Original clinical science
Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer?

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Background

Azithromycin may reverse or halt the decline of pulmonary function (FEV1) 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 FEV1, 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

FEV1 increased ≥10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV1 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.

Section snippets

Study design and population

All LTx procedures performed from July 1991 to January 2009 at our center were retrospectively evaluated. Patients who were part of a randomized, placebo-controlled trial of AZI (enrollment from July 2005 to December 2007, n = 83) were excluded from the current study. In case of retransplantation, evolution over time after each LTx procedure was taken into account for outcome analysis. Patients included were classified based on AZI use and those who received ≥3 months of treatment with AZI for

Study population

Long-term macrolide therapy was used in 43.2% (164 of 380) of all LTx recipients at our center (Figure 1). In these patients, AZI was initiated for BOS in 65.8% (n = 108/164) and for other indications in 34.1% (56 of 164) of patients. One patient in the BOS cohort initiated on AZI was excluded from further analyses, as subsequent evolution of FEV1 could not be assessed because of follow-up <3 months due to the patient's death. Because AZI was introduced at our center starting in 2003, the “AZI

Discussion

This cohort study, which is the largest and has the longest follow-up with AZI thus far (mean 3.1 ± 1.9 years, median 1.7 [0.7 to 4.0] years), has demonstrated that long-term AZI therapy significantly improves pulmonary function in about 40% of LTx recipients with BOS. No severe adverse events were noted with long-term AZI therapy. The current data confirm previous case series9, 16, 17, 18, 19, 20 and retrospective cohort studies of long-term macrolide treatment for BOS.8, 21 However, 33% of

Disclosure statement

The first three authors (R.V., B.M.V., A.O.) contributed equally to this study. This investigation was supported by the Research Foundation-Flanders (FWO: G.0518.06, G.0643.08, and OT10/050). We thank the following individuals for their support: C. Jans, C. Rosseel and M. Meelberghs (Lung Transplant Unit Outpatient Clinic); Dr. A. Van Den Eeckhout, Prof. Dr. C. Dooms, J. Foulon and F. Vandeweyer (Department of Bronchoscopy); F. Rochette and Y. Dewandeleer (Department of Pulmonary Function); and

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    Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.