An Overview of Hemophagocytic Lymphohistiocytosis

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1 An Overview of Hemophagocytic Lymphohistiocytosis Ysabella M. Esteban, MD; Jill L. O. de Jong, MD, PhD; and Melissa S. Tesher, MD ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by a dysregulated hyperinflammatory response associated with aberrant activation of lymphocytes and macrophages that results in hypercytokinemia. It is classically divided into two types: (1) primary or familial HLH and (2) secondary HLH. Familial HLH is generally an autosomal recessive condition, whereas secondary HLH is usually associated with infectious diseases, autoinflammatory and autoimmune diseases (where it is more commonly known as macrophage activation syndrome), malignancy, immunosuppression, hematopoietic stem cell transplantation, organ transplantation, HIV infection, and metabolic diseases. Although its clinical presentation is often similar to bacterial sepsis or systemic inflammatory response syndrome, HLH can be life-threatening. As such, it is imperative to recognize and diagnose HLH in a timely manner to optimize care. [Pediatr Ann. 2017;46(8):e309-e313.] Hemophagocytic lymphohistiocytosis (HLH) was first described in 1939 by Scott and Robb-Smith. 1 At that time, it was known as histiocytic medullary reticulosis (HMR), and was originally thought to be a form of atypical Hodgkin s disease. Scott and Robb-Smith described four cases of adult patients who exhibited similar clinical courses of fever, lymphadenopathy, splenomegaly, and hepatomegaly, and later in their disease courses they developed jaundice, purpura, anemia, and leukopenia. 1 Postmortem examination of these patients revealed histiocytes phagocytosing erythrocytes. In addition, Scott and Robb-Smith examined six other case reports of patients with similar findings; these patients were between the ages of 26 to 69 years, and both genders were affected. 1 Thirteen years later, in 1952, Farquhar and Claireaux 2 described two siblings with HMR who both presented in infancy with rapidly progressing organ failure resulting in fatality. In this review, the etiologies of HLH are explored, as well as the resulting pathogenesis, clinical manifestations, and subsequent diagnosis and treatment. Ysabella M. Esteban, MD, is a Resident, Department of Pediatrics. Jill L. O. de Jong, MD, PhD, is an Assistant Professor, Department of Pediatrics, Section of Hematology/Oncology. Melissa S. Tesher, MD, is an Assistant Professor, Department of Pediatrics, Section of Rheumatology. All authors are affiliated with The University of Chicago Medicine. Address correspondence to Ysabella M. Esteban, MD, Comer Children s Hospital, 5721 S. Maryland Avenue, K155, Chicago, IL 60637; Ysabella.Esteban@uchospitals.edu. Disclosure: The authors have no relevant financial relationships to disclose. doi: / ETIOLOGY AND EPIDEMIOLOGY HLH can be broadly categorized into primary and secondary forms, with respective subtypes. Primary HLH, also known as familial HLH (F-HLH), has autosomal recessive inheritance and incomplete penetrance. A number of genetic mutations have been identified that result in F-HLH, although some genetic lesions are still unknown (Table 1). In addition, certain immunodeficiency syndromes and hereditary disorders are closely linked to HLH, including Chediak-Higashi syndrome and Griscelli syndrome-2, as well as X-linked lymphoproliferative syndromes types 1 (XLP1) and 2 (XLP2), Hermansky- Pudlak syndrome type II, and Wiskott- Aldrich Syndrome. 3,4 F-HLH is most commonly diagnosed during the first year of life. The incidence in children younger than age 1 year is 1.1 per 100,000, with a median age of onset of 5.1 months. 5 However, being older than age 1 year does not exclude the diagnosis of F-HLH. For example, there are cases of late-onset F-HLH among teenagers with defects in PRF1. The frequency of HLH subtypes differs between populations. Mutations of PRF1, UNC13D, and STX11 were identified in 80% of patients with HLH who were of Turkish descent, as well as in 30% of German patients. 6,7 In patients with F-HLH in North America, the PRF1 mutation is the most common, followed closely by UNC13D and STXBP2. 8,9 Secondary, or acquired, HLH is usually associated with infectious, oncologic, rheumatologic, or other underlying causes. 3 The most common infection associated with acquired HLH is Epstein- Barr virus (EBV). 8 In Japan, 40% of all e309

2 TABLE 1. Primary HLH Subtypes and Related Genetic Mutations Type Gene Protein Affected Function 1 Unknown, located on chromosome 9q Unknown Unknown 2 PFR1 Perforin Released by cytotoxic lymphocytes and is essential for normal down-regulation of immune response by forming pores in target cells, resulting in apoptosis 3 UNC13D Munc 13-4 Priming of cytolytic granules, defective degranulation 29 4 STX11 Syntaxin 11 Membrane fusion, intracellular transport 8 5 STXBP2 Syntaxin binding protein 2, or Munc18-2 Abbreviation: HLH, hemophagocytic lymphohistiocytosis. Membrane fusion, intracellular transport, release of cytotoxic granules 30 patients with HLH have an associated EBV infection. 9 Curiously, when EBV is associated with HLH, the predominantly infected cells are T cells or B and T cells equally, as opposed to primarily B cells. 10 Respiratory syncytial virus, rotavirus, and adenovirus infections are also implicated causes of secondary HLH. 3 If HLH develops in the presence of malignancy, it is known as malignancy-associated hemophagocytic syndrome (MAHS). In one study of 52 children with MAHS, 60% of cases were associated with non- Hodgkin s lymphoma (primarily T-cell type), followed by acute leukemias, myelodysplastic syndromes, Langerhans cell histiocytosis, and histiocytic sarcoma. 3 When HLH is observed in the context of rheumatological diseases, secondary HLH is commonly known as macrophage activation syndrome (MAS), and is most often found as a complication of systemic juvenile idiopathic arthritis (sjia). MAS has been found to occur in at least 7% to 13% of sjia patients. 10,11 However, it can also be associated with systemic lupus erythematosus, mixed connective tissue disease, and other rheumatic diseases. HLH has also been observed in the setting of immune suppression after transplant, including kidney, liver, and hematopoietic stem cell transplants. Cases of HLH have occurred after prolonged periods of total parenteral nutrition that include soluble lipids, in which case it is known as fat overload syndrome. 3 Moreover, a case of HLH was reported in a neonate in association with mitochondrial respiratory chain disorder. 12 PATHOPHYSIOLOGY Much of what is known about the pathophysiology of HLH has been discovered in the context of F-HLH. The exact mechanisms underlying the pathophysiology of secondary HLH are not yet completely elucidated and are likely multifactorial. Altered function of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) with accompanying dysregulated response to antigen presenting cells (APCs), are common to the pathogenesis of the varied HLH subtypes. In patients with an intact immune system, NK cells and CTLs kill infected cells and APCs via a perforin-dependent pathway. 10 The former possess secretory lysosomes composed of perforin and granzymes. Jenkins et al. 13 demonstrated in their mouse and human cell models that when an NK cell recognizes an APC, it becomes activated, forming an immunological synapse (IS) between the two cells. Perforin and granzymes are transported along this synapse toward the APC. 13 The IS is also responsible for releasing inflammatory cytokines and chemokines, which further facilitate the immune response. Working together with perforin, granzymes facilitate apoptosis of the APC or infected cell. The dying cell then releases a caspasedependent enzymatic cascade which destroys the IS, and thereby downregulates the immune response. Patients with F-HLH have defects in this perforin-dependent and granzyme-dependent pathway, resulting in the inability of the NK cells or CTLs to down-regulate the immune response. For example, patients with F-HLH type 2 have mutations affecting perforin. 10,14 Additionally, those with F-HLH types 3, 4, and 5 harbor mutations affecting secretory lysosome processing, transporting, docking, and exocytosis. It has been suggested that heterozygous variants in genes related to this pathway contribute to the development of secondary HLH. 15 For example, in MAS, Kaufman et al. 16 demonstrated that of 14 MAS cases associated with sjia, 5 were heterozygous for at least one mutation in the known genes related to F-HLH. However, in other forms of secondary HLH, the initial pathogenesis remains to be elucidated. In EBV-HLH, it is still unknown if susceptibility to developing secondary HLH is caused by genetic predisposition or EBV-induced immunological dysregulation, although infection of T cells by e310 Copyright SLACK Incorporated

3 the virus is associated with development of HLH. 17 This could be secondary to the observation by Lay et al. 18 that infection of T cells by EBV increases expression of tumor necrosis factor-alpha and interferon-gamma, leading to increased macrophage activation. Despite the variations in the predispositions or inciting factors of HLH, after NK cells, lymphocytes, and macrophages become increasingly activated and they secrete high levels of cytokines and chemokines, which results in the clinical and laboratory findings. 10 Interleukins and tumor necrosis factor-alpha generate fever. Cytokines suppress lipoprotein lipase, leading to hypertriglyceridemia. Macrophages secrete ferritin, 10 leading to increased plasminogen activator, resulting in hyperfibrinolysis and hypofibrinogenemia. SIGNS AND SYMPTOMS The signs and symptoms of HLH can be nonspecific, ranging from persistent fevers to sepsis physiology, so the index of suspicion must be kept high to make the diagnosis. 19 The main symptoms associated with HLH include prolonged high fever, hepatosplenomegaly, and cytopenias. 10 Other clinical findings include hepatitis, neurological symptoms (such as seizures, meningismus, decreased level of consciousness), rash, pulmonary dysfunction, and lymphadenopathy. Central nervous system (CNS) involvement should also be a consideration when diagnosing HLH. Changes in mental status, especially during the initial stages of therapy, should be immediately addressed. During this time, there is a risk of posterior reversible encephalopathy syndrome, which is characterized by headache, confusion, seizures, and visual loss, and associated with cyclosporine use and hypertension. 8 Laboratory findings exhibit a myriad of abnormalities, including cytopenias (affecting at least two cell lineages in the peripheral blood), hyperferritinemia, hypertriglyceridemia (especially in secondary HLH), hypofibrinogenmia, elevated serum transaminases, hyperbilirubinemia, abnormal coagulation studies, hyponatremia, and hypoproteinemia. 4 Ferritin levels >500 ng/ml should raise the suspicion for HLH; and a ferritin level >10,000 ng/ml was shown to be 90% sensitive and 96% specific for HLH. 20,21 DIAGNOSIS Diagnosis of HLH can be established by either molecular means or by meeting clinical and laboratory criteria. A combination of high index of suspicion, clinical presentation, and basic laboratory findings could point the clinician toward a diagnosis of HLH, promoting prompt referral for quick treatment. Primary HLH can be diagnosed by clinical findings, although genetic testing alone is sufficient. However, it should be noted that the latter is not an expedient process, and one should focus more on clinical findings when immediate diagnosis is required. Genetic testing is also commonly used for siblings and to confirm a suspected diagnosis; it is important to distinguish HLH from sepsis, as estimated survival is <10% when left untreated. 5 It should also be noted that patients with CNS involvement often have a genetic etiology, especially when no CNS infection can be identified. 8 In secondary HLH, family history and typical genetic mutations associated with F-HLH would not be expected. A set of diagnostic criteria established by the HLH Study Group of the Histiocyte Society helps guide the diagnosis of primary and secondary HLH, requiring that patients exhibit at least 5 of 8 criteria to receive the diagnosis or that the diagnosis is confirmed at the molecular level. 22 These criteria are listed in Table 2. TABLE 2. Diagnostic Guidelines for HLH Molecular diagnosis or The patient fulfills at least 5 of the following 8 diagnostic criteria: 1. Fever 2. Splenomegaly 3. Cytopenias (affecting 2 of 3 cell lineages) i. Hemoglobin level <9 g/dl (<10 g/dl in infants younger than age 4 weeks) ii. Platelets < /mcl iii. Neutrophils < /mcl 4. Hypertriglyceridemia and/or hypofibrinogenemia i. Fasting triglyceride level of 3 mmol/l ( 265 mg/dl) ii. Fibrinogen level of 1.5 g/l 5. Hemophagocytosis in bone marrow or spleen or lymph nodes, and no evidence of malignancy 6. Low or absent natural killer-cell activity 7. Ferritin level of 500 mcg/l 8. Soluble CD25 level of 2,400 U/mL Abbreviation: HLH, hemophagocytic lymphohistiocytosis. Data from Henter et al. 22 It is important to note that in practice, patients with secondary HLH due to a known rheumatologic condition (usually MAS) may not meet full criteria for HLH. In light of the high morbidity and mortality associated with MAS, rheumatologists may begin empiric treatment for suspected MAS in patients with a known predisposing condition (especially systemic onset JIA), even in the absence of a definitive diagnosis. Hemophagocytosis can also be found in bone marrow, spleen, and lymph nodes, 9 as well as in the cerebrospinal fluid, 5 and prevalence can range from 25% to 100%. 23 However, this finding is nonspecific and can also be observed in e311

4 infections, after blood transfusions, with other autoimmune disease, and with bone marrow failure. Moreover, hemophagocytosis is not always observable at initial presentation; 20 therefore, the diagnosis should not be delayed in the absence of hemophagocytosis. TREATMENT Treatment of HLH depends on the underlying cause, as well as the severity of the presentation. Two considerations to take into account are suppression of hyperinflammation and targeting of the underlying disease if possible. 10 In 1994, the Histiocyte Society published an international treatment protocol for HLH (HLH-94), 24 which resulted in a survival rate of 54% ± 6%, with median follow-up of 6.2 years. This significantly improved overall survival, as prior to this protocol untreated F-HLH had a median survival time of less than 2 months. 25 This protocol focuses on combining chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporine A, and in certain patients, intrathecal methotrexate), followed by bone marrow transplant for patients with F-HLH or recurrent disease. Etoposide is useful in therapy directed toward histiocytic and monocytic diseases, 8 and cyclosporine A is known for its specific inhibition of T lymphocytes. 26 The HLH-94 protocol consisted of an initial 8-week induction period aimed at suppressing and controlling the hyperinflammatory process associated with HLH. The goals of the induction period are either to wean off therapy at the end of 8 weeks, or to transition to bridge or continuation therapy until a bone marrow transplant can be performed. In 2004, the Histiocyte Society designed a new protocol, HLH-2004, 22 that included the addition of cyclosporine to the beginning of the induction phase and added corticosteroids alongside methotrexate to intrathecal therapy. In addition to this regimen, other therapies may be considered that are directed at the underlying disease causing HLH. When faced with EBV-associated HLH, rituximab may be helpful; intravenous immunoglobulin can also be appropriate for most viral associations. 8 Anakinra, an interleukin-1 inhibitor, was also found to be associated with decreases in C- reactive protein and ferritin in a small cohort of pediatric intensive care patients. 27 It is also useful in patients diagnosed with MAS in association with sjia. 4 Among children with MAS secondary to systemic onset JIA, careful and complete treatment of the underlying rheumatologic disease is of paramount importance. This treatment typically encompasses biologic interleukin-1 or interleukin-6 antagonists, such as anakinra or tocilizumab, in combination with steroids and cyclosporine to specifically treat MAS. In pediatric and adult patients with refractory HLH, alemtuzumab, an antibody directed against CD52 expressed by T cells and histiocytes, was found to be helpful in a single-center study. 28 SUMMARY In conclusion, although HLH is a life-threatening medical condition, the signs and symptoms, including prolonged fever and hepatosplenomegaly, can be nonspecific. The index of suspicion must be kept high, especially in the context of certain clinical disorders, such as rheumatologic, infectious, and hematologic diagnoses and immunosuppressed states. The treatment is multipronged and aimed at reducing the hyperinflammatory response while simultaneously targeting the underlying pathologic mechanism. Early diagnosis with timely management is imperative as the survival rate is dismal if left untreated. New therapies are warranted, as almost 50% of patients succumb to HLH despite optimal treatment. REFERENCES 1. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet. 1939;ii: Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136): Mehta RS, Smith RE. Hemophagocytic lymphohistiocytosis: a review of literature. Med Oncol. 2013;30(4):740. doi: /s Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med. 2006;38(1): doi: / Erker C, Parker-Murray P, Talano JA. Usual and unusual manifestations of familial hemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis. Pediatr Clin North Am. 2017;64(1): doi: /j. pcl Züre K, Bay A, Albayrak M, Koak U, Yenicesu I, Gursel T. Prognostic factors and long-term outcome in 52 Turkish children with hemophagocytic lymphohistiocytosis. Pediatr Crit Care Med. 2015;e165-e173. doi: /PCC Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat. 2006;27: doi: / humu Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat lymphophagocytic lymphohistiocytosis. Blood. 2011;118(15): doi: / blood Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47. doi: / fped Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013: doi: / asheducation Boom V, Anton J, Lahdenne P, et al. Evidenced-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online. 2015;13:55. doi: /s Fuwa K, Kubota M, Kanno M, et al. Mitochondrial disease as a cause of neonatal hemophagocytic lymphohistiocytosis. Case Rep Pediatr doi: /2016/ Jenkins MR, Rudd-Schmidt JA, Lopez JA, et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp e312 Copyright SLACK Incorporated

5 Med. 2015;212(3): doi: / jem Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286: Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online. 2017;15(5). doi: /s Kaufman M, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2014;66(12): doi: /art Beutel K, Gross-Wieltsch U, Wiesel T, et al. Infection of T lymphocytes in Epstein-Barr virus associated hemophagocytic lymphohistiocytosis in children of non-asian origin. Pediatr Blood Cancer. 2009;53: doi: /pbc Lay JD, Tsao CJ, Chen JY, Kadin ME, Su IJ. Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest. 1997;100(8): doi: /JCI Sifers TM, Raje N, Dinakar C. Hemophagocytic lymphohistiocytosis: a concise review for the practicing physician. Allergy Asthma Proc. 2016;37(3): Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63: doi: /annurevmed Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6): doi: /pbc Henter JI, Horne AC, Arico M, et al. HLH- 2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48: doi: /pbc Gupta A, Weitzman S, Abdelhaleem M. The role of hemophagocytosis in bone marrow aspirates in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(2): doi: /pbc Trottestam H, Horne AC, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17): doi: / blood Henter JI, Samuelsson-Home A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7): doi: / blood Matsuda S, Koyasu S. Mechansims of action of cyclosporine. Immunopharmacology. 2000;47(2-3): Rajasekaran S, Kruse K, Kovey K, et al. Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children. Pediatr Crit Care Med. 2014;15: doi: / PCC Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1): doi: /pbc Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013;161: doi: /bjh Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119(25): doi: /blood e313

Hemophagocytic Lymphohistiocytosis Secondary to T cell/histiocyte-rich Large B-cell Lymphoma

Hemophagocytic Lymphohistiocytosis Secondary to T cell/histiocyte-rich Large B-cell Lymphoma Katherine Devitt, M.D., Benjamin Chen, M.D., Ph.D., Hongbo Yu, M.D., Ph.D., Bruce Woda, M.D. 1 1 Department