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Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma. [ABSTRACT FROM AUTHOR]

Background: Several biological treatments have become available for management of severe asthma. There is a significant overlap in the indication of these treatments with lack of consensus on the first‐line biologic choice and switching practice in event of treatment failure. Aims: To evaluate outcomes of biologic treatments through analysis of the UK Severe Asthma Registry (UKSAR), and survey of the UK severe asthma specialists' opinion. Methods: Patients registered in the UKSAR database and treated with biologics for severe asthma in the period between January 2014 and August 2021, were studied to explore biologic treatments practice. This was complemented by survey of opinion of severe asthma specialists. Results: A total of 2490 patients from 10 severe asthma centres were included in the study (mean age 51.3 years, 61.1% female, mean BMI 30.9 kg/m2). Biologics use included mepolizumab 1115 (44.8%), benralizumab 925 (37.1%), omalizumab 432 (17.3%), dupilumab 13 (0.5%) and reslizumab 5 (0.2%). Patients on omalizumab were younger and had earlier age of onset asthma than those prescribed mepolizumab or benralizumab. Patients prescribed mepolizumab and benralizumab had similar clinical characteristics. Those on benralizumab were more likely to continue treatment at approximately one year follow‐up (93.9%), than those on mepolizumab (80%), or omalizumab (69.6%). The first‐choice biologic differed between centres and changed over the study time period. Experts' opinion also diverged in terms of biologic initiation choice and switching practice. Conclusion: We observed significant variation and divergence in the prescribing practices of biologics in severe asthma that necessitates further research and standardization. [ABSTRACT FROM AUTHOR]

Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-β given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes 4 days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit. [ABSTRACT FROM AUTHOR]

To explore whether fractional exhaled nitric oxide (FeNO) non-suppression identifies corticosteroid resistance, we analysed inflammatory mediator changes during a FeNO suppression test with monitored high-intensity corticosteroid therapy. In linear mixed-effects models analysed over time, the 15 clinically distinct 'suppressors' (ie, ≥42% FeNO suppression) normalised Asthma Control Questionnaire scores (mean±SD, start to end of test: 2.8±1.4 to 1.4±0.9, p<0.0001) and sputum eosinophil counts (median (IQR), start to end of test: 29% (6%-41%) to 1% (1%-5%), p=0.0003) while significantly decreasing sputum prostaglandin D2 (254 (89-894) to 93 (49-209) pg/mL, p=0.004) and numerically decreasing other type-2 cytokine, chemokine and alarmin levels. In comparison, the 19 non-suppressors had persistent sputum eosinophilia (10% (1%-67%) despite high-intensity therapy) with raised end-test inflammatory mediator levels (1.9 (0.9-2.8)-fold greater than suppressors). FeNO non-suppression during monitored treatment implies biological corticosteroid resistance. [ABSTRACT FROM AUTHOR]

Introduction: Work-related asthma accounts for ≥25% of asthma in working-age populations, though the relationship between work exposures and symptoms is frequently missed, leading to poor health and employment outcomes. We hypothesised that inhalable exposures at work are associated with poor asthma control in severe asthma (SA)., Methods: We searched the Birmingham (UK) Regional NHS SA Service clinical database (n=1453 records; 1 March 2004 to 1 March 2021) and undertook a cross-sectional study using baseline data collected at diagnosis. We included all employed patients aged 16-64 with documented current occupation (n=504), and collected socio-demographic, general health and asthma-specific data, including Asthma Control Questionnaire 7 (ACQ7) score. The Occupational Asthma Specific Job-Exposure Matrix (OAsJEM) was employed to determine the likelihood of exposure to respiratory sensitisers, irritants, cleaning agents and detergents; associations between exposures and ACQ7 were investigated using binary and multinomial regression., Results: Frequently reported occupations were care assistants (7%) and nurses (6%); 197/504 (39%) patients were exposed to an asthmagen, including respiratory sensitisers (30%), airway irritants (38%) and cleaning products/disinfectants (29%). ACQ7 score was available for 372/504 (74%) patients, of whom 14% had adequate control (ACQ7=0-1.5). After adjustment for major confounders there were no significant associations between inhaled asthmagens and ACQ7 score (either as binary or multinomial outcomes)., Conclusion: JEM-determined workplace exposures to inhaled asthmagens are not associated with asthma control in SA; 29-39% of patients may have current exposure to workplace asthmagens. Routine collection of lifetime occupational data including current job role and level of exposure, in the national asthma registry, would give further insights into this relationship., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Asthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive approach to investigate lung diseases. We hypothesised that molecular differences in upper airway epithelium reflect asthma-associated differences in the lower airways and are associated with clinical expression of asthma., Methods: We analysed nasal epithelial gene expression data from 369 patients with asthma and 58 non-asthmatic controls from the Assessment of Small Airways Involvement in Asthma study. Unsupervised hierarchical clustering was performed on asthma-associated genes. Asthma-associated gene signatures were replicated in independent cohorts with nasal and bronchial brushes data by comparing Gene Set Variation Analysis scores between asthma patients and non-asthmatic controls., Results: We identified 67 higher expressed and 59 lower expressed genes in nasal epithelium from asthma patients compared with controls (false discovery rate<0.05), including CLCA1, CST1 and POSTN , genes well known to reflect asthma in bronchial airway epithelium. Hierarchical clustering revealed several molecular asthma endotypes with distinct clinical characteristics, including an endotype with higher blood and sputum eosinophils, high fractional exhaled nitric oxide, and more severe small airway dysfunction, as reflected by lower forced expiratory flow at 50%. In an independent cohort, we demonstrated that genes higher expressed in the nasal epithelium reflect asthma-associated changes in the lower airways., Conclusion: Our results show that the nasal epithelial gene expression profile reflects asthma-related processes in the lower airways. We suggest that nasal epithelium may be a useful non-invasive tool to identify asthma endotypes and may advance personalised management of the disease., Competing Interests: Competing interests: The ATLANTIS study is supported by Chiesi. MK has received grants or contracts or consulting fees or payment or honoraria or support for meetings from National Institutes of Health, American Lung Association, Synairgen, Janssen, Astra-Zeneca, Sanofi, Chiesi, GSK, Kinaset, Genentech, European Respiratory Society, has patents planned, issued or pending from CoFounder and Chief Medical Officer, RaeSedo, has participated on advisory boards for ALung DSMB and has received stock or stock options from Equity ownership in RaeSedo, and other financial or non-financial interests from Section Editor, UptoDate. MCN has received grants or contracts or support for meetings from Chan Zuckerberg Initiative, European commission, Lung Foundation Netherlands, Stichting Astma Bestrijding, Belgian Respiratory Society and has a leadership role in Lung Bionetwork of the Human Cell Atlas. IHH has received grants or contracts from Boehringer Ingelheim, Roche, Rousselot. BB has received payment or honoraria from AZ, GSK, Guidotti,Chiesi, Menarini. KFR has received payment or honoraria from Astra Zeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie, Roche Pharma, has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, Sanofi & Regeneron, and has a leadership role in German Center for Lung Research (DZL), German Chest Society (DGP), American Thoracic Society (ATS). AP has received grants or contracts or consulting fees from Chiesi, AstraZeneca, GSK, Sanofi, Agenzia Italiana del farmaco (AIFA), Novartis,Avillion, ELPEN Pharmaceuticals, has received payment or honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharma, IQVIA, Avillion, ELPEN Pharmaceuticals, has participated on Advisory Board for Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, IQVIA, Avillion, ELPEN Pharmaceuticals. CB has received grants or contracts or consulting fees from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Chiesi, Novartis, Mologic, Areteia. DS has received consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GlaxoSmithKline, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance Biopharma, Verona Pharma. TvdM has received payment or honoraria or support for attending meetings from GSK, Chiesi. SS has received consulting fees or payment or honoraria from Chiesi, Astra Zeneca, GSK, Areteia therapeutics, CSL Behring, AZ, Medscape. SC has received grants or contracts or consulting fees from NIH, American Lung Association, Sanofi, Regeneron, GlaxoSmithKline, AstraZeneca, Glenmark Pharmaceuticals, Amgen, Axon Advisors, and has received payment or honoraria from Sanofi/Regeneron, MJH Holdings: Physicians’ Education Resource, UpToDate, Wolters Kluwer Health, GlaxoSmithKline, has received support for attending meeting from AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron, has participated on advisory boards for anofi/Regeneron, AstraZeneca, GlaxoSmithKline, and has leadership or fiduciary role in American Thoracic Society. MvdB has received grants or contracts from GlaxxoSmithKline, Astra Zeneca, Novartis, Genentech, Roche., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Asthma is a very heterozygous disease, divided in subtypes, such as eosinophilic and neutrophilic asthma. Phenotyping and endotyping of patients, especially patients with severe asthma who are refractory to standard treatment, are crucial in asthma management and are based on a combination of clinical and biological features. Nevertheless, the quest remains to find better biomarkers that distinguish asthma subtypes in a more clear and objective manner and to find new therapeutic targets to treat people with therapy-resistant asthma. In the past, research to identify asthma subtypes mainly focused on expression profiles of protein-coding genes. However, advances in RNA-sequencing technologies and the discovery of non-coding RNAs as important post-transcriptional regulators have provided an entire new field of research opportunities in asthma. This review focusses on long non-coding RNAs (lncRNAs) in asthma; these are non-coding RNAs with a length of more than 200 nucleotides. Many lncRNAs are differentially expressed in asthma, and several have been associated with asthma severity or inflammatory phenotype. Moreover, in vivo and in vitro functional studies have identified the mechanisms of action of specific lncRNAs. Although lncRNAs remain not widely studied in asthma, the current studies show the potential of lncRNAs as biomarkers and therapeutic targets as well as the need for further research. [ABSTRACT FROM AUTHOR]

Introduction: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype.Methods: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma.Results: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs.Conclusion: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma. [ABSTRACT FROM AUTHOR]

Background: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N 2 SBW) and nitrogen multiple breath washout (N 2 MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N 2 SBW and N 2 MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S III at N 2 SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV 1 ) in MCT., Study Design and Methods: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N 2 SBW (S III ), N 2 MBW (Lung clearance index (LCI), S cond , S acin ), MCT (FEV 1 and sGeff) as well as N 2 SBW between each methacholine dose., Results: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N 2 SBW was pathological in 10.6% at baseline and N 2 MBW abnormality ranged widely (LCI 81%, S cond 18%, S acin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N 2 SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N 2 MBW., Conclusions: Both MCT and N 2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease., Competing Interests: Competing interests: DS (second author) is currently employed at Tillotts Pharma AG, however, during the period of the study was an employee of the University Hospital of Basel. AMD has received a grant from University Hospital Basel, PL has a grant/contract to Vertex and OM Pharma. DS (last author) reports grants from Astra-Zeneca AG, Curetis AG, BostonScientific, Novartis AG, GSK AG, Roche AG, Zambon, Pfizer, Schwabe Pharma AG, Vifor AG. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Airway inflammation plays a key role in asthma pathogenesis but is heterogeneous in nature. There has been significant scientific discovery with regard to type 2-driven, eosinophil-dominated asthma, with effective therapies ranging from inhaled corticosteroids to novel biologics. However, studies suggest that approximately 1 in 5 adults with asthma have an increased proportion of neutrophils in their airways. These patients tend to be older, have potentially pathogenic airway bacteria and do not respond well to classical therapies. Currently, there are no specific therapeutic options for these patients, such as neutrophil-targeting biologics.Neutrophils comprise 70% of the total circulatory white cells and play a critical defence role during inflammatory and infective challenges. This makes them a problematic target for therapeutics. Furthermore, neutrophil functions change with age, with reduced microbial killing, increased reactive oxygen species release and reduced production of extracellular traps with advancing age. Therefore, different therapeutic strategies may be required for different age groups of patients.The pathogenesis of neutrophil-dominated airway inflammation in adults with asthma may reflect a counterproductive response to the defective neutrophil microbial killing seen with age, resulting in bystander damage to host airway cells and subsequent mucus hypersecretion and airway remodelling. However, in children with asthma, neutrophils are less associated with adverse features of disease, and it is possible that in children, neutrophils are less pathogenic.In this review, we explore the mechanisms of neutrophil recruitment, changes in cellular function across the life course and the implications this may have for asthma management now and in the future. We also describe the prevalence of neutrophilic asthma globally, with a focus on First Nations people of Australia, New Zealand and North America. [ABSTRACT FROM AUTHOR]

Background: There is conflicting research about the association between asthma and poor educational attainment that may be due to asthma definitions. Our study creates seven categories of current chronic and acute asthma to investigate if there is an association for poorer educational attainment at age 6-7 years, and the role of respiratory infections and school absence.Methods: This study used a population-based electronic cross-sectional birth cohort 1998-2005, in Wales, UK, using health and education administrative datasets. Current asthma or wheeze categories were developed using clinical management guidelines in general practice (GP) data, acute asthma was inpatient hospital admissions and respiratory infections were the count of GP visits, from birth to age 6-7 years. We used multilevel logistic regression grouped by schools to ascertain if asthma or wheeze was associated with not attaining the expected level in teacher assessment at Key Stage 1 (KS1) adjusting for sociodemographics, perinatal, other respiratory illness and school characteristics. We tested if absence from school was a mediator in this relationship using the difference method.Results: There were 85 906 children in this population representative cohort with 7-year follow-up. In adjusted multilevel logistic regression, only asthma inpatient hospital admission was associated with increased risk for not attaining the expected level at KS1 (adjusted OR 1.14 95% CI (1.02 to 1.27)). Lower respiratory tract infection (LRTI) GP contacts remained an independent predictor for not attaining the expected level of education. Absence from school was a potential mediator of the association between hospital admission and educational attainment.Conclusions: Clinicians and educators need to be aware that children who have inpatient hospital admissions for asthma or wheeze, or repeated LRTI, may require additional educational support for their educational outcomes. [ABSTRACT FROM AUTHOR]

Background: It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population., Methods: We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV 1 ) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL)., Results: FEV 1 decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p<0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p<0.0001) per 10 ppb higher FeNO. Adjusted FEV 1 decline in mL/year was 18 (95% CI 17 to 20) in those with BE<300 cells/µL and FeNO<20 ppb, 22 (19-25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21-33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend<0.0001). Corresponding FEV 1 declines were 24 (19-29), 33 (25-40) and 44 (31-56) in AR (0.002), 26 (14-37), 36 (12-60) and 56 (24-89) in APO (0.07), 32 (27-36), 31 (24-38) and 44 (24-65) in COPD (0.46), and 27 (21-33), 35 (26-45), and 37 (25-49) in NAL (0.10), respectively., Conclusions: Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV 1 decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype., Competing Interests: Competing interests: YÇ reports grants from Sanofi and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Sanofi outside the submitted work. JV reports personal fees from ALK, AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline and Teva outside the submitted work. PL reports grants and personal fees from AstraZeneca and Sanofi and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi outside the submitted work. SA, JLM and BGN have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT)., Objective: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT., Methods: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort., Results: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p = 0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p = 0.006) for subjects with a higher number of elevated T2 biomarkers., Conclusions: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype., Trial Registration Number: NCT01433523., Competing Interests: Competing interests: IH is an employee of ALK-Abelló A/S. KB has acted as a paid consultant for ALK-Abelló A/S, AstraZeneca, Boehringer Ingelheim and Sanofi. TS is an employee of ALK-Abelló A/S. SB was an employee of ALK-Abelló A/S when data analysis took place. MHS receives grant support via Imperial College London from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, Medical Research council, ALK-Abelló A/S, Regeneron, and serves as a consultant for Allergy Therapeutics, Angany, and UCB. EDB is a member of the Science Committee and Board of GINA. He reports personal fees from ALK-Abelló A/S in relation to the current submission, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Novartis, Orion, Regeneron and Sanofi Genzyme, outside the submitted work. EB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has served as a paid consultant for ALK-Abelló A/S, AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Regeneron, Sanofi Genzyme and TEVA, outside the submitted work. PSA is an employee of ALK-Abelló A/S., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The tobacco industry is accountable for an annual global death toll of approximately 8 million people and cigarette smoking is the foremost risk factor for several types of cancer. In addition, the tobacco industry has a long and controversial history of trying to influence scientific research and of engaging in other morally problematic practices. In September 2021, the respiratory community was alarmed by the takeover of Vectura Group (Vectura) by Philip Morris International. As a reaction to this acquisition, strict measures were imposed by the International Respiratory Societies to prohibit the involvement of Vectura in respiratory research and its participation in societies' activities. International Respiratory Societies argued that Vectura had become part of the tobacco industry due to this takeover and is, therefore, subject to the same rules and restrictions. From a healthcare and historical perspective, the reaction and imposed measures are very understandable. However, for researchers that were already affiliated with Vectura through long-standing agreements and for research that was funded by Vectura, the imposed measures have serious consequences. With this article, we provide an example of these consequences. By reflecting on this issue, we would like to start a conversation regarding the current measures and to encourage the respiratory community to begin thinking of a way to avoid these consequences in the future. In addition, we hope that with this conversation the Respiratory Societies can set an example for other medical societies on how to cope with possible morally tainted affiliations (eg, fast food companies, alcohol manufacturing companies) in the future., Competing Interests: Competing interests: NJ has nothing to disclose. WBvdB has nothing to disclose. WBvdB reports grants from Vectura Group Plc (research agreement was signed in 2018 for the duration of 4 years, Vectura Group was taken over by Philip Morris International in 2021), outside the submitted work. HT reports other grants and other from Novartis, grants from CFF, grant from Vectura, outside the submitted work; In addition, Erasmus MC and Telethon Kids Institute have licensed the use of PRAGMA-CF to Thirona and Resonance Health. Unconditional research grants from Novartis, and Vectura. Research grants by IMI, CFF, ECFS, Sophia foundation. Honoraria and travel expenses for lectures and participation in expert panels from Novartis, Insmed and Vertex. He is heading the Erasmus MC core laboratory Lung Analysis which is a not-for-profit core image analysis laboratory. The financial aspects of the laboratory are handled by the Erasmus MC., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma.Methods: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b-/- mice were used for allergic models.Results: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b-/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice.Conclusion: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma. [ABSTRACT FROM AUTHOR]

Asthma attacks (exacerbations) are common, accounting for over 90 000 UK hospital admissions per annum. They kill nearly 1500 people per year in the UK, have significant associated direct and indirect costs and lead to accelerated and permanent loss of lung function. The recognition of asthma as a heterogeneous condition with multiple phenotypes has revolutionised the approach to the long-term management of the condition, with greater emphasis on personalised treatment and the introduction of the treatable traits concept. In contrast asthma attacks are poorly defined and understood and our treatment approach consists of bronchodilators and systemic corticosteroids. This review aims to explore the current limitations in the description, assessment and management of asthma attacks. We will outline the risk factors for attacks, strategies to modify this risk and describe the recognised characteristics of attacks as a first step towards the development of an approach for phenotyping and personalising the treatment of these critically important events. By doing this, we hope to gradually improve asthma attack treatment and reduce the adverse effects associated with recurrent courses of corticosteroids. [ABSTRACT FROM AUTHOR]

Luis Pérez de Llano,1,* Borja G Cosío,2,3,* Amanda Iglesias,3 Natividad de las Cuevas,4 Juan Jose Soler-Cataluña,3,5 Jose Luis Izquierdo,6 Jose Luis López-Campos,3,7 Carmen Calero,7 Vicente Plaza,3,8–10 Marc Miravitlles,3,11 Alfons Torrego,8–10 Eva Martinez-Moragon,12 Joan B Soriano,13 Antolin Lopez Viña,14 Irina Bobolea15 On behalf of the CHACOS Study Group 1Department of Respiratory Medicine, Hospital Lucus Augusti, Lugo, Spain; 2Department of Respiratory Medicine, Hospital Universitario Son Espases-IdISBa, Palma de Mallorca, Spain; 3CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; 4Department of Allergy, Hospital 12 de Octubre, Madrid, Spain; 5Department of Respiratory Medicine, Hospital Arnau de Vilanova, Valencia, Spain; 6Department of Respiratory Medicine, Hospital Universitario de Guadalajara, Guadalajara, Spain; 7Department of Respiratory Medicine, Hospital Virgen del Rocío, Sevilla, Spain; 8Department of Respiratory Medicine, Hospital de la Santa Creu y Sant Pau, Barcelona, Spain; 9Institut d’Investigació Biomédica Sant Pau, IIB Sant Pau, Barcelona, Spain; 10Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 11Department of Respiratory Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 12Department of Respiratory Medicine, Hospital Dr Peset, Valencia, Spain; 13Instituto de Investigación Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; 14Department of Respiratory Medicine, Hospital Puerta de Hierro, Madrid, Spain; 15Servei de Pneumologia i Alergia, Hospital Clinic, Barcelona, Spain *These authors contributed equally to this work Introduction: The asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. Objectives: We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. Methods: This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity 10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. Results: In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61–3.57] vs 1.11 [0.12–2.42] pg/mL, respectively; p=0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61–13.12] vs 7.03 [4.69–10.44] pg/mL, respectively; p

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) reportedly promotes, or conversely, resolves inflammation in asthma. In this study of TRAIL and cell receptors in sputum, bronchoalveolar lavage and biopsy from subjects in the Severe Asthma Research Program at Wake Forest, the high TRAIL group had significant increases in all leucocytes, and was associated with increased type 1, type 2 and type 17 cytokines, but not type 9 interleukin 9. Two variants at loci in the TRAIL gene were associated with higher sputum levels of TRAIL. Increased TRAIL decoy receptor R3/DcR1 was observed on sputum leucocytes compared with death receptor R1/DR4, suggesting reduced apoptosis and prolonged cellular inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Parkin (Park2), an E3 ubiquitin ligase, is critical to maintain mitochondrial function by regulating mitochondrial biogenesis and degradation (mitophagy), but recent evidence suggests the involvement of Parkin in promoting inflammation. In the present study, we determined if Parkin regulates airway mitochondrial DNA (mtDNA) release and inflammatory responses to type 2 cytokine interleukin (IL)-13 and allergens.Methods: We measured Parkin mRNA expression in brushed bronchial epithelial cells and mtDNA release in the paired bronchoalveolar lavage fluid (BALF) from normal subjects and asthmatics. Parkin-deficient primary human tracheobronchial epithelial (HTBE) cells generated using the CRISPR-Cas9 system were stimulated with IL-13. To determine the in vivo function of Parkin, Parkin knockout (PKO) and wild-type (WT) mice were treated with IL-13 or allergen (house dust mite, HDM) in the presence or absence of mtDNA isolated from normal mouse lungs.Results: Parkin mRNA expression in asthmatic airway epithelium was upregulated, which positively correlated with the levels of released mtDNA in BALF. IL-13-stimulated HTBE cells increased Parkin expression. Moreover, IL-13 induced mtDNA release in Parkin-sufficient, but not in Parkin-deficient HTBE cells. PKO (vs WT) mice attenuated airway mtDNA release and inflammation following IL-13 or HDM treatments. mtDNA amplified airway inflammation in mice treated with IL-13 or HDM. Notably, Parkin also mediated mtDNA-induced exacerbation of airway inflammation.Conclusion: Our research findings suggest that Parkin promotes mtDNA release and inflammation in airways, thus improving our understanding of the complex role of Parkin and mitochondrial dysfunction in asthma pathogenesis. [ABSTRACT FROM AUTHOR]

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease. [ABSTRACT FROM AUTHOR]

Introduction: Asthma and its associated exacerbation are heterogeneous. Although severe asthma attacks are systematically prescribed corticosteroids and often antibiotics, little is known about the variability of response to these therapies. Blood eosinophils and fractional exhaled nitric oxide (FeNO) are type 2 inflammation biomarkers that have established mechanistic, prognostic and theragnostic values in chronic asthma, but their utility in acute asthma is unclear. We speculate that the clinical and biological response to those treatments varies according to inflammometry and microbiological test results., Methods and Analysis: An observational longitudinal pilot study with multimodal clinical and translational assessments will be performed on 50 physician-diagnosed ≥12-year-old asthmatics presenting with an asthma attack and 12 healthy controls, including blood eosinophil count (venous and point-of-care (POC) capillary blood), FeNO and testing for airway infection (sputum cultures and POC nasopharyngeal swabs). People with asthma will be assessed on day 0 and after a 7-day corticosteroid course, with home monitoring performed in between. The primary analysis will be the change in the forced expiratory volume in 1 s according to type 2 inflammatory status (blood eosinophils ≥0.15×10 9 /L and/or FeNO ≥25 ppb) after treatment. Key secondary analyses will compare changes in symptom scores and the proportion of patients achieving a minimal clinically important difference. Exploratory analyses will assess the relationship between clinical, lung function, inflammatory and microbiome parameters; satisfaction plus reliability indices of POC tests; and sex-gender variability in treatment response. Ultimately, this pilot study will serve to plan a larger trial comparing the clinical and biological response to systemic corticosteroids according to inflammatory biomarkers, offering valuable guidance for more personalised therapeutic strategies in asthma attacks., Ethics and Dissemination: The protocol has been approved by the Research Ethics Committee of the CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada (#2023-4687). Results will be communicated in an international meeting and submitted to a peer-reviewed journal., Trial Registration Number: ClinicalTrials.gov Registry (NCT05870215)., Competing Interests: Competing interests: CAC-P reports he has received speaker honoraria from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; and received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. PL reports speaker honoraria from AstraZeneca, Sanofi-Regeneron, GlaxoSmithKline, Boehringer Ingelheim and Novartis outside of the submitted work; and received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. AC reports she has received non-restricted research grants from the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire and GlaxoSmithKline; received speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma; and received consultancy fees for AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma. She advised the Institut national d’excellence en santé et services sociaux (INESSS) for an update of the asthma general practice information booklet for general practitioners. SC reports the following interests: he has received non-restricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire, AstraZeneca, bioMérieux and Sanofi-Genyme-Regeneron; he is the holder of the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine and is a clinical research scholar of the Fonds de recherche du Québec; he received speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma; he received consultancy fees for FirstThought, AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; he has received sponsorship to attend/speak at international scientific meetings by/for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry—a company developing a FeNO device (myBiometry). He advised the INESSS for an update of the asthma general practice information booklet for general practitioners., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Exposure to cleaning products has been associated with adverse respiratory outcomes. This study aimed to investigate the medically reported incidence, trends in incidence and occupational determinants of work-related respiratory disorders attributed to cleaning agents and to explore the role of 'Quantitative Structure Activity Relationships' (QSAR) in corroborating the identification of chemical respiratory sensitisers.Methods: Respiratory diagnoses attributed to cleaning agents were extracted from The Health and Occupation Research (THOR) surveillance network, 1989-2017. Incidence, trends in incidence and incidence rate ratios by occupation were investigated. Agents were classified by chemical type and QSAR hazard indices were determined for specific organic chemicals.Results: Approximately 6% (779 cases) of the (non-asbestos) THOR respiratory cases were attributed to cleaning agents. Diagnoses were predominantly asthma (58%) and inhalation accidents (27%) with frequently reported chemical categories being aldehydes (30%) and chlorine/its releasers (26%). No significant trend in asthma incidence (1999-2017) was observed (annual average change of -1.1% (95% CI -4.4 to 2.4)). This contrasted with a statistically significant annual decline in asthma incidence (-6.8% (95% CI -8.0 to -5.6)) for non-cleaning agents. There was a large variation in risk between occupations. 7 of the 15 organic chemicals specifically identified had a QSAR generated hazard index consistent with being a respiratory sensitiser.Conclusion: Specific occupations appear to be at increased risk of adverse respiratory outcomes attributed to cleaning agents. While exposure to agents such as glutaraldehyde have been addressed, other exposures, such as to chlorine, remain important. Chemical features of the cleaning agents helped distinguish between sensitising and irritant agents. [ABSTRACT FROM AUTHOR]

A common explanation for the origins and rising prevalence of asthma is that they involve complex interactions between hereditary predispositions and environmental exposures that are incompletely understood. Yet, emerging evidence substantiates the paradigm that environmental exposures prenatally and during very early childhood induce epigenetic alterations that affect the expression of asthma genes and, thereby, asthma itself. Here, we review much of the key evidence supporting this paradigm. First, we describe evidence that the prenatal and early postnatal periods are key time windows of susceptibility to environmental exposures that may trigger asthma. Second, we explain how environmental epigenetic regulation may explain the immunopathology underlying asthma. Third, we outline specific evidence that environmental exposures induce epigenetic regulation, both from animal models and robust human epidemiological research. Finally, we review some emerging topics, including the importance of coexposures, population divergence, and how epigenetic regulation may change over time. Despite all the inherent complexity, great progress has been made toward understanding what we still consider reversible asthma risk factors. These, in time, may impact patient care. [ABSTRACT FROM AUTHOR]

Purpose of Review: Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear. Recent Findings: Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences. Summary: In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population. [ABSTRACT FROM AUTHOR]

In asthma, supine posture and sleep increase intrathoracic airway narrowing. When humans are supine, because of gravity fluid moves out of the legs and accumulates in the thorax. We hypothesized that fluid shifting out of the legs into the thorax contributes to the intrathoracic airway narrowing in asthma. Healthy and asthmatic subjects sat for 30 min and then lay supine for 30 min. To simulate overnight fluid shift, supine subjects were randomized to receive increased fluid shift out of the legs with lower body positive pressure (LBPP, 10-30 min) or none (control) and crossed over. With forced oscillation at 5 Hz, respiratory resistance (R5) and reactance (X5, reflecting respiratory stiffness) and with bioelectrical impedance, leg and thoracic fluid volumes (LFV, TFV) were measured while subjects were seated and supine (0 min, 30 min). In 17 healthy subjects (age: 51.8 ± 10.9 yr, FEV1/FVC z score: -0.4 ± 1.1), changes in R5 and X5 were similar in both study arms (P = 0.05). In 15 asthmatic subjects (58.5 ± 9.8 yr, -2.1 ± 1.3), R5 and X5 increased in both arms (ΔR5: 0.6 ± 0.9 vs. 1.4 ± 0.8 cmH2O·l-1·s-1, ΔX5: 0.3 ± 0.7 vs. 1.1 ± 0.9 cmH2O·l-1·s-1). The increases in R5 and X5 were 2.3 and 3.7 times larger with LBPP than control, however (P = 0.008, P = 0.006). The main predictor of increases in R5 with LBPP was increases in TFV (r = 0.73, P = 0.002). In asthmatic subjects, the magnitude of increases in X5 with LBPP was comparable to that with posture change from sitting to supine (1.1 ± 0.9 vs. 1.4 ± 0.9 cmH2O·l-1·s-1, P = 0.32). We conclude that in asthmatic subjects fluid shifting from the legs to the thorax while supine contributed to increases in the respiratory resistance and stiffness. [ABSTRACT FROM AUTHOR]

Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma., Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo., Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity., Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma., Competing Interests: Competing interests: VSRRA, SPa, GL, NZK, JS, JT, SD, Y-KG, PMH, SPh, JH and MBS have nothing to disclose. EFM reports grants from Janssen, Bristol Myers Squibb, UCB, Merck Serono and Eli Lilly outside the submitted work. In addition, EFM has patents 7,709,514 and 7,863,313 issued. KFC has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and TEVA regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. IA and PS report grants from the public private European Union Innovative Medicines Initiative during the conduct of the study. RD reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA; consultation for TEVA and Novartis as member of advisory boards; and participation in a scientific discussion about asthma organised by GlaxoSmithKline. RD is a cofounder and current consultant and has shares in Synairgen, a University of Southampton spin-out company., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The L-arginine metabolome is dysregulated in asthma, though it is not understood how longitudinal changes in L-arginine metabolism differ among asthma phenotypes and relate to disease outcomes., Objectives: To determine the longitudinal associations between phenotypic characteristics with L-arginine metabolites and their relationships with asthma morbidity., Methods: This is a prospective cohort study of 321 patients with asthma followed semiannually for over 18 months with assessments of plasma L-arginine metabolites, asthma control, spirometry, quality of life and exacerbations. Metabolite concentrations and ratios were transformed using the natural logarithm., Results: There were many differences in L-arginine metabolism among asthma phenotypes in the adjusted models. Increasing body mass index was associated with increased asymmetric dimethylarginine (ADMA) and depleted L-citrulline. Latinx was associated with increased metabolism via arginase, with higher L-ornithine, proline and L-ornithine/L-citrulline levels, and was found to have higher L-arginine availability compared with white race. With respect to asthma outcomes, increasing L-citrulline was associated with improved asthma control and increasing L-arginine and L-arginine/ADMA were associated with improved quality of life. Increased variability in L-arginine, L-arginine/ADMA, L-arginine/L-ornithine and L-arginine availability index over 12 months were associated with increased exacerbations, OR 4.70 (95% CI 1.35 to 16.37), OR 8.69 (95% CI 1.98 to 38.08), OR 4.17 (95% CI 1.40 to 12.41) and OR 4.95 (95% CI 1.42 to 17.16), respectively., Conclusions: Our findings suggest that L-arginine metabolism is associated with multiple measures of asthma control and may explain, in part, the relationship between age, race/ethnicity and obesity with asthma outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood., Objectives: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections., Methods: We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils., Measurements and Main Results: Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) and FEV 1 (weighted median estimator, SD FEV 1 /FVC: -0.054 (95% CI -0.078 to -0.029), effect only prominent in individuals with asthma)., Conclusions: Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD., Competing Interests: Competing interests: MDT and LVW receive funding from GSK for collaborative research projects outside of the submitted work. IH has funded research collaborations with GSK, Boehringer Ingelheim and Orion., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Purpose: A high prevalence of asthma and bronchial hyperresponsiveness (BHR) is reported in swimmers and cross-country skiers. It has been suggested that increased parasympathetic nervous activity is involved in asthma development in endurance athletes. We aimed to assess the associations of BHR to parasympathetic activity in healthy and asthmatic swimmers and cross-country skiers and healthy nonathletes. Methods: Parasympathetic activity was measured by pupillometry and heart rate variability at the onset of exercise with the cardiac vagal index calculated in 28 cross-country skiers (♂18/♀ 10), 29 swimmers (♂17/♀ 12), and 30 healthy nonathlete controls (♂ 14/♀ 16) on two different days. All subjects performed a methacholine bronchial challenge with the provocation dose causing 20% decrease in the forced expiratory volume in 1 s calculated (PD20met). Data were analyzed by robust regression analysis and presented as β coefficients with 95% confidence intervals (CI). Results: PD20met was negatively associated with cardiac vagal index (-13.9, 95% CI= -26.8 to -1.0) in all subjects. When adjusted to the type of sport, this association was stronger in swimmers (-8.3, 95% CI = -13.0 to -3.6) as compared with controls and nonsignificant in crosscountry skiers. Percent pupil constriction was significantly associated with PD20met in swimmers (-9.4, 95%CI= -15.4 to -3.4) only after adjusting for the type of sport. Fourteen swimmers (48%) and 16 cross-country skiers (57%) had doctor-diagnosed asthma in combination with current BHR and/or current use of asthma drugs. Seventy-two percent swimmers, 44% cross-country skiers, and 39% controls had a PD20met ≤8 Kmol (P = 0.015). Fourteen swimmers had a PD20met ≤2 µmol as compared with one cross-country skier (P < 0.001). Conclusion: Parasympathetic activity measured in the heart is more closely related to BHR as compared with parasympathetic activity measured in the pupils. The type of sport influences BHR severity and its relationship to parasympathetic activity. [ABSTRACT FROM AUTHOR]

Cord blood 25-hydroxyvitamin D (25OHD) has been reported in association with risk of early life recurrent wheeze. In a subset of infants who participated in the Vitamin D Antenatal Asthma Reduction Trial, we demonstrated that higher cord blood 25OHD at birth (>31 ng/mL) was associated with a reduced risk of recurrent wheeze in the first year of life. We then identified a module of co-expressed genes associated with cord blood 25OHD levels >31 ng/mL. Genes in this module are involved in biological and immune pathways related to development and progression of asthma pathogenesis including the Notch1 and transforming growth factor-beta signalling pathways. [ABSTRACT FROM AUTHOR]

Background: Obese children for unknown reasons report greater asthma symptoms. Asthma and obesity both independently associate with gastro-oesophageal reflux symptoms (GORS). Determining if obesity affects the link between GORS and asthma will help elucidate the obese-asthma phenotype.Objective: Extend our previous work to determine the degree of associations between the GORS and asthma phenotype.Methods: We conducted a cross-sectional study of lean (20%-65% body mass index, BMI) and obese (≥95% BMI) children aged 10-17 years old with persistent, early-onset asthma. Participants contributed demographics, GORS and asthma questionnaires and lung function data. We determined associations between weight status, GORS and asthma outcomes using multivariable linear and logistic regression. Findings were replicated in a second well-characterised cohort of asthmatic children.Results: Obese children had seven times higher odds of reporting multiple GORS (OR=7.7, 95% CI 1.9 to 31.0, interaction p value=.004). Asthma symptoms were closely associated with GORS scores in obese patients (r=0.815, p<0.0001) but not in leans (r=0.291, p=0.200; interaction p value=0.003). Higher GORS scores associated with higher FEV1-per cent predicted (p=0.003), lower airway resistance (R10, p=0.025), improved airway reactance (X10, p=0.005) but significantly worse asthma control (Asthma Control Questionnaire, p=0.007). A significant but weaker association between GORS and asthma symptoms was seen in leans compared with obese in the replicate cohort.Conclusion: GORS are more likely to associate with asthma symptoms in obese children. Better lung function among children reporting gastro-oesophageal reflux and asthma symptoms suggests that misattribution of GORS to asthma may be a contributing mechanism to excess asthma symptoms in obese children. [ABSTRACT FROM AUTHOR]

Variable airflow obstruction is a pathophysiological hallmark of asthma; however, the interactions between acute bronchoconstriction and the cough reflex are poorly understood. We performed a randomised, single-blind, placebo-controlled, crossover study to investigate the interaction between bronchoconstriction and cough in asthma. Capsaicin was administered to evoke coughs and methacholine to induce bronchoconstriction. We demonstrated that acute bronchoconstriction increased capsaicin-evoked coughs, which improved as airway calibre spontaneously resolved. However, capsaicin-evoked coughing had no impact on methacholine-induced bronchoconstriction. This study provides evidence that bronchoconstriction increases the activation of capsaicin-responsive airway nerves, but the precise mechanisms and mediators involved require further evaluation.Trial Registration Number: ISRCTN14900082. [ABSTRACT FROM AUTHOR]

Background: Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1-4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models.Methods and Results: It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4(-/-)) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1-3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis.Conclusion: This study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions. [ABSTRACT FROM AUTHOR]

Objective To explore asthma pathogenesis using data from upper and lower airways. Data Source English-language papers on human asthma and nasal polyp subjects from 1990 onwards. Study Selection High-quality studies in established journals. Results The recognition of its inflammatory nature led to a quantum leap in the understanding and treatment of asthma, with lives saved by inhaled corticosteroids. Further work at genetic, molecular, histological and clinical levels has shown that asthma is polymorphic and rarely involves isolated Th2 bronchial inflammation. Viral infections may act as an initiating event in children and adults, showing synergy with atopy. Chronic staphylococcal colonization of the mucosa may act as a promoter, as in atopic dermatitis. These two observations may be linked, with viruses providing an entry for bacteria into the mucosal epithelium. Conclusions Most asthma begins in the nose and involves allergy and infection: both viral and bacterial. The combination of atopy and infection suggests new possibilities for therapy. [ABSTRACT FROM AUTHOR]

Background: Airway epithelial cells (AEC) from patients with asthma, appear to have an impaired interferon (IFN)-β and -λ response to infection with rhinovirus.Objectives: To determine if impaired IFN responses can be identified in young children at risk of developing asthma due to atopy and/or early life wheeze, and if the site of infection or the infecting virus influence the antiviral response.Methods: Nasal (N) and tracheal (T) epithelial cells (EC) were collected from children categorised with atopy and/or wheeze based on specific IgE to locally common aeroallergens and a questionnaire concerning respiratory health. Submerged primary cultures were infected with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV), and IFN production, inflammatory cytokine expression and viral replication quantified.Results: Nasal epithelial cells (NEC), but not tracheal epithelial cells (TEC), from children with wheeze and/or atopy produced less IFN-β, but not IFN-λ, in response to RSV infection; this was associated with higher viral shedding. However, IFN-regulated factors IRF-7, Mx-1 and CXCL-10, and inflammatory cytokines were not differentially regulated. NECs and TECs from children with wheeze and/or atopy demonstrated no impairment of the IFN response (β or λ) to hMPV infection. Despite this, more hMPV was shed from these cells.Conclusions: AECs from children with wheeze and/or atopy do not have an intrinsic defect in the production of IFN-β or -λ, however, this response is influenced by the infecting virus. Higher viral load is associated with atopy and wheeze suggesting an impaired antiviral response to RSV and hMPV that is not influenced by production of IFNs. [ABSTRACT FROM AUTHOR]

Introduction: Cellular circadian rhythms regulate immune pathways and inflammatory responses that mediate human disease such as asthma. Circadian rhythms in the lung may also contribute to exacerbations of chronic diseases such as asthma by regulating observed rhythms in mucus production, bronchial reactivity, airway inflammation and airway resistance. Primary human airway epithelial cells (AECs) are commonly used to model human lung diseases, such as asthma, with circadian symptoms, but a method for synchronising circadian rhythms in AECs has not been developed, and the presence of circadian rhythms in human AECs remains uninvestigated., Methods: We used temperature cycling to synchronise circadian rhythms in undifferentiated and differentiated primary human AECs. Reverse transcriptase-quantitative PCR was used to measure expression of the core circadian clock genes ARNTL, CLOCK, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2 ., Results: Following temperature synchronisation, the core circadian genes ARNTL, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2 maintained endogenous 24-hour rhythms under constant conditions. Following serum shock, the core circadian genes ARNTL, NR1D1 and NR1D2 demonstrated rhythmic expression. Following temperature synchronisation, CXCL8 demonstrated rhythmic circadian expression., Conclusions: Temperature synchronised circadian rhythms in AECs differentiated at an air-liquid interface can serve as a model to investigate circadian rhythms in pulmonary diseases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: several biological treatments have become available for management of severe asthma. There is a significant overlap in the indication of these treatments with lack of consensus on the first-line biologic choice and switching practice in event of treatment failure., Aims: to evaluate outcomes of biologic treatments through analysis of the UK Severe Asthma Registry (UKSAR), and survey of the UK severe asthma specialists' opinion., Methods: patients registered in the UKSAR database and treated with biologics for severe asthma in the period between January 2014 and August 2021, were studied to explore biologic treatments practice. This was complemented by survey of opinion of severe asthma specialists., Results: a total of 2,490 patients from 10 severe asthma centres were included in the study (mean age 51.3 years, 61.1% female, mean BMI 30.9kg/m 2 ). Biologics use included mepolizumab 1,115 (44.8%), benralizumab 925 (37.1%), omalizumab 432 (17.3%), dupilumab 13 (0.5%), and reslizumab 5 (0.2%). Patients on omalizumab were younger and had earlier age of onset asthma than those prescribed mepolizumab or benralizumab. Patients prescribed mepolizumab and benralizumab had similar clinical characteristics. Those on benralizumab were more likely to continue treatment at approximately one year follow up (93.9%), than those on mepolizumab (80%), or omalizumab (69.6%). The first choice biologic differed between centres and changed over the study time period. Experts' opinion also diverged in terms of biologic initiation choice and switching practice., Conclusion: We observed significant variation and divergence in the prescribing practices of biologics in severe asthma that necessitates further research and standardisation., (This article is protected by copyright. All rights reserved.)

Asthma is a frequent respiratory condition whose pathophysiology relies on altered interactions between bronchial epithelium, smooth muscle cells (SMC) and immune responses. Those leads to classical hallmarks of asthma: airway hyper-responsiveness, bronchial remodelling and chronic inflammation. Airway smooth muscle biology and pathophysiological implication in asthma are now better understood. Precise deciphering of intracellular signalling pathways regulating smooth muscle contraction highlighted the critical roles played by small GTPases of Rho superfamily. Beyond contractile considerations, active involvement of airway smooth muscle in bronchial remodelling mechanisms is now established. Not only cytokines and growth factors, such as fibroblats growth factor or transforming growth factor-β, but also extracellular matrix composition have been demonstrated as potent phenotype modifiers for airway SMC. Although basic science knowledge has grown significantly, little of it has translated into improvement in asthma clinical practice. Evaluation of airway smooth muscle function is still limited to its contractile activity. Moreover, it relies on tools, such as spirometry, that give only an overall assessment and not a specific one. Interesting technics such as forced oscillometry or specific imagery (CT and MRI) give new perspectives to evaluate other aspects of airway muscle such as bronchial remodelling. Finally, except for the refinement of conventional bronchodilators, no new drug therapy directly targeting airway smooth muscle proved its efficacy. Bronchial thermoplasty is an innovative and efficient therapeutic strategy but is only restricted to a small proportion of severe asthmatic patients. New diagnostic and therapeutic strategies specifically oriented toward airway smooth muscle are needed to improve global asthma care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The importance of monitoring exhaled nitric oxide (NO) in asthma remains controversial. Objective: To measure exhaled NO, postnebulized albuterol/ipratropium spirometry, and Asthma Control Test (ACT) during asthma exacerbation requiring 8- to 10-day tapering oral corticosteroid in nonsmoking patients with moderate-to-severe asthma on moderate-dose inhaled corticosteroid and long-acting β2-agonist but not maintenance oral corticosteroid. Methods: After measuring the fraction of exhaled NO (Feno [ppb]) at 50, 100, 150, and 200 mL/s, the total Feno at 50 mL/s (ppb), large central airway NO flux (J′awNO [nL/s]), and peripheral small airway/alveolar NO concentration (CANO [ppb]) were calculated and corrected for NO axial back-diffusion. Outpatient exacerbation required the patient with asthma to be afebrile with normal chest x-ray and white blood cell count. Results: Group 1 included 17 patients (6 men) with asthma, age 52 ± 12 years, studied at baseline, during 18 exacerbations with abnormal Feno at 50 mL/s, J′awNO, and/or CANO, and post 8- to 10-day tapering 40 mg prednisone (recovery). Baseline: IgE, 332 ± 243 Kμ; total blood eosinophils, 304 ± 266 cells/μL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV1, 2.5 ± 0.7 L (86% ± 20% predicted); exacerbation: FEV1, 1.7 ± 0.4 L (60% ± 17%) (P < .001); recovery: FEV1, 2.5 ± 0.7 L (85% ± 13%) (P < .001). Group 2 included 11 (7 men) similarly treated patients with asthma, age 49 ± 14 years, studied at baseline, during 15 exacerbations with normal Feno at 50 mL/s, J′awNO, and CANO. Baseline: IgE, 307 ± 133 Kμ; total blood eosinophils, 296 ± 149 cells/μL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV1, 2.7 ± 0.9 L (71% ± 12% predicted); exacerbation: FEV1, 1.7 ± 0.6 L (54% ± 19%) (P < .006); recovery: FEV1, 2.7 ± 0.9 L (70% ± 14%) (P = .002). On comparing group 1 versus group 2, there was no significant difference for baseline IgE, eosinophils, body mass index, and ACT and similar significant (≤.006) decrease from baseline in FEV1 (L) during exacerbation and similar increase (≤.006) at recovery. Conclusions: Increased versus normal exhaled NO during outpatient exacerbation in patients with moderate-to-severe asthma on inhaled corticosteroid and long-acting β2-agonist but not maintenance oral corticosteroid does not preclude a robust clinical and spirometric response to tapering oral prednisone. [Copyright &y& Elsevier]