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

Désirée Larenas-Linnemann, Chin Kook Rhee, Alan Altraja, John Busby, Trung Tran, Eileen Wang, Todor Popov, Patrick Mitchell, Paul Pfeffer, Roy Alton Pleasants, et al.

► To cite this version:

Désirée Larenas-Linnemann, Chin Kook Rhee, Alan Altraja, John Busby, Trung Tran, et al. International Severe Asthma Registry (ISAR): 2017-2024 Status and Progress Update. Tuberculosis and Respiratory Diseases, 2025, 88 (2), pp.193-215. 10.4046/trd.2024.0198. hal-04934294

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

Désirée Larenas-Linnemann<fnref n="1" />, Chin Kook Rhee<fnref n="2" />, Alan Altraja<fnref n="3" />, John Busby<fnref n="4" />, Trung N Tran<fnref n="5" />, Eileen Wang<fnref n="6" /> <fnref n="7" />, Todor A Popov<fnref n="8" />, Patrick D Mitchell<fnref n="9" />, Paul E Pfeffer<fnref n="10" /> <fnref n="11" />, Roy Alton Pleasants¹² ¹³, Rohit Katial<fnref n="6" />, Mariko Siyue Koh¹⁴ ¹⁵, Arnaud Bourdin¹⁶, Florence Schleich¹⁷, Jorge Máspero¹⁸ ¹⁹, Mark Hew²⁰ ²¹, Matthew J Peters²² ²³, David J Jackson²⁴, George C Christoff²⁵, Luis Perez-de-Llano²⁶ ²⁷, Ivan Cherrez-Ojeda²⁸ ²⁹ ³⁰ ³¹, João A Fonseca³², Richard W Costello³³, Carlos A Torres-Duque³⁴ ³⁵, Piotr Kuna³⁶, Andrew N Menzies-Gow³⁷ ³⁸, Neda Stjepanovic³⁹, Peter G Gibson⁴⁰ ⁴¹, Paulo Márcio Pitrez⁴², Celine Bergeron⁴³ ⁴⁴, Celeste M Porsbjerg⁴⁵, Camille Taillé⁴⁶, Christian Taube⁴⁷, Nikolaos G Papadopoulos⁴⁸ ⁴⁹, Andriana I Papaioannou⁵⁰, Sundeep Salvi⁵¹, Giorgio Walter Canonica⁵² ⁵³, Enrico Heffler⁵² ⁵³, Takashi Iwanaga⁵⁴, Mona S Al-Ahmad⁵⁵ ⁵⁶, Sverre Lehmann⁵⁷ ⁵⁸, Riyad Al-Lehebi⁵⁹ ⁶⁰, Borja G Cosio⁶¹, Diahn-Warng Perng⁶² ⁶³, Bassam Mahboub⁶⁴ ⁶⁵, Liam G Heaney⁶⁶, Pujan H Patel⁶⁷, Njira Lugogo⁶⁸, Michael E Wechsler⁶⁹, Lakmini Bulathsinhala⁷⁰ ⁷¹, Victoria Carter⁷⁰ ⁷¹, Kirsty Fletton⁷⁰ ⁷¹, David L Neil⁷⁰ ⁷¹, Ghislaine Scelo⁷⁰ ⁷¹, David B Price⁷⁰ ⁷¹ ⁷²

<footnote n="1">¹ Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico.</footnote>

<footnote n="2">² Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.</footnote>

<footnote n="3">³ Department of Pulmonology, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia.</footnote>

<footnote n="4">⁴ Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.</footnote>

<footnote n="5">⁵ BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA.</footnote>

<footnote n="6">⁶ Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA.</footnote>

<footnote n="7">⁷ Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.</footnote>

<footnote n="8">⁸ University Hospital St. Ivan Rilski, Sofia, Bulgaria.</footnote>

<footnote n="9">⁹ School of Medicine, Trinity College Dublin, Dublin, Ireland.</footnote>

<footnote n="10">¹⁰ Department of Respiratory Medicine, Barts Health NHS (National Health Services) Trust, London, UK.</footnote>

<footnote n="11">¹¹ William Harvey Research Institute, Queen Mary University of London, London, UK.</footnote>
¹² Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA.

¹³ Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.

¹⁴ Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore.

¹⁵ Duke-National University, Singapore Medical School, Singapore, Singapore.

¹⁶ PhyMedExp, Univ Montpellier, CNRS (National Center for Scientific Research), INSERM (The National Institute of Health and Medical Research), CHU (Centre Hospitalier Universitaire) Montpellier, Montpellier, France.

¹⁷ Department Pneumology CHU Liege, GIGA I3 Research Group Exercise Physiology Lab, University of Liege, Liege, Belgium.

¹⁸ Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina.

¹⁹ University Career of Specialists in Allergy and Clinical Immunology at the Buenos Aires University School of Medicine, Buenos Aires, Argentina.

²⁰ Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Victoria, Australia.

²¹ Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

²² Department of Thoracic Medicine, Concord Hospital, Sydney, New South Wales, Australia.

²³ Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.

²⁴ Guy's Severe Asthma Centre, School of Immunology & Microbial Sciences, King's College London, London, UK.

²⁵ Faculty of Public Health, Medical University, Sofia, Bulgaria.

²⁶ Pneumology Service, Lucus Augusti University Hospital, EOXI Lugo, Monforte, Cervo, Lugo, Spain.

²⁷ Department of Psychiatry, Radiology, Public Health, Nursery and Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.

²⁸ Universidad Espiritu Santo, Samborodón, Ecuador.

²⁹ The Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
³⁰ The Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany.

³¹ Respiralab Research Group, Guayaquil, Ecuador.

³² CINTESIS@RISE (Center for Health Technology and Services Research at Health Research Network), MEDCIDS (Departamento Medicina da Comunidade, Informação e Decisão em Saúde/Department of Community Medicine, Information and Health Decisions), Faculty of Medicine of the University of Porto, Porto, Portugal.

³³ Clinical Research Centre, Smurfit Building Beaumont Hospital, Department of Respiratory Medicine, RCSI (Royal College of Surgeons Ireland), Dublin, Ireland.

³⁴ CINEUMO (Centro Internacional de Investigación en Neumología), Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia.

³⁵ Doctoral Biosciences, Universidad de La Sabana, Chia, Colombia.

³⁶ Division of Internal Medicine Asthma and Allergy, Medical University of Lodz, Lodz, Poland.

³⁷ BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK.

³⁸ Lung Division, Royal Brompton & Harefield Hospital, London, UK.

³⁹ BioPharmaceuticals Medical, AstraZeneca, Gothenburg, Sweden.

⁴⁰ Australian Severe Asthma Network, Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South Wales, Australia.

⁴¹ Hunter Medical Research Institute, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.

⁴² Pulmonology Division, Hospital Santa Casa de Porto Alegre, Porto Alegre, Brazil.

⁴³ Department of Medicine, Centre for Lung Health, Vancouver General Hospital, Vancouver, British Columbia, Canada.

⁴⁴ Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.

⁴⁵ Department of Respiratory Medicine and Infectious Diseases, Research Unit, Bispebjerg Hospital, Copenhagen, Denmark.

⁴⁶ Department of Respiratory Diseases, Bichat Hospital, AP-HP (L'Assistance Publique - Hôpitaux de Paris), Nord-Université Paris Cité; Paris, France.

⁴⁷ Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany.
⁴⁸ Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK.

⁴⁹ Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece.

⁵⁰ 2nd Respiratory Medicine Department, National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece.

⁵¹ Pulmocare Research and Education Foundation, Pune, India.

⁵² Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy.

⁵³ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

⁵⁴ Sleep Medicine Centre, Kindai University Hospital, Osakasayama, Japan.

⁵⁵ Microbiology Department, College of Medicine, Kuwait University, Kuwait City, Kuwait.

⁵⁶ Al-Rashed Allergy Center, Ministry of Health, Kuwait City, Kuwait.

⁵⁷ Section of Thoracic Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.

⁵⁸ Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.

⁵⁹ Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia.

⁶⁰ College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

⁶¹ Son Espases University Hospital-IdISBa (Institut d'Investigació Sanitària Illes Balears)-Ciberes, Mallorca, Spain.

⁶² School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

⁶³ Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

⁶⁴ Rashid Hospital, Dubai Health (DH), Dubai, United Arab Emirates.

⁶⁵ College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.

⁶⁶ Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.

⁶⁷ Respiratory Medicine, Royal Brompton Hospital, London, UK.

⁶⁸ Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
69 National Jewish Health Cohen Family Asthma Institute, Department of Medicine, National Jewish Health, Denver, CO, USA.

70 Observational and Pragmatic Research Institute, Singapore, Singapore.

71 Optimum Patient Care Global, Cambridge, UK.

72 Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

**Keywords:**

Core variables; Delphi consensus; International Severe Asthma Registry (ISAR); Optimum Patient Care Global; Quality improvement; Real-world data.
Abstract

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched QISAR, a web-based data acquisition and reporting system, which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.
<figure><img src="image_2.png" /><figcaption>**Figure 1.** International Severe Asthma Registry (ISAR) state in the World 2017 to 2024. UAE: United Arab Emirates; UK: United Kingdom. Map by www.freeworldmaps.net.</figcaption></figure>

**Introduction**

The International Severe Asthma Registry (ISAR) is a pioneering, collaborative initiative dedicated to advancing the understanding of severe asthma and its management, with the ultimate objective of improving patient care and outcomes globally1,2. Since it was established in 2017, ISAR has enabled local, regional, and national registries worldwide to standardize and pool their data on adults with severe asthma, generating a comprehensive, centrally curated dataset that is shared seamlessly between stakeholders to apply existing knowledge, promote research, and gain novel insights1,2. Today, ISAR has expanded to become the largest and preeminent data resource for real-world studies on severe asthma; at the time of writing, ISAR curated standardized data on nearly 35,000 patients submitted by more than 250 local registries in 28 countries from all over the world (Figure 1); meanwhile, researchers have published more than 25 papers based on ISAR data, which have provided valuable insights on the characteristics, burdens, and real-world treatment of severe asthma1-
28. These achievements underscore global recognition of ISAR in spearheading severe asthma research29-31. This progress update describes ISAR's origins, organization and operation, research outputs, ongoing quality improvement (QI) program, and vision for the future.

## Origins and Objectives

ISAR was conceived to address longstanding challenges. Severe asthma is a heterogenous disease that is often difficult to treat2—less than 25% of patients have well controlled disease despite standard-of-care treatments5. Although severe asthma affects a minority of all patients with asthma, it is associated with substantial morbidity and mortality, impaired psychosocial well-being and quality of life, and significant healthcare utilization and expenditure2,4,5. Addressing the significant unmet healthcare needs of this patient population is a priority for asthma research3,4. Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine, but have low external validity; real-world studies can provide complementary data on treatment effectiveness beyond highly-selective RCT patient populations1,29,31. RCTs in severe asthma, especially those for biologic therapies, are often unrepresentative1,29,32; only 5.3% of ISAR patients in one study met standard RCT inclusion criteria27. Registries bridge this ‘efficacy- effectiveness’ gap, providing valuable sources of real-world data on asthma characteristics, trends, and treatment outcomes, which can inform improved management strategies1-3,29,31. However, the severe asthma population is relatively small, sparsely dispersed, and heterogenous, and the fragmentary registry landscape preceding ISAR made it challenging to conduct largescale studies and to compare data across patient populations and geographical regions1,2. The few existing national/regional registries were discrete and relatively small, used differing definitions of severe asthma, and collected disparate data of varying quality and completeness1,3-5. These limitations precluded interoperability and restricted the statistical power of single-registry severe asthma studies, depending on their patient numbers1,2. Responding to the clear need for a unified approach, ISAR was established to accrue a standardized global dataset from multiple registries worldwide, which would ensure data consistency, comparability, and quality, promote interoperability and collaboration, and provide ample statistical power for real-world studies to answer key clinical and research questions1,2,4. Importantly, this large-scale registry facilitates the identification and analysis of patient subgroups with differing characteristics and care needs, including regional differences between patients and in their management. Moreover, these data from the broad patient population in real-world practice can provide information and answer questions that are not amenable to investigation in RCTs1,29,31. By standardizing and consolidating comprehensive data collected from severe asthma populations worldwide, ISAR has unlocked the potential to conduct robust research that is advancing the understanding of severe asthma and contributing to the evolution of best practice in asthma management and patient care on a global scale1,2,4,5,29,31.

## 1. Founding principles and mission

ISAR operates according to core guiding principles of openness, inclusivity, and collaborative data sharing and research discussions1; 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 studies2.

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 evolution2. 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 strategies2. 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 care1,2. 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 management1,2.

**Organization, Oversight, and Operation**

ISAR is a joint initiative of Optimum Patient Care Global Limited (OPC), a not-for-profit social enterprise, and AstraZeneca, its co-founders and sponsors since May 2017; a third core collaborator is the Respiratory Effectiveness Group (REG), an investigator-led initiative to promote real-world research2. OPC operates ISAR and is responsible for data management, processing and analysis, REG provides academic support, and Astra- Zeneca gives strategic input2.

ISAR is governed and managed by several complementary bodies (Figure 2): the ISAR Steering Committee (ISC), the REG, the Anonymized Data Ethics & Protocol Transparency (ADEPT) Committee, an Operational Committee, and the QISAR Operational Committee. The ISC comprises 50 experts specializing in severe asthma from 31 countries across five continents, including representatives from AstraZeneca and OPC, who provide scientific leadership and regulatory and strategic oversight. The ADEPT Committee is commissioned by the REG to review the quality of ISAR research protocols and ensure that research using ISAR data complies with the highest ethical standards. The Operational Committee includes research staff in participating countries and is involved in running ISAR day-to-day1,2. The QISAR Operational Committee manages ISAR QI initiatives. The ISC and other key committees meet regularly to maintain continuing expert input in steering the development and expansion of ISAR, and to ensure that its research is clinically relevant, up- to- date, and delivers value to stakeholders in pursuing its mission to improve severe asthma care2.

ISAR is open, inclusive, and actively welcomes new partnerships, offering support to establish local registries, which includes providing its standardized variables list and electronic data capture technology1, which can be translated into local languages. ISAR participants or any third-party, including academic or commercial researchers, can submit research proposals, which require approval by both the ISC and ADEPT. All proposals are reviewed annually and prioritized based on their scientific rigor, feasibility, and compliance with ethical standards. Each member country and Astra- Zeneca have one vote on project
selection, with OPC holding a casting vote to resolve ties. To avoid potential bias, AstraZeneca is recused from votes on proposals from other commercial entities1,2. Core research themes in the first years of operation have included the epidemiology and clinical characteristics of severe asthma, including comparing eosinophilic and noneosinophilic phenotypes, and evaluating responsiveness to different classes of biologic asthma therapy2. The ISC's prioritized project for 2024 is a study investigating associations between differing initiation timings of biologic therapy for severe asthma, and outcomes of disease progression and the likelihood of remission.

<caption>Figure 2. International Severe Asthma Registry (ISAR) organization and governance.</caption>

ADEPT: Anonymised Data Ethics & Protocol Transparency; OPC: Optimum Patient Care. This work is modified from FitzGerald et al.² BMC Med Res Methodol 2020;20:212. Licensed under CC BY 4.0.

<figure><img src="image_3.png" /></figure>

National, regional, and local registries participating in ISAR retain ownership of their own data but allow access to and share de-identified patient data for independent research projects approved by the ISC and ADEPT, according to a data sharing agreement that details the frequency and manner of data transfer to OPC2. ISAR participation allows research using either ISAR multi-country data, subject to ISC and ADEPT approval, or standardized country-specific data, as member countries are free to conduct their own research based on local governance. ISAR is registered with the Heads of Medicines Agencies/European Medicines Agency Catalogues of real-world data sources.

# 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 smoking2. 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 guidelines34.
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 settings². 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 measures²,³. Collection and reporting of all specified core variables is a condition of ISAR participation²,³. 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 metrics²,⁴.

## Research Outputs and Insights from ISAR

Within just 7 years of its inception, ISAR research has already made substantive contributions to characterizing severe asthma, describing associated risk factors and burdens, assessing outcomes among different treatment groups, and accruing real-world evidence on current treatment strategies. More than 25 articles on these topics and related research were published from 2019 to 2024 (Table 1 and Figure 3).

### 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 worldwide⁵,³⁵. 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 impacts²,⁵. 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 morbidities⁵. 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 asthma³⁶, 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 unaffordable⁴¹. Notably, use of moderate-high doses of inhaled corticosteroids has also been associated with adverse outcomes, which included cardiovascular events, pulmonary embolism, and pneumonia⁴². 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 <0.75, 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 asthma12,37,39,48. 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 benefit8.

Characterization of severe asthma phenotypes in the ISAR population using an eosinophilic gradient algorithm, showed that most had type 2 inflammation9, for which targeted treatments are available; accordingly, GINA has been recommending add-on biologic therapies for severe eosinophilic asthma since 202148,49. 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 tezipelumab50, management guidelines from Mexico51 and Germany52, and guidance on asthma care in older people53.
<table><caption>Table 1. International Severe Asthma Registry research project outputs and related publications</caption><thead><tr><th>Topic area, article title (study acronym)</th><th>Key Insights</th></tr></thead><tbody><tr><td><strong>ISAR & severe asthma data collection</strong></td><td></td></tr><tr><td>Development of the International Severe Asthma Registry (ISAR): a modified Delphi study<sup>1</sup></td><td>Early national/region-specific asthma registries collected disparate data of varying quality. First standardized set of core severe asthma registry variables established.</td></tr><tr><td>International severe asthma registry (ISAR): protocol for a global registry<sup>2</sup></td><td>This first global registry for adult severe asthma provides a rich real-life data resource for research to understand severe asthma better and improve patient care worldwide.</td></tr><tr><td>International Severe Asthma Registry: mission statement<sup>3</sup></td><td>ISAR expires to achieve global reach, standardize metrics, ensure ethical and clinically appropriate research, and disseminate findings.</td></tr><tr><td>Adult severe asthma registries: a global and growing inventory<sup>4</sup></td><td>Standardized data collection enables registries to collect unified data and increase the statistical power of studies on severe asthma.</td></tr><tr><td><strong>Severe asthma characteristics and epidemiology</strong></td><td></td></tr><tr><td>Characterization of severe asthma worldwide: data from the International Severe Asthma Registry<sup>5</sup></td><td>Clinical presentations, biomarkers, and treatments vary internationally. High OCS usage and fixed airways obstruction are global problems.</td></tr><tr><td>Potential severe asthma hidden in UK primary care<sup>6</sup></td><td>Many UK patients with potential severe asthma are underrecognized in primary care.</td></tr><tr><td>Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study<sup>7</sup></td><td>Asthma exacerbations accelerate lung function decline, especially in younger patients.</td></tr><tr><td>Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (BRISAR)<sup>8</sup></td><td>Biomarker positivity overlaps but distinct expression clusters suggest discrete patterns of underlying inflammatory pathway activation.</td></tr><tr><td>Eosinophilic and noneosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort<sup>9</sup></td><td>The severe asthma eosinophilic phenotype is phenotypically distinct and more prevalent than was previously recognized.</td></tr><tr><td>Biomarker-defined clusters by level of type 2 inflammatory involvement in severe asthma (EMBER)<sup>10</sup></td><td>Clusters varied in biomarker elevation, highlighting the complexity of T2 inflammatory involvement in severe asthma. A predominantly female cluster had low biomarker levels, suggesting low T2 involvement.</td></tr><tr><td>Impact of socioeconomic status on adult patients with asthma: a population-based cohort study from UK primary care (RADIANT)<sup>11</sup></td><td>Asthma control and exacerbation rates worsen with socioeconomic deprivation, yet the most deprived patients have referral rates similar to the least deprived.</td></tr><tr><td>Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry (PRISM I)<sup>12</sup></td><td>Comorbidity/multimorbidity affects most adults with severe asthma and is associated with poorer asthma-related outcomes. Patients with OCS-related comorbidities had more frequent exacerbations.</td></tr><tr><td>International variation in severe exacerbation rates in patients with severe asthma<sup>13</sup></td><td>Patients with similar characteristics but from different jurisdictions have varied severe exacerbation risks, suggesting that unknown patient or system-level factors are involved. Risk prediction models and guidelines should be tailored accordingly.</td></tr><tr><td>Individualized risk prediction model for exacerbations in patients with severe asthma: protocol for a multicentre real-world risk modelling study<sup>14</sup></td><td>Developing and validating a model for predicting the risk of severe exacerbations in patients with severe asthma has potential clinical utility in guiding asthma treatment escalation.</td></tr><tr><td>Heterogeneity of asthma-chronic obstructive pulmonary disease (COPD) overlap from a cohort of patients with severe asthma and COPD<sup>15</sup></td><td>Patients with pure severe asthma or pure chronic obstructive pulmonary disease (COPD) have similar prevalence of overlapping asthma/COPD (ACO). Patients in each group with ACO have comparable exacerbation risk and lung function impairment.</td></tr></tbody></table>
<table><caption>Table 1. Continued</caption><thead><tr><th>Topic area, article title (study acronym)</th><th>Key insights</th></tr></thead><tbody><tr><td><strong>Biologic treatments: usage, responsiveness, and outcomes</strong></td><td></td></tr><tr><td>Real world biologic use and switch patterns in severe asthma: data from the International Severe Asthma Registry and the US CHRONICLE study (SUNNIE)¹⁸</td><td>Patients who stopped/switched biologics had comparatively lower lung function, higher baseline eosinophil count and exacerbation rate, and more healthcare resource utilization.</td></tr><tr><td>Global variability in administrative approval prescription criteria for biologic therapy in severe asthma (BACS)¹⁷</td><td>The Biologic Accessibility Score highlighted marked between-country differences in ease of access to biologic treatments.</td></tr><tr><td>Clinical outcomes and emergency healthcare utilization in patients with severe asthma who continued, switched or stopped biologic therapy: results from the CLEAR study (CLEAR)¹⁸</td><td>Biologic switchers (25.5%) or quitters (14.5%) had higher rates of exacerbations and uncontrolled asthma than patients who continued an initial biologic; switchers had a higher long-term OCS dose and more hospitalizations and emergency visits.</td></tr><tr><td>Comparative effectiveness of anti-IL6 and anti-IgE biologic classes in patients with severe asthma eligible for both (FIRE)¹⁸</td><td>Both anti-IgE and anti-IL6/5R improved asthma outcomes in eligible patients, but anti-IL6/5R more effectively reduced exacerbations and long-term OCS use.</td></tr><tr><td>Characterization of Patients in the International Severe Asthma Registry with High Steroid Exposure Who Did or Did Not Initiate Biologic Therapy (GLITTER I)²⁰</td><td>Approximately 30% of patients with severe asthma who had high OCS exposure did not receive biologics despite a high exacerbation rate similar to that of biologics initiators.</td></tr><tr><td>Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry (GLITTER II)²¹</td><td>Patients with high OCS use who initiated biologics had greater improvements in severe asthma outcomes, including OCS exposure, exacerbation rate and healthcare utilization, compared to others who continued long-term or frequent rescue OCS.</td></tr><tr><td>Association between T2-related comorbidities and effectiveness of biologics in severe asthma (PRISM II)²²</td><td>Chronic rhinosinusitis, with or without nasal polyps, and nasal polyps alone predict the effectiveness of biologic treatments for severe asthma.</td></tr><tr><td>Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma (BEAM)²³</td><td>Exacerbations, long-term OCS use, and asthma control can assess response to biologics. Responsiveness varied by domain assessed and increased with baseline impairment, which was worst in anti-IL6/5R initiators.</td></tr><tr><td>Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma (IGNITE)²⁴</td><td>Higher baseline blood eosinophil count, fraction of exhaled nitric oxide, and both together, predict biologic-associated lung function improvement.</td></tr><tr><td>Exploring definitions and predictors of response to biologics for severe asthma (FULL BEAM I)²⁵</td><td>Many biologic responders have residual symptoms post-initiation; predictors of response vary with the outcome assessed.</td></tr><tr><td>Exploring definitions and predictors of severe asthma clinical remission after biologic treatment in adults (FULL BEAM II)²⁶</td><td>Remission was more likely in patients with less severe asthma and shorter disease duration at baseline; biologic treatment should not be delayed if remission is the goal.</td></tr><tr><td>Real-world biologics response and super-response in the International Severe Asthma Registry cohort (LUMINANT)¹⁷</td><td>Responses/super-responses in all outcome domains were more frequent in biologic initiators than in non-initiators; however, 40-60% of biologic initiators did not meet response criteria.</td></tr><tr><td>Disease burden and access to biologic therapy in patients with severe asthma, 2017-2022: an analysis of the International Severe Asthma Registry (EVEREST)²⁸</td><td>Patients without access to biologics or not receiving them have a substantial disease burden; many biologic recipients respond sub-optimally, with persisting exacerbations, uncontrolled asthma, healthcare utilization, and long-term OCS use.</td></tr></tbody></table>

<footnote>*Study analyzed data from the International Severe Asthma Registry and Optimum Patient Care Research Database. ¹Study analyzed data from the Optimum Patient Care Research Database. OCS: oral corticosteroid; IgE: immunoglobulin E; IL6: interleukin 6; IL1R: interleukin 1 receptor.</footnote>
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<sup>6</sup>. 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<sup>11</sup>. 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<sup>31</sup>. 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<sup>21</sup>. 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<sup>21</sup>. 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<sup>54</sup>. 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<sup>21</sup>. 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<sup>18</sup>. A study that compared the effectiveness of anti-immunoglobulin E (IgE) to anti-interleukin 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 long-term OCS exposure<sup>19</sup>. 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<sup>16</sup>. 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<sup>16</sup>. 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 countries¹⁷. More than 60% of patients in the CLEAR study were not prescribed biologics despite meeting the eligibility criteria⁵⁴, 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 initiators²⁰. Standardized prescription and access criteria are needed to overcome current barriers to wider availability and implementation of precision medicine for patients with severe asthma¹⁷.

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 response²³. PRISM II revealed that the presence of chronic rhinosinusitis, with or without nasal polyps, predicts greater effectiveness of biologic treatments for severe asthma²². 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 duration²⁶. 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 therapy²⁴. 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 levels¹⁰. 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 criteria²⁵,²⁷, or respond suboptimally, with persisting exacerbations, uncontrolled asthma, healthcare utilization, and long-term OCS use²⁵,²⁸.

Further research is needed to understand how various factors may limit biologic responsiveness and to explore ways to optimize treatment²⁵. One salient question is whether initiating biologics earlier may preempt irreversible lung damage and thereby improve patient outcomes⁸,²⁵,²⁸.

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.
<figure><img src="image_4.png" /><figcaption>**Figure 3.** International Severe Asthma Registry (ISAR) research journey and milestones, 2017 to 2024.
T2: type 2; BEC: blood eosinophil count; FeNO: fraction of exhaled nitric oxide; OCS: oral corticosteroids; HRQoL: health-care resource utilization; IL6: interleukin 6; IgE: immunoglobulin E. Road design adapted from PresentationGO (www presentationgo.com).</figcaption></figure>
## Data Collection and Quality Improvement Initiatives

QI—applying formal or informal tools to assess and enhance healthcare provision—is crucial to improving patient outcomes, which also benefits health services and the economy<sup>55</sup>. However, while healthcare providers are increasingly embracing this concept, QI can be challenging to implement and incorporate into routine practice<sup>55</sup>. In collaboration with primary care clinicians, OPC has developed and refined automated QI programs that require modest resources and involve both clinic staff and patients, to promote a long-term culture of QI (Figure 4)<sup>55</sup>.

ISAR's vision is to progress from changing clinical thinking via research to changing real-world practice through QI initiatives that improve both registry data quality and severe asthma care. Table 2 summarizes the ISC's ongoing QI agenda. The immediate goal is to improve the completeness and accuracy of data on specified ISAR core research variables (Supplementary Table S1). An important future goal is to minimize longterm (maintenance) use of systemic corticosteroids.

To these ends, ISAR rolled out two major QI initiatives in 2023–2024, a second Delphi exercise to refine the core ISAR research variables and improve the collection of high-quality data, based on 6 years of research experience, and an innovative QI program and data acquisition, processing, and reporting system—QISAR—which integrates data collection with clinical consultations and facilitates the assessment and review of patients with severe asthma.

### 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<sup>56</sup>; indeed, this is increasingly necessary given the introduction of composite outcome measures of response or remission that require high-quality data across multiple domains<sup>57</sup>. 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.
<figure><img src="image_5.png" /><figcaption>Table 2. International Severe Asthma Registry (ISAR) quality improvement agenda</figcaption></figure>

<table><thead><tr><td>Priority</td><td>Quality improvement goal</td><td>Timeframe</td></tr></thead><tbody><tr><td>1</td><td>Collect 100% of key research variables* agreed by the 2024 Delphi exercise from all patients with severe asthma in long-term follow-up</td><td>2024 onward</td></tr><tr><td>2</td><td>Eliminate long-term (maintenance) use of systemic corticosteroids to treat severe asthma</td><td>2025 onward</td></tr><tr><td>3</td><td>Maximize achievement of clinical remission by patients with severe asthma†</td><td>Future goal</td></tr><tr><td>4</td><td>Improve the visualization of the longitudinal patient journey in severe asthma, focusing on core outcome measures‡</td><td>Future goal</td></tr><tr><td>5</td><td>Integrate asthma care pathways and management between primary and secondary care§, to expedite specialist management for patients with high-risk asthma, standardize care, and facilitate clinical trial recruitment.</td><td>Ongoing</td></tr></tbody></table>

The inaugural ISAR Delphi study in 2017 reached consensus on 95 initial core variables, with the expectation that participating ISAR centers would achieve at least 90% collection and submission of these data to ISAR3. 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 therapies22, which limits its utility as a research variable; some countries do not even collect data on

<footnote>*Participating ISAR centers undertake to collect 100% of key research variables and 90% of core variables, as defined by the ISAR 2023/24 Delphi exercise (Supplementary Table S1). †Both short-term, by using the best biologic for each patient, and long-term, by starting biologic treatment earlier. ‡Remission, long-term OCS use, exacerbations, lung-function, and asthma control. §Where health-care systems permit (i.e. electronic medical records exist, and primary care data are accessible).</footnote>
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<sup>58</sup>, 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.
## Vision for the Future

The ISC convened at the 2023 European Respiratory Society Congress to set out their priorities for the future. ISAR envisions a world where: QISAR tools are used to collect standardized data during consultations and to track and optimize each patient's treatment journey; long-term systemic corticosteroid use is eliminated; asthma management is tailored to achieving clinical remission; timely specialist referral and initiation of biologic therapy are facilitated; and primary and secondary asthma care pathways and management are integrated to expedite specialist management of severe asthma and improve patient care and clinical trial recruitment. Embedding clinical trials into real-world practice will facilitate development of the best possible care in severe asthma.

## ISAR State in the World

Over seven successful years, ISAR has become a preeminent resource for global research on severe asthma and its management in real-world clinical settings. ISAR successfully established the first global adult severe asthma registry, which uniquely allows multiple national and regional registries to pool standardized data to create a comprehensive central dataset with sufficient statistical power to answer key research questions. Operating on the principles of openness and inclusivity, ISAR has catalyzed the assembly of a global community with the shared goal of enhancing care for patients with severe asthma through high-quality research. Since 2017, ISAR has expanded to include 29 countries across five continents, and curated data on nearly 35,000 patients worldwide at the time of writing. ISARs key strengths lie in its global reach and wealth of experience in data capture and management, coupled with a strong governance framework that supports robust and ethical scientific research. Building on these foundations, ISAR research has already made substantial contributions to progress in identifying the right patients, at the right time, for the right treatments, while ongoing QI initiatives will facilitate the management of patients in the right ways. Our overarching ongoing mission is to continue to contribute to improving global health, both by influencing guidelines and healthcare policy and practice, and through advocacy and stakeholder engagement to reduce inequalities and address unmet needs.

## Ethics Statement

ISAR database is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/ DSPP/23720). ISAR has ethical approval from the Anonymised Data Ethics Protocols and Transparency committee (ADEPT0218). All data collection sites in the ISAR have obtained regulatory agreement in compliance with specific data transfer laws, country-specific legislation, and relevant ethical boards and organizations. This review paper did not involve procurement of patient data, and as such a study-specific data sharing agreement or ethics review was not applicable.

## Authors' Contributions

Conceptualization: Price DB, Fletton K, Bulathsinhala L, Neil DL. Data curation: all authors. Funding acquisition: Price DB. Project administration: Price DB. Visualization: Neil DL.
Writing - original draft preparation: Neil DL, Price DB, Scelo G. Writing - review and editing: all authors. Approval of final manuscript: all authors.

## Conflicts of Interest

Désirée Larenas-Linnemann reports personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Novartis, Pfizer, Sanofi, Siegfried, and Carnot, and grants for guideline development from Abbvie, Bayer, Chiesi, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline, outside the submitted work.

Chin Kook Rhee received consulting/lecture fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, Organon, Roche, and Bayer.

Alan Altraja has received lecture fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, Orion, Sanofi, and Zentiva; sponsorship from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Sanofi, Shire Pharmaceuticals, and Teva.

John Busby has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work.

Trung N. Tran is an employee of AstraZeneca and may own stocks or stock options in AstraZeneca. AstraZeneca is a co-funder of the International Severe Asthma Registry (ISAR).

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.

Todor A. Popov declares research support from Novartis and Chiesi Pharma, outside the submitted 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.

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.
Roy Alton Pleasants is a consultant for AstraZeneca and Grifols and receives research support through institutions from AstraZeneca and GlaxoSmithKline.

Rohit Katial declares honoraria from Amgen, AstraZeneca, Sanofi/Regeneron, GlaxoSmithKline, and Grifols.

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.

Arnaud Bourdin has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, Sanofi-Regeneron, and has consultancies with AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi.

Florence Schleich reports consultancy work for GlaxoSmithKline, AstraZeneca, Sanofi-Advisory board, received speaker fees from GlaxoSmithKline, AstraZeneca, Chiesi, Teva, ALK-Abelló, and research grants from GlaxoSmithKline, AstraZeneca, and Chiesi.

Jorge Máspero reports speaker fees, grants, or advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor.

Mark Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects.

Matthew J. Peters declares personal fees and non-financial support from AstraZeneca, GlaxoSmithKline, and Sanofi.

David J. Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and Boehringer Ingelheim, and research funding from AstraZeneca.

George C. Christoff declares relevant research support from AstraZeneca and Sanofi.

Luis Perez-de-Llano reports grants, personal fees, and non-financial support from AstraZeneca; 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; 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.

Ivan Cherrez-Ojeda declares no conflict of interest.

João A. Fonseca reports grants from research agreements with AstraZeneca, Mundipharma, Sanofi Regeneron, and Novartis. Personal fees for lectures and attending advisory boards: AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi Regeneron, and Teva.
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.

Carlos A. Torres-Duque has received fees as 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; has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis.

Piotr Kuna reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, Zentiva, outside the submitted work.

Andrew N. Menzies-Gow is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. AstraZeneca is a co-funder of ISAR.

Neda Stjepanovic is an employee of AstraZeneca and may own stock options in AstraZeneca. AstraZeneca is a co-funder of ISAR.

Peter G. Gibson has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis.

Paulo Márcio Pitrez received fees as a speaker or for consultations from GlaxoSmithKline, AstraZeneca, Sanofi, and Aché.

Celine Bergeron reports advisory board participation of Sanofi-Regeneron, AstraZeneca, Takeda, ValeoPharma, consultant for Areteia, honorarium for presentations for AstraZeneca/Amgen, GlaxoSmithKline, Grifols, Sanofi-Regeneron, ValeoPharma and grants paid to The University of British Columbia from BioHaven, Sanofi-Regeneron, AstraZeneca, and GlaxoSmithKline.

Celeste M. Porsbjerg has attended advisory boards for AstraZeneca, 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, Novartis, TEVA, GlaxoSmithKline, ALK-Abelló, and Sanofi-Genzyme.

Camille Taillé has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, Stallergenes, and Novartis, for unrelated projects.

Christian Taube declares no relevant conflict of interest.

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, Faes Farma, Medscape, Menarini, Merck Sharp & Dohme, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris.

Andriana I. Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. Sundeep Salvi declares research support and speaker fees from Cipla, Glenmark, and GlaxoSmithKline.

Giorgio Walter Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, ALK-Abelló, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas.

Enrico Heffler declares personal fees for advisory boards participation and/or speaker activities from: Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes-Greer, Circassia, Bosch, Celltrion-Healthcare, Chiesi, and Almirall.

Takashi Iwanaga received speaker bureau fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca, and Sanofi.

Mona S. 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).

Sverre Lehmann has been an investigator on clinical trials sponsored by GlaxoSmithKline and AstraZeneca, for which his institution has received funding.

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.

Borja G. Cosio declares grants from Chiesi, Menarini, and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/ speaking engagements from Sanofi, Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work.

Diahn-Warng Perng received 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.

Bassam Mahboub reports no conflict of interest.

Liam G. Heaney has received grant funding, participated in advisory boards and given lectures at meetings supported by 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.

Pujan H. Patel has received advisory board and speaker fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi/Regeneron.

Njira Lugogo received consulting fees from Amgen, AstraZeneca, Avillion, 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.

Michael E. Wechsler reports grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound Biologics, Incyte, and Kinaset.

Lakmini Bulathsinhala is an employee of the OPRI. OPRI conducted this study in collaboration with Optimum Patient Care (OPC), a co-funder of the ISAR. Victoria Carter is an employee of OPC. OPC is a cofunder of the ISAR.

Kirsty Fletton is an employee of Optimum Patient Care Global (OPCG), a co-funder of the ISAR.

David L. Neil is an employee of the OPRI. OPRI conducted this study in collaboration with OPC, a cofunder of the ISAR.

Ghislaine Scelo is a consultant for OPRI. OPRI conducted this study in collaboration with OPC, a cofunder of the ISAR.

David B. Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through OPRI 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 and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/ meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, Teva Pharmaceuticals.; owns 74% of the social enterprise OPC Ltd. (Australia and UK) and 92.61% of OPRI Pte Ltd. (Singapore); is 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.

Acknowledgments

We gratefully acknowledge the following Optimum Patient Care Global (OPCG) and Observational and Pragmatic Research Institute (OPRI), Singapore, staff: Mr. Aaron Beastall (M.Sc.) for data analysis, Mr. Alexander Sterling (M.B.B.C.H., BS.c., M.R.S.B.) for contributions to draft text and figures, Ms. Angelica Tatam (B.A.) for ISAR registry variables data analysis, Ms. Shilpa Suresh (M.Sc.) and Ms. Pui Yee Lai (M.A.) for editorial and formatting assistance, which supported the development of this publication. Finally, a big thank you to all of our International Severe Asthma Registry collaborators(Appendix 1).

Funding

This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte. Ltd. and was funded by Optimum Patient Care Global, a co-funder of the International Severe Asthma Registry (ISAR).

References

1. ISAR Study Group. International Severe Asthma Registry: mission statement. Chest 2020;157:805-14.

2. FitzGerald JM, Tran TN, Alacqua M, Altraja A, Backer V, Bjermer L, et al. International Severe Asthma Registry (ISAR): protocol for a global registry. BMC Med Res Methodol 2020;20:212.

3. Bulathsinhala L, Eleangovan N, Heaney LG, Menzies- Gow A, Gibson PG, Peters M, et al. Development of the International Severe Asthma Registry (ISAR): a modified Delphi study. J Allergy Clin Immunol Pract 2019;7: 578-88.

4. Cushen B, Koh MS, Tran TN, Martin N, Murray R, Uthaman T, et al. Adult severe asthma registries: a global and growing inventory. Pragmat Obs Res 2023;14:127-47.

5. Wang E, Wechsler ME, Tran TN, Heaney LG, Jones RC, Menzies-Gow AN, et al. Characterization of severe asthma worldwide: data from the International Severe Asthma Registry. Chest 2020;157:790-804.

6. Ryan D, Heatley H, Heaney LG, Jackson DJ, Pfeffer PE, Busby J, et al. Potential severe asthma hidden in UK primary care. J Allergy Clin Immunol Pract 2021;9:1612-23.
7. Soremekun S, Heaney LG, Skinner D, Bulathsinhala L, Carter V, Chaudhry I, et al. Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study. Thorax 2023;78:643-52.

8. Denton E, Price DB, Tran TN, Canonica GW, Menzies- Gow A, FitzGerald JM, et al. Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry. J Allergy Clin Immunol Pract 2021; 9:2680-8.

9. Heaney LG, Perez de Llano L, Al-Ahmad M, Backer V, Busby J, Canonica GW, et al. Eosinophilic and noneosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort. Chest 2021;160:814-30.

10. Price D, Burkill S, Wang E, Wechsler ME, Denton E, Tran TN, et al. Biomarker-defined clusters by level of type 2 inflammatory involvement in severe asthma. Eur Respir J 2022;60(suppl 66):2814.

11. Busby J, Price D, Al-Lehebi R, Bosnic-Anticevich S, van Boven JF, Emmanuel B, et al. Impact of socioeconomic status on adult patients with asthma: a population-based cohort study from UK primary care. J Asthma Allergy 2021;14:1375-88.

12. Scelo G, Torres-Duque CA, Maspero J, Tran TN, Murray R, Martin N, et al. Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry. Ann Allergy Asthma Immunol 2024;132:42-53.

13. Lee TY, Price D, Yadav CP, Roy R, Lim LH, Wang E, et al. International variation in severe exacerbation rates in patients with severe asthma. Chest 2024;166:28-38.

14. Lee TY, Sadatsafavi M, Yadav CP, Price DB, Beasley R, Janson C, et al. Individualised risk prediction model for exacerbations in patients with severe asthma: protocol for a multicentre real-world risk modelling study. BMJ Open 2023;13:e070459.

15. Choi JY, Rhee CK, Yoo KH, Jung KS, Lee JH, Yoon HK, et al. Heterogeneity of asthma-chronic obstructive pulmonary disease (COPD) overlap from a cohort of patients with severe asthma and COPD. Ther Adv Respir Dis 2023;17:17534666231169472.

16. Menzies-Gow AN, McBrien C, Unni B, Porsbjerg CM, Al-Ahmad M, Ambrose CS, et al. Real world biologic use and switch patterns in severe asthma: data from the International Severe Asthma Registry and the US CHRONICLE study. J Asthma Allergy 2022;15:63-78.

17. Porsbjerg CM, Menzies-Gow AN, Tran TN, Murray RB, Unni B, Audrey Ang SL, et al. Global variability in administrative approval prescription criteria for biologic therapy in severe asthma. J Allergy Clin Immunol Pract 2022;10:1202-16.

18. Ali N, Chen S, Tran TN, Cook B, Altraja A, Bourdin A, et al. Clinical outcomes and emergency healthcare utilization in patients with severe asthma who continued, switched or stopped biologic therapy: results from the CLEAR study. Chest 2022;162(4 Supplement):A23-7.
19. Pfeffer PE, Ali N, Murray R, Ulrik C, Tran TN, Maspero J, et al. Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both. Allergy 2023;78:1934-48.

20. Chen W, Sadatsafavi M, Tran TN, Murray RB, Wong CB, Ali N, et al. Characterization of patients in the international severe asthma registry with high steroid exposure who did or did not initiate biologic therapy. J Asthma Allergy 2022;15:1491-510.

21. Chen W, Tran TN, Sadatsafavi M, Murray R, Wong NC, Ali N, et al. Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry. J Allergy Clin Immunol Pract 2023;11:2732-47.

22. Wechsler ME, Scelo G, Larenas-Linnemann DE, Torres- Duque CA, Maspero J, Tran TN, et al. Association between T2-related comorbidities and effectiveness of biologics in severe asthma. Am J Respir Crit Care Med 2024;209:262-72.

23. Perez-de-Llano L, Scelo G, Canonica GW, Chen W, Henley W, Larenas-Linnemann D, et al. Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma. Ann Allergy Asthma Immunol 2024;132:610-22.

24. Porsbjerg CM, Townend J, Bergeron C, Christoff GC, Katsoulotos GP, Larenas-Linnemann D, et al. Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma. Front Immunol 2024;15:1361891.

25. Scelo G, Tran TN, Le TT, Fageras M, Dorscheid D, Busby J, et al. Exploring definitions and predictors of response to biologics for severe asthma. J Allergy Clin Immunol Pract 2024;12:2347-61.

26. Perez-de-Llano L, Scelo G, Tran TN, Le TT, Fageras M, Cosio BG, et al. Exploring definitions and predictors of severe asthma clinical remission after biologic treatment in adults. Am J Respir Crit Care Med 2024;210:869-80.

27. Denton E, Hew M, Peters MJ, Upham JW, Bulathsinhala L, Tran TN, et al. Real-world biologics response and super- response in the International Severe Asthma Registry cohort. Allergy 2024;79:2700-16.

28. Le TT, Price DB, Erhard C, Cook B, Quinton A, Katial R, et al. Disease burden and access to biologic therapy in patients with severe asthma, 2017-2022: an analysis of the International Severe Asthma Registry. J Asthma Allergy 2024;17:1055-69.

29. Urdova V, Rogers L, Jesenak M, Seys SF. Real-life studies and registries of severe asthma: the advent of digital technology. Respir Med 2023;220:107429.

30. Kim SH, Kim Y. Big data research on severe asthma. Tuberc Respir Dis (Seoul) 2024;87:213-20.

31. Paoletti G, Pepys J, Casini M, Di Bona D, Heffler E, Goh CY, et al. Biologics in severe asthma: the role of real- world evidence from registries. Eur Respir Rev 2022; 31:210278.
32. Brown T, Jones T, Gove K, Barber C, Elliott S, Chauhan A, et al. Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur Respir J 2018;52: 1801444.

33. Global Initiative for Asthma. Global strategy for asthma management and prevention (2018 update) [Internet]. Fontana: GINA; 2018 [cited 2025 Mar 16]. Available from: https://ginasthma.org/archived-reports.

34. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73.

35. GBD 2019 Chronic Respiratory Diseases Collaborators. Global burden of chronic respiratory diseases and risk factors, 1990-2019: an update from the Global Burden of Disease Study 2019. EClinical Medicine 2023;59:101936.

36. Menzies-Gow AN, Tran TN, Stanley B, Carter VA, Smolen JS, Bourdin A, et al. Trends in systemic glucocorticoid utilization in the United Kingdom from 1990 to 2019: a population-based, serial cross-sectional analysis. Pragmat Obs Res 2024;15:53-64.

37. Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry. Thorax 2016;71:339-46.

38. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther 2017;39:2216-29.

39. Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy 2018;11:193-204.

40. Heatley H, Tran TN, Bourdin A, Menzies-Gow A, Jackson DJ, Maslova E, et al. Observational UK cohort study to describe intermittent oral corticosteroid prescribing patterns and their association with adverse outcomes in asthma. Thorax 2023;78:860-7.

41. Global Initiative for Asthma. Diagnosis and management of difficult-to-treat & severe asthma [Internet]. Fontana: GINA; 2023 [cited 2025 Feb 13]. Available from: https://ginasthma.org.

42. Bloom CI, Yang F, Hubbard R, Majeed A, Wedzicha JA. Association of dose of inhaled corticosteroids and frequency of adverse events. Am J Respir Crit Care Med 2024;211:54-63.

43. Blakey J, Chung LP, McDonald VM, Ruane L, Gornall J, Barton C, et al. Oral corticosteroids stewardship for asthma in adults and adolescents: a position paper from the Thoracic Society of Australia and New Zealand. Respirology 2021;26:1112-30.

44. Bleecker ER, Al-Ahmad M, Bjermer L, Caminati M, Canonica GW, Kaplan A, et al. Systemic corticosteroids in asthma: a call to action from World Allergy Organization and Respiratory Effectiveness Group. World Allergy Organ J 2022;15:100726.
45. Price D, Bourdin A. Proactive risk management: a novel approach to embedding oral corticosteroid stewardship into asthma care. Eur Med J Respir 2022;10(Supplement 2):1-10.

46. Ortega H, Yancey SW, Keene ON, Gunsoy NB, Albers FC, Howarth PH. Asthma exacerbations associated with lung function decline in patients with severe eosinophilic asthma. J Allergy Clin Immunol Pract 2018;6:980-6.

47. Lyu J, Rhee CK, Tran TN, Katial R, Martin N, Peters M, et al. Demographic and clinical characteristics of patients with severe asthma in the Asian Pacific Region: data from the International Severe Asthma Registry (ISAR). Respirology 2023;28(S1):3-413.

48. Reddel HK, Bacharier LB, Bateman ED, Brightling CE, Brusselle GG, Buhl R, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Eur Respir J 2021;59:2102730.

49. Global Initiative for Asthma. Global strategy for asthma management and prevention (2023 update) [Internet]. Fontana: GINA; 2023 [cited 2025 Feb 13]. Available from: https://ginasthma.org/2023-gina-main-report/.

50. National Institute for Health and Care Excellence. Tezepelumab for treating severe asthma: technology appraisal guidance [Internet]. London: NICE; 2023 [cited 2025 Feb 13]. Available from: https://www.nice.org.uk/guidance/ta880.

51. Larenas-Linnemann D, Salas-Hernandez J, Del Rio-Navarro BE, Luna-Pech JA, Navarrete-Rodriguez EM, Gochicoa L, et al. MIA 2021, comprehensive asthma management: guidelines for Mexico. Rev Alerg Mex 2021;68 Suppl 1:s1-122.

52. Lommatzsch M, Criee CP, de Jong CC, Gappa M, Gebner C, Gerstlauer M, et al. Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023: published by the German Respiratory Society (DGP) e. V. Pneumologie 2023;77:461-543.

53. Khosa JK, Louie S, Lobo Moreno P, Abramov D, Rogstad DK, Alismail A, et al. Asthma care in the elderly: practical guidance and challenges for clinical management: a framework of 5 “Ps”. J Asthma Allergy 2023;16:33-43.

54. Ali N, Chen S, Tran TN, Cook B, Altraja A, Bourdin A, et al. Clinical outcomes in patients with severe asthma who had or had not initiated biologic therapy: results from the CLEAR study. Chest 2022;162(4 Supplement):A28-32.

55. Evans A, Soremekun S, Stanley B, Appiagyei F, Couper A, Taylor O, et al. Strategies that promote sustainability in quality improvement activities for chronic disease management in healthcare settings: a practical perspective. Qual Prim Care 2020;28:55-60.

56. Van Ganse E, Louis R. International severe asthma registry: closer to the full picture of asthma care and outcomes? Chest 2024;166:3-4.

57. Khaleva E, Rattu A, Brightling C, Bush A, Bourdin A, Bossios A, et al. Definitions of non-response and response to biological therapy for severe asthma: a systematic review. ERJ Open Res 2023;9:00444-2022.
58. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377-81.