COMMENTARY

Clinical Presentations and Treatment Implications of Asthma

Challenges and Opportunities

Aaron B. Holley, MD

Disclosures

March 01, 2018

About 7% of Americans have asthma, and population prevalence estimates are as high as 18% in some countries.[1] Given its burden to global health, significant resources have been devoted to studying the biophysiologic mechanisms responsible for asthma. The recent approval of monoclonal antibodies targeting interleukin-5 (mepolizumab and reslizumab) and its receptor (benralizumab) highlight the potential benefits from phenotyping asthma and understanding the underlying molecular pathways.

The American Journal of Respiratory and Critical Care Medicine started the new year with a review article[2] summarizing what we know about the different clinical, cellular, and molecular types of asthma.

This review starts by dividing asthma into two cellular categories: eosinophilic asthma and noneosinophilic asthma (NEA). Unfortunately, this isn't as easy as it might sound. Although there is general agreement on the definitions for sputum (> 2%-3%), bronchoalveolar lavage (> 2%-3%), and endobronchial (> 20 eosinophils/mm2) eosinophilia, sputum analysis is technically difficult, and patients with asthma do not routinely have a bronchoscopy. Serum eosinophils are routinely obtained, but they fluctuate over time and a clear threshold for "eosinophilia" has not been defined. The review suggests using the definitions from the clinical trials for interleukin-5 inhibitors.[2] The authors acknowledge this can be misleading, given there is a somewhat linear relationship between serum eosinophil levels and response to therapy.[3] Most would agree that levels > 300-400 cells/µL constitute eosinophilia.

Categorization gets more difficult from there. Gone are the days when eosinophilia equals atopy/allergy, which corresponds to excellent response to corticosteroids. The review lists up to eight different phenotypes with elevated eosinophils. Types with limited atopy include "severe late-onset hypereosinophilic," "exacerbation prone," and "exercise-induced" asthma. Underlying these eight phenotypes are several different molecular pathways or endotypes. Unfortunately, it is difficult to test routinely for cytokines and other markers that might help identify each phenotype.

The review notes that 50% of asthmatics will have NEA, and these patients are less well studied. There are four subphenotypes: two with neutrophilia and two with absence of airway inflammation. Criteria for defining neutrophilia range anywhere from 40% to > 76% of sputum counts, and serum neutrophils are not strongly correlated with airway counts. Corticosteroids have variable efficacy in neutrophilic phenotypes, and no efficacy for obesity-induced and paucigranulocytic asthma. In contrast to eosinophilic phenotypes, targeted biologics have generally not been effective. Macrolides, statins, glitazones, and phosphodiesterase-4 inhibitors have shown improvements in specific outcomes in small studies.

For targeted asthma therapy, it is not clear whether the glass is half-empty or half-full. On one hand, molecular studies have successfully identified effective, steroid-sparing agents for severe asthmatics. We know infinitely more about the biological pathways that lead to airway abnormalities, and this knowledge should eventually translate to effective treatments. On the other hand, phenotypes remain difficult to define in clinical practice, biologics are expensive, and treatment options for NEA are limited.

I'm staying positive. There is no doubt we are better able to treat asthma now than we were 10 years ago. There is no reason to think that improvements won't continue.

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