What is hypereosinophilic syndrome (HES) and how is it diagnosed?

Hypereosinophilic Syndrome: Definition and Diagnosis

What is Hypereosinophilic Syndrome?

Hypereosinophilic syndrome (HES) is defined as persistent blood eosinophilia ≥1.5 × 10⁹/L on two examinations at least one month apart (or tissue hypereosinophilia) with end-organ damage attributable to eosinophil infiltration, after excluding secondary causes such as parasitic infections, allergic disorders, and malignancies. 1

HES represents a heterogeneous group of disorders where eosinophils cause tissue damage through direct infiltration and release of toxic granule proteins, affecting primarily the heart, lungs, gastrointestinal tract, skin, and nervous system. 1, 2

Diagnostic Criteria

Core Requirements

The diagnosis requires three essential elements 1:

• Peripheral blood hypereosinophilia: ≥1.5 × 10⁹/L eosinophils on two separate examinations at least one month apart 1
• End-organ damage attributable to eosinophilia: Evidence of tissue infiltration, fibrosis, thrombosis, or extensive deposition of eosinophil granule proteins 1
• Exclusion of other disorders: No secondary causes (parasitic infections, allergies, malignancies) or other conditions explaining the organ damage 1

Important caveat: In life-threatening end-organ damage, diagnosis can be made immediately without waiting for the one-month interval to avoid treatment delay. 1

Tissue Hypereosinophilia Criteria

Tissue HES is diagnosed when 1:

• Bone marrow eosinophils exceed 20% of nucleated cells, OR
• Pathologist confirms extensive tissue eosinophil infiltration, OR
• Marked deposition of eosinophil granule proteins is present

Diagnostic Workup Algorithm

Step 1: Initial Clinical Assessment

History must specifically address 1, 3:

• Travel history (especially tropical areas for parasitic infections)
• New medications (NSAIDs, beta-lactams, nitrofurantoin)
• Recurrent infections suggesting immunodeficiency
• Family history of eosinophilia or autoimmune disease

Physical examination must evaluate 1, 3:

• Skin lesions and rashes
• Hepatosplenomegaly by palpation
• Signs of immunodeficiency
• Cardiac findings (murmurs, signs of heart failure)

Step 2: Mandatory Laboratory Testing

Initial blood work 1, 3:

• CBC with differential and peripheral blood smear review (assess for dysplasia, monocytosis, circulating blasts)
• Comprehensive metabolic panel with uric acid and LDH
• Liver function tests
• Serum tryptase levels (elevated in myeloproliferative variants, especially PDGFRA-rearranged cases) 1, 3
• Vitamin B12 levels (elevated in myeloproliferative variants) 1, 3

Secondary cause exclusion 1:

• Strongyloides and parasitic infection serology
• Stool ova and parasites with GI PCR
• Quantitative immunoglobulin levels including IgE
• Aspergillus-specific IgE (for allergic bronchopulmonary aspergillosis)
• Antineutrophil cytoplasmic antibodies and antinuclear antibodies

Step 3: Bone Marrow Evaluation

Bone marrow aspirate and biopsy with 1:

• Immunohistochemistry for CD117, CD25, and tryptase
• Reticulin/collagen stains for fibrosis
• Conventional cytogenetics (minimum 15 metaphases)
• FISH for CHIC2 deletion (detects FIP1L1-PDGFRA, the most common fusion gene, undetectable by standard cytogenetics) 1
• RT-PCR for tyrosine kinase fusion genes: PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, FLT3 1

Critical point: Standard karyotyping cannot detect FIP1L1-PDGFRA; FISH with specific probes for CHIC2 deletion is mandatory. 1

Step 4: Lymphocytic Variant Assessment

If lymphocytic variant HES (L-HES) is suspected 1:

• Flow cytometry (preferred) to identify aberrant T-cell populations
• Typical immunophenotype: CD3-, CD4+, CD7-, CD5+ 1
• Alternative phenotypes: CD3+/CD4+/CD7- or CD3+/CD4-/CD8- 1
• Molecular analysis for clonal TCR gene rearrangements if flow cytometry equivocal 1

Step 5: End-Organ Damage Assessment

Cardiac evaluation (most critical for prognosis) 1:

• ECG, cardiac troponin, NT-proBNP
• Echocardiogram (mandatory)
• Cardiac MRI if troponin elevated or clinical cardiac features present

Pulmonary assessment 1:

• Chest X-ray
• Pulmonary function tests
• Bronchoscopy with bronchoalveolar lavage if respiratory symptoms

Other organ systems 1:

• Electromyography and nerve biopsy for peripheral neuropathy
• ENT evaluation for sinusitis, nasal polyposis, hearing loss
• Endoscopy with mucosal biopsy (IHC for CD25, CD117, tryptase) for GI involvement
• Deep skin biopsy including fascia with MRI for eosinophilic fasciitis
• Organ-directed biopsies (skin, lung, liver) as clinically indicated

Classification After Diagnosis

Once HES is confirmed, classify into subtypes 1:

Primary (neoplastic) HES (HES-N): Underlying myeloid or stem cell neoplasm with clonal eosinophils; includes cases with PDGFRA/PDGFRB/FGFR1/JAK2 rearrangements or chronic eosinophilic leukemia-NOS 1

Secondary (reactive) HES (HES-R): Cytokine-driven nonclonal eosinophilia, including lymphocytic variant with clonal T-cells producing IL-5 1

Idiopathic HES: Diagnosis of exclusion when no underlying cause, no family history, and no clonal markers identified 1

Hereditary HES: Familial clustering without immunodeficiency or identifiable cause 1

Common Diagnostic Pitfalls

Do not miss 3:

• Failing to test for PDGFRA rearrangements with FISH (these patients respond dramatically to imatinib)
• Overlooking parasitic infections, especially Strongyloides, in travelers
• Not assessing cardiac involvement early (irreversible heart failure determines prognosis)
• Assuming standard cytogenetics can detect FIP1L1-PDGFRA (it cannot)

Next-generation sequencing via myeloid mutation panels may establish clonality when tyrosine kinase fusion genes are absent, helping distinguish clonal hematopoiesis from idiopathic HES. 1