Editorial Withdrawal of immunosuppression in liver transplantation: Lessons learned from PTLD In this issue of Pediatric Transplantation, Hur- witz et al. present a thorough retrospective ana- lysis of children undergoing liver transplantation (LTx) who subsequently developed Epstein-Barr virus (EBV) infection or post-transplant lympho- proliferative disorder (PTLD) and had complete cessation of immunosuppression (IMS) as a uniform component of therapy. IMS was stopped in all 19 patients with PTLD and in 19 of 31 (61%) children with EBV infection. Eight (21%) children have remained off IMS for a mean of nearly 4.2 yr. Twenty-one children required re-institution of IMS for acute rejection at a mean time of 107 +/) 140 days (range 7– 476). This experience highlights several import- ant lessons in regard to the optimal management of EBV/PTLD after LTx and the implications of these findings to our understanding of clinical transplant tolerance. IMS withdrawal as therapy for PTLD Early reports of the management of EBV infection and PTLD included therapeutic modulation of IMS (1–3). Indeed, many of the earliest documen- ted cases of freedom from IMS in LTx were in patients, mostly children, who had IMS discon- tinued either temporarily (4) or for apparently permanent periods of time (5–7) as part of treat- ment for PTLD. Current therapy for this condi- tion has benefited from monitoring using EBV PCR technology (8), more accurate diagnostic tools,andahighdegreeofawarenessofthedisease with subsequent improved management (9, 10). Furthermore, preemptive therapy now is often able to decrease the incidence of progression of EBV viremia to PTLD (11–13). Although mortal- ityfromEBVorPTLDinpediatricLTxisdecreas- ing (14), most post-transplant morbidity and mortality in children remains related to infection and IMS (15) mandating continued attention to minimizing unnecessary long-term IMS. The article by Hurwitz et al. demonstrates that IMS can be safely withdrawn as part of therapy for EBV and/or PTLD, in that the majority of patients who develop acute cellular rejection (ACR) may be successfully treated with steroids without excessive graft loss. One patient in their cohort developed de novo chronic rejection although no deaths were caused by graft loss from acute or chronic rejection. Although one may argue that less drastic immunosuppressant reduction may achieve similar outcomes (perhaps without the morbidity of treatment for ACR), this approach would also clearly deny the clin- ically tolerant patients, the opportunity to achieve drug freedom. As opposed to heart or intestinal transplantation that requires more gentle dose decrements to avoid a life threatening or morbid rejection, complete IMS withdrawal in pediatric LTx appears to be associated with an acceptable and manageable incidence of ACR and, thus far, little chronic rejection. Hurwitz et al. do not comment on the subsequent levels of immunosuppressants required in their patients who needed re-institution of IMS and this is important information. In our experience, how- ever, even patients who resumed IMS usually achieved equilibrium at doses that were lower than their baseline IMS (16). Taken together, this reinforces the concept that the majority of these children are over-immunosuppressed. In our own and othersÕ experience, patients have been withdrawn from IMS because of non- compliance (6, 17), or by protocol for infection indications, drug-related side effects or to min- imize potential drug toxicity (16, 18, 19). In a preliminary report, Reyes reported five of six children who maintained normal graft function with a mean time off drugs of nearly 2 yr (5). Currently, our center follows 14 patients who are maintained off IMS for a mean time of 8.5 +/ ) 4.1 years (range 1.8–13) after abrupt IMS Pediatr Transplantation 2004: 8: 210–213 Printed in UK. All rights reserved Copyright Ó 2004 Blackwell Munksgaard Pediatric Transplantation 210