title: Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations.
abstract: BACKGROUND
  Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation.
  
  
  METHODS
  The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR.
  
  
  RESULTS
  Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity.
  
  
  CONCLUSIONS
  MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah. Electronic address: akfoury@imail.org.
authors.forename: Abdallah G
authors.initials: AG
authors.lastname: Kfoury
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; University of Utah School of Medicine, 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: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah.
authors.forename: Greg L
authors.initials: GL
authors.lastname: Snow
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Kia
authors.initials: K
authors.lastname: Afshar
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Josef
authors.initials: J
authors.lastname: Stehlik
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Stavros G
authors.initials: SG
authors.lastname: Drakos
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Deborah
authors.initials: D
authors.lastname: Budge
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: James C
authors.initials: JC
authors.lastname: Fang
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: M Patricia
authors.initials: MP
authors.lastname: Revelo
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Alharethi
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Gilbert
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: William T
authors.initials: WT
authors.lastname: Caine
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Stephen
authors.initials: S
authors.lastname: McKellar
authors.affiliation: Primary Children's Hospital, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Molina
authors.affiliation: Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.
authors.forename: M Elizabeth H
authors.initials: MEH
authors.lastname: Hammond
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014181:Transplantation Immunology; D055815:Young Adult
chemical_list: D000906:Antibodies
keywords: antibody-mediated rejection; cellular rejection; clinical; heart transplantation; mixed rejection; pathology