Phenotyping of Adult Asthmatics Visiting Pulmonology OPD of A Tertiary Care Hospital in South India

Amal Johnson¹, Sumi M Sam², Narasimhan R³

¹Post graduate – Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, India
²Physician Assistant – Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, India
³Senior Consultant Pulmonologist, Apollo Hospitals, Greams Road, Chennai, India

Corresponding Author: Dr. Amal Johnson, Post graduate, Department of Respiratory Medicine, Apollo Hospitals, Greams Road, Chennai, India

Asthma is a heterogeneous disease characterized by respiratory symptoms such as wheeze, breathing difficulty, chest tightness and cough that vary over time, in intensity, together with variable expiratory airflow limitation¹. The
chronic respiratory disease affects 1-18% of the population^2-4. The episodic flare in asthma is triggered by various stimuli, such as allergens, climate change, respiratory infections, exercise and irritants. The pathophysiology of asthma is complex involving airway inflammation, intermittent airflow obstruction and bronchial hyperresponsiveness¹.
Phenotype is defined as “The composite, observable characteristics of a disease, resulting from interaction between its genetic make-up and environmental influences, which are relatively stable, but not invariable, with time”. The purpose of phenotyping of asthma is to primarily understand the pathophysiology and to cluster patients that will respond to a specific treatment⁵.

A retrospective study conducted by JL Kuhlen et al⁶ entitled “Identification of Asthma Phenotypes
in a Tertiary Care Medical Center” pubished in Americal Journal of Medical Sciences (2014) in 139 consecutive patients from January 2010 to May 2012 clustered patients with asthma into 5 groups based on SARP(Severe Asthma Research Program Simple Algorithm) by Moore et al⁷. as following 1) Pediatric onset type, atopic type light asthma 2) Pediatric onset, atopic asthma 3) Adult-onset type, primarily nonatopic type 4) Pediatric onset type, atopic type, serious asthma 5) Adult-onset type, atopic type, serious asthma.
In study entitled “Cluster analysis and clinical asthma phenotypes” published by Halder et al⁸ in
Americal Journal of Respiratory and critical care medicine in 2008, he categorized asthma into five phenotypes as following 1) Early onset atopic asthma 2) Obese, noneosinophilic asthma 3) Benign asthma 4) Early symptom predominant asthma 5) Inflammation-predominant asthma.

To categorize diagnosed adult asthmatics visiting OPD of Pulmonology in a tertiary care hospital into various multiple phenotypes based on age of onset, difference in triggers, pattern of airflow obstruction, response to treatment, frequency of exacerbation, co morbidities and type of inflammation.

STUDY TYPE: Cluster analysis
SAMPLE SIZE: 100 consecutive patients with Asthma diagnosed according to GINA guidelines (2019) visiting OPD of Pulmonology
PLACE OF STUDY: Apollo Hospitals, Greams Road, Chennai
DURATION OF STUDY: January 2019 to March 2019
EXCLUSION CRITERIA: Patients were excluded if Age 12% and 200ml). Demographic and clinical data collected included Age, Gender, BMI, age of asthma onset, personal history of allergies(allergic rhinitis/atopic dermatitis), family history of asthma/allergies, smoking history, history of asthma triggers including exercise and NSAIDS use, occupation history, history of exacerbations, history of
respiratory infections, history of comorbidites, drug history including frequency of rescue inhaler use and oral corticosteroids with dose and duration, lung function by PFT, FENO, Serum neutrophil, Absolute eosinophil count and Total IgE.

The various phenotypes for categorization used in the study are
1. Atopic asthma
2. Late onset asthma including asthma in the elderly
3. Aspirin induced Asthma
4. Infection induced Asthma
5. Smoking asthmatic excluding AsthmaCOPD overlap.
6. Exercise induced Asthma
7. Exacerbation prone Asthma
8. Persistent airflow obstruction including reversible restrictive airway disease
9. Obese asthmatic excluding Asthma-COPD overlap
10. Work related asthma – occupational asthma, irritant induced asthma
11. Symptom based phenotype – SOB predominant, wheeze predominant, cough predominant
12. Corticosteroid dependent and resistant asthma
13. Inflammatory phenotype – Eosinophilic, Neutrophilic, Mixed granulocytic, paucigranulocytic

Demographics
Age – Ranged from 18 to 88 with mean of 40 years
Sex – 54 males and 46 females
BMI – Ranged from 16.6 to 41.1 with average of 26.1 kg/mm². BMI was >30 in 13 patients.
Atopic and Non Atopic Asthma
Out of the 100 patients, 75 patients were Atopic asthma and 25 were Non Atopic asthma.
In patients with Atopic asthma, childhood history of asthma in 27 patients (36%), history of atopy (Allergic rhinitis/Atopic dermatitis) in 70(93%) patients and family history of Asthma present in 36(48%) patients. There was a male predominance (60%). Total IgE was elevated in 40(53%) patients with Atopic asthma. FeNO >25 in
all patients and FeNO >50 in 5 patients. In non Atopic Asthma, there was a female predominance(70%) with FeNO > 25 in 50% of patients. Total IgE was elevated in 2 patients.
Inflammatory phenotypes
In our study, based on the serum neutrophil and absolute eosinophil count patients were classified into inflammatory cell predominant phenotype as follows

Eosinophilic – 35%
Neutrophilic – 28%
Mixed cellular – 2%
Paucigranulocytic – 35%

Sputum based phenotype
SOB predominant – 46%
Wheeze predominant – 46%
Cough predominant – 8%

Other relevant phenotypes
There were 16 asthmatics who smoked currently. Six patients diagnosed as Sensitizer induced Occupational asthma (4 cement exposure, 1 coal exposure, 1 chalk dust exposure) and 1 patient diagnosed RADS. One patient developed
asthma post tuberculosis therapy. No exercise induced asthma and aspirin induced asthma cases were noted in the study group.
One patient had exacerbation prone asthma and one patient had corticosteroid dependent/resistant asthma.

Asthma is a chronic inflammatory disease of the airways manifested as variable airflow obstruction with symptoms like cough, shortness of breath and chest tightness.
Characterization of asthma phenotypes is important in order to
1. better understand the etiological mechanisms of asthma
2. identify specific causes
3. guide the development of new therapeutic measures that will be effective for all asthmatic patients
4. enable better management and prevention of asthma⁹

• Atopic asthma
•  Late onset asthma including asthma in the elderly
•  Aspirin induced Asthma
•  Infection induced Asthma
• Smoking asthmatic excluding AsthmaCOPD overlap.
•  Exercise induced Asthma
•  Exacerbation prone Asthma
•  Persistent airflow obstruction including reversible restrictive airway disease
•  Obese asthmatic excluding Asthma-COPD overlap
•  Work related asthma – occupational asthma, irritant induced asthma
•  Symptom based phenotype – SOB predominant, wheeze predominant, cough predominant
•  Corticosteroid dependent and resistant asthma
•  Inflammatory phenotype – Eosinophilic, Neutrophilic, Mixed granulocytic, paucigranulocytic

This is the most common phenotype of asthma and the onset is typically during childhood/adolescence with male predominance. It is a Th2 dominant inflammatory process with both airway and blood eosinophilia. This phenotype of
asthma usually accompanies history of allergic rhinitis/dermatitis with family history of allergy. This subtype responds well to steroids and omalizumab.
In contrast to atopic asthma, there is a late onset, female predominance without allergic sensitization. Most of the patients do not give personal or family history of allergy. This phenotype is more severe than allergic asthma and less responsive to steroids.
In our study, Out of the 100 patients included, 75 patients were Atopic asthma and 25 were Non Atopic asthma.
In patients with Atopic asthma, childhood history of asthma in 27 patients (36%), history of atopy (Allergic rhinitis/Atopic dermatitis) in 70(93%) patients and family history of Asthma present in 36(48%) patients. There was a male predominance (60%). Total IgE was elevated in 40(53%) patients with Atopic asthma. FeNO >25 in
all patients and FeNO >50 in 5 patients.
In non Atopic Asthma, there was a female predominance (70%) with FeNO > 25 in 50% of patients. Total IgE was elevated in 2 patients.
This is in concordance with the results of Moore et al⁷. where Atopic allergic asthma was seen in 82% of patients and almost all patients had elevated IgE. FeNO was >35 in Atopic asthma whereas it is around 10-12 in non atopic asthma. There was a female premodinance in severe asthmatics both in atopic and non atopic type.

This phenotype is associated with HLA-DW2 and DPB1. The usual age of onset of symptoms is 20-35 years. Patients with ASA experience rhinorrhea and nasal congestion followed by severe bronchospasm within 2 hours after ingestion of NSAID aspirin. The prevalence of AIA is 21 % according to study by Varghese et al.30 but we did not have any patients with AIA.

Infection induced asthma¹³

In this phenotype, the respiratory infection influences asthma in association with onset of disease/exacerbation of disease/persistence of disease. In our study, one patient developed asthma post tuberculosis therapy.

Smoking asthmatics^{14, 15}

Patients with asthma who smoke have severe symptoms, accelerated decline in lung function, quality of life and impaired therapeutic response to corticosteroids and theophylline. Smoking greatly modifies inflammation that is associated with asthma by various mechanisms. The prevalence of smoking in asthmatics is around 25% according to
Parasuramalu et al31 and was 16% in our study.

*Criteria for diagnosis of Asthma-COPD overlap

Major –

• Age >=40 years
• Post bronchodilator FEV1/FVC =10 pack years of tobacco or equivalent indoor or outdoor air pollution
• Documentation of asthma before age 40 years or BDR of >=400ml in FEV1

Minor –

• Documentation of allergic rhinitis or atopic disease
• BDR >=200ml and 12% from baseline values on two or more encounters
• Peripheral serum eosinophil counts >=300 cells/ml

If all major and at least one minor criteria are present, it is termed positive.

Exercise induced asthma(EIA)16

Due to evaporation of heat and water loss from the airway Starts within 3-5mins with peak bronchoconstriction occurring at 10-15 minutes.
Usually defined as >=10% decrease in FEV1 after exercise. Exercise induced asthma may be followed by refractory perior of 4 hours during which repeated exercise causes less bronchoconstriction. Symptoms may be relieved
with beta agonist therapy. The prevalence of EIA was 5-20% according to Weiler et al³². but we did not see any patients with EIA in our study.

Exacerbation prone asthma17-19

This phenotype is characterized with history of severe exacerbation requiring an emergency room visit or hospitalization atleast once in 3 months. The increased exacerbation is independent of asthma control. On stable condition, they were mild-moderate asthmatics rather than severe asthmatics.
We had one exacerbation prone asthma in our study compared to Global prevalence of 10% according to study by Stanojevic et al³³.

Persistent airflow obstruction20

This is a unique phenotype characterized by reduced FEV1/FVC in a patient receiving treatment with high dose ICS during stable phase of disease for at least 4 weeks. The decreased response to short acting bronchilators is due to airway remodeling caused by chronic inflammation of airways.
We had one patient under this subtype in our study compared to the global prevalence of 7.5% according to Roche et al34.

*Risk factors for persistent airflow obstruction –

Earlier age of onset
Longer disease duration
More severe asthma
Non atopic disease/absence of rhinitis
Very frequent exacerbations
Smoking
More inflammatory cells in sputum
Greater smooth muscle hypertrophy

Importance of earlier identification of this subtype is to avoid misdiagnosis of COPD and intensive follow-up of the patients for prompt management.

Inflammatory phenotypes21

Based on the predominant inflammatory cell involved in bronchitis, asthma can be phenotyped into aucigranulocytic, eosinophilic, neutrophilic and mixed granulocytic. Eosinophilic asthma (40%) is early onset allergic asthma (Th2 mediated inflammation) and responsive to steroids and biological agents . Non eosinophic asthma is severe
asthma phenotype (Th17 mediated inflammation) characterized by poor symptom control and corticosteroid resistance.
In our study, based on the serum neutrophil and absolute eosinophil count patients were classified into inflammatory cell predominantphenotype as follows
Eosinophilic – 35%
Neutrophilic – 28%
Mixed cellular – 2%
Paucigranulocytic – 35%
In our study, 35% patients were eosinophilic and paucigranulocytic each with neutrophilic(28%) followed by mixed cellular. This is in concordance with SARP analysis by Moore et al⁷.

Obese Asthma22-24

Obese asthma is characterized by early onset allergic asthma complicated by development of obesity in later age. The asthma is worsened by intra abdominal and chest wall mass which causes increased pressure on the diaphragm and chest wall causing lower tidal volume hindering bronchodilator action.
According to GC forte et al35, the prevalence of BMI >30 in asthmatics is around 13% and this is in concordance with our study.

Work related asthma^25-27

• Occupational asthma

1. Sensitizer induced asthma
2. RADS(Reactive airway dysfunction
syndrome)

• Work exacerbated asthma

*Occupational asthma
Sensitizer induced asthma – appears after a latency period of sensitization to the causal agent
RADS (Reactive airway dysfunction syndrome) – Clinical criteria

• Documented absence of preceding respiratory complaints
• Onset of symptoms occurred after a single specific exposure to irritant
• High concentration of irritant exposure(gas/fume/spray)
• Onset 3 months
• Symptoms simulated asthma with cough, wheeze and dyspnea predominant
•  Spirometry show reversible airflow obstruction
• Methacholine challenge test was positive
• Other types of pulmonary diseases were ruled out

*Work exacerbated asthma – Patients with pre existing asthma developed worsened symptoms when exposed to occupational allergens.
In our study, six patients diagnosed as Sensitizer induced Occupational asthma (4 cement exposure, 1 coal exposure, 1 chalk dust exposure) and 1 patient diagnosed RADS. This is in concordance with results of RD Caldaeira et al where prevalence of work related asthma is 4.2%.

Symptom based phenotype28

SOB phenotype – respond well to ICS
Cough predominant – respond well to Montelukast
Wheeze predominant – respond well to ICS + Montelukast

In our study, breathing difficulty and wheeze were predominant symptoms followed by cough predominant in only 8% of patients as in study by Zedan et al²⁸.

Corticosteroid dependent and corticosteroid resistant asthma²⁹

Corticosteroid resistant asthma is defined as <=15% improvement in FEV1 after 2 weeks of oral prednisolone therapy 40 mg once daily. Corticosteroid dependent asthma is defined as 15-30% improvement in FEV1 after 2 weeks of oral
prednisolone therapy 40 mg once daily. Patients experience cushingoid side effects due to high dose steroid use and experience withdrawal symptoms along with worsening of symptoms and lung function after stepping down or temporary stoppage of steroid therapy.
In our study we had one patient with corticosteroid dependent asthma compared to 5-10% by SK Lukhadia et al29.

Conclusion

Asthma is not a single disease but rather a syndrome with various presentations and differential response to same treatment. There is no current guideline evidence for treatment based on phenotype so far. Future direction for research in this aspect will assist in making individualized specific treatment plan and better control of the
disease. This study is an elementary attempt to categorize diagnosed adult asthmatics into various clusters based on onset, difference in triggers, pattern of airflow obstruction, response to treatment, frequency of exacerbation, co-morbidities and type of inflammation.

Acknowledgment

We sincerely thank the management of Apollo Hospitals for the constant support in our pursuit of excellence.

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