Natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus infection

We describe a 69-year-old female who developed natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus (CAEBV) infection. Examination of the patient's pleural effusion revealed large abnormal lymphocytes, which were CD2(+), CD7(+), CD30(+), CD56(+), CD3(-), and CD4(-). No rearrangement of T cell receptor genes was detected. Clonal proliferation of Epstein-Barr virus (EBV)-infected cells in pleural effusion was demonstrated by Southern blot hybridization analysis. Human herpesvirus type-8 (HHV-8) DNA was not detected in these cells. The patient achieved a complete remission with combination chemotherapy. Prior to the clinical onset of lymphoma, high fever of unknown origin had persisted for 21 months. IgG antibodies to EBV-viral capsid antigen and to EBV-early antigens, types D and R were not high (1:160 and less than 1:10, respectively). Two months after the onset of fever, however, retrospective quantitative PCR assay revealed a high EBV DNA load in plasma, indicating that CAEBV infection had been the cause of the patient's recurrent fever. The remarkable features of this case are (i) the development of lymphoma following CAEBV infection that demonstrated a normal pattern of EBV-specific antibodies, (ii) the development of HHV-8-negative body cavity lymphoma, and (iii) the effectiveness of combination chemotherapy.     

Prognostic factors for chronic active Epstein-Barr virus infection

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, > or = 8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4) platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia (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, thrombocytopenia, and T cell infection had significantly poorer outcomes.     

严重慢性活动性EB病毒感染1例报告

正1病例资料患者男性,23岁,13年来肝功能反复异常,转氨酶轻度到中度升高,间断予以保肝治疗,转氨酶可降至正常,但仍反复,B超示肝肿大、巨脾,先后行两次肝穿刺活组织病理检查(图1a、b),病理报告慢性肝炎病因未明,予保肝治疗。2012年2月出现发作性意识不清,持续15 min至数小时,无口吐白沫、     

Large-vessel arteritis associated with chronic active Epstein-Barr virus infection

This report describes an autopsy case of large-vessel arteritis associated with chronic active Epstein-Barr virus (EBV) infection in a 10-year-old Japanese girl. All of the 3 main coronary arteries, bilateral common carotid and subclavian arteries, abdominal aorta and its major branches, and bilateral common iliac arteries were involved, and all showed aneurysmal dilation of the lumens. Histopathologic examination revealed mesoarteritis characterized by moth-eaten-appearing destruction of the medial elastic laminae, with T lymphocyte infiltration around the vasa vasorum and severe intimal thickening. The EBV DNA genome was detected in the diseased aortic tissue by polymerase chain reaction, and in the infiltrating lymphocytes by in situ hybridization. The clinical symptoms and histopathologic manifestations of the arterial lesions in this patient were obviously different from those of Kawasaki disease and Takayasu arteritis, and the arteritis was considered to be associated with the EBV infection.     

Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis

We report a 22-year-old female who presented with pyrexia, pancytopenia and liver dysfunction. The patient showed mild liver dysfunction with low-grade fever and mild hepatosplenomegaly 6 years previously, and autoimmune hepatitis (AIH) was diagnosed based on the examination of the laboratory data and liver biopsy. On admission, both markers of Epstein-Barr virus (EBV) and in-situ hybridisation from a liver biopsy specimen indicated chronic active EBV infection (CAEBV). The patient was administered an immunosuppressive agent and antiviral drug added to steroid therapy, but ultimately died from liver failure and virus-associated haemophagocytosis 10 months after the definite diagnosis. Retrospective examination of the serum at the diagnosis of AIH revealed extremely high titres of antibody to EBV, and EBV-DNA was also detectable by polymerase chain reaction. These results suggest the possibility that the patient may already have suffered from CAEBV at the initial diagnosis. We presume that hepatic involvement of CAEBV should be considered as differential diagnosis in cases showing liver dysfunction with clinical and biochemical features observed in AIH.     

Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection

Since the initial report of unusual manifestations possibly associated with chronic active Epstein-Barr virus (EBV) infection (CAEBV), nearly three decades have passed. During this period, reported cases with this entity have dramatically increased in the world. Additionally, recent development of diagnostic procedures, including molecular biological and immunological techniques, have provided us with the ability to define certain diseases, especially malignant disorders. Guidelines, derived mainly from the current literature and recent experiences with CAEBV in Japan, for diagnosing CAEBV are proposed to clarify this enigmatic disease.     

Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection

A 45-year-old man with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with natural killer cell type developed pulmonary arterial hypertension (PAH). After chemotherapy, he showed marked depression of the EBV DNA genome in the peripheral blood, but PAH sustained. He died of heart failure due to PAH, and the histo-pathological examination revealed pulmonary vascular abnormalities without lung disease on autopsy. Although the EBV DNA genome and the infiltrating lymphocytes were not detected in the lung, his clinical course suggested that his PAH might be caused by CAEBV. This is the first reported case of PAH associated CAEBV in an adult.     

Clinical and virologic characteristics of chronic active Epstein-Barr virus infection.

Thirty patients with chronic active Epstein-Barr virus (CAEBV) infection were analyzed. The study group included 18 male and 12 female patients, ranging in age from 5 to 31 years with a mean age of 14.2 years. Not all patients had high titers of EBV-specific antibodies, but all patients had high viral loads in their peripheral blood (more than 10(2.5) copies/microg DNA). Fifty percent of the patients displayed chromosomal aberrations, and 79% had monoclonality of EBV. Patients were divided into 2 clinically distinct groups, based on whether the predominantly infected cells in their peripheral blood were T cells or natural killer (NK) cells. Over a 68-month period of observation, 10 patients died from hepatic failure, malignant lymphoma, or other causes. Patients with T-cell CAEBV had a shorter survival time than those with NK-cell type of disease.     

慢性活动性EB病毒感染转为淋巴瘤1例报道

慢性活动性EB病毒感染（chronicactive Epstein—Barrvirus infection．CAEBV）以反复发作的发热和肝、脾、淋巴结肿大为特征,可持续数月至数年,程度不一,严重者出现肝衰竭或多器官衰竭,可表现为典型的嗜血细胞性淋巴组织细胞增生或导致淋巴瘤的发生。该病可能与EBV感染T淋巴细胞和自然杀伤（natural killer．NK）细胞有关,可发展成霍奇金病或NK细胞白血病,总体预后不良。     

Chronic, active Epstein-Barr virus infection

Chronic active Epstein-Barr virus (EBV) infection is an uncommon outcome of EBV infection and may present as a waxing and waning or fulminant syndrome. Unlike acute infectious mononucleosis, wherein EBV establishes lifelong infection and survives by maintaining a delicate balance with the host as a latent infection, in chronic active EBV infection the host-virus balance is disturbed. The mechanisms by which this balance becomes perturbed are likely to be heterogenous and may involve host immune factors, viral factors, or both. A number of subtle immunologic defects have been reported in patients with chronic active EBV infection. Enhanced expression of viral genes has also been noted in some cases. Treatment of chronic active EBV infection has proven difficult, but new modalities including etoposide-based regimens and adoptive transfer of EBV-specific cytotoxic T lymphocytes have shown promise.     

罕见成人慢性活动性EB病毒感染1例报告

正1病例资料患者男性,27岁,因反复发热7周,发现肝功能异常1个月于2014年8月20日入本院。患者于7周前无明显诱因出现发热,多发生于晚间(约16∶00~19∶00),体温最高为38.5℃,伴有咽痛,偶有咳嗽、咳痰,痰为白色泡沫样,伴有散在皮肤疱疹,约米粒大小,自服布洛芬后体温逐渐降至正常,不曾系     

Overview and problematic standpoints of severe chronic active Epstein-Barr virus infection syndrome

Epstein-Barr virus (EBV) is an ubiquitous human herpesvirus. Its infection is generally subclinical. However, in certain circumstances, EBV causes infectious mononucleosis (IM) and lymphoproliferative disorders (LPD) in immunologically compromised individuals. Furthermore, EBV infection is etiologically linked to human malignancies such as Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC) and miscellaneous malignant diseases because of the presence of viral genome in their tumor tissues. Since the late 1970s, a chronic undefined illness possibly associated with EBV infection, named such as severe chronic active EBV infection syndrome (SCAEBV), has been of interest due to its unique manifestations that often result in a poor prognosis. This review is an overview of SCAEBV with respect to its; history, diagnosis, pathogenesis, therapeutic approaches, and ideas on how to further recognize this enigmatic disease.     

The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection

Aim

The protective role of invariant natural killer T cells (iNKTs) against hepatitis B virus (HBV) infection remains controversial. We sought to clarify the role of peripheral iNKT cells during chronic HBV infection.

Methods

Sixty patients with chronic HBV infection were categorized into an immune tolerance phase (HBV-IT) (n = 16), an immune clearance phase (HBV-IC) (n = 19) and an inactive carrier phase (HBV-IA) (n = 25). Twenty healthy individuals were enrolled as healthy controls. Another 21 HBeAg-positive patients were administrated with entecavir (0.5 mg/day) for 6 months. The percentages of circulating iNKT cells and their IFN-γ and IL-4 expression levels were examined by flow cytometry. The relationships between serum HBV DNA, ALT levels, the percentages of iNKT cells, and their IFN-γ and IL-4 levels were analyzed.

Results

Compared to healthy controls, the percentage of iNKT cells decreased in HBV-IT, but increased in HBV-IC and HBV-IA. Circulating IFN-γ-producing iNKT cells gradually increased, whereas IL-4-producing iNKT cells gradually decreased from HBV-IT stage to HBV-IC and HBV-IA stages. The frequency of iNKT cells and their IFN-γ levels were reversely correlated with viral load. The levels of IL-4 expressed by iNKT cells were positively correlated to viral load and the serum ALT levels. After anti-virus therapy, the percentage of IFN-γ-producing iNKT cells increased while the percentage of IL-4-producing iNKT cells decreased.

Conclusions

During chronic HBV infection, the percentages of peripheral iNKT cells and its cytokines expressions of IFN-γ and IL-4 showed dynamic changes. The expression levels of IFN-γ and IL-4 were correlated with the clearance of HBV and liver injury.

     

Successful treatment of natural killer (NK) cell leukemia following a long-standing chronic active Epstein-Barr virus (CAEBV) infection with allogeneic bone marrow transplantation

The optimal treatment for natural killer (NK) cell leukemia after chronic active Epstein-Barr virus (CAEBV) infection has not been determined. A 15-year-old boy presented with NK cell leukemia following CAEBV infection for 5 years. The peripheral blood and BM had an increased number of CD3(-)CD56(+) large granular lymphocytes and a monoclonal integration of the EBV genome was detected. Chemotherapy was not sufficiently effective to control the disease. Allogeneic BMT from an HLA-identical sister was performed using a conditioning regimen consisting of total body irradiation, cyclophosphamide and thiotepa. The patient is disease-free with a perfect performance status 24 months after BMT. This is the first report to show that allogeneic BMT is potentially able to cure NK cell leukemia after CAEBV infection.     

An adult case of severe chronic active Epstein-Barr virus infection syndrome.

A 23-year-old man with persisting high fever developed hepatosplenomegaly, lymphadenopathy and massive pericardial effusion. Immunological examination revealed a marked elevation of anti-Epstein-Barr virus antibodies (anti-viral capsid antigens IgG-antibody 1:10,240, anti-early antigens-DR IgG-antibody 1:5,120), decreased activities of Epstein-Barr virus specific cytotoxic T lymphocytes, natural killer cells and lymphokine activated killer cells. A liver biopsy showed moderate sinusoidal lymphocytosis with punched-out lesions. These findings suggested severe chronic active Epstein-Barr virus infection syndrome. The patient was treated with recombinant human interleukin-2, but it was discontinued because of an adverse reaction. Twelve months later, he died of suspected pulmonary infection.     

Clonal lymphoproliferation following chronic active Epstein-Barr virus infection and hypersensitivity to mosquito bites

In order to elucidate the possibility of lymphoproliferation in cases of chronic active Epstein-Barr virus infection (CAEBV), to clarify the clonality and genotype of proliferating lymphocytes, and to search for the factors that induce lymphoproliferation, we studied 11 cases of CAEBV, using genetical and immunological techniques. Epstein-Barr virus (EBV) DNA in peripheral mononuclear cells was detected in eight cases by Southern blotting. Among those eight cases, monoclonal proliferation of EBV DNA-positive cells was observed in three cases and oligoclonal proliferation in three cases. In the cases of monoclonal proliferation, one case manifested T-cell lymphoproliferation and the rest natural killer (NK) cell lymphoproliferation. The anti-EBV antibody titers in the study did not have any relativity to lymphoproliferation. On the other hand, three of the four cases of NK cell lymphoproliferation and one of the two cases of T-cell lymphoproliferation exhibited hypersensitivity to mosquito bites (HMB) in their clinical histories, while none of the three nonlymphoproliferation cases did. These facts indicate that T-cell and NK cell lymphoproliferative diseases (LPDs) could be more closely associated with EBV infection than we had previously expected. Also, the anti-EBV antibody titers may not be the indicator of EBV-associated LPD, and HMB may be one of the factors that induce EBV-associated LPD. Am. J. Hematol. 54:276–281, 1997. © 1997 Wiley-Liss, Inc.     

The "chronic, active Epstein-Barr virus infection" syndrome and primary fibromyalgia

Fifty patients with primary fibromyalgia who had been followed in an academic rheumatology practice frequently reported symptoms thought to be typical of "chronic Epstein-Barr virus infection," but not of fibromyalgia: recurrent sore throat (54%), recurrent rash (47%), chronic cough (40%), recurrent adenopathy (33%), and recurrent low-grade fevers (28%). In 55% of the patients, illness had begun suddenly, with what seemed to be a viral syndrome. Antibody titers to Epstein-Barr virus in the patients with fibromyalgia, however, were not significantly different from those in age- and sex-matched "healthy" and "unhealthy" control subjects.     

A case of a long-time survivor with chronic active Epstein-Barr virus infection

Epstein-Barr virus (EBV) is associated with hypersensitivity to mosquito bites (HMB) and fatal EBV-associated hemophagocytic syndrome (HPS). The prognosis of patients with chronic active EBV infection (CAEBV) is very poor. We report a rare case of an adult woman patient with a 28-yr history of HMB, who developed EBV-HPS. EBV genome was detected in the serum and peripheral blood lymphocytes. Clonal proliferation of EBV was demonstrated by Southern blot analysis using an EBV genome terminal-repeat probe. This is a very rare case of a long-term survivor with CAEBV. The patient was initially treated with immunochemotherapy and achieved complete remission. However, the patient immediately relapsed and underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. Peripheral blood cell recovered well, and EBV genome disappeared from the peripheral blood. Allogeneic BMT may be effective in eradicating EBV-HPS. Unfortunately, the patient died of graft vs. host disease on the 92nd day after BMT.     

Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection

Unusual Epstein-Barr virus (EBV) infection into T or natural killer cells plays a pivotal role in the pathogenesis of acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV). The precise frequency and localization of EBV genome in lymphocyte subpopulations especially within T-cell subpopulations are unclear in these EBV-related disorders. This study analyzed the frequency of EBV-infected cells in circulating lymphocyte subpopulations from 4 patients with acute EBV-HLH and 4 with CAEBV. EBV- encoded small RNA-1 in situ hybridization examination of peripheral blood lymphocytes showed a significantly higher frequency of EBV-infected cells of 1.0% to 13.4% in EBV-HLH and 1.6% to 25.6% in CAEBV, respectively. The patterns of EBV infection in lymphocyte subpopulations were quite different between acute EBV-HLH and CAEBV. EBV infection was predominant in CD8(+) T cells in all EBV-HLH patients, whereas the dominant EBV-infected cell populations were non-CD8(+) lymphocyte subpopulations in CAEBV patients. Phenotypical analysis revealed that EBV-infected cell populations from both EBV-HLH and CAEBV were activated. There was no predominance of any EBV substrain of latent membrane protein-1, EBV-associated nuclear antigen (EBNA)-1, and EBNA-2 genes between the 2 abnormal EBV-associated disorders, and self-limited acute infectious mononucleosis. These results showing differential virus-cell interactions between acute EBV-HLH and CAEBV indicated different pathogenic mechanisms against EBV infection between the 2 EBV-associated diseases, which accounts for the difference in clinical manifestations between the 2 diseases.     

Epstein-Barr virus (EBV) load and cytokine gene expression in activated T cells of chronic active EBV infection

To identify the role of T cells in chronic active Epstein-Barr virus (EBV) infection, EBV and cytokine gene expression was quantified by use of real-time polymerase chain reaction (PCR) among 6 patients who fulfilled the diagnostic criteria for chronic active EBV infection. Four of these patients showed clonal expansion of EBV-infected T cells. Quantitative PCR for EBV DNA in peripheral blood of patients with symptomatic chronic active EBV infection showed higher copy numbers of virus (mean, 1.45 x 10(5) copies/mL) than were seen in blood from patients with infectious mononucleosis (3.08 x 10(3) copies/mL) or with EBV-associated hemophagocytosis (2.95 x 10(4) copies/mL). Fractionated CD3(+) HLA-DR(+) cells from patients with chronic active EBV infection contained higher copy numbers than did CD3(+) HLA-DR(-) cells. Quantitative PCR for cytokines revealed that interferon-gamma, interleukin (IL)-2, IL-10, and transforming growth factor-beta genes were expressed at higher levels in HLA-DR(+) than in HLA-DR(-) T cells. These results suggest that activated T cells in chronic active EBV infection expressed high levels of EBV DNA and both Th1 and Th2 cytokines. EBV-infected T cells may contribute to the unbalanced cytokine profiles of chronic mononucleosis.