Current research on chronic active <scp>E</scp>pstein–<scp>B</scp>arr virus infection in <scp>J</scp>apan

Fujiwara, Shigeyoshi; Kimura, Hiroshi; Imadome, Ken Ichi; Arai, Ayako; Kodama, Eiichi N.; Morio, Tomohiro; Shimizu, Norio; Wakiguchi, Hiroshi

doi:10.1111/ped.12314

Cited by 73 publications

(83 citation statements)

References 67 publications

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“…For primary cases, hematopoietic stem cell transplantation (HSCT) is required for cure, [17][18][19] and may also be necessary for some forms of sHLH such as chronic active Epstein-Barr virus (EBV) infection. 20,21 Three decades ago, long-term survival in HLH was ,5%.…”

Section: Introductionmentioning

confidence: 99%

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Bergsten

Horne

Aricò

et al. 2017

Blood

512

444

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Key Points• Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 .06).• HLH-2004 may be improved by risk-group stratification, less therapy reduction weeks 7 to 8 for verified FHL patients, and earlier HSCT.Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n 5 168) and without (n 5 201) family history/ genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n 5 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P 5 .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P 5 .020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL,(70)(71)(72)(73)(74)(75)(76)(77)(78)). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly. (Blood. 2017;130(25):2728-2738 Medscape Continuing Medical Education onlineIn support of improving patient care, this activity has been planned and

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Section: Introductionmentioning

confidence: 99%

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Bergsten

Horne

Aricò

et al. 2017

Blood

512

444

View full text Add to dashboard Cite

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“…hile Epstein-Barr virus (EBV) establishes lifelong latency in B cells and is associated with B-cell malignancies, it is also associated with malignancies and diseases that originate from T cells, including NK/T-cell lymphomas (1), hemophagocytic lymphohistiocytosis (2), hydroa vacciniforme (HV) (3), and chronic active EBV (CAEBV) (4,5). In these diseases, EBV can be detected in CD4…”

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confidence: 99%

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

Coleman

Wohlford

Smith

et al. 2015

J Virol

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Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin.EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have generally failed to readily infect mature T cells in culture. The difficulties in performing in vitro T-cell experiments have left questions regarding the role of EBV in the pathogenesis of EBV-positive T-cell lymphoproliferative diseases largely unresolved. We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T cells in vitro, demonstrating a propensity for CD8 ؉ T cells. EBV-2 infection of purified T cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed toward chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell processes. Collectively, these novel findings identify a previously unknown cell population potentially utilized by EBV-2 to establish latency and lay the foundation for further studies to elucidate the role of EBV in the pathogenesis of T-cell lymphoproliferative diseases. IMPORTANCE The ability of EBV to infect T cells is made apparent by its association with a variety of T-cell lymphoproliferative disorders.However, studies to elucidate the pathogenic role of EBV in these diseases have been limited by the inability to conduct in vitro T-cell infection experiments. Here, we report that EBV-2 isolates, compromised in the capacity to immortalize B cells, infect CD3 ؉ T cells ex vivo and propose a working model of EBV-2 persistence where alteration of T-cell functions resulting from EBV-2 infection enhances the establishment of latency in B cells. If indeed EBV-2 utilizes T cells to establish a persistent infection, this could provide one mechanism for the association of EBV with T-cell lymphomas. The novel finding that EBV-2 infects T cells in culture will provide a model to understand the role EBV plays in the development of T-cell lymphomas. While Epstein-Barr virus (EBV) establishes lifelong latency in B cells and is associated with B-cell malignancies, it is also associated with malignancies and diseases that originate from T cells, including NK/T-cell lymphomas (1), hemophagocytic lymphohistiocytosis (2), hydroa vacciniforme (HV) (3), and chronic active EBV (CAEBV) (4, 5). In these diseases, EBV can be detected in CD4 ϩ T cells, CD8 ϩ T cells, or ␥␦ T cells (6, 7), with the virus predominantly existing as a latent infection (8, 9). The etiology of these T-cell diseases, and in particular whether EBV infection of T cells is an aberrancy in a virus known for its B-cell tropism in vitro and in vivo, remains unknown.Based on genetic differences in the Epstein-Barr nuclear ...

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“…Chronic active Epstein–Barr virus infection is a rare but important disorder in children because of its poor prognosis. The major symptoms of CAEBV are fever, hepatosplenomegaly, lymphadenopathy, and liver dysfunction, which are similar to those of infectious mononucleosis . Other symptoms such as sinusitis and skin diseases are observed in only a limited number of cases .…”

Section: Discussionmentioning

confidence: 99%

“…The major symptoms of CAEBV are fever, hepatosplenomegaly, lymphadenopathy, and liver dysfunction, which are similar to those of infectious mononucleosis. 5 Other symptoms such as sinusitis and skin diseases are observed in only a limited number of cases. 6 The present patient did not have any of the typical major symptoms.…”

Section: Discussionmentioning

confidence: 99%

Chronic active EBV infection with features of granulomatosis with polyangiitis

Shimomura

Morishita

Meguro

et al. 2016

Pediatrics International

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Herein, we report the case of a 13-year-old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein-Barr virus (EBV)-encoded RNA (EBER) in most lymphocytes in the same sample. The EBER-positive lymphocytes were mainly CD4-positive T cells. The EBV-DNA load in the peripheral blood was also abnormally increased (1.0 × 10(4) copies/μg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA.

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Current research on chronic active Epstein–Barr virus infection in Japan

Cited by 73 publications

References 67 publications

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

Chronic active EBV infection with features of granulomatosis with polyangiitis

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