Infectious Mononucleosis (IM) in Emergency Medicine Workup

Updated: Nov 11, 2022
  • Author: Michael S Omori, MD; Chief Editor: Gil Z Shlamovitz, MD, FACEP  more...
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Laboratory Studies

White blood cell count

The WBC count and differential can be useful in establishing a diagnosis of infectious mononucleosis. [7]

WBC count results usually show a modest elevation, with a peak of 10,000-20,000 during the second or third week of the illness.

Findings consistent with infectious mononucleosis include a differential that demonstrates greater than 50% lymphocytes, an absolute lymphocyte count greater than 4500, or an elevated lymphocyte count with greater than 10% atypical lymphocytes.

Liver function tests

Liver function tests (LFTs) are abnormal in more than 90% of patients with infectious mononucleosis. [7]

Serum transaminase and alkaline phosphatase levels usually are modestly elevated.

The serum bilirubin may be increased in approximately 40% of patients, but jaundice only occurs in approximately 5% of infectious mononucleosis cases.


Other Tests

Heterophile test

The heterophile test is the most common and specific test to confirm the diagnosis of infectious mononucleosis. [7]

Paul and Bunnell first described the presence of heterophile antibody in patients with infectious mononucleosis in 1932. The heterophile antibody is an immunoglobulin M (IgM) antibody produced by infected B lymphocytes.

It is not directed against Epstein-Barr virus (EBV) or EBV-infected cells, but it is a result of the infection and the subsequent transformation of the B cell to a plasmacytoid state.

In the heterophile test, human blood is first absorbed by a guinea pig kidney. Then, it is tested for agglutination activity that is directed against horse, sheep, or cow erythrocytes. Successive dilutions yield a titer; a titer of 40 or greater is considered a positive test.

The heterophile antibody is present in 40-60% of patients with infectious mononucleosis in the first week of the illness and in 80-90% of cases by the third or fourth week.

Repeated testing may be indicated in patients with the clinical syndrome who tested negative early in the course of the illness. As few as 50% of patients who are younger than 4 years may develop the heterophile antibody.

The heterophile response usually persists for 3 months, although it may be present for as long as a year following onset. While the heterophile test is a quantitative assay, the various Monospot tests are qualitative.

Monospot tests are slightly more sensitive (85%) than the heterophile assay, but false-positive findings may occur in children or in patients with other viral illnesses.

EBV-specific antibodies

While these assays are more expensive and time consuming, they may be indicated in patients with atypical presentation in whom EBV infection is suspected or in patients who present with persistently negative heterophile testing despite a clinical presentation consistent with EBV-related illness.

Young children, in particular, usually do not demonstrate heterophile antibodies, and EBV-specific antibodies may be the only serologic markers in such cases.

The EBV-specific antibodies are directed against EBV antigens, which develop in a typical time course reflective of the viral replication cycle.

These antigens are classified as early, late, or latent, depending on the phase of viral replication in which they appear. They also are differentiated by their location within the infected cells and by their response to methanol treatment.

Early antigens (EAs) become detectable 3-4 weeks following the onset of symptoms in approximately 70% of patients, especially those with severe symptoms.

Antibodies to these antigens include anti–EA-D antibody, which is found in a diffuse pattern within the cytoplasm and nucleus, and the anti–EA-R antibody, which is restricted to the cytoplasm of infected cells.

These antibodies usually persist for 3-6 months. EA-D antibodies are markers for patients with chronic active EBV infection and are prominent in patients with EBV-associated nasopharyngeal carcinomas. EA-R antibodies are less commonly detected in patients with chronic active EBV disease.

Viral capsid antigen (VCA) is considered a late phase antigen and represents viral structural protein. Immunoglobulin M (IgM) anti-VCA antibody is detectable at the onset of symptoms and persists for 1-3 months.

Immunoglobulin G (IgG) anti-VCA antibody also appears early in the course of the illness and reaches a peak 2-3 months following the outset. It then gradually declines to a steady state level, which persists for life. Antibodies to nuclear antigens (anti-EBNA) are considered latent phase markers.

These antibodies appear 3-6 weeks after the onset of disease and persist for life in patients who are immunocompetent. They may be undetectable in patients with chronic active disease.