Hypereosinophilic Syndrome (HES)

Diagnosis, variant classification, end-organ damage assessment, and treatment of hypereosinophilic syndrome including PDGFRA-driven disease and IL-5–targeted biologics

Key Points

• HES is defined by persistent blood eosinophilia ≥1,500/μL on two occasions ≥1 month apart, plus evidence of eosinophil-mediated end-organ damage — cardiac, neurologic, cutaneous, pulmonary, or gastrointestinal.
• The FIP1L1-PDGFRA fusion (cryptic 4q12 deletion) defines a myeloproliferative variant that is exquisitely sensitive to imatinib at low doses (100–400 mg/day); this molecular test must be performed in every HES patient before treatment decisions.
• Cardiac involvement — Loeffler endocarditis progressing to endomyocardial fibrosis and restrictive cardiomyopathy — is the leading cause of morbidity and mortality; echocardiography and troponin should be obtained at diagnosis and monitored throughout treatment.
• Lymphocytic HES (L-HES) is driven by a clonal T-cell population producing IL-5 and other eosinophilopoietic cytokines; T-cell clonality studies (TCR gene rearrangement) and immunophenotyping are essential in PDGFRA-negative patients.
• Mepolizumab (anti-IL-5 monoclonal antibody) is FDA-approved for HES; it reduces eosinophil counts and flare frequency in patients without PDGFRA rearrangement.
• Serum tryptase elevation in an HES patient should raise suspicion for concomitant systemic mastocytosis or mast cell involvement — PDGFRA-rearranged disease characteristically features both eosinophilia and mast cell expansion.

Definition, Classification, and Pathophysiology

**Diagnostic criteria for HES:** HES requires all three of the following: 1. Peripheral blood eosinophilia ≥1,500/μL on at least two separate occasions ≥1 month apart (or tissue hypereosinophilia with end-organ damage) 2. Eosinophil-mediated end-organ damage and/or dysfunction 3. Exclusion of reactive (secondary) eosinophilia and other primary hematologic disorders that better account for the eosinophilia **Hypereosinophilia (HE) without organ damage** — a related term — is defined as sustained eosinophilia ≥1,500/μL without end-organ involvement; these patients warrant monitoring but do not…

Clinical Features and End-Organ Damage

End-organ assessment at diagnosis determines urgency of treatment and dictates monitoring intensity. **Cardiac involvement — the most dangerous manifestation:** Loeffler endocarditis is the hallmark cardiac complication of HES and occurs in three sequential stages: - **Stage 1 — Acute necrotic stage**: eosinophilic myocarditis with endomyocardial necrosis; may be silent or present with fever, heart failure, and troponin elevation; occurs in first weeks to months of untreated HES - **Stage 2 — Thrombotic stage**: mural thrombi form on the damaged endocardium, particularly at the cardiac apex…

Diagnostic Workup and Molecular Testing

A systematic diagnostic approach distinguishes HES variants and guides targeted therapy selection. **Initial evaluation:** - CBC with differential (eosinophil absolute count; confirm ≥1,500/μL) - Comprehensive metabolic panel, LFTs, creatinine - Serum tryptase (elevation suggests mast cell involvement or PDGFRA-rearranged disease) - Serum IgE (elevated in L-HES and atopic/parasitic causes) - Serum B12 (elevated in M-HES/myeloproliferative variants) - LDH, uric acid (tumor burden markers) - Troponin I and BNP/NT-proBNP (cardiac involvement) - Echocardiography at diagnosis **Exclusion of…

Treatment by Variant

**FIP1L1-PDGFRA–positive disease:** - **Imatinib (Gleevec)**: the treatment of choice; near-universal response at doses as low as 100 mg/day (much lower than the CML dose); complete hematologic remission in >95% and complete molecular remission (PCR-negative) in the majority with long-term therapy - Standard dose: imatinib 100–400 mg/day orally; start at 100 mg/day and increase if response is incomplete - Response monitoring: CBC monthly × 3 months, then every 3 months; repeat FIP1L1-PDGFRA RT-PCR at 3, 6, and 12 months - Resistance (rare): T674I mutation in PDGFRA (analogous to BCR-ABL…