Is there a role for macrolides in severe asthma?

Abstract

Severe asthma is a heterogeneous syndrome, encompassing several distinct clinical phenotypes. Different molecular and cellular pathways or endotypes determine the type of underlying airway inflammation in patients with severe asthma, which can be categorized as eosinophilic asthma (allergic and nonallergic) or noneosinophilic asthma (neutrophilic and paucigranulocytic). In this review, we discuss the potential role of macrolides in the treatment of severe asthma in adults. Maintenance treatment with low-dose macrolides such as erythromycin and azithromycin provides clinical benefit in several chronic neutrophilic airway diseases, including cystic fibrosis (CF), non-CF bronchiectasis and exacerbation-prone chronic obstructive pulmonary disease. Although several short-term studies of macrolides in mild-to-moderate asthma have failed to improve lung function, the AzIthromycin in Severe Asthma trial has demonstrated a significant reduction in the rate of exacerbations in patients with exacerbation-prone noneosinophilic severe asthma. As chronic macrolide use is associated with the risks of population antimicrobial resistance, this add-on treatment should be restricted to severe asthma patients at greatest unmet need despite optimal asthma management. Further clinical, translational and basic research is needed to better phenotype patients with severe asthma, to determine the risk-benefit ratio of macrolide maintenance treatment in neutrophilic severe asthma and to elucidate the principal mechanisms of action of macrolides.