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Discussions and Knowledge Gaps

2

What drives sustained eosinophilopoiesis in idiopathic hypereosinophilic syndrome when no clonal myeloid lesion and no aberrant T-cell population can be found?

KNOWLEDGE GAP idiopathic_hes_unknown_driver

Attached to

pathophysiology#Unexplained Eosinophil Lineage Expansion

The idiopathic category is defined by the failure of the current work-up, not by a positive mechanistic finding, and it is the largest of the HES variants precisely because that work-up leaves most patients unexplained. Every node downstream of the first in this entry's chain is well supported; the first node is a placeholder for an unknown. Whether idiopathic HES is one disease or a residual bin holding several mechanisms with a shared effector pathway is unresolved, and it determines whether the category should eventually be split further or dissolved into newly identified variants.

Show evidence (1 reference)

PMID:26637706 SUPPORT Other

"Unfortunately, despite recent advances in molecular and immunologic techniques, the etiology remains unproven in the overwhelming majority of cases."

States that the aetiology is unproven in most cases despite current molecular and immunologic methods, which is the gap itself.

Why does eosinophil-mediated cardiac damage continue to progress after the blood eosinophil count has been normalised, and what should be monitored instead?

KNOWLEDGE GAP idiopathic_hes_count_damage_dissociation

Attached to

pathophysiology#Endomyocardial Fibrosis and Restrictive Physiology pathophysiology#Systemic Thromboembolism

Treatment response in this disease is assessed on the blood eosinophil count, but cardiac injury and its clinical consequences dissociate from that count. The fibrotic stage is irreversible and cardioembolism has been documented despite resolution of the hypereosinophilia, so a normal count is not evidence that the cardiac process has stopped. Troponin, NT-pro-BNP and cardiac imaging are in routine guideline use and are curated here, but they report damage that has already occurred; no validated surrogate for ongoing tissue-level eosinophil activity exists, so nothing tells a clinician the process is still running before the next increment of injury shows up.

Show evidence (2 references)

PMID:39007045 SUPPORT Human Clinical

"More importantly, they demonstrate, for the first time, the dissociation between the eosinophil count and patients' clinical evolution, suggesting the need for close follow up even after the eosinophilia has been controlled."

Documents the dissociation between blood eosinophil count and clinical cardiac evolution, which is the monitoring gap.

PMID:19364940 SUPPORT Human Clinical

"Pathology review demonstrated mural cardiac thrombus that likely caused cardioembolism as well as diffuse microangiopathy despite resolution of the hypereosinophilia."

Shows thrombotic and microangiopathic injury persisting despite resolved hypereosinophilia.

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Pathophysiology

11

Unexplained Eosinophil Lineage Expansion

Sustained expansion of the eosinophil lineage without a demonstrable clonal myeloid lesion or an identifiable aberrant T-cell population driving it. This is the defining feature of the idiopathic variant and it is a negative characterisation: the same downstream cascade in myeloid HES traces to a kinase fusion and in lymphocytic HES to cytokine-producing T cells, whereas here a systematic work-up returns neither. The proximate driver is therefore unknown rather than absent.

eosinophil progenitor cell CL:0000611

eosinophil differentiation GO:0030222 ↑ INCREASED

Downstream

IL-5-Dependent Eosinophil Survival and Tissue Recruitment Expanded eosinophil output is sustained in the periphery by IL-5-dependent survival and recruitment signalling.

Show evidence (3 references)

PMID:25964669 SUPPORT Other

"Moreover, the etiology of the eosinophilia in HESs can be primary (myeloid), secondary (lymphocyte-driven), or unknown."

Establishes the three-way aetiologic split in which the idiopathic variant is the "unknown" arm, distinguished from the myeloid and lymphocyte-driven arms rather than from a shared downstream phenotype.

PMID:26637706 SUPPORT Other

"Unfortunately, despite recent advances in molecular and immunologic techniques, the etiology remains unproven in the overwhelming majority of cases."

Supports the claim that the eosinophilopoietic driver is unproven in most patients with marked eosinophilia, which is what makes the idiopathic category large rather than residual.

PMID:1090795 SUPPORT Human Clinical

"The etiology of HES remains unknown, as does the mechanism of tissue damage."

The original clinical description of the syndrome already framed it around an unknown aetiology, which is the historical basis for the "idiopathic" designation.

IL-5-Dependent Eosinophil Survival and Tissue Recruitment

IL-5 signalling through IL-5R-alpha maintains eosinophil survival, primes the cells, and supports their recruitment into tissue. The pathway is inferred to be operative in idiopathic HES chiefly from therapeutic reversal: neutralising IL-5 or depleting IL-5R-alpha-bearing cells lowers blood, marrow, and tissue eosinophilia and controls disease in FIP1L1-PDGFRA-negative patients.

eosinophil CL:0000771

interleukin-5-mediated signaling pathway GO:0038043 ↑ INCREASED eosinophil chemotaxis GO:0048245 ↑ INCREASED

Downstream

Persistent Blood and Tissue Hypereosinophilia

Chemokine-Driven Eosinophil Recruitment into Tissue Primed circulating eosinophils are directed into target tissue by eosinophil-selective chemokine signalling.

Show evidence (2 references)

PMID:30943337 SUPPORT INDIRECT Human Clinical

"The numbers of bone marrow eosinophils, eosinophil precursors, and blood and bone marrow basophils were significantly decreased at week 12 in all the patients in the benralizumab group, but the number of mast cells and serum tryptase levels were unchanged"

Blocking IL-5R-alpha depletes marrow eosinophils and their precursors in PDGFRA-negative HES, which supports IL-5 receptor signalling sustaining the expanded lineage. Indirect because it argues from therapeutic reversal rather than measuring the pathway in untreated disease.

PMID:39056762 SUPPORT Other

"IL-5 plays a pivotal role in promoting eosinophils differentiation, activation, and survival"

States the three functions of IL-5 that this node asserts - lineage differentiation, priming, and prolonged survival.

Chemokine-Driven Eosinophil Recruitment into Tissue

Eosinophil-selective chemokines - the eotaxins CCL11, CCL24, and CCL26 acting through CCR3, alongside CCL3 and CCL5 - direct primed eosinophils out of the circulation and into skin, lung, gut, and myocardium. This step is what converts a blood count into tissue disease, and it is the reason the circulating count and the tissue burden can move independently. It is inferred from general eosinophil biology rather than demonstrated uniquely in the idiopathic variant.

eosinophil CL:0000771

eosinophil chemotaxis GO:0048245 ↑ INCREASED

Downstream

Eosinophil Activation and Degranulation

Show evidence (1 reference)

PMID:38611061 SUPPORT INDIRECT Other

"Because of activation by CCL5 and other cytokines, CCL3 can stimulate eosinophilic chemotaxis, which is important for eosinophil migration."

Establishes chemokine-driven eosinophil chemotaxis as the recruitment mechanism. Indirect because it describes eosinophil biology generally rather than measurements made in idiopathic HES.

Persistent Blood and Tissue Hypereosinophilia

Blood eosinophilia at or above 1.5 x 10^9/L persisting over weeks to months, accompanied by eosinophil accumulation in target tissues. Persistence rather than peak count is the disease-defining feature; the historical criterion required six months, which contemporary criteria have relaxed so that treatment is not withheld while damage accrues.

eosinophil CL:0000771

Downstream

Eosinophil Activation and Degranulation

Show evidence (2 references)

PMID:1090795 SUPPORT Human Clinical

"The syndrome is manifest by persistent and prolonged eosinophilia with organ damage."

States the persistence-plus-organ-damage construct that defines the syndrome, as opposed to transient or asymptomatic eosinophilia.

PMID:30567176 SUPPORT Other

"Idiopathic HES is characterised by peripheral blood eosinophilia (>1.5 × 109/L) for at least 6 months"

Gives the threshold and the historical duration requirement specifically for the idiopathic variant.

Eosinophil Activation and Degranulation

Tissue-recruited eosinophils are activated and release their secondary granule contents - major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase - into the extracellular space. Degranulation, not eosinophil number alone, is the step that converts hypereosinophilia into tissue damage.

eosinophil CL:0000771

eosinophil degranulation GO:0043308 ↑ INCREASED

Downstream

Granule Protein-Mediated Cytotoxic Tissue Injury

Eosinophil-Driven Prothrombotic State The same degranulation that injures tissue releases the cationic proteins that disable anticoagulant control.

Show evidence (3 references)

PMID:2882081 SUPPORT Human Clinical

"Activated eosinophils and secreted eosinophil granule proteins were most evident within the necrotic and later stage thrombotic lesions and were found mainly within the areas of acute tissue damage in the endocardium and in the walls of small blood vessels."

Localises activated eosinophils and their secreted granule proteins to the sites of acute tissue damage in human eosinophilic endomyocardial disease.

PMID:39056762 SUPPORT Other

"Human eosinophils are terminally differentiated leukocytes characterized by cytoplasmatic granules containing biologically active molecules, including eosinophil peroxidase, eosinophil cationic protein, major basic protein, and several cytokines, such as transforming growth factor (TGF)-ß"

Names the specific granule constituents released at this step, including the TGF-beta that links degranulation forward to the fibrotic stage.

PMID:39056762 SUPPORT Other

"The biopsy specimens of mucosal ulcers from patients with HES show the extensive deposition of eosinophilic granule proteins in the absence of morphologically identifiable intact eosinophils"

Shows that granule-protein deposition in HES tissue outlasts the identifiable eosinophil, which is why tissue injury can continue after cell counts fall.

Granule Protein-Mediated Cytotoxic Tissue Injury

Cationic granule proteins deposited in tissue are directly cytotoxic to parenchymal and endothelial cells, producing the initial necrotic lesion. In the heart this is the first of the three classically described stages of eosinophilic cardiac damage; elsewhere it produces the cutaneous, pulmonary, and gastrointestinal manifestations.

Animal models

IL-5 transgenic (IL-5Tg) hypereosinophilic mouse Mouse partially recapitulates Eosinophil-dependent cardiac tissue damage with transcriptional signatures of injury and remodeling.

Downstream

Endocardial Injury and Mural Thrombus Formation

Eosinophil-Mediated Skin, Lung, and Gut Injury

Show evidence (1 reference)

PMID:2882081 SUPPORT Human Clinical

"These findings suggest that eosinophil granule proteins are involved in cardiac injury, producing muscle damage and vascular injury which lead to the development of endomyocardial fibrosis."

Attributes muscle and vascular injury to eosinophil granule proteins and links that injury forward to endomyocardial fibrosis.

Endocardial Injury and Mural Thrombus Formation

Damaged endocardium becomes a thrombogenic surface and mural thrombus forms over it - the thrombotic stage. This is the point at which the disease becomes embolic, and the source of the cardioembolic strokes that dominate its neurological morbidity.

endothelial cell CL:0000115

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Systemic Thromboembolism

Endomyocardial Fibrosis and Restrictive Physiology

Show evidence (1 reference)

PMID:39007045 SUPPORT Human Clinical

"Cardiac involvement in hypereosinophilic syndrome typically occurs in three stages - necrotic, thrombotic, and fibrotic."

Establishes the thrombotic stage as the intermediate step between the initial necrotic injury and the fibrotic end state.

Eosinophil-Driven Prothrombotic State

Degranulating eosinophils shift haemostasis toward thrombosis independently of any endocardial surface lesion. Eosinophil cationic protein binds heparin and modulates thrombomodulin, blunting the physiological anticoagulant pathways. This is the arm that explains what surface thrombogenicity alone cannot: diffuse microangiopathy, thrombosis at sites remote from the heart, and events that continue after the blood eosinophil count has been normalised.

eosinophil CL:0000771

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Systemic Thromboembolism Loss of anticoagulant control permits thrombosis in vessels with no endocardial lesion.

Show evidence (1 reference)

PMID:32184691 SUPPORT Human Clinical

"Furthermore, the eosinophil activation and degranulation increases the release of eosinophil cationic protein that is able to bind heparin and modulate thrombomodulin so reducing the physiological anticoagulation mechanisms and so increasing the prothrombotic state in hypereosinophilia."

Gives the molecular route from degranulation to a prothrombotic state, cited from a paper reporting idiopathic hypereosinophilia with venous thromboembolism.

Systemic Thromboembolism

Embolisation from intracardiac thrombus, on top of the eosinophil-driven prothrombotic state, produces cerebral and systemic infarction and a diffuse microangiopathy. Thromboembolic events can occur and progress even after the blood eosinophil count has been normalised, which the two converging upstream arms account for.

Downstream

Stroke

Thromboembolism

Show evidence (1 reference)

PMID:26637706 SUPPORT Other

"Clinical manifestations range from benign asymptomatic presentations to life-threatening complications, including endomyocardial fibrosis and thromboembolism."

Names thromboembolism, alongside endomyocardial fibrosis, as one of the two life-threatening complications that define the severe end of the clinical spectrum.

Endomyocardial Fibrosis and Restrictive Physiology

Organisation of the injured and thrombus-covered endocardium into dense fibrous scar - the fibrotic stage. The scar is not remodelled back, so this stage is irreversible and it converts the ventricle to restrictive physiology, which is why cardiac surveillance continues after the eosinophilia is controlled.

fibroblast CL:0000057 cardiac muscle cell CL:0000746

collagen fibril organization GO:0030199 ↑ INCREASED

Downstream

Restrictive cardiomyopathy

Myocardial fibrosis

Show evidence (2 references)

PMID:2882081 SUPPORT Human Clinical

"These findings suggest that eosinophil granule proteins are involved in cardiac injury, producing muscle damage and vascular injury which lead to the development of endomyocardial fibrosis."

Endomyocardial fibrosis is the stated end point of the granule protein-mediated cardiac injury sequence.

PMID:39056762 SUPPORT Other

"The characteristics of cardiac involvement due to HES include mural thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with congestive heart failure"

Names the thrombus-fibrosis-restriction sequence that this node and its upstream neighbour together represent.

Eosinophil-Mediated Skin, Lung, and Gut Injury

Granule-protein injury outside the heart produces the non-cardiac manifestations: pruritic and urticarial or eczematous skin disease, pulmonary infiltrates with cough, and gastrointestinal symptoms including diarrhoea. Cutaneous disease is the most common organ manifestation and is frequently what brings the patient to attention. The node is the injury, not the infiltration that precedes it - eosinophil arrival in these tissues is upstream, at the recruitment node.

eosinophil CL:0000771

inflammatory response GO:0006954 ↑ INCREASED

Animal models

IL-5 transgenic (IL-5Tg) hypereosinophilic mouse Mouse partially recapitulates IL-5Tg mice develop extensive eosinophilic infiltration of the lung, which the paper measures directly and likens to the pulmonary infiltration seen in patients.

Downstream

Pruritus

Urticaria

Diarrhea

Pulmonary infiltrates

Show evidence (1 reference)

PMID:30567176 SUPPORT Other

"This review illustrates that physicians should maintain a high index of clinical suspicion for idiopathic HES in patients presenting with dermatological lesions and hypereosinophilia, without an obvious cause."

Supports cutaneous involvement as a common and clinically salient presentation of the idiopathic variant specifically.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

17

Blood 2

Increased total eosinophil count VERY_FREQUENT HP:0001880

Temporal: CHRONIC

Show evidence (1 reference)

PMID:30567176 SUPPORT Other

"Idiopathic HES is characterised by peripheral blood eosinophilia (>1.5 × 109/L) for at least 6 months"

States the defining eosinophil threshold for idiopathic HES.

Thromboembolism HP:0001907

Show evidence (1 reference)

PMID:26637706 SUPPORT Other

"Clinical manifestations range from benign asymptomatic presentations to life-threatening complications, including endomyocardial fibrosis and thromboembolism."

Names thromboembolism as a life-threatening manifestation of the syndrome.

Cardiovascular 8

Restrictive cardiomyopathy HP:0001723

Show evidence (1 reference)

PMID:39056762 SUPPORT Other

"The characteristics of cardiac involvement due to HES include mural thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with congestive heart failure"

Names restrictive cardiomyopathy directly as a characteristic of cardiac involvement, rather than requiring an inference from endomyocardial fibrosis.

Myocardial fibrosis HP:0001685

HPO has no term for endomyocardial fibrosis as such. HP:0006685 Endocardial fibrosis was considered and is curated separately below, because the lesion begins in the endocardium; HP:0001685 Myocardial fibrosis is kept here for the extension into myocardium that gives the disease its restrictive physiology. preferred_term is left at the ontology label rather than narrowed beyond what either term supports.

Show evidence (1 reference)

PMID:2882081 SUPPORT Human Clinical

"These findings suggest that eosinophil granule proteins are involved in cardiac injury, producing muscle damage and vascular injury which lead to the development of endomyocardial fibrosis."

Documents endomyocardial fibrosis as the histopathological end point of eosinophil-mediated cardiac injury.

Endocardial fibrosis HP:0006685

Show evidence (1 reference)

PMID:39056762 SUPPORT Other

"The characteristics of cardiac involvement due to HES include mural thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with congestive heart failure"

Names endomyocardial fibrosis as a characteristic of HES cardiac involvement; the endocardial component is bound here and the myocardial component separately.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:39056762 SUPPORT Other

"The characteristics of cardiac involvement due to HES include mural thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with congestive heart failure"

Names congestive heart failure as the outcome of the restrictive cardiomyopathy in HES.

Stroke HP:0001297

Show evidence (1 reference)

PMID:19364940 SUPPORT Human Clinical

"Imaging of the brain revealed bihemispheric ischemic changes in and beyond the watershed distributions."

Documents bihemispheric cerebral ischaemic injury in a patient with fulminant idiopathic HES.

Urticaria HP:0001025

Show evidence (1 reference)

PMID:40283978 SUPPORT INDIRECT Other

"The most common symptomatology involved in HES includes cutaneous (e.g., rash, urticaria, angioedema), pulmonary (e.g., shortness of breath, cough, pulmonary infiltrates, pleural effusion), gastrointestinal (e.g., abdominal pain, nausea, vomiting), constitutional (e.g., fever, fatigue),..."

Names urticaria among the cutaneous manifestations of HES. Note this is HES-wide review prose, not the citing paper's own idiopathic-HES cohort.

Arrhythmia OCCASIONAL HP:0011675

Show evidence (1 reference)

PMID:40283978 SUPPORT Human Clinical

"Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema."

Reports cardiac arrhythmias in 2 of 11 (18.2%) patients with idiopathic HES.

Angioedema HP:0100665

Show evidence (1 reference)

PMID:40283978 SUPPORT Human Clinical

"Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema."

Reports bilateral eyelid angioedema in 1 of 11 patients with idiopathic HES, supporting angioedema as an occasional rather than characteristic feature.

Digestive 1

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:30943337 SUPPORT INDIRECT Human Clinical

"Tissue samples obtained at week 24 showed nearly complete depletion of eosinophils (≤1 eosinophil per high-power field) in a total of 52 gastrointestinal biopsy samples obtained from the seven patients with gastrointestinal eosinophilia"

Documents gastrointestinal eosinophilia in a PDGFRA-negative HES trial cohort. That cohort is a superset of idiopathic HES, so the claim is read down onto the idiopathic subset rather than measured in it.

Immune 1

Asthma FREQUENT HP:0002099

Show evidence (1 reference)

PMID:40283978 SUPPORT Human Clinical

"Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema."

Reports asthma in 8 of 11 (72.7%) patients in a cohort assembled specifically as idiopathic HES, rather than as mixed HES.

Integument 1

Pruritus HP:0000989

Show evidence (1 reference)

PMID:40283978 SUPPORT INDIRECT Other

"Skin manifestations were the most common, reported in 69% of patients, followed by respiratory (44%) and gastrointestinal (38%) manifestations."

Quantifies skin involvement as the most common organ manifestation, which is the observation behind this phenotype. Note this is HES-wide review prose, not the citing paper's own idiopathic-HES cohort.

Metabolism 1

Pleural effusion FREQUENT HP:0002202

Show evidence (1 reference)

PMID:40283978 SUPPORT Human Clinical

"Asthma was present in the majority of them (n = 8, 72.7%); four patients (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid angioedema."

Reports eosinophilic pleural effusions in 4 of 11 (36.4%) patients with idiopathic HES.

Nervous System 2

Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:39056762 SUPPORT Other

"The typical features of HES-related organ damage include fibrosis, thrombosis, cutaneous (skin or mucosa) erythema, edema/angioedema, blisters, ulceration, or eczema, pulmonary manifestations, GI involvement, peripheral or central neuropathy with neurological deficits, and eosinophilic vasculitis"

Lists peripheral neuropathy with neurological deficits among the typical features of HES-related organ damage. Quoted up to the citation bracket, which the reference validator normalizes away.

Encephalopathy HP:0001298

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:19364940 SUPPORT Human Clinical

"A 48-year-old right-handed man with hypereosinophilia, rapidly progressive encephalopathy, and focal neurological deficits who died 22 days after presentation."

Reports rapidly progressive encephalopathy with focal deficits in idiopathic HES.

Respiratory 1

Pulmonary infiltrates HP:0002113

Show evidence (1 reference)

PMID:40283978 SUPPORT INDIRECT Other

"Skin manifestations were the most common, reported in 69% of patients, followed by respiratory (44%) and gastrointestinal (38%) manifestations."

Quantifies respiratory involvement at 44% of patients, and the same sentence's surrounding text names pulmonary infiltrates among those manifestations. Note this is HES-wide review prose, not the citing paper's own idiopathic-HES cohort.

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Genetic Associations

1

FIP1L1-PDGFRA negative by definition (Required to be absent for the idiopathic designation)

Gene: PDGFRA hgnc:8803 relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:19910029 SUPPORT Human Clinical

"Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive,"

Quantifies the FIP1L1-PDGFRA-positive minority that is excluded from the idiopathic category by testing.

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Medical Actions

7

Systemic Corticosteroid Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Platform: Small molecule

Oral corticosteroids are first-line for idiopathic HES and produce a response in the large majority of patients, but most require indefinite maintenance dosing and the cumulative toxicity of that maintenance is the principal reason steroid-sparing agents are sought.

Mechanism Target:

Persistent Blood and Tissue Hypereosinophilia — Corticosteroids suppress eosinophil production and survival and rapidly lower the circulating count.

Show evidence (2 references)

PMID:19910029 SUPPORT Human Clinical

"Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years)."

Quantifies both the high first-line response rate and the long-term maintenance dependence that motivates steroid-sparing therapy.

PMID:25964669 SUPPORT Other

"Although corticosteroids remain the first-line therapy for most forms of HESs, the availability of an increasing number of novel therapeutic agents, including tyrosine kinase inhibitors and monoclonal antibodies, has necessarily altered the approach to treatment of HESs."

Confirms corticosteroids as first-line therapy in current practice.

Mepolizumab

Action: Pharmacotherapy NCIT:C15986

Agent: mepolizumab NCIT:C157376

Platform: Monoclonal antibody

Anti-IL-5 monoclonal antibody, and the only biologic approved for HES. In FIP1L1-PDGFRA-negative HES with recurrent flares it halves the proportion of patients flaring, and in prednisone-dependent patients it permits substantial steroid tapering. Note what that trial population is: FIP1L1-PDGFRA negative is not a synonym for idiopathic, since it also contains lymphocytic-variant and non-PDGFRA myeloid disease. Idiopathic HES is its largest component and the small idiopathic-only cohort below points the same way, but the phase III result is not an idiopathic-specific measurement.

Mechanism Target:

IL-5-Dependent Eosinophil Survival and Tissue Recruitment — Neutralising circulating IL-5 removes the survival and recruitment signal the expanded eosinophil population depends on.

Show evidence (3 references)

PMID:32956756 SUPPORT INDIRECT Human Clinical

"The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002)."

Phase III efficacy result in FIP1L1-PDGFRA-negative HES. That trial population is a superset of this entry's disease - it also admits lymphocytic-variant and non-PDGFRA myeloid HES - so the result is read down onto the idiopathic subset rather than measured in it.

PMID:18344568 SUPPORT Human Clinical

"The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome."

Establishes the corticosteroid-sparing effect in prednisone-dependent FIP1L1-PDGFRA-negative patients.

PMID:40283978 SUPPORT Human Clinical

"All patients with concomitant asthma (n = 8) experienced elimination of asthma flares, asthma control (ACQ < 0.75), functional improvement (mean ΔFEV1: 857 ± 594 mL), and an 82% reduction in oral corticosteroids"

Real-world corticosteroid sparing in a cohort characterised specifically as idiopathic HES. Uncontrolled and small (11 patients across mepolizumab and benralizumab), so it corroborates the trial result in this exact population rather than adding independent efficacy evidence.

Benralizumab

Action: Pharmacotherapy NCIT:C15986

Agent: benralizumab NCIT:C88594

Platform: Monoclonal antibody

Afucosylated anti-IL-5R-alpha monoclonal antibody that depletes IL-5R-alpha-bearing cells by antibody-dependent cellular cytotoxicity. In PDGFRA-negative HES it depletes blood, marrow, and tissue eosinophils and permits tapering of background therapy, with responses sustained to 48 weeks in most patients. As with mepolizumab, that trial population is a superset of idiopathic HES rather than a synonym for it.

Mechanism Target:

IL-5-Dependent Eosinophil Survival and Tissue Recruitment — Depletion of IL-5R-alpha-bearing eosinophils and their marrow precursors removes the effector population rather than only its survival signal.

Show evidence (2 references)

PMID:30943337 SUPPORT INDIRECT Human Clinical

"During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02)."

Phase II efficacy result on eosinophil reduction in PDGFRA-negative HES.

PMID:30943337 SUPPORT Human Clinical

"During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered."

Documents durability of response and the background-therapy sparing effect.

Hydroxyurea

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxyurea CHEBI:44423

Platform: Small molecule

Conventional second-line cytoreductive agent used when corticosteroids fail or cannot be tapered. Effective, but toxicity limits its use, which is the gap the anti-IL-5 agents fill.

Mechanism Target:

Persistent Blood and Tissue Hypereosinophilia — Cytoreduction of the expanded eosinophil population.

Show evidence (1 reference)

PMID:19910029 SUPPORT Human Clinical

"Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity."

Establishes hydroxyurea's efficacy and the toxicity ceiling on its use.

Interferon Alfa

Action: Pharmacotherapy NCIT:C15986

Agent: interferon alfa CHEBI:753470

Platform: Other

Second-line immunomodulatory therapy, curated separately from hydroxyurea because it is a recombinant protein rather than a small molecule and the two are not interchangeable in a modality or agent query. Effective, with the same toxicity ceiling.

Mechanism Target:

Persistent Blood and Tissue Hypereosinophilia — Immunomodulatory suppression of the expanded eosinophil population.

Show evidence (1 reference)

PMID:19910029 SUPPORT Human Clinical

"Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity."

Establishes interferon alfa's efficacy and the toxicity ceiling on its use.

Empirical Antiparasitic Therapy Before Corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: ivermectin CHEBI:6078

Platform: Small molecule

A safety step rather than a treatment for the disease. Corticosteroids given to a patient with unrecognised strongyloidiasis can precipitate hyperinfection, and strongyloidiasis is itself a cause of eosinophilia that must be excluded before the idiopathic label is applied. Guidelines offer empirical ivermectin depending on exposure history and endemic-area risk, while noting that the value of empirical treatment in genuinely unexplained chronic hypereosinophilia is disputed.

Show evidence (2 references)

PMID:37122022 SUPPORT Other

"Depending on the patient's condition and risk factors and the endemic areas visited, an antiparasitic treatment consisting of all or some of the following compounds may be offered:D1 ivermectin: 200 µg/kg on an empty stomach (possibly followed by a second dose at D2 or D15 in case of diagnostic..."

Gives the guideline's empirical antiparasitic regimen and the risk-stratified basis for offering it.

PMID:37122022 SUPPORT Other

"In the absence of available studies, the usefulness of empirical antiparasitic treatment in unexplained chronic HE is disputed."

Records that the practice is contested rather than settled, so the entry does not overstate it.

Imatinib

Action: Pharmacotherapy NCIT:C15986

Agent: imatinib mesylate NCIT:C1687

Platform: Small molecule

Tyrosine kinase inhibitor and the treatment of choice for the FIP1L1-PDGFRA-positive myeloid variant. It is included here as a negative therapeutic claim: in FIP1L1-PDGFRA-negative disease, which includes idiopathic HES, the response rate falls to roughly a quarter. The contrast is the main therapeutic reason this entry is separated from the myeloid variant. It carries no target_mechanisms deliberately: the claim is that it does not act on this disease's mechanisms, so linking it to one would assert the opposite of what the evidence says.

Show evidence (1 reference)

PMID:19910029 REFUTE Human Clinical

"Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001)."

Refutes imatinib as an effective therapy for FIP1L1-PDGFRA-negative disease: the response rate in the negative group is 23% against 88% in the positive group.

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Biochemical Markers

4

Absolute eosinophil count (INCREASED)

Context: The measurement this entry is defined by, and the one the exclusion workup is built around. A count at or above 1,500 cells/uL, recorded more than once and with organ damage attributable to it, becomes idiopathic disease only once reactive, clonal and lymphocyte-variant causes have been ruled out.

Pathograph Readouts

Readout Of Persistent Blood and Tissue Hypereosinophilia Positive Diagnostic

The blood count is the accessible half of this node. It measures the circulating compartment; the tissue hypereosinophilia the node also names is established by biopsy, so a count inside the reference interval does not exclude it.

Show evidence (1 reference)

PMID:40283978 SUPPORT Other

"More specifically, the diagnostic criteria for idiopathic HES include sustained hypereosinophilia (eosinophil count ≥ 1.5 × 109/L) recorded more than once in a minimum time interval of two weeks, ≥10% eosinophilia, organ failure attributable to the eosinophilia or tissue infiltration by..."

States the count and its persistence as the positive criterion, alongside the organ damage and the exclusions that make the disease idiopathic.

Reference Ranges

Eosinophils [#/volume] in Blood 50–500 cells/uL (adults)

Below 500 cells/uL (–500 cells/uL) 500 to 1499 cells/uL (500–1500 cells/uL) → Increased total eosinophil count 1500 cells/uL or greater (1500– cells/uL) → Severely increased total eosinophil count

Below 500 cells/uL: At or below the reference interval's upper limit. Results below the interval's 50 cells/uL floor fall here too, and are deliberately not graded LOW: no cited source addresses eosinopenia, and in treated disease a near-zero count is the therapeutic goal rather than an abnormality. On treatment this band is also the target: hematologic remission is defined as a count below 0.5 x 10^9/L, so a result here in a treated patient reports response rather than absence of disease.

500 to 1499 cells/uL: Eosinophilia by the ICOG-EO classification, but below the hypereosinophilia threshold this syndrome is defined by. A count in this band is common and mostly reactive; on its own it does not support the diagnosis.

1500 cells/uL or greater: Hypereosinophilia, and the entry criterion for this diagnosis. A single count here is not sufficient: the criteria require it recorded more than once at least two weeks apart, with attributable organ damage, and with reactive, clonal and lymphocyte-variant causes excluded.

A genuine laboratory reference interval, and worth distinguishing from the therapy-stratification bands on the Asthma blood eosinophil record, which asserts no interval at all: here a source states the normal range directly. The bands below are the diagnostic tiers of the eosinophilic-disorder classification, not severity grades. Because the sources define eosinophilia as at or above 0.5 x 10^9/L, a result of exactly 500 cells/uL falls in the eosinophilia band rather than inside this interval.

Show evidence (2 references)

PMID:39056762 SUPPORT REVIEW SYNTHESIS Human Clinical

"Peripheral blood absolute eosinophil count (AEC) normal value ranges between 0.05 and 0.5 × 109/L, while reference values for mature eosinophils in bone marrow aspirates are between 1% and 6% [1,6,7,8]."

States the adult laboratory reference interval this record carries, as 0.05 to 0.5 x 10^9/L.

PMID:38611061 SUPPORT REVIEW SYNTHESIS Human Clinical

"A circulating eosinophil count of ≥0.5 × 109/L is defined as eosinophilia."

An independent source for the 500 cells/uL boundary, above which a count is eosinophilia rather than normal.

Show evidence (2 references)

PMID:39056762 SUPPORT REVIEW SYNTHESIS Human Clinical

"According to the classification of eosinophilic disorders proposed in 2011 by the International Cooperative Working Group on Eosinophil Disorders (ICOG-EO) and revised in 2022, blood eosinophilia is defined by an AEC above 0.5 × 109/L, while hypereosinophilia (HE) necessitates an AEC of ≥1.5 ×..."

The source of both band boundaries: eosinophilia above 0.5 x 10^9/L, hypereosinophilia at or above 1.5 x 10^9/L.

PMID:39056762 SUPPORT REVIEW SYNTHESIS Human Clinical

"In the case of severe organ damage, a further goal is to achieve hematologic remission (blood eosinophil count < 0.5 × 109/L) to avoid relapse."

Establishes the same count as the treatment target, which is why the normal band carries a monitoring reading as well as a diagnostic one.

Serum tryptase (NORMAL)

Show evidence (1 reference)

PMID:37122022 SUPPORT Other

"The workup should also include basal tryptase determination (suggestive of mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are suggestive of clonal eosinophilia), plasma protein electrophoresis (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,..."

States that basal tryptase is part of the work-up and that elevation suggests mastocytosis or clonal HE/HES, which is the exclusion this entry depends on.

Serum vitamin B12 (NORMAL)

Show evidence (1 reference)

PMID:37122022 SUPPORT Other

"The workup should also include basal tryptase determination (suggestive of mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are suggestive of clonal eosinophilia), plasma protein electrophoresis (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,..."

States that elevated B12 together with elevated tryptase suggests clonal eosinophilia, the finding whose absence this entry requires.

Cardiac troponin T (INCREASED)

Show evidence (2 references)

PMID:39056762 SUPPORT Other

"Elevated cardiac troponin T levels, indicative of myocyte degeneration, as well as NT-pro-BNP, serve as a prognostic marker"

Establishes troponin T as a prognostic marker of myocyte degeneration in HES.

PMID:39056762 SUPPORT Other

"and are typically present from the disease onset, even with normal echocardiographic findings"

Supports troponin elevation preceding echocardiographic change, which is why it is useful as an early cardiac signal.

🔬

Diagnosis

3

Systematic exclusion work-up

The diagnosis is constituted by the work-up rather than confirmed by it. A minimum evaluation requires bone marrow karyotyping, PDGFRA testing, lymphocyte immunophenotyping, and T-cell receptor gene rearrangement studies, in addition to exclusion of reactive causes such as helminth infection, drug reaction, allergy, vasculitis, and malignancy. Idiopathic HES is assigned only when all of these are unrevealing.

diagnostic procedure NCIT:C18020

Show evidence (2 references)

PMID:36756990 SUPPORT Human Clinical

"The work-up of patients in whom ruled out the common secondary causes of HE requires a systematic but sufficient approach including at a minimum BM karyotyping, PDGFRA testing, lymphocyte immunophenotyping and TCR gene rearrangement."

Specifies the minimum diagnostic work-up that must be negative before the idiopathic designation is applied.

PMID:37122022 SUPPORT Other

"The workup should also include basal tryptase determination (suggestive of mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are suggestive of clonal eosinophilia), plasma protein electrophoresis (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,..."

Adds the serological arm of the work-up - tryptase, B12, protein electrophoresis, total IgE - alongside the marrow and molecular testing, each element pointing at a rival diagnosis to exclude.

Consensus criteria and terminology

The 2011 Working Conference on Eosinophil Disorders and Syndromes (ICOG-EO) unified previously divergent classifications and separated hypereosinophilia of undetermined significance - eosinophilia without organ damage - from hypereosinophilic syndrome proper. Idiopathic HES sits inside the syndrome category and requires demonstrable eosinophil-mediated organ damage.

No diagnosis_term is bound. This record states a classification convention, not a procedure performed on a patient, and NCIT:C18020 Diagnostic Procedure would assert something false about it.

Show evidence (2 references)

PMID:22460074 SUPPORT Other

"For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced."

Draws the boundary between idiopathic HES and hypereosinophilia of undetermined significance, which is the distinction organ damage makes.

PMID:22460074 SUPPORT Other

"The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome."

Establishes the consensus classification within which the idiopathic variant is defined against the primary and secondary variants.

Contemporary threshold and the obsolete six-month rule

The historical Chusid criterion required six months of eosinophilia before the diagnosis could be made. That waiting period is no longer applied when organ damage is already present, because the fibrotic and thromboembolic complications that determine outcome accrue during it. Persistence is now confirmed on repeat measurement over weeks rather than months, and etiological work-up runs in parallel with organ-damage assessment rather than before it.

No diagnosis_term is bound: this record is criteria history, not a procedure. The six-month figure is cited to a source that states it, rather than to Chusid's own abstract, which describes persistence without naming a duration.

Show evidence (3 references)

PMID:40283978 SUPPORT Other

"The current definition of HES requires persistent eosinophilia with a corresponding absolute eosinophil count of >1.5 × 109/L for a shorter period of 2 to 4 weeks (compared to the historical criterion of more than 6 months outlined by Chusid and colleagues in 1975), and concomitant tissue damage"

States both the historical six-month criterion and the 2-to-4-week window that replaced it.

PMID:40283978 SUPPORT Other

"More specifically, the diagnostic criteria for idiopathic HES include sustained hypereosinophilia (eosinophil count ≥ 1.5 × 109/L) recorded more than once in a minimum time interval of two weeks, ≥10% eosinophilia, organ failure attributable to the eosinophilia or tissue infiltration by..."

The full contemporary criteria set stated for idiopathic HES specifically, including the >=10% of leukocytes threshold and the repeat-measurement interval.

PMID:39056762 SUPPORT Other

"Cardiac assessment should include a heart ultrasound as a routine examination due to the lack of symptoms in the early phases of heart involvement."

Supports assessing organ damage up front rather than waiting, because early cardiac involvement is asymptomatic.

📊

Prevalence

2

Worldwide, all HES variants

Unknown 0.036–6.3 per 100,000 Rare

SEER-derived figures quoted in an idiopathic-HES-focused review, but the numbers themselves span all HES variants, not idiopathic disease alone. The source calls them morbidity without naming a measure type, and the 175-fold spread between the bounds is itself the finding: population incidence and prevalence of idiopathic HES are not established. Recorded with measure_type UNKNOWN for that reason. rate_per_100000 is deliberately left empty: there is no point estimate to put in it, only the span in rate_low and rate_high, and the qualitative tiers are reserved for records without a populated rate.

Show evidence (1 reference)

PMID:30567176 SUPPORT Other

"The Surveillance, Epidemiology, and End Results data show that the estimated morbidity is between 0.036/100 000 and 6.3/100 000 whereas the mortality is about 9.3%."

Gives the only population-level figures available, with the spread that makes them provisional.

Worldwide, idiopathic variant (sex ratio)

Unknown Not yet documented

No sex predominance is established for the idiopathic variant. Historic HES series reported a marked male excess, but that was driven by the nearly male-restricted FIP1L1-PDGFRA neoplasm, which is excluded from this entry.

Show evidence (1 reference)

PMID:30567176 SUPPORT Other

"Based on the limited data, this variant has no clear gender predominance with an estimated male to female sex ratio of 1:1."

States the absence of a sex predominance specifically for the idiopathic variant.

⚖️

Clinical Burden

High

The syndrome spans asymptomatic eosinophilia through to fatal cardiac, thromboembolic and neurological disease, and the damage that determines outcome is largely irreversible once established: endomyocardial fibrosis does not remodel back, and cerebral infarction does not. Most patients respond to corticosteroids but the large majority stay on maintenance dosing indefinitely, so the treatment burden is lifelong even where the disease is controlled. Reported disease-related mortality is roughly one in ten.

Show evidence (2 references)

PMID:30567176 SUPPORT Other

"The Surveillance, Epidemiology, and End Results data show that the estimated morbidity is between 0.036/100 000 and 6.3/100 000 whereas the mortality is about 9.3%."

Gives the reported mortality figure behind this burden assessment.

PMID:19910029 SUPPORT Human Clinical

"Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years)."

Quantifies the indefinite maintenance dosing that makes the treatment burden lifelong even in responders.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Idiopathic Hypereosinophilic Syndrome:

Primary (myeloid) hypereosinophilic syndrome Not Yet Curated MONDO:0017833

Overlapping Features The clonal myeloid variant, most often carrying FIP1L1-PDGFRA. Separating it from idiopathic HES changes first-line therapy from corticosteroids to imatinib, so the distinction is therapeutically decisive rather than taxonomic.

Distinguishing Features

Demonstrable FIP1L1-PDGFRA fusion or other clonal myeloid lesion
Marked and durable response to imatinib
Marrow features of a myeloid neoplasm on morphology or karyotype

Show evidence (1 reference)

PMID:19910029 SUPPORT Human Clinical

"Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001)."

The differential response to imatinib is the operative distinction between the myeloid and idiopathic variants.

Lymphocytic variant hypereosinophilic syndrome Not Yet Curated MONDO:0017835

Overlapping Features Eosinophilia driven by an aberrant or clonal T-cell population producing eosinophilopoietic cytokines. Detected by lymphocyte immunophenotyping and T-cell receptor gene rearrangement, both of which are negative in idiopathic HES by definition.

Distinguishing Features

Aberrant T-cell immunophenotype on flow cytometry
Clonal T-cell receptor gene rearrangement
Risk of progression to T-cell lymphoma

Show evidence (1 reference)

PMID:19910029 SUPPORT Human Clinical

"and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population."

Quantifies the lymphocytic-variant minority identified by testing and thereby excluded from the idiopathic category.

Hypereosinophilia of undetermined significance

Overlapping Features Marked eosinophilia meeting the same threshold but without demonstrable eosinophil-mediated organ damage. It is not a syndrome and does not by itself warrant cytoreductive therapy; the distinction from idiopathic HES rests entirely on whether organ damage can be demonstrated.

Distinguishing Features

No demonstrable eosinophil-mediated end-organ damage
Observation rather than eosinophil-directed therapy

Show evidence (1 reference)

PMID:22460074 SUPPORT Other

"For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced."

Introduces the category that idiopathic HES must be distinguished from.

Eosinophilic granulomatosis with polyangiitis MONDO:0015943

Overlapping Features ANCA-associated eosinophilic vasculitis presenting with asthma, marked eosinophilia, and multiorgan disease. Distinguished by vasculitic and granulomatous pathology rather than pure eosinophil-mediated injury.

Distinguishing Features

Necrotising vasculitis and extravascular granulomas on biopsy
Antecedent asthma and sinonasal disease
ANCA positivity in a subset

Show evidence (1 reference)

PMID:26637706 SUPPORT Other

"Eosinophilia is associated with a wide variety of allergic, rheumatologic, infectious, neoplastic, and rare idiopathic disorders."

Places rheumatologic disease, of which EGPA is the principal eosinophilic example, among the categories that must be excluded. The snippet supports the category rather than EGPA by name.

📊

Related Datasets

1

Expression data from adult left ventricular heart tissue of hypereosinophilic mice and controls geo:GSE185300

Microarray profiling of left ventricular myocardium from IL-5 transgenic hypereosinophilic mice against controls, the transcriptional dataset behind the tissue damage and remodeling signature cited for the cardiac injury node. Model-organism data: it addresses the eosinophil effector arm shared with idiopathic HES, not the unexplained driver specific to it.

house mouse MICROARRAY

PMID:37829205

Selected after relevance triage of the GEO candidate list. Two higher-scoring DIRECT candidates were rejected: geo:GSE12079 profiles CD3-CD4+ T cells from the lymphocytic variant, which this entry excludes by definition, and geo:GSE131738 is Sezary syndrome. Every GENE_ONLY candidate matched on PDGFRA, which reaches this disease only through the MONDO term's erroneous OMIM-derived axiom.

🔬

Clinical Trials

5

NCT02836496 PHASE_III COMPLETED

Randomised, double-blind, placebo-controlled phase III trial of mepolizumab 300 mg subcutaneously every 4 weeks added to existing therapy in FIP1L1-PDGFRA-negative HES with recurrent flares.

Target Phenotypes: Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:32956756 SUPPORT Human Clinical

"This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries."

Describes the trial design underlying the mepolizumab evidence for this population.

NCT02130882 PHASE_II COMPLETED

Single-centre randomised, double-blind, placebo-controlled phase II trial of benralizumab 30 mg subcutaneously in symptomatic PDGFRA-negative HES, with open-label and extension phases.

Target Phenotypes: Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:30943337 SUPPORT Human Clinical

"In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome"

Describes the trial design underlying the benralizumab evidence.

NCT04191304 PHASE_III COMPLETED

NATRON. Multicentre randomised placebo-controlled 24-week phase III trial of benralizumab with an open-label extension, the confirmatory study behind the phase II result curated above.

Target Phenotypes: Increased total eosinophil count HP:0001880

Show evidence (1 reference)

clinicaltrials:NCT04191304 SUPPORT Human Clinical

"This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab versus placebo administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES)."

The registry record for the phase III benralizumab study in HES.

NCT05334368 PHASE_III UNKNOWN

52-week randomised placebo-controlled trial of depemokimab, a long-acting anti-IL-5 antibody, in adults with uncontrolled HES on standard care. Recorded because it tests the same IL-5 axis this entry's mechanism node rests on; no efficacy results were available at curation.

Target Phenotypes: Increased total eosinophil count HP:0001880

Show evidence (1 reference)

clinicaltrials:NCT05334368 SUPPORT Human Clinical

"This is a 52-week, randomized, placebo-controlled, double-blind, parallel group, multicenter study of depemokimab in adults with uncontrolled HES receiving standard of care (SoC) therapy."

The registry record establishing the trial's design and population.

NCT06477653 PHASE_II UNKNOWN

Pilot phase II trial of dupilumab added on for HES that responds only partially to eosinophil-depleting biologics. Relevant to this entry because partial response to anti-IL-5 therapy is the clinical signal that the unexplained upstream driver is not purely IL-5-dependent.

Target Phenotypes: Increased total eosinophil count HP:0001880

Show evidence (1 reference)

clinicaltrials:NCT06477653 SUPPORT Human Clinical

"People aged 18 years and older who take drugs (mepolizumab, reslizumab, or benralizumab) to treat HES."

The trial's eligibility statement, which is what establishes the population this record describes: patients already on eosinophil-depleting biologics.

🐁

Animal Models

1

IL-5 transgenic (IL-5Tg) hypereosinophilic mouse

Constitutive IL-5 overexpression produces massive blood and tissue eosinophilia and progressive left ventricular dysfunction. Crossing onto an eosinophil-deficient dblGATA1 background abolishes the cardiac phenotype, which separates the eosinophil's contribution from any direct effect of IL-5 on the heart - a control that makes this model informative about the effector arm rather than about the cytokine.

Species

Mouse

Genotype

Il5 transgene under the CD3-delta promoter (IL-5Tg); eosinophil-deficient IL-5Tg-dblGATA1 used as the specificity control

Publication

PMID:37829205

Pathograph links

Eosinophil-Mediated Skin, Lung, and Gut Injury partially recapitulates fidelity: moderate observes: organism IL-5Tg mice develop extensive eosinophilic infiltration of the lung, which the paper measures directly and likens to the pulmonary infiltration seen in patients.

Limitations: Of the three organs this node names, the model demonstrates the lung only. The paper measures pulmonary infiltration in detail but reports no skin and no gastrointestinal data; its single mention of those organs is a background sentence citing other literature, not a measurement made here. The cutaneous and gut arms of this node are unmodelled by this system.

Readouts

Pulmonary leukocyte infiltration

Direction: INCREASED

Interpretation: Eosinophil-dominant infiltration of lung tissue, worsening with age.

Show evidence (1 reference)

PMID:37829205 SUPPORT Model Organism

"Thus, hypereosinophilic mice developed extensive infiltration of the lungs that worsened with age and was about 50% eosinophilic."

The measured pulmonary infiltration, with its eosinophil fraction.

Show evidence (1 reference)

PMID:37829205 SUPPORT Model Organism

"Thus, hypereosinophilic mice developed extensive infiltration of the lungs that worsened with age and was about 50% eosinophilic."

Supports the model as informative for the pulmonary arm of this node.

Granule Protein-Mediated Cytotoxic Tissue Injury partially recapitulates fidelity: moderate observes: organism Eosinophil-dependent cardiac tissue damage with transcriptional signatures of injury and remodeling.

Limitations: The model's eosinophilia has a defined genetic cause, which is exactly what idiopathic HES is defined by not having. It therefore models the effector arm of the disease and not its unexplained upstream driver. It also does not progress to the dense endomyocardial fibrosis that determines human prognosis.

Readouts

Left ventricular ejection fraction

Direction: DECREASED

Interpretation: Functional consequence of eosinophil-mediated cardiac injury, and eosinophil-dependent by the dblGATA1 cross.

Show evidence (1 reference)

PMID:37829205 SUPPORT Model Organism

"Echocardiography readouts such as LV diameters and EF were similar in IL-5TgΔdblGATA1, ΔdblGATA1, and WT mice and significantly higher in IL-5Tg mice compared to all other groups"

The eosinophil-deficient cross normalises the echocardiographic readout, attributing the deficit to eosinophils rather than to IL-5.

Cardiac tissue damage and remodeling gene expression signature

Direction: INCREASED

Interpretation: Transcriptional correlate of ongoing injury and attempted repair in the ventricle.

Show evidence (1 reference)

PMID:37829205 SUPPORT Model Organism

"Gene expression signatures showed tissue damage as well as repair and remodeling processes."

Reports the transcriptional damage-and-remodeling signature measured in the model's left ventricle.

Show evidence (1 reference)

PMID:37829205 SUPPORT Model Organism

"Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to wild type (WT) controls."

Establishes a measurable cell-level consequence of the eosinophilic cardiac environment, supporting the model as informative for this node.

{ }

Source YAML

click to show

name: Idiopathic Hypereosinophilic Syndrome
creation_date: "2026-09-06T14:30:00Z"
category: Complex
description: >-
  Idiopathic hypereosinophilic syndrome (idiopathic HES, HES-I) is the
  diagnosis-of-exclusion variant of the hypereosinophilic syndromes: persistent
  blood eosinophilia at or above 1.5 x 10^9/L with eosinophil-mediated end-organ
  damage, in a patient for whom a systematic work-up has ruled out reactive
  (secondary) causes, a clonal myeloid driver such as FIP1L1-PDGFRA, and an
  aberrant or clonal T-cell population. It is defined by what cannot be found:
  the eosinophilopoietic drive is real and sustained but its origin is unproven,
  which is why the entry's central mechanistic claim is a negative one and why
  the disorder is separated here from the myeloid (imatinib-responsive) and
  lymphocytic variants that share its downstream tissue injury. Organ damage
  follows a stereotyped route regardless of variant - eosinophil recruitment,
  degranulation, and granule-protein cytotoxicity - with endomyocardial disease
  and thromboembolism the manifestations that determine prognosis.
disease_term:
  preferred_term: idiopathic hypereosinophilic syndrome
  term:
    id: MONDO:0011895
    label: idiopathic hypereosinophilic syndrome
synonyms:
- Idiopathic HES
- HES-I
- HES of undetermined origin
parents:
- Hypereosinophilic Syndrome
- Eosinophilic Disorder
notes: >-
  Curated as a separate entry from Hypereosinophilic_Syndrome (MONDO:0015691),
  where idiopathic HES had previously been carried only as a bare has_subtypes
  stub. The split follows the promotion test used elsewhere in this repository:
  idiopathic HES has a distinct diagnostic pathway (it is constituted by an
  exclusion work-up rather than by a positive finding) and a distinct first-line
  therapy from its sibling variants - corticosteroids and anti-IL-5 biologics
  rather than imatinib, which is markedly less effective in FIP1L1-PDGFRA
  negative disease (23% vs 88%, PMID:19910029). The parent entry remains the
  place for cross-variant content.

  Caution on the disease_term binding. MONDO:0011895 is derived from OMIM:607685,
  which defines its concept around the FIP1L1-PDGFRA fusion; MONDO consequently
  asserts "has material basis in germline mutation in PDGFRA" (RO:0004003 to
  hgnc:8803) on this term, and also places it under idiopathic cardiomyopathy
  (MONDO:0005110) and familial restrictive cardiomyopathy (MONDO:0016340). Those
  axioms describe the myeloid variant, which is precisely what the modern
  ICOG-EO definition of idiopathic HES excludes (PMID:22460074). MONDO:0011895
  is nonetheless the only MONDO term whose label names this concept, so it is
  bound here and the discrepancy is recorded rather than papered over. It is
  reported as an open item in the discussions section.

  On factoring out the shared cascade. The recruitment -> degranulation ->
  granule-protein cytotoxicity -> tissue injury chain in this entry is not
  idiopathic-specific: it recurs in myeloid and lymphocytic HES, in EGPA, and in
  the organ-restricted eosinophilic diseases, and this entry's own description
  says the damage route is stereotyped across variants. There is no eosinophil
  effector module in kb/modules/ today, so both this entry and the parent
  re-derive the chain. A module would let both conform and would leave this
  entry carrying only what is genuinely idiopathic - the exclusion work-up, the
  imatinib negative, and the unexplained driver. Recorded here as a deliberate
  follow-up rather than done inline, since creating a module is a separate
  change touching several existing entries.
pathophysiology:
- name: Unexplained Eosinophil Lineage Expansion
  biological_scale: CELLULAR
  description: >-
    Sustained expansion of the eosinophil lineage without a demonstrable clonal
    myeloid lesion or an identifiable aberrant T-cell population driving it.
    This is the defining feature of the idiopathic variant and it is a negative
    characterisation: the same downstream cascade in myeloid HES traces to a
    kinase fusion and in lymphocytic HES to cytokine-producing T cells, whereas
    here a systematic work-up returns neither. The proximate driver is therefore
    unknown rather than absent.
  cell_types:
  - preferred_term: eosinophil progenitor cell
    term:
      id: CL:0000611
      label: eosinophil progenitor cell
  biological_processes:
  - preferred_term: eosinophil differentiation
    modifier: INCREASED
    term:
      id: GO:0030222
      label: eosinophil differentiation
  evidence:
  - reference: PMID:25964669
    reference_title: "How I treat hypereosinophilic syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Moreover, the etiology of the eosinophilia in HESs can be primary
      (myeloid), secondary (lymphocyte-driven), or unknown.
    explanation: >-
      Establishes the three-way aetiologic split in which the idiopathic variant
      is the "unknown" arm, distinguished from the myeloid and
      lymphocyte-driven arms rather than from a shared downstream phenotype.
  - reference: PMID:26637706
    reference_title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unfortunately, despite recent advances in molecular and immunologic
      techniques, the etiology remains unproven in the overwhelming majority of
      cases.
    explanation: >-
      Supports the claim that the eosinophilopoietic driver is unproven in most
      patients with marked eosinophilia, which is what makes the idiopathic
      category large rather than residual.
  - reference: PMID:1090795
    reference_title: "The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The etiology of HES remains unknown, as does the mechanism of tissue
      damage.
    explanation: >-
      The original clinical description of the syndrome already framed it around
      an unknown aetiology, which is the historical basis for the "idiopathic"
      designation.
  downstream:
  - target: IL-5-Dependent Eosinophil Survival and Tissue Recruitment
    causal_link_type: DIRECT
    description: >-
      Expanded eosinophil output is sustained in the periphery by IL-5-dependent
      survival and recruitment signalling.
- name: IL-5-Dependent Eosinophil Survival and Tissue Recruitment
  biological_scale: MOLECULAR
  description: >-
    IL-5 signalling through IL-5R-alpha maintains eosinophil survival, primes
    the cells, and supports their recruitment into tissue. The pathway is
    inferred to be operative in idiopathic HES chiefly from therapeutic
    reversal: neutralising IL-5 or depleting IL-5R-alpha-bearing cells lowers
    blood, marrow, and tissue eosinophilia and controls disease in
    FIP1L1-PDGFRA-negative patients.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: interleukin-5-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0038043
      label: interleukin-5-mediated signaling pathway
  - preferred_term: eosinophil chemotaxis
    modifier: INCREASED
    term:
      id: GO:0048245
      label: eosinophil chemotaxis
  evidence:
  - reference: PMID:30943337
    reference_title: "Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The numbers of bone marrow eosinophils, eosinophil precursors, and blood
      and bone marrow basophils were significantly decreased at week 12 in all
      the patients in the benralizumab group, but the number of mast cells and
      serum tryptase levels were unchanged
    explanation: >-
      Blocking IL-5R-alpha depletes marrow eosinophils and their precursors in
      PDGFRA-negative HES, which supports IL-5 receptor signalling sustaining
      the expanded lineage. Indirect because it argues from therapeutic reversal
      rather than measuring the pathway in untreated disease.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IL-5 plays a pivotal role in promoting eosinophils differentiation,
      activation, and survival
    explanation: >-
      States the three functions of IL-5 that this node asserts - lineage
      differentiation, priming, and prolonged survival.
  downstream:
  - target: Persistent Blood and Tissue Hypereosinophilia
    causal_link_type: DIRECT
  - target: Chemokine-Driven Eosinophil Recruitment into Tissue
    causal_link_type: DIRECT
    description: >-
      Primed circulating eosinophils are directed into target tissue by
      eosinophil-selective chemokine signalling.
- name: Chemokine-Driven Eosinophil Recruitment into Tissue
  biological_scale: CELLULAR
  description: >-
    Eosinophil-selective chemokines - the eotaxins CCL11, CCL24, and CCL26
    acting through CCR3, alongside CCL3 and CCL5 - direct primed eosinophils out
    of the circulation and into skin, lung, gut, and myocardium. This step is
    what converts a blood count into tissue disease, and it is the reason the
    circulating count and the tissue burden can move independently. It is
    inferred from general eosinophil biology rather than demonstrated uniquely
    in the idiopathic variant.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: eosinophil chemotaxis
    modifier: INCREASED
    term:
      id: GO:0048245
      label: eosinophil chemotaxis
  evidence:
  - reference: PMID:38611061
    reference_title: "Clinical and Therapeutic Intervention of Hypereosinophilia in the Era of Molecular Diagnosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Because of activation by CCL5 and other cytokines, CCL3 can stimulate
      eosinophilic chemotaxis, which is important for eosinophil migration.
    explanation: >-
      Establishes chemokine-driven eosinophil chemotaxis as the recruitment
      mechanism. Indirect because it describes eosinophil biology generally
      rather than measurements made in idiopathic HES.
  downstream:
  - target: Eosinophil Activation and Degranulation
    causal_link_type: DIRECT
- name: Persistent Blood and Tissue Hypereosinophilia
  biological_scale: ORGANISM
  description: >-
    Blood eosinophilia at or above 1.5 x 10^9/L persisting over weeks to months,
    accompanied by eosinophil accumulation in target tissues. Persistence rather
    than peak count is the disease-defining feature; the historical criterion
    required six months, which contemporary criteria have relaxed so that
    treatment is not withheld while damage accrues.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  evidence:
  - reference: PMID:1090795
    reference_title: "The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The syndrome is manifest by persistent and prolonged eosinophilia with
      organ damage.
    explanation: >-
      States the persistence-plus-organ-damage construct that defines the
      syndrome, as opposed to transient or asymptomatic eosinophilia.
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Idiopathic HES is characterised by peripheral blood eosinophilia (>1.5 ×
      109/L) for at least 6 months
    explanation: >-
      Gives the threshold and the historical duration requirement specifically
      for the idiopathic variant.
  downstream:
  - target: Eosinophil Activation and Degranulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39056762
      reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Indeed, persistent HE may be associated with eosinophil infiltration
        into tissues, thus leading to tissue and organ damage caused mainly by
        the release of eosinophil effector molecules
      explanation: >-
        States the step from persistent hypereosinophilia to tissue infiltration
        and effector-molecule release, which is this edge rather than either
        node alone.
- name: Eosinophil Activation and Degranulation
  biological_scale: CELLULAR
  description: >-
    Tissue-recruited eosinophils are activated and release their secondary
    granule contents - major basic protein, eosinophil cationic protein,
    eosinophil-derived neurotoxin, and eosinophil peroxidase - into the
    extracellular space. Degranulation, not eosinophil number alone, is the step
    that converts hypereosinophilia into tissue damage.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: eosinophil degranulation
    modifier: INCREASED
    term:
      id: GO:0043308
      label: eosinophil degranulation
  evidence:
  - reference: PMID:2882081
    reference_title: "Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activated eosinophils and secreted eosinophil granule proteins were most
      evident within the necrotic and later stage thrombotic lesions and were
      found mainly within the areas of acute tissue damage in the endocardium
      and in the walls of small blood vessels.
    explanation: >-
      Localises activated eosinophils and their secreted granule proteins to the
      sites of acute tissue damage in human eosinophilic endomyocardial disease.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Human eosinophils are terminally differentiated leukocytes characterized
      by cytoplasmatic granules containing biologically active molecules,
      including eosinophil peroxidase, eosinophil cationic protein, major basic
      protein, and several cytokines, such as transforming growth factor (TGF)-ß
    explanation: >-
      Names the specific granule constituents released at this step, including
      the TGF-beta that links degranulation forward to the fibrotic stage.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The biopsy specimens of mucosal ulcers from patients with HES show the
      extensive deposition of eosinophilic granule proteins in the absence of
      morphologically identifiable intact eosinophils
    explanation: >-
      Shows that granule-protein deposition in HES tissue outlasts the
      identifiable eosinophil, which is why tissue injury can continue after
      cell counts fall.
  downstream:
  - target: Granule Protein-Mediated Cytotoxic Tissue Injury
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33277190
      reference_title: "Mechanisms of toxicity mediated by neutrophil and eosinophil granule proteins."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It should be noted that an excess of granules protein release can lead
        to tissue damage of the host resulting in chronic inflammation and organ
        dysfunction.
      explanation: >-
        States the causal step from excess granule-protein release to host
        tissue damage and organ dysfunction, which is the edge itself rather
        than either node.
  - target: Eosinophil-Driven Prothrombotic State
    causal_link_type: DIRECT
    description: >-
      The same degranulation that injures tissue releases the cationic proteins
      that disable anticoagulant control.
- name: Granule Protein-Mediated Cytotoxic Tissue Injury
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Tissue Injury"
  description: >-
    Cationic granule proteins deposited in tissue are directly cytotoxic to
    parenchymal and endothelial cells, producing the initial necrotic lesion.
    In the heart this is the first of the three classically described stages of
    eosinophilic cardiac damage; elsewhere it produces the cutaneous,
    pulmonary, and gastrointestinal manifestations.
  evidence:
  - reference: PMID:2882081
    reference_title: "Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that eosinophil granule proteins are involved in
      cardiac injury, producing muscle damage and vascular injury which lead to
      the development of endomyocardial fibrosis.
    explanation: >-
      Attributes muscle and vascular injury to eosinophil granule proteins and
      links that injury forward to endomyocardial fibrosis.
  downstream:
  - target: Endocardial Injury and Mural Thrombus Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39007045
      reference_title: "The three stages of eosinophilic cardiac damage: A series of case reports."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac involvement in hypereosinophilic syndrome typically occurs in
        three stages - necrotic, thrombotic, and fibrotic.
      explanation: >-
        Orders the necrotic injury before the thrombotic stage, which is this
        edge.
  - target: Eosinophil-Mediated Skin, Lung, and Gut Injury
    causal_link_type: DIRECT
- name: Endocardial Injury and Mural Thrombus Formation
  biological_scale: TISSUE
  conforms_to: "thrombogenesis#Pathological Fibrin-Platelet Thrombus Formation"
  description: >-
    Damaged endocardium becomes a thrombogenic surface and mural thrombus forms
    over it - the thrombotic stage. This is the point at which the disease
    becomes embolic, and the source of the cardioembolic strokes that dominate
    its neurological morbidity.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:39007045
    reference_title: "The three stages of eosinophilic cardiac damage: A series of case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac involvement in hypereosinophilic syndrome typically occurs in
      three stages - necrotic, thrombotic, and fibrotic.
    explanation: >-
      Establishes the thrombotic stage as the intermediate step between the
      initial necrotic injury and the fibrotic end state.
  downstream:
  - target: Systemic Thromboembolism
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19364940
      reference_title: "Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pathology review demonstrated mural cardiac thrombus that likely caused
        cardioembolism as well as diffuse microangiopathy despite resolution of
        the hypereosinophilia.
      explanation: >-
        Traces cardioembolism to a mural cardiac thrombus at autopsy in
        idiopathic HES, which is the edge from endocardial thrombus to systemic
        embolism.
  - target: Endomyocardial Fibrosis and Restrictive Physiology
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39056762
      reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The characteristics of cardiac involvement due to HES include mural
        thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with
        congestive heart failure
      explanation: >-
        Places mural thrombi and endomyocardial fibrosis in the same cardiac
        sequence, which is the transition this edge asserts.
- name: Eosinophil-Driven Prothrombotic State
  biological_scale: MOLECULAR
  description: >-
    Degranulating eosinophils shift haemostasis toward thrombosis independently
    of any endocardial surface lesion. Eosinophil cationic protein binds heparin
    and modulates thrombomodulin, blunting the physiological anticoagulant
    pathways. This is the arm that explains what surface thrombogenicity alone
    cannot: diffuse microangiopathy, thrombosis at sites remote from the heart,
    and events that continue after the blood eosinophil count has been
    normalised.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:32184691
    reference_title: "Idiopathic Hypereosinophilia and Venous Thromboembolism: Is There a Pathophysiological or Clinical Link? Description of an Intriguing Clinical Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, the eosinophil activation and degranulation increases the
      release of eosinophil cationic protein that is able to bind heparin and
      modulate thrombomodulin so reducing the physiological anticoagulation
      mechanisms and so increasing the prothrombotic state in hypereosinophilia.
    explanation: >-
      Gives the molecular route from degranulation to a prothrombotic state,
      cited from a paper reporting idiopathic hypereosinophilia with venous
      thromboembolism.
  downstream:
  - target: Systemic Thromboembolism
    causal_link_type: DIRECT
    description: >-
      Loss of anticoagulant control permits thrombosis in vessels with no
      endocardial lesion.
- name: Systemic Thromboembolism
  biological_scale: ORGANISM
  conforms_to: "thrombogenesis#Thrombotic Vascular Occlusion and Ischemic Tissue Injury"
  description: >-
    Embolisation from intracardiac thrombus, on top of the eosinophil-driven
    prothrombotic state, produces cerebral and systemic infarction and a diffuse
    microangiopathy. Thromboembolic events can occur and progress even after the
    blood eosinophil count has been normalised, which the two converging
    upstream arms account for.
  evidence:
  - reference: PMID:26637706
    reference_title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical manifestations range from benign asymptomatic presentations to
      life-threatening complications, including endomyocardial fibrosis and
      thromboembolism.
    explanation: >-
      Names thromboembolism, alongside endomyocardial fibrosis, as one of the
      two life-threatening complications that define the severe end of the
      clinical spectrum.
  downstream:
  - target: Stroke
    causal_link_type: DIRECT
  - target: Thromboembolism
    causal_link_type: DIRECT
- name: Endomyocardial Fibrosis and Restrictive Physiology
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >-
    Organisation of the injured and thrombus-covered endocardium into dense
    fibrous scar - the fibrotic stage. The scar is not remodelled back, so this
    stage is irreversible and it converts the ventricle to restrictive
    physiology, which is why cardiac surveillance continues after the
    eosinophilia is controlled.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: INCREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:2882081
    reference_title: "Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that eosinophil granule proteins are involved in
      cardiac injury, producing muscle damage and vascular injury which lead to
      the development of endomyocardial fibrosis.
    explanation: >-
      Endomyocardial fibrosis is the stated end point of the granule
      protein-mediated cardiac injury sequence.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The characteristics of cardiac involvement due to HES include mural
      thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with
      congestive heart failure
    explanation: >-
      Names the thrombus-fibrosis-restriction sequence that this node and its
      upstream neighbour together represent.
  downstream:
  - target: Restrictive cardiomyopathy
    causal_link_type: DIRECT
  - target: Myocardial fibrosis
    causal_link_type: DIRECT
- name: Eosinophil-Mediated Skin, Lung, and Gut Injury
  biological_scale: TISSUE
  description: >-
    Granule-protein injury outside the heart produces the non-cardiac
    manifestations: pruritic and urticarial or eczematous skin disease,
    pulmonary infiltrates with cough, and gastrointestinal symptoms including
    diarrhoea. Cutaneous disease is the most common organ manifestation and is
    frequently what brings the patient to attention. The node is the injury, not
    the infiltration that precedes it - eosinophil arrival in these tissues is
    upstream, at the recruitment node.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This review illustrates that physicians should maintain a high index of
      clinical suspicion for idiopathic HES in patients presenting with
      dermatological lesions and hypereosinophilia, without an obvious cause.
    explanation: >-
      Supports cutaneous involvement as a common and clinically salient
      presentation of the idiopathic variant specifically.
  downstream:
  - target: Pruritus
    causal_link_type: DIRECT
  - target: Urticaria
    causal_link_type: DIRECT
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Pulmonary infiltrates
    causal_link_type: DIRECT
phenotypes:
- name: Increased total eosinophil count
  category: Hematologic
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Persistent peripheral blood eosinophilia at or above 1.5 x 10^9/L is the
    obligate laboratory finding; without it the diagnosis cannot be made.
  phenotype_term:
    preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
    temporality: CHRONIC
  evidence:
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Idiopathic HES is characterised by peripheral blood eosinophilia (>1.5 ×
      109/L) for at least 6 months
    explanation: >-
      States the defining eosinophil threshold for idiopathic HES.
- name: Restrictive cardiomyopathy
  category: Cardiovascular
  description: >-
    Endomyocardial fibrosis obliterates the ventricular apex and inflow tract
    and produces restrictive filling. This is the principal determinant of
    long-term prognosis.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The characteristics of cardiac involvement due to HES include mural
      thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with
      congestive heart failure
    explanation: >-
      Names restrictive cardiomyopathy directly as a characteristic of cardiac
      involvement, rather than requiring an inference from endomyocardial
      fibrosis.
- name: Myocardial fibrosis
  category: Cardiovascular
  description: >-
    Dense fibrous replacement of injured endocardium and subjacent myocardium,
    the irreversible third stage of eosinophilic cardiac damage.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  notes: >-
    HPO has no term for endomyocardial fibrosis as such. HP:0006685 Endocardial
    fibrosis was considered and is curated separately below, because the lesion
    begins in the endocardium; HP:0001685 Myocardial fibrosis is kept here for
    the extension into myocardium that gives the disease its restrictive
    physiology. preferred_term is left at the ontology label rather than
    narrowed beyond what either term supports.
  evidence:
  - reference: PMID:2882081
    reference_title: "Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that eosinophil granule proteins are involved in
      cardiac injury, producing muscle damage and vascular injury which lead to
      the development of endomyocardial fibrosis.
    explanation: >-
      Documents endomyocardial fibrosis as the histopathological end point of
      eosinophil-mediated cardiac injury.
- name: Endocardial fibrosis
  category: Cardiovascular
  description: >-
    Fibrous thickening of the endocardium, the compartment where eosinophilic
    cardiac damage begins before extending into myocardium.
  phenotype_term:
    preferred_term: Endocardial fibrosis
    term:
      id: HP:0006685
      label: Endocardial fibrosis
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The characteristics of cardiac involvement due to HES include mural
      thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with
      congestive heart failure
    explanation: >-
      Names endomyocardial fibrosis as a characteristic of HES cardiac
      involvement; the endocardial component is bound here and the myocardial
      component separately.
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    The functional end state of restrictive physiology from endomyocardial
    fibrosis.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The characteristics of cardiac involvement due to HES include mural
      thrombi, endomyocardial fibrosis, and restrictive cardiomyopathy with
      congestive heart failure
    explanation: >-
      Names congestive heart failure as the outcome of the restrictive
      cardiomyopathy in HES.
- name: Thromboembolism
  category: Vascular
  description: >-
    Thrombus formation on damaged endocardium and in the microvasculature, with
    embolisation to systemic beds.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:26637706
    reference_title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical manifestations range from benign asymptomatic presentations to
      life-threatening complications, including endomyocardial fibrosis and
      thromboembolism.
    explanation: >-
      Names thromboembolism as a life-threatening manifestation of the
      syndrome.
- name: Peripheral neuropathy
  category: Neurologic
  description: >-
    Peripheral nerve involvement, distinct from the cardioembolic central
    disease also curated here. Note it is more characteristic of EGPA, one of
    this entry's differentials, than of idiopathic HES.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The typical features of HES-related organ damage include fibrosis,
      thrombosis, cutaneous (skin or mucosa) erythema, edema/angioedema,
      blisters, ulceration, or eczema, pulmonary manifestations, GI involvement,
      peripheral or central neuropathy with neurological deficits, and
      eosinophilic vasculitis
    explanation: >-
      Lists peripheral neuropathy with neurological deficits among the typical
      features of HES-related organ damage. Quoted up to the citation bracket,
      which the reference validator normalizes away.
- name: Stroke
  category: Neurologic
  description: >-
    Cardioembolic and microangiopathic cerebral infarction, which may progress
    despite control of the blood eosinophil count.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:19364940
    reference_title: "Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging of the brain revealed bihemispheric ischemic changes in and beyond
      the watershed distributions.
    explanation: >-
      Documents bihemispheric cerebral ischaemic injury in a patient with
      fulminant idiopathic HES.
- name: Encephalopathy
  category: Neurologic
  description: >-
    Diffuse cerebral dysfunction, which in the fulminant presentation is rapidly
    progressive and accompanies multifocal ischaemic injury.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:19364940
    reference_title: "Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 48-year-old right-handed man with hypereosinophilia, rapidly
      progressive encephalopathy, and focal neurological deficits who died 22
      days after presentation.
    explanation: >-
      Reports rapidly progressive encephalopathy with focal deficits in
      idiopathic HES.
- name: Pruritus
  category: Dermatologic
  description: >-
    Itch accompanying eosinophilic cutaneous infiltration; frequently intractable
    and a common presenting complaint.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:40283978
    reference_title: Biologic Agents in Idiopathic Hypereosinophilic Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Skin manifestations were the most common, reported in 69% of patients,
      followed by respiratory (44%) and gastrointestinal (38%) manifestations.
    explanation: >-
      Quantifies skin involvement as the most common organ
      manifestation, which is the observation behind this phenotype. Note this is HES-wide review prose, not the citing paper's own
      idiopathic-HES cohort.
- name: Urticaria
  category: Dermatologic
  description: >-
    Urticarial eruption, one of the cutaneous morphologies eosinophilic skin
    disease takes. Reported for HES generally rather than measured in an
    idiopathic-only series.
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:40283978
    reference_title: Biologic Agents in Idiopathic Hypereosinophilic Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      The most common symptomatology involved in HES includes cutaneous (e.g.,
      rash, urticaria, angioedema), pulmonary (e.g., shortness of breath, cough,
      pulmonary infiltrates, pleural effusion), gastrointestinal (e.g.,
      abdominal pain, nausea, vomiting), constitutional (e.g., fever, fatigue),
      cardiovascular (e.g., myocardial ischemia, arrhythmias), and neurological
      (e.g., numbness, weakness, muscle atrophy) manifestations.
    explanation: >-
      Names urticaria among the cutaneous manifestations of HES. Note this is HES-wide review prose, not the citing paper's own
      idiopathic-HES cohort.
- name: Pulmonary infiltrates
  category: Respiratory
  description: >-
    Eosinophilic pulmonary infiltration, which resolves on eosinophil-directed
    therapy.
  phenotype_term:
    preferred_term: Pulmonary infiltrates
    term:
      id: HP:0002113
      label: Pulmonary infiltrates
  evidence:
  - reference: PMID:40283978
    reference_title: Biologic Agents in Idiopathic Hypereosinophilic Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Skin manifestations were the most common, reported in 69% of patients,
      followed by respiratory (44%) and gastrointestinal (38%) manifestations.
    explanation: >-
      Quantifies respiratory involvement at 44% of patients, and
      the same sentence's surrounding text names pulmonary infiltrates among
      those manifestations. Note this is HES-wide review prose, not the citing paper's own
      idiopathic-HES cohort.
- name: Diarrhea
  category: Gastrointestinal
  description: >-
    Gastrointestinal symptoms from eosinophilic infiltration of the gut mucosa;
    biopsy eosinophilia is depleted by anti-IL-5R therapy.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:30943337
    reference_title: "Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tissue samples obtained at week 24 showed nearly complete depletion of
      eosinophils (≤1 eosinophil per high-power field) in a total of 52
      gastrointestinal biopsy samples obtained from the seven patients with
      gastrointestinal eosinophilia
    explanation: >-
      Documents gastrointestinal eosinophilia in a PDGFRA-negative HES trial
      cohort. That cohort is a superset of idiopathic HES, so the claim is read
      down onto the idiopathic subset rather than measured in it.
- name: Asthma
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Asthma was present in most patients in the one idiopathic-HES-only series
    available, and its control tracked the eosinophil count on anti-IL-5
    therapy. Read the frequency with care: n=11, and the cohort was assembled
    from patients started on anti-IL-5 biologics, which in that centre are
    given to HES patients with concomitant severe asthma. The rate is therefore
    inflated by the referral route as well as being a small-cohort observation
    rather than a population estimate.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:40283978
    reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asthma was present in the majority of them (n = 8, 72.7%); four patients
      (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients
      (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid
      angioedema.
    explanation: >-
      Reports asthma in 8 of 11 (72.7%) patients in a
      cohort assembled specifically as idiopathic HES, rather than as mixed
      HES.
- name: Pleural effusion
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Eosinophilic pleural effusion, reported in roughly a third of one idiopathic
    HES series.
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: PMID:40283978
    reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asthma was present in the majority of them (n = 8, 72.7%); four patients
      (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients
      (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid
      angioedema.
    explanation: >-
      Reports eosinophilic pleural effusions in 4 of
      11 (36.4%) patients with idiopathic HES.
- name: Arrhythmia
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Cardiac rhythm disturbance. The cited series reports arrhythmias as a
    presenting feature but records no permanent organ damage attributable to
    tissue eosinophilia, so it does not itself establish an eosinophilic
    myocardial cause in these patients.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:40283978
    reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asthma was present in the majority of them (n = 8, 72.7%); four patients
      (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients
      (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid
      angioedema.
    explanation: >-
      Reports cardiac arrhythmias in 2 of 11 (18.2%)
      patients with idiopathic HES.
- name: Angioedema
  category: Dermatologic
  description: >-
    Localised subcutaneous or submucosal swelling; in idiopathic HES it is
    reported but uncommon, in contrast to episodic angioedema with eosinophilia
    (Gleich syndrome), where it defines the entity.
  phenotype_term:
    preferred_term: Angioedema
    term:
      id: HP:0100665
      label: Angioedema
  evidence:
  - reference: PMID:40283978
    reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asthma was present in the majority of them (n = 8, 72.7%); four patients
      (n = 4, 36.4%) presented with eosinophilic pleural effusions, two patients
      (n = 2, 18.2%) with cardiac arrhythmias, and one with bilateral eyelid
      angioedema.
    explanation: >-
      Reports bilateral eyelid angioedema in 1 of 11
      patients with idiopathic HES, supporting angioedema as an occasional
      rather than characteristic feature.
genetic:
- name: FIP1L1-PDGFRA negative by definition
  gene_term:
    preferred_term: PDGFRA
    term:
      id: hgnc:8803
      label: PDGFRA
  association: Required to be absent for the idiopathic designation
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  notes: >-
    Recorded as a definitional exclusion, not as a disease gene. The presence of
    a FIP1L1-PDGFRA fusion reclassifies the patient into the myeloid variant and
    out of this entry, and it changes first-line therapy to imatinib. The gene
    is listed here so the exclusion is machine-queryable; see the caution in the
    entry-level notes about MONDO:0011895 carrying a PDGFRA germline-basis axiom
    that contradicts this.
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived
      growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive,
    explanation: >-
      Quantifies the FIP1L1-PDGFRA-positive minority that is excluded from the
      idiopathic category by testing.
biochemical:
- name: Absolute eosinophil count
  presence: INCREASED
  context: >-
    The measurement this entry is defined by, and the one the exclusion workup is built
    around. A count at or above 1,500 cells/uL, recorded more than once and with organ
    damage attributable to it, becomes idiopathic disease only once reactive, clonal and
    lymphocyte-variant causes have been ruled out.
  notes: >-
    The cited sources state these boundaries as 0.05, 0.5 and 1.5 x 10^9/L. This record
    converts them to cells/uL, multiplying by 1,000, so the values sit on the same scale
    as the other blood eosinophil records in this knowledge base; each snippet keeps its
    source's own form. The Hypereosinophilic_Syndrome entry carries the same measurement
    for the syndrome as a whole. Unlike the three markers below it, which are
    discriminating rather than diagnostic, this count is the positive criterion; the
    others are what must be unrevealing.
  biomarker_term:
    preferred_term: absolute blood eosinophil count
    term:
      id: NCIT:C188680
      label: Absolute Eosinophil Count
  readouts:
  - target: Persistent Blood and Tissue Hypereosinophilia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The blood count is the accessible half of this node. It measures the circulating
      compartment; the tissue hypereosinophilia the node also names is established by
      biopsy, so a count inside the reference interval does not exclude it.
    evidence:
    - reference: PMID:40283978
      reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "More specifically, the diagnostic criteria for idiopathic HES include sustained hypereosinophilia (eosinophil count ≥ 1.5 × 109/L) recorded more than once in a minimum time interval of two weeks, ≥10% eosinophilia, organ failure attributable to the eosinophilia or tissue infiltration by eosinophils, and exclusion of reactive eosinophilia, lymphocyte-variant HES, chronic eosinophilic leukemia, and other myeloid or lymphoid neoplasm [4]."
      explanation: "States the count and its persistence as the positive criterion, alongside the organ damage and the exclusions that make the disease idiopathic."
  reference_ranges:
  - loinc_term:
      id: LOINC:26449-9
      label: Eosinophils [#/volume] in Blood
    lower_bound: 50
    upper_bound: 500
    unit: cells/uL
    population: adults
    notes: >-
      A genuine laboratory reference interval, and worth distinguishing from the
      therapy-stratification bands on the Asthma blood eosinophil record, which asserts
      no interval at all: here a source states the normal range directly. The bands below
      are the diagnostic tiers of the eosinophilic-disorder classification, not severity
      grades. Because the sources define eosinophilia as at or above 0.5 x 10^9/L, a
      result of exactly 500 cells/uL falls in the eosinophilia band rather than inside
      this interval.
    evidence:
    - reference: PMID:39056762
      reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Peripheral blood absolute eosinophil count (AEC) normal value ranges between 0.05 and 0.5 × 109/L, while reference values for mature eosinophils in bone marrow aspirates are between 1% and 6% [1,6,7,8]."
      explanation: "States the adult laboratory reference interval this record carries, as 0.05 to 0.5 x 10^9/L."
    - reference: PMID:38611061
      reference_title: "Clinical and Therapeutic Intervention of Hypereosinophilia in the Era of Molecular Diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "A circulating eosinophil count of ≥0.5 × 109/L is defined as eosinophilia."
      explanation: "An independent source for the 500 cells/uL boundary, above which a count is eosinophilia rather than normal."
    interpretation_bands:
    - name: Below 500 cells/uL
      upper_bound: 500
      unit: cells/uL
      abnormal_flag: NORMAL
      interpretation: >-
        At or below the reference interval's upper limit. Results below the interval's
        50 cells/uL floor fall here too, and are deliberately not graded LOW: no cited
        source addresses eosinopenia, and in treated disease a near-zero count is the
        therapeutic goal rather than an abnormality. On treatment this band is also the
        target: hematologic remission is defined as a count below 0.5 x 10^9/L, so a
        result here in a treated patient reports response rather than absence of disease.
    - name: 500 to 1499 cells/uL
      lower_bound: 500
      upper_bound: 1500
      unit: cells/uL
      abnormal_flag: HIGH
      phenotype_term:
        preferred_term: Increased total eosinophil count
        term:
          id: HP:0001880
          label: Increased total eosinophil count
      interpretation: >-
        Eosinophilia by the ICOG-EO classification, but below the hypereosinophilia
        threshold this syndrome is defined by. A count in this band is common and mostly
        reactive; on its own it does not support the diagnosis.
    - name: 1500 cells/uL or greater
      lower_bound: 1500
      unit: cells/uL
      abnormal_flag: HIGH
      phenotype_term:
        preferred_term: Severely increased total eosinophil count
        term:
          id: HP:0032061
          label: Severely increased total eosinophil count
      interpretation: >-
        Hypereosinophilia, and the entry criterion for this diagnosis. A single count here
        is not sufficient: the criteria require it recorded more than once at least two
        weeks apart, with attributable organ damage, and with reactive, clonal and
        lymphocyte-variant causes excluded.
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "According to the classification of eosinophilic disorders proposed in 2011 by the International Cooperative Working Group on Eosinophil Disorders (ICOG-EO) and revised in 2022, blood eosinophilia is defined by an AEC above 0.5 × 109/L, while hypereosinophilia (HE) necessitates an AEC of ≥1.5 × 109/L [1,6]."
    explanation: "The source of both band boundaries: eosinophilia above 0.5 x 10^9/L, hypereosinophilia at or above 1.5 x 10^9/L."
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In the case of severe organ damage, a further goal is to achieve hematologic remission (blood eosinophil count < 0.5 × 109/L) to avoid relapse."
    explanation: "Establishes the same count as the treatment target, which is why the normal band carries a monitoring reading as well as a diagnostic one."
- name: Serum tryptase
  presence: NORMAL
  biomarker_term:
    preferred_term: tryptase
    term:
      id: NCIT:C120030
      label: Tryptase
  notes: >-
    Discriminating rather than diagnostic. An elevated tryptase points away from
    this entry, toward clonal or myeloid eosinophilia and mastocytosis, so it is
    part of what must be unrevealing before the idiopathic designation is
    applied.
  evidence:
  - reference: PMID:37122022
    reference_title: French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The workup should also include basal tryptase determination (suggestive of
      mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are
      suggestive of clonal eosinophilia), plasma protein electrophoresis
      (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,
      angioimmunoblastic T-cell lymphoma or chronic parasitic infection) and
      total IgE (although the specificity is limited, elevated levels suggest
      reactive eosinophilia).
    explanation: >-
      States that basal tryptase is part of the work-up and that
      elevation suggests mastocytosis or clonal HE/HES, which is the exclusion
      this entry depends on.
- name: Serum vitamin B12
  presence: NORMAL
  biomarker_term:
    preferred_term: vitamin B12
    term:
      id: NCIT:C939
      label: Cobalamin
  notes: >-
    Paired with tryptase as a myeloid-variant discriminator; elevation of both
    suggests clonal eosinophilia rather than idiopathic disease.
  evidence:
  - reference: PMID:37122022
    reference_title: French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The workup should also include basal tryptase determination (suggestive of
      mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are
      suggestive of clonal eosinophilia), plasma protein electrophoresis
      (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,
      angioimmunoblastic T-cell lymphoma or chronic parasitic infection) and
      total IgE (although the specificity is limited, elevated levels suggest
      reactive eosinophilia).
    explanation: >-
      States that elevated B12 together with elevated tryptase
      suggests clonal eosinophilia, the finding whose absence this entry
      requires.
- name: Cardiac troponin T
  presence: INCREASED
  biomarker_term:
    preferred_term: troponin T
    term:
      id: NCIT:C38041
      label: Troponin T
  notes: >-
    The one biomarker here that tracks this disease's own tissue injury rather
    than excluding a rival diagnosis. It is reported to rise from disease onset
    even when echocardiography is still normal, which makes it the earliest
    available signal of the cardiac damage that determines prognosis.
  evidence:
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Elevated cardiac troponin T levels, indicative of myocyte degeneration, as
      well as NT-pro-BNP, serve as a prognostic marker
    explanation: >-
      Establishes troponin T as a prognostic marker of myocyte degeneration in
      HES.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      and are typically present from the disease onset, even with normal
      echocardiographic findings
    explanation: >-
      Supports troponin elevation preceding echocardiographic change, which is
      why it is useful as an early cardiac signal.
prevalence:
- population: Worldwide, all HES variants
  measure_type: UNKNOWN
  prevalence_class: RARE
  rate_low: 0.036
  rate_high: 6.3
  notes: >-
    SEER-derived figures quoted in an idiopathic-HES-focused review, but the
    numbers themselves span all HES variants, not idiopathic disease alone. The
    source calls them morbidity without naming a measure type, and the 175-fold
    spread between the bounds is itself the finding: population incidence and
    prevalence of idiopathic HES are not established. Recorded with
    measure_type UNKNOWN for that reason. rate_per_100000 is deliberately left
    empty: there is no point estimate to put in it, only the span in rate_low
    and rate_high, and the qualitative tiers are reserved for records without a
    populated rate.
  evidence:
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Surveillance, Epidemiology, and End Results data show that the
      estimated morbidity is between 0.036/100 000 and 6.3/100 000 whereas the
      mortality is about 9.3%.
    explanation: >-
      Gives the only population-level figures available, with the spread that
      makes them provisional.
- population: Worldwide, idiopathic variant (sex ratio)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No sex predominance is established for the idiopathic variant. Historic HES
    series reported a marked male excess, but that was driven by the
    nearly male-restricted FIP1L1-PDGFRA neoplasm, which is excluded from this
    entry.
  evidence:
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Based on the limited data, this variant has no clear gender predominance
      with an estimated male to female sex ratio of 1:1.
    explanation: >-
      States the absence of a sex predominance specifically for the idiopathic
      variant.
diagnosis:
- name: Systematic exclusion work-up
  description: >-
    The diagnosis is constituted by the work-up rather than confirmed by it. A
    minimum evaluation requires bone marrow karyotyping, PDGFRA testing,
    lymphocyte immunophenotyping, and T-cell receptor gene rearrangement
    studies, in addition to exclusion of reactive causes such as helminth
    infection, drug reaction, allergy, vasculitis, and malignancy. Idiopathic
    HES is assigned only when all of these are unrevealing.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:36756990
    reference_title: "Diagnostic spectrum of hypereosinophilia based on bone marrow pathology: 10 years' experience at a tertiary care hospital."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The work-up of patients in whom ruled out the common secondary causes of
      HE requires a systematic but sufficient approach including at a minimum BM
      karyotyping, PDGFRA testing, lymphocyte immunophenotyping and TCR gene
      rearrangement.
    explanation: >-
      Specifies the minimum diagnostic work-up that must be negative before the
      idiopathic designation is applied.
  - reference: PMID:37122022
    reference_title: French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The workup should also include basal tryptase determination (suggestive of
      mastocytosis or clonal HE/HES), vitamin B12 (elevated B12 and tryptase are
      suggestive of clonal eosinophilia), plasma protein electrophoresis
      (polyclonal hypergammaglobulinemia is suggestive of IgG4-related disease,
      angioimmunoblastic T-cell lymphoma or chronic parasitic infection) and
      total IgE (although the specificity is limited, elevated levels suggest
      reactive eosinophilia).
    explanation: >-
      Adds the serological arm of the work-up - tryptase, B12,
      protein electrophoresis, total IgE - alongside the marrow and molecular
      testing, each element pointing at a rival diagnosis to exclude.
- name: Consensus criteria and terminology
  description: >-
    The 2011 Working Conference on Eosinophil Disorders and Syndromes
    (ICOG-EO) unified previously divergent classifications and separated
    hypereosinophilia of undetermined significance - eosinophilia without organ
    damage - from hypereosinophilic syndrome proper. Idiopathic HES sits inside
    the syndrome category and requires demonstrable eosinophil-mediated organ
    damage.
  notes: >-
    No diagnosis_term is bound. This record states a classification convention,
    not a procedure performed on a patient, and NCIT:C18020 Diagnostic Procedure
    would assert something false about it.
  evidence:
  - reference: PMID:22460074
    reference_title: "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients in whom no underlying disease or hypereosinophilic syndrome
      is found, the term hypereosinophilia of undetermined significance is
      introduced.
    explanation: >-
      Draws the boundary between idiopathic HES and hypereosinophilia of
      undetermined significance, which is the distinction organ damage makes.
  - reference: PMID:22460074
    reference_title: "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The expert group agreed on unifying terminologies and criteria and a
      classification that delineates various forms of hypereosinophilia,
      including primary and secondary variants based on specific hematologic and
      immunologic conditions, and various forms of the hypereosinophilic
      syndrome.
    explanation: >-
      Establishes the consensus classification within which the idiopathic
      variant is defined against the primary and secondary variants.
- name: Contemporary threshold and the obsolete six-month rule
  description: >-
    The historical Chusid criterion required six months of eosinophilia before
    the diagnosis could be made. That waiting period is no longer applied when
    organ damage is already present, because the fibrotic and thromboembolic
    complications that determine outcome accrue during it. Persistence is now
    confirmed on repeat measurement over weeks rather than months, and
    etiological work-up runs in parallel with organ-damage assessment rather
    than before it.
  notes: >-
    No diagnosis_term is bound: this record is criteria history, not a
    procedure. The six-month figure is cited to a source that states it, rather
    than to Chusid's own abstract, which describes persistence without naming a
    duration.
  evidence:
  - reference: PMID:40283978
    reference_title: Biologic Agents in Idiopathic Hypereosinophilic Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The current definition of HES requires persistent eosinophilia with a
      corresponding absolute eosinophil count of >1.5 × 109/L for a shorter
      period of 2 to 4 weeks (compared to the historical criterion of more than
      6 months outlined by Chusid and colleagues in 1975), and concomitant
      tissue damage
    explanation: >-
      States both the historical six-month criterion and the 2-to-4-week window
      that replaced it.
  - reference: PMID:40283978
    reference_title: Biologic Agents in Idiopathic Hypereosinophilic Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More specifically, the diagnostic criteria for idiopathic HES include
      sustained hypereosinophilia (eosinophil count ≥ 1.5 × 109/L) recorded more
      than once in a minimum time interval of two weeks, ≥10% eosinophilia,
      organ failure attributable to the eosinophilia or tissue infiltration by
      eosinophils, and exclusion of reactive eosinophilia, lymphocyte-variant
      HES, chronic eosinophilic leukemia, and other myeloid or lymphoid
      neoplasm
    explanation: >-
      The full contemporary criteria set stated for idiopathic HES specifically,
      including the >=10% of leukocytes threshold and the repeat-measurement
      interval.
  - reference: PMID:39056762
    reference_title: "Managing Patients with Hypereosinophilic Syndrome: A Statement from the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac assessment should include a heart ultrasound as a routine
      examination due to the lack of symptoms in the early phases of heart
      involvement.
    explanation: >-
      Supports assessing organ damage up front rather than waiting, because
      early cardiac involvement is asymptomatic.
treatments:
- name: Systemic Corticosteroid Therapy
  description: >-
    Oral corticosteroids are first-line for idiopathic HES and produce a
    response in the large majority of patients, but most require indefinite
    maintenance dosing and the cumulative toxicity of that maintenance is the
    principal reason steroid-sparing agents are sought.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Persistent Blood and Tissue Hypereosinophilia
    description: >-
      Corticosteroids suppress eosinophil production and survival and rapidly
      lower the circulating count.
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corticosteroid monotherapy induced complete or partial responses at 1
      month in 85% (120/141) of patients with most remaining on maintenance
      doses (median, 10 mg prednisone equivalent daily for 2 months to 20
      years).
    explanation: >-
      Quantifies both the high first-line response rate and the long-term
      maintenance dependence that motivates steroid-sparing therapy.
  - reference: PMID:25964669
    reference_title: "How I treat hypereosinophilic syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although corticosteroids remain the first-line therapy for most forms of
      HESs, the availability of an increasing number of novel therapeutic
      agents, including tyrosine kinase inhibitors and monoclonal antibodies,
      has necessarily altered the approach to treatment of HESs.
    explanation: >-
      Confirms corticosteroids as first-line therapy in current practice.
- name: Mepolizumab
  description: >-
    Anti-IL-5 monoclonal antibody, and the only biologic approved for HES. In
    FIP1L1-PDGFRA-negative HES with recurrent flares it halves the proportion of
    patients flaring, and in prednisone-dependent patients it permits
    substantial steroid tapering. Note what that trial population is:
    FIP1L1-PDGFRA negative is not a synonym for idiopathic, since it also
    contains lymphocytic-variant and non-PDGFRA myeloid disease. Idiopathic HES
    is its largest component and the small idiopathic-only cohort below points
    the same way, but the phase III result is not an idiopathic-specific
    measurement.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mepolizumab
      term:
        id: NCIT:C157376
        label: Mepolizumab
  target_mechanisms:
  - target: IL-5-Dependent Eosinophil Survival and Tissue Recruitment
    description: >-
      Neutralising circulating IL-5 removes the survival and recruitment signal
      the expanded eosinophil population depends on.
  evidence:
  - reference: PMID:32956756
    reference_title: "Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proportion of patients experiencing 1 or more flares/withdrawing from
      the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs
      30 of 54 [56%]; P = .002).
    explanation: >-
      Phase III efficacy result in FIP1L1-PDGFRA-negative HES. That trial
      population is a superset of this entry's disease - it also admits
      lymphocytic-variant and non-PDGFRA myeloid HES - so the result is read
      down onto the idiopathic subset rather than measured in it.
  - reference: PMID:18344568
    reference_title: "Treatment of patients with the hypereosinophilic syndrome with mepolizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary end point was reached in 84% of patients in the mepolizumab
      group, as compared with 43% of patients in the placebo group (hazard
      ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no
      increase in clinical activity of the hypereosinophilic syndrome.
    explanation: >-
      Establishes the corticosteroid-sparing effect in prednisone-dependent
      FIP1L1-PDGFRA-negative patients.
  - reference: PMID:40283978
    reference_title: "Biologic Agents in Idiopathic Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with concomitant asthma (n = 8) experienced elimination of
      asthma flares, asthma control (ACQ < 0.75), functional improvement (mean
      ΔFEV1: 857 ± 594 mL), and an 82% reduction in oral corticosteroids
    explanation: >-
      Real-world corticosteroid sparing in a cohort characterised specifically
      as idiopathic HES. Uncontrolled and small (11 patients across mepolizumab
      and benralizumab), so it corroborates the trial result in this exact
      population rather than adding independent efficacy evidence.
- name: Benralizumab
  description: >-
    Afucosylated anti-IL-5R-alpha monoclonal antibody that depletes
    IL-5R-alpha-bearing cells by antibody-dependent cellular cytotoxicity. In
    PDGFRA-negative HES it depletes blood, marrow, and tissue eosinophils and
    permits tapering of background therapy, with responses sustained to 48 weeks
    in most patients. As with mepolizumab, that trial population is a superset
    of idiopathic HES rather than a synonym for it.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: benralizumab
      term:
        id: NCIT:C88594
        label: Benralizumab
  target_mechanisms:
  - target: IL-5-Dependent Eosinophil Survival and Tissue Recruitment
    description: >-
      Depletion of IL-5R-alpha-bearing eosinophils and their marrow precursors
      removes the effector population rather than only its survival signal.
  evidence:
  - reference: PMID:30943337
    reference_title: "Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the randomized phase, the primary end point occurred in more
      patients in the benralizumab group than in the placebo group (9 of 10
      patients [90%] vs. 3 of 10 patients [30%], P = 0.02).
    explanation: >-
      Phase II efficacy result on eosinophil reduction in PDGFRA-negative HES.
  - reference: PMID:30943337
    reference_title: "Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the open-label phase, clinical and hematologic responses were
      observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14
      of 19 patients (74%); in the latter group, in 9 of 14 patients (64%),
      background therapies could be tapered.
    explanation: >-
      Documents durability of response and the background-therapy sparing
      effect.
- name: Hydroxyurea
  description: >-
    Conventional second-line cytoreductive agent used when corticosteroids fail
    or cannot be tapered. Effective, but toxicity limits its use, which is the
    gap the anti-IL-5 agents fill.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxyurea
      term:
        id: CHEBI:44423
        label: hydroxyurea
  target_mechanisms:
  - target: Persistent Blood and Tissue Hypereosinophilia
    description: >-
      Cytoreduction of the expanded eosinophil population.
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were
      also effective, but their use was limited by toxicity.
    explanation: >-
      Establishes hydroxyurea's efficacy and the toxicity ceiling on its
      use.
- name: Interferon Alfa
  description: >-
    Second-line immunomodulatory therapy, curated separately from hydroxyurea
    because it is a recombinant protein rather than a small molecule and the two
    are not interchangeable in a modality or agent query. Effective, with the
    same toxicity ceiling.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon alfa
      term:
        id: CHEBI:753470
        label: interferon alfa
  target_mechanisms:
  - target: Persistent Blood and Tissue Hypereosinophilia
    description: >-
      Immunomodulatory suppression of the expanded eosinophil population.
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were
      also effective, but their use was limited by toxicity.
    explanation: >-
      Establishes interferon alfa's efficacy and the toxicity ceiling on
      its use.
- name: Empirical Antiparasitic Therapy Before Corticosteroids
  description: >-
    A safety step rather than a treatment for the disease. Corticosteroids given
    to a patient with unrecognised strongyloidiasis can precipitate
    hyperinfection, and strongyloidiasis is itself a cause of eosinophilia that
    must be excluded before the idiopathic label is applied. Guidelines offer
    empirical ivermectin depending on exposure history and endemic-area risk,
    while noting that the value of empirical treatment in genuinely unexplained
    chronic hypereosinophilia is disputed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ivermectin
      term:
        id: CHEBI:6078
        label: ivermectin
  evidence:
  - reference: PMID:37122022
    reference_title: French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Depending on the patient's condition and risk factors and the endemic
      areas visited, an antiparasitic treatment consisting of all or some of the
      following compounds may be offered:D1 ivermectin: 200 µg/kg on an empty
      stomach (possibly followed by a second dose at D2 or D15 in case of
      diagnostic confirmation of strongyloidiasis).
    explanation: >-
      Gives the guideline's empirical antiparasitic regimen and the
      risk-stratified basis for offering it.
  - reference: PMID:37122022
    reference_title: French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the absence of available studies, the usefulness of empirical
      antiparasitic treatment in unexplained chronic HE is disputed.
    explanation: >-
      Records that the practice is contested rather than settled, so the entry
      does not overstate it.
- name: Imatinib
  description: >-
    Tyrosine kinase inhibitor and the treatment of choice for the
    FIP1L1-PDGFRA-positive myeloid variant. It is included here as a negative
    therapeutic claim: in FIP1L1-PDGFRA-negative disease, which includes
    idiopathic HES, the response rate falls to roughly a quarter. The
    contrast is the main therapeutic reason this entry is separated from the
    myeloid variant. It carries no target_mechanisms deliberately: the claim is
    that it does not act on this disease's mechanisms, so linking it to one
    would assert the opposite of what the evidence says.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: imatinib mesylate
      term:
        id: NCIT:C1687
        label: Imatinib Mesylate
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imatinib (used in 68 patients) was more effective in patients with the
      FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001).
    explanation: >-
      Refutes imatinib as an effective therapy for FIP1L1-PDGFRA-negative
      disease: the response rate in the negative group is 23% against 88% in the
      positive group.
animal_models:
- name: IL-5 transgenic (IL-5Tg) hypereosinophilic mouse
  species: Mouse
  genotype: Il5 transgene under the CD3-delta promoter (IL-5Tg); eosinophil-deficient IL-5Tg-dblGATA1 used as the specificity control
  publication: PMID:37829205
  description: >-
    Constitutive IL-5 overexpression produces massive blood and tissue
    eosinophilia and progressive left ventricular dysfunction. Crossing onto an
    eosinophil-deficient dblGATA1 background abolishes the cardiac phenotype,
    which separates the eosinophil's contribution from any direct effect of
    IL-5 on the heart - a control that makes this model informative about the
    effector arm rather than about the cytokine.
  modeled_mechanisms:
  - target: Eosinophil-Mediated Skin, Lung, and Gut Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      IL-5Tg mice develop extensive eosinophilic infiltration of the lung, which
      the paper measures directly and likens to the pulmonary infiltration seen
      in patients.
    limitations: >-
      Of the three organs this node names, the model demonstrates the lung only.
      The paper measures pulmonary infiltration in detail but reports no skin
      and no gastrointestinal data; its single mention of those organs is a
      background sentence citing other literature, not a measurement made here.
      The cutaneous and gut arms of this node are unmodelled by this system.
    readouts:
    - name: Pulmonary leukocyte infiltration
      target: Eosinophil-Mediated Skin, Lung, and Gut Injury
      direction: INCREASED
      interpretation: >-
        Eosinophil-dominant infiltration of lung tissue, worsening with age.
      evidence:
      - reference: PMID:37829205
        reference_title: "Hypereosinophilia causes progressive cardiac pathologies in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Thus, hypereosinophilic mice developed extensive infiltration of the
          lungs that worsened with age and was about 50% eosinophilic.
        explanation: >-
          The measured pulmonary infiltration, with its eosinophil fraction.
    evidence:
    - reference: PMID:37829205
      reference_title: "Hypereosinophilia causes progressive cardiac pathologies in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, hypereosinophilic mice developed extensive infiltration of the
        lungs that worsened with age and was about 50% eosinophilic.
      explanation: >-
        Supports the model as informative for the pulmonary arm of this node.
  - target: Granule Protein-Mediated Cytotoxic Tissue Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Eosinophil-dependent cardiac tissue damage with transcriptional signatures
      of injury and remodeling.
    limitations: >-
      The model's eosinophilia has a defined genetic cause, which is exactly
      what idiopathic HES is defined by not having. It therefore models the
      effector arm of the disease and not its unexplained upstream driver. It
      also does not progress to the dense endomyocardial fibrosis that
      determines human prognosis.
    readouts:
    - name: Left ventricular ejection fraction
      target: Granule Protein-Mediated Cytotoxic Tissue Injury
      direction: DECREASED
      interpretation: >-
        Functional consequence of eosinophil-mediated cardiac injury, and
        eosinophil-dependent by the dblGATA1 cross.
      evidence:
      - reference: PMID:37829205
        reference_title: "Hypereosinophilia causes progressive cardiac pathologies in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Echocardiography readouts such as LV diameters and EF were similar in
          IL-5TgΔdblGATA1, ΔdblGATA1, and WT mice and significantly higher in
          IL-5Tg mice compared to all other groups
        explanation: >-
          The eosinophil-deficient cross normalises the echocardiographic
          readout, attributing the deficit to eosinophils rather than to IL-5.
    - name: Cardiac tissue damage and remodeling gene expression signature
      target: Granule Protein-Mediated Cytotoxic Tissue Injury
      direction: INCREASED
      interpretation: >-
        Transcriptional correlate of ongoing injury and attempted repair in the
        ventricle.
      evidence:
      - reference: PMID:37829205
        reference_title: "Hypereosinophilia causes progressive cardiac pathologies in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Gene expression signatures showed tissue damage as well as repair and
          remodeling processes.
        explanation: >-
          Reports the transcriptional damage-and-remodeling signature measured
          in the model's left ventricle.
    evidence:
    - reference: PMID:37829205
      reference_title: "Hypereosinophilia causes progressive cardiac pathologies in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiomyocytes from IL-5Tg mice exhibited significantly reduced
        contractility relative to wild type (WT) controls.
      explanation: >-
        Establishes a measurable cell-level consequence of the eosinophilic
        cardiac environment, supporting the model as informative for this node.
datasets:
- accession: geo:GSE185300
  title: Expression data from adult left ventricular heart tissue of hypereosinophilic mice and controls
  description: >-
    Microarray profiling of left ventricular myocardium from IL-5 transgenic
    hypereosinophilic mice against controls, the transcriptional dataset behind
    the tissue damage and remodeling signature cited for the cardiac injury
    node. Model-organism data: it addresses the eosinophil effector arm shared
    with idiopathic HES, not the unexplained driver specific to it.
  data_type: MICROARRAY
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:37829205
  notes: >-
    Selected after relevance triage of the GEO candidate list. Two higher-scoring
    DIRECT candidates were rejected: geo:GSE12079 profiles CD3-CD4+ T cells from
    the lymphocytic variant, which this entry excludes by definition, and
    geo:GSE131738 is Sezary syndrome. Every GENE_ONLY candidate matched on
    PDGFRA, which reaches this disease only through the MONDO term's erroneous
    OMIM-derived axiom.
differential_diagnoses:
- name: Primary (myeloid) hypereosinophilic syndrome
  disease_term:
    preferred_term: primary hypereosinophilic syndrome
    term:
      id: MONDO:0017833
      label: primary hypereosinophilic syndrome
  description: >-
    The clonal myeloid variant, most often carrying FIP1L1-PDGFRA. Separating it
    from idiopathic HES changes first-line therapy from corticosteroids to
    imatinib, so the distinction is therapeutically decisive rather than
    taxonomic.
  distinguishing_features:
  - Demonstrable FIP1L1-PDGFRA fusion or other clonal myeloid lesion
  - Marked and durable response to imatinib
  - Marrow features of a myeloid neoplasm on morphology or karyotype
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imatinib (used in 68 patients) was more effective in patients with the
      FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001).
    explanation: >-
      The differential response to imatinib is the operative distinction between
      the myeloid and idiopathic variants.
- name: Lymphocytic variant hypereosinophilic syndrome
  disease_term:
    preferred_term: lymphocytic hypereosinophilic syndrome
    term:
      id: MONDO:0017835
      label: lymphocytic hypereosinophilic syndrome
  description: >-
    Eosinophilia driven by an aberrant or clonal T-cell population producing
    eosinophilopoietic cytokines. Detected by lymphocyte immunophenotyping and
    T-cell receptor gene rearrangement, both of which are negative in idiopathic
    HES by definition.
  distinguishing_features:
  - Aberrant T-cell immunophenotype on flow cytometry
  - Clonal T-cell receptor gene rearrangement
  - Risk of progression to T-cell lymphoma
  evidence:
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal
      T-cell population.
    explanation: >-
      Quantifies the lymphocytic-variant minority identified by testing and
      thereby excluded from the idiopathic category.
- name: Hypereosinophilia of undetermined significance
  description: >-
    Marked eosinophilia meeting the same threshold but without demonstrable
    eosinophil-mediated organ damage. It is not a syndrome and does not by
    itself warrant cytoreductive therapy; the distinction from idiopathic HES
    rests entirely on whether organ damage can be demonstrated.
  distinguishing_features:
  - No demonstrable eosinophil-mediated end-organ damage
  - Observation rather than eosinophil-directed therapy
  evidence:
  - reference: PMID:22460074
    reference_title: "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients in whom no underlying disease or hypereosinophilic syndrome
      is found, the term hypereosinophilia of undetermined significance is
      introduced.
    explanation: >-
      Introduces the category that idiopathic HES must be distinguished from.
- name: Eosinophilic granulomatosis with polyangiitis
  disease_term:
    preferred_term: eosinophilic granulomatosis with polyangiitis
    term:
      id: MONDO:0015943
      label: eosinophilic granulomatosis with polyangiitis
  description: >-
    ANCA-associated eosinophilic vasculitis presenting with asthma, marked
    eosinophilia, and multiorgan disease. Distinguished by vasculitic and
    granulomatous pathology rather than pure eosinophil-mediated injury.
  distinguishing_features:
  - Necrotising vasculitis and extravascular granulomas on biopsy
  - Antecedent asthma and sinonasal disease
  - ANCA positivity in a subset
  evidence:
  - reference: PMID:26637706
    reference_title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Eosinophilia is associated with a wide variety of allergic, rheumatologic,
      infectious, neoplastic, and rare idiopathic disorders.
    explanation: >-
      Places rheumatologic disease, of which EGPA is the principal eosinophilic
      example, among the categories that must be excluded. The snippet supports
      the category rather than EGPA by name.
discussions:
- discussion_id: idiopathic_hes_unknown_driver
  kind: KNOWLEDGE_GAP
  prompt: >-
    What drives sustained eosinophilopoiesis in idiopathic hypereosinophilic
    syndrome when no clonal myeloid lesion and no aberrant T-cell population can
    be found?
  rationale: >-
    The idiopathic category is defined by the failure of the current work-up,
    not by a positive mechanistic finding, and it is the largest of the HES
    variants precisely because that work-up leaves most patients unexplained.
    Every node downstream of the first in this entry's chain is well supported;
    the first node is a placeholder for an unknown. Whether idiopathic HES is one
    disease or a residual bin holding several mechanisms with a shared effector
    pathway is unresolved, and it determines whether the category should
    eventually be split further or dissolved into newly identified variants.
  attaches_to:
  - pathophysiology#Unexplained Eosinophil Lineage Expansion
  evidence:
  - reference: PMID:26637706
    reference_title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unfortunately, despite recent advances in molecular and immunologic
      techniques, the etiology remains unproven in the overwhelming majority of
      cases.
    explanation: >-
      States that the aetiology is unproven in most cases despite current
      molecular and immunologic methods, which is the gap itself.
- discussion_id: idiopathic_hes_count_damage_dissociation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does eosinophil-mediated cardiac damage continue to progress after the
    blood eosinophil count has been normalised, and what should be monitored
    instead?
  rationale: >-
    Treatment response in this disease is assessed on the blood eosinophil
    count, but cardiac injury and its clinical consequences dissociate from that
    count. The fibrotic stage is irreversible and cardioembolism has been
    documented despite resolution of the hypereosinophilia, so a normal count is
    not evidence that the cardiac process has stopped. Troponin, NT-pro-BNP and
    cardiac imaging are in routine guideline use and are curated here, but they
    report damage that has already occurred; no validated surrogate for ongoing
    tissue-level eosinophil activity exists, so nothing tells a clinician the
    process is still running before the next increment of injury shows up.
  attaches_to:
  - pathophysiology#Endomyocardial Fibrosis and Restrictive Physiology
  - pathophysiology#Systemic Thromboembolism
  evidence:
  - reference: PMID:39007045
    reference_title: "The three stages of eosinophilic cardiac damage: A series of case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More importantly, they demonstrate, for the first time, the dissociation
      between the eosinophil count and patients' clinical evolution, suggesting
      the need for close follow up even after the eosinophilia has been
      controlled.
    explanation: >-
      Documents the dissociation between blood eosinophil count and clinical
      cardiac evolution, which is the monitoring gap.
  - reference: PMID:19364940
    reference_title: "Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathology review demonstrated mural cardiac thrombus that likely caused
      cardioembolism as well as diffuse microangiopathy despite resolution of
      the hypereosinophilia.
    explanation: >-
      Shows thrombotic and microangiopathic injury persisting despite resolved
      hypereosinophilia.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    The syndrome spans asymptomatic eosinophilia through to fatal cardiac,
    thromboembolic and neurological disease, and the damage that determines
    outcome is largely irreversible once established: endomyocardial fibrosis
    does not remodel back, and cerebral infarction does not. Most patients
    respond to corticosteroids but the large majority stay on maintenance dosing
    indefinitely, so the treatment burden is lifelong even where the disease is
    controlled. Reported disease-related mortality is roughly one in ten.
  evidence:
  - reference: PMID:30567176
    reference_title: "Idiopathic hypereosinophilic syndrome with cutaneous involvement: a comparative review of 32 cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Surveillance, Epidemiology, and End Results data show that the
      estimated morbidity is between 0.036/100 000 and 6.3/100 000 whereas the
      mortality is about 9.3%.
    explanation: >-
      Gives the reported mortality figure behind this burden assessment.
  - reference: PMID:19910029
    reference_title: "Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corticosteroid monotherapy induced complete or partial responses at 1
      month in 85% (120/141) of patients with most remaining on maintenance
      doses (median, 10 mg prednisone equivalent daily for 2 months to 20
      years).
    explanation: >-
      Quantifies the indefinite maintenance dosing that makes the treatment
      burden lifelong even in responders.
clinical_trials:
- name: NCT02836496
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomised, double-blind, placebo-controlled phase III trial of mepolizumab
    300 mg subcutaneously every 4 weeks added to existing therapy in
    FIP1L1-PDGFRA-negative HES with recurrent flares.
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:32956756
    reference_title: "Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This randomized, multicenter, double-blind, placebo-controlled, phase III
      trial was conducted across 39 centers in 13 countries.
    explanation: >-
      Describes the trial design underlying the mepolizumab evidence for this
      population.
- name: NCT02130882
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Single-centre randomised, double-blind, placebo-controlled phase II trial of
    benralizumab 30 mg subcutaneously in symptomatic PDGFRA-negative HES, with
    open-label and extension phases.
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:30943337
    reference_title: "Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this randomized, double-blind, placebo-controlled, phase 2 trial, we
      administered a series of three monthly subcutaneous injections of either
      benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients
      who had PDGFRA-negative hypereosinophilic syndrome
    explanation: >-
      Describes the trial design underlying the benralizumab evidence.
- name: NCT04191304
  phase: PHASE_III
  status: COMPLETED
  description: >-
    NATRON. Multicentre randomised placebo-controlled 24-week phase III trial of
    benralizumab with an open-label extension, the confirmatory study behind the
    phase II result curated above.
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: clinicaltrials:NCT04191304
    reference_title: "A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24-Week Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a multicentre, randomised, double-blind (DB), parallel-group,
      placebo-controlled, 24-week Phase III study to compare the efficacy and
      safety of benralizumab versus placebo administered by SC injection Q4W in
      patients with hypereosinophilic syndrome (HES).
    explanation: >-
      The registry record for the phase III benralizumab study in HES.
- name: NCT05334368
  phase: PHASE_III
  status: UNKNOWN
  description: >-
    52-week randomised placebo-controlled trial of depemokimab, a long-acting
    anti-IL-5 antibody, in adults with uncontrolled HES on standard care.
    Recorded because it tests the same IL-5 axis this entry's mechanism node
    rests on; no efficacy results were available at curation.
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: clinicaltrials:NCT05334368
    reference_title: "A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Depemokimab in Adults With Hypereosinophilic Syndrome (HES)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a 52-week, randomized, placebo-controlled, double-blind, parallel
      group, multicenter study of depemokimab in adults with uncontrolled HES
      receiving standard of care (SoC) therapy.
    explanation: >-
      The registry record establishing the trial's design and population.
- name: NCT06477653
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    Pilot phase II trial of dupilumab added on for HES that responds only
    partially to eosinophil-depleting biologics. Relevant to this entry because
    partial response to anti-IL-5 therapy is the clinical signal that the
    unexplained upstream driver is not purely IL-5-dependent.
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: clinicaltrials:NCT06477653
    reference_title: A Pilot Phase 2 Study of the Safety and Efficacy of Dupilumab as Add-on Therapy for Hypereosinophilic Syndrome With Partial Clinical Response to Eosinophil-Depleting Biologic Agents
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      People aged 18 years and older who take drugs (mepolizumab, reslizumab, or
      benralizumab) to treat HES.
    explanation: >-
      The trial's eligibility statement, which is what establishes the
      population this record describes: patients already on eosinophil-depleting
      biologics.
references:
- reference: PMID:22460074
  title: "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes."
- reference: PMID:25964669
  title: "How I treat hypereosinophilic syndromes."
- reference: PMID:26637706
  title: "Eosinophilia: a pragmatic approach to diagnosis and treatment."

📚

References & Deep Research

References

3

PMID:22460074

Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes.

No top-level findings curated for this source.

PMID:25964669

How I treat hypereosinophilic syndromes.

No top-level findings curated for this source.

PMID:26637706

Eosinophilia: a pragmatic approach to diagnosis and treatment.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Idiopathic Hypereosinophilic Syndrome · 2026-09-06T23:17:14Z · View source

New entry for idiopathic hypereosinophilic syndrome (MONDO:0011895), promoted out of the bare has_subtypes stub it had been carrying in kb/disorders/Hypereosinophilic_Syndrome.yaml (MONDO:0015691). Why a separate entry. The promotion test used elsewhere in this repository asks for a distinct diagnostic pathway or first-line therapy. Idiopathic HES has both: it is constituted by an exclusion work-up rather than by a positive finding, and its first-line therapy is corticosteroids and anti-IL-5 biologics rather than the imatinib that defines management of the FIP1L1-PDGFRA-positive myeloid sibling (88% vs 23% response, PMID:19910029). The parent entry keeps the cross-variant content and its subtype description now points here. MONDO term caveat, recorded in the entry's notes and worth a reviewer's attention. MONDO:0011895 derives from OMIM:607685, which builds its concept around the FIP1L1-PDGFRA fusion. MONDO therefore asserts "has material basis in germline mutation in PDGFRA" (RO:0004003 to hgnc:8803) on the term and places it under idiopathic cardiomyopathy (MONDO:0005110) and familial restrictive cardiomyopathy (MONDO:0016340). Those axioms describe the myeloid variant, which the modern ICOG-EO definition of idiopathic HES excludes (PMID:22460074). It is still the only MONDO term whose label names this concept, so it is bound and the discrepancy is recorded rather than papered over. This is also what makes `just preflight-dr` WARN on the report (PDGFRA=8, JAK2=5): the report discusses the myeloid genes because ruling them out is the definition, not because it drifted to another disease. Deep research. One provider, falcon (Edison Scientific), run 2026-09-06, 717s: research/Idiopathic_Hypereosinophilic_Syndrome-deep-research-falcon.md. Its own reference validation reports 15/15 references resolved, 0 unresolved, 0 off topic, confabulation_rate 0.0. `needs_review: true` in the frontmatter is driven only by term validation flagging MONDO:0011895 as "mislabelled", which is the template placeholder string "if available" being compared to the ontology label, not a real binding error. The report cites by author-year key with DOIs rather than PMIDs (it says so explicitly), so its sources were recovered through the PMC ID Converter and cited by PMID in preference: PMID:39056762, PMID:37122022, PMID:38611061, PMID:39389714, PMID:34052871, PMID:40283978. One DOI (10.1002/ajh.26966, the 2023 ICC paper) has no PubMed record reachable by DOI search and was not cited. GeneReviews. Searched PubMed for a GeneReviews chapter; none exists. Expected for a non-Mendelian exclusion diagnosis, so no baseline was applied. Content. A nine-node causal chain rather than a bucket list: unexplained eosinophil lineage expansion, IL-5-dependent survival and recruitment, chemokine-driven tissue recruitment, persistent hypereosinophilia, degranulation, granule-protein cytotoxicity, then branching into the cardiac arm (endocardial injury and mural thrombus, then endomyocardial fibrosis and restrictive physiology, and systemic thromboembolism) and the skin/lung/gut arm. Three nodes carry conforms_to against fibrotic_response and thrombogenesis. Three causal edges carry their own evidence separate from the nodes they connect. The first node is a deliberate negative: idiopathic HES is defined by what cannot be found, so that node is cited to the sources saying the aetiology is unproven rather than to a mechanism, and a KNOWLEDGE_GAP discussion is attached to it. A second KNOWLEDGE_GAP covers the dissociation between blood eosinophil count and cardiac progression (PMID:39007045, PMID:19364940), which is why surveillance continues after the count normalises. Imatinib is curated as a `supports: REFUTE` treatment item rather than omitted, because "does not work here" is the therapeutic fact that separates this entry from the myeloid variant. PDGFRA appears in `genetic:` as a definitional exclusion with relationship_type DISPUTED, not as a disease gene. Phenotype frequencies come from PMID:40283978, a cohort assembled specifically as idiopathic HES (n=11), rather than from mixed-HES series; the entry says in its descriptions that these are small-cohort observations, not population estimates. Animal model. The IL-5 transgenic mouse (PMID:37829205) is linked to two pathophysiology nodes with readouts. It is PARTIALLY_RECAPITULATES against the injury node, with the limitation stated plainly: its eosinophilia has a defined genetic cause, which is exactly what idiopathic HES is defined by not having, so it models the effector arm and not the unexplained driver. Dataset triage. geo:GSE185300 (IL-5Tg mouse left ventricle) was accepted and verified with `just verify-datasets`; its GEO_*.md cache file is committed. Two higher-scoring DIRECT candidates were rejected as Named Entity Confusion: geo:GSE12079 profiles CD3-CD4+ T cells from the lymphocytic variant this entry excludes by definition, and geo:GSE131738 is Sezary syndrome. All nine GENE_ONLY candidates matched on PDGFRA and reach this disease only through the erroneous MONDO axiom above. Validation. `just validate-disorders` over both changed files: schema clean, term validation clean, 100/100 snippets verified against the committed cache. Per-file gates clean: check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms. Whole-KB gates clean with no new baseline entries: check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-term-cache-integrity, check-cache-order. Compliance 89.8% (the parent HES entry is 85.8%). All evidence uses PMIDs; no DOI-keyed evidence items, so nothing bypasses the gating validator. Four references_cache files unrelated to this change (PMID_31367340, PMID_39156600, clinicaltrials_NCT02836496, clinicaltrials_NCT04191304) were upgraded from abstract to full text as a side effect of the research validator's pass and were reverted rather than staged; they belong to other entries.

Falcon ▸

Idiopathic Hypereosinophilic Syndrome: Disease-Characteristics Report

Edison Scientific Literature 63 citations 2026-09-06T14:52:08.816297

Idiopathic Hypereosinophilic Syndrome: Disease-Characteristics Report

Scope and evidence date. This report focuses on idiopathic hypereosinophilic syndrome (iHES), not the broader group of all hypereosinophilic syndromes. Evidence available through 2024 is prioritized; selected 2025–2026 findings are clearly labeled as later developments. Many publications combine HES subtypes, so phenotype frequencies from mixed cohorts should not be interpreted as iHES-specific. PMID values were not present in the retrieved records; DOI and ClinicalTrials.gov URLs are therefore supplied rather than risking incorrect PMID assignment.

Executive summary

iHES is an exclusion-defined, heterogeneous disorder in which persistent blood or tissue hypereosinophilia causes organ damage, but no reactive, autoimmune, lymphocytic-variant, or clonal/neoplastic cause can be established. Current ICC criteria require peripheral eosinophils ≥1.5 × 10⁹/L and ≥10% of leukocytes, attributable tissue injury, generally normal marrow morphology apart from eosinilia, and no defining clonal genetic abnormality. The old six-month waiting requirement is obsolete when organ injury demands prompt treatment. (caminati2024managingpatientswith pages 2-3, wang2023theinternationalconsensus pages 8-8)

The skin, respiratory tract, gastrointestinal tract, and cardiovascular system are most often involved. Cardiac inflammation, intracardiac thrombosis, endomyocardial fibrosis, thromboembolism, and neurologic injury are the most consequential complications. Corticosteroids remain first-line therapy; mepolizumab 300 mg subcutaneously every four weeks is the best-supported and, as of 2024, only biologic specifically approved for HES. (wang2023theinternationalconsensus pages 8-9, ezekwe2024biologicsinhypereosinophilic pages 3-4, jackson2022eosinophilsandeosinophilic pages 3-4)

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 (wang2023theinternationalconsensus pages 8-8, caminati2024managingpatientswith pages 2-3)	10.1002/ajh.26966; 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 (groh2023frenchguidelinesfor pages 5-7, wang2023theinternationalconsensus pages 8-9)	10.1186/s13023-023-02696-4; 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 (nguyen2024clinicalandtherapeutic pages 9-10, wang2023theinternationalconsensus pages 8-8, caminati2024managingpatientswith pages 8-10, nguyen2024clinicalandtherapeutic pages 5-7)	10.1002/ajh.26966; 10.3390/cells13141180; 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 (mora2025mepolizumabforhypereosinophilic pages 1-2, wang2023theinternationalconsensus pages 8-9, valent2021eosinophilsandeosinophilassociated pages 6-8, jackson2022eosinophilsandeosinophilic pages 3-4)	10.1007/s00281-021-00863-y; 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 (ezekwe2024biologicsinhypereosinophilic pages 3-4, NCT02836496 chunk 1)	NCT02836496; 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 (ezekwe2024biologicsinhypereosinophilic pages 3-4)	NCT04191304; 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 (papaioannou2025biologicagentsin pages 4-6, papaioannou2025biologicagentsin pages 1-2)	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 (OpenTargets Search: idiopathic hypereosinophilic syndrome, caminati2024managingpatientswith pages 2-3, longhino2025clinicalandimmunological pages 1-2)	Open Targets; 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.

1. Disease information

Definition and classification

Hypereosinophilia (HE): absolute eosinophil count (AEC) ≥1.5 × 10⁹/L. Contemporary statements usually confirm persistence on at least two measurements separated by ≥2 weeks; moderate HE is 1.5–5.0 × 10⁹/L and severe HE is >5.0 × 10⁹/L. (caminati2024managingpatientswith pages 2-3)
HES: HE plus organ damage or dysfunction attributable to eosinophilic infiltration or eosinophil-derived products.
iHES: HES for which no reactive, autoimmune, neoplastic, or lymphocytic-variant cause is found after adequate investigation. It is a diagnosis of exclusion rather than a single molecular disease. (wang2023theinternationalconsensus pages 8-8)
HE of unknown significance (HEus): unexplained HE without attributable organ damage; it is not iHES. (caminati2024managingpatientswith pages 2-3)

Important boundaries: FIP1L1::PDGFRA-positive disease and other tyrosine-kinase-fusion disorders are myeloid/lymphoid neoplasms, not iHES. Lymphocytic-variant HES has an aberrant cytokine-producing T-cell population. Reactive HES has a recognizable trigger such as infection, drug exposure, allergy, autoimmune disease, or malignancy. EGPA requires a vasculitic clinical context and is not classified as iHES. Organ-restricted eosinophilic disorders lack systemic HES involvement. (roufosse2007hypereosinophilicsyndromes pages 1-2, nguyen2024clinicalandtherapeutic pages 9-10, wang2023theinternationalconsensus pages 8-8)

Identifiers and synonyms

MONDO: MONDO:0011895, idiopathic hypereosinophilic syndrome, confirmed in Open Targets, although no associated target was returned at search time. (OpenTargets Search: idiopathic hypereosinophilic syndrome)
Common labels: idiopathic HES, iHES, HES-I, idiopathic hypereosinophilic syndrome.
Coding caution: ICD and MeSH resources often code the broader HES category rather than the rigorously exclusion-defined idiopathic subtype. ICD-10-CM commonly uses D72.11, hypereosinophilic syndrome; local verification is recommended before using it as an iHES-specific identifier. A uniquely verified OMIM entry was not identified, consistent with the absence of a defined Mendelian cause.
The evidence summarized here is aggregated disease-level literature and trial evidence, not individual EHR-derived data, except where retrospective clinical cohorts are explicitly described.

2. Etiology

iHES has no established initiating cause. “Idiopathic” should be assigned only after excluding secondary/reactive and clonal conditions. No reproducible causal germline variant, susceptibility locus, inheritance pattern, founder allele, or protective allele is established. Somatic variants associated with clonal hematopoiesis may occur, especially with age, but do not by themselves prove chronic eosinophilic leukemia. (wang2023theinternationalconsensus pages 8-8, nguyen2024clinicalandtherapeutic pages 9-10)

Potential environmental or infectious causes—medications, helminths, fungi, allergic exposures, and infections—are differential diagnoses rather than demonstrated risk factors for genuine iHES. Drug-associated eosinophilia often begins 2–8 weeks after exposure; implicated classes include antibiotics, antiepileptics, NSAIDs, sulfonamides, allopurinol, immune-checkpoint inhibitors, and occasionally dupilumab. Identifying such a trigger reclassifies the condition as reactive rather than idiopathic. (groh2023frenchguidelinesfor pages 5-7)

No validated lifestyle risk or protective factor involving smoking, diet, alcohol, exercise, occupation, or pollution is known. Likewise, no robust iHES-specific gene–environment interaction has been demonstrated. Apparent associations with atopy or infection require caution because they can represent alternative diagnoses.

3. Phenotypes

Clinical expression is adult-predominant but can occur at any age. Severity ranges from mild chronic symptoms to rapidly fatal cardiac, thrombotic, or neurologic disease. AEC magnitude correlates imperfectly with severity; activation state and tissue infiltration matter more. (roufosse2007hypereosinophilicsyndromes pages 1-2, groh2023frenchguidelinesfor pages 5-7)

Laboratory: persistent eosinophilia—suggest HP:0001880, Eosinophilia. Recent molecularly evaluated cohorts had median AECs around 3.0–3.9 × 10⁹/L. Mild cytopenias occur in approximately 10%–20%, but prominent anemia, thrombocytopenia, blasts, or dysplasia should raise concern for neoplasia. (wang2023theinternationalconsensus pages 8-9)
Skin: pruritus, eczema/dermatitis, urticaria, angioedema, erythroderma, nodules, or ulceration; generally fluctuating or relapsing. Suggested HPO: Pruritus, Urticaria, Eczema, Angioedema, Erythroderma. Mixed-HES evidence estimates cutaneous presentation near 37%, not specifically iHES. (mora2025mepolizumabforhypereosinophilic pages 1-2, jackson2022eosinophilsandeosinophilic pages 3-4)
Respiratory: cough, dyspnea, asthma-like disease, pulmonary infiltrates, pleural effusion, and eventually fibrosis. Suggested HPO: Dyspnea, Cough, Pulmonary infiltrates, Pleural effusion, Pulmonary fibrosis, Asthma. (papaioannou2025biologicagentsin pages 1-2, jackson2022eosinophilsandeosinophilic pages 3-4)
Gastrointestinal: abdominal pain, diarrhea, enteritis, colitis, or eosinophilic gastroenteritis. Suggested HPO: Abdominal pain, Diarrhea, Gastrointestinal inflammation. (roufosse2007hypereosinophilicsyndromes pages 1-2, jackson2022eosinophilsandeosinophilic pages 3-4)
Cardiovascular: myocarditis, pericarditis, intracavitary thrombus, endomyocardial fibrosis, valvular entrapment/regurgitation, arrhythmia, and heart failure. Suggested HPO: Myocarditis, Pericarditis, Intracardiac thrombus, Endomyocardial fibrosis, Cardiac arrhythmia, Heart failure. Broad recent HES estimates place cardiovascular complications near 5%, but historic cohorts were substantially higher and subtype ascertainment differs. (mora2025mepolizumabforhypereosinophilic pages 1-2, valent2021eosinophilsandeosinophilassociated pages 6-8, jackson2022eosinophilsandeosinophilic pages 3-4)
Neurologic/vascular: embolic stroke, encephalitis, peripheral neuropathy, arterial or venous thrombosis. Suggested HPO: Ischemic stroke, Encephalitis, Peripheral neuropathy, Venous thrombosis, Arterial thrombosis. Mixed-HES neurologic complication estimates near 4% are not iHES-specific. (mora2025mepolizumabforhypereosinophilic pages 1-2, valent2021eosinophilsandeosinophilassociated pages 6-8)
Other: hepatomegaly, splenomegaly, ocular inflammation, musculoskeletal and endocrine involvement are reported but less common. Hepatosplenomegaly or cytopenias should also prompt renewed evaluation for clonal disease. (roufosse2007hypereosinophilicsyndromes pages 1-2, wang2023theinternationalconsensus pages 8-9)

Symptoms, chronic glucocorticoid exposure, diagnostic delay, fatigue, organ dysfunction, and fear of relapse impair daily function. The 2024 SIAAIC statement calls the quality-of-life effect substantial, but validated iHES-specific EQ-5D, SF-36, or PROMIS norms and per-phenotype effect sizes remain unavailable. (caminati2024managingpatientswith pages 2-3)

4. Genetic and molecular information

There is no accepted causal gene or pathogenic variant for iHES, no Mendelian inheritance, and therefore no meaningful iHES carrier frequency, penetrance, anticipation, or founder effect. Open Targets returned zero disease–target associations for MONDO:0011895, emphasizing the current evidence gap rather than proving absence of biology. (OpenTargets Search: idiopathic hypereosinophilic syndrome)

Molecular findings that exclude iHES include rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. Context-specific testing includes BCR::ABL1, KIT, JAK2 V617F, CALR, and MPL. CEL-NOS may harbor mutations in ASXL1, DNMT3A, EZH2, TET2, SRSF2, SETBP1, or CBL, accompanied by supportive morphology. These are somatic neoplastic or CHIP-associated findings, not established iHES variants. (nguyen2024clinicalandtherapeutic pages 9-10, caminati2024managingpatientswith pages 8-10)

No validated iHES-specific modifier gene, DNA-methylation signature, histone alteration, chromosomal abnormality, metabolomic signature, lipidomic profile, or spatial/single-cell atlas was established through 2024. A 2025 pilot of 21 patients found elevated eosinophil cationic protein and κ free light chains and correlations with AEC and steroid use, but these remain exploratory biomarkers rather than causal molecular lesions. (longhino2025clinicalandimmunological pages 1-2)

5. Environmental information

Environmental, occupational, dietary, smoking, alcohol, or exercise exposures have not been shown to cause iHES. Diagnostic assessment must nevertheless investigate travel, helminth exposure—especially Strongyloides before corticosteroids—new drugs, supplements, allergic disease, immunocompromise, and malignancy. A positive causal exposure generally changes the diagnosis to secondary/reactive eosinophilia. (taurisano2025hypereosinophiliaclinicaland pages 6-7, groh2023frenchguidelinesfor pages 5-7, nguyen2024clinicalandtherapeutic pages 5-7)

6. Mechanism and pathophysiology

Ordered causal chain

An unknown initiating lesion or dysregulated immune stimulus leads to excessive eosinophil production, survival, or activation; this initiating step is inferred and undefined in iHES.
Increased IL-5–IL-5Rα, with contributions from IL-3 and GM-CSF, leads to eosinophil-lineage differentiation, marrow release, priming, and prolonged survival. (nguyen2024clinicalandtherapeutic pages 4-5, valent2021eosinophilsandeosinophilassociated pages 4-5)
IL-4/IL-13/TNF-driven eotaxins CCL11, CCL24, and CCL26 acting through CCR3 lead to eosinophil chemotaxis into target tissues. (nguyen2024clinicalandtherapeutic pages 4-5, valent2021eosinophilsandeosinophilassociated pages 4-5)
Tissue accumulation and activation lead to degranulation and extracellular deposition of MBP1/2, ECP, eosinophil peroxidase, and EDN, plus cytokines, leukotrienes, prostaglandins, and DNA traps. (taurisano2025hypereosinophiliaclinicaland pages 1-2, valent2021eosinophilsandeosinophilassociated pages 4-5)
These mediators lead to epithelial/endothelial injury and branch into: (a) inflammation, edema, bronchoconstriction, mucus production and tissue dysfunction; (b) platelet/endothelial activation, PAI-2 activity and antifibrinolysis leading to thrombosis; and (c) fibroblast activation, TGF signaling and remodeling leading to fibrosis. Some organ-specific links are mechanistically inferred from broader eosinophil biology rather than demonstrated uniquely in iHES. (valent2021eosinophilsandeosinophilassociated pages 6-8, valent2021eosinophilsandeosinophilassociated pages 8-10)
Persistent injury leads to myocarditis/endomyocardial fibrosis and heart failure; pulmonary infiltrates/fibrosis; dermatitis; enteritis/colitis; microvascular injury, thromboembolism, stroke, or neuropathy. (valent2021eosinophilsandeosinophilassociated pages 6-8, jackson2022eosinophilsandeosinophilic pages 3-4)

Upstream processes: eosinophilopoiesis, cytokine signaling, survival and trafficking. Downstream processes: degranulation, oxidative/cytotoxic injury, inflammation, coagulation, thrombosis, remodeling and fibrosis.

Suggested GO biological-process terms include eosinophil differentiation, eosinophil migration, eosinophil activation, leukocyte chemotaxis, cytokine-mediated signaling pathway, inflammatory response, blood coagulation, wound healing, and fibroblast proliferation. Suggested Cell Ontology terms include eosinophil (CL:0000771), eosinophil progenitor, CD4-positive T cell, type-2 innate lymphoid cell, mast cell, basophil, natural-killer cell, fibroblast, endothelial cell, and platelet. Cytokine-producing cells can include TH2 cells, ILC2s, mast cells, mesenchymal cells, basophils, NK cells, and eosinophils themselves. (nguyen2024clinicalandtherapeutic pages 4-5, groh2023frenchguidelinesfor pages 2-4)

No iHES-specific energy-metabolic defect, organelle dysfunction, autophagy lesion, or reproducible epigenomic/multi-omic mechanism is established.

7. Anatomical structures affected

Primary systems are hematopoietic/bone marrow and circulating blood, followed by skin, lung and upper airways, gastrointestinal tract, heart/endocardium/myocardium, vascular endothelium, and central or peripheral nervous systems. Suggested UBERON concepts include bone marrow, blood, skin, lung, bronchus, gastrointestinal tract, heart, myocardium, endocardium, blood vessel, brain, and peripheral nerve. (nguyen2024clinicalandtherapeutic pages 5-7, wang2023theinternationalconsensus pages 8-9)

At tissue level, eosinophils infiltrate epithelium, lamina propria, interstitium, myocardium/endocardium, and perivascular or neural tissues. Histology may show intact eosinophils or only extracellular MBP/EPX after cytolysis. Relevant GO cellular components include eosinophil granule, secretory granule lumen, extracellular region, plasma membrane/IL-5 receptor complex, and nucleus for extracellular DNA-trap formation. Lateralization is not characteristic; pulmonary, cutaneous, vascular, and neurologic lesions may be focal, multifocal, unilateral, or bilateral depending on the affected organ. (caminati2024managingpatientswith pages 2-3, valent2021eosinophilsandeosinophilassociated pages 4-5)

8. Temporal development

Onset is commonly young-to-middle adulthood but spans pediatric to geriatric ages. It is usually subacute or insidious, although myocarditis, thrombosis, or neurologic injury may present acutely. The course is heterogeneous—chronic persistent, fluctuating, episodic, or relapsing during treatment taper. (roufosse2007hypereosinophilicsyndromes pages 1-2, groh2023frenchguidelinesfor pages 5-7)

There is no formal staging system. A useful clinical sequence is: uncomplicated HE → symptomatic eosinophilic infiltration → reversible organ dysfunction → thrombotic/fibrotic irreversible damage. This is a management framework, not validated staging. Remission is usually treatment-induced; spontaneous durable remission is insufficiently quantified. The key therapeutic window is before cardiac thrombosis/fibrosis or permanent neurologic injury. Current experts emphasize simultaneous etiologic investigation and organ-damage assessment rather than waiting months to satisfy historical duration criteria. (groh2023frenchguidelinesfor pages 5-7, nguyen2024clinicalandtherapeutic pages 5-7)

9. Inheritance and population

The population incidence and prevalence of iHES are unknown. An older estimate for all HES was approximately 0.36 new cases per million persons per year, which should not be treated as iHES-specific. Historic HES series reported a male:female ratio of 4–9:1, but this was strongly influenced by the nearly male-restricted FIP1L1::PDGFRA neoplasm; contemporary iHES should not be assumed to share that ratio. (roufosse2007hypereosinophilicsyndromes pages 1-2, groh2023frenchguidelinesfor pages 5-7)

No consistent ethnic, ancestry, geographic, consanguinity, or familial enrichment is established for iHES. Because no causal germline lesion is defined, inheritance, penetrance, mosaicism, carrier frequency, prenatal testing, and cascade genetic screening are not applicable.

10. Diagnostics

Current diagnostic criteria

Confirm persistent PB HE—typically AEC ≥1.5 × 10⁹/L on two occasions ≥2 weeks apart; ICC additionally uses ≥10% eosinophils.
Demonstrate organ damage/dysfunction attributable to eosinophils or eosinophil products.
Exclude reactive, infectious, allergic, drug-related, autoimmune/vasculitic, and malignant causes.
Exclude L-HES and clonal/neoplastic eosinophilia.
Show marrow that is generally normal apart from increased eosinophils and no defining clonal molecular abnormality. (wang2023theinternationalconsensus pages 8-8, caminati2024managingpatientswith pages 2-3)

Recommended work-up

Initial tests: serial CBC/differential and smear; renal/hepatic chemistry; inflammatory markers; immunoglobulins/IgE; medication, travel, infection, allergy and immune-deficiency assessment; Strongyloides IgG and stool parasite testing where epidemiologically appropriate. (taurisano2025hypereosinophiliaclinicaland pages 6-7, nguyen2024clinicalandtherapeutic pages 5-7)
Hematologic evaluation: bone-marrow aspirate/biopsy, morphology, fibrosis and blast assessment; flow cytometry; karyotype; FISH/PCR for FIP1L1::PDGFRA and other kinase fusions; targeted myeloid NGS or RNA sequencing when standard testing is negative. (nguyen2024clinicalandtherapeutic pages 9-10, caminati2024managingpatientswith pages 8-10)
L-HES: T-cell immunophenotyping and TCR rearrangement. Typical clues are an sCD3−CD4+ population, elevated IL-4/IL-5, IgE and TARC. TCR clonality alone is not specific: it occurs in roughly 17%–27% of otherwise unexplained eosinophilia, while only about half of L-HES shows demonstrable clonality. (nguyen2024clinicalandtherapeutic pages 9-10, caminati2024managingpatientswith pages 8-10)
Organ staging: troponin, ECG and echocardiography; cardiac MRI if myocarditis/fibrosis is suspected; chest CT and pulmonary-function tests; PET/CT where malignancy or organomegaly is a concern; GI endoscopy/biopsy, skin biopsy, neurologic examination/EMG or organ-specific imaging as indicated. (nguyen2024clinicalandtherapeutic pages 5-7)
Tissue HE: extensive infiltration, >20% eosinophils among marrow nucleated cells, or marked extracellular eosinophil-protein deposition can support tissue involvement. (caminati2024managingpatientswith pages 2-3)

The differential includes parasitic infection, drug reaction/DRESS, allergy/atopy, ABPA, autoimmune disease, EGPA, eosinophilic GI or pulmonary disease, adrenal insufficiency, solid tumor/lymphoma, systemic mastocytosis, L-HES, MLN with tyrosine-kinase fusion, CEL-NOS, AML, and other MPN/MDS entities. Population screening, newborn screening, and screening of asymptomatic relatives are not indicated.

11. Outcome and prognosis

After overt hematopoietic neoplasia is excluded, iHES is often indolent, but long-term disease-related mortality is estimated at 10%–15%. Poorer prognosis is associated with age >60 years, cardiac involvement, anemia or thrombocytopenia, lymphopenia, high neutrophil-to-lymphocyte ratio, and hepatosplenomegaly. (wang2023theinternationalconsensus pages 8-9)

Major causes of morbidity are irreversible heart failure/endomyocardial fibrosis, intracardiac or systemic thrombosis, stroke, pulmonary fibrosis, neuropathy, chronic GI disease, recurrent flares, and treatment toxicity. Cardiac injury is the most important preventable threat. Historic survival estimates are not applicable to modern molecularly classified iHES because older cohorts mixed neoplastic and idiopathic disorders. (roufosse2007hypereosinophilicsyndromes pages 1-2, wilkins2005hypereosinophilicsyndromean pages 1-2)

12. Treatment

Strategy

Urgent organ-threatening disease: initiate systemic glucocorticoids promptly while etiologic work-up continues. Corticosteroids usually lower AEC and improve dysfunction rapidly; taper after clinical control and AEC <1.5 × 10⁹/L. Approximately 20% are resistant or intolerant. (wang2023theinternationalconsensus pages 8-9)
Steroid-dependent/refractory iHES: favor eosinophil-targeted biologic therapy, especially mepolizumab. Conventional alternatives include hydroxyurea, interferon-α, cyclosporine, methotrexate or other immunosuppressants, selected according to phenotype and toxicity. Alemtuzumab and allogeneic transplantation are reserved for exceptional refractory disease because of substantial risk. (curtis2016hypereosinophilicsyndrome pages 10-11, nguyen2024clinicalandtherapeutic pages 17-19)
Genotype-directed correction: imatinib is highly effective for PDGFRA/PDGFRB-rearranged disease, but such patients do not have iHES. Empiric imatinib has limited relevance after comprehensive negative molecular testing.

Biologics and trials

Mepolizumab—anti-IL-5; suggested NCIt concept: Mepolizumab. In phase 3 NCT02836496, 108 patients received 300 mg SC every four weeks for 32 weeks; it reduced clinical flares by approximately 50% versus placebo and improved five of six symptom domains without a new safety signal. It was the only HES-approved biologic as of 2024. (ezekwe2024biologicsinhypereosinophilic pages 3-4, NCT02836496 chunk 1)
Benralizumab—anti-IL-5Rα with NK-cell-mediated antibody-dependent cytotoxicity; suggested NCIt concept: Benralizumab. A small phase 2 study found >50% AEC reduction in 9/10 treated versus 3/10 placebo patients, with hematologic/clinical improvement in 17/19 during extension. It remained investigational for HES through 2024; phase 3 NATRON was NCT04191304. (ezekwe2024biologicsinhypereosinophilic pages 3-4)
Depemokimab, long-acting anti-IL-5, is being tested every six months in phase 3 NCT05334368; efficacy results were not available in the retrieved 2024-era evidence. (ezekwe2024biologicsinhypereosinophilic pages 3-4)
Dupilumab, anti-IL-4Rα, is being studied as add-on therapy for persistent symptoms despite eosinophil-depleting biologics in phase 2 NCT06477653. It is not established or approved as primary iHES therapy, and IL-4R blockade can itself be associated with blood eosinophilia. (NCT06477653 chunk 1, ezekwe2024biologicsinhypereosinophilic pages 9-10)

Later real-world development (published 2025): among 11 carefully investigated iHES patients, mepolizumab 300 mg/month or benralizumab 30 mg every four weeks reduced median AEC from 3,000 to 50/µL at 12 months, eliminated observed flares, allowed 82% to discontinue oral steroids, and improved mean FEV₁ by 857 ± 594 mL in eight patients with asthma; no treatment-related adverse events were reported. The uncontrolled, very small cohort cannot establish comparative efficacy. (papaioannou2025biologicagentsin pages 4-6, papaioannou2025biologicagentsin pages 1-2)

There is no validated pharmacogenomic dosing algorithm, gene therapy, RNA therapy, routine surgery, or approved cell therapy for iHES. Surgery is complication-directed—for example, valve or thrombotic sequelae—not disease-modifying. Rehabilitation, pulmonary therapy, cardiac care, thrombosis management, vaccination, bone protection and infection-risk mitigation should be individualized.

13. Prevention

No primary prevention exists because the initiating cause is unknown. There is no iHES vaccine, carrier screening, prenatal test, or population-screening program.

Secondary prevention consists of early recognition of persistent HE, prompt exclusion of Strongyloides and drug causes, and simultaneous screening for cardiac, pulmonary, neurologic and thrombotic injury. Tertiary prevention includes maintaining eosinophil control, minimizing cumulative corticosteroid exposure, cardiac surveillance, managing thrombosis according to standard indications, and monitoring for relapse and treatment toxicity. Early eosinophil-lowering therapy is intended to prevent irreversible organ damage. (groh2023frenchguidelinesfor pages 5-7, wang2023theinternationalconsensus pages 8-9)

14. Other species and natural disease

No naturally occurring animal disorder is established as a faithful ortholog of human iHES. Dogs, cats, horses, and other species can develop eosinophilic syndromes, but these are heterogeneous veterinary conditions and cannot be mapped directly to MONDO:0011895 without species-specific evidence. There is no zoonotic transmission. Relevant conserved genes/pathways include IL5, IL5RA, CCR3, CCL11, GATA factors, and the β-common cytokine-receptor pathway, but conservation of eosinophil biology does not establish shared idiopathic etiology.

15. Model organisms

IL-5-transgenic mice (Mus musculus, NCBI Taxon 10090) develop marked, lineage-selective eosinophilia—reported as ≥65- to 265-fold above littermates—with eosinophils in marrow, spleen, lung, lymphoid tissue and gut. These models demonstrate that IL-5 is sufficient for eosinophil differentiation and expansion. Their major limitation is that some animals remain macroscopically well apart from splenomegaly, showing that eosinophilia alone does not fully reproduce human iHES organ injury.
FIP1L1-PDGFRA plus IL-5 models produce HES/CEL-like disease and demonstrate cooperation between a myeloid oncogenic driver and cytokine signaling. They model neoplastic eosinophilia, not idiopathic HES.
Eosinophil-deficient mice can have normal lifespan without spontaneous illness, helping evaluate eosinophil function but not modeling HES. (wilkins2005hypereosinophilicsyndromean pages 2-4, jackson2022eosinophilsandeosinophilic pages 3-4)

These systems are useful for eosinophilopoiesis, trafficking, granule-mediated injury, fibrosis, thrombosis and therapeutic target validation. None recreates the unknown initiating lesion or full phenotypic heterogeneity of iHES. No validated iHES-specific zebrafish, Drosophila, organoid, patient-derived iPSC, or CRISPR-screen model was identified.

Authoritative interpretation and evidence gaps

Current expert consensus is that the most urgent practical problems are diagnostic delay, incomplete phenotyping, and failure to detect silent organ injury—not simply the eosinophil count. A multidisciplinary “two-track” approach should investigate etiology and organ damage simultaneously. (caminati2024managingpatientswith pages 2-3, groh2023frenchguidelinesfor pages 5-7, nguyen2024clinicalandtherapeutic pages 5-7)

The central conceptual limitation is that iHES is likely a residual category containing several undiscovered endotypes. Accordingly, absence of a recognized fusion or reactive trigger does not prove a single shared mechanism. Prospective natural-history cohorts, ancestry-stratified epidemiology, standardized patient-reported outcomes, pediatric data, serial tissue and single-cell profiling, and head-to-head biologic studies remain major unmet needs.

Selected exact abstract quotations

“Hypereosinophilic syndrome (HES) encompasses a heterogeneous and complex group of different subtypes within the wider group of hypereosinophilic disorders.” — Caminati et al., published July 2024, DOI: https://doi.org/10.3390/cells13141180. (caminati2024managingpatientswith pages 2-3)

“HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES).” — Stella et al., published January 2021, DOI: https://doi.org/10.3390/ijms22020486. (nguyen2024clinicalandtherapeutic pages 4-5)

“Mepolizumab is identified as the only biologic with regulatory approval for HES.” — evidence synthesis from Ezekwe et al., published November 2024, DOI: https://doi.org/10.1016/j.iac.2024.07.003. (ezekwe2024biologicsinhypereosinophilic pages 3-4)

These quotations support broad HES concepts; they should not be used to imply a known iHES-specific causal lesion.

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(ezekwe2024biologicsinhypereosinophilic pages 9-10): Ejiofor Ezekwe, Andrew L. Weskamp, Luke M. Pittman, and Amy D. Klion. Biologics in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis. Nov 2024. URL: https://doi.org/10.1016/j.iac.2024.07.003, doi:10.1016/j.iac.2024.07.003. This article has 7 citations and is from a peer-reviewed journal.
(wilkins2005hypereosinophilicsyndromean pages 2-4): H. Jeffrey Wilkins, Martin M. Crane, Kelly Copeland, and William V. Williams. Hypereosinophilic syndrome: an update. American Journal of Hematology, 80:148-157, Oct 2005. URL: https://doi.org/10.1002/ajh.20423, doi:10.1002/ajh.20423. This article has 151 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	3
Resolved	3
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0011895 (5 mentions) - the report calls it "if available"; MONDO calls it idiopathic hypereosinophilic syndrome

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OpenScientist Report

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Clinical Burden

Differential Diagnoses

Related Datasets

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Idiopathic Hypereosinophilic Syndrome: Disease-Characteristics Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Current diagnostic criteria

Recommended work-up

11. Outcome and prognosis

12. Treatment

Strategy

Biologics and trials

13. Prevention

14. Other species and natural disease

15. Model organisms

Authoritative interpretation and evidence gaps

Selected exact abstract quotations

Artifacts

Reference Validation

Term Validation

Terms the report names something else