Chronic active Epstein-Barr virus (CAEBV) infection is an EV-associated lymphoproliferative disease defined by illness lasting 6 months; infiltration of tissues with lymphocytes; elevated EBV DNA, RNA, or proteins in affected tissues; and the absence of any other immunosuppressive condition It has 2 forms: EV-associated T/natural killer (NK) cell proliferation, and EV-associated B cell proliferation In addition to chronic mononucleosis symptoms, the clinical spectrum includes mucocutaneous disease, uveitis, encephalitis, vasculitis, myocardium, and hemophagocytosis, thus potentially mimicking rheumatic disease

A 9-year-old girl presented with recurrent demanding and mouth ulcers following 6 months of periodical rash, fevers, night sweats, headaches, and weight loss. Examination revealed periodontal edema, tongue and lip swelling, and diffuse oral mucous ulceration , tachycardia, hepatocyte, and bilateral anterior uveitis. Electrocardiography revealed coronary aneurysms, but further testing was not suggestive of vasculitis. Infectious investigation revealed high EBV viral load > 58,000 copies/ml peripheral blood, indicating active EBV infection despite serology consistent with past exposure. A mucous biopsy reviewed by the National Institutes of Health confirmed CAEBV by demonstrating increased EV-positive cells that were CD3+ and CD20− on double-staining, consistent with the T/NK cell sub type.

Abstract

Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high-morbidity disease. To clarify the prognostic factors, a national survey was performed in Japan, and data for 82 patients who met the criteria for CAEBV were analyzed. Of these 82 patients, 47 were alive and 35 had already died. Multivariate analysis revealed that thromobocytopenia and age at disease onset were correlated with mortality. The probability of 5-year survival was 0.45 for older patients (onset age, ⩾8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombolytic (platelet count <12×10 ⁴ platelets/μL at diagnosis), and 0.76 for patients without thrombolytic (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival times than patients with natural killer cell infection (probability of 5-year survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease, thrombolytic, and T cell infection had significantly poorer outcomes

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of the T-/BK-cell type, systemic form is a rare and potentially life-threatening illness caused by persistent EBV infection. The highest incidence is found in children and adolescents with increased frequency among Asians and Native Americans, while the disease is uncommon in Western countries. Typically patients present with unspecific symptoms, like fever, nephropathy, phenomenological and liver dysfunction. Due to fatal complications including hemorrhagic syndrome, coagulopathy, multiple organ failure and development of EV-positive lymphoproliferative disease (LPD) or lymphoma early diagnosis is critical for successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected group of patients, diagnosis can be challenging. Inhere we describe the anthropological findings of an African adult with CAEBV associated LPD with a brief review of the literature.

Case presentation

A 42-year-old African man with fever, enlargement of the spleen and a suspected epileptic seizure was referred to our hospital. Diagnostic testing repeatedly revealed a massive EB V-DNA load in peripheral blood. Whole-body PET-CT-scan presented a strong uptake at multiple bone marrow sites, the thyroid and the adrenal glands. Histopathology analysis of bone marrow and thyroid gland revealed a highly proliferating, atypical and predominantly intramuscular toxicity T-cell population with extracellular EBV-encoded RNA. Clonality analysis revealed the presence of poly clonal T-cell-receptor. Based on these findings a CAEBV of the T-/KN-cell type, systemic form was diagnosed. Subsequent therapy including three cycles of chemotherapy with phosphodiesterase, rubicund, instinctive and prednisone resulted in decreased EBV load, clinical improvement and ongoing complete remission.

Conclusion

Adult-onset CAEBV of T/KN-cell type usually comprises a poor prognosis and is extremely rare in Western countries. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Treatment options include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic stem cell transplantation. Given the limited data these options need to be decided upon in each patient individually considering severity of the disease, comorbidity and response.

Epstein-Barr virus (EBV) is a member of the human herpes virus family that infects more than 95 percent of the U.S. population. Most infections occur in childhood and cause no symptoms; in adolescents and adults, EBV often causes infectious mononucleosis. It has also been associated with certain forms of cancer. Chronic Epstein-Barr virus (CAEBV) is a rare disease, primarily of children and young adults, that leads to life-threatening infections.

This study seeks to identify genetic mutations responsible for CAEBV. A secondary goal is to learn more about the natural history of CAEBV.

The study will examine blood and tissue samples from up to 50 patients (age 3 and above) with CAEBV and up to 150 of their relatives (age 2 and above). Autopsy samples may be included in the study. Up to 300 anonymous blood samples from the NIH Clinical Center Blood Transfusion Medicine will also be examined for comparison.

No more than 450 milligrams (30 tablespoons) of blood per 8 weeks will be drawn from adult patients, and no more than 7 milliliters per kilogram of blood per 8 weeks will be drawn from patients under age 18. Local health care providers will refer patients to the study and will obtain the samples. Some patients may also be seen at the NIH Clinical Center. Those patients will have a full medical history and physical examination, along with chest X-ray, blood counts, blood chemistry, EBV serology, and viral load. Other tests, such as CT scan or MRI, may be performed if medically indicated. Patients will be asked to undergo hemispheres.

In nitro tests on the blood or tissue samples will include analysis for proteins or genes that are involved in the immune response; cloning of portions of patient DNA; transformation of B cells with EBV; measurement of the ability of patient blood cells to kill EV-infected cells; determination of lymphocyte subsets; and determination of antibodies to EBV or other herpes viruses.

If a genetic cause for CAEBV is found, the investigators will be available to discuss the results with patients in person or by telephone. Genetic indications of risk for other diseases will also be discussed with patients.