Case Report: Adult EBV-associated hemophagocytic lymphohistiocytosis with presumed primary EBV infection: a report of three cases and diagnostic considerations

Adult Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a clinically heterogeneous syndrome comprising biologically distinct disease entities. We report three adults with EBV-HLH and describe their diagnostic evaluation and clinical course. We presumed primary EBV infection from anti-VCA IgM positivity, anti-EBNA negativity, and a history of possible saliva-mediated exposure in all three patients. Personal and family histories did not suggest familial HLH (fHLH), and genetic analysis performed in one patient did not identify pathogenic variants of fHLH. No history nor clinical findings suggested an inborn error of immunity. Whole-body computed tomography did not show any mass lesions suggestive of malignancy, and bone marrow examination showed hemophagocytosis without abnormal lymphoid proliferation or other findings suggestive of lymphoma. No clonal immunoglobulin heavy-chain or T-cell receptor gene rearrangements were detected in any patient. EBV-infected cell phenotype was assessed by bone marrow pathology in two patients; EBER-positive CD3-positive T cells were identified in one, whereas the infected cell phenotype could not be determined in the other because of the limited number of cells. In the remaining patient, EBV-DNA quantification in sorted peripheral blood mononuclear cell fractions showed EBV infection of CD8-positive T cells. All patients responded to HLH-94/HLH-2004-based therapy including etoposide and were managed without hematopoietic stem cell transplantation (HSCT). During follow-up at our department for 345–1,067 days, no confirmed HLH recurrence was observed, although EBV-DNA remained detectable for more than one year in two patients. These cases suggest that EBV-DNA may remain detectable after clinical remission in adult HLH associated with presumed primary EBV infection. The indication for HSCT should be considered carefully, not on the basis of EBV-DNA positivity alone, but through longitudinal clinical assessment and reassessment for CAEBV, EBV-positive lymphoma, fHLH, and underlying immunodeficiency.