American Journal of Respiratory and Critical Care Medicine

Over two decades have passed since long-term survival was first achieved after lung transplantation in humans (1, 2). Outcome has improved dramatically, although this has been almost entirely due to improvements in early (90-day) survival. Despite intense follow-up, patients who have done well initially after lung transplantation continue to develop bronchiolitis obliterans syndrome (BOS), frequently progressing to death due to respiratory failure. The recurrence of severe respiratory disability refractory to treatment is “cruel and unusual punishment” to patients and families, and has led to an air of despondency among lung transplant physicians. Hopes have been recurrently raised by sporadic reports suggesting a slowing of the natural history of the disease with a number of therapeutic interventions, including modification of conventional immunosuppression (3), use of antilymphocyte globulin (4), and therapy with total lymphoid irradiation (5). However, to date, only retransplantation has been shown to lead convincingly to improved lung function after the occurrence of BOS.

In this issue, Yates and colleagues (pp. 772–775) describe a case series of 20 patients with post-transplant BOS where the use of the neomacrolide antibiotic azithromycin (250 mg on alternate days) led to improved lung function (6). The improvement was modest (median, 110 ml) and the follow-up short (mean, 6.25 months). Nevertheless, indicative of our collective frustration with present therapeutic options, these results are very exciting. The findings are concordant with two other small case series, one by Gerhardt and colleagues (7) of six lung transplant recipients (mean FEV1 improvement, 500 ml; 3.5 months' follow-up) and one by Verleden and Dupont (8) of eight lung transplant recipients (mean improvement, 328 ml; 3 months' follow-up). The study of Yates and colleagues also shows considerable heterogeneity of response, with one patient's FEV1 improving 730 ml (of note, Gerhardt and coworkers had one patient improve 1,380 ml). Half the patients reported by Yates and colleagues had no significant (< 15%) improvement in FEV1 (as compared with four of eight patients in the article by Verleden and Dupont), although an arrest in the FEV1 decline was demonstrable in most patients, as also noted by Verleden and Dupont (8). This response to azithromycin is not entirely unexpected when we consider a developing body of literature in diseases that also are associated with small airway injury, such as cystic fibrosis and diffuse panbronchiolitis (9). Understanding what these diseases have in common with BOS and the mechanism of action of azithromycin may substantially advance our understanding of the pathogenesis of BOS.

The question therefore is: How might azithromycin work? (10). A potential mechanism may be through suppressing the growth of important pathogens, such as Pseudomonas aeruginosa. In addition, azithromycin may exert antiinflammatory effects that inhibit classic alloimmune responses and, perhaps more importantly, more primitive innate immune responses. This may well be an important mechanism of action since cystic fibrosis, panbronchiolitis, chronic obstructive pulmonary disease (COPD), and BOS are all neutrophilic airway diseases, and azithromycin seems to significantly reduce airway neutrophilia after 3 months' treatment, at least in patients with BOS (11). Moreover, in a double-blind, placebo-controlled study, clarithromycin, another neomacrolide, has been shown to significantly reduce interleukin (IL)-8 levels in induced sputum from patients with COPD (12). IL-8 is known to be an important chemoattractant for neutrophils, and its level is increased in bronchoalveolar lavage fluid from patients with COPD as well as with BOS (13). In addition, there may be more direct effects of azithromycin on airway remodeling. Macrolides also increase gastric motility, and it is possible that a reduction in gastroesophageal reflux and consequent aspiration could be an important mechanism of action.

The potential mechanisms of action for azithromycin parallel an important shift in thinking regarding BOS. Two important articles, an update of the diagnostic criteria for BOS by Estenne and colleagues (14) and an authoritative review by Estenne and Hertz (15), have focused our thinking on the multiple pathogenic factors leading to BOS. Although classic alloimmunity has a significant role in the development of BOS, a persistent inflammatory response to viral (16), bacterial and fungal infections, as well as to gastroesophageal reflux, particularly with aspiration, probably plays an important role as well. If azithromycin shows sustained effects in BOS, this will refocus our attention to the mechanisms outlined above rather than simply trying to address BOS in the post-transplant setting by intensifying our immunosuppression therapy.

It is clear that a well-designed, multicenter, randomized, placebo-controlled trial of azithromycin both as a preventative strategy and also as a treatment strategy for established BOS is required. This is a prerequisite now, not only to provide the definitive clinical evidence for the beneficial effects of azithromycin but also to give insight into its mechanisms of action and why azithromycin is not effective in all patients with BOS. There are some very important questions as to the logistics of conducting such a study of a drug that has been marketed for many years, where such a study, while extremely important, may be of low commercial value to the company marketing the agent. The lung transplant community seems to be particularly afflicted by this problem, because the efficacy of, for instance, many new immunosuppressive agents is proven in other organ transplants, and we are told to accept by inference that they will be of equal benefit in our lung transplant patients. Regrettably, the fine balance between infection in the allograft and the potential damage that persistent, even low-grade, rejection causes, make this a thoroughly unwarranted assumption.

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3. Verleden GM, Bankier A, Boehler A, Corris P, Dupont L, Estenne M, Fisher S, Lerut T, Reichenspurner H. Bronchiolitis obliterans syndrome after lung transplantation: diagnosis and treatment. Eur Respir Mon 2004;29:19–43.
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10. Verleden GM, Dupont LJ, Van Raemdonck DE. Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal? Eur Respir J 2005;25:221–224.
11. Verleden GM, Dupont LJ, Vanaudenaerde BM, Van Raemdonck DE. Azithromycin reduces airway neutrophilia in patients with bronchiolitis obliterans syndrome [abstract]. J Heart Lung Transplant 2005;24(Suppl):S59.
12. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother 2004;38:1400–1405.
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14. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, Mallory GB, Snell GI, Yousem S. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310.
15. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002;166:440–444.
16. Westall GP, Michaelides A, Williams TJ, Snell GI, Kotsimbos TC. Bronchiolitis obliterans syndrome and early human cytomegalovirus DNAaemia dynamics after lung transplantation. Transplantation 2003;75:2064–2068.

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