Clinical manifestations and treatment of Epstein-Barr virus infection

INTRODUCTION — Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is spread by intimate contact between susceptible persons and asymptomatic EBV shedders. EBV is the primary agent of infectious mononucleosis (IM), persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas, T cell lymphomas, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinomas in certain patients [1]. Reactivation disease is not a prominent issue with EBV, in contrast to other common herpesviruses, but it has been associated with an aggressive lymphoproliferative disorder in transplant recipients [2]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

The clinical manifestations and treatment of EBV infections will be reviewed here. The diagnosis of EBV as pertains to infectious mononucleosis is discussed separately. (See "Infectious mononucleosis".)

EPIDEMIOLOGY — Most primary EBV infections throughout the world are subclinical. There are two major EBV Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution. Approximately 90 to 95 percent of adults are EBV antibody seropositive; however, studies suggest that primary EBV infection may be occurring at a later age in children residing in the developed world. As an example, in a large public university in the United States, the seroprevalence of EBV antibodies among entering freshman declined from 64 percent in 2006 to 52 percent in 2022 [3,4].

VIROLOGY — Like other members of the herpesvirus family, EBV has a latency phase. The principal human host cells for EBV are limited to B lymphocytes, T lymphocytes, NK cells, epithelial cells and myocytes. Unlike herpes simplex (HSV) or cytomegalovirus (CMV), EBV is capable of transforming B cells but does not routinely display a cytopathic effect. A detailed discussion of the virology of EBV is found elsewhere. (See "Virology of Epstein-Barr virus".)

PRIMARY INFECTION — Primary EBV infection can cause a number of clinical manifestations, can lead to complications, and can induce a variety of malignancies.

Acute infectious mononucleosis — Infectious mononucleosis (IM) is the best known acute clinical manifestation of EBV [3,5]. IM often begins with malaise, headache, and low-grade fever before development of the more specific signs of tonsillitis and/or pharyngitis, cervical lymph node enlargement and tenderness, and moderate to high fever [6]. Affected patients usually have peripheral blood lymphocytosis, with atypical lymphocytes (picture 1). (See "Infectious mononucleosis", section on 'Hematologic abnormalities'.)

The lymphadenopathy characteristically is symmetric and involves the posterior cervical chain more than the anterior chain. Tonsillar exudate is a frequent component of the pharyngitis; the exudate can have a white, gray-green, or necrotic appearance.

Severe fatigue may be prominent, while other less common findings include palatal petechiae, periorbital or palpebral edema, and maculopapular or morbilliform rashes. Nausea, vomiting, and anorexia are frequent in patients with IM, probably reflecting the mild hepatitis encountered in about 90 percent of infected individuals. Splenomegaly occurs in as many as 50 percent of patients, but jaundice and hepatomegaly are uncommon.

Most patients with IM caused by EBV have prominent pharyngeal symptoms [7]. There are, however, several other forms of the illness. Some individuals with IM present with the so-called "glandular" form of the disease in which lymph node enlargement is out of proportion to the pharyngeal symptoms; others develop a systemic form of the infection in which fever and fatigue predominate, while lymphadenopathy and pharyngitis are mild or absent. Some patients have hepatitis in the absence of other typical features of IM. One study suggests that the onset and severity of IM is related to past infections with other viruses, like influenza virus, which expand the numbers of T cells that react to EBV infection [8].

Most individuals with primary EBV infection recover uneventfully and develop a high degree of durable immunity. Acute symptoms resolve in one to two weeks, but fatigue often persists for weeks to months.

Primary EBV infection in infants and children — Primary EBV infections in young infants and children are common and frequently asymptomatic. When symptoms do occur, a variety of manifestations have been observed, including otitis media, diarrhea, abdominal complaints, upper respiratory infection, and IM [9,10].

One series described 32 children younger than four years of age with IM, who were selected from a population of 200 children by review of blood smears (more than 50 percent mononuclear cells and more than 10 percent atypical lymphocytes) [10]. Most of these children had clinical manifestations compatible with IM (significant cervical adenopathy and tonsillar pharyngitis); respiratory symptoms were frequently prominent, especially in young infants.

In this series, the heterophile antibody test was only positive in 27 percent of children ages 10 to 24 months, whereas antiviral capsid antigen (VCA) IgM was positive in 60 percent of infants [10]. Since the heterophile antibody tests are more likely to be negative in infants and children younger than four years of age compared with older children, EBV-specific serologic studies are typically required to establish the diagnosis. A discussion of diagnostic testing is presented elsewhere. (See "Infectious mononucleosis", section on 'Diagnosis'.)

Congenital and perinatal infections — Intrauterine infection with EBV is rare because fewer than 5 percent of pregnant women are susceptible to the virus. In addition, prospective studies of susceptible (ie, seronegative) women have not found evidence of congenital abnormalities among infants of women who did develop primary EBV infection during pregnancy [11]. While isolated cases of infants with some evidence for EBV infection and congenital anomalies (biliary atresia, congenital heart disease, hypotonia, micrognathia, cataracts and thrombocytopenia) have been reported [12], the evidence argues against EBV as a significant cause of congenital infection. Specifically, no evidence of EBV infection has been demonstrated in large studies of children with congenital anomalies or in cord blood samples [13].

Other manifestations — EBV can affect virtually any organ system and has been associated with such diverse disease manifestations as pneumonia, myocarditis, pancreatitis, mesenteric adenitis, myositis, glomerulonephritis, and genital ulceration [14]. A number of other uncommon manifestations have also been associated with primary EBV infection:

●Neurologic syndromes can include Guillain-Barré syndrome, facial nerve palsy, meningoencephalitis, aseptic meningitis, transverse myelitis, peripheral neuritis, and optic neuritis [15].

●Hematologic abnormalities can include hemolytic anemia, thrombocytopenia, aplastic anemia, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, and disseminated intravascular coagulation.

COMPLICATIONS — EBV infection is associated with a number of acute complications and, in certain hosts, more delayed effects.

Acute complications of infectious mononucleosis

Rash — One of the more common complications of infectious mononucleosis (IM) is a morbilliform rash, which may follow the administration of ampicillin and, to a lesser extent, penicillin or other antibiotics. The incidence was initially reported to be as high as 70 to 90 percent but appears to be much lower. A more detailed discussion of rash in the setting of IM is presented elsewhere. (See "Infectious mononucleosis", section on 'Rash'.)

Airway obstruction — Obstruction of the upper airway due to massive lymphoid hyperplasia and mucosal edema is an uncommon but potentially fatal complication of IM. Severe obstruction can be successfully treated by tracheotomy or endotracheal intubation. The use of corticosteroids to reduce pharyngeal edema and lymphoid hypertrophy is advocated for individuals with incipient obstruction. (See 'Corticosteroids' below.)

Splenic rupture — Splenic rupture is a rare and potentially life-threatening complication of IM and is estimated to occur in approximately one to two cases per thousand [16,17]. Almost all cases have been in males. Several observations about splenic rupture have been made:

●Splenic rupture may be the first symptom of IM that brings the patient to medical attention; it is spontaneous in more than one-half of reported cases, with no history of a specific injury.

●For those patients who had previously been seen by a physician, the spleen was not palpably enlarged in approximately one-half despite its two- to threefold increase in size (based upon surgical evaluation).

●Rupture typically occurs between the 4^th and 21^st day of symptomatic illness and does not correlate with the clinical severity of IM or with laboratory findings.

Despite its life-threatening potential, fatality from this complication is rare. The management of splenic rupture is similar to other forms of splenic injury. Nonoperative treatment with intensive supportive care and splenic preservation has been successfully carried out in some cases, while others require splenectomy [18].

A discussion on how to prevent splenic rupture is found elsewhere. (See "Infectious mononucleosis", section on 'Avoiding splenic rupture'.)

Lemierre's disease — Case series suggest that there may be an association between IM and subsequent Lemierre's disease [19,20]. As an example, in one series that evaluated five patients diagnosed with Lemierre’s disease over a six-year period, three had evidence of acute EBV infection, including one related to Fusobacterium necrophorum [19]. However, in a larger series that evaluated 23 patients with Lemierre's syndrome related to F. necrophorum, only one patient had evidence of concomitant mononucleosis [21]. In that series, another patient who died from Lemierre's syndrome had a high number of EBV copies in the CSF and serum; however, it was unclear if the patient had acute EBV since anti-EBV antibodies were not obtained.

Delayed complications

Chronic active EBV infection — Chronic active Epstein-Barr virus (CAEBV) infection is a rare, life-threatening lymphoproliferative disorder that may involve B lymphocytes, T lymphocytes, or NK cells. The syndrome is characterized by a persistent infectious mononucleosis (IM)-like syndrome and EBV viremia [22]. Clinical manifestations may include fever, swelling of lymph nodes, and hepatosplenomegaly along with liver function test abnormalities and cytopenias [23]. Patients with untreated T cell CAEBV often develop systemic organ disease due to T cell infiltration of tissues, hemophagocytic lymphocytosis, liver failure, or coronary artery aneurysms [24,25].

Diagnostic criteria are not well defined, but the presence of persistent viremia and hypogammaglobulinemia, as well as the detection of a clonal proliferation of B, T, or NK cell population, support the diagnosis [26]. A common misconception is to label patients with fatigue alone as having chronic EBV based only upon positive serologic markers without any of the above abnormalities. However, IgG antibodies to antiviral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) are present for life in patients with prior EBV exposure and are not markers of an active process suggesting true chronic active EBV infection. (See "Infectious mononucleosis", section on 'EBV-specific antibodies'.)

While the pathogenesis is not well understood, EBV infection of hematopoietic stem cells may be the initiating factor in CAEBV [27]. EBV sequencing studies have found that certain intragenic deletions are associated with CAEBV and NK lymphoproliferative disorders [28]. Early data suggest the effect of the deletions is to simultaneously promote more efficient lytic cycle reactivation, avert cell lysis, and drive lymphomagenesis.

The only treatment regimen that has been curative is hematopoietic stem cell transplantation [25,29]. Other treatment options that have been used include high-dose corticosteroids or antiviral therapy (eg, ganciclovir) used individually or in combination with proteasome inhibitors (eg, bortezomib) or histone deacetylase inhibitors [30].

EBV infection has received a great deal of attention as a possible etiologic agent for chronic fatigue syndrome (CFS). This topic is discussed in detail elsewhere. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome".)

Multiple sclerosis (MS) — EBV infection has been associated with MS for several decades. Early studies showed that EBV infection was more prevalent in patients with MS and that EBV-specific antibodies were higher when compared with controls [31]. Subsequent seroepidemiologic studies further supported EBV as a cofactor for the development of MS [32]. A cohort study, which compared 801 individuals who developed MS with 1577 controls, found that the risk of developing MS was 32-fold higher following EBV infection but not after infection with other viruses [33].

Mechanistic studies to explain the role of EBV in the pathogenesis of MS are incomplete with molecular mimicry recently being the most plausible hypothesis [34,35].

Oral hairy leukoplakia — Another EBV-mediated mucocutaneous manifestation is oral hairy leukoplakia (OHL), which is an unusual disease of the lingual squamous epithelium [36]. OHL generally affects the lateral portions of the tongue, although the floor of the mouth, the palate, or the buccal mucosa may also be involved. The lesions are described as white corrugated painless plaques that, unlike candida, cannot be scraped from the surface to which they adhere (picture 2). They are not generally associated with fever.

The OHL lesions, while initially described in individuals with human immunodeficiency virus (HIV) infection, can also be seen in other immunocompromised patients (eg, organ transplant recipients, patients with malignancy, those receiving systemic or inhaled steroids) [36-38]. Rare cases have been reported in immunocompetent individuals, but evaluation for underlying immune suppression has not always been reported [38]. The use of potent antiretroviral therapy appears to have reduced the incidence of OHL in persons with HIV [39,40].

OHL is associated with intense EBV replication and the action of EBV-encoded proteins such as latent membrane protein-1 [36]. In addition, studies in which EBV replication has been suppressed by valacyclovir have demonstrated persistent, nonproductive EBV infection and continued EBV entry from the blood into the tongue [41]. These observations suggest a role for entry, persistence, and reactivation of oral epithelial EBV in the pathogenesis of OHL.

OHL is not considered a premalignant lesion, being unlikely to progress to squamous cell carcinoma [36]. Anecdotal treatment with zidovudine, acyclovir, ganciclovir, foscarnet, and topical podophyllin or isotretinoin has been reported, although therapy is usually not indicated.

Lymphoproliferative disorders — EBV infection is associated with a variety of lymphoproliferative disorders [42]. More than a dozen single gene mutations causing primary immune deficiency disorders are associated with severe EBV–induced disease [43,44].

Hemophagocytic lymphohistiocytosis — EBV is one of the recognized initiating causes of hemophagocytic lymphohistiocytosis (HLH), a potentially fatal disorder characterized clinically by persistent fever, hepatosplenomegaly, cytopenias and characterized pathologically by generalized histiocytic proliferation and hemophagocytosis (picture 3) [45]. Patients with this unusual syndrome present with fever, generalized lymphadenopathy, hepatosplenomegaly, hepatitis, pancytopenia and coagulopathy. T cell proliferation is a primary feature of HLH. The pathogenesis, diagnosis and treatment of this disorder are discussed in detail elsewhere. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Lymphomatoid granulomatosis — Lymphomatoid granulomatosis is an angiodestructive disorder of the lymphoid system, which has been associated with EBV infection. In most cases, EBV infected B cells are present, and the B cell proliferation is clonal [46,47]. Patients often have evidence of immunodeficiency including congenital and acquired conditions such as HIV infection [48]. Clinical features include fever, cough, malaise, weight loss, with involvement of lung, kidney, liver, skin and subcutaneous tissue, and the central nervous system (CNS) with typical histologic changes [49-51]. It appears to arise from EBV-infected B cells and affected patients may respond to interferon alfa [52]. (See "Pulmonary lymphomatoid granulomatosis".)

X-linked lymphoproliferative disease — X-linked lymphoproliferative (XLP) disease is characterized by a selective immunodeficiency to EBV, manifested by severe or fatal IM and acquired immunodeficiency [43]. Two genetic defects that cause XLP have been identified. XLP1, the more common of the two forms, is due to a defect in a gene (ie, SH2D1A) that encodes a protein, which plays an important role in signal transduction pathways in T lymphocytes. This mutation prevents normal activation-induced cell death, resulting in the uncontrolled CD8 T cell proliferation that is observed in patients with XLP. XLP2 is due to a defect in the XIAP gene that encodes the X-linked inhibitor of apoptosis. (See "X-linked lymphoproliferative disease".)

Post-transplant lymphoproliferative disease — EBV is associated with the majority of cases of post-transplant lymphoproliferative disease (PTLD) [53]. The abnormalities range from benign polyclonal B cell proliferation to malignant B cell lymphoma. The frequency of PTLD is related to the degree and type of immunosuppression and is most common in EBV-negative recipients who develop primary EBV infection, usually from a graft from an EBV-positive donor [54]. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

MALIGNANCY — EBV is a transforming virus and has been causally linked to a variety of malignancies, including lymphomas in transplant recipients [42]. Malignancies include Burkitt lymphoma, tumors in patients with HIV, Hodgkin lymphoma, nasopharyngeal and other head and neck carcinomas, gastric carcinoma, and T cell lymphoma. Recent studies by Li et al have shown that EBNA 1, the only EBV protein expressed in all EBV-associated malignancies, binds to a specific palindromic DNA sequence on chromosome 11 resulting in breaks and genome instability [55]. (See "Overview of the pathobiology of the non-Hodgkin lymphomas" and "Epidemiology and risk factors for head and neck cancer".)

Burkitt lymphoma — Burkitt lymphoma (BL), which is characteristically localized in the jaw, is the most common childhood malignancy in equatorial Africa [56]. More than 95 percent of African children are infected with EBV by age three, whereas, in affluent countries, primary infection is often delayed until adolescence [57].

Tumor cells from areas where BL is endemic contain copies of the EBV genome more frequently than sporadic cases of BL from areas of low incidence (>95 percent versus 15 to 20 percent) [58,59]. Analysis of the EBV genome terminal repeat frequency in endemic Burkitt lymphomas has demonstrated that the tumors originate in the lineage of a single EBV-infected B cell [60-62].

Malignant cells obtained from fresh tumor biopsies consistently display a homogeneous surface phenotype including the pan B cell marker CD20, the common acute lymphoblastic leukemia antigen (CALLA, CD10), and the BL-associated antigen (CD77) [63]. These cells do not express the B cell activation antigens CD23, CD30, CD39, and CD70 or the cell adhesion molecules LFA-1 (CD11a/18), ICAM-1 (CD54), and LFA-3 (CD58) [64,65]. Fresh BL tumor cells retain a resting B cell phenotype and typically express only EBNA-1 [66]. (See "Virology of Epstein-Barr virus" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Immunophenotype'.)

The internal Gly-Ala repeat of EBNA-1 inhibits antigen processing of peptides recognized by EBV specific cytotoxic lymphocytes [67]. This observation, along with reduced expression of MHC class I antigens [68] and the lack of adhesion molecules [64,65], probably contribute to the ability of these cells to escape T cell-mediated destruction.

Effect of coinfection with malaria — Malaria and EBV infection are considered cofactors in the genesis of Burkitt lymphoma [69]. An epidemiologic link is suggested by the number of endemic cases that occur in discrete geographic climates located along the malaria belt across Africa.

Various hypotheses have been proposed to explain the role of malaria in pathogenesis. These include:

●Acute malaria infection may increase the EBV viremia set point. One study of quantitative EBV genome loads within peripheral blood mononuclear cells among 57 EBV-seropositive Gambian children suggested that acute malaria was associated with a sixfold increase in viremia compared to age-matched EBV-seropositive controls without malaria [70].

●Malaria may provide a chronic stimulus for reactivation of EBV in latently infected B lymphocytes [69]. In one study of 43 children with malaria, anti-malarial therapy led to a significant decline in EBV deoxyribonucleic acid (DNA) plasma levels by day 14 of treatment [57]. The clearance of circulating EBV after antimalarial treatment suggests a direct relationship between active malaria infection and reactivation of EBV.

●Chronic reactivation of EBV, caused by malaria infection, may impair EBV-specific T cell immunity through exhaustion and lead to loss of viral control [69].

These findings correlate with epidemiologic data, which show a peak incidence of Burkitt lymphoma in children ranging in age from five to nine years.

Malignancies and HIV infection — Among persons with HIV, EBV infection has been associated with non-Hodgkin lymphoma and, in children, smooth muscle tumors. Oral hairy leukoplakia is another EBV-induced manifestation in HIV-infected patients but is not considered to represent a premalignant lesion [36]. (See 'Rash' above.)

●Non-Hodgkin lymphoma – Non-Hodgkin lymphomas (NHL) occur approximately 60 to 100 times more frequently than expected in patients infected with the human immunodeficiency virus (HIV) [71,72]. These tumors are often associated with EBV infection [73,74]. A study conducted in Los Angeles county from 1984 to 1992 showed that EBV was associated with 39 of 59 (66 percent) HIV-related systemic lymphomas [73]. Analysis of EBV terminal repeats in these lymphomas again confirmed their monoclonal origin, and c-myc rearrangements were noted in 40 percent. (See "HIV-related lymphomas: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Given the profound immune defects in some HIV-infected patients, along with the known role of cytotoxic lymphocytes in controlling EBV-induced proliferation, it is not surprising that the number of EBV-infected B cells in the peripheral blood of patients with HIV may be higher than in the general population [75]. Furthermore, the development of lymphoma may be preceded by a decline in EBV-specific cytotoxic lymphocytes, suggesting that failing EBV control may be an important pathogenetic step [76].

HIV associated NHL, usually of B cell origin, is a relatively late manifestation of HIV infection [71,77]. For unknown reasons, a much higher percentage of EBV-associated NHLs in HIV-infected patients present as primary CNS lymphomas [72]. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)

●Smooth muscle tumors – Children infected with HIV appear to have a higher propensity for developing smooth muscle tumors (leiomyomas and leiomyosarcomas), which are ordinarily very rare [78,79]. EBV probably plays a pathogenic role in the development of these tumors as illustrated by the following observations:

•EBV can infect smooth muscle cells in HIV-infected individuals, and high levels of EBV genomes have been found in tumor tissue [79]

•Smooth-muscle tumors containing clonal EBV developed in three children after liver transplantation [80].

Hodgkin lymphoma — EBV genomic DNA was first reported in tissue specimens from patients with Hodgkin lymphoma (HL) in 1987 [81]. The finding that the malignant cells in HL, including the characteristic Reed-Sternberg cells, contain the EBV genome in up to 50 percent of "Western" cases supports a pathogenic role for EBV in this malignancy [82]. One retrospective study of 34 patients also demonstrated a strong association between EBV infection and HL-associated hemophagocytic syndrome; 94 percent of tumor cells from nodal and extranodal tissues had EBV antigens as measured by immunoperoxidase techniques and in situ hybridization [83].

While Burkitt lymphoma has distinct geographic predilections, it appears that the epidemiology of HL associated with EBV is more complex. In a number of South American countries, a high percentage of cases of classical HL have been found to contain EBV transcripts within Reed-Sternberg cells (94 percent in Peru) [84]. However, geography does not appear to be the critical determinant for the prevalence of EBV-associated HL.

●In one study comparing cases in Kenya and Japan, EBV-encoded ribonucleic acid (RNA) (EBER-1) was detected in 79 and 59 percent of cases, respectively, and in 100 percent of patients younger than the age of 9 years in both countries [85].

●Comparing EBV-associated cases of HL in Brazil and the United States adjusting for histiotype, EBV was linked to Reed-Sternberg cells and their variants and to age ≤10 years, not to geography [86].

Healthy western populations are infected with predominantly type 1 EBV [87], and not surprisingly, the majority of EBV detected in HL is type 1 [88]. In contrast, there is an almost equal frequency of type 1 and type 2 EBV in HIV-associated NHL [89] and endemic Burkitt lymphoma [90].

The type of EBV latency in HL most closely resembles the type-II latency described in nasopharyngeal carcinoma [91]. EBER-1 and latency membrane protein- (LMP) 1 are the two EBV markers most often expressed in HL [92]. (See "Virology of Epstein-Barr virus".)

Nasopharyngeal carcinoma — Nasopharyngeal carcinoma is relatively rare in most populations. However, it is one of the most common cancers in southern China with age-adjusted incidence rates of up to 55 per 100,000 [93]. In contrast to Burkitt lymphoma, the association of EBV with nasopharyngeal carcinoma is highly consistent in both low- and high-incidence areas and EBV is present in every anaplastic nasopharyngeal carcinoma cell [94]. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

A large body of evidence supports the role of EBV as the primary etiologic agent in the pathogenesis of nasopharyngeal carcinoma, although the great majority of EBV-infected patients in China do not develop this tumor [95]. The presence of a single clonal form of EBV in preinvasive lesions, such as nasopharyngeal dysplasia or carcinoma in situ, indicates that EBV-induced cellular proliferation precedes invasion of these tumors [96].

Nasopharyngeal carcinoma cells express a specific subgroup of EBV latent proteins, including EBNA-1 and two integral membrane proteins, LMP-1 and LMP-2, along with the BamHI-A fragment of the EBV genome [97,98]. The recent work by Li et al have shown that 81 percent of NPCs show structural variations on chromosome 11 consistent with the genome instability induced by EBNA 1 [55]. In light of the molecular link between LMP-1 and cell growth [99], the universal presence of LMP-1 in nasopharyngeal carcinoma makes it a likely prerequisite for this multistep neoplastic transformation. (See "Virology of Epstein-Barr virus".)

Gastric carcinoma — It is estimated that 9 to 10 percent of gastric carcinomas worldwide carry the EBV genome. EBV-induced gastric carcinoma may be one of the most common EBV malignancies. The type of EBV latency in gastric carcinomas most closely resembles EBV type 1 latency pattern with EBNA-1 driven by the Qp promoter.

EBV-induced gastric carcinomas usually involve the upper third of the stomach and, like nasopharyngeal carcinoma, levels of EBV VCA IgA antibodies are higher in individuals who subsequently develop EBV-induced gastric carcinoma compared with controls [100].

T cell lymphoma — T cells are also susceptible to EBV infection as illustrated in studies of EBV-infected tonsillar tissues in individuals with IM [101]. This observation is consistent with the description of T cell lymphomas in individuals with chronic EBV infection [102]. The expression of EBV latent genes EBNA-1, LMP-1, LMP-2 has been demonstrated in EBV-associated peripheral T cell lymphomas similar to the expression in nasopharyngeal carcinoma [103].

A fulminant form of T cell lymphoma has been described following acute EBV infection. One series of five patients described a clinical illness characterized by fever, hepatosplenomegaly and pancytopenia; significant erythrophagocytosis was detected in tissue specimen [104]. The disease was uniformly fatal. Molecular analysis demonstrated clonal proliferation of otherwise morphologically unimpressive T cells. Serologic markers for EBV in serum were variable in these cases, but EBER1 of EBV was present in the majority of cells by in situ hybridization and polymerase chain reaction revealed clonal gene rearrangements in all but one case.

Nasal/nasal type angiocentric lymphoma — Nasal/nasal type angiocentric lymphomas are rare diseases that are endemic to Asian countries as well as Central and South America [105-107]. The sites of involvement include the nasal septum, palate, GI tract, and less commonly skin, testis and peripheral nerve. EBV is found in virtually all cases in the neoplastic cells. Although originally thought to be T cells, the malignant cells express CD2, CD56 but lack CD3 and T cell receptor gene rearrangements [108]. Thus, these tumors are probably of NK cell origin.

DIAGNOSIS — EBV infection is suspected when patients present with typical signs and symptoms, and supportive evidence for infection is derived from the peripheral blood smear and antibody studies.

The diagnosis of EBV infection is discussed primarily in the context of infectious mononucleosis, and a detailed discussion of the diagnosis of this disorder is found separately. Although this topic is devoted to patients with infectious mononucleosis, patients with other manifestations of suspected EBV infection can also be diagnosed using these serologic and virologic methods. (See "Infectious mononucleosis", section on 'Diagnosis'.)

TREATMENT — Primary EBV infections rarely require more than supportive therapy. Even in clinical situations where an antiviral or immunomodulatory treatment would be desirable, it is not clear that EBV responds.

Symptomatic treatment — The mainstay of treatment for individuals with infectious mononucleosis (IM) and other manifestations of primary EBV disease is supportive care. Acetaminophen or nonsteroidal antiinflammatory drugs are recommended for the treatment of fever, throat discomfort, and malaise. Provision of adequate fluids and nutrition is also appropriate. Although getting adequate rest is prudent, bed rest is unnecessary. However, strenuous activity should be avoided for at least three weeks after onset of IM. A detailed discussion of when these activities can be resumed is presented elsewhere. (See "Infectious mononucleosis", section on 'Return to sports'.)

Corticosteroids — The use of corticosteroids in the treatment of EBV-induced IM has been controversial. In a multicenter, placebo-controlled study of 94 patients with acute IM, the combination of acyclovir and prednisolone reduced oropharyngeal shedding of the virus but did not affect the duration of symptoms or lead to an earlier return to school or work [109]. Studies focusing on steroid therapy alone suggest that these agents may induce a modest improvement with reduction of lymphoid and mucosal swelling [110].

We do not recommend corticosteroid therapy for routine cases of IM since it is generally a self-limited illness and there are theoretical concerns about immunomodulation of a virus with transforming potential. However, a trial of corticosteroids is warranted in individuals with impending airway obstruction (manifested clinically by difficulty breathing or dyspnea in the recumbent position) and should be considered in those suffering from severe complications (eg, liver failure, aplastic anemia). Data supporting the benefit of corticosteroids in the latter two settings are lacking.

Antiviral treatment — Acyclovir is a nucleoside analogue that inhibits permissive EBV infection through inhibition of EBV DNA polymerase but has no effect on latent infection. Specific therapy of acute EBV infections with intravenous and oral formulations of acyclovir has been studied [109,111]. As noted above, while short-term suppression of viral shedding can be demonstrated, significant clinical benefit has been lacking. A meta-analysis of five randomized controlled trials of acyclovir in the treatment of acute IM, including two trials of intravenous therapy in patients with severe disease, also failed to show a clinical benefit compared to placebo [112]. Oropharyngeal shedding of the virus decreased significantly by the end of therapy in the groups receiving acyclovir but this difference was no longer observed three weeks after therapy was discontinued. These results are not surprising since there is little evidence that ongoing viral replication plays a role in the symptomatic phase of EBV-induced mononucleosis. (See "Acyclovir: An overview".)

In most of the EBV-associated malignancies in which the stage of the virus life cycle has been characterized, there is little evidence for permissive (lytic) infection. Since acyclovir is only effective in inhibiting replication of linear EBV DNA there is little to be gained by its use in diseases associated with latent infection. There is anecdotal support for the use of acyclovir in EBV-induced hemophagocytic lymphohistiocytosis where evidence of replicating EBV was demonstrated [45]. (See "Virology of Epstein-Barr virus".)

Other therapies — Anecdotal use of other agents such as interleukin-2, interferon alfa, and intravenous immunoglobulins in EBV-associated diseases have been reported. No clear benefits of such modalities have been demonstrated with the possible exceptions of lymphomatoid granulomatosis and post-transplant lymphoproliferative disease [52]. (See 'Lymphomatoid granulomatosis' above and 'Post-transplant lymphoproliferative disease' above.)

Adoptive cell therapy with EBV specific cytotoxic T lymphocytes (CTL) is also being evaluated in patients with EBV associated lymphoproliferative disorders and EBV associated malignancies [113,114]. In 2015, the US Food and Drug Administration granted breakthrough therapy designation for EBV-CTL in the treatment of refractory EBV-post transplant lymphoproliferative disorders. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

PREVENTION

Exposure to EBV — For patients with active Epstein-Barr virus (EBV) infection (eg, primary, chronic active), measures such as frequent handwashing and not sharing eating utensils, drinking glasses, and toothbrushes may reduce transmission of EBV to others. Although there are no data to guide this approach, studies suggest that primary EBV infection may be occurring at a later age in children residing in the developed world [3], and it is possible that delayed acquisition of primary EBV infection is related to good hygiene.

In patients undergoing solid organ or hematopoietic cell transplant, exposure to EBV may be prevented by selecting EBV-naïve donors for EBV-naïve recipients; however this is not always possible. Thus, patients are typically monitored for EBV infection, and strategies to reduce the risk of post-transplant lymphoproliferative disease are implemented if EBV viremia is detected. This is discussed in detail elsewhere. (See "Prophylaxis of infections in solid organ transplantation", section on 'Epstein-Barr virus' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Epstein-Barr virus' and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Prevention'.)

Active immunization — The large body of evidence implicating EBV in the etiology of a variety of human neoplasms has made the prospect of developing a viral-based vaccine effective against human cancers very appealing. Glycoprotein (gp) 350/220 is one of the most abundant viral proteins present in lytically infected cell plasma membranes and the most abundant protein on the outer surface of the virus coat; it also binds to the CD21 receptor on the B cell which is responsible for the initiation of infection. In addition, most of the human EBV neutralizing antibody response is directed against gp350/220 [115,116]. For these reasons, gp350/220 is the major EBV lytic-cycle gene being pursued in the development of a subunit vaccine. (See "Virology of Epstein-Barr virus".)

In animal studies, immunization with partially purified gp350/220 antigen induces EBV-neutralizing antibody, which protects a portion of cotton-top tamarins against a normally lethal, lymphoma-producing challenge with EBV [117]. A recombinant EBV subunit gp350 vaccine has been studied in four clinical trials. The vaccine was shown to be safe and immunogenic; although it did not prevent EBV infection, the vaccine reduced clinical symptoms [3].

Phase I trials evaluating the safety and efficacy of two mRNA-based EBV vaccines are underway.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Infectious mononucleosis (mono) in adults and adolescents (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Background – Epstein-Barr virus (EBV) is a widely disseminated herpesvirus that is spread by close contact between susceptible persons and asymptomatic EBV shedders. EBV is the primary agent of infectious mononucleosis (IM) and is associated with the development of B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. (See 'Introduction' above.)

●Subclinical infection – Most primary EBV infections throughout the world are subclinical and inapparent. (See 'Epidemiology' above.)

●Infectious mononucleosis – Infectious mononucleosis (IM) usually begins with malaise, headache, and low-grade fever before onset of more specific signs of the infection, such as pharyngitis and cervical lymph node enlargement. Patients usually have a peripheral blood lymphocytosis, with atypical lymphocytes. (See 'Acute infectious mononucleosis' above.)

●Primary infection in infants and children – Primary EBV infections in young infants and children are common but are frequently asymptomatic. When symptoms do occur, a variety of manifestations have been observed, including otitis media, diarrhea, abdominal complaints, upper respiratory infection, and symptoms and signs consistent with infectious mononucleosis. (See 'Primary EBV infection in infants and children' above.)

●Congenital and perinatal infections – Intrauterine infection with EBV is rare because fewer than 5 percent of pregnant women are susceptible to the virus. In addition, congenital abnormalities have not been documented among infants of women who did develop primary EBV infection during pregnancy. (See 'Congenital and perinatal infections' above.)

●Complications – EBV infection is associated with a number of acute complications and, in certain hosts, more delayed effects (see 'Acute complications of infectious mononucleosis' above and 'Delayed complications' above). As examples:

•Morbilliform rashes sometimes follow the administration of ampicillin in a patient with IM. The mechanism responsible for this rash is not understood. (See 'Rash' above and "Infectious mononucleosis", section on 'Rash'.)

•Splenic rupture is a rare but potentially life-threatening complication of IM and may be the first manifestation of IM that brings the patient to medical attention. (See 'Splenic rupture' above.)

•Oral hairy leukoplakia is described as white, corrugated, painless plaques that usually affect the lateral portions of the tongue among patients with advanced HIV infection. (See 'Oral hairy leukoplakia' above.)

•EBV infection is associated with a variety of lymphoproliferative disorders. More than a dozen single gene mutations causing primary immune deficiency disorders are associated with severe EBV-induced disease. (See 'Lymphoproliferative disorders' above.)

●Supportive care – The mainstay of treatment for patients with infectious mononucleosis and other manifestations of primary EBV disease is supportive care. (See 'Treatment' above.)