09-Pediatrics in Review, September2009 PDF

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contents
PediatricsinReview Vol.30 No.9 September 2009

Articles
Asthma Epidemiology, Pathophysiology,
and Initial Evaluation
331
337 Thinking About HIV Infection
350 Coping With Death
357 Index of Suspicion
Vanessa L. Hill, Pamela Runge Wood
Evelyn P. Simpkins, George K. Siberry, Nancy Hutton
Jennifer S. Linebarger, Olle Jane Z. Sahler, Kelsey A. Egan
Case 1: Daniel H. Reirden

Case 2: Alexandra N. Menchise, Brian Knox, Rani Gereige
Case 3: Tamara Howard, Erica L. Thomas, Rosina Connelly
Case 4: Sarah Tyler, Katie McPeak
364 Research and Statistics:
Cohort Studies
Raquel G. Hernandez, Peter C. Rowe
371 Pediatrics in the Community:
Bulletproof: Using Media as a Tool for Advocacy

Alexander Zusman, Tricia Michels Tayama
In Brief
Parental Monitoring and
Discipline in Middle Childhood
366
368 Cholelithiasis and Cholecystitis
369 Clarification
Internet-Only Article
Abstract appears on page 370.
e66 The Floppy Infant:

e77 Cover Art Contest
Evaluation of Hypotonia
Dawn E. Peredo, Mark C. Hannibal
The printing and production of Pediatrics in Review is

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Cover: The artwork on the cover of this months issue is

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Answer Key:
1. D; 2. A; 3. B; 4. E; 5. B; 6. B; 7. D; 8. B; 9. E;
10. B; 11. E; 12. E
Asthma Epidemiology, Pathophysiology, and Initial Evaluation

Vanessa L. Hill and Pamela Runge Wood
Pediatr. Rev. 2009;30;331-336
DOI: 10.1542/pir.30-9-331
The online version of this article, along with updated information and services, is
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Article
allergy & immunology
Asthma Epidemiology, Pathophysiology, and

Initial Evaluation
Vanessa L. Hill, MD,*
Pamela Runge Wood,
MD
Author Disclosure
Objectives
1.
2.
3.
4.
After completing this article, readers should be able to:
Describe the underlying pathophysiology of asthma.

Discuss the role of atopy in the development of asthma.
Identify risk factors for death from asthma.
List conditions to be considered in the differential diagnosis of wheezing in children.
Drs Hill and Wood

have disclosed no
financial relationships
relevant to this
article. This
commentary does not
contain a discussion
of an unapproved/
investigative use of a
commercial
product/device.
Introduction
Asthma is a disease of airway inflammation characterized by hyperresponsiveness and
airflow obstruction that lead to symptoms such as cough and wheezing (Fig. 1). Childhood asthma continues to cause significant morbidity and burden in the United States.
This article reviews the pathophysiology, epidemiology, and recommendations for initial
evaluation of asthma. Recommendations are based on the 2007 Expert Panel Report 3:
Guidelines for the Diagnosis and Management of Asthma (2007 Guidelines). (1)
Epidemiology
Prevalence and Burden of Disease
The prevalence of asthma rose steadily from 1980 until the late 1990s, when it reached a
plateau. In 2007, 9% of children 0 to 17 years of age (6.7 million children) had asthma,
according to data from the National Health Interview Survey. The lifetime prevalence of
asthma in children is 13%. (2)
The burden of disease in the United States from pediatric asthma is alarming, according
to a recent report based on national surveys. In 2003, 12.8 million days of missed school
were attributed to asthma. In 2004, hospitalizations for asthma totaled 198,000 or 3% of
all pediatric admissions. Asthma resulted in 750,000 emergency department (ED) visits in
that same year (2.8% of all pediatric ED visits). Although children ages 0 to 4 years of
age represent only a small proportion of the total asthma population, they account for a
sizeable proportion of the hospitalizations and ED visits. (3)
Natural History
The natural history of asthma is variable. Most individuals who develop chronic asthma,
measured by a decrease in lung function and persistence of symptoms, have a genetic
predisposition. In addition, exposure of the airway epithelium to environmental insults in
such susceptible individuals contributes to the development, severity, and persistence of
asthma.
The Tucson Childrens Respiratory Study, a longitudinal
community-based study of 1,246 children who were followed from birth until early adulthood, provides data on the
Abbreviations
natural history of respiratory disease in children. (4) Data
from this study show that wheezing in the first 3 years after
ED: emergency department
birth often is associated with a lower respiratory tract infecFEV1: forced expiratory volume in 1 second
tion, most commonly respiratory syncytial virus (RSV).
Ig:
immunoglobulin
Thirty-two percent of all children have wheezing with acute
IL:
interleukin
lower respiratory tract infections in the first year after birth,
RSV: respiratory syncytial virus
17% in the second year, and 12% in the third year. More than
Th: T-helper
80% of infants who have a history of wheezing in the first
VCD: vocal cord dysfunction
postnatal year do not wheeze after age 3 years.
*Assistant Professor of Pediatrics.
Clinical Professor of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Tex.
Pediatrics in Review Vol.30 No.9 September 2009 331
asthma epidemiology, pathophysiology, evaluation
2004, the mortality rate from

asthma was 2.5 per 1 million children for a total of 186 deaths per
year. Therefore, it is crucial to identify children at risk of death from
asthma. In general, the rate of
death from asthma is higher in severe, uncontrolled disease. Specific
risk factors include: one or more
life-threatening exacerbations of
asthma, severe asthma requiring
chronic oral corticosteroids, poor
control of daily asthma symptoms
requiring frequent short-acting
beta2 agonist medication, abnormal forced expiratory volume in
1 second (FEV1), frequent ED
visits, low socioeconomic status,
family dysfunction, and patient
psychological problems. (6)
Racial disparities are significant
in asthma. Prevalence rates for
asthma are highest among Puerto
Rican and African American children. Compared with white chilFigure 1. Mechanisms underlying the clinical symptoms of asthma. Adapted from the dren, African American children
National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for have higher rates of ED visits but
the Diagnosis and Management of Asthma. 2007.
lower outpatient and ambulatory
visits. African American children
The investigators also identified three distinct wheezcontinue to have higher rates of mortality than other
ing phenotypes that occur during childhood. Transient
children, despite a downward trend in overall asthma
wheezers are those infants whose wheezing is associated
mortality rates. (3) Such disparity reflects limited access
with one or more lower respiratory tract infections and
to outpatient health services compared with other chilwho cease to wheeze after 3 years of age. Nonatopic
dren. (7)
wheezers are children who have relatively more reactive airways, a higher incidence of previous RSV infecPathophysiology
tion, and persistent wheezing after age 3 years, which may
Inherent to asthma is airway inflammation that is mediresolve over time. Atopic wheezers are the group of
ated by a variety of cell subtypes, resulting in hyperchildren who are most likely to develop persistent asthma.
responsive airways, ultimately limiting airflow and causing
They have higher immunoglobulin E (IgE) concentrations,
variable symptoms. Initial airway bronchoconstriction is
are prone to allergen-mediated airway hyperresponsivefollowed by airway edema and exaggerated mucus proness, and have more profound lung function deficits at an
duction, accompanied by airway hyperresponsiveness,
early age compared with nonatopic wheezers. In genand followed by chronic changes in the airway epithelium
eral, 60% of children who have asthma are symptom-free
(airway remodeling). Current medical management tarby adulthood. However, only 5% to 30% of children who
gets various points along this continuum. However, no
have severe asthma or asthma associated with atopy outclear evidence suggests that early or aggressive treatment
grow their asthma by adulthood. (5)
with anti-inflammatory medications, such as inhaled corticosteroids, can prevent airway remodeling.
Mortality and Health Disparities
Airway inflammation is mediated by a variety of cytoAlthough mortality rates have fallen since 1999, asthma
kines and chemokines (cytokines that are specific for
remains a preventable cause of death in children. In
chemotaxis and activation of leukocytes). Cytokines are
332 Pediatrics in Review Vol.30 No.9 September 2009
produced by a number of cell types, including lymphocytes, eosinophils, and mast cells. Proinflammatory cytokines (interleukin-4 [IL-4], IL-5, and IL-13), produced
primarily by the T-helper (Th)2 lymphocytes, are believed to trigger the intense inflammation of allergic
asthma. An imbalance between Th1 and Th2 lymphocytes (specifically, decreased Th1 activity with increased
Th2 activity) contributes to chronic inflammatory
asthma. Chemokines play a key role in inflammation.
These proteins recruit proinflammatory cells, including
Th2 lymphocytes, mast cells, neutrophils, and eosinophils. Eosinophils and mast cells have a distinct role in
asthma pathogenesis. These cell types produce proinflammatory cytokines as well as leukotrienes, which cause
bronchoconstriction.
The airway epithelium is a target for infectious, noxious, and environmental insults that cause injury via
influx of proinflammatory cells and cytokines (Fig. 2).
Both viral infections and airborne allergens can precipitate a biphasic response that ultimately leads to asthma
symptoms. IgE plays a pivotal role in this process, as
shown by evidence that administration of anti-IgE
monoclonal antibodies reduces asthma symptoms and
improves lung function. (8) The IgE-mediated earlyphase or immediate response to an allergen challenge
causes mast cells and basophils to degranulate, precipitating bronchospasm as well as the release of proinflammatory cytokines and chemokines. This cascade of inflammatory responses results in the subsequent latephase obstruction of air flow, which occurs 4 to 12
hours following exposure to the environmental insult.

Bronchodilators can relax airway smooth muscle, if administered during the initial period of bronchospasm.
However, due to the increased airway hyperresponsiveness and inflammation that occur with the late-phase
response, bronchodilator therapy is not as effective, and
anti-inflammatory medication is required.
Asthma also is characterized on a cellular level by
structural alterations in the airway epithelium. Airway
remodeling can occur and is associated with the following changes in the underlying structural components of
the epithelium: mucous gland hyperplasia, thickening
of the epithelial basement membrane, fibrotic changes in
the sub-basement membrane, bronchial smooth muscle
hypertrophy, and eventually angiogenesis.
Clinical Aspects
Asthma is characterized by intermittent, recurrent symptoms of airway obstruction that is at least partially reversible. Common symptoms include cough (which may
be the only symptom), wheezing, difficulty breathing,
and chest tightness. Nighttime symptoms are common. In addition, symptoms often occur or worsen in the
presence of common asthma triggers, such as exercise,
changes in the weather, viral respiratory infections, and
exposure to allergens or airway irritants (eg, environmental tobacco smoke). To diagnose asthma, the physician
must exclude other conditions. The diagnosis may be
particularly difficult in very young children because
wheezing is common in early childhood and many diseases can cause symptoms similar to
those seen in asthma.
Evaluation
Figure 2. Cellular mechanisms involved in airway inflammation. ILinterleukin,
IgEimmunoglobulin E, LTB4leukotriene B4. From the National Asthma Education and

Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management
of Asthma. 1997.
Initial evaluation should begin with

a detailed medical history, including the pattern of symptoms
and observed precipitating factors
(asthma triggers). Past medical history should include information
about risk factors for asthma (particularly atopy), prior exacerbations, treatments used, and their
effects. A positive family history of
parental asthma substantially increases the risk of asthma in a child.
Evaluation also should include an
assessment of the impact of asthma
on the child and family. The physical examination of a child who has
asthma often yields normal findPediatrics in Review Vol.30 No.9 September 2009 333
ings, although there may be signs of atopy, such as

eczema or allergic rhinitis, which are strongly associated
with asthma.
The 2007 Guidelines recommend objective measurement of pulmonary function (spirometry) as part of the
initial evaluation. Most children older than age 6 or 7
years are capable of performing a forced expiratory maneuver, if coached by an experienced technician. Some
centers can test children as young as 5 years of age.
Spirometry should be performed before and after administration of a short-acting bronchodilator. FEV1 that
increases by 12% or more following the administration
of bronchodilators indicates reversible airway obstruction, even if baseline FEV1 is normal. Spirometry results
may be normal, particularly in children who have mild
asthma. Baseline chest radiography may be useful to rule
out other conditions, particularly in very young children
or in patients manifesting atypical signs and symptoms.
Differential Diagnosis
The differential diagnosis of asthma is broad and includes
upper airway disease as well as obstruction of large airways and other causes of small airway obstruction. Upper
airway disease, such as allergic rhinitis or sinusitis, can
cause recurrent coughing, particularly at night, but often
has other signs or symptoms that help distinguish it from
asthma. Extrinsic or intrinsic obstruction of the large
airways (eg, tracheomalacia, vascular ring, mass, or foreign body) may present with signs and symptoms similar
to those of asthma. Specific findings, such as a change in
airway symptoms with position or failure of symptoms to
respond to usual asthma treatment, may be helpful in the
diagnosis. Individuals who have ingested a foreign body
often have a history of acute onset of symptoms following a choking episode, but this history is more difficult to
elicit in very young children. Recurrent aspiration or
gastroesophageal reflux also can result in recurrent bouts
of coughing or other respiratory symptoms that might
be confused with asthma. A careful history that examines
the pattern of symptoms and looks for evidence of
risk factors for reflux or aspiration, such as prematurity,
feeding difficulties, or neurologic impairment, may be
helpful.
Vocal cord dysfunction (VCD) presents with wheezing or breathlessness associated with paradoxic vocal
cord adduction during inspiration and may be difficult to
distinguish clinically from asthma. Although VCD is a
distinct diagnosis, it also may coexist with asthma and
complicate its management. VCD, which is more common in adolescents and young adults, does not respond
to asthma medications and, therefore, should be in334 Pediatrics in Review Vol.30 No.9 September 2009
cluded in the differential diagnosis of atypical or difficultto-control asthma. The diagnosis may be suspected
based on clinical history and spirometry that shows a
flattened inspiratory loop. Definitive diagnosis usually is
made by a specialist and based on viewing of the vocal
cords during an episode.
A number of conditions that cause obstruction of the
small airways may result in wheezing or other symptoms
similar to those found in asthma. These include bronchiolitis, cystic fibrosis, congestive heart failure, and chronic
lung disease of prematurity. Recurrent episodes of bronchiolitis may occur in young children and sometimes are
difficult to distinguish from asthma. A detailed past medical history and careful physical examination often help to
distinguish the latter three conditions from asthma.
Asthma is particularly difficult to diagnose in infants
and toddlers. Recurrent wheezing episodes are common
in young children. Data from the Tucson Childrens
Respiratory Study showed that almost 50% of children
have at least one wheezing episode prior to age 6 years; in
most of these children, the wheezing is transient and
resolves prior to age 6 years. (4) These data were used to
build a risk index for asthma in young children. Specifically, children experiencing four or more episodes of
wheezing per year that last more than 1 day and affect
sleep are likely to develop asthma if they also have one
of the following major risk factors: 1) parental history of
asthma, 2) atopic dermatitis, and 3) sensitization to
aeroallergens or two of the following minor risk factors:
1) sensitization to foods, 2) more than 4% eosinophilia,
or 3) wheezing apart from colds. According to the 2007
Guidelines, the young child who has a positive risk index
is at a high risk of developing asthma and should be
started on anti-inflammatory therapy.
In summary, asthma cannot be diagnosed based on a
single episode of wheezing, but rather requires observation of the pattern of symptoms over time. Individuals
manifesting atypical signs and symptoms or clinical
asthma that does not respond to asthma medications may
Summary
The prevalence of asthma and the burden of disease
remain high, despite efforts to improve public
awareness about and medical management of
asthma.
Asthma is a disease of airway inflammation that has
a variable natural history.
Atopy is the most important risk factor for the
development of asthma.
require additional diagnostic studies (eg, specialized imaging of the chest or bronchoscopy) and referral to a
pulmonary specialist for additional evaluation.
NOTE. An article on the management of asthma will
be published in next months issue of Pediatrics in
Review.
References
1. National Asthma Education and Prevention Program. Expert
Panel Report 3: Guidelines for the Diagnosis and Management of
Asthma. Full Report 2007. NIH Publication 07-4051. Bethesda,
Md: National Heart, Lung, and Blood Institute; 2007. Available at:
http://www.nhlbi.nih.gov/guidelines/asthma/. Accessed June 2009
2. Bloom B, Cohen RA. Summary health statistics for U.S. children: National Health Interview Survey, 2007. National Center for
Health Statistics. Vital Health Stat. 2009;10(239). Available at:
www.cdc.gov/nchs/nhis.htm. Accessed June 2009
3. Akinbami LJ. The state of childhood asthma, United States,

1980 2005. Advance Data from Vital and Health Statistics; No
381. Hyattsville, Md: National Center for Health Statistics; 2006.
Available at: http://www.cdc.gov/nchs/data/ad/ad381.pdf. Accessed June 2009
4. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ,
Martinez FD. Tucson Childrens Respiratory Study: 1980 to
present. J Allergy Clin Immunol. 2003;111:661 675
5. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma
Study: 1964 1999. J Allergy Clin Immunol. 2001;109:189 194
6. Strunk RC. The fatality-prone asthmatic child and adolescent.
Immunol Allergy Clin North Am. 1998;18:8597
7. McDaniel M, Paxson C, Waldfogel J. Racial disparities in childhood asthma in the United States: evidence from the National
Health Interview Survey, 1997 to 2003. Pediatrics. 2006;117:
e868 e877
8. Busse W, Corren J, Lanier BQ, et al. Omalizumab, antiIgE recombinant humanized monoclonal antibody for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:
184 190
PIR Quiz
Quiz also available online at pedsinreview.aappublications.org.
1. An 11-month-old boy presents with fever, runny nose, and difficulty breathing for 1 day. Physical
examination shows an axillary temperature of 37.8C, respiratory rate of 32 breaths/min, and heart rate of
110 beats/min. Diffuse expiratory wheezes are audible bilaterally. He had similar illness 2 months ago. The
mother is concerned about her son developing asthma during his childhood. Which of the following is the
most appropriate response to her concerns about her son?
A. If he has two more episodes of wheezing during the next year, his chances of having asthma during
childhood are greater than 80%.
B. If he responds to bronchodilators such as albuterol, there is a greater than 80% risk that he will have
asthma during childhood.
C. If the respiratory infection is due to RSV, he should have less than a 20% risk of developing asthma
during childhood.
D. More than 80% of infants who have a history of wheezing after respiratory infection in the first
postnatal year do not wheeze after age 3 years.
E. More than 80% of infants younger than 1 year of age who have respiratory tract infections wheeze
during their illness.
2. A 3-year-old boy who has a previous history of allergic rhinitis and eczema presents to your office with
cough and wheezing for 2 days. The symptoms started after he visited his uncles house and played with a
cat. Which of the following statements about his current state is true?
A. Airway inflammation has occurred due to action of cytokines and chemokines.
B. Airway remodeling has occurred, characterized by mucous gland hyperplasia and bronchial smooth
muscle hypertrophy.
C. Current illness represents the early phase of mast cell activation, causing bronchospasm.
D. Eosinophils have been activated by IgE, causing IL-4 release.
E. Th1 lymphocyte activation by IgA has caused airway hyperreactivity.
3. A 6-year-old girl is brought in for evaluation of nighttime cough and wheezing after being exposed to
secondhand smoke. A pulmonary function test (PFT) using a forced expiratory maneuver to display a flowvolume curve is ordered. Which of the following statements is most accurate regarding PFT in this
situation?
A. Flattening of the inspiratory portion of the flow volume loop and decreased forced vital capacity
suggest the presence of asthma.
B. Increase in FEV1 by at least 12% after administration of a bronchodilator is indicative of asthma.
C. Normal PFT indicates that the patient does not have airway hyperresponsiveness and, therefore, retesting
with a bronchodilator is unnecessary.
D. PFT assessment in those younger than age 8 years is unreliable due to lack of patient cooperation.
E. PFT should be performed after challenging the patient with secondhand smoke and retesting after
administration of a bronchodilator.
4. A 15-year-old girl who has a known history of asthma is hospitalized for exacerbations of cough,
wheezing, and shortness of breath. Her asthma has become increasingly unresponsive to bronchodilators
and corticosteroids in the past 5 years. Flow-volume loop using a forced expiratory maneuver shows
flattening of the inspiratory loop. Flexible fiberoptic laryngoscopy shows adduction of vocal cords and
narrowing of the subglottic area during inspiration. Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Laryngomalacia.
Subglottic hemangioma.
Subglottic stenosis.
Tethered vocal cord.
Vocal cord dysfunction.
Find it in September NeoReviews

The American Academy of Pediatrics online neonatology journal at http://
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Thrombocytopenia in the Neonatal Intensive Care UnitSaxonhouse/
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Immune-mediated Neutropenia in the NeonateBlack/Maheshwari
Preeclampsia and Neonatal NeutropeniaMoallem/Koenig
Index of Suspicion in the NurseryArevalo/Wetzel/Cabrera
Strip of the Month: September 2009 Druzin/Peterson
Asthma Epidemiology, Pathophysiology, and Initial Evaluation

Vanessa L. Hill and Pamela Runge Wood
Pediatr. Rev. 2009;30;331-336
DOI: 10.1542/pir.30-9-331
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Thinking About HIV Infection

Evelyn P. Simpkins, George K. Siberry and Nancy Hutton
Pediatr. Rev. 2009;30;337-349
DOI: 10.1542/pir.30-9-337
Article
infectious diseases

Evelyn P. Simpkins, MD,*
George K. Siberry, MD,
MPH, Nancy Hutton,
MD
Author Disclosure
Drs Simpkins, Siberry,
and Hutton have
disclosed no financial
Objectives
1. Recognize the important role that the general pediatrician plays in the prevention,
detection, and care of human immunodeficiency virus (HIV)-infected and -affected
patients.
2. Select the proper HIV testing plan for pediatric and adolescent patients based on age,
history, and physical assessment.
3. List the clinical conditions suggestive of HIV infection.
4. Provide counseling to reduce risk behaviors as part of routine adolescent health care.
5. Discuss comprehensive primary care for HIV-exposed infants.
relationships relevant
to this article. This
commentary does not
of an unapproved/
commercial
product/device.
Case Studies
Case Study 1
A 20-year-old woman, who is a recent emigrant from Ethiopia, brings in her 4-month-old
infant for a health supervision visit. The baby has had no immunizations, and his mother
reports having had no prenatal care. She is breastfeeding exclusively. The infants 25-year-old
father recently died after being very sick for 2 years. The mother states that he had bad lungs.
What are your next steps?
Case Study 2
A 17-year-old honor student comes to your office with a maculopapular rash on his face, trunk,
palms, and soles. He also complains of a sore throat and fever and states that he recently
returned from visiting his grandmother in Georgia. During his visit, he went hunting with his
uncles and his grandmothers dog. During the interview, which involves asking routine
psychosocial questions in a nonthreatening manner (Table 1) to elicit sensitive information, he
states that he has been sexually active with women for 2 years
and with men for 6 months. He does not use condoms with
either. He denies any contacts with sick persons or substance
Abbreviations
abuse, including injection drug use (IDU). What are your
next steps?
AIDS: acquired immunodeficiency syndrome
CCR5:
CD4:
EIA:
HIV:
IDU:
MMR:
mRNA:
MTCT:
NNRTI:
NRTI:
OI:
PCP:
PCR:
PI:
chemokine coreceptor 5
a glycoprotein on the surface of T helper cells
enzyme-linked immunoassay
human immunodeficiency virus
injection drug use
measles-mumps-rubella
messenger RNA
mother-to-child transmission
non-nucleoside reverse transcriptase inhibitor
nucleoside reverse transcriptase inhibitor
opportunistic infection
Pneumocystis jiroveci pneumonia
polymerase chain reaction
protease inhibitor
Introduction
The epidemiology, diagnosis, prevention, and treatment of
HIV infection and acquired immunodeficiency syndrome
(AIDS) in the pediatric and adolescent population have
changed dramatically over the past 25 years. In countries that
have good resources, such as the United States, rates of new
infections in infants have plummeted with the implementation of effective screening and prevention strategies. Children born with HIV early in the epidemic now are surviving
into young adulthood, facing unpredicted challenges and
opportunities in their physical health and social and emotional well-being. Todays adolescents are acquiring HIV at
an alarming rate. The role of the pediatrician varies with the
type of practice, the prevalence of HIV in the local commu-
*Fellow in Adolescent Medicine, Division of General Pediatrics & Adolescent Medicine.
Assistant Professor of Pediatrics, Division of General Pediatrics & Adolescent Medicine & Division of Infectious Diseases.
Associate Professor of Pediatrics, Division of General Pediatrics & Adolescent Medicine, Johns Hopkins University School of
Medicine, Baltimore, Md.
infectious diseases
HIV infection
HEEADSSS* Interview for

Adolescents
The Pediatricians Role in

HIV Care
Home
Education and employment
Eating
Activities
Drugs
Sexuality
Suicide/depression
Safety
Health Maintenance Care
Table 1.
*The mnemonic HEEADSSS reminds the clinician of important aspects of an adolescents life that require inquiry. Sensitive information
should be elicited in a nonthreatening manner.
Table 2.
HIV-exposed newborns
Immunizations
Growth and nutritional status
Neurodevelopment
Acute and Chronic Illness Care
Clinical syndromes suggestive of underlying HIV
infection
Common problems in HIV-infected infants, children,
and adolescents
Collaboration With HIV Specialist
nity, and the ease of access to HIV specialty care and

consultation. All pediatricians should be prepared to
provide care for HIV-exposed newborns and their siblings, to screen for and diagnose HIV infection in children and adolescents, and to provide routine HIV prevention counseling to adolescents. Many pediatricians
provide primary care for HIV-infected children and adolescents in collaboration with HIV specialists (Table 2).
Epidemiology
Worldwide, 33.2 million people live with HIV infection,
2.5 million of whom are children younger than 15 years
of age. In 2007, 2.1 million AIDS deaths occurred, of
whom 330,000 were children. In the United States,
2,181 cases of AIDS were reported among children and
adolescents through age 24 years for the year 2006. Only
38 of these cases were in children younger than the age of
13 years, a sharp and steady reduction from the early
1990s when nearly 1,000 children annually were reported as having AIDS. Clearly, the pediatric burden
of infection and disease now rests in the adolescent
population. Many children who had HIV at birth in the
1980s and early 1990s now are adolescents and young
adults living with HIV/AIDS. In addition, the number
of new cases of AIDS reported is increasing in all age
categories within the 13- to 24-year-old population.
Despite widespread availability of HIV testing and effective treatment, it is estimated that 25% of people living
with HIV/AIDS do not know that they are infected, a
proportion that increases to nearly 50% for infected
adolescents.
Pathogenesis
Understanding the basics of the HIV viral life cycle can
help pediatricians to employ HIV laboratory tests confi338 Pediatrics in Review Vol.30 No.9 September 2009
Evaluation and staging

Antiretroviral treatment
Prevention of opportunistic infections
Counseling and Support
Primary and secondary HIV prevention
Coping with diagnosis and prognosis
Adherence with care and treatment
School and sports participation
Transition to adult health care
Advance care planning and palliative care
Universal PrecautionsStandard Precautions
dently and to understand the current approach to HIV

prevention and treatment. HIV is a lentivirus in the
retrovirus family. Susceptible hosts are infected when the
virus enters the body and binds to CD4 receptors on host
T lymphocytes. Through a complex process of specific
HIV glycoprotein binding to host T-lymphocyte CD4
receptor and chemokine coreceptor 5 (CCR5) coreceptors, HIV fuses its envelope with the lymphocyte cell
membrane. Viral RNA and enzymes such as reverse
transcriptase enter the host cell, and the viral RNA is
reverse transcribed into DNA. Viral DNA then enters the
nucleus of the host cell and is integrated into the cellular
genome.
When the host cell is activated, transcription takes
place, allowing viral DNA to be converted to genomic
and messenger RNA (mRNA). mRNA is translated into
viral proteins that combine with copies of genomic RNA
to become complete virions that subsequently are released from the host cell. The cycle of infection, replication, and release continues rapidly in the newly infected
host, creating billions of virions per day.
This initial viremic phase precedes antibody response
infectious diseases
and is the period of highest infectivity due to the very

high viral load. During this time, dissemination of the
virus in the body and seeding of lymphoid organs is
widespread. The newly infected person may experience
acute retroviral syndrome, characterized by fever, lymphadenopathy, rash, myalgia, arthralgia, headache, diarrhea, oral ulcers, leukopenia, thrombocytopenia, and
transaminitis. During this window period between
host cell infection and host antibody response, an infected person has a negative HIV antibody test result, but
HIV RNA testing results are positive. Seroconversion,
the demonstrated presence of HIV antibody, may occur
as early as 10 to 14 days after infection but usually occurs
within 3 or 4 weeks. Nearly all patients seroconvert
within 6 months of acquiring the infection. Infection
with HIV is lifelong because HIV infects long-lived
memory T cells.
Preventing HIV Transmission to Children and

Adolescents
HIV infection is transmitted by two principal modes in
the pediatric age group: mother-to-child and behavioral.
Mother-to-child transmission (MTCT) can occur antepartum through transplacental transfer; intrapartum
through exposure to maternal blood, amniotic fluid, and
cervicovaginal secretions during delivery; and postpartum through breastfeeding. MTCT is preventable in
almost all cases by the proper use of combination antiretroviral therapy to achieve an undetectable viral load in
the mother, intrapartum maternal zidovudine, neonatal
zidovudine, and safe replacement infant feeding.
In addition, elective cesarean section prior to the
onset of labor can reduce MTCT risk in women who
have persistent viremia due to lack of or ineffective antiretroviral therapy during pregnancy. In the United
States, MTCT now occurs in fewer than 2% of births to
HIV-positive women, a decrease from 25% in nonbreastfed infants prior to the routine use of antiretroviral
therapy for the prevention of MTCT. It is important to
remember that some infected infants escaped detection
early in the United States epidemic and now are being
identified as new cases in the adolescent age group.
Adolescents are exposed to HIV through risky behaviors that involve the exchange of infected blood or semen, such as unprotected sex (homosexual and heterosexual) or injection drug use with sharing of needles or
syringes. Factors that increase the risk of sexual transmission include traumatic sex (voluntary or involuntary), in
which the genital, anal, or oral epithelium is compromised (with those reporting receptive anal sex at highest
risk); active genital ulcer disease in either partner; and
HIV infection
(for females) douching before sex. Adolescent females

are at even higher risk than adult women of acquiring
sexually transmitted infections, including HIV, because
of the presence and vulnerability of the cervical ectropion, an area of endocolumnar cells on the ectocervix
that regresses into the endocervical canal as the adolescent matures. Behaviors that increase the likelihood of an
adolescent male or female being exposed to an HIVpositive sexual partner include exchanging sex for money
or drugs, having multiple sex partners, and using recreational drugs, including alcohol.
Studies of discordant partnerships (one person has
HIV infection, the other does not) reveal that consistent
and correct use of condoms made of latex, polyurethane,
or other synthetic materials offers a high degree of protection from HIV and other sexually transmitted infections spread by the exchange of body fluids (as opposed
to infections spread by direct contact with lesions, such as
herpes simplex).
Testing for HIV Infection: Who, What,

When?
The Tests
Several laboratory tests are approved for screening and
diagnosing HIV infection (Table 3). The pediatrician
must select the correct test based on the patients age and
the clinical indication (Table 4). Most commercially
available tests detect HIV antibody. For patients older
than age 18 months, the confirmed presence of antibody
to HIV is diagnostic of HIV infection. Standard HIV
antibody testing is performed on a blood specimen in
two steps: screening enzyme-linked immunoassay (EIA)
is performed and if reactive, a confirmatory test such as
Western blot is performed. Both steps must be positive
for the overall test result to be reported as positive.
Table 3.
HIV Tests
Antibody Tests in Laboratories

Enzyme-linked immunosorbent assay
Western blot
Immunofluorescence assay
Antibody Tests in Clinical Settings (Rapid Tests)
Blood
Saliva
Viral Detection Tests in Laboratories
DNA polymerase chain reaction (PCR) (qualitative)
RNA PCR (quantitative)
infectious diseases
Table 4.
HIV infection
HIV Screening and Diagnostic Testing
Who
What
When
Pregnant women
HIV-exposed newborns
Children of HIV mother
Adolescents
Antibody
DNA PCR
Antibody
Antibody*
Antibody
Clinical suspicion
Antibody**
Prenatal enrollment; repeat in third trimester

Optional at birth; 2 to 3 weeks, 1 to 2 months, at or after 4 months
Optional after age 12 months to confirm seronegativity
No maximum age
Single screen at/after age 13 years; repeat annually if sexually active
or injecting drugs
Any age if clinical presentation is suggestive of underlying HIV
infection
*Use infant testing algorithm if antibody-positive and younger than age 18 months.
**Use additional HIV RNA testing if clinical presentation is suggestive of acute retroviral syndrome
PCRpolymerase chain reaction
Newer rapid tests also detect antibody; they are performed on blood or saliva and allow the clinician to
provide a result to a patient in approximately 20 minutes.
Positive screening results must be confirmed by standard
antibody testing. Specific HIV viral detection using
DNA or RNA polymerase chain reaction (PCR) is necessary in two clinical situations when antibody testing is
nondiagnostic: in infants of HIV-infected mothers and in
patients of any age who are suspected of having acute or
early HIV infection. All infants born to HIV-positive
mothers test positive for HIV antibody due to the transfer of maternal immunoglobulin across the placenta;
HIV DNA or RNA PCR identifies those who have true
HIV infection. Older children and adolescents who have
symptoms of acute retroviral syndrome may not yet have
detectable HIV antibody; HIV RNA PCR is a sensitive
test for early HIV infection. A definitive diagnosis of HIV
infection requires that two different specimens test positive (eg, in children older than 18 months, two antibody
tests or one antibody one RNA) using appropriate
techniques based on the age of the patient and the
clinical indication.
Counseling and Consent

National HIV testing guidelines recommend counseling
and testing as a routine part of regular medical care in
addition to continued efforts to reach out to individuals
at higher risk. The goal is to identify all HIV-positive
individuals, engage them in HIV care for their own
health, and reduce the transmission of HIV to others.
Clear, understandable information about the benefits of
HIV testing should be provided in a manner that protects patient privacy and provides emotional support as
needed. Key messages include that: 1) HIV infection is a
treatable condition, 2) HIV infection is a serious health
condition, 3) early detection of HIV infection permits
early treatment to prevent disease progression and maintain health, and 4) people who have HIV infection can
prevent its transmission to others. The opt-out counseling approach informs patients that HIV testing will be
performed as part of their routine care unless they decline, reducing barriers associated with mandatory prevention counseling and written consent. Adolescents in
the United States can seek confidential testing and treatment for HIV independently, although family support is
encouraged.
Parents or guardians seek care on behalf of infants and
children. Children should be included in developmentally appropriate discussions about care. Anticipating the
need for HIV disclosure to the child is an important
component of the pediatric counseling process. Helping
adult caregivers understand the importance of sharing
simple and truthful information provides a strong foundation for later disclosure. The indication for diagnostic
testing may help frame the conversation (eg, mother is
HIV-positive, sibling is HIV-positive, child has worrisome clinical findings). Counseling messages include:
All ages: Inform child that a blood test will be performed, give simple details of the procedure, help choose
a coping strategy, and offer comfort.
4 to 6 years of age: I am worried that you keep
getting sick. I need to do a blood test to help me figure
out why.
getting sick. I wonder if your immune system, the part of
your body that fights off infections, isnt working the way
it should. I want to do blood tests to help me figure this
out.
getting sick. I wonder if your immune system, the part of
your body that fights off infections, isnt working the way
it should. I want to do blood tests to help me figure this
infectious diseases
out. One of the tests looks for HIV. Have you ever heard
of that?
The most important guideline is never lie. Partial
truthfulness can be supplemented at later visits or at older
ages. Deliberate misinformation, even under the guise of
protecting the child, leads to loss of trust and is very
difficult to undo.
Screening Pregnant Women

Universal HIV counseling and voluntary HIV testing
using an opt-out approach is the recommended standard
of care for all pregnant women in the United States. This
practice provides the opportunity for HIV-positive
women to access HIV care for their own health and to
prevent HIV transmission to their babies. The opt-out
approach informs all pregnant women receiving care that
an HIV test will be performed unless she opposes testing.
Initial testing is performed early in pregnancy. Repeat
testing is recommended in the third trimester (before
36 weeks gestation) for women who live in high HIV
prevalence areas or for women who have specific highrisk factors (exchange sex for money or drugs, IDU,
sexual partner who engages in IDU, new diagnosis of
sexually transmitted infection during pregnancy).
For women who have not received prenatal care,
intrapartum testing should be offered by using rapid test
kits or expedited EIA. Mothers who decline screening at
any of these opportunities should be offered testing again
at every opportunity, including rapid antibody testing in
the immediate postpartum period. Practitioners also can
offer rapid antibody testing of newborns as an indicator
of HIV exposure when the mothers status cannot be
determined. In most cases, maternal consent is needed
for testing newborns, but some states allow testing of
high-risk newborns without consent.
Testing HIV-Exposed Infants

Infants born to HIV-positive mothers should undergo
specific diagnostic testing; HIV DNA or RNA PCR
should be used as part of their health maintenance care.
Testing is recommended at age 14 to 21 days, at 1 to 2
months, and again at 4 to 6 months. Due to the low
sensitivity of tests in the first 48 hours after birth, testing
is optional at birth. If performed, blood samples from the
umbilical cord should not be used because of possible
contamination with maternal blood. In nonbreastfed
infants, the sensitivity of HIV DNA PCR increases to
93% by 14 days of age. By 28 days, the sensitivity increases to 96% and the specificity is 99%. Sensitivity and
specificity of the HIV RNA assay are similar. Any positive
test requires repeat confirmatory testing as soon as pos-
HIV infection
sible. Some practitioners use HIV DNA PCR for initial

testing and HIV RNA assay for confirmatory testing.
HIV infection is reasonably excluded when results of
two virologic tests are negative, the first at 14 days or
older and the second at 1 month of age or older. Definitive exclusion requires negative results for two virologic
tests, the first at age 1 month or older and the second at
4 months of age or older. In older infants for whom early
testing was not performed, an alternate strategy is to
confirm the absence of HIV antibody. If infection already has been excluded definitively, HIV antibody testing between 12 and 18 months of age to confirm the loss
of maternal antibody is optional.
Breastfeeding causes continued HIV exposure and is
not recommended in the United States where safe replacement (formula) feeding can be provided. Testing
should continue throughout the period of breastfeeding
and for 6 months after cessation when an infant is breastfed.
Testing Children and Adolescents

HIV antibody tests are used for screening and diagnosis
in children older than age 18 months. All children of
HIV-positive mothers should be screened for HIV infection regardless of age or healthy appearance. Children or
adolescents who present with clinical conditions suggestive of HIV infection should undergo HIV testing as part
of the diagnostic evaluation, regardless of risk history.
All adolescents should be offered HIV testing as part
of routine health care. Annual testing is recommended
for those at high risk of acquiring HIV infection. Rapid
tests offer the advantage of providing test results at the
same visit. HIV-negative individuals can be reassured
and counseled to avoid future HIV exposure. HIVpositive individuals can be engaged immediately into
care and support.
If a practitioner suspects acute infection or acute
retroviral syndrome, he or she should order HIV antibody and nucleic acid testing (HIV RNA) to look for
evidence of infection. A positive nucleic acid test result in
the presence of a negative or indeterminate antibody test
result is consistent with acute HIV infection. Antibody
testing is recommended 10 to 12 weeks later to confirm
seroconversion.
Evaluation and Staging of the HIV-Positive

Patient
Patients who have positive HIV test results should be
referred to an HIV specialist for comprehensive evaluation (Table 5) so the clinical and immunologic stage of
disease can be assessed and treatment recommended.
infectious diseases
HIV infection
Initial evaluation of an HIV-infected pediatric patient

should include the mothers medical history, childs
medical history, family history, and social history. A comprehensive physical examination should be performed
and documented, including a developmental evaluation.
Assessment of HIV-infected adolescent patients (generally, 11 years of age and older), as for all adolescents,
should include a sexual history, substance use history,
and sexual maturity staging.
Initial laboratory testing in an HIV-positive patient
should include CD4 percentage and absolute cell counts,
plasma HIV RNA concentration (viral load), HIV genotype to assess for baseline resistance mutations, complete
blood count with differential count, serum chemistries
with liver and renal function tests, a lipid profile, and
urinalysis. For children younger than 5 years of age, CD4
percentage is the preferred test for monitoring immune
status because the absolute CD4 cell count (number of
CD4 cells/mm3) in this age group varies with agerelated changes in absolute lymphocyte count. Screening
for hepatitis B and C infection as well as for tuberculosis
is recommended for all HIV-infected patients. In addition, sexually active adolescents should be screened for
Chlamydia infection, gonorrhea, syphilis, and human
Table 5.
Evaluation and Staging
History
Physical Assessment
Laboratory Assessment
Confirm HIV infection
HIV RNA (viral load)
HIV resistance profile (genotype)
CD4 percentage and absolute count
Complete blood count with differential count
Chemistry panel (liver transaminases, bilirubin,
electrolytes, urea nitrogen, creatinine, calcium,
phosphorus, glucose, cholesterol, triglycerides,
amylase, lipase)
Coinfections: cytomegalovirus, Toxoplasma, hepatitis
B and C, varicella
Urinalysis (dipstick and microscopic)
Tuberculin skin test
In sexually active individuals, screen for gonorrhea,
Chlamydia infection, syphilis
Consider chest radiography, electrocardiography, dualenergy x-ray absorptiometry scan for bone mineral
density
papillomavirus infections. In contrast to the guidelines

for cervical cancer screening in healthy women, cervical
Papanicolaou smears are indicated routinely in all sexually active, HIV-infected adolescent girls, with colposcopy recommended for evaluation of abnormal results.
Similarly, most experts perform anal Pap smears in HIVinfected adolescent men who have sex with men and
HIV-infected sexually active women; anoscopy is recommended for evaluation of abnormal results.
HIV infection is a multisystem disease; clinical manifestations range from asymptomatic to complications
affecting virtually every organ system (Table 6). The
Centers for Disease Control and Prevention classification
system designates clinical categories based on the patients medical history and immunologic function categories based on CD4 percentage (Table 7). This information permits an estimated risk for future morbidity
and mortality and provides a rationale for instituting
specific opportunistic infection prophylaxis and initiating
or deferring antiretroviral therapy.
HIV-specific Treatment
Antiretroviral Therapy
The goal of anti-HIV therapy is to maximize the quality
and longevity of life through:
Complete suppression of viral replication (goal of nondetectable viral load)

Preservation or restoration of immunologic function
(goal of normal CD4 percentage or count)
Prevention of or improvement in clinical disease (goal
of asymptomatic state)
National treatment guidelines for HIV-infected children

and adolescents are updated routinely and are available on
the Internet (http://www.aidsinfo.nih.gov/Guidelines/).
Current recommendations are summarized in the text and
in Table 8. The pediatric treatment guidelines updated in
2008 recommend antiretroviral treatment for all infected
infants (12 months old); simplifies treatment initiation
recommendations into three age categories (12 months
old, 1 to 4 years old, and 5 years old) instead of four;
places greater emphasis on simplified, age-based CD4
thresholds for treatment initiation than on viral load; and is
consistent with adult guidelines for initiation of antiretroviral treatment in children 5 years of age and older. Clinical
and immune statuses are key predictors of morbidity and
mortality and form the basis for these recommendations.
Viral load is more useful for monitoring adherence and
effectiveness of therapy than as an indicator of when to
initiate antiretroviral therapy.
Treatment is recommended for: AIDS or severe symp-
infectious diseases
Table 6.
HIV infection
Relative Frequency of Clinical Conditions in Untreated HIV Infection

Relative Frequency
Body System or Illness Category*
Specific Conditions
Common
Infections: recurrent, severe, or

unusual (opportunistic)
Recurrent or chronic otitis, sinusitis

Recurrent or severe pneumonia
Recurrent or severe bacteremia
Opportunistic infections, such as PCP, MAC, invasive candidal
infections
Generalized lymphadenopathy
Hepatomegaly
Splenomegaly
Parotid enlargement
Lymphoid interstitial pneumonitis
Failure to thrive
Weight loss, wasting
Stunting
Delayed puberty
Neurodevelopmental delay or regression
Abnormal tone (increased or decreased)
Gait disturbance
Peripheral neuropathy
Stroke
Bacterial pneumonia
Lymphoid interstitial pneumonitis
Bronchiectasis
Pneumothorax
Cardiomyopathy
Pericardial effusion
Conduction abnormalities
Hypertension
Vasculopathy
Gastritis
Duodenitis
Hepatitis
Pancreatitis
Cholecystitis
Diarrhea
Gastrointestinal bleeding
Abdominal pain
Proteinuria
Renal tubular acidosis
Renal failure
Hypertension
Anemia
Neutropenia
Thrombocytopenia
Seborrhea
Eczema
Urticaria
Zoster
Herpes simplex infections
Tinea corporis, capitis, unguium
Bacterial infections
Molluscum contagiosum
Warts (HPV)
HPV-related dysplasia (cervical, anal)
Pelvic inflammatory disease
Delayed puberty
C
C
C
C
Lymphoreticular system
Growth
Neurologic
Pulmonary
Cardiovascular
Gastrointestinal
Renal
Hematologic
Dermatologic
Genital/Reproductive
Uncommon
C
C
C
C
C
C
C
C
C
C
C
C
U
U
C
C
U
U
U
U
U
U
U
C
C
U
U
U
C
U
C
C
U
U
U
C
C
C
C
C
U
C
C
C
C
C
C
C
C
C
*Some conditions belong to more than one category. HPVhuman papillomavirus, MACMycobacterium avium complex, PCPPneumocystis jiroveci
pneumonia
infectious diseases
Table 7.
HIV infection
HIV Clinical Classification System
Clinical Categories
N
A
B
C
Immune Categories
1
2
3
No symptoms*
Mild symptoms (eg, generalized
lymphadenopathy)
Moderate-to-severe symptoms
(eg, thrombocytopenia)
AIDS-defining conditions (eg,
Pneumocystis jiroveci
pneumonia)
CD4 >25%
CD4 15% to 24%
CD4 <15%
Normal
Moderate suppression
Severe suppression
*Class N in pediatric classification system only (children 13 years of age)
toms, CD4 percentage of less than 25% (1 to 4 years) or

absolute CD4 count of less than 350 cells/mm3 (5 years
and older) regardless of symptoms, all infected infants
younger than 12 months of age, and all pregnant adolescents.
Treatment is considered for: patients whose HIV
RNA is more than 100,000 copies/mL and who have
mild or absent symptoms and adequate CD4 cells (CD4
percentage of more than 25% [1 to 4 years] or absolute
CD4 count of more than 350 cells/mm3 [5 years and
older]).
Treatment can be deferred for: mild or absent symptoms and adequate CD4 values (CD4 percentage of
more than 25% [1 to 4 years] or absolute CD4 count of
less than 350 cells/mm3 [5 years and older]) and RNA of
less than 100,000 copies/mL.
Antiretroviral therapy should be planned and moniTable 8.
tored in collaboration with an HIV

specialist. Strong evidence supports the use of triple-drug combination antiretroviral therapy to
maximize virologic response and
minimize the emergence of viral
resistance. Initial therapy consists
of three drugs from two categories: one non-nucleoside reverse
transcriptase inhibitor (NNRTI)
OR protease inhibitor (PI) PLUS
two nucleoside or nucleotide
reverse transcriptase inhibitors
(NRTIs).
Important issues to consider
when selecting specific drugs include:
Age, weight, sexual maturity stage of patient

Baseline HIV resistance pattern
Likelihood of developing resistance to selected drugs if
patient has difficulty adhering to the regimen (low
versus high barrier to resistance)
Likelihood of becoming pregnant while taking selected
drugs (eg, efavirenz)
Ease of administration (formulation, schedule, food
restrictions)
Planning treatment collaboratively with the patient

and family strengthens the therapeutic relationship and
promotes successful adherence and HIV control. Enlisting adult support in the home is beneficial regardless of
the patients age. Frequent clinical follow-up with viral
load testing allows the clinician to identify problems early
and help patients and families find successful solutions.
When to Initiate Antiretroviral Therapy

Children Older Than 1 Year of Age and Nonpregnant Adolescents
Immune Status
CD4 Percentage
(1 to 4 years old)
Absolute CD4 cell count
(5 years and older)
>25%
>350 cells/mm3
<25%
<350 cells/mm3
Infants <12
Months of
Age
Pregnant
Adolescents
TREAT
TREAT
TREAT
TREAT
N or A
(Asymptomatic or
Mild Symptoms)
B
(Moderate-to-severe
Symptoms)
C
(AIDS Conditions)
RNA
<100,000 copies/mL
DEFER
TREAT
TREAT
TREAT
TREAT
RNA
>100,000 copies/mL
CONSIDER
TREAT
infectious diseases
Patients in whom the virus shows no drug resistance and

in whom therapy is initiated with currently available
medicines should achieve a nondetectable viral load
within 3 to 6 months. Failure to achieve this goal
strongly suggests suboptimal adherence to the recommended regimen rather than viral resistance.
Once HIV infection is controlled on a stable regimen,
most patients are seen every 3 to 4 months for routine
monitoring of viral load, CD4 cell response, and clinical
status, including evaluation for potential medication adverse effects or toxicities. Patients who experience treatment failure have additional treatment options, including new drugs in existing classes (PIs, NNRTIs, NRTIs)
as well as new drug classes such as entry inhibitors (fusion
inhibitors and CCR5 antagonists) and integrase inhibitors.
Preventing Opportunistic Infections

The profound immunodeficiency caused by uncontrolled
HIV infection allows serious and life-threatening infections
to occur in children and adolescents. Evidence supports the
primary prevention of common opportunistic infections
(OIs) based on age and CD4 guidelines. Full recommendations are available at http://aidsinfo.nih.gov.
Pneumocystis jiroveci pneumonia (PCP) is the most
common OI. Cotrimoxazole is recommended for all
HIV-exposed infants until HIV infection is reasonably
excluded, for all HIV-infected infants until age 12
months, and for HIV-infected children and adolescents
older than 1 year of age whose CD4 values fall into the
severe immune suppression category (CD4 percentage
15% or CD4 count 200 cells/mm3).
Primary prevention of Mycobacterium avium complex
by using azithromycin or clarithromycin is recommended at lower CD4 values (6 years old with CD4
count of 50 cells/mm3; ages 2 to 5 years with CD4
count of 75 cells/mm3; 1 to 2 years with CD4 count of
500 cells/mm3; 1 year old with CD4 count of
750 cells/mm3).
Toxoplasmosis is less common in children than in
adults, but its prevention with daily cotrimoxazole is
recommended in HIV-infected children and adolescents
who are Toxoplasma immunoglobulin G-seropositive
and have severe immunosuppression (CD4 percentage
15% for children 6 years old; CD4 count 100 cells/
mm3 for children 6 years old).
Immunizations
The 2009 immunization schedule for HIV-exposed infants and for HIV-infected infants, children, and adolescents is the same as for their healthy peers, with only a few
HIV infection
exceptions. Patients who have severely symptomatic illness or CD4 percentages of less than 15% or CD4 counts
of less than 200 cells/mm3 should not receive measlesmumps-rubella (MMR) or varicella vaccines due to the
risk of opportunistic disease from the live attenuated
virus strains in the vaccines. HIV-infected children who
have higher CD4 counts should receive MMR and varicella separately, not as the combined MMR-V. The
higher titer of varicella in MMR-V has not been tested for
safety in HIV-infected children. Annual influenza immunization is recommended for all children older than age 6
months, but only the killed, injectable formulations of
the influenza vaccine are recommended for HIV-infected
children and adolescents.
HIV-infected children and adolescents need certain
additional vaccines and doses. Pneumococcal polysaccharide vaccine is recommended in addition to the regular pneumococcal conjugate vaccine series. Specific and
comprehensive recommendations for immunizations in
HIV-infected children, adolescents, and adults are available at http://aidsinfo.nih.gov/.
Counseling and Support

Primary and Secondary Prevention of HIV
Infection
Health education messages to avoid HIV infection and
to prevent its spread to others should be routine in every
pediatric and adolescent practice. It is important for
clinicians to be prepared to offer prevention counseling,
including abstinence and safe sex as best options for
preventing HIV transmission. Clinicians should be able
to teach all adolescents about correct use of male latex
condoms and emphasize that consistent use is essential
for prevention. Screening all patients ages 13 years and
older for HIV infection identifies asymptomatic patients
unaware of their HIV infection status, providing them
the opportunity to enroll in HIV-specific care for their
own benefit and to reduce the risk of transmitting HIV to
others. HIV-negative adolescents who engage in behaviors through which HIV can be transmitted should be
tested at least annually.
Coping With the Diagnosis and Prognosis

Learning of a new diagnosis of HIV infection for oneself
or ones child is emotionally devastating for most people.
While providing a listening ear and emotional support,
clinicians also can offer hope and reassurance about the
availability of effective treatment that can result in improved quality of life and survival for people living with
HIV infection in the United States. Referral to the HIV
infectious diseases
HIV infection
specialist allows prompt access to specific medical care

and psychosocial supports.
Disclosure of HIV Infection Status

HIV infection remains a stigmatizing diagnosis. Ignorance, misinformation, and fear in families and communities cause people living with HIV infection to keep
their status a secret. However, this practice has negative
consequences, such as isolating the HIV-positive individual from social support and risking additional spread of
HIV to sexual partners. Planned disclosure to family
members and friends can increase practical and emotional support for the HIV-positive person. Sexual partners can make informed decisions about how to protect
themselves from exposure to HIV.
In contrast to adolescents and adults, disclosure of
HIV status to children should be undertaken over time,
providing sequential pieces of practical health information that match the developmental capacity of the child.
This process builds a strong foundation for children to
participate meaningfully in their HIV care.
Adherence to Care and Treatment

Most people do not adhere to the treatment recommendations of their health-care practitioners all of the time.
Adolescence is a particularly vulnerable age for nonadherence in those who have chronic health conditions
such as HIV infection. Poor adherence leads to poor
health outcomes in many diseases such as asthma and
diabetes. However, HIV treatment is unique in its requirement for 90% to 100% adherence to drug regimens
to avoid the development of viral resistance and the loss
of future efficacy of anti-HIV drugs. The need for intensive education and support for children and adolescents
living with HIV infection cannot be overstated.
Transition to Adult Health Care

Children born with HIV infection in the United States
during the 1980s are now young adults. They continue
to be the pioneers who challenge our assumptions and
identify unmet needs for care and support services. No
one anticipated the current need to develop and implement programs to transition youth successfully to adult
HIV health-care clinicians. Practical concerns such as
transmitting a complete and coherent medical record
and psychological concerns such as the loss of long-term
supportive relationships must be addressed.
Advance Care Planning and Palliative Care

Advance care planning is recommended for all who live
with chronic and life-threatening conditions. HIVinfected parents should plan for the care of their dependent children. HIV-infected adolescents and young
adults should designate a person they trust to make
health-care decisions for them if they should become
unable to speak for themselves due to illness or injury.
One approach is to normalize this decision as part of
routine health care when reaching adulthood. This practice is particularly important for youth who have no
clearly identified next of kin, such as those who are
orphaned and have experienced sequential foster homes.
There continue to be patients who experience distressing medical complications of HIV infection that, if
not reversed, lead to death. Integrating palliative care
with HIV-specific care reduces distress by managing
specific physical and emotional symptoms, encouraging
clear communication, and promoting effective decisionmaking. This approach provides the best opportunity to
improve a patients quality of life regardless of how long
the patient survives.
Managing Potential HIV Exposure

School and Sports Participation
Children and adolescents who have HIV infection can
participate fully in the educational and extracurricular
activities in school. There is no obligation to notify
school personnel of a students HIV infection status. Any
sport may be played if the students health status allows.
For all athletes, regardless of HIV infection status, skin
lesions should be covered properly, and athletic personnel should use standard precautions when handling
blood or body fluids that have visible blood. Certain
high-contact sports (such as wrestling and boxing) may
create a situation that favors viral transmission (likely
bleeding plus skin breaks). Some experts advise athletes
who have a detectable viral load to avoid such highcontact sports.
The pediatrician may be called on to respond to questions about HIV exposure. Such questions may be about
occupational exposures, such as a needle stick injury to a
health-care worker, or nonoccupational, such as a child
finding a discarded needle and syringe or an adolescent
who is a victim of sexual assault. The basic approach to
any of these scenarios is to assess the likelihood that
exposure to potentially infectious fluids actually occurred, determine how severe or extensive the exposure
was, and evaluate the likelihood that the fluids are HIVcontaminated. If the exposure is of high risk and the
source is known to be HIV-infected, postexposure prophylaxis with antiretroviral drugs should begin as soon as
possible after the exposure, but no later than 72 hours.
Guidelines for evaluating risk and recommending post-
infectious diseases
exposure prophylaxis can be found at http://

aidsinfo.nih.gov.
Having a High Degree of Suspicion

In case study 1, the clinician is presented with a 4-monthold infant of immigrant African parents whose father died
as a young man with bad lungs and whose mother is
breastfeeding exclusively. The clinicians next steps include performing a careful history and physical examination to assess the infants growth and development and
to look for conditions suggestive of HIV infection. HIV
antibody testing should be recommended to the mother
for her own health and for planning the care of her baby.
If such testing cannot be arranged promptly, testing the
infant for HIV antibody would indicate the mothers
HIV infection status. If the mother is HIV antibodynegative and not engaging in risky behaviors, the infant
does not need additional HIV testing. However, if the
mother is HIV-positive, virologic testing of the infant
with HIV DNA or RNA PCR is indicated throughout
the period of breastfeeding and for 6 months after cessation. Counseling should be provided about the availability of safe and affordable formula feeding and prompt
weaning recommended. Age-appropriate immunizations should be administered and cotrimoxazole prescribed for PCP prophylaxis until HIV infection is
excluded.
Case study 2 involves a 17-year-old male who has a
rash, fever, and sore throat and recently has traveled to
Georgia, a trip that included a hunting trip. In addition,
the patient reports having sex with both females and
males and no condom use. The scenario leads to consideration of Rocky Mountain spotted fever in the differential diagnosis. However, it is important to remember that
acute retroviral syndrome in adolescents presents with
fever 96% of the time and both rash and pharyngitis 70%
of the time. Additional signs and symptoms include
lymphadenopathy, myalgia, arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, and
transaminase elevation. In this patient, HIV antibody
testing and HIV RNA testing are indicated as part of
the medical evaluation. Counseling should be provided to reduce the risk of sexually transmitted infections.
Conclusion
Although it is important to remember that HIV infection
is a multisystem disease requiring regular medical attention, including health maintenance care, it is equally
important to remember that some of the greatest chal-
HIV infection
lenges young people face have little to do with their

physical illness. Many are in the midst of social complexities that neither they nor their families can begin to
navigate without support. Despite these challenges,
HIV-positive young people are resilient, strong, caring,
appreciative, and worthy of our respect. They are our
teachers, presenting diagnostic, therapeutic, and psychosocial challenges that open new avenues for clinical investigation, stimulate our continuous professional development, and remind us of our core human values. They
lead the way as we strive to find better ways to manage
their illness and improve the quality of their lives.
Summary
Mother-to-child transmission of HIV can occur
during pregnancy, labor, delivery, and breastfeeding.
Evidence-based interventions (routine screening of
pregnant women, initiation of antiretroviral drugs
for mothers treatment or prevention of MTCT, and
avoiding breastfeeding) have reduced transmission
rates in the United States from 25% to 30% to less
than 2%.
Triple-drug combination antiretroviral therapy
effectively controls HIV infection and improves
survival and quality of life for HIV-infected children
and adolescents. Initial regimens use combinations
of two NRTIs together with an NNRTI or a ritonavirboosted PI. These regimens have been shown to
increase CD4 counts and achieve virologic
suppression.
Prevention of serious and opportunistic infections
reduces morbidity and mortality in children and
adolescents who have HIV infection. Recommendations
for immunizations and chemoprophylaxis vary with the
patients CD4 count.
Condoms made from latex, polyurethane, or other
synthetic materials have been shown to decrease the
transmission of STIs, including HIV infection.
Suggested Reading and Useful Websites

HIV Epidemiology
Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2006. Vol 18. Atlanta, Ga: United States
Department of Health and Human Services, Centers for Disease Control and Prevention; 2008:155. Available at: http://
www.cdc.gov/hiv/topics/surveillance/resources/reports/. Accessed June 2009
HIV Disease Classification

1994 revised classification system for human immunodeficiency
virus infection in children less than 13 years of age. MMWR
Recomm Rep. 1994;43(RR-12):110. Available at: http://
www.cdc.gov/MMWR/preview/MMWRhtml/00032890.htm.
Accessed June 2009
infectious diseases
HIV infection
1993 revised classification system for HIV infection and expanded

surveillance case definition for aids among adolescents and
adults. MMWR Recomm Rep. 1992;41(RR-17). Available at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.
htm. Accessed June 2009
National HIV Treatment and Prevention

Guidelines (http://aidsinfo.nih.gov):
Guidelines for the Use of Antiretroviral Agents in Pediatric HIV
Infection
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected
Adults and Adolescents
Public Health Service Task Force Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-Infected Women for
Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States
United States Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis
Management of Possible Sexual, Injection-Drug-Use, or Other
Nonoccupational Exposure to HIV, Including Considerations
Related to Antiretroviral Therapy
Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children
Incorporating HIV Prevention into the Medical Care of Persons
Living with HIV
Revised Recommendations for HIV Testing of Adults, Adolescents,
and Pregnant Women in Health-Care Settings
American Academy of Pediatrics Statements

Committee on Pediatric AIDS. Disclosure of illness status to children and adolescents with HIV infection. Pediatrics. 1999;103:
164 166
Committee on Pediatric AIDS. HIV testing and prophylaxis to
prevent mother-to-child transmission in the United States.
Pediatrics. 2008;122:11271134
Havens PL and Committee of Pediatric AIDS. Postexposure prophylaxis in children and adolescents for nonoccupational exposure to human immunodeficiency virus. Pediatrics. 2003;111:
14751489
Havens PL, Mofenson LM and the Committee on Pediatric AIDS.
Evaluation and management of the infant exposed to HIV-1 in
the United States. Pediatrics. 2009;123:175181
Read JS and the Committee on Pediatric AIDS. Diagnosis of HIV
infection in children under 18 months of age in the United
States. Pediatrics. 2007;120:e1547 e1562
Rice SG and the Council on Sports Medicine and Fitness. Medical
conditions affecting sports participation. Pediatrics. 2008;121:
841 848
National Palliative and Supportive Care

Guidelines
National Consensus Project for Quality Palliative Care. Clinical
Practice Guidelines for Quality Palliative Care. 2nd ed. Pittsburgh, Pa: National Consensus Project; 2009. Available at:
http://www.nationalconsensusproject.org. Accessed June
2009
ONeill JF, Selwyn PA, Schletinger H, eds. A Clinical Guide on
Supportive and Palliative Care for People with HIV/AIDS, 2003.
Available at: http://hab.hrsa.gov/tools/palliative/. Accessed
June 2009
infectious diseases
HIV infection
PIR Quiz
Quiz also available online at pedsinreviews.aappublications.org.
5. A Sudanese woman who is newly arrived in the United States is Western blot-positive for HIV and is in her
seventh month of pregnancy. Assuming she is begun on appropriate combination antiretroviral medications
and takes them as directed during the remainder of gestation, which of the following is the most
appropriate method of establishing the presence of HIV infection in her neonate?
A.
B.
C.
D.
E.
Measure
Measure
Measure
Measure
Measure
HIV DNA PCR in the infants cord blood.

HIV DNA PCR in the infants venous blood.
the HIV viral load in the mother.
the infants HIV antibody concentration.
the titer of HIV antibody in the mother.
6. An 18-year-old homosexual male presents with a history of fever, malaise, myalgia, and headache for the
past week. Your differential diagnosis includes HIV infection. Assuming this represents the acute retroviral
syndrome, you would expect to find which of the following sets of results on testing his blood?
A.
B.
C.
D.
E.
Negative HIV EIA, negative HIV RNA PCR.

Negative HIV EIA, positive HIV RNA PCR.
Positive HIV EIA, negative HIV RNA PCR.
Positive HIV EIA, negative Western blot.
Positive HIV EIA, positive Western blot.
7. Proper immunization of children who have HIV is imperative. An HIV-infected 12-month-old boy who has a
CD4 percentage of more than 25% should:
A.
B.
C.
D.
E.
Not receive the MMR vaccine.

Not receive the varicella vaccine.
Receive neither the MMR nor the varicella vaccine.
Receive separate varicella and MMR vaccines.
Receive the combined MMR-V vaccine.
8. You are conducting a health maintenance examination on a 15-year-old girl. As part of counseling her
about prevention of blood- and semen-borne sexually transmitted infections, your most correct statement
is that:
A.
B.
C.
D.
E.
Anal intercourse is the safest form of receptive sex.

Condoms, properly used, protect against HIV.
Douching before sex is useful in preventing HIV.
Adolescent girls have a lower risk of acquiring HIV through vaginal sex than do adult women.
HIV acquisition is not associated with fellatio.

Evelyn P. Simpkins, George K. Siberry and Nancy Hutton
Pediatr. Rev. 2009;30;337-349
DOI: 10.1542/pir.30-9-337
Updated Information
& Services


Infectious Diseases
http://pedsinreview.aappublications.org/cgi/collection/infectious
_diseases Fetus and Newborn Infant
http://pedsinreview.aappublications.org/cgi/collection/fetus_new
born_infant Adolescent Medicine/Gynecology
http://pedsinreview.aappublications.org/cgi/collection/adolescent
_medicine_gynecology Ethics for the Primary Care
Pediatrician
http://pedsinreview.aappublications.org/cgi/collection/ethics_pe
diatrician

Reprints

Coping With Death

Jennifer S. Linebarger, Olle Jane Z. Sahler and Kelsey A. Egan
Pediatr. Rev. 2009;30;350-356
DOI: 10.1542/pir.30-9-350
Article
psychosocial
Coping With Death

Jennifer S. Linebarger,
MD,* Olle Jane Z. Sahler,
MD, Kelsey A. Egan
Author Disclosure
Drs Linebarger and
Objectives
1.
2.
3.
4.
Describe a developmental approach to understanding death.

Know how to counsel a family or child facing death.
Recognize the spectrum of grief reactions, including complicated bereavement.
Understand the importance of communication skills and resources to use when dealing
with a family that must cope with death.
Sahler and Ms Egan

have disclosed no
financial relationships
Introduction
relevant to this
The death of a loved one is a time of powerful emotional upheaval. Infants, children,
adolescents, parents, and pediatricians all sense that power and respond in different, highly
personal ways. Through vignettes and discussion, this article addresses childrens cognitive
and behavioral approaches to death, the childs understanding of his or her own impending
death, and the response of families (including siblings) to the death of a child as well as
communication tools to help the pediatrician in each of these areas.
article. This
commentary does not
of an unapproved/
commercial
Cognitive and Behavioral Response to Death
product/device.
A mother brings her 4-year-old son to the office because she is concerned about his lack of
appetite over the past few days. During the interview, while you are asking about food, the boy
asks if Rover can eat. On further questioning, you learn that Rover, the family dog, died
1 week ago.
A childs understanding of death and expression of grief are influenced by his developmental level, his experiences with death, and the familys cultural and religious beliefs.
Chronologic age alone is not a reliable indicator but can serve as a starting point for
discussion, particularly in combination with psychologist Jean Piagets levels of cognitive
development (Table 1).
Children younger than 2 years of age are in the sensorimotor stage, using their senses
and developing motor skills to learn about the world. They are able to express feelings
through their behavior. Although children in this stage do not understand death, they can
sense both separation and the emotions of those around them who are experiencing loss.
In response, children may withdraw, decreasing their activity, responsiveness, or appetite,
or may become irritable.
During the preoperational stage from age 2 to 6 years, childrens cognitive understanding of death evolves, but they do not yet have the capability to think logically. Initially,
children use the word dead to mean not alive. They may confuse death with sleep or
being away and believe that death is temporary. They may wonder in what activities the
dead can still engage (Does Rover still eat?). They sense the sorrow of others and respond
by mimicking crying or being consoling. Because children in this stage lack full understanding of what can cause death and that death is irreversible, they may use magical
thinking or ask specific questions for which there may be no real answers.
Magical thinking, the belief that thoughts can cause actions, may lead to guilt and fear.
The boy in the scenario may believe that Rover is dead because he was mad at the dog
for eating his crayons. If the child appears to be wondering about what caused the death
and his potential role in it, it is important to provide reassurance with simple, straightforward explanations directed at correcting misconceptions.
*Division of Adolescent Medicine, Golisano Childrens Hospital, the University of Rochester Medical Center, Rochester, NY.
Professor of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Undergraduate Student, Cornell University, Ithaca, NY.
psychosocial
coping with death
Cognitive and Behavioral Aspects of Developing an Understanding

of Death
Table 1.
Age
Developmental Stage
(Piaget)
<2 years
Sensorimotor
2 to 6 years
Preoperational
6 to 10 years
Concrete operational
Adolescence
Formal operational
Perception or Concept
Anticipated Response
Sense separation and the emotions

of others
DeadNot alive
Death as temporary
Morbid interest in death
Others die 3 I die
Adult understanding
Existential implications
Withdrawal
Irritability
Wonder about what the dead do
Magical thinking
Exaggerated behavioral reactions to
the idea of death and dead things
Why not me?
Death as an adversary
The specific questions children ask stem from their

intense curiosity about death, even when they have not
personally experienced the death of someone they know
and love. Some children may ask repeatedly when a
deceased loved one is coming back. These questions are
part of the struggle for consistency and understanding of
the permanence of death.
As children move into the concrete operational stage
around age 6 years, they develop logical thinking about
the physical world and become more verbally communicative about their thoughts. An almost morbid interest
in dead things, the symbols of death (eg, graveyards or
skeletons), and the biologic aspects of death may develop. By this age, children recognize that death is final.
Possibly because of this realization, grieving children can
have heightened behavioral reactions. Children may develop school phobias, hypochondriacal concerns, aggressive and destructive behaviors, withdrawal, or separation
anxiety. Throughout this stage, children move from
thinking that death only happens to others (especially
older people) to an awareness that they, too, will die. By
the age of 9 or 10 years, childrens use of the word
dead approximates adult understanding of the term
as final, universal, and potentially happening to them.
However, their actual level of awareness of the concept of
death varies greatly and is especially dependent on their
life experiences.
Developmental and behavioral pediatrician Schonfeld
describes four major concepts that comprise an adult
understanding of death: irreversibility, nonfunctionality,
universality, and causality. (1) Irreversibility is the understanding that death is permanent and is a necessary
concept for detaching from the deceased and mourning
to occur. Nonfunctionality is the realization that lifedefining body functions cease on death. Difficulty grasping this concept may lead to a preoccupation with the
physical suffering of the deceased. Causality relates to

things dying as a result of physiologic malfunctions, and
universality is the understanding that all living things die.
If children do not comprehend these concepts, they may
rely on magical thinking, view death as punishment, or
develop excessive guilt.
As children enter the teenage years and the formal
operational stage of development, abstract thinking allows them to question the existential implications of
death. The grieving teen often asks the question, Why
not me? in an attempt to reconcile the death of a friend
or loved one. Teens also may attempt to confront or deny
death as if it were an adversary. As such, high-risk behaviors that challenge mortality may occur as the egocentric teen thinks about the unlikelihood of his or her own
death.
The Dying Child

Peter was diagnosed with cystic fibrosis before 1 year of age.
At the age of 15 years, he was admitted to the hospital for his
first unscheduled therapy. He had struggled to stay on task
with his therapy regimen and now had pneumonia. He was
sick and seemed depressed, but when asked if there was
anything he wanted to talk about, the conversation turned
toward getting his drivers license in several months. Peter
went home after 2 weeks and did well for a time, but had to
return to the hospital 1 month later. His thoughts during
this admission focus on getting better so he can attend an
upcoming rock concert. At his discharge follow-up visit, he
asks if he is going to die.
In the United States, approximately 50,000 children
younger than 19 years of age die each year. More than
50% of those deaths occur in the first year after birth.
Although the major causes of death after 1 year of age are
accidental, how a child copes with his or her own anticipated death deserves special attention. Physicians
psychosocial
coping with death
should encourage families to discuss the illness and its

likely outcome with their children. Even when no words
about diagnosis or prognosis are spoken, seriously ill
children understand that something is going on. They
wonder and fear what could be so bad that there are no
words to describe it. When the topics of illness and death
are avoided by adults, children feel as if they should not
talk about them either.
Even infants feel pain, sense fear and anxiety in their
caregivers, and respond to changes in routine and environment. It is important to remember the infants basic
need for comfort and the development of trust in caregivers. For the infant, as for people of all ages, simple
measures such as dimming the lighting, lowering the
noise level, or altering position may help the infant cope
with a stressful time.
Children entering the why? phase have many questions and tend to focus on the physical aspects of their
illness and death. Older children may want facts and
details about their disease. In The Private Worlds of Dying
Children, sociologist Bluebond-Langer outlines how
children acquire factual information about their disease
through experiences and how those experiences are followed by changes in their sense of self. (2) As Peter in the
vignette experienced more frequent illnesses, it is likely
that he thought of other patients he knew who had cystic
fibrosis and the trajectory leading to their deaths, raising
his awareness of the possibility of his own death.
Some children do not want to talk about their
changed sense of self and the end of life, and that choice
should be respected. Other children want to talk about
the changes but are not sure where to begin. Still others
want to talk but are afraid of the consequences: Will
talking make others around them sad? Will talking cause
death to come sooner? Will people be honest with their
answers? When patients such as Peter start to ask the
difficult questions, one of the best responses is, Tell me
what youre thinking. This response, in actuality, says
Lets keep talking and gives the child an opportunity
to express what is on his or her mind and ask questions.
For children who have trouble asking questions of
those most intimately involved with their care, the role of
the primary care pediatrician, who understands the medical condition and the family but may not be the one
calling the shots, cannot be underestimated. The primary care practitioner can work with the specialists in
defining expectations or goals of care with the child and
family and be a liaison for the parents, siblings, and child.
While in the hospital, children may turn to therapists,
child life specialists, or even a familiar volunteer to help
them understand what is happening and how they are
feeling. This understanding may give them a sense of

control over chaotic times. Children of all ages can seem
to have a sense of urgency as they do their best to live in
the now, and it often has been noted that children seem
to live until they die. Maintaining routines, avoiding
overindulgence, and encouraging participation in standard childhood activities may help the child retain a sense
of normalcy.
As the time of death nears, one of the most important
things for any child to know is that he or she will be
comfortable, pain-free, and loved. Some children may
have questions about what it feels like to die, with
particular concern about how much pain it will cause
them. It is important to keep answers simple, honest, and
compassionate. Bluebond-Langer charges, Do not say
to a child what you do not believe. Instead, speculate
with the child: No one has ever come back to tell us, but
I dont think it is going to hurt.
Many children are most worried about what will happen to those they leave behind. Some find comfort in
leaving a legacy, others want to help plan their funerals,
and others simply want a chance for final goodbyes.
Children are comforted in knowing that they are not
alone. As the terminal phase progresses, children may
seem to withdraw from their caregivers. Some children
wait for the permission-giving of their parents before
they feel the peace that allows them to die. How the
family manages during this terminal phase of the illness is
a major determinant of how they will cope after the
childs death.
Response of Families to the Death of a Child

Valerie is born unexpectedly at 24 weeks gestation with a
severe congenital heart defect. After a very tenuous first
24 hours, her parents elect to withdraw cardiopulmonary
support. They bring Valeries siblings in to the hospital for a
goodbye. The 3-year-old delivers a bright red balloon to her
sister. The 8-year-old strokes Valeries hand and whispers,
I love you. Valerie dies peacefully in her mothers arms
with her family at her side.
Every family has their own communication and coping style, and addressing their stress at the time of a
childs death requires sensitivity and compassion. Families appreciate support and encouragement that they are
doing their best at a difficult time. They may turn to the
pediatrician for help in doing the right thing for the
dying child, themselves, and the siblings. Although there
is never one right way, ongoing conversations with the
family may illuminate an approach that leaves them with
the fewest regrets. Conversations between the medical
team and families should include discussions with both
psychosocial
the dying child and the siblings about what to tell, when
to tell, and who should do the telling. Including siblings
at the deathbed is a personal decision. Should they be
included, it is important to prepare the child for the
sights, sounds, and smells at the bedside. Nursing staff
and child life specialists can be very helpful in this preparation. Younger children may have many questions;
older children and adolescents may have questions but be
too embarrassed or afraid to ask. Offering explanations
can help trigger conversation. As in the scenario, providing the sibling with a small task such as bringing in a
balloon or simply holding the childs hand can help him
or her feel included. If a child wants to give a memento or
a message to the dying loved one but is overwhelmed by
the sickbed, someone else can make the delivery and
report back to the child.
Family members should be encouraged to be with
their child after the death. They may wish to hold, rock,
or bathe their child regardless of the childs age or length
of life. Parents begin to bond with their infant from the
moment they are aware of the pregnancy. During those
months of waiting, dreams and hopes for the child-to-be
develop. Parents and families become attached to these
possibilities and potentials. It is important to remember
that stillbirth or perinatal death represents a painful loss
to parents and the entire family and that giving up a child
for adoption can engender similar feelings of loss.
Current bereavement recommendations recognize
the importance of a memory box: molds of feet or hands,
a lock of the childs hair, clothing, personal items, and
nonclinical photographs. These tangibles help start a
memorial to the deceased and provide families with a way
to revisit their loss as they move through the grieving
process.
Parents desire to protect their surviving children
from the pain and suffering of loss. This sentiment is
well-intended but may prevent the siblings from communicating and processing their own grief. A pediatricians
job may include helping families balance involving the
surviving children in the process with demanding too
much from them. Identifying opportunities for involvement without implying that there is a right or wrong
way is crucial. Surviving children may want to help in the
funeral planning by choosing the outfit, the burial site, or
the music played at the service. For other children, such
involvement may be too much to ask. Regardless of the
surviving childrens level of interaction, they sense the
changes occurring around them. It is important to maintain childrens regular daily routine (bedtime, on-time
meals, homework expectations) because this order de-
coping with death
creases the number of adaptive changes asked of them in

the midst of extreme stress.
Questions about childrens attendance at funerals are
common, and again, there is no right or wrong answer.
Children can be given the option of attending services,
but this should be an informed decision, made after
receiving information about what they might see or hear.
When children attend the service, it is critical that they
have a familiar, supportive person available to answer
questions, hug them, or take them out to play. Should
children later regret a decision not to attend a service, it
is important to acknowledge what a difficult decision it
was and to reassure them that they did the best thing for
them at the time.
Regardless of funeral attendance, it is important to
include the survivors in commemorating and memorializing the loss. Including children in the sorting and
saving of possessions can provide them with the opportunity to remember, use the deceased persons name,
recall happy times and laugh, and remember disappointments. Being able to cope actively and find something
positive even in difficult situations is associated with
improved adjustment.
Grief reactions occur in the emotional, cognitive,
physical, and social domains. Reactions are individual
and are influenced by developmental stage, family coping
style, cultural and religious background, and the circumstances surrounding the death. Common expressions of
grief include repeated questioning, regressive behaviors,
and extreme emotions such as anger or fear. Psychiatrist
Kubler-Ross introduced the concept of the stages of grief
(denial, anger, bargaining, depression, and acceptance),
not as sequential stages but rather as emotional states.
These states can occur in any order and frequently recur
many times as the individual moves toward acceptance of
the inevitability of death. Not everyone reaches acceptance, and some seem to accept and then become angry
or move back into denial or bargaining. Thus, we now
understand that grief is an ongoing process, continues
across development, and may come in waves. Understanding the fluidity of the emotions that surround the
dying process and death itself helps the practitioner to
expect as normal, rather than to react negatively to,
minute-by-minute changes in the patient and family
members. Grief that is softening, no matter how slowly,
is not likely pathologic.
Children within the same family or of similar ages may
have different styles of grieving. Because grieving parents
often are experiencing overwhelming grief themselves,
they may feel isolated or may not be able to recognize
complicated bereavement in their children (Table 2). It is
psychosocial
coping with death
Complicated
Bereavement
Table 2.
Preschool Children
Persistent separation anxiety more than 6 months

after a predictable home life has been established
Continuing or worsening regressive behavior beyond
6 months from the death
School-age Children
Persistent or worsening school phobia or academic

performance 3 months after the death
Detachment from peers or development of new social
phobias
Increasing behavioral concerns (eg, depression,
moodiness, anger) 3 to 6 months after the death
Physical complaints without organic cause 3 months
after the death
Adolescents
Increasing high-risk behaviors with drugs, alcohol,

delinquency, or precocious sexual activity
Withdrawal from peer interactions or group activities
Persistent somatic complaints for 3 months after the
death
Adapted from the work of Grace H. Christ, DSW (www.childrensgrief.com)
important for others to help them. For example, families

should notify the school of their loss so teachers can
monitor the surviving children. Pediatricians should provide follow-up appointments within a month following
the death to focus on how both the adults and the
children are faring and to provide information about
normal and complicated grief reactions. Referral to a
grief counselor should be discussed as an option.
In retrospect, parents and children become aware that
they are different after the death of a loved one. Recovering from the death of a loved one requires redefining
personal identity as well as taking on a new role in a
different family constellation. Often, survivors feel that
they have matured and have developed coping strategies
and a level of empathy they did not have before. Their
strength and skills can help the medical community learn
new approaches to others in similar situations.
Communication from the Pediatrician

Benjamin arrives in the emergency department 20 minutes
after being struck by a car while riding his bicycle. His
mother arrives a few minutes after the ambulance. The
emergency medical technicians report that during resuscitation at the scene, Benjamin regained a faint central
pulse but that he remains unresponsive. Despite additional

resuscitation attempts, Benjamin dies within the hour.
Communication at the time of death and throughout
the grieving process is powerful and lasting. Just as every
family approaches death individually, so does every physician. Many pediatricians worry about finding the right
words for breaking the news of a diagnosis; for expressing
sorrow at the time of death; and for providing support in
the days, months, and years that follow. Much has been
written about the key components of such communication. However, the concept of just being present to
provide support at a difficult time cannot be overestimated.
Pediatricians often develop an emotional as well as a
professional bond with the families they serve. When a
medical crisis strikes a family, they turn to their primary
pediatrician to help them negotiate the health-care system and make the best possible decisions for their child.
Throughout the illness, the pediatrician should be an
advocate for the child and family. The pediatrician can
ensure that the family receives information to enable
them to meet their childs needs at each stage of an
illness. Although child health professionals may be hesitant to discuss a bad outcome in advance, thoughtful
conversation can help plant the seeds of bereavement.
When the decisions to be made are about end-of-life
planning, the pediatrician can provide information and
support and remind the family that they have always
acted in the childs best interest.
Recently, physicians have become more aware of patient and family needs to understand the loss of a young
life in the larger context of their, and their childs,
relationship to God, nature, or a spiritual force. Different
names are given to the feeling that there is something
larger than the individual that is good, nurturing, and
protective. The physician portrayed by Norman Rockwell probably went to the same place of worship as the
patient or at least shared similar world views. Talking
about Gods Plan, for example, was natural. Physicians
moved away from that type of intimacy as medicine
became more mechanistic. However, retrieving some of
that important human being-to-human being bond by
asking about spiritual beliefs or whether they believe in
an afterlife is important as children and families struggle
to find meaning in death as well as in life. The issue is not
what the physician believes but what the family believes.
Whether the pediatrician shares the point of view of the
family, it always is appropriate to have the family meet
with their own spiritual adviser. The adviser may be
particularly helpful in observing certain rituals or other
practices important to their sense of doing what is best
psychosocial
and right for their child, which is key to their acceptance

of death.
At the time of death, the pediatricians affect and
emotional attitude leave lasting impressions. Parents appreciate the depth of their doctors feelings, and most
pediatricians have come to realize that showing emotion
is appropriate. It is important to recognize the deceased
as a person first and as a patient who has an illness or
injury second.
When death is anticipated, information about what to
expect and effective counseling can assist constructive
parental bereavement. For families such as those in the
scenario, there is no opportunity for anticipatory grief, so
all the work of the grieving process must be done after
the death. The pediatrician can help such families face a
wholly unexpected future, especially the other children
in the family.
After the death, many pediatricians attend the funeral
or calling hours. Scheduling an appointment with the
family about 1 month after the death provides an opportunity to address coping concerns and, if necessary, reinforce with parents that their decisions were thoughtful
and based on what seemed best at the time. Some sources
recommend reaching out to the siblings during individual appointments, asking how they and the family are
doing. Members of the deceased childs family should
view the pediatrician as someone who is not embarrassed
to talk about the dead child and the changes in their lives.
Often, grief is greatest at the time of the birthday of the
deceased or the anniversary of the death. It is appropriate
for the pediatrician to let the family know that he or she
remembers, too.
Pediatricians may experience feelings such as anger or
guilt that may be shared with colleagues, who have likely
experienced similar feelings. Having resources and support within the medical community can help pediatricians cope most effectively as they face the death of a
patient.
The suggestions in this section are only a few of many
that others have offered to address this complex and
evolving area of pediatrics. The American Academy of
Pediatrics recently released a technical report addressing
communication with children and families. (3) Within
the report, Levetown offers general recommendations
for breaking bad news, with specifics about patients in
intensive care units, the emergency department, or the
delivery room. The Institute of Medicine also focuses
attention on physician-patient-family communication,
with particular attention to discussions of diagnosis,
prognosis, and goals of care, in their report on pediatric
coping with death
palliative care. (4) Both of these reports can serve as

resources for those interested in gaining more specific
skills in this area.
Summary
Childrens concept of death is influenced by
experience, culture, and developmental stage.
Dying children benefit from open communication
about death, based on research findings and clinical
experience (summarized in Hurwitz, 2004).
Everyone in the family is affected by the loss of a
loved one, even the youngest family members.
Pediatricians can help families by listening and
supporting them during the processes of loss and
bereavement.
References
1. Lewis M, Schonfeld DJ. Dying and death in childhood and
adolescence. In: Lewis M, ed. Child and Adolescent Psychiatry:
A Comprehensive Textbook. 3rd ed. New York, NY: Lippincott
Williams & Wilkins; 2002:1239 1245
2. Bluebond-Langer M. Private Worlds of Dying Children. Princeton, NJ: Princeton University Press; 1978
3. Levetown M. Communicating with children and families: from
everyday interactions to skill in conveying distressing information.
Pediatrics. 2008;121:e1441 e1460
4. Institute of Medicine. When Children Die: Improving Palliative
and End-of-Life Care for Children and Their Families. Washington,
DC: The National Academies Press; 2003
Suggested Reading and Websites

American Academy of Hospice and Palliative Medicine. Fast Facts
Archive. Available at: http://www.aahpm.org/cgi-bin/wkcgi/
search?fastfact1&search1. Accessed June 2009
Childrens Hospice and Palliative Care Coalition website. Available
at: www.childrenshospice.org. Accessed June 2009
Gold KJ, Dalton VK, Schwenk TL. Hospital care for parents after
perinatal death. Obstet Gynecol. 2007;109:1156 1166
Grace H. Christs website. Available at: www.childrensgrief.com.
Accessed June 2009
Helping Children Grieve (one of the most comprehensive and
annotated bibliographies online). Available at: http://www.
aplacetoremember.com/frames/bibchild.html. Accessed June
2009
Hurwitz CA, Duncan J, Wolfe J. Caring for the child with cancer at
the close of life: There are people who make it, and Im hoping
Im one of them. JAMA. 2004;292:21412149
National Hospice and Palliative Care Organization. Childrens
Project on Palliative/Hospice Services. Available at: http://www.
nhpco.org/i4a/pages/index.cfm?pageid3409. Accessed June
2009
Wessel M. The role of a primary pediatrician when a child dies. Arch
Pediatr Adolesc Med. 1998;152:837 838
psychosocial
coping with death
PIR Quiz
Quiz also available online at pedsinreview.aappublications.org.
9. You are the pediatrician for a family of six. The youngest boy has just died after a long course of
leukemia. Of the following, the most appropriate action for you to take with the family is to:
A.
B.
C.
D.
E.
Avoid mentioning the patients name at future appointments with family members.
Help the family make funeral arrangements.
Insist that all discussions regarding spirituality be conducted with the chaplain rather than you.
Refrain from expressing tearful emotions in conversations with the family.
Schedule an appointment with the other children approximately 1 month after his death.
10. The mother of one of the families in your practice has just been killed in a car accident. All five of the
children are expressing grief in various ways. Considering cognitive and behavioral aspects of the
understanding of death, which of the following correctly matches the age of the children with their most
likely response to the mothers death?
A.
B.
C.
D.
E.
The
The
The
The
The
18-month-old feels that her mother died because she did something wrong.
3-year-old wonders if her mother will be back by Christmas.
4-year-old worries that she is going to die soon.
8-year-old asks, Why not me?
13-year-old develops separation anxiety.
11. Among the following, which concept is more characteristic of a childs thinking than an adults thinking?
A.
B.
C.
D.
E.
All creatures eventually die.

Bodily functions cease after death.
Death is a permanent condition.
Dying occurs because of physiologic malfunctioning.
Having bad thoughts about someone can cause their death.
12. A recently widowed mother calls you to discuss her 17-year-old daughters behavior since her father died
of a brain tumor 2 months ago. She is concerned that her daughter is not coping with the death
appropriately. Which of the following behaviors is most suggestive of complicated bereavement?
A.
B.
C.
D.
E.
Crying most nights before going to sleep.

Having frequent periods of moodiness.
Having new complaints of frontal headaches.
Looking at old pictures of her father every day.
Withdrawing from previously enjoyed social activities.
Coping With Death

Jennifer S. Linebarger, Olle Jane Z. Sahler and Kelsey A. Egan
Pediatr. Rev. 2009;30;350-356
DOI: 10.1542/pir.30-9-350
Updated Information
& Services


Behavioral and Mental Health Issues
http://pedsinreview.aappublications.org/cgi/collection/behavioral
_mental_health Psychosocial Issues and Problems
ial_issues_problems

Reprints

Index of Suspicion
Daniel H. Reirden, Alexandra N. Menchise, Brian Knox, Rani Gereige, Tamara
Howard, Erica L. Thomas, Rosina Connelly, Sarah Tyler and Katie McPeak
Pediatr. Rev. 2009;30;357-363
DOI: 10.1542/pir.30-9-357
index of suspicion
Case 1 Presentation
The reader is encouraged to write

possible diagnoses for each case before
turning to the discussion. We invite
readers to contribute case presentations
and discussions. Please inquire first by
contacting Dr. Deepak Kamat at
[email protected].
Author Disclosure
Drs Reirden, Menchise, Knox, Gereige,
Howard, Thomas, Connelly, Tyler, and
McPeak have disclosed no financial
relationships relevant to these cases.
This commentary does not contain a
discussion of an unapproved/
investigative use of a commercial
product/device.
A 15-year-old boy presents with

pain, swelling, and limited movement of his right elbow for 4 days.
He denies other joint involvement,
trauma, headache, diarrhea, visual
disturbances, or dysuria but has experienced night sweats. He had streptococcal pharyngitis and a mononucleosis-like illness 3 months ago.
He has no pets, and his only travel
occurred more than 1 year ago when
he visited Mexico. He is not sexually
active. Naproxen helped initially, but
his symptoms have worsened.
Physical examination reveals a nontoxic adolescent boy whose temperature is 37.4C, heart rate is 74 beats/
min, and blood pressure is 127/
69 mm Hg. There is no erythema
around his right elbow, but it is swollen, tender, and warm, and it feels
boggy. His elbows range of motion
is limited from 90 to 120 degrees.
The rest of his examination findings
are normal.
His WBC is 5.9103/mcL (5.9
9
10 /L), with a normal differential
count, Hgb is 13.9 g/dL (139 g/L),
Hct is 41.7% (0.42), and platelet count
is 245103/mcL (245109/L). His
ESR is 50 mm/hr and C-reactive
protein measures 11.3 mg/dL. Elbow aspiration reveals cloudy fluid,
with 9,761 red blood cells and 3,967
WBCs but no crystals. Gram stain
shows moderate neutrophils but no
organisms. Aspirate is sent for bacterial and fungal cultures.
The patient is discharged on
naproxen and instructed to obtain a
follow-up appointment in a few days.
A call from the laboratory 4 days later
helps to establish the diagnosis.
Case 2 Presentation
A 7-year-old boy presents to a hospital in Florida with 3 weeks of headache refractory to acetaminophen
and 1 day of altered mental status,

diplopia, and photophobia.
On physical examination, the
well-developed, prepubertal boy has
a weight of 37.7 kg (97th percentile), temperature of 36.8C, heart
rate of 101 beats/min, and blood
pressure of 121/79 mm Hg. He is
difficult to arouse and is confused.
He vomits once in the ED. He has no
skin lesions, signs of meningeal irritation, or joint swelling. He has bilateral papilledema and photophobia.
The rest of his examination findings
are unremarkable.
Initial studies include a brain CT
scan that shows slight prominence of
the ventricles and a WBC of
15.8103/mcL
(15.8109/L)
with 85% segmented neutrophils.
The lumbar puncture reveals an elevated CSF opening pressure (36 mm
Hg), 48 WBCs/mcL (90% lymphocytes, 10% monocytes), 2 red blood
cells/mcL, a glucose concentration
of 48 mg/dL, and a protein value of
33 mg/dL. Following the lumbar
puncture, the boys headache and
mental status improve, and he requires one more therapeutic lumbar
puncture during this admission. Additional history and extensive laboratory evaluation of his CSF reveal the
final diagnosis.
Case 3 Presentation
A 15-year-old girl presents with a
3-day history of right flank pain
and right-sided abdominal pain. The
pain is constant and graded 7/10 in
severity. She developed a temperature of 39.5C yesterday. She has
complained of several episodes of
painful urination within the past year
and has been treated with over-thecounter urinary analgesics. Her most
recent episode was 1 month ago. She
denies any current urinary symptoms, nausea or vomiting, history of
trauma, or sexually transmitted infecPediatrics in Review Vol.30 No.9 September 2009 357
index of suspicion
tions. She recently had an upper respiratory tract infection and noted an
infected insect bite on her right arm
2 weeks ago. She currently is menstruating and reports normal duration, interval, and flow.
On physical examination, she is
alert, responsive, and in moderate
distress from pain. She remains febrile at 40.4C. Her abdomen is
tender to palpation over the right
flank and right hemi-abdomen. The
remaining physical findings are
normal.
Initial laboratory values include
a WBC count of 13.1103/mcL
(13.1109/L) with 76% neutrophils, 15% lymphocytes, 7% monocytes, and 2% eosinophils. Results of
the basic metabolic profile, including
BUN and creatinine, are within normal limits. Urinalysis shows 7 WBCs
and few bacteria per high-power field
and is negative for nitrites or leukocyte esterase. CT scan of the abdomen shows a nonspecific fluid collection around the right kidney. She is
admitted for intravenous ciprofloxa-
Frequently Used Abbreviations

alanine aminotransferase
aspartate aminotransferase
blood urea nitrogen
complete blood count
central nervous system
cerebrospinal fluid
computed tomography
electrocardiography
emergency department
electroencephalography
erythrocyte sedimentation
rate
GI:
gastrointestinal
GU: genitourinary
Hct: hematocrit
Hgb: hemoglobin
MRI: magnetic resonance imaging
WBC: white blood cell
ALT:
AST:
BUN:
CBC:
CNS:
CSF:
CT:
ECG:
ED:
EEG:
ESR:
cin therapy for presumptive pyelonephritis. Urine culture later is reported

to be negative. An additional imaging study leads to the diagnosis.
Case 4 Presentation
An 11-year-old boy is transferred
from another hospital because of
persistently low carbon dioxide values. He had presented at that hospital with a sore throat, fatigue, and a
barking cough, but no fever, congestion, or rhinorrhea. He was admitted
for 24 hours and treated with intravenous (IV) steroids and inhaled albuterol for presumed croup. Numerous electrolyte panels performed at
that hospital showed low carbon dioxide concentrations.
He has had recurrent crouplike
episodes since 2 years of age, chronic
nausea, and emesis often associated
with exertion, anxiety, and chronic
headaches. His mother had a history
of seizure disorder, acquired deafness, and depression and died at age
44 years from stroke and encephalitis. His maternal grandmother also
died in her 40s.
Physical examination reveals a
very thin boy who appears ill but in
no distress. His height is at the 10th
percentile for age with weight at less
than the 3rd percentile. The remainder of the examination yields normal
results.
A chest radiograph appears normal. Laboratory results include a venous blood gas panel showing a pH
of 7.17, PCO2 of 24 mm Hg, PO2
of 111 mm Hg, bicarbonate of
8 mEq/L (8 mmol/L), and base
deficit of 20 mEq/L. A serum lactate concentration is 5.7 mmol/L.
A urine drug screen is negative, and
salicylate is not detected in the serum. An additional laboratory study
reveals the diagnosis.
Case 1 Discussion
Four days following the elbow aspiration, the joint fluid culture grew
a gram-negative coccobacillus, and
the patient was admitted to the
hospital for intravenous antibiotics.
Consultation with the infectious diseases department and the microbiology laboratory suggested infections
with Brucella, Francisella tularensis,
Neisseria, and HACEK organisms
(Haemophilus, Actinobacillus [Haemophilus] actinomycetemcomitans,
Cardiobacterium hominis, Eikenella,
and Kingella kingae). The initial antibiotic regimen was ceftriaxone,
doxycycline, and rifampin. An MRI
showed no osteomyelitis. The patient reported resolution of night
sweats within 24 hours of antibiotic
administration, and his temperature
was normal by the second day of
hospitalization. Four days later, the
State Health Department identified
the organism as Brucella by polymerase chain reaction (PCR). Additional
history revealed that the boys grandfather had visited from Mexico 2
months ago and brought with him
unpasteurized goat cheese.
The boy was treated with 2 weeks
of IV gentamicin and a total of
6 weeks of oral doxycycline and rifampin. His joint pain resolved in
10 days, and his orthopedic examination 2 months after his admission
yielded normal results.
The Condition
Brucellosis is an important zoonotic
infectious disease worldwide, but it
has been largely eradicated in the
United States. Most cases of brucellosis reported in the United States
today are the result of travel to endemic countries or ingestion of imported unpasteurized milk products,
particularly from Mexico.
Brucella infections may result
from four subspecies: B melitensis, B
index of suspicion
abortus, B canis, or B suis. The organisms are facultative intracellular

pathogens. They may gain entry into
a human host through skin abrasions, GI absorption, respiratory
inhalation, or conjunctival contamination. The bacteria spread via lymphatics and hematogenously, resulting in localized infection of organs
rich in reticuloendothelial tissue.
The clinical manifestations of
brucellosis are highly variable and
nonspecific. Although Brucella is a
well-known cause of fever of unknown origin, it may affect almost
any organ system. Brucellosis has been
described as being similar to syphilis
and tuberculosis in its propensity for
protean manifestations. Symptoms
commonly include night sweats, fatigue, weight loss, myalgias, and
arthralgias. Often, the only clinical
findings are lymphadenopathy or
hepatosplenomegaly. Depression has
been described, and physical complaints may not be matched by clinical findings or laboratory abnormalities.
Approximately 33% of affected
patients have a presentation of localized symptoms. The organ systems
affected most often are osteoarticular, genitourinary, neurologic, cardiac,
and hepatic. Osteoarticular manifestations commonly include sacroiliitis,
although monarticular arthritis is a
well-described osteoarticular manifestation that has a predilection for
weightbearing joints such as hips,
knees, and ankles. Neurologic complications include meningitis, encephalitis, radiculopathies, and psychosis.
Cardiac complications are uncommon, but endocarditis accounts for
most of the mortality associated with
brucellosis. Genitourinary complications are rare and include epididymoorchitis, glomerulonephritis, and renal abscesses.
Diagnosis
Due to the protean nature of the
clinical presentation of brucellosis,
clinicians must be vigilant in obtaining histories of travel, animal exposures, or ingestions of unpasteurized
milk products to recognize the infection.
Routine laboratory tests may not
be helpful in diagnosing brucellosis.
WBC counts often are normal. Occasionally, a mild anemia, leukopenia,
or thrombocytopenia is detected.
ESR values reported in the literature
range from normal to highly elevated. Mild transaminitis has been
reported frequently.
Culture and serology are the
mainstays of diagnosis. Culture can
be performed on blood or any other
body tissue or fluid. It is important to
note that the organisms are notoriously slow-growing, and if brucellosis is suspected, the laboratory should
be notified so the samples can be
held longer. Serologic tests such as
serum agglutination and enzymelinked immunosorbent assay can be
used to make the diagnosis. As in this
patient, PCR testing may be used to
confirm the diagnosis.
Differential Diagnosis
In cases of monarticular arthritis, infectious causes always must be considered and investigated rapidly because of the potential for rapid joint
destruction. In an otherwise healthy
adolescent, nongonococcal bacterial infections with staphylococci or
streptococci are common.
Neisseria gonorrhoeae must be
considered in any sexually active patient; it is the most common cause of
bacterial arthritis among those ages
18 to 24 years. Classically, it presents
with wrist involvement or tenosynovitis, but any joint may be involved.
Gram stain and joint culture typically
yield negative results, so gonococcal
infection should be evaluated by ob-
taining genital, oropharyngeal, or

rectal specimens. Lyme disease can
present with a monarthritis, although the knee often is involved.
Less common infectious causes are
viral (herpes, hepatitis B, human immunodeficiency, coxsackie B virus),
fungal (sporotrichosis, cryptococcus,
blastomycosis), and mycobacterial
(tuberculosis).
Crystalline arthritis, such as gout
or calcium pyrophosphate dihydrate
(pseudogout), is rare among adolescents. Trauma, such as occult fractures or ligamentous injuries, may
result in monarthritis. Systemic inflammatory diseases, such as rheumatoid arthritis, lupus, or spondyloarthropathies, often are polyarticular,
but they may present initially with
only single-joint involvement.
Treatment
Treatment of brucellosis requires antibiotic therapy. Doxycycline (100 mg
orally twice daily) plus rifampin
(600 to 900 mg orally daily) for
6 weeks is the recommended treatment for those older than age 8 years.
Trimethoprim-sulfamethoxazole
may be substituted for doxycycline in
children younger than age 8 years.
When focal disease, such as arthritis
or endocarditis, is present, the addition of gentamicin is recommended
by some experts. It is administered
intravenously for 2 weeks in addition
to the doxycycline and rifampin.
Lessons for the Clinician
Brucella infections have shifted

epidemiologically; travelers to endemic countries or those consuming imported dairy products from
countries such as Mexico are at
highest risk of infection.
The clinical manifestations are protean, ranging from vague somatic
complaints to focal disease, includPediatrics in Review Vol.30 No.9 September 2009 359
index of suspicion
ing arthritis, meningitis, and endocarditis.

Clinicians must maintain a high degree of suspicion and include travel
and food consumption in their
history-taking when such clinical
presentations occur.
(Daniel H. Reirden, MD, The

University of Colorado Denver School
of Medicine, The Childrens Hospital,
Aurora, Colo.)
Case 2 Discussion
CSF was sent for Lyme titers, and
the Western blot revealed 2 positive
bands of immunoglobulin (Ig)G and
0 bands of IgM. Serum for Lyme
antibodies was positive for IgG with
5 bands, and IgM was negative with
1 band.
The patient was diagnosed as having Lyme meningoencephalitis and
treated for 28 days with IV ceftriaxone (100 mg/kg per day). He was
discharged taking acetazolamide to
control his symptomatic increased
intracranial pressure. Although he
continued to have elevated intracranial pressures (pseudotumor cerebri)
during a 5-month course of illness
requiring two hospitalizations, he
suffered no long-term neurologic
sequelae.
Additional questioning revealed
that while in Connecticut 2 months
prior to this admission, he had developed erythema migrans, was diagnosed as having Lyme disease, and
was treated with 21 days of cefuroxime.
The Condition
Neurologic manifestations of Lyme
disease include lymphocytic meningitis, encephalitis, cranial neuropathy, and less commonly, pseudotumor cerebri. Pseudotumor cerebri is
rare in the pediatric population. Secondary causes of pseudotumor cere360 Pediatrics in Review Vol.30 No.9 September 2009
bri include otitis media, venous sinus

thrombosis, renal failure, arteriovenous malformations, and medications (eg, tetracycline, isotretinoin,
steroid use/withdrawal, oral contraceptives). Aseptic meningitis, medulloblastoma, endocrine abnormalities, and trauma also should be
considered.
Lyme-associated
pseudotumor
cerebri is a disorder associated with
increased intracranial pressure without clinical, laboratory, or radiologic
evidence of an intracranial spaceoccupying lesion. Clinical symptoms
include headache, vomiting, diplopia, and somnolence. Obesity and
female predominance commonly accompany Lyme-associated pseudotumor cerebri in pubertal children
and adults, but these associations do
not apply to prepubertal patients.
Pathogenesis
The pathogenesis of Lyme-associated
pseudotumor cerebri remains unknown. Five mechanisms are proposed: vasogenic parenchymal edema,
increased cerebral blood volume, excessive CSF production, compromised CSF resorption, and venous
outflow obstruction.
Some data suggest that the
pseudotumor cerebri in neuroborreliosis is caused by an autoimmune
process, such as autoantibodies to
myelin basic protein due to a shared
antigenic determinant between B
burgdorferi and human tissue. Some
data suggest that pseudotumor cerebri that follows Lyme meningitis
is a direct consequence of B burgdorferi CNS infection. These processes could contribute to parenchymal edema and, therefore, could lead
to a pseudotumor cerebri-like syndrome.
Diagnosis
Diagnosis of Lyme meningitis should
be based on positive Lyme serology
and CSF pleocytosis (8 WBCs/

mm3). This patients diagnosis of
Lyme meningoencephalitis was based
on positive Lyme serology, CSF
pleocytosis, and altered mental status. In CNS Lyme disease, lymphocytic pleocytosis and an elevated CSF
protein concentration usually are
present.
Because this patients meningoencephalitis resolved, he was diagnosed
subsequently as having pseudotumor
cerebri because of his increased intracranial pressure, normal CSF findings, and a CT scan that showed no
evidence of venous obstructive disease.
Management and Treatment

The recommended treatment of late
neuroborreliosis is IV ceftriaxone
(2 g daily for 2 to 4 weeks). Response
usually is slow, but symptoms gradually resolve over 3 to 4 weeks.
Although there are reports of
Lyme-associated pseudotumor cerebri presenting acutely after treatment
for Lyme disease, there are no reports
of chronic Lyme-associated pseudotumor cerebri in the pediatric population. Little in the literature could
explain why this patient developed
chronic Lyme-associated pseudotumor cerebri requiring serial lumbar
punctures.
Although rare, pseudotumor cerebri represents an important manifestation of Lyme disease.

Pseudotumor cerebri that does not
resolve after treatment of Lyme infection does not represent treatment failure.
There is no evidence that longer
courses of antibiotics for the treatment of Lyme meningoencephalitis are superior to placebo in
improving symptoms. After the
recommended course of antibiotics
index of suspicion
is completed, the patient may require symptomatic treatment with

serial lumbar punctures for several
months without the addition of antibiotics.
The prognosis of acute Lymeassociated pseudotumor cerebri is
favorable in the pediatric population, and patients usually recover
without any sequelae. There is little
information about the prognosis
of chronic Lyme-associated pseudotumor cerebri. Therefore, close
ophthalmologic surveillance is recommended.
course of IV vancomycin. A second

attempt by interventional radiology
under general anesthesia yielded an
additional 40 mL of blood aspirated
from the right perinephric hematoma, and a drain was placed with the
assistance of the urologist. The patients pain and fever resolved over
the next few days, although a repeat
CT scan several days after the procedure showed only a minimal decrease
in the size of the fluid collection.
(Alexandra N. Menchise, MD,

Brian Knox, MD, and Rani Gereige,
MD, MPH, Department of Pediatrics,
University of South Florida, Tampa,
Fla.)
This patients first condition was a

perinephric hematoma, which subsequently was infected with MRSA. After a clotting disorder was ruled out,
the question remained as to how
she initially developed the perinephric hematoma. On additional questioning, the patient recalled falling
off of a fence, about 6 feet high,
approximately 2 weeks prior to presentation. We presumed that this
trauma was sufficient to cause bleeding around her right kidney, with
hematoma formation, followed by
seeding with MRSA during an episode of transient bacteremia. The
patient was recovering from a softtissue infection on her right arm,
which was believed to be the source
of the MRSA.
The kidney may be injured following abdominal trauma, either
blunt or penetrating injury. When
evaluating abdominal trauma, CT
scan is the modality of choice in the
emergency setting. Other situations
that may prompt abdominal imaging
include a history of injury and hematuria or injury and hemodynamic instability. Although ultrasonography
can help delineate deeper processes
that are not readily evident on examination, MRI should be obtained
when a deep-seated process is suspected.
Case 3 Discussion
The girl continued to have a temperature to 40.4C, developed nausea
and emesis, and experienced worsening right-sided flank and abdominal
pain over the next 2 days. Renal ultrasonographic findings were consistent with right perinephric abscess.
The infectious diseases specialist recommended adding IV vancomycin
to the therapy. A repeat CT scan
showed a 563-cm right perinephric fluid collection and inflammatory changes in the right lower
abdominal quadrant. The interventional radiology service attempted
CT-guided drainage of the perinephric fluid collection. After approximately 20 mL of blood was obtained,
the procedure was stopped because
of concerns of renal hemorrhage.
The blood was sent for cultures,
and methicillin-resistant Staphylococcus aureus (MRSA) was isolated.
Laboratory tests for coagulation disorders were negative. Ciprofloxacin
was discontinued, and the patient
was scheduled to complete a 6-week
The Condition
The Complication
S aureus, a gram-positive, catalaseand coagulase-positive coccus, is a
ubiquitous bacterium and a common
cause of skin and soft-tissue infections. The ability to produce proteolytic enzymes facilitates the abscess
formation. S aureus can spread hematogenously to nearly any tissue or
organ in the body. When deep tissues
and organs such as the kidney are
affected, patients usually present
with fever and localized pain and tenderness.
New Perspective on an Old

Agent
Just a few decades ago, most
community-acquired or communityassociated S aureus infections were
due to methicillin-sensitive S aureus
(MSSA). Only hospital-acquired or
healthcare-associated infections were
due to MRSA. Infections due to
MRSA were described initially in
the 1960s, always in association with
significant health-care exposure. In
the 1980s, MRSA began to cause
infection in otherwise healthy children who did not have significant
health-care exposure. MRSA is now
the most common causative agent
of soft-tissue skin infections in the
community.
Recent studies have described
some cellular mechanisms that may
explain the increased virulence of
community-acquired MRSA (CAMRSA). Different genetic factors determine the pathogens ability to
overcome the healthy human hosts
immune system. One cytolytic toxin,
the Panton-Valentine leukocidin
(PVL), has been associated with abscess formation, necrotizing pneumonia, and increased virulence of
CA-MRSA. Genes for PVL have
been found in almost all MRSA isolates, but only in about 50% of the
MSSA isolates and rarely in hospitalacquired MRSA (HA-MRSA) strains.
index of suspicion
Other microbiologic characteristics

of CA-MRSA include genotype
USA300, possession of staphylococcal chromosome cassette mec
(SCCmec) types IV or V alleles, and
susceptibility to most non-betalactam antimicrobials. The SCCmec
carries the mecA gene, which provides resistance to methicillin. The
SCCmec types IV and V have been
implicated in increased transmission
of resistance in the CA-MRSA due
to their relatively smaller size. In
contrast, the HA-MRSA strain lacks
PVL, is more often genotype USA100
clone, possesses SCCmec types I to
III alleles, and typically is multidrugresistant.
Treatment
Treatment of MRSA infections varies
with their clinical manifestations
from incision and drainage without
antibiotic treatment for uncomplicated small skin and soft-tissue
infections to IV antibiotics and surgical drainage for deep-seated infections. Empiric antibiotic therapy
should target CA-MRSA strains
with clindamycin, trimethoprimsulfamethoxazole, tetracycline, and
linezolid. Of note, some strains susceptible to clindamycin in vitro can
develop resistance to clindamycin
during therapy and result in treatment failure. The D-zone test easily
identifies the presence of inducible
resistance to clindamycin. IV vancomycin should be used for inpatient
treatment of severe infections.
When a patient who has a suspected infectious process fails to

improve within 24 to 48 hours
after initiation of broad-spectrum
antibiotic therapy, the clinician
should re-evaluate the initial diagnosis.
In addition to considerations of
antibiotic resistance patterns in the

community or potentially inappropriate initial antibiotic choice, additional imaging studies should
be considered to rule out deeper
and more extensive infectious processes.
Consultation with infectious diseases specialists should be sought
for a multidisciplinary approach to
complicated invasive infection cases.
(Tamara Howard, MD, Erica L.

Thomas, MD, Baylor College of Medicine, Houston, Tex; Rosina Connelly,
MD, MPH, University of South Alabama, Mobile, Ala.)
Case 4 Discussion
A genetic test revealed the diagnosis
of mitochondrial myopathy, encephalopathy, and lactic acidosis with
stroke-like episodes (MELAS) syndrome. This patients chronic history
of headache, fatigue, recurrent respiratory distress, and GI symptoms was
significant. In addition, the maternal
history of early death with hearing
loss, encephalopathy, and stroke was
extremely telling, despite her never
having been diagnosed. It was these
historic factors in combination with
his persistent metabolic acidosis that
led to the correct diagnosis.
The genetics, neurology, and pulmonary services were involved in his
care during hospitalization. Behavioral health also was consulted to
manage his anxiety. His evaluation in
the hospital included MRI of his
brain, electrocardiography, hearing
screen, and upper GI radiographic
series, all of which yielded normal
results. His lactic acidosis improved
over the course of admission but did
not resolve completely. He was
started on coenzyme Q10, carnitine,
and B100 complex vitamin prior to
discharge. He continues to be followed by the genetics and neurology
services and has persistent issues with

anxiety.
The Condition
MELAS syndrome is one of the most
common inherited mitochondrial
disorders. The mitochondrial defects
primarily affect tissues that have a
high energy requirement, including
skeletal muscle and the brain. Three
classic criteria of MELAS include
strokelike episodes before age 40
years; encephalopathy characterized
by seizures, dementia, or both; and
lactic acidosis, ragged red fibers on
the histology of skeletal muscles, or
both. Most patients present between
ages 2 and 20 years, but presentation
can be as late as 60 years of age. The
syndrome is progressive, with worsening neuromuscular function and
encephalopathy over time. Strokelike episodes often begin as early as
15 years of age. The number and
severity of such episodes are indicators of neurologic prognosis.
Most patients afflicted with
MELAS syndrome experience headaches, nausea, exercise intolerance,
and cognitive dysfunction. Psychiatric illness also is extremely prevalent.
Other common features include
sensorineural hearing loss, short stature, cardiomyopathy, ophthalmoplegia, and diabetes mellitus.
Pathophysiology
In general, the term mitochondrial
disease refers to disorders that involve impaired oxidative phosphorylation. Thus, there is a defect in generation of adenosine triphosphate,
and affected patients live in a chronic
state of energy failure. There is a
shunting of pyruvate to lactate,
which results in chronic lactic acidosis and multiorgan disease.
Inheritence
Mitochondrial DNA (mtDNA) is inherited almost exclusively through
index of suspicion
the mother. Mutations in the

mtDNA can be inherited or somatic
and may include deletions, point mutations, and duplications. Mitochondrial disease has a complex, nonmendelian pattern of inheritance.
Affected fathers cannot transmit disease to their children. The amount
of mutant DNA can be highly variable among different tissues and can
change with time. More than 200
mutations to the mitochondrial genome have been reported. This variety, in conjunction with variable tissue distribution, causes a wide range
of clinical phenotypes.
Diagnostic Evaluation
The most common laboratory abnormality present in patients afflicted
with MELAS syndrome is elevated
serum or CSF lactate concentrations,
indicating mitochondrial dysfunction. Prudent imaging evaluation includes brain MRI, which typically
shows lesions in the occipital and parietal lobes. Interestingly, such lesions generally do not follow vascular
territories and may involve basal ganglia. Muscle biopsy also is indicated.
On histologic study, ragged red fibers are visible in skeletal muscle,
indicating the presence of mitochondrial proliferation. This proliferation
also can be found in blood vessels,
suggesting a possible important
pathologic mechanism.
Treatment
Although understanding of the pathophysiology of MELAS syndrome has
made significant advances, therapeutic interventions have lagged. Currently, no consensus guidelines for
treatment of the disorder exist. Management is based on experience from

a limited number of cases. It is widely
accepted that current medical therapy may reduce symptoms but has
not been shown to alter the ultimate
progressive disease course. Given disease heterogeneity, the frequently
relapsing and remitting course, and
the limited number of affected patients, clinical trials are difficult to
undertake. Of great importance is
the symptomatic management of comorbid conditions, such as cardiomyopathy, renal disease, growth failure, and diabetes.
A handful of medications are used
in an attempt to improve mitochondrial function and to reduce production of harmful reactive oxygen
species. These agents include electron acceptors and cofactors, including thiamine, riboflavin, nicotinamide, coenzyme Q10, succinate,
and cytochrome c. Current management strategies also include corticosteroids, creatine, and arginine. For
patients who have epilepsy, management typically includes antiepileptic
drugs. Valproic acid generally is
avoided because of concern for fulminant liver failure in patients who
have mitochondrial cytopathies. Genetic counseling also is recommended.
Prognosis
The correlation between clinical severity and level of mutant mitochondrial DNA usually is poor. Family
members inherit different mutant
loads of mitochondrial DNA, which
results in extreme intrafamilial disease variability. Hence, determining
the prognosis is very difficult.
Lessons For The Clinician
MELAS is one of the most common inherited mitochondrial disorders.

Given the genetic heterogeneity
and variable natural history of the
syndrome, MELAS often is undiagnosed. Patients may present with
a variety of symptoms, specifically
constitutional, GI, and neurologic
complaints. A positive family history, particularly on the maternal
side, provides additional supportive evidence.
Diagnosis is based on early recognition of the constellation of clinical features and on findings of laboratory and imaging studies.
(Sarah Tyler, MD, Katie McPeak,

MD, Childrens Hospital of Pittsburgh, Pittsburgh, Pa.)
EDITORS NOTE. This case was selected for publication from the 10
finalists in the 2008 Clinical Case
Presentation program for residents
held by the Resident Section of the
American Academy of Pediatrics. Dr
Tyler was a resident when she wrote
the case. Choosing which case to
publish involved consideration of the
teaching value and excellence of writing but also the content needs of the
journal. Another case will be chosen
from the finalists presented at this
years AAP National Conference and
Exhibition and published in 2010.
DK
To view Suggested Reading lists
for these cases, visit pedsinreview.
aappublications.org and click on Index of Suspicion.
Index of Suspicion
Daniel H. Reirden, Alexandra N. Menchise, Brian Knox, Rani Gereige, Tamara
Howard, Erica L. Thomas, Rosina Connelly, Sarah Tyler and Katie McPeak
Pediatr. Rev. 2009;30;357-363
DOI: 10.1542/pir.30-9-357
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& Services

Supplementary Material
Supplementary material can be found at:

/DC1

Infectious Diseases
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_diseases Musculoskeletal Disorders
http://pedsinreview.aappublications.org/cgi/collection/musculos
keletal_disorders Neurologic Disorders
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c_disorders Genetics/Dysmorphology
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dysmorphology Metabolic Disorders
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_disorders Respiratory Disorders
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y_disorders Psychosocial Issues and Problems
ial_issues_problems Renal Disorders
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rders

Reprints

Research and Statistics: Cohort Studies

Raquel G. Hernandez and Peter C. Rowe
Pediatr. Rev. 2009;30;364-365
DOI: 10.1542/pir.30-9-364
research and statistics
Cohort Studies
Raquel G. Hernandez, MD, MPH,* Peter C. Rowe, MD*
were two to four times more likely to

experience health symptoms, including
abdominal pain, over the course of a
school year. You wonder whether the
results of this study are accurate and
how they could be relevant to your patient.
sessed. In our case, abdominal pain

was one outcome of interest, although investigators also studied
whether bullying increased the risk
of developing depression, sleeping
problems, headaches, and other
symptoms, thus allowing for a broad
assessment of the potential effects of
bullying.
Cohort Studies
Author Disclosure
Drs Hernandez and Rowe have
disclosed no financial relationships
relevant to this article. This
commentary does not contain a
product/device.
Case Study
You are seeing a previously healthy 10year-old boy for a complaint of periumbilical abdominal pain. He reports
that over the past several weeks, the
pain has occurred intermittently,
without fever, nausea, or diarrhea.
His mother adds that he has asked to
stay home from school due to this pain
numerous times. The physical examination yields unremarkable results.
His mother asks you whether bullying
could be the cause of his abdominal
pain.
You recall a recent article that
posed the question, Do bullied children get ill or do ill children get bullied? (1) This cohort study demonstrated that children who were bullied
*Division of General Pediatrics & Adolescent

Medicine, Johns Hopkins University, Baltimore, Md.
Cohort studies are essential to answering the proverbial question of

what came first . . . the chicken or
the egg. Unlike cross-sectional or
case-control studies, in which a timesequence often cannot be assessed,
cohort studies follow a group of people forward in time from exposure to
outcome, thereby allowing inferences
of causality. In the aforementioned
study, investigators compared the
onset of symptoms (outcome) in a
group of school-age children who
were bullied (exposed) with the experiences of children who did not report bullying (unexposed).
Advantages of a cohort design include allowing an estimation of the
incidence or natural history of a disease or health problem (eg, bullying): How often is bullying reported in this group of children?
and What symptoms occur in children who are bullied? Data derived
from observing patients over time
also allow reporting of relative risks,
hazard ratios, and survival curves,
which often facilitate understanding
of associations between exposure and
outcome. This study design is especially relevant when there is already
good evidence (clinical, physiologic,
or otherwise) to suggest an association of a disease with a certain exposure. Although the groups frequently
are defined by a single exposure
event, multiple outcomes can be as-
Critical Evaluation of Cohort

Studies
Grimes and Schultz propose consideration of four questions when critically evaluating a cohort study to determine its clinical relevance. (2)
How Much Selection Bias is

Present?
Most cohort studies have a component of selection bias, or bias in the
way individuals are enrolled in the
exposed and unexposed groups. Were
steps taken to reduce the differences
between the two groups on items
other than the exposure? In the bullying study, where the sample was
obtained from multiple schools, it
would be important to consider
how different school environments
may have affected selection of the
exposed and unexposed participants.
Did most of the bullied group come
from the rough side of town, resulting in children from more affluent neighborhoods comprising most
of the nonbullied group?
After reviewing this type of study,
the answer to the question of who
is exposed and who is unexposed?
should be readily apparent. Without
such clarity, selection bias may significantly limit an understanding of the
relationship between exposure and
outcome. Thus, for investigators to
determine whether a true relation-
research and statistics
ship actually exists between a complex problem such as bullying and

health outcomes, they first must define systematically the group of children who met their criteria for bullying. In the study, the exposed group
consisted of students reporting being
bullied a few times or more when
asked the question, How often did
other children bully you in recent
months, since summer break?
Using the same internal population
(persons from the same time and place
such as a hospital or school) to identify
the control or unexposed group reduces the risk for selection bias and
improves the estimate of the background rate of the outcome. When
this arrangement is not possible and an
external control must be recruited (often termed a double-cohort study), investigators must be careful to select
populations that have similar baseline
risks for the outcome.
What Steps Were Taken to

Minimize Information Bias?
Information bias refers to a difference in the quality of information
obtained from the exposed and unexposed groups with respect to exposure and outcome. Methods by
which information bias can be reduced include using validated instruments or tests to define outcomes
consistently and having investigators
blinded to exposure to reduce disparities in identifying the outcome of
interest based on their knowledge of
the participants.
Retrospective studies are particularly challenging in this respect because
participant data are obtained from past
records and may not contain key information. In cases where the outcome
of interest is subjective (eg, pain, erythema, mood), attempting to keep
those measuring the outcome blinded
from the participant exposure status is
critical to reducing information bias.
When objective measures such as
death, fever, or positive serologic testing are used, blinding is not believed to
be a necessary step to minimize information bias. Investigators in the bullying study were not blinded to the
childrens reports of bullying, but validated questionnaires were administered to all enrolled children and used
to identify the symptoms of interest.
How Complete Was the

Follow-up of Both Groups?
Nonresponse bias and bias from loss
to follow-up can skew comparisons
significantly between the exposed
and unexposed groups. For example,
children who enrolled in the bullying
cohort at the start of the school year
but then remained home due to illness after being bullied for the subsequent surveys mistakenly could be
considered nonresponders in the
study. If, however, both bullied and
nonbullied children were found to
have equal rates of nonresponse (or
absence from school to prevent study
participation), the nonresponse bias
could be assumed more accurately
not to affect the study results.
Participant attrition is an expectation in most longitudinal studies. Yet
discontinuation from a study can reflect a nonrandom event related to
the exposure and outcome. When
loss to follow-up is disproportionate,
it is critical to evaluate what differences may have contributed to the
losses to follow-up and how this phenomenon might affect the relationship between exposure and outcome.
Were Potential Confounding

Factors Sought and
Controlled for in the
Analysis?
Examples of potential confounders
(variables that relate to both the exposure and outcome) for the relationship between being bullied and
child health outcomes could include
factors such as child ethnicity, social
background, and prior health status.

Because the current study did not
account for these factors, questions
that arise regarding the study conclusions include, Does race or ethnicity play a role in the relationship
between bullying and health outcomes? and What effect does socioeconomic status have on child
health outcomes in those being
bullied? The greater the degree
to which potential confounders are
considered in a cohort, the greater
the potential for valid conclusions regarding the exposure and outcome.
Conclusion
Your patient and his mother are anxiously awaiting your return. As a diligent practitioner, you have noted the
advantages and potential limitations
of the bullying cohort study. You decide
that the conclusions regarding bullying as an antecedent to the onset of
abdominal pain and other health
symptoms in school-age children are
relevant to your patient and may validate the mothers suspicion of the effect
of the childs school experiences on his
pain. In your patients case, it may
require a more detailed history to determine what came first. However,
critically understanding the results of
a relevant cohort study can help you
start to make the connections.
References
1. Fekkes M, Pijpers FIM, Fredriks AM, et
al. Do bullied children get ill, or do ill
children get bullied? A prospective cohort
study on the relationship between bullying
and health-related symptoms. Pediatrics.
2006;117:1568 1574
2. Grimes D, Schulz K. Cohort studies:
marching towards outcomes. Lancet. 2002;
359:341345
Suggested Reading
Gordis L. Epidemiology. Philadelphia, Pa:
WB Saunders Company; 1996
Research and Statistics: Cohort Studies

Raquel G. Hernandez and Peter C. Rowe
Pediatr. Rev. 2009;30;364-365
DOI: 10.1542/pir.30-9-364
Updated Information
& Services


Behavioral and Mental Health Issues
http://pedsinreview.aappublications.org/cgi/collection/behavioral
_mental_health Research and Statistics
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tatistics

Reprints

Pediatrics in the Community: Bulletproof: Using Media as a Tool for Advocacy

Alexander Zusman and Tricia Michels Tayama
Pediatr. Rev. 2009;30;371
DOI: 10.1542/pir.30-9-371
pediatrics in the community
Bulletproof: Using Media as a

Tool for Advocacy
Author Disclosure
Drs Zusman, Tayama, and Aligne
have disclosed no financial
relationships relevant to this article.
This commentary does not contain a
product/device.
The United States has the highest

youth homicide rate among wealthy
nations, and violence is a major cause
of serious injuries in teens, especially
in inner cities. Residents in the Pediatric Leadership for the Underserved
(PLUS) Program at the University of
California at San Francisco decided
to address youth violence in their
community of San Francisco by producing a short documentary film that
tells the story of several youth in different stages of recovery from violent
injury. The film builds on the already
existing Wraparound Project that
uses intensive case management to
link injured patients with communitybased organizations that provide
vocational training, anger management, and other positive skills to
reduce the incidence of reinjury in
at-risk youth. Started by trauma surgeon Rochelle Dicker, the program
has contributed to the proportion
of repeat trauma patients dropping
from about 40% to 5%. (1)
Drs. Alexander Zusman, Tricia
Michels Tayama, and Kajal Khanna
partnered with the Wraparound case
managers to form relationships in the
Bayview/Hunters Point and Mis-
sion neighborhoods of San Francisco.

These neighborhoods are urban areas
of high poverty that are affected disproportionately by violence. Drs. Zusman, Tayama, and Khanna attended
school board meetings and community forums and spoke with teens to
brainstorm what could be done at a
broader level to decrease violent deaths
and injuries. Faculty mentors included
Clement Donahue, MD, a pediatrician
who heads the Teen Trauma Recovery
program at San Francisco General
Hospital, and Anda Kuo, MD, who
directs the PLUS Program.
Inspired by the success of mass media messaging in arenas such as tobacco control, (2) these physicians decided to make a movie as a way of
spreading information about violence
prevention throughout the community. With help from the San Francisco
Film Arts Foundation and the Berkeley
Digital Media Institute, the team created a 23-minute documentary film
(Bulletproof) that portrays youths stories of recovery and reintegration following serious violence-related injury.
The goals of the film project were
to:
Inform health professionals, such as

physicians and social workers, about
youth violence and the best practices
for reducing violence, such as the
Wraparound Project model
Increase awareness of effective prevention programs among at-risk
youth
Foster dialogue among community
members about the best ways to
change social norms related to behaviors that lead to violent injuries
On a personal level, said Dr Zusman, we found hearing the teens stories very challenging and were grateful
for all that they shared in giving us such

privileged insight into their lives. An
unexpected benefit of the project is
that youth in the film are developing
leadership skills by becoming spokespersons for the film. This movie is a
first step at the grassroots level in developing a mass media campaign to
decrease community violence. (Alexander Zusman, MD, Tricia Michels
Tayama, MD, University of California,
San Francisco, Calif.)
SECTION EDITORS NOTE. Not long
ago, doctors were smoking inside hospitals. Now that is unthinkable. Tobacco control is a model for how to
decrease unhealthy behaviors. (3) Gun
injuries will decrease when lethal violence no longer is seen as a socially
appropriate first resort for dealing with
interpersonal problems. (C. Andrew
Aligne, MD, MPH)
SHARE YOUR STORY. Those interested in submitting a story of a resident
community project should contact the
Section Editor: C. Andrew Aligne,
MD, MPH, Co-Director of the PLC
Program, Department of Pediatrics,
University of Rochester School of
Medicine, 601 Elmwood Avenue, Box
777, Rochester, NY 14642 or Andrew
[email protected]
References
1. Cunningham R, Knox L, Fein J, et al.
Before and after the trauma bay: the prevention of violent injury among youth. Ann
Emerg Med. 2009;53:490 500
2. Wakefield M, Flay B, Nichter M,
Giovino G. Effects of anti-smoking advertising on youth smoking: a review. J Health
Commun. 2003;8:229 247
3. Chapman S. Global perspective on tobacco control. Part II. The future of tobacco control: making smoking history? Int
J Tuberculosis Lung Dis. 2008;12:8 12
Pediatrics in the Community: Bulletproof: Using Media as a Tool for Advocacy

Alexander Zusman and Tricia Michels Tayama
Pediatr. Rev. 2009;30;371
DOI: 10.1542/pir.30-9-371
Updated Information
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Parental Monitoring and Discipline in Middle Childhood

Seth J. Scholer and Janet R. Serwint
Pediatr. Rev. 2009;30;366-367
DOI: 10.1542/pir.30-9-366
in brief
In Brief
Seth J. Scholer, MD, MPH
Vanderbilt University
Nashville, Tenn.
Author Disclosure
Drs Scholer and Serwint have
relevant to this In Brief. This
product/device.
Parental Monitoring and the Prevention of Child and Adolescent Problem Behavior: A Conceptual and
Empirical Formulation. Dishion TJ,
McMahon RJ. Clin Child Fam
Psychol Rev. 1998;1:6175
A Developmental Perspective on
Antisocial Behavior. Patterson GR,
Debaryshe BD, Ramsey E.
Am Psychol. 1989;44:329 335
Parental Rules and Monitoring of
Childrens Movie Viewing Associated
With Childrens Risk for Smoking
and Drinking. Dalton MA, AdachiMejia AM, Longacre MR. Pediatrics.
2006;118:19321942
Guidelines for Effective Discipline.
American Academy of Pediatrics,
Committee on Psychosocial Aspects
of Child and Family Health.
Pediatrics. 1998;101:723728
Parental monitoring during middle

childhood (ages 5 to 10 years) can have
a lifelong effect on childrens health.
Parental monitoring includes parents
tracking their childs behavior at home,
in school, and in community environments. Accomplishing this task effectively can be challenging because mon366 Pediatrics in Review Vol.30 No.9 September 2009
itoring must balance the promotion of

independence with communication of
genuine concern about and interest in a
childs activities.
Specific parental monitoring behaviors vary considerably, depending on
the age of the child, individual family
values, the relationship between the
parent and the child, and other influences. By keeping these factors in mind,
parents can ask questions and provide
guidance regarding what children are
doing and with whom they are associating. Parents regularly should be asking questions, such as Where will you
be?, What will you be doing?, and
With whom will you be?
Health-care professionals have reason to be involved because they see
children annually during middle childhood. Clinicians are firsthand witnesses
to the many health-related problems
that can result from poor parental
monitoring, including injuries, antisocial behavior, substance abuse, and
sexually transmitted infections. Mounting evidence suggests that many of
these outcomes can be prevented by
parental monitoring.
Studies have demonstrated that
children who are poorly monitored are
at higher risk of injuries, including poisonings, exposure to hazards in the
home, playground injuries, and sunburn.
Multiple studies have demonstrated
that lower levels of parental monitoring
are associated with higher levels of
aggression in boys. It also is known that
persistent early childhood aggression is
a risk factor for violence later in life.
Although long-term studies are needed,
improved parental monitoring of child
behavior could, in theory, reduce rates
of violence in our society.
Preteens and adolescents who perceive less parental monitoring are more
likely to drink alcohol and smoke. Exposure to media intended for adult
audiences may play a role in this link.
In one study, 55% of children ages 9 to
12 years of age reported that they were
allowed to view R-rated movies. Childrens relative risk of smoking and
drinking decreased by more than 40% if
their parents prohibited the viewing of
R-rated movies compared with children
who were allowed to view such movies.
Poor parental monitoring during the
teen years is associated with an increased likelihood of risky sexual behavior. Adolescents who report less
monitoring are more likely to test positive for a sexually transmitted infection.
For parental monitoring to be effective, a trusting and loving relationship
between a parent and a child is necessary. Parents and children need to be
able to communicate without excessive
conflict to prevent a flight to peer
response, a distancing strategy in which
children spend more time with peers,
resulting in a greater amount of unmonitored activities. A poor parentchild relationship can decrease a parents desire to monitor because the
parent may develop an attitude that
behaviors not seen do not need to be
corrected. Parents can be encouraged
to spend time talking with their children about family values, attending
their childrens activities, listening to
their childrens concerns, and becoming
acquainted with their childrens friends.
In addition to a poor parent-child
relationship, additional barriers to parental monitoring include parental
health (eg, chronic illness) and mental
health problems (eg, depression), pov-
in brief
erty, unemployment, marital conflicts,

and parental attitudes about monitoring their childrens behavior. Employment also can be a barrier if it results in
more hours of unmonitored activity. If
the health-care professional identifies
barriers of concern to parental monitoring during a health supervision visit,
he or she can refer the families to
appropriate community resources (eg,
parenting classes, mental health services, a social worker).
For misbehavior, monitoring must
be coupled with discipline. Parents
should be encouraged to use nonphysical responses such as discussing why
the behavior is wrong, setting limits,
redirecting toward a positive behavior,
promoting empathy, and withdrawing
privileges. Parents should offer frequent
praise for desirable behavior. Physicians
can learn more about discipline options
from guidelines published by the American Academy of Pediatrics.
In summary, health-care clinicians
can help parents understand the basic
tenets of parental monitoring. Appropriate parental monitoring and discipline can result in an increasingly inde-
pendent child who has a healthier

lifestyle.
Comment: Dr Scholer addresses an
anticipatory guidance concept that we
need to emphasize more in health supervision visits. Parental monitoring
demonstrates to children that their parents care and allows parents the opportunity to be more informed about
their childrens activities. Although
balancing monitoring with the childs
growing autonomy, parents also must
ensure that their children are accountable to the values that the parents
have helped to instill. Still, parental
monitoring can be more involved than
it appears at first glance. One example
is monitoring movie viewing, which can
include a parent and child watching
movies together at home, parents accompanying the child to the video store
when renting movies, parents determining what movies their children are
watching when going to the theater
with their friends, and parents knowing
what movies the children will watch at
other friends homes as well as the level
of supervision. The scope and intensity
of the monitoring changes with age,

but some monitoring always is prudent.
As the child gets older, such monitoring
extends past the home and child care
arrangements to school, the neighborhood, and the larger community. The
preventive benefits of parental monitoring have been demonstrated.
Pediatricians need to discuss the
importance of parental monitoring and
guide parents to see this function as a
strategy for healthy parenting. The art
of the parent-child interchange is to set
expectations early and have this exchange be a dialogue of caring rather
than an inquisition. Parents need to be
taught what questions to ask and be
assured that their children will benefit
from such monitoring. Parental monitoring is not about lack of trust between parent and child, but rather
about parental interest in their childrens welfare and activities, demonstrating that they are accountable to
their parents and, in the long run, to
themselves.
Janet R. Serwint, MD
Consulting Editor

Seth J. Scholer and Janet R. Serwint
Pediatr. Rev. 2009;30;366-367
DOI: 10.1542/pir.30-9-366
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Reprints

Cholelithiasis and Cholecystitis

Susan Guralnick and Janet Serwint
Pediatr. Rev. 2009;30;368-369
DOI: 10.1542/pir.30-9-368
in brief
In Brief
Susan Guralnick, MD
Stony Brook University Medical Center
Stony Brook, NY
Author Disclosure
Drs Guralnick and Serwint have
relevant to this In Brief. This
product/device.
Biliary Tract Disease in Children.

McEvoy CF, Suchy FJ. Pediatr Clin
North Am. 1996;42:7598
Cholelithiasis. Friedman JR, Crawford
Kennedy M. eMedicine Specialties, Pediatrics: General Medicine, Gastroenterology. 2009. Available at: http://
www.emedicine.com/ped/topic381.htm.
Accessed June 2009
Cholecystitis. Hebra A, Miller M.
eMedicine Specialties, Pediatrics:
General Medicine, Gastroenterology.
2008. Available at: http://emedicine.
medscape.com/article/927340overview. Accessed June 2009
Gallbladder Disease. ONeill J, Grosfeld J,
Fonkalsrud E. In: Principles of Pediatric Surgery. 2nd ed. St. Louis, Mo:
Mosby; 2004
Cholelithiasis is an uncommon occurrence in healthy children, with an incidence ranging from 0.15% to 0.22%.
The condition is seen more frequently
in children who have certain predisposing conditions. Cholelithiasis can occur
at any age, including prenatally, but is
most common during puberty. Females
are at significantly higher risk, with an
overall 4:1 female-to-male predomi368 Pediatrics in Review Vol.30 No.9 September 2009
nance that increases to 11 to 22:1

during adolescence.
Gallstones form when bile is supersaturated with cholesterol or bilirubin
to the point that the substances no
longer are soluble. This effect, along
with bile stasis, allows the cholesterol
or calcium bilirubinate crystals to remain in the gallbladder (or ductal system for brown stones) long enough to
aggregate and form stones. There are
three types of gallstones. Cholesterol
stones, the most common, are composed of cholesterol, calcium salts, and
glycoproteins and are radiolucent.
Black or pigment stones are radiopaque and result from hemolytic disease. Brown stones are orange, soft,
and greasy; radiolucent; and associated
with infection.
The risk of gallstone formation increases with age in the general pediatric population, with 10% of cases occurring between the ages of 0 and 6
months, 21% between 6 months and
10 years, and 69% between 11 and
21 years. Stone formation has many
predisposing risk factors. Certain ethnic
groups, such as Pima Indians, Scandinavians, and Hispanics, have an increased incidence of cholelithiasis.
Important risk factors for cholelithiasis
include sepsis, hemolytic disease, abdominal surgery (especially ileal resection), malabsorption, receipt of parenteral nutrition, bronchopulmonary
dysplasia, necrotizing enterocolitis,
hepatobiliary disease, cystic fibrosis,
chemotherapy, and an artificial heart
valve.
In older children and adolescents,
obesity, pregnancy, and the use of oral
contraceptives become significant risk
factors. Patients afflicted with sickle
cell disease are at very high risk for
cholelithiasis because of their chronic

hemolytic process. This risk increases
with age through adolescence. Approximately 12% of those affected with
sickle cell disease have cholelithiasis at
ages 2 to 4 years and 42% at ages 15 to
18 years.
Most children are asymptomatic,
with the cholelithiasis discovered incidentally. Only 10% have symptoms
within 5 years of diagnosis, and 25%
are symptomatic by 10 years after diagnosis. Symptomatic children usually
present with intermittent abdominal
pain of variable intensity. Infants may
present with obstructive symptoms,
such as irritability, cholestatic jaundice,
and acholic stools. Diagnosis is made by
ultrasonography of the liver and gallbladder. Liver function tests usually
yield normal findings. Therapy for simple cholelithiasis is symptomatic.
Cholecystitis develops when irritation and inflammation of the gallbladder mucosa develop. Cholecystitis
can be acute or chronic as well as
calculous or acalculous. Acute calculous cholecystitis develops when a gallstone becomes impacted in the cystic
duct, resulting in gallbladder distention
and edema, followed by biliary stasis
and bacterial overgrowth. The most
common organisms involved are Escherichia coli, enterococci, and Klebsiella.
Complications include gallbladder infarction, gangrene, and ultimately,
perforation.
Acalculous cholecystitis is believed
to result from gallbladder dysfunction.
Certain medications are associated
with this form of cholecystitis, including ceftriaxone, furosemide, octreotide,
and cyclosporine. Acute acalculous
cholecystitis also is associated with
acute and chronic infections or sys-
in brief
temic illnesses. Associations have been

found with streptococcal disease, infection by gram-negative organisms,
infection with parasites, and systemic
vasculitis.
Patients who have acute cholecystitis commonly present with nausea,
vomiting, jaundice, and low-grade fever. On physical examination, they
have right upper quadrant pain and
tenderness, sometimes with guarding.
The Murphy sign is the classic physical
finding in patients who have acute
cholecystitis. With this maneuver,
deep palpation of the right upper
quadrant results in arrest of inspiration.
The white blood cell count is elevated,
with a predominance of polymorphonuclear leukocytes and bands. Bilirubin,
alkaline phosphatase, and gammaglutamyltransferase values often are
elevated, accompanied by a direct hyperbilirubinemia. Transaminases and
amylase may be mildly elevated.
Chronic cholecystitis is more common in children than is acute cholecystitis. Cholelithiasis leads to a cycle of
inflammation and chronic obstruction,
resulting in poor contractile function,
biliary stasis, and subsequent bacterial
overgrowth that further exacerbates
the inflammatory response. Chronic
cholecystitis usually presents with episodic attacks of upper abdominal pain,
which can be mild to severe. The patient may have a history of intolerance
of fatty foods. Right upper quadrant
tenderness is not a consistent finding.
Laboratory values may be elevated similarly to those in acute cholecystitis, but
the values may be within normal limits.
Treatment of both acute and chronic
cholecystitis is cholecystectomy. Laparoscopic cholecystectomy is the standard of care in routine cases. In acute
cholecystitis, the patient should be
treated for dehydration and infection
before undertaking surgery. Compli-
cations of cholecystitis can include

choledocholithiasis, biliary obstruction
with or without cholangitis, and biliary
pancreatitis. The Charcot triad (right
upper quadrant pain with fever and
jaundice) indicates common bile duct
obstruction with acute cholangitis and
is considered a surgical emergency.
Comment: Understanding the anatomy and pathophysiology involved in

cholelithiasis and cholecystitis is important in determining who may be
asymptomatic versus those who present
with urgent symptoms that need immediate treatment. In view of our current obesity epidemic, I worry that we
may see an increase in the incidence
of cholesterol stones resulting in cholelithiasis.
Janet Serwint, MD
Consulting Editor
Clarification
On page 162 of the article on pneumococcal infections by Alter in the May issue
(Pediatr Rev. 2009;30:155), in the last sentence of the first paragraph, two different
values of a white blood count are given, neither of which is correct. The sentence
should read, Blood for culture (usually drawn with the CBC) should be submitted if
the white blood cell (WBC) count is 15.0103/mcL (15.0109/L) or greater.
Regarding question #2 in the March issue (Pediatr Rev. 2009;30:93): The question should read, According to recent studies, approximately what percentage of the
risk of developing alcohol dependence is due to genetic factors?
Regarding question # 7 in the May 2009 issue (Pediatr Rev. 2009;30:173): The
purpose of this question is to point out that in cases of isolated primary nocturnal
enuresis, the only laboratory study needed is a screening urinalysis. The question
should not have included the phrase and screening urinalysis but should have just
mentioned the normal physical examination findings.

Susan Guralnick and Janet Serwint
Pediatr. Rev. 2009;30;368-369
DOI: 10.1542/pir.30-9-368
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The Floppy Infant: Evaluation of Hypotonia

Dawn E. Peredo and Mark C. Hannibal
Pediatr. Rev. 2009;30;e66-e76
DOI: 10.1542/pir.30-9-e66
http://pedsinreview.aappublications.org/cgi/content/full/30/9/e66
Article
neurology

Dawn E. Peredo, MD,*
Mark C. Hannibal, MD,
PhD
Author Disclosure
Drs Peredo and
Hannibal have
disclosed no financial
Objectives
1.
2.
3.
4.
5.
Characterize the distinguishing features of hypotonia and muscle weakness.

Describe the differences between central and peripheral causes of hypotonia.
Generate a differential diagnosis of hypotonia in infants.
Discuss the appropriate medical and genetic evaluation of hypotonia in infants.
Understand the need to suspect infant botulism in an infant younger than 6 months of
age who has signs and symptoms such as constipation, listlessness, poor feeding, weak
cry, a decreased gag reflex, and hypotonia.
relationships relevant
to this article. This
commentary does not
of an unapproved/
commercial
product/device.
Introduction
The floppy infant represents a diagnostic challenge to general pediatricians. Infants can
present with hypotonia that is due to central or peripheral nervous system abnormalities,
myopathies, genetic disorders, endocrinopathies, metabolic diseases, and acute or chronic
illness (Table 1). A systematic approach to a child who has hypotonia, paying attention to
the history and clinical examination, is paramount in localizing the problem to a specific
region of the nervous system.
It is important to distinguish weakness from hypotonia. Hypotonia is described as
reduced resistance to passive range of motion in joints; weakness is reduction in the maximum
power that can be generated. A more useful definition of hypotonia is an impairment of the
ability to sustain postural control and movement against gravity. Thus, floppy infants
exhibit poor control of movement, delayed motor skills, and hypotonic motor movement
patterns. The abnormal motor patterns include alterations in postural control, increased
range of motion of joints, and abnormal stability and movement mechanics. Weak infants
always have hypotonia, but hypotonia may exist without weakness.
Because dysfunction at any level of the nervous system can cause hypotonia, the
differential diagnosis is extensive. Central causes, both acute and chronic, are more common
than are peripheral disorders. Central conditions include hypoxic-ischemic encephalopathy,
other encephalopathies, brain insult, intracranial hemorrhage, chromosomal disorders, congenital syndromes, inborn errors of metabolism, and neurometabolic diseases. Peripheral
disorders include abnormalities in the motor unit, specifically in the anterior horn cell (ie,
spinal muscular atrophy), peripheral nerve (ie, myasthenia), neuromuscular junction (ie,
botulism), and muscle (ie, myopathy). Several studies have shown that central causes
account for 60% to 80% of hypotonia cases and that peripheral causes occur in 15% to 30%.
The most common central cause of hypotonia is cerebral palsy or hypoxic encephalopathy
in the young infant. However, this dysfunction may progress in later infancy to hypertonia.
The most common neuromuscular causes, although still rare, are congenital myopathies,
congenital myotonic dystrophy, and spinal muscular atrophy. Some disorders cause both
central and peripheral manifestations, such as acid maltase deficiency (Pompe disease).
Differentiating Central Versus Peripheral Causes

Infants who have hypotonia and do not track visually, fail to imitate facial gestures, or
appear lethargic are more likely to have cerebral or central disorders. Central causes of
hypotonia often are associated with a depressed level of consciousness, predominantly axial
*Developmental Pediatrics, Madigan Army Medical Center, Tacoma, Wash.; Division of Developmental Medicine, Department of
Pediatrics, University of Washington School of Medicine, Seattle, Wash.
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine; Seattle Childrens
Hospital, Seattle, Wash.
e66 Pediatrics in Review Vol.30 No.9 September 2009
neurology
Differential Diagnosis of
Neuromuscular Disorders
Presenting in Newborns
Table 1.
Anterior Horn Cell Disorders
Acute infantile spinal muscular atrophy

Traumatic myelopathy
Hypoxic-ischemic myelopathy
Neurogenic arthrogryposis
Infantile neuronal degeneration
Congenital Motor or Sensory Neuropathies
Hypomyelinating neuropathy
Congenital hypomyelinating neuropathy
Charcot-Marie-Tooth disease
Dejerine-Sottas disease
Hereditary sensory and autonomic neuropathy
Neuromuscular Junction Disorders
Transient acquired neonatal myasthenia

Congenital myasthenia
Magnesium toxicity
Aminoglycoside toxicity
Infantile botulism
Congenital Myopathies
Nemaline myopathy
Central core disease
Myotubular myopathy
Congenital fiber type disproportion myopathy
Multicore myopathy
Muscular Dystrophies
Dystrophinopathies
Congenital muscular dystrophy with merosin deficiency
Congenital muscular dystrophy without merosin deficiency
Congenital muscular dystrophy with brain
malformations or intellectual disability
Walker-Warburg disease
Muscle-eye-brain disease
Fukuyama disease
Congenital muscular dystrophy with cerebellar atrophy/
hypoplasia
Congenital muscular dystrophy with occipital argyria
Early infantile facioscapulohumeral dystrophy
Congenital myotonic dystrophy
Metabolic and Multisystem Diseases
Disorders of glycogen metabolism

Acid maltase deficiency
Severe neonatal phosphofructokinase deficiency
Severe neonatal phosphorylase deficiency
Debrancher deficiency
Primary carnitine deficiency
Peroxisomal disorders
Neonatal adrenoleukodystrophy
Cerebrohepatorenal syndrome (Zellweger)
Disorders of creatine metabolism
Mitochondrial myopathies
Cytochrome-c oxidase deficiency
the floppy infant
weakness, normal strength with hypotonia, and hyperactive or normal reflexes. Other clues to central hypotonia
are abnormalities of brain function, dysmorphic features,
fisting of the hands, scissoring on vertical suspension, and
malformations of other organs. A newborn who has
cortical brain dysfunction also may have early seizures,
abnormal eye movements, apnea, or exaggerated irregular breathing patterns. Central disorders can result from
an injury or an ongoing injury or they can be static,
predominantly genetic or developmental. Hypoxicischemic encephalopathy, teratogens, and metabolic disorders may evolve into hyperreflexia and hypertonia, but
most syndromes do not. Infants who have experienced
central injury usually develop increased tone and deep
tendon reflexes; infants who have central developmental
disorders do not (Table 2).
If a hypotonic infant is alert, responds appropriately to
surroundings, and shows normal sleep-wake patterns,
the hypotonia likely is due to involvement of the peripheral nervous system, specifically the motor unit, which
includes the anterior horn motor neurons of the spinal
cord. Peripheral causes are associated with profound
weakness in addition to hypotonia and hyporeflexia or
areflexia. Disorders of the anterior horn cell present with
hypotonia, generalized weakness, absent reflexes, and
feeding difficulties. In the classic infantile form of spinal
muscular atrophy, fasciculations of the tongue can be
seen as well as an intention tremor. Affected infants have
alert, inquisitive faces but profound distal weakness. Peripheral causes also are associated with muscle atrophy,
lack of abnormalities of other organs, the presence of
respiratory and feeding impairment, and impairments of
ocular or facial movement. Children who have motor
unit disorders are less likely to show involvement of the
brain and spinal cord (Table 2).
Clinical Aspects
The first step in evaluating an infant who exhibits hypotonia is to take a family and past medical history (prenatal, perinatal, and neonatal assessment). The prenatal
history should include information on fetal movement in
utero, fetal presentation, and the amount of amniotic
fluid present. The obstetric history occasionally may
identify both a cause and the timing of onset. Maternal
exposures to toxins or infections suggest a central cause.
Low Apgar scores may suggest floppiness from birth, and
a hypotonic newborn should be considered septic until
proven otherwise. A term infant who is born healthy but
develops floppiness after 12 to 24 hours may have an
inborn error of metabolism. Cervical spinal cord trauma
is a complication of a breech delivery or cervical presenPediatrics in Review Vol.30 No.9 September 2009 e67
neurology
Table 2.
the floppy infant
Localization of Disorders Producing Hypotonia

Central
Injury
Central
Developmental
Anterior
Horn Cell
Peripheral
Nerve
Neuromuscular
Junction
Muscle
Normal or
slight
weakness
Normal to
increased
/
Persistent
Normal or slight
weakness
Weakness
Weakness
Weakness
Weakness
Normal
Decreased
Decreased
Decreased to absent
/
Persistent/Absent
Normal to
decreased
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Prominent
Absent
Absent
Absent
Normal or
disuse
atrophy
Normal or disuse
atrophy
Prominent
atrophy
(proximal)
Distal
atrophy
Normal or
decreased
Sensation
Normal
Normal
Normal
Normal
Tone
Decreased
evolving
to
increased
Decreased
Decreased
Increased
or
decreased
Decreased
Proximal atrophy;
increased or
decreased distal
pseudohypertrophy
Normal
Variable
Strength
Deep tendon
reflexes
Babinski sign
Infantile
reflexes
Muscle
fasciculations
Muscle mass
tation and can present with hypotonia, with other neurologic signs appearing days to weeks later. After the
newborn period, the course of floppiness can be revealing. Central congenital hypotonia does not worsen with
time but may become more readily apparent, whereas
infants suffering central injury usually develop increased
tone and deep tendon reflexes.
The physical examination should include the assessment of pertinent clinical features (eg, the presence of
fixed deformities), a comprehensive neurologic evaluation, and an assessment for dysmorphic features. The
diagnosis of myotonic dystrophy in a floppy newborn is
suggested by a history of uterine dystonia and a difficult
delivery, as well as by examination of the handshake of
the mother, who demonstrates an inability to relax her
hand.
Clinical evaluation includes a detailed neurologic assessment examining tone, strength, and reflexes. To begin assessing tone, a clinician should examine an infants
head size and shape, posture, and movement. A floppy
infant often lies with limbs abducted and extended.
Plagiocephaly frequently is present. Additional techniques for positioning and examining tone include horizontal and vertical suspension and traction. To demonstrate decreased tone, an infant is suspended in the prone
position with the examiners palm underneath the chest
(horizontal suspension). The head and legs hang limply,
Decreased or
normal
Decreased
forming an inverted U posture (Fig. 1). An infant who

has hypotonia slips through at the shoulders when the
examiner grasps him or her under the arms in an upright
position (vertical suspension) (Fig. 2). Head lag or hyperextension is evident when the infant is pulled by the
arms from a supine to sitting position (traction) (Fig. 3).
Figure 1. Infant who has trisomy and hypotonia, showing U

posture with horizontal suspension.
neurology
the floppy infant
Figure 3. A 15-month-old boy who has developmental delay
and hypotonia, as evidenced by significant head lag with

traction.
siflexion. Abnormalities in stability and movement may

manifest in an older infant as a combat crawl, W-sitting
(Fig. 6), a wide-based gait, genu recurvatum, and hyperpronation of the feet. In addition, the child who has
hypotonia may exhibit oral-motor dysfunction, poor respiratory support, and gastroesophageal reflux. Deep
tendon reflexes (DTRs) often are hyperactive in central
conditions, and clonus and primitive reflexes persist; DTRs
Figure 2. A 2-year-old girl who has developmental delay and

hypotonia, as evidenced by the shoulder slip through response with vertical suspension.
Other pertinent findings may include poor trunk extension, astasias (inability to stand due to muscular incoordination) in supported standing, decreased resistance to
flexion and extension of the extremities (Figs. 4, 5),
exaggerated hip abduction, and exaggerated ankle dor-
Figure 4. Hyperlaxity of the finger/wrist joints.

Pediatrics in Review Vol.30 No.9 September 2009 e69
neurology
the floppy infant
Figure 5. Hyperlaxity of hand/wrist/finger joints.
are normal, decreased, or absent in peripheral disorders.

Hypotonia also may manifest in the face (Figs. 7, 8).
Weakness also can manifest as decreased strength and
frequency of spontaneous movements. A complete assessment for weakness includes evaluating for cry, suck,
facial expressions, antigravity movements, resistance to
strength testing, and respiratory effort. Infants who can
generate a full motor response when aroused are more
likely to be hypotonic than weak. The distribution and
course of weakness is crucial to note, that is, if the face is
spared versus the trunk and extremities.
The clinician should note if the hypotonia is fluctuating, static, or progressive. This differentiation discriminates between a static encephalopathy (as is seen in
intellectual disability) and a degenerative neurologic
condition (eg, spinal muscular atrophy). The presence or
absence of dysmorphic features also should be noted on
physical examination.
Figure 7. A 15-month-old boy who has developmental delay,
hypotonia, and hypotonic facies.
Many heritable disorders are associated with hypotonia. The more common syndromes should be considered
with the initial evaluation. Some of these disorders are
described in this article, and frequencies are presented in
Table 3. Refer to specific GeneReviews articles (www.
genetests.org) for additional details.
Specific Disorders
Figure 6. W sitting, a physical finding indicative of joint
hyperlaxity, which can accompany hypotonia.

Trisomy 21 (Down syndrome) is the most common

chromosomal abnormality causing developmental disability. It is characterized by hypotonia, intellectual disability, and congenital heart defects (in 50%). Particular
physical features in the neonate include flattened posterior occiput with brachycephaly, flat facial profile and
nasal bridge, upslanting palpebral fissures, small or
neurology
Figure 8. A 3-year-old girl who has global developmental

delay and hypotonic facies. Note the shape of the mouth and
the eyelid lag.
anomalous ears, short neck with excess nuchal folds,

single transverse palmar creases, hypoplasia of the midphalanx of the fifth digit with clinodactyly, joint hyperextensibility, dysplasia of the pelvis, and a poor Moro
reflex. A high-resolution chromosomal study is diagnostic for most patients. If chromosomes are normal on high
resolution and concern remains, a trisomy screen or
fluorescence in situ hybridization (FISH) testing should
be requested for partial mosaic trisomy.
Fragile X syndrome is another genetic condition characterized by mild-to-profound intellectual disability,
poor eye contact, autistic features, macrocephaly, large
ears, epicanthal folds, a thickened nasal bridge, and increased testicular size in puberty. An expansion of a
trinucleotide repeat (CGG) in the promoter region of
the FMR1 gene at Xq27.3 is responsible for the phenotype and is the basis for the molecular diagnosis of the
disorder. Affected individuals have more than 200 re-
the floppy infant
peats. Premutation carriers also can be detected in this

manner. Although hypotonia generally is a feature during infancy, it is mild, and most children who have fragile
X syndrome are not diagnosed early in life until a delay in
developmental milestones is detected.
Prader-Willi syndrome is characterized by hypotonia,
hypogonadism, intellectual disability, short stature, and
obesity. Affected patients present at birth with profound
hypotonia and feeding problems until 8 to 11 months of
age, when they develop low-normal muscle tone and
insatiable appetites. Prominent physical features during
childhood include a narrow bifrontal diameter, strabismus, almond-shaped eyes, enamel hypoplasia, and small
hands and feet. The genetic abnormality in 75% of patients is a deletion of the long arm of chromosome 15 at
q11-q13. In all cases studied, the paternally derived
chromosome has been deleted. Maternal uniparental
disomy accounts for an additional 20% of cases. The
remaining 5% are due to a mutation of the imprinting
center or to a chromosomal translocation. Methylation
analysis can detect all three molecular defects. If the
methylation study result is abnormal, a FISH study can
be used to define the diagnosis further.
Kabuki syndrome is a multiple congenital anomaly
syndrome associated with hypotonia and feeding problems and is characterized by specific facial features (Fig.
9), mild-to-moderate intellectual disability, postnatal
growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns that have prominent fingertip pads.
Physical features include long palpebral fissures with
eversion of the lateral lower eyelid, large protuberant
ears, cleft palate, tooth abnormalities, skeletal abnormalities, and cardiac and renal defects. Blue sclerae and a
tethered nasal tip also are present. In the absence of
major birth defects, this syndrome is difficult to recognize in neonates. No definitive genetic test or mechanism
of inheritance has been determined, but research is ongoing.
Hypotonia in infancy and developmental delays are
common manifestations in individuals afflicted with
X-linked mental retardation (XLMR). Affected children
typically present with decreased muscle tone early in life,
and striking progression to spasticity may occur. Thirty
syndromes exist in which infantile hypotonia is associated
with XLMR, and recent studies have identified five genes
associated with syndromal intellectual disability. Early
diagnosis often is difficult because distinctive syndromic
findings may be absent in the early years and only hypotonia and developmental delays may exist. One such
disorder is the ATRX syndrome (alpha thalassemiaPediatrics in Review Vol.30 No.9 September 2009 e71
neurology
Table 3.
the floppy infant
Prevalence of Causes of Hypotonia
Cause of Hypotonia
Percentage
in Three
Hypotonic Series
(n277)
Hypoxic-ischemic Encephalopathy
Genetic/Chromosomal Syndromes
Down syndrome
Prader-Willi syndrome
19%
31%
13%
5%
Other dysmorphic syndromes

Other chromosomal anomalies
Fragile X syndrome
9%
4%
1:800 to 1:1,000
1:10,000 to
1:30,000
1:4,000 males
1:8,000 females
1:5,000 to
1:6,000
1:5,000 to
1:10,000
*
1:4,000 to
1:6,400
1:7,500
1:10,000
1:15,000 to
1:25,000
1:14,000
1:50,000
1:30,000
1:20,000 to
1:50,000
Trisomy 18 (Edwards syndrome)

1p36 deletion syndrome
22q13 deletion syndrome
22q11.2 deletion syndrome
(velocardiofacial/DiGeorge syndrome)
Williams syndrome
Trisomy 13 (Patau syndrome)
Smith-Magenis syndrome
Sotos syndrome
Wolf-Hirschhorn syndrome
Kabuki syndrome
Cri du chat syndrome
Brain anomalies
Myopathies
Central core disease
Nemaline myopathy
X-linked myotubular myopathy
Congenital myotonic dystrophy
Metabolic disorders
Peroxisome biogenesis disorders, Zellweger
syndrome spectrum
Smith-Lemli-Opitz syndrome
Prevalence
Distinguishing
Features
Test Available?
Karyotype
Methylation
Karyotype
FMR1 test
Karyotype
Array CGH
Array CGH
Array CGH
Array CGH
Karyotype
Array CGH
Array CGH
Array CGH
None
Karyotype
13%
5%
4%
3%
**
1:50,000
1:50,000
1:100,000
1:50,000
1:20,000 to
1:60,000
1:14,000 to
Cardiomegaly GAA gene; Alpha
1:100,000
glucosidase
1:40,000
(in United States)
Glycogen storage disease Pompe (Type II)
Benign neonatal hypotonia

Spinal muscular atrophy
Muscular dystrophies
3%
2%
2%
Joint laxity
Neuropathy
Teratogens
Brain tumor
Myoclonic encephalopathy
Neuromuscular junction disorder
Familial infantile myasthenia (not transient)
1.4%
1.4%
1%
0.4%
0.4%
0.4%
Unknown
13%
1:10,000
1:20,000 to
1:40,000
1 to
4.4:1,000,000
Decremental EMG,
negative antibodies,
multiple gene tests
for AcHR
AcHRanticholine receptor, EMGelectromyography, CGHcomparative genomic hybridization

*Second most common subtelomeric deletion after 1p36 deletion syndrome (GeneReviews)
**Most common congenital myopathy (GeneReviews)
neurology
Figure 9. Child who has Kabuki syndrome. Note epicanthal
folds, eversion of lateral half of eyelids, and hypotonic facies

with protuberant tongue.
intellectual disability), which is associated with hypotonic

facies and developmental delays. XNP is the causative gene.
Myotonic dystrophy is a multisystem disorder transmitted by autosomal dominant inheritance and caused
by an unstable DNA trinucleotide repeat on chromosome 19 that can expand in successive generations.
Symptoms usually begin in young adult life and include
weakness of the face and distal limb muscles, cataracts,
multiple endocrinopathies, frontal baldness in males, and
myotonia. Congenital myotonic dystrophy (Steinert disease) can afflict infants born to affected mothers. Polyhydramnios is common, labor is prolonged, and delivery
usually requires mechanical assistance. Severely affected
infants have inadequate diaphragm and intercostal muscle function and require assisted mechanical ventilation.
Perinatal asphyxia can be a consequence of a prolonged
and difficult delivery and resuscitation. Facial diplegia,
generalized muscular hypotonia, joint deformities, gastrointestinal dysfunction, and oral motor dysfunction can
occur. Affected infants have a characteristic facial appearance, with tenting of the upper lip, thin cheeks, and
wasting of the temporalis muscles. They also tend to have
dislocated hips, arthrogryposis, and club feet. Limb
weakness is proximal, tendon reflexes usually are absent,
and myotonia may not be elicited on electromyography
(EMG). The patients tend to have intellectual deficits.
the floppy infant
Cardiomyopathy contributes to early death, and the

long-term prognosis is poor. Respiratory failure and an
increased risk of aspiration also lead to early death. If the
infant survives the first 3 postnatal weeks, motor function
may improve, although facial diplegia usually persists.
Spinal muscular atrophies are a heterogeneous group
of disorders, usually genetic in origin, characterized by
the degeneration of anterior horn cells in the spinal cord
and motor nuclei of the brainstem. Symptoms can
present from birth to adult life. Disorders that begin in
infancy are marked by a generalized distribution of weakness. Several clinical syndromes of infantile spinal muscular atrophy exist, one form manifesting between birth
and 6 months of age (Werdnig-Hoffmann disease). Inheritance is autosomal recessive. Newborns often have
arthrogryposis at birth, and weakness progresses rapidly
to respiratory insufficiency and death.
Myasthenia syndromes can be caused by genetic defects or can occur as a transitory phenomenon in 10% to
15% of infants born to women who have myasthenia.
Most myasthenia syndromes are transmitted via autosomal recessive inheritance and are rare (Table 3). Many
infants require assisted ventilation at birth. Arthrogryposis may be present, as well as ptosis and generalized
weakness. The infants are able to be weaned from mechanical ventilation in weeks, but persistent episodes of
weakness and apnea may occur. The diagnosis is established by the patients response to an intravenous or
subcutaneous injection of edrophonium chloride
(0.15 mg/kg). Ptosis and oculomotor paresis are the
only functions that can be tested reliably.
The transitory myasthenic syndrome is due to the
passive placental transfer of antibodies against the
acetylcholine receptor protein from the mother who has
myasthenia to her unaffected fetus. The severity of symptoms correlates with the newborns antibody concentration. Difficulty feeding and generalized hypotonia are
the major clinical features. Symptoms usually occur
within hours of birth or up to 3 days later. Respiratory
insufficiency is uncommon. Although weakness initially
worsens, dramatic resolution subsequently occurs. The
duration of symptoms averages 18 days, and recovery is
complete. The transitory disorder is diagnosed by the
presence of antibodies in the infants blood and the temporary reversal of weakness with injection of edrophonium.
Laboratory Evaluation
The initial laboratory evaluation of the hypotonic newborn is directed at ruling out systemic disorders. Routine
studies should include an evaluation for sepsis (blood
culture, urine culture, cerebrospinal fluid culture and
neurology
the floppy infant
analysis); measurement of serum electrolytes, including

liver functions and ammonia, glucose, calcium, magnesium, and creatinine; a complete blood count; and a
urine drug screen. If hepatosplenomegaly is present and
calcifications are noted on head ultrasonography,
TORCH titers (toxoplasmosis, rubella, cytomegalovirus
infection, herpesvirus infections) and a urine culture for
cytomegalovirus should be undertaken.
If the hypotonia is considered to be central, the practitioner should evaluate for genetic and metabolic causes.
A karyotype is indicated when several significant dysmorphic features are present and can disclose any obvious
cytogenetic defects. Array comparative genomic hybridization study, methylation study for 15q11.2 (PraderWilli/Angelman) imprinting defects, and testing for
known disorders with specific mutational analysis are
now available. Molecular genetic testing provides the
advantage of speed and diagnostic specificity without
invasive procedures. These tests should be chosen according to the clinical presentation of the infant.
If the clinical evaluation suggests complex multisystem involvement, screening for inborn errors of metabolism is indicated. If acidosis is present, plasma amino
acids and urine organic acids (aminoacidopathies and
organic acidemias), serum lactate (disorders of carbohydrate metabolism, mitochondrial disease), pyruvate, ammonia (urea cycle defects), and acylcarnitine profile (organic acidemia, fatty acid oxidation disorder) should be
measured. Very long-chain fatty acids and plasmalogens
are specific for the evaluation of a peroxisomal disorder.
A creatine kinase and acylcarnitine/carnitine concentration should be determined if the child is weak and
exhibits hypotonia to aid in diagnosis of a muscular
dystrophy or carnitine deficiency. The list of neurometabolic conditions associated with hypotonia is immense
and beyond the scope of this review.
To evaluate causes of peripheral hypotonia, creatine
kinase concentrations should be measured. This value is
elevated in muscular dystrophy but not in spinal muscular atrophy or in many myopathies. Specific DNA testing
can be performed for myotonic dystrophy and for spinal
muscular atrophy. Other potentially useful screening
tools include electrophysiologic studies, which show abnormalities in nerves, myopathies, and disorders of the
neuromuscular junction. With the exception of a few
myopathies, normal EMG findings suggest that the hypotonia is central in origin. Muscle biopsy with immunohistochemical staining and electron microscopy is the
method of choice for differentiating myopathies and
muscular dystrophies, although it is more invasive. If
biopsy shows specific abnormalities, it can be an essential
part of the diagnostic evaluation in the newborn to guide

subsequent DNA molecular diagnostic studies.
Radiologic Evaluation
Neuroimaging is a valuable tool for detecting central
nervous system abnormalities. Magnetic resonance imaging can delineate structural malformations, neuronal migrational defects, abnormal signals in the basal ganglia
(mitochondrial abnormalities), or brain stem defects
(Joubert syndrome). Deep white matter changes can be
seen in Lowe syndrome, a peroxisomal defect. Abnormalities in the corpus callosum may occur in SmithLemli-Opitz syndrome; heterotopias may be seen in
congenital muscular dystrophy. Magnetic resonance
spectroscopy also can be revealing for metabolic disease.
Other Diagnostic Considerations

The findings of an enlarged heart in a floppy, weak infant
who has delayed milestones should alert the clinician to
the possibility of a glycogen storage disease (type II Pompe
disease or acid maltase deficiency). This condition is
caused by a deficiency in the lysosomal enzyme acid alpha
glucosidase, present in all tissues, which hydrolyzes maltose to yield glucose but has no function in maintaining
blood glucose. Absent enzyme activity in the infantile
form of Pompe disease results in abnormal glycogen
deposition in the skeletal, cardiac, and smooth muscles,
leading to hypertrophic cardiomyopathy, feeding abnormalities, hypotonia, weakness, respiratory insufficiency,
and ultimately, death. Inherited in an autosomal recessive pattern, the infantile form may present perinatally,
but onset of symptoms usually occurs in the second
postnatal month. Profound generalized hypotonia without atrophy and congestive heart failure are the initial
signs. Hypotonia is the result of glycogen storage in the
brain, spinal cord, and muscle, producing a mixed central
and peripheral clinical picture. Cardiomegaly almost always is diagnostic. Most patients die of cardiac failure by
12 months of age.
The diagnosis of Pompe disease is established by muscle
biopsy, with a definitive diagnosis being demonstrated by
deficient acid maltase activity in fibroblasts or other tissues.
Early diagnosis of Pompe disease results in early institution
of enzyme replacement therapy, which minimizes morbidity and prolongs survival. However, improving the function
of skeletal muscle has proven to be a more challenging
prospect for enzyme replacement therapy, which has not
been shown to affect outcomes in severe cases presenting in
the first few postnatal months with associated congenital
anomalies or ventilator dependence. Recent assays using
neurology
the floppy infant
covery generally is complete, although relapse can occur in

tandem mass spectrometry are likely to prove useful for
up to 5% of infants.
early diagnosis and institution of therapy.
The most common clinical condition, although a
Other important diagnostic considerations for the
diagnosis of exclusion, is benign congenital hypotonia.
primary care clinician include the presentation of an acute
This nonprogressive neuromuscular disorder presents at
or subacute episode of hypotonia. Human botulism ordibirth with delays in achieving developmental milestones.
narily results from eating foods contaminated by preformed
Benign congenital hypotonia improves with the maturity
exotoxin of the organism Clostridium botulinum. The exoof the central nervous system. Characteristics include
toxin blocks the release of acetylcholine at the neuromusgeneralized symmetric flaccidity of muscles and hypercular junction, which results in cholinergic blockade of
mobile joints. Because this is a diagnosis of exclusion, the
skeletal muscle and end organs innervated by autonomic
history must not suggest any neurologic or metabolic
nerves. Infantile botulism is an age-limited disorder in
disorders. Muscle stretch reflexes are normal or only
which C botulinum is ingested, colonizes the intestinal
slightly exaggerated, and routine laboratory test results
tract, and produces toxin in situ. In only 20% of cases,
are within normal limits. Patients must be counseled
contamination with honey or corn syrup is identified.
about the possibility of joint dislocations in the future.
Historically, infants afflicted with botulism are beAn increased incidence of intellectual disability, learning
tween 2 and 26 weeks of age, usually live in a dusty
disability, or other sequelae of cerebral abnormality often
environment adjacent to construction or agricultural soil
is evident later in life, despite the recovery of normal
disruption, and become symptomatic between March and
muscle tone. A high familial incidence also is reported.
October. A prodrome of constipation, lethargy, and poor
This condition must be differentiated from congenital
feeding is followed in 4 to 5 days by progressive bulbar and
muscular dystrophy, which has a high risk of lifeskeletal muscle weakness and loss of DTRs. Progressive
threatening malignant hyperthermia from anesthesia.
muscle paralysis can lead to respiratory failure. Symmetric
The cause of hypotonia in most affected patients is
bulbar nerve palsies manifested as ptosis, sluggish pupillary
central. The greatest diagnostic yield starts with a deresponse to light, ophthalmoplegia, poor suck, difficulty
tailed medical history and examination, including a neuswallowing, decreased gag reflex, and an expressionless face
rologic evaluation and the search for dysmorphic feaare primary features of infantile botulism.
tures. The selective use of neuroimaging, genetic studies,
The differential diagnosis includes sepsis, intoxication,
and biochemical investigations can contribute to a diagdehydration, electrolyte imbalance, encephalitis, myasthenia gravis, and polyneuropathies such as Guillain-Barre
syndrome. Spinal muscular Table 4.
atrophy type I and metabolic
% Successfully
disorders can mimic infantile
Method of Diagnosis
Diagnosed
botulism. Patients who have
History and Physical Examination (Step 1)
50%
spinal muscular atrophy type I
Family history
generally have a longer history
Pregnancy and delivery
of generalized weakness, do
Clinical and neurologic examination
not typically have ophthalmoImaging Study (CT or MRI/MRS) (Step 2)
13%
plegia, and have normal anal
Clinical Genetic Evaluation (Step 3)
9%
Genetic Testing (Step 4)
6%
sphincter tone. Treatment for
Karyotype, FISH, CGH
infantile botulism should be
Biochemical Evaluation (Step 5)
6%
instituted promptly with inAmino acids, organic acids, peroxisomes, carnitine, CDG test
travenous human botulism
Neuromuscular Testing (Step 6)
6%
immune globulin, which neuCK, EMG, NCV, DNA for SMA and CMD, muscle biopsy
Follow-up Testing
7%
tralizes all circulating botuliSome tests repeated/Further tests
num toxin, and supportive
therapy for airway mainteCKcreatine kinase, CMDcongenital muscular dystrophy, CDGcongenital disorder of glycosylation,
CGHcomparative genomic hybridization, CTcomputed tomography scan, EMGelectromyography,
nance, ventilation, and nutriFISHfluorescence in situ hybridization, MRImagnetic resonance imaging, MRSmagnetic resonance spection. Infantile botulism usutrography, NCVnerve conduction velocity, SMAspinal muscular atrophy,
Adapted from Paro-Panjan D, Neubauer D. Congenital hypotonia: is there an algorithm? J Child Neurol.
ally is a self-limited disease
2004;19:439 442
lasting 2 to 6 weeks, and re-
Diagnostic Yield
neurology
the floppy infant
nosis in an additional subset of patients. Invasive studies

with EMG and muscle biopsy only contribute to a small
fraction of diagnoses. A suggested algorithm by ParoPanjan is detailed in Table 4.
pling anatomic deformities. Genetic counseling is an important adjunct for the family.
Treatment
Balmakund J. Hypotonia in children: an approach for evaluation

and treatment. Resid Staff Physician. 1997;43(9):74 89
Battaglia A, Hoyme HE, Dallapiccola B, et al. Further delineation
of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental
retardation. Pediatrics. 2008;121:404 410
Bergen BJ. Evaluation of the hypotonic or floppy infant. Minn Med.
1985;68:341344
Birdi K, Prasad AN, Prasad C, et al. The floppy infant: retrospective
analysis of clinical experience (1990 2000) in a tertiary care
facility. J Child Neurol. 2005;20:803 808
Crawford TO. Clinical evaluation of the floppy infant. Pediatr Ann.
1992;21:348 354
DiMario FJ. Genetic diseases in the etiology of the floppy infant.
Rhode Island Med J. 1989;72:357359
Dubowitz V. Evaluation and differential diagnosis of the hypotonic
infant. Pediatr Rev. 1985;6:237243
Francisco AM, Arnon SS. Clinical mimics of infant botulism. Pediatrics. 2007;119:826 828
GeneReviews at GeneTests: Medical Genetics Information Resource
(database online). Copyright, University of Washington, Seattle, 19972009. Available at: http://www.genetests.org. Accessed July 2009
Igarashi M. Floppy infant syndrome. J Clin Neuromusc Med. 2004;
6:69 90
Jones KL. Smiths Recognizable Patterns of Human Malformation.
6th ed. Philadelphia. Pa: WB Saunders; 2005
Laugel V, Cosse M, Matis J, et al. Diagnostic approach to neonatal
hypotonia: retrospective study on 144 neonates. Eur J Pediatr.
2008;167:517523
Martin K, Inman J, Kirschner A, et al. Characteristics of hypotonia
in children: a consensus opinion of pediatric occupational and
physical therapists. Pediatr Phys Ther. 2005;17:275282
Miller VS, Delgado M, Iannaccone ST. Neonatal hypotonia. Semin
Neurol. 1992;13:73 82
Muensterer O. Infant botulism. Pediatr Rev. 2000;21:427
Paine R. The future of the floppy infant: a follow up study of 133
patients. Dev Med Child Neurol. 1963;5:115124
Paro-Panjan D, Neubauer D. Congenital hypotonia: is there an
algorithm? J Child Neurol. 2004;19:439 442
Prasad AN, Prasad C. The floppy infant: the contribution of genetic
and metabolic disorders. Brain Dev. 2003;27:457 476
Richer LP, Shevell MI, Miller SP. Diagnostic profile of neonatal
hypotonia: an 11-year study. Pediatr Neurol. 2001;25:3237
Vasta I, Kinali M, Messina S, et al. Can clinical signs identify newborns
with neuromuscular disorders? J Pediatr. 2005;146:7379
Zalneraitis EL. The pathophysiology of the floppy infant. Rhode
Island Med J. 1989;72(10):351354
Treatment of the infant who has hypotonia must be tailored

to the specific responsible condition. In general, therapy is
supportive. Rehabilitation is an important therapeutic consideration, with the aid of physical and occupational therapists. Nutrition is of primary importance, often achieved
through nasogastric or percutaneous gastrostomy tubes for
additional caloric supplementation. It also is important to
maximize muscle function and minimize secondary crip-
Summary
Hypotonia is characterized by reduced resistance to
passive range of motion in joints versus weakness,
which is a reduction in the maximum muscle power
that can be generated. (Dubowitz, 1985; Crawford,
1992; Martin, 2005)
Based on strong research evidence, central hypotonia
accounts for 60% to 80% of cases of hypotonia,
whereas peripheral hypotonia is the cause in about
15% to 30% of cases. Disorders causing hypotonia
often are associated with a depressed level of
consciousness, predominantly axial weakness, normal
strength accompanying the hypotonia, and
hyperactive or normal reflexes. (Martin, 2005;
Igarashi, 2004; Richer, 2001; Miller, 1992;
Crawford, 1992; Bergen, 1985; Dubowitz, 1985)
Based on some research evidence, 50% of patients
who have hypotonia are diagnosed by history and
physical examination alone. (Paro-Panjan, 2004)
Based on some research evidence, an appropriate
medical and genetic evaluation of hypotonia in infants
includes a karyotype, DNA-based diagnostic tests, and
cranial imaging. (Battaglia, 2008; Laugel, 2008; Birdi,
2005; Paro-Panjan, 2004; Prasad, 2003; Richer, 2001;
Dimario, 1989)
Based on strong research evidence, infant botulism
should be suspected in an acute or subacute
presentation of hypotonia in an infant younger than
6 months of age who has signs and symptoms such
as constipation, listlessness, poor feeding, weak cry,
and a decreased gag reflex. (Francisco, 2007;
Muensterer, 2000)
Suggested Reading

Dawn E. Peredo and Mark C. Hannibal
Pediatr. Rev. 2009;30;e66-e76
DOI: 10.1542/pir.30-9-e66
Updated Information
& Services

http://pedsinreview.aappublications.org/cgi/content/full/30/9/e66

Neurologic Disorders
http://pedsinreview.aappublications.org/cgi/collection/neurologi
c_disorders Genetics/Dysmorphology
http://pedsinreview.aappublications.org/cgi/collection/genetics_
dysmorphology

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Publisher: American Academy of Pediatrics

PediatricsinReview Vol.30 No.9 September 2009

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