What is hypereosinophilic syndrome (HES) and what causes it?

Hypereosinophilic Syndrome: Definition and Causes

Hypereosinophilic syndrome (HES) is defined as persistent elevated eosinophil count >1.5 x 10^9/L in blood and/or tissue with evidence of eosinophil-induced organ damage, after exclusion of other disorders or conditions as the primary cause of organ damage. 1

Definition and Classification

HES represents a heterogeneous group of disorders characterized by abnormal accumulation of eosinophils that can lead to significant tissue damage and organ dysfunction. According to international consensus criteria, hypereosinophilia (HE) is classified into four variant types:

1. Hereditary (familial) HE (HE FA) - Genetic/inherited causes
2. Primary (clonal/neoplastic) HE (HE N) - Neoplastic proliferation of eosinophils
3. Secondary (reactive) HE (HE R) - Reactive expansion due to underlying conditions
4. HE of undetermined significance (HE US) - No identifiable cause 1

The term HES is applied when any of these HE variants is associated with eosinophil-induced tissue or organ damage. When organ damage is present without an identifiable underlying cause, the condition is termed idiopathic HES.

Causes of Hypereosinophilic Syndrome

1. Primary (Neoplastic) HES

• Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes
  • PDGFRA rearrangements (most common: FIP1L1-PDGFRA fusion)
  • PDGFRB rearrangements
  • FGFR1 rearrangements
  • PCM1-JAK2 rearrangements
  • FLT3 and ABL1 rearrangements 1
• Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS)
  • Characterized by increased blasts (5% to <20%) and/or nonspecific cytogenetic/molecular abnormalities 1

2. Secondary (Reactive) HES

• Allergic disorders (most common cause, ~80% of cases)

  • Allergic asthma
  • Food allergies
  • Atopic dermatitis
  • Drug reactions 1

• Parasitic infections (second most common cause)

  • Strongyloidiasis (Strongyloides stercoralis)
  • Other helminthic infections 1, 2

• Immunodeficiency syndromes

  • Hyperimmunoglobulin E syndrome (Job syndrome)
  • Omenn syndrome
  • Wiskott-Aldrich syndrome 1

• Pulmonary eosinophilic diseases

  • Allergic bronchopulmonary aspergillosis (ABPA)
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) 1

• Dermatologic conditions

  • Atopic dermatitis
  • Urticaria
  • Eczema 1

• Malignancies

  • Solid tumors (especially advanced stage)
  • Lymphoid malignancies (particularly T-cell lymphomas)
  • Hodgkin lymphoma 1

3. Lymphocytic Variant HES

• Characterized by clonal T-cells that produce eosinophilopoietic cytokines
• Considered a subvariant of secondary (reactive) HES 1, 3

4. Idiopathic HES

• No identifiable underlying cause despite thorough evaluation 1, 4

Clinical Presentation and Organ Involvement

HES can affect virtually any organ system, with the most commonly involved being:

1. Skin - Rash, urticaria, angioedema, pruritus
2. Lungs - Cough, dyspnea, rhinitis
3. Gastrointestinal tract - Abdominal pain, diarrhea, nausea
4. Heart - Endomyocardial thrombosis and fibrosis (particularly with FIP1L1-PDGFRA fusion)
5. Nervous system - Peripheral or central neuropathy 1, 3

Common presenting symptoms include:

• Weakness and fatigue
• Cough and dyspnea
• Myalgias or angioedema
• Rash or fever
• Rhinitis 1

Diagnostic Approach

The diagnosis of HES requires:

1. Persistent eosinophilia >1.5 x 10^9/L
2. Evidence of eosinophil-mediated organ damage
3. Exclusion of secondary causes of eosinophilia 1, 4

A comprehensive evaluation should include:

• Complete blood count with differential
• Peripheral blood smear
• Comprehensive metabolic panel with liver function tests
• Serum tryptase (elevated in myeloproliferative variants)
• Vitamin B12 levels (often elevated in myeloproliferative variants)
• Cytogenetic and molecular testing for tyrosine kinase fusion genes
• Bone marrow examination when appropriate 1, 2

Treatment Considerations

Treatment varies based on the HES subtype:

• Myeloproliferative HES with PDGFRA/B rearrangements:

  • Imatinib is highly effective (first-line therapy) 5, 3

• Idiopathic HES and other variants:

  • Corticosteroids (prednisolone 30-60 mg/day) as first-line therapy 2
  • Eosinophil-targeted biologic agents (mepolizumab, benralizumab) for refractory cases 6

• Secondary HES:

  • Treatment of the underlying condition 1, 2

Pitfalls and Caveats

1. Diagnostic challenges: Extensive evaluation is needed to rule out secondary causes before diagnosing idiopathic HES.

2. Organ damage monitoring: Regular assessment for end-organ damage is crucial, particularly cardiac complications which can be life-threatening.

3. Treatment resistance: Development of resistance to conventional therapies is common, necessitating close monitoring and potential treatment adjustments.

4. Tyrosine kinase inhibitor resistance: Some patients with PDGFRA mutations may develop resistance mutations (T674I and D842V) to imatinib, requiring alternative treatments 1.

5. Long-term management: HES often requires long-term therapy with careful monitoring for treatment-related toxicities.