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Laboratory Tests for Infectious Mononucleosis

King, Brent R. MD

Pediatric Rounds: Part 3 in a Series

Dr. King is an associate professor of emergency medicine and pediatrics, and the chairman of the department of emergency medicine at the University of Texas Houston Medical School.

A rash following treatment with amoxicillin in an adolescent is evidence that the actual diagnosis is mononucleosis

Rashes can be associated with infectious mononucleosis, and the likelihood of rash increases greatly for patients with infectious mononucleosis who receive ampicillin or amoxicillin. The rash is generally described as an erythematous maculopapular exanthem, and typically occurs between five and nine days after the initiation of antibiotic treatment.

The pathophysiology of this rash has not yet been described, but it does not seem to represent a true allergic reaction. In the adolescent with apparent streptococcal pharyngitis, a rash following treatment with amoxicillin should be consider de facto evidence that the actual diagnosis is mononucleosis.

The most common test for detecting Epstein-Barr virus uses heterophile antibodies

Although rare, a few neurologic conditions have been associated with infectious mononucleosis. The most common are Guillain-Barre syndrome, cranial nerve palsies, aseptic meningitis, and meningoencephalitis. Additionally, a very rare neuropsychiatric condition known as metamorphopsia sometimes occurs.

Also known as the Alice in Wonderland syndrome, this condition results in significant deficits in perception that the affected patient is unable to determine the size and shape of objects and has impairment in spatial orientation.

Unfortunately, the degree to which these neurological conditions are related to infectious mononucleosis is unknown because the association is generally a temporal one, and in many cases, the actual virus was not identified.

It is difficult to determine how often infection with Epstein-Barr virus results in fatal disease. Some estimates suggest that Epstein-Barr is fatal in one of 3000 cases, but many cases in the literature are of questionable validity. Certainly, it is known that some patients succumb to severe upper airway obstruction or to splenic rupture. Additionally, some neurologic complications of infectious mononucleosis have resulted in death.

A majority of 20 patients with infectious mononucleosis in a 1970 literature review died of neurologic complications. Liver failure in association with infectious mononucleosis also has been noted. There also is an aggressive form of Epstein-Barr virus infection known as the hemophagocytic syndrome. This aggressive illness is usually but not always described in immunocompromised hosts. Finally, there is an X-linked syndrome in which there is ineffective regulation of the cytotoxic cellular response to Epstein-Barr virus infection. This condition is also fatal, and generally occurs in early childhood.

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Laboratory Tests

Most patients with infectious mononucleosis have a benign course of illness, and because no therapy exists for Epstein-Barr virus, it could be argued that there is little sense in making a laboratory diagnosis in the presence of strong clinical evidence of infection. But most clinicians would like to confirm their clinical impressions, and a variety of laboratory tests have been developed and used to make a more definitive diagnosis.

These tests come in essentially two varieties. The most common are those utilizing heterophile antibodies. These tests detect nonspecific antibodies produced in reaction to Epstein-Barr virus infection. They are found in up to 70 percent of patients by the end of the first week of illness and 80 to 90 percent by the third week of illness. These antibodies are IGM antibodies, and are called heterophile because they react to a variety of organisms.

Other infections that produce these antibodies create lower antibody levels than those by the Epstein-Barr virus. In their simplest form, heterophile antibody-type tests are the basis for the monospot test, a qualitative laboratory test that measures the presence of heterophile antibodies. When a patient with clinical symptoms of infectious mononucleosis has a positive monospot test, the clinician can be reasonably sure that his diagnosis is correct.

The monospot test can be performed in approximately two minutes, and will be positive in 70 percent of patients within five to seven days of symptom onset. If the clinician requires more support, then a quantitative heterophile antibody test demonstrating high concentrations of antibody provides even greater evidence of an Epstein-Barr virus infection. Many rapid commercial kits are available, and have sensitivities ranging from 63 to 84 percent.

They do tend to be highly specific, 84 to 100 percent. With almost all of these commercial kits, some false positives and false negatives exist. At least one of these kits is based upon ELISA technology, and actually measures the presence of an Epstein-Barr virus-specific antibody. In at least one study comparing this technique with Epstein-Barr virus-specific serology performed by indirect immunofluorescence, the rapid test had several false positives.

Rapid heterophile antibody tests are not useful in children under 4. Only 20 percent of patients in this group will have positive heterophile antibody tests. Another problem with heterophile tests is that they remain positive for nearly a year after infection, so a positive test does not necessarily imply active disease.

Certainly, there are several tests that detect Epstein-Barr virus-specific antibodies. In conjunction with typical symptoms, these techniques provide the most accurate means of diagnosing infectious mononucleosis caused by Epstein-Barr virus. Compared with rapid tests, though, these techniques are expensive and time-consuming. Although they may be useful in cases in which a child has a mononucleosis-like syndrome and a negative monospot test, they are of little use to the emergency physician.

These tests also may be useful in identifying Epstein-Barr virus as the cause of an unidentified constellation of symptoms that does not resemble infectious mononucleosis. They may be useful in young children and in those patients with prolonged symptoms. Finally, because the Epstein-Barr virus-specific antibodies are produced at different periods during the infectious process, Epstein-Barr virus-specific serologies can be used to identify the phase of the illness.

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Suggested Reading

1. Hickey SM, Strasberger VC. What every pediatrician should know about infectious mononucleosis in adolescents. Pediatr Clin of NA 1997;44:1541.
    © 2003 Lippincott Williams & Wilkins, Inc.