Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial

Abstract

Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1.

Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: A Workshop Report

“…In a pilot study, montelukast has been tried in fibroproliferative post-lung transplant BOS and showed slowing of decline in FEV 1 [87]. However, a recent trial by Ruttens et al showed no additional survival benefit with montelukast compared with placebo [88]. Several studies reported that a combination of inhaled fluticasone, azithromycin, and montelukast (FAM) could be an effective treatment in patients with BOS [89].…”

Detection, classification, and management of rejection after lung transplantation

“…Sixty-one percent of patients were free from CLAD progression, defined by a less than 10% decrease or increase in FEV 1 . However, a small, randomized controlled study by the same group failed to demonstrate a survival benefit or difference in rate of change of FEV 1 with montelukast compared with placebo (56). Findings in this study were likely limited by a sample size of only 30 patients.…”

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

“…227 In this study, the rate of FEV 1 decline slowed after the introduction of montelukast. 227 A subsequent randomized placebo-controlled trial of montelukast for treatment of BOS was published as a conference abstract, 228 although a peerreviewed publication is still not available at the time of this review. Montelukast reportedly had no effect on the evolution of lung function in the overall cohort.…”

“…However, for patients with stage 1 BOS, there was a significant benefit of montelukast on lung function relative to placebo. 228 Montelukast is generally well tolerated and relatively inexpensive, making a trial of therapy a reasonable option for CLAD.…”