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Introduction: After puberty, females are more likely to develop asthma and in a more severe form than males. The associations between asthma and sex are complex with multiple intrinsic and external factors., Aim: To evaluate the sex differences in the characteristics and treatment of patients with severe asthma (SA) in a real-world setting., Methods: Demographic, clinical and treatment characteristics for patients with SA in the UK Severe Asthma Registry (UKSAR) and Optimum Patient Care Research Database (OPCRD) were retrospectively analysed by sex using univariable and multivariable logistic regression analyses adjusted for year, age and hospital/practice., Results: 3679 (60.9% female) patients from UKSAR and 18 369 patients (67.9% female) from OPCRD with SA were included. Females were more likely to be symptomatic with increased Asthma Control Questionnaire-6 (UKSAR adjusted OR (aOR) 1.14, 95% CI 1.09 to 1.18) and Royal College of Physicians-3 Question scores (OPCRD aOR 1.29, 95% CI 1.13 to 1.47). However, they had a higher forced expiratory volume in 1 second per cent (FEV 1 %) predicted (UKSAR 68.7% vs 64.8%, p<0.001) with no significant difference in peak expiratory flow. Type 2 biomarkers IgE (UKSAR 129 IU/mL vs 208 IU/mL, p<0.001) and FeNO (UKSAR 36ppb vs 46ppb, p<0.001) were lower in females with no significant difference in blood eosinophils or biological therapy. Females were less likely to be on maintenance oral corticosteroids (UKSAR aOR 0.86, 95% CI 0.75 to 0.99) but more likely to be obese (UKSAR aOR 1.67, 95% CI 145 to 1.93; OPCRD SA aOR 1.46, 95% CI 1.34 to 1.58)., Conclusions: Females had increased symptoms and were more likely to be obese despite higher FEV 1 % predicted and lower type 2 biomarkers with consistent and clinically important differences across both datasets., Competing Interests: Competing interests: LL has no conflicts of interest. JB has attended advisory boards for NuvoAir, outside the submitted work. RM has no conflicts of interest. TB has received speaker fees from Astra Zeneca, Glaxo Smith Kline, Sanofi, Teva, Novartis and Chiesi; honoraria for advisory board attendance from Astra Zeneca, Sanofi and Teva; sponsorship to attend international scientific meetings from Sanofi, GSK, Teva, Chiesi and Napp Pharmaceuticals. HB has attended advisory board for AstraZeneca, GlaxoSmithKline and Sanofi; has given lectures at meetings with/without lecture honoraria supported by AstraZeneca, GlaxoSmithKline and Chiesi; has attended international conferences with AstraZeneca and Chiesi; has taken part in clinical trials sponsored by AstraZeneca, Chiesi, GlaxoSmithKline, Teva and Sanofi. RC has received lecture fees from GSK, AZ, Teva, Chiesi, Sanofi and Novartis; honoraria for Advisory Board Meetings from GSK, AZ, Teva, Chiesi, Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GSK and a research grant to her Institute from AZ for a UK multicentre study. PD has received honoraria/consultancy fees/sponsorship from Teva, AZ, GSK, Novartis and Omron. JWD declares he has received honoraria for participating in advisory boards and given lectures at meetings supported by GSK, Boerhinger Ingelheim, Chiesi, AstraZeneca, Fisher & Paykel, Aerogen; he has received sponsorship for attending international scientific meetings from Chiesi; he has also taken part in asthma clinical trials sponsored by Sanofi, AstraZeneca, Chiesi for which his institution received remuneration. SD has received lecture fees from GSK, AZ, and Sanofi; honoraria for Advisory Board Meetings from GSK, AZ and Novartis; sponsorship to attend international scientific meetings from AZ, Chiesi, Sanofi and GSK. SF has received speaker fees/sponsorship to attend specialty meetings from AstraZeneca, GlaxoSmithKline, Chiesi, Novartis and Sanofi. RG has received speaking/lecture fees from GSK, AstraZeneca, Sanofi and Novartis. EI has no conflicts of interest. DJJ has received lecture fees from GSK, AZ, Teva, Chiesi, and Sanofi; honoraria for Advisory Board Meetings from GSK, AZ, Teva, Chiesi, Sanofi and Novartis; sponsorship to attend international scientific meetings from AZ, Chiesi, Napp, Sanofi and GSK and research grants to his Institute from AZ. MP has no conflicts of interest. TP has received sponsorship for attending international scientific meetings from Chiesi, GlaxoSmithKline and Sanofi Genzyme; he is also taking part in asthma clinical trials sponsored by AstraZeneca and Sanofi Genzyme for which his institution receives remuneration. IP has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca, Boehringer Inglehiem, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK and payments for organising educational events from AZ, GSK, Sanofi/Regeneron and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, Astra Zeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, Astra Zeneca, Teva and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. PEP has attended advisory board for AstraZeneca, GlaxoSmithKline and Sanofi; has given lectures at meetings with/without lecture honoraria supported by AstraZeneca and GlaxoSmithKline; has attended international conferences with AstraZeneca; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis and Sanofi; and is conducting research funded by GlaxoSmithKline for which his institution receives remuneration. DBP has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Viatris, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals and Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Viatris, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Viatris, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Viatris, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Circassia, Mundipharma, Novartis, Teva Pharmaceuticals and Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. HR has received lecture fees from GSK, AZ, Chiesi, and Sanofi; honoraria for Advisory Board Meetings from GSK, AZ and Teva; sponsorship to attend international scientific meetings from AZ and Sanofi and research grants to her Institute from GSK and AZ. SS has received honoraria for speaking or providing advisory services from AstraZeneca, Boehringer Inglehiem, GSK, CSL Behring, Chiesi, MUDIPHARMA, Owlstone Medical, ERT Medical. LGH declares he has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; he has received grants from MedImmune, Novartis UK, Roche/Genentech, and Glaxo Smith Kline, Amgen, Genentech/Hoffman la Roche, Astra Zeneca, MedImmune, Glaxo Smith Kline, Aerocrine and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by 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. AM-G is an employee of Astra Zeneca., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Type-2 biomarkers and related cytokines (IL-5, IL-13), lung function and asthma symptoms were measured in 44 poorly-controlled severe oral corticosteroid (OCS)-dependent asthmatics for up to 88 days after a 7-day prednisolone boost (0.5 mg/kg). High-dose OCS reduced median blood eosinophils (-60 cells/µl; 95% CI -140 to 10), periostin (-8.4 ng/mL; -11.6 to -2.8), FeNO (-19.0 ppb; -28.5 to -4.0), IL-5 (-0.17 pg/mL; -0.28 to -0.08) and IL-13 (-0.15 pg/mL; -0.27 to -0.03). There were small improvements in mean FEV 1 (0.16 L; 0.05 to 0.27) and (Asthma Control Questionnaire) ACQ-7 score (0.3; 0.0 to 0.7). Study measures returned to baseline 1-month postintervention. Following rescue OCS, 1 month is sufficient before using type-2 biomarkers to guide long-term treatment. TRIAL REGISTRATION NUMBER: NCT01948401., Competing Interests: Competing interests: CH, AC, JGM, TS are (or were at time of study) employees of Genentech Inc., a Member of the Roche Group and own Roche stock. RC has attended Advisory Board Meetings for AstraZeneca, GSK, Novartis and Teva and been a speaker at meetings for AstraZeneca. She has attended conferences supported by Boehringer, Teva, AstraZeneca and received educational grants from Novartis and Aerocrine. AHM received personal and department funds for talks and advisory board meetings and was sponsored to attend national and international conferences from pharmaceutical companies that include GlaxoSmithKline, Astra Zeneca, Novartis, NAPP, Boehringer Ingelheim, Roche, Chiesi. AM-G has attended advisory boards with GlaxoSmithKline, Novartis, AstraZeneca, Boehringer Ingelheim and Teva. He has received speaker fees from Novartis, AstraZeneca, Vectura, Boehringer Ingelheim, Sanofi and Teva. He has participated in research with Hoffman La Roche, GlaxoSmithKline, Boehringer Ingelheim and Astra Zeneca. He has attended international conferences with Teva and Boehringer Ingelheim and has consultancy agreements with AstraZeneca, Sanofi and Vectura. RN has received an unrestricted grant of £10,000 from Novartis in 2010 towards development of clinical services at the University Hospital of South Manchester. He has run preceptorship programmes in 2015 and 2016. These programmes have resulted in payment to the University Hospital of south Manchester for amounts not exceeding £10,000. He has also performed lecturing at Pharmaceutically sponsored meetings for the following pharmaceutical companies in the last 3 years: Astra Zeneca (<£1000), Boehringer Ingelheim (<£2000) Boston scientific (<£5000) Chiesi (<£1000), Novartis < £10,000, Napp (<£2000), Teva (<£2000). He has sat on advisory boards for the following companies in the last 3 years (Astra Zeneca, Boehringer Ingelheim, Boston scientific, Chiesi, GSK, Novartis Vectura and Teva), receiving reimbursement not exceeding £5000 per company. He has received sponsorship support to attend international academic meetings from Astra Zeneca, Boehringer ingelheim, Novartis, GSK, Chiesi and TEVA. RN (or any members of his family) has no shares or any pecuniary interest in any pharmaceutical industry and has no shareholdings or dividends and is not a paid consultant for any company. LGH is Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma., Design: Cross-sectional observational study., Setting: The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry., Participants: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)-severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control)., Main Outcome Measures: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group., Results: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified., Conclusions: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Severe refractory asthma poses a substantial burden in terms of healthcare costs but relatively little is known about the factors which drive these costs. This study uses data from the British Thoracic Society Difficult Asthma Registry (n=596) to estimate direct healthcare treatment costs from an National Health Service perspective and examines factors that explain variations in costs. Annual mean treatment costs among severe refractory asthma patients were £2912 (SD £2212) to £4217 (SD £2449). Significant predictors of costs were FEV1% predicted, location of care, maintenance oral corticosteroid treatment and body mass index. Treating individuals with severe refractory asthma presents a substantial cost to the health service., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear., Objective: To identify common genetic variants affecting susceptibility to severe asthma., Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies., Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance., Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Background: Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function., Methods: Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography-tandem mass spectrometry methods., Results: 390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and 'during an exacerbation' COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and 'during an exacerbation' COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide., Conclusion: The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis.

Background: Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma., Methods: 54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers., Results: At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014)., Conclusion: The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.

Background: Cigarette smokers with asthma are insensitive to short term inhaled corticosteroid therapy, but efficacy when given for a longer duration at different doses is unknown., Methods: Ninety five individuals with mild asthma were recruited to a multicentre, randomised, double blind, parallel group study comparing inhaled beclomethasone in doses of 400 microg or 2000 microg daily for 12 weeks in smokers and non-smokers. The primary end point was the change in morning peak expiratory flow (PEF). Secondary end points included evening PEF, use of reliever inhaler, number of asthma exacerbations, spirometric parameters, and asthma control score., Results: After 12 weeks of inhaled beclomethasone there was a considerable difference between the morning PEF measurements of smokers and non-smokers with asthma (-18 (95% CI -35 to -1), adjusted p = 0.035). Among those receiving 400 microg daily there was a difference between the mean (95% CI) morning PEF (l/min) in smokers and non-smokers (-25 (95% CI -45 to -4), adjusted p = 0.019) and in the number of asthma exacerbations (6 v 1 in smokers and non-smokers, respectively, p = 0.007). These differences were reduced between smokers and non-smokers receiving 2000 microg inhaled beclomethasone daily., Conclusions: Compared with non-smokers, smokers with mild persistent asthma are insensitive to the therapeutic effect of low dose inhaled corticosteroid treatment administered for a 12 week period. The disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid. These findings have important implications for the management of individuals with mild asthma who smoke.