Increased Capsaicin Sensitivity in Patients With Severe Asthma Is Associated With Worse Clinical Outcome

To study the role of capsaicin cough reflex sensitivity (C-CS) as a marker of airway neuronal dysfunction in severe asthmatics.

The study included 157 adults with asthma based on symptoms, positive methacholine challenge, and treatment response to inhaled corticosteroids, of which 122 patients had severe asthma based on Global Initiative for Asthma (GINA) guidelines. Patients were enrolled between November 2016 and October 2019. Current smokers were excluded.

This is an observational prospective cohort study. All enrolled participants completed the asthma control test (ACT), FeNO measurement, spirometry and a capsaicin challenge test. Capsaicin concentrations inhaled were serially increased until at least 5 coughs were induced (C5). C5 was stratified arbitrarily at the 25th percentile as low/high (low C5 indicated heightened sensitivity). Additionally, presence of comorbidities, atopy, and biomarkers were assessed. Severe asthma was based on European Respiratory Society/American Thoracic Society asthma guidelines [ACT<20, exacerbations ≥2 per year bursts of systemic corticosteroids, ≥ 1 per year hospitalizations, FEV1<80%].

Heightened C-CS was seen more often among severe asthmatics [17.2% vs 50% with a low C5 among high versus low ACT score, P < .0001; 24.8% vs 50% with a low C5 among those with <2 vs ≥2 exacerbations/year, P = .008; 25.7% vs 58.8% with a low C5 among those with 0 vs ≥1 admissions/year; no effect on airflow limitation]. A heightened C-CS was seen especially among non-atopic patients as compared with atopic individuals (P = .02). In a multivariate model with C5 values, biomarkers, and comorbidities, a heightened C-CS increased odds of poor asthma control (OR 4.83, 95% CI 1.97–10.4); frequent exacerbations (OR 2.83, 95% CI 1.04–7.71) and a possible trend toward hospitalizations (not statistically significant).

A heightened C-CS could be a potential marker of the airway neuronal dysfunction underlying severe asthma, especially in non-atopic asthma.

Despite substantial advances in the therapeutic landscape for asthma with several emerging biologics, our understanding of non-atopic phenotypes in asthma remains limited with a paucity of potential therapeutic options. Cough hyper-responsiveness via the TRPV1 (transient receptor potential vanilloid-1) pathway in airway sensory nerves is thought to be the pathophysiology underlying heightened C-CS especially in non-atopic individuals. Capsaicin activates TRPV1 so increased response to this stimulus may help to identify severe asthmatics. While capsaicin does not cause bronchoconstriction in most mild-moderate asthmatics, the tolerability of capsaicin as a routine cough challenge agent has yet to be established. The concept of airway neuronal dysfunction as a potential therapeutic target is interesting, but the impact of anti TRPV1 antagonists in non-atopic asthma remains to be seen.