Chronic Active Epstein-Barr Virus Infection (CAEBV): Diagnosis and Workup
Chronic active Epstein-Barr virus infection (CAEBV) is characterized by persistent EBV-infected T or NK cells with high viral loads, requiring confirmation of both high EBV DNA levels (≥10,000 IU/mL in whole blood) and identification of infected T or NK cells for diagnosis. 1
Definition and Clinical Presentation
CAEBV is a potentially life-threatening condition characterized by:
- Persistent or recurrent infectious mononucleosis-like symptoms
- Systemic inflammation
- Clonal proliferation of EBV-infected T or NK cells 2, 1
Common clinical manifestations include:
- Prolonged or intermittent fever
- Lymphadenopathy
- Hepatosplenomegaly
- Persistent hepatitis
- Recurrent or continuous debilitating fatigue
- Sore throat and lymph node tenderness
- Headache, myalgia, and arthralgia 2, 3
Additional complications may include:
- Hematological disorders (thrombocytopenia)
- Digestive tract manifestations
- Neurological symptoms
- Pulmonary involvement
- Ocular manifestations
- Dermatological findings
- Cardiovascular disorders (including aneurysm and valvular disease) 2
Some patients develop cutaneous lesions such as hypersensitivity to mosquito bites 2
Diagnostic Criteria
According to the updated guidelines, diagnosis of CAEBV requires fulfillment of all three criteria:
- Persistent or recurrent infectious mononucleosis-like symptoms
- Unusual pattern of anti-EBV antibodies with raised anti-VCA and anti-EA, and/or detection of increased EBV genomes in affected tissues, including peripheral blood
- Chronic illness that cannot be explained by other known disease processes at diagnosis 2, 1
The 2023 updated guidelines specifically require:
- Confirmation of high EBV DNA load (≥10,000 IU/mL in whole blood)
- Identification of EBV-infected T or NK cells 1
Diagnostic Workup
1. Serological Testing
- EBV-specific antibody panel:
2. Molecular Testing
- Quantitative PCR for EBV DNA in peripheral blood
3. Identification of Target Cells
- Determine which cell populations are infected (T cells, NK cells)
- Methods include:
- Double staining of EBNA
- Detection of EBER (EBV-encoded RNAs) by in situ hybridization
- Detection of EBV DNA with markers for B, T, NK cells or monocytes/macrophages/histiocytes
- Immunofluorescence
- Immunohistological staining
- Magnetic bead separation 2
4. Tissue Sampling
- Biopsy of affected tissues (lymph nodes, liver, etc.)
- Analysis should include:
- General histopathology
- Immunohistological staining
- In situ hybridization for EBER
- Southern blotting (including clonality of EBV)
- Chromosomal analysis
- Rearrangement studies (immunoglobulin, T-cell receptor) 2
5. Immunological Studies
- General immunological evaluation
- Peripheral blood marker analysis (including HLA-DR)
- Cytokine analysis 2
Differential Diagnosis
CAEBV must be distinguished from:
- Primary EBV infection (infectious mononucleosis)
- Other viral infections
- Autoimmune disorders
- Primary immunodeficiencies
- Lymphoproliferative disorders
- Hemophagocytic lymphohistiocytosis 3, 5
Prognostic Factors
Poor prognostic factors include:
- Late onset of disease
- Thrombocytopenia
- EBV infection of T cells (versus NK cells) 2
Treatment Considerations
While not the focus of this diagnostic overview, it's important to note that:
- Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment 1, 6
- Chemotherapy may be used to control disease activity before HSCT 1
- Some cases may respond to prednisolone and cyclosporine A with or without etoposide 6
- Rituximab may be beneficial in some cases, particularly for reducing viral load 7
Monitoring
Regular monitoring of EBV DNA levels is essential for:
- Assessing disease activity
- Evaluating response to treatment
- Early detection of complications 4
Without appropriate treatment, CAEBV typically progresses to severe complications including hemophagocytic syndrome and has a high mortality rate 6, 5.