Hypereosinophilic Syndromes

 Produced in the bone marrow  Function to combat parasitic infections, ectoparasites, certain viral infections, and amplify responses of mast cells in atopy  This is largely accomplished by generating ribonucleases, oxidative species = apoptosis, and inducing degranulation of basophils and mast cells  Eosinophils are attracted to tissues by certain chemokines (RANTES, CCL11/24) and leukotrienes  They require IL-5 (Eosinophil growth factor, secreted by T-cells) for proliferation and to prevent apoptosis  They are VERY sensitive to steroids Eosinophils – The Basics

 These granules are full of: Major Basic Protein = toxic to helminths and epithelial cells Major Basic Protein = toxic to helminths and epithelial cells Ribonuclease A (aka Eosinophil Cationic Protein) Ribonuclease A (aka Eosinophil Cationic Protein) Eosinophil Peroxidase = generation of hypobromite used to combat Helminths and TB Eosinophil Peroxidase = generation of hypobromite used to combat Helminths and TB Proteases that are involved in tissue remodeling Proteases that are involved in tissue remodeling Eosinophils – The Basics

 Represents a heterogenous group of uncommon disorders marked by blood or tissue eosinophilia Known causes of secondary or reactive eosinophilia must be ruled out Known causes of secondary or reactive eosinophilia must be ruled out Range from benign idiopathic eosinophilia to eosinophilic leukemia Range from benign idiopathic eosinophilia to eosinophilic leukemia  Pretty rare, 50 total documented cases between 1971 – 1982  Previously defined by Chusid et al in 1975 by the following: Greater than or equal to 1500 eosinophils/mm3 for at least 6 months Greater than or equal to 1500 eosinophils/mm3 for at least 6 months Lack of evidence for secondary etiologies of hypereosinophilia Lack of evidence for secondary etiologies of hypereosinophilia Presumptive signs and symptoms of organ involvement Presumptive signs and symptoms of organ involvement Hypereosinophilic Syndromes

Secondary (reactive) causes of eosinophilia Secondary (reactive) causes of eosinophilia Hypereosinophilic Syndromes

 Morbidity and mortality associated with these syndromes = usually due to cardiac and neuropathic complications  These represent medical emergencies that require emergent treatment with corticosteroids Hypereosinophilic Syndromes  Main DDx include: Systemic mastocytosis Systemic mastocytosis Occult malignancy, solid (adenocarcinoma) or liquid (leukemia/lymphoma) Occult malignancy, solid (adenocarcinoma) or liquid (leukemia/lymphoma) Churg Strauss Churg Strauss Atopy Atopy Parasitic infections Parasitic infections Chronic TB Chronic TB Other granulomatous disease such as sarcoid and IBD Other granulomatous disease such as sarcoid and IBD Endocrine causes such as hypoadrenalism Endocrine causes such as hypoadrenalism

 Primary cardiac complications include cardiogenic shock or heart failure due to Loeffler’s endocarditis = a restrictive cardiomyopathy from eosinophilic infiltration leading to fibrotic thickening Loeffler’s endocarditis = a restrictive cardiomyopathy from eosinophilic infiltration leading to fibrotic thickening Endomyocardial fibrosis (aka Davies Disease, seen in the tropics) Endomyocardial fibrosis (aka Davies Disease, seen in the tropics)  Other clinical manifestations include: Skin and mucosal ulcerations Skin and mucosal ulcerations Thromboembolic disease Thromboembolic disease Splenomegaly Splenomegaly Pleural effusions and/or pulmonary fibrosis Pleural effusions and/or pulmonary fibrosis Hypereosinophilic Syndromes

 More recent analyses differentiate the spectra of hypereosinophilic diseases as the following varients: FIP1L1/PDG positive, aka myeloproliferative variant HES FIP1L1/PDG positive, aka myeloproliferative variant HES Lymphocyte variant HES = significant eosinophilopoiesis Lymphocyte variant HES = significant eosinophilopoiesis Familial HES Familial HES Associated HES (from reactive eosinophilia) Associated HES (from reactive eosinophilia) Overlap HES Overlap HES

Clinical Approach CBC with diff, serum tryptase, strongyloides antibody, peripheral lymphocyte clonal studies CBC with diff, serum tryptase, strongyloides antibody, peripheral lymphocyte clonal studies Bone marrow biopsy with FISH/Flow, ANA, SPEP Bone marrow biopsy with FISH/Flow, ANA, SPEP TTE, CT chest and abdomen TTE, CT chest and abdomen

Treatment Corticosteroids 1mg/kg/day with good success Corticosteroids 1mg/kg/day with good success Imatinib therapy if the FIP1L1/PDG fusion protein is present Imatinib therapy if the FIP1L1/PDG fusion protein is present Anti-IL-5 therapy with mepolizumab Anti-IL-5 therapy with mepolizumab

References Klion, A. How I treat hypereosinophilic syndromes. Blood, 2009;114(18): Klion, A. How I treat hypereosinophilic syndromes. Blood, 2009;114(18): Chusid, DC et al. The hypereosinophilic syndrome. Medicine. 1975;54(1):1-27 Chusid, DC et al. The hypereosinophilic syndrome. Medicine. 1975;54(1):1-27 Cools, J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. New England Journal of Medicine. 2003;348(13): Cools, J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. New England Journal of Medicine. 2003;348(13):

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