Low smoking exposure and development and prognosis of COPD over four decades: A population-based cohort study.

A diagnosis of chronic obstructive pulmonary disease (COPD) is mainly considered in individuals with more than 10 pack-years of smoking. We tested the hypothesis that low smoking exposure, below the critical threshold of 10 pack-years, increases risk of COPD and leads to poor prognosis.We followed non-obstructive adult smokers from the Copenhagen City Heart Study for COPD, defined as forced expiratory volume in one second [FEV1]/forced vital capacity [FVC]<0.70 and FEV1<80% predicted, and for related clinical outcomes. First, we followed individuals for 5years according to baseline smoking for risk of developing COPD, and hereafter for up to four decades for severe exacerbations and death.In 6098 non-obstructive smokers, 1781(29%) developed COPD after 5 years follow-up; 23% in individuals with <10pack-years of smoking at baseline, 26% in those with 10-19.9pack-years, 30% in those with 20-39.9pack-years, and 39% in those with ≥40pack-years. During four decades follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10pack-years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94(95% confidence interval:1.36-2.77) in those without COPD with ≥10pack-years, 2.83(1.72-4.66) in those with COPD with <10pack-years, 4.34(2.93-6.43) in COPD with 10-19.9pack-years, 4.39(2.98-6.47) in COPD with 20-39.9pack-years, and 4.98(3.11-7.97) in COPD with ≥40pack-years. Corresponding HRs for all-cause mortality were 1.20(1.10-1.32), 1.33(1.14-1.56), 1.59(1.40-1.80),1.81(1.62-2.03), and 1.81(1.55-2.10), respectively.Low smoking exposure below the critical threshold of 10 pack-years increases risk of COPD in middle-aged adults within 5 years, and these individuals have increased risk of severe exacerbation and early death over four decades.

Housing conditions and risk of incident COPD: a Danish cohort study, 2000-2018.

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 (< 1962), not statistically significant though (IRR 0.83 (95% CI 0.68-1.03)). Likewise, the IR of COPD was 15% higher among individuals living in the densest households compared with individuals living in the least dense households, not statistically significant though (IRR 1.15 (95% CI 0.92-1.45)). This was primary seen among smokers. There was no difference in risk among individuals with different perceived indoor environments. Overall, similar patterns were seen when stratified by smoking status with exception of perceived indoor environment, where opposite patterns were seen for smokers and never smokers. CONCLUSION: Individuals living in semi-detached houses or rented homes had a higher risk of developing COPD compared to individuals living in detached or owned homes. Individuals living in cities with < 50.000 residents had a lower risk of COPD compared to individuals living in cities with ≥ 50.000 residents.

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a real-life setting: the NOVEL observational longiTudinal studY.

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 (FEV1) 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 FEV1 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).

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a study performed in a real-life setting: the NOVELTY studyBackground: Asthma and chronic obstructive pulmonary disease (COPD) have many symptoms in common. To confirm diagnosis, doctors use spirometry, a test to measure the amount of air that can be breathed out from the lungs and how fast it can be blown out. The relationship between these measurements and symptoms in asthma and COPD is not well understood.Objectives: The aim of this research is to describe the characteristics, treatment, and impact of asthma and/or COPD in patients who are receiving their usual medical care.Methods: NOVELTY is a large study of around 12,000 patients across 19 countries. This analysis of NOVELTY looked at the relationships between two spirometry measurements and the symptoms of asthma and/or COPD experienced by patients. The spirometry measurements were: - forced expiratory volume in 1 second (FEV₁) ­ the amount of air that can be blown out of the lungs in 1 second- forced vital capacity (FVC) ­ the amount of air that can be forcibly breathed out from the lungs after taking the deepest breath possibleResults: The lower the FEV₁ and FVC, the more common the symptoms of breathlessness, wheeze attacks, night-time awakening, and coughing up of phlegm or mucus. These relationships were similar for FEV₁ and FVC. Lower FEV₁ was more strongly associated with worse symptoms in COPD than in asthma.Conclusion: These findings help to improve our understanding of the relationships between spirometry measures and symptoms in patients with asthma and/or COPD.

The fibroblast hormone endotrophin is a biomarker of mortality in chronic diseases.

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PRO-C6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO-C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N=15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95% CI 1.75-2.52) for a 2-fold increase in PRO-C6, with some heterogeneity observed between the studies (I2=70%). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.

Advances in COPD imaging using CT and MRI: linkage with lung physiology and clinical outcomes.

Recent years have witnessed major advances in lung imaging in patients with COPD. These include significant refinements in images obtained by computed tomography (CT) scans together with the introduction of new techniques and software that aim for obtaining the best image whilst using the lowest possible radiation dose. Magnetic resonance imaging (MRI) has also emerged as a useful radiation-free tool in assessing structural and more importantly functional derangements in patients with well-established COPD and smokers without COPD, even before the existence of overt changes in resting physiological lung function tests. Together, CT and MRI now allow objective quantification and assessment of structural changes within the airways, lung parenchyma and pulmonary vessels. Furthermore, CT and MRI can now provide objective assessments of regional lung ventilation and perfusion, and multinuclear MRI provides further insight into gas exchange; this can help in structured decisions regarding treatment plans. These advances in chest imaging techniques have brought new insights into our understanding of disease pathophysiology and characterising different disease phenotypes. The present review discusses, in detail, the advances in lung imaging in patients with COPD and how structural and functional imaging are linked with common resting physiological tests and important clinical outcomes.

Inhaled versus systemic corticosteroids for acute exacerbations of COPD: a systematic review and meta-analysis.

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.

The many faces of COPD in real life: a longitudinal analysis of the NOVELTY cohort.

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.

Susceptible Young Adults and Development of COPD Later in Life.

RATIONALE: Chronic obstructive pulmonary disease (COPD) has its origin in early life, and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposes a pre-disease state "pre-COPD". OBJECTIVE: We tested the hypothesis that susceptible young adults identified with chronic bronchitis and subtle lung function impairment will develop COPD later in life. METHODS: We followed random non-obstructive individuals aged 20-50years from two population-based cohorts from different smoking eras, the Copenhagen General Population Study from 2003(N=5497) and Copenhagen City Heart Study from 1976-78(N=2609), for 10 and 25years for development of COPD(forced expiratory volume in one second[FEV1]/forced vital capacity[FVC]<0.70) and COPD GOLD 2-4 (additionally FEV1<80% predicted). MEASUREMENTS AND MAIN RESULTS: After 10 years follow-up, 28% developed COPD and 13% COPD GOLD 2-4 in individuals susceptible to COPD compared to 8% and 1% in those without any susceptibility to COPD. Correspondingly, after 25years, 22% versus 13% developed COPD and 20% versus 8% developed COPD GOLD 2-4. More than half of incident COPD cases developed from a susceptible state. Compared to those without susceptibility to COPD, multivariable adjusted odds ratios in those susceptible to COPD were 3.42(95% confidence interval:2.78-4.21) for COPD and 10.1(6.77-15.2) for COPD GOLD 2-4 after 10years, and 1.54(1.23-1.93) and 2.12(1.64-2.73) after 25years. The ability of a COPD risk score consisting of the susceptibility state to COPD with smoking and asthma as risk factors to predict COPD later in life was high. CONCLUSIONS: Our study suggests the existence of a pre-disease state of COPD, which can be used for early identification of susceptible individuals at risk for COPD later in life.

Predicting exacerbations in COPD in the Danish general population.

BACKGROUND: Risk of exacerbations in individuals with mild chronic obstructive pulmonary disease (COPD) in the general population is less well described than in more advanced disease. We hypothesized that in addition to history of previous exacerbation also other clinical characteristics predict future moderate exacerbations. METHODS: In 96,462 individuals in the Copenhagen General Population Study, we identified 3175 with clinical COPD defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 and FEV1 <80% predicted in symptomatic individuals without asthma. We estimated the importance of age, sex, FEV1, modified Medical Research Council (mMRC) dyspnea scale, chronic bronchitis, exacerbation history, comorbidities, cohabitation, body mass index, smoking, and blood eosinophils for the 1-year and 3-year future risk of moderate COPD exacerbations and developed a prediction tool for future exacerbations in COPD in the general population based on easily available clinical information. RESULTS: We observed 265 exacerbations in 2543 maintenance treatment naïve individuals with COPD and 197 exacerbations in 632 individuals with COPD on maintenance treatment. In the maintenance treatment naïve group, exacerbation history (hazard ratio (HR): 8.53), low FEV1 (HR: 4.82 for <30% predicted versus 50-79% predicted), and higher age (HR: 1.46 for ≥75 years versus <65 years) were significant predictors of future exacerbations. In the group on maintenance treatment, male sex and mMRC ≥2 also predicted higher risk with borderline significance. CONCLUSIONS: In addition to exacerbation history also higher age and lower FEV1 predict future exacerbation risk in COPD in the general population.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Type-2 inflammation and lung function decline in chronic airway disease in the general population.

BACKGROUND: It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population. METHODS: We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV1) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL). RESULTS: FEV1 decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p<0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p<0.0001) per 10 ppb higher FeNO. Adjusted FEV1 decline in mL/year was 18 (95% CI 17 to 20) in those with BE<300 cells/µL and FeNO<20 ppb, 22 (19-25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21-33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend<0.0001). Corresponding FEV1 declines were 24 (19-29), 33 (25-40) and 44 (31-56) in AR (0.002), 26 (14-37), 36 (12-60) and 56 (24-89) in APO (0.07), 32 (27-36), 31 (24-38) and 44 (24-65) in COPD (0.46), and 27 (21-33), 35 (26-45), and 37 (25-49) in NAL (0.10), respectively. CONCLUSIONS: Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV1 decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype.

Prevalence and clinical implications of respiratory viruses in asthma during stable disease state and acute attacks: Protocol for a meta-analysis.

INTRODUCTION: Viruses are detected in over 50% of acute asthma attacks and in a notable proportion of patients with asthma during stable disease state They are associated with worse outcomes. We will conduct a series of systematic reviews and meta-analyses to quantify the prevalence and clinical burden of various respiratory viruses in stable asthma and acute asthma attacks. In addition, we will assess the viral loads of respiratory viruses during stable and acute asthma, to explore whether viral load could differentiate attacks triggered by viruses versus those where viruses are present as "innocent bystanders". MATERIALS AND METHODS: Based on a prospectively registered protocol (PROSPERO, ID: CRD42023375108) and following standard methodology recommended by Cochrane, we will systematically search Medline/PubMed, EMBASE, the Cochrane Library and relevant conference proceedings for studies assessing the prevalence or clinical burden of respiratory viruses in asthma. Methodological rigour of the included studies will be appraised using a tool specific for prevalence studies and the Newcastle-Ottawa Scale respectively. In anticipation of significant clinical and methodological heterogeneity, we will conduct random effect meta-analyses. For evaluating the prevalence of viruses, we will perform meta-analyses of proportions using the inverse variance method, and the Freeman-Tukey transformation. We will conduct meta-regression analyses for exploring heterogeneity. CONCLUSION: We envisage that these systematic reviews and meta-analyses will quantify the prevalence and burden of respiratory viruses in stable and acute asthma and will drive future research and clinical practice.

Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population.

Background: Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality. Methods: The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up. Findings: Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality. Interpretation: The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment. Funding: Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.

Clinical trials of pneumonia management assess heterogeneous outcomes and measurement instruments.

OBJECTIVES: To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes. STUDY DESIGN AND SETTING: Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome. RESULTS: We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs. CONCLUSION: This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.

Measuring spirometry in a lung cancer screening cohort highlights possible underdiagnosis and misdiagnosis of COPD.

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 <0.70. Results: Out of 3920 LHC attendees undergoing spirometry, 17% had undiagnosed airflow obstruction with respiratory symptoms, representing potentially undiagnosed COPD. Compared to those with a primary care COPD code, this population had milder symptoms, better lung function and were more likely to be current smokers (p≤0.001 for all comparisons). Out of 836 attendees with a primary care COPD code who underwent spirometry, 19% did not have airflow obstruction, potentially representing misdiagnosed COPD, although symptom burden was high. Discussion: Spirometry offered alongside LDCT screening can potentially identify cases of undiagnosed and misdiagnosed COPD. Future research should assess the downstream impact of these findings to determine whether any meaningful changes to treatment and outcomes occur, and to assess the impact on co-delivering spirometry on other parameters of LDCT screening performance such as participation and adherence. Additionally, work is needed to better understand the aetiology of respiratory symptoms in those with misdiagnosed COPD, to ensure that this highly symptomatic group receive evidence-based interventions.

Trends in smoking-related diseases by socioeconomic position following a national smoking ban in 2007: a nationwide study in the Danish population.

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.