In HLH-94, the first prospective international treatment study for 
hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria 
(fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or 
hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria 
are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble 
interleukin-2-receptor levels. Altogether five of these eight criteria must be 
fulfilled, unless family history or molecular diagnosis is consistent with HLH. 
HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A 
upfront and, in selected patients, intrathecal therapy with methotrexate and 
corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is 
recommended for patients with familial disease or molecular diagnosis, and 
patients with severe and persistent, or reactivated, disease. In order to 
hopefully further improve diagnosis, therapy and biological understanding, 
participation in HLH studies is encouraged.