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

<div><p>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.</p></div

Patient characteristics of the montelukast and placebo group.

<p>Values are presented as n-value (percentage) or mean (standard error of mean). AZA = azathioprine, BMI = body mass index, BOS = bronchiolitis obliterans syndrome, CF = cystic fibrosis, CLAD = chronic lung allograft dysfunction, CRP = C-reactive protein,CsA = cyclosporine A, FK = tacrolimus, HLTx = heart-lung transplantation, ILD = interstitial lung disease, MMF = mycophenolate mofetil, n = n-value, PHT = pulmonary arterial hypertension, POD = post-operative day, SLTx = single lung transplantation, SSLTx = double lung transplantation.</p

FEV₁ evolution (% predicted, absolute value) comparing montelukast to placebo in BOS stage 1 patients (upper part) and BOS stage 2 and 3 (lower part).

<p>MLK = montelukast. Dotted line is the time-point of inclusion.</p

Kaplan-Meier survival curve of the placebo and the montelukast arm at 2 years.

<p>Kaplan-Meier survival curve of the placebo and the montelukast arm at 2 years.</p

FEV₁ evolution (% predicted, absolute value) comparing montelukast to placebo.

<p>MLK = montelukast. Dotted line is the time-point of inclusion.</p

Flow chart of the randomized controlled trial of montelukast versus placebo in LTx patients with BOS.

<p>IIT = intention to treat analysis.</p

Patient characteristics of the montelukast and placebo group (BOS stage I only).

<p>Values are presented as n-value (percentage) or mean (standard error of mean). AZA = azathioprine, BMI = body mass index, BOS = bronchiolitis obliterans syndrome, CF = cystic fibrosis, CLAD = chronic lung allograft dysfunction, CRP = C-reactive protein, CsA = cyclosporine A, FK = tacrolimus, HLTx = heart-lung transplantation, ILD = interstitial lung disease, MMF = mycophenolate mofetil, n = n-value, PHT = pulmonary arterial hypertension, POD = post-operative day, SLTx = single lung transplantation, SSLTx = double sided lung transplantation.</p

Long function evolution of the montelukast and placebo group.

<p>Patients were subdivided in stable (110%-90% FEV1 compared to the FEV1 at the moment of CLAD diagnosis), increase (>110%) and decrease (<90%), no difference was observed (p = 0.16). No result = no result could be obtained in 2 patients in the placebo group and 3 patients in the montelukast groups due to mortality, concurrent infection, missed appointment. MLK = montelukast.</p

Additional file 1: of The aging lung: tissue telomere shortening in health and disease

Supplementary materials, methods and results. (DOCX 21 kb

Video_3_The nature of chronic rejection after lung transplantation: a murine orthotopic lung transplant study.mp4

IntroductionChronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation.Methods40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling.ResultsChronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset.ConclusionAgainst the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.</p