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

SIMPLE SUMMARY: Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a rare syndrome of unknown etiology characterized by prolonged infectious mononucleosis-like symptoms and proliferation of EBV-infected T and/or natural killer cells. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. The clinical course of CAEBV is heterogeneous ranging from an indolent and occasionally self-limiting disease to an aggressive and fatal condition, but its prognosis is generally poor. This heterogeneous clinical picture does not suggest a simple etiology for the syndrome. Clinicopathological investigations of CAEBV suggest that it has aspects of both malignant neoplasm and immunodeficiency. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept. 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.