Epstein-Barr virus (EBV), belonging to the gamma subfamily of herpesviruses, was first identified in 1964 by Epstein, Archong and Barr in an established Burkitt lymphoma cell line. In immunocompetent individuals, primary infection with EBV replicates in oropharyngeal epithelial cells and eventually latently in B-lymphocytes, resulting in asymptomatic or infectious mononucleosis (IM), which is self-limiting and resolves in a few weeks. In cases of congenital immunodeficiency or acquired immunosuppression, childhood EBV infection can cause lymphoproliferative disorder (LPD) or lymphohistiocytic hemophagocytic syndrome (HLH). In individual cases, in individuals who are not clearly immunocompromised, EBV infection may be accompanied by chronic or recurrent symptoms of infectious mononucleosis and abnormal changes in EBV antibodies, called chronic active EBV infection (CAEBV). The pathogenesis of CAEBV CAEBV occurs in individuals who are not clearly immunocompromised, and its exact etiology is unknown. In CAEBV, antiviral capsid antigen (VCA)-IgG and EBV early antigen (EA)-IgG antibody titers are elevated, whereas EBV nuclear antigen (EBNA)-IgG titers are low or undetectable, presumably related to the inability of EBV to enter latent infection or to return from latent infection to lytic infection. New research suggests that, unlike IM, which is self-limiting, EBV infection of T and NK cells and their clonal proliferation is the key to CAEBV pathogenesis, and that abnormal T cell activation and cytokine disruption after EBV infection of T cells are among the causes of cell proliferation in CAEBV, which can also be accompanied by HLH. Diagnostic criteria for CAEBV The current diagnostic criteria applied by the National Institutes of Health are The diagnostic criteria for CAEBV are based on Straus’ 1988 revised criteria for severe, chronic EBV infection (Table 1). CAEBV has been studied for more than 50 years and has been referred to as chronic EBV infection (CEBV) and severe chronic active EBV infection. According to Okano et al. in Japan, CEBV is a disease with clinical manifestations associated with EBV infection without a significant increase in antibody titers against EBV replication-related antigens. In contrast, SCAEBV refers to a disease with severe clinical manifestations, especially those complicated by hematologic abnormalities, and abnormally elevated EBV-associated antibodies (Table 2). CAEBV can be divided into T-cell type and NK-cell type according to the main types of EBV-infected cells in peripheral blood, and T-cell type CAEBV mainly presents with fever and high titers of EBV-associated antibodies, and its pathological mechanism is mainly T-cell activation and cytokine release leading to severe inflammation and fever. NK-cell CAEBV is characterized by mosquito allergy and corresponding skin lesions, increased granulocytosis and elevated IgE titers in bone marrow or peripheral blood, and more chromosomal abnormalities than T-cell type. Both types may develop into T/NK cell lymphoproliferative disorders or even malignant lymphoma or NK cell leukemia. Overall, the prognosis is poor, especially in those with severe complications, and more than half of them die within 5 years from the onset of the first symptoms due to severe complications. The main causes of death are liver failure, heart failure, various types of lymphoproliferative disorders, opportunistic infections, and HLH. The prognosis is better for those who develop CAEBV at the age of 8 years or older, and worse for those with clinically combined thrombocytopenia. There is a lack of standardized and effective treatment protocols for CAEBV, and most of the effective treatment cases are limited to isolated clinical reports, and most of them are in temporary remission, and there are few cases of complete cure. Antiviral therapy such as adenosine can reduce the viral load, but the effect is short-lived, and the viral load rises again after stopping the drug. In severe cases, especially in combination with HLH, immunochemotherapy including pedialyte glycosides, hormones, and cyclosporine A can be applied. CAEBV treatment should be based on re-establishing effective immunity to EBV and completely eliminating EBV-infected or clonally proliferating lymphocytes. Therefore, transfusion of autologous or donor EBV-specific T cells or hematopoietic stem cell transplantation is a promising treatment. However, because patients with CAEBV often have multi-organ damage, the risk of complications after stem cell transplantation is high.