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Introduction COPD is underdiagnosed, and measurement of spirometry alongside low-dose computed tomography (LDCT) screening for lung cancer is one strategy to increase earlier diagnosis of this disease. Methods Ever-smokers at high risk of lung cancer were invited to the Yorkshire Lung Screening Trial for a lung health check (LHC) comprising LDCT screening, pre-bronchodilator spirometry and a smoking cessation service. In this cross-sectional study we present data on participant demographics, respiratory symptoms, lung function, emphysema on imaging and both self-reported and primary care diagnoses of COPD. Multivariable logistic regression analysis identified factors associated with possible underdiagnosis and misdiagnosis of COPD in this population, with airflow obstruction defined as forced expiratory volume in 1 s/forced vital capacity ratio

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. Methods BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1

Populations with COPD demonstrate higher survival in overweight and obese compared with normal weight; the “obesity paradox”. Relationships in less-severe COPD are unclear, as is the impact of cardiovascular risk, and few studies include individuals at extremes of obesity. We examined the relationship between body mass index (BMI; defined as underweight: 40 kg·m−2, suggesting that obesity may not remain protective at the extremes in this population.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes.

Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Multiple flow rates FeNO data two-compartment mathematical modelling can estimate NO airway wall concentration (CawNO), airway wall diffusing capacity (DawNO), alveolar concentration (CalvNO) and maximal NO flux (JawNO). To compare modelling based on linear, non linear and mixed linear and non linear analyses in COPD. FeNO was measured using the Niox analyser (Aerocrine) at flow rates: 10, 30, 50, 100 and 200ml/s in 50 COPD patients and the data applied to 4 different methods. All methods showed that current smoking reduced CawNO. JawNO data differed between methods (Table 1). All the methods showed that current smoking did not affect CalvNO or DawNO. Comparison of the methods showed that CalvNO and DawNO data were significantly different between all methods, JawNO was different for most between method comparisons, while there was agreement between all the methods for CawNO. Smoking in COPD reduces CawNO , but not CalvNO and DawNO. JawNO, CalvNO and DawNO data are model dependent parameters. CawNO findings were model independent, and hence the most robust modelled parameter.

Abstract Background More knowledge is needed on the risk of developing chronic obstructive pulmonary disease (COPD) associated with housing conditions and indoor environment based on cohort studies with a long follow-up time. Objective To examine the association between housing conditions and indoor environment and the risk of developing COPD. Methods In this cohort study, we followed 11,590 individuals aged ≥ 30 years free of COPD at baseline. Information on incident COPD and housing conditions and indoor environment was obtained from the Danish national registers and the Danish Health and Morbidity Survey year 2000. Poisson regression of incidence rates (IRs) were used to estimate incidence rate ratios (IRRs) of COPD. Results The overall IR of COPD was 8.6 per 1,000 person-years. Individuals living outside the biggest cities vs. living in the biggest cities (≥ 50,000) had a lower risk of COPD (200-4,999; IRR 0.77 (95% CI 0.65-0.90). Individuals living in semi-detached houses had a higher risk compared to individuals living in detached houses (IRR 1.29 (95% CI 1.07-1.55)). Likewise, individuals living in rented homes had a higher risk (IRR 1.47 (95% CI 1.27-1.70)) compared to individuals living in owned homes. The IR of COPD was 17% higher among individuals living in dwellings build > 1982 compared with individuals living in older dwellings (

RationaleLong-acting muscarinic antagonists (LAMAs) reduce the risk of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), usually taken once daily in the morning. However, the circadian activity of autonomic regulation suggests that the highest need for anticholinergic therapy may be in the late night/early morning. This is supported by evidence that AECOPD most often begins in the morning. Furthermore, the trough spirometry effect of LAMA is lower than the peak effect, which further argues that evening dosing may be more optimal than morning dosing. This trial aims to determine whether evening administration of LAMA reduces hospitalization-requiring AECOPD or death from all causes within 1 year as compared to morning administration of the same LAMA.MethodsRandomized controlled open-label trial. Persons aged 30 years or older with a once-daily LAMA prescription and a confirmed COPD diagnosis were recruited. Participants were randomized in a 1:1 ratio to either morning or evening LAMA administration. Complete follow-up for the primary outcome, hospitalization-requiring AECOPD, or death from all causes within 1 year was captured from the Danish National Health Register, as were patient-reported outcome assessments at 6 and 12 months.ResultsA total of 10,013 participants were randomized, and the recruitment process started on 9 March 2023. Secondary outcomes include (i) moderate COPD exacerbations; (ii) all-cause hospitalization; (iii) ICU admission; (iv) need for non-invasive ventilation; and (v) all-cause mortality, among others. All outcomes will be evaluated 12 months after recruitment.Clinical trial registration:ClinicalTrials.gov, NCT05563675.

Background: The relationships between spirometric assessment of lung function and symptoms (including exacerbations) in patients with asthma and/or chronic obstructive pulmonary disease (COPD) in a real-life setting are uncertain. Objectives: To assess the relationships between baseline post-bronchodilator (post-BD) spirometry measures of lung function and symptoms and exacerbations in patients with a physician-assigned diagnosis of asthma and/or COPD. Design: The NOVEL observational longiTudinal studY (NOVELTY) is a global, prospective, 3-year observational study. Methods: Logistic regression analysis was used to evaluate relationships. Spirometry measures were assessed as percent predicted (%pred). Symptoms were assessed at baseline, and exacerbations were assessed at baseline and Year 1. Results: A total of 11,181 patients in NOVELTY had spirometry data (asthma, n = 5903; COPD, n = 3881; asthma + COPD, n = 1397). A 10% lower post-BD %pred forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) – adjusted for age and sex – were significantly associated with dyspnea (modified Medical Research Council ⩾ grade 2), frequent breathlessness [St George’s Respiratory Questionnaire (SGRQ)], frequent wheeze attacks (SGRQ), nocturnal awakening (Respiratory Symptoms Questionnaire; ⩾1 night/week), and frequent productive cough (SGRQ). Lower post-BD %pred FEV 1 and, to a lesser extent, lower post-BD %pred FVC were significantly associated with ⩾1 physician-reported exacerbation at baseline or Year 1. This association was stronger in patients with COPD than in those with asthma. Conclusion: In a real-life setting, reduced lung function is consistently associated with symptoms in patients with asthma, COPD, or asthma + COPD. The relationship with exacerbations is stronger in COPD only than in asthma. Trail registration: clinicaltrials.gov identifier: NCT02760329 ( www.clinicaltrials.gov ).

This meta-analysis compares the efficacy and safety of inhaled versus systemic corticosteroids for COPD exacerbations. Following a pre-registered protocol, we appraised eligible randomised controlled trials (RCTs) according to Cochrane methodology, performed random-effects meta-analyses for all outcomes prioritised in the European Respiratory Society COPD core outcome set and rated the certainty of evidence as per Grading of Recommendations Assessment, Development and Evaluation methodology. We included 20 RCTs totalling 2140 participants with moderate or severe exacerbations. All trials were at high risk of methodological bias. Low-certainty evidence did not reveal significant differences between inhaled and systemic corticosteroids for treatment failure rate (relative risk 1.75, 95% CI 0.76–4.02, n=569 participants); breathlessness (mean change: standardised mean difference (SMD) −0.11, 95% CI −0.36–0.15, n=239; post-treatment scores: SMD −0.18, 95% CI −0.41–0.05, n=293); serious adverse events (relative risk 1.47, 95% CI 0.56–3.88, n=246); or any other efficacy outcomes. Moderate-certainty evidence implied a tendency for fewer adverse events with inhaled compared to systemic corticosteroids (relative risk 0.80, 95% CI 0.64–1.0, n=480). Hyperglycaemia and oral fungal infections were observed more frequently with systemic and inhaled corticosteroids, respectively. Limited available evidence suggests potential noninferiority of inhaled to systemic corticosteroids in COPD exacerbations. Appropriately designed and powered RCTs are warranted to confirm these findings.

Abstract Background National comprehensive smoke-free legislation has been found to decrease the incidence of several smoking-related diseases. In 2007, Denmark introduced a national smoking ban, which banned smoking indoor in workplaces and public places, although only partial restrictions were applied in certain settings. We examined the impact of the smoking ban on smoking-related diseases and whether this differed across socioeconomic groups. Methods Interrupted time series analyses of nationwide register data were performed using Poisson regression models to examine the differential impact of the smoking ban on monthly incidence rates of acute myocardial infarction, chronic obstructive pulmonary disease, and smoking-related cancers from 2002 to 2015. Immediate changes in incidence rates after the smoking ban and long-term changes in disease trends were estimated by comparing data from the pre- and post-ban period. Models were stratified by socioeconomic position. Results Overall, we found neither immediate changes in rates of acute myocardial infarction, chronic obstructive pulmonary disease, and smoking-related cancers following the smoking ban nor long-term post-ban changes in disease trends as compared to before the ban. Results did not differ across socioeconomic groups. A pronounced socioeconomic gradient in incidence rates was observed for all outcomes both before and after the smoking ban. Conclusion The national smoking ban was not associated with a lower incidence of smoking-related diseases in the post-ban period compared to pre-ban levels and no differences between socioeconomic groups were observed. Future tobacco control in Denmark should consider which measures most effectively target the low socioeconomic groups to decrease the current strong socioeconomic inequality in health.

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) have a high incidence of cardiovascular disease including thromboembolisms. Fibrin degradation products, like D-dimer, have been associated with death from all causes in healthy individuals and COPD patients. We aimed to determine the (i) association between D-dimer levels and all-cause mortality and time being alive and out of a hospital, (ii) possible modifying effect of anticoagulant treatment,, and (iii) distribution of D-dimer in patients with moderate to severe COPD. Methods Results of routinely measured stable phase D-dimer samples from COPD-outpatients at Copenhagen University Hospital – Herlev and Gentofte, COPD-outpatient clinic were collected using the Danish registries. These were used to examine whether COPD-patients with a D-dimer level in the upper quartile, had a higher risk of death from all causes within 365 days. Results In the unadjusted Cox proportional hazards regression we found an association between high D-dimer and all-cause mortality: Hazard ratio (HR): 2.3 (95% Confidence Interval (CI) 1.1–4.7). In the fully adjusted regression, the HR was 1.8 (CI 0.8–3.9). We did not find any interaction between D-dimer and anticoagulant or antiplatelet therapy. For the secondary outcome, proportion of days alive and out of hospital in 365 days (pDAOH), the unadjusted multiple linear regression had an association between high D-dimer level and pDAOH: -2.7% points (pp) (CI -3.9 pp - -1.5 pp), which was attenuated to -1,7pp (-2.9pp – -0.4pp) in the fully adjusted regression. Conclusions In patients with moderate to severe COPD, patients with a high level of D-dimer were more likely to die; however, the signal was not strong in the adjusted analyses and our results do not support unselected risk stratification with D-dimer in COPD-outpatients.

Background The diagnosis of COPD requires the demonstration of non-fully reversible airflow limitation by spirometry in the appropriate clinical context. Yet, there are patients with symptoms and relevant exposures suggestive of COPD with either normal spirometry (pre-COPD) or preserved ratio but impaired spirometry (PRISm). Their prevalence, clinical characteristics and associated outcomes in a real-life setting are unclear. Methods To investigate them, we studied 3183 patients diagnosed with COPD by their attending physician included in the NOVELTY study (clinicaltrials.gov identifier NCT02760329), a global, 3-year, observational, real-life cohort that included patients recruited from both primary and specialist care clinics in 18 countries. Results We found that 1) approximately a quarter of patients diagnosed with (and treated for) COPD in real life did not fulfil the spirometric diagnostic criteria recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and could be instead categorised as pre-COPD (13%) or PRISm (14%); 2) disease burden (symptoms and exacerbations) was highest in GOLD 3–4 patients (exacerbations per person-year (PPY) 0.82) and lower but similar in those in GOLD 1–2, pre-COPD and PRISm (exacerbations range 0.27–0.43 PPY); 3) lung function decline was highest in pre-COPD and GOLD 1–2, and much less pronounced in PRISm and GOLD 3-4; 4) PRISm and pre-COPD were not stable diagnostic categories and change substantially over time; and 5) all-cause mortality was highest in GOLD 3–4, lowest in pre-COPD, and intermediate and similar in GOLD 1–2 and PRISm. Conclusions Patients diagnosed COPD in a real-life clinical setting present great diversity in symptom burden, progression and survival, warranting medical attention.

Abstract In chronic obstructive pulmonary disease (COPD), comorbidities and worse functional status predict worse outcomes, but how these predictors compare with regard to different outcomes is not well studied. We thus compared the role of cardiovascular comorbidities for mortality and exacerbations. Data from baseline and up to four follow-up visits of the COSYCONET cohort were used. Cox or Poisson regression was employed to determine the relationship of predictors to mortality or mean annual exacerbation rate, respectively. Predictors comprised major comorbidities (including cardiovascular disease), lung function (forced expiratory volume in 1 s [FEV1], diffusion capacity for carbon monoxide [TLCO]) and their changes over time, baseline symptoms, exacerbations, physical activity, and cardiovascular medication. Overall, 1817 patients were included. Chronic coronary artery disease (p = 0.005), hypertension (p = 0.044) and the annual decline in TLCO (p = 0.001), but not FEV1 decline, were predictors of mortality. In contrast, the annual decline of FEV1 (p = 0.019) but not that of TLCO or cardiovascular comorbidities were linked to annual exacerbation rate. In conclusion, the presence of chronic coronary artery disease and hypertension were predictors of increased mortality in COPD, but not of increased exacerbation risk. This emphasizes the need for broad diagnostic workup in COPD, including the assessment of cardiovascular comorbidity. Clinical Trials: NCT01245933.

Abstract Adults with congenital heart disease (CHD) face increased risk of various comorbid diseases. Previous work on lung dysfunction in this population has mainly focused on restrictive lung disease, in patients with severe CHD phenotypes. We examined the association of mild CHD with chronic obstructive pulmonary disease (COPD) in the UK Biobank (UKB). Electronic health records (EHR) were used to identify 3385 CHD cases and 479,765 healthy controls in UKB, before performing a case–control analysis over a 20-year study period for a total of > 9.5 M person-years of follow-up. Our analysis showed that UKB participants with CHD are at substantially greater risk of developing COPD than healthy controls (8.7% vs 3.1% prevalence, unadjusted OR 2.98, 95% CI 2.63, 3.36, P = 1.40e−53). Slightly increased rates of smoking were observed amongst CHD cases, however the association with COPD was shown to be robust to adjustment for smoking and other factors known to modulate COPD risk within a multivariable-adjusted Cox regression framework (fully adjusted HR 2.21, 95% CI 1.97, 2.48, P = 5.5e−41). Care for adults with CHD should aim to mitigate their increased risk of COPD, possibly via increased smoking cessation support.

Background . Ambient air pollution has been associated with exacerbations of chronic obstructive pulmonary disease (COPD) and asthma; however, little is known about indoor environmental factors. Our aim was to study the association between perceived indoor environment and the long-term risk of exacerbations of COPD or asthma. Methods . We followed 2,317 individuals aged ≥16 years with COPD or asthma from the Danish Health and Morbidity Survey from 2000 to 2018. Individuals developing COPD or asthma during the study period were included at the time of incident diagnosis. Individuals were grouped according to their patterns of perceived indoor environment and followed up for exacerbations defined based on information from the Danish National Health Registers. The association between perceived indoor environment and exacerbations was examined using a generalized mixed model with the Poisson distribution of the number of exacerbations and logarithmic transformation of follow-up time as offset. Analyses were adjusted for age, sex, education, household income, smoking, calendar year, construction year, urbanization, home ownership, and resident density. Results . A total of 5,352 exacerbations were recorded in 2,317 individuals during a median of 13.9 years (interquartile range, 7.9–18.2 years). The adjusted incidence rate ratio (IRR) of exacerbations were 1.40 (95% CI 0.85–2.29 and 0.82 (95% CI 0.49–1.38) among individuals with medium and high levels om annoyances, respectively. For annoyances related to temperature and traffic the IRR was 0.88 (95% CI 0.61–1.27) and 1.39 (95% CI 0.88–2.19), respectively. Conclusion . We found no association between indoor environment assessed as annoyances at a single time-point and exacerbations of COPD and asthma.

Background As mortality from coronavirus disease 2019 (COVID-19) is strongly age-dependent, we aimed to identify population subgroups at an elevated risk for adverse outcomes from COVID-19 using age-/gender-adjusted data from European cohort studies with the aim to identify populations that could potentially benefit from booster vaccinations. Methods We performed a systematic literature review and meta-analysis to investigate the role of underlying medical conditions as prognostic factors for adverse outcomes due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including death, hospitalisation, intensive care unit (ICU) admission and mechanical ventilation within three separate settings (community, hospital and ICU). Cohort studies that reported at least age and gender-adjusted data from Europe were identified through a search of peer-reviewed articles published until 11 June 2021 in Ovid Medline and Embase. Results are presented as odds ratios with 95% confidence intervals and absolute risk differences in deaths per 1000 COVID-19 patients. Findings We included 88 cohort studies with age-/gender-adjusted data from 6 653 207 SARS-CoV-2 patients from Europe. Hospital-based mortality was associated with high and moderate certainty evidence for solid organ tumours, diabetes mellitus, renal disease, arrhythmia, ischemic heart disease, liver disease and obesity, while a higher risk, albeit with low certainty, was noted for chronic obstructive pulmonary disease and heart failure. Community-based mortality was associated with a history of heart failure, stroke, diabetes and end-stage renal disease. Evidence of high/moderate certainty revealed a strong association between hospitalisation for COVID-19 and solid organ transplant recipients, sleep apnoea, diabetes, stroke and liver disease. Interpretation The results confirmed the strong association between specific prognostic factors and mortality and hospital admission. Prioritisation of booster vaccinations and the implementation of nonpharmaceutical protective measures for these populations may contribute to a reduction in COVID-19 mortality, ICU and hospital admissions.

Patients with chronic obstructive pulmonary disease (COPD) are prone to developing arterial hypertension, and many patients are treated with the calcium channel blocker amlodipine. However, it remains unclear whether using this drug potentially affects the risk of acute severe exacerbations (AECOPD) and all-cause mortality in these patients. The data were collected from Danish national registries, containing complete information on health, prescriptions, hospital admissions, and outpatient clinic visits. The COPD patients (n = 48,488) were matched via propensity score on known predictors of the primary outcome in an active comparator design. One group was exposed to amlodipine treatment, and the other was exposed to bendroflumethiazide, since both of these drugs are considered to be the first choice for the treatment of arterial hypertension according to Danish guidelines. The use of amlodipine was associated with a reduced risk of death from all causes at the 1-year follow-up (hazard ratio 0.69, 95% confidence interval: 0.62–0.76) compared with the use of bendroflumethiazide in the matched patients. No difference in the risk of severe AECOPD was found. In the COPD patients, amlodipine use was associated with a lower risk of death from all causes compared with the use of bendroflumethiazide. Amlodipine seems to be a safe first choice for the treatment of arterial hypertension in COPD patients.

Synthetic corticosteroids are widely used due to their anti-inflammatory and immunosuppressant effects. Their use has been associated with venous thromboembolism, but it is unknown whether thromboembolism has a causal relationship with corticosteroid treatment. In a randomised, double-blind, placebo-controlled trial in normal to overweight healthy men, the effect of the corticosteroid prednisolone on haemostasis using either 50 mg prednisolone or matching placebo once daily for ten days was investigated. The primary outcome was a change from baseline in the viscoelastic measurement maximal amplitude of clot in kaolin-activated thromboelastography (TEG). Changes from baseline in other TEG measurements, D-dimer, von Willebrand factor (VWF) antigen, and ristocetin cofactor activity (RCo), antithrombin, protein C, prothrombin, fibrinogen, INR, APTT, and platelet count were secondary outcomes. Thirty-four men participated in this study. Compared to placebo, prednisolone treatment did not affect maximal amplitude of clot (difference −0.77 (95% confidence interval (CI) −2.48, 0.94) mm, p = 0.37, missing: n = 2), but it altered VWF antigen (28%, p = 0.0004), VWF:RCo (19%, p = 0.0006), prothrombin (5%, p = 0.05), protein C (31%, p < 0.0001), antithrombin (5%, p = 0.013), and fibrinogen (−15%, p = 0.004). Thus, prednisolone treatment did not alter TEG-assessed maximal amplitude of clot, despite that it affected prothrombotic markers (increased prothrombin, VWF antigen, VWF:RCo, prothrombin, and decreased fibrinogen) and increased antithrombotic markers (protein C and antithrombin).

Abstract Background Systemic corticosteroid administration for severe acute exacerbations of COPD (AECOPD) reduces the duration of hospital stays. Corticosteroid-sparing regimens have showed non-inferiority to higher accumulated dose regimens regarding re-exacerbation risk in patients with AECOPD. However, it remains unclear whether 14-day or 2–5-day regimens would result in shorter admission durations and changes in mortality risk. We explored this by analysing the number of days alive and out of hospital based on two randomised controlled trials with different corticosteroid regimens. Methods We pooled individual patient data from the two available multicentre randomised trials on corticosteroid-sparing regimens for AECOPD: the REDUCE (n = 314) and CORTICO-COP (n = 318) trials. In the 14-day regimen group, patients were older, fewer patients received pre-treatment with antibiotics and more patients received pre-treatment with systemic corticosteroids. Patients randomly allocated to the 14-day and 2–5-day regimens were compared, with adjustment for baseline differences. Results The number of days alive and out of hospital within 14 days from recruitment was higher for the 2–5 day regimen group (mean 8.4 days; 95% confidence interval [CI] 8.0–8.8) than the 14-day regimen patient group (4.2 days; 95% CI3.4–4.9; p

Abstract Background Long-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy. Methods The CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits. Results CTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group. Conclusion Short-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients. Trial registration ClinicalTrials.gov Identifier: NCT02857842 . Submitted August 2nd, 2016.

Abstract Background Advanced chronic obstructive pulmonary disease (COPD) often leads to hospitalisation and invasive aspergillosis (IA) is a serious complication. Aspergillus sensitisation may worsen symptoms in COPD. Methods We identified published papers between January 2000 and May 2019 with > 50 subjects and GOLD criteria for grade II, III or IV (FEV1/FVC 0.05). Conclusions The prevalence of COPD is much higher than previously estimated. Overall COPD mortality may be higher than estimated and IA probably contributes to many deaths. Improved rapid diagnosis of IA using culture and non-culture based techniques is required in COPD hospital admissions to reduce mortality.

Abstract Background Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as the hormone endotrophin. Endotrophin has been shown to promote fibrosis and inflammation, whereas von Willebrand factor (VWF) is a crucial part of wound healing initiation. Here, we assessed the released and activated form of VWF and endotrophin, the pro-peptide of type VI collagen, serologically to investigate their association with mortality in COPD subjects alone or in combination. Methods One thousand COPD patients with 3 years of clinical follow-up from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort were included. Serum and heparin plasma were collected at 6 months and 1 year, respectively. Competitive ELISA utilizing specific monoclonal antibodies assessed endotrophin/type VI collagen formation (PRO-C6), VWF release (VWF-N), and activated VWF (VWF-A). Biomarker levels were dichotomized into high and low as defined by receiver operating characteristic (ROC) curves based on mortality data. Kaplan-Meier analysis was used to determine hazard ratios for all-cause mortality for biomarkers alone or in combination. Results High levels of PRO-C6, VWF-A, and VWF-N have previously been shown to be individually associated with a higher risk of mortality with hazard ratios of 5.6 (95% CI 2.4–13.1), 3.7 (1.8–7.6), and 4.6 (2.2–9.6), respectively. The hazard ratios increased when combining the biomarkers: PRO-C6*VWFA 8.8 (2.8–27.7) and PRO-C6*VWFN 13.3 (5.6–32.0). Notably, PRO-C6*VWF-N increased more than 2-fold. Conclusion We demonstrated that by combining two pathological relevant aspects of COPD, tissue remodeling, and wound healing, the predictive value of biomarkers for mortality increased notably.

BackgroundSingle-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD).MethodsIn an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs.ResultsThe prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively.ConclusionsIn total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Abstract Background Identifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high risk of mortality, is plasma fibrinogen. In this study, we benchmarked two biomarkers of basement membrane remodeling, a characteristic of COPD, against plasma fibrinogen alone and as a combination. The biomarkers of basement membrane remodeling are two neoepitopes from of the alpha 3 chain of type IV collagen (COL4A3). Materials and methods COL4A3 degradation was assessed by the biomarkers C4Ma3 and tumstatin (TUM) in year 1 plasma samples in 984 COPD subjects, 95 non-smoking controls and 95 smoking controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. They were measured by competitive ELISA using monoclonal antibodies recognizing two specific MMP-generated cleavage site within COL4A3. The level of fibrinogen was previously assessed in year 1 plasma. Results In COPD subjects, plasma C4Ma3 levels were significantly correlated with plasma fibrinogen levels (0.389 (P

Background: Investigation of the natural history of chronic obstructive pulmonary disease (COPD) has led to the recognition that individuals with higher than normal lung function may have lower risk of developing COPD. We tested the hypothesis that individuals with supernormal lung function have lower risk of COPD. Methods: We followed 108,246 adults from the Copenhagen General Population Study recruited between 2003 and 2015 for clinical COPD outcomes until 2018. A subset of 16,892 attended another examination approximately 10 years later, allowing to investigate lung function decline and COPD development (forced expiratory volume in 1 se (FEV1)/forced vital capacity (FVC)upper limit of normal (ULN). Findings: At baseline, 3944(4%) had supernormal lung function, 91,938(85%) normal lung function, and 12,364(11%) had below normal lung function. Individuals with baseline supernormal versus normal lung function had higher FEV1 decline but did not differ in FEV1/FVC decline. None had COPD at 10 years in those with supernormal lung function, while 3% had in those with normal lung function. Early-life risk factors associated with COPD development and smoking exposure in different stages of life were less common in individuals with supernormal lung function. Compared to individuals with normal lung function, multivariable adjusted hazard ratios in those with supernormal lung function were 0·19(95% confidence interval:0·08–0·46) for acute obstructive lung disease hospitalisations, 0·56(0·45–0·69) for pneumonia hospitalisations, and 0·81(0·72–0·91) for all-cause mortality. Interpretation: Supernormal lung function is associated with lower risk of developing COPD. Funding: Herlev and Gentofte Hospital and Lundbeck Foundation.

Evidence to support clinical decision making must be based on safety data that have been captured, analysed and interpreted in a robust and reliable way. Randomised real-world evidence (RRWE) studies provide the opportunity to evaluate the use of medicines in patients and settings representative of routine clinical practice. However, elements that underpin the design of RRWE studies can have a significant impact upon the analysis, interpretation and implications of safety data. In this narrative review, we use data from the Salford Lung Study; two prospective, 12-month, open-label, parallel-group, phase III randomised controlled trials conducted in primary care in the UK; to highlight the importance of capturing treatment modifications when attempting to evaluate safety events according to actual treatment exposure. We demonstrate that analysing safety data by actual treatment received (i.e. accounting for the treatment modifications that occur routinely in the primary care setting) provides additional insight beyond analysing according to randomised treatment strategy only. It is therefore proposed that understanding of safety data from RRWE trials can be optimised by analysing both by randomised group and by actual treatment received.

BackgroundPeople living with HIV (PLWH) have increased systemic inflammation, and inflammation has been suggested to contribute to the pathogenesis of emphysema. We investigated whether elevated cytokine concentrations (interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), soluble CD14 (sCD14) and sCD163 were independently associated with radiographic emphysema in PLWH.MethodsWe included PLWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study without hepatitis B and C co-infection and with a plasma sample and a chest computed tomography scan available. Emphysema plus trace emphysema was defined as the percentage of low attenuation area under −950 Houndsfield Unit (%LAA-950) using a cut-off at 5%. Cytokine concentrations were measured by ELISA or Luminex immunoassays. An elevated cytokine concentration was defined as above the 75th percentile.ResultsOf 783 PLWH, 147 (18.8%) had emphysema. PLWH were predominantly male (86.0%) and 743 (94.9%) had undetectable viral replication. PLWH with emphysema had higher concentrations of TNFα (median (IQR): 8.2 (6.4-9.8) versus 7.1 (5.7-8.6) pg/ml, p

Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65–1.48), VWF-N: HR 1.56 (95% CI 1.07–2.27), and VWF-A: HR 0.78 (95% CI 0.52–1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population.

The 2019 coronavirus disease (COVID-19) pandemic is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Clinical outcomes, including mortality, are worse in males, older individuals and patients with comorbidities. COPD patients are included in shielding strategies due to their susceptibility to virus-induced exacerbations, compromised pulmonary function and high prevalence of associated comorbidities. Using evidence from basic science and cohort studies, this review addresses key questions concerning COVID-19 and COPD. First, are there mechanisms by which COPD patients are more susceptible to SARS-CoV-2 infection? Secondly, do inhaled corticosteroids offer protection against COVID-19? And, thirdly, what is the evidence regarding clinical outcomes from COVID-19 in COPD patients? This up-to-date review tackles some of the key issues which have significant impact on the long-term outlook for COPD patients in the context of COVID-19.

Randomised controlled trials (RCTs) are the gold standard for evaluating treatment efficacy in patients with obstructive lung disease. However, due to strict inclusion criteria and the conditions required for ascertaining statistical significance, the patients included typically represent as little as 5% of the general obstructive lung disease population. Thus, studies in broader patient populations are becoming increasingly important. These can be randomised effectiveness trials or observational studies providing data on real-world treatment effectiveness and safety data that complement efficacy RCTs. In this review we describe the features associated with the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) in the real-world clinical practice setting. We also discuss how RCTs and observational studies have reported opposing outcomes with several treatments and inhaler devices due to differences in study design and the variations in patients recruited by different study types. Whilst observational studies are not without weaknesses, we outline recently developed tools for defining markers of quality of observational studies. We also examine how observational studies are capable of providing valuable insights into disease mechanisms and management and how they are a vital component of research into obstructive lung disease. As we move into an era of personalised medicine, recent observational studies, such as the NOVEL observational longiTudinal studY (NOVELTY), have the capacity to provide a greater understanding of the value of a personalised healthcare approach in patients in clinical practice by focussing on standardised outcome measures of patient-reported outcomes, physician assessments, airway physiology, and blood and airway biomarkers across both primary and specialist care.

Introduction We investigated risk of coronary heart disease and heart failure in phenotypes of obstructive airway disease.Methods Among 91 692 participants in the Copenhagen General Population Study, 42 058 individuals were classified with no respiratory disease, and 11 988 individuals had different phenotypes of obstructive airways disease: asthma with early onset or late-onset, chronic obstructive pulmonary disease (COPD) with forced expiratory volume in one second (FEV1) above or below 50% of predicted value (%p) or asthma-COPD overlap (ACO).Results During a mean follow-up of 5.7 years we registered 3584 admissions for coronary heart disease and 1590 admissions for heart failure. Multivariable Cox regression analyses of time to first admission were used with a two-sided p value of 0.05 as significance level. Compared with no respiratory disease the highest risks of coronary heart disease and heart failure were observed in ACO with late-onset asthma and FEV1

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Introduction Both stable chronic obstructive pulmonary disease (COPD) and acute exacerbations represent leading causes of death, disability and healthcare expenditure. They are complex, heterogeneous and their mechanisms are poorly understood. The role of respiratory viruses has been studied extensively but is still not adequately addressed clinically. Through a rigorous evidence update, we aim to define the prevalence and clinical burden of the different respiratory viruses in stable COPD and exacerbations, and to investigate whether viral load of usual respiratory viruses could be used for diagnosis of exacerbations triggered by viruses, which are currently not diagnosed or treated aetiologically.Methods and analysis Based on a prospectively registered protocol, we will systematically review the literature using standard methods recommended by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. We will search Medline/PubMed, Excerpta Medica dataBASE (EMBASE), the Cochrane Library, the WHO’s Clinical Trials Registry and the proceedings of relevant international conferences on 2 March 2020. We will evaluate: (A) the prevalence of respiratory viruses in stable COPD and exacerbations, (B) differences in the viral loads of respiratory viruses in stable COPD vs exacerbations, to explore whether the viral load of prevalent respiratory viruses could be used as a diagnostic biomarker for exacerbations triggered by viruses and (C) the association between the presence of respiratory viruses and clinical outcomes in stable COPD and in exacerbations.Ethics and dissemination Ethics approval is not required since no primary data will be collected. Our findings will be presented in national and international scientific conferences and will be published in peer reviewed journals. Respiratory viruses currently represent a lost opportunity to improve the outcomes of both stable COPD and exacerbations. Our work aspires to ‘demystify’ the prevalence and clinical burden of viruses in stable COPD and exacerbations and to promote clinical and translational research.PROSPERO registration number CRD42019147658.

COPD and asthma prevalence is associated with socioeconomic status (or “deprivation”), yet deprivation is rarely considered in typical large-scale efficacy randomised controlled trials that recruit highly selected patient populations. In this post hoc analysis of the Salford Lung Studies in COPD and asthma (two 12-month, open-label, effectiveness randomised controlled trials conducted in UK primary care), we evaluated the impact of patient deprivation on clinical outcomes with initiating fluticasone furoate/vilanterol versus continuing usual care. Patients were categorised into deprivation quintiles based on postcode and a countrywide database of indices of deprivation, and trial outcomes by quintile were assessed. 52% of patients in the COPD study were included in the most deprived quintile, contrasting with 20% in the asthma study. Greater deprivation was associated with higher rates of primary/secondary healthcare contacts and costs. However, the treatment effect of fluticasone furoate/vilanterol versus usual care for primary (COPD: moderate/severe exacerbations; asthma: Asthma Control Test responders at week 24) and secondary/other (healthcare consumption, adherence, treatment modifications, study withdrawals, exacerbations, serious adverse events) outcomes was similar across deprivation quintiles. Our findings support the recruitment of participants from all socioeconomic strata to allow assessment of data generalisability to routine clinical practice.

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or “cure” of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006–2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required.

Abstract Background Change in forced expiratory volume in one second (FEV1) is important for defining severity of chronic obstructive pulmonary disease (COPD). Serological neoepitope markers of collagen turnover may predict rate of change in FEV1. Methods One thousand COPD subjects from the observational, multicentre, three-year ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (NCT00292552, trial registration in February 2006) were included. Matrix metalloproteinase (MMP)-generated fragments of collagen type I, and type VI (C1M and C6M) were assessed in month six serum samples. A random-coefficient model with both a random intercept and a random slope was used to test the ability of the markers to predict post-dose bronchodilator FEV1 (PD-FEV1) change over two years adjusting for sex, age, BMI, smoking, bronchodilator reversibility, prior exacerbations, emphysema and chronic bronchitis status at baseline. Results Annual change of PD-FEV1 was estimated from a linear model for the two-year study period. Serum C1M and C6M were independent predictors of lung function change (p = 0.007/0.005). Smoking, bronchodilator reversibility, plasma hsCRP and emphysema were also significant predictors. The effect estimate between annual change in PD-FEV1 per one standard deviation (1SD) increase of C1M and C6M was +10.4 mL/yr. and +8.6 mL/yr. C1M, and C6M, had a significant association with baseline FEV1. Conclusion We demonstrated that markers of tissue turnover were significantly associated with lung function change. These markers may function as prognostic biomarkers and possibly as efficacy biomarkers in clinical trials focusing on lung function change in COPD. Trial registration NCT00292552 , Retrospectively registered, trial registration in February 2006.