to the walls. In this scenario,
Immediate action in response to penetration syn- rigid bronchoscopy offers high-caliber instru-
drome can result in dislodgement of the foreign ments for dealing with different types of foreign
body. In an infant, this involves slapping the bodies, together with good control of the airway
child’s back while he or she is being held with his during the extraction.
or her head downward, with or without chest Extraction with flexible bronchoscopy is also
compression. In an older child, the classic possible according to the experience of different
Heimlich maneuver can be performed. centers. In the largest series (described by Tang
Treatment in response to inhalation of a for- et  al.) involving 1027 cases between 2000 and
eign body is based on endoscopic extraction. 2008, which included children between the ages
There is no consensus as to the best anesthetic of 5 months and 14 years (average age 17 months),
protocol, but there is more support for having the 938 foreign bodies (91.3%) were extracted by
patient pharmacologically paralyzed than for flexible bronchoscopy, and only 34 (3.5%)
maintaining spontaneous ventilation. required use of a rigid bronchoscope after an
27  A Children with an Airway Foreign Body 259

Foreign
body

Child with background suggestive of FB aspiration

Present symptoms No symptoms

• Abnormal physical examination • Normal physical examination
• Chest X rays altered • Chest X rays are normal

Bronchoscopy Observation

Rigid Bronchoscopy if: Flexible Flexible if: Symptoms

• There is asphyxia • Abnormal physical examination
• FB is radiopaque • Chest X rays altered
• Deviation of the mediastinum
• Massive atelectasis
• Pneumothorax

Fig. 27.5  Algorithm for studying foreign bodies

attempt with a flexible one. The flexible broncho- should be available in case of failure with a flexi-
scopes that were used had external diameters of ble bronchoscope, because of which it is neces-
2.8–3.9  mm, with a 1.2  mm working channel. sary to have an operator familiar with both
The most commonly used extraction tools are techniques or to have two operators, usually a
basket forceps with three or four spiral strands, pulmonologist and an otolaryngologist.
and biopsy and mouse-toothed forceps, the most Periendoscopic morbidity is higher if the
popular being the basket forceps. A laryngeal foreign body remains in the airway for more
mask is currently considered to provide the best than 7  days (in particular, in the case of dried
control of the airway when a flexible endoscope fruit), a period during which more severe edema
is used, although it can also be introduced through and inflammation develop and the consistency
an endotracheal tube or a rigid bronchoscope. of the foreign body diminishes, making treat-
Flexible endoscopy may be preferable when ment more difficult. In this respect, it can be
dealing with a distal foreign body and particularly very difficult to dislodge a vegetal foreign body
in the upper lobules, which are difficult to access trapped in the granulated tissue that it triggers,
with a rigid endoscope. The consistency, size, and to which must be added possible loss of visibil-
shape of the foreign body should always be con- ity in the area of work because the inflamed
sidered in order to assess the risk of fragmenta- mucosa can easily bleed. Systematic applica-
tion or laryngeal interlocking during its extraction, tion of steroids for several days is recom-
which should be done in a way that keeps it intact mended, followed by antibiotics, before another
during its removal by the endoscope. The option attempt at extraction is made. Another consid-
of converting to extraction by rigid bronchoscopy eration is that if pressure is lost during the
260 J. de Blic and A. León Cortés

extraction and the foreign body falls into the • Training the general population in the classic
trachea, it should be pushed until it reaches the Heimlich maneuver and the modified maneu-
bronchi again. If the foreign body begins to ver for infants.
move and it lodges in the bronchi, it is prefera-
ble to invest 20 seconds in optimizing the per-
meability of the inflamed bronchus where the Sources
foreign body is located (using adrenaline,
lavage, aspiration) before attempting another AAP policy statement: prevention of choking among chil-
dren. Pediatrics. 2010;125:601–7.
extraction. Adaletli I, Kurugoglu S, Ulus S, et  al. Utilization of
The complementarity of rigid and flexible low-dose multidetector CT and virtual bronchoscopy
bronchoscopy should be emphasized. Together, in children with suspected foreign body aspiration.
they provide maximum yield and safety in the Pediatr Radiol. 2007;37:33–40.
Bhat KV, Hegde JS, Nagalotimath US, Patil
extraction, where the flexible bronchoscope con- GC. Evaluation of computed tomography virtual bron-
tributes the diagnostic certainty of a minimally choscopy in paediatric tracheobronchial foreign body
invasive procedure, the ability to remove a distal aspiration. J Laryngol Otol. 2010;124:875–9.
foreign body, and an easier and better view of the Boufersaoui A, Smati L, Benhalla KN, et al. Foreign body
aspiration in children: experience from 2624 patients.
airway following extraction. The need for a tho- Int J Pediatr Otorhinolaryngol. 2013;77:1683–8.
racotomy is becoming rare, but this procedure is Centers for Disease Control and Prevention (CDC).
done in cases with very distal migration of a for- Nonfatal choking-related episodes among children:
eign body in the airway. United States, 2001. MMWR Morb Mortal Wkly Rep.
2002;51:945–8.
Cohen S, Avital A, Godfrey S, et  al. Suspected foreign
body inhalation in children: what are the indications
Prevention for bronchoscopy? J Pediatr. 2009;155:276–80.
Fidkowski CW, Zheng H, Firth PG. The anesthetic con-
siderations of tracheobronchial foreign bodies in
Minimization of risks associated with children children: a literature review of 12,979 cases. Anesth
aspirating a foreign body is a responsibility Analg. 2010;111:1016–25.
shared by society, parents, and all adults with Foltran F, Ballali S, Passali FM, et  al. Foreign bod-
responsibility for children. Some important con- ies in the airways: a meta-analysis of pub-
lished papers. Int J Pediatr Otorhinolaryngol.
siderations are: 2012;76(Suppl 1):S12–9.
Foltran F, Ballali S, Rodríguez H, et  al. Inhaled foreign
• Educating the general population to avoid bodies in children: a global perspective on their epi-
children under the age of 3 years having access demiological, clinical, and preventive aspects. Pediatr
Pulmonol. 2013;48:344–51.
to objects or foods that can be inhaled because
Heyer CM, Bollmeier ME, Rossler L, et al. Evaluation of
of their shape and size. clinical, radiologic, and laboratory prebronchoscopy
• Expressly warning about the danger of findings in children with suspected foreign body aspi-
asphyxia through inhalation on the packaging ration. J Pediatr Surg. 2006;41:1882–8.
Karakoc F, Karadag B, Akbenlioglu C, et al. Foreign body
of risky foods (e.g., peanuts, popcorn, hard
aspiration: what is the outcome? Pediatr Pulmonol.
candies, and beans). 2002;34:30–6.
• Complying with recommendations regarding Karakoc F, Cakir E, Ersu R, et al. Late diagnosis of for-
age limits on toy packaging and not allowing eign body aspiration in children with chronic respi-
ratory symptoms. Int J Pediatr Otorhinolaryngol.
children under these age limits to have access
2007;71:241–6.
to toys with small parts. Kiyan G, Gocmen B, Tugtepe H, et al. Foreign body aspi-
• Not trying to abruptly remove an object from ration in children: the value of diagnostic criteria. Int J
a child’s mouth, as this can provoke crying, Pediatr Otorhinolaryngol. 2009;73:963–7.
Midulla F, Guidi R, Barbato A, et al. Foreign body aspira-
which in turn can result in the child aspirating
tion in children. Pediatr Int. 2005;47:663–8.
the object. Ramirez-Figueroa JL, et al. Foreign body removal by flex-
• Not feeding children while they are playing, ible fiberoptic bronchoscopy in infants and children.
laughing, crying, or frightened. Pediatr Pulmonol. 2005;40:392–7.
27  A Children with an Airway Foreign Body 261

Righini CA, Morel N, Karkas A, et al. What is the diag- Tang LF. Airway foreign body removal by flexible bron-
nostic value of flexible bronchoscopy in the initial choscopy: experience with 1027 children during
investigation of children with suspected foreign 2000–2008. World J Pediatr. 2009;5(3):191–5.
body aspiration? Int J Pediatr Otorhinolaryngol. WISQARS [Web-Based Injury Statistics Query and
2007;71:1383–90. Reporting System]. Leading causes of death reports,
Rodrigues AJ, et  al. Bronchoscopic techniques for 1999–2001. National Center for Injury Prevention
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Pediatr Pulmonol. 2012;47(1):59–62. leadcaus10_us.html.
 Epidemiology of Respiratory
Infections
28
Luis Avendaño Carvajal and Cecilia Perret Pérez

Contents
Viral Respiratory Infections........................................................................................  264
Diagnosis........................................................................................................................  266
 mergent Infections........................................................................................................  266
E
Pathogeny of Viral Infections.........................................................................................  267
Epidemiological Management: The Winter Plan......................................................  268
 pidemiology of the Most Frequent Bacterial Infections.........................................  269
E
Streptococcus pneumoniae.............................................................................................  269
Bordetella pertussis........................................................................................................  271
Sources...........................................................................................................................  272

The relationship between living disease agents— in the study and application of advances in indi-
viruses, bacteria, fungi, and parasites—and their vidual curative medicine.
human or animal hosts can be studied at different Epidemiology is the study of health at a human
levels. Biologists and biochemists analyze this population scale, including transmissible and
relationship at the molecular and cellular levels, nontransmissible diseases. It also considers dis-
and are constantly making advances in knowl- eases that affect animals. It analyses factors
edge about the pathogenesis of infections, as well depending on the agent, host, and environment
as diagnosis and control through use of vaccines that come into play in the population’s health. Its
and medicines. Clinicians play the leading roles contribution to the health field can be summa-
rized as the following goals:

L. Avendaño Carvajal 1. Collaboration with clinical and laboratory

Faculty of Medicine, Universidad de Chile, diagnosis: Epidemiology functionally defines
Santiago, Chile suspicious and confirmed cases, using specific
e-mail: [email protected]
laboratories with validated techniques.
C. Perret Pérez (*) 2. Prediction of the appearance tendencies of
Department of Pediatrics, School of Medicine,
infectious and noninfectious diseases: Epide­
Pontificia Universidad Católica de Chile,
Santiago, Chile miology provides a record of information and
e-mail: [email protected] an appropriate collection of samples.

© Springer Nature Switzerland AG 2020 263

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_28
264 L. Avendaño Carvajal and C. Perret Pérez

(a) Impact: Epidemiology describes mortal- ism from both school and work. Their seasonal
ity, morbidity, life-years lost through form of appearance and high infectivity place
death or disability, and other parameters viruses as being responsible for the majority of
to measure the impact of different agents; acute respiratory infections. According to post-
it also predicts the appearance tenden- neonatal mortality estimates, lower respiratory
cies of infectious and noninfectious tract infections cause 20% of deaths, with respi-
diseases. ratory syncytial virus (RSV) and influenza virus
(b) Pathogeny: Epidemiology analyses the being most common (9.5%). Advances in viral
successive stages of disease, considering diagnosis have confirmed the participation of
the source, transmission mechanism, por- viruses in respiratory pediatric pathology, with
tal of entry, human dissemination, defense frequencies that go from more than 50% (if they
mechanisms, and elimination from the compromise the lower respiratory tract) to 90%
community. (if they affect the upper respiratory tract). In
3 . Proposition and evaluation of measures of adults, the scenario of upper respiratory tract
control, including resource planning. infections is similar, but in lower respiratory tract
(a) Prevention: These measures include infections a predominance of bacterial etiologies
(i) vaccines, (ii) education, (iii) the envi- has been described. However, application of
ronment, (iv)  biosecurity, (v)  chemopro- molecular viral diagnosis shows significant par-
phylaxis, and (vi) passive immunization. ticipation of respiratory viruses in lower respira-
(b) Treatment: This involves application of tory tract infections. This fact acquires more
antibacterials, antivirals, antifungals, and relevance when considering the aging of a
other support measures such as oxygen population.
treatment or mechanical ventilation. Several viruses are included in the group of
“respiratory viruses” because they have the respi-
ratory system as a target organ. Nevertheless,
Viral Respiratory Infections other viruses can also compromise the respira-
tory system while a systemic infection takes
Several indicators illustrate the big global impact place (measles, chickenpox, enterovirus, hantavi-
that acute respiratory infections (ARIs) have on rus), especially in immunocompromised individ-
public health, through morbidity and mortality. uals (cytomegalovirus, herpesvirus, shingles).
According to the World Health Organization Furthermore, studies always show an important
(WHO), respiratory infectious diseases take first group of cases without a proven etiology,
place in the ranking of the burden of disease mea- although the number of such cases has dimin-
sured by years lost through death or disability ished with the application of molecular diagnosis
(disability-adjusted life-years (DALYs)). Lower techniques because many potentially pathogenic
respiratory tract infections represent the third agents are now being detected or discovered
leading cause of death in the world, after cardiac (Table 28.1).
and encephalic vascular illnesses; however, in The clinical manifestations of viral respira-
countries of low economic status, they take first tory diseases vary from asymptomatic cases to
place. fatal infections, with several intermediate sce-
Many regional or global estimates have identi- narios. Some viruses tend to produce infections
fied acute respiratory infections as a primary mainly in the upper respiratory tract (rhinovirus,
cause of ambulatory consultations, hospitaliza- coronavirus, adenovirus), while others can simi-
tions, and deaths. In Chile, they take second place larly compromise the lower respiratory airways,
and third place in the leading causes of death in with variable severity (adenovirus, RSV, meta-
children and adults, respectively. Furthermore, pneumovirus, influenza, and parainfluenza). In
several studies point toward them as the main general, it is an accepted fact that any respiratory
causes of ambulatory consultations and absentee- virus can compromise one or several levels of the
28  Epidemiology of Respiratory Infections 265

Table 28.1  Main causes of disease worldwide (World Table 28.2 Predominant viruses in the respiratory
Health Organization 2004) system
DALYs Total Varieties: types, serotypes,
Disease or injury (millions) burden (%) Virus genotypes, and other
1 Lower respiratory 94.5 6.2 Rhinovirus Species A, B, and C: >101
tract infection serotypes
2 Diarrhea 72.8 4.8 Coronavirus Alpha: 229E, NL63; beta:
3 Unipolar depression 65.5 4.3 OC43, HKU1, SARS, MERS
4 Cardiac ischemia 62.6 4.1 Respiratory syncytial A and B groups; genotypes and
5 HIV/AIDS 58.5 3.8 virus lineage
6 Encephalic vascular 46.6 3.1 Metapneumovirus A and B groups; genotypes
disease Adenovirus 55 serotypes
7 Prematurity 44.3 2.9 Influenza Types A, B, and C; subtypes A
8 Asphyxia and 41.7 2.7 H1–3, N1–2; several strains
neonatal trauma Parainfluenza 4 serotypes
9 Traffic accidents 41.2 2.7 Bocavirus ? 1 serotype
10 Neonatal infections 40.4 2.7 Others Hantavirus, enterovirus,
AIDS acquired immunodeficiency syndrome, DALYs measles, chickenpox,
disability-­adjusted life years, HIV human immunodefi- cytomegalovirus
ciency virus MERS Middle East respiratory syndrome, SARS severe
acute respiratory syndrome

respiratory system and cause clinical and sub- sonable certainty, considering associated clinical
clinical infections, but there is a certain prefer- cases and detection of viruses at sentinel sites.
ence of viruses for compromising specific levels Thus, a winter outbreak that involves infants
of the respiratory system (Table  28.2). In this under 1 year old and causes cases of obstructive
way, during an epidemic of a virus such as RSV bronchial illness will be due to RSV. A charac-
or influenza, the major proportion of upper and teristic trait of influenza is an epidemic of dis-
lower respiratory tract infections will be caused ease that is marked by fever, cough, headache,
by the prevalent virus. In addition, there will be and musculoskeletal aches, and that compro-
an important incidence of subclinical infections, mises preschool children, schoolchildren, and
which act as efficient sources of transmission. As young adults. Parainfluenza virus outbreaks are
a result of herd immunity, important epidemics associated with symptoms of hoarseness, gruff-
of multiple different viruses do not usually coex- ness, and cough, besides lower respiratory tract
ist in a community; instead, they alternate in infections, in infants. Adenoviruses are feared
terms of their presence in the community. For because they sometimes cause intense feverish
example, in Chile, the most commonly observed conditions and severe nosocomial infections.
pattern involves parainfluenza outbreaks, fol- Epidemiology contributes a lot to clarifying
lowed by influenza outbreaks, and then RSV out- these situations, because alongside defining “sus-
breaks; later, during winter–spring, picious cases” it implements diagnostic systems
metapneumovirus appears. Thus, the apexes of for circulating viruses (Fig.  28.1). The high
the epidemics follow one another and rarely infectivity of viruses makes epidemiological
overlap unless they affect populations of differ- information vitally important in etiological clini-
ent ages. This phenomenon of viral interference cal diagnosis, especially in terms of contact
may be explained by generation of interferon in between sick patients and their relatives or close
infected patients, which “interferes” with the people in the community. The two kinds of respi-
development of an infection of other viruses cir- ratory virus that have the greatest impact on
culating at the same time. global health are RSV, which affects infants and
These characteristics allow us to suspect spe- elderly patients, and influenzas A and B, which
cific causes of outbreaks or epidemics with rea- compromise all of the population. Vaccines and
266 L. Avendaño Carvajal and C. Perret Pérez

80
1994 1996 2000 2002
70 1989 1998
1990
60 1992 2001 2003 2004
1997
1999
50
1995
40
30

20
10

0
1 2 3 4 1 2 3 4 12 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

ADV RSV INFLUENZA PI

Fig. 28.1  Viral monitoring at Hospital Roberto del Río rescence in infants hospitalized for acute lower respiratory
(Santiago, Chile). Detection of respiratory viruses (adeno- tract infection in 1989–2004
virus, RSV, influenza, and parainfluenza) by immunofluo-

antivirals have been developed just for influenza ity and specificity, allowing appropriate study of
virus. cases that need it. Nowadays, molecular tech-
Viral respiratory infections are a very good niques (polymerase chain reaction (PCR) and
example of a model of acute viral infection, in reverse transcription PCR) are also available in
which viruses affect the individual, with or with- many laboratories; they have high sensitivity and
out symptoms, and then they leave him or her specificity, and provide results in less than
within a period of days or weeks. The course of 24  hours. The great sensitivity of these tech-
infection depends on the interaction of various niques enables detection of many agents, even in
factors depending on: (1)  the human host: age, the same sample, raising questions about their
immune status (based on previous infections and interpretation. In severe cases or in deceased
vaccinations), activity, tobacco use, etc.; (2) the patients, they should always be implemented to
virus: infecting dose, type, serotype, and viral establish the causes.
strain; and (3) the environment: season, weather,
humidity, contamination, geographical location,
rural/urban setting, hospital/community, etc. Emergent Infections
From the host standpoint, acute respiratory infec-
tions are more frequent in childhood, particularly Among respiratory viruses, very good examples
in infants and children under 2 years old, who of “viral emergencies” are found, the most classic
represent the group with the biggest serious risk. being the occurrence of global epidemics of
influenza  A virus derived from birds or pigs in
1918, 1957, 1968, and 2009; on these occasions,
Diagnosis the virus broke through the species barrier and,
thanks to multiple mutations, was able to transmit
Specific diagnosis of respiratory viruses is quite itself efficiently and establish itself as a “human
attainable nowadays because there are several virus.” A pandemic of severe acute respiratory
immunodiagnostic techniques (immunofluores- syndrome (SARS) due to a coronavirus is another
cence, enzyme-linked immunosorbent assay example of a phenomenon that has threatened the
(ELISA), immunochromatography) available at world and was able to be controlled. During
public and private centers. They are easy to August 2014, an outbreak of lower respiratory
implement, with reasonably acceptable sensitiv- tract infections in children, associated with
28  Epidemiology of Respiratory Infections 267

enterovirus D68, started in the USA, and its evo- Table 28.3  Respiratory syndromes
lution is ongoing. Likewise, an emergency Syndrome Responsible virusa
involving the Middle East respiratory syndrome Common cold Rhinovirus ++++
(MERS) coronavirus (MERS-CoV) started in Coronavirus ++
Saudi Arabia in 2012. Probably of animal origin Pharyngitis Adenovirus +++
Influenza virus ++
(camels and bats) and transmissible through air, it Parainfluenza virus ++
has caused over 900 cases (30% lethal); luckily, it Laryngitis Parainfluenza virus ++++
has not expanded efficiently in other territories. Influenza virus ++
Influenza Influenza viruses A and B ++++
Parainfluenza viruses 1–3 ++
Hantavirus
Pathogeny of Viral Infections Bronchiolitis Respiratory syncytial virus ++++
Metapneumovirus +++
Some viruses have certain particularities that Parainfluenza virus ++
require special consideration (Table  28.3). This Pneumonia Respiratory syncytial virus +++
Influenza virus ++
process is described considering a population as a
Metapneumovirus ++
host. There are over 200 respiratory viruses capa- Parainfluenza virus 3 ++
ble of infecting humans, with diverse structures— Adenovirus +
RNA or DNA, naked or enveloped—and although SARS virus
Hantavirus
they can be grouped into a few families, the great
Subclinical infection Any of the viruses listed above
variety of serotypes, genotypes, and strains that
SARS severe acute respiratory syndrome
can be identified entails the existence of many a
The number of plus symbols listed for each virus denotes
different potential pathogens. its relative degree of responsibility for the relevant
The source of infection is usually another syndrome
human carrier of the virus with or without an evi-
dent clinical infection. Even though viral shedding threats because of the emergence of animal
is greater in symptomatic cases, the relative isola- strains that have acquired the character of pan-
tion that viruses suffer when the host is resting in demics (e.g., SARS).
bed makes viral dissemination less efficient; in The infection mechanism works through
contrast, in slight or subclinical cases, despite respiratory secretions that are eliminated as big
eliminating smaller amounts of the virus in secre- particles (>5 μm in size), which remain both on
tions, patients continue doing their normal activi- the hands and in the environment (on aprons,
ties, actively contributing to viral diffusion. In toys, medical instruments, and furniture), or
many respiratory infections, preschool children small particles (<5 μm in size: Flügge droplets),
and schoolchildren are the main disseminators of which can form aerosols and stay suspended in
the virus because they satisfy the following two the environment. A sneeze or a cough can expel
conditions: shedding of high virus concentrations secretions at 65 km/h over a distance of 9 meters.
through secretions, and regular and close contact For some viruses, such as rhinovirus or RSV,
with their schoolmates and relatives. contact with contaminated hands represents the
Likewise, the chance of infection from ani- main form of transmission.
mals exists, as in hantavirus cardiopulmonary The upper respiratory mucosa is the portal of
syndrome, in which the source of the virus is a entry (including the ocular conjunctiva for some
rodent. Emergence of influenza pandemics viruses) and also represents the target organ of
always represents a latent threat because they these viral infections. Dissemination within the
have origins in avian or swine viruses. These new organism happens because of the contiguity of
strains have been able to adapt to the human host, the mucosa, contaminated secretions, or virus
converting him or her into a viral reservoir. Also, diffusion due to the proximity of infected cells
coronaviruses, which usually cause upper respi- and healthy cells. Even though the virus can
ratory tract infections, have represented global escape into the blood and other territories, this
268 L. Avendaño Carvajal and C. Perret Pérez

phase of viremia is not essential to the pathogeny Prevention of viral respiratory infections is diffi-
of the infection, and this is why respiratory virus cult because high infectivity is favored by the
are considered localized infections. presence of subclinical infections, human socia-
The following pathogenic facts explain five bility, and unavailability of vaccines, except for
basic clinical and epidemiological concepts influenza virus vaccines. Treatment is fundamen-
shared by respiratory viruses: tally symptomatic and essentially consists of
maintenance of the permeable airway, oxygen
1. The incubation time is very short, from hours administration, and assisted mechanical ventila-
to 5 days. tion in extreme cases. Use of antiallergics, anti-­
2. There is abundant production of the virus at inflammatories, steroids, bronchodilators, and
the portal of entry, which facilitates viral prophylactic antibiotics is very controversial, and
shedding and high infectivity. this is discussed in other chapters in this book.
3. Viral diffusion via mucosal proximity causes Antivirals are available just for influenza viruses
simultaneous and bilateral compromise of and, if they are administrated early, they shorten
more than one segment of the respiratory air- the symptomatic period but seemingly do not
ways and their annexes—for example, the prevent development of serious illness in high-­
paranasal sinuses and the middle ear. risk patients.
4. The defense mechanisms in play—both innate
and specifically acquired (immunoglobu-
lin A)—are mainly of a local character. Epidemiological Management:
5. Specific immunity is temporary and lasts only The Winter Plan
for some months (Table 28.4).
In countries with temperate weather, the inci-
dence of acute respiratory infections increases in
Table 28.4  Clinical and epidemiological consequences cold seasons because of the appearance of viral
of the pathogeny of respiratory viral infections
epidemics. RSV is the virus most responsible for
Consequences this and usually coincides with influenza out-
Transmission
breaks. In addition, respiratory adenoviruses
 Directly from person to person
 Through big droplets (>5 μm in size) deposited in appear endemically, with unpredictable increases
the environment (secretions on hands, clothes, that can acquire relevance because of their clini-
furniture, toys) and small droplets (<5 μm in size) cal seriousness and propensity to cause inpatient
that form aerosols
infections at times of overload in hospitals.
 Potential animal sources of influenza virus (birds,
pigs, and others) and hantavirus Despite prevention not being efficient and the
Portal of entry = target organ fact that there is no specific treatment for respira-
 Short incubation time, from hours to a few days tory viruses, health care (both public and private)
 High infection rate in the community can be organized for prevention of severe cases
Localized infection = local defense mechanisms prevail
 Innate immunity: epithelial barrier (cilia, coughing,
and deaths.
associated lymphatic tissue) and inflammatory RSV appears “all winter” and its outbreak lasts
response (leukocytes, macrophages, fever, cytokines) for 3–5 months. It has been estimated that 60% of
 Acquired immunity: local (immunoglobulin A) and children who are born are infected during the first
general (immunoglobulin G), T lymphocytes
CD8–CD4 (type 1 and type 2 helper T cells);
year of life, and all children have had contact with
short-duration immunity with frequent reinfections it by their second year; 25–40% of primary infec-
Propagation by proximity tions evolve as acute lower respiratory tract infec-
 In individuals, it simultaneously compromises many tions, and 2% of them require hospitalization.
levels of the respiratory system in a bilateral way
Influenza viruses usually appear in autumn in epi-
 In the community, it affects various members with
close contact within the family, at school, or at work; demics that last for 6–8 weeks. Accordingly, the
it is hard to contain with isolation measures or demand for pediatric care increases during every
physical barriers winter; the emergence of RSV dominates bed
28  Epidemiology of Respiratory Infections 269

availability for infants in hospitals and increases of oxygen. Institutional conventions are also
the need for ambulatory care, while influenza established for facilitating transfer of severely
viruses dominate consultations for preschool chil- ill patients.
dren, schoolchildren, and adults. • Ensuring the availability of cubicles for isola-
This increase in the demand for pediatric tion of individual patients (for admissions
ambulatory and hospital care forces us to adopt and for cases of suspected or confirmed
special measures for management of acute lower adenovirus).
respiratory tract infections—the most serious
pathology. They have to be implemented at both In Chile, these measures have been applied every
the ambulatory and hospital levels. The objective year since 1990, with great success in reducing
of this “winter campaign” is to prevent deaths deaths, though morbidity has not decreased,
from acute lower respiratory tract infections, and because that depends on the development of vac-
it should be directed preferentially toward those cines of high effectiveness (Fig. 28.2).
children and adults who are at greater risk of
developing severe illness.
At the ambulatory level, the campaign should  pidemiology of the Most Frequent
E
be focused on two aspects: Bacterial Infections

• Education of the population for recognition of Unlike respiratory infections with a viral cause,
serious symptoms (long-lasting fever, respira- infections of bacterial origin, while frequent,
tory distress, wheezes, apnea, etc.) to encour- affect a smaller group of the population, given
age early medical consultation, particularly in their characteristics in terms of pathogenicity,
higher-risk populations such as preterm transmissibility, and preventive measures such as
infants, chronic disease patients, immunosup- use of specific vaccines.
pressed patients, and, in general, patients In the following sections, we discuss the epi-
under 3 months of age. demiology of respiratory infections caused by
• Increased pediatric ambulatory care, including Streptococcus pneumoniae and Bordetella
prolongation of clinic hours (afternoons, pertussis.
nights) for pediatric and kinesiotherapy care,
increased availability of bronchodilators (sal-
butamol) and antimicrobial medication Streptococcus pneumoniae
(amoxicillin), and implementation of ambula-
tory oximetry and oxygen therapy. Pneumococcus is the main cause of bacterial
pneumonia in all age groups across the globe.
At the hospital level, the following measures are Its incidence varies according to the age
recommended: group, the development status of the country,
and employment of specific vaccines. It is
• Anti-influenza and antipneumococcal now by far the most frequent causal agent of
vaccination. pneumonia since the incidence of pneumonia
• Local implementation of rapid diagnosis of caused by Haemophilus influenza type B was
RSV, influenza, and adenovirus (using immu- reduced by introduction of a specific vaccine,
nofluorescence or ELISA). which practically made infections with that
• Reinforcement of medical and paramedical at causal agent disappear. The most relevant risk
emergency medical clinics and in hospital groups are infants <2  years old, adults over
emergency rooms and intensive care units. For 60 years old, and immunosuppressed patients.
this purpose, operating rooms are “repur- The WHO estimates that this agent causes the
posed” and realigned for attention to respira- deaths of 700,000 to one million people every
tory cases, with equipment for administration year.
 270 L. Avendaño Carvajal and C. Perret Pérez

3.5

2.5
Rate for 1,000 LB

ARI Program
2

ARI Program +
1.5 winter campaign
Expansion
ARI rooms
1

0.5
85 86 87 88 89 90 91 92 93 94 95 96 97 98

Fig. 28.2  Infant mortality due to pneumonia in Chile, 1985–1998 (Rev Chil Pediatr (2001))

In Chile, we know, with reasonable accuracy, cination period they were serotypes 15, 1, and 7F,
the epidemiology of invasive pneumococcal followed by serotypes 3, 19A, 6A, and 6B,
infections (meningitis, septicemia, bacteremia), although there were reductions in serotypes 15,
since they are under laboratory monitoring. 1, 5, and 6B. Since the introduction of vaccines,
Nevertheless, the great majority of pneumococ- the proportions of serotypes 3, 19A, and 6A have
cal pneumonias are not bacteremic, which is why increased in all age groups; those serotypes are
the incidence of pneumococcal pneumonia is not contained in the 10-valent vaccine but are
unknown; there are just data extrapolated from included in the 13-valent one.
monitoring of pneumonia in hospitalized patients, Susceptibility to penicillin in pneumococcal
assuming that pneumococcus is the primary infection is an emergent topic that greatly wor-
cause of bacterial pneumonia at any age. ries clinicians, although management of pneu-
Before universal vaccination with a pneumo- monias is not as important as management of
coccal conjugate vaccine was introduced, the pneumococcal meningitis. Since changes in the
incidence of this disease in Latin America was cut-off points in the definition of resistance to
between 61/100,000 in patients under 2 years old infections outside the central nervous system,
and 32/100,000  in patients under 5  years old, susceptibility to penicillin has remained low.
subsequently decreasing with age. Resistance to penicillin is greater in patients
In Chile, vaccination with a 10-valent pneu- under 5 years old than in other age groups, which
mococcal conjugate vaccine was introduced in is why this topic is more relevant to pediatric
2011 for children born since November 2010. populations.
Between 2011 and 2014 the rate of invasive The most recent report of the Chilean Public
infections in patients under 2 years old decreased Health Institute showed that the rates of interme-
from approximately 39/100,000 to 8.7/100,000, diate sensitivity to penicillin and cefotaxime
although there has been no impact of vaccination were 1–3% in the preceding 2 years, and the rate
in other age groups; on the contrary, an increase of resistance was 0%. When analyzed by age
in cases has been seen among patients over group, it was observed that for patients under
65 years old (Fig. 28.3). 5  years old, the rate of intermediate sensitivity
The most prevalent serotypes prior to the use was 4% for penicillin and 5% for cefotaxime
of vaccines were 5, 14, and 1. In the last postvac- between 2007 and 2014, with a 0% rate of resis-
28  Epidemiology of Respiratory Infections 271

900 25%

800
114 121
700 20%
139
120 103 92 45
77 41 42
600
104 100 50
90 15%
Nº of strains

500

Percentage of strains
400
22 10%
300 22

200
5%
100 168
149 123 136 141 113 156
86
0 0%
2007 2008 2009 2010 2011 2012 2013 2014
Years
< 12 m 12 - 23 m 24 - 59 m 5 - 14 y 15 - 29 y 30 - 49 y
50 - 59 y 60 - 64 y ≥ 65 y % < 12 m % 12 - 23 m % ≥ 65 y

Fig. 28.3  Confirmed cases of invasive pneumococcal disease in Chile

Rate for every 100,000 inhabs.

1400
Under 6 months
1200 6 to 11 months
1000 1 to 4 years
5 to 19 years
800 Over 20 years

600
400
200
0
2007 2008 2009 2010 2011 2012 2013

Fig. 28.4  Incidence of whooping cough in Chile

tance to these antibiotics. The rate of resistance to Its distribution is ubiquitous, with over 50 mil-
macrolides in the same age group reached 47%, lion cases and 300,000 deaths annually. The
while the rate of susceptibility to levofloxacin majority of the mortality is concentrated in
and vancomycin remained at 100%. patients under 1  year old, particularly in those
under 6 months old.
In Chile, during the early 1990s, a sustained
Bordetella pertussis increase in the incidence started to be registered,
starting from less than 4/100,000 and reaching
B. pertussis is a causal agent of respiratory infec- 25/100,000 between 1996 and 2000. After 2010
tions that pose a serious risk of mortality in young and 2012, a new increase in cases, with incidence
infants, especially those under 6  months old. rates of up to 35/100,000, was observed.
Thanks to the introduction of vaccines in the Incidence rates vary according to the age
1950s and 1960s, the incidence and mortality group, reaching the highest rate (136/100,000) in
rates have decreased significantly. However, infants under 12 months old and then dropping to
despite the high coverage rates for the vaccine, 19/100,000 in children between 1 and 4 years old
and although humans are the only reservoir for (Fig.  28.4). Cases in patients under 1  year old
B. pertussis, control and elimination of its circu- represent 42% of all notified cases and, of those,
lation have not yet been accomplished. 82% are under 6 months old.
272 L. Avendaño Carvajal and C. Perret Pérez

A feature shared by all of these epidemic infants, to reduce the risk of transmission in the
outbreaks is that mortality is concentrated in former and to reduce mortality in the latter.
young infants, who are not protected by the
primary scheme of three vaccine doses, which
is not completed until the child is 6 months of Sources
age.
Several studies on the source of infection of Avendaño LF, Palomino MA, Larrañaga C. Surveillance
for respiratory syncytial virus in infants hospitalized
B. pertussis in young infants have shown that the for acute lower respiratory infection in Chile (1989 to
main sources are intrafamily contacts. The vac- 2000). J Clin Microbiol. 2003;41:4879–82.
cine loses its effectiveness 5 to 7 years after the Bill & Melinda Gates Foundation Group. Global and
vaccination is completed, which is why adoles- regional mortality from 235 causes of death for 20
age groups in 1990 and 2010: a systematic analysis
cents and adults can be infected. for the Global Burden of Disease Study 2010. Lancet.
Since whooping cough does not always mani- 2012;380:2095–128.
fest as classic clinical cases in adolescents and Departamento de Epidemiologia, Ministerio de Salud.
adults but, rather, is characterized by a persistent Buscar influenza o infecciones respiratorias agudas,
por años de informes. http://epi.minsal.cl. Accessed
cough, suspicion levels are low and appropriate March 2019.
diagnosis is often not made; thus, there is no Girardi G, Astudillo P, Zúñiga F. El programa IRA
timely treatment. This situation facilitates infec- en Chile: hitos e historia. Rev. chil. pediatr. 2001;​
tion of infants within a family group. 72(4):292–300. ISSN 0370–4106.
Luchsinger V, Ruiz M, Zunino E, Martínez MA, Machado
On the basis of this epidemiology, between C, Piedra PA, Fasce R, Ulloa MT, Fink MC, Lara P,
2011 and 2012 the Capullo control program took Gebauer M, Chávez F, Avendaño LF.  Community-­
place in Chile, in which the entire family groups acquired pneumonia in Chile: the clinical relevance in
of newborns and vaccination of adolescents in the detection of viruses and atypical bacteria. Thorax.
2013;68:100–6.
the eighth grade was performed. In 2013 the inci- Mahony JB. Detection of respiratory viruses by molecular
dence dropped to less than 12/100,000, and in methods. Clin Microbiol Rev. 2008;21(4):716–47.
2014 the aggregated incidence reached Perret C, Viviani T, Peña A, Abarca K, Ferrés M. Fuente de
4.6/100,000. infección de Bordetella pertussis en lactantes hospitaliza-
dos por coqueluche. Rev Méd Chile. 2011;139:448–54.
These numbers show us that whooping cough Unidad de Epidemiología, Ministerio de Salud. Tos fer-
is a disease that affects all age groups, but its big- ina o coqueluche. Boletín Epidemiológico Trimestral
gest impact in terms of both morbidity and mor- 2014; 110(3).
tality is in patients under 6 months old. Valenzuela MT, O’Loughlin R, De La Hoz F, Gomez E,
Constenla D, Sinha A, et al. The burden of pneumo-
Multiple strategies have been tested interna- coccal disease among Latin American and Caribbean
tionally, but none of them have been very effec- children: review of the evidence. Rev Panam Salud
tive. A combination of different strategies seems Publica/Pan Am J Public Health. 2009;25(3):
to be the key, such as systematic and permanent 270–9.
Vigilancia de enfermedad invasora Streptococcus pneu-
vaccination in pregnant women, adolescents, and moniae. Chile, 2007–2014. Boletín de Instituto de
family groups. Creation of a vaccine with proven Salud Pública de Chile 2014;4(11).
high efficacy in controlling this disease in the World Health Organization. The global burden of disease.
short term has not yet been accomplished. 2004. https://www.who.int/healthinfo/global_burden_
disease/GBD_report_2004update_full.pdf. Accessed
Clinical suspicion is very important for appro- 15 October 2019.
priate treatment of cases, in both adults and
 Laryngitis (Croup)
29
Ida Concha Murray and Cecilia Perret Pérez

Contents
Epidemiology...............................................................................................................   273
Etiology and Physiopathology...................................................................................   274
Clinical Manifestations..............................................................................................   275
Severity Scores............................................................................................................   275
 ownes Score...............................................................................................................  275
D
Westley Score...............................................................................................................  275
Diagnostic Focus.........................................................................................................   276
Treatment....................................................................................................................   276
Etiological Treatment...................................................................................................  279
Hospitalization............................................................................................................   279
Indications for Hospitalization..................................................................................   279
Criteria for Patient Release from an Emergency Service.......................................   280
Complications.............................................................................................................   280
Specialist Follow-Up...................................................................................................   280
Summary.....................................................................................................................   280
Sources.........................................................................................................................   281

Epidemiology school children, with a 3:2 male-to-female

ratio.
Acute laryngitis (croup) is more common in the The causal agent is spread by direct person-
cold months of autumn and winter, but it can to-­person contact through sneezing, coughing,
occur throughout the year. It affects 2% of pre- and droplets of contaminated nasopharyngeal
­secretions on the hands. The most common eti-
ological agent identified in monitoring studies
I. Concha Murray ∙ C. Perret Pérez (*) of respiratory viruses is the parainfluenza virus,
Department of Pediatrics, School of Medicine, which is active throughout the year but usually
Pontificia Universidad Católica de Chile,
Santiago, Chile
has a higher incidence during winter (Fig. 29.1).
e-mail: [email protected]; [email protected] Serological studies have shown that 50% of
© Springer Nature Switzerland AG 2020 273
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_29
274 I. Concha Murray and C. Perret Pérez

children have acquired the parainfluenza virus and 200 nm, and has six proteins. There are four
by the time they are 1 year old. In terms of its types of parainfluenza virus, the most common of
incidence, it is generally the third most com- which are types 1–3. Types 1 and 2 generally pro-
mon virus after influenza and the respiratory duce acute or obstructive laryngitis, while type 3
syncytial virus (RSV), depending on the season. produces infections of the lower respiratory tract,
In infants under 1  year of age, it occupies such as bronchitis and pneumonia. Type 4 is less
second place for incidence (Fig.  29.2). Acute often detected and can cause upper and lower
obstructive laryngitis accounts for 7% of fever- respiratory infections.
and respiratory-related hospitalizations of chil- The HN glycoprotein adheres to the host cell
dren under 5 years old. Half of these situations and facilitates F  protein initiation of virus–cell
are due to parainfluenza 3.

Etiology and Physiopathology 6% 2%
VRS
The most common etiological agents are parain- 18% Influenza A
fluenza viruses 1 and 3. Less common agents are Influenza B
parainfluenza  2, influenza viruses A and  B, 54% 11% Parainfluenza
RSV, adenovirus, measles, and Mycoplasma Metaneumovirus
9% Adenovirus
pneumoniae.
Parainfluenza is a single-strand, enveloped
RNA virus that belongs to the Paramyxoviridae
family. It is pleomorphic, measures between 100 Fig. 29.2  Respiratory virus

450

400

350
Number of virus identified

300

250

200

150

100

50

0
Eno 2 3 4 5 feb 7 8 9 10 11 12 13 Apr 15 16 17May19 20 21 Jun 23 24 25 Jul 27 28 29 30Aug 32 33 34 35Sep 3738 39 Oct 41 42 43 Nov 45 46 4748 Dec 5051 52
1 6 Mar 14 18 22 26 31 36 40 44 49

Influenza A Influenza B Parainfluenza

Adenovirus VRS Metaneumovirus Month/Week epidemiology

Fig. 29.1  Vigilance against respiratory virus infections

29  Laryngitis (Croup) 275

membrane fusion. It also facilitates the binding Changes in the mental state occur in this phase,
of the nucleocapsid (formed by NP, P, and L pro- with agitation or lethargy. The patient is unable to
teins linked to the viral genome) to the genome of cry or speak, and there is no stridor and no air
the host cell, thus initiating viral replication. In entering the lungs, but there is a paradoxical
addition to its basic proteins, the parainfluenza movement of the chest, with signs of hypoxemia
virus expresses other proteins such as C, V and respiratory failure.
and  D.  V  and  C neutralize innate immunity Fortunately, the majority of cases of acute
through suppression of activity by interferon 1. obstructive laryngitis are mild and resolve within
Initially, the virus infects epithelial cells of the 7  days, although coughing can continue for
nose and oropharynx, and then it extends to the weeks.
cell cilia and bronchial epithelial alveoli, as well
as to the large and small airways. Viral replica-
tion peaks at 2–5 days and begins to decline by Severity Scores
the seventh day.
Cellular or tissue damage is fundamentally There are different severity scores to assess the
caused by the host response, with minimal direct seriousness of the clinical picture, such as the
cytopathic effects of the virus itself. It induces an Downes score and the Wesley score, the latter
innate immune response with production of CD4 being the most often used for studies.
and CD8, interferon, and local and systemic
immunoglobulin A and immunoglobulin G, all of
which contribute to elimination of the virus. The Downes Score
hyperresponsiveness that is often seen in patients
may be due to immunoglobulin E production and • Grade I—mild: stridor during crying or activ-
histamine release. ity, absence of retraction
The result of this process is diffuse inflamma- • Grade II—moderate: inspiratory stridor at
tion of the airway, with a greater intensity at the rest, suprasternal and intercostal retraction at
levels of the larynx and trachea, particularly in rest, but without agitation
the subglottic space. This causes a reduction of • Grade III—severe: major inspiratory or bipha-
the lumen and increased resistance to the entry sic stridor, with marked suprasternal and
of  air in the lungs, resulting in greater work of ­intercostal retraction, and with agitation; signs
breathing and appearance of the cardinal sign, a of respiratory difficulty
stridor. • Grade IV—imminent respiratory failure:
weak cough, altered level of consciousness,
signs of hypoxemia
Clinical Manifestations

After an incubation period of 2–7 days in the case Westley Score

of parainfluenza virus, the patient presents coryza
and a fever, which can be high or low, and in • Stridor:
24–48  hours the characteristic signs appear: a –– 0: absent
barking cough and a stridor. If the edema and nar- –– 1: during crying
rowing of the airway increase, the breathing rate –– 2: at rest
rises, the patient becomes increasingly more agi- • Retraction:
tated (to the extent that respiration is more diffi- –– 0: absent
cult), and the use of accessory musculature –– 1: slight
appears, with suprasternal drainage, intercostal –– 2: moderate
and subcostal retraction, and even cyanosis. –– 3: severe
276 I. Concha Murray and C. Perret Pérez

• Entry of air: Possible noninfectious causes are:

–– 0: normal
–– 1: reduced but audible • Foreign body in the airway
–– 2: very reduced, hardly audible • Airway trauma
• Cyanosis (O2  saturation <92%; fraction of • Congenital caustic injuries and/or scarring
inspired oxygen (FiO2) 0.21): (stenosis)
–– 0: absent • Spasmodic croup
–– 4: with agitation • Angioneurotic edema
–– 5: at rest
• Level of awareness:
–– 0: normal Treatment
–– 5: diminished
• Total score: 0–1 = mild; 2–7 = moderate; ≥8 = First, a rapid primary evaluation should be per-
severe formed to assess the patient’s awareness, stridor
intensity, and respiratory distress, using the
Downes score or Westley score and the patient’s
Diagnostic Focus hemodynamic parameters (distal perfusion, heart
rate, and blood pressure, among others). With
The diagnosis is clinical. A virus identification this, it is possible to determine if the patient
study is sometimes requested in severe cases, requires immediate therapy. The intensity of the
which can include a viral etiological study of a stridor can be used to classify the patient’s status
respiratory sample (either a nasopharyngeal as mild, moderate, or severe, in order to then
swab, nasopharyngeal aspirate, bronchoalveo- adopt an appropriate clinical management algo-
lar lavage fluid, or tracheal aspirate). The para- rithm for acute obstructive laryngitis (Fig. 29.3).
influenza virus can be identified by direct If the patient’s state of awareness is compro-
immunofluorescence or polymerase chain mised, there is severe retraction with no air entry
reaction (PCR). There are rapid immunochro- or with poor air entry at the pulmonary level, or
matographic tests for RSV, influenza, and the oxygen saturation is <92%, the patient has
adenoviruses. severe laryngitis (grade III–IV) according to the
X-ray examinations are done only when there Downes score or a Westley score of ≥8, and rapid
is suspicion of a differential diagnosis. intervention is required to avoid further
The airway is assessed endoscopically only in ­deterioration such as respiratory or cardiorespira-
severe cases in which an adequate response to the tory arrest. As a first measure, to reduce respira-
established therapy is not observed and signifi- tory difficulty, nebulized adrenaline (epinephrine)
cant obstructive symptoms persist after 48 hours should be administered in either a general form
of treatment. or a racemic form diluted in physiological serum,
Differential diagnosis: In general, the other with an air or oxygen flow of at least 6–8 l/min.
diagnostic alternatives are much less common Epinephrine reduces edema in the airway by
but, because they require other assessments and/ producing vasoconstriction, given its α-adrenergic
or treatments, the clinician should always keep effect. It has become the standard therapy for
them in mind, especially if the patient does not treatment of moderate and severe laryngitis.
evolve as expected. Traditionally, racemic adrenaline (composed of
The most common infectious causes are: the same proportions of L and  D isomers) was
used for treatment of acute laryngitis on the basis
• Bacterial tracheitis that its cardiovascular effects would be less than
• Epiglottis those of common adrenaline (L-adrenaline).
• Retro- or parapharyngeal abscess Three studies have confirmed a moderate to
29  Laryngitis (Croup) 277

Acute
obstructive
laryngitis

• Keep the children in a comfortable position with her/his parents

• Do not draw blood test
• Do not take chest x ray

Evaluate severity of respiratory disease, ABC

MODERATE (II)
SEVERE (III-IV)
MILD (I) Stridor at rest
Increased RF
No stridor at rest Normal or increased RF
Severe retraction
Normal RF Slight retraction
Air intake reduced
Normal O2 saturation Air intake reduced
O2 saturation £ 93%
Normal consciousness O2 saturation > 92%
Altered consciousness
Normal consciousness
Score 0-1
Score > 8
Score 2-7

Racemic adrenaline
Racemic adrenaline
nebulization (0.05 ml/kg, 1 ml
nebulization or normal
Oral dexamethasone or maximum) or normal (0.5
IV dexamethasone 0.6 mg/kg
betamethasone ml/kg) with 3-3.5ml of saline
Mask bag ventilation
(0.15-0.03 mg/kg, 4 mg solution
Intubation, if required
maximum) Oral dexamethasone or
Give ICU notice
betamethasone 0.03 mg/kg,
only once)

Soothe parents Wait 2-3 hours

Educate parents when they
seek a second visit
Send home
Ad-hoc instructive Improves Does not improve Improves Does not improve

ADMISSION
ADMISSION TO ICU
intermedio

Fig. 29.3  Algorithm for clinical management of acute obstructive laryngitis

major reduction in the severity score at 30 min- A small-scale study showed that common
utes after nebulization. This effect lasts for adrenaline is as effective as the racemic form if it
2 hours (level of recommendation: A). is used in an equimolar dose. The frequency of
278 I. Concha Murray and C. Perret Pérez

adverse effects is similar with use of either of the gas monitoring to show the severity of the obstruc-
two forms. Neither should be used according to a tion. If respiratory acidosis persists and the partial
schedule; rather, they should be used according pressure of carbon dioxide (pCO2) remains ele-
to need. There is a report in the literature of a vated, intubation is recommended. This is a dan-
previously healthy patient who had an acute gerous procedure in inexperienced hands, so it
myocardial infarction after three nebulizations should be done by the most expert member of the
within 1  hour. Vital signs should be monitored, team—ideally, an anesthesiologist.
and the nebulization should consist of a 0.05 ml/ Fortunately, moderately severe laryngeal
kg/dose with a maximum of 1  ml of racemic symptoms (grade  II or a Westley score of 2–7)
adrenaline, with the medication diluted in are more common, with a normal oxygen satura-
3–3.5 cc of physiological serum for a maximum tion of >92%, a stridor at rest, and a normal or
of 10 minutes with an air or oxygen flow of 6–8 l/ slightly elevated respiratory rate, which on aus-
min. The equivalency of racemic and common cultation is accompanied by decreased air intake.
adrenaline is described below: In this case, there is an indication to nebulize the
patient with adrenaline and give a dose of oral
• 2.25% racemic adrenaline = (L + D) adrena- dexamethasone (0.3 mg/kg) if the patient can tol-
line 22.5 mg/ml = L-adrenaline 11.25 mg/ml erate it. If not, it is administered intravenously or
+ D-adrenaline 11.25 mg/ml intramuscularly. If the stridor stops and the
• Common adrenaline 1/1000 = L-adrenaline patient is in good condition, which is usually the
1 mg/ml case, he or she should be observed for 2 hours to
• Consequently, racemic adrenaline 0.5  ml = ensure that greater respiratory distress (previ-
common adrenaline 5 ml ously known as respiratory rebound) does not
return. If the patient has no stridor 2 hours after
Secondly, 0.6 mg/kg of dexamethasone should nebulization, he or she can be sent home. If the
be administered venously. If there are hemody- stridor returns, nebulization with adrenaline can
namic alterations, 20  cc/kg of physiological be applied again, but if the stridor appears a third
serum is recommended. Patients should be moni- time, it is advisable to hospitalize the patient in
tored and watched, with adequate oxygenation an intermediate unit.
maintained above 94% through a reliable oxygen When patients have a stridor only when they
delivery system such as a Campbell mask with a cry or during physical effort, or if they have a
venturi system. A nonrebreathing mask is recom- history of a stridor (mild laryngitis grade I or a
mended in more serious cases. If an intense stri- Westley score of 0–1), only one dose of steroids
dor at rest returns or persists, the patient should is recommended, preferably oral dexametha-
be nebulized with adrenaline again. If this does sone (0.15–0.3  mg/kg) or its equivalent (beta-
not work, there have been reports that delivery of methasone) in an anti-inflammatory strength.
a mixture of helium with oxygen through a mask The patient can then be sent home with clear
has decreased respiratory difficulty. instructions to return if the stridor becomes
Helium is less dense than air and oxygen, and, permanent.
with use of a mixture of oxygen and helium, there The use of glucocorticoids has become a stan-
is less resistance to gas flow in narrow airways dard treatment for croup and has been supported
and hence less respiratory work. This option by numerous works: 30 randomized studies and
should be used only in units that have this gas controlled studies, and three meta-analyses (level
available and have experience in critical airway of recommendation:  A). Steroids improve the
treatment. Routine use of it is not recommended symptoms of obstructive laryngitis as fast as
(level of recommendation: C). within 6 hours and for up to 12 hours after treat-
Along with clinical evaluation of critically ill ment. They lower the Westley score at 6 hours and
patients, it is recommended to determine the 12 hours after being administered and reduce the
degree of compromise by, at least, venous blood number of consultations with emergency services,
29  Laryngitis (Croup) 279

the need for hospitalization, the use of adrenaline, have not been shown to be useful in clinical
the number and duration of intubations, and the studies.
need for reintubation in an intensive care unit. There have been no controlled studies of use
In a Canadian study that included administra- of antibiotics that have shown their utility.
tion of dexamethasone versus placebo in response
to mild croup, dexamethasone reduced the num-
ber of patients requiring further consultations Etiological Treatment
(7% versus 15%) and notably decreased the stri-
dor score at 48 hours. Consequently, dexametha- Treatment is generally symptom driven. There
sone is recommended for even mild croup. are no specific treatments for infections by para-
The standard dose of dexamethasone is influenza virus, RSV, or adenovirus. The pres-
0.6  mg/kg, but studies have shown the value of ence of laryngitis as the only manifestation of
lower doses (0.15–0.3 mg/kg), because of which infection by influenza virus or M. pneumoniae is
we recommend lower doses in mild to moderate very uncommon, and the impact of specific treat-
cases. ments in these cases has not been assessed.
These medications are equally effective when
administered parenterally or orally; thus, oral
administration is recommended except when the Hospitalization
patient is intolerant of it.
There have been no studies that support the It is recommended that the patient remains in an
use of repeated doses versus a single dose. Some intermediate unit during the first 24  hours to
authors recommend a repeat dose 24 hours later monitor airway stability and provide any neces-
if there have been no clinical improvements. sary treatment in a rapid and timely manner. The
Nebulized budesonide at 2  mg is equally patient’s condition can worsen to a point where
effective and is recommended in several English-­ emergency intubation is required, so the patient
speaking countries for moderate croup, but it is must be monitored. Given the degree of inflam-
not available in Chile. Budesonide can be mixed mation of the airway that is characteristic of acute
with adrenaline and administered together with it obstructive laryngitis, this is a more difficult pro-
in serious cases. cedure that should be performed by the most
Because an oral formulation of dexametha- expert professional available—ideally, an
sone is not available, a vial for injection can be anesthesiologist.
administered orally and has proven efficacy. The patient should continue to be nebulized
Betamethasone has the same potency and with adrenaline as needed and monitored in the
duration of action as dexamethasone, so it is a intermediate unit.
suitable replacement at equimolar doses. Oral There is no evidence recommending new
betamethasone comes in a 0.5  mg/ml presenta- doses of steroids, although some experts recom-
tion (Cidoten or Coritex), giving a dose of 0.15– mend repeat doses of dexamethasone after
0.3 mg/kg. Prednisone 1 mg/kg/day for 2–3 days 24 hours if the stridor has not improved.
can be used to give a comparative dosage in terms
of potency and duration.
In effect, the degree of benefit provided by ste- Indications for Hospitalization
roids in response to acute obstructive laryngitis is
so remarkable that if five patients are treated, an A patient should be hospitalized if respiratory
improvement in the symptoms of one of them will symptoms such as retraction and a stridor persist
be obtained (number needed to treat (NNT) = 5). or recur within 2 hours of therapy (two nebuliza-
Other therapies—such as cold vapor, nonste- tions with adrenaline and a steroid). When a
roidal anti-inflammatories, antitussives, and patient arrives at an emergency service in a seri-
decongestants—have been widely used, but they ous condition (with compromised awareness,
280 I. Concha Murray and C. Perret Pérez

cyanosis, or with a toxic appearance) or if evalua- treated vigorously with intravenous antibiotics
tion of the patient raises suspicion of bacterial tra- that cover Staphylococcus aureus, the most com-
cheitis or another serious differential diagnosis, mon causative organism.
he or she should be hospitalized. Infants and chil- Another feared complication is complete
dren who have acute obstructive laryngitis and obstruction of the airway, which can lead to
require oxygen, have poor ingestion of liquids, or respiratory or cardiorespiratory arrest and even-
are dehydrated should also be hospitalized. tual death or neurological sequelae. Therefore, it
The indications for hospitalization are rela- is essential that the patient’s first hours of hospi-
tive. How far away the patient is from a health talization are monitored adequately. Finally,
care center and how easy it is to get there should pneumonia is an uncommon complication and is
be taken into account when hospitalization of the usually a result of the same virus that causes
patient is being considered. It is also recom- laryngitis.
mended to hospitalize patients if the parents are
experiencing severe anxiety and have made
repeated visits to emergency services within the Specialist Follow-Up
last 24 hours.
Patients with a number of conditions should be
seen by an otolaryngologist and a bronchopulmo-
 riteria for Patient Release
C nary specialist to evaluate possible differential
from an Emergency Service diagnoses that can be confirmed or discarded by
fiber bronchoscopy, laryngoscopy, or other exam-
If the patient has minimal symptoms and does not inations. The conditions include a long-term stri-
have a stridor at rest, or after a period of observa- dor (lasting >1  week), severe acute obstructive
tion of 2–3 hours after one or two nebulizations, laryngitis, obstructive laryngitis with atypical
he or she can be sent safely home. This must be evolution, acute obstructive laryngitis in a child
carefully evaluated beforehand; the patient must under 3  months of age, or craniofacial
have normal oxygen saturation, show a normal dysmorphism.
level of awareness, have good intake of air into
the lungs, and be able to drink fluids.
The parents should be instructed as to what Summary
clinical conditions they should describe in any
subsequent consultation with an emergency ser- The prognosis of acute obstructive laryngitis is
vice. It is expected that around 5% of patients generally benign without sequelae when treat-
will present for another consultation because ment is timely.
their symptoms have worsened. If the patient has moderate to severe obstruc-
tive laryngitis, he or she should receive racemic
adrenaline or an equimolar dose of common
Complications adrenaline to relieve the obstructive symptoms
rapidly.
It is necessary to intubate fewer than 1% of hos- A single dose of a steroid is the standard ther-
pitalized patients with acute obstructive laryngi- apy for all degrees of laryngitis. If the patient has
tis, since there are now equally effective therapies good tolerance, the oral route should always be
such as nebulized adrenaline and steroids. chosen.
The appearance of bacterial tracheitis can If the patient is hospitalized, he or she should
complicate and aggravate an initial condition of be monitored for at least the first 24 hours in an
viral laryngotracheobronchitis and should be intermediate unit.
29  Laryngitis (Croup) 281

Sources Luria JW, et  al. Efectiveness of oral or nebulized dexa-

methasone for children with mild croup. Arch Pediatr
Adolesc Med. 2001;155(12):1340–5.
Beckmann KR, Brueggemann WM.  Heliox treatment of
Russell KF, Liang Y, O’Gorman K, Johnson DW, Klassen
severe croup. Am J Emerg Med. 2000;18:753–6.
TP.  Glucocorticoids for croup. Cochrane Database
Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson
Syst Rev. 2011;1:CD001955.
DW.  Nebulized epinephrine for croup in children.
Terregino CA, Nairn SJ, Chansky ME.  The effect of
Cochrane Database Syst Rev. 2013;10:CD006619.
heliox on croup: a pilot study. Acad Emerg Med.
Bjornson C, Klassen TP, Williamson RN, et al. Randomized
1998;5:1130–3.
trial of a single dose of oral dexamethasone for mild
Waissman Y, et al. Prospective randomized double-blind
croup. N Engl J Med. 2004;351(13):1307–13.
study comparing L-epinephrine and racemic epineph-
Fitzgerald DA. The assessment and management of croup.
rine aerosols in the treatment of laryngotracheitis
Paediatr Respir Rev. 2006;7:73–81.
(croup). Pediatrics. 1992;89:302–6.
Holmgren N, Concha I. El niño hospitalizado. Laringitis.
http://escuela.med.puc.cl/publ/pediatriaHosp/
Laringitis.html. Accessed August 2016.
 Bronchiolitis
30
Miriam Pérez and Giovanni Piedimonte

Contents
Historical Perspective.................................................................................................   283
Epidemiology...............................................................................................................   284
Pathogenesis and Physiopathology............................................................................   285
Microbiology...............................................................................................................   285
Clinical Manifestations..............................................................................................   290
Treatment....................................................................................................................   291
Prevention....................................................................................................................   294
Sources.........................................................................................................................   297

Historical Perspective end of 1930, the United States had witnessed sev-
eral serious outbreaks of respiratory diseases in
Bronchiolitis is the most frequent disease of the infants, which led John Adams to publish several
lower respiratory tract in infants and small chil- reports related to these epidemics, wherein he
dren. Its most common cause is respiratory syn- described the seasonal variety as well as the
cytial virus (RSV). In 1850, John Eberle physical and pathological manifestations of the
published the first medical description of acute disease, relating it to a viral infection.
bronchiolitis. He described a “catarrhal effect” in In 1955, some scientists from the Walter
children under 1 year old, which was accompa- Reed Army Institute of Research isolated a virus
nied by breathing difficulty, coughing, and from the nasal secretions of young chimpanzees
wheezing, similar to an “asthma crisis.” By the who had sneezing and mucopurulent rhinorrhea.
Having identified this new virus, which they
called “chimpanzee coryza agent,” they could
M. Pérez reproduce the same viral syndrome after having
Cleveland Clinic Children’s Hospital,
Cleveland, OH, USA exposed other chimpanzees to the same agent.
Robert J.  Chanock isolated the same virus in
G. Piedimonte (*)
The Cleveland Clinic at Cleveland, two children: one child had bronchiolitis and the
Cleveland, OH, USA other child had pneumonia that replicated in
e-mail: [email protected] ­cellular cultures and had the ability to produce

© Springer Nature Switzerland AG 2020 283

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_30
284 M. Pérez and G. Piedimonte

giant multinuclear cells, which are characteris- Epidemiology

tic of a massive syncytium, and therefore he
called it RSV. The World Health Organization (WHO) esti-
Chanock continued studying this disease, mates that RSV causes more than 60% of acute
and during the 1960s he published a more viral infections in children around the globe, and
detailed description of the epidemiology, recur- more than 80% of these infections appear in chil-
rent infections, and clinical manifestations of dren who are under 1 year old: this places it as the
RSV.  During this period, with collaboration most common cause of bronchiolitis and pneu-
with Robert Parrott, he started to develop a vac- monia in pediatric populations.
cine against this virus. The first tests using a Seasonal outbreaks during winter months hap-
formol-­ inactivated virus began in 1966. The pen each year around the world, but the begin-
vaccine was at first administered to the children ning, peak, and duration period of the season
of military personnel in Washington, DC, changes from one year to the next, and the out-
Colorado, and California. During the outbreaks breaks are very difficult to predict. In the United
of that year, infants who were vaccinated devel- States of America (USA) and in the Northern
oped infections at the same rate as those who Hemisphere, the outbreak generally starts in
had received a placebo, but a greater cause for November, reaching a maximum peak between
concern was that 80% of the children who January and February and ending in May.
received the vaccine had to be hospitalized Regional variability is significant, and subtropi-
because of bronchiolitis or serious pneumonia, cal zones such as Florida show a stable pattern
in comparison with only 5% of children in the during the year, with no seasonal predisposition
placebo group. and epidemic peaks that are difficult to predict.
In this study, two children who were vacci- Throughout the Southern Hemisphere, outbreaks
nated died, which caused serious concern relative are similarly present during the winter months.
to the safety of the following implemented clini- At 2  years of age, all children have been
cal trials that aimed to develop a new vaccine infected with RSV at least once, and half the chil-
against RSV, and to date there is no available vac- dren will have had two or more infections. In
cine. Nevertheless, it is important to highlight total, approximately 40% will develop an acute
that today there are several trials assessing the infection of the lower respiratory tract. It is esti-
administration to healthy children of intranasal mated that each year in the USA about 126,000
vaccines with attenuated live virus. These studies children (24.3 per 1,000) are hospitalized because
seek to prevent the onset of lower respiratory of bronchiolitis, and approximately 2% to 5% of
tract infections caused by RSV, and some of the them require mechanical ventilation. Even
vaccines are in preclinical and early clinical test- though this is a burden for the country, the num-
ing phases (including Phase I/II). bers in other parts of the world are also impres-
Up to today, investigation of RSV is still sive. At the worldwide level, it is considered that
being developed, but a great obstacle has been yearly 1 of every 200 children is hospitalized for
the lack of an adequate animal model to faith- treating bronchiolitis caused by RSV, with a
fully reproduce the clinical and pathological worldwide mortality rate that ranges from 5% to
characteristics of the infection in human beings. 25%. The infection has a great morbidity rate,
The virus only produces a clinically identical especially in preterm newborns (<35  weeks of
syndrome in chimpanzees, which is a very gestation), children with pulmonary chronic dis-
costly animal model, and therefore it is a great ease (for example, pulmonary dysplasia or cystic
limitation for research. The animal model has fibrosis), and in children with significant congen-
had a very important role in understanding the ital heart disease.
clinical progression of the infection caused by The maximum incidence of serious disease
this virus, as well as the safe development of appears between 2 and 3 months of age when the
experimental vaccines against it. infant reaches the lowest point of postnatal
30 Bronchiolitis 285

maternal immunoglobulin, which passes through and their subsequent inoculation via large respi-
the placenta during the last trimester of preg- ratory droplets in the nose or eyes. Small aerosol-
nancy. Because premature newborns miss this ized particles seem less likely to propagate the
window for IgG transplacental transfer, they are infection. The virus can persist intact on hard sur-
born with minimum humoral protection against faces (for example, counters) up to 6 h, on rubber
infections, if they have any at all, and this causes gloves up to 90 min, and in the skin as long as
increased risk of serious disease and hospitaliza- 20 min. Because of this prolonged survival rate,
tion in this age group. This risk is even greater measures such as handwashing and contact pre-
when a chronic pulmonary disease has pro- cautions are important to limit the propagation of
gressed, as well as any other illness that may the infection. The incubation period can vary
impair pulmonary functional reserve. from 2 to 8 days, and immunocompetent subjects
Other risk factors for serious disease include may excrete the virus up to 3 weeks, although on
male gender, overcrowding, lack of maternal average this is limited to 8  days. Excretion in
breastfeeding, and any other type of immunodefi- immunocompromised subjects may continue for
ciency. Besides numerous publications that have several months.
explored the role of environmental exposure to
tobacco smoke, there is still no definitive recom- During the past decades we have achieved a
mendation. RSV mortality in the world is greater better understanding of the physiopathological
than 1 million children per year. In infants under effects caused by RSV infection, which has made
1  year old, this rate is 10 times higher than the possible the developing and testing of new thera-
mortality rate related to influenza. Although there pies for the treatment of this disease. Particularly,
has been an important reduction in the mortality the purine ribosine rivabirin analogue was devel-
rate (from 4500 deaths in 1985 to 390 deaths in oped for the treatment of active infection caused
1999), the economic burden is still very high, and by RSV, as well as IV immunoglobulin. Both
the yearly hospitalization cost from bronchiolitis approaches were very promising in the begin-
is more than 700 million dollars. Infection caused ning, but they turned out to be very disappoint-
by RSV does not grant persistent immunity, even ing. Palivizumab, a humanized monoclonal
when there are significant antibody titers against antibody, has proven to be an effective and safe
the virus. Nevertheless, it has been proven that a method to prevent the serious presentation of the
high presence of antibody titers may alleviate the disease caused by this virus in high-risk infants.
course of the disease. Reinfection is very com- Currently, it is the only approved strategy for pro-
mon, and the disease can repeat itself in all age tection against the infection caused by RSV in
groups during the same epidemic. The first and this population. In developed countries, a remark-
second infection episodes usually appear during able reduction in the mortality caused by this
the first 2 years of life, and they tend to be more virus has been achieved, and this is in part thanks
serious. Most subsequent infections affect the to palivizumab use, in addition to the advances
upper respiratory tract and have a much more achieved relative to the supportive care for chil-
benign progression, although the disease may dren infected by this virus.
progress with more serious symptoms and respi-
ratory difficulty along with lower respiratory
tract compromise. Microbiology

Respiratory syncytial virus (RSV) is a single-­

Pathogenesis and Physiopathology stranded RNA virus that belongs to the
Paramyxoviridae, genus Pneumovirus (Fig. 30.1).
Transmission  Respiratory syncytial virus The virion is composed of a nucleocapsid con-
(RSV) transmission is mainly caused through tained within a lipid double layer, created from
direct contact with infected respiratory secretions the plasma membrane of the cell of the host. The
286 M. Pérez and G. Piedimonte

Fig. 30.1  Taxonomy of

Paramyxoviridae virus
VIRUS

Paramyxovirinae Pneumovirinae

Parainfluenza
Orthopneumovirus Metapneumovirus

hPIV-41 hSRV aMPV hMPV

Sendai bSRV
oSRV
Mice pneumovirus

nucleocapsid contains the viral genome, which present; however, it is still debatable if the sub-
consists of a single strand of nonsegmented RNA type A is related to more serious disease, and
and negative polarity, including 10 genes, which therefore it may be the cause of an increasing
code a total of 11 proteins. Eight of these func- number of cases admitted into the intensive care
tion as structural proteins and superficial glyco- unit.
proteins, and the rest directly handle viral
replication. Replication  Viral replication takes place at the
RSV, particularly, expresses two superficial beginning of the nasopharyngeal epithelium,
glycoproteins: fusion (F) protein and binding and it then propagates toward the bronchiolar
proteins (G). These glycoproteins are very impor- epithelium, where replication is much more effi-
tant in the virus lack of effectiveness and viral cient (Fig. 30.2). This progression can be caused
pathogenesis, and they are the main objectives of by the cell itself, through direct transmission
the host’s protective antibody production. G pro- from one cell to another, or through direct aspi-
tein regulates the binding to the cell of the host. ration of upper respiratory tract secretions.
Then, F protein allows the binding of the plasma Additionally, the virus can be propagated
membranes of the virus and the host, which through blood flow, or through the infection of
allows the virus to move into the cell. F protein inflammatory cells (monocytes, for example),
also promotes the fusion of its plasma mem- which can also cause the dissemination of the
branes, through which the virus can be transmit- disease in immunocompromised patients.
ted from one cell to another. An interesting note Nevertheless, in most cases the infection is lim-
is that these “syncytia” are rarely seen in  vivo, ited to the respiratory tract. Viral replication is
but they are commonly observed by in vitro viral followed by necrosis of the bronchiolar epithe-
detection. lium, which is accompanied by peribronchiolar
There are two generic subgroups of the RSV: lymphocytic infiltration and submucosal edema.
A and B. Within these subgroups there is great Mucus secretions increase in quantity and vis-
variability and a general antigenic reaction of cosity, and also mix with cellular detritus, which
approximately 25%, mostly caused by G pro- causes the blockage of small airways and also
tein, which shows only 1% to 7% of antigenic increases expiratory resistance, causing partial
activity. F protein is much less variable, with air trapping. With the combination of these fac-
approximately 50% of antigenic reaction. tors, the classic triad of wheezing, atelectasis,
During outbreaks, both subtypes are generally and hyperinflation is formed.
30 Bronchiolitis 287

Total cells RSV-infected

180
RSV 31.8%

Events
Nasal

0
100 101 102 103 104
FITC RSV

120
Events
Tracheal

RSV 33.2%

0
100 101 102 103 104
FITC RSV

180
Bronchial

Events
RSV 42.3%

0
100 101 102 103 104
FITC RSV

Fig. 30.2  Epithelial cell infection in the respiratory tract. susceptible to RSV infection. Flux cytometry data show
(a) Cells from human nose, trachea, and bronchial epithe- the percentage of fluorescent cells (infected) on each
lial cells after being infected with RSV GFP expressing panel in comparison to control cells (not infected) (shaded
(rgRSV) to 1 MOI (multiplicity of infection) for 48 h. The histogram). Data are expressed as median ± SEM (n = 4
clear field panels (left) show the total number of cells. The experiments). ∗∗∗P < 0.001 when compared to nasal or
green fluorescence color (center) represents those actively tracheal cells
infected with RSV. (b) Bronchial epithelial cells are more

Immune Response  Historically, it has been con- capacity to induce a protective response of the
sidered that the seriousness of the disease caused neutralizing antibodies.
by RSV is related to the intensity of the host
immune response. This perception comes from The infection caused by the RSV induces both
the postmortem examination of two children who humoral and cellular immune activity, and
died because of a pneumonia caused by this virus although this response does not achieve a com-
during the study of the formol-inactivated vac- plete response in relation to reinfection, it does
cine. These findings suggest that immunopatho- seem to reduce the seriousness of subsequent
logical mechanisms have an important role in the infections. In infants, high titers of neutralizing
serious presentation of the disease caused by antibodies against RSV, which come from the
RSV. Also, studies done in animal models have mother and are located in the umbilical cord
indicated an amplified immunity for Th2 and serum, are related to much less risk of hospital-
activated cytotoxic cells, which would be respon- ization because of bronchiolitis caused by this
sible for this response, although several aspects virus. This protection can also be obtained by the
of the physiopathology are still very controver- exogenous administration of specific immuno-
sial. Formol inactivation has been involved in globulin. Also, reduction of titers against RSV in
what seems to be the cause of the immunogenic- the serum has been linked to a significant increase
ity amplification of the specific viral antigen, in the risk of developing a symptomatic infection.
especially for the G protein of RSV. Nevertheless, Cellular immunity probably has a function in the
the inactivation also caused an alteration in the control of the active infection and the elimination
288 M. Pérez and G. Piedimonte

of the virus. This idea is highlighted by the obser- monocytic responses in the respiratory tract,
vation that immunocompromised subjects, whose when they have been infected by the RSV. This
cell-mediated immunity is reduced, tend to suffer finding suggests that neuroimmune interactions
a much more serious and extended RSV infec- created by neurotrophic pathways are very
tion; also, they eliminate the virus for longer peri- important in the systemic and local inflammation
ods of time. against viral pathogens. This important inflam-
A recent study offers an alternate explanation matory mechanism is to a great extent resistant to
of the physiopathology of serious diseases steroids, which would give a plausible explana-
caused by this virus. This study examined the tion for the poor therapeutic activity of these
autopsy samples of 20 Chilean children who drugs in children with wheezing induced by this
died of pneumonia with no intervention with virus.
mechanical respiration assistance. The authors
compared the results with those of other infants Mastocytes and Leukotrienes  Some studies in
who died of an infection caused by influenza, animal models indicate that RSV has a dramatic
and there was no evidence of an inflammatory impact on the number, distribution, and function
response in the most serious stage of the dis- of mastocytes in the mucosal respiratory tract
ease. There was no activation of cytotoxic T (Fig.  30.3). Histopathological examination with
cells, but there was significant apoptosis induced an antibody against tryptase has identified numer-
by epithelial detachment. The authors interpret ous mastocytes in the secretions originated in rat
that the serious infection caused by RSV is the lungs infected by RSV. The data show an increase
result of an insufficient adaptive immunity, and of approximately sevenfold in comparison to
the elimination of the virus still depends greatly noninfected control lungs. Further, most of these
on a less efficient innate immunity. mast cells were spatially closely related to nerve
fibers, which suggests that there may be a func-
Neuroimmune Interactions  Some recent stud- tional interaction in nerve cells that could be
ies have shown that RSV infection during the similar to what has previously been observed in
early stages of life promotes a great increase in other organs and systems, specially the central
nerve growth factor (NGF) and its receptors nervous system, gastrointestinal tract, and the
during the development of the respiratory tract, skin.
proteins that control the structural development
of peripheral neurons, both afferent and effer- Among the inflammatory mediators released
ent, and these cause changes in their functional by the mastocytes, the cysteinyl leukotrienes
activity in several ways that collectively define (CysLT) have been proven to cause inflammation
their “neural plasticity.” NGF overexpression of the respiratory tract, besides the contraction of
induced by RSV may cause changes in both the smooth muscle, during RSV infection, which
short and long term related to the distribution causes the wheezing observed in bronchiolitis.
and reactivity of sensorial and motor nerves Greater levels of LTC4 have been detected in the
through the respiratory tract. This change causes nasopharyngeal secretions of children who are
the unspecific hyperreactivity of the airway undergoing the acute phase of RSV infection,
before and after the infection, which can be and its concentration is related to the clinical seri-
increased by chronic exposure to environmental ousness of the disease, which is more severe
pollution. when the lower respiratory tract has been affected,
in comparison to children who only manifest the
Studies in animal models indicate that overex- disease in the upper respiratory tract. Another
pression in the NGF is crucial for the production clinical study showed that urinary LTE4 (the ter-
of mucosal edema, mediated by neurogenic minal product of the CysLT metabolism) is con-
response, as well as innate lymphocytic and siderable higher during bronchiolitis caused by
30 Bronchiolitis 289

*
a b 150

2
Mast cells / mm
100

50

0
Pathogen RSV
free infected

Fig. 30.3  Mastocytes in pulmonary tissue. Lung sections was found in the lung sections of rats infected with respi-
of weanling rats, killed 5  days after being intranasally ratory syncytial virus (RSV), in comparison to those who
inoculated with virus-free environment (a) or suspension were free of the pathogen (right). Inner scale  =  40  m.
(b). Mastocytes have been identified through immunohis- ∗P < 0.05 significantly different to the rats who were free
tochemistry, using a tryptase-specific monoclonal anti- of the pathogen
body. A sevenfold average increase in mastocyte density

Medical history Family history

300 120
*** Controls *
200 60
RSV LRTI
100 40
LTE4 (ng/mmol)

0 0
– Eczema + – Eczema + – Atopy + – Atopy +

* 300 **
160
120 200
60
100
40
0 0
– Cough + – Cough + – Asthma + – Asthma +
< 6 months ≥ 6 months < 6 months ≥ 6 months
Age Age

Fig. 30.4  Leukotrienes synthesis. Urinary excretion of tion of LTE4, clinical history of eczema or dry coughing,
LTE4 (terminal product of CysLT metabolism) is and/or a familial history of asthma, an intrinsic predispo-
increased in children with bronchiolitis caused by RSV sition to develop atopy, or hyperreactivity of the respira-
when compared to control samples with no respiratory tory tract. Age or atopy alone does not seem to affect
infection. Overproduction of CysLT shown by this marker leukotriene synthesis when there is no infection.
is accentuated in younger patients (<6  months old) ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 significantly differ-
infected with this virus. Further, the effect of the virus ent from the control group of the same age free from
seems to be amplified in infants with a higher concentra- respiratory infection

RSV in younger children (<6  months old) who but could also be an important factor in the link
have an atopic/asthmatic background (Fig. 30.4). between RSV and asthma.
As is already known, CysLT not only seems to Analysis of infected pulmonary tissue has
develop a crucial role in asthma physiopathology shown that the RSV effect in the leukotriene syn-
290 M. Pérez and G. Piedimonte

thesis is temporary. The maximum levels are

present during days 3 to 5 after the beginning of
the infection and then return to baseline state
after 30 days. These findings collectively suggest
that the acute inflammatory response of the respi-
ratory airways infected by RSV during the first
years of life involves releasing CysLT, as well as
the activation of the CysLT receptor. This effect
can be observed in the antiinflammatory effect
found in animal and human models in relation-
ship to the leukotriene receptor antagonists, such
as Montelukast. After the early phase of viral
respiratory infection, leukotriene production and
release quickly return to basal levels, but they can Fig. 30.5 Acute bronchiolitis. Chest X-ray obtained
be reactivated when there are irritants present in from a child with bronchiolitis caused by RSV shows
bilateral hyperinflation, irregular atelectasis, and peri-
the air (such as tobacco smoke), which can once
bronchial enlargement. Seriously ill patients may also
again stimulate the nerve nociceptive fibers con- present symptoms consistent with pneumonia, with inter-
nected to the numerous mastocytes, which are stitial infiltration areas
still present in the pulmonary tissue.
well as patients with cardiorespiratory disease or
immunodeficiency, are also at risk to suffer a
Clinical Manifestations serious infection of the lower respiratory tract.
Older children and healthy adults usually mani-
The RSV infection in children almost always fest symptoms compromising the upper respira-
causes clinical manifestations, although it may tory airway, but they may as well present with a
vary greatly in its seriousness, depending on the tracheobronchitis.
age of the patient, present comorbidities, envi- Apnea is a well-known complication of RSV
ronmental exposure, and history of previous in small infants and can be sufficiently serious to
infections. Infants generally present with symp- cause death. It affects about 20% of babies
toms related to the upper respiratory airway, younger than 6 months of age who have under-
such as congestion and rhinorrhea. These symp- gone hospitalization. It is frequently the first clin-
toms can progress in 2 to 4 days and involve the ical manifestation of virus infection, and its
lower respiratory tract, accompanied by cough, presence is not related to the seriousness of the
wheezing, increase of respiratory effort, and disease or other related symptoms. Because of
cyanosis. During auscultation, diffuse poly- this, it is believed that the virus may be involved
phonic wheezing and gross crackles can be in at least some cases of infant sudden death,
heard. Chest X-rays usually show bilateral which also shares several epidemiological simi-
hyperinflation, irregular atelectasis, and peri- larities with RSV infection, such as seasonal
bronchial enlargement (Fig. 30.5). impact and risk factors.
Patients undergoing serious involvement of Some studies suggest that infection by RSV
the lower respiratory tract can also show changes significantly prolongs the duration of central
on chest X-ray images that are more consistent apnea caused by a peripheral sensorineural stim-
with pneumonia, presenting areas of interstitial ulation reflex. The specific blockage of the cen-
infiltration. The resulting respiratory difficulty tral GABA-A receptors or the P (NK1) substance,
may differ greatly in seriousness, ranging from as well as their high-affinity receptors, suppresses
minimum to extensive, and it can even be fatal. the influence originated by the RSV infection in
Infants tend to be lethargic, lack appetite, and relation to the apnea caused by sensorineural
present with otitis media. Elderly patients, as stimulation. This finding suggests that the P
30 Bronchiolitis 291

s­ ubstance, released by the primary sensorineural Hospitalized infants reduce their nutrient
neurons in the nodose ganglion, activates second-­ intake because of respiratory difficulty and the
order GABAergic interneurons in the dorsal horn increase of insensible losses, and therefore they
at the medulla. This process inhibits the function may require volume and nutritional support.
of the medullary inspiratory neurons, which When there is significant respiratory difficulty in
causes the apnea. these patients, continuous oral feeding may
increase the risk of aspiration. If the patient can-
not tolerate oral feeding and enteral nutrition is
Treatment considered unsafe, a feeding tube, nasogastric or
orogastric, must be used to ensure that an ade-
Support Measures  Most children infected by quate amount of fluids and nutrition is being
RSV have a mild disease, which is self-limited, delivered.
and may only require symptomatic treatment that
consists of a close follow-up, especially related Pharmacological Interventions  Although many
to the progression of respiratory difficulty, oxy- efforts have been made to identify pharmacologi-
gen need, and hydration. Children who refuse to cal therapies that may improve the clinical pro-
be fed, who present with respiratory distress or gression of this infection, the most effective
need of supplemental oxygen, must be admitted treatment is still limited to the support measures
into the hospital for closer observation and more already mentioned.
aggressive management. Independently of where
the patient is being treated, the base of the treat- Bronchodilators  Bronchodilators are frequently
ment is always to provide support care: this used in infants with wheezing secondary to lower
includes respiratory assistance and an adequate respiratory tract infections caused by
management of liquids and nutrition. RSV. Nevertheless, their routine use is still con-
troversial, and most randomized controlled assays
Children whose oxygen saturation levels are have failed to find objective evidence of clinical
92% or less must receive oxygen through a ther- benefit. In a recent Cochrane review comprising
mal humidification system. Nasal obstruction is a 22 studies, which combined in total 1428 infants
very frequent problem, and considering that small with bronchiolitis, the efficiency of salbutamol in
children are compulsory nasal breathers, this can acute treatment was evaluated. The measured
cause a significant worsening of the respiratory results included improvement in the clinical score,
difficulty. Simple nasal cleaning using saline oxygenation, hospital admittance, and the dura-
solution drops as well as a suction bulb may tion of time in the hospital. The authors found that
improve respiratory function. Chest physiother- there was a minimally significant improvement in
apy is usually administered in an effort to mobi- the clinical scores of the children who received a
lize secretions and rescue the lung segments with bronchodilator treatment in comparison to those
atelectasis; nevertheless, the evidence shown by a who received a placebo, but this improvement
Cochrane systematic review does not recommend was not clinically relevant. In the same way, there
its use. Children with supplemental oxygen was no statistically significant improvement in
refractory hypoxemia, with persistent respiratory oxygenation, hospital admission rate, and length
difficulty, or who present with increasing respira- of stay in the hospital. The authors concluded that
tory insufficiency may require noninvasive sup- bronchodilators are not recommended for routine
port, continuous positive nasal pressure, or use in infants with bronchiolitis and a first wheez-
endotracheal intubation. Mechanical ventilation ing episode. An attempt to use bronchodilators
with positive pressure has been an important type while monitoring the patient may be justified, but
of treatment for children with bronchiolitis and the treatment must be suspended if there is no
significantly reduces the mortality rate. objective improvement. A Cochrane review that
292 M. Pérez and G. Piedimonte

intended to evaluate the efficacy of epinephrine, children randomly assigned to receive nebulized
through the comparison of albuterol and epineph- dexamethasone or saline solution. Both groups
rine versus placebo, including hospitalized and also received nebulized epinephrine. This study
ambulatory patients, concluded that the available did not show any statistically significant differ-
information does not support using epinephrine in ences in the clinical scores or in oxygen satura-
hospitalized patients. However, its use in ambula- tion. Nevertheless, there was significant reduction
tory patients may offer a modest short-­ term in the length of stay in the hospital for the dexa-
improvement, and therefore it would be prefera- methasone group, especially in the subgroup of
ble to use in comparison to albuterol or nebulized premature newborns. Another study carried out
saline solution for bronchiolitis treatment. by Plint et  al., which was conducted as a large
Anticholinergics have not proven to be effective multi-centric study, attempted to evaluate the
for treating bronchiolitis caused by RSV. hospital admittance rates after the administration
of treatment with oral dexamethasone and nebu-
Systemic Steroids  A systematic review of 13 tri- lized racemic epinephrine. This study showed
als including 1198 children under 30 months old that the combination therapy was efficient in the
with wheezing showed a reduction in the hospital reduction of hospital admittance rates. Some spe-
stay of 0.38 days per patient; however, it was not cific patient populations may benefit from a ste-
statistically significant. There were no differ- roid therapy attempt, depending on the personal
ences in the clinical scores of severity, respiratory medical history (eczema, atopy), family history
frequency, and oxygen saturation. Related to of atopy (parental asthma or atopy), and accord-
patients treated in the emergency department, ing to the atopic predisposition.
there was no difference in the rates of hospital
admissions. The authors warn about the signifi- Antivirals  The only licensed antiviral drug
cant heterogeneity of the studies included, as that can be used in the therapy of serious infec-
well as their results, which makes it difficult to tions caused by RSV is ribavirin, a synthetic
have a final analysis to interpret with confidence. nucleoside analogue with a broad-spectrum
However, the authors concluded that this therapy virustatic activity in vitro. The first studies were
offers no significant clinical benefit when com- promising, but a recent review conducted by
pared to a placebo, and therefore it is not indi- Ventre, which included 12 studies published
cated for this group of patients. between 1983 and 1999, showed only small
improvements with no statistical significance
Inhaled Steroids  Several studies have evaluated related to mortality, length of time for mechani-
the use of inhaled steroids in patients with bron- cal ventilation, clinical condition, or length of
chiolitis and have showed no significant benefit. stay in the hospital. Although ribavirin effi-
Bloom et al. carried out a Cochrane review of five ciently inhibits RSV replication in  vitro, its
studies, totaling 374 newborns, in whom they failure to do so in vivo is not surprising, because
evaluated the use of inhaled steroids to prevent the first clinical symptoms begin to appear
post-bronchiolitis wheezing. This analysis (acute rhinitis) toward the end of the virus
showed no reduction in the rates of wheezing or exponential replication in the lungs, and after
admission when systemic steroids were used, and this, a fast reduction of the virus titers can be
the same result was seen with the use of observed. For now, when the classical signs of
bronchodilators. bronchiolitis are diagnosed, few virus remain in
the lungs, while the immune response of the
Combination Therapy  Several studies have host is the predominant trait in the physiopa-
evaluated the usefulness of the combined admin- thology. Today, ribavirin is used to treat infec-
istration of steroids and nebulized racemic epi- tions caused by RSV by itself or combined with
nephrine. The results have been very promising. anti RSV antibodies, but only for some selected
A recent randomized clinical trial compared 61 immunocompromised hosts.
30 Bronchiolitis 293

Antibiotics  It is not unusual for children with the treatment with rhDNase as a mucolytic should
bronchiolitis to receive antibiotic therapy. It is yield some benefit. Nevertheless, a recent multi-­
estimated that antibiotics are used in 34% to 99% centric, randomized, placebo-controlled study
of the cases of non-complicated bronchiolitis. assessed the efficacy of rhDNase in 225 hospital-
This therapy is administered early during the ized children, who were oxygen dependent, and
treatment because the patient is febrile, but con- no actual benefit was found.
sidering the fever itself, viral infections cannot be
accurately differentiated from bacterial ones. As Hypertonic Solution  Hypertonic saline solution
a matter of fact, the risk of bacterial superinfec- has been previously used to improve mucociliary
tion in febrile infants with bronchiolitis is quite clearance in patients with asthma and cystic
low (0.2%), even when the body temperature is fibrosis, and it has drawn interest as a potential
greater than 39  °C.  Nevertheless, in the case of therapy for infants with bronchiolitis. A Cochrane
intubated infants with acute bronchiolitis, the rate review conducted in 2008 by Zhang et  al. dis-
of secondary bacterial infection is much higher, cussed four trials totaling 254 infants with acute
reaching 26%. bronchiolitis (189 hospitalized patients and 65
ambulatory patients) who received nebulized
When a secondary bacterial infection is diag- saline solution at 3% versus 0.9%, with or with-
nosed, the most common affected structures are out a bronchodilator. The primary results were
the urinary tract and the middle ear. In particular, related to the length of stay in the hospital for the
children with secondary infections tend to have admitted patients and admittance rates for ambu-
infections in the urinary tract, rather than a bacte- latory patients. This review concluded that nebu-
remia or meningitis (12% versus 0.43%). Acute lized saline solution may reduce by nearly 1 day
otitis media can also be seen as a complication of (25.9% reduction) the length of stay in the hospi-
the infection caused by the RSV (57–67%), but tal for infants who were already hospitalized in
its presence does not seem to impact the serious- comparison to infants who received placebo.
ness of the fever, respiratory difficulty, or the Considering the enormous financial burden that
global clinical progression of the disease. signifies the hospitalization of infants with bron-
A study that included 24 children with bron- chiolitis, for their parents and also for healthcare
chiolitis examined middle-ear aspirations and systems all over the world, its small cost makes it
confirmed the presence of RSV in the middle seem even more attractive.
ear of 17 patients. Bacterial pathogens were
also isolated in all the patients who suffered Surfactant  Beyond its function in reducing the
from acute otitis media. The most common superficial tension in alveoli and bronchioles,
were Streptococcus pneumoniae, Haemophilus with subsequent improvement of alveolar per-
influenzae, and Moraxella catarrhalis. Otitis meability and the small airways, surfactant has
media should be treated according to the cur- protein components (A and D) that bond to
rent recommendations of the American superficial markers, both viral and bacterial,
Academy of Pediatrics (AAP). facilitating the immune-mediated elimination. It
Antibiotics should be used in patients with has also been proven that surfactant protein D
bronchiolitis only when there is specific evidence promotes the production of free radicals in alve-
of a coexistent bacterial infection. olar ­macrophages. In the presence of acute
bronchiolitis, the production of these proteins is
Recombinant Human Deoxyribonuclease (rhD- reduced; these return to their normal levels after
Nase)  Because neutrophils are important for the disease resolution.
early immune response against RSV infection,
and the DNA released from its lysis is often The administration of exogenous surfactant to
found in the thick secretions present when there newborns with severe respiratory failure caused
is bronchiolitis, it seems reasonable to think that by bronchiolitis seems promising, and the several
294 M. Pérez and G. Piedimonte

meta-analyses that have been conducted to assess configuration of acute bronchiolitis, and they
this therapy have yielded encouraging results. A could possibly avoid or reduce the recurrence of
recent meta-analysis by Ventre et  al. included wheezing episodes post bronchiolitis. A small
three studies, totaling 79 patients. The authors pilot study involving hospitalized children with
reported a decrease in the length of mechanical acute bronchiolitis drew great interest and hope,
ventilation use and length of stay in the intensive but another recently finished study, which was
care unit. Besides this, it seems to show some larger, multi-centric, and double blind, found no
improvement in pulmonary mechanics and gas significant differences between montelukast and
exchange. It is important to note that available placebo in relationship to the symptom-free days.
studies are scanty and have small statistical It would be interesting to compare the effect of
power, so larger additional studies are needed. the antileukotriene therapy during the infection
Nevertheless, the treatment with exogenous sur- along with its prophylactic use before the RSV
factant does seem promising for patients who season, as well as its posterior effect on subse-
have severe respiratory failure secondary to quent asthma incidence.
bronchiolitis.

Heliox  Barach described for the first time the Prevention

use of helium for treating asthma and the obstruc-
tion of upper respiratory airways during the In the nonclinical setting, several interventions
1930s. Heliox is a mixture of helium and oxygen have proven to be effective in limiting the proba-
in a proportion of 70:30 or 80:20. Its theoretical bility of acquiring an infection caused by RSV.
advantage lies in the fact that it sustains the lami- Handwashing is probably the most effective way
nar flow, and therefore there is less turbulence in to prevent its propagation. Specific recommenda-
the airways, in comparison to air. In patients with tions for those who take care of high-risk babies
a disease of the lower tract airways, this trans- are advisable, as well as avoiding the exposure to
lates into ventilation improvement with reduced tobacco smoke and restricting the use of nurser-
work of breathing. Several investigators have ies during the yearly seasonal activity. Besides
studied heliox for the treatment of bronchiolitis. this, considering the available evidence relative
Some of the authors have obtained small improve- to the transmission of immunoglobulin from
ments in clinical scores, as well as a reduction in mother to child during breastfeeding, it is impor-
both tachypnea and the effort of breathing. The tant to support the recommendation for breast-
equipment needed to administer heliox is large feeding, especially for high-risk infants.
and cumbersome, which can make its use prob-
lematic. Also, as the therapy is more effective Immunoprophylaxis  To this day, only two prod-
when it uses high helium concentrations in rela- ucts have been developed for clinical use: IGIV-­
tion to oxygen, it would be minimally efficient RSV, which is a polyclonal hyperimmune
for patients who have significant oxygen needs. immunoglobulin, and palivizumab, which is a
The current evidence for heliox use in the treat- humanized monoclonal antibody. Motivzumab is a
ment of bronchiolitis is scarce, conflictive, and second-generation humanized monoclonal ­antibody
has small statistical power. that is still not available for commercial use.

Antileukotriene Drugs  As was previously dis- Immunoglobulin Against the SRV (IGIV-­RSV) 
cussed, strong experimental evidence in animal IGIV-RSV is a purified polyclonal human immu-
models and several clinical studies indicates that noglobulin, elaborated from donors with high
CysLT are released during the infection caused titers of neutralizing antibodies against RSV. In
by RSV, which contributes to hyperreactivity and high-risk infants who are premature or who have
the inflammation of respiratory airways. a chronic pulmonary disease, a significant reduc-
Therefore, it could be thought that leukotriene tion in hospitalizations was shown, as well as a
antagonists may have a therapeutic use in the reduction in the duration of the hospitalization
30 Bronchiolitis 295

period. Nevertheless, its use was also related to Palivizumab  The use of monoclonal antibodies
an increase in surgical morbidity and in the mor- has several advantages. These drugs tend to have
tality rate of children with congenital heart dis- no immunosuppressive effect in children, and
ease. As IGIV-RSV may interfere with the essentially they have no contagion risk for dis-
immune response to vaccines with attenuated eases transmitted by blood or other adverse
live virus, it is necessary to delay the administra- effects involved in the use of plasma. Besides
tion of the vaccine against measles, mumps, and this, these drugs tend to have greater titers of neu-
rubeola (MMR). The MMR vaccine can be tralizing antibodies, and therefore they can be
administered 9  months after the last dose of prepared in smaller volumes, which makes them
IGIV-RSV vaccine. The main disadvantages of appropriate for intramuscular administration in
using IGIV-RSV involved the need of a repeated ambulatory patients, or even at home, which
IV access, as well as a long IV infusion period eliminates the risk of fluid overcharge and the
(4–6 h), and therefore it requires medical super- subsequent need of diuretic rescue.
vision in the hospital. The administered volume
was also quite considerable: The recommended Palivizumab is an IgG1-humanized monoclo-
dose was 15 ml/kg, which importantly increases nal antibody developed using recombining DNA
the risk of fluid overcharge in babies, who are technology. It has been considered as a very suc-
naturally sensitive to fluids, and therefore treat- cessful treatment, which has placed it as one of
ment with diuretics was frequently needed. It the pioneers in the worldwide expansion and suc-
also had the potential to transfer pathogens cessful use of biological products. With this tech-
through blood flow, and the supply of eligible nology, specific complementary sequences of the
donors was not trustworthy. Another practical A antigenic site in the F protein of the mouse
disadvantage was the high combined costs, RSV are inserted within a human frame
resulting from the acquisition and supervised (Fig. 30.6). The effectiveness of pavilizumab lies
administration of this immunoglobulin. in limiting the spread toward the lower respira-

Mouse Human
monoclonal monoclonal antibody
antibody

-s-s-

-s-s-
-s-s-

Specific SRV Non-specific SRV

Specific humanized SRV

Fig. 30.6 Humanized monoclonal antibodies. This has a wide reactive activity to both RSV subtypes. The
schematic representation shows mouse-originated free substitution of 13 amino acid residues in the definition
sequences for the A antigenic site of F protein corre- complementarity regions of palivizumab originates
sponding to RSV inserted on a human IgG frame. The motavizumab, a second-­generation antibody, which has
result is palivizumab, an antibody that is considered to an affinity 70 times greater relative to the F protein
be human in 95% or more; it is not immunogenic, and present in RSV
296 M. Pérez and G. Piedimonte

tory tract. The Impact-RSV assay included 1502 90

preterm infants, who had been born before 80 78
35 weeks of gestation and/or who had pulmonary
70
chronic disease. The children were randomized
60 58
to receive either placebo or palivizumab as

% Reduction
monthly doses of 15 mg/kg IM, during the RSV 50
seasonal activity time. The children who received 40 39
palivizumab showed a reduction of 55% in hospi- 30 29
talization rate, and the hospitalization periods
20
were reduced from 62.6 days per 100 children to
36.4  days. A dramatic reduction in the clinical 10
score used to evaluate the seriousness of the dis- 0
ease was observed. Other reductions observed Preterm Infants Infants Infants
infants with BPD with with
were related to the use of the intensive care unit (without) acyanotic cyanotic
and supplemental oxygen. In spite of this, no dif- BPD) CHD CHD
ference was observed for the use of mechanical
Fig. 30.7  Palivizumab protection effects. Combined data
ventilation. Another multicenter clinical trial from the fundamental randomized clinical trials show that
evaluated the effectiveness of prophylaxis using palivizumab is a good protective agent for newborns without
pavalizumab. Included were 1287 children with borderline personality disorder (BPD), as well as children
significant congenital heart disease, for whom a with acyanotic congenital heart disease. In contrast, this pro-
tection is less dramatic in infants with bronchopulmonary
45% relative reduction rate in hospitalizations dysplasia or cyanotic congenital heart disease. It is also
was observed in comparison to the placebo worth noting that most of the post-­commercialization infor-
group. For acyanotic patients, a 58% reduction in mation suggests that the protection granted by palivizumab
the hospitalization rates was observed, and for may be substantially greater than the protection estimated
using the randomized clinical trials, but because there is no
cyanotic patients this reduction was 29%. control information, these data can be difficult to interpret
Therefore, combining the data of the aforemen-
tioned pivotal studies, we can conclude that pavi- bronchiolitis caused by the RSV in preterm
lizumab is an effective protection for preterm newborns, could later reduce recurrent wheez-
newborns without bronchopulmonary dysplasia. ing. A cohort of 191 preterm newborns who
This conclusion also applies for children with received palivizumab and who were not hospi-
significant acyanotic congenital heart disease. talized because of RSV was compared to 230
The protective effect of pavilizumab in infants preterm newborns who never received palivi-
with bronchopulmonary dysplasia or cyanotic zumab (76 of those were hospitalized because
congenital heart disease is less dramatic of RSV and 154 were not hospitalized). The
(Fig. 30.7). follow-up of these children lasted 24  months,
Palivizumab is usually well tolerated and is and their average age of the beginning of the
administered monthly as a 15 mg/kg intramuscu- follow-up was 19  months. The incidence of
lar dose during the RSV active season recurring wheezing diagnosed by a physician
(Table  30.1). Adverse events most commonly was approximately 50% lower in those subjects
reported are upper respiratory tract infections, treated with pavilizumab when compared to all
otitis media, fever, rhinitis, skin rash, diarrhea, the subjects who did not receive this treatment,
cough, vomiting, gastroenteritis, and wheezing. as well as the 154 patients in the subgroup who
An acute hypersensitivity may appear, but its were not hospitalized because of bronchiolitis
incidence is rare, with fewer than 1 anaphylaxis caused by the RSV.  This finding suggests that
case per 100,000 patients. using pavilizumab to prevent bronchiolitis
A recent study sponsored by the industry caused by RSV may reduce the subsequent
proposed the hypothesis that palivizumab, recurrent wheezing in preterm babies. This
through the improvement or early prevention of study needs to be repeated and confirmed in
30 Bronchiolitis 297

Table 30.1  Prophylaxis recommendations for respiratory syncytial virus (RSV) (Academy of Pediatrics, AAP)
1. Infants with chronic pulmonary disease under 24 months old who have received medical treatment within the
6 months after the beginning of the RSV season may benefit from a monthly dose beginning the first month of
the RSV season, totaling 5 doses.
2. Infants born before the 28th week of gestation can benefit from monthly doses, starting the first month of the
RSV season, totaling 5 doses.
3. Infants born between the 29th and 32th weeks of gestation, and who are under 6 months old at the beginning
of the RSV season, may benefit from a monthly dose beginning the first month of the RSV season, totaling 5
doses
4. Infants born between the 32th and 35th weeks of gestation, who are under 3 months old at the beginning of the
RSV season, and who attend daycare, or have a sibling who is under 5 years old, can benefit from monthly
doses until they reach 3 months of age. In this category, the maximum number of doses that may be
administered for this category is 3, and in many cases only 1 or 2 doses will be administered.
5. Infants with respiratory tract congenital anomalies and who are under 1 year old can benefit from a monthly
dose beginning the first month of the RSV season, totaling 5 doses.
6. Infants with neuromuscular disease who are under 1 year old can benefit from a monthly dose beginning the
first month of the RSV season, totaling 5 doses.
7. Infants with hemodynamically significant congenital heart disease and who are under 2 years old can benefit
from a monthly dose beginning the first month of the RSV season, totaling 5 doses.
8. Infants with serious immunodeficiency can benefit from a monthly dose beginning the first month of the RSV
season, totaling 5 doses.

larger samples, including term infants in double-­ talization from respiratory syncytial virus infection
blind protocols. Once this is done, a formal and in high-risk infants. The IMpact-SRV Study Group.
Pediatrics. 1998;102:531–7.
widespread recommendation could be done rela- Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS,
tive to RSV prophylaxis to independently reduce Wang SC, Dormitzer M, O’Grady J, Koenig S, Tamura
the incidence of postviral wheezing in infants. JK, Woods R, Bansal G, Couchenour D, Tsao E, Hall
WC, Young JF.  Development of a humanized mono-
clonal antibody (MEDI-493) with potent in vitro and
in  vivo activity against respiratory syncytial virus. J
Infect Dis. 1997;176:1215–24.
Sources Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA,
Stewart CE. An epidemiologic study of altered clinical
Bruhn FW, Mokrohisky ST, McIntosh K.  Apnea asso- reactivity to respiratory syncytial (RS) virus infection
ciated with respiratory syncytial virus infection in in children previously vaccinated with an inactivated
young infants. J Pediatr. 1977;90:382–6. RS virus vaccine. Am J Epidemiol. 1969;89:405–21.
Chanock R, Roizman B, Myers R. Recovery from infants Legg JP, Hussain IR, Warner JA, Johnston SL, Warner
with respiratory illness of a virus related to chimpan- JO.  Type 1 and type 2 cytokine imbalance in acute
zee coryza agent (CCA). I.  Isolation, properties and respiratory syncytial virus bronchiolitis. Am J Respir
characterization. Am J Hyg. 1957;66:281–90. Crit Care Med. 2003;168:633–9.
Gadomski AM, Bhasale AL.  Bronchodilators for Piedimonte G.  Neural mechanisms of respiratory syn-
bronchiolitis. Cochrane Database Syst Rev. cytial virus-induced inflammation and prevention of
2006;3:CD001266. respiratory syncytial virus sequelae. Am J Respir Crit
Hall CB, McBride JT, Walsh EE, Bell DM, Gala CL, Care Med. 2001;163:S18–21.
Hildreth S, Ten Eyck LG, Hall WJ. Aerosolized riba- Piedimonte G, Renzetti G, Di Marco A, Auais A, Tripodi
virin treatment of infants with respiratory syncytial S, Colistro F, Villani A, Di Ciommo A, Cutrera
viral infection. A randomized double-blind study. N R.  Leukotriene synthesis during respiratory syncy-
Engl J Med. 1983;308:1443–7. tial vi-rus bronchiolitis: influence of age and atopy.
Hartling L, Wiebe N, Russell K, Patel H, Klassen Pediatr Pulmonol. 2005;40:285–91.
TP. Epinephrine for bronchiolitis. Cochrane Database Sabogal C, Auais A, Napchan G, Suguihara C, Bancalari E,
Syst Rev. 2004(1):CD003123. Piedimonte G. Effect of respiratory syncytial virus on
Hu C, Wedde-Beer K, Auais A, Rodriguez MM, apnea in weanling rats. Pediatr Res. 2005;57:819–25.
Piedimonte G.  Nerve growth factor and nerve Shay DK, Holman RC, Newman RD, Liu LL, Stout
growth factor receptors in respiratory syncytial virus-­ JW, Anderson LJ.  Bronchiolitis-associated hospi-
infected lungs. Am J Physiol Lung Cell Mol Physiol. talizations among US children, 1980–1996. JAMA.
2002;283:L494–502. 1999;282:1440–6.
IMPACT-SRV.  Palivizumab, a humanized respiratory Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman
syncytial virus monoclonal antibody, reduces hospi- B. Respiratory syncytial virus bronchiolitis in infancy
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is an important risk factor for asthma and allergy at Walsh EE, Falsey AR, Hennessey PA. Respiratory syncy-
age 7. Am J Respir Crit Care Med. 2000;161:1501–7. tial and other virus infections in persons with chronic
Simões EA, Carbonell-Estrany X, Rieger CH, Mitchell cardiopulmonary disease. Am J Respir Crit Care Med.
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tory syncytial virus on subsequent recurrent wheez- Welliver TP, Garofalo RP, Hosakote Y, Hintz KH,
ing in atopic and nonatopic children. J Allergy Clin Avendano L, Sanchez K, Velozo L, Jafri H, Chavez-­
Immunol. 2010;126:256–62. Bueno S, Ogra PL, McKinney L, Reed JL, Welliver
Tortorolo L, Langer A, Polidori G, Vento G, RC Sr. Severe human lower respiratory tract ill-
Stampachiacchere B, Aloe L, Piedimonte G. ness caused by respiratory syncytial virus and
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Ventre K, Randolph A. Ribavirin for respiratory syncytial Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen
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 Community-Acquired Pneumonia
31
María Lina Boza Costagliola

Contents
Definition.......................................................................................................................  299
Epidemiology.................................................................................................................  299
Etiology..........................................................................................................................  300
Physiopathology............................................................................................................  301
Clinical Manifestations................................................................................................  301
Diagnostic Approach....................................................................................................  302
 hest X-ray.....................................................................................................................  302
C
Basic Laboratory Analysis..............................................................................................  303
Microbiology..................................................................................................................  304
Differential Diagnosis...................................................................................................  304
Treatment......................................................................................................................  305
 utpatient.......................................................................................................................  305
O
In Hospital......................................................................................................................  305
Antibiotic Resistance of Streptococcus..........................................................................  306
Complications...............................................................................................................  306
Prevention......................................................................................................................  306
Conclusion.....................................................................................................................  307
Sources...........................................................................................................................  307

Definition Epidemiology

Community-acquired pneumonia (CAP) is an In spite of the development of new antibiotics and

infection of the distal part of the breathing airway vaccines, community-acquired pneumonia is still
and the pulmonary parenchyma in the extra-­ a frequently occurring disease, which usually
hospital environment. presents in children under 5 years of age. It is one
of the main causes of mortality annually world-
wide, especially in developing countries: 2 mil-
M. L. Boza Costagliola (*)
Pediatrics, Respiratory diseases, University of Chile, lion deaths, of which 20% correspond to children.
Santiago, Chile In Chile, it is the main cause of pediatric hospital-

© Springer Nature Switzerland AG 2020 299

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_31
300 M. L. Boza Costagliola

ization during winter and spring, corresponding to 7% to 20% of lower respiratory infections in this
52% of hospital admissions to the hospital in the age group. In past years, rhinovirus and coronavi-
first 2 years of life. It is the first cause of late infant
rus have also been described as causing
mortality, with a 0.18/1000 ratio in children under community-­acquired pneumonia.
1 year old (2010), although it has experimented a Bacterial etiology increases with age: as many
dramatic decrease since 1990, when the mortality as 50% of hospitalized children are older than
rate of community-acquired pneumonia was 60% 5  years. Streptococcus pneumoniae causes the
(see Minsal 2013). Currently, the infection caused most common bacterial infection at any age,
by the human immunodeficiency virus (HIV) has about 20–30%. It is predominant during winter
increased the number of deaths caused by pneu- and spring times. Other bacteria include
monia (with a risk six times higher in comparison Haemophilus influenzae, which is a rare causative
to those not infected), particularly in underdevel- agent because of mandatory vaccination, although
oped countries. nontypified serotypes can cause serious presenta-
tions: Staphylococcus aureus, which has a quick
and serious progression, but currently is excep-
Etiology tional; and Streptococcus pyogenes, which has a
variable clinical course, but may cause serious
The biggest challenge in pneumonia is to deter- disease with shock and pulmonary suppuration.
mine the causative agent. The identification Other less frequent agents include Chlamydia
depends on such factors as age, disease severity, trachomatis, which is an infection acquired
immunological condition, geographic location, through the birth canal, with a clinical onset
year season, epidemiological situation, and between 2 to 12 weeks of life. It does not include
immunizations. Therefore, identification of the fever, but it does involve tachypnea, rhinitis, con-
causative agent varies between 10% and 85%, junctivitis, and coughing fits. A hemogram shows
depending on the method used. eosinophilia, and the chest X-ray is unspecific, but
Etiology differs according to the patient’s age. shows interstitial pattern predominance. Bordetella
In newborns, group B Streptococcus and gram-­ pertussis causes a whooping cough clinical syn-
negative bacteria are the most common agents; in drome and mainly interstitial pulmonary compro-
infants, the most common agent is usually a mise. Atypical agents such as Mycoplasma
virus, corresponding to 50% to 60% in Chile, for pneumoniae and Chlamydia pneumoniae are com-
example, whereas in developed countries this mon causes agents in children between the ages of
percentage increases to 80%. Among the viral 5 and 10 years, respectively (Table 31.1).
agents, respiratory syncytial virus (RSV) is the Coinfection with different pathogens is possi-
most frequent agent, and adenovirus causes the ble. The most frequent combinations are RSV or
most serious disease (B7h serotype). Among influenza virus with Streptococcus pneumoniae,
common etiological agents, we can mention in 30% of the cases, and Mycoplasma pneumoniae
influenza, parainfluenza, and metapneumovirus: with Streptococcus pneumoniae or Chlamydia
human metapneumovirus (hMPV) causes about pneumoniae in 15% of cases (Table 31.2).

Table 31.1  Etiological orientation for pneumonia

Etiology Bacterial Viral Mycoplasma
Age Any <2 years 5–15 years
Season All year Winter All year
Presentation Sudden Variable Insidious
Fever High Variable Low
Tachypnea Common Common Infrequent
Coughing + ++ +++
Related symptoms Chest pain Acute rhinitis, conjunctivitis Pharyngitis
31  Community-Acquired Pneumonia 301

Table 31.2  Etiological agents according to age

RN 1–3 months 4–24 months Preschool School
Virus
RSV + +++ ++++ ++ −
ADV − + ++ + −
Influenza − − + ++ +++
Parainfluenza − + + + −
Metapneumovirus − + + + −
Bacteria
Streptococcus pneumoniae + + ++ ++++ ++++
Mycoplasma pneumoniae − − + ++ ++++
Haemophilus influenzae − + + − −
Staphylococcus aureus + + + + +
Streptococcus agalactiae +++ + − − −
Escherichia coli and other gram-negative bacilli ++ + − − −
Chlamydia trachomatis − − − + +
Chlamydia pneumoniae − − + + ++
Streptococcus pyogenes − − − + +

Physiopathology always, with no functional compromise. Virus

cause epithelial damage which may progress to
The following factors protect the respiratory sys- necrosis and diffuse alveolar damage in varying
tem from infections: degrees. There is evidence suggesting that the
virus could be a factor for the increase of bacte-
1. Mechanics: nasal filter of inhaled air, gag rial infections, because it may take advantage of
reflex, cough reflex, and mucociliary the alterations of the mechanical or immunologi-
clearance cal barrier of the host.
2. Immunological, involving: alveolar macro-
phages, immunoglobulins, local inflammatory
response, complement, cytokines, antiprote- Clinical Manifestations
ases, lysozyme, fibronectins
3. Immune cellular response. The clinical picture fluctuates in seriousness and
depends on age, etiological agent, and extension.
Under normal circumstances, mucociliary The classic triad is fever, cough, and respiratory
clearance removes efficiently inhaled agents; distress Nevertheless, cough may appear later,
however, if the inoculum is big, the agent is espe- because there are a few receptors in the lower air-
cially aggressive, or the defense mechanisms are ways that are only irritated when cellular lysis
altered, the pulmonary parenchyma will develop and inflammatory exudate appear.
an infection. The inhalation of infectious agents In the newborn, when there is a history of pre-
(virus or bacteria), or the aspiration of germs mature membrane rupture related to respiratory
through the mouth and upper airway (bacteria), is distress during the first hours of life, along with
common. Contiguous hematogenous spread or cardiovascular collapse, group B Streptococcus
endogenous reactivation, as in tuberculosis, is must be suspected. Infants under 3  months old
rare. frequently present with tachypnea, usually above
Bacteria cause alveolar damage accompanied 60 breaths per minute, along with a retraction of
by inflammatory exudate, edema, fibrin, and the soft chest structures. This is frequently asso-
afterward, invasion of polymorphonuclear leuko- ciated to unspecific symptoms such as hypother-
cytes. General resolution is complete almost mia, hyperthermia, fatigue food intolerance,
302 M. L. Boza Costagliola

somnolence, diarrhea, or apnea. High fever must with viral pneumonia or, in children over 5 years
alert the clinician to rule out septic shock second- old with atypical pneumonia agents such as
ary to a respiratory infection. Mycoplasma pneumoniae. A normal respiratory
In older infants, there is usually a history of examination does not rule out pneumonia, espe-
upper airway symptoms with coughing and rhi- cially during the first 48  h, named the “silent
norrhea. Soon after, fever, tachypnea (>50/min), period.”
general status deterioration, and grunting and
nasal flaring appear. High fever, especially in those
under 2 years old, can be related to the seriousness Diagnostic Approach
of the disease, although it is not a sign that can be
used to determine a specific etiology. Preschool Diagnosis suspicion is mainly clinical.
and school-age children present with high fever,
accompanied by shivers, coughing, and chest pain
(pain resembling a side stitch). Abdominal pain Chest X-ray
may be present when there is compromise of the
inferior lobules, and often acute appendicitis must No routine chest X-rays are needed for the diag-
be ruled out, particularly in school-age children. nosis in the ambulatory setting, and administra-
Pain in the shoulder area suggests pleural compro- tion of treatment must not be delayed. However,
mise. Dry or productive cough, rhinorrhea, general the chest X-ray is considered the gold standard to
discomfort, headache, myalgia, and abdominal confirm the diagnosis of community-acquired
pain are nonspecific signs that may or may not pneumonia, except when acquired very early
accompany bacterial and viral infections. Physical (24 h) in the clinical progression when sensibility
examination results vary and fluctuate depending is low.
on the age of the patient. Tachypnea is a very sen- Chest X-rays do not differentiate among bac-
sitive sign in patients under 5 years old. Younger terial, viral, or atypical agents, but a lobar con-
infants and newborns present with reduced breath densation pattern suggests bacterial infection and
sounds but only a few crackles. Condensation syn- an interstitial pattern suggests viral or atypical
drome—bronchophony, dullness when percussing, agent infection (Figs.  31.1 and 31.2). Chest
bronchial murmur, and fine crackles—is fre- X-rays are best when used to rule out pneumonial
quently present in children over 2  years of age. complications such as empyema or abscess.
Crackles have a sensitivity of 75% and specificity When the clinical picture shows a persistent fever
less than 60%. Wheezing may be present in infants after starting antibiotic treatment and/or dullness

Fig. 31.1  Consolidated pneumonia

31  Community-Acquired Pneumonia 303

Fig. 31.2  Interstitial pneumonia

Fig. 31.3  Rounded pneumonia

when percussing the chest, which can be pre- echography is useful when there is a suspicion of
sented as an acute respiratory difficulty syn- effusion to evaluate the amount and presence of
drome, accompanied by hypoxemia, and/or septa or recollection areas.
hemodynamic instability, a chest X-ray is manda-
tory. This test also must be considered in patients
with no response to treatment, lobar atelectasis, Basic Laboratory Analysis
round-shaped consolidation, persistent symp-
toms, and complicated pneumonia. White cell blood count, neutrophil count,
A chest X-ray follow-up at 4 weeks must be C-reactive protein, sedimentation rate, and pro-
done in cases of recurrent pneumonia, lobar atel- calcitonin are not useful to identify the etiology.
ectasis, suspicion of malformation, or Several prospective studies have proven that
­slow-­resolution pneumonia (Fig.  31.3). Chest acute-phase reactants have a low sensitivity and
304 M. L. Boza Costagliola

specificity when it comes to distinguishing urine antigen with acute-­phase reactants may be a
between a viral or bacterial infection. good predictor for bacterial pneumonia. The effec-
tiveness of the immune complex for Streptococcus
pneumoniae has shown better specificity and sen-
Microbiology sitivity to diagnose Mycoplasma pneumoniae, and
for Chlamydia pneumoniae serum tests such as
Microbiological identification does not have any IgM are used. They have the limitation of allowing
clinical impact for most children with community-­ the diagnosis only after the first week, and there-
acquired pneumonia. Nevertheless, for patients fore they are not useful for early diagnosis.
undergoing the most serious course and/or hospi- Protein chain reaction (PCR) technique has a
talized, etiological investigation is important. 73% sensitivity and a specificity of 94%, so the diag-
When facing the possibility of a viral etiology, nosis can be done early and rapidly within the pro-
direct immunofluorescence (DIF) or ELISA tests gression of the disease. Invasive methods such as
are useful, although it must be considered that for bronchoalveolar lavage (BAL) may have better
adenovirus the sensitivity is not greater than 50% results, but their indication for community-­acquired
in most cases. DIF on incubated cells (shell-vial pneumonia is restricted to patients with a compli-
technique) yields better results. It is advisable to cated course, generally with a poor response to
request this technique in cases having negative empirical treatments, and when serological or fast
results with a high clinical suspicion. Currently, microbiological methods (PCR, ELISA, DIF) have
the amplification of specific viral genome frag- failed to yield a diagnosis. These observations are
ments has a high sensitivity and specificity. It uses especially true for i­mmunocompromised patients
minimum quantities of DNA, with the simultane- presenting with feverish neutropenia, lymphopenia,
ous detection of multiple virus; it is easy to stan- AIDS, or bone marrow or another organ transplant.
dardize, with quick results (8 h), and therefore it is When treating these patients, especially those in
very useful in hospitalized patients. When facing whom Pneumocystis jirovecii is suspected, it is sug-
the possibility of a bacterial infection, hematic cul- gested to obtain an induced sputum sample, which
tures have a low positive rate, so they are consid- can be a noninvasive method that may be effective
ered only for patients who show poor clinical and secure in relationship to bronchoalveolar lavage.
response. In infants, hematic culture yields poorly
(around 2%) but it is similar in older children
(about 10%). In patients with pleural effusion, Differential Diagnosis
direct pleural space, Gram stain, and culture are
less than 30% positive. Nevertheless, cytochemi- It is difficult to make an etiological differential
cal analysis can help to precisely locate an empy- diagnosis in pneumonia. For some recurrent events,
ema. In older children, Gram stain and other diseases may explain its origin (Table 31.3).
expectoration culture may be useful when there
are agents that differ from those that usually colo- Table 31.3  Pneumonia differential diagnosis
nize the upper airway, particularly when its intra- Recurrent pneumonia: same Foreign body
cellular location corresponds to macrophages or location aspiration
polymorphonuclear leukocytes. To validate the Pulmonary
malformation
sample, it is necessary to have at least 25 white Recurrent pneumonia: Cystic fibrosis
blood cells and fewer than 25 epithelial cells per different location Chronic aspiration
field. Serum antigen detection for Streptococcus Immunosuppression
pneumoniae and Haemophilus influenzae in blood, Noninfectious pneumonia Gastric content
urine, or pleural effusion liquid has a low specific- aspiration
Hydrocarbon
ity and sensitivity, yielding false-positives in naso-
aspiration
pharyngeal colonization or in patients who have Lipid aspiration
recently received immunization, and therefore Pneumonia in Noncommon agents
they are not recommended. The combination of immunodeficient patients
31  Community-Acquired Pneumonia 305

Treatment should be used as follows: 200,000 U/kg/day

IV every 12  h (maximum of 4 million U/day)
Outpatient until tolerance is recovered, and continue with
oral amoxicillin. The use of macrolides is con-
General Measures sidered for older children who are suspected of
Most patients will respond to outpatient treat- having Mycoplasma pneumoniae, or Chlamydia
ment. For infants, medical monitoring is recom- pneumoniae, or penicillin allergy: azitromicin
mended at 24 h, and for preschoolers this can be 10 mg/kg/day on a daily dosage, without food,
up to 48  h. Monitoring must be foreseen for for 5 days (maximum 500 mg/day); claritromi-
worsening of the condition caused by food rejec- cin 15 mg/kg/day every 12 h for 10 days (maxi-
tion, medication intolerance, increase in respira- mum 1  g/day); or erythromycin 50  mg/kg/day
tory difficulty, irritability (persistent crying), or divided into four doses, for 10 days (maximum
compromised consciousness. The use of anti- 2  g/day). As an alternative to macrolides use,
pyretics and analgesics is indicated to keep the quinolones can be indicated: daily levofloxacin
child in better condition and to reduce the meta- in 10 mg/kg doses for 10 days. In epidemic epi-
bolic and oxygen requirements. The physician sodes, influenza A virus must be ruled out, and
must insist that the caregivers look for medical early treatment with antivirals (oseltamivir)
advice in case of symptom worsening, axillar must be started.
fever greater than 38.5°C for longer than 3 days,
respiratory difficulty (tachypnea, cyanosis, rib
retraction), food rejection, or notable weakness. In Hospital

Kinetic Therapy Hospitalization Criteria

Kinesiotherapy is not indicated for pneumonia • No clinical response to outpatient therapy
management. It does not accelerate the recovery • Vomiting and dehydration, which may make
process and may delay symptom progression. oral treatment difficult
Cough assistance techniques, postural drainage, • Total or partial respiratory insufficiency:
diaphragmatic reeducation, and early mobiliza- transcutaneous saturation <93%
tion may help to expand poorly ventilated areas • Under 3 months of age, because of apnea and
and improve symptoms of respiratory distress to risk of cardiorespiratory arrest
achieve these objectives. • Relevant comorbidity: cardiac, pulmonary,
neuromuscular, immunological
Antibiotics • Complicated pneumonia: effusion, excavated
Antibiotic treatment is empirical, and given the lesions
difficulty in isolating the etiological agent, it • Serious disease: Hemodynamic instability,
should be based on the best possible etiology, alteration of consciousness, seizures, toxic
depending on the patient’s age and the epide- presentation
miological timing. In children under 5  years
old, antibiotics should not be routinely indi- General Measures
cated, because in most cases the disease will be Oxygen for patients whose saturation is less than
caused by a virus. If bacterial etiology is sus- 93 mmHg in environment air.
pected, amoxicillin should be prescribed at Avoid prolonged fasting, especially in infants
80–100  mg/kg/day, fractioned every 12  h dur- who are under 1  year old. Because of this, it is
ing 5 to 7 days (using a maximum of 2 g/day). recommended to administer fractionated feeding,
In children who are over 5 years old, amoxicil- feeding in small volumes, or through a small
lin can be prescribed at 50–80  mg/kg/day. If nasogastric tube, to avoid worsening the respira-
there is poor oral tolerance, sodium penicillin tory difficulty.
306 M. L. Boza Costagliola

Antibiotics third-generation cephalosporins. Observations

Newborns and infants who are under 6  weeks made in patients with community-acquired pneu-
old: ampicillin 100 mg/kg/day every 8 h, IV, plus monia caused by resistant Streptococcus pneu-
amikacin 15  mg/kg each 24  h, IV, during moniae who still have a good response to
7–10 days to ensure a good coverage for enteric treatment have increased the chosen cutoff points
gram-negative bacteria: group B Streptococcus, to determine penicillin and cefotaxime resistance
type D Enterococcus, and Listeria monocyto- (CIM > 8 ug/ml).
genes. After the first week of life, as an alterna-
tive to amikacin, cefotaxime can be indicated
(150  mg/kg/day), given a lower risk of Listeria Complications
monocytogenes, which may require adding ampi-
cillin to the synergic effect of an aminoglycoside. Whenever a patient persists with fever after
In patients with progressive worsening, or for 48–72 h, the presence of some complication such
whom a resistant Streptococcus pneumoniae is as effusion, pleural empyema, abscess, pneuma-
suspected, high doses of amoxicillin, of third- or tocele, bacterial resistance, or choice of an inad-
second-generation cephalosporins, or IV ampi- equate antibiotic must be suspected. The presence
cillin, should be used. Ampicillin, which is a of some extrapulmonary focus (pericardium,
derivative from penicillin, is a very good choice joints, meninges) must be ruled out. Pleural effu-
for patients who are under 24 months of age, and sion or empyema is a possible complication in up
it has a similar efficiency to oral amoxicillin or to 40% of hospitalized children.
parenteral cephalosporins, with a significantly
lesser cost. The association of macrolides with a
beta lactam antibiotic is indicated in hospitalized Prevention
children when there is a strong suspicion of atyp-
ical agents. In the infections caused by The use of vaccines for Bordetella pertussis, mea-
Staphylococcus aureus, depending on the sensi- sles, Haemophilus influenzae, and influenza have
tivity, cloxacillin, clindamycin, or vancomycin is reduced the occurrence of community-­ acquired
indicated. pneumonia. Important effects have been registered
in relation to its prevention and suppurative compli-
cations after the incorporation of vaccines for type
Antibiotic Resistance of Streptococcus B Haemophilus influenzae. The national rate of
invasive disease reported for 2003 was of
The appearance of resistant Streptococcus is a 2.5/100,000 inhabitants, and the effectivity preven-
worldwide concern, and its degree of resistance tion for the bacterial community-­acquired pneumo-
degree is variable, depending on geographic dis- nia and empyema was 80%. It must be considered
tribution. The risk of having an invasive disease that 6% to 16% of infections caused by Haemophilus
caused by a resistant Streptococcus pneumoniae influenzae are caused by noncapsulated agents
is related to being 5  years old or younger (spe- against which the vaccine offers no protection.
cially under 2 years old), use of antibiotics within Influenza vaccine has a double effect: it reduces
the precedent month, middle-ear infection, and virus infection rate in high-­risk populations, and, as
daycare attendance. Resistance is caused by a parallel effect, it decreases bacterial community-
mutations of penicillin protein-binding (PPB) acquired pneumonia caused by Streptococcus pneu-
sites, with a reduction in the protein affinity that moniae and Staphylococcus aureus, related to
binds to the antibiotic. This genetic change is post-influenza virus infection. In Chile, when man-
caused by the DNA acquisition from resistant datory vaccination was introduced in 2000 for risk
species such as Streptococcus viridans. The groups, pneumonia incidence was clearly reduced.
reduction of the affinity could be countered by For those children under 2  years old, 10- and
increasing the penicillin dosage or with the use of 13-valent pneumococcal conjugate vaccines are
31  Community-Acquired Pneumonia 307

less effective for preventing pneumonia (30%) than of age: clinical practice guidelines by the Pediatric
Infectious Diseases Society and the Infectious
other invasive diseases such as sepsis and meningi- Diseases Society of America. Clin Infect Dis.
tis (97%). Both vaccines have a good immunoge- 2011;53(7):617–30.
nicity and herd immunity. The 13-valent vaccine Coria de la HP. Recomendaciones para el manejo en niños
includes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, de las neumonías adquiridas en la comunidad. Rev
Chil Infect. 2004;21(S1):S7–S12.
19F, and 23F serotypes. Premature newborns, with Galetto-Lacour A, Alcoba G, Posfay-Barbe KM, Cevey-­
chronic lung damage and other risk factors, must Macherel M, Gehri M, Ochs MM, Brookes RH,
receive monoclonal antibody prophylaxis for syn- Siegrist CA, Gervaix A.  Elevated inflammatory
cytial respiratory virus. markers combined with positive pneumococcal uri-
nary antigen are a good predictor of pneumococcal
community-­acquired pneumonia in children. Pediatr
Infect Dis J. 2013;32(11):1175–9.
Conclusion Harris M, Clark J, Coote N, Fletcher P, Harmen A, McKean
M, Thompson J.  British Thoracic Society guidelines
for the management of community-acquired pneumo-
Community-acquired pneumonia is still a preva- nia in children. Thorax. 2011;66:1–23.
lent disease in children. The etiological diagnosis Heffelfinger J, Dowell S, Jorgensen J, Klugman K, Mabry
cannot be done by X-ray studies, hemograms, or L, Musher D, et  al. Management of community-­
acute-phase reactants, so the development of acquired pneumonia in the era of pneumococcal resis-
tance: a report from the drug-resistant Streptococcus
materials for rapid diagnosis is an unmet need pneumoniae therapeutic Working Group. Arch Intern
required to avoid the indiscriminant use of antibi- Med. 2000;160:1399–408.
otics, which is an important factor in the appear- Kronman MP, Hersh AL, Feng R, Huang YS, Lee
ance of bacterial resistance. Penicillin derivatives, GE. Ambulatory visit rates and antibiotic prescribing
for children with pneumonia, 1994–2007. Pediatrics.
especially oral amoxicillin, continue to be the 2011;127:411.
treatment of choice when Streptococcus pneu- Lee GE, Lorch SA, Sheffler-Collins S, Kronman MP,
moniae is suspected; macrolides are used when a Shah SS. National hospitalization trends for pediatric
pneumonia caused by atypical agents is suspected, pneumonia and associated complications. Pediatrics.
2010;126(2):204–13.
especially in schoolchildren more than 5 years old. Lynch JP III, Zhanel G. Streptococcus pneumoniae: epi-
Coverage with effective vaccines is important, demiology and risk factors, evolution of antimicrobial
according to the regional needs, which may con- resistance, and impact of vaccines. Curr Opin Pulmon
tribute to the prevention of the disease. National Med. 2010;16:217–25.
Minsal. Guía Clínica Auge Infecciones respiratorias agu-
programs, when systematically applied to have das en menores de 5 años. 2013. https://www.minsal.
primary care coverage, have contributed to the sig- cl/portal/url/item/7220fdc4341244a9e04001011f01
nificant decrease of morbidity and mortality. 13b9.pdf.
Plosker GL. 13-Valent pneumococcal conjugate vaccine:
a review of its use in infants, children, and adolescents.
Paediatr Drugs. 2013;15(5):403–23.
Sources Swingler GH, Zwarenstein M. Chest radiograph in acute
respiratory infections in children. Cochrane Database
Bradley JS, Byington CL, Shah SS, Alverson B, Carter Syst Rev. 2000;2:CD001268.
ER, Harrison C, Kaplan SI, Mace SE, MacCracken GH Williams JV, Harris PA, Tollefson SJ. Human metapneu-
Jr, St Peter SD, Stockwell JA, Swanson JT. Executive movirus and lower respiratory tract disease in oth-
summary: the management of community-­ acquired erwise healthy infants and children. N Engl J Med.
pneumonia in infants and children older than 3 months 2004;350:443–50.
 Atypical Pneumonia
32
Ricardo Kogan Alterman
and Julio Maggiolo Massone

Contents
Definition.......................................................................................................................  309
Pneumonia Caused by Mycoplasma pneumoniae.......................................................  310
 icrobiology..................................................................................................................  310
M
Pathogenesis...................................................................................................................  310
Epidemiology.................................................................................................................  311
Clinical Presentation.......................................................................................................  312
Extrapulmonary Manifestations.....................................................................................  313
Laboratory Diagnosis.....................................................................................................  314
Pathology........................................................................................................................  315
Treatment........................................................................................................................  315
Prevention.......................................................................................................................  316
Prognosis........................................................................................................................  317
Pneumonia Caused by Chlamydophila pneumoniae..................................................  317
 icrobiology..................................................................................................................  317
M
Etiopathogenesis.............................................................................................................  317
Epidemiology.................................................................................................................  318
Clinical Presentation.......................................................................................................  318
Radiology.......................................................................................................................  319
Relationship of CP with Other Diseases........................................................................  320
Treatment........................................................................................................................  320
Summary.......................................................................................................................  320
Sources...........................................................................................................................  321

Definition

R. Kogan Alterman (*) Atypical pneumonia is known as a pneumonia

Department of Pediatrics, Faculty of Medicine, that differs in the clinical picture and chest reticu-
Universidad de Chile, Santiago, Chile
e-mail: [email protected] lonodular images from the usual presentation of
classic bacteria or virus infections. Cough
J. Maggiolo Massone
Department of Pediatrics, Hospital Exequiel appears as the main characteristic symptom, and
González Cortés, San Miguel, Chile there is a dissociation between the severity of the

© Springer Nature Switzerland AG 2020 309

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_32
310 R. Kogan Alterman and J. Maggiolo Massone

symptoms and the findings of the respiratory ment to the membrane cells of the respiratory
physical examination, which tend to be incon- epithelium. Mycoplasma pneumoniae reproduces
stant and slow or late on onset. The main etio- through binary fission, which takes 6 h to accom-
logical agents that cause atypical pneumonia in plish, and therefore its culture process is slow
the pediatric population are Mycoplasma pneu- (5–20  days). Because it lacks a cell wall, these
moniae and Chlamydophila pneumoniae. pathogens are not affected by beta-lactam antibi-
Sometimes this terminology is used for Legionella otics and cannot be visualized by Gram stain.
pneumophila and Chlamydia psittaci, which are MP has a great affinity with the respiratory
very infrequent in pediatrics. These pathogens epithelium: it adheres to the ciliary cells, causes
are not considered in this chapter, because in our tissue destruction, and produces cytotoxic prod-
opinion they deviate from the characteristic atyp- ucts, such as hydrogen peroxide and superoxide
ical profile. anion. Ciliary paralysis explains the irritating
cough that accompanies the disease during days
or weeks. Other biological properties that deter-
 neumonia Caused by Mycoplasma
P mine its virulence are the competition for nutri-
pneumoniae tion consumption, antigenic variation which
avoids the host defenses, and the secretion of
Microbiology enzymes such as phospholipases, ATPases,
hemolysin, proteases, and nucleases, which cause
Thirteen species of Mycoplasma pneumoniae localized tissue alteration and intracellular host-
(MP) can infect humans; however, only 4 have ing. This effect creates chronic latent states, and
been identified as pathogens. It is the smallest the immune mechanisms are avoided through its
known bacterium in relation to cellular dimen- identification in cerebrospinal fluid and serum,
sions: 1–2 nm in length and 0.1–0.2 nm wide, as which supports its dissemination.
in the size of the genome. The bacteria have an MP has been considered an extracellular
autonomous life; they are prokaryotes with no organism, although its genomic structure sug-
cell wall, pleomorphic, and surrounded by a tri- gests that it is the product of a genetic reduction
ple cellular membrane containing sterols, which process, which is characteristic of intracellular
determines their antigenicity and allows their bacteria, inducing oxidative stress, damage to the
adherence to the respiratory epithelium. They host membrane, and nutrients obtained from the
grow in environments where there are no cells, inside of the cell. This mechanism would be an
contain DNA and RNA, and require a great adaptive process, which would explain the obser-
amount of nutrients for their growth. Mycoplasma vation of MP in respiratory secretions for a pro-
are facultative anaerobes and their way of life is longed period of time, even after successful
strictly parasitic. They are demanding and grow therapy, and this contributes to the presence of
slowly; they develop well in anaerobic environ- the pathogen agent in nonrespiratory tissues.
ments and ferment glucose. When placed on agar,
they create colonies with a dense central zone
and a peripheral region with lower density in the Pathogenesis
shape of blackberries.
Mycoplasmas produce enzymes such as MP enters the body through a canicular line,
nucleases and proteases, and they find nutrients descendant, and bronchogenic. After this, it
in eukaryotic cells, using their ability to lyse red binds to the cells of the respiratory tract through
blood cells through the production of hydrogen adhesin P1, which allows it to bind to the cells of
peroxide. the host, with other adherence proteins also.
Mycoplasmas are short bacilli, rod shaped, Thus, the pathogen can colonize mucous mem-
with an organelle on one end. The main protein, branes and their cell surface. This cytoadherence
called adhesin (P1), is responsible for its attach- is the first step in the pathogen virulent process,
32  Atypical Pneumonia 311

which is accompanied by ciliostasis and exfolia- antibodies. The antigenic variation of the surface
tion of the infected cells. Cytotoxicity is caused adhesins may explain the ability of the MP to
by hydrogen peroxide, which causes oxidative cause a chronic infection and transform healthy
stress. After opsonization of the MP, whether it hosts into carriers. The immunopathological pro-
is by complement or by antibodies, macrophagic cesses triggered by the infection are responsible
activation takes place as well as proinflamma- for the appearance of the clinical conditions,
tory cytokine releases that infiltrate the lung with which are generally moderate in 5-year-old or
a mononuclear response, CD4, T and B cells, younger children (pharyngitis, tracheobronchitis)
plasma cells with lymphocyte proliferation, anti- and more severe (pneumonia) in older children,
body production, and tumor necrosis factor- because of the immune hyperresponse.
alpha (TNF-α) release, as well as interferon,
interleukin (IL)-1, IL-5, and IL-6, and chemo-
kine IL-8 (which is a powerful neutrophil activa- Epidemiology
tor). These immunological processes may stop
the disease, reinforcing the defensive mecha- MP causes between 20% and 40% of pneumonia
nisms, or exacerbate the clinical condition cases in the pediatric population, and its inci-
through lesions secondary to the immunological dence is greater among schoolchildren who are
damage. The autoimmune reaction occurs as a 5  years old or younger, with the incidence
consequence of the homology between the adhe- decreasing during adolescence. It is necessary to
sin sequence of the MP and a variety of human highlight the pneumonia caused by MP in chil-
tissues, red blood cell antigen I, CD4, and dren under 5  years of age, and even in infants
immune complexes, and because of the poly- (10%). In our experience, MP is responsible for
clonal activation of B and T cells. 28% of outpatient pneumonia, usually in spring-
During the progression of the infection, neu- time. The infection is endemic, with epidemic
tralizing antibodies and autoantibodies are pro- outbreaks every 4 or 5 years. MP infection is 10
duced. Among these, agglutinins against the to 20 times higher as the cause for tracheitis,
lung, brain, and smooth muscle can be included, bronchitis, and other diseases than pneumonia.
which explains the systemic compromise. The The distribution of the infection is worldwide,
immunopathological process, which involves and children represent an asymptomatic reservoir
epithelial damage ciliary dysfunction, is stimu- for family outbreaks. Transmission takes place
lated through the generation of specific IgE or from person to person, through infected droplets.
inflammatory cytokines, especially type 2 inter- Possible transplacental transmission has been
leukins (IL-6). The dimension of the cytokine- described, which causes a congenital pneumonia.
and cell-mediated immune response corresponds Reinfections can be observed throughout the life-
to the extent of tissue damage. The host immu- time because of the lack of protection after the
nity does not efficiently block the cell adherence first infections. Mortality is low, although the
of the MP, which would explain the high reinfec- infection can progress to a serious pneumonia,
tion rates. Adhesins have sequence homology with serious extrapulmonary manifestations,
with the host structural proteins, and this mim- which has become more frequent as resistance to
icry explains the appearance of autoimmune macrolides has emerged in some countries.
events, which are mainly expressed as extrapul- Family outbreaks appear slowly, given the long
monary manifestations. Direct invasion and dis- incubation period (2–3 weeks), and this can also
semination have been verified as damage be observed among children in kindergartens,
mechanisms in different parts of the body. It is schools, and other closed environments where an
likely that the intracellular localization is medi- easier dissemination of the microorganism can
ated by the fusion of the pathogen with the host occur. Pharyngeal carriers can be observed in 2%
cells through the membranes that contain choles- to 15% of the cases, depending if they are related
terol and protect the MP against antibiotics and to intrafamilial contacts with index patients
312 R. Kogan Alterman and J. Maggiolo Massone

infected by MP during epidemic outbreaks or ryngeal erythema with no exudate, bullous myrin-
children with no contact with infected patients gitis, dysphonia, conjunctivitis, or skin rash. It is
during usual periods. important to highlight the frequent clinical disso-
nance with the radiological findings: there are few
findings related to the physical examination,
Clinical Presentation whereas the chest X-ray is quite expressive. The
progression of the disease includes moderate
Pneumonia caused by MP has some special char- fever that does not persist during more than 5 to
acteristics. After a long period of incubation, it 7 days, but the cough persists for a long period of
gradually begins with malaise, headache, myal- time (2–3  weeks). Timely treatment reduces the
gia, fever that can vary in its magnitude, cough, persistence of the symptoms. The clinical and
which starts as dry cough, and then progresses to radiological profile, which is usually composed
productive cough, with some mucous expectora- by a typical condensing syndrome (10–20%), can
tion, of paroxysmal frequency, which seriously be similar to pneumonia caused by Chlamydia
bothers the patient and can be accompanied by pneumoniae (CP), and sometimes it can also be
odynophagia, acute rhinitis, and, in some patients, similar to the infection caused by Streptococcus
otalgia. Cough, which gradually becomes more pneumoniae (SP). MP has an unfavorable pro-
cumbersome, is the central sign in the clinical gression in patients who present with an extensive
progression (Tables 32.1 and 32.2). Physical bilateral compromise, pleural effusion, or respira-
examination usually reveals a patient who does tory failure, which may even require hospitaliza-
not seem to be in a serious condition; there is no tion in the intensive care unit. The disease can
dyspnea, and during auscultation in the pulmo- progress to a serious pneumonia in patients with
nary examination fine crackles can be heard in sickle cell disease, Down syndrome, or immuno-
compromised areas, usually at the lobar bases. suppression. When there is coinfection (CP and
Sometimes there is wheezing, pulmonary sounds SP are most frequent), the clinical condition tends
are reduced, and in cases where there is a related to be severe, with prolonged hospitalization and
atelectasis, a condensation syndrome can be aus- greater risks of complications. MP is occasionally
cultated. It is possible, in some cases, to identify a responsible for pulmonary sequelae, such as bron-
painful enlargement of the cervical ganglia, pha- chiectasis and bronchiolitis obliterans.

Table 32.1  Etiological and clinical orientation for pneumonia

Bacterial Viral Mycoplasma
Age Any Mainly less than 2 years old 3–15 years old
Season Year-round Winter Spring
Presentation Sudden Variable Insidious
Fever High Variable Variable
Tachypnea Common Common Infrequent
Cough Scarce Frequent Frequent and intense
Related symptoms Chest pain Acute rhinorrhea  Exanthema
Conjunctivitis
 Arthralgias
 Otalgia
Pulmonary  Condensation syndrome Wheezing is frequently
examination present
Condensation is sometimes  Wheezing or condensation
present syndrome
 Bronchial sounds, fine
crackles
 Bronchophony  Localized fine crackles
32  Atypical Pneumonia 313

Table 32.2  Clinical manifestations of pneumonia caused by Mycoplasma

Very frequent Frequent Regular frequency Infrequent
Cough Headache Myalgias Conjunctivitis
Odynophagia
Fever Lack of energy Wheezing Skin rush
Otalgia
Expectoration Vomiting
Acute rhinitis
Crackles Adenopathy
Pharyngitis

Extrapulmonary Manifestations

According to the subsets of patients studied, a

variable percentage (10–20%) may have extra-
pulmonary compromise, which happens before,
during, or after the pulmonary infection caused
by MP, even when no symptoms are present. The
most common ones are these:

Cutaneous  Present in 15–20% of the patients

and are self-limited. Among them we have the
following skin conditions: maculous eruptions,
morbilliform rashes, papulovesicular rash, urti- Fig. 32.1  Interstitial-alveolar pneumonia. Chest X-ray of
caria, erythema nodosum, erythema multiforme 9-year-old schoolchild shows a right lower lobe
major (Steven–Johnson), and bullous. interstitial-­alveolar image

Neurological  The first cause of extrapulmonary Radiology

pathology. There have been cases of encephalitis, The chest X-ray usually shows a segmented con-
meningitis, aseptic meningoencephalitis, trans- densation that compromises the inferior lobes, in
verse myelitis, Guillain–Barré syndrome, periph- one or both sides, or the central perihilar regions.
eral neuropathy, cerebellar syndrome, and mental The usual image is nonhomogeneous, irregular,
confusion. There is evidence that direct invasion with interstitial or alveolar shadows, and some-
and autoimmunity are the pathogenesis of neuro- times atelectasis may be present. Sometimes the
logical compromise. following can be observed: a lobar or multilobar
condensation of a greater extension, small pleu-
1. Hematological: Hemolytic anemia caused by ral effusions, diffuse or nodular interstitial infil-
cold agglutinins, autoimmune hemolysis, dis- trations, hilar adenopathy, abscess, or
seminated intravascular coagulation, throm- peribronchovascular enlargements, which are
bocytopenic purpura, and aplastic anemia. rare (Figs.  32.1, 32.2, and 32.3). Our studies
2. Articular: Mono- or polyarthritis (most fre- show interstitial images in 22.6% of patients,
quent cause according to our experience in mixed in 28%, and alveolar in 48%; 10% pre-
Chile). sented with pleural compromise, and no chest
3. Cardiac: Myocarditis, pericarditis, arrhyth- tubes were needed for the pleura. Local experi-
mia, and heart failure. ence suggests that 20% of the pulmonary images
4. Renal: Acute nephritis, IgA nephropathy. caused by MP are indistinguishable from those
5. Oculars: Conjunctivitis, anterior uveitis, iritis, of classic pneumococcal pneumonia or of the CP
hemorrhagic retinitis (very rare). chest X-ray pattern. X-ray findings may persist
314 R. Kogan Alterman and J. Maggiolo Massone

to appear. Consequently, most laboratories do not

conduct this test. FC is a technique that measures
a mixture of IgM and IgG. The antigens used are
related to several microorganisms and tissues,
which causes unspecific reactions and yields
false-positives. Because there usually is a high
IgG level in the population, caused by previous
infections, this technique requires serum-matched
samples to prove seroconversion.

Serological Diagnosis
IgM detection is the most common test ordered in
Fig. 32.2  Alveolar pneumonia. Chest X-ray of 6-year-­ general pediatrics to diagnose pneumonia caused
old schoolchild presenting with an extensive bilateral by MP. Although its sensitivity depends on the
lobar consolidation (similar to that caused by humoral immune response and the time at which
Streptococcus pneumoniae)
the test was taken, generally IgM appears some-
where between 7 to 10 days after the onset of the
clinical condition, and it rapidly increases, which
makes it a fundamental pillar in the diagnosis of
the infection caused by this microorganism, with
a sensitivity of 80% or more. Nevertheless, in
some patients, especially those under 2 years old,
the IgM does not develop until 2 weeks after the
beginning of the disease, which limits the sensi-
tivity of this diagnostic procedure. IFI to deter-
mine IgM considers as a positive a number of
1/32 titers, and it is a classic technique for the
diagnosis, but its reading requires trained person-
Fig. 32.3 Alveolar pneumonia and pleural effusion. nel. Enzyme immune assays (EIA) are techniques
Chest X-ray of 7-year-old schoolchild presenting with that are easy to implement in clinical laboratories
nasal bilateral condensation and left pleural effusion and can detect IgM and IgG separately, which
eases the differentiation between an active infec-
during 2 to 6 weeks, depending on how early the tion and a previous one. It has been proven that
antibiotic treatment is prescribed. IgM in children can have sensitivity levels as high
as 89% to 92%. Also, the specificity of IgM detec-
tion done through enzyme-linked immunosorbent
Laboratory Diagnosis assay (ELISA) can vary in about 25% to 90%,
depending on the commercial kit being used.
Classic Diagnosis Techniques
Culture and serology using the complement fixa- DNA Amplification Polymerase Chain
tion (FC) test have their limitations in clinical Reaction (PCR)
practice. Complex nutritional sources are Nucleic acid amplification techniques have a
required for isolation, and although the specific- great potential for MP diagnosis, because of
ity of the procedure is total (100%), its sensitivity their specificity and because they quickly deliver
varies between 60% and 70%. MP grows slowly results. Also, they are the best diagnostic tool
in culture media; it is a cumbersome microorgan- when treating immunocompromised children
ism, and visible colonies take from 2 to 6 weeks and infants who have not reached the first year of
32  Atypical Pneumonia 315

life. These patients have a lower humoral Pathology

immune response when facing this agent.
Nevertheless, the presence of MP in the upper There are not many pathological findings about
respiratory tract may be an obstacle, particularly community-acquired pneumonia caused by MP
during epidemics. In Chile, it has been detected because of its low severity and mortality rates. In
in 2% of healthy children. In children between 1 deadly cases where the patient was previously
to 4 years of life, it was detected in 1.9%, and in healthy, diffuse alveolar pneumonia can develop,
children between the ages of 4 to 15 it appeared with infant respiratory distress syndrome, besides
in 5% of cases. During the periods in which the involving the liver, spleen, and brain. Other evi-
incidence of MP is greater, the presence of MP dence shows myocarditis and interstitial lung dis-
also increases. A 15% increase in relationship to ease. Lung biopsies show that tracheal,
the MP presence has been observed in children bronchiolar, and peribranchial tissues are
who are in contact with family members who are affected, with purulent exudate. There are meta-
undergoing respiratory infections caused by plastic cells in both bronchi and bronchoalveolar
these bacteria. The new nucleic acid amplifica- linings, besides monocytes (plasma cells),
tion techniques, such as the nucleic acid enlargement of the peribranchial septa, and type
sequence-based amplification (NASBA) and II monocyte hyperplasia. There is also scalping in
conventional, nested, or real-time PCR the ciliary epithelium, which explains the intense
(Fig.  32.4), are attractive alternatives when cough that is the main symptom of pneumonia.
determining the diagnosis. For ARN, NASBA is
intrinsically more sensitive than conventional
amplification techniques, and further, NASBA Treatment
can also measure the microbial load in the sam-
ple. PCR in real time can identify an active Antimicrobial therapy significantly reduces the
infection through the detection and quantifica- progression of the pneumonia caused by MP,
tion of the accumulation of amplified DNA as reducing the intensity and frequency of the
the reaction develops. cough, lowering the fever, and improving the

277pb

326pb

100pb

L 1 2 3 4 5 6 7 8 9

Fig. 32.4  Electrophoresis for Mycoplasma pneumoniae negative for M. pneumoniae; Channels 4 and 6 are posi-
in agarose gel for the amplification products using simple tive for M. pneumoniae; Channels 8 and 9 are negative
polymerase chain reaction (PCR) for M. pneumoniae control and positive for M. pneumoniae, respectively. L,
(gene 16S rRNA) and human β-globulin gene. Channels marker of molecular weight of 100 pb
1, 3, 5, and 7 present positive beta-globulin; Channel 2 is
316 R. Kogan Alterman and J. Maggiolo Massone

general condition of the patient. In the same way, Table 32.3 Treatment for infection caused by
Mycoplasma pneumoniae
it partially avoids the dissemination of the agents
among the contacts of the patients through the Medications
Antibiotics:
reduction in the number of microorganisms per
 Oral erythromycin at 50 mg/kg/day in 4 doses,
sputum volume unit. Because the microorganism 10–14 days
does not have a cell wall, it is refractory to beta-­  Oral clarithromycin at 15 mg/kg/day in 2 doses,
lactam antibiotics, but it responds adequately to 10–14 days
the use of macrolides. MP can live intracellularly,  Oral azithromycin at 10 mg/kg/day in 1 dose,
which explains the difficulty for eradicating it, as without food, during 5 days if there is resistance or
clinical refractory disease
it survives in bronchial secretions during a long  Oral ciprofloxacin at 20 mg/kg/day in 2 daily doses
time after the end of treatment. The effect of anti- during 10 days
biotic therapy in relation to the extrapulmonary  Doxycyclines for children over 8 years old at 100 mg
manifestations is unknown; nevertheless, it is in 1 dose or 50 mg every 12 h during 10–14 days
always used even when there is no extrapulmo- Bronchodilators
Beta-adrenergic dilators are used if there is airway
nary compromise. In our environment, resistance obstruction (7–10 days)
to macrolides is a rare exception because of the Kinesiotherapy
reduction of antibiotic affinity in relation to ribo- Kinesiotherapy treatment for bronchial hypersecretion
somes. However, during the past 10  years we or atelectasis
have observed an alarming resistance increase, Hospitalized patients
which has been reported in several studies, espe- Medications
 Antibiotics: As indicated for ambulatory patients. In
cially in Asia. This new reality has caused, in patients with a serious disease, use IV ciprofloxacin
some situations, the combination of a refractory at 10 mg/k/day during 10–14 days
disease evolution and a longer disease progres-  Bronchodilators for airway obstruction
sion. Also, during epidemic outbreaks, we have  Systemic steroids in usual dosage for serious cases
observed a more severe presentation of the dis- with severe obstruction and neurological
manifestations (methylprednisolone)
ease with a greater number of complications.
Kinesiotherapy: Bronchial hypersecretion or atelectasis
Mutations A20636, A20646, and A20676 consti- Chest drainage: Only if significant effusion is present
tute 98% of the resistance cases. Involved factors
are progressive increase of macrolides usage,
Table 32.4  Hospitalization because of infection caused
which triggers a selective pressure phenomenon;
by Mycoplasma pneumoniae
a greater demographic density in some geo-
Patient in serious condition with toxic appearance since
graphic areas, and the increase of travel between
admittance
neighboring countries with large populations. Poor response to initial ambulatory treatment (fever
The appearance of this resistance creates a chal- persistence, dyspnea, or significant cough increase)
lenge in the management of the refractory patient Extensive bilateral compromise
or the patient who progresses to a serious condi- Clinical and radiological progression
tion, which requires administration of medica- Respiratory failure
Important pleural effusion, abscesses, necrosis
tions that are not free of controversy, such as
Extrapulmonary manifestations
quinolones, doxycycline, and even steroids. In
Chile vigilance is scarce, as well as the informa-
tion available about the issue, although clinical Prevention
published experience shows a good response to
macrolides in the pediatric population. Sensitivity The use of prophylactic antibiotics in a member
tests are not performed in the management of of a family who has been exposed to MP shows a
individual cases. See Table 32.3 for the treatment reduction in the clinical disease appearance,
scheme in case of MP; Table  32.4 specifies the although seroconversion is not avoided. Some
hospitalization criteria. authors believe that antibiotics should be used in
32  Atypical Pneumonia 317

the case of intrafamilial index only when symp-

toms start. We agree with this opinion, and we
recommend it to our patients. There has been no
success in the use of protective vaccines against
MP, and during past years the interest in these
has decreased.

Prognosis

In most cases, pneumonia caused by MP pro-

gresses positively with adequate treatment,
although there may be some severe cases that
may involve hospitalization, with oxygen or ven-
tilation support. Depending on the affected sys- Fig. 32.5  Chlamydophila pneumoniae
tem or organ, extrapulmonary manifestations
may also need to be treated with a more strict and adhering to the base of the microvilli and several
specific treatment, especially in neurological or entrance mechanisms that depend on the cell and
cardiac cases. In asthma patients, this pneumonia the infection route (Fig. 32.5).
can trigger the acute obstruction of the airways or
worsening of the chronic asthma symptoms.
There are reports of lung sequelae after suffering Etiopathogenesis
from an infection caused by Mycoplasma pneu-
moniae. Computed tomography scans of the CP is characterized by a unique development
chest show mosaic attenuation, peribronchovas- cycle, which has a different morphology depend-
cular enlargement, bronchiectasis, bronchiolitis ing on whether it is in its infectious or reproduc-
obliterans, and even pulmonary fibrosis. tive form, EB or reticulate body (RB), and also
has a gram-negative coating. Some recent studies
have revealed that EB and RB code proteins cre-
 neumonia Caused by
P ating a complete pathway for the synthesis of
Chlamydophila pneumoniae peptidoglycan, including proteins that bind to
penicillin, which would make them relatively
Microbiology sensitive to beta-lactam antibiotics. After the
infection, EB (which has a 0.3  μm diameter)
Chlamydophila pneumoniae (CP) is an intracel- binds to the host cell through electrostatic union
lular bacterium that grows through binary divi- and enters the cell by endocytosis. In this way,
sion and uses the energetic system of the cells. the EB remains in the phagosome membrane,
The TWAR serovariety for CP has been estab- which does not fuse together with the lysosome.
lished using DNA homology studies and the EB differentiates from RB, which divides by
unique morphology of its elementary body (EB), binary fission after 36 h. Then, 48 h later, all the
which is pear shaped and is functionally impor- RB is expelled by cytolysis or exocytosis, leaving
tant, contrasting with the round body of the other the cells intact. CP can progress to a persistent
species. CP is more homogeneous than the other state after the effect of cytokines, such as
two species (Chlamydophila trachomatis and C. interferon-­gamma (IFN-γ), antibiotic treatments,
psittaci) and the main protein (adhesin) of its or restriction of certain nutrients. In that state,
external membrane is less complex. The small metabolic activity is reduced, which explains its
distal end is the location site of adherence to the ability to cause a subclinical infection. CP enters
cell, which causes a cell invasion (endocytosis) through the airway and infects the leukocytes and
318 R. Kogan Alterman and J. Maggiolo Massone

pulmonary macrophages, which enter the blood Table 32.5  Presence of IgG antibodies for Chlamydia
pneumoniae sorted by age (Santiago, Chile)
flow once they are infected (marker of chronic
infection). Infection of endothelial cells in Number of seropositive
Age Samples serum samples
smooth muscle takes place, as well as microvas-
(years) (IgG > 1:32), n (%)
cular activation in the NF-KB pathway, express- 6 months–4 years 22 1 (4.5)
ing adherence molecules and proinflammatory 5–9 years 28 4 (14.3)
cytokines (IL-1, IL-6, TNF-α, IFN-γ) and proco- 10–14 41 10 (31.7)
agulant proteins. The CP life cycle during the 15–19 27 15 (37.0)
intracellular period favors the development of 20–29 62 31 (50.0)
chronic infections, which also happens because 30–39 61 34 (55.7)
40–49 65 40 (61.5)
of its ability to survive in monocytes and macro-
50–59 43 28 (65.2)
phages, allowing the bacteria to disseminate to 60–89 54 39 (72.2)
different organs of the host. On the one hand, the
presence of CP stimulates the inflammatory reac-
tion and the tissue damage that is secondary to pneumonias). Other studies around the world
infection; on the other hand, it produces patho- suggest a frequency of about 5% to 20% of pneu-
genic activity against the host, and it also affects monia is caused by CP in school-age children
the immunological response against foreign anti- and adolescents. CP transmission is probably
gens. This action creates chronic inflammation, person to person through respiratory secretions,
which is usually accompanied by a very broad although there is no direct evidence.
noninfectious pathology. Dissemination of the disease is very slow, and the
interval between each case can span up to
30  days, which explains the slow spreading of
Epidemiology epidemic outbreaks. In some people, asymptom-
atic infections are crucial in the dissemination of
CP is a common human pathogen, with a wide the disease, whereas others are ineffective trans-
geographic distribution, and it affects patients of mitters. Infections caused by CP are endemic and
all ages. Evidence indicates that even though the epidemic, with an increase in the incidence dur-
microorganism was recently discovered, its ing 2 to 3 years, or with short 4-month outbreaks.
capacity to cause disease in humans is not new. The periods of low incidence can last up to
Current published information suggest that pneu- 3 years. Around 2–5% of adults and children are
monia caused by this pathogen is infrequent in asymptomatic carriers, and only a small percent-
preschool-age children and more common in age of those infected progress to pneumonia.
school-age children and during adolescence. The
greatest incidence is observed in older adults and
in patients with comorbidity (asthma and chronic Clinical Presentation
pulmonary obstructive disease). Virtually all peo-
ple are infected at some point in their lives, and The clinical characteristics of CP can be similar
reinfection is common. Also, the infection would to those presented by MP, and in some cases it
be more common in tropical weather countries, may be similar to a pneumococcal pneumonia.
and, for reasons unknown, in males. Chile has a Nevertheless, it frequently presents a
high seroprevalence, which is low in those under ­symptomatology with some features that differ-
5  years old, but it gradually increases until it entiate it from other respiratory pathogens. It has
reaches 32% in children who are between 10 and a gradual onset, starting with odynophagia,
14 years old (Table 32.5). hoarseness, dysphonia, and moderate fever. It
We have published our results about pneumo- improves after days or even weeks, when persis-
nia etiology in children 1–14  years of age, in tent dry cough appears, which progresses to pro-
whom we found 2.3% of CP (3 cases of 108 ductive cough, and, sometimes, to paroxysmal
32  Atypical Pneumonia 319

cough. In this way, the progression profile of the

disease turns biphasic. Sometimes it is accompa-
nied by headache and rhinorrhea (rhinosinusal
compromise); pulmonary auscultation is vari-
able, sometimes with isolated fine crackles, or
wheezing and rhonchus. Pneumonia caused by
CP resolves adequately with standard therapy,
but cough and lack of energy can persist for
weeks. Hospitalized patients are few, usually
older adults or, at any age, patients who are
chronic carriers of the disease.

Radiology
Fig. 32.7  Interstitial-alveolar pneumonia. Chest X-ray of
11-year-old schoolchild presenting with interstitial-­
Chest X-ray presents isolated subsegmented alveolar compromise in the right superior lobe, caused by
images, with alveolar-interstitial shadows, non- Chlamydophila pneumoniae
homogeneous, and with irregular borders. In
some cases, there is lobar or multi-lobar compro- removed to reduce cross reactions between spe-
mise of a greater extension, which usually has a cies. The cutoff points for acute infection caused
more serious progression, especially for MP by CP are the presence of IgM titers ≥1:16, or at
coinfection (Figs.  32.6 and 32.7). Pleural effu- least a fourfold increase in the IgG titers for
sion is exceptional and scarce. matched serum samples (acute and convales-
cent). IgG titers ≥1:512, whether they are unique
Specific Diagnosis or sustained, should be considered as previous
Indirect immunofluorescence is used in the sero- infections. For now, no serological procedure can
logical diagnosis of Chlamydophila pneumoniae, overcome two important problems in the sero-
although its real usefulness is debatable. Some logical study of CP: the slow appearance of anti-
commercial kits use antigens from which the bodies for this species and its high seroprevalence
lipopolysaccharide (LPS) (which is a common in the adult population, caused by past infections
antigen among the Chlamydia species) has been or even current asymptomatic infections. There
are two serological patterns: primo-infection,
which is usually present in children, and the rein-
fection pattern, caused by this agent and seen in
adults. During primo-infection, IgM appears
after the third week, and IgG appears between 7
and 8 weeks after the infection has taken place.
During the reinfection, generally there is no IgM
response, and IgG appears between 3 and 5 weeks
after the infection has occurred. The serology
study provides retrospective results, which have
little clinical application as a diagnostic tech-
nique. The technique of nucleic acid amplifica-
tion (PCR) is a quick and sensitive alternative for
the diagnosis of CP. Nasopharyngeal aspiration
Fig. 32.6 Condensing pneumonia. Chest X-ray of
10-year-old schoolchild presenting with bilateral alveolar
samples are the most used samples for the diag-
compromise caused by Chlamydophila pneumoniae and nosis. Nested PCR has proven to be more sensi-
Mycoplasma pneumoniae tive relative to conventional PCR for the CP
320 R. Kogan Alterman and J. Maggiolo Massone

diagnosis in respiratory samples. Besides this, day of oral erythromycin every 6  h during 2 to
about 2% to 5% of children and adults have been 3 weeks; or 15 mg/kg/day of oral clarithromycin
identified as asymptomatic respiratory carriers, every 12 h during 2 to 3 weeks, or 10 mg/kg/day
which emphasizes the need to critically analyze of oral azithromycin as a daily dose for 5 days,
the microbiological results for each patient. As combined with oral cefuroxime in doses of 20 to
happens with MP, the molecular techniques that 30 mg/kg/day every 12 h during 2 to 3 weeks. For
can be used to quantify the microbial load in clin- children younger than 5 years old, use only oral
ical samples have great potential for future dif- cefuroxime in doses of 20 to 30 mg/kg/day every
ferentiation between carriers and infected 12 h during 2 to 3 weeks. If the patient has been
patients. Currently, cell culture is used with a hospitalized and is in serious condition, cefurox-
variable correlation along with PCR. ime should be used in doses of 100  mg/kg/day
combined with an oral macrolide.

Relationship of CP with Other

Diseases Summary

For some time, asthma and lower tract respiratory Atypical pneumonia is a disease caused by MP
infection caused by CP have been known to be and CP. MP is a small bacillus, with autonomous
related, and it has been proven that acute infec- life, pleomorphic, with no cell wall, which pro-
tion may trigger an asthma crisis in the same way duces enzymes and has an organelle that attaches
as other pathogens, such as viruses and MP. to the respiratory epithelium. CP has a DNA
Reinfections or persistence can be the cause of homology that differs from other Chlamydia: its
exacerbations of asthma episodes. In these cases, body has a characteristic pear-shaped form.
treatment with macrolides improves the clinical These pathogens share their clinical presentation
evolution and the functional parameters. The of frequent and tormenting cough, moderate
hypothesis is that chronic infection causes hyper- fever, and a progression profile that is insidious,
reactivity and inflammation in susceptible chil- gradual, and usually not serious. MP and CP are
dren. There are numerous studies relating CP community acquired, and the contagion is pro-
with ischemic disease (atherosclerosis), acute duced by droplets.
infarction, chronic obstructive pulmonary dis- The typical chest X-ray shows interstitial
ease, arthritis, pericarditis, thyroiditis, multiple infiltrations, although there is a minor percent-
sclerosis, Alzheimer’s, erythema nodosum, age where a great variety of mixed images can
Guillain-Barré, or lung cancer. An increase in the be observed: reticulonodular infiltrations, atel-
antibodies, as well as the evidence of the agent ectasis, and even lobar shadows (MP and CP).
presence in atheromatous plaques obtained The diagnosis is made through laboratory
through PCR and electronic microscopy, have exams, particularly PCR and serology (ELISA
been proven, although the role of Chlamydophila and IFI) for MP, and only PCR for CP.
pneumoniae in these pathologies is still not suf- Pulmonary examination usually reveals crackles
ficiently clear. and/or wheezing. Both MP and CP can cause
extrapulmonary complications or serious pro-
gression of the disease, related to complex
Treatment immunological events. MP is accompanied by
the presence of cytokines, CD4, T and B cells,
The main drugs used are macrolides or doxycy- and interferon; CP is accompanied by cyto-
clines (patients >8 years old) and cephalosporins, kines, TNF-α, IFN-γ, and HSP60.
in prolonged therapies to avoid relapses. Most Treatment for complicated atypical pneumo-
cases respond favorably. Our suggestion for chil- nia caused by MP involves macrolides, and if the
dren who are 5 years or older is to use 50 mg/kg/ response is not favorable, or there is resistance, or
32  Atypical Pneumonia 321

if the progress of the disease is serious, ciproflox- raphy after Mycoplasma pneumonia. Pediatrics.
2000;105:372–8.
acin or doxycycline can be used (>8 years old), Kogan R, Astudillo P, Maluenda J, Cortés C. Clinical and
with or without steroids. For CP, in children who epidemiologic characteristics of Mycoplasma pneu-
are 5  years old or older, macrolides combined moniae infections in Santiago, Chile. Eur Respir J.
with cefuroxime are used, and for those under 2002;20:S337.
Kogan R, Martínez MA, Rubilar L, Puppo H, Girardi G,
5 years old, only cefuroxime. Castro-Rodriguez JA.  Comparative randomized trial
of azithromycin versus erythromycin and amoxicillin
for treatment of community acquired pneumonia in
Sources children. Pediatr Pulmonol. 2003;35:91–8.
Kicinski P, Wisniewska-Ligier M. Pneumonia caused by
Mycoplasma pneumoniae and Chlamydophila pneu-
Abramo C, Leinonen M, McCracken GH. Mycoplasma
moniae in children: comparative analysis of clínical
pneumoniae treatment of community-acquired pneu-
picture. Adv Med Sci. 2011;56(1):56–63.
monia in ambulatory disease: clinical spectrum, patho-
Kurz H, Gopfrich H. Role of Chlamydophila pneumoniae
physiology, epidemiology, and children. Pediatr Infect
in children hospitalized for community-acquired
Dis J. 1999;18:98–104.
pneumonia in Vienna, Austria. Pediatr Pulmonol.
Aizen L, Wang L.  Combined treatment for child refrac-
2009;44:873–6.
tory Mycoplasma pneumoniae pneumonia with cip-
Martínez MA, Diomedi A, Kogan R, Borie C. Taxonomía
rofloxacin and glucocorticoid. Pediatr Pulmonol.
e importancia clínica de las nuevas familias del orden
2011;46:1093–7.
Chlamydiales. Rev Chil Infect. 2001;18:203–11.
Averibrich D, Hidalgo-Grauss C. Macrolide resistance in
Michelow IC, Katz K. Systemic cytokine profile in chil-
Mycoplasma pneumoniae, Israel, 2010. Emerg Infect
dren with community-acquired pneumonia. Pediatr
Dis. 2011;17(6):1079–82.
Pulmonol. 2007;42:640–5.
De Barbeyrac B, Bébéar C. Histoire naturelle des infec-
Mulholland S, Gavranich JB. Antibiotic for community-­
tions à Chlamydia physiopathologie des infections à
acquired lower respiratory tract infections secondary
Chlamydia: conséquences diagnostiques et thérapeu-­
to Mycoplasma pneumoniae in children (Review).
tiques. Arch Pèdiatr. 2005;12:526–31.
Cochrane Library 2010 issue 7
Dowel SF, Peeling RW, Boman J.  Standardizing
Lung DC, Lam Shu Yan D. Rapid defervescence after dox-
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pneumoniae-associated community-acquired pneu-
(USA) and the Laboratory Centre for Disease Control
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(Canada). Clin Infect Dis. 2001;33:492–503.
de los Ángeles Paúl DM, Vega-Briceño L, Sánchez
Hammerschlag MR. Pneumonia due to Chlamydia pneu-
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moniae in children: epidemiology, diagnosis, and
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hospitalizados. Rev Chil Infect 2009;26(4):343–349.
Hong BK, Choi EH. Macrolide resistance of Mycoplasma
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 Complicated Pneumonia
33
Francisco Prado Atlagic,
Rodrigo Vásquez-De Kartzow,
Pamela Salinas Flores,
and Pamela Navarrete Contreras

Contents
Definition.......................................................................................................................   323
Epidemiology.................................................................................................................   324
Etiology..........................................................................................................................   325
Empyema Physiopathology..........................................................................................   325
 leural Effusion, Classification, and Progression Phases.........................................   326
P
Clinical Manifestations...................................................................................................  326
Diagnosis........................................................................................................................  326
Basic Laboratory Tests...................................................................................................  327
Microbiological Study....................................................................................................  328
Thoracentesis..................................................................................................................  328
Treatment........................................................................................................................  329
Antibiotics......................................................................................................................  329
Repeated Thoracentesis..................................................................................................  329
Pleural Chest Tube..........................................................................................................  330
Pleural Drainage Tube with Associated Fibrinolytics....................................................  331
Surgery............................................................................................................................  331
Follow-Up.......................................................................................................................  332
Prognosis........................................................................................................................  332
Summary.........................................................................................................................  332
Sources...........................................................................................................................   333

F. Prado Atlagic (*)

Department of Pediatrics, Hospital Clínico San Borja Definition
Arriarán, Santiago, Chile
R. Vásquez-De Kartzow Complicated pneumonia includes all clinical sit-
Department of Pediatrics, Faculty of Medicine, uations in which the deterioration caused by the
Universidad de Chile, Santiago, Chile
disease jeopardizes complete recovery. These are
P. Salinas Flores classified as suppurated or nonsuppurated com-
Pediatric Service, Clínica Las Lilas,
Providencia, Chile
plications (Table  33.1). Suppurated complica-
tions are related to the extension of the
P. Navarrete Contreras
Department of Pediatrics, Hospital de Los Ángeles,
inflammatory component, mainly considering the
Los Ángeles, Chile pleura, with an increase of pleural fluid, which in

© Springer Nature Switzerland AG 2020 323

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_33
324 F. Prado Atlagic et al.

Table 33.1 Complications in community-acquired quickly to multiple cavitations within the con-

pneumonia solidated parenchyma, associated with ipsilateral
Extrapulmonary empyema. This suppurated complication is dif-
Pulmonary complications complications ferent from the appearance of a thin-walled air-­
Suppurated pleuropulmonary Immunological/
filled image, named a pneumatocele, within the
complications infectious complications
 Necrotizing pneumonia  Sepsis resolution of a pneumonia. In necrotizing pneu-
 Pneumatocele,  Toxic shock monia, it is possible to observe a bronchopleural
pyopneumatocele syndrome fistula, corresponding to the communication
 Pulmonary abscess  Hemolytic-uremic between the pleural space and the peripheral air-
 Parapneumonic pleural syndrome
effusion  Distant focus: septic way, which is caused by the infected and necro-
 Pleural empyema arthritis, meningitis, tized parenchyma. A pneumatocele may cause
 Mechanical complications myocarditis, mechanical complications because of the hyper-
of suppurated pneumonias: pericarditis, insufflation and parenchyma or airway compres-
Air escaping endocarditis
(pneumothorax and sion, or because of a pleural tear, if its location is
bronchopleural fistula) subpleural, with the formation of a secondary
Nonsuppurated complications pneumothorax.
 Acute respiratory failure
 Atelectasis
Epidemiology

the beginning is sterile (parapneumonic effu- Pneumonia is one of the most common infections
sion), but afterward becomes infected and is in children around the world, with associated
named an empyema. morbidity and mortality, but it is especially
Among other complications we can consider severe in children under 1 year old in developing
pulmonary abscess, as cavitated pulmonary countries.
parenchyma with pus-filled material. In contrast WHO has estimated that every year about 156
to pyo-pneumatocele, which presents with a thin million cases of pneumonia affect children under
wall and with an appearance secondary to 5 years old, of which about 12.5 million children
abscesses in the terminal bronchiole, pulmonary are hospitalized (8%) because of serious and/or
abscess is less frequent in patients with complicated pneumonias. Pneumonia is the main
community-­ acquired pneumonia. Pulmonary cause of death in children under 5 years old, reach-
abscess presents with thick and irregular walls ing 1.4 million deaths/year over all the world.
and usually requires prolonged antibiotic treat- In Latin America, pneumonia is one of the
ment. Surgery may be an option of treatment for most frequent causes of hospital admission for
some patients when there is a bronchopleural fis- children under 5  years of age. Mortality varies
tula with no response to medical therapy, the from 4 to 300 deaths/1000 live births. Considering
presence of persistent hemoptysis, or if the air- the Latin American countries, Chile and Uruguay
way is compressed. Pulmonary abscess is have the lowest mortality rate related to
observed in patients with massive aspiration Streptococcus pneumoniae, whereas Bolivia,
pneumonia, chronic lung damage with bronchi- Peru, and Guyana have the highest mortality rate.
ectasis, pulmonary malformations, or in patients In Chile, pneumonia is an important public
with complicated pulmonary hydatidosis. health issue, with a rate per year of 2000 to 3000
Infection by Streptococcus pneumoniae and cases per 100,000 children less than 2  years of
Staphylococcus aureus, which have become age. Half of those who seek attention in the
agents seen as suppurating more often than pre- emergency room require admission to the hospi-
viously, produces necrotizing pneumonia, which tal, most because of acute respiratory failure and
presents as pneumonia with multiple confluent suppurative complications. Estimation of the fre-
microabscesses, usually septic, that follow quency in which bacterial pneumonias progress
33  Complicated Pneumonia 325

to parapneumonic effusion, or noncomplicated A study conducted in the United States

exudate, is about 0.6–5%. Empyema has been between 1993 and 2001 showed an increase of
estimated at about 3.3 per 100,000 children with 24% of cases of pneumonia with pulmonary
community-acquired pneumonia. empyema. After 2000, the cases reduced in rate
Pleural empyema is the main suppurated com- because of the introduction of the anti-­
plication. Around 40% of children with pneumo- pneumococcal conjugate vaccine. Since 2002,
nia who require hospitalization present with and mainly among children under 1 year old, an
pleural effusion, and up to 2% of these present increase of pneumonia resulting in pleural effu-
with empyema. Its incidence is greater during sion caused by Staphylococcus aureus has been
winter and spring. Epidemiological reports from observed.
Europe and the United States have confirmed an Among other microorganisms that may cause
increase of this complication over recent years. pleural effusion less frequently, such as virus
(adenovirus, influenza, parainfluenza), we can
mention Mycoplasma pneumoniae, which may
Etiology present pleural effusion in 5–20% of the cases,
but which rarely requires a pleurocentesis.
The agents most commonly involved in empyema Mycobacterium tuberculosis, gram-negative,
are Streptococcus pneumoniae, Streptococcus and anaerobic bacilli are much less common
aureus, Haemophilus influenzae, and Strepto­ than in the adult population, in which they must
coccus pyogenes. only be suspected in the presence of aspiration
Currently, S. pneumoniae is the bacterial agent pneumonia, pulmonary abscesses, and subdia-
that causes most complicated pneumonias. The phragmatic abscesses. Haemophilus influenzae
use of systematic conjugated vaccines against S. is an infrequent etiological agent in empyemas,
pneumoniae has modified their behavior, which but it must be considered as a potential infec-
may have been related to the recent appearance of tious agent.
serotypes related to a greater frequency of pul- Community-acquired strains of S. aureus
monary suppuration (19A, 7F, 1, and 5). In spite resistant to methicillin that have emerged over
of this, etiological identification by hemocultures recent years are responsible for serious suppu-
and pleural fluid culture is low. It is possible to rated pneumonias.
isolate this bacterium using hemoculture in up to
10% of children hospitalized with pneumonia.
Nasopharyngeal culture does not yield further Empyema Physiopathology
information about the etiology, because generally
the isolated agents are commensal flora of the Pleural space is virtual and is limited by the vis-
upper respiratory system. Determining the uri- ceral and parietal pleura. There is a continuous
nary antigen as a pneumococcus has a limited fluid filtration process from the capillary space to
sensitivity and specificity. There is no solid basis the subpleural one, and to the pleural cavity,
to recommend the routine use of fiberoptic bron- which depends on the balance between the hydro-
choscopy with a protective catheter or bronchoal- static and oncotic pressures of both spaces, in
veolar lavage for children. accordance with the Starling law.
The use of polymerase chain reaction (PCR) The presence of bacteria activates the inflam-
for S. pneumoniae in pleural fluid samples has matory cascade in mesothelial cells, which
increased isolation in more than 75% of the cases. release cytokines that cause the appearance of
Pneumonia caused by Staphylococcus aureus neutrophils, lymphocytes, and eosinophils in
and Streptococcus pyogenes, as happens with the pleural space, which breaks the balance
anaerobic microorganisms, often tends to present between filtration and reabsorption of the pleu-
complications with empyema, and to have a ral liquid. At the same time, the coagulation
higher rate of positive cultures. cascade activates, reducing fibrinolysis and
326 F. Prado Atlagic et al.

fibrin deposit in the pleural space, which causes Clinical Manifestations

loculations or segmentations. This process
causes an increase in the metabolic activity of Complications of pneumonia must be suspected
inflammatory cells and bacteria, which initiates in every patient with probable bacterial
a decrease in pH and glucose levels of the pleu- community-­ acquired pneumonia who persist
ral fluid, as well as an increase in the LDH febrile after 48  h of adequate antibiotic treat-
concentration. ment or who seek attention after 72 h of disease
deterioration. The first possibility to rule out is
pulmonary empyema.
 leural Effusion, Classification,
P The classic clinical picture includes lethargy,
and Progression Phases anorexia, persistent fever, usually above 39  °C
with chills, cough (it is not the main symptom),
Pleural empyema has different progression and tachypnea. Chest pain and grunting may be
phases that are well defined and impact treatment present. Abdominal pain is a frequent symptom
success. This process is dynamic and can be of pneumonia located in the lower lobes. In the
approached through escalated treatments. The most serious cases, the child may adopt an antal-
exudative phase is the starting phase, usually gic position (scoliosis toward the affected side).
within the first 48 h of febrile progression; free The physical examination of the affected side
and sterile fluid is present. In the fibrinopurulent will reveal a diminished chest excursion, dullness
phase, segmentations appear and loculations are at percussion, and abolished normal breath
formed in the pleural space. In the organization sounds. In the upper limit of the effusion a pleu-
or late phase, fibroblasts and pleural enlargement ral murmur may be heard, besides egophony and
appear. Nevertheless, children achieve a com- aphonic pectoriloquy. In infants and preschool-
plete recovery and rarely present restrictive ers, these signs are partially present and often
adherences that may compromise respiratory absent. Dullness is the most important clinical
mechanics. sign. Large effusions may produce contralateral
Pleural effusions related to pneumonia can be mediastinum deviation.
classified as follows:

1. Parapneumonic effusion: Accumulation of Diagnosis

pleural fluid related to a pneumonia or pulmo-
nary abscess. At first the exudate is sterile, Chest X-ray (anteroposterior and lateral) is the
with a pH  >  7.2 and glucose >40  mg/dl. In first image to acquire when a complicated
adults it is related to an LDH < 1000 UI/l. pneumonia is suspected. There is controversy
2. Empyema: Pus presence in pleural fluid, bac- about the real utility of a projection of the
teria in the direct study (Gram or acridine affected side in lateral recumbent position with
orange stain) or culture or pleural fluid horizontal ray to evaluate fluid displacement as
pH  <  7.20. The presence of one or more of an indicator of free effusion. The earliest sign is
these criteria sets the diagnosis of pleural the obliteration of the costophrenic angle and
empyema. Other biochemical characteristics the meniscus sign, in which the rim of the effu-
may suggest empyema, but they do not deter- sion ascends toward the lateral chest wall
mine it. (Figs. 33.1 and 33.2).
3. Segmented empyema: Occupation of the If there are greater amounts of fluid, enlarge-
pleural space without displacement in the ment of the intercostal spaces can be seen, as well
chest X-ray in lateral recumbent position as mediastinal displacement. When there is a “white
with horizontal ray, or the presence of locu- lung” image, it may not be possible to differentiate
lations with segmentations in the chest pleural effusion from a consolidated pneumonia
echography. pulmonary mass or pulmonary filled cyst.
33  Complicated Pneumonia 327

a b

Fig. 33.1 (a) Pleural effusion. Chest X-ray of 8-year-old X-ray of the same patient in lateral recumbent position
schoolchild presenting with high fever for 48 h showing a with horizontal ray showing displacement of pleural effu-
consolidated pneumonia in right upper lobe, costophrenic sion <10 mm on the left side
recess obliteration, and pleural meniscus sign. (b) Chest

present can be estimated, as well as differentiat-

ing if it is free or loculated and determining its
echogenicity (Figs. 33.3 and 33.4).
At the same time, chest echography is useful
for therapeutic procedures, as a guide of puncture
site and for the insertion of a pleural chest tube. It
has the disadvantage of depending on availability
and the operator’s experience.
Chest computerized axial tomography is not
considered a routine examination because it
does not differentiate a parapneumonic effusion
from an empyema. Also, it does not provide
information about the stage of the condition. It is
indicated for special cases, such as suspicion of
pulmonary abscesses, bronchopleural fistulas,
immunodepressed patients, or in empyemas that
do not respond to the usual medical manage-
ment. In those cases, it is necessary to define
anatomical details before a surgical intervention
Fig. 33.2  Empyema. Chest X-ray in 10-year-old school- (Figs. 33.5 and 33.6).
child shows necrotizing pneumonia in the right lower lobe
and right medial lobe, besides ipsilateral empyema
Basic Laboratory Tests
Chest echography may detect fluid in the pleu-
ral cavity, and therefore it is useful for “white C-reactive protein is useful for follow-up. A
lung” evaluation. Although the stage of the effu- study conducted in Chile showed that when a
sion cannot be determined, the amount of fluid final control after 48–72 h showed reduction up
328 F. Prado Atlagic et al.

Fig. 33.6  Computerized axial tomography of the chest

Fig. 33.3  Chest echography of 10-year-old schoolchild shows right lower lobe with empyema, necrotizing pneu-
with evolving pneumonia shows free anechoic fluid with monia, and bronchopleural fistula
no septum
to 50% relative to the initial value of the CRP, it
could be used to predict a shorter hospitalization
stay (<10  days). The use of procalcitonin may
have prognostic importance when assessing the
suppuration risk.

Microbiological Study

If there is a suspicion of pneumonia that has been

complicated by pleural effusion, or if there are
risk factors related to the patient of severe dete-
rioration, two hemocultures must always be
taken. For complicated pneumonia, positive
results increase up to 10% to 22%, and it gives
Fig. 33.4  Chest echography of 6-year-old child evolving information about etiology in accordance to the
with empyema shows septum (arrows) and anechoic fluid
antibiogram and minimum inhibitory concentra-
collected
tion (MIC), especially for pneumococcal suppu-
rated pneumonias.
Sputum study is not recommended in chil-
dren, with the exception of special cases, such as
if there is suspicion of tuberculosis.

Thoracentesis

This procedure must be performed when the

pleural space is filled and larger than 10  mm,
more than a fourth of the hemithorax is com-
promised, and also when a differential diagno-
sis is needed. Before the procedure, certain
possible situations that would increase the com-
Fig. 33.5  Computerized axial tomography of the chest
shows right upper lobe pulmonary abscess: thick wall, plication risks must be assessed: hemorrhagic
filled cavity, and air level diathesis, thrombocytopenia <50,000, dermic
33  Complicated Pneumonia 329

compromise in the puncture site, and mechani- Antibiotics

cal ventilation using high pressures. The pleural
fluid sample must be taken under anaerobic Antibiotics use is guided by local epidemiology
conditions and its pH must be tested immedi- (most frequent bacteria, antibiotic resistance) and
ately. The amount of pleural fluid to be obtained how serious is the clinical condition of the child.
must be sufficient for microbiology and cyto- Antibiotics must cover Streptococcus pneu­
chemistry analysis. moniae. In our environment in Chile, ampicillin
A pleural sample can be analyzed by different and penicillin are the first choice for antibiotics,
studies: and they reach adequate concentrations in the
pleural fluid. Staphylococcus aureus coverage
• Microbiology: Gram staining, aerobic culture, must be considered, especially when managing a
anaerobic culture (infrequent), latex pneumatocele (Fig. 33.8) or when there is a pre-
­agglutination test or PCR for pneumococcus, vious history of transient immune suppression of
microbacteria, or other agents, staining for viral infections such as smallpox, influenza, and
acid/alcohol-resistant bacillus, culture for measles. The addition of antibiotic coverage for
microbacteria anaerobic and gram-negative microorganisms
• Cytology: Differential cell count, analysis of must be considered in children with aspiration
malignant cells risk and with secondary pulmonary abscess
• Biochemistry: pH, glucose, LDH, proteins, (Fig. 33.9), surgery, or trauma. When the culture
adenosine deaminase (ADA), amylase, cho- results are ready, the antibiotic therapy is
lesterol, and triglycerides adjusted according to the microorganism and its
sensitivity.
Intravenous antibiotic therapy is always rec-
Treatment ommended, for no less than 7 days, and it should
be maintained during 3  days after the fever has
The objectives of treatment are to stop the infec- resolved and after the chest tube has been
tion, restore the normal physiology of the pleural removed, to complete 2–3  weeks of full treat-
fluid, and restore the normal function of the lung. ment. The initial schedule is ampicillin (200 mg/
To achieve this, the pleural cavity has to be steril- kg/day) for children who are under 2 years old,
ized and the lung expanded as early as possible. and penicillin G sodium (200,000 U/kg/day) for
Nevertheless, treatment of septic compromise patients over 2 years old. When a resistant strain
must be a priority. Patients must be admitted to is suspected, cefotaxime (150 mg/kg/day) or cef-
intensive medical care units according to the seri- triaxone (75–100  mg/kg/day) may be used. For
ousness of their condition. patients whose condition is serious, other treat-
Available treatment alternatives include these: ment is used in combination (FiO2 > 40%, ICU
admittance, related shock, abscess present), such
• Intravenous antibiotics. as cloxacillin (150–200 mg/kg/day) or clindamy-
• Therapeutic thoracentesis. cin (30 mg/kg/day), plus a third-generation ceph-
• Chest pleural tube. alosporin (ceftriaxone or cefotaxime). Rarely,
• Intrapleural fibrinolytics (IPF). vancomicine is used at 40–60 mg/kg/day.
• Surgery: Minimally invasive thoracotomy,
video-assisted thoracoscopic surgery (VATS),
and, rarely, open decortication. In these cases, Repeated Thoracentesis
it is necessary to create a tiered work algo-
rithm to minimize hospitalization days while Thoracentesis is a procedure that requires seda-
at the same time ensuring the best efficacy and tion and technical ability. As part of the diagnosis
efficiency (Fig. 33.7). process, its usefulness is clear to define what
330 F. Prado Atlagic et al.

Pneumonia
+
Pleural effusion

Echography or chest x ray in lateral

recumbent position with horizontal ray

Empyema:
Parapneumonic effusion: Thoracentesis empyema: Thoracentesis
< 10 mm of fluid on x ray >10 mm of fluid on x ray Non-modifiable pleural effusion
Echography: Pleural echo with fluid on chest x ray
minimal fluid < ¼ in chest, occupying ¼ - ½ of chest, Pleural echo with fluid and
pleura with no septum no septums septum occupying > ½ of chest

Septum Option 1 Option 2

IV antibiotic treatment Centhesis + pleural tube Videothoracoscopy Pleural chest tube

during 24-48 hours if pH < 7,2/Pus/Gram + + fibrinolytics IV
without fever bacteria + IV antibiotic TT IV antibiotic TT antibiotic TT
Control x ray in 24-48 X ray control after placing X ray control after X ray control after
hours if there is no pleural chest tube placing pleural placing pleural
improvement chest tube chest tube

Not improving: Improvement:

• fever for more • No fever for at Not improving: Improv ement:
Improvement:
than 48 hours least 48 hours • Fever for more
• No fever for at • No fever at least
• X ray progression • No oxygen than 48 hours
least 48 hours 48 hours
• X ray progression • No oxygen
• No oxygen
Not improving:
VATS

Surgical
14-21 days of antibiotic
7-10 days of antibiotic decortication or
oral treatment in total
oral treatment in total change in the
antibiotic therapy

Fig. 33.7  Treatment algorithm for pleural empyema

approach to follow, although as a therapeutic line, over the superior rim of the rib, in the point
measure in children it has not been validated, and where an imaginary line goes from the nipple to
even though it is less invasive, it represents a the tip of the scapula.
repeated trauma, and therefore early insertion of The placement of a chest tube is indicated for
a chest tube is preferable. every complicated pleural effusion or empyema
occupying more than half the thorax, or more than
a fourth of the thorax, which does not respond to
Pleural Chest Tube antibiotics or diagnostic and evacuation thoracen-
tesis, or if there is related respiratory difficulty.
In the same way as happens with thoracentesis, It is recommended to perform this as early as
this insertion must be done in the medial axillary possible, because as time passes fluid aspiration
33  Complicated Pneumonia 331

If after 48 h there is still high fever, the output

is scarce or nonexistent, or there is no improve-
ment in the chest X-ray, the recommendation is
to conduct an echography to rule out the presence
of liquid in cysts, or extensive or necrotizing
underlying pneumonia.
The chest tube must stay in place until the out-
put is less than 25–50  ml/day, or 1–1.5  ml/ kg/
day for infants, with improvement in the X-ray
and clinical conditions.

Fig. 33.8  Pneumatocele. Chest X-ray in 10-month-old Pleural Drainage Tube

infant shows left upper lobe pneumatocele with Associated Fibrinolytics

The pleural drainage tube is the recommended

nonsurgical option in septated empyemas. The
use of intrapleural fibrinolytics (IPF) is based on
the idea of smoothing the fibers and cleaning the
lymphatic pores, thus improving the drainage of
the accumulated fluid. The most frequent adverse
effects described are fever, sometimes pain,
hypersensitivity reactions, and, rarely, pleural
hemorrhage. Nevertheless, urokinase has been
studied only in randomized and controlled stud-
ies in children, showing effectivity and safety,
and reducing the days of use of the pleural tube
and hospitalization.
Fig. 33.9  Pulmonary abscess. Chest X-ray in 14-month-­ The recommended dose of urokinase for those
old infant evolving with sepsis and pulmonary abscess in
the right middle lobe patients over 10 kg is 40,000 U in 40 ml intrave-
nous saline at 0.9%, twice per day for 3 days. If
becomes more complicated, because of the quick the patient’s weight is less than 10 kg, the dose
appearance of septa. must be reduced to 10,000  U diluted in 10  ml
This procedure must be performed by trained intravenous saline. The results reported are simi-
medical personnel, under adequate sedation and lar for children with septated empyemas in com-
anesthesia, using sterile technique, and ideally parison to children who underwent primary
using chest echography visualization. video-assisted thoracoscopic surgery.
The patient must be connected to a drainage
system with unidirectional flow, which must be
positioned lower in relation to the patient and Surgery
must have a water seal. Every pleural chest tube
must be controlled with X-rays and the output Surgery is indicated in situations of complicated
and permeability must be regularly checked. The empyema, with multiple segmentations, or when
use of pigtail chest tubes placed using the conservative treatment with antibiotics and drain-
Seldinger technique has advantages when plac- age using pleural tubes has failed.
ing the optimum drainage of the pleural cavity, Among the surgical possibilities we have min-
and even more so when used in combination with imum thoracotomy or video-assisted thoraco-
fibrinolytics. scopic surgery. In both procedures the purulent
332 F. Prado Atlagic et al.

material, with nonrecoverable tissue and detritus, the optimal management of this pathology per-
is removed, and then the area is profusely irri- sists, and the therapeutic choice is still dependent
gated to clean the cavity. It is important to con- on the experience of the facility where treatment
duct these procedures when the patient is takes place.
hemodynamically stable and with a postsurgical
phase in a critical care unit.
Video-assisted thoracoscopic surgery is done Follow-Up
using two or three small chest incisions through
which the instruments and the camera are A chest X-ray must be done as a control test 4 to
inserted. It allows conducting an early cleaning 6 weeks after hospital discharge. In this control,
of the pleural space in those empyemas that have the pulmonary examination still may be altered,
progressed to phase II or are fibrinopurulent, with with reduced pulmonary murmur and some
inefficiently drained loculations. During the past degree of dullness in the affected area, which
years its superiority over the minimum thoracot- can be explained by the residual pleural
omy has been proven, because it is less invasive, enlargement.
compromises fewer structures, and reduces pain, Immunity studies are recommended in patients
infection, movement limitation, and allows heal- with recurrent infections or an infection caused
ing. In the beginning it was used as rescue ther- by atypical agents. It is recommended to conduct
apy when the initial treatment of the empyema a sweat test in patients who have complicated
failed. The average of hospitalization days for a pneumonias caused by Staphylococcus aureus or
child with pleural empyema treated with the clas- Pseudomonas aeruginosa.
sic treatment is between 15 and 21 days, which is
significantly superior to the average number of
hospitalization days for other acute pediatric Prognosis
pathologies. Hospitalization extension is a factor
that increases the costs of any pathology, and in The prognosis of pleural empyema in children is
this way the impacts of these prolonged hospital- excellent. Follow-up studies have shown that no
izations are translated into a high economic and matter what treatment was administered, most of
social cost, besides school and work absentee- the children fully recover and pulmonary func-
ism, along with a greater risk of nosocomial tion returns to normal levels. Chest radiography
infections. is normal in 60% to 80% of the cases after
There is recent evidence suggesting that the 3  months, 90% at 6  months, and all cases after
use of video-assisted thoracoscopic surgery 18 months.
reduces hospitalization days, as well as fever and
needed pleural drainage, in hospitalized pediatric
patients because of a septated empyema, with a Summary
minimal post-procedure morbidity if the proce-
dure is done by experienced surgery groups. Suppurated complications of pneumonia during
Nevertheless, all the published studies are retro- pediatric age are more frequent in infants,
spective, and therefore the results do not provide ­especially in the population with little to no cov-
concluding evidence that may allow us to recom- erage of conjugate vaccines for Haemophilus
mend video-assisted thoracoscopic surgery as the influenzae and Streptococcus pneumoniae.
primary choice treatment when facing a septated Special populations such as immunosuppressed
empyema. For complicated empyema in chil- or immunodeficient patients, and patients with
dren, the use of intrapleural fibrinolytics is one nosocomial pneumonia, particularly those using
option whose results are comparable to those invasive mechanical ventilation, require a special
obtained when primary video-assisted thoraco- approach, wherein a different microbiology as
scopic surgery is used. So, the controversy about well as the risk factors must be considered.
33  Complicated Pneumonia 333

Empyema is the most common suppurated able MIC. The exception are those countries that
complication. It causes prolonged hospitaliza- have high rates of resistant pneumococcus (MIC
tions, although when compared to the adult popu- >2 μg/ml), community-resistant Staphylococcus
lation, there is a lower death rate. During the past aureus, or low adherence to conjugated immuni-
years, this pathology has increased even in devel- zation against Streptomyces aureus.
oped countries or slightly underdeveloped, as
Chile is within Latin America. This epidemio-
logical fact is related to pneumococcus strains, Sources
which are more suppurated, even when they are
at MIC less than 2 μg/ml, and it is also related in Arancibia F, Vega-Briceño L, Pizarro ME, Pulgar D,
Holmgren P, Bertrand P, Rodríguez JI, Sánchez
some countries to methicillin-resistant commu- I.  Empiema y efusión pleural en niños. Rev Chil
nity Staphylococcus aureus. Infect. 2007;24(6):454–61.
Management should be gradual in accordance Avansino JR, Goldman B, et al. Primary operative versus
with the amount and presence of suppuration in nonoperative therapy for pediatric empyema: a meta-­
analysis. Pediatrics. 2005;115:1652–9.
the pleural space. An important support element Balfour-Lynn IM, Abrahamson E, Cohen G, Hartley J,
in the diagnosis is chest echography with King S, Parikh D, Spencer D, Thomson AH, Urquhart
Doppler, which shows the extension of the effu- D, Paediatric Pleural Diseases Subcommittee of the
sion and the presence of loculations. BTS Standards of Care Committee. BTS guidelines
for the management of pleural infection in children.
Computerized axial tomography must be reserved Thorax. 2005;60:i1–i21.
for studying complications that may potentially Bradley J, Byington CL, Shah S, et al. The management
require a surgical solution, such as bronchopleu- of community-acquired pneumonia in infants and
ral fistulas or pulmonary abscesses that do not children older than 3 months of age: clinical practice
guidelines by the Pediatric Infectious Diseases Society
respond to medical treatment. and the Infectious Diseases Society of America. Clin
In fibrinopurulent states, where more than Infect Dis. 2011;53:e25–76.
25% of the pleural space is occupied and the Fuchs S, Fischer GB, Black RE, Lanata C.  The burden
patients have a septic appearance, besides respi- of pneumonia in children in Latin America. Pediatr
Respir Rev. 2005;6:83–7.
ratory failure, chest tubes should be placed early Holmgren L, Chateau B.  Pleuroneumonía. In: Sánchez
in the therapy. The use of pigtail chest tubes I, Prado F, editors. En: Enfoque clínico de las enfer-
inserted using the Seldinger technique, in asso- medades respiratorias del niño. Santiago: Ediciones
ciation with IV beta-lactam antibiotics, yields an Universidad Católica de Chile; 2007.
Liu YH, Lin YC, Liang SJ, et al. Ultrasound-guided pig-
adequate disease resolution in most cases. When tail catheters for drainage of various pleural diseases.
there are partitioned empyemas, usually at more Am J Emerg Med. 2010;28:915–21.
than 72 h of evolution when the diagnosis is done Paz F, Céspedes P.  Derrame pleural y empiema compli-
(late diagnosis), or in patients who do not respond cado en niños. Evolución y factores pronósticos. Rev
Méd Chile. 2001;129:1289–96.
to early chest tube insertion, a video-assisted tho- Rudan I, Boschi-Pinto C, Biloglav Z, et al. Epidemiology
racoscopic surgery (VATS) can be used, as well and etiology of childhood pneumonia. Bull WHO.
as intrapleural fibrinolytics. In relation to antibi- 2008;86:408.
otic treatment, beta-lactam antibiotics, especially Schultz KD, Fan LL, Pinsky J, Ochoa L, Smith EO,
Kaplan SL, Brandt ML. The changing face of pleural
ampicillin for patients less than 2  years old, is empyemas in children: epidemiology and manage-
still the treatment of choice because of its favor- ment. Pediatrics. 2004;113(6):1735–40.
 Pneumonia Caused by Emerging
Viral Agents
34
Cecilia Perret Pérez and Marcela Ferrés Garrido

Contents
Middle East Respiratory Syndrome...........................................................................  335
Severe Acute Respiratory Syndrome/Asian Pneumonia...........................................  337
HCoV-NL 63 and HCoV-HKU1..................................................................................  337
Avian Influenza.............................................................................................................  338
Hantavirus.....................................................................................................................  339
Enterovirus D68............................................................................................................  340
Polyomavirus.................................................................................................................  341
Sources...........................................................................................................................  341

Emerging viruses that cause pneumonia in (SARS). In this chapter we review agents that
humans have a common trait: they are all zoono- have provoked major concern outside their coun-
ses. Normally, these agents circulate in the ani- try of origin, but also Hanta virus, because of the
mal population, often without causing morbidity, endemic nature it has acquired in Chile.
but under certain circumstances they can move to
human hosts, which determines the occurrence of
a new type of disease. Nature holds many exam- Middle East Respiratory Syndrome
ples of such diseases, including avian influenza,
Ebola, and severe acute respiratory syndrome The Middle East respiratory syndrome (MERS)
is caused by MERS-CoV, a recently identified
coronavirus. Several coronaviruses can cause
upper respiratory tract infections, but in some
cases they can also produce lower respiratory
tract infections and flu-like states. The SARS
coronavirus and MERS-CoV are two pathogens
C. Perret Pérez ∙ M. Ferrés Garrido (*) from the coronavirus family that predominantly
Department of Pediatrics, School of Medicine, cause serious lower tract respiratory infections
Pontificia Universidad Católica de Chile,
Santiago, Chile with a high mortality rate, but they are geneti-
e-mail: [email protected]; [email protected] cally different viruses.

© Springer Nature Switzerland AG 2020 335

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_34
336 C. Perret Pérez and M. Ferrés Garrido

MERS-CoV was first identified in 2012 follow- Genetic analysis shows that the human MERS-­
ing the death of a patient in Saudi Arabia with a CoV is quite similar to the virus found in bats and
serious respiratory infection. This finding led to the essentially identical to that observed in camels.
retrospective diagnosis of the first cases of an in- The virus appears to have originated in bats, tran-
hospital outbreak during 2012  in Jordan. Most sitioning through camels, probably in Africa, and
cases have been recorded in the Middle East, with afterward being transmitted to humans.
more than 75% of the cases in Saudi Arabia and Serological studies do not show its presence in
some cases outside this region affecting travelers. humans before 2012, but it has been observed in
The mortality rate of MERS is approximately 30%. camels since the 1990s. This observation suggests
Information about the MERS mechanism of that camels are the reservoirs of the virus, which
transmission is still limited, but it is likely to can be transmitted to humans through direct con-
occur through droplets and by direct and indirect tact with these animals or through consumption of
contact with infected respiratory secretions. their milk: 1599 cases had been diagnosed by July
Aerosol transmission has not been ruled out. 2015, with 574 deaths [World Health Organization
Currently, transmission between humans is lim- (WHO)]. Of these patients, 63% are male, with an
ited and occasional, with a low secondary attack average age of 48 years (Fig. 34.1). In children,
rate. Isolated cases have been recorded, consist- the disease tends to be milder or asymptomatic,
ing of nosocomial and household outbreaks, but with severe cases resulting from a comorbidity.
transmission is not sustained over time. This was Incubation, defined as the period between the pri-
the situation in the major South Korean outbreak, mary and the secondary case, is estimated to last
which originated through a case in Saudi Arabia an average of 5 days (2–14 days).
and affected more than 180 people. Adequate Clinical presentation is characterized by fever,
infection control measures in healthcare rapidly cough, myalgia, and diarrhea. The disease has a
limit in-hospital transmission. wide symptomatic spectrum, which can range

90-99

80-89

70-79

60-69

50-59
Age

40-49

30-39

20-29

10-19
Men
00-09 Women

100 90 80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70 80 90 100
Number of cases

Fig. 34.1  Age distribution for MERS. (Source: http://ecdc.europa.eu/en/publications/Publications/RRA-MERS-CoV-

thirteenth-update.pdf)
34  Pneumonia Caused by Emerging Viral Agents 337

from asymptomatic infections to fulminant respi- five clear objectives, which were achieved in
ratory failure, which is related to high mortality. record time: identification of the etiological
Patients evolve rapidly (5-day period on average) agent, development of diagnostic tests for virus
to respiratory and kidney failure, requiring venti- detection, creation and evaluation of epidemio-
lation support and intensive care management in logical treatment protocols to reduce morbidity
more than 60% of cases. Diagnostic confirmation and mortality, definition of key epidemiological
is achieved through viral isolation in laboratories parameters to control transmission, and formula-
with biosecurity clearance level 3; alternatively, tion of appropriate public health measures.
the virus is detected in respiratory samples SARS demonstrated that coronaviruses can
through molecular biology techniques (poly- cause serious lower respiratory infections, which
merase chain reaction, PCR), which are only would later be observed for HCoV-NL63 and
available in reference laboratories. In patients HCoV-HKU 1. To date, no new circulation of this
who have displayed symptoms for more than agent has been proven.
14 days, the determination of specific antibodies
is recommended.
There is no specific treatment, because no HCoV-NL 63 and HCoV-HKU1
antiviral therapy is available, only support mea-
sures in intensive care for the most serious cases. Coronavirus NL 63, which belongs to coronavi-
There is no specific preventive vaccine. This rus group I, was discovered for the first time in a
infection should be suspected in every traveler child with bronchiolitis in the Netherlands in
who reports having traveled to the Arabian 2004, and then ratified in small children hospital-
Peninsula during the past 14 days and who also ized for serious respiratory infections. HKU1,
presents with respiratory symptoms and fever. which belongs to the coronavirus group II identi-
fied in 2005, was also shown to be capable of
causing a lower respiratory tract infection. Both
 evere Acute Respiratory
S have been described throughout the world, prov-
Syndrome/Asian Pneumonia ing their ubiquity. This virus is detected in up to
10% of acute respiratory disease cases, and its
SARS is the first identified coronavirus capable symptoms range from upper respiratory disease,
of producing a serious pulmonary disease, unlike including flu-like disease, fever, rhinitis, odyno-
those previously known (HCoV-229E and phagia, and cough, to serious conditions with a
HCoV-OC 43), which cause the common cold. rapidly progressing respiratory disease. Infection
SARS emerged in late 2002 in China and quickly by HCoV-N63 in children manifests as an
disseminated through Southeast Asia, Europe, obstructive laryngotracheitis in up to 45% of
Africa, and America. Bats were its presumed res- cases in comparison with children not infected by
ervoir, and it was transferred to humans through this virus.
civets. This virus caused great international alarm The first HCoV-HKU1 viruses were described
because of its rapid progression and its serious- in elderly patients with preexisting conditions
ness, resulting from extensive and rapidly pro- that caused their death. Some later studies, which
gressing pneumonia with a mortality rate around considered children as well as adults, have con-
50%. Health workers were particularly affected. firmed that infection caused by this coronavirus
The most constant symptoms during admissions may worsen the health status of individuals with
were high fever, malaise, cough, and headache, underlying diseases, so that they need to be hos-
followed by diarrhea and prolonged fever. pitalized more often. As with HcoV-N63, infec-
More than 8000 cases were noted, causing tion causes upper respiratory tract symptoms,
more than 700 deaths. Thanks to international such as fever, coryza, odynophagia, and cough-
coordination under WHO leadership, the epi- ing. Wheezing, pneumonia, and bronchiolitis
demic was controlled in July 2003. There were may also be present. In children a greater fre-
338 C. Perret Pérez and M. Ferrés Garrido

quency of feverish convulsions has been observed The first cases of human infection caused by
in comparison with children who were not H7N9 influenza A were reported in China during
infected by HCoV-HKU1. 2013, and most of these were related in one way
HCoV-NL63 and HCoV-HKU1 are viruses or another to contact with poultry, whether direct
that tend to manifest as a common cold, just as or environmental in markets where live birds are
the usual coronaviruses HCoV-229E and commercialized. By 2015 there had been 488
HCoV-OC43; nevertheless, in small children, confirmed H7N9 influenza cases in China since
elderly patients, and immunosuppressed patients, the beginning of the outbreak, with 185 deaths.
they can cause serious respiratory disease with a This virus does not seem to spread easily among
high mortality rate. humans, and there has been no proof of sustained
human transmission, although its transmission
potential seems to be more effective than that of
Avian Influenza the H5N1 influenza A virus. A couple of cases
have been reported outside China: a traveler in
The influenza A virus is widespread in nature: its Malaysia who stayed in China and a man and his
main reservoir is domestic and feral birds. Several wife who were diagnosed in Canada in January
types exist, according to their hemagglutinin (H) 2015 after traveling to China (WHO). There are
and neuraminidase (N) makeup, only two of no recorded secondary cases in these countries,
which have recently circulated among humans which confirms its low probability of human-to-­
and are causing seasonal outbreaks: H1N1 and human transmission.
H3N2. Cases have been observed during the coldest
The animal reservoir of the virus is large and seasons in China. From December 2014 to
varied. Several subtypes have been described, February 2015, 83 new cases were diagnosed,
which include 17 hemagglutinin and 9 neuramin- with an average age of 56 years and 19 deaths. Of
idase types. These zoonotic viruses may cause these newly diagnosed patients, 72% are male,
diseases and infections in several animals, gener- and 93% of patients have had direct contact with
ally pigs and poultry. These zoonotic viruses in poultry markets. The incubation period is 4 days
particular adapt very poorly to humans, so they (2–8  days). Even though mild cases have been
seldom cause human diseases, which are limited described, most diagnoses have been serious,
to outbreaks circumscribed in terms of time and with a mortality rate close to 35%. Hospitalized
population. Nevertheless, human cases of A patients have a febrile disease, with temperatures
H5N1 were observed in Hong Kong for the first above 102.2  °F and cough. The disease pro-
time in 1997 and have continued being reported gresses swiftly from moderate to severe. In con-
to date. More than 700 cases have been notified, trast to human seasonal influenza, most patients
all in Asia and Northern Africa, with 413 deaths. do not report rhinorrhea or odynophagia.
Most cases are isolated, with some intrafamilial In a set of hospitalized patients, the disease
clusters being described. Human-to-human trans- progressed swiftly for an average of 3 days after
mission is rare, which reflects the poor ability of its onset, counting from the beginning of the
the virus to adapt to human respiratory mucosa. symptoms until hospitalization. Almost 70%
The persistence of the circulation of these viruses required invasive mechanical ventilation, with a
and the great genetic variability of the influenza death rate of 30%. Deaths from respiratory fail-
A virus make us fear that the avian virus may ure reached 38%, and 62% were caused by septic
adapt to humans, which would ease its transmis- shock. Most deaths corresponded to elderly
sion among the human population, potentially patients and with a underlying disease, as well as
causing a pandemic: this is what happened with to the use of systemic steroids. Diagnosis is per-
the H1N1 influenza A, which had a porcine ori- formed by identifying viral RNA through
gin and adapted to humans, creating a pandemic RT-PCR in respiratory tract samples, obtained
in 2009. through swabbing or nasal suctioning.
34  Pneumonia Caused by Emerging Viral Agents 339

As well as other avian influenza A virus, this birthing periods, cold, or habitat interventions
virus is sensitive to oseltamivir and is resistant to such as logging, have been associated with
adamantines. Oseltamivir is indicated for hospi- greater virus excretion in these rodents. Mice
talized or ambulatory patients, whether they have excrete the virus through their feces, urine, and
been confirmed or are under suspicion of being saliva, contaminating the environment. The most
infected by H7N9 influenza, even if more than representative virus-carrying rodents are
48  h have passed since the onset of symptoms. Peromyscus maniculatus or “deer mouse” (which
The dosage and timeframe of therapy are not carries the no-name virus), Oligoryzomys longi-
clearly established for serious patients, but a lon- caudatus or “long-tailed mouse,” and Calomys
ger timeframe is suggested, around 10 days and laucha, among others. Humans acquire the infec-
in higher doses. In patients with mild and non- tion through the inhalation of secretions (stools,
complicated infections, therapy must continue urine, saliva) of infected rodents. The Andes
for 5  days. Patients with mild infection, who virus, predominant in Southern Argentina and the
require ambulatory treatment and whose only single causal agent in Chile, is only transmitted
exposure factor is travel to an area where there through close human-to-human contact.
are recorded cases, in humans or birds, have no Hantaviruses are spherical viruses with a tri-­
empirical indication for oseltamivir. segmented RNA genome with a lipid envelope
Isolated cases of avian origin in humans through which two glycoproteins (Gn and Gc)
caused by the influenza H10N8 virus and H6N1 protrude. These three segments code through
have been observed in China. These facts prove proteins such as RNA polymerase (L segment);
that in these zoonotic influenza cases vigilance is glycoproteins Gn and Gc (M segment), which are
extremely important, given its pandemic poten- important in the recognition of β3 integrins that
tial, so it is crucial to pay close attention to travel- the virus use as receptors; and nucleoprotein (S
ers and enforce local vigilance. segment), a highly conserved protein used for the
laboratory diagnosis of these agents. The lipid
envelope is sensitive and is destroyed by deter-
Hantavirus gents, chloride, desiccation, and sun exposure.
All these actions form the basis of the prevention
In 1993, a new virus from the the Bunyaviridae and control recommendations for hantavirus
family was identified in the United States of infections.
America. It was named “virus with no name” and The agent enters the respiratory tract through
was deemed responsible for what is now known inhalation of the aerosolized virus in the environ-
as cardiopulmonary hantavirus syndrome (sín- ment or through contaminated human secretions.
drome cardiopulmonar por hantavirus, SCPH), a After an incubation period that ranges from 1 to
feverish disease characterized by respiratory 6 weeks (18 days on average), nonspecific symp-
insufficiency and shock. This discovery, which toms begin, including fever, myalgias, and head-
was a new zoonosis, in practice extended over the ache, plus digestive symptoms (more common in
next years across the whole American continent. children). This stage is followed by progressive
In this process, new clinical manifestations were respiratory disease and finally by respiratory fail-
recognized and new agents identified, including ure, which is the most serious manifestation of
the Andes, Laguna Negra, Araquara, and Choclo this infection. In 100% of the cases of acute
viruses, which are prevalent in Chile, Argentina, infection, the virus is present in all the white cells
Paraguay, Brazil, and Panama, respectively. and, in variable proportions, in plasma, respira-
Their natural reservoir are Sigmondontinae tory secretions, saliva, and urine. Also, viral RNA
rodents, which belong to the Muridae family. has been detected in white cells up to 15  days
These animals develop a chronic infection with before and 90 days after the first symptoms.
an intermittent viral and asymptomatic excretion. Interaction with β3 integrins and the replica-
Stress situations, such as lack of food during tion of viral endothelial cells of various tissues
340 C. Perret Pérez and M. Ferrés Garrido

appear to alter the modulation functions of per- breathing support, restriction of liquids, and
meability in these cells, especially increasing the vasoactive drugs. The use of an antiviral such as
permeability in small lung vessels, which favors ribavirin has not been shown to be an effective
arterial hypotension, thrombocytopenia, and treatment. Extracorporeal membrane oxygen-
hypoxia from plasma flooding into alveolar ation (ECMO) has been used as a rescue therapy
spaces. Protein N and superficial glycoproteins in some cases of serious cardiopulmonary failure
stimulate the production of specific and neutral- that do not respond to conventional ventilation
izing antibodies, which have been associated and vasoactive drugs.
with better survival outcomes when they increase In Chile, two therapeutic options have been
prematurely. investigated for hantavirus: methylprednisolone
Patients who progress to the cardiopulmonary in high doses and immune plasma with high neu-
phase, where respiratory failure sets in, require tralizing antibody titers. Only the latter strategy
supplementary oxygen; in addition, more than two has shown promising results relative to mortality
thirds need mechanical ventilation, and 50% of rate reduction when used immediately after
patients develop cardiogenic shock, which consti- symptom onset.
tutes a poor prognosis factor. The increased vascu- As a control measure in hospitalized patient
larity rate explains the pulmonary edema observed management, and considering that hantavirus has
during this stage. This functional alteration is tran- been described as capable of causing nosocomial
sitory, lasting from 48 to 72 h; afterward, pulmo- transmission, standard precautions must be taken:
nary function is quickly recovered following a ideally, interning the patient in an individual
brief period of noticeable diuresis. Cardiogenic room and wearing protection equipment [apron,
shock is difficult to manage and is the main cause gloves, face mask (no. 95) with a high efficiency
of death. The lethality of hanta cardiopulmonary filter, and security glasses], especially in proce-
syndrome is about 35%, and most deaths occur dures during which there is close contact with the
during the first 48 h of evolution. patient’s fluids, such as intubation, secretion suc-
The hemogram is the most useful general labo- tioning, and retrieval of samples for laboratory
ratory test for hypothesizing a diagnosis, because tests.
it can, from an early stage, reveal manifest reduc-
tions in the number of platelets as well as the pres-
ence of lymphocytes, which take the shape of Enterovirus D68
immunoblasts. A late onset of hematocrit increase
has been observed, which is concomitant with the This viral agent, enterovirus D68, has been
beginning of the cardiopulmonary phase of the known since 1962, when it was isolated in chil-
disease. dren suffering from bronchiolitis and pneumonia.
It is also helpful to test for LDH and transami- Because no widely available trials have been con-
nases, which increase nonspecifically. A chest ducted, not much is known about its epidemiol-
X-ray may change in a matter of hours from a ogy and clinical manifestations. During the fall
nonspecific interstitial pattern to diffuse pulmo- of 2014, Missouri and Illinois hospitals reported
nary edema. The virological diagnosis is con- an unusual rise in the number of serious cases of
firmed through RT-PCR in white cells or through children, with or without a background of
the ELISA detection of specific IgM/IgG for obstructive disease, who presented with acute
each regional virus. respiratory infection. Enterovirus D65 was
Currently, there is no specific treatment for detected in these patients by applying molecular
hantavirus infection other than cardiopulmonary biology techniques to respiratory samples.
support. Patient should be monitored closely, The infection is more frequent in school-age
preferably in an intensive care unit, to provide children, whose most relevant clinical antecedent
measures such as mechanical ventilation for was the presence of previous persistent coughing,
34  Pneumonia Caused by Emerging Viral Agents 341

asthma, or wheezing episodes that may have syndrome coronavirus infection. Ann Intern Med
2014;160:389–397.
required intensive care unit (ICU) management. Confirmed human cases of avian influenza A (H7N9)
The virulence of this agent is more impressive reported to WHO. Report 18: data in WHO/HQ as of
than that of other enteroviruses, considering that 14 July 2001. Disponible en: http://www.who.int/influ-
it was also identified as a causal agent of obstruc- enza/human_animal_interface/influenza_h7n9/18_
report-webh7n9number_20140714.pdf?ua=1.
tive episodes in previously healthy children who, Ferres M, Vial P, Marco C, Yanez L, Godoy P, Castillo C,
when treated with antiasthma therapy, did not et al. Prospective evaluation of household contacts of
respond adequately and had to be hospitalized in persons with hantavirus cardiopulmonary syndrome in
intensive care because of hypoxemia and, with Chile. J Infect Dis. 2007;195(11):1563–71.
Figueiredo LT, Souza WM, Ferres M, Enria
some exceptions, had to receive mechanical DA. Hantaviruses and cardiopulmonary syndrome in
ventilation. South America. Virus Res. 2014;187:43–54.
The most common laboratory findings were Forster J, Ihorst G, Rieger CH, Stephan V, Frank HD,
high total neutrophils and chest X-ray showing Gurthet H, et  al. Prospective population-based study
of viral lower respiratory tract infections in children
peribronchial interstitial infiltrations, hyperinsuf- under 3 years of age (the PRIDE study). Eur J Pediatr.
flation, and atelectasis. 2014;163:709–16.
As diagnostic tests improve in sensitivity and Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et  al.
specificity, and their use becomes more wide- Human infection with a novel Avian-origin influenza
A (H7N9) virus. N Engl J Med. 2013;368:1888–97.
spread in pediatric centers, our understanding of Manigold T, Vial P. Human hantavirus infections: epide-
the epidemiology and pathogeny of this viral miology, clinical features, pathogenesis and immunol-
agent will increase. ogy. Swiss Med Wkly. 2014;144:w13937.
Martinez-Valdebenito C, Calvo M, Vial C, Mansilla R,
Marco C, Palma RE, et  al. Person-to-person house-
hold and nosocomial transmission of Andes hanta-
Polyomavirus virus, Southern Chile, 2011. Emerg Infect Dis.
2014;20(10):1629–36.
Two polyomaviruses with respiratory tropism Memish ZA, Al-Tawfiq JA, Assiri A, Al Rabiah FA, Al
Hajjar S, Albarrak A, et  al. Middle East respiratory
were discovered in 2007 through deep sequenc- syndrome coronavirus disease in children. Pediatr
ing of samples taken from respiratory secretions Infect Dis J. 2014;33:904–6.
of symptomatic patients: polyomaviruses KI MINSAL.  Guía Clínica de Prevención, Diagnóstico
(KIPyV) and WU (WUPyV). These viruses can y Trata-miento del Sindrome Cardiopulmonar por
Hantavirus web site MINSAL; 2013.
be found in the lower and upper respiratory tract Pyrc K, Berkhout B, van der Hoek L.  The novel
of immunocompetent as well as immunocompro- human coronaviruses NL63 and HKU1. J Virol.
mised patients. Their pathogenic role is not com- 2007;81(7):3051–7.
pletely clear, because they usually occur at low Rha B, Rudd J, Feikin D, Watson J, Curns AT, Swerdlow
DL, et al. Update on the epidemiology of Middle East
frequency, have a low viral load, and are related Respiratory Syndrome Coronavirus (MERS-CoV)
to pathogens whose morbidity is better character- infection, and guidance for the public, clinicians, and
ized. Diagnosis requires molecular techniques public health authorities: January 2015. MMWR.
(real-time PCR), whose inclusion in future 2015;64(3):61–2.
Schountz T, Prescott J.  Hantavirus immunology of
research will allow us to better characterize the rodent reservoirs: current status and future directions.
epidemiology and clinical spectrum of the infec- Viruses. 2014;6(3):1317–35. https://doi.org/10.3390/
tions caused by these agents. v6031317.
WHO.  Middle East respiratory syndrome coronavi-
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Sources WHO/MERS/RA/15.1.
Yang Y, Guo F, Zhao W, Gu Q, Huang M, Cao Q, et al.
Arabi YM, Arifi AA, Balkhy HH, Najm Hani, Aldawood Novel Avian-Origin Influenza A (H7N9) in critically
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of critically ill patients with Middle East respiratory
 Pulmonary Tuberculosis
35
Carlos Casar Collazo, María Elena Guarda Barros,
and Carolina Gvirtzman

Contents
Introduction..................................................................................................................   343
Epidemiology.................................................................................................................   344
Etiology and Pathophysiology.....................................................................................   344
Pulmonary Presentations................................................................................................  345
Disseminated Presentations............................................................................................  347
Diagnostic Approach......................................................................................................  348
Treatment......................................................................................................................   350
 CG Vaccination............................................................................................................  350
B
Chemoprophylaxis..........................................................................................................  350
Simple Primary Complex...............................................................................................  351
Pulmonary Tuberculosis with Negative Bacteriology....................................................  352
Extrapulmonary Tuberculosis.........................................................................................  352
Tuberculous Meningitis and Miliary Tuberculosis.........................................................  352
Adjunct Drugs................................................................................................................  352
HIV Coinfection.............................................................................................................  352
Follow-Up and Control.................................................................................................   352
 dverse Reaction to Anti-tuberculosis Drugs................................................................  352
A
Sources...........................................................................................................................   353

Introduction Plague,” “lung weakness,”, or “phthisis.” Only in

the 1890s was Robert Koch able to demonstrate
Tuberculosis has been present throughout the his- that the disease was caused by Mycobacterium
tory of mankind since ancient times and has been tuberculosis.
variously described as “consumption,” “White Currently, tuberculosis is still the most com-
mon disease in the world, causing the death of
almost 2 million people per year and infecting
C. Casar Collazo (*) · M. E. Guarda Barros almost a third of the world’s population.
Department of Pediatrics, Hospital Roberto del Río,
Tuberculosis is an infectious disease caused by
Santiago, Chile
Mycobacterium tuberculosis, known as Koch’s
C. Gvirtzman
bacillus. This bacterium grows slowly, has a low
Department of Pediatrics, Hospital Garrahan,
Buenos Aires, Argentina primary toxicity, and is light sensitive.

© Springer Nature Switzerland AG 2020 343

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_35
344 C. Casar Collazo et al.

Epidemiology Etiology and Pathophysiology

Tuberculosis distribution is universal, although The tuberculosis bacillus has multiple defensive
there are great differences in the incidence of mechanisms to protect itself against the immune
different countries, with very high rates in system and to avoid being promptly recognized,
Africa and Northern Asia and very low rates in which allows the affected individual to remain
North America and Western Europe. In asymptomatic until the invasion has reached an
America there are also notable differences advanced level. The main mechanism of immu-
between countries, with rates ranging from 12 nological defense for Koch’s bacillus is cellular
per 100,000 inhabitants, as in Chile, Uruguay, immunity, which manages to isolate and elimi-
Costa Rica, and Cuba, up to rates of 200 per nate the bacillus, although this often causes tissue
100,000 inhabitants in countries such as Haiti. damage.
Large differences can be observed in each Tuberculosis transmission is mostly transmit-
country. In Chile, for instance, there are regions ted through the airway, with the exception of gas-
with a rate of 40 per 100,000 inhabitants and trointestinal infection acquisition through
other areas with a rate of 9 per 100,000 inhabit- contaminated milk, which has been solved by
ants, which yields an average of 13 per 100,000 controlling bovine tuberculosis and industrializ-
inhabitants for the total population and an ing milk production.
average of 1.4 per 100,000 inhabitants under Pediatric tuberculosis is closely related to
15 years old. adult tuberculosis. When a child has tuberculosis,
The fact that a country or region may have a an adult gave that child the disease. If tuberculo-
low tuberculosis rate does not mean that the dis- sis increases in a population under 15 years old, it
ease has been eradicated from that area, because must be assumed that the tuberculosis program is
we know that tuberculosis infections acquired not functioning well.
during childhood or youth can be reactivated dur- In children, bacteriology has a low yield for
ing adulthood or old age. This realization forces bacilloscopy and positive culture, because these
us to sustain elimination and disease control pro- patients tend to have a low bacillus count and the
grams for many years before eradication can be bacteria are often absent from the airway, which
declared. serves as a communication path for the environ-
Factors such as overcrowding and poor-­quality ment. So, providing accurate diagnoses in this
housing permit the transmission of the disease. population is difficult. Most of the tuberculosis
Koch’s bacillus is very light sensitive: just 5 min cases in children are related to a primary infec-
of light exposure are enough to inactivate this tion caused by Koch’s bacillus.
organism. Another important factor to consider is Most children who are exposed for the first time
the reappearance of tuberculosis toward the end to Mycobacterium tuberculosis do not develop the
of the 1980s in developed countries, caused by disease, but only a latent infection, so they do not
the human immunodeficiency virus (HIV) epi- present with clinical or radiological evidence of the
demic, which in itself constituted a determinant disease. Only children under 5 years old (and par-
factor for the death of these patients. ticularly those under 2  years old) and those who
Vaccination programs using the Calmette and have some kind of immunosuppression develop
Guérin Bacillus, or BCG, vaccine have not tuberculosis. Pulmonary and extrapulmonary com-
changed the general tuberculosis prevalence for promise commonly appears between 2 and
some of the countries in the region, but they have 12 months after the primary infection.
made a difference for the most serious presenta- Bacilli that manage to enter the bronchial air-
tions, miliary tuberculosis and tuberculous men- ways reach the alveoli and produce a localized
ingitis, especially in countries where coverage is inflammatory process in the pulmonary paren-
very high (98%), as in Chile. chyma. From there, the bacilli will pass through
35  Pulmonary Tuberculosis 345

Clinical
Presentations of
TUBERCULOSIS

Disseminated
Pulmonary Extrapulmonary Presentations

Primary Serofibrinous
Complex Pleurisy Miliary Tuberculosis

Progressive Pulmonary Tuberculous

Ganglionary Tuberculosis
Presentation Meningitis

Osteoarticular
Pulmonary Tuberculosis Tuberculosis
Adult Type peritoneal, renal,
genital, cutaneous

Fig. 35.1  Tberculosis clinical manifestations

the regional lymph nodes and, therefore, to the nonspecific respiratory symptoms such as cough
lymphatic system. The triad of pulmonary focus, and secretions, often it goes unnoticed and is
local lymphangitis, and lymph nodes compro- confused with a banal viral infection. Phlyctenular
mise is called the primary complex or “Ghon keratoconjunctivitis and nodular erythema are
complex.” Bacilli enter the systemic circulation infrequent signs. Small children and adolescents
through either the bloodstream or the lymph tend to be more symptomatic. Chest X-ray may
nodes. So, a hidden bacteremia is caused before show the classic radiological image of hilar ade-
the body can develop an adequate immune nopathy and, less frequently, a figure resembling
response to control the infection. Once Koch’s a loaded barbell, which denotes Ghon’s primary
bacillus reaches the target organs, it can survive complex. Radiological signs tend to take
as a latent infection during a long period and will 6–12 months to disappear, although calcifications
cause extrapulmonary tuberculosis. Patients in may develop in the future.
whom the bacteremia is not controlled through Patients are diagnosed through a positive PPD
their immune response will present with dissem- test or a boosted PPD test, in the context of a con-
ination (miliary tuberculosis). During adoles- tact study of a bacilliferous case. In these cases, it
cence, reactivation of Koch’s bacillus can is important to implement a treatment, because the
produce tuberculosis with pulmonary or extra- probability of developing the disease with pulmo-
pulmonary presentations (Fig. 35.1). nary or extrapulmonary presentations increases
during the first 2 years after the primary infection.

Pulmonary Presentations  ulmonary Disease: Progressive

P
Pulmonary Presentations
 ulmonary Infection or Classic Primary
P Nowadays, this presentation is highly exceptional.
Complex The development of this clinical manifestation is
This presentation is the most common one (90%) basically determined by the immunity of the host,
and appears in a self-limited form. By having so it increases in children younger than 2 years old,
346 C. Casar Collazo et al.

children with a poor nutritional state, those who

did not receive the BCG vaccine, or are HIV pos-
itive, as well as those who are exposed to close
contact with bacilliferous sick patients. The pul-
monary manifestation is very similar to the clini-
cal presentation of any pneumonia: coughing,
fever, expectoration, and dyspnea, and the differ-
ential diagnosis includes the suspicion of this
possibility when there is no adequate clinical
response. When there is a parenchymal progres-
sion to cavitary presentations, caseous pneumo-
nia, or primary phthisis, the following symptoms
can also be observed: asthenia, adynamia, night
sweats, weight loss, and hemoptysis.
Chest X-ray shows condensations that become
cysts from necrosis, which happens in necrotiz-
ing pneumonia in connection with the presence
of large adenopathies. These adenopathies are
rarely symptomatic, except when they compress
a main bronchus or erode and drain the brionchus
(bronchogenic dissemination). A positive culture
result for Koch’s bacillus is observed in more
than 80% of the cases (Fig. 35.2). At times, bron-
chial compromise may progress to a complete
expansion of the lung. In such situations, distal
lesions disappear with radiological resolution. Fig. 35.2  Tuberculosis with bronchogenic dissemination
in 10-year-old patient with an HIV infection responding
poorly to antiretroviral therapy. Anteroposterior (AP)
Adult-Type Tuberculosis chest X-ray shows primary alveoli compromise in right
In high school seniors or adolescents, primary upper lobe (RUL) (a) and during computed tomorgraphy
infection progresses to adult-type manifestations. (CT) (b), where bronchial invasion is observed in RUL
In these patients there is a general health state bronchus and subsequent lumen obstruction
compromise, fever, coughing, expectoration,
hemoptoic or hemoptysis tear, and weight loss. During the examination, the adenopathy is
Radiological images show infiltration, predomi- mobile, painless, and without erythema. If it is
nantly apical, in addition to excavations or cav- not treated, it increases in size and a caseous
erns. Lesions in these patients are highly necrosis appears. In this stage, the adenopathy
bacilliferous and connected to the external acquires a typical erythema tone, with a fluid
­environment, so bacteriological tests are usually texture in the centre. If this adenopathy breaks,
positive (Fig. 35.3). it may cause a skin fistula or scrofula, which
chronically leaks. Pulmonary compromise must
Tuberculous Adenitis be ruled out for these patients. Differential diag-
Tuberculous adenitis is the most frequent extra- noses include lymphoma and certain infectious
pulmonary presentation. It usually presents as a causes, so a biopsy is fundamental for making a
localized adenopathy on a lymph node or lymph definitive diagnosis.
pack. It can involve any lymph group, but it usu-
ally appears on the head and neck. Others
Adenopathy can cause a subacute presenta- Patients can present with osteoarticular, renal,
tion with mild general symptomatology or none. genitourinary, abdominal, adrenal, parotid,
35  Pulmonary Tuberculosis 347

Fig. 35.3  Adult-type tuberculosis. AP radiography of Fig. 35.4  Miliary tuberculosis. AP chest X-ray of an
14-year-old adolescent who presented clinically with a infant with no BCG vaccine and intrafamilial contact with
prolonged fever and coughing with bacilliferous expecto- an adult with bacilliferous tuberculosis. Diffuse bilateral
ration. Condensation in RUL is observed, secondary to granular compromise can be observed, consistent with
alveolar compromise and atelectasis of the same zone, miliary tuberculosis
probably caused by lymph node compression of the cor-
responding bronchus ular images (<2 mm) in both lung areas. Lesions
can be detected early in the retrocardiac space of
ocular, and skin compromise. However, these a lateral radiography. PPD tends to be negative in
extrathoracic presentations of tuberculosis are these patients, and diagnosis is made through
infrequent. physical examination, thoracic radiography, tho-
racic computed axial tomography scan, and eye
examination (choroidal tuberculous can be seen).
Disseminated Presentations Confirmation can be obtained through bacterio-
logical tests of expectorations, gastric content,
Disseminated presentations are serious and are pulmonary puncture, or mieloculture. Given the
characterized by a high mortality rate. They can high meningitis risk, lumbar puncture is always
be clinically present in three ways, depending on recommended. Early clinical suspicion of menin-
the immunological state of the patient and the gitis is very important given its high morbidity
number of bacilli that enter the bloodstream. and mortality rate as well as its neurological
sequelae (Fig. 35.4).
Miliary Tuberculosis
This presentation is more common in children Tuberculous Meningitis
who are younger than 5  years old, have with a This presentation is a meningoencephalitis that
poor nutritional state, and are immunosup- mostly compromises the base of the brain and
pressed. The onset is 2–6  months after the first the circle of Willis. Three developmental stages
infection. Clinical manifestations are mixed and can be identified, which progress during 1 to 2
may depend on the number of bacilli that enter weeks. In infants and small children, progres-
the bloodstream and the patient’s immune sion can be faster, lasting only a few days.
response. Miliary tuberculosis can present itself During stage 1, nonspecific signs are predomi-
as an unspecific infection, with an insidious nant, including fever, lack of energy, irritability,
onset, and without apparent seriousness or acute vomiting, constipation, and delays in psycho-
symptoms. As the infection progresses, fever, motor development. During stage 2, an intense
coughing, weight loss, anorexia, and night sweats headache appears, as well as explosive vomit-
start to appear. Three weeks after the onset of the ing, disorientation, and seizures. In this stage,
symptoms, chest X-ray shows diffuse micronod- physical examination shows meningeal signs,
348 C. Casar Collazo et al.

compromise of the cranial pairs, focal neuro- 1 . Children exposed to a bacilliferous patient.
logical signs, or hemiparesis and endocranial 2. Children with an unresolved pneumonia,

hypertension. Stage 3 is the most serious one, as which does not respond to normal antimicro-
patients display severe consciousness impair- bial treatment, or with persistent signs in
ment, which ranges from stupor to coma, hemi- images.
plegia, or tetraplegia. Severe endocranial 3. Children with an adult-type presentation and
hypertension, besides decerebrate or decorticate compatible clinical findings.
posture, can also be observed. These patients
tend to have a negative PPD test, with thorax The process begins with chest X-ray, both pro-
chest X-ray revealing parenchymal compro- jections (anteroposterior and lateral), PPD test-
mise. Computerized tomography (CT) shows ing, and expectoration bacilloscopy. Thorax
several brain areas affected by strokes and radiography will show different images depend-
infarctions, although in some cases tuberculo- ing on the tuberculosis presentation affecting the
mas may also be observed in the cerebral paren- patient. Complementary imaging with a comput-
chyma. Diagnosis is based on alterations of the erized axial tomography scan is recommended
cerebrospinal fluid (CSF), which is characteris- when diagnosis is uncertain.
tically clear and low in glucose. Cytochemical There are tests showing immune response to
analysis also shows a minor presence of chlo- Koch’s bacillus:
ride, a high protein level, and a slight increase in
predominantly mononuclear cells. Koch’s cul- PPD Testing
ture, amplification methods, and adenosine The PPD test (protein purified derivative) is a
deaminase (ADA) in the CSF are useful. protein concentrate of Koch’s bacillus,
Calmette–Guérin (BCG), and nontuberculous
Connatal Tuberculosis mycobacteria. The PPD test is highly sensitive
Connatal tuberculosis is fortunately a rare dis- but nonspecific for Mycobacterium tuberculosis
ease. It has a very high mortality rate, even when infection. The test consists of 2–10  U of this
treated. It is sanguineously transmitted through concentrate delivered intradermally in the exter-
the umbilical cord or through amniotic fluid aspi- nal radial side of the left forearm. Subsequently,
ration during childbirth. Symptoms include the cellular immunity response to PPD inocula-
respiratory failure, hepatosplenomegaly, lymph- tion is measured. The test uses a hypersensitive
adenopathies, fever, abdominal distension, leth- delayed response, the value of which peaks at
argy, and irritability. Skin lesions, jaundice, 72 h. At this point, the extent of the transverse
seizures, otorrhea, and diarrhea are seen less fre- induration is measured (pencil test).
quently. Some newborns present with severe sep- Internationally, a PPD test is considered positive
tic shock. when it has an induration area equivalent to or
greater than 10  mm. In children younger than
4 years old, with malnutrition, immunosuppres-
Diagnostic Approach sion (HIV infection), or without BCG vaccine, a
test is considered positive if induration reaches
Tuberculosis diagnosis in children is still a major or surpasses 5  mm. A tuberculous boost is
challenge. In spite of numerous studies aimed at defined as an induration increase greater or
developing new techniques or improving on tra- equal to 10  mm with a difference greater than
ditional ones, especially those associated with 6 mm, which happens in 3-month intervals (up
HIV infection, these techniques are not within to 2  years). This reaction is compatible with a
the reach of the general population; therefore, recent infection. The PPD test can yield a “false
treatment onset is frequently delayed. negative” after a viral infection, live virus vac-
In children, the diagnostic process starts when cination, immunosuppression, and in severe
the clinician suspects the following situations: tuberculosis presentations, especially for the
35  Pulmonary Tuberculosis 349

most widespread forms: 5% to 10% of tubercu- additional weeks when resistance is suspected.
lous diseases yield a negative PPD test. This is a slow process, but it provides a better
PPD test interpretation is difficult and may identification of Koch’s bacillus and drug resis-
lead to confusion, particularly in countries with tance. This medium is available in regional labo-
high BCG vaccine coverage. The PPD test is use- ratories throughout our country. The liquid
ful for diagnosing double tuberculous infections medium technique takes from 1 to 3 weeks and
in countries with a low endemic rate of relies on a continuous automated reading of bac-
Mycobacterium tuberculosis, low infection inci- terial growth, which affords greater sensitivity. It
dence for nontuberculous mycobacteria, and high has a higher contamination rate, although it is
BCG vaccine coverage. difficult to identify the morphology of the colo-
nies. There are also nonradiometric cultures,
IGRAS such as MGIT (Mycobacteria Growth Indicator
IGRAS assays (interferon-gamma release Tube), the BACTEC9000MB system, and ESP
assays) measure lymphocytic response to Culture System II Myco, available in central
interferon-γ when lymphocytes have been laboratories.
exposed to the Koch’s bacillus antigen. Assays Samples for bacteriological studies rarely
are more specific than PPD tests when diag- come from the expectorations of sick children. In
nosing an infection, but their sensitivity var- these cases, it is recommended to obtain samples
ies. Because of this, they do not discriminate by sputum induction, using a nebulized hyper-
between latent and active infection. The cur- tonic saline solution, or aspiration of gastric con-
rent techniques are Quantiferon-TB GIT and tent (three samples). The output of this sample is
Elispot-TB. IGRAS assays are mainly recom- up to 30% in children, even for immunosup-
mended for patients under high clinical suspi- pressed patients with extrapulmonary tuberculo-
cion in whom PPD or culture have produced sis. If the sample cannot be obtained with the
negative results. The widespread use of IGRAS aforementioned techniques, a bronchoalveolar
assays is limited by their high cost. lavage can be performed through bronchoscopy.
Samples from other parts of the body, such as
• Bacteriological study. Mycobacterium tuber- pleural effusion, cerebrospinal fluid, pericardial
culosis must be identified, which is especially fluid, peritoneal fluid, synovial fluid, and urine,
difficult in children, because their lesions have are useful when extrapulmonary presentations
a low bacillus count and they are usually are suspected.
poorly connected to the central airway.
• Amplification technique for nucleic acids.
Bacilloscopy requires at least 5000 BK/ml These techniques can be considered in patients
(two samples) to yield a positive result. A Ziehl– under suspicion of resistance to anti-­
Neelsen stain is used, which requires a micro- tuberculosis drugs. They have a high sensitiv-
scope with 1000× or greater magnification, and ity (96%) and specificity (85–95%) for
10–15 min of exposure; alternatively, it is possi- positive bacilloscopy samples, so they can
ble to use a fluorophore stain, which requires a rapidly detect a few copies of nucleic acid.
400× reduction in the magnification, and takes They do not need to be performed in a high
2–3 min of exposure. WHO recommends the lat- security laboratory (level 3), and the newest
ter technique. techniques also detect drug resistance and
Culture requires 10 BK/ml to get a positive identify specific microbacteria. Nevertheless,
result and is the gold standard for diagnosis. In they are not too sensitive (66%) for negative
children it is rarely positive, except for the cases bacilloscopy samples, which is the most com-
in which there are excavated lesions communi- mon situation in children, and they are not
cating with the central airway. Löwenstein– available in higher prevalence areas, where
Jensen culture requires from 3 to 6 weeks, plus 3 they are most needed.
350 C. Casar Collazo et al.

At present, the most frequently used tests are • Children with disseminated and infected skin
these: conditions, which may compromise the injec-
tion site

a. Line probe assays (LPA) (2–7  days).
Recommended by WHO for BK+  and cul- The vaccine is intradermally delivered in the
tures. These assays detect infections and left shoulder, although in some countries, such as
genetic resistance to RIF: rpoB (INNO-Lippa Peru, the right shoulder is used. It produces a
Mycobacteria, Genotype Mycobacterium subcutaneous reaction and an adenopathy (pri-
Assay). mary complex) around the fourth week which
b. Xpert MTB/RIF Assay. Fully automated,
progresses for 2–4 months and even longer
very fast: 100  min. It can be used to detect periods.
MTB + gen for R to RIF at S = 98%. In 2010, Complications associated to the vaccine are
WHO recommended this test to be used in very rare, consisting mostly of local lesions in the
countries prone to epidemic or HIV-related injection site and axillary adenopathy. The skin
TB, also declaring it to be a diagnostic in these areas can sometimes become enlarged,
cornerstone. turn soft, and even fistulize. Progression is gener-
ally benign, but on occasion treatment is required.
In patients with some kind of immunodeficiency,
Treatment BCG spreading may be developed. This situation
has a high rate of morbidity and mortality. BCG
Tuberculosis control is only possible with a modifies the PPD reaction, so in countries with a
national or regional program suited to the broad vaccination coverage it is difficult to inter-
population’s epidemiological and clinical pret this test.
characteristics.

Chemoprophylaxis
BCG Vaccination
The rationale for treating pediatric patients is that
BCG vaccination (Calmette–Guérin bacillus) children younger than 5 years old with a recent
consists of the application of a measured dose of infection may develop the disease, with dissemi-
attenuated Mycobacterium bovis in noninfected nation risk being proportionally inverse to the
children under risk of exposure to create a pri- patient’s age. In addition, children with a latent
mary and nonpathogenic infection. When infection are at risk of developing an active dis-
exposed to Koch’s bacillus, it protects against ease during adulthood and then transmitting it.
tuberculous meningitis and miliary forms of TB, Isoniazid yields good results and has a very low
although it does not grant immunity against the probability of developing resistance as the bacil-
primary infection or late reactivation. lus population is small.
In Chile, this vaccine is part of the Expanded Two types of chemoprophylaxis can be identi-
Immunization Programme (Programa Ampliado fied: chemoprophylaxis, which is indicated in
de Inmunizaciones, PAI) and is mandatory from patients with a particular susceptibility for conta-
the moment of birth. gion (negative PPD test) to protect them from
Contraindications: tuberculous infection; and secondary chemopro-
phylaxis, which is used in patients who are
• Newborns who weigh less than 2000 g already infected with Mycobacterium tuberculo-
• Newborns whose mothers have active sis (positive PPD test) to prevent them from
tuberculosis developing the disease.
• Newborns whose mothers are HIV positive, Chemoprophylaxis is contraindicated for
until reaching a normal CD4 lymphocyte patients with active tuberculosis, liver damage
count secondary to isoniazid, adverse reactions to this
35  Pulmonary Tuberculosis 351

drug, or decompensated liver failure. The rec- Treatment

ommended approach for individuals in contact The treatment for all types of tuberculosis is based
with tuberculous patients and newborns whose on the use of bactericidal and bacteriostatic drugs.
mother has tuberculosis is summarized in As a general principle, this treatment must be
Tables 35.1 and 35.2. associated, extended, and supervised. Empirically,
three or more drugs are used, which are then
Table 35.1  Management of tuberculosis exposure adjusted in accordance to bacillary sensitivity.
Health state Monotherapy should be avoided, as it entails the
of mother Management Follow-up risk of producing resistant strains. The treatment
PPD (+) with Chemoprophylaxis must be long enough to eliminate or reduce bacil-
or without during 6 months lary population to a minimum. It must be a
BCG HIV
Directly Observed Treatment, Short Course
Normal chemoprophylaxis
radiography during 9 months (DOTS), because this is the only way to ensure
PPD (−) Chemoprophylaxis PPD (−) and that the foregoing conditions are met. The scheme
without BCG during 3 months normal Rx: to be used depends on the estimation of bacillary
Normal Repeat PPD and vaccinate load as per the extension of lesions and bacillus
radiography thorax radiography PPD (+)
(boosted) and
elimination rate. It comprises a daily initial phase
normal Rx: HIN and a triweekly continuation phase (Table 35.3).
6 months in
total
PPD (−) with Chemoprophylaxis PPD (−): Simple Primary Complex
BCG during 3 months suspend HIN
Normal Evolution follow-up PPD (+)
radiography (boosted) and Simple primary complex is the most benign form
normal Rx: HIN of pulmonary tuberculosis in children. Because
6 months in
of the low estimation of bacillary load, a simpli-
total
fied primary scheme is indicated, consisting of 50
The child must not be separated from the mother unless
he/she is seriously ill. Suspend maternal breast feeding daily doses of isoniazid and rifampicin followed
by 48 triweekly doses of isoniazid and rifampicin
(Table 35.4).
Table 35.2  Management for newborns born to mothers
with tuberculosis
Table 35.3  Tuberculosis treatment scheme
Health state of
mother Child management Follow-up Drug Daily phase Triweekly phase
Bacilloscopy BCG vaccination 50 doses 48 doses
(−) (10 weeks) (16 weeks)
Bacilloscopy Clinically ill children Isoniazid 10 mg/kg 15 mg/kg
(+) during or under suspicion of (max. 400 mg) (max. 600 mg)
pregnancy or congenital TB: obtain Rifampicine 15 mg/kg 20 mg/kg
childbirth samples and provide (max. 600 mg) (max. 600 mg)
full treatment for TB Pirazinamide 35 mg/kg
Normal radiography PPD (−) Ethambutol 20 mg/kg
and clinical condition: Normal Rx:
chemoprophylaxis suspend HIN
during 3 months and and introduce Table 35.4  Treatment for the simple primary complex
PPD and Rx BCG
vaccination Drug Daily phase Triweekly phase
PPD (+) 50 doses 48 doses
(boosted): (10 weeks) (16 weeks)
complete Isoniazid 10 mg/kg (max. 15 mg/kg (max.
6 months for 400 mg) 600 mg)
HIN; strict Rifampicine 15 mg/kg (max. 20 mg/kg (max.
follow-up 600 mg) 600 mg)
352 C. Casar Collazo et al.

Pulmonary Tuberculosis Table 35.7  Disseminated tuberculosis

with Negative Bacteriology Drug Daily phase Triweekly phase
50 doses 84 doses
Treat as primary complex, adding pirazinamide (10 weeks) (28 weeks)
Isoniazid 10 mg/kg 15 mg/kg (max.
during the first phase (Table 35.5). (max. 400 mg) 600 mg)
Rifampicine 15 mg/kg 20 mg/kg (max.
Pulmonary Tuberculosis with Positive (max. 600 mg) 600 mg)
Bacteriology Pirazinamide 35 mg/kg
First phase with four treatment drugs, consisting Ethambutol 20 mg/kg
of isoniazid, rifampicin, pirazinamide, and eth-
ambutol, followed by 48 doses of isoniazid and Adjunct Drugs
rifampicin triweekly (Table 35.6).
For tuberculous meningitis, corticoid use reduces
morbidity and mortality through reduction of
Extrapulmonary Tuberculosis vasculitis, inflammation, and intracranial
hypertension.
Extrapulmonary tuberculosis requires the same Adjunct drugs are indicated when there is
treatment as pulmonary tuberculosis with posi- compression of the bronchial tree caused by
tive bacteriology, unless there is tuberculous pericarditis-­related adenopathies. Prednisone is
meningitis or miliary meningitis. the most widely used steroid, with a dose of
1–2 mg/kg/daily during 4–6 weeks.

 uberculous Meningitis and Miliary

T
Tuberculosis HIV Coinfection

Treatment is the same as for pulmonary tubercu- Coinfections of HIV with tuberculosis are possible,
losis, extending the triweekly phase to 7 months and in small children dissemination caused by BCG
(Table 35.7). must be ruled out. The treatment must be discussed
with infectious disease specialists, given the interac-
Table 35.5 Pulmonary tuberculosis with negative tion between antiretroviral and anti-tuberculosis
bacteriology drugs. It is advisable to start the anti-tuberculosis
Drug Daily phase Triweekly phase treatment first and add the antiretroviral treatment
50 doses 48 doses afterward (because of the risk of causing an immune
(10 weeks) (16 weeks)
recovery syndrome). The triweekly treatment phase
Isoniacid 10 mg/kg 15 mg/kg
(max. 400 mg) (max. 600 mg) should be extended for 7 months at least, depending
Rifampicine 15 mg/kg 20 mg/kg on the immunological condition of the patient.
(max. 600 mg) (max. 600 mg)
Pirazinamide 35 mg/kg
Follow-Up and Control
Table 35.6 Pulmonary tuberculosis with positive
bacteriology Bacilliferous patients require monthly bacillos-
Drug Daily phase Triweekly phase copy and bacterial susceptibility tests.
50 doses 48 doses
(10 weeks) (16 weeks)
Isoniazid 10 mg/kg 15 mg/kg
(max. 400 mg) (max. 600 mg)
 dverse Reaction to Anti-
A
Rifampicine 15 mg/kg 20 mg/kg tuberculosis Drugs
(max. 600 mg) (max. 600 mg)
Pirazinamide 35 mg/kg If an adverse reaction to anti-tuberculosis drugs
Ethambutol 20 mg/kg is suspected, therapy must be suspended and
35  Pulmonary Tuberculosis 353

Table 35.8  Adverse reactions to anti-TB drugs Crofton J, Horne N, Millar F.  Tuberculosis Clínica.
MacMillan Education Ltd. 1992 (Unión Internacional
Drug Adverse reaction
contra la Tuberculosis y Enfermedades Respiratorias).
Isoniazid Jaundice and increase in transaminases Farga V. Tuberculosis. Santiago: Mediterráneo, 2011. 3rd
(infrequent) edn. Auspiciado por la Unión Internacional Contra la
Peripheral neuritis that can be treated Tuberculosis y Enfermedades Respiratorias.
with pyridoxine (infrequent) Garcia-Peña P, Guillerman RP, editors. Pediatric chest
Dermatitis and lupus-like reactions imaging, medical radiology. Diagnostic imaging.
(rare) Berlín-Heidelberg: Springer; 2013.
Rifampicin Skin rash, jaundice, and transaminases Hamzaoui A, Yaalaoui S, Tritar F, Slim L, Berraies
increase (infrequent in children, A.  European Respiratory Update Tuberculosis.
information to consider in patients with Childhood tuberculosis: a concern of the modern
liver damage) world. Eur Respir Rev. 2014;23:278–91.
Flu-like reactions followed by renal Marais BJ, Rabie H, Cotton MF. TB and HIV in children
impairment advances in prevention and management. Paediatr
Thrombocytopenia Respir Rev. 2010;12:39–45.
Pirazinamide Liver damage Miller FJW.  Tuberculosis in children evolution, epide-
Hyperuricemia, arthralgia, vomiting, miology, treatment, prevention. Edinburgh: Churchill
dysuria, and fever (rare) Livingstone; 1982.
Streptomycin Skin rash Ministerio de Salud, Subsecretaría de Salud Pública,
División de Prevención y Control de Enfermedades.
VIII pair injury, vertigo and/or hearing
Programa.
loss
Nacional de Control de la Tuberculosis. Actualización de
Kidney damage Normas Técnicas. 2014.
Ethambutol Optical neuritis Pediatrics. Vol 134, Number 6, December 2014. Technical
Report: Interferon-γ Release Assays for Diagnosis
of Tuberculosis Infection and Disease in Children.
complications must be ruled out. After this has Jeffrey R.  Starke, MD, FAAP and Committee on
been resolved, the treatment may be reintroduced Infectious Diseases.
with a programmed and independent desensitiza- World Health Organization. Global tuberculosis report.
tion scheme. These adverse reactions are The burden of disease caused by TB. Geneva: World
Health Organization; 2012. WHO/HTM/TB/2012.6
extremely infrequent (Table 35.8). World Health Organization, Global Tuberculosis
Report. Drug resistant TB.  Geneva: World Health
Organization.; 2012. WHO/HTM/TB/2012.6
Sources

Center for Disease Control and Prevention. Essential
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program: recommendations of the Advisory Council
for the Elimination of TB. MMWR. 1995;44:1–15.
 Respiratory Diseases
in the Newborn
36
José Luis Tapia Illanes, Paulina Toso Milos,
and Javier Kattan Said

Contents
Respiratory Physiology................................................................................................   355
Approaching the Newborn with Respiratory Disease...............................................   356
 lassification of the Respiratory Problems of the Newborn.....................................   359
C
Respiratory Problems Related to Perinatal Asphyxia.....................................................  359
Respiratory Problems Related to Prematurity and Lung Fluid Reabsorption................  361
Respiratory Problems Conditioned by Pulmonary Circulation Diseases.......................  366
Respiratory Infections of the Newborn: Pneumonia......................................................  368
Respiratory Problems Caused by Congenital Alterations of the Airway and Lungs......... 370
Sources...........................................................................................................................   370

Respiratory Physiology rity can be measured using this information in the

amniocentesis, as well as the analysis of the leci-
To understand respiratory diseases during this thin–sphingomyelin ratio (L/E) and phosphati-
period, knowledge of normal respiratory physiol- dylglycerol (PG).
ogy is helpful. During intrauterine life, the lungs The fetus has intermittent respiratory move-
produce liquid and are filled with it. During the ments, which may work to move this lung fluid
last trimester of pregnancy, this lung fluid goes out, with the objective to train its postnatal func-
through the trachea and provide all the substances tion. During childbirth, lymphatic reabsorption
to the amniotic fluid, even surfactant. Lung matu- of the lung fluid takes place, probably through
cortisol, thyroid hormones, and catecholamines,
which are boosted with the air pulmonary expan-
sion when the child has been born. Once the new-
born starts to breathe, the first efforts must be
very vigorous (around 40 cm H2O of pressure) to
expel lung fluid and establish a residual lung vol-
J. L. Tapia Illanes · P. Toso Milos · J. Kattan Said (*) ume. The beginning of breathing facilitates an
Department of Pediatrics, School of Medicine,
important reduction in lung vascular resistance
Pontificia Universidad Católica de Chile,
Santiago, Chile caused by the mechanical expansion of the lung
e-mail: [email protected]; [email protected] as well as the increase in PaO2 and pH, and

© Springer Nature Switzerland AG 2020 355

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_36
356 J. L. Tapia Illanes et al.

release of humoral vasodilators. Increase in PaO2 Table 36.1  Respiratory physiology of the newborn
is also responsible for constraining and function- High pressures in the first breaths
ally closing the patent ductus arteriosus (preterm  Expulsion of lung fluid
infants are more resistant to this closure). Besides  Decrease in lung vascular resistance
this, systemic pressure rises when circulation to  Constriction and functional closure of the arteriosus
ductus
the placenta is stopped. These changes allow the High distensibility of the rib cage
transition of the blood flow from fetal to neona-  Low functional residual capacity
tal. Pulmonary arterial smooth muscle is propor-  Increased pulmonary resistance
tionately greater in the newborn; therefore, when  Low lung distension
hypoxemia arises, pulmonary hypertension may  High respiratory rate
easily develop, and thus the lung would go back  Nasal breathing
 Lower CO2 ventilatory response in preterm infants
to a “fetal circulation.”
 Paradoxical hypoxemia response
Breathing control is more vulnerable during
 High minute ventilation
the neonatal period. Although there is a ventila-  Increase of dead space in preterm infant
tion response to CO2 level increase, it is less pow-  High oxygen consumption
erful in the preterm newborn and is further  Active Hering-Breuer’s and Head’s reflexes
reduced by hypoxemia. Newborns present a para-  Pulmonary arteries with larger muscles
dox response to hypoxemia. For a few seconds, a
transient hyperventilation occurs (caused by
stimulation of chemoreceptors), which then pro- other ages, and this higher rate may be useful to
gresses to a central respiratory depression. In the maintain keep lung volume through the reduction
preterm newborn, the hyperventilation phase is in expiratory time (Table 36.2).
reduced, and it can even be absent in those who
are very immature. Respiratory reflexes such as
the Hering-Breuer (vagal inhibition) and Head Approaching the Newborn
(inspiratory response to lung inflation) are fully with Respiratory Disease
functional (Table 36.1).
Distensibility of the rib cage is greater in The respiratory distress syndrome (RDS) symp-
the newborn, especially in the preterm infant, toms are tachypnea, retraction, grunting, cyano-
which makes it difficult to maintain an ade- sis, and apnea. Nevertheless, these can present
quate lung residual capacity, and can also ease from pulmonary and extrapulmonary causes
alveolar collapse when there is a low lung (Fig. 36.1). A detailed perinatal anamnesis based
distension. on risk factor determination and an exhaustive
Of the resistance forces, 20% correspond to physical examination are essential for determin-
the friction of the lung against the rib cage and ing a precise diagnosis and adequate
80% correspond to airway resistance. In the management.
newborn, the nostrils are the point of greatest Excluding hyaline membrane disease, the risk
airflow resistance in the airway. This is impor- factors related to respiratory diseases are as
tant, considering that during this period, breath- follows:
ing is done mostly through the nose. Lung
airway resistance is greater in the newborn than • Conatal pneumonia: Masculine sex, feverish
in the adult. In addition, because of the small mother, chorioamnionitis, premature labor,
size of the airway in the newborn, any obstruc- prolonged membrane rupture, prolonged
tive process will noticeably increase lung labor, streptococcal maternal colonization,
resistance. Guillain–Barré syndrome, tracheoesophageal
In absolute terms, lung distensibility is less in fistula.
the newborn than in the adult, but when correc- • Meconium aspiration syndrome: (TTN)
tion per weight is done the values are similar. Amniotic fluid stained by meconium, fetal dis-
Respiratory rate in the newborn is greater than at tress, post maturity, small for gestational age.
36  Respiratory Diseases in the Newborn 357

Table 36.2  Comparison of respiratory variables per age

Newborn Adult
Respiratory frequency (f) 34–45 13 rpm
Tidal volume (Vt or Vc) 6–8 7 ml/kg
Alveolar volume (Va) 3.8–5.8 4.8 ml/kg
Anatomical dead space (VD) 2–2.2 2.2 ml/kg
Minute ventilation (Ve) 200–260 90 ml/kg/min
Alveolar ventilation (Va) 100–150 60 ml/kg/min
Functional dead space (VD) 77–99 30 ml/kg/min
Dead space/tidal volume (VD/Vt) 0.27–0.37 0.3
Oxygen consumption (VO2) 6–8 3.2 ml/kg/min
Lung resistance (R) 20–30 3–4 cm H2O/l/s
Dynamic lung distensibility (Cd) 4–6 100–150 ml/cm H2O
Functional residual capacity (FRC) 20–30 34 ml/kg
BPM breaths per minute
Note: Preterm newborns have a higher dead space/tidal volume ratio (0.5) and greater pulmonary resistance

Cyanosis
Retractions
Grunting
Pulmonary Tachypnea Extrapulmonary

Common Rare Cardiac Metabolic CNS Blood

HMD Choanal atresia Cyanotic Hypoglycemia Drugs Hyperviscosity

Aspiration T-E Fistula Pulm Flow Hypothermia Hemorrhage Hypovolemia
Pulm flow Methahemoglobin
TTN Congenital
Acidosis Edema
Diaphragmatic CO
Pneumothorax Thyrotoxicosis
Hernia
Pneumonia Laryngomalacia Myocarditis
Cysts, tumors
Hemorrhage Lobar
PPH emphysema
Thoracic
hypoplasia

Fig. 36.1  Differential diagnosis for RDS

• Transient tachypnea of the newborn: Cesarean A history of polyhydramnios is related to dia-

section, fast labor, neonatal depression, mater- phragmatic hernia and tracheoesophageal fistula.
nal sedation. A history of oligohydramnios is related to pulmo-
• Pneumothorax: History of resuscitation nary hypoplasia, prolonged membrane rupture,
through manual ventilation. and renal agenesis. In relation to the anamnesis, it
• Persistent pulmonary hypertension: (PPH) is important to consider the following issues:
Meconium aspiration syndrome, neonatal
depression, pneumonia, polycythemia, con- • Maternal history: Health state before preg-
genital diaphragmatic hernia, ingestion of nancy and during previous pregnancies, pre-
aspirin or antiinflammatories, hyaline mem- natal care, prenatal ultrasound, family
brane disease, cold stress. diseases, pregnancy diseases, drugs and
358 J. L. Tapia Illanes et al.

medications, cause of hospital admittance, Table 36.3  Causes of changes in thoracic volume
labor time, fetal state, amount of amniotic Bilateral
fluid (maturity, infection signs, meconium), Volume Transient tachypnea, meconium
bleeding, fetal distress, type of labor, increase aspiration syndrome, pulmonary
hypertension, cystic lung diseases
approximate gestational age.
Volume Hyaline membrane disease, pulmonary
• Newborn history: General condition at birth, reduction hypoplasia, thoracic wall restricted
need for resuscitation, Apgar score, vital Unilateral
signs, evaluation during transition period. Low-­ Atelectasis, unilateral pulmonary
• Physical examination: Nutritional state, pres- volume hypoplasia
disease
ence and distribution of cyanosis. Acrocyanosis
High-­ Pneumothorax, unilateral interstitial
or distal cyanosis in feet and hands are com- volume emphysema, pulmonary cystic disease,
mon findings within the first days of life. disease Diaphragmatic disease, chylothorax
However, central cyanosis is always abnor-
mal, and it is evident when deoxygenated which lasts from 5 to 10 s. It is important to
hemoglobin exceeds 3 g/dl, and this suggests notice the height of the tip of the heart, as it
the presence of hypoxemia. Cyanosis from will be displaced if there are pulmonary
crying is possible because a short circuit is masses, pneumothorax, or pulmonary hypo-
caused by the Valsalva maneuver through the plasia. A scaphoid abdomen is typical of dia-
foramen ovale. Paleness may suggest shock, phragmatic hernias, where part of the
vasoconstriction, anemia, and obstruction of abdominal content is placed in the thoracic
the cardiac outflow tract. Polycythemia may cavity, which does not allow an adequate
be suspected if the child looks plethoric; if the development of abdominal cavity, but it looks
child has meconium stains, then meconium similar to the abdomen of a child who has
aspiration is suspected, and if there is exan- eliminated meconium in the uterus. Abdomen
thema or a bad smell, it must be considered distension can be seen when there is a tracheo-
that the cause of the breathing difficulty is a esophageal fistula, especially when positive
pneumonia. Nasal flaring shows the new- pressure has been used. If the belly button
born’s need for air. The shape of a barrel chest moves toward one side during inspiration or
suggests a volume increase, and a bell-shaped presents a “belly button dance” sign, it may be
chest suggests a volume decrease (Table 36.3). a sign of diaphragmatic paralysis in the side to
Extremely preterm newborns (<1000 g) have which it is moving. When there is pulmonary
a very compliant thoracic wall. During normal hyperinsufflation, the liver and spleen can be
breathing a negative interpleural pressure is easily palpated.
created, but it goes even further when the lung
is sick, causing an evident intercostal and Considering lung sounds, grunting is the most
xiphoid retraction, with a tendency to col- characteristic. It is caused by the opposition of
lapse. This collapsing and protruding of the vocal cords at the end of the expiration phase.
abdominal content, caused by the diaphragm Grunting causes positive pressure toward the end
moving downward, are the factors that cause of the expiration, which keeps the small airways
“swing” or paradoxical breathing, which is open and improves ventilation distribution.
typical of the severe breathing difficulty syn-
drome. Tachypnea is considered when the • Stridor suggests an obstruction of large air-
newborn has more than 60 breaths per minute ways. If the obstruction is extrathoracic,
and is the most sensible sign. Normal prema- stridor will be greater at inspiration,
ture and term newborns will present a respira- although it can be heard in both inspiration
tory pattern called periodical breathing, which and expiration when the obstruction is
consists of shallow breaths followed by the severe. Pulmonary murmur can be evaluated
cease of respiratory efforts or short apneas, according to its intensity, length, symmetry,
36  Respiratory Diseases in the Newborn 359

presence of crepitus, ronchi, or wheezing, ease. It can also be used for treatment, as
although these alterations are less frequent there are different goals, depending on the
in newborns. gestational age and the type of disease.
• Laboratory tests –– Hyperoxy test: Hypoxemia is considered
–– Chest X-rays: Very useful in the differential when extrapulmonary short circuits from
diagnosis of respiratory and nonrespiratory right to left are suspected (congenital heart
diseases. Lateral and anteroposterior pro- disease and pulmonary hypertension).
jections are essential for a good evaluation Oxygen is provided at 100% and gases are
of pneumothorax, catheter position, and controlled. If the disease is pulmonary,
pleural tubes. Bones, soft tissues, and the PaO2 increases significantly.
visible portion of the abdomen must be –– General tests: Hematocrit must be con-
systemically evaluated before focusing on trolled, because polyglobulic conditions
the heart and lungs. Also, each chest X-ray may cause hypoxemia, and acute anemia
film must be used to reevaluate the position may cause difficulties in starting spontane-
of tubes and catheters because they usually ous breathing during resuscitation. In every
migrate. pathological process glycemia must be
The trachea is easily curved because of controlled because of the immaturity of the
its great flexibility, and it can even seem to regulation systems, which is related to a
have a mass effect, through its compression greater energetic expenditure and reduced
by other abnormal structures (Table 36.4). intake.
–– Cell blood count and cultures: Infections
must be actively sought, because of what a
prompt treatment involves and also because Classification of the Respiratory
of the difficulty of making a differential Problems of the Newborn
diagnosis, especially when differentiating
from hyaline membrane disease. I. Respiratory problems caused by perinatal
–– Pulmonary function test: Initially it was asphyxia.
only performed under investigative condi- II. Respiratory problems related to immaturity
tions, but today many ventilators are and lung liquid reabsorption.
equipped with sensors that allow measur- III. Respiratory problems related to lung circula-
ing this function. It is very useful to deter- tion. Respiratory problems conditioned by
mine tidal volumes (if they are not lung circulation diseases.
increased) and pulmonary overdistension
IV. Respiratory infections in the newborn:
signs, which can contribute to neonatal pneumonia.
lung damage. V. Respiratory problems caused by congenital
–– Blood gases: One of the most useful tests to alterations of the airway and lungs.
determine the physiopathology of the dis-

Table 36.4  Common findings and variants in neonatal  espiratory Problems Related
R
chest X-ray to Perinatal Asphyxia
Normal findings Normal variants
Uniform lung fields Pleural fissures  ardiorespiratory Depression at Birth
C
Less prominence of Tracheal twisting and As many as 10% of newborns requires some kind
pulmonary hilums indentation of support to start breathing spontaneously. It is
8–9 ribs expansion Mediastinal lines
crucial to anticipate this situation by determining
Tracheal deviation to the Pseudohyperlucid lung
right which childbirths may produce depression at
Air bronchogram Apical or intercostal hernia birth. Because of this, it is important to have at
Cardiac silhouette <60% Radiolucency of the each childbirth at least one qualified person who
of thorax suprasternal space may provide the initial resuscitation steps, and
360 J. L. Tapia Illanes et al.

another person who may perform advanced 34 weeks, the anal sphincter does not relax dur-
resuscitation. The action flowchart is taught at the ing asphyxia. Hypoxemia also causes the fetus to
Neonatal Resuscitation Program, which is regu- initiate deep breathing efforts, and so the fetus
lated by the American Academy of Pediatrics and aspirates the amniotic fluid containing meco-
the American Heart Association. nium. During birth the risk of meconium aspira-
During childbirth the fetus may be exposed to tion is greater, as a consequence of the first
periods of temporary hypoxia, caused by the breaths. Meconium impacts different levels of the
decrease of the placenta blood flow. The fetus thinner airways, which causes an obstructive
adapts to these periods by redistributing the respiratory disease with entrapped air, and altera-
blood flow to favor the brain, heart, and adrenal tion of alveolar stability, along with its inflamma-
glands. During hypoxic periods, the respiratory tory reaction. Entrapped air is one of the causes
system has adaptation mechanisms that are not of the high rate of pneumothorax in this disease.
efficient in either the fetus or the newborn: this is In almost 50% of the cases, respiratory failure is
called paradoxical response to hypoxia. It hap- related and complicated by an important degree
pens when the fetus and newborns who have suf- of pulmonary hypertension. Ventilatory mechan-
fered hypoxia increase their respiratory rate and ics are altered: airway resistance is increased,
respiratory effort (tidal and minute volume functional residual capacity is also increased
increase), but this is transitory, and it rapidly because of the entrapped air, pulmonary distensi-
progresses into apnea. Therefore, it is not uncom- bility is reduced, and there is compromise of the
mon to face a perinatal hypoxia sign consisting ventilation/perfusion ratio. The result is a respira-
of no respiratory effort at birth, which will tory distress situation with hypoxemia and
require resuscitation techniques to start sponta- hypercarbia.
neous breathing. Depending on how long the Generally, the patient is a term or postterm
fetus has been hypoxic, the apnea may be pri- newborn. Sometimes they are small considering
mary or secondary. Secondary apnea implies a their gestational age, with a history of perinatal
greater time suffering hypoxia, wherein compen- asphyxia, which has been certified through the
satory vascular mechanisms have been over- presence of meconium in the amniotic fluid, as
whelmed, and this is reflected in the fall of well as alteration in the fetal heartbeat and car-
arterial pressure. When resuscitating a child with diorespiratory depression at birth, which requires
secondary apnea it is crucial to provide ventila- resuscitation. There can be meconium in the
tion with effective positive pressure, and, less umbilical cord, and the skin of the newborn may
frequently, to use cardiac massage and drugs. have meconium impregnations. Polypnea and
respiratory distress signs appear early: chest
 erinatal Asphyxia and Respiratory
P retraction, grunting, and nasal flaring. The thorax
Distress Syndrome Caused by curves outward, with increased anteroposterior
Meconium Aspiration diameter. There is a noticeable cyanosis, which,
Respiratory distress syndrome caused by aspira- at the beginning of the clinical presentation, usu-
tion of meconium is a common complication of ally responds to an increase in the oxygen
perinatal asphyxia, and sometimes it is a serious inspired fraction, unless there is a serious pulmo-
one; this is frequently found in a postterm new- nary hypertension. During auscultation there can
born. Its prevention depends on good control and be a reduction of the pulmonary murmur and
perinatal management. crackles. Other concomitant complications
Intrauterine asphyxia stimulates gastrointesti- caused by asphyxia, and which may require spe-
nal motility and the relaxation of the anal sphinc- cific treatment, must be investigated, such as
ter, which allows the meconium to enter the hypoxic-ischemic encephalopathy, renal impair-
amniotic fluid, but this is uncommon before ment, cardiogenic shock, and alterations of the
37 weeks of gestation. If the fetus is younger than coagulation process.
36  Respiratory Diseases in the Newborn 361

If the aforementioned clinical history and Depending on the additional problems and the
signs are considered, diagnosis is generally clear. evolution of the patient who has undergone
The aim of the laboratory examinations is to cor- asphyxia and meconium aspiration, other exami-
roborate the diagnose of meconium aspiration, nations may be necessary if there is suspicion of
evaluate the presence of other complications an important pulmonary hypertension: glycemia,
from asphyxia, and for follow-up. calcemia, cardiac and brain isoenzymes, coagula-
The following examinations must be done: tion tests, brain ultrasound, and echocardiogra-
phy, when an important pulmonary hypertension
• Anteroposterior and lateral chest X-ray. is suspected.
X-rays will show irregular opacities as nod- Prevention includes good pregnancy control
ules or cords, following the distribution of the and newborn attention at birth. Meconium aspira-
bronchial tree next to hyperinsufflation zones. tion from the trachea, using endotracheal intuba-
The diaphragm is sometimes flat. It is impor- tion when the newborn is hypotonic, is a common
tant to rule out the presence of pneumothorax practice, although it has not been validated.
(Fig. 36.2). Management consists of adequate oxygenation,
• Arterial gases. Arterial gases will show the ventilation support as needed, antibiotics use
degree of respiratory failure. These measures until an infection is ruled out, and management
must be serially controlled every 48  h, as of complications such as pneumothorax, pulmo-
needed. This information will be key for deliv- nary hypertension, and other issues related to
ering a prompt and adequate treatment, to asphyxia and sepsis. It has been proven that the
evaluate its efficacy as well as the progression administration of diluted surfactant reduces the
of the disease. need of extracorporeal membrane oxygenation
• Cell blood count and blood culture. These and the risk of death.
tests are important to obtain hematocrit values
and detect a possible infection. Meconium is a
good culture medium.  espiratory Problems Related
R
to Prematurity and Lung Fluid
Reabsorption

 yaline Membrane Disease

H
Hyaline membrane disease (or respiratory dis-
tress syndrome, RDS) is a respiratory disease
characteristic of the premature newborn, caused
by pulmonary surfactant deficiency. Surfactant is
produced in the type II pneumocytes. It is com-
posed of phospholipids with small quantities of
neutral fat, cholesterol, and proteins. The primary
active molecule is saturated dipalmitoyl phospha-
tidylcholine, but phosphatidylglycerol and unsat-
urated phosphatidylcholine are also present.
Surfactant reduces superficial tension, adhering
to the alveolar surface and displacing water mol-
ecules. It has four proteins: A, B, C, and D. Protein
Fig. 36.2  Meconium aspiration syndrome. Chest X-ray A is more abundant and it is hydrosoluble. It has
of a term newborn combines alveolar interstitial shadows a key part in the surfactant recycling process and
with slightly collapsed areas with pneumothorax to the some capacity to protect the lung. Protein B
left side, partially leaking with the insertion of a chest
tube. Patient is intubated and connected to venoarterial
intervenes in the surfactant recycling process.
extracorporeal membrane oxygenation (ECMO) Protein C increases surfactant reabsorption and
362 J. L. Tapia Illanes et al.

production. Protein D has a defensive function in Table 36.5  Risk factors related to hyaline membrane
the lungs. Type II pneumocytes appear in the disease (HMD)
lung from 20 to 24 gestational weeks. Steroids Increased risk Reduced risk
and thyroid hormones increase the transcription Masculine sex Female sex
and synthesis rate of limiting enzymes. The func- White race Black race
L/E < 2.0 for premature L/E > 2.0a
tion of the pulmonary surfactant is to reduce the newborns
superficial tension in the alveoli to maintain pul- Previous brother with HMD Maternal preeclampsia
monary stability and volume during exhalation. It Maternal diabetes (A, B, C) Maternal diabetes (D, F,
is crucial to have an adequate amount of surfac- R)
tant in the liquid–air interface to sustain alveolar Maternal hypotension Maternal drug abuse
stability. As a result of surfactant deficiency, Cesarean section without Antenatal steroids
labor
there is a tendency to alveolar collapse, which Third-trimester hemorrhage Chronic abruption
causes a progressive atelectasis, with an intrapul- Second twin Prolonged membrane
monary blood flow short circuit that evolves into rupture
an increasing hypoxia. Functional alterations Fetal hydrops Intrauterine growth
characteristic of hyaline membrane disease are retardation
Neonatal depression Vaginal childbirth
reduction of pulmonary distensibility and of the
Lecithin/sphingomyelin
a
functional residual capacity, accompanied by an
alteration of the perfusion–ventilation ratio. This
alteration of pulmonary mechanics originates a
global respiratory failure with hypoxemia and
hypercarbia, which is worsened by the fatigue of
the respiratory muscles. Hypoxemia and acidosis
increase pulmonary vascular resistance, which
worsens the condition.
Hyaline membrane disease is the main cause
of respiratory morbidity and mortality in the pre-
mature newborn. Its incidence is estimated in
about 50% of children who are younger than
29 weeks of gestational age and only about 5% of
those older than 34 weeks. In the South American
region, an incidence of 74% has been found
among newborns whose weight is less than 1500
Fig. 36.3  Hyaline membrane disease. Chest X-ray in
g at birth. Related risk factors have been described newborn whose lung volume is lightly reduced (because
(Table 36.5). the newborn has undergone intubation and receives posi-
Hyaline membrane disease is characterized by tive pressure), frosted glass sign, and air bronchogram
an early-onset progressive respiratory difficulty,
usually starting at birth or during the first 6 h of pathognomonic, showing a homogeneous
life. It causes a respiratory grunting, usually increase of pulmonary density, described as a
audible, nasal flaring, retraction, polypnea, and frosted glass on which air bronchogram images
FiO2 requirements that increase rapidly. Vesicular can be seen (Fig. 36.3).
murmur tends to be reduced during auscultation. Blood gases show oxygen requirements that
Anteroposterior thoracic diameter is reduced. In need to be addressed rapidly with fraction of
severe cases, breathing can become paradoxical inspired oxygen (FiO2) above 30–40%.
or in “swings.” There is generally edema and Depending on the seriousness of the case, there
reduced diuresis. may be respiratory or metabolic acidosis.
Chest X-ray is essential for the diagnosis. The The most important and difficult differential
radiological image is characteristic, but not diagnosis is conatal pneumonia produced by
36  Respiratory Diseases in the Newborn 363

group B streptococcus. The clinical and radio- improving the survival rate. There are natural
logical findings may be identical. Perinatal his- and artificial surfactants: the first are extracted
tory is important for making a differentiation, from the amniotic fluid of animals and the sec-
and in the case of pneumonia, a fast progression ond are synthesized, which mainly includes sur-
with a greater tendency to cardiovascular com- factant phospholipids, but not its proteins. A
promise. During the first hours it can also be con- range of studies have shown that both natural
fused with transient tachypnea of the newborn. and artificial exogenous surfactants significantly
The benign course and good lung volume of this reduce morbidity and mortality rate in this dis-
last disease differentiates the two. ease. Other recent studies do not show signifi-
Prevention of hyaline membrane disease is cant differences when using different kinds of
essentially perinatal: diversion of risk pregnan- natural surfactant, which are those most used
cies to specialized centers, prevention and man- currently. The most effective approach is the
agement of premature labor, determination of early administration of the surfactant, before 2 h
fetal lung maturity depending on the case, and of life. It has also been used as prophylaxis in the
the acceleration of fetal pulmonary maturity. higher-risk groups, such as those younger than
Following the pioneer study done by Liggins 30 weeks. Nevertheless, it is becoming increas-
and Howie in 1972, several investigations have ingly common to use it with nasal continuous
confirmed that antenatal steroids are related to a positive airway pressure (CPAP) for the initial
significant reduction in the presentation of hya- respiratory stabilization in very low weight pre-
line membrane disease. In the same way, it has mature newborns, which seems to be a more
been demonstrated that antenatal steroids reduce appropriate approach than the prophylactic use
mortality and the incidence of intraventricular of surfactant. The INSURE technique has been
hemorrhage. Therefore, beyond traditional usage widely incorporated into clinical practice: this is
recommendations for the fetus who is INtubation-SURfactant-Extubation, with nasal
24–34 weeks of gestational age and at risk of pre- continuous positive airway pressure. During
mature birth, in many centers steroids are used recent years several studies have administered
before the 24  weeks. Their administration surfactant to the airway, through a fine tube, but
between 34 and 36  weeks is currently under results have not been conclusive.
study, given the impact of the currently named Respiratory assistance includes the prophylac-
“late-term premature newborns.” In all cases, the tic or early use of continuous nasal positive pres-
benefits obtained surpass the potential risks of sure, which reduces the need of mechanical
steroid usage, although repeated cycles must only ventilation, as well as INSURE. The use of non-
be used for investigation protocols, given the invasive nasal ventilation through nasal devices
association with a worse neurological outcome. that avoid the use of tracheal intubation is still
Treatment consists of 2 doses of 12 mg IM beta- being studied. Regarding oxygen administration
methasone, with a 24-h difference, or 6 mg dexa- to the premature newborn, current experts recom-
methasone IM with a 12-h difference. Optimal mend to start resuscitating with a FiO2 of 21–30%
benefits start 24 h after initiating therapy and per- to avoid oxidative damage. The saturation goal
sist up to 7 days after. for respiratory distress syndrome is to keep it
These children must be admitted to the inten- between 90% and 95%.
sive care unit. Ideally, they are born in a special- Other diseases have been related to hyaline
ized perinatal center, or at least they are promptly membrane disease, such as alveolar rupture,
taken to a tertiary neonatal center. infection, persistent arteriosus ductus, intraven-
Therapy with exogenous surfactant is, with- tricular hemorrhage, and pulmonary hyperten-
out doubt, the most significant therapeutic sion. It is possible that with an adequate treatment
advance for hyaline membrane disease. The or prevention for the hyaline membrane syn-
therapy has changed the natural progression of drome, all these diseases can be prevented or
the disease, making it shorter, and significantly made less stressful.
364 J. L. Tapia Illanes et al.

The chronic disease most usually related to • Primary or idiopathic newborn apnea. It is the
hyaline membrane disease is bronchopulmonary most common one. Its origin is unknown but it
dysplasia. In the long term, newborns who sur- is probably related to immaturity in the central
vive this disease seems to have a greater fre- and peripheral mechanisms of breathing con-
quency of respiratory diseases during the first trol. Its onset is usually between the second or
years of life. third day of life, and it disappears when the
We must note that congenital surfactant defi- newborn is 34–35  weeks of adjusted age,
ciency does exist. SP-B deficiency is the first although 2% of premature newborns with very
known cause of genetic neonatal respiratory dis- low birth weight at birth can continue to pres-
tress, and it is usually an autosomal recessive dis- ent apneas beyond 40  weeks of gestational-­
order. It is usually presented as a respiratory adjusted age.
difficulty syndrome in a term newborn who does • Apnea secondary to other disease. It can
not respond to any therapy, with progression is appear in premature and term newborns. The
death. most common triggers are metabolic prob-
The deficiency of transport protein ABCA3 lems (hypoglycemia, hypocalcemia, hypona-
(ATP-binding cassette member A3) has also been tremia), neurological alterations (intracranial
described, which is related to the transcellular hemorrhage, asphyxia, seizures), infections,
transport of surfactant and the assembly of lamel- respiratory distress conditions, bronchopul-
lar bodies. ABCA3 gene mutations have an auto- monary dysplasia, persistent ductus arterio-
somal recessive transmission. SP-C congenital sus, hypothermia, and anemia. The most
deficiency has also been described. These two important action is to treat the triggering
can appear during neonatal age, and later during cause.
childhood, as chronic respiratory disease.
In these conditions, the diagnosis is through According to their presentation, apneas are
determination of the protein content in the surfac- classified as follows:
tant, which has been collected from the fluid
obtained in the bronchoalveolar lavage, DNA • Central apnea: Absence of airflow and stop-
genetic testing oriented to identify blood muta- ping of breathing movements.
tions, electron microscopy, and immunohisto- • Obstructive apnea: There are respiratory
chemical dying for surfactant proteins on an movements, but no airflow.
available tissue sample.
There is no treatment for these congenital sur- (It must be considered that this type of apnea
factant deficits. Lung transplant does not present is not detected by the respiratory monitor. This
encouraging results, and the hope for the future diagnosis must be suspected in newborns with
may lie in gene therapy. bradycardia crisis and/or cyanosis with no appar-
ent etiology.)
Newborn Apnea
Newborn apnea consists in the absence of an air- • Mixed apnea. During the same episode, both
flow in the respiratory airway during a period of presentations are mixed. Generally, it appears
at least 20 s. It can be fewer than 20 s if bradycar- as an obstructive apnea that stops breathing
dia or cyanosis is present. It must be differenti- efforts through hypoxemia.
ated from periodic breathing, as already
described. With the intention of an early diagnosis, it is
Neonatal apnea especially compromises the recommended to routinely monitor every newborn
premature newborn, and it is present in 50% of who is younger than 34 weeks, given the high risk
children of gestational age less than 32 gesta- of apnea. It is important to consider that newborn
tional weeks. According to etiology, the classifi- hypoxemia, especially if the child is premature,
cation is as follows: has a depressing effect on the respiratory center.
36  Respiratory Diseases in the Newborn 365

When the diagnosis of premature newborn cardiovascular problems. If the baby was born
idiopathic apnea has been established, the follow- through vaginal birth, this diagnosis must be
ing therapeutic measures must be taken: cardiore- reconsidered, and pneumonia must be suspected.
spiratory monitoring and permanent O2 saturation, The respiratory distress clinical presentation
keep the neck in a neutral position, aspire secre- mainly consists in tachypnea. Oxygen require-
tions, keep body temperature as stable as possible, ments are usually low, and they are important for
close to the lower point of thermoneutrality, cor- the differential diagnosis. When they are higher
rect hypoxemia, and use methylxanthines, than 0.40 FiO2, the diagnosis must be
because they stimulate the respiratory center and ­reconsidered; this is a crucial element to differen-
improve the diaphragm contraction capacity. tiate it from a hyaline membrane disease. The
Theophylline has been the treatment most used chest has an increased or regular anteroposterior
for premature newborn apnea, with very good diameter. Auscultation may be normal, or the
results. As an alternative, caffeine may be used, pulmonary murmur may be slightly reduced.
which has fewer adverse effects, and higher doses Progression usually tends to the improvement of
can be administrated. In this way, other tools have the situation during the first 24–48  h. In some
been used for the treatment of apneas, such as cases, progression may take more time.
proprioception and olfactory stimuli. The chest X-ray may be normal or show vas-
In those cases of serious apnea that do not cular congestion and liquid at the fissures, and
respond to the previous measures, and that by sometimes in the pleural space (wet lung)
their intensity produce an important decline in (Fig. 36.4).
the child’s condition, an option is to use nasal Oxygen is administered to maintain a normal
continuous positive pressure in higher airflows. If PaO2 according to the requirements determined
there is no improvement, mechanical ventilation by the blood gases. pCO2 is slightly increased.
must be started. While the FiO2 is close to 0.40 and the respira-
tory frequency has a rate of 70/min, there should
 ransient Tachypnea of the Newborn
T be no oral intake.
Transient Tachypnea of the Newborn is a clinical
condition caused by a temporal alteration of the
neonatal breathing adaptation. It presents as a
respiratory distress disease, characterized mainly
by tachypnea, usually with a benign course,
short, and self-limited. It is more frequent in the
term or near-term newborns, as well as those
delivered by a cesarean section.
It is thought that this disease is caused by a
delay in the lung fluid reabsorption that is nor-
mally present during fetal life. The relationship
to a cesarean delivery, especially when this has
been an elective procedure, is caused by the fact
that labor would stimulate lung liquid reabsorp-
tion, probably mediated by catecholamines
secretion.
Even though there are clinical and radiological
facts that characterize neonatal transient tachy-
pnea, this entity is an exclusion diagnosis. The Fig. 36.4  Transient tachypnea of the newborn. Chest
X-ray in newborn, where good pulmonary volume is
main differential diagnosis is hyaline membrane highly visible, with vascular congestion and visible fis-
disease, pneumonia, post-asphyxia situations, and sure, at the right side
366 J. L. Tapia Illanes et al.

 espiratory Problems Conditioned by

R
Pulmonary Circulation Diseases Hypoxemia
Hypothermia
Acidosis
 ersistent Pulmonary Hypertension
P Hypotension
Persistent pulmonary hypertension (PPH) is
characterized by an alteration in the evolution
Asphyxia Vasoconstriction
from fetal to neonatal blood flow. The pressure of Anaerobic Pulmonary
the pulmonary artery and pulmonary vascular metabolism Hypertension

resistance are maintained at high values, as hap-

pens during the fetal period, which translates in
pulmonary hypoperfusion and short circuits from
right to left through the ductus and oval foramen. L-R Shunt
Mixed venous
Clinically, this presents through cyanosis and blood
PAD
Oval foramen
hypoxemia that do not respond to increase of the
fraction of inspired oxygen. This problem can
present as an isolated condition (idiopathic PPH),
but more frequently it is related to other diseases, Fig. 36.5  Cycle of events that perpetuate persistent pul-
monary hypertension (PPH)
particularly asphyxia, pneumonia, and meconium
aspiration.
Reduction of the resistance and pressure of the PaO2, even when FiO2 has not significantly
pulmonary artery during the hours immediately changed. Small reductions in this may be diffi-
after birth is central to the conversion from fetal to cult to recover. Other signs that may be present
newborn blood flow. There are predisposing fac- are those typical of heart failure and a systolic
tors for this situation: chronic and acute hypoxia, murmur with a reinforcement in the second
acidosis and hypercarbia, prenatal maternal use of sound.
prostaglandin inhibitors, insufficient anatomical Signs are not specific, and it can be difficult to
development in the cases of pulmonary hypopla- evaluate when there is other related respiratory
sia, as happens with diaphragmatic hernia or Potter disease. In some cases, especially in the i­ diopathic
syndrome; and respiratory difficulty syndromes, presentation, it is essential to consider the differ-
especially as caused by meconium aspiration. ential diagnosis of congenital heart disease. In
Pathological analyses of lungs from children 50% of newborns, there will be saturation differ-
with persistent pulmonary hypertension (PPH) ences greater than 20% between the preductal
show a thickening of the medium muscular layer territory (left arm) and the post-ductal territory
of the pulmonary arterioles as well as an abnor- (other limbs).
mal extension of the muscular layers in the intra-­ The chest X-ray will show particular signs of
acinar arteries. This fact has been presented as an the associated disease. In its idiopathic presenta-
explanation for the great lability and sensitivity tion, free and darker lung fields can be seen
of the pulmonary vasculature present in these because of the pulmonary flow reduction. When
children when faced with hypoxia, acidosis, and there is a left ventricular failure, pulmonary
other factors that affect it. Some mild hypoxemia venous congestion will be present.
episodes can be translated as important changes Doppler echocardiography is the most impor-
in the pressure of the pulmonary artery and oxy- tant diagnostic exam. It shows the short circuits
gen requirements (Fig. 36.5). from right to left through the ductus and oval
The cardinal clinical sign is cyanosis that foramen, and in most cases, it will exclude heart
does not improve when oxygen is adminis- structural abnormalities, which is the most
trated. Considering parenchymal disease, there important differential diagnosis. If there is a tri-
is a disproportionate hypoxemia and weak oxy- cuspid failure, the pressure of the pulmonary
genation. There is an important brittleness in artery can be estimated.
36  Respiratory Diseases in the Newborn 367

Prevention must consider all the factors that Sedation has proven to be of great help
increase pulmonary resistance and blood flow because the fight against the ventilator, as painful
pressure, before and after the birth. Fetal hypoxia stimuli, affects oxygenation much more than in
treatment must be avoided, and no anti-­ other disease. It is worth noting that with this
prostaglandins should be used when facing early treatment we do not have the ability to estimate
labor symptoms. During the postnatal period, a the compromise related to the underlying disease
good resuscitation must be done at birth. and the prolonged hypoxia.
Meconium aspiration must also be prevented, as It may be necessary to deliver volume or use
well as hypoxemia and acidosis. Hypoglycemia, vasoactive drugs to keep systemic pressure over
hypocalcemia, and polyglobulia must be identi- the estimated pulmonary pressure. Required
fied and corrected. Room temperature must be doses and drugs must be titrated to keep enough
neutral, and an adequate arterial pressure must be systemic pressure to revert the extrapulmonary
maintained. These measures are preventive, but short circuit without causing vasoconstriction
once the persistent pulmonary hypertension state because of drug excess.
has settled in, they must be considered as part of Since 1980 the use of extracorporeal membrane
the treatment. oxygenation (ECMO) has been described as being
Further, treatment requires the use of mea- especially efficient in pulmonary conditions
sures that will cause pulmonary vasodilatation. related to persistent pulmonary hypertension in
Oxygen is a potent vasodilator, and therefore newborns. Chile has had this resource since 2003.
therapy must try to keep a PaO2 within the high With this therapy the lungs are left resting during a
range of the normal numbers and a pH around few days while blood is being oxygenated through
7.40, to have a better oxygen delivery at tissue an external membrane. By avoiding pulmonary
level, always considering the hemoglobin disso- injure during mechanical ventilation, PaO2
ciation curve. Different means of mechanical improvement and the underlying disease recovery
ventilation have been used with some success. It time, the pulmonary vasoconstriction is reduced
does not matter which mode is used: the goal is to by the end of 5 to 10 days, allowing obtaining a
achieve a sufficient mean airway pressure survival rate greater than 85% for patients with no
(MAWP) and adequate ventilation. Often this is related malformations. It is a highly complex pro-
achieved with high-frequency ventilation. It is cedure, and costly, and it does entail risks. It is
recommended to use inhaled nitric oxygen (iNO), indicated for patients with a high probability of
which produces a selective vasodilatation in the death (IO >40 and/or PaO2 ≤40). This procedure
pulmonary vascular territory, when the oxygen- has technical limitations (indicated for children
ation index (IO) is greater than 20 (IO = MAWP who are past 34 weeks gestational age and weigh
× FiO2 × 100/PaO2). Transferring the patient to a more than 2 kg) as well as ethical limitations (neu-
center with iNO capacity is recommended to rological conservation). To improve the efficacy of
avoid any risks for the patient: it is recommended this therapy, it is recommended to transfer the
to transfer the patient when IO reaches 15 and patient 4 to 6 h before the onset of serious persis-
does not improve. iNO response is variable when tent pulmonary hypertension.
there is a persistent pulmonary hypertension
related to malformations, such as a diaphrag- Persistent Arteriosus Ductus
matic hernia. Methemoglobin may be present, as Persistent arteriosus ductus (PAD) is a blood ves-
this complication has been described when iNO sel that is characteristic of fetal blood flow, which
has been used at high ranges during prolonged communicates the pulmonary trunk with the
periods. A recent multi-centric study in Chile descending aorta. During fetal life, it allows most
proved that mortality rate is reduced through the of the cardiac output from the left ventricle to go
administration of endotracheal surfactant, in rela- to the aorta, because the pulmonary artery pres-
tion to the use of iNO in newborns whose IO was sure is greater. This function is normal and essen-
greater than 20 (González et al.). tial for fetal blood flow.
368 J. L. Tapia Illanes et al.

The finding of a persistent ductus arteriosus in

a term newborn is generally related to an anatom-
ical defect, which may or may not be linked to
other heart malformations or genetic syndrome.
In the premature newborn, the persistent arte-
riosus ductus is fundamentally related to immatu-
rity, with an inversely proportional increase in
consideration to gestational age. Ductus sensibil-
ity to produce a strong contraction when facing
PaO2 is lowered as the gestational age decreases,
and its vasodilatation is greater with prostaglan-
dins. Persistent arteriosus ductus alters pulmo-
nary mechanics as well as the gas exchange,
which results in a left-sided heart failure.
Generally, the clinical history corresponds to a
preterm newborn whose weight is very low. And Fig. 36.6 Persistent arterial duct. Chest X-ray of a
notably, during the improvement stage in rela- 31 weeks newborn who, at 10 days of life, presents with
tionship to hyaline membrane disease, when the respiratory worsening related to a hemodynamically
pulmonary vascular resistance decreased, a sys- important ductus
tolic ejection murmur appeared. This murmur is
rarely continuous, and it can be better auscultated through it, and, to a lesser degree, the relationship
in the left infraclavicular region and the left supe- between the size of the left atrium and the aorta.
rior parasternal border, commonly radiating to In preterm newborns whose weight is less
the side. Its intensity can vary in a short time, and than 1000 g, it is necessary to be careful in ductus
sometimes it is not perceived during auscultation. detection as it would be easier for this condition
The onset of the persistent arteriosus ductus may to impact the hemodynamic system.
be accompanied by hyperactive precordium, Treatment considers keeping an adequate oxy-
tachycardia, and jumpy pulses in the postductal genation and ventilation support, hematocrit
region. Sometimes the heartbeat can be perceived between 40% and 45%, fluid restrictions, a high
in the palm of the hand of the newborn. Mean suspicion of concomitant infection, and pharma-
arterial pressure drops at the beginning according cological closure using prostaglandin inhibition,
to the diastolic pressure, which produces differ- such as indomethacin or ibuprofen. The use of
ential pressures (PS-PD)  >  25–30  mmHg. oral or IV paracetamol is still experimental.
Tachypnea is also present, along with an increase When these measures fail and hemodynamic
in the apnea pattern and general worsening, with compensation persists, surgical closure is per-
an increase of oxygen requirements, ventilation formed to avoid secondary pulmonary damage.
support, and even including the use of vasoactive
drugs. Hypoxemia can be seen in the blood gases,
and respiratory or metabolic acidosis may be Respiratory Infections
present, if the ductus is present with systemic of the Newborn: Pneumonia
hypoperfusion.
Chest X-ray can show cardiomegaly and pul- The lung is the organ most frequently affected by
monary congestion signs (Fig.  36.6). infections developed during the first 24 h of life:
Bidimensional Doppler echography is used to 90% of fatal infections involve respiratory com-
confirm the diagnosis and allows calculating promise. Conatal infection is usually ascendant,
approximately the degree of hemodynamic related to the rupture of membranes, but it tends
impact, according to the size of the ductus at the to happen with intact membranes when they are
pulmonary end, the magnitude of the blood flow contaminated by the maternal genital or anal
36  Respiratory Diseases in the Newborn 369

flora at childbirth, and less frequently, transpla- sis and air bronchogram that cannot be
cental. The other common cause of infections of distinguished from hyaline membrane disease.
the airway is the nosocomial in hospitalized new- Culture of airway secretions provides guid-
borns, especially preterm newborns. ance relative to the etiological agent. Cultures
Because of their immunity limitations and must be performed early through tracheal aspira-
anatomical features, newborns are greatly sus- tion during the progress of the infection. Positive
ceptible to developing lung infections. The most hemocultures and an altered chest X-ray confirm
frequent microbial agents are these: the diagnosis. A complete blood count (CBC)
may show leukocytosis or leucopenia, as well as
• Conatal bacterial infections: Group B a deviation to the left. These changes may also
Streptococcus (GBS), Escherichia coli, and appear in cases of perinatal asphyxia or other
Listeria: also, Streptococcus pneumoniae, stressful situations. After the first week of life,
Haemophilus influenzae, and Salmonella, changes in the CBC give better signs of infection.
among others. C-reactive protein is more useful in nosocomial
• Conatal viral infections: Herpes simplex, infection situations. Procalcitonin has also been
cytomegalovirus, rubella, influenza virus, used as an acute-phase reactant in infections with
adenovirus, and echovirus. After the first a good correlation.
days, nosocomial bacteria appear, such as These children require treatment in intensive
Klebsiella, Pseudomonas, Enterococcus, care units. Their treatment includes general con-
Staphylococcus, and E. coli. Cytomegalovirus, trol measures of vital signs and internal medium
type II herpes, Ureaplasma, and Pneumocystis stability: blood gases, glycemia, calcemia, and
jirovecii (previously known as P. carinii) have hematocrit. Many of them require breathing and
been identified as causal agents in late pneu- hemodynamic support with vasoactive drugs. A
mopathies, which may produce clinical pre- serious complication is the aforementioned lung
sentations similar to those of hypertension. Specific treatment must be chosen
bronchopulmonary dysplasia. in accordance to the causal agent.
When a conatal bacterial infection is sus-
Candida albicans affects premature newborns pected, antibiotic treatment must be implemented
who receive parenteral feeding and broad-­ early, right after the samples for culture are taken.
spectrum antibiotics, or who have undergone If the child is referred to a specialized unit, the
intestinal surgery. antibiotic treatment must start immediately after
Chlamydia trachomatis is an organism that the samples for culture are taken and before the
can frequently cause neonatal conjunctivitis, and transfer. The scheme used, in accordance to the
it can also cause a late-onset pneumonia most frequent infections, is ampicillin and one
(2–12  weeks of life), in spite of its perinatal aminoglycoside, which will be modified if it is
acquisition. Its main symptoms are polypnea, necessary when the agent has been identified or
grunting, and cyanosis, which rapidly worsen depending on the clinical response.
when they are not treated. Early apneas suggest Given the high frequency and severity of the
conatal infection. Crackles and abolished pulmo- infections caused by group B Streptococcus
nary murmur, which are a particular characteris- (GBS), some preventive strategies have been
tic of the breastfeeding baby, are not usually developed. The most effective one is to identify
found in the newborn. The presence of metabolic mothers who are GBS carriers through perineal
acidosis with no clear etiology, as well as a ten- culture at 35 to 37 weeks of pregnancy. For them,
dency to shock, suggest an infection. antibiotic prophylaxis during childbirth is indi-
Chest X-ray may reveal areas with pulmonary cated. If this previous information is not known,
infiltration, condensations and/or pleural effu- a prophylaxis treatment is indicated for the preg-
sions. Nevertheless, it is common to see atelecta- nant women who are at risk because of their
370 J. L. Tapia Illanes et al.

clinical history, such as previous children with When there is no prenatal information, the
GBS infections, chorioamnionitis, membranes clinical presentation, thoracic radiography,
ruptured after 18 h, or preterm birth. tomography, IRM, and endoscopic studies help
us to a precise diagnosis and the actions to be
taken. In some cases, only pathological anatomy
 espiratory Problems Caused by
R will give us a precise diagnosis. When a breath-
Congenital Alterations of the Airway ing tree malformation is confirmed, it is neces-
and Lungs sary to determine if this is associated with other
malformations or if they are part of a specific
There are several types of malformations. syndrome.
Because these are extensive, and because this text Some of these lung and airway malformations
is only one chapter about the issue, we only men- can be treated in very specialized university cen-
tion them (Table  36.6). Regular maternal ultra- ters for fetal therapy, where successful in utero
sound has allowed us to determine or suspect the interventions using fetoscopy tracheal occlusion
diagnosis before childbirth, and in some selected have been performed to treat diaphragmatic her-
cases, these malformations can even be treated nias; cystic adenomatoid malformations, when
during the prenatal phase. Nuclear magnetic res- they cause hydrops, with thoracoamniotic shunt-
onance has been more frequently used during the ing or radiofrequency ablation. These therapies
past decade to obtain further details, especially are still under evaluation in multicenter research
about malformations related to the central ner- protocols, so they are not yet standard therapies.
vous system, lungs, heart, and kidneys. In these During childbirth, fetal therapies centers have
situations, the suggested approach is to refer the collaterally developed procedures such as EXIT
mothers to high-volume specialized centers and (ex utero intrapartum treatment), which is cur-
to diagnostic and fetal therapy centers. rently used in patients suspected of having a non-­
open airway at birth (cervical teratomas, cystic
Table 36.6 Malformations that can compromise the hygroma, bronchogenic cyst, laryngeal atresia,
respiratory system etc.), whose main principle is to maintain placen-
Congenital Choanal atresia, Pierre Robin tal blood circulation during the 30 to 45  min
malformations sequence, macroglossia, velopalatal while the airway is being secured using i­ ntubation
of the upper insufficiency, laryngomalacia, vocal assisted through laryngoscopy or tracheostomy.
airway cord paralysis, laryngeal tumors,
esophageal atresia combined with
tracheoesophageal fistula, tracheal
agenesis, congenital tracheal
stenosis, tracheobronchomalacia, Sources
vascular rings, laryngeal cysts and
membranes, laryngeal atresia,
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compromise (e.g., teratomas).
tress syndrome. Cochrane Database Syst Rev.
Congenital Congenital lobar emphysema, 2012;11:CD001456.
malformations bronchogenic cyst, neurentenic cyst, Committee on Fetus and Newborn; American Academy
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lung lung sequestration, arteriovenous birth. Pediatrics. 2014;133:171–4.
parenchyma fistula, congenital pulmonary Fehlmann E, Tapia JL, Fernández R, Bancalari A, Fabres
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dysplasia, pulmonary aplasia or Ceriani Cernadas JM, Grupo Colaborativo Neocosur.
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diaphragm and skeletal dysplasias. Study Group of the Eunice Kennedy Shriver
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versus surfactant in extremely preterm infants. N Murphy KE, Hannah ME, Willan AR, et  al. MACS
Engl J Med. 2010;362(21):1970–9. Collaborative Group. Multiple courses of antena-
González A, Sosenko Y, Chandar J y cols. Influence of tal corticosteroids for preterm birth (MACS): a ran-
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González A, Fabres J, D’Apremont I, Urcelay G, Avaca 1995;273(5):413–18.
M, Gandolfi C, Kattan J.  Randomized controlled Porta NF, Steinhorn RH.  Pulmonary vasodilator therapy
trial of early compared with delayed use of inhaled in the NICU: inhaled nitric oxide, sildenafil, and
nitric oxide in newborns with a moderate respira- other pulmonary vasodilating agents. Clin Perinatol.
tory failure and pulmonary hypertension. J Perinatol. 2012;39(1):149–64.
2010;30(6):420–4. Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus
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Perinatol. 2002;22:2–7. Rev. 2012;3:CD000510.
Hahn S, Choi HJ, Soll R, Dargaville PA. Lung lavage for Tapia JL, Urzúa S, Bancalari A, Meritano J, Torres G,
meconium aspiration syndrome in newborn infants. Fabres J, Toro CA, Rivera F, Céspedes E, Burgos
Cochrane Database Syst Rev. 2013;4:CD003486. JF, Mariani G, Roldán L, Silvera F, González A,
Halliday HL, Sweet D.  Endotracheal intubation at birth Domínguez A. Randomized trial of early bubble con-
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 Bronchopulmonary Dysplasia
37
Alberto Toso Milos, Jorge Fabres Biggs,
and Pablo Bertrand

Contents
Introduction..................................................................................................................  373
Epidemiology.................................................................................................................  374
Physiopathology............................................................................................................  374
Diagnosis........................................................................................................................  375
Complications and Treatment.....................................................................................  376
 espiratory.....................................................................................................................  376
R
Cardiovascular................................................................................................................  378
Metabolic: Nutritional....................................................................................................  378
Neurological...................................................................................................................  379
Follow-Up Plan...............................................................................................................  379
Nutrition.........................................................................................................................  379
Oxygen Therapy.............................................................................................................  380
Precautions and Prevention Measures for Respiratory Infections..................................  380
Recurring Wheezing and Asthma...................................................................................  380
Prolonged Mechanical Ventilation..................................................................................  381
Sources...........................................................................................................................  381

Introduction prevalence of their complications. One of these,

bronchopulmonary dysplasia (BPD), has a sig-
Advances in neonatal intensive care have contrib- nificant impact in the morbidity and mortality of
uted to an increase in the survival rate of prema- this population. Its management, follow-up, and
ture patients, and also in an increase in the prognosis have great economic costs. Thus,
research is crucial to have a proper approach that
may prevent complications which, in the end,
cause deterioration in the quality of life of these
A. Toso Milos ∙ J. Fabres Biggs patients.
P. Bertrand (*) BPD is a term used for the first time in 1967
Department of Pediatrics, School of Medicine, by Northway, who described the clinical, radio-
Pontificia Universidad Católica de Chile,
Santiago, Chile logical, and anatomo-pathological characteristics
e-mail: [email protected]; [email protected] of premature newborns that had developed severe

© Springer Nature Switzerland AG 2020 373

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_37
374 A. Toso Milos et al.

hyaline membrane disease, requiring mechanical fibrosis. The originating factors can be divided as
ventilation and supplementary oxygen. These in the following.
newborns did not present the usual progression of
improvement within days, and started to present Oxygen/Mechanical Ventilation  Providing high
a chronic disease course, with radiological and oxygen concentrations favors the development of
histopathological changes in the lower airways. oxidative stress in the lung tissues, which causes
In its original description, the disease was related inflammation, fibrosis, alteration of alveolar per-
to the use of mechanical ventilation with high meability, formation of hyaline membranes, pro-
positive pressures and exposure to high concen- liferation of alveolar capillaries, atelectasis,
trations of oxygen. hemorrhages, necrosis, among others. Volutrauma
Since then, BPD has been described as a pro- is the main damage described, caused by mechan-
longed neonatal respiratory failure in children ical ventilation in animal models, which is differ-
requiring mechanical ventilation and oxygen ent from what was previously thought to be
dependence for more than 28  days of life, or barotrauma. Other damaging agents are atelec-
after 36 weeks of corrected gestational age, asso- trauma, caused by use of low ventilation pres-
ciated with the persistence of radiological sures and the damage related to poor
alterations. humidification and warming of the inspired air,
and the mechanical damage to the endotracheal
tube, which causes necrosis in the epithelium and
Epidemiology alteration of ciliary transport.

BPD is the most frequent cause of chronic pul- • Prematurity. Prematurity and low weight at
monary disease with sequelae in infants, with birth favors the development of
an incidence rate between 5% and 50% in pre- BPD. Maturation factors, alveolar and pulmo-
mature babies who also suffer hyaline mem- nary vascularity (endothelial alterations)
brane disease, although it is variable among development, are important factors that are
different neonatal units, and clear correlations absent or altered in premature newborns,
cannot be established. The prevalence of BPD especially for infants under 32 weeks of gesta-
is inversely related to weight at birth, which tional age or less than 1500 g at birth.
increases from 5% in children within the range • Infections. Many studies have proven that
of 1250–1500 g to 46% in children within the BPD is related to the increase of inflammatory
range of 500–750 g. In spite of the advances in and fibrotic products in the newborn, even
the “gentle” neonatal ventilation management, before birth, because they are already present
the use of prenatal and postnatal steroids, and in the amniotic fluid. This inflammatory dam-
the incorporation of surfactant, the incidence of age, attributed in a great extent to mechanical
BPD has not diminished during the past years. ventilation and oxygen therapy, is also impor-
Incidence has been stable or it has increased, tantly related to the presence of chorioamnio-
because there has been an increase of the nitis and conatal infection (example,
extreme premature newborn population during Ureaplasma urealyticum), and also postnatal
the past 20 years. infection related to healthcare attention.
• Nutrition. BDP has been related to amino acid
deficiency, micronutrient deficiency, and is
Physiopathology also strongly associated to vitamin A defi-
ciency. Besides this, the relationship between
The pathogenesis of BPD depends on many ele- malnutrition and the inadequate development
ments and is the result of the coincidence of of pulmonary tissue, low production of surfac-
many factors, with clear lesions and tissue dam- tant, and mechanical respiration immaturity
age in the lung, with its posterior healing and includes factors that justify the importance of
37  Bronchopulmonary Dysplasia 375

nutrition in the development of this disease. Besides this, there is the “new” BPD that
Excessive hydric support has also been related appears during the surfactant period, in prema-
to a greater incidence of this disease. ture newborns who have a very low or extremely
• Persistent arterial duct. The presence of per- low weight at birth, who recover from the first
sistent arterial duct causes pulmonary hyper- respiratory distress, or simply do not present it as
flow, which causes pulmonary edema, and such. These diseases progress with a grace or
consequently, pulmonary damage. It is related “honeymoon” period, in which their additional
to prematurity and infection, so either one of oxygen requirements importantly decrease, but
those conditions favors its appearance, thus the newborns then again develop respiratory dif-
contributing to the different factors for the ficulty and persistent hypoxemia, which requires
development of the disease. oxygen, but has a more benign progression than
• Other factors. Masculine gender has a greater the classic presentation, along with subtler
relation to BPD.  Besides this, it has been changes in the X-rays, such as diffuse interstitial
linked to endocrine factors, such as basal corti- infiltrations and pulmonary edema (Fig.  37.2).
sol deficit during the first days of life or deficit
in the protein related to parathyroid hormone
produced by type II alveolar cells to maintain
alveolar hemostasis. Recently, there has been
greater interest in the search for hereditary and
predisposing factors in the molecular pathways
of development and healing of pulmonary tis-
sues, which opens new areas of investigation to
intervene in these pathways, thus preventing
the development of BPD. In this same way, the
eventual presence of predisposing factors for
premature childbirth is also interesting,
because these factors could also intervene. Fig. 37.1  Classic bronchopulmonary dysplasia.
Anteroposterior chest X-ray shows interstitial images,
with diffuse cystic shadows in a 50-day-old child, a
34-week premature newborn whose weight at birth was
Diagnosis 1980 g. Patient did not receive surfactant and underwent
permeable ductus surgery
During the past 20 years, by the development of
intensive neonatal care and the improvement of
the survival rate in very low weight newborns,
two types of BPD have been identified: the “clas-
sic” type, typical of the pre-surfactant era, which
is present in premature newborns who survive
hyaline membrane disease and who have high
requirements of mechanical ventilation and oxy-
gen concentrations (Fig.  37.1). These patients
show persistent hypoxemia and hypercarbia,
besides radiological alterations progressing from
frosted glass appearance to cystic chronic lesions
and interstitial densities. At tissue level there is a
pronounced damage of the airway with diffuse Fig. 37.2  New bronchopulmonary dysplasia.
Anteroposterior chest X-ray shows subtle and diffuse
fibrosis, inflammation, hypertrophy of the muco- interstitial images in a 60-day-old child, who was a
sal glands, and alveolar destruction, with reduced 27-week premature newborn, with birth weight 1280 g,
alveolar multiplication. and received surfactant treatment
376 A. Toso Milos et al.

Table 37.1  Main differences between classic and new appear after the maintenance period, being
bronchopulmonary dysplasia (BPD)
related to the healing process when there already
Classic BPD New BPD is pulmonary damage.
Initial Severe Mild-moderate
During the acute period, gentle ventilation
respiratory
distress management has substantially improved the
O2 initial High Low results obtained in high-risk patients. Adequate
requirements ventilatory management includes the following
Mechanical High positive Low positive recommendations, which can be modified accord-
ventilation pressure and pressure and
ing to each patient:
requirements invasive support noninvasive
support
Pulmonary Metaplasia, Arrest of • Early CPAP and early surfactant must be con-
lesions inflammation, pulmonary sidered [the possibility of performing the
fibrosis, and development and Insure procedure (intubate–surfactant–extu-
alveolar distortion mild fibrosis
Pulmonary Frequent Occasional
bate must be assessed], thus avoiding mechan-
hypertension ical ventilation. (The use of surfactant does
Air scape Frequent Minimum not reduce BPD incidence, but it does reduce
Mortality rate Variable Low mortality rates and changes the “classic” BPD
Presence of Frequent Occasional for the “new” one, which has a more benign
sequelae
progression.)
Oxygen Prolonged Brief
dependence • Synchronized ventilation and low ventilation
pressures with VT at 4–5 ml/kg, PEEP 4–5 cm
of water, short inspiration time (0.3–0.4  s),
The changes at tissue level show the arrest of high RF 40–60 x′, to reach O2 saturations
alveolar development, with simplified and around 90%.
enlarged air spaces, as well as a general reduction • Ventilation support with permissive hypercap-
in the alveoli quantity, with less compromise of nia, tolerating pCO2 up to 60 mmHg so long as
the central airway (Table 37.1). pH is maintained above 7.25 to avoid hyper-
Along with this, in 2001 Jobe and Bancalari ventilation, which increases the risk of BPD
published the results of the National Institutes of and central nervous system compromise.
Health (NIH) consensus, creating the new defini- • Early extubation, using transition ventilation
tion and classification of BPD, considering gesta- support with CPAP to increase the chances of
tional age, oxygen requirements, and ventilation having a successful procedure.
support. With this, they classify it as mild, mod-
erate, and severe (see Jobe and Bancalari 2001). The use of supplementary oxygen, avoiding
hyperoxia, is fundamental to prevent the develop-
ment of BPD during the immaturity phase of the
Complications and Treatment premature infant. The optimal goals for these
patients have been studied relative to pulse arte-
BPD appears with variable clinical manifesta- rial saturation, which may avoid retinopathy
tions, depending on how severely the parenchyma onset, and at the same time decrease neonatal
is affected. mortality as well as obtaining a good neurologi-
cal result. Currently, the recommendation is to
look for a safety range of oxygen supply that
Respiratory reaches a SaO2 range of 88–94%.
During the maintenance phase, the already
Respiratory clinical symptoms can be present damaged pulmonary parenchyma starts a healing
during the first 4 weeks of life, and they are process that is related to pulmonary fibrosis and
related to multifactorial lung injury, but they also active pulmonary growth. In this stage the venti-
37  Bronchopulmonary Dysplasia 377

lation support must be modified and a more ade- muscular fatigue, and after this, apnea is also
quate ventilation for the child must be determined, present. These episodes can be easily confused
using longer inspiratory times and greater pres- with pulmonary edema (secondary to left or
sures. When doing this, it is important to keep in global heart failure), pulmonary hypertension
mind that the main objective is to suspend the episodes (secondary to shunt increase caused by
support as soon as possible. At the same time, the a permeable ductus or an open oval foramen by
goal of oxygen therapy is to avoid hypoxemia, the sudden increase of pulmonary artery pres-
but the scenario changes once the child has sure), and accidents to the airway such as obstruc-
acquired a certain retinal maturity, which tion, or endotracheal tube or tracheostomy tube
decreases the probability that complications displacement.
related to hyperoxia appear; on the contrary, the Patients with severe BPD have a greater risk
oxygen supply will yield evident benefits for for ventilation support during the first months of
alveolar growth. Therefore, the objective is to life, and some of them cannot be weaned from the
reach SpO2 levels within the range of 90–94%. mechanical ventilation because of global respira-
Hypoxemia tolerance must not be so permissive, tory failure, or the attempts to extubate are not
because the periods of SpO2 fall may be pro- successful because the airway is unstable, mainly
longed, which may directly impact the neurologi- caused by tracheomalacia. In those cases, the
cal growth and development, besides producing decision to perform a tracheostomy for prolonged
an increase of pulmonary vascular resistance, ventilation must not be delayed to facilitate the
with the corresponding progression to persistent improvement of the global development related to
pulmonary hypertension. early stimulation in these children. Once this sta-
During the transition to the patient’s home, it bility has been achieved, the transition to the
is very important to analyze the oxygen require- patient’s home may be planned under strict vigi-
ments by performing a SpO2 study for 8 h con- lance, called domiciliary hospitalization.
tinuous, wherein the objective condition of the In patients with BPD, congestive heart failure
patient can be evaluated. The requirements may and hydric overload may cause pulmonary edema
vary when facing situations that increase oxygen with hypoxemia and respiratory mechanical
consumption, such as feeding times or crying, alterations. Generally, its management is through
and it can be reduced in resting periods and dur- hydric restriction, with VT, about 130–150  ml/
ing sleep. The objective for patients presenting kg/day, and diuretics. The diuretics most com-
pulmonary hypertension should be individual- monly used are loop-acting diuretics, such as
ized, but clearly the goal is to reach SpO2 levels furosemide. It has been confirmed that furose-
within a range greater than 93% and 96%. mide reduces pulmonary resistance and increases
The most common cause of respiratory acute pulmonary compliance in patients with BPD, but
worsening is the crisis of BPD, with acute respi- it has a short-term effect, and therefore the
ratory distress episodes, great irritability and agi- adverse effects, such as hydroelectrolytic disor-
tation, progressing to cyanosis. In some cases, ders and metabolic alkalosis, must be assessed
positive-pressure ventilation is required by the and considered. Besides this, furosemide can
presence of apneas and bradycardia. This crisis is cause hypokalemia and hypercalciuria, causing
the result of several incidents that take place as a nephrocalcinosis, and also it can intensify meta-
result of irritation or painful stimulation. In the bolic bone disease in the premature newborn.
beginning, the patient develops anxiety and a Because of this, its recommended use is for acute
sudden change in intrapleural pressures, which episodes during 2 to 3 days.
causes the obstruction of the proximal airway, These patients may present some feeding dif-
usually of the trachea and major bronchus, with ficulties, which are related to episodes of aspira-
secondary hypoventilation. As the child sustains tion, and which can cause recurrent bronchospasm,
the effort and tries to overcome the obstruction, pneumonia, and wheezing. In patients with BPD
evident dyspnea appears, along with cyanosis, and persistent or recurrent wheezing, particularly
378 A. Toso Milos et al.

in children with neurological damage, a swallow- tent pulmonary hypertension cases, as well as
ing disorder must be ruled out, and the signifi- sildenafil for acute management as well as
cance of gastroesophageal reflux may have be chronic. The already mentioned use of diuretics
assessed. requires caution, but without doubt it is one of the
The use of postnatal systemic steroids to pillars of the management of persistent pulmo-
reduce the risk of BPD is controversial. During nary hypertension, especially when there is con-
the first weeks of life, studies have shown that 10 gestive heart failure.
patients at risk must be treated to reduce 1 case of During an acute crisis of persistent pulmonary
BPD, but with the risk of developing neurologi- hypertension, sedation has a fundamental role in
cal sequelae. Thus, it is not recommended univer- the management to reduce vascular reactivity as
sally. It has been confirmed that after the first 4 well as mechanical ventilation and the use of
weeks of life steroids improve the clinical condi- inhaled nitric oxygen. Nevertheless, the effec-
tion and pulmonary function, thus reducing the tiveness of chronic inhaled nitric oxide use as a
time of use of mechanical ventilation without regulator of pulmonary vasculature and angio-
modifying the mortality rate. For selected cases, genesis has not been confirmed.
the short-term use of steroids may be considered If right ventricular hypertrophy and pulmo-
for the aforementioned reasons, considering the nary hypertension are not resolved within 3 to
adverse effects. 6 months, a heart evaluation must be performed,
For the chronic stage of these patients, chest with a search for the cause of hypoxemia, as we
physiotherapy management is important to cor- already pointed out. Systemic arterial hyperten-
rectly handle secretions, avoid atelectasis, and sion tends to be present in these patients, and it
improve respiratory musculature. appears during the first 6 months of life. A non-­
minor group, about 50%, will require pharmaco-
logical control and treatment for arterial
Cardiovascular hypertension.

Persistent pulmonary hypertension, which is the

classic cardiovascular complication of BPD, is Metabolic: Nutritional
produced by structural changes in pulmonary
vasculature. Remodeling is caused by stimuli Adequate nutritional support is one of the keys in
such as hypocapnia, hypoxia, and acidosis, which the treatment of the child with BPD, in such a
generates an increase in pulmonary vascular way that an inadequate weight gain is a marker of
resistance, with its corresponding overcharge of the severity of the disease. The somatic growth of
right cavities (cor pulmonale) and can progress to the body develops in parallel to growth and matu-
a congestive heart failure. Given the great pulmo- rity of the respiratory system; therefore, a close
nary vascular reactivity, persistent pulmonary follow-up of weight gain is a good measure of
hypertension usually appears as a chronic condi- pulmonary growth and directly related to neuro-
tion, with crisis episodes in relation to diverse logical growth. An inadequate weight gain may
stimuli or infections. Management and follow-up reflect a scarce nutrient supply, increase of the
must be done with strict medical vigilance of the energetic demand because of respiratory work,
clinical and laboratory parameters. It is recom- and/or silent hypoxia that causes inefficient cell
mended to check the management of permanent metabolism in anaerobic conditions. It may be
hydric restriction at 130–150 ml/kg/day. Further, related to a short intestine, swallowing disorder,
oxygen must be supplied according to the require- etc.
ments, tolerating greater saturations to favor oxy- The caloric supply for a child with BPD must
gen effect in pulmonary vasodilation. Chronic be between 120 and 140  kcal/kg/day, which is
use of vasodilators with calcium blockers, such adjusted according to the weight gain. In patients
as nifedipine, can be considered for severe persis- who present with hydric restriction or poor toler-
37  Bronchopulmonary Dysplasia 379

ance to the 130–150 ml/kg/day supply, the mater- prognosis of these children is directly linked to
nal milk must be optimized by fortifying it using the access to neurorehabilitation, besides pro-
appropriate infant formulae. In this scenario, the grammed sessions with occupational therapists
additional carbohydrate supply generates a and the training of the parents for constant work.
greater CO2 production in comparison to lipid-­
based feeding support. This change can be
reflected in the increase of chronic respiratory Follow-Up Plan
acidosis, and therefore the lipid-based feeding
support is preferred. Protein intake must be at The follow-up plan for a patient with BPD begins
least 3 g/kg/day, and micronutrients must also be when the patient has reached a clinically stable
provided. The use of intramuscular vitamin A in stage in the neonatal unit and is moving to the
doses of 5000 IU three times per week, during the patient’s home. In this moment, the specialist in
first month of life, has shown to have a protective respiratory diseases is involved in the treatment of
effect relative to BPD, but its use is not the child with BPD and plans, along with the neo-
universal. natology specialists, the ambulatory follow-up.
The preferred feeding method is through oral As a general rule, the follow-up plan includes
suction, but frequently premature patients pres- monthly visits to the specialist in respiratory dis-
ent with swallowing disorders during the first eases while the ventilation support or oxygen
months of life, which forces the use of nasogas- therapy continues, and then every 2 months until
tric tubes and, sometimes, to avoid aspiration, the child reaches the first year of life. After this,
desaturations, and apneas, besides easing the the follow-up must be annual until the child is
feeding process. Sometimes, antireflux surgery 6 years old.
with fundoplication is needed.
Metabolic alterations are common in patients
with BPD, because of the use of drugs and nutri- Nutrition
tional intake using minerals in high concentra-
tions. Thus, it is mandatory to be vigilant about Nutritional support must be optimal for the child
the appearance of alterations in bone metabolism with BPD to achieve an adequate growth and
as well as metabolic alterations, such as meta- avoid further complications. As has been previ-
bolic alkalosis, hypokalemia, hypochloremia, ously established, the mentioned requirements
and hypercalciuria. must be pursued in the long-term follow-up with
insistence and precision to obtain an adequate
somatic growth. Generally, this means providing
Neurological a generous amount of calories. However, it has
recently been established that an excessive
Patients who develop BPD suffer the usual neu- weight gain during the first years of life in prema-
rological injuries present in premature newborns. ture children without BPD is related to recurrent
Intraventricular hemorrhage, hydrocephalus, and wheezing and asthma during a 4-year follow-up,
periventricular leukomalacia can be present. which could even be more notable in patients
More severe neurological complications are with BPD.
related to a greater pulmonary compromise, and An unsatisfactory weight gain during the first
vice versa. Generally, this disease has been iden- months of life is a scenario that must approached
tified as a statistical risk factor, independently of with a multidisciplinary focus, because its conse-
the psychomotor development compromise these quences can be devastating. The follow-up
patients may have in the future. In the long term, involves different specialists: neonatologist,
they show poorer motor and cognitive functions. nutritionist, speech and swallow therapist, and
These patients also develop attentional deficit, as bronchopulmonary physician. Individually, the
well as language and learning disorders. The caloric intake must be adjusted and the energetic
380 A. Toso Milos et al.

consumption must be reduced, starting with Patients with BPD present a high probability
enteral feeding progressing to ventilation support of hospitalization caused by respiratory infec-
that allows for breathing rests. tions during the first and second year of life. This
likelihood makes it mandatory to use protection
strategies, such as protecting the family and care-
Oxygen Therapy takers with vaccines against influenza and
Bordetella pertussis; the use of monoclonal anti-
During the first few weeks at home the child will bodies against the syncytial respiratory virus
need assistance in her/his environment, and there- must also be considered. Administration is vari-
fore it is recommended to maintain oxygen sup- able, because the reality in different countries in
port and closely monitor SpO2 during resting relationship to several factors must be assessed,
periods, as well as during feeding and sleep. After such as the degree of prematurity of the child and
verifying that the patient continues to be clinically the extent of the virus epidemic. In Chile an
stable and has an adequate weight gain for at least immunization plan has been implemented, con-
a month, it is possible to start reducing oxygen sisting of palivizumab (15 mg/kg/month) during
supply during the day under strict SpO2 vigilance. the winter epidemic for all patients younger than
After suspension of oxygen supply during the day 32 weeks of gestational age and with BPD during
has been well tolerated and accomplished, prog- the first year of life.
ress to the suspension of oxygen during the night Respiratory exacerbations often compromise
is allowed. It is recommended to perform a con- the small airway, obstructing bronchi and bron-
tinuous SpO2 study during 8  h during a night. chioles. Although the evidence for using bron-
Recommendations for oxygen withdrawal are chodilators and systemic steroids is poor, it is
variable according different centers. In our reasonable to perform a therapeutic test during
University Hospital we have agreed that a normal the course of a bronchiolitis episode, and this
SpO2 study should result in an average SpO2 of information will be relevant in the later follow-up
93%, and the maximum total time of SpO2 levels when facing new episodes.
below 90% must be less than 3%. When facing respiratory exacerbations, it is
The average length of oxygen therapy for still possible to find some compromise of the lar-
patients with BPD in our center is 3 months after ynx and trachea, mainly in the subglottic space,
discharge from the neonatal unit, although it may caused by intubation injuries: subglottic stenosis,
be extended depending on the severity of the dis- larynx cysts, granulomas, and laryngeal mem-
ease, respiratory exacerbations, and SpO2 goals branes. Although these complications may appear
proposed. as a failed endotracheal tube weaning in the neo-
natal unit, they can also appear triggered by
respiratory infections.
Precautions and Prevention
Measures for Respiratory Infections
Recurring Wheezing and Asthma
As happens in the neonatal unit, at home the pre-
cautions for respiratory contact and isolation, when The general characteristics of the lung in a child
needed, are fundamental measures for patients with with BPD may vary, from a restrictive disease,
BPD.  These measures must include universal caused by pulmonary hypoplasia, to an obstruc-
washing of hands, contact precautions for the par- tive disease caused by the compromise of the
ents and therapists when there is suspicion of viral small airways, although generally there is a com-
infection, but also general measures such as avoid- bination of both components. Studies of pulmo-
ing going outside, limiting home visits, and elimi- nary function in infants with BPD show that even
nating every source of indoor pollution, such as when there is recovery of the pulmonary disten-
kerosene heaters and tobacco smoke exposure. sion early in life, analysis shows obstruction of
37  Bronchopulmonary Dysplasia 381

the airway during the first 2 years of life, even mainly tracheomalacia or subglottic stenosis,
though these patients suffered from the “new” will need a tracheostomy. This intervention deter-
type of BPD. Up to 30% of these patients show a mines a high-risk scenario that must be managed
reversible response to bronchodilators, imitating to progress to its transition to the patient’s home.
patients with asthma, but with a lesser degree of Caretakers of these children must train them-
atopy and persistent inflammation of the airway. selves in the routine management of the tracheos-
In all the studies of pulmonary function in chil- tomy tube, but especially, they must be aware of
dren aged from 6 to 19 years old, in which chil- their complications. Progress in the long term
dren with BPD are compared to control patients, tends to be very satisfactory, and allows most
FEV1 is consistently reduced in children with children to be completely weaned from artificial
BPD, with no difference if early treatment with ventilation as the somatic growth of the new pul-
surfactant and gentle ventilation was used in monary parenchyma and stabilization of the
comparison to conventional treatment. This evi- proximal airway develop. Those with a fixed
dence suggests that obstructive disease that pres- alteration of the proximal airway, such as sub-
ents itself with wheezing episodes in infants with glottic stenosis, may require balloon dilation or
BPD can be explained, mainly, as a structural reconstructive surgery, whichever is needed.
change in the smaller airway.
Respiratory infections will be the main trig-
gers of the wheezing episodes, caused by the Sources
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Patients with BPD may present a dynamic ria for bronchopulmonary dysplasia. Semin Perinatol.
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quence of prolonged ventilation and the immatu- ture birth. N Engl J Med. 2007;357:1946–55.
rity of the airway, which is called tracheomalacia Carlo WA.  Gentle ventilation: the new evidence from
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agitation, because the stability of the airway chopulmonary dysplasia. Curr Opinion Pediatr.
depends of the intra-chest pressure changes. Some 2011;23:305–13.
of these patients have a paradoxical reaction to the Jobe AH.  The new bronchopulmonary dysplasia. Curr
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use of bronchodilators, because the stability of the Jobe A, Bancalari E.  NICHD/NHLBI/ORD workshop
airway depends mainly on the muscular structure, summary. Bronchopulmonary dysplasia. Am J Respir
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Pulmonary function is an objective and nonin- org/doi/pdf/10.1164/ajrccm.163.7.2011060.
Linares M.  La nueva displasia broncopulmonar desde
vasive follow-up method to check the growth of el punto de vista del neumólogo pediatra. Neumol
the airway in children with BPD, and it is desir- Pediatr. 2015;10(3):111–7.
able to perform this routine evaluation in the fol- Mandy G, Malkar M, Welty S, Brown R, Shepherd E,
low-­up plan of these children until they reach Gardner W, Moise A, Gest A. Tracheostomy placement
in infants with bronchopulmonary dysplasia: safety
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Meyer S, Kronfeld K, Gräber S, Butzer R, Wahl H,
Gortner L.  Vitamin A to prevent bronchopulmonary
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7058.2012.745499. Epub 2012 Nov 28.
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 Allergic Diseases, from the Infant
to the Adolescent
38
Mario Calvo Gil and Fernando Iñiguez Osmer

Contents
Definition.......................................................................................................................   383
Epidemiology.................................................................................................................   383
Etiology and Physiopathology.....................................................................................   384
Clinical Manifestations................................................................................................   385
 ewborn Period..............................................................................................................  385
N
Infant Period...................................................................................................................  386
Preschool Period.............................................................................................................  388
School Period..................................................................................................................  389
Adolescence Period........................................................................................................  389
Therapy.........................................................................................................................   389
Summary.......................................................................................................................   391
Sources...........................................................................................................................   391

Definition Epidemiology

Allergic diseases are in general adverse reactions Allergic diseases constitute a global health issue,
to substances that are innocuous to most people. affecting hundreds of millions of people all
These diseases are characterized by their high around the world, and it is one of the most com-
complexity and are denominated hypersensitiv- mon causes for primary health care attendance.
ity. They are the most common chronic diseases According to the Global Initiative for Asthma
during the pediatric age. (GINA), 20% of the population would be affected
by a disease mediated by immunoglobulin E
M. Calvo Gil
(IgE). Its incidence has increased during past
Department of Pediatrics, School of Medicine, decades, especially in developed countries, which
Universidad Austral, Valdivia, Chile has led to the creation of the name “noninfectious
e-mail: [email protected] epidemic.” The Worldwide Health Organization
F. Iñiguez Osmer (*) (WHO) estimates that by 2020 the cases will dou-
Department of Pediatrics, Hospital de Puerto Montt, ble in developed countries, and it will increase
Puerto Montt, Chile

© Springer Nature Switzerland AG 2020 383

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_38
384 M. Calvo Gil and F. Iñiguez Osmer

even more in undeveloped countries, where most be shared by some of them, for example, AD and
of the world population lives. BA.  It is possible that in the future a specific
It has not been possible to determine the exact locus will be determined for each disease.
causes of this increase in allergic diseases, but a Currently, the genes that predispose to bronchial
complex interrelationship among several factors hyperreactivity (BHR) have been described, and
that causes its manifestation has been confirmed. other genes have been identified for their capacity
Such factors include the genetic constitution of to produce IgE specific to Dermatophagoides,
the person who is affected by this disease, a type and specific loci for eczema, bronchial asthma,
Th2 inflammatory response, environmental fac- allergic rhinitis, positive skin test, etc.
tors within the pediatric age, factors related to the
antigen, such as modulators and adjuvants, solu-
bility in the microenvironment, size of the sensi- Etiology and Physiopathology
tizing particle, permeability of the respiratory
mucosa, viral infections, and a greater or lower The etiology of this kind of disease changes
capacity of the effector cells to liberate media- according to the age in which it manifests, and
tors. Other factors to be considered are environ- the same mechanisms can have different clinical
ment pollution, exposure to tobacco smoke, progressions depending on the onset age.
lifestyle, and hygiene habits. The first manifestations of allergy in the infant
The advances in genetic medicine have are FA and AD; BA is less frequent. During the
allowed us to understand better this group of dis- school period, FA manifestations tend to
eases, but there is no unique genetic structure. decrease, AD tends to maintain the same level,
Different genes have been proposed as candi- and the frequency of BA increases. In the school-
dates, and the manifestation of the disease differs child the most common manifestations of allergy
according to the genotype of each of these pathol- are respiratory signs, such as BA and AR. In the
ogies: food allergy (FA), atopic dermatitis (AD), teenager, AR is predominant over BA.  Each of
bronchial asthma (BA), and allergic rhinitis (AR), these is analyzed in further detail in relation to
each with different phenotypes. They are charac- the clinical manifestations according to age
terized by a polygenic dominant inheritance, with group (Fig. 38.1).
a large number of genes that predispose to suffer- From the physiopathological aspect, the syn-
ing the disease. These genetic determinants can dromes are characterized by the capacity of the
Incidence

Eczema

Food allergies

Asthma

Rhinitis
0 5 10 15
Years
IgE blood levels

Fig. 38.1  Atopic march

38  Allergic Diseases, from the Infant to the Adolescent 385

affected person to manifest an allergic hypersen- early signs of allergic reaction: rhinorrhea,
sitivity, whether it is mediated by IgE or not. This sneezing, and pruritus in the nasal cavities, bron-
capacity has a strong genetic basis, which allows choconstriction, and erythema, along with skin
the person to respond to different antigens that itching. Cellular infiltration, activated by the
are common environmental proteins. release of these mediators and its persistent
IgE-mediated allergy develops by interaction action, explains late signs, such as persistent
with proteins that have the potential to cause nasal obstruction, bronchial hyperreactivity, and
sensitization. An allergen is absorbed by the remodeling (Figs. 38.2 and 38.3). The union of
mucosa (gastrointestinal, cutaneous, respira- the IgE allergenic complex to low-affinity recep-
tory) through a disruption in the affected epithe- tors (FcεRII, CD23), expressed in lymphocytes,
lium and is then recognized by the monocytes, macrophages, and platelets, stimu-
antigen-presenting cell (APC). The most impor- lates the lymphocyte activity, thus increasing the
tant cells of this kind are the dendritic cells, allergic response by promoting a greater Th2
which migrate with the allergen toward the lym- response. The predominance of Th2 lympho-
phatic tissue. These cells present small peptide cytes originates the abnormal synthesis of IL-4,
fragments, resulting from processing to the class IL-5, IL-9, and IL-13, which are closely related
II major histocompatibility complex with native to IgE synthesis, and the immediate and late
LT CD4+. Depending on the type of cytokines allergic reaction, with bronchial hyperreactivity
present in the initial interaction with the APC, eosinophilia and remodeling of the airway.
native CD4 cells can be differentiated in five
effector cells subgroups: Th1, Th2, Th17, Th22,
and Treg. In allergic diseases, the presence of Clinical Manifestations
interleukin (IL)-4 promotes the differentiation
from T cells to Th2 cells, which are specific for Allergic diseases can appear at any time in the
allergens and produce great quantities of IL-4, life of a child, and the clinical manifestation
IL-5, and IL-13, along with no or a minimum depends on the age of the patient. A chronologi-
amount of interferon-gamma (IFN-γ). IL-4 is cal analysis of these manifestations follows.
the greatest change factor that makes B cells
synthesize IgE. The presence of IL-12 and IL-17
favors the differentiation to Th1 cells, which Newborn Period
produce large quantities of IFN-γ, which is a
potent antagonist of IL-4 and inhibits the differ- Allergic reactions in a child under 1 month old
entiation to Th2 cells. IgE-mediated diseases are very uncommon, and when they are present
appear by a Th2 predominance because of the they can be FA (cow’s milk proteins) or AD,
lack of regulation that Th1 and Treg must accom- which are further analyzed in the infant stage sec-
plish, which is a high production of IgE-specific tion. During intrauterine life, in the maternofetal
antibodies for the antigen that caused the pro- interface, the period of response to specific anti-
cess, which bond to its high-specificity receptor gens begins between the fourth to seventh month
(FcεRI), from different effector cells, such as of pregnancy. It has been confirmed that the fetus
mastocytes and eosinophils. A new union may produce specific IgE from the 11th week of
between the specific antigen and two IgE mole- intrauterine life. Reactivity to different allergens
cules fixes these effector cells, causing the in the blood of the fetus is seen by week 22 of
release of several chemical mediators, such as gestation, when IL-4 and INF-γ are already pres-
histamines, leukotrienes, brachinine, platelet ent. At 16–17  weeks, IL-10 predominates over
activation factor, and others, which migrate to INF-γ in the human amniotic fluid, which predis-
the tissue where the allergic inflammation pro- poses to a Th2 response. The tissues of the fetus
cess has started. The release of an important that are more exposed to the antigens present in
group of chemical mediators is the cause of the amniotic fluid are the skin and the intestine,
386 M. Calvo Gil and F. Iñiguez Osmer

eFcRI Histamine Early symptoms

Mastocyte Leukotriene of allergic reaction
Prostaglandins
Bradykinin, PAF • Rhinorrhea, sneezing
• Bronchoconstriction
IgE • Weal and rash
b
Lymphocyte
Alergen

IL - 4
VCAM-1 Late symptoms
IL - 13 of allergic reaction
dc
CD80/56 • Nasal obstruction
• BHR
CD28 Eosinophils
• Hives
Th2 IL - 3, IL - 5
Lymphocyte GM - CSF

Fig. 38.2  Allergic reaction

a patient. At 2  years old, 50% of the atopic

IFN -¡ Th1 IFN -¡ patients present with symptoms of FA and AD,
and at 5 years old, 60% of them; in this same age
group, 40% of the atopic patients have symptoms
of BA and 25% of AR.
IL -4 Th2 IL -4 FA has an early onset during the first months
of life, beginning an important decrease, depend-
ing on the problematic food, between 2 and
IL -6 Th17 IL -17 3  years old. Its prevalence is greater during the
first years of life, around 6% in patients who are
under 3 years old. It is infrequent in patients over
TGF -b IL -10 5 years old, and its frequency continues to be low
T-reg
until adolescence.

Fig. 38.3  Interregulation among the different subgroups

Food allergy  FA is the immunological reaction
of T-CD4+ cells mediated by IgE or another hypersensitivity
mechanism to one or more components of a food,
and secondarily the respiratory system, which and it must be differentiated from the adverse
would explain why the first allergic manifesta- reactions to certain foods, which is the abnormal
tions of extrauterine life are in these organs. clinical response caused by some food or addi-
tive, caused by nonimmunological mechanisms.
Its clinical manifestations are characterized by a
Infant Period wide variety of symptoms and signs, which may
be localized or systemic. In infants the most com-
As already mentioned, FA and AD are the earliest mon signs are irritability and gastrointestinal
manifestations of allergies, constituting the first symptoms, such as nausea, vomiting, recurring
clinical elements that allow us to suspect atopy in abdominal pain such as colic, diarrhea, and even-
38  Allergic Diseases, from the Infant to the Adolescent 387

tually blood in the stools. It may be present along and popliteal fossa). Atopy in the family back-
a stationary growth curve, or show weight loss, in ground may or may not be present. Food allergy
most severe cases. The foods most likely to cause to the aforementioned foods is one of the frequent
food allergy are the following. causes of AD. The NICE clinical guide includes
the signs for its clinical diagnosis, diagnostic cri-
• Milk: Milk contains several potentially aller- teria, and evaluation of degree of seriousness.
gen proteins, and the manifestations of the
allergy are presented in about 2.5% of infants; Different follow-up prospective studies have
about 85% achieve tolerance when the patient determined the risk factor these pathologies may
is between 3 and 5 years old. These patients have in the posterior development of BA or
have more than 50% of possibilities to develop AR. So, if an infant with AD at 3 months has the
other allergies, and more than 80% of chances background of one of the parents or a sibling hav-
of developing allergies to inhaled allergens ing atopy, this patient has a more than 50%
later in life. chance of presenting BA when he is 5–6  years
• Egg: The manifestation frequency of egg old and about 75% of suffering from this disease
allergy in infants is estimated as 2.5%; it con- during the school years.
tains the most allergen proteins, mainly in the AR and AB, along with anaphylaxis, are less
egg white, and its tolerance is achieved around common symptoms in infants. Even though they
the third year of life. As happens with milk, sen- can be present in infants, these symptoms tend to
sitization to egg is related to an increased risk of appear later in life.
developing allergies to inhaled allergens.
• Peanut: In countries where the consumption Bronchial asthma  It begins early in the life of
of peanut begins early (incorporated into other the atopic child, who can manifest respiratory
foods or as butter), an allergy frequency of symptoms during this stage of life, although it
0.6% is reported, and this tends to last during tends to be predominant later in life. Traditionally
several years, or even for the lifetime. Its toler- the groups of symptoms and signs these patients
ance is described as less than 20% at the sec- present are classified as wheezing, polypnea,
ond year of life. retraction of soft parts, and prolonged exhalation,
• Less frequent: Soy (0.3–0.4%), wheat, fish, during periods that can be related or not to viral
fruits, and vegetables, which are more fre- conditions, such as an acute wheezing episode. A
quent later in life and during adulthood. group of these infants (about 25–30%) have
bronchial asthma, and although pulmonary tests
Allergy to cow’s milk generally remits at the are not routinely performed to confirm the diag-
third year of life, and allergy to egg usually remits nosis, clinical and laboratory criteria provide ori-
before puberty, although if it severe it may last entation in the diagnosis, even during the infant
for the lifetime. Allergies to fish, crustaceans, period. The asthma predictive index (API) (pub-
nuts, and peanuts may not totally improve, but lished by J.A.  Castro-Rodríguez, then modified
they can be less severe later in life. by T. Gilbert) is detailed in Table 38.1. Following
the criteria of the first, it is known that if an infant
Atopic dermatitis  AD is a recurrent chronic has more than three acute wheezing episodes
skin disease characterized by reddish lesions, within a year and positive (+) API, it is possible
intense pruritus, and usually patches of dry skin to affirm that there is a 77% chance that this child
in different parts of the body. These lesions usu- will be affected by BA during the school-age
ally present at first in the cheeks, and after that years (6–13  years old). On the contrary, with a
they may expand to the forehead, ears, scalp, negative (−) API, we can affirm, with 68% cer-
chest, genitals, and limbs. Later in life the lesions tainty, that the condition of this child will tend to
tend to be drier and to be located in skin folds disappear in time and the child will not have
(retroauricular fold, neck, wrists, cubital fossa, bronchial asthma in the future. In other words,
388 M. Calvo Gil and F. Iñiguez Osmer

Table 38.1  Asthma predictive index (API) during this period. It must be suspected when the
Original APIa Modified APIb infant has some of the already mentioned atopic
Major criteria Major criteria manifestations, has a family background, and
 Asthma family history  Asthma family history presents clear rhinorrhea, sneezing, nasal pruri-
 Medical diagnosis of  AD tus, and nasal obstruction, although this condition
AD
is less frequent during this age. See Pérez el al.
 Sensitizing to (Björkstén
1999) 1 air allergen and Mullol et al. for the backgrounds and symp-
Minor criteria Minor criteria toms that suggest the existence of allergic rhinitis
 AR medical diagnosis  Sensitivity to milk, and its classification according to its seriousness.
peanut, or egg
 Wheezing without flu  Wheezing without flu
 Hematic eosinophilia  Hematic eosinophilia Preschool Period
(Björkstén 1999), 4% (Björkstén 1999), 4%
Castro-Rodríguez JA. J Allergy Clin Immunol. 2010;126: In this transition period, sensitivity to foods tends
212–6
Guilbert TW, et  al. J Allergy Clin Immunol. 2004;114: to decrease or disappear according to the food, as
1282–7 was previously described. AD usually decreases,
AD Atopic dermatitis, AR allergic rhinitis but present lesions become less humid and tend
a
A positive index is defined when recurring wheezing epi- to be localized in flexion areas.
sodes are reported within the last years with two major
criteria or two minor criteria During this period the greatest recurrence of
b
A positive index is defined when four or more wheezing respiratory symptoms appears, with or without
episodes are reported, at least confirmed by a doctor, and previous sensitization (for example, to foods), or
one major criteria or two minor criteria if they are in tolerance stage. The main predomi-
nance in the atopic child is, first, BA, and some
infants with a positive API have a sevenfold years later, AR. It is useful to remember that
increase in their risk to suffer from bronchial within this age group there are children with
asthma during their school age in comparison to non-­atopic bronchial asthma, usually triggered
those who are API negative. by acute viral infections, and even when they
have BHR, clinical background and laboratory
The importance of diagnosing and differenti- indexes show that they are not suffering from
ating these patients lies in the anticipation and atopy. This group also includes the infants who,
adequate prognosis for the family, by enforcing even though they do not suffer from atopy, pre-
adequate therapeutic measures. About 80% of sented with severe bronchiolitis caused by respi-
patients with BA begin to wheeze during the first ratory syncytial virus, and afterward they
years of life, usually before 4  years old. The manifested symptoms of BHR, which tends to
greatest risk factors are atopy and BHR. Infants persist until before adolescence. Generally, the
with atopic BA are born with a normal pulmo- children with non-­atopic BA symptoms have a
nary function, and then experience a significant better prognosis than children with atopic BA,
worsening in the function during the first 6 years because in a greater percentage, the clinical man-
of life, which is maintained until they reach ifestations will disappear, and their quality of life
18  years of life, and it is not recovered during will improve as they progress in development
adulthood. In these patients early sensitizing into adolescence. In this age, besides family and
increases the risk of inflammation of the airway. personal background, the pillars of the diagnosis
are the laboratory tests, especially cutaneous
Allergic rhinitis  Its presentation is less common tests, and by this age most of them can perform
in infants and its diagnosis is more difficult. About pulmonary function tests, such as the exercise
25% of atopic patients develop AR symptoms test and spirometry.
38  Allergic Diseases, from the Infant to the Adolescent 389

School Period chial asthma, which must be treated as indicated

in the guidelines. The education of the allergic
Patients who reach school age with FA and AD patient and her/his family is one of the therapeu-
will maintain their clinical conditions during the tic pillars, because it is a low-cost measure
rest of their lives, although with few symptoms. proven to reduce the use of medications. The
The most important manifestations for the atopic same situation is faced with environmental con-
child within this age group are BA and AR. The trol, which as an isolated measure does not mod-
group of patients with non-atopic BA symptoms ify the evolution of the disease, but it allows
start to experience an important decrease in their controlling the symptomatology in a better way
symptomatology and, by the end of this period, with fewer therapeutic resources. Preventive
or during the beginning of their adolescence, they pharmacotherapy, although it does not modify
tend to be symptom free. This is specially the the natural progression of the disease, signifi-
case for children who previously had BHR, with cantly reduces its manifestations, prevents
a background of severe bronchiolitis caused by sequelae, and improves the quality of life of the
respiratory syncytial virus and who did not suffer affected patient. Immunotherapy has precise
from atopy. indications, according to its clinical indication
During this period a new phenotype may and the cost–benefit relationship.
appear in a group of patients with symptoms of
BA. Usually they are schoolgirls who present
with obesity between 6 and 11 years of age. This Therapy
group has a sevenfold increase in the possibility
of presenting BA in relationship to eutrophic The specific treatment for each one of these
children. It has been demonstrated that obesity pathologies is detailed in the corresponding sec-
precedes and predicts BA, but there is no inverse tion. Below, we present some general concepts
relationship; this means that BA does not cause that, although they do not modify the natural pro-
obesity. Even though the relationship between gression of the disease, reduce the symptoms and
obesity and bronchial asthma is causal, there is lead to a reduced use of medication for control-
still no confirmed relationship between obesity ling the disease.
and allergic disease. The first principle is to avoid contact with the
antigen, when possible. If sensitization to cer-
tain foods is identified, a crucial part of the treat-
Adolescence Period ment is the suppression of the causative food.
Inhaled antigens are difficult to avoid, but even
Most atopic children present with their symp- in this situation, environmental measures must
toms localized mainly in the respiratory system, be taken to avoid contact with the most common
with manifestations such as AR and BA. Besides antigens: Dermatophagoides (house dust mites)
these symptoms, those manifestations of FA and and pollen.
AD can also be added, in the few patients who The WHO has favored every effort that pro-
could not overcome this. The patient who before motes the use of primary prevention in risk
adolescence was obese and had bronchial asthma patients. This strategy consists in a group of mea-
will maintain those respiratory symptoms during sures destined to currently healthy population,
adolescence, although the patient may no longer but who are at risk of developing the disease, and
be obese. it includes measures to be implemented before
As happens in every age group, the evaluation any atopic sensitizing is manifested, along with
of allergic diseases requires a global approach, perinatal interventions. These measures must be
and in this age it is focused on the two most fre- applicable to all the population, have a low cost,
quent manifestations, acute rhinitis and bron- and be free of risks:
390 M. Calvo Gil and F. Iñiguez Osmer

• Avoid smoking habits and passive exposure to atopy sensitization in small children, but this
cigarette smoke during pregnancy and first does not apply to asthma or wheezing.
childhood (A-B Evidence). Secondary prevention strategies are the group
• Control humidity conditions at home and of measures aimed at children who do not have a
reduce in-house contaminants (C Evidence). defined allergic phenotype, but who nevertheless
• Exclusive breastfeeding until 4–6 months (A possess markers indicating a high risk of mani-
Evidence) with no special diet for the breast- festing the disease later. These measures must be
feeding mother. implemented after the sensitization to allergens
• Reduce inhaled allergens in high-risk chil- has taken place and before the disease becomes
dren, specially house dust mites, cockroaches, evident. These strategies are indicated during the
and pets (B Evidence). first years of life:

Relative to dietary measures during pregnancy, • Treat AD in the infant and child to prevent
even though some reports indicate a certain ben- respiratory allergies (Evidence D).
eficial effect when reducing the sensitization fre- • Treat acute rhinitis to reduce the risk of devel-
quency of some food and skin atopy, most of oping asthma (Evidence D).
them indicate that frequency is kept at similar • In small children already sensitized to pets,
levels, even when the mother suspends, during dust mites, or cockroaches, reduce exposure to
pregnancy and breastfeeding, certain foods which prevent the progression of the allergic disease
may be potentially sensitizing. Categorically, in (Evidence B).
follow-up studies covering 10 years, there is no • Remove from their workplace those patients
effect in reducing the frequency of the positive who have developed symptoms caused by
skin test, asthma symptoms frequency, and atopy allergic occupation sensitization (Evidence C).
frequency in general. According to this, there is
currently no evidence that may justify special Subcutaneous immunotherapy with allergens
diets for the mother during her pregnancy, and her is still a controversial subject, but in patients with
adequate nutrition must always be protected. In acute rhinitis, it significantly reduces the percent-
spite of the controversial role of exclusive breast- age of patients who afterward develop BA in
feeding in relation to atopy disease, according to relationship to the control group, and it is one of
the most recent evidence, it is safe to state that the preventive measures highlighted by the expert
most studies assign it a protective effect in the panel on immunotherapy at the WHO, which has
development of food allergy, and atopic dermati- been newly considered in recent publications.
tis, but this is not true for the reduction of inci- Immunotherapy in BA with mite allergens,
dence of bronchial asthma. It must be considered according to different meta-analyses, showed an
that this beneficial effect may decrease in time. improvement of 2.7 fold for asthma symptoms,
It has been observed that the use of probiotics 4.2 fold for medication reduction, and 13.7 fold
(for example, Bifidobacterium lactis and for BHR. The patient must be carefully selected
Lactobacillus GG) has some part in preventing when indicating immunotherapy, which should
and improving AD in children previously breast- be considered for patients whose symptoms are
fed. It has been confirmed that probiotics increase mainly induced by an allergen, mono-sensitized.
the IgA and IL-10 levels, and also suppress TNF-­ Immunotherapy can also be considered for
α. Also, probiotics modify intestinal flora to pre- patients whose symptoms have been present for a
vent antigen capture through the intestinal barrier, prolonged time, as long as pharmacotherapy, or
and increase the IFN-γ levels in peripheral blood when therapy produces a serious adverse effect.
mononuclear cells, favoring immune deviation to In the case of acute rhinitis, it is indicated if the
Th1. A recent meta-analysis indicates that early patient presents persistent symptoms, and for
life probiotic administration is effective in reduc- BA, it must be persistent or moderate, along with
ing IgE levels, as well as reducing the risk of normal pulmonary function.
38  Allergic Diseases, from the Infant to the Adolescent 391

Tertiary prevention is defined as the group of Summary

measures taken to suppress the symptoms and the
progression of the disease once the disease has Allergic diseases constitute a group of very prev-
manifested. These measures are enforced when alent pathologies whose frequency is increasing.
the allergic disease is already present: The mortality rate is very low, but the diseases
severely affect the quality of life of the patient
• For infants who are allergic to cow’s milk, and the patient’s family. This disease is becoming
avoid its proteins and/or use hypoallergenic more and more common as the result of various
formulas (Evidence B). environmental factors, so the general practitioner
• For patients with BA, AR, or AD sensitized to must be capable of recognizing them and starting
house dust mites, cockroaches, or pets, the preventive and treatment measures. Current ther-
allergens should be eliminated or the exposure apeutic options, although they do not modify the
to them should be reduced to have a better natural progression of the disease, allows the
control the symptoms and avoid exacerbations patients suffering from allergic disease to have a
(Evidence A-B). normal life.
• Pharmacotherapy is indicated to treat the
inflammatory underlying process (Evidence A).
• Avoid acetylsalicylic acid and other nonsteroi-
Sources
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Three Study Group, et al. Worldwide time trends in the
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cation of antihistamines is used to try to sup- juctivitis and eczema in childhood: ISAAC phases one
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Durhan S. Allergen injection immunotherapy for sea-
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Castro-Rodríguez J, Holberg C, Wright A, Martínez F. A
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Martínez F.  Increase incidence of asthma-like symp-
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 Latin America Asthma
Epidemiology and Related Risk
39
Factors

Viviana Aguirre Camposano, Manuel Soto Martínez,

and Manuel Soto Quirós

Contents
Introduction..................................................................................................................  393
Asthma in Latin America: Phase I and Phase III ISAAC Studies...........................  394
Risk Factors...................................................................................................................  396
Asthma Epidemiology in Chile....................................................................................  398
Sources...........................................................................................................................  399

Introduction The World Health Organization (WHO) and

the Global Initiative for Asthma (GINA) estimate
Asthma is the most common chronic disease in that asthma affects around 200 million people in
children worldwide. Its high heterogeneity makes the world. It causes a considerable amount of lost
it a very complex disease, in which several risk schooldays and workdays, besides the worsening
factors, protector factors, and the genetic predis- of the quality of life, particularly in those patients
position of the patient interact to express the dis- who are poorly controlled. The disease is costly to
ease in different ways and at different times. the public health, because in many cases treatment
During the past decades an important increase in must be continued for years, and patients may
the prevalence of this disease has been observed, present with exacerbations requiring multiple vis-
as well as for other allergic diseases such as aller- its to the emergency room or hospital admissions.
gic rhinitis, rhinoconjunctivitis, eczema, and The greatest limitation of asthma epidemio-
even food allergies. logical studies, as happens with other allergic
diseases, lies in the methods obtained for the
V. Aguirre Camposano diagnosis, which are based mainly on question-
Department of Pediatrics, School of Medicine,
naires, with limited studies using more objective
University of Santiago, Santiago, Chile
measures such as pulmonary function tests,
M. Soto Martínez
allergy studies, or allergen determination.
Department of Pediatrics, School of Medicine,
University of Costa Rica, San José, Costa Rica The most important investigation relative to
asthma prevalence in children is the International
M. Soto Quirós (*)
Department of Pediatrics, Hospital San José, Study of Asthma and Allergies in Childhood
San José, Costa Rica (ISAAC), in which the same questionnaire was

© Springer Nature Switzerland AG 2020 393

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_39
394 V. Aguirre Camposano et al.

applied to children from 6 to 7 years old or ado- reported by several countries, with a greater ten-
lescents from 13 to 14 years old, worldwide, with dency rate in countries with tropical weather.
their respective translations to the local language. Five to 10  years after the phase I of ISAAC
Phase I of the ISAAC featured questionnaires was implemented, Phase III of ISAAC was exe-
including questions about the presence of symp- cuted. In Phase III, a total of 1,187,496 children
toms related to asthma, rhinitis, and eczema. In participated from 237 centers in 98 countries.
Phase II of ISAAC, which followed Phase I by Approximately 85% of the countries that partici-
about 5 years, the main objective was to examine pated in Phase I also participated in Phase III. The
the variation within the tendencies of these dis- design of the study was very similar, but it also
eases, but it also included an environmental included an environmental questionnaire.
questionnaire. The change in the average of prevalence rates
Phase II of ISAAC was developed with the of wheezing within the past 12 months between
intent to prove certain hypotheses that were gen- Phase I and Phase III was 11.1% to 11.6% for
erated during the analysis of Phase I. Nevertheless, children who were from 6 to 7 years old (0.13%
this second phase included a smaller number of increase per year), and 13.2% to 13.7% in chil-
participants from Latin America. dren who were 13 to 14 years old (0.06 increase
At the same time, besides the epidemiologi- per year) (Table  39.1). In Latin America, as in
cal studies about disease prevalence, several many other regions in the world, there was an
investigations appeared relative to possible risk increase in the prevalence rate of the disease for
factors associated with asthma development both age groups (+0.07% and +0.32%, respec-
and other allergic diseases such as rhinitis and tively) (Table 39.2.). It is worth mentioning that
eczema. Many of these studies determined that independently of the ISAAC phase, most of the
atopy family history is among the main risk fac- centers in Latin America reported the highest
tors for developing asthma, rhinitis, and prevalence rates of the disease in the world.
eczema, in addition to the presence of multiple There was a worldwide increase in the symp-
environmental factors, which are considered toms for at least two diseases. In the group of 6-
key factors influencing the expression of the to 7-year-olds there was an increase in the
disease. proportion of the three diseases from 0.8% to
1.0%, and in the group of 13- to 14-year-olds the
change was 1.1% to 1.2%.
 sthma in Latin America: Phase
A Phase III of ISAAC, and other epidemiologi-
I and Phase III ISAAC Studies cal investigations, show very clear increasing
tendencies in the asthma prevalence rate in chil-
In Phase I of ISAAC, a questionnaire was used to dren worldwide. It is also important to consider
determine the prevalence and severity of symp- the increase in the prevalence rate of symptoms
toms that suggest the presence of asthma and of eczema and rhinoconjunctivitis, which was
other allergic diseases, such as rhinitis and even greater than the increase of asthma symp-
eczema. This phase involved about 257,800 chil- toms. This finding presents a new hypothesis
dren who were between 6 and 7 years old, distrib- relative to potential modification and risk factors
uted around 91 centers in 38 countries, and for the appearance of these diseases.
463,801 children between 13 and 14 years of age, Anther factor to consider was the variability
distributed in 155 centers in 56 countries around prevalence rate for asthma and other allergic dis-
the world. eases in Latin America, where some countries
The prevalence of respiratory symptoms that reported the highest disease proportions at the
suggested the presence of asthma and other aller- worldwide level (Costa Rica), and other coun-
gic diseases in children in the region was very tries reporting very low prevalence rates
high and very similar to the prevalence rates (Mexico). The most interesting issue is that this
reported by developed countries. There was great variability has yet no explanation, because in the
variability in the prevalence rates of asthma results of ISAAC it is observed that this is
39  Latin America Asthma Epidemiology and Related Risk Factors 395

Table 39.1  Asthma prevalence information within the past 12 months

Years between Number of Phase I of Phase III of Change per
phases children ISAAC (%) ISAAC (%) year SD
6–7 years old
Africa (English 7.0 2,396 4.8 5.6 0.10 0.19
speaking)
Asia-Pacific 6.3 43,403 10.0 8.9 −0.06 0.09
Eastern 6.3 13,990 6.8 11.7 0.79 0.08
Mediterranean
Indian subcontinent 7.5 18,877 6.2 6.8 0.06 0.17
Latin America 7.1 21,112 19.9 21.4 0.07 0.12
North America 7.5 4,014 16.8 19.1 0.32 0.12
North and East of 6.4 21,984 9.7 9.6 0.05 0.06
Europe
Oceania 9.4 13,841 24.3 21.8 −0.21 0.06
West of Europe 7.2 53,787 8.1 9.7 0.20 0.03
GLOBAL TOTAL 7.1 193,404 11.1 11.6 0.13 0.04
13–14 years old
Africa (English 6.6 17,686 13.5 15.4 0.18 0.15
speaking)
Africa (French 6.0 10,711 7.7 10.2 0.15 0.40
speaking)
Asia-Pacific 6.4 57,389 8.7 8.8 0.07 0.07
Eastern 6.3 19,887 12.0 11.6 −0.10 0.13
Mediterranean
Indian Subcontinent 7.1 20,767 6.7 6.4 0.02 0.14
Latin America 6.9 44,550 17.8 18.8 0.32 0.10
North America 6.5 4,920 19.7 21.5 0.12 0.24
North and East of 6.9 32,608 8.1 11.6 0.26 0.09
Europe
Oceania 9.0 13,317 29.7 26.7 −0.39 0.13
West of Europe 7.4 82,844 15.4 15.2 −0.07 0.10
GLOBAL TOTAL 7.0 304,679 13.2 13.7 0.06 0.05
SD Standard deviation
Data taken from Asher et al. Worldwide trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis,
and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet
2006;368(9537):733–743

i­ndependent of weather, geographic, cultural, common in urban areas for the group 6 to 7 years
­ethnical, or language factors. These results are old; in contrast, in the group 13 to 14 years old
probably more related to the environment, such this risk was greater if they lived in areas with
as humidity and flora, in addition to outdoor and temperatures below 20 °C and at an altitude over
indoor pollutants. 1000  m. Living in a rural area with a weather
In general, not only for the region, children in temperature above 20  °C increased the risk of
the 6- to 7-year-old group had a greater inci- dry cough and respiratory symptoms in this same
dence of respiratory symptoms in comparison to age group.
the 13- and 14-year-old group. In relationship to There are multiple hypotheses about the
gender, boys 6 to 7 years old had a greater preva- increase of the prevalence of this disease in many
lence of wheezing and asthma within the past countries. It is possible that the asthma increase
12  months than did girls, although girls had a is caused by an improvement in diagnosis.
greater prevalence of respiratory symptoms in Nevertheless, high levels of risk and sensitizing
the group from 13 to 14 years old. The presence factors have been reported, which influence the
of wheezing during the past 12 months was more appearance and poor control of the disease, for
396 V. Aguirre Camposano et al.

Table 39.2  Asthma prevalence information within the past 12 months (Latin America)
Years between Number of Response Phase I of Phase III of Change per
phases children (%) ISAAC (%) ISAAC (%) year SD
6–7 years old
Brazil 7.0 3,047 68.2 21.3 24.4 0.44 0.20
Chile (3) 7.0 9,310 88.9 18.2 17.9 −0.06 0.12
Costa 8.0 3,234 80.9 32.1 37.6 0.69 0.20
Rica
Mexico 8.0 2,579 84.3 8.6 8.4 −0.03 0.11
Panama 6.0 2,942 92.5 23.5 22.7 −0.13 0.20
13–14 years old
Argentina 5.0 3,445 99.4 11.2 13.6 0.48 0.24
Brazil (5) 7.4 15,681 91.5 22.7 19.9 −0.42 0.17
Chile (3) 6.7 9,175 89.3 10.2 15.5 0.84 0.13
Costa 8.0 2,436 69.6 23.7 27.3 0.46 0.24
Rica
Mexico 8.0 1,431 85.9 6.6 11.6 0.63 0.13
Panama 6.0 3,183 92.9 17.6 22.9 0.88 0.19
Paraguay 5.0 3,000 99.3 19.4 20.9 0.31 0.32
Peru 6.0 3,022 99.2 26.0 19.6 −1.06 0.57
Uruguay 8.0 3,177 90.8 19.0 17.9 −0.13 0.20
Data taken from Asher et al. Worldwide trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis,
and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet
2006;368(9537):733–743
SD Standard deviation

example, passive and active smoke tobacco expo- Available information about asthma risk fac-
sure during pregnancy, and genetic as well as tors, which comes from several studies conducted
nutritional factors, outdoor and indoor pollutants, in countries in all the regions of the world,
and respiratory infections during the first years of describes the following:
life.
• Genetics. The studies conducted in families
and twins establish that asthma has a genetic
Risk Factors predisposition, although the genes involved in
its pathogenesis are many and can vary accord-
There are many published studies aimed to iden- ing to different ethnic groups. Information
tify asthma risk factors, and many times the gathered from the different studies has identi-
results are contradictory. Factors that have been fied at least 18 genomic regions and more than
proven to be protectors for this disease in other 100 genes associated with asthma and aller-
countries, especially in developed countries, gies in 11 different populations. Besides the
include the high number of children per family, genes that predispose to suffering from
high percentage of viral respiratory infections, asthma, there are others related to treatment
gastrointestinal parasitosis, and lack of hygiene. response. The genetic characterization of
However, these factors do not seem to have a sig- asthma has been difficult, and there is still
nificant role in Latin America. On the contrary, much to be discovered because of the exten-
these factors appear to be risk factors in Latin sive heterogeneity of the genetic base of
America, which suggests that socioeconomic sta- asthma and its wide interaction with the
tus may be a factor. Nevertheless, correlation environment.
analyses in several countries of South America • Obesity. Asthma is more frequent and more
did not find a significant variation. difficult to treat in obese patients. Although
39  Latin America Asthma Epidemiology and Related Risk Factors 397

the obese patient has a reduced pulmonary siblings, attending daycare, living in an agricul-
function and a higher comorbidity, obesity is tural environment, and having contact with pets
usually present before asthma, and the exist- and farm animals. However, this hypothesis
ing studies suggest maternal obesity during does not explain the observed increase of
pregnancy has a role. Although the mecha- asthma prevalence rate in underdeveloped
nism through which obesity is a risk factor is countries with poor hygiene conditions.
not completely understood, it has been pro- Early infection by rhinovirus and respira-
posed that it may result from a combination of tory syncytial virus has been related to the
several factors, such as the development of a onset of the asthma phenotype. It has been
pre-inflammatory state caused by the release described that up to 40% of the children hos-
of cytokines and mediators through adipo- pitalized because of respiratory syncytial
cytes, or a respiratory pattern that may alter virus continue to present with wheezing or
the plasticity and function of the smooth mus- asthma during childhood. Nevertheless,
cle in the airway. All these factors must be there is also evidence that certain early
considered besides a genetic, hormonal, or infections such as measles, tuberculosis, and
neurogenic influence. even respiratory syncytial virus may protect
• Gender. During childhood, the asthma preva- against asthma.
lence rate in boys is almost double the rate in The interaction between atopy and viral
girls. As the child grows, this difference is infection is complex because the atopic state
reduced, and during adulthood it is inverted, may influence the viral response of the lower
with women having a greater prevalence rate airway, and at the same time, the viral infec-
for asthma. The reasons for this are not very tion may influence the development of allergy
clear, although at birth male lung size smaller sensitization. Also, the interaction between
than that of women, but during adulthood the these two factors may occur when the indi-
lung of men is larger. vidual is exposed simultaneously to allergens
• Aeroallergens. Atopic sensitizing to inhaled and virus. Although in general parasite infec-
allergens, especially permanent ones, is an tions do not protect from asthma, ancylosto-
important risk factor related to asthma. miasis may reduce the risk.
Although it is clear that both outdoor and • Antibiotics. The use of antibiotics during the
indoor allergens cause asthma exacerbations, first year of life has been related to a greater
their role for asthma appearance is not clear. asthma risk, but the results are controversial,
Sensitizing to room dust, cat and dog hair, and the current recommendation is to avoid
cockroaches, and Aspergillus are risk factors the use of broad-spectrum antibiotics during
for asthma symptoms during the first 3 years early childhood.
of life. Relative to cats and dogs, the epide- • Tobacco. Exposition to tobacco smoke during
miological studies are contradictory. pregnancy and after birth is related to a greater
• Infections. Current knowledge is contradictory. risk of developing asthma symptoms during
Interest about the impact of bacterial products the first years of childhood. Tobacco use dur-
and its relation to asthma development has pro- ing pregnancy is related to alterations in pul-
duced the hygiene hypothesis, which suggests monary development. The children of mothers
that infections during the early stages of life who smoke have a fourfold-increased risk to
help the child’s immunological system to present with wheezing during their first year
develop through a nonallergic path, therefore of life.
reducing the risk for asthma and other allergic • Indoor and outdoor pollution. The role of out-
diseases. This hypothesis would explain the door pollution as a cause of asthma can be dis-
reduced asthma risk in the long term for chil- cussed, although it clearly is a trigger of
dren exposed to situations that increase the pos- asthma exacerbations. The role of indoor
sibility of infection, such as having older ­pollutants is also controversial, such as smoke
398 V. Aguirre Camposano et al.

and gas vapors, as well as combustible bio- paracetamol consumption during pregnancy
mass used for heating and refrigerating, and and during the first year of the child’s life, pres-
the same exacerbations occur with the pres- ence of jaundice during the neonatal period,
ence of fungus and cockroach infestations. and environmental stress surrounding the child
Recent information suggests that the during the first year of life. However, all these
immune response of the child may be altered factors must be confirmed in future studies. It is
if the mother was exposed to environmental important to highlight the asthma risks
pollution during pregnancy and during the described for infants with recurring wheezing
first years of childhood; this would increase episodes. In these patients, the family history of
the appearance of asthma and allergies. parents with asthma, the presence of eczema,
• Diet. Infants fed with breast milk have a lower allergic rhinitis, wheezing episodes not related
incidence of wheezing disease during early to colds, and peripheral eosinophilia above 4%
childhood, in comparison to patients who have during the first 3 years of life are greater risks to
been fed with cow’s milk or soy milk, although suffer asthma during childhood.
there is not enough evidence to support its
protective effect in the development of asthma After many epidemiological studies, we rec-
during childhood. ognize that asthma and allergic diseases in Latin
Even though there is information suggesting America are a great public health problem for
that the Occidental diet may have contributed to most countries, with a high morbidity, complex-
the increase of asthma and atopic diseases in ity in treatment and follow-up, and high health
general, there is still not enough evidence to costs, and carrying a significant alteration in the
support the protector effect of some kind of diet quality of life of the patients. Although many risk
during pregnancy or lactation to avoid asthma and protection factors have been recognized,
development. Recently, it has been described there is a great degree of variability in Latin
that vitamin D deficiency is related to a increase America, which makes it difficult to place highly
in the risk for asthma appearance, and ongoing effective preventive measures.
studies using supplements of vitamin D will
confirm this in future.
• Social factors and inequity. Generally, there is Asthma Epidemiology in Chile
a positive relationship between poverty and
greater asthma morbidity, but the relationship Studies about asthma prevalence symptoms in
to a greater prevalence rate can be discussed, Chile mainly derive from the reports of the
probably from the presence of many covari- ISAAC, and they oscillate between 17.9%, for
ables related to this condition, such as ethnic schoolchildren within the age group of 6 to 7 years
group, age of the mother at birth, maternal old, and 15.3% for schoolchildren 13 to 14 years
breastfeeding, attending daycare, urban/rural old (0.84% on average per year). These numbers
environment, obesity, and maternal and envi- locate Chile in an intermediate position relative to
ronmental stress. Studies that originated from asthma in Latin America, and above the average
ISAAC in relationship to environmental factors prevalence at world level. For the group of infants,
associated with asthma, rhinitis, and eczema the most recent information comes from the
found a positive relationship between these International Study of Wheezing in Infants
three diseases and the geographic gross product (Estudio Internacional de Sibilancias en Lactantes,
of each country, although the prevalence rate of EISL), which indicates that in Chile the preva-
severe asthma was inversely correlated. lence of recurrent wheezing (three or more epi-
• Other factors involved. A greater asthma risk sodes) is 21.6% in those under 1  year old, with
has been described for children born by urgent 57% of severe episodes, 70% of visits to urgency
cesarean section, particularly for children with services, and 29% of hospitalization because of
the following risk factors: parent allergies, wheezing.
39  Latin America Asthma Epidemiology and Related Risk Factors 399

Although the hospitalization rate from asthma prevalence of symptoms of asthma, allergic rhinocon-
junctivitis, and eczema in childhood: ISAAC Phases
is low (0.68% of the total of hospital admittances One and Three repeat multicountry cross-sectional
for those under 20  years old) and mortality is surveys. Lancet. 2006;368(9537):733–43.
practically nil, the use of medical resources repre- Asher MI, Stewart AW, Wong G, Strachan DP, García-­
sents a significant cost in healthcare. During 2012, Marcos L, Anderson HR, et al. Changes over time in
the relationship between symptoms of asthma, rhino-
26.8% of all the medical consultations related to conjunctivitis and eczema: a global perspective from
respiratory diseases within the primary attention the International Study of Asthma and Allergies in
services corresponded to wheezing and asthma Childhood (ISAAC). Allergol Immunopathol (Madr).
for those under 15  years old, which represented 2012;40(5):267–74.
Beasley RW, Beasley RW, Clayton TO, Crane J, Lai CK,
4.4% of all emergency consults of those under Montefort SR, Mutius E, et al. Acetaminophen use and
15  years old during 2011. These numbers are risk of asthma, rhinoconjunctivitis, and eczema in ado-
probably underestimated, because they do not lescents: International Study of Asthma and Allergies
consider asthma exacerbations, which may be in Childhood Phase Three. Am J Respir Crit Care
Med. 2011;183(2):171–8.
within the diagnoses of pneumonia, influenza, Boneberger A, Haider D, Baer J, Kausel L, Von Kries
bronchitis, and acute upper tract respiratory infec- R, Kabesch M, Radon K, Calvo M.  Environmental
tion, for those patients suffering from asthma. risk factors in the first year of life and childhood
Studies about the risk factors for asthma in asthma in the Central South of Chile. J Asthma.
2011;48(5):464–9.
children are scarce. Boneberger et  al. recently Brehm JM, Celedón JC, Soto-Quiros ME, Avila L,
published a study of rural population children in Hunninghake GM, Forno E, et  al. Serum vita-
which they described that the precedent of attend- min D levels and markers of severity of childhood
ing daycare within the first year of life and regu- asthma in Costa Rica. Am J Respir Crit Care Med.
2009;179(9):765–71.
lar contact with farm animals was related to a Chong Neto HJ, Rosario NA, Sole D, Latin American
lower asthma risk, whereas the precedent of IG.  Asthma and rhinitis in South America: how dif-
pneumonia and fungus/humidity at home was ferent they are from other parts of the world. Allergy
related to a greater risk. Asthma Immunol Res. 2012;4(2):62–7.
Huang L, Bao Y, Xu Z, Lei X, Chen Y, Zhang Y, Zhang
To conclude, according to the reports deliv- J.  Neonatal bilirubin levels and childhood asthma in
ered by the Chilean Ministry of Health, the Public the US collaborative perinatal project, 1959–1965.
Health Care Network keeps a follow-up (infor- Am J Epidemiol. 2013;178(12):1691–7.
mation dated December 2013) of 192,717 chil- Lai CK, Beasley R, Crane J, Foliaki S, Shah J, Weiland
S, International Study of Asthma and Allergies in
dren who are under 15 years old. These children Childhood Phase Three Study Group. Global varia-
have moderate or severe asthma and are incorpo- tion in the prevalence and severity of asthma symp-
rated to the program of explicit guarantees in toms: phase three of the International Study of
health (garantías explícitas en salud, GES). The Asthma and Allergies in Childhood (ISAAC). Thorax.
2009;64(6):476–83.
evaluation of the impact of this public policy is Ly NP, Soto-Quirós ME, Avila L, Hunninghake GM,
still pending, although there has been a progres- Raby BA, Laskey D, et  al. Paternal asthma, mold
sive reduction in the number of patients with exposure, and increased airway responsiveness
severe asthma. among children with asthma in Costa Rica. Chest.
2008;133(1):107–14.
Mallol J, Solé D, Asher I, Clayton T, Stein R, Soto-­
Quiroz M.  Prevalence of asthma symptoms in Latin
Sources America: the International Study of Asthma and
Allergies in Childhood (ISAAC). Pediatr Pulmonol.
Antó JM. Recent advances in the epidemiologic investiga- 2000;30(6):439–44.
tion of risk factors for asthma: a review of the 2011 lit- Mallol J, Aguirre V, Aguilar P, Calvo M, Amarales L,
erature. Curr Allergy Asthma Rep. 2012;12:192–200. Arellano P, Palma R.  Cambios en la prevalencia de
Asher MI. Recent perspectives on global epidemiology of asma en escolares chilenos entre 1994 y 2002. Rev
asthma in childhood. Allergol Immunopathol (Madr). Méd Chile. 2007;135:580–6.
2010;38(2):83–7. Mallol J, García-Marcos L, Solé D, Brand P, the EISL
Asher MI, Montefort S, Björkstén B, Lai CK, Strachan Study Group. International prevalence of recurrent
DP, Weiland SK, et al. Worldwide time trends in the wheezing during the first year of life: variability, treat-
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ment patterns and use of health resources. Thorax. gens, and current wheezing, rhinitis, and eczema
2010;65:1004–9. among children in Costa Rica. Pediatr Pulmonol.
Odhiambo JA, Williams HC, Clayton TO, Robertson CF, 2002a;33(4):237–43.
Asher MI, Group IPTS. Global variations in prevalence Soto-Quiros ME, Soto-Martinez M, Hanson
of eczema symptoms in children from ISAAC Phase LA.  Epidemiological studies of the very high preva-
Three. J Allergy Clin Immunol. 2009;124(6):1251– lence of asthma and related symptoms among school
1258. e23. children in Costa Rica from 1989 to 1998. Pediatr
Pedersen SE, Hurd SS, Lemanske RF Jr, Becker A, Allergy Immunol. 2002b;13(5):342–9.
Zar HJ, Sly PD, Manuel Soto-Quiroz M, Wong G, The International Study of Asthma and Allergies in
Bateman EED.  Global strategy for the diagnosis Childhood (ISAAC) Steering Committee. Worldwide
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Celedón JC.  Maternal history, sensitization to aller-
 Evaluation of Asthma Risk
in Infants and Preschoolers
40
José Antonio Castro-Rodríguez

Contents
Wheezing Phenotypes and Their Risk Factors..........................................................   402
Asthma Predictive Indexes...........................................................................................   404
Sources...........................................................................................................................   406

Recent cohort studies have provided important three wheezing phenotypes were described dur-
information about several issues: natural progres- ing the first years of life, besides correlating the
sion of wheezing during the first years of life, risk presence of wheezing with variables linked to
factors for asthma development, and the efficacy genetics, immunology, physiology, and environ-
of different preventive strategies. mental factors.
The most representative of these studies is the Another cohort study started in 1989 was
Tucson Children’s Respiratory Study (TCRS), conducted in 1456 children born in the prov-
which began in 1980, including 1246 newborns ince of Wight Island, United Kingdom. This
who were enrolled shortly after birth, in Tucson, study used questionnaires to recollect clinical
Arizona, United States of America. This study information at 1, 2, 4, 10, and 18 years of life.
was designed as a prospective cohort to obtain Further, allergy cutaneous skin tests were con-
information about potential risk factors related to ducted at 4, 10, and 18 years of life, with total
lower respiratory tract disease. Participants com- IgE level, lung function tests, and bronchial
pleted questionnaires at 1, 3, 6, 11, and 16 years challenging tests at 10  years of life. New
of life and were evaluated with periodic allergic wheezing phenotypes were described. The
cutaneous skin tests, E immunoglobulin (IgE), Multicenter Allergy Study (MAS) that started
and eosinophil count, with pulmonary function in Germany in 1990 included 1314 children.
and lung function tests. Using this information, Participants were followed and evaluated at 1,
3, 6, 12, 18, and 24 months of life. After this,
the follow-ups were done yearly until the par-
J. A. Castro-Rodríguez (*) ticipants reached 13  years of age. This study
Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile,
recollected information through questionnaires,
Santiago, Chile specific IgE against food and inhaled allergens
e-mail: [email protected] (at 1, 2, 3, 5, 7, and 10  years of life), besides

© Springer Nature Switzerland AG 2020 401

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_40
402 J. A. Castro-Rodríguez

lung function tests (at ages of 7, 10, and 13).  heezing Phenotypes and Their
W
Thus, this study gathered information about the Risk Factors
relationship between allergic sensitizing during
early childhood and wheezing. The existence of several wheezing phenotypes
In 1995, the Manchester Asthma and Allergy and their distinctive characteristics offer a
Study (MAAS) was started in the United glimpse of asthma development and its natural
Kingdom, including 1186 infants who were progression, as well as showing that asthma is a
afterward evaluated through the use of respira- complex disease with multiple physiopathologi-
tory questionnaires at 1, 3, 5, and 8  years of cal mechanisms. The identification of these phe-
life. Additionally, lung functions tests were notypes is important to study the ways in which
done at 3, 5, and 8  years of life, with allergy asthma progresses, as well as the mechanisms
cutaneous tests and IgE levels at 1, 3, 5, and underlying the disease. This information can help
8  years of life. The atopic state of the partici- to decide which is the most adequate therapy and
pants was specified in further detail: early, mul- how to predict the clinical progression of the
tiple, multiple late, related to house dust mites, patients.
and not related to house dust mites. There was a The TCRS classified patients in four wheezing
significant association between early multiple phenotypes: “transient early wheezing,” “persis-
atopic state and persistent wheezing. These tent wheezing,” “late-onset wheezing” and non-­
associations described related type and number wheezing. Children who presented with one or
of allergens as well as the age when allergic more wheezing episodes, but improved before
sensitizing takes place. 6 years of life, were classified as transient early
The Avon Longitudinal Study of Parents and wheezing. Those who presented with wheezing
Children (ALSPAC) investigation studied 14,062 episodes after 3 years of life and persisted until
children born in the province of Avon, United 6 years of life were classified as suffering from
Kingdom, in 1991. Clinical information was col- late-onset wheezing. Finally, children who pre-
lected annually using respiratory questionnaires sented with wheezing episodes before 3 years of
between 1 and 7 years of life, as well as conduct- life that persisted until 6 years of life were classi-
ing pulmonary function and allergy cutaneous fied as persistent wheezing. Some risk factors
tests when the participant reached 7 to 8 years of were identified for each one of the phenotypes:
life. maternal tobacco exposure was related to the
The Prevalence and Incidence of Asthma and phenotype of transient early wheezing, and
Mite Allergy (PIAMA) started in the Netherlands maternal asthma, being of masculine sex, and the
in 1996, with 3963 children 1 and 8  years old. presence of allergic rhinitis within the first year
The authors interviewed their caretakers annually of life were related to late-onset wheezing.
and conducted serum measures for specific IgE Maternal asthma, maternal use of tobacco, and
when the participants were 4 to 8 years old. When presence of allergic rhinitis and atopic dermatitis
the participants were 8 and 9  years old, lung during the first year of life, with being of mascu-
function and bronchial challenge tests were line sex, were predictors for persistent wheezing.
conducted. The fact that each one of the phenotypes has dif-
The trials mentioned included similar vari- ferent risk factors suggests that each phenotype
ables in their analyses, but differences in their reflects different physiopathological entities.
reported results may be explained by the differ- After conducting cutaneous allergy tests at
ences between employed methodology, number 6 years of life, the TCRS created an additional
and moment of assessment of the participants, classification of the wheezing phenotypes,
and size samples. Nevertheless, all these studies which consisted of three categories: transient
could determine several types of wheezing phe- early wheezing, non-atopic, and asthma/wheez-
notypes during the first years of life. ing related to IgE, based on the results of the
40  Evaluation of Asthma Risk in Infants and Preschoolers 403

methacholine challenge test, the variation of greatly reduced pulmonary function). The
maximum expiratory flow during the daytime, PIAMA study only added the phenotype of inter-
and the answers to a questionnaire inquiring mediate onset. In these two studies, each pheno-
about the presence or absence of wheezing/ type had similar features, not only in relation to
atopy. prevalence rates, but also relative to atopic sensi-
The study conducted in Wight Island and the tization, lung function tests, and bronchial
MAS and MAAS studies adopted similar classifi- hyperreactivity.
cations to those used in Tucson, but the age crite- These studies have increased knowledge about
ria were different: the study in Wight Island the mechanisms and natural progression of
conducted evaluations at 4 and 10  years of life, wheezing during the first years of life, and risk
the MAS study conducted evaluations 3 and factors for persistent asthma symptoms, as well
7 years of life, and the MAAS study did so 3 and as predicting lung function test. Nevertheless, in
5  years of life. The predictors for persistent daily clinical practice it is very difficult, if not
wheezing were family history of asthma, recur- altogether impossible, to classify an identified
rent respiratory infections at early ages, and aller- patient with recurrent wheezing in one of those
gic sensitization. The presence of wheezing in late phenotypes,. Recently, a new classification sys-
childhood was used as the criterion to classify tem based on symptoms has been proposed in a
participants. In the study conducted at Wight consensus about wheezing in preschoolers, con-
Island, the patients who still presented with ducted by the European Respiratory Association
wheezing episodes at 10  years of life were sub- (ERS). This tool divides preschoolers with
classified as suffering from atopic wheezing and wheezing into the categories episodic viral
non-atopic wheezing, each with different risk fac- wheeze (EVW) and multiple trigger wheeze
tors. The presence of asthma in brothers, atopic (MTW). According to this definition, the EVW
dermatitis during the first year of life, rhinitis at phenotype corresponds to children whose exacer-
4 years of age, and masculine sex were the most bations are exclusively triggered by respiratory
prevalent features in atopic patients suffering viral infections, without symptoms between epi-
from wheezing, whereas maternal asthma with sodes. In contrast, the MTW phenotype corre-
recurrent respiratory infections at 2 years of life sponds to children who present wheezing in
were the most prevalent features in non-­atopic response not only to respiratory viral infections,
patients suffering from wheezing. In the MAS but also to other triggers, such as allergens, phys-
study, the presence of wheezing at 13  years old ical activity, weather changes, or exposure to
was used to subclassify the patients; it was related tobacco smoke.
to atopy in parents and in patients, high levels of At first, this classification was conceived as
IgE at early ages, and excessive exposure to pragmatic and useful in daily clinical practice for
indoor allergens. The MAAS study included the preschooler patients with recurrent wheezing.
measure of specific airway resistance (sRaw) at This tool involved some potential therapeutic
early ages, and it was included as a risk factor for proposal, such as low doses of inhaled steroid
persistent wheezing at 5 years of life. continuously for children with the MTW pheno-
In the ALSPAC and PIAMA studies, the type, but not for children with the EVW pheno-
authors used the classification system used in the type, besides continuous or intermittent therapy
TCRS, but with longitudinal latent class analy- with montelukast and high intermittent doses of
ses, and they added other subgroups. The inhaled steroids, which may have some useful-
ALSPAC study phenotypes described were “pro- ness for children with the EVW phenotype.
longed early wheezing” (related to maternal However, it has been recently criticized for sev-
asthma, reduced pulmonary function, mild bron- eral reasons. There is scarce evidence supporting
chial hyperreactivity, with no atopy), and the idea that these two phenotypes are related to
“intermediate-­onset wheezing” (associated with longitudinal patterns of wheezing or to different
atopy, severe bronchial hyperreactivity, and pathological patterns. This classification has not
404 J. A. Castro-Rodríguez

been objectively validated with lung function Table 40.1  Asthma Predictive Index (API)
tests or markers of airway inflammation. Major criteria Minor criteria
Therefore, it is unknown if EVW and MTW phe- Father or mother with Allergic rhinitis
notypes represent different conditions with dif- asthma diagnosed by a diagnosed by medical
medical doctor. doctor
ferent pathogen mechanisms, or if they are simply Eczema diagnosed by Wheezing episodes not
degrees of seriousness of the same disease, medical doctor. related to colds
despite the MTW phenotype having inferior lung Eosinophilia in
function compared to the EVW phenotype. peripheral blood (>4%)
Finally, this classification does not allow sep- Recurrent wheezing (>3 episodes/year) during the first
aration of wheezing episodes by other respira- 3 years of life
tory symptoms, such as cough, cold episodes, or
chest congestion. These two phenotypes appear respectively, and the positive and negative likeli-
to be unstable in time, as it has been shown that hood ratios were 7.3 and 0.80, respectively.
an important proportion of patients (close to A modified API (mAPI) was used in a ran-
50%) move from one phenotype to the other domized clinical study that involved 285 partici-
after a 1-year follow-up. Therefore, it is cur- pants, included allergic sensitization to one or
rently thought that there is little evidence for the more allergens as another major criterion, and
EVW/MTW classification system. allergic sensitizing to milk, eggs, or peanuts as a
minor criterion, which replaced the medical diag-
nosis of allergic rhinitis from the original
Asthma Predictive Indexes API. Other predictive indexes were developed to
predict persistent wheezing.
The identification of preschoolers with recurrent In 2003 Kurukulaaratchy et  al. developed a
wheezing that will present as asthma in the predictive index using the information gathered
future makes possible setting prevention actions, from 1456 participants of the Wight Island study.
as well as therapeutic strategies for those This study found that having a family with a
patients. To help with the identification of these background history of asthma, positive cutaneous
preschoolers at greater risk of suffering from allergy tests at 4 years of life, and lower respira-
asthma, several predictive indexes have been tory tract infections at 2 years of life were related
developed. The Asthma Predictive Index (API) to an increase in the probability of presenting
is currently the most used predictive tool. API with asthma symptoms at 10  years of life.
combines simple clinical and laboratory param- Sensitivity, specificity, and positive and negative
eters that are easy to perform. An identified predictive ratio were 10%, 98%, 83%, and 64%,
patient is considered to have a positive API if respectively, and the positive and negative likeli-
she/he has had more than three recurrent wheez- hood ratios were 7.9 and 0.91, respectively.
ing episodes during the first 3  years of life, in However, external validation studies are still
addition to having one of these major criteria needed to confirm this information.
(medical diagnosis of atopic dermatitis, wheez- In 2009, Caudri et  al., using the information
ing not related with cold-like episodes, and gathered from 3963 children from the PIAMA
eosinophilia in peripheral blood greater than study, developed a predictive index named risk
4%) (Table 40.1). The TCRS cohort determined score PIAMA, based on eight clinical parameters
that in comparison to children who had a nega- easily obtained in daily clinical practice (mascu-
tive API, children with a positive API had a prob- line sex, birth after term, educational level of the
ability 2.6 to 13 times greater of having asthma parents, parent use of inhaled medications, fre-
between 6 and 13 years of life. The sensitivity, quency of wheezing episodes, wheezing not
specificity, and positive and negative predictive related to cold-like episodes, number of infec-
value of API to predict asthma between 6 and tions of the respiratory airway, and diagnosis of
8 years of life were 22%, 97%, 77%, and 90%, atopic dermatitis). When this index was used for
40  Evaluation of Asthma Risk in Infants and Preschoolers 405

the cohort in the PIAMA study, the participants reached 6  years of age, when the diagnosis of
with a score of 30 or greater had a 40% probabil- asthma was based on the clinical combination,
ity of developing asthma at 7 to 8 years of life. use of antiasthma medication, and pulmonary
Predictive asthma indexes, especially API, function (methacholine hyperreactivity, or bron-
have been questioned. The indexes have been chial reversibility by spirometry). This study
used in clinical practice without having a valida- showed a negative and positive predictive value
tion procedure in different populations (external of 0.74 to 0.78, respectively, but external valida-
validation). They have not been probed to predict tion studies are needed.
long-term wheezing, the most severe wheezing It is important to highlight that the best param-
episodes in children. They have also been found eter to determine the use of a diagnostic test is the
relatively complex with no real benefit over using probability or coefficient variation (positive like-
more simple prediction rules based only on the lihood ratio), which for API is 7.3. Thus, for a
frequency of wheezing episodes. Nevertheless, population at low, moderate, or high risk of suf-
recently the API index and PIAMA risk score fering from asthma during school age (for exam-
have been validated in independent populations ple, 10%, 20%, and 40%), if a child is evaluated
(Colombia, 130 children; England, 1954 chil- for recurrent wheezing, API application increases
dren). The API is a broad-use predictive index the probability of asthma prediction by 4.3 to 2
easily obtainable in any health center. API has fold, respectively. In other words, the asthma pre-­
been used with several purposes, such as a crite- test frequency will change from 10% to 42%,
rion of high-risk asthma development in random- from 20% to 62%, and from 40% to 80%, respec-
ized clinical trials, as well as a guide in clinical tively. Additionally, the most useful feature of the
practice for the treatment of preschoolers with API is its ability to estimate the probability that
recurrent wheezing. API has been included in the preschoolers with recurrent wheezing continue to
most important guidelines for asthma manage- have asthma symptoms during school age.
ment in the world, such as the Global Initiative Therefore, the use of API and other indexes of
for Asthma (GINA) and the proposal made by the asthma prediction are valid within the clinical
National Institutes of Health (NIH) of the United context to reduce morbidity in preschoolers with
States of America. recurrent wheezing who are at a greater risk of
A recent study designed to validate the modi- developing asthma. All these measures are
fied PIAMA risk index (term-born was replaced intended to avoid the unnecessary prescription of
by prematurity as a criterion, and the infections follow-up therapies in children who tend to have
in the respiratory system were eliminated) in a only transient conditions instead of asthma.
multiethnic cohort in the Netherlands (R There are three important reasons to diagnose
Generation) showed that it has an acceptable dis- asthma in children under 5  years old who have
crimination rate and a good calibration in com- recurrent wheezing along with a positive predic-
parison with the original PIAMA cohort. It was tor index. First, about 80% of patients with asthma
also noted that it was independent of different present symptoms during the first 5 years of life.
ages and the ethnic origin of preschoolers. In Second, the greater reduction in pulmonary func-
comparison to the original PIAMA, the modified tion happens before reaching 5  years of life.
index had a discrete better negative value predic- Third, even in developed countries, the population
tion, a poorer positive value prediction, and a of children with the poorest asthma control are
similar positive and negative likelihood ratio children less than 5  years old. Therefore, it is
(97% versus 95%, 74% versus 76%, 2.4 versus probable that parents will adhere better to deter-
2.5, and 0.5 versus 0.5, respectively). The Clinical mined prolonged follow-up treatment if they
Asthma Prediction Score (CAPS) followed 711 know that the cause of recurrent wheezing their
Danish preschoolers who sought primary atten- child presents is a chronic disease called asthma,
tion for cough, wheezing, or respiratory distress. instead of a disease with a milder-­sounding name
These children were followed up until they as sometimes mentioned (“allergy” or “bronchial
406 J. A. Castro-Rodríguez

hyperreactivity,” “­ recurrent bronchitis,” “asthma- dren who wheeze during early life. Eur Respir J.
2003;22:767–71.
like bronchitis,” “obstructive bronchitis,” “pre- Lau S, Nickel R, Niggemann B, Gruber C, Sommerfeld
asthma,” or “principles of asthma”). We know that C, Illi S, et al. The development of childhood asthma:
adherence, measured by electronic dosimeters, to lessons from the German Multi-centre Allergy Study
inhaled steroids when treating chronic asthma in (MAS). Paediatr Respir Rev. 2002;3:265–72.
Leonardi NA, Spycher BD, Strippoli MP, et al. Validation
children is only about 50%. Poor adherence to of the Asthma Predictive Index and comparison
preventive treatment is one of the most important with simpler clinical prediction rules. J Allergy Clin
risk factors for uncontrolled asthma and Immunol. 2011;127:1466–1472, e6.
hospitalization. Lowe LA, Simpson A, Woodcock A, Morris J, Murray
CS, Custovic A, et  al. Wheeze phenotypes and lung
function in preschool children. Am J Respir Crit Care
Med. 2005;171:231–7.
Sources Martinez FD, Wright AL, Taussig LM, Holberg CJ,
Halonen M, Morgan WJ.  Asthma and wheezing in
Brand PL, Baraldi E, Bisgaard H, et al. Definition, assess- the first six years of life. The Group Health Medical
ment and treatment of wheezing disorders in preschool Associates. N Engl J Med. 1995;332:133–8.
children: an evidence-based approach. Eur Respir J. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ,
2008;32:1096–110. Guilbert TW, et al. Outcome of asthma and wheezing
Castro-Rodriguez JA.  The Asthma Predictive Index: a in the first 6 years of life: follow-up through adoles-
very useful tool for predicting asthma in young chil- cence. Am J Respir Crit Care Med. 2005;172:1253–8.
dren. J Allergy Clin Immunol. 2010;126:212–6. Rodriguez-Martinez CE, Sossa-Briceno MP, Castro-­
Castro-Rodriguez JA.  The necessity of having asthma Rodriguez JA.  Discriminative properties of two
predictive scores in children. J Allergy Clin Immunol. predictive indices for asthma diagnosis in a sample
2013;132:1311–3. of preschoolers with recurrent wheezing. Pediatr
Castro-Rodriguez JA, Holberg CJ, Wright AL, et  al. A Pulmonol. 2011;46:1175–81.
clinical index to define risk of asthma in young chil- Savenije OE, Granell R, Caudri D, Koppelman GH,
dren with recurrent wheezing. Am J Respir Crit Care Smit HA, Wijga A, et  al. Comparison of childhood
Med. 2000;162:1403–6. wheezing phenotypes in 2 birth cohorts: ALSPAC and
Garcia-Marcos L, Martinez FD. Multitrigger versus epi- PIAMA. J Allergy Clin Immunol. 2011;127:1505–12.
sodic wheeze in toddlers: new phenotypes or severity Schultz A, Brand PL.  Episodic viral wheeze and mul-
markers? J Allergy Clin Immunol. 2010;126:489–90. tiple trigger wheeze in preschool children: a use-
Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic char- ful distinction for clinicians? Paediatr Respir Rev.
acteristics of children with recurrent wheezing at 2011;12:160–4.
high risk for the development of childhood asthma. J Schultz A, Devadason SG, Savenije OE, et al. The tran-
Allergy Clin Immunol. 2004;114:1282–7. sient value of classifying preschool wheeze into epi-
Guilbert TW, Morgan WJ, Zeiger RS, et  al. Long-term sodic viral wheeze and multiple trigger wheeze. Acta
inhaled corticosteroids in preschool children at high Paediatr. 2010;99:56–60.
risk for asthma. N Engl J Med. 2006;354:1985–97. Simpson A, Tan VY, Winn J, Svensen M, Bishop CM,
Hafkamp-de Goren E, Lingsma HF, Caudri D, et  al. Heckerman DE, et al. Beyond atopy: multiple patterns
Predicting asthma in preschool children with asthma-­ of sensitization in relation to asthma in a birth cohort
like symptoms: validating and updating the PIAMA study. Am J Respir Crit Care Med. 2010;181:1200–6.
risk score. J Allergy Clin Immunol. 2013;132:1303–10. Sonnappa S, Bastardo CM, Wade A, et  al. Symptom-­
Henderson J, Granell R, Heron J, Sherriff A, Simpson A, pattern phenotype and pulmonary function in preschool
Woodcock A, et al. Associations of wheezing pheno- wheezers. J Allergy Clin Immunol. 2010;126:519–26.
types in the first 6 years of life with atopy, lung func- Van der Mark LB, van Wonderen KE, Mohrs J, et  al.
tion and airway responsiveness in mid-childhood. Predicting asthma in preschool children at high risk
Thorax. 2008;63:974–80. presenting in primary care: development of a clini-
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 Asthma: Clinical and Diagnosis
Approach
41
Guido Girardi Briere

Contents
Definition.......................................................................................................................   407
Etiopathogenesis...........................................................................................................   408
Physiopathology............................................................................................................   409
Clinical Aspects.............................................................................................................   409
 sthma Clinical Spectrum..............................................................................................  410
A
Differential Diagnosis.....................................................................................................  411
Diagnosis........................................................................................................................   411
 iagnosis Rationale........................................................................................................  411
D
Classification..................................................................................................................  412
Asthma Control Levels...................................................................................................  412
Sources...........................................................................................................................   413

Definition relationship with the severity of the disease has

been questioned.
Asthma is a chronic inflammatory disease of the Asthma is characterized by recurrent episodes
airway that is caused by multiple interactions of cough, wheezing, and dyspnea, which espe-
among cells in the epithelium and those that pro- cially appear during the night and at sunrise.
mote inflammation through the liberation of Asthma presents variable degrees of reversible
inflammation mediators, specially mastocytes, bronchial obstruction. The presence of bronchial
eosinophils, and lymphocytes. This disease hyperreactivity (BHR) when facing different
mainly affects the small airways, but it also com- stimuli in genetically predisposed subjects deter-
promises the central airway. It has been thought mines an exaggerated response and is a pillar in
that persistent inflammation may progress to irre- the diagnosis procedure.
versible structural changes in the airway, cur- Asthma is a multifactorial condition, and it is
rently named “remodeling”; nevertheless, its mainly caused by the interaction of genetic and
environmental factors. The genetic factors
involved in asthma have been known from a long
G. Girardi Briere (*)
Faculty of Medicine, Universidad de Chile, time. Multiple genes have been described in dif-
Santiago, Chile ferent chromosomes that codify diverse proteins

© Springer Nature Switzerland AG 2020 407

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_41
408 G. Girardi Briere

involved in the airway inflammation. Nowadays animal dandruff or hair, pollens, and fungus.
it is not possible to identify an exact relationship Tobacco and the possibility of indoor pollution
between the described genes and a particular facilitate the sensitization process. Even though
phenotype. Some population studies have shown there is no evidence that viruses cause asthma,
the importance of the parents in relationship to they are important agents for its genesis at an
the risk of developing asthma, which is three early age or in its recurrences, as well as being
times higher when one of the parents has asthma. the main triggers of asthma episodes.
Also, there are several environmental factors A recent publication showed that when two
involved. The Western lifestyle explains some of countries, England and Scotland, applied anti-­
these factors that favor the appearance of atopic tobacco laws, the risk of hospitalization caused
asthma. In this situation there is scarce exposure by acute asthma episodes was lowered.
to endotoxins, which require adequate lympho-
cytes and CD14 levels to facilitate the formation
of interferon-γ. This situation also involved an Etiopathogenesis
exaggerated use of antibiotics that destroys the
intestinal flora, besides a low occurrence of infec- The inflammation of the airway is the result of
tions that would stimulate a protective TH1 the interaction of different effector cells and pro-
response, such as hepatitis and measles. It has inflammatory mediators. In patients with atopic
been described also that an early exposition to asthma, the predominance of type Th2 lympho-
allergens may facilitate sensitization and atopy cytes produces a proinflammatory state, with the
with a Th2-lymphocyte response. participation of dendritic neuronal cells and
In developed countries, atopy, a hypersensitiv- release of cytokines such as interleukin (IL)-3,
ity state mediated by elevated IgE titers, is the IL-4, IL-5, and IL-10, which affect local cells,
main predisposing factor for suffering from including epithelial cells, but also affect recruited
asthma. However, the atopy prevalence rate (30– cells, such as eosinophils. Other cells, such as
50%) in the general population is significantly macrophages and mastocytes, interact to boost
lower than the asthma prevalence rate. this permanent state of inflammation. The release
Other factors such as low weight at birth, of second mediators such as leukotrienes, hista-
exposure to maternal tobacco, severe viral infec- mines, and prostaglandins produces the most
tions during the infancy period, environmental common epithelial alterations of a patient with
pollution, and being overweight, increase the risk asthma, such as bronchoconstriction, hypersecre-
of suffering from asthma and allergic tion, and epithelium disruption. In a preferably
sensitizing. eosinophilic inflammation environment, the
For non-atopic asthma, factors related to pov- enlargement of the reticular layer in the basal
erty are considered, such as overcrowding, infec- lamina, and hyperplasia of mucosal glands as
tions, indoor pollution, maternal use of tobacco, well as smooth muscle and vascular tissues,
and humidity. Differences relative to asthma increase the width of the bronchus wall, which
prevalence rate and gender tend to disappear makes the bronchi more rigid and reduces the
during puberty. transversal section of the airway: this causes a
Exposure to tobacco smoke during the intra- reduction of pulmonary function and a greater
uterine period, or after birth during the pulmo- unspecific BHR.  These changes in the airway
nary growth phase, also has an important structure would be responsible for the most seri-
influence. Atmospheric contaminants, such as ous presentation of the disease and of its chronic
environmental pollution, are also an influence, condition. These mechanisms explain that the
although there is less evidence about this. disease may be reversible when treated, or it will
Airway sensitization depends mainly on only be partially reversible because of the dam-
inhaled allergens. Among allergens, some are age caused. Therefore, there are multiple media-
worth highlighting: house dust mites, house dust, tors involved in promoting the inflammation and
41  Asthma: Clinical and Diagnosis Approach 409

Fig. 41.1 Inflammation
physiopathology
INFLAMMATION
CASCADE

Environmental
ASTHMA
• Allergy PHYSIO-PATHOLOGY
• Virus Genes:
• Exercise 5 q 31-32
• Irritants Mastocytes activation 6 q 21-28
Recruiting and activation: 11 q 13
Inflammation • Eosinophils 12 q
• Neutrophils
13 q
• Th2 cells
Bronchial Activation of epithelial cells 14 q
hyper-reactivity

Histamine
↑Cytokines (IL-4, IL-5, IL-13,

• Hyper-reactivity
• Bronchoconstriction
ASTHMA • Smooth muscle proliferation
• Mucosa edema
• Hyper-secretion of mucus

obstruction of the airway, although their relative alveolar hypoventilation with global respiratory
importance is difficult to determine (Fig. 41.1). failure.
The degree of BHR is related to the degree of
present inflammation and the enlargement of the
Physiopathology bronchial wall. Respiratory infections are the
most frequent trigger of asthma crisis for all ages,
The main asthma mechanism is caused by the especially in children that present with episodic
reduction of the caliber of the airway. Factors that disease. In infants and preschoolers, respiratory
may contribute to this are enlargement of the syncytial virus, rhinovirus, and parainfluenza
bronchial wall caused by edema and cellular virus are the most common triggers.
infiltration. Every time a major inflammation
trigger appears (as it happens when there is a
viral infection), the reduction of the bronchial Clinical Aspects
caliber will increase the resistance of the airway,
with a reduction in the expiration flow and air Asthma is a chronic disease with one of the high-
entrapment with pulmonary hyperinflation. est prevalence rates in childhood, and it is the
These changes are related to the increase of respi- most important cause of school absenteeism and
ratory work, altering the ventilation/perfusion frequent hospitalizations, with a corresponding
ratio, and according to the severity, hypoxemia in high cost for health systems.
the beginning. Only if the obstructive phenome- Because of the edema, bronchospasm, and
non progresses until it surpasses the capacity of increase of bronchial secretions, the most com-
the respiratory muscles does it cause fatigue and mon symptoms of asthma appear: cough, chest
410 G. Girardi Briere

whistle and rhonchus, chest oppression, and vari- intensity as the child grows. Allergic conjunctivi-
ous degrees of respiratory failure. If symptoms tis may also be present.
progress, the patient will present an acute asthma During an asthma crisis the child is usually
crisis that will be proportional to the degree of agitated, has difficulty speaking and feeding,
airway obstruction. To measure the intensity of with orthopnea, anguish, chest oppression, feel-
the compromise of the airway, clinical scores ing of lack of air or suffocation, tachypnea,
have been designed, plus pulse oximetry. intense chest retraction, hyperresonant chest, eas-
A complete clinical evaluation is always ily heard wheezing, sometimes crackling from
important, with a detailed anamnesis and a good small airway obstruction, and reduction of pul-
physical examination. Laboratory tests can be monary murmur in the most severe cases, along
useful because they help determine the severity of with cyanosis and alteration in consciousness.
the obstruction. In the periods between episodes,
the patient may present no symptoms or signs.
There is no unique phenotype for asthma in Asthma Clinical Spectrum
children, and therefore the initial symptoms may
be unspecific. During the first years, asthma can • Recurrent wheezing syndrome in infants or
be presented as a crisis of cough and wheezing preschoolers, or atopic or non-atopic persis-
that are indistinguishable from infant transient or tent wheezing, which can be reversed with the
early wheezing. Nevertheless, the diagnosis of use of inhaled beta-agonist.
asthma can be suspected if there is also a persis- • Recurrent obstructive acute laryngitis in
tent rhinitis, an atopic dermatitis, asthma family infants and preschoolers, alternating with epi-
history, and a good clinical response to inhaled sodes of recurrent wheezing.
salbutamol. A predictor index (API+) can certify • Classic asthma, with its cough and chest
an atopic asthma, although this is not as useful wheezing exacerbations. Respiratory distress
for non-atopic asthmatics. may be absent or present.
Children may only present with persistent • Exercise-induced asthma in teenagers as the
cough, which may be dry or productive, and in only symptom, as the consequence of BHR
the lung examination a prolonged exhalation (characteristic feature of more severe asthma),
along with rhonchus, without wheezing. and night asthma caused by greater fluctua-
Sometimes it is recommended to manually com- tions of the peak expiratory flow (PEF), along
press the chest during exhalation to evidence the reduction of pulmonary function during early
presence of wheezing that is not perceptible dur- morning.
ing auscultation. In children who are under • Chronic cough, recurrent tracheitis that is
3  months old, a small airway obstruction may alarming to the family. Methacholine test may
produce crackles instead of the expected wheez- be positive, which helps confirm the
ing, which can still be treated with inhaled diagnosis.
salbutamol. • Allergic chronic rhinitis, chronic rhinosinus-
If the child has no symptoms, the appearance itis, recurrent hoarseness from posterior dis-
of cough and/or wheezing during playtime, charge, which in a child may cause oral
laughing, crying, cold, smoke exposure, and breathing. Snoring may also be present.
excitement is a strong indicator of a diagnosis • Recurrent pneumonia (pneumonia or pseudo-­
based on bronchial hyperreactivity, and it consti- pneumonia, atelectasis).
tutes a good parameter for treatment efficacy. It is
convenient to ask if there is a seasonal preva- A 4-year follow-up in newborns showed that
lence, specially during spring, which would indi- among children who did not present with wheez-
cate pollen allergy. ing only 11% was complicated with pneumonia;
Allergic rhinitis signs tend to coexist and are in contrast, 78% of the children who had persis-
usually underrated, but they will increase their tent wheezing presented with pneumonia.
41  Asthma: Clinical and Diagnosis Approach 411

Differential Diagnosis allergic rhinitis, are seen. The functional diagno-

sis can benefit from laboratory tests that may
If the patient’s asthma does not respond to treat- confirm the clinical suspicion, such as spirometry
ment, among other matters it is convenient to con- and flow measurement, which show the reduction
firm the diagnosis and rule out other causes that of the exhalation flow rates, especially for FEV1,
may secondarily cause an obstructive bronchial Tiffeneau (FEV1/FVC) under 70%, and a signifi-
syndrome, such as cystic fibrosis, foreign body cant response to salbutamol. Bronchial challenge
aspiration, heart disease, bronchopulmonary dys- tests, such as the exercise test, must also be con-
plasia, ciliary dyskinesia, voice cord malfunction, sidered if they show drops more than 15% in the
or malformations of the airway that may go unno- PEF and more than 10% for the VEF1. Chest
ticed if there is no clinical suspicion. X-rays may also be useful, as they can rule out
complications and support the differential
diagnosis.
Diagnosis The severity of the crises in infants and pre-
schoolers can be measured with a clinical score,
In children, asthma diagnosis is mainly clinical, as the one presented in Table 41.1, which has a
especially if the child is under 5  years old, lineal correlation with oxygen saturation.
although it can be suspected in an infant. Table  41.2 can be used for schoolchildren and
Diagnosis is based on the presence of at least adolescents.
three episodes with a suggestive clinical condi-
tion: cough crisis, wheezing, and chest rhonchus
with spontaneous improvement, or if a good Diagnosis Rationale
response to inhaled salbutamol is confirmed. In
the older child, paleness, allergic shiners, pres- –– Reversibility of bronchial obstruction: Total
ence of the Morgagni fold, rough skin, and hyper- or partially reversible spontaneously (con-
keratosis in the extension surface of limbs, with firmed by history or flow measure), or after

Table 41.1  Clinical score in infants and preschoolers

Respiratory
Score frequency Wheezing Cyanosis Use of accessory muscles
<6 m >6 m
0 <40 <30 No No No
1 41–55 31–45 Expiration only Perioral with crying +
2 56–70 46–60 Inspiration and expiration Perioral at rest ++
3 70 >60 Inspiration and expiration at distance Generalized at rest +++
Severeness classification: low, 0–4; moderate, 5–8; severe, 9–12

Table 41.2  Clinical score in schoolchildren and adolescents

Parameter Low Moderate Severe
Dyspnea Walking Speaking Resting
Speaking Long phrases Short phrases Only words
Consciousness Anxious Agitated Very agitated
Respiratory frequency Normal or small increase Increased Very increased (>30 × min)
Heart rate <100 × min 100–120 × min >120 × min
Accessory muscles No Chest retraction + Chest retraction ++/a +++
Wheezing End of exhalation Inspiration–expiration Easily heard
PEF post B2 >80% 60–80% <60%
O2 saturation >95% 9195% <90%
412 G. Girardi Briere

the use of inhaled salbutamol (confirmed by –– NO (exhaled nitric oxide): This substance has
history, physical examination, and flow mea- shown a great specificity for eosinophilic
surement). Relative to laboratory results for inflammation, which is not always available.
pulmonary function, reversibility corresponds –– Atopy: Laboratory tests for atopy identifica-
to a 12% improvement in the exhalation vol- tion are very useful in allergic asthma, but it is
ume of VEF1 after a bronchodilator. A 30% not a criterion for its diagnosis besides the
improvement in the PEF 25–75, and 15% of family and personal background. Skin tests
the PEF, are highly compatible with asthma. identify the allergens involved in the specific
–– Bronchial hyperreactivity to different stim- sensitization of each patient. It is important to
uli: Several triggering events can be found in remember that in undeveloped countries the
the history of the patient: exercise, laughter, skin test may yield a positive result in no more
crying, emotion, and irritating allergens such than 50% of the cases.
as tobacco smoke. The bronchial exercise
challenge test is very specific, but its sensi-
tivity is poor. In contrast, the bronchial chal- Classification
lenge test with methacholine is highly
sensitive, but its specificity is poor. However, During the past few years, it has been preferred to
if it is negative, the asthma diagnosis can be classify asthma as controlled, partially con-
reasonably ruled out. trolled, or uncontrolled (Table  41.3), which has
–– Variability: It is suggestive of asthma to deter- the advantage of measuring the response to phar-
mine a variability greater than 20% in the spi- macological therapy, which can be gradually
rometry, although this is not definitive of increased or reduced as required by the
diagnosis. situation.
–– Inflammation: Inflammation markers such as
nasal and bronchial eosinophils, eosinophil cat-
ionic protein, and exhaled nitric oxide are use- Asthma Control Levels
ful to measure inflammation. Along with this,
nasal or bronchial eosinophils obtained by During these past years we have observed what
bronchoalveolar lavage or induced sputum are may be a different phenotype of labile asthma.
highly dependent on the operator who performs These patients do not seem to have a severe dis-
the counting, where more than 10% suggests a ease, and therefore the pharmacological therapy
positive diagnose. All the other laboratory as well as medical follow-ups are insufficient,
methods are still not well ­standardized for all and the patients present with sudden crises that
population groups, and they are usually evolve in few hours, requiring hospitalization in
reserved for investigation studies. special care units, sometimes with ventilation

Table 41.3  Levels of asthma control

A. Evaluation of current control (past 4 weeks)
Characteristics Under control Partially under control Uncontrolled
Daily symptoms None (2 or fewer/ More than 2 times/week Three or more characteristics
week) of partially controlled asthma
Activity limitations No Any
Night symptoms No Any
Rescue medications are No (2 or fewer/ More than 2 times/week
needed week)
Pulmonary function Normal <80% predictive value or better
(PEF/FEV1) personal value
B. Evaluation of future risks (exacerbation risks, instability, quick reduction of pulmonary function, adverse
effects)
41  Asthma: Clinical and Diagnosis Approach 413

support. The patients usually have a background Castro-Rodriguez JA, Wright AL, Taussig LM, Martinez
FG. A clinical index to define risk of asthma in young
of previous hospitalizations in critical care units. children with recurrent wheezing. Am J Respir Crit
Strangely, there is sparse literature about this Care Med. 2000;162:1403–6.
issue. In our experience and to a certain extent, Castro-Rodríguez JA, Ramírez AM, Toche P, Pavón D,
this presentation of asthma has replaced what is Pérez MA, Girardi G, et  al. Clinical and functional
and epidemiological difference between atopic and
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 Asthma: Treatment
42
Pablo Bertrand and Andrea Beckhaus Faccin

Contents
Introduction..................................................................................................................  415
Treatment......................................................................................................................  416
Nonpharmacological Treatment..................................................................................  416
 rimary Prophylaxis.......................................................................................................  416
P
Secondary Prophylaxis...................................................................................................  416
Asthma Education..........................................................................................................  417
Pharmacological Treatment.........................................................................................  417
 reatment of Acute Asthma Exacerbations....................................................................  417
T
Chronic Asthma Treatment.............................................................................................  422
Exercise-Induced Asthma...............................................................................................  426
Sources...........................................................................................................................  427

Introduction objectives of the treatment, which must be in line

with the expectations of the child and his family.
Asthma is the most common chronic respiratory For many parents and patients, the persistence of
disease during childhood, and it is associated symptoms during the regular activities of the
with a major burden in health costs. It has been child may be seen as a great disability, although
shown that adequate treatment controls asthma patients and family have different perceptions of
symptoms, and reduces asthma exacerbations, the disease. It is important to discover those criti-
which increases the quality of life for the patients. cal aspects of the child’s regular life to obtain the
Thus, every time that a patient with asthma is maximum potential for every individual without
evaluated, it is necessary to outline the general letting the treatment be a heavier load than the
disease itself.
In general terms, all guidelines are focused on
P. Bertrand (*) ∙ A. Beckhaus Faccin symptoms and exacerbations control that meets
Department of Pediatrics, School of Medicine,
the expectations of the family.
Pontificia Universidad Católica de Chile,
Santiago, Chile This chapter describes the global treatment of
e-mail: [email protected] asthma, for both exacerbations and chronic con-

© Springer Nature Switzerland AG 2020 415

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_42
416 P. Bertrand and A. Beckhaus Faccin

trol. In both situations there are different aspects asthma reduction in some patients. Therefore, it
to consider, which are listed with the current level is only a matter of identifying this particular
of evidence for each one. population.
Further, exposure to tobacco smoke during
pregnancy and after childbirth involves a greater
Treatment risk for the child to suffer from wheezing epi-
sodes and asthma, as well as presenting with
Treatment of a chronic disease such as asthma decreased lung function during the first years of
involves different aspects, seeking control of the life. It is strongly recommended to avoid tobacco
symptoms in the long term. Recommendations smoke exposure for both the expectant mother
must be oriented for each patient, highlighting and the child. This prohibition should be main-
different times of the day and the seasons of the tained until adulthood to avoid the consumption
year, as well as different activities. For treatment of tobacco during adolescence.
to be successful, parents must have some general
knowledge of asthma, as well as the measures
that may contribute to reducing symptoms and Secondary Prophylaxis
avoiding exacerbations.
Universal nonpharmacological measures for all
patients do not seem to be relevant in the control
Nonpharmacological Treatment of the disease, although they may be of great
importance for patients who are already sensi-
The ideal objective of asthma treatment is to tized to a specific agent.
avoid its appearance or favor its disappearance. It is important to identify and avoid specific
With this objective in mind, many investigators triggers such as allergens (Evidence D) and non-
have tried to intervene before the onset of the dis- specific triggers such as tobacco smoke
ease (primary prophylaxis) or after the diagnosis (Evidence A), and the risk factors, because they
has been made (secondary prophylaxis), although can cause or increase inflammation in the air-
there are no known measures that consistently way. Effective control interventions for
reach this objective. Dermatophagoides are to reduce the relative
humidity of the room to less than 50%, use bar-
rier covers in the bed, eliminate articles that may
Primary Prophylaxis favor mite growth (carpets, plush toys, etc.), and
clean carpets with vacuum cleaners with high-
There is an association between early exposure efficiency particulate air filters. To avoid aller-
to common allergens and allergic sensitization; gies triggered by an animal, all contact must be
however, this is not sufficient to prove that early avoided. It is recommended to effectively con-
exposure to allergens predisposes to asthma trol fungus exposure, using special solutions and
onset. There is evidence to recommend mater- adequate painting, besides constant cleaning and
nal breastfeeding as a protective action in ventilation. Seasonal allergies are variable in dif-
asthma development, especially in children ferent latitudes and weathers, so additional inter-
with an atopic family background. Diet modifi- ventions should be guided by the local situation
cations, such as modified formula use, fish oil, of each patient. Avoiding inhalation of allergens
dietary supplements, late introduction of solid when the specific index is high is useful, espe-
foods, and use of probiotics (both for the child cially when there is a correlation between the
and for the mother during pregnancy) have clinical history and testing of the child. Tobacco
shown contradictory results. Nevertheless, and wood combustion smoke are especially irri-
there are studies that have found a direct rela- tant to the airway. To avoid exposure to these
tionship between some interventions and agents, it is recommended to avoid smoking in
42  Asthma: Treatment 417

any circumstance, inside the house or in the car, is a core part of the process (Evidence A), and
as well as avoiding contaminating heating involves recognizing asthma exacerbation, but
options such as wood-burning and kerosene also avoiding triggers, such as infections and
heaters. In the same way, it is important to con- allergens, besides other environmental factors
sider that atmospheric contamination, especially such as tobacco smoke exposure. It should also
during winter months, may combine its action be considered that measurement of peak expira-
with viral infections. In this scenario, it is rec- tory flow (PEF) has been validated as a method
ommended to avoid leaving the house with for management in a difficult-to-control asthma
minor infants if it is not necessary, as well as sus- situation (Evidence B), especially for adolescents
pending physical activities when the pollution and adults.
indexes are high. Teaching instruments such as brochures,
If a limited sensitization to allergen has been games, and interactive sites on the Internet with
confirmed, the possibility of a specific immuno- educative content are useful. Monitoring through
therapy may be considered (Evidence D), simple clinical cards, such as the asthma control
whether it is subcutaneous or sublingual, in a test (ACT) and the asthma control questionnaire
specialized center. (ACQ), have been validated to objectively report
Dietary modifications aiming to reduce weight the degree of control of the disease, which eases
do improve the control of the disease in the long the decision-making process. Training in the use
term, but specific measures such as the adminis- of the inhalers with spacer is important to improve
tration of fish oil, antioxidants, magnesium, and drug deposition in the lower airway and to avoid
the use of probiotics have not shown to be useful deposition in the mouth, which carries potential
when treating asthma. Patients who suffer from adverse effects. Drug formulation is always
difficult-to-control asthma could benefit from changing, so it is crucial to maintain the proper
family therapy. Complementary measures such training for each device (Figs. 42.1, 42.2, 42.3).
as acupuncture, ionizers, homeopathy, relaxation
therapies, and Chinese herbs have not shown
consistent results in asthma. Pharmacological Treatment

 reatment of Acute Asthma

T
Asthma Education Exacerbations

Aiming to improve the control of the disease, the Treatment of an exacerbation starts with the rec-
creation of education programs has been pro- ognition of symptoms by the patient or his/her
posed. These programs would include informa- caregiver. Appearance of cough, dyspnea, and,
tion about asthma treatment, clinical monitoring, frequently, easily audible wheezing are specific
and triggers. Asthma education facilitates an alli- markers of an exacerbation. Along with a good
ance between attending physicians and the knowledge of the self-care guideline, the patient
patient and her/his family. This bonding is crucial can start with a written plan for the appearance of
for the implementation and success of the thera- the symptoms. Respiratory distress may be objec-
peutic plan (Evidence A-B). It is important to tively evaluated at home using a PEF monitor, but
emphasize the significance of an adequate adher- only by patients who have been properly trained
ence to recommendations, even when there are and can cooperate. When self-care indications
no symptoms. Also, educating parents and chil- have failed, the patient is forced to seek attention.
dren so that they can recognize the symptoms and The evaluation of this patient must include a com-
signs of an acute exacerbation is basic for ade- plete clinical history of her/his diagnosis, mainte-
quate asthma control. Knowing this, caregivers nance treatment, and therapeutic interventions
may proceed commensurately to the severity of performed. After this, the information must be
the symptoms. Self-monitoring and self-control completed with a complete physical e­ xamination.
418 P. Bertrand and A. Beckhaus Faccin

Fig. 42.1 Inhalation a b
technique using
salbutamol (MDI) and
spacer with mouthpiece

c d

Using a clinical score (Table 42.1), the severity of

the crisis can be quantified to determine the action
course to take during the first hours (Fig. 42.4). It
is important to consider two situations that are
warnings of greater severity: respiratory fatigue
that appears as reduction of the respiratory rate,
reduction of the sternal retraction and thoracoab-
dominal asynchrony, and severe hypoventilation
manifested as silent chest during auscultation or
when the patient cannot speak.

Fig. 42.2  MDI and spacer with mask inhalation tech- Oxygen
nique. The spacer must be placed in the child’s face in
The administration of oxygen is the easiest and
such a way that it covers mouth and nose. The MDI device
is shaken well and then activated, waiting for the child’s most efficient intervention to reduce hypoxemia
spontaneous breathing, at least three times. during an acute asthma exacerbation. It can com-
42  Asthma: Treatment 419

are evaluated in the emergency room should be

hospitalized. Patients with a moderate score or
those who have respiratory distress when they
seek medical attention should be evaluated again
after 24–48 h, even if they responded adequately
to the treatment used in the first hours of the med-
ical visit, especially those patients who are diffi-
cult to follow up, have poor treatment adherence,
or have a previous history of hospitalizations
caused by asthma.

Bronchodilators
Short-acting beta-2 agonists (SABA) inhaled
bronchodilators, such as salbutamol, fenoterol,
and terbutaline, are the first-line treatments for
acute asthma exacerbation (Evidence A).
Administration of inhaled salbutamol (MDI) with
a spacer with valve is just as effective as the nebu-
lization of the same drug, and saves time and
reduces the need of professional supervision in
the emergency room. Additionally, the use of
inhaled salbutamol with a spacer causes fewer
adverse effects. Salbutamol should be adminis-
tered proportionally to the seriousness of the cri-
sis, and the clinical effect should be closely
monitored and recorded. It is recommended to
perform two to eight inhalations each time, and
Fig. 42.3  Inhalation technique with a DPI. The dry pow-
repeat them during the first hour of treatment until
der inhaler (DPI) must be active according to the manu- the desired clinical response has been achieved.
facturer’s recommendation, because its use technique may Salbutamol administered in frequent intervals is
vary. A deep inhalation is done with the device placed in more efficient, although it is important to assess
the mouth, then the breath must be held, followed by a
normal exhalation. It is recommended to rinse the mouth
for adverse effects, which also allows us to guide
after the inhalation. the adequate doses and frequency for each patient.
For those patients with high oxygen requirements
(FiO2  >  30%) the administration of nebulized
pletely correct respiratory insufficiency in most bronchodilators should be considered. In these
patients, only excepting those with severe cases, it is recommended to use a dose of 2.5–5 mg
hypoventilation. Oxygen is administered through (standard dose) each time, using the same princi-
a nasal tube, non-rebreathing mask, or Venturi ple of dosage titling. For serious crises, continu-
mask system, according to the need and tolerance ous nebulization has been described as a more
of each patient. effective way of bronchodilator treatment until a
Medical oxygen is a dry gas that must be clinical response is achieved.
humidified to avoid problems related to drying of Anticholinergic bronchodilators (ipratropium
the respiratory mucosa when high flow is used. bromide) in repeated doses add their effect to those
The objective of oxygen administration is to of beta-2 agonists in the treatment of moderate and
avoid hypoxemia, which can be indirectly mea- severe exacerbations (Evidence B). Combination
sured through pulse oximetry (SpO2), aiming for with SABA has been associated with a lower risk
a value  >93% (Evidence C). Those patients of hospitalization. They are available combined
requiring supplementary oxygen at the time they for both inhalation and nebulization.
420 P. Bertrand and A. Beckhaus Faccin

Table 42.1  Evaluation of asthma exacerbation

Parameter Mild Moderate Severe
Dyspnea When walking; it can also be When speaking, prefers to be sitting When resting, the infant
present when lying down Crying low and short in infants, has cannot be fed
difficulties when feeding.
Speaks in Long sentences Short sentences Isolated words
Consciousness Patient can be agitated Usually agitated Usually agitated
Respiratory Increased Increased Very increased
frequency
<2 min: <60
2–12 min: <50
1–5 to <40
6–8 to <30
Heart rate <100 bpm 100–120 bpm >120 bpm
2–12 min:
<160 bpm
1–2 to <120 bpm
2–8 to <110 bpm
Accessory No use, generally Yes Yes
muscles
Wheezing Moderated: only at the end of Intense Usually intense
exhalation
Pulsus paradoxus Absent: <10 mmHg May be 10–25 mmHg Present 20–40 mmHg
PEF post β2a >80% 60–80% <60%
SaO2 (FiO2: 21%) >95% 91–95% <90%
PEF is conducted only in children who can cooperate and if the procedure does not delay treatment administration
a

Steroids with bronchodilators. Systematic reviews have

Systemic steroids are the preferred antiinflamma- shown that the therapeutic effect would be com-
tory treatment for acute asthma exacerbations parable to using oral steroids; nevertheless, its
(Evidence A). Early use is recommended to use must be part of a supervised treatment plan to
reduce the risk of hospitalization. The treatment avoid confusion or abuse of the drug. Currently,
should be administered over 3 to 5 days, which in there is no strong recommendation about this
most cases is enough to control the crisis. Oral issue.
administration of steroids is as effective as their
intravenous administration, and therefore the oral Other Therapies
option is recommended for its availability and Nebulized magnesium sulfate could reduce the
reduced cost. The only exceptions are those hospitalization risk in patients who have serious
patients who must receive the intravenous drug acute asthma exacerbations that do not respond to
because their condition is serious. Every patient bronchodilators. There is no strong evidence to
with moderate or severe asthma exacerbations recommend its use in mild to moderate crises
must receive systemic steroids within the first (Evidence A). IV magnesium sulfate may be con-
hour of treatment in the emergency room. Those sidered for serious asthma crises, when the
patients with a mild crisis and who have used patient is hospitalized in the intensive care unit
bronchodilators, but with a poor response, should (Evidence B), as this medication must be super-
also receive steroids as a central part of their vised by specialists in intensive care.
treatment. Aminophylline and salbutamol can be used in
The administration of inhaled or nebulized the management of severe and acute exacerba-
steroids for the acute asthma crisis is still being tions, but under strict supervision in critical
evaluated when they are used in combination patients as an additional therapy. The effects of
42  Asthma: Treatment 421

Assessment
Risk factor for severe crisis Consider other diagnoses
• Severe exacerbations (children < 2 year old)
• Hospitalizations and ER visits ASTHMA CRISIS • Broncholung dysplasia
• Use of bronchodilators and (ABC sequence) • Congenital cardiopathy
steroids • Viral bronchiolitis
• History of pneumothorax, • Upper respiratory tract obstruction
massive atelectasis

SEVERITY ASSESMENT *
(consider PRAM clinical score)

Mild Moderate Severe

• MDI Salbutamol (100 mcg/puff) • Oxygen for SaO2 ≥ 93% • Oxygen with no recirculation system
2-8 puff c/10 min x 3 times. Continue • Salbutamol (same as in mild case) • Saline solution bolus, infused
according with clinical progression • Ipratropium bromide MDI
(60 seg pauses) • Continuous salbutamol nebulization
(20 mcg/puff) 2-8 puff or nebulization
• Ipratropium bromide nebulization
0,25-0,5 mg nebulization with
• Methylprednisolone or hydrocortisone
• Salbutamol nebulization (0,5%) salbutamol use
2,5-5 mg x 10 min (FiO2 > 30%) x • Magnesium sulfate IV (50 mg/kg) only
• Methylprednisolone 1-2 mg/kg IV or
3 times if under strict monitoring and if there is a
hydrocortisone 5-7 mg/kg IV delayed for ICU admittance
• Prednisone 2 mg/K vo. max. 40/day

Re-evaluate in 1 h Re-evaluate in 1 h Re-evaluate in 1 h

ICU hospitalization

Mild Mild Moderate

SaO2 > 95% SaO2 > 93% SaO2> 93%
FEM > 80% FEM > 70% FEM > 50%

Repeat in 1 h

DISCHARGE Moderate
INTERMEDIATE CARE UNIT
SaO2> 93% HOSPITALIZATION
• Written plan with
PEF > 70%
warning signs • Oxygen for SaO2 ≥ 93%
• Bronchodilators every 4- (Venturi mask)
8 h for 7 days • Salbutamol + Ipratropium
• Prednisone: 5-7 days bromide every 3-4 h. Use
• Follow-up in 3-4 days HOSPITALIZATION ROOM MDI or nebulization,
• Oxygen for SaO2 ≥ 93% according to the patient
• Continue treatment with
• Bronchodilators every 3-4 h
steroids for 7 days
• Continue treatment with • Consider viral identification
steroids
• Consider chest x rays and
• Consider viral identification other exams

Fig. 42.4  Treatment algorithm for asthma crises

422 P. Bertrand and A. Beckhaus Faccin

both treatments have been compared, and no dif- undergoing mechanical ventilation, use of mor-
ferences have been found in their clinical efficacy phine and muscle blockers is discouraged.
(Evidence B).
In severe and acute exacerbations, helium in Hospitalization Criteria
different concentrations mixed with oxygen can Recurrent clinical evaluation after interventions
be used to gain some time while other measures is critical to make decisions about admissions to
are being placed to avoid the progression of respi- the hospital (Fig. 42.4). Some factors to be con-
ratory distress. Even so, there is no high-­quality sidered are these:
evidence to recommend its use (Evidence B).
There is no clinical evidence to use IV leukot- • Progressive dyspnea and/or increased work of
riene inhibitors in the treatment of acute asthma breathing
exacerbations. • Signs and symptoms of moderate or severe
There is no evidence to recommend the use of exacerbations
chest physiotherapy during acute asthma exacerba- • Poor response to treatment after 2 h
tions, and some maneuvers, such as chest percus-
sion or forced compressions, are contraindicated. Treatment of acute asthma exacerbations in
In the same way, antibiotics, as well as antihis- hospitals follows the same principles as for the
tamines, sedatives, and mucolytic drugs, have no emergency room, although drug prescription may
role in the treatment and their use is discouraged. vary, because the clinical response can be verified
by frequent clinical supervision.
Mechanical Ventilation
Mechanical ventilation is an alternative in Discharge Criteria
patients with a severe asthma exacerbation in • Good general conditions. Feeding can be done
respiratory failure. Indications for its use are normally.
based on clinical criteria, although there are • SpO2 ≥ 93 during 8–12 h without additional
absolute indications, such as severe hypoxemia, oxygen support.
compromise of consciousness, and cardiopulmo- • Maintenance treatment with verified adminis-
nary failure. Preliminary evidence suggests the tration (specifically for administration of
use of noninvasive ventilation for patients who inhaled steroids).
can cooperate to avoid development of muscular • Discharge plan with clear and written
fatigue. This therapy is not an alternative to inva- instructions to follow up: warning symp-
sive ventilation; it is only a previous step aiming toms, monitoring with peak expiration flow
to avoid endotracheal intubation. In those patients (PEF), and the drugs to be used and their
requiring ventilation support, pressure-limited adequate doses.
delivery and low flow volumes should be used. • Clinical follow-up with treating physician has
The suggested baseline parameters are tidal vol- been scheduled.
ume (TV) 8–12 ml/kg, inspiratory time (TI) 0.7–
1.5 s, and maximum inspiratory pressure (MIP)
40  cm H2O.  Alveolar ventilation should be Chronic Asthma Treatment
­optimized with an increase in the time constant,
but at the same time favoring prolonged exhala- Long-term asthma treatment must be commensu-
tion times to avoid auto-positive end-expiratory rate with the seriousness of the disease, consider-
pressure (PEEP). ing the severity of the symptoms and the alteration
Mechanical ventilation in patients with asthma of lung function. In general terms, controlling
exacerbation is a therapy that can trigger some asthma includes environmental control, patient
complications arising from the high pressures education, and pharmacological treatment. To
required, such as barotrauma and hemodynamic achieve this objective, it is necessary to fulfill the
alterations. If it is necessary to sedate patients following criteria:
42  Asthma: Treatment 423

• Educate about the disease. Asthma shows different presentations accord-

• Educate about adherence and provide train- ing to the age of the patient, ranging from infancy
ing relative to appropriate inhalation until adolescence, so many considerations are
technique. important when a treatment is proposed for
• Identify individual triggers of asthma exacer- patients who are so different. The recommenda-
bations and teach how to avoid them. tions stated in this chapter are not applicable to
• Propose a treatment plan for asthma patients under 2 years old who present wheezing
exacerbations. episodes related to viral infections; their manage-
• Set a treatment proportional to asthma ment is explained in detail in a corresponding
seriousness. chapter.
• Monitor the clinical response to pharmaco- If asthma presents in episodes, and the main
logical treatment based on the use of rescue characteristic is the presence of crisis between
medications, appearance of symptoms, and normal intermediate periods, treatment must be
lung function. oriented to exacerbations and controlling the trig-
• Modify the treatment scheme based on the gering factors. Pharmacological treatment will
clinical response. depend on the recurrence and severity of the
asthma exacerbations. The guidelines of the
In general terms, the disease can be classified Global Initiative for Asthma (GINA) recommend
from the mildest degree, with intermittent symp- beginning regular therapy when there are one or
toms, to the most severe degree, presenting more risk factors for exacerbations, even when
symptoms that are persistent and incapacitating. intercritical symptoms may not be present.
Although the evaluation of severity is useful for Among these factors we can mention the abnor-
each patient, especially when diagnosing, catego- mal lung function (FEV <60% of predictive
rization may vary in time, and therefore the rec- value), severe exacerbation requiring steroids use
ommendations must be adjusted according to during the last 12  months, admittance into an
how much the disease has been controlled. ICU because of asthma exacerbations, symptoms
Currently, national and international guidelines of noncontrolled asthma, and frequent use of res-
suggest a level-based pharmacological approach cue treatment (Evidence D). For those patients
(Table 42.2), according to how well the disease with none of these conditions, the use of rescue
has been controlled. To make the right decision to medication as needed is recommended. The med-
increase or reduce treatment, it is necessary to ication most strongly recommended is salbuta-
categorize asthma as controlled, partially con- mol. The clinical response to ipratropium
trolled, or noncontrolled. bromide, by itself or combined with fenoterol, as

Table 42.2  Chronic treatment of asthma

Reduction Stages of the treatment Increase
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Asthma education
Environmental control
Fast-acting B2 as Fast-acting B2 as needed
needed
Options for ­ Select one Select one For stage 3, select one or For stage 4, add one
asthma-­controlling more alternative
treatment
Low doses of Low doses of ICS + Medium or high doses of Oral steroids (low
ICS∗ long-acting B2 ICS + long-acting B2 doses)
Leukotriene Medium or high doses Leukotriene modifier Omalizumab
modifier∗∗ of ICS
Low doses of ICS +
leukotriene modifier
ICS inhaled corticosteroids
*

Receptor antagonist or synthesis inhibitors

**
424 P. Bertrand and A. Beckhaus Faccin

rescue treatment has been evaluated, and no dif- Table 42.3  Comparison of inhaled steroids for children
ferences have been found relative to clinical Medium High
score, lung function, or hospitalizations. Drug Low dose dose dose
Beclometasone 100– 200–400 μg >400 μg
In other scenarios, if a patient requires more
200 μg
than one salbutamol canister per month, or more Budesonide 200 μg 200–400 μg >400 μg
than 12 inhalations per day, the patient must be Fluticasone 100– 200–500 μg >500 μg
assessed and considered for regular treatment. 200 μg
For those patients with frequent exacerbations Ciclesonide 80–160 μg 160–320 μg >320 μg
(six or more episodes per year) or who have a Mometasone 200– 400–800 μg >800 μg
400 μg
persistent symptoms profile, that is, asthma
Triamcinolone 400– 800–1200 μg >1200 μg
symptoms and signs for prolonged periods, treat- 800 μg
ment must be oriented to symptoms and exacer-
bations control, whose minimal initial period is
between 3 and 6 months. patients between 2 and 18  years old, in com-
It is common to observe clear deterioration parison to placebo. Its dosage depends on the
in the quality of life of a patient with a persis- age of the patient and the severity of the dis-
tent asthma, which may limit the normal devel- ease. For this purpose, a dosage guideline has
opment of the child. In most patients the disease been created (Table  42.3) that considers low,
is controlled using one medication, but there is intermediate, and high doses for pediatric
a percentage of patients who require more than patients. It is recommended to start with a
one medication, known as combined therapy. budesonide dosage of 200  μg per day; flutica-
Available medications for asthma control are sone 100  μg, or its equivalent, for children
supported by a large number of clinical trials under 5  years old; and for older children,
and systematic reviews that validate their use. budesonide 400 μg per day, fluticasone 200 μg
The election of one or another drug must utilize per day, mometasone 200 μg, ciclesonide 80 μg,
the best possible evidence which, along with or its equivalent. ICS are available as MDI or
the particular characteristics of each patient, dry powders in their different dosages. Their
will point to the best therapeutic choice in each adverse effects depend on the doses used and
case. generally appear when using 800 μg budesonide
per day or its equivalent. Adverse effects to be
Steroids considered are growth delay, adrenal suppres-
It has been well established that treatment with sion, and osteoporosis. All these effects that
inhaled corticosteroids (ICS) is the treatment of have been described when using high doses and
choice for most patients who have a persistent the medication has been used for a long time. It
asthma (Evidence A). ICS choice is based on is important to keep in mind local adverse
the characteristics that each has, such as effects such as the appearance of oropharyngeal
strength, bioavailability, and cost, but the treat- candidiasis and hoarseness. These symptoms
ment should be individualized to obtain the best have a low frequency because of the widespread
efficiency. The usefulness of ICS has been con- use of a spacer, which reduces the drug deposit
firmed using multiple clinical parameters such in the pharynx (Figs.  42.1, 42.2, 42.3). Most
as symptom improvement, reduction of rescue medications have been approved to be used two
medications, and reduction in the number of times per day from the beginning of the treat-
exacerbations; it is also based on functional ment; nevertheless, there are currently some
methods such as FEV1 volume, improvement of medications available (mometasone, cicle-
morning peak expiratory flow (PEF), as well as sonide) that are administered once per day.
improvement in challenge tests. Systematic Most inhaled steroids achieve a drug deposit
review evidence supports their use for asthma, in the airway of about 8% to 15% of the total
strongly recommending these methods for administered using good technique and a proper
42  Asthma: Treatment 425

Fig. 42.5 Distribution
of the inhaled drug

Nasopharynx
Oropharynx
Larynx

Inferior vena cava

Hepatic vein

Esophagus
Airways
Bronchial
circulation
Stomach

Liver
Portal vein

Lung absorption Digestive absorption

Non-absorbed drug
in the digestive tract

Feces
Urine

spacer. Nevertheless, there are new formulations Long-Acting Beta-Agonists

and new drugs (beclomethasone HFA and cicle- The usefulness of the long-acting bronchodilators
sonide) that achieve a better airway deposit, (LABA) salmeterol, formoterol, and vilanterol in
which may even reach 50% of the total, mainly combination with steroids has been verified as an
the result of the size of the particle, delivery alternative in the combined treatment for asthma.
speed, and temperature when delivering the drug. Formoterol works faster than salmeterol, which
Most have a very low oral bioavailability improves treatment compliance. In the past, the
(budesonide, fluticasone, mometasone), which use of these bronchodilators was aimed at manag-
increases their security profile before use. An ing the symptoms of the disease, and it was com-
additional advantage to inhaled steroids such as a mercialized as monotherapy. Nevertheless, recent
prodrug (ciclesonide) is that it activates once it evidence forced its suspension as monotherapy,
reaches the airway, and also it is rapidly metabo- because it contributed to asthma mortality, appar-
lized when it enters the systemic blood flow ently because of tachyphylaxis in the adult popu-
(Fig. 42.5). lation caused by the drug. Guidelines recommend
Studies conducted to assess the daily use of its use as first-line additional therapy besides
inhaled steroids, when compared to the intermit- inhaled corticosteroids (ICS) for persistent
tent use of the same drug, favor the continuous asthma, both moderate and severe, when asthma
use when considering PEF improvement, number control has not been achieved with doses of 400
of symptom-free days, need of rescue medica- μg budesonide or an equivalent. The efficacy of
tions, and fraction of exhaled nitric oxide combining ICS with LABA, versus the sole use of
(FENO). Even so, there are no significant differ- high doses of ICS in children with uncontrolled
ences for the risk of suffering exacerbations. disease, lies in the changes of lung function and
Currently, the intermittent use is based on sparse morning flow measurement, but there are no sig-
and low-quality evidence in relation to relevant nificant differences in the risk of suffering asthma
clinical parameters, and therefore it has not been crises, use of oral steroids, hospitalization, or
standardized in the treatment of asthma with per- symptom-free days. Nevertheless, patients using a
sistent symptoms. combined treatment need rescue medications less
426 P. Bertrand and A. Beckhaus Faccin

frequently and have a better growth rate in the Theophyllines

long term. It is important to consider that there is Today, the use of theophyllines in the manage-
little evidence and information about security ment of chronic asthma is quite individualized
related to the use of long-­acting bronchodilators (Evidence B). The multiple potential adverse
in combined treatment for those patients under effects should be considered and monitored.
5  years old, so the specialist is encouraged to Even though theophyllines are administered
closely monitor these children and use this treat- orally, use may be considered for patients with
ment with extreme caution. poor adherence to the chronic treatment, or for
those patients who almost exclusively present
Leukotriene Inhibitors symptoms during the night, when it could be as
The use of these drugs has been increasing during effective as using steroids.
past years. They are effective in improving symp-
toms and lung function and preventing exacerba-  onoclonal Antibody Against IgE
M
tions (Evidence A). Nevertheless, the evidence The specific monoclonal antibody against immu-
obtained during the past years shows that their noglobulin E, omalizumab, is now available, and
strength is less when compared with inhaled ste- it has been shown to be effective in reducing the
roids, particularly in relation to the measures of levels of circulating IgE in selected patients, with
lung function, and some studies show a relation- associated clinical benefits.
ship with a poorer protection against exacerba- Systemic reviews in the adult and pediatric
tions (Evidence A). For patients with frequent or population have shown that those patients treated
persistent asthma, its use is recommended as with omalizumab are at a lower risk of suffering
monotherapy when inhaled steroids cannot be asthma exacerbation after receiving treatment
used, particularly for those patients with exercise-­ with inhaled steroids, long-lasting bronchodila-
induced asthma, Its greatest utility lies in excel- tors, and leukotrienes inhibitors (Evidence B).
lent chronic treatment adherence in patients
under 5 years old. There is preliminary evidence Systemic Steroids
about the intermittent use of leukotriene inhibi- In patients with severe or moderate asthma, when
tors in children under 12 years old, but currently the disease has not been steadily controlled with
it is still not possible to recommend their use. The two or more drugs, and who require frequent use
use of leukotriene inhibitors as an additional ther- of steroids, its permanent use should be consid-
apy, in addition to inhaled steroids, has shown ered. However, the physician must keep in mind
that, in comparison with long-acting bronchodi- the adverse effects that this indication implies,
lators, there are no differences in the risk of exac- such as hypertension, diabetes mellitus, osteopo-
erbations that require oral steroids. The evidence rosis, and cataracts. The objective is to control
is stronger in the adolescent population, showing the disease with the minimum dosage, aiming to
better results when bronchodilators are used with suspend the administration of the drug as soon as
inhaled steroids. possible. To achieve this, the recommendation is
to gradually replace the dosage of 1000 μg
Chromone budesonide, or its equivalent. It is also possible to
Chromones are airway antiinflammatories whose combine leukotrienes inhibitors, long-lasting
usefulness has been well proven for the treatment beta-2 agonists, and theophyllines for 6  weeks
of frequent episodic asthma and mild persistent until the changes have been verified.
asthma in children and infants. These drugs have
an excellent security profile, and adverse effects
have been rarely reported. Nevertheless, its limi- Exercise-Induced Asthma
tations lie in the frequency of their administration
(3–4 times per day) and their discrete strength in In most patients, the appearance of bronchocon-
comparison to inhaled steroids. striction induced by exercise is only an indicator
42  Asthma: Treatment 427

of a poor control of the disease. This is the best rent wheezing and asthma: a systematic review with
meta-analysis. Pediatrics. 2009;123:e519–25.
argument to name this condition as exercise-­ Castro-Rodriguez JA, Rodrigo GJ, Rodriguez-­Martinez
induced bronchospasm (EIB) instead, to avoid CE.  Principal findings of systematic reviews for
confusion in its origin. EIB must force the physi- chronic treatment in childhood asthma. J Asthma.
cian to review control therapy and its administra- 2015;52(4):407–16.
Chauhan BF, Chartrand C, Ducharme FM.  Intermittent
tion mode before considering changes. Initial versus daily inhaled corticosteroids for persistent
treatment consists of short-acting beta-2 agonists asthma in children and adults. Cochrane Database Syst
before exercising. This intervention has shown Rev. 2013;2:CD009611.
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ticosteroids of long-acting beta-2-agonists versus
cebo, with quality evidence. When the rescue anti-leukotrienes for chronic asthma. Cochrane
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pared to inhaled corticosteroids in the management of
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agonists, theophyllines, and chromones may be Cochrane Database Syst Rev. 2012;(5):CD002314.
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Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson
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 Primary Ciliary Dyskinesia
43
Nils Linus Holmgren Palmen,
Ximena Fonseca Arrieta,
and Sergio González Bombardiere

Contents
Definition.......................................................................................................................  429
Epidemiology.................................................................................................................  430
Etiology and Physiopathology.....................................................................................  430
Cilia................................................................................................................................  430
Clinical Condition.........................................................................................................  432
Diagnosis........................................................................................................................  433
 creening Methods.........................................................................................................  433
S
Diagnosis Methods.........................................................................................................  433
Other Studies..................................................................................................................  434
Diagnostic Approach....................................................................................................  435
Evaluation and Treatment...........................................................................................  435
 espiratory Treatment....................................................................................................  435
R
Otorhinolaryngology Treatment.....................................................................................  437
Future Perspectives.........................................................................................................  437
Prognosis........................................................................................................................  437
Sources...........................................................................................................................  438

Definition

N. L. Holmgren Palmen Primary ciliary dyskinesia (PCD) is a term used

Department of Pediatrics, Clínica Alemana to describe the diseases that directly result from
and Universidad del Desarrollo, Santiago, Chile congenital defects in the cilia. It is a hereditary
X. Fonseca Arrieta autosomal recessive defect in the cilia ultrastruc-
Otorhinolaryngology, Pontificia Universidad Católica ture. This definition includes Kartagener syn-
de Chile, Santiago, Chile
drome, immotile ciliary syndrome, ciliary
S. González Bombardiere (*) dysmotility, and primary ciliary orientation prob-
Pathological Anatomy, Pontificia Universidad
Católica de Chile, Santiago, Chile lems. Kartagener syndrome is composed of the
e-mail: [email protected] triad of situs inversus, chronic sinusitis, and

© Springer Nature Switzerland AG 2020 429

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_43
430 N. L. Holmgren Palmen et al.

bronchiectasis. Situs inversus is present in 30% Radial spoke

to 50% of all patients with PCD, and 6% present
Dynein ext. arm
with heterotaxia.
Dynein int. arm

Nexin
Epidemiology
A microtubule
The incidence of the disease has been estimated
to be between 1/10,000 and 1/20,000 per live B microtubule
births.
Fig. 43.1  Ciliary structure

Etiology and Physiopathology
central microtubules and nine pairs of peripheral
Cilia microtubules, which are connected by other
structures (Fig.  43.1). Each pair of peripheral
Cilia are organelles that are structurally related to microtubules is constituted of alpha- and beta-­
the flagellum in the protozoa. They are classified tubulin heterodimers, which are grouped in 13
according to their microtubule composition: protofilaments in the A tubule and 11 protofila-
motile (9 + 2) and primary (9 + 0). Motile cilia ments in the B tubule. They are oriented toward
have nine pairs of peripheral microtubules and the adjacent central cilium, which is important
two central pairs. In contrast, primary cilia have for the production and coordination of the cilia
nine peripheral pairs, but lack the central pair. wave beat. Each microtubule at the central pair is
Motile cilia have a great inherent capacity to composed of 13 protofilaments that contain 23
beat at variable frequencies, and they are in all polypeptides, which are unique and differ in their
the respiratory epithelium, uterine tubes in the function and biochemistry. Other very important
female genital tract, ductus deferens in the mas- proteins are the microtubule-associated proteins
culine genital tract, ependymal canal in the brain, (MAP), which constitute the internal and external
and spermatozoa. arms of dynein. Dyneins are ATPases. External
Primary cilia can be subdivided into sensory dynein binds to the A microtubule at one end
cilia and nodal cilia. Sensory cilia do not move; through an alpha-tubulin, and the other end binds
they are in most vertebrate cells, and function as to the B microtubule of the adjacent pair through
mechanoreceptors or antennas that communicate a beta-tubulin. ATP hydrolysis determines the
with the extracellular environment. They are movement of the dynein head through the axis of
present in the lumen of the kidney tubule, retinal the B microtubule, defining the coordinated
rods and cones, ciliary cochlear cells, canals, and action of all the microtubules that the cilium
olfactory sensory neurons. Additionally, nodal bends. Other microtubules include nexin, which
cilia are those cilia with movement and are pres- connects the peripheral microtubules among each
ent in the embryonic node. These cilia determine other, and the radial spokes, which connect the
organ laterality in mammals. Their alteration peripheral microtubules to the central microtu-
causes anomalies in rotation, such as situs bules. An interflagellar transportation system of
inversus. protein particles maintains and assembles the
cilia structure. Anterograde flow is determined by
Cilia Structure the kinesin II complex, and the retrograde flow is
Cilia are composed of more than 200 different determined by the dynein cytoplasmic complex
types of polypeptides. Each cilium has a pair of (Fig. 43.2).
43  Primary Ciliary Dyskinesia 431

external factors (temperature, humidity), and

pharmacological effects.
To have an efficient motility and effective
mucociliary clearance, it is crucial to conserve
the ciliary structure intact, besides keeping an
adequate amount and quality of secretions that
allow good movement, as well as a good syn-
Fig. 43.2  Normal cilia. Cross section of normal cilium chronization in the ciliary motility with a correct
and primary ciliary dyskinesia (PCD). Uranyl acetate and
frequency of ciliary beat.
lead citrate. ×100,000
Age has no impact on the frequency of ciliary
beat, which is similar for patients between
Ciliary Function 3 months old and 74 years old.
A cylindrical pseudostratified mucosa covers the Ciliary function can be affected by external
respiratory epithelium, which ensures factors, such as bacterial toxins and inflammation
­mucociliary transport. This structure is one of the mediators, which cause ultrastructural cilium
most important first-line defenses of the airway, alterations and ciliary dysfunction.
for both the lower tract and upper tract, including
the paranasal sinus and middle ear. Thus, the  lterations in Ciliary Structure
A
entrance of particles and infection agents is The ciliary structure may sustain different types
avoided, protecting the person. This function is of morphological alterations, such as the absence
the so-called mucociliary clearance. Impairment of internal and external dynein arms, alteration of
of this system may cause infections in the respi- the radial spokes, and cilium fusion.
ratory tract. Anomalies of the cilium ultrastructure may be
The movement of the microtubule doublets divided into primary defects, which are those
determines the ciliary beat. The external arm of observed in PCD, and secondary defects, which
dynein controls ciliary frequency, and the inter- are caused by infections, cigarette smoke, or pol-
nal arm of the dynein directs the shape of the lutants. These secondary alterations are different
wave. Radial spokes, which are related to the from those found in PCD, and they consist mainly
central pair of microtubules, are in charge of acti- of defects in the microtubules and composed
vating the dynein arms. The central pair/radial cilia, affecting up to 10% of cilia in normal
spoke complex is the regulating key for the acti- patients, and when challenged by severe respira-
vation of the dynein arms. tory infections, up to 17% of the cilia may be
Cilia have a rhythmic beat. Each cycle has affected.
two active components: one movement during Structural anomalies known to cause ciliary
which the cilium is completely extended per- dyskinesia are described in Table 43.1.
pendicularly relative to the cellular surface, and In one phenotype of PCD, the ultrastructure is
a recovery movement in which the inclined cil- normal, but the cilia are not normally oriented in
ium moves parallel to the cellular surface, relation to other cilia. This orientation disorder
toward its original position. The duration of this may be primary, but it may as well occur second-
phase depends on the frequency of the ciliary ary to an infection.
beating. Analysis using a scanning electron micro-
Cilia in adjacent cells are coordinated to beat scope shows the number of studied cilia that
simultaneously and at the same time. In this way, present a specific anomaly. In this way, the per-
an effective cilia motility is caused, which expels centage and type of alterations present can be
the mucus. The frequency of the ciliary beat classified. Most authors consider 20% or more of
oscillates between 13 and 27  Hz in the respira- absent dynein internal and/or external arms as
tory mucosa. It is known that multiple factors significant to classify the case as a PCD.  Some
affect ciliary motility, such as neural control, examples can be seen in Figs. 43.3 and 43.4.
432 N. L. Holmgren Palmen et al.

Table 43.1  Primary ciliary dyskinesia (PCD) structural

abnormalities
A. Dynein arms
 Absence or reduction of the number of internal and
external arms
 Absence or reduction of the number of internal arms
 Absence or reduction of the number of external arms
B. Radial spokes
 Absence
C. Microtubules
 Defects on the peripheral microtubules
 Absence of the central pair with the transposition of
a peripheral pair to the center
D. Complete ciliary aplasia
E. Orientation defect

Fig. 43.4  Ciliary dyskinesia

they do not contain ciliary cells in adequate num-

bers and lack preservation quality.

Clinical Condition

Clinical characteristics in PCD depend on the age

of the patient.

Antenatal manifestations
• Situs inversus or heterotaxia in antenatal
echography
• Mild brain ventriculomegaly in antenatal
Fig. 43.3  Ciliary dyskinesia. Cross section of cilium echography
showing complete absence of dynein external and internal
arms in peripheral microtubules. Uranyl acetate and lead
Neonatal manifestations
citrate. ×120,000
• Respiratory distress in term newborn, without
risk factors for transitory tachypnea or neona-
The most frequent ultrastructural findings, as tal pneumonia
published in several studies, are the absence of • Permanent nasal congestion since the first day
both dynein arms (range, 24–57%), absence of of life
only the external dynein arm (range, 2.9–43%), • Situs inversus or dextrocardia
absence of only the internal dynein arm (range, • Complex congenital heart disease related to
29–37%), and anomalies of the central microtu- laterality disorders (heterotaxia)
bules (4%). • Biliary atresia
Ultrastructural diagnosis requires trained and • Hydrocephalus
experienced specialists, as well as the strict appli-
cation of morphological and diagnostic criteria. Infancy and childhood manifestations
Diagnosis is more reliable when samples have • Persistent wet cough
been optimally obtained and processed. Up to • Atypical wheezing that does not respond to
40% of the samples can be labeled as useless, as steroids therapy
43  Primary Ciliary Dyskinesia 433

• Recurrent pneumonia Screening Methods

• Bronchiectasis of unclear etiology
• Frequent rhinosinusitis Screening methods measure the speed of mucous
• Otitis media with chronic effusion transportation, from the nostrils to the pharynx
• Persistent otorrhea after the insertion of venti- (by saccharine test or technetium-99  m-labeled
lation tubes colloid albumin), or by nasal fractional exhaled
• Situs inversus associated to sinusitis and nitric oxide (nasal FENO).
bronchiectasis
• Severe gastroesophageal reflux a. Saccharine test: A piece of saccharine placed
in the lower part of the nostril will migrate
Manifestations during adulthood toward the pharynx by the ciliary movement.
• The same manifestations as present during The patient should be able to perceive the taste
school-age period in the mouth before 30 min. The precision of
• Greater percentage of ectopic pregnancies and this test is poor; it depends on several vari-
reduced fertility in women ables, and it has no value in children under
• Greater percentage of infertility in men 10  years old. The result is considered to be
• Chronic mucopurulent bronchorrhea openly abnormal if the patient needs 60 min or
• Digital clubbing more in perceiving the saccharine taste.
• Nasal polyposis/halitosis b. Technetium-99  m-labeled colloid albumin
• Function tests show mixed or obstructive pattern test: 50 mCi technetium-99 dissolved in 2.5 μl
saline solution is placed in the lower part of
The clinical manifestations most commonly the nostril, 1  cm deep. The migration of the
published in the different series are recurrent sinus- tracer is measured with a gamma camera. The
itis (77%), persistent rhinitis (76%), neonatal respi- result is abnormal if there is no tracer move-
ratory distress syndrome or tachypnea (20–67%), ment within 10 min. It can be used in children
recurrent otitis media (57%), recurrent pneumonia under 10 years old. Sensitivity is 100%, but it
(46–56%), difficult-to-control asthma (26%), bron- has a moderate specificity. It has a low posi-
chiectasis (8.6–24%), and situs inversus (18–69%). tive predictive value but perfect negative pre-
The average age at diagnosis is 4 years, but with a dictive value.
high clinical suspicion it can be diagnosed earlier, c. Fractional exhaled nitric oxide (FENO) mea-
even within the first month of life. sure: Very low levels of exhaled nitric oxide
have been measured in the nasal mucosa of
these patients. This finding is not exclusive of
Diagnosis this pathology, but the diagnosis of PCD
should be reconsidered if there are high nitric
The diagnosis of PCD is based on a combination oxide levels. It is very unlikely that the patient
of clinical evaluation and analysis of the ciliary has PCD if the value of NO exceeds 105 ppb.
ultrastructure and function, and it can be difficult Other clinical conditions that tend to be
to determine this diagnosis in some patients. The accompanied by low FENO are cystic fibrosis,
clinical phenotype is wide and overlaps with panbronchiolitis, complete nasal blockage,
other chronic diseases of the airway. and nasal polyposis. Each center should have
The patient must be thoroughly studied to rule its own reference values.
out other pathologies (allergies and immunologi-
cal studies, X-rays, gastroesophageal reflux,
sweat test, etc.) that may be responsible for the Diagnosis Methods
clinical condition.
The screening and diagnosis methods for cili- Diagnostic procedures should be used in those
ary dyskinesia are detailed next. patients with a positive screening test, or in those
434 N. L. Holmgren Palmen et al.

patients who could not undergo the screening biopsy should be repeated to rule out radial spoke
tests because of their age or availability. A bron- pathology or a defect in the transposition of the
choscopic brush is used to take samples of the microtubules.
respiratory epithelium through a nasal brushing. Some patients have a normal ultrastructure
No sedation is required. Sometimes it is comple- and primary ciliary disorientation. Ciliary disori-
mented with bronchial lavage and/or biopsy of entation has recently been described as a possible
the nasal and bronchial mucosa. To avoid false-­ variant of PCD. These patients present a normal
positives, the patient must be free of any respira- structure, as well as a normal, or almost normal,
tory infection in the upper respiratory tract for at beat frequency; but their cilia lack efficiency
least 4–6 weeks. because their beat direction is disarranged. These
The diagnosis is confirmed if the patient pres- patients have disorientation rates of 20% to 25%;
ents alterations in both ciliary motility and ultra- between 10% and 15% is considered normal.
structure. If only one of these tests is positive, Ciliary disorientation can be seen more fre-
then the diagnosis is only presumptive. quently as a part of secondary ciliary alterations,
and therefore if there are doubts, it is recom-
a. Measuring the frequency of ciliary beat with a mended to take another sample after the infection
light microscope: Few centers in the world and inflammation of the patient have been treated.
conduct this test. A fresh sample of the respi-
ratory epithelium is needed. A normal ciliary
motility discourages a PCD diagnosis. Other Studies
Abnormal beat patterns include rotation
movements, independent movement in each Genetic study will probably be a useful tool in the
cilium, and complete absence of ciliary future. The cilium contains more than 200 differ-
motion. ent types of proteins, and therefore multiple genes
b. Measuring the frequency of ciliary beat after could be involved. It has been demonstrated that
ciliogenesis: This test involves analyzing a the disease is genetically heterogeneous, even
section of mucosa that has been previously when it presents the same ultrastructural altera-
cultured for this purpose. The frequency of the tions, which makes it difficult to investigate
beat after ciliogenesis may show the real fre- related genetic alterations. Currently, there are
quency value of the ciliary motility, because it several recognized mutations: DHAH5, DNAI1;
is not influenced by the external conditions DNAH11, TXNDC3, DNAI2, KTU, LRRC50;
causing secondary ultrastructural and func- RPGR, OFD1, RSH9, RSPH4A, CCDC39, and
tional alterations. CCDC40. The details of approximated frequency,
c. Study of respiratory mucosa cells: Study of clinical phenotype, chromosomal location, and
ciliary ultrastructure and orientation with the ultrastructural findings can be seen in Table 43.2.
electronic microscope suggests ciliary dyski- Currently, it is not recommended to conduct a
nesia (whether it is primary or secondary) if genetic study on a routine basis for the diagnosis
20% of the studied cilia lack dynein arms. procedure, although it can be done if some of the
Some centers consider 10% as abnormal. An mutations that are present with a greater fre-
adequate sample must be obtained, with at quency (DnAH5 and DNAI1) are suspected
least five good cross sections of cilia, includ- because of the phenotype and ultrastructural find-
ing at least 10 different and nonadjacent cells. ings. These tests can also be offered to family
members to provide genetic advice.
In the cases of PCD there is one type of identi- In the future, the development of marked anti-
cal anomaly in all the cilia, whereas secondary bodies (immunofluorescence) against the depen-
anomalies usually present a variety of defects. If dent proteins of the most common mutations will
the patient has an abnormal cilia motility and a make possible identifying abnormal proteins in
few cilia available for examination, then the the cells of the respiratory epithelium.
43  Primary Ciliary Dyskinesia 435

Table 43.2  PCD mutations

Gene Locus Structural defect Phenotype Total of patients with mutations (%)
DNAH5 5p15 AEDA PDC + KS 28
DNAI1 9p21-p133 AEDA PDC + KS 7.5
DNAH11 7p15:3-21 Normal PDC + KS ?
TXNDC3 7p14,-1 AEDA KS ?
DNAI2 17q25,1 AEDA PDC + KS ?
KTU 14q21,3 AEDA+ AIDA PDC + KS ?
LRRC50 16q24,1 AEDA+ AIDA PDC + KS ?
RPGR Xp21,1 Variable PDC + RP ?
OFD1 Xp22 Unknown PDC + MR ?
RSPH9 6p21 CP PDC ?
RSPh4A 6q22 CP PDC ?
CCDC39 3q26,33 AEDA + CP PDC + KS ?
CDCD40 17q25,3 AEDA + CP PDC + KS ?
AEDA Absence of external dynein arm, AIDA absence of internal dynein arm, CP central pair defect, PCD primary cili-
ary dyskinesia, RP retinitis pigmentosa, MR mental retardation, KS Kartagener syndrome

well as pulmonologists, otorhinolaryngologists,

Diagnostic Approach respiratory physiotherapists, and psychologists.

Those patients who have a clinical condition that

is compatible with PCD, after other secondary Respiratory Treatment
causes have been ruled out, should be studied
first with a mucociliary clearance test (saccharine Patients must be checked every 2 to 3  months.
test or technetium-99 m-labeled colloid albumin This evaluation should include monitoring of
test) or nasal FENO.  The study of ciliary beat respiratory frequency, O2 capillary saturation,
with an electronic microscope is reserved for and spirometry. Chest X-rays must be taken when
those cases in which screening tests yield abnor- there are respiratory exacerbations. A sputum
mal results. If any of these methods is not avail- culture is recommended every 3 months to deter-
able or cannot be used because of the age of the mine what organisms are colonizing the airway.
patient, a direct sample of the respiratory mucosa If bronchiectasis is being suspected, it should be
must be taken (Fig. 43.5). confirmed with a computed tomography (CAT)
scan; however, it is not recommended to serialize
this study in the follow-up. The patient and their
Evaluation and Treatment family must be educated about the disease, the
importance of avoiding exposure to environment
The objective of the therapy is to prevent pulmo- pollutants, especially tobacco smoke, and to seek
nary complications, such as the appearance of early medical follow-up when there is clinical
chronic lung damage and bronchiectasis, as well worsening, even if it is minimal. Yearly vaccina-
as reducing sinus and ear complications. tion against influenza is recommended, as well as
There are no properly designed studies evalu- vaccination against Streptococcus pneumoniae, if
ating the effectiveness of different types of ther- the patient has not yet been vaccinated.
apy for the different patients affected by The two therapeutic columns are chest physio-
PCD.  Most recommendations are based on the therapy and the intensive use of antibiotics for
opinions of experts, besides extrapolations done respiratory exacerbations.
considering other diseases such as cystic fibrosis. Adequate secretion clearance can be achieved
These patients require a multidisciplinary through chest physiotherapy, consisting of bron-
assessment, including general pediatricians as chial drainage and repeated deep inspiration tech-
436 N. L. Holmgren Palmen et al.

PCD
Study

Dextrocardia
Situs inversus
Non-resolved sinopulmonary infections

Screening tests

Mucociliary Clearance Study

>12 years old Study non-available in the
Nasal FENO
Saccharin test <12 years center
Label albumin test

SEM study
Normal Abnormal Abnormal Normal
Ciliary beat measurement

<10% of altered cilia >20% of altered cilia >20% of altered cilia

Ciliary motility not Abnormal ciliary motility
Normal ciliary motility available

Presumptive Definite
PCD unlikely diagnosis of PCD diagnosis of PCD

PCD unlikely

Fig. 43.5  PCD study algorithm

niques, in combination with chest percussion. At The organism that usually infects these
least 20  min, twice per day, is recommended. patients is Haemophilus influenzae (80%), fol-
Using β2-agonists may be useful, but ideally the lowed by Staphylococcus aureus (13%) and
response to this drug should be documented with Streptococcus pneumoniae (10%). Infection
spirometry before and after using the bronchodi- caused by Pseudomonas aeruginosa occurs in as
lator. Exercise determines the improvement of many as 20% of the pediatric population. In adult
expiratory flows in the spirometry in a much bet- patients it has been isolated in 25% of cases, and
ter way than β2-agonists. Ideally, the patient in 15% of cases atypical mycobacteria were pres-
should engage in some kind of physical activity ent. For episodes of cough and sputum, an intense
before chest physiotherapy sessions, to promote a and prolonged antibiotic therapy must be started
greater clearance of the secretions. The use of (>14  days), using antibiotics adequate for the
Flutter or Acapella has not been studied, but they agents involved. An initial ambulatory treatment
can be considered for older children. in high doses is recommended. The use of IV
43  Primary Ciliary Dyskinesia 437

antibiotics must be reserved for patients who do gested if a complication is suspected or if a

not respond to oral therapy, who are infected by surgery is planned. The recommended treatment
Pseudomonas aeruginosa, are hospitalized is lavage with high volumes of saline solution,
because of great respiratory distress, or need whether it is isotonic or hypertonic (“nasal
oxygen. shower”), twice as a day as a routine, with the
There is no evidence to support the chronic intention of creating a mechanical flushing of the
use of nebulized rhDNAse, nebulized hypertonic secretions. If the patient does not respond to the
serum, n-acetylcysteine, or macrolides. nasal lavage, then topical nasal steroids are gen-
erally recommended. For those patients who do
not respond to the aforementioned therapies,
Otorhinolaryngology Treatment antibiotic therapy should be considered, and
eventually, surgery.
Hearing evaluation must be done in series,
through audiometry and impedance audiometry.
These patients have a very high rate of otitis Future Perspectives
media with effusion, which alters hearing and
affects language development. Chhin showed that, using a lentivirus as a vector,
There is controversy relative to what treatment a normal (therapeutic) gene could be transferred
should be used in patients with hearing loss to human nasal mucosa cells. After this, the trans-
because of otitis media. Some authors do not rec- ferred gene could be transcribed and expressed,
ommend the use of ventilation tubes, because thus reestablishing ciliary ultrastructure and func-
persistent otorrhea may appear after their tion in those cells. The importance of this study
implanting. For those patients who have lost 40 lies in the fact that it is possible to insert therapeu-
decibels or more, hearing aids may help the child tic genes in the cellular genome and thus it offers
to acquire proper language; but persistent otitis new perspectives for the treatment of PCD.
media along with effusion may cause a retraction
of the posterior tympanic membrane, which will
have consequences in the future. Of 33 patients at Prognosis
the Hospital Clínico de la Universidad Católica
de Chile who were assessed between 1993 and Prognosis is generally good, with a normal life
2003, tympanostomy tubes indicated for 19. The expectancy. If treatment is not adequate, how-
follow-up of these patients while they had the ever, there may be some serious complications
tubes implanted showed that 13 of them improved secondary to recurrent infections and iatrogenic
satisfactorily without otorrhea episodes, 2 had at complications. The appearance of these compli-
least one episode of otorrhea, and 4 presented cations will depend on the ultrastructural altera-
with three or more episodes. Currently, consider- tion type, how early the diagnosis was made, if
ing the level of evidence, both the conservative there was bronchiectasis or lung damage when
option of using hearing aids as the surgical option the diagnosis was done, and the therapy received.
are viable treatment alternatives for this group of From the reproductive aspect, subfertility occurs
patients who have suffered hearing loss. in both men and women, and they should be
Ideally, for patients with chronic otorrhea referred to fertility clinics for counseling and
caused by Pseudomonas aeruginosa, topical treatment. In patients with severe lung damage
antibiotics should be used, and sometimes IV and dependent on oxygen, lung transplant is a
antibiotics therapy is recommended, which valid option to extend and improve lifespan.
should be prolonged for rebel cases. To summarize, early diagnosis and the right
Chronic rhinosinusitis is present in more than treatment yield an adequate survival rate, a better
90% of the patients. Routine sinus X-ray evalua- quality of life, and fewer complications in these
tion is not recommended. A CAT scan is sug- patients.
438 N. L. Holmgren Palmen et al.

Sources De Boeck K, Proesmans M, Mortelmans L, Van Billoen

B, Jorissen M.  Mucociliary transport using 99m
Tc-albumin colloid: a reliable screening test for pri-
Barbato A, Frischer T, Kueinni CE, Snijerds D, et  al.
mary ciliary dyskinesia. Thorax. 2005;60:614–7.
Primary ciliary dyskinesia: a consensus statement on
Eley L, Yates L, Goodship J. Cilia and disease. Curr Opin
diagnostic and treatment approaches in children. Eur
Genet Dev. 2005;15:308–14.
Respir J. 2009;34(6):1264–76.
Hjeij R, Loges NT, Omran H.  Immunofluorescence
Busquets RM, Caballero-Rabasco MA, Velasco M,
microscopy (IFM) analysis of primary ciliary dyski-
Lloreta J, García-Algar O. Discinesia ciliar primaria:
nesia (PCD) patients with suspected inner dynein arm
criterios clínicos de indicación de estudio ultraestruc-
defects (IDA). Cilia. 2012;1(suppl 1):23.
tural. Arch Bronconeumol. 2013;49(3):99–104.
Iñiguez R, Fonseca X, Hernández J, González S, Sánchez
Chhin B, Negre D, Merrot O, Pham J, Tourneur Y,
I. Disquinesia ciliar: diagnóstico ultraestructural, evo-
Ressnikoff D, et  al. Ciliary beating recovery in
lución clínica y alternativas de tratamiento. Rev Med
deficient human air-way epithelial cells after
Chile. 2007;135:1147–52.
lentivirus ex  vivo gene therapy. PLoS Genet.
Mener DJ, Lin SY, Ishman SL, Boss EF. Treatment and
2009;5:e1000422.
outcomes of chronic rhinosinusitis in children with
Chodhari R, Mitchison H, Meeks M. Cilia, primary ciliary
primary ciliary dyskinesia: where is the evidence?
dyskinesia and molecular genetics. Paedit Respir Rev.
A qualitative systematic review. Int Forum Allergy
2004;5:69–76.
Rhinol. 2013; https://doi.org/10.1002/alr.21227.
Corbelli R, Brigolf-Isler B, Amacher A, Sasse B,
Noone PN, Leigh MW, Sannuti A, Minnix SL, et  al.
et  al. Nasal nitric oxide measurements to screen
Primary ciliary dyskinesia. Diagnostic and phe-
children for primary cliary dyskinesia. Chest.
notypic features. Am J Respir Crit Care Med.
2004;126(4):1054–9.
2004;169:459–67.
Coren M, Meeks M, Morrison I, Buchdal RM, Bush
Steinkamp G, Seithe H, Nublein T.  Therapy of primary
A.  Primary ciliary dyskinesia: age at diagnosis and
ciliary dyskinesia. Pulmonologie. 2004;58:179–87.
symptom history. Acta Paediatr. 2002;91:667–9.
 Cystic Fibrosis: Clinical
and Diagnosis Approach
44
Claudio Castaños, Lilien Chertkoff,
and Luis Gravina

Contents
Introduction..................................................................................................................   439
Epidemiology.................................................................................................................   440
Pathophysiology............................................................................................................   440
Diagnosis........................................................................................................................   441
Clinical Manifestations................................................................................................   441
 ung Compromise..........................................................................................................  441
L
Intestinal Obstruction.....................................................................................................  443
Gastrointestinal Alterations............................................................................................  443
Growth Delay.................................................................................................................  444
Sweat Glands..................................................................................................................  444
Vas Deferens...................................................................................................................  444
Diabetes Mellitus............................................................................................................  445
Edematous Ascitic Syndrome.........................................................................................  445
Family History of CF......................................................................................................  445
Laboratory Methods....................................................................................................   445
 weat Test.......................................................................................................................  445
S
Malabsorption Test.........................................................................................................  446
Semen Analysis..............................................................................................................  447
Membrane Potential........................................................................................................  447
Molecular Diagnosis.....................................................................................................   447
I ndications for a Molecular Study..................................................................................  448
CF Neonatal Screening.................................................................................................   448
Screening Strategies.......................................................................................................  448
Sources...........................................................................................................................   450

Introduction

Cystic fibrosis (CF) is a multi-systemic and auto-

C. Castaños (*) · L. Chertkoff · L. Gravina
Hospital Garrahan, Buenos Aires, Argentina
somal recessive disease that affects the respira-
e-mail: [email protected]; tory, digestive, and reproductive systems. It is
[email protected] caused by a mutation in the gene called cystic

© Springer Nature Switzerland AG 2020 439

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_44
440 C. Castaños et al.

fibrosis transmembrane conductance regulator ing to current nomenclature), which is present in

(CFTR). two thirds of the CF alleles in the world.
From the first descriptions of CF by Andersen Studies conducted in different Latin American
in 1938, more than 50 years passed until a respon- countries have shown a wide spectrum of CFTR
sible gene could be identified in 1989. From this gene mutations: about 100 different mutations
moment on, important advances in the medical have been described. The allele sequence of
knowledge of the disease have greatly affected mutation DF508 varies among the countries in
the diagnosis procedure and its treatment. During Latin America: Venezuela-Cuba-Ecuador-Chile
these years an improvement of the clinical situa- (29–34%), Mexico-Colombia-Uruguay (40%),
tion of these patients was achieved, which has Brazil (40–48%), and Argentina (56–60%). This
yielded a better life expectancy in developed variability reflects the different ethnic back-
countries, currently reaching 40 years of age. In grounds between Latin American countries
Latin America the life expectancy is lower, depending on the greater or smaller predomi-
although there are only isolated data from some nance of European immigration.
countries. Even so, every year more patients The second most common mutation is G542X,
reach adulthood. Because of the advances present in about 5% among them all. The fre-
achieved during the last decades, currently CF quency of 15 other mutations (N1303K, W1282X,
should be considered a chronic disease, of which 1717-1G>A, 3849+10KbC>T, R334W, G85E,
the progression can be favorably modified if early DI507, 2183AA>G, 2789+5G>A, 1811+1, 6Kb
therapeutic interventions are implemented. A>G, R1162X, R553X, R1066C, 621+1G-T, and
3120+1G>A) is about 1%.

Epidemiology
Pathophysiology
CF is the lethal hereditary disease most frequent
in the white population, with an incidence of CF is an autosomal recessive disease caused by
around 1:3200 newborns. In non-Caucasian pop- mutations in the gene CFTR, localized in the
ulations, such as Afro-Americans and Asians, the long arm of chromosome 7 (7q31,2), which is
incidence is substantially lower. Even though 250 kb and composed of 27 exons. It codifies a
there are no definitive data for Latin America, the protein made of 1480 amino acids, composed of
Hispanic population in the United States of two transmembrane domains, two union and two
America presents an incidence of 1 in 9000 new- ATP-binding and hydrolysis domains, and one
borns. In Argentina, where neonatal screening phosphorylation regulation domain (Fig.  44.1).
has been carried out since 1995, the reported data In normal conditions, this protein is present in the
indicate an incidence of 1 in 7000 newborns. This apical membrane of the cells in the exocrine epi-
number is likely related to the ethnic characteris- thelium, where it mainly acts in active chloride
tics of this population, caused by the integration ion transportation, and it seems to be capable of
within the native population of different regulating the function of other ionic channels.
European-Caucasian immigration flows. The presence of mutations in the CFTR gene
From the genetics aspect, the distribution of causes a defective epithelial ionic transport.
mutations in the CFTR gene also varies greatly From the functional aspect, mutations are
according to the ethnic origin and the geographic grouped in five classes (I–V). Most of these
localization of each group of people. About 2000 cause complete channel failure, whether they
mutations have been reported for the CFTR gene, affect the biosynthesis of the protein (class I), its
which have been systematically registered in an maturity process (class II), or its function (class
open access database (Cystic Fibrosis Mutation III). In contrast, in class IV and V mutations, the
Database, http://www.genet.sickkids.on.ca). The proteins produced retain certain residual activity.
most frequent mutation is a phenylalanine dele- Generally, class I, II, and III mutations are
tion in position 508 (DF508 or p.F508del accord- related to serious manifestations of the disease,
44  Cystic Fibrosis: Clinical and Diagnosis Approach 441

MSD1 NBD1 R MSD2 NBD2

MSD1 MSD2

Transmembrane
NH2 domains
nucleotide-binding
domain NBD1 NBD2
R

COOH
Regulatory
domain

Fig. 44.1  Cystic fibrosis transmembrane conductance regulator (CFTR) gene and protein

which include pancreatic insufficiency, whereas • Two positive sweat tests

class V mutations present mild manifestations, • Presence of two mutations in the CFTR gene
or even oligo-symptomatic (traditionally named • An abnormal transepithelial membrane
nonclassic presentations, and currently named potential
diseases related to CTFR), such as the congenital
bilateral absence of the vas deferens (CBAVD), Nevertheless, a percentage of patients do not
idiopathic chronic pancreatitis, and bronchiecta- have complete expression of the disease, and the
sis, among others. physician must be aware to determine the diagno-
Understanding of the physiopathological sis (Table 44.1).
nature of the disease at the molecular level has According to the International Cystic Fibrosis
improved during the past years. This knowledge Association (ICFA), these factors favor delayed
prompted the development of new therapeutic diagnosis:
strategies oriented to correct the gene dysfunc-
tion. Thus, genotyping patients with CF also (a) Poor knowledge about the disease among
became important for determining specific treat- health professionals
ments according to the mutation class (allele-­ (b) Lack of information for timely diagnosis

specific therapies). within the first health attention levels
(c) Diagnosis inaccessibility, given difficulties
to conduct the sweat test at a location near
Diagnosis the patient’s domicile

The disease is diagnosed using clinical criteria

and laboratory methods. The presence of two or Clinical Manifestations
more of the following clinical criteria suggest the
disease: chronic pulmonary disease, chronic Lung Compromise
sinus disease, malabsorption, obstructive azo-
ospermia in males, family history of cystic fibro- The onset age of respiratory symptoms is vari-
sis, and salt-wasting syndrome. able, and some symptoms can appear even during
Diagnosis confirmation is through these the neonatal phase, although they always appear
means: during the first years of life. The symptoms may
442 C. Castaños et al.

Table 44.1  Important clinical elements for diagnosis 3. Chronic bronchitis, with cough and mucopu-
Respiratory rulent expectoration
 Upper airway
  Nasal polyps Older children may present with bronchial
  Chronic sinusitis obstruction, cough, and expectoration, which
 Lower airway
vary according to the compromise of the patient.
   Persistent tachypnea and retraction
   Wheezing with persistent hyperinflation
CF must be considered and ruled out for children
  Chronic cough with asthma symptoms who do not respond to the
  Sputum culture positive for Haemophilus treatment.
influenzae, Staphylococcus aureus, When the disease has progressed because of
or Pseudomonas aeruginosa the persistence of infections and chronic obstruc-
  Recurrent pneumonia
tion, bronchiectasis may be observed, with or
  Bronchiectasis
  Hemoptysis
without hemoptysis.
 Chest X-rays Extrapulmonary signs of chronic lung disease
   Bilateral air trapping may be observed, such as increase of chest
  Persistent atelectasis (particularly anteroposterior diameter and digital clubbing.
in the right upper lobe)
 Gastrointestinal
  Meconium ileus
CF must be ruled out in every child with
   Prolonged neonatal jaundice
  Malabsorption–steatorrhea asthma symptoms who does not respond to
  Rectal prolapse treatment with bronchodilators or shows
   Cirrhosis and portal hypertension failure to thrive.
 Other
  Growth failure
   Positive family history
  Salty sweat
A characteristic of the disease, granted by the
   Edema and hyponatremia basic genetic alteration, is infection of the airway,
  Digital clubbing which in many cases ultimately causes a chronic
   Azoospermia and absence of vas deferens infection. In the first stages of CF, the most fre-
  Metabolic alkalosis quent agents are nontypeable Haemophilus influ-
enzae (HI) or Staphylococcus aureus (SA). As the
be nonspecific, but the pediatrician must suspect disease progresses and the patients become older,
and consider CF. Pseudomonas aeruginosa (PA) is the main agent.
Respiratory disease causes greater morbidity
and mortality rates. More than 95% of the patients
with CF present with respiratory symptoms, and The physician should suspect the disease
with malabsorption, it is the most common clini- when there is persistence of bronchial secre-
cal presentation. tions in patients who are positive for non-
The CFTR protein defect causes an alteration typeable Haemophilus influenzae (HI) or
in the mucociliary clearance, where there is inad- Staphylococcus aureus (SA), and who have
equate depuration of the respiratory secretions, not received mechanical ventilation support.
which tend to be thick, thus favoring bronchial If Pseudomonas aeruginosa appears on the
obstruction and chronic infection of the airway. cultures, CF must be ruled out.
Because of this defect, the clinical presentation
during this stage of life may include these:
At first, the chest X-ray may show hyperinfla-
1 . Recurrent or prolonged bronchiolitis tion, but it then progresses to bronchitis with
2. Recurrent or persistent atelectasis patchy areas with consolidations. These changes
44  Cystic Fibrosis: Clinical and Diagnosis Approach 443

Intestinal Obstruction

Meconium ileus  Meconium ileus appears in

10–15% of patients with CF, and it is the most
common manifestation during neonatal age. It
occurs secondary to water reduction in the intes-
tines, and most of these patients also have pan-
creatic insufficiency.

Starting from the 18th week of gestation, it can

Fig. 44.2  Bronchiectasis. Computerized axial tomogra- be recognized through echography. This condition
phy of a 16-year-old patient shows bronchial enlargement may also appear after childbirth, with abdominal
and cystic deformations, mainly in the middle lobe enlargement and scarce stools with mucus, or no
defecation at all, as well as biliary vomiting. The
are gradual and increase with the progression of obstruction is usually located in the small intestine
the disease. proximal to the ileocecal valve. Encapsulated
In chest computerized axial tomography, meconium peritonitis appears in more than 50% of
cylindrical bronchiectasis can be observed during the patients with meconium ileus.
the beginning of the disease, which afterward In the abdominal X-rays, the intestine can appear
progress to a varicose and then to a saccular type enlarged, with areas of air mixed with dehydrated
(Fig. 44.2). meconium, usually in the abdomen right lower
The presence of cylindrical bronchiectasis, quadrant. Calcifications images may also appear.
mainly in the superior lobes, is suggestive of the
disease, which must be ruled out with a sweat
test. The presence of meconium ileus in a new-
Lung compromise is also observed in lung born is almost synonym for CF, and it should
function tests, which can be present even in the be ruled out. The existence of duodenal atre-
early stages of the disease. sia has also been related to CF in more than
50% of the patients, and therefore any type
Upper airway of intestinal obstruction in an infant is sug-
Compromise of the upper airway is caused by gestive of CF, which must be ruled out.
the hyperreactivity of the mucus secretion
glands. This, with the alterations in mucociliary
transport, causes hypertrophy and edema in the Equivalent of meconium ileus  Also called
mucosa membranes, as well as obstruction of distal intestinal obstruction syndrome, this can
sinus ostia. be an important complication in some patients,
Almost all patients with cystic fibrosis present particularly in adolescents. It is characterized by
with opacification in the paranasal sinus X-rays, constipation, vomiting, abdominal pain, recur-
and many have chronic sinusitis symptoms, rent colic, and palpable fecal matter in the right
which may cause infectious exacerbations in the iliac fossa, or in the right side.
lower airway. More than 25% of all patients with
CF have nasal polyps.
Gastrointestinal Alterations

If there are nasal polyps and the cause has Prolonged jaundice  Neonatal cholestatic jaun-
not been established, CF must be ruled dice can appear in patients with meconium ileus
out. (50%), but it can also appear in newborns without
meconium ileus.
444 C. Castaños et al.

Exocrine pancreatic insufficiency (intestinal Growth Delay

malabsorption)  Between 85% and 90% of the
patients with cystic fibrosis present with pancre- These patients frequently present with a delay in
atic insufficiency at birth. growth, which is caused by a combination of sev-
eral factors: (a) increase of calorie intake; (b)
The clinical presentation is abundant fetid chronic lung disease; (c) poor digestion, with cor-
stools, with fat presence characteristics (lack of responding intestinal malabsorption; and (d) low
color, shiny, oily). Malabsorption is confirmed appetite, caused by active lung inflammation.
using the stool elastase test, or with the collection Intestinal malabsorption can be confirmed
of 72 h of stools and analyzing the fat contained, observing the increase in depositions, with abnor-
named the Van de Kamer test. mal stool color and consistency. Malabsorption,
About 10% to 15% of the patients have pan- especially of fats, also involves a deficiency in
creatic sufficiency with some degree of residual the absorption of liposoluble vitamins.
pancreatic activity. Given that these patients do
not suffer from malabsorption, diagnosis is dif-
ficult and it usually takes longer. Sweat Glands

CFTR causes the sweat glands to be the only

Patients with pancreatic sufficiency may ionic channel capable of reabsorbing sweat chlo-
develop pancreatic insufficiency as the dis- ride; therefore, the patient with CF has a chloride
ease progresses, and therefore elastase concentration in the skin five times greater than
must be controlled annually. that of normal patients, which is almost the same
as the plasmatic concentration. This abnormality
is the base of the diagnostic test of the disease.
The sweat of the affected patients tends to be
In older patients or in adults, persistent or salty, and the loss could be so important that salt
recurrent pancreatitis of unknown cause is sug- crystals could appear in the hair line. Salt loss
gestive of CF. during heat waves can be serious and cause hypo-
natremic dehydration, as well as serious hypo-
Rectal prolapse  It can be present in about 20% chloremic alkalosis, which require immediate
of the patients who are under 5 years old and who intervention. This loss could be the first presenta-
have never been treated for CF. This sign is sec- tion of the disease.
ondary to the lack of treatment for intestinal
malabsorption.
Vas Deferens
Liver disease  Around 5% of the patients with
CF develop liver disease. The process is charac- Even though the testicles of males with CF are
terized by focal or diffuse cirrhosis, and the com- normal, the epididymis either cannot be palpated
plications include splenomegaly, varicose veins, or is reduced, and the vas deferentia are absent in
and bleeding: this is the cause of death of 1–2% almost every patient.
of patients with cystic fibrosis. Up to 95% of males who suffer from CF are
infertile because of azoospermia, caused by the
Another complication related to liver disease congenital bilateral absence of a vas deferens.
is biliary lithiasis, which has a greater incidence Women may be sterile because of thickening of
in patients with CF. the cervical mucus or nutritional state.
44  Cystic Fibrosis: Clinical and Diagnosis Approach 445

Diabetes Mellitus To perform this test correctly and obtain valid

results, it is important to apply the procedure
Changes in the glucose mechanism of CF patients using a standardized methodology, in centers
were described in 1938, but the relationship where an adequate number of tests are being car-
between cystic fibrosis and diabetes was described ried out, to have a good quality control. The test
later, in 1953. The cause of diabetes is the pro- consists in the stimulation of sweat glands
gressive fibrosis of the pancreas, which in princi- through pilocarpine iontophoresis, the sweat col-
ple is only present in the exocrine pancreas and lection in gauze or in filter paper (Gibson and
then extends to the endocrine portion of the gland. Cooke), and the concentration of electrolytes
Reported incidence in different studies is quite (chloride, or chloride and sodium), is quantified.
variable, with a range between 21% and 75%. A Macroduct device can also be used.
The range is so wide that it may be caused by dis-
similar criteria used for different studies. • The minimal weight of accepted sweat is
75 mg, and the sweat rate must be more than
1 g/m2/min.
Edematous Ascitic Syndrome • The results of the sweat test must always be
evaluated considering the clinical presentation
In children under 6 months of age, about 5% of and the age of the patient, and it should not be
CF patients may also present edema, anemia, and the only element in the diagnosis, because
hypoproteinemia. These patients need to be nutri- false results may be obtained.
tionally recovered before conducting the sweat • The reference values for the sweat test are
test, to avoid the possibility of false-negatives. shown in Table 44.2.
• Those patients with uncertain results must be
reevaluated until a diagnosis can be
The triad edema, anemia, and hyponatre- confirmed.
mia is considered to be a CF until it been • Some data state that for children under
ruled out. 3 months of age a concentration greater than
30 mmol/l is highly suggestive of CF.

Warning  No technique of direct reading,

Family History of CF
whether by conductivity or by the specific or
selective ion electrode system, chloride indicator
A family history of CF it is very useful when CT
patch, osmolarity measure, etc.; may be used as a
is suspected.
confirmation method, nor they should be used as
the base for a definitive diagnose of cystic
Other less frequent clinical presentations 
fibrosis.
Arthropathy, with arthritis and vasculitis, can be
detected. Amyloidosis can be a complication of
The sweat conductivity test measures the elec-
the chronic inflammation activity caused by an
tric conductivity of the ions; uses the Macroduct
infection. Autoimmune processes and malignant
device for collecting and the Wescor Sweat-Chek
diseases have also been described.

Table 44.2  Reference values for sweat test

Laboratory Methods
Under Over
6 months old 6 months old
Sweat Test Normal ≤29 mmol/l ≤39 mmol/l
Intermediate or 30–59 mmol/l 40–59 mmol/l
Quantitative measures of electrolytes in sweat uncertain
excretion is still the most important test to con- Pathologically ≥60 mmol/l ≥60 mmol/l
firm the clinical suspicion of this disease. compatible with CF
446 C. Castaños et al.

analyzer. It is a screening method, which must be • Nephrogenic diabetes insipidus∗

confirmed by the Gibson and Cooke method. • Adrenal insufficiency∗
• Familial hyperparathyroidism∗
Practical considerations for the sweat test: • Eczema∗
• Test must be done in stable patients. • Protein and calorie malnutrition∗
• It is recommended to apply it for asymptomatic • Ectodermal dysplasia
children older than 2 weeks of life and whose • Prostaglandin E-1 infusion
weight exceeds 2 kg. For symptomatic patients • Anorexia nervosa∗
(for example, meconium ileus), it can be done • Autonomic dysfunction
when the patient has reached 48 h of life. • Glucose-6-phosphatase deficiency
• The site of choice for the recollection of sweat • Mauriac syndrome
is usually the forearm; in some circumstances • Pseudo-hypoaldosteronism∗
the sweat can be collected from the thigh. • Familial cholestasis
• Samples from different parts of the body must
not be added to obtain the minimum amount ∗Sweat test yields normal results when condition
of sweat. has been resolved.
• Chloride or chloride and sodium concentra-
tions are assessed; when only one ion is quan- 1. False-negative sweat test
tified, chloride is the one considered. The • Technical tests: Low sweat rate
simultaneous determination of chlorides and • In patients with cystic fibrosis:
sodium, particularly, may be useful when –– Edema and hypoproteinemia∗
dealing with limit values in the test results. –– Some mutations that yield “uncertain”
• In patients with CF the concentrations of both chloride results:
ions should be proportionately elevated, and –– R117H (7T)
the difference between them should be no –– 3849+10kb C-to-T
more than 15 mmol/l. –– G551S
• Values above 160 mmol/l are not physiologi- –– D1152H
cally possible and should be considered as –– A455E
mistakes in the test. –– IVS8-5T
• Around 98% of the patients have a chloride ∗Repeat the test when the situation has been
concentration greater than 60 mmol/l, and 2%, corrected.
who present atypical phenotypes, may present
with normal or limit values. Sweat test must be repeated if:
• Most people with normal tests have chloride • The test is positive
values less than 30 mmol/l. • The result falls in the uncertainty range
• Clinical evolution is not as expected
Factors affecting the concentration of electro-
lytes in sweat:
• The main reasons for obtaining false-positive Malabsorption Test
or false-negative-results are generally related
to nonstandardization issues as well technical Malabsorption tests can show the loss of fats
mistakes. through stools or chymotrypsin deficit in the duo-
denum. The test can be very simple or very
Pathologies that may be related to high electro- complex.
lytes levels in sweat The most common used ones are these:
• Fucosidosis
• Glycogen storage disease type I • Van de Kamer test: Normal values are less
• Mucopolysaccharidosis than 2.5 g fat per day. It is the study of choice
• Untreated hypothyroidism∗ to confirm malabsorption.
44  Cystic Fibrosis: Clinical and Diagnosis Approach 447

• Steatocrit according to the mutation range of each popula-

• Globules of fat tion to ensure adequate sensitivity levels (≥70%).
• Chymotrypsin in stools Although most of the mutations described in
• Elastase in stools the CFTR gene are punctual substitutions as well
as small deletions or insertions, during recent
years different large deletions have been
Semen Analysis described in the CFTR gene that may involve
from only one exon to the complete gene, which
Obstructive azoospermia is strong evidence of CF, affects the activity of the protein, totally or par-
and therefore semen analysis may be important to tially. These rearrangements escape detection in
diagnose patients who are monosymptomatic. the conventional methods routinely used in
molecular biology laboratories, and therefore the
real frequency may be underestimated. The
Membrane Potential development of techniques that may establish the
extent of the involvement in a determined region
The respiratory epithelium, including the nasal of the genome has eased the detection of these
epithelium, regulates the composition of the fluid extensive rearrangements.
that bathes the surface of the airway, transporting To reach greater levels of sensitivity, it is
sodium and chloride. This active transportation possible to create a sequence of all the CFTR
creates an electric transepithelial potential differ- gene exons, using a procedure that is quite com-
ence, which can be measured in vivo. plex and expensive, besides being time consum-
Abnormalities in ionic transportation in the ing. For this reason, in most populations this
respiratory epithelium of patients with CF are method is only used where there is a high clini-
related to a characteristic pattern of potential dif- cal suspicion that could not be confirmed using
ference in comparison to the normal epithelium: other methods. Also, complete sequencing iden-
basal potential tending to negativity, greater tifies all kinds of alterations in the CFTR gene,
changes when exposed to amiloride, and null or ranging from mutations that cause the disease to
poor response when the mucosa is perfused with mutations related to mild or monosymptomatic
free chloride solution. manifestations, besides alterations whose path-
It is very important to have standard tech- ological consequences may not be well defined.
niques and methods before interpreting test Thus, in some cases interpretation of the results
results. Measurement must not be carried out in may be complex. During past years new
patients with rhinitis, polyps, or tubes which may sequencing technologies (next-generation
erode the nasal epithelium. The test may have sequencing) have been developed, which simul-
diagnostic utility in atypical cases. taneously analyze millions of fragments, exe-
cuting a quick sequencing of large DNA
extensions. Although accessing these new tech-
Molecular Diagnosis nologies is difficult, it is expected that sequenc-
ing costs will be reduced within the coming
Currently, molecular characterization uses com- years, and so sequencing of the CFTR gene will
mercial kits developed to detect the most com- be a possible diagnostic method for most coun-
mon mutations for the Caucasian population in tries within the region.
Europe and in the United States. These tests gen- To interpret the consequences of a certain
erally include the aforementioned mutations. mutation, an open access database named CFTR2
However, the rate of detection of these kits in project (Clinical and Functional Translation of
Latin American countries will vary depending on CFTR, http://www.cftr2.org) can be helpful. The
the ethnic predominance of each population. As a objective of this project is to provide complete
consequence, their use should be evaluated clinical and functional information that is up to
448 C. Castaños et al.

date and has been reviewed by experts, relative to preventive and attention measures, in the United
a large group of CFTR mutations: it gathers all States of America the life expectancy of the
the clinical and molecular data from 40,000 patients with CF increased from 27 years old in
patients worldwide. 1985 to 38 years old in 2010.

Indications for a Molecular Study Screening Strategies

• Confirmation of suspicious cases (limit or Although developed countries have managed to

unclear chloride values in the sweat test) implement CF screening effectively for more than
• Diagnosis in newborns with suggestive 30  years, and guidelines and recommendations
symptoms have been published, there is still no unique ana-
• Presymptomatic diagnosis in newborn and lytic protocol that has been universally accepted.
infants where CF is suspected because of fam- The different strategies that have been imple-
ily history or positive neonatal screening mented during these years share, as a first step,
• Confirmed genotypical definition of patients the determination of IRT on dry blood stains on
with CF and detection of asymptomatic carri- paper. Nevertheless, an IRT isolated measure-
ers in the family, to provide them with ade- ment has a low specificity and low positive pre-
quate genetic counseling dictive value (PPV). Therefore, the diagnostic
• Diagnosis of atypical manifestations performance should be improved by combining
• Prenatal diagnosis through amniocentesis or IRT study with other tests, as for example, the
biopsy of chorionic villi same IRT in a second sample, the detection of
• Preimplantation diagnosis mutations in the CFTR gene (DNA), and measur-
ing the pancreatitis-associated protein (PAP).
Knowing the genotype is also useful to predict The different described protocols combine the
certain phenotypical characteristics, such as pan- mentioned studies, which differ in their sensitiv-
creatic function (genotype–phenotype correla- ity, specificity, positive PPV, recall rate, complex-
tion), as well as categorizing the patients for the ity, and costs. The following are the main
implementation of future therapeutic strategies. strategies:

• IRT/IRT
CF Neonatal Screening • IRT/DNA
• IRT/DNA/IRT
In the beginning of the decade of the 1980s, • IRT/IRT/DNA
Crossley et al. described measuring immunoreac- • IRT/PAP
tive trypsin (IRT) in dry blood stains as a simple
method for screening newborns for CF. From this Depending on the strategy followed, if the first
point on, the first programs of Newborn Screening sample yields a positive IRT result, there are
for Cystic Fibrosis (NSCF) were developed in three alternatives that can be followed:
New Zealand and Australia. Currently, these pro-
grams exist in diverse countries in Europe, North 1. Obtaining a second sample before the first
America, Oceania, and, to a lesser extent, in Latin month of life to do a second IRT determina-
America. tion. This option is used in the IRT/IRT and
The early detection of CF through these IRT/IRT/DNA strategies. In the IRT/IRT
screening programs has made possible the deliv- strategy, if an abnormal result is repeated in
ery of preventive care measures to improve nutri- the second sample, the patient is recalled
tion, growth, and pulmonary function, as well as and a sweat test is indicated to confirm or
reducing hospitalizations. As a result of these rule out CF.  In contrast, the IRT/IRT/DNA
44  Cystic Fibrosis: Clinical and Diagnosis Approach 449

strategy, when facing a second positive sam- The decision of what strategy to use will
ple, uses the same IRT sample to search for depend on several factors: the ethnic composition
mutations in the CFTR gene. The presence of of the population to be screened, the frequency
two mutations confirms the diagnosis. If the and distribution of the mutations in the CFTR
molecular study yields no definitive diagno- gene, the infrastructure of the laboratory, and the
sis, the newborn is scheduled for a sweat test availability of ideal staff who can handle more
(Fig. 44.3). complex techniques. In the same way, it is crucial
2. Molecular studies using the same sample to consider the costs and consider the objective of
obtained for the initial IRT test. IRT/DNA and the program, which is to know if the aim is to
IRT/DAN/IRT strategies are used. If the molec- detect individuals who carry the gene and mild
ular analysis is not conclusive (presence of a forms of cystic fibrosis, which are generally not
mutation or a high IRT value with no identifi- considered objectives within a screening program
able mutation), the patient is recalled for a sweat (Table 44.3).
test (IRT/DNA strategy), or a second sample is Although currently many programs still use
requested to perform a second IRT (IRT/DNA/ the IRT/IRT strategy, this technique has a lower
IRT strategy). After this point, the strategy is sensitivity, specificity, and PPV thresholds rela-
more similar to the IRT/IRT (Fig. 44.4). tive to the other techniques. For these reasons,
3. PAP measurement in relation to the same sam- most of the protocols applied in Europe, North
ple obtained for the initial test. In this strategy, America, and Oceania include the analysis of
which is known as IRT/PAP, if the result of the mutations in the CFTR gene, aiming to obtain a
PAP also yields an increased result, then the better balance between false-negative and false-­
sweat test is indicated. positive results.

FIRST
SCREENING: IRT
Negative screening

< cut off value > cut off value

< cut off value

2° IRT sample

> cut off value

Patient recall Sending blood sample

Sweat test Molecular Study

Positive 2 mutations

CF CF

IRT/IRT Strategy IRT/IRT/DNA Strategy

Fig. 44.3  Algorithm for screening: IRT/IRT and IRT/IRT/DNA strategies

450 C. Castaños et al.

FIRST SCREENING:
IRT
Negative screening
< cut off value

> cut off value

No mutation 2 mutations
Molecular study CF

1 mutation

Patient recall Patient recall

Sweat test 2nd IRT sample

IRT/IRT Strategy IRT/IRT/DNA Strategy

Fig. 44.4  Algorithm for screening: IRT/IRT and IRT/DNA/IRT strategies

Table 44.3  Advantages and Disadvantages of Strategies

IRT/IRT IRT/DNA IRT/DNA/IRT IRT/IRT/DNA IRT/PAP
Sensitivity < >> > < >
Specificity < >> >> > >
Positive predictive value < >> >> > >
Patient follow-up Yes No Yes Yes No
Detection of carriers No Yes Yes Yes No
Detection of mild forms No Yes Yes Yes No
Time needed to make a diagnosis > << < > <<
Sweat test requirements +++ ++ + ++ +
Cost + +++ +++ ++ +

Castellani C, Southern KW, Brownlee K, et al. European

Screening with negative double-­ trypsin best practice guidelines for cystic fibrosis neonatal
screening. J Cyst Fibros. 2009;8:153–73.
does not rule out the disease. The sweat test Comité de Neumonología, Nutrición,Gastroenterología
is indicated if there is suspicion of CF. e Infectología. Sociedad Argentina de Pediatria. Arch
Arg Ped (en prensa).
De Boeck K, Derichs N, Fajac I, et al. New clinical diag-
nostic procedures for cystic fibrosis in Europe. J Cyst
Fibros. 2011;10(suppl 2):S53–66.
Sources Farrell PM, Rosenstein BJ, White TB, Accurso FJ,
Castellani C, Cutting GR, et al. Guidelines for diag-
Andersen DH. Cystic fibrosis of the pancreas and its rela- nosis of cystic fibrosis in newborns through older
tion to celiac disease: a clinical and pathologic study. adults: Cystic Fibrosis Foundation consensus report.
Am J Dis Child. 1938;56:344–99. J Pediatr. 2008;153:S4–S14.
Aranzamendi RJ, Breitman F, Asciutto C, Delgado N, Gibson L, Cooke R. A test for concentration of electro-
Castaños C.  Deshidratación y alcalosis metabólica: lytes in sweat in cystic fibrosis of the pancreas uti-
presentación inusual de un niño con fibrosis quística. lizing pilocarpine iontophoresis. Pediatrics. 1959;23:
Arch Argent Pediatr. 2008;106(5):443–6. 549–63.
44  Cystic Fibrosis: Clinical and Diagnosis Approach 451

Guía de diagnóstico y tratamiento de fibrosis quística. Quinton P. Missing Cl conductance in cystic fibrosis. Am
Actualización 2013. J Physiol. 1986;251:C649–52.
Kerem B, Rommens J, Buchanan J.  Identification of Rowntree RK, Harris A. The phenotypic consequences
the cystic fibrosis gene: genetic analysis. Science. of CFTR mutations. Ann Hum Genet. 2003;67:
1989;245:1073–80. 471–85.
Knowles M, Stutts J. Spock y cols. Abnormal ion perme- Sontag MK, Wright D, Beebe J, Accurso FJ, Sagel
ation through cystic fibrosis respiratory epithelium. SD.  A new cystic fibrosis newborn screening algo-
Science. 1983;221:1067–70. rithm: IRT/ IRT1 upward arrow/DNA.  J Pediatr.
Lay-Son G, Puga A, Astudillo P, Repetto GM, 2009;155(5):618–22.
Collaborative Group of the Chilean National Cystic The Cystic Fibrosis Genetic Analysis Consortium
Fibrosis Program. Cystic fibrosis in Chilean patients: (CFGAC). Disponible en http://www.genet.sickkids.
analysis of 36 common CFTR gene mutations. J Cyst on.ca/cftr.
Fibros. 2011;10(1):66–70. The National Committee for Clinical Laboratory
Massie RJ, Curnow L, Glazner J, Armstrong DS, Francis Standards. Sweat testing: sample collection and quan-
I. Lessons learned from 20 years of newborn screening titative analysis; approved guideline.
for cystic fibrosis. Med J Aust. 2012;196(1):67–70.
 Cystic Fibrosis: Treatment
45
Felix Ratjen and María Ester Pizarro Gamboa

Contents
General Considerations................................................................................................   453
Minimum Standard of a Cystic Fibrosis Center........................................................   454
Nutritional Support and Enzyme Supplements.........................................................   455
Treatment of Lung Disease..........................................................................................   456
Gene Therapy and Pharmacotherapy..............................................................................  456
Elimination of Airway Secretions..................................................................................  457
Treatment of Infections in the Airway............................................................................  459
Antiinflammatory Treatment..........................................................................................  462
Other Therapies..............................................................................................................  464
Treatment of Complications...........................................................................................  465
Sources...........................................................................................................................   465

General Considerations The follow-up of the patients must be carried

out regularly in a center specialized in CF, which
Cystic fibrosis (CF) treatment requires a health needs to have adequate resources to ensure high-­
team that includes patients and parents as active quality attention. There must be a multidisci-
members. Thus, once the diagnosis has been plinary team of health professionals who are
established, the parents and the patient (if the trained and experienced in CF. This administra-
patient can cooperate) must be educated by the tive aspect has been an important factor in real-
multidisciplinary team. izing better clinical results.
All patients with CF must routinely receive
immunizations according to the regular agenda,
F. Ratjen (*)
The Hospital for Sick Children, University besides vaccines for hepatitis A and B, influenza,
of Toronto, Toronto, ON, Canada and anti-pneumococcal vaccination.
e-mail: [email protected] Nutritional support is crucial for all patients. It
M. E. Pizarro Gamboa is important to intervene early to normalize the
Pediatrics, Respiratory Diseases, Associate Asociado, nutritional state, especially during the first year
School of Medicine, Pontificia Universidad Católica of life. Each clinical visit must record weight,
de Chile, Santiago, Chile
e-mail: [email protected] size, and cranial circumference (in infants), using

© Springer Nature Switzerland AG 2020 453

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_45
454 F. Ratjen and M. E. Pizarro Gamboa

adequate curves, and register the body mass are typical of this disease, or when no cultures are
index (BMI), for infants, schoolchildren, and available.
adolescents. As part of the follow-up, it is important to rule
Exocrine pancreatic function must be estab- out related complications, such as allergic bron-
lished when the diagnosis is made through clini- chopulmonary aspergillosis through IgE and dia-
cal evaluation and stool elastase measurement. betes by annual checks, using an oral glucose
Those patients with normal pancreatic function tolerance test, starting from 10 years of age.
must be reassessed when it is clinically The transition to adult care must use a close
indicated. management plan, and a network for the patient’s
The standard follow-up for clinical visits rec- attention must be available, because only some
ommends to regularly evaluate lung function CF centers will have all the services available
using spirometry starting at 5–6 years of life, as it (for example, lung transplant).
gives guidance for treatment decisions.
In many centers an annual chest X-ray is
taken, although its clinical usefulness has not  inimum Standard of a Cystic
M
been well established. Chest computerized Fibrosis Center
tomography is more sensitive for detecting early
changes in lung disease, but it is currently A center specialized in the care of patients with
reserved for specific indications in most CF cystic fibrosis must have adequate infrastructure
centers. and resources to receive patients for ambulatory
Microbiological vigilance is crucial in clinical care and for hospitalization. Also, the patient
attention, which is controlled by a sputum sample must have access to the center 24 h/day. A spe-
or pharynx swab on each ambulatory visit and on cialized CF center must have at least 50 patients
each pulmonary exacerbation. It is recommended with cystic fibrosis, including adults and chil-
to have a microbiological laboratory with the dren, but the universal recommendation is to have
capability to isolate specific agents of CF using at least 100 patients.
selective media. Currently there is no evidence The multidisciplinary team must include the
supporting the routine use of bronchoalveolar following professionals:
lavage (BAL) for the diagnosis and treatment of
lung infection in children with CF, but its use is • Pulmonologist/pediatrician: As the profes-
recommended in those patients who do not sional must keep pace with the current new
respond to antibiotic therapy. information, it is recommended that this pro-
It is important to avoid cross-infections among fessional devotes at least 50% of his time to
patients in CF centers, and so contact precautions CF patients.
are recommended, besides standard precautions • Infectious disease/pediatrician: This profes-
for all the patients with cystic fibrosis, because sional should have specific knowledge of CF,
cross-infection outbreaks of Burkholderia cepa­ besides having a close working relationship
cia complex, as well as epidemic strains of with the microbiological laboratory, partici-
Pseudomonas aeruginosa and Mycobacterium pating in the diagnostic and treatment of
abscessus, have been described. This precaution infections as well as the development of their
is also valid for the ambulatory setting and for prevention measures.
hospitalized patients infected by the Burkholderia • Specialized nurse: This nurse should have the
cepacia complex. Generally, the contact between necessary knowledge to educate and support
patients with cystic fibrosis must be limited to patients in the different stages of the disease,
avoid the transmission of potential pathogen such as diagnosis procedures, hospitalizations,
agents, whether it is through droplets, indirect or use of IV antibiotic treatment in the domicile,
direct contact, or even for those patients who diagnosis of comorbidities, transition to the
have a negative culture for pathogenic agents that adult attention scheme, gynecological problems
45  Cystic Fibrosis: Treatment 455

related to pregnancy, transplants, and palliative ventional radiology (with experience in emer-
care. The nurse must be in direct contact with gency bronchial artery embolization).
the patients and parents. The staff caring for hospitalized patients
• Respiratory physiotherapist: Must lead the must have experience in the management of the
attention of the patient in relation to respira- disease, allowing for a space for the parents to
tory physiotherapy, exercise, and inhalation accompany the patients during hospitalization,
therapy. This professional must be capable of as well as educational support. Also, there must
taking care of the follow-up of the patients be resources and available personnel for the
through lung function tests and have experi- administration of IV antibiotic treatments in
ence in the management of patients with non- their home.
invasive ventilation and lung rehabilitation. A microbiological laboratory must be avail-
• Nutritionist: Must lead the optimization of the able. This facility must be capable of adequately
nutritional state of the patient, including edu- processing sputum samples, and performing live
cating them in this area. blood analysis and pharyngeal culture, as well as
• Psychologist/psychiatrist: Must provide sup- correctly identifying Burkholderia spp. and
port for the patients and their families, ensur- Pseudomonas aeruginosa, as well as infections
ing that they have an adequate emotional caused by fungus and mycobacteria.
support network. Centers who attend pediatric patients must
• Social assistant: Must have specific knowl- focus in preventing the progression of the dis-
edge about the disease and the different health ease, and communication and teamwork with the
systems, besides knowing about the govern- adult centers is very important, even before the
ment programs and funding systems, to deliver transition is made.
the best economic support for the families. Communication between different centers, at
• Pharmacist: In charge of maximizing the both national and international levels, is crucial.
effect of different treatments, assessing treat- In this way, together we can improve the knowl-
ment adherence and administration of the edge of this condition.
medications; besides minimizing the risks of
adverse effects related to the therapy and mon-
itoring adverse effects. Finally, the pharmacist  utritional Support and Enzyme
N
is in charge of optimizing the resources spent Supplements
in the treatment for this group of patients.
• Geneticist: Collaborates in the genetic diagno- Nutritional support is based on a high-calorie and
sis of the disease, advising the family and the high-protein diet, with a supply of pancreatic
patient about reproductive issues. Also, the enzymes, vitamins, and minerals. To maintain a
professional creates a database of the muta- good nutritional state, it is important to control
tions found in the patients. other aspects of the disease, as happens when fac-
• Administrative staff and coordinator of a data- ing respiratory infections, diabetes, etc.
base: Collect complete and organized infor- Good nutritional state positively influences
mation to have a better understanding of the both life quality and patient survival. The recom-
progression of the disease, along with evaluat- mendation is to administer a diet with 120–140%
ing the results of each center, at national and of the daily calories recommended, not restrict-
international levels. ing fats or other ingredients, as well as rich in
calories and salt. Caloric requirements fluctuate
Besides this, when needed, the center must among patients, and calorimetry may help to
have access to other specialists, such as gastroen- clarify individual intake needs.
terology/hepatology (with experience in endos- When weight gain and growth are insufficient,
copy procedure and esophageal varices ligation), it is recommended to increase the nutritional sup-
diabetes expert, endocrinology, ENT, and inter- port (±20% on average), and if the nutritional
456 F. Ratjen and M. E. Pizarro Gamboa

compromise persists, then the support must be ments, such as antioxidant and omega-3 fatty
more aggressive; a nasogastric tube may be rec- acids, is still very unclear.
ommended, or a gastrostomy for continuous
night enteral feeding if the weight/stature rela-
tionship is below the 90% ideal, or if there is a Treatment of Lung Disease
clear reduction in the growth curve.
The use of pancreatic enzymes in patients It is possible to classify the different therapies
with pancreatic insufficiency is considered stan- and their correlation with the physiopathology of
dard care. The common preparations are made lung disease in the following way (Fig. 45.1).
from pig pancreatic enzymes, which are coated
microspheres resistant to gastric pH, and they are
dissolved in the duodenum. Nevertheless, ingest- Gene Therapy and Pharmacotherapy
ing high concentrations of pancreatic enzymes is
a risk factor for the development of fibrosing Gene therapy involves the insertion of a DNA
colonopathy, and therefore it is not recommended copy that codifies a normal cystic fibrosis trans-
to exceed the dose of 10,000 units of lipase/kg/ membrane conductance regulator (CFTR) protein
day. Patients who are not well controlled with within the defective respiratory cells, using differ-
sufficient enzyme doses must be evaluated for ent vectors. Adenovirus have been shown to be
other malabsorption causes and the benefit of efficient vectors in single-dose studies, but it has
adding gastric acid inhibitors in the therapeutic also been shown that they induce an inflammation
regime verified. in the host when higher doses are used, which
Replacement therapy of pancreatic enzymes limits their clinical application. At the same time,
must be tailored and adapted to each meal. viral vectors induce an immune response that lim-
Depending on how long each meal will last, the its the efficiency of repeated doses. Other vectors
enzymes are administered at the beginning of the such as cationic liposomes have shown to be safer,
meal, or they are divided in one half or two thirds but less efficient, achieving thus a partial correc-
at the beginning of the meal, and the other half or tion of the defective CFTR, without improving all
third at the end of the meal. Capsules must not be the aspects of the disease related to CFTR, such as
chewed, as the enzymes would be released in the sodium hyperreabsorption. Although some tran-
oral cavity, where they may harm the mucosa. If sient effects on CFTR expression and function
it is necessary to open the capsules, they can be have been achieved, no study has been able to
administered with juice, water, or apple puree, show a long-­term effect. Even though studies of
avoiding alkaline liquids. gene replacement are currently being performed,
Supplementing with taurine and ursodeoxy- the main focus of the treatment of CF nowadays is
cholic acid to prevent the progression of hepatic directed to pharmacotherapy.
anomalies in patients with CF is controversial, The objective of pharmacotherapy is to
because although these often improve liver func- improve CFTR traffic, expression, or function.
tion, it is not clear there is positive impact in the For patients who have class I mutations, the treat-
progression of the disease. ment with ataluren, a compound that promotes
Patients with CF tend to lose significant salt early reading through truncated codons in the
quantities in their sweat, specially infants in CFTR mRNA, has proven to increase CFTR
warm weather, and so they should receive salt expression. Nevertheless, phase 3 clinical trials
supplements. Because of pancreatic insufficiency have shown benefits in only a subgroup of
and fat malabsorption, liposoluble vitamins patients.
(ADEK) intake is reduced, and supplements are For patients with G551D mutation (class III),
considered standard care in all patients with pan- Ivacaftor was approved by the FDA in 2012 to be
creatic insufficiency. The role of other supple- used in children over 6 years old. Ivacaftor is a
45  Cystic Fibrosis: Treatment 457

Fig. 45.1 Treatment
for cystic fibrosis CFTR genetic defect • Gene replacement therapy

Ion transport defect • Pharmacotherapy for CFTR

Depletion of the liquid in • Hypertonic solution

the Surface of the ainvay • Manito)

Mucociliary clearance • Respiratory kinesiotherapy

alteration • Dornesealfa

• Antifungal and antibiotic

Infection
treatment

• Azithromycin
Inflammation • Ibuprofen
• Steroids

• Oxygen therapy
Chronic lung damage • Ventilation support
• Lung transplant

function potentiator, which activates the defec- place in the airway cell membrane, as well as
tive CFTR in the cellular surface. In clinical stud- improving the function as a chloride channel. It
ies, patients who carried at least one copy of the has been shown that this provides a limited ben-
G551D mutations received ivacaftor orally; lung efit in the patients with CF, but preliminary stud-
function improved, lung exacerbations were ies in association with ivacaftor have shown an
reduced, and weight gain and improvement of improvement in lung function. Currently, two
respiratory symptoms were associated. It was phase 3 clinical trials are ongoing.
also observed that it significantly reduced sweat
chloride concentrations in treated patients, which
reflects the impact of the medication in the basic Elimination of Airway Secretions
defect of CF.  No important safety issues have
been reported in treated patients, but long-term  espiratory Physiotherapy: Physical
R
experience is still limited. Some recent studies Exercise
have shown a similar efficacy in patients with Aerobic exercise is recommended for patients
other class III mutations. Their use is recom- with CF as an adjuvant treatment to clear the air-
mended for the patients who are carriers of at way and improve general health. Physical training
least one copy of the G551D gene. is designed to increase physical performance, car-
For patients with the F507 mutation, lumi- diovascular function, and muscle strength; thus
caftor, a CFTR “corrector,” has been designed to lung function is preserved, by reestablishing spu-
move the CFTR defective protein to the correct tum elimination and reducing residual volume.
458 F. Ratjen and M. E. Pizarro Gamboa

Good adherence to physical training contrib- preferred techniques are those that can be self-
utes to relief dyspnea, improves exercise toler- administered by the patients when they are old
ance, and is related to a lower reduction of the enough to do so. There is still no solid evidence
forced expiratory volume during 1  s (FEV1). It to prove that a certain technique is superior to
also stimulates the appetite and contributes to a others, but a recent study showed that the posi-
more positive body image. Besides this, exercise tive expiratory pressure (PEP) mask was better
may delay the appearance of osteoporosis by pre- than the high-­frequency chest wall oscillation
venting reduction in bone mineral density. Other (HFCWO) vest regarding pulmonary exacerba-
benefits of physical training are reduction of anx- tions. Respiratory physiotherapy should be tai-
iety and depression, increased feelings of well-­ lored according to age and the preference of the
being as well as improved performance at work, patient.
besides improving recreational activities. It is not
clear how much training is required to achieve Dornase Alfa
these benefits, or what combination of aerobic Inflammation in the airway attracts neutrophils,
and anaerobic exercise is necessary. and their degradation increases the DNA content
Respiratory physiotherapy is recommended in the sputum, which contributes to an increase in
for all patients with CF to improve secretion the viscosity of bronchial secretions. It has been
clearance in the airway, as well as for maintain- proven that administering nebulized dornase alfa
ing lung function. Many techniques have shown breaks down the DNA and reduces sputum vis-
benefits in the short term, but the efficacy of cosity. Clinical studies with dornase alfa have
long-term information is still very limited. shown an improvement in lung function in
Current practice starts with respiratory physio- patients with moderate and serious disease,
therapy soon after the diagnosis. besides reducing lung exacerbations. In children
Different techniques are available within the 6–10 years old range with normal lung
(Table 45.1). Some of them can be self-adminis- function, it was also shown that the rate of lung
tered by the patient, whereas others require the exacerbations was reduced. An improvement in
help of a trained therapist, or a caregiver. The lung function was also observed.

Table 45.1  Respiratory physiotherapy techniques (RKT)

Conventional RKT Postural drainage, percussions, huffing, and cough
Active cycle of breathing Self-administered technique that combines respiration control with chest
technique (ACBT) expansion and the technique of forced exhalation.
Positive expiratory pressure Breathing with a positive expiratory pressure of 10–25 cm of water. This
(PEP) mask technique can be self-administered, but it requires a device.
High PEP (HPEP) mask Complete forced expiration against a fixed mechanical resistance, with
pressures from 40 to 100 cm of water This technique can be self-­administered,
but it requires a device.
Oscillating devices Includes flutter, cornet, acapella, and intrapulmonary percussive ventilation.
This technique can be self-administered, but it requires a device.
Autogenic drainage (AD) Self-administered respiration technique that uses expiratory optimal flow rates
in different pulmonary volumes to move mucus and avoid blockage of the
airway.
High-frequency chest VestTM and the Hayek oscillator provide external compression of the chest
compression devices wall. This technique can be self-administered, but it requires a device.
Resistive inspiratory maneuver Includes inhalation and exhalation against a resistance after forced exhalation,
(RIM) as well as repeated inhalations in 80% of the maximum inhalation pressure
sustained. This technique can be self-administered, but it requires a device.
Physical training Aerobic training involves continuous exercise period at an objective intensity
(bike or running)
Anaerobic training involves exercise of high intensity during a short period
(weights or resistance training or speed races)
45  Cystic Fibrosis: Treatment 459

Long-term therapy has shown decreased Treatment of Infections in the Airway

inflammation of the respiratory airway, as well as
a reduction in the loss of lung function in time. During the past decades, intensive treatment of
Currently there is solid evidence to recommend it respiratory infections has been the main cause of
for patients that need to improve lung function or the increase in survival rate for the patients with
reduce lung exacerbations. The adverse effects CF.  Respiratory infections in these patients are
include voice alterations, pharyngitis, and facial quite complex, and treatment strategies have
edema, which are transient in spite of mainte- been developed for traditional bacteria in CF,
nance of the treatment. such as Staphylococcus aureus and Pseudomonas
aeruginosa, which has led to the appearance of
 ypertonic Saline Solution and Manitol
H other emerging bacteria, which are treated
Nebulized hypertonic saline (HS) solution acts as separately.
an osmotic agent and increases salt concentration Antibiotics therapy may be used with different
in the luminal side of the respiratory epithelium, objectives in CF:
which attracts water, thus increasing the fluid in
the surface of the airway, and hydrates the mucus, • Treatment of the first bacterial isolation
which improves mucociliary depuration. Manitol, • Treatment of acute respiratory exacerbations
a sugar prepared as a dry powder formulation, • Chronic suppressive therapy
has a similar action mechanism. • Prophylactic treatment
For patients who are 6 years and older, nebu-
lized hypertonic saline solution at a 7% concen-  reatment of the First Bacterial
T
tration, used twice per day, has shown modest Isolation
improvements in FEV1, along with a reduction in Currently, all guidelines strongly recommend
the rates of lung exacerbations. Studies in chil- treating the first isolation (eradication) of
dren under 6 years old have failed to reduce the Pseudomonas aeruginosa with nebulized antibi-
exacerbation rate, but a pilot study showed a otics (tobramycin or colistin) or in combination
reduction in the index of lung clearance in this with oral antibiotics (ciprofloxacin). When using
group. Studies have shown that nebulized hyper- tobramycin, studies have not shown additional
tonic saline solution is well tolerated and safe, benefits if oral ciprofloxacin is added. There are
even in infants and small children, with adverse not similar data available for inhaled colistin.
effects in less than 10% of the patients. These One of the main problems when managing
adverse effects include bronchospasm, salty Staphylococcus aureus and other bacteria that
taste, nauseas, dyspnea, and chest pain. A pre- colonize the superior airway tract, such as
treatment with bronchodilator is required to Haemophilus influenzae, is that a significant
reduce the risk of bronchospasm. It is currently proportion of healthy individuals carry these
recommended to reduce exacerbations and bacteria in their oropharynx, and therefore a
improve lung function, with a level of moderate positive culture, specially a pharyngeal swab,
evidence. does not necessarily indicate an infection of the
Manitol as an inhaled dry powder has been lower tract airway. In the case of methicillin-
tested in concluded phase 3 studies, and it is sensitive Staphylococcus aureus (MSSA), its
available for adults in Europe and Australia, but impact in the long term is not clear, and there-
the FDA has not yet approved its use in the fore its eradication is not considered standard
USA. Research has shown improvement in lung care. Some authors recommend treating the first
function, but hemoptysis rates increased in chil- positive culture with oral treatments such as flu-
dren, which is currently being studied. One of its cloxacillin for 2–4  weeks. In the same way,
advantages when compared to nebulized hyper- some authors use amoxicillin/clavulanic acid
tonic saline solution is that it requires less time for 2–4  weeks for the first positive culture of
for its administration. Haemophilus influenzae.
460 F. Ratjen and M. E. Pizarro Gamboa

 reatment of Acute Respiratory

T Studies comparing the use of aminoglycoside
Exacerbations once versus three times per day have not shown
There is clear evidence showing the importance significant differences between the groups rela-
of early and intensive treatment in acute respira- tive to efficacy. Also, creatinine changes favored
tory exacerbations in patients with CF, recom- the once per day treatment in children.
mending a low threshold for the beginning of the There is no evidence supporting the idea that
treatment and orientating the treatment through inhaled antibiotics are an adequate alternative to
the presence of nonspecific symptoms and clini- IV antibiotics for lung exacerbations. Further,
cal signs (Table 45.2). The presence of fever and systemic therapy has a more homogeneous anti-
leukocytosis is rare and it is a late sign, so these biotic distribution in poorly ventilated areas,
entities should not be considered to start the treat- which is an important aspect of serious lung dis-
ment. Antibiotic choice and administration pro- ease. However, when IV therapy is challenging
cedure are based on the sensitivity of bacteria and hospitalization or treatment at home with IV
isolated in the most recent sputum cultures, the antibiotics cannot be done for social reasons, an
functional condition of the patient, and previous oral quinolone (such as ciprofloxacin) and a neb-
clinical history. If there is no information about ulized antibiotic can be an alternative. If there is
the bacteria, antibiotic treatment should be aimed an adequate support system, IV therapy at home
to the characteristic pathogens in CF. More seri- is safe, reduces social disruption, and may be cost
ous lung exacerbations tend to be treated with IV effective. Home IV antibiotic administration
antibiotics; oral therapy is used for less severe must be made according to the individual situa-
situations. These patients present with differ- tion, considering comorbidities, how serious is
ences in the clearance rate of the antibiotic, and the exacerbation, and local resources. It is recom-
they require doses approximately 50% greater mended to start IV antibiotic treatment in the
than those used in patients without CF. The anti- hospital.
biotic treatment should last from 14 to 21 days. There is some evidence supporting the use of
Treatment for patients infected by long IV catheters instead of short IV lines, rela-
Pseudomonas aeruginosa combines two classes tive to how long the line can be used and patient
of antibiotics, associating an aminoglycoside satisfaction. Patients with CF and recurrent
with a third-generation cephalosporin, or a semi-­ exacerbations, requiring regular and frequent
synthetic penicillin, which optimizes clinical IV antibiotic treatments, often lose their periph-
efficacy and reduces the development of bacterial eral vein access, and some of them require a
resistance. Thus, oral ciprofloxacin is reserved central venous catheter, such as a Port-a-cath
for less serious exacerbations. system device.

Table 45.2  Symptoms and signs of a lung exacerbation

Symptoms Physical signs Laboratory findings
Increase of cough frequency, Increase of respiratory effort, 10% or more FEV1 reduction in
duration, and intensity intercostal retractions, and use of comparison with the best value in 6
accessory muscles previous months
Sputum appearance or production Increase of respiratory frequency Increase of air trapping or new
increase infiltration in chest X-ray
Sputum change Appearance or increase of crackles Leucocytosis
in chest examination
Hemoptysis appearance or increase Increase of air trapping Reduction of oxygen saturation (SaO2)
Appearance or increase of dyspnea, Fever
reduction of exercise tolerance
Compromise of the general Weight loss
condition, fatigue increase, weakness,
lack of appetite
45  Cystic Fibrosis: Treatment 461

In the case of infants and preschoolers with der inhaler, which allows a faster and more com-
frequent viral infections, the clinical progression fortable administration.
must be closely monitored, and if the symptoms Inhaled aztreonam, when compared to pla-
persist or they are more severe than expected, cebo in patients with moderate to severe disease
they should be treated as a bacterial exacerbation (FEV1 < 70%), also showed FEV1 improvement,
and include antibiotic therapy, considering the extended the time until the next exacerbation,
results of the last cultures. reduced hospitalization days, and improved qual-
ity of life. Nevertheless, in patients with mild dis-
Chronic Suppression Treatment ease (FEV1  >  70%), only a small improvement
The objective is to reduce bacterial load in the for FEV1 and quality of life was shown.
lung and in this way reduce toxins produced by European and US guidelines recommend
these bacteria, reducing inflammation and lung using tobramycin and aztreonam in patients with
damage. This objective reduces the worsening chronic infection caused by Pseudomonas aeru­
rate of pulmonary function as well as the fre- ginosa. The therapeutic effect is greater in those
quency of exacerbations. Several inhaled antibi- patients with moderate to severe disease, in com-
otics have proven to be efficient, achieving high parison to those who have preserved lung
sputum concentrations and minimizing systemic function.
toxicity. The drugs currently most used are tobra- A comparative study for inhaled tobramycin
mycin, aztreonam, and colistin; others are being and aztreonam confirmed the efficacy for this
developed, such as inhaled liposomal amikacin, treatment. Both have been studied during cycles
levofloxacine, vancomycin, and ciprofloxacine. including 28 days of use and 28 days of rest, and
Therapy has been investigated and focused on therefore many physicians have started to use
patients with chronic infection caused by both treatments in alternate months for patients
Pseudomonas aeruginosa, which is the most with severe disease to avoid worsening of the
common pathogen agent in the airway of older condition during the resting period. More studies
patients with CF. Mucoid presentation of this dis- are needed to determine the optimum approach to
ease is related to a faster reduction of lung func- start and continue the increasing inhaled antibi-
tion and a decreased survival rate. Inhaled therapy otic spectrum to improve lung function and
is considered standard care for these patients. A reducing secondary effects to a minimum.
Cochrane review showed a better lung function
(FEV1) and fewer exacerbations in the group Prophylactic Treatment
treated with inhaled antibiotics, and no hearing In the United Kingdom, anti-staphylococcal pro-
loss or kidney failure was found. At the moment phylactic antibiotics (flucloxacillin) currently are
there is no concluding evidence to support the indicated from the diagnosis to patients up to
use of regular IV or oral antibiotic treatments in 3 years old, which has caused a lower isolation
these patients. rate of Staphylococcus aureus. Nevertheless, the
The use of inhaled tobramycin for the treat- clinical importance of this finding is uncertain.
ment of moderate to severe lung disease The United States Cystic Fibrosis Foundation
(FEV1 < 70%) in children older than 6 years has does not recommend its use, as some studies have
shown to increase FEV1, reduce lung exacerba- shown that it can increase Pseudomonas aerugi­
tions, and improve the quality of life. In patients nosa colonization.
with mild disease (FEV1  >  70%), use has also
shown a significant reduction of exacerbations Emerging bacteria
(11% versus 25.6%), a discrete improvement of • Although methicillin-resistant Staphylococcus
pulmonary function, a reduction of days using aureus (MRSA) is an important emerging
antibiotics (17% versus 48%), and a reduction in pathogen in CF, there is no consensus for its
antibiotic courses (1.4% versus 2.8%). Since management. Children with persistent infec-
2013, tobramycin is also available as a dry pow- tion require more IV antibiotic cycles. Adults
462 F. Ratjen and M. E. Pizarro Gamboa

show a greater worsening of lung function, IV antibiotics. The treatment of an acute pul-
along with higher mortality rates. The results monary exacerbation caused by Stenotro­
of several nonrandomized studies suggest that phomonas maltophilia always includes two
it is possible to eradicate it, but the clinical antibiotics, oral or IV, according to the sensi-
impact would be uncertain. Different proto- tivity of the cultures. For the treatment of less
cols have been developed to eradicate the first serious pulmonary exacerbations, oral TMP-­
MRSA isolation without establishing a unique SMX, levofloxacin, and doxycycline can be
regime of treatment. Rifampicin with fusidic used.
acid and inhaled vancomycin have been suc-
cessfully used. The decision to treat this Nontuberculous mycobacteria (the most com-
chronic infection must be made in accordance mon ones are Mycobacterium avium and
with the clinical condition of the patient. Mycobacterium abscessus) are isolated in the
• Infection caused by the Burkholderia cepacia respiratory tract in about 5% to 20% of the
complex is associated with a worse prognosis. patients with CF.  In some cases, they are com-
It is inherently resistant to colomycin and is mensals and have no significant impact on the
frequently resistant to aminoglycosides and respiratory function or the nutritional state, but in
beta-lactamics. Further, a specific efflux pump other cases they cause lung disease, which
may cause resistance to quinolones, chloram- quickly reduces lung function and even causes
phenicol, and timethroprim. Multidrug resis- death. Of all the mycobacteria, Mycobacterium
tance is common in  vitro, and 50% of the abscessus is most probably related to important
bacteria are resistant to the ten most common lung disease, as well as being the most difficult to
antibiotics used in CF.  For patients with treat. Antibiotic choice depends on the species
chronic infections, trimethoprim/sulfa- that has been isolated. Generally, lung disease
methoxazole (TMP-SMX) or doxycycline are caused by Mycobacterium avium is treated with a
efficient in treating mild exacerbations, but for combination of a macrolide (clarithromycin or
more serious infections the treatment is azithromycin) and rifampicin or rifabutin and
meropenem in association with ceftazidime or ethambutol. Mycobacterium abscessus is more
chloramphenicol, or TMP-SMX IV, plus high resistant to antimicrobial agents, so the recom-
doses of inhaled tobramycin. Eradication is mendation is to use a combined therapy of clar-
possible in a few cases, and most of the time ithromycin, amikacin, and cefoxitin or imipenem.
the infections remain as a chronic condition. Antibiotic treatment of lung infections caused by
Treatment of exacerbations caused by the nontuberculous mycobacteria can potentially
Burkholderia cepacia complex may require improve lung function, reduce the frequency of
prolonged antibiotic therapy (weeks or lung exacerbations, and eradicate infections, but
months) before a clinical response can be there is no information about the efficacy of early
obtained. antibiotic treatment to eradicate nontuberculous
• Stenotrophomonas maltophilia is one of the mycobacteria or about antimicrobial chronic sup-
most common multiresistant organisms pressive treatment to avoid the worsening of lung
infecting patients with CF, and its prevalence function in patients with CF.  Recently, inhaled
is on the rise. It has been isolated in about 8% amikacin has shown promising results as a pos-
to 10% of CF patients in North America and sible maintenance therapy for patients with per-
about 4% to 30% in Europe. Risk factors for sistent infection.
its isolation in the respiratory tract are the use
of IV antibiotics and oral quinolones. It has
been recently shown that chronic infection Antiinflammatory Treatment
caused by Stenotrophomonas maltophilia
independently predicts acute lung exacerba- Cystic fibrosis is characterized by an intense neu-
tions associated to hospitalization and use of trophil inflammation, and lung destruction is the
45  Cystic Fibrosis: Treatment 463

result of the vicious cycle of infection and inflam- lial cell mediators in the airway, reducing the
mation. This inflammatory process happens early adhesion and migration of neutrophils, thus
in life, which is documented in a recent study that accelerating their apoptosis, reducing virulence
showed that 4-month-old infants presented with factors that increase the activity of Pseudomonas
inflammation. Besides this, the studies have dem- aeruginosa, such as the production of a mucus
onstrated that the inflammatory response can be biofilm, altering the conversion of nonmucoid
detected even in the airway of those patients who strain to mucoid and interrupting the method
present with a clinically mild disease. There is a through which bacteria interact with one another.
hypothesis that proposes that prolonged use of Modulation of chloride alternative channels has
antiinflammatory therapy may prevent progres- also been described, as well as effects in the pro-
sive lung damage and respiratory morbidity. The duction of nitric oxide and the increase of anti-
challenge is to achieve inflammation reduction oxidant activity. At the same time, azithromycin
without fettering the response of the host against achieves great tissue concentrations, long half-­
chronic infections. life, and can be used three times a week, which is
attractive for patients with CF.
Steroids Patient with chronic infection caused by
Oral steroids in doses of 1–2 mg/kg prednisolone Pseudomonas aeruginosa and treated with
on alternate days seem to slow lung disease pro- azithromycin for 6  months showed a consistent
gression in patients with CF who also present improvement in their FEV1 indexes, and they
with chronic infection caused by Pseudomonas were twice as likely to be free from lung exacer-
aeruginosa, but they should not be used because bation, besides showing a significant reduction in
of the high risk of related important adverse the use of oral antibiotics, with a greater increase
effects, such as glucose intolerance, alteration in in their weight.
growth, arterial hypertension, oral candidiasis, According to several studies, when treatment
and less frequently, cataracts and osteoporosis. is provided, pediatric patients not infected by
Short treatments have been used during acute Pseudomonas aeruginosa did not show an
exacerbations, according to the degree of airway improvement in lung function, but basal lung
obstruction, but a pilot study showed that this is function was normal for most of these patients,
not related to a better treatment response. and similarly, in patients infected with
Inhaled steroids (IS) are not related to these Pseudomonas aeruginosa, a reduction of more
adverse effects, but a sustained effect in relation- than 50% was observed in lung exacerbations, as
ship to the inflammation of the airway and lung well as a reduction in the inflammation markers.
function has not been proven. Approximately Adverse events were uncommon, and the
40% of patients with CF use IS although there is treatment was associated with a reduction of
no evidence supporting their use, and studies with Staphylococcus aureus in the cultures, along with
treatment interruption have not shown any change a significant increase of macrolides resistance.
in the clinical parameters for the patients who do The American Cystic Fibrosis Foundation rec-
not have asthma. It is necessary to confirm bron- ommends the chronic use of azithromycin for all
chial hyperreactivity (BHR) with a FEV1 increase patients older than 6  years, for those who have
of at least 12% after the use of a bronchodilator, or Pseudomonas aeruginosa as well as for those
a positive methacholine bronchial challenge test, who do not have Pseudomonas aeruginosa, to
to justify the treatment, which happens in about reduce exacerbations.
25–49% of patients with CF.
Ibuprofen
Azithromycin High doses of ibuprofen would reduce the influx
Different mechanisms have been proposed to of neutrophils to the airway, probably through a
explain the action of azithromycin in CF, such as mechanism mediated by LTB4. However, animal
the effect of expression and liberation of epithe- studies suggest that low serum levels of ibuprofen
464 F. Ratjen and M. E. Pizarro Gamboa

would increase neutrophil migration. Because effect in the lung function tests, whether for the
of this, it is key to maintain an ibuprofen con- long term or the short term.
centration between 50 and 100 mg/ml, for which Bronchodilators are widely indicated in CF
serum level control is needed. In a study in only for different reasons, including relief of symp-
one center, which considered children under toms caused by asthma, as a complement of
12 years old, high ibuprofen doses significantly respiratory physiotherapy to improve sputum
reduced the annual reduction rate of the pulmo- elimination, and before using nebulized therapies
nary flow according to FEV1, with forced vital (for example, tobramycin), to prevent symptoms
capacity (FVC) and forced expiratory flow such as bronchoconstriction, as well as allowing
between 25% and 75% (FEF 25–75%). It was a better deposit of the drug. Their use is recom-
also related to a reduction in the use of IV anti- mended before exercise and respiratory therapy.
biotics, improvement in chest X-rays, as well as
nutritional condition. No adverse effects were  xygen and Ventilation Support
O
reported, but the power of the study was too low Oxygen is used in patients with CF and advanced
to identify them, and significant gastric hemor- lung disease along chronic hypoxemia (Fig. 45.2)
rhage appeared in selected cases. A multi-cen- to relieve the symptoms of dyspnea and fatigue
tric study did not show improvement on FEV1, and to retard the appearance of cor pulmonale. If
but a tendency to improvement was observed in oxygen saturation is low during a lung exacerba-
FVC.  A further analysis of the study suggests tion, it is important to reevaluate the condition
that the treatment could positively affect the during a stable period, using pulse oximetry at
worsening of the lung function. Although some night, and if the saturation is still low (saturation
guides have recommended this treatment, its use <90%, >3% of the time), then night oxygen in the
is still uncommon. domicile should be considered. In these cases,
the morning CO2 must be controlled, as it can
increase with oxygen therapy.
Other Therapies Some recent studies have shown that noninva-
sive mechanical ventilation (NIMV) reduces
Bronchodilators
Approximately 25–40% of patients with CF have
bronchial hyperreactivity, which is defined by a
positive bronchodilator response. This phenotype
is not constant in time, and therefore it is impor-
tant to evaluate the patients in regular intervals.
β2-agonists have a direct effect in smooth muscle
relaxation and increase the frequency of ciliary
beat, but their effect in the reduction of the fluid
in the airways may reduce its potential benefit in
the patients with CF.
When compared to placebo, short-acting β2-­
agonists increase FEV1 in the short term and PEF
in the long term for patients who present with
bronchial hyperreactivity or respond to broncho-
dilators. For short-term results, when compared
to placebo, long-acting β2-agonists increase FEV1
and (FEF 25–75) in patients who have a positive Fig. 45.2  Severe lung disease. Chest X-ray of 14-year-­
old girl with CF presenting with dyspnea and chronic
response to the bronchodilator, but they yield hypoxemia. Air trapping can be observed along linear and
inconsistent results in long-term trials. A short-­ cyst images. Bilateral bronchiectasis, condensation, and
acting anticholinergic had no additional consistent bullae at the apex of the right lung
45  Cystic Fibrosis: Treatment 465

muscular fatigue and increases muscle perfor- causes 56% of deaths within the first 60  days,
mance, alveolar ventilation, and gas exchange. infections cause 40% of deaths during the first
NIMV has been used in CF as a treatment for year after the transplant, and finally, obliterative
hypercapnic respiratory failure, in night hypoven- bronchiolitis causes 67% of late deaths.
tilation, or as a bridge to lung transplant. It can
also be used as a complement to respiratory phys-
iotherapy and to ease exercise. Preferably it Treatment of Complications
should be used during sleep, because hypoventi-
lation tends to occur during REM sleep. Some Allergic Bronchopulmonary
patients experience a significant improvement in Aspergillosis (ABPA)
their quality of life, although the long-term effect ABPA is a type TH2 hypersensitivity response to
in relation to survival or sleep quality has not Aspergillus fumigatus that appears in 7–9% of
been thoroughly studied yet. the patients with CF.  ABPA is characterized by
acute or subacute clinical worsening that cannot
Lung Transplant be explained by other causes, along with serum
When therapy aimed at improving or maintaining IgE concentrations greater than 1000 IU/ml, pos-
pulmonary function fail, double-lung transplant itive skin prick test, specific antibodies for
becomes an option. Depending on the center and Aspergillus fumigatus, positive precipitins or IgG
the waiting times for the transplant, the indica- for Aspergillus fumigatus, and alterations in the
tions include short life expectancy (between 6 chest X-rays or CAT scan with no response to
and 24  months), FEV1  <  30%, relative to the regular therapy.
baseline condition, PaO2  <55  mmHg, or The treatment is aimed to control the acute
PaCO2  >50  mmHg, and lung hypertension. episode and avoid chronic worsening. Steroids
Contraindications will vary according to the cen- therapy quickly reduces eosinophilic infiltrates
ters: Some centers do not admit patients who are and the associated symptoms. The drug of choice
carriers of the Burkholderia cepacia complex, is prednisone, starting with 2  mg/kg/day for
whereas other centers have confirmed a survival 1  week, followed by 1  mg/kg/day for another
rate benefit, even for this high-risk population. week. After this, the dose is gradually reduced
During 2010, the International Society for until reaching a dose of 0.5  mg/kg/ in alternate
Heart and Lung Transplantation (ISHLT) reported days, which is maintained for 3 months. In this
that 26% of all lung transplant patients had period the patient must be closely monitored,
CF.  According to the information of the United checking the symptomatology, performing clini-
Network for Organ Sharing (UNOS), among the cal examinations, IgE levels, and chest X-rays;
pediatric transplants done during the period and if there is a relapse, the prednisone dose
2008–2009, graft failure rate was 3.4% at should be increased again.
6  months, 13.6% after a year, and 19.8% at Antifungal treatments, such as itraconazole,
3 years. For lung transplants performed during the should be considered as adjunct treatment for the
2006–2007 period, graft failure at 5  years was steroids therapy, helping reduce their dose.
51.4%, and for lung transplants done in the 2000– Omalizumab use may be considered as an
2001 period, graft failure at 10 years was 68.6%. adjunct, but there are not enough controlled and
It is important to recognize that even though randomized studies to ensure its security and
lung transplant improves the quality of life for efficacy.
most patients, complication rates are high, and
although the results have improved, they are still
below the success rate of other transplants. Sources
ISHLT reported the survival rate in all the recep-
Borowitz D, Robinson KA, Rosenfeld M, Davis SD,
tors of bilateral lung transplant from January Sabadosa KA, Spear SL, Michel SH, Parad RB, White
1994 until June 2012, the median of which was TB, Farrell PM, Marshall BC, Accurso FJ.  Cystic
7.5 years in the patients with CF. Graft rejection Fibrosis Foundation evidence-based guidelines for
466 F. Ratjen and M. E. Pizarro Gamboa

management of infants with cystic fibrosis. J Pediatr. Kerem E, Conway S, Elborn S, Heijerman H. Standards of
2009;155:S73–93. care for patients with cystic fibrosis: a European con-
Conway S, Balfour-Lynn IM, De Rijcke K, Drevinek P, sensus. J Cyst Fibros. 2005;4:7–26.
Foweraker J, Havermans T, et  al. European Cystic Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G,
Fibrosis Society Standards of Care: framework for the Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa
Cystic Fibrosis Centre. J Cyst Fibros. 2014;13(suppl K, Marshall B. Cystic fibrosis pulmonary guidelines,
1):S3–S22. chronic medications for maintenance of lung health.
Döring G, Flume P, Heijerman H, Elborn JS. Treatment of Am J Respir Crit Care Med. 2013;187(7):680–9.
lung infection in patients with cystic fibrosis: current O’Sullivan BP, Freedman SD.  Cystic fibrosis. Lancet.
and future strategies. J Cyst Fibros. 2012;11:461–79. 2009;373:1891–904.
Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp
Rosenblatt RL, Kuhn RJ, Marshall BC.  Cystic G, Heijerman HG, Robberecht E, Doring G. Nutrition
fibrosis pulmonary guidelines. Treatment of pul- in patients with cystic fibrosis: a European Consensus.
monary exacerbations. Am J Respir Crit Care Med. J Cyst Fibros. 2002;1:51–75.
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consensus. J Cyst Fibros. 2009;8:295–315. S43–59.
 Pulmonary Aspergillosis
46
Claudio Castaños, Verónica Aguerre,
and Verónica Giubergia

Contents
Epidemiology.................................................................................................................   467
Etiology and Physiopathology.....................................................................................   467
Invasive Pulmonary Aspergillosis................................................................................   468
Chronic Necrotizing Pulmonary Aspergillosis...........................................................   470
Aspergilloma.................................................................................................................   470
Allergic Bronchopulmonary Aspergillosis..................................................................   471
Allergic Bronchopulmonary Aspergillosis in Asthma...............................................   471
Allergic Bronchopulmonary Aspergillosis in CF.......................................................   472
Sources...........................................................................................................................   473

Epidemiology Etiology and Physiopathology

Clinical presentations are determined by the sus- Although more than 200 species of Aspergillus
ceptibility of the host. Immunocompromised have been identified, the most common pathogen
patients may present with saprophytic or invasive associated with respiratory disease is Aspergillus
aspergillosis. Immunocompetent patients tend to fumigatus (AF). Aspergillus niger, A. terreus, A.
present with hypersensitivity, and sometimes nidulans, and A. flavus have also been related to
saprophytic disease. Although these entities are pulmonary disease, but to a much lesser extent.
well defined, some patients present with charac- In most cases, Aspergillus enters the respiratory
teristics of more than one disease, and the disease system after the inhalation of spores as an opportu-
could progress from one presentation to another. nistic mycosis. The integrity of the host defense
mechanisms is important to prevent the disease. In
the lungs, alveolar macrophages are the first line of
C. Castaños (*) · V. Aguerre · V. Giubergia defense against the conidia. Toll receptors, dectin-1
Hospital Garrahan, Buenos Aires, Argentina
and mannose, bind to lectin, and participate in fun-
e-mail: [email protected];
[email protected]; gus identification and in the recruiting of neutro-
[email protected] phils that set the immune response in motion.

© Springer Nature Switzerland AG 2020 467

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_46
468 C. Castaños et al.

Inhalation of Af
spores

Immunocompetent host Immunocompromised host

No PCD With PDC

Asthma / CF Cavity Mild Mod / severe

No Chronic Invasive
ABPA Aspergilloma
consequences pulmonary pulmonary
aspergillosis aspergillosis

Af: Aspergillus fumigatus, PDC: Chronic pulmonary disease, CF: Cystic fibrosis, ABPA: Allergic pulmonary aspergillosis

Fig. 46.1  Clinical presentations of pulmonary aspergillosis. AF Aspergillus fumigatus, PDC chronic pulmonary dis-
ease, CF cystic fibrosis, ABPA allergic pulmonary aspergillosis

Clinical presentations include invasive pulmo- Aspergillus enters the lower respiratory tract
nary aspergillosis, chronic pulmonary aspergillo- through spore inhalation, and less frequently,
sis, and allergic pulmonary aspergillosis the infection can initiate in other locations,
(Fig. 46.1). such as the paranasal sinus, digestive tract, or
the skin. The most frequent presentation forms
of IPA include pulmonary and upper airway
Invasive Pulmonary Aspergillosis disease, both with a high mortality. Clinically,
its presentation is nonspecific: febrile syn-
The greatest risk factors for invasive pulmonary drome, productive cough, and dyspnea. Pleura
aspergillosis (IPA) in the pediatric population are pain may be present, as well as hemoptysis,
the presence of neutropenia, chronic steroids associated with vascular microthrombosis and
therapy, immunosuppression therapy, neoplastic small areas of pulmonary infarction. IPA is one
disease, and acquired immunodeficiency. Use of of the most common causes of hemoptysis in
chemotherapy and immunosuppressive agents neutropenic patients, and it may be associated
has increased the rate of aspergillosis during the with cavity appearance during neutrophil recov-
past decades. In a study examining the autopsies ery. From the radiological aspect, early findings
of immunocompromised patients between 1978 are also nonspecific, with rounded opacities
and 1992, the rate for invasive aspergillosis var- tending to appear, besides pleural base infiltra-
ied between 0.4% and 3%, with a rate increase tions that may suggest lung necrosis and cavi-
between 17% and 60% in the autopsies per- tated lesions.
formed during the past years. The mortality rate Hematogenic dissemination to other organs is
exceeds 50% for neutropenic patients, and it may possible, fundamentally to the central nervous
reach 90% in receptors of bone marrow system, developing meningitis, epidural abscess,
transplant. brain stroke, etc.
46  Pulmonary Aspergillosis 469

A significantly lower percentage of patients no pathognomonic signs may be present.

have presented tracheobronchitis caused by Multiples nodules, early presence of the halo sign
Aspergillus, which is the isolated invasion of the (area of attenuation secondary to hemorrhage sur-
tracheobronchial tract. Three presentations have rounding the nodule) and late presence of the
been described for this disease: obstructive, pseu- half-moon sign (hyperlucid area secondary to
domembranous, and ulcerative. necrosis in the original nodule region) are charac-
The diagnosis of IPA is based on the presence teristic and suggest the diagnosis (Fig. 46.2).
of risk factors, signs, symptomatology, chest Bronchoalveolar lavage (BAL) may be useful,
X-ray findings, histopathological findings, and although Aspergillus recovery percentages in the
the development of Aspergillus in the culture. fluid obtained are very variable. It can be used to
Its diagnosis is difficult in immunocompro- search for anti-Aspergillus antibodies and rule
mised patients. It is necessary to keep a high sus- out other infections.
picion index when working with higher-risk Recently, Aspergillus antigen detection tech-
groups. Definitive diagnosis is based on the histo- niques have been used, such as galactomannan in
pathological identification of hyphae invading body fluids. This antigen can be present days
the lung tissue, along with a positive culture for before the appearance of symptoms, signs, and
Aspergillus in the same site. Histopathological radiological alterations. Its main limitations are
findings and the type of local antiinflammatory its low positive predictive power and the possibil-
reaction will depend on the immunological con- ity of false positives and false negatives.
dition of the host. IPA is associated with high mortality rates.
The steps to follow after Aspergillus has been The treatment considers amphotericin B as first
isolated in the sputum will depend on the condi- line drug, which is associated to nephrotoxicity,
tion of the host. Generally, immunocompetent hydroelectric alterations, and hypersensitivity.
patients will present a colonization with no clini- New liposomal presentations of this drugs have
cal consequences, and thus antifungal therapy less secondary effects, with usually adequate
would not be indicated, but IPA should be ruled antifungal action. Voriconazole has been
out. In contrast, when Aspergillus has been iso- approved as first line drug for the treatment of
lated in immunocompromised patients, it has a IPA, and is associated to less adverse effects, thus
high positive predictive value for this infection. it is more tolerable. Generally, treatments must
Nevertheless, negative sputa do not rule out IPA. be indicated for prolonged periods, up to a year.
Early chest computed tomography (CT) helps Caspofungin, micafungin, and anidulafungin are
to have a prompt Aspergillosis diagnosis, although therapeutic options for patients with refractory

Fig. 46.2  Invasive pulmonary aspergillosis. Chest computed axial tomography of an immunosuppressed teenager pre-
senting with nodular subpleural lesions and halo sign (a) and half-moon sign with condensation (b)
470 C. Castaños et al.

IPA when the usual treatment has been used, or if posed of the hyphae of the fungus, inflammatory
the patient cannot tolerate it. cells, fibrin, mucus, and remaining tissue. Some
Surgical resection should be considered in the cavitating lung diseases such as tuberculosis,
cases of massive hemoptysis, lung lesions close sarcoidosis, bronchiectasis, bronchial cysts, and
to vital structures (great vessels, pericardium) or bullas may be complicated by aspergillomas.
residual lesions in patients who are still The fungal ball can move within the cavity, but it
immunosuppressed. does not invade the pulmonary parenchyma or
the blood.
In a study conducted on 544 patients with pul-
 hronic Necrotizing Pulmonary
C monary cavities secondary to tuberculosis, 11%
Aspergillosis had radiological evidence of aspergilloma.
Most of the patients are asymptomatic. When
Chronic necrotizing pulmonary aspergillosis is there are symptoms, most patients present
very infrequent, and there are only isolated cases hemoptysis. Less frequently, cough and dyspnea
or case reports for this type of presentation of the related to the underlying disease may also appear.
disease. Fever is secondary to the underlying disease, or
It has been mostly described in adults with alter- to bacterial overinfection. Poor prognosis risk
ations of local defense mechanisms associated with factors include the seriousness of the underlying
chronic pulmonary disease (chronic obstructive pulmonary disease, the increase in the size or the
pulmonary disease, sarcoidoisis, tuberculosis or number of the lesions, immunosuppression, the
radiotherapy history) or with systemic diseases that increase of IgG-specific antibody titers, and
cause mild degrees of immunosuppression (malnu- hemoptysis.
trition, connective tissue diseases, chronic liver dis- Diagnosis is made considering the clinical and
ease, alcoholism, liver failure, etc). radiographic characteristics showing a mobile
Clinically, it can have a certain degree of over- intracavity mass, located in a preexistent cavity
lapping with aspergilloma, and it is characterized with a peripheral half-moon space, with micro-
by the presence of general symptoms (fever, biological and serological evidence of Aspergillus
fatigue, weight loss), productive cough, and spp. Computerized axial tomography (CAT) con-
hemoptysis. Image studies evidence consolida- firms the findings. Sputum cultures for Aspergillus
tion, pleural enlargement, and cavitary lesions, spp. are positive only in 50% of the cases. IgG
which progress slowly. Sputum cultures tend to antibodies against Aspergillus are positive in
be positive for Aspergillus. The confirmation of most cases.
the diagnosis is done through the histopathologi- Treatment is considered only when the
cal findings of hifa in lung tissue and positive cul- patients present with symptoms, usually with
ture for the fungus. The treatment consists in the hemoptysis. There is no agreement about the
administration of antifungal agents such as itra- best treatment. Administration of percutaneous
conazole or voriconazole. The surgical option amphotericin B guided by chest CT seems to be
should be used only for completely localized efficient, especially in patients with massive
lesions in patients with good respiratory reserve hemoptysis. There is not enough knowledge
or if the therapy fails. about the use of IV amphotericin B. Itraconazole
has a high tissue penetration, and it may be use-
ful in some patients, showing improvements in
Aspergilloma 50% of cases. The role of voriconazole has not
been established.
Aspergilloma is the most common lung disease Surgical removal of the cavity with exeresis of
that usually takes place in a preexistent cavity of the fungal ball is indicated for patients with
the lung. An aspergilloma, or fungal ball, is com- recurrent hemoptysis.
46  Pulmonary Aspergillosis 471

Allergic Bronchopulmonary lung infiltrations and central bronchiectasis, that

Aspergillosis are not so useful as in asthma, because they are
commonly found as a consequence of the
This disease is caused by the hypersensitivity of disease.
AF antigens. Although this is the main pathogen Lung function tests do not yield characteristic
causing allergic bronchopulmonary aspergillosis results of ABPA, and show reversible obstructive
(ABPA), there may be other related pathogens lung disease, which becomes irreversible in the
involved. In most cases, it affects patients with advanced stages of the disease. Oral steroids are
asthma or cystic fibrosis. It has been estimated the main treatment, which will vary according to
that 2% of asthmatic patients, and around 7–14% the stage of the disease and if the patient suffers
of asthmatic patients who are steroid dependent, from asthma or CF.
have ABPA.  Incidence is greater in atopic
patients.
In the case of CF, it is variable in relation to Allergic Bronchopulmonary
different locations, but according to several Aspergillosis in Asthma
authors, around 1–5% of patients with CF may
develop ABPA at some point. The pathogenesis Sensitization of AF antigens occurs in 28% of
of ABPA is currently unknown. It has been pro- patients with asthma, but ABPA is found in 2% of
posed that inhaled spores are trapped in the asthma patients, 7–14% of steroid-dependent
mucus of the large airway. The spores may ger- asthma patients, and 33% of severe asthma
minate when they develop hyphae, which release patients. Sensitization to AF antigens may cause
antigens and cause the immune response. The severe obstruction of the air flow and therefore
hypersensitivity reaction they cause is character- greater use of oral steroids.
ized by IgG and IgE production, as well as spe- The criteria for the diagnosis of ABPA in
cific antibodies for AF. This reaction, combined patients with asthma have been standardized, as
with the production of cytotoxic metabolites, shown in Table 46.1.
such as AF proteolytic enzymes, cause a local Clinical evolution is divided into five stages,
immunosuppression reaction, phagocytosis inhi- which do not necessarily appear in order. The
bition, and flaking of epithelium cells. As a first four are potentially reversible, with no long-­
whole, this reaction causes AF colonization and term sequelae.
allows for its persistence in the airway, with lung
infiltrations, tissue damage, and finally lung tis- • Stage I or acute phase. Increased IgE, positive
sue destruction. antibodies, eosinophilia, lung infiltrations,
ABPA tends to be clinically suspected, and it and AF IgE and IgG. Patients are rarely identi-
is confirmed through serum tests and chest X-ray. fied in this stage.
Most patients present with episodic wheezing,
sputum expectorations, dark blockages, dyspnea,
pleural chest pain, fever, and sometimes hemop- Table 46.1  Diagnosis criteria for ABPA in asthma
tysis that do not respond to the usual therapy. Classic Minimal criteria
Chest X-ray can be normal during the first Positive specific skin test Immediate skin reactivity
stages of the disease. During exacerbations, brief for AF (prick test) to AF antigens
central lung infiltrations appear in the superior Serum precipitins for AF Total IgE 1000 UI/ml
Increase of AF-specific IgE Increase of AF-specific
lobes, along with atelectasis. In subsequent stages
and IgG IgE and IgG
of the disease, central bronchiectasis and lung 1000 UI/ ml for total IgE Central bronchiectasis
fibrosis may appear. Chest CT images can show Current or previous
bronchiectasis in more than three lobes, centri- pulmonary infiltrations
lobular nodules, and mucoid impaction, which all Central bronchiectasis
suggest this diagnosis. In CF, chest CT may show Eosinophilia (1000 cells/ml)
472 C. Castaños et al.

• Stage II or remission. IgE may decrease, but it shows a frequency of 7.8%, with great variances
is usually maintained at high levels; there is no between countries. Its development is not related
eosinophilia, and chest X-ray is normal. AF to any CFTR genotype in particular.
IgG antibodies may be slightly increased. The diagnosis of ABPA in patients who suffer
• Stage III or exacerbation. The findings of from CF may be difficult, and is mainly based on
phase I are repeated in patients with ABPA immunological evidence, because the lung infil-
diagnosis. IgE doubles from the reference trations and central bronchiectasis that appear in
level. the chest CT are usually found in patients with
• Stage IV or steroid dependency. It appears in CF.  The United States Foundation for Cystic
patients who suffer from asthma, requiring Fibrosis proposed the minimum criteria shown in
steroids in high doses. The asthmatic condi- Table 46.2.
tion is worsened, and X-ray changes can be In imaging, ABPA cannot be differentiated
appreciated, with IgE increase. Frequently, from the underlying disease. Chest CT shows
chest CT shows central bronchiectasis. infiltrations or bronchiectasis that may not appear
• Stage V. In this stage the disease is irreversible in the chest X-ray. ABPA bronchiectasis is cen-
because of lung fibrosis and bronchiectasis. tral, and if there is CF, may be peripheral or cen-
Dyspnea, cyanosis, rhonchus, and cor pulmo- tral, which makes its diagnosis impossible to
nale may be observed. Fortunately, few differentiate. Varicose and cystic bronchiectasis
patients progress to this condition. are more associated with ABPA than with CF.
Worsening of lung function is more acute in
Oral steroids are the principal treatment. The those patients with CF and ABPA, and therefore
treatment varies according to the stage of the dis- early diagnosis and treatment are very important
ease. For stage I, oral steroids are indicated for to prevent severe, and potentially irreversible,
2  weeks (0.5–2  mg/kg oral prednisone; maxi- lung damage.
mum, 60 mg/day). After the symptoms remit, the Treatment of ABPA in patients with CF is
oral steroid may be reduced and suspended. For similar to that proposed for ABPA patients with
the stage II condition, use 0.5–2 mg/kg/day, alter- asthma. Patients with CF present particular
nating the days, during 1–2 weeks, and it can be ­characteristics, such as vulnerability and toxicity
suspended in 2–3  months. Treatment with itra- to steroids, altered pharmacokinetics, and a dif-
conazole is indicated for relapses (stage III) or if ferent interaction with the drug. Steroids are the
the patient suffers from steroid-dependent asthma drug of choice for the treatment of ABPA in the
(stage IV). patient with CF, at the doses recommended for
Although inhaled steroids control asthma asthma. They may be used orally or parenterally
symptoms, their effectivity in the treatment of
ABPA has not been confirmed. Table 46.2  Diagnosis criteria for ABPA when the patient
Serum IgE is a marker of the activity of the has cystic fibrosis (CF)a
disease, and it must be reassessed 6–8  weeks Acute or subacute clinical worsening of the condition,
after the start of the therapy, and then every which cannot be explained by other causes or
exacerbation.
8 weeks during a year, until the IgE values return
Total IgE > 500 UI/ml (ABPA suspicion, IgE between
to normal levels. 200 and 500 UI/ml if the patient receives steroids. In
this case, IgE must be repeated every 1–3 months, or
when steroids are suspended).
Allergic Bronchopulmonary AF-specific skin test (prick test over 3 mm).
AF-specific IgE increase.
Aspergillosis in CF
New or recent abnormalities in chest X-ray
(infiltrations, mucus blockages) or CAT scan
The prevalence of ABPA in CF varies between (bronchiectasis) that do not improve or disappear with
0% and 25%, in part because of differences in antibiotics.
diagnosis criteria. The European CF Registry According to the US Cystic Fibrosis Foundation
a
46  Pulmonary Aspergillosis 473

(with fewer adverse effects): methylprednisolone Greenberger PA, Patterson R.  Diagnosis and manage-
ment of allergic bronchopulmonary aspergillosis. Ann
in pulses of 10–15 mg/kg/day for 3 days. No ben- Allergy. 1986;56:444–8.
efits have been shown with the use of inhaled Herbrecht R, Denning DW, Patterson TF, et  al.
steroids. Voriconazole versus amphotericin B for primary
Itraconazole (5  mg/kg/day; maximum dose, therapy of invasive aspergillosis. N Engl J Med.
2002;347:408–15.
400 mg/day, using dose in blood) is used in com- Horger M, Hebart H, Einsele H, et al. Initial CT manifes-
bination with steroids. Recently, oral voricon- tations of invasive pulmonary aspergillosis in 45 non-
azole has been used, which has the same activity HIV immunocompromised patients: association with
against AF with better absorption. patient outcome? Eur J Radiol. 2005;55:437–44.
Horvath JA, Dummer S. The use of respiratory-tract cul-
Treatment time is variable: it may require tures in the diagnosis of invasive pulmonary aspergil-
6–12 months. IgE serum levels are used to evalu- losis. Am J Med. 1996;100:171–8.
ate treatment response. When these values return Kotloff RM, Ahya VN, Crawford SW.  Pulmonary com-
to normal levels, treatment may be suspended. plications of solid organ and hematopoietic stem
cell transplantation. Am J Respir Crit Care Med.
2004;170:22–48.
Kousha M, Tadi R, Soubani A.  Pulmonary aspergillo-
Sources sis: a clinical review. Eur Respir Rev. 2011;20(121):
156–74.
Agarwal R, Aggarwal AN, Gupta D, et  al. Aspergillus Mastella G, Rainisio M, Harms HK, et al. On behalf of the
hypersensitivity and allergic bronchopulmonary investigators of the Epidemiologic Registry of Cystic
aspergillosis in patients with bronchial asthma: sys- Fibrosis. Allergic bronchopulmonary aspergillosis in
tematic review and meta-analysis. Int J Tuberc Lung cystic fibrosis. A European epidemiological study. Eur
Dis. 2009;13:936–44. Respir J. 2000;16:464–71.
Albelda SM, Talbot GH, Gerson SL, et  al. Pulmonary Moss R. Allergic bronchopulmonary aspergillosis, chap-
cavitation and massive hemoptysis in invasive pulmo- ter 28. In: Taussig L, Landau L, editor. Pediatric respi-
nary aspergillosis. Influence of bone marrow recovery ratory medicine. 2nd ed: Mosby; 2008.
in patients with acute leukemia. Am Rev Respir Dis. Moss R.  Allergic bronchopulmonary aspergillosis and
1985;131:115–20. Aspergillus infection in cystic fibrosis. Curr Opin
Burgos A, Zaoutis TE, Dvorak CC, et  al. Pediatric Pulmon Med. 2010;16:598–603.
invasive aspergillosis: a multicenter retrospective Patterson K, Strek ME.  Allergic bronchopulmonary
analysis of 139 contemporary cases. Pediatrics. aspergillosis. Proc Am Thorac Soc. 2010;7:237–44.
2008;121(5):e1286–94. Pfeiffer CD, Fine JP, Safdar N.  Diagnosis of invasive
Curtis AM, Smith GJ, Ravin CE. Air crescent sign of inva- aspergillosis using a galactomannan assay: a meta-­
sive aspergillosis. Radiology. 1979;133:17–21. analysis. Clin Infect Dis. 2006;42:1417–27.
De Pauw B, Walsh TJ, Donnelly JP, et  al. Revised defi- Segal BH, Walsh TJ. Current approaches to diagnosis and
nitions of invasive fungal disease from the European treatment of invasive aspergillosis. Am J Respir Crit
Organization for Research and Treatment of Cancer/ Care Med. 2006;173:707–17.
invasive fungal infections cooperative group and the Spanakis EK, Aperis G, Mylonakis E, et al. New agents for
National Institute of Allergy and Infectious Diseases the treatment of fungal infections: clinical efficacy and
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group. Clin Infect Dis. 2008;46:1813–21.
 Post-Infectious Bronchiolitis
Obliterans
47
Alejandro Colom, Gilberto Fischer,
and Alejandro Teper

Contents
Prevalence......................................................................................................................   475
Pathology.......................................................................................................................   476
Etiology..........................................................................................................................   476
Clinical Findings...........................................................................................................   478
Diagnosis........................................................................................................................   478
 adiological Clinical Score (BO Score) ........................................................................  480
R
Evolution and Prognosis..............................................................................................   481
Treatment......................................................................................................................   482
Sources...........................................................................................................................   482

Prevalence 1979. During the past decades, different coun-

tries have reported cases, particularly Chile,
Interest in BO increased with the publication Brazil, Korea, Turkey, and Argentina
of the first cases related to serious respiratory (Fig. 47.1). In Europe and in the United States
infection caused by adenovirus in Argentina in of America, most cases are secondary to bone
marrow and pulmonary transplants, but the
A. Colom (*) Southern Cone of South America the cases are
Pediatric Pulmonology, Hospital Ricardo Gutiérrez, mostly secondary to infections, especially
Buenos Aires, Argentina those caused by adenovirus (Table  47.1).
G. Fischer There are no epidemiological studies deter-
Pediatric Pulmonology, Federal University of Health mining the prevalence of this disease in the
Sciences of Porto Alegre,
population. Published data allow us to infer a
Porto Alegre, Brazil
e-mail: [email protected] higher prevalence of post-infectious bronchi-
olitis obliterans (PIBO) in Chile, Brazil, and
A. Teper
Faculty of Medicine, Universidad de Buenos Aires Argentina.
and Division of Pediatric Pulmonology, Hospital
Ricardo Gutiérrez, Buenos Aires, Argentina

© Springer Nature Switzerland AG 2020 475

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_47
 476 A. Colom et al.

350 corresponds to proliferative BO, characterized by

315 the obstruction of the space in the small airway
300
by polyps caused by granulation tissue. If the
granulation tissue extends toward the alveoli, the
250
lesion is named BO with organizing pneumonia
N of patients reported

200
(BOOP). The second category is constrictive BO,
which is characterized by peribronchiolar fibro-
150 sis, with different degrees of narrowing of the
bronchial lumen.
100 Post-infectious BO is mainly characterized by
72 a constrictive BO pattern, with different degrees
50 41 39 of inflammation and obliteration of the airway. In
these patients the signs of airway disease are fre-
0 quent, such as bronchiolar inflammation,
mucostasis, macrophage accumulation, and
sia
rica

pe
a
eric

ro

ia/A
me

bronchiolar distortion and dilation. Bronchiolar

Eu
Am

ean
in A

dilations are more frequent in patients with post-­

rth

Oc
Lat

No

infectious BO, in comparison to other causes.

Fig. 47.1 Frequency of post-infectious bronchiolitis Histological analysis is limited by the multifocal
obliterans (PIBO) nature of the disease.

Table 47.1  Causes of bronchiolitis obliterans (BO)

Etiology
Transplant Graft versus host after bone marrow
transplant
Chronic rejection after lung transplant Different respiratory viruses, such as influenza,
Infections Virus Adenovirus: 3, 5, 7h, 21 parainfluenza, respiratory syncytial virus (RSV),
Influenza and especially adenovirus, have been associated
Parainfluenza with BO.  Other infectious etiologies include
Measles Mycoplasma pneumoniae, measles virus, and
Mycoplasma
human immunodeficiency virus-1. Also, in lung
Other Collagen disease
Toxic inhalation (NH3, NO2) transplant patients, infection caused by cytomeg-
Mineral dust alovirus was associated with the development of
Drugs BO bronchiolitis.
Aspiration
Steven–Johnson syndrome Adenovirus  In 2006 a case-control study con-
ducted in Buenos Aires was published that
included 109 patients with bronchiolitis who
Pathology developed BO and 99 control patients, patients
with bronchiolitis who did not progress to
Bronchiolitis obliterans (BO) is characterized by BO. Risk factors for developing BO were ade-
the partial or total occlusion of the terminal respi- novirus infection (OR 49) and the need for
ratory bronchiole space, caused by inflammatory mechanical ventilatory assistance (OR 11).
tissue and fibrosis. Pathological findings in their Although mechanical ventilatory assistance
different etiologies suggest that it would be the was an independent risk factor, the results did
final process of response to different aggressions not identify if ventilatory support was by itself
to the lower respiratory tract. the cause of the injury or if it was only an indi-
From the pathological aspect, BO may be cator of the seriousness of the disease. The
classified in two main categories. The first one main role of the infection caused by adenovirus
47  Post-Infectious Bronchiolitis Obliterans 477

in the development of BO was widely docu- Patients with a serious infection caused by
mented. In our study, 72% of the patients who adenovirus present with immune complex in the
developed BO presented with adenovirus infec- lung containing adenovirus antigens, as well as
tion. In 1984 a new adenovirus genotype, 7h, high levels of interleukin (IL)-6, IL-8, and tumor
was described as one of the most virulent types, necrosis factor (TNF)-α serum.
but other adenovirus such as serotypes 3, 5, and Susceptibility to developing BO seems to be
21 can also cause BO. related to the geographic origin of human groups.
The populations of native children in New
Adenovirus 7h is responsible for 20% of all Zealand, Canada, Alaska, and South America
the infections caused by this agent, according to have a greater incidence of post-infectious BO
publications issued by the World Health when compared to the populations of Europe and
Organization (WHO). In the Southern other regions of America. Recent studies con-
Hemisphere the incidence of the B subgene ade- ducted in Argentina in patients with this disease
novirus and serotypes 4 and 7 is greater. show that the HLA haplotype DR8-DQB1∗0302,
Epidemiological studies between 1991 and and native aborigines, determined by the mtDNA
1994  in children hospitalized for lower acute markers, are increased in relationship to control
respiratory infection in Argentina, Chile, and groups.
Uruguay identified that 71% of the infections Although the studies are limited, the innate
caused by adenovirus where of the B subgene, immunological response would have a prepon-
and 61.2% of them corresponded to the 7h derant role in the seriousness of the adenovirus
genome. infection and the development of BO in predis-
Other studies have shown that the global posed populations.
prevalence of adenovirus genotypes changes in
relationship to time and geographic region, Mycoplasma pneumoniae  Infection caused by
which makes it difficult to develop a vaccine Mycoplasma pneumoniae is a frequent cause of
with global effectiveness. In Argentina, during atypical pneumonia in older children. It was
the past decade, a reduction of serious and fatal identified as an etiology of BO in 1986, although
cases caused by this virus has been observed, its development in patients with Mycoplasma
which could be explained by a reduction of infections is a rare complication. In other areas,
genotype 7 incidence, besides an increase of such as Malaysia and Korea, it is the second most
genotype 3. A reduction of infections caused by common etiological agent for BO, after adenovi-
adenovirus has also been observed since 2004, rus infection. In these countries, infection by
perhaps because of an interference of infections Mycoplasma was present in 20% of the patients
caused by rhinovirus or the A H1N1 influenza with BO, most of these secondary to Mycoplasma
pandemic in 2009. epidemic outbreaks.
Three different types of epidemics are caused
by adenovirus: Influenza  Up to 20% of influenza patients
develop complications, particularly small chil-
1. Epidemics during the winter months among dren (0–4 years old). In spite of this, BO is a rare
hospitalized infants (generally under 2  years complication of influenza infection, and few
old), which cause a high rate of serious infec- cases in infants and small children have been
tions and death. published.
2. Nonseasonal periodic epidemic outbreaks,

community-driven, which compromise older Measles virus  BO is an infrequent complication
children and adults, but cause few and infre- of measles. Viral load and the initial immunologi-
quent respiratory sequelae. cal condition, as well as the virus persistence in
3. Epidemic outbreaks of acute respiratory dis- the lung parenchyma, probably determine chronic
eases among military recruits. lung damage.
478 A. Colom et al.

Respiratory syncytial virus  This virus circula- oxygen saturation is reduced. Some patients with
tion has an epidemic pattern during winter months, nosocomial pneumonia caused by adenovirus
and it is the most common cause of lower respira- with an important respiratory compromise pres-
tory tract infection. Association between BO and ent a similar progression, requiring long hospital-
respiratory syncytial virus is rare and it is not izations and intensive care.
clearly defined. Simultaneous infection of syncy-
tial virus and adenovirus can happen. In these
cases, it seems more likely that the development of Diagnosis
BO is caused by the adenovirus infection.
The objective of diagnosis methods is to show the
obliteration of the small airway, which is an
Clinical Findings anatomopathological lesion of this disease.
Because of this, lung biopsy yields the best
In most cases, the disease starts very early, before results. Lung function tests can show severe and
the first year of life. However, age has not been fixed obstruction. Indirect signs of the disease
confirmed as a risk factor for developing post-­ can appear in the lung images.
infectious BO. Chest X-ray images are not specific: air trap-
Initially patients start showing symptoms that ping, atelectasis, peribronchial enlargement, and
are not different from those of a regular viral bron- areas with a honeycomb appearance (Fig. 47.2).
chiolitis caused by syncytial virus. Most patients Some patients present unilateral compromise in
present serious bronchospasm, with hypoxemia, one lobe/lung with an area with hyperclarity in a
and in many cases they need mechanical ventila- smaller lobe/lung, known as Swyer–James or
tion. Physical examination is not specific. MacLeod syndrome. These images result from
Wheezing and rhonchus can be heard bilaterally. If the loss of vascular structure and air trapping.
a patient with an adenovirus infection does not Occasionally these findings may be observed as
improve in 3 weeks, BO should be suspected. the only image in patients with a less serious pre-
After the clinical condition of the patient sentation of the disease.
becomes stable, tachypnea persists, wheezing Lung grammagraphy shows perfusion defects,
and productive cough become permanent, and with a subsegmental, segmental, or lobar pattern.

Fig. 47.2  Post-infectious bronchiolitis obliterans (PIBO). Chest X-ray of a 7-year-old schoolchild shows air trapping,
atelectasis, and bronchiectasis
47  Post-Infectious Bronchiolitis Obliterans 479

When comparing pulmonary perfusion with the bent position may be useful to identify air trap-
chest X-ray, gammagraphy findings correspond ping in patients who show a reduction mosaic
to the most affected areas, with bronchial enlarge- pattern.
ment and bronchiectasis. This technique of pul- Lung function in infants with post-infec-
monary perfusion may not describe the nature of tious BO was described in 1999 and studied at
the bronchopulmonary anomaly, but it does show first using the technique of fast thoracoabdomi-
an objective evaluation of the extension, distribu- nal compression. In these patients, respiratory
tion, and seriousness of the lesion. Its usefulness mechanics is altered, with an increase of resis-
for diagnosing BO is not relevant. tance and severe alterations of pulmonary elas-
The most characteristic sign of BO in high-­ tic retraction. In the curves of forced partial
resolution computerized tomography (HRCT) volume flows it can be observed that the maxi-
is areas showing a mosaic pattern, caused by mum flow at functional residual capacity (V′max
air trapping and vascular shunt from the FRC) is very reduced and it does not respond
hypoventilated areas toward normal or over- to bronchodilator administration. Because
ventilated areas. Perfusion is impoverished in V′max FRC is an index used to evaluate the cali-
reduction areas of the parenchyma because of ber of the airway, we may conclude that the
the vasoconstriction caused by tissue hypoxia patients with PIBO have an important compro-
(Fig.  47.3). Other signs include air trapping, mise of the pulmonary function, which mani-
especially observed during exhalation, and fests itself as a severe and fixed obstruction of
bronchiectasis. Air trapping can be detected the airway. These patients have a more serious
during exhalation in the HRCT.  This study compromise of the small airway in comparison
method is considered as the most sensitive and to other diseases, such as bronchopulmonary
early step when BO is suspected, as was dysplasia or asthma, which in many cases
described for the first time in relation to a respond to bronchodilators. These findings
transplant, and which has an important role in represent the functional expression of the his-
the initial diagnostic suspicion. In small topathological damage of BO bronchiolitis
patients who do not cooperate, a lateral recum- (Fig. 47.4).

Fig. 47.3  PIBO. Chest computerized tomography of a 14-year-old adolescent shows mosaic pattern areas, atelectasis,
and bronchiectasis
480 A. Colom et al.

Fig. 47.4 Lung 320

function. A forced
partial volume/flow
curve, with severe V’maxFRC: 24% of
obstruction of the air theoretical value
flow expressed in
reduction of the
maximum flow level of
the residual functional 160
capacity (V’max FRC:
24% of theoretical
value) in a 11-month
infant with BO caused
by adenovirus

80 160
0
0

-160

Another factor related to BO that may cause Radiological Clinical Score (BO Score)
deterioration in lung function is gastroesophageal
reflux, which is frequent in these patients (54%). The diagnostic criteria of posttransplant BO have
Currently, there are no studies of its prevalence in been clearly defined, but they have not been as
patients with BO. well defined as for post-infectious BO. Definitive
To summarize, when other causes of chronic diagnosis of BO is done by lung biopsy, although
pulmonary disease have been ruled out, clinical conducting it on these patients is related to high
history, chest X-ray, and HRCT are sufficient in morbidity and mortality, especially in very seri-
most cases to confirm the diagnosis and differen- ously ill patients. Lung function has great value
tiate this disease from others. This evaluation because of its characteristic pattern, but this is not
should be considered along with pulmonary available for most pediatric pneumonologists.
function. If there are doubts about the diagnosis, A study was developed with the objective to
a lung biopsy must be considered. accurately establish diagnostic criteria for post-­
Lung biopsy is the gold standard for the diag- infectious BO in children under 2  years of age
nosis of BO. The main difficulty of its application with chronic lung disease. In this study, a scale
is the clinical condition of the patient. During the was created and validated, wherein specificity is
diagnosis stage, most of the patients are seriously favored over sensitivity to make it more reliable
compromised, and therefore the decision to con- in positive cases, and 125 patients under 2 years
duct an open lung biopsy is difficult, because of old with chronic lung disease were evaluated.
the associated morbidity and mortality rates. The The following variables were significantly asso-
output of this procedure is limited by the patchy ciated with the diagnosis:
distribution of lung damage. Because of this, lung
biopsy is only done for those patients about whom • “Typical clinical history” (4 points), defined as
there are still doubts about the diagnosis after hav- previously healthy patient, with a serious epi-
ing done all the aforementioned procedures. sode of bronchiolitis/pneumonia developing
47  Post-Infectious Bronchiolitis Obliterans 481

chronic hypoxemia (sat O2  <  92%) for more are frequent and are caused by lower respiratory
than 60 days; tract airway infections. The number of hospital-
• “History of infection caused by adenovirus” izations and the oxygen requirements progres-
(3 points); “HRCT with mosaic pattern” (4 sively decrease during the years in which the
points) (Table 47.2). disease progresses. Lung function does not
change significantly during the first years of age.
A score of 7 or greater predicts the diagnosis From the systematic follow-up of the pulmo-
of post-infectious BO with a high degree of accu- nary function in children and young people
racy (100% specificity and 67% sensitivity). It between 5 and 21  years old, we could observe
must be highlighted that a negative score (<7) that FVC and FEV1 increase by 11% and 9% per
does not completely rule out the diagnosis of BO, year, respectively, and the relationship FVC/
as only very sick patients have been included. FEV1 decreases 1.9% per year (Fig.  47.5). The
fact that FVC increases more than FEV1 could be
explained by a differentiated growth of the lung
Evolution and Prognosis parenchyma and respiratory airways, indicating
an asymmetrical growth of the lung. In other
Clinical evolution of the patients with post-­ words, this recovery of pulmonary growth and
infectious BO is characterized by a slow and airways after the initial lesion could be possible
gradual improvement. Most patients require sup- in terms of the number of alveoli, called neo-­
plementary oxygen. In our series, the median alveolarization. This lung growth could be not so
duration of this treatment was 5 months (range, important in relation to the size of the airway.
2–26 months) after discharge. Hospitalizations Besides this, although lung function increased in
absolute values, the Z score of FVC and FEV1
Table 47.2  Radiological clinical score were reduced in 0.07 and 0.09 Z score/year,
Value respectively, showing that the degree of lung
Predictor variable Present Absent development is slower than that of the general
Typical clinical history 4 0 population of the same age (Fig. 47.5).
Infection by adenovirus 3 0 In the same way that the values of spirometry
HRCT with mosaic pattern 4 0 parameters increase, plethysmography studies
Range of score is from 0 to 11 show a reduction of the air trapping (residual

Fig. 47.5  Progression of pulmonary function. Follow-up of pulmonary function (FVC/FEV1) in 46 patients with BO
between 6 and 21 years of age. (Source: Thorax 2015;70:169)
482 A. Colom et al.

volume decreases). Respiratory mechanics mea- When the disease is established, the main
sured with forced oscillation technique show a treatment consists of support measures, which
low distensibility and an increased resistance. include bronchodilators, respiratory physiother-
In most patients, perfusion defects observed at apy, antibiotics for acute respiratory infections,
the beginning of the disease persist, and some- and diuretics. Gastroesophageal reflux has been
times they improve. increasingly recognized as a factor that may sig-
Cardiopulmonary assessment during exercise nificantly contribute to patient morbidity, and
shows reduced functional capacity, which has therefore treatment is mandatory.
been confirmed by cardiac stress test, or by the Some patients develop chest deformity, which
6-min walking test, a simpler test to perform. consists of an asymmetrical keel chest, and the
Although lung function remains severely most severe cases require surgical correction.
compromised, presenting from intense to moder- These abnormalities would be the result of a com-
ate airway obstruction, during childhood only a bination of bone demineralization and chronic air
few patients require supplementary oxygen. The trapping. It is plausible that these deformities in
clinical improvement observed in these patients the chest wall may be clinically harmful because
may be caused by lung growth, and it probably is of interference with respiratory mechanics.
not a sign of small airway pathology recession. In patients with localized bronchiectasis that
The mortality rate of post-infectious BO is not cannot be adequately controlled with clinical treat-
known with certainty, and it varies according to ment, a lobectomy may be done to improve their
the different series published, according to the quality of life. The indication to perform a chest sur-
different grade of impact in the condition of the gery in these patients must be carefully considered,
included patients. because complications such as infections, pneumo-
The individual prognosis of a certain patient thorax, and bronchial fistulas are common.
may be related to different factors, such as time Although the evolution of these patients is
requiring oxygen and the severity of the airway almost always satisfactory, lung transplant is the
reinfections. last therapeutic option for those patients whose
life prognosis is serious.

Treatment

Therapeutic interventions aiming to avoid initial Sources

damage are based on the suppression of the
inflammatory response. Anti-inflammatory Andrade CF, Melo IA, Holand AR, Silva ÉF, Fischer GB,
Felicetii JC. Surgical treatment of non-cystic fibrosis
treatments, such as steroids, chloroquine, and
­ bronchiectasis in Brazilian children. Pediatr Surg Int.
hydroxychloroquine, have been used in studies 2014;30(1):63–9.
involving a few cases with unsuccessful results. Castro-Rodriguez J, Daszenies C, Garcia M, Meyer
Because BO is an infrequent disease, it has not R, Gonzales R.  Adenovirus pneumonia in infants
and factors for developing bronchiolitis obliterans:
been possible to conduct controlled and random- a 5-year follow-up. Pediatr Pulmonol. 2006;41:
ized studies. 947–53.
Different cytokines have been identified in the Chang A, Masel J, Masters B. Post-infectious bronchiol-
pathogenesis of post-infectious BO, TNF-α and itis obliterans: clinical, radiological and pulmonary
function sequelae. Pediatr Radiol. 1998;28:23.
fibroblast production among them. A successful Colom AJ, Andrada G, Teper A. Development of a clinical
treatment case of BO after bone marrow transplant prediction rule to diagnose post-infectious bronchiol-
was published. The treatment involved a TNF-α itis obliterans in children. Am J Respir Crit Care Med.
blocker (infliximab) for an 8-year-old child. 2008;177:A703.
Colom AJ, Maffey A, Garcia Bournissen F, Teper A.
Other studies suggest that a maintenance treat- Pulmonary function of a pediatric cohort of patients
ment with macrolides has a potential role, with postinfectious bronchiolitis obliterans. A long
because of its antiinflammatory properties. term follow up. Thorax. 2015;70:169.
47  Post-Infectious Bronchiolitis Obliterans 483

Colom AJ, Teper AM, Vollmer WM, Diette GB. Risk fac- con bronquiolitis obliterante por adenovirus. Rev Chil
tors for the development of bronchiolitis obliterans in Enferm Respir. 2011;27:191–5.
children with bronchiolitis. Thorax. 2006;61:503–6. Teper A, Colom A, Bailliet G, et al. Association between
Fischer GB, Sarria EE et  al. Post infectious bronchi- the incidence of bronchiolitis obliterans (BO) in
olitis obliterans in children. Paediatr Respir Rev. Argentine children and their native-American mater-
2010;11(4):233–9. nal and paternal lineage. Am J Respir Crit Care Med.
Gerhardt S, McDyer J, Girgis R, et  al. Maintenance 2003;167:998.
azithromycin therapy for bronchiolitis obliterans syn- Teper AM, Kofman CD, Maffey AF, et al. Lung function
drome. Results of a pilot study. Am J Respir Crit Care in infants with chronic pulmonary disease after severe
Med. 2003;168:121–5. adenoviral illness. J Pediatr. 1999;134:730–3.
Linares PM, Meyer PR, Soto GG. Evaluación de la respu- Teper AM, Marcos CY, Theiler G, Colom AJ, Fainboim
esta broncodilatadora en pacientes secuelados de ade- L.  Association between HLA and the incidence of
novirus. Rev Chil Pediatr. 2004;5:37–44. bronchiolitis obliterans (BO) in Argentina. Am J
Maffey A, Colom A, Kofman C, Vidaurreta S, Teper Respir Crit Care Med. 2004;169:382 (abstract).
A. Longitudinal study of pulmonary function in infants Vega-Briceño L, Zenteno D et al. Guía clínica para el di-
with postviral chronic pulmonary disease (PCPD). Am agnóstico y cuidado de niños/adolescentes con bron-
J Respir Crit Care Med. 1996;153:498. quiolitis obliterante post-infecciosa, 2009. Rev Chil
Mattiello R, Sarria EE, Stein R, Fischer GB, Mocelin Enferm Respir. 2009;25:141–63.
HT, Barreto SS, Lima JA, Brandenburg D. Functional Yalçına E, Dogrua D, Haliloglub M, et al. Postinfectious
capacity assessment in children and adolescents with bronchiolitis obliterans in children: clinical and radio-
post-infectious bronchiolitis obliterans. J Pediatr. logical profile and prognostic factors. Respiration.
2008;84(4):337–43. 2003;70:371–5.
Nayar E, Saavedra M, Escobar AM, Vidal A.  Función
pulmonar y calidad de vida en niños y adolescentes
 Obstructive Sleep Apnea
Syndrome in Children
48
Asher Tal, Pablo Brockmann Veloso,
and Aviv Goldbart

Contents
Introduction..................................................................................................................   486
Epidemiology.................................................................................................................   486
Physiopathology............................................................................................................   486
Physiopathological Consequences..................................................................................  487
Clinical Presentation....................................................................................................   488
 ighttime Symptoms......................................................................................................  488
N
Daytime Symptoms........................................................................................................  489
Extrapulmonary Clinical Manifestations........................................................................  489
Growth............................................................................................................................  489
Cardiovascular Manifestations.......................................................................................  490
Development and Neurocognitive Symptoms................................................................  490
OSAS in Children with Craniofacial Dysmorphology...................................................  490
Obesity and OSAS..........................................................................................................  491
OSAS and Asthma..........................................................................................................  491
OSAS and Inflammation.................................................................................................  491
Diagnosis........................................................................................................................   492
 aboratory Exams..........................................................................................................  492
L
Stages..............................................................................................................................  493
Treatment......................................................................................................................   493
 edical Treatment..........................................................................................................  493
M
Surgical Treatment..........................................................................................................  493
CPAP...............................................................................................................................  494
Oxygen...........................................................................................................................  494
Sources...........................................................................................................................   494

A. Tal · A. Goldbart
Ben Gurion University of Negev, Beersheba, Israel
e-mail: [email protected]; [email protected]
P. Brockmann Veloso (*)
Department of Pediatrics, School of Medicine,
Pontificia Universidad Católica de Chile,
Santiago, Chile
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 485

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_48
486 A. Tal et al.

Introduction region to region, and the prevalence is higher in

Afro-American and Hispanic populations. Multiple
The spectrum of sleep-disordered breathing (SDB) risk factors affect the prevalence of SDB, and the
ranges from primary snoring to obstructive sleep sociodemographic factor is an important one.
apnea syndrome (OSAS). Primary snoring appears These factors are more frequent in children of
during sleep and is associated with a greater respi- lower socioeconomic status, premature, and obese.
ratory effort, but it does not evidently present The prevalence of OSAS linearly varies according
micro-awakenings or alterations in the gas to the body mass index of the patients studied, and
exchange. The upper airway resistance syndrome it was present in about 60% of morbidly obese
is characterized by brief and intermittent awaken- patients. In Chile, studies have shown an SDB
ings associated with respiratory events during prevalence of 18% in the pediatric population.
sleep, with no apneas or alterations in gas exchange.
OSAS is characterized by a partial or complete
obstruction of the airway that alters ventilation and Physiopathology
causes a disruption in normal sleep architecture,
with alterations in gas exchange (Fig. 48.1). To understand the physiopathology and mecha-
Physiopathological mechanisms associated nisms involved in OSAS, it is important to con-
with the described consequences of SDB are fun- sider the following principles:
damentally sleep disruption, intermittent night
hypoxemia, and chronic inflammation of the • Ventilation control that regulates upper airway
airway. tone and awakening response; both physiolog-
ically decrease during sleep.
• Residual functional capacity decreases and
Epidemiology may cause hypoxemia and apnea, which is
caused by a reduction of the intercostal mus-
The prevalence of sleep-disordered breathing cular and upper airway tone, especially during
(SDB) is estimated to be about 10–20%, and OSAS REM sleep.
prevalence is estimated to be about 1% in children • The tone of the upper airway tract is reduced
under 15 years old. These numbers fluctuate from during sleep and causes an increase of its

Fig. 48.1  Polysomnography in severe obstructive sleep Desaturations (in green) can be observed toward the end
apnea syndrome (OSAS). Lines represent 60  s of sleep of the obstructive events
N2. Two obstructive events are shown (in red).
48  Obstructive Sleep Apnea Syndrome in Children 487

resistance, which at the same time may impact trol subjects. The explanations for this can lie in
ventilation and gas exchange. a reduced distensibility or a greater resistance.
• Progressively, and as a result of the aforemen- Studies that have involved the denervated upper
tioned phenomena, hypoxemia and hypercar- airway have shown that lack of muscle tone may
bia will be present during sleep. This cause a greater collapse. It was recently proven
physiological phenomenon worsens if it coex- that children have active upper airway responses
ists with any other lung or airway disease. to both negative pressures and hypercapnia dur-
ing sleep. Healthy children could compensate the
Besides this, children with OSAS tend to have small size of the airway by increasing ventilatory
an airway with reduced space. They generally command. This compensation mechanism could
present with a narrowing of the airway related to be reduced or absent in children with this
intermittent hypercarbia and hypoxia. The site of syndrome.
greater obstruction tends to be more distal than in To summarize, a combination of the structure
adults, usually including the oropharynx and of the airway with neuromuscular control, besides
hypopharynx. Children with this symptom have other genetic, hormonal, and metabolic factors,
inspiratory aphasic activity in the muscles of the cause the appearance of OSAS in children.
upper tract of the airway during sleep.
Infants and children normally have a narrower
airway than adults. Nevertheless, they usually Physiopathological Consequences
snore less and show fewer obstructive apneas in
comparison to adults, which could be explained Increase of respiratory work  This increase
by anatomical differences and also by a different could be a factor that causes poor growth in chil-
muscular tone of the upper airway. Critical pres- dren with OSAS. As a result of the greater diag-
sure reflects the balance between the anatomical nosis and consciousness about this syndrome,
structure and the muscle tone of the airway; how- most children are detected before they can pres-
ever, it is very difficult to determine a critical ent any lack in their growth, and currently it is
pressure in children as the airway is very resistant very infrequent.
to collapse, probably because children have a
greater ventilatory drive. Because of this, it is Intermittent hypoxemia  Children with OSAS
possible that children have greater activation of tend to present (Fig.  48.2) with intermittent
the muscles of the upper airway when responding hypoxemia that can contribute to the increase of
to different stimuli. lung pressure and the development of cor pulmo-
The upper airway in children with OSAS is nale in advanced stages. Nevertheless, the most
more collapsible in comparison to control chil- frequent consequence, and probably the one that
dren without this syndrome, for both awake or causes most sequelae in this syndrome, is neuro-
sleep and anesthesia periods. A series of mecha- cognitive and behavior problems. The relation-
nisms may create a greater degree of collapsibil- ship between the duration of hypoxemia and the
ity in these patients, among which we can degree of desaturation versus secondary cogni-
mention lower muscle tone, increase of airway tive damage is still unknown.
distensibility, and increase in the inspiratory
pressure, caused by the narrowing of the proxi- Sleep fragmentation  Sleep fragmentation is a
mal airway. well-documented consequence of OSAS in
A recent study used magnetic resonance imag- adults, but it is not yet fully understood in chil-
ing to evaluate the changes in the shape and size dren. Although micro-awakenings have a protec-
of the sectional area in the airway during breath- tive role in this syndrome, their increase in
ing at tidal volume. In this study, it was shown frequency can cause a disruptive sleep instead of
that children with this syndrome have greater a reparative one. Sympathetic activation, as well
fluctuations in the airway when compared to con- as the activation of secondary inflammation
488 A. Tal et al.

Fig. 48.2  Hypnogram in severe OSAS.  Record of 4  h in a 1-year-old patient showing frequent obstructive events
(in red) and cluster desaturations (in green)

mediators, has similar or even worse conse- Table 48.1  Symptoms Related to OSAS in Children
quences than intermittent hypoxemia. The identi- Daytime
fication of micro-awakenings in adults is based  Behavioral problems
on ECG interpretation. In contrast, in children  Hyperactivity
more variables have to be considered, as most  Belligerence
micro-awakenings are subcortical and are not  Poor school performance
 Lack of appetite
necessarily observable through ECG.
 Daytime sleepiness
 Poor concentration
Alveolar hypoventilation  Associated with Nighttime
OSAS, alveolar hypoventilation is the result of  Snoring
long periods of upper airway increased resistance  Respiratory distress
and hypercapnia, with or without hypoxemia. In  Apnea as reported by parents or caregivers
the end, this causes long-term effects in the neu-  Nonrestful sleep
 Frequent awakenings
ral tissue and vasomotor tone. CO2 increase is the
 Night sweats
main characteristic of this condition.  Night enuresis

Clinical Presentation specific symptom of OSAS.  Every child who

usually snores is a primary snorer, although the
Nighttime Symptoms child may not present apnea, hypopnea, or oxy-
gen desaturation during sleep. Most children
Snoring  Snoring is the most characteristic with primary snoring do not progress to this
symptom of OSAS in children (Table  48.1). syndrome, and those who do, usually have a
Generally, this condition worsens when children mild presentation of it. Nevertheless, some
have an upper airway infection. Compared to recent studies have shown behavioral and neu-
adults, small children can snore in any position, rocognitive ­consequences, even when there are
and it does not necessarily worsen with the no polysomnography alterations to suggest this
supine position. Common snoring is not per se a syndrome.
48  Obstructive Sleep Apnea Syndrome in Children 489

Respiratory distress during sleep  Such dis- Daytime Symptoms

tress is a subjective manifestation usually
informed by the parents of children with In many children with OSAS, symptoms may
OSAS. Usually, they describe paradoxical respi- be the result of sleep disruption that involves an
ratory movements in which “the abdomen low- alteration during the day. In contrast with
ers, while the chest rises.” adults, in which day sleepiness is characteristic,
children present this symptom with less fre-
Apneas  Parents frequently describe breathing quency. Attentional deficit and clear hyperac-
stops during sleep, and some of them mention tivity may be present. Also, these diseases have
that respiratory noises stop for a few seconds, been associated with poor school performance.
which are followed by a “grunt” or energic Children with adenotonsillar hypertrophy may
breathing. present as well with mouth breathing, recurrent
These three cardinal symptoms are the most respiratory infections, and language problems.
consistent ones in children with this syndrome. Morning headaches are infrequent in children
At the beginning of the 1980s, Brouillete et  al. with OSA.
used these to create the “OSA Score.” This score
states that those children who snore every night
had sleep respiratory distress, and those whose Extrapulmonary Clinical
parents have witnessed apneas would have Manifestations
OSAS.  Although the predictive positive value
was acceptable (50–75%), this was not true for Children with OSAS are frequent users of health
the predictive negative value (25–80%). services. They present recurrent respiratory
infections such as pharyngitis, otitis, and
Nonrestful sleep  Unrestful sleep is the conse- ­bronchitis in greater frequency than in control
quence of repeated micro-awakenings during subjects. After surgery for tonsils and adenoids,
sleep. Parents usually describe a child who moves visits to health services are significantly reduced.
and has diverse postures during sleep, sometimes
with the head in hyperextension.
Growth
Frequent awakening  Such awakenings are a
commonly reported clinical situation. At first, Growth failure and delay are classic conse-
parents may believe that this is related to behav- quences described during decades in OSAS. The
ior, hunger, or thirst during sleep. main causes related to these consequences are
these:
Night sweats  Night sweats are the result of
respiratory distress during sleep and micro-­ 1 . Low caloric intake: Children with tonsillar
awakenings and movements. It can be observed hypertrophy lack appetite and have dyspha-
in an important number of children affected. gia, which causes a low caloric intake.
2. Increase of energy expenditure because of the
Enuresis  Enuresis has been reported in 8–47% respiratory work increase during sleep.
of children with OSAS. A recent study has shown 3. Growth hormone (GH) secretion is altered in
that two thirds of the children with this syndrome children with OSAS.  Insulin growth factor
have primary enuresis, and one third of them type-1 (IGF-1) is reduced in these children.
have secondary enuresis. The risk of presenting After tonsils and adenoid surgery it is com-
with enuresis is greater in all children with SBD, mon to observe weight gain and the reestab-
even when do not suffer from this syndrome. lishment of normal GH and IGF-1 values.
490 A. Tal et al.

Cardiovascular Manifestations consequences of OSAS. An extremely high prev-

alence of this syndrome was reported in first-­
Lung hypertension is one of the most common degree students in a study conducted in the
causes of cardiovascular complications in chil- United States. Besides this, an important
dren. The first cases described in the literature in improvement of school performance could be
the 1960s show how nasopharyngeal obstruction confirmed after adenotonsillectomy. A recent ret-
caused cardiomegaly, cor pulmonale, and severe rospective study suggests that children who fre-
lung edema. Currently, a reduction in the fre- quently snore have a greater risk of developing
quency of these complications has been observed. neurocognitive problems, which do not seem to
Diagnosis is done through an echography, where be completely reversible. In our center, a study
the degree of tricuspid failure can be estimated, has shown an improvement in neurocognitive
as well as a ventricular failure. alterations in long-term follow-up of children
Systemic arterial hypertension is also a fre- between 5 and 9  years old after adenotonsillec-
quent complication in children with OSAS, and it tomy, showing results which could be compared
should be timely diagnosed. According to some to those of children who do not snore.
reports, diastolic tensional numbers during sleep It is likely that both intermittent hypoxemia as
persist during wakefulness hours in these chil- well as the disruption in sleep architecture have a
dren. A recently studied group of children showed role in the pathogeny and neurocognitive conse-
changes in the left ventricular wall, besides an quences associated with this syndrome in chil-
increase in the afterload. Arrhythmias have also dren. Studies in adults could show a correlation
been observed in these children. between blood gases and neurocognitive perfor-
mance. The degree of night hypoxemia has been
positively related to the seriousness of the conse-
Development and Neurocognitive quences in attention measurement tests, problem-­
Symptoms solving tests, and short-term memory tests.
Deficits in executive functions have generally
Concentration problems, hyperactivity, and been associated with problems in the prefrontal
learning difficulties have been consistently docu- cortex of patients with this syndrome. In some
mented in children with OSAS.  Even from the cases, these alterations would persist despite the
first reports from the nineteenth century, attention treatment.
and neurocognitive problems have been related
to this syndrome.
There is solid evidence supporting the associa-  SAS in Children with Craniofacial
O
tion between OSAS, respiratory sleep disorders, Dysmorphology
even primary snoring, with attentional deficit with
hyperactivity in children. Although we currently Adenotonsillar growth is the main risk factor for
have this evidence, it is not possible to attribute the appearance of OSAS in children. Other risk
syndrome causality in this association. Children factors are obesity, family predisposition, race,
with this syndrome present symptoms suggesting and prematurity. Nevertheless, there are patients
attentional deficit, without having all the criteria with genetic syndromes that have constantly been
for attentional deficit with hyperactivity. associated to OSAS.  These syndromes include
Although daytime sleepiness is more common those related to micrognathia and midface
in children, it has been estimated that many chil- hypoplasia.
dren with hyperactivity or attention problems
will afterward develop some degree of Pierre Robin sequence  Consists in the triad of
sleepiness. micrognathia, tongue placed further back than
Learning problems and poor school perfor- normal, and cleft palate; it is frequently associ-
mance are considered as one of the most severe ated to SBD. It usually appears early during life,
48  Obstructive Sleep Apnea Syndrome in Children 491

even in newborns. Infants may develop reflux or including tongue, pharynx, trachea, and bronchi.
stridor related to this condition. Treatment Usually, adenotonsillectomy is not useful, and it
includes jaw distraction, intraoral devices, and may require CPAP or even tracheotomy in
eventually continuous positive airway pressure selected cases.
(CPAP).

Obesity and OSAS
Treacher Collins syndrome  Caused by muta-
tions in chromosome 5 (5q32-32.2), which codi- Obesity in children significantly increases the
fies a treacle protein, this syndrome causes jaw risk to develop OSAS. Its persistence after ade-
hypoplasia, malar hypoplasia, antimongoloid notonsillectomy is significantly greater in obese
palpebral fissure, and characteristic fascia. children in comparison to their non-obese peers.
Coloboma and ocular alterations may also be Besides this, there are certain distinct physio-
present. pathological mechanisms in this syndrome asso-
ciated to obesity. Considering these differences, a
Among other causes of midface hypoplasia classification was created: OSAS type I refers to
we can mention the Crouzon, Apert, and Pfeiffer children with adenotonsillar hypertrophy who are
syndrome. In these children, the worsening of not obese, and OSAS type II refers to obese chil-
OSAS can be invariably observed in different dren without adenoid and/or amygdale
degrees as they grow up. hypertrophy.
Achondroplasia is another strongly related
condition to OSAS. It is characterized by a domi-
nant skeletal dysplasia, which frequently causes OSAS and Asthma
obstruction but also central apneas. Up to two
thirds of the patients will required noninvasive Asthma and OSAS share several epidemiological
ventilation as treatment. risks. Further, patients with asthma tend to have a
Children with Down syndrome will usually greater development risk in comparison to those
present with OSAS because of their hypotonia, a patients who do not have asthma. It seems that
smaller size of craniofacial structures, and a asthma and OSAS involve a common inflamma-
smaller nose. Also, it has been possible to tory and physiopathological mechanism. One of
observe an increase in adenotonsillar tissue in the modifiable asthma risk factors in children is
patients with Down syndrome, easing the appear- precisely SBD.  OSAS treatment is related to a
ance of OSAS. stabilization and eventual symptomatic improve-
Arnold Chiari-type malformations may be ment in children with asthma.
associated with a greater risk to suffering from
this symptom, because of the compression of the
brainstem. Nevertheless, respiratory drive com- OSAS and Inflammation
promise, as well as compromise of the nuclei of
the cranial nerves, can cause the appearance of Some recent studies show that both children and
central apneas. adults with OSAS present local and systemic
Children with Prader–Willi syndrome, con- inflammation. Inflammatory changes found show
sisting of hypotonia, obesity, hypogonadism, an activation of different inflammatory paths,
and some degree of cognitive impairment, may such as lipoxygenase, which is involved in other
very frequently present with OSAS, and there- inflammatory conditions in children and adults,
fore they should be considered at risk. At the such as allergic asthma and rhinitis. In children
same time, all patients with mucopolysacchari- with OSAS, an increase in  local and systemic
dosis will present with a narrowing of the airway leukotrienes has been observed. An increase in
caused by the deposit of mucopolysaccharides, C-reactive protein in the blood level in children
492 A. Tal et al.

with OSAS is probably the best evidence of sys- which is clinically determined by the occupying
temic inflammation. It has been possible to cor- space in the oropharynx inspection. Tonsils that
relate the levels of C-reactive protein in these occupy about 25% or less of the pharyngeal space
patients to the indexes of apnea, hypopnea, desat- are defined as grade 1, <50%, grade 2, <75%,
urations, and micro-awakenings. Several other grade 3, and those that touch in the medial line
inflammatory markers have been studied in chil- are grade 4 (kissing tonsils).
dren with OSAS: interleukin-6, interferon-­
gamma, interleukin (IL-8), tumor necrosis factor
(TNF)-α, and fibrinogen. It is difficult to differ- Laboratory Exams
entiate between the inflammatory mechanisms
that cause a sleep respiratory disorder and those Night polysomnography is considered the gold
which are secondary to this disease. Therefore, it standard to diagnose OSAS in children.
is not clear if inflammation is the cause or the Nevertheless, other tools and exams can be used
effect of OSAS.  The importance of identifying for screening.
OSAS-related inflammatory mechanisms lies in Lateral neck X-ray could indicate adenoidal
the possibility of using antiinflammatory medica- hypertrophy. Direct visualization is only possible
tion as treatment. through nasoendoscopy, which is much more
reliable than X-rays. Electrocardiogram and
echocardiography may show signs of ­hypertrophy
Diagnosis in the right cavities, and even lung hypertension
in advanced stages of the disease. The use of
The first step to diagnose OSAS is the identifica- video or audio recordings in the patient’s home
tion of high-risk children; for example, those has been suggested as a diagnosis option with a
with craniofacial malformations, neuromuscular good positive predictive value (>90%), but with a
weakness, and genetic conditions. In healthy poor negative predictive value (<30%). Night
children it should be suspected if there is snoring, pulse oximetry is another simple way to detect
movements during sleep, awakenings, night serious presentations of OSAS. Unfortunately, it
sweats, and enuresis. Other symptoms to con- is not an acceptable tool, because of its poor neg-
sider are behavioral problems, school or perfor- ative predictive value (<50%). These observa-
mance problems, hyperactivity, and concentration tions have been confirmed in adults with
problems. It must be clear that clinical history by OSAS. Besides this, because most events happen
itself is insufficient to diagnose OSAS, and it is during REM sleep, abbreviated polysomnogra-
not possible to differentiate primary snoring phy or nap studies are no longer recommended.
using only the interview. Night polysomnography done in a sleep labo-
Recent recommendations of the American ratory is considered the gold standard to diag-
Academy of Sleep Medicine include directly ask- nose OSAS in children. Nevertheless, the precise
ing about snoring in every well-child care visit. sensitivity and specificity of polysomnography
The first stage of physical examination is obser- have not been stablished with certainty. The rec-
vation to recognize alterations such as microgna- ommendation of the American Academy of
thia, Pierre Robin sequence, or craniofacial Sleep Medicine is to conduct polysomnography
dysmorphisms. Genetic diseases, such as Down in children who snore for whom a diagnosis has
syndrome, are known risk factors to develop not been made for clinical or observational rea-
OSAS.  In healthy children, body mass index sons. Polysomnography is very useful to deter-
must be calculated, because obesity has been mine the degree of OSAS severity based on an
associated to a greater OSAS prevalence. index. Polysomnography includes electroen-
Characteristic adenoid facia and mouth breathing cephalography channels to study micro-awaken-
are present in many children with OSAS.  It is ings and phases of sleep. It also includes
important to observe and define tonsillar size, electro-­ oculography, electrocardiography, chin
48  Obstructive Sleep Apnea Syndrome in Children 493

and leg movement electromyography, nasal flow, tions versus placebo. In a noncontrolled study
chest and abdominal movements, ETCO2, snor- our group could even confirm an improvement
ing, and body position. In very selected cases, in children with mild OSAS.  A randomized,
pHmetry, intraesophageal pressure, and video controlled, double-­ blind study conducted by
recording can be used. Goldbart et al. showed that a 12-week treatment
Polysomnography studies in children are done with daily montelukast reduces OSAS severity
in sleep laboratories, especially adapted and with and tonsils size. By comparing 23 patients
qualified staff to read the studies in these chil- treated with daily montelukast to 23 untreated
dren. The use of drugs or sedatives to induce patients, a reduction in the size of the adenoids,
sleep is not recommended. and improvement in the symptoms, as well as in
several polysomnography indexes, could be
observed. The hypopnea–apnea index was
Stages reduced by more than 50% in 65.2% of the chil-
dren treated. Besides this, its use in children
Wakefulness/sleep and sleep stages can be with moderate to severe OSAS requires more
divided according to the recommendations of evidence before it may be recommended.
Rechtschaffen and Kales in 1968. In 2007 a
change was made in the new guidelines of the
American Academy of Sleep Medicine. Micro-­ Surgical Treatment
awakenings should be evaluated with the consen-
sus recommendation of the American Academy Because adenotonsillar hypertrophy is the most
of Sleep Medicine. To summarize, they define frequent and important cause of the OSAS in
awakenings as a wakefulness time of more than children, adenotonsillectomy is proposed as the
15  s in the electroencephalogram. Micro-­ first-line treatment for this disease.
awakenings and awakenings index is calculated Adenotonsillectomy is a very common proce-
as the number of these events per sleep hour. dure with a very low rate of complications, but a
Obstructive apneas and hypopneas should be possible rate of morbidity and mortality should
identified according to the consensus of the be considered. Adenotonsillectomy must be as
American Academy of Sleep Medicine. The objective as possible, ideally with a previous
hypopnea–apnea index is calculated considering diagnostic polysomnography. Risk factors for the
all the respiratory events corresponding to apnea development of complications after surgery in
or hypopnea divided by the hours of sleep. children with OSAS are age under 3 years, severe
Average SpO2 should also be recorded in the OSAS, cor pulmonale, growth alteration, morbid
polysomnography record. Desaturation index is obesity, neuromuscular diseases, prematurity,
calculated as the number of desaturation events and craniofacial alterations.
with 4 or more percentage points per hour of Most children with OSAS improve in symp-
sleep. The consolidated time the child spent tomatology after surgery; thus, their indexes of
under 90% of SpO2 is also added to the report. hypopnea apnea, night hypoxemia, and micro-­
awakenings are reduced. Studies comparing pre-
and post-adenotonsillectomy conditions in
Treatment children with OSAS have shown an improvement
in the right ventricular function, increase in
Medical Treatment growth factors, improvement in life quality and
behavior, reduction of general morbidity, and less
Medications for OSAS include using of intrana- need of health services.
sal steroids and leukotriene receptor antago- A recent multicenter, randomized study com-
nists. Improvement has been consistently pared adenotonsillectomy with a follow-up obser-
confirmed in the parameters of polysomnogra- vation in children with OSAS.  Investigators
phy for those patients who use these medica- included 464 children, from 5 to 9 years old, to
494 A. Tal et al.

one of the two aforementioned treatments. well tolerated in children and even in infants
Polysomnography and neurocognitive test series with obstructive sleep apneas. The treatment
were evaluated at baseline and 7 months after that. should be long term. It is recommended to do a
A significant improvement in symptoms was con- titer measurement with a polysomnography to
firmed, but there were no important differences in evaluate the pressure range at which the respi-
relation to neurocognitive testing of either group. ratory events, such as apneas and hypopneas,
A detailed analysis showed that more than 50% of disappear.
non-obese children and more than 50% of
non-Afro-American children in the control group
(only receiving follow-up without surgery) would Oxygen
not be within the normal values for polysomnog-
raphy. It has been concluded that medical treat- There are cases in which oxygen can be used as a
ment and very close follow-up may be an option transition treatment toward a definitive one, but
for those patients with a milder form of OSAS. in general its use is not routinely recommended
Also, those children who present symptoms for children with obstructive sleep apnea.
and have a hypopnea index greater than 5.0
should be considered candidates for surgery. In
these cases, the suggestion is to conduct a poly- Sources
somnography evaluation, besides analyzing the
clinical symptoms and consequences the patients American Academy of Pediatrics. Section on Pediatric
Pulmonology, Subcommittee on Obstructive sleep
are presenting. A multidisciplinary team, com- apnea: Clinical practice guideline: diagnosis and man-
posed of sleep expert physicians, otorhinolaryn- agement of childhood obstructive sleep apnea syn-
gologists, maxillofacial specialists, and drome. Pediatrics. 2002;109:704–12.
respiratory physicians, would be of great help. American Thoracic Society. Standards and indications
for cardiopulmonary sleep studies in children. Am J
The surgery to perform is still under debate. Respir Crit Care Med. 1996;153:866–78.
Tonsils and adenoids extirpation is suggested, but Chervin RD, Ruzicka DL, Archbold KH, Dillon J.
it should be discussed in randomized future stud- Snoring predicts hyperactivity four years later. Sleep.
ies. Particularly, the group of smaller children 2005;28:885–90.
Friedman BC, Hendeles-Amitai A, Kozminzki E,
and infants should be studied to find the best Leiberman A, Friger M, Tarasiuk A, Tal A.
treatment possible. Adenotonsillectomy improves neurocognitive func-
Uvulopalatopharyngoplasty, diversions, tongue tion in children with obstructive sleep apnea syn-
surgeries, osteotomy, and hyoid suspensions drome. Sleep. 2003;26:999–1005.
Goldbart A, Greenberg-Dotan S, Tal A.  Montelukast
should be considered only for exceptional cases for children with obstructive sleep apnea: a
of children with OSAS, and not as a first-­line double-­ blind, placebo-controlled study. Pediatrics.
treatment. In some rare cases, usually related to 2012;130:e575–80.
an underlying disease, tracheotomy is required. Gozal D.  Sleep-disordered breathing and school perfor-
mance in children. Pediatrics. 1998;102:616–20.
Marcus CL, Moore RH, Rosen CL, the Childhood
Adenotonsillectomy Trial (CHAT). A randomized
trial of adenotonsillectomy for childhood sleep apnea.
CPAP N Engl J Med. 2013;368:2366–76.
Marcus CL, Omlin KJ, Basinski DJ, Bailey SL, Rachel
Continuous positive airway pressure (CPAP) in AB, Von Pechman WS, Keens TG, Ward SL. Normal
children without adenotonsillar hypertrophy polysomnogram values for children and adolescents.
Am Rev Respir Dis. 1992;146:1235–9.
and with severe sleep obstructive apneas has Tal A, Bar A, Leiberman A, Tarasiuk A.  Sleep char-
been seldom used. In high-risk groups such as acteristics following adenotonsillectomy in chil-
children with Down syndrome, morbid obesity, dren with obstructive sleep apnea syndrome. Chest.
and neuromuscular defects, CPAP is a very 2003;124:948–53.
Tarasiuk A, Simon T, Tal A, Reuveni H.
effective therapy, and it is an option to adeno- Adenotonsillectomy in children with obstructive
tonsillar surgery, which in these cases may fail. sleep apnea syndrome reduces health care utilization.
The use of nasal CPAP is generally safe and Pediatrics. 2004;113:351–6.
 Sudden Infant Death Syndrome
49
María Angélica Oyarzún
and Pablo Brockmann Veloso

Contents
Introduction..................................................................................................................   495
Epidemiology.................................................................................................................   496
Etiology..........................................................................................................................   496
Risk Factors and Clinical Presentation......................................................................   496
Prevention and Approach............................................................................................   499
Conclusions...................................................................................................................   500
Sources...........................................................................................................................   500

Introduction Its diagnosis involves ruling out other possible

death causes, and it forces the physician to
Sudden infant death syndrome (SIDS) is the main exhaust all other probable diseases involved in
cause of death in children under 1  year old in this type of events, justifying the implementation
developed countries. It is defined as such when a of strict investigation protocols, as well as ruling
child dies before the first year of life and, after an out differential diagnosis. Detailed necropsies are
exhaustive physical examination, laboratory also needed.
exams, autopsy, and inspection of the place where During past decades, countries in the
the infant dies, it is not possible to state a definite Northern Hemisphere have started prevention
cause of death. campaigns that have demonstrated an important
reduction in the mortality caused by this syn-
M. A. Oyarzún (*) drome. One of them is the campaign “back to
Pontificia Universidad Católica de Chile, sleep,” in European countries and in North
Santiago, Chile America, recommending that parents place their
P. Brockmann Veloso children in dorsal supine position when sleep-
Department of Pediatrics, School of Medicine, ing. With this intervention, a great reduction of
Pontificia Universidad Católica de Chile,
Santiago, Chile the number of cases of sudden death has been
e-mail: [email protected] observed in this group.

© Springer Nature Switzerland AG 2020 495

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_49
496 M. A. Oyarzún and P. Brockmann Veloso

Epidemiology related to prone positions, co-sleeping, and using

soft surfaces/cushions for sleeping.
SIDS incidence varies. Some series conducted in
the United States of America show an approxi-
mate frequency of 0.5/1000 live births: It is more Etiology
common in black children and less common in
Hispanic children. In South America, specifically For years, multiple studies have approached
in Argentina, a review showed an incidence of sudden death, which has increased the knowl-
0.49 every 1000 live births, and in a more edge about related factors. Nevertheless, its eti-
restricted group in the South of Brazil, a rate of ology is still not clear. SIDS is a multifactorial
0.55 every 1000 live births was observed. polygenic condition, whose main factors are
A recently published Chilean study identified genetic, environmental, and sociocultural. The
1442 cases reported as sudden deaths between “triple risk model” proposed by Wedgwood in
1997 and 2009, with a rate of 0.45 every 1000 1972, and supported by studies conducted after-
live births. This rate was similar to the average wards by Kahn et al., explains this phenomenon
of developed countries during the 1990s, before according to three factors: (1) inherent patient
prevention campaigns, comparable to those risk; (2) risk age; and (3) predisposing
published in neighboring countries, but still condition.
very distant from the rates of Netherlands and A sudden alteration in the awakening thresh-
Japan, with 0.1 and 0.16 every 1000 living old has recently been proposed as the main mech-
births, respectively. anism in sudden death. Anomalies in the serotonin
A recent publication (Hauck and Tanabe) receptors in the ventral medulla have been
gathered information about sudden death in 13 reported, possibly because of a dysfunction in the
countries and showed a generalized reduction, cardiorespiratory responses to excitation/awak-
with ranges oscillating between 40% and 87%. ening. Also, some studies have shown a greater
This decrease may be related to the implementa- frequency of certain polymorphisms of a gene of
tion of educational campaigns since 1990, which the serotonin transport protein in infants who
informed the general population about sudden died because of sudden death. Polymorphisms in
death and its prevention. One of these campaigns the gene of the sodium channel have also been
was the already mentioned “back to sleep,” described, which is associated with a prolonged
through which a significant reduction was QT interval, as well as genes that affect the devel-
achieved, once that it was established as a public opment of the autonomic nervous system.
health policy. In Chile, a decrease of 25% has Therefore, certain children may have a genetic
been recorded in a period of 13 years, which is a predisposition that manifests when certain trig-
lower reduction rate than those experienced in gers are present, such as tobacco exposure or
the mentioned countries. Although in our coun- prone decubitus position.
tries there is a general knowledge about the rec-
ommendation of the dorsal decubitus position,
massive health campaigns are still not in place.  isk Factors and Clinical
R
Another factor that could contribute to the reduc- Presentation
tion in the rates of sudden death is the increase of
other causes of unexpected sudden deaths of chil- There are multiple risk factors related to
dren. This factor is explained by the advances and SIDS. The triple risk model proposes that this is
optimization for investigating the cause of deaths, caused by an inherent vulnerability, age, and
recognizing other child deaths related to sleep, exogenous damage. Age is considered as one the
such as asphyxia mortality, accidental suffoca- most important factors involved, as most of the
tion or strangulation in the bed, and poorly cases correspond to children between 3 and
defined or unspecified deaths, which are usually 5 months of life (90% happens before 6 months).
49  Sudden Infant Death Syndrome 497

Among the factors described as part of this racy in the notification of the disease.
inherent vulnerability are the alterations in the Nevertheless, these hypotheses must be con-
awakening when certain stimuli, such as hypox- firmed in future studies.
emia and hypercarbia, appear. Awakening con-
trol would be less developed in some patients, Pacifier  Several studies, including two meta-­
particularly in premature babies. This particular analysis, have supported the use of a pacifier as a
vulnerable situation may be worsened by exter- protective factor with an OR adjusted 0.39–0.48.
nal factors, such as prone position while sleep- The mechanism through which its use would
ing, respiratory infections, smoking at home, reduce sudden death rate is not clear, and a reduc-
excessive blankets, and co-sleeping. In the tion in the excitation threshold, or autonomic
national study it was confirmed that almost 25% response during the sleep transition to awaken-
of the cases would be premature babies. As it ing, have been proposed as explanations. In this
was shown in previous publications, boys have a age group, it has been confirmed that using a
greater rate than girls, and the reason for this is pacifier does not cause breastfeeding or odonto-
unknown. Besides this, several parameters logical problems. The American Academy of
related to low socioeconomic level were notably Pediatrics recommends the use of the pacifier as
present, such as the educational level of the a strategy to reduce the risk of SIDS, and it should
mother. This information corroborates what has be introduced once breastfeeding has been well
been found in international studies that have established, after 2–4 weeks of age.
associated low socioeconomic level and over-
crowding with sudden death. Smoking  Maternal smoking increases the risk of
Other noticeable characteristics of sudden SIDS up to 40 fold. Both prenatal and postnatal
death in Chile are the distribution of cases within smoking have been associated. Besides this, there
the year, showing an increase during winter are studies relating in-home smoke of any family
months (Fig. 49.1), and geographic distribution, member with sudden death. This habit is one of
which shows an increase in the southern parts of the preventable factors most strongly related to
the country (Fig. 49.2). The reasons for this geo- the disease.
graphic difference could be several, as, for exam-
ple, a different prevalence rate of respiratory Vaccines  There is no current evidence relating
diseases, different sleep habits, or a greater accu- sudden death to vaccines and immunizations.

Fig. 49.1  Sudden infant 200

death (SID) in Chile
(1997–2009) (n = 1442):
seasonal distribution of
1442 SID in Chile 150

100
n

50

0
1 2 3 4 5 6 7 8 9 10 11 12
Month
498 M. A. Oyarzún and P. Brockmann Veloso

Fig. 49.2  Sudden infant

death rate
0.021 I. Tarapacá Region

0.35 II. Antofagasta Region

0.35 III. Atacama Region

0.27 IV. Coquimbo Region

0.22 V. Valparaíso Region

0.39 Santiago Metropolitan Region

0.16 VI. Libertador General Bernardo
O‘Higgins Region
0.16 VII. Maule Region
0.25 VIII. Biobío Region
0.46 IX. Araucanía Region

0.41 X. Los Lagos Region

0.72 XI. General Carlos Ibáñez del

Campo Aysen Region

0.57 XII. Magallanes and Chilean

Antartic Region

There are reports relating cases of diphtheria, of maternal breastfeeding against SIDS, with
tetanus, and pertussis vaccine to sudden death, an approximate reduction of 50% when the
although there is no information supporting this child is breastfed, and this effect would be
statement. A meta-analysis published in 2007 greater when the child is exclusively breastfed.
showed that immunization reduced the risk of Physiological studies have shown that breastfed
SIDS in 46%. infants have a lower awakening threshold in
comparison to their peers who received for-
Maternal breastfeeding  The protective role of mula, which could support the argument of the
maternal breastfeeding has been discussed over protection of breastfeeding against sudden
the years, but the experts have still not issued a death. Other possible reasons for this protective
consensus. Some recent reports, including a effect include the prevention of infectious dis-
meta-analysis in 2011, show a protective effect eases and global immune benefits.
49  Sudden Infant Death Syndrome 499

SIDS and ALTE  The association between sud- bitus, are dangerous, and should be avoided.
den death and an apparent life-threatening event Prone and lateral position have shown a reduc-
(ALTE) is still controversial. Although it is the tion in the micro-awakening thresholds.
main cause of death of children suffering from an 3. Avoid having too soft surfaces where the
ALTE, only 3% to 7% of infants who died of sud- infant sleeps.
den death have had a previous ALTE episode. 4. Avoid soft objects such as plush toys, blankets,
There is still not enough evidence sustaining such and similar items in the crib of the infant.
an association. Suffocation caused by any soft item near the
infant must be avoided.
5. Suspend maternal tobacco use and postnatal
Prevention and Approach exposure to tobacco. Tobacco use is the main
modifiable factor to prevent sudden death.
Reducing sudden death risk lies in controlling Both prenatal and postnatal tobacco exposure
and eliminating the risk factors already men- have been related to an increased chance of
tioned, and therefore recommendations for “safe SIDS.
sleeping” have been published (Fig. 49.3). 6. Suggest that the infant sleeps close (in a crib)
to the parents. It is not recommended that
1. Promote supine position for sleeping infants. infants and parents sleep in the same bed. Co-­
An association between prone position and an sleeping is not recommended.
increase of SIDS rate has been confirmed. 7. Do not use excessive blankets during sleep.
After the massive introduction of the cam- 8. Do not use a cardiorespiratory monitor as a
paign “back to sleep,” a reduction in the rate preventive method for sudden death. It should
of sudden infant death could be observed in only be indicated when it is really justified.
the countries that applied it. It has been shown
that sleeping in lateral position has increased No known study has confirmed a real preven-
the number of death cases caused by sudden tion of SIDS when using cardiorespiratory moni-
death, and therefore it should not be recom- tors. “Apneas” as the sole mechanism are not
mended as an alternative. convincing as a reliable cause of sudden death.
2. Avoid prone and decubitus lateral positions. The Collaborative Home Infant Monitoring
As it has been previously pointed out, all other Evaluation (CHIME) 26, which included more
positions, with the exception of supine decu- than 1000 patients in California, showed similar

Toys outside of the sleep area

No pillows
Head uncovered

Consider using pacifier

Firm well supported mattress

Sleeping on the
back
Free of smoke environment
Sleep in their crib Avoid excessive blankets

Fig. 49.3  Recommendations for “safe sleeping”

500 M. A. Oyarzún and P. Brockmann Veloso

sudden death rates in groups with and without Franco P, Szliwowski H, Dramaix M, Kahn A. Decreased
cardiorespiratory monitors. Further, it is well autonomic responses to obstructive sleep events in
future victims of sudden infant death syndrome.
documented that patients correctly connected to a Pediatr Res. 1999;46(1):33–9.
cardiorespiratory monitor have died. Guntheroth WG, Spiers PS.  The triple risk hypoth-
eses in sudden infant death syndrome. Pediatrics.
9. Consider using a pacifier when sleeping. 2002;110(5):e64.
Hauck FR, Tanabe KO.  International trends in sudden
However, its use must not be forced once the infant death syndrome: stabilization of rates requires
child lets go of it. further action. Pediatrics. 2008;122(3):660–6.
Hauck FR, Thompson JM, Tanabe KO, Moon RY,
Vennemann MM.  Breastfeeding and reduced risk
of sudden infant death syndrome: a metaanalysis.
Conclusions Pediatrics. 2011;128(1):103–10.
Horne RS, Sly DJ, Cranage SM, Chau B, Adamson
Although reduction in its rate has been con- TM. Effects of prematurity on arousal from sleep in the
firmed, sudden infant death syndrome is still one newborn infant. Pediatr Res. 2000;47(4 pt 1):468–74.
Kahn A. Sudden and unexplained infant death. Bull Mem
of the main causes of death in this age group. As Acad R Med Belg. 1983;138(3):225–35.
a health team, we must know about its existence Leach CE, Blair PS, Fleming PJ, Smith IJ, Platt MW,
and the factors associated to the population. Berry PJ, et al. Epidemiology of SIDS and explained
Delivering consistent messages and use of public sudden infant deaths. CESDI SUDI Research Group.
Pediatrics. 1999;104(4):e43.
health campaigns are crucial to reduce the gener- Mitchell EA, Blair PS, L’Hoir MP.  Should pacifiers be
alized feeling that these deaths are unavoidable. recommended to prevent sudden infant death syn-
drome? Pediatrics. 2006;117(5):1755–8.
Moon RY, Fu L.  Sudden infant death syndrome: an
update. Pediatr Rev. 2012;33(7):314–20.
Sources Sawaguchi T, Namiki M.  Recent trend of the incidence
of sudden infant death syndrome in Japan. Early Hum
Ball HL, Volpe LE. Sudden infant death syndrome (SIDS) Dev. 2003;75(suppl):S175–9.
risk reduction and infant sleep location—moving the Task Force on Sudden Infant Death Syndrome, Moon
discussion forward. Soc Sci Med. 2013;79:84–91. RY. SIDS and other sleep-related infant deaths: expan-
Beckwith JB. Defining the sudden infant death syndrome. sion of recommendations for a safe infant sleeping
Arch Pediatr Adolesc Med. 2003;157(3):286–90. environment. Pediatrics. 2011;128(5):1030–9.
Brockmann P, Oyarzún MA, Villarroel L, Bertrand Vennemann MM, Höffgen M, Bajanowski T, Hense
P.  Sindrome de muerte súbita del lactante: prevalen- HW, Mitchell EA.  Do immunisations reduce the
cia y cambios en los últimos años en Chile. Rev Méd risk for SIDS? A metaanalysis. Vaccine. 2007;
Chile. 2013;141:589–94. 25(26):4875–9.
Brockmann PE, Abara S, Campos C, et  al. Consenso Wedgwood R, editor. Review of USA experience. Sudden
sobre el manejo de eventos de aparente amenaza a and unexpected death in infancy (cot deaths). Bristol:
la vida del lactante (ALTE). Comisión de Sueño de Wright; 1972.
Sochinep, 2013. Rev Chil Pediatr. 2014;85(3):378–87. Willinger M, James LS, Catz C.  Defining the sudden
Carpenter RG, Irgens LM, Blair PS, England PD, Fleming infant death syndrome (SIDS): deliberations of an
P, Huber J, et  al. Sudden unexplained infant death expert pan-el convened by the National Institute
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2004;363(9404):185–91. Pathol. 1991;11(5):677–84.
 Primary Immunodeficiencies
and Immune Diseases
50
Eduardo Talesnik Guendelman
and Cecilia Méndez Rivera

Contents
Introduction..................................................................................................................   502
Primary Immunodeficiencies (PID)............................................................................  503
Antibody Immunodeficiencies.....................................................................................   504
Cellular and Combined Immunodeficiency...............................................................   506
Phagocytes Immunodeficiencies..................................................................................   508
Clinical Case..................................................................................................................   508
Complement Immunodeficiencies...............................................................................   509
Non-classified PID........................................................................................................   509
Clinical Case..................................................................................................................   509
Immunological Diseases...............................................................................................   511
 tiopathogenesis.............................................................................................................  511
E
Vasculitis and Lung Compromise...................................................................................  511
Henoch-Schonlein Purpura.............................................................................................  511
Kawasaki Disease...........................................................................................................  512
Polyarteritis Nodosa.......................................................................................................  512
Systemic Vasculitis Associated to Anti-neutrophil Cytoplasmic Antibodies.................  512
Granulomatosis with Polyangiitis (Wegener Granulomatosis) ......................................  512
Microscopic Polyangiitis................................................................................................  513
Churg-Strauss Syndrome................................................................................................  513
 onnective Tissue Diseases and Lung.........................................................................   513
C
Systemic Erythematosus Lupus......................................................................................  513
Mixed Connective Tissue Disease/Undifferentiated Connective Tissue........................  514
Juvenile Dermatomyositis..............................................................................................  514
Juvenile Systemic Sclerosis............................................................................................  514

E. Talesnik Guendelman (*) · C. Méndez Rivera

Pediatrics, Immunology and Rheumatology, Pontificia
Universidad Católica de Chile, Santiago, Chile
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 501

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_50
502 E. Talesnik Guendelman and C. Méndez Rivera

Juvenile Idiopathic Arthritis...........................................................................................  515

Goodpasture Syndrome..................................................................................................  515
Autoinflammatory Diseases of the Lung.....................................................................   515
Sources...........................................................................................................................   516

Introduction Table 50.1  Recurrent respiratory infections

A. Predisposing factors
Immunodeficiencies are a heterogeneous group    Immune system development in children under
of diseases caused by one or more alterations in 2 years old
   Lack of maternal breastfeeding
the immune system. The most common clinical
   Family exposition to infections (number of brothers)
manifestation tends to be a predisposition to    Daycare attendance
infections. Immunodeficiencies may be primary,    Passive smoking
associated with genetic disorders, or acquired    Allergy
immunodeficiency diseases of the immune B. Secondary immunodeficiencies
system.    Diseases with anatomical compromise: Adenoid
Clinical history and physical examination are hypertrophy, airway malformations, foreign body,
bronchiectasis, ciliary dyskinesia, congenital heart
key in the differential diagnosis of the different diseases, splenectomy, aspiration associated with
predisposing causes of recurrent respiratory oropharyngeal incoordination, gastroesophageal
infections, secondary immunodeficiencies, and reflux, etc.
primary immunodeficiencies (PID). Predisposing    Diseases with systemic compromise: Cystic fibrosis,
alpha-1-antitrypsin deficiency, malnutrition,
factors of recurrent infections are more frequent neoplasia, systemic lupus erythematosus, nephrotic
than secondary immunodeficiencies, and these syndrome, HIV infection, measles, etc.
are more common than PID (Table 50.1).    Drugs and immune reconstitution: Bone marrow
Recurrent viral respiratory infections are com- transplant, steroids, immunosuppressors, etc.
mon in children under 2 years old, whose immune C. Primary immunodeficiencies
   Innate immunity
system is still maturing, and they are caused by
   Acquired immunity
exposure to infectious agents at home or at day-
care. Six or more high respiratory tract infections
during the first years of life are considered nor- nitis has been associated with pneumonia and
mal. Tobacco exposure is also a relevant predis- recurrent sinusitis, respectively.
posing factor for recurrent respiratory diseases. In children and adolescents with recurrent
Recurrent lung suppurative infections in the respiratory infections, the possible association of
same site suggest malformation, obstruction, or two or more causes should be considered; for
foreign object in the airway. In contrast, aspira- example, allergic rhinitis and asthma, both related
tion related to oropharyngeal incoordination, to adenoid hypertrophy, or alterations in antibody
gastroesophageal reflux, cystic fibrosis, ciliary immunity, such as polysaccharide antibody
dyskinesia, and alpha-1-antitrypsin deficiency, as deficiency.
well as PID and secondary immunodeficiencies Considering the wide differential diagnosis
(SID), should be considered in patients who have in children and adolescents with recurrent
a history of recurrent multifocal pneumonia. infections, the clinical and imaging studies,
Allergy is a common predisposing factor for besides the laboratory tests to be requested,
recurrent respiratory infections, and inadequate depend on the clinical orientation of each indi-
treatment in patients with asthma and allergic rhi- vidual case.
50  Primary Immunodeficiencies and Immune Diseases 503

Primary Immunodeficiencies (PID) • PID diagnosed in siblings or family, where

there are no clinical symptoms.
More than 200 PID have been described, and • Lung, sinus, and otic recurrent suppurative
most of them have been identified as to the caus- bacterial infections: four or more episodes of
ative gene. Diagnosis should be done under high acute otitis within 1  year, two or more epi-
suspicion, as delays in diagnosis are frequent and sodes of acute sinusitis within 1 year, two or
are related to greater morbidity and mortality. more episodes of pneumonia within 1 year.
PID are characterized by a greater susceptibility • Lung, sinus, and otic chronic infections.
to infections, but there is also an increased risk • Infections caused by opportunistic agents.
for autoimmunity, and less frequently, cancer. • Need to use IV antibiotics to treat infections.
Incidence has been estimated as 1 in every 10,000 • Persistent infections with poor or no response
live births to 2  in every 20,000 live births, to antibiotic treatments.
although relative incidence is variable. Some are • Recurrent cutaneous or organ abscess.
frequent, such as IgA deficiency, with incidence • Failure to thrive.
up to 1 in 700, and most are very infrequent, such • Recurrent lung infections associated to persis-
as severe combined immunodeficiency, with an tent or chronic diarrhea, intestinal malabsorp-
incidence estimated as 1  in 100,000. Onset age tion, chronic sinusitis, bronchiectasis,
spans from newborn to adult life, but the clinical neutropenia, or skin abscess.
manifestations of most of these diseases begin • Recurrent infections associated with autoim-
during childhood. Some of their presentations munity: among these, autoimmune cytopenia,
may be transient during childhood, and others thyroiditis, or rheumatological diseases.
develop as the patient grows.
PID may be monogenic or polygenic and may • Two or more serious infections or sepsis
compromise one or more of its components • Early-onset autoinmune diseases
(innate immune response, antibody adaptive • Adverse reactions to vaccines: paralytic polio,
immune response, cellular immunity, phago- CGB dissemination
cytes, or complement system). • Persistent ganglionar suppuration
Essential genes for immune function are dis- • Recurrent or persistent candidiasis, oral or
tributed along the genome; nevertheless, a domi- cutaneous
nance of immunodeficiency is associated to the X • Graft-versus-host reaction
chromosome, as a result of homozygosity in • Combination of eczema and thrombocytope-
males, but also from frequent and new spontane- nia (Wiskott–Aldrich syndrome), ataxia and
ous mutations of these genes related to the X telangiectasia (ataxia-telangiectasia syn-
chromosome. PID have also been recognized as drome), delayed umbilical cord detachment,
autosomal recessive, as autosomal dominant, and and soft tissue infections (leukocyte adhesion
others that do not have an evident inheritance pat- deficiency type 1), oculocutaneous albinism
tern. Different clinical syndromes may be caused (Chediak–Higashi syndrome)
by different mutations in the same gene, and the
same syndrome may be caused by different The respiratory system is one of the main
genetic causes. PID by chromosomal deletion organs targeted by infections in patients with
have been described, such as 22q11,2, with a PID. Besides the susceptibility to specific infec-
DiGeorge syndrome phenotype. tions, the clinical presentation depends on the
area of the immune system that has been compro-
Clinical history suggesting PID: mised (Table 50.2).
• Consanguineous parents Antibody PID is more frequent, followed by
• Family history of serious infections in small well-defined PID syndromes, PID combined cel-
children or deaths caused by infections in chil- lular and antibodies, and phagocytes. The relative
dren, adolescents, or young adults. PID frequency can be observed in Table 50.3.
504 E. Talesnik Guendelman and C. Méndez Rivera

Table 50.2  Association between primary immunodefi- charide pneumococcal vaccine to evaluate the
ciencies (PID) and infections response to polysaccharide antigens. If the patient
Infection has one of the more serious presentations of PID,
immunodeficiency quantification of total B lymphocytes and B mem-
Cellular Virus, fungus, gram-­
ory lymphocytes with isotopic changes is needed to
negative bacteria,
protozoans, Pneumocystis conduct an advanced study.
jirovecii, Antibody immunodeficiencies are caused by
Candida albicans, development alterations of B lymphocytes.
Calmette–Guérin bacillus Figure 50.1 shows different stages of B-lympho­
(CGB)
Antibodies, complement: Extracellular bacteria:
cyte development, until the production of serum
classic and alternative Staphylococcus aureus, immunoglobulins.
path, lectins, and C3 Streptococcus pneumoniae,
IRAK4 Haemophilus influenzae X-linked agammaglobulinemia  This immuno-
Combined cellular and Opportunistic germs,
deficiency is related to the X chromosome. Its
antibody extracellular bacteria
Phagocytes Staphylococcus aureus, origin is the lack of development of B lympho-
Serratia, Nocardia, cytes, caused by Bruton tyrosine kinase defi-
Aspergillus ciency (Btk), which is essential for the
Complement terminal Neisseria gonorrhoae and development of B lymphocytes (Fig. 50.1). It is
components: C5–C9 Neisseria meningitidis
predominant in males starting at 6  months of
Cytokines: IFN-γ, IL-12 Mycobacteria, Calmette–
Guérin bacillus (CGB, life, without lymphatic ganglion and bacterial
Salmonella) pyogenic recurrent infections caused by
Toll-like receptors (TLR) Meningococcus, Pseudomonas, Mycoplasma, and enteroviral
TLR-4 pneumococcus, septic meningoencephalitis. Predominant infections
shock
are located in the upper and lower airway. As
many as 50% of the patients develop chronic
Table 50.3  PID Frequency lung disease, bronchiectasis, atelectasis, and
PID antibodies 53.2 enlargement of the bronchial wall. Lymphocyte
PID combined cellular and antibodies 9.5 B count is very low or nonexistent, as well as
PID defined syndromes 22.65 serum immunoglobulins and antibody response
PID phagocytes 8.6
to vaccines. Septic arthritis and gastrointestinal
PID complement 2.8
Immune regulation alterations 3.3 infections are also frequent.
Source: Registro Latinoamericano IDP (LAGID). 3321
patients Common variable immunodeficiency  Common
variable immunodeficiency (CVID) is the most
common form of humoral PID, requiring monthly
Antibody Immunodeficiencies IV gamma globulin. It appears in children older
than 2 years of age when alterations in the final
Antibody PID, also called humoral PID, are usu- stages of B lymphocytes develop.
ally related to otic, sinus, or lung recurrent infec-
tions. The most useful laboratory exams for the Approximately 20% of the patients with
quantitative study of antibodies are serum immu- CVID have a family history of PID, and spe-
noglobulins IgG, IgA, IgM, as well as the IgG sub- cific genetic mutations have been found in 10%
classes (IgG1, IgG2, IgG3, IgG4), considering of these: transmembrane activator and CAML
both reference tables for each age group. Qualitative interactor (TACI), inducible costimulatory
response is measured through isohemagglutinins, (ICOS), B-cell activating factor receptor
preferring antibody response to vaccines, for (BAFF-R), and CD 19 (superficial molecule of
instance, tetanus toxoid (diphtheria toxoid) to eval- B lymphocytes; binds to receptor antigen for B
uate the response to protein antigens, and polysac- lymphocytes).
50  Primary Immunodeficiencies and Immune Diseases 505

IgG

B IgA
Btk

Lymphoid Pre B IgM

Immature Mature Plasma
progenitor Pro B cell cell
B lymphocite B lymphocite cell

Memory B cell

Fig. 50.1  Lymphoid cell development

More than 95% of the patients present with IgA deficiency  This deficiency is the most com-
sinus and lung infections caused by non-­ mon PID, occurring in 1 in 700 (1 in 396 to 1 in
typifying Haemophilus influenzae and 2000) live births, and it is characterized by an
Streptococcus pneumoniae. Infections caused IgA serum level less than 7 mg/dl, with normal
by Moraxella catarrhalis and other IgG and IgM levels, in children over 4 years old.
Streptococcus sp. are less common. Infections Most patients are asymptomatic, and some pres-
caused by Mycoplasma have also been ent with recurrent respiratory and gastrointestinal
described. Recurrent bronchitis is the usual clin- infections, in whom IgG2 deficiency and specific
ical presentation; this initially responds to anti- antibody deficiency should be studied. A greater
biotics but may progress to bronchiectasis. frequency of chronic allergies and autoimmune
Persistent sinusitis progresses to a chronic con- diseases has been described, such as systemic
dition. Intestinal infections caused by Giardia lupus erythematosus, juvenile idiopathic arthri-
lamblia and Campylobacter jejuni, as well as tis, and rheumatoid arthritis.
arthritis and meningoencephalitis caused by
enterovirus, may also appear. Approximately IgG subclasses deficiency  This deficiency is
20% present with autoimmunity manifestations, characterized by lack of IgG2, IgG3, or both,
and among these, cytopenia is the most com- with a normal value for total IgG. IgG2 is a het-
mon. Also, autoimmune thyroiditis, primary erogeneous group of alterations, ranging from
biliary cirrhosis, and rheumatological diseases transient to persistent presentations, isolated or in
have been found in the pediatric population. At combination with IgA deficiency or specific anti-
the same time, these patients have a greater sus- body deficiency. It appears with recurrent sinus
ceptibility to present with adenopathy, spleno- and lung recurrent infections, otitis media, and
megaly, lymphocytic interstitial pneumonia, disseminated infection caused by Streptococcus
gastrointestinal lymphoid hyperplasia, and lym- pneumoniae. Patients with IgG3 have the same
phoreticular neoplasia. type of infections, but these infections tend to be
The diagnostic criteria are IgG and IgA < 2 SD, moderate and transient.
usually related to IgM < 2 SD, considering age,
absence of isohemagglutinins, poor response to Specific antibody deficiency  This is a frequent
vaccines composed of protein antigens (tetanus PID in children over 2 years old, characterized by
toxoid), and polysaccharide (polysaccharide a deficient specific response to polysaccharide
pneumococcal vaccine, 23-valent), excluding the antigens, with normal levels of serum
secondary causes of hypogammaglobulinemia. ­immunoglobulin. In some patients, the immune
Lymphocyte B count is normal or low. response to pneumococcal conjugate vaccines is
506 E. Talesnik Guendelman and C. Méndez Rivera

normal. Its pathogeny is unknown, and it has Table 50.4  Poor response to pneumococcal vaccines
been estimated that it corresponds to 55% to 10% Failure IgG antibodies after IgG antibodies after
of children referred by recurrent infections. severity vaccination vaccination
Specific antibody deficiency can be associated to 2–5 years old ≥6 years old
other PIDs such as IgA deficiency, IgG2 sub- Severe No protection level No protection level
in any serotype in any serotype
classes, Wiskott–Aldrich syndrome, and deletion
Moderate Protection level Protection level
22q11,2, DiGeorge syndrome phenotype. ≤50% serotypes ≤70% serotypes

Specific antibody deficiency has been found in

of life, with IgG levels <2DS, in comparison with
children with their complete scheme of conjugate
normal values per age, and it has been associated
pneumococcal vaccines (with four doses at 2, 4,
with a reduction in immunoglobulin isotypes. It
6, and 12 months of life, or with three doses at 2,
has been found in younger children, with no his-
4, and 12 months, in Chile), and also in patients
tory of infections, who have relatives with PID,
with an initial adequate response to polysaccha-
and with recurrent infections: otitis media, recur-
ride vaccines, whose antibody titers are progres-
rent bronchitis, and bacterial meningitis. This is a
sively reduced.
transient disease and does not require treatment
Patients present with recurrent bacterial infec-
with gamma globulin in most cases, but 10% to
tions: otitis, bronchitis, sinusitis, and recurrent
20% may develop CVID or other
pneumonia caused by Streptococcus pneumoniae.
dysgammaglobulinemia.
Infections caused by Haemophilus influenzae,
Branhamella catarrhalis, and Staphylococcus
aureus have also been reported. Most patients
respond to the usual antibiotic treatment. Cellular and Combined
Polysaccharide vaccine 23-valent is recom- Immunodeficiency
mended to study these patients through the deter-
mination of specific antibodies to pneumococcus Hyper-IgM syndrome  This syndrome is an het-
(14 serotypes in the United States, 10 serotypes erogeneous group of genetic diseases with altera-
in Chile), 4–6 weeks after the vaccine, which is tions in the change of immunoglobulin isotypes.
therapeutic in a large percentage of these patients. The most common form is deficiency of the
About 80% and 90% of those who do not respond CD40 ligand linked to the X chromosome. CD40
to the polysaccharide vaccines do respond to a is one of the receptors of tumoral necrosis factor
conjugate vaccine dose. (TNF), expressed by B lymphocytes, dendritic
The molecular defect of specific antibody cells, and macrophages (Fig. 50.2). Its activation
deficiency has not been found, and some of the is fundamental for the proliferation of B lympho-
most serious presentations have a deficiency of cytes and immunoglobulin production, which
memory B lymphocytes. occur as a result of the union to its natural ligand
The serum level considered as protective for CD154 or CD40, expressed on the activated T
pneumococcal antibodies after the administration lymphocytes. Another form is autosomal reces-
of 23-valent pneumococcal vaccine is ≥1.3 μg/ml sive caused by CD40 deficit, associated with anti-
or a fourfold increase in 50% of the basal level body immunodeficiency.
for 10 studied serotypes in children from 2 to
5 years old; 70% of these serotypes are present in The hyper-IgM syndrome is caused by a muta-
older children (Table 50.4). tion in genes CD154 (HIGM1), bound to the X
chromosome or CD40 (HIGM3), respectively.
Transient hypogammaglobulinemia of infancy  This syndrome is characterized by very low
This deficiency is defined by the accentuation ­levels of IgG, IgA, and IgE, with normal or ele-
and prolongation of physiological hypogamma- vated IgM. The predominant clinical manifesta-
globulinemia observed between 3 and 6 months tions are viral and bacterial respiratory infections
50  Primary Immunodeficiencies and Immune Diseases 507

IgE
IL-2 IgA Activation of
IL-4 IgM complement
IL-7 IgG+Ag
Ag
IL-Rγe
IgM
Rag1,2
CD40L CD40 Rag1,2
Jack3
TCR MHC
T
Zap 70 B
Btk
ADA CD28 B7
ADA
IL-Rγe
CD40L
CD40
FcR IL-1
IL-2
TNF-α
IL-4 IFN-α,β
IL-7
IFN-γ IL-Rγe
NADPH
MØ Oxidase

IFN-Rγ

Fig. 50.2  Mediators involved in immunodeficiencies. which are present in the diagram. (Source: Carrión F,
Schematic representation of T and B lymphocytes, macro- Figueroa, F, Rodríguez C.  La inmunología clínica: una
phages, and their soluble mediator interaction. Several perspectiva molecular. Rev Méd Chile. 2000; 120: 650–
immunodeficiencies mentioned in the text are caused by 568. Creative Commons License)
genetic defects that alter the expression of some patients,

in both the high and lower airways. In patients and 1 in 100,000. A series of molecular effects have
with CD40 linked to the X chromosome, intersti- been identified, the most common one related to
tial lung infection caused by Pneumocystis jir- the X chromosome in 50% to 60% of the cases,
ovecii can be found. Infections related to humoral located at the γ-chain of the interleukin-­2 receptor
deficiency and diarrhea caused by (IL-2R γc), IL-4, IL-7, IL-9, IL-15, and IL-21.
Cryptosporidium parvum can also appear.
Sclerosing colangitis, and aplastic anemia Clinical manifestations present after the neo-
induced by parvovirus, are also found. natal period or during the first months of life, and
are characterized by oral candidiasis, persistent
Severe combined immunodeficiencies  This diarrhea, failure to thrive, BCG vaccine dissemi-
group of genetic diseases is characterized by the nation, eczema, skin abscess, meningitis, hepati-
absence and dysfunction of T and B cells, and in tis, and cholangitis, as well as systemic infections
some situations, of natural killer (NK) cells. The caused by cytomegalovirus or Epstein–Barr
frequency of severe combined immunodeficiencies virus. Higher and lower respiratory tract infec-
(SCID) has been estimated to be about 1 in 75,000 tions are very common: otitis media, sinusitis,
508 E. Talesnik Guendelman and C. Méndez Rivera

chronic bronchitis causing bronchiectasis and Phagocytes Immunodeficiencies

pneumonia caused by common bacteria, as well
as interstitial pneumonia caused by Pneumocystis Chronic granulomatous disease  This disease is
jirovecii and serious or deadly respiratory infec- present in 1 in 125,000 live births, and it is caused
tions caused by adenovirus, respiratory syncytial by a failure in the production of superoxide radi-
virus, and type 3 parainfluenza. Most patients cals, oxygen peroxide, and other oxygen radicals
present with lymphopenia, and their levels of that are fundamental for the intracellular death of
serum immunoglobulin are low or undetectable. microorganisms, where a specific b-cytochrome
T-lymphocyte count is reduced, in combination of phagocytes and NADPH oxidase are required.
with low counts of B lymphocytes or NK cells, Chronic granulomatous ­disease (CGD) may be
according to the CVID type. During past years a caused by mutations in any of the four structural
neonatal screening method has been developed genes of NADPH oxidase. In 65% of the cases,
for its early diagnosis, through the detection of an the disease is associated to the X chromosome
early precursor in the development of T lympho- where a mutation of the gene that codifies the
cytes: the T-cell-receptor excision circle (TREC). 91-kDa chain (gp 91 phox) has been found. Three
other mutations are autosomal recessive. Clinical
DiGeorge Syndrome (DGS)  This syndrome is presentation appears during the first years of life
characterized by compromise in the development with suppurative adenitis, granulomas, or skin,
of facial, heart, parathyroid, and thymus struc- liver, lymph nodes, and lung infections caused by
tures, caused by defects in the formation of the Staphylococcus aureus, Burkholderia cepacia,
3rd and 4th laryngeal pouch. Up to 90% of these Serratia marcescens, and Nocardia and
patients present a microdeletion in the chromo- Aspergillus species. Lung compromise is very fre-
somal region 22q11,2. In most patients, cell quent, including hilar lymphadenopathy, pneumo-
immunodeficiency is mild to moderate, with nia, empyema, and lung abscess. Diagnosis is
T-lymphocyte function in order. Less than 5% made through the respiratory burst test using flow
presents with cellular immunodeficiency with cytometry with dihydrorhodamine. Lung image
quantitative and functional compromise of T study reveals chronic condensation, pleural retrac-
lymphocytes, along with a risk of opportunistic tion, interstitial enlargement, and hilar or medias-
infections. Patients present with facial dysmor- tinal adenopathy. Diagnosis is confirmed with the
phia, micrognathia, palatine fissure, low implan- test of respiratory burst and genetic study.
tation ears, short philtrum, and hypertelorism,
along with conotruncal heart disease and hypo-
calcemia secondary to hypoparathyroidism. Clinical Case

Malformations of the airway have been described A 15-year-old male was diagnosed with chronic
from the supraglottis to the segmental bronchi. granulomatous disease at 10  months when he
Malformations in the larynx and laryngeal mem- presented with episodes of suppurative adenitis
brane have been associated with recurrent respira- caused by Serratia marcescens. The nitroblue tet-
tory distress. Laryngomalacia and tracheomalacia, razolium test and respiratory burst test were 0%,
and bronchomalacia combined with conotruncal the gp 9 phox mutation. The patient was on co-­
congenital heart disease, have been observed in trimoxazole and itraconazole with no important
patients with recurrent lung infections. infections until 12 years of age, when lobar pneu-
Velocardiofacial syndrome, also related to monia with cavitation appeared in the left upper
microdeletion of the chromosomal region lobe. He was started on ciprofloxacin, vancomy-
22q11,2, presents with velopharyngeal failure. cin, and voriconazole with partial clinical and
A specific antibody deficiency to polysaccha- radiological response. Interferon gamma was
rides has been described in about 50% of the added, three times a week, with significant clini-
patients who have a 22q11,2 deletion. cal and radiological improvement (Fig. 50.3a, b).
50  Primary Immunodeficiencies and Immune Diseases 509

Fig. 50.3  Chronic granulomatous disease. Chest com- of treatment with interferon-γ (a) and after 6 months treat-
puted axial tomography shows cavitation pneumonia of ment (b) in a 15-year-old child with chronic granuloma-
the left upper lobe (LUL) of the lung before the beginning tous disease

Complement Immunodeficiencies phase, skin lesions can be similar to those of

atopic dermatitis. Coarse facies, scoliosis, delay
Complement deficiencies  Complement defi- in the appearance of primary dentition, ligamen-
ciencies correspond to 2% and 3% of PID. This tous laxity, and recurrent fractures have also
deficiency of the initial components of the com- been found. Many cases are sporadic, but fami-
plement cascade is characterized by recurrent lies with dominant recessive and autosomal
infections caused by encapsulated bacteria, inheritance have been reported. Some patients
Hemophilus influenzae b and Streptococcus present a mutation in STAT3.
pneumoniae, and it can be associated with auto-
immunity clinical manifestations. C3 is a relevant
opsonin, and the clinical presentation of its defi- Clinical Case
ciency is similar to those of hypogammaglobu-
linemia. C2 deficiency is the most frequent one A 6-year-old female presented with history of
and it has been related to autoimmune diseases, suppurative skin lesions and persistent rhinitis
as with other early components of the classic and sinusitis starting the first year of life. She
pathway from C1 to C4. Component deficiency was admitted to the hospital with complicated
from C5 to C9 is associated to a greater suscepti- pneumonia caused by a Staphylococcus abscess
bility to infections caused by Neisseria. (Fig. 50.4).
Hyper-IgE syndrome was suspected because
of some findings: coarse facies, double set of
Non-classified PID temporary and permanent teeth, hypermobility,
and scoliosis. Diagnosis was confirmed with
Hyper-IgE syndrome  This syndrome is an IgE level  =  2000 UI/ml and a mutation in the
infrequent PID characterized by recurrent skin STAT3 gene.
abscesses, recurrent pneumonia with lung
abscesses, and pneumatocele caused by Wiskott–Aldrich syndrome  This early-onset
Staphylococcus aureus, high IgE levels, >2000 PID is characterized by eczema, thrombocytope-
UI/ml, and poor lymphocyte response to diverse nia with microplatelets, and recurrent infections.
antigens. Infections by fungi, Haemophilus It is associated with the X chromosome, and it is
influenzae b, and Streptococcus pneumoniae caused by a defect in the WASP protein, which is
have also been found. During the newborn responsible for the polymerization of cytoskele-
510 E. Talesnik Guendelman and C. Méndez Rivera

mon variable immunodeficiency. These diseases

have been related to diagnosis delay and starting
the treatment with IV gamma globulin, which
involves a poorer patient prognosis.
Lung interstitial disease appears late in the
variable common immunodeficiencies, and its
frequency in children and adolescents is low.

PID treatment  Early diagnosis and treatment of

infections is relevant in all PID. IgA deficiency,
and some transient PID such as childhood
hypo-­ gammaglobulinemia, do not require spe-
cific treatment.
Fig. 50.4  Hyper-IgE syndrome. Chest computed axial
tomography in a 6-year-old child with hyper-IgE syn-
Preventive antibiotic treatment with cotri-
drome shows an abscess in the LUL of the lung moxazole and itraconazole is mandatory in
granulomatous disease, as well as cotrimoxa-
tal actin. Levels of IgA and IgE are high, IgM is zole for PID with reduced CD4 lymphocyte
reduced, and IgG quantification is variable. count. In the case of antibody diseases with poor
Nevertheless, the patients have a diminished response to IV gamma globulin, amoxicillin, or
response to polysaccharide antigens and a mod- cotrimoxazole and azithromycin, can be
erate response to protein antigens. They also suggested.
present with recurrent infections in different Patients with PID should not receive live virus
organs and lung infections caused by vaccines, nor the BCG vaccine. Patients with IgA
Streptococcus pneumoniae, herpes, and deficiency and transient immunodeficiencies can
Pneumocystis jirovecii. receive these vaccines.
IV gamma globulin treatment is absolutely
Alterations of IL-12 pathway and interferon-γ  indicated in agammaglobulinemia linked to the X
Alterations in the IL-12 pathway and interferon-γ chromosome, hyper-IgM syndrome, variable
present through infections caused by specific common variable immunodeficiency, and severe
microorganisms. Disseminated infections combined immunodeficiencies while waiting for
caused by tuberculous mycobacteria or infec- bone marrow transplant. The recommended dose
tions caused by herpesvirus or Salmonella have is 400–600 mg/kg every 4 weeks, and the objec-
been reported. tive of the treatment is to reduce the frequency of
the infections and avoid complications such as
Patients with PID may present lung sequelae bronchiectasis and worsening of lung function,
secondary to infections, pneumatoceles, maintaining IgG levels above 500 mg/dl.
abscesses, and empyema. Bone marrow transplant is the treatment of
Noninfectious lung complications have been choice for severe combined immunodeficiency,
also described in PID secondary to chronic and the prognosis has been related to how early
inflammation and associated autoimmunity. the therapy is executed, with a high percentage of
Findings are air trapping, enlargement of the immune reconstitution. In Wiskott–Aldrich syn-
chest wall, atelectasis, and bronchiectasis. Some drome the transplant of hematopoietic cells has
patients may present with bronchial obstruction, been successful. For other PID, such as chronic
interstitial lymphocyte infiltration, or lung granu- granulomatous disease, protocols are being
lomatous disease. developed.
Bronchiectasis is associated with some PID, Genic therapy is still a treatment in investiga-
such as X-linked agammaglobulinemia and com- tion. Advances have been reported for lentiviral
50  Primary Immunodeficiencies and Immune Diseases 511

genic therapy for severe combined immunodefi- Table 50.5 Immunological Diseases with Lung
ciency with deficit of adenosine deaminase, Compromise
Wiskott–Aldrich syndrome, and chronic granulo- Systemic erythematous lupus
matous diseases. Systemic juvenile idiopathic arthritis
Dermatomyositis juvenile
Systemic esclerodermia
Kawasaki disease
Immunological Diseases Polyarteritis nodosa
Schönlein–Henoch purpura
Connective tissue disease represents a group of Wegener granulomatosis
diseases characterized by the presence of abnor- Churg–Strauss vasculitis
malities in the immune system, whose most Microscopic polyangiitis
Connective tissue mixed disease
usual clinical manifestations are caused by
Goodpasture syndrome
acute and chronic musculoskeletal inflamma- Sjogren syndrome
tion, blood vessels, and skin. It can compromise
different organs. Vasculitis are characterized by
Diverse immunological mechanisms have
the immunologically mediated inflammation of
been proposed as involved in lung damage of
blood vessels, with a wide range of compro-
rheumatological diseases: the damage can be
mised vessels and clinical manifestations. Some
allergic, mediated by IgE. Gell and Coombs dam-
of these diseases may present lung and airway
age type II is mediated by antibodies and has
compromise, but this is uncommon during
been observed in vasculitis associated with
childhood.
ANCA(+) and neonatal lupus. The damage type
Lung compromise usually appears at the same
III mechanism is caused by the immune complex
time or after the beginning of the disease. Besides
in systemic erythematosus lupus (SLE), as well
lung compromise, it can affect the higher airway
as T failure and presence of antibodies for this
and the pleura. Pleural effusion can be the first
disease. Damage type IV mechanism has been
clinical manifestation of diseases such as sys-
related to the formation of granulomas observed
temic erythematous lupus.
in sarcoidosis.
Laboratory studies include CBC, sedimenta-
tion rate, biochemical profile, creatinine, and
urine test. In several of these diseases, the directed Vasculitis and Lung Compromise
study of antibodies is essential, as well as factors
of the C3 and C4 complement; and in some Several rheumatological diseases in children and
patients, study of the functional system of the adolescents are associated to lung vasculitis,
complement CH50. Image studies in these dis- which is characterized by a compromise of small
eases include chest X-ray and computer axial arterioles, venules, and capillaries.
tomography. Bronchoalveolar lavage is relevant
for the study of some of these diseases, as well as
for lung function study. Henoch-Schonlein Purpura
Table 50.5 shows the pediatric rheumatologi-
cal diseases that most frequently involve lung Henoch-Schonlein purpura is a vasculitis with
compromise. generalized small vessel compromise, affecting
skin, joints, intestines, and kidneys. It is one of
the most common vasculitis in childhood. A sub-
Etiopathogenesis clinical lung compromise with lung interstitial
disease and alteration of gas exchange has been
The etiology of most of these diseases is reported. Lung hemorrhage with respiratory fail-
unknown, but several environmental and genetic ure has been observed in adolescents and adults,
factors are combined. but is uncommon before puberty.
512 E. Talesnik Guendelman and C. Méndez Rivera

Kawasaki Disease these diseases. Children and adolescents present

vasculitis associated to positive anti-­
neutrophil
Kawasaki disease is a multi-systemic vasculitis cytoplasmic antibodies, including these:
that compromises median vessels and has a par-
ticular predilection for the coronary arteries. It 1. Granulomatosis with polyangiitis (Wegener

preferentially affects children under 5 years old. granulomatosis)
Respiratory compromise is infrequent in 2. Microscopic poluangiitis (MPA)
Kawasaki disease. In children under 6  months, 3. Churg-Strauss vasculitis
and in the atypical presentation, tachypnea, dys-
pnea, cough, and acute rhinitis have been
reported. Lung consolidation has been reported Granulomatosis with Polyangiitis
in patients during the febrile phase of this disease (Wegener Granulomatosis)
showing reticulogranular and interstitial pattern,
pleural effusion, and atelectasis. Granulomatosis with polyangiitis, previously
known as Wegner granulomatosis, corresponds to
a necrotizing vasculitis, with predominance in
Polyarteritis Nodosa the small vessels, which is characterized by gran-
ulomatosis inflammation of the upper and lower
Polyarteritis nodosa is a systemic necrotizing respiratory airway, associated to pauci-immune
vasculitis, which can affect the medium-sized crescentic glomerulonephritis. It is a rare disease
and small arteries. It may compromise any mus- in the pediatric population. During childhood,
cular arteria, and therefore it compromises a wide subglottic stenosis may appear and predominate
variety of organs: skin, lymph nodes, muscles, in females. Airway compromise is present in
central nervous system, eyes, kidneys, testicles, around 80% of the patients, and the most com-
heart, gastrointestinal tract and, lungs. This dis- mon clinical manifestations are sinusitis, epi-
ease begins with unspecific constitutional symp- staxis, and less frequently, oral ulcers, acute otitis
toms, such as fever, weight loss, headache, media, nasal ulcers, sensorial-conductive deaf-
abdominal pain, arthralgias, and myalgias. ness, nose shaped as a saddle, subglottic stenosis,
Lung compromise is infrequent and is mani- and nasal septum perforation.
fested by cough, dyspnea, pleuritis, interstitial Nasal disease appears as a mucus discharge
pneumonia, lung infiltrations, and lung and nasal obstruction, nasal ulcers, and septal
hemorrhage. perforation. Laryngotracheal disease can appear
It has been associated with hepatitis B and without symptoms and clinical presentation
C.  Laboratory exams reflect a systemic inflam- includes from snoring to stridor with airway
mation, and alterations in the urine test, such as obstruction. Lung compromise is very frequent,
proteinuria and hematuria, can also be observed. and the most common symptoms are cough,
Biopsy of compromised organs using an angio- pleuritis, and hemoptysis. Lung hemorrhage is a
graphic study is important for the diagnosis. serious emergency of this disease.
A localized presentation of this disease com-
promising the airway has been described: it is
Systemic Vasculitis Associated characterized by the formation of granulomas in
to Anti-neutrophil Cytoplasmic the upper or lower airway, with no systemic com-
Antibodies promise or constitutional symptoms, and it is
completely different from polyangiitis granulo-
Anti-neutrophil cytoplasmic antibodies (ANCA) matosis (Wegner granulomatosis), because of the
are associated to several systemic vasculitis syn- lack of systemic vasculitis.
dromes with kidney and lung damage. Its pres- Most common chest X-ray findings are pleuri-
ence has been considered as a pathogenic factor in tis and nodule lobes, which usually have multiple
50  Primary Immunodeficiencies and Immune Diseases 513

and bilateral presentations, and can be cavitated. Connective Tissue Diseases

Observing granulomatous inflammation in the and Lung
biopsy is relevant. The most useful laboratory
exams are the altered urine test and the presence Systemic Erythematosus Lupus
of c-ANCA, directed against proteinase 3 (PR-3),
which appears in about 85% of the patients. Systemic erythematosus lupus (SLE) is a multi-­
Positive rheumatoid factor is present in about systemic disease caused by immune dysregula-
60% of the patients, as well as anticardiolipins, tion at different levels of the production of
and lupus anticoagulant. antibodies. Criteria from the American College
of Rheumatology are used for its diagnosis. It is
more frequent in females, and the estimated inci-
Microscopic Polyangiitis dence in patients under 19 years old is 6 and 18.9
cases per 100,000.
Microscopic polyangiitis is a necrotizing vasculi- Lung compromise is common in children and
tis of the peripheral vessels, without granulomas, adolescents with SLE, about 25–75% of patients.
which affects capillary, venules, and arterioles, The presentation varies from asymptomatic to
but middle-sized vessels can also be affected. It lung function compromise, presence of pleural
appears with unspecific symptoms such as fever, pain, or lung hemorrhage, which is infrequent,
myalgias, arthralgias, and high respiratory tract but its prognosis is poor and its mortality is high
symptoms. The most common clinical manifesta- (between 50% and 90% of the cases). Compromise
tion is focalized severe glomerulonephritis seg- of the upper airway has also been described.
mentation, which can be associated with lung Clinical presentations are pleuritis, interstitial
compromise, particularly lung hemorrhage. Most disease, acute lupus pneumonitis, secondary
common respiratory symptoms are cough, dys- acute infectious pneumonia, lung hemorrhage,
pnea, and hemoptysis. It is characterized by the lung hypertension, and pneumothorax. Less fre-
presence of p-ANCA, with myeloperoxidase quent manifestations are diaphragmatic compro-
reactivity. This is a serious disease, with a signifi- mise or shrinking lung syndrome, lung vasculitis,
cant risk of chronic kidney failure, besides mor- and lung thrombosis.
tality by lung compromise. Airway compromise involves ulcers in the lar-
ynx, edema, and vocal chords paralysis.
Subglottic stenosis and epiglottitis may also be
Churg-Strauss Syndrome present and both are severe.
The most common lung manifestation of SLE
Churg-Strauss syndrome is a very rare vasculitis is unilateral or bilateral pleuritic. Patients present
during childhood. The first phase, or prodromes of with chest pain and variable degrees of respiratory
the disease, appears with allergic rhinitis or asthma compromise. SLE affects about one third of the
symptoms, which can persist for several years. patients at the beginning of the disease, and
The second phase is characterized by worsening of approximately 40% during its progression. Pleural
the asthma symptoms, peripheral eosinophilia, fluid is an exudate with low LDH, normal pH, and
and lung infiltrations. In the third phase the sys- glucose. Mild pleuritis can be treated with nonste-
temic vasculitis appears along weight loss, fever, roidal antiinflammatory drugs, but generally the
arthralgias, myalgias, nodular exanthema, and use of steroids is required.
neuropathy, besides a regression of the symptoms Parenchymal compromise is infrequent. Lung
of asthma. Antineutrophil cytoplasmic antibodies hypertension, interstitial disease, which can be
(ANCA) directed against PR-3 and MPO have exacerbated by a lupus crisis, and thromboem-
been found. Biopsy of affected tissues is usually bolic disease, associated to anticardiolipin and
diagnostic, with perivascular eosinophilic infiltra- lupus anticoagulant, have been described. Lung
tions and, occasionally, extravascular granulomas. hemorrhage and acute lupus pneumonitis
514 E. Talesnik Guendelman and C. Méndez Rivera

constitute medical emergencies with an acute ini- sion, and pulmonary hypertension have been
tial phase with cough, dyspnea, hypoxemia, and described. The most frequent clinical manifesta-
progressive respiratory distress. In lung hemor- tions are exercise dyspnea and persistent cough.
rhage, hemoglobin and hematocrit levels are Chest pain may also be present. Nevertheless,
reduced. In contrast, acute lupus pneumonitis can some patients with mixed connective tissue dis-
be associated with fever. Considering its serious- ease and lung compromise may not present clini-
ness, diagnosis must be considered, and early cal symptoms.
treatment for these complications should be The following have been reported:
administered.
Chest computerized axial tomography and 1. Restrictive lung disease in about 35% of

bronchoalveolar lavage must be done early, to patients
establish the diagnosis and determine if the respi- 2. Reduction in CO diffusion in 24–42% of

ratory compromise is caused by the autoimmune patients
disease, by an opportunistic agent if immunosup- 3. Lung fibrosis in up to 30% of patients
pressed, or by the immunosuppression 4. Pulmonary hypertension in 6–9% of patients
treatment.
The initial study and the follow-up of labora- Lung compromise must be ruled out in mixed
tory exams such as CBC, VHS, complete urine connective tissue disease, even when there are no
tests, biochemical profile, creatinine, C3, C4, and clinical symptoms, through the study of images
autoantibodies (ANA, DNA, ENA profile, anti- and lung function.
cardiolipin, lupus anticoagulant) are relevant
when studying SLE in children and adolescents.
Juvenile Dermatomyositis

 ixed Connective Tissue Disease/

M Juvenile dermatomyositis (JDM) is an inflamma-
Undifferentiated Connective Tissue tory vascular disease that mainly affects muscles
and skin, but it can also compromise the airway
Mixed connective tissue disease is characterized and lungs. Weakness of respiratory muscles and
by the combination of different manifestations of diaphragmatic dysfunction with secondary lung
the several connective tissue diseases. Its fre- compromise has been reported in up to a third of
quency is low: the Kasukawa diagnostic criteria the patients. Infrequent complications of JDM
have been used in pediatric presentation: reported are exercise dyspnea from aspiration,
interstitial fibrosis, vascular lung damage caused
• Raynaud syndrome, finger inflammation, or by lymphoproliferative compromise of arterioles
both and small muscular arteria, and damage to the
• Positive RNP antibodies small airway, causing cryptogenic organizing
pneumonia (previously named bronchiolitis
Compromise of at least one of the following: obliterans with organizing pneumonia, BOOP).
Reduction in ventilatory capacity is frequent in
(a) Systemic lupus erythematosus signs or patients suffering from JDM without respiratory
symptoms symptoms.
(b)
Juvenile systemic sclerosis signs or
symptoms
(c) Dermatomyositis signs or symptoms Juvenile Systemic Sclerosis

Lung compromise has been found in about Juvenile systemic sclerosis (JSE) is a multi-­
40% of the patients with mixed connective tissue systemic chronic disease that greatly compro-
disease. Interstitial lung diseases, pleural effu- mises the microvascular and vascular tissue,
50  Primary Immunodeficiencies and Immune Diseases 515

characterized by the enlargement of the skin and presentation of this disease. Pleural disease is
fibrosis of diverse organs such as esophagus, more common than lung parenchyma compro-
intestine, heart, kidneys, and lungs. Its appear- mise. Some cases of transient interstitial lung
ance during childhood is infrequent. infiltration have been reported, with hyperplasia
Respiratory compromise is an important cause of the bronchial-associated lymphoid tissue, and
of morbidity and mortality in the systemic pre- lymphocytic interstitial pneumonia. Some of the
sentation of scleroderma, but it is not observed in less frequently reported complications in patients
the localized presentation. Lung compromise with juvenile idiopathic arthritis are lung hemo-
without clinical symptoms is frequent, and it can siderosis and lipoid pneumonia.
be observed in lung function studies. Patients
may present with dry cough and exercise dys-
pnea: the rates of presentation are 15% of the Goodpasture Syndrome
patients at the beginning of the disease, and 40%
during progression. Initial interstitial lung fibro- This syndrome is characterized by glomerular
sis in the base of the lungs, which progresses, is a nephritis associated with the appearance of
complication with a poor prognosis, but its fre- lesions, lung hemorrhage, and antibodies against
quency is low during childhood. Pulmonary the glomerular basal membrane. Lung compro-
hypertension may appear secondary to lung mise appears as hemoptysis, anemia, and lung
fibrosis, but it can be observed alone. It has been infiltrations in chest X-rays, as well as an increase
described in later stages of constriction diseases, in lung diffusion, caused by the presence of
caused by the enlargement of the skin in the chest hemoglobin in the alveoli.
wall.
In juvenile systemic sclerosis, lung compro-
mise must be directly sought, even when there Autoinflammatory Diseases
are no clinical symptoms, with imaging studies of the Lung
as well as examination of lung function. High-­
resolution chest computerized axial tomography Autoinflammatory diseases are a group of dis-
may show lung disease, even when the chest orders of the innate immune system, character-
X-ray is normal, and therefore it is the study of ized by inflammation episodes, with no evident
choice in lung parenchyma evaluation for patients cause, and with no relationship to autoantibod-
with juvenile systemic sclerosis. The most fre- ies or to a specific T-cell response. Monogenic
quent findings are ground glass appearance, sub- periodic fevers have been described, with
pleural micronodules, linear opacity, and Mendelian inheritance, but also with polygenic
honeycomb images. inheritance and noninherited. The range of
Lung diffusion study and spirometry are sen- these diseases has been broadened to include
sitive tools to assess lung compromise in juvenile Behçet’s syndrome and systemic juvenile idio-
systemic sclerosis. Echography is an important pathic arthritis.
test for the early confirmation of pulmonary Most autoinflammatory diseases do not have
hypertension, dilation of the right ventricle, and lung compromise. The TNF receptor-associated
arterial pressure in the lung artery. periodic syndrome (TRAPS) presents fever epi-
sodes every 1–4 weeks, as well as synovial, cuta-
neous, and serosal inflammation, peritonitis,
Juvenile Idiopathic Arthritis pericarditis, or pleuritis. Deficiency of the
interleukin-­1-receptor antagonist (DIRA), which
Juvenile idiopathic arthritis (JIA) is a group of has a low frequency, appears during the first
diseases characterized by chronic arthritis in chil- weeks of life with pustulosis, aseptic otitis, and
dren under 16 years old. Pleural compromise is periostitis without fever. Half the reported patients
present in 4–8% of children with the systemic present with pulmonary compromise, interstitial
516 E. Talesnik Guendelman and C. Méndez Rivera

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vasculopathy caused by a mutation in the Clin N Am. 2005;52:547–75.
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ciency disorders in children. Front Pediatr. www.fron-­
ger or toe gangrene), nasal septum perforation, tierssin.org July 2014/Vol 2/Article 77.
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lung disease, lung fibrosis, paratracheal adenopa- Warzywoda M, Brn’borowicz A, Pawlak B.  Hyper
thy, and alteration of lung function. IgE syndrome (job syndrome, HIES): radiological
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HR, Sewell EM, Chattew J.  Pulmonary manifesta- tion syndrome (DiGeorge and velocardiofacial syn-
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 Acquired Immune Deficiency
Syndrome
51
Anamaría Peña Donati and Marcelo Laufer

Contents
Introduction..................................................................................................................   517
Epidemiology.................................................................................................................   518
Physiopathology............................................................................................................   518
Clinical Aspects.............................................................................................................   519
I nfectious Complications................................................................................................  519
Noninfectious Complications.........................................................................................  526
Sources...........................................................................................................................   528

Introduction characteristic symptoms appear: immune system

deterioration, opportunistic infections, and ner-
The human immunodeficiency virus (HIV) is an vous system damage. HIV binds to specific
RNA virus enclosed by a dual capsid. It is a receptors present in many parts of the body, such
member of the genus Lentivirus, family as the hematopoietic system and brain, skin,
Retroviridae, with two serotypes, HIV-1 and intestine, bone, and lung tissue. It can cause dam-
HIV-2. Its main characteristic is an enzyme-­ age directly or as a result of infections derived
labeled reverse transcriptase that enables it to from the immune suppression that it produces.
synthesize DNA by integrating its RNA into the Lung diseases are common in children with
host cell. HIV was discovered in the 1980s in the HIV and tend to be the first manifestation of
blood serum of humans who suffered from these infections. Recurrent respiratory infections
acquired immune deficiency syndrome (AIDS). in a child who also suffers from dermatitis, gen-
It has a lengthy incubation period, after which its eralized lymphadenopathy, chronic parotid com-
promise, hepatomegaly, splenomegaly, growth
deficit, chronic diarrhea, or psychomotor devel-
A. Peña Donati (*) opment retardation must also raise suspicions of
Pontificia Universidad Católica de, Santiago, Chile
e-mail: [email protected] an HIV infection.
Lung infections represent 65% of the diseases
M. Laufer
Pediatrics, Infectious Diseases, Nicklaus Children’s associated with AIDS and are the main cause of
Hospital, Miami, FL, USA morbidity and mortality in children with AIDS in

© Springer Nature Switzerland AG 2020 517

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_51
518 A. Peña Donati and M. Laufer

developing countries. In this chapter, we describe Physiopathology

both the infectious and noninfectious lung mani-
festations of HIV infection. HIV produces cellular and humoral immunodefi-
ciency. The selective loss of CD4+ T lympho-
cytes occurs because they are the main target cell.
Epidemiology HIV infects these cells and then becomes part of
their genome to destroy them. Thus, newborns
In 2013, UN/AIDS estimated that 35 million peo- with an HIV infection display a marked reduction
ple are infected with HIV globally, with 2 million in their total number of CD4+ T lymphocytes
being adolescents and 3 million under 15 years of during their first 2 years of life.
age. Most of the infected children live in Sub-­ From an immunological point of view, clas-
Saharan Africa (92%) and the Asia-Pacific region sification depends not only on the absolute num-
(6%). Data from 2013 indicate that 240,000 chil- ber of CD4+ T lymphocytes, but also on their
dren acquired the infection during that year, relative percentage. Absolute number varies
which amounts to 1 child infected every 2 min. with age and is higher during a person’s first
Similarly, 1.3 million infected women gave birth years of life. Percentage is a better predictor of
to 199,000 infected newborns (vertical transmis- progression to AIDS or death in children under
sion rate = 16%). 1  year old, whereas absolute count is more
Perinatal transmission is still the most com- appropriate for children over 6 years of age. The
mon cause of infections in children, despite the immunological classification described in
positive impact of the program for detecting Table 51.1 is important because it enables prac-
infections in pregnant women. Transmission to titioners to make a more accurate estimation of
newborns can occur in utero (35%), during child- opportunistic infection risk in children infected
birth (65%), or in the postpartum stage during with HIV, which is higher when immunological
breastfeeding (14–29%). Maternal viral load is deterioration is severe.
directly related to the likelihood of transmission The virus also infects monocytes, macro-
to the child, although the use of antiretroviral phages, and dendritic cells, but the destructive
drugs during pregnancy and childbirth cause a effect on them is not as strong as on CD4+ T lym-
significant reduction. When used during preg- phocytes; therefore, these cells become a reposi-
nancy and childbirth, zidovudine (AZT) can tory for the virus and enable it to be distributed
achieve a reduction in transmission rates ranging throughout the rest of the body. When these cells
from 8% to 26%. are infected, phagocytosis, chemotaxis, and anti-
Currently, pregnant women benefit from highly gen presentation are affected. These anomalies
effective antiretroviral regimes (HAART) com- increase susceptibility to infections.
bined with cesarean sections (in childbirths last- HIV produces an overstimulation of B lym-
ing more than 12  h) and maternal breastfeeding phocytes, which results in polyclonal hypergam-
suppression, all of which reduces transmission maglobulinemia mainly based on IgG, which
risk to less than 1%. In developed countries, verti- appears earlier than the selective loss of CD4+ T
cal transmission causes fewer HIV cases in peo- lymphocytes. This polyclonal hypergammaglob-
ple under 18 years old than sexual transmission. ulinemia is inefficient and behaves as functional

Table 51.1  Immunological classification

Immune category Age: <12 months Age: 1–5 years Age: 6–13 years
CD4/μl (%) CD4/μl (%) CD4/μl (%)
No immunosuppression ≥1500 (≥25) ≥1000 (≥25) ≥500 (≥25)
Moderate immunosuppression 750–1499 (14–24) 500–999 (14–24) 200–499 (14–24)
Severe immunosuppression <750 (<15) <500 (<15) <200 (<15)
51  Acquired Immune Deficiency Syndrome 519

hypo- or agammaglobulinemia, leading to a high Table 51.2  Respiratory system compromise

infection rate from encapsulated bacteria and an Infections not suggestive of AIDS
insufficient response to antibodies, which Persistent or recurrent upper acute respiratory
explains the recurrence of infections and the infections (otitis, sinusitis)
Acute pneumonia, pleuropneumonia (1 episode in
deficient response to immunization.
1 year)
In lung tissue, as in the peripheral blood- Bronchial infections, lung infections from herpes
stream, the virus also infects lymphocytes and simplex virus (in <1 month of life)
causes a reduction in CD4+ T lymphocytes; in Bronchial infections, lung infections from
addition, there is an increase in CD8+ T lym- cytomegalovirus (in <1 month of life)
phocytes that infiltrate interstitial and alveolar Lung infection caused by Mycobacterium tuberculosis
Infections suggestive of AIDS
spaces.
Bacterial pneumonia (2 or more episodes in 2 years)
Pneumonia from Pneumocystis jirovecii
Pneumonia from cytomegalovirus (in >1 month of age)
Clinical Aspects Bronchitis, pneumonitis from herpes simplex virus (in
>1 month of age)
Respiratory diseases secondary to HIV infection Pneumonia from Candida
Disseminated or extrapulmonary infection caused by
can be infectious or noninfectious in nature and
Mycobacterium tuberculosis
have a wide range of clinical presentations. Lung infection fromto non-tuberculous Mycobacterium
Some of these resemble those observed in (M. avium complex and others)
healthy children, which are caused by common Noninfectious causes
bacteria or viruses, whereas others are atypical, Chronic lung disease
being caused by opportunistic agents. Both can Lymphoid interstitial disease/lymphoid interstitial
pneumonitis
have a progressive and severe development, Bronchiectasis
causing acute and chronic morbidity, sequelae, Immune reconstitution syndrome
and death (Table 51.2). Tumors
The etiology of lung infections as well as their
severity, development, and outcome depend on
the patient’s immunosuppression level. In two Therefore, the current recommendation is to initi-
thirds of the children infected perinatally, who ate antiretroviral treatment in all children under
are neither diagnosed nor treated with antiretro- 1 year of age with a confirmed infection to pre-
viral drugs in a timely fashion, viral load increases vent immunological deterioration.
rapidly during the first months of life. Afterward,
the absolute count of CD4+ T lymphocytes drops
sharply, which leads to the development of severe Infectious Complications
opportunistic infections with a high mortality.
These patients are known as rapid progressors. Infections in HIV-positive children can have a
Another patient subgroup has a slower and more bacterial, viral, or fungal etiology. In general,
benign progression, with lower viral loads and they present with rapid-onset respiratory symp-
relatively high CD4+ T-lymphocyte counts that toms, increased breathing effort, fever, usually
prevent the development of opportunistic infec- with a clear chest X-ray; in contrast, noninfec-
tions. They develop bacterial infections that are tious complications are characterized by progres-
similar to normal children, but recurrent. These sive and slow starting respiratory symptoms with
cases are referred to as slow progressors. In a chest X-ray shadows.
third group, progression is intermediate.
Unfortunately, no reliable markers have been Bacterial Infections
identified earlier than 24  months of age that Upper airway bacterial infections (sinusitis and
would enable clinicians to identify the progres- otitis media) are more common in children with
sion and behavior of the virus in each individual. HIV and can be classified as clinical stage A or
520 A. Peña Donati and M. Laufer

mildly symptomatic. Recurrent respiratory bacte-

rial infections must cause clinicians to suspect an
HIV infection when they are associated with
other unspecific manifestations such as adenopa-
thy, chronic parotid swelling, hepatomegaly, or
splenomegaly.
Among the severe bacterial infections, bacte-
rial pneumonia is the most frequent infectious
entity in all stages of the disease, even without
immune deterioration, and especially during the
first 12 months of life.
During the AIDS stage, there is a high risk
of complications that is directly proportional
Fig. 51.1 Necrotizing pneumonia. Chest X-ray of
to the viral load and inversely proportional to 2-year-old girl shows a bilateral condensation pattern with
the absolute count and percentage of CD4+ T a right apical abscess. Streptococcus pneumoniae was iso-
lymphocytes. Its incidence has been reduced lated in the bronchoalveolar lavage and hemoculture
from 11 to 2 per 100 children-year with
HAART and immunizations (especially the Any episode of pneumonia or confirmed bac-
conjugate Streptococcus pneumoniae and terial pleuropneumonia indicates clinical stage B
Haemophilus influenza type b vaccines), but it or moderate symptomatology, and two or more
remains the most prevalent infection in this episodes over a 2-year period indicate clinical
group. The etiology of bacterial pneumonia is stage C or severe symptomatology.
diverse. Even though it is not easy to make an
etiological diagnosis, authors have described Treatment  Treatment for bacterial pneumonia
infections caused by gram-positive, gram-neg- is similar to that recommended for the general
ative, and mixed bacteria. pediatric population. All guidelines propose
The main cause of bacterial infection is using amoxicillin as an initial antibiotic therapy
Streptococcus pneumoniae, although Staphylo­ associated with macrolides when clinical or
coccus aureus now is more important given the radiological signs suggest the presence of an
high levels of oxacillin (50%) and clindamycin Mycobacterium pneumoniae or Chlamydia
resistance (22–30%). The most common gram- pneumoniae infection. In the case of
negative bacteria are Haemophilus influenzae Haemophilus influenzae (encapsulated or non-
(encapsulated and non-encapsulated), Escherichia encapsulated) and Moraxella catarrhalis, the
coli, Salmonella non-typhi, and Pseudomonas use of clavulanic acid or sulbactam is
aeruginosa. Other agents that cause lower respi- recommended.
ratory infections include Mycoplasma pneu­
moniae and Chlamydophila pneumoniae. Prophylaxis  Primary prophylaxis involves
In patients with HIV, bacterial pneumonia can immunizations and the administration of intrave-
lead to concomitant bacteremia and suppurative nous immunoglobulin for patients with absolute
complications such as empyema and necrotizing (IgG <400 mg/dl) or functional hypogammaglob-
pneumonia (Fig. 51.1). Long-term complications ulinemia (insufficient IgG production in response
in patients who have had severe and recurrent to specific immunizations).
lower respiratory infections include bronchiecta-
sis, which was much more common before Secondary prophylaxis is conducted with
HAART. Its clinical behavior was similar to that intravenous immunoglobulin or trimethoprim
observed in patients with cystic fibrosis colo- sulfamethoxazole (TMP-SMX) in patients with
nized by organisms such as Klebsiella sp. and more than two confirmed episodes of severe bac-
Pseudomonas sp. terial infections.
51  Acquired Immune Deficiency Syndrome 521

The conjugate pneumococcal vaccine has interleukins 1 and 6, proinflammatory substances

caused a 60-fold reduction in invasive pneumo- that foster the replication of HIV in infected
coccal disease in this population versus a 15-fold areas, thus increasing viral load and accelerating
reduction in normal children. Patients who do not the progression to AIDS and death. In this patient
receive HAART display a marked decrease in group, more treatment failures are observed
anti-pneumococcal titers over a period of 2 to because of the increasing multiresistance of the
4 years; therefore, periodic reinforcement is rec- TB bacillus (resistance to rifampicin and
ommended. It is useful to conduct an anti-­ isoniazid).
pneumococcal antibody titer test in patients with TB can appear at any point of the HIV infec-
a history of frequent or severe pneumonias to tion in children, either in the non-AIDS stage
indicate the reinforcement of the 13-valent conju- (lung compromise) or in the AIDS stage (dissem-
gate vaccine, followed by the administration of inated or extrapulmonary compromise), and
the 23-valent polysaccharide vaccine 6–8 months either with or without immunological
later in children with low titers. The conjugate H. deterioration.
influenzae type B vaccine, included in immuniza- Latent TB infection occurs when the tubercu-
tion programs, has had a positive impact on the lin test (PPD) or the interferon-γ test are reac-
incidence of invasive disease in these patients. tive in an asymptomatic patient, with a negative
bacillus smear and normal chest X-rays. Active
 ycobacterium Infections
M TB disease occurs when the patient is symptom-
The global reemergence of tuberculosis (TB) atic, sputum cultures are positive, and chest
resulting from the AIDS epidemic, among other X-rays are abnormal. In addition, PPD can be
factors, is currently followed by WHO as a global positive.
emergency. TB/HIV coinfection, manifested as Clinical presentation in HIV-positive children
either latent tuberculous infection or as active is atypical and severe, depending on the level of
tuberculous disease, is a major public health immunosuppression. Miliary compromise and
problem. Estimates suggest that, in 2009, 1.1 extrapulmonary manifestations are more com-
million new coinfections had occurred globally mon than in HIV-negative children. In general,
and 24,000 in the Americas. Because of its high they appear in children with a history of contact
prevalence, every time a TB case is diagnosed, it with TB or diagnosed TB and symptoms such as
is necessary to rule out HIV infection, and vice fever, major weight loss, sweating, tachypnea,
versa. In HIV-positive children, it is generally a and unsolved condensing or interstitial pneumo-
primary infection transmitted by an adult with an nia with persistent X-ray signs despite the treat-
active infection. High risk results from the reduc- ment administered.
tion in T1 lymphocytes, the subsequent limited Diagnosing TB in children is hard, especially
production of interferon-gamma (IFN-γ), and the in HIV-positive children. If the treating physician
functional alteration of the macrophage systems, suspects TB, it is essential to obtain samples to
all of which constitute the basic defenses of the confirm its etiology through bacteriology.
body against Mycobacterium tuberculosis. As
cellular immunodeficiency affects patients with Laboratory tests:
HIV, the infection is poorly controlled, which • Tuberculin test (PPD): Only 10–35% of
fosters its progression to TB disease, its dissemi- HIV-­positive patients infected with the bacil-
nation, the development of extrapulmonary lus have a positive PPD.  Also, given that
forms, its recurrence, and its high fatality rate miliary and meningeal infections in children
(causing the death of up to one third of patients under 2 years of age usually yield a negative
with AIDS). In addition, the reservoir that these PPD, this test is normally unhelpful for diag-
patients constitute increases the risk of transmis- nosis. In HIV-positive patients, an indura-
sion to the community. TB bacillus induces the tion of 5 or more mm is considered to be
macrophage to produce tumor necrosis factor and positive.
522 A. Peña Donati and M. Laufer

Tests that rely on interferon-γ (QuantiFERON in extrapulmonary presentations. In menin-

and T Spot) have the advantage of being objec- geal tuberculosis, brain CT scans reveal atro-
tive thanks to the use of positive and negative phy and ventricular compromise.
control tests, which makes it possible to differen- • Ganglion biopsy: Histology reveals granulo-
tiate tuberculin-positive patients caused by a mas and caseous necrosis.
recent BCG vaccination, and do not identify pos-
itive cases resulting from the booster effect of Treatment  Anti-tuberculosis therapy entails
frequent PPD in vaccinated patients. Current US several difficulties and must be tailored for each
guidelines recommend using QuantiFERON as patient. It is necessary to select drugs whose
soon as HIV is diagnosed. Patients infected peri- metabolism does not interfere with the metabo-
natally require a first test between 3 and lism of antiretroviral drugs. Rifampicin, being a
12  months of age and an annual test if the first cytochrome P450 inducer, can interact with nevi-
one is negative. rapine (a reverse-transcriptase inhibitor) and with
protease inhibitors. The ideal course of action is
• Bacillus smear: At least six sputum samples to use two nucleoside analogue reverse-­
preceded by nebulizations with hypertonic transcriptase inhibitors as antiretrovirals, plus a
saline solutions must be obtained. Other use- non-nucleoside reverse-transcriptase inhibitor.
ful samples include bronchoalveolar lavage
(80–90% positivity), ganglion tissue, urine, Initial anti-tuberculosis treatment must
cerebrospinal fluid, or other sterile fluids. include these four drugs: isoniazid, rifampicin,
• Koch culture in a Loewenstein-Jensen pirazinamide, and ethambutol or streptomycin;
medium, observed for at least 8 weeks, or in when the bacillus is confirmed to be susceptible
radiometric liquids that shorten observation to to the first three, the fourth can be suspended.
10 days. Cultures are more useful when bacil- After the first 2 months of induction therapy, iso-
lus smears are negative. niazid and rifampicin are used for 7 additional
• Semiautomatic hemoculture through lysis-­ months.
centrifuge procedure automated through a When HIV is diagnosed, soon before or after
radiometric method in disseminated tuberculosis, and HAART has not yet been initi-
presentations. ated, the decision to start administering it depends
• Polymerase chain reaction (PCR) (Xpert MTB on the patient’s immunological status and the clin-
/RIF [Xpert]), which makes it possible to ical stage, because this can lead to an immune
quickly identify the bacillus and determine the reconstitution syndrome in patients with AIDS and
presence of markers of resistance to isoniazid severe immunological deterioration. If there is no
and other drugs. immunological deterioration or if it is mild and the
• Chest X-ray: Persistent radiological images patient has not entered the AIDS stage, anti-tuber-
caused by lymphoid interstitial pneumonitis or culosis treatment must be initiated and even com-
bronchiectasis secondary to HIV infection can pleted before starting HAART.  If the patient has
confound diagnosis. In patients with tubercu- entered the AIDS stage and immunological dete-
losis, X-rays can be normal or reveal unspe- rioration is moderate or severe, HAART must be
cific images, with multifocal diffuse interstitial delayed for as long as 2 to 4 weeks after the start of
infiltrates, similar to those produced by other anti-tuberculosis therapy, or at least until the
opportunistic agents. Lymphadenopathies are induction phase has been completed. If an HIV-
often observed, with pleural effusion also positive patient is diagnosed with tuberculosis,
being possible, but X-rays tend to be normal in HAART should be suspended; alternatively, dos-
cases of advanced AIDS. age adjustments should be implemented or a
• Other imaging resources: Ultrasound and regime without rifampicin be adopted.
abdominal CT scans can reveal intraabdomi- HIV-positive patients are more likely to
nal adenopathies and necrotic visceral lesions become infected with isoniazid-resistant bacilli or
51  Acquired Immune Deficiency Syndrome 523

even with bacilli resistant to various agents. In host immunity as they do not cause diseases in
such cases, treatment must include three drugs immunocompetent patients.
with no resistance for 12  months. Options are With respect to the Mycobacterium avium
streptomycin, cycloserine, ethionamide, clarithro- complex, infections, manifestations, and prog-
mycin, azithromycin, ciprofloxacin, or linezolid. nosis are CD4+ and T-dependent. It can mani-
fest itself as a localized disease (cervical
Prophylaxis  Patients with latent tuberculosis adenitis, pneumonia, hepatitis, splenomegaly,
receiving monotherapy (isoniazid) have a signifi- or local abscesses) or as a generalized disease
cantly lower risk of progression to TB. The WHO (fever of unknown origin, weight loss, chronic
recommends prophylactic isoniazid in HIV-­ diarrhea, and pancytopenia). Cervical lymph-
positive children under 1  year of age in high-­ adenitis is more common in children aged 1–4
prevalence areas for up to 3 years, regardless of years. It is generally unilateral, has an insidi-
their PPD results. Isoniazid is also recommended ous presentation, and evolves toward fistuliza-
for 6 to 9  months, regardless of PPD, in HIV-­ tion and chronic suppuration. Lung infection
positive patients who have been in contact with usually coexists with other opportunistic infec-
confirmed tuberculosis cases once the active dis- tions and may disseminate. Chest X-rays reveal
ease has been ruled out. The bacillus Calmette– nodular or cavitary opacities and bronchiecta-
Guérin (BCG) vaccine is contraindicated in sis (Fig. 51.2).
HIV-positive children and must be delayed in
perinatally exposed newborns until a normal Diagnosis
CD4+ T-lymphocyte count is observed. • Bacillus smear: Reveals acid/alcohol-resistant
bacilli, but it does not differentiate them from
Non-tuberculosis Mycobacterium infections tuberculous bacilli.
are less frequent in children. This group includes • Culture: Blood, sputum, bronchoalveolar
the Mycobacterium avium complex (MAC), of lavage, lung tissue, ganglion tissue, bone mar-
which two species are known: M. avium and M. row, or any sterile fluids. It is recommended to
intracellulare, slow-growing (10–21 days), acid/ conduct an automated hemoculture, reseeding
alcohol-resistant, non-chromogenic coccobacilli. in a Loewenstein-Jensen medium, and per-
These microorganisms are widely distributed in forming a final diagnosis after 4–12 weeks.
the environment—water, soil, plants, and ani- • Specific tests: Amplification of specific
mals—and their pathogenicity depends on the DNA sequences, high-performance liquid

a b

Fig. 51.2  Pneumonia caused by Mycobacterium avium firmed through a PCR test of lung tissue biopsy (a). Chest
complex (MAC). Chest X-ray of a 12-year-old girl CT scan of the same patient displays condensation and
recently diagnosed with HIV displays a condensation pat- atelectasis of the left upper lobe (b)
tern and atelectasis in the left upper lobe. MAC was con-
524 A. Peña Donati and M. Laufer

chromatography, and hybridization probe be made by examining respiratory samples with

assays for identifying species and immunofluorescence, short culture, or PCR, as
genotype. well as by using PCR in blood for cases of sys-
temic infection.
Prophylaxis  Mycobacterium avium complex Cytomegalovirus is among the opportunistic
infection usually is a disseminated infection and agents that most commonly infect HIV-positive
mortality is inversely proportional to CD4+ children. Infection risk is greater than in healthy
T-counts. Infection occurs in advanced stages children, either via congenital acquisition
with severe immunosuppression (CD4+ (because of the high level of coinfection in HIV-­
T  <  100  cells/μl). Primary prophylaxis with a positive pregnant women) or via postnatal infec-
macrolide is recommended, considering patient tion (usually during the first years of life).
age and CD4+ T count (<1 year: CD4+ <750/μl; Cytomegalovirus infection risk is higher in cases
1–2 years: CD4+ <500/μl; 2–6 years: CD4+ <75/ of severe immunosuppression (CD4+ T <50 cells/
μl; >6 years: CD4+ <50/μl). It can be interrupted μl). It causes high morbidity; its fatality rate can
when the patient has received HAART and has reach 30% in HIV-positive children, and repre-
achieved immune recovery for a 6-month period. sents 8–10% of AIDS-indicating diseases. It is
often the first manifestation of an HIV infection
Treatment  Localized forms are treated with at and is associated with a faster progression of the
least two drugs (a macrolide and ethambutol) to disease and greater central nervous system com-
prevent or delay resistance. In cases of dissemi- promise. The most common presentation is inter-
nated disease, one or two antibiotics are added stitial pneumonia, which can progress to
(rifampicin, rifabutin, ciprofloxacin, amikacin, or respiratory failure or respiratory distress or
clofazmine). It is recommended to conduct a sus- become part of a systemic disease (Fig. 51.3). It
ceptibility test to rule out resistance. Treatment is occurs often as a coinfection with opportunistic
considered to have failed if no clinical response is agents such as Pneumocystis jirovecii, tuberculo-
observed and if bacteremia persists 8–12 weeks sis, and Candida, among others. Therefore, it is
after therapy. Treatment is ineffective when not necessary to demonstrate the presence of viral
complemented with HAART, because the infec- replication in lung samples to confirm a cytomeg-
tion becomes fatal if no immune recovery is alovirus disease.
achieved.

Viral Infections
Upper and lower respiratory tract infections of a
viral origin have the same incidence as in normal
children but tend to be severe. The pathogens
involved can be common viruses affecting chil-
dren such as the respiratory syncytial virus
(RSV), adenoviruses, parainfluenza (PI), influ-
enza, metapneumovirus, and rhinovirus; in cases
of systemic diseases, they can include varicella
zoster (VZ), herpes simplex (HS), Epstein–Barr,
and cytomegalovirus (CMV), which can cause
extensive and necrotizing pneumonias. Viral
excretion last longer than in normal children, up
to 30  days for parainfluenza, 90  days for RSV, Fig. 51.3  Pneumonia caused by Cytomegalovirus. Chest
and several months for adenovirus. Chest X-rays X-ray of 5-month-old infant with a multifocal pattern and
fast progression to acute respiratory distress.
show interstitial pattern, multifocal condensa- Cytomegalovirus was isolated from bronchoalveolar
tion, and pleural effusion. A quick diagnosis can lavage
51  Acquired Immune Deficiency Syndrome 525

Prophylaxis  Administration of influenza vac- P. jirovecii adheres to alveolar walls and pro-
cine from 6 months of age onward is one of the liferates in the extracellular, causing epithelial
few preventive measures available. The prophy- cell shedding followed by the generation of an
laxis of cytomegalovirus can be considered in exudate that fills the alveoli and prevents oxygen
special cases (serum antibodies IgG and CD4+ exchange. It can have an insidious or abrupt man-
T  <50  cells/μl) as well as in the maintenance ifestation with dry cough, fever, tachypnea, inter-
period after the completion of the daily treatment costal retraction, and hypoxia. Auscultation can
phase and until the patient has received HAART be normal in the beginning but, as the disease
for 6  months with immune recovery (TCD4+ progresses, a generalized reduction in air intake
≥500 cells/μl or ≥15% [1–5 years]; ≥200 cells/ and rhonchi or crackles are heard. Laboratory
μl or ≥15% [≥6 years]. tests confirm hypoxemia; also, the value of lac-
tate dehydrogenase (LDH) is very high. Chest
Treatment  Early treatment with antivirals X-rays can be initially normal or display hyper-
makes a difference in the evolution of viral aeration and diffuse interstitial images. As the
infection. Oseltamivir, when administered disease progresses, interstitial images and bilat-
within the first 72 h after symptoms begin, can eral alveolar filling can be observed, with a
reduce the severity of the disease and its compli- “ground glass” or granular reticle appearance. It
cations. It is the treatment of choice even in vac- is less frequent to observe condensation, pneu-
cinated patients and can be used as a prophylactic matocele, pneumothorax, or pleural effusion
measure in patients who have been exposed. (Fig. 51.4).
Oral acyclovir oral has a deficient absorption
level (20%); therefore, parenteral administra- Diagnosis  Pathogen identification must be
tion is recommended in severe cases of HS or confirmed, either via silver stain, identification
VZ disease. Intravenous ganciclovir is the drug of the antigen with a monoclonal antibody, or
of choice for cytomegalovirus, in association PCR of bronchial fluid obtained through bron-
with immunoglobulin IV. Valganciclovir has a choscopy or lung biopsy. Sputum induced by
50–60% oral absorption rate and is a viable hypertonic serum or nasopharyngeal aspirate
alternative for maintenance therapy. Foscarnet have less sensitivity, although they can be used
must be used in resistant cases. to identify the pathogen while avoiding invasive
methods.
Fungal Infections

Pneumocystis jirovecii
An agent currently categorized as a fungus, it was
the most common cause of atypical pneumonia in
HIV-positive children, with an incidence rate of
up to 42%. This entity, classified as an AIDS-­
indicating disease, can progress quickly with no
treatment, even leading to respiratory failure with
a fatality rate of up to 50%, especially when asso-
ciated with cytomegalovirus. It affects children
under 1 year old, particularly before 6 months of
age, and can mark the beginning of an HIV infec-
tion even if the CD4+ T-lymphocyte count is nor-
mal; however, in children over 1  year old, Fig. 51.4  Pneumonia caused by Pneumocystis jirovecii.
incidence is inversely proportional to the CD4+ Chest X-rays of 6-month-old infant with a nodular reticle
pattern and “ground glass” image associated with hypox-
T-count, with risk increasing when immunosup- emia. P. jirovecii was confirmed in a sample of bronchoal-
pression is severe. veolar lavage
526 A. Peña Donati and M. Laufer

Treatment  The therapy of choice is intravenous lung, or liver tissue). Histoplasma can be
TMP-SMX, even in patients receiving prophy- detected by measuring the antigen in urine or
lactic treatment with this antimicrobial drug. blood. Candida tends to infect the gastrointesti-
Therapeutic alternatives are pentamidine, atova- nal rather than the tracheobronchial system;
quone, dapsone, or primaquine in combination however, dissemination can follow infection in
with clindamycin. This antimicrobial drug must any of these two locations. Aspergillus infection
be combined with steroids (prednisone or equiva- is uncommon, but it occurs in late states of the
lent; 2  mg/kg/day divided into two doses, fol- disease with severe immunosuppression and can
lowed by decreasing doses over the next 7–14 affect the paranasal sinuses, the nasal cavity,
days) during the first 5–7 days. and the lung, producing necrotic lesions.
Diagnosis is made with PCR, galactomannan
Prophylaxis  Prophylaxis is effective and is rec- measurements (both of which can be used as
ommended in all children under 1 year old, both follow-up strategies), and chest CT scans sug-
infected or undergoing tests (undetermined sta- gestive of infection.
tus), in those with perinatal exposure regardless
of CD4+ T-count, and in children over 1 year old Treatment  Prognosis for these infections has
with severe immunosuppression (immunological changed given the multiple therapeutic alterna-
stage 3) or at clinical stage C. Prophylaxis can be tives currently available. Polyenes (amphoteri-
suspended in newborns not fed with breast milk cin and combinations with various lipophilic
after ruling out infection from perinatal exposure vehicles) have been replaced by two types of
and in infected children who have received anti-­
mycotics: azoles (fluconazole, itracon-
HAART for ≥6  months with immune recovery azole, voriconazole, and posaconazole, with the
(CD4+ (≥500  cells/μl or ≥15% [1–5  years]; latter three targeting molds and yeasts) and
≥200  cells/μl or ≥15% [≥6  years]. In younger echinocandins (micafungin, caspofungin, and
children, it must be maintained until the child anidulafungin).
reaches 12 months of age, regardless of HAART
length and immune recovery. The prophylactic
drug of choice is TMP-SMX three times per Noninfectious Complications
week. Alternatives are dapsone, oral atovaquone,
and nebulized pentamidine.  hronic Lung Disease
C
This entity is relatively frequent in the pediatric
Other fungi that affect the respiratory system population infected with HIV, especially in chil-
are Candida sp., Cryptococcus neoformans, dren who do not receive HAART. Previous to this
Histoplasma capsulatum, Coccidiodes immitis, therapy, up to one third of children under 4 years
Penicillium marneffei, and Aspergillus. of age displayed chronic chest X-ray changes
These infections often produce invasive and associated to low CD4+ T count and high viral
disseminated diseases with general symptoms load: persistent consolidation for ≥3  months
such as fever, appetite loss, depressed mood, and (8%), nodular changes for >3  months (8%), or
weight loss. reticular changes and increase in bronchovascular
Cryptococcosis is usually complicated with marking lasting ≥6 months (14%). These patients
meningitis. Histoplasma, a dysmorphic fungus present with clubbing, persistent crackles, tachy-
whose mold form in nature can enter the lung pnea, hypoxemia, and exercise intolerance.
through inhalation, commonly causes pneumo- The following conditions include the spec-
nia first, but dissemination to other organs is trum of manifestations described in these patients
very frequent. Etiological diagnosis is made whose clinical and radiological presentation is
using cultures (blood, bone marrow, and lymph, juxtaposed:
51  Acquired Immune Deficiency Syndrome 527

• Lymphocytic interstitial pneumonia

• Chronic bacterial infections
• Bronchiectasis
• Interstitial pneumonia

Lymphocytic interstitial pneumonia (LIP) is

the most common of these entities. This is the
only B-category condition that classified the
patient as having AIDS, but they have become
uncommon after HAART. It is important to
remember it when working with patients who
have not started HAART or who have displayed
poor treatment adherence. It is a noninfectious Fig. 51.5 Lymphocytic interstitial pneumonia. Chest
radiological entity. Its etiology is unknown and X-ray of 5-year-old girl with a persistent reticulonodular
probably multifactorial, although it has been sug- pattern, no response to treatment, and negative etiological
tests
gested that it related to a lymphoproliferative
response, with hyperproduction of cytokines
against HIV and other agents such as Epstein– Bronchiectasis can occur as a sequela of recur-
Barr virus. rent bacterial pneumonia, lymphocytic interstitial
LIP commonly starts during the second year pneumonia, infection from Pneumocystis pneu­
of life, although some chest X-ray changes have moniae, and non-tuberculosis Mycobacterium
been described before 12 months in asymptom- disease, among other diseases. Chest X-ray
atic patients. It presents with cough, tachypnea, changes persisting for over 6 months, including
and exercise intolerance, progressing to respira- small cystic lesions, opaque areas, atelectasis,
tory failure with cyanosis, clubbing, dyspnea, and loss of volume from lung destruction, should
and progressive hypoxemia. It is accompanied by cause clinicians to suspect bronchiectasis
the same lymphoproliferative response in lymph (Fig.  51.5). High-resolution CT scans reveal
nodes, liver, spleen, and parotid glands, mani- bronchial dilation, thickening of the bronchial
fested by adenopathy, hepatomegaly, splenomeg- wall from fibrosis, and air entrapment.
aly, and parotid hypertrophy. Chest X-rays show
bilateral reticulonodular interstitial infiltrate with I mmune Reconstitution Syndrome
or without perihilar adenopathy that persists Immune reconstitution syndrome is a paradox-
despite treatment. Patients have hypergamma- ical state of clinical deterioration that follows
globulinemia with IgG levels over 2000  mg/dl. the start of treatment for an opportunistic
Definitive diagnosis is achieved by histology of a infection concomitant with antiretroviral ther-
lung biopsy showing interstitial, diffuse, and apy. It results from the patient’s immunologi-
peribronchiolar infiltration of lymphocytes and cal recovery, which causes an exaggerated
plasma cells, but generally, diagnosis be could be inflammatory response to certain antigenic
based on the observation of persistent chest X-ray stimuli. This clinical entity can occur in
images despite antimicrobial treatment for patients who have suffered multiple opportu-
2 months and the absence of a detectable agent. nistic infections that have been treated or
All chest X-ray changes described can respond to before subclinical and atypical infections nei-
HAART and patients who display undetectable ther diagnosed nor treated. It has been
viral loads for over 6  months improve signifi- described in infections produced by mycobac-
cantly. Patients who have been unable to benefit teria, cytomegalovirus, herpes simplex and
from HAART require support treatment: oxygen zoster, Cryptococcus neoformans, lung capil-
therapy, bronchodilators, and sometimes antimi- lary wedge pressure, among others. In patients
crobial agents. with tuberculosis, it manifests itself through
528 A. Peña Donati and M. Laufer

the appearance or worsening of symptoms that Sources

had initially receded: Fever, lung infiltration,
skin lesions, peripheral and mediastinal ade- Centers for Disease Control and Prevention. Revised
nopathies, and serous gland and central ner- surveillance case definition for HIV infection-United
States, 2014. MMWR. 2014;63(RR-3):1–10.
vous system damage, all of which are CDC.  Guidelines for the use of antiretroviral agents in
potentially severe symptoms. PPD also pediatric HIV infection 1994 revised classification
becomes positive. system for human immunodeficiency virus infec-
Immune reconstitution syndrome appears dur- tion in children less than 13  years of age. MMWR.
1994;43(RR-12):1–10.
ing the first 3 months after the start of antiretrovi- CDC. Guidelines for prevention and treatment of oppor-
ral therapy, generally during the first 15–21 days. tunistic infections among HIV-exposed and HIV-­
It is self-limited and can last for up to 40 days. infected children. MMWR. 2013;62(44):889. http://
Etiological tests yield negative results. In some aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guide-
lines_pediatrics.pdf
cases, it is necessary to administer steroids to Coinfección TB-VIH.  Guía clínica, versión actualizada
control the patient’s symptoms. 2010. Washington DC: Organización Panamericana
Diagnosis is clinical and requires ruling out de la Salud (OPS); 2010.
treatment failure, adverse effects of the medica- Dankner W, Lindsey J, Levin M, Pediatric AIDS Clinical
Trials Group Protocol Teams. Correlates of oppor-
tions, associated infections, or tumors. Also, it tunistic infections in children infected with the
must meet the following conditions: temporal human immunodeficiency virus managed before
connection with the start of antiretroviral therapy, HAART. Pediatr Infect Dis J. 2001;20(1):40–8.
severe immunosuppression when starting antiret- Graham SM.  Non-tuberculosis opportunistic infections
and other lung diseases in HIV-infected infants and
roviral administration, and good immunological children [State of the Art]. Int J Tuberc Lung Dis.
and virological response to this therapy. To pre- 2005;9(6):592–602.
vent the appearance of the immune reconstitution Kilborn T, Zampoli M. Immune reconstitution inflamma-
syndrome, it is necessary to rule out the presence tory syndrome after initiating highly active antiretro-
viral therapy in HIV-infected children. Pediatr Radiol.
of opportunistic infections before administering 2009;39(6):569–74.
antiretrovirals; also, infections must be treated Nachman S, Gona P, Dankner W, Weinberg A, Yogev R,
adequately some weeks before initiating antiret- Gershon A, et al. Rate of serious bacterial infections
roviral therapy. among HIV-infected children with immune reconsti-
tution who have discontinued opportunistic infection
prophylaxis. Pediatrics. 2005;115(4):488–94.
Neoplasia Panel on Antiretroviral Therapy and Medical Management
Although neoplasias are infrequent in children of HIV-Infected Children. Guidelines for the Use of
affected by HIV, their incidence is higher than in Antiretroviral Agents in Pediatric HIV Infection.
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pedi-
normal children. After being diagnosed with atric-guidelines.pdf. Accessed on July 15th of 2015;
AIDS, 2.5% of these children develop malignant table 7, page F-9.
tumors. The most common neoplasms are non-­ Peña A, Larrañaga C, Luchsinger V, Villarroel J, Chávez
Hodgkin lymphoma, Kaposi’s sarcoma, leiomyo- A, Wu E y Comité Nacional de SIDA Pediátrico,
Sociedad Chilena de Pediatría. Enfermedad por cito-
sarcoma, and Hodgkin’s lymphoma. Neoplasms megalovirus (CMV) en niños chilenos infectados por
tend to be highly undifferentiated. el virus de la inmunodeficiencia humana (VIH). Rev
These tumors can start in the lung or spread to Chil Infectol. 2007;24(6):477–84.
it. Clinical presentation is similar to that of pneu- Theron S, Andronikou S, George R, du Plessis J, Goussard
P, Hayes M, Mapukata A, Gie R. Non-infective lung
monia with cough, fever, hemoptysis, and exer- disease in HIV-positive children. Pediatr Radiol.
cise intolerance. Because lymphatic tissue is 2009;39(6):555–64.
abundant in the airway, lymphatic proliferation is UNAIDS.  The Gap report. Acceso 24 de octubre
common in HIV infection, and pseudo-­ de 2014 http://www.unaids.org/en/resources/
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lymphomas are usually detected.
 Sickle Cell Disease
52
Ofelia Álvarez and María Angélica Wietstruck

Contents
Definition........................................................................................................................ 529
Epidemiology................................................................................................................. 530
Etiology and Physiopathology...................................................................................... 530
Clinical Manifestation of Sickle Cell Disease............................................................. 532
 espiratory Clinical Manifestations, Diagnostic Approach and Treatment........... 532
R
Acute Chest Syndrome................................................................................................... 532
Pulmonary Function Tests............................................................................................... 535
Airway Hyperreactivity and Asthma.............................................................................. 536
Hypoxemia...................................................................................................................... 537
Sleep Obstructive Apnea................................................................................................. 537
Thromboembolism.......................................................................................................... 538
Chronic Pulmonary Disease............................................................................................ 538
Lung Hypertension.......................................................................................................... 538
Sources........................................................................................................................... 540

Definition globin beta-chain in the hemoglobin (Hb) mole-

cule, which results in a substitution of glutamic
Sickle cell disease (SCD) is a type of recessive acid by a valine in the 6th position of the chain,
autosomal hemoglobinopathy. It is caused by a thus creating HbS. This Hb is polymerized in the
specific mutation in the gene that codifies the red blood cell, causing an alteration in its shape
and hemolysis, which causes acute events and
progressive damage in different organs. In 1910
O. Álvarez (*) James Herrick was the first to describe the char-
Clinical Pediatrics, University of Miami, acteristic shape of the red blood cell (drepano-
Coral Gables, FL, USA
e-mail: [email protected] cytes, sickle cell, from the Latin falx, falcis:
“sickle shape”). Subsequently, Pauling et  al.
M. A. Wietstruck
Pediatrics, Oncology, Pontificia Universidad Católica identified electrophoresis anomalies in HbS, and
de Chile, Santiago, Chile proposed the term “molecular disease” in 1949,
e-mail: [email protected] thus demonstrating for the first time that the
© Springer Nature Switzerland AG 2020 529
P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_52
530 O. Álvarez and M. A. Wietstruck

p­ roduction of an abnormal protein could be the therefore Hb is polymerized within the red blood
cause of a genetic disorder. cell, and its membrane is distorted, originating a
There are several genotypes of the disease, rigid cell with poor deformability. Hb polymers
causing different clinical manifestations. The trigger a cascade of events within the cell:
concept of sickle cell anemia refers to the most
usual presentation, in which the patient inherits a. Activation of transport channels, with potas-
HbS from both parents, thus being homozygote sium loss and cellular dehydration.
for the disease (HbSS); those who inherent an b. Disruption of the red blood cell membrane,
S-gene and another causing alteration in the thus exposing it to membrane components,
β-chain will have other presentations of sickle cell such as band 3 protein, which binds to specific
disease, such as HbSC or HbS/β thalassemia (β0 antibodies, promoting erythrophagocytosis
when there is no production of β chains; β+ when caused by macrophages.
there is partial production). In all of these, HbS c. Liberation of hemoglobin in the plasma, with
represents the greatest proportion of Hb in the Fe3+, which promotes oxidative damage in the
erythrocyte. Heterozygous patients inherent only microenvironment.
one allele from their parents: the other allele is
normal (HbA), and they are named carriers Vaso-occlusive crises are caused by erythro-
(HbAS), and have what is known as “sickle cell cyte and leukocyte entrapment in the microcircu-
trait.” Carriers are usually asymptomatic. lation, originating vascular obstruction and tissue
ischemia. Although this process requires HbS
polymerization, the trigger event for vascular
Epidemiology obstruction is a type of inflammation. This
inflammation results from an interaction between
The distribution of HbS in the world indicates the erythrocyte and vascular endothelium, caus-
two factors: migration and the selection of indi- ing obstruction and ischemia episodes, which are
viduals who are HbS carriers because of their followed by a restitution of the vascular flow,
resistance to malaria in endemic regions. The causing tissue damage mediated by reperfusion.
greatest prevalence of SCD is in tropical Africa. Then, oxidative stress is triggered, which causes
It has been estimated that every year 230,000 adhesion molecule overexpression, increasing
children affected by this disease are born in this inflammatory cytokines synthesis and leukocyto-
region (0.74% of all live births), in comparison to sis. Hemolysis also contributes to vaso-­occlusion.
the 2,600 children born in the United States, and Hemoglobin liberation in plasma, caused by
1,300 in Europe. Migrations have spread the dis- intravascular hemolysis, generates superoxide
ease in America, not only in the African popula- radicals and hydroxyl, which are potent inhibi-
tion, but also in their descendants. Diagnosis is tors of nitric oxide (NO). This compound is pro-
confirmed with Hb analysis through electropho- duced under normal conditions in the endothelium
resis or chromatography. and regulates the basal vasodilator tone, inhibits
platelets, hemostatic activation, and the expres-
sion of adhesion molecules dependent on the
Etiology and Physiopathology nuclear factor kβ (FNkβ). Hb release into the
plasma also causes endothelial dysfunction and
The physiopathological manifestations of SCD are NO resistance. Hemolysis also liberates arginase-
hemolysis and vaso-occlusion (Fig.  52.1). When ­1 in the erythrocyte, which metabolizes arginine
red blood cells flow in microcirculation, Hb deox- into ornithine, exhausting the substrate required
ygenation is caused, which involves a change in to synthesize NO.  All of this helps to maintain
the composition of the molecule. HbS is less solu- hypercoagulability, with an increase in the
ble in a deoxygenated environment (which can ­platelet activation and the levels of procoagulant
also be caused by stress, hypoxia, or acidosis), and ­factors in the blood.
 Pain
strokes Acute chest syndrome
52  Sickle Cell Disease

Osteonecrosis, nephropathy

Erythrocyte oxigenated with Hb S Inflammation

Adhesion molecules expression
Hypercoagulability
Hemolysis

Vaso-occlusion

Hb free, non-NO activation

Generation of free radicals

Nitric oxygen (NO)

Deoxygenated erythrocyte with HbS poly. Reperfusion
Pulmonary hypertension
Priapism
Ulcers in legs
Cerebrovascular disease

Vasculopathy and endothelial dysfunction

Dehydrated erythrocyte
(drepano cyte)

Fig. 52.1  Physiopathology of sickle cell anemia. (Source: Adapted from Rees DC et al. Lancet. 2010;376:218–222)
531
532 O. Álvarez and M. A. Wietstruck

It is important to note that acute and chronic may present growth and puberty delay, cognitive
inflammatory events happen in the lung because alterations, and cerebrovascular accidents. Adults
erythrocytes are exposed to relatively low O2 ten- tend to have articular pain, chronic ulcers in the
sions, as well as the slow flow of the cells. The legs, kidney failure, and neurocognitive
airway and vascular system are in close connec- disorders.
tion, which eases the transference of inflamma- Sickle cell anemia complications can appear
tory mediators among each other. in any organ, and some of them can be very seri-
ous. In this chapter we only present the pulmo-
nary complications (Table 52.1).
 linical Manifestation of Sickle Cell
C
Disease
 espiratory Clinical Manifestations,
R
SCD has considerable phenotypical heterogenic- Diagnostic Approach and Treatment
ity, influenced by genetic and environmental fac-
tors. Hb of fetal concentration (HbF), coexistence Acute Chest Syndrome
of other hemoglobinopathies, and certain types of
polymorphism in simple nucleotides modulate the Acute chest syndrome (ACS) is a symptom of
risk of certain complications. Among environ- sudden pulmonary damage, defined as an infiltra-
mental factors, environmental humidity, cold, and tion of new consolidated alveoli in chest X-rays,
pollution negatively influence the patient, and with no evidence of atelectasis, and which
particularly by increasing vaso-occlusive events. involves at least a whole lung segment. Generally,
Complications worsen with age. In infants, the patient presents with chest pain, fever, tachy-
dactylitis (painful inflammation of the fingers pnea, wheezing, cough, and hypoxemia. The
and toes), anemia, hyperbilirubinemia, spleno- Cooperative Study of Sickle Cell Disease
megaly, and infections in the respiratory tract are (CSSCD) reported an incidence of 29% (12.8
common. Among other complications, children episodes for 100 patient-years) in patients with
sickle cell anemia type SS.  Almost half the
Table 52.1  Respiratory problems associated with sickle patients with sickle cell anemia will present with
cell anemia one episode of acute chest syndrome, which is
Pulmonary Respiratory the second cause of hospitalization, after vaso-­
manifestation symptoms Causes occlusive crisis (VOC). This may be the initial
Acute chest Hypoxemia and Multifactorial
presentation, although it can also appear after the
syndrome dyspnea
Crackles first 3 days, in 10% to 20% of the cases during
Sound reduction their hospital stay. Children between 2 and
in lung fields 4  years of age have the greatest incidence
Asthma Wheezing Airway (25.3 years per patient).
Dyspnea hyperreactivity
Alterations in Asymptomatic Restrictive and
Risk factors for this complication involving
lung function Hypoxemia obstructive lung having HbSS or HbS/β0, thalassemia, asthma,
disease chronic hypoxemia, low HbF, tobacco smoke
Obstructive Flow oximetry Increase of lymph exposure, general anesthesia, and surgery, mainly
sleep apnea reduction during tissue in Amygdale
abdominal, and during the winter season. There
sleep and adenoids
Apnea are multiple causes for ACS. The National Acute
Day Hypoxemia Hemoglobin Chest Syndrome Study Group (NACSSG) stud-
hypoxemia Dyspnea desaturation ied the causes in 671 episodes presented in 538
Pulmonary fibrosis patients. Infections were the main cause in 29%
Pulmonary Hypoxemia Hemolysis
hypertension Dyspnea Endothelial
of the cases. It is thought that respiratory infec-
Exercise dysfunction tions promote an inflammatory response in the
intolerance lung. Pneumonia caused by Chlamydia was the
52  Sickle Cell Disease 533

most common cause, followed by the pneumonia reduction of hemoglobin levels of 0.7  g/dl on
caused by Mycoplasma, viral pneumonia, and average, and sometimes thrombocytopenia is
bacterial infections last. also present. Thrombocytopenia is an indepen-
Another cause for the acute chest syndrome is dent risk factor to suffer from multilobe ACS, as
fat embolism. During a bone ischemic event, a well as for needing assisted ventilation. Although
piece of the marrow or bone that is detached most patients can be treated without problems,
because of a bone marrow stroke migrates 13% may require assisted ventilation. CSSCD
through the blood flow to the lungs. As a conse- investigators reported a mortality of 1.1% of chil-
quence, sudden inflammation appears. This syn- dren and 4.3% in adults. Other studies have
drome caused by fat embolism tends to have a reported a rate of almost 9% in adults.
severe clinical presentation, and it tends to appear During an episode of vaso-occlusive crisis, it
with pain, neurological symptoms, thrombocyto- is recommended to constantly monitor the oxim-
penia, and increase in transaminases. etry. If the patient develops hypoxemia (oxime-
Activation of the secretory phospholipase A2 try <95%), or if during auscultation symptoms or
hydrolyzes the fat emboly in sn-2 position, creat- signs compatible with acute chest syndrome
ing free fat acids and lysophospholipids, which appear, a chest X-ray will be required. The diag-
cause lung damage. When arachidonic acid is nosis is confirmed by the finding of a new con-
caused by this hydrolysis, a series of inflamma- solidation in the chest X-ray. Consolidations are
tion mediators appear, such as thromboxane, leu- more common in lower and medial lung fields
kotrienes, and prostaglandins. Secretory (Fig. 52.2). There may be pleural effusion, usu-
phospholipase A2 increases (336  ±  209  ng/ml; ally sterile. This infiltration is long lived, usually
basal level 10 ± 8.4 ng/ml) during an acute chest continuing between 10 and 12 days, especially if
syndrome presentation, and this increase can pre- an infection is involved. Computerized tomogra-
dict the disease within the following 24–48  h. phy gives a better view of hyperfusion, reduced
Nevertheless, this analysis is still not commer- number of arterioles and venules, and areas with
cially available, and it has to be validated as a ground glass presentation.
diagnostic test. It is recommended to repeat the hemogram to
A third mechanism of the ACS is pulmonary diagnose anemia and thrombocytopenia, as well
strokes. This phenomenon has not been carefully as obtaining a crossed histocompatibility test, in
studied, and it could be an exclusion diagnosis. case a transfusion is needed. Obtaining a gaso-
Recently, it has been observed that patients may metric analysis will be of use during the treat-
have pulmonary artery thrombosis. This etiology ment, particularly if the patient presents with a
was discovered in 17% of the cases using multi- case of respiratory distress. If fever is present, a
detector computed tomography (CT). Most of the blood culture is required, to identify the bacterial
positive findings (81%) in the study by Mekontso agent in a reduced number of patients (3.5%).
Dessap et  al. were partial defects in blood ves- The following are not routine tests: sputum cul-
sels. Patients received anticoagulation treatment. ture, D-dimer exam, and computerized
Risk factors involved were thrombocytosis and tomography.
less evidence of hemolysis. Bronchoscopy is not necessary for diagnosis
The clinical presentation of the ACS fluctuates and it is not recommended. Nevertheless, in spe-
in severity. The physician must be alert to detect cial cases, if the patient’s condition worsens con-
the beginning of this process. The typical clinical siderably in spite of the treatment, it could help to
presentation is characterized by chest or limb find a cause such as plastic bronchitis. This com-
pain, and fever, followed by hypoxemia and dys- plication consists of a mucus blockage caused by
pnea. Sometimes the patient has yellow sputum, bronchial secretions that worsens the hypoxemic
probably related to fat embolism. Lung examina- state and lung condensations. In this case, the
tion may reveal crackles, wheezing, and reduc- procedure improves the patient’s condition, both
tion of lung sounds. It is common to find a clinically and radiographically. Secretion block-
534 O. Álvarez and M. A. Wietstruck

a b

Fig. 52.2  Acute chest syndrome (ACS) shown in chest X-ray in 12-year-old schoolchild with ACS (a) at admittance
caused by coronavirus (CoV), and (b) after ACS has been established

ages can be removed with saline washing and red blood cells must be S negative. Blood replace-
continuous suction of the blockage, which is then ment is recommended for the cases when the ini-
attached to the tip of the bronchoscope; after this, tial hemoglobin is high (Hb  ≥  10  g/dl) and the
the bronchoscope is removed, with the blockage patient requires transfusion. Other indications for
of the airway attached to it. blood replacement are severe hypoxemia in spite
Figure 52.3 summarizes the algorithm of diag- of oxygen therapy, patients who need an artificial
nosis and management of ACS. One of the most respirator, multilobe ACS, and also if there is no
important measures to avoid in this syndrome is improvement after a simple transfusion.
directed spirometry with 10 maximum inspira- An echocardiography is recommended for
tions every 1–2  h when the patient is awake. patients who need intensive care to detect lung
Small children who do not know how to use the hypertension. If this is the case, patients must
equipment may blow soap bubbles. Another receive intensive treatment with blood
important measure is to adequately manage pain, replacement.
without oversedation. Maintenance hydration is Because of airway hyperreactivity in SCD,
important during the vaso-occlusive process, some investigators propose the routine use of
because patients with SCD do not concentrate bronchodilators, although others only use it for
urine correctly and tend to dehydrate. treating wheezing or prolonged expiration.
Nevertheless, excessive liquids should be Use of steroids such as IV dexamethasone
avoided, as this promotes lung edema. 0.3 mg/kg every 12 h at four doses may shorten
A combination of an IV cephalosporine, such hospitalization time, but it is associated to relapses
as cefuroxime, with a macrolide such as oral in up to 25% of the patients once the treatment is
azithromycin, is the standard care. As an alternate interrupted, and therefore its use is controversial.
regime, in case of allergies, a quinolone or a mac- Although NO seems to be related to the pathology
rolide with a beta-lactam antibiotic is recom- of the hemolysis, as well as improving ACS in
mended. Oxygen must be supplied to keep the preliminary trials, it did not reduce the duration of
saturation over 95%. Blood transfusion must not the vaso-occlusive crisis. Therefore, it had no
surpass a maximum of Hb 10–11  g/dl to avoid impact on the development of this syndrome in
increasing viscosity. This precaution may prevent clinical trials done afterward.
ACS worsening, and is are recommended for ACS morbidity is wide, both in the short and
severe anemia or persistent hypoxemia. Transfused long term. This syndrome may be conditioned to
52  Sickle Cell Disease 535

Hypoxemia
Fever Reduction of
Chest pain pulmonary sounds
Dyspnea Crackles and
wheezing

Symptoms and signs

Chest x ray with new

consolidation without Worsening of anemia
evidence of atelectasis

Diagnosis

Respiratory
support, including Treatment
Cefuroxime
oxygen or more
Azithromycin
advanced help if
Bronchodilators
needed.
Spirometry
Transfusion if
needed.

Fig. 52.3  Algorithm of diagnosis and management of ACS

the development of chronic lung disease, acute The prevalence of acute kidney damage
lung hypertension during the episode (specially increases with the severity of the chest syndrome.
in adults), and respiratory failure (13% of Patients with this syndrome may develop multi-
NACSSG patients). Wide lobal affectation, plate- ple organ failure. Hydroxyurea, a drug that has
lets <200,000/mm3, and a history of heart disease the capacity to increase HbF, or a chronic regime
are independent prognosis factors for respiratory of monthly transfusions could reduce the recur-
failure. For difficult cases of respiratory failure rence or severity of the episodes. Patients who
that do not respond to conventional treatment, continue to experiencing episodes even when
high-frequency oscillator and extracorporeal treated with hydroxyurea or transfusions are
membrane oxygenation (ECMO) have been used. candidates for bone marrow transplant, espe-
­
Neurological events are other complications cially if they have a histocompatible sibling.
during ACS, appearing in 11% of the patients.
The most common events are alterations of the
mental state, convulsions, and neuromuscular Pulmonary Function Tests
abnormalities. A platelet count under
200,000  mm3 is a risk factor for neurological Spirometry, lung volume, diffusing capacity, or t
complications. transfer factor of the lung for carbon monoxide
536 O. Álvarez and M. A. Wietstruck

Table 52.2  Lung function As patients age, lung function worsens. Only
↓Functional residual capacity (FRC) 10% of the adults with sickle cell disease have a
↓Forced expiratory volume in 1 s (FEV1) normal lung examination according to the
↓Forced vital capacity (FVC) CSSCD analysis, which was conducted before
↓Peak expiratory flow (PEF) the general use of hydroxyurea. Generally, adult
Normal FEV1/FVC
patients showed a reduced lung cavity of about
No change when using bronchodilator
70  ±  15% on average in relationship to the
↓Peak expiratory pressure (PEP)
expected value, with restrictive pattern and a
DLCO adjusted for 64 ± 20% expected value of
(DLCO), corrected for hemoglobin, and reactiv- hemoglobin. Spirometry was within normal, with
ity measures of the reversible airway with bron- FEV1 and FVC values about 83% and 84% of
chodilator are routine lung function tests for what was expected, respectively.
patients with SCD.  The methacholine parasym- Therefore, a yearly evaluation of lung function in
pathetic agonist challenge test is not done rou- children who can cooperate and adults is important
tinely, because of the low risk to induce to detect changes. The exam must be preferentially
vasoconstriction and vaso-occlusion. done when the patient is stable, and at least 2 weeks
These patients suffer from lung dysfunction after a painful episode. Although hydroxyurea
(Table 52.2). During childhood, obstructive ven- reduces the number of ACS events in both adults and
tilatory dysfunction may appear in 35% to 37% children, there is currently not enough information
of the cases, and restrictive ventilatory dysfunc- to know if it will modify the changes in lung func-
tion may appear in 8%. The Wedderburn study, tion. The study BABY HUG Follow Up II, spon-
which included children with SCA who were sored by the National Institute of Health in the
5–16 years old, concluded that functional resid- United States, will evaluate if this drug preserved
ual capacity (FRC), forced expiratory volume in lung function after 10 years, in comparison to those
1  s (FEV1), vital forced capacity (VFC), and children who have not received hydroxyurea.
peak expiratory flow (PEF) are lower in com-
parison to healthy children, but the FEV1/VFC
proportion is the same. These differences persist Airway Hyperreactivity and Asthma
after receiving a bronchodilator, which suggests
a mild restrictive disease. After the 10 years of Airway hyperreactivity, measured after broncho-
age, 14% of the patients had restrictive or dilator use or subfreezing air hyperventilation, is
obstructive alterations. Children with sickle cell more common in children with SCD than in con-
anemia may lose 3% of FEV1 and 2% of total trol patients, particularly for younger children.
capacity per year. Prevalence of such hyperreactivity may be as
Besides this, patients with SCA have a reduced high as 85% in children with SCD and asthma,
percentage of peak expiratory pressure (PEP), in and 64% for SCD patients without asthma.
comparison to peak inspiratory pressure (PIP), Hyperreactivity detected after methacholine is
which is the inverse proportion of normal adults 78% in patients with SCD, in comparison to 18%
and children. This PEP deficiency may contribute in children in the general population.
to a reduction in lung volume, as well as atelecta- As a comparison, Valdivia et  al. pointed out
sis. Changes in expiratory muscle force are that there was a 9% prevalence of asthma, and
caused by the fact that abdominal and internal 20% of wheezing, during the last 12  months
intercostal muscles are supplied by epigastric and before the study in Chilean schoolchildren. In the
intercostal arteries, which do not have extensive United States, 16.8% of 291 children with SS
collaterals. On the contrary, the diaphragm con- hemoglobin, who were followed as part of the
tributes to inspiration, and it is supplied by sev- multi-centric observational study of the CSSCD,
eral arteries, and therefore is more resistant to had bronchial asthma. This prevalence is similar
ischemic processes. to the asthma prevalence among Afro-Americans.
52  Sickle Cell Disease 537

It is important to point out that asthma patients desaturation in sickle cell anemia is in part
have a two- to four fold risk to develop acute caused by the movement to the right of the
chest syndrome during a hospitalization for a hemoglobin dissociation curve, due to HbS
vaso-occlusive crisis, as well as having long hos- properties and the effects of chronic anemia
pitalizations, and to be readmitted 3  days after through biphosphoglycerate 2.3. A retrospective
they were discharged. Also, asthma is associated analysis reported by Quinn, which involved 585
to a double death risk among patients with SCD. children under 20 years old, with an average age
It is not clear why asthma may complicate of 9 years old, found that patients with SS or S/
SCD. The explanation may lie in common mech- β0 thalassemia had an average pulse oximetry
anisms, such as leukotrienes. Leukotrienes are saturation (Sat O2) of 96.3%; 33% presented
lipids derived from arachidonic acid that mediate with a saturation  <96%, and 2.8% presented a
inflammation. Phospholipase A2 releases arachi- saturation under 90%. When compared to the
donic acid from the cellular membranes and patients who had HbSC or S/β+ thalassemia,
causes the production of A4 leukotriene. they had an average O2 saturation of 98.7%;
Leukotriene B4, which is produced in this pro- 3.6% had a saturation level <96%, and 0.5% at
cess, is involved in the activation and chemio- <90%. A good saturation was correlated with
taxis of neutrophils and cysteine leukotrienes, higher Hb, reticulocyte count, and lower age in
causing bronchoconstriction, smooth muscle pro- the patients with SS/Sβ0.
liferation, mucus production, and airway edema; It is recommended to control O2 saturation
these may be associated to pain pathogeny. during the follow-up of these patients. It is also
The clinical record must include questions about important to check those patients who received
the onset of respiratory distress and wheezing, exer- IV opioids during pain exacerbations to pre-
cise intolerance, and family history of asthma. vent a prolonged hypoxemia. Oxygen adminis-
Patients can be evaluated at the same time with tration in hypoxemic patients with sickle cell
questionnaires to detect asthma. Controlling envi- disease is a safe treatment that does not
ronmental factors and the possibility of other condi- increase anemia.
tions, such as gastroesophageal reflux, sinusitis, and
obstructive sleep apnea, must be considered.
A patient with asthma and SCD must be treated Sleep Obstructive Apnea
as any other, following the recommendations for
asthma diagnosis and treatment summarized by a Snoring prevalence during sleep tends to be
group of experts at the National Institute of Health increased in patients with sickle cell disease
(NIH) in the United States, which are also avail- (37%), and the same happens for sleep obstruc-
able on the Internet. Although there is some evi- tive apnea (19%), because of the increase in the
dence that systemic steroids may exacerbate a lymphatic tissue of amygdale, adenoids, and ret-
vaso-occlusive crisis, the benefit of asthma control ropharyngeal nodes, which may increase because
exceeds the risks. Therefore, inhaled or systemic of the functional asplenia. At the same time,
steroids should be administered if they are needed. apnea/hypopnea and night hypoxemia are related
If a beta-3 agonist is needed, it may be necessary to priapism, pain exacerbations, and
to have an electrocardiogram to evaluate the QTc cerebrovascular events. Clinical history must
­
interval, because such agonists may increase mor- include questions about sleep disorders, and if
bidity in patients who have a prolonged QTc. there is a suspicion of such, a polysomnography
must be requested.
Obstructive sleep apnea can be treated through
Hypoxemia amygdalotomy or adenoidectomy, if there is
hyperplasia in these structures. For resistant
Hypoxemia is defined as a hemoglobin satura- cases, oxygen should be administered, with or
tion in the oximetry under 95%. Hemoglobin without a BiPAP machine.
538 O. Álvarez and M. A. Wietstruck

Table 52.3  Stages of chronic lung disease

Categories Stage 1 Stage 2 Stage 3 Stage 4
Chest pain Substernal pain and Pain increase Severe pain in medial Severe and prolonged pain
chronic cough considering stage 1 line with resting dyspnea
Arterial O2 normal saturation O2 normal saturation Basal hypoxia with O2 Basal hypoxia with O2
gases partial pressure of partial pressure of 60 mm
70 mm Hg Hg
X rays Reduced distal Fine and diffuse Lung fibrosis Severe lung fibrosis
vascularity, interstitial fibrosis in
hyperinflation, evidence all lung lobes
of increased interstitial
marks
Lung FVC, FEV1, TLC, and FVC, EFV1, TLC, FVC, VEF1, TLC, Patient has difficulties to
function FEV1/FVC in 80% of DLCO, and EFV1/ DLCO, and FEV1/FVC complete the test because
the expected value FVC in 60% of the in 40% of the expected of hypoxia
expected value value
ECG and Left ventricle Biventricular Right ventricle Severe hypertrophy of the
ECO hypertrophy hypertrophy hypertrophy and right ventricle and right
enlargement of the right atrium. T-ischemic waves
atrium. Progressive in V1 and V2 and lung
increase in heart size pressure
Lung Normal Normal Normal or minimum Increase with lung
arterial increase normal hypertension
pressure

Thromboembolism patient with a corrected DLCO for Hb under 40%

has a severe lung disease. Sometimes, different
Patients with sickle cell disease are not free from levels of chronic lung disease are referenced in
suffering from venous thrombosis and lung sickle cell anemia (Table 52.3).
embolism, because anemia is a procoagulant con-
dition, and if this is added to the bedridden condi-
tion of pain exacerbations, the risk increases. Lung Hypertension
Doppler ultrasound tests of the limbs and chest
helicoidal computerized tomography are useful Lung hypertension is defined as media lung arte-
to detect lung embolism. The management of rial pressure (mPAP)  ≥25  mm Hg, determined
these complications is the same as for any other through heart catheterization, and it is responsi-
type of patients. ble for the death of 30% of adults with SS:
It is thought that lung hypertension is caused by
hemolysis and NO reduction, as was discussed in
Chronic Pulmonary Disease the physiopathology section. Both NO and endo-
thelin-1 are opposing vaso-active factors that regu-
Although advanced chronic pulmonary disease is late lung vascular tone. Endothelin-1 and the
rare in children with sickle cell disease, this dis- plasminogen activator inhibitor-1 (PAI-1) are
ease is related to acute and recurrent events of increased by the effect of hypoxia-inducible fac-
vascular etiology, such as acute chest syndrome, tor 1-alpha (HIF-1α) subunit in endothelial cells
lung edema, and chronic fibrosis. Fibrosis can be of lung microvasculature. At the same time,
observed mainly in the bases of the lung, and it HIF-1α is produced by the placental growth fac-
can be detected through high-resolution tomogra- tor, which is a pro-angiogenic factor, produced by
phy or chest X-ray. Chronic lung disease tends to sickle cells. Plasma hemin may also contribute to
be progressive, worsening hypoxemia, dyspnea, the activation of the immune system and inflam-
and reducing the parameters for lung function. A mation. Other clinical factors that contribute are
52  Sickle Cell Disease 539

chronic lung disease, hypercoagulability condi- using a modified Bernoulli equation:

tion of the sickle cell anemia, such as low levels of mPAP = 0.61sPAP + 2, where sPAP is the systolic
C and S protein, and a previous history of pressure of the lung artery, which is estimated
splenectomy. through the formula sPAP = 4 × TRR(Kanter and
The American College of Cardiology Kruse-Jarres 2013) + right atrium pressure. TRR
Foundation and the American Heart Association prevalence at ≥2.6 m/s is present in 11% of the
recommend a yearly evaluation for the patients children. In adults, 30% will have a TRR ≥ 2.5 m/s,
under risk of developing lung hypertension, such but only 6–10% have lung hypertension because
as patients with sickle cell anemia. of catheterization.
Echocardiograms may be used as a test of adverse Besides the echocardiography evaluation,
prognostic if tricuspid regurgitation rate (TRR) is N-terminal pro-b-type natriuretic peptide
≥2.5 m/s, which is the value of two standard devi- (NT-proBNP), the 6-min walk test, and use of a
ations above the median. At the same time, TRR catheter are steps in the diagnostic process
is used to calculate mPAP. mPAP is estimated (Fig. 52.4).

Lung hypertension

Tricuspid regurgitation Tricuspid regurgitation Tricuspid regurgitation

<2.5 m/s 2.5-2.9 m/s ≥3.0 m/s

Observation and yearly Heart

Pro NT-BNP
evaluation catheter

Pro NT-BNP Pro NT-BNP ≥160

pg/mL specially if the 6
<160 pg/mL minute walk test
≤333 m

6-minutes walk 6-minutes

test walk test

≥333 m ≤333 m

Fig. 52.4  Diagnostic algorithm of lung hypertension

540 O. Álvarez and M. A. Wietstruck

Lung hypertension can be arterial, venous, or has not been reported. An adolescent with sickle
mixed: 50% of patients with lung hypertension cell anemia and lung hypertension, which was
have the arterial presentation (mPAP ≥25  mm resistant to sildenafil, bosentan, and treprostinil,
Hg) and lung capillary pressure (PCP  ≤15  mm who continued with severe symptoms, underwent
Hg), which means that the vasculopathy is mainly a bilateral lung transplant successfully after
located in the arterial lung system. Further, 50% 1-year follow-up.
of patients have venous-lung hypertension with
mPAP ≥25 mm Hg, and besides this, the diastole
final pressure of the left ventricle is >15 mm Hg, Sources
or there is evidence of diastolic failure. If the
transpulmonary pressure gradient is <12 mm Hg, Adekile AD. What’s new in the pathophysiology of sickle
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Hg, it is mixed. ease from childhood through adulthood. Blood Rev.
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into therapies aimed to anemia, such as hydroxy- Klings ES, Wyszynski DF, Nolan VG, Steinberg
MH.  Abnormal pulmonary function in adults with
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study “Treatment: Progression of pulmonary A.  Asthma in children with sickle cell disease and
the association with acute chest syndrome. Thorax.
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nafil treatment” was designed to treat those Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato
patients with a tricuspid regurgitation GJ, Gordeuk VR, et  al. Hospitalization for pain in
rate >2.7 m/s with sildenafil. There were 483 par- patients with sickle cell disease treated with sildenafil
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placebo. No differences in efficiency were found. C, Melica G, Renaud B, et al. Pulmonary artery throm-
Another alternative for lung hypertension is to bosis during acute chest syndrome in sickle cell dis-
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 Congenital Malformations
of the Airway
53
Ilse Contreras Estay, Luis Enrique Vega-Briceño,
and Ignacio Sánchez

Contents
Epidemiology................................................................................................................. 543
Clinical Presentation.................................................................................................... 543
Laryngomalacia.............................................................................................................. 544
Tracheomalacia/Bronchomalacia................................................................................... 545
Tracheal Stenosis............................................................................................................ 546
Vascular Rings................................................................................................................ 547
Sources........................................................................................................................... 549

Epidemiology laryngeal and tracheal malformations, or malfor-

mations associated to high tracheal impact, such
Congenital malformations of the airway include as esophageal atresia.
a wide list of diseases that are generally infre- There is no consensus in relation to its classi-
quent in occurrence but that can have a very rel- fication, and different proposals have been made
evant repercussion. It is one of the groups with based on anatomical factors, pathogenesis, and
the greatest mortality, only surpassed by cardio- association with malformations of other systems.
vascular and neurological mortality. Its exact Because of this, it is even more difficult to esti-
incidence is unknown. Clinical approximations mate its frequency.
yield 1 case in 5,000 to 50,000 newborns for

Clinical Presentation
I. Contreras Estay
Department of Pediatrics, Hospital Padre Hurtado,
Santiago, Chile Patients with airway congenital malformations
have no healthy periods between exacerbations,
L. E. Vega-Briceño (*)
Faculty of Medicine, Universidad del Desarrollo, so they present symptoms permanently and their
Santiago, Chile symptoms increase with exacerbations, which
e-mail: [email protected] are usually common respiratory infections during
I. Sánchez childhood. Depending on the anatomical level of
Department of Pediatrics, School of Medicine, the airway obstruction, symptoms will be related
Pontificia Universidad Católica de Chile, to respiratory distress and transmission noises
Santiago, Chile

© Springer Nature Switzerland AG 2020 543

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_53
544 I. Contreras Estay et al.

caused by the lumen airway obstruction. At the esophageal reflux as a primary cause, but this
same time, the cardinal sign will be stridor when relationship has not been confirmed.
extrathoracic compromise is dominant, and The characteristic inspiratory noise has a high
wheezing will be the cardinal sign when the com- tone, and it is intermittent. It is usually not pres-
promise is intrathoracic. ent at birth, but it appears within the first 2 weeks
of life, increases in intensity up to 6  months of
life, and then it gradually disappears. In general,
Laryngomalacia at 18  months most patients have no stridor,
although it can persist for years in a small per-
Laryngomalacia (LM) is the most frequent cause centage of the patients. Typical stridor is exacer-
of congenital stridor as well as the most common bated during effort situations, such as crying,
congenital laryngeal anomaly, corresponding to agitation, feeding, and when in supine position.
up to 75% of congenital stridor. It is more fre- Stridor tends to be reduced with cervical exten-
quent in males, in a 2:1 ratio. LM is caused by a sion and prone position. Most severe cases may
laryngeal obstruction in the supraglottis, second- present with respiratory difficulties, as well as
ary to flaccidity of cartilage or muscle arytenoid cyanosis and apneas exacerbations. These symp-
structures, arytenoid epiglottic folding, or a com- toms are associated to alterations in feeding, gas-
bination of these (Fig. 53.1). It has been proposed troesophageal reflux, and lack of growth. Usually,
that probable mechanisms are (1) anatomical stridor is not associated with cough, wheezing, or
causes, such as omega epiglottis, short aryepi- significant respiratory distress, and some degree
glottic ligaments, and redundant arytenoids; (2) of retraction may be observed. Stridor intensity is
histological causes, because of a degree of carti- not necessarily correlated with the degree of col-
lage immaturity, such as an intrinsic weakness lapse. LM severity has been classified in several
and tendency to collapse during inspiration; and ways, according to different anatomical and clin-
(3) neurological causes, because of muscle con- ical findings (Table  53.1). Airway endoscopic
trol immaturity, which would be associated to evaluation is indicated if there is extreme anxiety
generalized hypotonia in the muscular support of on behalf of the parents, doubts about the diagno-
the larynx. This last theory proposes that the sis, stridor persistence after 9 to 12  months, or
relaxation of the interior concomitant esophageal stridor increase after 6  months. The most com-
sphincter would explain the presence of gastro- mon associated morbidity in LM is gastroesopha-
geal reflux, which is present in 65% to 100% of
the cases. Nevertheless, a systematic review of 27

Table 53.1  Laryngomalacia severity scale

Severity Respiratory
level symptoms Feeding symptoms
Mild Inspiratory stridor Occasional cough or
when crying regurgitation
Saturation 98–100%
at rest
Moderate Inspiratory stridor Frequent
Saturation ~96% at regurgitation or
rest feeding disorders
Severe Inspiratory stridor at Aspiration or poor
rest growth increase
Fig. 53.1  Laryngomalacia. In laryngeal endoscopic visu- Cyanosis, apnea,
alization, the collapse of the arytenoid cartilage can be retraction
appreciated, occluding the lumen of the airway, in infant Saturation ~90% at
with persistent stridor rest
53  Congenital Malformations of the Airway 545

studies that evaluated the relationship of these Tracheomalacia/Bronchomalacia

two diseases concluded that there is limited evi-
dence to indicate a casual relationship. The pre- Tracheomalacia5 is a weakness of the tracheal
sumptive diagnostic is clinical if the complete wall caused by an alteration in the elastic fibers in
history and physical examinations yield the clas- the membrane or cartilage support. It is more fre-
sical results of inspiratory stridor progression, quently located at intrathoracic level, and there-
and this does not require a routine endoscopic fore its main symptoms are present during
examination. The X-ray study is usually normal, expiration, as the lumen size is reduced. This
but the definitive diagnosis is made through alteration may be localized or diffuse, and com-
endoscopic study of the airway in 88% of the promise the cartilage support of the first- or
cases. second-­ generation bronchi, being called bron-
A complete airway study is recommended in chomalacia (BM). Its appearance may be primary
patients with LM associated with other serious or secondary. A reduction in tracheal diameter of
symptoms, such as severe respiratory distress, one third during expiration is considered mild, a
growth impairment, cyanosis crises, apneas, reduction of one half is moderate, and a reduction
possible deglutition or aspiration disorder, that compromises three fourths of the airway is
recurrent wheezing or pneumonias, and those considered severe (Fig. 53.2).
patients with an underlying condition. In these Primary or congenital tracheomalacia, the
cases, an association with another lower airway most common congenital tracheal alteration,
abnormality can be found in as many as 15% of appears with a greater incidence in premature
the cases. newborns. This alteration is attributed to tissue
For those patients with LM and hypotony, immaturity, but it is also associated to some
neuromuscular disorders, or genetic syndromes, genetic syndromes, or to disease that causes some
it has been suggested to complete the study with alteration of the cartilage matrix or collagen
polysomnography, because of the increase in fibers, such as mucopolysaccharidosis. TM is
central apneas (in 46%), and echocardiography present in all the patients who have a tracheo-
for those who also have heart congenital diseases, esophageal fistula, or different degrees of esoph-
or suspicion of hypoxemia related to LM. ageal atresia.
Prognosis is good, and therefore a great percent- Because this is a defect in embryonic develop-
age requires only clinical observation to support ment, it would still be significantly present even
a spontaneous improvement in 75% of the cases,
and an additional 15% to 20% improve when
they reach 18 months of life. Those with persis-
tent stridor at 2 years of age should also be endo-
scopically assessed. Up to 5% to 15% of cases
may present serious obstructive symptoms and
require surgery. Supraglottoplasty is the tech-
nique of choice, as well as an arytenoepiglotto-
plasty, to avoid chronic hypoxemia and eventual
cor pulmonale. In surgery cases it is suggested to
associate treatment to block acid reflux. Currently,
tracheotomy has been displaced, and its indica-
tion is only when supraglottoplasty fails, or for
an underlying condition.
Use of noninvasive ventilation would be an Fig. 53.2  Tracheomalacia. Endoscopic visualization of
the intrathoracic trachea shows the collapse of the poste-
option for children with severe LM and respira- rior wall moderately occluding the lumen (>60%), in an
tory distress, as well as obstructive sleep apneas infant with Down syndrome, heart disease, and recurrent
waiting for a definitive surgical resolution. wheezing
546 I. Contreras Estay et al.

after surgical repair. In primary cases not related to Imaging studies can be very useful, as, for
other diseases, the evolution of tracheomalacia is example, the evaluation using contrast agents in
self-limited, normalizing close to the second or fistulas, esophageal atresia, or vascular rings. In
third year of life. Secondary TM is more frequent tracheomalacia, high-resolution computerized
than the primary presentation, and it is predomi- tomography (HRCT) can show slides and recon-
nant in males. It appears following a degeneration struction of the airway, as well as showing the
of the tracheal cartilage, because of prolonged intu- defect. Ideal diagnosis is done through a dynamic
bation, tracheotomy, local injury (oxygen-caused evaluation of the airway under pseudo anesthesia
toxicity, infections, ulcerations, or necrosis caused and spontaneous breathing, with a bronchial
by local damage), or extrinsic prolonged compres- endoscopy. In older children, suspicion starts
sion (vascular rings, hypertrophy of the left atrium). when a spirometry has a fluctuant obstruction in
Its pathogeny is not clear, but it has been pro- the air flow, namely in the flow/volume curve
posed that the following could be predisposing (inspiratory or expiratory branch, depending of
factors: genetic alteration in genes such as Sox9 the case). In an important percentage of patients
and Shh, alteration in type I collagen, which is with TM and BM, the disease spontaneously pro-
involved in the formation of the airway; or type II, gresses to its resolution during the first 2 years of
which intervenes in the tension of the cartilage. life. The recommendation is to avoid viral infec-
In histopathological terms, it has been tions and inappropriate treatments. Chest physio-
observed that there is an imbalance between mus- therapy is suggested for patients with ineffective
cle and cartilage structure; the first one is pre- cough, atelectasis, or abundant secretions. Use of
dominant, whereas the second one is scarce. TM bronchodilators is controversial, as a reduction in
incidence is estimated as 1  in 1500–2500 chil- the muscle tone would favor airway collapse,
dren; this number would increase significantly if although the role that the bronchospasm may
we only considered premature newborns. The have in the airway must be considered.
most usual symptoms of TM are respiratory stri- In the most severe cases, or those who do not
dor and croup cough, which generally appear improve, according to the experience of the cen-
during the first weeks of life, and sometimes, in ters, they can be managed with continuous posi-
the mild cases, it is only present when there are tive pressure in the airway (CPAP), tracheotomy,
viral infections. Stridor appears frequently, and mechanical ventilation. A surgical treatment
because of the collapse of the proximal area, can also be considered for those who have pre-
when there is an increase in the pressure gradient sented vital risk or no resolution, such as aorto-
caused by obstruction. Feeding disorders may pexy, tracheopexy, resection, and tracheal
appear, as well as increase of secretions in the reconstruction with cartilage implants. Use of
lumen, or reflex apnea, in those patients in whom stent support tracheal devices (metallic or sili-
there is vascular compression. In TM and BM, a cone) has been shown to be effective, and they
clinical history of recurrent wheezing, and atelec- would be useful in the short term, but they are
tasis and recurrent ipsilateral pneumonias, are related to other important complications: granu-
frequent. In severe TM and BM, airway obstruc- lomas, tearing, bleeding, etc. The stents are indi-
tion may appear, as well as cyanosis during exac- cated after other techniques have failed, and it
erbations. The most important action for the has been suggested to use preferentially those
diagnosis is clinical suspicion after a careful that are auto-expandable and thermoplastic.
anamnesis and physical examination, differenti-
ating it from asthma, foreign body aspiration, and
atelectasis caused by a different entity, among Tracheal Stenosis
other possibilities. If the newborn is premature,
or there are genetic syndromes, heart diseases, or Tracheal stenosis is a very infrequent disease.
neuromuscular disorders, this entity must be The trachea is characterized by the presence of
suspected. approximately 20 cartilages along its length,
53  Congenital Malformations of the Airway 547

which can range from 5.5 to 8 cm, from birth to magnetic resonance image (MRI) may be
2 years of life. These cartilages support the lumen requested as a complement. In older children, a
of the respiratory airway, but they are not com- spirometry presenting a fixed obstruction in the
plete in the posterior tracheal segment, where the intrathoracic airway in the flow–volume curve
membranous section is located. Tracheal stenosis strongly suggests tracheal stenosis.
is characterized by a reduction in the tracheal Treatment may be conservative for mild or
lumen in diverse diameters and lengths, caused moderate cases, where there is no early respira-
by the presence of complete tracheal rings and tory distress, extubation failure, or poor growth,
the absence of the membranous section in the and the follow-up can be made through endos-
smooth muscle fibers, which may be congenital copy during the first 2–3 years of life, but its reso-
or acquired. Three types of lesions have been lution is usually surgical. Tracheoplasty may be
described: segmental stenosis with variable considered, resecting the stenosis area and using
length, hourglass stenosis, and funnel stenosis, as end-to-end anastomosis for small lesions.
well as generalized tracheobronchial hypoplasia. However, in children with tracheal compromise,
It is difficult to estimate its incidence, and it var- in whom more than 50% of tracheal length is
ies among different centers. It has been reported compromised, a slide tracheoplasty may be
that the congenital tracheal stenosis rate is about needed, as well as the interposition of cartilage,
10% and the rate of acquired stenosis is 90%, thus widening the tracheal lumen in critical
secondary to prolonged intubation (75–90%), situations.
trauma, connective tissue diseases, neoplasia, or
idiopathic causes. Clinical manifestations are
variable and depend on the degree of severity, Vascular Rings
newborn respiratory distress, cyanosis, persistent
or recurrent inspiratory stridor with prolonged Vascular rings (VR) are congenital anomalies of
progression, recurrent wheezing, atelectasis, and the aortic arch and its branches that cause tra-
pneumonia. In other cases, the diagnosis has cheal or esophagus compression, or both. They
been suspected in children who have undergone are infrequent, and their incidence is not clear,
an early surgery in their life and weaning has not but they have been estimated to be about 1–3% of
been successful. the congenital cardiovascular anomalies. They
Recently, a review of approximately 310 chil- are classified as complete and incomplete
dren showed that there is predominance in the VR.  The most common ones are the complete
masculine gender and that almost half the chil- ones, which in almost 90–95% of the cases are
dren affected have some associated comorbidity. represented by the double aortic arch (DAA) and
The most common comorbidities were pulmo- its subtypes (right dominant arch, left dominant
nary artery ring, defects in the ventricular sep- arch, balanced arch), and right aortic arch (RAA)
tum, defects of the atrium septum, persistent and its subtypes (RAA and left aberrant subcla-
arteriosus ductus, lung agenesis, Fallot tetralogy, vian artery, and RAA+ and mirror vessels pat-
and aortic restriction. A minority had associated tern). The most frequent complete ring is DAA,
genetic syndromes. This diagnosis is proposed at about 75–90% of all, and second in place is
for children with persistent wheezing, or ‘seal RAA, at about 12–25%. Incomplete vascular
cough’ associated with compatible X-rays. rings do not form a complete ring around the tra-
Definitive diagnosis is through tracheal endos- chea and the esophagus, but they do compress
copy, which allows visualizing the obstruction, them. These rings are represented by innominate
its diameter, and degree of compromised length. artery compression, pulmonary artery ring, and
Chest HRCT with airway reconstruction gives a left aortic arch (LAA), with right aberrant subcla-
better characterization of the lesion and helps to vian artery. It is thought that this last entity is
decide the type of corrective surgery. In some subdiagnosed or its diagnosis is done late, as it
cases, if other malformations are suspected, a tends to be asymptomatic. In 38% of cases it is
548 I. Contreras Estay et al.

related to Down syndrome. An aberrant innomi- rior esophageal compression, which appears
nate artery represents 10% of the VR, and com- later.
presses the trachea through its anterior surface; it Diagnosis must be done through clinical sus-
presents more symptoms if it is related to tra- picion in those patients with persistent symp-
cheomalacia or esophageal atresia, when there is toms, prolonged progression of the disease or
no dysphagia. A pulmonary artery ring is com- poor response to usual treatments, because they
monly associated with a full cartilage ring, which share symptoms with other more common dis-
determines the greatest cause of mortality caused eases, and tend to be confused with asthma. It
by VR, and it is related to tracheobronchial alter- appears between 2 and 18 months of life, but in
ations, such as TM, hypoplasia, or tracheal steno- some cases it has been diagnosed in patients
sis, as well as being related to heart diseases such more than 50 years old. A cervical X-ray shows
as persistent arteriosus ductus, or ventricular or the relationship between the trachea and the aor-
atrial communications. Sometimes VRs have tic arch (DAA, RAA, and LAA), besides indenta-
been reported as associated with other congenital tions, retro-tracheal opacity, hyperinflation, and
malformations, such as kidney (agenesis, ectopy, T-shaped trachea. A barium esophagogram is the
horseshoe kidney), tracheoesophageal fistula, exam of choice and it is very useful to show a
hiatal hernia, diaphragmatic eventration, imper- VR, where an indentation is observed in the tra-
forated or ectopic anus, PHACE syndrome (pos- chea/esophagus level in more than 90% of the
terior cranial fossa alteration, facial hemangioma, cases, but a normal exam does not rule it out. It is
alteration of brain, cardiovascular, and eye arter- requested when feeding symptoms are present.
ies), and some genetic syndromes, such as tri- An image of indentation posterior suggests an
somy 21, deletion 22q11. aberrant subclavian artery, whereas a bilateral
VRs frequently present symptoms early in indentation image suggests a double aortic arch
life, which depend on the type and degree of (Fig. 53.3), and if the image shows a reduction in
compression of the clinical manifestations. the anterior pulse caliber using lateral projection,
Usually VR appear with stridor, persistent cough, it suggests a ring of the pulmonary artery.
respiratory distress, or dysphagia, especially with Evaluation of the airway with flexible bron-
solid foods (late symptom). Cough has been choscopy is important in the study of stridor and
described “like a seal,” or tracheal, with a metal- persistent wheezing for the differential diagnosis,
lic tone, and it is very noticeable when there are where an anterior or lateral pulsatile external
unimportant respiratory infections. Stridor is compression can be observed. If there is a strong
generally biphasic, but it can appear as only one suspicion of a VR, the study should be completed
sound during expiration, which is monophonic with angio-CAT or angio-MRI to differentiate it
and persistent and should be called wheezing. All from other extrinsic compressions, such as bron-
symptoms tend to increase with crying, feeding, chogenic cysts, hemangiomas, or mediastinal
playtime, or respiratory infections. Respiratory tumors, thus defining the specific alteration and
symptoms are present in 70% to 97% of all the its path and to plan the surgical approach. Both
children, according to several studies, and they exams are very good, and there is no clear con-
may cause a poor growth. Less frequently, and sensus about which one offers the best perfor-
only when there is a significant tracheal compres- mance. The angio-CAT availability is wider, and
sion, it may appear during the newborn period it requires less time, and therefore it only requires
with respiratory distress, suprasternal and costal sedation or pseudo-anesthesia. Besides this, it
retraction, tendency to cervical hyperextension, allows for the reconstruction of the airway and
cyanosis, reflex apnea, and extubation failure. virtual bronchoscopy. The advantage of MRI is
The VRs that present more symptoms are the that it can picture more accurately the relation-
DAA and the RAA, caused by early tracheal ship between the structures, the presence of heart
compression, although the aberrant subclavian anomalies, as well as ventricular function and
artery may also be evident, because of the poste- heart flow function, and it does not present irra-
53  Congenital Malformations of the Airway 549

a b c

Fig. 53.3  Double aortic arch. Anteroposterior X-ray (a) tion); in axial slice at the aortic arch level, nuclear mag-
and lateral projection (b) show indentation caused by the netic resonance in sequence T1 (c) shows a DAA (D, right;
double aortic arch (DAA) (arrows show level of indenta- I, left) compressing the esophagus (E) and trachea (T)

diation. The great disadvantage is that it is not so life. Many VRs can be asymptomatic for long
readily available and it has a greater cost, and as periods of time, so there would be no mandatory
it takes more time, it requires anesthesia for indication of a surgery. Surgical management is
smaller children. reserved for those cases with serious symptoms,
Cardiological evaluation (ECG and Doppler such as cyanosis or apneas, extubation failure,
echocardiogram) must be done if there is a VR with more than 50% of airway compression, or
diagnosis because heart disease is present in when there is no response to conservative man-
12–30% of cases. Lung function evaluation with agement. Surgical technique varies according to
spirometry may be done from preschool age in the type of ring, arteriopexia in some types of
children with respiratory symptoms and an rings in the pulmonary artery or ligament sec-
obstructive pattern that does not respond to bron- tions when they are the complete components of
chodilator use, as these are signs which can be the rings. Operation may be through open thora-
observed when there are VRs. This fixed obstruc- cotomy or by video-assisted thoracoscopy
tion of the airway appears as a reduction in the (VATS). In general, the prognosis is very good,
expiratory flows, and a plateau at the beginning with a low index of complications if it is not
of the expiration flow–volume curve can be related to a complex heart disease or underlying
observed. When this defect appears in the inspi- disease. Those patients with significant external
ratory phase, both respiratory times are compro- tracheal compression may afterward progress to
mised. During past decades, with the variable degrees of tracheomalacia and respira-
improvements in fetal ultrasonography studies tory symptoms.
and specialized centers, the diagnosis of some
VRs can be done early, through visualization of
the origin and flow of the vessels. Sources
Treatment will depend on the clinical condi-
Contreras I, Roza G, Navarro H, Bertrand P, Cuevas
tion and the type of anomaly. In children with
M, Sánchez I, Caussade S.  Estridor en el paciente
mild or intermittent symptoms, management is pediátrico: estudio descriptivo. Rev Chil Pediatr.
conservative, avoiding respiratory infections or 2004;75:247–53.
treating them when they are present, using phys- Digoy GP, Burge SD. Laryngomalacia in the older child:
clinical presentations and management. Curr Opin
iotherapy if needed. Most of the cases in which
Otolaryngol Head Neck Surg. 2014;22:501–5.
the innominate artery is compressed spontane- Dobbie AM, White DR. Laryngomalacia. Pediatr Clin N
ously remit during the first and second year of Am. 2013;60:893–902.
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Kir M, Saylam GS, Karadas U, Yilmaz N, Çakmakçi H, Thompson DM.  Laryngomalacia: factors that influ-
Uzuner N, et al. Vascular rings: presentation, imaging ence disease severity and outcomes of manage-
strategies, treatment, and outcome. Pediatr Cardiol. ment. Curr Opin Otolaryngol Head Neck Surg.
2012;33:607–17. 2010;18:564–70.
Licari A, Manca E, Rispoli GA, Mannarino S, Pelizzo Thorne MC, Garetz SL, et  al. Paediatr Respir Rev.
G, Marseglia GL.  Congenital vascular rings: a clini- 2015;s1526-0542(15):00009–3.
cal challenge for the pediatrician. Pediatr Pulmonol. Ywaquin R, El-Hakim H.  Congenital tracheal steno-
2015;50:511–24. sis managed conservatively: systematic review
Pan W, Peng D, Luo J, Liu E, Luo Z, et al. Clinical features of the literature. J Otolaryngol Head Neck Surg.
of airway malacia in children: a retrospective analysis 2012;41:288–302.
of 459 patients. Int J Clin Exp Med. 2014;7:3005–12. Zgherea D, Pagala S, Mendiratta M, Marcus MG,
Perillán J.  Traqueobroncomalacia en niños. Neumol Shelov SP, Kazachkov M.  Bronchoscopic findings
Pediatr. 2012;7:6–12. in children with chronic wet cough. Pediatrics.
Sittel C.  Pathologies of the larynx and trachea in child- 2012;129:e364–9.
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Surg. 2014;13:1–15.
 Congenital Lung Malformations
54
Juan Carlos Pattillo Silva, Sergio Zúñiga Rocha,
and José Vuletin Solís

Contents
Embryology...................................................................................................................  551
Epidemiology................................................................................................................  552
 ongenital Malformations of the Lung......................................................................  552
C
Cystic Adenomatoid Malformation................................................................................  552
Lung Sequestration........................................................................................................  554
Congenital Lobar Emphysema or Congenital Lobar Hyperinflation.............................  555
Bronchogenic Cyst and Esophageal Duplication Cyst..................................................  555
Lung Agenesis, Aplasia, and Hypoplasia.......................................................................  557
Diagnosis.......................................................................................................................  558
Treatment......................................................................................................................  558
Sources..........................................................................................................................  559

Embryology tors, extracellular matrix proteins, and adhesion

molecules).
To know the details of the origin of these malfor- Multiple exogenous and endogenous factors
mations, it is necessary to study the embryology can affect this process, originating changes in
and development of the respiratory system. This growth, maturation, and lung function. The
process is directed by a finely tuned interaction development of the lung in the human, which
between the mesenchyme (vessels) and the epi- starts with the embryonic phase, has its origin in
thelium, which controls the time and space the anterior primitive intestine, and begins toward
expressions of multiple regulatory elements the end of the third month of gestation, with an
needed for the creation of the lung (transcription invagination in the surface of this primitive intes-
factors, growth factors, and their cellular recep- tine, which originates the laryngotracheal groove.
In the caudal end of the invagination a bifurcation
J. C. Pattillo Silva · S. Zúñiga Rocha appears: lung or bronchial buds, which by sepa-
J. Vuletin Solís (*) rating from the esophagus or primitive anterior
Pediatric Surgery, Pontificia Universidad Católica de
intestine, migrate toward the caudal end, intro-
Chile, Santiago, Chile
e-mail: [email protected]; [email protected]; ducing themselves in the mesoderm.
[email protected] Mesenchymal cells that surround these buds will

© Springer Nature Switzerland AG 2020 551

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_54
552 J. C. Pattillo Silva et al.

Fig. 54.1  Origin of the

different Trachea
bronchopulmonary
malformations Congenital Lobe
Bronchogenic cyst emphysema

Aorta

Cystic
Adenomatoid Lung sequestration
malformation

generate the tracheal and bronchial walls. Then, related to esophagus, lung sequestration (LS),
after the fifth week, secondary buds appear. The early genesis in embryonic development, before
adjacent mesoderm begins to differentiate in the the separation of aortic and lung circulations, and
parenchyma of each lung lobe. Tertiary bronchi cystic adenomatoid malformation (CAM), which
appear during the seventh week, and so the divi- is probably the product of the bronchial matura-
sions continue until reaching 17 at the moment of tion arrest, along with the growth of mesenchy-
birth. This second stage, characterized by rapid mal elements (Fig. 54.1).
bronchial proliferation that happens between the
fifth and seventeenth week, is named the pseudo-­
glandular phase. Most bronchopulmonary mal- Epidemiology
formations take place in one of these two initial
stages, after the canalicular phase begins (weeks It has been difficult to estimate the precise inci-
16–26), and then the saccular phase (weeks dence of lung malformations, and because they
24–38), when all the lung structure is developed. are asymptomatic lesions, many authors consider
Starting at week 24 and until week 28, the cuboi- that their frequency may be undervalued. In
dal epithelium of the terminal air sacs starts to 2008, the European Record for the vigilance of
transform into a flat structure; this originates congenital malformations (Eurocat) estimated an
alveolar cells type I and type II, which will pro- incidence rate of congenital chest malformations
duce surfactant. By continuing the differentia- at 3.5 per 10,000 live births. The estimated inci-
tion, the appearance of the lung tissue changes, dence of cystic adenomatoid malformation was
from a glandular one to a highly vascularized pic- 0.7 per 10,000 live births.
ture, such as the alveolar organ, which will reach
maturity toward the end of week 28. Finally, after
birth and up to 2 to 3 years of life, the lung goes Congenital Malformations
through a phase of microvascular maturation. of the Lung
Anomalies in this development process may
have different presentations (see Stocker). In this Cystic Adenomatoid Malformation
way, we may observe a congenital lobe emphy-
sema (CLE), caused by the alteration in the The first case of cystic adenomatoid malforma-
development of a lobar or segmental bronchi, tion described was published by Ch’in and Tang
bronchogenic cysts (BC), or more appropriately, in 1947. In 1975, Garret conducted the first ante-
cysts of lung buds, caused by an eventual previ- natal diagnostic report of a cystic adenomatoid
ous origin before bronchi formation: they may be malformation using echography. Today, almost
54  Congenital Lung Malformations 553

90% of these malformations are diagnosed before forms of cystic adenomatoid malformation. Type
birth, and correspond to small lesions that are 0, or acinar dysplasia, refers to a tracheobron-
almost always asymptomatic, at least during the chial defect characterized by hard and small
neonatal period. lungs connected to a tracheobronchial path,
These malformations are cystic lesions that whereas type 4 corresponds to an alveolar defect
are circumscribed to a segment or lung lobe in located in the periphery of the lung. Only types 1
more than 95% of the cases, and any lobe may be and 3 are adenomatoid, and types 1, 2, and 4 are
compromised. Bilateral lesions are rare (<3%) cystic. Stocker himself has proposed to change
and have a poor prognosis. Histology reveals a the name of cystic adenomatoid malformation to
proliferation of terminal bronchioles, which form congenital lung airway malformation, which has
communicated cysts covered in respiratory epi- become popular, although it has not been univer-
thelium with different degrees of differentiation, sally adopted (Table 54.1, Fig. 54.2).
as well as a reduction in the number of alveoli.
There is no cartilage and there is an increase of
the elastic fibers. The exact cause of cystic ade- 0
nomatoid malformation is unknown, and there
are arguments to sustain that its different types
can originate in different stages of the lung devel- 1
2
opment process. Bronchiolar types (type 1, 2, and
3
3) may develop during the pseudo-glandular 4
phase, while those of the acinar-alveolar type
(type 4) may be the consequence of a late injury
in the saccular stage. It has been proven that in
cystic adenomatoid malformations there is an
increase in the proliferation and a reduction of
apoptosis. All these details give strength to the
hypothesis of a localized interruption during lung
maturation.
Fig. 54.2  Congenital malformation of the lung airway.
At first, Stocker classified them in three types Classification of the congenital malformation in the lung
based on postnatal histology. Afterward, he added airway or cystic adenomatoid malformation, according to
types 0 and 4, which correspond to infrequent the supposed origin during lung development

Table 54.1  Classification of congenital lung malformations in the lung airway

Incidence Size of cysts Histology Notes
0 Infrequent Complete failure of development after pseudo-­ Congenital acinar dysplasia
glandular phase (lethal)
1 Frequent >2 cm, may be Dilated alveolar structure, with scarce to minimum
50% multiple adenomatoid component. Ciliated pseudostratified
columnar epithelium, with interposition of mucosal
cells
2 Frequent Multiple cysts, Dilation of structures with bronchial appearance, Associated with
40%–45% small, with interposition of the alveolar parenchyma. genitourinary and
“sponge” Occasional presence of striated muscle. gastrointestinal
malformations
3 Infrequent Solid (cysts Bronchiolar structures separated by small air spaces
5% <3 mm) covered by the cuboidal epithelium, similar to late
fetal lung
4 Very Large cysts Peripheral cysts with alveolar or bronchial Related to type
infrequent epithelium on elastic mesenchymal tissue pleuropulmonary blastoma
554 J. C. Pattillo Silva et al.

The clinical presentation forms of cystic ade- primitive intestine that descends toward the cau-
nomatoid malformation are variable. During the dal along with the esophagus. Extralobar seques-
antenatal period, large cystic lung lesions may tration may be related to other esophageal and
cause mediastinal deviation, poor venous return, bronchial malformations, as well as diaphrag-
hydrops, and fetal mortality during the third tri- matic defects. Most lung sequestration cases do
mester. During the first months of life, respira- not present symptoms during the neonatal period,
tory distress, caused by compression or and they present as an incidental image in a rou-
pneumothorax because of the rupture of a cyst, tine chest X-ray. They are usually located in the
can be an early indication of surgery in about inferior lobes: 70% are in the left inferior lobe;
20% of the cases. Older children tend to be 10% are under the diaphragm; and in 20% of the
asymptomatic, and the infection of the anoma- cases arterial irrigation comes from the infradia-
lous tissue will cause recurrent pneumonias. The phragmatic aorta. In infants, the most frequent
median for the development of the symptoms presentation form of lung sequestration is the
caused by infections is 10 months. The treatment presence of recurrent pneumonia, which may
is surgery, which consists of resecting the affected cause localized bronchiectasis, and a particular
lobe or segment (Fig. 54.3). complication is congestive heart failure, which is
not present in cystic adenomatoid malformation,
and is caused by the presence of aberrant circula-
Lung Sequestration tion, and in some cases, by a significant shunt.
Lung sequestration may be diagnosed through
Lung sequestration is defined by the presence of echography and Doppler, but computerized axial
lung tissue inside or outside the visceral pleural tomography with contrast agent is the examina-
(intra- or extralobar sequestration), with no con- tion of choice, for planning and studying the sur-
nection to the normal tracheobronchial path, and gical treatment of these lesions. This treatment
characterized by an anomalous blood delivery in consists of resection of the pathological tissue
the systemic veins. Venous drainage of intralobar with anomalous vasculature control (Fig.  54.4).
sequestration runs toward the pulmonary veins, There is a superposition between cystic adeno-
while the extralobar sequestration runs to the matoid malformation and lung sequestration in
azygous vein. It has been estimated that lung several surgical series of lesions that do not
sequestration is a consequence of an anomalous exactly fulfill some of the previous categories
accessory lung bud, which was created in the and that are classified as mixed:

a b

Fig. 54.3  Cystic adenomatoid malformation. (a) Chest Complementary study of the patient with computerized
X-ray of 1-year-old infant with persistent cough shows a tomography shows a unique cystic lesion, with fine
radiolucent region in the superior left lobe. (b) septations
54  Congenital Lung Malformations 555

costal retraction, cyanosis), which will depend on

the degree of hyperinflation of the affected
region. Children with CLE usually have no symp-
toms at birth and start to present symptoms
­during the first years of life: 50% of the patients
present symptoms around the first month of life,
and almost all of them present symptoms around
6 months of life. The development of respiratory
distress may be sudden in some patients, but in
others the progression is insidious. A chest X-ray
helps in the diagnostic approximation, showing a
lobe with fewer grids and mediastinal displace-
ment toward the contralateral section, besides
diaphragmatic flatness and compression in the
rest of the lung parenchyma. The diagnostic
Fig. 54.4  Lung sequestration. Three-dimensional (3D) study may be completed with a computerized
reconstruction of computerized tomography of patient
with an antenatal diagnosis created when the patient was axial tomography or magnetic resonance scan.
6 months old to plan lesion extirpation. Emergence of the Routine echocardiography evaluation is recom-
aberrant vessel is directly from the chest aorta mended to rule out associated heart diseases.
When there is doubt, flexible bronchoscopy is
• Anatomical extralobar sequestration, but with useful to rule out other diseases that may appear
cystic adenomatoid malformation histology as a congenital lobe emphysema (foreign body,
• Extralobar sequestration and cystic adenoma- localized bronchomalacia).
toid malformation in the same patient Once the diagnosis has been confirmed, treat-
• Cystic adenomatoid malformation in one lobe, ment consists of resecting the affected lobe.
but with systemic irrigation Recovery is fast and without sequelae, with lung
re-expansion and early relocation of the medias-
tinum after the operation. Some patients with late
 ongenital Lobar Emphysema or
C clinical presentation or with few symptoms may
Congenital Lobar Hyperinflation be followed and treated with surgery if there are
repeated infections or progression of the respira-
Congenital lobar emphysema (CLE) or congeni- tory failure (Fig. 54.5).
tal lobar hyperinflation is the overinflation of one
or more lung lobes. As this lobe increases in size,
it compresses and displaces mediastinal struc-  ronchogenic Cyst and Esophageal
B
tures and the rest of the lung. The most common Duplication Cyst
cause is the presence of a valve type of bronchial
obstruction, followed by the intraluminal obstruc- Duplication cysts of the anterior intestine are
tion caused by secretions or granulation tissue. lesions that emerge during the embryonic period
Poor development of the cartilage that supports (week 4–8) from the esophagus, known as enteric
the bronchi of the affected lobe is found in only cysts, or from the upper airway, known as bron-
half the cases. The left upper lobe is the most chogenic cysts (BC). A third way of duplication
commonly affected. It is more frequent in males, is that one caused by neurenteric cysts. As a
and it is related to congenital heart disease in group, these lesions are responsible for 20% of
15% of the cases (ventricular septal defect, patent the mediastinal masses, half of them
ductus arteriosus). corresponding
­ to bronchogenic cysts.
Clinical presentation includes bronchial Localization of bronchogenic cysts depends on
obstruction and respiratory distress (tachypnea, the moment of development where the separation
556 J. C. Pattillo Silva et al.

worsen when crying and feeding. Another pre-

sentation mode of bronchogenic cysts is the
recurrent infection, characterized by fever, cough,
and pneumonia. Lung examination is usually
normal, but hypersonority and signs of bronchial
obstruction may be found.
A chest X-ray is useful at the beginning: It
shows round or oval lesions, with uniformed den-
sity, and hydro-aerial levels can be observed.
Mediastinum cysts are generally located at sub-
carinal level; lung cysts appear in the periphery.
Computerized axial tomography (CAT) scan or
magnetic resonance images (MRI) are used to
define the anatomy of bronchogenic cysts, as
Fig. 54.5  Congenital lobe emphysema. Computerized well as their delimitation and relation with adja-
tomography of 10-month-old infant with congenital lobar cent organs, to plan the surgical resection
hyperinflation. Left upper lobe is more radiolucent than (Fig. 54.6).
the right upper lobe because of the amount of air in the Surgical resection is the treatment of broncho-
lung parenchyma
genic cysts, as these cysts have a tendency to
become malignant, present infections, and com-
of the bronchial path took place; if it was early in promise the airway (Fig. 54.7). If the cyst cannot
the development, it will be located in the medias- be completely removed, it is recommended to
tinum; if it was late in the development, it will be fulgurate the mucosa.
located in the lung parenchyma. Bronchogenic Esophageal duplication cysts are caused by
cysts have a thin wall; they are covered by cili- an error in the esophagus vacuolization during
ated pseudostratified columnar epithelium and embryonic development. Other malformations
usually contain elements of tracheobronchial may be associated, such as esophagus atresia,
structure, such as cartilage, smooth muscle, and other duplications, and vertebral anomalies.
bronchial glands. In general, these cysts are They are more common in men than in women,
unique, unilocular, and round. The size varies and tend to be present in the right hemithorax,
between 2 and 10  cm. According to their loca- toward the inferior esophagus. The cysts may be
tion, they are classified as mediastinal cysts or attached or be a part of the esophageal wall, and
lung cysts. Most of the bronchogenic cysts are in up to 10% of the cases they are communicated
located at the same level as the carina, in the through their lumen. It may be discovered as an
superior part of the trachea, where they compress asymptomatic finding, or appear with respiratory
the airway. They can also be paratracheal, hiliar, compromise, dysphagia, increase of localized
or paraesophageal. volume in the neck, or enlargement of the medi-
The presentation of bronchogenic cysts is astinum, in association with epigastric or
variable, and mainly appears during childhood, retrosternal pain.
although some cases in adults have also been Such cysts can be suspected in the chest X-
described. Diagnosis can be made during the ray by the enlargement of the mediastinum,
antenatal period using echography. In about one which may be deviated, or tracheal compression.
third of the children this is a finding in an asymp- A barium study may show the effect of the mass
tomatic patient: 50% have respiratory symptoms on the esophagus. Computerized tomography
associated, 10% present gastrointestinal prob- and magnetic resonance are the options for fur-
lems, and 5% may have chest pain. Among the ther study of these entities. These cysts should
respiratory symptoms, respiratory distress is be operated. If there is communication with the
included, in different degrees of severity or inter- esophagus lumen, a primary reparation may be
mittent, wheezing, stridor, and cyanosis, which done.
54  Congenital Lung Malformations 557

Fig. 54.6  Bronchogenic cyst. (a) Anteroposterior (AP) (b) Chest computerized tomography confirms the pres-
and left chest X-ray in an adolescent shows a circumferen- ence of a cystic lesion in the posterior mediastinum
tial lesion, well delimited in the posterior mediastinum.

 ung Agenesis, Aplasia,

L
and Hypoplasia

Agenesis refers to the total absence of lung, vascu-

lar, and bronchial tissue. Aplasia consists of a rudi-
mentary pouch, and hypoplasia is characterized by
a reduction in the number and size of the airway,
alveoli, and lung vascular structures. Agenesis and
aplasia re caused by an event during the embryonic
period, affecting only one lung, and generally the
contralateral lung presents a compensatory hyper-
Fig. 54.7  Bronchogenic cyst in image captured in video
plasia. It may be associated to other congenital thoracoscopy with patient in lateral decubitus position.
malformations, such as heart or gastrointestinal The bronchogenic cyst is easily identified, and its resec-
malformations. Clinical presentation includes tion is conducted manually
558 J. C. Pattillo Silva et al.

respiratory distress in variable degrees and recur- known that even large lesions can disappear.
rent respiratory infections. Absence of the right They reach a growth plateau at 28 weeks of ges-
lung may be a serious situation, as the compensa- tation, and after this they are reduced in size,
tory growth of the left lung may displace the heart probably the result of apoptosis. Cases of hydrops
toward the right side, as well as causing sudden resolution after this period have been reported. If,
death by compression of the great vessels. Chest on the contrary, the hydrops progresses, some
X-rays show a homogeneous density in the affected kind of fetal treatment can be proposed, such as
side, with no lung web. The mediastinum is devi- conducting a thoracentesis, or a pleuroamniotic
ated and the healthy lung presents hernias. shunt. When handling microcystic lesions of a
Computerized tomography confirms the absence of considerable size, open fetal surgery may be pro-
blood vessels and lung parenchyma. Lung agenesis posed. For patients who are not candidates for
may be confirmed through flexible bronchoscopy fetal surgery, or if this alternative is not available,
where there is no carina. the use of maternal steroids is suggested, which
Medical treatment consists of chest physio- would advance the plateau in lesion growth.
therapy to avoid respiratory infection, bronchodi- Lung sequestration appears in echography as
lators, and antibiotics. Lung hypoplasia is more echo-dense masses, well defined, and homoge-
frequent than the other entities, and half the cases neous, with systemic circulation. It is important
are related to heart and genitourinary malforma- to look for associated malformations, particularly
tions, or congenital diaphragmatic hernia. Chest those in the heart. Antenatal management of a
X-rays show poorly ventilated lung tissue, fetus lung sequestration with hydrops will depend
ascended diaphragm, and mediastinal deviation. on the gestational age: a 30-week-old fetus may
Management is medical, and surgery is only pro- be a candidate for thoracoamniotic shunt.
posed for those patients with localized hypopla- It is important to highlight that although an
sia or to correct a diaphragmatic hernia as a antenatal management may be successful, these
determinant factor. patients require important extrauterine ventila-
tion support, and they may even need extracorpo-
real membrane oxygenation (ECMO). Therefore,
Diagnosis the birth should be planned in centers with ade-
quate neonatal support and pediatric surgery
As previously mentioned, the wide use of obstet- available.
ric echography has made the discovery of antena-
tal congenital lung lesions more common. In
part, this has helped the study of the natural his- Treatment
tory, although as it happens in intrauterine life,
these are not always single lesions. Echography There is a consensus that patients with symptoms
is quite precise to detect lesions such as cystic with postnatal diagnosis of a lung lesion should
adenomatoid malformations, represented in the be urgently operated for treatment. For a cystic
characteristic way through echogenic lung adenomatoid malformation, lung lobectomy is the
images. This test also makes it possible to evalu- resection technique of choice; however, in
ate the lesion size, presence of mediastinal devia- selected cases a segmental resection may be
tion, hydrops, and polyhydramnios. The presence ­sufficient. For lung sequestration, surgery is rela-
of sequestration or mixed lesions can be sus- tively simple, once the vascularization of aberrant
pected when there are systemic circulation ves- vessels has been controlled. If there are heart
sels entering the lung. When the differential decompensations, it is possible to perform selec-
diagnosis is uncertain, a fetal magnetic resonance tive embolizations as a definitive treatment or in
study may be used. combination with the previous surgical resection.
The antenatal progression of a cystic adeno- Any congenital lung lesion that presents
matoid malformation is highly variable, and it is symptoms because of an infection should be ade-
54  Congenital Lung Malformations 559

quately treated before performing a surgical possibility of pneumothorax, sudden enlarge-

resection. ment of the lesion, hemoptysis, and lesion stroke.
Even in those patients who do not present Because of the risk of developing infections
symptoms, or in whom an echography regression and malignancy, surgery in these patients should
of an antenatally diagnosed lung lesion is sus- take place during childhood. We propose con-
pected, a computerized tomography scan will be ducting a computerized tomography scan before
needed after birth. Some authors perform it early, the first 6 months of life (depending on the X-ray
between 4 and 6 weeks of life; others wait until findings), and planning the surgery at some point
6 months if the lesion is not visible in the chest in time between 6 months and 1 year of life. The
X-ray. If the lesion does not appear in computer- reason for this delay is waiting for the patient to
ized tomography, the patient can be followed up, reach an adequate weight and size to undergo a
and a new study can be considered if there are minimally invasive surgery.
respiratory infections. Care must be taken when
labeling as cystic adenomatoid malformation the
lesions of antenatal diagnosis that “disappear,” Sources
because often a histological diagnosis is done
through an echography lesion, and these lesions Azizkhan RG, Crombleholme TM. Congenital cystic lung
disease: contemporary antenatal and postnatal man-
may correspond to other types of lesions, such as agement. Pediatr Surg Int. 2008;24(6):643–57.
mucus blockages or neuroblastomas, for Chen HW, Hsu WM, Lu FL, Chen PC, Jeng SF, Peng SS,
example. Chen CY, Chou HC, Tsao PN, Hsieh WS. Management
Development of lung infections is, without of congenital cystic adenomatoid malformation and
bronchopulmonary sequestration in newborns. Pediatr
doubt, the most common manifestation of con- Neonatol. 2010;51(3):172–7.
genital lung lesions in children beyond the neo- Davenport M, Warne SA, Cacciaguerra S, Patel S,
natal period. They can be often confused with a Greenough A, Nicolaides K. Current outcome of ante-
cystic adenomatoid malformation with a residual nally diagnosed cystic lung disease. J Pediatr Surg.
2004;39(4):549–56.
pneumatocele after an infection. Bronchiectasis Kotecha S, Barbato A, Bush A, Claus F, Davenport
or hemoptysis may be observed in older patients. M, Delacourt C, Deprest J, Eber E, Frenckner B,
Neoplasia is a well-documented fact of lesions Greenough A, Nicholson AG, Antón-Pacheco JL,
attributed to lung congenital cysts, such as pleu- Midulla F.  Antenatal and postnatal management of
congenital cystic adenomatoid malformation. Paediatr
ropulmonary blastoma (infants and small chil- Respir Rev. 2012;13(3):162–70.
dren). In a recent series of lung tumors in infancy, Laberge JM, Puligandla P, Flageole H.  Asymptomatic
8.6% of these were associated with a previously congenital lung malformations. Semin Pediatr Surg.
existent lung malformation. There is a clear asso- 2005;14(1):16–33.
Stocker JT.  Cystic lung disease in infants and chil-
ciation between cystic adenomatoid type 1 mal- dren. Fetal Pediatr Pathol. 2009;28(4):155–84.
formation and bronchoalveolar carcinoma. Available in https://www.tandfonline.com/doi/
Other secondary complications attributed to full/10.1080/15513810902984095.
congenital cysts or lung sequestration include the
 Gastroesophageal Reflux
and Respiratory Diseases
55
María Francisca Jaime Méndez,
José San Martín Prieto,
and Juan Cristóbal Gana Ansaldo

Contents
Introduction..................................................................................................................   561
Proposed GER Damage Mechanisms in Respiratory Diseases................................   562
Asthma...........................................................................................................................   562
Chronic Cough..............................................................................................................   563
Swallow Disorders........................................................................................................   563
Obstructive Sleep Apnea..............................................................................................   564
Apnea and ALTE..........................................................................................................   564
Subglottic Stenosis........................................................................................................   564
Laryngomalacia............................................................................................................   565
Recurrent Laryngitis....................................................................................................   565
Recurrent Laryngeal Papillomatosis..........................................................................   565
Diagnosis........................................................................................................................   566
Treatment......................................................................................................................   566
Conclusions...................................................................................................................   568
Sources...........................................................................................................................   568

Introduction event in most cases and may appear during all ages
in life, but it is more frequent before the first year of
Gastroesophageal reflux (GER) occurs when gas- life, usually for a brief period of time during the
tric content goes back to the esophagus, sometimes postprandial period. GER may present as a disease
even reaching the mouth. GER is a physiological when it causes symptoms or complications directly
related to this phenomenon, whether they are
M. F. Jaime Méndez · J. San Martín Prieto esophageal or extraesophageal.
J. C. Gana Ansaldo (*) Laryngopharyngeal reflux or extraesophageal
Pontificia Universidad Católica de Chile, Santiago, Chile
e-mail: [email protected]; [email protected]
reflux occurs when the gastric content passes to

© Springer Nature Switzerland AG 2020 561

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_55
562 M. F. Jaime Méndez et al.

the pharynx and larynx, and it can even get into pump. It is important to highlight that using these
the nasal cavity, middle ear, and airway (trachea, medications reduces the gastric pH, but it does
bronchi, lungs). not affect enzyme secretion, and it does not
GER has been related to obesity, neurologic directly impact gastrointestinal motility.
diseases, esophageal atresia history, hiatal hernia, Pepsin is a protease that has the greatest activ-
achalasia, prematurity, some chronic respiratory ity when the pH is around 1.9–3.6 and is inactive
diseases, and lung transplant. In addition, GER when pH is above 6.0. However, it does not natu-
has been associated with different respiratory ralize itself, and therefore it has been observed in
conditions, such as asthma, recurrent bronchitis, animal models to cause damage when it adheres
chronic cough, swallow disorders, poor growth, itself to the esophageal mucosa, being reactivated
persistent dysphonia, acute laryngitis, laryngo- at a posterior reflux episode, with a lower pH.
malacia, subglottic stenosis, recurrent respiratory It has been confirmed that bile salts cause
papillomatosis, apparent life-threatening event direct damage in the esophageal and extraesoph-
(ALTE) episodes, recurrent otitis media, and per- ageal mucosa, including lungs. In vitro and ani-
sistent rhinosinusitis. Nevertheless, these associ- mal studies have shown damage in the mucosa
ations do not imply causality. because of an increase of proton permeability,
In this chapter, we will review the relationship and even cellular death, at the lung level.
between gastroesophageal reflux and the follow- Among pancreatic proteolytic enzymes, we
ing respiratory diseases: asthma, chronic cough, have trypsin and chymotrypsin. Trypsin is active
swallowing disorders, obstructive sleep apnea, within a pH range of 6.0–10.0, and around 8.0 is
ALTE, subglottic stenosis, laryngomalacia, the optimum level. In order for trypsin to damage
recurrent laryngitis, and recurrent laryngeal proximal stomach tissue, the pH value must be
papillomatosis. 2.0, which may be present in patients using pro-
ton pump inhibitors.
Recent clinical studies have described an
 roposed GER Damage Mechanisms
P association between acid suppression therapy
in Respiratory Diseases and an increase in pneumonia risk. It has been
proposed that the cause would be a bacterial
GER may contribute to extra-esophageal syn- overgrowth in the stomach, which would be a
dromes, whether by a direct mechanism of aspi- consequence of the change in the luminal pH.
ration (reflux theory) or by an indirect mechanism,
mediated by vagal mechanisms (reflex theory).
The presence of gastric fluid may damage the Asthma
airway, which is not prepared to be in contact
with acidic material (or sometimes alkaline mate- Asthma and GER disease have a high prevalence
rial, if it comes from the duodenum), and enzy- rate, and therefore the presence of both in the same
matic activity. This reflux will cause damage patient is frequent. A systematic review of 2010,
depending on the intensity of exposure (quantity, which included 19 studies, described a prevalence
length of time, frequency), intrinsic resistance of of GER disease in asthma patients from 19% to
the parenchyma, and the presence of comorbidi- 80%, with a cumulative average of 23%. This high
ties or local concomitant alterations. variability reported is explained by the differences
Within the agents present in the gastric juice, in the methodologies used in the study: question-
which may be potentially harmful in both the naires, pH-metry, and endoscopy.
esophageal and extraesophageal mucosa, we may Several potential interaction mechanisms have
mention gastric acid, pepsin, bile salts, pancreatic been described between esophagus and lung:
proteolytic enzymes, and bacterial reflux content.
This last component would be particularly impor- • Embryonic origin and shared innervation
tant in patients who use inhibitors of the proton through the vagus nerve. In association with
55  Gastroesophageal Reflux and Respiratory Diseases 563

this, bronchoconstrictive vagus reflex has reports, which may be partly determined by
been described. It consists of bronchoconstric- methodological problems.
tion caused when there is acid and esophageal Esophageal reflux may trigger cough through
distention. There are also local reflexes where the indirect stimulation of the nerves involved in
esophageal neurons project axons to the tra- cough reflex, as it was described for asthma. In
chea, causing edema in the airway when faced adults with chronic cough evaluated through high
with acid in the esophagus, mediated by resolution manometry, it has been described that
tachykinins and substance P. partial clearing of food in the distal esophagus
• Intrathoracic pressure effect: During exacer- can stimulate cough reflex.
bations, because of the increase of respiratory Use of pH-metry plus impedantiometry has
work, negative intrathoracic pressure also improved the detection of GER episodes, classi-
increases. Under these circumstances, the fying them as “non-acidic” (pH >7), “mildly
capacity of the internal inferior esophageal acidic” (pH 4 a 7) and “acidic” (pH <4). Only the
sphincter may be overcome, and reflux epi- last two are detectable through conventional pH-­
sodes can increase. metry. In a study of patients with chronic cough,
• Asthma treatment: Medications used for in over 78% the association between cough and
asthma, including theophylline, aminophyl- GER was detected. In infants, a greater relation-
line, and β 2 agonists inhaled, may increase ship between cough and “mildly acidic” reflux
GER by causing a reduction in the pressure of was detected, while in preschoolers and school-
the inferior esophageal sphincter. Oral ste- children a greater relationship with “acidic”
roids increase the contact time between esoph- reflux was detected.
ageal mucosa and the acid. A Cochrane review updated in 2010, which
included 6 pediatric studies, with high heteroge-
In spite of this, two systematic reviews per- neity, found that the treatment with proton pump
formed in 2002 and 2009, found no use in reflux inhibitor was not useful for improving respira-
treatment for asthma. A randomized study pub- tory symptoms.
lished in 2012  in patients with non-controlled The fact that, in infants, cough is more related
asthma, which used lansoprazole versus placebo, to mildly acidic and non-acid reflux could explain
found no improvement, but a greater amount of the inconstant response to acid block therapy.
respiratory infections in the treated group. Other Nevertheless, more studies with adequate meth-
studies suggest that there may be some subgroups odology are needed, which may enable us to
that could benefit from the treatment, which are identify what subgroups of patients will benefit
not well characterized yet. These variable results from reflux treatment.
could translate the results of a treatment in a het-
erogeneous population, and so in some patients
GER is a concomitant event, and in other patients Swallow Disorders
GER may have a role in the physiopathology of
the disease. Currently, GER treatment is not rec- Swallowing is a complex process where different
ommended for patients with difficult-to-control structures and mechanisms intervene to allow the
asthma who have no proven reflux. transit of the bolus from the mouth to the stom-
ach, in a safe and effective way. In normal condi-
tions, the food goes from the pharynx to the
Chronic Cough esophagus, without penetrating the larynx or the
distal airway. For this, structural, motor, and sen-
Chronic cough study is one of the more frequent sitive indemnity is required. Pharyngolaryngeal
indications for pH-metry. The association reflux causes a chronic inflammation state in the
between them varies according to different superior aerodigestive airway, mainly at the oro
564 M. F. Jaime Méndez et al.

and hypopharynx, which reduces the sensitivity study was small, and therefore we still cannot
in the mucosa. Then, transport of food is not have conclusions for usual clinical practice.
timely detected, altering the complex mecha-
nisms ruling swallowing, as well as the airway
protection mechanisms. Eventually, food or flu- Apnea and ALTE
ids may enter the larynx, and may be aspirated to
the distal airway. GER has been related to apnea episodes. Around
Larynx sensitivity may be studied through the 30–50% of infants who present ALTE are diag-
evaluation of the laryngeal adductor reflex, which nosed with GER disease and are frequently
is triggered by the laryngeal stimulation through treated with anti-reflux medications to prevent a
an air impulse performed with a laryngoscope. recurrent event.
The objective is to determine the threshold to Two main mechanisms have been proposed to
trigger the reflex. A value above 4 mmHg is con- explain its relationship: first, laryngopharyngeal
sidered abnormal. In a study of cases with swal- reflux, which puts fluid from the stomach in con-
lowing disorder where this reflex was altered, and tact with the larynx and/or trachea, creates a
patients with other neurological diseases were laryngospasm episode caused by direct irritation.
excluded, it was observed that GER treatment for Second, a reflex mechanism is activated by the
at least 3  months with acid inhibition improves presence of gastric fluid in the distal esophagus,
pharyngolaryngeal sensitivity, and therefore it which also triggers a laryngospasm episode. It
improves the swallowing disorder. Larynx sensi- does not matter which mechanism causes the
tivity measured by laryngeal adductor reflex spasm, if it is long enough, it can cause severe
improved from 6.3 to 3.7 mmHg after the GER hypoxemia and eventually infant deaths.
treatment (p  <  0.001), while the proportion of In a study that conducted polysomnography
patients who presented aspiration was reduced and pH-metry, the diagnosis of GER by a func-
from 85% to 14% (p < 0.001). tional study did not affect the risk of ALTE recur-
rence, and GER treatment did no reduce this risk.
Another study performed in premature
Obstructive Sleep Apnea patients who were under 33 weeks of age and had
recurrent apneas, detected an association between
As it happens with asthma, both GER and apneas and GER episodes, particularly non-acid
obstructive sleep apnea syndrome (OSAS) are reflux, which had not been detected by isolated
prevalent diseases, and therefore both may be fre- pH-metry.
quently present in the same patient, but not nec- The use of proton pump inhibitors, as well as
essarily in a cause–effect relationship. GER thickened formulas, has not been confirmed to
could trigger apnea. Prolonged exposure to acid reduce the frequency of apneas related to reflux
in the respiratory tract causes local edema and an or ALTE recurrence, and therefore its general use
increase in respiratory secretions, which may is not currently recommended.
contribute to cause an obstructive apnea.
There are few studies evaluating the relation-
ship between GER and obstructive sleep apneas Subglottic Stenosis
in the pediatric population. In a study that
included 37 pediatric patients, 21 of them with Laryngopharyngeal reflux has frequently been
OSAS and reflux disease were treated with pro- associated with subglottic stenosis, and its pres-
ton pump inhibitors for 4–8  weeks. A variable ence has been estimated to be four times greater in
response was observed: from non-significant comparison to children without stenosis. Studies in
changes in the polysomnography in preschoolers, both children and adults have confirmed the pres-
to a complete resolution in schoolchildren with ence of GER in up to 80% of these patients. Other
mild OSAS.  Nevertheless, the sample for this more frequently associated factors are trauma and
55  Gastroesophageal Reflux and Respiratory Diseases 565

local infection. It has been proposed that laryngo- treatment in patients with laryngomalacia, anti-­
pharyngealreflux creates inflammation and mucosa GER treatment is still widely used in these
damage, impairing re-­epithelization and promoting patients, which justifies conducting more quality
the increase of connective tissue. Different reports studies that may define the real usefulness of this
show benefits of treating GER in patients with sub- therapy.
glottic stenosis by reducing symptoms. A study
that included 25 children with subglottic stenosis
who planned to undergo corrective surgery found Recurrent Laryngitis
that GER treatment avoided surgery in nine cases.
Patients who will require surgery usually are initi- Laryngopharyngeal reflux has been considered
ated on GER treatment. one of the causes of recurrent croup. Patients
with recurrent laryngitis who underwent pH-­
metry or endoscopy with esophageal biopsy have
Laryngomalacia been found with GER at a rate around 47–100%.
Chronic inflammation of the larynx caused by
Laryngomalacia is the most common cause of laryngopharyngealreflux plus viral respiratory
persistent congenital stridor during infancy. This infections explains this susceptibility.
condition is caused by neuromuscular immaturity
of the pharynx and by the flaccidity and redun-
dancy of supraglottic structures. It is mainly Recurrent Laryngeal Papillomatosis
manifested by inspiratory stridor, which varies in
its intensity. Besides this, according to how Laryngeal recurrent papillomatosis is a benign
severe it is, it may cause dyspnea, cough, chock- infectious disease caused by the human papillo-
ing episodes, swallowing disorders, and it may mavirus. The number of patients where latent
even impact the nutritional state and growth in papilloma virus can be found in the laryngeal epi-
infants. thelium is greater than the number of patients
Laryngomalacia is frequently associated with who actually develop laryngeal papillomatosis. It
laryngopharyngealreflux. There are studies that is not clear which factors activate the virus and
show that up to 2/3 of the children with laryngo- trigger the growth of papilloma, but it has been
malacia present GER, and that in cases of moder- proposed that laryngopharyngealreflux could be
ate to severe laryngomalacia the risk of presenting one of them. There are reports of patients where
GER is almost ten times greater. Nevertheless, GER treatment in mild to moderate papillomato-
the causality relationship between these two enti- sis may improve or even cure the disease. For
ties is not clear. In a prospective study published example, in a series of four cases of children with
in 2007, a strong correlation between GER treat- difficult-to-treat laryngeal papillomatosis, who
ment and reduction of laryngomalacia symptoms were also diagnosed and treated for GER, a sub-
was reported. In this study, patients were sepa- stantial improvement of papillomatosis in all the
rated into three groups: mild laryngomalacia, cases was observed, and two of them had a com-
moderate laryngomalacia, and severe laryngoma- plete resolution of the disease. Besides this, it has
lacia. Almost 89% of the patients who had mod- been observed that anti-GER therapy may cause
erate and severe laryngomalacia showed a reduction of secondary complications due to
improvement after receiving anti-GER treatment multiple resection surgeries, as happens with
for 7  months. Nevertheless, these conclusions anterior scars and laryngeal membranes.
have been questioned because improvement of Although it is not recommended to use GER
the symptoms may be caused by the natural pro- treatment as the only measure against laryngeal
gression of the disease instead of the therapy. papillomatosis, it does seem adequate to use it as
Although there are no more quality studies that a coadjutant to minimize consequences or arrest
actually compare the effectivity of the anti-GER the progression of the disease.
566 M. F. Jaime Méndez et al.

Diagnosis have not been completely defined, and the same

happens with children impedance values, which
Diagnosis of GER may be complex, mainly in makes it difficult to interpret the results obtained.
patients who have presented subtle and/or pro- In relation to endoscopy studies, gastric and
longed symptoms. It should be suspected in chil- duodenum endoscopy is useful to register esoph-
dren with the above clinical conditions, as well as in agitis macroscopic signs, as well as for obtaining
those with feeding problems, non-explained airway histological samples, especially when associated
problems, or who do not respond to other treat- diseases, such as eosinophilic esophagitis, are
ments. The process must start with a clinical detailed suspected. Besides this, flexible laryngoscopy is
history with special emphasis in symptoms related a non-invasive fast procedure, which does not
to swallowing and the aerodigestive path. require sedation, and it can be studied at any age
In relation to swallowing (and its eventual dis- through the anatomy of the aerodigestive path-
orders), it is crucial to ask for characteristics, way. In this case, special emphasis must be made
such as how long do meals take, stress or uncom- on the characteristics of the pharynx and larynx.
fortableness when feeding, signs of respiratory There are studies showing a correlation between
difficulty when feeding (for example, tachypnea, the findings of this exam and the results of the
wet voice or crying, increasing nasal congestion, ph-metry. Among the most significant endo-
chocking, cough, cyanosis), and growth. scopic findings are arytenoid edema and ery-
Request for complementary tests must be ori- thema (RR 2.46), lingual tonsil hypertrophy (RR
ented to the answer of a certain question, for 2.24), edema and erythema in the posterior laryn-
example, does this patient have some anatomical geal commissure (RR 3.19), edema in the poste-
condition that favors GER? How can GER be rior laryngeal commissure (3.19), vocal cord
attributed to the extradigestive symptoms of this edema (RR 12.15), and subglottic stenosis (RR
patient? Is the patient receiving enough treatment 2.5). Nevertheless, the presence of these findings
for GER?, etc. is not pathognomonic of GER.
Currently, the consensus reached between the The tests are summarized on Table 55.1.
North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition
(NASPGHAN) and the European Society for Treatment
Paediatric Gastroenterology Hepatology and
Nutrition (ESPGHAN) considers that pH-metry There are pharmacological and non-­
is useful to evaluate the correlation between the pharmacological measures for patients with con-
symptoms and the presence of GER, as well as firmed disease caused by gastroesophageal
those patients with respiratory symptoms where reflux. For pediatric patients, the strategy of
GER could be worsening the clinical condition. “empirical treatment” with no clear symptoms of
Particularly, pH-metry with multichannel intralu- GER has not been confirmed as sensitive or spe-
minal impedance, detects changes in electric con- cific for the diagnosis of this disease, and there-
ductivity between electrodes, and so it can assess fore it is not recommended as a diagnosis
the pathway for foods, liquids, and even gases; it method.
is considered superior to isolated pH-metry, Use of thick or “anti-regurgitation” formulas,
because impedancemetry can detect acid reflux, although they reduce the number of regurgita-
mildly acidic reflux, and non-acid reflux, whose tions observed by the caregivers, is not translated
relationship with respiratory disease has been in pH-metry improvement. Formula thickened at
previously discussed. Although these two tests home with rice cereal increases weight in infants,
are useful, the fact that they take 24 hours makes considering the caloric density it involves.
it difficult to conduct them in children. Besides In older children and adolescents, weight
this, pH normal or basal values for hypopharynx reduction is recommended in children with
55  Gastroesophageal Reflux and Respiratory Diseases 567

Table 55.1  Study in patients with gastroesophageal reflux

Study Usefulness Observations
Esophageal pH-metry Evaluates the presence of acidic fluid Does not detect mildly
Useful to evaluate anti-GER treatment acidic or non-acidic fluids
Esophageal pH-metry Evaluates the presence of acid, mildly acidic, and Impedance normal values
multichannel intraluminal non-acid reflux for pediatric age are
impedance Useful to evaluate the effectiveness of anti-GER missing
treatment and its association with extradigestive
symptoms (cough, difficult-to-control asthma, chest
pain)
Esophagus-duodenum-­ Anatomical evaluation when malformations are Should not be used to
stomach x ray suspected diagnose GER or quantity of
Gastric endoscopy Evaluation of macroscopic signs of esophagitis and If no macroscopic
taking of histological samples for differential diagnosis alterations are found it may
of other pathologies (eosinophilic esophagitis) not diagnose GER
Flexible laryngoscopy Evaluates the anatomy of the aerodigestive way and Findings are not
macroscopic signs of laryngopharyngealreflux necessarily related to GER
Gastroesophageal Evaluation of postprandial and aspiration GER Lack standardization
scintigraphy technique and normal
values for each age

excess malnutrition. Although suspending certain lanzoprazole. Proton pump inhibitors are consid-
foods a priori is a commonly used strategy, it has ered to be better than the H2RA in suppressing
not been confirmed that it actually reduces GER acid effects, which also present tachyphylaxis
episodes. Instead, it is recommended to reduce after 6 weeks of use, and even reactions like irri-
certain foods according to each case. tability, headache, and sleepiness may be
It has been shown that prone and lateral decu- wrongly interpreted as GER worsening. It has
bitus position reduces GER episodes. been confirmed that proton pump inhibitors are
Nevertheless, these positions have been associ- better than histamine receptor inhibitors in treat-
ated with an increased rate in sudden death syn- ing erosive esophagitis. Nevertheless, it has
drome, and therefore supine position is some difficulties in the dosage and administra-
recommended for those patients who are under tion, because there is no syrup presentation. In
1 year of life and also have GER. Prone position general, the use of costumed preparations is not
can be kept when they are awake and always recommended, as there are few studies support-
supervised. ing the stability and bioavailability of these sub-
In relation to pharmacological measures, there stances. Besides this, the use of proton pump
are medications that have a buffer effect on the inhibitors is not risk free, because idiosyncratic
acid, a barrier effect on the mucosa, anti-acid reactions may occur, as well as diarrhea, consti-
secretors, and prokinetics. pation, nauseas, hypergastrinemia with its
Evidence about pediatric use of antacids is chronic use, hyperplasia of enterochromaffin-
limited, and special care must be taken with like cells, and in the long term, micronutrients
those drugs containing aluminum, in relation to malabsorption (iron and B12 vitamin). In prema-
milk-­alkali syndrome. They are generally not ture babies an increased risk of necrotizing
recommended for the treatment of GER in enterocolitis and candidemia was observed.
children. Table 55.2 shows the recommended dosages for
Acid secretion inhibitors are ion histamine H2RA and proton pump inhibitors.
type 2 receptor agonist (H2RA), such as raniti- Prokinetics such as cisapride reduce the GER
dine and famotidine, and the proton bomb inhib- index; nevertheless, its use has been limited by its
itors, such as omeprazole, esomeprazole, and association with prolonged QTc interval in the
568 M. F. Jaime Méndez et al.

Table 55.2  Gastroesophageal reflux treatment

Type Medication Doses Observations
H2RA Ranitidine 5–10 mg/Kg/day, divided in 2–3 Tachyphylaxis
doses
Famotidine 1 mg/Kg/day, divided in 2 doses Tachyphylaxis
PPI Omeprazole 0.7–3.3 mg/Kg/day Formulation: 10 and 20 mg capsules
MUPS in 10 and 20 mg
Lansoprazole 0.7–3 mg/Kg/day 30 mg envelopes
15 and 30 mg capsules
Mouth dissolving tablet 15 and 30 mg
Esomeprazole 0.7–3.3 mg/Kg/day Formulation: 10 g envelopes. Capsules and tablets of 20
and 40 mg
H2RAs Histamine type 2 receptor agonist
PPI Proton pump inhibitor

electrocardiogram. The efficiency of domperi- when there is a specific clinical question.

done, widely used for the treatment of GER, has Testing is not for every patient.
not been confirmed. It has been observed that 4. Currently, there are few studies with a correct
metoclopramide reduces the GER index as mea- methodology that may establish which
sured by pH-metry, but its use is limited by its patients with respiratory symptoms will ben-
adverse effects, which particularly affects extra- efit from anti-GER therapy. In these circum-
pyramidal structures, and in general its use is not stances, empirical treatment of patients with
recommended. no symptoms of gastroesophageal reflux is not
In those cases where there is documented recommended.
GER, where the optimal medical therapy has
failed, who depend on therapy during prolonged
periods or who may have life-threatening compli-
cations, surgical treatment can be considered, Sources
including open and laparoscopic fundoplication,
and even limited experiences through endoscopy. Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske
LA.  Gastro-oesophageal reflux treatment for pro-
Nevertheless, evidence of its use in pediatrics is longed non-specific cough in children and adults.
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E, Martini S, Battistini B, Faldella G.  A thickened
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esophageal reflux in preterm infants. Neonatology.
2013;103(2):98–102.
Conclusions Ghezzi M, Guida E, Ullmann N, Sacco O, Mattioli G,
Jasonni V, Rossi GA, Silvestri M.  Weakly acidic
gastroesophageal refluxes are frequently triggers in
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young children with chronic cough. Pediatr Pulmonol.
must be differentiated from the physiological 2013;48(3):295–302.
gastroesophageal reflux, which is particularly Hartl TT, Chadha NK.  A systematic review of laryngo-
malacia and acid reflux. Otolaryngol Head Neck Surg.
frequent in infants. 2012;147(4):619–26.
2. There is an association between gastroesopha- Holland BW, Koufman JA, Postma GN, McGuirt WF Jr.
geal/laryngopharyngeal reflux and diverse Laryngopharyngeal reflux and laryngeal web forma-
respiratory diseases. Nevertheless, in most of tion in patients with pediatric recurrent respiratory
papillo-mas. Laryngoscope. 2002;112(11):1926–9.
them causality has not been confirmed. Karkos PD, Leong SC, Apostolidou MT, Apostolidis
3. Only a minority of patients require additional T. Laryngeal manifestations and pediatric laryngopha-­
tests, and these tests should only be requested ryngeal reflux. Am J Otolaryngol. 2006;27(3):200–3.
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Lightdale J, Gremse D and Section on Gastroenterology McKenna M, Brodsky L.  Extraesophageal acid reflux
Hepatology, and Nutrition. Gastroesophageal reflux: and recurrent respiratory papilloma in children. Int J
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2013;131:e1684. Pearson JP, Parikh S, Orlando RC, et al. Review article:
Little JP, Matthews BL, Glock MS, Koufman JA, reflux and its consequences-the laryngeal, pulmonary
Reboussin DM, Loughlin CJ, McGuirt WF Jr. and oesophageal manifestations. Aliment Pharmacol
Extraesophageal pediatric reflux: 24-hour double-­ Ther. 2011;33(Suppl 1):1–71.
probe pH monitoring of 222 children. Ann Otol Rhinol Rosen R, Nurko S. The importance of multichannel intra-­
Laryngol Suppl. 1997;169:1–16. luminal impedance in the evaluation of children with
May JG, Shah P, Lemonnier L, Bhatti G, Koscica J, persistent respiratory symptoms. Am J Gastroenterol.
Coticchia JM.  Systematic review of endoscopic 2004;99(12):2452–8.
airway findings in children with gastroesopha- Rudolph CD. Supraesophageal complications of gastroe-­
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Miura MS, Mascaro M, Rosenfeld RM.  Association 2006;116(8):1397–403.
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a systematic review. Otolaryngol Head Neck Surg. as-sessment of airway protection in pediatric patients.
2012;146(3):345–52. Am J Med. 2003;115(Suppl 3A):166S–8S.
 Pneumothorax and Thoracic
Trauma
56
Claudia Fuentes Sáez and Raúl Bustos Betanzo

Contents
Pneumothorax  571
Definition  571
Epidemiology  571
Etiology and Pathophysiology  572
Clinical Manifestations  573
Diagnostic Approach...  574
Quantification of Pneumothorax Size  575
Treatment  575
Thorax Trauma  577
Summary  577
Sources  578

Pneumothorax traumatic, or iatrogenic. Spontaneous pneumo-

thorax can also be classified as primary or sec-
Definition ondary to a preexisting respiratory disease.

The pleural space is a virtual space filled with a

minimum amount of fluid between the visceral Epidemiology
and parietal pleura. When air gets into the pleural
space, it is called pneumothorax and it modifies The incidence of spontaneous pneumothorax in
intrapleural pressure and causes partial or total children is from 7.4 to 18 per 100,000 males and
lung collapse. It is classified as spontaneous, from 1.2 to 6 cases per 100,000 females, with a
ratio of 2:1. The average age of onset has been
reported between 14 and 16 years of age. In gen-
C. Fuentes Sáez (*) eral, patients are tall males with decreased body
Pediatrics, Respiratory Diseases, Hospital Regional mass index. Mortality is rare.
de Concepción, Concepción, Chile Although the incidence of secondary spontane-
R. Bustos Betanzo ous pneumothorax is not well defined, patients
Pediatrics, Intensive Care at Clínica Sanatorio with asthma and cystic fibrosis have the greatest
Alemán, Concepción, Chile risk. In these patients, the probability of secondary
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 571

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_56
572 C. Fuentes Sáez and R. Bustos Betanzo

spontaneous pneumothorax occurrence increases

as lung function decreases, with morbidity and
mortality being greater due to the reduced lung
volumes in an affected lung. In cystic fibrosis, the
appearance of pneumothorax is considered a late
complication and a sign of poor prognosis. Several
studies show that between 16% and 20% of
patients with cystic fibrosis older than 18  years
will experience a pneumothorax during their lives.
Most of them (75%) have a FEV1 <40%, which
has been associated with high mortality.
Infectious causes, such as Pneumocystis jir-
ovecii pneumonia and necrotizing pneumonia
(anaerobes, gram-negative or Staphylococcus
Fig. 56.1 Iatrogenic Pneumothorax. Anteroposterior
aureus), are associated with a high incidence of chest X-ray of a 2-year-old patient on mechanical ventila-
secondary pneumothorax. Patients with connec- tion due to convulsive status. It shows right-sided pneu-
tive tissue diseases, such as Marfan and Ehlers-­ mothorax secondary to insertion of a central venous
Danlos syndromes, are also at high risk. The catheter into the internal jugular vein on the same side
most frequent causes of secondary pneumothorax
appear in Table 56.1. and positive support by mechanical ventilation
When considering pediatric thoracic trauma, (Fig. 56.1). The internal jugular vein and subcla-
pneumothorax may occur in up to a third of vian vein catheterization are procedures with a
patients, most of them associated with extratho- high-risk for developing pneumothorax. The use
racic and intrathoracic injuries, but one third may of ultrasound techniques has reduced the inci-
present only pneumothorax. dence of pneumothorax by central venous cathe-
Iatrogenic pneumothorax is a consequence of terization and thoracentesis in adults. Strategies
medical procedures, most of them being per- of protective lung ventilation, with tidal volumes
formed in the emergency room or intensive care limitation and plateau pressures, have enabled
units. The most frequently associated procedures the diminishment of the effects of barotrauma
are central venous catheterization, thoracentesis, secondary to mechanical ventilation.

Table 56.1  Causes of secondary pneumothorax

Etiology and Pathophysiology
Airway disease Asthma, cystic fibrosis, interstitial
emphysema
Postinfectious Pneumocystis jirovecii, tuberculosis, The increase in transpulmonary pressure is the
lung abscess, necrotizing pneumonia, mechanism described in the appearance of spon-
HIV, parasites taneous pneumothorax. This causes alveolar dis-
Connective Marfan syndrome, Ehlers–Danlos tension, and if the gradient is high enough,
tissue diseases syndrome, juvenile idiopathic
arthritis, systemic lupus
alveolar rupture. It can occur secondary to
erythematosus, dermatomyositis, increased work of breathing, a Valsalva maneu-
Birt–Hogg–Dube syndrome ver, positive pressure ventilation, and airway
Oncological Lymphoma, pulmonary metastasis obstruction that causes an obstruction ball valve
diseases
effect, among others.
Congenital Cystic adenomatoid malformation
malformations Congenital lobar emphysema
Once alveolar rupture occurs, air may reach the
Foreign body perivascular space producing pneumomediasti-
aspiration num; if the air pressure increases, it can go to the
Catamenial Related to menstrual cycle neck and face (subcutaneous emphysema), advance
pneumothorax toward the peritoneal cavity ­(pneumoperitoneum),
56  Pneumothorax and Thoracic Trauma 573

A familial form of primary spontaneous pneu-

mothorax has been described, related to a mutation
in the folliculin gene, located on chromosome 17,
which plays a role in the definition of cell shape,
size, and movement. This condition has been asso-
ciated with the Birt–Hogg–Dube syndrome, in
which there is a predisposition to the formation of
multiple lung cysts that lead to the development of
primary spontaneous pneumothorax.
Secondary spontaneous pneumothorax results in
systemic or local inflammation of the lung tissue
caused by an underlying disease. In children,
asthma and cystic fibrosis are the most commonly
recognized chronic respiratory diseases. The mech-
Fig. 56.2  Postinfectious Pneumothorax. Anteroposterior
chest x-ray of an 8-month-old patient with severe pneu- anism involved in asthma is the chronic inflamma-
monia due to adenovirus. It shows pneumothorax, pneu- tion of the small airway, which allows creation of
momediastinum, pneumopericardium, and subcutaneous the necessary pressure for the air to escape to the
emphysema secondary to mechanical ventilation pleural space, although secondary spontaneous
pneumothorax has been observed in asthma patients
or penetrate the pericardium (pneumopericardium) without respiratory exacerbation. The mechanism
(Fig. 56.2). involved in cystic fibrosis is inflammation and
Spontaneous pneumothorax seems to occur obstruction of the distal airway, due to thick secre-
due to changes in the connective tissue that pre- tions that lead to air entrapment in the alveoli. When
dispose air leaks from the airways into the pleural the alveolar pressure exceeds the interstitial fluid
space. The mechanisms proposed for both pri- pressure, the air moves to the interstitium, reaching
mary and secondary pneumothorax are multiple. the hilum, and escaping to the mediastinal pleura.
Frequently, the existence of subpleural bullae, or Other mechanisms described are rupture of sub-
bullas, has been associated with the production of pleural bulas at the level of the visceral pleura and
primary pneumothorax. In studies performed Pseudomonas sp. or Burkholderia cepacia infec-
with computerized axial tomography scans, bul- tions (Figs. 56.3 and 56.4).
las have been detected in between 28% and 100% In newborns, the most common causes of sec-
of the cases that developed a primary pneumo- ondary spontaneous pneumothorax are meco-
thorax and between 70% and 95% in patients nium aspiration syndrome (MAS) and hyaline
who required video-assisted thoracoscopy sur- membrane disease (HMD).
gery (VATS) due to this pathology. In newborns,
high transpulmonary pressures during the first
breaths contribute to the appearance of primary Clinical Manifestations
pneumothorax.
The role of tobacco, both in the development Symptoms and signs of pneumothorax vary accord-
of primary and secondary spontaneous pneumo- ing to the patient’s age, level of lung collapse and
thorax, has also been widely analyzed, especially previous lung volumes. Small pneumothoraxes can
in adults. Prevalence of smoking in children with be asymptomatic and show normal vital signs.
primary pneumothorax is between 11% and 14%, Spontaneous pneumothorax occurs mostly at rest,
while in adults is between 24% and 88%. This but it may be caused by situations that increase
supports the theory between time exposure to intrathoracic pressure through the Valsalva maneu-
tobacco and changes in connective tissue and/or ver (such as lifting objects or stretching).
chronic bronchiolitis that are observed in adult Acute chest pain and dyspnea are the most fre-
patients and predisposition to pneumothorax. quent symptoms in pediatric spontaneous pneumo-
574 C. Fuentes Sáez and R. Bustos Betanzo

thorax. Even without treatment, the symptoms

resolve in 1–3  days; however, pneumothorax per-
sists in most patients. Physical examination find-
ings depend on the size of the pneumothorax. Small
ones may not be detected clinically. Clinical signs
include decreased pulmonary sounds, dyspnea,
tachycardia, hyperresonance on percussion, and
decreased vocal fremitus. In a minority of patients it
can present itself as tension pneumothorax, with
respiratory distress, hypoxemia, tachycardia, and
arterial hypotension. The latter is a respiratory
emergency and requires immediate intervention.

Diagnostic Approach

Once the pneumothorax diagnosis is suggested

by the presentation and clinical examination, it is
confirmed with an anteroposterior and lateral
chest X-ray. Expiratory X-rays have been sug-
gested for detecting small pneumothoraxes,
although low yield has been demonstrated. Chest
X-rays in lateral decubitus position may be use-
ful in emergencies or intensive care units. In criti-
cally ill patients, when pneumothorax is
suspected, most chest X-rays are taken in supine
position. In these cases, the air moves toward an
anterior or sometimes medial location adjacent to
the mediastinum, sub pulmonary or lateral, and
the lateral costophrenic angle can be distended to
Fig. 56.3  Pneumothorax in Chronic Disease.
the caudal direction, which causes the so-called
Anteroposterior and lateral chest X-ray of a 14-year-old
patient with cystic fibrosis and advanced lung disease. It deep sulcus sign, showing asymmetry of the lat-
shows lateral and anterior pneumothorax on the right side eral costophrenic recesses due to a greater depth
and radiolucency of one of them; the angle can
even extend to the hypochondrium and adopt a
triangular morphology (Fig. 56.5).

Ultrasound  In recent studies, chest ultrasound

has been used to diagnose pneumothorax in the
adult population, having found a sensitivity of up
to 95% for diagnosis. It seems that the diagnostic
accuracy of ultrasound would be superior to chest
X-rays in trauma and critically ill patients. There
is not enough evidence to routinely recommend
chest ultrasound in children. In addition, the
quantification of pneumothorax is difficult with
Fig. 56.4  Pneumothorax in Chronic Disease. Chest CAT
scan in a patient with cystic fibrosis. It shows left apical this method and therefore it will hardly replace
pneumothorax and multiple bilateral subpleural bullas chest X-rays for diagnosis in children.
56  Pneumothorax and Thoracic Trauma 575

guidelines of the British Thoracic Society in adult

patients with stable clinical condition, define a
large pneumothorax as the presence of a visible
edge of up to 2 cm between the lung image and the
chest wall on an anteroposterior chest X-ray.
According to the guidelines of the American
College of Chest Physicians, the apical distance
must be greater than 3 cm. In children, the defini-
tion of large pneumothorax, according to the previ-
ously described guidelines, can result in an error,
because the thorax size differs in relation to the age
and body type of the patient. It is important to con-
sider that when defining the management strategy
of spontaneous pneumothorax, clinical status is
Fig. 56.5  Deep Sulcus Sign. Decubitus anteroposterior more important than size estimated by radiology.
chest X-ray in infant with severe pneumonia. It shows left
pneumothorax with deep sulcus sign
Treatment
Computerized axial tomography scan  When
there is an important clinical suspicion of pneu- Scarce evidence in the pediatric population makes it
mothorax, with negative chest X-rays, a comput- difficult to establish some explicit therapeutic
erized axial tomography scan could be considered guidelines, so that management follow adult recom-
in the diagnosis of subtle pneumothorax. This mendations. Pediatric guidelines for the manage-
could be relevant in the detection of secondary ment of spontaneous pneumothorax do not exist in
pneumothorax in patients with an underlying dis- the scientific literature. The guidelines for the man-
ease who have low lung volumes, in order to help agement of spontaneous pneumothorax in adults do
in a possible evacuation. not include recommendations for pediatric patients.
In thorax trauma, computed tomography has Treatment depends on the extent and type of
become the method of choice to identify pneumo- pneumothorax, in addition to the severity of the
thorax. Recently, volumetric measurements of the symptoms. It should be remembered that estimat-
pneumothorax have been used with three-­ ing the magnitude of the pneumothorax can be dif-
dimensional images through multidetector com- ficult due to different thorax sizes according to age.
puted tomography, which have reached 100% Treatment options for spontaneous pneumotho-
sensitivity in diagnosis. On the other hand, in pri- rax in a clinically stable patient include: monitoring
mary spontaneous pneumothorax, it has been on high oxygen concentration administration, sin-
described that the detection of bullas by computed gle evacuation puncture, small-bore pleural cathe-
tomography could be a predictive sign of recurrent ter (10–14  F), large-bore catheter (>20  F) or
pneumothorax, especially when they are detected thoracotomy tubes.
on the contralateral side of the pneumothorax. There are several reported cases, including
adults and children, in which conservative man-
agement has been followed. A total of 68 of 82
Quantification of Pneumothorax Size cases reach a spontaneous remission of primary
spontaneous pneumothorax, but they required up
Different methods to calculate the size of pneumo- to 32 days.
thorax in adults have been applied in children with Standard recommendations in adults for the
inconsistent results; thus, currently, there are no treatment of small primary spontaneous pneumo-
validated methods for estimating the pneumotho- thorax, without respiratory distress and clinically
rax volume in the pediatric population. The stable, is monitoring for 3–6 hours in the emergency
576 C. Fuentes Sáez and R. Bustos Betanzo

department; after this, clinical follow-up in small-bore catheters (10–14  F). An adult study
12–24  hours or before in the case of worsening shows similar results regarding the resolution of the
symptoms. Not recognizing the deterioration of the pneumothorax when comparing the installation of a
patient is one of the risks of this type of treatment. pigtail catheter versus large-bore catheters. When
Administration of oxygen at high concentra- the pneumothorax occurs in a patient with cystic
tions (100%) creates a partial pressure gradient fibrosis, clinical guidelines propose hospital admis-
between the pleural cavity and the capillary web; sion and thoracotomy tube insertion. In traumatic
diminished nitrogen partial pressure in the blood pneumothorax, the use of traditional pleural drain-
produces an increase in the pressure gradient of age catheters is recommended. Iatrogenic pneumo-
the gases between the pleura and the venous thorax, which is associated with barotrauma, will
blood, favoring the absorption of all air. require the insertion of thoracotomy tubes. A study
Management of primary spontaneous pneu- evaluating 70 patients on mechanical ventilation
mothorax in unstable patients involves a fine who developed pneumothorax showed that the use
needle evacuation puncture, which is as effective of pigtail catheters was beneficial in only 43% of
as the use of a small-bore catheter, and it would the cases, requiring most of them to change to tradi-
reduce hospital days. tional pleural drainage due to clinical deterioration.
For secondary spontaneous pneumothorax, An algorithm for treating of pediatric pneumotho-
guidelines recommend hospitalization and use of rax is presented below in Fig. 56.6.

Pneumothorax
treatment

(Patient’s age, underlying pathology and NT size should be considered)

Secondary
Primary spontaneous Traumatic Iatrogenic
spontaneous
pneumothorax pneumothorax pneumothorax
pneumothorax

STABLE PATIENT: • Always • Traditional pleural • In symptomatic

• Observation in hospitalization catheter insertion patients consider fine
emergency room • Insertion of small- needle aspiration. If
• O2 in high bore catheter there is no lung
concentrations • In patients with cystic expansion, insertion of
• home discharge if fibrosis, consider small-bore catheter or
there is no clinical thoracotomy tube traditional tube
deterioration insertion • In patients with
SYMPTOMATIC mechanical ventilation
PATIENT OR always use traditional
DISTANCE> 2 CMS pleural tubes
IN CHEST X-RAY:
Fine needle aspiration
and subsequent
observation
· Insertion of small-
bore catheter

Fig. 56.6  Algorithm for the treatment of pneumothorax

56  Pneumothorax and Thoracic Trauma 577

If there is no resolution and the air leak per- extremities. The most frequent chest lesions are
sists (3–5 days), or if there is recurrence, the use pulmonary contusions with or without rib frac-
of video-assisted thoracoscopy surgery (VATS) ture; tracheobronchial tree, heart, aorta, esopha-
should be considered. Reports in the pediatric gus or diaphragm compromise are rarely
population indicate a recurrence of pneumotho- observed.
rax up to 60%, but most authors recommend Pulmonary contusion is the result of the direct
VATS only after the second episode. Some surgi- application of high energy in the lung paren-
cal indications of pneumothorax are: ipsilateral chyma. After the contusion, anatomical changes
pneumothorax (second episode), first contralat- appear, including hemorrhage, edema, and con-
eral pneumothorax, synchronous bilateral spon- solidation, which reduce pulmonary compliance,
taneous pneumothorax, persistent air leak leading to ventilation/perfusion alteration,
(according to guidelines >4–7  days), failure of hypoventilation, and hypoxia. Up to 20% of
lung expansion despite the drainage tubes, spon- patients develop pneumonia after a pulmonary
taneous hemothorax, high-risk professions that contusion. If the contusion is accompanied by
have experienced an episode of pneumothorax laceration, air leak and pneumothorax may
(pilots), and pregnancy. appear, and sometimes hemothorax as well. If
Different methods have been used to treat there is a massive pneumothorax secondary to
persistent air leaks, including prolonged use of tracheobronchial injuries, air accumulates not
pleural drainage, surgical repair, chemical only in the pleural space, but also in the medias-
pleurodesis (via injection of sclerosing agents, tinum, neck, and subcutaneous tissue.
such as tetracycline or talcum powder) or Most traumatic lung injuries are treated with
pleurodesis with autologous blood patch. Some respiratory support and pleural drainages.
recent studies support the use of the latter method Massive hemothorax requires exploratory thora-
due to its efficacy, good tolerance, minimal col- cotomy. Persistent air leak, which may corre-
lateral effects, decrease in complications, and spond to a tracheobronchial rupture, requires
shorter hospital stay. intubation, endoscopic airway evaluation, and
eventual reparative surgery. In the case of open
pneumothorax, the defect must be sealed.
Thorax Trauma

Thoracic trauma corresponds to less than 10% of Summary

the traumas in children. Different pediatric series
have reported a mortality rate between 8% and Pneumothorax is the presence of air between the
26%. The classification of thoracic trauma is parietal and visceral pleura. It is classified as
shown in Table 56.2. spontaneous, traumatic, and iatrogenic. Primary
Most trauma occur in children during their spontaneous pneumothorax is an infrequent
first decade of life and are secondary to traffic entity in pediatrics outside the neonatal period.
accidents and falls. They are high energy impacts Secondary spontaneous pneumothorax is associ-
and usually involve other regions of the body; ated with multiple lung conditions, the most
approximately half of the children with chest common being asthma and cystic fibrosis. Chest
trauma have lesions in the skull, abdomen, and X-ray is the first choice test to confirm diagnosis,
although computed tomography is a good alter-
Table 56.2  Classification of thoracic trauma native to detect subtle pneumothorax and to esti-
Non-penetrating trauma mate their magnitudes.
 Does not involve opening of the chest There are no guidelines for the treatment of
 Corresponds to 80–90% of cases pneumothorax in pediatrics, so its management
Penetrating trauma in school children and adolescents is based on
 Causes an open injury recommendations for the adult population. In
578 C. Fuentes Sáez and R. Bustos Betanzo

infants and preschoolers, an exhaustive study in Dotson K, Johnson LH.  Pediatric spontaneous pneumo-
thorax. Pediatr Emerg Care. 2012;28:715–20.
search of the etiology is necessary to establish the Flume PA, Mogayzel PJ Jr, Robinson KA, Rosenblatt RL,
appropriate treatment. It is important to consider Quittell L, Marshall BC, Clinical Practice Guidelines
that the estimation of the extension of the pneu- for Pulmonary Therapies Committee, Cystic Fibrosis
mothorax in this group of patients can be diffi- Foundation Pulmonary Therapies Committee. Cystic
fibrosis pulmonary guidelines: pulmonary complica-
cult, due to the differences in the thorax size tions: hemoptysis and pneumothorax. Am J Respir
according to age. The choice of the different Crit Care Med. 2010;182:298–306.
therapeutic methods will depend on the type of Flume PA.  Pneumothorax in cystic fibrosis. Curr Opin
pneumothorax, age of patient, associated condi- Pulm Med. 2011;17:220–5.
Johnson NN, Toledo A, Endom EE. Pneumothorax, pneu-
tion, and severity of the clinical picture. Most momediastinum and pulmonary embolism. Pediatr
pneumothorax can be managed conservatively; Clin N Am. 2010;57:1357–83.
however, in patients with preexisting pulmonary Light RW. Pleural controversy: optimal chest tube size for
disease or recurrence, there are more aggressive drainage. Respirology. 2011;16:244–8.
MacDuff A, Arnold A, Harvey J, BTS Pleural Disease
and definitive treatment options that should be Guideline Group. Management of spontaneous pneu-
considered (VATS). mothorax: British Thoracic Society Pleural Disease
Future research is needed to assess the benefit Guideline 2010. Thorax. 2010;65(Suppl 2):ii18–31.
of the various therapeutic interventions available Manley K, Coonar A, Wells F, Scarci M. Blood patch for
persistent air leak: a review of the current literature.
in the pediatric population and to determine if Curr Opin Pulm Med. 2012;18:333–8.
current adult guidelines can be used in children. Robinson PD, Cooper P, Ranganathan SC.  Evidence-­
based management of paediatric primary spontaneous
pneumothorax. Paediatr Respir Rev. 2009;10:110–7.
Shaireen H, Rabi Y, Metcalfe A, Kamaluddeen M, Amin
Sources H, Akierman A, Lodha A. Impact of oxygen concen-
tration on time to resolution of spontaneous pneu-
Alrajab S, Youssef AM, Akkus NI, Caldito G.  Pleural mothorax in term infants: a population-based cohort
ultra-sonography versus chest radiography for the study. BMC Pediatr. 2014;14:208.
diagnosis of pneumothorax: review of the literature Tomà P, Owens CM. Chest ultrasound in children: critical
and meta-analysis. Crit Care. 2013;17:R208. appraisal. Pediatr Radiol. 2013;43:1427–34.
Ayres J, Gleeson F. Imaging of the pleura. Semin Respir Tovar JA, Vazquez JJ.  Management of chest trauma in
Crit Care Med. 2010;31:674–88. children. Paediatr Respir Rev. 2013;14:86–91.
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 Nutrition in Chronic Respiratory
Disease
57
Salesa Barja Yáñez

Contents
Introduction  579
Factors that Influence Nutritional Status  580
Mechanisms Involved in Malnutrition  580
Interaction Between Nutrition and Lung Function  581
Specific Diseases  582
Bronchopulmonary Dysplasia  582
Post-infectious Chronic Lung Damage  583
Cystic Fibrosis  583
Asthma  583
Patients with Prolonged Ventilatory Support  583
 utritional Support In Chronic Respiratory Diseases
N  584
Regular Monitoring of Food Intake  584
Regular Monitoring of Nutritional Status  584
Early Nutritional Intervention  585
Laboratory Tests  585
Specific Measures of Nutritional Management  586
Conclusion  589
Sources  589

Introduction ment of these patients is part of the multidisci-

plinary treatment and is increasingly complex.
Changes in the epidemiological profile of infant The prevalence of malnutrition in Chilean chil-
morbidity and mortality has made secondary dren under the age of 6 in outpatient setting is less
malnutrition an emerging problem. As a result, than 0.4%, and short stature is 2%; however, in
infectious diseases have decreased and the sur- children’s hospitals it has been reported between
vival of preterm children and others with serious 25% and 30%. This is mainly associated with
illnesses has improved. The nutritional manage- chronic diseases in patients who require complex,
high-cost treatments and whose prognosis is bet-
ter because of nutritional improvement. The high-
S. Barja Yáñez (*) est proportion is related to chronic respiratory
Pontificia Universidad Católica de Chile, Santiago, Chile diseases, with 30% of acute ­malnutrition and up
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 579

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_57
580 S. Barja Yáñez

to 50% of growth delay in the most serious cases. Table 57.1  Interaction Between Drugs and Nutrients
At the opposite extreme, obesity has increased, Drug Nutritional effect
associated with asthma in childhood and interre- Anticonvulsants: Folate, Ca, Vit B12, B6, D,
lated diseases in its genesis and progression. C. Dyslipidemias
 Phenytoin Folate, Ca, Vit B12, B6, K,
C. Dyslipidemias
 Phenobarbital
 actors that Influence Nutritional
F Anti-­ Vit C, Fe
Status inflammatories:
 Aspirin Proteins, fats, glucose, Zn, K,
Several factors compromise the nutritional status Na, Ca
 Corticosteroids
of children with chronic diseases, which are also
Antimicrobials: ↓Endogenous Vit K in the bowels
applicable to chronic respiratory diseases:
 Isoniazid Vit B6, niacin
 Trimethoprim Folate
• Type of underlying disease: Both patients with  Penicillin K
cystic fibrosis and bronchopulmonary dyspla- Cathartics: Vit A, D, E, K, carotene, Ca
sia in which there is also post infectious lung  Mineral oil
damage require particular nutritional Others: K, Mg, Ca
approaches, as it will affect nutritional recov-  Digitalis Zn, Ca, Na, K
 Furosemide Ca, Vit A, Fe, phosphate
ery and future growth.
 Antiacids B12, Fe
• Age of onset, duration, and severity of the  H2 antagonists Fe, Ca
pathology: Severe, early-onset chronic respi-  Inhibitor b. Vit A, D, E, K, Ca, fats
ratory diseases will affect further growth. For Protons
example, children with bronchiolitis obliter-  Cholestyramine
ans whose infection occurred before 6 months Beta-agonists ↑GERD in infants, K
of age, have greater nutritional deterioration
than those patients where the infection occurs deduce different mechanisms involved in malnu-
afterward. trition in children with chronic respiratory dis-
• Prevention, early detection of malnutrition, eases (Fig. 57.1). Often several coexist, the most
and timely support: The anticipatory and regu- frequent being the decrease in food intake and the
lar nutritional evaluation by a multidisci- increase in total energy expenditure.
plinary team enables them to efficiently
prevent and manage problems that must be Lower food intake  Anorexia caused by chronic
approached in an integral manner. diseases can increase with acidosis, drugs, infec-
• Drugs: They can interact with nutrients or tions, and specific deficits (iron or zinc, the latter
modify energy expenditure, bone metabolism, producing dysgeusia). Food intake is also
body composition, or decrease growth affected by infant’s fatigue, water restriction in
(Table 57.1). those with bronchopulmonary dysplasia, altera-
tion of swallowing maturation processes due to
immaturity and prolonged use of probes, and the
Mechanisms Involved in Malnutrition development of behavioral disorders. Moreover,
frequent hospitalizations are associated with
The energy balance results from the difference lower intake and even setbacks concerning
between the energy that enters the organism achieved milestones.
(nutrients) and the total daily energy expenditure
(TDEE). The latter is the sum of basal metabolic • Resting metabolic rate (RMR) increase: It has
rate (BMR)  +  diet induced thermogenesis been demonstrated in children with
(DIT) + losses + energy for growth + expenditure ­bronchopulmonary dysplasia, cystic fibrosis,
for physical activity. From this equation we and in those with steroid treatment. Infection,
57  Nutrition in Chronic Respiratory Disease 581

Fig. 57.1 Mechanisms Intake Requirements

of malnutrition in
children with chronic
• Anorexy • GERD
respiratory diseases
• Fatigue • Infections
• Suction loss • Breathing work
• Rejection, aversion • Overfeeding
• Water restriction • Inflammation
Insufficient contribution, • Stress
• iatrogenis • Drugs

Malnutrtion
Use Losses

• Chronic hypoxemia • Vomiting

• Anaerobic metabolism • Secretions, drainages
• Acidosis • Fecal losses

inflammation or stress increase energy require- I nteraction Between Nutrition

ments, anorexia, and low weight. Although the and Lung Function
work of breathing constitutes only 2–3% of the
BMR, in preterm infants its impact is greater. The interaction between nutrition and lung func-
Excessive inputs can increase TDEE, although tion is complex. Chronic respiratory diseases
normally only 10% corresponds to the challenge childhood growth and development
DIT. This occurs especially if the excess is pro- and malnutrition alters lung growth and develop-
tein, whose storage expense is greater than that ment. This interaction has a greater impact dur-
of carbohydrates (and greater than that of fat). ing the first 2  years of life, due to lung and
In children with bronchopulmonary dysplasia, respiratory musculature development (Fig. 57.2)
a high load of glucose via parenteral adminis- with an increase in work of breathing and predis-
tration increases breathing work, with less position to infections. In turn, this increases the
effect if enterally administered. requirements and promotes a vicious circle with
• Anaerobic metabolism: It has lower energy greater morbidity and mortality. Malnutrition
efficiency; chronic hypoxemia, even mild damages the lung defense mechanisms; physical
(during sleep or feeding), affects growth. barriers are less efficient and cellular immunity is
Moreover, acidosis decreases protein accre- impaired to a greater degree than humoral
tion and exacerbates anorexia. immunity.
• Digestive losses: These increase with vomit- It has been suggested that in preterm infants
ing associated with cough, especially in malnutrition begins in prenatal life, so it precedes
infections or worsening of the disease. the development of bronchopulmonary dysplasia
Gastroesophageal reflux is common in chil- and interacts later with other factors, decreasing
dren with bronchopulmonary dysplasia, neu- the lung regeneration mechanism, the defense
rological diseases, or who are tube-fed. In against hyperoxic damage, the response to infec-
addition, dysphagia and esophagitis cause a tions, and lung growth. Nutritional improvement
decrease in intake due to pain. In cystic fibro- promotes a better evolution of the underlying
sis there are intestinal losses due to steator- ­disease and improvement in lung damage con-
rhea and, also, there may be protein loss tributes to optimize the nutritional status.
through secretions or drainages (bronchiecta- Malnutrition by excess can also affect lung
sis, cystic fibrosis). function and defense mechanisms. Although in
582 S. Barja Yáñez

Fig. 57.2 Interaction
between nutrition and
lung function
Malnutrition

Lung growth
↑ Nutritional
Infections
Requirements
And muscle development

↓ LUNG
FUNCTION

children nutritional deficit continues to determine (ZH/A) of −0.8 and −1.5 a year. However, they
the prognosis, this would be worse in adults with have lower lean mass and lower total body fat
severe obesity who suffer from acute pulmonary after the sixth month than term infants. The
infections, as it was demonstrated in the epidemic impact of pre and postnatal corticosteroids on
of influenza A (H1N1). height and bone mineral accretion has been rec-
ognized, although its use is justified considering
the benefit–cost ratio.
Specific Diseases The greatest nutritional deficiency in chil-
dren with bronchopulmonary dysplasia occurs
Bronchopulmonary Dysplasia within their first three years of life; in the neona-
tal period, low nutritional intake is caused pre-
Preterm patients who develop bronchopulmo- dominantly by delay in initiating and achieving
nary dysplasia are a group at high risk of malnu- enteral supply, high requirements, volume
trition. The factors of prematurity or intrauterine restriction, and comorbidity. These patients usu-
growth restriction are added to those of the dis- ally develop suction–swallowing disorders, gas-
ease during a period of high demand and acceler- troesophageal reflux, and subclinical hypoxemia,
ated growth. In the period immediately following recurrent infections or obstructive episodes,
neonatal discharge, malnutrition ranges between with repeated hospitalizations. However, long-
30% and 67%. Subsequently, infants have accel- term growth would be affected to a greater
erated weight gain until the sixth month, fol- extent by factors derived from prematurity, in
lowed by deceleration. At 1 year corrected age, comparison to factors related to bronchopulmo-
they have a weight-for-age Z-score (ZW/A) of nary dysplasia.
−1.5 and −2.7 (male and female). Regarding The prevention of bronchopulmonary dyspla-
height, they progress at a normal rate, but in sia by nutritional modification or supplementation
smaller numbers and reach height-for-age is controversial and is related to protection against
57  Nutrition in Chronic Respiratory Disease 583

oxidative damage. There is greater evidence of the children with severe bronchiolitis obliterans and
preventive role of vitamin A, which promotes re- similar height deficits, it was possible to achieve
epithelialization and tissue repair. Its use in pre- growth and height recovery with adequate man-
term infants <1000g was linked with a lower agement. However, in those patients in which
occurrence of death or O2 requirement at 1 month there is no such recovery and have less physical
of age (RR 0.75–0.93), a trend similar to 36 weeks activity, the development of obesity is also pro-
of gestational age, with decreased retinopathy. moted, so that they require adequate follow-up
This was not linked with a better long-­term prog- and nutritional advice.
nosis and although other deleterious effects have
not been demonstrated, the most effective route is
painful and the dose is high (intramuscular, Cystic Fibrosis
5000  IU, 3  times per week for 4  weeks). More
studies are required, especially if it coexists with Cystic fibrosis constitutes a model of interaction
corticosteroid therapy that increases plasma levels between chronic lung disease and nutritional status.
of retinol. The evidence is scarce for the protec- Along with improvement of survival, it has been
tive role of vitamin E and polyunsaturated fatty possible to observe the impact of the nutritional sta-
acids, and insufficient for inositol, selenium, and tus optimization on the prognosis, without consider-
magnesium. ing malnutrition as an unavoidable condition. The
Preterm infants, with or without bronchopul- corresponding chapter discusses the multidisci-
monary dysplasia, have a higher risk of develop- plinary approach that several consensuses have
ing recurrent wheezing. The influence of pre or delineated to anticipate and modulate the different
postnatal factors, within which the development nutritional variables that intervene in its treatment.
of obesity is found, has been studied. Also, pre-
term infants have a higher risk of chronic dis-
eases and higher cardiovascular risk in adulthood. Asthma
It has been suggested that the intrauterine pro-
gramming of those with low birth weight (in par- There is controversy about the relationship
ticular, small for gestational age), accentuated by between obesity and asthma. As both are multi-
the accelerated gain of postnatal weight, are sig- factorial in nature, it is difficult to demonstrate
nificant factors that would explain it. For both common causality, which is discussed in the cor-
reasons, it is advisable that once the initial period responding chapter. In clinical and epidemiologi-
of nutritional deficit is over, excess contributions cal studies there is a higher prevalence of obesity
are avoided and a healthy diet and an active life- in asthma. A balanced diet, decreased sedentary
style are stimulated, preventing a sedentary life- lifestyle, and increased physical activity are the
style that is frequent in these patients. most valuable tools to prevent and treat obesity in
these patients.

Post-infectious Chronic Lung Damage

Patients with Prolonged Ventilatory
Nutritional compromise usually develops later Support
after a variable period of normal growth.
However, growth can be significantly affected if Children who require chronic ventilatory support
malnutrition is premature, leading to a delayed have different nutritional problems according to
growth in height. Thus, in a group of 18 Brazilian their underlying disease; those with severe
children with post-viral chronic lung damage, chronic respiratory diseases tend to develop pro-
oxygen-dependent, 4.5  ±  2.7  years, 47% had tein–caloric malnutrition, and patients with neu-
short stature (Z-score for H/A ≤2). This is not romuscular diseases may present malnutrition
necessarily irreversible: in a group of 21 Chilean due to deficit or excess. Malnutrition affects
584 S. Barja Yáñez

respiratory function, since it reduces muscle during the hospital stay can be reviewed in the
mass and contractile force, which results in references, and that of children with cystic fibro-
decreased respiratory effort, endurance, and vital sis or asthma, in the corresponding chapter. Some
capacity. These effects are, in general, reversible general principles of nutritional support can be
with nutritional improvement. Chronic ventila- considered first, and specific management mea-
tory support in infants promotes nutritional pro- sures can be considered later.
gression and, conversely, it is possible to confirm
in clinical practice that the withdrawal of ventila-
tory support may be associated with lower weight Regular Monitoring of Food Intake
development and should be done gradually, mon-
itoring oxygenation, and in parallel to a greater Because one of the main causes of poor weight
nutritional contribution if required. gain in patients with chronic respiratory diseases
Some children with neurological diseases and is low intake, it is important to make a detailed
chronic ventilatory support may have higher nutritional history, considering the previous and
caloric expenditure, such as those with hypertonia, present dietary history: feeding schedules, com-
severe seizure syndromes or increased move- position of milk formula and meals, method of
ments, but most of them have decreased muscle preparation, use of supplements, volume offered
mass (more active metabolic tissue) combined and received, feeding time, and respiratory and
with less mobility and growth. This determines a gastrointestinal tolerance. In older children, one
lower energy requirement, so that proper contribu- should ask for food between meals and general
tions for their sex, age, and weight can lead to a habits. Food records of 2 or 3 days a week pro-
greater fat mass deposition in most of them, vide very useful objective information.
although not necessarily reflected in the rates of
overweight or obesity. This increases immobility,
breathing work, loss of bone mass, and impairs  egular Monitoring of Nutritional
R
motor and respiratory rehabilitation. Thus, energy Status
requirement must be corrected by the muscle tone
and degree of physical activity. However, the It is necessary to monitor growth, since the
excessive limitation of the contribution in order to sequential measurement of the improvement in
prevent obesity can lead to protein, mineral, and weight, height, and cranial circumference allows
trace element depletion, so there must be monitor- early identification of the deceleration or lack of
ing and follow-up by an multi-disciplinary team improvement. It is essential to graph the evolu-
that including a nutrition specialist. tion of the particular patient, which allows clear
visualization of the tendency in its growth. In
preterm infants it is recommended to adjust the
 utritional Support In Chronic
N chronological age up to 2 years and in cases of
Respiratory Diseases children of less than 28 weeks, up to 3 years.
For children up to age 5, the most appropriate
The main objective of the nutritional support in chil- growth reference is the WHO 2006 standard.
dren with chronic respiratory diseases is to optimize Children from 5 to 19-years-old use the CDC-­
their growth and development, to promote a better NCHS 2000 reference, although WHO 2007 is
evolution of their disease and quality of life, as well also available, which corresponds to a reconstruc-
as to prevent the chronic disease of adulthood. tion of the previous one. The following anthropo-
The following describes the nutritional man- metric indexes are calculated and integrated:
agement of children with chronic lung damage in
the period after discharge from the neonatal unit, • Weight/age (W/A) is the most sensitive index in
in the case of preterm infants with bronchopul- detecting malnutrition, being able to overesti-
monary dysplasia. The nutritional treatment mate it in those with low genetic or family size.
57  Nutrition in Chronic Respiratory Disease 585

• Height/age (H/A) is less sensitive than W/A, manner. It also makes it possible to use a more
and it is more strongly affected in periods of physiological diet, potentiates regular feeding,
rapid growth; indicates long-term nutritional and avoids the inappropriate or excessive use of
status. protein or caloric supplements, which are more
• Weight/height (W/H) is sensitive, although it expensive and can displace the intake of foods
underestimates the deficit in children with that make up a balanced diet, promoting a greater
short stature. It indicates an adequacy of the fat deposition and later eating disorders.
weight for the height, a relation that can also
be expressed as Waterlow index (%)  =  (cur-
rent weight/ideal weight) × 100. Laboratory Tests
• Body mass index (BMI) also expresses the har-
mony between weight and height and it is usu- Laboratory tests are sometimes supportive mea-
ally considered after 2  years of life. In cystic sures, but in general they do not determine the
fibrosis, a close correlation between BMI and diagnosis of nutritional compromise.
pulmonary function has been demonstrated,
which guides the nutritional management. • Plasma markers: Albumin is a late marker of
protein depletion for its half-life of 15–20 days,
To evaluate growth in children with neuro- and although this is lower for prealbumin,
logical diseases, specific growth curves are both levels are altered in situations of stress or
available for cerebral palsy and some neuromus- infections, and have an adaptive preservation
cular diseases. In them, when height measure- in states of chronic depletion. Other more sen-
ment is difficult due to hypertonia or posture, it sitive markers of protein deficiency have no
is possible to approximate it by measuring body clinical application. The plasma levels of vita-
segments. mins are useful for specific cases, and as for
Along with assessing normal staturo-ponderal minerals, cell blood count allows the evalua-
development, it is important to also consider its tion of anemia and the plasma ferritin indi-
quality, that is, the body composition. Because of cates depletion of iron deposits. Zinc status is
this and because in older children medical check-­ difficult to measure in clinical practice and is
ups are more spaced in time and can be focused considered only if there is a marginal intake or
primarily on intercurrent pathologies, it is recom- compatible clinical picture. Finally, the levels
mended that these patients be managed by an of calcium, phosphorus, and alkaline phos-
interdisciplinary team that includes a nutrition phatases make it possible to understand the
specialist. Although it has limitations, clinical situation of bone metabolism and the mea-
estimation of the fat mass by means of skinfold surement of 25 OH vit D in plasma, the status
measurement allows the optimization of nutri- of vitamin D.
tional management. This prevents overcorrection • Measurement of energy expenditure: Indirect
of the deficit in hypercaloric diets that promote calorimetry measures the REE and allows, in
fat mass deposition (not protein accretion), devel- an objective manner, adjustment of the caloric
opment of obesity, and appearance of chronic intake and assess the composition of the diet,
diseases in adult life. with the calculation of the respiratory quotient
(RQ = VCO2 produced/VO2 consumed). The
RQ is 1.0 for the metabolism of carbohy-
Early Nutritional Intervention drates, 0.8 for proteins, and 0.7 for fats. A
mixed diet has an RQ of 0.85 (optimal range
Intervening early in children with chronic dis- of 0.8–0.9), if it is <0.7 this indicates under-
eases, in stages in which there is less nutritional nourishment, lipolysis or oxidation of ketones
compromise, allows the improvement of the and if it is >1.0, overfeeding, lipogenesis or
growth rates that are affected in a reversible excessive production of CO2.
586 S. Barja Yáñez

This test requires careful monitoring in demands for their illness. The contribution must
children with ventilatory support systems to be gradual and individualized, considering that
avoid failures in the circuit’s indemnity and the best indicator of its adequacy is a normal
variations in the FIO2 that can determine growth and height development. In older chil-
greater variability in the results. dren who have short stature as a consequence
• Measurement of body composition: It is very (not recoverable), the achievement of a har-
useful, especially in patients with chronic ven- monic weight to size ratio must be considered,
tilation who have decreased physical activity particularly in the current context of high preva-
and high risk of demineralization. Bone densi- lence of obesity and the increased risk of chronic
tometry allows the evaluation of both body diseases in adult life.
composition (fat and lean mass percentage) General recommendations for protein intake
and bone mass, but it still has a high economic have decreased (Table 57.4), although in preterm
cost. Although bioelectrical impedance analy- and malnourished infants, due to their acceler-
sis is a simpler and lower cost alternative, it ated growth, these must be greater for the synthe-
has high variability, does not evaluate bone sis of new tissues (lean mass): about 3  g per
mass, and it is highly dependent on the degree kilogram per day. Finally, the water volume
of hydration. requirement can be estimated according to the
weight (Holliday-Segar method) or body surface
(Table 57.5).
 pecific Measures of Nutritional
S
Management Contribution of Micronutrients
The updated contributions of vitamins and min-
 nergy, Macronutrients, and Water
E erals according to age are available in the
Contribution references.
The nutritional requirements of reference for cal- Children with severe chronic respiratory dis-
ories, volume, macro and micronutrients in pre- eases, vitamin D deficiency can reach 40%, with
term infants have been well studied and appear in short-term effects on lung function as well as
extensive references, adapted for optimal growth being associated with bronchial hyperresponsive-
comparable to the intrauterine growth. ness, immunological disorders, and asthma. This,
In order to calculate the energy required, the along with the effect on the bone metabolism of
REE is estimated in infants and older children these children who have less sun exposure, justi-
using WHO formulas and corrected for different fies daily supplementation with 400  IU of vita-
factors (Table 57.2). Children with bronchopul- min D, adjusting the dose according to the plasma
monary dysplasia are given a contribution of level of 25OH vitamin D. In addition, up to 20%
between 120% and 150% of the recommenda- of children with chronic respiratory diseases may
tions for healthy children (Table  57.3), to have anemia promoted by their chronic condi-
achieve catch-up growth and to meet the greater tion, low iron intake, higher losses, and frequent

Table 57.2  Energy contribution for children with chronic respiratory diseases
Components Age Male Female
REE calculation formulas (WHO 0–3 (60.9 × weight) − 54 (61 × weight) − 51
1985) 3–10 (22.7 × weight) + 495 (22,5 × weight) + 499
10–18 (17.5 × weight) + 651 (12,2 × weight) + 746
Correction factors (+) Contribution for food metabolization (10%)
Growth (10–25%)
Degree of physical activity (10–25%)
Weight recovery (5 calories per extra gram daily)
Disease severity factor
57  Nutrition in Chronic Respiratory Disease 587

Table 57.3  Energy requirements Route of Feeding

Age Male Female If an adequate oral intake is not achieved, either
(months, years) (cal/k/day) (cal/k/day) by respiratory or gastrointestinal intolerance, or
0–1 m 113 107 by rejection; or if, despite achieving it, an ade-
1.1–2 m 104 101
quate improvement is not obtained, it is advis-
2.1–3 m 95 94
3.1–4 m 82 84
able to use the enteral route through a nasogastric
4.1–5 m 81 83 tube if its use is short-term. The use of a nasoje-
5.1–6 m 81 82 junal catheter is reserved for patients with risk of
6.1–9 m 79 78 pulmonary aspiration due to the coexistence of
9.1–12 m 80 79 gastroesophageal reflux disease (GERD) or gas-
1.1–3 y 82.4–83.6 80.1–80.6 tric emptying disorders, together with airway
3.1–6 y 79.7–74.5 76.5–71.5
protection mechanisms that are insufficient.
6.1–9 y 72.5–68.5 69.3–63.8
9.1–12 y 66.6–62.4 60.8–54.8
In the medium- or long-term, the use of gas-
12.1–15 y 60.2–55.6 52.0–47.0 trostomy is indicated either as a temporary or
15.1–18 y 53.4–50.3 45.3–44.1 definitive measure, according to clinical follow-­up
Total daily energy expenditure (TDEE) plus the energy of the patient. Gastrostomy is performed simulta-
required for growth and the average level of physical neously with a fundoplication when pathological
activity in people older than 1 year is considered. ↓15% gastroesophageal reflux coexists with aspiration
for mild physical activity and ↑15% for vigorous physical
activity
risk, which is common in patients with associated
neurological damage. It has been demonstrated
Table 57.4  Tolerable upper intake level (UL) for protein
that early use of gastrostomy in children with
for children and adolescents bronchopulmonary dysplasia and malnutrition sig-
Age (years) WHO 1985 (g/k/day) UL 2002 (g/k/day) nificantly improves nutritional deficit, and its late
0–6 m 2.2 1.8 indication increases morbidity and mortality.
6 m–12 m 1.6 1.5 When the enteral route is a temporary mea-
1–3 years 1.2 1.1 sure, the use of a pacifier should be encouraged
4–6 years 1.2 0.95 and oral stimulation should be maintained, super-
7–10 years 1.0 0.95 vised by a specialized team. When these capaci-
11–14 years 1.0 0.8
ties have been lost or not developed, future
15–18 years 0.9 0.8
rehabilitation of swallowing is slower and harder.

Table 57.5  Water requirements Feeding Frequency

Weight The increase in oral feeding frequency is a useful
Method (kg) Amount per day
measure, but it must consider fasting periods of
Vol/weight 0–10 kg 100 ml/kg/day
10–20 kg 1000 ml + 50 cc per each
at least 3  hours that allow a complete gastric
k > 10 k emptying and appetite appearance for the next
>20 kg 1500 ml + 20 cc per each feeding. When the enteral route is used, bolus
k > 20 k feeding, which is more physiological, should be
Vol/body 0–70 1500–1700 ml/m2 preferred. However, to optimize the absorption
surfacea
of nutrients or respiratory or gastrointestinal tol-
Vol/calories 0–70 100 ml/100 Cal
metabolized erance, s­ ometimes continuous infusion is
Body surface = √ [Weight (k) × height (cm)]/3600
a required, always considering short periods of
intestinal rest.
infections. It is recommended to monitor the
reserves with plasma ferritin before decreasing Breastfeeding
plasma hemoglobin or, otherwise, consider pro- In infants with bronchopulmonary dysplasia, a
phylactic supplementation with 1–2 mg Fe++ per low percentage of mothers manage to initiate and
kilogram per day. maintain breastfeeding through expressed milk,
588 S. Barja Yáñez

at first, and then directly through the breasts. The If water restriction is required or if there is
composition of the breast milk of mothers of pre- poor weight development, the concentration of
term infants differs from those of term infants the formula can be increased by 1–2% and forti-
and needs to be fortified with specific products fied simultaneously with 2% maltodextrin and
that increase the caloric, protein, vitamin, and 1% medium-chain triglycerides (MCT oil) or
mineral content, to adapt it to the child’s greater long-chain triglycerides (canola, raps, or sun-
requirements. An alternative is to add 5–10% of flower vegetable oil), and if necessary, 0.5% of
preterm milk formula to the expressed breast modular protein. This provides 1 cal/mL without
milk. If, nevertheless, the child does not have an reducing the protein intake or greatly increasing
adequate growth, it can be supplemented with the renal solute load. Tolerance and weight
milk formula for preterm infants. Patients with improvement should be evaluated, considering
exclusive breastfeeding should be supplemented, that an excess of glucose polymers can increase
as all preterm, with vitamin D (400UI per day), osmotic load in the intestine, promoting diarrhea.
iron (2 mg Fe ++ per kilogram per day), and zinc An excess of lipids can cause steatorrhea, and an
(3 mg per day), up to 12 months corrected age. excess of MCT oil increases CO2 production.
Infants with bronchopulmonary dysplasia or
 dapted and Enriched Formulas
A chronic lung damage, older than 1 year, who do
Different studies have shown that post-discharge not progress well, can be maintained with forti-
growth in preterm infants with bronchopulmo- fied formulas as described above, whether as a
nary dysplasia is enhanced by a formula with a continuation or based on cow’s milk. Fortification
higher protein and mineral content. Compared to must be balanced: cereal (3–5%), maltodextrin
a fortified formula for term infants, at 3 months it (3–5%) or oil (1.5–2%), together with an increase
is associated with better height and weight devel- of 2 to 3% in the formula concentration, with pro-
opment, as well as bone mineral and lean mass teins representing between 10% and 15% of total
accretion, but if it is discontinued, the effect is calories, to optimize their accretion.
reversed when the child reaches 1  year of age Another alternative at this stage is the use of liq-
(corrected age). The recommendation is to main- uid or powdered polymeric formulas, which have
tain, until then, preterm infant formulas, with low viscosity, high caloric density (1 cal/mL), and
higher energy, protein, and mineral content than are isotonic to plasma (±300 mO/l). In proper vol-
formulas for term children (Table 57.6). umes, they provide the requirements of vitamins

Table 57.6  Composition of macronutrients of different formulas (in 100 mL)

Formula Energy (Cal) Proteins (g) P% Carbohydrates (g) Lipids (g)
Starter formula (term infant) 67 1.5–1.8 7.5 3.6
9–10
Starter formula (preterm infant) 81 2.3–2.6 8.6–9.2 3.9–4.4
10–12
Preterm formula, modifieda 105 2.75 11.7 4.9
10.4
Modified continuation formulab 94 2.5 13.8 2.6
10.6
Hyperproteic hypercaloric formulac 111 3.5 13.6 4.75
12.6
Polymeric formulad 100–108 3.0–2.9 11–12.8 5.0–4.9
12–10.7
a
↑Concentration in 2% + 2% maltodextrin +1% MCT or oil
b
↑Concentration in 2.5% + 5% cereal +3% maltodextrin
c
Fortified whole milk at 12.5% + 3% cereal +3% maltodextrin +3% sucrose +1.5% oil
d
Pediasure® 20%. Abbott Laboratory
57  Nutrition in Chronic Respiratory Disease 589

and minerals when they are used as a single source to optimize the intake. Counseling and periodic
of food, particularly for patients enterally fed. follow-up are important in order to avoid exag-
Contributions and micronutrients should be moni- gerated weight gain, especially at the expense of
tored to avoid excessive fat deposition. fat mass in older children. Excessive use of
In adults, there is evidence that specific for- dietary supplements tends to displace the foods
mulas for lung diseases, with high fat content that constitute a balanced and healthy diet, so it is
(±55%) and low in carbohydrates (±28%), preferable to use them complementary to a nor-
decrease CO2 production and breathing work, mal diet. Eating habits and support must be
which is a favorable effect in patients with CO2 emphasized in those patients who have had
retention. However, these are not appropriate for enteral nutrition for prolonged periods, to pre-
infants, due to their unbalanced composition and vent, identify, and treat eating disorders.
high protein, osmotic, and solute load. In infants
with bronchopulmonary dysplasia receiving par-
enteral nutrition with high glucose levels, an
Conclusion
increase in the O2 requirement and CO2
­production have been demonstrated. A prospec- Children with chronic respiratory diseases require
tive randomized study in 10 infants with bron- a special emphasis in the care of their nutritional
chopulmonary dysplasia compared the seven-day status. Regular monitoring of their growth pattern
effect of a term formula supplemented with glu- allows early detection of abnormalities and timely
cose polymers (52% of calories) versus an isoca- intervention, which is promoted by a coordinated
loric formula with high fat content (67% of interdisciplinary team management. Adequate
calories). In those who received the latter, a nutrition allows normal growth and development,
reduction of 11% and 12% in the CO2 produced promotes a better evolution of their disease, and
was obtained, without being associated with probably decreases the later appearance of eating
improvement in lung function. However, patients disorders and other chronic diseases.
had greater steatorrhea and lower weight gain.
Therefore, more evidence is needed to evaluate
the possible benefits versus the long-term delete-
rious effects of the use of formulas with this Sources
composition, in aspects such as growth, gastro-
Abrams SA. Chronic pulmonary insufficiency in children
intestinal tolerance, impact on the lipid profile and its effects on growth and development. J Nutr.
and development of organic acidurias due to 2001;131:938s–41s.
problems in the long chain fatty acids oxidation. Ambrosino N, Clini E. Long term mechanical ventilation
and nutrition. Respir Med. 2004;98:413–20.
Besides this, the energy increase through carbo-
Atkinson SA.  Special nutritional needs of infants for
hydrates is related to a lower protein oxidation pre-vention of and recovery from BPD.  J Nutr.
reduction, but it is not necessarily related to a 2001;131:942s–6s.
better nitrogen balance. A higher CO2 concomi- Barja S, Capo E, Jakubson L, Briceño L, Méndez M,
Becker A.  Anemia y déficit de hierro en niños con
tant production may have physiological reper-
enfermedades respiratorias crónicas. Nutr Hosp.
cussions in patients with a CO2 retention 2013;28:787–93.
problem, with a PCO2 > 55 mm Hg. Barja S, Rebollo MJ.  Manejo nutricional de niños y
adolescentes con fibrosis quística. Rev Chil Pediatr.
2009;80:274–84.
Solid Feeding
Barja S, Espinoza T, Cerda J, Sánchez I.  Evolución
In preterm infants with or without bronchopul- nutricional y función pulmonar en niños y adoles-
monary dysplasia, it is recommended to start centes chilenos con fibrosis quística. Rev Med Chile.
solid feeding at 6 months of corrected age, upon 2011;139:977–84.
Bosa VL, Mello ED, Mocelin HT, Benedetti FJ, Fischer
reaching sufficient intestinal maturation.
GB.  Assessment of nutritional status in children and
Frequently, the use of liquefied food is prolonged, adolescents with post-infectious bronchiolitis obliter-
either by slow or late acquisition in food skills, or ans. J Pediatr. 2008;84:323–30.
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Chateau B, Prado F, Méndez M, Barja S. Nutritional Status monar en el neonato de bajo peso al nacer. Rev Chil
of children with Chronic Respiratory Insufficiency. Pediatr. 2005;76:12–24.
ATS Congress, San Francisco CA, May 2007. Am J Ministerio de Salud de Chile. Estadística nutricional.
Resp Crit Care Med. 2007;175:A722. Programa Nacional de Alimentación Complementaria
Darlow BA, Graham PJ.  Vitamin A supplementation to (PNAC) del Prematuro Extremo. Displasia broncopul-
pre-vent mortality and short and long-term morbidity monar del prematuro: guías clínicas. Accedido el 19
in very low birthweight infants. Cochrane Database de julio de 2014. Disponible en: http://web.minsal.cl/
Syst Rev. 2011;10:CD000501. programas_alimentarios.
Dumas C, Skaff C, Just J, et  al. Body composition of Moreno M, Maya MJ, Bustos E, Astudillo C, Barja
children with chronic lung disease. Pediatr Pulmonol. S.  Evaluación y evolución nutricional en niños con
1997;16:174–6. bronquiolitis obliterante. 53° Congreso Chileno de
Guimber D, Michaud L, Storme L, Deschildre A, Turk D, Pediatría, II Conferencia de actualización en Pediatría,
Gottrand F. Gastrostomy in infants with neonatal pul- ALAPE. Santiago, Noviembre 2013. Rev Chil Pediatr.
monary disease. JPGN. 2003;36:459–63. 2013;84(S1):91.
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 Diseases Caused by Pollutants
and Tobacco Exposure
58
Lidia Amarales Osorio,
María José Prieto Correa,
and Gabriela Muñoz Gómez

Contents
Introduction  591
 tmospheric Pollution (AP) 
A  592
Epidemiology in Chile  593
Respiratory Morbidity Associated with Atmospheric Pollutants  594
Strategies and Recommendations  594
I ndoor Pollution (IP)   595
Respiratory Morbidity and Mortality Associated with Indoor Pollution  596
Recommendations  596
 moking, a Pediatric Disease
S  597
Epidemiology of Smoking in Chile  597
Physiopathology  598
Passive Smoking: Second-Hand and Third-Hand Smoking  599
Respiratory Morbidity and Mortality Associated with Tobacco Exposure  599
Diagnostic Approach and Recommendations  602
Sources  603

Introduction dose of pollutants per weight kilogram, but also

because their respiratory and immune systems
Environmental pollution is an increasing and are still in the development phase. The anatomi-
avoidable risk factor for respiratory disease, cal and physiological characteristics of the respi-
which impacts children with greater strength, ratory system that contribute to this susceptibility
because they are exposed to a greater effective are: smaller volume and alveolar surface, greater
respiratory frequency, and greater minute ventila-
tion per body mass unit at rest, absence of contra-
L. Amarales Osorio (*) lateral ventilation (Kohn pores and Lambert
Ministry of Health, Santiago, Chile
channels), greater resistance of the peripheral
M. J. Prieto Correa airway, lower cough effectivity, and greater diffi-
Respiratory Kinesiology, Academic at UMCE,
UNAB, Santiago, Chile culty eliminating particles.
Environmental pollution can be divided in
G. Muñoz Gómez
Faculty of Medicine, Universidad de Chile, atmospheric pollution (AP) or in-house pollution
Santiago, Chile (HP). HP is the main component of environmental

© Springer Nature Switzerland AG 2020 591

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_58
592 L. Amarales Osorio et al.

pollution and is defined as the atmospheric pres- to suffer from acute and chronic respiratory dis-
ence of one or several substances in large enough eases, as well as cardiovascular diseases. The
quantities to cause health problems. HP is the effects are directly related with the effective dose,
emission of pollutants at home, whether by solid determined by three factors: time of exposure,
combustibles (gas kerosene) or biomass (firewood concentration of the pollutant per area, and pul-
or coal), combined with the infiltration of atmo- monary ventilation. High-pollutant concentra-
spheric contaminants to indoor environments, tions, although it may be for short periods of
and/or contamination caused by environmental time, cause acute effects and worsen chronic dis-
tobacco smoke (ETS). eases. Up to 80% of premature deaths related to
The WHO has declared that the global burden pollution in the exterior air are caused by isch-
of morbidity caused by indoor and outdoor air emic cardiopathy and cerebrovascular accident,
pollution causes millions of premature deaths, while 14% are caused by a chronic obstructive
which are associated with tobacco risks, cur- pulmonary disease, or acute infection of lower
rently represent the greatest sanitary risks around airways, and 6% to lung cancer. AP at the same
the globe, only surpassed by hypertension and time has effects later in time, such as mutagenesis
malnutrition. It has been estimated that around and carcinogenesis, which may appear long after
3% of the total world deaths attributed to AP cor- the interruption to the exposure and extend to
respond to children under 5 years of age, and this future generations.
number increases to 13% when considering During the past decades, AP has become an
deaths by HP in this same age group. important and serious global problem, caused by
a lack of development planning, which along
with the production of the energy and its use, are
Atmospheric Pollution (AP) responsible for the emission of the pollutants.
The emission of man-made gases is increasing
AP is presented as an aerosol, with its gas com- the atmospheric concentration of those gases
ponents and particulate material (PM), causing that catch energy and heat from the sun, which
great damage to ecosystems and altering the amplifies the natural “greenhouse effect”, which
quality of life of the population. AP has a greater makes life on Earth possible. Of these gases, the
effect on the health of those who already have an one with the greatest concentration is carbon
underlying disease and in the most vulnerable dioxide (CO2), which comes mainly out of fossil
groups: children, elderly, and poor families with combustibles (coal, oil, gas), which causes an
limited access to medical assistance. Children increase in the atmospheric temperature and
with chronic diseases, such as cystic fibrosis and greatly impacts ecosystems. Nevertheless, the
asthma, are particularly vulnerable to pollutant risks to health are also caused by exposure to
effects. gases, such as ozone (O3), nitrogen dioxide
Intrauterine and perinatal periods, as well as (NO2), and sulfur dioxide (SO2), whose concen-
the first years of life in children, are character- trations are usually high in urban areas of middle
ized by a greater vulnerability to pollutants. In and low-income countries.
these stages the respiratory system is more sus- PM is the pollutant most associated with mor-
ceptible to damage, which will damage the lung tality and morbidity events in the population.
capacity that will be acquired as an adult, along PM is defined as solid or liquid particles that are
with an increase in infection susceptibility. There in suspension. We classified them according to
is evidence supporting that this is associated size and origin. Thus, particles smaller than 10
with multiple respiratory morbidity, pulmonary μm are called PM10, and those that are smaller
function alteration, and greater incidence of than 2.5 μm, PM2.5. Considering that the diame-
child cancer. ter of a human hair is around 60 μm, PM10 has
The effects that AP may have in the long and almost the tenth part, and the finer particles
short-term are many, including an increased risk PM2.5 are even smaller and can enter very deeply
58  Diseases Caused by Pollutants and Tobacco Exposure 593

in the respiratory tract. These particles are diffi- Epidemiology in Chile

cult to remove and carry with them other chemi-
cals when they settle themselves, such as When estimating the attributed burden per risk
sulfates, nitrates, carbon, metals, and organic factor, the Ministry of Health of Chile (MINSAL)
material, while large particles tend to have mate- issued the Disease Burden Study, which described
rials, such as silica, rubber, salts, and pollen. that 13 deaths are directly caused by the levels of
There is a close relationship between expo- urban pollution and one of every 11 deaths is
sure to high concentrations of PM10 and an directly caused by active smoking (sub-estimated
increase in morbidity and mortality. This is true information, without considering the effects in
for both daily exposure and the one that persists the passive smoker). The relative importance of
in time. On the contrary, when there is PM the risk factors is similar to high-income coun-
reduction, related mortality is also reduced. tries; nevertheless, urban air pollution has an
Repeated exposures may create greater effects unusually high place in the world ranking, as it
on health than a single exposure. Although the would be characteristic of a less developed
acute and long-­term effects are not the total sum country.
of the acute exposure, these are greater, suggest- Concern for the high pollution levels dates
ing that they do not correspond to exacerbations from the 1980s, and so a monitoring network was
but to a progression of an underlying disease. set in place, with daily measures of PM10, PM2.5,
There is also toxicological and clinical evidence and other pollutants. This, along with the records
of the effect of particles originated during com- of morbidity and mortality, has enabled us to
bustion, where short-term exposure (less than conduct timely studies of the acute effects of
1  hour to a few hours), also carries immediate atmospheric pollution, where an association has
physiological changes. Biological mechanisms been made between the concentration increase
of exposure are related to systemic inflamma- and daily mortality, urgency pediatric visits
tion, oxidative stress, alterations in heart bio- because of a respiratory cause, and visits for car-
markers, coagulation effects, and thrombosis diovascular causes.
increase. The main results of Chilean national studies
AP affects both developed and undeveloped done in the Metropolitan Region refer to a sig-
countries. It has been estimated that it causes the nificant increase in the daily risk rate of 4% in the
death of almost 3.7 million people in the world, general population. The increase in hospital
caused mainly by PM ≤10 exposure. Up to 88% admittances caused by lower tract respiratory dis-
of these deaths take place in countries with mid- eases when PM10 concentration increases to
dle and low-incomes, affecting 82% of the popu- 50  μg/m3 is: 4–12% increase for patients under
lation worldwide. The America continent 2  years old, and 3–9% increase for children
contributes with around 140 thousand deaths. between 3 and 15  years old. Another study
Although older adults have the greatest risk for showed that 3 days after a 45 μg/m3 increase in
mortality, the evidence shows that during the the daily concentrations average of PM2.5, there
postnatal period the risk of death due to a respira- was an increase of 6.7% in pneumonia cases. In a
tory cause increases. cohort study including children under 4 months
Deregulated concentrations of both gases in the South of Santiago, Pino confirmed a 5%
and particles affect the health condition. increase of the cases of wheezing associated with
Therefore, pollutant emissions are now thor- an increase of 10  μg/m3 in PM2,5. In downtown
oughly being studied, and there is also the need Santiago (2001–2006) it was determined that the
to reduce their production. Most of environ- increase of urgent medical visits because of
mental pollutant sources are beyond individual respiratory disease, particularly in children under
control, and public policies are required in sec- 1  year, was caused by high PM2,5 levels due to
tors, such as transportation, energy, construc- vehicle and industrial contamination. Cifuentes
tion, and agriculture. et  al. showed that there was a 4.2% increase in
594 L. Amarales Osorio et al.

daily mortality in the Metropolitan Region when have been conducted. These studies exposed the
PM2,5 levels were at 64 μg/m3 (daily average level cells to Rhinovirus, and pro-inflammatory activ-
of 47.3 μg/m3). ity markers where used to study the response.
Thus, evidence was obtained in relation to the
mechanisms through which environmental oxi-
 espiratory Morbidity Associated
R dative pollution (NO2-O3) may exacerbate viral
with Atmospheric Pollutants respiratory infections in  vivo. Therefore, expo-
sure to oxidative pollutants (NO2, among others)
The World Health Organization (WHO 2013) has has the potential to exacerbate the inflammatory
documented the effects of PM10 pollution during effects of viral infections in the lower tract air-
pregnancy, for both the fetus and the mother. way, causing the release of inflammatory media-
Pollution can affect the blood pressure of the tors, ciliary dyskinesia, epithelium damage,
mother, increasing it, as well as cause changes in bronchoconstriction, and bronchial hyper-­
the size of the fetus, usually associated with the reactivity (BHR).
reduction of some parameters, such as head cir- Besides this, there is a correlation between
cumference, size or weight at birth, and also pre- high pollutant levels and an increase in hospital-
mature childbirth, which are all parameters izations caused by asthma. After periods with
associated with a poorer health expectancy for high O3 levels, the frequency of asthma exacerba-
the child. tions can increase up to 40%, and for urgency
Several national and international studies have medical visits, the increase can be of up to 37%.
shown that there is an association between the When facing atmospheric pollution caused by
level of pollutant concentrations, such as MP, O3, MP, the physiological increase in lung function is
SO2, and NO2, and the incidence of premature impaired, which normally appears as the patient
deaths and child respiratory morbidity. At the cel- grows. This is an additional factor in critical situ-
lular level, environmental pollutants may cause ations, such as viral infection.
damage, even if the exposure is brief and the pol- The effects of pollution on children lung func-
lutant levels are low. Sulfuric acid components tion, with its corresponding growth alteration in
may interfere in the mucociliary transport and their spirometry values, can be observed in the
sulfur dioxide may cause bronchoconstriction if Integrated Science Assessment (ISA) 2009 docu-
there is asthma. Besides this, O3 may impair the ment (see EPA), where the most significant scien-
actions of the immune system against infections, tific evidence is gathered.
contribute to a persistent infection in the airway, In Chile, toward the end of the decade of 1980,
as well as increasing permeability in pneumo- Belmar et al. showed the differences in spirome-
cytes, easing the access of substances and pro- try values of children living in Santiago city ver-
moting allergen sensitization. It seems that sus Los Andes. Thirty years later, this condition
contaminants interact with other environmental remains the same when spirometry function val-
factors, such as allergens, virus, and diet, which ues are compared to those of healthy children in
would have a role in how pollutants globally Cerro Navia (Metropolitan Region). This is a sig-
affect the respiratory health of children. nificant worsening of lung function, in compari-
There is a correlation between the high levels son to Los Andes.
of pollutants and an increase of acute respiratory
diseases requiring hospitalizations, particularly
in preschoolers, where admittance caused by Strategies and Recommendations
wheezing may be tripled. A study conducted in
European countries showed that pollution causes The recently published Encyclical Letter
more than 290,000 bronchitis cases in children “Laudato si” states that “technology based on the
under 15 years old. At the same time, clinical tri- use of highly polluting fossil fuels — especially
als studying nasal and bronchial epithelium cells coal, but also oil and, to a lesser degree, gas —
58  Diseases Caused by Pollutants and Tobacco Exposure 595

needs to be progressively replaced without tion promoting power plants that use clean and
delay”. This document proposes that the deterio- renewable sources instead of coal, improvements
ration of the environment is caused by consumer- in the energy efficiency of buildings and manu-
ism and the economic and financial system that facturing facilities, promoting and improving
smothers the poor. public transportation and use of bicycles, instead
Chile is not excluded from this analysis, as its of relying on private cars. At the same time, it is
strong economic growth and high dependence on important to raise awareness in the population
natural resources has had a cost in the condition about relatively simple interventions, such as
of the environment, particularly in relation to the improving the use of wood and using public
quality of the air. The use of renewable energy transport system, which can help to reduce the
sources is mainly limited to hydroelectric power AP levels, thus yielding important health
plants, and the energy needs of the country are, to improvements.
a large extent, satisfied importing fossil fuels. Effectively following-up the interventions is
The mechanisms to promote the adoption of another important way to increase awareness, as
clean technologies are still insufficient. it helps to create norms which will bring health
Because of this, the WHO (2005) has created and environmental benefits.
guidelines that provide a general orientation Although significant advances have been
about the limit thresholds for key atmospheric made in mega cities, such as Los Angeles, México
pollutants, which are related to current health City, São Paulo, and Santiago, where constant
risks. In the ISA study from 2009, as well as in efforts are being made to reduce pollution levels,
the WHO study from 2013, the range of annual there is still a lot to do. Several successful cases
PM10 concentrations that cause health deteriora- have been developed and public policies aiming
tion in the long-term is between 20 and 40 μg/m3. to reduce urban air pollution have been set in
According to the estimations made by the WHO, place. Public transport integrated systems devel-
if the median of PM10 annual concentration is oped in Curitiba (Brazil) and Bogotá (Colombia)
reduced from 70 to 20 μg/m3, a 15% of the mor- have become a model for other large cities in the
tality rate caused by AP in the long-term can be region (México City, São Paulo, and Santiago de
avoided. Chile) as well as in Europe (Bilbao and Sevilla).
Chile has national-wide quality air norms, Even though many countries in the region
which regulate the concentration of the six main have a legal framework to control air pollution,
types of harmful pollutants: PM10, PM2.5, SO2, current standing norms vary a lot, some of which
NO2, CO, O3, and lead (Pb), plus daily and annual do not set limits for some parameters, or consider
norms of PM10, 150, and 50 μg/m3, respectively. limits over the ones recommended in the WHO
These values exceed the values of 50 and 20 μg/ guidelines.
m3 recommend by the WHO, which would be More investment is needed for continuous
permissive enough to prevent health effects and monitoring of air quality, as well as searching for
avoid excesses in mortality rates. Because of this, options to reduce emissions, investigation
it is crucial to enforce daily and annual norms research associated with the creation of regional
and regulations recommended by international norms, and participation of the society to reduce
organisms and experts in order to improve air exposure during environmental eventualities.
quality. The aim of these measures is to control
atmospheric pollutants, thus protecting the popu-
lation against these pollutants and therefore Indoor Pollution (IP)
decreasing the morbidity load.
Cities must determine which are the main IP or household air pollution is also a serious
sources of air pollution and enforce strict policies health problem for over 3 trillion people, particu-
as well as adequate interventions that will larly in underdeveloped countries that still depend
improve air quality. Among these, we can men- on solid fuels. IP can exceed AP in many c­ ountries
596 L. Amarales Osorio et al.

in the world, and so it is the most important envi-  espiratory Morbidity and Mortality
R
ronmental risk factor. IP is responsible for 5% of Associated with Indoor Pollution
the global load of these diseases, and it is also the
highest load in low-income countries. IP causes Generally, pollutants cause airway and lung inflam-
around 4.3 million early deaths, 81 thousand of mation, thus hindering the immune response and
them happen in America (2012). Greater equality impairing the capacity for oxygen transportation in
in energy access at the worldwide level would the blood. SO2 and NOx are gases that cause irrita-
benefit the development of communities and pop- tion of the airway, reduce lung function, and leave
ulation health. the patient in a vulnerable state, which makes them
In Santiago de Chile, in the households within more susceptible to suffer from diseases, such as
the extreme poverty band, where parents smoke colds or bronchopulmonary problems. Although
in over 50% of the households, it was found that high concentrations of these gases do not cause a
the concentration of pollutants (PM, SO2, and swift death as happens with CO, prolonged expo-
CO) was greater inside of the house than outside sure may cause severe respiratory complications,
of the households, and these concentrations were particularly for children and elderly patients.
higher than those defined in the national norms. In small children, IP exposure, including tobacco
The carcinogenics found inside of the households smoke, increases mortality rate and the risk of suf-
was 6.5 times higher than outside of the house- fering acute respiratory infections. Pneumonia risk
holds. Although all domestic energy sources may in children under 5 years old who are exposed to
have deleterious effects on health, the most solid combustibles is 1.8 times higher. In general,
important direct risk is the pollution caused by PM10 exposure quadruples the risk of upper respira-
the incomplete combustion of paraffin, petro- tory infections (OR 4.30) and doubles the risk of
leum, coal, and other sources used for cooking, lower respiratory infections. Besides this, there is an
lighting, and/or heating. association between the size of the particles and the
The Household Environment Observatory risk of developing wheezing in children who are
studied and compared the different types of heat- under 3  years old (OR) –PM1: 5.9, PM5: 5.5, and
ing systems used in Chile. With this information, PM10: 3.4–. More than 50% of deaths caused by
a value chart was created. This chart showed the pneumonia in children under 5 years old are related
emission values for gases and PM.  Both tradi- to household air pollution. Women and children,
tional and modern paraffin heaters have the great- who are the ones who spend more time at home, are
est pollution indexes for all pollutants. New particularly vulnerable.
convective heaters have the lowest pollution lev-
els, whether they are powered by natural gas or
liquefied petroleum gas (LPG), although these Recommendations
heaters emit a high level of nitric oxide (NOx)
gases. Coal heaters are the ones with the highest The WHO has generated a series of three guide-
rates of CO emission, which is dangerous lines to improve the quality of indoor air:
(Table 58.1). ­dampness and mold (2009), specific pollutants

Table 58.1  Pollution indexes according to different types of heating sources

Value chart for gases
PM CO SO2 NOx and PM emission
Traditional paraffin 2.3–3.6 2.3–3.2 3.4–4.0 1.9–2.7
Modern paraffin 2.1–3.1 1.7–2.1 3.4–4.3 7.6–8.0 0: Optimum
NG Convective 0.4–1.6 0.4 0 5.7 0–2: Regular
NG Radiant 1.0–1.2 0.8 0 1.1–2.7 2–10: Poor
LPG Convective 0.4–1.2 0.3 0 6.5 >10: Dangerous
LPG Radiant 1.2 0 2.7–3.4
Coal 72.9
58  Diseases Caused by Pollutants and Tobacco Exposure 597

(2010), and indoor combustion fuels pollut- several initiatives at the worldwide level to reduce
ants (2014). its use, and therefore, the consequences for the
In poorly ventilated households, the level of general population as well as for the individual
PM2.5 emissions and other contaminants may be patient. In 2009, the WHO declared the Global
higher than the levels recommended by the Tobacco Epidemic as a preventable cause of
WHO. This increase can be up to 100 times over death, which annually takes the lives of more
these suggested levels. One of the most effective than 5 million people.
ways to guarantee cleaner indoor air is control- During the past years in Chile, the regulation
ling the emission of pollutants expelled by the about tobacco use has advanced (Law 20.105,
sources of energy used in the households. year 2006, and since 2013, Law 20.660), advo-
Coal must not be used as house fuel, because cating for environments free of smoke in every
of the high mortality associated with CO, and public place, among other multiple measures rec-
also because it is a carcinogen. Besides this, ommended by the WHO Framework Convention
when it has not been processed, it usually con- on Tobacco Control, with a clear benefit for the
tains toxic elements, such as arsenic, fluoride, children. Nevertheless, there is still much to do in
lead, selenium, and mercury, which is not relation to cultural changes and tobacco use, par-
destroyed when the fuel is burnt. The use of par- ticularly in relation to women, in order to reduce
affin as home fuel is not recommended, because its high prevalence and therefore reduce even
of the emission of highly harmful pollutants, as more second-hand and third-hand pollution.
well as an increased risk in burnings, fires, and Health teams have some ineludible responsibili-
poisoning. Although there are few studies of ties, especially pediatricians and specialists, who
clean fuels, such as biogas and ethanol, the evi- should inform the parents about the passive
dence gathered from emissions tests suggests that smoker status of their children, thus achieving to
these fuels, along with electricity, are the best eliminate the tobacco use of the parents. In this,
alternatives to solid fuels. All of this indicates the burden of the disease in the family, especially
that the practices of energy use at home originate children, will be reduced.
high pollution levels. Nevertheless, considering
the prevalence and the importance of deleterious
health effects, the main indoor pollutant is ciga- Epidemiology of Smoking in Chile
rette smoke.
Tobacco use is the most important preventable
risk factor in chronic non-communicable dis-
Smoking, a Pediatric Disease eases, which is present in children exposed to
passive smoking. In Chile, 16,532 people die
Smoking is a pediatric disease, although most of every year, 45 people die every day, which has an
the diseases related to tobacco exposure appear annual cost for the State that is equivalent to
later in life. This is caused by the fact that envi- 11.5% of the national health budget (MINSAL
ronmental tobacco smoke (ETS) affects several 2014). Mortality attributed to tobacco use is 25%
diseases in each of the pediatric stages of life for diseases, such as sudden death or sudden
(fetus, childhood, and adolescence). Besides this, infant death syndrome (1985–2005). At the
the diseases caused by tobacco use in adults sub-­ national level, the monthly and daily prevalence
clinically appear during the first two decades of of tobacco use in the general population is 34%
life, and 90% of the smokers present this addic- and 21.9%, respectively, which is higher in the
tion before reaching 18 years of life. lower socioeconomic levels (SENDA 2012). A
More than 5 decades ago, the US Public sustained and significant reduction has been
Health Service presented the first report that observed since 2006, with the first modification
showed how tobacco use is harmful for the health to the Tobacco Law. Until 2008, Chile was first
of a person, thus beginning the development of place for smoking prevalence in adolescents
598 L. Amarales Osorio et al.

Fig. 58.1 Smoking Chile 34.2

Prevalence in Mexico 27.1
schoolchildren Colombia 26.2
(13–15 years old) Ecuador 20.5
Uruguay 20.2
Argentina 18.5
Haiti 17.6
Peru 16.5
Bolivia 16.3
Jamaica 15.4
Guatemala 14.8
Brazil 13.7
USA 13.0
Trinidad and Tobago 12.9
Saint Lucia 12.7
San Vicente 12.0
Barbados 11.6
Dominica 11.5
Paraguay 10
Grenada 10.2
Cuba 10.0
Costa Rica 9.6
Venezuela 9.2
Guyana 8.1
Belize 7.7
Suriname 6.9
Bahamas 5.2
Panama 4.3
Antigua and Barbuda 3.6
Virgin Islands 3.4
0 5 10 15 20 25 30 35 40

between 13 and 15 years old at the regional level, dependence and addiction, and nicotine depen-
which was 34.2%, with significant differences dence is quickly established during adolescence.
with other countries, which varied between 3.4% Clearly, when parents smoke, it is an important
up to 27.1% (Fig. 58.1). It also had the first place factor in adolescents: Adolescents who smoked
in the world of smoking prevalence among are 2.1  times more likely to smoke than those
women: 39.9%, which is even more serious adolescents whose parents do not smoke.
(EMTA 2008).
Currently, monthly and daily tobacco con-
sumption in schoolchildren at the national level Physiopathology
(8th grade to last year of high school) is estimated
to be 26.7% and 7.3%, respectively. These num- Tobacco smoke is a complex mixture of chemical
bers also show a sustained and significant reduc- products containing over 4000 chemical sub-
tion, associated with a progressive increase in the stances, particles, and gases, including chemical
perception of smoking as a dangerous activity irritants and 70 carcinogens. Each one of them
(SENDA 2013). has different deleterious effects in all the organs
Chilean adolescents start to smoke very early: and systems, including the respiratory system. Its
among the ones who smoked during the last effects range from neuroendocrine stimulation
month, 5.5% start before they are 7 years old, and and depression, causing addictions, besides
between 74.6% and 81.7% start before reaching inflammation, humoral and cellular immune
13  years of age. Among the adolescents who alterations, allergic sensitization, increase of
smoke, the risk of being a smoker in 5 years is bronchial hyper reactivity, carcinogenesis,
8.4 times higher in comparison to non-smokers. ­toxicity related to ciliary genesis, transport alter-
Therefore, an early onset is strongly related to ation, and oxygen use.
58  Diseases Caused by Pollutants and Tobacco Exposure 599

 assive Smoking: Second-Hand

P and or entertainment venues are daily situations
and Third-Hand Smoking that increase the frequency or degree of exposure
for the child.
Second-hand smoking happens when the patient Second-hand and third-hand smoke are clearly
inhales the ETS emitted by other people while related and coexist. While second-hand smoke
smoking. Although the smoke has a similar com- can be reduced ventilating the spaces, pollutants
position to the one exhaled by the smoker, the in third-hand smoke may persist in the environ-
concentrations of toxins and carcinogens are ment, homes, or cars, for several hours, days, or
often higher. Children have no control on their months after the cigarette has been smoked.
tobacco polluted environment, which has effects There is no safe level of third-hand environmen-
in the uterus and particularly during the first tal tobacco exposure, thus causing potentially
years of life, while they eat, play, crawl, or sleep harmful exposures. The only effective way to
at home. protect children from tobacco smoke is to elimi-
Several studies show that the children of par- nate the parent’s tobacco use, particularly tobacco
ents who smoke are passive second-hand smok- use of the mother and that of caregivers educating
ers. This has been confirmed through the presence the child, besides having the home and cars com-
of significantly higher levels of mediators—coti- pletely free from tobacco smoke. ETS has been
nine in the urine and nicotine/cotinine in the widely recognized as a significant cause of dam-
hair—in children under 10 years old, particularly age, for both short- and long-term, particularly
in those children under 1 year old, whose parents impacting the health of children. Children are
smoke, in comparison to children whose parents particularly vulnerable, as they present a greater
do not smoke. This situation is worsened when risk for several respiratory diseases.
the first cigarette is smoked 30 minutes after get-
ting up, as well as when there is partial or no
restriction at all to tobacco use at home, when  espiratory Morbidity and Mortality
R
compared to a total restriction. Third-hand smoke Associated with Tobacco Exposure
exposure is the result of the inhalation, ingestion,
and skin absorption of pollutants that remain in Epigenetics
the air, dust of the room, surfaces, clothing and Prenatal exposition to pollutants, such as tobacco
hair of the parents, caregivers, care providers, or smoke and other substances, may active or silence
educators who smoke. Small children are more genes related to immunity, with substantial
vulnerable to third-hand smoke, as they are rou- effects in immune programming, thus determin-
tinely in contact with carpets, floor, furniture, and ing the risk to suffer from several diseases. The
other contaminated objects, which they usually epigenetic action from tobacco smoke is trans-
place in their mouth. It is particularly risky in lated in the remodeling of pro-inflammation
homes with children who are under 1  year old, genes, with an increase in the expression of
and smoking outside of the house reduces, but inflammation mediators.
does not protect, from ETS.  ETS exposure and T helper cells differentiation in a Th1 or Th2
pollution is 5–7  times higher in the homes of phenotype is partially directed by the expression
smokers who try to protect their children smok- or repression of specific genes, and it was the
ing in an open space, when compared to homes of foundation of the hygiene hypothesis that
non-smokers. Urine cotinine measured in infants appeared some years ago, which regulated Th1/
indirectly exposed is 7.5 times higher in compari- Th2, and that explained the increase of asthma
son to non-exposed infants. and allergic diseases. Currently, it has been
In Chile, the National Health Survey of 2009– ­confirmed that the development of the immune
2010 showed that smoking was allowed in 30.7% system is epigenetically regulated, and Th1/Th2
of Chilean homes. At the same time, exposure to differentiation is related to tobacco exposure dur-
tobacco smoke in transport vehicles and/or parks ing pregnancy, activating or silencing these
600 L. Amarales Osorio et al.

genes, thus altering the balance of the neonatal tobacco, there is a clear association to several
immune response. Therefore, we may propose respiratory child diseases, such as early wheez-
that maternal tobacco use, or exposure to ETS, ing, recurrent wheezing, visit to emergency room,
may alter the immune function in the fetus, con- or hospitalization because of lower respiratory
tributing to a greater risk to suffer respiratory dis- infections and asthma, among others. Studies
ease, asthma, and allergic diseases in children. conducted by Mallol in Chile show that the chil-
This could explain, among other factors, the sig- dren of mothers who smoked during pregnancy
nificant increase of early childhood allergy, had a significantly greater risk to suffer from
wheezing rates, and the appearance of asthma at wheezing, acute respiratory diseases, and hospi-
the worldwide level, with its corresponding talization because of pneumonia, in comparison
national correlation, as confirmed by the with the children of non-smokers mothers.
International Study of Asthma and Allergies in In relation to the greater risk of acute otitis
Childhood (ISAAC). media, a prospective cohort composed of 8556
pregnant women showed a clear dose–response
Fetal Tobacco Syndrome relationship between the degree of tobacco use
The description from 1985 summarizes the effect by the mother during the 1st trimester of preg-
that tobacco has in the pregnant woman and the nancy and the risk for this affection until the fifth
newborn. This greater fetal risk is caused by year of life.
maternal anemia, fetal hypoxia, and polycythe-
mia, causing poor perinatal growth and alteration  udden Infant Death Syndrome
S
of the brain morphological substrate, which A systematic review concluded that after adjust-
results from the fetal response to hypoxia. ing for confusing factors, such as sleep position
Table 58.2 summarizes works that confirm dam- and socioeconomic situation, if the mother uses
age that intrauterine tobacco causes. Among tobacco after birth, the risk for sudden infant
these risks we may mention the association death syndrome is doubled. In 59% of the cases,
between prenatal mother use of tobacco and sud- children who were exposed to ETS did so because
den infant death syndrome, which doubles and the mother smoked. Besides this, other studies
almost quadruples this probability. Besides a show that there is a greater nicotine concentration
clear association to prenatal maternal use of in pulmonary tissue of infants who died because
of sudden infant death syndrome, as well as
Table 58.2  Impact on child health because of exposure observing that the relationship depends on the
to tobacco smoke in uterus dose. The number of cases of sudden infant death
Effects on pregnancy Evidence syndrome has been significantly reduced in those
Reduced fetal growth +++ countries where tobacco use has also decreased.
Premature childbirth +++
Fissures ++  hild Respiratory Morbidity
C
Effects on the newborn and Mortality
Low weight at birth +++ Passive smoking doubles the risk of respiratory
Sudden infant death syndrome ++
infections in children. The main mechanisms are
Reduced pulmonary function ++
Effects in infants and school-age children related to structural and immunological changes.
Overweight +++ Within the structural changes we can mention the
Reduction of pulmonary function ++ ones related to the anatomical damage caused in
Bronchial asthma +++ the upper and lower airway (inflammation, reduc-
Infections + tion in mucociliary transport, Eustachian tube
Acute otitis media ++ blockage, among others) and the increase of bac-
Evidence: + = Some retrospective studies, or studies for terial adherence to respiratory mucosa. Nicotine
cases and control groups; ++ = several retrospective stud-
ies, few prospective studies; +++  =  many prospective
and other products of tobacco smoke favor the
studies and metanalysis microorganism invasion of the middle ear, which
58  Diseases Caused by Pollutants and Tobacco Exposure 601

colonize the nasopharynx. Immunological quent respiratory entity in our country, and
changes include inhibition of the phagocytic feared because of its seriousness in infants,
activity of the neutrophil and alveolar macro- presents a greater incidence when it is associ-
phages, as well as altering specific cell and ated with passive smoking. Cough, one of the
humoral immunity response: Nicotine inhibits most prevalent and frequent symptoms for child
cellular Th1 response, reducing the production of visits, is associated with ETS, as well as hyper-
IgG and IgA, as well as stimulating Th2 response, secretion and respiratory distress. The relation-
along with an increase of IgE and eosinophil ship between infant wheezing and tobacco use
production. has been widely documented, especially when
A common problem in pediatrics, which the mother smokes, and it increases when both
causes a considerable morbidity, is acute and parents smoke. Besides this, a risk gradient is
chronic middle ear disorder. There is a clear asso- observed according to the quantity of cigarettes
ciation between tobacco use of any of the parents smoked, with a greater gradient if the mother
and middle ear infectious pathology. Particularly, smokes.
chronic middle ear disease is 20–50% more fre- In relation to asthma and rhinitis, a study con-
quent in children exposed to ETS, related to ducted in 27 European countries describes an
recurrent otitis media, middle ear effusion, or ear increase between 7% and 11% in the number of
surgery, with a positive association between asthma episodes in <14  years-old exposed to
duration of the effusion and the number of smok- ETS. ISAAC (Table 58.3) shows the risk associ-
ers at home during the first and second year of ation between passive smoking and asthma and
life. Sinusitis is also related to ETS: among the severe asthma symptoms, but especially if the
children who present sinusitis, 68.8% are exposed mother smokes during the first year of life of the
to passive smoking at home, according to some child in the lower age group. At the same time, a
investigators. crescent gradient related to tobacco use of each
Children of parents who smoke are at double of the parents was described. Association of rhi-
risk to suffer from a serious respiratory disease nitis with tobacco use of the parents is certainly
during childhood. This risk is greater in chil- weaker, with a greater risk of conjunctivitis in
dren under 2 years old, especially for children the 6–7 years old age group, a greater risk when
with low weight at birth (OR 4.5). Besides this, the mother smokes, and an even greater risk if
there is a dose–response correlation for acute both parents smoke, with no relation to dose
respiratory infections depending on the number dependence.
of smokers in the house and/or quantity of ciga- In Punta Arenas city the study conducted by
rettes smoked by the mother. Bronchiolitis Amarales L. as a collaborator of ISAAC (2001)
caused by syncytial respiratory virus, a fre- shows that children who smoke in the older age

Table 58.3  Pediatric morbidity among tobacco exposure

Symptoms Only mother smokes Only father smokes Both parents
6–7 years old OR (95% CI) OR (95% CI) OR (95% CI)
Recurrent wheezing 1.31 (1.22–1.41) 1.13 (1.08–1.18) 1.37 (1.29–1.45)
Recurrent rhinoconjunctivitis 1.13 (1.04–1.23) 1.07 (1.02–1.12) 1.16 (1.09–1.24)
symptoms
Asthma 1.28 (1.19–1.38) 1.07 (1.02–1.12) 1.29 (1.22–1.38)
Severe asthma symptoms 1.31 (1.18–1.46) 1.19 (1.11–1.27) 1.46 (1.34–1.59)
13–14 years old OR (95% CI) OR (95% CI) OR (95% CI)
Recurrent wheezing 1.27 (1.19–1.36) 1.13 (1.07–1.18) 1.43 (1.36–1.51)
Recurrent rhinoconjunctivitis 1.15 (1.08–1.23) 1.12 (1.07–1.17) 1.27 (1.21–1.34)
symptoms
Asthma 1.16 (1.09–1.23) 1.04 (0.99–1.08) 1.21 (1.16–1.28)
Severe asthma symptoms 1.28 (1.18–1.39) 1.16 (1.09–1.23) 1.57 (1.47–1.67)
602 L. Amarales Osorio et al.

group (13–14 years old) significantly presented a for the 3rd hand smoke, when they argue that
greater prevalence of asthma symptoms in rela- they smoke out of the house and minimize the
tion to non-smoking children (16.8% vs 10.7%), damage. Even so, it is frequent that specialists,
dose-dependence, and a greater prevalence of when facing recurrent pathologies, start a detailed
exercise induced asthma symptoms (19.98% vs study to obtain an etiopathogenic diagnose, with-
15.07%). out having first conducted an exhaustive anamne-
People exposed to ETS inhale a pulmonary sis about family tobacco use, which could be an
carcinogen that metabolizes and is cleared RF in these pathologies.
through urine. These urinary metabolites are Informing the parents about the harm that ETS
present in up to 90% of children exposed, with a causes in the corresponding pathology may
correlation between the cigarettes smoked per reduce or eliminate tobacco use rates in the par-
day at home and the urinary levels of those ents, therefore reducing the exposure or eliminat-
metabolites, clearly showing that in-house smok- ing children’s exposure. Because of this, the
ing is an important source of child exposure to a American Medical Association has proposed the
pulmonary carcinogen. At the same time, 3rd need for pediatricians to approach the parent’s
hand exposure to tobacco smoke is genotoxic in tobacco use. The recommendations of the
human cellular lines. Treatment of tobacco use in children and adoles-
cents guidelines includes: (a) asking pediatric
and adolescents patients about tobacco use, (b)
Diagnostic Approach send a strong message about the importance of
and Recommendations completely abstaining from using tobacco, (c)
have counsel interventions to help them quit
Pediatricians and pulmonologists have a strate- smoking, hopefully with written information, (d)
gic and privileged place to avoid tobacco dam- promote abstinence and quitting tobacco use for
age. Within the obligations, prevention and the parents who smoke, along with a brief coun-
protection to the fetal, child, and juvenile popu- seling, and (e) set follow-up visits. Brief counsel-
lation must be encouraged, particularly for ling made by the physician increases the quitting
pathologies related to passive smoking. At the rate in 66%, in comparison to a lack of interven-
same, the onset of active tobacco use must be tion. Therefore, pediatric visit must be an oppor-
prevented during pre-adolescence and youth, tunity to discuss the risks associated with tobacco
through sustained actions coordinated with the use in people of all ages, influence the beliefs of
parents and teachers, besides stimulating par- the parents about 2nd and 3rd hand tobacco dam-
ents and family members who smoke to quit the age, promote smoke free environments, and quit-
habit. The diagnose of personal (for schoolchil- ting tobacco use of both adolescents and parents
dren and adolescents) or familial use of tobacco who smoke.
is crucial, and it should be mandatory in every Lastly, measures will probably be more effec-
pediatric visit, particularly with the specialists, tive if they are placed within a juvenile tobacco
as well as treating active tobacco use during the prevention program, framed within an integral
first years of juvenile addiction. The diagnosis is program involving population policies, such as
made in only 33–35% of medical visits, as well the current law in Chile (Free from tobacco
as the anti-­ tobacco counseling in adolescents smoke), reduction of advertising, and taxes
who smoke. increase (greater taxes and effective inspection);
It is important to consider that parents who incorporating lack of tobacco as a guaranteed
smoke are frequently unaware of the damage that public and private offer, avoiding presenting
ETS cause in their children, or the relationship tobacco use as an “activity for grown-ups”, and
between tobacco exposure with the correspond- emphasizing how tobacco industry addresses
ing diseases, particularly when these are recur- young people, making them addicted to nicotine
rent respiratory diseases. This is especially true from an early age.
58  Diseases Caused by Pollutants and Tobacco Exposure 603

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cinogen in children exposed to secondhand or third-
human cells. Mutagenesis. 2013;28(4):381–91.
hand tobacco smoke in their homes. Cancer Epidemiol
Horak F, Fazekas T, Zacharasiewicz A, Eber E, Kiss
Biomark Prev. 2011;20(6):1213–21.
H, Lichtenschopf A, Riedler J.  The Fetal Tobacco
Vargas C.  Efectos de la fracción gruesa (PM10-2.5) del
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Pediatrics and Adolescence Medicine (ÖGKJ) as
 Nursing Care Education in Chronic
Respiratory Diseases
59
Ana Moya Isamitt

Contents
Introduction  606
 ursing Care Management 
N 608
Characteristics of a Correct Educational Instance for Self-Care  608
Objectives of Educational Programs  609
Characteristics of an Efficient Education  609
Learning Areas  609
Evaluation of Educational Instances  609
Minimum Contents of an Effective Educational Instance  610
Self-Care in Asthma  610
Basic Knowledge about Asthma  610
Treatment Description  610
Educational Factors  611
 elf-Care in Cystic Fibrosis
S  612
Nurse Specialized in Cystic Fibrosis  612
Basic Knowledge About the Disease  613
Cystic Fibrosis Signs and Symptoms  613
Fundamental and Permanent Pillars for the Disease  613
Respiratory Physiotherapy  613
Inhalation Therapy  614
Physical Activity  614
 elf-Care in Sleep Disorders
S  614
Sleep Hygiene during the First Months of Life  615
Sleep Hygiene Starting at 6 Months of Age  616
Sleep Hygiene Starting at 12 Months of Age  616
Sleep Hygiene Starting at 18 Months of Age  616
Sleep Hygiene Between 2 and 5 Years of Age  616
Sleep Hygiene from 11 Years of Age  617
Sleep Hygiene in Adolescence  617

A. Moya Isamitt (*)

School of Health, Duoc UC, Santiago, Chile

© Springer Nature Switzerland AG 2020 605

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_59
606 A. Moya Isamitt

Self-Care in Allergies  617

Basic Knowledge About Physiology of Food Allergies  618
Rules to Avoid Triggering Allergens  618
Description of Different Treatments  620
Educational Factors  620
Rules of Management of the Disease  620
Conclusions  621
Sources  621

Introduction • They need long periods of caregiving and

treatments for their control and counteracting
Recently, important changes have taken place in the effects of the disease.
life expectancy and quality of life of patients with • They carry feelings of loss as a specific and
chronic respiratory diseases, which have created predominant component of any kind of
a huge challenge for nursing care to improve chronic disease.
attention for our patients, because they are more
involved in their healthcare. When a person is diagnosed with, or suffers
A chronic disease is the alteration in the health from a chronic respiratory disease, it affects his/
state that persists in time and requires continuous her physical, psychological, family, social, and
and permanent care, such as in the case of cardio- work aspects, depending on the nature of the dis-
vascular diseases, diabetes, cancer, respiratory order and its severity, as well as on individual
diseases, and AIDS, among several others. aspects of the patient. Physical problems, inde-
Chronic diseases have an important place in the pendent of their nature, can be originated from
epidemiological profile. They usually cause mul- the disorder itself or as consequences of medical
tisystemic sequels, which generate significant treatment. Labor problems directly influence
changes in the lifestyle, adding special and spe- family, which is forced to adapt or completely
cific needs, for both care and self-care, according abandon their work activities, or they have to use
to the disabilities or limitations that its progres- prolonged medical licenses. In the family area,
sion may cause. the most relevant conflicts are linked to the loss
A big part of chronic diseases share aspects of role of parent and becoming main caregiver
associated with physical and emotional suffering, (for the most part, mothers). Social problems
which meaningfully affect the person who con- largely depend on loss of relationships and emo-
fronts the disease and the family, with a big tional bonds, the most important being caused by
impact in life quality, because of the needs and change of status related to job loss, social isola-
demands of care and support they require. tion, free time usage, and quantity and quality of
These diseases have common characteristics: social interactions. The experience is always
individual for each nuclear family, where percep-
• They are permanent and irreversible, pro- tion and meaning differ from one person to the
gressing with residual alterations. next, even though they share trigger conditions
• They are multi-causal and must be confronted and their effects, or have the same therapeutic
from this perspective. and social resources for their attention.
• They require specific training of patients and Development of attention and care strategies
their family, for securing caregiving, and col- demand a continuous effort of the nursing team
laboration of both with the healthcare team. and others health professionals, through which
59  Nursing Care Education in Chronic Respiratory Diseases 607

the approach of physical, biological, psychologi- thing—strengthening the care of the person’s
cal, sociocultural, and spiritual dimensions that whole life—to respond to the patient’s aspira-
involve human experience may be approached. A tions and patterns, particularly in relation to a
very useful tool that is available for the health- circumstantial dimension of the disease or a
care team is the education of health contents for limitation provoked by it. The disease by itself
patients. does not define the needs of the individual or
Educational intervention requires the collabo- his/her family, but rather when the disease
ration of teams, so they can act in a coordinated appears, is resolved, or increases because of the
way at the hospital, home, and school, which also way that the experience is lived. The nurse has
applies to the coordination of all available a privileged position in the explanation to oth-
resources and the active participation of parents, ers about the patient’s world, family, and pro-
since they are the most stable agents in the child’s cesses that happens within, because they know
development. Because of that, in these instances, those universes in a way that none other disci-
the most important thing is to educate parents and pline does.
children in consideration to their age. Among the most used theories nowadays,
It is a challenge to advance in pragmatic there is the Dorothea Orem’s theory, which
implementation of nursing theories, but contrib- conceives the human being as a biological,
utes to differentiating it from other health pro- rational, and thinking organism. Human beings
fessions involving usage of a distinct professional have the ability to reflect about themselves and
language. Even then, in this aspect, concepts of their surroundings, ability to symbolize what
person, environment, health, and nursing are they experience, and to use symbolic creations
used from the perspective of applied theory. (ideas, words) for thinking, communicating,
Using theories contributes to distancing nursing and directing efforts for making things that are
from the biomedical focus that has predominated beneficial for themselves and others. Nursing
for a long time and has influenced care. care helps the individual to accomplish and
Healthcare has been identified as the essence of keep self-care actions for conservation of health
nursing, despite other disciplines, aside from and life, recover from the disease, and confront
nursing, having approached and described the its consequences. The environment is under-
concept. stood in this model as all those physical, chemi-
The study of healthcare has allowed the cal, biological, and social factors, whether they
understanding of the importance and magnitude are family or community ones, which can influ-
of nursing attention for human health, develop- ence and interact with the person. Finally, the
ment, and survival. Nevertheless, this is not an concept of health is defined as a state in which,
exclusive action of nursing, since a large part of for the person, it means different components
activities made around human healthcare are and changes according to the person’s human
done in a non-professional level, in the scope of and biological characteristics (Fig.  59.1). The
everyday life. most important concept is self-care, which is a
Caring refers to those acts of assistance, sup- behavior that exists in particular situations of
port, help, and conservation, which allow and life, aimed to the persons or their surroundings,
make it easy for persons who need to improve for regulating factors that affect their own
their life conditions, to accomplish that, and to development and functioning for the benefit of
anticipate those needs. their life, health, and well-being. It is an activ-
Nursing care in chronic patients requires ori- ity learnt by individuals and directed toward an
entation with holistic efforts, and a primary objective.
608 A. Moya Isamitt

Fig. 59.1 Self-care Culture Knowledge

theory Social group Abilities

External factors

Internal factors

Control
Requirements Self-care
Practice
Habits
Behavior

Nursing Care Management delivering tools for health self-care. “The self-­
care agency is the group of powers and abilities
Management of care involves clinical processes within the patient which allows him/her to com-
linked to people’s healthcare. Management of mit to self-care”. This complex ability maintains
clinical processes can be seen as the most appro- or enforces the integrity of human structure, its
priate for adjusting the criterion of the health functioning, and promotion of well-being, and it
team according to the most dominant sanitary is acquired to satisfy continuous care require-
criterion in management teams, having links ments which regulate different processes.
between clinical logic, which has the individual For all diseases, adherence to treatment is the
patient as its thrust, and sanitary logic, which most important factor, but as it is susceptible of
considers collective users/patients. being modified, it compromises the results of
In order to generate an effective management of treatments.
care, we have to consider available evidence through The diversity of diseases makes educational
different updated publications, patient’s preferences needs in children with a chronic disease heterog-
in relation to what are his/her educational needs, enous, diverse, unstable, shifting, and less pre-
and the environment and available resources. dictable than those presented in other children.
The new model of global hospital management is These special educational needs are of three
based on the integral model of health attention, types:
which is defined as the group of actions that enforce
and facilitate efficient, effective, and opportune 1. Needs derived from diagnosis and treatment
attention directed not to specific incidents but toward of the disease: adherence to treatments and
persons considered in their physical and mental control of the disease, family, and school
completeness, and as social beings belonging to dif- environment.
ferent types of families and communities that are in 2. Needs derived from emotional and social dis-
a permanent process of integration and adaptation to orders, for the adapting of parents and chil-
their physical, social, and cultural environment. dren: psychological support to the child and
family.
3. Needs related to school curriculum and early
Characteristics of a Correct attention for favoring an appropriate cogni-
Educational Instance for Self-Care tive, motor, affective, and social development
of the child: early attention services, school
In the outpatient field, and particularly in a pul- units of support in hospital institutions, educa-
monary function laboratory, the diversity of tional domiciliary attention, and school cen-
patients gives a rich educational instance for ters of reference.
59  Nursing Care Education in Chronic Respiratory Diseases 609

In early childhood, the objectives of educa- Among the items to consider in an efficient
tional attention are: educational instance, there are:

(a) Adaptation of hospital, family, and school • Education is very important for the child that
environment to the needs derived from has a chronic disease.
the disease, for eliminating associated risk • Education must involve the patient, his/her
factors. family, and school environment.
(b) Education of parents about how to control • Education must start when the diagnosis is
the disease and obtaining adherence to treat- made.
ments. It represents a priority objective in • Education is continuous, and it is comple-
this stage of the development of the child. mented until accomplishing self-management.
(c) Child’s control of the disease: management • The main objective of education for self-care is
of devices, preparation for diagnostic tests to increase quality of life with no limitations.
and treatments. This objective is accom- • For establishing a good, effective educational
plished by incorporating the child to the edu- plan it is required to previously identify the
cational instances. real educational needs and the core of the dis-
ease presented in the child and his/her family.
Since 2009, there has been a program in our
institution named “Education for health self-­
care”, where according to the patient’s pathology, L
 earning Areas
certain topics are addressed for improving his/her
health and to clarify question of his/her parents When raising educational instances, we must
about basic care or general measures for main- consider three learning areas:
taining good control of the disease.
• Affective: The main caregiver will recognize
the importance of his/her participation in car-
Objectives of Educational Programs ing activities.
• Cognitive: The caregiver can describe the
• Emphasizing the concept of disease; signs of the chronic disease that affects the
• Encouraging prevention according to the patient.
disease; • Psychomotor: The caregiver is capable of
• Directing the educational program to target showing through supervised repetition each
group (depends on age group). technique taught in the educational instance.

Educational programs have shown that they

modify life quality and adherence to treatment. Evaluation of Educational Instances

They consider learning outcomes, whether the

Characteristics of an Efficient evolution of the disease is beneficial or not, and
Education the way in which the patient, family, tutor, or
main caregiver manages his/her everyday life. It
Education must be understood as a continuous is required to determine to what degree each
and dynamic process, adapted to the patient’s agreed objective has been accomplished, the
needs, for obtaining changes in attitudes and life- quality and effectiveness of applied techniques,
styles of the patient and the family, which will and the quality of teachers in charge of transmit-
surely produce an improvement in their life qual- ting the educational plan, and that is why the con-
ity, allowing self-control and autonomous deci- tinuous training of the whole health team is so
sion making. important. In order to clearly satisfy defined
610 A. Moya Isamitt

objectives, readjustments in the educational Frequent questions presented by parents are about
sequence have to be made, considering the learn- adverse effects of the treatment, tachycardia asso-
ing capacity of the patient, family, or tutor, and ciated with bronchodilators, and low height gain
their personal peculiarities. associated with steroids.

Prescription and Sequence
 inimum Contents of an Effective
M of Utilization
Educational Instance Asthma treatment pursues two objectives: to
obtain and maintain control of clinical signs and
In a center of reference of respiratory diseases, symptoms, preventing exacerbations, chronic
the health professional is in contact with several obstruction of air flow, and decreasing mortality.
diseases, as well as the patients and their fami- Pharmacological treatment of asthma is based
lies. Asthma, cystic fibrosis, sleep disorders, and on controlling inflammation, which is treated by
food allergies are reviewed in this chapter. anti-inflammatory drugs (basically, steroids, and
in some cases, chromones or leukotriene antago-
nists), whereas bronchodilator drugs are applied
Self-Care in Asthma as symptomatic drugs, also named rescue
medications.
It must be highlighted that education is not just There is plenty of evidence that shows that
informing. Information is necessary, but insuffi- patients do not correctly use the inhalation tech-
cient. The objective is that the child and his/her nique and that even the health personnel ignore
family acquire abilities for controlling asthma. the technique. It has been described that up to
Education must be stepwise, from basic knowl- 80% of patients do not know how to use the
edge, to self-control, if possible. In addition, it inhaler, and to avoid this it is important to con-
must be continuous, progressive, and adapted. sider the following elements:
Authors themselves say that the use of educa-
tional programs generates a decrease in unsched- 1. Choosing the most appropriate device before
uled medical visits, emergency visits, and prescription, which can be detected by the
hospitalizations, as well as school absenteeism. nursing personnel in the first encounter with
the patient for educational instance.
2. As we have seen, verifying the technique in
Basic Knowledge about Asthma
every instance and showing in a physical way
the technique and asking to repeat, to know
A simple description, also adapted to the age of
whether both patient and tutor understood the
anatomical and functional changes that happen in
technique.
asthma. For that, we count on educational prim-
ers, which include some simple data, which are
addressed by answering the following questions  echniques for Medication Use
T
This is put into practice during the time exams
• What is asthma? are being made, which is the best instance for
• What factors influence in the emergence of educating, because the patient stays at least
asthma? 15–60  minutes with the nurse or nurse techni-
• Rules for avoiding triggering allergens cian. In the medical visit, some contents can be
reinforced.
Patients must correctly use the inhalation
Treatment Description technique, which will be different according to
the inhalation system used. An incorrect inhala-
Patients and their relatives must know what rescue tion technique is equal to not taking the medica-
medications are and how to use them, along with tion. In addition, a high and increasing number of
knowing about preventive control medications. commercial products for inhalation therapy exist:
59  Nursing Care Education in Chronic Respiratory Diseases 611

metered dose inhalers (MDI), holding chambers, about his/her disease and his/her opinion about
dry powder inhaler (DPI), unit doses, multi-­ the treatment, letting him/her choose, as far as
doses, auto-trigger systems, among others. possible, his/her inhalation device, as long as the
In toddlers, medium doses of MDI and small child has a good command of the technique. In
volume chambers with a mask are favored, many occasions, especially in adolescents, talk-
whereas in school children (because of capacity), ing to the patient alone is useful, without the
DPI or medium dose of MDI and chambers with presence of the parents. Starting with the infor-
a mouth piece are favored. We discourage mouth mation and correct application of the abilities
direct administration of MDI. Assessment of the acquired, self-control will be the ability to under-
technique must be a part of every encounter in stand clinical situations and make the right deci-
children with asthma. Families must know how sions for them.
to keep chambers clean, verify the device’s cor- In order to act in case of deterioration, there has
rect functioning, know when few doses of the to be a previously made self-treatment plan. On the
drug are left if it does not have a dose counter, basis of a control of symptoms or measurement of
and buccal hygiene rules after its administration. peak expiratory flow (PEF), there must be a written
maintenance treatment: when to use rescue medi-
cation, when to increase the dose of anti-inflamma-
Educational Factors tory inhalation medication, when to start a pattern
of oral steroids, and when, how, and whom to ask
For a satisfactory self-control of asthma in chil- for medical help.
dren, it is necessary to master what we call self-­ In pediatrics, the strategy for recognizing
care abilities: signs and symptoms of progressive obstruction of
the airway and developing a plan depends on fac-
• Recognizing and avoiding triggering factors tors, such as age, sociocultural level of the fam-
• Ability to monitor symptoms ily, and also involving the older child or
• Correctly mastering drug inhalation techniques. adolescent in the process, the severity of the
• Ability to recognize when asthma is worsening asthma or whether it is persistent or seasonal.
In breastfed and young children, symptoms
Knowing how to act pre-emptively before any registrations are often utilized, as well as in older
variation of the process is essential. children who cooperate and in persistent asthma.
Self-care abilities will be applied by families More rarely, PEF and symptoms registration may
in cases of breastfed babies and infants, and pro- be followed using a so-called warning zone or
gressively, according to growth, the child will be color system (Fig. 59.2).
involved in the control of his/her disease. There The importance of peak expiratory flow in self-
has to be room for the child to express feelings control of asthma lies in the possibility of home

No symptoms - PEF between 80 and 100% Controlled asthma

- No limitation in activities of normal personal value. - Follow usual treatment.
- Attend to scheduled
consultation.
Daily symptoms - PEF between 50 and 80% Precaution
- Cough, wheeze, limitation in activities, of normal personal value. - Adjust treatment.
nighttime awakenings, etc. Rescue - Attend to medical control
medication must be used as per written while managing
instructions, variation in undercurrent symptomatology.
treatment.
Progressive worsening - PEF between 40 and 60% Danger
- Progressive fatigue, cough, wheeze that do of normal personal value. - Treatment prescribed by
not respond to short-acting bronchodilators. - Attend emergency a doctor.
department.

Fig. 59.2  Self-control measures (warning system)

612 A. Moya Isamitt

use, because the PEF measuring device is small in • Oxygen therapy teaching and control;
size and easily transportable, its use is basic, and • Non-invasive ventilation teaching and control,
provides objective and quantifiable values. in required cases;
• Home assistance.
Throughout the years, parents become spe-
Self-Care in Cystic Fibrosis cialists in the disease, and the level of response
they expect requires a trained health team.
Cystic fibrosis (CF) is the most frequent autoso- Specialist nursing personnel is actively involved
mal recessive disease in the white race. in the decision making related to the treatment
Commonly, this results in development of chronic and monitoring of medical attention in these
obstructive pulmonary disease and secondary patients that are with the health team for years.
malnutrition. Since pulmonary damage flourishes Nursing personnel must coordinate the atten-
progressively, early diagnosis and focusing on tion between patient and family, besides extra-­
respiratory and nutritional management are cru- hospital services, both at a practical level and
cial for improving the prognosis of these patients. through support and advice. This is accomplished
Medical advances achieved during the last through their function as a teacher, reliable care-
30  years have increased survival rate, which is giver, advisor, and confidant. Trusting this pro-
now up to 40 years of life. As it is a multisystem fessional must have a benefit in the good
and progressive disease, whose treatment management of acute and chronic symptoms.
includes different daily measures affecting nutri- Patients have the responsibility of taking the
tion and the respiratory system, patients and care- correct doses of the prescribed medications in a
givers have a great responsibility in controlling timely manner and in the right order. Normally,
the disease and applying treatment measures, patients with cystic fibrosis have very complex
aiming for a better general health condition as pharmacological regimes. The clinical pharma-
well as slowing the progression of the disease. ceutical professional can help in educating
Educational intervention helps patients and fami- patients about correct drug reconstitution, inhala-
lies to solve problems, set goals, and plan some tion, and the correct order of the drugs.
changes in their lifestyles in order to better man- Education of the patient with cystic fibrosis is
age the disease. considered fundamental, since he/she has to be
The role performed by the patient and family aware of the disease in all its aspects, because
members in the active management of their atten- patients that know their problem (progression,
tions is now considered relevant for increasing treatment to follow, etc.) get much more involved
the probability of positive health results. in therapeutic guides, both of medicines and its
Educational programs in cystic fibrosis tradition- rehabilitation, and they are more motivated to
ally provided specific knowledge with the only fight for its healing or relief.
purpose to fulfill the pharmacological treatment.
Currently, educational programs are oriented
toward placing patients and their relatives as Nurse Specialized in Cystic Fibrosis
experts that work collaboratively with sanitary
professionals in the treatment of the disease. He/she has responsibilities with patients, relatives,
The group of professionals dedicated to work- and personnel involved in medical attention of
ing with patients with cystic fibrosis has the fol- patients, so he/she has to commit to care for them.
lowing objectives: The responsibilities of a nurse in charge of an
educational program about cystic fibrosis are:
• Education of the patient and her/his relatives;
• Aforementioned respiratory physiotherapy • Advocating for each patient and having
and muscular training; updated information about current treatment
• Psychosocial and nutritional control; practices.
59  Nursing Care Education in Chronic Respiratory Diseases 613

• Maintaining and teaching clinical experience which at the moment of diagnosis can be confus-
and practice. ing and generate stress in the patient’s environ-
• Support and advice. ment. A simple way of confronting this is:
• Education and investigation.
• Relationship with patients and relatives. • Upper airway manifestations: Symptoms and
signs of the upper airway according to age.
As a chronic disease, with differences in its • Lower airway manifestations: Symptoms and
development, educational stages overlap when signs of lower airway according to age.
working with the patient. • Respiratory exacerbations: Most patients
Some of the objectives that must emerge with have an insidious respiratory worsening, that
a patient with cystic fibrosis are: is characterized by exacerbations of its chronic
pulmonary infection. It is taught to parents or
• Decreasing respiratory symptoms and flare-ups; tutors to recognize these changes and to have
• Improving state of mind (increasing motivation); a meticulous registration of pulmonary
• Increasing tolerance to efforts (by improving images, cultures, and lung function tests.
muscular function); • Microbiology: Patients are colonized according
• Decreasing number of hospital admissions; to the disease’s progression and the accompa-
• Reducing days of hospitalization; nying flora varies over the course of the disease,
• Prolonging survival. for this purpose, active vigilance during exacer-
bations is important. In this process, patients
Hereunder, we deliver some topics as an and relatives have a leading participation.
example to educate family and patient: • Pulmonary complications: They are taught to
recognize the presence of atelectasis, bronchi-
ectasis, hemoptysis, and pneumothorax
Basic Knowledge About the Disease according to the disease’s progression.
• Pancreatic, hepatic, and urogenital complica-
Cystic fibrosis is an inherited and incurable dis- tions: They are taught about signs and appear-
ease, which mainly affects the digestive tube, ance of complications according to the
lungs, and pancreas. It is one of the most common disease’s advance, in order to detect them in a
chronic pulmonary diseases in boys, girls, and timely manner.
young adults. Cystic fibrosis is caused by an
abnormal gene that produces a thick and sticky liq-
uid called mucus, which accumulates in airways  undamental and Permanent Pillars
F
and pancreas. This causes pulmonary infections for the Disease
that can be complex, as well as digestive problems,
and may affect the male reproductive system. • To obtain an appropriate nutrition status;
• To use medicines against respiratory infec-
tions and inflammation;
Cystic Fibrosis Signs and Symptoms • To do physical therapy regularly: respiratory
physiotherapy, thoracic musculature strength-
Symptoms do not appear simultaneously, but ening exercises to prevent deformities.
many times they do it gradually. That is why it is
important to mention them in each educational
instance to make the patient, family, or main Respiratory Physiotherapy
caregiver alert for symptoms that can appear in
the course of this chronic disease. If the patient is aware of the importance of chest
Education can be separated by organs, to ease physiotherapy there will be much more adher-
the education process of the parents or tutors, ence to it. The same can be said about aerosol
614 A. Moya Isamitt

therapy (how to execute the sessions correctly, of disorders in all other systems, such as neuro-
cleaning of the device, etc.) and daily drugs that endocrine, metabolic, cardiovascular, etc. These
need to be taken, as well as oxygen guidelines in in turn can vary from mild to severe depending
the case of having home oxygen therapy (how on compromise of such alterations, and finally
many liters to carry, its risks). If this educational they can involve the family environment and psy-
aspect is correctly led, it will have better results chological profile of people.
in the life quality of the patient. Sleep problems are often a source of stress
for parents, as well as learning and behavior
difficulties in children, so it is important to con-
Inhalation Therapy front them and provide appropriate information
about all their questions and concerns. At the
• Appropriate inhalation device (or devices) same time, both parents and children need to
selection; learn new behavior patterns, thus obtaining an
• Patient or family training in its optimal use; appropriate management of these disorders that
• Management, cleaning, and necessity of main- can generate behavior or learning issues in the
tenance and substitution of the device; child.
• Treatments for clearing secretions of the It must be highlighted that there is important
airway. evidence about the effectiveness of educational
programs, with a behavior focus that integrates
elements of sleep hygiene. These elements have
Physical Activity been applied in adult groups, with results that
allow having records about factors proven to be
Physical activity allows clearing secretions and effective and which can be extrapolated to the
prevents the appearance of osteoporosis, a pathol- child population.
ogy with a high incidence in patients with cystic The optimal thing is to initiate programs for
fibrosis. For a design exercise plan, a previous the prevention of sleep disorders, consisting in
stress test is needed. the creation of advice that is explained and given
The challenge that emerges in this instance is in writing to the relatives in the health examina-
that the team of cystic fibrosis has to work tions. The ideal thing is to be able to educate in a
together, and sometimes, a professional acquires calm environment, with the child and both par-
prominence at commanding the work oriented ents present.
toward improving the quality of life. Those who are part of the pediatric ambula-
tory team are the professionals who best know
the child, adolescent, and his/her family. Thus,
Self-Care in Sleep Disorders they are in a privileged position for establishing
preventive or health-promoting measures that
Sleep is an essential organic function for the controls these issues to a good extent.
appropriate health of the individual, and as every Among the topics we must address, there are
physiological activity, it can present several five relevant points at the moment of an
alterations. The amount of sleep needed for rest- intervention:
ing varies according to age, going from 12 to
16 hours in breastfed babies and newborns, to an 1. Wakeup schedules;
average of 10.5  hours in schoolchildren and 2. Bedtime schedules;
preschoolers. 3. Activities prior to sleep;
Among entities that affect sleep, we find not 4. Meals prior to bedtime;
only respiratory disorders but also involvement 5. Comfort in bed.
59  Nursing Care Education in Chronic Respiratory Diseases 615

1. Waking up at the same time, having in mind: seems uneasy). This kind of sleep is normal
 Child’s age and we don’t have to interrupt it, usually lasts
 Scheduled day activity for 30–40  minutes where he/she enters in a
2. Reasonable time for going to bed
 Awakening hours, number of sleep hours needed
deeper sleep, which we call “quiet sleep”.
for his/her age • Parents must keep the baby awake while eat-
3. Relaxing before going to bed ing; if the baby falls asleep, they must stimu-
 Avoiding hectic games 2 hours prior late him/her to wake up before lodging the
 Bath decreases body temperature and helps to baby in the cradle.
relax
4. Light dinner, avoiding:
• After eating, lodge the child in the cradle,
 Excess of liquids while still awake.
 Stimulating beverages • Parents must stay with the baby for soothing
5. Comfort in bed him/her but not for sleeping with him/her.
 Temperature between 18 °C and 23 °C
• Starting with the instauration of maternal
 Darkness
 Silence breastfeeding, a pacifier can be used.
• It is advisable that the main caregiver follows
Depending on age group that we have to assist, the same sleep schedules as the child.
we must check the following points, which have • Parents must facilitate a proper schedule and
to be handed out in writing and spoken with the place for sleeping.
parents. Ideally, they should be done in health
controls of the patient or in nurse interventions in The objective is that the child recognizes the
health centers. pleasure of sleeping by him/herself.
Reinforce in this instance:

 leep Hygiene during the First

S • Crying is not hunger
Months of Life • Feeding moments during nighttime must be
brief, the child should learn that night is for
Accomplishments in this phase: sleeping.
Parents have to clearly understand that chil- • When the child wakes up during nighttime to
dren learn to fall asleep by themselves, and they get breastfed, light should not be turned on;
must know how to recognize active sleep, so that breastfeeding must take place silently and
they do not act incorrectly, and the mother or with the least possible stimulation.
main caregiver should be able to adapt to the • The last memory before falling asleep must be
sleep schedule of the child. This is a complex the cradle and not breastfeeding. The child has
phase for parents, who ask lots of questions, and to incorporate the cradle as a familiar, night-
that is why the reception is important for the time environment.
delivery of information. • Children take 20–30 minutes to fall asleep. It
Topics to address in this instance are: must be explained to the parents that they
• Children have to learn to fall asleep by must not be present in that time, and must
themselves. know that, as a minimum, 6% of the time that
• Each child set his/her own pace for sleeping. the child is in the cradle, he/she will stay
Not every child is the same. awake and every child wakes up during
• Do not use strolls or cradlings for getting the nighttime.
baby to sleep; it is possible that, in later phases • If the child cries when putting him/her in bed,
he/she will have sleep problems. he/she must be comforted, but the parents
• Until 2 months of age, after eating, the child should try to put him/her in the cradle before
starts what we call “active sleep” (the child falling asleep.
616 A. Moya Isamitt

 leep Hygiene Starting at 6 Months

S thrown off balance. Breast, baby bottle, or dummy
of Age should not be used as a sleep inducer. Each family
has their own level of tolerance and beliefs: there
Accomplishments in this phase: are not good or bad systems, just different ones.
Parents have to clearly understand that night- Reinforce in this instance
time awakenings are physiological and normal.
The child starts to sleep fewer hours and stays • Do not self-impose cut-off times for getting
awake longer during the day. the child to sleep. Probably these times will
Reinforce in this instance: not be met and will generate stress.
• Restrict yourself to follow the rules.
• DO NOT feed the child if he/she wakes up. In • React calmly when the child wakes up during
this age, the last feeding is at midnight. the night.
Maternal breast or baby bottle are not neces- • Must transmit the message that the child is
sary during nighttime. able to enjoy sleeping by him/herself. If he/
• DO NOT turn the lights on. she gets mad, this will only upset him/her
• DO NOT get him/her out of the cradle. even more.
• Comfort should be through loving words. • If there has been a recent change in the life of the
• Seek a washable cuddly toy to be his/her part- child, do not expect that he/she sleeps deeply.
ner in the cradle. • Allowing the child to sleep outside of bed will
• Let the room door be open. not help at all for her/him learning to fall
asleep by him/herself. Consider that by sleep-
ing in the same bed as the parents, the child’s
 leep Hygiene Starting at 12 Months
S sleep physiology is altered, in addition to the
of Age parent’s. Sleep of older children that sleep
with their parents is less restful and with a big-
Accomplishments in this phase: ger risk of suffocation.
Parents or main caregivers must avoid long • Breast, baby bottle, or pacifier seem very use-
naps in children, 45  minutes of day sleep are ful for falling asleep, but the child will end up
enough, in all phases and especially in this one needing them every time that he/she has to fall
the child has to learn to sleep without help. asleep and once the child awakes.
Reinforce in this instance
Take turns: you will get more rest and the
• If the child has tantrums, parents must ignore child will not “direct” the night. If not possible,
him/her and leave the room; if the child gets take a break when you notice that you are losing
out of bed, he/she must be put into bed quickly, your patience. The important thing is to transmit
avoiding interaction with the child. educational serenity and confidence.
• Same routine must always be followed.
• Parents must transmit the message of teaching
 leep Hygiene Between 2 and 5 Years
S
him/her to sleep, independently, and that it is
of Age
not about a punishment or an argument
between parents and child.
Accomplishments in this phase:
If the child is not able to fall sleep, the parents
must keep in mind that this is a good instance for
 leep Hygiene Starting at 18 Months
S talking some minutes about the events of the day.
of Age Reinforce in this instance:
Accomplishments in this phase: • During the day, is advisable that children take
Before awaking, parents or main caregivers a nap, as a complement to night sleep, 45 min-
must provide confidence, so he/she does not gets utes as maximum.
59  Nursing Care Education in Chronic Respiratory Diseases 617

• Parents or main caregiver must not self-­ encourage sports activities and avoid internet,
impose a cut-off time for sleeping. It will be mobile phones, and videogames before sleeping.
very hard to meet and it will increase distress Reinforce in this instance
and unease.
• The message we want to transmit to the patient • Must have regular schedules
is: “you are capable of enjoying sleeping by • Keep the television out of the room
yourself”. • Do not take stimulants (caffeine, cola drinks),
• Do not allow use of electronic games for fall- especially after the midday meal
ing asleep. • Regularity in meal schedules
• Keep the television out of the room. • Must not fall asleep with TV on (reduces
sleep’s depth)
• Practice physical exercise regularly
Sleep Hygiene from 11 Years of Age • Do not study during the night

Accomplishments in this phase: Weekday schedules must be the same as the

In this phase the sleep pattern is well estab- weekend’s, since they start to go out during the
lished, but it is also a period in which it is very night and sleep disorders arise again.
probable that sleep disorders may appear Prevention is effective, reduces medical
because of the type of activities that the patient spending, and improves the quality of life of the
carries out. child and his/her surroundings. This has allowed
Reinforce in this instance: decreasing the prevalence of sleep issues in our
assisted population.
• We must inform the parents or caregivers The final message is to pay attention to sleep
about the changes in adolescence, especially issues of these patients with chronic diseases,
about the physiological delay of sleep start, since a correct diagnosis and appropriate treat-
more need to sleep, and sleep alterations ment of these problems can have a beneficial
caused by the use of cellphones, internet, etc., effect on psychological, academic, and physio-
before going to bed. It is ideal to turn off these logical aspects in the patient. Even more, it can
devices. have a favorable impact in other family members
• Recognize the signs of sleep deprivation: irri- and caregivers of the child, thus obtaining a global
tability, hard to wake up, recovery during the improvement in the life quality of the patient.
weekend.
• A family dialogue must be established about
sleeping and its importance. Create awareness Self-Care in Allergies
about the importance of sleeping.
• Encourage a good environment toward the end Food allergies are a group of diseases where
of the afternoon. symptoms are produced by an immune response
• Importance of the example on behalf of the of the organism when confronting an allergen
parent, remember than in this period the par- present in some foods. Clinical manifestations
ents are role models. mostly affect the gastrointestinal tract, respira-
tory tract, and skin; gastrointestinal manifesta-
tions predominating in breastfed babies and
Sleep Hygiene in Adolescence young children.
Of the population, 20% has symptoms of an
Accomplishments in this phase: adverse food reaction during their lifetime. In the
In this phase, sleep disorders arise again. The last three decades, concern about food allergies
child must have regular schedules, even on week- in occidental developed societies has increased.
ends. Exposure to intense light in the morning Food allergies are a kind of adverse reaction to
will help to regulate the sleep cycle. Parents must food products generated by immune mechanisms.
618 A. Moya Isamitt

The main causes of food allergies are cow milk, Time period to consider: highly suspicious
peanut, nuts, fish, and seafood. They have differ- foods are those consumed within the first 2 hours
ent levels of severity: from simple itching, inflam- before the reaction, and those consumed more
mation, or urticaria (which are the most frequent), than 24  hours earlier than the reaction are low
to other more severe reactions with digestive, suspicious foods. During the first 2 hours, usually
respiratory, and circulatory symptoms. the allergy mechanism is IgE mediated, and in
Allergy to a food product is frequent in early later reactions a cellular response may intervene.
ages, varies from mild reaction to anaphylaxis, Late reactions tend to appear with eczema, gas-
and typically its trigger is accidental or unaware trointestinal symptoms, and probably eosino-
exposure (inhalation, ingestion, contact, etc.) to philic mediation. It is common to see a patient
the allergen. that has tolerated a suspicious food product dur-
Eliminating food product or products is the ing a short period of time and afterward presents
basis of treatment for immediate reactions, espe- a reaction after the contact. This first phase is the
cially in cases of anaphylaxis. Most allergies will phase of sensitization, where the specific immune
improve after some years, except the allergy to response is established. For the cases of milk and
peanut, nuts, fish, and seafood. The objective of egg, reactions can occur after the first direct con-
the nurse is to provide continuous education in tact, which is occasioned by the child’s contact to
every chance where there is interaction with the proteins of these foods through breast milk or by
patient. consumption of products that contain milk or egg
as ingredients.
Knowing if the patient has tolerated the suspi-
 asic Knowledge About Physiology
B cious food product in new exposures can help to
of Food Allergies discard an allergy or, in the case of several suspi-
cious ingredients, to refine the diagnosis. It is
 hat Is a Food Allergy?
W possible that the patient has generated tolerance
Food allergies are a high sensitivity reaction to the food. The type of food tolerated must be
(hyper-sensitivity) to external substances called recorded, since if it is a very cooked product, it
allergens, which are present in food. People that cannot be stated that the patient will not react to
present these kinds of reactions produce a large less cooked versions. Patient’s symptoms and
amount of specific antibodies (proteins), which reaction time after exposure help to define
are called immunoglobulins E (IgE). whether the patient is allergic or not.

 hat Factors Influence the Onset

W
of Symptoms? Rules to Avoid Triggering Allergens
Genetic factors or early contact with the aller-
gens facilitate the appearance of symptoms. For Initial management consists in a proper educa-
detecting food products, it is essential to record tion directed toward the complete restriction of
in a log what foods the patient has consumed. the suspicious food product. In case of children
In the case of foods with several ingredients, a under 2 years old, it may be necessary to add a
list of all of them must be made, emphasizing nutritionist’s evaluation to avoid disorders in the
whether there is one of the eight most common child’s development.
allergy-inducing food products, especially Among the indications, there is one consisting
milk, egg, or any food that is usual in the envi- in recording the day when the reaction appeared,
ronment. It is also required to ask about the what the patient was doing and what she/he ate,
kind of cooking of the food, and to discard con- in order to detect crossed allergies or foods that
tact with other likely sources of reaction, such match the days that had reactions, and attaching
as underlying infectious processes and medica- the labels of those commercial made products
tions use. consumed.
59  Nursing Care Education in Chronic Respiratory Diseases 619

If the food has already been identified, it is • Identification of students with food allergies.
important to teach parents to organize where to • Carrying food products from home, since food
keep food (out of children’s reach). from school is not advisable, to avoid
School plays a fundamental role. Below are cross-contamination.
some of the tools the school can provide:
Father, mother or legal caregiver is responsi- The patient
ble for: Students with food allergies, according to
their abilities, should:
• Informing the educational center, as soon as
possible, about diagnosis through a medical • Know what the allergy is, why it is caused,
report, so they can quickly initiate the required what are the symptoms of emergencies that
actions for generating a safe environment for could occur. The rest of the students should
the patient. also know these matters, and discuss them
• Contributing in the elaboration of a custom- with teachers with the help and orientation
ized plan of precautions for the allergic stu- from specialized personnel, who will facilitate
dents in the educational center. the required information (Table 59.1).
• Facilitating a written authorization to the edu- • Conduct all tasks appropriate for his/her age
cational center to administrate the medication and development phase, actively collaborat-
and educate the child in its administration. ing, in any situation, with teachers, equals,
• Providing the educational center with specific and other members of the educational com-
material and medication. munity, as well as the health professionals.
• Cooperating with the school in anything needed • Avoid using the allergy as an excuse for dis-
to control the allergy of son or daughter. tinction or advantage.

Table 59.1  Plan for facing an allergic reaction at school

Step 1: Assessing and treating
Major Self-injectable
Symptoms risk adrenaline Doctor
1. Mouth itching, mild rash surrounding mouth or lips, swollen No Yes Yes
mouth
2. Urticaria, welts, rash, itching, or swelling of limbs or other zone No Yes Yes
of the body
3. Nausea, abdominal pain, diarrhea, vomits No Yes Yes
4. Eye itching, red eyes, tearing, nose itching, repetitive sneezes, Yes Yes Yes
abundant white mucus
5. Closed throat, hoarseness, repetitive cough, swollen tongue/ Yes Yes Emergency
eyelid/lips/ears
6. Shortness of breath, repetitive cough, dry cough, lips exhaustion, Yes Yes Emergency
or bluish skin
7. Weak pulse, low blood pressure, fading, paleness, bluish lips or Yes Yes Emergency
skin
• In quick progressive reactions, although symptoms are not severe (number 1–4), it is advised to prematurely admin-
istrate self-injectable adrenaline to avoid progression to a severe reaction (5–7 symptoms)
•  In children with severe symptoms (7), it is desirable to keep them lying down with their legs elevated
•  After administrating adrenaline, it is important to take the patient to the emergency room (ER)
Step 2: Alerting
Emergency call
Never leave the child alone
Call to ER and state that it is an evolving allergic reaction
Even if parents/caregivers cannot be contacted, the child must be taken to emergency services
620 A. Moya Isamitt

• Learn and use all available instruments for To avoid allergies:

autonomously controlling the allergy, secur-
ing supervision and help from an adult. • Discard meals out of home
• Carry an identification that facilitates recogni- • Avoid prepared food
tion of the food-allergic condition. • Precaution in the way of cooking (breading,
pre-breaded, sauces)
• Carefully reading food composition before eat-
Description of Different Treatments ing it (not all labels contain all components)

The main treatment is avoiding the food prod- Cross-reactions:

uct, besides explaining the self-injectable adren- They are frequently associated with food
aline. This role must be conducted by specialists groups, for example:
and reinforced by the health team in every
consultation. • Cow milk: There is a cross-reaction between
The most important thing is that the patient, proteins of other mammals’ milk (goat,
when he/she is able to be responsible of the medi- sheep). In 20% it also occurs with meat.
cation, always carries it with him/her, particu- • Egg: There is a cross-reaction between eggs
larly when going to his/her school activities and from different birds, and between egg-white
food consumption cannot be supervised. and yolk.
• Fishes; It is possible that some species can be
tolerated, but it must be confirmed.
Educational Factors • Some children react to seafood and crusta-
ceans but have not shown cross-reactions.
There are special events, such as birthdays or • Nuts: The person that is allergic to a type of
gatherings with friends, where it is important to nut usually presents reactions to other nuts.
inform about food allergies. Eating outside of • Latex-fruits: Half of people allergic to latex
home is also an issue for food-allergic patients, show an allergy associated with certain food
and it is important to ensure that cross-­ products, being the most usual to bananas,
contamination does not take place. On occasions, kiwis, chestnuts (when they are consumed raw).
crises are related to physical exercise. In princi-
ple, the person tolerates the food product, but
when doing physical exercise after consuming it, Rules of Management of the Disease
an urticaria–angioedema picture appears (face,
eyelids, lips, ears swelling) or anaphylaxis • It is a widespread allergic reaction provoked
(severe allergic reaction). especially by food, insect bites, or medica-
In relation to the food product, it is important tions in people allergic to them. It appears
to consider whether its presentation is raw or suddenly and puts the person’s life in serious
cooked, because some substances that provoke danger. In general, it starts with tingling in the
allergy are thermolabile (they are inactivated mouth, heat, nasal congestion, tearing, and
with heat) and are tolerated if previously cooked, subsequently, bronchospasms, hoarseness,
for example, some fruits and vegetables. Also, it and then respiratory distress, shock, and death.
is important whether it is the complete food or • Emergency treatment consists in administra-
just a part of it: skin or pulp, egg-white or yolk, tion in the exterior part of the thigh of adrena-
etc. The peels of fruits usually produce more line through a preloaded syringe, according to
allergies, and some people tolerate pulp and only the patient’s weight.
react when eating the complete fruit or are in • Education delivered to the patient must be
contact with the skin. reinforced in every interaction about the
59  Nursing Care Education in Chronic Respiratory Diseases 621

importance of the management of food calm the anguish of parents/caregivers, which are
­allergies. School or places where the patient our main focus of attention.
lives must be safe places. Education also involves applying systematic
• The role of the nurse team in the communica- registrations and working experiences, as a pos-
tion with the patient, as well as empower the sibility for finding practice and academic col-
patient. leagues from different places, conducting
encounters or exchanges of experiences through
Food allergies are still an issue that compli- different communication and socialization media;
cate school and home environments, which is creating and maintaining networks of informa-
why organized teaching, where direct communi- tion, work, and support that facilitate a better
cation with the health professional can take place, attention for the patient.
would decrease the patient’s risk and calm his/her
environment.
Sources

Conclusions Ayala R, Torres MC, Calco MJ.  Gestión del cuidado en

enfermería. Santiago: Ed. Mediterráneo; 2009.
Guzmán MA.  Alergia, guía clínica. 2ª ed. Santiago: Ed
The evaluation of the nurse in relation to a per- Mediterráneo; 2012.
son with a chronic disease, using theoretical ori- Herrera AM, León A, Ubilla C, Pérez MA, Lozano
entation, allows the construction of a profile that J.  Utilidad de la educación en asma bronquial
infantil: experiencia piloto. Rev Chil Enf Respir.
clarifies problems related to the patient’s health 2014;30:197–202.
and life where she/he can intervene and where Manrique JJ.  Higiene del sueño. Acta de
she/he cannot. Besides, it encourages interrela- Otorrinolaringología & Cirugía de Cabeza y Cuello.
tions of the professional team in order to contrib- 2011;39(3-Suplemento):49–51.
Saieh C, Pinto V.  Manual de pediatría ambulatoria.
ute in the consolidation of the professional Santiago: Ed. Mediterráneo; 2013.
identity, around the chronic disease’s nature, Sánchez I, Prado F, editors. Enfoque clínico de las enfer-
goal, and objective. medades respiratorias del niño. Santiago: Ediciones
Education, a tool incorporated in our profes- Universidad Católica de Chile; 2007.
Valenzuela P, Moore R, editors. Pediatría ambulato-
sional instruction, helps to decrease sequels of ria. Un enfoque integral. 3ª ed. Santiago: Ediciones
pathologies, to improve quality of life, and to Universidad Católica de Chile; 2011.
 Evidence-Based Medicine
for Respiratory Diseases
60
Carlos Ubilla Pérez,
María Angélica Palomino Montenegro,
and José Antonio Castro-Rodríguez

Contents
Introduction  623
 ow to Practice Evidence-Based Medicine
H  623
Turn the Problem into an Answerable Question  624
Search for Information  624
Critical Analysis of the Evidence  625
Classification of Quality of Evidence and Strength of Recommendations  631
Sources  632

Introduction been incorporated particularly in internal medi-

cine and progressively in pediatrics and pediatric
The concept of evidence-based medicine (EBM) pulmonology.
has been in medical literature since the1990s, and Training in EBM techniques is a powerful tool
it basically refers to the adequate integration of that allows a more comprehensive approach to
research data to clinical decision-making. There the increasing medical information, which not
is a controversy surrounding the real relevance of infrequently is contradictory or out of date. Not
evidence-based medicine in clinical practice, and every physician will have the same EBM skills,
many of these criticisms come from incorrectly and EBM will change throughout the lifetime of
highlighting the relevance of clinical skills, the physician. However, for a specialist who pre-
patient preference, and health care expenses. fers to remain updated, it is important to learn
Fortunately, we can say that nowadays EBM has how to critically assess primary information
sources or to accept protocols and guides based
on evidence as summarized by the experts.
C. Ubilla Pérez · M. A. Palomino Montenegro
Faculty of Medicine, Universidad de Chile,
Santiago, Chile  ow to Practice Evidence-Based
H
e-mail: [email protected];
[email protected]
Medicine
J. A. Castro-Rodríguez (*)
Department of Pediatrics, School of Medicine,
When facing a clinical situation and information
Pontificia Universidad Católica de Chile, is necessary, the steps in Table 60.1 are required.
Santiago, Chile

© Springer Nature Switzerland AG 2020 623

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_60
624 C. Ubilla Pérez et al.

Table 60.1  Steps for evidence-based medicine practice therapeutic alternative to standard treatment or
Turn the problem into a valid question. placebo, allowing no risk of exposure, or diagno-
Efficiently locate the best fitting evidence in: Clinical sis test considered as the standard of reference.
history/physical exam, laboratory diagnoses,
publications (“research evidence”), and other sources.
O: Outcome endpoint  This point corresponds
Critically evaluate the evidence regarding its validity
(proximity to truth), measure of results, and clinical to what is observed, measured or expected as an
applicability. important clinical result of the intervention.
Apply the results of the critical evaluation to regular
clinical practice. T: Type of study  This point identifies the best
Evaluate our performance.
type of design to answer the question.

 urn the Problem into an Answerable

T For example: In the case of infants suffering
Question from viral bronchiolitis (problem), does hyper-
tonic saline solution treatment (intervention),
Often, clinical practice presents questions, many when compared to physiological saline solution
of which are easy to solve. Preparation questions (comparison), shorten hospital stay (outcome)?
are part of the general knowledge of a certain [Therapy.]
condition, with available answers in books or In the case of infants without a family history
journal articles. In the case of action questions of asthma or atopy (problem), is respiratory syn-
for a specific clinical situation during therapy, cytial virus-induced bronchiolitis (intervention)
diagnosis, or prognosis, the clinical problem at the cause of asthma (outcome)? [Prognosis.]
hand must be thought of as a question that can Comparison is not always necessary.
find precise answers in the medical literature. In brief, a structured question constitutes a
Clinical questions are structured in a number of fundamental step in clearly defining the problem,
components, summarized by the acronym of streamlining the necessary evidence and study
PICOT.  The aim of this format is to define the design, which enables us to decide if it can be
problem, identify keywords to assist in the effi- applied to our patients.
cient search for information, and define an ade-
quate test design.
Search for Information
 omponents of a Clinical Action
C
Question From a good clinical question we can extract the
P: Patient, population or problem of inter- necessary information to design a research strat-
est  It entails a brief, but precise description of a egy. Sensitivity and specificity search will be
patient group by specific characteristics, such as based on the aim and the amount of time we have.
age, sex, severity, etc., matching our group as By sensitivity search we mean an exploration that
inclusion criteria or clinically relevant character- covers a wide range of research articles; however,
istics that may influence the results. specificity search will only include the more rel-
evant articles, at risk of excluding other impor-
I: Intervention or action  This part is essential, tant articles. We favor specificity search and
with an etiological, prognosis-related, or faster queries for our action questions.
exposure-­related factor, the exactness of a diag- Relevant databases are available on the inter-
nosis test, preventive measures, therapeutic effi- net. Primary sources such as Medline allow com-
ciency, or damage. In this step, the formulation of prehensive searches. Secondary sources like
the question must be quite specific. Cochrane Library publish systematic literature
reviews. High quality clinical guides with the
C: Comparison  This element is what we will adequate methodology—of which are many for
compare our intervention to, which may be a this specialization—are also considered a good
60  Evidence-Based Medicine for Respiratory Diseases 625

source. Meta-searchers, such as Tripdatabase and Table 60.2  Therapy article analysis
Epistemonikos, allow fast and specific access to 1. Are the results valid?
high quality evidence. The advantage of using  (a) Did the experimental and control groups start the
them is their fast and simultaneous search across study under similar prognostic factors?
 (b) Were patients randomized?
the most relevant sites, with a rapid response time
 (c) Was the randomization blind?
for the most pertinent information about the  (d) Were base prognostic factors the same?
search. The steps to take in our search will be:  (e) Was prognostic balance maintained throughout
Choice of database, logically combined key- the study?
words, setting boundaries for the search. We do  (f)    Was group assignment kept blind to patients,
not intend to elaborate further on this topic, but it health personnel, data collectors, and analysts?
 (g)  Were prognostic factors kept at the end of the
is doubtlessly necessary to have training in search
study?
strategies or having the help of a specialist.  (h) Was follow-up completed?
 (i)      Was the study stopped early in case it showed
benefits?
Critical Analysis of the Evidence  (j)     Were patients analyzed in the randomized group?
2. What were the results?
 (a) How large was the treatment effect?
Once the research articles have been picked, a
 (b) How precise was the estimate of the treatment
critical analysis is due in order to define internal effect?
validity or risk of bias, magnitude and precision 3. How can I apply these results to patient care?
of the results and, lastly, external validity or  (a) Were the study patients similar to my patients?
applicability to our clinical practice.  (b) Were all the relevant outcomes considered?
 (c) Is there a higher probability of benefits than harm
and costs?
 ow to Analyze a Therapy Article
H
The optimal design to answer a question regard-
ing the effectiveness of a certain therapy, screen- ing during treatment applied independently from
ing test, or preventive measure is a randomized the intervention. This can be achieved by ran-
controlled therapeutic trial (RCT), or even better, domly assigning patients to each group. The
a systematic review of trials. The publication of a researcher must distribute every factor or charac-
clinical trial requires a detailed, exact, and clear teristic of the patient, such as sex, age, comor-
description of its design, execution, analysis, and bidities, etc., evenly in both groups. In order to
results. In 1996, the Consolidated Standard of avoid the risk of bias, researchers must randomly
Reporting Trials (CONSORT) guidelines were assign the participants using a hidden list. This
published considering 25 indispensable items to will allow the base prognostic factors to be simi-
be included on every RCT report. This is a type lar. Patients, health personnel, and data analysts
of experimental design were patients are random- must be blind to the group assignment, some-
ized in two groups following a specific time thing that can be achieved by using placebos.
frame. One of the groups is subject to an inter- Sometimes a blind study may not be possible, as
vention, whereas the other group undergoes regu- for instance in surgical treatments. In this case, it
lar therapy or placebo, obtaining by the end of the must be the clinical output reviewers who are be
trial a result or outcome. Its critical analysis blind. Follow-up must be comprehensive and
requires answering some questions (Table 60.2). with enough time to evaluate the results and
avoid the bias that comes from patients leaving a
Are the results valid or with a low risk bias? study, either because of a personal decision,
During a controlled randomized therapeutic trial, death, or adverse effects. Patients must be ana-
both the experimental and placebo groups must lyzed on an intention-to-treat basis, that is,
be equal regarding their relevant prognostic fac- according to the group they were randomly
tors except at the point of intervention, which assigned to. This is the most recommended form
must be maintained throughout the trial, includ- of analysis as it is the closest to clinical practice.
626 C. Ubilla Pérez et al.

On the other hand, analyses on the basis of proto- inversely calculated to ARR and it describes
col are at a higher risk of bias. In addition, some- how many patients will need treatment in
thing to consider is whether the outcome is order to avoid an event. The lower the NNT,
relevant, as for instance, asthma exacerbations the more efficient the drug will be. The rele-
defined as oral steroid use or emergency consul- vance of the NNT value will depend on the
tation vs. average lung function. event being studied. In our example, NNT will
be 1/ARR = 1/0.57 = 1.75. Since patients can-
• What were the results? not be treated in fractions, we can round that
We must consider if the results were relevant number up and say that two patients will need
and precise. The estimator to measure con- treatment to avoid an asthma exacerbation.
trolled randomized therapeutic trial results is • How do I apply these results to my patients?
relative risk (RR), which is obtained by divid- If the study is at a low risk of bias and its
ing the rate of events (R1) of the treated group results are relevant and precise, we must
by the rate of events in the control group (R2). define whether the intervention can be applied
For instance, administering a new asthma to our own patients. That is why we must con-
treatment to 40 patients, compared to 40 sider if our patients are similar to those in the
patients who received a placebo, showed study and if they are at a similar risk of death
asthma exacerbations in 10 patients (R1 as the patients of the controlled randomized
10/40 = 0.25 or 25%) from the treated group therapeutic trial by evaluating potential differ-
compared to 33 from the control group (R2 of ences of the following type: socio-­
33/40 = 0.825 or 82.5%). Relative risk, that is, demographic, other risks, age, sex, etc.
R1/R2, is 0.25/0.825 = 0.3. This demonstrates Something else to verify is whether all the
the protective capacity of the new therapy as it outcomes were taken into consideration. How
showed how it reduced the risk of asthma will the intervention act in real life? Is it fea-
exacerbations by 70%. Each of these values sible to incorporate it in my environment?
must be followed by a 95% confidence inter- What are the expectations or opinions of the
val (CI 95%), setting boundaries to the range patients? An evaluation of the benefits vs.
of the real value of the result 95% of the times. risks or costs must be done in order to reach a
The smaller the CI, the more precise the final decision.
results will be. Relative risk reduction (RRR)
is the difference between the rate of events in  ow to Analyze a Study on Diagnostic
H
the control group and the experimental group, Tests
divided by the rate of events in the control In clinical practice we postulate diagnostic
group, describing relative results. In our hypotheses, which are relevant when we decide
example, RRR = (0.82 – 0.25)/0.82 = 0.57/0. what treatment to apply, establish a protocol and,
82 = 0.695, rounded up to 0.7 or 70% for prac- generally speaking, give quality attention. In
tical purposes. A simpler way to calculate it is cases when the disease is frequent, the physician
1-RR. (RRR = 1 – 0.3 = 0.7 or 70%.) Absolute usually has some level of experience, and the dis-
terms include absolute risk reduction (ARR) ease appears with its typical presentation, diag-
and number needed to treat (NNT). Absolute nosis tends to be fast and safe. Here the physician
risk reduction (ARR), or risk differences, is makes use of a powerful tool: Pattern recogni-
the absolute difference between the event rate tion, a key element when training physicians. In
in the control group (0.82) and the event rate less frequent diseases or those with atypical
in the experimental group (0.25). The ARR in ­presentation, an analytic strategy becomes neces-
our example will be 0.82 – 0.25 = 0.57. If we sary. In this case more information is called for,
treat 100 patients, 57 would stop having with diagnostic tests needed to improve accuracy.
asthma exacerbations because of the treatment There is a growing development of new diagnos-
when compared to the placebo. The NNT is tic tests, but achieving a high prognostic accuracy
60  Evidence-Based Medicine for Respiratory Diseases 627

Table 60.3  Analysis of articles on diagnostic tests affect the decision of performing a reference
1. Are the results valid? standard.
 (a) Was there diagnostic uncertainty? • What are the results?
 (b) Was there a blind comparison with an Once the results are valid, we have to see what
independent reference standard?
the results were and how important they are. A
 (c) Did the test result affect the decision to perform
the reference standard? 2 × 2 table should be identified or made. In
2. What were the results? this way we can get the typical values, such as
3. What was the likelihood ratio (LR)? sensitivity and specificity, fixed values that are
4. How can I apply these results when treating my intrinsic to the diagnostic test and immutable
patients? to prevalence. Predictive values, defined as the
 (a) Can the test be reproduced?
probability that in the case of a positive test
 (b) Do the results apply to my patients?
 (c) Will the results change how I manage my
result the patient will present the disease (pos-
patients? itive), or the probability that, in the case of a
 (d) Will my patients improve because of the exam? negative result the patient will not present the
disease (negative), are modified with preva-
can be expensive, invasive or simply impossible. lence values, as they provide useful data when
To better understand the clinical role before a the population in the study is similar to our
specific prognostic probability, it is important to patients. If the pre-test probability of present-
understand the concept of decision thresholds. ing a certain condition is very different to that
The therapeutic threshold is given when our in the study, these values will not be directly
diagnostic probability is enough to decide on a applicable to our situation.
treatment without further exams. The diagnostic
threshold is the diagnostic probability on which The most useful aspect of a diagnostic test is
we discard, on a reasonable basis, a disease with- measured by its capacity to modify a pre-test
out further exams. These thresholds are not probability into a new post-test probability. The
invariable for different pathologies and will possibility to cause such a change is evaluated
depend on the properties of the diagnostic test, through likelihood ratios (LR). A positive LR
cost, safety, prognosis, effectiveness, and safety refers to how more likely the probability of a
of treatment. A critical analysis of an article on positive result will be in patients when com-
diagnostic tests requires us to follow certain steps pared with healthy individuals. A negative LR
for a critical reading (Table 60.3). refers to how more likely the probability will be
of a negative result in healthy individuals when
• Are the results valid? compared with patients. A positive LR of 10 or
It is important for the studied group to have higher and a negative LR of less than 0.1 are of
diagnostic uncertainty. This means that sub- clinical relevance. However, this is a relative
jects with the studied condition should have number, as the real benefit of LR comes when
similar symptoms to those without the condi- either the diagnostic or therapeutic threshold is
tion, and there should be an adequate range of crossed, moving our position past uncertainty.
clinical manifestation. A blind comparison to For a better implementation of LR, we can use
an acceptable and independent reference stan- Fagan’s nomogram (Fig.  60.1). Thus, calculat-
dard is required. This is of the utmost impor- ing pre-test probability and knowing the LR val-
tance for the validity of the study, ues and results of our test, we can infer the
understanding a reference standard as the best post-test probability. For instance, a study to
diagnostic method as accepted by the medical evaluate the usefulness of night oximetry as
community. It is sometimes necessary to com- compared with polysomnography for diagnos-
bine exams and patient progression in order to ing obstructive sleep apnea in children gave a
define the reference standard. Something else positive LR of 19.4 and a negative LR of 0.58.
to keep in mind is not to allow the test result to In this study, the pre-test probability is set at
628 C. Ubilla Pérez et al.

Fig. 60.1 Fagan 0.1 99

nomogram
Draw a line connecting
0.2
the pre-test probability
and the likelihood ratio
for the study and extend
0.5 1000 95
this line to the post-test
probability column to
determine the results 1 90
500

2 200
80
100
50 70
5 60
20
10 50
10
5 40
2 30
20
1
30 20
0.5
40 0.2
10
50 0.1
60 0.05 5
70 0.02
0.01
80 2
0.005
0.002
90 1

95 0.5
0.001

0.2

99 0.1
Pre-test Likelihood Post-test
probability ratio probability
Draw a line connecting the pre-test probability and the likelihood ratio for the study
and extend this line to the post-test probability column to determine the results.

60%. If the test result is positive, it becomes a • How can I apply these results to my patients?
post-test probability of 97%. If the test result is Once the results are valid and relevant, we
negative, the probability becomes 47%. It is must evaluate if the diagnostic test is repro-
important to note that the usefulness of these ducible and applicable to my patients. We
LRs will depend on the validity and accuracy of must take into account if the studied subjects
the results. It is interesting to notice that LRs do share similar characteristics with our patients.
not change with disease prevalence, or in other Finally, we must evaluate if the diagnostic test
words, it is applicable to different pre-test diag- results will modify our management strategy
nostic probabilities. and if patients will benefit from the exam.
60  Evidence-Based Medicine for Respiratory Diseases 629

 ow to Analyze Systematic Reviews

H eligible studies. This risk is minimized when
and Meta-analyses searching through at least three databases
Unstructured reviews are useful to get a general (Medline, Embase, and Cochrane Central). It is
view of a clinical condition, but they do not pro- necessary to use multiple synonyms and key-
vide us with a certain and impartial answer to a words for each concept. Additional references
specific clinical question. Systematic reviews can be identified by using clinical study regis-
(SR), on the other hand, can give us an answer to tries, reference lists from the studies themselves,
a specific clinical question in a structured and conference proceedings, by contacting experts in
reproducible fashion. This will usually come the area or through the databases kept by the
together with a meta-analysis, a statistical aggre- pharmaceutical industry and agencies such as
gate of the results of different studies, giving us a the FDA.
unique estimate of the effect.
Individual clinical studies may not be repre- Was the selection criteria and evaluation of
sentative of general evidence, or they may be at a the studies reproducible?
risk of bias. On the other hand, collecting and The authors of systematic reviews must decide
evaluating multiple studies requires time and which studies to include, their risk of bias, and
skills that physicians usually lack. Systematic what data from the study abstracts is worth cover-
reviews usually occur with a wider range of ing. And even if there is a standard protocol,
patients than an individual study, potentially some decisions will remain being subjective and
increasing confidence that the results can be thus prone to error. Having two or more review-
applied to our patients. A meta-analysis can also ers participating in the study will reduce this risk.
present the opportunity to explore the reasons as
to why there might be inconsistencies between Did the reviewers deliver the results ready for
different studies. One of the constraints of sys- clinical application?
tematic reviews and meta-analysis lies in the fact A meta-analysis can estimate the proportion of
that they only produce trustable estimates when the effect (magnitude of difference between
the studies included are trustable themselves. groups). This effect will depend on the nature of
Systematic reviews have two parts: credibility the outcome or measured effect (relative risk,
and confidence in their estimates. Credibility is odds ratio, risk difference, hazard ratios, stan-
based on having both design and execution free dardized mean difference), which will allow the
of wrong results, failure when correctly synthe- comparison between different studies notwith-
sizing results, or an inadequate literature search. standing the different units of measure or scales
Even if credibility is adequate, results may have they may have used.
low confidence. The most common reasons for The results of the meta-analysis are usually
this are high bias risk in the studies, inconsistent displayed as a forest plot. The results of each
results or a small sample size in the body of evi- study are represented by squares with sizes pro-
dence, all of which leads to inaccurate estimates. portional to the weight of the study and horizon-
tal lines representing their confidence interval.
Was the methodology of the systematic review More precise studies (shorter confidence inter-
credible? val) will have more weight and higher influence
Systematic reviews of treatment questions must over the combined final result. The total added
be very clear and answer questions as particularly effect of all the studies, or their pooled estimate,
determined by patients, interventions, compari- is represented by a diamond, where its width cor-
sons, and outcomes. responds to its confidence interval. For binary
outcomes, accuracy will depend on the number
Was the review exhaustive regarding relevant of events and sample size. For continuous out-
studies? comes, weight will also depend on the accuracy
Systematic reviews are at risk of bias if they fail of the study, sample size, and standard deviation
to obtain a complete or representative sample of or variability.
630 C. Ubilla Pérez et al.

Usually, the most frequent meta-analyses are case their confidence intervals do not overlap, the
the ones using the information of each study, or more likely it is that results will not be reliable.
“study-level-information”. Nevertheless, when The most common statistic used to measure het-
the information of each individualized patient erogeneity is I2. If there is considerable heteroge-
included in the study is considered, then the neity (usually I2 > 40%), the physician should
meta-analysis done is called “patient-level-­ expect some explanations from the authors, and
information”, which makes it easier to do a more in this case, there should be subgroup analyses.
detailed study of, for instance, subgroups or those
who are intended to undergo treatment. How precise are the results?
Continuous outcomes can also be presented in There are two reasons a study may be deceiving:
a more useful manner when relating or compar- because of a systematic error or bias and because
ing them with pre-established clinical scales. of a random error. This last type has a bigger
impact when sample size is small or the number of
Did the reviewers focus on the confidence on events is reduced, giving way to inaccurate results.
the estimate of the effect? When results are inaccurate, we lose confidence in
A well performed systematic review must inform our estimate of the effect. Meta-­regression does
the risk of bias of each study included in it, some- not simply estimate the average of the effect across
thing that could explain their heterogeneity. studies, but it also gives us a confidence interval.
That way, physicians can judge the accuracy of the
What is the confidence level of the estimate of results by checking their minimum value and max-
the effect? imum confidence interval.
The level of confidence of studies is generally
based on the design of the study. Randomized Are results directly applicable to my
studies are assigned a high level of confidence, patients?
but it can decrease in the case of high risk of bias, The best evidence to make decisions comes when
inconsistencies, inaccuracy, or direct applicabil- interventions are of clinical interest and when
ity of publication bias. In observational studies, they evaluate population and relevant outcomes.
when the impact of the effect is large, its assigned If population, intervention, and outcomes in the
confidence may increase. study are different from those we are interested
in, evidence may be taken as indirect.
How serious is the risk of bias in the body of
evidence? Is there any problem with reporting or
A well done systematic review should inform us publication bias?
of the risk of bias of each study. Differences in When researchers decide to publish their work on
risk of bias may explain important differences the basis of magnitude, direction or statistical sig-
between results. Less rigorous studies may some- nificance of the results, there is a systematic error
times overestimate therapeutic effects or preven- called reporting bias. This is the hardest kind of
tive interventions. There is no single correct way bias to solve in systematic reviews. When a study
to face this risk of bias. The Cochrane Risk of is not reported, the correct term is reporting or
Bias Tool is frequently used to evaluate random- publication bias. The magnitude and direction of
ized studies. the results are usually taken as both decisive and
the most important part of a publication, even
Are results consistent across studies? more so than design, relevance or quality of the
Readers of systematic reviews must judge study. When the authors or sponsored studies only
whether the results differ from one study to the publish outcomes or specific analyses, the term
next (variability or heterogeneity). This can be “selective outcome reporting bias” is used.
done visually through a forest plot. The bigger Reporting bias may cause errors in the estimate of
the difference between estimated points, or in the the effect. However, detecting publication bias in
60  Evidence-Based Medicine for Respiratory Diseases 631

Table 60.4  Critical analysis of systematic reviews while also establishing different recommenda-
1. Are the results valid? tions. By quality of evidence we mean how reli-
 (a) Was there an explicit question? able the estimate of a certain effect is, and by
 (b) Was there a detailed and exhaustive search of strength of recommendation we understand how
relevant studies?
much we can trust that the recommendation will
 (c) Was the methodological quality of the primary
studies high? lead to more benefits than risks.
 (d) Were the included studies evaluated as There are multiple evidence classification and
reproducible? recommendation strength systems. A type of
2. What were the results? classification that has been progressively incor-
 (a) Were the results similar across studies? porated by different scientific societies and health
 (b) What were the global results of the study?
institutions is the Grading of Recommendations
 (c) How accurate were the results?
3. How can I apply these results to the care of my
Assessment, Development and Evaluation
patients? (GRADE) system. This system incorporates
 (a) Were all the relevant outcomes considered? other relevant aspects beyond study design and
 (b) Were all the posited effects on the subgroups potential biases. What this methodology does is
credible? categorize relevant outcomes (hospitalizations)
 (c) Are the benefits and costs potential risks?
and their relative relevance. Then the quality of
the evidence is assessed for each of the outcomes,
a systematic review is complex. When reviews obtaining a global quality of the evidence, and
include a meta-analysis, one thing to check is finally the strength of the recommendations is
whether the results of small-scale studies are too graded. This process is complex and requires
different from those of large-scale studies, and the training. The clinician—the main user of
funnel plot graph may also be consulted. Another evidence-­based medicine—must understand the
thing to check is the number of studies included in implications of this classification.
the review. Empirically speaking, 30 studies These are classified in the following way:
should be an adequate amount. Of course, if the
systematic review was successful in including • Quality of evidence
unpublished studies, this would work as a solution High: There is high confidence that the esti-
to overcome this bias (Table 60.4). mator of the effect is very close to the real
effect.
• Is there a reason to increase the confidence Moderate: There is moderate confidence in
value? the estimator of the effect, and it is likely that
There are situations that increase the confi- it is close to the real effect, but with the chance
dence value of the estimated effects from that there may be substantial differences.
observational studies: When treatment reaches Low: Confidence in the estimator of the effect
a strong effect in a short amount of time; or in is low, and it may be substantially different to
patients with a known condition whose condi- the real effect.
tion would worsen without the intervention, Very low: There is very low confidence in the
for example, epinephrine when used to pre- estimator of the effect, and it is very likely that
vent mortality in anaphylaxis. it will be substantially different from the real
effect.
Strength of recommendations
Classification of Quality of Evidence Strong: The benefits exceed the risks and costs
and Strength of Recommendations (or vice versa). It applies to most patients
without reservations.
One of the beneficial consequences of evidence-­ Weak: The benefits are in close balance with
based medicine is the development of clinical the risks and costs, or they are uncertain. Any
guides to evaluate the quality of the evidence alternative may be just as reasonable.
632 C. Ubilla Pérez et al.

Strong recommendations emerge from high Guyatt GH, Oxman AD, Vist GE, GRADE Working
methodological quality, clearly reflecting that the Group, et al. GRADE: an emerging consensus on rat-
ing quality of evidence and strength of recommenda-
benefits outweigh risks and costs. They point to a tions. BMJ. 2008;336(7650):924–6.
sufficient amount of evidence to advise or dis- Higgins JPT, Green S. Cochrane handbook for systematic
courage a specific intervention. On the other reviews of interventions. Version 5.1.0 ed. Chichester:
hand, weak recommendations come from regular Wiley; 2011.
Moher D, Schulz KF, Altman D.  The CONSORT state-
or low-quality evidence, as for instance, observa- ment: revised recommendations for improving the
tional studies or series of cases, and they do not quality of reports of parallel group randomised
reflect a sufficient efficacy test. This points to the trials. The CONSORT Group Lancet. Lancet.
need for other decision-making criteria, such as 2001;357:1191–4.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA
costs, risks, availability, or patient preference. A Group. Preferred reporting items for systematic
strong recommendation is equivalent to an reviews and meta-analyses: the PRISMA statement. J
“always do it” (or never do it) sort of recommen- Clin Epidemiol. 2009;62(10):1006–12.
dation, whereas a weak recommendation should Murad MH, Montori VM, Ioannidis JP, et al. How to read
a systematic review and meta-analysis and apply the
be taken as a “you may do it, but take into account results to patient care: users’ guides to the medical lit-
other factors before making a decision.” erature. JAMA. 2014;312(2):171–9.
Sackett D, Staus SE, Richardson WS, Rosenberg W,
Haynes RB. Medicina basada en la evidencia. Cómo
practicar y enseñar la medicina basada en evidencias.
Sources 2da ed. Madrid: Ed. Harcourt; 2000.
Schünemann HJ, Jaeschke R, Cook DJ, et  al. An offi-
Brouillette R, Morielli A, Leimanis A, et  al. Nocturnal cial ATS statement: grading the quality of evidence
pulse oximetry as an abbreviated testing modal- and strength of recommendations in ATS guidelines
ity for pediatric obstructive sleep apnea. Pediatrics. and recommendations. Am J Respir Crit Care Med.
2000;105:405–12. 2006;174(5):605–14.
Claro JC, Lustig N, Soto M, Rada G. El primer paso: la pre- Staus SE, Richardson WS, Glaszious P, Haynes RB. How
gunta clínica. Rev Méd Chile. 2012;140(8):1067–72. to practice and teach evidence based medicine. 3rd
Guyatt G, Rennie D.  User’s guides to the medical lit- ed. Edimburgo: Ed. Elsevier Churchill Livingstone;
erature. Essentials of evidence-based clinical prac- 2005.
tice. The Evidence-Based Medicine Working Group. Valenzuela L, Cifuentes L.  Validez de estudios de test
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Medical Association; 2002.
 Inhalation Therapy
61
Fernando Iñiguez Osmer
and Viviana Aguirre Camposano

Contents
Physical Characteristics of Aerosols  633
Aerosol Deposition Mechanisms  635
 eneral Factors That Affect Airway Aerosol Deposition
G  635
Aerosol-Dependent Factors 636
Patient-Dependent Factors  636
Equipment-Dependent Factors  637
Advantages and Disadvantages of Aerosol Drug Therapy  637
Aerosol Generating Systems  637
Sources  641

Physical Characteristics of Aerosols sity of one (r = 1), which has the same terminal
settling velocity as the particle under consider-
Definition  An aerosol is a suspension of liquid ation. When analyzing the characteristics of the
or solid particles in a gaseous medium. Inhalation particle, this independent variable can correlate
therapy is the administration of an aerosol to a the effect of geometric diameter and particle den-
patient for therapeutic purposes. sity, as described in the following equation, with
particles greater than 1 μm, where d corresponds
Particle size and mass  The size of the particles to the actual sphere diameter, r to the particle
is a very important physical characteristic when density, and ρ0 to 1 density (of water). Expressed
considering the efficiency in the lung deposition more simply, da corresponds to the product of the
of an aerosol. The aerodynamic diameter (da) is, particle diameter multiplied by the square root of
by definition, the diameter of a sphere with den- the particle density. The latter is valid for spheri-
cal particles in which the shape correction factor
is not applied, and so it is registered by multiply-
F. Iñiguez Osmer (*) ing ρ0.
Department of Pediatrics, Hospital de Puerto Montt,
Puerto Montt, Chile
V. Aguirre Camposano ρ
d ae = d
Department of Pediatrics, School of Medicine, ρ0
University of Santiago, Santiago, Chile

© Springer Nature Switzerland AG 2020 633

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_61
634 F. Iñiguez Osmer and V. Aguirre Camposano

Mass median aerodynamic diameter (MMAD) greater influence on it, and it will remain sus-
is a particle size (in microns, μm) that divides the pended for a shorter time.
mass in such a way that half of the particles of that
aerosol have a larger diameter and the other half a Physical Nature of the Particles
diameter smaller than the diameter of the
MMAD. The geometric standard deviation (GSD) • Hygroscopicity: It is the intrinsic tendency of a
is the ratio between the MMAD and the diameter material to absorb moisture from its environ-
of the particles at a median standard deviation (or ment. It is influenced by the material crystal-
84th percentile). When the GSD is less than 1.22, linity and the morphology of the particles.
an aerosol is considered monodisperse; if this Hygroscopic drugs pose a greater risk of phys-
value is higher, it is considered polydisperse. The ical and chemical instability. For dry powder
greater the MMAD, the greater the average size of drugs, moisture gain or loss due to changes in
the particles; the greater the GSD, the wider the relative humidity can lead to dissolution and
dispersion of particle sizes in that aerosol. Most subsequent recrystallization, hindering deag-
aerosols for medical use are polydispersed. glomeration and therefore affecting drug deliv-
The mass median aerodynamic diameter stan- ery from the device.
dardizes the size of the particle to the behavior of Moisture can be captured within the device
a spherical water drop, which by definition has a prior to delivery (e.g., dry powder inhaler or
density of 1. Since medical aerosols never have a DPI) or after the dose goes into the airway,
uniform diameter, shape, or density, the mass where the particle is in a moist and warm envi-
median aerodynamic diameter is determined by ronment (37 °C and 99% relative humidity in
inertial impact, laser diffraction or digital image the carina). The susceptible particle will expe-
processing methods, among others. rience hygroscopic growth, which increases
The primary method for defining the diameter its mass and dimensions. When inhaled, this
of the particles and their distribution is the use of particle tends to be deposited in the airway in
an inertial cascade impactor. For example, the a more proximal location than that of a non-
Andersen Cascade Impactor has 8 different hygroscopic aerosol particle. This is because
stages (collectors), capturing particles from 0.43 hygroscopic ones tend to coalesce, creating
to 9.0 μm when operating at a flow rate of 28 L/ particles of greater mass and volume that tend
min. The Next Generation impactor has 7 stages to be suspended for less time.
and captures particles from 0.24 to 11.7  μm at • Tonicity: It refers to solute concentration in a
30 L/min. The aerodynamic particle size distribu- solution regarding the concentration in body
tion is determined by the quantities of drug fluids. When creating an aerosol with a hyper-
deposited in each collector. The total mass of tonic solution (>0.9% NaCl) its particles will
drug collected is reported as the delivered dose. be hygroscopic, increasing its size. An iso-
When the partial mass of drug collected in the tonic solution (0.9% NaCl) will create aerosol
smaller diameter collectors is measured, the particles with neutral affinity for water that
respirable or fine particle dose is obtained. The tend to remain stable. A hypotonic solution
limit of this can be set arbitrarily in particles (<0.9% NaCl) will create aerosol particles
smaller than 6.4, 5.0 or 3.0 μm. Frequently, the with a tendency to release water, therefore
fine particle dose includes those with diameters decreasing in size and mass.
between 1 and 5 μm. • Electric charge: Because of the methods used
When an aerosol particle increases in size, so to create an aerosol, the particles have an elec-
does its mass. By doubling the radius of a sphere, tric charge. This phenomenon seems to have
the volume grows approximately 8 times little physiological effect on the patient, but it
(V  =  4  ×  k  ×  r3). As the volume increases, the influences the lung deposition since there are
mass increases proportionally. When the mass of interactions between the particles and the
an aerosol particle increases, gravity will have a walls of the devices used.
61  Inhalation Therapy 635

Aerosol Deposition Mechanisms Large particles traveling at high speed are

more likely to impact the airway proximal
The particles are deposited in the airway when regions. This mechanism is responsible for the
they are definitively removed from the laminar filter role carried out by the upper airway on the
flow that has been created by the inspiratory inspired air, since particles larger than 10  μm
movement. The knowledge of the processes and tend to be deposited. Impaction increases dra-
factors that influence the deposition of particles matically with high inspiratory flows; and it is the
in different regions of the airway makes it easier predominant mechanism of deposition in the first
for the clinician to choose the best therapy for seven generations of the airway.
their patient. There are five mechanisms by
which a particle can be deposited in the airway: (b) Gravitational sedimentation  It is a time-­
inertial impaction, sedimentation, diffusion, dependent mechanism, in which the particles set-
interception, and electrostatic precipitation. The tle by the action of gravity. It is related to particle
first two mechanisms are directly related to the size and the flow velocity of the inhaled gas. This
size of the particle, while the third is inversely is the primary deposition mechanism for particles
related to it. Interception depends on the shape with a MMAD <2  μm, although it can affect
of the particle and occurs when two of them larger particles in low flow conditions. This mech-
meet, which is more common for elongated par- anism optimizes lung deposition. Gravitational
ticles. Electrostatic precipitation is related to the sedimentation increases when the patient per-
electric charge, when two particles of opposite forms an apnea technique; and predominates as a
charges meet. The most relevant mechanisms are deposition mechanism after the eighth generation
the first three. of the airway, given the flow decrease and the
smaller diameter.
(a) Inertial impaction  Occurs when aerosol
particles have sufficient momentum (mass × (c) Diffusion  Occurs in particles <0.5 μm, less
velocity) to maintain their trajectory despite a influenced by gravity, in which Brownian motion
change in the air flow direction, thus colliding plays a more important role and favors the coales-
with the walls of the airway. The probability of cence of the particles. This mechanism is influ-
inertial deposition increases when the particle is enced by electrical charge. A significant
able to travel long distances, which depends on percentage of these particles are exhaled.
its mobility, mass, and speed. This is expressed in
the following equation, where S corresponds to
distance, B to mobility (velocity × unit force), m  eneral Factors That Affect Airway
G
to mass, and v to particle velocity. Aerosol Deposition

S = B⋅m⋅v Medical aerosols vary not only in the distribution

of the particles according to their size but also in
The Stokes number (Stk) is dimensionless and
other factors that affect the lung deposition:
describes the airway particle deposition probabil-
physical state (solid or liquid), density, shape,
ity by impaction. The greater the number of
and speed. In addition, a system of dynamic
Stokes, the more likely is the particle deposition
forces confronts the particle in its journey through
by inertial impaction, according to the following
the airway, such as gravity, resistance to inspira-
equation, where ρp is the density of the particle, d
tory flow, and inertial force. The balance between
its diameter, V is gas velocity, h its viscosity, and
these forces, influenced by the properties of the
R is the radius of the airway.
aerosol, is what eventually determines the pre-
dominant lung deposition mechanism for the
ρp ⋅ d 2 ⋅ V
Stk = aerosol particles. Several factors affect the ability
18 ⋅ η ⋅ R of an aerosol to be deposited in a patient’s airway.
636 F. Iñiguez Osmer and V. Aguirre Camposano

Table 61.1  Factors of stability and airway deposition of change in the direction of the gas flow in
an aerosol which it is suspended. Large particles
Physical nature of the particle: size and mass, (>10 μm) tend to be removed in the upper air-
hygroscopicity, tonicity, electric charge way, while smaller particles can reach more
Aerosol: Particle size, gravity, inertia, gas temperature,
and gas humidity
distal regions.
Patient: Age, respiratory pattern, airway anatomy, • Temperature and humidity: There is a close
respiratory mechanics relationship between these two factors
Equipment: Aerosol generator, type of drug, propellant, related to the percentage of aerosol particles
holding chamber or spacer device that remain in suspension. When the tem-
perature of gas increases and humidity
These factors can be grouped into three catego- remains stable, particles lose water and
ries: Those dependent on the physical character- decrease in size. By increasing gas humidity
istics of the aerosol, those dependent on the and keeping the temperature stable, particles
patient, and those dependent on the equipment collect water, depending on their hygro-
used (Table 61.1). scopic capacity, and tend to coalesce and
increase their size. For very small particles
that are deposited by diffusion, an increase
Aerosol-Dependent Factors in temperature favors this mechanism due to
greater Brownian motion.
Particle size, gravity, and density  If the size
and mass of the particle increase, the gravita-
tional forces exerted on it have a greater influence Patient-Dependent Factors
and tend to remove it from the suspension.
Ideally, most particles should have a mass such • Respiratory pattern: This factor has a huge
that the influence of gravity promotes deposition influence on the amount of lung deposition. In
by sedimentation in the desired place, because spontaneous ventilation, a slow and deep
when the particles are very small they lean to inspiration followed by a voluntary apnea of
remain suspended, achieving minimum lung 6–10 seconds increases the deposition by sed-
deposition and resulting in that many of them are imentation. On the contrary, the cry of an
exhaled. The optimal size for a proper deposition infant prompts an opposite effect, since the
in the respiratory bronchioles ranges from 1 to inspiration is short and expiration prolonged,
5 μm (breathable dose). minimizing lung deposition. Some elements
to consider in this regard are: age, respiratory
A denser particle will have a greater mass rate, tidal volume, inspiratory/expiratory time
median aerodynamic diameter and a larger Stokes ratio, and aerosol delivery time regarding the
number. respiratory cycle.
• Anatomy of the airway and respiratory
• Inertia: It is related to the size and mass of the mechanics: Anatomical alterations influence
particle. According to Newton, kinetic energy the deposition fraction (dose deposited/nomi-
is equal to 50% of the product of the mass nal dose) of an aerosol, since they affect gas
times speed squared. When a larger mass par- flow velocity. In areas where the airway bifur-
ticle is set in motion it will have more inertia cates (bronchial carinae), impaction of the
than a smaller mass particle, even when both particles may occur, depending on their iner-
move at the same speed. When a particle starts tia. In regions with anatomical (bronchial
moving, it tends to stay that way unless exter- ­stenosis, mucous plug) or functional (bron-
nal forces act on it. Owing to its greater chospasm) narrowness, a low deposition frac-
momentum, a particle of large mass tends to tion may occur. Although it is true that slow
travel in a straight line even though there is a flow favors deposition by sedimentation, this
61  Inhalation Therapy 637

means that the total amount of gas that reaches Spacer device  Spacers and valved holding
the distal region is lower, so fewer aerosol chambers are used together with pMDIs to
particles are available to be deposited. This administer drugs to patients with spontaneous
happens in areas with high resistance to gas ventilation. Volume, type of interface (oral or
flow. naso-oral), presence of valves, and static are fac-
tors that affect the performance of a chamber.

Equipment-Dependent Factors
Advantages and Disadvantages
• Type of aerosol generating device: Nebulizers, of Aerosol Drug Therapy
pressurized metered-dose inhalers (pMDI),
and dry powder inhalers (DPI) are available to Inhalation therapy is so firmly incorporated in
administer aerosols. Their performances clinical practice that there is often little time to
depend on the limitations and advantages of reflect on the advantages of this modality when
each one of them. compared with other routes of drug administra-
• Type of drug: In pMDIs it may be a combina- tion, such as oral, intravenous or intramuscular
tion (short-acting beta-2 agonist plus ipratro- (Table 61.2).
pium, long-acting beta-2 agonist plus steroid)
or a single drug (salbutamol, ipratropium, ste-
roid). Certain drugs can only be administered Aerosol Generating Systems
as aerosols when they are nebulized (adrena-
line, dornase alfa, mucolytics). Inhalation therapy considers the delivery of a
• Propellant: The aerosol generating device large number of drugs, such as bronchodilators,
requires a propulsive energy, which in the steroids, antimicrobials, mucoactive drugs, pro-
case of nebulizers is a source of compressed teins, peptides, anti-inflammatories, prostacy-
air (air network, oxygen, balloon) or electri- clin analogs, and analgesics, among others. In
cal energy, in pMDIs and in dry powder pediatric age, the most frequent use of inhala-
inhalers the propellant is the patient’s own tion therapy is focused on the first two drugs
inspiratory effort. mentioned.

Table 61.2  Advantages and disadvantages of inhalation therapy

1. Advantages
  Dosage: Doses of aerosol drug are usually lower than those of systemic administration.
  Onset of action: Faster with inhaled drugs than with oral drugs.
  Systemic exposure: The drug reaches the lungs directly, with minimal systemic exposure.
  Adverse effects: Less frequent and less severe with inhaled therapy than with systemic delivery (e.g., salbutamol).
  Comfort of administration: In general, aerosol therapy is well tolerated, since it is not painful and is usually
comfortable for the patient.
2. Disadvantages
  Deposition fraction: Lung deposition is a relatively low fraction of the total dose delivered (nominal dose)
  Influence of multiple variables: There are many variables that influence lung deposition. This increases the
possibility of error in therapy
  Lack of knowledge of professionals and patients: The correct use of the device that creates the aerosol must be
known first by the professional who indicates or uses the therapy, an essential requirement so that they can teach
its use to the patient
  Different devices confuse the patient: A patient may be confused between the controller drug (steroid) and the
reliever drug (salbutamol). If a patient uses two or more types of devices (e.g., DPI plus pMDI), it may be
confusing, since higher inspiratory flows are required when using a dry powder inhaler.
  Absence of quality technical information on inhalers for clinicians: At present, clinical guidelines on inhalation
therapy are not readily available to guide the physician in choosing the most appropriate device for his patient or
in educating him about its use.
638 F. Iñiguez Osmer and V. Aguirre Camposano

Aerosol drugs can be generated from pMDIs, and the manufacturing conditions of the device.
nebulizers, and dry powder inhalers. There are Owing to the high speed with which the parti-
advantages and disadvantages for each device, cles are released, the size of these particles,
and in recent years, the increase in the variety of their low temperature, and the need for good
these has caused confusion in patients and coordination between shooting and inhalation,
doctors. the use of a holding chamber (or spacer) is rec-
ommended when administering aerosols deliv-
Pressurized metered-dose inhaler  This is ered by a pressurized metered-dose inhaler.
the most commonly used device because it is This decelerates and divides the expelled par-
small in size, portable, relatively inexpensive, ticles, warms the mixture, and favors coordina-
does not require drug preparation, can deliver tion between shot and inhalation.
multiple doses quickly, and its contents are There are two types of spacers or holding
protected from contamination by pathogens. chambers: valved and non-valved. Both can have
Its great disadvantage is that the dose of drug a facemask or a mouthpiece. In infants and pre-
deposited is highly dependent on the patient’s schoolers, a double-valve holding chamber should
technique. be used to separate inhalation from exhalation,
thus optimizing lung deposition; in schoolers and
The design consists of a plastic holder with adolescents a spacer can be used. Ideally, the
a cap. In the cap, there is a metal canister with device should be metallic to avoid electrostatic
a delivery valve and a sprayer. Inside the canis- charging, although plastic ones specially manu-
ter there is a mixture of the drug, propellant, factured to reduce their static charge can be used;
and excipients in solution or suspension or treating them by washing them with detergent.
(Fig.  61.1). When used, a fixed dose of this Its maintenance also should include washing them
mixture is released at high speed (between 10 in water with detergent and air drying. Although
and 100  m/s) with particles of varying size, there is no consensus on the frequency, doing it
depending on the drug, the propellant used, once a week seems reasonable. Finally, the spacer

Fig. 61.1 Pressurized Canister

metered-dose inhaler
(pMDI) Gas phase

Liquid phase (formulation)

Actuator

Retaining cup

Elastomeric seal
Metering valve
Stem

Metering chamber Cloud or

plume

Expansion chamber Exit orifice

61  Inhalation Therapy 639

a b c

Fig. 61.2  Recommendations for administering a drug same procedure for the following doses. In infants (c)
using a pMDI. (a) Schoolchildren and adults: spacer with always use an air chamber. With the child sitting in the
mask. (b) Preschoolers, schoolchildren and adults: hold- adult's arms, remove the pMDI cover, shake it vertically
ing chamber with mouthpiece. (c) Infants and preschool- and connect it. Attach the holding chamber covering the
ers: holding chamber with mask mouth and nose and trying to avoid leaks. With the hold-
Recommendations for administering a drug through a ing chamber in horizontal position, press the inhaler once,
pMDI: for (a, b) choose a spacer or holding chamber wait for the patient to complete at least 6–8 respiratory
according to age, shake the pMDI and connect, attach cycles observing the thoracic or valve movements. Rinse
only to the mouth, administer 1 puff and then inhale or perform oral hygiene after inhalations to prevent caries
slowly, from residual volume to total lung capacity; hold (salbutamol) and fungi (steroids)
your breath for 6–10 seconds; exhale slowly; repeat the

must have a proper length that allows deceleration metered-dose inhalers (more consistent) compared
of the particles (15–18 cm) and a volume accord- to those propelled by chlorofluorocarbons.
ing to the age of the patient (Fig. 61.2).
Since the Montreal agreement in 1987, chlo- Nebulizers  Generally, it should always be pre-
rofluorocarbons (CFCs), as harmful propellants ferred to use pressurized metered-dose inhalers
for the ozone layer, have been replaced by hydro- or dry powder inhalers, limiting the use of nebu-
fluoroalkane (HFA), which generate aerosols lizers to precise indications: administration of
with smaller plumes that are warmer and with drugs in patients with oxygen requirements, high
lower exit velocity compared to pressurized and continuous doses of a bronchodilator,
metered-dose inhalers that use chlorofluorocar- absence of formulation of a drug (e.g., adrena-
bons. In the case of solution aerosols (beclometh- line, antibiotics, DNase).
asone, ciclesonide) with HFA as a propellant,
extra fine particles can be generated, which There are several types of nebulizers:
improves lung deposition (~50% of the nominal
dose) when compared to ones with chlorofluoro- • Jet (or pneumatic) nebulizers: Use a com-
carbons (<20%). The most modern pressurized pressed air source to convert a drug in liquid
metered-dose inhalers overcome the coordination state into an aerosol and to produce a fine mist
problem between the trigger and the inhalation using the Bernoulli’s principle. According to
since they are activated by inspiration, requiring the aerosol delivery during respiration, jet
a minimum inspiratory flow (around 20–30  L/ nebulizers can be classified into: (1) conven-
min) and patient collaboration (Autohaler®, tional, with constant output through the respi-
Easibreathe®, K-haler®, MD Turbo®, Xcelovent®, ratory cycle; (2) favored by breathing, with
Smartmist®). constant output but increased during inspira-
Although most pressurized metered-dose inhal- tion; (3) triggered by breathing: this only
ers contain a larger number of doses than labeled, produces aerosol during inspiration, which
­
once this number is reached the amount of drug minimizes aerosol loss.
released is erratic, which has led the recommenda- • Ultrasonic nebulizers: Use electricity to
tion that all devices have a dose counter. This phe- vibrate a piezoelectric crystal at very high fre-
nomenon occurs less in HFA-propelled pressurized quency. This vibration produced is transmitted
640 F. Iñiguez Osmer and V. Aguirre Camposano

to a reservoir containing the solution, creating the advantage that they do not require coordina-
a series of waves that on the surface will sepa- tion with patient inhalation; they also allow the
rate particles from the liquid to form an aero- administration of a wide range of products in
sol. There is an increase in the temperature of high doses, and generate particles with lower
the solution during its operation, which is why velocity, so they do not need spacers (only face-
they are not suitable for nebulizing biological masks or mouthpieces). However, they are more
products (proteins). expensive, require a management system (nebu-
• Mesh nebulizers: Use the ultrasonic principle lizer, compensated flow meter, air or oxygen
to generate drops that will be impelled through compressor), and the administration procedure
a vibrant mesh (Aeroneb Go®, Aeroneb Pro®, takes more time. In addition, its generating sys-
Pari eFlow®, ODEM TouchSpray®, Pfeiffer tem is less efficient than pressurized metered-­
Michrohaler®) or a static mesh (Omron dose inhalers. It is not recommended to mix
MicroAir®) to form a plume. Some of these drugs: pentamidine, ribavirin, and tobramycin
nebulizers include sensors to provide systems have been approved for use with specific nebuliz-
that activate or integrate with breathing. ers and compressors (e.g., PARI LC® plus with
• Soft Mist Inhaler: It is a recently developed PARI BOY® compressor and tobramycin). New
type of nebulizer (Respimat®) that atomizes breath actuated nebulizers (AeroEclipse®) or
the drug solution using mechanical energy favored by it (iNeb®, AKITA®) have been
that comes from a spring. When the spring is developed.
released the solution is forced through a nar- Nebulization technique must comply with a
row nozzle system, which produces a slow-­ series of requirements that ensure a better lung
moving fine mist that has less deposition in deposition (Fig.  61.3). The use of low-power
the oropharynx and greater lung deposition compressors that do not produce the necessary
(39%). flow for a proper aerosol generation should be
avoided. For its use at home, it is recommended
The most commonly used are the conventional to clean nebulizers after each use with sterile or
jet nebulizers with constant output. These devices distilled water and then to air dry it on an absor-
are charged with a certain volume of liquid and bent paper. Once or twice a week wash it with
connected to an air or oxygen flow that will soapy water and disinfect it with a mixture of dis-
divide the solution drops in small particles whose tilled water and white vinegar at 1.25%. In health
size will depend on the characteristics of each centers, nebulizers should follow the usual disin-
brand and device in particular. Generally, unless fection guidelines.
otherwise stated by the manufacturer, the filling Inhalation therapy with aerosols generated by
volume is 4–5 mL and necessary flow for proper pressurized metered-dose inhalers or a nebulizer
operation is 6–8  L/min, preferring the use of a can also be administered to patients receiving ven-
mouthpiece over the facemask. Nebulizers have tilatory assistance, both invasive and non-invasive.

Fig. 61.3  Recommendations for nebulization mouthpiece in children from 4-years-old; calm breathing
Fill with 4–5 mL (drug and saline); use a 6–8 L/min flow, at tidal volume; facial cleaning and eye protection with
enriched with oxygen only if necessary; 5–7 minutes of anticholinergic use when mask is used
nebulization; mask firmly attached to the face and use of
61  Inhalation Therapy 641

Table 61.3  Technique for administering a drug through a DPI

1. Patient sitting or standing.
2. Verify in the dose indicator that there is drug available.
3. Prepare the dose according to the manufacturer’s instructions. Keep the device in position avoiding putting the
mouthpiece down.
4. Exhale slowly until reaching residual volume and take care not to do it inside the inhaler.
5. Place the mouthpiece between the lips ensuring a good seal. Do not block the mouthpiece with your tongue.
6. Aspire quickly, energetically, and continuously to full lung capacity.
7. In apnea, remove the inhaler. Keep the apnea for 6–10 seconds.
8. Cap or close the device and store it in its box in a dry place.
9. Rinse mouth.

Dry powder inhalers  Are devices in which the Spiros®, Airmax®). The use of a dry powder inhaler
drug has been formulated in pure form or mixed must follow certain recommendations (Table 61.3).
with an inactive excipient such as lactose (trans-
porter). In this powder the crystals are agglomer-
ated, so they must be disaggregated and converted
into an aerosol in a complex process known as flu- Sources
idization, by means of an appropriate inspiratory
flow that varies between the different available Aguilar P, Mallol J. Flujos inspiratorios máximos en niños
de 4–8 años. Implicancias para la inhalación de medi-
devices (minimum 30 L/min). These devices can camentos en polvo. Arch Bronconeumol. 2000;36:3.
be used for children from 4 to 5-years-old. This Amirav I, Newhouse M. Review of optimal characteristics
system has the advantages of being portable, hav- of facemasks for valved holding chambers (VHCs).
ing a dose counter, being propellants-free, having Pediatr Pulmonol. 2008;43:268–74.
Barrueto L, Aguirre V, Aguilar P.  Aerosolterapia. In:
a lung deposition similar or greater to pressurized Paris E, Sánchez I, Beltramino D, Copto A, editors.
metered-dose inhalers, being activated by the Meneghello Pediatría. 6ª ed. Madrid: Editorial Médica
inspiratory flow (passive device), and not requir- Panamericana; 2013. p. 1193.
ing the use of a spacer. It also allows using single Carvalho T, Peters J, Williams R. Influence of particle size
on regional lung deposition. What evidence is there?
or multiple doses depending on the type of device Int J Pharm. 2011;406:1–10.
used. Within its limitations are their high cost and Dhand R. Aerosol therapy in patients receiving noninva-
the different forms of use between different types sive positive pressure ventilation. J Aerosol Med Pulm
of dry powder inhalers. Currently, there are a num- Drug Deliv. 2012;25:63–78.
Dolovich M, Ahrens R, Hess D, et al. Device selection and
ber of devices to deliver drugs, both in single doses outcomes of aerosol therapy: evidence-based guide-
(Diskhaler®, Cyclohaler®, Spinhaler®, Aerolizer®, lines. American College of Chest Physicians/American
Handihaler®) and in multiple doses (Turbuhaler®, College of Asthma, Allergy and Immunology. Chest.
Rotahaler®, Diskus®, Clickhaler®, Easihaler ®, 2005;127:335–40.
Geller D.  Comparing clinical features of the nebulizer,
Maghaler®, Novolizer®, Pulvinal®, Spiromax®, metered-dose inhaler, and dry powder inhaler. Respir
Twisthaler®, Genuair®, Airmax®, Swinghaler®, Care. 2005;50:1313–21.
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Iñiguez F. Terapia inhalatoria en los pacientes con venti- Newman S.  Principles of metered-dose inhaler design.
lación mecánica domiciliaria. Neumología Pediátrica. Respir Care. 2005;50:1177–90.
2008;3:87–99. Rottier B, Rubin B. Asthma medication delivery: mist and
Laube B, Janssens H, de Jongh F, et al. What the pulmo- myths. Pediatr Respir Rev. 2013;14:112–8.
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Lavorini F. The challenge of delivering therapeutic aero- ing pulmonary delivery of dry powders. Ther Deliv.
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 Pulmonary Anti-Inflammatory
Effects of Macrolides
62
Luis Enrique Vega-Briceño and Ignacio Sánchez

Contents
Introduction  643
Macrolides  643
Physiopathology 644
Clinical Effectiveness  646
Adverse Effects  647
Limits of the Treatment  648
Sources  648

Introduction Macrolides

The aim of this chapter is to present a brief update Macrolides are a complex and wide family of
on the role of macrolides and their anti-­ antibiotics derived from the Streptomyces family,
inflammatory effect on the lungs, and their effi- discovered in the middle of last century, on
cacy and safety regarding other specific Philippine soil. They are characterized by the
respiratory conditions, such as cystic fibrosis presence of a lactonic ring with at least one amino
(CF), bronchiectasis, asthma, obliterative bron- sugar in their structure. Owing to their strong
chiolitis, and sinusitis. antibiotic effect on aerobic gram positive, anaer-
obic, and gram negative bacteria, there are an
increasing number of studies revealing their
immunomodulatory and anti-inflammatory prop-
erties both in children and adults. These drugs do
not present a bacteriostatic or bactericide effect
against Pseudomona aeruginosa almost at all,
L. E. Vega-Briceño (*)
Faculty of Medicine, Universidad del Desarrollo, which is why the idea that there must be a differ-
Santiago, Chile ent mechanism for its clinical effect to happen
e-mail: [email protected] has been a point of discussion.
I. Sánchez Macrolides’ anti-inflammatory effect was
Department of Pediatrics, School of Medicine, first recorded during simple observations on
Pontificia Universidad Católica de Chile, patients with severe asthma in 1959, when
Santiago, Chile

© Springer Nature Switzerland AG 2020 643

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_62
644 L. E. Vega-Briceño and I. Sánchez

Kaplan and Goldin reported that a group of across the inflammatory cascade both in vitro and
patients with severe asthma—daily steroid in vivo (Fig. 62.1).
users—required a smaller dose of steroids after
being administered troleandomycin. Later, in the • Modulation of the inflammatory cascade.
1970s, Itkin et al. reported the benefit of admin- Macrolides inhibit the production and dis-
istering macrolides, managing to reduce the ste- charge of pro-inflammatory cytokines (IL-1,
roid dose in patients with “infectious asthma.” IL-6, IL-9, and TNFα), both in  vitro and in
These two anecdotal experiences were the first blood samples and bronchoalveolar lavage
published “evidence” suggesting a non-antibi- (BAL) in patients with diffuse panbronchiol-
otic property of macrolides. itis. It is assumed that the cause of this effect
The most convincing demonstration of the is the inhibition of nuclear factor kappa B
anti-inflammatory effect of macrolides on the (NF-Kb), an essential protein for the tran-
lung was the treatment of diffuse panbronchiol- scription of the genes that encode pro-­
itis (DBP) carried out in Japan. This disease of inflammatory molecules like IL-8. This
unknown origins was first reported by Homme in molecule is released as a response to lipopoly-
1969 as generally initiating symptoms after the saccharides, immune complexes, and other
fourth decade of life with clinical characteristics cytokines. IL-8 is a powerful chemotactic fac-
similar to cystic fibrosis: Obstructive-restrictive tor for neutrophils, eosinophils, and other
ventilatory pattern, Pseudomona aeruginosa col- inflammatory mediators. Generally speaking,
onization, and development of bronchiectasis, macrolides inhibit the expression of the induc-
and in individuals whose survival rate after ible nitric oxide synthase enzyme, reducing
5  years was lower than 30%. A retrospective the formation of superoxide anions and free
study of 498 adults suffering from diffuse pan- radicals, which may have a role in chronic
bronchiolitis showed that subjects who used lung conditions where the oxidative factor is
erythromycin for different periods presented a prevalent, as in cystic fibrosis.
significant increase in their survival rate over • Effect on neutrophils. Many studies have
10  years of up to 90%, along with reduction in shown a reduction in neutrophil migration and
morbidity and improvement in lung function. chemotactic activity after being exposed to
This effect was clearer in older patients colonized macrolides, as they inhibit the formation of
by P. aeruginosa who suffered from diffuse cytokines, B4 leukotrienes, and other neces-
panbronchiolitis. sary macromolecules for the adhesion of these
The effectiveness of macrolides as anti-­ cells, such as ICAM.  In vitro models show
inflammatory agents seems to be limited to mem- that erythromycin increases the levels of
bers of the lactone 14 and 15 groups, such as AMPc in neutrophils depending on dosage,
erythromycin, clarithromycin, and azithromycin. accelerating cellular apoptosis with a marked
These drugs have been shown to improve lung reduction in the number of neutrophils in the
function and reduce morbidity and mortality in sputum.
patients with diffuse panbronchiolitis and cystic • Biofilm. Permanent (mucoid and non-mucoid)
fibrosis. P. aeruginosa colonization occurs in around
70% of patients with diffuse panbronchiolitis
and around 80% of patients with cystic fibro-
Physiopathology sis at some point during the disease. This colo-
nization reduces the survival rate of patients as
Many studies have developed interesting hypoth- the number of polymorphonuclears and prote-
eses to explain the immunomodulatory effect dis- ase in the sputum increases, therefore increas-
played by macrolides in different respiratory ing lung damage. Macrolides modify the
conditions. There probably is no single mecha- virulence of P. aeruginosa, reducing the
nism for their action, given that these drugs act release of elastase, protease, phospholipase,
62  Pulmonary Anti-Inflammatory Effects of Macrolides 645

Macrolides

Ciliary
Neutrophil Cytokines Biofilm
transport

Reduction of
Reduction of Increase in Reduction of Reduction of Reduction of
mucus
free radicals apoptosis IL-8 P. aeruginosa viscosity
production

Reduction of Reduction of
neutrophil alginate
migration production

Inflammation reduction

Fig. 62.1  Anti-inflammatory mechanisms of macrolides Pseudomona aeruginosa on the mucus biofilm or by
Macrolides act on neutrophils and reduce the production increasing ciliary transport and reduction of its viscosity.
of free radicals while increasing cellular apoptosis. The All these effects together translate into a reduction of the
stimulation of some cytokines inhibits the release of IL-8. inflammatory cascade in the airway
In addition, they reduce the count of colonies of

and exotoxins. Mucoid P. aeruginosa pro- than the minimal inhibitory concentration
duces alginate, forming a biofilm that inter- against this germ, suggesting that its anti-­
feres with the elimination of this bacterium. It bacterial effect is not responsible and indi-
behaves like a specific antibody–antigen reac- cates the presence of a different mechanism.
tion, inducing antigen on the surface of the An in vitro study comparing the combination
airway. Production of alginate has also been of ciprofloxacin and azithromycin versus cip-
reported in other forms of P. aeruginosa. rofloxacin showed that combined therapy
Azithromycin reduces serum immune com- increased the elimination of P. aeruginosa,
plexes, secondary inflammation, and adher- suggesting a higher degree of penetration by
ence of P. aeruginosa to the respiratory the quinolone in the biofilm, favored by the
epithelium of the airway. Some randomized action of the macrolide.
and controlled studies in patients with cystic • Aspects of the mucus. Macrolides inhibit the
fibrosis have shown that daily treatment with expression of genes that produce mucin in the
azithromycin for at least 3 months reduces the cells of the bronchial epithelium, therefore
number of respiratory exacerbations without reducing the production of mucus by goblet
significantly altering the respiratory flora. cells. In patients with cystic fibrosis colonized
This effect becomes clearer in patients infected by P. aeruginosa, macrolides reduce the vis-
by P. aeruginosa. The doses used are smaller cosity of mucus in up to 80% compared to a
646 L. E. Vega-Briceño and I. Sánchez

placebo, perhaps related to the decrease in • Bronchiectasis. There is little evidence of the
production of alginate. Rubin and company usefulness of macrolides in patients with
compared mucus discharges in healthy bronchiectasis not associated with cystic
patients against those suffering from purulent fibrosis. A study did not find any differences
rhinitis. After 2  weeks of therapy with clar- in lung function tests when monitoring
ithromycin, a reduction of mucus discharges patients treated with roxithromycin for
was observed in both groups, but the group 12 weeks, but there was a reduction in bron-
with purulent rhinitis also saw a reduction in chial hyperresponsiveness (BHR) and an
viscosity. improvement in mucus viscosity in the treated
• Bronchoconstriction. Macrolides reduce the group. Many of these studies conclude that
expression of endothelin-1, a powerful natu- subjects with cystic fibrosis colonized by P.
ral vasoconstrictor and bronchoconstrictor. aeruginosa suffer from bronchiectasis, which
An in vitro study showed that administering is why it is hard to isolate the cause of either
erythromycin inhibits the contraction of of the inflammatory components. There are
smooth muscle cells of the human bronchial valid reasons to test small-dose long-term
epithelium as a response to the electric stim- plans in subjects able to undergo lung function
ulus. This action would happen when inhib- tests that allow observing and monitoring the
iting the cholinergic response, because response, or, failing this, in those who do not
administering acetylcholine blocks this bio- respond to conventional treatments. Some
logical effect. countries in Europe recommend testing nebu-
lized deoxyribonuclease for 2  months in
patients who fail a macrolide test.
Clinical Effectiveness • Asthma. Asthma is the prototypical inflamma-
tory airway disease. Some patients suffering
• Cystic fibrosis. On the basis of the similarities from severe asthma who depend on systemic
between cystic fibrosis and diffuse panbron- steroids and have received macrolides are
chiolitis, a pilot study on children with cystic capable of reducing or suppressing steroids
fibrosis and P. aeruginosa infection showed a without worsening their lung function. Using
short-term improvement in lung function with azithromycin has produced some benefits,
the use of macrolides. Afterward, some con- despite the fact that it does not interact with the
trolled studies evaluated the effect of macro- steroid metabolism, thus suggesting direct
lides in the treatment of cystic fibrosis, anti-inflammatory activity of macrolides,
showing an improvement in FEV1 of 3.5–5.5% which would reduce bronchial hyperactivity.
as well as a reduction in the use of antibiotics Patients with allergic asthma are able to reduce
and the number of respiratory exacerbations. the levels of IL-8 released by eosinophils in a
A trial of 185 patients with preliminary data dose- and time-dependent manner. Low mac-
suggested a substantial improvement in lung rolide doses could be systemic steroid ‘savers’
function in patients who received macrolides in patients with more severe asthma, either
chronically. On the other hand, the Cochrane because of lymphocyte proliferation inhibi-
group concluded that the benefits of azithro- tion, reduction in the accumulation of neutro-
mycin in patients with cystic fibrosis are lim- phils, mucus, or contraction of the smooth
ited but significant. Similarly, administering muscle, because of its direct (inhibitory) action
nebulized deoxyribonuclease to patients suf- on nuclear factor NF-Kb or because of the
fering from cystic fibrosis has shown an induced reduction of eosinophils’ apoptosis.
increase in VEF1, FVC, as well as a reduction Macrolides are effective in reducing bronchial
in the number of acute exacerbations attrib- hyperresponsiveness and eosinophilic inflam-
uted to the reduction in the DNA levels of the mation. Amayasu et al. measured bronchocon-
bronchoalveolar lavage samples. striction caused by inhaling methacholine in
62  Pulmonary Anti-Inflammatory Effects of Macrolides 647

17 patients suffering from asthma who received on alternate days for 12  weeks in 20 adults,
a placebo or 200 mg of clarithromycin twice a observing in this way an improvement in FCV
day for 8 weeks, with a significant decrease in and FEV1 of 20% and 22%, respectively.
all inflammatory indexes, symptoms, bron- Another recent open and unreviewed study
chial hyperresponsiveness, and eosinophil lev- evaluated six lung transplant recipients who
els within the treated group. A possible received azithromycin on alternate days,
explanation for the shown effects is the role showing a considerable average improvement
that some infections by atypical germs play in in FEV1 of 17.1% over the base value before
the persistence of the airway inflammation. M. treatment. Even though its mechanisms are
pneumonia can start or perpetuate an asthma still unknown, there was good drug tolerance.
attack in previously healthy or stable subjects. However, more studies are required to deter-
Also, it causes the expression of RANTES in mine the safety and benefit of these therapies.
cell cultures, an effect that becomes inhibited • Chronic sinusitis. Since 1991, many, but
after the use of macrolides. The anti-inflamma- mainly Japanese publications, have shown
tory effect on asthma of macrolides is widely that macrolides, particularly clarithromycin
discussed because of its frequent association on ~500 mg doses twice a day, produce better
with M. pneumoniae and C. pneumoniae, not mucociliary clearance, a decreased discharge
only because of the role they play in respira- volume, and a reduction in inflammation
tory exacerbations but also as being responsi- markers on the mucus of chronic sinusitis
ble for prolonging the inflammatory process. patients. Sinus symptoms have been reduced
Treatment with macrolides significantly at a rate of 50–100% according to a study
improves FEV1 in asthmatic patients with posi- using 600 mg/day doses of clarithromycin for
tive isolation for M. pneumoniae and C. pneu- 7 months. At the same time, patients suffering
moniae through PCR techniques. There also from chronic sinusitis and nasal polyposis saw
was a reduction in inflammatory mediators, a reduction in the size of their polyps corre-
such as IL-5 and IL-12, and in neutrophil and lated to the degree of IL-8 reduction. Clinical
IL-8 released by eosinophils in atopic patients. improvement was documented at 5%, 48%,
Most patients require at least 2 months of treat- 63%, and 71%, respectively after 2, 4, 8, and
ment before showing improvement, and the 12  weeks of treatment. The authors of the
benefits disappear after suspending macrolide study speculated that the clinical effects they
treatment for longer than 3  months. Lacking found were secondary to a circulating cyto-
double-blind peer-reviewed studies it is not kine release control and their previously
possible to recommend the use of macrolides reported action on the nasal epithelium. Their
for asthma treatment. Despite the complica- long-term recurrence effects after suspending
tions in identifying and isolating inflammatory treatment have not been evaluated.
component vs. the infections component
(cause-effect), the possibility of infection by
atypical bacteria must be considered for Adverse Effects
patients with asthma who do not respond to the
usual dose of inhaled steroids. In general, new macrolides are well tolerated and
• Obliterative bronchiolitis. Since the 1980s, most adverse effects are mild. The most common
bronchiolitis obliterans (OB) has been recog- alterations are nausea and diarrhea (6%), dyspep-
nized as a severe complication after lung sia, abdominal pain or headaches (1.6%). A minor,
transplant. Even though its pathogenesis is but typical, secondary effect of clarithromycin was
unknown, there are well identified risk condi- altered taste in between 9% and 14% of patients.
tions. Diagnosis is usually complex. Khalid From 1% to 6% of patients have abandoned treat-
et  al. evaluated administering 500  mg. of ment because of their secondary effects, a similar
azithromycin for 3 days, followed by 250 mg rate to other antibiotics or placebos. Some aspects
648 L. E. Vega-Briceño and I. Sánchez

of distribution volume must be considered in Feldman C.  The use of antiinflammatory therapy and
patients with cystic fibrosis, as they usually receive macrolides in bronchiectasis. Clin Chest Med.
2012;33(2):371–80.
higher doses at different intervals than known Fouka E, Lamprianidou E, Arvanitidis K, Filidou E,
standards. Kolios G, Miltiades P, Paraskakis E, Antoniadis A,
On the other hand, patients with cystic fibrosis Kotsianidis I, Bouros D.  Low-dose clarithromycin
do not usually metabolize macrolides, so in order therapy modulates Th17 response in non-cystic fibrosis
bronchiectasis patients. Lung. 2014;192(6):849–55.
to obtain beneficial effects, long treatments are Gielen V, Johnston SL, Edwards MR.  Azithromycin
required, which is why the correct dose for this induces anti-viral responses in bronchial epithelial
patient subgroup is unknown. Despite the theo- cells. Eur Respir J. 2010;36(3):646–54.
retical risk, overusing antibiotics may produce a Haworth CS, Bilton D, Elborn JS.  Long-term mac-
rolide maintenance therapy in non-CF bronchi-
dangerous increase in bacterial resistance, ectasis: evidence and questions. Respir Med.
demanding constant monitoring. Still, the admin- 2014;108(10):1397–408.
istered immunomodulating doses are small. Koutsoubari I, Papaevangelou V, Konstantinou GN,
Finally, yearly monitoring of liver enzymes must Makrinioti H, Xepapadaki P, Kafetzis D, Papadopoulos
NG. Effect of clarithromycin on acute asthma exacer-
be considered for patients with cystic fibrosis bations in children: an open randomized study. Pediatr
who have been administered these drugs. Allergy Immunol. 2012;23(4):385–90.
McCallum GB, Morris PS, Chang AB.  Antibiotics for
persistent cough or wheeze following acute bron-
chiolitis in children. Cochrane Database Syst Rev.
Limits of the Treatment 2012;(12):CD009834.
Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis
It is clear that some patients improve their condi- EJ, Perletti G, Verleden GM, Vos R.  Azithromycin:
tion after being exposed to macrolides. Yet, some mechanisms of action and their relevance for clinical
applications. Pharmacol Ther. 2014;143(2):225–45.
patients do not. Currently, there is no way to predict Rudmik L, Soler ZM.  Medical therapies for adult
the response to this treatment. Beyond sputum bac- chronic sinusitis: a systematic review. JAMA.
teriology or bronchoalveolar lavage, their usage 2015;314(9):926–39.
must be suspended if there is no clear evidence of Shi ZL, Peng H, Hu XW, Hu JG. Effectiveness and safety
of macrolides in bronchiectasis patients: a meta-­
response to the treatment. Research is still in prog- analysis and systematic review. Pulm Pharmacol Ther.
ress in this area, and “cut-off points” regarding 2014;28(2):171–8.
their potential benefits are still necessary. Spagnolo P, Fabbri LM, Bush A.  Long-term macrolide
treatment for chronic respiratory disease. Eur Respir
J. 2013;42(1):239–51.
Spurling GK, Doust J, del Mar CB, Eriksson L. Antibiotics
Sources for bronchiolitis in children. Cochrane Database Syst
Rev. 2014;(10):CD005189.
Brusselle GG, Vanderstichele C, Jordens P, et  al. Wong C, Jayaram L, Karalus N, Eaton T, Tong C,
Azithromycin for prevention of exacerbations in Hockey H, Milne D, Fergusson W, Tuffery C,
severe asthma (AZISAST): a multicentre random- Sexton P, Storey L, Ashton T.  Azithromycin for
ized double-blind placebo-controlled trial. Thorax. prevention of exacerbations in non-cystic fibro-
2013;68(4):322–9. sis bronchiectasis (EMBRACE): a randomised,
Cameron EJ, McSharry C, Chaudhuri R, Farrow S, double-blind, placebo-­ controlled trial. Lancet.
Thomson NC.  Long-term macrolide treatment of 2012;380(9842):660–7.
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efits and future developments. Clin Exp Allergy. of macrolides in asthma: current evidence and future
2012;42(9):1302–12. directions. Lancet Respir Med. 2014;2(8):657–70.
Corris PA, Ryan VA, Small T, Lordan J, Fisher AJ, Zarogoulidis P, Papanas N, Kioumis I, Chatzaki E,
Meachery G, Johnson G, Ward C. A randomised con- Maltezos E, Zarogoulidis K. Macrolides: from in vitro
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 Chest Physiotherapy
63
Homero Puppo Gallardo
and Gonzalo Hidalgo Soler

Contents
Introduction  649
Objectives  650
Bases  650
Therapeutic Intervention  652
 echniques of Respiratory Physical Therapy
T  653
Manual Physical Therapy Techniques  653
Instrumental Physical Therapy Techniques  655
Conclusions  658
Sources  658

Introduction sive care units performing respiratory physio-

therapy and participating in the severely
Respiratory physiotherapy has had a constant and compromised patient’s functional recovery,
sustained development thanks to a better under- especially involved in inhalation therapy,
standing of the function of the natural defense medicinal gases, and mechanical ventilation.
mechanisms in the lung, the physiopathology of 2. Primary health care: In aspects of education,
respiratory diseases, and the effect of non-­ prevention, evaluation, and treatment of
pharmacological interventions on the respiratory patients with severe chronic respiratory dis-
system. This has resulted in the inclusion of the eases and rehabilitation of all conditions with
respiratory physiotherapist as a part of the team respiratory compromise.
in respiratory care: 3. Home respiratory care: Involved in follow-up
and treatment of chronic respiratory patient on
1. Hospital level: In mid and high complexity both invasive and non-invasive mechanical
patients, their role is highlighted in the inten- ventilation.

There are two approaches to respiratory phys-

H. Puppo Gallardo (*) · G. Hidalgo Soler
Respiratory Kinesiology, Faculty of Medicine,
iotherapy management in children. An approach
Universidad de Chile, Santiago, Chile called conventional physiotherapy, used in
e-mail: [email protected] Anglo-Saxon countries, and another branch

© Springer Nature Switzerland AG 2020 649

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_63
650 H. Puppo Gallardo and G. Hidalgo Soler

called non-conventional physiotherapy, espe- that supports its prescription, because studies are
cially applied in French-speaking countries and too heterogeneous regarding sample size and
Latin American countries. The conventional baseline diagnosis included, investigation type in
physiotherapy approach was initially applied in the application of techniques, and mainly the
adults with surgery respiratory complications and application of inadequate techniques for the age
chronic respiratory diseases, such as bronchiecta- range. However, it is habitually prescribed in
sis and chronic obstructive pulmonary disease. many health centers in cases where bronchial
Conventional kinetic respiratory techniques (pos- hypersecretion is present with—at least—moder-
tural drainage, percussions, vibrations, and ate bronchoconstriction.
forced expiration) were used in respiratory con-
ditions without adequately considering the inher-
ent characteristics of growth and development of Bases
the respiratory system in children, especially in
infants. In these patients, the configuration of the Mucociliary drainage participates in the protec-
thoracic cavity is trapezoidal, and the position of tion of the respiratory system against harmful
the fibers in the costal area of the diaphragm agents that enter with the inspired air. Under nor-
changes, losing the apposition zone, leaving the mal circumstances, the respiratory system pro-
infant in mechanical disadvantage, especially in duces daily between 10 and 100 ml of secretions
situations of greater breathing work. The infant that are eliminated by the permanent activity of
presents a narrower airway, which increases the the mucociliary system. The speed of the bron-
frictional resistance with even small decreases in chial drainage depends on two interrelated fac-
radius. They also have higher susceptibility to tors: The viscoelastic capabilities of mucus and
fatigue of the respiratory musculature due to the the frequency of cilliary movement. The visco-
composition of diaphragm having fewer type I elastic properties are altered by illness (asthma,
fibers (fatigue resistant) than older children. In cystic fibrosis), dry air, tobacco, and other envi-
addition, infants have an inherent hyper reactivity ronmental pollutants. The ciliary shaking fre-
of the airway, a higher thoracic compliance and quency decreases with age and during sleep, and
lung elastance. All these factors determine that conversely, increases during physical exercise,
the session of respiratory physiotherapy has to be application of beta2-agonists, coughing, and
preceded by a careful evaluation, graded accord- vibration maneuvers. The imbalance between the
ing to clinical and laboratory parameters, and viscoelastic qualities of mucus and cilliary move-
performed with intensity and precision for brief ment will provoke a stasis of secretions. It is gen-
periods in severe diseases. erally assumed that secretion stasis contributes to
the obstruction of the lower airway and predis-
poses the development of lung infections.
Objectives In respiratory disease conditions, there is an
exponential increase in the production of bron-
The goal of respiratory physiotherapy is to par- chial secretions. When the mucus gel coat is
ticipate in the resolution of cases in which bron- more than 5 μm thick, the action of the mucocili-
chial hygiene is compromised, resolution of ary chain will be surpassed (Fig. 63.1). Coughing
collapsed lung zones (atelectasis) or alteration in is not effective beyond the seventh bronchial gen-
which gas exchange or thoraco-pulmonary eration. Under these conditions, forced expira-
mechanic is compromised, contributing to opti- tory flows of turbulent characteristics are truly
mize the ventilation/perfusion ratio and secretion responsible for the draining secretions of the
draining, with the objective of decreasing airway proximal airway. By performing a forced expira-
resistance, thus decreasing the breathing work. tion, a point of equal pressure is produced in the
On the other hand, in cases where bronchospasm airway, which suffers a dynamic compression,
or parenchymal compromise, respiratory physio- creating a choke point, which moves in the distal
therapy has not had support from the literature direction. This dynamic compression produces in
63  Chest Physiotherapy 651

Fig. 63.1 Airway Airway lumen

epithelium

Gel coat 0.5 to 5.0 micron

Periciliary
7 micron
layer

Hair Hair Hair

cells cells Globet cell cells
Globet cell Basal cell

Towards Distal

(a) The choke point moves and gets

A closer the mucous plug
Towards Proximal AIR FLOW

towards Distal

Towards Distal

(b) The plug is tapped at the level of

B Air flow the choke point

Towards Distal

Towards Distal

(c) it is removed and it alters its viscositu

C through stenosis of the airway and the
Air flow
forced expiratory flow

Towards Distal

Fig. 63.2  Forced expiration and choke point. (a) The (c) It is removed and it alters its viscosity through ste-
choke point moves and gets closer to the mucous plug. nosis of the airway and the forced expiratory flow
(b) The plug is tapped at the level of the choke point.

turn an increase of the local expiratory flow that point, which will in the end allow the fragmented
displaces in a proximal direction, favoring the displacement of the bronchial secretions toward
closeness of the mucous plugs with the choke the central airways (Fig. 63.2).
652 H. Puppo Gallardo and G. Hidalgo Soler

At more distal levels, the two-phase flow pathological disorder is characterized by the
(interaction between the airflow and the mucus decrease of the diameter of the central or
layer over the ciliary epithelium) has a central peripheral airways, with an increment of the
role in the hygiene of the middle airways, and airflow resistance and flow decrease, espe-
even the more peripheral ones. It has been cially expiratory flows, which will result in a
described that at this level, slow and prolonged significant increase in the work of breathing
expiratory flows that aim to obtain flows with and the following hypoxemia (partial breath-
laminar characteristics enhance the natural action ing insufficiency) and even hypercarbia
of the two-phase flow, producing a significant (global breathing insufficiency) in some
effect in the mobilization of secretions from the severe cases, such as in acute severe
distal airways to the proximal airways. bronchiolitis.
Considering that airway compromise is not
homogeneous, it is very important to focus on the The restrictive physiopathological disorder
compromised area by auscultation, as well as set- encompasses a group of diseases in which the
ting therapeutic objectives in proportion to the most important physiopathological disorder is a
findings, to be able to choose the correct technique restriction of expansion that limits the pulmonary
that results in the most benefit for the patient. volumes, with the consequent possibility of los-
When there are areas with loss of air content ing recruited alveolar units, as in atelectasis.
(e.g., atelectasis), techniques that contribute to In any type of functional disorder there is a
increase the inspired volume should be favored, possibility of loss of effectiveness of coughing,
to recruit collapsed zones. It is necessary to stress which will result in higher secretion retention
that lung recruitment will also favor the permea- and the possibility of creating a feedback loop
bilization of the middle airway and even the dis- that will determine the recovery of the functional
tal one, because there will be a higher lung level of the child.
volume that will allow an increment of the Apart from determining the physiopathologi-
expired volume, which will favor the depurative cal disorder the patient presents, the severity of
action of the two-phase flow. the compromise must be established, e.g., mild,
moderate or severe obstruction.

Therapeutic Intervention 2. Level of cooperation: It refers to the level of

potential cooperation of the patient inasmuch
In daily practice and as a sequential order to make as they can follow the instructions of the phys-
decisions for choosing respiratory physical ther- iotherapist when a particular technique is being
apy techniques that apply to each patient, we pro- performed. One classification is the coopera-
pose the following action flow. This flow should tive patient is able to follow instructions of the
be discerned after having evaluated the patient. treating therapist, to cooperate, help and per-
form active and assisted-active techniques
1 . Determine the physiopathological disorder without problems. On the other hand, it is the
2. Identify the degree of collaboration from the uncooperative patient who doesn’t have the
patient physical, cognitive or psychomotor abilities to
3. Establish the level of compromise follow the instructions of the physiotherapist to
perform a certain technique.
3. Level of compromise: It has to do with the
1. Physiopathological disorder: Refers to the zone of the respiratory system affected by the
identification of a determined ventilation physiopathological or biomechanical disor-
function syndrome (obstructive, restrictive or der, which may be the thoracic cavity, respira-
mixed) present at the moment of the evalua- tory musculature, lung parenchyma, or the
tion of the patient. The obstructive physio- proximal, mid or distal airway. Each one of
63  Chest Physiotherapy 653

these levels has different functions regarding them. In order to obtain this, it is necessary to
thoracic mobility, ventilation, conduction, and place the bronchial segment to drain as vertical
air conditioning. as possible; placing the patient in different
positions, many of them will be Trendelenburg
positions. It is traditionally advised to simulta-
 echniques of Respiratory Physical
T neously apply percussions and vibrations
Therapy while the postures are sustained. One of its
main limitations is the appearance of adverse
The techniques of respiratory physical therapy effects associated with technique execution
can be classified into two main groups: manual (gastroesophageal reflux, desaturation, or ele-
and instrumented. vation of intracranial pressure).
• Forced Expiration Technique: The forced
expiration technique (FET) consists in making
Manual Physical Therapy Techniques forced expirations with open an open glottis
starting with different lung volumes:
• Thoracic vibration: Oscillatory movement
produced by the isometric muscle contraction Low, mid, and high, interspersed with still
of the upper limbs which is transmitted by one breathing at tidal volume. The aim is to mobi-
or both hands of the therapist to the chest of lize the bronchial secretions to the central air-
the patient during expiration. The oscillation way where they can be swallowed or
frequency must not be less than 3 Hz. The goal expectorated. In the specialized literature in
is to obtain a maximum expiratory flow at English it is also known as the Huffing tech-
least 10% more than the maximum inspiratory nique, and it is justified from the physiological
flow, which would allow increasing the two-­ concept of point of equal pressure and must be
phase flow and loosen and decrease the vis- applied cautiously in chronic patients (e.g., cys-
cosity of the secretions of the bronchial walls, tic fibrosis) where stability of the bronchial
allowing their mobilization to proximal walls is so altered that compression during the
airways. application of this technique results in the col-
• Thoracic percussion (clapping): Rhythmic lapse of the airway and the following impact of
tapping performed with cupped hands on the secretions at a distal level of the collapse. This
ventral, dorsal, and lateral zones of the chest collapse warrants the avoidance of the forced
in both phases of breathing. It is generally expiration technique in these patients or its use
applied while the patient maintains a specific only later in the bronchial hygiene process,
position of postural drainage. It is contraindi- when the secretions have been mobilized to the
cated under clinical evidence of broncho- central airways.These four techniques are con-
spasm. Both vibrations and percussions have sidered conventional chest physiotherapy. The
the goal of generating an oscillatory effect of techniques described below are considered non-
the chest wall that will be transmitted to the conventional chest physiotherapy.
lungs and airways, aimed at increasing ciliary
activity and loosening and mobilizing secre- • Prolonged slow expiration: Passive technique
tions adhered to the bronchial wall, which of expiratory aid applied to the uncooperative
would depend of the value of the oscillation patient (from infancy to 8 years), through slow
frequency transmitted through the thorax. manual thoraco-abdominal pressure that starts
This frequency is close to 15–25 Hz, but it is at the end of a spontaneous expiration and
limited in these manual techniques that only continues toward a residual volume. Its aim is
reach 2–8 Hz frequencies. to obtain a greater expiratory volume than in a
• Postural drainage: Consists in easing secretion normal expiration, to promote the two-phase
transport through the action that gravity has on low and thus contribute to the mobilization of
654 H. Puppo Gallardo and G. Hidalgo Soler

secretions in the periphery of the respiratory manner avoids bronchial collapsing and
tree to the central airway. allows a greater displacement of the inferolat-
• Autogenic draining: This technique for the eral diaphragm toward the proximal end. The
cooperative patient combines slow inspiratory narrowing of the bronchial lumen in the infer-
and expiratory flows with forced expirations olateral lung and the increase of its ventila-
and coughs in a three-phase sequential cycle: tion, due to the adopted position, creates a
–– First phase, loosening of secretions: Slow higher friction of particles of air over mucus
inspirations/expirations must be per- (two-phase flow) and thus favors its move-
formed, with breathing located in the dia- ment toward the proximal end.
phragm, mobilizing small volumes from
the functional residual capacity to later The aim of this technique is to loosen and
gradually increase the inspiratory and expi- move the bronchial secretions from the mid and
ratory volume, achieving a gradually distal zones of the respiratory tree to move them
increased pulmonary capacity, with the aim toward the proximal ways to be eliminated with
of unsticking and mobilizing secretions the forced expiration technique. It is useful in
from the periphery to the central airway. patients of 8 years of age or older, since the child
–– Second phase, collection of secretions: In starts to present the inferolateral respiratory pat-
higher volumes than the normal current tern that is preferred and characteristic in an
volume, but maintaining slow expiratory adult.
flows, the secretions are accumulated in the
central airways. • Active respiratory cycle: It is a technique that
–– Third phase, evacuation: Three to four combines the voluntary ventilatory exercises
expirations are performed until the total with forced expiration techniques. Its aim is to
pulmonary capacity is reached, to conclude mobilize and remove the bronchial
with a forced expiration with open glottis secretions.
or a voluntary cough.
• Slow expiration with glottis opened in lateral It has three phases:
posture (ELTGOL): It is an active–assisted –– First phase, breath control exercises: It
technique, in which the patient is in the lateral starts with soft respiratory cycles, at tidal
decubitus position with the lung to be treated volume that directs the movement to the
specifically in the support plane (dependent) lower part of the chest, relaxing the mus-
and thus making the superolateral lung and the cles of the upper thorax.
mediastinum help with is maximum exsuffla- –– Second phase, thoracic expansion exer-
tion during expiration. Owing to the position cises: The patient performs deep nose
adopted, the pressure of the abdominal viscera inspirations with thorax elevation, followed
will raise the diaphragm of the support lung. by a slow and prolonged expiration. These
In this position, with an open mouth (or kept respiratory movements are performed four
open by a cylindrical mouth accessory), the to six consecutive times, taking care not to
physiotherapist presses the abdomen with one provoke hyperventilation that could gener-
hand at the level of the lung and eases the rise ate respiratory alkalosis.
of the diaphragm, and applies pressure with –– Third phase, forced expiration technique:
the other hand on the superolateral chest wall, Breath control exercises and forced expi-
producing a pressure against the contralateral rations are performed again with low vol-
shoulder which will ease the reduction of the umes and an open glottis, followed by
transversal diameter that favors a complete deep inspiration followed by cough or a
exsufflation of the inferolateral lung, always high volume forced expiration that
controlling that the expiration is slow and pro- enables one to swallow or expectorate
longed. Applying the maneuver in a slow secretions.
63  Chest Physiotherapy 655

• Controlled inspiratory flow exercise: It is an patient and asking for a deep inspiration
active–passive technique, where the patient is followed by a forced expiration, and then
in the lateral decubitus position, with the area asking for a cough. At the same time,
to be treated in the superolateral position. abdominal pressure, or thoracic vibropres-
Slow inspiratory exercises with a low flow and sure that goes together with the accelera-
high volume, stopping when the inspiration tion of the expiratory flow generated by the
ends. The exercises of controlled inspiratory cough.
flow in the lateral decubitus position take –– Glossopharyngeal breathing (RGF):
advantage of the effect of the passive expan- Described in 1951 by Clarence Dail, this
sion of the more peripheral air spaces that technique acts on the inspiratory phase of
result from the relative hyperinflation of the the cough. It consists in taking multiple
superolateral lung and the increase of the insufflations through movements of the
transversal diameter of the chest, which results mouth, cheeks, tongue and larynx to be
from the patient’s position and profound and able to “swallow air” that is sent to the
sustained inspiration. lungs. The objective is substituting the
• Huffing: Series of slow and tiered inspirations, weak respiratory musculature by the action
starting from residual functional capacity until of the oropharyngeal musculature. In order
total lung capacity, including a pause at the for the technique to be effective, glottis
end of the inspiration. must be intact; patient must cooperate, and
• Thoracic compression: Manual pressure on the patient must learn the maneuver well.
the chest during the inspiration phase. Its To get a final volume over the tidal vol-
objective is to increase volume and exhaled ume, each insufflation must consist of at
volume. least 80 ml.
• Thoracic decompression: Maneuver per- –– Air stacking (AS): The classic technique
formed after an expiratory compression, describes a manual reanimation bag, a uni-
which corresponds to the sudden removal of directional bag, a 20–30  cm corrugated,
the hands of the therapist from the chest of the and a nose pin if there is an air leakage.
patient at the beginning of the inspiratory This technique acts during the inspiratory
phase. phase and it provides multiple inflations of
• Thoracic blockage: Manual pressure that is air through a bag of manual reanimation,
applied in a region of the chest attempting to aiming to reach the maximum inspiratory
restrict its expansion through several respira- capacity. This technique increases the
tory cycles, aiming to direct the air volume to inspired volume and replaces the periodic
the unblocked, affected contralateral zone. inflations (sighs), also contributing to
• Manual techniques to assist coughing: The improve thoracic mobility and to prevent
efficacy of coughing is related directly to the atelectasis. It is reported as being most effi-
inspiratory volume before the expulsive cacious in patients with neuromuscular
maneuver is performed. conditions and medullar lesions with cer-
–– Induced cough (TP): It is performed in the tain degree of cooperation.
uncooperative patient and it consists in the
stimulation of the mechanic receptors of
the cough reflex in the extrathoracic tra- Instrumental Physical Therapy
chea, at the level of the sternal notch, to be Techniques
able to increase the air volume expired
when the cough is inefficient or it is not They can be subdivided in mechanical devices of
spontaneously produced. lung expansion, mechanical and electromechani-
–– Assisted cough (TA): It consists in placing cal devices of bronchial hygiene, and mechanical
the therapist’s hands in the chest of the devices to assist coughing.
656 H. Puppo Gallardo and G. Hidalgo Soler

 echanical Lung Expansion Devices

M oscillatory or discontinuous expiratory posi-
• Incentive Spirometers: These are devices that, tive pressure.
through slow and deep inspirations, aim to • Continuous expiratory positive-pressure
prevent or treat alterations in which the lung systems: As indicated by the name, the posi-
volume is compromised by using a visual tive pressure that is produced in the airway
incentive that gives feedback to the patient is continued during the expiratory phase.
during the inspiratory effort which must be They were initially developed in Denmark
performed with a pause of at least 3 seconds at in the 1970s. There are many models in the
the end of the inspiration. Volume incentive market (PEPmask®; TheraPEP®; PiPEP®;
spirometers are used (Voldyne® and Coach®) PariPEP®; AeroPEP®) and all of them have
from 500 to 5000  ml or flow meters (Triflo a unidirectional valve connected to an
II®, CliniFLO®) from 100 to 1200 ml/sec. adjustable piece, with many holes of differ-
Some models have a connection for addi- ent sizes where a resistance or stop to the
tional oxygen. The main objective is to recover expiration is generated. The smaller the
the functional residual capacity and re-expand hole, the higher the resistance and greater
the collapsed zones through the increase of the the positive expiratory pressure in the air-
transpulmonary pressure, increase of the inspi- way of the patient.
ratory capacity, and simulations of the effects
of the physiological sigh that could contribute A pressure gauge in the system allows the
to the prevention or treatment of atelectasis monitoring of the pressure applied by each one
caused by a diaphragmatic malfunction. They of the holes and it is generally established
are normally indicated for thoracic and high between 10 and 20 cm H2O. There is a small dif-
abdomen surgeries, prolonged immobility, ference in the device ThresholdPEP® where the
especially in patients with chronic respiratory resistance is generated by the tension of an
disease and neuromuscular conditions. adjustable spring which is incorporated in the
device.
 echanical Devices for Bronchial
M
Hygiene • Oscillatory or discontinuous expiratory posi-
• Expiratory positive-pressure systems: They tive pressure: Initially developed in
are devices that, at the mouth level and during Switzerland, the devices with the most biblio-
the active expiration of the patient, produce a graphical support are Flutter®VRP1,
stop in the expiration that generates a positive Acapella®, and Cornet®, capable of produc-
pressure that is transmitted to the airway and ing an oscillating expiratory resistance that
aims to avoid or delay the premature closure generates retrograde vibration waves in the
(collapsing) of the airway, which is a common airway. The aim is modifying the viscoelastic
occurrence in chronic diseases like cystic properties of the Bronchial mucus and main-
fibrosis and that we technically know as the taining the beneficial characteristics of the
dynamic compression of the airways. This expiratory positive pressure described above.
early closure prevents an effective movement The Flutter®VRP1 is a pipe-shaped device
and elimination of the bronchial secretions, formed by a mouthpiece, a plastic cone, a steel
among other negative effects. With the appli- sphere, and a pierced lid. During expiration,
cation of positive expiratory pressure, the the airway suffers internal vibrations pro-
expiratory time is prolonged, the collateral voked by the vibrations of the expired air and
ventilation increases and the early closure of the changes in pressure inside the bronchi.
the airways is minimized. There are mainly The inclination angle of the Flutter®VRP1
two types of expiratory positive-pressure will modify the resistance to the movement of
instruments: The ones using continuous expi- the steel sphere and, with it, the generated
ratory positive pressure, and the ones using expiratory pressure. The optimal work incli-
63  Chest Physiotherapy 657

nation is 30° to obtain an oscillatory pressure • Intrapulmonary percussion–vibration: The

between 12 and 75 cm H2O and an oscillation device is made up of a high-pressure flux
frequency between 15 and 32 Hz. generator, a valve to interrupt the flux and a
breathing circuit with a nebulizer that can be
The Acapella® has in it a magnetized lever that connected simultaneously to the mouthpiece
intermittently closes a cone inside the dispositive to inhale sprays. The device produces a two-­
during the expiration. This produces a positive phase vibration in the inspiration and expira-
expiratory pressure and makes an oscillating expi- tion, with positive pressure that is overlapped
ratory flow. On the other side of the device, a by the breathing pattern of the individual.
revolving part allows the regulation of the magne- The small high frequency air pulses (50–
tized lever mechanism and thus the higher or lower 150 cycles/min) that lead to an internal vibra-
resistance. There are four Acapella® models (Blue tion of the airways, together with the
DM®, Green DH®, Choice®, and Duet®). The oscillating expiatory pressure, aim to recruit
Acapella® models, unlike the Flutter®VRP1, collapsed units and increase the transport and
have the advantage of being usable in any position elimination of proximal secretions. Their use
(standing, sitting, lying down). must be avoided in patients with osteopenia
The RC Cornet® is a device with a horn shape, or osteoporosis, uncontrolled chest pain, cos-
and it has a mouthpiece fixed to a curved tube tal fractures, or coagulopathies, and it must
that has rubber on the inside. The rubber on the not be used directly over implanted devices
inside of the horn produces the vibration in the such as gastrostomies. There are many mod-
airways when the patient blows through it. els in the market adapted to the age of the
The RC Cornet® offers less resistance than patient (Flimm- Fighter Percussor®; G5
the Flutter®VRP1, and unlike it, it can be used in Neocussor®; Fluid Flo 2500®; Electro Flo
any position. 5000®).

 ronchial Hygiene Electromechanical

B  echanical Devices for Cough
M
Devices Assistance
These are devices that use a source of electrical Today there are many devices (Cough Assist
power to function. In-exsufflator®, New Respironics T70 Cough
Assist®, Pegaso® , and Nippy Clearway Cough
• High frequency oscillatory compression of the Assistor®) that allow the mechanical improve-
thoracic wall: A generator of air pulses trans- ment of the inspiratory or expiratory phases of
mits compression/oscillation forces to an coughing, either passively or with the collabora-
inflatable vest that is firmly adjusted over the tion of the patient.
thorax and offers externally oscillatory com-
pressions to the thoracic wall with a frequency • Inflator–exsufflator: A mechanical device
between 5 and 25  Hz. The mechanism of provides a deep insufflation, followed by a
action can be explained by the increase of the forced exhalation, simulating a natural
airflow and the production of drag forces simi- cough. This insufflation is generated by a
lar to the ones produced by coughing. The device that provides positive pressure when
vibrations can also reduce the viscoelastic inspiring and negative pressure when expir-
properties of the secretions. The manufactur- ing (suction effect) of at least +40 to −40 cm
ers recommend 1–2 daily sessions of H2O.  This mechanical device can be con-
20–30 minutes each. There are many models nected to the patient through an oral or naso-
in the marked adapted to age (Vest Airway buccal interface or through a tracheotomy.
Clearance System®; Afllo Vest®; Respin 11® Some authors have suggested that the use of
Bronchial Clearance System; SmartVest®; mechanical cough assistance can diminish or
InCourage® System). avoid the need of secretion suctioning in
658 H. Puppo Gallardo and G. Hidalgo Soler

patients with neuromuscular conditions, Bach JR.  Mechanical insufflation-exsufflation.

because the maximum coughing flow Comparison of peak expiratory flows with manually
assisted and unassisted coughing techniques. Chest.
obtained is enough to eliminate them, avoid- 1993;104(5):1553–62.
ing the negative effects of repeated vacuum- Bach JR, Bianchi C, Vidigal-Lopes M, Turi S, Felisari
ing in the airway mucosa. Finally, these G. Lung inflation by glossopharyngeal breathing and
devices are not available to all professionals, “air stacking” in Duchenne muscular dystrophy. Am J
Phys Med Rehabil. 2007;86(4):295–300.
due to their high cost. However, it can be Del Corral T, Herrero B, Muñoz G, Ríos A.  Técnicas
used with multiple patients if the strict cir- manuales para el drenaje de secreciones bronquiales:
cuit cleaning and sterilization standards are técnicas espiratorias lentas. En: Manual de proced-
followed, in a similar way as is applied to imientos SEPAR: técnicas manuales e instrumentales
para el drenaje de secreciones bronquiales en el paci-
the mechanical ventilation devices. ente adulto. Martí JD y Vendrell M, coords. Barcelona:
Ed. Respira-Fundación Española del Pulmón-SEPAR;
2013.
Conclusions Fahy JV, Dickey BF. Airway mucus function and dysfunc-
tion. N Engl J Med. 2010;363(23):2233–47.
Fink JB. Forced expiratory technique, directed cough, and
The physiotherapist who works in respiratory autogenic drainage. Respir Care. 2007;52:1210–21.
care must have a good knowledge of physiology, Guía Clínica AUGE: infección respiratoria baja de
biomechanics, and physiopathology of the manejo ambulatorio en menores de 5 años. Serie
Guías Clínicas, Ministerio de Salud de Chile. 2013.
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Hidalgo G, Puppo H, Romero J.  Kinesiterapia respira-
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and will require a combination of techniques Mediterráneo; 2012.
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anatómicas y funcionales entre el lactante y el adulto.
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techniques are adapted to the commitment level del niño. Santiago: Ed. Universidad Católica; 2007.
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To perform such techniques, it is vitally impor- twophase gas–liquid flow mechanism: asymmetric
periodic flow model. J Appl Physiol. 1987;62:959–71.
tant to know and to correctly apply an optimal McCarren B, Alison JA.  Phyiological effects of vibra-
modulation of the inspiratory and expiratory tion in subjects with cystic fibrosis. Eur Respir J.
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volumes. Myers TR.  Positive expiratory pressure and oscillatory
positive expiratory pressure therapies. Respir Care.
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Acknowledgement Acknowledgements to professors Oberwaldner B.  Physiotherapy for airway clearance in
Jordi Vilaró C. (Universidad Blanquerna, Spain) and paediatrics. Eur Respir J. 2000;15:196–204.
Rodrigo Torres-Castro (Universidad de Chile) for their Postiaux G. Principales técnicas de fisioterapia de limp-
valuable suggestions to the final writing of this chapter ieza broncopulmonar en pediatría. En: Fisioterapia
and to Rodrigo Gajardo R. for the drawings included in it. respiratoria del niño. Madrid: Ed. McGraw-Hill e
Interamericana; 2000.
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Med J. 1979;2(6187):417–8. 2005;146(2–3):291–300.
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M, Louis A, et al. Cough determinants in patients with
 Pulmonary Rehabilitation
in Children with Chronic
64
Respiratory Diseases

Rodrigo Torres Castro, Homero Puppo Gallardo,

and Daniel Zenteno Araos

Contents
Definition  661
Goals of a Pulmonary Rehabilitation Program  661
 arts of a Pulmonary Rehabilitation Program
P  662
Assessment  662
Treatment  665
Education  667
Final Comments  667
Sources  667

Definition The team in charge of the pulmonary rehabili-

tation program should ideally be composed of a
Pulmonary rehabilitation is a comprehensive pediatric pulmonologist, chest physiotherapist,
intervention based on a thorough evaluation of nurse, occupational therapist, nutritionist, psy-
the patient followed by personalized therapies, chologist, speech therapist, and a social worker.
which include muscle training, education, psy- In addition, specialists, such as psychiatrist, neu-
chosocial intervention, and changes in life habits, rologist, and others, that are necessary to meet
in order to improve the physical and psychologi- the requirements of each child should also be
cal condition of people with chronic respiratory included.
disease, as well as promoting adherence to
healthy behaviors that improve their quality of
life in the long term.  oals of a Pulmonary Rehabilitation
G
Program

The goals should be focused on reducing

symptoms and exacerbations, increasing toler-
R. Torres Castro · H. Puppo Gallardo
ance to exercise and increasing participation in
Respiratory Kinesiology, Faculty of Medicine, educational, recreational, and social activities,
Universidad de Chile, Santiago, Chile with the corresponding increase in quality of
D. Zenteno Araos (*) life.
Department of Pediatrics, Universidad de
Concepción, Concepción, Chile

© Springer Nature Switzerland AG 2020 661

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_64
662 R. Torres Castro et al.

 arts of a Pulmonary Rehabilitation

P not reach a maximum level of oxygen consump-
Program tion. It has a wide acceptance by patients: well
tolerated and easy to perform. It has been vali-
To carry out a pulmonary rehabilitation program, dated in children as well as in healthy people and
the professional team needs to develop three com- people with chronic respiratory diseases.
ponents: evaluation, treatment, and education. To carry out the test, an ideally roofed place is
needed, which must have a corridor of 30 meters
long, with cones located 50 centimeters before
Assessment each end, where the child can walk for 6 minutes.
The circuit must have visible marks every 3
 eneral Physical Ability Assessment
G meters and at least 2 seats on the way in case the
Owing to the systemic nature of chronic respira- child wants to stop. In case the child stops, this
tory diseases, it is necessary to assess the physi- should be recorded, but the test is completed
cal ability to perform daily activities. This when reaching 6  minutes. Before starting, the
assessment includes specific laboratory tests, child should be at rest for at least 10 minutes and
which are less accessible, and field tests, which have proper clothing for physical exercise.
usually do not require large equipment and are It is important to stress that for dyspnea assess-
easier to perform (Table 64.1). ment a Borg scale, especially modified for pedi-
atric population, should be used (Fig. 64.1). One
Six-Minute Walk Test (6MWT) of the most important parameters to register is
This field test is used to assess the ability of a lower limbs fatigue, because chronic respiratory
subject to perform physical exercise and is con- diseases condition a multisystemic compromise,
sidered a submaximal exercise test, since it does so the cause of stops is not dyspnea but alteration

Table 64.1  Evaluation tests of a pulmonary rehabilitation program

General physical ability Respiratory muscles
1. Exercise tolerance test 1. Respiratory muscle strength
 Six-minute walk test  Maximum inspiratory pressure
 Constant workload exercise test  Maximum expiratory pressure
2. Determining the training load or symptoms that limit exercise 2. Respiratory muscle endurance
 Incremental shuttle walking test  Sustained maximal inspiratory pressure
 Maximal incremental exercise test  Time limit

Fig. 64.1 Modified
Borg scale for dyspnea

0 Nothing at all
0.5 Very, very weak
1 Very weak
2 Weak (slight)
3 Moderate
4 Somewhat strong
5 Heavy
6 Intermediate
7 Very strong
9 Almost maximal
10 Maximal
0 1 2 3 4 5 6 7 8 9 10
64  Pulmonary Rehabilitation in Children with Chronic Respiratory Diseases 663

Table 64.2  Six-minute walk (6MWT) test reference values

6 years 7 years 8 years 9 years 10 years 11 years 12 years 13 years 14 years
Women 562.5 ± 568.2 ± 556.5 ± 575.7 ± 585.7 ± 606.7 ± 629.4 ± 631.4 ± 638.5 ±
39.1 31.6 48.9a 53.2 28.7 60.3 20.3 50.2a 20.9
Man 562 ± 597.11 ± 605.8 ± 611.4 ± 618.7 ± 608.7 ± 636.1 ± 673.9 ± 674.3 ±
43.1 33.6 62.2a 47 67.5 35.9 47.3 45a 54.2
Total 562.3 ± 580.9 ± 580.1 ± 587.6 ± 603.7 ± 607.8 ± 633 ± 650.3 ± 657.2 ±
39.8 34.7 59.9 52.8 55 47.3 36.8 51.8 44.7
Source: Rev Med Chile 2012; 140: 1014 Creative Commons Licence 4.0
a
p < 0.05

of glycolytic mechanisms that decrease the fati- has fatigue symptoms or dyspnea that prevent him
gability threshold. from continuing.
The most important factor to be determined in The values to be recorded are the walked
the test is the distance walked, which must be distance and the last level of shuttle completed,
compared with reference values. In Chile, for the which corresponds to the maximum speed
pediatric population, we recommend the use of reached.
values of Gatica et  al. (Table  64.2). The final
report should consider the distance that was Cardiopumonary Exercise Testing (CPET)
walked, the lower limit of the ideal distance, and Cardiopulmonary exercise testing is a laboratory
the percentage of the distance that was walked test that measures workload during exercise and
over the lower limit of the ideal distance. analyzes the physiological components of oxy-
gen consumption. In addition, it allows the iden-
Shuttle Walking Test (SWT) tification of the mechanisms that limit the ability
Described in 1992 by Singh et  al. for chronic to exercise: respiratory, cardiovascular, or meta-
obstructive pulmonary disease, it is an incremen- bolic. Owing to its high reproducibility and
tal load test in which the participant must walk repeatability, it is the gold standard of exercise
between two markers located in a corridor 10 tests. It can be performed on most children from
meters long after an auditory signal. As time 6 years old. Its utility lies in establishing the max-
passes, speed increases, so the time between each imum training load and detecting which symp-
sound stimulus is reduced. toms limit the maximum exercise.
It provides very useful information because, Cardiopulmonary exercise testing must be
from the oxygen consumption standpoint, it cre- performed in a pulmonary function lab and be
ates a condition similar to an incremental load carried out by trained personnel, with knowledge
test with a cycle ergometer. of exercise physiology and cardiopulmonary
For its implementation, a 10-meter corridor, in resuscitation. It can be done on a treadmill or
which cones must be placed 50 centimeters from cycle ergometer. The treadmill is mainly used in
each end, is needed. The distance from one end to children with a size less than 120 cm who cannot
the other will be considered a shuttle. In addition, reach the pedals of a traditional cycle ergometer.
it is necessary to have standardized audio, which is There are several incremental protocols;
divided into two types of signals. One beep is used among them, modified Balke or Harbord.
to indicate the start of the walking and 3 beeps are
used to indicate change in speed. The initial walk- (a) Constant load exercise test
ing speed is 0.5 m/sec and it increases by 0.17 m/
sec in each of the 12 levels until ­reaching a maxi- Another way to assess physical resistance of a
mum speed of 2.37 m/sec. It presents a moderate patient with chronic respiratory disease is the
correlation with 6MWT (r = 0.68). The test is fin- constant load exercise test. This test consists of
ished when the participant is not able to complete exposing the patient to a high and constant evalu-
the shuttle for a second consecutive time or when ation load (70–80%), and thus measuring the
664 R. Torres Castro et al.

amount of time the patient is able to maintain the

effort before stopping. In general, this is the most
susceptible test to be modified after a pulmonary
rehabilitation protocol that includes general
physical training.

 ssessment of the Respiratory Muscles

A
Respiratory muscles, as the skeletal muscles,
from the standpoint of their morphology and
functioning, are striated muscles, so they can be
evaluated in both their strength and resistance.
Some children with chronic respiratory dis-
eases have weak respiratory muscles. Although
Fig. 64.2  Evaluation of Respiratory Muscle Strength
the diaphragm muscle is the main breathing (MIP/MEP)
motor, these children often resort to the use of
accessory muscles to supplement the action of given of what is sought and the characteristics of
the diaphragm subjected to high respiratory the orders that will be taught. A nozzle is then
workloads. introduced into the mouth which is connected to
Therefore, an objective assessment of the a 3-way valve that has a 2 mm diameter hole (to
strength and resistance of the respiratory muscles avoid glottic closure during MIP and the involve-
should be made, particularly in children with ment of the face muscles in MEP), which is
neuromuscular diseases in which the decrease in attached to an aneroid manometer. The child is
inspiratory muscle strength is the first indicator asked to breathe two or three times normally so
when there is compromise of the ventilatory that after starting from a maximum expiration,
pump, even before the reduction of forced vital close to the residual volume, the main operator
capacity. blocks the inspiratory branch of the 3-step valve
and requests, with an energetic order, that the
Assessment of the Inspiratory child make an inspiration as strong and main-
and Expiratory Muscle Strength tained as possible (lasting at least 1–2 seconds).
The assessment of the inspiratory and expiratory The child must be able to perform the maneuver
muscle strength can be done through measuring in a repeatable way three times with a difference
respiratory pressures at the mouth, which is a of less than 10%. If he does not get a good
non-invasive method of assessment of strength, maneuver on the eighth try, he should be sched-
easy to perform and inexpensive. From this eval- uled for another day. The MEP maneuver is per-
uation, maximum inspiratory pressure (MIP, formed in the same position (with the same
through the Müller maneuver) and maximum connection but with a positive pressure gauge)
expiratory pressure (MEP, through the Valsalva and with similar initial orders of the MIP,
maneuver) can be determined. although after an inspiration up to total lung
To perform the maneuver, two operators are capacity, requesting a maximum expiration of at
needed (Fig. 64.2), the main one with extensive least 2 seconds long.
experience. The assistant will stand behind the The final report should consider: reference
patient and will have to compress his cheeks to values used, values of the best MIP and MEP
avoid the action of both buccinator muscles and measured, average ideal values and lower limits
any possible leak through the corners of the to be reached, and percentage of MIP and MEP
mouth. To perform the MIP maneuver, the child obtained concerning lower limits of the reference
must be seated with both feet on the ground and values used.
the main operator in front of him. As it is not a It is recommended to use the reference values
familiar maneuver, a careful explanation must be of Szeinberg et al.,
64  Pulmonary Rehabilitation in Children with Chronic Respiratory Diseases 665

(b) Assessment of inspiratory muscle endurance training as a process through which organs and
systems are stimulated, periodically and system-
Endurance of the inspiratory muscles can be atically, in order to obtain a specific response
evaluated through the ventilatory endurance test dependent on the stimulus applied. The funda-
or the test based on the ability of these muscles to mental principles of muscle training are: progres-
create sustained high-pressure levels. sive overload, specificity, and reversibility. In
addition, the subject’s initial physical capacity
• Sustained maximal inspiratory pressure must always be taken into account. The profes-
(SMIP): It is an incremental load test described sional who prescribes the exercise, supervises it,
by Nickerson and Keens, and has proven to be and applies it should be highly trained in exercise
the most reproducible and best tolerated test. physiology, indications, and muscular training
It is performed asking a child to breathe programming, knowing its beneficial and harm-
through an external threshold-type device, in ful effects.
which every 2 minutes the resistance increases In adults, there is ample evidence of the
between 5% and 10% (of the previously effectiveness of aerobic training programs.
obtained MIP) until reaching the maximum However, in pediatrics, only cystic fibrosis has
load that the subject is capable of sustaining produced an increasing number of publications
for two full minutes, and the maximal inspira- with training protocols that have shown positive
tory pressure that is capable of being created results for the different parameters evaluated.
during that period (sustained maximal inspira- Vigorous physical activity increases exercise
tory pressure, SMIP). Once the value of the tolerance in children with cystic fibrosis,
SMIP is obtained, it must be related to the increases work capacity, improves cardiorespi-
child’s PIM.  It has been established that a ratory fitness, respiratory and peripheral mus-
SMIP/MIP index must be higher than 65% to cles endurance, and contributes to improve
determine that the respiratory muscles have a immune function. Recently, in a nine-year fol-
proper resistance. Minor values may deter- low-up, it was demonstrated that high levels of
mine that the child is a candidate for specific physical activity in subjects with CF are associ-
training of his respiratory muscles. ated with a lower decline in lung function mea-
• Time limit test: It is a constant load test in sured through FEV1.
which the child must breathe as long as pos- The best results have been obtained in super-
sible against a constant resistance that leads to vised programs. Other programs that included
fatigue. Use of high loads (over 60–80%) is swimming, cycling, and trampoline showed posi-
recommended, although in patients with neu- tive effects on exercise tolerance, work capacity,
romuscular diseases (especially Duchenne and improvement in physical capability, lower
muscular dystrophy) the use of low loads (35– extremity strength, sputum production, dyspnea,
40%) is recommended. The value to be and pulmonary function.
recorded as result is the total time (in seconds) Among children with asthma, the vast major-
of the test duration. ity should have a physical performance similar to
normal subjects. The fact that asthma patients
have physical deconditioning and a sedentary life
Treatment would be given by the restriction to the realiza-
tion of physical activity imposed mainly by his
General Physical Training parents and the doctor, without a strong scientific
Sustained activity of the skeletal muscles, with a basis.
set up intensity and duration, produces adaptive There are several studies that show that
changes in their structure and in their perfor- general exercise programs, performed on a
mance. Physical training is a fundamental part of regular basis, improve aerobic physical capac-
a pulmonary rehabilitation program. We define ity, work capacity, and VO2max in children
666 R. Torres Castro et al.

with asthma. After reviewing 48 articles on I nspiratory Muscle Training (IMT)

physical activity of patients with asthma, Satta Ventilatory muscles, as well as skeletal muscles,
found: less need for medication, reduced num- can change their strength and endurance in
ber of visits to emergency rooms, less school response to a specific training program.
absenteeism and, in addition, an improvement The observable responses after a specific
in spirometry parameters. Poor physical per- inspiratory muscles training process are:
formance of these subjects could be related to
their poor nutritional status, myopathy due to (a) Improvement in strength and endurance of
the use of corticosteroids or their physical respiratory muscles
deconditioning. (b) Greater ability to perform exercises
In neuromuscular diseases, the evidence of (c) Decreased dyspnea
the benefit of physical activity is dissimilar (d) Delays onset of muscle fatigue
regarding the intensity of exercise. In slowly
(e) Restoration in the mechanical ventilation
progressive diseases, moderate endurance exer- weaning process
cise programs have been shown to be effective,
but high-load exercise programs have proven to Patients eligible to undergo inspiratory muscle
be counterproductive. training are:
There are several recommended protocols
of physical training, which must be adapted to (a) Restrictive diseases: kyphoscoliosis, neuro-
age, collaboration level, compromise degree, muscular symptoms, etc.
and available resources. In preschool, physical (b) Obliterative bronchiolitis
activity should be encouraged through games, (c) Muscle weakness after prolonged mechani-
according to the interests and motivations of cal ventilation
their age. On the other hand, in schoolchildren (d) Cystic fibrosis
and adolescents sports activities, especially in
groups, will have a more important role. The most used inspiratory muscle training
Regarding their degree of deterioration, atten- system today is the threshold valve, which uses a
tion should be paid to children who use supple- 2  cm diameter valve with a spring that keeps it
mental oxygen. To avoid hypoxemia, associated closed. To be able to inspire, the subject must cre-
with exercise should be evaluated increasing ate a certain pressure with their inspiratory mus-
the fraction of inspired oxygen. In addition, cles, such that it can overcome a preset load (30%
training adaptations should be considered if it of the MIP is usually recommended, combining
is conducted in a hospital environment, in pri- efforts up to 70% of the MIP) allowing to open
mary care or in the community (Table 64.3). the valve and thus starting the inspiratory flow.
This training system has the advantage that the
load determined by the spring tension is indepen-
Table 64.3  Physical training recommendations dent of the flow that the patient uses.
Intensity 60–80% of the maximal work rate of the In children, studies that apply specific inspira-
cardiopulmonary exercise test (cycle tory muscle training are scarce. Sawyer et  al.
ergometer) indicate that 10  weeks of inspiratory muscle
60–80% treadmill
In primary care it is possible to use training in children with cystic fibrosis showed
60–80% of the average speed of the 6MWT improvement in exercise tolerance and inspira-
or 60–80% of the heart rate reserve tory muscle function parameters. In 1999, Gozal
Type Intervallic/continuous et al. demonstrated an improvement in the respi-
Frequency 3 times per week ratory muscle function parameters of up to 30%
8 sessions: 60%
8 sessions: 70% of the MIP in a year in patients with Duchenne’s
8 sessions: 80% disease and type III spinal muscular atrophy after
Duration 24 sessions (at least 30 minutes) specific ventilatory muscle training. They also
64  Pulmonary Rehabilitation in Children with Chronic Respiratory Diseases 667

noted that after stopping the training the patient Final Comments
returns to baseline values approximately
3  months after the end of the program. Topin The scientific application of physical exercise for
applied a load of 30% of the MIP in subjects with therapeutic purposes is the main component of a
Duchenne muscular dystrophy and found a sig- pulmonary rehabilitation program. At present,
nificant improvement in inspiratory muscle the World Health Organization recommends sys-
endurance, showing that this load amount is tematic physical activity as one of the main strat-
effective and does not cause baseline MIP dete- egies in the prevention of the global increase of
rioration in these patients. It has also been estab- chronic noncommunicable diseases. However,
lished that, based on current knowledge, pulmonary rehabilitation does not consist exclu-
inspiratory muscle training should be applied sively in physical training, but also in a series of
along with general physical training to obtain components whose main objectives are to inter-
maximum clinical and quality of life benefits. vene in organic, functional, and social aspects
In summary, specific training of the inspira- that minimize the progression of the disease and
tory muscles with appropriate equipment and improve the quality of life of chronic patients. It
with an inspiratory muscle training program that is essential that each health center be responsible
considers using low training loads of 30–40%, for developing a comprehensive pulmonary reha-
together with moderate loads of 50–60%, for at bilitation program that involves a multidisci-
least 20 minutes a day, 3–5 times per week for a plinary team of professionals who are highly
minimum of 8 weeks, will achieve positive results motivated and coordinated, maximize the bene-
in multiple types of pediatric diseases, especially fits of each of the components of the program,
in aspects related to muscle endurance. However, always aiming to promote a healthy lifestyle to
based on current evidence, it should be taken into the patients.
account that loads prescribed to children with The quality of pulmonary rehabilitation pro-
Duchenne’s disease do not exceed 30% of the grams developed in centers of excellence should
MIP. For all the above, application of inspiratory be ensured in such a way that their benefits can
muscle training should always be considered in be transferred to less specialized health centers,
rehabilitation programs of chronic respiratory in order to secure better accessibility for all
patients, further studies being necessary for its patients.
systematic application in pediatrics. Finally, we must not forget that “incurable is
not the same as untreatable”.

Education
Sources
Education is a fundamental component in the
success of a pulmonary rehabilitation program. It Beroiza T, Cartagena C, Caviedes I, Céspedes J,
must be done by all the professional team and Gutiérrez-­Navas M, Oyarzún M, et  al. Prueba de
caminata de seis minutos. Rev Chil Enferm Respir.
focused on improving therapeutic compliance 2009;25(1):15–24.
and promoting a healthy lifestyle. Gatica D, Puppo H, Villarroel G, San Martín I, Lagos
Among the educational interventions are: R, Montecino JJ, Lara C, Zenteno D.  Valores de
­referencia del test de marcha de seis minutos en niños
sanos. Rev Méd Chile. 2012;140(8):1014–21.
• Supervision of the indicated treatment, in par- Güell R, Díaz Lobato S, Rodríguez-Trigo G, Morante F,
ticular of the inhaled drugs, checking periodi- San Miguel M, Cejudo P, et  al. Normativa SEPAR
cally their use and good execution. Rehabilitación respiratoria. Arch Bronconeumol.
• Recognition of early symptoms on the part of the 2014;50(8):322–44.
Matecki S, Topin N, Hayot M, Rivier F, Echenne
patient for timely detection of exacerbations. B.  Prefaut evaluation of respiratory muscle endur-
• Information about the benefits of physical ance in patients with Duchenne muscular dystrophy.
activity and a balanced diet. Neuromuscul Disord. 2001;11:171–7.
668 R. Torres Castro et al.

Pianosi P, LeBlanc J, Almudevar A. Peak oxygen uptake tests in children with cystic fibrosis. Pediatr Pulmonol.
and mortality in children with cystic fibrosis. Thorax. 2003;35(2):133–8.
2005;60:50–4. Singh SJ, Morgan MD, Scott S, Walters D, Hardman
Santuz P, Baraldi E, Filippone M, Zachello F.  Exercise AE.  Development of a shuttle walking test of dis-
performance in children with asthma: is it differ- ability in patients with chronic airways obstruction.
ent from that of healthy controls? Eur Respir J. Thorax. 1992;47:1019–24.
1997;10:1254–60. Spruit MA, Singh SJ, Garvey C, Zuwallack R, Nici L,
Satta A. Exercise training in asthma. J Sports Med Phys Rochester C, et  al. An official American Thoracic
Fitness. 2000;40:277–83. Society/European Respiratory Society statement: key
Sawyer E, Clanton T.  Improved pulmonary function concepts and advances in pulmonary rehabilitation.
and exercise tolerance with inspiratory muscle con- Am J Respir Crit Care Med. 2013;188(8):e13–64.
ditioning in children with cystic fibrosis. Chest. Topin N, Matecki S, Hayot M, Le Bris S, Rivier F,
1993;104:1490–7. Echenne B, et  al. Dose-dependent effect of indi-
Schneiderman J, Wilkes D, Atenafu E, Nguyen T, vidualized respiratory muscle training in children
Wells G, Alarie N, et  al. Longitudinal relation- with Duchenne muscu-Lar dystrophy. Neuromuscul
ship between physi-cal activity and lung health Disord. 2002;12:576–83.
in patients with cystic fibro-sis. Eur Respir J. Zenteno D, Puppo H, Vera R, Torres R, Kuo CH, Salinas
2014;43:817–23. P, et al. Guías de Rehabilitación Pulmonar para Niños
Selvadurai HC, Cooper PJ, Meyers N, Blimkie CJ, Smith con Enfermedades Respiratorias Crónicas. Neumol
L, Mellis CM, Van Asperen PP. Validation of shuttle Pediatr. 2008;3(Supl 1):25–33.
 Prolonged Hospitalization
Due to Chronic Respiratory
65
Diseases

Mireya Méndez Raggi
and Claudia Astudillo Maggio

Contents
Introduction  669
Definitions  670
 hronic Hospitalization Outside the Intensive Care Unit
C  670
Aims of Chronic Hospitalization  671
Goals of Chronic Hospitalization  671
Medical Team  671
Role of the Professional Team  672
Infrastructure and Equipment  672
Monitoring of Chronic Respiratory Ill Patient by Level of Complexity  672
Routine Monitoring to Avoid in-Hospital Infections  673
Additional Activities  673
Progression  674
Discharge Planning  674
Sources  674

Introduction 100,000 children. Taking into account that this

population is at a higher risk of disease, hospital-
The population with chronic respiratory disease ization, and death, they entail a large economic
is diverse, and it includes multiple congenital and and social cost for the country.
acquired conditions. In the United States there is During the past few decades there has been a
an estimated prevalence of 6–14 patients per sustained improvement in different Chilean
health indices due to the implementation of pro-
M. Méndez Raggi · C. Astudillo Maggio (*) grams, such as pregnancy control, national
Pediatrics, Respiratory Diseases, Hospital Josefina immunization program, and national program
Martínez, Puente Alto, Chile for acute respiratory infections. In addition,
Pontificia Universidad Católica de Chile, great technological developments in neonatol-
Santiago, Chile ogy and pediatric units have increased the sur-
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 669

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_65
670 M. Méndez Raggi and C. Astudillo Maggio

vival rate of very low weight preterm newborns

or seriously ill children, thus generating patients Medically fragile or special needs popula-
with mainly respiratory and neurological tion. They depend on technology, including
sequelae. chronic oxygen therapy, invasive or non-
Infants and children who suffer from chronic invasive ventilatory support, periodic car-
diseases are at the highest risk of physical, devel- diorespiratory monitoring, chronic dialysis,
opmental, behavioral or emotional problems tracheotomy, ventriculoperitoneal bypass
requiring special health care, adequate infrastruc- valve, gastrotomy, or central venous cathe-
ture, and management by qualified personnel. ter carrier; additionally, patients with
There is a particularly relevant group of critically severe delayed psychomotor development
ill chronic patients who depend on mechanical or suffering from three or more chronic
ventilation, patients who have undergone trache- conditions.
otomy or those who are oxygen-dependent. They
constitute a special challenge for the health care
system. Most of these patients are hospitalized in This type of patient would then be susceptible
pediatric intensive care and neonatal intensive to chronic hospitalization. However, what would
care units, where even though they are a minority be the best scenario for these children? Their
of admissions, their long stays consume a great home, without a doubt. When this is not possible
amount of resources. This has made the existence for different reasons, hospitalization must be
of step-down units or long-stay hospitals much done in an environment that allows their compre-
more necessary, so that these patients can con- hensive development with the aim of home dis-
tinue their treatment and be discharged into a charge. Ideally, this must be done outside of the
home hospitalization system. There have been intensive care unit.
national programs proposed in Chile to cover
these needs, such as the ambulatory oxygen ther-
apy program from 2003 and the domiciliary inva-  hronic Hospitalization Outside
C
sive and non-invasive mechanical ventilation the Intensive Care Unit
program from 2006.
The Josefina Martínez Hospital, founded in
Santiago de Chile in 1945, is a pediatric center
Definitions specialized in respiratory and integral care in
children suffering from chronic respiratory dis-
It is not easy to find a pediatric definition for pro- eases. It was created as a treatment center for
longed mechanical ventilation dependent children diagnosed with tuberculosis, later focus-
patients, or for those who have had to use any ing on treating patients with mainly post-viral
other sort of technology. There is, however, a obliterative bronchiolitis, bronchopulmonary
consensus on concepts, such as chronic mechani- dysplasia, and cystic fibrosis in mechanical venti-
cal ventilation and medically fragile patients or lation dependent patients. In 2006 the hospital
patients with special needs. started treating patients under both invasive and
non-invasive mechanical ventilation. Currently,
the hospital has 54 beds intended for patients suf-
Prolonged mechanical ventilation. Longer fering from chronic respiratory disease, neuro-
than 3 weeks with invasive or non-­invasive muscular diseases, or airway diseases, most of
ventilatory support. which have undergone tracheotomy and depend
on mechanical ventilation. The average length of
65  Prolonged Hospitalization Due to Chronic Respiratory Diseases 671

stay varies from months to years, with the most initial evaluation by the multidisciplinary team in
frequent prolongation cause being problems of a order to plan how the attention will be delivered
social nature (habitability, precarious family con- and what the aims will be depending on each
ditions) and neurological compromise of the child’s base condition and prognosis. At the same
patient. time, there must be a close interconnection
between intensive care units, so that the patient
can be transferred swiftly in case of a decompen-
Aims of Chronic Hospitalization sation beyond the level of complexity the long
term stay center can handle, and the home care
1.
Receive care unavailable in outpatient service, in order to achieve an expeditious and
programs. safe transition to home care when conditions
2. Facilitate the transition from critical care units allow it.
to home care, allowing the stabilization of the
patient.
3. Educate the family, patients, and health care Goals of Chronic Hospitalization
team about outpatient attention.
4. Evaluate, select equipment, choose ventila-
1. Perform weaning, decannulation or pro-

tory modality, and title the parameters for grammed oxygen assistance removal when
chronic mechanical ventilation. possible.
5. Manage respiratory exacerbations. 2. Restore swallowing, phonation, general and
6. Prevent caregiver fatigue. This last point has respiratory musculature.
been raised in some countries with the aim of 3. Insert the patient in a preschool or school

allowing parents to rest. environment as applicable.
4. Collaborate both in the social and psychologi-
Centers that treat chronic respiratory patients cal recovery of the child and their family.
must coordinate with the technical and human 5. Transferring the patient home, ideally after
facilities to deliver respiratory and integral care overcoming the reasons for admittance.
in order to allow the harmonious development of
children. Results will depend on a rigorous selec- In order to reach these goals, the hospital or
tion of qualifying patients (Table  65.1) and an unit must have a highly specialized multidisci-
plinary team with defined roles, monitoring
Table 65.1  Admittance conditions
teams and ventilatory support, while also hav-
ing access to support diagnosis and therapeuti-
Clinic Social-ethic
cal units.
Hemodynamic stability during the Ethics committee
past 2 weeks if necessary
Stable ventilatory parameters for Agreement to
the past 3 weeks, with FiO2 lower transfer by parents Medical Team
than 0.4. Last arterial blood gasses or guardians
without acidosis Updated
Permeable airway, mature psychosocial The leader of the team must be a pediatric pulmo-
tracheotomy report nologist, coordinating diagnosis, treatment, and
Negative viral respiratory study rehabilitation, designating the starting and end
made during epidemic period
point of mechanical ventilation and oxygen,
Carriage of multi-resistant bacteria
study (enterococcus, positive picking out the team and ventilatory strategy,
ESBL, MRSA) performed during organizing diagnostic and therapeutic proce-
the 7 days prior to transfer dures, while also performing, interpreting, and
672 M. Méndez Raggi and C. Astudillo Maggio

reporting tests on pulmonary function, bronchos- in the case of a sensorimotor disfunction that
copy, polysomnography, oximetry, and continu- limits patient functionality.
ous capnography. • Occupational therapist: Promotes the acquisi-
The team’s pediatrician is in charge of giving tion of daily life skills (independence and
clinical attention, diagnosing, and treating respi- autonomy). Designs, elaborates, and applies
ratory exacerbations, coordinating health atten- technical assistance (orthosis). Promotes play,
tion related to the general pathologies occurring social participation, and schooling of the
from the child’s developmental status. child.
The team’s child neurologist must organize • Dietist: Supervises the implementation of the
the neurorehabilitation team and evaluate, diag- diet as indicated by the nutritionist.
nose, and indicate pharmacological treatment of Collaborates in diagnosis and prescription of
the neurological pathology. nutritional therapy with the physician.
The physiatrist is in charge of managing the • Speech-language pathologist: Performs reha-
rehabilitation team, performing diagnosis, indi- bilitation of swallowing and phonation with or
cating orthosis, and carrying out the necessary without assistance devices (like phonation
therapeutical procedures such as applying botox. valves).
The nutritionist manages the clinical nutrition • Psychologist: Does psychological and social
team and performs the nutritional evaluation and diagnoses. Gives psychological therapy to
monitoring, diagnosing, as well as indicating the children in prolonged hospitalization.
nutritional therapy to follow (energy intake and Comforts and supports parents and relatives of
supplements). The dietitian is also in charge of the patients.
defining the specifications and means of feeding. • Social worker: Evaluates habitability through
the use of instruments and support networks’
management.
Role of the Professional Team

It is of the utmost importance for comprehensive Infrastructure and Equipment

treatment to involve all professionals who consti-
tute the health team. This team performs a com- Adequate treatment requires non-invasive moni-
plementary role and their functions are described toring equipment, ventilators and flow genera-
as follows: tors that deliver invasive and non-invasive
mechanical ventilation, exhalation systems,
• Nurse: Manages care on the basis of models as oxygen and vacuum network, drug and feeding
the primary nurse and self-care, coordinates infusion pumps, pulse oximetry and continuous
and supervises daily attention to the child, capnography, and access to diagnosis support
involving specific techniques and procedures. and therapy units, such as a lung function labo-
Trains professionals, technicians, and ratory, sleep studies, bronchoscopy, radiology,
caregivers. and clinical laboratory.
• Respiratory physiotherapist: Delivers respira-
tory care and ventilatory therapy, implements
manual and assisted airway permeation tech-  onitoring of Chronic Respiratory
M
niques, performs pulmonary function tests, Ill Patient by Level of Complexity
and assists in the rehabilitation of respiratory
musculature. Performs and monitors weaning From the time of admittance, children begin a
and decannulation. dynamic and individualized process that takes
• Motor physiotherapist: Determines motor into account their characteristics and potentials,
diagnosis in the area of neurorehabilitation in going through their different levels of complexity
order to develop the treatment plan. Intervenes (Table 65.2).
65  Prolonged Hospitalization Due to Chronic Respiratory Diseases 673

Table 65.2  Classification of most frequent diagnoses from a professional, a technician, or a well-­
Neuromuscular Spinal muscular atrophy, muscular trained caregiver who could interpret alarming
diseases dystrophy signs.
Central nervous Congenital central hypoventilation
system diseases syndrome, Arnold Chiari
Airway diseases Subglottic stenosis, malacias, Pierre
Robin sequence and other genetic  outine Monitoring to Avoid
R
disorders causing the obstruction of in-Hospital Infections
the upper airway
Lung parenchyma Bronchopulmonary dysplasia,
diseases bronchiolitis obliterans, cystic Prolonged hospitalization is not a linear process,
fibrosis because the patient may suffer from exacerba-
Miscellaneous Congenital scoliosis tions or decompensation from their base condi-
tion that may delay or change the progression of
the disease. Healthcare associated infections are
The concept of health care safety is particu- still an important cause of morbidity and mortal-
larly relevant for such patients at high risk of ity. That is why it is so important to consider a
adverse effects, such as accidental decannula- monitoring system for multi-resistant or emer-
tion, obstruction of the airway, displacement of gent pathogens, such as vancomycin-resistant
the gastrostomy tube or the cannula. This calls enterococci or extended-spectrum beta-lacta-
for permanent monitoring and continuous mase bacteria and a system to control associated
supervision, making sure of not interfering in infections to healthcare emphasizing hand sani-
the patient’s psychomotor development. tation in addition to the rational use of antimi-
Therefore, the monitoring system must fit the crobial agents.
therapeutic strategy and the risk level of each
patient.

• Patient with ventilatory support through tra- Additional Activities

cheotomy: Such a patient must have perma-
nent non-invasive monitoring for cardiac The complete human development of the child
frequency and hemoglobin saturation with or requires other additional, but no less important,
without capnography (particularly useful activities, such as play. There must be adequate
when changing parameters or managing exac- spaces to develop therapeutic play activities
erbations). Arterial blood gas to obtain instant guided by therapists, psychologists, techni-
information in case of decompensation or fol- cians, and preschool educators, depending on
low-­up of the patient. the age of the patient. Many of these children
• Patient with non-invasive ventilatory support: have spent their whole lives under hospital care,
Non-invasive cardiac frequency and saturation which is why it is so important to be with them
monitoring. Arterial blood gas if necessary. during their process of socializing and discov-
• Tracheotomized patient without ventilatory ering the world beyond the hospital by visiting
support: Non-invasive monitoring at least dur- parks, the beach, the zoo, and by partaking in
ing sleep. Arterial blood gas or capnography if cultural and entertainment activities like the
necessary. movies, circus, museum, etc. Every child has
• Oxygen assistance dependent patient: Isolated the right to receive an education. Some centers
monitoring of hemoglobin saturation except have created their own in-hospital classrooms,
in unstable or exacerbated patients, who may but it seems that the option of sending the child
require permanent monitoring. to a kindergarten or school beyond the hospital
walls, despite coming at a higher physical and
It is important to note that any monitoring human cost, is an enriching experience within
system must go hand in hand with direct control their integration process.
674 M. Méndez Raggi and C. Astudillo Maggio

Progression to find out the skills that they have already

acquired. It is recommended to have a struc-
Progression and hospitalization time will be tured training plan, including basic anatomy and
determined by the characteristics of the patient, physiology, learning, and skill acquisition. A
underlying pathology and prognosis, as well as successful transition to home care will require
their rehabilitation potential. The patient may having all these factors in mind.
move from permanent invasive mechanical venti-
lation to partial or complete independence from
the ventilator. A tracheotomized patient may also Sources
have to undergo corrective airway surgery, lead-
ing to a successful decannulation. There will Carson S. Definitions and epidemiology of the chronically
critically ill. Respir Care. 2012;57(6):848–56.
invariably remain patients who depend on venti- Dasgupta A, Rice R, Masha E, Litaker D, Stoller J. Four
lation, but they may be able to use a wheelchair, year experience with a unit for long term ventilation
improving their quality of life. (respiratory special care unit) at the Cleveland Clinic
Foundation. Chest. 1999;116(2):447–56.
Dursun O, Osel D.  Early and long-term outcome after
tracheostomy in children. Pediatr Int. 2011;53:202–6.
Discharge Planning Escarravil J, Casolivé V. Terapias respiratorias y cuidados
del paciente neuromuscular con afectación respirato-
Discharge must be planned once the cause for ria. Manual SEPAR de Procedimientos 2012.
González-Cortés R, López-Herce-Cid J, García-­
hospitalization has been overcome or stabilized. Figueruelo A, Tesorero-Carcedo G, Botrán-Prieto M,
In chronic patients, discharge is a process that Carrillo-Álvarez A.  Ingreso prolongado en la uni-
starts the moment of admission and ends when dad de cuidados intensivos pediátricos: mortalidad
the child is transferred back home. Discharge y consumo de recursos asistenciales. Med Intensiva.
2011;35(7):417–23.
planning must be undertaken by the coordinated Graf J, Montagnino B, Hueckel R, McPherson
efforts of the medical team at the hospital center, M.  Pediatric tracheostomies: a recent experience
the family or caregivers, and the health team that from one academic center. Pediatr Crit Care Med.
will tend to the patient at home. There is a home 2008;9(1):96–100.
Lenker C, Slayton D, Gutiérrez H. Planificación del alta en
ventilation support program in Chile supported el niño con trastorno pulmonar crónico. En: Sánchez
by the Ministry of Health. Networks formed by I y Prado F.  Enfoque clínico de las enfermedades
the treating team, the home care team, and the respiratorias del niño. Santiago de Chile: Ediciones
health team at the closest hospital to the patient’s Universidad Católica de Chile; 2007. p. 511–9.
Méndez M, Prado F, Navarro S, Sánchez I.  Rol de un
home are established much like they did before hospital especializado en los cuidados respiratorios
discharge. de pacientes con enfermedades pulmonares cróni-
When transferring the patient home is not an cas. En: Sánchez I y Prado F.  Enfoque clínico de
option, other alternatives must be offered, such las enfermedades respiratorias del niño. Santiago de
Chile: Ediciones Universidad Católica de Chile; 2007.
as finding capable and willing relatives, hospi- p. 521–8.
tals close to the patient’s home, or institutions Monteverde E, Fernandez A, Poterala R, Vidal N, Siaba A,
that have the technology that the patient requires. Castelani P, et al. Characterization of pediatric patients
Education of the health personnel and caregiv- receiving prolonged mechanical ventilation. Pediatr
Crit Care Med. 2011;12(6):287–91.
ers is perhaps the most critical factor regarding Paulides F, Plötz F, Verweij-van den Oudenrijn L, van
the safety and success of home care. That is why Gestel J, Kampelmacher M.  Thirty years of home
it deserves careful attention and planning. mechanical ventilation in children: escalatin need for
Training must be carried out in an organized pediatric intensive care beds. Intensive Care Med.
2012;38:847–52.
manner without making assumptions about the Peterson-Carmichael S, Cheifetz I. The chronically criti-
education level of the health personnel, the cally III patient: pediatric considerations. Resp Care.
tutors, or caregivers. A probe must be conducted 2012;57(6):993–1002.
 Oxygen Therapy
66
Alejandra Zamorano Wittwer
and Claudia Astudillo Maggio

Contents
Introduction  675
 hysio Pathological Basis 
P  676
Causes of Hypoxemia.. 676
Oxygen Prescription....  677
Complications  680
Conclusions  681
Sources  681

Introduction the arterial oxygen pressure and the hemoglobin

saturation are maintained within normal ranges.
Oxygen therapy is a therapeutic procedure It is important to consider that low oxygen
designed to prevent and treat the symptoms of availability can have different etiologies, since it
hypoxia, mainly hypoxemic, such as increased not only depends on oxygen delivery but also on
cardiovascular and respiratory work, depression ventilation, concentration and saturation of the
of the central nervous system, cyanosis, and irri- hemoglobin, along with the cardiac output. This
tability. This is achieved by increasing the oxy- is why we can distinguish different hypoxia
gen content in the arterial blood through the types: hypoxic hypoxia or hypoxemia with low
administration of additional oxygen in the air that PaO2 and low hemoglobin saturation; anemic
the patient breathes, in sufficient quantity so that hypoxia with low concentration of hemoglobin;
cardiac hypoxia due to low cardiac output; dis-
sociative hypoxia with decreased capacity of
A. Zamorano Wittwer (*) hemoglobin saturation, increased affinity of
Department of Pediatrics, School of Medicine, hemoglobin (Hb) for oxygen. It is in hypoxemia
Pontificia Universidad Católica de Chile, where additional oxygen therapy is the most sig-
Santiago, Chile nificant. In the other causes of hypoxia there is a
C. Astudillo Maggio secondary clinical benefit, but treatment of the
Pediatrics, Respiratory Diseases, Hospital Josefina underlying cause and disease is fundamental.
Martínez, Puente Alto, Chile
Administration of oxygen is indicated in the
Pontificia Universidad Católica de Chile, presence of acute or chronic hypoxemia with
Santiago, Chile

© Springer Nature Switzerland AG 2020 675

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_66
676 A. Zamorano Wittwer and C. Astudillo Maggio

PaO2 < 60 mmHg, where the affinity of Hb for extreme in the case of absence of ventilation,
O2 decreases rapidly, affecting the total content as in massive atelectasis or extended consoli-
of O2 and the oxygenation of tissues. dated pneumonia, called intrapulmonary
Use of oxygen therapy dates back to the first shunt. Intracardiac shunt or vascular shunt
decades of the twentieth century and is currently the occur when the blood bypasses the pulmonary
fundamental therapeutic tool in treatment of patients vessels by a cardiac defect or arteriovenous
with respiratory failure, both acute and chronic. In malformations. Shunts are a frequent cause of
recent years, we have seen an increase in its indica- differential diagnosis in patients with hypox-
tion as long-term therapy in pediatrics, explained by emia in which a respiratory cause is not found.
a rise in chronic respiratory diseases and by techno- Oxygen administration, even 100%, only
logical progress of neonatology and intensive care. gives a small increase in arterial PaO2.
In these cases, benefits, such as a shorter time of 3. Hypoventilation. Hypoventilation occurs
hospitalization, improved growth, better physical when the amount of fresh gas that reaches the
and neurological development of the child, alveoli per unit time (alveolar ventilation) is
increased tolerance to exercise, better sleep quality, reduced. It always causes a concomitant ele-
and prevention of pulmonary hearth disease or cor vation of the PaCO2 that allows differential
pulmonale, have been demonstrated. diagnosis. It is usually caused by diseases
outside the lungs, such as respiratory center
depression secondary to drugs use; medulla
Physio Pathological Basis oblongata diseases, such as encephalitis,
hemorrhages and neoplasms; abnormalities
Causes of Hypoxemia of the spinal cord such as those related to
upper cervical spine dislocations; anterior
It is essential to analyze which mechanism is horn diseases such as poliomyelitis; nerve
responsible for hypoxemia, since it is closely diseases that causes innervation in the respi-
related to the real benefit of oxygen therapy. ratory muscles such as Guillain-Barré syn-
These physiopathological mechanisms can coex- drome; neuromuscular junction diseases
ist in the same patient simultaneously and in an such as myasthenia gravis; respiratory mus-
evolutive form over time. cles diseases, such as Duchenne muscular
dystrophy, thoracic cage abnormalities, or
1. Ventilation–perfusion mismatch. Ventilation– upper airway obstruction.
perfusion mismatch occurs when ventilation
and blood flow are unbalanced in different The hypoxemia caused by hypoventilation,
lung regions, making all gas transfer ineffi- which is rarely severe, is easily reversed by add-
cient. It is the most common and frequent ing a moderate oxygen supply to the inspired gas,
mechanism of hypoxemia in children. Its most but it does not reverse its main problem, hypoven-
prominent causes are obstructive pulmonary tilation and hypercarbia.
diseases, such as asthma and bronchiolitis, and
restrictive disease, such as pneumonia and 4. Diffusion Limitation. Diffusion limitation
atelectasis. Other causes are interstitial lung occurs when the gases for interchange are
disease and vascular disorders, such as pulmo- dilated with inappropriate balance between
nary embolism. Under these circumstances, pulmonary capillary blood PCO2 and alveolar
the administration of oxygen at low rate is usu- gas. At rest, capillary blood PCO2 reaches the
ally very effective in improving arterial PaO2. balance of the alveolar gas after a third of the
2. Shunt. A pulmonary shunt occurs when an total contact time of three quarters of a second
important part of the blood reaches the arterial available in the capillary. In intense exercise,
system without passing through the lung ven- where the contact time is reduced to a quarter
tilated regions. This situation can be an of a second, balance almost always occurs. In
66  Oxygen Therapy 677

some diseases where blood–air barrier is Table 66.1  Oxygen therapy: chronic diseases
thickened, diffusion is so delayed that this bal- Lung diseases
ance is incomplete. Examples of diseases that  Intrinsic parenchymal  Restrictive lung disease
disease  Neuromuscular diseases
can cause this disorder are: asbestosis, sar-
 Chronic neonatal lung  Chest wall diseases
coidosis, pulmonary fibrosis, interstitial pneu- disease  Upper airway obstruction
monia, and collagenopathies that compromise  Pulmonary hypoplasia  Primary pulmonary
the lungs, such as scleroderma, rheumatoid  Congenital hypertension (PPH)
diaphragmatic hernia  PPH secondary to lung
arthritis, lupus erythematosus, Wegener’s
 Interstitial lung disease
granulomatosis, Goodpasture syndrome, and diseases
alveolar cell carcinoma. A moderate increase  Idiopathic pulmonary
of inspired oxygen concentration corrects the fibrosis
 Advanced cystic
hypoxemia.
fibrosis
5 . Diminished Inspired PAO2. Alveolar PAO2 is  Advanced
decreased at high altitude because atmo- bronchiolitis
spheric pressure is low and oxygen pressure  Bronchiectasis
decreases proportionally with lower basal Heart disease with PPH
Palliative care
oxygen saturation levels.

extrapulmonary problems. Table  66.1 lists the

Oxygen Prescription main causes of prescribing for long-term oxygen
therapy.
Acute Hypoxia
Respiratory Failure with Arterial High Altitude  The World Health Organization
Hypoxemia  Oxygen therapy is prescribed if recommends the administration of additional
PaO2  <  60  mm Hg or Hb saturation is <93% oxygen in patients living at altitude >2500 meters
according to national guidelines or ≤92% above sea level with SpO2 ≤ 87%.
according to British and Canadian guidelines. Air travel is a situation to consider in chil-
Blood gases results are not needed to initiate dren with respiratory disease, as they could be
oxygen therapy. When the patient presents with at risk of developing hypoxemia events.
signs of possible hypoxemia, such as tachypnea, Commercial flights are pressurized, so their
increased work of breathing or tachycardia, it is altitude is equivalent to a range between 1525
enough to start therapy with oxygen. It is impor- and 2440 meters. In a normal child, compensa-
tant to evaluate the clinical response and titrate tion occurs with no distress, but in a child with
the oxygen amount according to clinical and respiratory disease, it may generate hypoxemia.
saturation values. General recommendations suggest waiting until
newborns are older than a week before air
Tissue Hypoxia without Hypoxemia  May occur travel; if they are preterm, they should have
secondary to situations of low cardiac output, some oxygen management system in the plane
such as anemia, heart failure, hypovolemic shock, if necessary; double oxygen administration
or carbon monoxide (CO) poisoning. Although during flight in oxygen-dependent patients; in
PaO2 and hemoglobin saturation may be normal, case of pneumothorax, wait 2 weeks after reso-
there will be benefits in administering oxygen, lution before flying. Perform the hypoxia alti-
improving tissue oxygenation. In the case of car- tude simulation test in patients with severe
bon monoxide poisoning, oxygen works against chronic respiratory disease.
its binding to hemoglobin.
Preterm and Newborns Infants  Oxygen
Chronic Hypoxemia  Causes are related to administration in newborns and particularly in
chronic respiratory failure due to pulmonary and preterm infants deserves special mention because
678 A. Zamorano Wittwer and C. Astudillo Maggio

of risks of toxicity with secondary lung injury patient. They will be chosen according to the
and of producing retinopathy of prematurity, needs of each patient individually, considering
among other complications. tolerance and compliance with therapy.
Current recommendations range from indica-
tion in the delivery room to patients who will  rescription of Long-Term Oxygen
P
require oxygen at home. In the delivery room it is Therapy
suggested to immediately place a pulse oximeter
sensor on the right wrist, maintain saturations Titration
between 85–92% the first 10 minutes of life and The oxygen flow titration required by the patient
initiate oxygen with FiO2 30%, if required. must be carried out when the patient is clinically
Regarding the early neonatal period, there are stable. If possible, the infant should be evaluated
studies that show that with low levels of satura- during feeding and the schoolchildren during
tion, although the risk of severe retinopathy exercise or during sleep, when nocturnal desatu-
decreases, there is an increase in mortality. ration events are suspected. Titration is carried
Current recommendations for this period sug- out through continuous pulse oximetry for a min-
gest maintaining saturations between 91–95% imum of 8 hours. Its interpretation will be carried
up to 36 weeks of gestational age and 93–95% at out according to the technical standards of each
later ages. country. In Chile, this means according to the
Devices for oxygen administration (Table 66.2) regulations of the Department of Health and its
are the interfaces that will carry the oxygen to the home oxygen program.

Table 66.2  Oxygen administration devices

System type Device Advantages Disadvantages
A. High-flow system: The 1. A Venturi mask delivers Provide specific FiO2
Venturi system is used, where an exact concentration of
oxygen is mixed in a oxygen, regardless of the
standardized way with patient’s breathing pattern.
ambient air through an 2. Halo: It is a closed and Provides high oxygen
opening of different diameter. compact bell used in concentrations
infants. It facilitates the breastfed
contact with the
environment
Allows oral feeding
Allows nebulized therapy
3. Face tent It is useful in patients who
cannot tolerate the mask or
present facial trauma
4. Tracheostomy mask High condensation
B. Low-flow systems: Use a 1. Nasal cannula: In children Best accepted by the Different FiO2
lower flow of oxygen for the use flow of up to 3 L/min patient according to the
inspiratory flow of the patient In newborns use a flow of They are light patient’s body
no more than 2 L/min They allow the patient to surface
talk and feed Decreased efficiency
They have a long lifespan in mouth respirators
2. Simple face mask It allows the use of flows
between 5 and 10 L/min,
which provide FiO2
between 0.35 and 0.50
3. Mask with reservoir: It is
a simple face mask with a
bag or a reservoir at its
lower end.
66  Oxygen Therapy 679

Selection of an Oxygen Administration cannula can be changed every 1 or 2 weeks and

Source the mask between 6 and 12 months. In children
According to the flow to be administered: If it is with tracheostomy, oxygen is delivered through
<2 liters per minute, prefer cylinders; if it is >2 filters designed for that purpose. Also, in all cases
liters per minute, prefer concentrators. oxygen must be humidified.

Sources of Oxygen Administration Determine Oxygen Administration Period

Cylinders  Cylinders contain pressurized gas and The requirements will depend on each particular
provide 100% oxygen. Its major limitation is its case: 24  hours, 12  hours, during feeding, during
capacity, which makes it necessary to change sleep, during exercise. At this point it is important
them continuously. Its installation at home must to monitor the patient in a clinical and gasometric
be carried out by trained personnel, ensuring its manner, and with their pulse oximetry record.
fixation and minimizing the risks associated with
manipulation. Other Material Needed
• Manometer: Indicates the amount of oxygen
• Liquid oxygen: Each liter of liquid oxygen pro- stored in a gas cylinder or a tank using a nee-
duces 863 liters of oxygen gas. The capacity of dle on a psi scale.
a tank goes from 25 to 40 liters of liquid oxy- • Flow meter: Indicates the oxygen flow to be
gen, so at a flow of 2 liters per minute it would administered to the patient, in liters per min-
last 11 days. Portable devices can give auton- ute, which is graduated using a floating ball.
omy of up to 8 hours to the patient. They are • Humidifier: Because oxygen is compressed
the best option for those who ambulate, allow- for storage, for its delivery it must be lique-
ing them to develop their daily activities such fied, cooled and dried. Before administering
as school attendance. There are new devices it, it must be humidified to protect the airway.
that release gas only during inspiration, reduc-
ing the loss that occurs with continuous release, Training of Parents or Caregivers
but these are not recommended for young chil- They must be able to act in case of emergencies;
dren due to a child’s small flow in spontaneous therefore, they have to learn about the warning
breathing. The main disadvantage of these signs, cardiopulmonary resuscitation, the use of
devices is their high cost. oxygen sources (cylinders, liquid oxygen back-
• Concentrators: These electrical devices work packs, concentrators), transportation of the sup-
by increasing the concentration of oxygen in ply sources, need for recharging, security and
the air by filtering the nitrogen. They take up prevention of accidents and infections.
little space and do not require recharging.
Recently, more portable concentrator models Follow-Up and Monitoring
have been developed. Their main disadvan- Depending on the clinical condition and location
tage is that they require electricity, making of the patient (hospital or home), follow-up and
treatment more expensive. monitoring of oxygen therapy will be carried out
through:
The selection of an oxygen delivery source at
home will depend on several factors, such as age, • Clinical
current clinical condition, ambulation and patient
autonomy, costs, and space at home or school. Parameters, such as respiratory rate, heart rate
and respiratory distress, will be evaluated. The
Selection of the Method of Oxygen normalization of these parameters suggests the
Administration success of the therapy.
At home, a nasal cannula should be preferred and Regarding long-term therapy, the child’s growth
the use of masks should be optional. The nasal and development must be evaluated. Anthropometric
680 A. Zamorano Wittwer and C. Astudillo Maggio

parameters such as stagnant weight and height or Complications

psychomotor development problems compel us to
review the oxygen prescription. Oxygen is a drug therapy that causes specific
biochemical and physiological actions, a wide
• Arterial Blood Gases range in the effective dose and well-defined
adverse effects in higher doses, so it must be
Arterial blood gas test is used to evaluate the administered in the right concentrations and
respiratory function condition. It measures pH, time. The biochemical basis for the effects of
partial pressure of CO2, partial pressure of O2 hyperoxia is the formation of oxygen free radi-
and HCO3. Among its advantages is the opportu- cals, which have one or several unpaired elec-
nity to evaluate the patient metabolic condition trons that makes them very unstable.
and knowing the PaCO2. Among its disadvan- Peroxynitrite, the product of the reaction
tages, we can mention a painful examination, between superoxide and nitric oxide, acts with
something important to consider especially in lipids, DNA, and proteins. These reactions trig-
children. It is essential in the initial evaluation in ger cellular responses ranging from subtle mod-
patients with respiratory failure and subsequently ulations of cellular signals to cell necrosis or
in suspected hypoventilation. apoptosis. When the time of exposure to oxygen
In patients with chronic respiratory failure is too long or when its concentration is too high,
treated with home oxygen therapy, it is useful to the cellular repair system is exceeded, which can
evaluate mainly PaCO2, which allows making cause damage and cell death.
decisions concerning the ventilatory management. The organism is affected in different ways
Its use is recommended in the event of changes in depending on the type of exposure to oxygen. If
therapeutic behavior caused by changes in clinical it is a short time, high oxygen pressures can lead
situations such as exacerbations. to central nervous system toxicity, for example,
in hyperbaric oxygen therapy. Longer exposure
• Pulse Oximeter times are required to cause pulmonary and ocular
toxicity. This can lead to acute respiratory syn-
Pulse oximeter allows estimating the arterial dromes, such as adult respiratory syndrome, or
oxygen saturation in a non-invasive manner, using chronic respiratory syndromes, such as broncho-
two LEDs and a receiver placed through a capil- pulmonary dysplasia or retinopathy of prematu-
lary bed. It is an easy-to-use method with which rity, the latter in preterm infants. In patients with
the patient can be monitored continuously. Among chronic hypercapnia, respiratory depression
the disadvantages of this method, we can mention caused by high oxygen concentrations can be
its dependence on the arterial pulse, so in situa- observed, so its administration should be
tions in which the perfusion is altered, such as restrained. Concentrations greater than or equal
shock, fever, cold, or movement or decrease in the to 50% may favor the appearance of atelectasis
amount of hemoglobin, it could provide errone- due to displacement of the nitrogen that gives sta-
ous information. To determine indication, suspen- bility to the alveolus.
sion or evaluation of a patient receiving long-term There may be other minor complications, such
oxygen therapy, continuous pulse oximetry is as dryness and irritation of the nasal mucosa,
used, which must be performed for periods of especially with flows greater than 3 L/min.
8  hours, ideally including sleep, feeding, and It is important to inform patients who use oxy-
activity with or without additional oxygen, based gen at home that it can speed up combustion, so it
on the target of the evaluation in each patient. The should be kept away from open flames and heat,
information obtained is processed with different avoid hitting the cylinder and the shut-off valve,
software, and its interpretation must be performed do not smoke nearby, and close the oxygen source
by a pediatric pulmonologist or a neonatologist. in case of fire.
66  Oxygen Therapy 681

 ithdrawal of Long-Term Oxygen

W Aguerre V.  Viaje en avión, riesgos y previsiones a
considerar en los niños. Arch Argent Pediatr.
Therapy 2012;110(1):66–9.
In general, weaning of oxygen is carried out Cherian S, Morris I, Evans J, Kotecha S.  Oxygen
when chronic respiratory failure is overcome, therapy in preterm infants. Paediatr Respir Rev.
this being common in diseases that affect preterm 2014;15(2):135–41.
De Lucas P.  Oxigenoterapia aguda y crónica. En:
infants such as bronchopulmonary dysplasia. It is Martin Ramos G y Sanchís J.  Medicina respirato-
less likely in cases of interstitial diseases and ria. 2ª ed. Madrid, España: Grupo Aula. Médica.
obliterative bronchiolitis, and it depends on the 2006:349–60.
age of the patient at the time of the injury, the Harris M, Clark J, Coote N, et  al. British Thoracic
Society guidelines for the management of community
possibility of recovery from their lung damage or acquired pneumonia in children: update 2011. Thorax.
if it is from progressive type diseases. In patients 2011;66(Suppl 2):iil–ii 23.
with bronchopulmonary dysplasia it is suggested Ministerio de Salud. Guía Clínica Displasia
to maintain saturations around 93–95% with Broncopulmonar del prematuro. MINSAL: Santiago;
2009.
<1% of the time under 85% and 5% under 90% Ministerio de Salud. Guía Clínica Auge Infección respi-
measured with continuous pulse oximetry. ratoria baja de manejo ambulatorio en menores de 5
It should be considered to start weaning once años: Serie de Guías Clínicas Minsal; 2013.
the supplemental oxygen requirements reach Sociedad Argentina de Pediatría, Subcomisiones, Comités
y Grupos de Trabajo. Guías para el manejo de la oxig-
0.1  L/min. Oxygen is maintained during sleep enoterapia domiciliaria en pediatría. Parte 1. Arch
and feeding. Finally, depending on the results of Argent Pediatr. 2013a;111(5):448–54.
the monitoring, administration of supplemental Sociedad Argentina de Pediatría, Subcomisiones, Comités
oxygen is suspended. y Grupos de Trabajo. Guías para el manejo de la oxig-
enoterapia domiciliaria en pediatría. Parte 2. Arch
Argent Pediatr. 2013b;111(6):549–55.
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Conclusions y Grupos de Trabajo. Seguimiento neumológico de los
niños con displasia broncopulmonar al alta de neo-
natología. Parte 2: Administración de oxígeno, trata-
Oxygen therapy is a fundamental tool in the treat- miento. Arch Argent Pediatr. 2013c;111(3):252–8.
ment of acute and chronic respiratory failure. Its SUPPORT Study Group of the Eunice Kennedy Shriver
employment at home is an alternative after hospi- NICHD Neonatal Research Network. Target ranges
tal discharge with proven benefits but not free of of oxygen saturation in extremely preterm infants. N
Engl J Med. 2010;362:1959–69.
danger or complications. For this reason, it is The BOOST II United Kingdom, Australia, and New
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Thomson L, Paton J.  Oxygen toxicity. Paediatr Respir
forms, and follow-up. Rev. 2014;15(2):120–3.
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Health Organization; 2012. p. 69–76.
 Acute Mechanical Ventilation
67
Andrés Castillo Moya

Contents
Historical Review of Mechanical Ventilation  683
Mechanical Ventilation Physiology  684
Special Characteristics of the Child  684
Ventilation and Oxygenation  684
Basic Elements of the Cardiopulmonary Interactions  687
Mechanical Ventilation Indications   688
Most Used Ventilatory Modes and Initial Parameters of Ventilation
in Pediatric Procedures  689
Practical Parameters of Ventilatory Management  691
Undesired Effects of Mechanical Ventilation  692
Ventilatory Weaning and Extubation  693
Conclusion  694
Sources  694

 istorical Review of Mechanical

H “restoring” the life of an animal by placing a tube
Ventilation in its trachea and blowing air through it. Despite
this, it was not until the late 1800s that Alfred
Mechanical ventilation has been in the mind of Woillez developed a tube-like ventilator that man-
humans since far before we might imagine. In 400 ually performed a process of changing internal
BC, Hippocrates had already mentioned the pos- pressures, which allowed an individual placed
sibility of insufflating air into the lungs through with their body inside this tube and their head out-
the trachea. Many centuries later, Andreas side to intake air into their lungs in a “noninva-
Vesalius, famous physician and anatomy teacher sive” way. Later, in 1931, John Emerson developed
of the sixteenth century, described in his treatise the “iron lungs”, negative pressure devices that
De humanis corporis fabrica the possibility of resulted in an improvement over the prototypes
developed by Woillez, Drinker, and Shaw.
During the 1950s, and in connection with the
A. Castillo Moya (*) polio epidemic, mechanical ventilation had a
Department of Pediatrics, School of Medicine, qualitative leap: the positive pressure ventilators
Pontificia Universidad Católica de Chile, Santiago,
Chile
were developed, which played an important role
e-mail: [email protected] during this epidemic. In 1953, Henry Lassen

© Springer Nature Switzerland AG 2020 683

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_67
684 A. Castillo Moya

published a report where he showed that the mere power for a turbulent flow; thus, small edemas can
introduction of mechanical ventilation as therapy determine a great increase in the resistance and a
in polio determined a plummeting of mortality high tendency of air trapping and insufflation. The
from rates over 80% to rates of less than 40% a thoracic wall in infants and children presents ribs in
few months after starting its use, becoming the a horizontal shape, which hinders the generation of
basis for today’s mechanical ventilation tech- intrathoracic negative pressure.
niques in the serious patient. On the other hand, the thoracic cavity is much
Mechanical ventilation in the child has been more complacent; it is described as becoming
developed from the principles and experience more rigid only after 2  years of age. Since the
derived from mechanical ventilation in the adult, thoracic wall is more complacent, it determines a
although its use in the pediatric population has minimal opposition to the natural tendency of the
had an increasing growth with a use of 20% of lung tissue to retract, which offers a lower resid-
the patients admitted in the pediatric ICU, reach- ual functional capacity (RFC) and a clear lower
ing numbers over 50% of the admissions in respi- functional reserve, adding to the fact that they
ratory infection season. The decision to place a require more breathing work to generate an ade-
patient in mechanical ventilation is a combina- quate ventilation per minute. Thus, this func-
tion of art and science, taking into consideration tional residual capacity increases with the age of
an appropriate and fair combination of clinical the patient, and it is increased with the total lung
judgment, symptoms and signs of breathing capacity and lung residual volume until puberty
insufficiency, and the incapability of the patient and adolescence, where it begins to have more
to maintain an adequate gas exchange or a per- stable levels until adult age.
meable airway. Regarding lung tissue, children can maintain
a continuous growth until adolescence. During
that growth, the number of alveoli grows more
Mechanical Ventilation Physiology than 10  times and the size of them increases
close to four times. Children do not present an
Special Characteristics of the Child adequate development of collateral ventilation
of alveolar units, a ventilation that plays an
Understanding that children are different from essential role in the presence of the obstruction
adults in anatomical and physiological terms is of the distal airway, and given that the distal air-
essential; thus, the most relevant aspects are ana- ways are proportionally smaller and their tidal
lyzed. The form of the airway is different and volumes are closer to the closing capacity (lung
children have a more prominent occiput, which volume under which the small airway collapses
makes the access to the airway more difficult, during breathing out), they have a greater ten-
because in dorsal decubitus this involves bending dency to develop atelectasis.
of the neck, determining a potential obstruction On top of this, the anatomical and functional
of the airway. The tongue is disproportionately differences described at the thoracic cavity and
big in relation to the oral cavity, the larynx is lung parenchyma level determine lung compli-
higher related to its position in the neck and it has ance or “distensibility”, different time constants
a funnel shape with its narrowest portion in the at different ages, and tidal volumes that vary
level of the cricoid cartilage, making a small related to weight and height, which are modified
edema in this zone a great increase in the resis- month by month and year by year.
tance to the airflow. Not only is the larynx nar-
rower but the rest of the breathing tree is much
narrower, determining a high probability of Ventilation and Oxygenation
obstruction as a result of small radius changes.
It is important to remember that the resistance in Mechanical ventilation corresponds to the ingress
the airflow is inversely proportional to the radius to and egress of airflow into the lungs, produced by
the fourth power for a laminar flow and to the fifth a machine external to the patient. This airflow is
67  Acute Mechanical Ventilation 685

propelled by a pressure gradient created by the tem of the child must be overcome. This air
machine, thus determining the lung expansion. In movement will modify and optimize the move-
most of the ventilators, the egress or expiration of ment of gas at the alveolar level (alveolar ventila-
the air that entered the lungs is produced pas- tion), the site where the equilibrium and
sively due to the reversion of the pressure gradi- elimination of CO2 will take place. Thus, ventila-
ent created during inspiration. The main goals of tion per minute can be divided in alveolar ventila-
mechanical ventilation are achieving an adequate tion and dead space ventilation, which is
ventilation and oxygenation of the patient, which constituted by the anatomical and physiological
are conditioned by their underlying physiopatho- dead space. The dead space does not perform the
logical condition. exchange because it lacks alveolar epithelium,
Oxygenation corresponds primarily to the gas and it can be augmented by using very long endo-
exchange at the alveolar level, which allows an tracheal tubes or extensions between the TET and
adequate PaO2 and fundamentally depends on the the ventilator. The physiological dead space cor-
mean airway pressure (mPaw). The main deter- responds to the alveolar volume that is due to
mining factors of mPaw are the tidal volume overdistension in most cases or because of cessa-
(Vc), the maximal inspiratory pressure (MIP), tion of the lung blood flow; it transforms in a por-
the inspiratory time (iT), and positive pressure tion of the alveolar volume that does not
end of expiration (PEEP). Any modification to participate in the exchange. The increase in the
these factors that results in an increase in mPaw anatomical or physiological dead weight will
will determine an increase in PaO2. determine a decrease in the alveolar ventilation
The ventilation corresponds to the movement and thus an increase in the CO2 (Fig. 67.1).
of gas inside and out of the lung. To achieve this Lung compliance (C) is defined as the change
airflow, airway resistance and lung compliance of volume in relation to the change of airway
forces (Table 67.1) present in the respiratory sys- pressure (Fig.  67.2), meaning ∆V/∆P, and it is
determined by the elastic forces inside the lung in
Table 67.1  Normal values
conjunction with the surface tension generated
by the air–tissue interface inside the alveolus.
Newborn 1 year 7 years Adult
Compliance (ml/cm 5 15 50 60–100
The described curve is a sigmoid curve with a
H2O) decrease of the slopes in the zones of low and
Resistance (cm 40 15 4 2 high lung volume. Compliance can then be
H2O/l/s) divided into dynamic compliance and static com-

Fig. 67.1 Ventilation Ventilation per minute = tidal volume (TV) × respiratory frequency (RF).
per minute and
physiological dead space TV = Alveolar volume (AV) + dead space volume (DSV)

DSV = Anatomical + physiological

Alveolar ventilation = VA × FR

Patient with air trapping = ≠ physiological DSV and Ø VA alveolar hypoventilation.

Alveolus Overdistension
Physiological dead space
normal
V/Q where Q = 0

Blood flow (Q) normal Flow = 0

686 A. Castillo Moya

pliance. Static compliance provides an estimate airway, the physical properties of the inhaled gas,
of the total compliance of the lung system; it is and the radius of the airway, the latter being the
calculated dividing the tidal volume by the differ- most important variable.
ence between plateau pressure or static inflation The time constant (TC) corresponds to the
pressure (Pplat) and PEEP. Dynamic compliance, measure of how fast an alveolar unit reaches a
on the other hand, includes and reflects the con- pressure equilibrium with the proximal airway,
tribution of the airway resistance to the airflow, both in the filling as in the emptying phase. In
and it is calculated dividing the tidal volume by operational terms, it is the product of C and R. In
the difference between maximal inspiratory pres- one CT, 63% of the equilibrium is reached:
sure (MIP) and PEEP. 85.5% in two, and 95% in 3-time constants
The airway resistance is the pressure differ- (Fig. 67.3). Owing to this, according to age and
ence between the mouth and the alveolus needed the CT, inspiratory times that vary from 3 CT to a
to move air through the airway in a constant flow. maximum of 5 CT are recommended, and it is
It is determined by the flow rate, the length of the important that the expiratory time has to have at
least the same duration of inspiration. In a
newborn, the CT can carry between 0.1 and
­
1200 Volume vs Pressure 0.15 seconds, with an acceptable average inspira-
tory time (IT) of 3 CT. It must be noted that the
1000
CT in an older child is raised to 0.2 or 0.25, and
800 thus the IT can reach 0.75.
Volume (ml)

600 All ventilation methods require that a pressure

gradient is established between the alveoli and
400 the airway (or atmospheric pressure) to produce a
200 gas movement. Thus, adequate pressure must be
generated to open the collapsed airway, so that
0
0 5 10 15 20 25 30 35 40 45 any method that does not reach that critical pres-
Pressure (cmH2O) sure point during inspiration will determine the
production of atelectasis and hypoxemia. The
Fig. 67.2 Lung compliance and hysteresis curve maximum pressure generated during the inspira-

Fig. 67.3 Relationship Expiration Inspiration

between pressure 100 99.8
equilibrium in the 100 98.2 99.3
95
airway and the time 90
constant 86.5
80

70
83.2
60

50
%

40
36.8
30

20
13.5
10
0 5 1.8 0.7
0 0.2
0 2 4 6

Time constants
67  Acute Mechanical Ventilation 687

Fig. 67.4 Pressure/
volume relationship in MP
volume-control mode. Pplat
MIP Maximal

Pressure
inspiratory pressure,
Pplat plateau pressure,
PEEP positive end
expiratory pressure, It PEEP
Inspiratory time, Et
Expiratory time
It Et

tory phase of the mechanical ventilation that racic pressure, which is transmitted to all struc-
allows the airflow to overcome the airway resis- tures inside the thorax, affecting atria filling and
tance is known as maximum inspiratory pressure ventricular ejection. During inspiration of posi-
(MIP). This is proportional to the resistance and tive pressure ventilation, the increase of intratho-
the tidal volume or mobilized volume during racic pressure will determine an increase of
inspiration, and it is inversely proportional to pressure in the right atrium and a decrease of the
lung compliance. venal return due to the decrease of the pressure
If one occludes the expiratory gate just before gradient between the big veins and the atrium,
the expiration and pauses, a static inflation pres- thus determining a decrease of the preload of the
sure or plateau pressure (Pplat) will be obtained, right ventricle.
which, in practice, is considered as approximat- On the other hand, the positive pressure venti-
ing the pressure that is reached in the distal alve- lation determined an increase of alveolar pres-
oli. On the other hand, apart from the pressure sure and, consequently, an increase of the
generated by inspiration, an adequate level of pressure of the alveolar vessels, determining a
pressure has to be maintained during expiration, subsequent increase of the lung vascular resis-
in order to not reach a critical point in which the tance, meaning an increase in the afterload of the
airway closes, generating atelectasis and hypox- right ventricle and in consequence, a decrease of
emia again. This continuous positive pressure of the lung blood flow. Despite an initial increase of
the airway that avoids collapsing at the end of the left atrium filling, after two to three cycles, a
expiration is known as PEEP (Fig. 67.4). diminishing of the venous return appears, and, as
a consequence, the preload of the left ventricle is
reduced.
Basic Elements Finally, the afterload off the left ventricle that
of the Cardiopulmonary Interactions is related to the resistance to the left ventricle exit
flow depends of the transmural pressure that
During mechanical ventilation, a series of inter- exists in it; in other words, in the difference
actions are caused between the blood flow that between the internal pressure of the left ventricle
enters and leaves the heart and the moments in and the intrathoracic pressure. During positive
which the lung is in inspiration or expiration as a pressure ventilation, the increase of intrathoracic
consequence of the intrathoracic pressure varia- pressure decreases the transmural pressure of the
tion. This intrathoracic pressure varies with the left ventricle, which determines a decrease of the
ventilatory maneuvers, and it affects the pressure afterload of the left ventricle and, in turn, an
gradient between the blood that returns to the increase of its stroke volume (Fig. 67.5).
heart (venous return) and the blood that leaves The understanding of cardiopulmonary inter-
the thorax (stroke volume of the left ventricle). actions is essential when considering the mechan-
In positive pressure ventilation, the increase of ical ventilator as another therapeutic tool, for
lung volume produces an increase in intratho- example, in heart failure, the use of invasive
688 A. Castillo Moya

PTVi = PVi - PIT PTVi = PVi - PIT

+100 +60

SV SV

PVi = 85 PVi = 85

PIT-15 PIT-15 PIT+25 PIT+25

Spontaneous inspiration Mechanical ventilation inspiration

Fig. 67.5  Cardiopulmonary interaction in the left ventricle in positive pressure ventilation. PTVi left ventricular trans-
mural pressure, PVi left ventricle peak pressure, PIT intrathoracic pressure, SV stroke volume

mechanical ventilation can be essential when Table 67.2  Indications to initiate mechanical
diminishing the left ventricle afterload and ventilation
improving cardiac output. The same consider- Alveolar hypoventilation: PaCO2 > 60
ations must be taken in patients with severe air Failure in arterial oxygenation (PaO2 < 70 con
FiO2 ≥ 60)
trapping or a significant restrictive illness that
Severe obstructive symptoms
could imply the use of mPaw that will deteriorate Apnea or respiratory arrest
the output and worsen the prognosis of the Neuromuscular condition
patient. Decrease of metabolic consumption: shock
Cardiogenic shock
Severe ECT
Mechanical Ventilation Indications Complicated polytrauma
Substitution of breathing work
Thoracic wall stabilization
The moment to start mechanical ventilation will Surgery, ICU procedures
depend of the desired clinical objective for the
patient that needs connection. Before connecting
the patient, the pediatrician must consider why The most common cause of mechanical ventila-
the patient requires it: are they a patient with a tion corresponds to the maintenance of gas
severe lung disease? Is the lung disease obstruc- exchange in the patient with respiratory failure,
tive, restrictive or mixed? Does the patient pres- because an adequate arterial oxygenation was not
ent neurological compromise? Does the patient achieved (PaO2 < 70 with FiO2 > 60) or an adequate
have a serious ECT or signs of endocranial alveolar ventilation was not achieved
hypertension? Is the patient in septic shock or (PaCO2 > 55–60 in the absence of chronic lung dis-
cardiogenic shock? Among other questions. All ease). Another indication of mechanical ventilation
the previous questions allow defining which con- is in those situations that require a decrease or sub-
dition determines the indication of ventilating the stitution of the breathing work, either because
patient invasively (Table 67.2). spontaneous breathing work is ineffective on its
67  Acute Mechanical Ventilation 689

Pressure

Pressure
Ventilation objective volume Ventilation object pressure

MIP MIP

PEEP PEEP

time time

Flow

Fig. 67.6.  Flow and pressure curves in invasive ventilation. MIP Maximal inspiratory pressure, PEEP Positive end-­
expiratory pressure

own, or because the respiratory system is incapa- determined volume or pressure (Fig.  67.6). The
ble of performing its function due to a muscular or end of the inspiratory phase or cycle is reached at
skeletal failure: scoliosis, trauma, thoracic cavity the moment that the objective of a determined
malformations, neuromuscular diseases, etc. volume, pressure, flow or time is reached accord-
Decrease of the oxygen consumption (VO2) ing to the programming of the ventilator. The
constitutes another general indication of mechan- most commonly used modes will be detailed next
ical ventilation, because in pathological circum- (Fig. 67.7).
stances, oxygen consumption by the respiratory In controlled ventilation, all respirations are
musculature can reach up to 50% of the total con- delivered by the ventilator, independently of the
sumption. Thus, mechanical ventilation allows an spontaneous effort of the patient, meaning that no
oxygen reserve to be used by other tissues, which spontaneous breathing is allowed, nor can the
can be crucial in certain pathologies, such as sep- patient initiate an inspiratory cycle. In general,
tic shock, cardiogenic shock, endocranial hyper- this ventilation mode is infrequently used, or
tension, among others. used during general anesthesia.
Finally, other indications of mechanical venti- Controlled-assisted ventilation consists in a
lation are the stabilization of the thoracic cavity preset volume or positive pressure delivered to
in cases of polytrauma, flail thorax, thoracic sur- the patient in a determined frequency, although
gery, or allowing sedation, analgesia, or muscle each time the patient starts a spontaneous respira-
relaxation during the postoperative care of com- tion with an inspiratory effort, the ventilator
plex surgery, or in invasive procedures in critical delivers an additional respiration similar to the
pediatric care. preset ones. Despite the patient being able to
increment the ventilation per minute according to
their demands, they run the risk of suffering
 ost Used Ventilatory Modes
M hyperventilation.
and Initial Parameters of Ventilation Intermittent mandatory ventilation allows the
in Pediatric Procedures patient to breathe spontaneously and with their
own effort in the mandatory ventilations.
The ventilation offered by the mechanical venti- Synchronized intermittent mandatory ventila-
lator is determined by an air flow provided to the tion (SIMV) also allows the patient to breathe
patient whose only objective is usually to offer a spontaneously between mandatory ventilations;
690 A. Castillo Moya

Pressure

Pressure
Mandatory ventilation

Controlled Time
Spontaneous effort
Ventilation
spontaneous

Tuned intermittent
mandatory ventilation

Pressure
Pressure

Mandatory ventilation
Support

Time
Spontaneous effort Spontaneous ventilation

Controlled assisted Ventilation with support pressure

Pressure

Pressure

Mandatory ventilation
CRAP

Time
Spontaneous ventilation Spontaneous ventilation
Intermittent mandatory ventilation CPAP

Fig. 67.7  Pressure/time curves on different ventilatory modes

however, this one allows synchronizing the man- Pressure-regulated, volume-controlled venti-
datory ventilations with the effort of the patient, lation corresponds to an increasingly common
which affects the patient–ventilator interaction. mode of use in which a determined tidal volume
Ventilation with support pressure or assisted or minute volume is programmed, and this is
pressure is a form of positive pressure ventilation delivered with a retardant flow that allows main-
that provides preset pressure assistance with each taining a constant volume, achieving the least
voluntary inspiration the patient makes during pressure the system allows. In some ventilators, a
the use of SIMV. maximum pressure limit can also be regulated,
where the ventilator aims to provide the pro-
67  Acute Mechanical Ventilation 691

grammed volume with flow changes without will have to be evaluated continually because
exceeding the maximum determined pressure. they will require precise adjustments, according
This mode can be used in patients with restrictive to the evolution of the patient and the degree of
lung disease, with risk of alveolar trauma or in lung compromise.
those who present changes too frequently in the
compliance due to their pathology. • Conventional ventilatory management in
restrictive lung diseases (ARDS, extensive
pneumonia, etc.):
 ractical Parameters of Ventilatory
P
Management Severe restrictive lung disease is characterized
by a heterogeneous lung compromise that varies
Once the decision to start the mechanical ventila- in intensity, producing the general effect of sig-
tion has been taken, the question is how to start, nificant decreasing of the functional residual
even though the ventilatory mode and the param- capacity (FRC). The use of lung protection strate-
eters that we use will depend on the interrelation gies is recommended for severe restrictive dis-
between the patient condition (motive for the use eases to avoid lung damage due to overdistension
of mechanical ventilation), equipment available, and aperture, and cyclical collapse of the alveoli,
underlying pathologies of the patient, and the also employing enough PEEP to achieve lung
experience of the pediatrician or intensive care recruitment and improve the FRC.
pediatrician that is treating the patient. As a practical matter, low tidal volumes are
suggested (6 and no more than 8  ml/kg), with
• Ventilatory parameters in patients with lungs Pplat under 30  cm of H2O, maintaining a suffi-
without a severe disease (postoperative, post-­ cient PEEP to achieve and maintain an adequate
procedure, neurological intubation cause, lung recruitment and establish a difference
minor lung disease, etc.): between Pplat and PEEP (driving pressure)
<20  cm of H2O, ideally <15  cm H2O.  In severe
The objective is to maintain a SaO2 and pCO2 lung failure, ventilatory management can be asso-
in physiological range. Mechanical ventilation ciated with a permissive management of the SaO2
always has to be started with FiO2 100%, MIP with target values ≥85%, as long as metabolic
between 20 and 25 (never more than 30), or tidal acidosis is not found and the patient does not have
volumes between 5 and no more than 10 ml/kg, other hypoxia symptoms. In the same line, pCO2
with PEEP from 4 to 5, and FR from 20 to 25 in can be allowed to increase if the pH ≥ 7.2 is kept
infants, 15–20  in preschoolers and children in constant. These strategies used in the severe lung
school, and between 10 and 20  in adolescents. failure are known as permissive hypoxemia and
The IT oscillates between 0.6 seconds for infants permissive hypercapnia, respectively, allowing
and 8.0 for adolescents, maintaining an inspira- management with a lower tidal volume and lower
tion: expiration ratio of approximately 1:2 for mPaw, in an effort to minimize the lung damage
children and 1:3 for adolescents. associated with mechanical ventilation.
Lastly, the PEEP will have to be titrated in
increments of 2 by 2 cm of H2O, to increment the • Ventilatory management in obstructive dis-
mPaw as much as necessary to achieve an ade- eases (severe asthma, bronchiolitis, etc.):
quate oxygenation according to the patient
pathology and thus regulate and decrease the Severe obstructive diseases are characterized by
FiO2 contribution, ideally reaching FiO2 ≤ 40% presenting significant air trapping secondary to
with saturations of ≥92–93%. These parameters expiratory flow obstruction. FRC is usually
intended to initiate mechanical ventilation in a increased with hypercapnia secondary to the
normal lung or a lung without significant damage decrease of the alveolar ventilation produced by an
692 A. Castillo Moya

increase of the dead space, especially the physio- Table 67.3  Lung damage associated with mechanical
logical space (Fig. 67.1). The recommendation in ventilation
these patients is initial management with a sedated Biophysical factors
and paralyzed patient, in volume-­controlled mode, Barotrauma:
with tidal volumes of 5–8 ml/kg and a per minute  Injury produced by high pressure
Volutrauma:
volume that maintains acceptable gases, even if
 Injury induced by overdistension
they are not normal, with Pplat under 30  cm of Atelectrauma:
H2O. A ratio of I:E is to be maintained, ideally 1:3,  Injury induced by the repeated collapse-recruitment
because with the increase of resistance, these cycle
patients have a significant increase of the CT, Biochemical factors
which determines the need for adequate inspiratory Biotrauma
 Lung damage induced by the release of mediators at
times and long expiratory times to avoid the air
the lung tissue level
trapping; this ratio can sometimes reach 1:4–1:6.
In these patients we should measure the intrin-
sic PEEP (PEEPi) or autoPEEP that is obtained opioids, and muscle relaxants, the risk of sub-
after making a sustained expiratory pause maneu- glottal stenosis, unscheduled extubation, and
ver, which will avoid the start of inspirations. the lung damage induced by the mechanical
This PEEPi is proportional to air trapping, so its ventilation, which we will mention below. The
magnitude will also determine the amount of lung parenchyma can be affected because the
extrinsic PEEP placed in the ventilator, which mechanical ventilation is not a physiological
should not normally exceed the PEEPi and the process (Table  67.3). The lung lesion can be
sum of both should not be more than 10–15 cm provoked due to biophysical factors, high pres-
H2O, over which a hemodynamic compromise sures (barotrauma), high volumes (volutrauma),
can be produced. In this way, the extrinsic PEEP and the closing and opening process of the alve-
should be established according to the degree of olar units.
air trapping detected by the X-ray, the physical In general, the high maximum inspiratoy pres-
exam, and the autoPEEP or measured PEEPi. In sures damage the airway, added to the alveolar
these patients, sustained inspiratory pause damage provoked by constant high Pplat and
maneuvers should also be realized, which will let alveolar overdistension determined by an exces-
us know the Pplat, by annulling the airway resis- sive volume. There are also biochemical factors
tance, due to the 0-flow produced in the inspira- that contribute to lung damage (biotrauma), due
tory pause. The gradient between MIP and Pplat to the liberation of inflammation mediators by
is proportional to the severity of the obstruction the airway and alveolar cells as a response to
and its measurement enables us to monitor the mechanical ventilation, which would increase the
results to the treatment being applied. lung damage together with the exacerbation pro-
Finally, in the ventilatory management of duced by the continuous production of atelectasis
these patients, the strategies of permissive and new recruitment of the same alveolar units
hypoxia and hypercapnia can also be applied, and (atelectrauma).
will be determined by the severity of the respira- At the hemodynamic level, mechanical ventila-
tory failure. tion can determine the decrease of the cardiac out-
put due to the reduction of the venous return and
the preload of both right and left ventricle. There is
 ndesired Effects of Mechanical
U also an increase of the afterload of the right ven-
Ventilation tricle, which provokes a right ventricle disfunc-
tion. In the kidney, it is capable of reducing kidney
Mechanical ventilation is associated with a myr- blood flow and diuresis, and, on the other hand, it
iad of complications, including the need for also provokes a decrease of the splanchnic and the
sedation, the prolonged use of benzodiazepine, pressure of cerebral perfusion. Another severe
67  Acute Mechanical Ventilation 693

complication related to mechanical ventilation is Table 67.4 Adequate parameters to start ventilatory

respiratory infection that can oscillate between weaning
6% and 26%, depending on the described series. FiO2 ≤ 50%
An increase of the risk after the fifth day of PEEP ≤5 cm H2O
ventilation is described. The most common infec- MIP ≤ 25–30 cm H2O
tions are pneumonia associated with mechanical Ventilatory frequency ≤20 per minute
ventilation, tracheobronchitis, and sinusitis. The
associated risk factors are the loss of normal extubation, without prolonging the mechanical
defense mechanisms of the respiratory tree pro- ventilation if it is not necessary, because it is not
voked by the endotracheal tube overstepping without risks. This has to be considered along-
these mechanisms and as a vehicle for the coloni- side the risk that an extubated patient has of need-
zation of the lower airway, the supine position, ing reintubation too early, which can be associated
the atelectasis, the deficient secretion clearance, with both complications of the procedure and the
and the underlying illness. lung and airway damage. The optimal duration of
the weaning and the correct moment of extuba-
tion is the result of the balance between objective
Ventilatory Weaning and Extubation parameters, science, and the experience of the
intensive care pediatric physicians in charge of
The weaning of the ventilatory support corre- the patient (Table 67.4).
sponds to the process that allows the movement The use of ventilatory weaning protocols in
of the patient from mechanical ventilation to infants and children in some studies has shown a
spontaneous ventilation. Today’s philosophy is shortening of the mechanical ventilation days
that a gradual decrease of the ventilatory support and lower rates of reintubation. Since there is no
of the patient is necessary once the cause that clear superiority of one protocol over another in
determined the connection to mechanical venti- the literature today, there are no standard recom-
lation is controlled. This allows for progressive mendations regarding this; however, most of the
training of the respiratory musculature until the patients are placed in modes with support pres-
successful extubation is reached. There is no sure or volume, which consider the work of the
pediatric literature that supports the duration of patient by decreasing parameters with the addi-
this weaning, and the gradual process is increas- tional support of their effort provided by the
ingly questioned. Here, it is essential to establish ventilator.
what the clinical objectives will be to establish The prediction of a successful extubation in
the rejection of the use of mechanical ventila- infants and children presents a great challenge in
tion, which will depend on the relationship pediatrics, not only because of the weight differ-
between the pathology or event that determined ences but also because of the variability of
the intubation and the state of the patient. In gen- pathologies that require ventilation. This is the
eral, it is considered that the process of weaning reason that the failed extubation rates vary in the
and extubation require the partial or total resolu- literature between 2% and 20%, depending on
tion of the problem that caused the intubation, the population studied. In our experience, the
which in global terms implies low levels of FiO2 pediatric population subject to congenital cardi-
and mPaw (which implies low ventilatory opathy surgeries is 9.9%, with greater incidence
parameters), hemodynamic stability (absence or on those who were exposed to deep hypothermic
decrease of vasoactive support), adequate neuro- cardiac arrest, patients with Down syndrome and
logical state that allows sustaining a permeable those under 6 months.
airway, and the correlation with the experience There are general accepted criteria of extuba-
of the treating team. tion that show evidence of adequate oxygenation
Notwithstanding the duration of the weaning, and ventilation, when the cause of intubation has
the objective to be accomplished is successful been overcome (Table 67.5).
694 A. Castillo Moya

Table 67.5  General criteria for extubation also the interaction between this machine and the
Adequate oxygenation underlying pathology. In this way, the under-
PaO2 > 65–70 or Saturation ≥94% with FiO2 ≤ 40 standing of the functioning of the ventilator, the
PaFi > 180–200 different modes, the different parameters to
Adequate ventilation apply, the management of diverse pathologies,
PaCO2 < 50 and secondary complications due to its use, will
Tidal volume >4–5 ml/kg
allow a proportionate management, with a
Negative maximum inspiratoy pressure. ≤ − 20 cm
H 2O decrease of the complications and a higher suc-
cess in the treatment of the cause that motivated
the connection.
Despite that there is not a single parameter
Finally, the continuous evaluation of the
validated as a predictor of successful extubation
patient will allow a process of retreat of the ven-
in the pediatric population, most of the studies
tilation to be reached, followed by a successful
coincide in using ventilometry, FiO2, respiratory
extubation using clinical judgment and objective
effort, and oxygenation parameters for the most
measurements.
important, alongside the performance of tests for
spontaneous ventilation, where patients are sub-
ject to spontaneous ventilation connecting the
Sources
endotracheal tube to a T tube or connecting the
ventilator with low PEEP, with no frequency and Adewale L. Anatomy and assessment of the pediatric air-
with support pressure, and after a period (of at way. Pediatr Anesth. 2009;19 (Suppl. 1:1–8.
least 30  minutes), measuring physiological and Bronicki R, Anas N. Cardiopulmonary interaction. Pediatr
clinical variables (FC, FR, PA, ventilatory Crit Care Med. 2009;10:313–22.
Carrillo A.  Ventilación mecánica en pediatría
effort), thus assessing the probability of extuba- (IV). Monitorización. Anales de Pediatría.
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Finally, despite what has been shown in Cheifetz IM. Invasive and noninvasive pediatric mechani-
today’s literature there is no reliable and replica- cal ventilation. Respir Care. 2003;48(4):442–53; dis-
cussion 453–448.
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weaning or to predict the success of extubation, orders of the respiratory tract in children. 7th ed.
so the clinical judgment of an experienced treat- Filadelfia, Pensilvania: Elsevier Saunders; 2006.
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Esteban A, Palacios K, Di Nunzio L, Fernandez G,
Bordon A, et  al. An evaluation of extubation failure
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Modalidades de ventilación. Anales de Pediatría.
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Fontela PS, Piva JP, Garcia PC, Bered PL, Zilles K. Risk
management of severe respiratory failure, and its factors for extubation failure in mechanically ven-
use is increasingly frequent in pediatric intensive tilated pediatric patients. Pediatr Crit Care Med.
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Oddo M, et al. Management of mechanical ventilation in 1998;69(4):142–7.
acute severe asthma: practical aspects. Intensive Care Rogers ND. Textbook of pediatric intensive care. 4th ed.
Med. 2006;32:501–10. Filadelfia: Lippincot Williams & Wilkins; 2008.
Prabhakaran P, Sasser W, Borasino S. Pediatric mechani- Rubenfeld GD.  Epidemiology of acute lung injury. Crit
cal ventilation. Minerva Pediatr. 2011;63:411–24. Care Med. 2003;31(4 Suppl):S276–84.
Prodhan P, Noviski N. Pediatric acute hypoxemic respira- Slutsky AS.  Ventilato-induced lung injury: from baro-
tory failure: management of oxygenation. J Intensive trauma to biotrauma. Respir Care. 2005;50(5):646–59.
Care Med. 2004;19(3):140–53. Valle P, Ronco R, Clavería C, Carrasco J, Castillo
Ramírez JB.  Ventilación mecánica en pediatría (III). A. Extubación fallida en pacientes pediátricos después
Retirada de la ventilación, complicaciones y de cirugía de cardiopatía congénita. Rev Chil Pediatr.
otros tipos de venti-lación. Anales de Pediatría. 2005;76(5):479–84.
2003;59(2):155–80. Vallejo-Manzur F, Perkins Y.  Andreas vesalius, the con-
Randolph AG, Wypij D, Venkataraman ST, Hanson JH, cept of an artificial airway. Resuscitation. 2003;56:3–7.
Gedeit RG, Meert KL, Luckett PM, Forbes P, Lilley Wheeler D, Wong H, et al. Children are not Small Adults.
M, Thompson J, et al. Effect of mechanical ventilator Open Inflamm J. 2011;4 (Suppl. 1–M2:4–15.
 Chronic Invasive Ventilation
68
Claudia Astudillo Maggio, Patricio 
Barañao Garcés, and Mireya Méndez Raggi

Contents
Epidemiology.................................................................................................................  697
 hronic Respiratory Insufficiency Causes.....................................................................  698
C
 hronic Mechanical Ventilation Indications..............................................................  699
C
Objectives of Chronic Mechanical Ventilation...............................................................  699
Selection of Ventilation Method.....................................................................................  699
Ventilation Modes...........................................................................................................  700
Equipment.......................................................................................................................  701
Monitoring......................................................................................................................  701
Sedation..........................................................................................................................  702
 eaning or Removal of Invasive Chronic Mechanical Ventilation..........................  702
W
Protocol of Removal of Chronic Mechanical Ventilation
(Hospital Josefina Martínez) .......................................................................................... 702
Protocol of decannulation (Hospital Josefina Martínez) ...............................................  703
Complications ................................................................................................................  703
Sources...........................................................................................................................  704

Epidemiology

Even when the exact prevalence of chronic

C. Astudillo Maggio (*) · M. Méndez Raggi mechanical ventilation in children is unknown,
Pediatrics, Respiratory Diseases, Hospital Josefina some recent studies about patients under mechan-
Martínez, Puente Alto, Chile
ical ventilation suggest a sustained increase of the
Pontificia Universidad Católica de Chile, need of this therapy in recent times. Indications of
Santiago, Chile
this therapy depend on ethical decisions, access to
e-mail: [email protected]
technologies, and diagnosis, leaving an undeter-
P. Barañao Garcés
mined number of patients with chronic respira-
Respiratory Kinesiotherapy, Hospital Josefina
Martínez, Puente Alto, Chile tory insufficiency with no ventilation support.
In England, an increase from 141 children in
Pontificia Universidad Católica de Chile,
Santiago, Chile chronic mechanical ventilation in 1998, to 933
e-mail: [email protected] children under the age of 17  years in 2008 has

© Springer Nature Switzerland AG 2020 697

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_68
698 C. Astudillo Maggio et al.

been observed. Of the total patients, 91% were in lation support through tracheostomy, and only
their homes; the rest were in hospitals as critical 5% are patients with non-invasive ventilation
patients or pediatric intensive care units. Most support. These data reflect the increasing need of
frequent pathologies that required the use of ven- this kind of attention, both in home and in
tilation were: neuromuscular diseases (43%), hospitals.
lung diseases (39%), and conditions related to the
central nervous system (18%). Of these patients,
71% had ventilation only while sleeping, and  hronic Respiratory Insufficiency
C
22% had ventilation through tracheostomy. In Causes
2002, in 46 Spanish intensive care units, 23.2%
of patients had chronic mechanical ventilation We define chronic respiratory insufficiency (CRI)
through tracheostomy. as that which persists for more than 3 weeks once
In Chile, according to data obtained at the the acute episode has been solved (Table 68.1).
Ministry of Health (Minsal), during 2003 and Chronic respiratory insufficiency causes can
2005 winter campaigns, between 20% and 30% be grouped according to:
of critical beds were used by patients with
extended mechanical ventilation. In 2006, the Level of failure:
national program of ventilatory support at home • Respiratory: Involving the lung parenchyma
started, and in October of 2014, 734 patients or airway.
under the age of 20 had joined this program. • Central nervous system: The beginning of the
From these, 69% receive non-invasive ventilation ventilation is affected, especially during deep
support, and 31% invasive ventilation support sleep.
through tracheostomy. • Respiratory pump: When nerve tracts, moto-
Josefina Martínez hospital, specialized in care neurons, neuromuscular plate, musculature, or
of patients with child chronic respiratory dis- thoracic cavity are affected.
eases, formed a ventilation support unit in 2006. • Mixed: Involving more than one of the afore-
Currently, it counts with 40 of its beds for venti- mentioned causes.
lation, 95% of its patients require invasive venti-

Table 68.1  Chronic respiratory failure causes

SNC alterations Congenital and acquired disorders of the Myelomeningocele and
control of the respiratory center Arnold-Chiari
malformations
Alterations in the Congenital hypotonias Myasthenia gravis Phrenic and
ventilation pump diaphragmatic
paralysis
Myopathy Muscular dystrophy Guillain-Barré
syndrome
Botulism Diaphragmatic hernia Spinal muscular
atrophy
Skeletal alterations Kyphoscoliosis Thoracic walls deformities
Alterations in the Obstruction of the high airway: Bronchopulmonary
airway and craniofacial malformative syndromes alterations
respiratory (Pierre Robin, Treacher Collins) Bronchopulmonary
parenchyma Laryngotracheomalasia dysplasia
Tracheoesophageal fistula Cystic fibrosis
Subglottic stenosis Lung hypoplasia
Vocal chords paralysis Obliterans bronchiolitis
Others Congenital and acquired cardiopathies Metabolic diseases
68  Chronic Invasive Ventilation 699

According to evolution or prognosis: Systemic objectives

• Susceptible to improvement: Such as broncho- • Extend and improve life quality
pulmonary dysplasia, airway malacia, Guillain-­ • Provide an environment which increases each
Barré syndrome, obliterans bronchiolitis. individual’s potential
• Stable or progressive: Includes neuromuscu- • Reduce morbidity
lar disease, hypoventilation syndrome. • Favor an appropriate child physical growth
and psychosocial development

Chronic Mechanical Ventilation

Indications Selection of Ventilation Method

The main indication of mechanical ventilation is to The selection of the method of mechanical venti-
maintain gaseous exchange. Therefore, it is indi- lation, whether invasive or non-invasive, in the
cated in patients with chronic respiratory insuffi- pediatric patient with chronic respiratory insuffi-
ciency, which include alterations of chest wall ciency, depends on some of the following
(severe scoliosis), alterations in breath control (cen- factors:
tral hypoventilation syndromes), serious alterations
of the airway (malacia in trachea or bronchus), and • Duration: Quantity of hours per day of need-
alterations of lung parenchyma, such as obliterans ing support. If more than 12  hours per day
bronchiolitis and bronchopulmonary dysplasia. are required, the invasive way through tra-
Must fulfill all physiological criteria and at cheostomy is preferred. If the need is equal
least one clinical criterion: or less than 12  hours, non-invasive way,
using the most appropriate interface for the
Physiological criteria patient.
• PaCO2 > 45 mmHg PaO2 < 65 mmHg • Tolerance to interfaces: This is an essential
factor in the success or failure of non-invasive
Clinical criteria ventilation. Anatomical, psychological, and
• Limited air intake mental health factors may provoke intolerance
• Use of accessory musculature to facial, nasal, or naso-buccal mask, and
• Decrease of physical activity therefore the patient must be ventilated
• Scarce weight gain through tracheostomy.
• Risk/benefit balance and ethical decisions:
The decision of using chronic ventilation and
 bjectives of Chronic Mechanical
O the method applied, force us to consider uni-
Ventilation versal ethical principles. For instance, the case
of limitation of therapeutic efforts.
Patients requirements are different, as well as • Scenario: Currently, chronic ventilation can
goals or objectives to achieve with each one. occur in different scenarios, such as in a criti-
In general, we may consider: cal patient unit or in the pediatric room of a
critical patients hospital, in a chronic patients
Respiratory ob.jectives hospital, or at home, depending on the degree
• Revert hypoxemia of complexity of the patient and access to
• Revert respiratory acidosis domiciliary programs.
• Alleviate respiratory work • Need for autonomy: Patients with night exclu-
• Decrease systemic or myocardial oxygen sive ventilation have a greater autonomy for
consumption doing daily life activities such as attending
• Stabilize chest wall school. In patients with total ventilation, this
• Decrease the lung iatrogenic lesion and other autonomy can be given through appropriate
ventilation complications equipment selection.
700 C. Astudillo Maggio et al.

Ventilation Modes tory cycle. It requires the patient to breathe

spontaneously and be able to start an effec-
Most used modes for chronic mechanical ventila- tive inhalation. It prevents the collapse of
tion in children are limited by pressure and time the upper and lower tract of the airway, as
cycles. In Josefina Martínez hospital a working well as in the alveoli, improving oxygen-
algorithm is used (Fig. 68.1) that allows choosing ation. It is used in patients with severe mala-
between modes from less to more complex: cia and when removing the mechanical
ventilation.
• CPAP: It delivers continuous positive pres- • Spontaneous (S): Two leveled pressure (IPAP/
sure in the airway during the whole respira- EPAP): It gives inspiratory and expiratory

CMV
limited by
pressure

Triggers

No Yes

Two-leveled S/T with RF Stable patient (2 weeks)

IPAP 10–18 Appropriate hemodynamics
EPAP 5–9 VC 6–8 ml/kg
RF 10–20 PaCO2 < 45 mmHgRF 10–20

Stable patient (2 weeks)

Appropriate hemodynamics Yes No
TV 6–8 ml/kg
PaCO2 < 45 mmHg
Two-level S
CPAP 6 IPAP 10–14
EPAP 5–8
Yes No

Continue Change to Stable patient (2 weeks) Stable patient (2 weeks)

weaning SIMV/PC Appropriate hemodynamics Appropriate hemodynamics
protocole mode or TV 6–8 ml/kg TV 6–8 ml/kg
(diagram 2) Dual mode PaCO2 < 45 mmHg PaCO2 < 45 mmHg

Yes No

Continue protocol. Continue protocol.

Two-leveled Transfer to Removal of chronic Removal of chronic
ST with RF PICU mechanical ventilation mechanical ventilation

Fig. 68.1  Selection of method of ventilation

68  Chronic Invasive Ventilation 701

pressure, without the need for backup rate. It given by the ventilator in each respiration
is used as a previous step at the employment and for those generated by the patient, if
of CPAP. present.
• Spontaneous/cyclic (S/T): Two leveled pres- • Autonomy: It refers to the possibility of func-
sure with respiratory frequency (RF). tioning without electric supply, in other words,
• Dual: Two leveled inspiratory pressure (IPAP whether the equipment possesses a battery or
max/IPAP min). With assured tidal volume not. In this case, the internal battery duration
with or without respiratory frequency. Both is important, because it will enable us to use
are utilized for the treatment of patients with the equipment for transferences, or for going
neuromuscular diseases or diseases of the with the patient to school or other daily life
lung parenchyma. activities.
• Intermittent synchronization (SIMV/PC): It
gives two leveled pressure (MIP/PEEP), In our hospital we’ve successfully utilized
backup respiratory rate, and programmable flow generators ventilators with turbines and
support pressure. In patients without ventila- two-leveled pressure (IPAP/EPAP-MIP/PEEP).
tory autonomy; for example, type I spinal This equipment was created for non-invasive
atrophy, severe bronchopulmonary dysplasia, ventilation, and because of their turbines, they do
or obliterans bronchiolitis. not require compressed air, so they can be imple-
mented outside of hospital environments, in
homes and transferences.
Equipment

When we choose the equipment for delivering Monitoring

chronic ventilation, we must know its technical
specifications and which advantages are obtained The monitoring level of the patient with invasive
compared to others (Table  68.2). Some of the chronic ventilation will depend on the scenario in
most important elements are: which the patient is in, the main objective being
the patient’s security.
• Registration: Through cards, which are Non-invasive monitoring through continuous
interpreted through a software, we can measuring of pulse oximetry and heart fre-
obtain information about hours of equip- quency, immediately gives information and
ment use, percentage of respirations trig- warning about complications, such as decannu-
gered by the patient, pressures and volume lation or cannula obstruction, which, if not

Table 68.2  Ventilation equipment

Equipment name Trilogy 100 or 202® Synchrony® Stellar Harmony®, Stellar
150 100
Limited by Pressure, volume or dual Pressure or dual Pressure
Modes CPAP, S, S/T, T, Simv (PC, VC), CPAP, S, S/T, T y PC CPAP, S and S/T
AC
Battery 2 internal per equipment Only Stellar 150 Solo Stellar 100
Circuit type Passive or active Passive Passive
Record system SD Card Encore Card/Pendrive Encore Card/Pendrive
League compensation Yes Yes Yes
Base with wheels Yes No No
Air mixer/O2 (FiO2) Only Trilogy 202 No No
Humidification thermos External Built-in to equipment Built-in to equipment
(HT)
Electric consumption 165 Watts/h with HT 130 Watts/h with HT 130 Watts with HT
702 C. Astudillo Maggio et al.

detected, could pose a risk to the life of the  eaning or Removal of Invasive
W
patient. This is the minimal monitoring that a Chronic Mechanical Ventilation
child must have at home.
Besides, monitoring represents an important Removal of mechanical ventilation, defined as
tool for tracking and clinical decision making in the transition from assisted ventilation to autono-
the case of exacerbations or the start of the mous ventilation, is possible when the cause that
removal of the mechanical ventilation. provoked the need of ventilatory support is over-
In hospital environments, monitoring is made come and, in consequence, is feasible to execute
through: in the case of pathologies susceptible to improve-
ment but not in stable or progressive ones.
• Non invasive monitoring: Pulse oximetry and The moment for starting the removal of venti-
permanent heart frequency. Vital signs con- lation is decided when it can be guaranteed:
trol: Blood pressure, temperature, respiratory
frequency. • An appropriate neuromuscular function, with
• Venous or arterial gases: Are made routinely a ventilatory pump functioning that allows
when the patient is admitted, and afterward sustaining respiratory work during wakeful-
are repeated with a frequency defined by the ness and sleep.
particular case. They are a vital tool in the • Minimal respiratory work.
management of exacerbations and decision • Clinical stability: no exacerbations in last
making like parameters changes or ventilation month.
removal.
• Chest x ray: Useful in the case of exacerba- Parameters which correlate with better chance
tions or behavior changes, and the evaluation of success are:
of the position of the cannula.
• Capnography: Not always available in every • TV > 6.5 ml/kg
center, but very useful, because it prevents • Mid pressure of the airway <5 cm H2O
arterial puncture and the pain it provokes in • PIM < 10 cm H2O and PEEP <6 cm H2O
the patient. It allows behavior changes and • FiO2 < 0.3
tracking in the case of respiratory
exacerbations. Another necessary element for taking the
• Polysomnography: It allows defining the decision of starting the removal is the airway and
beginning of ventilatory, fixing or modifying lung parenchyma structural and functional
parameters, and deciding the removal of indemnity. This requires an evaluation through
ventilation support. In chronic mechanical fibro bronchoscopy or thoracic images, such as
ventilation, the examination musts have con- X-rays or computed tomography.
tinuous capnography which allows measur- The weaning or removal can be done follow-
ing exhaled CO2. ing clinical criteria established by the treating
doctor or through a ventilation removal protocol
such as that presented hereunder:
Sedation

It does not require the use of sedation, because  rotocol of Removal of Chronic
P
one of our objectives with chronic mechanical Mechanical Ventilation (Hospital
ventilation is the patient’s comfort and integral Josefina Martínez)
development. This is achieved by choosing the
appropriate interface and ventilatory mode, 1. Decrease to the point that maximum inspira-
which meets the needs of the patient. tory pressure (MIP or IPAP), maintaining
68  Chronic Invasive Ventilation 703

PEEP or EPAP, and supporting with gases on • Obstruction

awakening. • Infection –– Granuloma –– Bleeding
2. In parallel, evaluate the trigger of the patient 2. Patient
using the registration cards that ventilation • Use of positive pressure: pneumothorax,
equipment possess, for starting the decreasing cardiopulmonary interactions
of back up frequency, to hit a spontaneous level. • Patient/ventilator asynchrony
3. Changes are executed slowly, every 2  weeks • Infections (pneumonia associated with
and one at a time (pressures or frequency), mechanical ventilation)
maintaining a differential pressure (IPAP-­ 3. Equipment: including ventilator and circuits –
PEEP) of 4 cm of H2O. technical malfunction
4. When IPAP hits 10 cm H2O, with a PEEP of • Disconnection
6  cm of H2O in spontaneous level, the next
step is to let the patient just with PEEP of 6. The frequency of major complications of tra-
5. Decrease to a PEEP of 5. cheostomy in children, such as hemorrhage,
6. After 2 weeks of clinical stability, ventilatory pneumothorax, pneumomediastinum, emphy-
support is suspended. sema, accidental decannulation, tracheoesopha-
7. Continue to protocol of decannulation. geal fistula, and cervical abscess, varies between
5% and 49%.
Congenital cardiopathies, prematurity, and
 rotocol of decannulation (Hospital
P age under 1  year, are characteristics associated
Josefina Martínez) with precocious mortality, before the 7 days after
tracheostomy in children. Accidental
1 . Airway visualization, through ­decannulation is one of the most important causes
fibro-bronchoscopy. of late mortality.
2. If there is no obstruction in the high airway, Accidental decannulation is a potentially
such as granulomas, laryngomalacia, cranio- lethal adverse event, and as well as pneumonia
facial malformations, proceed to the next step. related to mechanical ventilation, it is an indica-
3. Measuring of the expiratory pressure main- tor of care quality. In Josefina Martínez hospital,
tained in the airway (Villarroel et al.). accidental decannulation represents 30% of
4. Use of phonation valve 24 hours a day. reported incidents between 2009 and 2014, hav-
5. Decrease the internal diameter of the TQT ing fatal consequences in one patient, and serious
cannula, until reaching at least 3.5. consequences, such as persistent vegetative state,
6. Use of cover of cannula throughout the day. in two patients. Rate of pneumonia associated
7. Cover cannula during sleep and execute night with mechanical ventilation (PAMV) is of 1.4 per
saturometry. 1000  days of ventilation. This number is far
below the ones reported in intensive care units.
• If patient does not present saturations of less Concerned about the increasing number of
than 90, decannulation can be programmed. pediatric patients with tracheostomy dependent
on technology, which potentially can present life-­
threatening complications, the American Heart
Complications Association, through their PALS continuous edu-
cational courses, spread the mnemonic rule
Complications can be classified according to DOPE (stands for displacement, obstruction, pul-
their cause, related to the use of tracheostomy, monary, equipment), which allows a practical
patient, or equipment. approach to the emergency.
Related to: Preventive protocols are necessary for pre-
venting the frequency or severity of these compli-
1. Tracheostomy: cations. Among these, we can mention the
• Displacement protocol of management of tracheostomy, which
704 C. Astudillo Maggio et al.

includes the periodic inspection of the hold col- strength training improves weaning outcome in fail-
ure to wean patients: a randomized trial. Crit Care.
lar. In any case, very well-trained personnel are 2011;15:R84.
needed, and they should constantly improve their Méndez M, Prado F, Navarro S, Sánchez I.  Rol de un
qualification. hospital especializado en los cuidados respiratorios
de pacientes con enfermedades pulmonares cróni-
cas. In: Sánchez I, Prado F, editors. Enfoque clínico
de las enfermedades respiratorias del niño. Santiago:
Sources Ediciones Universidad Católica de Chile; 2007.
p. 521–8.
Bach J. The use of mechanical ventilation is appropriate Monteverde F, Fernandez A, Poterala R, Vidal N,
in children with genetically proven spinal muscular Siaba A, Castelani P, Albano I, Podesta F, Farias
atrophy type 1: the motion for. Paediatr Respir Rev. J. Characterization of pediatric patients receiving pro-
2008;9:45–50. longed mechanical ventilation. Pediatr Crit Care Med.
Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff 2011;12(6):e287–91.
E. Long-term survival in Werdnig–Hoffmann disease. Nava S, Fasano L. Inspiratory muscle training in difficult
Am J Phys Med Rehabil. 2007;86:339–45. to wean patients: work it harder, make it better, do it
Bertrand P, Fehlmann B, Lizama M, Holmgren N, Silva faster, makes us stronger. Crit Care. 2011;15:153.
MY, Sánchez I.  Asistencia ventilatoria domiciliaria Overman A, Liu M, Kurachek S, Shreve M, Maynard
en niños chilenos: 12 años de experiencia. Arch R, Mammel M, Moore B.  Tracheostomy for infants
Bronconeumol. 2006;42(4):165–70. requiring prolonged mechanical ventilation: 10 years’
Graham R, Fleegler E, Robinson W.  Chronic ventilator experience. Pediatrics. 2013;131:e1491.
need in the community: A 2005 Pediatric Census of Prado F, Salinas P, Astudillo P, Méndez M.  Ventilación
Massachusetts. Pediatrics. 2007;119:e1280. mecánica invasiva domiciliaria (VMI). Una propu-
Guzmán C. Ventilación mecánica en niños. In: Reyes M, esta para un nuevo programa. Rev Neumolog Pediátr.
Aristizábal G, Leal F, editors. Neumología pediátrica. 2007;2:49–60.
5th ed. Editorial Médica Panamericana: Bogotá; 2006. Smith B, Bleiweis M, Neel C, Martin D. Inspiratory mus-
p. 713–20. cle strength training in infants with congenital heart
Harikumar G, Moxham J, Greenough A, Rafferty G. disease and prolonged mechanical ventilation: a case
Measurement of maximal inspiratory pressure in ven- report. Phys Ther. 2013;93:229–36.
tilated children. Pediatr Pulmonol. 2008;43:1085–91. The Cochrane Collaboration. Protocolized versus non-­
MacIntyre N, Epstein S, Carson S, Scheinhorn D, protocolized weaning for reducing the duration of
Christopher K, Muldoon S.  Management of patients invasive mechanical ventilation in critically ill paedi-
requiring prolonged mechanical ventilation. Chest. atric patients. 2013.
2005;128:3937–54. Wallis C, Paton JY, Beaton S, Jardine E. Children on long-­
Martin D, Smith B, Davenport P, Harman E, Gonzalez-­ term ventilatory support: 10  years of progress. Arch
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 Long-Term Non-invasive
Ventilation
69
Francisco Prado Atlagic, Pamela Salinas Flores,
and Gerardo Ferrero

Contents
Physiological Bases.......................................................................................................  705
 enefits of Non-invasive Ventilation in Chronic Patients..........................................  706
B
Equipment for NIV Delivery: Technical Considerations...............................................  707
Bi-Level Positive Airway Pressure.................................................................................  707
Non-invasive Ventilation Modes with Bi-level Flow Generators...................................  708
Volume Assist-Control Ventilation (ACV) ....................................................................  708
Pressure-Control Ventilation (PCV) ..............................................................................  709
Interfaces........................................................................................................................  709
Humidification Systems..................................................................................................  710
Oxygen Therapy.............................................................................................................  710
NIV as a 24 Hours per Day Prolonged Mechanical Ventilation Method.......................  710
Ethical Dilemmas..........................................................................................................  711
Conclusions...................................................................................................................  712
Sources...........................................................................................................................  712

Physiological Bases in the airway. It does not require an artificial air-

way, avoiding the complications generated by an
Non-invasive ventilation (NIV) is a form of endotracheal tube or tracheostomy. Accordingly,
mechanical ventilation that is based on the appli- a nasal, nasolabial, or facial mask is used as an
cation of cyclical or continuous positive pressure interface and can be implemented for managing
acute and chronic respiratory insufficiency.
F. Prado Atlagic (*) In adults and children, there is enough evi-
Department of Pediatrics, Hospital Clínico San Borja dence to support its use in patients with chronic
Arriarán, Santiago, Chile
diseases that may present acute scenarios, espe-
P. Salinas Flores cially in patients with neuromuscular diseases
Pediatric Service, Clínica Las Lilas, Providencia,
and also in pathologies with lung parenchyma
Chile
and distal airways compromise, such as chronic
G. Ferrero
obstructive pulmonary disease (COPD) and cys-
Respiratory Kinesiology and Physiatry, Hospital
Rehabilitación Respiratoria María Ferrer, tic fibrosis. In this scenario, when compared to
Buenos Aires, Argentina invasive mechanical ventilation (IV), NIV shows
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 705

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_69
706 F. Prado Atlagic et al.

lower mortality rates, fewer days of hospitaliza- • Active assisted exercise to improve compli-
tion, and fewer complications. ance of the developing thoracic cage, with ten-
In addition, the evidence of its benefits as a dency toward restriction due to weakness of
prolonged mechanical ventilation strategy in inspiratory muscles in patients with neuro-
patients with neuromuscular problems such as muscular pathology.
kyphoscoliosis has been established, relating its
early onset, at the time of nocturnal hypoventila- Positive pressure decreases thoracic deformity
tion, with a better prognosis, better health-related and helps its rectification and expansion.
quality of life (HRQoL), and lower related costs. Sustained use of this therapy improves respi-
ratory center sensitivity to CO2. This fact favors
patients with chronic ventilatory insufficiency
Benefits of Non-invasive Ventilation who receive non-invasive ventilation, presenting
in Chronic Patients less acute exacerbations and hospitalizations. By
lowering fatigability thresholds and mitigating
From physiological studies in adults, it has respiratory work overload, the patient achieves a
been demonstrated that non-invasive ventila- baseline condition, granting a better faces prepa-
tion manages to diminish the electromyo- ration for decompensation, leading to an improve-
graphic activity of the diaphragm, the ment in health-related quality of life.
transdiaphragmatic pressure, and the respira- Non-invasive ventilation in chronic patients is
tory frequency. In addition, it increases tidal delivered as the main strategy for long-term home
volume, which translates into less work of mechanical ventilation. Indications and selection
breathing and an increase in ventilation per criteria for this are shown in Tables 69.1 and 69.2.
minute, reversing chronic hypoventilation.
Among the main benefits of non-invasive venti- Table 69.1  Indications for home non-invasive
lation in chronic patients it is possible to mention: ventilation
NIV indications
• Upper airway stability, which is especially (a) Patients with chronic respiratory failure and
important during sleep, as this allows a normal sleep-related hypoventilation syndromes with at
least one criterion:
air flow with minimum resistance and achieves
   Frequent SpO2 <90% in continuous 8-hour
less work of breathing, which also adds to an observation
improvement in sleep architecture. This justi-    FVC <50%; PiMax <40 cm H2O; Cough Peak Flow
fies its use in patients with obstructive sleep <150 L/min
apnea syndrome (OSAS) and in those with    PaCO2 >50 mmHg; BE>4 mEq /L
craniofacial syndromes. (b) Patients with compromised control of ventilation
and OSAS
• There is a lower O2 consumption by decreas-
   Frequent SpO2 <90% in continuous 8-hour
ing the work of breathing, lower CO2 produc- observation
tion, and lower energy consumption by    Apnea-Hypopnea Index>5; TcCO2 >50 mmHg for
respiratory muscles. Added to these benefits is more than 50%
the increase of resistance to fatigue during the
day when ventilatory support is used at night. Table 69.2 Selection criteria for home non-invasive
• Increased functional residual capacity (FRC) ventilation
in patients with restrictive ventilatory defect, NIV selection criteria
by providing support for transpulmonary pres- Stable clinical condition that allows respiratory
sure, which results in a lower predisposition to autonomy outside non-invasive ventilation
hypoxemia and lower O2 requirements because NIV requirements in less than 12 hours
Hypercapnia without respiratory acidosis; oxygen
it decreases the tendency to alveolar collapse
requirement <2 L/min to maintain SpO2 >93%
(atelectasis) and improves ventilation/perfu- Socioeconomic status that allows having appropriate
sion ratio. The increase in lung compliance facilities and basic amenities. Level of education that
optimizes the mechanics of the lung-chest allows compliance with the indications
system, improving gas exchange. Caregivers committed to monitoring and controls
69  Long-Term Non-invasive Ventilation 707

 quipment for NIV Delivery:

E Bi-level positive airway pressure can be used
Technical Considerations in different modes, with differences between
available options by the different existing
Non-invasive ventilation uses pressure-controlled equipment.
ventilation, which involves setting inspiratory and Household equipment usually does not have
expiratory pressure limits. There are exclusive an internal battery, which limits non-invasive
flow generators for this, less expensive than con- ventilation in transport or in the event of a power
ventional positive pressure respirators. Among outage. This can be solved with optional external
them the bi-level equipment stands out, which is batteries appropriate for the equipment which
transportable, electric, and of continuous flow, allows its operation, although this usually only
using a turbine connected to a compressor. works for the flow generator and not the associ-
ated humidifier. New equipment comes with
lithium-­ion batteries that deliver a minimum of
Bi-Level Positive Airway Pressure 4 hours of autonomy.
Flow generators allow recognizing and com-
It delivers a positive airway pressure in two levels pensating involuntary leaks in the system; more
with independent adjustment: inspiratory posi- traditional equipment triggers inspiratory flow to
tive airway pressure (IPAP) and expiratory posi- deliver programmed IPAP when they sense in the
tive airway pressure (EPAP). The difference system a flow generated by the patient of 40 ml/s
between the two is the pressure support level. for more than 30  ms. Inspiration ends when it
Inspiratory positive airway pressure (IPAP): lasts for more than 3 s or the flow has dropped to
Sets the inspiratory pressure limit and controls a quarter of the maximum flow. The VPAP II, III,
ventilation. The higher the IPAP is, the higher the Stellar 100 and 150, and VS lll (Resmed) equip-
tidal volume during inspiratory phase. The per- ment can be programmed to deliver a minimum
centage of inspiratory time will determine the and maximum inspiratory time (Ti Control).
IPAP duration. Equipment, such as S/T-D 30, Vision, Harmony,
Expiratory positive airway pressure (EPAP): Synchrony (Respironics), and currently Trilogy,
Sets the expiratory pressure limit above atmo- A30 and A-40 (Philips), have a sensitivity algo-
spheric pressure. It improves functional residual rithm defined as Auto-Trak, which detects patient
capacity and oxygenation. flow pattern, automatically adjusting sensitivity
Pressure support (IPAP–EPAP): The differ- thresholds through three algorithms: (1)
ence between IPAP and EPAP generates a pres- Inspiratory trigger threshold of 6 ml/s in a period
sure gradient called pressure support. Ventilation of 30 ms; (2) Triggering algorithm determined by
occurs as a consequence of the difference the flow curve shape from IPAP to EPAP and
between these pressures. EPAP to IPAP; (3) Trigger according to sponta-
Two pressure levels are useful in restrictive neous expiratory threshold to cycle to EPAP.
disorders that require increasing the functional Conventional microprocessor-based mechani-
residual capacity and decreasing the work of the cal ventilators, which have a pressure support and
respiratory muscles. For example, in patients built-in non-invasive mode (New Port Wave or
with neuromuscular diseases (Duchenne muscu- New Port E500, Evita XL or Savina by Dräger,
lar dystrophy, congenital muscular dystrophy, Vela and Aveas by Vyasis, I-Vent by Versamed,
congenital myopathy, congenital spinal muscular Servo I Maquet and Galileo, G1 and G5 of
atrophy), severe cases of kyphoscoliosis, and in Hamilton, among others), can be used for non-­
diseases that compromise the central nervous invasive ventilation in patients in pediatric inten-
system, such as myelomeningocele and type I sive care units. Its administration through a
and II Chiari malformations. It could also be used conventional ventilator allows to determine the
in alterations of the respiratory center (central inspired oxygen concentration (the new genera-
hypoventilation syndromes). tion of hybrid equipment has internal oxygen
708 F. Prado Atlagic et al.

mixers), to prevent rebreathing due to use of dou- In sum, flow generators work with pressure
ble tubing, and to use the ventilator monitors and programming and are usually limited by flow (to
alarms. The vast majority of these ‘heavy’ prevent undesirable prolongation of inspiration
mechanical or institutional-use ventilators have when there is a leak in the interface or an obstruc-
non-invasive ventilation modes. For this, it is tive pathology) or by inspiratory time (to prevent
necessary to change the active exhalation option, short Ti in patients with decreased compliance).
through an exhalation valve, to passive exhala- At present, there is equipment that, while cycling
tion (in the mask or in the proximal exhalation by pressure, deliver an “assured” tidal volume in
port), or to maintain the exhalation through the the range of 2 IPAP, maximum and minimum.
exhalation valve of the ventilator, requiring in This feature decreases the risk of hypoventila-
these cases non-vented masks (they are indicated tion: these methods may have tidal volume tar-
by their light blue elbow). The disadvantage of gets (AVAPS™, Philips Respironics), or alveolar
using these ventilators is that they do not produce ventilation targets (iVAPS™, ResMed Inc).
good leak compensation, which creates a strong Rise Time regulates the air entry speed during
adjustment pressure of the mask to the face, caus- inspiratory time: the higher the Rise Time, the
ing discomfort, poor tolerance, and complica- longer it will take to reach the set IPAP within a
tions such as pressure ulcers. cycle, improving tolerance in some patients. This
The choice of the ventilator for the adminis- time should be minimal in patients with dyspnea
tration of non-invasive ventilation will depend on due to restrictive lung diseases. The values oscil-
the variety and particular characteristics of the late between 0.1 and 0.9 s. It is important to note
available equipment, the type of patient, the cir- that Rise Time should not exceed 40% of the total
cumstances in which it is applied, and the opera- inspiratory time, since it has a direct implication
tor experience. on the final tidal volume delivered.
Ramp time refers to a characteristic that some
equipment has, in which there is a latency
Non-invasive Ventilation Modes expressed in minutes for the pressures selected
with Bi-level Flow Generators by an operator to be achieved. In general, the
minimum EPAP to start ramp time is 4 cm H2O
These devices regulate a constant flow of air and and the time to reach planned pressures is
have the capacity to change that flow to achieve 5–30 minutes. This method of progressive deliv-
certain pressures chosen by an operator. The ery of expiratory pressure in the airway is partic-
exhalation is usually established passively ularly useful and comfortable in patients with
through the interface (masks with exhalation sleep apnea, giving them enough time to fall
port) in the units that work with tubing for inspi- asleep.
ration and exhalation, as is the case in the vast
majority of flow generators marketed for home
use. Regardless of the method to establish non-­ Volume Assist-Control Ventilation
invasive ventilation, a device capable of correct- (ACV)
ing the leakage flow (Q leak) is required; some
equipment even requires a minimum Q leak of 13 Volume assist-control ventilation (ACV) is
LPM.  The turbine establishes accelerated flows defined as a time or patient-triggered, flow-­
that decline once the IPAP is achieved, with cycle limited, and volume-cycled mode. A constant
times and inspiratory duration determined by the flow waveform is used, although a decelerating
percentage of the total time of the chosen cycle flow waveform can be used if the ventilator soft-
for inspiration, by direct programming of the ware allows it. The latter is recommended for the
inspiratory time, and by the maximum fixed flow application of non-invasive ventilation (NIV),
percentage; traditionally, this last parameter is since it is the most comfortable one for the
established in a quarter of the maximum Q. patient.
69  Long-Term Non-invasive Ventilation 709

The ventilator delivers a predetermined tidal port ventilation (PSV) mode due to a leak around
volume in response to the patient’s inspiratory the mask: in PCV, since inspiratory time is fixed,
effort (assisted mechanical ventilation or AMV). the cycle to expiration will be according to the
If the patient does not trigger the respirator, it will patient’s demand, despite the system leak. Thus,
give him the tidal volume added to a predeter- the operator will determine the ventilator inspira-
mined respiratory frequency (controlled mechani- tory time according to the patient inspiratory
cal ventilation or CMV) or the combination of time (usually between 0.6 and 1.2 sec, depending
both (ACMV). In the case of long-term home on age and underlying pathology).
non-invasive ventilation, this method is the first
choice in those patients with neuromuscular dis-
orders with advanced symptoms, mainly for Interfaces
cough assistance (increase in inspiratory capacity
and consequent increase in peak cough flow There are a wide variety of interfaces that adjust to
(PCF) or because there is no other ventilator avail- the age and the morphology of the face of the patient.
able that offers more sophisticated or comfortable This choice is essential to achieve an adequate pres-
options for the patient (PSV, Bilevel, iVAPS) sure transfer to the airway, which translates into
proper ventilation and no unwanted side effects such
as injuries where the pressure points are.
Pressure-Control Ventilation (PCV) The interfaces must be made of soft, flexible,
silicone material, transparent, with a smooth and
In pressure-control ventilation (PCV) all breaths padded adaptation surface (inflatable or gel-like
are time- or patient-triggered (in assisted mode), material), and latex-free.
pressure-limited (inspiratory pressure), and time-­ The nasal mask is the one that is better toler-
cycled (inspiratory time). The flow waveform is ated and is generally the choice for patients using
decelerating. home non-invasive ventilation. The naso-buccal
The tidal volume will depend on the patient’s mask is preferred in mouth breathers and in
thoraco-pulmonary impedance: the greater the patients with acute respiratory failure and high
latter, maximal inspiratory pressure will be ventilatory parameters. Full face mask is rarely
obtained more quickly and with a smaller volume used in pediatrics, although it is an alternative for
of alveolar ventilation. children with craniofacial morphology variations
With pressure ventilation, the maximal inspi- or with lesions where the pressure points are. An
ratory pressure is the variable to be programmed alternative to masks is the high-flow nasal can-
instead of the Vt as in the volumetric mode. In nula. It is recommended for use at low pressures
addition, the operator must place a minimum or for daytime use in patients with long-term
respiratory rate, an inspiratory time (Ti) or I:E non-invasive ventilation.
ratio, and the sensitivity level of the trigger. Interfaces must be fixed through elastic sys-
The main differences between the pressure tems, minimizing involuntary leaks and at the
and the volumetric modes are the tidal volume same time allowing the patient to be as comfort-
consistency and the peak inspiratory pressure able as possible, avoiding ocular occlusion, buc-
(PIP): the PIP is constant with the control pres- cal movements, or excessive compression. It
sure, but the tidal volume can vary. Its main must be remembered that equipment designed for
advantage over NIV is that the flow is variable non-invasive ventilation compensates for leaks,
and can be adjusted to the patient’s flow demand, and what matters is that they do not cause dis-
within the framework of a pre-established pres- comfort to patients.
sure delta: the higher the delta, the greater the To avoid lesions, it is recommended to install
capacity to generate higher flows. This mode is the interface on a clean face, do rotatory mas-
chosen when the patient does not achieve an ade- sages at the pressure points, and wash the inter-
quate ventilator adaptation in the pressure sup- face daily.
710 F. Prado Atlagic et al.

Humidification Systems tubing, which can serve as a reservoir and deter-

mine a more stable FiO2. This will depend on the
Conditioning respiratory gas is essential to treat mixture produced during the inspiratory and
patients who need medical gases, oxygen ther- expiratory cycle between O2 flow from its admin-
apy, invasive mechanical ventilation, and non-­ istration source (concentrator, cylinder, or net-
invasive ventilation. work) and the flow created by the bi-level, with
Mucociliary clearance is probably the respira- less than 3  L/min O2 flows. In general, only a
tory function most sensitive to changes in humid- bubble type humidifier is required. In case of
ity and temperature of inspired gas. Dried up larger flows, it may be required to use traditional
secretions can lead to alterations in ciliary activ- humidifiers, such as passover or those compatible
ity, inflammatory changes, and respiratory epi- with flow generators. Leaks through the interface
thelium necrosis, retained thick and adherent are frequent causes of desaturation, which will
secretions with secondary impactation, bacterial not be corrected with an increase in O2 concen-
colonization, atelectasis, and pneumonia. tration but repositioning and adapting the mask to
In cases of acute respiratory failure, ineffec- the patient’s face. It must also be ruled out that
tive or insufficient humidification would be the desaturation cause is not excess of secretions,
directly related to failed non-invasive ventilation. which are treated by applying assisted cough
For this reason, in patients who require non-­ protocols.
invasive ventilation for more than 12 consecutive The use of antibacterial filters is not recom-
hours, it is necessary to provide an efficient air- mended, since they increase resistance, affect the
way humidification, either with traditional sys- operation of triggers, and there is no evidence
tems as passover humidification or with those that these prevent infections associated with
compatible with flow generators. health care.
Use of passive humidification delivered by a
heat and moisture exchanger (HME) is not rec-
ommended for non-invasive ventilation with a NIV as a 24 Hours per Day Prolonged
flow generator, because it increases system resis- Mechanical Ventilation Method
tance and dead space, alters trigger response, and
delivers insufficient conditioning of inspired air. Patients with nocturnal non-invasive ventilation
It is reserved only for transportation. (NIV) who have dyspnea during daytime hours,
respiratory infections despite assisted cough, and
CO2 >45  mmHg or SpO2 <95% with room air,
Oxygen Therapy require daytime NIV.  This happens naturally in
children, adolescents, and adults with NMD.
In patients with motor neuron disease (MND) Nocturnal and diurnal non-invasive ventila-
who present desaturation, oxygen administration tion is preferably performed with bi-level flow
is a mistake if there is not a proper management generators plus nasal masks. It is recommended
with assisted cough and proper ventilation to have two different mask models to vary the
protocols. pressure points. The advantages offered by the
In patients with chronic lung damage, O2 nec- bi-level in nocturnal hypoventilation prevention
essary for SpO2 greater than or equal to 93% will by using pressure-limited equipment (30 or
be provided. Flow generators, except for most 40 cm H2O maximum delivery) with high differ-
modern hybrid equipment, do not have an inter- ential pressure, not less than 7 cm H2O, and that
nal mixer. For this reason, the FiO2 will vary allow leak compensations and even average vol-
depending on flows delivered by programmed ume assured pressure support (AVAPS™,
pressures and on gas leak. The best alternative to IVAPS™) are increased in patients who require
deliver O2 is by means of a T-connection placed continuous non-invasive ventilation due to a
at the exit of the BiPAP, prior to connection to the greater dependence.
69  Long-Term Non-invasive Ventilation 711

Those patients with greater ventilatory demand, cols. This also means an improvement in the
with little ventilatory autonomy and with NIV HRQoL of the patient and their family environ-
requirements greater than 16 hours per day should ment. However, expected results are not always
be evaluated for continuous assisted ventilation. achieved, and psychological, social, and financial
Continuous NIV is defined as the use of it for more burdens constitute topics that require developing
than 20 hours per day, as an alternative more effec- assessment criteria in the bioethics domain. The
tive than mechanical ventilation by TQT.  This therapeutic challenges, which are possible thanks
strategy is carried out with volume-­controlled ven- to the new applied technologies, require includ-
tilators, with active exhalation valves in assist/con- ing bioethical principles considered as the sum of
trol mode (S/T-PCV) and with pressure trigger to knowledge that orient in a rational sense the
avoid auto-trigger. To avoid alarms, a minimum human action of promoting good and avoiding
respiratory rate of 1–2 per minute is set and an evil. These can be summarized as autonomy,
angled 15 mm mouthpiece is used. beneficence, equity (justice), and
As there is always a leak flow around the noz- non-maleficence.
zle, higher tidal volumes should be used than if a The development of non-invasive ventilation
TQT was used, on 500  ml (700–1.200  ml) and has allowed improving the natural history of
inspiratory times of 1–1.5 s that generate inspira- some NMD, especially DMD. However, in some
tory flows > at 40  L/m. When these flows pass neuromuscular diseases with progressive deterio-
through a system with specific resistance (angled ration, such as spinal muscular atrophy type 1,
mouthpiece), they generate an opposing pressure characterized by its fatal evolution without venti-
that prevents the activation of the low-pressure latory support, there is controversy about the
alarm. Currently, there are ventilators that include technical feasibility of non-invasive ventilation
the option of a mouthpiece that allows delivering support during the early stages of life (<6 months)
breathing cycles when they are needed and per- and on the bioethical implications of the deci-
forming air-stacking maneuvers, optimizing com- sion. This is especially true with infants with
plementary assisted cough protocols, impossible swallowing disorder due to bulbar compromise
to achieve with continuous flow equipment such within the first 3  months of life that prevents
as bi-levels. To achieve efficient ventilation, it is holding SpO2 stable above 95%. However, the
necessary that the patient has sufficient control of rest of children whose bulbar involvement is not
the bulbar muscles and cervical mobility. This severe can benefit from non-invasive ventilation,
alternative is for daytime use. During sleep, con- assisted cough protocols, and gastrostomy feed-
ventional non-invasive ventilation with interfaces ing, regardless of their ventilatory autonomy
is used. Another alternative is volume-­cycled ven- level. Thus, without tracheostomy it is possible to
tilation via mask, as previously mentioned. maintain language and positively impact on
Indication of TQT should be reserved for HRQoL.
patients without respiratory autonomy with sub- Bioethical aspects involved in managing
glottic stenosis, a vocal cord dysfunction due to patients with chronic, progressive, and poten-
severe bulbar involvement, which produces tially lethal diseases must be considered strongly
secretion or saliva aspiration that prevents main- when deciding together with patients and their
taining a SpO2 >95%. families on mechanical ventilation therapies. It is
essential to communicate all possible alterna-
tives, such as non-invasive ventilation, ventila-
Ethical Dilemmas tion through TQT or only accompaniment.
Treatment decisions must consider not only tech-
Survival of patients with NMD and technology nical feasibility aspects, but the aforementioned
dependent has improved, among other things, by bioethical principles. Respecting the principle of
specialized respiratory care, such as prolonged justice, it is essential that healthcare systems
mechanical ventilation and assisted cough proto- understand the importance of addressing the nec-
712 F. Prado Atlagic et al.

essary reimbursements for home care services patients with spinocerebellar ataxia type one for
that include such cost-effective and cost-efficient more than 10 years, avoiding tracheostomy.
coverage.

Sources
Conclusions
Bach J, Goncalves M, Hon A, Ishikawa Y, Devito E, Prado
F, Domínguez ME.  Changing trends in the manage-
Non-invasive ventilation is an alternative to inva- ment of end-stage neuromuscular respiratory muscle
sive mechanical ventilation in patients who failure. Am J Phys Med Rehabil. 2013;92(3):266–77.
evolve with acute and chronic respiratory failure, Boitano LJ.  Equipment options for cough augmenta-
who meet selection criteria. As the patient will be tion, ventilation, and noninvasive interfaces in neu-
romuscular respiratory management. Pediatrics.
at home, it is necessary to organize activities
2009;123(Suppl 4):S226–30.
there that include monitoring of clinical parame- Dohna-Schwake C, Podlewski P, Voit T, Mellies U. Non-­
ters, supervision of professionals, and continuing invasive ventilation reduces respiratory tract infections
education to the patient and their family. Within in children with neuromuscular disorders. Pediatr
Pulmonol. 2008;43:67–71.
the group of children with chronic respiratory
Fauroux B, Lofaso F.  Non-invasive mechanical ven-
diseases, it is useful in particular in NMD, kypho- tilation: when to start for what benefit? Thorax.
scoliosis, obstructive sleep apnea syndrome, and 2005;60:979–80.
cystic fibrosis, being able to alter the beginning Fauroux B, Le Roux E, Ravilly S, Bellis G, Clément
A. Long-term noninvasive ventilation in patients with
of the natural history of the disease when identi-
cystic fibrosis. Respiration. 2008;76:168–74.
fying hypoventilation at night, without waiting Ferrero G. Modos ventilatorios en ventilación no invasiva.
until functional clinical deterioration is already Consenso l Chileno de ventilación no invasiva. Rev
obvious in wakefulness. Chil Enf Respir. 2008;24:175–6.
Respiratory compromise in neuromuscular González X, Salinas P, Farías A, Rodríguez C. Aspectos
éticos de la ventilación mecánica domiciliaria.
diseases is a frequent cause of morbidity and Neumol Pediatr. 2008;3:83–6.
mortality and ventilatory insufficiency of prema- Graham R, Fleegler E, Robinson W.  Chronic ventilator
ture mortality. Over the past 10  years, we have need in the community: a 2005 pediatric census of
gone from the consideration of the natural history Massachusetts. Pediatrics. 2007;119(6):e1280–7.
Hill NS.  Saving face: better interfaces for noninvasive
of these diseases to both anticipatory and com- ventilation. Intensive Care Med. 2002;28:227–9.
prehensive recommendations in respiratory care. Mellies U, Ragette R, Dohna Schwake C, Boehm
The most substantial change in these recom- H. Long-term noninvasive ventilation in children and
mendations is the routine inclusion of non-­ adolescents with neuromuscular disorders. Eur Respir
J. 2003;22:631–6.
invasive ventilation and complementary protocols Prado F, Salinas P.  Asistencia ventilatoria no inva-
of assisted cough. Consequently, not only has the siva domiciliaria en niños: impacto inicial de un
role of non-invasive ventilation been consoli- programa nacional en Chile. Rev Chil Pediatr.
dated when it is initiated in a timely manner after 2011;82(4):287–97.
Prado F, Salinas P, Pizarro G, Campos C, Zenteno
confirming nocturnal hypoventilation but it has D.  Asistencia ventilatoria no invasiva: consideracio-
also been consolidated as the best strategy for nes teórico-prácticas en pediatría. Rev Chil Pediatr.
delivering prolonged mechanical ventilation to 2008;6:580–92.
those patients who require total ventilatory sup- Prado F, Salinas P, Zenteno D, Vera R, Flores E, et  al.
Recomendaciones para los cuidados respiratorios del
port or for more than 20  hours a day, reserving niño y adolescente con enfermedades neuromuscula-
the indication of TQT exclusively for those who res. Rev Neumol Pediátr. 2010;5:74–88.
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Toussaint M, Chatwin M, Soudon P.  Mechanical venti- Ward S, Chatwin M, Heather S, Simonds AK. Randomised
lation in Duchenne patients with chronic respiratory controlled trial of non-invasive ventilation (NIV) for
insufficiency: clinical implications of 20 years pub- nocturnal hypoventilation in neuromuscular and chest
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Wallgren-Petterssona C, Bushbyb K, Melliesc U, Simonds Thorax. 2005;60:1019–24.
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 Tracheotomy
70
Bernardita Chateau Infante
and Constanza Beltrán Morales

Contents
Introduction..................................................................................................................  715
Anatomy........................................................................................................................  716
Indications.....................................................................................................................  716
Tube Selection...............................................................................................................  717
Complications...............................................................................................................  718
Early Complications.....................................................................................................  718
Late Complications.......................................................................................................  719
Care................................................................................................................................  720
Stoma and Skin Care......................................................................................................  720
Changing the Cannula....................................................................................................  721
Thermal Humidifying.....................................................................................................  721
Inhaling Discharges........................................................................................................  721
Fixation...........................................................................................................................  721
Phonation........................................................................................................................  722
Decannulation...............................................................................................................  722
Sources...........................................................................................................................  722

Introduction

Tracheotomy is the communication between the

trachea and the external environment, performed
B. Chateau Infante (*) through a surgical procedure. The first references
Department of Pediatrics, Clínica Los Andes, made to such a procedure date back to the year
Santiago, Chile
e-mail: [email protected] 1500 BC in India. In AD 1546, Musa performed
the first successful tracheotomy, but it was not
C. Beltrán Morales
Department of Otorhinolaryngology, School of until 1620 that Habicot attempted to perform the
Medicine, Universidad de los Andes, Santiago, Chile first pediatric tracheotomy. At the beginning of
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 715

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_70
716 B. Chateau Infante and C. Beltrán Morales

the twentieth century, American laryngologist for tracheotomy in cases of airway obstruction are
Chevalier Jackson standardized the technique of those that allow elective intervention, such as sub-
the procedure, reducing morbidity and mortality glottic stenosis secondary to prolonged intubation
associated with this intervention. during the neonatal stage, bilateral vocal cord
paralysis, and injury to the high airway, such as
burns and fractures, generally requiring tempo-
Anatomy rary tracheotomy. Subglottic stenosis is one of the
main indications for tracheotomy in children.
The pediatric airway anatomically differs from Mature newborns have a lumen of at least 4 mm;
those of adults in important ways. They are of a a smaller lumen is considered stenosis. In older
smaller size and caliber, making them more sus- children, the reduction of subglottic caliber is
ceptible to swelling-induced obstruction, mucus, determined by age and graded by percentage fol-
or foreign bodies. In comparison with adults, its lowing the Myer–Cotton system (Table 70.2).
position is more cephalic and anterior, causing Most instances of stenosis in children happen
neck hyperextension to reduce the diameter of as a result of endotracheal intubation, because
the airway. the sub glottis, contained by the cricoid cartilage
In 2003, Litman studied the larynxes of 99 —a full ring that cannot dilate nor accommo-
pediatric patients through nuclear magnetic reso- date— becomes swollen at the epithelium by the
nance (NMR), determining that the smallest mechanical injury of the tube, reducing the cali-
diameter is the transverse diameter of the glottis. ber of the airway. When these scars narrow, the
After that, Dalal et  al. verified these results result is subglottic stenosis. Grade IV stenosis
through bronchoscopy, determining that the pedi- by Myer–Cotton’s system has an absolute indi-
atric larynx presents a conical shape, rather than cation of tracheotomy, but for grade II and III
a cylindrical one. However, despite the fact that stenosis it will depend on the degree of respira-
the glottis is the narrowest area of the larynx, the tory compromise.
cricoid cartilage is the area with the highest risk
of obstruction and injury, given its rigid structure Table 70.1  Indications for tracheotomy by origin
that does not allow for distention and its elliptic
1. High airway obstruction
aperture with a larger anteroposterior diameter. Congenital Craniofacial dimorphism
Paralysis of the vocal chords
Subglottic hemangioma
Indications Subglottic membrane
Upper subglottic or tracheal stenosis
Tracheotomy began to be considered a treatment Pharyngeal collapse
Severe laryngomalacia
as an emergency procedure for dealing with criti-
Acquired Secondary subglottic stenosis
cal obstruction of the airway. The latest develop- Severe obstructive sleep apneas
ments in this area have created two other Papillomatosis
indications: when prolonged invasive mechanical Burn injuries
ventilation is needed and for lung hygiene. Tumors
Critical obstruction of the airway can be clas- 2. Prolonged need of MV
sified by origin: congenital or acquired (infec- Congenital Neuromuscular disorders
Central hypoventilation
tion, injury, etc.); or by location: craniofacial,
Diaphragmatic hernia
larynx, or trachea (Table 70.1). Severe bronchopulmonary dysplasia
The decision to perform a tracheotomy will Acquired Traumatic chest injuries
depend on the degree of obstruction, possibility of CNS tumors
spontaneous resolution within a reasonable Severe chronic lungs damage
amount of time, and the possibility of definitive Severe scoliosis
corrective surgery. Currently, the main indications 3. Lung hygiene
70 Tracheotomy 717

Table 70.2 Classification of degree of subglottic • With cuff or balloon: there is an inflatable

obstruction
device on the distal end of the tube. These
From To tubes may be: high volume/low pressure, low
I degree
volume/high pressure, and foam balloon. High
volume/low pressure is the preferred option
No obstruction 50% of lumen
obstruction given their lower injury risk to the airway.
II degree Indications for using balloon are given mainly
to lower the risk of aspiration, need of mechan-
51% of lumen 70% of lumen ical ventilation at high pressure, night ventila-
obstruction obstruction tion, and for patients with chronic aspiration.
III
• Fenestrations: they improve trans-laryngeal flux
degree
and phonation, while also improving the han-
71% of lumen 99% of lumen
obstruction obstruction dling of discharges. However, different studies
IV No detectable lumen have shown that these promote the emergence
degree of granulomas on the fenestration area, so the
use of the technique has been limited.
• Internal cannula: these tubes are indicated for
For patients with respiratory failure caused by patients with abundant thick discharges that
severe lung disease or by neuromuscular, neuro- stick to the walls of the tube. In this way, it is
logical, or heart diseases, who also depend on only necessary to remove the internal cannula
mechanical ventilation for over 12  hours a day, during the cleaning procedure, thus avoiding
tracheotomy is considered. In the case of acute frequent tracheotomy tube switching.
respiratory failure requiring mechanical ventila-
tion for over 21 days, tracheotomy may also be It is of the utmost importance to choose the
considered. The benefit of prolonged mechanical precise cannula for each patient. The tracheot-
ventilation through tracheotomy lies in the reduc- omy tube must be of the right size for the airway,
tion of laryngeal damage, improving the level of with the exact shape and length to keep the tube
comfort for the patient, and improving their daily secured to the airway without pressing the struc-
activities like mobility, speech, and oral feeding. tures lying next to the trachea or the neck
(Table  70.3). When choosing, the following
parameters must be considered:
Tube Selection
• Age: patients under 1 year must use cannulas
Once the tracheotomy has been performed, it is nec- that are specially designed for newborns.
essary to insert a tube in order to keep the airway • Reason for tracheotomy: in case of upper air-
open and permeable. This tube is the tracheotomy way obstruction or if prolonged mechanical
cannula. There are different kinds of tubes designed ventilation is needed.
to adjust to the appropriate needs of each patient. • Diameter and curvature of the tube: the size of
tracheotomy tubes is based on internal diameter,
By material: much like the selection of endotracheal tubes.
• Metal (stainless steel, silver): rigid tubes When choosing the right diameter, many factors
• PVC (polyvinyl chloride): may be rigid or must be considered, including lung mechanics,
flexible upper airway resistance, need for ventilation/
• Polyurethane union, and procedure indications. The diameter
• Silicone: these tubes are preferred for their must be wide enough to avoid damage to the
flexibility, as they adapt to the size and shape wall of the trachea, minimize respiratory work,
of the patient’s trachea and promote laryngeal airflow. It should not
exceed two thirds of the diameter of the trachea,
By structure: thus avoiding damage to the wall of the trachea
• Simple or double tube and allowing trans-­laryngeal flow. Its curvature
718 B. Chateau Infante and C. Beltrán Morales

Table 70.3  Characteristic of tracheotomy cannulas

Age PT-1 m 1–6 m 6–18 m 18 m -3a 3–6 a 6–9 a 9–12 a 12–14 a
Trachea Diameter (mm) 5 5–6 6–7 7–8 8–9 9–10 10–13 13
Shiley Size 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
ID (mm) 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
ED (mm) 4.5 5.2 5.9 6.5 7.1 7.7 8.3 9.0
Length NB (mm) 30 32 34 36 – – – –
Length PED (mm) 39 40 41 42 44∗ 46∗ – –
Length PDL (mm) – – – – 50∗ 52∗ 54∗ 56∗
Portex Size 2.5 3.0 3.5 4.0 4.5 5.0 5.5 –
ID (mm) 2.5 3.0 3.5 4.0 4.5 5.0 5.5 –
ED (mm) 4.5 5.2 5.8 6.5 7.1 7.7 8.3 –
Length NB (mm) 30 32 34 36 – – – –
Length PED (mm) 30 36 40 44 48 50 52 –
Tracoe Size 2.5–3.0 3.5 4.0 4.5 5.5 5.5 6.0 –
ID (mm) 2.5–3.0 3.5 4.0 4.5 5.5 5.5 6.0 –
ED (mm) 3.6–4.3 5.0 5.6 6.3 7.0 7.6 8.4 –
Length NB (mm) 30 32 34 36 – – – – –
Length PED (mm) 32 36 40 44 48 50 55 62 –
Rüsch Size – 3.0 4.0 – 5.0 – 6.0 –
ID (mm) – 3.0 4.0 – 5.0 – 6.0 –
ED (mm) – 4.8 6.0 – 7.0 – 8.2 –
m months, y years, ID internal diameter, ED external diameter, NB newborn, PED pediatric, PDL pediatric long
*
with balloon

must be such that the distal portion of the can- Globally speaking, between 25% and 50% of
nula becomes aligned and concentric toward the pediatric tracheotomy patients will develop some
trachea. It is recommended to confirm both form of complication. Children younger than
position and adequate size of the cannula the 3  years of age usually have more problems than
first time it is placed in the larynx through a older children. When comparing emergency tra-
neck X-ray or a fibrobronchoscopy. cheotomy to an elective procedure, the former has
• Length of the cannula: the length of the can- a higher rate of complications: 75% versus 35%.
nula must be at least 2 cm beyond the stoma Regarding newborns, premature children present a
and remain 1–2 cm over the carina. higher rate of complications with regard to full-
term children, just like newborns weighing less
A commercial tube can be used for most than regular weight children (55% versus 34% in
patients. In limited cases, it may be necessary to children who weight 2000 g. at birth). Complications
use an individually customized tube. All trache- are more common in children who suffer from
otomy cannulas must have a 15  mm universal obstruction of the upper airway (33%), followed by
terminal at their opening in order to connect to central nervous system disorders (22%).
assisted ventilation when necessary.

Early Complications
Complications
• Hemorrhage. Bleeding of surgical wound.
Tracheotomy complications can be analyzed Infrequent. May represent a medical emer-
according to the moment they emerge during pro- gency. Depending on quantity, the patient
gression, considering early apparition during the must undergo medical ward examination and
first week after the procedure, and late apparition surgical resolution.
when it occurs at a later point. • Accidental decannulation, up to 5% of cases.
70 Tracheotomy 719

• Tube displacement or insertion of the tube in • Tracheal granulomas: This is the most fre-
wrong path. It is suggested that the first time quent late complication, with granulomas
the cannula is swapped, the surgeon in charge being commonly seen on the rear wall of the
of the procedure should perform the swapping trachea over the stoma. Distal granulomas
in a safe environment. may also be observed because of the contact
• Acute obstruction of the tube caused by secre- between the distal end of the cannula and the
tions or foreign body. anterior or rear wall of the trachea. Treatment
• Tracheoesophageal fistula. It is a rare compli- depends on their size, with a conservative
cation and is caused by the erosion of the pos- approach if they are small, or a surgical
terior wall in the trachea created by the inflated approach if these are large or symptomatic.
balloon or tube. It appears as discharges, dys- • Infections: Recurring infections are one of the
pnea, gastric distention, or food aspiration most common complications. The direct con-
through the cannula. Diagnosis is done tact between the airway and the environment,
through direct visualization through bron- without regular defense mechanisms and given
choscopy or through an image contrast study usual handling, bacterial colonization occurs
leading to surgical resolution. and there is a higher risk of infection.
• Surgical wound infection. It is evidenced by Colonization is defined as the isolation of a
local inflammatory signs. pathogen within a tracheal culture for at least
• Acute occlusion of the tube caused by dis- 4 weeks without clinical signs of acute infec-
charges or foreign bodies. tion. Moreover, in some cases bacterial bio-
• Tracheoesophageal fistula. This is a rare com- films may complicate antibiotic management,
plication that happens when the pressure favoring recurring infections. The most com-
exerted by the cannula or the inflated balloon monly isolated agents are Pseudomona aerugi-
erodes the posterior wall of the trachea. It is nosa, Streptococcus pneumoniae, Hemophilus
evidenced by an increase of local inflamma- influenzae, Moraxella catarrhalis, gram nega-
tory signs. tive enteric bacilli, and Staphylococcus aureus.
• Laryngeal nerve damage. It is common during Most infections tend to be local stomas and
surgery. It is hard to diagnose. Since there is tracheitis. Microbiological surveillance with
no laryngeal flow after the tracheotomy, the serial cultures is questioned, but it may guide
condition goes unnoticed. Common signs are the initial antibiotic treatment if necessary.
dysphonia, bitonal voice, or stridor. Topical antibiotic treatment of the stoma may
• Air leakage. Subcutaneous emphysema, pneu- reduce colonization and ­infection in children,
momediastinum, or pneumothorax because of but there are no supporting studies to confirm
interruption of the airway with adjacent this treatment.
spaces. It is detected by cutaneous crackles or • Decannulation/displacement of the cannula:
progressive breathing complications. These Losing the artificial airway may lead to death.
are accompanied by compatible X-ray images. Safe fastening systems must be employed to
avoid this complication, as well as monitoring
of the patient in selected cases.
Late Complications • Tube obstruction: Very frequent in children as
shorter diameter cannulas may become easily
There is a direct relation between the length of obstructed by discharges.
the tracheotomy and late postoperative complica- • Tracheomalacia/tracheal stenosis: By using a
tions. These are reported in 11% of tracheosto- medical instrument that is frequently manipu-
mies that lasted less than 100  days; 55% in lated in the airway, the structure of the trachea
tracheostomies that lasted between 101 and may be altered and cause stretching or mala-
500 days; and in over 80% of tracheostomies that cia. It should be more common when positive
lasted over 500 days. pressure is applied (mechanical ventilation).
720 B. Chateau Infante and C. Beltrán Morales

• Erosion of the tracheal wall or tracheoesopha- • D for dislodgement: check the position of the
geal fistula. cannula.
• Persistent tracheocutaneous fistula: • O for obstruction: proceed to aspire the can-
Persistence of the stoma will depend on tech- nula and check if it is permeable; when in
nique and length of the tracheotomy. Surgical doubt, remove and change it.
closure may be needed in some cases. • P for pulmonary: check if the respiratory dis-
• Bleeding/hemorrhage: During late stages of the tress is due to a different respiratory cause
treatment, bleeding is unusual. When it does unrelated to the cannula.
happen, it tends to be minimal, mainly caused by • E for equipment: check that all the connec-
local infections. Treatment should deal with base tions, drains and sensors are in the right posi-
infection. Hemorrhages are uncommon and are tion and in contact.
associated with traumatic vascular injuries.
• Tracheal fistula on the innominate artery: This All the daily and emergency care materials
is an uncommon, but severe complication. It must be available and close to the patient at all
happens because of contact and erosion of the times:
anterior wall of the trachea and the innominate
artery. It is generally caused by an excess –– Humidifying equipment
manipulation of the tracheotomy tube, exces- –– Discharge aspiration probes and equipment
sively pressured balloons or when the cannula –– Tracheotomy cannulas: — One of the same
reaches below the third tracheal ring. It number  — One of a lower number Basic
requires urgency surgical management. airway equipment: oxygen, self-inflating
bag.
–– Lubricating gel.
Care –– Sterile gauzes, fixing tape, scissors, clean-up
basin, physiological saline.
The first step in tracheotomy care is knowledge. –– Personal biosafety material: Sterile gloves,
In most cases, patients are not capable of self-­ mask, coats, and safety goggles depending on
care as is the case with most adult patients, which specific needs.
is why people under medical care must be edu-
cated and trained. They must have basic anatomy
knowledge as well as about care and emergency Stoma and Skin Care
materials in case of clinical signs of respiratory
distress and infection, and an easy and express These are simple measures to prevent macera-
means of communication in case of emergency. tion and infection of the stoma. Use of the asep-
They must be trained in tracheotomy aspiration, tic technique is related to a decrease in infection
cannula switching (when and how), and how to rates. It is recommended to wash the area of the
proceed in case of emergency. neck with water and soap daily, clean the stoma
Undergoing tracheotomy with a medical from the medial border to the distal border with
instrument in the airway is, in and of itself, a sterile gauze covered in physiological saline
potential risk. Caregivers should recognize emer- solution, and then cover the area with gauze to
gency situations and how to proceed with them. It protect it from humidity and tracheal dis-
is thus very useful and pertinent to establish pro- charges. It is not recommended to make routine
tocols and flow diagrams on how to proceed. use of creams or similar items. Monitor for
When facing respiratory distress in a trache- signs of infection (swelling, erythema, pain,
otomy patient, a useful acronym to remember is discharges) or the emergence of friction-
DOPE: induced granulomas.
70 Tracheotomy 721

Changing the Cannula Inhaling Discharges

The first scheduled cannula change must be done Scheduled and serial inhaling is not recom-
between the first 5–7 days on an empty stomach at mended in order to avoid unnecessary manipula-
the hospital, in a safe environment, and performed tion of the airway, and it is only indicated when
by the surgical team. Later on, the caregivers are there is evidence of discharges in the airway, sus-
allowed to do it under supervision as part of their picion of obstruction, or before cannula swap or
training. The maneuver must be swift and accu- balloon deflating.
rate, with a round movement as the cannula enters, The recommended adequate technique is:
avoiding sharp angles in order to avoid eroding
and later damage. How often and regularly the • In a safe environment and with easy and work-
cannula must be replaced is a matter of discus- ing access to all the available material.
sion, and it depends on the composition of the • Place the patient, ideally on an empty stomach
cannula. On the one hand, having only brief peri- and having previously aspirated the secre-
ods between cannula swaps implies a higher tions, lying on their back.
degree of manipulation, carrying related compli- • Keeping hands washed and wearing gloves.
cations with it (eroding, granulomas), while on The technique must be performed under ster-
the other hand, longer periods between swaps ile conditions at the hospital due to the risk
favor discharge-related obstructions and infec- and control of in-hospital infections. However,
tion. Two to four weeks is considered a reasonable when done at home, it is enough to use the
period of time. What matters is monitoring the clean technique (non-sterile gloves).
good condition and permeability of the cannula. • Adjust inhaling pressure (pressure limits
between 80 and 100 mmHg).
• Probe with an adequate size for the cannula
Thermal Humidifying (approximately half of the diameter of the
cannula) and marked to the maximum intro-
Given that tracheotomy is a direct opening to the duction distance (not going beyond 0.5  cm
lower airway, air is not filtered and thermally from the distal end of the cannula).
humidified in a regular way, producing damage to • Avoid touching the distal end, lubricate the
the mucous membrane and altering mucociliary end of the probe with physiological saline
transport, thus increasing the risk of infection and solution, softly introduce it, occluding it in
obstruction. It is then essential to deliver humid- order to generate suction and administer inhal-
ity and warmth to the air inhaled by such patients. ing both at the entry and at the end of the
Thermal humidifying may be active or pas- probe, and perform a circular movement of the
sive. Active methods use equipment and tubes, catheter with the thumb and index fingers. Do
making inhaled air pass through a hot water sys- not do it for longer than 5 seconds in order to
tem before reaching the inspiratory part of the avoid atelectasis.
flow-volume loop. These methods are more
effective, but they are also more expensive and
usually require being connected to the electricity Fixation
grid. Passive humidifiers include a filter installed
on the cannula or between the ventilator and the For tracheotomy patients, fixation is of vital rel-
cannula that collects the heat and humidity of the evance. There are multiple materials for the fixa-
exhaled air for its use during inhaling. Ideally, tion system, such as cotton tapes with velcro,
the system allows the conditioning of inhaled air, elastic tapes with hooks, and stainless-steel
reaching temperatures of 32°–34  °C and an chains. Whatever the system, it must ensure the
absolute humidity of 36–40 mg/l at the level of fixation of the cannula in its place. It is funda-
the carina. mentally important for the fixing to provide
722 B. Chateau Infante and C. Beltrán Morales

enough tension to avoid displacement of the can- Decannulation

nula and accidental decannulation, but it must
also allow for changes in neck size caused by cry- When deciding on decannulating a pediatric
ing, laughing, and feeding. It is recommended to patient, a number of criteria must be confirmed.
fasten the fixation system with enough space to
insert a finger between the neck and the system • Permeable upper airway. In the case of an ear-
itself. In order to lessen the pressure on the stoma lier obstruction, this must be solved.
and to keep it dry, a dressing is applied between ­Confirmation should be performed visually.
the cannula and the stoma. In the case of ventila- Rigid or flexible laryngo-bronchoscopy.
tion circuits connected to the cannula, they must • Independence from mechanical ventilation at
be fastened in order to avoid producing more ten- least for the last 3  months, ideally including
sion or movement on the cannula. respiratory intercurrences.
• Regular swallowing, without clinical evidence
or inhalation images. Must be confirmed by a
Phonation video swallowing study.
• Adequate clearance of respiratory discharges.
Given the fact that there is a flow through the can-
nula of tracheotomy patients, the air flow is lost There are a number of decannulation proto-
through the larynx, also taking away verbal lan- cols for patients who fulfill the previous criteria.
guage. This loss alters the psycho-social develop- Most of them consider breathing and blocked
ment of children. There are a number of options cannula tolerance evaluations by hours and days,
to allow the flow of air toward the glottis, such as with sleep and activity tests, then reducing the
using fenestrated cannulas or deflating the bal- size of the cannula for some days in order to
loon in case there is one, but often this is not finally decannulate in a safe environment under
enough to allow phonation. There are devices care and monitoring for 24–48 hours.
that can connect to the cannula and are specifi- After successful decannulation, the stoma
cally designed to favor phonation. Its working must be covered with gauze, waiting for closure
principle is allowing airflow through the inhaling by secondary intention. However, up to 40% of
cannula, but applying resistance to exhalation, cases require surgical closure.
redirecting the airflow toward the vocal chords. It
is therefore basic and fundamental to have space
around the cannula (check free tracheal space on Sources
the X-ray and deflate the balloon) and a perme-
able upper airway. There are special models that Al-Samri M, Mitchell I, Drummond D, Bjornson
may be employed when under mechanical C.  Tracheostomy in children: a population-based
ventilation. experience over 17 years. Pediatr Pulmonol.
2010;45(5):487–93.
As additional effects, phonation valves Climent FJ, García M, Villalobos E. Manejo y cuidados
improve the efficiency of coughing by producing del niño con traqueostomía. Actualizaciones SEPHO
mucociliary clearance, and since there is a back- 2014.
ward flow through the larynx, it would reduce the Davis G. Tracheostomy in children. Paediatr Respir Rev.
2006;7(Suppl 1):S206–9.
risk of inhaling in patients who feed orally while Deutsch E.  Tracheostomy: pediatric considerations.
also optimizing olfaction. Respir Care. 2010;55(8):1082–90.
There are phonation valve tolerance evalua- García R, Beltrán C, Chateau B. Infecciones respiratorias
tion protocols for candidate patients. These pro- asociadas a traqueostomías en niños. Neumol Pediatr.
2011;6(3):134–7.
tocols demonstrate that a registered pressure of McGrath B, Bates L, Atkinson D, Moore JA.  National
10–12 cm/H2O at the moment of exhaling is asso- Tracheostomy Safety Project. Multidisciplinary
ciated with good tolerance. guidelines for the management of tracheostomy and
70 Tracheotomy 723

laryngectomy airway emergencies. Anaesthesia. Pérez-Ruiz E, Pérez-Frías FJ, Caro-Aguilera P. Cuidados

2012;67(9):1025–41. del niño con traqueostomía. An Pediatr. 2010;72(Supl
Mitchell R, Hussey H, Setzen G, Jacobs I, Nussenbaum E1):41–9.
B, Dawson C, Brown C, Brandt C, Deakins K, Trachsel D, Hammer J.  Indications for tracheostomy in
Hartnick C, Merati A. Clinical consensus statement: children. Paediatr Respir Rev. 2006;7(3):162–8.
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Paz F, Zamorano A, Paiva R, Hernández J, Mödinger P, mantenida en la vía aérea como indicador de toleran-
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 Airway Surgery and Endoscopic
Procedures
71
Patricio Varela Balbontín

Contents
Larynx Diseases............................................................................................................  725
Congenital Laryngeal Anomalies................................................................................  725
 aryngomalacia..............................................................................................................  725
L
Congenital Subglottic Stenosis.......................................................................................  726
Laryngeal Diaphragm or Webs.......................................................................................  726
Subglottic Hemangioma.................................................................................................  728
Congenital Tracheal Anomalies...................................................................................  728
Tracheomalacia-bronchomalacia....................................................................................  729
Congenital Tracheal Stenosis (Congenital Tracheal Rings)...........................................  729
Laryngotracheal Cleft.....................................................................................................  731
Technical Aspects..........................................................................................................  731
 ediatric Airway Frequently Acquired Lesions.........................................................  732
P
Acquired Subglottic Stenosis.........................................................................................  732
Surgical Treatment..........................................................................................................  732
Tracheal and Bronchial Stenosis Acquired After Intubation..........................................  734
Summary.......................................................................................................................  735
Sources...........................................................................................................................  735

Larynx Diseases forms are diverse and constitute a spectrum of

possibilities in each of their types.
Diseases that affect the larynx and trachea can be
classified according to their congenital and
acquired nature (Table  71.1). The congenital Congenital Laryngeal Anomalies

Laryngomalacia

It is the most frequent cause of stridor in new-

borns. More common in males, it constitutes
P. Varela Balbontín (*)
Pediatric Surgery, Hospital Luis Calvo Mackenna, 60% of the airway congenital anomalies, and it is
Universidad de Chile, Santiago, Chile usually a benign and self-limiting disease.

© Springer Nature Switzerland AG 2020 725

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_71
726 P. Varela Balbontín

Symptoms generally start between weeks 2 and Congenital Subglottic Stenosis

4, with progression until months 2 and 3. Most
patients improve spontaneously after 12 and up It is a congenital narrowing of the subglottic
to 24  months of age, if the treatment is space of less than 4 mm in term newborn infants
­conservative. Less than 15% correspond to severe and 3  mm in preterm newborn infants. It is the
cases. In them, supraglottoplasty is the method third larynx congenital malformation (10%), and
used, which is performed with microlaryngeal it is a consequence of a recanalization failure of
instruments or by using CO2 laser. This surgery is the laryngeal lumen during the embryonic period.
performed endoscopically and requires general In its embryological process, it is related to laryn-
anesthesia. The patient remains intubated geal atresia and congenital laryngeal diaphragms.
24 hours and is extubated in an intensive care unit Symptomatology is variable and is related to the
(Fig. 71.1). degree of stenosis. It can appear as mild stridor at
birth or severe obstructive symptomatology that
requires an emergency tracheotomy (Fig.  71.2).
Table 71.1  Congenital and acquired airway diseases
In the case of severe stenosis, it is usually required
Congenital to perform a tracheotomy to ensure proper venti-
 Laryngomalacia
lation. A final reconstructive surgery is performed
 Vocal cord paralysis
 Congenital subglottic stenosis
at around 1 year of life and consists of a partial
 Subglottic hemangioma cricoid resection with trachea-thyroid anastomo-
 Congenital laryngeal web sis. The tracheotomy is removed. In cases of con-
 Laryngal atresia genital subglottic stenosis the cricoid is
 Laryngotracheoesophageal cleft malformed, with a narrower lumen and a charac-
 Tracheomalacia teristic elliptical shape.
 Bronchomalacia
 Congenital tracheal stenosis
 Tracheal agenesis
Acquired Laryngeal Diaphragm or Webs
 Subglottic stenosis
 Glottic stenosis Diaphragms or congenital laryngeal webs are the
 Tracheal stenosis result of an incomplete recanalization of the
 Bronchial stenosis primitive larynx. They appear as an obstruction

Fig. 71.1  Laryngomalacia. Omega shaped epiglottis, short aryepiglottic folds. (a) Expiration, (b) Inspiration
71  Airway Surgery and Endoscopic Procedures 727

Fig. 71.2 Subglottic stenosis. Direct laryngoscopy Fig. 71.3  Laryngeal web. Type III laryngeal web with
shows a severe narrowing of less than 1 mm of the sub- 75% of lumen obstruction
glottic space in a newborn with respiratory distress

of the upper airway, and characteristically with

stridor. Newborn’s crying is abnormal and can
even cause aphonia. There are two types of con-
genital diaphragms: one is a thin web that is
delimited to the glottis; the other is a thick dia-
phragm that extends into the subglottis. The lat-
ter is thought to correspond to a lower degree of
laryngeal atresia rather than a real web. They are
infrequent and constitute 5% of the congenital
anomalies of the larynx. There is a genetic asso-
ciation with DiGeorge syndrome, which is char- Fig. 71.4  Laryngeal web. Laryngoscopy performed in a
acterized in some cases by a microdeletion of newborn with laryngeal web that shows 95% glottis
obstruction and reduction of interarytenoid space
chromosome 22q11. The acquired webs are usu-
ally postintubation and produce a variable degree
of synechia in the vocal cords. Most laryngeal laryngeal diaphragm diagnosis and severe airway
diaphragms have associated subglottic stenosis obstruction during the first hours of life charac-
and thickening of the cricoid cartilage, espe- teristically corresponds to a case of diaphragm
cially grades III and IV.  According to Cohen’s with severe obstruction of the glottic space, and
classification, they can be grouped into four in many cases emergency surgery is required to
types depending on the morphology and the secure the airway (tracheotomy). In patients with
degree of laryngeal obstruction they cause thin and anterior diaphragms, an endoscopic cut
(Figs. 71.3 and 71.4). can be performed. In thick diaphragms, with mild
Initial diagnosis is made with a nasolaryngos- to moderate symptoms, later repair is suggested,
copy conducted while the patient is awake, which because it is easier in technical terms. In children
will rule out other possible diagnoses, such as with more severe symptoms, the intervention
laryngomalacia or vocal cord paralysis. A final must be done early. To relieve obstruction, tra-
evaluation requires direct laryngoscopy. Different cheotomy is also endorsed as an option while the
therapeutic options are available: a newborn with child grows, in order to repair at a later age.
728 P. Varela Balbontín

In the majority of type III and IV diaphragms, Currently, the treatment of choice is the admin-
open surgery involves a two-stage repair that istration of propranolol; however, there are other
includes the division of the diaphragm and treatment options that are second-line therapy that
enlargement of the subglottic space. The current should be analyzed in each patient, considering
recommended technique consists of performing the size of the lesion, age, degree of obstruction,
anterior laryngofissure with a siliconized laryn- and response to steroids and propranolol.
geal stent placement plus a temporary tracheot- Observation is appropriate for older patients, in
omy. The purpose of this laryngeal prosthesis is whom there is little or minimal associated symp-
to allow an adequate epithelization of the medial tomatology of respiratory obstruction.
border of the cords that was congenitally adhered In cases where airway obstruction caused by
and thus prevent them from adhering again. hemangioma is less than 50% of the lumen and
Between 6 and 8 weeks later, the laryngeal pros- the symptoms are mild, the alternative to observe
thesis is removed endoscopically, and then it is and re-evaluate is valid. Endoscopic techniques of
possible to remove the tracheotomy. As men- intralesional steroids injection, submucosal dis-
tioned, it is advisable to expand the airway using section with microdebrider, and laser ablation can
an anterior or posterior graft of costal cartilage only achieve partial removal of the lesion and
due to the frequent association that this pathol- cause some degree of damage to the mucosa or
ogy has with subglottic space stenosis. In grade cricoid cartilage, so currently there is controversy
III patients, having to enlarge the subglottic space regarding these therapies. Temporary tracheot-
in the posterior plate and the anterior wall occurs omy offers a stable airway during the growth and
frequently. In mild forms, the approach is endo- involution phase of the hemangioma. In case of
scopic surgery conducted by experts, and requires opting for this alternative, the presence of the
cutting off the web using a laser, and also a muco- stoma should be considered for a period of
sal flap in the cords to prevent posterior synechiae approximately 10–30  months. The advantage of
and recurrence. The insertion of a keel endoscop- this option is that the involution of the lesion is
ically, between the medial borders of the sepa- achieved without a surgical intervention that may
rated cords, is another endorsed alternative in be associated with cord injury. However, it should
older patients. also be considered that tracheotomy in infants has
associated morbidity and mortality and requires
special care. Open surgical resection is the treat-
Subglottic Hemangioma ment of choice in symptomatic patients with large
hemangiomas that grow quickly. It would also be
It is a benign vascular tumor located in the sub- indicated in patients in whom the involution of the
glottic space, specifically in the left posterolateral hemangioma has not occurred within 2 years (and
region, close to the vocal cord on the same side. where a tracheotomy or observation was chosen).
It corresponds to 1.5%–3% of all benign lesions Endoscopic excision with CO2 laser, open resec-
of the larynx, and its evolution is self-limited, tion, endoscopic resection with microdebrider,
starting to remit after 18 months. Hemangiomas and tracheostomy are the main surgical alterna-
of posterior localization, left and bilateral, are tives. However, propranolol treatment currently
less common. In our experience, we have evalu- prevails in most hemangiomas.
ated eight subglottic hemangiomas, one of them
posterior bilateral associated with congenital nar-
rowing of the subglottic space. Because initial Congenital Tracheal Anomalies
treatment with propranolol was not enough, sur-
gery had to be done, resecting the hemangioma, Infrequent events, with an incidence of 1 per
removing the cricoid posterior mucosa, and per- 60,000 live births. Most common congenital tra-
forming a partial cricoid resection and a primary cheal anomalies are tracheomalacia, bronchoma-
thyrotracheal anastomosis without tracheotomy. lacia, tracheal cleft, and tracheal stenosis.
71  Airway Surgery and Endoscopic Procedures 729

Tracheomalacia-bronchomalacia

Surgical alternatives, such as aortopexy, broncho-

pexy, intraluminal supports (stents), partial resec-
tions, and tracheotomy are reserved for severe
cases: apneas, respiratory obstruction episodes dur-
ing feeding, and recurrent respiratory infections.

Aortopexy  Indicated when there is a collapse

greater than 50% of the tracheal lumen. It con-
sists of a suspension of the anterior wall of the
aortic arch to the internal wall of the sternal
manubrium in order to increase the space of the
mediastinum, so that the malacic airway segment
Fig. 71.6  Bronchomalacia. Patient with complete bron-
is free of compression by the vascular structures chial compression after cardiac surgery. The stent allowed
that surround it. reexpansion of the obstructed left main bronchus

Stents  Intraluminal supports that keep the air- Once in situ, it can remain for a long time or be
way lumen expanded (Figs.  71.5 and 71.6). Its removed as needed.
effectivity has been confirmed. The insertion is
done by endoscopy. The types of stents available
are mainly metallic (Palmaz, nitinol, wallstents) Congenital Tracheal Stenosis
and silicone (Dumon, Montgomery). Currently, (Congenital Tracheal Rings)
self-expandable and heat-moldable stents are
available, thus achieving a better resistance and It is a very infrequent malformation character-
effectiveness to solve a severe airway collapse. ized by an anomaly of the tracheal skeleton, with
They can be inserted into the tracheal or bron- presence of complete circular tracheal rings that
chial lumen unilaterally or bilaterally as required. are distributed along the stenosis and that deter-
mine a fixed narrowing of the tracheal lumen
(Figs. 71.7. and 71.8).
The radiological study with chest X-ray can
suggest the diagnosis. Bronchography is also a
useful study tool (Figs. 71.9. and 71.10).
Symptomatology is variable and is related to the
degree of the lumen narrowness; 50% are associated
with vascular malformations, and the ring of the left
pulmonary artery is the most f­requent. There is a
morphological classification of congenital tracheal
stenosis that divides them into four groups:

Type I  Long narrow segment. It is the most com-

mon morphology and usually the stenosis com-
promises 80% or more of the tracheal length.

Type II  Funnel morphology.

Fig. 71.5  Tracheomalacia. Inserted stent in the lower Type III  Short segment. Stenosis compromises
third of the trachea less than 50% of the tracheal length.
730 P. Varela Balbontín

Fig. 71.7  Tracheal stenosis. Patient with complete bron-

chial compression after cardiac surgery. The stent allowed
reexpansion of the obstructed left main bronchus

Fig. 71.9  Tracheal stenosis. 4-year-old child neck X-ray

showing a trachea with an hourglass narrowing

Fig. 71.8  Histology of a complete tracheal ring

Type IV  It is characterized by the presence of an

anomalous upper right bronchus and a long-left
bronchus as a bridge, with presence of circular
rings, which bifurcates to distal and originates
Fig. 71.10  Tracheal stenosis. Bronchography shows the
main bronchus. morphology of trachea and bronchi in a 6-year-old child

Surgical indication depends more on the pres- plex airway abnormality. The most common ones
ence of associated respiratory symptomatology involve resection and anastomosis for short steno-
than on the morphology itself. Multiple surgical sis cases. In longer stenosis, the extension of the
techniques have been devised to correct this com- tracheal lumen with pericardial graft or costal car-
71  Airway Surgery and Endoscopic Procedures 731

nation under anesthesia in the operation room.

Grade I laryngeal cleft does not always have to be
repaired. Some patients are asymptomatic and if
there is no clinical, radiological, or lung evidence
of aspiration, repair is not necessary. Grade II
clefts and onward require surgical repair. In some
cases, it will be necessary to perform a tracheot-
omy, gastrostomy, or anti-reflux surgery. A one
stage cleft repair without tracheotomy is ideal.
When a tracheotomy is performed, it should
remain for at least 2–3 years. This is because the
Fig. 71.11  Congenital tracheal stenosis repair. Patient associated tracheomalacia that these patients
with long segment tracheal stenosis undergoing extracor- present is further aggravated by the presence of
poreal circulation (ECC) repair
the tracheotomy, making it more difficult and
delaying a successfully decannulation. Surgical
tilage was considered for many years. In the past repair can be done endoscopically or by cervical
decade, a tracheal enlargement technique called or thoracic surgery.
slide tracheoplasty has been predominant, which
uses native tissue without graft, allowing a greater
enlargement of the stenotic lumen. Corrective sur- Technical Aspects
gery can be performed through cervical or tho-
racic route, both techniques combined, or median Endoscopic repair is indicated for grades I and II.
sternotomy. Long segment tracheal stenosis usu- An anterior translaryngeal transtracheal is the
ally requires repair with support of extracorporeal choice approach and all types of clefts can be
circulation (ECC) (Fig.  71.11) or extracorporeal repaired in this way. A two layer repair is required,
membrane oxygenation (ECMO), ensuring ade- dividing the esophageal plane from the tracheal
quate ventilation and oxygenation while the tra- and closing both mucous membranes separately.
cheal lumen remains open. After this, the posterior tracheal wall is closed. It
is recommended to interpose synthetic fibrin
between both layers. Then, the anterior tracheal
Laryngotracheal Cleft wall is sutured with separate stitches (Fig. 71.12).

Laryngotracheal cleft is an abnormal communi-

cation between the trachea and the esophagus.
The extension of it is variable, from a cleft at lar-
ynx level exclusively to a wide abnormal com-
munication between both conduits that can
extend even to the bronchi. When the cleft goes
beyond the cricoid cartilage, it is called a laryn-
gotracheoesophageal cleft. Clefts are classified
into five types (I-V), according to length (See
Monnier)
Diagnosis is based on index of suspicion.
Symptoms are sometimes vague, but most have
typical associated respiratory manifestations as
cough or drowning secondary to aspiration of
food or gastric contents. Laryngomalacia and tra-
Fig. 71.12 Type III laryngotracheal cleft. Surgery
cheomalacia are frequently associated. Definitive through the neck. Communicated esophagus and trachea
diagnosis must be made after endoscopic exami- are observed. Nasogastric tube is seen in the esophagus
732 P. Varela Balbontín

In more extensive clefts cases (IV–V), ventila- Grade I  Narrow lumen <50%
tory assistance with ECMO is recommended.
Grade II  Narrow lumen between 50 and 75%

 ediatric Airway Frequently

P Grade III  Narrow lumen between 75 and 99%
Acquired Lesions
Grade IV  Absence of lumen.
Acquired Subglottic Stenosis
This grading system correlates directly with
Subglottic stenosis (Fig. 71.13) corresponds to a the prognosis of decannulation after surgery and
subglottic space narrowing and is usually associ- is closely related to the surgical technique to be
ated with tracheal intubation. Other less common used. Philippe Monnier has modified this classifi-
causes are trauma, tumors, and burns. It should cation, adding subgroups depending on the pres-
be suspected in all patients who have stridor and ence of glottic compromise and comorbidities.
who have history of a previous tracheal intuba- According to this modification, it is now possible
tion. The most specific study to assess subglottic to define more accurately the prognosis of the
stenosis is endoscopic evaluation. Detailed evalu- injury and the most favorable surgical
ation of vocal cords should be obtained, verifying procedure.
their mobility and eventual paralysis. Stenosis is
assessed in its thickness, length, location, and
maturity (acute, subacute, chronic, or fibrous). Surgical Treatment
The Cotton–Myer classification to define the
narrowness degree is used, which is based on an Endoscopic techniques using argon or CO2 lasers
objective graduation system of the subglottic space are reserved for mild forms. Most severe forms
lumen, established by calibration with endotra- have a higher success rate with open reconstruc-
cheal tubes and that considers four grades accord- tive surgery. In cases of acute or subacute inju-
ing to subglottic lumen narrowness percentage: ries, endoscopic dilation with endotracheal tubes
or balloon, plus topical use of mitomycin C, is an
alternative with good results.

Open reconstructive surgery types:

A. Extension without graft: Indicated in new-
borns who have failed extubation on several
occasions. It is an alternative to tracheotomy.
The original technique considers opening the
anterior wall of the cricoid cartilage, the
lower third of the thyroid cartilage, and the
first two tracheal rings without the need for
grafting. The patient is then kept intubated for
a period of 7–10  days in an intensive care
unit. Sedation should avoid movement of the
endotracheal tube as much as possible.

Criteria to perform this surgery are: failure in

extubation at least on two occasions as a result of
subglottic pathology, weight greater than 1500
Fig. 71.13  Acquired subglottic stenosis. Surgery through
the neck. Communicated esophagus and trachea are grams, absence of ventilation requirements in the
observed. Nasogastric tube is seen in the esophagus last 10 days, oxygen requirements less than 30%,
71  Airway Surgery and Endoscopic Procedures 733

and absence of respiratory infection at the time of C. Stenotic zone resection (cricotracheal resec-
evaluation. tion): Partial resection of the cricoid and first
tracheal rings, with a primary anastomosis
B. Enlargement with cartilage graft: It consists between the thyroid cartilage and trachea. It
in opening the anterior wall of thyroid carti- is a procedure indicated in patients with
lage lower third, cricoids, and first tracheal restenosis after failed laryngotracheal recon-
rings. This stenotic lumen enlargement can be struction and as a primary procedure for a
combined with a cricoid section in its poste- selected group of patients with severe laryn-
rior lamina and lateral quadrants, depending gotracheal stenosis (treatment of choice for
on the degree of severity and morphology of grade II and IV stenosis). It is also useful in
the stenosis. wide cricoid and tracheal resections for
tumors (Figs. 71.15a, b).
Costal cartilage graft is most commonly used
(Fig.  71.14). Other alternatives consider hyoid, Most procedures are performed in one stage,
auricular, and thyroid cartilage. that is, stricture and closure of the stoma is
resolved. In a smaller number of patients, surgery
is performed in more than one stage, maintaining
the tracheotomy temporarily. In cases where the
subglottic stenosis also compromises the glottis
(glotosubglottic stenosis), the recommended sur-
gery is a partial cricotracheal resection extended
in two stages, maintaining a transitory tracheos-
tomy, with section of the interarytenoid muscle
and placement of a siliconized laryngeal implant
(LT Mold de Monnier), which is maintained for
Fig. 71.14  Cartilage graft. Costal cartilage attachment in 6–8 weeks and subsequently removed by simple
anterior laryngotracheal wall ambulatory endoscopic procedure (Fig. 71.16).

a b

Fig. 71.15 (a) Cricoid resection. Thyroid cartilage and is ascended then anastomosed to the thyroid cartilage.
posterior cricoid lamina are observed. The anterior arch Posterior cricoid is covered with posterior tracheal flap
has been resected. (b) Tracheal cricoid resection. Trachea
734 P. Varela Balbontín

Fig. 71.17  Tracheal resection. End-to-end anastomosis

in a patient undergoing tracheal resection for acquired
stenosis

 racheal and Bronchial Stenosis

T
Fig. 71.16  Laryngeal stent. LT Mold Monnier’s silicon
stent is observed. Removal is done endoscopically Acquired After Intubation
6–8 weeks after the procedure
In children, the main cause of tracheal stenosis is
secondary to previous intubations. Initial treat-
Postoperative management should be done ment may consider a plan of periodic dilatations
in the intensive care unit. In this period, the when stenosis is diagnosed early and there is no
patient is intubated with a nasotracheal tube. fibrous stenotic scar. Dilatations can be per-
During the first hours, sedation is preferable. formed with endotracheal tubes or vascular
During the following days, sedation and anal- ­balloons. The treatment of choice for critical and
gesia without paralysis are preferable, depend- fibrous stenosis is surgical resection and primary
ing on the patient’s tolerance. In general, older anastomosis (Fig. 71.17).
children tolerate this period very well (intu- The approach is mostly cervical anterior,
bated) with minimal administration of seda- which allows excellent access to a significant
tives. Intubation time will depend mainly on the proportion of the trachea. In less frequent cases
type of surgery. In patients older than 5  years of distal stenosis or close to the carina, the cervi-
and in whom reconstruction has required only a cal approach should consider an upper medial
graft in the anterior wall, extubation can be per- sternotomy or directly a lateral sternotomy at the
formed in the immediate postoperative period third intercostal space. In cases of distal stenosis
and the patient can be transferred extubated to that compromise the carina, it is recommended to
the intensive care unit. In case of maintaining perform tracheal and bronchi reconstruction in
intubation, time required is less than 5 days. In extracorporeal circulation, ensuring adequate and
cases in which an extension is made with ante- safe oxygenation during the procedure. In cases
rior and posterior graft, intubation is prolonged of stenosis of one of the main stem bronchi,
for 5–7  days, similarly for tracheal cricoid endoscopic repair using balloons is recom-
resections. A follow-up endoscopy is performed mended. The procedure is performed through a
4  weeks later to verify graft epithelization, rigid bronchoscope, which allows ventilating the
chordal motility, and eventual development of patient while the procedure is performed, in addi-
granulomas in the suture areas, which must be tion to a direct visualization through Hopkins
removed. optics of 0° (Figs. 71.18a, b).
71  Airway Surgery and Endoscopic Procedures 735

a b

Fig. 71.18 (a) Bronchus intermedius stenosis. (b) Endoscopic balloon dilatation

Summary piled for more than a decade and are part of his
personal experience as an airway surgeon.
Airway surgery requires tertiary health care cen-
ters, with professionals organized in airway units Note All the photographies of surgery procedures and
whose primary purposes are to diagnose and endoscopies were done by the author.
offer timely therapies for various congenital mal-
formations and acquired injuries that affect the
larynx, trachea, and bronchi. Sources
The main congenital malformations that affect
Alarcon A, Rutter MJ.  Pediatric laryngotracheal recon-
larynx and trachea are laryngomalacia, vocal cord struction. Otolaryngol Clin N Am. 2008;41(5):959–80.
paralysis, congenital subglottic stenosis, subglot- Donoso C, Varela P, Gómez N, Borel C, Herrera
tic hemangioma, congenital laryngeal web, laryn- O.  Estenosis traqueal congénita. Serie clínica. Rev
gotracheal cleft, congenital tracheal stenosis, Chil Pediatr. 2006;77(3):274–81.
Gustafson LM, Hartley BE, Liu JH, Link DT, Chadwell
tracheal and bronchomalacia, and tracheal agene- J, Koebbe C, Myer CM, Cotton RT.  Single-stage
sis. Acquired lesions that we most frequently laryngotracheal reconstruction in children: a
diagnosed and treated are post-­intubation stenotic review of 200 cases. Otolaryngol Head Neck Surg.
lesions, mainly subglottic and tracheal stenosis. 2000;123(4):430–4.
Hartnick CJ, Brigger MT, Willging JP, Cotton RT, Myer
Bronchial lesions are less common and in those CM. Surgery for pediatric vocal cord paralysis: a retrospec-
cases endoscopic therapy is used. tive review. Ann Otol Rhinol Laryngol. 2003;112(1):1–6.
This chapter describes the main anomalies that Monnier P. Pediatric airway surgery. Ed. Berlin: Springer;
affect adolescents and children’s airway, empha- 2011a.
Monnier P. Pediatric airway surgery. Berlín, Heidelberg:
sizing the importance of an early and accurate Springer-Verlag; 2011b.
diagnosis as well as defining modern treatment Myer CM, O’Connor DM, Cotton RT. Proposed grading
alternatives that include complex reconstructive system for subglottic stenosis based on endotracheal
surgeries and endoscopic therapies. tube sizes. Ann Otol Rhinol Laryngol. 1994;103(4 Pt
1):319–23.
The author illustrates this text with photo- Prado F, Varela P, Boza M, Koppmann A. Estenosis sub-
graphs of endoscopic and surgical records of a glótica adquirida: tres años de experiencia. Rev Chil
wide spectrum of anomalies, which he has com- Enf Respir. 2003;19:71–7.
736 P. Varela Balbontín

Rutter MJ, Cohen AP, de Alarcon A. Endoscopic airway Vijayasekaran S, White DR, Hartley BE, Rutter MJ,
management in children. Curr Opin Otolaryngol Head Cotton RT. Open excision of subglottic hemangiomas
Neck Surg. 2008;16(6):525–9. to avoid tracheostomy. Ach Otolaryngol Head Neck
Torre M, Yankovic F, Herrera O, Borel C, Latorre JJ, Surg. 2006;132(2):159–63.
Aguilar P, Varela P, Rutter MJ, Cotton RT, Azizkhan White DR, Cotton RT, Bean JA, Rutter MJ.  Pediatric
RG, Manning PB.  Slide tracheoplasty for the man- cricotracheal resection: surgical outcomes and risk
agement of complete tracheal rings. J Pediatr Surg. factor analysis. Arch Otolaryngol Head Neck Surg.
2003;38(6):928–34. 2005;131(10):896–9.
Varela P, Haecker S, Herrera O, Fielbaum O, Osorio White DR, Bravo M, Vijayasekaran S, Rutter MJ, Cotton
W.  Estenosis traqueal congénita. Reparación con RT, Elluru RG. Laryngotracheoplasty As an alternative
injerto de pericardio, en by pass cardiopulmonar. to tracheotomy in infants younger than 6 months. Arch
Reporte de caso clínico. Rev Chil Pediatr. 1999;70:4. Otolaryngol Head Neck Surg. 2009;135(5):445–7.
 Lung, Chest Cavity, and Dorsal
Spine Surgery
72
Mauricio Campos Daziano, José Vuletin Solís,
and Juan Carlos Pattillo Silva

Contents
Introduction  737
 urgery of Congenital Malformations of the Chest Cavity
S  737
Pectus Excavatum........   738
Pectus Carinatum.........   740
Lung Surgery  741
Thoracotomy  741
Videothoracoscopy......   742
 orsal Spine Surgery 
D  743
Introduction  743
Sources  747

Introduction also disturbances in the concomitant develop-

ment of the lung parenchyma (e.g., alveolar mul-
The subtle interaction between the chest and its tiplication) that could eventually cause permanent
contents is not only evidenced in the pathological functional cardiopulmonary sequelae. In this
states where restrictive ventilatory complications chapter we address the eventual functional effects
determine alterations in the chest. In particular, of the pathologies and the treatments that directly
the critical periods of the developments of pathol- affect the chest or its components.
ogies that affect the chest cavity or its compo-
nents (e.g., dorsal spine or sternum) can provoke
changes not only in ventilatory mechanics but Surgery of Congenital
Malformations of the Chest Cavity
M. Campos Daziano
Pontificia Universidad Católica de Chile, The thorax is composed by multiple independent
Santiago, Chile bones (vertebrae, sternum, and ribs) that form the
e-mail: [email protected] chest cavity along with several muscles that cover
J. Vuletin Solís (*) · J. C. Pattillo Silva it. The chest cavity is often seen only as protec-
Pediatric Surgery, Pontificia Universidad Católica de tion for intrathoracic organs, but the chest is a
Chile, Santiago, Chile dynamic system that enables respiratory f­ unction.
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2020 737

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_72
738 M. Campos Daziano et al.

Thus, any condition that results in its malfunction Preoperative Evaluation

will significantly affect the respiratory system The objective of the preoperative evaluation is to
and the intrathoracic organs. define the morphology and seriousness of the
Malformation of the chest cavity means any deformation of the sternum, and its functional
abnormality that affects the normal structure and repercussions both in the lungs and the heart. It is
impairs chest function. These malformations can also important to demonstrate that the subject is
be divided into two main categories: congenital and not allergic to the metallic compounds used when
acquired. The deformities of the chest cavity can be repairing the pectus excavatum, which is present
divided into two groups: the ones that have a in 2% of the cases.
depression or protrusion of the sternum and those Computerized tomography or magnetic reso-
that have different degrees of aplasia or dysplasia nance is used in the evaluation of the level of seri-
(Table 72.1). The most frequent malformations are ousness of the pectus excavatum when calculating
pectus excavatum (88%) and pectus carinatum the Haller index. This consists in the transverse
(5%), which we will describe in this chapter. diameter of the chest divided by the anteroposte-
rior diameter of the point of the sternum with the
greatest depression (Fig. 72.1).
Pectus Excavatum In the lung evaluation, abnormalities in the
lung function can be shown by measuring the
Pectus excavatum is the anterior depression of forced vital capacity, forced expiratory volume in
the costal wall. It is the most common malforma- 1 second, and forced expiratory flow of 25–75%
tion of the chest cavity, with an incidence of 1 in of the forced vital capacity.
400 births. It is more common in men than in Regarding the cardiac assessment, the echo-
women, with a ratio of 5:1. It is more common in cardiographic assessment is important, which can
the white race, and it is more frequently presented show cardiac compression with alterations in the
from the first year of life, progressing and becom- filling and emptying of the right ventricle, while
ing more noticeable during the puberty growing showing deformations of the mitral ring, with pro-
phase. The mechanism that provokes it is not lapse and regurgitation of the mitral valve.
completely identified. Some histological studies The symptoms produced in the patient are an
have shown a weakening in the components of important part of the preoperative evaluation.
the costal cartilages, which would allow for pos- Symptoms, such as exercise intolerance, low
terior sternal migration. There is no chromosomal endurance, and shortness of breath, are reported
defect, but it has been reported in conjunction by the patients with pectus excavatum. Another
with Marfan syndrome, Ehlers–Danlos syn- important aspect is the cosmetic effect that this
drome, osteogenesis imperfecta, syndactyly, and produces. It limits the normal life of some
Klippel–Feil syndrome. Also, a genetic predispo- patients, because they avoid places where the
sition of approximately 40% of the patients has
been detected, who report having a family mem-
ber with medical history of being a carrier of a Haller Index = a/b
malformation of the chest wall.

Table 72.1 Congenital malformations of the chest

cavity
Funnel chest Pigeon chest Aplasia or dysplasia
Pectus Pectus Ectopia cordis
excavatum carinatum
Cleft sternum
Poland’s syndrome
Asphyxiating thoracic
dystrophy Fig. 72.1  Haller index (TAC)
72  Lung, Chest Cavity, and Dorsal Spine Surgery 739

chest deformity will have to be exposed, such as Today, the surgical treatments that are more
the beach or pools. It has been proven that widely used to correct pectus excavatum are the
patients with pectus excavatum have a lower open technique or Ravitch procedure, and the
quality of life and that the treatment statistically minimally invasive repair technique or Nuss pro-
improves their bodily image. cedure. The Ravitch technique, described in
1949, consists in an open repair of the defect by a
Treatment transverse inframammary incision, through
Surgical correction for pectus excavatum is rec- which the malformed sternum and the costal car-
ommended when the patient has one of the fol- tilages are exposed. Through the anterior
lowing criteria: approach, costal cartilages are resected, preserv-
ing the perichondrium, and anterior sternal oste-
1. Computerized axial tomography or magnetic otomies are performed to correct the sternal
resonance that shows heart or lung compres- depression defect. The wound is closed moving
sion with a Haller index of 3.25 or more. pectoral muscle flaps.
2. Restrictive lung disease proven by a lung
The minimally invasive surgery for pectus
function test. excavatum or Nuss procedure was described in
3. Heart compression with abnormalities in the 1998 by Dr. Donald Nuss. This technique allows
mitral valve, either prolapse or regurgitation. the correction of the pectus excavatum without
4. Exercise intolerance, decrease in endurance, the need for a great incision in the skin or the
and shortness of breath during exercise. resection of costal cartilages. In short, a lateral
5. Recurrence after an open or minimally inva- incision is performed in the thorax, through
sive surgery. which, assisted by videothoracoscopy, a convex
6. Cosmetic effect produced in patients. metal bar is inserted behind the sternum, which is
exteriorized on the other side of the chest
The optimal correction age is between 10 and (Fig. 72.2). When the bar is flipped 180° the ster-
14 years of age. In this period the chest cavity is nal defect pops up (Fig. 72.3). The bar is fixed to
more malleable, which allows for a lower rate of the ribs by stabilizers. This device is installed in
recurrence. the patient for 2–3 years.

Fig. 72.2  Insertion of the retrosternal bar

740 M. Campos Daziano et al.

Fig. 72.3  Flipping of the retrosternal bar to pop out the sternal defect

Recently, a prospective, multicenter study was Table 72.2  Result of the surgical treatment of pectum
described in which the functional results were excavatum
analyzed when correcting the pectus excavatum, Preoperative Postoperative
whether by Ravitch technique or Nuss procedure. (average) (average)
Haller index 4.4 3.0
The results of this work show an important cor-
FVC (predicted %) 88.0 93.0
rection to Haller index and a significant improve- FEV 1 (predicted 87.0 90.0
ment in the cardiac and pulmonary function tests %)
(Table 72.2). TLC (predicted %) 94.0 100.0
The complications of the surgical correction VO2 during exercise 3.18 3.50
of pectus excavatum are uncommon, the most (l/min)
Pulse oximetry 13.58 16.16
common being the displacement of the metallic
during exercise
devices, having to reoperate the patient to reposi- (VO2/FC)
tion the bar. Other more infrequent complications FVC forced vital capacity, FEV1 forced expiratory vol-
are wound infections, retrosternal hematomas, ume in 1 second, TLC total lung capacity, VO2 oxygen
pneumothorax, hemothorax, myocardial lesions, consumption
and allergic reactions to metal. These complica-
tions tend to be more frequent after the Nuss
procedure. sternum with different morphologies will allow
the classification of the malformation in its dif-
ferent types. Type 1 or chondrogladiolar is the
Pectus Carinatum one that protrudes in the gladiolus or sternal
body and lower cartilages. Type 2 or chondro-
Pectus carinatum is the second most frequent manubrial is less common. Here the manu-
congenital malformation of the costal wall. Like brium sterni and the higher cartilages protrude.
pectus excavatum, it is more frequent in men than Type 3 or lateral deformities are those in which
in women, with a ratio of 4:1. It is more frequent there is a unilateral protrusion or sternal rota-
to have a late consultation, because it tends to tion. There are also mixed forms. Most of the
appear after age 11, worsening during puberty. patients will not present symptoms, being
mainly a cosmetic problem, which signifi-
Preoperative Evaluation cantly influences the development of a negative
Medical history and complete physical exami- body image. Some patients may report muscu-
nation are necessary. The protrusion of the loskeletal pain in the thorax and epigastrium.
72  Lung, Chest Cavity, and Dorsal Spine Surgery 741

The posteroanterior and lateral chest X-ray,

and in some cases computerized tomography
or magnetic resonance can be useful to have a
surgical plan. Patients with a Haller index
between 1.2 and 2.0 benefit from the correction
of the deformity.

Treatment
Unlike pectus excavatum, the first line of treat-
ment in pectus carinatum is the compressive ther-
apy with orthosis according to the deformity
type. In patients under 18 years of age, where the
chest cavity is more malleable, the success rate
varies between 65% and 80%. Dr. Marcelo
Martínez-Ferro, a pediatric surgeon in Buenos
Aires, developed a dynamic compression system
that allows measuring the compression force
electronically, with which he reports an 88% suc-
cess rate (Fig. 72.4). Regarding the surgical treat-
ment, it was initially described by Ravitch in
1952. The procedure is similar to the one for pec-
tus excavatum, where the deformed costal carti-
lages are resected, keeping the perichondrium,
and the sternal osteotomies are performed,
depending on the type of information. Dr. Fig. 72.5  Correction technique. Correction technique for
pectus carinatum in a minimally invasive way developed
Horacio Abramson, from Buenos Aires, pub- by Dr. Horacio Abramson
lished a paper in 2009 that described a minimally
invasive technique to correct pectus carinatum. It
is similar to the Nuss technique for pectus exca- Lung Surgery
vatum, but the bar goes through the sternum,
allowing the retraction of the deformity Thoracotomy
(Fig. 72.5).
Posterolateral thoracotomy is the classic way of
accessing the thorax for the surgical treatment of
lung lesions. The first lung lobectomy with ana-
tomical dissection was performed in 1930. In
1941, Haight performed the first repair of an
esophageal atresia in one stage through a left lat-
eral thoracotomy. This kind of thoracotomy has
an excellent access to the thorax, but to be able to
perform it, the muscles of the costal wall (latis-
simus dorsi, trapezius, rhomboid, and serratus
anterior) must be transected. It is associated with
important adverse effects in the pediatric popula-
tion, such as significant postoperative pain,
Fig. 72.4  Dynamic compression system. Dynamic com-
pression system developed by Dr. Marcelo winged scapula, alteration of the mobility of the
Martínez-Ferro shoulder, scoliosis and, cosmetically, a big scar.
742 M. Campos Daziano et al.

Another technique for the open approach to simus dorsi and serratus anterior must be located.
the chest in the pediatric population is the thora- Then, the anterior edge of the latissimus dorsi is
cotomy with preservation of the muscle, unlatched and retracted, exposing the serratus
described by Bianchi et al. in 1998. Kucukarslan anterior, to which the posterior edge will be
et  al. compared the results of the classic thora- detached and retracted, exposing the intercostal
cotomy with that of muscle preservation. space, accessing the pleural space through the
Regarding musculoskeletal deformities, the tho- fourth or fifth intercostal space. Once the surgery
racotomy with preservation of the muscle signifi- is finished, similar to the posterolateral thoracot-
cantly reduces the apparition of scoliosis (16% omy, a pleural drainage is used; unlike the pos-
vs. 2.5%), shoulder elevation (30% vs. 7.5%), terolateral thoracotomy, it is not necessary to
and winged scapula (38% vs. 12.5%). Besides, it close so many muscular planes.
significantly reduces the scale of pain and the
hospitalization days.
Videothoracoscopy
Technique
The patient adopts the lateral decubitus position Introduction
with a roll under the ribs to better open the inter- Thoracoscopy has been used since the early
costal spaces on the operation side. It is recom- twentieth century. However, the development and
mended to mark the important anatomical points miniaturization of instruments, such as video
before starting the surgery, as to have them as a cameras, optical devices, and surgical and hemo-
reference during surgery (Fig. 72.6). stasis equipment, has caused its popularity to
For the thoracotomy with preservation of the grow exponentially over the past decades.
muscle, the place of the incision must be planned Nowadays, all thoracic pathologies in children
strategically to allow the most direct access to the are treated with a thoracoscopy approach, which
pleural cavity. When the skin is opened, the latis- has reduced postsurgical pain, recovery periods,
and morbidity rates, as well as the long-term
sequelae of these procedures (Table 72.3).
In comparison with the open approach, thora-
coscopy offers a superior exposure due to the
visual magnification and closeness of the sur-

Table 72.3  Indications for pediatric thoracoscopy

Lung biopsy
Lung lobectomy
Cysts resection
Lung decortication
Resection of lung sequestration
Resection of intestinal duplication cysts
Esophageal myotomy
Anterior vertebral arthrodesis
Hernia repair or diaphragmatic plication
Patent ductus arteriosum ligation
Thoracic duct ligation (chylothorax)
Repair of esophageal atresia
Aortopexy
Resection and biopsy of mediastinal masses
Thymectomy
Sympathectomy
Fig. 72.6  Thoracotomy position Pericardial window
72  Lung, Chest Cavity, and Dorsal Spine Surgery 743

geon’s work area. Along with the lower morbid-

ity rate of the minimally invasive procedures
involved, this suggests that thoracoscopy should
be the first-choice technique in virtually all tho-
racic procedures in children; however, we must
recognize there is currently a lack of randomized
studies supporting this proposal.

Preoperative Evaluation
and Anesthetic Considerations
In general, both imaging studies, computerized
axial tomography scan or magnetic resonance,
provide guidance and can inform adequate plan-
ning for tackling most lesions.
The most important consideration when per-
forming a thoracoscopy procedure in children is
the creation of an actual space within the thorax Fig. 72.7  Bronchial blocker
which allows the surgeon to visualize and manip-
ulate surgical instruments. This necessarily
involves collapsing, at least partially, the ipsilat- For example, a posterior mediastinum lesion is
eral lung. There is no specific preoperative test better faced with the patient in a semiprone posi-
which may enable us to foresee if a child will tol- tion, making the lung fall forward. Similarly,
erate mono-pulmonary ventilation. Nevertheless, when placing the patient and the trocars, care
most patients, even those with mechanical venti- must be taken to maintain the eye-camera-­
lation, will tolerate short periods of mono-­ monitor axis to facilitate the work of the surgeon.
pulmonary ventilation. The same applies to the planning of a conversion
In order to achieve mono-pulmonary ventila- to open surgery, if needed.
tion in children, patient size is a limiting factor. In Finally, the postoperative care of these patients
patients over 30  kg, it is possible to use double is not different from the usual handling of those
lumen catheters in the same way as in adults. In with open thoracic surgery, having a better recov-
smaller patients, it is possible to perform a selec- ery due to the lower requirement of analgesics.
tive bronchial blockage (Fig. 72.7). The bronchial
blocker can even be used outside of the endotra-
cheal tube and placed under bronchoscopy. In Dorsal Spine Surgery
even smaller patients, when it is not possible to
employ this technique, a selective mono-bron- Introduction
chial intubation can be performed, with a medium
tube in a smaller size than the one advised for the The pathological processes that can determine
patient. However, all these precautions may not be alterations in the child’s spine can be many: con-
enough to obtain an adequate working space. In genital or neuromuscular anomalies, alterations of
such cases, we can use a discrete CO2 insufflation bone development, skeletal dysplasias, traumatic,
to the thorax, with low pressure and low current infectious, iatrogenic, or neoplastic pathologies,
volumes, as a useful supplementary tool. etc. It is basic to consider this ­ heterogeneity
The positioning of the patient is key to achieve regarding natural history, physiopathology, and
the best access to the lesion. In general, imaging comorbidities to formulate an adequate treatment.
techniques allow for an adequate planning for Additionally, regarding the child’s spine, the
direct access, avoiding that any kind of tissue is growing and developing dynamics will modulate
interposed between the operator and the lesion. the types and opportunities of the treatment.
744 M. Campos Daziano et al.

 ormal Development and Growth

N the progression of the deformities can accelerate,
of the Spine meriting more frequent checks.
During the first three or four weeks of gestation Also very importantly, there is a delicate inter-
the organogenesis takes place in concomitance dependence between the development of the
with the formation of somites, mesenchymal chest cavity and spine with the development of
molds for the future vertebrae. The appearance the lung parenchyma. This can affect the respira-
of a noxa in this developmental stage explains tory function of the child and shorten their sur-
the coexistence of malformations in other vival. The most crucial stage for this is the first
organs in up to 30% of the cases, such as the five years of life, especially the two first years
central nervous system, and renal or cardiac when more than 80% of the alveoli are formed,
systems. This is why it is important that patients together with the growth of the dorsal spine and
with spine malformations have a multidisci- wall. Thus, any alteration that affects the devel-
plinary evaluation to detect and eventually treat opment of the spine or the chest cavity can poten-
these comorbidities. tially generate not only a severe spinal deformity
Notwithstanding the cause of the deformity, in the future but it can also determine a decrease
its prognosis will greatly depend on its serious- in the definitive lung function, beyond the tho-
ness at the moment of the diagnosis and the racic restriction. Thus, Campbell et  al. defined
growth potential that the child has. This is why it the term thoracic insufficiency syndrome as the
is of the utmost importance to know the critical inability of the thorax to support normal ventila-
and accelerated growth periods of the axial skel- tory mechanics and lung growth. This is gener-
eton: the first occurs between birth and 3–4 years ally present in the context of patients with
of age, and the second during the pubertal growth vertebral malformations and a complex thoracic
spurt. In these lapses, a longitudinal growth of wall, for whom an early spinal fusion has no ben-
1.75–2  cm/year is produced in the segments of efit, because the lung function remains below
the spine, and it coincides with periods in which normal (Fig. 72.8).

Fig. 72.8 Thoracic
insufficiency syndrome.
a b
Patient of 2 years and
2 months of age, with
multiple vertebral
malformations and
costal fusions,
congenital left
diaphragmatic hernia,
without neurological or
cognitive deficit, with
recurring episodes of
lung infection. (a) Total
posteroanterior spine
X-ray and (b) 3D
reconstruction
computerized axial
tomography in posterior
vision
72  Lung, Chest Cavity, and Dorsal Spine Surgery 745

Preoperative Evaluation pathology, such as diastematomyelia, syringomy-

While it is not recommended to extrapolate the elia, or tethered spinal cord. In other cases, where
management between the different causes of spi- the base pathology presents a high prevalence of
nal deformities, most of the indications of surgery anomalies of the central nervous system, the reso-
in this age group are based on the projected risk, nance is indicated independent from the physical
progression or worsening of the deformity, in the exam. In patients with idiopathic scoliosis of the
context of the natural history of its base pathol- adolescent with normal neurological exam, the
ogy. This includes patients in whom the conserva- preoperative resonance is not indicated, because
tive corset management fails, and in whom a its efficacy would be under 3%.
radiological progression is evident in the serial- The lung function can be altered in many of
ized monitoring. Even though it’s controversial, these patients, due to the precocious formation of
avoiding the progression of thoracic curves in the curve or the seriousness of the restrictive phe-
patients with potential restrictive pathologies nomenon. In these cases, it is essential to involve
(e.g., muscular dystrophy) would have a protec- anesthesia and pediatric bronchopulmonary spe-
tive effect in the long run, decreasing the speed of cialists, anticipating an eventually difficult air-
degeneration of the lung function. The reach of way and prolonged postoperative mechanical
this measure has to be evaluated in conjunction ventilation needs. Moreover, it must be consid-
with the morbidity associated with surgery and ered that some of these children have vertebral
the natural progression of the condition. Finally, cervical malformations (for example Klippel–
in some congenital malformation cases, the risk Feil syndrome) that might make intubation diffi-
of neurological compromise is up to 12%, which cult. This includes considering early pre or
reinforces the indication of surgery. postoperative tracheostomy in cases with mar-
As has been previously stated, many of these ginal lung function, especially taking into account
children have a multisystem condition of which that up to a 60% decrease is reported in spirom-
the spine is just a part. Additionally, the severe etry tests in the postoperative of scoliosis surgery
and rigid deformities they can have require wider in some series. However, the use of noninvasive
and more invasive surgery. Thus, many of these mechanical ventilation has lowered this indica-
children are exposed to a higher rate of perioper- tion and has enabled the performance of surgery
ative complications regarding wound infection, in patients that were previously considered out-
pneumonia, implant failure, non-union, pseudo- side the reach of surgery. In cases where a tho-
artrhosis, augmented blood loss, respiratory post- racic insufficiency syndrome is suspected, and
operative failure, and even death. given the difficulties for spirometry tests in
Owing to multiple presentations, in complex younger patients, the evaluation of the chest vol-
cases, the planning and preoperative preparation ume by a computerized axial tomography can be
must be multidisciplinary and individualized. considered. This has been well correlated in stud-
Associated anomalies and comorbidities must be ies with spirometry tests. Additionally, Gollogly
anticipated and evaluated, such as cardiac, renal, et al. have published the volumes of normal lung
and central nervous system malformations. A renal parenchyma for the different ages and genders.
ultrasound scan is a simple and effective exam to Other important aspects in the preoperative
evaluate urogenital malformations. If there is clini- planning of these patients are the nutritional
cal suspicion, a referral to cardiology and an echo- aspects, because regularly these patients present
cardiogram could discover interauricular or symptoms of protein–calorie malnutrition, whose
ventricular septum alterations, persistent ductus presence has been correlated with postoperative
arteriosum, transposition of great vessels, lung ste- results. Some of these cases are carriers of clot-
nosis, etc., among 10% and 26% of the congenital ting or immunity alterations, having to plan
scoliosis cases. In patients with evidence of neuro- beforehand the availability of the blood elements
logical deficit, it is recommended to request a needed in each situation with the anesthesia team
magnetic resonance to rule out an intraspinal and the blood bank. The multidiscipline manage-
746 M. Campos Daziano et al.

ment needed for these complex patients must be deformities and the need of unplanned revision
stressed. The implementation of management surgery have brought back the interest to develop
algorithms coordinated among multiple disci- systems that allow the correction of the curve but
plines for these patients’ preoperative stage has retain growth.
managed to diminish the general and ICU stay, In generic terms these are called “growing”
along with a reduction in the rate of postoperative systems, and they are generally made through a
complications in some series. posterior way of approach to the column. Owing
to the enormous osteogenetic potential of chil-
Surgical Techniques dren, the idea is not to touch the central zone with
Traditionally, the most used technique to treat the instrumentation, latching only to the sides.
spinal deformities is the correction and instru- Thus, the spontaneous fusion is avoided, placing
mented spinal fusion. This was even applied for the connective bars in subcutaneous or subfascial
early start deformities (<5–10  years) under the areas. These systems can be performed with a
precept that a short spine without a deformity single bar or double bars connected with elonga-
was better than allowing the curve progression. tors. After the initial installation of the system,
However, it has recently been demonstrated that the periodic elongations only need to address this
even early correction and fusion procedures that connective piece with the following minimiza-
were considered successful result in the long tion of surgery needed to produce growth
term in a decrease of almost 50% of the FVC and (Fig.  72.9). The goal in general is to elongate
FEV-1. Additionally, the frequent recurrence of until 10 years of age to later perform the defini-

a b c

Fig. 72.9  Spinal fixation with growing bars. Patient with ing” bars was performed (b), and after seven elongations
DiGeorge syndrome that presents progressive scoliosis in the space of four years (c). Note the progressive correc-
despite treatment with orthosis. A preoperative X-ray is tion of the deformity and the increase of the longitude
presented (a), after the first surgery with the dual “grow- T1–T12
72  Lung, Chest Cavity, and Dorsal Spine Surgery 747

Fig. 72.10 Spinal
fixation with fixed bars. a b
Patient with type II
spinal atrophy and
severe neuromuscular
scoliosis (Cob Index
>100°). Preoperative (a)
and postoperative (b)
anteroposterior X-rays
are shown. Note the
typical pelvic
obliqueness indicating
neuromuscular scoliosis

tive fusion. Another parameter to follow is to In patients with severe progressive deformi-
manage a T1–T12  >  18  cm longitude toward ties around or after 10 years of age, the defini-
skeletal maturity. Values below these are associ- tive correction and fusion is preferred. Although
ated to FVC below 45%. multiple ways to approach this exist (anterior,
A separate mention has to be made for the posterior, combined), the most used today is the
VEPTR (Vertical Expandable Prosthetic Titanium instrumented (Fig.  72.10). With the develop-
Rib) used mainly for congenital spine deformities ment of modern column instrumentation and
associated with costal malformations and fusions, techniques, the ability to reduce and consoli-
provoking chest insufficiency. In these cases, the date the deformities has increased up to 90%.
elongation of the spine would not provoke the The stability of definitive constructs has also
expansion of the compromised hemithorax, so an eliminated the need for rest and postoperative
expansive thoracotomy, together with costal orthosis. The morbidity derived from these pro-
instrumentation, is also subject to be progressively cedures depends on the base pathology, being
elongated. However, all these “growing” systems minimal for the adolescent idiopathic scoliosis
share the same kind of disadvantages: need for and maximal for deformities in neuromuscular
multiple surgery procedures to produce “growth”, patients.
frequent complications, implant fractures, promi-
nent instrumentation, considering that many of
these patients are very small, the need to use a Sources
postoperative corset and the cost, among others.
Although in general these complications are not Abramson H, D’Agostino J, Wuscovi S. A 5-year experi-
ence with a minimally invasive technique for pectus
serious, they happen in up to 48% of the cases, and carina-tum repair. J Pediatr Surg. 2009;44(1):118–23;
they are more common when the surgeries start at discussion 123–114.
a younger age. Given these factors, this group of Campbell RM Jr, Smith MD, Mayes TC, et al. The charac-
patients is considered serious, and the controversy teristics of thoracic insufficiency syndrome associated
with fused ribs and congenital scoliosis. J Bone Joint
about the best treatment system persists. Surg Am. 2003;85-A(3):399–408.
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Campos MA, Weinstein SL.  Pediatric scoliosis and Kucukarslan N, Kirilmaz A, Arslan Y, Sanioglu Y, Ozal
kyphosis. Neurosurg Clin N Am. 2007;18(3):515–29. E, Tatar H. Muscle sparing thoracotomy in pediatric
Fonkalsrud EW.  Current management of pectus excava- age: a comparative study with standard posterolateral
tum. World J Surg. 2003;27(5):502–8. thoracotomy. Pediatr Surg Int. 2006;22(10):779–83.
Gill I, Eagle M, Mehta JS, Gibson MJ, Bushby K, Bullock Lam MW, Klassen AF, Montgomery CJ, LeBlanc JG,
R.  Correction of neuromuscular scoliosis in patients Skarsgard ED.  Quality-of-life outcomes after surgi-
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 Extracorporeal Circulation
Membrane Oxygenation Therapy
73
for Acute Respiratory Diseases

Javier Kattan Said, Álvaro González Morandé,

and Andrés Castillo Moya

Contents
Introduction..................................................................................................................  749
ECMO Physiology..........................................................................................................  752
Selection Criteria for Applying ECMO......................................................................  753
Managing ECMO.........................................................................................................  754
Complications...............................................................................................................  756
Prognosis and ECMO Programs in Latin America...................................................  756
Conclusions and Future Considerations.....................................................................  758
Sources...........................................................................................................................  759

Introduction cardiac support over an extended period of time,

generally ranging from 1 to 4 weeks. It is used on
Extracorporeal circulation membrane oxygen- patients with reversible pulmonary failure caused
ation (ECMO), or extracorporeal life support by lung, heart, and other diseases. ECMO ‘makes
(ECLS), is a therapy that uses a modified partial time’ for resting the lungs or heart, thus creating
cardiopulmonary bypass to give pulmonary or a chance for recovery. Since ECMO therapy is
invasive, there are potential risks associated with
it, which is why there are criteria to choose
patients with a prediction of mortality between
50% and 100%. The ideal candidate has a high
value in their prediction of mortality but suffers
J. Kattan Said · A. Castillo Moya (*) from a potentially reversible lung or cardiovascu-
Department of Pediatrics, School of Medicine, lar injury.
Pontificia Universidad Católica de Chile, The first survivor of ECMO therapy was
Santiago, Chile
treated in 1971 by J.  Donald Hill, who used a
e-mail: [email protected]; [email protected]
Bramson oxygenator on an adult patient with
Á. González Morandé
multiple injuries. This therapy was, however,
Pediatrics, Neonatology, Pontificia Universidad
Católica de Chile, Santiago, Chile abandoned because of its poor results. Years
e-mail: [email protected] later, the therapy reemerged for newborn and

© Springer Nature Switzerland AG 2020 749

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_73
750 J. Kattan Said et al.

pediatric patients due to Robert Bartlett’s efforts, ECMO survival Discharge survival
who in 1975, at Orange County Medical Center, 90 84
80
treated his first newborn patient who survived 74
80
this type of therapy, an abandoned newborn who 68
62 64
suffered from respiratory distress syndrome. The 70
use of this therapy on newborns increased during 60
the late 1980s, with survival rates close to 80% 41
50 40
in patients with a predicted mortality between

%
40
60% and 80%. Because of this increase in usage
on newborn patients, a voluntary alliance 30
between active ECMO centers was born in 1989, 20
giving form to the Extracorporeal Life Support
10
Organization (ELSO). Added to the good results
0
in newborns since the 1990s, there has been a
considerable increase in pediatric patients

rt

l
ta
es

ea

To
ER
R

H
treated with ECMO, with over 14,000 registered
cases, claiming a survival rate of up to 66% in Fig. 73.1  Survival rate of newborns. Survival rate of
pediatric patients suffering from respiratory 34,650 newborns after reported ECMO to the
conditions. Extracorporeal Life Support Organization (ELSO),
grouped by cause of admission to ECMO (ERCP
By the year 2009, around 80% of patients
Extracorporeal cardiopulmonary resuscitation)
treated with ECMO were newborns or children.
During the past few years, ECMO on adult
patients suffering from respiratory conditions 100 94
84
increased progressively by 1000%, and ECMO 90
77
on pediatric patients suffering from respiratory 80 73 74
conditions increased by 100%, which is partially 70 61 58
explained by the influenza H1N1 pandemic and 60 51
the new evidence emerged from controlled stud- 50
%

ies in adults.
40
During the 1990s, new therapies against car-
30
n = 8.684

diorespiratory diseases were developed, such as n = 7.228

20
high-frequency oscillatory ventilation (HFOV),
surfactant, or inhaled nitric oxide (iNO). These 10

therapies, in association with ECMO centers, 0

MAS HMD PPHN Sepsis PTX Other MN CDH
have managed to significantly lower morbidity in
more developed countries. Fig. 73.2  Survival rate of Nnwborns. Survival rate to dis-
During the past decade, ECMO has been used charge of 27,728 newborns treated with ECMO, reported
to ELSO by respiratory condition (MAS Meconium aspi-
as a rescue therapy in almost 800 newborns
ration syndrome, HMD Hyaline membrane disease,
reported to ELSO every year. These newborns PPHN Persistent pulmonary hypertension of the newborn,
did not respond to intensive care with HFOV or PTX Pneumothorax, PN Pneumonia, CDH Congenital
iNO.  Currently, ECMO use rate for newborns diaphragmatic hernia)
suffering from respiratory failure in the United
States sits at around 1 per every 6000 living new- For pediatric patients with respiratory condi-
borns This therapy has shown a clear increase in tions, the indications that lead to using ECMO
global survival rate (Figs. 73.1 and 73.2), better are more diverse and harder to define than during
long-term quality of life, and being more cost-­ the newborn stage, but during the past few years
effective for newborns with severe respiratory there has been an increase in the number of
failure. reported cases to ELSO, with close to 350 cases a
73  Extracorporeal Circulation Membrane Oxygenation Therapy for Acute Respiratory Diseases 751

year displaying a global survival rate of 57% at pathophysiological mechanism leading to respira-
the discharge (Figs. 73.3 and 73.4). tory ECMO, of which viral pneumonia takes first
It is worth noting that survival rate in pediatric place (22%), followed by respiratory failure
patients varies according to the disease that deter- (18%), bacterial pneumonia (10%), acute respira-
mined the connection, with survival rates reported tory distress, and aspiration pneumonia. Acute
as high as 83% for severe asthma attack. Acute viral pneumonia shows a survival rate of up to
hypoxic respiratory failure is the most frequent 70% as described for VRS, with an average of
64% for viral pneumonia. Survival rates are also
high in the pediatric group for aspiration pneumo-
Sobrevida ECMO Sobrevida al alta nia and post-traumatic ARDS (Fig. 73.5). Patients
80 are oftentimes admitted because of immunosup-
66 66 64 pression and suspected sepsis. These patients usu-
70
57 ally display multi-organ failure. Pediatric patients
60 55 52
50 with the worst prognosis are those who have
50 41 received bone marrow ­ transplants, those who
40 have suffered from Bordetella pertussis induced
%

pneumonia and pulmonary hypertension, and

30
those admitted to ECMO with multi-organ fail-
20 ure, as opposed to the positive prognosis for those
10 who only show isolated lung involvement.
0 In 1972, Bartlett reported the first case of suc-
cessful prolonged post-operative cardiac support
ry

rt

l
ta
ea

in a 2-year-old patient who suffered from post-­

to

To
ER
ra

H
pi

surgery heart failure after a Mustard procedure

es
R

because of transposition of great arteries. At pres-

Fig. 73.3  Survival rate of pediatric patients. Survival rate ent, more than half of patients requiring periop-
of 16,253 pediatric patients after ECMO reported to the
erative heart ECMO are those suffering from
Extracorporeal Life Support Organization (ELSO),
grouped by cause of admission to ECMO (ERCP complex cyanotic congenital heart diseases. The
Extracorporeal cardiopulmonary resuscitation) largest group of patients requiring ECMO sup-

Fig. 73.4  Survival rate 80

of pediatric patients. 68
70 65
Survival rate of 6569 62 59
discharged pediatric 60 54 54
51 52
patients treated with
ECMO reported to 50
ELSO by respiratory
%

40
condition (ARDS Acute
respiratory distress
n = 1.450

30
syndrome)
20

10

0
ia

ia

ia

re

ia

er
D

D
on

on

on

on
ilu

th
AR

AR

O
m

um

um

fa

m
eu

eu
ry
a

a
ne

ne
m

m
pn

to

pn
lp

lp
au

au

ira
n

is
ra

ria
/tr

-tr

sp
tio

t
ys
Vi

op

on
e

re
ra

ct

oc
st

N
pi

Ba

m
Po
As

ut

eu
Ac

Pn
752 J. Kattan Said et al.

100 95 temperature monitors are used during therapy. It

90 85 is of vital importance to continually monitor
78 77
80 coagulation through the hourly measurement of
70
activated clotting time (ACT) and the measure-
60 60
ment of anti-factor Xa, fibrinogen, platelet count,
60
PT, APTT and, in some patients, anti-thrombin
%

50
III levels, and a thromboelastography.
40
There are in principle two different forms of
30 ECMO:
20
10 (a) Veno-arterial (VA): Blood is drained from
0 the right atrium through a cannula inserted
into the right internal jugular vein, the femo-
AS

l
ta
sp
si

us
D

To
ep

ral vein, or directly to the right atrium; and it

M

re
C

ca
/s

er

rt
ia

th

is picked back up at the thoracic aorta through

ea
on

H
m

a right carotid cannula, a femoral cannula or

eu
Pn

an aortic cannula. VA ECMO provides heart-­

Fig. 73.5  Survival rate to discharge. Survival rate to dis- lung support. It is common to use a transtho-
charge of 143 patients (123 newborns and 20 pediatric racic cannula (right ventricle and aortic
patients) treated in the Newborn-Pediatric ECMO Program
at the Clinical Hospital of the Pontificia Universidad cannula) in patients who have endured heart
Católica de Chile (ECMO-UC) 2003–2014, reported to operations.
ELSO by main diagnosis (MAS Meconium aspiration syn- (b) Veno-venous (VV): Blood is drained from the
drome; CDH Congenital diaphragmatic hernia) right atrium through the posterior and infe-
rior orifices of a double-lumen cannula
port is those who, after cardiotomy, present com- inserted into the right jugular vein and
plete AV canal (20%), complex single ventricle returned to the same right ventricle through
anomaly (17%), and tetralogy of Fallot (14%). the anterior orifices of the cannula, which are
Among the chief causes requiring perioperatory pointed toward the tricuspid valve. One of
heart ECMO are hypoxia (36%), cardiac arrest the limits of this method lies in the recircula-
(24%), and failure after leaving extracorporeal tion of already oxygenized blood through the
circulation support (14%). double lumen cannula. This has been cor-
rected with the new design for VV cannulas.
VV ECMO may also be performed in older
ECMO Physiology children through the use of two cannulas,
draining blood from the jugular vein and
During extracorporeal circulation support, blood returning it through the femoral vein. VV
is drained from the patient to an outside pump ECMO requires a well-functioning heart.
(either a roller or a centrifugal pump), which is This modality of ECMO prevents cannula-
pushed through an exchange membrane (a sili- tion in the carotid or femoral arteries, thus
cone or a polymethylpentene oxygenator) for reducing complications arising from cannu-
oxygenation and CO2 removal. Then it passes lation or ligation of these arteries, as well as
through a heat exchanger and finally returns the those arising from air entering the ECMO
blood to the patient’s blood flow (Fig. 73.6). This circuit. This method has seen an increase in
therapy requires anticoagulation of the circuit usage during recent years, covering 40% and
and the patient through heparin administered to 50% of respiratory cases in newborn and
the ECMO circuit so as to avoid the activation of pediatric patients, respectively. Oxygen is
the coagulation cascade in the system. In addition delivered during ECMO by the combination
to that, a variety of pressure, flow, bubble, and of blood oxygenation through the membrane,
73  Extracorporeal Circulation Membrane Oxygenation Therapy for Acute Respiratory Diseases 753

Venous saturation
monitor
36
Temperature monitor

Flow
Hemofilter/
control
shunt
Transonic flow
measurement
10

Pressure Sample
monitor
100

Pressure monitor

Centrigugous
pump Oxigenator

Heparin Alarm
infusion
Bubble detector

Fig. 73.6  Diagram of veno-arterial ECMO with pump through the right carotid artery. (Diagram used with per-
and oxygenator. Venous blood is obtained from the right mission from ECMO Manual of the Children’s National
atrium through the right internal jugular vein. It is then Medical Center, George Washington University,
pumped, oxygenized, heated and returned to the aorta Washington DC, 2010)

blood flowing through the extracorporeal cir- bypass, except for occasional waves. However,
cuit, native lung oxygenation, and native it is normal for VA ECMO to only involve
heart output. In turn, oxygenation at the about an 80% bypass, allowing a blood flow of
ECMO membrane is a function of its geom- 20% or more through the left heart and lungs,
etry, material composition and thickness, resulting in a reduced but visible pulse wave.
blood and FiO2 laminar thickness, time of The kidney is without doubt the most affected
permanence of red blood cells in the organ by the absence of pulsatility, producing
exchange area, hemoglobin concentration, an antidiuretic effect because of juxtaglomer-
and O2 saturation. On the other hand, CO2 ular stimulation. In addition, non-pulsatile
removal during ECMO is a function of the flow has been linked to stimulation of the
geometry, materials, and surface area of the pressure receptors in the carotid sinus, causing
membrane, blood PCO2 and, to a lesser a large release of catecholamines, with dam-
extent, it depends on blood and gas flows aging effects to microcirculation.
through the membrane.

• In a VA ECMO, the bypass generates an  election Criteria for Applying

S
essentially non-pulsatile blood flow. In this ECMO
way, as the blood flow to the extracorporeal
circuit increases, the pulse wave decreases, Selection criteria differ for newborn (Table 73.1)
completely ceasing when it reaches a 100% or pediatric patients (Table 73.2), depending on
754 J. Kattan Said et al.

Table 73.1  Selection criteria for newborns Table 73.3  General exclusion criteria in the pediatric
population
Gestational age ≥34 weeks
Weight at birth ≥2000 grams Over 14 days with mechanical ventilation
Unresponsive to maximum medical care (including Over 7 days of high ventilatory settings, given the
HFOV, iNO, surfactant) possibility of iatrogenic lung damage
Reversible cardiopulmonary condition Acute or irreversible brain damage
Mechanical ventilation ≤14 days Chronic acute or irreversible lung disease
High pulmonary mortality (50–100%), considering: Severe coagulopathy or uncontrolled bleeding
 Oxygenation index (OI) >35–40 for 4–6 hours (iNO, Untreatable congenital cardiopathy
HFOV) Chromosomal syndrome with limited prognosis
 PaO2 < 40 mmHg for 4 h (100% O2) Cardiopulmonary arrest unless there is an
 OI ≥ 25 after 72 h with HFOV-iNO extracorporeal cardiopulmonary resuscitation program
Unmanageable metabolic acidosis (ph < 7.15 for 2 h) (post-arrest ECMO or E-RCP) at the ECMO center
Reduced cardiac output with reversible etiology
Impossibility to wean from cardiopulmonary bypass
As a bridge for heart transplant discussed by the ECMO team. In summary,
No untreatable congenital cardiopathy or injuries after selection criteria have evolved and continue to do
heart surgery so as a result of discussion, debate, experience,
Absence of major intracranial hemorrhage (≥ III and the emergence of new treatments and tech-
degree)
niques. Currently, there are no unique or exclu-
Absence of uncontrollable hemorrhage
No evidence of irreversible brain damage
sive criteria, and not withstanding general
No malformations or genetic syndromes with fatal inclusion criteria, the decision to exclude a
prognosis patient must be discussed by the team, taking into
account all possible points of view, without
excluding any party from this discussion.
Table 73.2  Selection criteria for pediatric patients
OI > 40 for 4–6 h or PaO2/FiO2 < 60 during mechanical
ventilation (MCV or HFOV)
OI > 35 for >12 h. High settings for mechanical Managing ECMO
ventilation, considering:
 Pressure plateau >35 cm H2O for 8–12 hours Before a patient is admitted to ECMO, both indi-
 PEEP >15 cations and exclusion criteria must always be
 Average airway pressure >20–25 cm H2O in MCV or
assessed, making it essential to perform a patient
>30–35 cm H2O in HFOV
Hypercapnic respiratory failure with pH < 7.1 for evaluation prior to ECMO, including at least age
4–6 hours despite maximum medical care and anthropometry, neurological status (general
Acute deterioration with optimal therapy exam, pupillary reactivity, electroencephalo-
gram, history of seizures, head ultrasound, and
ideally a brain CT scan for pediatric patients);
whether the primary cause of admission is car- respiratory and cardiovascular evaluation (oxy-
diac or respiratory. These are general criteria and genation index, vasoactive support and, if possi-
must be individualized for each patient, assessing ble, an echocardiography), electrolytic and
the risks and benefits of applying ECMO.  The acid–base evaluation, coagulation and renal func-
basic selection criteria for pediatric patients with tion evaluation, evaluation of infectious parame-
respiratory failure are similar to those for new- ters, and an assessment of current or previous
borns, with particular emphasis on whether the vascular accesses.
patient faces a serious pulmonary condition with The initial ECMO parameters seek to achieve
a high risk of death, or whether it is a process that a bypass of at least 50% or more of estimated car-
can be reversed through respiratory, gasometri- diac output (with cardiac output estimated at
cal, and hemodynamic rest. On the other hand, 200  mL/kg/min for newborns, 150  mL/kg/min
there are general exclusion criteria (Table 73.3), for pediatric patients under 10 kg and 2400 mL/
though none of them are absolute and must be m2sc/min for patients over 10  kg), and are
73  Extracorporeal Circulation Membrane Oxygenation Therapy for Acute Respiratory Diseases 755

adjusted to maintain adequate oxygenation, arte- Meticulous attention to all aspects of the
rial pressure, and acid–base state. In patients with patient is essential. Frequent checks of blood gas
heart failure, VA-ECMO is the preferred choice. are required for the patient and the ECMO cir-
At present, when proper cardiac function is cuit, as well as clotting and kidney function
­preserved and the main pathology is pulmonary, checks, and an ultrasound assessment of the brain
VV-ECMO is considered to be of assistance in to identify intracranial hemorrhage and cerebral
oxygenation and ventilation. infarction.
The main points of access will depend on the Both arterial and venal saturation of the patient
modality of ECMO being used. For VA-ECMO, must be continually monitored, taking into
the right internal jugular vein and the right com- account saturation levels of the blood extracted
mon carotid artery may be used as well as the from the patient before it enters the oxygenator
femoral veins and arteries. For VV-ECMO, either (ideally over 70–75%). Saturation of the superior
the right internal jugular vein and the femoral vena cava should also be monitored. However,
vein may be used, or a long unique double-lumen something to keep in mind for these last two is
cannula inserted into the right internal jugular that there should be no doubt that there is no
vein, reaching the right atrium. In post-operative unnoticed source of short circuit of oxygenated
cardiac patients, direct transthoracic cannulation blood.
is common. Anticoagulation is essential in managing
At present, most oxygenators use polymethyl- patients, both for ensuring an adequate duration
pentene fibers. These have microscopic pores, of the circuit and to avoid severe bleeding from
making the exchange of gases easier and avoid- excessive anticoagulation. In this regard, hourly
ing ‘dripping’. They are quickly and easily managing of levels of ACT from 180 to 200 sec.,
primed, displaying low trans-membrane pres- with a platelet count of over 100,000 and fibrino-
sure. This avoids the loss of proteins and other gen levels of over 150  mg/dl is thought to be
components. In fact, by having a more homoge- adequate.
nous surface they produce less hemolysis and At least during the first days, patients must
preserve platelet activity. receive adequate sedoanalgesia with continuous
The strength with which blood is pumped opiate infusions and benzodiazepines, consider-
through the circuit depends on the pumps, which ing the eventual use of muscle relaxants in some
may be of the roller or centrifugal type. cases. There has been a current increase in con-
Centrifugal pumps are increasingly preferred sidering the benefits of using a smaller amount of
given the advantage of not being occlusive, which anesthesia, with some groups even keeping
causes less pressure on the circuit and less hemo- patients awake during the procedure. This par-
lysis. They do not need a reservoir, are primed ticularly applies to older patients.
faster, and help preserve the circuit for a longer Once ECMO support is being used, the
period. Their man disadvantage lies in their high mechanic ventilator settings should be set to rest.
cost, which is why some units still use roller Despite the lack of a proper definition for this, it
pumps. is considered so for pediatric patients with PEEP
ECMO treatment may vary between 1 and of 6–8  in order to avoid unrecruited lung, tidal
3 weeks or even longer. In January 2014, pediat- volumes that do not surpass 8 mL/kg, and an FR
ric respiratory ECMO lasted an average of of 12–18 per minute with FiO2, usually at 21%.
11.6  days, with a described maximum of In addition, emergency settings must always be
129  days. On the other hand, pediatric cardiac kept in mind in case of an ECMO malfunction, in
ECMO generally take less time, with an average which case FiO2 must be considered at 100%.
of 6.7  days with a described maximum of During ECMO, water balance and diuresis are
120 days. For respiratory patients, improvement needed as soon as possible, as well as volume
is generally noticed after a few days or even overload prior to its commencement. Positive
weeks. water balance and oligo-anuria must be avoided,
756 J. Kattan Said et al.

because once hemodynamics is stable, water bal- Intracranial hemorrhage is the primary cause
ance should become negative by using a propor- of death during ECMO, and the appearance of
tional diuresis, and afterwards, neutral. If these convulsions is a sign of a poor prognosis.
objectives are not achieved, or if the patient Additionally, there are complications arising
develops an oligo-anuric kidney injury, continu- from circuit failure either in the oxygenator or in
ous hemofiltration or hemodiafiltration should be the equipment used during ECMO.
considered for as long as diuretics are used and if
adequate hemodynamics did not manage to
restore an adequate kidney function to achieve  rognosis and ECMO Programs
P
the required balance. in Latin America
Finally, prophylactic antibiotics are not gener-
ally considered for this treatment. Using antibiot- Post-ECMO survival in newborn patients varies
ics in most patients depends either on the depending on their underlying disease, though
underlying disease, which for a large percentage respiratory causes present the most positive out-
of patients corresponds to an infectious disease, or come with a survival rate of close to 75% after
if there is a suspicion of superimposed infections discharge. ECMO treatment for meconium aspi-
and as the result of surveillance or secondary cul- ration syndrome is usually of the veno-venous
tures under clinical suspicion of infection. type, which is associated with a lower risk rate
As the patient’s condition improves, ECMO and fewer complications, such as cerebral infarc-
support is gradually reduced. The patient is decan- tion and convulsions, and to minor changes in
nulated when tolerance to minimal ECMO sup- blood flow patterns. During the past few years,
port is achieved (10% bypass in VA-ECMO) with ECMO has been used as a tool for cardiopulmo-
low to moderate mechanical ventilation parame- nary resuscitation after cardiac arrest yielding
ters. ECMO treatment generally lasts between 5 mixed results, with a survival rate of close to 40%.
and 10 days for newborn patients with respiratory Newborns were the first age group for which
diseases, though this is extended in cases of con- ECMO therapy showed vast superiority over
genial diaphragmatic hernia, bacterial pneumo- maximum conventional therapy, as shown by a
nia, and myocarditis (10–11 days in average). controlled and randomized multicenter study
with 185 newborns suffering from severe respira-
tory insufficiency in 55 hospitals in the United
Complications Kingdom. This study showed that mortality and
severe disability assessed after 1, 4, and 7 years
The ECMO procedure presents varying compli- of life decreased significantly after ECMO ther-
cation risks as a consequence of the severity of apy (59% for the conventional therapy group vs.
the condition of the patient, the use of anticoagu- 37% for the ECMO group). At the seventh year
lants, and changes to the blood flow (lower pulsa- of follow-up, 76% of children presented normal
tility blood flow). Among the most common cognitive development.
complications are hemorrhage (surgical site 6%, The most recent systematic reviews show that
pulmonary 4%, gastrointestinal 2%), infarction ECMO therapy used in close to term newborns
or brain hemorrhage (9% and 5% respectively), with severe but potentially reversible respiratory
convulsions (11%), cardiac dysfunction (myo- failure significantly improves survival without
cardial stunning 6%, arrhythmia 4%), kidney increasing severe disability while also being cost-­
failure (4%), sepsis (6%), hyperbilirubinemia effective when compared to other intensive care
(9%), arterial hypertension (12%), and hemolysis therapies. Regarding ECMO as a rescue therapy
(13%). The most common complication with for congenital diaphragmatic hernia with severe
cardiac-based ECMO is, by far, the need for respiratory failure, evidence from controlled pro-
vasoactive drugs during extracorporeal support, spective studies only suggests a decrease in early
followed by surgical site bleeding. mortality. However, a meta-analysis of retrospec-
73  Extracorporeal Circulation Membrane Oxygenation Therapy for Acute Respiratory Diseases 757

tive studies and our own reported experience cardiac and pediatric surgeons, nurses, perfusion-
show a higher short- and long-term survival rate ists, respiratory therapists, and psychologists)
for congenital diaphragmatic hernia in units that had undergone training in ECMO centers
where ECMO is available. affiliated with ELSO in the United States. At the
Survival rate and neurological prognostic after same time, ECMO equipment was procured in
5 years in patients who underwent ECMO for non- order to establish the first ECMO units according
cardiac causes is generally very positive, but it to ELSO recommendations. The main selection
worsens for lower gestational age groups, lower criteria applied were: reversibility of lung or
weight at birth, and higher oxygenation index (OI) heart condition, failure to respond to maximum
before ECMO. Patients with a septic shock diag- conventional treatment, weight 3 of 2 kg, gesta-
nosis and congenital diaphragmatic hernia display tional age of 34 weeks, oxygenation index >40,
the worst survival rate and neurological evolution mechanical ventilation <14 days, and absence of
outcomes. However, it is the pre-­existent factors severe brain injury or multi-organ failure. This is
and the severity of the condition of the newborn the first ECMO program in Latin America to join
when entering ECMO that apparently determines ELSO. From May 2003 to December 2014, the
the long-term neurological prognosis. program treated 143 patients for both severe
Long-term respiratory prognosis depends on respiratory and cardiac pathologies. Of these
the base etiology, degree of barotrauma, and patients, 77% survived till hospital discharge and
length of exposure to oxygen. Between 10% and are currently being monitored. The 35 patients
30% of patients suffering from congenital dia- who died had as base diseases: CDH (n  =  13),
phragmatic hernia have episodes of wheezing by congenital heart disease operated with failure to
age 10, with close to 50 suffering from hyper wean from cardiopulmonary bypass or arrhyth-
insufflation and episodes of airway obstruction. mias (n = 9), persistent pulmonary hypertension
Pediatric post-ECMO survival rate is lower than secondary to sepsis, pneumonia, meconium aspi-
that of newborns, but the respiratory failure group ration syndrome, SP-B or ABCA3 deficiency or
presents a better prognosis, particularly for without a defined cause (n = 12), and pneumonia
patients with aspiration pneumonia, viral pneu- due to Bordetella pertussis (n  =  1). Among
monia, and post-operative ARDS or ARDS devel- patients treated with ECMO, a relevant group of
oped after traumatic injury. Viral pneumonia is children treated with CDH stands out with a sur-
the most common condition leading to pediatric vival rate of 78% (45/48) at discharge.
ECMO, and among its etiologies, respiratory In order to understand the impact of establish-
syncytial virus presents the highest post-ECMO ing a neonatal ECMO program on the survival
survival rate at 70%. On the other hand, patients rate of newborns with severe respiratory failure
suffering from pneumonia caused by other in a developing country such as Chile, we studied
viruses and by Bordetella pertussis report lower the data of newborns with severe respiratory fail-
survival rates of 56% and 39%, respectively. ure and OI  >  25 before and after ECMO treat-
Given the evidence that shows an increased ment was available. ECMO was initiated for a
survival rate and the cost-effectiveness relation of newborn with acute refractory respiratory failure
this therapy, the newborn intensive care unit at who did not respond to iNO or HVOF. Data com-
the Pontifical Catholic University established a piled from treatment of 259 newborns were ana-
newborn-pediatric ECMO program following the lyzed, resulting in a significant increase in
standards advocated by the Extracorporeal Life survival rate, from 72% before ECMO to 89%
Support Organization (ELSO) for patients with during the ECMO period. During the ECMO
severe but reversible cardiovascular or respira- period, 98 out of 159 patients with respiratory
tory insufficiency refractory to maximum con- failure (62%) were rescued using iNO or HFOV,
ventional treatment. Work began in 1999 with the while 61 (38%) did not improve their condition;
formation of a multidisciplinary team (composed 52 out of these 61 patients underwent ECMO
of neonatologists, intensive care pediatricians, treatment. The survival rate at discharge after
758 J. Kattan Said et al.

ECMO was 85%. Severity of OI, late arrival to ing countries, but it must be implemented by
the referral center, presence of a pneumothorax, high-complexity neonatal and pediatric centers
and a diagnosed CDH were associated with the with trained personnel and a high level of
need for ECMO treatment or death. commitment.
One hundred percent of the survivors from our Future patients to be treated with ECLS will
program are currently undergoing a special progressively present more complex conditions,
ECMO follow-up program. Among neurological which is why new ECLS modalities will be
follow-up exams, Bayley II tests at 12–18 months required. These will have to be simpler, auto-
show that over 90% of tested children had normal matic, and with a lower need for anticoagulants
or slightly altered mental development indices so as to minimize risks and make its extended use
(MDI), and over 70% of them had normal or possible. In that way newborns and children with
slightly altered psychomotor development indi- severe conditions can be submitted to ECLS
ces (PDI). In addition, no patient displayed dis- while waiting for heart or lung transplant, or as a
abling visual or auditive alterations bridge for ventricular assistance devices. Even
Regarding respiratory follow-up, 83% of premature newborns with severe cardiopulmo-
patients had a normal or slightly altered clinical nary failure can benefit from partial umbilical
broncho-pulmonary evaluation at 12–18 months. ECLS in the future. New low-resistance micro-
During the first year of life, 30–40% of them pore oxygenators will not require the use of a
required hospitalization because of acute respira- pump, with the umbilical artery and vein used as
tory syndrome. Close to one third of patients an arteriovenous shunt. Moreover, newborns with
present bronchial hyperreactivity diagnosed CDH could go through an early ECLS admission
through a methacholine test in the medium-term. in order to minimize lung damage and promote
As happened in Chile, new neonatal-pediatric lung growth, using, for instance, growth factors
ECMO programs have been constituted during or liquid ventilation with perfluorocarbon associ-
the past few years in high-complexity, high-­ ated with ECLS.  Some centers, such as Boston
volume centers in several countries in Latin Children’s Hospital, have applied ex-utero intra-
America, such as Argentina, Colombia, Brazil, partum treatment (EXIT) to ECMO for patients
and Mexico, most of which have progressively either with CDH and prenatal markers of poor
joined ELSO, forming the Latin American chap- prognosis, or in order to ensure an effective ven-
ter of ELSO in 2012. The mission of this new tilation of newborns who do not possess a safe
ELSO chapter is to contribute to the dissemina- airway or for whom it is expected suffer from
tion of ECMO therapy according to ELSO stan- severe respiratory failure at birth (CDH, cervical
dards, practical and theoretical education through teratoma, airway pathologies, large pulmonary
courses and workshops, as well as encouraging masses, bronchial cysts, etcetera).
collaborative work between Latin American cen- The progressive increase of pediatric patients
ters, of which 15 can be found across five differ- who benefit from the use of ECLS is worth not-
ent countries, with close to 200 newborns and 120 ing, and it is something that has been increas-
children as reported to ELSO by December 2014. ingly determined by the growing number of
pathologies that may indicate severe respiratory
failure within this population. This has lead
Conclusions and Future patients with sepsis, immunocompromised
Considerations patients, patients suffering from heart failure and
other complex pathologies, to be ECLS candi-
ECMO therapy, or more broadly, extracorporeal dates. Continuous technical improvements have
life support (ECLS), is a standard therapy in neo- created a technique that is both safer and easier to
natology and pediatrics with proven benefits in perform, so it is expected that in the coming years
the short and long term. It can be incorporated to we will witness a sustained increase in pediatric
intensive therapy with positive results in develop- patients who can benefit from ECLS therapy.
73  Extracorporeal Circulation Membrane Oxygenation Therapy for Acute Respiratory Diseases 759

In this way, we hope that ECLS will enable us Kattan J, Gonzalez A, Becker P, Faunes M, Estay A, Toso
P, et al. Survival of newborn infants with severe respi-
to keep assisting pulmonary or cardiac function- ratory failure before and after establishing an extracor-
ing in a more rational way while severe but poreal membrane oxygenation program. Pediatr Crit
reversible cardiopulmonary processes are Care Med. 2013;14:876–83.
repaired. Keller RL, Steinhorn RH. Extracorporeal membrane oxy-
genation in resource-limited countries. Pediatr Crit
Care Med. 2013;14:900–2.
McNally H, Bennett CC, Elbourne D, Field DJ.  United
Sources Kingdom collaborative randomized trial of neonatal
extracorporeal membrane oxygenation: follow-up to
Alvarado-Socarras JL, Gomez C, Gomez A, Cruz M, age 7 years. Pediatrics. 2006;117:e845–54.
Diaz-Silva GA, Nino MA.  Current state of neonatal Moreno GE, Magliola R, Pilan ML, Althabe M, Balestrini
extra-corporeal membrane oxygenation in Colombia: M, Lenz AM, et  al. Mechanical circulatory support
de-scription of the first cases. Arch Cardiol Mex. in pediatrics. Experience at the hospital de Pediatria
2014;84:121–7. Dr. Juan P.  Garrahan. Argentina. Arch Cardiol Mex.
Arens J, Schoberer M, Lohr A, Orlikowsky T, Seehase M, 2014;84(4):256–61.
Jellema RK, et al. NeonatOx: a pumpless extracorpor-­ Morini F, Goldman A, Pierro A. Extracorporeal membrane
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ECMO: extracorporeal cardiopulmonar support in brane oxygenation for severe respiratory failure in
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 Pediatric Lung Transplantation
74
Anand Patel and Albert Faro

Contents
History  762
Indications  762
Contraindications 763
 isease Specific Indications and Contraindications
D  763
Cystic Fibrosis  763
Surfactant Dysfunction Syndromes  764
Pulmonary Vascular Disorders  764
Donor Evaluation  765
Surgical Technique  766
Immunosuppression  766
 ost-operative Monitoring and Management
P  767
Fluids and Nutrition Management  767
Ventilator Management  767
Surgical Complications  768
Primary Graft Dysfunction  768
Post-transplantation Monitoring  768
Post-transplantation Complications  768
Infections  768
Post-transplant Lymphoproliferative Disease (PTLD)   770
Gastrointestinal Complications  770
Neurological Complications  770
Diabetes  771
Renal Dysfunction.......  771
Rejection  771
Acute Rejection  771
Antibody Mediated Rejection  771

A. Patel · A. Faro (*)

Washington University in St. Louis School
of Medicine, St. Louis, MO, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 761

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6_74
762 A. Patel and A. Faro

Chronic Lung Allograft Dysfunction  772

Outcomes  773
Future Considerations  773
Sources  774

History for children receiving lung transplants are listed

in Table  74.1 determining which children may
Dr. James Hardy performed the first lung trans- benefit from lung transplantation is often not
plant in 1963 at the University of Mississippi as straightforward. In addition, determining the
Medical Center in a 58 year old convict serving appropriate time to proceed is often challeng-
a life sentence. The patient succumbed to renal ing. Transplant physicians thoughtfully gage
failure 18  days after the procedure. There were when a patient has entered the transplant win-
many subsequent attempts, but it was not until dow. This is the point in time where the patient
1983 at the University of Toronto that Dr. Joel is sick enough to warrant lung transplantation
Cooper performed the first successful long-term but not so sick that the odds of a good outcome
lung transplant. Dr. Denton Cooley attempted the have markedly deteriorated. Multiple variables
first heart-lung transplantation in a child in 1968. must be carefully considered including the tra-
The patient was a 2  month old with pulmonary jectory of the underlying disease. Lung trans-
hypertension and a complete AV canal, but they plantation is a procedure of last resort and, when
only survived for 14  hours. The first successful performed, should provide the patient with not
isolated lung transplant in a child was performed
at the University of Toronto in 1987 in a 16 year
old boy with pulmonary fibrosis. The 1990s wit- Table 74.1 Common indications for pediatric lung
transplantation by age group
nessed a rapid growth in the number of pediatric
lung transplants performed annually. However, Infants (<1 year of age)
 Congenital heart disease 16.7%
unlike lung transplantation in adults, that growth
 Surfactant protein B deficiency 16.7%
has not continued in the 2000s. At present, there  Idiopathic pulmonary hypertension 12.5%
are approximately 100 lung transplants done  Idiopathic pulmonary fibrosis 10.4%
worldwide per year in children.  Pulmonary vascular disease 8.3%
 Other pulmonary fibrosis 7.3%
Preschool children (age 1–5 years)
Indications  Idiopathic pulmonary hypertension 22.4%
 Idiopathic pulmonary fibrosis 16.8%
 Other pulmonary fibrosis 8.8%
In general, lung transplantation should be con-  Retransplantation 8.8%
sidered in children suffering from life threaten-  Congenital heart disease 8.0%
ing end-stage lung disease or pulmonary vascular  Bronchiolitis obliterans (not retransplant) 8.0%
disease refractory to medical therapy. The indi-  Pulmonary vascular disease 5.6%
cations in childhood vary by age. Pulmonary School aged children (age 6–10 years)
hypertension, secondary to congenital heart  Cystic fibrosis 53.0%
 Idiopathic pulmonary hypertension 8.7%
disease or other pulmonary vascular disorders,
 Bronchiolitis obliterans (not retransplant) 6.8%
is the leading indication in infancy followed by  Retransplantation 6.4%
interstitial lung disease, including surfactant  Idiopathic pulmonary fibrosis 5.7%
protein abnormalities. For older children and Adolescents (age 11–17 years)
adolescents cystic fibrosis (CF) accounts for  Cystic fibrosis 70.6%
half to three quarters of all lung transplant pro-  Idiopathic pulmonary hypertension 7.8%
cedures. Although the most common diagnoses  Retransplantation 5.3%
74  Pediatric Lung Transplantation 763

only an improved likelihood of survival over difference is based on experience, expertise, and
their underlying disease but also an improve- the center’s view of the available data. In other
ment in their quality of life. words, an absolute contraindication at one cen-
Lung transplantation is a lifelong commit- ter may be a relative contraindication at another.
ment to a complex and demanding regimen that There is general agreement that multi-organ dis-
includes daily immunosuppressive therapy, fre- orders, active malignancy, or certain types of
quent physician visits, routine surveillance pro- active infection are absolute contraindications
cedures, including bronchoscopy, transbronchial to transplant. At some centers multi-organ trans-
biopsy, radiographic examinations, and blood plantation may be possible in select individu-
work. Therefore, the pediatric patient must have als. This may include heart-lung transplantation
adequate family support and access to transplant and in patients with CF combined liver–lung
services and medications as well as demonstrate transplantation.
a willingness and ability to adhere to this admit-
tedly complex regimen.
For the referring center, the correct timing  isease Specific Indications
D
of the referral to a transplant center is at times and Contraindications
difficult to determine. Even for CF, where many
investigators have rigorously studied this ques- Cystic Fibrosis
tion, the answer remains unclear. Therefore, it is
best for the referring center to consider the pos- Several different models have been developed
sibility of lung transplantation in a child whose over the years to predict survival in CF; however,
pulmonary disease has a well defined trajectory none has demonstrated any greater accuracy
of continued decline and whose life expectancy is than Kerem’s criteria. This model found that a
severely limited by the disease process. forced expiratory volume in 1 second (FEV1) of
less than 30% predicted was associated with an
increased risk of death within 2 years; associated
Contraindications factors include decreased arterial oxygen tension
(PaO2), an increase in arterial carbon dioxide
Contraindications can be divided into two cat- tension (PaCO2) on room air, younger age, and
egories: absolute and relative (Table 74.2). These female gender.
often vary from one transplant program and the
Specific indications  Progressive lung disease
Table 74.2  Examples of contraindications to lung trans- and worsening quality of life despite optimal
plantation (varies by transplant center) medical therapy; FEV1 <30% predicted.
Absolute Relative
Active malignancy Poorly controlled Specific contraindications  Varies by individual
diabetes transplant centers, but most commonly center
Multiorgan failure Pleurodesis
around microbiologic concerns with Burkholderia
HIV Scoliosis
Sepsis Markedly abnormal
cenocepacia constituting one of the more com-
body mass index mon absolute contraindications. Many centers
Severe neuromuscular disease Osteoporosis now consider infection with Mycobacterium
Documented, refractory Prolonged mechanical abscessus either an absolute or relative contrain-
nonadherence ventilation dication and this can vary from center to center
Hepatitis C ECMO
based on whether the patient is only culture
Chronic airway infection with Chronic airway
Burkholderia cenocepacia or infection with ­positive and smear negative or culture positive
Mycobacterium abscessus multi-drug resistant and smear positive. The data presently available
organisms suggest that outcomes for patients infected with
Active tuberculosis Renal insufficiency other nontuberculous mycobacteria are not sub-
764 A. Patel and A. Faro

stantially different than for patients not infected and ABCA3. Mutations in the gene can lead to
with those organisms. Other potential relative brain–thyroid–lung syndrome so that patients
contraindications may include malnutrition, may present with hypothyroidism or benign cho-
poorly controlled diabetes, osteoporosis, previ- rea in addition to ILD.
ous pleurodesis (especially talc), and liver fail-
ure, if the center cannot perform a combined Specific indications  Once a decision to pursue
liver–lung transplant. transplant has been made, patients with SPB defi-
ciency should be transferred as soon as a possible
to the transplant center. For the other surfactant
Surfactant Dysfunction Syndromes processing abnormalities, lung transplantation is
indicated for refractory respiratory failure or pro-
Four distinct genetic surfactant deficiency syn- gressive respiratory insufficiency unresponsive to
dromes have been identified and vary in their medical interventions.
presentation. The diagnosis can be confirmed by
genetic analysis. Lung biopsy may demonstrate Specific contraindications  Significant neuro-
diffuse alveolar type II cell hyperplasia, alveo- logic injury and, at some centers, VA-ECMO.
lar proteinosis, and septal thickening. Surfactant
protein B deficiency is an autosomal recessive
disorder. It presents in the newborn period with Pulmonary Vascular Disorders
respiratory failure and is typically lethal within
the first year of life. There is no effective medical In this broad group of disorders characterized by
therapy. Lung transplantation is the only inter- pulmonary hypertension, we will include idio-
vention with the potential to sustain life. pathic pulmonary hypertension (IPH), pulmonary
Surfactant protein C deficiency has a more vein anomalies, congenital heart disease (CHD),
variable presentation and is inherited in autoso- and patients with an inadequate pulmonary vas-
mal dominant pattern. The age of disease onset cular bed. These patients may die from progres-
spans from the newborn period to adulthood. sive right heart failure, arrhythmias, or massive
In addition, even infants presenting with more hemoptysis. In general, a decreased cardiac index,
severe findings such as respiratory failure can elevated pulmonary vascular resistance, right
improve over time. This variability suggests that atrial pressures >7.4 mm Hg, and right ventricu-
other genetic or environmental modifiers may lar end diastolic pressure of >10.4 mm Hg predict
influence the course. Corticosteroids, hydroxy- mortality and are indications for transplant. Other
chloroquine, and azithromycin have been used factors that may impact survival include elevated
in isolated cases, but the results are difficult to von Willebrand factor, uric acid levels, and brain
interpret. natriuretic peptide concentrations.
Adenosine triphosphate binding cassette pro- Advances in pharmacotherapy have dramati-
tein member A3 (ABCA3) deficiency has two cally changed the landscape for patients with
distinct ways of presenting. It can be found in IPH so that lung transplantation should only be
newborns with respiratory failure, but a milder considered in patients who have failed medical
form also exists that is found in older children therapy. The same cannot be said for pulmo-
presenting with interstitial lung disease. Dense nary venous anomalies, such as pulmonary vein
lamellar bodies are seen by electron microscopy stenosis (PVS) or pulmonary veno-occlusive
­
of lung tissue. disease (PVOD), which are not only poorly
Mutations in the NKX2.1 gene, also known responsive to medical therapy but also poorly
as the thyroid transcription factor gene, may responsive to cardiac catheterization or surgical
cause findings similar to any of the previously interventions.
mentioned surfactant abnormalities as NKX2.1 The timing of transplantation in patients with
is important for the expression of SP-B, SP-C, pulmonary hypertension associated with CHD,
74  Pediatric Lung Transplantation 765

including those with Eisenmenger syndrome, Beyond the basics of matching for size and blood
remains unclear. Many of these patients can live type, the characteristics outlined in Table  74.3
for years after diagnosis. An added decision that may contribute to both short- and long-term out-
must be made for this group of patients is whether comes and determine whether the donor lungs
or not the cardiac defect can be repaired or if the will be accepted by a transplant center.
patient will require a combined heart–lung trans-
plant. Unfortunately, the need for two organs can
Table 74.3  Ideal donor characteristics
markedly prolong the time on the waiting list. If
1. Donor age
the patient has an atrial septal defect, ventricular
Ideal Less than 55 years old
septal defect or patent ductus arteriosus, these are donor
relatively simple repairs and can be performed at Evidence There is data to support poorer outcomes
the time of lung transplantation. with older donors, especially if combined
For patients with an inadequate pulmonary with ischemic times of greater than 6 hours.
2. Donor ABG
vascular bed, such as those with pulmonary
Ideal PaO2 greater than 300 on FiO2 1.0, PEEP of
atresia, congenital diaphragmatic hernia, and donor 5 cm H2O
ventricular septal defect with multiple aorto- Evidence Inadequate data to either support or refute
pulmonary collaterals, lung transplantation is this cutoff. Studies mainly focus on
high risk, but it may be the sole life prolonging interventions to increase donor PaO2 to over
300 and then procure them.
intervention.
3. Radiographic findings
Ideal Clear CXR
Specific indications  Idiopathic pulmonary donor
hypertension – patients who have failed medical Evidence No data in regard to use of abnormal chest
management films. If finding is suggestive of atelectasis,
aggressive airway clearance and use of the
Pulmonary venous anomalies – upon making bronchoscope to remove mucus plugs may
the diagnosis urgent referral is recommended salvage an otherwise unusable lung.
Congenital heart disease or inadequate pulmo- 4. Ischemic time
nary vascular bed – progressive severe hypoxia, Ideal 4–6 hours
syncope, massive hemoptysis donor
Evidence Reports describe successful outcomes with
ischemic times from 6 to 11 hours. Poor
Specific contraindications  Multiple prior thora- outcomes clearly associated with older
cotomies associated with development of exten- donors and prolonged ischemic times.
sive collateral circulation and/or significant 5. Size matching
presence of preformed antibodies. Ideal Most centers use height and or predicted
donor TLC. Accepted ranges are plus or minus
20%.
Evidence Data demonstrates no adverse effect on
Donor Evaluation outcome when using donor lungs within
75–125% of recipient TLC.
Unfortunately, not only does there continue to be 6. Airway secretions
Ideal No purulent secretions on bronchoscopy,
a shortage of donors but data from the OPTN/ donor negative gram stain
SRTR database in the United States shows that, Evidence Infection is a major source of early
in 2012, of the 8143 organ donors only 1708 post-transplant morbidity and mortality.
donated lungs. In other words, only 21% of However, evidence suggests that a positive
sputum gram stain does not correlate with
organ donors had lungs that were deemed suit-
the development of pneumonia. There is
able for procurement. The reasons are varied and data to suggest that it is the amount of
include the mechanism of death, consequences of purulent secretions that may be of
mechanical ventilation, and donor management, importance in predicting outcome
post-transplant.
but they highlight the importance of understand-
ing what characteristics make a donor acceptable. (continued)
766 A. Patel and A. Faro

Table 74.3 (continued) of stenosis seen with a telescopic anastomosis.

7. Smoking Many centers will cover the anastomosis with
Ideal Less than 20 pack year history peribronchial lymphatic tissue. It is important to
donor
note that the bronchial circulation, lymphatic sys-
Evidence There is no data that either supports or
refutes this criterion. Concerns include the tem, and nervous system are not reanastomosed.
development of malignancy post-transplant However, a few centers do advocate direct bron-
as well as the potential for increased risk for chial revascularization.
a poor peri-operative outcome. If a cardiac repair is necessary, it is done after
8. Malignancy
the pneumonectomies but prior to implantation
Ideal No cancer history
donor as this provides the surgeon with a bloodless
Evidence Little data, particularly in donors with a past operative field. After the second lung has been
history of a malignancy. The potential risk is implanted, they are inflated to expand all of the
likely based on histology, tumor stage, and atelectatic portions. The patient is then weaned
length of cancer free survival. Primary CNS
tumors rarely spread. Risk factors include off of bypass. Two chest tubes are left in each
medulloblastoma or glioblastoma, previous pleural space. The pulmonary veins can be
craniotomy, venticular shunt, tumor assessed at this time with transesophageal echo-
radiation. Renal cell carcinoma is the most cardiography, and the pulmonary artery anasto-
common type of cancer that is transmitted
from a donor. moses can be evaluated upon arrival to cardiac
9. Length of mechanical ventilation intensive care unit with a perfusion scan.
Ideal Ventilated for less than 3 days Living lobar transplantation has fallen out
donor of favor in the United States because lungs are
Evidence Greater than 2 days of mechanical allocated on the basis of a disease severity score
ventilation is a risk factor for the
development of ventilator associated
rather than just time spent on the list. This has
pneumonia. However, donors with obviated the most common reason for living
prolonged courses and clear X-rays and lobar transplantation, presenting to a transplant
good gas exchange may in fact be better center in extremis and not having accrued enough
donors since the sequelae of aspiration may
not be evident within the first 24–48 hours.
time on the list to realistically receive an organ in
10. Serologies time. However, this procedure is commonly used
Ideal Seronegative for HIV and hepatitis A, B & in Japan with excellent outcomes reported.
donor C
Evidence Higher risk of morbidity/mortality
associated with immunosuppression.
Immunosuppression

Immunosuppressive regimens vary between

Surgical Technique transplant centers. About half of the lung trans-
plant centers throughout the world use induction
The surgical technique used in children is similar in the hopes of preventing early acute rejection.
to that used in adults with the following excep- There is also a great deal of variability in the
tions: (i) virtually all children will require car- induction regimen of choice. Some centers will
diopulmonary bypass, (ii) in children bilateral, utilize an interleukin (IL)-2 receptor antagonist
as opposed to single, lung transplantation is such as basiliximab. Other centers will use a lym-
much more common. The typical approach is a pholytic agent such as rabbit antithymocyte glob-
bilateral sequential procedure with a transster- ulin (RATG) or equine antithymocyte globulin
nal bilateral anterior thoracotomy, referred to as (ATGAM). These preparations are derived from
the clamshell incision, which provides excellent animal serum and contain antibodies to human
access and visualization for the procedure. At lymphocytes that can induce opsonization and
our center, an end-to-end anastomosis is favored phagocytosis of T lymphocytes, modulating their
for the airway because of the higher incidence activation.
74  Pediatric Lung Transplantation 767

Table 74.4  Immunosupressive agents used in pediatric and transplant pulmonologist discuss all impor-
lung transplantation
tant aspects and meet at least once if not twice
Class of drug Potential side effects daily to round as a group. Some key aspects of
Calcineurin inhibitors
post-operative care are discussed below, as well
Tacrolimus Infection, hyperglycemia,
hypertension, seizure, renal as in the subsequent section on complications that
dysfunction, PTLD occur both early and late after lung transplanta-
Cyclosporine infection, hirsutism, gingival tion. More in-depth discussion of all aspects can
hyperplasia, hypertension, seizures, be found in the references.
renal dysfunction, PTLD
Cell cycle toxin inhibitors
Mycophenolate Infection, leukopenia, vomiting,
mofetil diarrhea, hepatic dysfunction, PTLD Fluids and Nutrition Management
Azathioprine Infection, leukopenia, PTLD
mTOR inhibitors Owing to both capillary leak and interrupted
Sirolimus Infection, delayed wound healing, lymphatic drainage, the transplanted lungs are
hypertriglyceridemia, interstial lung
disease, PTLD
particularly fluid sensitive, and thus reaching a
Everolimus Infection, interstitial lung disease, negative fluid balance within the first 48  hours
renal dysfunction, stomatitis, post-operatively is important. Colloids and pres-
leukopenia sors should be used to reduce the amount of stress
placed on the kidneys, as overly aggressive diure-
sis, when combined with CNI nephrotoxicity, can
Because of the relative high frequency of quickly lead to renal failure, resulting in fluid
acute rejection among lung transplant recipients, overload and subsequent pulmonary compro-
a maintenance strategy of triple drug immuno- mise. Thus, while one will always use diuretics
suppression is commonly employed (Table 74.4). in this setting, one must do so carefully. Enteral
The three drugs will typically consist of a calci- nutrition should be started as soon as is appropri-
neurin inhibitor (CNI), a cell cycle toxin inhibi- ate but may be delayed for anticipated extubation
tor, and systemic corticosteroids. In pediatrics or other procedures.
especially, we attempt to minimize steroid expo-
sure, and during the first post-transplant year we
wean the steroid dose from 0.5 mg/kg to 0.2 mg/ Ventilator Management
kg; at our center it typically remains at that dose.
Foremost, the goal is to wean off the ventilator
rapidly with the goal of extubation. The for-
Post-operative Monitoring mer should be done per the general practice of
and Management the experienced intensivist. Pressure-controlled
ventilation is recommended because it places
After the procedure is completed, patients are limits on peak airway pressures that protect not
transferred to the intensive care unit, still intu- only the parenchyma but also the healing airway
bated and on mechanical ventilator support, with anastomoses. At our center, a bronchoscopy is
some patients still requiring ECMO. Monitoring performed 1  day post-operatively to inspect the
must require at minimum cardiorespiratory anastomoses, and to obtain BAL if infection is
monitoring, including pulse oximetry, careful suspected. Airway clearance is important in the
measurement of fluid input and output, and mea- initial post-operative period, with appropriate
surement of arterial blood gases. While initial limits in place to avoid anastomotic complica-
management of ventilator support and ECMO, if tions. Physiotherapy and mobilization are also
needed, is done by the intensivist, all aspects of important, as these will not only help mobilize
care are best delivered through a team approach, secretions but will also enhance chest tube drain-
where the intensivist, the cardiothoracic surgeon, age and alveolar recruitment.
768 A. Patel and A. Faro

Surgical Complications both provide lung rest and minimize iatrogenic

trauma to the graft.
Airway anastomotic complications occur in
~13% of recipients. They primarily manifest as
stenosis with resulting airflow obstruction. This Post-transplantation Monitoring
can generally be managed with bronchoscopic
interventions. As the bronchi of children grow After the perioperative recovery period, recipi-
with the recipient, stents are avoided if possible ents continue to require monitoring. Regular
in favor of repeated balloon dilation. Partial or evaluation, initially at the transplant center, fol-
complete dehiscence of the anastomosis is rarely lowed by close monitoring by a local physician
seen but can be catastrophic. with discussion with the transplant team, is nec-
Vascular anastomotic complications are also essary to identify and manage post-transplant
rare. At our center, a perfusion lung scan is rou- complications. Routine monitoring includes
tinely performed within 24  hours of the trans- measurement of CNI and antimetabolite levels,
plantation to evaluate the vascular anastomoses. routine laboratory tests, pulmonary function test-
Any significant discrepancy between right- and ing, and chest imaging. While controversial, we
left-sided perfusion should be immediately believe that bronchoscopy with BAL and trans-
evaluated in consultation with the cardiotho- bronchial biopsies by trained bronchoscopists an
racic surgeons. important part of post-transplant surveillance.
Although scheduled surveillance bronchoscopy
can detect asymptomatic acute rejection, allow-
Primary Graft Dysfunction ing therapeutic interventions to occur sooner, a
clear benefit in terms of outcomes has not been
Primary Graft Dysfunction (PGD) occurs found. In infant lung transplant recipients, the use
within 72  hours of transplant and is charac- of surveillance bronchoscopy is more important
terized by non-specific alveolar injury, non- as ambulatory lung function testing is not possi-
cardiogenic pulmonary edema, and resulting ble and patients are less able to report symptoms.
decreased compliance and hypoxemia. It is
caused by multiple factors, including isch-
emia–reperfusion injury, inflammation second- Post-transplantation Complications
ary to donor death, and other factors. In 2005,
the ISHLT developed a classification system Infections
using chest X-ray infiltrates and PaO2/FiO2
ratio to grade PGD 0–3. On the basis of this Given the degree of immunosuppression
classification, severe PGD (PaO2/FiO2 <200 needed to prevent acute rejection of the lung,
at 48  hours post-transplant) occurs in 15% of infections are a predictable complication of
recipients, which is concerning as severe PGD lung transplantation. Selected infections are
is associated with increased graft failure and discussed in Table  74.5. However, virtually
mortality. Management of severe PGD is simi- any pathogen, known and unknown, can pres-
lar to the management of patients with acute ent post-lung transplant. Clinicians must be
respiratory distress syndrome (ARDS), includ- vigilant and aggressive in managing these
ing fluid restriction while maintaining perfu- infections to preserve both graft function and
sion to end organs, lung protective ventilator the patient’s well-­being. A close working rela-
strategies, and nitric oxide. When the amount tionship with infectious disease specialists is
of oxygen and ventilator support is high and extremely advantageous to lung transplant pro-
thus contributing to further lung injury, early grams, with some programs including one on
ECMO is an important option to consider to their transplant team.
74  Pediatric Lung Transplantation 769

Table 74.5 Infections
Pathogen/infection Notes
Bacterial
Bloodstream infections Occur in 25% of recipients, usually early, when central lines are still in place.
Lower respiratory tract Occur across the course of time post-transplant, seen in 80% of recipients.
infections
Gram-negative bacteria Cystic fibrosis recipients often have return of colonization from sinuses including
(including multi-drug resistant bacteria (P. aeruginosa, MRSA, etc.)
resistant isolates)
Burkholderia cenocepacia Absolute contraindication at nearly all centers due to poor post-transplant outcomes
(genomvar III)
Burkholderia gladioli Associated with increased post-transplant mortality, relative contraindication
Burkholderia multivorans No contraindication, no increased risk
(Genomvar II)
Clostridium difficile Occurs in 5–8% of recipients, most frequently within the first 6 months post-
transplant, re-appearing as a late complication (>2 years post-­transplant). Associated
with significantly increased mortality, particularly when early post-transplant.
Viral
CMV The most important viral infection post-transplant, can promote rejection. Requires
months of antiviral prophylaxis (length is center specific) if either donor or recipient
with positive serology, started at time of transplant. All recipients monitored using
blood PCR, frequency depends on pre-transplant status.
HSV Can be reactive post-transplant, thus if not on antiviral prophylaxis for CMV, and
recipient or donor with history of HSV, consider prophylaxis with acyclovir or
valacyclovir.
VZV Immunization pre-transplant strongly recommended. If exposed, treat with varicella
zoster immune globulin or intravenous immunoglobulin immediately.
Respiratory viruses Occur in more than half of recipients, often detected in the lower respiratory tract via
(including rhinovirus, bronchoscopy. Important to detect quickly and treat, as data suggest RSV can trigger
influenza, parainfluenza, rejection, data less clear for other viruses. Recommend recipients <2 years of age
respiratory syncytial virus, receive pavilizumab prophylaxis for RSV, all should get influenza vaccine yearly.
and all other respiratory
viruses)
Mycobacteria
Tuberculosis Increased risk of active infection post-transplant, ~4% donor derived, others a
combination of reactivation of latent TB and new infection. Tuberculin skin test and
if ≥5 years of age, Interferon Gamma Release Assay (i.e., Quantiferon Gold)
recommended pre-transplant. Active infection should prompt discussion of delaying
transplant until infection cleared. Latent infection requires 9 months isoniazid,
pre-transplant if possible. Donor screening recommended. Treatment post-transplant
challenging due to drug-drug interactions and diagnostic difficulty due to
immunosuppression causing anergy
Non-tuberculous Mycobacterium avium-­intracellulare is treatable; however, M. abscessus is a
mycobacteria contraindication due to observed disseminated infection post-­transplant, unless
sputum can be cleared pre-transplant, chelonae is also treated this way.
Fungi
Aspergillus & candida Invasive fungal infections with Aspergillus and Candida can cause anastomotic
complications, particularly early post-transplant, along with invasive pulmonary or
disseminated disease. Detection requires vigilance; treatment requires aggressive
approaches and consultation with infectious disease specialists. Antifungal azoles
interact with calcineurin inhibitors and mTOR inhibitors, thus caution and close
monitoring of drug levels must be used.
Pneumocystis jirovecii Post-transplant prophylaxis with TMP/SMX started no later than 3 weeks post-
transplant for the life of the recipient. Alternative agents include dapsone and
pentamidine. TMP/SMX also provides prophylaxis for Nocardia spp., and
Toxoplasma gondii.
Other fungi Cryptococcus and other fungi have been seen post-transplant and are important
considerations in any illness of an immunosuppressed recipient
770 A. Patel and A. Faro

Post-transplant Lymphoproliferative bowel regimens (i.e., lactulose or Miralax),

Disease (PTLD) particularly in the early post-­operative period
to avoid obstruction. Gastroesophageal reflux
By 5  years post-transplant, 14% of pediatric deserves special mention, as data suggest that
recipients have had a malignancy of some type, diagnosis and treatment of GER with anti-
nearly all of which are PTLD. The most common reflux surgery may prevent the development of
form of PTLD is caused by Epstein–Barr virus bronchiolitis obliterans and ameliorate its pro-
infection causing transformation of a CD20 cell, gression if present, but these data have not been
resulting in a B-cell lymphoma, most commonly replicated in children. As mentioned above,
polymorphic. Patients who develop primary EBV PTLD can present as intussusception, obstruc-
infection post-transplant are at greatest risk. For tion, bowel perforation, feeding intolerance or
CD20 positive PTLD, anti-CD20 antibody (ritux- abdominal pain. For GI complications, medical
imab) therapy has revolutionized the management management for resolution is preferred. If this
and allows successful treatment when combined is not possible, elective surgical procedures are
with regimens of low-dose chemotherapy and well tolerated, while data suggests that emer-
reduced baseline immunosuppression. This gent surgical procedures carry a high morbidity
approach causes far less toxicity than prior treat- and mortality risk.
ment options. Prognosis is substantially worse
for CD20-negative PTLD, due to a combination
of a lack of good therapeutic options and the tox- Neurological Complications
icity of the available regimens. Overall, per the
ISHLT registry (1/1992–6/2012), PTLD caused Forty-seven percent of recipients have some
3.3% of deaths in pediatric lung recipients, with neurological complications. The most com-
other malignancies causing 0.8% of deaths. mon complication is seizures, generally felt
The major challenge in PTLD is diagnosis, to be related to calcineurin inhibitor induced
as it can present with anything from asymptom- cerebral vasoconstriction. Posterior reversible
atic pulmonary nodules on CT scan, neurologi- encephalopathy syndrome (PRES) can also be
cal or gastrointestinal symptoms, bone pain, or seen. PRES ­consists of seizure activity in 92%
sinus pain. Further, although peak incidence is at of cases, along with headaches, visual abnor-
6 months post-transplant, it can be seen as a late malities, nausea/vomiting, other focal neuro-
complication as well. Thus, careful evaluation logical signs, and varying degrees of impaired
and assessment, including biopsies and imaging, consciousness, ranging from confusion, somno-
are needed to make the diagnosis. lence, and lethargy to encephalopathy or coma.
The diagnosis requires both symptoms and neu-
roimaging findings, with MRI being superior
Gastrointestinal Complications to CT scan for identifying PRES. Consultation
with a neurologist is also recommended; how-
Gastrointestinal complications are seen in up ever, long-term medication is not generally
to 50% of recipients. Clostriduim difficile is an needed for seizures related to lung transplanta-
important consideration, covered previously. tion. Hypertension can be present and contribu-
Other GI issues seen include esophagitis, pan- tory, and should be managed accordingly. While
creatitis, gastroparesis, ileus, CMV infections calcineurin inhibitor toxicity is felt to contribute
of the gut and liver, cholecystitis, peptic ulcer to both seizures and PRES, the correlation with
disease, gastroesophageal reflux, and peptic levels and severity or incidence is incomplete.
ulcer disease. Patients with cystic fibrosis con- Although some patients respond to switching
tinue to be at risk for distal intestinal obstruc- CNI (i.e., from tacrolimus to cyclosporine or
tion syndrome and must continue to take vice versa) or alternative regimens, no general
pancreatic enzyme supplements, along with recommendation exists.
74  Pediatric Lung Transplantation 771

Diabetes The A score reflects the intensity and composi-

tion of infiltrating immune cells and the extent
Diabetes is seen in 20% of recipients in 1 year, of parenchymal involvement (A0, no rejection,
30% at 5  years, and is seen most commonly in A1–4 minimal to severe acute rejection). The B
patients with cystic fibrosis and is thus likely score reflects airway involvement.
related to pre-existing and ongoing pancreatic Only acute rejection episodes graded A2 or
islet cell injury. Tacrolimus and corticosteroids higher are treated, generally with 3–4  days of
both appear to increase the risk of diabetes. pulse IV methylprednisolone (10–20 mg/kg/day),
with follow-up biopsy in 2–4  weeks. Persistent
acute rejection is treated with additional pulse
Renal Dysfunction steroids, anti-T-cell antibody therapy, and aug-
mented baseline immunosuppression. Acute
Nearly all recipients develop hypomagnesemia rejection is infrequent after the first year post-
post-transplant, with some developing renal transplant and is less common in infants than in
tubular acidosis, and both are generally man- older children.
aged with oral supplements. Early renal fail-
ure suggests pre-transplant renal insufficiency.
Thus, measurement of glomerular filtration rate Antibody Mediated Rejection
is a mandatory aspect of pre-transplant evalua-
tion, as patients with GFR <50 have a suspected While hyperacute antibody-mediated rejection
risk for poor outcomes, and it thus represents a caused by pre-formed anti-donor antibodies pres-
contraindication to transplant at some centers. ent at the time of transplant is a well established
Chronic effects of exposure to CNI and resulting cause of acute graft failure, it is rare. Antibody
renal vasoconsctriction contributes significantly mediated rejection (AMR) outside that context
to renal insufficiency and renovascular hyper- is now recognized as an important complication
tension post-transplant. Generally, this is man- in lung transplantation. As diagnostic criteria are
aged with calcium channel blockers. Five years still evolving, and retrospective evaluations in
of CNI based immunosuppression carries a 2.3% progress, the exact incidence of AMR in pediatric
incidence of renal failure requiring dialysis, and lung transplantation is as yet unknown. AMR can
1% require renal transplantation at some point present as progressive worsening of lung func-
post-transplant. tion in the absence of acute or chronic rejection,
and can rapidly result in death due to graft failure.
Currently, diagnosis of AMR requires three
Rejection features be present, including evidence of
allograft dysfunction, presence of circulating
Acute Rejection donor-specific antibodies, and histopathologic
findings of AMR.  However, this is complicated
Acute cellular rejection is common in the first by the significant overlap of these patterns with
weeks to months post-transplant. While often pathology seen in other forms of lung injury,
asymptomatic, fever, hypoxemia, and dyspnea including high-grade or persistent acute cellular
can be seen. CXR findings include infiltrates rejection, diffuse alveolar damage, high-grade or
and bilateral pleural effusions. Similarly, a 10% persistent lymphocytic bronchiolitis, obliterative
decrease in either FEV1 or FVC on home spiro- bronchiolitis, arteritis without rejection, or other
metric monitoring should prompt further evalua- graft dysfunction without clear morphological
tion. Biopsies are graded per the 2007 Revision explanation.
of the 1996 working formulation for the standard- Treatment of antibody mediated rejection is
ization of nomenclature in the diagnosis of lung still evolving. As such, the components of ther-
rejection. The score consists of two components. apy, rather than specific regimens, will be dis-
772 A. Patel and A. Faro

cussed. Plasmapheresis or therapeutic plasma diaphragm dysfunction, or other causes, CLAD

exchange is a process for removal of antibodies is not diagnosed.
and other circulating proteins from the recipi- CLAD is divided into restrictive CLAD and
ent’s bloodstream by filtration and thus directly obstructive CLAD. Restrictive CLAD, also called
removes the responsible antibodies. Pulse corti- restrictive allograft syndrome, is named for the
costeroids are also generally used and have been pulmonary function picture, which includes
found to impair T-cell and B-cell function, impair TLC ≤ 90% baseline and/or FEV1/FVC normal
antibody and complement binding, and decrease or increased, with FEV1 and/or FVC decline ≤
levels of serum immunoglobulins. Rituximab, 80% of baseline. HRCT findings will include
an anti-CD20 antibody used for PTLD, is also infiltrates, ground glass opacities, and upper
used in AMR, as it targets the B-cells that make lung zone fibrotic changes. Restrictive CLAD
antibody. Its use in AMR mirrors its successful (R-CLAD) carries a significantly worse progno-
use in antibody-mediated autoimmune diseases sis than BOS, with median survival of 541 days
such as rheumatoid arthritis. Together, these for patients with R-CLAD compared to 1421 for
three interventions make up the initial treatment patients with BOS.
of AMR. After 3  years post-transplant, obstructive
In summary, while antibody mediated rejec- CLAD or BOS becomes the major cause of death
tion is clearly an important process, the exact in pediatric recipients, and at 5  years, 50% of
pathobiology, incidence, diagnostic approach, surviving recipients carry a diagnosis of BOS. In
treatment, and understanding outcomes remain obstructive CLAD or BOS, the picture is domi-
in evolution. Ongoing studies will help to deter- nated by the drop in FEV1, and FVC and TLC
mine how to best diagnose and treat this entity in are stable or significantly less affected. HRCT
pediatric lung recipients. findings will include air trapping.
In terms of diagnosing BOS, the new CLAD
classification system overlaps with the prior
Chronic Lung Allograft Dysfunction ­definitions of bronchiolitis obliterans syndrome
(BOS). For example, BOS 0p is defined as a ≥
Chronic lung allograft dysfunction (CLAD) is a 10 but <20% drop in post-bronchodilator FEV1
newer term used to define the varying patterns of from baseline or FEF25–75 < 75% of baseline. In
long-term respiratory decline and failure seen in this group there appears to be a group of patients
lung recipients. It encompasses both bronchiol- with what has been termed azithromycin-­
itis obliterans and restrictive long-term allograft responsive allograft dysfunction (ARAD).
dysfunction. Azithromycin entered use in bronchiolitis oblit-
Acute lung allograft dysfunction (ALAD) erans syndrome in the early 2000s, after it was
is defined as any acute cause of a drop in lung noted that patients on thrice-weekly azithromy-
function, defined as a 10% drop from baseline in cin, as used in cystic fibrosis, could have stabi-
post-­bronchodilator FEV1 and/or FVC, includ- lization and even improvement of lung function
ing acute rejection and infection. If this persists in the setting of bronchiolitis obliterans, despite
for more than 3  weeks, it is termed suspected lack of a clear mechanism of action, though both
CLAD, and evaluation should include bronchos- anti-inflammatory and anti-fibrotic activities of
copy with biopsies. Should these prove non- azithromycin are posited as being responsible for
diagnostic, and should lung function not recover, this therapeutic efficacy.
open lung biopsy is also an important consider- Once pulmonary function testing suggests
ation in pediatric recipients, particularly smaller BOS, either by a drop in FEV1, or a drop in
children in which the diagnostic yield of trans- FEF25–75, which has been shown to be more
bronchial biopsies is limited by the use of small sensitive and detects small airways dysfunction
forceps. If there is evidence of persistent acute earlier, diagnosis requires biopsy to confirm the
rejection, infection, anastomotic complication, presence of small airway obliteration by a fibrotic
74  Pediatric Lung Transplantation 773

process. Currently, open or thoracoscopic lung numbers of re-transplants are too small to make
biopsy is used at our center when BOS is sus- a definitive conclusion. Further, these outcomes
pected but cannot be confirmed by transbronchial have been relatively stable over the past 10 years,
biopsies. demonstrating the urgent need for new ways of
Treatment of BOS is varied, and over time has managing recipients in order to preserve graft
included use of augmented immunosuppression, function and ultimately life.
change in baseline immunosuppression, azithro-
mycin, extracorporeal photopheresis (ECP), and
total lymphoid irradiation. Currently, our practice Future Considerations
is to use pulse corticosteroids accompanied by
10 days of anti-thymocyte antibodies, along with Several areas of active research offer the possi-
initiation of azithromycin thrice-weekly. If this bility of improved outcomes in lung transplan-
does not stabilize symptoms, ECP is initiated. tation. One such area is the expansion of donor
This is consistent with the current best evidence. lung availability using ex  vivo lung perfusion.
While inhaled cyclosporine and mTOR inhibi- In this procedure, marginal donor lungs that are
tors have both been shown to be effective in small not accepted for transplant initially are ventilated
studies, larger trials have not found a consistent and perfused ex  vivo and allowed to recover.
benefit in the use of either to prevent the develop- Lungs have been successfully transplanted this
ment of BOS, or in its treatment. Surgical treat- way, and expanding the donor pool provides the
ment of gastroesophageal reflux has been shown opportunity to save patients that still, at present,
to be beneficial in adults in managing and pre- die waiting for organs. This procedure needs to
venting BOS, but this has not been replicated in be extended into children as soon as possible.
children. Similarly, retrospective reviews suggest Another such area is the use of pumpless oxy-
that statin therapy can prevent BOS and may be genators as a bridge to lung transplantation. In
beneficial in treating BOS. conventional ECMO, a pump takes blood from
the patient, into the oxygenator then returns it.
Recently, pumpless oxygenator systems have
Outcomes been used in candidates awaiting lung transplan-
tation (i.e., NovaLung). While pediatric specific
Outcomes in lung transplantation as a whole systems are still being developed, we have used
continue to lag behind those of other solid a neonatal membrane oxygenator (Quadrox)
organ transplants, and this is also true in chil- to successfully bridge an infant suffering from
dren. While 1-year survival rates have improved alveolar capillary dysplasia to transplant. Both
to ~85%, 3  year survival is ~65%, and median pumpless oxygenators and venovenous ECMO
survival is 4.9  years, lower but not statistically are being increasingly used as ways to less inva-
significantly different than the 5.4  year median sively bridge candidates to transplant for longer
survival in adult recipients. As discussed previ- periods of time than conventional ECMO, which
ously, long-­term survival is determined primarily requires significant sedation, mechanical ventila-
by the development of BOS. While retransplan- tion, and immobility, which while buying some
tation continues to be offered at a small num- time, also leads to progression of the primary
ber of pediatric centers for allograft failure, lung disease, all of which limit the time a candi-
outcomes are worse for retransplantation than date can be bridged on conventional ECMO. Last,
primary transplantation (45% versus 58% sur- an array of anti-cytokine therapeutic antibodies
vival at 3  years post-transplant), irrespective of being developed for other therapeutic indications
whether or not re-transplantation was for BOS (i.e., anti-­IL-­13, anti-IL-5R, anti-IL-17, and oth-
or other causes of graft failure. Data suggest that ers) provide an opportunity to manipulate these
patients re-­transplanted at least 1 year after their mediators, all seen in different forms and stages
primary transplant had better outcomes, but the of lung transplant rejection, in order to treat or
774 A. Patel and A. Faro

prevent rejection, and potentially to promote Dysfunction part I: introduction and methods. J Heart
Lung Transplant. 2005b;24:1451–3.
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In pediatrics, the small number of recipients D, Kuklinski CA, Sweet SC.  Lung transplanta-
worldwide limits performing adequately powered tion in infants and toddlers from 1990 to 2004 at
trials. While this is not the case in adult recipients, St. Louis Children’s Hospital. Am J Transplant.
2009;9(4):719–26.
trials are generally done at single centers, and this Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz
has resulted in underpowered studies that have M, Mallory GB, Snell GI, Yousem S.  Bronchiolitis
failed to show differences between therapies that obliterans syndrome 2001: an update of the diagnostic
have beneficial trends (i.e., everolimus compared criteria. J Heart Lung Transplant. 2002;21:297–310.
Faro A, Hamvas A.  Lung transplantation for inherited
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In pediatrics, the International Pediatric Lung PJ Jr, Danziger-Isakov L, Michaels M, Sweet
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mortality beyond the first year of transplant, such Grady RM, Gandhi S, Sweet SC, Mao J, Huddleston
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are desperately needed to improve outcomes in Heart Lung Transplant. 2009;28(11):1221–5.
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Elidemir O, Woo MS, Mallory GB, International
 Index

A blood replacement, 534

Abnormal lung development, 12 in chest X-ray, 533, 534
Aborted sudden death, 227 clinical presentation, 533
Absolute risk reduction (ARR), 626 definition, 532
Acapella®, 657 echocardiography, 534
Accidental decannulation, 703 gasometric analysis, 533
Achondroplasia, 491 hydroxyurea, 535
Acid suppression therapy, 562 IV cephalosporine, 534
Acidotic breathing, 32 IV dexamethasone, 534
Acquired immune deficiency syndrome (AIDS), 517 morbidity, 534
bacterial infections, 519 neurological events, 535
bacterial pneumonia, 520 pulmonary strokes, 533
causes of, 520 Acute epiglottitis, 111
primary prophylaxis, 520 Acute hypoxemia, 675
secondary prophylaxis, 520, 521 Acute hypoxia
clinical aspects, 519 chronic hypoxemia, 677
epidemiology, 518 high altitude, 677
fungal infections, Pneumocystis jirovecii, 525, 526 preterm and newborns infants, 677, 678
Mycobacterium infections, 521–524 respiratory failure with arterial hypoxemia, 677
noninfectious complications tissue hypoxia without hypoxemia, 677
chronic lung disease, 526, 527 Acute hypoxic respiratory failure, 751
immune reconstitution syndrome, 527, 528 Acute lower respiratory tract infections, 117
neoplasias, 528 early pneumonia, 121
physiopathology, 518, 519 hidden pneumonia, 119
viral infections interstitial lung disease with bronchial obstruction, 119
cytomegalovirus, 524 interstitial pneumonia, 120
diagnosis, 524 left basal pneumonia with uncomplicated pleural
pathogens, 524 effusion, 122
prophylaxis, 525 lobar pneumonia, 120
treatment, 525 multifocal pneumonia, 121
Acquired subglottic stenosis, 732 pneumatoceles, 120
Actigraphy, 138, 139 pulmonary abscess, 120
Active respiratory cycle, 654 pulmonary tuberculosis, 122, 123
breath control exercises, first phase, 654 right-sided pneumonia with parapneumonic pleural
forced expiration technique, third phase, 654 effusions, 123
thoracic expansion exercises, second phase, 654 viral infections, 117, 119
Active sleep, 615 Acute lung allograft dysfunction (ALAD), 772
Acute alveolar damage, 51, 52 Acute mechanical ventilation, see Mechanical ventilation
Acute cellular rejection, 771 Acute-onset stridor, 196, 197
Acute chest pain, 573 Acute respiratory distress syndrome (ARDS), 768
Acute chest syndrome (ACS), 532–535 Acute respiratory exacerbations, 460, 461
airway hyperreactivity, 534 Acute respiratory infections (ARIs), 264
algorithm of diagnosis and management, 535 Acute respiratory syndromes, 680

© Springer Nature Switzerland AG 2020 777

P. Bertrand, I. Sánchez (eds.), Pediatric Respiratory Diseases,
https://doi.org/10.1007/978-3-030-26961-6
778 Index

Acute rhinitis (AR) therapy, 391 Air stacking (AS), 655

Acute stridor, 156 Air trapping, 124
Acute viral pneumonia, 751 Airway
Adaptive immunity, 49, 50 with flexible bronchoscopy (see Flexible
Adenoidal hypertrophy, 492 bronchoscopy)
Adenopathy, tuberculous, 346 imaging methods, 110–114
Adenosine, 40, 43 persistent stridor, 198, 199
Adenosine triphosphate binding cassette protein member respiratory failure, treatment, 173, 175
A3 (ABCA3) deficiency, 764 with rigid endoscopy
Adenotonsillar hypertrophy, 493 advantages, 163
with obesity, 201 bronchoscopes, 164, 165
without obesity, 201 complications, 166, 167
OSA, 203 documentation and teaching, 165, 166
Adenotonsillectomy, 493 history, 161, 162
Adenovirus, 476, 477 indications for, 163
Adult-type tuberculosis, 346, 347 laryngoscopes, 164
Aerosol, particle size and mass, 633 patient, assessment of, 162
Aerosol therapy, 613–614 symptoms and signs of airway obstruction, 162,
advantages, 637 163
aerosol-dependent factors, 636 secretions, elimination of
inertia, 636 dornase alfa, 458, 459
temperature and humidity, 636 hypertonic saline (HS) solution, 459
definition, 633 manitol, 459
deposition mechanisms respiratory physiotherapy, physical exercise, 457,
diffusion, 635 458
electrostatic precipitation, 635 treatment of infections, 459
gravitational sedimentation, 635 acute respiratory exacerbations, 460, 461
inertial impaction, 635 antibiotics therapy, 459
disadvantages, 637 chronic suppression, 461
dry powder inhalers, 641 first bacterial isolation, 459
equipment-dependent factors prophylactic, 461, 462
aerosol generating device, 637 Airway compromise, 513
drug, types of, 637 Airway hyperreactivity, 536
propellant, 637 Airway inflammation, 408
factors of stability and airway deposition of, 636 Airway obstruction, 196, 716, 717, 728
nebulizers, 640 Airway resistance, 19–21, 23, 24, 94, 95
advantages, 640 Airway stenosis, 153
jet (pneumatic) nebulizers, 639, 640 Airway surgery and endoscopic procedures
mesh nebulizers, 640 acquired subglottic stenosis, 732
recommendations for, 640 congenital subglottic stenosis, 726
soft mist inhaler, 640 congenital tracheal stenosis, 729–731
ultrasonic nebulizers, 639 laryngeal diaphragm/webs, 726–728
particle size and mass laryngomalacia, 725, 726
aerodynamic diameter, 633 laryngotracheal cleft, 731
Andersen Cascade Impactor, 634 open reconstructive surgery, 732–734
electric charge, 634 subglottic hemangioma, 728
GSD, 634 technical aspects, 731
hygroscopicity, 634 tracheal and bronchial stenosis acquired after
MMAD, 634 intubation, 734
moisture, 634 tracheomalacia-bronchomalacia, 729
Next Generation impactor, 634 Albumin, 585
tonicity, 634 Allergic bronchopulmonary aspergillosis (ABPA), 465,
patient-dependent factors 471
anatomy of airway and respiratory mechanics, 636 in asthma
respiratory pattern, 636 clinical evolution, 471
pressurized metered-dose inhaler, 638, 639 diagnosis criteria for, 471
spacer device, 637 oral steroids, 472
Agenesis, 557, 558 serum IgE, 472
Air leakage, 719 chest X-ray, 471
Index 779

cystic fibrosis CAP, 305, 306

diagnosis, 472 empyema, 329, 331
diagnosis criteria for, 472 Antibody-mediated rejection (AMR), 771, 772
treatment, 472, 473 Antibody primary immunodeficiencies
incidence, 471 common variable immunodeficiency (CVID), 504, 505
Allergic chronic rhinitis, 410 IgA deficiency, 505
Allergic diseases IgG subclasses deficiency, 505
adolescence period, 389 specific antibody deficiency, 505, 506
atopic march, 384 transient hypogammaglobulinemia of infancy, 506
definition, 383 X-linked agammaglobulinemia, 504
epidemiology, 383, 384 Anticholinergic bronchodilators, 419
etiology, 384 Anticholinergics, 292
infant period Anticoagulation, 755
allergic rhinitis, 388 Anti-inflammatory inhalation medication, 611
atopic dermatitis, 387 Anti-inflammatory mechanisms of macrolides, 645
bronchial asthma, 387, 388 adverse effects, 647, 648
food allergy, 386, 387 clinical effectiveness
newborn period, 385, 386 asthma, 646, 647
physiopathology, 384, 385 bronchiectasis, 646
preschool period, 388 chronic sinusitis, 647
school period, 389 cystic fibrosis, 646
therapy, 389–391 obliterative bronchiolitis, 647
Allergic rhinitis (AR), 33, 183, 384, 398 limits of treatment, 648
adolescence period, 389 physiopathology
infant period, 388 biofilm, 644, 645
preschool period, 388 bronchoconstriction, 646
school period, 389 modulation of inflammatory cascade, 644
Allergological assessment, 181 mucus, aspects of, 645, 646
Allergy, 502 neutrophil, effect on, 644
Allergy cutaneous skin tests, 401 Anti-inflammatory treatment
Alveolar carbon dioxide pressure (PACO2), 170 cystic fibrosis
Alveolar development, 5 azithromycin, 463
Alveolar hypoventilation, 488 ibuprofen, 463, 464
Alveolar oxygen pressure (PAO2), 170, 171 steroids, 463
Alveolar pneumonia, 314 post-infectious bronchiolitis obliterans, 482
and pleural effusion, 314 Antimicrobial therapy, Mycoplasma pneumoniae, 315
Alveolar pressure, 19 Anti-neutrophil cytoplasmic antibodies (ANCA), 512
Alveolar stage, lung development, 8 Anti-regurgitation formulas, 566
Alveolar ventilation (VA), 19, 170, 171 Anti-thymocyte antibodies, 773
Ambrisetan, 540 Anti-tuberculosis therapy, 183, 522
Ambroxol, 184 Antitussive drugs, 183
Amikacin, 462, 524 Antivirals, bronchiolitis, 292
Aminophylline, 563 Aortopexy, 729
Amoxicillin, 179, 183, 459, 510, 520 Apert syndrome, 33
Ampicillin, 306 Aplasia, 557, 558
Amyloidosis, 445 Apnea, 32, 40, 195, 564
Anaerobic metabolism, 581 Apnea crisis, 227
Anamnesis, see Clinical history Apoptosis, 8
Anatomical differences in babies, 9 Apparent life-threatening event (ALTE), 499, 564
Angiogenesis, 8, 10 cardiorespiratory monitoring
Angiotensin-converting enzyme (ACE) inhibitors, 180 duration, 230
Anidulafungin, 469, 526 indications, 230
Anorexia, 580 causes, symptoms and findings
Anterior translaryngeal transtracheal, 731 and suggested studies, 228
Antiacids, 580 diagnosis, 227
Antibiotic resistance, 306 management algorithm, 227–230
Antibiotics risk factors, 227
asthma exacerbation treatment, 422 Arnold Chiari-type malformations, 491
bronchiolitis, 293 Arrhythmias, 490
780 Index

Arterial blood gas test, 680 etiopathogenesis, 408

Arterial hypoxemia, respiratory failure with, 677 genetic factors, 407
Arterial oxygen saturation and GER, 562, 563
factors, affect oxygen saturation measurement ISAAC
hemoglobin and skin pigmentation, influence of Phase I, 394
changes, 130, 131 Phase II, 394
hyperoxemia and hypoxemia, 131, 132 Phase III, 394
motion artifacts, 130 prevalence information, 394–396
peripheral perfusion, 129 non-atopic asthma, 408
response time, 130 non-pharmacological treatment
sensor types and its placement, 129 education programs, 417–419
specific algorithms, influence of, 131 primary prophylaxis, 416
oxygen transport in blood, 127, 128 secondary prophylaxis, 416, 417
SpO2 reference values, 131, 132 nursing care education, self-care, 610
transcutaneous measurement of oxygen saturation, educational factors, 611, 612
128, 129 prescription and sequence
transcutaneous oxygen (TCPO2) measurement, 132, of utilization, 610
133 techniques for medication use, 610, 611
Arterial pulse oxygen saturation (SpO2), 248, 249 nutrition in chronic respiratory disease, 583
Arterial/venous lung hypertension, 217 OSAS, 491
Arthropathy, 445 persistent cough, 183
Arytenoepiglottoplasty, 545 pharmacological treatment
Asperger syndrome, 44 chronic treatment, 422–427
Aspergilloma, 470 exacerbation (see Asthma exacerbations)
Aspergillosis, 239 physiopathology, 409
Aspergillus infection, 239, 526 prevalence, 393
Aspirin, 580 prevalence rate, 394
Assisted cough (TA), 655 pulmonary attacks in, 61, 62
Asthma, 68, 536, 537 risk factors
ABPA aeroallergens, 397
clinical evolution, 471 ancylostomiasis, 397
diagnosis criteria for, 471 antibiotics, 397
oral steroids, 472 atopy and viral infection, 397
serum IgE, 472 gender, 397
airway sensitization, 408 genetics, 396
allergic diseases, 393, 394, 398 indoor pollution, 397
anti-inflammatory mechanisms of macrolides, 646, milk, 398
647 obesity, 397
atopy, 408 occidental diet, 398
characteristics, 407 outdoor pollution, 397
classification, 412 tobacco, 397
clinical evaluation vitamin D deficiency, 398
allergic rhinitis, 410 vitamin D supplements, 398
anamnesis, 410 wheezing (see Wheezing)
clinical spectrum, 410 Asthma-associated cough, 180
laboratory tests, 410 Asthma exacerbations
lung examination, 410 aminophylline, 420
physical examination, 410 antibiotics, 422
symptoms, 409 bronchodilators, 419
control levels, 412, 413 clinical score, 418
definition, 407 discharge criteria, 422
diagnosis evaluation, 420
chest X-rays, 411 helium, 422
clinical condition, 411 hospitalization criteria, 422
clinical score, 411 mechanical ventilation, 422
differntial diagnosis, 411 nebulized magnesium sulfate, 420
functional diagnosis, 411 oxygen, 418, 419
rationale, 411, 412 respiratory distress, 417
environmental factors, 408 salbutamol, 420
epidemiological studies, limitation of, 393 steroids, 420
epidemiology in Chile, 398, 399 treatment algorithm, 421
Index 781

Asthma predictive index (API), 387, 388, 404–406 atypical bacteria, 149
Ataluren, 456 mycobacteria, 149
Atelectasis, 157, 257 traditional bacteria, 148
Atmospheric pollution (AP), 591 Bacterial infection, 51
epidemiology in Chile, 593 lung infections, 237
greenhouse effect, 592 Bacterial pneumonia, 520
high-pollutant concentrations, 592 Bacterial respiratory infections
intrauterine and perinatal periods, 592 Bordetella pertussis, 271, 272
particulate material, 592, 593 Streptococcus pneumoniae, 269–271
respiratory morbidity associated with, 594 Bacterial tracheitis, 280
risk for mortality, 593 Basiliximab, 766
strategies and recommendations, 594, 595 BEARS Questionnaire, 140
Atopic dermatitis (AD), 384 Beckwith–Wiedemann syndrome, 33
adolescence period, 389 Behçet’s syndrome, 515
infant period, 387 Benign childhood myoclonus, 45
preschool period, 388 Benzodiazepines, 755
school period, 389 Bernoulli effect, 194
therapy, 391 Bilateral synchrony, 39
Atovaquone, 526 Bi-level positive airway pressure, 707, 708
Atropine, 154 Biliary lithiasis, 444
Attention deficit–hyperactivity disorder (ADHD), 43 Bioelectrical impedance analysis, 586
Atypical bacteria, 149 Biofilm, 644, 645
Atypical pneumonia Biot’s respiration, 32
caused by Chlamydophila pneumoniae (see Birt–Hogg–Dube syndrome, 573
Chlamydophila pneumoniae) Body mass index (BMI), 585
caused by Mycoplasma pneumoniae (see Body plethysmography, 78, 79
Mycoplasma pneumoniae) Bone marrow transplant, 510
definition, 309 Bone morphogenic protein, 10
etiological agents, 310 Bordetella pertussis, 271, 272, 757
Auscultation technique, 34, 35 Borg scale, 662
breath sounds, classification of, 35 Bosentan, 540
crackles, 36 Botox, 672
grunting, 36 BO with organizing pneumonia (BOOP), 476
pleural friction rub, 36 Boyle’s law, 92
stridor, 36 Bradypnea, 31
tracheal breathing sound, 35 Breath control exercises, 654
wheezing, 35, 36 Breath sounds, classification of, 35
Auscultatory asymmetry, 256 Breathing grunt, 33
Autogenic draining, 654 Brief Infant Sleep Questionnaire (BISQ), 140
collection of secretions, second phase, 654 Brodie score, 56
evacuation, third phase, 654 Bromhexine, 184
loosening of secretions, first phase, 654 Bronchial asthma (BA), 384
Autoinflammatory diseases of lung, 515, 516 adolescence period, 389
AutoPEEP, 692 infant period, 387, 388
Avon Longitudinal Study of Parents and Children preschool period, 388
(ALSPAC), 205, 402, 403 school period, 389
Azathioprine, 767 therapy, 391
Azithromycin, 462, 463, 510, 523, 534, 645, 764, 772, 773 Bronchial atresia, 112, 115
Azithromycin-responsive allograft dysfunction (ARAD), Bronchial blocker, 743
772 Bronchial circulation, development of, 8
Azoles, 526 Bronchial hygiene electromechanical devices
Azoospermia, 444, 447 high frequency oscillatory compression of thoracic
Aztreonam, 461 wall, 657
intrapulmonary percussion–vibration, 657
Bronchial hygiene, mechanical devices for
B continuous expiratory positive-pressure systems, 656
Bacilloscopy, 349 expiratory positive-pressure systems, 656
Bacillus Calmette–Guérin (BCG) vaccine, 350, 523 oscillatory or discontinuous expiratory positive
Bacillus smear, 522, 523 pressure, 656, 657
Bacterial bronchitis, 179 Bronchial hyperreactivity (BHR), 91, 384, 463, 464
Bacterial diagnosis Bronchial hyperresponsiveness (BHR), 206, 646
782 Index

Bronchial provocation tests, 89, 90 Caspofungin, 469, 526

Bronchial sequelae, 257 Catamenial pneumothorax, 572
Bronchial stenosis, 734, 735 Catarrhal effect, 283
Bronchiectasis, 65, 124, 125, 413, 433, 435, 437, 443, Cathartics, 580
527, 646 Cavitary lung tuberculosis, 217
Bronchiolitis Cefoxitin, 462
chest X-ray, 290 Ceftazidime, 462
historical perspective, 283, 284 Cefuroxime, 534
RSV (see Respiratory syncytial virus) Chlamydophila pneumoniae, 320
Bronchiolitis obliterans (BO), 124 Cellular and combined immunodeficiency
causes of, 476 DiGeorge Syndrome (DGS), 508
characterization, 476 hyper-IgM syndrome, 506, 507
Bronchiolitis obliterans syndrome (BOS), 772–774 severe combined immunodeficiencies, 507, 508
Bronchoalveolar lavage (BAL), 152, 155, 157, Central apnea, 364
454, 469, 644 Central bronchiectasis, 471, 472
Bronchoconstriction, 646 Central microtubules, 430
Bronchodilator, 291, 292, 464 Cephalosporin, 460
Bronchogenic cyst (BC), 115, 116, 555–557 Chlamydophila pneumoniae, 320
Bronchography, 729 Cerebral paralysis, 201
Bronchomalacia (BM), 545, 546, 729 Cervical lymphadenitis, 523
Bronchopulmonary dysplasia (BPD), 130, 582, 583, Cervical malformations, 196
586–589 CFTR2 project, 447
chronic pulmonary disease, 374 CHARGE syndrome, 33
complications and treatment Chemoprophylaxis, 350
cardiovascular, 378 Chervin Pediatric Sleep Questionnaire (PSQ), 141
follow-up plan, 379 Chest deformity, 482
metabolic alterations, 379 Chest magnetic resonance imaging, 109
neurological injuries, 379 Chest palpation, 34
nutritional support, 378–380 Chest physiotherapy, 291
oxygen therapy, 380 Chest physiotherapy, see Respiratory physiotherapy
respiratory, 376–378 Cheyne–Stokes respiration, 32, 189
diagnosis, 375, 376 Chimpanzee coryza agent, 283
epidemiology, 374 Chlamydia pneumoniae (CP), 312
hyaline membrane disease, 374 Chlamydia trachomatis, 369
physiopathology, 374, 375 Chlamydophila pneumoniae (CP), 317
precautions and pevention, 380 asthma, 320
proximal airway alterations, 381 chronic infection, 320
tracheostomy, 381 clinical characteristics, 318, 319
wheezing and asthma, 380, 381 diagnosis
Bronchopulmonary malformations, 552 indirect immunofluorescence, 319
Bronchoscopes, 164–166, 533 serological diagnosis, 319
indications for, 198 epidemiology, 318
Bronchus-associated lymphoid tissue (BALT), 48 etiopathogenesis, 317, 318
Bronchus intermedius stenosis, 735 IgG antibodies, 318
Bruni Sleep Disturbance Scale for Children (SSSC), 141 lower tract respiratory infection, 320
Bruton tyrosine kinase deficiency (Btk), 504 microbiology, 317
Bruxism, 45 radiology, 319
Butamirate, 184 reinfections, 320
treatment, 320
TWAR serovariety, 317
C Chlophedianol, 184
Calcineurin inhibitor (CNI), 767 Chloramphenicol, 462
Calcineurin inhibitor toxicity, 770 Chloroquine, 482
Candida, 239, 526 Cholestyramine, 580
Candida albicans, 369 Chromones, 426
Capillaritis, 217, 218 Chronic asthma treatment
Capillary oxygen pressure (PcO2), 171, 172 chromones, 426
Capnography, 249, 702 exercise-induced asthma, 426, 427
Carcinogenesis, 592 inhaled drug, 425
Cardiopulmonary exercise testing (CPET), 663, 664 inhaled steroids (IS), 424, 425
Cardiopulmonary hantavirus syndrome, 339 LABA, 425, 426
Index 783

leukotriene lnhibitors, 426 general physical ability assessment, 662–664

level-based pharmacological approach, 423 general physical training, 665, 666
monoclonal antibody against immunoglobulin E, 426 goals of, 661
theophyllines, 426 inspiratory muscle training, 666, 667
Chronic cough, 410, 563 respiratory muscles, assessment of, 664, 665
Chronic disease Chronic respiratory insufficiency (CRI),
characteristics, 606 causes, 698, 699
definition of, 606 Chronic rhinitis, 63
Chronic dysphony, 196 Chronic rhinosinusitis, 410, 437
Chronic granulomatous disease (CGD), 508, 509 Chronic sinusitis, 647
Chronic hospitalization, 670, 671 Chronic stridor, see Persistent stridor
admittance conditions, 671 Chronic suppression treatment, 461
goals of, 671 Chronic ventilatory support, 584
Chronic hypoxemia, 675, 677 Chronology, 195
Chronic inflammation, 445 Churg-Strauss syndrome, 513
Chronic lung allograft dysfunction (CLAD), 772, 773 Chymotrypsin, 562
Chronic lung diseases, 526, 527 Cilia
cystic fibrosis (CF) alterations in ciliary structure, 431, 432
exacerbation, 60 function, 431
improved phenotyping, 66 motile, 430
pulmonary attacks (see Pulmonary attacks) primary, 430
wheezing in preschool children, 65, 66 sensory, 430
lymphocytic interstitial pneumonia (LIP), 527 structure, 430, 431
Chronic mechanical ventilation Ciliary bronchopulmonary disease, 62
clinical criteria, 699 Ciliary disorientation, 434
complications, 703, 704 Ciliary dyskinesia, 125
epidemiology, 697–699 Ciliary paralysis, 310
equipment, 701 Ciliopathy
modes, 700, 701 genetics of, 62
monitoring, 701, 702 intraflagellar transport, 63
capnography, 702 primary cilia, 63
chest x ray, 702 primary ciliary dyskinesia, 63–65
non-invasive, 701, 702 pulmonary and systemic manifestations of, 64
polysomnography, 702 types of cilia, 62
venous/arterial gases, 702 Ciprofloxacin, 57, 460, 523, 524, 645
physiological criteria, 699 Ciprofloxacine, 461
removal of mechanical ventilation, 702 Cisapride, 567
decannulation, protocol of, 703 Clarithromycin, 183, 462, 523
definition, 702 Clarithromycin acid, 179
parameters, 702 Classic asthma, 410
protocol of, 702, 703 Classic Kartagener syndrome, 65
respiratory objectives, 699 Clavulanic acid, 179, 183, 459
sedation, 702 Clinical diagnosis of respiratory disease, 29
selection of method, 699, 700 Clinical history, 29–31
duration, 699 exercise, 30
need for autonomy, 699 feeding, 30
risk/benefit balance and ethical decisions, 699 mendelian genetic component, 31
scenario, 699 symptom, 29
tolerance to interfaces, 699 caused by, 31
systemic objectives, 699 characterization, 30
Chronic necrotizing pulmonary aspergillosis, 470 duration of, 30
Chronic obstructive pulmonary disease (COPD), 66 Clobutinol, 184
Chronic pulmonary disease, 538 Clofazmine, 524
Chronic renal insufficiency (CRI), 60 Clofedanol, 184
Chronic respiratory disease Closed Benjamin–Lindholm laryngoscope, 164
nursing care education (see Nursing care education) Clostriduim difficile, 770
nutrition (see Nutrition in chronic respiratory Cochrane Risk of Bias Tool, 630
disease) Codeine, 184
pulmonary rehabilitation, 667 Colistin, 461
definition of, 661 Colomycin, 57, 462
education, 667 Common variable immunodeficiency (CVID), 504, 505
784 Index

Community-acquired pneumonia (CAP) hypoplasia, 558

clinical manifestations, 301, 302 lung sequestration, 554, 555
complications, 306 treatment, 558, 559
definition, 299 Congenital malformations, 12
diagnosis Congenital malformations of airway
chest X-ray, 302, 303 clinical presentation
laboratory analysis, 303 bronchomalacia (BM), 545, 546
microbiological identification, 304 laryngomalacia (LM), 544, 545
differential diagnosis, 304 tracheal stenosis, 546, 547
epidemiology, 299, 300 tracheomalacia, 545, 546
etiology vascular rings (VR), 547–549
agents according to age, 300, 301 epidemiology, 543
bacterial etiology, 300 Congenital malformations of chest cavity, surgery of,
causative agent identification, 300 737, 738
coinfection, 300 pectus carinatum
in newborns, 300 preoperative evaluation, 740, 741
orientation, 300 treatment, 741
physiopathology, 301 pectus excavatum
prevention, 306, 307 incidence of, 738
treatment preoperative evaluation, 738, 739
in hospital, 305, 306 treatment, 739, 740
outpatient, 305 Congenital pulmonary airway malformation (CPAM),
Complement immunodeficiencies, 509 113–117
Complete blood count (CBC), 369 Congenital pulmonary hyperinflation, 112
Compliance of respiratory system (CRS), 9 Congenital stridor, 156
Computerized tomography (CT), 108–110, 117, 121, Congenital tracheal anomalies
196, 469, 738 congenital tracheal stenosis, 729–731
Conatal bacterial infections, 369 laryngotracheal cleft, 731
Conatal pneumonia, 356 tracheomalacia-bronchomalacia, 729
Conatal viral infections, 369 aortopexy, 729
Concentrators, 679 stents, 729
Condensation syndrome, 302 Congenital tracheal stenosis, 111, 729–731
Condensing pneumonia, 319 Conjugate pneumococcal vaccine, 521
Confusional arousal, 45 Connatal tuberculosis, 348
Congenital and acquired airway diseases, 726 Connective tissue disease, 511
Congenital bilateral absence of the vas deferens Connective tissue diseases and lung
(CBAVD), 441 glomerular nephritis, 515
Congenital bronchopulmonary anomalies, 110–112 juvenile dermatomyositis (JDM), 514
Congenital heart disease (CHD), 764 juvenile idiopathic arthritis (JIA), 515
Congenital laryngeal anomalies juvenile systemic sclerosis (JSE), 514, 515
congenital subglottic stenosis, 726, 727 mixed connective tissue disease, 514
laryngeal diaphragm/webs, 726–728 Connective tissue diseases and lung systemic
laryngomalacia, 725, 726 erythematosus lupus (SLE), 513, 514
subglottic hemangioma, 728 Consolidated pneumonia, 302
Congenital lobar emphysema (CLE), 555, 556 Consolidated Standard of Reporting Trials (CONSORT)
Congenital lobar hyperinflation, 555, 556 guidelines, 625
Congenital lobar overinflation, 114 Constant load exercise test, 663
Congenital lobe emphysema (CLE), 552 Continuous expiratory positive-pressure systems, 656
Congenital lung malformation Continuous positive airway pressure (CPAP), 491, 494, 700
agenesis, 557, 558 Continuous slow-wave sleep, 39
aplasia, 557, 558 Controlled-assisted ventilation, 689
bronchogenic cyst, 555, 556 Controlled inspiratory flow exercise, 655
congenital lobar emphysema/congenital lobar Controlled ventilation, 689
hyperinflation, 555, 556 Conventional kinetic respiratory techniques, 650
cystic adenomatoid malformation, 552–554 Conventional microprocessor-based mechanical
classification of, 553 ventilators, 707
clinical presentation forms, 554 Conventional physiotherapy, 649
Stocker classification, 553 Cooperative Study of Sickle Cell Disease (CSSCD), 532
diagnosis, 558 Coronavirus, 267
embryology, 551, 552 MERS-CoV, 335–337
epidemiology, 552 NL 63, 337, 338
esophageal duplication cyst, 556 SARS, 337
Index 785

Corticosteroids, 580, 583, 764 diagnosis, 441

Costal cartilage graft, 733 clinical elements of, 442
Co-trimoxazole, 508, 510 factors for delayed diagnosis, 441
Cotton–Myer classification, 732 family history, 445
Cough, definition of, 177 malabsorption test, 446, 447
Cough-variant asthma, 179 membrane potential, 447
Crackles, physical examination, 36 neonatal screening, 448–450
Craniofacial dysmorphology, children with semen analysis, 447
pierre robin sequence, 490 sweat test, 445, 446
treacher collins syndrome, 491 early neonatal detection and clinical evolution, 56
Craniofacial malformations, 196 epidemiology, 440
Craniofacial syndromes, 201 FEV1, 59
Creatine, NMDs treatment, 252 gene therapy, 57
Cricotracheal resection, 733 genetic mutations in, 58
Croup, see Laryngitis imaging methods, 124, 125
Crouzon syndrome, 33 Infant Study of Inhaled Saline (ISIS), 56
Cryptococcosis, 526 lung transplantation, 763
Cutaneous hemangiomas, 196 contraindications, 763, 764
Cyanosis, 195 indications, 763
Cyclic alternating pattern (CAP), 44 microbiome, 66, 67, 69
Cycloserine, 523 clinical pediatric pneumology dead, 69, 70
Cyclosporine, 767, 773, 774 in early wheezing disorders, 68, 69
Cysteinyl leukotrienes (CysLT), 288–290 in healthy children, 67, 68
Cystic adenomatoid malformation (CAM), 552–554 solid food diet, 69
classification of, 553 molecular diagnosis, 447
clinical presentation forms, 554 aforementioned mutations, 447
diagnosis, 558 indications for, 448
Stocker classification, 553 nebulized therapy, 57
Cystic fibrosis (CF), 216, 217, 222, 573, 576, 583, 585, 762 nursing care education, self-care, 612, 613
ABPA fundamental and permanent pillars for disease,
diagnosis, 472 613
diagnosis criteria for, 472 inhalation therapy, 614
treatment, 472, 473 nurse specialized in, 612, 613
allergies to antibiotics, 59 physical activity, 614
anti-inflammatory mechanisms of macrolides, 646 respiratory physiotherapy, 613
chronic lung disease signs and symptoms, 613
exacerbation, 60 pathophysiology, 440, 441
pulmonary attacks (see Pulmonary attacks) resistant organisms, selection of, 59
chronic lung diseases small molecules, 57, 58
improved phenotyping, 66 treatment, 457
wheezing in preschool children, 65, 66 azithromycin, 463
chronic renal insufficiency (CRI), 60 bronchodilator, 464
ciliopathy, 62 center, minimum standard of, 454, 455
genetics of, 62 complications, 465
intraflagellar transport, 63 dornase alfa, 458, 459
primary cilia, 63 enzyme supplements, 456
primary ciliary dyskinesia, 63–65 follow-up of patients, 453
pulmonary and systemic manifestations of, 64 gene therapy, 456
types of cilia, 62 hypertonic saline (HS) solution, 459
clinical manifestations ibuprofen, 463, 464
amyloidosis, 445 immunizations, 453
diabetes mellitus, 445 infections in airway, 459–462
edematous ascitic syndrome, 445 lung transplant, 465
gastrointestinal alterations, 443, 444 manitol, 459
growth delay, 444 nutritional support, 453, 455
intestinal obstruction, 443 oxygen and ventilation support, 464, 465
lung compromise, 441–443 pharmacotherapy, 456, 457
sweat glands, 444 physical exercise, 457, 458
vas deferens, 444 salt supplements, 456
complex mutations, 58, 59 steroids, 463
definition of, 613 taurine and ursodeoxycholic acid,
delicate secondary effects, with longevity, 59 supplement of, 456
786 Index

Cystic Fibrosis Questionnaire—Revised (CFQ-R), 57 Downes score, 275

Cystic fibrosis transmembrane conductance regulator Doxycycline, 462
(CFTR), 439–442, 444, 447–449, 456 Chlamydophila pneumoniae, 320
Cystic lung lesions, 554 Drugs and nutrients, 580
Cytochemical analysis, 348 Dry powder inhalers (DPI), 611, 637, 641
Cytomegalovirus (CMV), 238, 524 Dual hypothesis, 43
Cytotoxicity, 311 Duchenne muscular dystrophy (DMD), 57, 246, 665, 676
Dynamic compression system, 741
Dynamic pulmonary compliance, 18
D Dyneins, 430, 431, 434
Dalton’s law of partial pressure, 24 Dysmorphic lung, 111
Dapsone, 526 Dyspnea, 573
Decannulation, 719, 722
Deep sulcus sign, 575
Deficiency of interleukin-1-receptor antagonist (DIRA), E
515 Early pneumonia, 121
Delayed sleep phase syndrome, 138 Echinocandins, 526
Dendritic cells, 49, 50 ECMO, see Extracorporeal circulation membrane
Dexmedetomidine, 165 oxygenation (ECMO)
Dextromethorphan, 184 Eczema, 394, 398
Diabetes mellitus, 445, 771 Edematous ascitic syndrome, 445
Diazepam, 13 Ehlers-Danlos syndromes, 572, 738
Diffuse alveolar hemorrhage syndrome (DAHS) Eisenmenger syndrome, 765
with capillaritis, 217, 218 Electromyography, 141–143
classification, 217 Emerging bacteria, 461, 462
with lung capillaritis, 218 Empyema, 123
without lung capillaritis, 219 agents, 325
not related to idiopathic pulmonary hemosiderosis, antibiotics, 329, 331
218, 219 definition, 324
Diffuse/focal diseases of pulmonary parenchyma diagnosis
air trapping, 124 chest echography, 327, 328
bronchial disease pattern, 124 chest X-ray, 326, 327
bronchiectasis, 124 computerized axial tomography, 327, 328
bronchiolitis obliterans, 124 laboratory tests, 327
consolidation pattern, 124 microbiological study, 328
ground glass pattern, 123 thoracentesis, 328, 329
honeycomb pattern, 124 exudative phase, 326
tree-in-bud pattern, 124 follow-up, 332
Diffuse panbronchiolitis (DBP), 644 ipsilateral, 324
Diffusing capacity of the lung for carbondioxide physiopathology, 325, 326
(DLCO), 79, 80 pleural, 325
Diffusion limitation, 676, 677 chest tube, 330, 331
DiGeorge syndrome (DGS), 503, 506, 508, 727 drainage tube, 331
Digestive losses, 581 effusions, 326
Digitalis, 580 prognosis, 332
Direct bronchoscopy, 198 surgery, 331, 332
Direct immunofluorescence (DIF), 146–148 thoracentesis, 329
Direct laryngoscopy, 198 treatment, 329, 330
Disability-adjusted life-years (DALYs), 264 Encapsulated meconium peritonitis, 443
Distal intestinal obstruction syndrome, 770 Endoscopic repair, 731
Domestic video, 139, 140 Endothelin-1, 538
Domperidone, 568 Energy requirements, 587
Dornase alfa, 458, 459 Enterovirus D68, 340, 341
Dorothea Orem’s theory, 607 Enuresis, 489
Dorsal spine surgery Environmental pollution, 591
normal development and growth of spine, 744 atmospheric pollution (AP), 591
preoperative evaluation, 745, 746 epidemiology in Chile, 593
surgical technique, 746, 747 greenhouse effect, 592
Double aortic arch (DAA), 113, 547, 549 high-pollutant concentrations, 592
Down syndrome, 33, 45, 201, 491, 492, 494 intrauterine and perinatal periods, 592
Index 787

particulate material, 592, 593 veno-venous (VV), 752, 753

respiratory morbidity associated with, 594 prognosis and ECMO programs in Latin America,
risk for mortality, 593 756–758
strategies and recommendations, 594, 595 selection criteria for, 754
indoor pollution (IP) newborns, 753, 754
definition, 595 pediatric patients, 753, 754
heating sources, 596 survival rate
value chart, 596 to discharge, 751, 752
in-house pollution (HP), 591 of newborns, 750
Environmental tobacco smoke (ETS), 592 of pediatric patients, 750, 751
Eosinophilic esophagitis, 566 veno-arterial ECMO with pump and oxygenator, 752,
Epidermal growth factor, 10 753
Episodic viral wheeze (EVW), 403, 404 Extracorporeal life support (ECLS), see Extracorporeal
Episodic wheezing, management, 210–212 circulation membrane oxygenation (ECMO)
Epistemonikos, 625 Extracorporeal Life Support Organization (ELSO), 750,
Epithelial cells, 49 757
Epoprostenol, 540 Extracorporeal membrane oxygenation (ECMO), 340,
Epstein–Barr virus, 527 367
Equivalent of meconium ileus, 443 Extracorporeal photopheresis (ECP), 773
Eroallergensinfections, 397 Extraesophageal reflux, 561
Erythromycin, 646 Extra-esophageal syndromes, 562
Esomeprazole, 568 Extralobar sequestration, 117, 119, 554
Esophageal atresia, 543 Extrapulmonary tuberculosis, 352
Esophageal duplication cyst, 556 Extrathoracic central airway, 197, 198
Esophagogastroduodenal transit study, 181 Extubation failure, 158
Ethambutol, 522, 524 Ex-utero intrapartum treatment (EXIT), 159, 758
Ethionamide, 523
European Respiratory Association (ERS), 403
Everolimus, 767 F
Evidence-based medicine (EBM) Fagan nomogram, 628
components of clinical action question, 624 Fallot tetralogy, 547
critical analysis Famotidine, 568
diagnostic tests, 626–628 Fat embolism, 533
meta-analysis, 629, 630 Fetal respiratory movement (FRM), 11
systematic reviews (SR), 629–631 Fibroblast growth factors (FGFs), 10
therapy article, 625, 626 Flexible bronchoscopy, 198
quality of evidence, 631 complications, 155, 156
search for information, 624, 625 contraindications, 152
steps for, 624 disadvantages, 163
strength of recommendations, 631, 632 indications, 152
training in, 623 performance of
Exercise-induced asthma, 410, 426, 427 acute stridor, 156
Exercise-induced bronchospasm (EIB), 427 atelectasis, 157
Exercise-induced provocation test, 90 congenital stridor, 156
Exhaled nitric oxide measurement, 95 difficult intubation, 158
Exocrine pancreatic function, 454 extubation failure, 158
Exocrine pancreatic insufficiency, 444 foreign body, 159
Expiration, definition of, 21 hemoptysis, 158
Expiratory imaging, 109 miscellaneous applications, 159, 160
Expiratory positive airway pressure (EPAP), 707 pneumonia in immunocompetent patients, 157
Expiratory positive-pressure systems, 656 pneumonia in immunocompromised patients, 157
Expiratory reserve volume (ERV), 87, 98 recurrent laryngitis, 156
Extracorporeal circulation membrane oxygenation recurrent wheezing and pneumonia, 157, 158
(ECMO), 749, 750, 758, 759, 767, 768, 773 upper airway obstruction (UAO), 156
complications, 756 technical aspects
exclusion criteria for, 754 bronchoalveolar lavage, 155
history, 749, 750 equipment, 152, 153
management, 754–756 procedure, 153, 154
physiology, 752 recovery, 155
veno-arterial (VA), 752 sedation, 154, 155
788 Index

Flexible endoscopy, 163 radiopaque foreign body, 257, 258

Flucloxacillin, 56, 459 radiotranslucent foreign body, 257
Fluconazole, 526 treatment
Fluidization, 641 absolute certainty, 258
Flutter®VRP1, 656, 657 endoscopic extraction, 258
Focal malformations, 111 flexible bronchoscopy, 258, 260
Food allergies (FA), 384, 617 flexible endoscopy, 259
adolescence period, 389 penetration syndrome, 258
causes of, 617 periendoscopic morbidity, 259
definition of, 618 rigid bronchoscopy, 258, 260
educational factors, 620 steroids, 259
infant period, 386 virtual endoscopy, 258
egg, 387 Foscarnet, 525
immunological reaction, 386 Fraction of exhaled nitric oxide (FeNO), 80, 433
milk, 387 Frontal Lobe Epilepsy And Parasomnias Scale (FLEP),
peanut, 387 141
wheat, fish, fruits and vegetables, 387 Functional differences in babies, 9
management, 620, 621 Functional hypogammaglobulinemia, 520
onset of symptoms, factors influence, 618 Functional residual capacity (FRC), 9, 75, 87, 91–92,
rules to avoid triggering allergens, 618–620 536, 691, 706
school period, 389 body plethysmography, 78, 79
treatment, 620 definition of, 78
Forced expiration technique (FET), 653 multiple-breath washout (MBW) method, 79
active respiratory cycle, 654 Fungal infections, 525, 526
breath control exercises, first phase, 654 lung infections, 238–240
forced expiration technique, third phase, 654 Fungal pneumonia, 239
thoracic expansion exercises, second phase, 654 Fungi diagnosis, 149
air stacking (AS), 655 Funnel stenosis, 547
assisted cough (TA), 655 Furosemide, 580
autogenic draining, 654
controlled inspiratory flow exercise, 655
glossopharyngeal breathing (RGF), 655 G
huffing, 655 Ganglion biopsy, 522
induced cough (TP), 655 García’s laryngeal mirror, 162
prolonged slow expiration, 653 Gastroesophageal reflux (GER), 41, 561, 773
slow expiration with glottis opened in lateral posture apnea and ALTE, 564
(ELTGOL), 654 asthma, 562, 563
thoracic blockage, 655 chronic cough, 563
thoracic compression, 655 damage mechanisms in respiratory diseases, 562
thoracic decompression, 655 diagnosis, 566, 567
Forced expiratory flow at 25–75% of FVC (FEF25–75), 87 laryngeal recurrent papillomatosis, 565
Forced expiratory flow, pulmonary function in infants, 74 laryngomalacia, 565
rapid thoracoabdominal compression technique at obstructive sleep apnea syndrome (OSAS), 564
current volume, 74, 75 recurrent laryngitis, 565
rapid thoracoabdominal compression technique at subglottic stenosis, 564, 565
volume with previous insufflation, 76, 77 swallow disorders, 563, 564
Forced expiratory volume in a given time (FEVt), 87 treatment, 566–568
Forced oscillation technique (FOT), 81 Gastrointestinal complications, 770
Forced vital capacity (FVC), 76, 98, 464 Gastrostomy, 587
Foreign body inhalation Gene therapy, 456, 510
algorithm, 259 cystic fibrosis (CF), 57
clinical presentation Geometric standard deviation (GSD), 634
chronic complications, 256, 257 Ghon complex, 345
obstruction level, 256 Gibson and Cooke method, 446
penetration syndrome, 256 Global Initiative for Asthma (GINA), 423
computerized tomography (CT), 258 Global Lung Function Initiative (GLI), 89
epidemiology, 255, 256 Global respiratory failure, 413
prevention, 260 Glomerular nephritis, 515
radiological study Glossopharyngeal breathing (RGF), 655
atelectasis, 257 Glotoscope, 161
lung hyperinflation, 256, 257 Goodpasture syndrome, 218, 223
Index 789

Grading of Recommendations, Assessment, foreign body aspiration, 216

Development, and Evaluations (GRADE) hemorrhagic diathesis, 217
system, 181, 183, 184, 631 infections, 217
Granulocyte–macrophage colony–stimulating factor, 10 pulmonary hemorrhage epidemic, 219
Granulomatosis with polyangiitis, 512, 513 trauma, 217
Greenhouse effect, 592 tumors, 217
Group B Streptococcus (GBS), 369 vascular malformation, 217
Growth delay, 444 physiopathology, 216
Growth factors, 10 treatment, 222–224
Grunting, physical examination, 36 Hemorrhage, 166, 216, 718, 720
Guaifenesin, 184 Hemorrhagic diathesis, 217
Guillain-Barré syndrome, 22, 676 Hemosiderophages, 220
Henoch-Schonlein purpura, 511
Hering–Breuer reflex, 78
H HERMES (Harmonised Education in Respiratory
Habitual snoring, 201 Medicine for European Specialists), 3
definition, 202 Heterotaxy syndromes, 65
screening, 203 Hidden pneumonia, 119
Haemophilus influenzae, 306 High-frequency chest wall oscillation (HFCWO), 458
Haemophilus influenzae type B, 269, 521 High frequency oscillatory compression
Haller index (TAC), 738 of thoracic wall, 657
Hantavirus, 339, 340 High-frequency oscillatory ventilation (HFOV), 750
Harmonised Education in Respiratory Medicine for Highly effective antiretroviral regimes (HAART), 518,
European Specialists (HERMES), 3 520–522, 524, 526, 527
HCoV-HKU1, 337, 338 Histamine type 2 receptor agonist (H2RA), 567
HCoV-N63, 337 Histoplasma, 526
HCoV-NL63, 338 HKU1, 337
HCoV-OC43, 338 HN glycoprotein, 274
HCoV-229E, 338 H1N1 influenza A, 338
Health-related quality of life (HRQoL), 706, 711 H7N9 influenza A, 338, 339
Healthy sleeping habits, 137 Holding chambers, 611
Heat and moisture exchanger (HME), 710 Holliday-Segar method, 586
Heliox, 294 Home hospitalization system, 670
Helium dilution, 92, 93 Home oxygen therapy, 680
Hematemesis, 219 Home respiratory care, 649
Hematocrit, 359 Hook’s law, 18
Hemoglobin (Hb), 127, 529, 530, 675 Hourglass stenosis, 547
Hemoglobin (Hb) dissociation curve, 26 HRQoL, see Health-related quality of life (HRQoL)
Hemolysis, 530 Huffing, 655
Hemophilia, 217 Human immunodeficiency virus (HIV), 517
Hemoptysis, 158 AIDS (see Acquired immune deficiency syndrome
conditions, 216 (AIDS))
diagnosis coinfections, 352
BAL, 220 lung diseases, 517
computerized angiotomography and angiography, serotypes, 517
220 Human virus, 266
CT scanning, 220 Humidification systems, 710
diagnostic algorithm, 220, 221 Humoral PID, see Antibody primary
differential diagnosis, 219 immunodeficiencies
fibrobronchoscopy, 220 Hyaline membrane disease (HMD), 374, 573
flexible bronchoscope, 220 chest X-ray, 362
lung biopsy, 222 hypoxemia and acidosis, 362
scintigraphy ventilation/perfusion, 220 late-term premature newborns, 363
upper airway hemorrhage, 219 morbidity and mortality, 362
epidemiology and etiology, 216 perinatal history, 363
etiology prevention, 363
cardiovascular causes, 217 pulmonary surfactant deficiency, 361
cystic fibrosis, 217 risk factors, 362
DAHS (see Diffuse alveolar hemorrhage steroids and thyroid hormones, 362
syndrome) transport protein ABCA3 deficiency, 364
factitious hemoptysis, 219 treatment, 363
790 Index

Hydrofluoroalkane (HFA), 639 ultrasound, 108

Hydroxychloroquine, 482, 764 Imipenem, 462
Hydroxyurea, 535, 536 Immotile ciliary syndrome, 125
Hygroscopicity, 634 Immune reconstitution syndrome, 527, 528
Hyperactivity studies in preschool children, 82 Immunochromatography, 146, 147
Hyperbaric oxygen therapy, 680 Immunodeficiencies, definition, 502
Hypercapnic respiratory failure, 465 Immunofluorescence, 147
Hypercarbia, 188, 413 Immunoglobulin against the SRV
Hypergammaglobulinemia, 527 (IGIV-RSV), 294, 295
Hyperglycemia, 13 Immunological defense mechanisms
Hyper-IgE syndrome, 509, 510 acute alveolar damage, 51, 52
Hyper-IgM syndrome, 506, 507 adaptive immunity, 49, 50
Hyperoxemia, 131, 132 immune Induction in lung, 48
Hyperplasia, 13 innate immunity, 48
Hyperresponsiveness, 275 damage and recognition of infection, 48
Hypertension, 770 damage-associated molecular patterns, 48
Hypertonic saline (HS) solution, 293, 459 dendritic cells, 49
Hypertrophy, 6 epithelial cells, 49
Hyperventilation, 21, 22, 176 macrophages, 49
Hypnogram, 488 monocytes, 49
Hypoplasia, 13, 558 neutrophils, 49
Hypopnea–apnea index, 493 NOD-like receptors, 49
Hypopnea index, 494 pathogen-associated molecular patterns, 48
Hypoventilation, 21, 22, 171, 172, 176, 465, 676, 708 receptors and ligands, 49
Hypoxemia, 22, 24, 33, 38, 129, 131, 132, 172, 188, 252, toll-like receptors, 48, 49
359, 360, 413, 537, 545 microbiome, 52
acute, 675 organization of respiratory immune system, 47, 48
causes of, 676 respiratory infections, immune responses to, 50, 51
diffusion limitation, 676, 677 tissue repair, 52
hypoventilation, 676 Immunological diseases, 511
inspired PO2, 677 anti-neutrophil cytoplasmic antibodies (ANCA), 512
shunt, 676 Churg-Strauss syndrome, 513
ventilation–perfusion mismatch, 676 etiopathogenesis, 511
chronic, 677 granulomatosis with polyangiitis, 512, 513
Hypoxia, 13, 675 Henoch-Schonlein purpura, 511
Kawasaki disease, 512
lung compromise, 511
I microscopic polyangiitis, 513
Iatrogenic pneumothorax, 572 polyarteritis nodosa, 512
Ibuprofen, 463, 464 vasculitis, 511
Idiopathic pulmonary hemorrhage (IPH), 219 with lung compromise, 511
Idiopathic pulmonary hemosiderosis (IPH), 218, 219 Immunoreactive trypsin (IRT), 448, 449
Idiopathic pulmonary hypertension (IPH), 764, 765 Immunosuppressed children with lung infections, see
IgA deficiency, 503, 505 Lung infections
IgG subclasses deficiency, 505 Immunosuppression, 766, 767
IL-12 pathway, alterations in, 510 Incentive spirometers, 656
Imaging methods Indirect immunofluorescence (IIF), 146
chest structure, evaluation of Indomethacin, 13
acute lower respiratory tract infections, 117, Indoor pollution (IP)
119–123 definition, 595
airways, 110–114 heating sources, 596
cystic fibrosis, 124, 125 value chart, 596
diffuse/focal diseases of pulmonary parenchyma, Induced cough (TP), 655
123, 124 Infant Study of Inhaled Saline (ISIS), 56
immotile ciliary syndrome, 125 Infections, 719, 768, 769
lung parenchyma, 110–119 in airway, treatment of, 459
chest x-ray, 107, 108 acute respiratory exacerbations, 460, 461
computerized tomography (CT), 108, 109 antibiotics therapy, 459
magnetic resonance imagining (MRI), 109 chronic suppression, 461
Index 791

first bacterial isolation, 459 Intrapulmonary percussion–vibration, 657

prophylactic, 461, 462 Intrathoracic airways, 19
PID, 504 Intra-thoracic central airway, 197
Inflammation, OSAS, 491, 492 Intrathoracic pressure effect, 563
Inflammatory response, 48, 50, 51 Intravenous ganciclovir, 525
Inflator–exsufflator, 657, 658 Intrinsic positive pressure end
Infliximab, 482 of expiration (PEEPi), 692
Influenza A virus, 338, 339 Invasive pneumococcal disease, 271
Influenza vaccine, 306 Invasive pulmonary aspergillosis (IPA), 468, 469
Influenza virus, 264, 268, 477 Aspergillus antigen detection techniques, 469
Inhalation therapy, 610, 614. See Also Aerosol therapy BAL, 469
Inhaled corticoids, 90 clinical presentations, 468
Inhaled mannitol, 57 diagnosis, 469
Inhaled nitric oxide (iNO), 750 high mortality rates, 469
Inhaled steroids (IS), 62, 292, 424, 425, 463 risk factors, 468
In-house pollution (HP), 591 surgical resection, 470
Innate immunity, 48 Invasive ventilation, 689
damage and recognition of infection, 48 Iodine compounds, 184
damage-associated molecular patterns, 48 IPAP, see Inspiratory positive airway pressure (IPAP)
dendritic cells, 49 Ipratropium, 637
epithelial cells, 49 Ischemic cardiopathy, 592
macrophages, 49 Isolated/single congenital cysts, 113, 115, 116
monocytes, 49 Isoniazid, 521–523, 580
neutrophils, 49 Itraconazole, 465, 470, 472, 473, 508, 510, 526
NOD-like receptors, 49 IV dexamethasone, 534
pathogen-associated molecular patterns, 48 Ivacaftor, 456
receptors and ligands, 49
toll-like receptors, 48, 49
Inorganic foreign bodies, 256 J
Insomnia, 38 Jactatio capitis, 45
Inspiration, definition of, 20 Jet (pneumatic) nebulizers, 639, 640
Inspiratory capacity (IC), 87 Jeune asphyxiating thoracic dystrophy, 63
Inspiratory muscle training (IMT), 666, 667 Juvenile dermatomyositis (JDM), 514
Inspiratory positive airway pressure (IPAP), 707, 708 Juvenile idiopathic arthritis (JIA), 515
Inspiratory reserve volume (IRV), 87 Juvenile systemic sclerosis (JSE), 514, 515
Insulin-like growth factor, 10
Interferon-gamma release (IGRAS) assays, 349, 350
Interferon-γ, 522 K
alterations in, 510 Kasukawa diagnostic criteria, 514
Intermittent hypoxemia, 487, 488, 490 Kawasaki disease, 512
Intermittent mandatory ventilation, 689 Keratinocyte growth factor, 10
International Study of Asthma and Allergies in Ketamine, 165
Childhood (ISAAC) Kinesiotherapy, 305
Phase I, 394 Kleine–Levin syndrome, 44
Phase II, 394 Klippel–Feil syndrome, 738, 745
Phase III, 394 Koch culture in Loewenstein-Jensen medium, 522
prevalence rates, 394–396 Koch’s bacillus, 344
Interrupter resistance (Rint) technique, 81, 82 immunological defense, 344
Interstitial-alveolar pneumonia, 313, 319 primary infection, 344
Interstitial diseases, 189 Kussmaul respiration, 32, 189
Interstitial lung disease with bronchial obstruction, 119 Kyphoscoliosis, 247
Interstitial pneumonia, 120, 303, 521, 524
Intestinal malabsorption, 444
Intestinal obstruction L
equivalent of meconium ileus, 443 Lansoprazole, 568
meconium ileus, 443 Laryngeal diaphragm/webs, 726–728
Intracardiac shunt, 676 Laryngeal nerve damage, 719
Intralobar sequestration, 117, 118 Laryngeal obstruction, 256
Intrapleural fibrinolytics (IPF), 331 Laryngeal recurrent papillomatosis, 565
792 Index

Laryngitis Loewenstein-Jensen medium, 522, 523

clinical manifestations, 275 Long-acting beta-agonists (LABA), 425, 426
complications, 280 Low risk bias, 625, 626
diagnosis, 276 Lumen airway obstruction, 544
emergency service, 280 Lumicaftor, 457
epidemiology, 273, 274 Lung angiography, 239
etiology and physiopathology, 274, 275 Lung carbon monoxide diffusion, 93–95
hospitalization, 279, 280 Lung clearance index (LCI), 56, 79
severity scores Lung compliance (C), 18, 19, 684–686
Downes score, 275 Lung compromise, 441–443, 511–515
Westley score, 275, 276 Lung damage, mechanical ventilation, 692
specialist follow-up, 280 Lung development
treatment definition of, 10
adrenaline, 277, 278 developmental anomalies, 11
auscultation, 278 fetal respiration and pulmonary fluid, 11, 13
betamethasone, 279 genetic control of, 10
clinical management algorithm, 276, 277 nutrition, 14
dexamethasone, 278, 279 peristaltic contractions, 13, 14
epinephrine, 276, 277 prenatal and postnatal factors, 11–13
etiological treatment, 279 stages in, 12
glucocorticoids, 278 active hyperplasia, 6
helium, 278 airway and lung vessels, 6
nebulized budesonide, 279 alveolar stage, 6, 8
primary evaluation, 276 canalicular stage, 6, 7
venous blood gas monitoring, 278 embryonic stage, 6, 7
Laryngomalacia (LM), 156, 195, 198, 544, 545, 725, hypertrophy, 6
726, 731 microvascular maturation, 6
GER, 565 postnatal growth, 8
morbidity in, 544 pseudoglandular stage, 6, 7
prognosis, 545 saccular stage, 6–8
severity scale, 544 steroids, 14
supraglottoplasty, 545 Lung exacerbations
symptoms, 545 azithromycin, 463
typical stridor, 544 dornase alfa, 458, 459
X-ray study, 545 symptoms and signs of, 460
Laryngopharyngeal reflux, 561, 564, 565 Lung function anomalies, 535, 536
Laryngoscopes, 164–166 Lung hypertension, 490, 538–540
Laryngotracheal cleft, 731 Lung infections
Laryngotracheal disease, 512 diagnosis
Larynx diseases, 725 clinical presentation, 241
Larynx sensitivity, 564 microbiological diagnosis, 241, 242
Latin American Pediatric Respiratory Society, 3 radiological findings, 234, 241
Left aortic arch (LAA), 547 sampling, 241, 242
Left basal pneumonia with uncomplicated pleural epidemiology, 233, 234
effusion, 122 etiology, 234
Lentivirus, 437 bacterial infection, 237
Leukotriene inhibitors, 426 fungal infections, 238–240
Leukotrienes, 288, 289 in hematopoietic precursor transplant recipients,
Levofloxacin, 461, 462 235, 236
Likelihood ratios (LR), 627 immunosuppression and infectious etiology, 237
Line probe assays (LPA), 350 mycobacteria, 240
Linezolid, 523 parameters, 235
Liposomal amikacin, 57, 461 parasites, 240
Lipoxygenase, 491 patients with AIDS, 237
Liquid oxygen, 679 in solid organ transplant recipients, 235, 236
Liver disease, 444 viral infections, 238
Living lobar transplantation, 766 physiopathology, 234
Lobar pneumonia, 120 treatment, 241–243
Lobectomy, 239 Lung parenchyma, 744
Localized bronchiectasis, 482 bronchial atresia, 112, 115
Index 793

congenital bronchopulmonary anomalies, 110–112 Lung volume/body weight index, 9, 10

congenital pulmonary airway malformation, 113–117 Lung volume, measurement of, FRC
congenital pulmonary hyperinflation, 112 body plethysmography, 78, 79
isolated/single congenital cysts, 113, 115, 116 definition of, 78
pulmonary sequestration, 117–119 multiple-breath washout (MBW) method, 79
Lung sequestration, 554, 555, 558 Lung weight/body weight ratio (LW/BW), 9
Lung suppurative infections, 502 Lymphocytic interstitial pneumonia (LIP), 527
Lung surgery
thoracotomy
history, 741, 742 M
technique, 742 Macroduct device, 445
videothoracoscopy, 742 Macroglossia, 33
anesthetic considerations, 743 Macrolides, 524, 534
indications, 742 anti-inflammatory effect, 643, 645
preoperative evaluation, 743 adverse effects, 647, 648
Lung transplantation, 235, 774 asthma, 646, 647
contraindications, 763 biofilm, 644, 645
cystic fibrosis, 763 bronchiectasis, 646
contraindications, 763, 764 bronchoconstriction, 646
indications, 763 chronic sinusitis, 647
treatment, 465 cystic fibrosis, 646
donor evaluation, 765–766 diffuse panbronchiolitis, 644
ECMO, 773 limits of treatment, 648
ex vivo lung perfusion, 773 modulation of inflammatory cascade, 644
history, 762 mucus, aspects of, 645, 646
immunosuppression, 766, 767 neutrophil, effect on, 644
indications, 762, 763 obliterative bronchiolitis, 647
outcomes in, 773 characterization, 643
post-operative management, 767 Chlamydophila pneumoniae, 320
fluids and nutrition management, 767 definition, 643
primary graft dysfunction (PGD), 768 Mycoplasma pneumoniae, 311, 316
surgical complications, 768 Macronutrients, 586, 588
ventilator management, 767 Macrophages, 49
post-operative monitoring and management, 767 Magnetic resonance imagining (MRI), 109
post-transplantation complications Mainzer–Saldino syndrome, 65
diabetes, 771 Malabsorption, 444
gastrointestinal complications, 770 Malabsorption tests, 446, 447
infections, 768, 769 Mallampati index, 33
neurological complications, 770 Malnutrition, 56, 579, 581
PTLD, 770 mechanisms of
renal dysfunction, 771 anaerobic metabolism, 581
post-transplantation monitoring, 768 digestive losses, 581
pulmonary vascular disorders lower food intake, 580
characterization, 764 resting metabolic rate (RMR) increase, 580, 581
contraindications, 765 mechnisms of, 581
inadequate pulmonary vascular bed, 765 NMDs, 250, 251
indications, 765 Manchester Asthma and Allergy Study (MAAS), 402,
pumpless oxygenators, 773 403
rejection Manitol, 459
acute cellular, 771 Marfan syndrome, 572, 738
antibody-mediated, 771, 772 Mass median aerodynamic diameter (MMAD), 634
chronic lung allograft dysfunction (CLAD), 772, Massive hemothorax, 577
773 Mastocytes, 288, 289
surfactant deficiency syndromes Matrix-assisted laser desorption/ionization time-of-flight
adenosine triphosphate binding cassette protein (MALDI-TOF) mass spectrometry, 148, 149
member A3 (ABCA3) deficiency, 764 Maximum expiratory pressure (MEP),
contraindications, 764 102, 249, 250, 664
diagnosis, 764 Maximum inspiratory pressure (MIP), 102, 249, 250,
indications, 764 664, 686, 687
surgical technique, 766 Maximum voluntary ventilation (MVV), 99, 100, 249
794 Index

Measles, mumps, and rubeola (MMR) vaccine, 295 Mixed connective tissue disease, 514
Measles virus, 477 Modified Bernoulli equation, 539
Mechanical lung expansion devices, 656 Modified Borg scale for dyspnea, 662
Mechanical ventilation Modified Pediatric Epworth Scale (MPES) score, 142
cardiopulmonary interactions, basic elements of, 687, Molecular biology, 147, 148
688 Monoclonal antibody against immunoglobulin E, 426
extubation, 693, 694 Monocytes, 49
history, 683, 684 Mood disorders, 44
indications, 688, 689 Morphine, 13, 154, 184
initial parameters, 689, 690 Motor neuron disease (MND), 710
and oxygenation, 684–687 mTOR inhibitors, 773
special characteristics of child, 684 Mucociliary clearance, 431, 710
undesired effects of, 692, 693 Mucolytic and expectorant drugs, 184
ventilatory management, practical parameters of, 691 Mucopolysaccharidosis, 545
in obstructive diseases, 691, 692 Mucormycosis, 239
in patients with lungs without severe disease, 691 Multicenter Allergy Study (MAS), 401
PEEPi, 692 Multifocal pneumonia, 121
in restrictive lung diseases, 691 Multiple-breath washout (MBW) method, 79
ventilatory modes, 689, 690 Multiple latency sleep test (MLST), 143
ventilatory weaning, 693 Multiple trigger wheeze (MTW), 403, 404
Meckel–Gruber syndrome, 65 Multitriggered wheezing, 209
Meconium aspiration syndrome (MAS), 356, 360, 361, management, 212
573 Munchausen syndrome, 219
Meconium ileus, 443 Muscular fatigue
Membrane potential, 447 definition of, 104
Mental development indices (MDI), 758 tension/time index (ITT), 104
Mesh nebulizers, 640 ventilometry, 104
Metered dose inhalers (MDI), 611 Muscular retraction, 256
Methacholine, 90, 94 Muscular strength assessment, 249, 250
Methacholine-induced bronchial test, 90, 91 Muscular weakness, 95
Methemoglobin, 367 Mustard procedure, 751
Methicillin-resistant Staphylococcus aureus (MRSA), 59, Mutagenesis, 592
461 Mycobacterium avium, 462
Methicillin-sensitive Staphylococcus aureus (MSSA), Mycobacterium avium complex (MAC), 523, 524
459 Mycobacterium bovis, 350
Micafungin, 469, 526 Mycobacterium infections, 149, 240, 521, 522
Microbiological vigilance, 454 bacillus smear, 522, 523
Microbiome, 52 chest X-ray, 522
cystic fibrosis, 66, 67, 69 cluture, 523
clinical pediatric pneumology dead, 69, 70 ganglion biopsy, 522
in early wheezing disorders, 68, 69 Koch culture in a Loewenstein-Jensen medium, 522
in healthy children, 67, 68 PCR, 522
solid food diet, 69 prophylaxis, 523, 524
definition of, 52 semiautomatic hemoculture, 522
Micronutrients, 586, 587 treatment, 522–524
MicroRNA, noncodifying, 10 Mycobacterium tuberculosis, 149, 344
Microscopic polyangiitis, 513 Mycophenolate mofetil, 767
Microtubule-associated proteins (MAP), 430 Mycoplasma pneumoniae (MP), 121, 477
Microvascular maturation, 8 clinical presentation, 312, 313
Midazolam with ketamine, 154 electrophoresis, 315
Middle East respiratory syndrome (MERS), 335–337 epidemiology, 311, 312
Middle East respiratory syndrome (MERS) coronavirus extrapulmonary manifestations
(MERS-CoV), 267 cutaneous, 313
Midface hypoplasia, 491 neurological, 313
Mild hypoxemia, 172 radiology, 313, 314
Miliary tuberculosis, 347, 352 hospitalization, 316
Milk-alkali syndrome, 567 laboratory diagnosis
Minimally invasive surgery for pectus excavatum, 739 complement fixation (FC) test, 314
Mitomycin C, 732 IgM detection, 314
Mixed apnea, 364 nucleic acid amplification techniques, 314, 315
Index 795

serological diagnosis, 314 6-minute walk test, 101

microbiology, 310 ventilation control, 100, 101
pathogenesis, 310, 311 muscular fatigue
pathology, 315 definition of, 104
prevention, 316 tension/time index (ITT), 104
prognosis, 317 ventilometry, 104
treatment, 315, 316 muscular strength
Myer–Cotton system, 716 nasal sniff test, 102, 103
peak cough flow, 103
static pressures, 102
N transdiaphragmatic pressure, 103
Nasal-associated lymphoid tissue (NALT), 48 pulmonary volume and capacity, 98–100
Nasal sniff test, 102, 103 spirometry flow/volume loops, 98
Nasojejunal catheter, 587 Neurorehabilitation, 251, 252
National Acute Chest Syndrome Study Group Neutrophils, 49
(NACSSG), 532 Nevirapine, 522
Nebulized pentamidine, 526 Newborn apnea, 364, 365
Nebulized therapy, cystic fibrosis (CF), 57 Newborn with respiratory disease
Nebulizers, 640 malformations, 370
advantages, 640 perinatal asphyxia
jet (pneumatic) nebulizers, 639, 640 cardiorespiratory depression at birth, 359, 360
mesh nebulizers, 640 meconium aspiration, 360, 361
recommendations for, 640 pneumonia
soft mist inhaler, 640 chest X-ray, 369
ultrasonic nebulizers, 639 conatal infection, 368
Necrotizing pneumonia, 520 frequency and severity, 369
Neo-alveolarization, 481 microbial agents, 369
Neonatal cholestatic jaundice, 443 treatment, 369
Neonatal membrane oxygenator (Quadrox), 773 prematurity and lung fluid reabsorption
Neoplasias, 528, 559 hyaline membrane disease, 361–364
Nerve growth factor (NGF), 288 neonatal transient tachypnea, 365
Neural plasticity, 288 newborn apnea, 364, 365
Neurological diseases (NMDs) pulmonary circulation diseases
clinical manifestations, 247, 249 persistent arteriosus ductus, 367, 368
diagnosis PPH (see Persistent pulmonary hypertension)
cardiological focus, 250 RDS (see Respiratory distress syndrome)
neurological diagnosis, 248 respiratory physiology, 355–357
respiratory focus, 248–250 Next-generation sequencing, 447
epidemiology, 245, 246 Night polysomnography, 492
ethical dilemmas, 252, 253 Nightmares, 45
etiology and physiopathology Nitrogen multiple-breath washout, 79
hypercapnia, 246 Nitrogen wash, 93, 94
hypoventilation, 246 NKX2.1 gene, mutation in, 764
kyphoscoliosis, 247 Nocturnal and diurnal non-invasive ventilation, 710
orthopedic alterations, 247 Nocturnal polysomnography (PSG), 142
sleep disorders, 247 body positions, 142
pathophysiology and clinical signs, 248 cardiorespiratory variables, 142
prognosis, 252, 253 electromyography of anterior tibial muscles, 142,
symptoms and signs, 249 143
treatment heartbeat, 142
assisted ventilation, 252 neurophysiological variables, 142
neurorehabilitation, 251, 252 snoring, 142
nutrition, 250, 251 Nocturnal terror, 45
oxygen therapy, 252 NOD-like receptors, 49
pharmacological treatment, 252 Non-classified primary immunodeficiencies
respiratory kinesiotherapy, 251 hyper-IgE syndrome, 509, 510
scoliosis, 251 IL-12 pathway, alterations in, 510
Neurological sequelae, 280 interferon-γ, alterations in, 510
Neuromuscular diseases (NMD), 201 Wiskott–Aldrich syndrome, 509
arterial gases and saturometry, 100 Non-conventional physiotherapy, 650
796 Index

Noninvasive mechanical ventilation (NIMV), 464 from 11 years of age, 617

Non-invasive ventilation (NIV) first months of life, 615
in chronic patients, 706 starting at 6 months of age, 616
active assisted exercise, 706 starting at 12 months of age, 616
bi-level positive airway pressure, 707, 708 starting at 18 months of age, 616
equipment for delivery, 707 Nuss procedure, 739
24 hours per day prolonged mechanical Nutrition, 14, 672
ventilation method, 710, 711 Nutrition in chronic respiratory disease
humidification systems, 710 asthma, 583
indications for, 706 bronchopulmonary dysplasia, 582, 583
interfaces, 709 cystic fibrosis, 583
lower O2 consumption, 706 early nutritional intervention, 585
modes with bi-level flow generators, 708 factors, influence nutritional status
oxygen therapy, 710 age of onset, duration and severity of pathology,
pressure-control ventilation (PCV), 709 580
selection criteria for, 706 drugs, 580
upper airway stability, 706 prevention, early detection of malnutrition and
volume assist-control ventilation (ACV), 708, 709 timely support, 580
ethical dilemmas, 711, 712 type of underlying disease, 580
physiological bases, 705, 706 laboratory tests
Non-rapid-eye-movement (NREM) sleep, 39, 43, 136 body composition, measurement of, 586
Nonsteroidal anti-inflammatory drugs, 60 energy expenditure, measurement of, 585, 586
Non-tuberculosis Mycobacterium infections, 240, 462, plasma markers, 585
523 and lung function, 581, 582
Noscapine, 184 mechanisms of malnutrition, 580
Number needed to treat (NNT), 626 anaerobic metabolism, 581
Nursing care education digestive losses, 581
asthma, self-care in, 610 lower food intake, 580
educational factors, 611 resting metabolic rate (RMR) increase, 580, 581
prescription and sequence of utilization, 610 nutritional management, measurement of
techniques for medication use, 610, 611 adapted and enriched formulas, 588, 589
caring, definition of, 607 breastfeeding, 587, 588
correct educational instance for self-care, 608, 609 energy, macronutrients and water contribution,
cystic fibrosis, self-care in, 612, 613 586, 587
fundamental and permanent pillars for disease, feeding frequency, 587
613 micronutrients, 586, 587
inhalation therapy, 614 route of feeding, 587
nurse specialized in, 612, 613 solid feeding, 589
physical activity, 614 post-infectious chronic lung damage, 583
respiratory physiotherapy, 613 prolonged ventilatory support, patients with, 583, 584
signs and symptoms, 613 regular monitoring of food intake, 584
Dorothea Orem’s theory, 607 regular monitoring of nutritional status, 584, 585
educational instances, evaluation of, 609
educational programs objectives of, 609
effective educational instances, minimum contents of, O
610 Obesity, 491
efficient education, characteristics of, 609 Obliterative bronchiolitis (OB), 647
food allergies, 617 Obsessive–compulsive disorder, 44
causes of, 617 Obstruction of upper airway, 193, 726–727
definition, 618 Obstructive apnea, 364
educational factors, 620 Obstructive apnea–hypopnea index (IAH), 142
management, 620, 621 Obstructive laryngitis, 163
onset of symptoms, factors influence, 618 Obstructive sleep apnea (OSA), 32, 138, 201
rules to avoid triggering allergens, 618–620 Obstructive sleep apnea syndrome (OSAS), 564, 706
treatment, 620 asthma, 491
learning areas, 609 cardiovascular manifestations, 490
self-care theory, 607, 608 characterization, 486
sleep disorders, sleep hygiene, 614, 615 craniofacial dysmorphology, children with
in adolescence, 617 pierre robin sequence, 490
between 2 and 5 years of age, 616, 617 treacher collins syndrome, 491
Index 797

daytime symptoms, 489 withdrawal of long-term oxygen therapy, 681

development and neurocognitive symptoms, 490 determine oxygen administration period, 679
diagnosis, 492 flowmeter, 679
laboratory exams, 492, 493 humidifier, 679
stages, 493 hypoxemia, causes of, 676, 677
epidemiology, 486 manometer, 679
extrapulmonary clinical manifestations, 489 methods of oxygen administration, 679
growth failure, 489 NMDs, 252
inflammation, 491, 492 non-invasive ventilation, 710
nighttime symptoms sources of oxygen administration, 679
apneas, 489 titration, 678
enuresis, 489 training of parents/caregivers, follow-up and
frequent awakening, 489 monitoring, 679, 680
night sweats, 489
nonrestful sleep, 489
respiratory distress during sleep, 489 P
snoring, 488 Palivizumab, 285, 380
obesity, 491 effectiveness, 295, 296
physiopathology, 486, 487 humanized monoclonal antibodies, 295
alveolar hypoventilation, 488 IgG1-humanized monoclonal antibody, 295
intermittent hypoxemia, 487, 488 prophylaxis recommendations, 296, 297
respiratory work, increase of, 487 protection effects, 296
sleep fragmentation, 487 recurrent wheezing, 296
polysomnography in, 486 Pancreatic enzymes, 456
treatment Pancreatitis-associated protein (PAP), 448
continuous positive airway pressure Parainfluenza, 274, 275
(CPAP), 494 Parapneumonic effusion, 326
medical, 493 Parasomnias, 45
oxygen, 494 Parenchymal compromise, 513
surgical, 493, 494 Partial/hypoxemic respiratory insufficiency, 413
Occlusion pressure, measurement of, 100, 101 Partial water vapor pressure, 24
Omalizumab, 62, 426, 465 Particulate material (PM), 592
Omeprazole, 568 Pathogen-associated molecular patterns (PAMPs), 49
Open reconstructive surgery Patient-level-information, 630
enlargement with cartilage graft, 733 Pattern recognition receptors (PRRs), 48
extension without graft, 732, 733 Peak cough flow (PCF), 103, 709
laryngeal stent, 734 Peak expiratory flow (PEF), 75, 87, 89, 536
postoperative management, 734 Peak inspiratory pressure (PIP), 536, 709
stenotic zone resection, 733 Pectus carinatum
Oral acyclovir, 525 preoperative evaluation, 740, 741
Oral atovaquone, 526 treatment, 741
Organic acidurias, 589 Pectus excavatum
Orthopnea, 32 incidence of, 738
Orthotopic lung transplantation, 774 preoperative evaluation, 738, 739
Oscillatory/discontinuous expiratory positive pressure, treatment, 739, 740
656, 657 Pediatric Daytime Sleepiness Scale (PDSS), 38
Oseltamivir, 525 Pediatric pulmonology, 623
Overlap syndromes, 65 Penetration syndrome, 110, 256
Oxeladin, 184 Penicillin, 580
Oxidative stress, 530 Pentamidine, 526
Oxygen administration devices, 678 Pepsin, 562
Oxygenation index (OI), 757 Percutaneous amphotericin B, 470
Oxygen hemoglobin saturation, 25 Perfusion ventilation, 24
Oxygen/mechanical ventilation, 374, 375 Perinatal transmission, 518
Oxygen saturation levels, 291 Periodic leg movements (PLMs), 141
Oxygen therapy, 176, 380, 675, 676 Peripheral microtubules, 430
for acute hypoxia, 677, 678 Perl’s reaction, 220
complications, 680 Peroxynitrite, 680
acute respiratory syndromes, 680 Persistent air leak, 577
dryness and irritation of nasal mucosa, 680 Persistent arteriosus ductus (PAD), 367, 368
798 Index

Persistent cough Pharmacotherapy, 456, 457, 764

causes of, 180 Pharyngolaryngeal reflux, 563
cough reflex anatomy, 178 Phenobarbital, 580
afferent nerves, 178 Phenytoin, 580
cough receptors, 178 Physical examination
effector muscles, 178 auscultation technique, 34, 35
efferent nerves, 178 breath sounds, classification of, 35
medullary center, 178 crackles, 36
definition of, 177 grunting, 36
diagnosis, 179–182 pleural friction rub, 36
etiology, 178, 179 stridor, 36
treatment, 181–183 tracheal breathing sound, 35
allergic rhinitis, 183 wheezing, 35, 36
antitussive drugs, 183 chest palpation, 34
asthma, 183 inspection, 31, 32
centrally acting antitussives, 184 asymmetry in chest expansion, 32
codeine and morphine, 184 auscultation, 31
dextromethorphan, 184 barrel-shaped chest, 33
diagnostic–therapeutic algorithms, 184, 185 Biot’s respiration, 32
guaifenesin and iodine compounds, 184 breathing grunt, 33
mucolytic and expectorant drugs, 184 breathing synchronization, 32
prolonged bacterial bronchitis, 183 Cheyne–Stokes respiration, 32
Persistent pulmonary hypertension (PPH), 357, 378 digital clubbing, 34
chest X-ray, 366 head and neck examination, 33
cycle of events, 366 Kussmaul’s breathing, 32
Doppler echocardiography, 366 nail clubbing, 34
idiopathic PPH, 366 of pharynx, 33
prevention, 367 respiratory frequency, 31
pulmonary hypoperfusion, 366 respiratory pattern, 31
treatment, 367 respiratory rates in children, 32
Persistent stridor respiratory rhythm, 32
applied physiopathology, 194, 195 thoracic configuration, 33
assessment percussion, 34
imaging, 196 Physical forces, 13
respiratory function, 196–198 Physiological basis of respiratory system
visualization of airway, 198, 199 airway resistance, 19–21, 23, 24
clinical history, 195 pulmonary circulation, 22
age at initiation, 195 pulmonary ventilation, 20, 21
apnea and cyanosis, association with, 195 alterations in, 21, 22
cervical/thoracic trauma/surgery, 195 definition of, 20
chronology, 195 expiration, 21
evolution timeline, 195 inspiration, 20
feeding difficulty, association with, 196 respiration, 20
form of initiation, 195 respiratory gases in blood, 24–27
intubation, 196 respiratory mechanics, 17, 18
modify stridor, 195 ventilation/perfusion (V/Q) ratio, 23, 24
physical growth, 196 Physiopathological disorder, 652
definition, 193 Pierre robin sequence, 490
differential diagnosis of acute-onset stridor, 196, 197 Pirazinamide, 352, 522
epidemiology, 193, 194 Plasma markers, 585
physical examination, 196 Plasmapheresis, 223
Persistent tachypnea Plasminogen activator inhibitor-1 (PAI-1), 538
definition of, 187 Plastic bronchitis, 533
diagnosis, 189, 190 Platelet-derived growth factor, 10
etiology, 188 Plethysmography, 91–93, 98
organic causes of, 189 Pleural compromise, 515
respiration control mechanisms, 188 Pleural effusion, 319, 511
World Health Organization, 187 Pleural friction rub, 36
Persistent tracheocutaneous fistula, 720 Pneumatoceles, 120, 331
Phagocytes immunodeficiencies, chronic granulomatous Pneumococcal vaccines, 506
disease, 508 Pneumococcus, 269–271
Index 799

Pneumocystis jirovecii, 240, 304, 525 Port-a-cath system device, 460

diagnosis, 525 Posaconazole, 526
pneumonia, 572 Positive expiratory pressure (PEP), 458, 656, 657
prophylaxis, 526 Positive expiratory pressure (PEP) deficiency, 536
treatment, 526 Positive pressure end of expiration (PEEP), 685–687,
Pneumonia, 413, 525 691
Chlamydia, 532 Positive pressure ventilation, 687, 688
Cytomegalovirus, 524 Posterior cranial fossa alteration, facial hemangioma,
in immunocompetent patients, 157 alteration of brain, cardiovascular, and eye
in immunocompromised patients, 157 arteries (PHACE) syndrome, 548
Mycobacterium avium complex (MAC), 523 Posterior reversible encephalopathy syndrome (PRES),
Pneumocystis jirovecii, 525 770
and recurrent wheezing, 157, 158 Post-infectious bronchiolitis obliterans (PIBO)
viral agents characterization of, 476
enterovirus D68, 340, 341 clinical findings, 478
hantavirus, 339, 340 diagnosis, 478–480
HCoV-HKU1, 337, 338 chest computerized tomography, 479
HCoV-N63, 337 chest X-ray, 478
HCoV-NL63, 338 high-resolution computerized tomography
HCoV-OC43, 338 (HRCT), 479
HCoV-229E, 338 lung biopsy, 480
HKU1, 337 lung function in infants, 479, 480
influenza A virus, 338, 339 lung grammagraphy, 478
MERS-CoV, 335–337 radiological clinical score, 480, 481
polyomavirus, 341 etiology, 476
SARS, 337 adenovirus, 476, 477
Pneumonia associated with mechanical ventilation influenza, 477
(PAMV), 703 measles virus, 477
Pneumonia complications Mycoplasma pneumoniae, 477
clinical manifestations, 326 respiratory syncytial virus, 478
in community-acquired pneumonia, 324 evolution, 481, 482
empyema (see Empyema) frequency of, 476
epidemiology, 324, 325 prevalence, 475
etiology, 325 prognosis, 481, 482
pneumatocele, 324 treatment, 482
pulmonary abscess, 324 Post-infectious chronic lung damage, 583
suppurated complications, 323 Postinfectious pneumothorax, 573
Pneumothorax, 167, 357, 413 Postnasal discharge rhinosinusitis, 179
in chronic disease, 574 Postnatal growth, lung development, 8
clinical manifestations, 573, 574 Post-transplant lymphoproliferative disease (PTLD), 770
definition, 571 Postural drainage, 653
diagnosis, 574 Prader–Willi syndrome, 491
computerized axial tomography scan, 575 Prednisolone, 463
ultrasound, 574 Prednisone, 352, 465
epidemiology, 571, 572 Premature apnea, 40
etiology, 572, 573 Premature newborn
pathophysiology, 572, 573 BPD (see Bronchopulmonary dysplasia)
size, quantification of, 575 Candida albicans, 369
treatment, 575–577 idiopathic apnea, 365
Poiseuille’s law, 194 late-term premature newborns, 363
Pollutant emissions, 593 neonatal apnea, 364
Polyarteritis nodosa, 512 oxygen administration, 363
Polyclonal hypergammaglobulinemia, 518 persistent arteriosus ductus, 368
Polycystin 1, 65 RDS (see Respiratory distress syndrome)
Polymerase chain reaction (PCR), 147–149, 189, 522 Pressure-control ventilation (PCV), 709
DNA amplification, 314, 315 Pressure-regulated, volume-controlled ventilation, 690
Polyomavirus, 341 Pressure support, 707
Polysaccharide vaccine 23-valent, 506 Pressure support ventilation (PSV), 709
Polysomnography (PSG), 100, 136, 137, 249, 486, 493, Pressurized metered-dose inhaler (pMDI), 637–639
494, 702 Prevalence and Incidence of Asthma and Mite Allergy
Portable/respiratory polygraph systems, 141, 142 (PIAMA), 402, 403
800 Index

Primaquine, 526 respiratory physiotherapist, 672

Primary ciliary dyskinesia (PCD), 62–65, 70 social worker, 672
clinical condition speech-language pathologist, 672
adulthood manifestations, 433 progression, 674
antenatal manifestations, 432 prolonged mechanical ventilation, 670
infancy and childhood manifestations, 432, 433 Prolonged mechanical ventilation, 670
neonatal manifestations, 432 Prolonged slow expiration, 653
definition of, 429 Prolonged ventilatory support, patients with, 583, 584
diagnosis, 433 Propofol, 154, 165
ciliary disorientation, 434 Propranolol, 728
frequency of ciliary beat after ciliogenesis, 434 Protein–calorie malnutrition, 745
frequency of ciliary beat with light microscope, 434 Protein chain reaction (PCR) technique, 304
genetic study, 434 Protein purified derivative (PPD) test, 348, 349
immunofluorescence, 434 Proton pump inhibitors, 183, 564, 567
mutations, 435 Pseudomonas aeruginosa, 463, 643–645
screening methods, 433 Psychogenic cough, 183
study algorithm, 435, 436 Psychomotor development indices (PDI), 758
study of respiratory mucosa cells, 434 Publication bias, 630, 631
epidemiology, 430 Pulmonary abscess, 120, 331
etiology and physiopathology, 430–432 Pulmonary aspergillosis
cilia, 430 allergic bronchopulmonary aspergillosis (ABPA), 471
evaluation and treatment in asthma, 471, 472
lentivirus as vector, 437 chest X-ray, 471
otorhinolaryngology treatment, 437 cystic fibrosis, 472, 473
respiratory treatment, 435–437 incidence, 471
prognosis, 437 aspergilloma, 470
Primary/congenital tracheomalacia, 545 chronic necrotizing pulmonary aspergillosis, 470
Primary graft dysfunction (PGD), 768 clinical presentations of, 468
Primary health care, 649 epidemiology, 467
Primary immunodeficiencies (PID), 502 etiology, 467, 468
characterization, 503 invasive pulmonary aspergillosis (IPA), 468, 469
clinical history, 503 Aspergillus antigen detection techniques, 469
frequency, 504 BAL, 469
and infections, 504 clinical presentations, 468
lymphoid cell development, 505 diagnosis, 469
monogenic/polygenic, 503 high mortality rates, 469
recurrent respiratory infections, 502 risk factors, 468
treatment, 507, 510, 511 surgical resection, 470
Primary pneumothorax, 573 physiopathology, 467, 468
Primary spontaneous pneumothorax, 573, 575 Pulmonary attacks, 60
computerized axial tomography scan, 575 in asthma, 61, 62
Procalcitonin, 369 in cystic fibrosis, 60, 61
Prokinetics, 567 Pulmonary circulation, 22
Prolonged hospitalization Pulmonary contusion, 577
additional activities, 673 Pulmonary exacerbations, see Pulmonary attacks
avoid in-hospital infections, routine monitoring to, 673 Pulmonary fibrosis, 762
chronic hospitalization, 670, 671 Pulmonary function in infants, 73
admittance conditions, 671 breathing analysis at current volume, 76–78
goals of, 671 diffusing capacity of lung for carbondioxide, 79, 80
discharge planning, 674 forced expiratory flow, measurement of, 74
infrastructure and equipment, 672 rapid thoracoabdominal compression technique at
medical team, 671, 672 current volume, 74, 75
medically fragile/special needs population, 670 rapid thoracoabdominal compression technique at
monitoring of chronic respiratory ill patient by level volume with previous insufflation, 76, 77
of complexity, 672, 673 fraction of exhaled nitric oxide (FeNO), 80
professional team indications to perform functional respiratory studies, 74
dietist, 672 Lung Clearance Index (LCI), 79
motor physiotherapist, 672 lung volume, measurement of, 78
nurse, 672 body plethysmography, 78, 79
occupational therapist, 672 FRC, definition of, 78
psychologist, 672 multiple-breath washout (MBW) method, 79
Index 801

measurement conditions, 74 hyperventilation, 22

respiratory mechanics, measurement of, 77, 78 hypoventilation, 22
Pulmonary function in preschool children definition, 20
forced oscillation technique (FOT), 81 expiration, 21
hyperactivity studies, 82 inspiration, 20
interrupter resistance (Rint) technique, 81, 82 respiration, 20
spirometry, 80, 81 Pulse corticosteroids, 772
Pulmonary function in schoolchildren and adolescents Pulse oximetry, 128–133, 680
airway resistance, 94, 95
bronchial provocation tests, 89, 90
exhaled nitric oxide measurement, 95 Q
flow/volume curve, 87–89, 91 Quadriplegic cerebral palsy, 246
helium dilution, 92, 93 Quality of life, 606, 609, 614, 617
lung carbon monoxide diffusion, 93–95 Quantiferon, 522
lung volumes, flows, and capacities, 87 Quiet sleep, 615
methacholine-induced bronchial test, 90, 91 Quinolones, 462
nitrogen wash, 93, 94 Mycoplasma pneumoniae, 316
peak expiratory flow (PEF), 89
plethysmography, 91–93
provocation test with exercise, 90 R
respiratory muscle strength, evaluation of, 95 Rabbit antithymocyte globulin (RATG), 766
spirometry, 86, 87, 89 Radiography, 110
static lung volume measurement, 91, 92 Ramp time, 708
volume/time curve, 87 Ranitidine, 568
Pulmonary function tests, 86 Rapid eye movement (REM), 39
Pulmonary hyperinflation, 19, 21 Rapid progressors, 519
Pulmonary hyperinsufflation, 358 Rapid thoracoabdominal compression technique at
Pulmonary hypertension, 762, 764 current volume, 74, 75
Pulmonary hypoplasia, 10 Rapid thoracoabdominal compression technique at
Pulmonary parenchyma, 8 volume with previous insufflation, 76, 77
Pulmonary rehabilitation, 667 Rapid-eye-movement (REM) sleep, 39–43, 136
definition, 661 Ravitch procedure, 739
general physical ability assessment, 662 RC Cornet®, 657
cardiopulmonary exercise testing, 663, 664 Recombinant human deoxyribonuclease (rhDNase), 293
evaluation tests, 662 Rectal prolapse, 444
shuttle walking test (SWT), 663 Recurrent hoarseness, 410
six-minute walk (6MWT) test, 662, 663 Recurrent laryngitis, 156, 565
goals of, 661 Recurrent obstructive acute laryngitis, 410
respiratory muscles, assessment of, 664 Recurrent pneumonia, 246, 410
inspiratory and expiratory muscle strength, 664, Recurrent tracheitis, 410
665 Recurrent wheezing
treatment atopy presence/absence, 209
education, 667 causes of, 208
general physical training, 665, 666 clinical characteristics, 207–209
inspiratory muscle training (IMT), 666, 667 diagnosis, 209, 210
Pulmonary–renal syndrome, 217, 218 differential diagnosis, 206
Pulmonary sequestration, 117–119 epidemiological phenotype, 208
Pulmonary strokes, 533 epidemiology, 205
Pulmonary subdistension, 13 etiology, 206
Pulmonary tuberculosis (TB), 122, 123 etiopathogenesis, 208
Pulmonary vascular disorders management
characterization, 764 episodic wheezing, 210–212
contraindications, 765 evolution and prognosis, 213
inadequate pulmonary vascular bed, 765 multitriggered wheezing, 212
indications, 765 severity assessment, 212, 213
Pulmonary vascular resistance, 23 physiopathology
Pulmonary vein stenosis (PVS), 764 airway inflammation, 207
Pulmonary veno-occlusive disease (PVOD), 764 bronchial hyperresponsiveness, 207
Pulmonary venous anomalies, 765 intraluminal obstruction, 207
Pulmonary ventilation, 20, 21 limitation of airflow, 207
alterations in, 21 triggers, 209
802 Index

Recurrent wheezing syndrome, 410 Respiratory mechanics, 17, 18, 175

Regulatory T lymphocytes (Tregs), 50, 67 pulmonary function in infants, 77, 78
Relative risk (RR), 626 Respiratory muscle strength, evaluation of, 95
Relative risk reduction (RRR), 626 Respiratory physiotherapy, 457, 458, 650
REM sleep, see Rapid-eye-movement (REM) sleep airway epithelium, 650, 651
Renal ciliopathies, 65 conventional physiotherapy, 649
Renal dysfunction, 771 cystic fibrosis, self-care in, 613
Reporting bias, 630, 631 forced expiration and choke point, 651
Rescue medications, 610 home respiratory care, 649
Residual functional capacity (RFC), 18 hospital level, 649
Residual volume (RV), 87 instrumental physical therapy techniques
Respimat®, 640 bronchial hygiene electromechanical devices, 657
Respiration, definition of, 169 bronchial hygiene, mechanical devices for, 656,
Respiratory compromise, 515 657
Respiratory difficulty, 175 cough assistance, mechanical devices for, 657,
Respiratory diseases in South America, 1–4 658
international networks and agreements, 3 mechanical lung expansion devices, 656
mixed-content programs, 2 manual physical therapy techniques
noninvasive ventilation for patients, 2 forced expiration technique (FET), 653–655
training programs, 1 postural drainage, 653
Respiratory distress syndrome (RDS) thoracic percussion (clapping), 653
differential diagnosis, 357 thoracic vibration, 653
grunting, 358 non-conventional physiotherapy, 650
hyaline membrane disease, 361–364 primary health care, 649
laboratory tests, 359 speed of the bronchial drainage, 650
maternal history, 357 therapeutic intervention
meconium aspiration, 360, 361 level of compromise, 652
neonatal chest X-ray, 359 level of cooperation, 652
newborn history, 358 physiopathological disorder, 652
oligohydramnios, 357 two-phase flow, 652
physical examination, 358 Respiratory physiotherapy techniques (RKT), 458
polyhydramnios, 357 Respiratory polygraph (PR) systems, 141, 142
risk factors, 356 Respiratory sleep disorders (RSDs), 201, 249
stridor, 358 asthma, 202
symptoms, 356 classification, 201
Respiratory exacerbations, 380 poor dental occlusion, 202
Respiratory failure, 757 rhinitis, 202
anatomical classification of types and causes, 170 type vs. type II, 202
with arterial hypoxemia, 677 Respiratory syncytial virus (RSV), 49, 264, 268, 274,
clinical symptoms, 172, 173 478
definition of, 169 clinical manifestations, 290, 291
diagnosis, 173, 174 epidemiology, 284, 285
physiopathology, 170 investigation, 284
hypoventilation, 171, 172 lower respiratory tract infections, 284
shunting, 172 microbiology
ventilation/perfusion alterations, 170, 171 CysLT, 288–290
signs of, 196 epithelial cell infection, 287
treatment, 173 glycoproteins, 286
airway, 173, 175 immune response, 287, 288
respiration, 175, 176 mastocytes, 288, 289
Respiratory frequency (RF), 21, 31, 175 neuroimmune interactions, 288
Respiratory gases in blood, 24–27 Paramyxoviridae virus, 285, 286
Respiratory infections, epidemiology subgroups, 286
bacterial infections (see Bacterial respiratory viral replication, 286
infections) outbreaks, 265
human population scale, 263, 264 pathogenesis and physiopathology, 285
viral infections (see Viral respiratory infections) physiopathological effects, 285
Respiratory insufficiency, see Respiratory failure prevention
Respiratory kinesiotherapy, 251 breastfeeding, 294
Index 803

handwashing, 294 Rigid endoscopy, airway with

immunoprophylaxis, 294–297 advantages, 163
transmission, 285 bronchoscopes, 164, 165
treatment complications
antibiotics, 293 edema during recovery from anesthesia, 166
antileukotriene therapy, 294 excessive injury to subglottis, 166
antivirals, 292 hemorrhaging, 166
bronchodilators, 291, 292 loss of control of airway, 166
combination therapy, 292 pneumothorax, 167
heliox, 294 recognize abnormalities, failure to, 167
hypertonic saline solution, 293 teeth/gums, injury to, 166
inhaled steroids, 292 documentation and teaching, 165
pharmacological interventions, 291 anesthesia, 165
rhDNase, 293 bronchoscope, 166
support measures, 291 laryngoscopy, 165, 166
surfactant, 293, 294 history, 161, 162
systemic steroids, 292 indications for, 163
vaccine against, 284 laryngoscopes, 164
Respiratory syndromes, 267 patient, assessment of, 162
Respiratory system, development of chronic airway symptoms, 162
alveolar development, 5 rapid beginning, 162
bronchial circulation, 8 severity of symptoms, 162
lung development, 12 symptoms and signs of airway
active hyperplasia, 6 obstruction, 162, 163
alveolar stage, 6, 8 Rituximab, 770, 772
canalicular stage, 6, 7 Rounded pneumonia, 303
developmental anomalies, 11
embryonic stage, 6, 7
fetal respiration and pulmonary fluid, 11, 13 S
genetic control of, 10 Saccharine tast, 433
hypertrophy, 6 Salbutamol, 637
microvascular maturation, 6 Sandifer syndrome, 45
nutrition, 14 Scoliosis, NMDs, 251
peristaltic contractions, 13, 14 Secondary immunodeficiencies (SID), 502
postnatal growth, 8 Secondary pneumothorax, 573
prenatal and postnatal factors, 11–13 causes of, 572
pseudoglandular stage, 6, 7 Secondary spontaneous pneumothorax, 573
saccular stage, 6–8 incidence of, 571
steroids, 14 treatment, 576
lung volume/body weight index, 9, 10 Segmental stenosis, 547
lung weight/body weight ratio (LW/BW), 9 Segmented empyema, 326
respiratory mechanics, 9 Seldinger technique, 333
Respiratory virus infections, 274 Selective outcome reporting bias, 630
vigilance, 273, 274 Self-care theory, 607, 608
Resting metabolic rate (RMR), 580, 581 Self-control measures (warning system), 611
Restrictive chronic lung allograft dysfunction Semen analysis, 447
(R-CLAD), 772 Semiautomatic hemoculture, 522
Resuscitation, 176 Semi-synthetic penicillin, 460
Retinitis pigmentosa, 64, 65 Sensenbrenner, 63
Retinoic acid, 10 Serine/threonine–type receptors, 10
Rheumatoid arthritis, 772 Serum antigen detection, 304
Rhinoconjunctivitis, 394 Severe acute respiratory syndrome (SARS), 266, 337
Rhinopharyngeal assessment, 181 Severe combined immunodeficiencies (SCID), 507, 508
Ribavirin, 292, 640 Short-acting beta-2 agonists (SABA), 419
Rifabutin, 462, 524 Shuttle walking test (SWT), 663
Rifampicin, 462, 521, 522, 524 Sickle cell anemia
Right aortic arch (RAA), 547 definition of, 530
Right-sided pneumonia with parapneumonic pleural physiopathology, 531
effusions, 123 pulmonary problems associated with, 532
804 Index

Sickle cell disease (SCD) at 12 months, 136

acute chest syndrome (ACS), 532–535 in young adults, 136
airway hyperreactivity, 536 Sleep obstructive apnea, 537
asthma, 536, 537 Sleep paralysis, 45
chronic pulmonary disease, 538 Sleep patterns of newborns and premature newborns, 40
clinical manifestations, 532 Sleep, physiological evolution of
definition of, 529, 530 academic performance, 44
epidemiology, 530 adolescents, 43, 44
etiology, 530, 532 education, 37
hypoxemia, 537 fetal stage, 38, 39
lung function anomalies, 535, 536 infancy, 41, 42
lung hypertension, 538–540 newborns, 39–41
physiopathology, 530, 532 premature newborns, 39, 40
sleep obstructive apnea, 537 preschool children and older infants, 42
thromboembolism, 538 risk factors, 44
Sickle cell trait, 530 schoolchildren and neuronal plasticity, 42, 43
Sildenafil, 540 specific sleep-associated symptoms, 45
Síndrome cardiopulmonar por hantavirus (SCPH), 339 Sleep routines, 38
Single- and multiple-occlusion techniques, 78 Sleep units, 202
Sirolimus, 767 Sleepwalking, 45
Situs inversus, 430 Slow expiration with glottis opened in lateral posture
Sivan video score, 140 (ELTGOL), 654
Six-minute walk (6MWT) test, 101, 662, 663 Slow progressors, 519
Sleep apnea, 137 Slow-sleep-wave activity, 42
Sleep apnea–hypopnea syndrome (SAHS), 140 Slow-wave non-rapid-eye-movement sleep, 43
Sleep-disordered breathing (SDB), 486 Slow-wave sleep, 39
Sleep disorders, 38, 42 Snoring
age and development, 38 diagnosis, 202, 203
domestic video, 139 prevalence, 201
family history of, 137 risk factors, 202
history and anamnesis, 38 Soft mist inhaler, 640
prevalence of, 38 Somnambulism, 45
sleep hygiene, self-care in, 614, 615 Sonic hedgehog (SHH), 10
in adolescence, 617 Spinal muscular atrophy (SMA), 246
between 2 and 5 years of age, 616, 617 Spirometry, 19, 80, 81, 88, 89, 94, 249, 250
from 11 years of age, 617 flow/volume loops, 98, 99
first months of life, 615 maximum voluntary ventilation (MVV), 99, 100
starting at 6 months of age, 616 pulmonary function in schoolchildren and
starting at 12 months of age, 616 adolescents, 86, 87, 89
starting at 18 months of age, 616 static pulmonary volume, measurement of, 98, 100
Sleep fragmentation, 487 volumes and flows of forced expirations, 98
Sleep in newborns to adolescents, 135, 136 Spontaneous pneumothorax, 573
beginning at 2–3 months of age, 136 incidence of, 571
between 6 and 10 years, 136 treatment, 575
diagnosis Ssleep breathing disorders (SBDs), see Respiratory sleep
actigraph/actimeter, 138, 139 disorders (RSDs)
actigraphy, 138 Staphylococcus aureus, 306, 324
anamnesis, 137 community-acquired strains, 325
complete physical exploration, 137 methicillin-resistant community, 333
complimentary test, 141 Static lung volume measurement, 91, 92
domestic video, 139, 140 Static pressures, 102
sleep diary, 138, 139 Statin therapy, 773
sleep duration percentiles, 138 Stenotrophomonas maltophilia, 462
sleep scales/questionnaires, 140, 141 Steroids, 14, 463, 465, 472, 482, 534, 610, 637, 646
functions of sleep, 136 asthma exacerbation treatment, 420
at intrauterine stage, 136 Stokes number (Stk), 635, 636
in newborns and 3-month-old infants, 136 Storz bronchoscopy with zero-degree optics, 165
NREM sleep, 136 Streptococcus pneumoniae (SP), 269–271, 306, 312, 324,
REM sleep, 136 325
at 2 years, 136 antibiotics, 329
Index 805

Streptococcus viridans, 306 risk of bias, 630

Streptomycin, 522, 523 selection criteria and evaluation of studies
Stridor reproducible, 629
inspiratory, 275 systematic error or bias, 630
intensity, 276 Systemic arterial hypertension, 378, 490
nebulization, 278 Systemic erythematosus lupus (SLE), 511, 513, 514
physical examination, 36 Systemic juvenile idiopathic arthritis, 515
Westley score, 275 Systemic lupus erythematosus, 218
Subcostal retraction, 32 Systemic steroids, 292
Subcutaneous immunotherapy, 390 Systemic vasculitis syndromes, 512
Subglottic hemangioma, 114, 728
Subglottic obstruction, 717
Subglottic stenosis, 158, 564, 565, 726, 727 T
Subtractive hybridization (SSH), 57 Tachypnea, 31, 302
Sudden infant death syndrome (SIDS), 495 Tacrolimus, 767
epidemiology, 496 Technetium-99 m-labeled colloid albumin test, 433
etiology, 496 Telescopes, 164–166
prevention and approach, 499, 500 Tension/time index (ITT), 104
risk factors, 497 Tertiary prevention, 391
risk factors and clinical presentation, 496, 497 Theophyllines, 13, 365, 426, 563
ALTE, 499 Thoracentesis, 328, 329
in Chile, 497 Thoracic blockage, 655
maternal breastfeeding, 498 Thoracic compression, 655
pacifier, 497 Thoracic decompression, 655
smoking, 497 Thoracic expansion exercises, 654
sudden infant death rate, 498 Thoracic insufficiency syndrome, 744, 745
vaccines, 497 Thoracic percussion (clapping), 653
Supraglottoplasty, 545 Thoracic trauma, 577
Suprasternal retraction, 32 classification of, 577
Surfactant, 293, 294 pulmonary contusion, 577
Surfactant deficiency syndromes Thoracic vibration, 653
adenosine triphosphate binding cassette protein Thoracic wall and pulmonary hypoplasia, 65
member A3 (ABCA3) deficiency, 764 Thoracotomy
contraindications, 764 history, 741, 742
diagnosis, 764 technique, 742
indications, 764 Thorax trauma, computerized axial tomography scan,
Surfactant protein C deficiency, 764 575
Suspension laryngoscopy, 166 ThresholdPEP®, 656
Sustained maximal inspiratory pressure (SMIP), 665 Thrombocytopenia, 533
Swallow disorders, 563, 564 Thromboembolism, 538
Sweat glands, 444 Thyroid transcription factor gene, 764
Sweat test, 446 Tidal volume (TV), 87
concentration of electrolytes, factors affecting, 446 Time constant (TC), 686
false-negative, 446 Time limit test, 665
high electrolytes levels, pathologies, 446 Timethroprim, 462
Macroduct device, 445 Tissue hypoxia without hypoxemia, 677
practical considerations for, 446 Tissue repair, 52
warning, 445 TNF receptor-associated periodic syndrome (TRAPS),
Swyer–James/MacLeod syndrome, 478 515
Synchronized intermittent mandatory ventilation Tobramycin, 57, 459, 461, 640
(SIMV), 689 Tolerable upper intake level (UL) for protein, 587
Systematic reviews (SR), 629, 630 Toll-like receptors, 48, 49
confidence in their estimates, 629 Tonicity, 634
confidence on estimate, 630 Tonsillar hypertrophy, 138
confidence value, 631 Total daily energy expenditure (TDEE), 580, 581
credibility, 629 Total lung capacity (TLC), 87, 98
critical analysis of, 631 Total lymphoid irradiation, 773
level of confidence, 630 Tracé discontinue, 39
random error, 630 Tracheal fistula on the innominate artery, 720
reporting/publication bias, 630 Tracheal granulomas, 719
806 Index

Tracheal obstruction, 256 adult-type tuberculosis, 346, 347

Tracheal stenosis, 546, 547, 719, 729–731, 734 anti-TB drugs, adverse reaction, 352, 353
Tracheobronchitis, 217 bacteriology, 344
Tracheoesophageal fistula, 159, 358, 719 with bronchogenic dissemination, 346
Tracheomalacia (TM), 157, 545, 719, 729, 731 clinical manifestations, 345
chest physiotherapy, 546 diagnosis
diagnosis, 546 clinician suspects, 348
predisposing factors, 546 IGRAS assays, 349, 350
primary or congenital, 545 PPD test, 348, 349
secondary, 546 disseminated presentations
stent support tracheal devices, 546 connatal tuberculosis, 348
symptoms of, 546 meningoencephalitis, 347, 348
Tracheomalacia-bronchomalacia, 729 miliary tuberculosis, 347
aortopexy, 729 epidemiology, 344
stents, 729 etiology and pathophysiology, 344, 345
Tracheoplasty, 547 pediatric, 344
Tracheotomy, 159, 703, 705 pulmonary disease, 345, 346
anatomy, 716 pulmonary infection, 345
care, 720 transmission, 344
cannula change, 721 treatment
fixation, 721, 722 adjunct drugs, 352
inhaling discharges, 721 BCG vaccination, 350
phonation, 722 chemoprophylaxis, 350
stoma and skin, 720 disseminated tuberculosis, 352
thermal humidifying, 721 exposure, 351
complications, 718 extrapulmonary tuberculosis, 352
decannulation, 722 HIV coinfections, 352
definition, 715 negative bacteriology, 352
early complications, 718, 719 newborns, 351
history, 715 positive bacteriology, 352
indications, 716, 717 scheme, 351
late complications, 719, 720 simple primary complex, 351
tube selection, 717, 718 Tuberculosis bacillus, 344
characteristic of tracheotomy cannulas, 718 Tuberculous meningitis, 347, 348, 352
fenestrations, 717 Tucson Children’s Respiratory Study (TCRS), 401
internal cannula, 717 Type I and II Chiari malformations, 707
by material, 717 Type 2 helper T cell (Th2) response, 48
simple/double tube, 717 Type III laryngotracheal cleft, 731
Transcutaneous measurement of oxygen saturation, 128, Typical sleep-specific sleep disorders, 137
129 Typical stridor, 544
Transcutaneous oxygen (TCPO2) measurement, 132, 133
Transdiaphragmatic pressure (TDP), 103
Transforming growth factor beta, 10 U
Transient hypogammaglobulinemia of infancy, 506 Ultrasonic nebulizers, 639
Transient Tachypnea of the Newborn, 365 Upper airway, 110, 156, 443, 487
Transsternal bilateral anterior thoracotomy, 766 Upper airway cough syndrome (UACS), 179
Treacher collins syndrome, 491 Upper airway obstruction (UAO), 156
Tregs (Regulatory T lymphocytes), 50, 67 Upper airway resistance syndrome, 486
Treprostinil, 540 Upper airway stability, 706
Trimethoprim, 580 Upper and lower respiratory tract infections, 524
Trimethoprim sulfamethoxazole (TMP-SMX), 462, 520, Uvulopalatopharyngoplasty, 494
526
Tripdatabase, 625
Triple risk model, 496 V
Troleandomycin, 644 Valganciclovir, 525
Trypsin, 562 Valsalva maneuver, 572, 573
Tube obstruction, 719 Van de Kamer test, 446
Tuberculin test (PPD), 521 Vancomycin, 461, 462
Tuberculosis (TB), 521–523 Vas deferens, 444
adenitis, 346 Vascular endothelial growth factor, 10
Index 807

Vascular rings (VR), 112, 113, 547–549 upper respiratory tract infections, 264
Vascular shunt, 676 vaccines and antivirals, 265–266
Vasculitis, 511 viral monitoring, 265, 266
Vasculogenesis, 7, 10 winter plan, epidemiological
Vasculopathy, 516 management, 268–270
Vaso-occlusive crisis (VOC), 530, 532, 533, 537 Virological diagnosis, 145
Velocardiofacial syndrome, 508 accelerated cultures, 146
Ventilating bronchoscopes, 164–166 immunochromatography, 146, 147
Ventilation/perfusion (V/Q) ratio, 23, 24 immunofluorescence, 146
Ventilation–perfusion mismatch, 676 molecular biology, 147, 148
Ventilation with support pressure or assisted pressure, viral cultures, 145
690 Vital capacity (VC), 87, 246
Ventilometry, 104 Vital forced capacity (VFC), 536
Vertical Expandable Prosthetic Titanium Rib (VEPTR), Volume assist-control ventilation (ACV), 708, 709
747 Volutrauma, 374
Video-assisted thoracoscopy surgery (VATS), 573, 577 von Willebrand disease, 217
Videothoracoscopy, 742 Voriconazole, 239, 469, 526
anesthetic considerations, 743 VX-770, 58, 59
indications, 742 VX-809 (lumacaftor), 58
preoperative evaluation, 743
Viral infections, 51, 117, 119, 145, 179
cytomegalovirus, 524 W
diagnosis, 524 Water requirements, 587
lung infections, 238 Waterlow index, 585
pathogens, 524 Wegener granulomatosis, 218
prophylaxis, 525 Wescor Sweat-Chek analyzer, 445–446
treatment, 525 Westley score, 275, 276
Viral laryngotracheobronchitis (LTB), 193–195 Wheezing, 35, 36, 302
Viral panel, 146 natural progression, 401
Viral pneumonia, 757 phenotypes, 401–404
Viral respiratory infections, 502 Wheezing bronchitis, 66
ARIs, 264 Wheezing episodes, 209, 398
causes of disease, 264, 265 Wheezing in preschool children, 65, 66
characteristics, 265 Whooping cough, incidence, 271
clinical manifestations, 264 Wiskott–Aldrich syndrome, 506, 509–511
emergent infections, 266, 267 Wright respirometer, 104
lower respiratory tract infections, 264
parainfluenza virus outbreaks, 265
pathogeny X
antivirals, 268 X-linked agammaglobulinemia, 504
clinical and epidemiological concepts, 268 Xpert MTB/RIF assay, 350
clinical and epidemiological consequences, 268
infection source, 267
respiratory syndromes, 267 Z
upper respiratory mucosa, 267 Zidovudine (AZT), 518
predominant viruses, 265 Ziehl–Neelsen stain, 149, 349
prevention, 268 Zoonotic influenza, 339
target organ, 264