Bronchoalveolar Bile Acids are Associated with Acute Rejection, Inflammation, and Allograft Survival: A Multi-Center Study

Abstract

Purpose Gastroesophageal reflux disease is common in lung transplant recipients and is thought to cause lung graft injury through aspiration of gastric contents. Bile acids in bronchoalveolar lavage (BAL) are putative markers of gastric microaspiration and associated with inflammation and earlier chronic lung allograft dysfunction (CLAD). Microaspiration is thought to augment CLAD risk through potentiation of acute rejection (AR), although this has not been demonstrated. We hypothesized that BAL bile acid levels would be associated with AR presence and severity. Methods Among all adult, first, bilateral lung transplants, performed at two large lung transplant centers 2010-2015, transbronchial biopsies obtained within the first-year post-transplant were categorized as spirometrically-significant or stable based on the presence or absence of ≥10% concurrent drop in FEV1. AR diagnosis was based histology and biopsies with concurrent infection were excluded. BAL supernatant levels of bile acids (taurocholic acid (TCA), glycocholic acid (GCA), cholic acid), and inflammatory proteins (IL6, CXCL8, S100A8, CCL2, IL1β, CCL5, IL1α, RAGE, S100A12, IL12) were compared between patient groups. Association between BA levels and subsequent CLAD or death/retransplant was assessed using Cox Proportional Hazards models, adjusted for relevant peri-transplant clinical covariates and AR group. Endpoints We identified 42 patients with spirometrically-significant AR, 56 patients with stable AR, and 81 patients with stable no-AR with available BAL samples (one sample per patient). BAL at time of spirometrically-significant AR, compared to other groups, had elevated levels of TCA (ANOVA