Azithromycin enhances epithelial antiviral immunity in uncontrolled asthma: results from the AZIMUNE randomised controlled trial

Background Viral respiratory infections are the leading trigger of asthma exacerbations, and impaired epithelial type I and III interferon (IFN) responses may contribute to more severe exacerbations. Azithromycin reduces exacerbations clinically, but its effects on epithelial antiviral immunity remain unclear. This study investigated whether azithromycin treatment enhances airway epithelial antiviral responses and modulates alarmin concentrations in patients with uncontrolled asthma. Methods In the investigator-initiated, double-blind, placebo-controlled AZIMUNE trial, 40 adults with uncontrolled asthma were randomised (1:1) to azithromycin (500 mg three times per week) or placebo (identical regimen) for 12 weeks. Bronchial epithelial cells were obtained via bronchoscopy at baseline and after week 12, and cultured and infected ex vivo with rhinovirus. Protein levels of IFN-β, IFN-λ, alarmins (interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP)) and pro-inflammatory cytokines were quantified. Results Azithromycin significantly increased rhinovirus-induced concentrations of IFN-β (p=0.047) and IFN-λ (p=0.013) in the azithromycin group (n=16) compared with baseline, whereas no change was seen in the placebo group (n=16). Azithromycin treatment also reduced IL-33 concentrations (p=0.001), while TSLP levels were unaffected. Clinical outcomes improved numerically in the azithromycin group, but differences versus placebo were not statistically significant. Conclusions Azithromycin enhances epithelial antiviral immunity and attenuates IL-33 concentrations in response to rhinoviral infection in asthma. The dual immunomodulatory effect of azithromycin supports its role as adjunctive therapy to prevent virus-induced exacerbations.