Does Smoking Status Modify the Efficacy of Azithromycin Prophylaxis in COPD? A Systematic Review

Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by recurrent  exacerbations that significantly contribute to morbidity and healthcare burden. Long-term azithromycin prophylaxis has been shown to reduce exacerbations; however, its efficacy may vary depending on patient characteristics, particularly smoking status.

Objective: To assess whether smoking status modifies the efficacy of long-term azithromycin therapy for exacerbation prevention in adults with COPD.

Methods: A systematic review was conducted following PRISMA guidelines. Literature was searched in PubMed, Cochrane Library, and ScienceDirect using predefined Booleankeywords. Eligible studies included adults with COPD receiving long-term azithromycin therapy for exacerbation prevention and reporting exacerbation-related outcomes with available smoking-status data. A qualitative synthesis was performed due to heterogeneity in study design and reporting.

Results: Four studies were included, comprising two randomized controlled trials, one retrospective cohort, and one model-based analysis. Sample sizes ranged from 20 to 1,142 patients. Azithromycin was associated with reduced exacerbation frequency, with first exacerbation hazard ratio 0.73 (95% CI 0.63–0.84) and prolonged time to first exacerbation (266 vs 174 days) in the largest trial. Additional studies demonstrated reductions in exacerbation rates from 3.22 to 1.94 events/year and from 6.8 to 2.8 events/year. Subgroup signals indicated that treatment response varied by smoking status, with reduced benefit observed in current smokers. Model-based analysis further suggested a net clinical benefit in former smokers but not in current smokers.

Discussion: The findings suggest that smoking status may modify the efficacy of azithromycin, potentially due to persistent airway inflammation and altered immune response in current smokers.

Conclusion: Long-term azithromycin therapy may reduce exacerbations in selected patients with COPD, particularly those with frequent exacerbations. However, evidence that smoking status modifies treatment effectiveness remains limited, and the apparent attenuation of benefit among current smokers should be considered hypothesis-generating rather than confirmatory.