Can Cytomegalovirus (CMV) cause a false positive or a true positive result in a heterophile antibody test?

Cytomegalovirus (CMV) and Heterophile Antibody Testing

CMV can cause false positive results in heterophile antibody tests, but it can also cause a true mononucleosis-like syndrome that would test negative on heterophile testing while being a true CMV infection. 1, 2

Relationship Between CMV and Heterophile Testing

False Positive Scenario

• CMV infection can cause false positive results in EBV-specific serologic tests, particularly in:
  • IgM antibody tests for EBV 2
  • Heterophile antibody tests in some cases 3

True Positive (CMV Mononucleosis) Scenario

• CMV can cause a mononucleosis-like syndrome that is clinically similar to EBV-induced infectious mononucleosis
• These patients typically have:
  • Infectious mononucleosis-type reactive blood smears
  • Negative heterophile antibody tests (not false positive, but true negative)
  • Mildly or moderately elevated liver enzymes
  • Evidence of subclinical hemolysis 4

Diagnostic Approach for Mononucleosis-Like Syndromes

Initial Testing

1. Heterophile antibody test (Monospot)
   • If positive: Suggests EBV-induced infectious mononucleosis
   • If negative: Consider other causes including CMV 1, 5

Follow-up Testing When Heterophile Test is Negative

When a patient has clinical features of mononucleosis but tests negative for heterophile antibodies:

1. EBV-specific serology:

   • Test for IgG and IgM antibodies to viral capsid antigen (VCA)
   • Test for antibodies to Epstein-Barr nuclear antigen (EBNA) 1

2. CMV-specific testing:

   • CMV IgM antibody testing (highly sensitive but may cross-react with acute EBV) 4
   • CMV PCR for definitive diagnosis in unclear cases 2

Prevalence of CMV in Heterophile-Negative Mononucleosis

Research shows that among patients with heterophile-negative tests who have absolute lymphocytosis or atypical lymphocytes:

• Approximately 39% test positive for CMV IgM antibodies
• About 40% test positive for EBV IgM antibodies
• When excluding patients with multiple positive viral tests, CMV accounts for 22% of cases 6

Potential Pitfalls in Interpretation

1. Cross-reactivity issues:

   • CMV IgM tests may show false positives in patients with autoimmune diseases like SLE 7
   • EBV IgM tests may show false positives in patients with acute CMV infection 3

2. Multiple infections:

   • Some patients may have evidence of both CMV and EBV infections simultaneously 4

3. Timing of testing:

   • Early in infection, serologic tests may be negative, requiring repeat testing 5

Clinical Differentiation

While clinical features overlap significantly, some laboratory findings may help differentiate:

• Downey type I lymphocytes may be more associated with CMV infection
• Downey type II atypical lymphocytes are more associated with EBV infection
• Downey type III lymphocytes are more associated with HHV-6 infection 6

In summary, when evaluating a patient with mononucleosis-like symptoms and a negative heterophile test, CMV should be high on the differential diagnosis, requiring specific CMV testing for confirmation.