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Chronic active Epstein–Barr virus – Is it real and how do you treat it?

Epstein–Barr virus (EBV) has been associated with numerous diseases. Demonstrating causation of EBV in any particular disease is difficult due to the ubiquitous nature of EBV infection in the human population. For example, it was noticed that many patients suffering from chronic fatigue syndrome had elevated titers to EBV antigens, but further epidemiologic studies failed to demonstrate EBV to be the causative agent (1). However, an entity, i.e., chronic active EBV (CAEBV), does exist that is characterized by recurrent fever, organomegaly, lymphadenopathy, and specific virologic criteria, including very high levels of EBV DNA in the peripheral blood (2). The pathogenesis of CAEBV is unclear. Though no genetic defect has been identified, this entity appears to be much more common in the Asian population. Patients usually have symptoms persisting over months to years. Clinical symptoms can be severe, and of note hypersensitivity to mosquito bites is a common finding. CAEBV is often lethal with a median survival of 3–5 yr. Death is resultant of hemophagocytic syndrome, lymphoproliferative disease – with NKand T-cell lymphomas being more common than B-cell lymphomas, and strangely up to 20% of CAEBV patients die of coronary aneurysm (3). Numerous therapeutic approaches to treat CAEBV have been reported, though no therapy has consistently been demonstrated to be effective. Therapies used to treat CAEBV include immunomodulation, i.e., intravenous gammaglobulin, corticosteroids, interferon, and immunosuppressants, as well as cytotoxic therapy, i.e., chemotherapy and allogeneic blood or marrow transplantation (BMT) (3). Certainly, EBV is associated with more pathology in patients with defects or deficiencies of the cellular immune system, which may be inherited or acquired. EBV certainly causes a spectrum of disease in the post-transplant patients. Some patients do indeed have persistent high level of EBV DNA in their blood post-transplant. Some of these patients will also have corresponding clinical symptoms of fevers and/or lymphoproliferations, even post-transplant liver disease, associated with high levels of EBV DNA. However, it is unlikely that the pathophysiology of ‘‘high EBV load carriers’’ or chronic reactivating EBV infection in the post-transplant patient is the same as CAEBV. Following transplant, ‘‘high load carriers’’ have the usual host restriction of latent viral infection to B-cells. However, in CAEBV, it has been demonstrated that the host cells for latent EBV infection are NK-cells and CD4+ T-cells, not B-cells (4). The case report in this issue by Matsunaga et al. (5) is illustrative of the issues of diagnosing and successfully treating CAEBV. As in this case, there is often a striking history of hypersensitivity to mosquito bites, which as in this case can be striking. There is often a period characterized by non-specific complaints and symptoms, which can be quite long, i.e., four yr in the boy reported in this case. When CAEBV was considered as a potential diagnosis, the investigators performed a thorough evaluation to confirm the diagnosis. In this case, the patient met specific EBV serologic criteria of CAEBV, had elevated EBV DNA levels in the peripheral blood and was found to have EBV latent infection restricted to NK cells. The patient was monitored closely over the next six yr, using corticosteroids to reduce severity of symptoms which was at first successful, but ultimately progressed to a point where multiagent chemotherapy was given without success. The child then underwent an allogeneic BMT, and remains free of symptoms with normal EBV DNA levels for over two yr post-BMT. Based on the results of the case by Matsunaga et al., it appears that immunologic replacement by allogeneic BMT is curative for CAEBV. Based on these findings, it is felt that the etiology of CAEBV represents an underlying defect in Pediatr Transplantation 2009: 13: 146–147 2008 Wiley Periodicals, Inc.