title: De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation.
abstract: BACKGROUND
  The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial.
  
  
  METHODS
  We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA).
  
  
  RESULTS
  We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001).
  
  
  CONCLUSIONS
  Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: morrellmr@upmc.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Morrell
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Gries
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pipeling
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Crespo
authors.affiliation: Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Ensor
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Yousem
authors.affiliation: Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jonathan
authors.initials: J
authors.lastname: D'Cunha
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Shigemura
authors.affiliation: Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Bermudez
authors.affiliation: Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000453:epidemiology* / Q000276:immunology / Q000401:mortality*; D001999:Bronchoscopy; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000276:immunology / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D014019:Tissue Donors
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015415:Biomarkers; D006680:HLA Antigens
keywords: bronchiolitis obliterans syndrome; death; donor-specific antibody; human leukocyte antigen; lung transplant