title: Natural history of focal moderate cardiac allograft rejection. Is treatment warranted?
abstract: BACKGROUND
  The rate of progression and potential long-term consequences of isolated foci of moderate acute rejection (FMR) on endomyocardial biopsy (EMB) have not been defined; therefore, whether FMR necessitates augmented immunosuppression remains controversial.
  
  
  RESULTS
  At our institution, recipients with EMBs having FMR, defined as one or two isolated foci of cellular infiltrates with associated myocyte damage (International Society for Heart and Lung Transplantation [ISHLT] grade 2 and a subset of grade 3A), do not routinely receive intensified immunosuppression. Accordingly, to determine the outcome of untreated FMR, we reviewed 4398 EMBs (mean, 4.4 samples each) obtained after orthotopic heart transplantation in 208 consecutive recipients maintained on triple immunosuppressive therapy. The incidence of progression versus resolution of FMR, the time interval after transplantation when FMR was detected, and the relation of untreated FMR to recipient survival were analyzed. FMR categorized as one (n = 312) or two (n = 89) foci was present in 401 EMBs (9% of total) obtained 10 days to 7.5 years after transplantation from 149 recipients (72%). EMBs with FMR resolved without treatment in 341 of 401 (85%), and only 60 of 401 (15%) progressed to higher grade rejection. EMBs that progressed occurred 7.5 +/- 7.9 months (mean +/- SD) after transplantation compared with 14.0 +/- 16.5 months after transplantation for those that resolved (P < .005). Of the 60 EMBs that progressed, 55% occurred within the first 6 months, 78% within the first year, and 97% within the first 2 years after transplantation. EMBs with two foci of FMR were no more likely to progress than those with one focus. Thirty-nine recipients experienced one (n = 25), two (n = 9), three (n = 3), or four (n = 2) episodes of FMR that progressed. One or more episodes of FMR that did not progress occurred in 110 recipients. By Kaplan-Meier analysis, survival at 1 and 5 years was similar in recipients with and those without FMR progression.
  
  
  CONCLUSIONS
  First, untreated FMR consisting of either one or two foci has a low rate of progression. Second, progression of FMR decreases with increasing postoperative interval and becomes rare after 2 years. Last, FMR progression did not identify recipients with decreased survival.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115.
authors.forename: G L
authors.initials: GL
authors.lastname: Winters
authors.forename: E
authors.initials: E
authors.lastname: Loh
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoen
mesh_terms: D001379:Azathioprine / Q000627:therapeutic use; D001706:Biopsy; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D004699:Endocardium / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000473:pathology / Q000628:therapy*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D011241:Prednisone / Q000627:therapeutic use; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D016572:Cyclosporine; D001379:Azathioprine; D011241:Prednisone