What is the differential diagnosis for a patient with recurrent Epstein-Barr Virus (EBV) infection, considering potential underlying immunodeficiency or malignancy?

Differential Diagnosis for Recurrent EBV Infection

When a patient presents with recurrent or persistent EBV infection, the primary differential diagnosis includes chronic active EBV infection (CAEBV), underlying primary immunodeficiency disorders, EBV-associated lymphoproliferative disorders, and EBV-triggered hemophagocytic lymphohistiocytosis (HLH). 1, 2

Primary Immunodeficiency Disorders

The most critical consideration in recurrent EBV is an underlying immunodeficiency that impairs EBV-specific immune surveillance:

X-Linked Lymphoproliferative Disease (XLP)

• XLP presents with severe EBV-induced loss of B cells and defective cytotoxic T cells and NK cells, leading to fulminant infectious mononucleosis, lymphoproliferative disease, or dysgammaglobulinemia 1
• Patients develop life-threatening complications specifically triggered by EBV infection 1

CD70 and CD27 Deficiency

• Novel mutations in CD70 or CD27 genes cause severe chronic EBV infection with hypogammaglobulinemia and EBV-driven lymphoproliferation 3
• These patients may present with recurrent periodic fever, tonsillitis, and adenitis following initial infectious mononucleosis 3
• Progressive reduction of immunoglobulin levels with increased CD20+ B cells is characteristic 3

Combined Immunodeficiency Disorders

• Hypomorphic mutations in RAG1/2, IL2RG, ADA, or other genes controlling T-cell function can present with recurrent EBV and hypogammaglobulinemia 1
• These patients have impaired EBV-specific cytotoxic T lymphocyte (CTL) responses, which are the most important mechanism for controlling EBV-infected cell proliferation 1

Good Syndrome (Thymoma with Immunodeficiency)

• Combined B- and T-cell defects leading to recurrent infections including EBV reactivation 1

Chronic Active EBV Infection (CAEBV)

CAEBV is characterized by persistent or recurrent infectious mononucleosis-like symptoms lasting weeks to months, with high IgG antibody titers against EBV VCA (≥1:640) and EA (≥1:160), and quantitative EBV PCR showing viral loads >10^2.5 copies/μg DNA in peripheral blood mononuclear cells 1, 2, 4

Clinical Features of CAEBV:

• Persistent or intermittent fever, lymphadenopathy, and hepatosplenomegaly beyond typical recovery period 1, 2
• Recurrent debilitating fatigue, sore throat, lymph node pain, headache, myalgia, and arthralgia 2
• Unusual antibody patterns including IgA antibodies against VCA and/or EA 2, 4

Pathological Progression:

• Patients may develop oligoclonal or monoclonal lymphoproliferation of T cells or NK cells, eventually progressing to T-cell or NK-cell malignant lymphomas 1
• Chromosomal abnormalities in the 6q region are frequently reported in affected tissues, particularly in NK cell lymphoproliferative disorders 1

EBV-Associated Lymphoproliferative Disorders

EBV-associated peripheral T-cell and NK-cell lymphoproliferative disorders/lymphomas have clinical and laboratory findings similar to CAEBV, and when pathologically confirmed, should be assigned the specific underlying disease name rather than CAEBV 1

Malignancies to Consider:

• T-cell or NK-cell malignant lymphomas (most common progression from CAEBV) 1
• B-cell neoplasms (anecdotally reported) 1
• Hodgkin disease-like presentations 1
• Post-transplant lymphoproliferative disorder (in transplant recipients) 5

Hemophagocytic Lymphohistiocytosis (HLH)

EBV-triggered HLH is a hyperinflammatory syndrome presenting with persistent fever, cytopenias, extremely elevated ferritin levels (>1000 ng/mL), and hemophagocytosis on bone marrow examination 2, 6

Key Features:

• Persistent high-grade fever beyond 10 days after EBV diagnosis 2
• Thrombocytopenia associated with poorer outcomes 6
• Novel mutations in perforin gene have been identified in some CAEBV patients who developed HLH 1
• Elevated inflammatory cytokines on cytokine analysis 2

HIV and Other Acquired Immunodeficiencies

HIV infection should be routinely screened in all patients with recurrent EBV, as it can present with EBV-related complications including cerebral vasculitis and encephalitis 7

• EBV-associated complications in HIV can occur even with relatively preserved CD4 counts 7
• Immunosuppression from medications (e.g., mercaptopurine, other immunosuppressants) can lead to severe EBV manifestations with spread to liver and bone marrow 8

Diagnostic Algorithm

Initial Evaluation:

1. Complete EBV antibody panel with titers: VCA IgM, VCA IgG, EA IgG, EBNA 2, 4
2. Quantitative EBV PCR on peripheral blood mononuclear cells (viral load >10^2.5 copies/μg DNA suggests CAEBV) 1, 2
3. Complete blood count with differential to assess for cytopenias, particularly thrombocytopenia 6
4. Comprehensive metabolic panel and ferritin level (ferritin >1000 ng/mL suggests HLH) 2, 6

Immunological Workup:

1. Quantitative immunoglobulin levels (IgG, IgA, IgM) to assess for antibody deficiency 1
2. Lymphocyte subset analysis including B-cell and T-cell phenotyping 1
3. HIV and HCV serologic testing in all adult patients 6
4. NK cell function and cytotoxicity assays if available 1

Advanced Testing When Indicated:

1. Bone marrow examination if HLH is suspected to look for hemophagocytosis 2
2. Lymph node biopsy if lymphadenopathy is persistent or progressive to evaluate for lymphoproliferative disorder 3
3. Genetic testing for primary immunodeficiency: Consider whole exome sequencing or targeted gene panels including XIAP, SH2D1A, ITK, CD27, CD70, perforin, RAG1/2 1, 3
4. Flow cytometry on sorted cells to determine which cell population harbors EBV (B cells, T cells, or NK cells) 3

Critical Clinical Pitfalls

• Assuming all EBV infections are self-limiting can lead to delayed diagnosis of CAEBV or HLH, both requiring aggressive management with poor prognosis if untreated 2, 4
• Persistent fever beyond 10 days after EBV diagnosis is not typical of uncomplicated primary EBV infection and warrants immediate further investigation 2
• Overlooking HLH can be life-threatening, requiring prompt recognition and immunosuppressive therapy 2
• Antibody titers from different laboratories are not comparable due to subjective immunofluorescence testing methods 2, 4
• Thrombocytopenia in chronic EBV infection is a negative prognostic indicator, particularly when EBV infects T cells 6, 4

Prognostic Considerations

Patients with CAEBV have poor prognosis, particularly with late disease onset, thrombocytopenia, and EBV infection of T cells rather than B cells 2, 4. The combination of persistent fever, lymphadenopathy, and hepatosplenomegaly is particularly concerning for CAEBV and requires aggressive evaluation 2. Some patients ultimately require stem cell transplantation for definitive treatment 2, 3.