Prevention and preemptive therapy of posttransplant lymphoproliferative disease in pediatric liver recipients

Background. We have previously reported a 10% incidence of posttransplant l ymphoproliferative disease (PTLD) in pediatric patients receiving first liv er grafts and primarily immunosuppressed with tacrolimus, To decrease the i ncidence of PTLD, we developed a protocol utilizing preemptive intravenous ganciclovir in high-risk recipients (i.e,, donor (D)(+), recipient (R)(-)), combined with serial monitoring of peripheral blood for Epstein Barr virus (EBV) by polymerase chain reaction (PCR). Methods. Consecutive pediatric recipients of a first liver graft were immun osuppressed with oral tacrolimus (both induction and maintenance), and low- dose prednisone, EBV serologies were obtained at the dime of orthotopic liv er transplant in recipients and donors. Recipients were divided into groups : group 1, high-risk. (D+R-), and group 2, low-risk (D+R+; D-R-; D-R+). In group 1 (high-risk), all patients received a minimum of 100 days of intrave nous ganciclovir (6-10 mg/kg/day), while, in group 2 (low-risk), patients r eceived intravenous ganciclovir during their initial hospitalization and th en were converted to oral acyclovir (40 mg/kg/day) at discharge, Semiquanti tative EBV-PCR determinations were made at 1-2-month intervals. In both gro ups, patients with an increasing viral copy number by EBV-PCR had tacrolimu s levels decreased to 2-5 ng/ml. Tacrolimus was stopped, and intravenous ga nciclovir reinstituted for PTLD. A positive EBV-PCR with symptoms, but nega tive histology, was defined as EBV disease; PTLD was defined as histologic evidence of polyclonal or monoclonal B cell proliferation. Results. Forty children who had survived greater than 2 months were enrolle d. There were 18 children in group 1 (high-risk; mean age of 14+/-15 months and mean follow-up time of 243+/-149 days) and 22 children in group 2 (low -risk; mean age of 64+/-65 months and follow-up time of 275+/-130 days). In group 1 (high-risk), there was no PTLD and one case of EBV disease (mononu cleosis-like syndrome), which resolved, In group 2 (low-risk), there were t wo cases of PTLD; both resolved when tacrolimus was stopped, Both children were 8 months old at time of transplant. Neither received OKT3, and they ha d one and two episodes of steroid-sensitive rejection, respectively. One ch ild had EBV disease (mild hepatitis), which resolved. Conclusions. Since instituting this protocol, the overall incidence of PTLD has fallen from 10% to 5% for children receiving primary tacrolimus therap y after OLT. No high-risk pediatric liver recipient treated preemptively wi th intravenous ganciclovir developed PTLD. Both children with PTLD were les s than 1 year at OLT and considered low-risk. However, their positive EBV a ntibody titers may have been maternal in origin and not have offered long-t erm protection. Serial monitoring of EBV-PCR after pediatric OLT is recomme nded to decrease the risk of PTLD by allowing early detection of EBV infect ion, which is then managed by decreasing immunosuppression and continuing i ntravenous ganciclovir.