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Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment
Joint Bone Spine 79 (2012) 356–361
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Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment Claire Larroche ∗ Service de médecine interne, université Paris-XIII, CHU Avicenne, 125, rue de Stalingrad, 93009 Bobigny cedex, France
a r t i c l e
i n f o
Article history: Accepted 14 October 2011 Available online 29 March 2012 Keywords: Macrophage activation syndrome Hemophagocytic lymphohistiocytosis
a b s t r a c t Hemophagocytic lymphohistiocytosis occurring as a primary or acquired disorder is a condition of chaotic and uncontrolled immune system stimulation. Cytotoxic cells and macrophages cause multiorgan damage, hemophagocytosis, and severe systemic inflammation. Clinical manifestations include a fever, organ enlargement, and weight loss. Laboratory tests show bicytopenia or pancytopenia, cytolysis and cholestasis, serum ferritin elevation, and clotting disorders. The reference standard for the diagnosis remains the presence in histological specimens of hemophagocytic macrophages, which may be lacking early in the disease, leading to diagnostic challenges. Inherited forms produce symptoms in early childhood and are fatal in the absence of specific treatment. In adults, the clinical spectrum ranges from mild and self-limited hemophagocytic lymphohistiocytosis to rapidly fatal multiorgan failure. Many questions remain unresolved regarding the diagnosis and treatment in adults. This update is an attempt at providing answers. © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Is the name “macrophage activation syndrome” appropriate? Several names have been or are still used to designate this disorder. In 1939, Bodley R. Scott and Robb-Smith described “histiocytic medullary reticulosis” (HMR) as an entity separate from atypical Hodgkin’s disease [1]. The characteristic abnormality was erythrophagocytosis by proliferating histiocytes in the lymphoreticular system. In 1966, HMR was classified among the malignant histiocytosis (MH), a decision that generated considerable debate in The Lancet between 1978 and 1983 [2]. A potential causal role for infectious agents was first suggested in 1979 by a case-series of 19 patients that comprised 13 renal transplant recipients with “virus-associated hemophagocytic syndrome” (VAHS). In 1984, three cases of “bacteria-associated hemophagocytic syndrome” were reported in adults [3]. In the last paper debating the nosology of hemophagocytic syndromes in The Lancet, VAHS was distinguished from HMR/MH [2] in 1983. Only in 2001 did studies establish that most cases of MH were large-cell anaplastic lymphomas. A 1988 case-series of 28 adults described “hemophagic histiocytosis” related to viral, bacterial, or fungal infections [4]. The name “macrophage activation syndrome” (MAS) was first used in 1993 by pediatric rheumatologists at the Necker Teaching Hospital in Paris, France, to designate a disorder seen in children with chronic inflammatory joint disease [5]. In 2002, Althreya argued
∗ Tel.: +33 1 48 95 53 51; fax: +33 1 48 95 54 50. E-mail address: [email protected]
that MAS was a secondary form of hemophagocytic lymphohistiocytosis (HLH) [6]. However, the name MAS is still used by pediatric rheumatologists today. A 1952 report by Farquhar and Claireaux described two siblings with “familial hemophagocytic reticulosis” [7]. In 1983, Janka reported a study of 121 personal and previously published cases of “familial hemophagocytic lymphohistiocytosis (FHL)”, a term still in use today [8]. Diagnostic criteria for HLH were first developed by Henter et al. in 1991. These criteria were validated in children and updated in 2004 [9]. The distinction between primary or inherited forms and secondary or acquired forms of HLH was reappraised by Henter and Elinder in 1995 (Fig. 1) [11]. These authors stated that secondary forms of HLH could be caused by immunosuppressant drugs, solid and hematological malignancies, and infections by viruses or other agents. They pointed out that a viral infection in a child with HLH does not rule out an underlying genetic disease, the main suspect being FHL [10]. The 1997 classification scheme by Favara et al. includes primary and secondary HLH among the “macrophagerelated hemophagocytic syndromes”, together with Rosai-Dorfman disease and solitary histiocytoma with macrophage phenotype [11]. The prevailing name today is “hemophagocytic lymphohistiocytosis (HLH)”, although some pediatric rheumatologists continue to prefer “macrophage activation syndrome (MAS)”. In French, the name is “syndrome d’activation macrophagique”, although “syndrome d’activation lympho-macrophagique/lympho-histiocytaire” would be more accurate and “hémophagocytose lymphohistiocytaire” has the advantage of producing the same acronym as the English name (HLH).
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.10.015
C. Larroche / Joint Bone Spine 79 (2012) 356–361
Familial Hemophagocytic Lymphohistiocytosis, FHL
Secondary (acquired) HLH
1 to 5 Chediak Higashi Griscelli type 2 Hermansky-Pudlak Hermansky Pudlak type 2
357
Infections
HLH
Malignancies
Medications
XLP 1 and2
Primary (inherited) HLH
Autoimmune/ Autoinflammatory y disorders
Fig. 1. Distinction between primary or inherited hemophagocytic lymphohistiocytosis (HLH) and secondary acquired HLH.
2. What is the best definition? The definition of HLH has evolved over the years, chiefly as a result of new pathophysiological insights into primary HLH provided by genetic studies. Before 2000, the macrophage was at the center of the pathophysiological hypotheses and HLH was defined as nonspecific proliferation and activation of macrophages in the reticulohistiocytic system, with blood-cell phagocytosis. Hemophagocytosis by macrophages became the reference standard for the diagnosis of HLH [12]. FHL-causing genes were first identified in 1999, establishing FHL as an inherited immune deficiency and indicating a key pathophysiological role for cytotoxic cells, namely, cytotoxic CD8+ T cells and natural killer (NK) cells. HLH can occur during the early stages or later on in the following primary immune deficiencies: FHL-1 to -5 (unknown gene at 9q21.3-22, PRF-1, UNC 13D, STX 11, and STX BP2, respectively), Chediak-Higashi syndrome (CHS1/LYST), Griscelli syndrome type 2 (RAB 27A), Hermansky-Pudlak syndrome type 2 (AP3B1), and the X-linked lymphoproliferative syndromes XLP-1 (SAP) and XPL-2 (XIAP) [13]. The functions of the proteins encoded by these disease-causing genes and studies in mutated mouse models have shed light on the steps involved in cytotoxic-cell granule exocytosis and established cytotoxicity as a key mechanism in lymphocyte homeostasis and immune response termination [13,14]. In HLH, after stimulation by a virus or another factor, the CD8+ T cells undergo unregulated polyclonal expansion and permanent activation, which leads to macrophage activation with hemophagocytosis. The clinical and laboratory features of HLH are due to multiorgan infiltration and damage (affecting the bone marrow, liver, spleen, lymph nodes, and central nervous system), as well as to the massive release of proinflammatory cytokines (including interferon gamma, interleukins 18 and 6, and TNF␣). HLH is the result of a highly stimulated and uncontrolled adaptive immune response. The phenotype is identical in familial and acquired forms. The molecular mechanisms that regulate cytotoxic-cell granule exocytosis are incompletely elucidated, and additional genes responsible for HLH remain to be identified [13]. 3. Is HLH recognized in the international classifications of diseases? The 10th version of the International Classification of Diseases and other health problems (ICD-10) developed by the World Health Organization includes an HLH category, with codes for FHL (D76.1) and infection-related hemophagocytic syndromes (D76.2). However, secondary HLH due to non-infectious causes and Griscelli
Fig. 2. Diagnosis of HLH in adults: clinical and biological symptoms. BMB: bone marrow biopsy; HM: hepatomegaly; SM: splenomegaly; ARDS: acute respiratory distress syndrome; glyc: glycosylated; -2m: -2 microglobulin; Fg: fibrinogen; DIVC: disseminated intravascular coagulation.
syndrome type 2 are not present in ICD-10. Chediak-Higashi syndrome and Hermansky-Pudlak syndrome are classified among the albinisms (E70.3) and XLP among the X-linked immune deficiencies (D82.3). Online Mendelian Inheritance in Man (OMIM, John Hopkins University patent) is a database of all known human genetic diseases. An MIM code is assigned to each disease and to each gene. The database includes the primary HLH phenotypes identified to date: 267700 (FHL-1), 603553 (FHL-2), 608898 (FHL-3), 603552 (FHL-4), 613101 (FHL-5), 607624 (GS-2), 214500 (CHS-1), 608233 (HP-2), 308240 (XLP-1), and 300635 (XLP-2). 4. Is the classical distinction between primary HLH as a pediatric disease and secondary HLH as an adult disease still valid? Although rare, primary HLH in adults does exist. To date, the oldest ages at diagnosis are 62 years for FHL-1 [15], 46 years for FHL-2 [16], 34 years for FHL-3 [17], 17 years for FHL-5 [18], 19 years for XLP-1, and 23 years for XLP-2 [19]. Polymorphisms and composite heterozygous mutations of the MUNC13-4 gene have been identified in patients with systemic juvenile idiopathic arthritis and HLH [20]. Nevertheless, routine testing for known causal genes in all adults with HLH would not be appropriate outside the research setting. In France, a publicly funded research program conducted under the aegis of the reference center for inherited immune deficiencies (CEREDIH) will seek to identify hypomorphic mutations in genes known to cause primary HLH. 5. Why is acquired HLH diagnosed late in adults? A fever is virtually always present. The other clinical features, in order of decreasing frequency, consist of rapid weight loss, enlargement of the liver and spleen in half the cases, lymphadenopathy, and jaundice. Less common manifestations include a skin rash and a variety of neurological manifestations of which the most common is encephalopathy (Fig. 2). Nearly all patients have bicytopenia (usually anemia and thrombocytopenia) or pancytopenia and serum ferritin elevation (often > 1000 ng/mL with less than 20% as the glycosylated form). Hepatic cholestasis and/or cytolysis are found in three-quarters of patients and LDH and triglyceride elevation in two-thirds of patients. Other laboratory abnormalities may include a decrease in serum fibrinogen with
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6. Can the Jan Inge Henter criteria be used in adults in everyday practice? Henter’s criteria as updated in 2004 are as follows: fever; splenomegaly; cytopenia involving at least two lines; increased triglycerides and/or decreased fibrinogen; evidence of hemophagocytosis in a bone marrow, liver, or node specimen; low or absent NK-cell activity; ferritin elevation to more than 500 g/L; and soluble IL-2 receptor alpha (sIL-2ra) elevation to more than 2400 U/mL. The presence of at least five of these eight criteria indicates HLH [9]. Tests for mutations in known genes can establish the diagnosis of primary HLH [9]. These criteria have been validated in pediatric patients but not in adults. Furthermore, tests for NK-cell activity and sIL-2ra levels are not available in everyday practice. Thus, Henter’s criteria cannot be used to diagnose HLH in adults. Given that evidence of hemophagocytosis requires time to develop, there is little to support the diagnosis at the early stage before the proinflammatory cytokine storm is fully developed, i.e., within the window of opportunity allowing a prompt recovery with effective treatment of the cause of HLH. One of the objectives of an ongoing prospective cohort study being conducted under the aegis of the CEREDIH is to identify diagnostic criteria suitable for use in everyday practice.
7. Can the levels of total and glycosylated ferritin help to diagnose acquired HLH in adults?
Fig. 3. Liver biopsy showing hemophagocytosis: a: erythrophagocytosis by a Küpffer cell; b: phagocytosis of a neutrophil by a Küpffer cell.
or without disseminated intravascular coagulation, hypoalbuminemia, hyponatremia due to inappropriate antidiuretic hormone secretion, -2 microglobulin elevation in blood and urine, serum lipase elevation, and/or lactic acidosis. Histological specimens showing hemophagocytic macrophages remain the diagnostic reference standard, which is unfortunate as this sign is often lacking in the early stages. A liver biopsy is more informative than a bone marrow aspiration and nearly always shows dilated sinusoids containing hyperplastic Küpffer cells phagocytizing erythrocytes and/or leukocytes, with no alterations in the normal liver architecture (Fig. 3). The liver biopsy can also indicate the cause of secondary HLH [21]. None of the clinical or laboratory manifestations is specific for HLH. The same manifestations can be caused by the disorders that trigger HLH, such as sepsis or lymphoma. Features that should suggest HLH are progressive organ enlargement, worsening cytopenia, greater ferritin elevation than expected based on the inflammatory syndrome, worsening liver function tests, and clotting disorders [22]. A longer time since symptom onset is associated with higher probabilities of a typical clinical and laboratory picture, histology showing hemophagocytic macrophages, and a fatal outcome. Events capable of triggering HLH include infections (e.g., with herpes viruses or mycobacteria), autoimmune and autoinflammatory diseases (e.g., systemic lupus erythematosus [SLE] or Still’s disease), malignancies (e.g., lymphomas), and drugs (Table 1). A comprehensive workup for a cause should be conducted rapidly to allow the identification and treatment of triggering factors. Of particular importance is measurement of the Epstein-Barr virus (EBV) load, which can suggest EBV-associated HLH, a condition that requires rapid treatment initiation [23].
As early as 1987, Japanese investigators reported major serum ferritin elevation in patients with viral HLH, to levels greater than 10,000 g/L [24]. Serum ferritin was not among the 1991 Henter’s criteria but was added in 2004, with a cutoff of 500 g/L having 84% sensitivity [9]. Of 330 patients seen at the Texas Children’s Hospital between 2003 and 2005 with serum ferritin levels greater than 500 g/L, the 10 patients with HLH had the highest mean ferritin values (5992 g/L [757–63,919] and 15,830 g/L [994–189,721], respectively), with levels far higher than in the 17 other diagnostic categories including malignancies, infections, and autoimmune disorders [25]. Peak ferritin levels greater than 10,000 g/L had 90% sensitivity and 96% specificity for HLH [25]. In an intensive care unit (ICU) study of patients with one or more organ failures, mean serum ferritin levels were significantly higher in the group with HLH, compared to the group without HLH (1822 ± 2751 g/L versus 397 ± 233 g/L, P = 0.01) [26]. Thus, when the clinical and laboratory features are suggestive, a serum ferritin value greater than 10,000 g/L strongly supports a diagnosis of HLH in patients without any of the differential diagnoses. Ferritin levels between 500 and 10,000 g/L raise a more challenging problem. The glycosylated ferritin level can be of assistance in this situation. In seven patients with acquired HLH, glycosylated ferritin levels were very low, with a mean of 8.4 ± 3% (< 5–42%) [27], and in 14 patients with acquired HLH the values were lower than in the controls, i.e., total ferritin 3344 g/L (2074–7334) with a 10% (3–14) glycosylated fraction versus 451 g/L (126–929) with a 36% (26–49) glycosylated fraction [28]. In a study of 29 patients with suspected HLH and 25 controls in China, the glycosylated ferritin fraction performed better for diagnosing HLH than did the total ferritin level (sensitivity: 86% vs. 82%, specificity: 71% vs. 43%, positive predictive value: 91% vs. 82%, and negative predictive value: 63% vs. 43%) [29]. Both total ferritin and the glycosylated fraction are easy to obtain in everyday practice and are of considerable assistance for diagnosing and monitoring HLH. Adult-onset Still’s disease and its pediatric equivalent systemic juvenile idiopathic arthritis (sJIA) are classified among the classical autoinflammatory diseases and can result in HLH, which may occur as the inaugural manifestation. In a study of adult-onset
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Table 1 Medications known to induce hemophagocytic lymphohistiocytosis. Reference
Medication (number of cases)
Underlying diseases
Causality
Sandhu et al. [47] Ramanan et al. J Rheumatol 2003;30:401–3
Etanercept (2)
Rheumatoid arthritis Systemic juvenile idiopathic arthritis
Strong
Kamiya et al. [50]
Rituximab (1)
Systemic lupus erythematosus
Strong
Lambotte et al. Am J Med 2002;112:592–4/Naitoh et al. Jpn J Clin Immunol 2009;32:492–8
Vancomycin (1) Trimethoprim sulfamethoxazole (2)
Sepsis + DRESS syndrome Systemic lupus erythematosus
Strong
Wang et al. Am J Hematol 2004;77:391–6
G-CSF and GM-CSF (1)
Myelodysplastic syndrome
Strong
Gumus et al. Pediatr Int 2007;49:672–3/Yang et al. Pediatr Neurol 2004;30:385–60/Descamps et al. Br J Dermatol 1997;137:605–8/Gutierrez-Ravé et al. South Med J 1991;84:949–50 Roth et al. Intensive Care Med 1993;19:111–4
Lamotrigine (2) Phenobarbital (1) Phenytoin (1)
Epilepsy ± DRESS syndrome
Strong
Lipid emulsions (1)
Total parenteral nutrition
Strong
Garcia-Suarez et al. Am J Hematol 2004;76:172–5
Retinoic acid (1)
Acute promyelocytic leukemia
Possible
Ravelli et al. J Rheumatol 2001;28:865–7/Yamanouchi et al. Ryumachi 1998;38:731–4/Tsuboi et al. Mod Rheumatol 2011 Bouayed et al. Arch Pediatr 2006;13:1156–9
Methotrexate (4)
Possible
Sulfasalazine (1)
Systemic juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis
Katoh et al. Internal Med 2007;46:1809–13
Bucillamine (1)
Rheumatoid arthritis
Possible
Still’s disease comparing patients with or without HLH, the group with HLH had a significantly higher mean total ferritin value (18,179 g/L [2215–185,000] vs. 3024 g/L [138–2200], P < 0.001) and a significantly lower mean glycosylated fraction (6.25% [5–15] vs. 19.6% [0–43], P = 0.006) [30]. 8. Have risk factors for mortality been identified in HLH? HLH associated with lymphomas has a considerably higher mortality rate compared to HLH due to infections and autoimmune diseases (overall survival 8% vs. 83%, P < 0.01) [31]. Worsening thrombocytopenia and anemia and worsening cholestasis significantly predict death in adults with HLH [32]. A rapid drop in total ferritin at treatment initiation is associated with better survival in pediatric HLH (odds ratio for death, 17.42 with a ferritin drop < 50% vs. > 96%; 95% confidence interval, 1.65–184.01) [33]. 9. Treatments for HLH in adults The treatment of primary HLH (i.e., FHL and the accelerated phases of Griscelli syndrome, Chediak-Higashi syndrome, and X-linked lymphoproliferative syndrome) relies on a combination of dexamethasone, etoposide, cyclosporine, and intrathecal methotrexate (HLH-94 then HLH-2004 protocols), followed by bone marrow transplantation. The HLH-2004 protocol is also indicated in all patients younger than 18 years of age who have severe and persistent or reactivated HLH [34]. It is also beneficial in a minority of young adults such as those with severe EBV-associated HLH, in which etoposide therapy within 4 weeks after the diagnosis is associated with significantly better survival [23]. The best treatment for acquired HLH in adults is not agreed on. Existing treatments and their indications are listed in Table 2. In every case, the underlying disease must be aggressively sought and treated, which may suffice to arrest the development of HLH. Elimination of a precipitating factor such as an immunosuppressive treatment should be discussed on a case-by-case basis. Close monitoring is in order and ICU admission may be required in patients with one or more organ failures, of which the most common are acute respiratory distress syndrome, coma, shock, acute renal failure, acute liver failure, and massive bleeding [35]. The HLH-2004 protocol includes very high dose glucocorticoid therapy. Dexamethasone is preferred, based on its better ability to cross the blood-brain barrier compared to prednisolone [9]. The use of glucocorticoid therapy depends on the cause of
Possible
HLH: causes requiring glucocorticoid therapy include autoimmune diseases, autoinflammatory diseases, and lymphomas associated with chemotherapy. Dexamethasone therapy is recommended in patients with predominant neurological manifestations. Except in the above-mentioned diseases, we no longer use high-dose methylprednisolone [36], which can increase the rate of infections capable of further exacerbating the HLH (personal communication). Intravenous etoposide (VP-16), whose effectiveness was first reported by Ambruso et al. [37], is now the drug of choice for treating HLH and is included in the HLH-94/2004 protocols [34]. Macrophage blockade is achieved within 24–48 hours. In secondary forms, etoposide has been effective in EBV-associated HLH [23], Table 2 Medications used in secondary hemophagocytic lymphohistiocytosis (HLH) with their indications. Medications
Indications in adults with HLH
Supportive care, hemofiltration, blood products Glucocorticoids (dexamethasone, methylprednisolone, prednisone)
All patients with HLH, as needed
Etoposide (VP-16) intravenously
Cyclosporine Intravenous immunoglobulins Rituximab (monoclonal anti-CD20)
Fontolizumab (monoclonal anti-IFN-␥) Monoclonal anti-TNF-␣ Anakinra (monoclonal anti-IL-1 Ra)
Daclizumab (monoclonal anti-CD25) Alemtuzumab (anti-CD52)
Dexamethasone if severe neurological involvement Treatment of the cause of HLH: Autoimmune and autoinflammatory diseases, lymphomas. . . HLH-EBV within 4 weeks, MCD, HLH in ICU patients All cases of secondary HLH with evidence of severe disease On a case-by-case basis Not indicated HLH-EBV, alone or with VP-16 MCD-HIV with VP-16 Diffuse large B-cell lymphoma and intravascular lymphoma, with combination chemotherapy (R-CHOP) Potentially helpful but not available Not indicated Autoinflammatory diseases (sJIA and Still) in combination with glucocorticoids Potentially helpful, limited availability Not indicated
sJIA: systemic juvenile idiopathic arthritis; EBV: Epstein-Barr virus; MCD: multicentric Castleman’s disease; ICU: intensive care unit; HIV: human immunodeficiency virus.
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multicentric Castleman’s disease [38], and ICU patients [35]. We use a single-drug low-dose etoposide regimen associated with brief bone marrow aplasia in adults with HLH (personal communication). The risk of secondary leukemia is low in the HLH-94/2004 protocol and in EBV-related HLH [39] and seems extremely small with our low-dose regimen for adults. The etoposide dosage should be adjusted according to the glomerular filtration rate and serum levels of albumin and bilirubin. In ICU patients receiving dialysis or hemofiltration, no pharmacological data allowing determination of the optimal etoposide dosage are available. We recommend total doses not greater than 100 mg per injection, with discussion on a case-by-case basis. Cyclosporine is used early in primary HLH [34] but is rarely given to patients with secondary HLH. Cyclosporine has been effective in a few patients with HLH due to viral infections or autoinflammatory diseases [40,41], at the cost of neurotoxicity (encephalitis, seizures) [42]. However, cyclosporine therapy may deserve discussion in selected patients with secondary HLH. Intravenous immunoglobulins were widely used at a time when this product was in abundant supply. Good results were obtained in patients with HLH due to infections, autoimmune diseases, or autoinflammatory diseases [43,44]. Now, the rapid effect of intravenous etoposide and shortage of intravenous immunoglobulins have prompted us to abandon this last treatment in adults with HLH.
10. Do antibody-based drugs have a role in the treatment of HLH? Proinflammatory cytokines play a central role in the pathophysiology of HLH. More specifically, interferon gamma (IFN-␥) is a pivotal factor, as established in the perforin-deficient mouse model [45]. Fontolizumab, a humanized anti-interferon gamma antibody to IFN-␥ that is being evaluated in Crohn’s disease, may have the strongest rationale for use in HLH but is not available [46]. Tumor necrosis factor (TNF) is among the Th1 cytokines overproduced in large amounts in active HLH. Monoclonal anti-TNF antibodies should not be used as they may either improve or exacerbate acquired HLH, particularly when the underlying cause is SLE, rheumatoid arthritis, or an autoinflammatory disease (sJIA, Still’s disease, and Crohn’s disease) [47]. In sJIA with HLH, the IL-1 receptor antagonist anakinra used alone or with glucocorticoid therapy either improved the symptoms or failed to prevent HLH flares during treatment [48]. Anakinra may deserve to be discussed on a case-by-case basis in patients with HLH associated with autoinflammatory diseases. The monoclonal anti-CD20 antibody rituximab may be helpful when used in combination with etoposide in EBV-related HLH [23] and HIV-positive Castleman’s disease with HLH [38], as well as in combination with chemotherapy for lymphomas with HLH (diffuse large B-cell lymphoma, intravascular lymphoma, EBV-positive lymphoproliferative disorders and, perhaps, Hodgkin’s lymphoma with HLH in which the EBV plays a central role) [49]. Rituximab can also result in HLH, as described in a patient with SLE [50]. Therefore, the risk/benefit ratio of rituximab in HLH must be assessed carefully. In theory, administration of the monoclonal anti-CD25 antibody daclizumab to block T cell activation should prove helpful. However, little evidence is available, probably because of the limited availability and high cost of this agent [51]. Finally, alemtuzumab, a monoclonal antibody to CD52, produced a remission that allowed subsequent stem-cell transplantation in a 39-year-old woman with HLH refractory to other treatments [52]. However, alemtuzumab is associated with a high risk of infections, and several cases of infection-related HLH have been reported in patients receiving this biological agent [52].
11. Conclusion Many issues about acquired HLH remain unresolved. The pathophysiological mechanisms are still incompletely elucidated, diagnostic criteria are lacking, and there is no consensus about the optimal treatment. However, the usefulness of low-dose etoposide in moderate-to-severe HLH deserves special emphasis. Aggressive investigations should be performed to identify the precipitating factor or factors, which must be treated as promptly as possible. Disclosure of interest The author declares that he has no conflicts of interest concerning this article. Acknowledgments The author is grateful to Centre de recherche et d’étude des déficits immunitaires héréditaires (CEREDIH) and extends special thanks to Doctor Coralie Bloch-Queyrat and Professor Olivier Hermine, who are coordinating the adult HLH registry and the adult HLH-gene study to be based on the registry data. References [1] Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet 1939;234:194–8. [2] Histiocytic medullary reticulosis. Lancet 1983;1:455–6. [3] Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. [4] Reiner AP, Spivak JL. Hematophagic histiocytosis. Medicine 1988;67:369–88. [5] Stéphan JL, Zeller J, Hubert P, et al. Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol 1993;11:451–6. [6] Athreya BH. Is macrophage activation syndrome a new entity? Clin Exp Rheumatol 2002;20:121–3. [7] Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519–25. [8] Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221–30. [9] Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol 2004;50:157–74. [10] Henter JI, Elinder G. Haemophagocytic lymphohistiocytosis: an inherited primary form and a reactive secondary form. Br J Haematol 1995;91:774–5. [11] Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997;29:157–66. [12] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29–33. [13] Pachlopnik Schmid J, Côte M, Ménager MM, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010;235:10–23. [14] De Saint Basile G, Ménasché G, Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 2010;10:568–79. [15] Nagafuji K, Nonami A, Kumano T, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 2007;92:978–81. [16] Gholam C, Grigoriadou S, Gilmour KC, et al. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol 2011;163:271–83. [17] Rohr J, Beutel K, Maul-Pavicic A, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 2010;95:2080–7. [18] Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 2010;116:2635–43. [19] Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 2011;117:1522–9. [20] Zhang K, Biroschak J, Glass DN, et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC134 polymorphisms. Arthritis Rheum 2008;58:2892–6. [21] Larroche C, Ziol M, Zidi S, et al. Liver involvement in hemophagocytic syndrome. Gastroenterol Clin Biol 2007;31:959–66. [22] Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95–109.
C. Larroche / Joint Bone Spine 79 (2012) 356–361 [23] Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol 2011;33:35–9. [24] Esumi N, Ikushima S, Todo S, et al. Hyperferritinemia in malignant histiocytosis and virus-associated hemophagocytic syndrome. N Engl J Med 1987;316:346–7. [25] Allen CE, Yu X, Kozinetz CA, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227–35. [26] Francois B, Trimoreau F, Vignon P, et al. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 1997;103:114–20. [27] Lambotte O, Cacoub P, Costedoat N, et al. High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. J Rheumatol 2003;30:1027–8. [28] Fardet L, Coppo P, Kettaneh A, et al. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum 2008;58:1521–7. [29] Wang Z, Wang Y, Wang J, et al. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol 2009;90:501–5. [30] Hot A, Toh ML, Coppéré B, et al. Reactive hemophagocytic syndrome in adultonset Still disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine 2010;89:37–46. [31] Takahashi N, Chubachi A, Kume M, et al. A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases. Int J Hematol 2001;74:209–13. [32] Kaito K, Kobayashi M, Katayama T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247–53. [33] Lin TF, Ferlic-Stark LL, Allen CE, et al. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer 2011;56:154–5. [34] Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124–31. [35] Buyse S, Teixeira L, Galicier L, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med 2010;36: 1695–702. [36] Chibane S, Feldman-Billard S, Rossignol I, et al. Short-term tolerance of three days pulse methyprednisolone therapy: a prospective study in 146 patients. Rev Med Interne 2005;26:20–6. [37] Ambruso DR, Hays T, Zwartjes WJ, et al. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516–20. [38] Stebbing J, Ngan S, Ibrahim H, et al. The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman’s disease. Clin Exp Immunol 2008;154:399–405.
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[39] Imashuku S. Etoposide-related secondary acute myeloid leukemia (t-AML) in hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48: 121–3. [40] Tsuda H, Shirono K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colonystimulating factor. Br J Haematol 1996;93:572–5. [41] Ravelli A, Viola S, De Benedetti F, et al. Dramatic efficacy of cyclosporine A in macrophage activation syndrome. Clin Exp Rheumatol 2001;19: 108. [42] Yakushijin K, Mizuno I, Sada A, et al. Cyclosporin neurotoxicity with Epstein-Barr virus-associated hemophagocytic syndrome. Haematologica 2005;90:ECR11. [43] Larroche C, Bruneel F, Andre MH, et al. Comité d’évaluation et de diffusion des innovation technologiques (CEDIT). Intravenously administered gammaglobulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP–HP. Ann Med Interne (Paris) 2000;151:533–9. [44] Emmenegger U, Frey U, Reimers A, et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 2001;68:4–10. [45] Jordan MB, Hildeman D, Kappler J, et al. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004;104:735–43. [46] Reinisch W, de Villiers W, Bene L, et al. Fontolizumab in moderate to severe Crohn’s disease: a phase II, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010;16:233–42. [47] Sandhu C, Chesney A, Piliotis E, et al. Macrophage activation syndrome after etanercept treatment. J Rheumatol 2007;34:241–2. [48] Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line diseasemodifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545–55. [49] Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008;47:531–4. [50] Kamiya K, Kurasawa K, Arai S, et al. Rituximab was effective on refractory thrombotic thrombocytopenic purpura but induced a flare of hemophagocytic syndrome in a patient with systemic lupus erythematosus. Mod Rheumatol 2010;20:81–5. [51] Olin RL, Nichols KE, Naghashpour M, et al. Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. Am J Hematol 2008;83:747–9. [52] Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin Oncol 2010;7:415–20.
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Review
Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment Claire Larroche ∗ Service de médecine interne, université Paris-XIII, CHU Avicenne, 125, rue de Stalingrad, 93009 Bobigny cedex, France
a r t i c l e
i n f o
Article history: Accepted 14 October 2011 Available online 29 March 2012 Keywords: Macrophage activation syndrome Hemophagocytic lymphohistiocytosis
a b s t r a c t Hemophagocytic lymphohistiocytosis occurring as a primary or acquired disorder is a condition of chaotic and uncontrolled immune system stimulation. Cytotoxic cells and macrophages cause multiorgan damage, hemophagocytosis, and severe systemic inflammation. Clinical manifestations include a fever, organ enlargement, and weight loss. Laboratory tests show bicytopenia or pancytopenia, cytolysis and cholestasis, serum ferritin elevation, and clotting disorders. The reference standard for the diagnosis remains the presence in histological specimens of hemophagocytic macrophages, which may be lacking early in the disease, leading to diagnostic challenges. Inherited forms produce symptoms in early childhood and are fatal in the absence of specific treatment. In adults, the clinical spectrum ranges from mild and self-limited hemophagocytic lymphohistiocytosis to rapidly fatal multiorgan failure. Many questions remain unresolved regarding the diagnosis and treatment in adults. This update is an attempt at providing answers. © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Is the name “macrophage activation syndrome” appropriate? Several names have been or are still used to designate this disorder. In 1939, Bodley R. Scott and Robb-Smith described “histiocytic medullary reticulosis” (HMR) as an entity separate from atypical Hodgkin’s disease [1]. The characteristic abnormality was erythrophagocytosis by proliferating histiocytes in the lymphoreticular system. In 1966, HMR was classified among the malignant histiocytosis (MH), a decision that generated considerable debate in The Lancet between 1978 and 1983 [2]. A potential causal role for infectious agents was first suggested in 1979 by a case-series of 19 patients that comprised 13 renal transplant recipients with “virus-associated hemophagocytic syndrome” (VAHS). In 1984, three cases of “bacteria-associated hemophagocytic syndrome” were reported in adults [3]. In the last paper debating the nosology of hemophagocytic syndromes in The Lancet, VAHS was distinguished from HMR/MH [2] in 1983. Only in 2001 did studies establish that most cases of MH were large-cell anaplastic lymphomas. A 1988 case-series of 28 adults described “hemophagic histiocytosis” related to viral, bacterial, or fungal infections [4]. The name “macrophage activation syndrome” (MAS) was first used in 1993 by pediatric rheumatologists at the Necker Teaching Hospital in Paris, France, to designate a disorder seen in children with chronic inflammatory joint disease [5]. In 2002, Althreya argued
∗ Tel.: +33 1 48 95 53 51; fax: +33 1 48 95 54 50. E-mail address: [email protected]
that MAS was a secondary form of hemophagocytic lymphohistiocytosis (HLH) [6]. However, the name MAS is still used by pediatric rheumatologists today. A 1952 report by Farquhar and Claireaux described two siblings with “familial hemophagocytic reticulosis” [7]. In 1983, Janka reported a study of 121 personal and previously published cases of “familial hemophagocytic lymphohistiocytosis (FHL)”, a term still in use today [8]. Diagnostic criteria for HLH were first developed by Henter et al. in 1991. These criteria were validated in children and updated in 2004 [9]. The distinction between primary or inherited forms and secondary or acquired forms of HLH was reappraised by Henter and Elinder in 1995 (Fig. 1) [11]. These authors stated that secondary forms of HLH could be caused by immunosuppressant drugs, solid and hematological malignancies, and infections by viruses or other agents. They pointed out that a viral infection in a child with HLH does not rule out an underlying genetic disease, the main suspect being FHL [10]. The 1997 classification scheme by Favara et al. includes primary and secondary HLH among the “macrophagerelated hemophagocytic syndromes”, together with Rosai-Dorfman disease and solitary histiocytoma with macrophage phenotype [11]. The prevailing name today is “hemophagocytic lymphohistiocytosis (HLH)”, although some pediatric rheumatologists continue to prefer “macrophage activation syndrome (MAS)”. In French, the name is “syndrome d’activation macrophagique”, although “syndrome d’activation lympho-macrophagique/lympho-histiocytaire” would be more accurate and “hémophagocytose lymphohistiocytaire” has the advantage of producing the same acronym as the English name (HLH).
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.10.015
C. Larroche / Joint Bone Spine 79 (2012) 356–361
Familial Hemophagocytic Lymphohistiocytosis, FHL
Secondary (acquired) HLH
1 to 5 Chediak Higashi Griscelli type 2 Hermansky-Pudlak Hermansky Pudlak type 2
357
Infections
HLH
Malignancies
Medications
XLP 1 and2
Primary (inherited) HLH
Autoimmune/ Autoinflammatory y disorders
Fig. 1. Distinction between primary or inherited hemophagocytic lymphohistiocytosis (HLH) and secondary acquired HLH.
2. What is the best definition? The definition of HLH has evolved over the years, chiefly as a result of new pathophysiological insights into primary HLH provided by genetic studies. Before 2000, the macrophage was at the center of the pathophysiological hypotheses and HLH was defined as nonspecific proliferation and activation of macrophages in the reticulohistiocytic system, with blood-cell phagocytosis. Hemophagocytosis by macrophages became the reference standard for the diagnosis of HLH [12]. FHL-causing genes were first identified in 1999, establishing FHL as an inherited immune deficiency and indicating a key pathophysiological role for cytotoxic cells, namely, cytotoxic CD8+ T cells and natural killer (NK) cells. HLH can occur during the early stages or later on in the following primary immune deficiencies: FHL-1 to -5 (unknown gene at 9q21.3-22, PRF-1, UNC 13D, STX 11, and STX BP2, respectively), Chediak-Higashi syndrome (CHS1/LYST), Griscelli syndrome type 2 (RAB 27A), Hermansky-Pudlak syndrome type 2 (AP3B1), and the X-linked lymphoproliferative syndromes XLP-1 (SAP) and XPL-2 (XIAP) [13]. The functions of the proteins encoded by these disease-causing genes and studies in mutated mouse models have shed light on the steps involved in cytotoxic-cell granule exocytosis and established cytotoxicity as a key mechanism in lymphocyte homeostasis and immune response termination [13,14]. In HLH, after stimulation by a virus or another factor, the CD8+ T cells undergo unregulated polyclonal expansion and permanent activation, which leads to macrophage activation with hemophagocytosis. The clinical and laboratory features of HLH are due to multiorgan infiltration and damage (affecting the bone marrow, liver, spleen, lymph nodes, and central nervous system), as well as to the massive release of proinflammatory cytokines (including interferon gamma, interleukins 18 and 6, and TNF␣). HLH is the result of a highly stimulated and uncontrolled adaptive immune response. The phenotype is identical in familial and acquired forms. The molecular mechanisms that regulate cytotoxic-cell granule exocytosis are incompletely elucidated, and additional genes responsible for HLH remain to be identified [13]. 3. Is HLH recognized in the international classifications of diseases? The 10th version of the International Classification of Diseases and other health problems (ICD-10) developed by the World Health Organization includes an HLH category, with codes for FHL (D76.1) and infection-related hemophagocytic syndromes (D76.2). However, secondary HLH due to non-infectious causes and Griscelli
Fig. 2. Diagnosis of HLH in adults: clinical and biological symptoms. BMB: bone marrow biopsy; HM: hepatomegaly; SM: splenomegaly; ARDS: acute respiratory distress syndrome; glyc: glycosylated; -2m: -2 microglobulin; Fg: fibrinogen; DIVC: disseminated intravascular coagulation.
syndrome type 2 are not present in ICD-10. Chediak-Higashi syndrome and Hermansky-Pudlak syndrome are classified among the albinisms (E70.3) and XLP among the X-linked immune deficiencies (D82.3). Online Mendelian Inheritance in Man (OMIM, John Hopkins University patent) is a database of all known human genetic diseases. An MIM code is assigned to each disease and to each gene. The database includes the primary HLH phenotypes identified to date: 267700 (FHL-1), 603553 (FHL-2), 608898 (FHL-3), 603552 (FHL-4), 613101 (FHL-5), 607624 (GS-2), 214500 (CHS-1), 608233 (HP-2), 308240 (XLP-1), and 300635 (XLP-2). 4. Is the classical distinction between primary HLH as a pediatric disease and secondary HLH as an adult disease still valid? Although rare, primary HLH in adults does exist. To date, the oldest ages at diagnosis are 62 years for FHL-1 [15], 46 years for FHL-2 [16], 34 years for FHL-3 [17], 17 years for FHL-5 [18], 19 years for XLP-1, and 23 years for XLP-2 [19]. Polymorphisms and composite heterozygous mutations of the MUNC13-4 gene have been identified in patients with systemic juvenile idiopathic arthritis and HLH [20]. Nevertheless, routine testing for known causal genes in all adults with HLH would not be appropriate outside the research setting. In France, a publicly funded research program conducted under the aegis of the reference center for inherited immune deficiencies (CEREDIH) will seek to identify hypomorphic mutations in genes known to cause primary HLH. 5. Why is acquired HLH diagnosed late in adults? A fever is virtually always present. The other clinical features, in order of decreasing frequency, consist of rapid weight loss, enlargement of the liver and spleen in half the cases, lymphadenopathy, and jaundice. Less common manifestations include a skin rash and a variety of neurological manifestations of which the most common is encephalopathy (Fig. 2). Nearly all patients have bicytopenia (usually anemia and thrombocytopenia) or pancytopenia and serum ferritin elevation (often > 1000 ng/mL with less than 20% as the glycosylated form). Hepatic cholestasis and/or cytolysis are found in three-quarters of patients and LDH and triglyceride elevation in two-thirds of patients. Other laboratory abnormalities may include a decrease in serum fibrinogen with
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6. Can the Jan Inge Henter criteria be used in adults in everyday practice? Henter’s criteria as updated in 2004 are as follows: fever; splenomegaly; cytopenia involving at least two lines; increased triglycerides and/or decreased fibrinogen; evidence of hemophagocytosis in a bone marrow, liver, or node specimen; low or absent NK-cell activity; ferritin elevation to more than 500 g/L; and soluble IL-2 receptor alpha (sIL-2ra) elevation to more than 2400 U/mL. The presence of at least five of these eight criteria indicates HLH [9]. Tests for mutations in known genes can establish the diagnosis of primary HLH [9]. These criteria have been validated in pediatric patients but not in adults. Furthermore, tests for NK-cell activity and sIL-2ra levels are not available in everyday practice. Thus, Henter’s criteria cannot be used to diagnose HLH in adults. Given that evidence of hemophagocytosis requires time to develop, there is little to support the diagnosis at the early stage before the proinflammatory cytokine storm is fully developed, i.e., within the window of opportunity allowing a prompt recovery with effective treatment of the cause of HLH. One of the objectives of an ongoing prospective cohort study being conducted under the aegis of the CEREDIH is to identify diagnostic criteria suitable for use in everyday practice.
7. Can the levels of total and glycosylated ferritin help to diagnose acquired HLH in adults?
Fig. 3. Liver biopsy showing hemophagocytosis: a: erythrophagocytosis by a Küpffer cell; b: phagocytosis of a neutrophil by a Küpffer cell.
or without disseminated intravascular coagulation, hypoalbuminemia, hyponatremia due to inappropriate antidiuretic hormone secretion, -2 microglobulin elevation in blood and urine, serum lipase elevation, and/or lactic acidosis. Histological specimens showing hemophagocytic macrophages remain the diagnostic reference standard, which is unfortunate as this sign is often lacking in the early stages. A liver biopsy is more informative than a bone marrow aspiration and nearly always shows dilated sinusoids containing hyperplastic Küpffer cells phagocytizing erythrocytes and/or leukocytes, with no alterations in the normal liver architecture (Fig. 3). The liver biopsy can also indicate the cause of secondary HLH [21]. None of the clinical or laboratory manifestations is specific for HLH. The same manifestations can be caused by the disorders that trigger HLH, such as sepsis or lymphoma. Features that should suggest HLH are progressive organ enlargement, worsening cytopenia, greater ferritin elevation than expected based on the inflammatory syndrome, worsening liver function tests, and clotting disorders [22]. A longer time since symptom onset is associated with higher probabilities of a typical clinical and laboratory picture, histology showing hemophagocytic macrophages, and a fatal outcome. Events capable of triggering HLH include infections (e.g., with herpes viruses or mycobacteria), autoimmune and autoinflammatory diseases (e.g., systemic lupus erythematosus [SLE] or Still’s disease), malignancies (e.g., lymphomas), and drugs (Table 1). A comprehensive workup for a cause should be conducted rapidly to allow the identification and treatment of triggering factors. Of particular importance is measurement of the Epstein-Barr virus (EBV) load, which can suggest EBV-associated HLH, a condition that requires rapid treatment initiation [23].
As early as 1987, Japanese investigators reported major serum ferritin elevation in patients with viral HLH, to levels greater than 10,000 g/L [24]. Serum ferritin was not among the 1991 Henter’s criteria but was added in 2004, with a cutoff of 500 g/L having 84% sensitivity [9]. Of 330 patients seen at the Texas Children’s Hospital between 2003 and 2005 with serum ferritin levels greater than 500 g/L, the 10 patients with HLH had the highest mean ferritin values (5992 g/L [757–63,919] and 15,830 g/L [994–189,721], respectively), with levels far higher than in the 17 other diagnostic categories including malignancies, infections, and autoimmune disorders [25]. Peak ferritin levels greater than 10,000 g/L had 90% sensitivity and 96% specificity for HLH [25]. In an intensive care unit (ICU) study of patients with one or more organ failures, mean serum ferritin levels were significantly higher in the group with HLH, compared to the group without HLH (1822 ± 2751 g/L versus 397 ± 233 g/L, P = 0.01) [26]. Thus, when the clinical and laboratory features are suggestive, a serum ferritin value greater than 10,000 g/L strongly supports a diagnosis of HLH in patients without any of the differential diagnoses. Ferritin levels between 500 and 10,000 g/L raise a more challenging problem. The glycosylated ferritin level can be of assistance in this situation. In seven patients with acquired HLH, glycosylated ferritin levels were very low, with a mean of 8.4 ± 3% (< 5–42%) [27], and in 14 patients with acquired HLH the values were lower than in the controls, i.e., total ferritin 3344 g/L (2074–7334) with a 10% (3–14) glycosylated fraction versus 451 g/L (126–929) with a 36% (26–49) glycosylated fraction [28]. In a study of 29 patients with suspected HLH and 25 controls in China, the glycosylated ferritin fraction performed better for diagnosing HLH than did the total ferritin level (sensitivity: 86% vs. 82%, specificity: 71% vs. 43%, positive predictive value: 91% vs. 82%, and negative predictive value: 63% vs. 43%) [29]. Both total ferritin and the glycosylated fraction are easy to obtain in everyday practice and are of considerable assistance for diagnosing and monitoring HLH. Adult-onset Still’s disease and its pediatric equivalent systemic juvenile idiopathic arthritis (sJIA) are classified among the classical autoinflammatory diseases and can result in HLH, which may occur as the inaugural manifestation. In a study of adult-onset
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Table 1 Medications known to induce hemophagocytic lymphohistiocytosis. Reference
Medication (number of cases)
Underlying diseases
Causality
Sandhu et al. [47] Ramanan et al. J Rheumatol 2003;30:401–3
Etanercept (2)
Rheumatoid arthritis Systemic juvenile idiopathic arthritis
Strong
Kamiya et al. [50]
Rituximab (1)
Systemic lupus erythematosus
Strong
Lambotte et al. Am J Med 2002;112:592–4/Naitoh et al. Jpn J Clin Immunol 2009;32:492–8
Vancomycin (1) Trimethoprim sulfamethoxazole (2)
Sepsis + DRESS syndrome Systemic lupus erythematosus
Strong
Wang et al. Am J Hematol 2004;77:391–6
G-CSF and GM-CSF (1)
Myelodysplastic syndrome
Strong
Gumus et al. Pediatr Int 2007;49:672–3/Yang et al. Pediatr Neurol 2004;30:385–60/Descamps et al. Br J Dermatol 1997;137:605–8/Gutierrez-Ravé et al. South Med J 1991;84:949–50 Roth et al. Intensive Care Med 1993;19:111–4
Lamotrigine (2) Phenobarbital (1) Phenytoin (1)
Epilepsy ± DRESS syndrome
Strong
Lipid emulsions (1)
Total parenteral nutrition
Strong
Garcia-Suarez et al. Am J Hematol 2004;76:172–5
Retinoic acid (1)
Acute promyelocytic leukemia
Possible
Ravelli et al. J Rheumatol 2001;28:865–7/Yamanouchi et al. Ryumachi 1998;38:731–4/Tsuboi et al. Mod Rheumatol 2011 Bouayed et al. Arch Pediatr 2006;13:1156–9
Methotrexate (4)
Possible
Sulfasalazine (1)
Systemic juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis
Katoh et al. Internal Med 2007;46:1809–13
Bucillamine (1)
Rheumatoid arthritis
Possible
Still’s disease comparing patients with or without HLH, the group with HLH had a significantly higher mean total ferritin value (18,179 g/L [2215–185,000] vs. 3024 g/L [138–2200], P < 0.001) and a significantly lower mean glycosylated fraction (6.25% [5–15] vs. 19.6% [0–43], P = 0.006) [30]. 8. Have risk factors for mortality been identified in HLH? HLH associated with lymphomas has a considerably higher mortality rate compared to HLH due to infections and autoimmune diseases (overall survival 8% vs. 83%, P < 0.01) [31]. Worsening thrombocytopenia and anemia and worsening cholestasis significantly predict death in adults with HLH [32]. A rapid drop in total ferritin at treatment initiation is associated with better survival in pediatric HLH (odds ratio for death, 17.42 with a ferritin drop < 50% vs. > 96%; 95% confidence interval, 1.65–184.01) [33]. 9. Treatments for HLH in adults The treatment of primary HLH (i.e., FHL and the accelerated phases of Griscelli syndrome, Chediak-Higashi syndrome, and X-linked lymphoproliferative syndrome) relies on a combination of dexamethasone, etoposide, cyclosporine, and intrathecal methotrexate (HLH-94 then HLH-2004 protocols), followed by bone marrow transplantation. The HLH-2004 protocol is also indicated in all patients younger than 18 years of age who have severe and persistent or reactivated HLH [34]. It is also beneficial in a minority of young adults such as those with severe EBV-associated HLH, in which etoposide therapy within 4 weeks after the diagnosis is associated with significantly better survival [23]. The best treatment for acquired HLH in adults is not agreed on. Existing treatments and their indications are listed in Table 2. In every case, the underlying disease must be aggressively sought and treated, which may suffice to arrest the development of HLH. Elimination of a precipitating factor such as an immunosuppressive treatment should be discussed on a case-by-case basis. Close monitoring is in order and ICU admission may be required in patients with one or more organ failures, of which the most common are acute respiratory distress syndrome, coma, shock, acute renal failure, acute liver failure, and massive bleeding [35]. The HLH-2004 protocol includes very high dose glucocorticoid therapy. Dexamethasone is preferred, based on its better ability to cross the blood-brain barrier compared to prednisolone [9]. The use of glucocorticoid therapy depends on the cause of
Possible
HLH: causes requiring glucocorticoid therapy include autoimmune diseases, autoinflammatory diseases, and lymphomas associated with chemotherapy. Dexamethasone therapy is recommended in patients with predominant neurological manifestations. Except in the above-mentioned diseases, we no longer use high-dose methylprednisolone [36], which can increase the rate of infections capable of further exacerbating the HLH (personal communication). Intravenous etoposide (VP-16), whose effectiveness was first reported by Ambruso et al. [37], is now the drug of choice for treating HLH and is included in the HLH-94/2004 protocols [34]. Macrophage blockade is achieved within 24–48 hours. In secondary forms, etoposide has been effective in EBV-associated HLH [23], Table 2 Medications used in secondary hemophagocytic lymphohistiocytosis (HLH) with their indications. Medications
Indications in adults with HLH
Supportive care, hemofiltration, blood products Glucocorticoids (dexamethasone, methylprednisolone, prednisone)
All patients with HLH, as needed
Etoposide (VP-16) intravenously
Cyclosporine Intravenous immunoglobulins Rituximab (monoclonal anti-CD20)
Fontolizumab (monoclonal anti-IFN-␥) Monoclonal anti-TNF-␣ Anakinra (monoclonal anti-IL-1 Ra)
Daclizumab (monoclonal anti-CD25) Alemtuzumab (anti-CD52)
Dexamethasone if severe neurological involvement Treatment of the cause of HLH: Autoimmune and autoinflammatory diseases, lymphomas. . . HLH-EBV within 4 weeks, MCD, HLH in ICU patients All cases of secondary HLH with evidence of severe disease On a case-by-case basis Not indicated HLH-EBV, alone or with VP-16 MCD-HIV with VP-16 Diffuse large B-cell lymphoma and intravascular lymphoma, with combination chemotherapy (R-CHOP) Potentially helpful but not available Not indicated Autoinflammatory diseases (sJIA and Still) in combination with glucocorticoids Potentially helpful, limited availability Not indicated
sJIA: systemic juvenile idiopathic arthritis; EBV: Epstein-Barr virus; MCD: multicentric Castleman’s disease; ICU: intensive care unit; HIV: human immunodeficiency virus.
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multicentric Castleman’s disease [38], and ICU patients [35]. We use a single-drug low-dose etoposide regimen associated with brief bone marrow aplasia in adults with HLH (personal communication). The risk of secondary leukemia is low in the HLH-94/2004 protocol and in EBV-related HLH [39] and seems extremely small with our low-dose regimen for adults. The etoposide dosage should be adjusted according to the glomerular filtration rate and serum levels of albumin and bilirubin. In ICU patients receiving dialysis or hemofiltration, no pharmacological data allowing determination of the optimal etoposide dosage are available. We recommend total doses not greater than 100 mg per injection, with discussion on a case-by-case basis. Cyclosporine is used early in primary HLH [34] but is rarely given to patients with secondary HLH. Cyclosporine has been effective in a few patients with HLH due to viral infections or autoinflammatory diseases [40,41], at the cost of neurotoxicity (encephalitis, seizures) [42]. However, cyclosporine therapy may deserve discussion in selected patients with secondary HLH. Intravenous immunoglobulins were widely used at a time when this product was in abundant supply. Good results were obtained in patients with HLH due to infections, autoimmune diseases, or autoinflammatory diseases [43,44]. Now, the rapid effect of intravenous etoposide and shortage of intravenous immunoglobulins have prompted us to abandon this last treatment in adults with HLH.
10. Do antibody-based drugs have a role in the treatment of HLH? Proinflammatory cytokines play a central role in the pathophysiology of HLH. More specifically, interferon gamma (IFN-␥) is a pivotal factor, as established in the perforin-deficient mouse model [45]. Fontolizumab, a humanized anti-interferon gamma antibody to IFN-␥ that is being evaluated in Crohn’s disease, may have the strongest rationale for use in HLH but is not available [46]. Tumor necrosis factor (TNF) is among the Th1 cytokines overproduced in large amounts in active HLH. Monoclonal anti-TNF antibodies should not be used as they may either improve or exacerbate acquired HLH, particularly when the underlying cause is SLE, rheumatoid arthritis, or an autoinflammatory disease (sJIA, Still’s disease, and Crohn’s disease) [47]. In sJIA with HLH, the IL-1 receptor antagonist anakinra used alone or with glucocorticoid therapy either improved the symptoms or failed to prevent HLH flares during treatment [48]. Anakinra may deserve to be discussed on a case-by-case basis in patients with HLH associated with autoinflammatory diseases. The monoclonal anti-CD20 antibody rituximab may be helpful when used in combination with etoposide in EBV-related HLH [23] and HIV-positive Castleman’s disease with HLH [38], as well as in combination with chemotherapy for lymphomas with HLH (diffuse large B-cell lymphoma, intravascular lymphoma, EBV-positive lymphoproliferative disorders and, perhaps, Hodgkin’s lymphoma with HLH in which the EBV plays a central role) [49]. Rituximab can also result in HLH, as described in a patient with SLE [50]. Therefore, the risk/benefit ratio of rituximab in HLH must be assessed carefully. In theory, administration of the monoclonal anti-CD25 antibody daclizumab to block T cell activation should prove helpful. However, little evidence is available, probably because of the limited availability and high cost of this agent [51]. Finally, alemtuzumab, a monoclonal antibody to CD52, produced a remission that allowed subsequent stem-cell transplantation in a 39-year-old woman with HLH refractory to other treatments [52]. However, alemtuzumab is associated with a high risk of infections, and several cases of infection-related HLH have been reported in patients receiving this biological agent [52].
11. Conclusion Many issues about acquired HLH remain unresolved. The pathophysiological mechanisms are still incompletely elucidated, diagnostic criteria are lacking, and there is no consensus about the optimal treatment. However, the usefulness of low-dose etoposide in moderate-to-severe HLH deserves special emphasis. Aggressive investigations should be performed to identify the precipitating factor or factors, which must be treated as promptly as possible. Disclosure of interest The author declares that he has no conflicts of interest concerning this article. Acknowledgments The author is grateful to Centre de recherche et d’étude des déficits immunitaires héréditaires (CEREDIH) and extends special thanks to Doctor Coralie Bloch-Queyrat and Professor Olivier Hermine, who are coordinating the adult HLH registry and the adult HLH-gene study to be based on the registry data. References [1] Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet 1939;234:194–8. [2] Histiocytic medullary reticulosis. Lancet 1983;1:455–6. [3] Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. [4] Reiner AP, Spivak JL. Hematophagic histiocytosis. Medicine 1988;67:369–88. [5] Stéphan JL, Zeller J, Hubert P, et al. Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol 1993;11:451–6. [6] Athreya BH. Is macrophage activation syndrome a new entity? Clin Exp Rheumatol 2002;20:121–3. [7] Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519–25. [8] Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221–30. [9] Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol 2004;50:157–74. [10] Henter JI, Elinder G. Haemophagocytic lymphohistiocytosis: an inherited primary form and a reactive secondary form. Br J Haematol 1995;91:774–5. [11] Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997;29:157–66. [12] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29–33. [13] Pachlopnik Schmid J, Côte M, Ménager MM, et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010;235:10–23. [14] De Saint Basile G, Ménasché G, Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 2010;10:568–79. [15] Nagafuji K, Nonami A, Kumano T, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 2007;92:978–81. [16] Gholam C, Grigoriadou S, Gilmour KC, et al. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol 2011;163:271–83. [17] Rohr J, Beutel K, Maul-Pavicic A, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 2010;95:2080–7. [18] Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 2010;116:2635–43. [19] Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 2011;117:1522–9. [20] Zhang K, Biroschak J, Glass DN, et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC134 polymorphisms. Arthritis Rheum 2008;58:2892–6. [21] Larroche C, Ziol M, Zidi S, et al. Liver involvement in hemophagocytic syndrome. Gastroenterol Clin Biol 2007;31:959–66. [22] Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95–109.
C. Larroche / Joint Bone Spine 79 (2012) 356–361 [23] Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol 2011;33:35–9. [24] Esumi N, Ikushima S, Todo S, et al. Hyperferritinemia in malignant histiocytosis and virus-associated hemophagocytic syndrome. N Engl J Med 1987;316:346–7. [25] Allen CE, Yu X, Kozinetz CA, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227–35. [26] Francois B, Trimoreau F, Vignon P, et al. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 1997;103:114–20. [27] Lambotte O, Cacoub P, Costedoat N, et al. High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. J Rheumatol 2003;30:1027–8. [28] Fardet L, Coppo P, Kettaneh A, et al. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum 2008;58:1521–7. [29] Wang Z, Wang Y, Wang J, et al. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol 2009;90:501–5. [30] Hot A, Toh ML, Coppéré B, et al. Reactive hemophagocytic syndrome in adultonset Still disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine 2010;89:37–46. [31] Takahashi N, Chubachi A, Kume M, et al. A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases. Int J Hematol 2001;74:209–13. [32] Kaito K, Kobayashi M, Katayama T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247–53. [33] Lin TF, Ferlic-Stark LL, Allen CE, et al. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer 2011;56:154–5. [34] Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124–31. [35] Buyse S, Teixeira L, Galicier L, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med 2010;36: 1695–702. [36] Chibane S, Feldman-Billard S, Rossignol I, et al. Short-term tolerance of three days pulse methyprednisolone therapy: a prospective study in 146 patients. Rev Med Interne 2005;26:20–6. [37] Ambruso DR, Hays T, Zwartjes WJ, et al. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516–20. [38] Stebbing J, Ngan S, Ibrahim H, et al. The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman’s disease. Clin Exp Immunol 2008;154:399–405.
361
[39] Imashuku S. Etoposide-related secondary acute myeloid leukemia (t-AML) in hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48: 121–3. [40] Tsuda H, Shirono K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colonystimulating factor. Br J Haematol 1996;93:572–5. [41] Ravelli A, Viola S, De Benedetti F, et al. Dramatic efficacy of cyclosporine A in macrophage activation syndrome. Clin Exp Rheumatol 2001;19: 108. [42] Yakushijin K, Mizuno I, Sada A, et al. Cyclosporin neurotoxicity with Epstein-Barr virus-associated hemophagocytic syndrome. Haematologica 2005;90:ECR11. [43] Larroche C, Bruneel F, Andre MH, et al. Comité d’évaluation et de diffusion des innovation technologiques (CEDIT). Intravenously administered gammaglobulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP–HP. Ann Med Interne (Paris) 2000;151:533–9. [44] Emmenegger U, Frey U, Reimers A, et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 2001;68:4–10. [45] Jordan MB, Hildeman D, Kappler J, et al. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004;104:735–43. [46] Reinisch W, de Villiers W, Bene L, et al. Fontolizumab in moderate to severe Crohn’s disease: a phase II, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010;16:233–42. [47] Sandhu C, Chesney A, Piliotis E, et al. Macrophage activation syndrome after etanercept treatment. J Rheumatol 2007;34:241–2. [48] Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line diseasemodifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545–55. [49] Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008;47:531–4. [50] Kamiya K, Kurasawa K, Arai S, et al. Rituximab was effective on refractory thrombotic thrombocytopenic purpura but induced a flare of hemophagocytic syndrome in a patient with systemic lupus erythematosus. Mod Rheumatol 2010;20:81–5. [51] Olin RL, Nichols KE, Naghashpour M, et al. Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. Am J Hematol 2008;83:747–9. [52] Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin Oncol 2010;7:415–20.