What are hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA)?

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Hypereosinophilic Syndrome (HES) and Eosinophilic Granulomatosis with Polyangiitis (EGPA): Definitions

Hypereosinophilic syndrome (HES) is defined as persistent blood eosinophilia >1500/μL (assessed twice at ≥2 weeks apart) with end-organ damage attributable to tissue eosinophil infiltration, while eosinophilic granulomatosis with polyangiitis (EGPA) is a rare ANCA-associated vasculitis characterized by asthma, eosinophilia, and necrotizing vasculitis of small-to-medium vessels with granulomatous inflammation. 1

Hypereosinophilic Syndrome (HES)

HES represents a heterogeneous group of disorders unified by marked eosinophilia causing tissue damage. The classification system distinguishes three main subtypes 1:

HES Subtypes

  • Primary (Neoplastic) HES (HESN): Underlying stem cell, myeloid, or eosinophilic neoplasm where eosinophils are clonal cells. Common molecular defects include PDGFRA, PDGFRB, FGFR mutations, or BCR/ABL1 fusion genes 1

  • Secondary (Reactive) HES (HESR): Eosinophils are non-clonal, cytokine-driven cells responding to an underlying condition. The lymphoid variant (clonal T cells driving eosinophilia) is a subvariant of secondary HES 1

  • Idiopathic HES: No identifiable underlying cause, no evidence of reactive or neoplastic disorder, but end-organ damage attributable to eosinophilia 1

Organ Involvement in HES

The most frequently affected organs include 2:

  • Pulmonary (39.0% of patients)
  • Gastrointestinal (30.5%)
  • Cutaneous (29.5%)
  • Peripheral nervous system (19.0%)
  • Cardiac (6.7%) - associated with poorer survival
  • Renal (4.8%)

Critical caveat: Absolute eosinophil count correlates with the number of involved organs and strongly predicts multiorgan involvement 2. Cardiac involvement, though less frequent, carries the worst prognosis and requires systematic screening.

HES-Related Organ Damage Criteria

Organ dysfunction must show 1:

  • Marked tissue eosinophil infiltrates and/or extensive deposition of eosinophil-derived proteins, PLUS
  • At least one of: fibrosis (lung, heart, GI tract, skin), thrombosis ± thromboembolism, cutaneous manifestations (erythema, angioedema, ulceration), or peripheral/central neuropathy with chronic deficit

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

EGPA is categorized as a secondary form of HES but distinguished by its vasculitic component 3. EGPA should be considered in any patient with asthma, chronic rhinosinusitis, and eosinophilia who develops end-organ involvement, particularly peripheral neuropathy, lung infiltrates, cardiomyopathy, or other complications (skin, gastrointestinal, or kidney involvement). 4

Key Clinical Features

Almost all EGPA patients present with 4, 5:

  • Asthma (nearly universal)
  • Chronic rhinosinusitis
  • Blood and tissue eosinophilia

ANCA Status and Clinical Phenotypes

ANCA testing should be performed in all suspected EGPA cases 4. ANCA positivity occurs in 30-40% of patients, with most testing positive for MPO-ANCA 4:

MPO-ANCA-positive phenotype (30-40% of patients):

  • Peripheral neuropathy
  • Glomerulonephritis
  • Purpura
  • Lower risk of pulmonary infiltrates and cardiac manifestations
  • More frequent relapses

ANCA-negative phenotype (60-70% of patients):

  • Cardiomyopathy (more common)
  • Pulmonary infiltrates
  • Worse overall survival (likely due to higher cardiac involvement frequency)

Important distinction: PR3-ANCA-positive EGPA is rare and phenotypically resembles granulomatosis with polyangiitis more than typical EGPA, with lung nodules, skin manifestations, and less frequent asthma 4.

Differentiating EGPA from HES

The critical distinguishing feature is vasculitis 5. EGPA demonstrates necrotizing pauci-immune small-vessel vasculitis, while HES shows eosinophilic infiltration without true vasculitis. However, this distinction can be challenging clinically, requiring:

  • Histopathological confirmation when feasible (showing necrotizing vasculitis, granulomatous inflammation, and eosinophilic infiltrates) 4
  • ANCA positivity supports EGPA diagnosis (though 60-70% are ANCA-negative) 4
  • Clinical pattern recognition: EGPA typically presents with the triad of asthma, eosinophilia, and vasculitic manifestations

Diagnostic Approach

There are no diagnostic criteria for EGPA 4. Classification criteria (1990 ACR, 2022 ACR-EULAR) have established sensitivity and specificity but should not be used diagnostically, as they were developed for research classification, not clinical diagnosis 4.

Diagnosis should be based on 4:

  1. Highly suggestive clinical features (asthma, eosinophilia, rhinosinusitis, end-organ involvement)
  2. Objective evidence of vasculitis (preferably histological)
  3. ANCA testing results
  4. Exclusion of other eosinophilic and vasculitic disorders

The diagnostic evaluation must be multidisciplinary 4, investigating:

  • Cardiac involvement (echocardiography, ECG, consider cardiac MRI)
  • Respiratory function and imaging
  • Renal function (urinalysis, creatinine)
  • Neurological assessment (peripheral neuropathy screening)
  • Skin examination
  • ANCA testing (MPO-ANCA and PR3-ANCA by ELISA)
  • Tissue biopsy when feasible

Prognostic Implications

ANCA-negative patients have worse overall survival 4, primarily due to higher cardiac involvement frequency. Conversely, ANCA-positive patients experience more frequent relapses but better long-term survival 4.

Five-Factor Score (FFS) identifies poor prognostic features 4:

  • Renal insufficiency
  • Proteinuria
  • Cardiomyopathy
  • Gastrointestinal involvement
  • Central nervous system involvement

Peripheral neuropathy and alveolar hemorrhage, though not in the original FFS, also indicate severe disease requiring aggressive treatment 4.

References

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.