DEPARTMENT OF PULMONARY MEDICINE

GMC, SRINAGAR
 CERTIFICATE

This is to certify that DR ZUHAIB YOUNUS has been registered as a

postgraduate student in the department of pulmonary medicine,
Government Medical College , Srinagar and adequate facilities for
her thesis entitled ““PREVALENCE OF SEVERE ASTHMA AND
VARIOUS ASTHMA PHENOTYPES IN COHORT OF ASTHMA
PATIENTS AT TERTIARY CARE CENTRE”” in the department of
Pulmonary Medicine, Government Medical College, Srinagar will
be provided to the candidate for this study and research.
Guide: Prof. (Dr.) Naveed Nazir Shah Co-Guide: Dr Fahim Manzoor
Professor and Head Associate Professor
Department of Pulmonary Medicine. Department of Pathology
SYNOPSIS FOR PG DISSEARTION UNDER KASHMIR
UNIVERSITY.

TOPIC: “PREVALENCE OF SEVERE ASTHMA AND

VARIOUS ASTHMA PHENOTYPES IN COHORT OF
ASTHMA PATIENTS AT
TERTIARY CARE CENTRE”

PG SCHOLAR:DR ZUHAIB YOUNUS

INTRODUCTION
Asthma is a common, chronic respiratory disease affecting 1–29% of the population in different countries.
Asthma is characterized by variable symptoms of wheeze, shortness of breath, chest tightness and/or cough,
and by variable expiratory airflow limitation [1.] Both symptoms and airflow limitation characteristically vary
over time and in intensity. These variations are often triggered by factors such as exercise, allergen or irritant
exposure, change in weather, or viral respiratory infections. Symptoms and airflow limitation may resolve
spontaneously or in response to medication, and may sometimes be absent for weeks or months at a time. On
the other hand, patients can experience episodic flare-ups (exacerbations) of asthma that may be life-
threatening and carry a significant burden to patients and the community. The majority of asthma deaths
occur in low- and middle-income countries. Asthma is usually associated with airway hyper-responsiveness to
direct or indirect stimuli, and with chronic airway inflammation. These features usually persist, even when
symptoms are absent or lung function is normal, but may normalize with treatment.

DEFINITION
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the
history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary
over time and in intensity, together with variable expiratory airflow limitation. [1]
This definition was reached by consensus, based on consideration of the characteristics that are typical of
asthma before ICS-containing treatment is commenced, and that distinguish it from other respiratory
conditions. However, airflow limitation may become persistent later in the course of the disease.

Patterns of respiratory symptoms that are

characteristic of asthma
The following features are typical of asthma and, if present, increase the probability that the patient has
asthma:
Respiratory symptoms of wheeze, shortness of breath, cough and/or chest tightness:
• Patients (especially adults) experience more than one of these types of symptoms.
• Symptoms are often worse at night or in the early morning.
• Symptoms vary over time and in intensity.
• Symptoms are triggered by viral infections (colds), exercise, allergen exposure, changes in weather, laughter,
or irritants such as car exhaust fumes, smoke or strong smells.
The following features decrease the probability that respiratory symptoms are due to asthma:
• Isolated cough with no other respiratory symptoms (see p.31)
• Chronic production of sputum
• Shortness of breath associated with dizziness, light-headedness or peripheral tingling (paresthesia)
• Chest pain
• Exercise-induced dyspnea with noisy inspiration.

DIAGNOSIS
The diagnosis of asthma is based on the history of characteristic symptom patterns and evidence of variable
expiratory airflow limitation. This should be documented from bronchodilator reversibility testing or other
tests. Test before treating, wherever possible, i.e. document the evidence for the diagnosis of asthma before
starting ICS-containing treatment, as it is often more difficult to confirm the diagnosis once asthma control has
improved. [1]

Additional or alternative strategies may be needed to confirm the diagnosis of asthma in particular
populations, including patients already on ICS-containing treatment, the elderly, and those in low-resource
settings.
Diagnostic flowchart for clinical practice:
SEVERE ASTHMA
Severe asthma is defined as asthma that remains uncontrolled despite optimized treatment with high-dose
ICS-LABA, or that requires high-dose ICS-LABA to prevent it from becoming uncontrolled. Severe asthma must
be distinguished from asthma that is difficult to treat due to inadequate or inappropriate treatment, or
persistent problems with adherence or comorbidities such as chronic rhinosinusitis or obesity,as they need
very different treatment compared with if asthma is relatively refractory to high-dose ICS-LABA or even oral
corticosteroids (OCS). [1]

ASTHMA PHENOTYPES
Asthma is a heterogeneous disease, with different underlying disease processes. Recognizable clusters of
demographic, clinical and/or pathophysiological characteristics are often called ‘asthma phenotypes’.16-18 In
patients with more severe asthma, some phenotype-guided treatments are available. more severe asthma,
some phenotype-guided treatments are available. However, except in patients with severe asthma, no strong
relationship has been found between specific pathological features and particular clinical patterns or
treatment responses.
Many clinical phenotypes of asthma have been identified[1]. Some of the most common are:
• Allergic asthma: This is the most easily recognized asthma phenotype, which often commences in childhood
and is associated with a past and/or family history of allergic disease such as eczema, allergic rhinitis, or food
or drug allergy. Total Serum IgE > 30 IU/ml with or without Eosinophils: >1.01% (sputum), >150 cells/ul
(blood). Examination of the induced sputum of these patients before treatment often reveals eosinophilic
airway inflammation. Patients with this asthma phenotype usually respond well to inhaled corticosteroid (ICS)
treatment.

• Non-allergic asthma: Some patients have asthma that is not associated with allergy. Total IgE <30 IU/ml
(Serum). The cellular profile of the sputum of these patients may be neutrophilic (>61% neutrophils in
sputum), eosinophilic (>1.01% eosinophils in sputum or >150 cells/ul of blood) or contain only a few
inflammatory cells (paucigranulocytic). Patients with non-allergic asthma often demonstrate a lesser short-
term response to ICS.

• Adult-onset (late-onset) asthma: Some adults, particularly women, present with asthma for the first time in
adult life. These patients tend to be non-allergic, and often require higher doses of ICS or are relatively
refractory to corticosteroid treatment. Occupational asthma (i.e. asthma due to exposures at work) should be
ruled out in patients presenting with adult-onset asthma.

• Asthma with persistent airflow limitation: Some patients with long-standing asthma develop airflow
limitation that is persistent or incompletely reversible. This is thought to be due to airway wall remodeling.

• Asthma with obesity: Some obese patients (BMI >30kg/m2), especially men, with asthma have prominent
respiratory symptoms and little eosinophilic airway inflammation.

EVALUATION OF PATIENTS WITH BRONCHIAL

ASTHMA
AIM OF THE STUDY
To determine the cases of Severe Asthma and to study Phenotypes among the patients of Asthma, visiting the
Government Chest Disease Hospital, Srinagar.

OBJECTIVES OF THE STUDY

To find the prevalence of Severe Asthma and various Phenotypes of Asthma.

MATERIALS AND METHODS

SETUP: The study will be conducted at Chest Disease Hospital, an associated hospital of GMC Srinagar,
which is a referral tertiary care chest disease hospital of the Kashmir Valley.

STUDY DESIGN: The study will be a cross-sectional study which will be conducted after approval
from ethical committee, in the department of pulmonary medicine, GMC Srinagar.

STUDY POPULATION: 1. Previously diagnosed cases of bronchial asthma based on

history/clinical features and Spirometry

2. Patients presenting with typical symptoms of Bronchial Asthma and positive Spirometry with BDR

3. Patients presenting with typical symptoms of Bronchial Asthma with normal Spirometry/BDR or unable to
perform Spirometry, however raised FeNO (>25 ppb) or increased small airway resistance on IOS, visiting the
OPD/IPD in Government Chest Diseases Hospital, GMC Srinagar.

INCLUSION CRITERIA:

All patients > 18 years with history/clinical features suggestive of bronchial asthma with Spirometrically
documented obstruction and reversibility and patients with typical symptoms of Bronchial Asthma with
normal Spirometry/BDR, however raised FeNO (>25 ppb) or increased small airway resistance on IOS.

EXCLUSION CRITERIA:

Patients with other co-existing respiratory diseases (e.g., COPD, ILD, Tuberculosis, Bronchiectasis).
Patients who negate to participate in the study.

METHODS:
The study will be conducted in the patients reporting to CD Hospital either on out-patient or in-patient basis
meeting the inclusion criteria. The panel of investigations that will be followed in patients as found relevant
(investigations will be individualised in each patient) for the phenotyping and Severity of disease will be as
follows:

Spirometry with Bronchodilator reversibility

Absolute Eosionophil Count

Total Serum IgE

Sputum analysis for eosinophils, neutrophils etc.

FeNO (if needed)

Impulse Oscillometry (if needed)

CBC with Differential counts

Chest X-ray P/A view

High resolution computed tomography Chest (if needed)

NCCT of sinuses (if needed)

In addition, information regarding various demographic parameters, BMI, duration of asthma, severity of
asthma, level of asthma control (using ACQ-5), asthma medications, comorbid illnesses, systemic steroid use,
history of exacerbation, will be recorded.

DATA GENERATION
All patients who present to the hospital whether on outpatient basis or inpatient or referral basis will be made
to go through all the above mentioned investigations till the phenotyping and severity of their disease is
identified.
REVIEW OF LITERATURE:
Chantal Raherison-Semjen , Eric Parrat, Cécilia
Nocent-Eijnani et al.
One thousand and four hundred twenty four patients from 107 centers
were included in this analysis. A five cluster model best described the
dataset. Cluster 1 comprised 47% of the cohort, had early onset allergic
asthma (52% with asthma before 12 years), cluster 2 (n=153, 10.5%,)
comprised obese asthma (63.4% with BMI>30 kg/m2), more often men,
cluster 3 (n=299, 20.4%) had late-onset asthma with 60.2% having
asthma after 40 years old, cluster 4 (n=143, 9.8%) comprised eosinophilic
asthma (51.7% had more than 500 eosinophils/mm3 ), and cluster 5
(n=139, 9.5%) had aspirin sensitivity asthma (with 63% had severe
asthma attacks).

F. Schleich, G. Brusselle, R. Louis, O. Vandenplas et al.

The cross-sectional analyses of Belgian registry included 350 severe
asthma from 9 Belgian centres, with at least one year follow up. SA was
seen more frequently in females (57%) and atopic (70%). Late-onset
asthma (≥40 yr) was observed in 31% of SA. Current smokers represented
12% while 31% were ex-smokers. Induced sputum was successful in 86
patients. Eosinophilic asthma (sputum Eos ≥ 3%) was the predominant
phenotype (55%) while neutrophilic (sputum Neu ≥ 76%) and
paucigranulocytic asthma accounted for 22% and 17% respectively.
Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal
polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%)
and depression (19%). In addition, 8% had aspirin-induced asthma and
3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20
and 77% with ACQ > 1.5.

Lucy Pembrey, Collin Brooks, Harriet Mpairwe et al.; the

WASP Study Group
The aim of this study was to compare asthma inflammatory phenotypes
in high-income countries (HICs) and low-and middle-income countries
(LMICs). This study assessed sputum inflammatory phenotypes in five
centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United
Kingdom (UK). Phenotyping of 115 patients was done in Brazil, out of
which 33% were Eosinophillic, 61% were Pauci-granulocytic, 04% were
Neutophillic and 02% were Mixed granulocytic.
Similarly phenotyping of 125 patients was done in Ecuador, out of which
28% were Eosinophillic, 62% were Pauci-granulocytic, 06% were
Neutophillic and 04% were Mixed granulocytic.
Phenotyping of 98 patients in Uganda revealed: 25% were Eosinophillic,
32% were Pauci-granulocytic, 35% were Neutophillic and 08% were
Mixed granulocytic.
Phenotyping of 98 patients in New Zealand revealed: 48% were
Eosinophillic, 43% were Pauci-granulocytic, 7% were Neutophillic and 2%
were Mixed granulocytic.
Phenotyping of 98 patients in UK revealed: 31% were Eosinophillic, 59%
were Pauci-granulocytic, 08% were Neutophillic and 03% were Mixed
granulocytic.
A total of 623 patients were studied and phenotyped, out of which 35%
were Eosinophillic, 50% were Pauci-granulocytic, 11% were Neutophillic
and 04% were Mixed granulocytic.
Sophie Demarche,corresponding author Florence Schleich,
Monique Henket et al.
A retrospective cross-sectional study on 833 asthmatics recruited from
the University Asthma Clinic of Liege and asthmatics were classified into
inflammatory phenotypes. 51% were Eosinophillic, 29% were Pauci-
granulocytic, 13% were Neutophillic and 07% were Mixed granulocytic.

Jodie L. Simpson Patrick McElduff Peter G. Gibson

The aim of this study was to determine the reproducibility of non-
eosinophilic asthma. One hundred and twenty two sputum samples were
obtained (success 94%). All cut points greater than 2% eosinophils were
reproducible and a 3% cut point resulted in the highest agreement with a
statistic of 0.538. Specificity and sensitivity were high for determining
inflammatory subtype after 1 or 3 sputum samples. A cut point of 3%
eosinophils should be used to distinguish eosinophilic from non-
eosinophilic airway inflammation in asthma. This allows a single sputum
sample to be used to reliably determine the presence of eosinophilia.

Wendy C. Moore, Deborah A. Meyers, Sally E. Wenzel et

al.
This study aimed at to identify novel asthma phenotypes using an
unsupervised hierarchical cluster analysis. Five groups were identified.
Subjects in Cluster 1 (n = 110) have early onset atopic asthma with
normal lung function treated with two or fewer controller medications
(82%) and minimal health care utilization. Cluster 2 (n = 321) consists of
subjects with early-onset atopic asthma and preserved lung function but
increased medication requirements (29% on three or more medications)
and health care utilization. Cluster 3 (n = 59) is a unique group of mostly
older obese women with late-onset nonatopic asthma, moderate
reductions in FEV1, and frequent oral corticosteroid use to manage
exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe
airflow obstruction with bronchodilator responsiveness but differ in to
their ability to attain normal lung function, age of asthma onset, atopic
status, and use of oral corticosteroids. Cluster 4 is characterized by equal
representation of both genders and many subjects with childhood onset
(72%) and atopic disease (83%), whereas Cluster 5 consists of more
women (63%) with mainly later-onset disease (69% late onset) and less
atopy (66%). Subjects in Cluster 4 have severe reductions in pulmonary
function at baseline (mean FEV1 57% predicted), but 40% of subjects are
able to reverse to the near normal range (>80% predicted) after six to
eight puffs of albuterol. In contrast, subjects in Cluster 5 have the most
severe airflow limitation at baseline (mean FEV1 43% predicted), and,
despite some response to maximum bronchodilator testing, 94% of
subjects remain with a FEV1 <80% predicted.

Pieter-Paul W Hekking , Reinier R Wener , Marijke Amelink

et al.
The aim of the present study is to make a reliable estimation of the
prevalence of difficult-to-control asthma and severe refractory asthma.
Questionnaires were sent to 5,002 patients, of which 2,312 were
analyzed. The diagnosis of asthma and degree of asthma control were
derived from questionnaires to identify patients with difficult-to-control
asthma. Inhalation technique was assessed in a random sample of 60
adherent patients (prescription filling, ≥80%). Patients with difficult-to-
control asthma, adherence to treatment, and a correct inhalation
technique were qualified as having severe refractory asthma. Results
were mirrored to the Dutch population. Of asthmatic adults, 3.6% (95%
CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma,
representing 10.4 patients per 10,000 inhabitants.

Anna von Bülow , Margit Kriegbaum , Vibeke Backer ,

Celeste Porsbjerg
A descriptive cross-sectional register study was performed. By using a
nationwide prescription database, we identified current patients with
asthma (age, 18-44 years) in 2010. Severity was classified as severe
versus mild-moderate asthma according to the level of antiasthma
treatment. Based on the level of treatment, 8.1% of a nationwide
population of current patients with asthma was classified as having
severe asthma

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1. Global Initiative for Asthma (GINA). Global strategy for asthma
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2. Raherison-Semjen C, Parrat E, Nocent-Eijnani C, Mangiapan G,
Prudhomme A, Oster JP, Aperre de Vecchi C, Maurer C, Debieuvre
D, Portel L; CPHG (College of French Non-academic Hospitals).
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French Severe Asthma Study using cluster analysis. Respir Res.
2021.
3. Schleich F, Brusselle G, Louis R, Vandenplas O, Michils A, Pilette C,
Peche R, Manise M, Joos G. Heterogeneity of phenotypes in severe
asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir
Med. 2014.
4. The ENFUMOSA cross-sectional European multicentre study of the
clinical phenotype of chronic severe asthma. European Network for
Understanding. Mechanisms of Severe Asthma. Eur Respir J. 2003.
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shouldthey guide evaluation and treatment? J Allergy Clin Immunol
Pract.2017.
6. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel
EH.The prevalence of severe refractory asthma. J Allergy Clin
Immunol. 2015.
7. von Bulow A, Kriegbaum M, Backer V, Porsbjerg C. The prevalence
of severe asthma and low asthma control among Danish adults. J
Allergy Clin Immu-nol Pract. 2014.
8. Schatz M, Hsu JW, Zeiger RS, Chen W, Dorenbaum A, Chipps BE, et
al. Phe-notypes determined by cluster analysis in severe or difcult-
to-treat asthma.J Allergy Clin Immunol. 2014.
9. Proceedings of the ATS workshop on refractory asthma: current
understanding, recommendations, and unanswered questions.
American Thoracic Society. Am J Respir Crit Care Med 2000.
10. Bel E.H., Sousa A., Fleming L., Bush A., Chung K.F., Versnel J., et. al.:
Diagnosis and definition of severe refractory asthma: an
international consensus statement from the Innovative Medicine
Initiative (IMI). Thorax 2011.
 11. Simpson JL, McElduff P, Gibson PG. Assessment and reproducibility
of non-eosinophilic asthma using induced sputum. Respiration.
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12. Pembrey L, Barreto ML, Douwes J, Cooper P, Henderson J, Mpairwe
H, Ardura-Garcia C, Chico M, Brooks C, Cruz AA, Elliott AM,
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Phenotypes (WASP) international collaboration. ERJ Open Res.
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PATIENT’S PROFORMA

EVALUATION OF ASTHMA PATIENTS AT TERTIARY CARE HOSPITAL IN KASHMIR VALLEY

Name_____________________________________ Age_____ (years) Sex_______ (Male/Female)

Residence___________________________________ Contact No.__________________________

Occupation________________________________ Aadhar Number: _________________________

Symptoms consistent with Asthma_____________________________________________(YES/NO).

History of Allergies/ Atopy ___________________(YES/NO) BMI__________kg/m2

On Medium/ High Dose ICS-LABA or Maintenance OCS ____________________________ (Yes/ No)

Modifiable Risk Factors/ Triggers (Beta Blocker/ NSAIDs)____________________________ (Yes/ No)

Inhaler Technique _____________ (Correct/ Incorrect) Adherence _________ (Optimal/ Suboptimal)

Comorbid Illness 1. ________________2. ________________ 3. ______________ 4. _____________

ACQ-5 Score ___________________

CLINICAL FEATURES:
Chest tightness_____________(Yes/No) Wheeze___________________(Yes/No)

Cough ____________________(Yes/No) Dyspnea __________________(Yes/No)

SIGNS:
Pulse___________(B/M) Respiratory Rate__________(B/M)
Polyphonic wheeze_______________(Yes/No) SpO2_________________ (% ORA)

LABS:
Pulmonary Function Test:

a)FEV1/FVC ____________________________________________________________________

b)BDR _________________________________________________________________________

FeNO _________________________________________________________________________

Serum Total IgE ________________________________________________________________

Absolute Eosinophil Count _______________________________________________________

Sputum analysis for eosinophils, neutrophils _________________________________________

Impulse Oscillometry (If required) _________________________________________________

RADIOLOGICAL INVESTIGATIONS:
CHEST X RAY _______________________________________________________________________

HRCT CHEST (If required) ____________________________________________________________

NCCT PNS (If required) ______________________________________________________________