Bronchoalveolar Lavage Pentraxin 3 Levels during Clinically-Stable Minimal Acute Rejection are Associated with CLAD and Death Risk

Abstract

Purpose Acute cellular rejection (ACR) remains the most significant risk factor for chronic lung allograft dysfunction (CLAD). While clinically-unstable and higher-grade ≥A2 ACR is generally treated with augmented immunosuppression (aIS), management of clinically-stable A1 ACR (CSA1R) remains controversial. At our center, patients with CSA1R are routinely not treated with aIS and constitute a unique population that enabled us to identify sub-phenotypes with differential risks. Our aim was to determine if bronchoalveolar lavage (BAL) biomarkers at the time of first CSA1R (fCSA1R) are predictive of subsequent CLAD or death. Methods Among all adult, first, bilateral lung transplants, performed 2010-2016, post-transplant transbronchial biopsies obtained within the first year, without concurrent infection, were categorized as clinically unstable or stable based on ≥10% concurrent drop in FEV1. fCSA1R episodes were defined as stable biopsy-FEV1 pairs not preceded by another ACR. 21 proteins previously associated with ACR or CLAD were measured in the BAL using a multiplex bead assay. Association between protein levels and subsequent CLAD or death was assessed using Cox PH models, adjusted for relevant peri-transplant clinical covariates. Results We identified 75 patients with fCSA1R at a median time of 98 days (range 48.5-197) post-transplant. Median time from transplant to CLAD or death was 1247 (756.5-1921.5) and 1641 days (1024.5-2326.5), respectively. In multivariable models, levels of IL6, S100A8, IL10, TNF-receptor 1, IL-1α and pentraxin 3 (PTX3) were associated with both CLAD development and death (P Conclusion Our data indicate that a focused BAL protein signature, with PTX3 having the strongest association, may be useful in determining a subset of CSA1R patients who are at increased risk and may benefit from a more aggressive management strategy.