Inhaled cyclosporine and pulmonary function in lung transplant recipients

Background: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. Methods: From 1998-2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsA patients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV₁ in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990-1995). Results: The average duration of ACsA and aerosol placebo was 400 days±306 and 433±256, respectively. The change in FEV₁ of ACsA patients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0±71.4mL/year vs. -107.9±55.3, p=0.007). The FEF _25-75 decreased by -220.3±117.7L/(second×year) vs. -412.2±139.2, p=0.07, respectively. Similarly, percent FEV₁ decline from maximal values was improved in ACsA patients compared to aerosol placebo and Novartis controls (ACsA -0.43±1.12%/year vs. aerosol placebo -4.08±1.4, p=0.04; ACsA vs. Novartis -4.7±0.31, p=0.007). Single-lung recipients receiving ACsA showed improvement in FEV₁ compared to Novartis controls (FEV₁ -0.8±1.8%/year vs. -4.94±0.4, p=0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV₁ -0.28±1.22%/year vs. -8.53±5.95, p=0.048). Conclusions: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single- and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.