Virus-associated Hemophagocytic Syndrome Characterized by Clonal Epstein-Barr Virus Genome

Abstract

Virus-associated hemophagocytic syndromes are a heterogeneous group of disorders in which viral infection is associated with a proliferation of hemophagocytic histiocytes throughout the reticuloendothelial system. The authors report the case of a 24-year-old Vietnamese male who developed a hemophagocytic syndrome associated with Epstein-Barr virus (EBV) and who died following a rapidly progressive course. A proliferation of reactive-appearing lymphoid cells was associated with an extensive proliferation of erythrophagocytic histiocytes. Immunophenotypically, the lymphoid infiltrate consisted of CD56+ natural killer cells, predominantly CD8+ T-cells and rare B-cells (CD20+). Double-label immunohistochemical studies showed CD3+ T-cells and CD56+ natural killer cells to be distinct cell populations. Combined immunohistochemical-in situ hybridization studies localized EBV to CD43+, CD3-, CD68-, lymphoid-appearing cells, indicating the presence of EBV within natural killer cells. Southern hybridization analysis of EBV genomic termini revealed clonal EBV genome. However, there was no detectable immunoglobulin or T-cell receptor gene rearrangements. The findings indicate that this case of hemophagocytic syndrome represents a clonal proliferation of natural killer cells containing EBV and highlights the importance of the analysis of EBV genomic termini for determination of clonality in EBV-associated proliferations. It is possible that other cases of fulminant EBV-associated hemophagocytic syndromes represent clonal natural killer cell proliferations.

Treatment of Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH) in young adults: A report from the HLH studyl center

“…We retrospectively analyzed 20 cases diagnosed with either EBV-HLH or EBV-related diseases with the clinical signs and symptoms of HLH. The latter cases mostly involved FIM and EBV-NK-LAHS, which are often complicated with hemophagocytosis [1,[8][9][10]. For example, Mroczek et al [2] have shown that 43 of 52 patients with FIM (80%) had clinicopathologic features of hemophagocytosis.…”

“…Information on the literature cases was obtained only by the article content, not through contact with the authors. As a result, only 9 cases were eligible [1,5,6,[9][10][11][27][28][29]. The eligible criteria for inclusion in this study were: (a) the age at disease onset of the patient was between 15 and 34, (b) the diagnosis was EBV-HLH, or an EBV-related disease with the clinical signs and symptoms of HLH [35], and (c) information on the treatment, particularly the timing of etoposide administration as well as outcome was available.…”

“…Epstein-Barr virus (EBV)-associated hemophagocytic syndrome has been reported to occur in association with infectious mononucleosis [1,2], chronic active EBV infection [3,4], EBV-positive T-cell lymphoproliferative disorder or lymphoma [5][6][7], and natural killer (NK)-cell granular lymphocyte proliferative disorders-or leukemiaassociated hemophagocytic syndrome (EBV-NK-LAHS) [8][9][10][11]. The syndrome is also known as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) [12], the term used in this study.…”

“…EBV-HLH occurs in both children [7,12] and young adults (defined as older than 15 years of age) [1,[3][4][5][6][8][9][10][11][27][28][29]. It is not clear whether the etoposide therapy would also be effective in young adults.…”

Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection

“…Several approaches to determine the relationship between individual EBV strains and EBV-related diseases such as malignant lymphoma, 27 nasopharyngeal carcinoma, 28 Burkitt lymphoma, 29 and gastric carcinoma 30 have been reported. The significance of type B in the immunocompromised host in Western countries 27 and the variants of EBNA-1 C-terminal region have been suggested.…”