What are the causes and treatments of non-Epstein-Barr Virus (EBV) mononucleosis?

Causes of Non-EBV Mononucleosis

The most common causes of non-EBV mononucleosis are cytomegalovirus (CMV), Toxoplasma gondii, and human immunodeficiency virus (HIV), with CMV being the predominant non-EBV etiology. 1

Viral Causes

Cytomegalovirus (CMV)

• Most frequent non-EBV viral cause of mononucleosis syndrome
• Key differences from EBV mononucleosis:
  • Heterophil antibody response is absent (heterophil-negative mononucleosis) 2
  • CMV is found in both polymorphonuclear and mononuclear leukocytes (vs. EBV which is restricted to B lymphocytes) 2
  • More likely to present with hepatitis and pneumonitis due to direct viral cytopathic effects 2
  • Less prominent tonsillopharyngitis compared to EBV mononucleosis

Human Immunodeficiency Virus (HIV)

• Acute HIV infection can mimic infectious mononucleosis 1
• Should be considered in patients with risk factors for HIV exposure
• Critical to diagnose early due to implications for treatment and transmission prevention

Parasitic Causes

Toxoplasma gondii

• Important cause of heterophil-negative mononucleosis 2, 1
• Complications can affect:
  • Heart
  • Skeletal muscle
  • Central nervous system
• Pathology related to direct invasion by the parasite 2
• Can cause severe congenital infections if acquired during pregnancy 1

Diagnostic Approach for Non-EBV Mononucleosis

1. Initial testing:

   • Complete blood count with differential (looking for lymphocytosis with atypical lymphocytes)
   • Heterophile antibody test (negative in non-EBV causes)
   • EBV-specific antibody panel (VCA IgM, VCA IgG, EBNA IgG) to rule out EBV 3

2. When heterophile test is negative but mononucleosis is suspected:

   • CMV IgM and IgG antibodies
   • Toxoplasma IgM and IgG antibodies
   • HIV testing (antigen/antibody combination test)
   • PCR-based viral panels can help identify specific viral infections 3

3. Interpretation challenges:

   • Cross-reactions between tests can occur
   • Markers of acute infection may persist for several months 1
   • IgG avidity testing can help distinguish between recent and past infection 3

Treatment Approaches

CMV Mononucleosis

• Primarily supportive care:
  • Adequate hydration
  • Analgesics
  • Antipyretics
  • Rest guided by patient's energy level 4
• No routine antiviral therapy recommended for immunocompetent patients
• Ganciclovir or valganciclovir may be considered in severe cases or immunocompromised patients 5

Toxoplasmosis

• Specific antimicrobial treatment with pyrimethamine plus sulfadiazine
• Treatment duration depends on severity and organ involvement

HIV

• Early initiation of antiretroviral therapy is recommended
• Short course of corticosteroids may be considered for severe inflammation 5

Special Considerations

Immunocompromised Patients

• Higher risk for severe complications with any infectious cause of mononucleosis
• More aggressive diagnostic workup and treatment approach needed
• Patients on immunosuppressive therapy, particularly anti-TNF agents, are at higher risk for viral reactivation 3

Complications to Monitor

• Hepatitis (more common with CMV)
• Pneumonitis (more common with CMV)
• Neurological manifestations (particularly with Toxoplasma)
• Hemophagocytic lymphohistiocytosis (HLH) - can be triggered by various viral infections 5

Prevention

• Standard hygiene measures:
  • Frequent handwashing
  • Avoiding sharing utensils, glasses, or food
  • Covering coughs and sneezes 3

Non-EBV causes of mononucleosis should be considered when patients present with mononucleosis-like symptoms but have negative heterophile antibody tests or atypical presentations. Proper identification of the specific etiology is crucial for appropriate management and prevention of complications.