Pediatr Blood Cancer 2007;48:124–131 REVIEW HLH-2004: Diagnostic and Therapeutic Guidelines for Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a disease with major diagnostic and therapeutic difficulties. HLH comprises two different conditions that may be difficult to distinguish from one another: a primary [1] and a secondary form [2]. The primary autosomal recessive form, familial hemophagocytic lymphohistiocytosis (FHL), has an estimated incidence of around 1:50,000 live-born children [3]. FHL is a fatal disease with a median survival of less than 2months after diagnosis if untreated, and that typically has its onset during infancy or early childhood [4]. Despite its name, family history is often negative since the disease is recessive. Importantly, the onset of FHL and bouts of the diseasemay be triggered by infections [5]. Secondary HLH (sHLH) may develop as a result due to strong immunological activation of the immune system, which may, for example, be caused by a severe infection. sHLH has been described in immunocompromised hosts in association with viral infections, virus(infection) associated hemophagocytic syndrome (VAHS, or IAHS) [2,6]. However, most patients with sHLH are not obviously immunosuppressed. sHLH may also develop during malignancies (malignancy-associated hemophagocytic syndrome, MAHS); it may either be the presenting clinical picture and initially mask an underlying malignancy, or it may develop during the treatment for a known malignancy [2]. In 1991, the Histiocyte Society presented the first set of diagnostic guidelines for HLH [7], and in 1994 the first prospective international treatment protocol (HLH-94) was introduced [8]. The cumulative experiences from HLH-94 and other studies have led to the development of a new treatment protocol presented here, HLH-2004, which includes updated diagnostic and therapeutic guidelines from the Histiocyte Society.