Search

Elise G De Smet,1 Leen JM Seys,1,2 Fien M Verhamme,1 Bart M Vanaudenaerde,3 Guy G Brusselle,1 Colin D Bingle,4 Ken R Bracke1 1Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; ²Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; 3Laboratory for Respiratory Diseases, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium; 4Academic Unit of Respiratory Medicine, Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, UK Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal inflammatory response in the lungs caused by the inhalation of noxious particles and gases. The airway epithelium has a protective function against these harmful agents by maintaining a physical barrier and by secreting defensive proteins, such as bactericidal/permeability-increasing fold-containing (BPIF) proteins, BPIFA1 and BPIFB1. However, inconsistent data regarding BPIFA1 expression in smokers and COPD patients have been reported to date. Therefore, we investigated the expression of BPIFA1 and BPIFB1 in a large cohort of never-smokers and smokers with and without COPD, both on the messenger RNA (mRNA) level in lung tissue and on the protein level in airway epithelium. Furthermore, we examined the correlation between BPIFA1 and BPIFB1 levels, goblet cell hyperplasia, and lung function measurements. BPIFA1 and BPIFB1 mRNA expressions were significantly increased in stage III–IV COPD patients compared with stage II COPD patients and subjects without COPD. In addition, protein levels in COPD patients were significantly increased in comparison with subjects without COPD. BPIFA1 and BPIFB1 levels were inversely correlated with measurements of airflow limitation and positively correlated with goblet cell hyperplasia. In addition, by the use of immunofluorescence double staining, we demonstrated the expression of BPIFB1 in goblet cells. In conclusion, we show that BPIFA1 and BPIFB1 levels are elevated in COPD patients and correlate with disease severity. Keywords: BPIFA1, BPIFB1, COPD

Eric Derom, Guy G Brusselle, Guy F Joos Department of Respiratory Medicine, Ghent University Hospital, Ghent, BelgiumAbstract: Tiotropium–olodaterol, formulated in the Respimat soft-mist inhaler, is an inhaled fixed-dose combination (FDC) of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), commercialized under the name of Spiolto or Stiolto. The efficacy of tiotropium–olodaterol 5–5 µg once daily in adult patients with COPD was documented in eleven large, multicenter trials of up to 52 weeks duration. Tiotropium–olodaterol 5–5 µg not only improved spirometric values to a significantly greater extent than placebo but also resulted in statistically significant beneficial effects on dyspnea, markers of hyperinflation, use of rescue medication, health-related quality of life, and exercise endurance. Improvements exceeded the minimal clinically important difference (MCID) for forced expiratory volume in 1 second (FEV1), dyspnea, and quality of life. Differences between tiotropium–olodaterol 5–5 µg and the respective monocomponents were statistically significant for FEV1, dyspnea, markers of hyperinflation, use of rescue medication, and health-related quality of life, but did not reach the MCID. However, dual bronchodilatation significantly increased the number of patients who exceeded the MCID for dyspnea and quality of life. Moreover, tiotropium–olodaterol 5–5 µg was significantly more effective than salmeterol–fluticasone (FDC) twice daily at improving pulmonary function. Differences between tiotropium–olodaterol and other LAMA/LABA FDCs were not observed for FEV1 or other efficacy markers. Therefore, tiotropium–olodaterol is a valuable option in the treatment of COPD patients who remain symptomatic under monotherapy. Keywords: COPD, bronchodilatation, dyspnea, exacerbation, exercise tolerance, LABA, LAMA, spirometry

Kristina Vermeersch,1 Maria Gabrovska,2 Griet Deslypere,3 Ingel K Demedts,4 Hans Slabbynck,5 Joseph Aumann,3 Vincent Ninane,2 Geert M Verleden,1 Thierry Troosters,1,6 Kris Bogaerts,7,8 Guy G Brusselle,9 Wim Janssens1 On behalf of the BACE Trial Investigators 1KU Leuven, Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Faculty of Medicine, Leuven, Belgium; 2Department of Pneumology, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; 3Department of Pneumology, Jessa Ziekenhuis, Hasselt, Belgium; 4Department of Respiratory Medicine, AZ Delta Roeselare-Menen, Roeselare, Belgium; 5Department of Respiratory Medicine, ZNA Middelheim, Antwerpen, Belgium; 6KU Leuven, Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, Leuven, Belgium; 7KU Leuven, Department of Public Health and Primary Care, I-BioStat, Leuven, Belgium; 8Hasselt University, Hasselt, Belgium; 9Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium Background: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions.Methods/design: Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge.Discussion: We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs. Keywords: COPD, acute exacerbation, macrolide antibiotics, azithromycin, physical activity, RCT

Rationale: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for ischemic stroke and the risk increases with severity of airflow limitation. Even though vulnerable carotid artery plaque components, such as intraplaque hemorrhage and lipid core, place persons at high risk for ischemic events, the plaque composition in patients with COPD has never been explored. Objectives: To investigate the prevalence of carotid wall thickening, the different carotid artery plaque components, and their relationship with severity of airflow limitation in elderly patients with COPD. Methods: This cross-sectional analysis was part of the Rotterdam Study, a prospective population-based cohort study performed in subjects aged 55 years and older. Diagnosis of COPD was confirmed by spirometry. Participants with carotid wall intima-media thickness greater than or equal to 2.5 mm on ultrasonography underwent high-resolution magnetic resonance imaging for characterization of carotid plaques. Data were analyzed using logistic regression. Measurements and Main Results: COPD cases (n = 253) had a twofold increased risk (odds ratio, 2.0; 95% confidence interval, 1.44-2.85; P < 0.0001) of presentation with carotid wall thickening on ultrasonography compared with control subjects with a normal lung function (n = 920). Moreover, the risk increased significantly with severity of airflow limitation. On magnetic resonance imaging, vulnerable lipid core plaques were more frequent in COPD cases than in control subjects (odds ratio, 2.1; 95% confidence interval, 1.25-3.69; P = 0.0058). Conclusions: Carotid artery wall thickening is more prevalent in patients with COPD than in control subjects. In elderly subjects with carotid wall thickening, COPD is an independent predictor for the presence of a lipid core, and therefore of vulnerable plaques. [ABSTRACT FROM AUTHOR]

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by substantial chronic inflammation in the pulmonary compartment as well as in the systemic circulation. Objectives: To investigate potentially causal association, we examined whether serum levels of high-sensitivity C-reactive protein (hsCRP) and variations in the CRP gene are associated with the risk of developing COPD. Methods: This study is part of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years or older. At baseline, 6,836 subjects without COPD had a blood sample available for assessment of hsCRP serum levels and haplotypes of the CRP gene. We analyzed the association between hsCRP levels, CRP gene haplotypes, and incident COPD with Cox proportional hazard models, adjusted for age, sex, and other confounders. Measurements and Main Results: High levels of hsCRP (>3 mg/L) were associated with a significantly increased risk of incident COPD (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.16-2.49) compared with persons with low levels (<1 mg/L). The risk remained increased after adjusting for potential confounders and introducing a latency period of 3 years. The risk was most pronounced in former smokers (HR, 2.2; 95% CI, 1.12-3.74). hsCRP was not a risk factor in never smokers. No CRP single nucleotide polymorphism or haplotype was associated with a significantly increased or decreased COPD risk. Conclusions: Increased hsCRP levels are predictive for the occurrence of COPD in smokers. However, haplotypes of the CRP gene, which influence hsCRP levels, are not associated with an altered risk of developing COPD. [ABSTRACT FROM AUTHOR]

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. It is unclear if dendritic cells (DC) participate in this inflammatory process. Objectives: To evaluate the presence of DC in small airways of patients with COPD. Methods: We evaluated DC infiltration in small airways by immunohistochemistry in patients with COPD (stage I-IV), never-smokers, and smokers without COPD. Chemokine ligand 20 (CCL20, the most potent chemokine in attracting DC) was determined in total lung by RT-PCR and in induced sputum by enzyme-linked immunsorbent assay. Chemokine receptor 6 (CCR6, the receptor for CCL20) expression on human pulmonary DC was evaluated by RT-PCR and flow cytometry. Measurements and Main Results: There is a significant increase in DC number in the epithelium (p = 0.007) and adventitia (p = 0.009) of small airways of patients with COPD compared with never-smokers and smokers without COPD. DC number in epithelium and adventitia increases along with disease severity. CCL20 mRNA expression in total lung and CCL20 protein levels in induced sputum are significantly higher in patients with COPD compared with never-smokers (p = 0.034 for CCL20 mRNA and p = 0.0008 for CCL20 protein) and smokers without COPD (p = 0.016 for CCL20 mRNA and p = 0.001 for CCL20 protein). DC isolated from human lung express CCR6 both at mRNA and at protein level. Conclusions: This is the first description of airway infiltration by DC in COPD. Moreover, interaction between CCL20 and CCR6 provides a possible mechanism for accumulation of DC in the lungs in COPD. [ABSTRACT FROM AUTHOR]

Background: The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK1 receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD.Methods: Tachykinin NK1 receptor knockout (NK1-R-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated.Results: Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK1-R-/- mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK1-R-/- mice, compared to WT controls, and correlated with an attenuated release of MIP-3alpha/CCL20 and TGF-beta1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK1-R-/- mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK1-R-/- mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK1 receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK1 receptor on CS-induced pulmonary inflammation.Conclusion: These data suggest that the tachykinin NK1 receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease. [ABSTRACT FROM AUTHOR]

Digital technologies (eg, smart inhalers, wearables, and sensors) allow for remote, objective, granular, and non-invasive data collection, making them attractive for research evaluating interventions in airways diseases with variable trajectories, such as asthma. Such technologies offer the opportunity to move towards decentralised clinical trials that are done partly or fully outside the classic clinical trial setting and are characterised by remote data collection and monitoring. This approach to evaluating clinical, pharmacological, or behavioural interventions could facilitate recruitment of inclusive and generalisable study populations, enhance personalisation and sustainability, reduce research costs, and accelerate the timeline to novel asthma treatments' market access. This Personal View discusses the application of digital technologies and endpoints within trials; the concept of hybrid and decentralised designs; describes a fully decentralised trial in asthma; and explores the strengths, weaknesses, opportunities, and threats regarding their implementation from the clinician, patient expert, low-resource, and regulator viewpoints., Competing Interests: Declaration of interests JFMvB reports grants, consultancy fees, or both from ALK Abello, Aardex, AstraZeneca, Chiesi, European Commission COST Action 19132 “ENABLE”, GSK, Novartis, Pfizer, Teva, Trudell Medical, and Vertex, all outside of the submitted work and paid to his institution (UMCG) and is co-chair of European Respiratory Society's Clinical Research Collaboration (ERS CRC) CONNECT. RWC has received funding from BioNTech, GSK, AstraZeneca, Novartis, Respirasense, Teva, and Vitalograph in the form of unrestricted grants, speaker fees, consultancies, and contracted research, all unrelated to this work and paid to his employer, and is a founder of Phyxiom, a spin-off company of the Royal College of Surgeons in Ireland whose work focuses on clinical decision support making use of digital technologies in daily care (ie, outside the clinical trial setting and thus unrelated to the content of this Personal View). KCBR is chair of the European Medicines Agency Methodology Working Party and senior assessor at the Dutch Medicines Evaluation Board. GGB reports being President of the Belgian Respiratory Society and has received fees for advisory boards and lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Novartis, MSD, and Sanofi Regeneron. JAK reports research funding from the US Patient-Centered Outcomes Research Institute, the American Lung Association, the COPD Foundation, and the National Institutes of Health; received consultancy fees from AstraZeneca, Verona Pharmaceuticals, Teva, CereVu Medical, BData, the American Board of Internal Medicine, CarePath, and Dynamed; received payment for expert testimony from Goodwin Law and Teva; reports fees for participation on Data Safety Monitoring Boards or Advisory Boards from the National Heart, Lung, and Blood Institute and Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge; is a co-chair of the American Thoracic Society project on home-based monitoring for chronic lung disease; is a member of the Medical and Scientific Advisory Committee of the COPD Foundation; and is a member of the Board of Directors for the Global Initiative for Asthma and for the Respiratory Health Association. SS has received consulting fees (for advisory boards and lectures, presentations, or both) from AstraZeneca, GSK, Areteia therapeutics, Medscape, CSL Behring, and Owlstone; is the ERS CRC Director; and sits on the ERS Science Council. CEB has received grants and consultancy fees from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi, all paid to his institution. NR has received research funds and fees from Boehringer Ingelheim, Novartis, Pfizer, GSK, and fees (advisory boards, consultation, education, and presentations) from AstraZeneca, Austral, Bayer, Biosency, Chiesi, Menarini, MSD, Nuvaira, Sanofi, and Zambon; received travel and meeting support from AstraZeneca, Chiesi, and GSK; acts as chair of the ERS Science Council; is a board member of the Respiratory Effectiveness Group; and is a member of the Global Initiative on Obstructive Lung Disease Science Committee. HP reports research grants from UK health service research funding bodies (the National Institute of Health and Care Research and the Medical Research Council), all payable via her institution; has received speaker fees from Teva and Sandoz for non-promotional talks at sponsored symposia; and is co-chair of ERS CRC CONNECT. AHYC reports research grants from the Health Research Council of New Zealand, the Auckland Medical Research Foundation, Asthma UK, the University of Auckland, Trudell Medical International, WHO, and Hong Kong University, outside of the submitted work and all paid to her institution (the University of Auckland); is the previous holder of a Robert Irwin Postdoctoral Fellowship; reports consultancy fees from AcademyeX, Spoonful of Sugar, and Active Healthcare; received payment for lectures from the American Academy of Allergy, Asthma, and Immunology, the Asian Pacific Society of Respirology, and the European Respiratory Society; received equipment from Trudell Medical; received support for attending meetings, travel, or both from AstraZeneca and the Asthma and Respiratory Foundation New Zealand; was previously on the Board of Asthma New Zealand; is in leadership roles in the Asthma and Respiratory Foundation New Zealand, Pharmacy Council of New Zealand, the International Pharmaceutical Federation, and the Commonwealth Pharmacists Association; is on the Medical Committee for Auckland Medical Research Foundation; is a member of the Respiratory Effectiveness Group; and is a working group lead for the ERS CRC CONNECT. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma., Methods: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV 1 ) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV 1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day., Results: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV 1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria., Conclusions: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Rationale: Research suggests that respiratory and cardiovascular drugs can ameliorate the rate of lung function decline. Objectives: To investigate the impact of respiratory and cardiovascular pharmacotherapy on lung function trajectories in the general population. Methods: Repeated spirometry was performed in the Rotterdam Study, a population-based cohort of adults aged ≥45 years. Exposure to long-acting beta2-agonists (LABA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), cardioselective beta-blockers, calcium channel blockers, ACE-inhibitors, angiotensin-II receptor blockers, and statins was quantified from pharmacy records to account for therapy adherence. Propensity-score matching and multinomial logistic regression were performed to model medication effects on lung function trajectories, which were previously identified based on FEV 1 and FVC patterns. Models were additionally stratified by genetic variation in each drug target. Measurement and Main Results: Among 3,783 individuals, 2,974 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Exposure to LABA (odds ratio (OR) =1.09 [95%-CI: 1.03-1.16] per 10% increase in exposure), ICS (OR=1.08 [95%-CI: 1.02-1.14]), and statins (OR=1.04 [95%-CI: 1.02-1.06]) significantly increased the odds of being an improver compared to a normal decliner. Beta 1 -blocker use was associated with higher odds of being a rapid decliner (OR=1.04 [95%-CI: 1.00-1.09]), which was driven by incident users. Pharmacogenetic analysis suggests that the effects of LABA, ICS, and beta 1 -blockers are dependent on genetic variation in their drug targets. Conclusions: Our study suggests that LABA, ICS, and statins may favorably modulate lung function trajectories in adults, while initiation of beta 1 -blockers was associated with rapid lung function decline.

Rationale: The pulmonary artery (PA) diameter-to-aorta ratio (PA:A) ratio is a novel marker in cardiovascular imaging for detecting pulmonary hypertension. However, we question the effect of the varying aorta diameter on the ratio, which complicates the interpretation of the PA:A ratio., Objective: Investigate the variability of the PA:A ratio by examining the correlation between PA:A ratio and aorta diameter and by comparing the associations of the PA diameter, aorta diameters, and PA:A ratio., Methods: We included 2197 participants from the Rotterdam Study who underwent non-contrast multidetector computed tomography to measure the PA and aorta diameters. Pearson correlation coefficient was calculated between the PA:A ratio and aorta diameter. Multiple linear regression analyses were performed to compare the determinants of the individual diameters and PA:A ratio., Results: We found a statistically significant correlation between the PA:A ratio and aorta diameter (r = -0.38, p < 0.001). The PA diameter was statistically significantly associated with, height, weight, diastolic blood pressure, blood pressure medication, prevalence of atrial fibrillation, prevalence of heart failure, and prevalence of stroke (p < 0.05). Except for blood pressure medication, the PA:A ratio had similar determinants compared to the PA diameter but was also statistically significantly associated with sex, and systolic blood pressure (p < 0.05), which were statistically significantly associated with the aorta diameter (p < 0.05)., Conclusion: The PA:A ratio should not be interpreted without taking into account the variability of the individual components (PA and aorta diameter) according to the anthropomorphic and clinical characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The implementation of exhaled nitric oxide fraction ( F ENO ) as a biomarker in patients with chronic cough requires sex-stratified F ENO reference values in general and sex-stratified cut-off levels in the management of unexplained chronic cough https://bit.ly/3JHi0vb., Competing Interests: Conflict of interest: the authors declare no conflict of interest with regards to the content of this manuscript., (Copyright ©The authors 2024.)

Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials., Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life., Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers., Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV 1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV 1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV 1 increase (adjusted R 2 : 0.751), compared to BEC (adjusted R 2 : 0.747) or FeNO alone (adjusted R 2 : 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE., Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline., Competing Interests: CP has attended advisory boards for AstraZeneca, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, TEVA, GlaxoSmithKline, ALK, and Sanofi-Genzyme. JT is an employee of the Observational and Pragmatic Research Institute OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. CB reports advisory board participation of Sanofi-Regeneron, AstraZeneca, Takeda, ValeoPharma, honorarium for presentations for AstraZeneca/Amgen, GlaxoSmithKline, Grifols, Sanofi-Regeneron, ValeoPharma and grants paid to UBC from BioHaven, Sanofi-Regeneron, AstraZeneca, GlaxoSmithKline. GCC declares relevant research support from AstraZeneca and Sanofi. GK has attended advisory boards for AstraZeneca, GlaxoSmithKline and Chiesi. He has also given lectures at meetings supported by Novartis, Sanofi-Genzyme, AstraZeneca, GlaxoSmithKline, and Boehringer-Ingelheim. DL reports personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from Abbvie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, GlaxoSmithKline, outside the submitted work. TNT is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. AstraZeneca is a co-funder of ISAR. RA-L has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi, and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. SB-A has received honorarium for participation in expert advisory boards and given lectures for Teva Pharmaceuticals, AstraZeneca, GlaxoSmithKline, Meda, Mundipharma, Sanofi, Mylan and received unrestricted research grants from Mylan, AstraZeneca, Teva, Mundipharma International, GlaxoSmithKline, and Viatris. JB has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work. MH declares grants and other advisory board fees made to his institutional employer from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects. KK received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, Gilead, GlaxoSmithKline, Menarini, Novartis, Sanofi, Specialty Therapeutics, WebMD. His department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GlaxoSmithKline, Menarini, Novartis and NuvoAir. NP has been a speaker and/or advisory board member for Abbott, Abbvie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. PEP has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures/webinars at meetings supported by AstraZeneca, Chiesi and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, Regeneron, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. TP declares relevant research support from Novartis and Chiesi Pharma. CR received consulting/lecture fees from MSD, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer-Ingelheim, Teva, Sanofi, and Bayer. MS has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva, and GlaxoSmithKline for purposes unrelated to the content of this manuscript and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. M-JT has received sponsorship to attend or speak at conferences, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Shionogi and Orient EuroPharma. CU reports personal fees for talks, participation in advisory boards etc. from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Orion Pharma, Sanofi Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, and Pfizer, outside the submitted work. MA-A has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline and received a grant from Kuwait Foundation for the Advancement of Sciences KFAS. AA has received lecture fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, MSD, Norameda, Novartis, Orion, Sanofi, and Zentiva; sponsorships from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, MSD, Novartis, Sanofi, and Teva. ABe is an employee of Optimum Patient Care Global, a co-funder of the International Severe Asthma Registry. LBu is an employee of the Observational and Pragmatic Research Institute OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. VC is an employee of Optimum Patient Care OPC. OPC is a co-funder of the International Severe Asthma Registry. BC declares grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work. KF is an employee of Optimum Patient Care Global OPCG, a co-funder of the International Severe Asthma Registry. LH has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; he has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, and GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, MedImmune, GlaxoSmithKline, Aerocrine, and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. RH is an employee for Observational and Pragmatic Research Institute OPRI which conducted this study in collaboration with Optimum Patient Care and AstraZeneca. PK reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, Zentiva, outside the submitted work. RM is a consultant for Observational and Pragmatic Research Institute OPRI which conducted this study in collaboration with Optimum Patient Care and AstraZeneca. TN received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Sanofi, and AstraZeneca. LP received research grants and lecture fees from GlaxoSmithKline, Menarini, Chiesi, AstraZeneca and Grifols. DC has received speaker fees from AstraZeneca, Boehringer Ingelheim, and has acted as an investigator for trials sponsored by AstraZeneca. FS reports consultancy work for GlaxoSmithKline, AstraZeneca, Sanofi - Advisory board, received speaker fees from GlaxoSmithKline, AstraZeneca, Chiesi, Amgen, Teva and research grants from GlaxoSmithKline, AstraZeneca, and Chiesi. MW reports grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound Biologics, Incyte, and Kinaset. ABo has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer-Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, Sanofi-Regeneron, and consultancies with AstraZeneca/MedImmune, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. GB has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis. He is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD Merck sharp & Dohme, Novartis, and Sanofi/Regeneron. LC has received speaker and consultancy fees and conference expenses from AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim and Menarini. ED declares grants to her institution from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects and speaker fees from Sanofi. JF reports grants from research agreements with AstraZeneca, Mundipharma, Sanofi Regeneron, and Novartis. Personal fees for lectures and attending advisory boards: AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi Regeneron, and Teva. FH declares honoraria from AstraZeneca, Sanofi, TEVA, GSK, and Genentech. She has been an investigator on clinical trials sponsored by GlaxoSmithKline, Genentech, and Sanofi, for which her institution has received funding. DJ has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, Boehringer Ingelheim and research funding from AstraZeneca. MK reports grant support from AstraZeneca, and honoraria for lectures and advisory board meetings paid to her hospital Singapore General Hospital from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi and Boehringer Ingelheim, outside the submitted work. LL has received personal fees from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Orion Pharma and Sanofi. NM is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. AstraZeneca is a co-funder of ISAR. AM-G is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. AstraZeneca is a co-funder of ISAR. PHwP has received honoraria for talks and advisory board meetings from GlaxoSmithKline, AstraZeneca, and Sanofi. AP has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. PHP has received advisory board and speaker fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi/Regeneron. LP-d-L reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from GlaxoSmithKline, grants, personal fees and non-financial support from Teva, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Sanofi, personal fees from MSD, personal fees from Techdow Pharma, grants, personal fees and non-financial support from Faes Farma, personal fees from Leo-Pharma, grants and personal fees from Gebro, personal fees from Gilead, outside the submitted work. MP declares personal fees and non-financial support from AstraZeneca, GlaxoSmithKline, and Sanofi. LR received fees as a speaker from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi. IS has received fees as advisory board participant and/or speaker from GlaxoSmithKline and Sanofi. CT-D has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Grifols and Novartis. EW has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech. She has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva, for which her institution has received funding. RC has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for GlaxoSmithKline and Novartis, has received grant support from GlaxoSmithKline and Aerogen and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence and prediction of exacerbations. PG has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. EH declares personal fees for advisory boards participation and/or speaker activities from: Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes-Greer, Circassia, Bosch, Celltrion-Healthcare, Chiesi, and Almirall. JM reports speaker fees, grants or advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini and Noucor. D-WP received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. FP reports having received lectures or advisory board fees from: Menarini, Mundipharma, Chiesi, Alk Abello, AstraZeneca, Boehringer Ingelheim, Guidotti, Malesci, GlaxoSmithKline, Hal Allergy, Novartis, Sanofi, Regeneron, Stallergenes Greer, Valeas, and Almirall. SS declares research support and speaker fees from Cipla, Glenmark, and GlaxoSmithKline. C-CS has received speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Pfizer, and has acted as an investigator for trials sponsored by AstraZeneca, Novartis, Roche, Sanofi-Regeneron, Galapagos, Shionogi, Aridis, Bristol Myers Squibb, Insmed, United Therapeutics, Enanta Pharmaceuticals, Areteia Therapeutics, Meiji, and Horizon Therapeutics. CT has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi and Novartis, for unrelated projects. TT is an advisory Board Member for Boehringer Ingelheim, AstraZeneca, Takeda, GlaxoSmithKline, MSD, Mundipharma, and Janssen. Honoraria were received for these advisory boards. Honoraria were received for speaking at CMEs for AstraZeneca in the past. Conference sponsorships from AstraZeneca, Boehringer Ingelheim, Merck Serono, GlaxoSmithKline, Norvatis, Mundipharma and MSD. Research grants from Merck Serono Concor Study, MSD Apbord study. LBj has in the last three years received lecture or advisory board fees from Alk-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Sanofi, Genzyme/Regeneron, and Teva. GWC has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. TI received speaker bureau fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca and Sanofi. LJ-M has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has participated in clinical trials for AstraZeneca, Novartis, and GlaxoSmithKline. DP has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies conducted through Observational and Pragmatic Research Institute Pte Ltd from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Commune Digital, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, Teva Pharmaceuticals; 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 92.61% 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. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Porsbjerg, Townend, Bergeron, Christoff, Katsoulotos, Larenas-Linnemann, Tran, Al-Lehebi, Bosnic-Anticevich, Busby, Hew, Kostikas, Papadopoulos, Pfeffer, Popov, Rhee, Sadatsafavi, Tsai, Ulrik, Al-Ahmad, Altraja, Beastall, Bulathsinhala, Carter, Cosio, Fletton, Hansen, Heaney, Hubbard, Kuna, Murray, Nagano, Pini, Cano Rosales, Schleich, Wechsler, Amaral, Bourdin, Brusselle, Chen, Chung, Denton, Fonseca, Hoyte, Jackson, Katial, Kirenga, Koh, Ławkiedraj, Lehtimäki, Liew, Mahboub, Martin, Menzies-Gow, Pang, Papaioannou, Patel, Perez-De-Llano, Peters, Ricciardi, Rodríguez-Cáceres, Solarte, Tay, Torres-Duque, Wang, Zappa, Abisheganaden, Assing, Costello, Gibson, Heffler, Máspero, Nicola, Perng (Steve), Puggioni, Salvi, Sheu, Sirena, Taillé, Tan, Bjermer, Canonica, Iwanaga, Jiménez-Maldonado, Taube, Brussino and Price.)

The delivery of RNA across biological barriers can be achieved by encapsulation in lipid nanoparticles (LNPs). Cationic amphiphilic drugs (CADs) are pharmacologically diverse compounds with ionizable lipid-like features. In this work, we applied CADs as a fifth component of state-of-the-art LNPs via microfluidic mixing. Improved cytosolic delivery of both siRNA and mRNA was achieved by partly replacing the cholesterol fraction of LNPs with CADs. The LNPs could cross the mucus layer in a mucus-producing air-liquid interface model of human primary bronchial epithelial cells following nebulization. Moreover, CAD-LNPs demonstrated improved epithelial and endothelial targeting following intranasal administration in mice, without a marked pro-inflammatory signature. Importantly, quantification of the CAD-LNP molar composition, as demonstrated for nortriptyline, revealed a gradual leakage of the CAD from the formulation during LNP dialysis. Altogether, these data suggest that the addition of a CAD prior to the rapid mixing process might have an impact on the composition, structure, and performance of LNPs.

Background: There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice., Methods: This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots., Results: In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments., Conclusion: Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs., Competing Interests: Competing interests: AFM, PRR, JAK and KMV work for a department that receives/received unconditional research grants from Amgen, Chiesi, Johnson and Johnson, UCB Biopharma, the European Medicines Agency and the Innovative Medicines Initiative. DP-A’s department has received grants from Amgen, Chiesi-Taylor, Lilly, Johnson and Johnson, Novartis, UCB Biopharma, the European Medicines Agency, and the Innovative Medicines Initiative. DP-A’s research group has received consultancy fees from Astra Zeneca and UCB Biopharma. DP-A’s department has organised training programmes funded or supported by Amgen, Astellas, Johnson and Johnson, Synapse Management Partners, and UCB Biopharma. JK’s institute has received grants from the American Lung Association, COPD Foundation, National Heart Lung and Blood institute, PCORI, Regeneron, Sergey Brin Family Foundation and US National Institutes of Health. JK has received consultancy fees from AstraZeneca, BData and GlaxoSmithKline. JK has received honoraria from University of Chicago, University of Washington/VA Puget Sound and travel support from the Global Initiative for Asthma, American Thoracic Society. GBB’s institute has received grants from Merck Sharp & Dohme. GBB has received honoraria from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Sanofi. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear., Methods: In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV 1 and lung diffusing capacity (D LCO c and D LCO c /alveolar volume [V A ]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression., Results: SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV 1 % predicted (β=-3.384 [-4.877, -1.892]), D LCO c (β=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV 1 %predicted was stronger in COPD (β=-6.362 [-9.055, -3.670]) than non-COPD (β=-1.712 [-3.306, -0.118]). Association of SAF with D LCO c and D LCO c/V A were confined to COPD (β=-0.550 [-0.909, -0.191]; β=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively)., Conclusions: Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD., Take-Home Message: Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD., (© 2024. The Author(s).)

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years., Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV 1 /FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV 1 /FVC ≥0.7 and FEV 1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression., Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV 1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV 1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV 1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV 1 and FEV 1 /FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters., Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population., Competing Interests: Conflict of interest: X. Bertels reports BOF.SIP.2020 funding for international mobility in relation to the submitted work. Conflict of interest: R. Faner reports grants from the Serra Húnter Program, Instituto de Salud Carlos III (PI21/00735) and European Research Council under the Horizon Europe research and innovation programme (101044387) outside the submitted work. Conflict of interest: M.H. Cho reports NHLBI funding (R01HL153248, R01HL149861 and R01HL147148), grants from Bayer and GSK, consulting fees from Genentech, AstraZeneca and Illumina, and honoraria for lectures from Genentech, AstraZeneca and Illumina outside the submitted work. Conflict of interest: G.G. Brusselle reports fees for advisory boards and/or lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Merck Sharp & Dohme, Novartis and Sanofi Regeneron outside the submitted work. Conflict of interest: L. Lahousse reports BOF.SIP.2020 funding for international mobility in relation to the submitted work, consulting fees from AstraZeneca, and speaking/lecture fees from Chiesi and IPSA (non-profit) outside the submitted work. Conflict of interest: J.C. Ross and M.A. Irfan declare no conflicts of interest., (Copyright ©The authors 2024.)

Competing Interests: ML reports grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft (DFG), and GSK; and consulting fees, travel expenses, or honoraria for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, Stallergenes, and Teva. RB reports grants, paid to his institution, from Boehringer Ingelheim, GSK, Novartis, and Roche; speaker fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva; and payment for advisory board participation from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva. GWC reports research or clinical trial grants, paid to his institution, from Menarini, AstraZeneca, GSK, Sandi, and Genzyme; and personal fees for lectures and advisory board participation from Menarini, AstraZeneca, Chiesi, Faes Farma, Genentech, Guidotti-Malesci, GSK, HAL Allergy, Innovacaremed, Novartis, OM Pharma, Red Maple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes, and Uriach Pharma. CDR reports funding for travel and speaker fees from Novartis, Sanofi, GSK, TEVA, MSD, Almirall, AstraZeneca, Chiesi, Menarini, Stallergens, ALK-Abello, Allergy Therapeutics, HAL Allergy, Immunotek, and Royal. HN reports grants from GSK and personal fees from AstraZeneca, GSK, Kyorin Pharmaceutical, Novartis, and Sanofi; he is a scientific advisor for GSK. GGB reports personal fees for advisory board participation and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi, outside of the submitted work. DJJ has received an investigator-initiated research grant from AstraZeneca and reports fees for advisory board participation and lectures from AstraZeneca, Sanofi, and GSK. In the past 5 years, IDP has received honoraria for speaking at sponsored meetings from AstraZeneca, Aerocrine, Chiesi, Sanofi/Regeneron, Menarini, and GSK; payments for organising educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva; honoraria for advisory panel participation from Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp; and sponsorship to attend international scientific meetings from GSK, AstraZeneca, Teva, and Chiesi. SK reports consulting fees and speaker fees from AstraZeneca, GSK, Chiesi, Sanofi, and Novartis. KM reports consulting fees and speaker frees from AstraZeneca, GSK, and Sanofi; and speaker fees from Chiesi and Novartis. JCV reports research grants from DFG, Land Mecklenburg-Vorpommern, GSK, and MSD; he has given independent lectures for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Lupin, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Regeneron, Revotar, Sandoz-Hexal, Sanofi-Aventis, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila; and participated on advisory boards and provided independent advice for AstraZeneca, Avontec, Bayer, Bencard, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma. CT declares no competing interests.

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab. Methods: Spontaneous reports were used from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities ® (MedDRA ® ). Safety signal strength was assessed by the Reporting Odds Ratio (ROR). Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was 55 years (interquartile range 24-63 years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4-29.3). Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation., Competing Interests: The research group from the Department of Medical Informatics receives/received unconditional research grants from Chiesi, GlaxoSmithKline (GSK), UCB, and Amgen, Johnson and Johnson, and the European Medicines Agency, none of which relate to the content of this manuscript. GB received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Boehringer-Ingelheim, Chiesi, GSK, Merck Sharp & Dohme (MSD), Novartis, and Sanofi, none of which relate to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pera, Brusselle, Riemann, Kors, Van Mulligen, Parry, de Wilde, Rijnbeek and Verhamme.)

Background: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts., Methods: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV 1 /FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model., Results: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI., Conclusions: AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only., Competing Interests: Competing interests: LL reports consulting fees from AstraZeneca and speaking/lecture fees from Chiesi and IPSA (non-profit) outside the submitted work. CHV reports presentations at symposia and/or served on scientific advisory boards sponsored by Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, Nuvaira, MedUpdate, Sanofi and Roche outside the submitted work. AA reports grants from GSK, AstraZeneca and Menarini and speaking/lecture fees from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron outside the submitted work, and is chair of the GOLD board of directors. JAW reports grants from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Novartis, Genentech, and 37Clinical, advisory board fees from AstraZeneca, Epiendo, GSK, Gilead, Novartis, Pieris and Pulmatrix, speaker fees from AstraZeneca, GSK, Boehringer, Recipharm and Novartis, and DSMB chair for Virtus outside the submitted work, and is Editor in Chief of AJRCCM. GGB reports fees for advisory boards and/or lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Merck Sharp & Dohme, Novartis, and Sanofi Regeneron outside the submitted work. HB reports personal fees from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline for presentations at scientific meetings outside the submitted work. AL reports speaking/lecture fees from Boehringer-Ingelheim and Novartis, and participation on a advisory board for AstraZeneca, GSK, Novartis, and Boehringer-Ingelheim outside the submitted work. KFC reports advisory board fees from GSK, AstraZeneca, Roche, Novartis, Merck, Nocion, Shionogi and Rickett-Beckinson and has been renumerated for speaking engagements for GSK, AstraZeneca and Merck outside the submitted work. IMA reports investigator-led awards from GSK and Sanofi in addition to travel awards, speakers' fees and advisory board fees from AZ, Chiesi, GSK, Eurodrug, Kineset, Sanofi and Sunovion outside the submitted work. None declared (XB, AE, JG-A, RF, HM, TS, PA, NO, NZK, GCD, ER, JMV and MvdB)., (© 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.)

The management of asthma has changed fundamentally during the past two decades. Precise assessment and phenotyping are now required to establish individually targeted treatment with disease-modifying anti-asthmatic drugs (DMAADs). Patients with asthma are often managed by primary care doctors or non-respiratory specialists in secondary care. However, the implementation of complex asthma guidelines in non-specialised care remains a challenge. There is a need for easy-to-understand, concise guides for general practice. In this Viewpoint, we propose a one-page practical guide for asthma management, titled A 2 BCD, with four components: dual assessment (A 2 ) of asthma (ie, diagnosis and phenotype, plus asthma control and future risks); basic measures (B; eg, education, self-management skills, regular physical activity, and avoidance of asthma triggers); identification and treatment of comorbidities (C) of asthma (eg, chronic rhinosinusitis, obesity, or sleep apnoea); and phenotype-specific, individually targeted treatment with DMAADs (D), including individual inhalation schemes based on inhaled corticosteroids, leukotriene modifiers, biologics, and allergen immunotherapy., Competing Interests: Declaration of interests ML has received grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft, and GlaxoSmithKline. He has received consulting fees or honoraria for lectures from ALK; Allergopharma; AstraZeneca; Berlin-Chemie; Boehringer Ingelheim; Chiesi; GlaxoSmithKline; HAL Allergy; Leti; Novartis; Merck, Sharp & Dohme; Sanofi; and Teva. He has received travel expenses from AstraZeneca and Novartis. GGB has received research funding, paid to his institution, from Merck, Sharp & Dohme and fees for advisory board membership and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi. MLL has received consultancy fees from Chiesi, Clement Clarke International, Respiri (Australia), SmartRespiratory, and Teva; fees for advisory board participation from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Orion Pharmaceuticals, and Trudel Pharmaceuticals; fees from Chiesi for data safety monitoring board participation; lecture fees from AstraZeneca, Chiesi, Menarini, Novartis, Orion Pharmaceuticals, Soar Beyond, and Teva; conference sponsorship from Chiesi, Orion Pharmaceuticals, and Napp; travel expenses and accommodation support from Orion and the Global Initiative for Asthma; an educational grant from Consorzio Futuro in Ricerca for work as a member of the ADMIT group; accommodation support from NAPP and Chiesi; fees for clinical leadership and mentorship and for assessment and reporting of outcomes from the National Services for Health Improvement; and fees as lead for asthma in developing dashboards for clinical care from Whole Systems Integrated Care, North West London. GWC has received consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, HAL Allergy, Menarini, Novartis, Regeneron, Sanofi, and Stallergenes; and honoraria for lectures from AstraZeneca, Chiesi, GlaxoSmithKline, HAL Allergy Menarini, Novartis, and Stallergens. IDP has received a research grant from Chiesi. He has received consultancy fees from Almirall; AstraZeneca; Boehringer Ingelheim; Chiesi; Circassia; Dey Pharma; Genentech; GlaxoSmithKline; Knopp Biosciences; Merck; Merck, Sharp & Dohme; Napp Pharmaceuticals; Novartis; Regeneron; RespiVert; Sanofi; Schering-Plough; and Teva. He has received payments to support US Food and Drug Administration approval meetings from GlaxoSmithKline; speaker's fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi, and Teva; scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Napp Pharmaceuticals, Regeneron, Sanofi, and Teva; and payment for the organisation of educational events from AstraZeneca, GlaxoSmithKline, Regeneron, Sanofi, and Teva. MS has received research funding, paid to his institution, from ALK; and royalties for educational contributions from UpToDate. MS is Editor-in-Chief of the Journal of Allergy and Clinical Immunology: In Practice and Principal Investigator for the Vaccines and Medications in Pregnancy Surveillance System. JCV has received grants for research from Deutsche Forschungsgemeinschaft; GlaxoSmithKline; and Merck, Sharp & Dohme. He has received consulting fees from Avontec; Boehringer Ingelheim; Chiesi; Essex, Schering-Plough; GlaxoSmithKline; Janssen-Cilag; MEDA; Merck, Sharp & Dohme; Mundipharma; Novartis; Regeneron; Revotar; Roche; Sandoz-Hexal; Sanofi-Aventis; Teva; and UCB, Schwarz-Pharma. He has received honoraria for lectures from AstraZeneca; Avontec; Bayer; Bencard; Bionorica; Boehringer Ingelheim; Chiesi; Essex, Schering-Plough; GlaxoSmithKline; Janssen-Cilag; Leti; MEDA; Merck; Merck, Sharp & Dohme; Mundipharma; Novartis; Nycomed, Altana; Pfizer; Revotar; Sandoz-Hexal; Stallergens; Teva; UCB, Schwarz-Pharma; and Zydus, Cadila. He has received fees for data safety monitoring board participation from Chiesi; and travel support from Sanofi and Boehringer Ingelheim., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD., Methods: We assessed RIPK1 expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 S25D/S25D kinase-deficient mice and the RIPK1 kinase inhibitor GSK'547., Results: RIPK1 expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition., Conclusions: RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach., Competing Interests: Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The RIPK1 kinase inhibitor GSK′547 was a kind gift from A.M. Beal (GlaxoSmithKline) who approved the manuscript but was not involved in funding or designing the study. T. Maes reports grants from FWO Flanders, Chiesi and GlaxoSmithKline, and is a shareholder of Oryzon Genomics and Mendelion Lifesciences SL, outside the submitted work. G.F. Joos reports consulting fees from GlaxoSmithKline and AstraZeneca, lecture honoraria from GlaxoSmithKline, AstraZeneca, Novartis, Lapharcon and EURECA VZW, travel support from GlaxoSmithKline, and acts as chair of the operational Committee IRC (International Respiratory Coalition) for the European Respiratory Society, outside the submitted work. G.G. Brusselle reports advisory board participation and lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merch Sharp & Dohme, Novartis and Sanofi, outside the submitted work. P.M. Hansbro reports grants from the National Health and Medical Research Council (APP1138004, Defining the roles and targeting interferon-epsilon as a new therapy for influenza in asthma and COPD; and APP1179092, Development of a novel effective therapy for asthma and COPD), outside the submitted work., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: The aging population and its burden on health care systems warrant early detection of patients at risk of functional decline and mortality. We aimed to assess frailty transitions and its accuracy for mortality prediction in participants with impaired spirometry (Preserved Ratio Impaired Spirometry [PRISm] or chronic obstructive pulmonary disease [COPD])., Methods: In participants from the population-based Rotterdam Study (mean age 69.1 ± 8.9 years), we examined whether PRISm (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ≥ 70% and FEV1 < 80%) or COPD (FEV1/FVC < 70%) affected frailty transitions (progression/recovery between frailty states [robust, prefrailty, and frailty], lost to follow-up, or death) using age-, sex- and smoking state-adjusted multinomial regression models yielding odds ratios (OR). Second, we assessed the diagnostic accuracy of frailty score for predicting mortality in participants with COPD using c-statistics., Results: Compared to participants with normal spirometry, participants with PRISm were more likely to transit from robust (OR 2.2 [1.2-4.2], p < .05) or prefrailty (OR 2.6 [1.3-5.5], p < .01) toward frailty. Participants with PRISm (OR 0.4 [0.2-0.8], p < .05) and COPD (OR 0.6 [0.4-1.0], NS) were less likely to recover from their frail state, and were more likely to progress from any frailty state toward death (OR between 1.1 and 2.8, p < .01). Accuracy for predicting mortality in participants with COPD significantly improved when adding frailty score to age, sex, and smoking status (90.5 [82.3-89.8] vs 77.9 [67.2-88.6], p < .05)., Conclusion: Participants with PRISm or COPD more often developed frailty with poor reversibility. Assessing physical frailty improved risk stratification for participants with impaired spirometry for predicting increased life years., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: It is unclear whether patients with asthma benefit from stepping up to high-dose inhaled corticosteroids (ICSs)., Objective: To determine the effectiveness of stepping up to high-dose ICSs., Methods: A historic cohort study of patients with asthma (≥13 years old), identified from 2 large UK electronic medical record databases, was conducted. Patients who remained on medium-dose ICSs were compared with those who stepped up from medium- to high-dose ICSs, whereas patients who stepped up from low- to medium-dose ICSs were compared with those who stepped up from low- to high-dose ICSs. Time to first severe exacerbation (primary outcome) between treatment groups was compared using multivariable Cox proportional hazards models, and the number of exacerbations and antibiotics courses was analyzed using negative binomial regression. Inverse probability of treatment weighting was used to handle confounding., Results: The mean follow-up time to first exacerbation was 2.7 ± 2.7 years for those who remained on stable medium-dose ICSs and 2.0 ± 2.2 years for those who stepped up from medium- to high-dose ICSs. A similar pattern was noted for those who stepped up from low- to medium-dose ICSs (2.6 ± 2.5 years) and from low- to high-dose ICSs (2.3 ± 2.5 years). Patients who stepped up from medium- to high-dose ICSs (n = 6879) had a higher risk of exacerbations during follow-up compared with those who remained on medium-dose ICSs (n = 51,737; hazard ratio, 1.17; 95% CI, 1.12-1.22). This was similar in patients stepping up from low- to high-dose (n = 3232) compared with low- to medium-dose (n = 12,659) ICSs (hazard ratio, 1.10; 95% CI, 1.04-1.17). A step-up to high-dose ICSs was also associated with a higher number of asthma exacerbations and antibiotics courses. No significant difference in associations was found across subgroups of patients with different blood eosinophil counts., Conclusions: We found no evidence that a step-up to high-dose ICSs is effective in preventing future asthma exacerbations., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Two opposing B cell subsets have been defined based on their cytokine profile: IL-6 producing effector B cells (B-effs) versus IL-10 producing regulatory B cells (B-regs) that respectively positively or negatively regulate immune responses. B-regs are decreased and/or impaired in many autoimmune diseases and inflammatory conditions. Since there is increasing evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD, the aim of this study was to investigate the presence and function of B-regs in COPD., Methods: First, presence of IL-10 producing regulatory B cells in human lung tissue was determined by immunohistochemistry. Secondly, quantification of IL-10 + B-regs and IL-6 + B-effs in peripheral blood mononuclear cells (PBMCs) from healthy controls, smokers without airflow limitation, and COPD patients (GOLD stage I-IV) was performed by flow cytometry. Thirdly, we exposed blood-derived B cells from COPD patients in vitro to cigarette smoke extract (CSE) and quantified IL-10 + B-regs and IL-6 + B-effs. Furthermore, we aimed at restoring the perturbed IL10 production by blocking BAFF. Fourthly, we determined mRNA expression of transcription factors involved in IL-10 production in FACS sorted memory- and naive B cells upon exposure to medium or CSE., Results: The presence of IL-10 producing regulatory B cells in parenchyma and lymphoid follicles in lungs was confirmed by immunohistochemistry. The percentage of IL-10 + B-regs was significantly decreased in blood-derived memory B cell subsets from smokers without airflow limitation and patients with COPD, compared to never smokers. Furthermore, the capacity of B cells to produce IL-10 was reduced upon in vitro exposure to CSE and this could not be restored by BAFF-blockade. Finally, upon CSE exposure, mRNA levels of the transcription factors IRF4 and HIF-1α, were decreased in memory B cells., Conclusion: Decreased numbers and impaired function of B-regs in smokers and patients with COPD might contribute to the initiation and progression of the disease., (© 2022. The Author(s).)

Competing Interests: GGB has received payments from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Sanofi for advisory boards and lectures on asthma, COPD, interstitial lung disease, and chronic cough. MH declares payments for advisory boards or lectures on asthma or pulmonary hypertension from Acceleron, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer, Chiesi, Ferrer, GlaxoSmithKline, Janssen, Merck, MorphogenIX, Novartis, Sanofi, Shou Ti, and United Therapeutics, and grants to his institution from Acceleron, AOP Orphan, Janssen, Merck, and Shou Ti.