Hypereosinophilic Syndrome

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Description

  • Hypereosinophilic syndrome (HES): a group of disorders characterized by an overproduction of eosinophils that subsequently infiltrate and damage multiple organs
  • Hypereosinophilia (HE): with eosinophilia-mediated organ damage
    • A persistent blood eosinophilia >1.5 × 109 cells/L on two examinations separated by at least 1 month and/or tissue HE
    • Exclusion of all other causes of organ damage and eosinophilia (“MAAACP”: malignancy, asthma, allergy, Addison disease [AD], connective tissue disease, parasitic infection)
    • Tissue HE defined by the following:
      • Eosinophils >20% of all nucleated cells on bone marrow section and/or
      • Extensive tissue infiltration on histopathology and/or
      • Marked deposition of eosinophil granular proteins in tissue
  • System(s) affected: hematologic, cardiac, cutaneous, pulmonary, neurologic, gastrointestinal (GI); rheumatologic, ocular

Epidemiology

A rare condition; prevalence 0.36 to 6.3/100,000 typically seen between 20 and 50 years

  • Clinically relevant variants:
    • T-cell lymphocytic (L-HES): benign polyclonal hypergammaglobulinemia but may progress to T-cell lymphoma. CD3−/CD4+, interleukin (IL)-5–producing T cells. Prominent skin findings include erythroderma, plaques, and/or urticaria.
    • Myeloproliferative (F/P+HES): almost exclusively in males with FIP1L1-PDGFRA fusion (FIP1-like-1 fused with platelet-derived growth factor receptor α [F/P] and increased serum vitamin B12, bicytopenia, organomegaly, increased serum tryptase, and positive mast cell abnormalities)
    • Familial HES: AD asymptomatic eosinophilia present at birth
    • Benign HES: HE without end-organ damage
    • Complex HES: multisystem organ involvement
    • Episodic HES: Periodic rise in IL-5 leads to angioedema and eosinophilia; resolves spontaneously; may progress to L-HES
    • Overlap HES: restricted eosinophilia to a single organ (GI, pulmonary, cardiac, vascular)
    • Other clinical situations with HE:
      • Churg-Strauss syndrome (eosinophilic vasculitis that can affect skin, sinuses, heart, lungs, peripheral nerves), Gleich syndrome (episodic HES with pruritus, urticaria, fever, weight gain, increase serum IgM, and leukocytosis)
      • Immunodysregulation (collagen vascular disease, sarcoid, ulcerative colitis, autoimmune lymphoproliferative syndrome, HIV)
      • HE of undetermined significance (no complications related to tissue eosinophilia)

Incidence

  • Peak incidence in 4th decade of life
  • Uncommon in children
  • Incidence decreases in elderly.
  • Predominant sex: male > female (9:1)

Etiology and Pathophysiology

  • Primary molecular defect resulting in clonal eosinophilic proliferation and/or overproduction or functional abnormalities of eosinophilopoietic cytokines and/or defects in normal suppressive regulation of eosinophilopoiesis
  • Three hematopoietic cytokines: IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate bone marrow myeloid progenitors to overproduce eosinophils; IL-5 is most specific for eosinophil differentiation.
  • Pathogenesis:
    • HES: Eosinophils infiltrate organs and release toxic granules containing major basic protein, eosinophil peroxidase, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Charcot-Leyden crystals, VIP, and substance P; neurotoxic, cytotoxic, and prothrombotic; creates oxidative burst, reactive oxygen species
    • EDN and ECP activate fibroblasts: fibrosis and organ dysfunction.

Genetics

  • F/P+HES: Microdeletion at 4q12 causing gene fusion creates constitutively active tyrosine kinase.
  • Other PDGFRA fusion partners besides FIP1L1; PDGFRB → translocation at 5q31-33 and FGFR1 → translocation at 8p11-13
  • PDGFRA mutations account for 14% of HES cases (1).
  • L-HES: clonal T-cell expansion; mutations such as 16q breakage, partial 6q or 10p deletions, trisomy 7
  • Familial eosinophilia: autosomal dominant, at 5q31 to q33; eosinophilia at birth often asymptomatic
  • Cardiac disease more in males, carriers of HLA-Bw44

Risk Factors

Male gender (F/P+HES)

General Prevention

No known preventive measures

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