title: Epithelial and Erythrocyte Microvesicles From Bronchoalveolar Lavage Fluid Are Elevated and Associated With Outcome in Chronic Lung Allograft Dysfunction.
abstract: BACKGROUND
  Chronic 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  The BALF-MV levels of epithelial and red blood cell (RBC) origin were significantly higher in CLAD patients (mean: 1533/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%.
  
  
  CONCLUSIONS
  Epithelial 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.
authors.affiliation: 1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 2 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. 3 Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Germany. 4 German Centre for Lung Research, BREATH, Hannover, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Harms
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuehner
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.forename: Arne
authors.initials: A
authors.lastname: Trummer
mesh_terms: D000328:Adult; D064591:Allografts; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology* / Q000276:immunology; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000473:pathology*; D002908:Chronic Disease; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology*; D004912:Erythrocytes / Q000276:immunology / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D008171:Lung Diseases / Q000209:etiology / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D016040:Lung Transplantation / Q000009:adverse effects* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers