Understanding Chronic Active EBV (CA-EBV): A Comprehensive Guide for Medical Professionals

Chronic Active EBV (CA-EBV) is a rare, progressive, and life-threatening lymphoproliferative disorder. It is distinct from the self-limiting "long COVID" style of post-viral fatigue or "Chronic Mononucleosis Syndrome." Under the WHO classification, it is categorized within EBV-positive T-cell and NK-cell lymphoproliferative diseases (LPDs).

Unlike typical Infectious Mononucleosis, where EBV infects B-cells, in CA-EBV, the virus infects T-cells and NK-cells. This leads to clonal expansion, cytokine storms, and potential malignant transformation.

1. Diagnostic Criteria (WHO)

A diagnosis requires all of the following criteria to be met:

• Chronic Symptoms: Infectious mononucleosis-like symptoms persisting for more than 3 months.

  
  

• Virological Evidence: Elevated EBV DNA load in peripheral blood, typically greater than 10,000 IU/mL.

  
  

• Pathological Evidence: Demonstration of EBV infection in T-cells or NK-cells through EBER in situ hybridization on biopsy or flow cytometry.

  
  

• Exclusion: There must be no evidence of other underlying immunosuppression (e.g., HIV) or primary lymphoma at onset.

  
  

2. Clinical Manifestations

The clinical presentation of CA-EBV is often systemic and inflammatory due to hypercytokinemia.

• Systemic Symptoms: Persistent fever (often hectic), hepatosplenomegaly, and generalized lymphadenopathy are common.

  
  

• Cutaneous Symptoms (Specific Clues):

- Hypersensitivity to Mosquito Bites (HMB): Severe local skin necrosis, ulceration, and high fever following mosquito bites.

- Hydroa Vacciniforme-like Eruptions: Vesiculopapular lesions on sun-exposed skin.

• Organ-Specific Symptoms: These may include hepatitis (liver dysfunction), interstitial pneumonia, uveitis, or myocarditis.

  
  

3. Pathogenesis

The pathogenesis of CA-EBV involves several key mechanisms:

• Cell Tropism: EBV aberrantly infects T-cells or NK-cells (CD4+, CD8+, or CD56+).

  
  

• Immune Evasion: Infected cells downregulate viral immunogenic proteins, evading cytotoxic T-cell (CTL) surveillance.

  
  

• Cytokine Storm: The infected cells secrete high levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6), leading to chronic inflammation and tissue damage.

  
  

4. Complications

CA-EBV is not a benign chronic infection; it is considered a pre-malignant condition. The complications include:

• Hemophagocytic Lymphohistiocytosis (HLH): A common and often fatal complication triggered by the cytokine storm.

  
  

• Malignant Transformation: There is a risk of progression to aggressive NK-cell leukemia or extranodal NK/T-cell lymphoma.

  
  

• Organ Failure: This may manifest as liver failure or coronary artery aneurysms.

  
  

5. Management

Management of CA-EBV is challenging because standard antivirals (Acyclovir/Ganciclovir) are ineffective. These antivirals target the lytic phase DNA polymerase, while CA-EBV cells are largely in the latent phase.

• Step 1: Cooling Therapy (Immunomodulation): Use of steroids, Cyclosporine, or Etoposide to control the cytokine storm and HLH.

  
  

• Step 2: Chemotherapy: Regimens such as CHOP or SMILE (used in NK/T-cell lymphoma) can help reduce the burden of EBV-infected clones.

  
  

• Step 3: Curative Therapy: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is currently considered the only curative option. Without it, mortality rates are extremely high.

  
  

6. Prognosis

The prognosis for CA-EBV is generally poor without transplantation. The disease typically follows a progressive course, with survival rates dropping significantly over five years due to HLH or malignant transformation.

Summary Table: Typical Mono vs. CA-EBV

Feature	Infectious Mononucleosis (IM)	Chronic Active EBV (CA-EBV)
Duration	Self-limiting (weeks)	Progressive (>3 months)
Target Cell	B-cells	T-cells or NK-cells
EBV Load	High initially, then clears	Persistently high
Treatment	Supportive	Chemotherapy & Stem Cell Transplant
Outcome	Recovery	Fatal without treatment

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