Can you contract infectious mononucleosis (mono) more than once and what tests are used to diagnose a second infection?

Can You Have Mono More Than Once?

True recurrent infectious mononucleosis from Epstein-Barr virus (EBV) is extremely rare because after primary infection, the virus establishes lifelong latency and individuals develop lasting immunity, making a second episode of clinical mononucleosis highly unlikely in immunocompetent patients. 1

Understanding EBV Infection and Immunity

After primary EBV infection, the virus persists in B-cells with minimal latent gene expression, controlled by EBV-specific cytotoxic T-lymphocytes. 1 Over 90% of adults worldwide are seropositive for EBV, indicating past infection and immunity. 1, 2 Once infected, antibodies to EBNA (Epstein-Barr nuclear antigen) develop 1-2 months after primary infection and remain detectable for life, providing lasting immunity. 1

What appears to be "recurrent mono" is typically one of the following:

• Initial misdiagnosis - The first illness may have been caused by cytomegalovirus (CMV), adenovirus, HIV, or Toxoplasma gondii, which can all cause mononucleosis-like syndromes 1
• Reactivation in immunocompromised patients - Not true recurrence but viral reactivation when T-cell immunosurveillance is impaired 1
• Different infection entirely - The second illness may be an unrelated condition mimicking mononucleosis 3

Testing for Suspected Second Infection

When a patient presents with mononucleosis-like symptoms and reports having had mono previously, the diagnostic approach should differentiate between true EBV reinfection (extremely rare), reactivation, or an alternative diagnosis:

Initial Testing Algorithm

1. Complete blood count with differential 4

   • Look for >40% lymphocytes and >10% atypical lymphocytes
   • Atypical lymphocytosis ≥20% or ≥10% atypical lymphocytes plus ≥50% total lymphocytosis strongly supports acute infection 3

2. Heterophile antibody test (Monospot) 1, 4

   • Sensitivity 87%, specificity 91% 4
   • Important caveat: False-negative results occur in approximately 10% of patients, especially in children <10 years and during the first week of illness 1, 4
   • Heterophile antibodies become detectable between days 6-10 after symptom onset 1

When Heterophile Test is Negative

If clinical suspicion remains high despite negative heterophile testing, proceed with EBV-specific antibody testing: 1

1. EBV Viral Capsid Antigen (VCA) and EBNA antibody panel 1

Interpretation patterns:

• Recent primary infection: VCA IgM positive (with or without VCA IgG), EBNA negative 1, 5
• Past infection (>6 weeks): VCA IgG positive, EBNA positive, VCA IgM negative 1
• Not EBV: All negative - consider alternative diagnoses like CMV, HIV, toxoplasmosis 1

If the patient has positive EBNA antibodies, this indicates infection occurred more than 6 weeks prior and EBV is NOT the cause of current symptoms. 1 In this scenario, you must investigate alternative causes of the mononucleosis-like syndrome.

Critical Clinical Caveats

• Approximately 5-10% of EBV-infected patients fail to develop EBNA antibodies, which can complicate interpretation 1
• Immunocompromised patients (transplant recipients, HIV patients, those on immunosuppressive therapy) can develop EBV-associated lymphoproliferative disease rather than typical mononucleosis, requiring EBV viral load testing via nucleic acid amplification testing (NAAT) 1
• In immunosuppressed IBD patients on thiopurines, primary EBV infection carries particular risk, with fatal cases reported 1
• Elevated liver enzymes increase clinical suspicion for infectious mononucleosis when heterophile testing is negative 4

Alternative Diagnoses to Consider

When evaluating suspected "recurrent mono," systematically exclude:

• Cytomegalovirus infection 1
• Acute HIV infection 1
• Toxoplasmosis 1, 3
• Streptococcal pharyngitis 3
• Adenovirus infection 1