Epstein-Barr virus (EBV), or human herpesvirus 4, is a gammaherpesvirus that infects more than 95% of the world's population. The most common manifestation of primary infection with this organism is acute infectious mononucleosis, a self-limited clinical syndrome that most frequently affects adolescents and young adults. Classic symptoms include sore throat, fever, and lymphadenopathy. Infection with Epstein-Barr virus in younger children is usually asymptomatic or mild. However, Epstein-Barr virus is also a human tumor virus, the first virus associated with human malignancy. Infection with Epstein-Barr virus is associated with lymphoproliferative disorders, especially in immunocompromised hosts, and is associated with various tumors, including nasopharyngeal carcinoma and Burkitt lymphoma.[1, 2]
See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.
Acute infectious mononucleosis was first described in the late 19th century as acute glandular fever, an illness consisting of lymphadenopathy, fever, hepatosplenomegaly, malaise, and abdominal discomfort in adolescents and young adults. In 1920, Sprunt and associates applied the name infectious mononucleosis to cases of spontaneously resolving acute leukemia associated with blastlike cells in the blood. Downey described the lymphocyte morphology in 1923. In 1932, Paul and Bunnell discovered that serum from symptomatic patients had antibodies that agglutinate the RBCs of unrelated species, the heterophile antibodies. This allowed enhanced diagnostic accuracy of infectious mononucleosis. The graph below demonstrates the antibody response to Epstein-Barr virus.
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Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Inf....
The search for the etiologic agent of infectious mononucleosis was unsuccessful for many years, partly because researchers did not appreciate that most primary infections are asymptomatic and that most adults are seropositive. In 1964, Epstein described the first human tumor virus when he found virus particles in a Burkitt lymphoma cell line.[3] Henle reported the relationship between acute infectious mononucleosis and Epstein-Barr virus in 1968.[4] Subsequently, a large prospective study of students at Yale University firmly established Epstein-Barr virus as the etiologic agent of infectious mononucleosis.[5]
Humans are the only known reservoir of Epstein-Barr virus. Epstein-Barr virus is present in oropharyngeal secretions and is most commonly transmitted through saliva. After initial inoculation, the virus replicates in nasopharyngeal epithelial cells. Cell lysis is associated with a release of virions, with viral spread to contiguous structures, including salivary glands and oropharyngeal lymphoid tissues. Further viral replication results in viremia, with subsequent infection of the lymphoreticular system, including the liver, spleen, and B lymphocytes in peripheral blood. Host immune response to the viral infection includes CD8+ T lymphocytes with suppressor and cytotoxic functions, the characteristic atypical lymphocytes found in the peripheral blood. The T lymphocytes are cytotoxic to the Epstein-Barr virus–infected B cells and eventually reduce the number of Epstein-Barr virus–infected B lymphocytes to less than 1 per 106 circulating B cells.
Primary infection with Epstein-Barr virus is followed by latent infection, a characteristic of herpesviruses. After acute Epstein-Barr virus infection, latently infected lymphocytes and epithelial cells persist and are immortalized. In vivo, this allows perpetuation of infection, while, in vitro, immortalized cell lines are established. During latent infection, the virus is present in the lymphocytes and oropharyngeal epithelial cells as episomes in the nucleus. These episomes rarely integrate into the cell genome but do replicate with cell division and are passed to subsequent generations of cells. The rate of viral reactivation within the population of latently infected cells is low. Epithelial cells are the primary source of new virus in latently infected individuals, infecting B cells as they circulate through the oropharynx.
Two strains, labeled EBV-1 and EBV-2 (also known as type A and type B), are observed. Although the genes expressed during latent infection have some differences, the acute illnesses caused by the 2 strains are apparently identical. Both strains are prevalent throughout the world and can simultaneously infect the same person.
Knowledge of the structure of Epstein-Barr virus and of which proteins are expressed during different stages of its life cycle is required to understand the laboratory tests used to determine if an individual has primary acute, convalescent, latent, or reactivation infection. A mature infectious viral particle, which may be present in the cytoplasm of an epithelial cell, consists of a nucleoid, a capsid, and an envelope. The nucleoid contains linear double-stranded viral DNA. It is surrounded by the capsid, an icosahedral constructed of capsomers, which are tubular protein subunits. An envelope derived either from the outer membrane or the nuclear membrane of the host cell encloses the capsid and nucleoid (ie, the nucleocapsid). The envelope also contains viral proteins that were constructed and placed in the host cell membrane before viral assembly began.
To initiate cellular infection, a viral particle attaches via its major outer envelope glycoprotein (ie, gp350/220) to the Epstein-Barr virus receptor CD21 on a B lymphocyte. The binding site on epithelial cells also may be CD21, but this has not been confirmed. One in vitro model has shown EBV infection of CD21-negative polarized epithelial cells can occur with the assistance of EBV-infected memory B cells. Epstein-Barr virus is then internalized into cytoplasmic vesicles. After fusion of virus envelope with the vesicle membrane, the nucleocapsid is released into the cytoplasm. The nucleocapsid dissolves, the genome is transported to the cell nucleus, and the linear genome then circularizes, forming an episome. The cell may then proceed with either lytic infection with release of infectious virus or latent infection of the host cell. B lymphocytes with latent infection undergo growth transformation.
Lytic infection occurs early after primary inoculation. As a result of lytic infection in oral epithelial cells, Epstein-Barr virus can be found in the saliva for the first 12-18 months after acquisition. Thereafter, epithelial cells and lymphocytes are latently infected, with a few spontaneously converting, leading to viral replication, host cell lysis and death, and release of mature virions. Thus, the virus can be isolated from oral secretions of 20-30% of healthy latently infected individuals at any time.
During latent infection, cell proteins are expressed in 1 of 3 patterns. Type I latency, associated with Burkitt lymphoma, is characterized by expression of only Epstein-Barr virus–encoded RNAs, Epstein-Barr early regions (EBERs), and Epstein-Barr nuclear antigen 1 (EBNA1). Type II latency, associated with nasopharyngeal carcinoma, is characterized by expression of 3 latent membrane proteins (LMP1, LMP2A, LMP2B), plus EBERs and EBNA1. Type III latency is a pattern generally only found in healthy cells with latent infection. All 3 latency patterns can be seen in healthy individuals because the association with neoplastic changes is not absolute. In addition to the EBERs and EBNA1 expressed in type I latency, other nuclear antigens (including EBNA2, EBNA3A, EBNA3B, EBNA3C, and LMP) are expressed in type III latency. As mentioned above, spontaneous reactivation can occur in latently infected cells, leading to viral shedding.
A Danish study used data from a cohort of 2,823,583 Danish children born between 1971 and 2011 to study familial aggregation of infectious mononucleosis (IM). The study found evidence of familial aggregation of IM that warrants genome-wide association studies on IM disease etiology, especially to examine commonalities with causal pathways in other Epstein-Barr virus-related diseases.[6]
A study by Langer-Gould reported that Epstein-Barr nuclear antigen-1 seropositivity was independently associated with increased risk of multiple sclerosis in all racial and ethnic groups.[7]
A study by Harley et al reported EBNA2 associations with systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.[8]
Epstein-Barr virus is not a reportable infection, and the exact frequency of symptomatic primary infection is not known. By age 5 years, approximately 50% of the US population is infected. During childhood, primary infection is usually asymptomatic or associated with mild elevation of liver function test findings. Epstein-Barr virus infection acquired during adolescence is asymptomatic or associated with the syndrome of acute infectious mononucleosis.
The incidence of acute infectious mononucleosis was approximately 45 cases per 100,000 population per year in the early 1970s, with the highest incidence in individuals aged 15-24 years. However, changes in economic status may have changed both the age of initial infection and the incidence of infectious mononucleosis since the large epidemiologic studies were completed. In lower socioeconomic groups, Epstein-Barr virus infection is more common, occurs at an earlier age, and is less likely to be associated with acute infectious mononucleosis.
Roommates of students with primary Epstein-Barr virus infection develop seroconversion at the same rate as the general population of college students.
Approximately 90% of the US population is infected with Epstein-Barr virus by age 25 years.
Epstein-Barr virus infection does not occur in epidemics and has relatively low transmissibility.
International
Epstein-Barr virus infection occurs with the same frequency and symptomatology in the developed nations of the world as in the United States.
Epstein-Barr virus is more frequently acquired in childhood in underdeveloped nations, and, therefore, the syndrome of acute infectious mononucleosis is unusual in these nations.
In Africa, the virus is associated with endemic Burkitt lymphoma in the setting of co-infection with Plasmodium falciparum.[4]
High numbers of Epstein-Barr virus episomes are found in the cells of undifferentiated or poorly differentiated nasopharyngeal carcinoma. This is the most common tumor in adult men in southern China and is also common in North American Inuits and North African whites.
Mortality/Morbidity
Most primary Epstein-Barr virus infections are asymptomatic. It is perhaps the most common reason for fever of unknown origin in young children and can present with fever in isolation or in the context of lymphadenopathy, fatigue, or nonspecific malaise.
Death is unusual in immunocompetent patients with acute infectious mononucleosis but may occur due to neurologic complications, upper airway obstruction, or splenic rupture.
Epstein-Barr virus infection is linked with numerous tumors. Endemic Burkitt lymphoma, the most common tumor of childhood in Africa, is associated with Epstein-Barr virus and malaria. Infection with P falciparum malaria stimulates polyclonal B-cell proliferation with Epstein-Barr virus infection and impairs the T-lymphocyte response to Epstein-Barr virus, apparently contributing to tumor pathogenesis.
In Asia, Epstein-Barr virus infection is related to development of nasopharyngeal carcinoma. Predisposing factors include a diet rich in nitrosamines, salted fish, Chinese race, and the HLA-A2 haplotype. Most non-Hodgkin lymphomas are associated with Epstein-Barr virus, and evidence of the Epstein-Barr virus genome is demonstrable in many of these tumors.
Epstein-Barr virus is also associated with Hodgkin lymphoma, in which the Epstein-Barr virus genome is present in the Reed-Sternberg cell. The EBNA1 protein interferes with tumor growth factor–beta signaling by downregulating Smad2; this interference with tumor-suppressor functions may contribute to tumor formation.[9] In addition, the same protein may play a role in immune evasion via recruitment of regulatory T-helper cells.[10] The precise mechanism by which Epstein-Barr virus may contribute to tumor pathogenesis are uncertain; some authors suggest that interleukin-10 may be linked to immune evasion, whereas others suggest it is linked to recovery.
Epstein-Barr virus infection in patients who are immunocompromised is associated with several syndromes and proliferative disorders.
Individuals with Duncan syndrome (ie, X-linked lymphoproliferative syndrome) may develop fatal primary Epstein-Barr virus infection due to a defect in the immune response to Epstein-Barr virus (poor anti-EBNA responses). The defective gene is the signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) and is found on the X chromosome. Boys with Duncan syndrome often develop fatal massive hepatitis, hemophagocytosis, or a disseminated lymphoproliferative disorder triggered by primary Epstein-Barr virus infection. The median age of presentation is 2.5 years, with a median survival of 33 days. Survivors of the initial infection develop B-cell lymphoma or hypogammaglobulinemia and usually die by age 10 years. In children with Duncan Syndrome, the paucity of normal class-switched mature B cells means the virus instead establishes itself in nonswitched memory B cells (as opposed to naive or transitional B cells).[11]
Other congenital immunodeficiencies are associated with the development of Epstein-Barr virus–associated lymphoproliferative disorders. These include ataxia-telangiectasia, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome, and common variable immunodeficiency.
Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal lymphoproliferative syndrome associated with Epstein-Barr virus and monoclonal or polyclonal expansion of B cells. It occurs in patients after organ transplantation, particularly after heart transplantation, and usually responds to decreased immune suppression.
Epstein-Barr virus–associated lymphomas occur in patients with secondary immunodeficiencies (eg, after cancer chemotherapy). Unfortunately, these tumors do not respond to decreased immunosuppression.
In patients with AIDS, Epstein-Barr virus is associated with hairy leukoplakia, leiomyosarcoma, CNS lymphoma, and lymphoid interstitial pneumonitis in children. However, only approximately one half of acquired immunodeficiency syndrome (AIDS)-associated Burkitt lymphomas contain Epstein-Barr virus genomes, which suggests a more complex interaction between chronic human immunodeficiency virus (HIV) infection and immune system defects. Acyclovir has been shown to have some potential benefit in treating patients with AIDS-associated Epstein-Barr virus disease.
Hemophagocytic lymphohistiocytosis (HLH) is an immune activation syndrome that can be triggered by EBV infection, especially in immunocompromised patients. HLH can also be triggered by other infections,[12] and inherited HLH exists as well, which typically presents at a very young age.
HLH is characterized by multiorgan dysfunction and cytopenias, and laboratory findings that overlap with severe EBV infection and leukemia. Typical presentations are fever, hepatosplenomegaly, rash, and pancytopenia. Various laboratory findings are suggestive of HLH, including high ferritin, high triglycerides, and low fibrinogen, as well as cytopenia in at least 2 cell lines. The most specific serologic marker is high levels of soluble interleukin 2 receptor. Low natural killer cell number and activity is also a sensitive marker for HLH.
Race
Epstein-Barr virus infection has no racial predilection; however, HLA-A2 haplotypes, which are more common in people of Chinese origin, are associated with a predisposition for nasopharyngeal carcinoma. The risk associated with HLA-A2 haplotypes is higher than any environmental risk posed by diet. First-generation US immigrants of Chinese origin have a higher risk for nasopharyngeal carcinoma.[13]
Large epidemiologic studies performed in the 1970s revealed that acute infectious mononucleosis was 30 times more likely to occur in whites than in African Americans. However, this correlated with lower social economic status and earlier asymptomatic infection in African Americans and, therefore, did not reflect a true racial difference.
Sex
The incidence of infectious mononucleosis is the same in men and women, although the peak incidence occurs 2 years earlier in females.
Postinfectious fatigue is more common in females.[14, 15]
Age
Epstein-Barr virus infection usually occurs during infancy or childhood and remains latent through life.
In developed nations, infection may not occur until adolescence or adulthood, and approximately 50% of adolescents who acquire Epstein-Barr virus develop the infectious mononucleosis syndrome.
Acute infectious mononucleosis has been reported in middle-aged and elderly adults; these individuals are usually heterophile antibody negative.
Acute infectious mononucleosis presents with a history of 1-2 weeks of fatigue and malaise; however, onset may be abrupt.
The incubation period in adolescents is 30-50 days; however, it is shorter in young children.
Symptoms include sore throat, headache, fever, myalgias, nausea, and abdominal pain. Sore throat is the most frequent presenting symptom. Gradually worsening over the first week, it may be the most severe sore throat the patient has experienced. Headache usually occurs during the first week and may be retro-orbital.
Left upper quadrant pain may be due to splenic enlargement. Abdominal pain should prompt suspicion of splenic rupture.
Symptoms usually persist for 2-3 weeks, but fatigue is often more prolonged.
Infants and young children with primary infection are usually asymptomatic.
Infectious mononucleosis is characterized by pharyngitis, generalized lymphadenopathy, and hepatosplenomegaly. Most clinical symptoms are due to T-cell proliferation and organ infiltration. Children younger than 4 years frequently have splenomegaly or hepatomegaly, rash, and symptoms of an upper respiratory tract infection.
Pharyngitis
Pharyngitis is exudative in one third of patients and is the most consistent physical finding.
Petechiae are present at the junction of the hard and soft palates in 25-60% of patients.
Tonsillar enlargement can be massive and occasionally causes airway obstruction. The enlargement can be associated with dehydration due to difficulty in swallowing.
Lymphadenopathy
Lymphadenopathy is prominent and most commonly affects the posterior cervical lymph nodes. Anterior cervical and submandibular nodal involvement is common, and axillary and inguinal nodes are also affected.
Enlarged epitrochlear nodes are highly suggestive of infectious mononucleosis.
Nodal enlargement is usually symmetric.
Nodes are mildly tender to palpation and are freely moveable.
Hepatomegaly
Although hepatomegaly is common, jaundice is rare. Percussion tenderness over the liver is common.
Splenomegaly
Splenomegaly is common. The spleen is often palpable 2-3 cm below the left costal margin and may be tender.
The spleen rapidly enlarges over the first week of symptoms, usually decreasing in size over the next 7-10 days.
The spleen can rupture from relatively minor trauma or even spontaneously.
Fever
More than 90% of patients develop fever, which is most severe in the afternoon, typically peaking at 38-39°C, but it may reach 40°C. Fever resolves over 10-14 days. Despite fever, the pulse is usually normal or relatively low, and tachycardia is unusual.
Maculopapular rash
A usually faint, widely scattered, and erythematous maculopapular rash occurs in 3-15% of patients and is more common in young children.
Treatment with amoxicillin or ampicillin is associated with rash in approximately 80% of patients. This is often encountered when primary Epstein-Barr virus (EBV) infection is initially misdiagnosed as strep throat and is treated as such.
Circulating immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to ampicillin are observed.
Eyelid edema
This may be present, especially in the first week of illness.
Genital ulcers
Genital ulcers have been described in girls and may be confused with genital herpes.[16]
Epstein-Barr virus is the etiologic agent in approximately 90% of acute infectious mononucleosis cases.
Cytomegalovirus (CMV), another herpesvirus, is most commonly associated with Epstein-Barr virus–negative infectious mononucleosis syndrome.
Other viruses associated with a similar acute illness include adenovirus; hepatitis A, hepatitis B, or hepatitis C; herpes simplex 1 and herpes simplex 2; human herpesvirus 6; rubella; and primary HIV in adolescents or young adults.
The etiology of most Epstein-Barr virus–negative infectious mononucleosis cases remains unknown.
The 3 classic criteria for laboratory confirmation of acute infectious mononucleosis include (1) lymphocytosis, (2) the presence of at least 10% atypical lymphocytes on peripheral smear, and (3) a positive serologic test result for Epstein-Barr virus (EBV).
CBC count
Leukocytosis with a WBC count of 10,000-20,000 cells/mL (10-20 X 109/L) is found in 40-70% of patients with acute infectious mononucleosis. By the second week of illness, approximately 10% of patients have a WBC count greater than 25,000 cells/mL.
Approximately 80-90% of patients have lymphocytosis with more than 50% lymphocytes. Lymphocytosis is most severe during the second and third weeks of illness and lasts for 2-6 weeks. Usually, 20-40% of the lymphocytes are atypical, although not all patients have more than 10% atypical lymphocytes.
The atypical lymphocytes of 3 Downey types are larger, have a lower nuclear-to-cytoplasmic ratio, and have a nucleus that is less dense than that of normal lymphocytes. Most of these atypical lymphocytes are polyclonal-activated CD8 cytotoxic-suppressor T lymphocytes, although CD4 helper T cells and CD11 natural killer cells are also present.
Mild thrombocytopenia occurs in 25-50% of patients.
Liver function tests
Most (ie, 80-100%) patients with acute infectious mononucleosis have elevated liver function test results.
Alkaline phosphatase, aspartate aminotransferase (AST), and bilirubin levels peak 5-14 days after onset, and gamma-glutamyltransferase (GGT) levels peak at 1-3 weeks after onset.
Occasionally, GGT levels remain mildly elevated for as long as 12 months, but most liver function test results are normal within 3 months.
Lactic acid dehydrogenase (LDH) levels are increased in approximately 95% of patients.
Serum ferritin can also be increased.
Heterophile antibody test
Epstein-Barr virus infection stimulates polyclonal secretion of antibodies by infected B cells, including transient production of heterophile antibodies. These are antibodies that agglutinate cells from other species and are not directed against Epstein-Barr virus. The Paul-Bunnell test for heterophile antibodies is based on the fact that serum obtained from patients with acute mononucleosis contains antibodies that agglutinate sheep RBCs in a tube dilution assay, whereas such antibodies are absent or nearly absent in the serum of healthy persons.
Differential absorption includes the following:
Antibodies other than those produced during acute infectious mononucleosis can agglutinate sheep RBCs. Such antibodies include those formed in serum sickness and during drug reactions and naturally occurring antibodies to the Forssman antigen.
Differential absorption permits identification of the antibody type. Bovine RBCs absorb infectious mononucleosis heterophile antibodies from serum but do not absorb Forssman antibodies. Guinea pig kidney cells absorb Forssman antibodies, leaving the infectious mononucleosis heterophile antibodies. Antibodies formed in serum sickness are absorbed by both guinea pig kidney cells and bovine RBCs. Thus, in terms of absorbing infectious mononucleosis heterophile antibodies, clinicians use the saying, "cow can, pig can't."
Serum from a patient with infectious mononucleosis agglutinates sheep RBCs after absorption with guinea pig cells, but no agglutination occurs after absorption with bovine RBCs.
Heterophile antibody titers include the following:
The titer of Paul-Bunnell—heterophile antibody is determined with tube dilution.
Depending on the dilution system, a titer of 1:40 or 1:28 after absorption with guinea pig cells is considered positive for acute infectious mononucleosis.
Titer level does not correlate with severity of clinical illness.
Heterophile antibodies are measurable in approximately 50% of patients in the first week of illness, and 60-90% of patients have test results that are positive for heterophile antibodies in the second or third weeks. The titer begins to decline during the fourth or fifth week and is often less than 1:40 within 2-3 months after symptom onset.
As many as 20% of patients have positive titer results 1-2 years after acquisition. Also, because horse RBC agglutinins are more sensitive than sheep RBCs, 75% of patients have positive horse RBC agglutinin findings at 1 year.
Only 10-30% of children younger than 2 years and 50-75% of children aged 2-4 years develop heterophile antibodies with primary Epstein-Barr virus infection.
Monospot includes the following:
Rapid slide agglutination tests, including Monospot assays, have been developed to measure acute infectious mononucleosis heterophile antibodies in a rapid qualitative fashion. Slide tests use either horse RBCs or bovine RBCs. Horse RBCs are more sensitive than sheep RBCs or bovine RBCs and can be treated with formalin to extend the shelf life of the test. Bovine RBCs are specific for acute infectious mononucleosis heterophile antibodies and, thus, do not require differential absorption.
All commercial kits for rapid diagnosis of acute infectious mononucleosis heterophile antibodies have low sensitivity (63-84%), with a negative predictive value of more than 10%.
Spot tests rarely yield false-positive results in patients with lymphoma or hepatitis.
Epstein-Barr virus serology
Infection with Epstein-Barr virus is characterized by development of the specific antibodies to antigenic components of the virus. These antigens appear at different stages of infection and differ in lytic versus latent infection.
Antibodies to Epstein-Barr virus antigens measured for clinical purposes include antibodies to viral capsid antigen (VCA), early antigens (EAs), and EBNA. EAs are expressed early in the lytic cycle, whereas VCA and membrane antigens are structural viral proteins expressed late in the lytic cycle. EBNA is expressed in latently infected cells.
Antibodies to membrane antigens are not usually measured, but their presence correlates with viral-neutralizing activity.
Antibodies to these proteins are measured with enzyme immunoassays, indirect immunofluorescence assays, and immunoblot assays.
EAs are expressed in cells early in the lytic cycle. These antigens are nonstructural Epstein-Barr virus proteins, which are classified into 2 groups based on cell distribution and stability with methanol treatment.
The restricted component of early antigens (EA/R) is found in the cytoplasm of infected cells and is methanol sensitive. Antibody to EA/R is usually measurable in children younger than 4 years with primary Epstein-Barr virus infection or in patients with nonsymptomatic infection.
Approximately 80% of patients with infectious mononucleosis have antibodies to the diffuse-staining component of EA (EA/D).
EA/D antibody levels are elevated in patients with nasopharyngeal carcinoma, and the levels of antibodies to EA/R are high in individuals with Epstein-Barr virus–associated Burkitt lymphoma. Patients who are immunocompromised and have persistent or reactivated Epstein-Barr virus infections often have high levels of antibodies to EA/D or EA/R.
In early primary Epstein-Barr virus infection, oropharyngeal epithelial cells are lytically infected, and the above antigens are expressed. Antibodies are measurable at the onset of clinical symptoms or even slightly before.
Although not always measurable, EA antibody levels increase upon symptom onset. EA/D is more common, although EA/R is present more often in patients with asymptomatic infection or in children younger than 4 years. The levels of antibodies to EA rise for 3-4 weeks, then usually quickly decline to undetectable levels by 3-4 months, although low levels may be intermittently detected for years. However, in patients with a more prolonged symptomatic illness, EA/D may become unmeasurable, and EA/R results may become positive.
VCA-IgM levels are usually measurable at symptom onset, peak at 2-3 weeks, and then decline and become unmeasurable within 3-4 months. VCA-IgG levels rise shortly after symptom onset, peak at 2-3 months, then drop slightly but persist for life. Antibodies to EBNA appear during convalescence and remain present for life.
Primary acute Epstein-Barr virus infection is associated with VCA-IgM, VCA-IgG, and absent EBNA antibodies.
The antibody pattern in recent infection (3-12 mo) includes positive findings for VCA-IgG and EBNA antibodies, negative VCA-IgM antibodies, and, usually, positive EA antibodies.
After 12 months, the pattern is the same as in recent infection, except EA antibodies are not present.
EBV viral polymerase chain reaction (PCR)
Viral PCR can be performed on whole blood and can be either qualitative or quantitative. Quantitative PCR can be useful in investigating EBV-associated disease in the context of immunosuppressed or immunodeficient patients. The symptoms of severe EBV-associated disease may mimic those of malignancy, graft-versus-host disease, or organ rejection, and measuring the viral load can help with deciding whether to increase or decrease immunosuppressive medications or perform further invasive testing.
Quantitative PCR can be used to measure Epstein-Barr virus DNA in plasma during acute infectious mononucleosis. Levels decline during convalescence and are rarely measurable in latently infected individuals. However, Epstein-Barr virus DNA in serum may be detectable with PCR with reactivation of infection, such as in patients with PTLD.
An Epstein-Barr early region (EBER) probe can be used to identify the Epstein-Barr virus messenger RNA in the nuclei of Epstein-Barr virus–infected lymphoid cells by in situ hybridization.
Studies have suggested that quantitative PCR in bronchoalveolar lavage fluid (BALF) for Epstein-Barr virus may be predictive of PTLD in lung-transplant recipients and is superior to plasma levels.[17]
In some patients who have an immune deficiency, the serologic response to EBV may be blunted or absent; the only way to detect EBV in that setting is with the use of PCR.
Longitudinal tracking of the quantitative viral load can help with judging the effectiveness of antiviral medications or the immune response to the infection.
Pathology/histology
Viral inclusions may be visible. Certain EBV-associated tumors have characteristic histology (eg, Reed Sternberg Cells). In situ testing with DNA probes or immunohistochemistry for viral proteins can be done to further demonstrate infection.
No specific imaging studies are indicated in diagnosing acute infectious mononucleosis.
Chest radiography reveals mediastinal adenopathy in fewer than 1% of patients. Mediastinal lymph node enlargement should prompt consideration of other diagnoses.
Abdominal CT scanning is the preferred imaging modality to assess for splenic rupture but can be performed only in patients who are hemodynamically stable. Ultrasonography or radionuclide scanning of the spleen may also assist in ascertaining the diagnosis.
Lateral neck films are occasionally helpful to document tonsillar hypertrophy and exclude epiglottis or retropharyngeal abscess in a patient with upper airway obstruction or stridor.
In bone marrow or solid organ transplant patients with PTLD, chest radiography may reveal nodular lesions. Chest CT scanning with contrast may reveal the characteristic peripheral nodules, and abdominal CT scanning with contrast can define the extent of intra-abdominal lesions.
Serum: Epstein-Barr virus infection is characterized by the presence of atypical lymphocytes in the peripheral blood. The cells are activated CD8 T cells, which are not infected but are mobilized to destroy the infected B cells.
Lymph nodes: During acute mononucleosis, lymph nodes are enlarged, with enlarged germinal centers and lymphoid follicles. Perifollicular areas of the tonsils contain many infected B lymphocytes, which express Epstein-Barr virus–specific antigens, including LMP1, EBNA1, and EBNA2.
Spleen: The spleen is larger, with lymphocytic infiltration of the capsule and trabeculae. Pleomorphic blast cells are present in the hyperplastic red pulp. Vascular congestion is coupled with focal and subcapsular hemorrhages.
Liver: Histologic changes in the liver are usually minimal, with mild swelling in hepatic sites and bile ducts and lymphocytic portal infiltration.
CNS: In fatal infectious mononucleosis, degenerative changes are observed in the neurons of the CNS. Neuronal degeneration, perivascular cuffing, and astrocytic hyperplasia may be present.
PTLD
This is characterized by homogeneous lymphocytic proliferation with an immunoblastic component. Lesions may efface lymphoid organ architecture or develop ectopically in nonlymphoid organs. The Epstein-Barr virus–infected cells in patients with PTLD express EBER.
HLH
Demonstration of hemophagocytosis in a bone marrow aspirate is diagnostic for HLH, although nonspecific findings such as dyserythropoiesis are common.
Infectious mononucleosis is a self-limited illness that does not usually require specific therapy in patients with mild or moderate illness. However, if the tonsils are markedly enlarged (kissing tonsils) or if the patient has prolonged illness, most experts recommend a short course of steroids (1-2 mg/kg of prednisone daily for 3-7 d).
Because of low transmissibility of Epstein-Barr virus (EBV), isolation is not indicated.
Most affected individuals can be evaluated and treated as outpatients. Inpatient therapy of medical and surgical complications may be required.
Patients with chronic post–Epstein-Barr virus fatigue may benefit from psychological and behavioral approaches.[18]
Splenic rupture is an acute abdominal emergency that usually requires surgical intervention.
Rupture may occur with trauma as minor as palpation, and is occasionally the presenting symptom.
Diagnosis can be confirmed using imaging procedures or peritoneal lavage in an unstable patient.
Splenectomy is usually required.
Occasionally, observation and supportive measures are adequate treatment for a hemodynamically stable patient.
Although partial splenectomy or suturing the capsular tear has been advocated to preserve splenic function, the acute changes that led to rupture militate against the success of this approach.
Surgical consultation should be sought when the patient has abdominal pain or evidence of shock.
Consultation with the appropriate subspecialist is indicated for management of significant complications (eg infectious diseases, hematology/oncology, immunology).
Acceptable activity level during the acute illness depends on severity of the patient's symptoms.
Extreme fatigue may require bed rest for 1-2 weeks.
Malaise may persist for 2-3 months, and activity can increase as tolerated.
Patients should not participate in contact sports or heavy lifting for at least 2-3 weeks, although some authors recommend avoiding activities that may cause splenic trauma for 2 months.
Guidelines on the diagnosis, prevention, prophylaxis, and treatment of Epstein-Barr virus–related posttransplant lymphoproliferative disorders in allogeneic hematopoietic stem cell transplant patients were published in 2016 by the Sixth European Conference on Infections in Leukemia. The guidelines recommend rituximab, immunosuppression reduction, and Epstein-Barr virus–specific cytotoxic T-cell therapy as first-line treatment in these patients. Unselected donor lymphocyte infusions and chemotherapy are recommended as second-line options, while antiviral drugs are not recommended for prophylaxis, with evidence indicating that they are ineffective against latent Epstein-Barr virus.[19]
Acute infectious mononucleosis is treated symptomatically. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat fever and discomfort. Corticosteroids do not significantly alter the course of infectious mononucleosis. Although they ameliorate symptoms, corticosteroids should not be used in the treatment of uncomplicated disease. They are used in patients with significant upper airway obstruction due to tonsillar or lymph node hypertrophy and in patients with severe thrombocytopenia or hemolytic anemia.
Numerous drugs inhibit Epstein-Barr virus (EBV) replication in vitro. Nonetheless, antiviral agents are not beneficial in patients with uncomplicated infectious mononucleosis. However, antiviral agents are used in the treatment of patients with interstitial pneumonitis, X-linked lymphoproliferative syndrome, PTLD, HLH, and other lymphoproliferative disorders.[20, 21, 22, 23] Intravenous immunoglobulin may be considered to modulate immune function in the presence of disease complications due to autoantibodies.
New therapies, including the use of interferon alpha and the infusion of donor T cells or Epstein-Barr virus–specific cytotoxic T cells, are being studied.
Corticosteroids are potent anti-inflammatory drugs that also modify the immune response. They are used to decrease the size of tonsils and upper airway lymph nodes in the presence of airway compromise and possible upper airway obstruction. They may be useful to treat severe thrombocytopenia or hemolytic anemia. Whether prednisone should be used for myocarditis, pericarditis, or CNS system involvement is unclear.
Clinical Context:
Foscarnet, a pyrophosphate analog, has been reported to be active against acyclovir- or ganciclovir-resistant herpes family viruses, including HSV, CMV, VZV, and EBV. Most of the data regarding its use in severe EBV infection are from isolated case reports, but they are generally positive.
Clinical Context:
Strains of HSV1 are most sensitive, followed by HSV2. Acyclovir also is sensitive to other herpesviruses, including, in descending order, varicella zoster, EBV, and CMV.
Numerous drugs inhibit Epstein-Barr virus replication in vitro. These include acyclovir, desciclovir, ganciclovir, interferon-alfa, interferon-gamma, adenine arabinoside, and phosphonoacetic acid. Acyclovir, which inhibits viral shedding from the oropharynx, is the only antiviral drug used to treat infectious mononucleosis in placebo-controlled clinical trials. However, the clinical course is not significantly affected in patients with uncomplicated infectious mononucleosis.
Clinical Context:
Intravenous immunoglobulin neutralizes circulating myelin antibodies through antiidiotypic antibodies; it down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase CSF IgG (10%).
Intravenous immunoglobulin is used to modulate immune function in the presence of autoantibodies. It has been used successfully in the treatment of immune thrombocytopenia associated with infectious mononucleosis.
Patients with uncomplicated infectious mononucleosis rarely require inpatient therapy.
Hospitalization is warranted in the presence of splenic rupture, airway compromise, dehydration, significant thrombocytopenia or hemolytic anemia, and neurologic or other major complications.
Nonspecific treatment includes saline gargles and acetaminophen or ibuprofen for sore throat, fever, and myalgia. Constipation may be treated with a laxative.
Acyclovir has no demonstrable benefit for treatment of uncomplicated infectious mononucleosis in placebo-controlled trials.
Various therapies are used for complications of Epstein-Barr virus (EBV) infection, although only a few have been studied in controlled trials. Corticosteroids are used for treatment of severe airway obstruction due to tonsillar enlargement, hemolytic anemia, and severe thrombocytopenia. They may decrease the duration of febrile illness and constitutional symptoms, but their routine use for treatment of a virus known to be related to tumor development is discouraged.
Interferon-alfa decreases shedding of Epstein-Barr virus in renal transplant recipients.[24]
Acyclovir and desciclovir can reverse Epstein-Barr virus–associated hairy leukoplakia in patients with HIV.[25] Acyclovir has been used to treat interstitial pneumonitis,[26] X-linked lymphoproliferative syndrome, and lymphoproliferative disorders. Posttransplant lymphoproliferative disorder (PTLD) has been treated with ganciclovir and cytomegalovirus (CMV) intravenous immunoglobulin (CytoGam). High-dose (20mg/kg/dose q8 hours, IV) is probably required to be effective.
Immune thrombocytopenia has been treated with intravenous immunoglobulin.[27]
Whether corticosteroids are beneficial or harmful in patients with encephalitis, pericarditis, and myocarditis is unclear.
Combination therapy with corticosteroids and acyclovir has been reported, with varying outcomes.
Isolation is not required. Epstein-Barr virus has low transmissibility and cannot be acquired from environmental surfaces or fomites.
Avoid contact with saliva. Epstein-Barr virus is present in throat washings of individuals with acute infectious mononucleosis. Virus can be cultured from the oropharynx for up to 18 months. It can be recovered from the oropharynx of 10-20% of healthy adults. Epstein-Barr virus infection is usually acquired through contact between a susceptible individual and the saliva of an asymptomatic individual who is shedding Epstein-Barr virus. In young children, saliva is spread by drooling and hand-to-mouth behaviors. In adolescents, infected saliva may be transferred by kissing, hence the label "kissing disease."
Do not kiss children on the mouth.
Maintain clean conditions, especially when young children are present (eg, in daycare), and avoid having children share toys.
Epstein-Barr virus can be transmitted by blood transfusion and by bone marrow transplantation. However, because the organism is so common, no procedures are in place to prevent this.
Vaccine development is proceeding, although the role of a vaccine is unclear. Animal studies suggest the antigenicity of a vaccinia-based vector.[28]
Hepatitis develops in more than 90% of patients with infectious mononucleosis. Liver function test results are mildly elevated but are usually no more than 2-3 times the reference range. Bilirubin levels are elevated in approximately 45% of patients, but jaundice occurs in only 5%. Liver abnormalities are most pronounced in the second and third weeks of illness.
Approximately 50% of patients with infectious mononucleosis develop mild thrombocytopenia. The platelet count is usually 100,000-140,000/mL. The platelet count usually reaches its nadir approximately 1 week after symptom onset and then gradually improves over the next 3-4 weeks. Thrombocytopenia may be caused by the production of antiplatelet antibodies and peripheral destruction, especially in the enlarged spleen.
Hemolytic anemia occurs in 0.5-3% of patients with infectious mononucleosis. Hemolytic anemia has been associated with cold-reactive antibodies, with anti-I antibodies, and with autoantibodies to triphosphate isomerase. Hemolysis is usually mild and is most significant during the second and third weeks of symptoms.
Upper airway obstruction due to hypertrophy of tonsils and other lymph nodes in the Waldeyer ring occurs in 0.1-1% of patients. Treatment with corticosteroids may be beneficial. Patients with severe tonsillar and lymph node enlargement with impending airway obstruction may require intubation or tracheostomy. Patients who require hospitalization may have concurrent streptococcal pharyngitis. Two thirds of patients admitted with infectious mononucleosis with upper airway obstruction and dehydration have alpha-hemolytic Streptococcus infection, usually due to group C streptococci.
Splenic rupture occurs in 0.1-0.2% of patients with infectious mononucleosis. A literature review by Bartlett et al indicated that the risk of splenic rupture is greatest in males under 30 years with infectious mononucleosis symptom onset within the previous 4 weeks.[29] Rupture may be spontaneous, although the patient often has a history of some antecedent trauma. Rupture is most likely during the second and third weeks of clinical symptoms. Patients can present with mild-to-severe abdominal pain below the left costal margin, sometimes with radiation to the left shoulder and supraclavicular area. Massive bleeding may be accompanied by peritoneal irritation and shifting dullness. Shock may be the only presenting symptom. Because bradycardia is common in infectious mononucleosis, tachycardia with pulse of faster than 100 beats per minute is an important sign. Neutrophilia (instead of lymphocytosis) can occur. Surgical intervention is usually required.
Hematologic complications are as follows:
Epstein-Barr virus has been implicated in hemophagocytic syndrome.[30, 31, 32]
Immune thrombocytopenic purpura occurs and may evolve to aplastic anemia. Aplastic anemia and neutropenia are sometimes associated with antineutrophil antibodies.
Epstein-Barr virus infection may accelerate hemolytic anemia in individuals with congenital spherocytosis or hereditary elliptocytosis.
Disseminated intravascular coagulation associated with hepatic necrosis has occurred.
Neurologic complications are as follows:
Neurologic complications occur in less than 1% of patients with Epstein-Barr virus infections and usually develop during the first 2 weeks. In some patients, especially children, the neurologic symptoms are the only clinical manifestation of infectious mononucleosis. Patients are often negative for the heterophile antibody. However, these complications are often severe. Complete recovery is the rule, but fatalities do occur.
Primary Epstein-Barr virus infection has been associated with aseptic meningitis, acute viral encephalitis, coma, meningitis, and meningoencephalopathy. Hypoglossal nerve palsy, Bell palsy, hearing loss, brachial plexus neuropathy, and multiple cranial nerve palsies have been described. Guillain-Barré syndrome, autonomic neuropathy, GI dysfunction secondary to selective cholinergic dysautonomia, acute cerebellar ataxia, and transverse myelitis have been reported. Metamorphopsia (ie, Alice in Wonderland syndrome) has been described.
Cardiac and pulmonary complications are as follows:
Pulmonary complications are extremely rare, although upper airway obstruction due to lymphoid hypertrophy is relatively common. Chronic interstitial pneumonitis and pleural effusion have been associated with Epstein-Barr virus infection.
Cardiac abnormalities that can occur with Epstein-Barr virus infection include myocarditis and pericarditis.
Autoimmune complications are as follows:
Autoimmune diseases and Reye syndrome have been associated with Epstein-Barr virus infection.
Infectious mononucleosis stimulates production of many antibodies not directed against Epstein-Barr virus. These include autoantibodies, anti-I antibodies, cold hemolysins, antinuclear antibodies, rheumatoid factors, cryoglobulins, and circulating immune complexes. These antibodies may precipitate autoimmune syndromes.
Miscellaneous complications are as follows:
Renal disorders associated with Epstein-Barr virus infection include immune deposit nephritis, renal failure, and paroxysmal nocturnal hemoglobinuria.
After cardiac bypass or transfusion, an infectious mononucleosis–like syndrome has been described. Epstein-Barr virus may cause this, but it is more commonly associated with primary CMV infection.
A syndrome of chronic fatigue, myalgias, sore throat, and mild cognitive dysfunction that primarily occurs in young adult females was initially attributed to Epstein-Barr virus. Current data suggest that Epstein-Barr virus is not the etiologic agent.
Immunocompetent individuals with acute infectious mononucleosis have a good prognosis, with full recovery expected within several months.
The common hematologic and hepatic complications resolve in 2-3 months.
Neurologic complications usually resolve quickly in children. Adults are more likely to be left with neurologic deficits.
All individuals develop latent infection, which usually remains asymptomatic.
Long-term fatigue can occur, is more common in females, and can last 1-2 years or longer. This is separate from the chronic fatigue syndrome mentioned above (although post–Epstein-Barr virus fatigue can occur, chronic fatigue syndrome has not been causally linked to Epstein-Barr virus).
Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP, Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center
Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.
Coauthor(s)
Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Mark R Schleiss, MD, Minnesota American Legion and Auxiliary Heart Research Foundation Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School
Disclosure: Nothing to disclose.
Chief Editor
Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Disclosure: Nothing to disclose.
Acknowledgements
Rosemary Johann-Liang, MD Medical Officer, Infectious Diseases and Pediatrics, Division of Special Pathogens and Immunological Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration
Rosemary Johann-Liang, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Infectious Diseases Society of America
Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.
Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.
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