title: Role of morphologic parameters on endomyocardial biopsy to detect sub-clinical antibody-mediated rejection in heart transplantation.
abstract: BACKGROUND
  The present study evaluated if morphologic parameters detect signs of early sub-clinical or latent stages of antibody-mediated rejection (AMR) and their correlation with C4d staining in cardiac transplants recipients.
  
  
  METHODS
  The study reviewed 1,270 endomyocardial biopsies (EMB) from 131 patients. Of these, 61 stained positive for C4d in the absence of acute cellular rejection >2R. Sixty-six EMB specimens negative for C4d were matched for pre-transplant diagnosis, time after transplantation, age, and acute cellular rejection (ACR) grading. Histopathologic evaluation and C4d staining were performed on formalin-fixed, paraffin-embedded sections using the C4d polyclonal antibody.
  
  
  RESULTS
  Of the 8 histologic characteristics evaluated, only endothelial swelling (78.7% sensitivity, 28.8% specificity; positive likelihood ratio, 1.10) and interstitial edema (77% sensitivity, 31.8% specificity; positive likelihood ratio, 1.13) could be considered fair predictors of C4d capillary positivity. The presence of mononuclear cells in capillaries in relation to C4d positivity showed 39.3% sensitivity and 68.2% specificity. Combining the parameters endothelial swelling and mononuclear cells in capillaries, sensitivity was 31.1% (95% confidence interval [CI] 19.9-44.3) and specificity was 71.2% (95 CI, 58.8-81.7), with a positive likelihood ratio of 1.08 (95% CI, 0.68-1.84).
  
  
  CONCLUSIONS
  Our results showed that histologic parameters did not always detect signs of early sub-clinical or latent stages of AMR. Combining the parameters of endothelial swelling and intracapillary mononuclear cells did not significantly improve the sensitivity or specificity. Screening recommendations should, therefore, be modified to include more sensitive tests such as C4d staining in the routine protocol to improve patient risk stratification.
authors.affiliation: Department of Medico-Diagnostic Sciences and Special Therapies, University of Padua, Padua, Italy.
authors.forename: Marny
authors.initials: M
authors.lastname: Fedrigo
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambino
authors.forename: Elena
authors.initials: E
authors.lastname: Benazzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Poli
authors.forename: Anna Chiara
authors.initials: AC
authors.lastname: Frigo
authors.forename: Francesco
authors.initials: F
authors.lastname: Tona
authors.forename: Alida L P
authors.initials: AL
authors.lastname: Caforio
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toscano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Feltrin
authors.forename: Gino
authors.initials: G
authors.lastname: Gerosa
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D001706:Biopsy; D015704:CD4 Antigens / Q000378:metabolism; D002196:Capillaries / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000276:immunology* / Q000473:pathology*; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015704:CD4 Antigens; D006680:HLA Antigens