Identification of Surrogate Outcome Biomarkers in Lung Allograft Recipients With Bronchiolitis Obliterans: Implications for Randomized Controlled Trials

BACKGROUND. – We developed a prospective, multicenter “registry” to evaluate the effect of extracorporeal photopheresis for lung transplant recipients who develop chronic lung allograft dysfunction (CLAD) with the bronchiolitis obliterans syndrome (BOS) phenotype (CLAD/BOS) and who are refractory to conventional standard-of-care therapy. METHODS. – Data from 258 lung transplant recipients enrolled in the Registry between April 2015 and April 2022 were included in this analysis. All recorded parameters (eg, demographics), including forced expiratory volume in 1 s (FEV₁) measurements and indices (FEV₁% baseline, FEV₁ rate of decline) at several time periods, were included in multivariate linear/logistic and Kaplan-Meier analyses to evaluate potential associations with survival. RESULTS. – Mortality at 6 and 12 mo after CLAD/BOS diagnosis was 5% and 14%, whereas mortality at 6 and 12 mo after enrollment was 15% and 26%, respectively. The primary cause of death in the cohort was respiratory failure or graft failure (74%). Rate of FEV₁ decline (log) at enrollment was independently associated with survival (log days) from CLAD/BOS diagnosis and enrollment (r = 0.55 and r = 0.3, respectively). The rates of FEV₁ decline among survivors were lower (–77 ± 89 mL/mo) compared with nonsurvivors (–148 ± 155 mL/mo) at 6 mo after enrollment (P = 0.0001). CONCLUSIONS. – The rate of FEV₁ decline quantified using at least 5 FEV₁ measurements is a robust surrogate outcome. We plan to use these findings to revise our randomized controlled trial to facilitate risk adjustment using FEV₁ rate of decline strata at enrollment and as a scientifically valid surrogate for outcome.