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Hypereosinophilia (HE) & Hypereosinophilic Syndrome (HES) — Complete Reference Guide

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1. DEFINITIONS

Percentages are unreliable - always use AEC. Relative counts can be falsely elevated/depressed due to neutrophilia (infection, steroids) or neutropenia (ethnic/Duffy variant).

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2. GRADING OF EOSINOPHILIA

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3. PATHOBIOLOGY OF TISSUE DAMAGE

• Degranulation - releases 4 cationic proteins:
  • MBP-1 (Major Basic Protein) - toxic to respiratory epithelium, cardiotoxic
  • ECP (Eosinophilic Cationic Protein) - neurotoxin, RNase
  • EDN (Eosinophil-Derived Neurotoxin) - demyelination
  • EPO (Eosinophil Peroxidase) - oxidative damage
• Piecemeal degranulation - selective cytokine release
• Leukotriene production - bronchoconstriction, profibrotic
• Fibroblast/mast cell activation - endomyocardial fibrosis (Loeffler endocarditis)
• Thrombogenesis - eosinophils directly promote platelet aggregation and clot formation

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4. CLASSIFICATION OF HYPEREOSINOPHILIA / HES

4A. WHO / ICC 2022-2024 Classification (Updated Shomali & Gotlib, AJH 2024)

Clonal expansion of eosinophils within a myeloid neoplasm

Eosinophilia driven by non-clonal IL-5/cytokine excess

Aberrant clonal CD3-CD4+ (or CD3-CD4-CD8-) T-cell subset secreting excess IL-5 (not truly malignant, but pre-lymphomatous risk)

• Identified by flow cytometry: CD3-CD4+ T cells (loss of CD3 surface expression with retained intracellular CD3)
• Elevated serum TARC/CCL17, sCD25, detectable IL-5
• Risk of T-cell lymphoma (10-20% over years)
• Responds to steroids; partial response to mepolizumab (reduced at standard dose)

All causes excluded; no clonal marker; no aberrant T cells; persistent HE with organ damage

Single-organ eosinophilic disease with features overlapping HES (eosinophilic gastroenteritis, eosinophilic fasciitis, EGPA, Gleich syndrome/episodic angioedema with eosinophilia)

Autosomal dominant; eosinophilia without end-organ damage usually; rare; genetic counseling needed

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5. CLINICAL MANIFESTATIONS BY ORGAN SYSTEM

5A. Cardiac (Most Prognostically Significant)

1. Acute necrotic stage (months): eosinophilic myocarditis, mural thrombus formation, troponin elevation
2. Thrombotic stage: intracardiac thrombi → embolic stroke, peripheral emboli
3. Fibrotic stage: endomyocardial fibrosis, restrictive cardiomyopathy, AV valve regurgitation (chordal involvement), heart failure

MRI is more sensitive than echo for endomyocardial fibrosis

5B. Neurological

• Peripheral neuropathy (most common)
• CNS emboli from cardiac thrombi
• Eosinophilic meningitis
• Cerebral venous thrombosis
• Encephalopathy

5C. Pulmonary

• Pulmonary infiltrates (Loeffler syndrome-type)
• Restrictive/obstructive ventilatory defects
• Pleural effusions (eosinophilic)
• Pulmonary fibrosis

5D. Dermatological (Especially in L-HES)

• Pruritic erythematous papules/nodules
• Angioedema/urticaria
• Mucosal ulcers
• Eosinophilic dermatitis

5E. GI

• Eosinophilic esophagitis, gastritis, enteritis, colitis
• Diarrhea, abdominal pain, malabsorption, protein-losing enteropathy
• Hepatosplenomegaly (especially in M-HES)
• Ascites

5F. Other

• Splenomegaly, lymphadenopathy (myeloid variant)
• Arthritis/synovitis
• Renal involvement (rare)
• Constitutional: fever, fatigue, weight loss

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6. DIAGNOSTIC APPROACH - STEP BY STEP

Step 1: Confirm and Grade HE

• Full CBC with differential on two occasions ≥4 weeks apart
• Calculate AEC (do not rely on percent eosinophils)
• Assess for end-organ damage urgency

Step 2: Initial Screen - Rule Out Common Reactive Causes

• Travel history (helminth exposure)
• Drug history (including supplements, herbal)
• Atopy / allergic disease
• Family history
• Occupational exposures

• Serum IgE (total)
• Serum tryptase (↑ in myeloid HES, mastocytosis)
• Serum vitamin B12 (↑ in myeloid HES - released from eosinophils and basophils)
• Stool ova and parasites ×3 + Strongyloides IgG serology + Toxocara IgG
• Filarial serology (if travel to endemic areas)
• Comprehensive metabolic panel, LFTs, LDH, uric acid
• Serum protein electrophoresis
• ANA, ANCA (if connective tissue disease/EGPA suspected)

Step 3: Assess End-Organ Damage (ALL patients with HE)

• Troponin (cardiac necrosis - urgent if elevated)
• Echocardiography (all patients; cardiac MRI if suspicious for Loeffler)
• ECG
• Pulmonary function tests (spirometry ± DLCO)
• CT chest/abdomen/pelvis (splenomegaly, lymphadenopathy, occult neoplasm)
• Serum creatinine, urinalysis
• Liver enzymes

Step 4: Evaluate for Myeloid/Lymphoid Variant

• Flow cytometry for T- and B-cell clonality (aberrant CD3-CD4+ T cells)
• T-cell receptor gene rearrangement
• BCR-ABL (to exclude CML)

• Aspirate + biopsy + trephine
• Standard cytogenetics (karyotype)
• FISH for FIP1L1-PDGFRA (del 4q12)
• Molecular panel: PDGFRA, PDGFRB, FGFR1, JAK2, ETV6-ABL1 rearrangements
• Next-generation sequencing (NGS) for somatic mutations

• Male sex
• Splenomegaly
• ↑B12 (>2× ULN), ↑tryptase
• Anemia/thrombocytopenia
• Marrow: ↑ mast cells, Charcot-Leyden crystals, eosinophilic infiltration

• Female predominance
• Angioedema, urticaria, skin lesions
• ↑IgE, ↑TARC, ↑sCD25
• Aberrant T cells on flow cytometry
• Absence of splenomegaly/B12 elevation

Step 5: Classify and Stage

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7. TREATMENT - EVIDENCE-BASED APPROACH

7A. Indications for Treatment

7B. First-Line Therapy

• Prednisone 40-60 mg/day initially (or 1 mg/kg/day)
• HES subtype predicts response: I-HES responds best; L-HES variable; M-HES may respond but short-lived; FIP1L1-PDGFRA-positive responds poorly to steroids alone
• ⚠️ Before starting steroids: Give ivermectin 200 µg/kg/day ×1-2 days in anyone with possible Strongyloides exposure (prevents fatal hyperinfection)
• Goal: AEC <1000/µL and resolution of symptoms; taper slowly

• Dose: 100 mg/day orally (lower than CML dose due to high sensitivity)
• Response rate: near 100% hematologic response; ~70% complete molecular remission
• Duration: minimum 12-24 months; can achieve durable remission; some patients may eventually discontinue with close monitoring
• Also effective: PDGFRB rearrangements (imatinib 400 mg/day), ETV6-ABL1
• Resistant: FGFR1 (use allogeneic SCT), JAK2 (use ruxolitinib)
• Rohmer et al., AJH 2020 - 151 patients: near-universal response, improved prognosis

7C. Second-Line Agents (Steroid-Refractory / Steroid-Sparing)

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8. BIOLOGIC THERAPY TRIALS - COMPLETE EVIDENCE BASE

8A. Anti-IL-5 Therapies

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MEPOLIZUMAB (anti-IL-5 monoclonal antibody, SB-240563)

• Design: Phase II RCT, placebo-controlled, 85 patients with idiopathic/lymphocytic HES on stable prednisone ≥10 mg/day
• Dose: Mepolizumab 750 mg IV every 4 weeks
• Primary endpoint: Proportion able to reduce prednisone to ≤10 mg/day
• Results: 84% vs 43% (mepolizumab vs placebo) achieved prednisone ≤10 mg/day (p<0.001); HES flare reduction 61% vs 43%
• This trial established IL-5 targeting as the key therapeutic approach in HES

• Systematic review + meta-analysis of mepolizumab in HES
• Consistent reduction in AEC, flare rate, and steroid dose
• Well-tolerated; adverse event profile similar to placebo

• 4 trials included
• Anti-IL-5 group: 95% reduction in AEC vs 41% in placebo (RR 2.32, 95% CI 1.67-3.22, p<0.00001, I²=0%)
• Flare incidence: 15% vs 30% in placebo group (RR 0.50, 95% CI 0.31-0.86, p=0.01)
• Adverse events: identical between groups (RR 0.99, p=0.81)
• Conclusion: Anti-IL-5 therapy is effective and safe

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BENRALIZUMAB (anti-IL-5Rα monoclonal antibody, afucosylated)

• 20 PDGFRA-negative HES patients
• Benralizumab 30 mg SC every 4 weeks (3 doses), then every 8 weeks
• Results: Near-complete blood eosinophil depletion within 24 hours of first dose; sustained at 48 weeks
• Clinical response in most; tissue eosinophilia also reduced

• 14 of 20 original patients followed long-term open-label extension
• 10 patients treated for ≥8 years (max 10.1 years)
• Peripheral eosinophils remained suppressed throughout
• 3 withdrawals: 2 loss of efficacy, 1 death unrelated to drug
• Attempt to extend dosing to every 2 months: 5/8 resumed monthly dosing due to symptom/count recurrence - most required q4w maintenance
• Safety: 11 SAEs (mostly infections, surgeries) - none attributed to benralizumab; immunoglobulin levels and lymphocyte subsets remained stable for up to 10 years
• Conclusion: Long-term benralizumab is effective, well-tolerated, immunologically safe

The most important recent HES trial

• Design: Randomized, double-blind, placebo-controlled, Phase 3 multicenter; 133 patients
• Population: FIP1L1::PDGFRA-negative HES (median age 51, 62% female)
• Intervention: Benralizumab 30 mg SC q4w vs placebo for 24 weeks + background therapy
• Primary endpoint: Time to first HES flare
• Results:
  • Hazard ratio 0.35 (95% CI 0.18-0.69, p=0.0024)
  • 65% reduction in risk of first flare
  • Improved fatigue symptom scores
  • Adverse events: 64.2% benralizumab vs 66.7% placebo - no excess harm
• AstraZeneca NATRON press release (Nov 2025, ACAAI): Benralizumab (FASENRA) significantly delays time to first flare or worsening of disease
• Note: This trial has an erratum (PMID 42086981) - minor correction published

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RESLIZUMAB (anti-IL-5, IV administration)

• Less studied in HES specifically
• Case series/small studies show AEC reduction
• Primarily approved for severe eosinophilic asthma
• No Phase III HES trial completed

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8B. Anti-IL-4/IL-13 and Anti-IL-4Rα

• Blocks IL-4 and IL-13 signaling
• Paradoxically causes transient eosinophilia in ~15-20% of patients (especially asthma/atopic dermatitis)
• Under investigation for overlap HES (eosinophilic GI disease)
• Not approved for HES; caution in patients with HE

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8C. Eosinophilic Myocarditis Evidence

• Eosinophilic myocarditis: 1-9% of all myocarditis cases; HES-associated most severe form
• Mortality up to 50% if untreated
• High-dose steroids (methylprednisolone 1 mg/kg or pulse therapy) + underlying HES treatment
• Immunosuppressive therapy in refractory cases
• Cardiac MRI: most sensitive for diagnosis (gadolinium enhancement, T2 signal)

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8D. Lymphocytic Variant HES - Specific Evidence

• 180+ reported L-HES cases reviewed
• CD3-CD4+ aberrant T-cell subset drives IL-5 overproduction
• Treatments: Steroids, IFN-α, cyclosporine, mepolizumab
• Risk of T-cell lymphoma necessitates long-term monitoring (skin biopsy, periodic PET/CT)
• Reduced response to mepolizumab at standard doses - may need higher dosing or alternative

• After diagnosing L-HES: exclude ATLL (HTLV-1 testing), mycosis fungoides
• Mepolizumab reduces flares but does not eliminate aberrant T-cell clone
• Consider systemic immunosuppression (cyclosporine, alemtuzumab) for progressive disease

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9. SPECIAL TREATMENT SCENARIOS

9A. Emergency / Life-Threatening HES

• IV methylprednisolone 1 g/day for 3 days (pulse therapy)
• Leukapheresis if AEC >100,000/µL and organ compromise
• Anticoagulation for intracardiac thrombus (bridging with heparin before warfarin/DOAC)
• Cardiology consultation for endomyocardial disease
• Cardiac surgery (endocardiectomy) for late fibrotic Loeffler disease with refractory heart failure

9B. FIP1L1::PDGFRA-Positive - Special Considerations

• Imatinib 100 mg/day (NOT the 400 mg CML dose - risk of severe toxicity at CML doses)
• Baseline echo before starting (if cardiac involvement, start steroids first 1-2 weeks to prevent imatinib-induced necrosis/acute decompensation)
• Monitor molecular response by PCR (aim for undetectable FIP1L1::PDGFRA)
• Resistance to imatinib: T674I mutation (similar to CML T315I) - use nilotinib or sorafenib
• Durable remission possible in ~50% after prolonged therapy

9C. Pregnancy

• Steroids generally safe; imatinib is teratogenic - avoid in pregnancy
• Mepolizumab: limited data; generally avoided in first trimester
• Monitor AEC throughout pregnancy (eosinophilia often improves in pregnancy)

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10. MONITORING AND FOLLOW-UP

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11. TREATMENT ALGORITHM (SUMMARY FLOWCHART)

Patient with AEC >1500/µL
          ↓
Confirm HE (×2 readings) + assess for organ damage
          ↓
     ┌─────────────────────────────────────────┐
     │  Emergent organ involvement?            │
     │  (↑troponin, neuro deficit, resp fail)  │
     └─────────────────────────────────────────┘
          YES → High-dose IV steroids immediately
                (ivermectin first if Strongyloides risk)
          NO  ↓
Exclude secondary causes (parasites, drugs, atopy, neoplasm)
          ↓
Aberrant T cells on flow? ─── YES → L-HES
↑B12/tryptase, splenomegaly? ─ YES → Bone marrow + FISH
          ↓
FIP1L1-PDGFRA+ → IMATINIB 100 mg/day (near 100% response)
PDGFRB+ → Imatinib 400 mg/day
FGFR1+ → Allo-SCT
JAK2+ → Ruxolitinib
CEL-NOS → Steroids + hydroxyurea ± imatinib trial
          ↓
No clonal marker found:
L-HES → Steroids + cyclosporine ± mepolizumab
I-HES → Steroids 40-60 mg/day → taper
     If refractory: mepolizumab 300 mg SC q4w (FDA approved)
              or benralizumab 30 mg SC q4w (NATRON: HR 0.35)
              or hydroxyurea/IFN-α/cladribine

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12. KEY TRIALS SUMMARY TABLE

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13. EMERGING / PIPELINE THERAPIES

• FGFR1 inhibitors (pemigatinib, fisogatinib): Under evaluation for FGFR1-rearranged myeloid neoplasms with eosinophilia (Shomali & Gotlib, AJH 2024)
• Tezepelumab (anti-TSLP): Reduces eosinophils in asthma; HES data emerging
• Itepekimab (anti-IL-33): Under study in eosinophilic diseases
• Etokinumab (anti-IL-31Rα): Eosinophilic dermatitis arm
• CAR-T / eosinophil-targeted approaches: Preclinical

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14. PROGNOSIS

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KEY CLINICAL PEARLS

1. Always exclude Strongyloides before giving steroids - ivermectin first to prevent hyperinfection syndrome
2. FIP1L1-PDGFRA: test FISH for del 4q12 (PCR on peripheral blood may miss it - bone marrow FISH preferred); imatinib at low dose (100 mg) is curative in many
3. Troponin elevation = cardiac emergency - escalate immediately
4. L-HES: flow cytometry can miss it if not specifically requested; CD3-CD4+ phenotype; TARC/CCL17 and sCD25 are useful biomarkers; annual lymphoma surveillance
5. NATRON trial (2026): benralizumab is now the first drug with positive Phase III data for PDGFRA-negative HES (HR 0.35, p=0.0024 for flare prevention)
6. Mepolizumab FDA approved (2020) at 300 mg SC q4w for I-HES; suboptimal in L-HES at standard dose
7. Eosinophil percentage is unreliable - always use AEC
8. Cardiac MRI superior to echo for detecting endomyocardial fibrosis
9. In imatinib-treated PDGFRA+ patients with cardiac disease: give steroids 1-2 weeks before starting imatinib to reduce risk of acute necrosis/hemodynamic deterioration from rapid cellular death
10. WHO/ICC 2024 update refined classification of TK-fusion associated myeloid neoplasms; NGS now integral to workup