Blood Reviews (2007) 21, 245253

www.elsevierhealth.com/journals/blre

REVIEW

Hemophagocytic syndromes
Gritta E. Janka
*

Department of Hematology and Oncology, Childrens Hospital, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany

KEYWORDS
Histiocytosis; Hemophagocytosis; Macrophage activation syndrome; Immune deciency; Review

Summary Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) represent a severe hyperinammatory condition with the cardinal symptoms prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages. Biochemical markers include elevated ferritin and triglycerides, and low brinogen. Whereas in children several inherited immune deciencies may lead to this syndrome, most adults with HLH have no known underlying immune defect. Nevertheless, impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is characteristic for both genetic and acquired forms of HLH. Frequent triggers are infectious agents, mostly viruses of the herpes group. Malignant lymphomas, especially in adults, may be associated with HLH. A special form of HLH in rheumatic diseases is called macrophage-activation syndrome. Initially HLH may masquerade as a normal infection since all symptoms, even though less pronounced, may also be found in immune competent patients. Patients with HLH, however, cannot control the hyperinammatory response which, if untreated, is fatal in genetic cases and in a high percentage of acquired cases. Awareness of the clinical symptoms and of the diagnostic criteria of HLH is important to start life-saving therapy with immunosuppressive/ immunomodulatory agents in time. c 2007 Elsevier Ltd. All rights reserved.

Hemophagocytosis by macrophages as an isolated phenomenon can be found in many situations such as hemolytic anemia, metabolic diseases or malignancies. In hemophagocytic lymphohistiocytosis (HLH), hemophagocytosis is part of a sepsis-like clinical syndrome caused by severe hypercytokin* Tel.: +49 40 42803 4270; fax: +49 40 42803 4601. E-mail address: janka@uke.uni-hamburg.de.

emia as the consequence of a highly stimulated but ineffective immune response.

Classication and terminology of HLH

HLH occurs in all age groups. It is not a single disease but a clinical syndrome that can be encountered in association with a variety of underlying

0268-960X/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.blre.2007.05.001

246 conditions leading to the same characteristic inammatory phenotype (Fig. 1).

G.E. Janka are viruses of the herpes group, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV); a frequent nonviral agent associated with HLH in children is leishmania.8,9 The identication of an infectious organism does not help to discriminate between genetic and acquired forms of HLH, since also most episodes in genetic HLH are triggered by infections.10,11 Acquired HLH in association with malignant diseases, especially lymphomas (lymphoma-associated hemophagocytic syndrome; LAHS), has been reported mostly in adults.12,13 HLH can develop before or during treatment, associated with an infection or without a known triggering factor. Interestingly, in patients with LAHS from Japan, the EBV genome was detected only rarely in patients with B-cell lymphoma but was present in more than 80% of patients with T/NK cell lymphoma.14 EBV-infected T/NK cells appear to play a major role in the development of LAHS as well as EBV-associated HLH without lymphoma.15 Macrophage-activation syndrome (MAS), a special form of HLH which occurs in children and adults with autoimmune diseases will be described below separately.

Genetic forms of HLH

Genetic (primary) HLH is inherited in an autosomal recessive or x-linked manner and can be divided into two subgroups: familial HLH (FHLH) in which the clinical syndrome of HLH is the only manifestation, and the immune deciencies Chediak-Higashi syndrome (CHS 1), Griscelli syndrome (GS 2) and xlinked proliferative syndrome (XLP) which have distinctive clinical features besides the sporadic, though frequent development of HLH. In FHLH the onset of the disease is below one year of age in 70-80% of the cases,1,2 however, several late-onset cases in adolescence and even adulthood have been published.3,4

Acquired forms of HLH

Acquired (secondary) HLH can occur in all age groups. It was rst described by Risdall and colleagues in adults with a viral infection following organ transplantation.5 Subsequently it became clear that most patients had no known underlying immune defect and that also nonviral agents such as bacteriae, protozoae and fungi could trigger HLH .6,7 Consequently the term virus-associated hemophagocytic syndrome (VAHS) was replaced by infection-associated hemophagocytic syndrome (IAHS), in many cases also without the proof of an infectious agent as long as the classical symptoms were present. Leading triggering agents in IAHS

Clinical symptoms and laboratory ndings

Prolonged fever, hepatosplenomegaly and cytopenias are the cardinal symptoms of HLH. Lymphadenopathy, rash, icterus or neurological symptoms

Figure 1

Histiocyte with phagocytosis of erythrocytes and platelets.

Hemophagocytic syndromes such as seizures or cranial nerve palsies are less frequent. Characteristic laboratory values include high levels of triglycerides, ferritin, transaminases, bilirubin and LDH and a low brinogen.1,9,10,16 The alpha chain of the soluble interleukin-2 receptor (sCD25) is a valuable disease marker because of constantly increased levels during active HLH.17 Hemophagocytosis (Fig. 2) is often absent initially but is usually found with progressive disease. In children the cerebrospinal uid shows a slightly elevated cell count and/or increased protein content in more than half of the patients. A hallmark of HLH, in genetic as well as in acquired cases, is impaired or absent function of natural killer (NK) and cytotoxic T-cells (CTL).18 In patients with FHLH, NK cell numbers are normal and the defect is usually persistent. Patients with acquired HLH may have low NK cell numbers and usually have decreased NK cell function with active disease. NK cell function usually reverts to normal after treatment. All symptoms of HLH can be explained by high concentrations of inammatory cytokines18,19 and organ inltration by activated lymphocytes and histiocytes: Fever is induced by interleukin-1 and interleukin-6, and pancytopenia is rather the consequence of high levels of tumor necrosis factor a (TNF a) and interferon c, than of hemophagocytosis. TNF a inhibits lipoprotein lipase leading to elevated triglycerides. Activated macrophages not only secrete ferritin but also plasminogen activator which results in high plasmin levels and hyperbrinolysis. Activated lymphocytes are the source for the high concentrations of the a-chain of the

247 soluble interleukin-2 receptor. Finally hepatosplenomegaly, increased liver enzymes and bilirubin as well as neurological symptoms are the consequence of organ inltration by activated lymphocytes and histiocytes. The pivotal role of INFc together with CD8+T cells for the development of HLH was demonstrated in a perforin knock-out mouse model.20 While many of these symptoms can also be found in immune-competent patients in response to an infectious agent, they are inappropriately pronounced in patients with HLH. In particular, the progression of organomegaly, of cytopenias and biochemical parameters should alert the physician that this could be an unusual response to an infectious organism. Without treatment in FHLH the uncontrolled hyperinammation leads to sustained neutropenia and death from bacterial and fungal infections or multiorgan failure. Cerebral dysfunction is another frequent cause of death. A mortality of 50% was reported for presumably acquired cases in children.6 Prognosis in adults seems to be worse, especially in LAHS .21,22

Genetics and pathophysiology

Upon triggering of the immune system with an (infectious) agent, histiocytes (macrophages and dendritic cells), NK cells and CTLs are activated and mutually stimulate each other. This concerted

Hemophagocytic lymphohistiocytosis
Genetic, primary HLH
FHLH
- Chromosome 9 linkage - PRF1 mutations - UNC13D mutations - STX11 mutations - Unknown mutations Exogenous agents - infectious organisms, toxins (VAHS, IAHS)

Acquired, secondary HLH

HLH

Endogenous products - tissue damage - radical stress - metabolic products

Immune deficiencies
- CHS - Griscelli syndrome - XLP Rheumatic diseases (MAS) Malignancies

Figure 2 Classication and underlying conditions of hemophagocytic lymphohistiocytosis Reprint in modied version with permission of Blackwell Publishing, Oxford.

248 action leads to killing of the infected cell, removal of antigen and termination of the immune response. Defective cytotoxic activity not only impairs the elimination of cellular targets expressing antigens, but also the down-regulation of the immune response. Sustained immune activation with persistently high cytokine levels then leads to the clinical picture of HLH. NK cells and cytotoxic T lymphocytes kill their targets through cytolytic vesicles (granules) containing perforin and granzyme. Upon contact between the effector killer cell and the target cell, an immunological synapse is formed and cytolytic vesicles trafc to the contact site, dock and fuse with the plasma membrane and release their contents.23 All known defects in HLH seem to be involved in this process (Table 1 and Fig. 3): Mutations in PFR124 lead to impaired perforin production and cytolytic effector molecules cannot be introduced into the target cell, thereby triggering apoptosis. UNC13D mutations25 impair granule exocytosis after docking at the membrane. Recently a third gene, STX 11, was identied in FHLH.26 The encoded protein, t-SNARE syntaxin 11, plays a role in intracellular trafcking. Since the protein was only detected in monocytes, STX11 mutations might impair cytolytic activity involving the interaction between dendritic and killer cells. Linkage analysis in 2 HLH families of Pakistani origin revealed a fourth putative disease gene which has not yet been identied.27 Depending on the ethnic origin, 13%50% of patients with FHLH have mutations in PFR1, and 17%30% in UNC13D. So far, mutations in STX11 have only been found in patients of Turkish origin.28 The LYSTgene, mutated in Chediak-Higashi syndrome type 1,29 plays a role in vesicle transport. Mutations in RAB27A, described in Griscelli syndrome type 2,30 impair the docking of vesicles. Rab27a associates with Munc 13-4; the complex seems to be an important regulator of

G.E. Janka secretory granule fusion with the plasma membrane. In the x-linked lymphoproliferative syndrome mutations in SH2D1A, encoding the SAP protein, impair signal transduction and activation of lymphocytes.31 It is less clear how the function of NK cells and CTLs is impaired in immune competent patients with acquired HLH. Viruses may interfere with CTL function by specic proteins, high levels of cytokines may have the same effect. In some patients a genetic susceptibility may be present as indicated by several mild episodes of HLH. The high prevalence of EBV-associated HLH in Asia also suggests a genetic basis. In patients with lymphomas, secretion of cytokines by the malignant cells is a possible explanation.

Macrophage activation syndrome

The macrophage activation syndrome (MAS), now considered a special form of HLH, occurs in children and adults with autoimmune diseases, especially systemic onset juvenile rheumatoid arthritis (sJRA) or adult-onset Stills disease, but also lupus erythematodes or other entities.32,33 MAS is estimated to occur in up to 7% of patients with sJRA;34 mortality is between 1020%. In publications dealing with HLH in adults, the term (reactive) macrophage activation syndrome is often used as a synonym for hemophagocytic syndrome or acquired HLH regardless of the underlying condition and without specic reference to rheumatic diseases.35 HLH in autoimmune diseases has many characteristic features of HLH, including clinical signs and symptoms, laboratory ndings (especially very high ferritin levels), and hemophagocytosis. In contrast to other forms of HLH, cytopenias may be less severe initially, leading to a proposal of modied criteria for MAS.36 Also in contrast to classical HLH, severe cardiac impairment appears to be

Table 1 Disease FHLH-1 FHLH-2 FHLH-3 FHLH-4 GS-2 CHS-1 XLP

Genetic defects in hemophagocytic lymphohistiocytosis. Chromosome location 9q21.3-22 10q21-22 17q25 6q24 15q21 1q42.1-42.2 Xq25 Associated gene not known PFR1 UNC13D STX11 RAB27A LYST SH2D1A Gene function not known induction of apoptosis Vesicle priming Vesicle transport Vesicle docking Vesicle transport Signal transduction and activation of lymphocytes

Hemophagocytic syndromes

249

Figure 3 Molecular mechanisms based on the identication of genetic defects associated with the clinical picture of familial hemophagocytic lymphohistiocytosis (FHLH), Griscelli syndrome (GS-2), and Chediak-Higashi syndrome (CHS). Cytotoxic granule processing involves a Rab27a/Munc13-4 complex and several other unknown proteins. Perforin and granzymes are secreted into the immunological synapse and lead to apoptosis of the target cell. The exact function of LYST and syntaxin 11 is not known. In case of syntaxin 11, monocytes or macrophages/dendritic cells may interact with cytotoxic cells by an unknown mechanism.

common and coagulopathy is more pronounced.37 Patients with MAS exhibit defective NK cell function and may have decreased expression of perforin or SAP, mimicking the defects associated with FHLH and XLP, respectively .3840 MAS can be triggered by viruses, but also drugs have been implicated. When arthritis is missing, some criteria may be helpful to differentiate MAS from other forms of HLH such as a very high C-reactive protein, only moderate cytopenias, reduced erythropoiesis, increased granulopoiesis with a left shift, and a high level of interleukin-1b.9

Diagnostic criteria and differential diagnosis

In 1991 the HLH Study Group of the Histiocyte Society published the rst diagnostic guidelines for HLH. The diagnostic criteria were recently revised41 and are shown in Table 2. When a patient presents with prolonged fever unresponsive to antibiotics, hepatosplenomegaly and cytopenias, HLH as differential diagnosis should be considered. Minimal diagnostic requirements are a complete blood count, liver enzymes, bilirubin, triglycerides, ferritin and a coagulation

prole including brinogen. Patients suspected of HLH should receive a bone marrow examination and lumbar puncture at an experienced center. A marrow with normal or increased cellularity is typical. Unfortunately hemophagocytosis is often absent initially but may be found by a repeat examination. Cranial magnetic resonance tomography is indicated in patients with neurological symptoms or pathological ndings in the cerebrospinal uid. Valuable diagnostic parameters are increased concentrations of sCD25 and decreased NK cell function. Other disease markers, secreted by activated macrophages, are b-2 microglobulin,42 MIP1a43 and soluble CD163, the hemoglobin scavenger receptor.35 A search for an infectious organism like EBV, CMV, herpes simplex virus, adenovirus, parvovirus B19 and leishmania is recommended, since most of these agents are treatable. The patients should be screened for an underlying immune deciency like GS, CHS, XLP, autoimmune diseases and malignancies by appropriate studies. In suspected genetic cases material for genetic analysis should be obtained. The main diagnostic problem is that initially HLH masquerades as a normal infection and too little attention is paid to the severity of symptoms. Much time may then be lost with extensive

250
Table 2 Diagnostic criteria for HLH.

G.E. Janka

1. Familial disease/known genetic defect 2. Clinical and laboratory criteria (5/8 criteria)  Fever  Splenomegaly  Cytopenia = > 2 cell lines Hemoglobin < 90 g/l (below 4 weeks < 120 g/l) Platelets < 100 109/l Neutrophils < 1 109/l  Hypertriglyceridemia and/or hypobrinogenemia Fasting triglycerides = > 3 mmol/l Fibrinogen < 1.5 g/l  Ferritin > 500 lg/l  sCD25 = > 2400 U/ml  Decreased or absent NK-cell activity  Hemophagocytosis in bone marrow, CSF or lymphnodes
Supportive evidence are cerebral symptoms with moderate pleocytosis and/or elevated protein, elevated transaminases, bilirubin, LDH. For methods see Schneider et al. Blood 2002.

work-up for an infectious disease or with prolonged antibiotic treatment. Ferritin, brinogen and triglycerides are not routinely determined in patients with fever; HLH has to be kept in mind to order these laboratory studies. Also progression of symptoms may be overlooked or not be considered unusual. Misleading may be that some patients improve with unspecic methods such as transfusions. The fever may subside and laboratory values may transiently return to normal. If these patients are not closely followed, signs like persisting splenomegaly or anemia may be overlooked. The absence of hemophagocytosis is often the reason why the diagnosis of HLH is ruled out unwarranted. Hepatosplenomegaly, fever and cytopenia are signs of acute leukemia (easily to be excluded by a bone marrow examination) and in children also of Langerhans cell histiocytosis (LCH). The characteristic skin rash, bone lesions, lack of meningeal involvement and a distinct histological picture clearly separate LCH from HLH. Organomegaly, abnormal liver function and high triglycerides in babies may suggest a metabolic disease for which, however, progressive cytopenias, prolonged fever and the characteristic immunological ndings would not be expected. Liver biopsies may be interpreted as chronic hepatitis because hemophagocytosing macrophages may be absent in the periportal inltrate. Increased erythropoiesis, often with marked dysplastic changes, may at times suggest a myelodysplastic syndrome. Patients with isolated involvement of the central nervous system or with hepatic failure as the leading symptom may present a formidable diagnostic challenge.4446

Treatment and prognosis

Life-threatening hyperinammation, caused by excessive levels of cytokines, can be treated by corticosteroids which are cytotoxic for lymphocytes and inhibit expression of cytokines and differentiation of dendritic cells. Since dexamethasone crosses the blood brain barrier better than prednisolone it is the preferred drug in pediatric protocols. In MAS high-dose prednisolone (30mg/kg 3days) is often used with good response.34 Cyclosporin A, affecting T-lymphocyte activation and macrophage function, has proved to be effective for maintaining remission in genetic HLH47 and for children with MAS .48 Immunoglobulins probably act by cytokine- and pathogen-specic antibodies; they have been mainly used in adults with HLH.35 Etoposide, which was introduced to the treatment of HLH in 1980, is highly active in monocytic and histiocytic diseases. A proposed mode of action is killing of pathogen-infected antigen-presenting cells to reduce the stimulus for the ongoing, but ineffective activation of cytotoxic cells. Antithymocyte globulin in combination with steroids and cyclosporin A was used successfully in France. In genetic HLH stem cell transplantation (SCT) as the only curative method is the ultimate aim. To treat a highly febrile and pancytopenic patient with immunosuppressive drugs is an unusal experience for a hematologist. However, if hyperinammation is not controlled, the patient may die form multiorgan failure and infections associated with prolonged neutropenia. Children below 1 year of age in whom genetic HLH is likely and all patients with severe signs and symp-

Hemophagocytic syndromes toms such as progressive pancytopenia, coagulation problems, liver dysfunction and cerebral symptoms are candidates for combination therapy with dexamethasone, cycloporin A and etoposide. This is irrespective of the identication of an infectious organism (to be treated if possible) with the exception of leishmaniasis for which liposomal amphotericin B is usually sufcient. Recently, it was shown that the prognosis for EBV-related HLH in children and young adults has improved considerably with immunochemotherapy including etoposide and corticosteroids. The early introduction of etoposidebased regimens was the only signicant variable for survival with a relative risk of death 14 times higher for patients not receiving etopside or receiving it later than 4 weeks after diagnosis.49 Inhibition of synthesis of EBV nuclear antigen by etoposide may explain the striking effect of this drug. Less severe cases, usually in older patients, may do well with corticosteroids and immunoglobulins, but have to be followed carefully for signs of progression. For patients with HLH associated with autoimmune diseases, corticosteroids with or without cyclosporin A are sufcient in most cases to control hyperinammation; however, there is no clear consensus or evidence to suggest any particular therapeutic strategy.34 In 1994 the FHLH Study Group of the Histiocyte Society opened a protocol for HLH which included an initial 8-week period with dexamethasone and etoposide, followed by maintenance with cyclosporin A and alternating pulses of etoposide and dexamethasone for patients with known or presumed familial disease because of incomplete response or relapses. Maintenance was continued until stem cell transplantation. In patients with resolved, non-familial disease, treatment was to be discontinued after 8 weeks. There were 23 patients alive (20 off therapy) who had not undergone SCT. All except one were above 1 year of age. Presumably these patients in retrospect had acquired HLH. Whereas FHLH used to be uniformly fatal without SCT, with this protocol the estimated 3-year probability of survival was 51% for veried familial cases and 55% for the whole group of patients.50 About 25% of the children did not reach bone marrow transplantation due to progressive disease. Matched related or unrelated donor transplants offered the same chance of long-term disease-free survival (approximately 70%) whereas haploidentical family donor transplants or mismatched unrelated donor transplants were less favorable with a probability of survival around 50%. Graft failure occurred in 10% of the patients. Transplant-related mortality was high (26/86 patients), with many deaths attributable to pulmonary and liver problems.51

251 The new follow-up protocol HLH-2004 is a modest modication of protocol HLH-94; cyclosporin A is moved up front to prevent relapses during the tapering of dexamethasone. The small number of cases with HLH, either genetic or acquired, precludes the possibility of randomized studies. Also the unpredictability of response and clinical course often necessitates individualization of the treatment. For nonresponders effective salvage regimens are missing. In genetic cases, relapses, especially in the central nervous system, may lead to long-term sequelae.

Concluding remarks
In patients with prolonged fever, unresponsive to antibiotics, together with pronounced hepatosplenomegaly and cytopenias, the differential diagnosis of HLH should be considered. Characteristic laboratory changes such as high ferritin and triglycerides, as well as low brinogen support the diagnosis. The progressive, life-threatening symptoms of hyperinammation are conditioned by an inherited or acquired immune defect leading to the inadequate control of an infectious agent and to the failure of terminating the immune response. Awareness of the symptoms of HLH is important to start prompt life-saving therapy.

Practice points
 HLH is not only an inherited disease; acquired cases in children and adults are more frequent.  HLH is still often overlooked since the clinical symptoms, even though less severe, are also found in immune competent patients with infections.  Although hemophagocytosis has given the disease its name, it is not an obligatory symptom, and treatment should not be delayed if it is absent.

Research agenda
 Uncover more genetic defects  Understanding the pathophysiology of acquired HLH  Salvage therapy for non responders  Decrease of transplant-related mortality.

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G.E. Janka
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