In a cytomegalovirus (CMV)-induced mononucleosis-like illness, can heterophile antibodies be positive?

Heterophile Antibodies in CMV Mononucleosis-like Illness

Heterophile antibodies can be positive in a mononucleosis-like illness caused by cytomegalovirus (CMV), although this is uncommon. 1

Serological Patterns in Viral Mononucleosis Syndromes

CMV vs. EBV Mononucleosis

• EBV is the most common cause of infectious mononucleosis and typically presents with:

  • Positive heterophile antibodies (Monospot test) in 70-92% of cases 2
  • Classic triad of fever, tonsillar pharyngitis, and lymphadenopathy 3

• CMV mononucleosis-like illness typically presents with:

  • Negative heterophile antibodies in most cases 4
  • Prolonged fever (average 20 days) 4
  • Less frequent lymphadenopathy compared to EBV mononucleosis 4
  • Atypical lymphocytosis and mild transaminitis 4

Diagnostic Considerations

False-Positive Heterophile Tests

• While uncommon, false-positive heterophile antibody tests can occur in CMV infection 1
• The first documented case of heterophile-positive mononucleosis syndrome caused by acute CMV infection in an elderly immunocompetent woman was reported in 2015 1
• Other conditions that can cause false-positive heterophile tests include:
  • Viral hepatitis
  • HIV
  • Leukemia/lymphoma
  • Pancreatic cancer
  • Systemic lupus erythematosus
  • Rubella
  • Dengue fever 5

Proper Diagnostic Approach

• When evaluating a mononucleosis-like illness:

  1. Consider heterophile antibody testing (Monospot) as initial screening
  2. If clinical suspicion for viral mononucleosis is high but heterophile test is negative, proceed with specific viral serologies
  3. For CMV diagnosis, test for CMV IgM and IgG antibodies 6
  4. PCR-based viral detection can confirm active viral replication 7

• For EBV diagnosis, the standard antibody panel includes:

  • Viral Capsid Antigen (VCA) IgM
  • Viral Capsid Antigen (VCA) IgG
  • Epstein-Barr Nuclear Antigen (EBNA) IgG 7

Clinical Pearls and Pitfalls

Pearls

• The combination of fever of unknown origin, negative heterophile antibody test, and presence of atypical lymphocytes (virocytes) should raise suspicion for CMV mononucleosis 4
• CMV mononucleosis typically presents with longer duration of fever and less lymphadenopathy compared to EBV mononucleosis 4

Pitfalls

• Relying solely on heterophile antibody testing can lead to misdiagnosis, as up to 10% of EBV mononucleosis cases are heterophile-negative 2
• Assuming that a positive heterophile test always indicates EBV infection can lead to missed diagnoses of other conditions, including CMV infection 1
• Not considering the timing of antibody testing can affect results, as antibody responses evolve over the course of infection 7

In summary, while heterophile antibodies are typically negative in CMV mononucleosis-like illness, rare cases of heterophile-positive CMV infection have been documented. Comprehensive serological testing is recommended when evaluating patients with mononucleosis-like syndromes to ensure accurate diagnosis.