Real-world walking cadence in people with COPD.

Introduction: The clinical validity of real-world walking cadence in people with COPD is unsettled. Our objective was to assess the levels, variability and association with clinically relevant COPD characteristics and outcomes of real-world walking cadence. Methods: We assessed walking cadence (steps per minute during walking bouts longer than 10 s) from 7 days' accelerometer data in 593 individuals with COPD from five European countries, and clinical and functional characteristics from validated questionnaires and standardised tests. Severe exacerbations during a 12-month follow-up were recorded from patient reports and medical registries. Results: Participants were mostly male (80%) and had mean±sd age of 68±8 years, post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57±19% predicted and walked 6880±3926 steps·day-1. Mean walking cadence was 88±9 steps·min-1, followed a normal distribution and was highly stable within-person (intraclass correlation coefficient 0.92, 95% CI 0.90-0.93). After adjusting for age, sex, height and number of walking bouts in fractional polynomial or linear regressions, walking cadence was positively associated with FEV1, 6-min walk distance, physical activity (steps·day-1, time in moderate-to-vigorous physical activity, vector magnitude units, walking time, intensity during locomotion), physical activity experience and health-related quality of life and negatively associated with breathlessness and depression (all p<0.05). These associations remained after further adjustment for daily steps. In negative binomial regression adjusted for multiple confounders, walking cadence related to lower number of severe exacerbations during follow-up (incidence rate ratio 0.94 per step·min-1, 95% CI 0.91-0.99, p=0.009). Conclusions: Higher real-world walking cadence is associated with better COPD status and lower severe exacerbations risk, which makes it attractive as a future prognostic marker and clinical outcome.

Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Real-World Characteristics of Patients with Severe Asthma prior to Starting Dupilumab: The ProVENT Study.

INTRODUCTION: Dupilumab is approved for the treatment of severe type 2 (T2) asthma; however, the characteristics of patients receiving dupilumab in routine clinical practice are incompletely understood. This study describes the characteristics of patients with severe asthma before dupilumab treatment in a real-world setting. METHODS: This interim analysis of an ongoing real-life study of dupilumab assessed baseline characteristics of the first patient cohort enrolled in the ProVENT study. RESULTS: A total of 99 patients (59% females) were analyzed (17% received another biologic before dupilumab treatment and 15% were on maintenance oral corticosteroid treatment). Adult-onset asthma (>18 years) and an allergic phenotype were documented in 58% and 48% of patients, respectively. Median (interquartile range) age was 54 (40-61) years; the median number of exacerbations in the last 24 months was 1 (0-3); median fractional exhaled nitric oxide (FeNO) value was 38 (23-64) ppb; and median blood eosinophils (bEOS) count was 184 (8-505) cells/µL. According to the United Kingdom Severe Asthma Registry classification, 53% of patients had T2 intermediate asthma (bEOS ≥150 cells/µL or FeNO ≥25 ppb), 17% had T2 high asthma (bEOS ≥150 cells/µL and FeNO ≥25 ppb), and 4% had T2 low asthma (bEOS <150 cells/µL and FeNO <25 ppb). At least one GINA criterion for T2 airway inflammation was documented in 70% of patients. T2 comorbidities were observed in 64% of patients. CONCLUSIONS: This analysis suggests that patients eligible for dupilumab treatment display various clinical and biochemical characteristics rather than one clear-cut phenotype.

Characteristics of Current Smokers versus Former Smokers with COPD and Their Associations with Smoking Cessation Within 4.5 Years: Results from COSYCONET.

Background: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the "real-life" COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study. Methods: The analysis was based on data from visits 1-5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1-4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation. Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation. Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.

Investigating the prognostic value of digital mobility outcomes in patients with chronic obstructive pulmonary disease: a systematic literature review and meta-analysis.

BACKGROUND: Reduced mobility is a central feature of COPD. Assessment of mobility outcomes that can be measured digitally (digital mobility outcomes (DMOs)) in daily life such as gait speed and steps per day is increasingly possible using devices such as pedometers and accelerometers, but the predictive value of these measures remains unclear in relation to key outcomes such as hospital admission and survival. METHODS: We conducted a systematic review, nested within a larger scoping review by the MOBILISE-D consortium, addressing DMOs in a range of chronic conditions. Qualitative and quantitative analysis considering steps per day and gait speed and their association with clinical outcomes in COPD patients was performed. RESULTS: 21 studies (6076 participants) were included. Nine studies evaluated steps per day and 11 evaluated a measure reflecting gait speed in daily life. Negative associations were demonstrated between mortality risk and steps per day (per 1000 steps) (hazard ratio (HR) 0.81, 95% CI 0.75-0.88, p<0.001), gait speed (<0.80 m·s-1) (HR 3.55, 95% CI 1.72-7.36, p<0.001) and gait speed (per 1.0 m·s-1) (HR 7.55, 95% CI 1.11-51.3, p=0.04). Fewer steps per day (per 1000) and slow gait speed (<0.80 m·s-1) were also associated with increased healthcare utilisation (HR 0.80, 95% CI 0.72-0.88, p<0.001; OR 3.36, 95% CI 1.42-7.94, p=0.01, respectively). Available evidence was of low-moderate quality with few studies eligible for meta-analysis. CONCLUSION: Daily step count and gait speed are negatively associated with mortality risk and other important outcomes in people with COPD and therefore may have value as prognostic indicators in clinical trials, but the quantity and quality of evidence is limited. Larger studies with consistent methodologies are called for.

Clinical factors linked to the type of respiratory medication in COPD: results from the COSYCONET cohort.

BACKGROUND: The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations. OBJECTIVES: We used the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances. DESIGN: COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD. METHODS: Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0-4 participating in visits 1-5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication. RESULTS: A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0-4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment. CONCLUSION: Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01245933.

Estimating the Health and Economic Impact of Improved Management in Prevalent Chronic Obstructive Pulmonary Disease Populations in England, Germany, Canada, and Japan: A Modelling Study.

Introduction: COPD is a leading cause of morbidity and mortality globally. Management is complex and costly. Although international quality standards for diagnosis and management exist, opportunities remain to improve outcomes, especially in reducing avoidable hospitalisations. Objective: To estimate the potential health and economic impact of improved adherence to guideline-recommended care for prevalent, on-treatment COPD populations in four high-income settings. Methods: A disease simulation model was developed to evaluate the impact of theoretical improvements to COPD management, comparing outcomes for usual care and policy scenarios for interventions that reduce avoidable hospitalisations: 1) increased attendance (50% vs 31-38%) of early follow-up review after severe exacerbation hospitalisation; 2) increased access (30% vs 5-10%) to an integrated disease management (IDM) programme that provides guideline adherent care. Results: For cohorts of 100,000 patients, Policy 1 yielded additional life years (England: 523; Germany: 759; Canada: 1316; Japan: 512) and lifetime cost savings (-£2.89 million; -€6.58 million; -$40.08 million; -¥735.58 million). For Policy 2, additional life years (2299; 3619; 3656) and higher lifetime total costs (£38.15 million; €35.58 million; ¥1091.53 million) were estimated in England, Germany and Japan, and additional life years (4299) and cost savings (-$20.52 million) in Canada. Scenarios found that the cost impact depended on the modelled intervention effect size. Conclusion: Interventions that reduce avoidable hospitalisations are estimated to improve survival and may generate cost savings. This study provides evidence on the theoretical impact of policies to improve COPD care and highlights priority areas for further research to support evidence-based policy decisions.

Impact of Heated Tobacco Products, E-Cigarettes, and Combustible Cigarettes on Small Airways and Arterial Stiffness.

Smoking cessation is difficult but maintaining smoke-free without nicotine replacement therapy is even harder. During the last few years, several different alternative products, including heated tobacco products (HTP), have been introduced to the market. In this study, we investigated the acute effects of IQOSTM and gloTM (two HTP) consumption on small airway function and arterial stiffness in a head-to-head design, comparing them to combustible cigarettes, nicotine-free e-cigarettes and a sham smoking group. Seventeen healthy occasional smokers were included in a single-center, five-arm, crossover study. The parameters of small airway function and hemodynamics were collected at several time points before and after consumption using Mobil-O-Graph™ (I.E.M., Stolberg, Germany) and TremoFlo® c-100 (THORASYS Thoracic Medical Systems Inc., Montreal, QC, Canada). Small airway obstruction and resistance were both significantly increased after the consumption of cigarettes and substitute products. All products containing nicotine led to similar significant increases in blood pressure and arterial stiffness. Hemodynamic parameters were also increased after the consumption of e-cigarettes without nicotine, but compared to nicotine-containing products, the increase was shorter and weaker. We conclude that, although it has yet to be determined why, HTP have acute harmful effects on small airway function, possibly even exceeding the effects of combustible cigarettes. Like other nicotine-containing products, HTP leads to a nicotine-related acute increase in arterial stiffness and cardiovascular stress, similar to combustible cigarettes, which associates these products with an increased cardiovascular risk.

Laboratory and free-living gait performance in adults with COPD and healthy controls.

Background: Gait characteristics are important risk factors for falls, hospitalisations and mortality in older adults, but the impact of COPD on gait performance remains unclear. We aimed to identify differences in gait characteristics between adults with COPD and healthy age-matched controls during 1) laboratory tests that included complex movements and obstacles, 2) simulated daily-life activities (supervised) and 3) free-living daily-life activities (unsupervised). Methods: This case-control study used a multi-sensor wearable system (INDIP) to obtain seven gait characteristics for each walking bout performed by adults with mild-to-severe COPD (n=17; forced expiratory volume in 1 s 57±19% predicted) and controls (n=20) during laboratory tests, and during simulated and free-living daily-life activities. Gait characteristics were compared between adults with COPD and healthy controls for all walking bouts combined, and for shorter (≤30 s) and longer (>30 s) walking bouts separately. Results: Slower walking speed (-11 cm·s-1, 95% CI: -20 to -3) and lower cadence (-6.6 steps·min-1, 95% CI: -12.3 to -0.9) were recorded in adults with COPD compared to healthy controls during longer (>30 s) free-living walking bouts, but not during shorter (≤30 s) walking bouts in either laboratory or free-living settings. Double support duration and gait variability measures were generally comparable between the two groups. Conclusion: Gait impairment of adults with mild-to-severe COPD mainly manifests during relatively long walking bouts (>30 s) in free-living conditions. Future research should determine the underlying mechanism(s) of this impairment to facilitate the development of interventions that can improve free-living gait performance in adults with COPD.

Effects of pharmacological and non-pharmacological interventions on physical activity outcomes in COPD: a systematic review and meta-analysis.

Rationale: The effect of pharmacological and non-pharmacological interventions on physical activity (PA) outcomes is not fully elucidated in patients with COPD. The objectives of the present study were to provide estimation of treatment effects of all available interventions on PA outcomes in patients with COPD and to provide recommendations regarding the future role of PA outcomes in pharmacological trials. Materials and methods: This review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and reported in line with PRISMA. Records were identified through searches of 12 scientific databases; the most updated search was performed in January 2023. Results: 74 studies published from 2000 to 2021 were included, with a total of 8140 COPD patients. Forced expiratory volume in 1 s % predicted ranged between 31% and 74%, with a mean of 55%. Steps/day constituted the most frequently assessed PA outcome in interventional studies. Compared to usual care, PA behavioural modification interventions resulted in improvements in the mean (95% CI) steps/day when implemented alone (by 1035 (576-1493); p<0.00001) or alongside exercise training (by 679 (93-1266); p=0.02). Moreover, bronchodilator therapy yielded a favourable difference of 396 (125-668; p=0.004) steps/day, compared to placebo. Conclusions: PA behavioural modification and pharmacological interventions lead to significant improvements in steps/day, compared to control and placebo groups, respectively. Compared to bronchodilator therapy, PA behavioural modification interventions were associated with a 2-fold greater improvement in steps/day. Large-scale pharmacological studies are needed to establish an intervention-specific minimal clinically important difference for PA outcomes as well as their convergent validity to accelerate qualification as potential biomarkers and efficacy end-points for regulatory approval.

Clinical Implications of Peak Inspiratory Flow in COPD: Post Hoc Analyses of the TRONARTO Study.

Background: In patients with COPD, inhalation ability should be assessed when considering inhaler choice. To evaluate whether the soft mist inhaler (SMI) is suitable for COPD patients irrespective of inhalation ability, the TRONARTO study investigated the efficacy of dual long-acting bronchodilator therapy delivered via the Respimat® SMI on lung function in patients with COPD stratified by inhalation ability. Tiotropium/olodaterol delivered via the SMI was effective both in patients with peak inspiratory flow (PIF) <60 L/min and PIF ≥60 L/min, measured against medium-low resistance. Methods: This congress compilation summarizes post hoc analyses from the TRONARTO study presented at the annual American Thoracic Society 2022 and European Respiratory Society 2022 meetings. These analyses evaluated PIF in over 200 patients, with PIF measurements taken daily at home for 4 weeks, and in the clinic at baseline, Weeks 2 and 4. Results: Overall, 57.9% of patients had a PIF range (difference between lowest and highest PIF measurements) <20 L/min (12.4% of patients had PIF range <10 L/min). At-home PIF range decreased over the study period, suggesting that inhaler training/repeated PIF measurements may help to make patients' inspiratory effort more consistent. Some patient characteristics correlated with lower PIF (female gender, shorter stature, more severe disease, worse airflow obstruction) and lower PIF range (more severe disease). PIF measurements differed between medium-low and high-resistance settings, highlighting the importance of measuring PIF at the resistance of a patient's inhaler. PIF correlated poorly with spirometry measurements. Conclusion: As indicated in COPD management guidelines, choice of inhaler is essential to optimize pharmacologic therapies for COPD. Poor inspiratory ability should be viewed as a treatable trait that can help to inform inhaler choice. Inhaler training and consideration of PIF (if patients use a dry powder inhaler) can reduce patient-to-inhaler mismatch, with potential consequences for health status and exacerbation risk.

Patients' acceptance of outcome and experience measurements during hospitalisation for COPD exacerbations: a CICERO Clinical Research Collaboration-European Lung Foundation online patient survey.

Background: The lack of standardised outcome assessments during hospitalisation and follow-up for acute COPD exacerbations has hampered scientific progress and clinical proficiency. The objective of the present study was to evaluate patients' acceptance of selected outcome and experience measurements during hospitalisations for COPD exacerbations and follow-up. Methods: An online survey was held amongst COPD patients in France, Belgium, The Netherlands, Germany and the UK. The European Lung Foundation COPD Patient Advisory Group was involved in the conceptualisation, development and dissemination of the survey. The survey was complementary to a previously obtained expert consensus. We assessed patients' views and acceptance of selected patient-reported outcomes or experiences and corresponding measurement instruments (for dyspnoea, frequent productive cough, health status and hospitalisation experience), and of selected clinical investigations (blood draw, pulmonary function test, 6-min walk test, chest computed tomography, echocardiography). Findings: 200 patients completed the survey. All selected outcomes and experiences were deemed important, and acceptance of their methods of assessment was high. The modified Medical Research Council scale and a numerical rating scale to address dyspnoea, the COPD Assessment Test for quality of life and frequent productive cough, and the Hospital Consumer Assessment of Healthcare Providers and Systems for hospital experiences were the instruments preferred by patients. Consensus on importance of blood draw and spirometry was higher compared with the other investigations. Interpretation: The survey results endorse the use of the selected outcome and experience measurements during hospitalisations for COPD exacerbations. They can be used to optimise standardised and patient-centred care and facilitate multicentric data collection.

A Phase 2 randomised study to establish efficacy, safety and dosing of a novel oral cathepsin C inhibitor, BI 1291583, in adults with bronchiectasis: Airleaf.

New therapies are needed to prevent exacerbations, improve quality of life and slow disease progression in bronchiectasis. Inhibition of cathepsin C (CatC) activity has the potential to decrease activation of neutrophil-derived serine proteases in patients with bronchiectasis, thereby reducing airway inflammation, improving symptoms, reducing exacerbations and preventing further airway damage. Here we present the design of a phase 2 trial (Airleaf™; NCT05238675) assessing the efficacy and safety of a novel CatC inhibitor, BI 1291583, in adult patients with bronchiectasis. This multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study has a screening period of at least 6 weeks, a treatment period of 24-48 weeks and a follow-up period of 4 weeks. ∼240 adults with bronchiectasis of multiple aetiologies will be randomised to placebo once daily, or BI 1291583 1 mg once daily, 2.5 mg once daily or 5 mg once daily in a 2:1:1:2 ratio, stratified by Pseudomonas aeruginosa infection and maintenance use of macrolides. The primary efficacy objective is to evaluate the dose-response relationship for the three oral doses of BI 1291583 versus placebo on time to first pulmonary exacerbation up to Week 48 (the primary end-point). Efficacy will be assessed using exacerbations, patient-reported outcomes, measures of symptoms, sputum neutrophil elastase activity and pulmonary function testing. Safety assessment will include adverse event reporting, physical examination, monitoring of vital signs, safety laboratory parameters, 12-lead electrocardiogram, and periodontal and dermatological assessments. If efficacy and safety are demonstrated, results will support further investigation of BI 1291583 in phase 3 trials.

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Minimal clinically important difference for impulse oscillometry in adults with asthma.

BACKGROUND: Impulse oscillometry (IOS) allows an effort-independent evaluation of small airway function in asthma. Unfortunately, well-determined minimal clinically important differences (MCIDs) for IOS measures are lacking. Here, we provide MCIDs for frequently used IOS measures, namely frequency dependence of resistance (FDR) and area of reactance (AX), in patients with asthma. METHODS: We performed IOS at baseline and 1 year later in adult patients with mild-to-severe asthma (n=235). In a two-step approach, we first applied a distribution-based method to statistically determine the MCID. Next, we validated the proposed MCID according to patient-reported outcome measures (PROMs): Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire-7 (ACQ-7) and Asthma Control Test (ACT). We used multivariable analyses to investigate the proposed MCIDs as predictors for improvements in PROMs compared with the established MCID of forced expiratory volume in 1 s (FEV1). RESULTS: The proposed MCID was a decline of ≥0.06 kPa·L-1·s-1 and ≥0.65 kPa·L-1 for FDR and AX, respectively. Patients who had changes beyond the MCIDs for both FDR and AX showed greater improvements in all PROMs than those who had not. The mean improvements in PROMs were beyond the established MCIDs for ACQ-7 and AQLQ, and approximated the MCID for ACT. Multivariable analyses demonstrated the MCIDs for both FDR and AX as independent predictors for the MCIDs of all PROMs. The MCID for FDR was a stronger predictor of all PROMs than the MCID for FEV1. CONCLUSIONS: This study provides MCIDs for IOS-derived measures in adult patients with asthma and emphasises that small airway function is a distinguished end-point beyond the conventional measure of FEV1.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Impact of Chewing Bags, E-Cigarettes, and Combustible Cigarettes on Arterial Stiffness and Small Airway Function in Healthy Students.

Several substitute products are discussed as a healthier alternative to smoking, thereunder e-cigarettes and smokeless tobacco products, e.g., chewing bags, which are increasingly used in this context. We investigated the acute effects of chewing bags compared to combustible cigarettes and e-cigarettes with and without nicotine on small airways and arterial stiffness in a head-to-head design. This single-center, four-arm cross-overstudy included 20 healthy occasional smokers (25 ± 0.6 years). On four test days, participants consumed one product per day. Before, during, and after consumption, peripheral and central hemodynamic as well as arterial stiffness parameters were measured by Mobil-O-Graph™ (I.E.M., Germany). Resistance and small airway function were assessed by tremoFlo® c-100 (THORASYS Thoracic Medical Systems Inc.). The combustible cigarette and the e-cigarettes with and without nicotine significantly increased the resistance of the small airways (p < 0.05), while chewing bags had no effect. All nicotine containing products (e-cigarette with nicotine, combustible cigarette, chewing bag) as well as the e-cigarette without nicotine significantly increased parameters of hemodynamic and arterial stiffness. Changes in blood pressure and arterial stiffness were similar after smoking, vaping, and using chewing bags. We conclude that e-cigarettes and combustible cigarettes have similar acute harmful effects on small airway dysfunction. All nicotine containing products are associated with an increased cardiovascular risk compared with no product use.

Standardized airway wall thickness Pi10 from routine CT scans of COPD patients as imaging biomarker for disease severity, lung function decline, and mortality.

BACKGROUND: Chest computed tomography (CT) is increasingly used for phenotyping and monitoring of patients with COPD. The aim of this work was to evaluate the association of Pi10 as a measure of standardized airway wall thickness on CT with exacerbations, mortality, and response to triple therapy. METHODS: Patients of GOLD grades 1-4 of the COSYCONET cohort with prospective CT scans were included. Pi10 was automatically computed and analyzed for its relationship to COPD severity, comorbidities, lung function, respiratory therapy, and mortality over a 6-year period, using univariate and multivariate comparisons. RESULTS: We included n = 433 patients (61%male). Pi10 was dependent on both GOLD grades 1-4 (p = 0.009) and GOLD groups A-D (p = 0.008); it was particularly elevated in group D, and ROC analysis yielded a cut-off of 0.26 cm. Higher Pi10 was associated to lower FEV1 % predicted and higher RV/TLC, moreover the annual changes of lung function parameters (p < 0.05), as well as to an airway-dominated phenotype and a history of myocardial infarction (p = 0.001). These associations were confirmed in multivariate analyses. Pi10 was lower in patients receiving triple therapy, in particular in patients of GOLD groups C and D. Pi10 was also a significant predictor for mortality (p = 0.006), even after including multiple other predictors. CONCLUSION: In summary, Pi10 was found to be predictive for the course of the disease in COPD, in particular mortality. The fact that Pi10 was lower in patients with severe COPD receiving triple therapy might hint toward additional effects of this functional therapy on airway remodeling. REGISTRATION: ClinicalTrials.gov, Identifier: NCT01245933.

[What have we learned from the German COPD cohort COSYCONET and where do we go from here?] / Was haben wir aus der deutschen COPD-Kohorte COSYCONET gelernt und wie geht es weiter?

COSYCONET 1 is the only German COPD cohort which is large enough to be internationally comparable. The recruitment, which started in 2010 and ended in December 2013, comprised 2741 patients with the diagnosis of COPD who were subsequently investigated in regular follow-up visits. All visits included a comprehensive functional and clinical characterisation. On the basis of this detailed data set, it was possible to address a large number of clinical questions. These questions ranged from the prescription of medication, the detailed analysis of comorbidities, in particular cardiovascular disease, and biomarker assessment to radiological and health-economic aspects. Currently, more than 60 publications of COSYCONET data are internationally available. The present overview provides a description of all the results that were obtained, focussing on the relationship between different clinical and functional aspects as well as their potential practical consequences. In addition, information on the follow-up study COSYCONET 2 is given.

Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial.

BACKGROUND: Selective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength in patients with chronic obstructive pulmonary disease (COPD) and impaired physical function. METHODS: 47 postmenopausal women and 50 men with COPD (forced expiratory volume in 1 s 30%-65% predicted; short physical performance battery score: 3-11) were enrolled into a randomised double-blind, placebo control trial. Patients were randomised 1:1 to once daily placebo or oral GSK2881078 (females: 1.0 mg; males: 2.0 mg) for 13 weeks with a concurrent home-exercise programme, involving strength training and physical activity. Primary endpoints were change from baseline in leg strength at 90 days (one-repetition maximum; absolute (kg) and relative (% change)) and multiple safety outcomes. Secondary endpoints included lean body mass, physical function and patient-reported outcomes. RESULTS: GSK2881078 increased leg strength in men. The difference in adjusted mean change from baseline and adjusted mean percentage change from baseline between treatment and placebo were: for women, 8.0 kg (90% CI -2.5 to 18.4) and 5.2% (90% CI -4.7 to 15.0), respectively; for men, 11.8 kg (90% CI -0.5 to 24.0) and 7.0% (90% CI 0.5 to 13.6), respectively. Lean body mass increased, but no changes in patient-reported outcomes were observed. Reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings. CONCLUSIONS: GSK2881078 was well tolerated and short-term treatment increased leg strength, when expressed as per cent predicted, in men with COPD more than physical training alone. TRIAL REGISTRATION NUMBER: NCT03359473.