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.
Highlights
Lung transplantation (LTx) is the ultimate treatment option for selected patients suffering from end-stage pulmonary disorders [1] Mortality rates after LTx remain relatively high, mainly due to the high prevalence of chronic lung allograft dysfunction (CLAD) [2]
The term CLAD is nowadays used to describe all causes of irreversible decline in pulmonary function, including restrictive allograft dysfunction (rCLAD/Restrictive allograft dysfunction (RAS)) [3] and the classical bronchiolitis obliterans syndrome (BOS) [4]
Baseline characteristics were similar in both groups, as was immunosuppressive management (Table 1)
Summary
Lung transplantation (LTx) is the ultimate treatment option for selected patients suffering from end-stage pulmonary disorders [1] Mortality rates after LTx remain relatively high, mainly due to the high prevalence of chronic lung allograft dysfunction (CLAD) [2]. BOS was only treated by changing or increasing the immunosuppressive regimen, resulting, at best, in a temporary stabilization of the decline in forced expiratory volume in 1 second (FEV1) [7,8]. It was demonstrated in a randomized controlled trial (RCT) that prophylactic azithromycin improved pulmonary function and reduced BOS prevalence at 2y after LTx [9]. Corris et al showed that azithromycin improves lung function in a significant proportion of patients with established BOS, compared to placebo [10]. Some positive effects of alemtuzumab (anti-CD52) in CLAD have been reported [15]
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