Estimating the incidence, prevalence and true cost of asthma in the UK: secondary analysis of national stand-alone and linked databases in England, Northern Ireland, Scotland and Wales-a study protocol.

INTRODUCTION: Asthma is now one of the most common long-term conditions in the UK. It is therefore important to develop a comprehensive appreciation of the healthcare and societal costs in order to inform decisions on care provision and planning. We plan to build on our earlier estimates of national prevalence and costs from asthma by filling the data gaps previously identified in relation to healthcare and broadening the field of enquiry to include societal costs. This work will provide the first UK-wide estimates of the costs of asthma. In the context of asthma for the UK and its member countries (ie, England, Northern Ireland, Scotland and Wales), we seek to: (1) produce a detailed overview of estimates of incidence, prevalence and healthcare utilisation; (2) estimate health and societal costs; (3) identify any remaining information gaps and explore the feasibility of filling these and (4) provide insights into future research that has the potential to inform changes in policy leading to the provision of more cost-effective care. METHODS AND ANALYSIS: Secondary analyses of data from national health surveys, primary care, prescribing, emergency care, hospital, mortality and administrative data sources will be undertaken to estimate prevalence, healthcare utilisation and outcomes from asthma. Data linkages and economic modelling will be undertaken in an attempt to populate data gaps and estimate costs. Separate prevalence and cost estimates will be calculated for each of the UK-member countries and these will then be aggregated to generate UK-wide estimates. ETHICS AND DISSEMINATION: Approvals have been obtained from the NHS Scotland Information Services Division's Privacy Advisory Committee, the Secure Anonymised Information Linkage Collaboration Review System, the NHS South-East Scotland Research Ethics Service and The University of Edinburgh's Centre for Population Health Sciences Research Ethics Committee. We will produce a report for Asthma-UK, submit papers to peer-reviewed journals and construct an interactive map

Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era.

BACKGROUND: The UK Severe Asthma Registry (UKSAR) is the world's largest national severe asthma registry collecting standardised data on referrals to UK specialist services. Novel biologic therapies have transformed the management of type 2(T2)-high severe asthma but have highlighted unmet need in patients with persisting symptoms despite suppression of T2-cytokine pathways with corticosteroids. METHODS: Demographic, clinical and treatments characteristics for patients meeting European Respiratory Society / American Thoracic Society severe asthma criteria were examined for 2225 patients attending 15 specialist severe asthma centres. We assessed differences in biomarker low patients (fractional exhaled nitric oxide (FeNO) <25 ppb, blood eosinophils <150/μL) compared with a biomarker high population (FeNO ≥25 ppb, blood eosinophils ≥150/µL). RESULTS: Age (mean 49.6 (14.3) y), age of asthma onset (24.2 (19.1) y) and female predominance (62.4%) were consistent with prior severe asthma cohorts. Poor symptom control (Asthma Control Questionnaire-6: 2.9 (1.4)) with high exacerbation rate (4 (IQR: 2, 7)) were common despite high-dose treatment (51.7% on maintenance oral corticosteroids (mOCS)). 68.9% were prescribed biologic therapies including mepolizumab (50.3%), benralizumab (26.1%) and omalizumab (22.6%). T2-low patients had higher body mass index (32.1 vs 30.2, p<0.001), depression/anxiety prevalence (12.3% vs 7.6%, p=0.04) and mOCS use (57.9% vs 42.1%, p<0.001). Many T2-low asthmatics had evidence of a historically elevated blood eosinophil count (0.35 (0.13, 0.60)). CONCLUSIONS: The UKSAR describes the characteristics of a large cohort of asthmatics referred to UK specialist severe asthma services. It offers the prospect of providing novel insights across a range of research areas and highlights substantial unmet need with poor asthma control, impaired lung function and high exacerbation rates. T2-high phenotypes predominate with significant differences apparent from T2-low patients. However, T2-low patients frequently have prior blood eosinophilia consistent with possible excessive corticosteroid exposure

Corticosteroid responsiveness following mepolizumab in severe eosinophilic asthma—a randomized, placebo-controlled crossover trial (MAPLE)

Mepolizumab inhibits interleukin-5 (IL-5) activity, reduces exacerbation frequency and maintenance oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma (SEA). Some patients remain dependent on OCS despite anti-IL-5 treatment suggesting residual corticosteroid responsive mechanisms. We aimed to determine the clinical and anti-inflammatory effects of OCS in patients with SEA on mepolizumab. We conducted a randomised, triple-blind, placebo-controlled crossover trial of prednisolone (0.5mg/kg/day, maximum 40mg/day, for 14±2 days) in adults with SEA after ≥12 weeks of mepolizumab. We compared change in asthma symptoms, quality of life, lung function measured by spirometry and airwave oscillometry, FeNO, and blood and sputum eosinophil cell count after prednisolone and placebo. 27 patients completed the study. Prednisolone did not improve ACQ-5 (mean difference in change for prednisolone vs placebo -0.23, 95% CI -0.58 to 0.11), mini-AQLQ (0.03, 95% CI -0.26 to 0.42), SGRQ (0.24, 95% CI -3.20 to 3.69) or VAS scores for overall asthma symptoms (0.11, 95% CI -0.58 to 0.80). The mean difference for FEV in favour of prednisolone was 105ml (95% CI -4 to 213 ml); FEF 484ml/s (95% CI 151 to 816 ml/s); FeNO reduction 41% (95% CI 25 to 54%); blood eosinophil count reduction 49% (95% CI 31 to 62%); and percentage of sputum eosinophil reduction 71% (95% CI 26 to 89%). OCS improved small airway obstruction and reduced biomarkers of type 2 inflammation but had no significant effect on symptoms or quality of life in patients with severe eosinophilic asthma receiving treatment with mepolizumab. [Abstract copyright: Copyright © 2022. Published by Elsevier Inc.

Quality of chronic disease care in general practice: the development and validation of a provider interview tool

BACKGROUND: This article describes the development and psychometric evaluation of an interview instrument to assess provider-reported quality of general practice care for patients with diabetes, cardiovascular disease and asthma – the Australian General Practice Clinical Care Interview (GPCCI). METHODS: We administered the GPCCI to 28 general practitioners (family physicians) in 10 general practices. We conducted an item analysis and assessed the internal consistency of the instrument. We next assessed the quality of care recorded in the medical records of 462 of the general practitioners' patients with Type 2 diabetes, ischaemic heart disease/hypertension and/or moderate to severe asthma. This was then compared with results of the GPCCI for each general practice. RESULTS: Good internal consistency was found for the overall GPCCI (Cronbach's alpha = 0.75). As far as the separate sub-scales were concerned, diabetes had good internal consistency (0.76) but the internal consistency of the heart disease and asthma subscales was not strong (0.49 and 0.16 respectively). There was high inter-rater reliability of the adjusted scores of data extracted from patients' medical notes for each of the three conditions. Correlations of the overall GPCCI and patients' medical notes audit, combined across the three conditions and aggregated to practice level, showed that a strong relationship (r = 0.84, p = 0.003) existed between the two indices of clinical care. CONCLUSION: This study suggests that the GPCCI has good internal consistency and concurrent validity with patients' medical records in Australian general practice and warrants further evaluation of its properties, validity and utility

Systematic meta-review of supported self-management for asthma: a healthcare perspective

BACKGROUND: Supported self-management has been recommended by asthma guidelines for three decades; improving current suboptimal implementation will require commitment from professionals, patients and healthcare organisations. The Practical Systematic Review of Self-Management Support (PRISMS) meta-review and Reducing Care Utilisation through Self-management Interventions (RECURSIVE) health economic review were commissioned to provide a systematic overview of supported self-management to inform implementation. We sought to investigate if supported asthma self-management reduces use of healthcare resources and improves asthma control; for which target groups it works; and which components and contextual factors contribute to effectiveness. Finally, we investigated the costs to healthcare services of providing supported self-management. METHODS: We undertook a meta-review (systematic overview) of systematic reviews updated with randomised controlled trials (RCTs) published since the review search dates, and health economic meta-analysis of RCTs. Twelve electronic databases were searched in 2012 (updated in 2015; pre-publication update January 2017) for systematic reviews reporting RCTs (and update RCTs) evaluating supported asthma self-management. We assessed the quality of included studies and undertook a meta-analysis and narrative synthesis. RESULTS: A total of 27 systematic reviews (n = 244 RCTs) and 13 update RCTs revealed that supported self-management can reduce hospitalisations, accident and emergency attendances and unscheduled consultations, and improve markers of control and quality of life for people with asthma across a range of cultural, demographic and healthcare settings. Core components are patient education, provision of an action plan and regular professional review. Self-management is most effective when delivered in the context of proactive long-term condition management. The total cost (n = 24 RCTs) of providing self-management support is offset by a reduction in hospitalisations and accident and emergency visits (standard mean difference 0.13, 95% confidence interval -0.09 to 0.34). CONCLUSIONS: Evidence from a total of 270 RCTs confirms that supported self-management for asthma can reduce unscheduled care and improve asthma control, can be delivered effectively for diverse demographic and cultural groups, is applicable in a broad range of clinical settings, and does not significantly increase total healthcare costs. Informed by this comprehensive synthesis of the literature, clinicians, patient-interest groups, policy-makers and providers of healthcare services should prioritise provision of supported self-management for people with asthma as a core component of routine care. SYSTEMATIC REVIEW REGISTRATION: RECURSIVE: PROSPERO CRD42012002694 ; PRISMS: PROSPERO does not register meta-reviews

Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate-to-severe asthma

Background: The inhaled corticosteroid, fluticasone propionate, and the long-acting b2-adrenergic agonist, formoterol fumarate, are both highly effective treatments for bronchial asthma. This study (NCT00393952/EudraCT number: 2006-005989-39) compared the efficacy and safety of fluticasone/formoterol combination therapy (flutiform®; 250/10 mg) administered twice daily (b.i.d.) via a single aerosol inhaler, with the individual components (fluticasone 250 mg b.i.d.; formoterol 10 mg b.i.d.), in adult and adolescent patients with moderate-to-severe asthma. Methods: This was a 12-week, double-blind, randomised, parallel-group, multicentre, placebocontrolled phase 3 study. The co-primary efficacy endpoints were: i) the mean change in the forced expiratory volume in the first second (FEV1) from morning pre-dose at baseline to pre-dose at week 12 (fluticasone/formoterol 250/10 mg vs. formoterol), ii) the mean change in FEV1 from morning pre-dose at baseline to 2 h post-dose at week 12 (fluticasone/formoterol 250/10 mg vs. fluticasone), and iii) the number of patients who discontinued prematurely due to lack of treatment efficacy (fluticasone/formoterol 250/10 mg vs. placebo). The secondary endpoints included measures of lung function, disease control, and asthma symptoms. Safety was assessed based on adverse events, vital signs, and clinical laboratory evaluations. Results: Overall, 395 (70.9%) patients completed the study. Fluticasone/formoterol 250/10 mg b.i.d. was superior to the individual components and placebo for all three co-primary endpoints and demonstrated numerically greater improvements for multiple secondary efficacy analyses. Fluticasone/formoterol combination therapy had a good safety profile over the 12 weeks. Conclusion: Fluticasone/formoterol combination therapy will provide clinicians with an efficacious alternative treatment option for patients with moderate-to-severe asthma

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND