Abstracts
PO101
Refractory Epstein-Barr Virus-associated hyperinflammation revealing EBV-positive polymorphic B-cell lymphoproliferative disorder in an immunocompetent young adult: a fatal case report
Introduction/Background/Significance: Epstein-Barr virus (EBV) is a well-established trigger of hemophagocytic lymphohistiocytosis (HLH), an intense hyperinflammatory syndrome driven by cytotoxic T-cell and macrophage activation. Severe cases of EBV-HLH failing B-cell-directed therapies like rituximab are classically driven by T- or NK-cell lymphoproliferative disorders (LPDs). EBV-positive polymorphic B-cell LPD, not otherwise specified (EBV+ poly B-LPD), is an International Consensus Classification entity characterizing EBV-driven polymorphic B-cell proliferations outside the post-transplant setting. EBV+ poly B-LPD in immunocompetent hosts remains exceedingly rare, and its clinical intersection with severe secondary HLH is poorly understood.
Materials and Methods/Case Presentation/Objective: A previously healthy 21-year-old woman presented with a one-month history of progressive pharyngitis, fatigue, fevers, and diffuse lymphadenopathy. Evaluation revealed profound pancytopenia (WBC 1.3 ×10⁹/L, Hgb 9.5 g/dL, Plts 71 ×10⁹/L), hyperferritinemia (2,377 ng/mL), and elevated LDH (1,193 U/L). Serology confirmed acute primary EBV infection (IgM positive, IgG negative) with a viral load of 33,000 IU/mL. PET-CT demonstrated diffuse, intensely FDG-avid lymphadenopathy (SUVmax >20) alongside splenomegaly and bone marrow hypermetabolism. Initial lymph node and bone marrow biopsies revealed reactive CD8+ T-cell expansion and EBER-positive B-cells without overt evidence of lymphoma.
Results/Description/Main Outcome Measure(s): The patient rapidly developed secondary HLH, meeting clinical criteria with massive immune activation (ferritin peaking at 7,807 ng/mL, fibrinogen 118 mg/dL, CXCL9 27,000 pg/mL, and IL-2 receptor 11,591 U/L). Despite treatment with high-dose dexamethasone, anakinra, ruxolitinib, etoposide, emapalumab, and rituximab, her EBV viral load rose to over 3 million IU/mL. Cell-sorted PCR unexpectedly demonstrated high-burden EBV viremia overwhelmingly compartmentalized within B-cells. While sorted PCR also detected a minor presence of EBV in T and NK cells, this occurred post-rituximab treatment and after other lines of therapy, making the primary cell driver complex to decipher. However, the profound B-cell localization was highly unexpected given her complete lack of clinical response to B-cell-directed therapy. Whole-genome sequencing revealed no known inborn errors of immunity.
Repeat excisional biopsies established a diagnosis of EBV+ poly B-LPD (NOS), characterized by a polymorphic lymphoid infiltrate with EBER positivity localized predominantly in plasmablastic B-cells. Her course was complicated by superior vena cava (SVC) syndrome due to progressive adenopathy and severe gastrointestinal hemorrhage secondary to extensive lymphoproliferative tract infiltration. Despite escalation to plasma-cell-directed therapies (bortezomib, daratumumab) with EPOCH chemotherapy and alemtuzumab, the patient developed a bowel perforation and multiorgan failure, ultimately graduating to comfort measures and passing away.
Conclusion(s).: This fatal case highlights a presentation of EBV+ poly B-LPD masked by severe secondary HLH in an immunocompetent young adult. Mechanistically, rituximab resistance usually implies a T- or NK-cell viral reservoir. Here, sorted PCR and pathology revealed a B-cell driving phenotype. Severe treatment resistance stemmed from plasmablastic differentiation, which downregulates surface CD20 expression and renders anti-CD20 therapy ineffective. The coexistence of an HLH-like syndrome and EBV-positive polymorphic B-cell LPD represents a profound diagnostic and therapeutic challenge. This case underlines the need to rapidly identify upstream drivers of HLH and highlights an urgent need for targeted protocols managing EBV+ poly B-LPD in immunocompetent hosts.
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Materials and Methods/Case Presentation/Objective: A previously healthy 21-year-old woman presented with a one-month history of progressive pharyngitis, fatigue, fevers, and diffuse lymphadenopathy. Evaluation revealed profound pancytopenia (WBC 1.3 ×10⁹/L, Hgb 9.5 g/dL, Plts 71 ×10⁹/L), hyperferritinemia (2,377 ng/mL), and elevated LDH (1,193 U/L). Serology confirmed acute primary EBV infection (IgM positive, IgG negative) with a viral load of 33,000 IU/mL. PET-CT demonstrated diffuse, intensely FDG-avid lymphadenopathy (SUVmax >20) alongside splenomegaly and bone marrow hypermetabolism. Initial lymph node and bone marrow biopsies revealed reactive CD8+ T-cell expansion and EBER-positive B-cells without overt evidence of lymphoma.
Results/Description/Main Outcome Measure(s): The patient rapidly developed secondary HLH, meeting clinical criteria with massive immune activation (ferritin peaking at 7,807 ng/mL, fibrinogen 118 mg/dL, CXCL9 27,000 pg/mL, and IL-2 receptor 11,591 U/L). Despite treatment with high-dose dexamethasone, anakinra, ruxolitinib, etoposide, emapalumab, and rituximab, her EBV viral load rose to over 3 million IU/mL. Cell-sorted PCR unexpectedly demonstrated high-burden EBV viremia overwhelmingly compartmentalized within B-cells. While sorted PCR also detected a minor presence of EBV in T and NK cells, this occurred post-rituximab treatment and after other lines of therapy, making the primary cell driver complex to decipher. However, the profound B-cell localization was highly unexpected given her complete lack of clinical response to B-cell-directed therapy. Whole-genome sequencing revealed no known inborn errors of immunity.
Repeat excisional biopsies established a diagnosis of EBV+ poly B-LPD (NOS), characterized by a polymorphic lymphoid infiltrate with EBER positivity localized predominantly in plasmablastic B-cells. Her course was complicated by superior vena cava (SVC) syndrome due to progressive adenopathy and severe gastrointestinal hemorrhage secondary to extensive lymphoproliferative tract infiltration. Despite escalation to plasma-cell-directed therapies (bortezomib, daratumumab) with EPOCH chemotherapy and alemtuzumab, the patient developed a bowel perforation and multiorgan failure, ultimately graduating to comfort measures and passing away.
Conclusion(s).: This fatal case highlights a presentation of EBV+ poly B-LPD masked by severe secondary HLH in an immunocompetent young adult. Mechanistically, rituximab resistance usually implies a T- or NK-cell viral reservoir. Here, sorted PCR and pathology revealed a B-cell driving phenotype. Severe treatment resistance stemmed from plasmablastic differentiation, which downregulates surface CD20 expression and renders anti-CD20 therapy ineffective. The coexistence of an HLH-like syndrome and EBV-positive polymorphic B-cell LPD represents a profound diagnostic and therapeutic challenge. This case underlines the need to rapidly identify upstream drivers of HLH and highlights an urgent need for targeted protocols managing EBV+ poly B-LPD in immunocompetent hosts.
Trademarked Items:
References:
