Hypereosinophilic Syndrome (HES)

AstraZeneca Medical's ambition is to address unmet needs for people living with inflammatory diseases driven by eosinophilic inflammation.

HES and Eosinophils
Diagnosis and Clinical Presentation
Treatment Goals and Unmet Need in HES

What is HES

HES is a rare, heterogeneous condition characterized by persistently high blood eosinophil counts (≥1.5 × 10⁹ cells/L and/or tissue eosinophilia) that can lead to organ damage and/or organ dysfunction.^1-3 HES can affect skin, lung, gastrointestinal, cardiac, neurologic and hematologic systems.^3-5

The true incidence and prevalence of HES is unknown.⁶ However, data from the US and UK report an annual incidence of <1 case per 100,000 individuals.^7-9

One of the most used HES definitions is the one by the ICOG-EO¹⁰

ICOG-EO consensus definition³

AEC ≥1.5 x 10⁹ cells/L on two examinations at least 2 weeks apart and/or tissue HE^a
Organ damage and/or dysfunction attributable to tissue HEᵃ and exclusion of other conditions as a major reason for organ damage
Includes multiple clinical classifications

^aHE-related organ damage (damage attributable to HE): organ dysfunction with marked tissue eosinophil infiltrates or/and extensive deposition of eosinophil-derived proteins such as eMBP1 or EPX (in the presence or absence of marked tissue eosinophils) and typical clinical, histopathological and laboratory-based signs of HE-induced organ damage.

Classifications and Subtypes of HES

HES is classified into six clinical subtypes.^3,10-12

M-HES

Myeloproliferative HES (M-HES) with documented or presumed clonal eosinophilic involvement
Includes PDGFRA-associated MPN, CEL-NOS, and idiopathic HES with myeloproliferative features^a
10–20% of patients³

Reactive HES

Underlying condition where eosinophils are considered non-clonal cells, and HES is considered to be cytokine driven and end-organ damage attributable to HES
Special variants of reactive HES include L-HES: abnormal T cells are often detected and HES-related organ damage is found
10–20% of patients³

Overlap HES^b

Refers to single-organ eosinophilic disease and recognized multi-system eosinophilic syndromes, accompanied by peripheral eosinophilia >1.5 x 10⁹cells/L
Includes eosinophilic gastrointestinal disease, single-organ chronic eosinophilic pneumonia and multi-organ EGPA

Associated HES^b

Eosinophilia >1.5 x 10⁹cells/L in the setting of a distinct diagnosis, in which eosinophilia has been described in a subset of affected patients
Includes primary immunodeficiency syndromes, such as autoimmune lymphoproliferative disease and hyper-IgE syndrome

Familial HES^b

HES occurring in multiple members of a single family
Includes autosomal dominant familial HE

Idiopathic HES

HES of unknown cause that does not meet criteria for any of the other subtypes
Features multisystem involvement
>50% of patients³

^aSuch as dysplastic eosinophils, circulating myeloid precursors, anemia, thrombocytopenia, splenomegaly, elevated serum B12, and/or tryptase levels, atypical mast cells, hypercellular marrow, and myelofibrosis.

^bThe relative frequencies of these variants in the general population are unclear, due in part to the lack of universally accepted definitions of HES and referral bias.³

What are Eosinophils?

Eosinophils are terminally differentiated granulocytes that play key roles in host defense, tissue remodeling and inflammation. They release cytotoxic granule proteins (EDN, ECP, EPO, MBP), extracellular traps, and lipid body inflammatory mediators and interact with other immune cells to perpetuate inflammation.^13-15

Eosinophil overproduction may arise from clonal expansion, cytokine dysregulation or other unknown mechanisms

Clonal eosinophilic proliferation¹⁶

A primary molecular defect involving hematopoietic stem cells and/or
Defects in signal transduction from the receptors that mediate eosinophilopoiesis.

Overproduction of eosinophilopoietic cytokines, such as IL-5^13,16

Involvement of cytokine overproduction and IL-5 in eosinophil production.

Other mechanisms^3,16

Defects in normal suppressive regulation of eosinophil survival and activation
Abnormalities in chemotaxis
Functional abnormalities of eosinophilopoietic cytokines related to enhanced or prolonged biologic activity (though not conclusively demonstrated).

Tissue infiltration

Overproduction and tissue infiltration of eosinophils leads to organ damage in HES.¹⁷

An array of chemokines targeting the chemokine receptor CCR3 promote eosinophil recruitment into organs and tissues.¹

A first set of target tissues hosts a population of regulatory eosinophils involved in the maintenance of immune homeostasis and functional integrity of specific organs.¹

Other tissues are targets for eosinophil infiltration during inflammation – commonly the gut, lungs and skin.¹

AEC	Absolute Eosinophil Count
CCL	Chemokine Ligand
CCR	Chemokine Receptor
CEL-NOS	Chronic Eosinophilic Leukemia-Not Otherwise Specified
ECP	Eosinophil Cationic Protein
EDN	Eosinophil-Derived Neurotoxin
EGPA	Eosinophilic Granulomatosis with Polyangiitis
eMBP1	Eosinophil Major Basic Protein 1
EPO	Eosinophil Peroxidase
EPX	Eosinophil Peroxidase
HE	Hypereosinophilia
ICOG-EO	International Cooperative Working Group on Eosinophil Disorders
IgE	Immunoglobulin E
IL	Interleukin
L-HES	Lymphocytic Hypereosinophilic Syndrome
MBP	Major Basic Protein
MPN	Myeloproliferative Neoplasm
PDGFRA	Platelet-Derived Growth Factor Receptor Alpha
UK	United Kingdom
US	United States

1. Chen MM, et al. J Allergy Clin Immunol Pract. 2022;10(5):1217‒1228.e3.

2. Gotlib J. Am J Hematol. 2017;92(11):1243‒1259.

3. Valent P, et al. Allergy. 2023;78(1):47–59.

4. Wechsler ME, et al. J Allergy Clin Immunol. 2023;151(6):1415–1428.

5. Ogbogu PU, et al. J Allergy Clin Immunol. 2009;124(6):1319–1325.e3.

6. Mikhail ES, Ghatol A. Hypereosinophilic Syndrome. StatPearls Publishing; 2024. Updated 11 January 2024. Accessed 12 February 2026. www.ncbi.nlm.nih.gov/books/NBK599558

7. Nguyen L, et al. Cancers. 2024;16(7):1383.

8. Shomali W, Gotlib J. Am J Hematol. 2022;97(1):129–148.

9. Requena G, et al. Immun Inflamm Dis. 2021;9(4):1447–1451.

10. Klion AD. Hematology Am Soc Hematol Educ Program. 2022;2022(1):47–54.

11. Klion AD. Hematology Am Soc Hematol Educ Program. 2015;2015:92–97.

12. Klion AD. Blood. 2015;126(9):1069–1077.

13. Ackerman SJ, Bochner BS. Immunol Allergy Clin North Am. 2007;27(3):357–375.

14. Jacobsen EA, et al. Annu Rev Immunol. 2021;39:719–757.

15. Cogan E, Roufosse F. Expert Rev Hematol. 2012;5(3):275–290.

16. Leru PM. Clin Transl Allergy. 2019;9:36.

17. Ramirez GA, et al. BioMed Res Int. 2018;2018:9095275.

Diagnosis of HES Is a Complex Clinical Challenge

HES can manifest as tissue-specific or widespread organ damage, resulting in diverse symptoms.¹

Some patients had multiple simultaneous manifestations. Percentages can vary depending on center and referral bias related to physician profile and sub-specialty.¹

^aPercentages represent the proportion of patients with subsequent clinical manifestation at the time of retrospective analysis.

Data from a real-world retrospective study suggest that >50% of patients with L-HES and I-HES at baseline and >60% of patients at year 1 of follow-up have ≥3 different organ systems with HES signs and/or symptoms.²

Common HES Manifestations

^ᵃCardiac complications in HES typically develop in a stepwise manner, although overlap between successive phases may occur.

Diagnostic Challenges

HES is characterized by diagnostic delays and is often misunderstood and may be misdiagnosed because of its varied presentation, which can lead to patients seeing multiple specialists before their condition is recognized.¹²

Often months pass between symptom onset to first consultation and toward diagnosis of HES.^13,a

^aHCP types that were consulted by patients included PCP/GP, hematologist, allergist/immunologist, dermatologist, gastroenterologist, rheumatologist, pulmonologist and internist, cardiologist, and neurologist.

Considerations for Diagnosis

Hypereosinophilia is a defining feature of HES¹⁴

Multiple potential causes of eosinophilia must be ruled out before diagnosis of HES, including¹⁵:

Infections

Medications

Hematologic/neoplastic disorders

Immune dysregulation

Allergic disorders

Other

A. Physical examination and detailed history¹⁶

Assess for signs associated with clonal (neoplastic) HE^14,16:

Risk factors and family history of cancer^a

Screen for secondary (reactive) causes of HE^16,17:

Evidence of primary immunodeficiency^b
Drug exposure (including non-prescription)
Travel history and lifestyle associated with risk of exposure to helminthic parasites

B. Microscopic examination of blood and body fluids¹⁶

Test for infections which cause secondary (reactive) HE^16,17:

Ova/larvae or helminthic parasites (such as Toxocara, Strongyloides, Ascaris)

C. Blood test/bone marrow exam^16,c

Seek evidence for HES including secondary (reactive) causes of HE¹⁶:

CBC with differential absolute eosinophil count and peripheral blood smear
Serum tryptase, vitamin B12, IgE, IgG, IgM and IgG4
ANCA^d
T-cell immunophenotyping by flow cytometry
Assessment for and quantification of blasts
Cytogenetic and molecular testing for PDGFRA/B, FGFR1, JAK2 rearrangements or mutations associated with clonal eosinophilia, TCR gene rearrangement analysis by PCR/NGS

^aClonal (neoplastic) HE is associated with underlying stem cell, myeloid, or eosinophil neoplasm, inducing HE¹⁴;  

^bHE may be associated with primary immunodeficiency disorders¹⁷;  

^cBone marrow examination should be considered in the following situations: phenotyping and/or cytogenetic tests suggesting myeloid or lymphoid variant HES, blood eosinophilia greater than 5 x 10⁹cells/L, elevated serum tryptase and lack of response to systemic corticosteroid treatment¹⁶;

^dAnti-PR3/anti-MPO testing by ELISA if ANCA detected.¹⁶

Cardiac

Serum troponin
Echocardiogram electrocardiogram
Cardiac MRI
Endomyocardial biopsy

Hematologic

Bone marrow biopsy
CT scans of chest/abdomen/pelvis
FDG-PET scan
Peripheral blood FISH/RT-PCR

Dermatologic

Skin biopsy

Gastrointestinal

GI endoscopy with biopsies
Abdominal CT scan
Blood chemistry: liver enzymes, amylase/lipase
Liver biopsy

Neurologic

Brain MRI or CT with contrast
Electroencephalogram
Nerve conduction studies

Vascular

Venous doppler ultrasound
Angiography

Renal

Kidney biopsy
Urinalysis

Pulmonary

PFT
Bronchoscopy with bronchoalveolar lavage and/or lung biopsy
Chest X-ray and/or CT

ANCA	Anti-Neutrophil Cytoplasmic Antibodies
CBC	Complete Blood Count
CT	Computed Tomography
ELISA	Enzyme-Linked Immunosorbent Assay
FDG-PET	Fluorodeoxyglucose Positron Emission Tomography
FGFR1	Fibroblast Growth Factor Receptor 1
FISH	Fluorescence In Situ Hybridization
GI	Gastrointestinal
GP	General Practitioner
HCP	Health Care Provider
HE	Hypereosinophilia
Ig	Immunoglobulin
I-HES	Idiopathic Hypereosinophilic Syndrome
JAK2	Janus Kinase 2
L-HES	Lymphocytic Hypereosinophilic Syndrome
MPO	Myeloperoxidase
MRI	Magnetic Resonance Imaging
NGS	Next Generation Sequencing
PCP	Primary Care Provider
PCR	Polymerase Chain Reaction
PDGFRA/B	Platelet-Derived Growth Factor Receptor Alpha/Beta
PFT	Pulmonary Function Test
PR3	Proteinase 3
RT-PCR	Reverse Transcription-Polymerase Chain Reaction
SD	Standard Deviation
TCR	T-Cell Receptor

1. Ogbogu PU, et al. J Allergy Clin Immunol. 2009;124(6):1319–1325.e3.

2. Dolin P, et al. Poster presented at: ASH; December 7-10, 2024; San Diego, CA. Poster P2316.

3. Leiferman KM, Peters MS. J Allergy Clin Immunol Pract. 2018;6(5):1462–1482.e6.

4. Kovacs N, et al. J Allergy Clin Immunol Pract. 2020;8(9):3209–3212.e8.

5. Dulohery MM, et al. Respir Med. 2011;105(1):114–121.

6. Zhang L, et al. Pulm Circ. 2018;9(1):1–4.

7. Kuang FL, et al. J Allergy Clin Immunol Pract. 2020;8(8):2718–2726.e2.

8. Parfitt JR, et al. Mod Pathol. 2006;19(1):90–96.

9. Jonakowski M, et al. Mult Scler Relat Disord. 2021;51:102871.

10. Ogbogu PU, et al. Immunol Allergy Clin North Am. 2007;27(3):457–475.

11. Bondue A, et al. Heart. 2022;108(3):164–171.

12. Wechsler ME, et al. J Allergy Clin Immunol. 2023;151(6):1415–1428.

13. Dolin P, et al. Poster presented at: EHA; June 13-16, 2024; Madrid, Spain. Poster P2008.

14. Valent P, et al. Allergy. 2023;78(1):47–59.

15. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240‒251.

16. Khoury P, et al. Mayo Clin Proc. 2023;98(7):1054–1070.

17. Nguyen L, et al. Cancers. 2024;16(7):1383.

18. Silver J, et al. J Allergy Clin Immunol Glob. 2025;4(3):100501.

HES Management Considerations

HES treatment considerations include controlling inflammation, addressing symptoms, and preventing disease relapse, while minimizing dose- and drug-related toxicity.^6,7

Decreasing eosinophil may alleviate inflammation and related symptoms, while preventing disease progression.⁷

Managing HES

There is a lack of comprehensive and clear guidelines for the treatment, management and follow-up of patients with HES.^1,2

In most cases, glucocorticoids are the mainstay of HES therapy, although it may differ in patients with FIP1L1-PDGFRA-positive disease.^1,2

However, lack of efficacy and intolerance due to treatment-related side effects can lead to discontinuation of therapy in a large proportion of patient cases.²

Treatments Utilized in HES^1,2

HES can have a negative impact on the quality of life of patients³

HES can impact multiple health domains. The overall physical impact can vary greatly across patients, depending on how organs are impacted. The majority of patients with HES experience negative impacts on walking ability, sleep, and feeling fatigued. Quality-of-life impacts may include the following:

Social impact

relationships with others, social activities and outings, work/school activities.

Emotional impact

feeling depressed/hopeless, anxious/worried, embarrassed/ashamed, cranky/irritated, or frustrated/annoyed.

Global physical impact

negative impact on walking ability, sleep, and feeling fatigued more often.

Cognitive impact

difficulty concentrating/memory problems, change in behavior, difficulty having conversations, or delayed reactions.

HES can impact multiple quality of life domains

Overall health status, impairment and fatigue increase as HES disease severity increases.⁴

HES presents a mortality risk, primarily due to cardiac dysfunction, infection, thromboembolic phenomena and vascular disease.⁵

FIP1L1-PDGFRA

Fusion of Factor Interacting with PAPOLA and PDGF Receptor Alpha

1. Wechsler ME, et al. J Allergy Clin Immunol. 2023;151(6):1415–1428.

2. Ogbogu PU, et al. J Allergy Clin Immunol. 2009;124(6):1319–1325.e3.

3. Kovacs N, et al. J Allergy Clin Immunol Pract. 2020;8(9):3209–3212.e8.

4. Schwaab J, et al. Poster presented at: ASH; December 7-10, 2024; San Diego, CA. Poster 5075.

5. Podjasek JC, Butterfield JH. Leuk Res. 2013;37(4):392–395.

6. Kuang FL, Klion AD. J Allergy Clin Immunol Pract. 2017;5(6):1502–1509.

7. Nguyen L, et al. Cancers. 2024;16(7):1383.

US-108222 Last Updated 1/26

Hypereosinophilic Syndrome (HES)

What is HES

One of the most used HES definitions is the one by the ICOG-EO10

Classifications and Subtypes of HES

M-HES

Myeloproliferative HES (M-HES) with documented or presumed clonal eosinophilic involvementIncludes PDGFRA-associated MPN, CEL-NOS, and idiopathic HES with myeloproliferative featuresa10–20% of patients3

Reactive HES

Underlying condition where eosinophils are considered non-clonal cells, and HES is considered to be cytokine driven and end-organ damage attributable to HESSpecial variants of reactive HES include L-HES: abnormal T cells are often detected and HES-related organ damage is found10–20% of patients3

Overlap HESb

Refers to single-organ eosinophilic disease and recognized multi-system eosinophilic syndromes, accompanied by peripheral eosinophilia >1.5 x 109 cells/LIncludes eosinophilic gastrointestinal disease, single-organ chronic eosinophilic pneumonia and multi-organ EGPA

Associated HESb

Eosinophilia >1.5 x 109 cells/L in the setting of a distinct diagnosis, in which eosinophilia has been described in a subset of affected patientsIncludes primary immunodeficiency syndromes, such as autoimmune lymphoproliferative disease and hyper-IgE syndrome

Familial HESb

HES occurring in multiple members of a single familyIncludes autosomal dominant familial HE

Idiopathic HES

HES of unknown cause that does not meet criteria for any of the other subtypesFeatures multisystem involvement>50% of patients3

What are Eosinophils?

Eosinophil overproduction may arise from clonal expansion, cytokine dysregulation or other unknown mechanisms

Clonal eosinophilic proliferation16

Overproduction of eosinophilopoietic cytokines, such as IL-513,16

Involvement of cytokine overproduction and IL-5 in eosinophil production.

Other mechanisms3,16

Defects in normal suppressive regulation of eosinophil survival and activationAbnormalities in chemotaxisFunctional abnormalities of eosinophilopoietic cytokines related to enhanced or prolonged biologic activity (though not conclusively demonstrated).

Tissue infiltration

Abbreviations

References

Diagnosis of HES Is a Complex Clinical Challenge

Common HES Manifestations

Dermatologic manifestations1,3

Pulmonary manifestations1,4-6

Gastrointestinal manifestations1,4,7,8

Neurological manifestations1,4,9

Cardiac manifestations1,10,11

Diagnostic Challenges

Considerations for Diagnosis

Infections

Medications

Hematologic/neoplastic disorders

Immune dysregulation

Allergic disorders

Other

Initial assessments for HES often include14,16,17:

A. Physical examination and detailed history16

B. Microscopic examination of blood and body fluids16

Test for infections which cause secondary (reactive) HE16,17: Ova/larvae or helminthic parasites (such as Toxocara, Strongyloides, Ascaris)

C. Blood test/bone marrow exam16,c

Assessments for End-Organ Damage15,16

Cardiac

Serum troponinEchocardiogram electrocardiogramCardiac MRIEndomyocardial biopsy

Hematologic

Bone marrow biopsyCT scans of chest/abdomen/pelvis FDG-PET scanPeripheral blood FISH/RT-PCR

Dermatologic

Skin biopsy

Gastrointestinal

GI endoscopy with biopsiesAbdominal CT scanBlood chemistry: liver enzymes, amylase/lipaseLiver biopsy

Neurologic

Brain MRI or CT with contrastElectroencephalogramNerve conduction studies

Vascular

Venous doppler ultrasoundAngiography

Renal

Kidney biopsyUrinalysis

Pulmonary

PFTBronchoscopy with bronchoalveolar lavage and/or lung biopsyChest X-ray and/or CT

Abbreviations

References

Social impact

relationships with others, social activities and outings, work/school activities.

Emotional impact

feeling depressed/hopeless, anxious/worried, embarrassed/ashamed, cranky/irritated, or frustrated/annoyed.

Global physical impact

negative impact on walking ability, sleep, and feeling fatigued more often.

Cognitive impact

difficulty concentrating/memory problems, change in behavior, difficulty having conversations, or delayed reactions.

Abbreviations

References

One of the most used HES definitions is the one by the ICOG-EO¹⁰

Myeloproliferative HES (M-HES) with documented or presumed clonal eosinophilic involvement
Includes PDGFRA-associated MPN, CEL-NOS, and idiopathic HES with myeloproliferative features^a
10–20% of patients³

Overlap HES^b

Refers to single-organ eosinophilic disease and recognized multi-system eosinophilic syndromes, accompanied by peripheral eosinophilia >1.5 x 10⁹cells/L
Includes eosinophilic gastrointestinal disease, single-organ chronic eosinophilic pneumonia and multi-organ EGPA

Associated HES^b

Eosinophilia >1.5 x 10⁹cells/L in the setting of a distinct diagnosis, in which eosinophilia has been described in a subset of affected patients
Includes primary immunodeficiency syndromes, such as autoimmune lymphoproliferative disease and hyper-IgE syndrome

Familial HES^b

HES occurring in multiple members of a single family
Includes autosomal dominant familial HE

HES of unknown cause that does not meet criteria for any of the other subtypes
Features multisystem involvement
>50% of patients³

Clonal eosinophilic proliferation¹⁶

Overproduction of eosinophilopoietic cytokines, such as IL-5^13,16

Other mechanisms^3,16

Defects in normal suppressive regulation of eosinophil survival and activation
Abnormalities in chemotaxis
Functional abnormalities of eosinophilopoietic cytokines related to enhanced or prolonged biologic activity (though not conclusively demonstrated).

A. Physical examination and detailed history¹⁶

B. Microscopic examination of blood and body fluids¹⁶

Test for infections which cause secondary (reactive) HE^16,17:

Ova/larvae or helminthic parasites (such as Toxocara, Strongyloides, Ascaris)

C. Blood test/bone marrow exam^16,c

Serum troponin
Echocardiogram electrocardiogram
Cardiac MRI
Endomyocardial biopsy

Bone marrow biopsy
CT scans of chest/abdomen/pelvis
FDG-PET scan
Peripheral blood FISH/RT-PCR

GI endoscopy with biopsies
Abdominal CT scan
Blood chemistry: liver enzymes, amylase/lipase
Liver biopsy

Brain MRI or CT with contrast
Electroencephalogram
Nerve conduction studies

Venous doppler ultrasound
Angiography

Kidney biopsy
Urinalysis

PFT
Bronchoscopy with bronchoalveolar lavage and/or lung biopsy
Chest X-ray and/or CT