Treatment patterns and disease burden of hypereosinophilic syndrome (HES) in the United States: A real-world observational, retrospective cohort study

Abstract

Background

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by persistent hypereosinophilia causing organ damage. Differences in underlying pathophysiology give rise to several variants, including idiopathic (I-HES) and lymphocytic (L-HES) subtypes. Oral corticosteroids (OCS) have been the mainstay of treatment for I-HES/L-HES, but long-term use is limited by toxicity. While biologics mark an important recent advance in the treatment of HES, unmet clinical needs in the management of patients remain. This retrospective cohort study examines real-world treatment patterns and disease burden for patients with I-HES/L-HES in the United States.

Methods

De-identified information from the TriNetX Linked network of electronic health records plus claims was used to establish the first recorded date of HES diagnosis (index date [ID]) for patients between October 01, 2020 and September 12, 2023. Baseline was defined as 12 months prior to ID; patients were followed up until either September 12, 2023, disenrollment from insurance, death, or 2 years post-ID, whichever came first. Primary objective was to describe clinical characteristics and disease burden in the overall I-HES/L-HES population. Secondary objectives included demographics, treatment patterns and clinical outcomes in the overall population, and patient journey to I-HES/L-HES diagnosis (incident cohort only). All analyses were descriptive.

Results

The overall population included 110 patients; 60.0% were male, mean (standard deviation [SD]) age at first HES diagnosis record was 43.8 (21.3) years, and 52.7% were White. The mean (SD) number of organ systems involved with HES signs and/or symptoms was 2.9 (2.1) at baseline and 2.1 (2.0) at Year 2 of follow-up. Among incident cases of HES (n = 53), the mean (SD) time from first eosinophil count ≥1500 cells/μL to HES diagnosis was 47.9 (75.8) months (n = 13), and the mean (SD) time from the first eosinophil count ≥1500 cells/μL to initiation of HES therapy was 29.0 (42.6) months (n = 6). In the overall population, 50% of patients did not receive treatment within 2 years of follow-up. OCS were the most prescribed therapy; few patients were treated with immunosuppressants, and the use of interleukin-5/receptor alpha-targeted therapies increased over the study period. By end of follow-up, less than 40% of patients had experienced a complete remission and few patients achieved a clinical response.

Conclusion

HES is associated with substantial disease burden. There remains an unmet need for earlier diagnosis and intervention, and for improved therapeutic options, in I-HES/L-HES.

Introduction

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by persistent hypereosinophilia in the blood and/or tissues that can lead to organ damage and/or dysfunction.1, 2, 3, 4 HES has an estimated prevalence in the United States of America between 0.315 and 6.3 per 100,000, based on data collected between 2001 and 2005.⁵ Patients with HES are at risk of potentially life-threatening organ damage due to extensive tissue infiltration by eosinophils, eosinophil-induced fibrosis, eosinophilic promotion of hypercoagulability, and various allergic mechanisms.⁶ The diagnosis of HES can be challenging, as it requires the exclusion of all secondary causes of hypereosinophilia (eg, tissue-invasive parasitic infections).⁷ Furthermore, the clinical phenotype of HES is highly heterogeneous,⁸ ranging from asymptomatic or mild, to severe and potentially fatal.² Skin, lungs and gastrointestinal tract are the organ systems more commonly affected, but patients may also present with cardiac and/or neurological symptoms.⁹ Crucially, because HES is so rare, clinicians may often lack the expertise necessary to recognize the condition. Given these diagnostic challenges, patients may experience many referrals and cycle between multiple specialists before receiving a confirmed diagnosis.¹⁰

HES can be classified into different subtypes depending on the underlying pathophysiology.⁷ Clonal or primary HES is associated with genetic variants in the PDGFRA, PDGFRB, and FGFR1 genes, while reactive HES is secondary to infections, inflammatory conditions, neoplasms, or use of specific drugs.^7,11 Around 55% of patients with HES have the idiopathic form (I-HES), in which the underlying cause is unknown: there are no reactive or neoplastic conditions responsible for the underlying hypereosinophilia, and organ damage is attributable to hypereosinophilia.^3,7 Lymphocytic HES (L-HES) accounts for 17–27% of HES cases,¹² and is driven by aberrant clonal T cell overproduction of cytokines, in particular interleukin-5 (IL-5), which plays a key role in the differentiation, activation, and survival of eosinophils.^7,11,13

Treatment goals in all HES subtypes are to reduce the eosinophil count in the blood and tissues, ameliorate symptoms and flares, and stop disease progression.¹³ Clonal and reactive HES subtypes are treated optimally with therapies targeting the underlying cause of eosinophilia. Current management of patients with I-HES/L-HES primarily involves the use of oral corticosteroids (OCS).¹ However, long-term OCS use is associated with significant failure rates and considerable toxicity, including infections, gastric conditions, psychiatric events, fractures, metabolic syndrome, and hypertension.^13,14 Patients who are unresponsive/resistant to OCS can be switched to cytotoxic, immunomodulatory, and immunosuppressive therapies, although use of these second-line agents may also be hindered by a lack of efficacy and/or toxicity.¹³

The development of biologic therapies targeting IL-5 (eg, mepolizumab) and IL-5 receptor alpha (IL-5Rα) (eg, benralizumab) represents an important advance in the treatment of HES. Mepolizumab is approved in the United States and Europe for the treatment of patients with uncontrolled HES without an identifiable non-hematologic secondary cause, severe eosinophilic asthma, and eosinophilic granulomatosis with polyangiitis (EGPA).15, 16 Following positive Phase 2 data,¹⁷ the Phase 3 NATRON study (NCT04191304) is investigating the efficacy and safety of benralizumab in patients with HES.¹⁸

Currently, the disease burden, clinical management, and treatment outcomes of patients with HES, in particular I-HES and L-HES, are not well characterized. This retrospective cohort study was carried out to provide real-world data on the clinical characteristics, demographics, patient journey, treatment patterns, and clinical outcomes for patients with I-HES/L-HES in the United States.

Methods

Study design

This was a retrospective cohort study, conducted using de-identified data of patients with either I-HES or L-HES from the TriNetX Linked electronic health record (EHR) and health insurance claims network, an anonymized EHR-derived database linked to closed claims data from healthcare organizations across the United States.

The index date (ID) was defined as the date of a patient's first HES diagnosis in either the medical record or insurance claims record between October 01, 2020 and September 12, 2023 (end of study period). Baseline was defined as 12 months prior to ID; Years 1 and 2 were defined as 12 and 24 months after ID, respectively. Patients were followed up until either September 12, 2023, disenrollment from insurance, death, or 24 months after ID, whichever came first. Informed patient consent and ethics committee approval were not required, as the study used de-identified EHR data in accordance with the Health Insurance Portability and Accountability Act.

Study population

Eligible patients were aged ≥18 years, diagnosed with HES identified by the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code (D72.11: “Hypereosinophilic syndrome”) between October 01, 2020 and September 12, 2023, with ≥12 months of continuous enrollment in a health insurance plan prior to ID (enrollment gaps in coverage ≤45 days were permitted). Manual chart adjudication and confirmation against full diagnostic workups were not feasible for these datasets.

Specific exclusion criteria were applied to identify a final cohort of patients with I-HES/L-HES only (ie, to ensure that patients with clonal or reactive variants of HES were excluded). These exclusion criteria included any mutation in PDGFRA, PDGFRB, or FGR1 genes; a history of BCR-ABL tyrosine kinase inhibitor use (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib); a history of myeloid leukemia, myeloproliferative disorder, myelodysplastic disorder, myelomonocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute panmyelosis with myelofibrosis; a history of helminthiasis or use of anthelmintic medications; a history of autoimmune disorders associated with hypereosinophilia (sarcoidosis, inflammatory bowel disease, IgG4 disease); and a history of use of specific drugs in the two-year period before HES diagnosis (antiepileptics, sulfonamides, allopurinol, immune checkpoint inhibitors). Patients were also excluded if they had a diagnosis record of EGPA (ICD-10-CM M30.1) after HES diagnosis, or if healthcare organizations failed to provide laboratory data during the study. Laboratory-confirmed diagnostic thresholds were not required for cohort entry as laboratory results were not uniformly available across contributing patients and time periods.

Prior to October 01, 2020, there was no unique ICD-10-CM code for HES, and it was not possible to differentiate HES from other eosinophilic disorders in EHR and health insurance claims databases. On October 01, 2020, the ICD-10-CM was modified in the United States and healthcare organizations began to use a specific code created for HES, namely D72.11. Patients with a first HES diagnosis record from October 01, 2020 to December 31, 2021 were presumed to be mainly pre-existing (ie, prevalent) HES cases with the new ICD-10-CM code first used at the annual follow-up visit. Patients with a first HES diagnosis record from January 01, 2022 to September 12, 2023 with ≥12-month baseline without a HES diagnosis code were presumed to be incident cases of HES. Data are presented for the overall patient population and stratified by incident and prevalent cases, and by therapeutic subgroups (anti-IL-5/Rα therapy users and conventional therapy only users).

Objectives and key variables

The primary objective was to describe the clinical characteristics and disease burden of patients with I-HES/L-HES (overall population). Secondary objectives were to describe the demographics, treatment patterns, and clinical outcomes in patients with I-HES/L-HES (overall population), and the patient journey to I-HES/L-HES diagnosis (incident I-HES/L-HES cohort only).

A subgroup analysis was conducted to describe all objectives in patients with I-HES/L-HES who were treated with anti-IL-5/Rα therapies (ie, mepolizumab, benralizumab) between October 01, 2020 and September 12, 2023. ID was the date of anti-IL-5/Rα therapy initiation. In a second subgroup analysis, clinical endpoints were quantified for patients with I-HES/L-HES who were treated with anti-IL-5/Rα therapies or conventional therapy only (OCS ± immunosuppressants) between October 01, 2020 to December 31, 2022. ID was the date of the first prescription for a relevant HES therapy (anti-IL-5/Rα therapy or conventional therapy) after HES diagnosis. Baseline was defined as 12 months prior to ID in both subgroup analyses.

Clinical characteristics of interest (ie, specific morbidities and other eosinophilia diagnoses) were assessed in the 12-month period preceding ID (ID inclusive). The disease burden of I-HES/L-HES (ie, HES-related signs/symptoms, organ involvement) was assessed in the 12 months prior to ID (ID inclusive), in the first year after ID (ie, +1 day to 12 months), and in the second year after ID (ie, months 13 through 24). HES signs and symptoms and corresponding codes are detailed in Supplemental Table 1. The disease burden of I-HES/L-HES was characterized by reporting the proportion of patients with individual organ system involvement and the number of organ systems involved as a proxy for disease severity. Disease burden was reported at organ level. Morbidities, other eosinophilic conditions, organ involvement and HES-related signs/symptoms were determined using ICD-9/10-CM codes. Asthma was defined by diagnosis code or inhaled corticosteroid (ICS)/short-acting beta agonist use. Codes of medications are detailed in Supplemental Table 2, laboratory tests in Supplemental Table 3, and procedures and encounters in Supplemental Table 4.

Endpoints to describe the patient journey to diagnosis of I-HES and L-HES included laboratory results, prior eosinophilia diagnoses, medical specialties seen in the 12-month period prior to HES diagnosis, and medical specialty who first made the HES diagnosis. The diagnostic phase in the patient journey was defined as the period from the earliest of either the first eosinophil count ≥1500 cells/μL or the first eosinophilia diagnosis record (ICD-10-CM D72.1) to the first HES diagnosis record.

Drug treatment patterns, including HES and non-HES therapies used (Supplemental Table 5), treatment pathways, and medication doses, were described in the 12-month period preceding ID (ID inclusive), and in Years 1 and 2 after ID. Clinical outcomes, including flares, clinical response, hematological remission, and blood eosinophil count, were described for the same time periods (for full definitions, see Supplemental Table 6). A patient was considered to have a definite flare if there was a record of a HES symptom(s) after the index date and an eosinophil count of ≥1000 cells/μL within 4 weeks of the symptom(s) and was considered to be in hematologic remission when their blood eosinophil count was ≤500 cells/μL, similar to the definition used in the phase 3 NATRON study.¹⁸

Statistical methods

Analyses were descriptive and not intended to identify independent risk factors for disease burden. Descriptive statistics were used to summarize categorical variables (frequencies, percentages) and continuous variables (means/standard deviations [SD], medians/interquartile ranges). Time-to-event analyses were described using Kaplan–Meier estimates.

Results

Study participation

The overall population included 110 patients (Supplemental Fig. 1), 53 of whom were incident cases of I-HES/L-HES. Thirteen patients were included in the subgroup treated with anti-IL-5/Rα therapies (Supplemental Fig. 1). In the subgroup of patients treated with anti-IL-5/Rα therapies or conventional therapy only, 12 patients were treated with anti-IL-5/Rα therapies and 28 were treated with conventional therapy only (Supplemental Fig. 2).

Demographics

In the overall population, the mean (SD) age was 43.8 (21.3) years at the date of first HES diagnosis record; 60.0% (66/110) of patients were male, 52.7% (58/110) were White, and 27.3% (30/110) were Black or African American (Table 1). Mean (SD) follow-up was 15.1 (7.7) months. Demographics of the prevalent and incident cases of HES are reported in Supplemental Table 7.

Table 1.

Demographics of patients with I-HES/L-HES (overall population).

	All patients (N = 110)
Calendar year of first HES diagnosis record (index date), n (%)
2020	12 (10.9)
2021	45 (40.9)
2022	32 (29.1)
2023	21 (19.1)
Age at first HES diagnosis record (index date) (years)
Mean (SD)	43.8 (21.3)
<18 years, n (%)	15 (13.6)
18–65 years, n (%)	75 (68.2)
>65 years, n (%)	20 (18.2)
Age at first EOS laboratory test (years)
Number of patients with EOS test prior to index date, n	78
Mean (SD)	40.1 (21.0)
Median (IQR)	39 (24, 59)
Min, Max	1, 79
Age at first EOS count ≥1500 cells/μL or first record of eosinophiliaa(years)
Number of patients with EOS lab test or record of eosinophilia, n	69
Mean (SD)	42.6 (22.2)
Median (IQR)	46 (25, 60)
Min, Max	0, 77
Age at first EOS count ≥1500 cells/μL (years)
Number of patients with EOS lab test, n	31
Mean (SD)	41.7 (22.6)
Median (IQR)	50 (22, 63)
Min, Max	1, 72
Sex, n (%)
Female	44 (40.0)
Male	66 (60.0)
Race, n (%)
Black or African American	30 (27.3)
White	58 (52.7)
Other	14 (12.7)
Unknown	8 (7.3)

Abbreviations: EOS, eosinophil; HES, hypereosinophilic syndrome; I-HES, idiopathic hypereosinophilic syndrome; IQR, interquartile range; L-HES, lymphocytic hypereosinophilic syndrome; Max, maximum; Min, minimum; SD, standard deviation.

^aFirst record of eosinophilia = ICD-10-CM code D72.1

Clinical characteristics

In the 12-month baseline period prior to ID, the most common morbidities recorded in the overall population included asthma (50.0%, 55/110), gastroesophageal reflux disease (GERD; 26.4%, 29/110), dorsalgia (24.5%, 27/110), hypertensive disease (19.1%, 21/110), and essential hypertension (12.7%, 14/110) (Table 2). Similar results for morbidities were observed in the incident cases of HES (Supplemental Table 8). Prior to their HES diagnosis, patients were misdiagnosed with other eosinophilic disorders. The most common misdiagnoses included unspecified eosinophilia (28.2%, 31/110), other eosinophilia (12.7%, 2/110), and eczema (11.8%, 13/110).

Table 2.

Baseline^a clinical characteristics of patients with I-HES/L-HES (overall population).

Morbidities prior to index date, n (%)	All patients (N = 110)
General	20 (18.2)
Malaise/fatigue	13 (11.8)
Fever, unspecified	11 (10.0)
Respiratory	61 (55.5)
Asthma (diagnosis code OR treated with ICS/SABA)	55 (50.0)
Chronic obstructive pulmonary disorder	10 (9.1)
Respiratory failure	8 (7.3)
Pneumonia, unspecified organism	8 (7.3)
Cardiovascular	28 (25.5)
Essential (primary) hypertension	14 (12.7)
Hypertensive disease	21 (19.1)
Ischemic heart disease	13 (11.8)
Myocardial infarction	3 (2.7)
Skin	7 (6.4)
Rash	7 (6.4)
Gastrointestinal	37 (33.6)
Nausea/vomiting	13 (11.8)
Diarrhea	5 (4.5)
Gastroesophageal reflux disease	29 (26.4)
Renal	15 (13.6)
Acute kidney failure	8 (7.3)
Chronic kidney failure	9 (8.2)
Nasal and vision	10 (9.1)
Chronic rhinitis	10 (9.1)
Musculoskeletal	27 (24.5)
Dorsalgia	27 (24.5)
Other eosinophilia diagnoses
Eosinophilia, unspecified	31 (28.2)
Eosinophilia in diseases classified elsewhere	2 (1.8)
Other eosinophilia	14 (12.7)
Other eosinophilia conditions
Eosinophilic endomyocardial disease	1 (0.9)
Eosinophilic esophagitis	6 (5.5)
Eosinophilic gastritis or gastroenteritis	3 (2.7)
Eosinophilic colitis	2 (1.8)
Pulmonary eosinophilia	7 (6.4)
Chronic eosinophilic pneumonia	1 (0.9)
Eosinophilic asthma	6 (5.5)
Atopic dermatitis	6 (5.5)
Eczema	13 (11.8)
Allergic bronchopulmonary aspergillosis	1 (0.9)

Abbreviations: ICS, inhaled corticosteroid; I-HES, idiopathic hypereosinophilic syndrome; L-HES, lymphocytic hypereosinophilic syndrome; SABA, short-acting beta agonist.

^aBaseline period = 1 year prior to index date (index date inclusive)

Disease burden

In the overall population, most patients had at least 1 organ affected over the 2 years of follow-up, with a significant proportion of patients having multiple organs affected (Fig. 1). The mean (SD) number of organ systems involved with HES signs and/or symptoms was 2.9 (2.1), 3.0 (2.0), and 2.1 (2.0) in the baseline period, Year 1, and Year 2 of follow-up, respectively. Pulmonary (60.9%, 67/110), ear, nose and throat (ENT; 43.6%, 48/110), and gastrointestinal (34.5%, 38/110) systems were most affected in the baseline period, with asthma (36.4%, 40/110), runny nose (33.6%, 37/110), and abdominal pain (23.6%, 26/110) the most common contributing symptoms to each organ system category, respectively (Supplemental Table 9). Pulmonary (58.3%, 14/24) and otolaryngological (41.7%, 10/24) systems remained the most affected by the end of Year 2 (Supplemental Table 9).

Fig. 1.

Number of organ systems with HES signs and/or symptoms (overall population). HES, hypereosinophilic syndrome.

In the subgroup of incident cases, the mean (SD) number of organ systems involved with HES signs and/or symptoms was 3.2 (2.3) at baseline and 2.7 (1.8) after Year 1 of follow-up (Supplemental Table 10) No patients with incident HES had 2 years of follow-up. The most common organ systems involved were similar to the overall cohort, although cardiovascular system involvement was more evident in the incident cohort (Supplemental Table 11).

Patient journey to diagnosis

The patient journey to diagnosis of I-HES/L-HES was described for incident cases only (Supplemental Table 12). Among the 44 patients with an eosinophil laboratory result in the diagnostic phase, the mean (SD) time from the first eosinophil laboratory record to HES diagnosis was 52.5 (65.8) months (Supplemental Table 12). A total of 13 patients had a first eosinophil count ≥1500 cells/μL prior to HES diagnosis (Fig. 2). Demographics of these 13 patients are shown in Supplemental Table 13. The mean (SD) time from the first eosinophil count ≥1500 cells/μL to HES diagnosis was 47.9 (75.8) months (Supplemental Table 12). The mean (SD) time from the first eosinophil count ≥1500 cells/μL to initiation of HES therapy was 29.0 (42.6) months (n = 6). In the 4 patients who initiated therapy prior to HES diagnosis, the mean (SD) time from the first eosinophil count ≥1500 cells/μL to first HES therapy was 42.2 (48.2) months. Two patients started therapy after HES diagnosis; the mean (SD) time from the first eosinophil count ≥1500 cells/μL to initiation of HES therapy was 2.5 (3.5) months. Patients who initiated therapy prior to an eosinophil count ≥1500 cells/μL were not included in these analyses. The medical specialties seen in the 12-month baseline period and the medical specialty making the first HES diagnosis were largely not recorded.

Fig. 2.

Patient journey from first EOS ≥1500 cells/μL to diagnosis and treatment (incident cohort). EOS, eosinophil; HES, hypereosinophilic syndrome; SD, standard deviation. ^aThe start of HES therapy was defined as the date of the first prescription of a HES-related therapy (prednisone, prednisolone, methylprednisolone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, mepolizumab, benralizumab, rituximab, dupilumab, interferon-alfa, hydroxyurea/hydroxycarbamide). HES therapy may have pre-dated HES diagnosis (index date).

Treatment patterns

In the 12-month baseline period, 42.7% (47/110) of patients in the overall population received a therapy for HES, with 46.4% (32/69) and 50.0% (12/24) of patients receiving HES treatment in Years 1 and 2 of follow-up, respectively. Among patients who received treatment, OCS (prednisone, prednisolone, methylprednisolone) were the most prescribed therapy. In the baseline period, 93.6% (44/47) of patients who received a HES-related therapy were prescribed OCS; this decreased to 81.3% (26/32) and 58.3% (7/12) in Years 1 and 2 of follow-up, respectively (Fig. 3a). The proportion of treated patients who received maintenance OCS (≥15 days of use) was 27.7% (13/47), 43.8% (14/32), and 33.3% (4/12) in the baseline, Year 1, and Year 2 periods, respectively (Fig. 3b). The mean daily OCS dose for patients on maintenance OCS fluctuated throughout the study period but overall decreased from baseline to the end of follow-up: patients received a mean (SD) OCS dose of 17.7 (14.5) mg at baseline, which increased to 21.9 (11.4) mg at Year 1 and decreased to 13.0 (6.2) mg at Year 2. The use of topical corticosteroids and ICS (both classed as non-HES therapies) decreased by the end of the study (Fig. 3b; see Supplemental Table 14 for ICS dose classifications).

Fig. 3.

Treatment patterns (a) and type of corticosteroid therapy used (b) during the baseline period and Years 1 and 2 (overall population). ICS, inhaled corticosteroids; OCS, oral corticosteroids. ^aOne patient received mepolizumab prior to the baseline period, had no biologic use during the baseline period, then received benralizumab in combination with another biologic during Year 1; ^bDose and dose schedules not reported. ^cPatients may have received ≥1 type of OCS course. ^dDefined as initiation of, or increase in, OCS use lasting for ≤5 days with daily dose >10 prednisone-equivalent mg/day, immediately followed by OCS discontinuation or a return to previous dose for ≥14 days. ^en = 16, n = 9, and n = 5 patients had unknown ICS dose at baseline, Year 1, and Year 2, respectively. ICS was analyzed at the class level and classified into low, medium, and high dose as defined in the Global Initiative for Asthma (GINA) guidelines.¹⁹ See Supplemental Table 14 for ICS dose classifications.

Use of any biologics increased from baseline through to Year 2 of follow-up, with 12.8% (6/47), 43.8% (14/32), and 58.3% (7/12) of the patients who were treated for HES receiving biologics in the baseline period, Year 1, and Year 2, respectively (Fig. 3a). Use of any anti-IL-5/Rα therapies also increased over the study period, with 8.5% (4/47), 31.3% (10/32), and 50.0% (6/12) of patients receiving mepolizumab or benralizumab in the baseline period, Year 1, and Year 2 of follow-up, respectively. No patients were treated with hydroxyurea or interferon-α.

Few patients with HES were treated with immunosuppressants (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mycophenolate mofetil). In the baseline, Year 1, and Year 2 periods, 6.4% (3/47), 12.5% (4/32), and 0.0% (0/12) of patients received immunosuppressant therapy, respectively (Fig. 3a).

Among all patients, topical corticosteroid use fluctuated over time with 13.6% (15/110), 18.8% (13/69), and 4.2% (1/24) of patients prescribed topical corticosteroids in the baseline period, Year 1, and Year 2 of follow-up, respectively (Fig. 3b). ICS use also fluctuated across the study period. At baseline, 33.6% (37/110) of patients were prescribed ICS. By Years 1 and 2 of follow-up, 40.6% (28/69) and 33.3% (8/24) of all patients had been prescribed ICS, respectively (Fig. 3b). Almost a third (30.4%, 21/69) of patients were treated with an ICS and long-acting beta agonist (LABA) combination during Year 1 of follow-up, an increase in combination use from baseline (23.6%, 26/110); however, no patients were treated with this combination by the end of Year 2.

Clinical outcomes

In the baseline period, 10.9% (12/110) of patients had a definite flare, 36.4% (40/110) had a definite or probable flare, and 68.2% (75/110) had a definite, probable, or possible flare (Fig. 4). The proportion of patients who experienced HES flares decreased over the study period. At Year 2 of follow-up, no patients (0/24) had a definite flare, 4.2% (1/24) of patients had a definite or probable flare, and 29.2% (7/24) had a definite, probable, or possible flare. The median (95% confidence interval [CI]) time from ID to first flare (n = 47) was 18.0 (11.0, not estimated [NE]) months.

Fig. 4.

HES flares during the baseline period or Years 1 and 2 (overall population). HES, hypereosinophilic syndrome; SD, standard deviation. ^aA record of a HES symptom after the index date and a blood eosinophil count of ≥1000 cells/μL within 4 weeks of the symptom; ^bA record of a HES symptom after the index date, but no blood eosinophil count within 4 weeks of the symptom, plus an initiation of medication to treat symptoms and/or change in existing medication regimen and/or eosinophilia-related hospitalization or emergency visit; ^cA record of a HES symptom but criteria for definite or probable flare were not met, and there was no blood eosinophil count data within 4 weeks of the symptom; ^dMean number of HES flares amongst patients who experienced at least 1 flare.

Few patients achieved clinical response, defined as ≥3 months with no HES symptoms and an eosinophil count ≤750 cells/μL, either at baseline (9.1%; 10/110), Year 1 (7.2%; 5/69), or Year 2 (4.2%; 1/24) of follow-up.

The proportion of patients who achieved complete hematological remission, defined as a blood eosinophil count ≤500 cells/μL, increased by the end of the study. In the baseline period, 27.3% (30/110) of patients had complete remission, with 29.0% (20/69) and 37.5% (9/24) of patients having complete remission during Years 1 and 2 of follow-up, respectively (Supplemental Fig. 3). Partial remission was achieved by 30.0% (33/110), 11.6% (8/69), and 8.3% (2/24) of patients during those evaluation periods, respectively. The median (95% CI) time from diagnosis to first complete or partial hematological remission (n = 52) was 15.3 (10.8, 21.6) months. Throughout the study, approximately half of patients had unknown remission status.

Overall, the proportion of patients with eosinophil records decreased over the study period. Approximately half of patients (46.4%, 51/110) had an eosinophil record in the 12-month baseline period, with 15.9% (11/69) of patients with a record in Year 1 and 12.5% (3/24) with a record in Year 2. Among patients with blood eosinophil data, the mean (SD) blood eosinophil count was 2235.3 (4351.7) cells/μL at baseline (n = 51), 833.6 (1396.0) cells/μL at Year 1 (n = 11), and 589.0 (616.0) cells/μL at Year 2 (n = 3) (Supplemental Fig. 4). The proportion of patients with a blood eosinophil count <500 cells/μL was 39.2% (20/51) at baseline, 63.6% (7/11) at Year 1, and 66.7% (2/3) at Year 2.

Subgroup analysis: patients treated with anti-IL-5/Rα therapies

In the subgroup of patients treated with anti-IL-5/Rα therapies, for which ID was the date of anti-IL-5/Rα therapy initiation, 13 patients had available data during the baseline period (ie, 12 months prior to ID), 12 had at least 1 year of follow-up and 5 had 2 years of follow-up. Demographics were largely similar to the overall cohort; mean (SD) age at the date of first HES diagnosis record was 45 (22.9) years, 61.5% (8/13) was male, 69.2% (9/13) White and 7.7% (1/13) Black or African American. In the 12-month baseline period, the most common morbidities recorded in the subgroup were asthma (84.6%, 11/13), dorsalgia (23.1%, 3/13), GERD (15.4%, 2/13), and chronic rhinitis (15.4%, 2/13).

The mean (SD) number of organ systems with HES signs and/or symptoms increased over the study from 3.2 (1.5) in the baseline period to 3.8 (2.6) by Year 2. Otolaryngological (84.6%, 11/13) and pulmonary (76.9%, 10/13) systems were commonly affected in the baseline period. By the end of the study, otolaryngological system involvement had decreased (60.0%, 3/5) and pulmonary system involvement increased (80.0%, 4/5).

Four patients were incident cases of HES. The mean (SD) time from the first eosinophil laboratory record to HES diagnosis was 49.4 (78.0) months among the 3 patients with an eosinophil count in the diagnostic phase. The mean (SD) time from the first eosinophil count ≥1500 cells/μL to HES diagnosis was 4.4 (2.3) months, which was shorter than the overall cohort. Medical specialties seen in the 12-month baseline period, and those responsible for making a HES diagnosis, were largely unknown (75.0%, 3/4).

OCS were also commonly prescribed in this subgroup, but use decreased over time, with 76.9% (10/13) of patients prescribed OCS in the baseline period, and 58.3% (7/12) and 40.0% (2/5) prescribed OCS in Years 1 and 2, respectively. Maintenance OCS use decreased over the study period, with 61.5% (8/13), 41.7% (5/12), and 40.0% (2/5) of patients receiving ≥15 days of OCS use during the baseline period, Year 1, and Year 2, respectively. However, the mean daily OCS dose for the patients treated with maintenance OCS increased throughout the study period, with patients on a mean (SD) of 12.1 (7.1) mg in the baseline period (n = 8), 17.8 (12.6) mg in Year 1 (n = 5), and 32.1 (2.9) mg in Year 2 (n = 5). A high proportion of patients also received ICS (baseline: 61.5%, 8/13; Year 1: 75.0%, 9/12; Year 2: 60.0%, 3/5). The use of ICS/LABA combination therapy decreased over time, with 1 patient (20.0%, 1/5) treated with ICS/LABA during Year 2 compared with 61.5% (8/13) in the baseline period.

In the 12-month baseline period, 23.1% (3/13) of patients had a definite HES flare, 53.8% (7/13) had a definite or probable flare, and 69.2% (9/13) had a definite, probable, or possible flare. By Year 2, no patients (0/5) had a definite flare, 1 patient (20.0%, 1/5) had a definite or probable flare, and 2 patients (40.0%, 2/5) had a definite, probable, or possible flare. The median (95% CI) time to first flare (using any definition) from ID was 6.5 (2.6, 11.4) months.

Only 1 patient (7.7%, 1/13) experienced a clinical response, which was during the baseline period. In the baseline period, 15.4% (2/13) of patients achieved a complete hematological remission and 46.2% (6/13) achieved a partial remission. In Year 1 of follow-up, complete remission was achieved by 58.3% (7/12) of patients, and decreased to 20.0% (1/5) of patients by Year 2. The median (95% CI) time from ID to first complete or partial hematological remission (n = 7) was 11.1 (3.5, NE) months.

Few patients had blood eosinophil count records; 38.5% (5/13) had records in the baseline period and 8.3% (1/12) had records in Year 1 of follow-up. No patients in this subgroup had eosinophil count records in Year 2. The proportion of patients with a blood eosinophil count <500 cells/μL was 40.0% (2/5) at baseline, 100.0% (1/1) at Year 1, and no patients at Year 2.

Subgroup analysis: clinical outcomes for patients treated with anti-IL-5/Rα therapies or conventional therapy only

The median (95% CI) time to first flare after ID (date of the first prescription for a relevant HES therapy [anti-IL-5/Rα therapy or conventional therapy] after HES diagnosis) in patients treated with anti-IL-5/Rα therapies (n = 9) was 7.1 (2, 13.8) months versus 10.8 (7.0, NE) months in patients treated with conventional therapy only (n = 15) (Supplemental Table 15). HES flares generally decreased in frequency over the study period in patients treated with anti-IL-5/Rα therapies only (n = 12) or conventional therapy only (n = 28). A higher proportion of patients treated with anti-IL-5/Rα therapies had flares (definite, probable, or possible) in the 12-month baseline period prior to ID (83.3%, 10/12) versus patients treated with conventional therapy only (64.3%, 18/28), but no patients in either group experienced definite flares between Years 1 and 2 of follow-up.

No patients treated with anti-IL-5/Rα therapies experienced clinical response at any point of evaluation. In the conventional therapy only group, 7.1% (2/28) of patients had clinical response in the baseline period. One patient in this group had clinical response in Months 0–6 of evaluation (3.6%, 1/28), but no patients had a sustained response into the follow-up periods.

A higher proportion of patients in the anti-IL-5/Rα therapy group than the conventional therapy group achieved complete remission (33.3% vs 21.4% after 6 months of follow-up and 36.4% vs 0% after 12 months of follow-up, respectively). The anti-IL-5/Rα group (n = 7) had a shorter median (95% CI) time to first complete or partial hematological remission than the conventional therapy only group (n = 12) (6.4 [0.3, NE] months vs 17.6 [12.5, NE] months, respectively).

The proportion of patients with eosinophil records in the conventional therapy group decreased over the study period. In the anti-IL-5/Rα therapy group, 33.3% (4/12) had an eosinophil record in the baseline period; this had decreased to 0.0% (0/3) by Year 2 of follow-up. In the baseline period, 37.5% (3/8) of patients treated with conventional therapy only with eosinophil laboratory records had an eosinophil count <500 cells/μL; no patients in this group had an eosinophil count <500 cells/μL by Year 2 of follow-up. Similarly, 25.0% (1/4) of anti-IL-5/Rα therapy users with laboratory records had an eosinophil count <500 cells/μL in the baseline period, and no patients had a count <500 cells/μL by Year 1–2 of follow-up.

Discussion

This real-world study provides insights on clinical characteristics, demographics, patient journey, treatment patterns, and clinical outcomes for patients with I-HES/L-HES following the implementation of a unique ICD-10-CM code for HES.

Our data on disease burden in patients with I-HES/L-HES are in line with previous real-world studies showing that cutaneous, gastrointestinal, and pulmonary systems are commonly affected.^1,3,9 Similarly, the pattern of organ involvement in this real-world study overlaps with the most common organ systems affected in the prospective COHESion study conducted in patients with HES.²⁰ Our study also found that there was a high proportion of cardiovascular system involvement reported in incident cases of HES. Given that HES is associated with early cardiac death,⁸ this highlights the need for prompt intervention.

Patients treated with anti-IL-5/Rα therapies in our study had a higher disease burden at baseline compared with the overall population, and the burden increased over the study period. However, the higher disease burden could be due to confounding by indication, as no adjusted analyses were performed to account for those with concomitant conditions. The subgroup also had a higher proportion of patients with pulmonary involvement versus the overall population. As both mepolizumab and benralizumab are approved for use in asthma, it is to be expected that patients with both asthma and HES would be more likely to be treated with anti-IL-5/Rα therapies.

This study found that patients with incident I-HES or L-HES may wait more than 2 years from eosinophilia onset to treatment initiation and approximately 4 years to diagnosis. Patients also visited multiple medical specialists in the 12 months prior to HES diagnosis. Given the disease burden and significant morbidity associated with HES, there is a need for greater disease awareness of HES among healthcare professionals to reduce the delays in diagnosis and improve the timeliness of treatment initiation.

We found that 50% of patients did not receive treatment for HES within 2 years of diagnosis. However, it is possible that these patient data were truncated due to a limited length of follow-up, resulting in an under-estimation of time to treatment. Additionally, some patients may not have received treatment due to other factors, such as misclassification or mild disease. Among patients with I-HES/L-HES who received treatment, OCS were the cornerstone of treatment but their use decreased over the course of the study period. Few patients with HES in this study received immunosuppressants. This pattern of immunosuppressant use is consistent with findings elsewhere, and contrasts with the treatment of patients with EGPA, for which immunosuppressants are an important part of the treatment regimen.^21,22 Although very few patients were treated with biologics overall, the proportion of patients with I-HES/L-HES who were treated specifically with mepolizumab (which was approved in the United States for the treatment of HES in September 2020)¹⁵ or benralizumab increased over the 2 years of follow-up. Evidence supports the use of biologics as efficacious and well tolerated treatments of HES,²³ so the findings from this study may mark an early shift towards biologics as alternative therapies to OCS. Despite their limitations, there is still an over-reliance on the use of OCS for the treatment of HES, so there is a need for a wider use of steroid-sparing therapeutic options for patients with I-HES/L-HES.

Overall, the proportion of patients experiencing flares (of any category) decreased over the follow-up period. Although the proportion of patients experiencing complete hematological remission did increase across the study, by study end this was experienced by only 40% of patients. Further, few patients achieved a clinical response. These findings align with those of Hwee et al who found that 23% of patients experienced a flare and only 40% of patients experienced a complete treatment response, proposing that this was indicative of suboptimal management of patients with HES.³ However, these data should be considered in the context of certain limitations. It was not determined whether elevated eosinophil counts were attributable to HES flares or comorbidities, potentially leading to an overestimation of HES flares. In addition, the flare and remission data were proxies derived from EHR data and ICD-9/10-CM codes rather than clinical assessments. Finally, the small sample size of the subgroups of patients treated with anti-IL-5/Rα therapies and conventional therapy only limits any meaningful interpretation.

This study had several strengths. Firstly, this was a relatively large cohort of patients (N = 110) considering the rarity of the disease and that the unique ICD-10-CM diagnosis code had only recently been implemented in the United States. Further, this study was novel as it only evaluated patients with I-HES/L-HES, rather than HES as a heterogeneous group, adding to the limited body of knowledge around I-HES/L-HES. However, there were also limitations. Reliance on ICD-10-CM code D72.11 without manual chart adjudication may have resulted in residual misclassification despite implemented safeguards, such as the extensive exclusion criteria used to remove clonal and reactive causes of HES and to exclude EGPA following HES diagnosis. Organ involvement and comorbidities were determined using ICD-9/10-CM codes rather than clinical judgment, thereby risking misclassification. Signs and symptoms of HES and HES-related organ involvement could not be definitively determined due to the potential influence of comorbidities. Therefore, symptoms and organ involvement were assumed to be attributable to HES, which may have resulted in an overestimation of their frequency. The retrospective nature of the study means it was prone to bias, despite methods employed to minimize it. Although all patients had at least 12 months of baseline and continuous enrollment, some may have had a first eosinophil count ≥1500 cells/μL outside of the TriNetX network or prior to enrollment in a health insurance plan. Some variables in the EHR had incomplete/missing data, which were partially mitigated via linked insurance claims data, but some outcomes may have still been underestimated. In addition, whilst the study primarily examined incident HES cases to provide a clearer understanding of the disease and treatment outcomes from the point of diagnosis, for some objectives there were not enough patients with incident HES cases who had sufficient follow-up data available. Similarly, the subgroup analysis data should be interpreted with caution given the small patient numbers. Finally, mepolizumab was approved in the United States for the treatment of HES in September 2020,15, 24 so it is probable that widespread access to mepolizumab at the start of this study may have been limited.

In summary, in this real-world study of patients with I-HES/L-HES in the United States, we confirm the considerable disease burden associated with HES. The lengthy patient journey to HES diagnosis and treatment highlights the need for greater disease awareness and improved multidisciplinary management of patients with HES. Less than half of patients with I-HES/L-HES in this study received therapy. Many of those patients who did receive treatment did not experience a complete hematological remission or achieve a clinical response, demonstrating the need for more effective therapies to better manage patients with I-HES/L-HES.

Ethics statement

All study data were accessed in compliance with data use principles and in accordance with Health Insurance Portability and Accountability Act (HIPAA) and applicable United States state and federal laws governing the privacy and security of health information and personal data. This retrospective database study was not classified as research involving human subjects United States Department of Health and Human Services (HHS) “Common Rule”, codified at 45 C.F.R. Part 46.101) for the following reasons: (i) there was no interaction with human subjects, (ii) all data were collected during routine clinical practice prior to accessing the final data cut from the TriNetX Linked Electronic Health Records + Claims network (no additional data were collected and/or documented beyond the data available in Linked), and (iii) all study data were de-identified and no patient identifiers were available to the study investigators or study sponsor.

Author contributions

All authors contributed equally to this work and give their consent for the publication of this article.

Data availability statement

The data that support the findings of this study were made available to AstraZeneca under license for the current study and restrictions apply to the availability of these data. These data are not publicly available. However, the data are commercially available from the authors with permission of AstraZeneca and TriNetX, LLC.

Disclosure of the use of generative AI and AI-assisted technologies

Nothing to disclose.

Funding

This study was funded by AstraZeneca.

Declaration of competing interest

The authors declare the following financial interests/relationships which may be considered as a potential conflict of interest:

TPo discloses research funding from AstraZeneca, Blueprint Medicines, Cogent Biosciences, GSK, Regeneron, and Sanofi. PD, BD, PJ, JR, CE, JME, and SYC are or were employees or contractors at AstraZeneca at the time of study conduct and may hold stocks in AstraZeneca. PD holds stocks in GSK. JR holds stocks in Roche. AMM, TPe, and KAC are employees of TriNetX and may hold stocks in TriNetX, which received funding from AstraZeneca for the conduct of this study. KAC discloses former employment with National Taiwan University and research funding from Boehringer Ingelheim and Amgen.

Appendix A. Supplementary data

The following is the Supplementary data to this article: