What is the recommended management for an adolescent or young adult patient presenting with mononucleosis syndrome, caused by recent exposure to Epstein-Barr Virus (EBV)?

Management of Mononucleosis Syndrome in Adolescents and Young Adults

Treatment of infectious mononucleosis caused by EBV is primarily supportive, with no role for routine antiviral therapy or corticosteroids in uncomplicated cases. 1, 2

Supportive Care

• Rest and activity modification are the cornerstones of management, with bed rest as tolerated and reduction of strenuous activities 1, 3
• Adequate analgesia should be provided for pharyngitis and systemic symptoms 3
• Hydration and nutrition support should be maintained, particularly given the severe pharyngitis that often accompanies the illness 1

Activity Restrictions

• Patients must avoid contact sports and strenuous exercise for 8 weeks from symptom onset or while splenomegaly persists, whichever is longer 1
• This restriction is critical because spontaneous splenic rupture occurs in 0.1-0.5% of patients and represents the most feared complication 1, 2
• Shared decision-making should guide return to athletic activity after the initial 3-week period, with current guidelines recommending at minimum 3 weeks of no athletic participation 2

Pharmacologic Therapy

Corticosteroids

• Corticosteroids are indicated only for specific complications: upper airway obstruction from tonsillar hypertrophy 3
• They may be considered for neurologic, hematologic, or cardiac complications, though evidence is limited 3
• Routine corticosteroid use is not recommended for uncomplicated infectious mononucleosis 2

Antiviral Agents

• Antiviral medications (acyclovir, ganciclovir) are not recommended for routine treatment of infectious mononucleosis in immunocompetent patients 2
• In immunocompromised patients with severe primary EBV infection, antivirals such as ganciclovir or foscarnet may be considered despite limited evidence 4

Diagnostic Confirmation

• Initial testing should include complete blood count with differential looking for >40% lymphocytes and >10% atypical lymphocytes 2
• Rapid heterophile antibody test (Monospot) has 87% sensitivity and 91% specificity and serves as the primary diagnostic test 4, 2
• If heterophile test is negative but clinical suspicion remains high, proceed with EBV-specific antibody testing: VCA IgM and IgG, plus EBNA 4, 5
• Recent primary infection shows: VCA IgM positive, EBNA negative 4, 5

Special Populations: Immunosuppressed Patients

Critical Considerations for Adolescents on Immunosuppression

• In EBV-seronegative adolescents and young adults who require immunosuppression (particularly thiopurines), consider alternative immunomodulators 6
• Primary EBV infection in patients on thiopurines carries risk of hemophagocytic lymphohistiocytosis (HLH), a rare but commonly fatal condition, with 80% of pediatric HLH cases being EBV-related and all associated with thiopurine exposure 6
• In immunocompromised patients with severe EBV infection, reduction or discontinuation of immunomodulator therapy may result in spontaneous regression of EBV-associated disease 4

Monitoring in Immunosuppressed Patients

• EBV viral load testing via nucleic acid amplification testing (NAAT) is required rather than standard serology in immunocompromised patients 4
• Immunocompromised patients can develop EBV-associated lymphoproliferative disease rather than typical mononucleosis 4

Prognosis and Follow-up

• Most patients have an uneventful recovery with symptoms resolving within several weeks 1, 7
• Fatigue may be profound but typically resolves within 3 months 1
• Infectious mononucleosis is a risk factor for chronic fatigue syndrome 1
• Monitor for complications including splenic rupture (most feared), upper airway obstruction, neurologic abnormalities, and hematologic complications 1, 3

Common Pitfalls

• Avoid prescribing ampicillin or amoxicillin, as these cause a characteristic maculopapular rash in 90% of patients with infectious mononucleosis
• Do not allow premature return to contact sports before 8 weeks or resolution of splenomegaly, as this significantly increases risk of splenic rupture 1
• Do not assume recurrent mononucleosis is EBV reinfection—true recurrent infectious mononucleosis from EBV is extremely rare because individuals develop lasting immunity after primary infection 4
• When evaluating suspected "recurrent mono," systematically exclude CMV, acute HIV, toxoplasmosis, and adenovirus 4