Chronic active Epstein–Barr virus infection: a bi-faceted disease with inflammatory and neoplastic elements

Abstract

Chronic active Epstein-Barr virus infection (CAEBV) is one of the Epstein-Barr virus (EBV)positive T-or NK-cell lymphoproliferative diseases. It is characterized by clonal proliferation of EBV-infected T or NK cells and their infiltration into systemic organs, leading to their failure. Inflammatory symptoms, fever, lymphadenopathy and liver dysfunction are main clinical findings of CAEBV. EBV itself contributes to the survival of the host cells via induction of CD40 and CD137 expression and constitutive activation of NF-jB. Accumulation of gene mutations in the infected cells may lead to the development of highly malignant lymphoma or leukemia. Furthermore, constitutive activation of STAT3 is detected in the infected cells, which not only promotes cell survival but also enhances production of inflammatory cytokines. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only effective treatment strategy for eradication of EBV-infected T or NK cells. However, active disease at the time of allo-HSCT (defined as presence of fever, liver dysfunction, progressive skin lesions, vasculitis or uveitis) is a negative prognostic factor. Establishment of chemotherapy regimens for effective resolution of disease activity in patients with CAEBV is a key imperative. Based on the recently unraveled molecular mechanisms CAEBV development, pathways mediated by NF-jB or JAK/STAT are potential novel therapeutic targets.

Clinicopathological findings of systemic Epstein-Barr virus-positive T-lymphoproliferative diseases in younger and older adults

“…Several patients with sEBV + TCL of childhood were reported to have past history of the systemic form of chronic active EBV (sCAEBV) infection [1,7,8]. Patients with sCAEBV reveal persistent infectious mononucleosis (IM)-like symptoms, primarily increased EBV + CD4 + , occasionally CD8 + T-cells and CD56 + NK-cells [9]. sEBV + TCL has previously been confused with lethal HLH and sCAEBV [2,9,10].…”

Chronic Active Epstein-Barr Virus Infection in a Patient with Enteritis, Myositis, and Pericardial Effusion: A Case Report

“…The last step suggested was RIC (HSCT, LDEC, fludarabine, melphalan, anti-thymocyte globulin, methylprednisolone, etoposide) followed by allo-HSCT (allogeneic hematopoietic stem cell transplant). Unfortunately, the resolution rate of CAEBV infection by the chemotherapies was very low, approximately 10% in unpublished data mentioned in a review (12). Initially, combination treatment with steroids and IVIG seemed effective for fever and fatigue in the current case despite disease relapse with fever, ongoing pericardial effusion, as well as disease progression with intestinal involvement, while the patient was not eligible for HSCT and had a high risk of adverse events, such as infection, for chemotherapies.…”

Clinicopathological Findings of Systemic Epstein-Barr-Positive CD8-positive T-lymphoproliferative Diseases in Younger and Older Patients 

“…EBV + nodal cytotoxic TCL has a primarily nodal presentation with limited extranodal disease [11,12]. sCAEBV presents mainly with IM-like symptoms persisting for 3 months, elevated peripheral blood EBV DNA (³ 10 2.5 copies/µg) and the presence of EBV + T-lymphocytes with mild nuclear atypia [9,14]. In this study, EBV + HLH was excluded because of small amounts of Epstein-Barr virus-encoded RNAs (EBERs)-positive cells [15], and we excluded CD8 + and CD56 + EBV + nasal type TNKCL [2,3].…”

“…Several patients with sEBV + TCL of childhood were reported to have past history of systemic from of chronic active EBV (sCAEBV) infection [1,7,8]. Patients with sCAEBV reveal persistent infectious mononucleosis (IM)-like symptoms, primarily increased EBV + CD4 + , occasionally CD8 + T-cells and CD56 + NK-cells [9]. sEBV + TCL has previously been confused with lethal HLH and sCAEBV [2,9,10].…”

“…Patients with sCAEBV reveal persistent infectious mononucleosis (IM)-like symptoms, primarily increased EBV + CD4 + , occasionally CD8 + T-cells and CD56 + NK-cells [9]. sEBV + TCL has previously been confused with lethal HLH and sCAEBV [2,9,10]. Additionally, EBV + nodal (nodebased) cytotoxic T/NK-cell lymphoma patients showed frequent hepatic and systemic tumor invasions without features of HLH, and followed a progressive clinical course [11,12].…”