Hypereosinophilic syndrome (HES) describes a group of disorders characterized by a persistent proliferation of eosinophils that infiltrate multiple organs, causing tissue damage. It can be primary (ie, neoplastic), secondary (ie, reactive), or idiopathic, as outlined below.

The 3 diagnostic criteria are:

1. Peripheral hypereosinophilia (HE) (> 1.5 x 10⁹/L) on 2 occasions separated in time by 4 weeks with or without marked tissue eosinophilia
2. HE-related organ damage or dysfunction:
• Greater than 20% eosinophils as compared to all nucleated cells on bone marrow section
• Extensive tissue infiltration by eosinophils as determined by pathologist
• Significant deposition of eosinophil granule proteins in tissue in absence of major tissue infiltration with eosinophils
3. Absence of another explanation for the organ damage

The term HES is applied regardless of the etiology, but it is subclassified as:

• Primary HES – Monoclonal HE due to an underlying stem cell, myeloid, or eosinophilic neoplasm.
• Secondary HES – Polyclonal HE due to an overproduction of eosinophilopoietic cytokines. Potential causes include allergic disorders, malignancy, parasitic infection, and drug reactions.
• Idiopathic HES – The underlying cause of the HE is unknown.

Variants:

• T-cell lymphocytic HES is associated with abnormal clones of T-cells producing Th-2 cytokines, specifically interleukin-5, which results in increased eosinophil production. These patients are at increased risk of developing lymphoma.
• Myeloproliferative HES is most commonly associated with the FIP1L1-PDGFRA fusion gene (encoding an activated tyrosine kinase), as well other chromosomal aberrations. This genetic mutation is found in various forms of myeloproliferative HES including eosinophilic leukemia.
• Familial HES is associated with autosomal dominant inheritance and linkage to chromosome 5q31-33. Although most affected individuals are asymptomatic, fatal progression of the disease has occurred.
• Other eosinophilic disorders: eosinophilic vasculitis; eosinophilic gastritis; episodic angioedema with eosinophilia (also known as Gleich syndrome); nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS) syndrome; etc.

The International Hypereosinophilic Syndromes Working Group has further adjusted the classification system for eosinophilic disorders. They describe 6 variants of hypereosinophilic syndrome.

1. Myeloproliferative variant (3 types):
• PDGFRA-associated HES (FIP1L1-PDGFRA: interstitial deletion of chromosome 4q12).
• Unknown etiology (FIP1L1-PDGFRA negative) associated HES.
• Chronic eosinophilic leukemia (CEL) characterized by cytogenetic abnormalities and/or peripheral blasts.
• Findings associated with the myeloproliferative variant are hepatosplenomegaly, anemia, thrombopenia, bone marrow dysplasia or fibrosis, and elevated cobalamin levels.
2. Lymphocytic variant: Associated with clonal proliferation of T-cells, and primarily characterized by skin disease. This follows a more benign course.
3. Idiopathic / undefined variant not associated with chromosomal or clonal abnormalities.
4. Overlap variant (organ-restricted eosinophilic disorders).
5. Associated variant (eosinophilia in association with a defined diagnosis, for example, Churg-Strauss syndrome).
6. Familial variant (familial history of documented persistent eosinophilia of unknown cause).

Worldwide frequency of HES is rare with an estimated prevalence of 0.32-6.3 per 100 000. Both sexes and all races / ethnicities may be affected. FIP1L1-PDGFRA-associated myeloproliferative HES is more common in males. Age of onset ranges from 20-50 (mean: 33 years). HES is especially rare in children and the elderly.

Morbidity and mortality from HES is variable. This condition may be quiescent or rapidly fatal from heart failure secondary to progressive restrictive cardiomyopathy. Poorer prognoses are associated with malignant transformation to eosinophilic leukemia, higher eosinophil counts, and cardiac or neurologic involvement.