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Epstein Barr Virus

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus spread by human contact with no know environmental reservoir. EBV infection typically occurs during one of two distinct time periods; the first wave of infection occurs during early childhood, before the age of 5 years, and the second wave occurs during the second and third decades of life. Most adults have been infected with EBV, and only 3 to 10% of adults older than 40 years of age have not been infected.

Infectious mononucleosis is the clinical syndrome associated with acute EBV infection.  EBV infection is subclinical in 90% of children. Symptomatic infectious mononucleosis is more common in adolescence and has a peak incidence between 15 and 24 years. IM is uncommon in older adults because they already have been exposed and produced antibody. , Older patients with primary EBV infection are less likely to present with pharyngitis and are more likely to have severe illness that necessitates hospitalization.

EBV replicates in the oropharyngeal epithelial cells and is released into the saliva. The virus infects B lymphocytes in the underlying lymph nodes, which then disseminate the infection throughout the lymphoreticular system. There is a 4 to 8 week incubation period from the time of infection to the development of clinical symptoms.

Viral transmission occurs primarily through saliva. Following infection, the virus can persist in the oropharynx for 32 weeks and up to 18 months after recovery. This long incubation period may explain why individuals with IM often do not recall being exposed to anyone with the disease.

The most common symptoms of IM are:

  • Fever and chills
  • Pharyngitis with tonsillar exudates
  • Lymphadenopathy
  • Headache and/or body aches
  • Extreme fatigue
  • Generalized rash, often associated with antibiotic use
  • Splenomegaly in up to 50% of cases

A complete blood count (CBC) often demonstrates an increased white blood cell count due to absolute lymphocytosis. Atypical lymphocytes and rouleaux may be present. A person can transmit Epstein-Barr virus (EBV) to others as long as the virus is present in his or her throat. This period can last from several months to many years.

EBV infected B lymphocytes stimulate the production of circulating antibodies against EBV antigens and well as antibodies to unrelated antigens on other cells. The latter include heterophile antibodies to antigens on other species including sheep, horse, ox and goat red blood cells. IgM antibodies to horse cells are utilized in the Monospot latex agglutination assay and in other enzyme linked immunoassays.

The Monospot test usually becomes positive within the first three weeks of illness.  Approximately 10-20% of adults and over 50% of children under four have a negative heterophile test.  For these patients, and patients with unusual clinical presentations, the more sensitive and specific EBV antibody panel may be appropriate. This panel includes: IgG antibody to viral capsid antigen (IgG-VCA), IgM antibody to viral capsid antigen (IgM-VCA), and IgG antibody to Epstein-Barr nuclear antigen (IgG-EBNA).

Most patients already have detectable levels of EBV specific antibodies when they become symptomatic because of the lengthy incubation period of 5 to 7 weeks following exposure to EBV.  IgM-VCA becomes positive within 2 weeks of exposure and disappears within 2-6 months in adults and even sooner in young children.  IgG VCA antibody develops later and persists throughout life.  EBNA antibodies tend to appear even later, 6 to 12 weeks after initial symptoms, and persist indefinitely.  EBV Antibody panel results are interpreted as follows:

VCA IgM VCA IgG EBNA Interpretation
- - - No previous infection
+ + - Recent infection
- + + Past infection
- + - Past infection
+ + + Past infection or reactivation


Detection of VCA IgM usually confirms acute EBV infection, because this antibody disappears by 3 months after the illness begins.  At least 90% of adults have previously been infected with EBV and have positive IgG-VCA and IgG-EBNA tests, since these antibodies remain elevated throughout life.  IgG-VCA and EBNA are markers of previous EBV infection and do not indicate chronic active EBV infection. Reactivation of latent EBV can occur in immunodeficient or immunosuppressed patients.  IgM-VCA antibodies may be transiently positive concurrently with rapidly rising high titers of IgG-VCA. Few patients (approximately 3%) who have been infected with EBV will fail to develop EBNA antibodies.

Positive VCA IgM results are not always due to acute infection. Low levels of VCA IgM have been reported in EBV reactivation. Low level VCA IgM may also represent crossover of VCA IgG. Although VCA IgM should be undetectable within 8 weeks after acute infection, it has been seen to persist for up to a year or more. False positive IgM levels have been reported due to cross-reactivity with cytomegalovirus (CMV), toxoplasma and herpes simplex antibodies. Rheumatoid factors may also cause false positive IgM results. An increased incidence of positive IgM (12%) has been reported in patients over 60 years of age.

Primary EBV infection is characterized by abnormal results on flow cytometry of the peripheral blood, including an inverted CD4:CD8 ratio and frequent down-regulation of certain pan–T-cell antigens. The presence of an expanded CD8+ T-cell population corresponds to the presence of atypical-appearing lymphocytes on peripheral-blood smears. Cytotoxic T cells play an essential role in controlling acute infection and the lifelong suppression of EBV. Patients lacking sufficient T cell cytotoxic response may develop poorly controlled EBV infection induced B cell lymphoproliferative disorders.

Biopsy specimens of affected lymph nodes and tonsils show a number of morphologic features that mimic the features of lymphoma, including architectural distortion, an immunoblastic proliferation with cytologic atypia, and necrosis. Several subtypes of aggressive lymphoma are associated with EBV infection, including Burkitt’s lymphoma, diffuse large B-cell lymphoma, lymphomatoid granulomatosis, and angioimmunoblastic T-cell lymphoma. However, these cancers are associated with latent, chronic EBV infection and not with acute EBV mononucleosis. In a patient with EBV viremia and diffuse lymphadenopathy that is worrisome for lymphoma, it is critical to perform viral serologic tests to rule out primary infection.

Several reports have suggested that patients with chronic fatigue syndrome or chronic mononucleosis have EBV antibody panels consistent with reactivated EBV infections.  However, it has been convincingly demonstrated that EBV serology is not helpful in the clinical evaluation of patients with chronic fatigue.

Approximately 10% of patients who present with an IM-like illness, but do not have detectable EBV antibody, will have cytomegalovirus (CMV), human immunodeficiency virus (HIV), toxoplasmosis, human herpesvirus 6 (HHV-6), hepatitis B, or possibly human herpesvirus 7 (HHV-7).

Specimen requirement is one SST tube of blood. 

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