Epstein-Barr virus DNA in lymphocytes of patients with the virus-associated hemophagocytic syndrome

The virus-associated hemophagocytic syndrome (VAHS) is a histiocytic proliferative disorder with bone marrow and liver failure for which the connection with a specific virus is often tenuous. Epstein-Barr virus (EBV) is one candidate for the association, but serologic or culture confirmation may be lacking in a particular case. As a means of directly identifying the presence of EBV in patients' cells, molecular hybridization studies were carried out using a radioactively labeled viral DNA segment. DNA from mononuclear cells of two children with VAHS had specific hybridization to the EBV DNA probe. One of the patients had serologic evidence for EBV infection. Several immunologic deficiencies were found. VAHS may represent one of several hematologic and/or immunologic dysfunctions caused by EBV.     

Human herpesvirus-6 (HHV-6)-associated hemophagocytic syndrome

Virus-associated hemophagocytic syndrome (VAHS) is characterized by histiocytic proliferation and phagocytosis triggered by virus infections. Viruses in the herpes group, especially the Epstein-Barr virus (EBV), are well known to cause VAHS; however, the relationship between this syndrome and human herpesvirus-6 (HHV-6) infection has rarely been reported. In this study, we describe a 23-month-old girl who exhibited typical manifestations of VAHS associated with HHV-6 infection. To the best of our knowledge, this case is the fifth reported case in the English literature.     

Macrophage activation syndrome and dysgammaglobulinemia. Role of the Epstein-Barr virus]

The case of a five-year-old boy with macrophage activation syndrome and Epstein-Barr virus infection is reported. Several unusual features were found, including an early major increase in IgA levels, persistent oligoclonal gammapathy, and delayed development of anti-EA antibodies accompanied with an increase in anti-VCA antibodies. Despite the negative family history, an immune deficit and Purilo syndrome are discussed as possible diagnoses in this child.     

Macrophage activation syndrome: a diagnostic challenge

Macrophage activation syndrome, or hemophagocytic syndrome, is a rare disease with high morbidity and mortality. It is a disorder of the mononuclear phagocyte system. Two forms have been described; primary or familial hemophagocytic lymphohistiocytosis and secondary or sporadic hemophagocytic syndrome. Diagnosis of macrophage activation syndrome poses a real challenge for the pediatrician and in many cases is only made at autopsy. We describe two patients with hemophagocytic syndrome associated with parvovirus B19 and Epstein-Barr virus infection.     

Hyperferritinemia in malignant histiocytosis, virus-associated hemophagocytic syndrome and familial erythrophagocytic lymphohistiocytosis. A survey of pediatric cases

Data on 28 patients with malignant histiocytosis (MH), fourteen patients with virus-associated hemophagocytic syndrome (VAHS) and two patients with familial erythrophagocytic lymphohistiocytosis (FEL) were collected from 21 hospitals in Japan to study the serum ferritin levels and clinical features. At diagnosis, the serum ferritin values were a median of 3,000 ng/ml (range, 59-270,000 ng/ml) in MH and 10,500 ng/ml (range, 44-68,600 ng/ml) in VAHS/FEL. Clinical signs and symptoms were not substantially different between MH and VAHS/FEL. Thus, serum ferritin markedly increased in the majority of MH/VAHS/FEL patients and should be a useful marker of disease activity in either neoplastic or reactive histiocytic proliferative disorders.     

Hyperferritinemia in Malignant Histiocytosis, Virus-Associated Hemophagocytic Syndrome and Familial Erythrophagocytic Lymphohistiocytosis

ABSTRACT. Data on 28 patients with malignant histiocytosis (MH), fourteen patients with virus-associated hemophagocytic syndrome (VAHS) and two patients with familial erythrophagocytic lymphohistiocytosis (FEL) were collected from 21 hospitals in Japan to study the serum ferritin levels and clinical features. At diagnosis, the serum ferritin values were a median of 3000 ng/ml (range, 59–270000 ng/ml) in MH and 10500 ng/ml (range, 44–68600 ng/ml) in VAHS/FEL. Clinical signs and symptoms were not substantially different between MH and VAHS/FEL. Thus, serum ferritin markedly increased in the majority of MH/VAHS/FEL patients and should be a useful marker of disease activity in either neoplastic or reactive histiocytic proliferative disorders.     

Acute severe hepatitis with coagulopathy: An unusual presentation of Kawasaki syndrome in association with Epstein-Barr virus

The first case of Kawasaki syndrome presenting as acute severe hepatitis with coagulopathy, in association with an acute Epstein-Barr virus infection is reported. This case supports the hypothesis that Epstein-Barr virus may play a role in the etiology of Kawasaki syndrome and serves as a reminder that a diagnosis of Kawasaki syndrome should be considered for a persistently febrile child, even in the face of an atypical presentation.     

Monoclonal proliferation of Epstein-Barr virus-infected T-cells in a patient with virus-associated haemophagocytic syndrome

Virus-associated haemophagocytic syndrome (VAHS) is a non-neoplastic, generalized histiocytic proliferation disorder showing marked haemophagocytosis associated with systemic viral infection. We describe the case of a 1-year-old girl with Epstein-Barr virus (EBV)-related VAHS, in whom Southern blot analysis showed monoclonal proliferation of bone marrow cells with the EBV genome; detected with the Xho-1 fragment of the latent infection membrane protein genome. EBV serology showed anti-Epstein-Barr virus nuclear associated antigen (EBNA), anti-viral capsid antigen (VCA)-IgG, anti-VCA-IgA elevation and positive EBNA of Sheep red blood cells (SRBC)-rosette-forming bone marrow cells in the late period of her clinical course, indicative of EBV infection. DNA analysis of her bone marrow cells showed monoclonal rearrangement of the T-cell receptor- and- chain genes but not of the immunoglobulin heavy chain genes. Those results suggest that EBV may infect T-cells, after which the cells proliferate monoclonally. Repeated administration of epipodophyllotoxin VP-16-213 induced remission, but adrenocortical steroid, vincristine, and cyclophosphamide had no effect on the patient's condition. Ours is a first case report of VAHS showing monoclonal proliferation of EBV-infected T-cells.     

Griscelli syndrome: a case report

A 10-year-old boy presented with partial albinism and typical clinical features of a macrophage activation syndrome (hepatosplenomegaly, fever, and pancytopenia), suggesting the diagnosis of Griscelli syndrome. The diagnosis was confirmed by light microscopic evaluation of hair that showed characteristic large aggregates of pigment granules irregularly distributed along the hair shaft. Immunosuppressive therapy controlled his macrophage activation syndrome successfully. Since early diagnosis is life saving and simple methods confirm the diagnosis, finding of partial albinism in children should alert clinicians to consider Griscelli syndrome.     

儿童病毒相关性噬血细胞综合征32例临床研究

目的探讨儿童病毒相关性噬血细胞综合征(VAHS)的临床特点、诊断、治疗及预后。方法回顾性分析2005年5月至2009年5月我院儿科诊治的32例儿童VAHS患儿临床资料,应用酶联免疫吸附测定法(enzyme-linked immunosorbent assay,ELISA)检测VAHS患儿血清病毒抗体。结果①年龄分布:<2岁～14岁。②性别分布:男18例,女14例。③病因特点:32例病例中爱泼斯坦病毒(Epstein-Bart Virus,EBV)单一感染者18例(56.3%)、巨细胞病毒(CMV)单一感染者8例(25%),腺病毒(ADV)单一感染者2例(6.3%),EBV与CMV复合感染者3例(9.4%),EBV、CMV、柯萨奇病毒(CVB)、ADV及呼吸道合胞病毒(RSV)复合感染者1例(3.1%)。④临床特点:持续高热(100%)、肝肿大(81.2%)、脾肿大(90.6%)、外周血细胞白细胞计数减少(84.4%)、血红蛋白<90 g/L(62.5%)、血小板减少(71.9%)、高甘油三酯(TG)血症(53.1%)、低纤维蛋白原血症(65.6%)、血清铁蛋白(SF)≥500μg/L(100%)、谷丙转氨酶(ALT)升高(71.9%)、谷草转氨酶(AST)升高(78.1%)、乳酸脱氢酶(LDH)升高(90.6%)、高密度脂蛋白(HDL)降低(100%),32例骨髓均找到噬血组织细胞;其中EBV感染及复合感染较其他病毒单一感染临床表现更重;随着患儿病情好转,体温下降,脾脏缩小,症状消失,复查SF、LDH逐渐恢复正常水平。⑤治疗及转归:治疗全部采用抗病毒、对症支持治疗及HLH-2004方案,32例中治疗痊愈15例(46.9%),完全缓解后继续治疗中3例(9.4%),完全缓解后失访3例(9.4%),复发治疗中2例(6.3%),放弃治疗4例(12.5%),死亡5例(15.6%)。结论①儿童VAHS以EBV感染多见,其临床主要表现持续高热,肝、脾肿大,实验室检查主要特点:白细胞计数降低、血小板低、肝功能异常、甘油三酯及LDH及SF升高、纤维蛋白原低、骨髓找到噬血细胞。②EBV感染及复合感染较其他病毒单一感染临床表现更重。③SF、LDH检测对于其早期诊断及治疗效果的评价意义较大;LDH发病时水平较高的提示预后不好。④早期应用HLH-2004方案治疗有较好疗效并可改善预后。     

感染相关性噬血细胞综合征的临床探讨

目的 探讨感染相关性噬血细胞综合征的临床特点和干预措施。方法 回顾性分析6例感染相关性噬血细胞综合征的临床过程、实验室检查和干预措施。结果EB病毒是感染相关性噬血细胞综合征的常见病原。对于血细胞减少的有些危重病例,临床必须考虑到噬血细胞综合征的可能。骨髓涂片查找噬血细胞有一定困难,临床支持该病,骨髓涂片应反复查找。结论 干预应早于诊断,临床怀疑噬血细胞综合征,不能因等待检查而耽误临床治疗,及早阻止噬血现象是性命攸关的。而预后与所用干预措施直接相关。     

Epstein-Barr virus infection and its role in the expanding spectrum of human diseases

Recent advances of the various laboratory tests to detect Epstein-Barr virus (EBV) infection have clarified the causative role for a spectrum of EBV-associated diseases. They include lymphoproliferative disorders (LPD), which occur in immunologically compromised individuals, Hodgkin's disease (HD), chronic active EBV infection (CAEBV), virus-associated hemophagocytic syndrome (VAHS), certain forms of T cell lymphoma, and some gastric carcinomas, in addition to the classical EBV-associated diseases such as EBV genome-positive Burkitt's lymphoma (BL), undifferentiated nasopharyngeal carcinoma (NPC) and infectious mononucleosis (IM). This review intends to introduce the recent progress of studies on EBV infection mainly from the clinical points of view.     

EB病毒感染相关噬血细胞综合征的诊治研究进展

噬血细胞综合征(hemophagocytic syndrome,HS)是一组病因及发病机制复杂.组织病理表现以良性组织细胞增生活化,伴随噬血细胞现象的一类综合征.HS分为原发性和继发性两大类,原发性是指家族遗传相关的免疫缺陷状态,继发性指后天获得所致,其中以EB病毒感染相关最为常见.EB病毒感染相关HS的病情进展快,病死率高,现就该病的诊治进展作一概述.     

Recurrent viral associated hemophagocytic syndrome in a child with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) with subsequent viral-associated hemophagocytic syndrome (VAHS) or secondary hemophagocytic lymphohistiocytosis (HLH) is extremely rare. A 15-month-old girl with disseminated LCH experienced three episodes of VAHS during maintenance therapy. Viral infection, with influenza A, herpes simplex, and adenovirus, respectively, was documented at each episode. She recovered each time after interruption of maintenance therapy. The occurrence of fever and pancytopenia in patients with chemotherapy-treated LCH can be associated with VAHS and not with relapsing LCH.     

Infection-Associated Hemophagocytic Syndrome Complicated by Infectious Lymphoproliferation: A Case Report

The case of a 7-year-old boy with virus-associated hemophagocytic syndrome (VAHS) and serologically proven parvovirus B-19 infection is described. The patient with VAHS presented with fever, hepatosplenomegaly, pancytopenia, and hyperlipidemia type IV. After induction therapy with VP-16 and prednisone, partial remission was achieved. Despite maintenance therapy, reinductions, and the addition of cyclosporine A for 3 months, several relapses occurred. The therapy was stopped because of life-threatening complications (Klebsiella sepsis, neutropenic enterocolitis, and stercoral peritonitis). The complications were treated successfully. The patient status was stabilized after splenectomy. However, hepatomegaly progressed slowly and the hyperlipidemia endured. Ten months after the diagnosis, leukocytosis with absolute T lymphocytosis appeared. Reactivation of VAHS was suspected and intravenous immunoglobin and then antilymphocyte immunoglobulin ALG therapy were started. The resultant decrease in leukocytosis was prompt, but lymphopenia did not occur. Virostatic treatment withfoscarnet was introduced based on human herpesvirus-6 seroconversion. Twenty-six months after the diagnosis, the patient is well, without any sign of VAHS or lymphoproliferation.     

Hemophagocytic lymphohistiocytosis in 2 pediatric patients secondary to hepatitis A virus infection

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by uncontrolled activation of cytotoxic T cells and antigen-presenting cells. Common clinical manifestations include high fever, maculopapular rash, neurological symptoms, coagulopathy, and abnormal liver function tests [1]. HLH can be either primary, that is, due to an underlying genetic defect, or secondary, associated with malignancies, autoimmune diseases, or infections. The true incidence of secondary HLH is difficult to define. Infection associated HLH are most commonly associated with viral infections mainly of the herpes group, with Epstein-Barr virus (EBV) that is proposed to be the most common cause [2]. Despite the high incidence of hepatitis A virus (HAV) infection in the pediatric population in general, there are few pediatric case reports in the literature about HAV-associated hemophagocytic syndrome [3]. We encountered 2 patients with HAV-associated hemophagocytic syndrome.     

巨噬细胞活化综合征的研究进展

巨噬细胞活化综合征是一种多见于儿童慢性风湿性疾病的严重、致命性并发症,其发病机制尚不完全清楚,目前仍没有统一的诊断标准,早期诊断有一定难度。文章综述了近几年巨噬细胞活化综合征发病机制的研究新进展以及早期诊断的生物学标志物。[临床儿科杂志,2012,30(5):496-498]     

Virus-associated histiocytic proliferations in children. Frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies

Nineteen children who presented with fever, hepato-splenomegaly, bone marrow and/or hepatic failure, and biopsy evidence of histiocytic proliferations were evaluated for lymphocyte dysfunction and evidence of prior viral infection. Seventeen of the children had erythrophagocytosis consistent with the previously described virus-associated hemophagocytosis syndrome (VAHS) or Familial erythrophagocytic lymphohistiocytosis (FEL). The other two had benign histiocytic proliferations in the central nervous system (CNS) with liver and bone marrow dysfunction. There were two sibling pairs and six patients with known disorders of immune deficiency. The remaining nine cases appeared to be sporadic and idiopathic. Epstein-Barr Virus (EBV) was identified in patients by serologic or DNA hybridization studies (15), EBV and cytomegalovirus (CMV) (1), adenovirus plus EBV and CMV (1), or adenovirus and EBV (1). Herpes zoster was associated with reactivation of symptoms in one patient. Immunologic impairment was evidenced by lymphopenia in 10 of 19 patients. More extensive evaluations could be done at diagnosis on only some of the children because the histiocytic proliferative syndrome was not recognized or because there were insufficient numbers of lymphocytes in samples obtained. For those who could be evaluated, the following immune deficiencies were found: decreased lymphocyte proliferation to mitogens (4 of 9), absent or markedly decreased natural killer function (5 of 5), and decreased cytotoxic lymphocyte reactivity to allogenic EBV-infected target cells (3 of 3). A new finding reported here is a higher than expected prevalence of HLA types A30, B8, and A1/B8 among the patients tested.     

Mononucleosis-like syndrome associated with a multisystem Coxsackie virus type B3 infection in adolescence

We describe a severe multisystem Coxsackie virus type B3 infection in a previously healthy 14-year-old girl who presented with a mononucleosis-like syndrome (MS). Initial observations included a prominent cervical lymphadenopathy, exudative pharyngitis and leucocytosis with atypical lymphocytosis. At the end of the 2nd week of illness the patient developed meningoencephalomyelitis and haemolytic anaemia. Subclinical myocarditis was also recorded. Prolonged hepatitis recrudescing at the time of recovery coincided with serological evidence of a reactivated Epstein-Barr virus infection. The diagnosis was based on a significant rise in serum antibody titres against Coxsackie virus type B3, using the neutralization test. Intrathecal synthesis of antibodies to Coxsackie virus type B3 was also demonstrated. Generalized Coxsackie virus infections in adolescence are rare and an MS has not, to our knowledge, been associated with Coxsackie virus type B3 infection.Abbreviations MS mononucleosis-like syndrome - EBV Epstein-Barr virus - VCA viral capsid antigen - EBNA Epstein-Barr nuclear antigen - CSF cerebrospinal fluid - ECG electrocardiogram - ALT alanine aminotransferase     

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。