title: The use of circulating donor specific antibody to predict biopsy diagnosis of antibody-mediated rejection and to provide prognostic value after heart transplantation in children.
abstract: BACKGROUND
  Antibody-mediated rejection (AMR) is a significant cause of mortality after heart transplantation (HT). Although the presence of donor specific antibody (DSA) is a risk factor for developing AMR, serial DSA testing is not widely performed. We aimed to investigate the predictive values and prognostic implications of circulating DSA using endomyocardial biopsy as the gold standard for AMR diagnosis in pediatric recipients of HT.
  
  
  METHODS
  We performed a retrospective study in pediatric recipients of HT followed during the period 2009-2013 with at least 1 biopsy paired with DSA testing. Positive DSA was defined at mean fluorescent intensity (MFI) ≥2,000 using single antigen bead testing. Statistical analyses included 2 × 2 contingency tables, receiver operating characteristic analysis for optimal MFI cutoffs, Spearman correlation of MFI strength to AMR grade, and Kaplan-Meier analysis of event-free survival.
  
  
  RESULTS
  Of 66 children included, 27 (41%) had ≥1 DSA positive test. DSA testing had a sensitivity of 92.6%, specificity of 62.2%, positive predictive value of 24.0%, and negative predictive value of 98.5% for biopsy diagnosis of AMR at our institution. There was a statistically significant correlation between higher MFI and higher AMR grade. Patients with positive DSA and AMR had similar survival early after DSA detection but trended toward lower cardiovascular event-free survival later compared with patients without DSA and a negative biopsy.
  
  
  CONCLUSIONS
  The results of DSA testing in this cohort showed excellent sensitivity and negative predictive value for biopsy-diagnosed AMR, suggesting that DSA testing may aid in the non-invasive prediction of AMR absence in HT. The correlation of DSA MFI strength with higher AMR biopsy grade and the trend toward differences in longer term cardiovascular outcomes provide evidence for routine DSA monitoring after pediatric HT.
authors.affiliation: University of Utah School of Graduate Medical Education, Salt Lake City, Utah.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Ware
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Malmberg
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Delgado
authors.affiliation: Intermountain Medical Center and Intermountain Healthcare, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hammond
authors.affiliation: Intermountain Medical Center and Intermountain Healthcare, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Dylan V
authors.initials: DV
authors.lastname: Miller
authors.affiliation: Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah; University of Utah School of Medicine, Salt Lake City, Utah; George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Josef
authors.initials: J
authors.lastname: Stehlik
authors.affiliation: Intermountain Medical Center and Intermountain Healthcare, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Kfoury
authors.affiliation: Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah; University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Monica P
authors.initials: MP
authors.lastname: Revelo
authors.affiliation: Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah; University of Utah School of Medicine, Salt Lake City, Utah; Primary Children's Hospital, Salt Lake City, Utah.
authors.forename: Aaron
authors.initials: A
authors.lastname: Eckhauser
authors.affiliation: Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah; University of Utah School of Medicine, Salt Lake City, Utah; Primary Children's Hospital, Salt Lake City, Utah. Electronic address: melanie.everitt@childrenscolorado.org.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Everitt
mesh_terms: D000906:Antibodies / Q000097:blood*; D001706:Biopsy; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000175:diagnosis*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D014019:Tissue Donors
chemical_list: D000906:Antibodies
keywords: antibody-mediated rejection; donor specific antibody; endomyocardial biopsy; heart transplantation; pediatrics