Neil Osterwell
April 24, 2009 (Paris, France) — In the never-ending search for therapies to prevent chronic lung allograft rejection, macrolide antibiotics, such as azithromycin, show promise, but only in about half of patients, report the authors of 2 European studies here at the International Society for Heart and Lung Transplantation 29th Annual Meeting and Scientific Sessions.
The first interim analysis from a randomized, double-blind trial comparing azithromycin and placebo showed that about half of patients with established bronchiolitis obliterans syndrome (BOS) had a response to azithromycin, reported Robin Vos, MD, a fellow in pathophysiology at Katholieke Universiteit and University Hospital Gasthuisberg, in Leuven, Belgium.
In addition, the efficacy of the drug appears to be related to grade of BOS, with close to half of patients with BOS grade 0p responding compared with only about 7% of patients with BOS grades 1 to 3, reported Federica Meloni, PhD, MD, from the Department of Hematological, Pneumological, and Cardiovascular Sciences, Respiratory Disease Section, at the University of Pavia, in Italy.
The results from the Belgian study support evidence of both an inflammatory and a fibroproliferative component to BOS, with the former likely to respond to azithromycin (Zithromax, Pfizer) and the latter unlikely to respond, the Belgian researchers suggested.
"We found an inflammatory phenotype with mainly neutrophils in the airways, and we found a phenotype with a more rapid decline in lung function later on, after transplantation, without cellular inflammation. We could clearly demonstrate that only those patients who have a high neutrophilia, without being infected, will respond to azithromycin, whereas the patients who don't have BAL [bronchoalveolar lavage] evidence of neutrophilia do not respond. So neutrophilia is really the driving force for an effect of azithromycin," said senior author Geert Verleden, MD, professor of immunology at Katholieke Universiteit, in an interview with Medscape Transplantation.
In the study, lung-transplant patients treated from September 2005 through December 2007 were randomized at discharge to receive either placebo or azithromycin 250 mg per day 3 times a week in addition to conventional therapies.
The primary study end points were BOS-free survival and overall survival at 2 and 3 years after lung transplantation. Under the protocol, patients who develop grade 1 or higher BOS are withdrawn from the study, started on open-label azithromycin, and are followed with forced expiratory volume at 1 second (FEV1) and airway inflammation studies.
At the most recent follow-up (2.3 years), 23 of the 83 enrolled patients discontinued because of the development of grade 1 or higher BOS, 5 had died (not from obliterative bronchiolitis), and 7 had dropped out because of adverse gastrointestinal events, suture problems, malignancy, or sepsis; 3 of these patients have since died.
Of the 23 who withdrew from the study as a result of BOS, 1 died and 22 were started on open-label azithromycin. Of this group, 12 were responders to azithromycin and 10 were nonresponders.
The researchers found that patients with airway neutrophilia in BAL at 3 months showed a trend toward the development of BOS (P = .05; correlation coefficient [r], 0.20). Azithromycin responders tended to have an earlier diagnosis of BOS than nonresponders (236.6 vs 322 days, respectively; P = .03), but the responders had a positive correlation with improvement in FEV1 after starting on azithromycin (P = .04; r = 0.6).
In the second study, Dr. Meloni and colleagues looked at the effects of 12 to 30 months of azithromycin therapy on 62 lung-transplant recipients, 43.5% with grade 0p BOS, 34% with grade 1 BOS, 8.1% with grade 2 BOS, and 14.5% with grade 3 BOS. As in the Belgian study, the patients received azithromycin 250 mg 3 times each week.
Patients with at least 12 months of follow-up (53 of the 62 patients) were stratified by change in FEV1 as being either responders (increase of greater than 10% in FEV1), having stable disease (change up or down within 10% of baseline), or nonresponders (decline of greater than 10% in FEV1).
There were a total of 12 responders, 10 of whom had grade 0p BOS, and 2 of whom had grade 1 to 3 BOS. Among patients with stable disease, 10 had grade 0p BOS and 21 had grade 1 to 3 BOS. Of the nonresponders, 2 had grade 0p BOS, and 8 had grade 1 to 3 BOS. The differences among the groups in the distribution of grades, on the basis of the chi-squared test, were statistically significant (P = .0045).
Among 23 patients with nearly 3 years of follow-up, the 7 nonresponders continued to show a decline in graft function, as measured by FEV1. Of patients with stable BOS, only 1 had a decline in function at 30 months, with a significant decline in FEV1 over baseline. Of the 8 responders, 7 showed improvement in FEV1 after starting on azithromycin, but 2 had a decrease in graft function at the last follow-up.
When they looked at peripheral blood cell parameters as possible indicators of efficacy, they found no significant differences, except for a significant decrease in the percentage of neutrophils at 12 months in the responders compared with the non responders, Dr. Meloni said. They also found that azithromycin significantly reduced proinflammatory chemokines, irrespective of treatment response.
The researchers concluded that chronic azithromycin therapy could result in long-term stabilization or improvement in graft function, but that this effect is highly dependent on disease grade, with 43% of patients with grade 0p disease having a response, compared with only 6.6% of those with grade 1 to 3 BOS.
A lung-transplant specialist who was not involved in the studies but who attended the session where they were presented said that the reason azithromycin is effective in some patients but not others needs to be elucidated.
"Are you dealing with 2 different diseases, 2 stages of a single disease, or . . . 2 different diseases coexisting in the same patient, like rheumatoid arthritis and osteoarthritis?" Marshall I Hertz, MD, professor of medicine at the University of Minnesota, in Minneapolis, wondered in an interview with Medscape Transplantation.
"A lot of us are working on biomarker development to get reproducible markers of one or the other phenotype so that you can measure biochemically something that we're not measuring very clinically. What we're doing right now is like treating hypertension by measuring strokes, when patients reach something very far down the road, when you'd really like something like a blood-pressure cuff."
Dr. Vos, Dr. Meloni, and Dr. Hertz have disclosed no relevant financial relationships.
International Society for Heart and Lung Transplantation (ISHLT) 29th Annual Meeting and Scientific Sessions: Abstracts 153 and 155. Presented April 23, 2009.
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