Q:

10/4/2013
I am following a 16 year-old girl who was diagnosed with infectious mononucleosis in April of this year. She initially had fever to about 100 degrees Fahrenheit, sore throat and persistent hoarseness. The fatigue slowly improved over 2-3 months but now she is more fatigued and is missing days of school. I checked her EB antibody screen and here are the results:
EBV VCA IgG -negative
EBV VCA IgM - positive
EBNA AB- negative

It has been 5 months and she has not produced EBNA antibodies, nor VCA IgG. I am tempted to repeat the tests but am looking for further advice to make sure I order the correct tests.

A:

Thank you for your inquiry.

The diagnosis of infectious mononucleosis can be difficult and, as you know, in many instances such a diagnosis is made without adequate verification. One of the things you might do at this time, especially if it has not been done, is order a test of heterophile antibodies. They can be done quickly. An example is a monospot, and an ELISA can also be performed. Assays for reactive heterophile antibodies are not highly sensitive, but are fairly specific. False-negative results are most common early in the course, and since your patient has had symptoms for a while, the false-negative rate should have declined. Rare false-positive heterophile tests have been reported in conditions which your patient does not appear to have including rubella, HIV infection, systemic lupus erythematosus, leukemia, lymphoma, and pancreatic cancer.

Heterophile antibodies should persist at low levels for as long as a year after the onset of the illness.

Also, as you have done, EBV specific antibodies are used. These are often not necessary because the many patients will be heterophile-positive, but specific EBV antibodies can be helpful in patients who are heterophile-negative. Both IgM and IgG antibodies directed against viral capsid antigen have a high sensitivity and specificity. Normally, IgM antibodies are present at the onset of the illness and wane considerably by three to four months. And, as you intimated, IgG antibodies follow the production of IgM and persist for life. The absence of an IgG antibody would therefore imply she did not have mononucleosis or she is unable to class switch from IgM to IgG.

It should also be noted that the presence of IgM VCA antibodies, although highly suggestive of acute EBV infection, can occur with infection with other herpes viruses. And during illnesses associated with intense immune activation, serological EBV reactivation with detectable EBV IgM VCA antibodies has been described.

In addition to the capsid antibodies, you might consider obtaining an IgG antibody to EBV nuclear antigen (EBVNA), a protein expressed only when the virus begins to establish latency - about 6 to 12 weeks after the onset of symptoms. This antibody persists for life.

Finally, you could consider ordering a test for the presence of EBV DNA. This is done through polymerase chain reaction on blood or plasma. This test is usually used for detection of infection after transplantation, and at this stage in your patient’s illness may not be positive, but would be definitive in terms of allowing you to know if the disease was active (nonetheless highly unlikely at this point).

All of the above are options for you, but at this point in time, I would, as you have mentioned, simply reorder IgM and anti-IgG VCA, and if M is positive and she has not converted, consider the more specific tests mentioned above.

Finally, if you do find the same results, you could also immunize with a T cell-dependent as well as a T cell-independent antigen. DT would be an example of the former, and Pneumovax of the latter. Pre-titers before immunization and post-titers four weeks later can be drawn to assess the adequacy of her immune response to each.

Thank you again for your inquiry and we would be happy to receive a follow-up if you perform these studies.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology