PEDIATRIC HEMATOLOGY Hemophagocytic lymphohistiocytosis

HLH was first described by Farquhar and Claireaux in 1952 as a familial disease [1]. Interestingly in their cases hemophagocytosis, which has given the disease its name, could not be found during lifetime but was prominent on autopsy. Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder with an estimated frequency of 0.12/100 000 children per year [2]. Several genetic defects have been described for FHLH (see below). In addition well-characterized immune deficiency syndromes such as Chédiak-Higashi syndrome (CHS), Griscelli syndrome (GS), and x-linked proliferative syndrome (XLP) may present initially with HLH or develop HLH later [3]. Whereas in FHLH the symptoms of HLH are the primary and only manifestation, the occurrence of HLH in these immune defects is optional. In 1979, Risdall et al. described a picture indistinguishable from FHLH in adults who received immunosuppressive treatment after organ transplantation and experienced a viral infection [4]. A few children were included and not in all patients a virus could be identified. The disease was named virusassociated hemophagocytic syndrome (VAHS). Subsequently it became evident that any infectious agent including bacteria, protozoa and fungi could trigger HLH [5,6]; thus the term infection-associated hemophagocytic syndrome (IAHS) replaced VAHS. Viruses, however, remain the most frequent triggering agents with Epstein-Barr virus as the leading organism, followed by cytomegalovirus and other herpes viruses. A fairly frequent cause for HLH is infection by leishmania, an organism for which very effective treatment exists. IAHS occurs in children and adults and is probably more frequent than the familial form. In contrast to the first publication by Risdall most patients with IAHS reported subsequently had no known underlying immune deficiency. It has to be emphasized that the identification of an infectious organism does not help to discriminate between FHLH and IAHS since the former is also triggered by an infection in most cases. Age is the only parameter which may be helpful to distinguish both forms: 70% of FHLH cases occur within the first year of life whereas IAHS patients are usually older. However, in the author’s experience about 10% of babies with HLH have a transient and therefore not familial form; on the other hand FHLH has occasionally been described in older children. The picture of HLH in patients with rheumatic diseases, especially systemic onset juvenile rheumatoid arthritis, is commonly named macrophage-activation syndrome (MAHS) [7]. It has recently been suggested that this condition be included as a separate entity in the category of acquired HLH [8]. HLH can also be a complication in patients with malignant diseases especially lymphomas and some inborn errors of metabolism [9].