Adult Severe Asthma Registries: A Global and Growing Inventory.

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests. Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised. Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases. Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.

Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study.

RATIONALE: Progressive lung function (LF) decline in patients with asthma contributes to worse outcomes. Asthma exacerbations are thought to contribute to this decline; however, evidence is limited with mixed results. METHODS: This historical cohort study of a broad asthma patient population in the Optimum Patient Care Research Database, examined asthma patients with 3+eligible post-18th birthday peak expiratory flow rate (PEF) records (primary analysis) or records of forced expiratory flow in 1 s (FEV1) (sensitivity analysis). Adjusted linear growth models tested the association between mean annual exacerbation rate (AER) and LF trajectory. RESULTS: We studied 1 09 182 patients with follow-up ranging from 5 to 50 years, of which 75 280 had data for all variables included in the adjusted analyses. For each additional exacerbation, an estimated additional -1.34 L/min PEF per year (95% CI -1.23 to -1.50) were lost. Patients with AERs >2/year and aged 18-24 years at baseline lost an additional -5.95 L/min PEF/year (95% CI -8.63 to -3.28) compared with those with AER 0. These differences in the rate of LF decline between AER groups became progressively smaller as age at baseline increased. The results using FEV1 were consistent with the above. CONCLUSION: To our knowledge, this study is the largest nationwide cohort of its kind and demonstrates that asthma exacerbations are associated with faster LF decline. This was more prominent in younger patients but was evident in older patients when it was related to lower starting LF, suggesting a persistent deteriorating phenotype that develops in adulthood over time. Earlier intervention with appropriate management in younger patients with asthma could be of value to prevent excessive LF decline.

Real World Biologic Use and Switch Patterns in Severe Asthma: Data from the International Severe Asthma Registry and the US CHRONICLE Study.

INTRODUCTION: International registries provide opportunities to describe use of biologics for treating severe asthma in current clinical practice. Our aims were to describe real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma, elucidate reasons underlying these patterns, and examine associated patient-level factors. METHODS: This was a historical cohort study including adults with severe asthma enrolled into the International Severe Asthma Registry (ISAR; http://isaregistries.org, 2015-2020) or the CHRONICLE Study (2018-2020) and treated with a biologic. Eleven countries were included (Bulgaria, Canada, Denmark, Greece, Italy, Japan, Kuwait, South Korea, Spain, UK, and USA). Biologic utilization patterns were defined: 1) continuing initial biologic; 2) stopping biologic treatment; or 3) switching to another biologic. Reasons for discontinuation/switching were recorded and comparisons drawn between groups. RESULTS: A total of 3531 patients were included. Omalizumab was the most common initial biologic in 2015 (88.2%) and benralizumab in 2019 (29.6%). Most patients (79%; 2791/3531) continued their first biologic; 10.2% (356/3531) stopped; 10.8% (384/3531) switched. The most frequent first switch was from omalizumab to an anti-IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti-IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater health care resource utilization. CONCLUSION: The description of real-life patterns of continuing, stopping, or switching biologics enhances our understanding of global biologic use. Prospective studies involving structured switching criteria could ascertain optimal strategies to identify patients who may benefit from switching.

Impact of Socioeconomic Status on Adult Patients with Asthma: A Population-Based Cohort Study from UK Primary Care.

INTRODUCTION: Asthma morbidity and health-care utilization are known to exhibit a steep socioeconomic gradient. Further investigation into the modulators of this effect is required to identify potentially modifiable factors. METHODS: We identified a cohort of patients with asthma from the Optimum Patient Care Research Database (OPCRD). We compared demographics, clinical variables, and health-care utilization by quintile of the UK 2011 Indices of Multiple Deprivation based on the location of the patients' general practice. Multivariable analyses were conducted using generalized linear models adjusting for year, age, and sex. We conducted subgroup analyses and interaction tests to investigate the impact of deprivation by age, sex, ethnicity, and treatment step. RESULTS: Our analysis included 127,040 patients with asthma. Patients from the most deprived socio-economic status (SES) quintile were more likely to report uncontrolled disease (OR: 1.54, 95% CI: 1.16, 2.05) and to have an exacerbation during follow-up (OR: 1.27, 95% CI: 1.13, 1.42) than the least deprived quintile. They had higher blood eosinophils (ratio: 1.03; 95% CI: 1.00, 1.06) and decreased peak flow (ratio: 0.95, 95% CI: 0.94, 0.97) when compared to those in the least deprived quintile. The effect of deprivation on asthma control was greater among those aged over 75 years (OR = 1.81, 95% CI: 1.20, 2.73) compared to those aged less than 35 years (OR: 1.22, 95% CI: 0.85, 1.74; pinteraction=0.019). Similarly, socioeconomic disparities in exacerbations were larger among those from ethnic minority groups (OR: 1.94, 95% CI: 1.40, 2.68) than white patients (OR: 1.24, 95% CI: 1.10, 1.39; pinteraction=0.012). CONCLUSION: We found worse disease control and increased exacerbation rates among patients with asthma from more deprived areas. There was evidence that the magnitude of socioeconomic disparities was elevated among older patients and those from ethnic minority groups. The drivers of these differences require further exploration.

Asthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities.

BACKGROUND: We developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry). OBJECTIVE: We sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU). METHODS: Patients age 13 years and older with active asthma and blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Database and the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinical and HCRU characteristics were described for each phenotype. RESULTS: Of 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year). CONCLUSIONS: The eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.

Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort.

BACKGROUND: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. RESEARCH QUESTION: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? STUDY DESIGN AND METHODS: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). RESULTS: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. INTERPRETATION: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

Potential Severe Asthma Hidden in UK Primary Care.

BACKGROUND: Severe asthma may be underrecognized in primary care. OBJECTIVE: Identify and quantify patients with potential severe asthma (PSA) in UK primary care, the proportion not referred, and compare primary care patients with PSA with patients with confirmed severe asthma from UK tertiary care. METHODS: This was a historical cohort study including patients from the Optimum Patient Care Research Database (aged ≥16 years, active asthma diagnosis pre-2014) and UK patients in the International Severe Asthma Registry (UK-ISAR aged ≥18 years, confirmed severe asthma in tertiary care). In the OPCRD, PSA was defined as Global INitiative for Asthma 2018 step 4 treatment and 2 or more exacerbations/y or at Global INitiative for Asthma step 5. The proportion of these patients and their referral status in the last year were quantified. Demographic and clinical characteristics of groups were compared. RESULTS: Of 207,557 Optimum Patient Care Research Database patients with asthma, 16,409 (8%) had PSA. Of these, 72% had no referral/specialist review in the past year. Referred patients with PSA tended to have greater prevalence of inhaled corticosteroid/long-acting ß2-agonist add-ons (54.1 vs 39.8%), and experienced significantly (P < .001) more exacerbations per year (median, 3 vs 2/y), worse asthma control, and worse lung function (% predicted postbronchodilator FEV1/forced vital capacity, 0.69 vs 0.72) versus nonreferred patients. Confirmed patients with severe asthma (ie, UK patients in the International Severe Asthma Registry) were younger (51 vs 65 years; P < .001), and significantly (P < .001) more likely to have uncontrolled asthma (91.4% vs 62.5%), a higher exacerbation rate (4/y [initial assessment] vs 3/y), use inhaled corticosteroid/long-acting ß2-agonist add-ons (67.7% vs 54.1%), and have nasal polyposis (24.2% vs 6.8) than referred patients with PSA. CONCLUSIONS: Large numbers of patients with PSA in the United Kingdom are underrecognized in primary care. These patients would benefit from a more systematic assessment in primary care and possible specialist referral.

International severe asthma registry (ISAR): protocol for a global registry.

BACKGROUND: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. METHODS: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. CONCLUSIONS: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Characterization of Severe Asthma Worldwide: Data From the International Severe Asthma Registry.

BACKGROUND: Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region. METHODS: The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017. RESULTS: We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles. CONCLUSIONS: Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study.