TABLE 3.
Classification of hypereosinophilic syndromes (HES) and related disorders/syndromes
| Variant | Typical features |
|---|---|
| Familial HES (HESFA) | Familial clustering, very rare, IEI‐EO excluded a , typical end organ damage attributable to HE, no evidence of a reactive or neoplastic condition/disorder underlying HE |
| Idiopathic HES (HESI) | No underlying cause of HE, no evidence of a reactive or neoplastic condition/disorder underlying HE; and: end organ damage attributable to HE. |
| Primary (neoplastic) HES (HESN) | Underlying stem cell, myeloid, or eosinophil neoplasm classified according to WHO criteria b , and end organ damage attributable to HE. Eosinophils are neoplastic (clonal) cells; in many patients, rearranged/fusion variants of PDGFRA, PDGFRB, FGFR1, JAK2, STAT5, FLT3, ABL1 or other driver genes, are found. |
| Secondary (reactive) HES (HESR) | Underlying condition/disease where eosinophils are considered non‐clonal cells, and HE is considered to be cytokine‐driven (HESR); and end organ damage attributable to HE. |
| Special variants of HESR: c | |
| a. Lymphoid variant of HES (L‐HES) | Abnormal clonal T cells are often detected, and HES‐related organ damage is found |
| b. Defined syndromes | |
| Episodic angioedema and eosinophilia (Gleich Syndrome) | Abnormal clonal T cells are often detected, angioedema, increased polyclonal IgM. |
| Eosinophilic granulomatosis with polyangiitis (eGPA) = Churg–Strauss syndrome | Polyangiitis, necrotizing angiitis, asthma, lung infiltrates; in a subset of patients, ANCA are detected (ANCA+ form of eGPA) |
| Eosinophilia myalgia syndrome (EMS) | Myalgia, muscle weakness, cramping, skin rash, dyspnea, fatigue. |
| IgG4‐related disease (IgG4‐RD) | Elevated serum IgG4 levels, HE, and HES‐like organ damages are found in about 30% of cases |
Abbreviations: ANCA, anti‐neutrophil cytoplasmic antibodies; FGFR, fibroblast growth factor receptor; HE, hypereosinophilia; HES; hypereosinophilic syndrome; IEI‐EO, inborn errors of immunity with eosinophilia; PDGFR, platelet‐derived growth factor receptor.
The clinical symptoms and germline variants detectable in various forms of IEI‐EO are depicted in Table S3. These conditions may also present with organ dysfunction or even organ damage, but the organ damage in these patients is generally not related to HE—therefore, these cases are not classified as HES.
A more detailed description of stem cell and myeloid neoplasms associated with HE or HES is shown in Tables S4 and S5. In these cases, clonality of eosinophils is often difficult to demonstrate or is not examined. However, if a myeloid or stem cell neoplasm known to present typically with clonal HE, for example a myeloid neoplasm with PDGFR‐ or FGFR‐ rearrangement, is detected, HE can be regarded as clonal.
These syndromes may occur without fulfilling the formal criteria of HES. However, in most cases, the observed organopathy will qualify as HE‐related organ damage and thus as HES.