What is the definition of hypereosinophilia?

Definition of Hypereosinophilia

Hypereosinophilia (HE) is defined as a persistent elevated eosinophil count greater than 1.5 × 10^9/L in blood on two examinations at least one month apart and/or tissue hypereosinophilia. 1

Diagnostic Criteria for Hypereosinophilia

• Peripheral blood eosinophil count >1.5 × 10^9/L on two examinations at least one month apart 1
• Alternatively, tissue hypereosinophilia can be defined by one of the following criteria:
  • Percentage of eosinophils in bone marrow exceeds 20% of all nucleated cells 1
  • Pathologist assessment that tissue infiltration by eosinophils is extensive 1
  • Marked deposition of eosinophil granule proteins (even without major tissue infiltration) 1

Classification of Hypereosinophilia

Hypereosinophilia is classified into four main variant types according to international consensus proposals:

1. Hereditary (familial) HE (HE-FA) 1

   • Pathogenesis unknown
   • Familial clustering
   • No signs of hereditary immunodeficiency
   • No evidence of reactive or neoplastic condition

2. Primary (clonal/neoplastic) HE (HE-N) 1

   • Characterized by neoplastic proliferation of eosinophils
   • Associated with WHO-defined myeloid and/or lymphoid neoplasms
   • Clonal eosinophilia with demonstrable molecular defects (e.g., PDGFR or FGFR mutations)

3. Secondary (reactive) HE (HE-R) 1

   • Underlying condition/disease where eosinophils are non-clonal
   • Usually cytokine-driven (particularly IL-5)
   • Common causes include allergic disorders, parasitic infections, and drug reactions

4. HE of undetermined significance (HE-US) 1

   • No underlying cause identified
   • No family history
   • No evidence of reactive or neoplastic condition
   • No end-organ damage attributable to hypereosinophilia

Hypereosinophilic Syndrome (HES)

• HES refers to any hypereosinophilia variant with evidence of eosinophil-induced tissue/organ damage 1
• Idiopathic HES is diagnosed when hypereosinophilia with associated organ damage is detected with no apparent underlying disease or syndrome 1
• Common organ systems affected include skin, heart, lungs, and central/peripheral nervous systems (in >50% of cases) 2
• Other complications include hepato/splenomegaly, eosinophilic gastroenteritis, and coagulation disorders 2

Clinical Implications and Management Considerations

• In cases of evolving life-threatening end-organ damage, diagnosis can be made immediately to avoid treatment delay 1
• Persistent eosinophilia of any degree, especially at high levels, can cause significant end-organ damage 1
• Patients with eosinophilia ≥1.5 × 10^9/L for more than 3 months without evidence of end-organ damage should be referred to a hematologist after exclusion of infectious causes 1
• Management goals focus on mitigating eosinophil-mediated organ damage, with treatment strategies varying based on the subtype of hypereosinophilia 3, 4

Distinguishing from Other Conditions

• Hypereosinophilic syndromes can be distinguished from isolated eosinophilic esophagitis (EoE) by the presence of peripheral eosinophilia (AEC >1500 cells/μL), which is rare in isolated EoE 1
• Patients with esophageal symptoms and hypereosinophilia should be evaluated for other organ involvement (skin, lung, heart, neurologic) consistent with multisystem HES 1

Understanding the definition and classification of hypereosinophilia is essential for proper diagnosis, risk stratification, and management of patients with elevated eosinophil counts.