D3.408 - When Angioedema Is Not Angioedema: EBV-Associated Lymphocytic Inflammation Mimicking Hereditary Angioedema

Background:

Chronic active Epstein–Barr virus infection (CAEBV) is a rare EBV-driven lymphoproliferative disorder characterized by persistent systemic inflammation and tissue infiltration. Cutaneous involvement may resemble angioedema, potentially leading to misdiagnosis as hereditary or bradykinin-mediated angioedema.

Case description:

We describe a 12-year-old boy with a one-year history of recurrent bipalpebral and facial edema without urticaria, initially suspected as hereditary angioedema. Episodes were associated with oral aphthae, periodic fever, and progressive hepatosplenomegaly.

Complement testing showed normal C3, C4, and C1 quantitative levels, with mildly reduced C1 functional activity (67%). Marked hypergammaglobulinemia was present (IgG 2483 mg/dL, predominantly IgG1). Lymphocyte subsets were within normal limits.

EBV serology revealed positive VCA IgG and EBNA IgG with negative IgM. Peripheral blood viral load was undetectable at evaluation. Skin biopsy demonstrated dense dermal and subcutaneous lymphoplasmacytic infiltration. Immunohistochemistry showed reactive CD3+, CD4+, and CD8+ T lymphocytes with low proliferative index (Ki67 <10%). EBER in situ hybridization was positive in scattered lymphocytes, confirming EBV-associated tissue involvement. No overt lymphoma was identified.

Results:

The absence of complement consumption excluded bradykinin-mediated angioedema. The combination of persistent systemic inflammation (>6 months), organomegaly, hypergammaglobulinemia, and EBER-positive tissue established the diagnosis of CAEBV. Immunomodulatory therapy with oral thalidomide was initiated. Following treatment, the frequency and severity of edema episodes decreased, with clinical stabilization under close monitoring.

Conclusion:

CAEBV may present as angioedema-like swelling secondary to EBV-driven lymphocytic tissue infiltration rather than increased bradykinin-mediated vascular permeability. Recognition of systemic inflammatory features and tissue EBV positivity is crucial to prevent misdiagnosis and inappropriate long-term treatment for hereditary angioedema.

Written informed consent for publication was obtained from the patient’s legal guardian.