EBV

First Viral Virus

Epstein–Barr virus

Epstein–Barr virus (EBV or human herpesvirus 4) causes infectious mononucleosis and is latent in most adults. EBV is commonly transmitted by infected saliva (hence the nickname the kissing disease). Primary infection involves epithelial cells of the oropharynx and parotid gland. Viral shedding occurs for weeks to months after infection. Following replication in epithelial cells, EBV infects B cells and quickly becomes latent. Latent EBV is a factor in the development of nasopharyngeal carcinoma, Burkitt's lymphoma, and other lymphoproliferative disorders in immunocompromised individuals. As it has been known for years that cells in tissue culture could be immortalized by EBV, we now realize that EBV is the prototypic gammaherpesvirus and is oncogenic in humans.

EBV Transactivation

Epstein–Barr virus, considered to be an oncogenic virus, is found in up to 60% of HHV-6-positive LD tissues. The intensity of signals obtained for EBV is weaker than for HHV-6, suggesting that EBV sequences are markedly less represented.7 We demonstrated that both viruses can be present in the same cells. The infection of EBV latently infected cells with HHV-6A results in activation of EBV replication, mediated via a cyclic AMP-responsive element located within the EBV ZEBRA promoter. This promoter controls the EBV gene product ZEBRA, which is responsible for disrupting EBV latency and initiating the lytic replication cascade.47 Activation of LMP1 and EBNA2 expression after HHV-6A infection of EBV-positive Burkitt's lymphoma cell lines has also been described. The presence of positive and negative regulatory elements responsive to HHV-6A infection in LMP1 regulatory sequences have also been demonstrated.48

III.D Other Tumors

EBV infection is also associated with other unusual malignancies such as leiomyosarcomas in immunosuppressed AIDS and transplant patients, natural killer lymphomas, and T-cell lymphomas. The role of EBV infection in the development of these tumors is interesting because these cell types are not thought to represent natural reservoirs of persistent infection. EBV infection has also been implicated in the development of other malignancies, e.g., breast cancer. However, because EBV infection is present in most adults, establishing a potential causal association between EBV infection and a certain type of malignancy requires careful investigation.

EBV Mechanisms

EBV infection appears to modify B-lymphocyte antigen presentation to CD4+ T cells. The EBV EBNA-3 protein binds the VDR, blocking its activation of target genes.197 EBV also produces a viral interleukin-10 (IL-10) mimetic198,199 capable of disrupting the cellular IL-10 signaling that is essential for Tr1 cells.171,200 EBV also produces viral peptide antigens that mimic myelin peptides and activate myelin-specific T cells.70,201,202 Thus, EBV infection of B lymphocytes may be distorting CD4+ T-cell activation toward a pro-inflammatory phenotype. In summary, EBV infection correlated with a 2- to 4-fold increased risk of MS and showed a weak association with latitude. However, EBV had no differential impact on females versus males, no preferential association with RRMS, and greatest relevance to MS risk in late adolescence and young adulthood.

Chronic Active EBV Infection (CAEBVI)

CAEBVI has been reported mainly in Asians, and appears to have two subtypes: a T-lymphocyte form and an NK-cell form, depending upon which cells are infected with EBV.199 Clinically, patients with CAEBVI have chronic or recurrent mononucleosis-like symptoms including fever, lymphadenopathy, and hepatosplenomegaly for at least 3 months. Hepatitis, pancytopenia, uveitis, interstitial pneumonitis, skin manifestations (e.g., photosensitivity), sicca syndrome, neuropathy, cardiomyopathy/carditis, neutropenia, eosinophilia, thrombocytopenia, and hyper- or hypogammaglobulinemia also can occur; a similar "cytokine storm" as is seen with HLH can be present.200 Occasionally, the disease can mimic leukemia. Rarely, coronary artery ectasia or aneurysms (as can occur in Kawasaki disease) are observed.201 Patients have prolonged, severe, relapsing, and often fatal courses. Death can be associated with respiratory failure secondary to interstitial pneumonia, or with diffuse T-lymphocyte infiltrate, lymphoma or hemophagocytic syndrome.202,203 Distinguishing clinically between CAEBVI and IAHS is difficult.

Patients with CAEBVI have abnormal EBV serologic responses, such as extremely high levels of antibody to the EA and VCA complexes and low or absent antibody to EBNA. Some patients have selective absence of antibody to EBNA-1.204 Impaired cytotoxic T-lymphocyte responses against EBV-infected NK cells have been reported.205 EBV loads typically are extremely high, especially in patients with complications. Elevated EBV load in cerebrospinal fluid in patients with CNS involvement is reported.206–209 There is no evidence of a prior immunologic abnormality. These patients do not have the gene defect associated with XLPS,210 although there is a case report of a patient with CAEBVI and a perforin gene defect.211

The NK-cell form of CAEBVI is characterized by high EBV DNA loads, high serum IgE, NK-cell lymphocytosis, and hypersensitivity to mosquito bites. The T-lymphocyte form of the disease is associated with anemia, and a worse prognosis. Other poor prognostic signs of CAEBVI are age >8 years and platelet counts <12,000/mm3.212

Several families have been described in which this syndrome has occurred in multiple members.213 Stem cell transplantation214 or autologous cytotoxic T-lymphocyte infusions are the most effective therapies;215 chemotherapy also has been used.216

Chronic active EBV infection must not be confused with chronic fatigue syndrome (CFS).217 In CFS, few, if any, objective signs of illness exist. EBV does not play an etiologic role in most cases of CFS,218 despite the finding that a few patients have elevated antibody titers to EA complex219 and may lack antibody to EBNA-1,204 and in some adolescents, the disease follows an episode of infectious mononucleosis.220

Clinical Illnesses

EBV infection is generally asymptomatic, particularly when it occurs during infancy. Up to 50% of primary EBV infections in adolescents and young adults produce infectious mononucleosis, a generally self-limited disease characterized by fever, sore throat, headache, fatigue, malaise, rash, lymphadenopathy, splenomegaly, and atypical lymphocytosis. The total duration of the illness is typically 2–3 weeks. Complications can include splenic rupture, airway obstruction, aplastic anemia, pneumonia, hemophagocytic lymphohistiocytosis, psychological/psychiatric disturbances, and cancer. EBV reactivation in the setting of immunosuppression, particularly in transplant recipients, can lead to uncontrolled B cell proliferation (posttransplant lymphoproliferative disorder) which may result in significant morbidity and mortality.

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Epstein-Barr Virus (Mononucleosis and Lymphoproliferative Disorders)

Ben Z. Katz, in Principles and Practice of Pediatric Infectious Diseases (Fifth Edition), 2018

Chronic Active Epstein-Barr Virus Infection

CAEBVI has been reported mainly in Asians and appears to have two subtypes: a T-lymphocyte form and an NK-cell form, depending on which cells are infected with EBV.220 Clinically, patients with CAEBVI have chronic or recurrent mononucleosis-like symptoms, including fever, lymphadenopathy, and hepatosplenomegaly, for at least 3 months. Hepatitis, pancytopenia, uveitis, interstitial pneumonitis, skin manifestations (e.g., photosensitivity, hypersensitivity to mosquito bites), sicca syndrome, neuropathy, cardiomyopathy and carditis, neutropenia, eosinophilia, thrombocytopenia, and hypergammaglobulinemia or hypogammaglobulinemia also can occur; a similar cytokine storm as previously described can be present.221 The disease is clonal and occasionally can mimic leukemia.222 Rarely, coronary artery ectasia or aneurysms are observed.223 Patients have prolonged, severe, relapsing, and often fatal courses. Death can be associated with respiratory failure secondary to interstitial pneumonia or with diffuse T-lymphocyte infiltrate, lymphoma, or hemophagocytic syndrome.224,225 Distinguishing clinically between CAEBVI and IAHS is difficult. A rare, chronic blistering photodermatosis, hydroa vacciniforme, also can be a part of this syndrome.223a

Patients with CAEBVI have markedly abnormal EBV serologic responses, such as extremely high levels of antibody to the EA and VCA complexes and low or absent antibody to EBNA. Some patients have selective absence of antibody to EBNA-1.226 Impaired cytotoxic T-lymphocyte responses against EBV-infected NK cells are reported.227 EBV loads typically also are extremely high, especially in patients with complications. Elevated EBV load in cerebrospinal fluid in patients with CNS involvement is reported.228–231 Before EBV infection, there is no clinical evidence of an immunologic abnormality. These patients do not have the gene defect associated with XLPS,232 although there is a case report of a patient with CAEBVI and a perforin gene defect.233 In general, a different apoptotic pathway (Fas[CD95]/Fas ligand) seems to be involved in this disease.234

The NK-cell form of CAEBVI is characterized by high EBV DNA loads, high serum IgE level, NK-cell lymphocytosis, and hypersensitivity to mosquito bites. The T-lymphocyte form of the disease is associated with anemia and a poor prognosis. In contrast to IAHS, mainly non-CD8+ T lymphocytes are involved in CAEBVI.235 Other poor prognostic signs are age >8 years and platelet count <12,000/mm3 on presentation.236

Several families have been described in which this syndrome has occurred in multiple members.237 Stem cell transplantation238 or autologous cytotoxic T-lymphocyte infusions are the most effective therapies, although mortality remains high (20%−50%)239; chemotherapy also has been used.240

Chronic active EBV infection must not be confused with chronic fatigue syndrome (CFS).241 In CFS, few, if any, objective signs of illness exist. EBV serologies are not helpful for diagnosis,242 despite the finding that a few patients have elevated antibody titers to EA243 and may lack antibody to EBNA-1.226 Six months after IM, about 10% of adolescents will meet the criteria for CFS; whether severity of illness, autonomic dysfunction, or other factors play a role in prolonged recovery from IM is unclear.244–249

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Tropical manifestations of common viral infections

Jashin J. Wu, ... Stephen K. Tyring, in Tropical Dermatology, 2006

Chronic active EBV (CAEBV) infection

CAEBV infection is a rare but serious condition that occurs in a previously healthy person after documented primary EBV infection. The peripheral blood has a significant increase of EBV load with infection of T and/or natural killer cells. The acute IM antibody pattern remains, including failure to produce antibodies to EBNA1, high IgG anti-VCA and early antigen, and sometimes persistence of anti-VCA IgM. Vital organ involvement often occurs, such as bone marrow hypoplasia, hepatitis interstitial pneumonia, and splenomegaly. CAEBV has a high morbidity and mortality rate due to hemophagocytic syndrome, hepatic failure, lymphoma, or sepsis. This condition is hard to treat, but adoptive immunotherapy7 or bone marrow transplantation8 has been reported to be useful.

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Primary T-cell immunodeficiencies

Françoise Le Deist, Alain Fischer, in Clinical Immunology (Third Edition), 2008

X-LINKED PROLIFERATIVE SYNDROME (XLP–PURTILO SYNDROME, DUNCAN DISEASE)

EBV infection can induce uncontrolled B-cell proliferation in patients with profound T-cell deficiencies, such as SCID, or following T cell-depleted BMT. In certain otherwise healthy kindreds, EBV infection was found to have severe consequences such as hepatitis, lymphohistiocytic activation and bone marrow aplasia. In these cases, if not fatal, B-cell lymphoma or agammaglobulinemia may also occur. Antibodies against EBV nuclear antigen, and occasionally to the VCA (viral capsid antigen) and EA (early antigen), are undetectable. These patients are not prone to other severe viral infections. This abnormal X-linked lymphoproliferative-disease gene has been mapped to Xq24-q27 and identified as SH2 domain-encoding. The gene product, SLAM-associated protein (SAP/SH2 D1), was described to interact with the transmembrane receptor SLAM85 expressed by T and B cells. SAP can act as a B-cell inhibitor by blocking the recruitment of SH2 domain-containing signal transduction molecule to SLAM, such as the phosphatase SHP-2. The absence of the inhibitor SAP leads to inability to handle the EBV infection. However, a frequent striking feature of XLP is the uncontrolled proliferation of CD8 T cells, much more prominent that the proliferation of EBV-infected B cells. Likewise, it is possible that SAP-deficient CD8 T cells undergo proliferation because of the faulty regulatory function of SAP while being poorly able to kill EBV-infected B cells. In this way, EBV infection would act as a potent trigger of T-cell responses, which are under the control of SAP-associated proteins. NK-cell activity and the EBV-specific CTL activity of SAP-deficient cells are deficient, potentially accounting for the immunodeficiency. Another gene might also be involved in XLP syndrome, as the SAP-encoding gene has been found mutated in only 50–70% of XLP male patients. Moreover, severe EBV infection in girls has also been described.

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Human DNA Tumor Viruses and Oncogenesis

Pravinkumar Purushothaman, Subhash Chandra Verma, in Animal Biotechnology, 2014

Ethical Issues

EBV infection and tumorigenesis is a complex process and is heavily affected by genetic constitution, socio-economic background, and geographical locations and subpopulation levels (Pipas and a., 2009). Generally, the prognosis and selection of the most appropriate treatment are assessed using both patient-related and standard tumor-related characteristics. The high mortality rate among patients with EBV-associated tumors is partly due to delays in diagnosis that result from the complexity of its initial clinical presentation. EBV-specific quantitative PCR is mostly employed to detect EBV from infected peripheral blood lymphocytes or biopsy samples (Robertson, 2005). A better understanding of viral gene expression in the context of EBV infections from diverse populations will prove useful in diagnosing and treating EBV-associated malignancies. Clinical research on patient samples or animal models involves an array of ethical issues and should be in accordance with World Health Organization (WHO) criteria. According to this, all clinical research involving patient samples should be approved and continuously monitored by a university or institutional ethical committee. Additionally, EBV has strict host specificity, which infects only humans; therefore, it is not practical to study the dynamics of protein expression during EBV infection and pathogenesis. However, an alternative method has been developed to study in vivo infection of EBV by generating a murine model known as "humanized mice." These mice have the potential to maintain human hematopoiesis, including human CD4+ leukocytes that can thereby support persistent EBV infection in vivo. Similar to clinical research, studies involving animal models also require approval from the institutional ethical committee. Above all, participating patients or their guardians should provide informed consent according to the institutional guidelines. Institutional ethical committees annually review the protocols and progress made in clinical research and have the authority to disapprove of a study if it is deviating from the original guidelines (Robertson, 2005).

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Epstein–Barr virus

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HHV-6 in Lymphohematopoietic Diseases

Sylvie Ranger-Rogez, in Human Herpesviruses HHV-6A, HHV-6B & HHV-7 (Third Edition), 2014

EBV Transactivation

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Viral Infections

Karen L. Roos, in Textbook of Clinical Neurology (Third Edition), 2007

EPIDEMIOLOGY AND RISK FACTORS

Epstein‐Barr virus (EBV) is a human B lymphotropic virus, the causative agent of infectious mononucleosis. The major route of transmission of EBV is through saliva, and EBV infects the epithelial cells of the oropharynx and adjacent structures as well as those of the uterine cervix. Epithelial cells may play a major role in the persistence of EBV by allowing chronic viral replication and release of infectious particles throughout the lifetime of a virus‐infected host. Eighty percent to 90% of children in developing countries are seropositive for EBV between 2 and 3 years of age. By the third decade, nearly 100% of adults have EBV serum antibodies.145

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Tumor Viruses: Human

R. Grassmann, ... H. Pfister, in Encyclopedia of Virology (Third Edition), 2008

Other Carcinomas

EBV is present in a high proportion (>90%) of lymphoepithelioma-like gastric carcinomas, which morphologically closely resemble NPC. About 5–25% of gastric adenocarcinomas are also associated with EBV. These tumors display a restricted pattern of EBV latent-gene expression, including EBNA1 and LMP2A. A possible role of EBV in the pathogenesis of gastric carcinomas seems to be confined to late tumorigenesis, which is suggested by the absence of EBV infection in premalignant gastric lesions. A subset of salivary gland carcinomas have also been found to be EBV-positive including the expression of latent genes like EBNA1 and LMP1 and 2 in parts of the tumors. Recently, EBV has also been detected in some carcinomas of the breast and liver.

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Epstein–Barr Virus: General Features

L.S. Young, in Encyclopedia of Virology (Third Edition), 2008

Taxonomy and Genome Structure

Epstein–Barr virus (EBV; species Human herpesvirus 4) is a member of the genus Lymphocryptovirus, which belongs to the lymphotropic subfamily Gammaherpesvirinae of the family Herpesviridae. EBV is closely related to the lymphocryptoviruses (LCVs) present in Old World nonhuman primates, including EBV-like viruses of chimpanzees and rhesus monkeys. These viruses share homologous sequences and genetic organization, and infect the B lymphocytes of their host species, resulting in the establishment of latent infection in vivo and transformation in vitro. A transforming, EBV-related virus has also been isolated from spontaneous B-cell lymphomas of common marmosets and is thus the first EBV-like virus to be identified in New World primates. The genome of this marmoset LCV revealed considerable divergence from the genomes of EBV and Old World primate EBV-related viruses, suggesting that this virus represents a more primitive predecessor of the LCVs infecting higher-order primates.

The EBV genome is composed of linear, double-stranded DNA, approximately 172 kbp in length. EBV has a series of 0.5 kbp terminal direct repeats (TRs) and internal repeat sequences (IRs) that divide the genome into short and long, largely unique sequence domains. EBV was the first herpesvirus to have its genome completely cloned and sequenced. Since the EBV genome was sequenced from an EBV DNA BamHI fragment cloned library, open reading frames (ORFs), genes, and sites for transcription or RNA processing are frequently referenced to specific BamHI fragments, from A–Z, in descending order of fragment size. The virus has the coding potential for around 80 proteins, not all of which have been identified or characterized.

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Infection and Systemic Sclerosis

Alexandra Balbir-Gurman, Yolanda Braun-Moscovici, in Infection and Autoimmunity (Second Edition), 2015

2.3 Epstein–Barr Virus

EBV has a unique capacity to infect and persist in B lymphocytes.30 CD8 + T cells are responsible for the deletion of infected B cells. In SSc, the number of CD8 + T cells falls, and the deletion of infected B lymphocytes is impaired. The pathologic vicious cycle includes circulation of autoreactive EBV-infected B cells and their targeting of specific organs followed by the tropism of CD4 + helpers, tissue and B cell damage, and release of EBV.31,32 Recently, evidence has linked EBV to the HLA DRB1 and HLA-DQB1 regions of MHC class II.33

Studies have documented elevated IgM to EBV capsid antigen in patients with SSc.34 SSc developed in a child with infectious mononucleosis.35 Reactivity of IgG and IgM to EBV extractable antigen was high in SSc patients,36 and in five lung biopsies from SLD patients, EBV DNA was detected.37

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Infections in Early Systemic Lupus Erythematosus Pathogenesis

Rebecka Bourn, ... Judith James, in Systemic Lupus Erythematosus, 2016

Dysregulation of Immune Responses

EBV interacts with inherent susceptibility to immune dysregulation in some individuals, resulting in altered immune responses to EBV that could influence the development or progression of autoimmune disease. Approximately 90% of healthy, EBV-infected adults make antibodies directed against EBNA-1, a response dominated by antibodies binding the central region of EBNA-1.29,30 In contrast, the humoral response against EBNA-1 in lupus patients is dominated by antibodies binding the amino and carboxyl regions of EBNA-1.30

The cellular response to EBV is also altered in SLE patients. Compared to healthy individuals, SLE patients have decreased EBV-specific cytotoxic T-cell responses and an increased frequency of EBV-specific CD69+ CD4+ T cells producing interferon-γ (IFN-γ) after EBV stimulation.15,31,32 EBV viral loads in SLE patients are positively correlated with EBV-specific CD69+ CD8+ T cells, suggesting that the CD69+ CD8+ response in SLE patients fails to control viral replication.15 Indeed, EBV-specific CD8+ T cells from SLE patients have a reduced ability to express IFN-γ after EBV stimulation, and EBV viral loads are remarkably higher in SLE patients than in healthy individuals.15,31,33,34 Similarly, antibodies against early antigen-D (EA/D), an indicator of EBV reactivation, are more prevalent in SLE patients (54%) than in healthy controls (17%).33,35 Thus, a fundamentally altered response to EBV appears to make SLE patients more susceptible to viral reactivation, leading to active EBV infection.16

In turn, EBV infection may enhance the clinical manifestations of lupus.36 For example, increased interferon expression, interferon-inducible gene expression profiles, and proinflammatory cytokines are now considered central to SLE pathogenesis and ongoing pathology.15 Studies demonstrated that EBV stimulates increased IFN-α expression and increased production of proinflammatory cytokines by plasmacytoid dendritic cells.15,37,38 Additional studies are needed to compare the plasmacytoid dendritic cell responses to EBV in SLE patients and healthy individuals. Finally, latent EBV infection of B cells can cause transactivation of the human endogenous retrovirus (HERV)-K18 superantigen, leading to the stimulation of large numbers of cells and differentiation of EBV-infected B cells to memory cells.1,4 Therefore, EBV can act through multiple channels to stimulate lupus autoimmunity and clinical disease in genetically predisposed individuals.

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Transfusion-Transmitted Diseases

Louis M. Katz MD, Roger Y. Dodd PhD, in Transfusion Medicine and Hemostasis (Third Edition), 2019

Epstein–Barr Virus

EBV is associated with a variety of diseases including infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma, and posttransplantation lymphoproliferative disease (PTLD). Natural EBV transmission is via infected saliva. Acute infection in children is generally not recognized. In adolescents and adults, it results in infectious mononucleosis. EBV is latent in B-lymphocytes.

Occasional cases of posttransfusion EBV infection, including PTLD, have been reported. Serological screening of blood donors is impractical due to the high population prevalence (∼90%). Donation age individuals with active infection (infectious mononucleosis) are usually symptomatic and would not qualify to donate. Contemporary leukoreduction processes reduce EBV genetic material to undetectable levels and may effectively reduce transmission risk.

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Molecular Basis of Diseases of the Gastrointestinal Tract

Antonia R. Sepulveda MD, PhD, Armando J. Del Portillo MD, PhD, in Molecular Pathology (Second Edition), 2018

Genomic Alterations in EBV-Associated Gastric Adenocarcinomas

EBV-associated gastric adenocarcinomas have a prominent CpG island methylator phenotype (CIMP) distinct from the MSI subgroup. For example, hypermethylation of the CDKN2A promoter is more prevalent in EBV-type cancers, and MLH1 promoter hypermethylation is more prevalent in MSI-type tumors. In EBV-associated cancers, amplification of a 9p locus is enriched, a locus that contains therapeutic targets such as JAK2, PD-L1, and PD-L2. EBV-associated cancers also frequently contain mutations in PIK3CA, ARID1A, and BCOR, but unlike other subtypes lack mutations in TP53.

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Oncoviruses

Austin Mattox, ... Sara I. Pai, in Oral, Head and Neck Oncology and Reconstructive Surgery, 2018

Overview

EBV is a prototypic member of the herpesvirus family and has a linear DNA viral genome encased within a nucleocapsid and a viral envelope.95 Greater than 90% of the world's population is infected with EBV, often from an early age, and EBV transmission is postulated to occur by salivary exchange.96 Primary infection with EBV is typically asymptomatic, although if infection is delayed until adolescence, EBV may present as infectious mononucleosis, which is characterized by prominent cervical lymphadenopathy, pharyngitis, and fever.97 Patients typically shed high viral titers from the lytic infection occurring in the oropharynx and have a characteristic IgM response. Latent infection in memory B cells can cause lymphomas in immunosuppressed individuals, including Hodgkin and Burkitt lymphomas. Of particular importance to otolaryngologists, malignant transformation associated with epithelial infection with EBV is associated with nasopharyngeal and certain salivary gland carcinomas98 (Fig. 4.4).

III.D Other Tumors

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Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases

Carl Allen, ... Stephen Gottschalk, in Hematology (Seventh Edition), 2018

Chronic Active Epstein-Barr Virus

CAEBV represents a range of clinical manifestations resulting from persistent, uncontrolled infection of B, T, and/or NK cells by EBV (Table 54.3).16 Inability to control infection is likely due to defects in cytotoxic immune function. CAEBV has considerable pathologic and clinical overlap with HLH, and immune dysfunction is likely due to a variety of causes. Early descriptions of CAEBV primarily reported disease in Asian patients, and almost all cases were due to proliferation of EBV-infected T or NK cells. A recent review of several centers in the United States found a predominance of B cell–associated CAEBV in the Western hemisphere.

To establish the diagnosis of CAEBV, patients must have (a) signs and symptoms for at least 6 months and (b) an abnormal EBV serology with high antibody titers of VCA-IgG and EA-IgG, and little or no antibodies against EBNA. Affected individuals may also have measurable EA-messenger-RNA or EBV-DNA in the peripheral blood, serum, or affected tissues. The life-threatening form of CAEBV is characterized by high fevers, hepatosplenomegaly, and extensive lymphadenopathy, followed by hepatic, cardiac, or pulmonary dysfunction. These patients have very high EBV-VCA titers and EBV-DNA levels in their peripheral blood. Although EBV usually resides in B cells, in severe CAEBV, either T or NK cells are often infected, predisposing the patient to lethal T-cell or NK-cell lymphomas. Severe, often fatal CAEBV is more common in Japan, whereas mild/moderate CAEBV is more common in the Western hemisphere and is predominantly associated with B-cell infection. These patients do not have XLP-associated SH2D1A or BIRC4 mutations, and while the etiology of CAEBV remains poorly understood a recent study demonstrated that GATA2 deficiency is associated with CAEBV and hydroa vacciniforme. Severe allergy to mosquito bites is associated with EBV-infected NK cells, whereas hydroa vacciniforme is associated with EBV-infected T cells. The proposed classification scheme of CAEBV-associated lymphoproliferative disease (LPD) includes three categories: (1) polymorphic LPD without clonal proliferation of EBV-infected cells, (2) polymorphic LPD with clonality, and (3) monomorphic LPD (T- or NK-cell lymphoma/leukemia) with clonality.17 In the 2016 WHO Classification of mature lymphoid, histiocytic, and dendritic neoplasms LPDs associated with EBV-infected T cells are classified as systemic EBV-positive T-cell LPDs of childhood; LPDs associated with EBV-infected NK cells, as hydroa vacciniforme-like lymphoproliferative disorder.

Although sporadic clinical improvements of mild/moderate CAEBV have been reported after infusion of IL-2, high-dose immunoglobulin, antiviral drugs, tumor necrosis factor (TNF)-α antibodies, or steroids, the only curative option for severe CAEBV is HSCT. Survival rates vary between 50% and 95%, with better outcomes for patients who (a) are transplanted early after diagnosis, (b) have fewer complications before transplant, and (c) have received a reduced intensity.18 Besides HSCT, the adoptive transfer of autologous EBV-specific T cells has been explored in five patients with mild or moderate CAEBV. Infusion of EBV-specific T cells resulted in resolution of fatigue, malaise, fever, lymphadenopathy, and splenomegaly lasting for 6 to 36 months. For severe CAEBV in which EBV resides in the T- or NK-cell compartment, the use of EBV-specific T cells has been investigated anecdotally. For example, we have infused donor-derived LMP2-specific T cells with a good partial response as judged by decreasing EBV-DNA load.

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Lung Infections

Ann E. McCullough MD, Kevin O. Leslie MD, in Practical Pulmonary Pathology: A Diagnostic Approach (Third Edition), 2018

Epstein–Barr Virus

EBV infections are usually acquired in childhood and are generally asymptomatic. The pathologist most often encounters this virus in the lung in the context of pulmonary lymphomas or in other EBV-associated lymphoproliferative disorders that can occur in transplant recipients and other immunocompromised patients. However, the most common symptomatic primary EBV infection is infectious mononucleosis. Most of these patients recover uneventfully, but a few develop one or more complications. Pneumonitis is one of them, albeit rare and not well characterized. The few reports describing pathology indicate a nonspecific lymphocytic interstitial pneumonitis, which may be bronchiolocentric (Fig. 7.108).361,362 CPE is absent, and although serologic studies can be supportive of a clinicopathologic diagnosis, etiologic proof of EBV infection requires the demonstration of the virus in lymphoid cells by in situ hybridization for EBV-encoded RNA-1 (EBER-1).

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Multiple Sclerosis in Women

C.E. Hayes, J.A. Spanier, in Nutrition and Lifestyle in Neurological Autoimmune Diseases, 2017

EBV Mechanisms

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Herpesviruses

Sara Oliver, Scott H. James, in International Encyclopedia of Public Health (Second Edition), 2017

Clinical Illnesses

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Etiologic Agents of Infectious Diseases

Ben Z. Katz, in Principles and Practice of Pediatric Infectious Diseases (Fourth Edition), 2012

Chronic Active EBV Infection (CAEBVI)

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Epstein-Barr Virus (Mononucleosis and Lymphoproliferative Disorders)

Ben Z. Katz, in Principles and Practice of Pediatric Infectious Diseases (Fifth Edition), 2018

Chronic Active Epstein-Barr Virus Infection

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Primary T-cell immunodeficiencies

Françoise Le Deist, Alain Fischer, in Clinical Immunology (Third Edition), 2008

X-LINKED PROLIFERATIVE SYNDROME (XLP–PURTILO SYNDROME, DUNCAN DISEASE)

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Human DNA Tumor Viruses and Oncogenesis

Pravinkumar Purushothaman, Subhash Chandra Verma, in Animal Biotechnology, 2014

Ethical Issues

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Epstein–Barr Virus: General Features

L.S. Young, in Encyclopedia of Virology (Third Edition), 2008

Gastric Carcinoma and Other Epithelial Tumors

EBV infection is also present in around 10% of typical gastric adenocarcinomas, accounting for up to 75 000 cases per year. These tumors resemble NPC in carrying monoclonal EBV genomes, having a restricted pattern of EBV gene expression (EBERs, EBNA1, LMP2A, BARTs, and BARF1) and in the appearance of virus infection as a relatively late event in the carcinogenic process. The geographical variation in the association of EBV with gastric adenocarcinomas probably reflects ethnic and genetic differences. EBV-positive tumors have distinct phenotypic and clinical characteristics compared with EBV-negative tumors.

A number of other more common carcinomas such as breast cancer and liver cancer have been reported to be infected with EBV. Difficulties in confirming these associations have raised concerns about the use of PCR analysis to detect EBV infection and about the specificity of certain monoclonal antibody reagents. It is possible, however, that a small proportion of tumor cells can be infected with EBV, perhaps sustaining a low-level replicative infection, and that this might contribute to the growth of the carcinoma.

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Jornal de Pediatria

Volume 92, Issue 2, March–April 2016, Pages 113-121

Review article

Atypical manifestations of Epstein–Barr virus in children: a diagnostic challengeManifestações atípicas do vírus de Epstein–Barr em crianças: um desafio diagnóstico☆

Author links open overlay panelVasileiosBolisSophiaTsabouri

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https://doi.org/10.1016/j.jped.2015.06.007Get rights and content

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open access

Referred to by

Gesmar R.S. Segundo

Atypical manifestations of Epstein-Barr virus: red alert for primary immunodeficiencies

Jornal de Pediatria, Volume 92, Issue 5, September–October 2016, Pages 539-540

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Vasileios Bolis, Christos Karadedos, Ioannis Chiotis, Nikolaos Chaliasos, Sophia Tsabouri

Atypical manifestations of Epstein‐Barr virus in children: a diagnostic challenge

Jornal de Pediatria (Versão em Português), Volume 92, Issue 2, March–April 2016, Pages 113-121

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Abstract

Objective

Clarify the frequency and the pathophysiological mechanisms of the rare manifestations of Epstein–Barr virus infection.

Sources

Original research studies published in English between 1985 and 2015 were selected through a computer-assisted literature search (PubMed and Scopus). Computer searches used combinations of key words relating to "EBV infections" and "atypical manifestation."

Summary of the findings

Epstein–Barr virus is a herpes virus responsible for a lifelong latent infection in almost every adult. The primary infection concerns mostly children and presents with the clinical syndrome of infectious mononucleosis. However, Epstein–Barr virus infection may exhibit numerous rare, atypical and threatening manifestations. It may cause secondary infections and various complications of the respiratory, cardiovascular, genitourinary, gastrointestinal, and nervous systems. Epstein–Barr virus also plays a significant role in pathogenesis of autoimmune diseases, allergies, and neoplasms, with Burkitt lymphoma as the main representative of the latter. The mechanisms of these manifestations are still unresolved. Therefore, the main suggestions are direct viral invasion and chronic immune response due to the reactivation of the latent state of the virus, or even various DNA mutations.

Conclusions

Physicians should be cautious about uncommon presentations of the viral infection and consider EBV as a causative agent when they encounter similar clinical pictures.

Resumo

Objetivo

Esclarecimento da frequência e dos mecanismos patofisiológicos das manifestações raras da infecção por vírus de Epstein–Barr.

Fontes

Estudos de pesquisas originais publicados em inglês entre 1985 e 2015 foram selecionados por meio de uma busca na literatura assistida por computador (Pubmed e Scopus). As buscas no computador utilizaram combinações de palavras-chave relacionadas a "infecções por VEB" e "manifestação atípica".

Resumo dos achados

O vírus de Epstein–Barr é um herpesvírus responsável por uma infecção latente vitalícia em quase todo adulto. A infecção primária ocorre principalmente em crianças e se apresenta como síndrome clínica da mononucleose infecciosa. Contudo, a infecção por vírus de Epstein–Barr pode apresentar diversas manifestações raras, atípicas e de alto risco. Ela pode causar infecções secundárias e diversas complicações dos sistemas respiratório, cardiovascular, geniturinário, gastrointestinal e nervoso. O vírus de Epstein–Barr também desempenha um papel significativo na patogênese de doenças, alergias e neoplasias autoimunes, com o linfoma de Burkitt sendo o principal representante das últimas. Os mecanismos dessas manifestações ainda não foram resolvidos. Portanto, as principais sugestões são invasão viral direta e resposta imune crônica devido à reativação do estado latente do vírus ou mesmo diversas mutações do DNA.

Conclusões

Os médicos devem tomar cuidado sobre apresentações incomuns de infecção viral e considerar o VEB um agente causador quando encontrarem situações clínicas semelhantes.

Keywords

Epstein–Barr virus

Infectious mononucleosis

Child

Complications

Palavras-chave

Vírus de Epstein–Barr

Mononucleose infecciosa

Crianças

Complicações

Introduction

Epstein–Barr virus (EBV) is a common infectious agent, found in approximately 95% of the world's population. Primary infection with EBV is more frequent during childhood and causes a mild infection, which usually presents with no symptoms.1 However, when primary infection occurs during adolescence, it leads to infectious mononucleosis (IM) in 30–70% of cases, where up to 20% of B lymphocytes are infected with EBV.1, 2

EBV is a DNA virus belonging to the herpes family, and is also known as human herpes virus 4. It is composed of a linear dsDNA genome enclosed by a capsid, which is surrounded by the tegument and a host cell membrane-derived envelope embedded with glycoproteins. EBV has a large genome, coding for 87 proteins. The functions of 72 of these proteins have been defined so far.1

EBV transmission is achieved with saliva it and initially infects epithelial cells in the oropharynx and nasopharynx. Afterwards, EBV enters the underlying tissues and infects B-cells. After a primary lytic infection, EBV is capable of remaining dormant in resting memory B-cells, from which it periodically reactivates. The ability of reactivation makes EBV a constant challenge to the host.1

IM is the main clinical entity caused by EBV. Diagnosis is based on clinical examination, revealing the classic triad of fever, lymphadenopathy, and pharyngitis,3 and laboratory findings including the presence of atypical lymphocytosis and heterophile antibodies.2 The disease is managed specifically with supportive care, since it is a self-limited infection.3 However, IM has been associated with numerous early or late complications, with a range of graveness.

This review focuses on the rare manifestations of IM in children. Original research studies published in English between 1985 and 2015 were selected through a computer-assisted literature search (PubMed and Scopus). Computer searches used combinations of key words relating to "EBV infections" and "atypical manifestation." In addition, the reference lists of the retrieved articles helped in the search for other relevant articles, which were not found during the searching procedure. Thus, 48 studies were selected and discussed here (24 case reports, 14 reviews, five case control studies, one population-based study, two letters to editor, one cohort study, one meta-analysis). The potential factors, which may bias the findings of this review, are restriction of articles to English, together with database and citation bias.

Secondary infections

Acute dacryocystitis

Acute dacryocystitis is a rare complication of IM, with only five reported cases. It is defined by a painful, palpable mass in the medial canthal area, usually accompanied by fever.4

The etiology is nasal epithelial edema and lymphoid hyperplasia from IM, which cause temporary nasolacrimal duct obstruction. Colonization of lacrimal saccontents by respiratory pathogens ultimately leads to acute dacryocystitis. This complication is likely to occur in children and young adults due to the smaller nasal anatomy and unique epidemiology of EBV.4

Patients with IM and acute dacryocystitis should be treated with antibiotics; drainage of the lacrimal sac abscess may be required.4

Respiratory complications

Upper airway obstruction

Upper airway obstruction is a conceivably life threatening complication of IM. Significant airway obstruction affects approximately 1–3.5% of cases. Suspicion should be raised in the presence of odynophagia, cervical lymphadenopathy, and symptoms of respiratory distress.5

IM causes inflammation of Waldeyer's ring, edema of the pharynx and epiglottis, and pseudomembrane formation in the large airways. Signs of severe upper airway obstruction are often absent during the first stages of the disease. Patients should be treated with corticosteroids, and in severe cases, acute tonsillectomy, endotracheal intubation, or tracheotomy may be mandatory in order to secure the airway.5

Pneumonia

Pulmonary involvement is found in 5–10% of the IM cases in children. Reports of severe EBV symptomatic lung infection are rare and frequently described in immunosuppressed adults. There have been five reported cases of severe lung involvement in EBV infection in children. Three of these children suffered from respiratory distress and interstitial pneumonitis, one from bilateral lower lobe consolidation and effusion complicated by hemoptysis, and the last one from pleuropneumonia.6

The pathophysiological mechanism includes lymphocytes infected by EBV, which infiltrate the lung during acute IM. However, it is questionable whether this pulmonary involvement is the result of direct viral invasion of lung or whether it represents an immunologic reaction to the virus. It has also been suggested that EBV acts as a co-pathogen or induces ax temporary immunosuppression, causing susceptibility to another infection.6

Cardiovascular complications

Acute myocarditis

Prevalence of EBV is estimated to be less than 1% in viral myocarditis,3 while there are several anecdotal reports of heart complications from IM during the last 60 years.7 EBV and CMV are associated with this pathology, particularly after heart transplantation.8

The pathophysiological progression is composed of three phases. During the first phase, destruction of the cardiomyocytes derives directly from virus-mediated lysis or indirectly from immune response with the expression of proinflammatory cytokines. During the second phase, T-cells detect the viral antigen and destroy the infected cardiac cells through cytokine or perforin secretion. In the last phase, the destroyed myocytes are replaced by diffuse fibrosis, leading to dilated ventricles and cardiac failure.8

Myocarditis, as well as other heart complications of EBV like pericarditis, might even precede clinical IM, hindering the diagnosis.7

Atherosclerosis

The role of EBV in the pathogenesis of atherosclerosis is based on findings suggesting that EBV DNA is commonly found in atheromatous plaques. However, EBV DNA presence in atheroma ranges from 12% to 80%, thus these findings are questionable.9

This complication regards only adults, and the possible mechanism is based on EBV-encoded enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase). dUTPase has been shown to induce the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1). Emotional and psychosocial stress is believed to deregulate immune repression of the virus, allowing its replication and the production of dUTPase. This mechanism provides an explanation for the connection between stress, EBV, and coronary artery events.10 EBV-induced gene 3 (Ebi3) is also implicated in atherosclerosis.11

Hematological complications

Thrombocytopenia

Mild thrombocytopenia occurs in 25–50% of uncomplicated cases during the acute phase of the disease. An occasional patient may have thrombocytopenia for 8 weeks or more. In contrast, severe thrombocytopenia (platelet count <20 × 109/L) is rare, with 38 reported cases. Twenty-eight of these patients were younger than 21 years old. Two of these patients died of complications from thrombocytopenia and hemorrhage.12 Although severe EBV-associated thrombocytopenia is rare, it can have life-threatening consequences. This complication should be considered in any patient with acute EBV infection and evidence of mucosal or dermal bleeding.13

It has been proposed that the pathophysiology of thrombocytopenia includes the presence of a platelet-destroying agglutinin produced in response to a viral agent–platelet bond. Other possible mechanisms include vascular damage due to the infectious agents, and hypersplenism or antibody formation in the spleen and the reticuloendothelial system.12

Aplastic anemia

Aplastic anemia following primary EBV infection or in association with reactivation of EBV infection has been reported in 24 cases in the literature. Seventeen of these cases were children under 18 years old. However, it is likely that some cases of aplastic anemia characterized as idiopathic are, in fact, triggered by an EBV infection, since in young children EBV infection presents with atypical symptoms.14

EBV infected B-cells may provoke oligoclonal expansion of suppressor T-cells (CD8+, CD28−), which prevent autologous marrow hematopoietic cells development. EBV-associated and idiopathic aplastic anemia have similar prognosis.14

Agranulocytosis

Mild neutropenia is a common manifestation in IM during the first weeks of illness, but agranulocytosis or severe neutropenia after IM is very rare, with only 29 cases reported.15

The pathogenesis of agranulocytosis after IM may involve decreased production or maturation of myeloid cells in the marrow, as a result of the direct effect of EBV or antibody-mediated peripheral destruction of myeloid cells. The hypothesis of maturation arrest of myeloid cells has been suggested because mature myeloid cells disappear in the patient's bone marrow. Anti-human neutrophil antigen-1a (anti-HNA-1a) and anti-HNA-1b antibodies are both associated with the pathophysiology in agranulocytosis after IM, although it is unknown whether anti-neutrophil antibodies are produced in EBV-infected B cells.15

Lymphohistiocytosis

Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease caused by a dysfunction of cytotoxic T cells and NK cells.16 Incidence of HLH is estimated at one case per 800,000 people, half of which are associated with EBV. EBV-associated HLH has been observed in infants, children, and adults, but 80% of the cases occur in children of 1–14 years of age. HPS can be either primary, i.e., due to an underlying genetic defect; or secondary, associated with malignancies, autoimmune diseases (macrophage activation syndrome), or infections. Infectious triggers are mainly viruses of the herpes group, with EBV being the most common.17

Possible mechanism includes T cell/NK cell deregulation, which leads to increased cytokine release, resulting in activation of histiocytes followed by hemophagocytosis. Histiocytic infiltration of the reticuloendothelial system causes hepatomegaly, splenomegaly, lymphadenopathy, and pancytopenia, eventually leading to multiple organ dysfunctions.16

Genitourinary system complications

Renal dysfunction

EBV infection's renal involvement varies from microscopic hematuria and mild proteinuria to acute renal failure.18 Renal dysfunction in IM is infrequent, mostly self-limited, and is rarely associated with failure of renal function. Evidence of mild renal involvement may be present up to 16% in patients with IM, but severe renal failure is rare.19

Hematuria or proteinuria can be found in 2% and 18% of IM cases respectively, whereas azotemia has been reported in only eight cases. Interstitial nephritis is the most common histologic abnormality. EBV is believed to play a vital role in the pathogenesis of IgA nephropathy. Occasional case reports of nephrotic syndrome, hemolytic uremic syndrome, hepatorenal syndrome, and rhabdomyolysis in patients with IM have also appeared.18 Acute renal failure, although less common, has been associated primarily with rhabdomyolysis and interstitial nephritis.19

Finally, membranous nephropathy is a result of a prolonged systemic viral proliferation and persistent antigenemia in IM patients who lack a fully competent immune system, thus leading to immune complex deposition in the kidney.19

The possibility of IM should be considered when patients present acute renal failure, particularly if other features such as fever, hemolytic anemia, hepatitis, or thrombocytopenia are present.18

Genital ulcers

Genital ulceration is an uncommon manifestation of primary EBV infection. Identified by the Austrian dermatologist Lipschütz as an acute disease with fever, genital ulceration, and lymphadenomegaly in young women in 1913 and called Lipschütz's ulcer, today it is attributed to EBV infection.20 Forty-one cases have been reported, with the vast majority being females.21, 22, 23

Patients develop one or more large ulcers with diameter between 0.3 and 4 cm.24 The EBV-associated ulcers are often quite deep and necrotic, with irregular edges, and may cause pain and urinary symptoms. The mean healing time is 18 days.20

There have been three hypotheses suggested for the pathogenesis of EBV genital ulcers. The first hypothesis includes type III hypersensitivity reaction to immune complexes produced in the acute phase of EBV infection. EBV genital ulcers could also result from cytolysis due to EBV replication in vulvar keratinocytes, along with the inflammatory response to viral agents. Finally, these ulcers might represent a type of aphthosis.23

EBV is also present elsewhere in the female genital tract; however, its pathogenic role in the cervix, uterus, fallopian tubes, and ovaries is poorly understood.22

Gastrointestinal complications

Hepatitis

Cholestatic hepatitis with mild liver dysfunction has been reported in more than 90% of patients with primary EBV infection, but severe liver dysfunction or gallbladder involvement is rare.25 Primary EBV infection can cause a mild self-limited hepatitis, which typically resolves without clinical importance; jaundice can be seen in 5–10% of cases. Liver function abnormalities most often occur during the second week of illness and resolve within 2–6 weeks.25

Acute acalculous cholecystitis

Eleven cases of acute acalculous cholecystitis (AAC) have been reported during the course of primary EBV infection, 10 of which were in children or young adults.24

The main cause of AAC is gallbladder stasis and stagnation of bile. Increased bile viscosity, gallbladder wall ischemia, and proinflammatory mediators like eicosanoid have also been implicated in the pathogenesis. Gallbladder wall thickening and sludge formation may occur during the course of viral hepatitis. Hydrops of the gallbladder may occasionally develop during IM. Whether the increased thickness of the gallbladder wall results from direct invasion of the gallbladder mucosa by EBV or whether EBV-associated cholestasis causes the gallbladder wall irritation or both is not established.24

Recovery in all reported cases was excellent without any surgical treatment. Clinicians should be aware that AAC may complicate IM, thus avoiding unnecessary invasive surgery and antibiotic therapy.24

Acute liver failure

Acute EBV infection is a rare cause of acute liver failure (ALF) in young adults, but the available data are insufficient and there are not reports for children. As demonstrated by an 1887 patient cohort study, EBV is responsible for only 0.21% of ALF cases. Most cases occur post-transplantation or are associated with immunodeficiency syndromes.26 Since EBV is a ubiquitous virus and lacks a specific treatment, there is a significant risk for children who are EBV negative before liver transplantation to be infected by an adult EBV positive liver. Rising EBV titers should be approached with reduction of immunosuppression.27 It is questionable if the pathophysiology of EBV-related ALF is due to a generalized host immune response to EBV antigens or increased viral replication.26

Splenic rupture

Splenomegaly is a common complication of IM and of other infectious conditions. It is frequently self-limited. Spontaneous splenic rapture, however, is a rare manifestation of IM, estimated at 0.1–0.5% of IM cases.28 Most of reported splenic ruptures occurred within 3 weeks after IM diagnosis, but rupture appears to occur even after 7 weeks.17

EBV infection is believed to damage the splenic architecture by invading the spleen with lymphocytes and atypical lymphoid cells. This infiltration weakens the fibrous support system of the spleen and the splenic capsule becomes thinner, promoting the rupture. The rupture may occur following a minor trauma or spontaneously. The spontaneous rupture is hypothesized to be a result of either an acute increase in portal venous pressure caused by Valsalva maneuver or the compression of the enlarged spleen by the contracted diaphragm or the abdominal wall.28

Most cases report full resolution of hematoma from 4 weeks up to 1 year. There is evidence supporting that the spleen can retain full function while maintaining a low risk for repeat rupture even after parenchymal disruption. Thus, non-operative management of splenic rupture during IM, in a stable trauma patient, appears to be the treatment of choice, when also considering the risks following a splenectomy.28

Since splenic rupture is more frequent within 3 weeks of the infection onset, it is suggested that patients should refrain from sports for a minimum 3 weeks or once clinical symptoms and findings are resolved.17

Neurological complications

Facial nerve palsy

There have been only 14 cases of EBV-associated facial nerve palsy (FNP). Of these, 36% of the cases were bilateral, although bilateral FNP among FNP patients ranges from 0.3% to 2%. Otomastoiditis caused by EBV may transmit the infection to the facial nerve leading to this type of FNP, since it was recognized in two of these cases. Another possible explanation is the direct viral invasion or immunological response to EBV by the central nervous system. The mean age of these patients compared to non-EBV-associated FNP patients was much lower. This is associated with increased incidence of EBV infection during childhood.29

EBV infection should be suspected in patients with FNP, especially when it is bilateral, even when systemic manifestations of EBV infection are absent. These patients do not require any special treatment.30

Guillain–Barre syndrome

There have been several case reports since 1947 reporting EBV infection to precede Guillain–Barre syndrome (GBS). It has also been reported that EBV is responsible for 10% of GBS cases. However, the criteria used in these reports are questionable, since EBV is ubiquitous.31 The excess risk of GBS in the 2 months following EBV infection is believed to be 20-fold.32

Encephalitis

The incidence of EBV encephalitis is less than 0.5%, but it may be increased to 7.3% among children who are hospitalized with IM.33 Fatalities occur in 0.1–1% of these cases.2 EBV encephalitis commonly presents with confusion, decreased level of consciousness, fever, and epileptic seizures. The manifestations of EBV encephalitis may exist before, during, or even after the symptoms of IM.34 However, most patients with EBV encephalitis do not show typical symptoms of IM; therefore, EBV should be considered a possible cause of acute childhood encephalitis, regardless the presence of IM symptoms.33 EBV encephalitis prognosis may vary from complete recovery to death.34

EBV encephalitis involves a wide diversity of locations in central nervous system, with the cerebellum, cerebral hemisphere, and basal ganglia as the most frequent. Patients with isolated brain stem involvement are characterized by the highest mortality, whereas patients with thalamic involvement were recognized with the most consequences. Isolated cortical involvement and involvement of spinal cord were associated with excellent prognosis.34

The pathogenesis of EBV-induced neurologic injury has not been elucidated, although it is suggested that immunologic mechanisms are mostly responsible rather than increased viral replication.33

Alice in Wonderland syndrome

Alice in Wonderland syndrome (AIWS) is characterized by metamorphopsia, the self-reported presence of somatosensory alteration, such as distortion in the perception of size and shape of a patient's body and illusions of changes in the size, distance, form, even colors or spatial relationships of objects.35 The illusions and hallucinations are similar to the strange incidents that Alice experienced in Lewis Carroll's "Alice's Adventures in Wonderland."36

AIWS is primarily described in patients with epilepsy or migraine and drug abusers, and has rarely been described in association with EBV and other viral infections.35 Four cases with AIWS secondary to IM have been reported, including two adolescents, a 9½ year-old boy and a 7-year-old girl with EBV encephalopathy.36, 37

Metamorphopsia may precede onset or follow the resolution of all clinical signs and symptoms. The duration of the visual illusion ranges between 2 weeks and 7 months, but with complete recovery in all described cases.35

AIWS diagnosis may be complicated if the visual disturbances precede the classic symptoms of IM or if IM follows a subclinical course.38 Therefore, patients compatible with AIWS symptoms should be suspected for EBV infection.35

Psychiatric complications

Psychotic episodes

Several studies suggest a link between early-life infection and adult schizophrenia and increased prevalence of EBV in the latter. EBV is a known neurotropic infectious agent, since it is a member of the Herpesviridae family. The human brain continues to develop through childhood and early adulthood, thus infection during this period, especially with neurotroping agents, could potentially increase the risk of neurological abnormalities.39

Possible pathophysiological mechanisms include inflammatory cytokines affecting the brain after the activation of the innate immune system. Early-life infection harms microglia, distorting neuronal survival and functioning. It is also believed that there is a connection between genetic psychosis background and vulnerability to infection.39

Fatigue

IM is a specific and strong risk factor for the development of fatigue, subsequently. However, it is possible that doctors are biased, thus overestimating the prevalence of post-IM fatigue compared to that of other viral infections. Conversely, doctors may not record fatigue after IM, considering it as an expected sequel of any viral infection. Fatigue is a subjective symptom and so is difficult to calculate as a feature of the illness. Possible risk markers for fatigue after IM are female sex, premorbid mood disorder, lack of physical fitness, inactivity, and illness perception. These markers may be used to target prevention strategies and explore etiological mechanisms.40

Depression

The association between infectious agents and depression has been controversial. Early clinical studies supported an association of raised antibody titers against HSV and EBV with depression. However, opposing results have also been reported that reveal no significant association between antibodies to HSV, influenza, or neurotropic viruses with depression. Findings suggest that smaller sample-sized studies tend to produce negative results, and identifying a significant association between EBV infection and depression may require a sufficiently large sample size.41

Autoimmunity

The major environmental risk factors for systemic autoimmune diseases are infections.1 EBV has been suggested to be associated with autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, multiple sclerosis (MS), inflammatory bowel diseases, autoimmune thyroiditis, insulin-dependent diabetes mellitus, Sjögren's syndrome, autoimmune liver diseases, systemic sclerosis, and myasthenia gravis.42

One of the main mechanisms of how infections may cause autoimmunity is molecular mimicry. It is believed that sequence or structural similarities between microbial and self-antigens cross-react with B-cells, T-cells, and antibodies. Such examples are anti-citrullinated protein antibodies in RA and autoantibodies against αB-crystallin in MS.42

An additional theory is referred to as bystander activation. In this case, the inflammatory background of an infection promotes activation or expansion of previously activated, autoreactive lymphocytes. Activation and expansion of autoreactive T-cells are known to occur due to the virus-induced severe local inflammation and intense local cytokine production.1 EBV proteins involved in immune evasion and suppression of apoptosis of transformed infected lymphocytes are likely to result in loss of tolerance and development of autoimmunity.42

It has been suggested that raised serum titers of antibodies against EBV in autoimmune diseases could be the result of polyspecific B-cell activation. In response to polyclonal stimuli, memory B-cells proliferate and differentiate into plasma cells; this may depict a natural mechanism for the perpetuation of a lifelong serological immunity.42

Another hypothesis is the accumulation of T-cells, due to EBV frequent reactivation. EBV specific CD8+ T-cells are enriched in or near the diseased organs of patients with RA and MS, and they also accumulate in synovial fluid from patients with psoriatic arthritis, osteoarthritis, and Reiter's syndrome. This could reflect a local immune response against EBV in the diseased organs.42

After many years of viral, immunological, and epidemiological research, it is still debated whether EBV is a causative agent of these autoimmune entities.42

Allergies

Hypersensitivity to mosquito bites

This disease has appeared mostly in Japanese children. More than 50 cases of hypersensitivity to mosquito bites (HMB) have been reported in Japan, and there are several reports of cases in Taiwan and Mexico. HMB is identified by intense local skin symptoms, which comprise bulla, erythema, and ulceration or scarring, and systemic symptoms such as lymphadenopathy, high fever, and hepatosplenomegaly.43

CD4+ T cells from HMB patients react to specific mosquito salivary gland extracts. These T cells induce the reactivation of latent EBV infection in NK cells. EBV-carrying NK cells in HMB patients overexpress surface Fas ligand (Fas L) and the enhanced Fas L might be related to tissue damage, such as excessive skin lesions at mosquito bite sites and liver dysfunction. It has been suggested that these patients show increased expression of viral oncogene LMP1 in EBV-infected NK cells, and the mosquito antigen also increases the expression and induces NK cell proliferation. LMP1 activates various signaling pathways during transformation, including PI3 kinase, Rac, NF-kB, and reactive oxygen signaling.43

Epidemiological observations suggest the possibility of endemic development of HMB, as a result of the patient's genetic background or the impact of multiple environmental factors.43

Neoplasms

It is estimated that each year EBV is responsible for 84,000 cases of gastric carcinomas, 78,000 cases of nasopharyngeal carcinoma, and 28,000 cases of Hodgkin lymphoma. It is notable that the risk of EBV-positive Hodgkin lymphoma culminates at 4 years after IM, while it decreases to normal after 10 years. Each year there are over 6000 cases of EBV associated Burkitt lymphoma (BL) in less developed countries. The prevalence of BL in central Africa is 20 cases per 100,000 in children between the ages of 5 and 9 years.44

EBV is also associated with malignancies in immunocompromised patients. EBV lymphoma, for example, is the second most common malignancy developing after organ transplantation, because of the respective immunodeficiency.44

The most relevant children's neoplasm derived from EBV is Burkitt lymphoma.45 Denis Burkitt observed a form of BL, endemic BL, which is most commonly seen in regions of sub-Saharan Africa. Regions of endemic BL have a very high frequency of disease, roughly 5–10 cases per 100,000 children. Viral genomes can be found in nearly 100% of endemic BL tumors.46

BL occurs worldwide at a much lower incidence in a form known as sporadic BL, which is also seen primarily in children, but has a lower association with EBV infection. Sporadic BL varies from 15% to 85% of viral tumors.46

The contribution of EBV to the pathogenesis of BL is similarly enigmatic. EBV leads to the development of transformed but not malignant lymphoblastoid cell lines (LCLs), by activating the proliferation of B cells. LCLs are responsible for the expression of numerous EBV-encoded latency proteins, many of which modulate key regulatory pathways such as PI3K and NF-kB, which have been solidly linked to cancer. In the absence of functional T cells or during continuous antigen presence, EBV-induced LCLs grow unhindered.47 EBV also inhibits the apoptosis of premalignant tumor cells, allowing transforming events to occur.1 The final steps of the oncogenic pathway are the translocations in MYC and TCF-3 genes. These are the most common mutations caused by EBV, which lead to the production of oncogenic transcription factors in BL.47

X-linked lymphoproliferative disease

Primary EBV infection in boys with X-linked lymphoproliferative disease (XLPD) leads to fulminant, often even fatal disease. In addition, the condition predisposes to considerably elevated incidence of lymphomas.48

Mutation or deletion of the SH2D1A gene causes lack of functional signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), which regulates T-cell apoptosis. The lack of SAP results in uncontrolled proliferation of CD8+ T-lymphocytes leading to XLPD. T-cell apoptosis, which is also inefficient in the IM mostly due to the Epstein–Barr virus nuclear antigen anti-apoptotic function, enhances the effects of SAP absence.48

Discussion

EBV infects virtually everyone by adulthood, and a lifelong latency is maintained. It infects children silently, whereas the majority of adolescents develop IM when infected.17 On rare occasions the symptoms of IM may persist in a chronic or recurrent form, and fatal IM occurs rarely. Depending on the type and degree of immune deficiency and the time the EBV infection occurs in the life cycle, various atypical outcomes can occur.1

These manifestations may be acute, such as genital ulcers and acute dacryocystitis,4, 20 or delayed, such as autoimmunity and atherosclerosis.10, 42 Some of them may be relatively benign like fatigue, allergies, and FNP13, 30, 43 and others may be life-threatening, like splenic rupture and ALF.17 The remaining EBV complications include myocarditis, renal dysfunction, hepatitis, and AAC,8, 19, 24, 25 as well as several hematological, neurological, and respiratory entities.16 Although these manifestations are quite rare, physicians and especially pediatricians should be aware of such cases in order to avoid unnecessary treatment and procedures, since IM would be easily treated only with supportive care.17, 24 When similar signs and symptoms to the aforementioned are present, the differential diagnosis should include EBV as a causative agent. The patient's history is of great importance and may provide the first indications for the appropriate diagnosis. Individualization and optimization of the patient's follow-up would also aid in preventing and treating possible complications.3 In other words, knowledge of these scenarios would be beneficial for both the child's health and the treatment cost, hence improving medical practice.

It is notable that there are many open questions regarding the mentioned manifestations and further studies are needed to elucidate the role of the immunological mechanism of EBV on various target organs.42 The full understanding of these mechanisms and the correlation between EBV and the pathological entities will assist in the treatment and prevention of severe morbidity.

Nonetheless, the immune system is critical in preventing the progression of EBV disease, since the immunological status of the patient plays a crucial role in the subsequent development of pathologies.1 As life expectancy increases and as more manipulations of the immune system are achieved, more unusual manifestations of EBV infection will appear, which will be a diagnostic challenge in the future.

Conflicts of interest

The authors declare no conflicts of interest.

Recommended articlesCiting articles (19)

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☆

Please cite this article as: Bolis V, Karadedos C, Chiotis I, Chaliasos N, Tsabouri S. Atypical manifestations of Epstein–Barr virus in children: a diagnostic challenge. J Pediatr (Rio J). 2016;92:113–21.

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