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 300mg 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 FEF25-75 decreased by -220.3 +/- 117.7 L/(second x 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.