Abstract Chronic cough, infections, and acute exacerbations contribute to Idiopathic Pulmonary Fibrosis (IPF) morbidity; macrolides’ immunomodulatory effects suggest a potential prophylactic role. We systematically reviewed azithromycin use in adult IPF. Following PRISMA guidelines, we searched PubMed, Embase, and Google Scholar (2015-2025) for studies of IPF patients on low-dose azithromycin. Eligible designs included RCTs, cohorts, and mechanistic studies; acute-exacerbation-only and non-IPF studies were excluded. Two reviewers independently screened data, and risk of bias was assessed (Cochrane RoB2 for RCTs, Newcastle-Ottawa for cohorts). No meta-analysis was performed due to heterogeneity. Four studies met the inclusion criteria: one randomized crossover trial, one prospective mechanistic sub-study, one retrospective cohort, and one laboratory fibroblast study. The retrospective UK cohort (n≈108 frequent-exacerbation IPF patients) found that one-year azithromycin prophylaxis (250 mg M/W/F) markedly reduced infection-related events (∼72% fewer non-elective hospitalizations) and antibiotic use. The RCT (n = 25) in Switzerland compared azithromycin 500 mg 3×/wk vs placebo (each for 12 weeks, crossover) in IPF patients with chronic cough. No significant difference was seen in cough-specific quality of life (Leicester Cough Questionnaire score) or objective cough frequency, but gastrointestinal side effects (diarrhea) were significantly more common on azithromycin (43% vs 5%, P = 0.03). A linked sub-study of 24 RCT participants analyzed airway samples (oropharyngeal swabs, sputum) via 16S rRNA sequencing. Three months of azithromycin altered the lung microbiota—diversity declined (especially in sputum) and composition shifted (↑Streptococcus, ↓Prevotella), with effects lasting ∼1 month post-therapy. Another in-vitro study demonstrated molecular-level effects. Azithromycin (50 μM) reduced collagen-I secretion and pro-fibrotic gene expression, impaired autophagy, and induced greater early apoptosis in IPF fibroblasts compared to controls, with attenuated ATP6V0D2 upregulation, suggesting heightened lysosomal dysfunction in IPF cells. No study demonstrated a benefit of azithromycin on pulmonary function decline or overall survival. Evidence for chronic azithromycin in IPF is limited and mixed. A retrospective cohort study suggested fewer infection-related hospitalizations and antibiotic use, whereas a randomized trial found no improvement in cough and more gastrointestinal effects. Mechanistic studies show persistent airway microbiome shifts and direct anti-fibrotic, pro-apoptotic actions in IPF fibroblasts. These findings suggest azithromycin may serve as an adjunct for high-risk patients prone to infections or exacerbations, but not as a substitute for antifibrotic therapy. Its role in disease progression remains uncertain, warranting larger randomized trials to clarify benefits, identify suitable patient subsets, and assess long-term safety and resistance. This abstract is funded by: None
Luthra et al. (Fri,) studied this question.