What are the diagnostic criteria for hypereosinophilic syndrome?

How to Diagnose Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) is diagnosed when you document peripheral blood eosinophilia ≥1.5 × 10⁹/L on two separate examinations at least 1 month apart (or tissue hypereosinophilia), demonstrate end-organ damage directly attributable to eosinophilic infiltration, and exclude all other causes of eosinophilia. 1

Core Diagnostic Criteria

The diagnosis requires all three of the following:

1. Hypereosinophilia (HE): ≥1.5 × 10⁹/L eosinophils in blood on 2 examinations (interval ≥1 month) OR tissue HE defined by:

   • Bone marrow eosinophils >20% of nucleated cells, OR
   • Extensive tissue infiltration by eosinophils (pathologist assessment), OR
   • Marked deposition of eosinophil granule proteins 1

2. End-organ damage attributable to HE: Must demonstrate organ dysfunction with marked tissue eosinophil infiltrates and/or extensive deposition of eosinophil-derived proteins, manifesting as:

   • Fibrosis (lung, heart, digestive tract, skin)
   • Thrombosis with or without thromboembolism
   • Cutaneous manifestations (erythema, edema/angioedema, ulceration, pruritus, eczema)
   • Peripheral or central neuropathy with chronic/recurrent neurologic deficit
   • Less commonly: liver, pancreas, kidney involvement 1

3. Exclusion of other disorders as the major reason for organ damage 1

Critical caveat: In life-threatening end-organ damage (especially cardiac involvement), make the diagnosis immediately to avoid treatment delay—do not wait for the 1-month interval 1.

Algorithmic Diagnostic Workup

Initial Evaluation

History must specifically assess:

• Travel history (parasitic infections)
• New medications (drug-induced eosinophilia)
• Recurrent infections (immunodeficiency syndromes)
• Family history of eosinophilia 1

Physical examination must focus on:

• Skin lesions
• Hepatosplenomegaly
• Lymphadenopathy
• Signs of immunodeficiency 1

Essential Laboratory Testing

First-tier labs 1:

• CBC with differential (confirm absolute eosinophil count)
• Comprehensive metabolic panel with uric acid
• Lactate dehydrogenase
• Liver function tests
• Serum tryptase (elevated in myeloproliferative variants, especially PDGFRA-positive cases)
• Vitamin B12 (elevated in myeloproliferative variants)
• Peripheral blood smear review for dysplasia, monocytosis, circulating blasts

Additional testing based on clinical suspicion:

• Serology for Strongyloides and other parasites
• Aspergillus-specific immunoglobulins (if ABPA suspected)
• Serum IgE (elevated in allergies, infections, L-HES—nonspecific) 1

Distinguishing Primary vs. Secondary HE

Suspect primary (neoplastic) HE when 1:

• Elevated serum tryptase
• Abnormal T-cell population
• Increased blasts (>2% peripheral blood or >5% bone marrow)
• Cytogenetic or molecular abnormality
• Bone marrow fibrosis
• Splenomegaly and/or lymphadenopathy

If primary HE suspected, proceed with:

1. Molecular testing for tyrosine kinase (TK) fusion genes 1:

   • PDGFRA (most commonly FIP1L1-PDGFRA)
   • PDGFRB
   • FGFR1
   • JAK2
   • ABL1
   • FLT3

2. Bone marrow evaluation:

   • Morphology assessment
   • Standard cytogenetics
   • FISH (especially for FIP1L1-PDGFRA, which is cryptic on standard karyotyping) 1

3. Flow cytometry with T-cell immunophenotyping (to evaluate for lymphocyte-variant HES):

   • Look for aberrant T-cell populations (CD3⁻CD4⁺, CD3⁺CD4⁻CD8⁻, or CD3⁺CD4⁺CD7⁻)
   • T-cell receptor (TCR) gene rearrangement analysis
   • Important: TCR clonality alone is insufficient for L-HES diagnosis 1

4. Next-generation sequencing (NGS) via myeloid mutation panels when TK fusion genes are negative—helps establish clonality and distinguish from clonal hematopoiesis of indeterminate potential 1

Cardiac Evaluation (Critical for Morbidity/Mortality)

Cardiac involvement is a major cause of death in HES 2. Perform:

• Echocardiography (routine): assess for left/right ventricular apical obliteration, thrombi, restrictive cardiomyopathy
• Troponin and NT-proBNP (if cardiac symptoms)
• Cardiac MRI or CT (useful adjuncts)
• Endomyocardial biopsy remains gold standard but rarely needed 2

Classification After Diagnosis

Once HES is confirmed, classify into subtypes 1:

• Idiopathic HES: No underlying cause identified after excluding reactive and neoplastic conditions
• Primary (neoplastic) HES (HESN): Underlying myeloid/stem cell neoplasm per WHO criteria; eosinophils are clonal
• Secondary (reactive) HES (HESR): Underlying condition with nonclonal, cytokine-driven eosinophilia (includes lymphoid variant HES with clonal T-cells)

Chronic eosinophilic leukemia, NOS (CEL-NOS) is diagnosed when TK fusion genes are absent but there are:

• Other cytogenetic abnormalities (trisomy 8, isochromosome 17), OR
• Increased blasts (>2% peripheral blood or >5% bone marrow, but <20% in both) 1

Common Pitfalls

• Do not delay diagnosis in cardiac emergencies: Troponinemia, elevated NT-proBNP, or abnormal echocardiogram warrant immediate corticosteroid initiation while completing workup 1
• Do not rely solely on TCR clonality for L-HES diagnosis—requires aberrant T-cell immunophenotype 1
• Do not miss FIP1L1-PDGFRA: Standard karyotyping cannot detect this cryptic deletion; FISH or RT-PCR is required 1
• Corticosteroid treatment can mask eosinophilia: Document eosinophilia before starting steroids when possible 3