| Domain | Key current finding | Quantitative data | Evidence type/year | Source DOI or NCT |
|---|---|---|---|---|
| Definition / ICC criteria | iHES requires persistent peripheral-blood hypereosinophilia, eosinophil-attributable tissue damage or dysfunction, exclusion of reactive, autoimmune, neoplastic, and lymphocytic-variant causes, generally normal marrow apart from eosinophilia, and no defining clonal genetic abnormality. | AEC ≥1.5 × 10⁹/L and eosinophils ≥10%; persistence commonly confirmed on ≥2 measurements at least 2 weeks apart. | International consensus classification, 2023; society statement, 2024 (pqac-00000010, pqac-00000016) | [10.1002/ajh.26966](https://doi.org/10.1002/ajh.26966); [10.3390/cells13141180](https://doi.org/10.3390/cells13141180) |
| Epidemiology / prognosis | Population incidence is poorly characterized. After overt hematopoietic neoplasia is excluded, iHES is usually relatively indolent, but cardiac and thrombotic disease can be life-threatening. Adverse factors include age >60 years, cardiac involvement, anemia or thrombocytopenia, lymphopenia, high neutrophil-to-lymphocyte ratio, and hepatosplenomegaly. | Older population estimate for HES: 0.36 new cases per million person-years; long-term disease-related mortality in iHES: approximately 10%–15%; cytopenias: approximately 10%–20%. | Guideline, 2023; ICC-era review, 2023 (pqac-00000013, pqac-00000015) | [10.1186/s13023-023-02696-4](https://doi.org/10.1186/s13023-023-02696-4); [10.1002/ajh.26966](https://doi.org/10.1002/ajh.26966) |
| Diagnostic exclusion genetics | Molecularly defined myeloid/lymphoid neoplasms and CEL-NOS must be excluded. Testing may use RT-PCR, FISH, karyotyping, targeted NGS, or RNA sequencing; flow cytometry and T-cell-receptor studies assess L-HES. Somatic CHIP variants require cautious interpretation and do not alone establish CEL. | Test for rearrangements involving **PDGFRA, PDGFRB, FGFR1, JAK2, FLT3**, and **ETV6::ABL1**; context-dependent testing includes **BCR::ABL1, KIT, JAK2 V617F, CALR**, and **MPL**. TCR clonality occurs in about 50% of L-HES and 17%–27% of otherwise unexplained eosinophilia. | Consensus/guideline and molecular-diagnostic review, 2023–2024 (pqac-00000009, pqac-00000010, pqac-00000012, pqac-00000014) | [10.1002/ajh.26966](https://doi.org/10.1002/ajh.26966); [10.3390/cells13141180](https://doi.org/10.3390/cells13141180); [10.3390/cancers16071383](https://doi.org/10.3390/cancers16071383) |
| Major organ phenotypes | Most often involves skin, gastrointestinal tract, lungs/upper airways, and cardiovascular system; neurologic, muscular, joint, and endocrine disease is less frequent. Complications include myocarditis, intracardiac thrombus, endomyocardial fibrosis, pulmonary infiltrates/fibrosis, dermatitis or urticaria, enteritis/colitis, embolic stroke, and peripheral neuropathy. | Broad HES evidence reports cutaneous presentation in approximately 37%, cardiovascular complications in 5%, and neurologic complications in 4%; these estimates are not iHES-specific. | Clinical reviews/cohort synthesis, 2021–2025 (pqac-00000004, pqac-00000015, pqac-00000027, pqac-00000031) | [10.1007/s00281-021-00863-y](https://doi.org/10.1007/s00281-021-00863-y); [10.1002/ajh.26966](https://doi.org/10.1002/ajh.26966) |
| Mepolizumab phase 3 | Add-on mepolizumab is the only biologic approved for HES as of 2024. In PDGFRA-negative, non-myeloid HES, it reduced clinical flares and improved most assessed symptom domains without a new safety signal. | 300 mg SC every 4 weeks for 32 weeks; 108 participants; approximately 50% reduction in patients experiencing flares versus placebo; symptom improvement in 5 of 6 domains. | Randomized, double-blind phase 3 trial; evidence summarized in 2024 (pqac-00000018, pqac-00000019) | [NCT02836496](https://clinicaltrials.gov/study/NCT02836496); [10.1016/j.iac.2024.07.003](https://doi.org/10.1016/j.iac.2024.07.003) |
| Benralizumab phase 2 / status through 2024 | Benralizumab depletes IL-5Rα-positive eosinophils through antibody-dependent cellular cytotoxicity. Phase 2 results supported hematologic and clinical activity in refractory PDGFRA-negative HES, but it remained investigational for HES through 2024; phase 3 NATRON was ongoing. | 30 mg SC every 4 weeks; >50% AEC reduction in 9/10 versus 3/10 placebo recipients; 17/19 showed hematologic or clinical improvement. JAK2-mutated cases did not respond, and all L-HES cases relapsed in the reported small study. | Randomized phase 2 plus extension; 2024 status review (pqac-00000018) | [NCT04191304](https://clinicaltrials.gov/study/NCT04191304); [10.1016/j.iac.2024.07.003](https://doi.org/10.1016/j.iac.2024.07.003) |
| Post-2024 real-world iHES | **Later evidence:** a small retrospective iHES cohort found marked eosinophil suppression, elimination of recorded flares, improved pulmonary function, and substantial corticosteroid sparing with mepolizumab or benralizumab. The uncontrolled sample does not establish comparative efficacy. | n=11; mepolizumab 300 mg/month (n=8) or benralizumab 30 mg every 4 weeks (n=3); median AEC 3,000→50/µL at 12 months (p=0.0002); flares 11/11→0/11; mean FEV₁ gain 857±594 mL in 8 patients with asthma; 82% discontinued oral corticosteroids; no treatment-related adverse events reported. | Retrospective real-world cohort, published 2025; treatment period 2019–2023 (pqac-00000020, pqac-00000023) | [10.3390/ph18040543](https://doi.org/10.3390/ph18040543) |
| Major evidence gaps | iHES remains an exclusion-defined and probably biologically heterogeneous syndrome. No reproducible causal germline variant, protective factor, validated iHES-specific molecular signature, epigenetic lesion, or robust gene–environment interaction has been established. Prospective natural-history, ancestry-stratified epidemiology, standardized quality-of-life, pediatric, comparative-effectiveness, and long-term safety data remain limited. | Open Targets listed 0 disease–target associations for MONDO:0011895 at search time; contemporary statements describe the prospective nonmalignant HES burden as unknown. | Database result and expert statements, 2024–2025 (pqac-00000000, pqac-00000005, pqac-00000003) | [Open Targets](https://platform.opentargets.org/); [10.3390/cells13141180](https://doi.org/10.3390/cells13141180) |


*Table: Concise evidence map of current iHES definition, diagnostic exclusions, clinical burden, prognosis, biologic-treatment data, and major knowledge gaps. Post-2024 findings are explicitly separated from evidence available through 2024.*