What are the symptoms and treatment options for a patient with Chronic Active Epstein-Barr Virus (CAEBV) infection?

Chronic Active Epstein-Barr Virus (CAEBV) Infection: Symptoms and Treatment

Clinical Symptoms

CAEBV presents with persistent or recurrent infectious mononucleosis-like symptoms lasting more than 3 months, including intermittent fever, lymphadenopathy, and hepatosplenomegaly. 1, 2

Primary Manifestations

• Persistent or intermittent fever lasting weeks to months beyond typical EBV recovery 1, 2
• Lymphadenopathy with tenderness and pain 1
• Hepatosplenomegaly detected on physical examination 1, 2
• Recurrent debilitating fatigue that is chronic and unremitting 1, 2
• Sore throat, headache, myalgia, and arthralgia occurring persistently 1

Serious Complications

• Hemophagocytic lymphohistiocytosis (HLH) with severe hypercytokinemia that can occur suddenly and prove fatal 2, 3
• Cardiovascular manifestations including coronary artery aneurysms and valvular disease 1, 4
• Hematological disorders including cytopenias 1
• Ocular complications such as severe uveitis 4
• Neurological, pulmonary, and dermal disorders 1
• Progression to T-cell or NK-cell malignant lymphomas through clonal proliferation 2, 5

Characteristic Skin Findings

• Hypersensitivity to mosquito bites associated with granular lymphocyte proliferation 1
• Hydroa vacciniforme-like eruptions linked to T-cell or NK-cell lymphoproliferative disorders 1

Diagnostic Criteria

Diagnosis requires meeting three criteria: persistent symptoms beyond 3 months, markedly elevated EBV markers, and confirmation of EBV-infected T or NK cells in affected tissues. 6, 5

Laboratory Thresholds

• EBV DNA ≥10,000 IU/mL in whole blood (or >10^2.5 copies/μg DNA in peripheral blood mononuclear cells) 2, 5
• VCA-IgG ≥1:640 and EA-IgG ≥1:160 are characteristic antibody patterns 2, 6
• Presence of IgA antibodies against VCA and/or EA, which is unusual in typical past infection 2

Essential Diagnostic Tests

• Quantitative EBV PCR on peripheral blood mononuclear cells to measure viral load 1, 2
• In situ hybridization for EBV-encoded RNAs (EBERs) in affected tissues 1
• Double staining to identify target cells (T cells, NK cells, or B cells) infected with EBV 1
• Cytokine analysis if HLH is suspected 2
• Bone marrow examination when hemophagocytosis is a concern 2

Critical Diagnostic Pitfall

Do not use "CAEBV" terminology if an underlying lymphoma or specific lymphoproliferative disorder is identified pathologically—use the specific disease name instead. 6

Treatment Algorithm

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment and should be pursued as soon as disease is adequately controlled. 6, 3, 5

Step 1: Disease Control Before HSCT

• Immunosuppressive therapy with prednisolone and cyclosporine A with or without etoposide for initial disease control 3
• Chemotherapy to control disease activity before proceeding to transplantation 5
• Rituximab 375 mg/m² once weekly for 1-4 doses for significant EBV DNA-emia until viral load negativity 6

Step 2: Proceed to HSCT Without Delay

• Complete the treatment pathway without watchful waiting to maximize survival and minimize late sequelae 3
• 3-year overall survival rate of 87.3% when HSCT is performed with controlled disease 6, 3
• 3-year overall survival drops to only 16.7% in patients with uncontrolled active disease at transplant 3

Step 3: Management of Acute Complications

• Aggressive immunosuppression for severe hypercytokinemia and hemophagocytic syndrome, with urgent consideration for HSCT 6, 3
• Emergent HSCT may be necessary when life-threatening complications develop suddenly 3

Poor Prognostic Indicators

Recognize these factors that predict worse outcomes and necessitate more aggressive early intervention: 6

• Late onset of disease 6
• Thrombocytopenia at presentation 6
• EBV infection specifically of T cells (versus NK cells) 6
• Chromosomal abnormalities in the 6q region 6

Critical Clinical Pitfalls to Avoid

• Assuming all EBV infections are self-limiting leads to delayed diagnosis of CAEBV or HLH, both requiring aggressive management with poor prognosis if untreated 2, 6
• Persistent fever beyond 10 days after EBV diagnosis is not typical of uncomplicated primary infection and warrants immediate further investigation 2
• Overlooking HLH can be life-threatening—monitor for persistent fever, cytopenias, and extremely elevated ferritin levels (>1000 ng/mL) 2
• Antiviral drugs are not recommended for chronic fatigue with elevated EBV antibodies, as they do not impact disease progression or symptoms in the absence of true CAEBV 6
• Antibody titers from different laboratories are not comparable due to subjective immunofluorescence testing methods 2