Chronic Active Epstein-Barr Virus Infection: Is It Immunodeficiency, Malignancy, or Both?

Abstract

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is a rare syndrome characterized by prolonged infectious mononucleosis-like symptoms and elevated peripheral blood EBV DNA load in apparently immunocompetent persons. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. In most cases of CAEBV, EBV induces proliferation of its unusual host cells, T or natural killer (NK) cells. The clinical course of CAEBV is heterogeneous; some patients show an indolent course, remaining in a stable condition for years, whereas others show an aggressive course with a fatal outcome due to hemophagocytic lymphohistiocytosis, multiple organ failure, or progression to leukemia/lymphoma. The pathogenesis of CAEBV is unclear and clinicopathological investigations suggest that it has aspects of both malignant neoplasm and immunodeficiency. Recent genetic analyses of both viral and host genomes in CAEBV patients have led to discoveries that are improving our understanding of the nature of this syndrome. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept.

Keywords: EBV; EBV-positive T/NK-cell lymphoproliferative disease; Epstein–Barr virus; chronic active EBV infection; hydroa vacciniforme; immunodeficiency; lymphoma; severe mosquito bite allergy.

Figure 1

Hypothetical factors and events in chronic active Epstein–Barr virus (CAEBV) pathogenesis. Shown above are factors and events supposed to play critical roles in the pathogenesis of CAEBV and related EBV-positive T/NK-cell LPDs that may develop in the clinical course of CAEBV. Host genetic factors are supposed to impair immunosurveillance on EBV-infected cells. A possible viral strain predisposed to T/NK-cell lymphoproliferation is considered a viral factor. Intragenic deletions of the EBV genome that facilitate an abortive lytic cycle are presumed to enhance oncogenesis. Mosquito antigens and UV light are environmental factors that are thought to induce local inflammation such as hydroa vacciniforme (HV)-like LPD and severe mosquito bite allergy (SMBA). Infection to lymphoid progenitor cells and infection via immunological synapses are hypothetical mechanisms of EBV infection to T/NK cells.