Treatment strategies for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH)

In Epstein-Barr virus (EBV) infection, the virus immortalizes B lymphocytes and cytotoxic T lymphocytes (CTLs) are directed toward both latent and lyt ic viral antigens expressed on EBV-infected B-cells. Various EBV-associated diseases occur as a result of this disruption of immune surveillance. In t he majority of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) cases, the major cell types containing EBV DNA are not B-cells, but clonall y proliferating T-cells or NK-cells. Proliferation of these cells produces severe immune reactions in the host, and the clinical features related to m assive cytokine production at the onset of disease are unique and distinct from other EBV-associated diseases. In the treatment of EBV-HLH, therapeuti c infusion of EBV-specific CTLs appears to be ineffective, and eradication of EBV-containing cells is useful but not sufficient to save lives, because of high incidence of acute mortality due to cytokine-induced multiple orga n failure and neutropenia-associated opportunistic infections. The optimal treatment strategy for this dis ease consists of three steps: (1) control o f cytokine storm including coagulopathy and multiple organ failure, (2) con trol of opportunistic infections, and (3) eradication of clonally prolifera ting EBV-containing T- or NK- cells by immunochemotherapy and, if necessary , hemopoietic stem cell/bone marrow transplantation (SCT/BMT).