From Burkitt's lymphoma to chronic active Epstein-Barr virus (EBV) infection: an expanding spectrum of EBV-associated diseases

Epstein-Barr virus (EBV) is one of 8 known human herpesviruses. EBV infection usually occurs in early childhood and is subclinical. However, primary infection in adolescence or adulthood causes infectious mononucleosis in approximately half of infected individuals. Recently, the spectrum of human diseases associated with EBV infection has increased, primarily due to methodological advances in EBV detection. Initially, EBV was isolated from a cultured Burkitt lymphoma cell line, and has been felt to be etiologically linked to the development of Burkitt lymphoma, as well as other human malignancies. This review mainly focuses on pathogenetic mechanisms, many of which remain enigmatic, for the various human diseases, which are considered to be associated with EBV infection.     

慢性活动性EB病毒感染的研究进展

慢性活动性EB病毒感染(chronic active Epstein-Barr virus infection,CAEBV)是一种定义未明疾病,以严重的慢性或复发性传染性单核细胞增多症(infectious mononucleosis,IM)样表现为主要特征,临床表现包括发热、肝脾肿大、持续性肝炎、全身淋巴结肿大等,常伴外周血EB病毒载量的明显升高和(或)EB病毒相关抗体的异常改变.本病治疗困难,预后差,病死率高,死因多为肝衰竭、机会性感染或淋巴组织增生性噬血细胞综合征,目前尚无明确的治疗方案.越来越多的证据表明,被EB病毒感染的T细胞或自然杀伤细胞克隆性增殖在发病中起至关重要的作用.     

慢性活动性EB病毒感染外周血淋巴细胞免疫亚群变化特征的研究

目的 研究慢性活动性EB病毒感染(CAEBV)宿主细胞免疫功能的变化.方法 应用流式细胞仪检测2004年3月至2008年4月住院的CAEBV患儿、急性EBV感染(acute EBVinfection,AEBV)患儿以及正常儿童外周血淋巴细胞免疫亚群.结果 CAEBV组外周血白细胞[3325×106/L,中位数(下同)]、淋巴细胞(1078×106/L)、NK细胞(68×106/L)、B细胞(84×106/L)、总T细胞(684×106/L)、CD4+T细胞(406×106/L)和CD8+T细胞(295×106/L)计数均高于AEBV组(P<0.05).CAEBV组CD4+功能、亚群的比例(94.5%)低于正常组(98.7%)(P<0.05),但高于AEBV组(74.0%)(P<0.05);而CD8+功能哑群的比例(40.7%)与正常组(48.3%)比较差异无统计学意义,但高于AEBV组(21.0%)(P<0.05).CAEBV组的调节亚群比例(5.0%)虽高于正常组(4.6%)(P<0.05),但低于AEBV组(5.8%)(P<0.05).CAEBV组初始T细胞比例(32.3%/37.5%)低于正常组(58.3%/56.6%)(P<0.05),其效应记忆T细胞的比例(23.9%/15.1%)低于较AEBV组(36.5%/69.8%)(P<0.05),而CD8+假初始T细胞(17.5%)的比例高于其他两组(12.0%和9.2%)(P<0.05).CAEBV组CD8+激活亚群(84.4%/34.0%)高于正常组(44.1%/16.7%)(P<0.05),但低于AEBV组(96.0%/95.0%)(P<0.05).结论 CAEBV患儿体内存在淋巴细胞亚群失衡和细胞免疫功能紊乱,可能与CAEBV的慢性活动性有关.检测外周血淋巴细胞亚群有助于CAEBV的诊断和鉴别诊断.     

慢性活动性EB病毒感染的研究进展

慢性活动性EB病毒感染（Chmnic active EBV infection,CAEBV）是一种少见的发生在无明确免疫缺陷个体的综合征,临床表现多种多样,其病理改变几乎可涉及到各个器官。主要表现为EBV感染后出现慢性或复发性传单样症状,伴随EBV抗体的异常改变或病毒载量的升高,病程中可出现严重的或致死的并发症。文章就其发病机制、临床表现、实验室检查及诊治方案进展作一介绍,以提高临床对慢性活动性EBV的诊治水平。     

Epstein-Barr virus load in cerebrospinal fluid of patients with chronic active Epstein-Barr virus infection

Chronic active Epstein-Barr virus (EBV) infection is a rare chronic mononucleosis syndrome involving clonally proliferating EBV-infected T-/NK-cells. EBV DNA was quantified in nonpleocytotic cerebrospinal fluid (CSF) of 9 patients. Three patients with neurologic and/or neuroimaging abnormalities showed high CSF copy numbers. In 1 patient, CSF copy number exceeded the peripheral blood value. CSF EBV-load may predict the central nervous system involvement of EBVT-/NK-cells.     

儿童慢性活动性EB病毒感染临床及实验室检查特征

目的 研究慢性活动性EB 病毒感染(CAEBV)患儿的临床及外周血淋巴细胞亚群等实验室检查特征,为CAEBV 的诊治提供依据.方法 分析13 例CAEBV 患儿的临床资料,包括患儿的临床表现、病毒学检测及淋巴细胞亚群测定结果,并与15 例急性EB 病毒感染(AEBV)病例作对照研究.结果 两组患儿临床表现类似,主要为发热、肝脾肿大、淋巴结肿大等传染性单核细胞增多症(IM)样症状,区别在于CAEBV 患儿病程较长,上述症状持续或反复出现.CAEBV 组患儿外周血EBV-DNA 载量明显高于AEBV 组(P<0.05).CAEBV 组VCA-IgG 明显高于AEBV 组(P<0.05).CAEBV 组外周血白细胞计数、淋巴细胞计数、B 细胞计数、总T 细胞计数、CD4+ T 细胞计数和CD8+ T 细胞计数均低于AEBV 组(P<0.05).随访13 例CAEBV 患儿,8 例死亡,2 例好转,2 例病情仍有反复,1 例转院后失访.15 例AEBV 患儿均治愈,随访1 年无病情反复.结论 CAEBV患儿临床表现多样,早期较难与AEBV 鉴别,预后差,病死率高.外周血EBV-DNA 载量、VCA-IgG 及淋巴细胞亚群的测定对CAEBV 诊断具有一定帮助.     

儿童慢性活动性EB病毒感染合并UNC13D基因突变3例临床分析

目的探讨儿童慢性活动性EB病毒感染(CAEBV)合并UNC13D基因突变的临床特点,为临床诊治提供思路。方法对北京儿童医院血液肿瘤中心收治的3例CAEBV患儿进行基因突变筛查,对临床病例资料进行回顾性总结分析。结果3例患儿均存在UNC13D杂合子突变,但突变位点不同。例1和例2给予抗病毒治疗后好转出院,院外分别随访38个月和26个月,期间均出现EB病毒活动表现。例3行异基因造血干细胞移植术,随访34个月,仍无病生存。结论儿童CAEBV可能存在UNC13D基因突变,该突变可能为CAEBV发病机制以及预后差的重要原因之一。小年龄起病的发热、肝脾淋巴结肿大患儿,若EBV-DNA持续高滴度,建议尽早进行UNC13D基因突变的筛查。CAEBV患儿单纯抗病毒治疗效果差,异基因造血干细胞移植是根治性治疗手段。     

Development of Langerhans cell histiocytosis associated with chronic active Epstein-Barr virus infection

Chronic active Epstein-Barr virus (CAEBV) infection is characterized by a status of lymphoproliferative disease of EBV-infected cells, resulting in chronic or recurrent infectious mononucleosis-like symptoms. CAEBV is always accompanied by life-threatening complications. We report the case of a 2-year-old female patient with CAEBV who subsequently developed Langerhans cell histiocytosis (LCH) presenting with bilateral exophthalmos, bone, and skin involvement. In situ hybridization for EBER revealed EBV-infected B-cells present in lesional tissue implying that interactions between EBV-infected B-cells and lesional Langerhans cells may be associated with the development of LCH.     

Rheumatic fever-mimicking carditis as a first presentation of chronic active Epstein-Barr virus infection

A 7-y-old girl presented with prolonged fever, arrhythmia and cardiomegaly during the treatment course of group A β-haemolytic streptococcal pharyngitis. The isolated rheumatogenic strain M1 suggested the diagnosis of rheumatic fever. However, serous pericardial effusion contained high levels of Epstein-Barr virus (EBV) DNA. Clonally proliferating EBV⁺ T cells were determined in the circulation. The atypical carditis without valvitis was then complicated by coronary artery dilatations. Four months after the start of prednisolone plus antiviral/bacterial therapy, EBV⁺ T-cell lymphoma developed in the thigh.
Conclusion: Atypical carditis may be a notable and life-threatening presentation of chronic active EBV infection to be differentiated from rheumatic fever.     

慢性活动性EB病毒感染致皮肤蕈样淋巴瘤1例临床资料

慢性活动性EB病毒感染（CAEBV）是一种结局不良的淋巴增殖性疾病,淋巴瘤作为其严重不良结局之一,由于临床表现的多样性而导致早期诊断困难,儿科临床人员应予以高度重视。     

Polyclonal proliferation of lymphocytes containing the epstein-barr virus genome in a patient dying of myocarditis in chronic active Epstein-Barr virus infection

An 11-year-old boy had intermittent fever and hepatosplenomegaly. The diagnosis of chronic active Epstein-Barr virus (EBV) infection was established from an abnormal pattern of anti-EBV antibody; EBV was detected in bone marrow cells. Immunochemotherapy alleviated the patient's symptoms. However, when a subsequent oral prednisolone dose was tapered, heart failure ensued and he died. Autopsy findings demonstrated that myocarditis resulted from infiltrating T lymphocytes with the EBV genome and a benign histologic appearance. A clonality study of T lymphocytes indicated no such evidence of monoclonality. EBV-infected T cells play an important role in the pathogenesis of myocarditis in chronic active EBV infection.     

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation

Abstract:  CAEBV is a high mortality and morbidity disease with life-threatening complications. Nevertheless, the treatment regimens for CAEBV have not yet been established. Although some reports have described CAEBV therapy involving treatments such as antiviral drugs, immunomodulatory agents, and immunochemotherapy, none of these treatments have been demonstrated to be effective. The only treatment reported to be effective is allogeneic SCT. However, the complications of SCT are severe, so treatment results have been poor. Recently, immunotherapy has been devised, but this is still in the developmental stage. In this report, two cases of CAEBV in which allogeneic SCT was performed soon after diagnosis are reported. In both cases, a high EBV genome titer in the peripheral blood was detected at onset. After SCT, the EBV genome titer decreased as CTL activity gradually increased. This fact suggested that not only high-dose chemotherapy as a preconditioning treatment of SCT but also increased CTL activity which could eliminate virus-infected cells might be effective, although additional cases should be studied in order to establish effective treatments.     

Defective activity of Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes in children with chronic active EBV infection and in their parents

Antibodies of Epstein-Barr virus (EBV), EBV-specific cytotoxic T lymphocyte (EBVCTL) activity and the lymphocyte subset of CTL were examined in 13 Japanese children with chronic active EBV infection (CAEBV) and their parents (eight fathers and 10 mothers). Anti-virus-capsid antigen (VCA)-IgG antibody titers ranged from 1: 640 to 1: 5120 in the patients with CAEBV and from 1: 40 to 1: 640 in the parents. While anti-VCA-IgM antibody was detected in three patients, anti-VCA-IgA antibody in five and anti-early-antigen (EA)-IgG antibody in 11, no antibody was detected in the parents except anti-EA antibody, which was positive in the mothers of cases 5 and 13 (1: 10 and 1: 40). Anti-EBV-associated nuclear antigen (EBNA) antibody was ≥ 1: 10 in six out of 13 patients with CAEBV and in 10 out of 18 parents tested. Epstein-Barr virus activity was significantly lower (P < 0.005) both in the children with CAEBV and in their parents than in seropositive age-matched controls. Proportions of a CTL subset (CD8⁺ CD11^? lymphocytes) in the patients with CAEBV were significantly higher (P< 0.005) than in controls, while those in the parents were at the same level as in controls. Defective EBVCTL activity and anti-EBNA-antibody responses were frequently observed both in children with CAEBV and in their parents, which may suggest that the abnormal immune response to EBV may be based on a familial disorder, though no familial involvement has been reported in Japanese children with CAEBV.     

Analysis of IgG subclasses in chronic active Epstein–Barr virus infection

BACKGROUND: Although elevated serum levels of immunoglobulins are frequently observed in patients with chronic active Epstein-Barr virus (EBV) infection, there have been no reports concerning levels of IgG subclasses. METHODS: Serum levels of IgG subclasses were measured by the enzyme-linked immunosorbent assay (ELISA) in 30 children with severe chronic active EBV infection. RESULTS: Serum levels of IgG1 were elevated in most patients, except for one who showed an abnormally low level of IgG1 and progressive hypogammaglobulinemia. Serum levels of IgG2, IgG3 and IgG4 in the patients were comparable to those in control children, while abnormally low levels of IgG2, IgG3 and IgG4 were observed in six, three and four cases, respectively. CONCLUSION: Although not always susceptible to bacterial infections, low levels of IgG2 were frequently observed in patients with chronic active EBV infection and elevated IgG1 is responsible for the increase of serum IgG in these patients.     

α干扰素治疗HBeAg阳性慢性乙型肝炎疗效的荟萃分析

目的评价α干扰素治疗HBeAg阳性慢性乙肝病毒感染儿童的长期疗效及安全性。方法检索PubMed和CHKD期刊全文数据库,并追查所有纳入研究的参考文献,进行荟萃分析。纳入用英文或中文发表的比较α干扰素与非抗病毒药物（安慰剂或空白对照）治疗HBeAg阳性慢性乙肝病毒感染儿童的随机对照试验。结果共纳入10个随机对照试验,包括542个HBsAg和HBeAg阳性的慢性乙型肝炎患儿。结果显示,随访6个月～2年,α干扰素组HBeAg转阴率高于对照组[31．1％vs12．4％,OR3．17,95％CI（2．00,5．02）,P〈0．00001],HBV—DNA转阴率高于对照组[33．9％vs16．2％,OR2．59,95％CI（1．70,3．96）,P〈0．0001],HBsAg转阴率高于对照组[5．5％vs1．2％,OR3．44,95％CI（1．20,9．89）,P=0．02],丙氨酸氢基转移酶（ALT）复常率高于对照组[43．0％vs27．7％,OR1．99,95％CI（1．16,3．42）,P=0．01],HBeAg血清学转换率高于对照组[30．4％vs12．8％,OR2．90,95％CI（1．56,5．39）,P=0．0008],两组差异均有统计学意义,但HBsAg血清学转换率与对照组相比[1．9％vs0,95％CI（0．42,18．13）,P=0．29],差异无统计学意义。结论对HBeAg阳性的慢性乙肝病毒感染患儿,α干扰素可能有使HBeAg转阴、HBV-DNA转阴、HBsAg转阴、ALT复常及HBeAg血清学转换的效应,但未能实现HBsAg血清学转换。受原研究质量和不同研究干预措施差异的影响,α干扰素的效应尚需更多高质量足够样本量的随机对照试验予以证实。