13/1/2557 Clinical manifestations and treatment of Epstein-Barr virus infection

Official reprint from UpToDate®

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Clinical manifestations and treatment of Epstein-Barr virus infection

Author Section Editors Deputy Editor

John L Sullivan, MD Martin S Hirsch, MD Jennifer Mitty, MD, MPH
Sheldon L Kaplan, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2013. | This topic last updated: มี .ค. 18, 2556.

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 and nasopharyngeal carcinomas in
certain patients. 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
[1]. (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 in adults and
adolescents".)

EPIDEMIOLOGY — The majority of primary EBV infections throughout the world are subclinical and inapparent.
Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution; approximately
90 to 95 percent of adults are EBV-seropositive. The host range of EBV is restricted to humans and certain
subhuman primates including squirrel monkeys and cotton top marmosets [2].

VIROLOGY — Like other members of the herpesvirus family, EBV has a latency phase. The host cells for the
organism in humans are limited to B lymphocytes, T lymphocytes, 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 — EBV can cause a number of primary infections, 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. 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 [3]. Affected patients usually have peripheral blood lymphocytosis, composed in large
measure of atypical lymphocytes (picture 1). (See "Infectious mononucleosis in adults and adolescents".)

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 [4]. There are, however, several

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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.

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 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 [5]. As an
example, one series reported 32 children younger than 4 years of age with IM, 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) [6]. The majority of these children had clinical evidence compatible with IM (significant cervical
adenopathy and tonsillar pharyngitis); respiratory symptoms were frequently prominent, especially in young
infants.

Children can have symptomatic primary EBV infection without the production of heterophile antibodies; as a
result, EBV-specific serologic studies are required to establish the diagnosis. In the above series of 32 children,
interpretation of the results of serology was most problematic in children below the age of two years [6].

The heterophile test was particularly insensitive (25 percent positive for ages 10 to 24 months versus 75
percent for ages 24 to 28 months).

Anti-viral capsid antigen (VCA) IgM was less frequently positive in infants (60 percent compared with 100
percent in older children and young adults); in addition, peak titers of VCA antibody were lower, and the
development of antibodies to early antigen was less common in infants.

Despite the reduction in antibody production, young infants can mount an EBV-specific cytotoxic T lymphocyte
response during acute EBV infection and that the latent proteins recognized are identical to those recognized
by young adults [7].

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 [8]. 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 [9], 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 [10].

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 [11]. A large number of other manifestations have 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 [12].

Hematologic abnormalities can include hemolytic anemia, thrombocytopenia, aplastic anemia,

thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, and disseminated intravascular
coagulation.

Chronic EBV infection — Chronic EBV infection is a rare disorder characterized by ongoing symptoms of an
infectious mononucleosis syndrome with active viremia. This entity is discussed elsewhere. (See "Infectious
mononucleosis in adults and adolescents".)

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

Rash — One of the more common complications of IM is a morbilliform rash following the administration of
ampicillin, and to a lesser extent, penicillin. The incidence initially was reported to be as high as 70 to 90
percent but is probably lower [13]. The mechanism responsible for this rash is not understood but has been
thought to involve circulating antibodies to ampicillin. Development of this rash during IM does not appear to
presage an ampicillin allergy; patients have subsequently tolerated ampicillin without an adverse reaction.

Oral hairy leukoplakia — Another EBV-mediated mucocutaneous manifestation is oral hairy leukoplakia
(OHL), which is an unusual disease of the lingual squamous epithelium [14]. 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 appear to be relatively specific for HIV infection, since they are only rarely observed in patients
with other immunodeficiencies [14,15]. The use of highly active antiretroviral therapy appears to have reduced
the incidence of OHL [16,17].

OHL is associated with intense EBV replication and the action of EBV-encoded proteins such as latent
membrane protein-1 [14]. 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 [18]. 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 [14].
Treatment with zidovudine, acyclovir, ganciclovir, foscarnet, and topical podophyllin or isotretinoin has been
reported, although therapy is usually not indicated.

Splenic rupture — Splenic rupture is a rare but potentially life-threatening complication of IM, estimated to
occur in between one and two cases per thousand [19,20]. Almost all cases have been in males. A number of
observations about splenic rupture have been made:

Splenic rupture is often 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 specific injury.

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

Rupture has occurred between the fourth and twenty-first day of symptomatic illness, and has not
correlated 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 [21].

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).

Lymphoproliferative disorders — EBV infection is associated with a variety of lymphoproliferative disorders

[22].

Hemophagocytic lymphohistiocytosis — EBV is one of the recognized initiating causes of

hemophagocytic lymphohistiocytosis (HLH), a potentially fatal genetic disorder characterized pathologically by
generalized histiocytic proliferation and hemophagocytosis (picture 3) [23]. 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
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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 the majority of cases, EBV infected B cells
are present, and the B cell proliferation is clonal [24,25]. Patients often have evidence of immunodeficiency
including congenital and acquired conditions such as HIV infection [26]. 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 [27-29]. It appears to arise from EBV-infected B cells and
affected patients may respond to interferon alfa [30]. (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. 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 [31]. XLP2 is due to a defect in the
XIAP gene that encodes the X-linked inhibitor of apoptosis. (See "X-linked lymphoproliferative disease".)

Posttransplant lymphoproliferative disease — EBV is associated with the majority of cases of

posttransplant lymphoproliferative disease (PTLD) [32]. 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 [33]. (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 in
addition to lymphomas in transplant recipients [22]. These include Burkitt lymphoma, tumors in HIV-infected
patients, Hodgkin lymphoma, nasopharyngeal and other head and neck carcinomas, and T cell lymphoma. (See
"The role of Epstein-Barr virus in Hodgkin lymphoma" and "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 [34]. 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 [35].

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) [36,37]. 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 [38-40].

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) [41]. 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) [42,43].
Fresh BL tumor cells retain a resting B cell phenotype and typically express only EBNA-1 [44]. (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 [45]. This observation, along with reduced expression of MHC class I antigens [46] and
the lack of adhesion molecules [42,43], probably contributes 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. An epidemiologic link is suggested by the number of endemic cases that occur in discrete
geographic climates located along the malaria belt across Africa [47]. Various hypotheses have been proposed

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to explain the role of malaria in pathogenesis:

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 malarial infection was associated with a sixfold increase in viremia compared to age-matched
EBV-seropositive controls without malaria [48].

Malaria may provide a chronic stimulus for proliferation of B lymphocytes, some of which carry latent
EBV. In one study of 43 children with malaria, anti-malarial therapy led to a significant decline in EBV
DNA plasma levels by day 14 of treatment [35]. The clearance of circulating EBV after antimalarial
treatment suggests a direct relationship between active malaria infection and reactivation of EBV.

Alternatively, malaria infection may impair EBV-specific T cell immunity and lead to loss of viral control
[49]. One study in Kenya demonstrated that children (1 to 14 years of age) living in malaria-endemic
regions had significantly fewer EBV-specific cytotoxic T-cell responses than did those living in areas with
unstable malaria transmission [50]. Evidence of suppression of EBV-related immunity was demonstrated
in patients up to nine years of age.

These findings correlate with epidemiologic data, which show a peak incidence of Burkitt lymphoma in children
ranging in age from 5 to 9 years.

Malignancies and HIV infection — Among HIV-infected patients, EBV infection has been associated with
non-Hodgkin lymphoma and, in children, smooth muscle tumors. Oral hairy leukopenia is another EBV-induced
manifestation in HIV-infected patients but is not considered to represent a premalignant lesion [14] (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) [51,52]. These
tumors are often associated with EBV infection [53,54]. 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 [53]. Analysis of EBV terminal repeats in these lymphomas again confirmed their
monoclonal origin, and c-myc rearrangements were noted in 40 percent. (See "AIDS-related lymphomas:
Clinical manifestations, diagnosis, and staging of systemic lymphoma", section on 'Diagnosis'.)

Given the profound immune defects in 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 HIV-infected patients is higher than the general population [55].
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 [56].

HIV associated NHL, usually of B cell origin, is a relatively late manifestation of HIV infection [51,57]. For
unknown reasons, a much higher percentage of EBV-associated NHLs in HIV-infected patients present
as primary CNS lymphomas [52]. (See "AIDS-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 [58,59]. 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 [59]

Smooth-muscle tumors containing clonal EBV developed in three children after liver transplantation [60].

Hodgkin lymphoma — EBV genomic DNA was first reported in tissue specimens from patients with Hodgkin
lymphoma (HL) in 1987 [61]. The finding that the malignant cells in HL, including the characteristic Reed-
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Sternberg cells, contain the EBV genome in up to 50 percent of "Western" cases supports a pathogenic role for
EBV in this malignancy [62]. 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
[63]. (See "The role of Epstein-Barr virus in Hodgkin lymphoma".)

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) [64].
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 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 [65].

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 [66].

Healthy western populations are infected with predominantly type 1 EBV [67], and not surprisingly, the majority
of EBV detected in HL is type 1 [68]. In contrast, there is an almost equal frequency of type 1 and type 2 EBV
in HIV-associated NHL [69] and endemic Burkitt lymphoma [70].

The type of EBV latency in HL most closely resembles the type-II latency described in nasopharyngeal
carcinoma [71]. EBER-1 and latency membrane protein- (LMP) 1 are the two EBV markers most often
expressed in HL [72]. (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 [73]. 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 [74]. (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 [75]. 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 [76].

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 [77,78].
In light of the molecular link between LMP-1 and cell growth [79], 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".)

T cell lymphoma — T cells are also susceptible to EBV infection as illustrated in studies of EBV-infected
tonsillar tissues in individuals with IM [80]. This observation is consistent with the description of T cell
lymphomas in individuals with chronic EBV infection [81]. 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 [82].

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 [83]. 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

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that are endemic to Asian countries as well as Central and South America [84-86]. 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 [87]. Thus, these tumors are probably of NK
cell origin.

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

The diagnosis of EBV 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 in adults and adolescents",
section on 'Diagnosis'.)

TREATMENT AND PREVENTION — 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 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.

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 [88]. Studies focusing on steroid therapy alone have been imperfect but do suggest that
these agents induce a modest improvement with diminishment of lymphoid and mucosal swelling [89].

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 overwhelming life-threatening infection (eg, liver failure) or other severe complications such as aplastic
anemia. Data supporting the benefit of corticosteroids in the last 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 [88,90]. 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
[91]. 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 the majority 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 [23]. (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 at this time with the possible exceptions of lymphomatoid granulomatosis and
posttransplant lymphoproliferative disease [30]. (See "Treatment and prevention of post-transplant

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lymphoproliferative disorders".)

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. Gp350/220 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 [92,93]. 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 cottontop tamarins against a normally lethal, lymphoma-producing challenge with
EBV [94]. A recombinant EBV subunit glycoprotein 350 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 [1].

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SUMMARY AND RECOMMENDATIONS

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.)

The majority of primary EBV infections throughout the world are subclinical and inapparent. (See
'Epidemiology' above.)

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 a significant proportion of atypical lymphocytes. (See
'Acute infectious mononucleosis' above.)

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.)

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.)

Morbilliform rashes sometimes follow the administration of ampicillin in a patient with infectious
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mononucleosis. The mechanism responsible for this rash is not understood but has been thought to
involve circulating antibodies to ampicillin. Development of this rash during IM does not appear to presage
an ampicillin allergy. (See 'Complications' above.)

Oral hairy leukoplakia (OHL) 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.)

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

The mainstay of treatment for patients with infectious mononucleosis 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. (See 'Treatment and prevention'
above.)

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GRAPHICS

Atypical lymphocytes in infectious mononucleosis

Peripheral smear from a patient with infectious mononucleosis shows

three atypical lymphocytes with generous cytoplasm.

Courtesy of Carola von Kapff, SH (ASCP).

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13/1/2557 Clinical manifestations and treatment of Epstein-Barr virus infection

Hairy leukoplakia

Well-demarcated white plaques are visible on the lateral aspects of

the tongue, which cleared with oral acyclovir.

Reproduced with permission from The Skin and Infection: A Color Atlas and
Text. Sanders CV, Nesbitt LT Jr (Eds) Williams and Wilkins, Baltimore 1995.

http://www.lww.com

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Infection-associated hemophagocytic syndrome

Bone marrow from a child with hemophagocytic syndrome, secondary

to Epstein-Barr virus infection. Reactive histiocytes show
phagocytosis of nucleated red blood cells (red arrows) and platelets
(black arrows). Wright-Giemsa stain.

From: Brunning RD, McKenna RW. Tumors of the bone marrow. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

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