Epstein-Barr virus infection and associated diseases in children

Epstein-Barr virus (EBV), an ubiquitous human B lymphotropic virus, is the cause of infectious mononucleosis. Moreover, EBV infection can be followed by lymphoproliferative diseases in patients with inherited and acquired immunodeficiencies. Primary EBV infection may be a threat to all children after marrow or organ transplantation or those receiving chronic immunosuppressive treatment for various other reasons. The virus has been also implicated in the pathogenesis of different malignant tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin disease and also some T-cell lymphomas. This review focuses on various aspects of virus-host interactions, immune mechanisms of the host, and the still experimental therapeutic approaches in EBV-associated diseases.     

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.     

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.     

91例EB病毒相关疾病儿童血浆EB病毒DNA的检测

目的了解EB病毒(EBV)感染患儿外周血血浆中游离EBVDNA的拷贝数,确定EBV原发感染后外周血血浆中EBV游离DNA的拷贝数与发病天数及病情轻重的关系。方法应用荧光定量PCR方法,测定73例EBV原发感染和18例EBV相关重症疾病患儿外周血血浆中EBV游离DNA。结果①原发EBV感染患儿外周血血浆中EBV游离DNA随发病天数呈下降趋势,发病2周后很难检测到。②EBV相关重症疾病组患儿外周血血浆中EBV游离DNA阳性率明显高于原发EBV感染组,差异有显著性(89%vs16%,P<0.05)。结论原发EBV感染后随病程天数的增加,病毒复制水平逐渐下降。血浆中EBV游离DNA检测对评价EBV相关疾病的严重程度有一定参考价值。     

SYSTEMIC TYPE EPSTEIN-BARR VIRUS-RELATED LYMPHOPROLIFERATIVE DISEASES IN CHILDREN AND YOUNG ADULTS: Challenges for Pediatric Hemato-Oncologists and Infectious Disease Specialists

Involvement of Epstein-Barr virus (EBV) has long been known in the development of various tumor-forming proliferating diseases, such as nasopharyngeal carcinoma in adults. However, in children and young adults more attention should be focused on systemic, severe type EBV-related diseases, such as fatal infectious mononucleosis, hemophagocytic syndrome, or chronic active EBV infection (CAEBV). These disorders show the typical clinical features of hemophagocytic lymphohistiocytosis (HLH). Although viral infectious diseases are mostly taken care of by infectious disease specialists, pediatric hemato-oncologists need to intervene in the treatment of this kind of disease because of their clonal and neoplastic disease characteristics and of their hematologically problematic, rapid, and life-threatening clinical courses.     

Systemic type Epstein-Barr virus-related lymphoproliferative diseases in children and young adults: challenges for pediatric hemato-oncologists and infectious disease specialists

Involvement of Epstein-Barr virus (EBV) has long been known in the development of various tumor-forming proliferating diseases, such as nasopharyngeal carcinoma in adults. However, in children and young adults more attention should be focused on systemic, severe type EBV-related diseases, such as fatal infectious mononucleosis, hemophagocytic syndrome, or chronic active EBV infection (CAEBV). These disorders show the typical clinical features of hemophagocytic lymphohistiocytosis (HLH). Although viral infectious diseases are mostly taken care of by infectious disease specialists, pediatric hemato-oncologists need to intervene in the treatment of this kind of disease because of their clonal and neoplastic disease characteristics and of their hematologically problematic, rapid, and life-threatening clinical courses.     

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.     

91例EB病毒相关疾病儿童血浆EB病毒DNA的检测

目的:了解EB病毒（EBV）感染患儿外周血血浆中游离EBV DNA的拷贝数,确定EBV原发感染后外周血血浆中EBV游离DNA的拷贝数与发病天数及病情轻重的关系。方法:应用荧光定量PCR方法,测定73例EBV原发感染和18例EBV相关重症疾病患儿外周血血浆中EBV游离DNA。结果:①原发EBV感染患儿外周血血浆中EBV游离DNA随发病天数呈下降趋势,发病2周后很难检测到。②EBV相关重症疾病组患儿外周血血浆中EBV游离DNA阳性率明显高于原发EBV感染组,差异有显著性(89% vs 16%, P＜0.05）。结论: 原发EBV感染后随病程天数的增加,病毒复制水平逐渐下降。血浆中EBV游离DNA检测对评价EBV相关疾病的严重程度有一定参考价值。［中国当代儿科杂志,2009,11（11）：897-900］     

Cytokine profiles in children with primary Epstein–Barr virus infection

Primary Epstein–Barr virus (EBV) infection causes infectious mononucleosis and hemophagocytic lymphohistiocytosis (HLH) in children, where EBV infects B and CD8⁺ T cells, respectively. We measured pro‐inflammatory and anti‐inflammatory cytokines in both diseases. Significantly higher concentrations of various mediators, including interferon‐γ, neopterin, interleukin (IL)‐6, IL‐10, IL‐18, and heme oxygenase‐1, were observed in EBV‐HLH. Because of their similarity to the profile of familial HLH, this profile was likely a consequence of HLH, but not ectopic infection. TNF‐α levels were elevated in both diseases. Elevation of those mediators may contribute to the disease pathogenesis of EBV‐HLH by activating and inhibiting host immune responses. Pediatr Blood Cancer 2013; 60: E46–E48. © 2013 Wiley Periodicals, Inc.     

Immunodeficiency as a factor in lymphomagenesis

The human immune system has evolved multiple cellular and humoral defense mechanisms against the lymphotropic virus, EBV. NK cells, suppressor T-cells, cytotoxic K-cells, memory T-cells, and humoral immune responses usually subdue the virus into latency. Individuals with immune deficiency are at great risk of developing immunoregulatory disturbances and lymphoproliferative diseases when confronted by EBV. The infection of B-cells by EBV provokes a marked activation of immunoregulatory T-cells and requires restoration of immune homeostasis during convalescence. This is accomplished with difficulty in an individual with significant immune defects. The X-linked lymphoproliferative syndrome is an exemplary model for studying EBV in immune deficient individuals. Boys with XLP can develop acquired agammaglobulinemia, aplastic anemia, chronic or fatal IM, and a variety of B-cell malignant lymphomas following infection by the virus. We have identified multiple immune defects in the patients and progressive immunoregulatory disturbances following infection by the virus. Other patients with immune deficiency syndromes, i.e., ataxia telangiectasia or the renal transplant recipient, are also at increased risk for developing EBV-induced lymphoproliferative diseases. Moreover, certain families are at increased risk for EBV-associated malignancies, especially those with a triad of manifestations (i.e., autoimmunity, immunodeficiency, and lymphoma). Chromosomal breakage as seen in patients with ataxia telangiectasia may predispose to leukemogenesis. Immunoregulatory defects are also probably predisposing factors to lymphomagenesis. Both inherited and acquired defects can render persons vulnerable to leukemia and lymphoma.     

EB病毒相关性肿瘤疾病

EB病毒（EBV）是一种能诱发肿瘤的疱疹病毒。近年来,有关EBV在人体内生存的机制、感染后的免疫调控、相关疾病的发病机制等方面均有了新的认识。现就近年来EBV相关性肿瘤的研究进展情况进行介绍。     

EB病毒相关性肿瘤疾病

EB病毒(EBV)是一种能诱发肿瘤的疱疹病毒.近年来,有关EBV在人体内生存的机制、感染后的免疫调控、相关疾病的发病机制等方面均有了新的认识.现就近年来EBV相关性肿瘤的研究进展情况进行介绍.     

Persistent Low Level Epstein-Barr Virus DNAemia in Childhood Cancer Survivors

Background: Clinical observation of Epstein-Barr virus (EBV) status has not documented in childhood cancer survivors (CCSs) sustaining long-term remission of malignant diseases. Thus, the aim of this study was to evaluate the EBV status in children with various malignant diseases after they completed their treatments. Patients and Methods: Thirty consecutive children with various malignant diseases previously received treatment at the University of Tsukuba Hospital. Nine cases had acute lymphoblastic leukemia (ALL), 10 had solid tumors, 4 had lymphoma, 4 had CNS tumors, and 3 had acute myeloid leukemia (AML). EBV DNA in 328 whole blood samples were monitored by real-time QPCR for all cases after treatment. Clinical records and laboratory data were also reviewed. Results: There were 6/30 (20%) cases with continuous detection of EBV DNA while there were 24/30 (80%) cases without continuous EBV DNA. EBV DNAemia was persistently observed in 4/9 (44.4%) cases with ALL and in 2/4 (50%) cases with lymphoma. Persistent EBV DNAemia can be observed for >5 years without any EBV associated symptoms or diseases. Conclusions: Childhood cancer survivors have persistent EBV DNAemia more frequently, which is thought to be observed in cases with ALL and lymphoma with higher tendency for >5 years after treatment. Persistent EBV DNAemia is frequent in CCSs aged 5–10 years. Any immunological alteration is speculative in a pathophysiology of persistent EBV DNAemia.     

Epstein-Barr virus infection is not associated with development of allergy in children

BACKGROUND: Differences in concentrations of antibodies to Epstein-Barr virus (EBV) in atopic and nonatopic children have been observed, suggesting that EBV infection may play a role in allergic diseases.AIM To assess the association between EBV infection and atopy in Swedish children at 4 years of age. MATERIALS AND METHODS: Were studied 2561 children born in 1994 through 1996 in Stockholm, Sweden. The children were enrolled in a prospective birth cohort study focusing on the relation of exposure to various environmental and life style factors during early childhood and development of atopy. Blood samples were obtained when the children were approximately 4 years old, and immunoglobulin G to EBV was determined by indirect immunofluorescence. The relationship between the seroprevalence to EBV and various allergic disorders was assessed, withthe use of logistic regression analysis to account for other risk factors. RESULTS: Totally 1347 of 2561 (52%) children were EBV-seropositive. Associations between EBV seropositivity and the occurrence of asthma [adjusted odds ratio (OR(adj)), 1.10; 95% confidence interval (95% CI) 0.81 to 1.49] or suspected allergic rhinitis (OR(adj) 0.97; 95% CI 0.76 to 1.25) were not apparent. In children whose mothers were up to 25 years old, a higher EBV seroprevalence was observed than in children of older mothers (OR(adj) 1.34; 95% CI 1.04 to 1.71). Also in children whose mothers smoked, the seroprevalence was higher than in children of nonsmokers (OR(adj) 1.29; 95% CI 1.02 to 1.63). CONCLUSIONS: The study does not support the hypothesis that EBV infection in early childhood plays an important role in the pathogenesis of allergic diseases in children.     

Clinical evaluation of a quantitative real time polymerase chain reaction assay for diagnosis of primary Epstein-Barr virus infection in children

BACKGROUND: Epstein-Barr virus (EBV) infectious mononucleosis is often diagnosed based on characteristic clinical features and either a positive heterophil antibody test or serology, both of which can be unreliable in young children. Real time quantitative PCR assays that measure EBV DNA load in serum or plasma are highly sensitive in young children, but serum and plasma contain inhibitors of PCR which must be removed by DNA extraction techniques. A real time TaqMan PCR assay was designed and evaluated for simultaneously measuring EBV DNA load and validating the removal of PCR inhibitors from serum samples. METHODS: A serum sample was available from patients classified serologically as primary EBV infection (n = 28), EBV-seronegative (n = 25) and EBV-seropositive (n = 26). Patients were classified as having EBV infectious mononucleosis if they had specified clinical findings and > or =10% atypical lymphocytes in peripheral blood or had a positive Monospot test result. DNA was purified by a spin column method and tested in PCR reactions with primers for EBV DNA polymerase gene and internal control targets. Amplification of the two PCR products was measured in real time with separate TaqMan DNA probes labeled with various fluorescent reporters. RESULTS: The mean age of study patients was 9 years, 4 months. Twenty-one (75%) of the patients in the primary EBV infection group, one (4%) of the seronegatives and none of the seropositives had detectable EBV DNA. Within the primary infection group, those with detectable virus were more likely than those without detectable virus to have evidence of lymphadenopathy (14 of 16 vs.1 of 5; P = 0.011), higher mean atypical (11.7 vs.0.9%; P = 0.002) and absolute atypical (1.5 vs.0.1 x 109/l; P = 0.004) lymphocyte count, higher mean absolute lymphocyte count (4.7 vs.2.3 x 109/l; P = 0.026) and higher mean aspartate aminotransferase value (119.8 vs.37.3 IU/l; P = 0.036). Ten patients, all in the primary infection group, had EBV infectious mononucleosis, and all had positive PCR results. No sample contained PCR inhibitors. CONCLUSIONS: A real time TaqMan PCR assay allows rapid identification of patients with primary EBV infection and those with EBV infectious mononucleosis.     

Clinical, virologic, and serologic evidence of Epstein-Barr virus infection in association with childhood pneumonia

To explore the association of Epstein-Barr virus infection with childhood pneumonia we studied two patients whose mononucleosis-like illnesses were accompanied by pneumonia; both had virologic and serologic evidence of current or recent EBV infection. We then analyzed the sera of 71 children (age range, 14 months to 9 years) with pulmonary infiltrates for the presence of four classes of antibody to EBV. Antibody responses consistent with current or recent EB virus infection were found in 15. Two children had IgM antibodies to the EBV viral antigen at titers greater than or equal to 1:160, indicating current infection, and all 15 patients had antibody to components of the early antigen complex, suggesting recent infection. A fourfold rise or drop in one or more EBV-specific antibody classes was noted in eight patients within 30 days following onset of clinical illness. Few patients had clinical features suggesting infectious mononucleosis. Eight of the 15 with serologic evidence of current or recent EBV infection also had clinical or serologic evidence of infection with another pathogen--bacterial, viral, or mycoplasmal. Thus, in childhood pneumonia, EBV may be a primary, co-primary, or secondary pathogen; it may be reactivated in the course of infection with another agent, or possibly, by suppressing immune function, it may precipitate infection with some other organism.     

Epstein-Barr virus associated with immune thrombocytopenic purpura in childhood: a retrospective study

OBJECTIVE: Although Epstein-Barr virus (EBV) is known to cause immune thrombocytopenic purpura (ITP), the epidemiology of this pathogen in children with ITP is not known. In the present study, the clinicoepidemiology and laboratory characteristics of EBV-associated ITP in childhood were analysed retrospectively. METHODS: The study cohort consisted of 108 children in whom ITP was diagnosed between 1990 and 1998. Patients were divided into EBV or non-EBV groups according to their serological status at diagnosis. RESULTS: Thirty-five (32.4%) of 108 children had ITP associated with acute EBV infection. The clinical manifestations and laboratory data were similar in children with and without acute EBV. Responses to various modalities of therapy were analysed. The average time to achieve complete remission (platelet count > or =150 x 10(9)/L) in EBV and non-EBV groups was 26 and 16 days, respectively. CONCLUSIONS: The incidence of childhood ITP associated with acute EBV infection is relatively high in Taiwan. Patients with EBV-associated ITP tended to resolve more slowly than those without EBV infection.     

Epstein-Barr virus burden in adolescents with systemic lupus erythematosus

OBJECTIVE: We sought to determine whether patients with systemic lupus erythematosus (SLE) and a presumed primary or reactivated Epstein-Barr virus (EBV) serologic response had evidence of an active EBV infection. BACKGROUND: Patients with SLE often have what appears to be a primary or reactivated EBV serologic response. If these patients then present with fever, fatigue, adenopathy or leukopenia, it is not clear whether these symptoms are caused by worsening SLE or EBV infection. Establishing the correct diagnosis is crucial for management. METHODS: We examined the EBV burden in 13 adolescents with SLE and a presumed primary or reactivated EBV serologic response. All were taking prednisone; 2 each were also on azathioprine or intravenous pulse cyclophosphamide. EBV serologies were performed for all, and EBV burdens were assessed via immortalization assays and EBV DNA amplification of blood and saliva at least once. RESULTS: Seven patients had serologic patterns indicative of a primary EBV infection, while six had serologies indicative of a reactivated (secondary) EBV infection. Two of the latter were the only ones in whom a small amount of biologically active EBV was detected. CONCLUSION: In our series active EBV infection was not seen in most patients, despite serologic data that could be interpreted as a primary or reactivated infection. Thus the serologic profiles were more likely a consequence of immune dysregulation secondary to SLE or its therapy rather than rampant infection with EBV.     

The X-Linked Lymphoproliferative Disease: From Autopsy Toward Cloning the Gene 1975-1990

Although X-linked lymphoproliferative disease (XLP) is rare (1-2 males per 1 × 10⁶), it serves as a model for discerning diverse diseases caused by Epstein-Barr virus (EBV) ranging from agammaglobulinemia to fatal infectious mononucleosis following infection with the virus. The study of patients with XLP has also paved the way to understanding how EBV induces diseases in children with primary immunodeficiency diseases, organ transplant recipients, and those with acquired immunodeficiency syndrome. This review is dedicated to the memory of Gordon Vawter, M.D., who generously provided insights into the causes of pathogenesis of immune deficiency and lymphoproliferative disorders.     

EB病毒抗体检测在儿童EBV感染相关疾病诊断中的应用价值

目的探讨EBV四种抗体(VCA-IgM、VCA-IgG、EA-IgG、EBNA-1-IgG)在儿童EB病毒感染相关疾病中的应用。方法采用酶联免疫吸附法(ELISA)检测78例EB病毒感染儿童血清样本的EBV四种抗体。结果(1)病例年龄2月~15岁,中位年龄3岁,<4岁53例,4~8岁16例,>8岁9例;(2)78例患儿传染性单核细胞增多症51例(65.4%),呼吸道感染7例(9.0%),另外还有原发性血小板减少性紫癜、急性再生障碍性贫血、肾炎、过敏性紫癜、肝炎及隐性感染病例。(3)VCA-IgM阳性57例,阳性率73.1%;结论EBV四种抗体能动态反应EB病毒感染后的抗体水平,其敏感性高、特异性强、检测方法简单,在EB病毒感染相关疾病诊断中很有价值,非常值得推广。