International Severe Asthma Registry (ISAR): 2017–2024 Status and Progress Update

1. Founding principles and mission

ISAR operates according to core guiding principles of openness, inclusivity, and collaborative data sharing and research discussions [1]; ISAR contributors own their data and share only anonymized data, collect and share specified ISAR core variables, and uphold the research standards governing ISAR. Impartiality is a fundamental precept, and the ISAR database cannot be used to conduct inferential drug-specific comparative studies [2].

ISAR’s primary objectives are to characterize and describe severe asthma internationally, both in the overall patient population and among different subgroups of interest, and to facilitate phenotyping and endotyping, so that patient groups can be distinguished by their disease burden, management patterns, and clinical evolution [2]. Important secondary objectives include supporting the development of effective diagnostic/prognostic modalities, evaluating the real-world effectiveness and safety of treatments for severe asthma, and improving patient outcomes—for example, by identifying potentially modifiable factors associated with poor outcomes and implementing steroid-sparing treatments and strategies [2]. The overarching aims are to consolidate knowledge about severe asthma and support research that will improve the care of adult patients globally, whether in primary, secondary, or tertiary care [1,2]. ISAR’s pursuit of these goals leverages key strengths, specifically: its global reach, inclusivity, and expertise; collecting standardized, comprehensive, and high-quality longitudinal individual-level data from countries worldwide; an organizational structure that supports robust and ethical scientific research; and extensive experience in data capture and management [1,2].

1. Patient selection and data collection

To be included by ISAR, patients at participating centers must meet eligibility criteria, which were chosen to capture a broad population of patients with severe asthma in real-world settings, including those with moderate-to-severe asthma and not excluding those with a history of smoking [2] Briefly, patients must be ≥18 years old and either receiving step 5 treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) [33] or have asthma ‘uncontrolled’ on GINA step 4 treatment, as defined by the European Respiratory Society/American Thoracic Society guidelines [34].

The first challenge that ISAR tackled was to standardize data collection by its international members and thereby enable the pooling, analysis, and robust interpretation of data across diverse patient populations and geographic and clinical settings [2]. ISC members conducted a modified Delphi process in 2017 to reach consensus on a standard set of core research variables; these comprised 95 variables in 13 categories, including demographics, medical history, clinical characteristics, lung function, biomarkers, and patient-reported outcome measures [2,3]. Collection and reporting of all specified core variables is a condition of ISAR participation [2,3]. Other standardized variables that were not included in the core set but may also be shared via ISAR or collected locally include safety and effectiveness bolt-on variables, such as adverse events potentially associated with use of biologic agents, and further optional variables deemed useful for research— for example, morbidities associated with exposure to corticosteroids, occupation, non-core biomarkers, and mental well-being or quality of life metrics [2,4].

1. Epidemiology and global burdens of severe asthma

Severe asthma is a complex, heterogeneous, and incompletely understood condition that affects 5%–10% of all patients with asthma—more than 13 million people worldwide [5,35]. Although severe asthma affects a minority of the whole asthma population, it imposes disproportionately high burdens of morbidity, mortality, and healthcare resource utilization, with substantial psychosocial and socioeconomic impacts [2,5]. In the first study to characterize severe asthma worldwide, based on data from ISAR and other registries internationally, severe asthma was estimated to account for more than 60% of total asthma-related healthcare costs, a large proportion of which are attributable to oral corticosteroid (OCS)-related morbidities [5]. Insights from ISAR that are informing improved asthma management and patient care will contribute to progress towards alleviating these burdens.

Exposure to systemic corticosteroids, which are widely used to treat asthma [36], significantly increases patients’ risk of multiple adverse outcomes, such as type 2 diabetes, osteoporosis, and cardiovascular diseases, starting from doses equivalent to only four short OCS courses per lifetime (0.5 to <1 g) [37-40]. Consequently, updated GINA guidelines for difficult-to-treat and severe asthma caution that low-dose OCS should only be added as a last resort, having first optimized treatment, and where steroid-sparing biologic therapy is unavailable or unaffordable [41]. Notably, use of moderate-high doses of inhaled corticosteroids has also been associated with adverse outcomes, which included cardiovascular events, pulmonary embolism, and pneumonia [42]. The ISAR PRISM study highlighted the extent of the burden of comorbidities in severe asthma: 55% of patients had three or more comorbidities and 68% had at least one potentially OCS-related comorbidity, which included obesity (42%), hypertension (23%), dyslipidemia (16%), osteoporosis (13%), diabetes (12%), and coronary heart disease (9%); patients with OCS-related comorbidities were more likely to experience exacerbations [12]. Such evidence underpins the concept of corticosteroid stewardship, which advocates prescribing corticosteroids only when clinically justified and at the lowest effective dose, and preferentially using steroid-sparing strategies and/or non-steroid alternatives, including targeted biologics, wherever appropriate [43-45]. Besides the burdens of OCS-related morbidity, patients with severe asthma are at risk for airway remodeling due to exacerbations, which is associated with accelerated lung function deterioration [7,46]. In a worldwide survey of severe asthma, including ISAR data, 51% of patients were receiving regular intermittent OCS, and fixed airway obstruction was prevalent; 44% worldwide had post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 [5], with even higher prevalence in the Asia-Pacific region [47]. Meanwhile, analysis of data from the United Kingdom (UK) Optimum Patient Care Research Database (OPCRD) has shown that asthma exacerbations accelerate lung function decline in adults, with a more pronounced association in younger patients [7]. An ISAR study found that the risks of severe exacerbations varied between patients with similar characteristics but who lived in different jurisdictions, suggesting the existence of unknown patient or health system factors [13]; hence, work is underway to develop a model to predict the risk of severe exacerbations patients with severe asthma, which could guide treatment escalation [14]. Data from Korean IASR patients and the Korean Chronic Obstructive Pulmonary Disease (COPD) Subgroup Study have shown similar prevalence of overlapping asthma/COPD (ACO) in patient groups with pure severe asthma or with pure COPD, with comparable lung function impairment and exacerbation risk in patients with ACO from either group [15].

2. Who, when, and how in treating severe asthma

Minimizing systemic corticosteroid exposure is key to reducing damage to the body and lungs in patients with severe asthma [12,37,39,48]. Analysis of real-world data from ISAR is contributing to realizing this objective by identifying appropriate treatments for the right patients at the right time. A study of inflammatory biomarker expression revealed distinct clusters of patients that exhibited unique clinical characteristics, which suggests discrete patterns of underlying inflammatory pathway activation. Understanding how these mechanisms affect individual patients with severe asthma will help clinicians to target precision medicines, such as biologic therapies, to patients likely to benefit [8].

Characterization of severe asthma phenotypes in the ISAR population using an eosinophilic gradient algorithm, showed that most had type 2 inflammation [9], for which targeted treatments are available; accordingly, GINA has been recommending add-on biologic therapies for severe eosinophilic asthma since 2021 [48,49]. Besides GINA, ISAR research has informed several other official guidelines; these include UK National Institute for Health and Care Excellence guidance on treating severe asthma with tezepelumab [50], management guidelines from Mexico [51] and Germany [52], and guidance on asthma care in older people [53].

Analyses of real-world patient data have also identified major barriers to specialist care for severe asthma. The earlier patients with severe asthma can be identified, the sooner they can receive appropriate treatment. Unfortunately, under-recognition of severe asthma in the primary care settings where patients with asthma are typically treated may be a barrier to referral for specialist care. A study of asthma patients from ISAR and the OPCRD estimated that although 8% of those managed long-term in primary care had potentially severe asthma, most (72%) had neither been referred nor received specialist care for more than a year despite being eligible [6]. Many patients with ‘hidden’ severe asthma may be managed with long-term OCS and lack access to specialist treatments, such as biologic therapies, with a more favorable risk/benefit ratio. Another OPCRD study showed that patients with asthma who were most socio-economically deprived had worse disease control and higher exacerbation rates compared with the least deprived, however, they were no more likely to be referred for specialist assessment and targeted treatments [11]. Registries such as ISAR and the OPCRD provide rich sources of real-world data that can be used to facilitate earlier identification of severe asthma in primary care and investigate the reasons for disparities in asthma management and how these could be addressed to improve patient outcomes.

The introduction of biologic asthma therapies has transformed the treatment landscape, and ISAR is providing valuable real-world data about the clinical applicability of biologics in patients with different characteristics and in different scenarios [31]. In an ISAR study that compared the effectiveness of initiating biologic therapies for severe asthma versus continuing long-term (≥1 year) or frequent rescue OCS (≥4 courses/year), both groups had improved outcomes at 1 year follow-up [21]. However, compared with ongoing OCS alone, biologic initiators had a significantly reduced exacerbation rate, were more likely to have a >50% reduction in OCS from baseline, and had lower risks of asthma-related emergency department visits and hospitalizations [21]. Similarly, in the ISAR CLEAR study, biologic initiators had a lower incidence of exacerbations during follow-up compared with non-initiators despite having more severe disease at baseline [54]. These results support the rationale for prescribing biologics, even in patients showing improvement on long-term or regular rescue OCS, as a potentially cost-effective strategy to further improve outcomes while minimizing OCS exposure [21]. The CLEAR study also highlighted the importance of timely initiation of the optimal biologic therapy; patients with severe asthma who switched (25.5%) or stopped (14.5%) a biologic therapy, had higher rates of exacerbations and uncontrolled asthma than those who continued their initial biologic prescription; switchers also had a higher long-term OCS dose and more hospitalizations and emergency visits [18]. A study that compared the effectiveness of anti-immunoglobulin E (IgE) to antiinterleukin 5 (IL5) or anti-IL5 receptor (IL5R) in ISAR patients eligible for either biologic class found that, although both improved asthma outcomes, anti-IL5/5R was more effective in reducing exacerbations and longterm OCS exposure [19]. Nevertheless, if the response to an initial biologic is limited, clinicians may consider changing to another that might be more beneficial. Pertinently, ISAR research has revealed that switching is not common in current real-world practice; the SUNNIE study discovered consistently low rates of biologic switching worldwide, with only 11% of patients switching their initial treatment and 10% stopping [16]. Possible barriers to switching include the difficulty of getting an initial biologic prescription, which may put people off attempting to change to another, uncertainty about whether another biologic will improve upon marginal benefit from the first or may be ineffective, and limited evidence for benefits from switching. Hence, there is a need for further research into which patients respond best to different biologics [16]. Systemic barriers also limit the global availability and choice of different biologics for individualizing asthma treatment. An ISAR study highlighted substantial differences in national criteria for prescription and reimbursement of biologic asthma therapies, which result in marked variability in the accessibility of biologic agents between countries [17]. More than 60% of patients in the CLEAR study were not prescribed biologics despite meeting the eligibility criteria [54], and 30% of patients with high OCS exposure in GLITTER I did not receive biologics, despite a high rate of exacerbation comparable to that of biologics initiators [20]. Standardized prescription and access criteria are needed to overcome current barriers to wider availability and implementation of precision medicine for patients with severe asthma [17].

Other ISAR studies have continued to evaluate the effectiveness of both biologic and non-biologic asthma therapies in real-world clinical practice and to characterize factors that influence treatment responsiveness and outcomes in patients with severe asthma. For example, BEAM demonstrated that asthma control, exacerbations, and long-term OCS use can all be used to assess responsiveness to biologic therapies, which varied depending on the domain assessed and increased with worse baseline impairment, showing baseline status to be an important consideration in assessing treatment response [23]. PRISM II revealed that the presence of chronic rhinosinusitis, with or without nasal polyps, predicts greater effectiveness of biologic treatments for severe asthma [22]. Another study, FULL BEAM II, showed that clinical remission was more likely in patients with less severe asthma and shorter disease duration before biologic initiation; the odds of achieving four-domain clinical remission decreased by 15% for every additional 10 years asthma duration [26]. These findings support the rationale for early biologic treatment to achieve remission. Meanwhile, in the IGNITE study, higher baseline type 2 biomarkers (blood eosinophil count and exhaled nitric oxide) predicted improved lung function after initiating biologic therapy [24]. However, the EMBER study has highlighted the complexity of T2 inflammatory involvement in severe asthma and identified clusters of patients with varying biomarker elevations, including a predominantly female cluster with low T2 biomarker levels [10]. Importantly, other studies have shown that while patients who receive biologic therapies generally have better responses than those prescribed non-biologic treatments, a substantial proportion either do not meet clinical response criteria [25,27], or respond suboptimally, with persisting exacerbations, uncontrolled asthma, healthcare utilization, and long-term OCS use [25,28]. Further research is needed to understand how various factors may limit biologic responsiveness and to explore ways to optimize treatment [25]. One salient question is whether initiating biologics earlier may preempt irreversible lung damage and thereby improve patient outcomes [8,25,28].

Ongoing ISAR studies are investigating how differing OCS exposure before patients start biologic treatments affects the phenotype and biomarker profile of severe asthma (STAR), and how biologic initiation affects the burden of OCS and the subsequent onset of potentially OCS-related adverse outcomes (SOLAR). Another is exploring patterns of asthma onset and associated phenotypes (PATH), and a post-authorization safety study (PASS) is comparing the risks of malignancy between patients with severe asthma, who receive benralizumab, other biologics, or non-biologic therapies. Data analysis in these studies is underway and results will be published once available.

1. Delphi exercise to refine ISAR research variables

Since ISAR first defined a standard set of core research variables, data completeness has improved measurably. Before 2017, fewer than half of patients who initiated biologics had pre-treatment and post-treatment data for at least one of four core outcome domains (exacerbation rate, lung function, asthma control, longterm OCS use)—by 2020, this had risen to nearly 60%. Nevertheless, there is scope to further improve the quality of data collected in routine clinical care and recorded in ISAR [56]; indeed, this is increasingly necessary given the introduction of composite outcome measures of response or remission that require high-quality data across multiple domains [57]. As the ISAR dataset matured over the years and has been applied in diverse analyses, it has become clearer which variables are the most important for conducting research to fill current knowledge gaps, and which others might either have limited utility or be more challenging to standardize and collect internationally. Consequently, the ISC conducted a second Delphi exercise in 2023–2024 to refine and reprioritize the set of variables collected and thereby ensure the highest possible data quality; a key goal was to identify a subset of research variables crucial to advancing the understanding of severe asthma and improving patient care.

The inaugural ISAR Delphi study in 2017 reached consensus on 95 initial core variables, with the expec-tation that participating ISAR centers would achieve at least 90% collection and submission of these data to ISAR [3]. During the second, four-round, modified Delphi process in 2023, with a follow-up in 2024, ISAR experts considered approximately 150 potential variables, including the original 95 plus others in ‘safety’ and ‘effectiveness’ categories, and eliminated those below a pre-specified consensus threshold in successive rounds, eventually reducing the number to 73 individual core variables across 10 data categories. Thirty-three of these are designated ‘key’ variables, deemed essential for clinical research, and for which participating centers are contractually obliged to collect and upload data from 100% of patients. Supplementary Table S1 summarizes the core and key data fields to be completed and reported at the first visit for severe asthma and at subsequent visits. Other variables, including some dropped from the core variables list and others newly proposed, may still be collected but are designated optional, due either being considered to have limited utility or because they would be too challenging to standardize and collect by all centers under current local circumstances.

Several noteworthy changes were decided in finalizing the ISAR 2024 variables. Allergic rhinitis was designated ‘core’ rather than ‘key’ because, although associated with atopic asthma, it has been found not to be a relevant factor in responses to biologic therapies [22], which limits its utility as a research variable; some countries do not even collect data on allergic rhinitis. The background asthma therapy start-date and dates of key serum biomarker tests, including the highest blood eosinophil count, IgE count, and fractional exhaled nitric oxide (FeNO) test at follow-up, were upgraded from ‘optional’ to ‘core’ variables, as these are all considered important research metrics. The baseline FeNO test result remains a key variable despite being challenging for some centers to collect, for example due to limited reimbursement or equipment, or not being done routinely; however, centers unable to provide these data for 100% of patients will be accommodated. Highest education level was added as an optional variable to provide a proxy measure of socioeconomic status. Use of steroid-sparing agents can be an informative metric but was demoted to ‘optional,’ as these products are seldom used in the era of biologics. The variable ‘Other factors contributing to severe asthma symptoms’ and several tests, including chest computed tomography scan, PC20 methacholine/histamine challenge, and bone densitometry, were also changed from ‘core’ to ‘optional’ due to consensus that these data were of limited utility. Serum IgE and adherence remain ‘key’ and ‘core’ respectively at baseline but have been designated ‘optional’ at follow-up visits.

2. QISAR

Since its inception, ISAR has recognized that improving the quality of care in severe asthma requires research data collection to be integral to routine clinical care. Building on a QI model that OPC Australia developed to facilitate the assessment and review of patients with difficult-to-treat asthma, ISAR launched a new QI platform—QISAR—in 2024. QISAR integrates two main data processing systems: a clinical toolset, hosted on the REDCap platform [58], and a suite of interactive digital dashboards provided by OPC to ISAR members. These tools aim to harmonize research data collection with clinical consultations and to improve the provision of evidence-based care.

The clinical tools include a new web-based clinical report form (CRF) inspired by the Denmark Severe Asthma Registry digital tool, a patient questionnaire designed to integrate seamlessly with the CRF, and automated instant clinical summary reports. These summaries can be integrated into electronic medical records to share with patients and primary care doctors, and can be extracted into a clinical letter template. This QI toolset minimizes duplicate data entry, automatically flags missing data, and was developed with input from clinical experts to make severe asthma consultations easier and more effective for both patients and clinicians.

All data, regardless of source, are processed centrally via the OPC database for visual output via a suite of interactive dashboard reports that enable longitudinal tracking of key outcomes, such as spirometry, longterm OCS use, exacerbations, and asthma control, at both individual patient and site/country levels. These interactive reports also provide evidence and databased practice change suggestions, and account for variations between countries in control score type, biologic eligibility criteria, input language, medication trade names, and treatment guidelines.