ATS 2012, SAN FRANCISCO – Researchers in the United Kingdom have determined that azithromycin, a broad-spectrum antibiotic that also has anti-inflammatory properties, can be an effective treatment option for patients suffering from bronchiolitis obliterans syndrome (BOS), a life-threatening complication that occurs in the majority of patients following lung transplantation.
BOS is the leading cause of mortality after the first year following transplantation, and occurs in part when the body repeatedly rejects the transplanted lung tissue. The syndrome causes the airways to become narrow and obstructed, resulting in a progressive decline in lung function and, eventually, respiratory failure. The exact full causes of the syndrome are unknown.
The study will be presented at the ATS 2012 International Conference in San Francisco.
The researchers evaluated the potential benefits of azithromycin, a type of antibiotic known as a macrolide, which works by inhibiting the ability of infection-causing bacteria to divide and replicate.
"In open studies, we and others have noted an improvement in lung function in BOS patients treated with macrolide antibiotics," said study lead author Paul Corris, professor of thoracic medicine at Newcastle University. "Other studies have not observed lung function gain with macrolide therapy, and there have been no randomized trials to date in patients with BOS."
"In this randomized study, we wanted to determine if patients treated with the antibiotic had improved lung function compared to patients who were treated with placebo," he said.
For their study, the researchers recruited 46 lung transplant patients with BOS and randomized them to receive either azithromycin (250mg on alternate days)or placebo. During the course of the study, 13 patients either withdrew or were withdrawn from the study; data from those individuals were included in a separate intent-to-treat (ITT) report.
To measure respiratory function, the researchers used a common lung function measurement called FEV1 (forced expiratory volume in the first second), which measures the volume of air (in millimeters, or ml) that can be forcibly exhaled in one second after taking a deep breath. By comparing patients' FEV1 values at the beginning of the study to FEV1 measurements made during the 12-week follow-up period, the researchers were able to determine if the patients' lung function had improved after being treated with azithromycin.
At the conclusion of their study, the researchers found that the patients who completed the study had a significant improvement in FEV1, with a mean difference of 358ml from baseline to 12 weeks; by comparison, patients in the placebo group experienced declines in their FEV1 measurements.
"Our randomized trial has confirmed that azithromycin improves lung function in patients with BOS following lung transplantation and this translates to improved survival for such patients," Dr. Corris noted. "There are ongoing studies trying to elucidate how the drug works which may well give clues to other potentially effective therapies."
"A Randomised Controlled Trial Of Azithromycin Therapy In Bronchiolitis Obliterans Syndrome (BOS) Post Lung Transplantation" (Session D13, Wednesday, May 23, 8:15 a.m., Room 2002-2004, Moscone Center; Abstract 27714)
* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.
Abstract 27714
A Randomised Controlled Trial Of Azithromycin Therapy In Bronchiolitis Obliterans Syndrome (BOS) Post Lung Transplantation
Type: Scientific Abstract
Category: 17.02 - Transplantation: Clinical (CP)
Authors: P. Corris1, T. Small2, V. Ryan3, J. Lordan2, A.J. Fisher1, G. Meachery2, G. Johnson2, C. Ward3; 1Freeman Hospital/Newcastle University - Newcastle Upon Tyne/UK, 2Freeman Hospital - Newcastle Upon Tyne/UK, 3Newcastle University - Newcastle Upon Tyne/UK
Abstract Body
RATIONALE BOS post lung transplantation has previously been regarded as irreversible. In open studies we and others (1) have noted an improvement in lung function in BOS patients treated with macrolide antibiotics. Other studies have not observed lung function gain with macrolide therapy (2,3), and there are no randomised trials.
METHODS. A prospective, single-centre randomised double blind placebo controlled study of Azithromycin (250mg on alternate days) or placebo, in lung transplant recipients with BOS. The primary outcome was change in FEV1 from baseline to 12 weeks.
RESULTS. Between November 2006 and December 2010 46 patients with BOS were randomised (23 Azithromycin, 23 placebo); randomisation was stratified for the presence of suppurative disease pre op and whether the patient had received single or bilateral lungs. Thirty-three patients completed the study (16 Azithromycin, 17 placebo), receiving 12 weeks of study treatment as randomised. All 46 patients received at least one dose of study treatment and were followed up for 12 weeks. The intention to treat (ITT) analysis reported here utilises FEV1 at the last pre-withdrawal observation for those 13 patients (7 Azithromycin, 6 placebo) who withdrew or were withdrawn from study treatment. All analyses are adjusted for baseline FEV1 and the randomisation stratification variables (4).
For the ITT population, the Azithromycin group had a mean gain in FEV1 from baseline of 37ml, 95% confidence interval (CI) for the change was −75ml to 140ml and the placebo group had a mean fall in FEV1 of 181ml, 95% CI for the change was −294ml to −69ml. The mean difference in the change in FEV1, Azithromycin minus Placebo, was 218ml and the 95% CI for the mean difference in the change was 60ml to 377ml (P=0.008). For study completers, the mean difference in the change in FEV1, Azithromycin minus Placebo, was 358ml and the 95% confidence interval for the mean difference in the change was 186ml to 530ml (P<0.001).
CONCLUSION. Our randomised trial has confirmed Azithromycin improves lung function in patients with BOS following lung transplantation.
Refs
1. Gerhardt SG et al Am J Respir Crit Care Med. 2003;168(1):121-5
2. Shitrit D, et al. J Heart Lung Transplant. 2005;24(9):1440-3.
3. Porhownik NR, et al. Can Respir J. 2008;15(4):199-202.
4. Senn S, Statistical Issues in Drug Development, 2nd Edition. Chichester: Wiley, 2007.
Funded by: United Kingdom Medical Research Council