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Background: Novel biomarkers and targeted treatments are needed for patients with chronic obstructive pulmonary disease (COPD)., Objective: To test the hypothesis that high plasma immunoglobulin (Ig)E concentrations associate with increased risk of exacerbation and mortality in individuals with COPD in the general population., Methods: Among 46,598 adults in the Copenhagen General Population Study, we included 1559 with COPD, defined as forced expiratory volume in 1 second/forced vital capacity < 0.70 and forced expiratory volume in 1 second < 80% predicted in individuals aged ≥ 40 years with chronic respiratory symptoms and smoking exposure ≥ 10 pack-years, and without asthma. We assessed risk of future severe exacerbation and all-cause mortality according to baseline plasma IgE ≥ 76 IU/mL, a clinical cutoff for omalizumab treatment in severe asthma., Results: During 14 years of follow-up (median, 6.9; interquartile range, 3.4), we recorded 224 severe exacerbations and 434 deaths in 1559 individuals with COPD. Individuals with COPD with IgE ≥ 76 IU/mL vs those with < 76 IU/mL had a multivariable adjusted hazard ratio (HR) of 1.43 (95% confidence interval, 1.07-1.89) for severe exacerbation and 1.30 (1.05-1.62) for all-cause mortality. Compared with individuals with IgE < 76 IU/mL and blood eosinophils < 300 cells/µL, the multivariable adjusted HR for severe exacerbation was 1.12 (0.76-1.67) for those with IgE < 76 IU/mL and blood eosinophils ≥ 300 cells/µL, 1.62 (1.17-2.24) for IgE ≥ 76 IU/mL and blood eosinophils < 300 cells/µL, and 1.06 (0.63-1.77) for those with IgE ≥ 76 IU/mL and blood eosinophils ≥ 300 cells/µL. Corresponding HRs for all-cause mortality were 1.27 (0.99-1.63), 1.47 (1.14-1.88), and 1.17 (0.83-1.64), respectively., Conclusion: High plasma IgE was associated with an increased risk of severe exacerbation and all-cause mortality in individuals with COPD in the general population, independent of blood eosinophils., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Differences in previous exacerbation history may influence prognosis of chronic obstructive pulmonary disease (COPD). We hypothesized that prognosis differs between individuals with a history of only medically treated exacerbations (moderate exacerbations) and those with a history of hospitalised exacerbations (severe exacerbations)., Methods: We included 98 614 adults from the Copenhagen General Population Study and assessed risk of moderate and severe exacerbations, pneumonia hospitalisation, and respiratory and all-cause mortality from 2003 until 2013 according to exacerbation history., Results: Among 6545 individuals with COPD, 6290 had no exacerbations in the preceding year, 109 had one moderate exacerbation, 108 had two or more moderate exacerbations, and 38 had one or more severe exacerbations. During 9.4 years of follow-up, we observed 926 moderate and 244 severe exacerbations, 477 pneumonias, and 707 deaths, including 69 from respiratory disease. Compared to individuals without previous exacerbations, lung function and symptom adjusted hazard ratios (HRs) for future moderate exacerbation were 4.68 (95% confidence interval:3.31-6.62) for individuals with one previous moderate exacerbation, 21 (13-33) for individuals with two or more previous moderate exacerbations, and 5.30 (3.44-8.15) for individuals with one or more previous severe exacerbations. Corresponding HRs were 1.62(0.78-3.34), 1.29(0.57-2.89), and 5.43 (2.56-12) for severe exacerbation, 1.86(1.06-3.27), 1.74(1.01-2.99), and 4.85 (2.94-8.02) for pneumonia, 0.53(0.10-2.99), 1.65(0.53-5.17), and 2.98 (1.14-7.83) for respiratory mortality, and 1.34(0.79-2.29), 1.57(1.00-2.47), and 1.49 (0.85-2.62) for all-cause mortality, respectively., Conclusion: Individuals with COPD and a history of hospitalised exacerbations carried the poorest prognosis compared to those with a history of only medically treated exacerbations, suggesting difference in risk profile., (Copyright © 2019. Published by Elsevier Ltd.)

We investigated whether the combination of increased exhaled nitric oxide fraction ( F eNO ) level and blood eosinophil count had an additive value in chronic airway disease in the general population.We included 4677 individuals aged 20-100 years from the Copenhagen General Population Study. Based on pre- and post-bronchodilator spirometry, self-reported asthma and smoking history, participants were subdivided into healthy never-smokers (n=1649), healthy ever-smokers (n=1581), asthma (n=449), chronic obstructive pulmonary disease (COPD) (n=404), asthma-COPD overlap (ACO) (n=138) and nonspecific airflow limitation (n=456).Compared to individuals with F  cells·L eNO <25 ppb and blood eosinophils <0.3×10 9  cells·L -1  cells·L F eNO ≥25 ppb or blood eosinophils ≥0.3×10 9  cells·L -1 and 2.14 (1.47-3.10) for individuals with F eNO ≥25 ppb and blood eosinophils ≥0.3×10 9  cells·L -1 Corresponding odds ratios were 1.13 (0.91-1.41) and 1.83 (1.20-2.79) for sputum production, 1.54 (1.22-1.94) and 3.26 (2.16-4.94) for asthma, 1.03 (0.80-1.32) and 0.67 (0.36-1.27) for COPD and 1.32 (0.88-1.96) and 2.14 (1.05-4.36) for ACO. Among individuals reporting respiratory symptoms, predicting the type of chronic airway disease did not differ between the two biomarkers and did not improve by combining them.Combination of F eNO and blood eosinophils may have an additive value in characterising chronic airway disease in the general population but still needs to be investigated further with regard to clinical application., Competing Interests: Conflict of interest: Y. Çolak reports personal fees from Boehringer Ingelheim and AstraZeneca outside the submitted work. Conflict of interest: P. Lange reports grants from AstraZeneca and GlaxoSmithKline, and personal fees from Boehringer Ingelheim, AstraZeneca, Novartis and GlaxoSmithKline, outside the submitted work., (Copyright ©ERS 2018.)

Aim: We hypothesized that medically treated exacerbations in COPD defined as treatments with oral corticosteroids alone or in combination with antibiotics by register linkage with a nationwide prescription registry is a valid, robust and low-biased measure of exacerbations., Methods: A total of 13,591 individuals with COPD in the Copenhagen General Population Study (2003-2013) were linked to the Danish prescription registry. Exacerbations were defined as dispensing of oral corticosteroids alone or in combination with antibiotics, dispensed less than four weeks apart during three years of follow-up. Construct validity of this definition of medically treated exacerbations was assessed by studying baseline determinants as well as by studying the association between GOLD 1 through 4 grades and time to first exacerbation during follow-up., Results: Among individuals with COPD, 964 individuals (7.1%) had at least one exacerbation during follow-up. At baseline, comparing those with versus without exacerbations during follow-up, FEV1, 72% of predicted vs. 85% (p < 0.001), previous exacerbations, 43% vs. 11% (p < 0.001), breathlessness, 33% vs. 14% (p < 0.001), and use of inhaled medications, 54% vs. 14% (p < 0.001) were associated with exacerbations. Compared to individuals with GOLD 1, the multivariable hazard ratio (HR) for exacerbations was HR = 17.4 (12.3-24.5, p < 0.001) for GOLD 4, HR = 4.8 (3.9-5.9, p < 0.001) for GOLD 3, and HR = 2.0 (1.7-2.3, p < 0.001) for GOLD 2. In sensitivity analyses, our definition of exacerbations was robust and without major biases., Conclusions: Compared to individuals with GOLD 1, the risk of exacerbations was 17-fold for GOLD 4, 5-fold for GOLD 3, and 2-fold for GOLD 2. Medically treated exacerbations defined by register linkage seem a valid, robust, and low-biased measure of exacerbations in COPD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: We tested the hypotheses that fibrinogen and α1-antitrypsin are observationally and genetically associated with exacerbations in COPD., Methods: We studied 13,591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455 (rs1800790, G>A) and FGB -448 (rs4220, G>A) and had plasma fibrinogen measured. Furthermore, 13,405 individuals were genotyped for the SERPINA1 S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma α1-antitrypsin. Exacerbations were defined as hospital admissions or treatments with systemic corticosteroids. We studied observational associations between plasma measurements and exacerbations in Cox regression analyses, associations between genotypes and exacerbations in logistic regression analyses and associations between genetically determined plasma levels and exacerbations in instrumental variable analyses., Results: Elevated fibrinogen and α1-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p<0.001) and 1.18 (1.11 to 1.25, p<0.001), respectively, per SD increase. Presence of the Z-allele was associated with increased odds of exacerbations, OR=1.25 (1.05 to 1.48, p=0.01), as was α1-antitrypsin level genetically lowered by the Z-allele, OR=1.07 (1.02 to 1.13, p=0.004), per SD decrease. Fibrinogen elevating genotypes, FGB -455 (AA) and FGB -448 (AA), were not associated with exacerbations, OR=0.96 (0.73 to 1.25, p=0.77) and OR=1.01 (0.75 to 1.33, p=0.90), respectively, and neither was genetically elevated fibrinogen level, OR=1.11 (0.76 to 1.63, p=0.58) per SD increase., Conclusions: Fibrinogen and α1-antitrypsin were observationally associated with increased risk of exacerbations. However, genetically, fibrinogen per se was not associated with exacerbations, while lowered α1-antitrypsin was associated with increased odds of exacerbations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Objective: We tested the hypothesis that gastro-esophageal reflux disease is a risk factor for exacerbations in individuals with chronic obstructive pulmonary disease (COPD)., Methods: Among 9622 participants in the Copenhagen City Heart Study, we identified 1259 individuals with COPD and information on gastro-esophageal reflux disease and the regular use of acid inhibitory treatment. These individuals were followed for 5 years with regard to medically treated COPD exacerbations, which we defined as a short course treatment with oral corticosteroids alone or in combination with antibiotics. We applied a multivariable Cox regression analysis with adjustment for well-established risk factors associated with COPD exacerbations or gastro-esophageal reflux disease, including COPD severity, and symptoms., Results: Individuals with COPD and gastro-esophageal reflux disease had more chronic bronchitis (31 vs 21%, P = 0.004), more breathlessness (39 vs 22%, P < 0.001), and more of them had a history of respiratory infections (6.8 vs 1.4%, P < 0.001) than individuals with COPD but without gastro-esophageal reflux disease. Among individuals with COPD and gastro-esophageal reflux disease, those who did not use acid inhibitory treatment regularly had an increased risk of COPD exacerbations during follow-up, hazards ratio (HR): HR = 2.7 (1.3-5.4, P = 0.006). Individuals with gastro-esophageal reflux disease, using acid inhibitory treatment regularly did not have an increased risk of exacerbations, HR = 1.2 (0.6-2.7, P = 0.63)., Conclusions: Gastro-esophageal reflux disease was associated with an increased risk of medically treated exacerbations of COPD, but only in those individuals who did not use acid inhibitory treatment regularly., (© 2014 Asian Pacific Society of Respirology.)

Background: We tested the hypothesis that statin use in individuals with COPD is associated with a reduced risk of exacerbations., Methods: We identified 5794 individuals with COPD and a measurement of C reactive protein (CRP) in the Copenhagen General Population Study (2003-2008). During 3 years of follow-up we recorded exacerbations with hospital admissions or oral corticosteroid treatment. In a nested case-control design, matching on age, gender, smoking, COPD severity and comorbidity, we estimated the association between statin use and exacerbations. In addition, we examined the association between statin use and high CRP (>3 mg/L), and the association between high CRP and exacerbations during follow-up., Results: Statin use was associated with reduced odds of exacerbations in crude analysis, OR=0.68 (95% CI 0.51 to 0.91, p=0.01), as well as in multivariable conditional logistic regression analysis, OR=0.67 (0.48 to 0.92, p=0.01). However, in the subgroup with the most severe COPD and without cardiovascular comorbidity, we observed a null association between statin use and exacerbations, OR=1.1 (0.5 to 2.1, p=0.83). Furthermore, statin use was associated with reduced odds of a high CRP, OR=0.69 (0.56 to 0.85, p<0.001), and a high CRP was associated with an increased risk of exacerbations, HR=1.62 (1.35 to 1.94, p<0.001). We estimated the percentage of excess risk of the association of statin use with exacerbations possibly mediated through a reduction of CRP to be 14% (4-51%)., Conclusions: Statin use was associated with reduced odds of exacerbations in individuals with COPD from the general population, although this was not apparent in those with the most severe COPD without cardiovascular comorbidity. Statins may thus only associate with reduced risk of exacerbations in patients with COPD with coexisting cardiovascular disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: We tested the hypothesis that use of and adherence to maintenance medication is low among individuals in the general population who have chronic obstructive pulmonary disease (COPD) , even in cases of severe and very severe COPD., Design and Participants: We identified 5,812 individuals with COPD from the Copenhagen General Population Study, and classified them according to the Global Initiative for Obstructive Lung Disease (GOLD) airflow limitation grades 1-4. Dispensing of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, long-acting anti-cholinergics, or long-acting beta2-agonists was identified in a nationwide registry. Use of medication was defined as medication dispensed during a one-year period , and adherence was calculated from dosages available in one year., Key Results: Use of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists varied from 2 % to 61 % (p < 0.001, test for trend), long-acting anti-cholinergics varied from 0.4 % to 36 % (p < 0.001), and long-acting beta2-agonists varied from 0.3 % to 11 % (p < 0.001. Among utilizers of these medications, adherence varied from 29 % to 56 % (p < 0.001, test for trend) across GOLD 1-4 for fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, from 51 % to 68 % (p = 0.11) for long-acting anti-cholinergics, and from 25 to 62 % (p = 0.01) for long-acting beta2-agonists., Conclusions: Use of and adherence to maintenance medication for COPD in the general population was associated with the severity of COPD as defined by GOLD, but even in severe and very severe COPD, use and adherence was low.

Little is known about changes in physical activity in subjects with chronic obstructive pulmonary disease (COPD) and its impact on mortality. Therefore, we aimed to study changes in physical activity in subjects with and without COPD and the impact of physical activity on mortality risk. Subjects from the Copenhagen City Heart Study with at least two consecutive examinations were selected. Each examination included a self-administered questionnaire and clinical examination. 1270 COPD subjects and 8734 subjects without COPD (forced expiratory volume in 1 s 67±18 and 91±15% predicted, respectively) were included. COPD subjects with moderate or high baseline physical activity who reported low physical activity level at follow-up had the highest hazard ratios of mortality (1.73 and 2.35, respectively; both p<0.001). In COPD subjects with low baseline physical activity, no differences were found in survival between unchanged or increased physical activity at follow-up. In addition, subjects without COPD with low physical activity at follow-up had the highest hazard ratio of mortality, irrespective of baseline physical activity level (p≤0.05). A decline to low physical activity at follow-up was associated with an increased mortality risk in subjects with and without COPD. These observational data suggest that it is important to assess and encourage physical activity in the earliest stages of COPD in order to maintain a physical activity level that is as high as possible, as this is associated with better prognosis., (©ERS 2014.)

Background: We wished to characterize undertreatment in COPD., Methods: Among 5,812 individuals with COPD defined by FEV1/FVC &lt; 0.7 participating in the Copenhagen General Population Study, we identified 920 individuals with FEV1 &lt; 60% predicted. Prescriptions were identified in an all-inclusive nationwide registry. For each individual, we examined treatment with medication in the year before the day of the baseline examination, as well as treatment in the first year after the examination. Multivariable logistic regression analyses were applied in individuals with FEV1 &lt; 60% predicted to identify predictors of treatment in the first year after baseline., Results: Only 30% of individuals with COPD and FEV1 &lt; 60% predicted were treated with medication in the year before the examination, whereas 42.2% were treated with medication in the first year after. Reporting six to 10 previous respiratory infections during the preceding 10 years that required consulting a doctor and/or staying home from work was the strongest predictor of treatment with medication (OR, 7.9; 95% CI, 3.5-19.8; P &lt; .001). Breathlessness, low FEV1, previous admissions with a discharge diagnosis of COPD, and former smoking were also predictors of treatment with medication, whereas comorbidity predicted lack of treatment. In subgroup analysis, among individuals with FEV1 &lt; 50% predicted, visits to the general practitioner and age were additional predictors of treatment, whereas male sex and being a widow/widower predicted lack of treatment., Conclusions: In this study, we observed important characteristics of a major undertreatment in individuals with COPD in the general population. Previous reported respiratory infections were the strongest predictors of treatment with medications, which indicates that most COPD treatment is initiated because of acute exacerbations.

The clinical significance of high heart rate in chronic obstructive pulmonary disease (COPD) is unexplored. We investigated the association between resting heart rate, pulmonary function, and prognosis in subjects with COPD. 16 696 subjects aged ≥40 years from the Copenhagen City Heart Study, a prospective study of the general population, were followed for 35.3 years, 10 986 deaths occurred. Analyses were performed using time-dependent Cox-models and net reclassification index (NRI). Resting heart rate increased with severity of COPD (p<0.001). Resting heart rate was associated with both cardiovascular and all-cause mortality across all stages of COPD (p<0.001). Within each stage of COPD, resting heart rate improved prediction of median life expectancy; the difference between <65 bpm and >85 bpm was 5.5 years without COPD, 9.8 years in mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), 6.7 years in moderate (GOLD stage II) and 5.9 years in severe/very severe COPD (GOLD stage III/IV), (p<0.001). Resting heart rate significantly improved risk prediction when added to GOLD stage (categorical NRI 4.9%, p = 0.01; category less NRI 23.0%, p<0.0001) or forced expiratory volume in 1 s % predicted (categorical NRI 7.8%, p = 0.002; category less NRI 24.1%, p<0.0001). Resting heart rate increases with severity of COPD. Resting heart rate is a readily available clinical variable that improves risk prediction in patients with COPD above and beyond that of pulmonary function alone. Resting heart rate may be a potential target for intervention in COPD.

Lung function level and decline are each predictive of morbidity and mortality. Evaluation of the combined effect of these measurements may help further identify high-risk groups. Using Copenhagen City Heart Study longitudinal spirometry data (n = 10,457), 16-21 year risks of chronic obstructive pulmonary disease (COPD) morbidity, COPD or coronary heart disease mortality, and all-cause mortality were estimated from combined effects of level and decline in forced expiratory volume in one second (FEV(1)). Risks were evaluated using Cox proportional hazards models for individuals grouped by combinations of baseline predicted FEV(1) and quartiles of slope. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated using stratified analysis by gender, smoking status, and baseline age (≤45 and >45). For COPD morbidity, quartiles of increasing FEV(1) decline increased HRs (95 % CI) for individuals with FEV(1) at or above the lower limit of normal (LLN) but below 100 % predicted, reaching 5.11 (2.58-10.13) for males, 11.63 (4.75-28.46) for females, and 3.09 (0.88-10.86) for never smokers in the quartile of steepest decline. Significant increasing trends were also observed for mortality and in individuals with a baseline age ≤45. Groups with 'normal' lung function (FEV(1) at or above the LLN) but excessive declines (fourth quartile of FEV(1) slope) had significantly increased mortality risks, including never smokers and individuals with a baseline age ≤45.

Background: In workplace respiratory disease prevention, a thorough understanding is needed of the relative contributions of lung function loss and respiratory symptoms in predicting adverse health outcomes., Methods: Copenhagen City Heart Study respiratory data collected at 4 examinations (1976-2003) and morbidity and mortality data were used to investigate these relationships. With 15 or more years of follow-up for a hospital diagnosis of chronic obstructive pulmonary disease (COPD) morbidity, COPD or coronary heart disease (CHD) mortality, and all-cause mortality, risks for these outcomes were estimated in relation to asthma, chronic bronchitis, shortness of breath, and lung function level at examination 2 (1981-1983) or lung function decline established from examinations 1 (1976-1978) to 2 using 4 measures (FEV(1) slope, FEV(1) relative slope, American College of Occupational and Environmental Medicine's Longitudinal Normal Limit [LNL], or a limit of 90 milliliters per year [ml/yr]). These risks were estimated by hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, height-adjusted baseline forced expiratory volume in 1 second (FEV(1)/height(2)), and height., Results: For COPD morbidity, the increasing trend in the HR (95% CI) by quartiles of the FEV(1) slope reached a maximum of 3.77 (2.76-5.15) for males, 6.12 (4.63-8.10) for females, and 4.14 (1.57-10.90) for never-smokers. Significant increasing trends were also observed for mortality, with females at higher risk., Conclusion: Lung function decline was associated with increased risk of COPD morbidity and mortality emphasizing the need to monitor lung function change over time in at-risk occupational populations.