Inhaled Cyclosporine and Pulmonary Function in Lung Transplant Recipients
AbstractBackground: 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 FEV 1 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 FEV 1 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 ± 71.4 mL/year vs. −107.9 ± 55.3, p = 0.007). The FEF 25–75 decreased by −220.3 ± 117.7 L/(second × year) vs. −412.2 ± 139.2, p = 0.07, respectively. Similarly, percent FEV 1 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 FEV 1 compared to Novartis controls (FEV 1 −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 (FEV 1 −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.