What are the clinical presentations and treatment options for hypereosinophilic syndrome (HES)?

Clinical Presentation of Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) presents with persistent peripheral blood eosinophilia (>1500 cells/μL) and organ damage from eosinophilic tissue infiltration, most commonly affecting the skin, gastrointestinal tract, heart, lungs, and nervous system. 1

Diagnostic Criteria

HES requires three essential components 1, 2:

• Peripheral blood eosinophil count >1.5 × 10⁹/L on two examinations at least one month apart OR tissue hypereosinophilia 2
• Organ damage and/or dysfunction attributable to tissue eosinophilic infiltration 1
• Exclusion of secondary causes (allergies, parasites, malignancies, drug reactions) 1

Clinical Manifestations by Organ System

Cardiovascular (Most Life-Threatening)

Endomyocardial thrombosis and fibrosis are frequently documented, particularly in primary (neoplastic) HES variants, especially those with FIP1L1-PDGFRA fusion genes. 1 Cardiac involvement represents the most critical prognostic factor and requires immediate echocardiography or cardiac MRI evaluation 3.

Gastrointestinal

• Up to 38% of HES patients develop gastrointestinal symptoms 1
• Esophageal involvement mimics eosinophilic esophagitis with dysphagia and food impaction 1
• Can affect any portion of the GI tract with eosinophilic infiltration 4
• Distinguished from isolated EoE by peripheral eosinophilia >1500 cells/μL, which is rare in EoE alone 1

Cutaneous

Skin manifestations are highly variable and may include 1, 5:

• Erythema, edema, and angioedema 1
• Urticaria and eczematous lesions 1
• Pruritus and ulceration 1
• May be the sole or initial presenting feature 5

Pulmonary

Respiratory involvement includes 1, 4:

• Airway inflammation and remodeling 4
• Pulmonary infiltrates and fibrosis 1
• Asthma-like symptoms 1

Neurologic

• Peripheral or central neuropathy with chronic or recurrent neurologic deficits 1
• Thromboembolic events affecting the nervous system 1, 6

Classification of HES Variants

Primary (Neoplastic) HES

Underlying myeloid or stem cell neoplasm where eosinophils are clonal cells 1:

• FIP1L1-PDGFRA fusion-positive cases (11% of patients tested) are critical to identify due to exquisite imatinib responsiveness 7, 8
• Associated with elevated serum tryptase and vitamin B12 levels 1
• Splenomegaly often present 1

Secondary (Reactive) HES

Cytokine-driven eosinophilia with non-clonal eosinophils 1:

• Lymphocyte-variant HES (L-HES) occurs in 17% of tested patients with clonal T-cells producing IL-4, IL-5, and IL-13 1, 8
• Characterized by aberrant T-cell immunophenotype (CD3-, CD4+, CD8- or double-negative) 1
• Elevated serum TARC and IgE levels 1
• 10-20% risk of progression to T-cell lymphoma or Sézary syndrome 1

Idiopathic HES

Diagnosis of exclusion when no underlying cause is identified and no clonal abnormalities detected 1, 2.

Essential Differential Diagnosis to Exclude

Before diagnosing HES, you must systematically exclude 1:

Most Common Secondary Causes

• Allergic disorders (80% of all eosinophilia cases): asthma, food allergies, atopic dermatitis, drug reactions 1, 4
• Parasitic infections (second most common): Strongyloides stercoralis is the most frequent culprit 1, 3

Other Critical Exclusions

• Eosinophilic granulomatosis with polyangiitis (EGPA): follows three-stage pattern (prodromal allergic phase, eosinophilic phase, vasculitic phase); only 30-40% are ANCA-positive 1, 4
• Solid tumors and lymphoid malignancies (Hodgkin lymphoma, T-cell lymphomas) 1
• Myeloid malignancies (CML, AML, systemic mastocytosis) 1
• Immunodeficiency syndromes (hyperimmunoglobulin E syndrome, Omenn syndrome, Wiskott-Aldrich syndrome) 1

Diagnostic Workup Algorithm

Initial Laboratory Evaluation

1. CBC with differential to confirm absolute eosinophil count >1500 cells/μL 3
2. Serum chemistries including LDH, uric acid, liver function tests 3
3. Vitamin B12 and serum tryptase (elevated in myeloproliferative variants) 1, 3
4. Serum immunoglobulins (IgG, IgA, IgM, IgE) 3
5. Inflammatory markers (CRP, ESR) 3

Exclude Secondary Causes

• Stool examination for ova and parasites (three samples) 3
• Strongyloides serology (may not be positive until 4-12 weeks post-infection) 4, 3
• Comprehensive medication review for drug-induced eosinophilia 1

Molecular and Cytogenetic Testing

If hypereosinophilia persists >3 months, refer to hematology for 3, 7:

• Bone marrow aspirate and biopsy with immunohistochemistry 3
• Conventional cytogenetics and FISH for tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1, JAK2) 3, 7
• Flow cytometry with T-cell immunophenotyping to detect aberrant T-cell clones 1

Organ-Specific Evaluation

Imaging and biopsy to document target organ involvement 1:

• Echocardiography and/or cardiac MRI (mandatory for cardiac assessment) 1, 3
• Pulmonary function tests and chest imaging 3
• Upper and lower GI endoscopy with biopsies if GI symptoms present 1, 3
• Skin biopsy for cutaneous manifestations 3
• Neurologic evaluation with imaging if neurologic symptoms 3

Treatment Approach

FIP1L1-PDGFRA-Positive Disease

Imatinib is the treatment of choice with 88% response rate in fusion-positive patients 7, 8. This represents the most critical molecular diagnosis to establish, as these patients have exquisite tyrosine kinase inhibitor responsiveness 7.

Corticosteroid Therapy

Corticosteroids remain first-line therapy for PDGFRA-negative HES, inducing complete or partial responses in 85% of patients at one month 6, 8:

• Typical maintenance dose is 10 mg prednisone equivalent daily 8
• Essential for acute, life-threatening presentations 6, 9

Steroid-Sparing and Alternative Agents

• Hydroxyurea and interferon-α demonstrate efficacy but are limited by toxicity 6, 8
• Mepolizumab (anti-IL-5 monoclonal antibody) is FDA-approved for idiopathic HES 7, 6
• Benralizumab (IL-5 receptor antibody) under investigation 7
• Pemigatinib recently approved for FGFR1-rearranged neoplasms 7

Lymphocyte-Variant HES

Corticosteroids are first-line therapy for L-HES 7, 9, with close monitoring for progression to T-cell lymphoma 1.

Critical Clinical Pitfalls

• Eosinophilia may be transient during tissue migration phase of parasitic infections when stool studies are negative 4
• Serologic tests for helminths may not become positive until 4-12 weeks post-infection and exhibit cross-reactivity 4
• In evolving life-threatening end-organ damage, diagnosis and treatment should be initiated immediately without waiting for complete workup 1, 2
• Failure to identify FIP1L1-PDGFRA fusion results in missed opportunity for highly effective imatinib therapy 7, 8
• Patients with esophageal symptoms and hypereosinophilia require screening of upper and lower GI tract plus monitoring for other organ involvement 1