Azithromycin in Bronchiolitis Obliterans: Is the Evidence Strong Enough?

To the Editor:

As transplant pulmonologists, we are continuously faced with the desperation of our patients with chronic rejection due to the lack of effective therapy to improve this disorder. Azithromycin has recently been introduced into the armamentarium of medications for treatment of bronchiolitis obliterans syndrome (BOS). In a pilot study published in AJRCCM, Gerhardt and colleagues reported on the use of azithromycin in six patients, of which five had significant improvement in pulmonary function testing (1). After the publication of this article, multiple centers, including ours, began using azithromycin in patients with BOS who had failed conventional medical therapy. Our experience in the initial eight patients with BOS started on azithromycin and now followed for over a year did not replicate these results. None of our patients had improvement in airflow obstruction. The recent article by Yates and colleagues reports the experience with a select cohort of 20 patients at a large transplant center (2). The authors conclude that azithromycin reverses airflow obstruction in patients with BOS. The data presented in this article raise important questions about this therapy, and we echo the authors' caution that this therapy should not be viewed as a panacea for the treatment of BOS.

Yates and coworkers report their results for FEV^sub 1^ as a percentage of change from baseline. Although these changes appear dramatic in Figure 1 of the article, they do not necessarily reflect a clinical benefit for these patients. The mean FEV, before initiation of therapy was 1.44 L (range, 0.54-3.28) and the mean improvement was 0.11 L (range, -0.07 to 0.73). This mean improvement represents an increase in FEV^sub 1^ of 8% for the overall group. The results were reported after 3 months; however, by 6 months, 8 of 20 patients (40%) had no improvement (5 who had experienced initial improvement no longer sustained this improvement, and 3 patients did not experience improvement). Finally, the follow-up period was relatively short. Nevertheless, it is important to acknowledge that in the article by Yates and coworkers (2) as well as the original publication by Gerhardt and coworkers (1), there were some patients with BOS treated with azithromycin who did experience a significant improvement in pulmonary function. The objective, as mentioned in the accompanying editorial by Drs. Williams and Verleden. should be to conduct a large clinical trial with long-term follow-up to determine which patients might benefit from this therapy (3).

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

LUIS F. ANGEL

DEBORAH LEVINE

JUAN SANCHEZ

STEPHANIE LEVINE

University of Texas Health Science Center

San Antonio, Texas

References

1. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168: 121-125.

2. Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, Lordan JL, Dark JH, Corris PA. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;172:772-775.

3. Williams TJ, Verleden GM. Azithromycin: a plea for multicenter randomized studies in lung transplantation. Am J Respir Crit Care Med 2005; 172:657-659.

From the Authors:

Since our initial observation of significant and occasionally dramatic reversal of airflow obstruction in bronchiolitis obliterans syndrome (BOS) (1), other groups have described their experience with this novel therapeutic approach for this most devastating long-term complication of lung transplantation (2-4). Verleden and Dupont (2) and, more recently, Yates and colleagues (3) observed a favorable response to azithromycin in a sizable proportion of their respective series. The letter from Dr. Angel and colleagues questions the clinical significance of the improvement in airflow obstruction documented by Yates and coworkers. They also describe their own experience showing little long-term improvement for a small cohort of patients treated at their institution, mirroring the disappointing results by Shitrit and coworkers (4). Clearly, the response to azithromycin is quite variable, which is not unexpected, given the likely heterogeneous nature of the factors involved in the pathogenesis of this clinical syndrome. Perhaps those patients with active airway inflammation or bronchoalveolar lavage neutrophilia and/or elevated interleukin-8 concentrations are more apt to respond (5).

We wholeheartedly agree with Dr. Angel and colleagues and Drs. Williams and Verleden (5) that a carefully designed, prospective, multicenter, randomized trial of azithromycin is needed urgently to determine conclusively whether this therapy is of benefit and to identify which patients are likely to respond. Given the lack of enthusiasm on the part of the pharmaceutical industry to support such a trial for a disease affecting a small patient population, alternative funding will be required. Recently, the National Institutes of Health convened a workshop on lung transplantation, with the expert panel concluding that multicenter studies were imperative (6). We believe the time has come to form a network of lung transplant centers to study important questions in lung transplantation, so as to move the field forward toward improved transplant outcomes and patient survival. We call on the National Institutes of Health to support such an initiative as suggested by the expert panel.

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

JONATHAN B. ORENS

JOHN F. MCDYER

REDA E. GIRGIS

Johns Hopkins University

Baltimore, Maryland

References

1. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168:121-125.

2. Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2004;77:1465-1467.

3. Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, Lordan JL, Dark JH, Corris PA. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;172:772-775.

4. Shitrit D, Bendayan D, Gidon G, Saute M, Bakal I, Kramer RM. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 2005;24: 1440-1443.

5. Williams TJ, Verleden GM. Azithromycin: a plea for multicenter randomized studies in lung transplantation. Am J Respir Crit Care Med 2005;172: 657-659.

6. Wilkes DS, Egan TM, Reynolds HY. Lung transplantation: opportunities for research and clinical advancement. Am J Respir Crit Care Med 2005; 172:944-955.

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