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Hemophagocytic Lymphohistiocytosis (HLH)
- 2. CONTENTS Histiocytosis- Classification HLH - Terminology - Pathophysiology - Genetics - Epidemiology - Evaluation and Diagnostic Testing - Diagnosis and DD’s - Treatment
- 6. INTRODUCTION • Hemophagocytic lympho-histiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. • Frequently affects infants from birth to 18 months of age, but can occur in children and adults of all ages. • HLH can occur as a familial or sporadic disorder • Infection is a common trigger both in those with a genetic predisposition and in sporadic cases. • Prompt treatment is critical, but the greatest barrier to a successful outcome is often a delay in diagnosis due to the rarity of this syndrome, variable clinical presentation, and lack of specificity of the clinical and laboratory findings.
- 8. TERMINOLOGY • HLH syndrome: A condition of pathologic immune activation that is often associated with genetic defects of lymphocyte cytotoxicity. The clinical presentation is described below. • HLH disease: HLH syndrome in which the distinctive immune activation is the core problem; HLH disease may be associated with a specific genetic and/or environmental causes, as described below. • HLH disease mimics: Disorders that resemble HLH syndrome but are caused by other conditions. • Macrophage activation syndrome (MAS): Form of HLH that occurs primarily in patients with juvenile idiopathic arthritis or other rheumatologic diseases. Some authors call this "reactive hemophagocytic syndrome."
- 10. PATHOPHYSIOLOGY • Immunologic abnormalities: The hyperinflammatory/dysregulated immune state is thought to be caused by the absence of normal downregulation by activated macrophages and lymphocytes. The cell types involved in the pathogenesis of HLH include the following: • Macrophages: In HLH, macrophages become activated and secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure • Natural killer cells and cytotoxic lymphocytes: NK cells eliminate damaged, stressed, or infected host cells such as macrophages, typically in response to viral infection or malignancy, in an MHC-unrestricted manner. • Hemophagocytosis: Hemophagocytosis refers to the engulfment of host blood cells by macrophages. Hemophagocytosis is characterized by the presence of red blood cells, platelets, or white blood cells (or fragments of these cells) within the cytoplasm of macrophages. • Hemophagocytosis can be observed in biopsies of immune tissues (lymph nodes, spleen, liver) or bone marrow aspirates/biopsies.
- 11. Cytokine storm: The persistent activation of macrophages, NK cells, and CTLs in patients with HLH leads to excessive cytokine production (cytokine storm) by all of these cell types, and is thought to be responsible for multiorgan failure and the high mortality of this syndrome Cytokines found at extremely high levels in the plasma of patients with HLH include: - Interferon gamma (IFN gamma), - Chemokine CXCL9 (which is regulated by IFN gamma) - Tumor necrosis factor alpha (TNF alpha) - Interleukins (IL) such as IL-6, IL-10, IL-12 - Soluble IL-2 receptor (CD25). - Elevated IL-16 levels may be important for a TH1-type response that recruits macrophages and other cells implicated in HLH • Unbound (free) IL-18 levels >24,000 pg/mL could distinguish MAS from familial HLH. MAS has IL-18 levels >100,000 pg/mL, which helped distinguish MAS from other autoinflammatory conditions.
- 12. Triggers: The two broad categories of triggers include those that cause immune activation and those that lead to immune deficiency. • Immune activation from an infection is a common trigger both in patients with a genetic predisposition and in sporadic cases with no underlying genetic cause identified. The most common infectious trigger is a viral infection, especially Epstein-Barr virus (EBV) • Excessive cytokine release in patients with chronic granulomatous disease (CGD) may also lead to HLH. • The coexistence of immune dysregulation with unchecked inflammation distinguishes HLH from other syndromes of immune activation, immunodeficiencies, and inflammatory states
- 13. TYPES
- 14. GENETICS Mutations at FHL loci • PRF1/ Perforin • UNC13D/ Munc13-4 . • STX11/ Syntaxin 11 • STXBP2/ Munc18-2 • RHOG/ RhoG • CDC42/ Cdc42 In children, homozygosity or compound heterozygosity for verified HLH-associated mutations: PRF1, UNC13D, STX11, STXBP2, Rab27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS) or gene defects of other immune regulatory genes (identified by whole exome sequencing In adults, heterozygosity of one of the above genes together with clinical findings associated with HLH
- 15. IMMUNODEFICIENCY SYNDROMES ASSOCIATED WITH HLH: • Griscelli syndrome (GS) • Chediak-Higashi syndrome (CHS) • X-linked lymphoproliferative disease • Interleukin-2-inducible T cell kinase (ITK) deficiency • CD27 (TNFRSF7) deficiency • Hermansky-Pudlak syndrome (HPS) • Lysinuric protein intolerance • Chronic granulomatous disease (CGD)
- 16. EPIDEMIOLOGY • HLH is primarily a paediatric syndrome. Infants are most commonly affected, with the highest incidence in those <3 months. • The male-to-female ratio is close to 1:1. • In adults, there may be a slight male predisposition
- 17. CLINICAL FEATURES Presents as an acute or subacute febrile illness associated with multiple organ involvement. Initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis, or encephalitis. • STXBP2 mutations reported hypogammaglobulinemia, severe diarrhoea, bleeding, and sensorineural hearing loss.
- 18. • Neurologic findings: Seizures, mental status changes (including severe changes consistent with encephalitis), and ataxia • Respiratory abnormalities: Acute respiratory distress syndrome. Deteriorating respiratory function may be due to worsening of the HLH • Renal dysfunction occurs in many patients and may present with hyponatremia, perhaps caused by a syndrome of inappropriate ADH (SIADH) mechanism. • Skin manifestations: Generalized rashes, erythroderma, edema, petechiae, and purpura. • Bleeding is also a common manifestation of HLH. It may be due to altered coagulation from liver failure, thrombocytopenia from bone marrow failure, or platelet function defects associated with an underlying genetic defect in platelet granule processing. • Patients with underlying immunodeficiency syndromes may also have syndrome-specific findings • Some have clinical features of Kawasaki disease, including conjunctivitis, red lips, and cervical lymphadenopathy.
- 19. LAB DIAGNOSIS • Cytopenias: Cytopenias, especially anemia and thrombocytopenia • Serum ferritin levels: A very high serum ferritin level is common in HLH. • While a very high ferritin level is helpful in suggesting the possibility of HLH, a low ferritin (eg, ferritin <500 ng/mL) does not exclude the possibility of HLH. • Macrophages are a primary source of ferritin, which may account for the association between HLH and very high ferritin levels. A protein responsible for modulation of iron homeostasis, growth differentiation factor 15, is dramatically upregulated in patients with HLH and is responsible for increased serum ferritin by enhancing the ferroportin-mediated iron efflux. • Liver function and coagulation abnormalities — Nearly all patients with HLH will have hepatitis, manifested by elevated liver function tests (LFTs), including liver enzymes (AST, ALT, GGT), lactate dehydrogenase (LDH), and bilirubin. Increased triglycerides and abnormal coagulation parameters (especially elevated D-dimer) caused by hepatic dysfunction and disseminated intravascular coagulopathy are also frequently seen. The degree of abnormality ranges from mild to hepatic failure; hydrops fetalis has been reported in neonates.
- 20. • Liver enzyme levels greater than three times the upper limit. • LDH is elevated. Bilirubin levels between 3 and 25 mg/dL. The GGT level is an especially sensitive number to follow because of biliary tract infiltration by lymphocytes and macrophages. • Hypertriglyceridemia can be due to severe liver involvement, but may not be elevated until the liver has been affected for some time. • Coagulation abnormalities due to impaired hepatic synthetic function and/or disseminated intravascular coagulation are common. • Bone marrow is normocellular to hypocellular with suppression of erythropoiesis and myelopoiesis. Megakaryocytes are normal or reduced. Marrow macrophages are markedly increased and many of them demonstrate phagocytosis of platelets, red cells, white cells and immature myeloid and erythroid cells • Liver biopsy shows lymphocytic infiltrates in patients with HLH. • On autopsy, the livers of patients who have died from HLH show chronic persistent hepatitis with periportal lymphocytic infiltration.
- 26. Associated illnesses Infections: Viral infections, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus, herpes simplex virus, varicella-zoster virus, measles virus, human herpes virus 8, H1N1 influenza virus, par echovirus, HIV, SARS-CoV-2. Bacteria: Brucella, gram negative bacteria, tuberculosis, Parasites: Leishmaniasis, malaria Fungi Malignancy: Commonly lymphoid cancers (including B, T, and NK cell) and leukemias, but also solid tumors.
- 27. • Rheumatologic disorders/MAS: Most common association is in children with systemic juvenile idiopathic arthritis (sJIA, formerly called Still's disease, systemic onset JIA, or systemic onset juvenile rheumatoid arthritis). The term macrophage activation syndrome (MAS) is used when a hemophagocytic syndrome develops in children with JIA and other rheumatologic conditions. • Other autoimmune diseases associated with HLH include dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome, Sjögren's syndrome, ankylosing spondylitis, vasculitis, and sarcoidosis . • Immunodeficiency: Acquired immunodeficiencies have also been associated with HLH, including HIV/AIDS, hematopoietic cell transplantation, or kidney or liver transplant
- 28. EVALUATION • Complete blood count with differential • Coagulation studies, including PT, aPTT, fibrinogen, D-dimer • Liver function tests, including ALT, AST, GGT, total bilirubin, albumin, and lactate dehydrogenase (LDH) • Serum triglycerides (fasting) • Serum ferritin • Soluble IL-2 receptor alpha (sCD25 or sIL-2R), IL-18, and CXCL9
- 29. DIAGNOSTIC CRITERIA • The diagnosis of HLH syndrome is based on a compatible clinical presentation in the setting of elevated inflammatory markers (eg, ferritin, sCD25, and/or CXCL9). • If neither sCD25 nor CXCL9 is elevated, the diagnosis of HLH is unlikely
- 31. DIFFERENTIAL DIAGNOSIS • Macrophage activation syndrome (MAS) • Infection/sepsis • Liver disease/liver failure • Multiple organ dysfunction syndrome • Encephalitis • Autoimmune lymphoproliferative syndrome (ALPS) • Drug reaction with eosinophilia and systemic symptoms (DRESS) • Child abuse • Kawasaki disease • Cytophagic histiocytic panniculitis • Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA)
- 32. DIFFERENTIAL DIAGNOSIS • Macrophage activation syndrome (MAS) – MAS should be thought of as a form of HLH associated with a rheumatologic disease, rather than as a separate clinical entity. There is NK cell and cytotoxic T cell dysfunction resulting in decreased control of cellular immune response and hypersecretion of TNF-a and IFN-y cytotoxicity is directed against Antigen processing cells (APCs) providing for a T-Cell mediated response. Clinical features are: non-remitting high fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, skin rash, liver dysfunction, hyper-triglyceridemia, hyper-ferritinemia, coagulopathy and low ESR. These patients have leucocytosis and thrombocytosis, raised ESR and S. fibrinogen unlike typical HLH. Soluble CD163 is raised in MAS, Bone marrow shows hemophagocytosis and may be associated with marrow necrosis. Fatality rate is 15- 60%.
- 34. • Infection/sepsis – Systemic infections and/or sepsis share many features with HLH, including fever, cytopenias, and hepatic involvement. Both sepsis and HLH can have findings of disseminated intravascular coagulation and widespread inflammation with cytokine abnormalities. • Liver disease/liver failure – Primary liver disease and HLH can both present with hepatomegaly and elevated LFTs. Both can cause a coagulopathy with prolonged PT and aPTT, low fibrinogen, and elevated D-dimer, and both can cause encephalopathy. Unlike liver disease, HLH is a multisystem disorder. • Multiple organ dysfunction syndrome – Multiple organ dysfunction syndrome (MODS) refers to progressive organ dysfunction in an acutely ill patient • Encephalitis – Encephalitis can result from infection, autoimmunity, and a number of viral infections; and the clinical manifestations can range from subtle neurologic deficits to complete unresponsiveness. The neurologic presentation of those with encephalitis can thus be identical to those with HLH. However, those with HLH typically have more extensive organ involvement, cytopenias, liver abnormalities, and high ferritin, whereas findings in encephalitis are typically confined to the central nervous system.
- 35. • Autoimmune lymphoproliferative syndrome (ALPS) – ALPS is an immune dysregulation syndrome caused by genetic defects in the machinery for FAS-mediated apoptosis, which leads to expansion of some autoreactive lymphocyte populations. Patients present with hepatosplenomegaly, rash, and autoimmune cytopenias, along with other autoimmune manifestations that could mimic findings of HLH (eg, autoimmune hepatitis, Guillain Barré syndrome). • Drug reaction with eosinophilia and systemic symptoms (DRESS): DRESS is a severe drug-induced hypersensitivity reaction possibly initiated by viral reactivation. Like HLH, DRESS is characterized by fever and liver function test abnormalities. DRESS can also be associated with hemophagocytosis, although this is rare. Unlike HLH, DRESS is characterized by temporal relationship to a drug, eosinophilia and skin rash. DRESS is unlikely to cause an extremely high ferritin or cytopenias, which are found in most patients with HLH.
- 36. • Child abuse – Child abuse and HLH may present with similar features involving the central nervous system. The majority of child abuse victims with brain injury also have some laboratory abnormalities such as a prolonged aPTT Kawasaki disease – Kawasaki disease (KD), a vasculitis that predominantly affects children, is characterized by widespread inflammation that include fever, rash, lymphadenopathy, elevated triglycerides, and abnormal cerebrospinal fluid. KD typically causes bilateral conjunctivitis and mucositis, as well as cardiac findings (eg, coronary artery aneurysms), which are much less common in HLH.
- 37. • Cytophagic histiocytic panniculitis – Cytophagic histiocytic panniculitis is a rare systemic disorder consisting of lobular panniculitis (ie, inflammation of the subcutaneous fat), fever, hepatosplenomegaly, and liver failure. This panniculitis can be associated with a form of T cell lymphoma • Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug- induced thrombotic microangiopathy (DITMA) – TTP, HUS, and DITMA (also called drug-induced TTP) are characterized by endothelial damage, microvascular thrombosis, and anemia; fever, neurologic findings, or renal failure may be present. Unlike the anemia of HLH, the anemia in these syndromes is microangiopathic (ie, Coombs negative, characterized by schistocytes). Patients with TTP, HUS, or DITMA generally do not have rising ferritin or liver function abnormalities.
- 38. • Transfusion-associated graft-versus-host disease (ta-GVHD) – The typical presentation includes fever, rash, pancytopenia, and elevated liver enzymes, 4 to 30 days after transfusion. High ferritin levels and hemophagocytosis in the bone marrow can also be seen. Unlike HLH, skin biopsy in ta-GVHD shows vacuolization of the basal layer and a histiocytic infiltrate, and sometimes the pathognomonic finding of satellite dyskeratosis.
- 39. TREATMENT
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