Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States

Abstract

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.

Figure 1

EBV RNA in both CD20⁺ and CD20⁻ B cells in a lymph node from patient 16. (A) Lymph node biopsy shows polymorphic B-cell lymphoma. (B) In situ hybridization shows that the tumor cells are positive for EBER. Few cells express the CD20 B-cell marker (C), whereas many cells express the CD3 T-cell (D), CD79 B-cell (E), and Pax-5 B-cell (F) markers.

Figure 2

EBV disease involving skin, lymph nodes, and spleen. Skin from patient 12 shows a perivascular lymphocytic infiltrate (A) that is positive for EBER (B). Lymph node (C) and spleen (D) with hemophagocytosis from patient 9.

Figure 3

Levels of antibody to EBV lytic proteins and EBNA1 by the luciferase immunoprecipitation system assay in EBV-seropositive control patients (CTRL), patients with CAEBV, and EBV-seronegative control patients. Each point represents an individual sample from an uninfected control or a person infected with EBV. Antibody titers are expressed in LU. P values were calculated with the Mann-Whitney U test. The solid horizontal lines indicate the geometric mean antibody titers in each group, and the vertical lines show the 95% confidence interval.

Figure 4

Cytokine levels in patients with CAEBV. Levels of IL-6, IL-10, TNF-α, and IFN-γ are shown in pg/mL. CTRL indicates healthy EBV-seropositive control patients; B, patients with B-cell CAEBV; B + T, combined patients with B-cell and T-cell CAEBV.

Figure 5

Clinical course. Clinical course for patients 12 (A) and 17 (B) is shown. Time from initial clinic visit is shown on the x-axis and EBV DNA viral load is on the y-axis. Chemo indicates chemotherapy; EPOCH-RF, etoposide-vincristine-doxorubicin-cyclophosphamide-prednisone-rituximab-fludarabine.