Diagnosing Epstein-Barr Virus Infection

Diagnosing EBV in chronic fatigue syndrome is fraught with controversy. Dr. Lerner and Dr. Glaser believe that increased levels of antibodies to nonstructural proteins indicate a smoldering but still problematic EBV infection. Dr. Montoya believes that high IgG levels are indicative of EBV reactivation (not a first-time infection). The CDC believes neither of these tests are indicative of an important infection.

Since the issues revolve around antibodies a short primer on the antibody response and antibodies is below.

The antibody response

Immunoglobulins or antibodies are produced by B-cells when they are triggered by the presence of antigens. Antigens are anything that stimulates the immune system but typically they are proteins produced by pathogens.

Not necessarily dangerous in themselves, they are signs of danger that provoke the immune system to attack.  antibodies in chronic fatigue syndromeAfter a B-cell is activated it turns into a plasma cell which produces antibodies designed to attack anything carrying the antigen which activated that B-cell.

Antibodies neutralize pathogens in various ways. Quite large in size they can stop pathogens from infecting cells simply by attaching themselves to pathogens and blocking their docking mechanisms.

Once they are attached antibodies also send signals to phagocytes and to the complement system to attack and remove the invader. Antibodies only attack pathogens found outside of cells they are unable to attack intracellular pathogens except when they are dispersed in the bloodstream.

Antibody production is a hallmark of the humoral or Th2 immune response responsible for killing extracellular pathogens. Antibodies can also neutralize toxins.

Since pathogens typically carry several antigens the immune system typically produces multiple types of antibodies for each pathogen. Since the different antigens are often associated with different stages of the pathogens life cycle, assessing the types of antibodies present can help physicians chart the course of an infection.

Antibody Tests

  • IgM antibodies – because IgM antibodies usually appear early in an infection and then disappear they are often a sign of a recent infection or reactivation.
  • IgG antibodies – since IgG antibodies to a protein on the viral coat (viral capsid antigen) peak early in an infection and usually persist for life they usually denote nothing more than that a person has been exposed to a pathogen. IgG antibodies to an antigen produced early in EBV’s life cycle (early antigen) are produced only for 3-6 months and are a good indicator of an active infection. Since about 20% of healthy people carry this antibody for years the IgG early antigen test is, not definitive. Dr. Montoya believes, however, high IgG levels found in combination with other clinical signs of chronic fatigue syndrome accurately  reflect EBV reactivation. The success of the B-cell depleting drug Rituximab in post infectious mononucleosis ME/CFS patients with high IgG titers but no other evidence of infection ( including serological tests) suggests Dr. Montoya may be correct (see EBV Part II).
  • EBV nuclear antigen (EBNA) – since EBNA antibodies are found two to four months following the onset of EBV infection and persist for life they simply indicate that a very recent infection has not occurred. Assessing the EBNA test is complicated by the different ways of measuring it; while the standard immunoflorescent test does not detect EBNA for two to four months some immunoassays can detect within a few weeks of the initial infection.

There’s obviously some real grey area here and situation is quite complicated. The CDC posts the following guidelines for assessing EBV tests. The CDC believes EBV reactivation plays no role  in chronic fatigue syndrome.

CDC Guidelines for Assessing EBV Infection

First-time or primary infection

A first time EBV infection is indicated if IgM antibody to the viral capsid antigen is present and antibody to EBV nuclear antigen, or EBNA, is absent. A rising or high IgG antibody to the viral capsid antigen and negative antibody to EBNA after at least 4 weeks of illness is also strongly suggestive of primary infection. In addition, 80% of patients with active EBV infection produce antibody to early antigen.
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Past Infection

If antibodies to both the viral capsid antigen and EBNA are present, then past infection (from to 6 months to years earlier) is indicated. Since 95% of adults have been infected with EBV, most adults will show antibodies to EBV from infection years earlier. High or elevated antibody levels may be present for years and are not diagnostic of recent infection.


In the presence of antibodies to EBNA, an elevation of antibodies to early antigen suggests reactivation. However, when EBV antibody to the early antigen test is present, this result does not automatically indicate that a patient’s current medical condition is caused by EBV. A number of healthy people with no symptoms have antibodies to the EBV early antigen for years after their initial EBV infection. Many times reactivation occurs subclinically.

Chronic EBV infection

Reliable laboratory evidence for continued active EBV infection is very seldom found in patients who have been ill for more than 4 months. When the illness lasts more than 6 months, other causes of chronic illness or CFS should be investigated.


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