What causes frequent flares of infectious mononucleosis (mono)?

Causes of Frequent Flares of Infectious Mononucleosis (Mono)

Frequent flares of infectious mononucleosis are primarily caused by reactivation of latent Epstein-Barr virus (EBV) in the setting of immune dysfunction or immunosuppression, rather than representing new infections. 1

Underlying Mechanisms of EBV Flares

Immune System Factors

• Immunosuppression: Patients on immunosuppressive therapy are at significantly higher risk for EBV reactivation 1
• Chronic Active EBV (CAEBV): Defined by persistent or recurrent infectious mononucleosis-like symptoms, unusual pattern of anti-EBV antibodies, and increased EBV genomes not explained by other diseases 1
• Immunocompromised state: Patients with compromised immune systems have atypical presentations and serologic responses, requiring more comprehensive testing including EBV viral load by PCR 1

Diagnostic Indicators of Reactivation vs. Primary Infection

• Primary infection: Characterized by positive VCA IgM and VCA IgG with negative EBNA IgG
• Past infection (>6 weeks): Indicated by positive EBNA IgG (with or without VCA IgG) 1
• Reactivation: May show elevated EBV viral load by PCR despite positive EBNA IgG 1

Risk Factors for Frequent Flares

Medication-Related Factors

• Immunosuppressive medications: Particularly anti-TNF agents which appear to confer higher risk for serious infections compared to other immunosuppressants 2
• Inadequate prophylaxis: Studies show 72.8% of patients with recurring infections had inadequate prophylaxis 2

Patient-Related Factors

• Age: Older patients are more likely to experience reactivation 1
• Post-infectious fatigue syndrome: Approximately 5-6% of patients develop this condition after acute EBV infection, which may be mistaken for flares 1
• Underlying autoimmune conditions: These can predispose to more frequent EBV reactivation 2

Clinical Presentation of Flares

Symptoms of Reactivation

• Intermittent mono-oligoarthritis: Can occur as flares that frequently coincide with skin manifestations 2
• Fatigue: May be profound and persist for months 3
• Fever, pharyngitis, lymphadenopathy: The classic triad may recur during flares 3
• Hepatosplenomegaly: Occurs in approximately 50% (spleen) and 10% (liver) of cases 3

Management Approach for Frequent Flares

Diagnostic Workup

1. Complete EBV serological panel: To distinguish between reactivation and new infection
2. EBV viral load testing by PCR: Particularly important if symptoms are severe or persistent 1
3. Rule out other causes: Evaluate for other infections, autoimmune conditions, or malignancies

Treatment Strategies

1. Supportive care: Rest, adequate hydration, and pain relievers for symptomatic relief 1
2. Activity modification: Avoid contact sports or strenuous exercise for at least 8 weeks or while splenomegaly is present 1
3. Consider referral: If symptoms persist beyond 6 months with no improvement, refer to an infectious disease specialist 1

Special Considerations

Immunocompromised Patients

• At increased risk for lymphoproliferative disorders 1
• May require more aggressive monitoring and management
• Consider temporary withholding of immunosuppressive therapy until resolution of active infection 2

Prevention Strategies

• Avoid direct contact with saliva of infected individuals 1
• Consider EBV IgG screening before initiation of immunomodulator therapy in certain patients 1
• No vaccine is currently available 1

Common Pitfalls in Managing EBV Flares

1. Misdiagnosis: Confusing reactivation with new infection or other conditions
2. Unnecessary treatments: Acyclovir therapy does not improve outcomes in otherwise healthy individuals 1
3. Inappropriate steroid use: Steroids may be indicated for airway obstruction but are not routinely recommended 1
4. Inadequate monitoring: Failing to monitor for complications such as splenic rupture, which occurs in 0.1-0.5% of patients 3
5. Premature return to activity: Allowing return to contact sports before resolution of splenomegaly 1

Remember that while most cases of infectious mononucleosis are self-limiting, persistent or recurrent symptoms warrant further investigation, particularly in immunocompromised patients or those on immunosuppressive therapy.