Hypereosinophilic Hypereosinophilic SyndromesSyndromes

Produced in the bone marrowProduced in the bone marrow Function to combat parasitic Function to combat parasitic

infections, ectoparasites, certain viral infections, ectoparasites, certain viral infections, and amplify responses of infections, and amplify responses of mast cells in atopymast cells in atopy

This is largely accomplished by This is largely accomplished by generating ribonucleases, oxidative generating ribonucleases, oxidative species = apoptosis, and inducing species = apoptosis, and inducing degranulation of basophils and mast degranulation of basophils and mast cellscells

Eosinophils are attracted to tissues Eosinophils are attracted to tissues by certain chemokines (RANTES, by certain chemokines (RANTES, CCL11/24) and leukotrienesCCL11/24) and leukotrienes

They require IL-5 (Eosinophil growth They require IL-5 (Eosinophil growth factor, secreted by T-cells) for factor, secreted by T-cells) for proliferation and to prevent apoptosisproliferation and to prevent apoptosis

They are VERY sensitive to steroidsThey are VERY sensitive to steroids

Eosinophils – The BasicsEosinophils – The Basics

These granules are full of:These granules are full of: Major Basic Protein = toxic to Major Basic Protein = toxic to

helminths and epithelial cellshelminths and epithelial cells Ribonuclease A (aka Eosinophil Ribonuclease A (aka Eosinophil

Cationic Protein)Cationic Protein) Eosinophil Peroxidase = Eosinophil Peroxidase =

generation of hypobromite used to generation of hypobromite used to combat Helminths and TBcombat Helminths and TB

Proteases that are involved in Proteases that are involved in tissue remodelingtissue remodeling

Eosinophils – The BasicsEosinophils – The Basics

Represents a heterogenous group of uncommon Represents a heterogenous group of uncommon disorders marked by blood or tissue eosinophilia disorders marked by blood or tissue eosinophilia

Known causes of secondary or reactive eosinophilia must be Known causes of secondary or reactive eosinophilia must be ruled outruled out

Range from benign idiopathic eosinophilia to eosinophilic Range from benign idiopathic eosinophilia to eosinophilic leukemialeukemia

Pretty rare, 50 total documented cases between 1971 – Pretty rare, 50 total documented cases between 1971 – 19821982

Previously defined by Chusid et al in 1975 by the Previously defined by Chusid et al in 1975 by the following:following:

Greater than or equal to 1500 eosinophils/mm3 for at least 6 Greater than or equal to 1500 eosinophils/mm3 for at least 6 monthsmonths

Lack of evidence for secondary etiologies of hypereosinophiliaLack of evidence for secondary etiologies of hypereosinophilia Presumptive signs and symptoms of organ involvementPresumptive signs and symptoms of organ involvement

Hypereosinophilic SyndromesHypereosinophilic Syndromes

Secondary Secondary (reactive) (reactive) causes of causes of eosinophiliaeosinophilia

Hypereosinophilic SyndromesHypereosinophilic Syndromes

Morbidity and mortality Morbidity and mortality associated with these associated with these syndromes = usually syndromes = usually due to cardiac and due to cardiac and neuropathic neuropathic complications complications

These represent These represent medical emergencies medical emergencies that require emergent that require emergent treatment with treatment with

corticosteroidscorticosteroids

Hypereosinophilic SyndromesHypereosinophilic Syndromes Main DDx include:Main DDx include:

Systemic mastocytosisSystemic mastocytosis Occult malignancy, solid Occult malignancy, solid

(adenocarcinoma) or liquid (adenocarcinoma) or liquid (leukemia/lymphoma)(leukemia/lymphoma)

Churg StraussChurg Strauss AtopyAtopy Parasitic infectionsParasitic infections Chronic TBChronic TB Other granulomatous disease Other granulomatous disease

such as sarcoid and IBDsuch as sarcoid and IBD Endocrine causes such as Endocrine causes such as

hypoadrenalismhypoadrenalism

Primary cardiac complications include Primary cardiac complications include cardiogenic shock or heart failure due tocardiogenic shock or heart failure due to Loeffler’s endocarditis = a restrictive cardiomyopathy Loeffler’s endocarditis = a restrictive cardiomyopathy

from eosinophilic infiltration leading to fibrotic from eosinophilic infiltration leading to fibrotic thickeningthickening

Endomyocardial fibrosis (aka Davies Disease, seen in Endomyocardial fibrosis (aka Davies Disease, seen in the tropics)the tropics)

Other clinical manifestations include:Other clinical manifestations include: Skin and mucosal ulcerationsSkin and mucosal ulcerations Thromboembolic diseaseThromboembolic disease SplenomegalySplenomegaly Pleural effusions and/or pulmonary fibrosisPleural effusions and/or pulmonary fibrosis

Hypereosinophilic SyndromesHypereosinophilic Syndromes

Hypereosinophilic SyndromesHypereosinophilic Syndromes

More recent analyses More recent analyses differentiate the spectra of differentiate the spectra of hypereosinophilic diseases as hypereosinophilic diseases as the following varients:the following varients:

FIP1L1/PDG positive, aka FIP1L1/PDG positive, aka myeloproliferative variant HESmyeloproliferative variant HES

Lymphocyte variant HES = Lymphocyte variant HES = significant eosinophilopoiesissignificant eosinophilopoiesis

Familial HESFamilial HES Associated HES (from reactive Associated HES (from reactive

eosinophilia)eosinophilia) Overlap HESOverlap HES

Clinical ApproachClinical Approach

CBC with diff, serum CBC with diff, serum tryptase, strongyloides tryptase, strongyloides antibody, peripheral antibody, peripheral lymphocyte clonal studieslymphocyte clonal studies

Bone marrow biopsy with Bone marrow biopsy with FISH/Flow, ANA, SPEPFISH/Flow, ANA, SPEP

TTE, CT chest and TTE, CT chest and abdomenabdomen

TreatmentTreatment

Corticosteroids Corticosteroids 1mg/kg/day with 1mg/kg/day with good successgood success

Imatinib therapy if Imatinib therapy if the FIP1L1/PDG the FIP1L1/PDG fusion protein is fusion protein is presentpresent

Anti-IL-5 therapy Anti-IL-5 therapy with mepolizumabwith mepolizumab

ReferencesReferences

Klion, A. How I treat hypereosinophilic Klion, A. How I treat hypereosinophilic syndromes. Blood, 2009;114(18):3736-3741syndromes. Blood, 2009;114(18):3736-3741

Chusid, DC et al. The hypereosinophilic Chusid, DC et al. The hypereosinophilic syndrome. Medicine. 1975;54(1):1-27syndrome. Medicine. 1975;54(1):1-27

Cools, J et al. A tyrosine kinase created by Cools, J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. New England hypereosinophilic syndrome. New England Journal of Medicine. 2003;348(13):1201-1214Journal of Medicine. 2003;348(13):1201-1214

Gratuitous photosGratuitous photos