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 -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 and anemia, and less frequently . 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 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 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 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 and/or .

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 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 monitored to restart therapy leading symptom in time.

Á/ neurological symptoms suggesting encephalitis Standard treatment for HLH is a combination of may precede systemic HLH for corticosteroids, cyclosporin A and . All

Á/ several months or be the only manifestation patients with known familial disease, suspected ge- netic disease due to age below 1 year and patients with All symptoms of HLH, however, to a lesser extent life-threatening symptoms such as coagulopathy, pro- may also be found in a normal immunological found cytopenia or neurological disease should re- response. It is the severity of the clinical picture and ceive therapy according to the present HLH 2004 laboratory findings and the progression of symptoms protocol (available at website: www.histio.org/society/ which should alert the physician that this is an protocols). Etoposide may be life-saving especially in impaired immune response leading to HLH. patients with EBV-associated HLH [17] There are a Whereas hemophagocytosis is very characteristic few patients with acquired HLH and mild symptoms and, if present, a valuable diagnostic criterium it in whom corticosteroids and immunoglobulins may should be emphasized that the lack of hemophagocy- be sufficient. However, disease may progress rapidly tosis does not exclude the diagnosis of HLH. and this risk outweighs the possible side effects of The diagnostic criteria for HLH which are based on etoposide. For children with MAS treatment with familial and infection-associated acquired cases may high doses of corticosteroids and/or cyclosporin A is not be relevant for patients with MAS. Accordingly recommended. these modified diagnostic criteria have recently been Reactivation during treatment is a frequent pro- advocated [15]. blem, either systemically or in the CNS. Immuno- suppressive treatment should be reinforced and SCT be performed as early as possible. Intrathecal therapy Therapy and prognosis is recommended in CNS relapses in view of the Untreated familial disease is fatal in all cases. Also deleterious long-term effects of uncontrolled CNS acquired IAHS has a high fatality rate of 50% in disease. children [16]. If a treatable organism is found appro- Most children respond to treatment within 1Á/4 priate therapy should be given but with the possible weeks. There is no established salvage therapy for exception of leishmaniasis antiinfectious therapy is non-responders. Antithymocyte globulin which was usually not sufficient to control HLH. The immediate shown to be effective as first line treatment [18] is aim of treatment is to suppress hypercytokinemia rarely effective when the HLH protocol fails. Single that is responsible for the life-threatening symptoms. patients have responded to daclizumab or alemtuzu- In familial cases this has to be followed by stem mab. cell transplantation (SCT) as the only curative dis- The results of the HLH 94 study have recently been published [19]. The overall survival rate in 113 Table III. Diagnostic criteria for HLH* children was 55% at 3 years. Patients with a transplant Familial disease/known genetic defect from a matched sibling donor (MSD) or matched Clinical and laboratory criteria (5/8 criteria) unrelated donor had the same results.

Á/Fever Á/Splenomegaly Á/Cytopenia/ /2 cell lines Conclusion Á/Hypertriglyceridemia and/or hypofibrinogenemia 1 HLH is a well described clinical entity characterized Á/Ferritin/ /500 ng ml 1 Á/sCD25/ /2400 U ml by fever, hepatosplenomegaly, cytopenias and various Á/Decreased or absent NK-cell activity laboratory changes. Hyperinflammation is due to Á/Hemophagocytosis in bone marrow, CSF or lymphnodes genetic or acquired cytotoxic defects of immune effector cells. HLH is still frequently overlooked. Supportive evidence are cerebral symptoms with moderate pleocy- tosis and/or elevated protein, elevated transaminases and bilirubin, Treatment with chemoimmunotherapy in due time 1 LDH/1000 Ul controls the disease in most patients and facilitates * Janka and Schneider 2004; 1For method see Schneider et al. 2002. SCT for genetic cases with a high cure rate. Hemophagocytic lymphohistiocytosis 107

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