Epithelial and Erythrocyte Microvesicles From Bronchoalveolar Lavage Fluid Are Elevated and Associated With Outcome in Chronic Lung Allograft Dysfunction

BACKGROUNDChronic lung allograft dysfunction (CLAD) is the major outcome limitation for lung transplant recipients (LTR) after the first year, and therapies targeting immunological pathways show only limited success. Because microvesicles (MV) are biomarkers of endothelial dysfunction and coagulation but are also involved in immunological responses, we hypothesized that MV, found in bronchoalveolar lavage (BAL) fluids (BALF) of LTR at CLAD diagnosis, are elevated and potential prognostic biomarkers. METHODSThe BALF was collected from 37 LTR at time point of CLAD diagnosis and 37 LTR without any complication at routinely performed BAL. The MV concentration and origin were determined by flow cytometry by detection of different antigens. Patient- and transplant-related risk factors were included in a retrospective statistical analysis. RESULTSThe BALF-MV levels of epithelial and red blood cell (RBC) origin were significantly higher in CLAD patients (mean1533/μL and 158/μL) compared to controls (436/μL, 57/μL). The LTR with high levels of epithelial MV >580/μL showed a significantly shorter overall survival at 4 years after BAL (39.5%) compared to patients with low MV (66.4%) and this proofed to be an independent prognostic factor in multivariate Cox analysis (hazards ratio = 3.05). Furthermore, LTR with high levels of RBC MV ≥225/μL were also associated with worse disease-specific survival, with probabilities at 4 years after BAL of 85.8% vs. 36.0%. CONCLUSIONSEpithelial and RBC BALF-MV are elevated at CLAD diagnosis, have a potential as biomarkers, and support the hypothesis of a pathway, including activation of coagulation and complement, endothelial barrier dysfunction, and microangiopathy.