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Rationale: Individuals who will develop chronic obstructive pulmonary disease (COPD) could be identified at an early age before clinical manifestations appear. Objectives: We investigated risk of clinical COPD 10 years later in young adults from the general population with and without early COPD with a focus on smoking exposure. Methods: We included 14,870 individuals aged 20-100 years from the Copenhagen General Population Study with spirometry 10 years apart. Early COPD was defined as baseline FEV1/FVC less than the lower limit of normal in individuals aged <50 years. Outcomes included clinical COPD at final examination 10 years later (chronic respiratory symptoms with FEV1/FVC <0.70 and FEV1 <80% predicted) and acute exacerbation hospitalizations during follow-up. Measurements and Main Results: Among 5,497 individuals aged <50 years at baseline with FEV1/FVC ≥0.70, 104 (3%) developed clinical COPD 10 years later; 4% of smokers with ≥10 pack-years had early COPD; 3% of smokers with <10 pack-years had early COPD; and 2% of never-smokers had early COPD. Among smokers with ≥10 pack-years, 24% developed clinical COPD in those with early COPD versus 4% in those without early COPD. Corresponding numbers were 10% and 1% in smokers with <10 pack-years and 3% and <1% in never-smokers, respectively. Among individuals with early COPD, odds ratios for clinical COPD 10 years later were 7.77 (95% confidence interval [CI], 4.10-14.7) in smokers with ≥10 pack-years and 8.56 (95% CI, 4.92-14.9) in all smokers, whereas hazard ratios for acute exacerbation hospitalizations were 4.16 (95% CI, 1.66-10.5) and 4.33 (95% CI, 1.89-9.93), respectively. Results were validated in the Copenhagen City Heart Study. Conclusions: Depending on amount of smoking exposure, <24% of young adults in the general population with early COPD develop clinical COPD 10 years later. A smoking exposure threshold for early COPD should be reconsidered, as younger individuals are less represented in those with high smoking exposure. [ABSTRACT FROM AUTHOR]

Background: Vitamin D may regulate the innate immune system, and randomised controlled trials suggest a beneficial effect of vitamin D supplementation against acute respiratory tract infections. By using a Mendelian randomisation approach, we tested the hypothesis that low 25-hydroxyvitamin D is associated with increased risk of bacterial pneumonia in observational and genetic analyses.Methods: We genotyped 116 335 randomly chosen white Danes aged 20 to 100 from the Copenhagen City Heart Study and Copenhagen General Population Study for plasma 25-hydroxyvitamin D decreasing genetic variants around CYP2R1 (rs117913124, rs12794714 and rs10741657), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458) and HAL (rs3819817). Information on plasma 25-hydroxyvitamin D was available on 35 833 individuals. Individuals were followed from 1981 through 2018 for hospital diagnoses of bacterial pneumonias.Results: During up to 38 years follow-up, we observed 6342 bacterial pneumonias in observational analyses and 13 916 in genetic analyses. In observational analyses, multivariable adjusted HR for bacterial pneumonias was 1.27 (95% CI: 1.16 to 1.40) for individuals with 25-hydroxyvitamin D<25 nmol/L compared with those with ≥25 nmol/L. In genetic analyses, the OR for bacterial pneumonia per 10 nmol/L lower plasma 25-hydroxyvitamin D was 1.12 (95% CI: 1.02 to 1.23) in Wald's ratio, 1.12 (95% CI: 1.04 to 1.20) in inverse-variance weighted, 1.63 (95% CI: 0.96 to 2.78) in MR-Egger and 1.15 (95% CI: 1.05 to 1.26) in weighted median instrumental variable analysis. This association was strongest for genetic variants around CYP2R1. There was no observational or genetic evidence to support that 25-hydroxyvitamin D is associated with risk of urinary tract infections, skin infections, sepsis or gastroenteritis, which were used as negative control outcomes.Conclusions: Low vitamin D is associated observationally and genetically with increased risk of bacterial pneumonias. [ABSTRACT FROM AUTHOR]

Background: The role and impact of chronic cough in individuals with COPD have not been described in the general population. This study hypothesized that comorbid chronic cough is a marker of disease severity in individuals with COPD.Methods: This study identified individuals with COPD and chronic cough, and recorded respiratory symptoms, health-care utilizations, lung function, and inflammatory biomarkers in blood in a nested cohort of 43,271 adults from the Copenhagen General Population Study (CGPS).Results: Among 43,271 individuals from the general population, 8,181 (19%) experienced COPD, of whom 796 (10%) had chronic cough. Individuals with COPD and chronic cough had a Leicester Cough Questionnaire median (25th-75th percentiles) total score of 17.7 (16.0-18.9), corresponding to 5.9 (5.3-6.3) for the physical domain, 5.6 (4.9-6.3) for the psychological domain, and 6.3 (5.8-6.8) for the social domain. Among individuals with COPD, those with chronic cough vs those without chronic cough more often experienced sputum production (60% vs 8%), wheezing (46% vs 14%), dyspnea (66% vs 38%), chest pain/tightness (9% vs 4%), nighttime dyspnea (8% vs 3%), episodes of acute bronchitis/pneumonias in the last 10 years (45% vs 25%), and ≥ 3 general practitioner visits in the past 12 months (53% vs 37%). Furthermore, these individuals had lower FEV1 % predicted (81% vs 89%) and FEV1/FVC (0.64 vs 0.66), as well as higher levels of high-sensitivity C-reactive protein, fibrinogen, leukocytes, neutrophils, eosinophils, and IgE in blood.Conclusions: Comorbid chronic cough in individuals with COPD is associated with a more severe disease in terms of more respiratory symptoms and health-care utilizations, lower lung function, and increased inflammation in blood. [ABSTRACT FROM AUTHOR]

Rationale: Identification of younger adults at high risk of developing chronic obstructive pulmonary disease (COPD) could lead to implementation of preventive measures before disease onset and halt progression.Objectives: To investigate the prevalence, characteristics, and prognosis of individuals with early COPD in the general population.Methods: We investigated 105,630 randomly chosen adults from a Danish contemporary population-based cohort. Early COPD was defined as FEV1/FVC less than the lower limit of normal in individuals under 50 years of age with 10 pack-years or greater of tobacco consumption.Measurements and Main Results: Among 8,064 individuals under 50 years of age with 10 pack-years or greater of tobacco consumption, 1,175 (15%) had early COPD, of whom 58% were current smokers. Individuals with early COPD more often had chronic respiratory symptoms, severe lung function impairment, asthma, and a history with bronchitis/pneumonia. During the 14.4-year follow-up, we observed 117 acute hospitalizations with obstructive lung disease, 227 acute hospitalizations with pneumonia, and 185 deaths among the 8,064 younger adults. Compared with individuals without COPD, those with early COPD had multivariable adjusted hazard ratios of 6.42 (95% confidence interval, 3.39-12.2) for acute obstructive lung disease hospitalizations, 2.03 (1.43-2.88) for acute pneumonia hospitalizations, and 1.79 (1.28-2.52) for all-cause mortality.Conclusions: Among individuals under 50 years of age and 10 pack-years or greater of tobacco consumption from the general population, 15% fulfill criteria of early COPD. Individuals with early COPD more often have chronic respiratory symptoms and severe lung function impairment, and an increased risk of acute respiratory hospitalizations and early death. [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin.Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption.Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers.Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal.Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status. [ABSTRACT FROM AUTHOR]

Background: Coronary artery calcification (CAC) is commonly assessed with Agatston score (AS). A higher sensitivity and precision for the detection of CAC has been demonstrated with calibrated mass score (cMS). We hypothesized that cMS would detect low-level CAC not detectable with AS in a large asymptomatic background population.Methods: Participants (N = 2985) from the Copenhagen General Population Study were evaluated for CAC using both conventional AS and cMS. The population was grouped according to number of traditional risk factors and heart score was used to assess the risk of event for those with no CAC, those with only cMS > 0 and those with both AS and cMS > 0.Results: In participants with an AS = 0, 11% had cMS > 0. The risk profile of this cMS-only group was between that of the CAC-negative participants and those with AS > 0 and cMS > 0. Overall, 6% of the population belonged to the cMS-only group independent of the number of risk factors.Conclusion: In individuals with AS = 0, a fraction was found to have cMS > 0. Based on traditional risk factors, this group has a higher 10-year risk than individuals with both AS = 0 and cMS = 0; cMS might offer very early cardiovascular risk assessment in asymptomatic individuals.Key Points: • In individuals with AS=0, a fraction has CAC with highly sensitive cMS. • This fraction has a higher 10-year risk of cardiovascular disease. • Regardless of risk factors, 6% has CAC detectable only with cMS. • cMS might offer very early cardiovascular risk assessment in asymptomatic individuals. [ABSTRACT FROM AUTHOR]

Background: A substantial proportion of individuals with airflow limitation are never-smokers. However, whether never-smokers with airflow limitation have undiagnosed asthma is unknown. We hypothesised that the majority of never-smokers with respiratory symptoms and airflow limitation but without known asthma have undiagnosed asthma by comparing characteristics and prognosis in never-smokers with airflow limitation and asthma (NS+AFL+A) with never-smokers with airflow limitation but without asthma (NS+AFL-A).Methods: Among 94 079 participants aged 20-100 years from the general population, 39 102 (42%) were never-smokers. In this group, 13 719 (35%) reported to have respiratory symptoms of whom 1610 (12%) had airflow limitation. We investigated characteristics and risk of complications (asthma or COPD exacerbations, pneumonias and all-cause mortality) and comorbidities (lung cancer, ischaemic heart disease, myocardial infarction, deep venous thrombosis and PE) during 4.5 years median follow-up.Results: NS+AFL-A compared with NS+AFL+A reported less allergy and respiratory symptoms, and had higher FEV1 and lower levels of eosinophils and IgE in peripheral blood. NS+AFL+A had increased risk of asthma and COPD exacerbations, but not of pneumonias; adjusted HRs in NS+AFL+A compared with NS+AFL-A were 16 (95% CI 3.7 to 73) for asthma exacerbations and 15 (2.8 to 80) for COPD exacerbations. Still, NS+AFL-A had increased risk of COPD exacerbations and pneumonias, but not of asthma exacerbations; adjusted HRs in NS+AFL-A compared with never-smokers without airflow limitation or asthma (NS-AFL-A) were 7.7 (2.8 to 21) for COPD exacerbations and 1.7 (1.3 to 2.3) for pneumonias. Risk of comorbidities or all-cause mortality was not increased in NS+AFL-A or NS+AFL+A compared with NS-AFL-A.Conclusions: Majority of NS+AFL-A do not seem to have undiagnosed asthma and may instead have airflow limitation caused by other risk factors. [ABSTRACT FROM AUTHOR]

Importance: Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed.Objective: To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades.Design, Setting, and Participants: Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13,704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first.Exposures: For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared.Main Outcomes and Measures: Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality.Results: The number of deaths during follow-up was 10,624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95%CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95%CI, 9-30]), and 5580 in the 2003-2013 cohort (6%;MR, 4/1000 person-years [95%CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI associated with the lowest all-cause mortality increased by 3.3 from the 1976-1978 cohort compared with the 2003-2013 cohort. [table: see text] The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95%CI, 1.23-1.39;MR, 46/1000 person-years [95%CI, 32-66] vs 28/1000 person-years [95%CI, 18-45]) in the 1976-1978 cohort, 1.13 (95%CI, 1.04-1.22; MR, 28/1000 person-years [95%CI, 17-47] vs 15/1000 person-years [95%CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95%CI, 0.92-1.07;MR, 5/1000 person-years [95%CI, 2-12] vs 4/1000 person-years [95%CI, 1-11]) in the 2003-2013 cohort. CONCLUSIONS AND RELEVANCE Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications. [ABSTRACT FROM AUTHOR]

Rationale: Whether high blood eosinophils are associated with chronic obstructive pulmonary disease (COPD) exacerbations among individuals with COPD in the general population is largely unknown.Objectives: To test the hypothesis that high blood eosinophils predict COPD exacerbations.Methods: Among 81,668 individuals in the Copenhagen General Population Study, we examined 7,225 with COPD based on spirometry. We recorded blood eosinophils at baseline and future COPD exacerbations longitudinally, defined as moderate (short-course treatment with systemic corticosteroids) or severe (hospitalization). We also assessed exacerbation risk in a subgroup of 203 individuals with clinical COPD, defined as participants with a smoking history of at least 10 pack-years, FEV1 less than 70% of predicted value, and at least one moderate or severe exacerbation in the year before baseline.Measurements and Main Results: During a median of 3.3 years of follow-up (range, 0.03-8.1), 1,439 severe and 2,864 moderate COPD exacerbations were recorded. Among all participants with COPD, blood eosinophils above versus below 0.34 × 10(9) cells per liter had multivariable-adjusted incidence rate ratios of 1.76 (95% confidence interval, 1.56-1.99) for severe exacerbations and 1.15 (1.05-1.27) for moderate exacerbations. Corresponding values in those with clinical COPD were 3.21 (2.49-4.14) and 1.69 (1.40-2.04). In contrast, using a cutpoint of 2% for blood eosinophils, the risk of exacerbations was increased for severe exacerbations only among individuals with clinical COPD and not in individuals in the broader population.Conclusions: Among individuals with COPD in the general population, increased blood eosinophil levels above 0.34 × 10(9) cells per liter were associated with a 1.76-fold increased risk of severe exacerbations. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility.Objectives: This study compared these approaches in a direct head-to-head fashion in a contemporary population.Methods: The study used the CGPS (Copenhagen General Population Study) with 37,892 subjects aged 40 to 75 years recruited in 2003 to 2008, all free of ASCVD, diabetes, and statin use at baseline.Results: Among the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC/AHA risk-based approach, the net reclassification index for eligibility for statin therapy among 40- to 75-year-old subjects from the CGPS was -0.21 for the trial-based approach and -0.13 for the hybrid approach.Conclusions: The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach. [ABSTRACT FROM AUTHOR]

Background: Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs).Objectives: The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins.Methods: Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs).Results: During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.Conclusions: VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk. [ABSTRACT FROM AUTHOR]