Can a person test positive for mononucleosis (mono) more than once?

Can a Person Test Positive for Mononucleosis More Than Once?

Yes, a person can test positive for mononucleosis more than once, though this represents either reactivation of latent Epstein-Barr virus (EBV) infection or, less commonly, a new infection with a different viral strain.

Understanding Recurrent Positive Tests

True Recurrence vs. Persistent Antibodies

The interpretation of repeat positive mono tests depends critically on which test is being used:

• Heterophile antibody tests (Monospot) typically become negative within several months after acute infection, so a positive test after documented clearance suggests reactivation or reinfection 1
• EBV-specific antibody patterns persist lifelong after primary infection, making interpretation more complex 2

Documented Cases of Recurrence

Recurrence of infectious mononucleosis after complete remission has been documented in adults, even after years of being symptom-free. A case report describes a 28-year-old man who developed recurrent IM with positive anti-EBV testing three years after initial remission, confirmed by clinical manifestations and laboratory evidence of viral reactivation 3. This demonstrates that EBV can reactivate after prolonged dormancy.

Diagnostic Approach to Suspected Recurrence

Initial Testing Strategy

When a patient presents with mono-like symptoms and prior history of infectious mononucleosis:

• Order complete blood count with differential looking for >40% lymphocytes and >10% atypical lymphocytes 1
• Perform heterophile antibody testing (sensitivity 87%, specificity 91%), recognizing it can be falsely negative in the first week of illness 1
• Check liver enzymes as elevated transaminases increase suspicion for IM even with negative heterophile testing 1, 3

Confirmatory Testing for Recurrence

If heterophile antibody testing is negative but clinical suspicion remains high:

• EBV viral capsid antigen (VCA) IgM antibody is the most valuable serologic finding during acute primary or reactivated EBV infection 2
• EBV-specific antibody panels are more sensitive and specific than heterophile testing, though more expensive and time-consuming 1
• The presence of VCA-IgM indicates active viral replication, whether from primary infection or reactivation 2

Clinical Patterns of Recurrence

Chronic Active EBV Syndrome

Some patients develop chronic symptoms with persistent serologic evidence of active EBV infection:

• 57% of patients with chronic mononucleosis syndrome achieved temporary remission after an average of 33 months, but sustained remission was rare 4
• These patients often show partial hypogammaglobulinemia (71%) and minor T-cell subset abnormalities 4
• 86% had concurrent serologic evidence of cytomegalovirus infection, suggesting broader immune dysregulation 4

Timing and Presentation

Recurrent IM typically presents with:

• Classic triad of fever, pharyngitis, and cervical lymphadenopathy 2, 3
• Tonsillar enlargement and systemic symptoms (fatigue, muscle pain) 3
• Possible mild liver damage with elevated transaminases 3

Important Clinical Caveats

False-Negative Heterophile Testing

The heterophile antibody test has significant limitations that can lead to missed diagnoses:

• False-negative results are common in children under 5 years 1
• False-negative results occur frequently during the first week of illness in adults 1, 5
• If clinical suspicion is high with negative heterophile testing, proceed directly to EBV-specific antibody testing 5

Alternative Diagnoses to Consider

When heterophile testing is negative, consider:

• Cytomegalovirus infection 5
• Toxoplasmosis 5
• Streptococcal pharyngitis 5
• Other viral infections 5

Management of Recurrent Disease

Treatment remains supportive, identical to primary infection:

• Adequate hydration, analgesics, and antipyretics 5
• Activity guided by patient's energy level rather than enforced bed rest 5
• Antiviral therapy, corticosteroids, and antihistamines are not recommended for routine treatment 5
• Corticosteroids reserved only for respiratory compromise or severe pharyngeal edema 5
• In documented recurrence cases, combination of antiviral, anti-infective, and hepatoprotective drugs with vitamin supplements has been used successfully 3

Return to Activity Restrictions

Patients must be withdrawn from contact or collision sports for at least 4 weeks after symptom onset due to splenic rupture risk, the most common potentially fatal complication 5, 2. Current guidelines recommend 3 weeks from symptom onset, with shared decision-making for return timing 1.

Long-Term Monitoring

Long-term follow-up and monitoring are essential for patients with recurrent IM 3. Fatigue, myalgias, and increased sleep requirements may persist for several months after acute infection resolution 5. EBV infection has been linked to nine types of cancer and some autoimmune diseases, warranting ongoing surveillance 1.