These were post hoc subgroup analyses of a retrospective, non-interventional, longitudinal, physician panel-based chart review study (GSK ID: 214657) of patients diagnosed with HES across five European countries (Germany, Italy, France, Spain and the UK), the methodology of which has been reported previously (22). Briefly, diagnosis date was defined as the date of HES diagnosis and index date was defined as the first clinical visit for any reason occurring between January 2015 and December 2019 (patients could have an existing diagnosis of HES or be newly diagnosed at the index date). For patients diagnosed before the index date, a pre-index period was utilized from which patient demographics and baseline clinical characteristics were identified. Follow-up included the period from index date to the earliest occurrence of death, loss to follow-up or end date of chart abstraction. The last date of follow-up was 14 July, 2021. The study included patients with a physician-confirmed HES diagnosis aged ≥6 years at time of diagnosis with ≥1-year follow-up from index, except where follow-up ended due to death.

Longitudinal patient-level data were obtained from demographically and geographically diverse, nationally representative populations. Physicians (N = 121) were the primary healthcare provider for ≥1 eligible patient with HES, with access to their medical records. Physicians abstracted medical charts of randomly selected patients. Physicians were from different practice settings (academic or community-based) and included targeted specialties (allergy, hematology, immunology, internal medicine, pulmonology and rheumatology) from each participating country. Only anonymized data were collected. Physicians were blind to the identity of the study sponsor and vice versa.

Demographic and baseline characteristic information were obtained from patient charts from the pre-index period (between HES diagnosis and the index date for patients diagnosed before index; these characteristics were also collected for patients diagnosed at index). Clinical manifestations and outcomes of HES and HCRU were assessed from the index date until the end of follow-up. Comorbid conditions and treatment patterns were assessed from HES diagnosis until end of follow-up, unless otherwise stated.

Data were summarized for the overall HES population and M-HES, L-HES and I-HES subtypes (defined post hoc) as follows: patient demographics and disease characteristics (including age at diagnosis, age at index and disease duration), diagnostic assessments, comorbidities, types of treatment (e.g., OCS, immunosuppressant/cytotoxic agents, biologics or other therapies), clinical manifestations, clinical outcomes and HES-related HCRU. Clinical outcomes included the occurrence of flares, defined as a worsening of HES-related symptoms or blood eosinophil counts requiring therapy escalation (dose increase or additional/new therapy) and responses to treatment. A complete response was defined as physician-reported improved or resolved symptoms and a normal eosinophil count (≤500 cells/ml) (27). Partial response reflected improved symptoms and eosinophil count that was improved but was not in the reference range and required more therapy.

Demographics, disease characteristics, comorbidities and HCRU were summarized for the subgroup of patients who had received biologic treatment between HES diagnosis and end of follow-up. For patients with a non-missing date for ≥1 biologics prescription pre- and post-biologic initiation periods were defined. The pre-biologics period was defined as 12 months before and including the initiation of biologics. Only events and person-years after HES diagnosis were included. The post-biologics period was defined as 12 months after the initiation of biologics, or until death or end of follow-up. The following outcomes were summarized for ≤12 months pre- and post- biologics initiation: OCS use (annualized rate of prescriptions and proportion of patients receiving ≥1 prescription), clinical manifestations (proportion of patients with manifestation) and clinical outcomes (flares and clinical response to treatment).

The subgroup analyses were defined post hoc. All study outcomes were summarized using descriptive statistics and no comparative testing was performed. Real-world flare-free survival (FFS) was assessed over the 6 years following the initial diagnosis date (6-year restricted mean survival time) using Kaplan–Meier analysis. Data analysis was performed using SAS Enterprise Guide Version 7.15 (SAS Institute Inc., Cary, NC, USA).

Of the 280 patients for whom data were collected, 265 had a physician-defined subtype and 15 had unknown disease subtype. Of those with a physician-defined subtype, 155 had I-HES, 66 had M-HES, 42 had L-HES and 2 had chronic eosinophilic leukemia. Overall patient demographics and physician characteristics have been published previously (22). HES subtype distribution varied between countries, although in all countries most patients had I-HES [51.9% in Spain (lowest), 61.5% in Italy (highest); 55.4% overall]. The highest proportion of patients with M-HES was in Spain (34.6%; 23.6% overall) and with L-HES was in the UK (22.6%; 15% overall).

A higher proportion of patients with M-HES were male (75.8%) and were older at diagnosis (mean age 47.0 years) than in the overall population (65.0% and 42.4 years, respectively) and other subtypes (Table 1). The median number of diagnostic assessments was similar across HES subtypes; however, types of testing performed varied according to disease subtype (Table 1). For example, allergy testing (83.3%) and kidney function testing (95.2%) were performed most frequently among patients with L-HES, whereas bone marrow aspiration and biopsy (80.3%) and molecular genetic testing (71.2%) were more frequent in patients with M-HES. Median duration of HES (2.5–2.9 years) and length of follow-up (2.3–2.5 years) were similar across subtypes. The highest median [interquartile range (IQR)] blood eosinophil count was observed in the M-HES subtype [2,300.0 (850.0, 4,500.0) cells/µl]; counts in L-HES and I-HES were 1,570.0 and 1,890.0 cells/µl, respectively (Table 1).

Asthma, anxiety or depression, nasal polyps and hypertension were the most common comorbidities across subtypes (Table 2). Asthma was most common in I-HES (52.3%) and less common in M-HES and L-HES subtypes (25.8%–47.6%, respectively). Anxiety or depression affected more patients with M-HES (48.5%) than L-HES (33.3%) or I-HES (34.2%). Nasal polyps were most common with I-HES (38.7%) and less common with the other subtypes (23.8%–27.3%); while rates of hypertension were reported in around one-third of patients (31.6%–36.4%) across subtypes (Table 2).

Mean [standard deviation (SD)] time from diagnosis to initiation of HES therapy was shortest for M-HES [0.4 (1.1) years] and longest for L-HES [1.0 (2.2) years; Table 3]. OCS were received by 80.3%–92.3% of patients across all subtypes and were most commonly used among patients with I-HES; however, the mean (SD) maximum daily OCS dose was lowest in the I-HES subtype [28.4 (19.3) mg] and highest with the M-HES subtype [38.6 (19.0) mg; Figure 1; Table 3]. The use of immunosuppressive and cytotoxic therapies was most common among the M-HES (71.2%) and L-HES (69.0%) subtypes. This included the targeted therapy imatinib, which was used by 39.4% of patients with M-HES, 2.4% with L-HES and 17.4% with I-HES (Table 3). Biologic use was highest in patients with L-HES (64.3%), followed by I-HES (43.9%) and M-HES (34.8%). The most common biologic therapies were mepolizumab (15.4%), benralizumab (12.1%) and rituximab (12.1%). Mean (SD) time from HES diagnosis to biologic initiation ranged from 2.7 (3.2) years for L-HES to 3.0 (3.6) years for I-HES (Table 3). The most common therapies reported as ongoing at end of follow-up were OCS in I-HES, immunosuppressants/cytotoxic therapies in M-HES and biologic therapies in L-HES (Figure 1; Supplementary Table 1).

A median (IQR) of 3.0 (1.0, 5.0) distinct clinical manifestations was observed for each HES subtype. The patterns of organ involvement varied across subtypes but constitutional, lung and skin manifestations were common across all (Figure 2). Gastrointestinal involvement was highest in M-HES (34.8%), cardiovascular involvement was highest in L-HES (26.2%) and neuropsychiatric involvement was highest in I-HES (16.8%). The most common distinct clinical manifestations were fatigue (54.2% I-HES, 52.4% L-HES and 42.4% M-HES), skin itch (36.4% M-HES, 35.7% L-HES and 33.5% I-HES) and pain (31.0% L-HES, 30.3% M-HES and 27.1% I-HES; Supplementary Table 2). These clinical manifestations were most commonly of moderate severity in each of the HES subtypes (moderate fatigue: 71.4% M-HES, 63.6% L-HES and 63.1% I-HES; moderate skin itch: 53.3% L-HES, 50.0% M-HES, 42.3% I-HES; and moderate pain: 80.0% M-HES, 73.8% I-HES, 69.2% L-HES; Supplementary Table 3).

The pattern of flare frequency and length, as well as clinical response, differed between subtypes (Table 4). The proportion of patients who experienced ≥1 flare/s was highest in the L-HES subtype (33.3%) and lowest in the M-HES subtype (18.2%). However, median flare duration was longest for M-HES (3.8 months) and shortest for I-HES (1.6 months). Clinical response rates were highest for I-HES (75.5%) than other subtypes (63.6%–66.7%) but with longer median time to first response with I-HES (13.9 months) than L-HES (7.2 months) or M-HES (8.2 months). Over 6 years of follow-up, mean FFS was 4.91 years overall, and 5.05, 4.24 and 5.04 years with the M-HES, L-HES and I-HES subtypes, respectively (Supplementary Figure 1). Over the same follow-up period, there were 6 deaths across all subtypes (Supplementary Figure 2).

HES-related hospitalizations were highest for L-HES (45.2%) than other subtypes (25.8%–30.3%) and the mean length of stay was longest with L-HES at 13.6 days, compared with 10.2 and 11.2 days for I-HES and M-HES, respectively (Supplementary Table 4). Emergency department visits were also most common with L-HES (47.6%) than other subtypes (22.6%–24.2%). The proportions reporting outpatient visits were similar (88%) across subtypes.

A total of 123 (43.9%) patients received biologics between HES diagnosis and end of follow-up. These patients had a mean age of 39.2 years at diagnosis, 58.5% were male and median blood eosinophil count was 1,000 cells/µl (Table 5). Over half of patients receiving biologics had I-HES (55.3%), while 22.0% had L-HES and 18.7% had M-HES. Asthma (56.9%), nasal polyps (48.8%), anxiety/depression (46.3%), hypertension (35.8%) and vasculitis (23.6%) were the most common comorbidities reported in patients receiving biologics (Table 6).

In total, 41.5% of patients with HES receiving biologics were hospitalized between the index date and end of follow-up, with an average stay of >11 days (Supplementary Table 5). Thirty-nine percent of patients required an emergency department visit and 89.4% attended outpatient visits between the index date and end of follow-up.

Clinical manifestations, OCS use and clinical outcomes were analyzed in the pre-biologic and post-biologic periods among patients who received biologics and who had non-missing dates for ≥1 biologics record (n = 107). The incidence of fatigue was lower in the 12-month post-biologic period (8.4%) than the pre-biologic period (15.9%), whereas the incidence of gastrointestinal manifestations, itching and pain were slightly higher in the post-biologic period (11.2%, 10.3% and 8.4%, respectively) than in the pre-biologic period (7.5%, 6.5% and 2.8%, respectively; Table 7). It should be noted, however, that patient numbers for each of these clinical manifestations were low.

The annualized rate of OCS prescriptions was reduced by 56.8% from 0.44 to 0.19 per person-year and the proportion of patients with ≥1 OCS prescription decreased by 64.7% (31.8% pre-biologics and 11.2% post biologics; Table 7). In terms of clinical outcomes, the proportion of patients with ≥1 response (complete or partial) was 3.6 times higher in the post-biologics period (23.4%) than in the pre-biologics period (6.5%), while the proportion of patients experiencing ≥1 flare was similar in the pre- and post-biologics periods (12.1% and 11.2%, respectively; Table 7).