Susceptible Young Adults and Development of Chronic Obstructive Pulmonary Disease 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 predisease state termed "pre-COPD." Objectives: 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 individuals without COPD ages 20-50 years from two population-based cohorts from different smoking eras-the Copenhagen General Population Study from 2003 (N = 5,497) and the Copenhagen City Heart Study from 1976-1978 (N = 2,609)-for 10 and 25 years, for the development of COPD (FEV1/FVC <0.70) and COPD GOLD Stages 2-4 (additionally, FEV1 <80% predicted). Measurements and Main Results: After 10 years, 28% developed COPD and 13% developed COPD GOLD Stages 2-4 in individuals susceptible to COPD, compared with 8% and 1% in those without any susceptibility to COPD. Correspondingly, after 25 years, 22% versus 13% developed COPD and 20% versus 8% developed COPD GOLD Stages 2-4. More than half of incident COPD cases developed from a susceptible state. Compared with 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 Stages 2-4 after 10 years and were 1.54 (1.23-1.93) and 2.12 (1.64-2.73) after 25 years. The ability of a COPD risk score-consisting of the state of susceptibility 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 predisease state of COPD, which can be used for early identification of susceptible individuals at risk for COPD later in life.

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.

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

BACKGROUND: A diagnosis of COPD is mainly considered in individuals with >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. METHODS: We followed non-obstructed adult smokers from the Copenhagen City Heart Study for COPD, defined as a forced expiratory volume in 1 s (FEV1)/forced vital capacity <0.70 and FEV1 <80% predicted, and for related clinical outcomes. First, we followed individuals for 5 years according to baseline smoking for risk of developing COPD, and thereafter for up to four decades for severe exacerbations and death. RESULTS: In 6098 non-obstructed smokers, 1781 (29%) developed COPD after 5 years of follow-up: 23% of individuals with <10 pack-years of smoking at baseline, 26% of those with 10-19.9 pack-years, 30% of those with 20-39.9 pack-years and 39% of those with ≥40 pack-years. During four decades of follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10 pack­years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94 (95% CI 1.36-2.76) in those without COPD and ≥10 pack-years, 2.83 (95% CI 1.72-4.66) in those with COPD and <10 pack-years, 4.34 (95% CI 2.93-6.43) in those with COPD and 10-19.9 pack-years, 4.39 (95% CI 2.98-6.46) in those with COPD and 20-39.9 pack-years and 4.98 (95% CI 3.11-7.97) in those with COPD and ≥40 pack-years. Corresponding HRs for all-cause mortality were 1.20 (95% CI 1.10-1.32), 1.31 (95% CI 1.13-1.53), 1.59 (95% CI 1.40-1.79), 1.81 (95% CI 1.62-2.03) and 1.81 (95% CI 1.55-2.10). CONCLUSION: 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.

Nationwide indoor smoking ban and impact on smoking behaviour and lung function: a two-population natural experiment.

INTRODUCTION: Many countries have implemented indoor smoking bans over the past two decades. Although smoking bans have been shown to reduce cardiovascular outcomes, little is known about their impact on respiratory health. This study investigated the impact of a nationwide indoor smoking ban on smoking behaviour and lung function. METHODS: We used repeated cross-sectional data from two large cohorts of the general population comprising 31 807 Swiss and 62 093 Danish adults. We compared associations between smoking ban and smoking prevalence and prebronchodilator lung function trends in Denmark (indoor smoking ban introduced in 2007) and Switzerland (indoor smoking ban introduced in 2010) from 2005 to 2010 using a quasi-experimental study design. We performed difference-in-difference analyses with linear regression models adjusted for age, sex, weight and height. RESULTS: Denmark had a stronger decrease in active smokers compared with Switzerland. Also, forced expiratory volume in the first second was higher in Danish adults than in Swiss adults: 26 mL (95% CI 2.4 to 49) 1 year, 88 mL (65 to 112) 2 years, and 74 mL (51 to 98) 3 years after smoking ban implementation. Correspondingly, forced vital capacity was higher in Danish adults compared with Swiss adults (80 mL (50 to 109) after 1 year and 126 mL (97 to 155) after two and 3 years). Improvements were observed in both never-smokers and ever-smokers, most pronounced in ever-smokers. CONCLUSIONS: Nationwide indoor smoking ban is associated with less smoking and improved lung function in the general population. Implementing an indoor smoking ban can improve lung function by influencing smoking behaviour and reducing secondhand smoke.

Faster lung function decline in people living with HIV despite adequate treatment: a longitudinal matched cohort study.

INTRODUCTION: Chronic lung disease is common among people living with HIV (PLWH). We hypothesised that PLWH receiving antiretroviral therapy (ART) have faster lung function decline than matched controls. METHODS: We performed a prospective matched cohort study by including ART-treated PLWH from the Copenhagen Co-morbidity in HIV Infection Study (n=705) and the INSIGHT Strategic Timing of Antiretroviral Treatment Pulmonary Substudy (n=425) and frequency matched population controls from the Copenhagen General Population Study (n=2895) in a 1:3 ratio. Eligible participants were ≥25 years old and had two spirometry tests separated by at least 2 years of follow-up. Forced expiratory volume in 1 s (FEV1) decline (mL/year) was compared between PLWH and controls using a linear mixed model adjusted for age, sex, ethnicity and smoking status. Effect modification by smoking was investigated in subgroup analyses. RESULTS: The majority of PLWH were virally suppressed (96.1%). The adjusted mean annual decline in FEV1 was faster in PLWH than in controls with 36.4 (95% CI 33.7 to 39.1) vs 27.9 (95% CI 26.9 to 28.8) mL/year, yielding a difference of 8.5 (95% CI 5.6 to 11.4) mL/year. The association between HIV and FEV1 decline was modified by smoking, with the largest difference in current smokers (difference: 16.8 (95% CI 10.5 to 23.0) mL/year) and the smallest difference in never-smokers (difference: 5.0 (95% CI 0.7 to 9.3) mL/year). FEV1 decline >40 mL/year was more prevalent in PLWH (adjusted OR: 1.98 (95% CI 1.67 to 2.34)). CONCLUSION: Well-treated PLWH have faster lung function decline than controls and smoking seems to modify this association, suggesting that smoking may lead to more rapid lung function decline in PLWH than in controls.

Characterization of mycophage endolysin cell wall binding domains targeting Mycobacterium bovis peptidoglycan.

Mycophage endolysins are highly diverse and modular enzymes composed of domains involved in peptidoglycan binding and degradation. Mostly, they are characterized by a three-module design: an N-terminal peptidase domain, a central catalytic domain and a C-terminal peptidoglycan binding domain. Previously, the affinity of cell wall binding domains (CBDs) to the mycobacterial peptidoglycan layer was shown for some of these endolysins. In this study, an in depth screening was performed on twelve mycophage endolysins. The discovered CBDs were characterized for their binding affinity to Mycobacterium (M.) bovis bacille Calmette-Guérin (BCG), a largely unexplored target and an attenuated strain of M. bovis, responsible for bovine tuberculosis. Using homology-based annotation, only four endolysins showed the presence of a known peptidoglycan binding domain, the previously characterized pfam 01471 domain. However, analysis of the secondary structure aided by AlphaFold predictions revealed the presence of a C-terminal domain in the other endolysins. These were hypothesized as new, uncharacterized CBDs. Fusion proteins composed of these domains linked to GFP were constructed and positively assayed for their affinity to M. bovis BCG in a peptidoglycan binding assay. Moreover, two CBDs were able to fluorescently label M. bovis BCG in milk samples, highlighting the potential to further explore their possibility to function as CBD-based diagnostics.

Prognosis of Patients with Chronic Obstructive Pulmonary Disease Not Eligible for Major Clinical Trials.

Rationale: Randomized controlled trials only include a subset of patients with chronic obstructive pulmonary disease (COPD) fulfilling strict inclusion criteria. Thus, most patients with COPD in a real-world setting do not have the necessary evidence to support treatment effectiveness. Objectives: To test the hypotheses that most individuals with COPD in the general population are not represented in major clinical trials despite clinically significant disease with exacerbations and early death. Methods: In 105,630 adults from a Danish contemporary population-based cohort, we defined COPD as age 40 or more years, chronic respiratory symptoms, history of smoking exposure, and airflow limitation with FEV1/FVC < 0.70. Outcomes included acute exacerbations and all-cause mortality. Symptomatic smokers without COPD were used as a reference group. Measurements and Main Results: Of all, 7,516 (7%) and 16,079 (15%) were symptomatic smokers with and without COPD. Only 44% of those with COPD were eligible for major clinical trials when applying FEV1 < 80% predicted, smoking history of 10 or more pack-years, and no comorbid asthma as common inclusion criteria. During the median 8.9 years of follow-up, we observed 2,130 acute exacerbations and 3,973 deaths in symptomatic smokers. Compared with symptomatic smokers without COPD, multivariable-adjusted hazard ratios for exacerbations were 7.45 (95% confidence interval, 5.41-10.3) and 29.0 (21.1-39.8) in those with COPD, respectively, excluded and eligible for clinical trials. Corresponding hazard ratios for all-cause mortality were 1.21 (1.11-1.31) and 1.67 (1.54-1.81), respectively. Conclusions: More than half of individuals with COPD in the general population are excluded from major clinical trials; however, these individuals have a clinically significant disease with exacerbations and early death compared with symptomatic smokers without COPD.

Plasma adiponectin and risk of asthma: observational analysis, genetic Mendelian randomisation and meta-analysis.

BACKGROUND: Adiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma. OBJECTIVE: We tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma. METHODS: In the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings. RESULTS: While a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma. CONCLUSION: Observationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.

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.

Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.

The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up.

Plasma immunoglobulin E and risk of exacerbation and mortality in chronic obstructive pulmonary disease: A contemporary population-based cohort.

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.

Risk of ulcerative colitis and Crohn's disease in smokers lacks causal evidence.

Smoking has been associated with opposing risks of ulcerative colitis and Crohn's disease. Whether these observational associations reflect actual causal associations, confounding, or reverse causation is unclear. Using a Mendelian randomization approach, we tested the hypothesis that smoking protects against ulcerative colitis and is a cause of Crohn's disease. We included 118,683 white Danes aged ≥ 20 from the Copenhagen General Population Study (2003-2015) and the Copenhagen City Heart Study (1991-94 and 2001-03). During follow-up until 2018, we investigated the association of smoking and CHRNA3 rs1051730, where the T-allele is strongly associated with nicotine dependence, with risk of ulcerative colitis and Crohn's disease. We identified 1312 cases of ulcerative colitis and 671 cases of Crohn's disease. Compared to never-smokers, multivariable adjusted hazard ratios (HRs) for ulcerative colitis were 1.69(95% confidence interval [CI] 1.32-2.15) in former smokers and 2.27(1.74-2.96) in current smokers. Corresponding HRs for Crohn's disease were 1.31(0.93-1.84) and 1.93(1.34-2.78), respectively. Among ever-smokers when compared to non-carriers of the CHRNA3 rs1051730 T-allele, age and sex adjusted HRs for risk of ulcerative colitis were 1.03(95%CI 0.89-1.18) in heterozygotes and 0.91(0.72-1.16) in homozygotes. Corresponding HRs for Crohn's disease were 1.05(0.87-1.28) and 1.02(0.74-1.41), respectively. In a meta-analysis combined with UK Biobank, there was no evidence that CHRNA3 rs1051730 was associated with risk of ulcerative colitis or Crohn's disease. In conclusion, current versus never-smoking was associated with unexpected 2.3-fold risk of ulcerative colitis and expected 1.9-fold risk of Crohn's disease in prospective analyses; however, genetic evidence of lifelong increased smoking intensity did not support causal relationships.

Trajectory of Preserved Ratio Impaired Spirometry: Natural History and Long-Term Prognosis.

Rationale: Natural history of preserved ratio impaired spirometry (PRISm), often defined as FEV1/FVC ⩾lower limit of normal and FEV1 <80% of predicted value, is not well described. Objectives: To investigate the natural history and long-term prognosis of the following PRISm trajectories: persistent PRISm trajectory (individuals with PRISm both young and middle-aged), normal to PRISm trajectory (individuals developing PRISm from normal spirometry in young adulthood), and PRISm to normal trajectory (individuals recovering from PRISm in young adulthood by normalizing spirometry while middle-aged). Methods: We followed 1,160 individuals aged 20-40 years from the Copenhagen City Heart Study from 1976 to 1983 until 2001 to 2003 to determine their lung function trajectory; 72 had persistent PRISm trajectory, 76 had normal to PRISm trajectory, 155 had PRISm to normal trajectory, and 857 had normal trajectory. From 2001-2003 until 2018, we determined the risk of cardiopulmonary disease and death. Measurements and Main Results: We recorded 198 admissions for heart disease, 143 for pneumonia, and 64 for chronic obstructive pulmonary disease as well as 171 deaths. Compared with individuals with normal trajectory, hazard ratios for individuals with persistent PRISm trajectory were 1.55 (95% confidence interval, 0.91-2.65) for heart disease admission, 2.86 (1.70-4.83) for pneumonia admission, 6.57 (3.41-12.66) for chronic obstructive pulmonary disease admission, and 3.68 (2.38-5.68) for all-cause mortality. Corresponding hazard ratios for individuals with normal to PRISm trajectory were 1.91 (1.24-2.95), 2.74 (1.70-4.42), 7.61 (4.21-13.72), and 2.96 (1.94-4.51), respectively. Prognosis of individuals with PRISm to normal trajectory did not differ from those with normal trajectory. Conclusions: PRISm in middle-aged individuals is associated with increased risk of cardiopulmonary disease and all-cause mortality, but individuals who recover from PRISm during their adult life are no longer at increased risk.

Importance of Early COPD in Young Adults for Development of Clinical COPD: Findings from the Copenhagen General Population Study.

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.

Low vitamin D and risk of bacterial pneumonias: Mendelian randomisation studies in two population-based cohorts.

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.

Occupational inhalant exposures and longitudinal lung function decline.

BACKGROUND: Airborne exposures at the workplace are believed to be associated with lung function decline. However, longitudinal studies are few, and results are conflicting. METHODS: Participants from two general population-based cohorts, the Copenhagen City Heart Study and the Copenhagen General Population Study, with at least two lung function measurements were followed for a mean of 9 years (range 3-27 years). Occupational exposure was assigned to each year of follow-up between the two lung function measurements by a job exposure matrix. Associations between mean occupational exposure per year and mean annual decline in forced expiratory volume in 1 s (FEV1) were investigated using linear mixed-effects models according to cohort and time period (1976-1983 and 2003-2015). We adjusted for sex, height, weight, education, baseline FEV1 and pack-years of smoking per year during follow-up. RESULTS: A total of 16 144 individuals were included (mean age 48 years and 43% male). Occupational exposure to mineral dusts, biological dusts, gases and fumes and a composite category was not associated with FEV1 decline in analyses with dichotomised exposure. In analyses with an indexed measure of exposure, gases and fumes were associated with an FEV1 change of -5.8 mL per unit per year (95% CI -10.8- -0.7 mL per unit per year) during 1976-1983, but not during 2001-2015. CONCLUSION: In two cohorts from the Danish general population, occupational exposure to dusts, gases and fumes was not associated with excess lung function decline in recent years but might have been of importance decades ago.

Lung Function Trajectories Leading to Chronic Obstructive Pulmonary Disease as Predictors of Exacerbations and Mortality.

Rationale: Chronic obstructive pulmonary disease (COPD) can develop not only through a lung function trajectory dominated by an accelerated decline of FEV1 from normal maximally attained FEV1 in early adulthood (normal maximally attained FEV1 trajectory) but also through a trajectory with FEV1 below normal in early adulthood (low maximally attained FEV1 trajectory).Objectives: To test whether the long-term risk of exacerbations and mortality differs between these two subtypes of COPD.Methods: The cohort included 1,170 young adults enrolled in the Copenhagen City Heart Study during the 1970s and 1980s. In 2001-2003, which served as the baseline for the present analyses, 79 participants had developed COPD through normal maximally attained FEV1 trajectory, 65 had developed COPD through low maximally attained FEV1 trajectory, and 1,026 did not have COPD.Measurements and Main Results: From 2001 until 2018, we observed 139 severe exacerbations of COPD and 215 deaths, of which 55 were due to nonmalignant respiratory disease. In Cox models, there was no difference with regard to risk of severe exacerbations between the two trajectories, but individuals with normal maximally attained FEV1 had an increased risk of nonmalignant respiratory disease mortality (using inverse probability of censoring weighting with adjusted hazard ratio [HR], 6.20; 95% confidence interval [CI], 2.09-18.37; P = 0.001) and all-cause mortality (adjusted HR, 1.93; 95% CI, 1.14-3.26; P = 0.01) compared with individuals with low maximally attained FEV1.Conclusions: COPD developed through normal maximally attained FEV1 trajectory is associated with an increased risk of respiratory and all-cause mortality compared with COPD developed through low maximally attained FEV1 trajectory.

Prevalence, Characteristics, and Prognosis of Early Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study.

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.

Fraction of Exhaled Nitric Oxide Levels Are Elevated in People Living With Human Immunodeficiency Virus Compared to Uninfected Controls, Suggesting Increased Eosinophilic Airway Inflammation.

BACKGROUND: Increased risk of asthma and chronic obstructive pulmonary disease has been reported in people living with human immunodeficiency virus (PLWH). Fraction of exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation. We assessed FeNO levels in PLWH and matched uninfected controls and investigated whether human immunodeficiency virus (HIV) status is independently associated with elevated FeNO. METHODS: FeNO was quantified by NIOX Vero and pulmonary function was assessed by spirometry in 432 PLWH from the Copenhagen Comorbidity in HIV Infection Study and in 1618 age- and sex-matched uninfected controls from the Copenhagen General Population Study. Elevated FeNO was defined as ≥25 parts per billion. Associations between FeNO and HIV status were adjusted for known potential confounders. RESULTS: Mean age of PLWH was 50.7 (standard deviation [SD], 11.1) years and 97.4% received combination antiretroviral therapy. PLWH had higher FeNO than uninfected controls (median, 17.0 [interquartile range {IQR}, 11.0-26.0] vs 13.0 [IQR, 9.0-19.0]; P < .001). Also, PLWH had a higher prevalence of elevated FeNO than uninfected controls (27.5% vs 12.3%; P < .001). This association remained after adjusting for age, sex, height, smoking status, use of airway medication, blood eosinophils, and immunoglobulin E (adjusted OR [aOR], 3.56 [95% CI, 2.51-5.04]; P < .001). Elevated FeNO was associated with self-reported asthma (aOR, 2.65 [95% CI, 1.66-4.24]; P < .001) but not with airflow limitation (aOR, 1.07 [95% CI, .71-1.62]; P = .745). CONCLUSIONS: HIV status was independently associated with elevated FeNO, suggesting increased eosinophilic airway inflammation. The potential impact on chronic lung disease pathogenesis needs further investigation.

Smoking, blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people.

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75-0·89, P = 2·0 * 10-108 ) for leukocytes, 0·09 (-0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42-0·64, P = 8·0 * 10-22 ) for haematocrit, 0·42 (0·34-0·51, P = 7·1 * 10-21 ) for haemoglobin, 0·19 (0·08-0·31, P = 1·2 * 10-3 ) for mean corpuscular haemoglobin (MCH), 0·29 (0·19-0·39, P = 1·6 * 10-8 ) for mean corpuscular volume (MCV), and 0·04 (-0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33-1·56; P = 1·8 * 10-19 ; I2  = 0%] in current smokers, 1·29 (1·15-1·44; P = 8·0 * 10-6 ; I2  = 0%) in ex-smokers, 1·49 (1·26-1·77; P = 4·4 * 10-6 ; I2  = 0%) in light smokers and 2·04 (1·74-2·39, P = 2·3 * 10-18 ; I2  = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.