Epstein-Barr virus (EBV) causes various acute and chronic diseases. Chronic active EBV infection (CAEBV) is characterized by infectious mononucleosis-like symptoms that persist for more than 6 months with high viral loads in peripheral blood and/or an unusual pattern of anti-EBV antibodies. Severe CAEBV is associated with poor prognosis with severe symptoms, an extremely high EBV-related antibody titer, and hematologic complications that often include hemophagocytic lymphohistiocytosis. However, CAEBV which led to the development of aplastic anemia (AA) has not been reported yet. A 73-year-old woman was admitted to our hospital with intermittent fever, general weakness and elevated liver enzymes. In the serologic test, EBV-related antibody titer was elevated, and real-time quantitative-PCR in peripheral blood showed viral loads exceeding 10(4) copies/microg DNA. Liver biopsy showed characteristic histopathological changes of EBV hepatitis and in situ hybridization with EBV-encoded RNA-1 was positive for EBV. Pancytopenia was detected in peripheral blood, and the bone marrow aspiration biopsy showed hypocellularity with replacement by adipocytes. AA progressed and the patient was treated with prednisolone but deceased 8 months after the diagnosis due to multiple organ failure and opportunistic infection. Herein, we report a rare case of severe CAEBV in an adult patient accompanied by AA and persistent hepatitis.
Aged ; Anemia, Aplastic/*complications ; Carbapenems/therapeutic use ; Chronic Disease ; DNA, Viral/blood ; Epstein-Barr Virus Infections/complications/*diagnosis/pathology ; Female ; Hepatitis/*complications ; Herpesvirus 4, Human/*genetics/isolation & purification ; Humans ; Real-Time Polymerase Chain Reaction ; Severity of Illness Index ; Urinary Tract Infections/drug therapy

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders.
B-Lymphocytes/*pathology/*virology ; Diagnosis, Differential ; Disease Management ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Lymphoproliferative Disorders/*diagnosis/*etiology/therapy

Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.
Cell Transformation, Viral ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Killer Cells, Natural/immunology/metabolism/*pathology/*virology ; Lymphoproliferative Disorders/diagnosis/*etiology/therapy ; T-Lymphocytes/immunology/metabolism/*pathology/*virology

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by intense skin reactions such as bulla and necrotic ulcerations at bite sites, accompanied by general symptoms such as high-grade fever and malaise occurred after mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. We describe here a Korean child who presented with 3-yr history of HMB without natural killer cell lymphocytosis. He has been ill for 6 yr with HMB. Close observation and examination for the development of lymphoproliferative status or hematologic malignant disorders is needed.
Child ; Epstein-Barr Virus Infections/complications ; Humans ; Hypersensitivity/*diagnosis/etiology ; Insect Bites and Stings/*diagnosis/pathology ; Killer Cells, Natural/immunology ; Lymphocytosis/complications/pathology ; Male ; Republic of Korea ; Skin/pathology

No abstract available.
Epstein-Barr Virus Infections/*complications/diagnosis ; Herpesvirus 4, Human/pathogenicity ; Humans ; Lymphoma, Follicular/complications ; Lymphoproliferative Disorders/*complications/diagnosis/virology ; Male ; Middle Aged ; *T-Lymphocytes/pathology/virology

The World Health Organization (WHO) recently defined systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPD) of childhood as a life-threatening illness. However, this rare disease has not been extensively studied. Here we report a case of systemic EBV-positive T-cell LPD in a previously healthy middle-aged man with a chief complaint of chronic diarrhea. The initial colon biopsy showed focal infiltration of EBV-positive small lymphocytes without any atypia. However, the disease rapidly progressed and the patient required a total colectomy due to severe gastrointestinal bleeding. Three and half months after admission, the patient died from a complication of disseminated intravascular coagulation. The resected colon showed diffuse infiltration of EBV-positive atypical lymphocytes with ischemic change. Most atypical lymphocytes were CD3+ or CD5+. The monoclonality of EBV was demonstrated by sequence variation analysis of the latent membrane protein 1 (LMP1) gene in the colectomy specimen as well as in the initial biopsy.
Chronic Disease ; Colonoscopy ; Diarrhea/*diagnosis ; Disseminated Intravascular Coagulation/diagnosis ; Epstein-Barr Virus Infections/complications/virology ; Feces/virology ; Gastrointestinal Hemorrhage ; Herpesvirus 4, Human/genetics/*isolation & purification ; Humans ; Lymphoproliferative Disorders/*diagnosis/immunology/virology ; Male ; Middle Aged ; RNA, Viral/analysis ; T-Lymphocytes/*immunology/pathology

Hypersensitivity to mosquito bites (HMB) is a disorder characterized by a necrotic skin reaction and generalized symptoms subsequent to mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer cell leukemia/lymphoma. We describe here a Korean child who had HMB associated with chronic EBV infection and natural killer cell lymphocytosis. A 5-yr-old boy was suffered from necrotic skin lesions on the right ear lobe. Type A EB virus was detected from hlood cells and bone marrow biospy recognized hemophagocyrosis.
Animals ; Child, Preschool ; Culicidae/*immunology ; Epstein-Barr Virus Infections/complications/*diagnosis ; Herpesvirus 4, Human/genetics/isolation & purification ; Humans ; Hypersensitivity/complications/*diagnosis ; Insect Bites and Stings/complications/*immunology ; Killer Cells, Natural/immunology/*pathology ; Lymphocytosis/complications/*diagnosis ; Male ; Polymerase Chain Reaction

BACKGROUNDChronic active Epstein-Barr virus infection (CAEBV) has been previously reported to be sometimes associated with an aggressive clinical course. The characteristics of CAEBV in Mainland Chinese pediatric patients are largely unreported. The main aims of this survey were to recognize the clinical features of CAEBV in children and to explore its diagnostic criteria and risk factors.

METHODSA retrospective study was performed on 53 pediatric patients (36 boys and 17 girls) with CAEBV who were admitted to Beijing Children's Hospital between 2003 and 2007. All their medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory data and outcome were collected. Independent-samples t test was used for statistical analysis.

RESULTSThe age at onset of CAEBV was from 2 months to 14.6 years (mean (5.3+/-3.3) years). At the time of onset, 43.4% patients had an infectious mononucleosis-like symptom. Most patients exhibited intermittent fever (92.5%, 49/53), hepatomegaly (81.1%, 43/53) and splenomegaly (77.4%, 41/53). Life-threatening complications including hemophagocytic syndrome (24.5%, 13/53), interstitial pneumonia (24.5%, 13/53), hepatic failure (15.1%, 8/53) and malignant lymphoma (11.3%, 6/53) were also observed. The serum EBV DNA level in 23 patients with CAEBV was in the range of 5.05 x 10(2)-4.60 x 10(6) copies/ml with a mean value of 10(3.7) copies/ml. Many patients with CAEBV generally had continuous symptoms during the observational period. Eleven out of 42 patients (26.2%) died 7 months to 3 years after onset. Deceased patients were more likely to have had lower platelet counts and albumin levels than the living patients (P<0.05 for all comparisons).

CONCLUSIONSThe study reveals that CAEBV in Chinese pediatric patients has a severe clinical course and prognosis is poor. Thrombocytopenia and decreases in albumin might potentially be risk factors for a poor prognosis. EBV loads should be measured and tissue should be stained on hybridization probes for EBV-encoded small RNA (EBER) if a patient presents with the known symptoms of CAEBV.

Adolescent ; Age Distribution ; Child ; Child, Preschool ; China ; epidemiology ; Chronic Disease ; Epstein-Barr Virus Infections ; diagnosis ; epidemiology ; etiology ; pathology ; Female ; Follow-Up Studies ; Humans ; Infant ; Male ; Risk Factors ; Serum Albumin ; analysis ; Thrombocytopenia ; complications

We report a case of pure red cell aplasia (PRCA), which was initially suspected as a result of bone marrow involvement of diffuse large B cell lymphoma. Persistent anemia without an obvious cause was observed in a 47-yr-old man diagnosed with relapsed diffuse large B cell lymphoma. The bone marrow study showed only erythroid hypoplasia without the evidence of bone marrow involvement with lymphoma cells, thus PRCA was suggested. However, parvovirus infection was excluded as a potential cause of PRCA because of negative IgM anti-parvovirus B19 antibody and negative parvovirus PCR in the serum. Latent Epstein-Barr virus (EBV) infection of bone marrow was suggested by in situ hybridization with EBV-encoded small RNA (EBER) that showed a strong positive expression in bone marrow cells. Thus, PRCA was thought to be associated with latent EBV infection in bone marrow cells. Although the finding of unexplained anemia is a possible predictor of bone marrow involvement with lymphoma cells, PRCA as a result of a viral infection including EBV should be considered in lymphoma patients. This is the first report of the occurrence of PRCA associated with latent EBV infection in a patient with non-Hodgkin's lymphoma.
Adult ; Bone Marrow/pathology ; Bone Marrow Diseases/*complications/diagnosis/pathology ; Bone Marrow Neoplasms/pathology ; Diagnosis, Differential ; Epstein-Barr Virus Infections/*complications/diagnosis ; Humans ; Lymphoma, Large B-Cell, Diffuse/*complications/pathology ; Male ; Red-Cell Aplasia, Pure/diagnosis/*etiology

BACKGROUND: Fibrin-ring granuloma (FRG), which can be found in bone marrow or the liver, is a subtype of epithelioid granuloma characterized by a central fat vacuole and annular peripheral fibrinoid materials. FRG has been proven to be associated with many etiologies such as several infectious organisms (Coxiella burnett; Epstein-Barr Virus, EBV; cytomegalovirus, CMV; and hepatitis A virus), allopurinol induced hepatitis, Hodgkin's lymphoma, and peripheral T-cell lymphoma. METHODS: We retrospectively reviewed 24 patients diagnosed with FRG by bone marrow biopsy at a single institute between 1995 and 2004. We reviewed clinical symptoms and laboratory findings of the patients, classified them by etiology, and compared prognosis of each group. RESULTS: The most common cause of FRG was acute or chronic EBV infection. Chronic or acute EBV infection was associated with 41.4% of patients (10/24). Of the remaining patients, 33.3% (8/24) were leukemia or lymphoma patients after chemotherapy, 4.2% (1/24) was a patient with hepatic failure, and 20.8% (5/24) were diagnosed as fever of unknown origin. The most common symptom and clinical finding were fever and cytopenia. EBV-associated group comprised chronic active EBV infection, EBV-associated hemophagocytic histiocytosis, acute EBV infection, EBV-associated lymphoproliferative disease, and Langerhans' cell histiocytosis. The EBV-associated group showed a lower survival probability compared with the non-EBV group (P<0.05). CONCLUSIONS: Patients with bone marrow fibrin ring granuloma accompanied by fever require an active workup to find out the cause of infectious agents including EBV infection particularly due to their poor prognosis.
Adolescent ; Adult ; Aged ; Bone Marrow Diseases/diagnosis/*etiology/pathology ; Child ; Child, Preschool ; Epstein-Barr Virus Infections/*complications/diagnosis ; Female ; Fibrin/analysis ; Granuloma/diagnosis/*etiology/pathology ; Herpesvirus 4, Human/immunology/isolation & purification ; Humans ; In Situ Hybridization ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Q Fever/diagnosis ; Retrospective Studies ; Survival Rate