Bronchoalveolar lavage cytokine-based risk stratification of clinically-stable lung transplant recipients with undefined rejection: Further insights from a follow-up investigation

Background: Surveillance bronchoscopies with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) are primarily used to detect acute cellular rejection (ACR) or infection in lung transplant (LTx) recipients. We previously identified a BAL protein signature associated with chronic lung allograft dysfunction (CLAD) or death/retransplant in patients with stable minimal (grade A1) ACR. This present study aimed to determine whether similar BAL biomarkers predict outcomes in stable patients when ACR grade is undetermined. Methods: The cohort included all adult, first bilateral LTx performed 2010–2017. Clinical status was categorized as unstable or stable based on the presence or absence of a ≥ 10% drop in FEV1. Clinically-stable patients with grade AX TBB (inadequate biopsies) during the first year post-transplant, not preceded by ACR (grade A≥1 or B≥1), were included. IL6, S100A8, IL10, TNF-receptor-1, IL1α, pentraxin3, and CXCL10 were measured in the BAL using a multiplex bead assay. Associations with subsequent CLAD or death/retransplant were assessed using multivariable Cox proportional hazards models, adjusted for relevant clinical covariates. Results: Among 107 patients with stable AX biopsies at a median of 188 days post-transplant, the median times from biopsy to CLAD and death/retransplant were 972 and 1410 days, respectively. CXCL10 was significantly associated with CLAD, while IL6, S100A8, pentraxin3, TNF-receptor-1, and IL10 were associated with death/retransplant (p < 0.05 for all). Conclusion: A focused BAL protein signature in stable patients with ungradable TBB early post-transplant may predict worse outcomes. Such select BAL biomarkers may identify patients who require more aggressive management strategies or closer monitoring.