Background: Viral respiratory infections are the leading trigger of asthma exacerbations and impaired epithelial type I and III interferon 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 concentration in patients with uncontrolled asthma.
Methods: In the investigator-initiated, double-blind, placebo-controlled AZIMUNE trial, 40 adults with uncontrolled asthma were randomized (1:1) to azithromycin (500 mg, three times/week) or placebo (500 mg/week) 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 (IL-33 and thymic stromal lymphopoietin (TSLP)), and proinflammatory cytokines were quantified.
Results: Azithromycin significantly increased rhinovirus-induced concentration of IFN-β (p=0.047) and IFN-λ (p=0.013) in azithromycin group (n=16) compared with baseline, whereas no change was seen in the placebo group (n=16). Azithromycin treatment also reduced IL-33 concentration (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 concentration in response to rhinoviral infection in asthma. The dual immunomodulatory effect of azithromycin supports its role as adjunctive therapy to prevent virus-induced exacerbations.
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