Epstein-Barr Virus Associated Disorders

National Institute Of Allergy And Infectious Diseases

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Abstract

Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with both B cell cancers (Hodgkin lymphoma, Burkitt lymphoma) and epithelial cell cancers (nasopharyngeal carcinoma, gastric carcinoma). The virus typically infects epithelial cells of the oropharynx and B cells circulating in the blood. The virus establishes a latent infection in B cells where it persists for life. An unusual complication of EBV disease is chronic active Epstein-Barr virus disease (CAEBV) which is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. We hypothesized that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immune-independent. Interferon is important for controlling herpesvirus infections. On the basis of this hypothesis, in 2023 we published the results of our investigation of the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. Patients with low-grade disease received dose-escalated interferon alfa-2b for up to 1 year past best response, and patients with high-grade disease received intravenous chemotherapy with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% (27 of 44) having a complete response. After initial treatment with chemotherapy (DA-EPOCH-R), the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response. The five year progression-free survival was 49% after initial treatment with interferon alfa-2b, and 25% after initial treatment with DA-EPOCH-R. Interferon alfa-2b was efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy. We found that programmed cell death protein-1 (PD-1) expression, a marker of exhaustion, and CD57 expression, a marker of senescence were higher in CD8+ T cells of patients with lymphomatoid granulomatosis than in healthy controls. Before treatment, CD8+ T cells of patients with lymphomatoid granulomatosis who later reached complete response after treatment with interferon alfa-2b had lower concentrations of CD57 compared with patients who did not have a complete response after treatment with interferon alfa-2b.