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

The Diagnostic Workup: Ruling Out Other Causes

At a Glance

Idiopathic HES is diagnosed only after doctors rule out secondary causes such as parasites, medications, allergies, and cancer, as well as abnormal blood-cell disorders. Bone marrow, genetic, and T-cell tests help determine whether another cause is present.

The diagnosis of Idiopathic Hypereosinophilic Syndrome (iHES) is not something doctors decide on lightly. Because “idiopathic” means the cause is unknown, it can only be confirmed after a thorough evaluation of likely secondary and clonal causes [1]. This process is a “diagnosis of exclusion,” and it requires a deep dive into your medical history and your genetic makeup [2]. In organ-threatening disease, treatment may need to begin while the workup is still being completed.

Phase 1: Ruling Out Secondary Causes

The first step is to ensure your high eosinophil count isn’t a “reactive” response to something else in your environment or body. These are called secondary causes [3]. Your doctor will investigate several areas:

  • Infections and Strongyloides: Parasitic infections (especially helminths or worms) are a common cause of high eosinophils [4]. Even if you haven’t traveled recently, certain infections can stay in the body for years [5]. Critical safety note: High-dose corticosteroids can precipitate life-threatening Strongyloides hyperinfection. Tell your doctor about your birthplace, travel, and soil exposure; they may use serology testing or empiric treatment to clear it safely.
  • Drug Reactions: Many medications, including antibiotics, anti-seizure drugs, and even herbal supplements, can trigger a surge in eosinophils [5].
  • Allergies and Autoimmunity: Conditions like severe asthma, skin disorders (eczema), or EGPA (Eosinophilic Granulomatosis with Polyangiitis)—a type of blood vessel inflammation—must be considered [6].
  • Other Cancers: Some solid tumors or lymphomas can produce chemicals that tell your body to make more eosinophils [7].

Phase 2: The Hematologic & Genetic Deep Dive

Once secondary causes are cleared, your care team must look at the “machinery” that creates blood cells: your bone marrow. To rule out primary blood cancers and support an idiopathic diagnosis, a bone marrow biopsy is often important [8]. During this workup, three main types of high-tech testing are used to look for “clonal” (cancerous) variants:

1. Cytogenetics and FISH

These tests look for broken, swapped, or missing pieces of your chromosomes. Specifically, doctors must rule out “fusion genes”—where two genes that shouldn’t be together join up and act like an “on” switch for cell growth [8].

  • PDGFRA and PDGFRB: The most common fusion is FIP1L1-PDGFRA. It is often found using a test called FISH (Fluorescence In Situ Hybridization) to look for a small missing piece of DNA called the CHIC2 deletion [9]. Doctors must also separately evaluate for PDGFRB rearrangements.
  • Other Fusions: Tests must also check for FGFR1, JAK2 (including PCM1-JAK2), and BCR-ABL1 [10][11].

2. Next-Generation Sequencing (NGS)

NGS is a highly sensitive way to read your genetic code to find tiny mutations that standard tests might miss. Finding mutations in genes like STAT5B, ASXL1, TET2, or EZH2 does not automatically mean you have an overt myeloid neoplasm; they can sometimes reflect age-related clonal hematopoiesis. These must be interpreted alongside your morphology and clinical context [12][13].

3. T-Cell Clonality

Sometimes, a specific group of immune cells called T-cells becomes abnormal and pumps out signals that tell the bone marrow to overproduce eosinophils. This is called Lymphocyte-variant HES (L-HES) [14]. Doctors use flow cytometry and TCR (T-cell receptor) gene rearrangement testing to evaluate this. Finding T-cell clonality alone can sometimes happen in reactive settings; L-HES requires a persistent aberrant population interpreted by a specialist [15][16].

Why This Matters

If specific genetic rearrangements (like a PDGFRA fusion) are found, your diagnosis can change, which may open up a targeted-treatment option depending on the specific alteration [10]. Only when all these tests are interpreted together, and evaluation does not point to these known causes, is the working diagnosis of Idiopathic HES confirmed [17][2].

Common questions in this guide

What does “idiopathic” mean in idiopathic HES?
“Idiopathic” means that no specific cause has been found. Doctors use this diagnosis only after evaluating secondary causes, such as infections, medications, allergies, and cancer, as well as abnormal blood-cell disorders and genetic changes.
How do doctors investigate a high eosinophil count?
The evaluation may include a detailed history, medication review, infection testing, and assessment for allergic or autoimmune disease. Doctors may also use a bone marrow biopsy, chromosome and gene tests, and tests of T-cell populations to look for a blood or immune-cell cause.
Why should Strongyloides infection be considered before corticosteroids?
Strongyloides is a parasitic infection that can remain in the body for years and may not cause obvious symptoms. High-dose corticosteroids can trigger life-threatening Strongyloides hyperinfection, so tell your clinician about travel, birthplace, soil exposure, or untreated-water exposure before treatment.
What do FIP1L1-PDGFRA and CHIC2 testing show?
These tests look for a genetic change involving PDGFRA that can cause eosinophilia and point to a different diagnosis than idiopathic HES. Finding an actionable rearrangement may allow a targeted treatment, depending on the specific result.
Does finding a mutation on an NGS panel mean I have blood cancer?
Not necessarily. Changes in genes such as STAT5B, ASXL1, TET2, or EZH2 can sometimes reflect age-related clonal hematopoiesis, so doctors interpret them together with the bone marrow appearance, blood counts, and the overall clinical picture.
How is lymphocyte-variant HES diagnosed?
Lymphocyte-variant HES occurs when an abnormal group of T-cells produces signals that drive eosinophil overproduction. Flow cytometry and T-cell receptor gene rearrangement testing can help identify it, but T-cell clonality alone does not prove the diagnosis because it can also occur in reactive conditions.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which secondary causes, like parasitic infections or drug reactions, have you already ruled out for me?
  2. 2.Did my bone marrow biopsy include 'FISH' testing for the FIP1L1-PDGFRA fusion and the CHIC2 deletion?
  3. 3.Was a 'Myeloid NGS' panel performed, and if so, were there any mutations like STAT5B, ASXL1, or TET2?
  4. 4.Have we ruled out 'Lymphocyte-variant HES' using T-cell flow cytometry and TCR clonality testing?
  5. 5.If my genetic tests come back negative, what specific findings in my bone marrow help you decide this is 'idiopathic' rather than a different blood disorder?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
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This page explains the idiopathic HES diagnostic workup for informational purposes only and does not constitute medical advice. Your hematologist should interpret your results and guide testing or treatment.

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