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Nanna Korsbæk,1,2 Eskild M Landt,1 Morten Dahl1,2 1Department of Clinical Biochemistry, Zealand University Hospital, Køge, Denmark; 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Morten DahlDepartment of Clinical Biochemistry, Zealand University Hospital, Lykkebækvej 1, Køge, DK-4600, DenmarkTel +4547325545Email modah@regionsjaelland.dkRationale: 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.Keywords: atopy, chronic obstructive pulmonary disease, passive smoking, pulmonary function, wheezing

Background: α 1 -Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α 1 -antitrypsin deficiency have increased susceptibility to cancer in the Danish population., Methods: In a nationwide nested study, we identified 2702 individuals with α 1 -antitrypsin deficiency and 26,750 control subjects without α 1 -antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years., Results: Individuals with α 1 -antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α 1 -antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α 1 -antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13)., Conclusion: Individuals with α 1 -antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

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., Competing Interests: Conflict of interest: B.G. Nordestgaard has consultancies with Amarin, Akcea, Amgen, AstraZeneca, Denka Seiken, Kowa, Novartis, Novo Nordisk and Silence Therap. No conflicts of interest exist for E.M. Landt, Y. Çolak, P. Lange and M. Dahl, (Copyright ©The authors 2024.)

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., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2023.)

Background: Individuals with α 1 -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 α 1 -antitrypsin deficiency is associated with increased risk of heart failure in two large populations., Methods: In a nationwide nested study of 2209 patients with α 1 -antitrypsin deficiency and 21 869 controls without α 1 -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 α 1 -Antitrypsin Deficiency Registry, all with genetically confirmed α 1 -antitrypsin deficiency., Results: Individuals with versus without α 1 -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 α 1 -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 α 1 -antitrypsin deficiency have increased risk of heart failure hospitalisation and heart failure-specific mortality in the Danish population., Competing Interests: Conflict of interest: B.G. Nordestgaard has consultancies with Amarin, Akcea, Amgen, AstraZeneca, Denka Seiken, Kowa, Novartis, Novo Nordisk and Silence Therap. Conflict of interest: No conflicts of interest exist for S.V. Winther, E.M. Landt, N. Seersholm and M. Dahl., (Copyright ©The authors 2023.)

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., Competing Interests: Conflict of interest: J. Freyberg, E.M. Landt, S. Afzal, B.G. Nordestgaard and M. Dahl have nothing to disclose., (Copyright ©The authors 2023.)

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., Competing Interests: Conflict of interest: C. Fisser has received grants or contracts from the German Foundation of Heart Research, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, CSL Behring, Novartis and Berlin-Chemie, outside the submitted work. E.M. Landt received the ERS grant for best abstract in “Chronic Cough” 2022, outside the submitted work. S.J.H. Vijverberg has received grants or contracts from Lung Foundation Netherlands, ERAPerMed/ZonMW, outside the submitted work; and is Chair of the Young Investigators Board, Netherlands Respiratory Society, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©ERS 2023.)

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/m 2 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., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Increased elastase activity in α 1 -antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α 1 -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 α 1 -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: α 1 -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). α 1 -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 α 1 -antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53-0.84)., Conclusions: Individuals with severe α 1 -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., (© 2022. The Author(s).)

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/m 2 ), normal weight (18.5-24.9 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), obese (30.0-34.9 kg/m 2 ) and severely obese (≥35.0 kg/m 2 )., 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., Competing Interests: Competing interests: YÇ reports personal fees from AstraZeneca, Boehringer Ingelheim and Sanofi Genzyme outside the submitted work. PL reports grants from AstraZeneca and GlaxoSmithKline and personal fees from Boehringer Ingelheim, Astra Zeneca, Novartis, and GlaxoSmithKline outside the submitted work. EML, BGN and MD have nothing to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)