Allograft rejection of ISHLT grade >/=3A occurring late after heart transplantation--a distinct entity?

The significance of International Society of Heart and Lung Transplantation (ISHLT) grade >/=3A rejection detected by routine endomyocardial biopsies beyond 2 years post-transplant remains uncertain.

We performed a retrospective analysis of our single-institution database consisting of 4,041 biopsies (188 patients) from 1986 to 2001. Incidence, clinical correlates and outcome of ISHLT grade >/=3A rejection beyond 2 years post-transplant were analyzed.

A total of 307 ISHLT grade >/=3A rejection episodes was diagnosed up to 10 years after transplantation, 69 of which occurred later than 2 years post-transplant in 33 of 139 patients ("late rejection") at therapeutic levels of immunosuppression. Late rejection was only marginally correlated with the incidence of moderate rejection within the first 2 post-transplant years (p = 0.09). The incidence of moderate rejection per patient-year decreased from 1.05 in Year 1 over 0.11 in Year 5 to 0.04 in Year 10. The technical failure rate of biopsies remained low throughout the post-transplant period (range 0.7% to 2.4%). Spontaneous resolution of ISHLT grade >/=3A rejection beyond 2 years post-transplant occurred in all 17 patients in whom specific anti-rejection therapy had been electively withheld. Mortality beyond 2 years post-transplant was lower (p = 0.033) in the "late rejecting" group (n = 33) than in the control group (n = 106).

Endomyocardial biopsy continues to detect episodes of moderate rejection even very late after heart transplantation, without a close correlation with the rejection frequency in the early post-transplant period. Even without specific treatment, late rejection carries a benign clinical prognosis and may represent a separate biologic entity. Potential long-term effects-for instance, on the pathogenesis of transplant vasculopathy-need further elucidation.