Association of Easier Biologic Access with Remission and Other Clinical Outcomes in Severe Asthma: A Global Real-World Study

Abstract

Purpose

Time to biologic initiation for the treatment of severe asthma (SA) is affected by many factors, including ease of access to biologics, which is often subject to approval by regulatory authorities and reimbursement criteria by relevant agencies. We investigated the association between ease of biologic access (using the biologic accessibility score [BACS] as a proxy) and post-biologic asthma outcomes, including remission.

Methods

This ecological study, using data from CHRONICLE (a US severe asthma registry), the International Severe Asthma Registry (ISAR), and the Optimum Patient Care Research Database (OPCRD), included patients with SA from 21 countries. Associations at the country level, between BACS, a composite score of prescription criteria for biologics in SA, and the proportion of patients with a favorable asthma outcome 1-year post-biologic in each setting (ie ISAR country or in the CHRONICLE or OPCRD datasets) were tested. Several definitions of favorable outcome were used, including proportion of patients who achieved clinical remission (defined using 2, 3 and 4 domains), experienced no exacerbations, had well- or partly controlled asthma, a percent predicted forced expiratory volume in 1 second (ppFEV₁) or percent predicted peak expiratory flow rate (ppPEFR) ≥80%, and no long-term oral corticosteroid (LTOCS) use.

Results

A total of 9,183 patients were included. A higher BACS (as a proxy of easier access to biologics) was associated with a higher likelihood of achieving clinical remission (p≤0.001), no exacerbations (p<0.001), well- or partly controlled asthma (p=0.047), a ppFEV₁ or ppPEFR ≥80% (p=0.004), and no need for LTOCS (p=0.045) 1 year post-biologic initiation.

Conclusion

Easier access to biologics for patients with SA, a prerequisite for shorter time-to-initiation, was associated with a greater probability of achieving clinical remission and other favorable asthma outcomes. Initiating biologics earlier in the asthma disease course may help unlock greater therapeutic potential in SA. These findings warrant confirmation in additional studies to further establish the causal relationship between biologic accessibility, timing of initiation, and clinical outcomes in SA.

Plain Language Summary

For people living with severe asthma, starting biologic treatment earlier by having easier access to these medicines, may lead to better health and quality of life. In this study, which included patients with severe asthma from 21 countries receiving routine clinical care, patients were more likely to experience better asthma outcomes when biologics were easier to access due to less restrictive prescription rules. In countries with easier access, patients had a greater likelihood of achieving clinical remission, experiencing fewer asthma attacks, breathing more easily, improving day-to-day symptom control, and avoiding long-term steroid treatment within one year of starting biologics. These findings suggest that improving access to biologic therapies and starting treatment promptly could help more patients with severe asthma live healthier lives and might unlock the full potential of biologics for managing severe asthma.

Introduction

Six biologics are currently approved for treating uncontrolled and/or severe asthma (SA) in different countries around the world. Benefits associated with biologic use include a reduction in exacerbations by approximately 50%, alleviation of symptoms, improved lung function and disease control, reduction or elimination of the need for oral corticosteroids (OCS), achievement of on-treatment clinical remission in 20–50% of patients with SA (depending on the definition used), and prevention of the development of new onset OCS-related comorbidities such as diabetes, major cardiovascular events and anxiety/depression.^1–8 Achieving remission is an important treatment goal in SA, as it is associated with improved symptom control, reduced exacerbations, lower inhaled and systemic corticosteroid exposure, better quality of life, and potentially improved long-term prognosis.^2,9–11 Given these benefits, biologics have transformed SA management.^1,9 However, variability in response to biologics has prompted researchers to investigate factors influencing their efficacy and effectiveness, and to identify predictors of response and remission, both in randomized controlled trials (RCTs) and real-world evidence studies. Generally, a better response is observed in those with more severe disease (ie, more room for improvement), but a higher chance of remission is observed in those with less severe disease at biologic initiation.^2,4,12 With the recognition that achieving remission is now an attainable goal for many patients with SA, it has been suggested that starting treatment earlier in the disease process may increase the possibility of achieving remission.^8,13 Early treatment with biologics is recommended in other chronic inflammatory conditions (eg rheumatoid arthritis).¹⁴ In asthma, early treatment with inhaled corticosteroids (ICSs) has already proven effective in achieving better disease control;^15–17 but it is not clear whether earlier therapy with biologics improves long-term outcomes.

Timing of treatment initiation is a complex issue.^18,19 It is also difficult to define in chronic, variable conditions like asthma, particularly as some of the pathophysiological changes may be present long before disease manifestations. This difficulty is exemplified by the considerable variation found in the literature to define “early” intervention with ICSs, including (but not limited to): “at diagnosis of persistent disease”, “before diagnosis of persistent disease”, “at an early age”, “in those presenting with mild disease”, “in preference to other treatments”, and “in patients with a diagnosis of asthma, but within a short period of time (<2 years) after the first symptoms”.¹⁷ The concept of time to biologic initiation is relatively new. At present, there is no universally accepted definition, consensus, or validated framework for its measurement or interpretation, but some proposed time-based proxies include time from: asthma diagnosis, development of potential SA, lung function impairment, and frequent exacerbations, before starting biologics.²⁰ However, multiple factors can delay biologic initiation, including misperceptions of asthma severity, poor recognition of the need for treatment intensification (ie, medical inertia), medical costs, suboptimal patient education, and prolonged referral times to specialist centers.^18,19 Moreover, access to biologics often involves a complex process of healthcare insurance or other funding/reimbursement systems and is subject to strict approval criteria set by many regulatory authorities.¹⁸

Variability in approval criteria by regulatory authorities has led to considerable global variability in biologic access for patients with SA. The European Respiratory Biologics Forum of 2018 noted variability by country in biologic prescriptions owing to differences in national health care systems regarding referral networks, access criteria and reimbursement policies,²¹ a finding corroborated by data from both the Severe Heterogeneous Asthma Research collaboration – Patient centred (SHARP)²² database and the International Severe Asthma Registry (ISAR).²³ In the latter publication, ease of access to biologics was measured using a composite score, called the Biologic Accessibility Score (BACS) (see methods for more details). The BACS was informed by country-specific biologic prescription criteria, with higher scores denoting easier access.²³ BACS, therefore, allows categorization and cross-country comparison of biologic access (a function of variability in biologic prescription criteria), but may also serve as a proxy of time-to-biologic initiation.²³ A lower BACS would suggest longer time to biologic initiation, by which time more complications (including irreversible damage) may have developed due to recurrent exacerbations, exposure to systemic corticosteroids, and airway remodelling. Indeed, a connection between BACS and time-to-biologic initiation is suggested from data obtained in the UK, with a BACS ranging from 40–55 for available biologics (ie, representative of moderately difficult access), and an average patient journey from referral to specialist center to biologic initiation taking 63.5 weeks.¹⁹ However, this association is yet to be validated.

To date, no RCT has investigated the effect of the lag time between SA diagnosis and initiation of biologics in terms of clinical outcomes, as it would not be feasible due to ethical considerations. This lack of RCT evidence is reflected in the position of biologics in current stepwise therapy guidelines, which recommend considering biologic therapy for those with uncontrolled disease despite high-dose ICS/long-acting β₂-agonist (LABA), evidence of T2 inflammation in most cases, and after consideration of local payer eligibility criteria, co-morbidities, predictors of response, and cost.²⁴ As a result, only a small proportion of patients who might benefit from biologics, receive them.²⁵ We hypothesized that easier biologic access would be associated with improved post-biologic asthma outcomes, possibly reflecting earlier biologic initiation due to easier access. This study aimed to investigate the association between BACS and post-biologic asthma outcomes, including remission.

Materials and Methods

Study Design and Data Source

This was an ecological study (ie analyses performed at the country rather than at the patient level) using pooled data from the CHRONICLE US severe asthma registry, ISAR (https://www.isar.opcglobal.org/), and the Optimum Patient Care Research Database (OPCRD; https://opcrd.optimumpatientcare.org/), and included data from 21 countries (Argentina, Bulgaria, Brazil, Canada, Colombia, Denmark, Estonia, Greece, Ireland, Italy, Japan, Kuwait, Mexico, Portugal, Saudi Arabia, Singapore, South Korea, Spain, Taiwan, UK, and USA). See e-Appendix 1 for registry details. The association between ease of biologic access (using the previously described BACS)²³ and clinical outcomes was assessed (Figure 1). The study was registered with the European Network Centers for Pharmacoepidemiology and Pharmacovigilance (HMA-EMA/ENCePP; EUPAS1000000530), and designed, implemented, and reported in compliance with the HMA-EMA/ENCePP and with all applicable local and international laws and regulations (e-Appendix 2).

Figure 1.

Study design BACS: the BACS quantifies the ease of access to biologic therapies for severe asthma, with higher scores indicating easier access.²³ Outcomes: nearest available to 1-year post-biologic initiation included assessments within the period 24–80 weeks post for lung-function and asthma control, 48–80 weeks for exacerbation rate, and 24–52 weeks for LTOCS use.

Abbreviations: BACS, Biologic Accessibility Score; Bx, biologic; ISAR, International Severe Asthma Registry; LTOCS, long-term oral corticosteroid; OPCRD, Optimum Patient Care Research Database.

Patients

Patients with SA were required to be aged ≥18 years at biologic initiation, have documented proof of biologic initiation (including initiation date), a documented BACS for the biologic they initiated, and data available for at least one asthma outcome. Within CHRONICLE and ISAR, SA was defined as receiving treatment at Global Initiative for Asthma (GINA) 2018 Step 5 or with uncontrolled asthma at GINA Step 4.²⁶ Uncontrolled asthma was defined as having SA symptoms or frequent exacerbations (≥2/year) requiring OCS. SA was similarly defined within OPCRD concerning GINA treatment steps for patients prescribed a biologic, with at least one year of data prior to the biologic initiation date. Uncontrolled asthma in OPCRD was defined as in the other data sources and also included poor asthma control scores and/or impaired lung function (ie, percent predicted forced expiratory volume in the first second [ppFEV_1] or percent predicted peak expiratory flow rate [ppPEFR] <80%). BACS were derived in 2021, following guidelines at that time. Patients who initiated their first biologic after 2022 were excluded from this study to avoid the risk of BACS criteria becoming out of date and the influence of other biologics being introduced.

Biologic Accessibility Score and Asthma Outcomes

The BACS is a composite score including 10 biologic prescription criteria, each with a maximum score of 10 points, referenced to European Medicines Agency marketing authorization specifications; a higher score reflects easier access (Table 1).²³ The access or accessibility to SA biologics investigated in our study, therefore, refers to prescription criteria, and not to conditions or barriers to access health services in each country. A higher BACS may be considered a proxy for earlier biologic initiation because it reflects how easily patients can qualify for and obtain biologic therapy within a healthcare system. Countries with higher BACS generally have fewer reimbursement restrictions, broader eligibility criteria, and lower administrative barriers, which may allow patients to commence biologics earlier in the course of SA rather than after prolonged disease burden or repeated exacerbations. Consequently, easier biologic accessibility may facilitate more timely treatment escalation and reduce delays associated with specialist referral, approval processes, or corticosteroid dependence. Full details may be accessed at https://www.jaci-inpractice.org/article/S2213-2198(21)01454-9/fulltext. and are summarized in Table 1.²³ BACS are only available at the country level. The score varied between different biologics within each country, so the most easily accessible biologic (ie highest BACS) within each country was used across all available biologics in 2021 to represent the ease of biologic access in that country. Our assumption was that patients would be offered a biologic if they met the criteria for the most easily available biologic.

Table 1.

Biologic Accessibility Scores (BACS) and Clinical Outcomes Assessed

Ease of Biologic Access
	Definition	Criterion Scoring	Total Score Categorization
BACSa	Composite score comprising 10 domains: (i) age, (ii) severity/phenotype, (iii) BEC (or Serum IgE for omalizumab), (iv) FeNO, (v) background therapy, (vi) adherence (allergic asthma Dx for omalizumab), (vii) OCS use, (viii) Exacerbation number, (ix), asthma control, and (x) lung function	Each criterion split into clinically relevant categories and scored from: 0 (most stringent) to 10 (less stringent)	Total BACS range 0–100 Access categorized as: 0: None 1–20: very difficult 21–40: difficult 41–60 moderately difficult 61–80: neither difficult nor easy 81–100: Easy
Primary asthma outcome
Remission	2-domain: No severe exacerbations in 12 months post-biologic initiation AND no LTOCS use or LTOCS use stopped in the 12 months post-biologic initiation 3-domain (2 definitions) Definition 1: 2-domain remission AND asthma control indicating good controlb 12 months post-biologic initiation date. Definition 2: 2-domain remission AND no lung function impairment (ie ppFEV1 or ppPEFR ≥80%) 4-domain: 2-domain AND well- or partly controlled asthmab AND no lung function impairment
Secondary asthma outcomes
Exacerbations	Number of exacerbations in the year post-biologic initiation
Asthma control	Latest in the year pre- and nearest available to 1 year post-biologic initiation
Lung function	Post-bronchodilator FEV1 – latest in the year pre- and nearest available to 1-year post-biologic initiationc
LTOCS	No LTOCS use or LTOCS use stopped in the 12 months post-biologic initiation

Notes: ^aFull details of BACS development, including criterion and total scoring and BACS results for 28 countries have previously been published.²³ bGood control defined as ACT>15, ACQ<1.5, RCP 0 or 1, aligning with GINA well- or partly-controlled categorization.²⁷ ACQ and/or ACT control categories were fitted to GINA 2020 control categories as follows – mean ACQ: well controlled (≤0.75), partly controlled (>0.75 to <1.5), uncontrolled (≥1.5); total ACT: well controlled (>19), partly controlled (>15 to ≤19), uncontrolled (≤15). Similar cut-offs and correlations^28,29 have been described and used by others.^30–32 cIf post-bronchodilator results were not available, pre-bronchodilator results were used instead. In OPCRD, PEFR was used if FEV₁ was not available.

Abbreviations: ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; BACS, biologic accessibility score; BEC, blood eosinophil count; Dx, diagnosis; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1^st second; GINA, Global Initiative for Asthma; LTOCS, long-term oral corticosteroid; OCS, oral corticosteroid; OPCRD, Optimum Patient Care Research Database; PEFR, peak expiratory flow rate; ppFEV₁, percent predicted forced expiratory volume in 1^st second; ppPEFR, percent predicted peak expiratory flow rate; RCP, Royal College of Physicians.

Clinical outcomes were assessed 1-year pre-biologic and as close as possible to 1-year post-biologic initiation (Figure 1). A 1-year follow-up period was considered sufficient to evaluate outcomes (ie remission, exacerbations, symptom control, lung function, and long-term oral corticosteroid (LTOCS) use) as clinically meaningful responses to biologic therapy are typically observed within the first 12 months of treatment. This timeframe is also commonly used in SA studies to assess treatment efficacy, effectiveness and disease stability.^2,33,34

Remission (defined across 2, 3, and 4 domains) was the primary outcome variable (Table 1). Secondary outcome variables included exacerbations, asthma control, lung function, and LTOCS use (Table 1).

Statistical Analyses

The statistical analysis plan was pre-defined. R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and Stata v18 (StataCorp., College Station, TX) were used.³⁵ Patient characteristics were summarized, by setting (individual countries within ISAR plus the OPCRD or CHRONICLE data sources), using means (standard deviation, SD), medians (interquartile range, IQR), or numbers (percent of non-missing values). Variables are described in e-Table 1. Associations between BACS and the proportion of patients with a favorable asthma outcome in each setting were tested using Pearson’s correlation. Countries included in different data sources were considered as different settings (eg UK ISAR and UK OPCRD). Patients with insufficient data to assess the outcomes of interest were excluded from the analyses. A favorable outcome was defined as the proportion of patients 1-year post-biologic with: 2-, 3-, and/or 4-domain remission; no exacerbations; well- or partly controlled asthma; ppFEV₁ or ppPEFR ≥80%; or no need for LTOCS use. The analyses examined only unadjusted correlations, adjusting for country size, but not for other potential confounders, including country-level socioeconomic status, gross domestic product (GDP), individual healthcare systems, and access. Investigation of mechanisms by which countries come to have different BACS, or the relative contribution of BACS and other socio-economic factors, was beyond the scope of the current study. Pearson’s correlations were weighted using the inverse of the variance of each estimate. This applied greater weight to settings for which the proportion of patients with a favorable outcome could be estimated more accurately (ie, settings in which the estimated proportions had lower variance due to larger sample sizes and/or values closer to 0 or 1. Each of the outcomes used in the correlation tests was tested for bivariate normality with BACS. Leave-one-out analysis was used to confirm whether any individual setting had undue influence on the associations observed. Correlation coefficients were categorized as moderate (r = 0.40–0.59), strong (r = 0.60–0.79), or very strong (r ≥ 0.80).³⁶ As a sensitivity analysis, the mean BACS of the biologic actually initiated by each patient was calculated for each country and used in the correlation analyses in place of the highest BACS per country.

P values ≤0.05 were considered statistically significant.

Results

Patients

Of a total of 16,463 eligible patients (N=3,020, N=12,220, and N=1,223 from CHRONICLE, ISAR, and OPCRD, respectively), 9,183 were included in the analysis (e-Table 2). Exclusions were due to missing biologic initiation date, missing BACS (ie, not included in original BACS publication),²³ biologic initiation date after 2022 and missing outcomes data (e-Table 2).

Baseline Demographic and Clinical Characteristics (Association Analysis)

The majority of patients were female (63.1%), of White race (79.7%), overweight/obese (72.7%), and never-smokers (65.6%). The median [IQR] age at study entry was 55 [44, 64] years, and the median [IQR] age of asthma onset was 30 [12, 46] years (Table 2 and Table 3). In the year before biologic initiation, 57.7% of patients had experienced ≥2 exacerbations, 64.5% had uncontrolled asthma, and 59.2% had impaired lung function (ie, ppFEV₁ or ppPEFR <80%) (Table 3). Most patients had elevated biomarker concentrations indicative of T2-high disease (ie, IgE IU/mL ≥75: 70.8%; fractional exhaled nitric oxide ≥25 ppb: 61.7%; and blood eosinophil count ≥300 cells/µL: 73.5%) (Table 3). Approximately 1/3 of patients had used LTOCS in the past year at a mean (SD) daily dose of 8.5 (8.6) mg. Anti–interleukin (IL)-5/5R was the most frequently prescribed biologic class (54.0%), followed by anti-immunoglobulin E (IgE) (33.8%) and anti–IL-4Rα (12.1%). There was some variability in baseline data observed between datasets; notably, a greater tendency for patients to: be overweight/obese, have a lower exacerbation rate, be less likely to have persistent airflow obstruction, more likely to have received leukotriene receptor antagonist (LTRA) or long-acting muscarinic antagonist (LAMA) add-on to ICS/LABA therapy, and to be treated with anti-IgE in the US-specific CHRONICLE study compared with ISAR and OPCRD (Table 2 and Table 3).

Table 2.

Patient Baseline Demographic Characteristics

	CHRONICLE	ISAR	OPCRD	Total
	(N=2,773)	(N=5,721)	(N=689)	(N=9,183)
Biologic initiation date,
Median	20sep2018	10apr2019	22may2020	07mar2019
[IQR]	[02dec2016, 15jan2020]	[16nov2017, 01feb2021]	[07nov2018, 17aug2021]	[29sep2017, 20oct2020]
Range {min-max}	[06jun2003-27dec2022]	[01jan2004-30dec2022]	[29mar2007-30dec2022]	[06jun2003-30dec2022]
Age, years,				53.3 (14.1)
Mean (SD)	53.0 (13.9)	53.6 (14.0)	51.1 (15.4)	54.5 [44.0, 63.7]
Median [IQR]	54.2 [43.7, 63.6]	54.9 [44.5, 63.9]	52.0 [40.0, 63.0]
Female, n (%)	1,855 (66.9)	3,511 (61.4)	432 (62.7)	5,798 (63.1)
Body mass index (kg/m2) at biologic initiation	N=2,738	N=5,634	N=683	N=9,055
Mean (SD)	33.0 (8.4)	28.2 (6.4)	30.9 (7.6)	29.8 (7.5)
Underweight (BMI<18.5), n (%)	20 (0.7)	110 (2.0)	12 (1.8)	142 (1.6)
Normal weight (BMI 18.5 to <25), n (%)	385 (14.1)	1,802 (32.0)	141 (20.6)	2,328 (25.7)
Overweight (BMI 25 to <30), n (%)	739 (27.0)	1,917 (34.0)	207 (30.3)	2,863 (31.6)
Obese (BMI ≥30), n (%)	1,594 (58.2)	1,805 (32.0)	323 (47.3)	3,722 (41.1)
Ethnicity	N=2,673	N=5,057	N=689	N=8,419
White, n (%)	2,075 (77.6)	4,037 (79.8)	602 (87.4)	6,714 (79.7)
Asian, n (%)	49 (1.8)	404 (8.0)	45 (6.5)	498 (5.9)
African, n (%)	473 (17.7)	96 (1.9)	9 (1.3)	578 (6.9)
Mixed, n (%)	NA	220 (4.4)	4 (0.6)	224 (2.7)
Other, n (%)	76 (2.8)	300 (5.9)	29 (4.2)	405 (4.8)
Smoking status at biologic initiation	N=2,770	N=5,640	N=689	N=9,099
Never smoker, n (%)	1,802 (65.1)	3,744 (66.4)	423 (61.4)	5,969 (65.6)
Ex-smoker, n (%)	829 (29.9)	1,731 (30.7)	229 (33.2)	2,789 (30.7)
Current smoker, n (%)	139 (5.0)	165 (2.9)	37 (5.4)	341 (3.7)

Abbreviations: BMI, body mass index; ISAR, International Severe Asthma Registry; OPCRD, Optimum Patient Care Research Database; SD, standard deviation; NA, Not applicable.

Table 3.

Patient Baseline Clinical Characteristics

	CHRONICLE	ISAR	OPCRD	Total
	(N=2,773)	(N=5,721)	(N=689)	(N=9,183)
Age at asthma onset (years)	N=2,616	N=3,742	N=681	N=7,039
Median [IQR]	30 [10, 48]	31 [15, 45]	28 [10, 42]	30 [12, 46]
Allergen test results	N=2,773	N=3,306	N=0	N=6,079
Positive, n (%)	593 (21.4)	1,875 (56.7)	NA	2,468 (40.6)
Asthma controla	N=254	N=1,921	N=362	N=2,537
Uncontrolled, n (%)	191 (75.2)	1,197 (62.3)	249 (68.8)	1,637 (64.5)
Partly controlled, n (%)	42 (16.5)	438 (22.8)	80 (22.1)	560 (22.1)
Well controlled, n (%)	21 (8.3)	286 (14.9)	33 (9.1)	340 (13.4)
Exacerbationsb in past year	N=411	N=3,489	N=689	N=4,589
Mean (SD)	1.6 (1.6)	2.6 (3.0)	3.3 (2.8)	2.6 (2.9)
0, n (%)	120 (29.2)	931 (26.7)	81 (11.8)	1,132 (24.7)
1, n (%)	108 (26.3)	575 (16.5)	126 (18.3)	809 (17.6)
2, n (%)	83 (20.2)	630 (18.1)	126 (18.3)	839 (18.3)
3–4, n (%)	78 (19.0)	723 (20.7)	169 (24.5)	970 (21.1)
5+, n (%)	22 (5.4)	630 (18.1)	187 (27.1)	839 (18.3)
Percent predicted FEV1 or PEFR	N=535	N=3,596	N=342	N=4,473
Mean (SD)	77.6 (21.8)	75.1 (22.1)	69.9 (21.1)	75.0 (22.0)
<60%, n (%)	117 (21.9)	889 (24.7)	108 (31.6)	1,114 (24.9)
≥60 - <80%, n (%)	180 (33.6)	1,232 (34.3)	121 (35.4)	1,533 (34.3)
≥80%, n (%)	238 (44.5)	1,475 (41.0)	113 (33.0)	1,826 (40.8)
FEV1/FVC ratio	N=538	N=3,622	N=151	N=4,311
Median [IQR]	0.74 [0.65, 0.81]	0.69 [0.59, 0.77]	0.68 [0.58, 0.77]	0.69 [0.60, 0.77]
<0.5, n (%)	26 (4.8)	386 (10.7)	18 (11.9)	430 (10.0)
≥0.5 - <0.7, n (%)	175 (32.5)	1,567 (43.3)	64 (42.4)	1,806 (41.9)
≥0.7, n (%)	337 (62.6)	1,669 (46.1)	69 (45.7)	2,075 (48.1)
Lung function impairment/obstructionc	N=674	N=3,852	N=548	N=5,074
n (%)	438 (65.0)	2,996 (77.8)	514 (93.8)	3,948 (77.8)
Highest blood eosinophil count (cells/µL)	N=862	N=4,333	N=654	N=5,849
Median [IQR]	326 [159, 600]	500 [290, 850]	700 [430, 1010]	500 [270, 840]
<100, n (%)	112 (13.0)	194 (4.5)	4 (0.6)	310 (5.3)
100- <300, n (%)	281 (32.6)	896 (20.7	62 (9.5)	1,239 (21.2)
300- <5000, n (%)	187 (21.7)	966 (22.3)	116 (17.7)	1,269 (21.7)
≥5000, n (%)	282 (32.7)	2,277 (52.6)	472 (72.2)	3,031 (51.8)
Latest total serum IgE (IU/mL)	N=977	N=3,371	N=160	N=4,508
Median [IQR]	143 [46, 390]	174 [66, 440]	350 [82, 772]	170 [61, 441]
≥75, n (%)	639 (65.4)	2,431 (72.1)	122 (76.2)	3,192 (70.8)
Latest FeNO (ppb)	N=320	N=2,765	N=0	N=3,085
Median [IQR]	25 [13, 50]	35 [18, 66]	NA	33 [17, 65]
≥25, n (%)	162 (50.6)	1,740 (62.9)	NA	1,902 (61.7)
Eosinophilic grade37	N=1,513	N=4,940	N=671	N=7,124
Grade 0: Unlikely/Non-eosinophilic, n (%)	39 (2.6)	93 (1.9)	4 (0.6)	136 (1.9)
Grade 1: Least likely, n (%)	83 (5.5)	213 (4.3)	12 (1.8)	308 (4.3)
Grade 2: Likely, n (%)	66 (4.4)	170 (3.4)	15 (2.2)	251 (3.5)
Grade 3: Most likely, n (%)	1,325 (87.6)	4,464 (90.4)	640 (95.4)	6,429 (90.2)
AR	N=2,773	N=4,828	N=689	N=8,290
n (%)	1,812 (65.3)	2,835 (58.7)	380 (55.2)	5,027 (60.6)
CRS	N=2,773	N=5,642	N=689	N=9,104
n (%)	662 (23.9)	3,322 (58.9)	265 (38.5)	4,249 (46.7)
Nasal polyposis	N=2,773	N=5,638	N=689	N=9,100
n (%)	302 (10.9)	2,130 (37.8)	174 (25.3)	2,606 (28.6)
Eczema/AD	N=2,773	N=5,560	N=689	N=9,022
n (%)	150 (5.4)	842 (15.1)	136 (19.7)	1,128 (12.5)
LTOCS user in past year	N=2,773	N=4,365	N=689	N=7,827
n (%)	562 (20.3)	1,530 (35.1)	273 (39.6)	2,365 (30.2)
LTOCS average daily dose in past year (mg)d	N=2,437	N=3,992	N=689	N=7,118
Mean (SD)	0.7 (3.1)	2.6 (6.4)	3.1 (5.7)	2.0 (5.5)
LTOCS average daily dose in past year in users (mg)d	N=226	N=1,157	N=273	N=1,656
Mean (SD)	7.1 (7.7)	8.9 (9.1)	7.8 (6.6)	8.5 (8.6)
Biologic class	N=2,773	N=5,721	N=689	N=9,183
Anti-IL4Rα, n (%)	353 (12.7)	762 (13.3)	0 (0.0)	1,115 (12.1)
Anti-IL5/5R, n (%)	1,157 (41.7)	3,364 (58.8)	439 (63.7)	4,960 (54.0)
Anti-IgE, n (%)	1,263 (45.5)	1,595 (27.9)	250 (36.3)	3,108 (33.8)
ICS use in past year	N=1,682	N=5,126	N=689	N=7,497
n (%)	1,664 (98.9)	5,081 (99.1)	689 (100.0)	7,434 (99.2)
LABA use in past year	N=1,695	N=5,021	N=689	N=7,405
n (%)	1,667 (98.3)	4,773 (95.1)	680 (98.7)	7,120 (96.2)
LAMA use in past year	N=830	N=4,085	N=689	N=5,604
n (%)	690 (83.1)	2,770 (67.8)	420 (61.0)	3,880 (69.2)
LTRA use in past year	N=1,322	N=4,102	N=689	N=6,113
n (%)	1,219 (92.2)	2,678 (65.3)	275 (39.9)	4,172 (68.2)
Theophylline use in past year	N=333	N=2,939	N=689	N=3,961
n (%)	47 (14.1)	327 (11.1)	198 (28.7)	572 (14.4)
Macrolide use in past year	N=329	N=3,015	N=689	N=4,033
n (%)	65 (19.8)	583 (19.3)	8 (1.2)	656 (16.3)

Notes: ^a Categorized according to Global Initiative for Asthma (GINA) 2020: uncontrolled/partly controlled/well controlled. When GINA symptom control score was not directly available, conversion from other tools were performed sequentially as follows: 1) Well controlled: Total Asthma Control Test (ACT) >19; partly controlled: Total ACT >15 and ≤19; uncontrolled: Total ACT ≤15 2) Well controlled: Mean Asthma Control Questionnaire (ACQ) ≤0.75; partly controlled: Mean ACQ >0.75 and <1.5; uncontrolled: Mean ACQ ≥1.5 3) Well controlled: Royal College of Physicians (RCP)3Q = 0; partly controlled: RCP3Q = 1; uncontrolled: RCP3Q = 2 or 3^b Requiring rescue steroids in the year before biologic initiation. A minimum of 48 weeks of data was required.^c FEV₁ or PEFR < 80%, and/or FEV₁/FVC ratio < 0.70 before biologic initiation ^d Prednisolone equivalent.

Abbreviations: AD, atopic dermatitis; AR, allergic rhinitis; BEC, blood eosinophil count; CRS, chronic rhinosinusitis; FeNO, fractional exhaled nitric oxide; FEV₁; forced expiratory volume in first second; FVC, forced vial capacity; ICS, inhaled corticosteroid; IgE, Immunoglobulin E; IL, interleukin; IQR, interquartile range; ISAR, International Severe Asthma Registry; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LTOCS, long-term oral corticosteroid; LTRA, leukotriene receptor antagonist; OPCRD, Optimum Patient Care Research Database; ppb, parts per billion; ppFEV₁, percent predicted forced expiratory volume in first second; ppPEFR, percent predicted peak expiratory flow rate; TSLP, thymic stromal lymphopoietin; NA, Not applicable.

Association Between BACS and Proportion of Positive Outcomes

Higher BACS was associated with a higher probability of achieving remission. The correlation was very strong for 2-domain (r=0.81; p<0.001; Figure 2A) and 3domain with lung function remission (r=0.81; p<0.001; Figure 2C), and strong for 3-domain with asthma control (r=0.67; p=0.001; Figure 2B) and 4-domain remission (r=0.71; p<0.001; Figure 2D) a year after starting biologics. Leave-one-out analyses confirmed that these correlations were not strongly dependent on the result from any one setting (e-Table 3). Correlations were also tested between BACS and the individual components of remission. Higher BACS was strongly correlated with no exacerbations (r=0.68; p<0.001; Figure 3A), and moderately correlated with absence of lung function impairment (r=0.58; p=0.004; Figure 3C), having well- or partly controlled asthma (r=0.42; p=0.047; Figure 3B) and non-use of LTOCS (0.42; p=0.045; Figure 3D) 1 year post-biologic initiation. In a sensitivity analysis using the mean BACS of the biologic actually initiated by each patient within each country, similar correlations with outcomes were observed (e-Table 4).

Figure 2.

Association between BACS and remission in the first-year post-biologic: (A), 2-domain remission (LTOCS + exacerbations); (B), 3-domain remission (2-domain + control); (C), 3-domain remission (2-domain + lung function); (D), 4-domain remission (2-domain + control + lung function). The association between ease of access (highest BACS) in each setting (ISAR country, OPCRD or CHRONICLE) and remission was assessed using Pearson’s correlation. Setting = ISAR country, OPCRD or CHRONICLE. Points represent the percentage of patients with a positive outcome vs the highest BACS for any biologic available in that country (one point for each ISAR country + one for each of OPCRD and CHRONICLE datasets). Area of the circles is proportional to the weighting used in each case. r = Pearson’s correlation coefficient. Correlations weighted using 1/var(proportion) within each country to apply greater weight to the results with greatest precision. See Table 1 for remission definitions. N refers to number of settings included. BACS - 41-60: Moderately difficult; 61–80: Neither easy nor difficult; 81–100: Easy.

Abbreviations: LTOCS, long-term oral corticosteroids; OPCRD, Optimum Patient Care Research Database.

Figure 3.

Association between BACS and (A) exacerbation rate, (B) asthma control, (C) lung function in the first-year post-biologic initiation, and (D) LTOCS non-use. The association between ease of access (highest BACS) in each setting (ISAR country, OPCRD or CHRONICLE) and asthma outcome was assessed using Pearson’s correlation. Setting = ISAR country, OPCRD or CHRONICLE. Points represent the percentage of patients with a positive outcome vs the highest BACS for any biologic available in that country (one point for each ISAR country + one for each of OPCRD and CHRONICLE datasets). Area of the circles is proportional to the weighting used in each case. r = Pearson’s correlation coefficient. Correlations weighted using 1/var(proportion) within each setting to apply greater weight to the results with greatest precision. Good control (aligning with GINA well- or partly-controlled categorization) defined as ACT>15, ACQ<1.5, RCP 0 or 1.²⁷ N refers to number of settings included. BACS - 41-60: Moderately difficult; 61–80: Neither easy nor difficult; 81–100: Easy. Setting = data-source x country/center.

Abbreviations: ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; BACS, biologic accessibility score; GINA, Global Initiative for Asthma; ppFEV₁, percent predicted forced expiratory volume in first second; ppPEFR, percent predicted peak expiratory flow rate; RCP, Royal College of Physicians; LTOCS, long-term oral corticosteroids.

Discussion

Global disparities in access to asthma biologics are well-documented.^23,38 Our study examined the association of variable biologic access on asthma outcomes, and the likely implications for asthma management with easier access and presumably earlier biologic initiation in a large, global, pooled patient population. This is the first study to report an association between ease of biologic access (ie higher BACS) and improved post-biologic asthma outcomes for patients with SA in real-life. Easier biologic access was associated with a significantly greater likelihood of achieving on-treatment clinical remission (all definitions assessed), experiencing no exacerbations, having a ppFEV₁ or ppPEFR ≥80%, having well- or partly controlled asthma and having no need for LTOCS. This latter finding should be interpreted cautiously, as the LTOCS outcome did not meet bivariate normality assumptions, because relatively few patients remained on LTOCS one year after biologic initiation. Considering the current benchmark of biologic efficacy/effectiveness when introduced later in the disease process (eg, achievement of 3- or 4-domain remission in approximately 20–35% of patients and reduction of exacerbation rate and LTOCS both by 50%),^2,39–41 more equitable access and timely initiation could “move the needle” for these outcomes, unlocking the true potential of biologics and providing patients with the best possible outcomes in keeping with a precision-based management strategy – the right treatment to the right patient AND at the right time. For low-access countries, our findings highlight the need for policies that improve affordability and equitable access, such as expanding reimbursement schemes, simplifying eligibility criteria, strengthening specialist SA services, and improving access to biomarker testing and referral pathways.

Evidence from other chronic inflammatory diseases suggests that earlier biologic treatment is associated with improved outcomes. In rheumatoid arthritis, studies have consistently demonstrated a “window of opportunity,” whereby earlier initiation of biologic or disease-modifying therapy is associated with improved remission rates, reduced radiographic progression, better physical function, and less irreversible joint damage.⁴² Similarly, in atopic dermatitis, earlier use of targeted biologic therapies has been associated with more rapid disease control, improved symptom burden, and reduced long-term inflammatory complications, supporting the concept that early intervention may alter disease trajectory and improve long-term outcomes.⁴³ However, defining optimal timing for biologic initiation in asthma is more challenging because of disease heterogeneity and variability in disease trajectories. We decided to approach the question from a non–time-based perspective using BACS as a surrogate measure of biologic accessibility. BACS has already been calculated for five biologics (ie, omalizumab, benralizumab, reslizumab, mepolizumab, and dupilumab) in 28 countries across five continents, captures prescription eligibility criteria across 10 domains, and is anchored to European Medicines Agency regulatory information.

Although evidence supporting earlier biologic intervention in asthma remains limited, several studies have identified predictors of biologic response and remission that indirectly support earlier treatment initiation. Predictors associated with better outcomes, suggestive of shorter time to biologic initiation, include shorter asthma duration, more preserved lung function, and shorter exposure to OCS.^2,39,44–48 For example, prolonged OCS exposure (>21 months) before biologic initiation was associated with a 71% reduced odds of achieving OCS elimination post-biologic compared to those exposed to OCS for ≤12 months.⁴⁴ Others demonstrated higher remission rates in those with recent onset SA (32%) compared to those with chronic SA (17%), characterized by longer disease duration.⁴⁸ Similarly, those with an asthma duration <10 years pre-biologic were >3 times more likely to achieve biologic super-response (vs those with duration >10 years), and had an equally elevated odds of achieving this super-response if their ppFEV₁ was ≥80% pre-biologic.⁴⁵ The association of shorter asthma duration and better pre-biologic lung function with better post-biologic outcomes was even more apparent in a small study of Japanese patients with SA, which found 10 times greater odds of achieving clinical remission post-biologic for those with an asthma duration ≤5 years.⁴⁷ A more recent study from ISAR found that the odds of achieving 4-domain remission decreased by 15% for every additional 10 years of asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00), and increased by 29% for every 5% greater ppFEV₁ before biologic initiation.²

Earlier biologic initiation may improve asthma outcomes by interrupting inflammatory pathways before irreversible airway changes occur. Current evidence suggests that biologics may reduce airway hyper-responsiveness,⁴⁹ slow accelerated lung function decline,^50,51 and potentially prevent or attenuate airway remodelling.⁵² Our observed association between easier biologic access and higher probability of preserved lung function 1 year post-biologic initiation supports this hypothesis. Biologics can produce rapid effects on glucocorticoid-unresponsive inflammation within days or weeks of starting treatment,^53,54 such as improvements in symptoms and lung function, and reduction in inflammation and structural changes, including small airway obstruction and mucus plugging.⁵² Emerging evidence also suggests that biologics may influence longer term structural changes, including basement membrane thickening,⁵⁵ airway smooth muscle hypertrophy/hyperplasia,^56,57 and neuronal remodelling,⁵⁸ suggesting a potential for reversing or ameliorating established airway remodelling.⁵² In addition, biologics may help prevent progression to chronic asthma,⁵⁹ development of secondary structural changes,⁶⁰ progressive loss of pulmonary function,⁶¹ long-term dependence on ICS and OCS therapy^62,63 and the development of new-onset OCS-related adverse outcomes in patients with SA.⁷ Collectively, these findings suggest that although biologics are beneficial when introduced at any time (eg, even at the latter part of the asthma disease process as currently recommended),²⁴ their utility may even be higher when introduced in the early stages of remodelling, and even earlier, before remodelling has occurred at all.

Our study has some limitations. As an ecological study, the analysis was adjusted for country size, but not for other potential confounders such as socioeconomic status, GDP, individual healthcare systems, and access. This may have limited individual-level inference. However, previous research found no correlation between GDP and BACS,²³ suggesting that GDP was unlikely to confound our findings. The ecological design of this study also meant that observed associations should not be interpreted as causal, as analyses were performed at the population rather than the individual patient level. Observed associations may be influenced by unmeasured confounding factors or country-level differences, and may not necessarily apply to individual patients (ie, the ecological fallacy). The BACS is also country-specific, not validated and may change over time as new biologic availability and reimbursement criteria evolve. However, the association of higher BACS with better asthma outcomes shown in the current study lends some validity to the score as a biologic accessibility metric. Moreover, the scores used in this study were from 2021, which is close to the median date for patients initiating a biologic in OPCRD, but slightly later than the median dates for the patients in ISAR and CHRONICLE (2019 and 2018, respectively). Regular BACS updates are planned for each country that contributes data to ISAR to ensure its continued utility and relevancy to future research. Ease of access may also have been greater or less at the time individual patients initiated biologic therapy. The highest BACS was used for each country, which may simplify within-country variability; however, similar correlations with outcomes were observed when mean BACS values for initiated biologics were used. Finally, the BACS does not capture all biologic accessibility issues, such as cost, permitted prescribers, health system factors (eg co-payment schemes or government subsidies) and time to referral to specialist care (if necessary). In the UK, for example, as many as 8% of patients managed in primary care have potential SA, but the vast majority are not referred.⁶⁴ Other limitations include those common to all observational studies, including inability to infer causality, regression to the mean, referral bias, and missing data (predominantly outcomes and mainly for ISAR and OPCRD).

The study is strengthened by inclusion of a large international cohort of patients with SA from 21 countries and multiple real-world data sources. Merging the CHRONICLE, ISAR, and OPCRD datasets increased statistical power and reduced the influence of individual countries. We also used routinely collected clinical data to define multiple outcomes, including a 4-domain definition of remission. Notwithstanding the limitations of the BACS as outlined above, the BACS is informed by structured reviews of health authority databases and guidelines and input from local prescribers of biologics to verify real-world practice, is based on a comprehensive range of clinical access criteria across 10 domains, and is agreed by consensus at the country level for each available biologic.²³ The wide range of BACS values across ISAR countries provided a valuable opportunity to examine associations between biologic accessibility and clinical outcomes across diverse healthcare settings, with the broad range strengthening correlation analyses, enabling assessment across a spectrum of access levels. Future avenues of research could include investigation of whether the association is consistent across phenotypes, endotypes, biologic classes, in the shorter-term and longer-term follow-up periods (eg, beyond 2 years), and a re-evaluation of associations using the most recent BACS (if available). Investigation of whether the correlation of BACS and asthma outcomes is independent of confounders (eg healthcare system and socio-economic status), and confirmation of our findings using other metrics of ease of biologic access is also warranted.

Conclusion

In conclusion, easier access to biologics for patients with SA has the potential to transform asthma care by increasing the probability of achieving better outcomes, including clinical remission. Earlier integration of biologics within stepwise treatment pathways may be associated with improved outcomes in SA.

Funding Statement

This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global Ltd (OPCG) and AstraZeneca. No funding was received by the OPRI for its contribution. The CHRONICLE study was funded by AstraZeneca. The International Severe Asthma Registry (ISAR) is operated by OPCG and co-funded by OPCG and AstraZeneca.

Abbreviations

Anti-IgE, anti-immunoglobulin E; Anti–IL-4Rα, anti-interleukin 4 receptor alpha; Anti–I-L5/5R, anti-interleukin 5/5-receptor; BACS, biologic accessibility score; FVC, forced vital capacity; GINA, Global Initiative for Asthma; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; ISAR, International Severe Asthma Registry; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; OPCRD, Optimum Patient Care Research Database; LTOCS, long-term oral corticosteroid; ppFEV₁, percent predicted forced expiratory volume in first second; ppPEFR, percent predicted peak expiratory flow rate; PSA, potential severe asthma; RCT, randomized controlled trial; SA, severe asthma; SD, standard deviation; TSLP, thymic stromal lymphopoietin.

Data Sharing Statement

The dataset supporting the conclusions of this article was derived from CHRONICLE, ISAR and OPCRD. The authors do not have permission to give public access to the study dataset; researchers may request access to the data for their own purposes.

Portions of the dataset included in this analysis were from the CHRONICLE study. The CHRONICLE study protocol received central institutional review board approval by Advarra (Columbia, MD, USA) on November 3, 2017, and was registered on ClinicalTrials.gov on December 14, 2017 (ClinicalTrials.gov identifier: NCT03373045). The CHRONICLE study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guidelines, and applicable regulatory requirements. A signed informed consent form was obtained at enrollment for study participation and to acquire medical records from other providers, including pharmacy records. The CHRONICLE study was sponsored by AstraZeneca. Requests from researchers for access to CHRONICLE study data should be made to the AstraZeneca Clinical Study Information Center (information.center@astrazeneca.com).

ISAR research requests and proposals can be made via the ISAR website (https://isaregistries.org/research-proposal-requests/) or via the enquiries Email to info@isaregistries.org. In line with ISAR governance restrictions, sharing individual deidentified participant data is subject to the consent of the ISAR steering committee in accordance with patient consent, patient confidentiality and ethical considerations. The study documents (protocol, statistical analysis plan, clinical study report) will be made available in accordance with the criteria of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS1000000530). Proposals should be directed to info@isaregistries.org; to gain access, if approved by the regulatory boards, data requestors will need to sign a data access agreement.

The dataset supporting the conclusions of this article was derived from the Optimum Patient Care Research Database (www.opcrd.co.uk). The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymised research data (Research Ethics Committee reference: 15/EM/0150). This study was approved by the Anonymised Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD. The authors do not have permission to give public access to the study dataset; researchers may request access to OPCRD data for their own purposes. Access to OCPRD can be made via the OCPRD website (https://opcrd.co.uk/our-database/data-requests/) or via the enquiries Email info@opcrd.co.uk.

Ethics Approval and Informed Consent

Ethics approval was obtained from the Anonymized Data Ethics Protocols and Transparency Committee (ADEPT1124). The ISAR database has ethical approval from ADEPT committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (HMA-EMA data source ID 32463). Our study was registered with the European Network Centers for Pharmacoepidemiology and Pharmacovigilance (HMA-EMA/ENCePP; EUPAS1000000530), and designed, implemented, and reported in compliance with the HMA-EMA/ENCePP and with all applicable local and international laws and regulations. The CHRONICLE study protocol was approved by a central institutional review board (Advarra, Columbia, MD, USA) and is registered on ClinicalTrials.gov (NCT03373045). A signed informed consent form was obtained at enrolment for study participation and to acquire medical records from other providers, including pharmacy records. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymized research data (Research Ethics Committee reference: 15/EM/0150).

Consent for Publication

This article contains aggregated de-identified data which has been included in this article with patients’ informed consent. No individual patient data is presented in this article, only aggregated data following patient consent.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception and design of the study, execution, acquisition of data, analysis and interpretation of data, or in all these areas. Formal analysis was conducted by Ghislaine Scelo, John Townend, Lakmini Bulathsinhala, and David B. Price. All authors took part in data interpretation. Supervision was provided by Victoria Carter and David B. Price. All authors took part in drafting, revising or critically reviewing the manuscript. All authors gave final approval of the version to be published, have agreed on the journal to which the article has been submitted, and agree to be accountable for all aspects of the work.

Disclosure

Susanne Hansen has received speaker’s fees from AstraZeneca and GlaxoSmithKline during the last 24 months. Ming-Ju Tsai has received sponsorship to attend or speak at conferences, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Shionogi and Orient EuroPharma. Trung N. Tran is an employee of AstraZeneca and may own stocks or stock options in AstraZeneca. AstraZeneca is the sponsor and funder of the CHRONICLE study and a co-funder of the International Severe Asthma Registry. John D. Blakey has received grants or contracts from Avant Mutual, Asthma Australia, MRFF, FHRI, Telethon Kids Institute, International Primary Care Respiratory Group, and the Charlies Foundation for Research. He has received payment or honoraria for lectures, presentations, or speaker bureaus from Chiesi, The Limbic, Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Sanofi. He has received support for attending meetings and/or travel from GlaxoSmithKline, Centre for Research Excellence in Treatable Traits, AstraZeneca, and The George Institute. He has participated in the study steering committee of GlaxoSmithKline, unrelated to this work. He has taken a leadership role in the Thoracic Society of Australia and New Zealand, and Asthma Australia. He has received medical writing/equipment from GlaxoSmithKline, and Novartis. Benjamin Emmanuel is an employee of AstraZeneca and may own stocks or stock options in AstraZeneca. AstraZeneca is the sponsor and funder of the CHRONICLE study and a co-funder of the International Severe Asthma Registry. Shawn D. Aaron has received honoraria from GlaxoSmithKline, AstraZeneca, Valeo Pharma, Methapharm and Sanofi-Regeneron. Yahya Habis has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi, and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Sanofi and Chiesi. Valeria Perugini declares no conflicts of interest in this work. Alan Altraja has received lecture fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, Orion, Sanofi, Takeda, Teva, and Zentiva; sponsorships from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, Takeda, Teva, The Estonian Respiratory Society and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Sanofi, Shire Pharmaceuticals, and Teva. Rohit K. Katial declares honoraria from Amgen, AstraZeneca, Novartis, Sanofi/Regeneron, GlaxoSmithKline, and Grifols. Served as an investigator on studies sponsored by, Regeneron and Takeda, for which her institution has received funding. Luis Perez-de-Llano reports grants, personal fees, and non-financial support from AstraZeneca; grants, personal fees, and non-financial support from Menarini; personal fees and non-financial support from GlaxoSmithKline; grants, personal fees and non-financial support from Teva; personal fees and non-financial support from Chiesi; grants, personal fees and non-financial support from Sanofi; personal fees from Merck Sharp & Dohme; personal fees from Techdow Pharma; Personal fees from Advanzpharma; grants, personal fees and non-financial support from Faes Farma; personal fees from Leo-Pharma; grants and personal fees from Gebro; personal fees from Gilead, outside the submitted work. Paul E. Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures/webinars at meetings supported by AstraZeneca, Chiesi, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, Regeneron, and Sanofi, for which his institution received remuneration; and has current research grants funded by GlaxoSmithKline and a quality improvement grant funded by AstraZeneca. Nikolaos G. Papadopoulos has been a speaker and/or advisory board member for Abbott, Abbvie, ALK-Abelló, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Integris Pharma SA, Berlin - Chemie AG, Vian S.A, Faes Farma, Medscape, Menarini, Merck Sharp & Dohme, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris; honoraria from Nestlé Nutrition Institute, DBV Technologies SA, Hyproca Nutrition USA INC, and ELPEN Pharmaceutical Co. Inc; grants from Numil Hellas SA, Vibrant America; consulting services from Danone Trading Medical B.V, Med Maps srl, Danone Global Research & Innovation Center B.V. John Townend is an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care, a co-funder of the International Severe Asthma Registry. Ghislaine Scelo is a consultant for Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care, a co-funder of the International Severe Asthma Registry. Aaron Beastall is an employee of Optimum Patient Care Global, a co-funder of the International Severe Asthma Registry. Lakmini Bulathsinhala is an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care, a co-funder of the International Severe Asthma Registry. John Busby is an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care, a co-funder of the International Severe Asthma Registry. Andrew W. Lindsley is an employee of Amgen and owns stock in Amgen. Wendy C. Moore has received consulting fees from AstraZeneca and GlaxoSmithKline and her institution received grant support from Areteia, AstraZeneca, Sanofi Regeneron, Genentech, NHLBI/NHLBI, and GlaxoSmithKline. She is also a member of the Publications Steering Committee for the CHRONICLE study as well as a PI of the clinical trial at Wake Forest. Reynold A. Panettieri Jr. has received research support from the National Institutes of Health, GlaxoSmithKline, Connect Biopharma LLC, Haleon US Holdings LLC, Syneos health LLC, Genentech Inc, Areteia Therapeutics Inc, Origo Pharma, Regeneron Pharm Inc., Pfizer, and AstraZeneca; is a consultant for AstraZeneca, and GlaxoSmithKline. He is a member of the Publications Steering Committee for the CHRONICLE study. He also reports pending patents to Thomas Jefferson University, National Institute of Health, and Albert Einstein College of Medicine. Giorgio Walter Canonica has received research grants, as well as lecture or advisory board fees from: A.Menarini, Anallergo, Allergy Therapeutics, AstraZeneca, Celltrion, Chiesi Farmaceutici, Faes, Firma, Genentech, Guidotti, GlaxoSmithKline, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, and Uriach Pharma. Enrico Heffler declares personal fees for advisory boards participation and/or speaker activities from: Sanofi, Regeneron, GlaxoSmithKline, AstraZeneca, Celltrion-Healthcare, Apogee Therapeutics, Stallergenes-Greer, Lofarma, Allergy Therapeutics, Circassia, Bosch, Chiesi, Orion Pharma, Gentili, Blueprint Medicines, Almirall, and Recordati. Cristina Cardini declares no relevant conflicts of interest in this work. Giuseppe Guida received lecture fees from Menarini, Sanofi, and AstraZeneca. Celeste M. Porsbjerg has attended advisory boards for AstraZeneca, Chiesi, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, Merck Sharp & Dohme, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Chiesi, Novartis, TEVA, GlaxoSmithKline, ALK-Abelló, and Sanofi-Genzyme. Anne-Sofie Bjerrum has received lecture fees from AstraZeneca, CellTrion, GlaxoSmithKline, Novartis and Sanofi, and attended advisory board for AstraZeneca, GlaxoSmithKline, and Sanofi. Anna von Bülow reports speaker’s fees and consultancy fees from AstraZeneca, GSK and Novartis, outside the submitted work. She has also attended advisory board for Novartis, GlaxoSmithKline, and AstraZeneca. Ole Hilberg declares lecture and advisory board fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Chiesi, Merck Sharp & Dohme, and Sanofi. Kjell Erik Julius Håkansson has received speaker’s fees, advisory board fees and/or unrestricted research grants from AstraZeneca, Chiesi, GlaxoSmithKline, NovoNordisk and Sanofi during the last 24 months. Marianne Baastrup Søndergaard reports speaker fees from GlaxoSmithKline, AstraZeneca, and Sanofi. Charlotte Suppli Ulrik reports personal fees for talks, participation in advisory boards etc. from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Orion Pharma, Sanofi Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, Pfizer, Novo Nordisk, Roche, IQVIA, Regeneron, Hikma Pharmaceuticals, and Novartis, outside the submitted work. Eileen Wang has received honoraria from AstraZeneca, GlaxoSmithKline, Amgen, and Genentech. She has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, and Sanofi, for which her institution has received funding. Michael E. Wechsler reports grants and/or personal fees from Abbvie, Allakso, Arrowhead, Roche, Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Gilead, General Medicines, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound Biologics, Incyte, Pfizer, Phylaxis, Jasper, Upstream Bio, Kymera and Kinaset. Nicholas Chapman reports no conflicts of interest in this work. Flavia Hoyte declares honoraria from AstraZeneca, Teva, Sanofi, and Apogee. She has been an investigator on clinical trials sponsored by GlaxoSmithKline, Genentech, and Sanofi, for which her institution has received funding. She also reports stock options from Amgen. Kanao Otsu declares no conflicts of interest in this work. Liam G. Heaney has received grant funding, participated in advisory boards and given lectures at meetings supported by Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; he has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, MedImmune, Aerocrine, and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. David J. Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, and Sanofi Regeneron; and research funding from AstraZeneca, and GlaxoSmithKline. Pujan H. Patel has received advisory board and speaker fees from AstraZeneca, Celltrion Healthcare, GlaxoSmithKline, Novartis, and Sanofi/Regeneron. Dermot Ryan has (in the last 3 years) lectured on behalf of, received sponsorship from, or acted as a paid advisor to Mylan, ALK-Abello, VIitalograph, and GPRI. Celine Bergeron reports advisory board participation for Sanofi-Regeneron, AstraZeneca, Takeda, ValeoPharma; and consulting fees from Areteia Therapeutics, honorarium for presentations from AstraZeneca/Amgen, GlaxoSmithKline, Grifols, Sanofi-Regeneron, Takeda and ValeoPharma; and grants paid to UBC from BioHaven, Sanofi-Regeneron, AstraZeneca, GlaxoSmithKline, Jasper Therapeutics, Areteia, and Amgen. Shelley Abercromby declares no relevant conflicts of interest in this work. Mohit Bhutani received grants paid to his institution by CIHR, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, Pfizer, Takeda. MB received speaker and consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi, Takeda, Pfizer, Valeo and Covis. Kenneth R. Chapman has received grants from AstraZeneca, Boehringer Ingelheim, Bellus, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Regeneron, Sanofi, Takeda, and Vertex; and consulting fees from AstraZeneca, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Sanofi, and Takeda. He has a leadership or fiduciary role in Alpha-1 Canada, Canadian Thoracic Society, Alpha-1 Foundation, and AlphaNet Canada. Andréanne Côté declares she has received speaking fees and consultant fees from Sanofi, Regeneron, AstraZeneca, and GlaxoSmithKline. She received unrestricted grant support from GlaxoSmithKline, and AstraZeneca. Beth E. Davis declares no conflicts of interest in this work. Delbert R. Dorscheid is on faculty at the University of British Columbia and is supported by the following grants: Canadian Institutes of Health Research, British Columbia Lung Association, and Michael Smith Foundation for Health Research. In addition, he has received speaking fees, travel grants, unrestricted project grants, writing fees and is a paid consultant for Pharma including Sanofi Regeneron, Novartis Canada, AstraZeneca, GlaxoSmithKline and ValeoPharma. He is an active member of Canadian Thoracic Society, American Thoracic Society, European Respiratory Society, and the Allergen Research Network. Dr. Dorscheid does not believe that any of the disclosed potential conflicts represent true conflicts with respect to the information and recommendations included in this manuscript. Leiana Hoshyari declares no conflicts of interest in this work. Brianne Philipenko has advisory board membership with AstraZeneca and Sanofi; payment for lectures/speaking engagements from AstraZeneca, GlaxoSmithKline, Pfizer, Sanofi, Roche, and Covis pharma. Hana Serajeddini reports advisory board participation for AstraZeneca, and Sanofi-Regeneron, and received speaking honoraria from GlaxoSmithKline, Sanofi, AstraZeneca, and Valeo. Florence Schleich reports consultancy work for GlaxoSmithKline, AstraZeneca, Sanofi, Advanz, Chiesi - Advisory board, received speaker fees from GlaxoSmithKline, AstraZeneca, Chiesi, Teva, ALK-Abelló, Sanofi, Advanz and research grants from GlaxoSmithKline, AstraZeneca, Sanofi and Chiesi. Renaud Louis has received grants and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi. Piotr Kuna reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, Chiesi, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Celon Pharma, GSK, Sanofi, Teva, and Zentiva, outside the submitted work. Borja G. Cosio declares grants from Bial, Chiesi, Menarini, and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; payment for lectures/speaking engagements from Sanofi, Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca; non-financial support from Gebro and Bial, outside the submitted work. Désirée Larenas-Linnemann reports personal fees from ALK-Abelló, Armstrong, AstraZeneca national and global, Chiesi, GSK national and global, Viatris, Megalabs Ecuador, Naos, Novartis, Pfizer, Sanofi, Siegfried, Syneos Health, grants from Abbvie, Lilly, Sanofi, Astrazeneca, Pfizer, Novartis, GSK, Chiesi, Biopharma, outside the submitted work; and Editor in chief of Immune System (Karger); Member of asthma committee ACAAI; Subgroup chair of allergen immunotherapy Practice parameter update JTF AAAAI/ACAAI 2024; Member of allergen immunotherapy committee AAAAI; Chair of allergen immunotherapy committee CMICA outside the submitted work. Carlos A. Torres-Duque has received fees as an advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. María José Fernández-Sánchez has received speaking fees, consultant fees, advisory board fees and travel grants from AstraZeneca, and GlaxoSmithKline; has received unrestricted grants for investigator-initiated studies at Clinica Cardiovid from AstraZeneca. Elizabeth Garcia declares that she has no conflicts of interest with respect to this work. Fabio Bolívar Grimaldos declares that he has no conflicts of interest with respect to this work. Libardo Jiménez-Maldonado has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has participated in clinical trials for AstraZeneca, Novartis and GlaxoSmithKline. Diana Jimena Cano Rosales has received speaking fees, consultant fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Sanofi-Aventis; has taken part in clinical trials from Areteia Therapeutics. Ivan Solarte has received fees as an advisory board participant and/or speaker from GlaxoSmithKline, AstraZeneca, and Sanofi. Riyad Al-Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi, and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. Adeeb A. Bulkhi has received speaker lecture fees from AstraZeneca, GlaxoSmithKline, Sanofi, Novartis, Takeda, and ALK. He also participated in advisory boards with GlaxoSmithKline, Sanofi, and Novartis. Mona Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline, and received a grant from Kuwait Foundation for the Advancement of Sciences (KFAS). Takashi Iwanaga received speaker bureau fees from Kyorin, GlaxoSmithKline, Novo Nordisk, Tanabe Pharma, Novartis, Boehringer Ingelheim, and AstraZeneca. Soichiro Hozawa has received honoraria from AstraZeneca, GlaxoSmithKline, Novartis Pharma, Kyorin Pharmaceutical, Sanofi and Regeneron. Hisako Matsumoto declares lecturer fees from Kyorin Pharma, AstraZeneca, Sanofi Co. Novartis Pharma, and GlaxoSmithKline. Tatsuya Nagano received lecture fees from Kyorin, Sanofi, GlaxoSmithKline, Novartis, and AstraZeneca. Tomoko Tajiri declares lecture fees from Sanofi Co, and GlaxoSmithKline. Bernt Bøgvald Aarli has received speaker honoraria and/or consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi, Vertex, Chiesi, Orion, Celltrion, Novartis and Grifols, outside the submitted work. Diahn-Warng Perng received a sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. Yi-Han Hsiao received honoraria for lectures from Boehringer Ingelheim, Sanofi, GlaxoSmithKline, AstraZeneca, Novartis, and Orient EuroPharma (OEP). He also received support for attending meetings and/or travel from Sanofi, GlaxoSmithKline, and AstraZeneca. Pin-Kuei Fu declares no relevant conflicts of interest in this work. Chau-Chyun Sheu has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Pfizer, and has acted as an investigator for trials sponsored by AstraZeneca, Novartis, Roche, Sanofi-Regeneron, GlaxoSmithKline, Pfizer, Galapagos, Shionogi, Aridis, Bristol Myers Squibb, Insmed, United Therapeutics, Enanta Pharmaceuticals, Areteia Therapeutics, Meiji, and Horizon Therapeutics. Konstantinos Kostikas has received honoraria for presentations and/or consultancy fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Guidotti, Menarini, Pfizer, Sanofi, and Specialty Therapeutics. His department has received funding and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini. He worked with AstraZeneca as Global Medical Head Respiratory Biologics – 02.09.2024 to 29.11.2024. He is a member of the GOLxD Assembly. Mina Gaga reports an EU grant for Lung Cancer Screening and a travel grant by Guidotti (Menarini Group), outside the submitted work. Athena Gogali has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, Guidotti, Menarini, and Pfizer. Maria Kallieri declares no relevant conflicts of interest in this work. Stelios Loukides has received payments for lectures and advisory boards from Chiesi, Sanofi, Menarini, GlaxoSmithKline, AstraZeneca, ELPEN, and Specialty Therapeutics. Michael Makris reports honoraria for presentations and consultancy fees from Novartis, GlaxoSmithKline, Menarini, AstraZeneca, Chiesi, Sanofi, Pfizer, SwixxPharma, Celldex Therapeutics, Thermofisher, and ELPEN, outside the submitted work. Maria Ntakoula has received honoraria for presentations from AstraZeneca, outside the submitted work. Andriana I. Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, Chiesi, Alector Pharmaceuticals, Opella, and Pfizer. Giannis Paraskevopoulos has received honoraria for presentations and consultancy fees from Menarini, AstraZeneca, Chiesi, Sanofi, AbbVie, and Pfizer. Fotios Psarros declares no conflicts of interest in this work. Bassam Mahboub reports no conflicts of interest in this work. Laila Salameh declares no relevant conflicts of interest in this work. Mariko Siyue Koh reports grant support from AstraZeneca, and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim, outside the submitted work. Mei Fong Liew declares honoraria for lectures and advisory board meetings paid to her hospital (Alexandra Hospital) from GlaxoSmithKline, AstraZeneca, and Sanofi, outside the submitted work. Esther Pang Pee Hwee has received honoraria for talks and advisory board meetings from GlaxoSmithKline, AstraZeneca, and Sanofi. Tze Lee Tan was an advisory Board Member for Boehringer Ingelheim, AstraZeneca, Takeda, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, and Janssen. Honoraria were received for these advisory boards. Honoraria were received for speaking at CMEs for AstraZeneca in the past. Conference sponsorships from AstraZeneca, Boehringer Ingelheim, Merck Serono, GlaxoSmithKline, Norvatis, Mundipharma and Merck Sharp & Dohme. Research grants from Merck Serono (Concor Study), Merck Sharp & Dohme (Apbord study). Tunn Ren Tay has received speaker fees and advisory board payments from AstraZeneca, GlaxoSmithKline and Sanofi paid to her institution and outside of the submitted work. Paulo Márcio Pitrez received fees as a speaker or for consultations from GlaxoSmithKline, AstraZeneca, Sanofi, and Aché. Chin Kook Rhee received consulting/lecture fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, Organon, Roche, and Bayer. Njira Lugogo received consulting fees from Abbvie, Apogee, Amgen, AstraZeneca, Avillion, Foresee, Incyte, Pfizer, Roche, Genentech, GlaxoSmithKline, Niox, Novartis, Regeneron, Sanofi, and Teva; honoraria for non-speakers bureau presentations from GlaxoSmithKline, TEVA and AstraZeneca; and travel support from AstraZeneca, SANOFI, TEVA, Regeneron and GlaxoSmithKline; her institution received research support from Amgen, AstraZeneca, Avillion, Bellus, Evidera, Gossamer Bio, Genentech, GlaxoSmithKline, Janssen, Niox, Regeneron, Sanofi, Novartis and Teva. She is an honorary faculty member of Observational and Pragmatic Research Institute (OPRI) but does not receive compensation for this role. She is a member of the Publications Steering Committee for CHRONICLE. Arjun Mohan received consulting fees for advisory board participation from Verona Pharma and Regeneron Pharm. João A. Fonseca reports grants from research agreements with AstraZeneca, Mundipharma, Sanofi Regeneron, and Novartis; and personal fees for lectures and attending advisory boards from AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi Regeneron, and Teva. Ana Alves da Silva declares no conflicts of interest in this work. Cláudia Chaves Loureiro has received (in the past three years) lecture or advisory board fees from AstraZeneca, GlaxoSmithKline, Menarini, Sanofi, and Teva, outside this work. Hadassa Cristhina de Azevedo Soares dos Santos declares no conflicts of interest in this work. Jorge Máspero reports speaker fees, grants, or fees for advisory board participation from AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor. Ledit R. F. Adrusso is an investigator for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Amgen, Chiesi, Bellus, Areteria, Insmed, and Optinose. María Eugenia Franchi has received speaker fees from GlaxoSmithKline, AstraZeneca, and Sanofi. Martin Sivori has received lecture fees for medical education programs of AstraZeneca, SANOFI, GlaxoSmithKline, and TEVA. Ana María Stok has acted as an investigator for GlaxoSmithKline, AstraZeneca, Sanofi, Chiesi, Novartis, and Bago. She reports speaker fees from GlaxoSmithKline, AstraZeneca, and Sanofi. Anahí Yañez has received grants/research supports from GlaxoSmithKline, AstraZeneca, Sanofi, Chiessi, Novartis, MDS, Roche, Faes, TEVA, Avillon, Janssen, Bayer, Sanofi Gynzene, and he has received consultation fees from GlaxoSmithKline, AstraZeneca, Sanofi, and Eurofarma. He has participated in a company sponsored speaker’s bureau from Sanofi, GlaxoSmithKline, Faes, Sanofi Gynzene, and AstraZeneca. George C. Christoff declares relevant research support from AstraZeneca and Sanofi. Todor A. Popov declares research support from Novartis and Chiesi Pharma, not related to this particular work. Patrick D. Mitchell has received speaker fees from GlaxoSmithKline, AstraZeneca, Teva and Novartis, and has received grants from AstraZeneca, and Teva. He has received advisor board fees from AstraZeneca. Sundeep Salvi declares research support and speaker fees from Cipla, Glenmark, and GlaxoSmithKline. Richard W. Costello has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for GlaxoSmithKline and Novartis, has received grant support from GlaxoSmithKline and Aerogen, and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence and prediction of exacerbations. Eve J. Denton declares grants paid to her institution from AstraZeneca in conjunction with Optimum Patient Care Global Ltd, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects and speaker fees from Sanofi, Menarini and Boehringer Ingelheim. Mark Hew is a steering committee of the ERS CONNECT Clinical Research Collaboration. He declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, Aravax, GlaxoSmithKline, Chiesi, Novartis, Stallergenes, Seqirus, Sanofi, and Teva, for unrelated projects. Christine Jenkins is a member of advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi and Chiesi. She has received payment for Advisory board attendance, honoraria, lectures and meeting participation as a speaker. She has no conflicts in relation to this work. David Langton declares no conflicts of interest in this work. Peter G. Middleton declares grant support from NH&MRC, HCF Australia, Canadian Institutes of Health, Board membership of the CF Foundation DSMB, and lecture fees and advisory boards for AstraZeneca, Limbic, MedEd, and Vertex, all unrelated to this work. Matthew J. Peters declares personal fees and non-financial support from AstraZeneca, GlaxoSmithKline, and Sanofi. Lauri Lehtimäki has received personal fees from ALK, Astellas Pharma, AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Orion Pharma, and Sanofi. He owns stocks of Ausculthing oy. Arnaud Bourdin has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, Sanofi-Regeneron, and consulting fees from AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Camille Taillé has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, Stallergenes, LeoPharma, Celtrion, and Novartis, for unrelated projects. Christian Taube declares no relevant conflicts of interest in this work. Zsuzsanna Csoma has received lecture fees from AstraZeneca, Berlin Chemie, Sanofi, and Chiesi; and travel support from Berlin Chemie and Sanofi. Dóra Lúdvíksdóttir has received lecture fees from GlaxoSmithKline, Sanofi and AstraZeneca. Job F.M. van Boven received grants and/or consultancy fees from Aardex, ALK, AstraZeneca, Chiesi, European Commission, COST (COST Action 19132), GlaxoSmithKline, Novartis, Pfizer, Pill Connect, Sanofi, Teva, Trudell Medical, and Vertex, outside the submitted work and all paid to his institution. James Fingleton reports grants, personal fees and non-financial support from AstraZeneca, grants from Genentech, grants from Sanofi, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Boehringer lngleheim, outside the submitted work. Leif Bjermer has (in the last three years) received lecture or advisory board fees from Airsonett, Acucort, Alk-Abello, AstraZeneca, Chiesi, GlaxoSmithKline, Sanofi, and Genzyme/Regeneron. Helena Emery declares no conflicts of interest in this work. Graham Lough declares no conflicts of interest in this work. Roy Alton Pleasants is a consultant for AstraZeneca and Grifols and receives research support through institutions from AstraZeneca and GlaxoSmithKline. Diego J. Maselli received consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, Insmed, and Amgen. Christopher S. Ambrose is an employee of AstraZeneca and may own stocks or stock options in AstraZeneca. AstraZeneca is the sponsor and funder of the CHRONICLE study and a co-funder of the International Severe Asthma Registry. Cathy Emmas was an employee of AstraZeneca at the time this work was completed. AstraZeneca is the sponsor and funder of the CHRONICLE study and a co-funder of the International Severe Asthma Registry. Andrew N. Menzies-Gow is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. AstraZeneca is the sponsor and funder of the CHRONICLE study and a co-funder of the International Severe Asthma Registry. Victoria Carter is an employee of Optimum Patient Care (OPC). OPC is a co-funder of the International Severe Asthma Registry. Nevaashni Eleangovan is an employee of Optimum Patient Care Global (OPCG), a co-funder of the International Severe Asthma Registry. Ruth B. Murray is a consultant for Observational and Pragmatic Research Institute (OPRI) which conducted this study in collaboration with Optimum Patient Care, a co-funder of the International Severe Asthma Registry. Chris A. Price is an employee of Optimum Patient Care (OPC). OPC is a co-funder of the International Severe Asthma Registry. Mohsen Sadatsafavi has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva, and GlaxoSmithKline for purposes unrelated to the content of this manuscript and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. David B. Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Inside Practice, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, and Teva Pharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); is a peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation Programme, and Health Technology Assessment; and he was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work.