How does azithromycin improve asthma exacerbations?

Abstract

We read with interest the Article by Peter G Gibson and colleagues (July 4, 2017, p 659),1Gibson PG Yang IA Upham JW et al.Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.Lancet. 2017; 390: 659-668Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar which clearly showed the beneficial effects of macrolide therapy on the incidence of asthma exacerbations. Increasingly, asthma is recognised as a heterogeneous disease with multiple phenotypes and endotypes. By contrast with the effects of anti-inflammatory treatment with inhaled corticosteroids, leukotriene receptor antagonists, and biological therapies—for which therapeutic efficacy depends on the inflammatory profile—Gibson and colleagues showed no differential benefit in terms of eosinophilic inflammation over non-eosinophilic inflammation. Macrolides have shown benefits across several respiratory diseases, with varied pathological processes and inflammatory profiles. The mechanism underlying these benefits is poorly understood, although the immunomodulatory and anti-infective properties of macrolides are usually credited. The positive effect of macrolides on the gastrointestinal tract is often overlooked. Reflux disease is prevalent in asthma and is recognised to contribute to exacerbations.2Havemann BD Henderson CA El-Serag HB The association between gastro-oesophageal reflux disease and asthma: a systematic review.Gut. 2007; 56: 1654-1664Crossref PubMed Scopus (227) Google Scholar Although acid suppression has not been shown to be beneficial in improving asthma control, it only targets acid production and, therefore, non-acid reflux will persist. Azithromycin has been shown to be a potent agonist of the hormone motilin.3Broad J Sanger GJ The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin.Br J Pharmacol. 2013; 168: 1859-1867Crossref PubMed Scopus (61) Google Scholar Motilin improves gastrointestinal motility, reducing reflux and aspiration.4Mertens V Blondeau K Pauwels A et al.Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients.Dig Dis Sci. 2009; 54: 972-979Crossref PubMed Scopus (86) Google Scholar The adverse effect profile of azithromycin reported in the study by Gibson and colleagues reflects this effect. We suggest that, as in chronic obstructive pulmonary disease and other diverse respiratory diseases, azithromycin's beneficial effect is due to a reduction in the deleterious effects of unrecognised reflux and aspiration. We declare no competing interests. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trialAdults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. Full-Text PDF How does azithromycin improve asthma exacerbations? – Author's replyTwo key findings of the AMAZES trial1 are relevant to asthma management. First, the addition of low-dose azithromycin to a combination of inhaled corticosteroids and long-acting bronchodilators led to a clinically significant reduction in asthma exacerbations in adults with poorly controlled asthma. This finding provides an additional therapeutic option for these patients. Second, the effect occurred equally in both eosinophilic and non-eosinophilic asthma, by an as yet unidentified mechanism, but acting on pathways other than type 2 inflammation. Full-Text PDF