Response: EBV reactivation in the immunosuppressed: to treat or not to treat?

Wondergem et al raise the issue that in certain patients with aplastic anemia treated with immunosuppressive therapy, Epstein-Barr virus (EBV) reactivation may sometimes transcend a subclinical stage and progress to an EBV-lymphoproliferative process. In our paper, the intention was to suggest that monitoring EBV and cytomegalovirus (CMV) viral load is not necessary for patients treated with standard immunosuppressive protocols, but with novel immunosuppressive schedules, more potent immunosuppressive agents or repeated treatments, an increased awareness of EBV (and CMV) disease is warranted.

Indeed, our study of prospective EBV monitoring was initiated because of a case similar to the one described by Wondergem et al. Our patient was a 32-year-old man with severe aplastic anemia who received horse antithymocyte globulin (ATG) with no response at 3 months and was then treated with rabbit antithymocyte globulin. Two weeks later, rapidly progressive massive lymphadenopathy developed in the neck, axillary, and mediastinal areas, requiring endotracheal intubation. Axillary lymph node biopsy revealed EBV lymphoproliferation, accompianied by an EBV viral load of 870 000 copies per 10⁶ mononuclear cells in the blood. Cyclosporine was discontinued and the patient received one cycle of cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (CHOP-R) with a rapid decrease in node size and in peripheral blood EBV copy numbers. He went on to unrelated hematopoietic stem cell transplantation for his aplastic anemia and 4 years later he is doing well with no further evidence of EBV disease.

Notwithstanding, EBV-lymphoproliferative disease after immunosuppression for aplastic anemia is very rare and its occurrences have been limited to case reports. We have now monitored EBV reactivations in more than 150 courses of immunosuppressive therapy with no additional cases of EBV disease, despite very high viral loads and prolonged periods of EBV polymerase chain reaction (PCR) positivity. In the past 18 months we have monitored EBV viral loads in patients who received rabbit ATG as initial therapy; higher viral loads were again observed in patients treated with the rabbit ATG up-front (similar levels to what was reported in the manuscript when rabbit ATG was administered as a second course only) compared with those who received horse ATG. Therefore, the EBV viral load cannot be interpreted in isolation as cut-off values that are predictive or diagnostic of disease have not been established. Rather than mandate routine testing for what we believe is a rare event, we would instead prefer to stress awareness of the potential for EBV reactivation and disease, with intervention only when there is clinical suspicion due to rising lactate dehydrogenase (LDH), lymphadenopathy, clinical deterioration in association with a high EBV viral load, and confirmatory lymph-node histology.