What is the diagnosis and treatment for Epstein-Barr Virus (EBV) infection?

Epstein-Barr Virus (EBV): Diagnosis and Treatment

Diagnosis of Acute EBV Infection (Infectious Mononucleosis)

For acute infectious mononucleosis, begin with a heterophile antibody test (monospot), which has 71-90% accuracy but carries a 25% false-negative rate in the first week of illness. 1

Initial Diagnostic Approach

• Heterophile antibody testing is the best initial test for diagnosing infectious mononucleosis, though the Paul-Bunnell and monospot tests are considered suboptimal by some guidelines 2
• Lymphocyte count below 4,000/mm³ makes infectious mononucleosis unlikely 1
• If heterophile testing is negative but clinical suspicion remains high, proceed to EBV-specific serology 1

EBV-Specific Serologic Testing

Primary EBV infection is confirmed by detecting IgM and IgG antibodies against viral capsid antigen (VCA) with negative EBNA1 IgG 2

The serologic pattern interpretation:

• Acute infection: VCA IgM positive, VCA IgG positive or negative, EBNA negative 3
• Past infection: VCA IgG positive, VCA IgM negative, EBNA positive (appears weeks to months after infection and persists indefinitely) 3
• Never infected: All antibodies negative 4

Clinical Presentation to Recognize

Suspect infectious mononucleosis when patients present with:

• Sore throat, fever, and tonsillar enlargement 1
• Fatigue, lymphadenopathy, and pharyngeal inflammation 1
• Palatal petechiae 1
• Atypical lymphocytes on blood smear 1, 5
• Abnormal liver function tests 5

Treatment of Acute EBV Infection

Symptomatic relief is the mainstay of treatment; aciclovir does not ameliorate the course of infectious mononucleosis in otherwise healthy individuals. 2

Management Approach

• Provide supportive care only - antivirals and glucocorticoids do not reduce the length or severity of illness 1
• Steroids may be indicated specifically for airway obstruction 2
• Restrict physical activity for the first three weeks to reduce risk of splenic rupture 1
• Monitor for complications, particularly in high-risk groups 1

Key Complications to Monitor

• Splenic rupture: Uncommon but serious; avoid athletic participation for three weeks 1
• Airway obstruction: Most common cause of hospitalization, highest risk in children 1
• Autoimmune hemolytic anemia: Rare but can occur with cold agglutinins 6
• Biliary stasis: Elevated transaminases and direct hyperbilirubinemia should raise suspicion 6

Diagnosis of Chronic Active EBV (CAEBV)

CAEBV requires three mandatory criteria: (1) persistent or recurrent IM-like symptoms, (2) unusual antibody patterns with markedly elevated VCA-IgG ≥1:640 and EA-IgG ≥1:160, and (3) chronic illness unexplained by other diseases. 2

Diagnostic Criteria for CAEBV

All three categories must be fulfilled 2:

1. Persistent or recurrent IM-like symptoms including fever, lymphadenopathy, hepatosplenomegaly, with possible complications affecting hematological, digestive, neurological, pulmonary, ocular, dermal, or cardiovascular systems 2

2. Unusual antibody patterns: VCA-IgG ≥1:640 and EA-IgG ≥1:160, often with positive IgA antibodies to VCA and/or EA 2

3. Exclusion of other known disease processes at diagnosis 2

Recommended Specific Laboratory Tests for CAEBV

• Quantitative PCR: More than 10^2.5 copies/mg DNA in peripheral blood mononuclear cells (note: healthy individuals occasionally show positive qualitative PCR) 2
• EBER in situ hybridization to detect EBV presence in tissues 2
• Identify target cells of EBV infection (B-cells, T-cells, NK-cells, or monocytes/macrophages) using double staining techniques 2
• Histopathological evaluation with immunohistological staining and chromosomal analysis 2

Critical Distinction

CAEBV is not the same as chronic fatigue following acute mononucleosis - it represents a rare, severe condition with poor prognosis, particularly when associated with late onset, thrombocytopenia, and T-cell infection 2

Associated Conditions

• Hemophagocytic lymphohistiocytosis may develop during illness course 2
• T-cell or NK-cell lymphoproliferative disorders/lymphomas often emerge 2
• Hypersensitivity to mosquito bites is characteristic in some patients 2
• Coronary aneurysms or valvular disease are of particular concern 2

Special Considerations for Immunosuppressed Patients

EBV IgG screening should be considered before initiating immunomodulator therapy, with anti-TNF monotherapy preferred over thiopurines in EBV seronegative patients. 2

Risk in Immunosuppressed Populations

• Primary EBV infection during immunosuppression poses particular threat, with two reported fatal cases of infectious mononucleosis in males under 50 on thiopurines 2
• Thiopurine therapy increases lymphoproliferative disorder risk with a hazard ratio of 5.28, resulting in one additional lymphoma per 300-1400 years of treatment 2
• Post-transplant lymphoproliferative disease (PTLD) requires biopsy with EBER in situ hybridization for diagnosis; immunohistochemistry alone is inadequate as viral proteins like LMP-1 are often not expressed 2
• Antivirals have no proven role in established PTLD due to limited productive viral infection 2