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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Hematology

Biology and Subtypes: Why Your HES Type Matters

At a Glance

Hypereosinophilic Syndrome (HES) is classified into four main subtypes: primary, secondary, lymphocytic, and idiopathic. Identifying your specific subtype through specialized testing is critical because it directly determines which targeted treatments will be most effective for your condition.

Understanding the biology of your diagnosis is the first step toward effective treatment. In Hypereosinophilic Syndrome (HES), the primary “actor” is the eosinophil, a white blood cell that typically defends the body against parasites [1]. In HES, these cells either multiply out of control due to a genetic error or are over-stimulated by other parts of the immune system [2].

The 2022 Classification System

The medical community recently updated how these disorders are categorized using the WHO (World Health Organization) and ICC (International Consensus Classification) standards [2][3]. Doctors now group HES into four main types based on what is driving the eosinophils to “misbehave.”

1. Primary (Clonal/Neoplastic) HES

This type is caused by a “glitch” in your bone marrow’s stem cells. The most common driver is the FIP1L1-PDGFRA fusion gene [4]. This mutation creates a hyperactive protein called a tyrosine kinase, which acts like a stuck “on” switch, telling the marrow to churn out eosinophils constantly [4][5].

  • Key Fact: This subtype is highly responsive to “targeted” drugs like imatinib, which can turn that switch off [6][7].

2. Secondary (Reactive) HES

In this version, the eosinophils themselves are normal, but they are reacting to something else in the body [8]. This could be an underlying infection, a hidden tumor, or another inflammatory condition that is signaling the eosinophils to multiply [2][9].

3. Lymphocytic Variant (L-HES)

L-HES is unique because it is driven by T-cells (another type of immune cell). A specific group of “clone” T-cells produces high levels of interleukin-5 (IL-5), a chemical messenger that tells the body to make more eosinophils [10]. This type often shows up first as skin rashes or swelling [11].

4. Idiopathic HES

This is a “diagnosis of exclusion” [9]. If a patient has HES but tests negative for all known genetic mutations and has no identifiable reactive causes, they are classified as idiopathic, meaning the exact cause is currently unknown [12][13].

Ruling Out Other Conditions

Before a doctor confirms HES, they must perform a differential diagnosis to ensure your symptoms aren’t caused by something more common:

  • Parasites: Infections like Strongyloides can mimic HES. Doctors must test for these before starting high-dose steroids, not just to confirm the diagnosis, but as a crucial safety measure to prevent a life-threatening reaction known as Strongyloides hyperinfection syndrome [13][14].
  • EGPA (Churg-Strauss): Eosinophilic Granulomatosis with Polyangiitis is a type of blood vessel inflammation. It often includes severe asthma and sinus issues, which help distinguish it from HES [15].
  • Simple Allergies: While allergies raise eosinophil levels, they rarely cause the deep organ damage seen in HES [16].

Why Subtypes Matter

Identifying your specific subtype is critical because it dictates your treatment plan [2]. For example, while imatinib is a miracle drug for those with the FIP1L1-PDGFRA mutation, it may not work for someone with the lymphocytic variant, who might need monoclonal antibodies like mepolizumab instead [6][17].

Common questions in this guide

What are the different types of Hypereosinophilic Syndrome (HES)?
HES is classified into four main types: primary (caused by bone marrow cell mutations), secondary (reacting to other conditions like infections), lymphocytic variant (driven by T-cells), and idiopathic (where the exact cause remains unknown).
Why is it important to know my exact HES subtype?
Your subtype identifies the underlying biological cause of your disease, which dictates the most effective treatment. For example, primary HES often responds well to targeted drugs like imatinib, while the lymphocytic variant may require monoclonal antibodies.
What does a FIP1L1-PDGFRA mutation mean?
The FIP1L1-PDGFRA mutation is a genetic error in your bone marrow stem cells that creates a hyperactive protein. This acts like a stuck 'on' switch, telling your body to constantly produce eosinophils, and is the main driver of primary HES.
Why do doctors test for parasitic infections before treating HES?
Doctors must perform tests to rule out parasites because some parasitic infections can mimic HES symptoms. Additionally, treating unrecognized parasitic infections with high-dose steroids (a common HES treatment) can cause a life-threatening reaction.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which of the four main HES subtypes do I have: primary, secondary, lymphocytic, or idiopathic?
  2. 2.Were my FISH or PCR tests negative for the FIP1L1-PDGFRA mutation?
  3. 3.Did the T-cell receptor (TCR) rearrangement test show evidence of a clonal T-cell population?
  4. 4.Which common causes—like parasites or EGPA—have you ruled out in my case?
  5. 5.How does my specific subtype change which medication you will prescribe first?

Questions For You

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References

References (17)
  1. 1

    Hypereosinophilic syndrome: approach to treatment in the era of precision medicine.

    Klion A

    Hematology. American Society of Hematology. Education Program 2018; (2018(1)):326-331 doi:10.1182/asheducation-2018.1.326.

    PMID: 30504328
  2. 2

    World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.

    Shomali W, Gotlib J

    American journal of hematology 2024; (99(5)):946-968 doi:10.1002/ajh.27287.

    PMID: 38551368
  3. 3

    The international consensus classification of eosinophilic disorders and systemic mastocytosis.

    Wang SA, Orazi A, Gotlib J, et al.

    American journal of hematology 2023; (98(8)):1286-1306 doi:10.1002/ajh.26966.

    PMID: 37283522
  4. 4

    When Blood Cell Counts Matter: Hypereosinophilic Syndrome as a Rare Cause of Ischemic Strokes.

    Kaur G, Rodriguez W, Ganev Y, et al.

    Cureus 2024; (16(5)):e60557 doi:10.7759/cureus.60557.

    PMID: 38887335
  5. 5

    Imatinib for the treatment of hypereosinophilic syndromes.

    Helbig G

    Expert review of clinical immunology 2018; (14(2)):163-170 doi:10.1080/1744666X.2018.1425142.

    PMID: 29303368
  6. 6

    When Hypereosinophilia Leads to Stroke.

    Chalayer E, Pelissier A, Tardy B

    European journal of case reports in internal medicine 2017; (4(6)):000614 doi:10.12890/2017_000614.

    PMID: 30755950
  7. 7

    Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome.

    Khoury P, Desmond R, Pabon A, et al.

    Allergy 2016; (71(6)):803-10 doi:10.1111/all.12843.

    PMID: 26797802
  8. 8

    [The Hypereosinophilic Syndromes in Childhood].

    Leu T, Simon HU, Hebestreit H, Kunzmann S

    Klinische Padiatrie 2015; (227(6-7)):308-13 doi:10.1055/s-0035-1555792.

    PMID: 26267413
  9. 9

    Cardiac Abnormalities in Hypereosinophilic Syndromes.

    Hotta VT, Nastari RR, Oishi GDSL, et al.

    Arquivos brasileiros de cardiologia 2024; (121(10)):e20240190 doi:10.36660/abc.20240190.

    PMID: 39607243
  10. 10

    Clinical Management of Persistent Hypereosinophilia.

    Helbig G, Czachor K

    European journal of haematology 2025; (114(5)):763-774 doi:10.1111/ejh.14396.

    PMID: 39961601
  11. 11

    JAK inhibition for CD3- CD4+ lymphocytic-variant hypereosinophilic syndrome.

    Faguer S, Groh M, Vergez F, et al.

    Clinical immunology (Orlando, Fla.) 2023; (251()):109275 doi:10.1016/j.clim.2023.109275.

    PMID: 36870379
  12. 12

    Hypereosinophilic syndrome: a rare cause of ST-elevation myocardial infarction and thrombus formation on the aortic valve.

    Jørgensen MD, Schneider IR, Thomsen GN, Dahl JS

    BMJ case reports 2024; (17(4)) doi:10.1136/bcr-2023-259494.

    PMID: 38627047
  13. 13

    [Hypereosinophilic syndrome, case report and diagnostic approach].

    Medina-Marroquín R, Espejel-Guzman JA, Maldonado-López CJ, Calzada-Rascón AC

    Revista medica del Instituto Mexicano del Seguro Social 2024; (62(2)):1-6.

    PMID: 39514634
  14. 14

    Eosinophilia and gastrointestinal symptoms in Immunosuppression: a classic but overlooked diagnosis.

    Lopes S, Carvalho A, Gamito É, Alves AL

    Revista espanola de enfermedades digestivas 2025; doi:10.17235/reed.2025.11284/2025.

    PMID: 40353443
  15. 15

    Hypereosinophilic syndrome associated with multiple thromboses requiring ICU admission: A case report.

    Ouanes I, Toumi S, Ben Cheikh Y, et al.

    La Tunisie medicale 2023; (101(10)):783-786.

    PMID: 38465762
  16. 16

    Idiopathic Hypereosinophilic Syndrome Presenting with Recalcitrant Oral and Genital Ulcers Responding Well to Thalidomide.

    Srinivas SM, Chebbi PG, Shivappa SK

    Indian dermatology online journal 2023; (14(5)):676-678 doi:10.4103/idoj.idoj_632_22.

    PMID: 37727572
  17. 17

    Eosinophilia and wheeze: thinking beyond asthma.

    Kuek SL, Pettman C, Neeland MR, et al.

    Breathe (Sheffield, England) 2024; (20(1)):230126 doi:10.1183/20734735.0126-2023.

    PMID: 38482189

This page explains HES biology and subtypes for educational purposes only. Always consult your hematologist or immunologist for an accurate diagnosis of your specific condition and subtype.

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