Early signs and risk factors for the increased incidence of Epstein-Barr virus-related posttransplant lymphoproliferative diseases in pediatric liver transplant recipients treated with tacrolimus

Background. Posttransplant lymphoproliferative disease (PTLD) is a life-threatening condition the incidence of which in pediatric solid organ transplantation may be related to the immunosuppressive load. It has been suggested that tacrolimus, a new and potent immunosuppressor, causes an increased incidence of this syndrome. Methods. The incidence, early signs, and risk factors for lymphoproliferative disease were reviewed in a cohort of 89 pediatric liver transplant recipients treated with tacrolimus. Results. Eighteen patients (20%) developed a PTLD-16 concomitant to a primary Epstein-Barr virus (EBV) infection and 2 with previous immunity against EBV. Three additional patients had preliminary signs of PTLD concomitant to primary EBV infection, but did not develop individualized lymphoid masses. Six patients died (6.7% of all tacrolimus-treated patients). Mean tacrolimus blood level during the 3 months preceding EBV infection reached 11.8+/-1.8 ng/ml in PTLD patients versus 9.4+/-3.4 ng/ml in non-PTLD patients (0.05<P<0.1). Previous OKT3 or antithymocyte globulin treatment was also significantly associated to PTLD. There was no association with age, rejection episodes, steroid-resistant rejection, prior cytomegalovirus infection, HLA mismatch, living donor or cadaveric organ transplantation, United Network for Organ Sharing status at the time of orthotopic liver transplant, and primary or rescue tacrolimus treatment. A significant increase of total gamma-globulin level occurred in PTLD patients, and mono/oligoclonal production was significantly associated to PTLD. Conclusion. In EBV-infected pediatric liver transplant recipients, use of OKT3 or antithymocyte globulin and high tacrolimus blood levels are risk factors for a significant increase in the incidence of PTLD, An increase in total gamma-globulin level and appearance of mono/oligoclonal immunoglobulin production are the major preliminary signs of the syndrome.