Predicting outcome from post‐transplant lymphoproliferative disease: A risky business

In the current issue of Pediatric Transplantation, Collins and colleagues report on their experience with 22 cases of histologically con®rmed Epstein± Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) among 471 children who had undergone solid-organ transplantation (SOT) or bone marrow transplantation (BMT) at their institution between 1989 and 1998 (1). Based upon their analysis, four major observations were made: (1) the presence of a low incidence but very high mortality rate for BMT recipients with EBV/ PTLD; (2) recognition of a higher mortality rate for patients developing EBV/PTLD in the ®rst 6 months compared to children who developed this complication late after transplant; (3) identi®cation of the absence of seroconversion against EBV as a risk factor for mortality from EBV/PTLD; and (4) a relatively good outcome observed for patients who had monomorphic PTLD. Each of these observations is potentially noteworthy. Accordingly, they are worthy of additional consideration and comment. Collins et al. identi®ed a relatively low incidence (2%) of EBV/PTLD in children undergoing BMT. Other large series of adults and children report an incidence range of 1±10% (2, 3). While the incidence of EBV/PTLD in BMT patients was low in the current series, the mortality rate was 100%. This extremely high mortality rate is consistent with most reports of EBV/PTLD in this population (2) and is explained in part by the severely compromised immune system on presentation. As in the current series, EBV/PTLD is typically diagnosed within the ®rst 6 months following BMT (2) During this period of time, BMT recipients would not be expected to have full reconstitution of their cell-mediated immune response. Thus, they would not be able to produce EBV-speci®c cytotoxic T lymphocytes (CTLs), which are the major component of the host defense against EBV infections. The inability to generate these CTLs explains the nearly uniform mortality observed in these patients. Unlike the situation for SOT patients, doctors of BMT recipients do not have the luxury of simply decreasing or stopping immunosuppressive medications in these children to allow recovery of the immune system. Recognition of the inability to generate CTLs, a critical component of the host immune response, has prompted development of the strategy of adoptive immunotherapy, where donor-derived EBV-speci®c CTLs are used as treatment for EBV/PTLD in BMT patients (3, 4). Subsequently, the use of donor-derived EBVspeci®c CTLs has evolved into a prophylactic strategy where the donor CTLs are infused early after transplant to provide speci®c protection against the development of EBV disease (3, 5). Before being able to consider the validity and potential importance of the remaining observations, the reader must determine whether the design of this study is suitable for identifying risk factors for mortality from EBV/PTLD. The report by Collins et al. is somewhat unique in that it includes children who had undergone both SOT and BMT. Combining these populations adds to the number of patients available for analysis; however, the populations may not be suf®ciently similar to allow for a combined risk assessment. While the predisposition to the development of EBV/PTLD in both populations is the lack of an adequate EBV-speci®c CTL response, the state and potential responsiveness of the immune system in these distinct patient groups is very different. Combining BMT and SOT populations might therefore lead to erroneous conclusions that cannot be extrapolated to either group. Collins and colleagues found that the development of EBV/PTLD in the ®rst 6 months following transplantation was a major risk factor for Pediatr Transplantation 2001: 5: 235±238