Chronic cough associated with COPD exacerbation, pneumonia and death in the general population.

Background: Chronic cough affects up to 10% of the general population and was previously perceived as a comorbidity of underlying conditions, but is nowadays classified as a disease in its own entity that could confer increased risk of morbidity and mortality. We tested the hypothesis that chronic cough is associated with increased risk of COPD exacerbation, pneumonia and all-cause mortality in the general population. Methods: We identified 2801 individuals with chronic cough, defined as cough lasting >8 weeks, among 44 756 randomly selected individuals from the Copenhagen General Population Study, and recorded COPD exacerbations, pneumonia and all-cause mortality during follow-up. Results: During up to 5.9 years of follow-up (median 3.4 years), 173 individuals experienced COPD exacerbation, 767 experienced pneumonia and 894 individuals died. Individuals with chronic cough versus those without had cumulative incidences at age 80 years of 12% versus 3% for COPD exacerbation, 30% versus 15% for pneumonia, and 25% versus 13% for death from all causes. After adjustment for age, sex and smoking, individuals with chronic cough versus those without had adjusted hazard ratios of 4.6 (95% CI 2.9-7.2) for COPD exacerbation, 2.2 (1.7-2.7) for pneumonia and 1.7 (1.4-2.0) for all-cause mortality. Among current smokers aged >60 years with airflow limitation, those with versus without chronic cough had an absolute 5-year risk of 10% versus 4% for COPD exacerbation, 16% versus 8% for pneumonia and 19% versus 12% for all-cause mortality. Conclusion: Chronic cough is associated with higher risks of COPD exacerbation, pneumonia and death, independent of airflow limitation and smoking.

Venous thromboembolism associated with severe dyspnoea and asthma in 102 792 adults.

Background: The most recent guideline on acute pulmonary embolism (PE) indicates possible long-term sequelae such as dyspnoea and chronic thromboembolic pulmonary hypertension after a PE event. However, effects on lung function or asthma risk have not been evaluated in the general population. Methods: We tested whether individuals with a venous thromboembolism (VTE) encompassing PE and deep vein thrombosis (DVT) have reduced lung function, or greater risks of dyspnoea and asthma using data from 102 792 adults from the Copenhagen General Population Study. Diagnoses of PE, DVT and asthma were collected from the national Danish Patient Registry. Factor V Leiden and prothrombin G20210A gene variants were determined using TaqMan assays. Results: Prevalences of PE, DVT and VTE were 2.2%, 3.6% and 5.2%, respectively. Individuals with VTE had forced expiratory volume in 1 s of 92% predicted compared with 96% pred in individuals without VTE (p<0.001). Individuals with VTE versus those without had adjusted OR (95% CI) for light, moderate and severe dyspnoea of 1.4 (1.2-1.6), 1.6 (1.4-1.8) and 1.7 (1.5-1.9), respectively. Individuals with VTE versus those without had an adjusted OR for asthma of 1.6 (95% CI 1.4-1.8). Factor V Leiden and prothrombin G20210A genotype also associated with increased risk of asthma (p for trend=0.002). Population-attributable fractions of severe dyspnoea and asthma due to VTE were 3.5% and 3.0%, respectively, in the population. Conclusion: Individuals with VTE have worse lung function and higher risks of severe dyspnoea and asthma, and may account for 3.5% and 3.0% of people with severe dyspnoea and asthma, respectively, in the general population.

α1-Antitrypsin deficiency associated with increased risk of heart failure.

Background: Individuals with α1-antitrypsin deficiency have increased elastase activity resulting in continuous degradation of elastin and early onset of COPD. Increased elastase activity may also affect elastic properties of the heart, which may impact risk of heart failure. We tested the hypothesis that α1-antitrypsin deficiency is associated with increased risk of heart failure in two large populations. Methods: In a nationwide nested study of 2209 patients with α1-antitrypsin deficiency and 21 869 controls without α1-antitrypsin deficiency matched on age, sex and municipality, we recorded admissions and deaths due to heart failure during a median follow-up of 62 years. We also studied a population-based cohort of another 102 481 individuals from the Copenhagen General Population Study including 187 patients from the Danish α1-Antitrypsin Deficiency Registry, all with genetically confirmed α1-antitrypsin deficiency. Results: Individuals with versus without α1-antitrypsin deficiency had increased risk of heart failure hospitalisation in the nationwide cohort (adjusted hazard ratio 2.64, 95% CI 2.25-3.10) and in the population-based cohort (1.77, 95% CI 1.14-2.74). Nationwide, these hazard ratios were highest in those without myocardial infarction (3.24, 95% CI 2.70-3.90), without aortic valve stenosis (2.80, 95% CI 2.38-3.29), without hypertension (3.44, 95% CI 2.81-4.22), without atrial fibrillation (3.33, 95% CI 2.75-4.04) and without any of these four diseases (6.00, 95% CI 4.60-7.82). Hazard ratios for heart failure-specific mortality in individuals with versus without α1-antitrypsin deficiency were 2.28 (95% CI 1.57-3.32) in the nationwide cohort and 3.35 (95% CI 1.04-10.74) in the population-based cohort. Conclusion: Individuals with α1-antitrypsin deficiency have increased risk of heart failure hospitalisation and heart failure-specific mortality in the Danish population.

Interview with the ECM Award winner 2022 and introducing the new ECM members.

This article presents the interview with the ERS Early Career Member Awardee 2022 (@MathioudakisAG) and provides a brief introduction to the new ECM members https://bit.ly/3BSRgV2.

Low-density lipoprotein cholesterol and risk of COPD: Copenhagen General Population Study.

Background: Randomised controlled trials found that low-density lipoprotein (LDL) cholesterol-lowering statins increase lung function and possibly decrease rate of exacerbations in individuals with COPD. However, it is unknown whether high levels of LDL cholesterol are associated with increased susceptibility to COPD. Methods: We tested the hypothesis that high LDL cholesterol is associated with increased risk of COPD, severe COPD exacerbation and COPD-specific mortality. We examined 107 301 adults from the Copenhagen General Population Study. COPD outcomes were ascertained at baseline and prospectively through nationwide registries. Results: In cross-sectional analysis, low LDL cholesterol was associated with increased risk of COPD (odds ratio for 1st versus 4th quartile: 1.07 (95% CI 1.01-1.14)). Prospectively, low LDL cholesterol was associated with increased risk of COPD exacerbations with hazard ratios of 1.43 (1.21-1.70) for 1st versus 4th quartile, 1.21 (1.03-1.43) for 2nd versus 4th quartile, and 1.01 (0.85-1.20) for 3rd versus 4th quartile of LDL cholesterol (p-value for trend=6×10-6). Finally, low LDL cholesterol was likewise associated with increased risk of COPD-specific mortality (log-rank test: p=0.0009). Sensitivity analyses with death as competing risk provided similar results. Conclusion: Low LDL cholesterol was associated with increased risks of severe COPD exacerbation and COPD-specific mortality in the Danish general population. As this is opposite of that observed in randomised controlled trials with statins, our findings might be a result of reverse causation indicating that individuals with severe phenotypes of COPD have lower plasma levels of LDL cholesterol due to wasting.

Risk of asthma in offspring of asthmatic fathers versus mothers: A population-based study of 21,000 individuals in Denmark.

Parental asthma or allergy have been linked to higher risk of asthma in a child; this occurs to a variable extent in different study populations. Moreover, it is debated whether maternal more so than paternal asthma history is a stronger predisposing factor: while in some countries/populations the maternal effect was clearly seen over paternal, in others the parental effects were equivalent, and in a few studies paternal effect dominated. Here we aimed to determine parental asthma and allergy effect in the Danish GEneral SUburban population Study (GESUS). This cross-sectional study has involved 21,362 adults aged 20+ years in the suburbs of Copenhagen. We used a combination of questionnaire approach, history of prescribed asthma medications and pulmonary function testing to determine odds ratios for maternal and paternal (and combined) asthma and allergy linked to asthma in the test subjects. We found that the input of maternal vs. paternal asthma effect was approximately equal (age and sex-adjusted OR 2.46, 95% CI: 2.15-2.81 for asthmatic mothers vs. 2.97, 2.58-3.42 for asthmatic fathers), except for the "ever asthma" age and sex-adjusted odds ratios where paternal allergy seems to have conferred a marginally greater effect (age and sex-adj. OR 1.96 for maternal allergy vs. 2.44 for paternal allergy, p = 0.03). Stratifying for gestational tobacco smoking did not affect the maternal results. We conclude that in the GESUS study parental asthma or allergy were strongly linked to higher asthma risk in offspring, without a prominent maternal or paternal effect.

Factors associated with medication adherence among adults with asthma.

OBJECTIVE: Asthma medication adherence is of crucial importance for successful disease management. The aim of this study was to identify and rank factors associated with medication adherence among adults with asthma in the general population. METHODS: We used data on physician-diagnosed asthma, medication adherence, and factors associated with asthma medication adherence from the Danish General Suburban Population Study using a cross-sectional study design. We ranked factors associated with asthma medication adherence based on the magnitude of odds ratios, and the population attributable fractions. RESULTS: Among 20,032 individuals from the general population, 1,128 (6%) suffered from asthma and 822 (73%) of these were adherent to asthma medications. Based on odds ratios, the three top-ranked factors associated with asthma medication adherence were asthma attacks within the past year (4.0; 95% CI: 2.9-5.5), allergy medication use (3.8; 2.6-5.6), and age above median (3.4; 2.4-4.7), followed by asthma severity markers like airway obstruction, and coughing with mucus. Based on population attributable fractions, the three top-ranked factors associated with adherence to asthma medications were asthma attacks within the past year (70%), age above median (57%), and use of allergy medication (49%). CONCLUSIONS: The study showed that in the general population recent asthma attacks, higher age, and taking allergy medication were the three most important factors associated with asthma medication adherence. The importance of maintaining adherence to asthma medications even in the absence of severe disease or expressed asthma symptoms should be better communicated to the general population.

Causal risk factors for asthma in Mendelian randomization studies: A systematic review and meta-analysis.

BACKGROUND: Several risk factors for asthma have been proposed; however, the causality of these associations is sometimes unclear. Mendelian randomization is a powerful epidemiological approach that can help elucidate the causality of risk factors. The aim of the present study was to identify causal risk factors for asthma through Mendelian Randomization studies. METHODS: A systematic search of PubMed and EMBASE was conducted, to identify studies investigating risk factors for asthma or respiratory allergies through Mendelian Randomization. When two or more studies investigated the same risk factor a meta-analysis was conducted. Of 239 studies initially identified, 41 were included. RESULTS: A causal association between adiposity and adult asthma risk was found in 10 out of 12 studies with a summary risk ratio of 1.05 per kg/m2 increase in BMI (95% CI: 1.03-1.07). Puberty timing (n = 3), alcohol (n = 2), and linoleic acid (n = 1) had causal effects on asthma risk, while vitamins/minerals (n = 6) showed no consistent effect on asthma. The effect of smoking on adult asthma conflicted between studies. Several of the significant associations of asthma with immune related proteins (n = 5) and depression (n = 2) investigated through multiple traits analyses could generally benefit from replications in independent datasets. CONCLUSION: This systematic review and meta-analysis found evidence for causal effects of adiposity, puberty timing, linoleic acid, alcohol, immune related proteins, and depression on risk of asthma.

Severe α1-antitrypsin deficiency associated with lower blood pressure and reduced risk of ischemic heart disease: a cohort study of 91,540 individuals and a meta-analysis.

BACKGROUND: Increased elastase activity in α1-antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α1-antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease. METHODS: We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α1-Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. 185 participants carried the ZZ genotype, 207 carried the SZ genotype and 91,148 carried the MM genotype. RESULTS: α1-Antitrypsin deficiency was associated with decreases in blood pressure of up to 5 mmHg for systolic blood pressure and up to 2 mmHg for diastolic blood pressure, in ZZ vs SZ vs MM individuals (trend test, P's ≤ 0.01). Plasma triglycerides and remnant cholesterol were reduced in ZZ individuals compared with MM individuals (t-test, P's < 0.001). α1-Antitrypsin deficiency was associated with lower risk of myocardial infarction (trend test P = 0.03), but not with ischemic heart disease, ischemic cerebrovascular disease or hypertension (trend test, P's ≥ 0.59). However, when results for ischemic heart disease were summarized in meta-analysis with results from four previous studies, individuals with versus without α1-antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53-0.84). CONCLUSIONS: Individuals with severe α1-antitrypsin deficiency have lower systolic and diastolic blood pressure, lower plasma triglycerides and remnant cholesterol, reduced risk of myocardial infarction, and a 34% reduced risk of ischemic heart disease.

Risk and impact of chronic cough in obese individuals from the general population.

BACKGROUND: Obese individuals may be at higher risk of chronic cough. We investigated the risk and impact of chronic cough in obese individuals from the general population. METHODS: We recorded chronic cough, body mass index (BMI) and other related clinical conditions in 44 554 adults from the Copenhagen General Population Study. Individuals with asthma and/or chronic obstructive pulmonary disease were excluded (n=10 977). BMI was divided into: underweight (BMI <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obese (30.0-34.9 kg/m2) and severely obese (≥35.0 kg/m2). RESULTS: Among 33 577 adults from the general population, 27 829 (83%) were non-obese and 5748 (17%) were obese. Compared with individuals with normal weight, multivariable adjusted ORs for chronic cough risk were 1.4 (95% CI 1.2 to 1.6) in overweight, 1.9 (95% CI 1.7 to 2.2) in obese and 2.6 (95% CI 2.1 to 3.2) in severely obese individuals. Mediation analyses showed that chronic cough due to obesity was up to 23% mediated by gastro-oesophageal reflux disease (GERD). Other mediators included low vegetable intake with 10% and occupational exposure with 8%. Among obese individuals, those with versus without chronic cough had worse accompanying respiratory symptoms, more often comorbidities including GERD and diabetes, greater healthcare utilisations, lower lung function and higher blood inflammation (all p<0.05). CONCLUSION: There is dose-response relationship between BMI and chronic cough, and chronic cough risk is twofold to threefold higher in obese individuals from the general population. This increased risk was partly mediated by GERD, low vegetable intake and occupational exposure, supporting that there may be benefit to gain by ameliorating some of these factors in obese individuals with chronic cough.

Second-Hand Smoke Exposure Associated with Risk of Respiratory Symptoms, Asthma, and COPD in 20,421 Adults from the General Population.

RATIONALE: Individuals exposed to second-hand smoking may be more susceptible to asthma and chronic obstructive pulmonary disease (COPD). We investigated the risk of respiratory symptoms, asthma, and COPD in adults exposed to second-hand smoking at different stages of life in the general population. METHODS: We identified individuals who had been exposed to second-hand smoking in childhood only, adulthood only, or lifelong in a cohort of 20,421 adults from the Danish General Suburban Population Study and recorded respiratory symptoms, lung function, asthma, and COPD as outcomes. RESULTS: Among 20,421 adults from the general population, 2,551 (12%) had been lifelong exposed to second-hand smoking, 459 (2%) had been exposed in adulthood only, and 13,998 (69%) had been exposed in childhood only; the mean ages of the three groups were 54 years, 55 years, and 57 years, respectably, compared with 56 years in non-exposed individuals (P<0.001). Equivalent values for the prevalence of current smoking were 25%, 20%, and 18% versus 12% (P<0.001). After adjustment for age, smoking, and sex, the odds ratios for wheezing, severe dyspnoea, cough on exertion, and asthma increased as a function of second-hand smoke exposure (Ps≤0.004); individuals who had been exposed to second-hand smoking lifelong, in adulthood only, or in childhood only versus non-exposed had increased odds ratios for wheezing of 1.62 (95% CI=1.41-1.87), 1.50 (1.15-1.94), and 1.16 (1.04-1.30). Corresponding values were 2.08 (1.52-2.85), 2.05 (1.22-3-44), and 1.23 (0.95-1.59) for severe dyspnoea, 1.56 (1.33-1.83), 1.53 (1.15-2.02), and 1.19 (1.05-1.35) for cough on exertion, 1.36 (1.14-1.63), 1.49 (1.09-2.05), and 1.13 (0.99-1.30) for asthma, and 1.24 (1.03-1.48), 1.25 (0.90-1.74), and 1.09 (0.96-1.24) for COPD. The population attributable fractions of asthma and COPD due to lifelong second-hand smoke exposure were 4.3% and 2.9%. CONCLUSION: Individuals exposed to lifelong second-hand smoking have increased risks of respiratory symptoms, asthma, and COPD, and may account for 4.3% and 2.9% of people with asthma and COPD in the general population.

Chronic Cough in Individuals With COPD: A Population-Based Cohort Study.

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.

REST-mediated recruitment of polycomb repressor complexes in mammalian cells.

Polycomb Repressive Complex (PRC) 1 and PRC2 regulate genes involved in differentiation and development. However, the mechanism for how PRC1 and PRC2 are recruited to genes in mammalian cells is unclear. Here we present evidence for an interaction between the transcription factor REST, PRC1, and PRC2 and show that RNF2 and REST co-regulate a number of neuronal genes in human teratocarcinoma cells (NT2-D1). Using NT2-D1 cells as a model of neuronal differentiation, we furthermore showed that retinoic-acid stimulation led to displacement of PRC1 at REST binding sites, reduced H3K27Me3, and increased gene expression. Genome-wide analysis of Polycomb binding in Rest⁻/⁻ and Eed⁻/⁻ mouse embryonic stem (mES) cells showed that Rest was required for PRC1 recruitment to a subset of Polycomb regulated neuronal genes. Furthermore, we found that PRC1 can be recruited to Rest binding sites independently of CpG islands and the H3K27Me3 mark. Surprisingly, PRC2 was frequently increased around Rest binding sites located in CpG-rich regions in the Rest⁻/⁻ mES cells, indicating a more complex interplay where Rest also can limit PRC2 recruitment. Therefore, we propose that Rest has context-dependent functions for PRC1- and PRC2- recruitment, which allows this transcription factor to act both as a recruiter of Polycomb as well as a limiting factor for PRC2 recruitment at CpG islands.