Epstein-Barr Virus (EBV)

The Epstein-Barr virus (EBV) is a member of the herpes group and the primary cause of infectious mononucleosis.  It mainly affects young adults and children, although in children it is usually so mild that it is often overlooked.  Infectious mononucleosis is fairly common and both sexes are affected equally; prognosis is excellent, and major complications are uncommon. In the early 1990s several papers were published that described patients with CFS and serologic test results consistent with reactivated or persistent Epstein-Barr virus (EBV) infection.  This proposed connection led to the use of terms such as "chronic mononucleosis", "chronic EBV infection" and "postviral fatigue syndrome".  Further investigation failed to establish a pattern of disease and chronic infection with EBV.

Signs and Symptoms

Acute EBV Infection. Symptoms of mononucleosis mimic those of other infectious diseases, including hepatic dusfunction (hepatitis), rubella and toxoplasmosis.  Early symptoms include headache, malaise, and fatigue followed by a triad of symptoms: sore throat, cervical lymphadenopathy, and temperature fluctuations / fever.  Other consequences include increased lymphocytes and monocytes, and development of heterophil antibodies.  Symptoms typically subside about 6 to 10 days after onset of the disease but may persist for weeks.

'Chronic' EBV Infection. It is important to note that symptoms related to infectious mononucleosis caused by EBV infection seldom last for more than 4 months.  When such an illness lasts more than 6 months, it is frequently called chronic EBV infection.  However, valid laboratory evidence for continued active EBV infection is seldom found in these patients.  The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome (CFS).  This process includes ruling out other causes of chronic illness or fatigue.

Diagnosis and Tests

In most cases of infectious mononucleosis the clinical diagnosis can be made from the characteristic triad of fever, pharyngitis, and lymphadenopathy lasting for 1 to 4 weeks.  Serologic test results include a normal to moderately elevated white blood cell count, an increased total number of lymphocytes, greater than 10% atypical lymphocytes, and a positive reaction to a "mono spot" test.  In patients with symptoms compatible with infectious mononucleosis, a positive Paul-Bunnell heterophile antibody test result is diagnostic, and no further testing is necessary.

Laboratory tests are not always foolproof.  For various reasons, false-positive and false-negative results can occur for any test.  However, the laboratory tests for EBV are for the most part accurate and specific.  Because the antibody response in primary EBV infection appears to be quite rapid, in most cases testing paired acute- and convalescent-phase serum samples will not demonstrate a significant change in antibody level.  Effective laboratory diagnosis can be made on a single acute-phase serum sample by testing for antibodies to several EBV-associated antigens simultaneously.  In most cases, a distinction can be made as to whether a person is susceptible to EBV, has had a recent infection, has had infection in the past, or has a reactivated EBV infection.

Antibodies to several antigen complexes may be measured.  These antigens are the viral capsid antigen, the early antigen, and the EBV nuclear antigen (EBNA).  In addition, differentiation of immunoglobulin G and M subclasses to the viral capsid antigen can often be helpful for confirmation.  When the "mono spot" test is negative, the optimal combination of EBV serologic testing consists of the antibody titration of four markers: IgM and IgG to the viral capsid antigen, IgM to the early antigen, and antibody to EBNA. 

IgM to the viral capsid antigen appears early in infection and disappears within 4 to 6 weeks.  IgG to the viral capsid antigen appears in the acute phase, peaks at 2 to 4 weeks after onset, declines slightly, and then persists for life.  IgG to the early antigen appears in the acute phase and generally falls to undetectable levels after 3 to 6 months.  In many people, detection of antibody to the early antigen is a sign of active infection, but 20% of healthy people may have this antibody for years.

Antibody to EBNA determined by the standard immunofluorescent test is not seen in the acute phase, but slowly appears 2 to 4 months after onset, and persists for life.  This is not true for some EBNA enzyme immunoassays, which detect antibody within a few weeks of onset.

Finally, even when EBV antibody tests, such as the early antigen test, suggest that reactivated infection is present, this result does not necessarily indicate that a patient's current medical condition is caused by EBV infection.  A number of healthy people with no symptoms have antibodies to the EBV early antigen for years after their initial EBV infection.

Therefore, interpretation of laboratory results is somewhat complex and should be left to physicians who are familiar with EBV testing and who have access to the entire clinical picture of a person.  To determine if EBV infection is associated with a current illness, consult with an experienced physician.