Epstein-Barr virus DNAemia and infectious complications after preemptive rituximab treatment.

Preemptive Rituximab Treatment We have read with great interest the recent article by Petropoulou et al. (1) assessing the impact of preemptive rituximab treatment on the risk of infectious complications in allogenic hematopoietic stem cell transplant (HSCT) recipients with reactivation of EpsteinBarr virus (EBV) infection. They reported a significantly higher 36-month cumulative incidence of bacterial infection in those patients receiving rituximab compared with matched controls free of EBV reactivation and therefore with no need for such therapy. This result is somewhat surprising because controlled clinical trials in various clinical settings have not shown a significant increase in infection rates associated with rituximab treatment (2Y4). In the solid organ transplant (SOT) population, an initial study reported a higher risk of infection-related death in rituximab-treated kidney transplant recipients (5), although significant methodologic shortcomings have been pointed out (6). In addition, further studies failed to confirm these results (7). Petropoulou et al. found that patients receiving rituximab had a delayed posttransplantation immune recovery for CD19, CD8, and CD4 lymphocyte subpopulations as well as a higher incidence of de novo hypogammaglobulinemia. Thus, the authors concluded that rituximab might pose an increased risk of life-threatening infections related to prolonged immunodeficiency after HSCT (1). Regardless of the potential impact of such mechanism, we would suggest an alternative explanation for this otherwise unexpected association. Our group has recently hypothesized that EBV DNAemia may act as a surrogate biomarker of the state of immunosuppression after SOT (8). In a cohort of 81 recipients (53 kidney, 21 liver, and 7 heart), we demonstrated that the presence of high EBV DNAemia in whole blood (91,500 copies/mL) throughout the first 6 posttransplantation months was an independent predictor of the subsequent occurrence of immunosuppressionrelated eventsVincluding severe and opportunistic infectionsVafter a median follow-up of 67 months. All the patients included in the analysis had a minimum of five sequential blood samples available for EBV viral load measurement (8). In view of these results, we suggest that EBV dynamics can be used to identify those SOT recipients at the highest risk of overimmunosuppression. We acknowledge that the extrapolation of our experience in SOT recipients to the HSCT setting might not be advisable and warrants further investigation to be eventually confirmed. Nevertheless, if such hypothesis is correct, the increased risk of infection found in HSCT recipients receiving preemptive rituximab due to EBV reactivation should reflect a higher burden of immunosuppression in that subgroup rather than be attributed to the impact of rituximab therapy itself. In that line, patients with EBV reactivation in the study by Petropoulou et al. were more likely to have undergone a myeloablative conditioning compared with controls (75% versus 58%, respectively), with a trend toward statistical significance (P=0.096). In summary, we propose that future prospective ad hoc studies, thoroughly taking into account the net state of immunosuppression in each group, should be conducted before inferring a causal relationship between rituximab therapy and the risk of infectious complications in HSCT or SOT recipients.