Epstein-Barr Virus

Author DisclosureDr. Junker did not disclose any financial relationships relevant to this article.After completing this article, readers should be able to: EBV was identified initially in 1964 in tumor tissue from a patient who had African Burkitt lymphoma (BL), a rapidly growing, usually fatal malignancy of the B lymphocyte. When a laboratory technician working with this new virus became ill with mononucleosis and seroconverted to EBV, the link between EBV and mononucleosis became apparent. Soon thereafter, seroepidemiologic studies revealed that EBV infects virtually all of the world’s population, usually as a subclinical or trivial illness in childhood. A decade later, reports of a familial X-linked disorder of fatal infectious mononucleosis highlighted the importance of immunogenetic factors in the management of EBV infection. Now, nearly 40 years after its discovery, EBV continues to captivate clinicians, virologists, oncologists, geneticists, and immunologists attempting to understand this highly successful human pathogen.EBV is a ubiquitous, worldwide pathogen that is harbored persistently by virtually all adults, regardless of geographic location. After primary infection, the virus latently infects circulating B cells and is shed silently into saliva and genital secretions. The colloquial term “kissing disease” acknowledges the oral route by which most people are infected. Spread is associated with close personal contact, so it is not surprising that the age at first infection varies according to living conditions. Infection occurs at an earlier age in the presence of poor hygiene and crowded living conditions; infection rates in young children are higher in developing countries and underprivileged societies. Depending on the population studied, the prevalence of EBV infection during childhood ranges from 20% to 80% by age 2 to 3 years. In industrialized countries that have high standards of living, it is more common for primary EBV infection to occur in adolescence. Infection at this time causes infectious mononucleosis (IM) in 30% to 50% of cases. IM does not show consistent seasonal or yearly variation in occurrence and rarely is associated with temporal clustering of cases. EBV infection of siblings in families can occur, and adult household members can show serologic evidence of recent (re)exposure. EBV also can be transmitted by blood product transfusion and with bone marrow and solid organ transplantation. Sexual transmission is suggested by the demonstration of virus in cervical and male genital secretions and in the significantly greater EBV seroprevalence among sexually active students. Congenital infection after primary disease of mothers during pregnancy is rare, probably because of the very low proportion of EBV-naive women.The two major strains of EBV (EBV type-1 and -2) differ biologically and in their geographic and ethnic prevalences, although they show no clear differences in associated clinical diseases. Minor genetic variations give rise to distinct EBV isolates or substrains. Healthy individuals can be coinfected with more than one distinct EBV isolate. Infection with a new strain may provide the basis for some cases of recurrent IM because initial infection with one EBV strain does not preclude subsequent superinfection.EBV is a gamma-type herpesvirus and shares the special characteristics of lymphotropism and neoplastic association with other members in this group, which includes the most recently identified Kaposi sarcoma-associated virus, human herpesvirus 8 (HHV8). The herpesviruses are large, complex DNA viruses that code approximately 100 proteins. These pathogens have coevolved with their hosts over millions of years, and both parties have developed highly sophisticated strategies for survival.Probably no other virus group has such an impact on the pediatric population. Members include herpes simplex (HSV) 1 and 2; varicella-zoster virus (VZV), the cause of chickenpox and “shingles”; cytomegalovirus (CMV), currently the most common cause of congenital infection; and herpesviruses 6 and 7, causes of exanthema subitum (roseola infantum). The infectiousness of EBV and its propensity to infect children at a young age with mild disease are features in common with these other pathogens. CMV can cause a mononucleosis syndrome, but most children suffer only trivial respiratory infections. Primary HSV infection is common in childhood and subclinical in 85% of cases. HHV6 is a well-recognized cause of nonspecific febrile illness in toddlers.After primary infection, it is usual for all of these viruses to establish a permanent, lifelong infection of their human host. Each virus has a preferred cell type and site of persistence and can reactivate, intermittently, with or in the absence of clinical disease. HSV infects the motor root ganglia, and reactivation can be silent or result in “cold sores.” VZV infects dorsal root ganglia, and reactivation presents as “shingles.” EBV and CMV regularly reactivate, but without signs or symptoms of clinical disease.Unlike the other herpesviruses, it has not been possible to identify EBV in clinical specimens by using traditional virus diagnostic laboratory techniques. EBV was identified initially by electron microscopy in BL cells, but only after these tumor cells had been “shocked” by culture as a cell suspension for some time. EBV does not replicate well in tissue culture systems, does not tend to carry out a full lytic cycle, and, thus, is not cytopathic. This feature means that clinical specimens from patients, even those heavily infected with EBV, are “culture-negative.” EBV has the ability to infect B lymphocytes. Rather than damaging the cells, EBV activates B cells and induces rapid expansion of the infected cell population by increasing cell numbers and extending cell survival. In years past, before the advent of molecular diagnostic tools, the presence of EBV was implied when filtered clinical specimens, applied to cultures of (EBV-naïve) cord blood lymphocytes, led to transformation of these cells into permanently growing, “immortalized” cell lines. EBV has been a valuable tool for immunology studies of B lymphocyte function in vitro because the virus is a potent stimulator of antibody production. Permanently growing B-lymphocyte cell lines, developed by in vitro EBV infection of patient B cells, have provided a sustainable source of material for metabolic and genetic studies.The current belief is that the B lymphocyte provides all the conditions necessary for EBV to maintain its life cycle. A balanced, generally benign, virus-host relationship has evolved, making it beneficial for both virus and host for EBV to adopt a strictly latent state in blood. If active and replicating, EBV can spread and infect tissues, but it also is vulnerable to rapid detection and elimination by cytotoxic T cells and natural killer (NK) cells. Residing in resting peripheral blood B cells, EBV remains virtually invisible to the immune system by expressing very few virus proteins. For years after acute EBV infection, latently infected B cells in peripheral blood are present at a frequency that ranges from 1 to 60/106 B cells (∼10 mL of blood). Each cell carries approximately two to five copies of an intact circular (latent, episomal) viral genome. Healthy individuals infected with EBV shed infectious EBV silently, sometimes continuously, into saliva and genital secretions. The source of this virus is believed to be B cells that have become activated and circulated to the mucosal epithelium. Mucosal shedding facilitates viral spread to susceptible individuals and possibly plays a role in bolstering local defenses against infection with new EBV strains.The patterns of antibody responses to EBV antigens were delineated soon after their discovery. Antibodies develop during acute infection to lytic cycle proteins, including membrane antigen, virus capsid antigen (VCA), and early antigens, and appear during convalescence to the latency-associated virus nuclear antigens (EBNA). Antibodies have little role in control of established EBV infection. Much work has been done to define the specific features of immunity that protect against infection, which is important for vaccine development. The lack of a permissive virus culture system and difficulty in handling T lymphocytes in vitro have delayed analysis of EBV-directed cellular immune responses, despite their obvious importance in managing EBV infection. Individuals who have congenital or acquired cellular immunodeficiency disorders suffer more complications, even death, with primary EBV infection and are less able to maintain the virus in a latent state. In the absence of effective cellular immunity, EBV promotes activation and proliferation of its host B cell, leading to B-lymphoproliferative disorders and risk for malignant transformation.Based on epidemiologic studies and because it is usual for patients who develop IM to have peak VCA-immunoglobulin (Ig)G levels at presentation, it is believed that EBV infection occurs at least 30 days prior to the appearance of IM signs and symptoms. There is a paucity of information about the events of early infection and an increasing suspicion that IM represents an eventually contained, but not normal, lymphoproliferative disorder. Host reactions account for the clinical manifestations of IM. The course of IM closely parallels the lymphoproliferative phase, in which there is a massive increase in the number of activated cytotoxic CD8+ T cells directed primarily against EBV lytic cycle proteins. This T-cellular response accounts for the traditional hematologic criteria of IM (absolute and atypical lymphocytosis) and the characteristic signs of lymphadenopathy, hepatomegaly, and splenomegaly. Fever and fatigue result from a massive T cell-induced production of cytokines, which include lymphotoxin, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6. Disease features resolve as EBV DNA levels in serum fall and T-cell numbers normalize. The reason for this exaggerated T-cell response that focuses on a few immunodominant epitopes of the virus lytic cycle is not clear, but this response distinguishes IM from asymptomatic primary EBV infection in which homeostatic T-cell numbers and diversity are maintained. In both circumstances, systemic EBV DNA levels are high, but there is an intriguing speculation that EBV establishes a different form of infection and pattern of gene expression in these two conditions. EBV DNA detected in IM could derive from virus replication and cell lysis; the DNA in asymptomatic primary infection could derive from B cells driven to proliferate by the virus.Complications occur in about 20% of patients recently infected with EBV; essentially no body system is free from potential harm. The respiratory, neurologic, and hematologic systems are involved most frequently. Airway obstruction resulting from the virus-induced B-cell proliferation and reactive T-cell expansion can be life-threatening and is the most common reason for hospital admission.Neurologic complications occur in about 5% of patients. EBV has been implicated in virtually every form of infection-related neurologic disorder. Quantitative polymerase chain reaction (PCR) and detection of EBV lytic cycle messenger RNA (mRNA) in cerebrospinal fluid indicates that direct EBV infection of the central nervous system is one mechanism of neuropathology.EBV is renowned for its intriguing ability to activate B lymphocytes to produce antibodies. During acute IM, about 1/5,000 (0.02%) peripheral blood B cells are infected with EBV, which is associated with the transient appearance of unusual antibodies, including heterophile (which forms the basis of the rapid “mono” tests), Wasserman, rheumatoid factor-like, cold agglutinins of anti-i specificity, and antinuclear antibodies. Autoreactive antibodies cause some of the more frequent hematologic complications, including immune hemolytic anemia or immune thrombocytopenia. About 10% of preschool-age children develop neutropenia that is characterized by fewer than 0.5×109 cells. It has been proposed that the heterophile antibody, which nonspecifically agglutinates red blood cells of other species, is an autoantibody that recognizes an antigen expressed on the human fetal erythrocyte. This abnormal antibody, a sign of B-cell activation, can be present up to 1 year after acute infection; a longer duration of detectable antibody correlates with the greater geometric mean titer found in acute sera. Generally, increased levels of Ig increase the propensity for immune complexes to be formed, which may account for other disease-associated features such as rash, myalgia, and arthralgia.Symptomatic acute EBV infection is recognized clinically as IM, characterized by fever, tonsillopharyngitis, hepatosplenomegaly, lymphadenopathy, and increased numbers of activated CD8+ T cells. The fever, present for 1 to 3 weeks, can range from a temperature of 99.5° to 104.9° F (37.5° to 40.5°C) (rectally). Lymph nodes are moderately tender and firm, but discrete. Cervical nodes, particularly those in the posterior chain, are involved principally, although generalized adenopathy can occur. The pharyngitis can vary from a mild erythema to a very painful throat that has a thick gray-white exudate. In young children, EBV seroconversion can be associated with nonbacterial tonsillitis or other poorly differentiated respiratory tract illness and enteric syndromes. Very young children may be more susceptible to failure to thrive (preceding manifestations of IM), pneumonia, and otitis media. However, classic EBV-IM is common in children and can occur in infants. The clinical picture and course of disease in young children is similar to that of adults.A distinct fatigue syndrome is associated with IM, lasting about 8 weeks; resolution generally coincides with normalization of T-cell responses. No objective measures characterize self-reported continuance of fatigue after IM.Antibiotic administration, particularly of ampicillin, has been linked to the subsequent development of rash in older patients who have IM. Rash occurs with IM in about 4% of older patients not receiving antibiotics; involves the trunk and face; and can be maculopapular, scarlatiniform, papulovesicular, urticarial, or hemorrhagic. Rash occurs with ampicillin treatment in about 10% of patients who do not have EBV infection. However, rash can develop in up to 100% of older IM patients receiving ampicillin. In young children, there may be no relationship between antibiotic administration and the occurrence of rashes. Patients who develop rashes while receiving antibiotics should not be deemed permanently hypersensitive to the drug without subsequent documentation by appropriate skin test and challenge studies. Consistent with EBV-induced B-cell activation, patients who have IM can show a transient rise in benzyl-penicilloyl-specific IgM antibodies that purportedly cause the reaction.Patients who have XLP can suffer extreme complications of EBV infection. More than 50% of boys who have XLP present with overwhelming IM at approximately age 5 years, and only 4% survive. Considerable, and as yet unexplained, variation occurs in the phenotypic expression of XLP among individuals within families and between pedigrees who have the same mutation and molecular effect. Other XLP-associated conditions include: 1) no disease, even with documented EBV infection, 2) dysgammaglobulinemia or common variable immunodeficiency, 3) aplastic anemia, 4) lymphoma, and 5) lymphoid granulomatosis with vasculitis. An XLP gene defect should be considered, even in the absence of a family history, in boys who present with variable immunodeficiency or an unusual lymphoproliferative disorder with or without evidence of EBV infection.Unusual EBV infiltration into immune cells other than B cells characterizes these often fatal disorders, which present with intense, prolonged (>6 mo) signs of EBV-related illness, including fever, marked lymphadenopathy, severe hepatosplenomegaly, hepatitis, interstitial pneumonitis, and pancytopenia. Histiocytic erythrophagocytosis in bone marrow and secondary lymphoid organs distinguish EBV-HLH. In the acute phase of EBV-HLH, activated CD8+ T cells are the principal targets of EBV infection. Hypersensitivity to mosquito bites, characterized by a bulla developing into necrosis, is an unusual associated feature of CAEBV. CD4+, CD8+, and NK cells are infected in CAEBV. It is not known if EBV infection of cells other than B cells causes these disorders or if the patients have a yet undefined primary susceptibility that makes them more inclined to this pattern of infection.EBV-associated occurs in about 10% of and the risk is for those who primary EBV infection while receiving high of the is increased in The organ is a common of EBV infection, and because is in the to occur early after is present in about of African the most frequent tumor in children 5 to years in EBV infection during the first after the risk of developing is a important The of BL has in the of has been by mosquito from BL is by the cell which infection. BL or have a or that the on 8 into one of the gene resulting in its which cell proliferation and of associated with T-cell and to increased activation of B cells and the potential for malignant is regardless of geographic location. In is the most common malignancy in and most common in cells latent EBV but the events leading to tumor have not been that virtually worldwide eventually is infected with this virus, the of EBV-related malignancy is studies of and other that factors are involved in the development of EBV-related malignancy in These factors include such as and genetic and temporal events such as age at first infection and to factors such as and is associated with about 50% of in a higher in developing and virtually 100% of EBV have been to cells that are recognized as B DNA has been identified in an increasing number of T-cell including and lymphoma, lymphadenopathy, and peripheral T-cell It is malignancy in these association of EBV with on geographic and More than 80% of the type of are with is associated with a risk for primary EBV infection can be implicated with the appearance of characteristic clinical signs and symptoms of IM and the hematologic criteria of and atypical the presence of heterophile antibody virtually acute EBV infection, and there usually is no reason for diagnostic very young children do not produce heterophile antibodies, there is a increase with age in children who have IM syndrome and produce detectable heterophile antibody is detected in more than 80% of children who have IM by age years. IM patients and those who have no classic IM features in EBV infection is serologic is present in more than 80% of acute and is the most valuable serologic of on the serologic linked generally are more than are traditional persistence of in the very young to and it is possible to is the potential for such that EBV-directed IgM antibodies with antigens from other herpesviruses such as can be detected in virtually 100% of acute IM and is of no diagnostic in IM. However, and seroconversion can EBV of EBV DNA by is a diagnostic of virus in serum or from patients is and specific for primary infection. of viral by or is in and lymphoproliferative disorders and with in it is not possible to be that a are to acute primary EBV infection. Other pathogens are of an lymphoproliferative response and, in cause a mononucleosis Other and conditions can be associated with B-lymphocyte activation, resulting in heterophile antibody and other abnormal antibody production. The detection of EBV in secretions or molecular is not to acute to acute EBV infection and its complications it is a usual but little evidence the that such the disease course or and should be the no longer is often are for management of obstruction or severe only evidence their to be by moderately ill patients with IM patients show no differences with in of resolution or of or on the The the replication of EBV DNA of the virus DNA treatment oral EBV but it does not levels of B cells. the symptoms and signs of IM to the T-cell it is not surprising that there is no evidence for the course of IM.

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