Long-term azithromycin therapy for bronchiolitis obliterans syndrome: divide and conquer?

Background: Azithromycin may reverse or halt the decline of pulmonary function (FEV(1)) in bronchiolitis obliterans syndrome (BOS). In this study we investigated the effects of long-term azithromycin treatment in lung transplant recipients with BOS.

Methods: A retrospective, observational, cohort study was performed on 107 patients with BOS (Stages 0p/1/2/3, n = 23/62/20/2), who were treated with azithromycin for 3.1 ± 1.9 years. Patients were evaluated 6.3 ± 3.8 years after transplantation and assessed for evolution of FEV(1), bronchoalveolar lavage neutrophilia and overall survival after initiation of azithromycin. Survival curves were analyzed using the log-rank test. Cox proportional hazard survival regression analysis was performed to estimate hazard ratios of clinical variables predicting outcome.

Results: FEV(1) increased ≥ 10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV(1) further declined in 78% and stabilized in 22% of the remaining non-responders. Pre-treatment neutrophilia was higher in responders: 29.3% (9.3% to 69.7%) vs 11.5% (2.9% to 43.8%) (p = 0.025), in whom it significantly decreased to 4.2% (1.8% to 17.6%) (p = 0.041) after 3 to 6 months of azithromycin. Responders demonstrated better survival compared with non-responders (p = 0.050), with 6 and 21 patients, respectively, dying during follow-up (p = 0.027). Multivariate analysis identified initial azithromycin response and earlier post-transplant initiation of azithromycin to be protective for both BOS progression/relapse (hazard ratio [HR] = 0.12 [95% confidence interval 0.05 to 0.28], p < 0.0001; and HR = 0.98 [95% confidence interval 0.97 to 0.98], p < 0.0001, respectively) and retransplantation/death during follow-up (HR 0.10 [95% confidence interval 0.02 to 0.48], p = 0.004; and HR 0.96 [95% confidence interval 0.95 to 0.98], p < 0.0001, respectively).

Conclusions: Long-term azithromycin benefits pulmonary function and survival in BOS, particularly in patients with increased lavage neutrophilia.