Could This Be Mono?
Yes, a young adult with mild lymphocytosis, elevated liver enzymes, and recent travel/exposure history could absolutely have infectious mononucleosis (EBV), and this clinical picture warrants immediate diagnostic testing with a heterophile antibody test and complete blood count with differential.
Diagnostic Approach
Initial Laboratory Testing
The most cost-effective and efficient initial workup includes 1:
Complete blood count with differential looking for:
Rapid heterophile antibody test (monospot) 3, 1:
- Sensitivity: 87%
- Specificity: 91%
- Critical caveat: Can be falsely negative during the first week of illness 1
When Heterophile Test is Negative
If the monospot is negative but clinical suspicion remains high (especially with elevated liver enzymes), proceed with 1:
- EBV viral capsid antigen (VCA) antibody testing - more sensitive and specific than heterophile testing 1
- Interpretation of EBV serology 4, 5:
- VCA IgM positive (with or without VCA IgG) + EBNA negative = recent primary infection
- VCA IgG >8.0 alone without IgM = past infection, not acute
- EBNA antibodies present = infection occurred >6 weeks ago
Diagnostic Probability Algorithm
Your patient has >20% probability of IM-like syndrome if at least 3 of these 4 predictors are present 2:
- Fever >7 days duration
- Lymphadenopathy (particularly posterior cervical)
- Elevated liver enzymes
- Lymphocytosis ≥40% of WBC
Clinical Context for Travelers
Important consideration: In febrile travelers returning from the tropics, IM-like syndromes account for 4% of presentations, but the pathogen distribution differs from typical domestic cases 2:
- CMV: 50% of IM-like cases
- Toxoplasma gondii: 22%
- EBV: 21%
- HIV primary infection: 7%
All four pathogens are clinically indistinguishable and should be tested simultaneously in travelers 2. The classic IM triad (fever, pharyngitis, lymphadenopathy) is often incomplete in travel-associated cases 2.
Key Clinical Features Supporting Mono
Classic Presentation 3, 1:
- Triad: fever, tonsillar pharyngitis, posterior cervical lymphadenopathy
- Profound fatigue (resolves within 3 months typically)
- Periorbital/palpebral edema (bilateral, occurs in 33% of cases) 3
- Splenomegaly (50% of cases) 3
- Hepatomegaly (10% of cases) 3
- Maculopapular rash (10-45% of cases) 3
Laboratory Findings 3:
- Peripheral blood leukocytosis
- Lymphocytes ≥50% of WBC differential
- Atypical lymphocytes >10% of total lymphocyte count
Critical Management Points
Activity Restriction
Patients must avoid contact sports and strenuous exercise for 8 weeks from symptom onset or while splenomegaly persists 3, as spontaneous splenic rupture occurs in 0.1-0.5% of cases and is potentially life-threatening 3.
Treatment
- Supportive care only - routine antivirals and corticosteroids are NOT recommended 1
- Activity reduction and rest as tolerated 3
Red Flags Requiring Further Investigation
If fever persists beyond 10 days after EBV diagnosis, this is NOT typical of uncomplicated primary infection and warrants evaluation for 6:
- Chronic Active EBV (CAEBV): Requires quantitative EBV PCR (viral loads >10^2.5 copies/μg DNA in peripheral blood mononuclear cells) 6, 4
- Hemophagocytic Lymphohistiocytosis (HLH): Check ferritin (>1000 ng/mL suggests HLH), cytokine analysis, consider bone marrow examination 6
- Secondary bacterial infection 6
Common Pitfalls to Avoid
- Don't assume negative heterophile test rules out EBV - test can be negative in first week of illness; proceed to VCA/EBNA serology 1
- Don't overlook elevated liver enzymes - this increases clinical suspicion for IM even with negative heterophile test 1, 7
- Don't forget to test for CMV, Toxoplasma, and HIV in travelers with IM-like syndrome, as these account for 79% of travel-associated cases 2
- Don't assume all EBV infections are self-limiting - persistent symptoms require thorough evaluation for CAEBV or HLH 6