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Hemophagocytic Lymphohistiocytosis Hematology, 2005; 10 Supplement 1: 104Á/107 PEDIATRIC HEMATOLOGY Hemophagocytic lymphohistiocytosis G. E. JANKA Universita¨ts-Kinderklinik, Ha¨matol./Onkologie Martinistr., Hamburg Hemophagocytic lymphohistiocytosis (HLH) is a life- ism, followed by cytomegalovirus and other herpes threatening disease characterized by unremitting viruses. A fairly frequent cause for HLH is infection fever, hepatosplenomegaly, cytopenias, as well as by leishmania, an organism for which very effective changes in coagulation and lipids. The symptoms treatment exists. are due to high levels of cytokines secreted by immune IAHS occurs in children and adults and is probably effector cells which display functional defects. more frequent than the familial form. In contrast to the first publication by Risdall most patients with IAHS reported subsequently had no known under- History and classification (Table I) lying immune deficiency. HLH was first described by Farquhar and Claireaux It has to be emphasized that the identification of an in 1952 as a familial disease [1]. Interestingly in their infectious organism does not help to discriminate cases hemophagocytosis, which has given the disease between FHLH and IAHS since the former is also its name, could not be found during lifetime but was triggered by an infection in most cases. Age is the only prominent on autopsy. Familial hemophagocytic lym- parameter which may be helpful to distinguish both phohistiocytosis (FHLH) is an autosomal recessive forms: 70% of FHLH cases occur within the first year disorder with an estimated frequency of 0.12/100 000 of life whereas IAHS patients are usually older. children per year [2]. Several genetic defects have However, in the author’s experience about 10% of been described for FHLH (see below). In addition babies with HLH have a transient and therefore not well-characterized immune deficiency syndromes familial form; on the other hand FHLH has occa- such as Che´diak-Higashi syndrome (CHS), Griscelli sionally been described in older children. syndrome (GS), and x-linked proliferative syndrome The picture of HLH in patients with rheumatic (XLP) may present initially with HLH or develop diseases, especially systemic onset juvenile rheuma- HLH later [3]. Whereas in FHLH the symptoms of toid arthritis, is commonly named macrophage-acti- HLH are the primary and only manifestation, the vation syndrome (MAHS) [7]. It has recently been occurrence of HLH in these immune defects is suggested that this condition be included as a separate optional. entity in the category of acquired HLH [8]. HLH can In 1979, Risdall et al. described a picture indis- also be a complication in patients with malignant tinguishable from FHLH in adults who received diseases especially lymphomas and some inborn immunosuppressive treatment after organ transplan- errors of metabolism [9]. tation and experienced a viral infection [4]. A few children were included and not in all patients a virus Genetics and pathophysiology could be identified. The disease was named virus- associated hemophagocytic syndrome (VAHS). Sub- HLH arises on the basis of various genetic or acquired sequently it became evident that any infectious agent immune deficiencies. Only recently several genetic including bacteria, protozoa and fungi could trigger defects have been described in FHLH: Mutations in HLH [5,6]; thus the term infection-associated hemo- the perforin gene [10], the UNC13D gene [11], and phagocytic syndrome (IAHS) replaced VAHS. the syntaxin 11 gene [12]. Whereas in our experience Viruses, however, remain the most frequent triggering mutations in one of these three genes can be found in agents with Epstein-Barr virus as the leading organ- 80% of the Turkish patients, only 30% of the German ISSN 1024-5332 print/ISSN 1607-8454 online # 2005 Taylor & Francis DOI: 10.1080/10245330512331390087 Hemophagocytic lymphohistiocytosis 105 Table I. Classification of hemophagocytic lymphohistiocytosis Table II. Symptoms and laboratory findings at first presentation and at diagnosis* Genetic forms Á/Familial HLH (M.Farquhar) At first presentation At diagnosis Á/Immune deficiency syndromes % of patients % of patients Chediak-Higashi syndrome Griselli syndrome Fever 78 100 X-linked lymphoproliferative syndrome Splenomegaly 78 98 Bicytopenia 56 98 Acquired forms 1 FibrinogenB/1.5 g l 23 65 Á/Infection-associated hemophagocytic syndrome 1 Triglycerides/3 mmol l 52 76 Á/Macrophage activation syndrome Hemophagocytosis 36 88 Á/Malignancy-associated hemophagocytic syndrome NK cell activity negative or 100 100 decreased 1 sCD25/ /2400 U ml 100 90 1 patients harbored a perforin or UNC13D mutation. Ferritin/ /500 ng nl 57 70 1 Mutations in syntaxin 11 so far have only been found LDH/ /500 Ul 55 51 1 in patients from Turkey. The genes implicated in the ALT/ /100 Ul 30 38 1 Bilirubin/ /34 mmoll 30 32 pathogenesis of Che´diak-Higashi syndrome (the 1 CSF cells/ /5 ml 32 39 LYST gene), Griscelli syndrome (The RAB27A 1 CSF protein/0.5 gl 32 46 gene) and x-linked proliferative syndrome (the SH2D1A gene) have also been identified. In a *(Janka et al. 2005) sCD25/a chain of the soluble interleukin 2 substantial number of patients thought to have genetic receptor; LDH/lactate dehydrogenase; ALT/alanine amino- transferase; CSF/cerebrospinal fluid. In some instances (sCD25, disease based on a positive family history or a LDH) percentage of patients with high values was lower at diagnosis relapsing course, the gene defect is as yet unknown. due to unspecific therapies. The clinical picture of HLH is due to hyperin- flammation caused by hypersecretion of inflammatory Typical laboratory values are thrombocytopenia cytokines by activated T-lymphocytes and histiocytes and anemia, and less frequently neutropenia. Pancy- infiltrating all organs. In spite of the excessive activa- topenia is progressive in untreated patients. Charac- tion and expansion of cytotoxic cells, patients with teristic biochemical findings are high triglycerides, a HLH have severe impairment of cytotoxic function of low fibrinogen or a global coagulation disorder, and natural killer cells and cytotoxic T cells [13]. All high ferritin. Less frequent are high transaminases, known defects in HLH are involved in the function of bilirubin and LDH, low total protein and hyponatre- cytolytic granules: granule trafficking (LYST), dock- mia [9]. A bone marrow examination is mandatory ing at the membrane (RAB27A), granule priming but only a minority of patients have hemophagocy- (UNC13D), deficient granule content (PFR), im- tosis at presentation. A bone marrow biopsy is usually paired lymphocyte activation (SH2D1A) and prob- even less sensitive. Characteristically the bone marrow ably impaired interaction between dendritic and killer is cellular in spite of profound peripheral pancytope- cells (syntaxin 11). Defective cytolytic activity seems nia. Erythropoiesis is usually increased and may to be the common denominator which predisposes to exhibit dysplastic changes. The cerebrospinal fluid HLH. shows a moderately increased cell count and/or The mechanisms leading to impaired cytotoxic protein content in more than 50% of the cases even function in apparently immune competent patients in the absence of neurological symptoms. with acquired HLH are less clear. Interference by A valuable disease marker is a high level of the a cytokines or virus-encoded proteins are possible chain of the soluble interleukin 2 receptor (sCD25). mechanisms. The prevalence of EBV associated Impaired natural killer (NK) cell activity is a hallmark HLH in Asia suggests a specific genetic susceptibility. of the disease. It is found in FHLH, CHS, GS and XLP as well as in acquired HLH. In the latter, Clinical symptoms and laboratory findings impaired NK cell activity may be due in part to (Table II) reduced numbers of NK cells and is usually reversible. The disease typically starts after a free interval weeks to months after birth. In rare cases already newborns Diagnostic criteria and problems become symptomatic. The initial symptoms at first The revised diagnostic criteria of the Histiocyte are compatible with a normal infection. The first sign Society are shown in Table III. is high fever frequently associated with signs of an At initial presentation the diagnosis may be difficult upper respiratory or gastrointestinal infection. Nearly because of several reasons: all patients have an enlarged liver and/or spleen. Enlarged lymph nodes, transient rashes and neurolo- Á/ an infectious organism is identified, a normal gical symptoms such as an opisthotonic posture, infection suspected and the severe symptoms of seizures or cerebral nerve palsies are less frequent [14]. HLH are overlooked 106 G. E. Janka Á/ not all necessary diagnostic criteria may be ease. Since many patients do not have a family history present or a proven genetic defect a surrogate marker for Á/ fever may subside spontaneously and recur after genetic disease is persistent disease activity or relapses days or weeks on or off treatment. In patients without family Á/ unspecific measures as transfusions may lead to history and complete resolution of all symptoms transient improvements elective cessation of therapy is recommended to Á/ organomegaly, disturbed liver function and high prevent an unnecessary SCT for transient, acquired triglycerides may suggest a HLH. This is not without risk since a relapse may be Á/ metabolic disorder accompanied by severe symptoms. Thus these pa- Á/ liver failure and severe coagulopathy may be the tients have to be closely
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