Using Phenotypes and Endotypes of Asthma in Treatment Paradigms

Asthma is a common respiratory disease in children and adults, affecting an estimated 8.2% of the US population and more than 300 million people worldwide.^1-3 Although asthma is largely characterized by airflow obstruction, wheezing, and cough, patterns of exacerbations and therapeutic responses leading to remission remain highly varied and heterogeneous. Patterns of treatment resistance are of great clinical concern, and evidence suggests they are likely due to important differences in underlying genetic and epigenetic influences that play important roles in molecular mechanisms.³

For the majority of patients, asthma is well controlled with standard corticosteroid therapies; however, there exists a known subset of patients who have persistent severe symptoms and signs of airway inflammation, even throughout continued courses of inhaled corticosteroids (ICS) and systemic corticosteroid treatments used to reduce inflammation.⁴ Nearly 50% of these treatment refractory patients will continue to have at least 1 exacerbation annually that often leads to impaired quality of life and possible life-threatening events.⁴

Application of SARP Phenotypes

Before 2000, different forms of severe asthma were not well defined in the literature.⁴ The National Heart, Lung, and Blood Institute’s Severe Asthma Research Program (SARP) delineated clinical, biological, and genetic features of severe asthma in both adults and children in 2001. Definitions of “severe” asthma were based on 2 primary features identified by an American Thoracic Society Workshop: (1) treatment with continuous high-dose ICS or continuous systemic corticosteroids and (2) at least 2 minor criteria that demonstrated poor asthma control or life-threatening disease.⁴

Five phenotypic asthma clusters were identified by SARP that differentiated phenotypes by age of onset, allergen sensitization, lung function, medications, healthcare utilization, and comorbidities.^1,4-6 Three of the phenotypes were found in children, and 2 were specific to adults.^1,4-6

Clusters 1 and 2 were considered mild to moderate, with early pediatric onset. “Mild” symptoms were those occurring less than once daily, causing sleep disturbances less than once weekly. Exacerbations were infrequent and responded sufficiently to glucocorticoid treatment for a return to normal lung function. Clusters 3 and 5 were defined as severe asthma occurring in adults. In general, adult-onset asthma has demonstrated a more severe course, although cluster 4 represented severe asthma in children. Adult asthma also shows a lower remission rate compared with pediatric onset and is less likely to be associated with comorbid allergies.¹ Severe symptoms in adults were most often accompanied by elevations of eosinophils and neutrophils detected with sputum analysis.⁴ 

Cluster 1 – Early-onset allergic/atopic asthma: Asthma onset most commonly occurs before age 6. Patients with this mild early-onset phenotype are more likely to experience recurrent infections and eczema than are those who develop asthma later.

Cluster 2 – Early onset, atopic asthma: This pediatric form of moderate asthma encompasses the largest group of patients with asthma and requires long-term use of corticosteroids, generally at higher doses than for cluster 1 patients.

Cluster 3 – Late onset, allergic asthma: Asthma type occurring in adult individuals with high disease impairment despite normal lung function. This phenotype applies more often to women than to men and is associated with obesity.

Cluster 4 – Severe, early onset allergic/atopic asthma: A severe form of asthma that has an early pediatric onset.

Cluster 5 – Late (adolescent/early adult) onset asthma: Symptoms are severe, with chronic airflow obstruction that is less likely to be sufficiently managed or improved with the use of bronchodilator therapies.

Since the introduction of phenotypes, asthma experts have sought to make them clinically meaningful, although this has proved disappointing.^1,3,4 Schoettler and Strek¹ wrote in a late 2019 review that, “Although SARP phenotypes have been important in identifying features that distinguish different clusters of patients with asthma, the phenotypes cannot be easily incorporated into clinical decision-making.” This led to exploration of endotypes, based on distinct functional or pathobiologic mechanisms that could be married to known phenotypes to help determine optimal therapies for individual patients.

Exploring Patterns of Endotypes

Immune profiling has allowed for more specific individual characteristics of asthma to be identified as targets for therapy. The Schoettler and Strek¹ review points out that currently, more than 60 genetic loci have been linked to asthma, many with direct associations to severe asthma, involving multiple genes, including IL33, IL1RL1, and CDHR3. Associations between asthma phenotypes and the airway microbiome have also emerged, as demonstrated by findings of high levels of Pseudomonadaceae and Enterobacteriaceae in sputum from patients with severe asthma. “Collectively, endotyping in severe asthma has highlighted the prominent role of several immune mechanisms,” the authors wrote.¹

One of the most prominent areas of exploration, Schoettler and Strek¹ suggested, is a high occurrence of Th2 inflammation in severe asthma that may be marked by immunoglobulin E (IgE) levels and blood eosinophil counts.¹ Immunotherapies that target the Th2 pathway have also been identified, including omalizumab, which along with other biologic therapies should be considered for asthma with concurrent allergen sensitization and an elevated IgE levels, whereas dupilumab was recently approved for treatment of moderate to severe asthma. They also pointed to potential benefits in using targeted therapies such as mepolizumab (an anti-interleukin 5 agent that has demonstrated potential to improve eosinophil counts), as well as interleukin blockers reslizumab and benralizumab, for severe asthma. All 3 agents have been shown to reduce asthma exacerbations.¹

With many targeted therapy studies under way, the strategies for asthma management continue to evolve rapidly, with hopes of increasing the options for individual patients with asthma, particularly those with treatment-resistant patterns of disease.

References

1. Schoettler N, Strek ME. Recent advances in severe asthma: from phenotypes to personalized medicine [published online October 31, 2019]. CHEST. doi:10.1016/j.chest.2019.10.009

2. Chung KF. Precision medicine in asthma: linking phenotypes to targeted treatments. Curr Opin Pulm Med. 2018;24(1):4-10.

3. Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA. The concepts of asthma endotypes and phenotypes to guide current and novel treatment strategies. Expert Rev Respir Med. 2018;12(9):733-743.

4. Fitzpatrick AM, Moore WC. Severe asthma phenotypes – how should they guide evaluation and treatment? J Allergy Clin Immunol Pract. 2017;5(4):901-908.

5. Koczulla AR, Vogelmeier CF, Garn H, Renz H. New concepts in asthma: clinical phenotypes and pathophysiological mechanisms. Drug Discov Today. 2017;22(2):388-396.

6. Hirose M, Horiguchi T. Asthma phenotypes. J Gen Fam Med. 2017;18(5):189-194.