*Purpose: There are very few ways to improve survival after bronchiolitis obliterans syndrome (BOS), the leading cause of death in lung transplant patients. Two long-term studies have found that prophylactic sirolimus + tacrolimus immunosuppression early after lung transplantation is associated with significantly improved survival and lower BOS risk compared to the traditional mycophenolate mofetil (MMF) + tacrolimus regimen, but among patients with BOS, data comparing survival between regimens are lacking.

*Methods: This study included lung transplant patients with BOS in the U.S. Scientific Registry for Transplant Recipients (SRTR), transplanted from May 2005-August 2016 and initially receiving traditional maintenance immunosuppression (tacrolimus/cyclosporine + MMF/azathioprine) and induction with basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or no induction. Patients missing data on BOS grade (1-3) or immunosuppression following BOS diagnosis were excluded. Survival was compared between BOS patients receiving tacrolimus + sirolimus [TS], tacrolimus + sirolimus + antimetabolite (MMF/azathioprine) [TSA], or tacrolimus + MMF [TM], based on Kaplan-Meier estimates and Cox regression adjusting for demographic and clinical factors, including transplant center-specific survival among BOS patients.

*Results: Combining BOS grades 1-3 without adjustment, 1-year survival and median [interquartile range] survival times by treatment group were, TSA: 100%, 4.5 [2.9-6.5] years, n=14; TS: 81%, 4.4 [1.6- -] years, n=37; TM: 78%, 3.5 [1.3-7.0] years, n=471. The groups had different distributions of BOS grades (p=0.004); prevalence of Grade 3 BOS at baseline was 36% in TSA, 51% in TS, and 27% in TM. Each group had patients from over 10 different centers. In adjusted analysis, TSA (HR=0.44, p=0.05) and TS (HR=0.55, p=0.03) were associated with better survival than TM. Effect sizes were larger when restricting to BOS Grade 3 patients; TSA again showed a trend towards the most favorable survival (HR=0.21, p=0.17) and TS (HR=0.35, p=0.04) also showed better survival, compared to TM.

*Conclusions: Maintenance immunosuppression combining sirolimus and tacrolimus may significantly improve survival in patients with BOS (especially Grade 3). Adding MMF or azathioprine to this combination appears promising, particularly for short-term survival in these patients with a high mortality rate, while being attentive to risks of possible over-immunosuppression with this strategy combining all 3 drug classes.

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