Predicting exacerbations in COPD in the Danish general population.

BACKGROUND: Risk of exacerbations in individuals with mild chronic obstructive pulmonary disease (COPD) in the general population is less well described than in more advanced disease. We hypothesized that in addition to history of previous exacerbation also other clinical characteristics predict future moderate exacerbations. METHODS: In 96,462 individuals in the Copenhagen General Population Study, we identified 3175 with clinical COPD defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 and FEV1 <80% predicted in symptomatic individuals without asthma. We estimated the importance of age, sex, FEV1, modified Medical Research Council (mMRC) dyspnea scale, chronic bronchitis, exacerbation history, comorbidities, cohabitation, body mass index, smoking, and blood eosinophils for the 1-year and 3-year future risk of moderate COPD exacerbations and developed a prediction tool for future exacerbations in COPD in the general population based on easily available clinical information. RESULTS: We observed 265 exacerbations in 2543 maintenance treatment naïve individuals with COPD and 197 exacerbations in 632 individuals with COPD on maintenance treatment. In the maintenance treatment naïve group, exacerbation history (hazard ratio (HR): 8.53), low FEV1 (HR: 4.82 for <30% predicted versus 50-79% predicted), and higher age (HR: 1.46 for ≥75 years versus <65 years) were significant predictors of future exacerbations. In the group on maintenance treatment, male sex and mMRC ≥2 also predicted higher risk with borderline significance. CONCLUSIONS: In addition to exacerbation history also higher age and lower FEV1 predict future exacerbation risk in COPD in the general population.

Fraction of exhaled nitric oxide is higher in liver transplant recipients than in controls from the general population: a cohort study.

Background: Fraction of exhaled nitric oxide with an expiratory flow of 50 mL/s (FENO50) is a biomarker of eosinophilic airway inflammation. Liver transplant recipients have an increased risk of pulmonary infections, but little is known about the burden of chronic pulmonary diseases in this group. We aimed to assess the prevalence of elevated FENO50 in liver transplant recipients and compare it to controls from the general population. Methods: FENO50 was measured in 271 liver transplant recipients from The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study and 1,018 age- and sex-matched controls from The Copenhagen General Population Study (CGPS). Elevated FENO50 was defined as ≥25 or ≥50 parts per billion (ppb). The analyses were adjusted for known and suspected confounders. Results: The median age of the liver transplant recipients was 55 years (interquartile range (IQR) 46-64), and 58% were men. The liver transplant recipients had a higher median FENO50 than the controls [16 ppb (IQR 10-26) vs. 13 ppb (IQR 8-18.), p < 0.001]. Furthermore, the liver transplant recipients had a higher prevalence of elevated FENO50 (for FENO50 ≥25 ppb 27% vs. 11%, p < 0.001 and ≥50 ppb 4% vs. 2%, p = 0.02). The results were similar after adjusting for age, sex, smoking status, use of airway medication, and blood eosinophil counts [the adjusted odds ratio (OR) for FENO50 ≥25 ppb was 3.58 (95% CI: 2.50-5.15, p < 0.0001) and the adjusted OR for FENO50 ≥50 ppb was 3.14 (95% CI: 1.37-7.20, p = 0.007)]. Conclusion: The liver transplant recipients had elevated FENO50, implying increased eosinophilic airway inflammation. The clinical impact of this finding needs further investigation.

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.

Susceptible Young Adults and Development of COPD 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 pre-disease state "pre-COPD". OBJECTIVE: 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 non-obstructive individuals aged 20-50years from two population-based cohorts from different smoking eras, the Copenhagen General Population Study from 2003(N=5497) and Copenhagen City Heart Study from 1976-78(N=2609), for 10 and 25years for development of COPD(forced expiratory volume in one second[FEV1]/forced vital capacity[FVC]<0.70) and COPD GOLD 2-4 (additionally FEV1<80% predicted). MEASUREMENTS AND MAIN RESULTS: After 10 years follow-up, 28% developed COPD and 13% COPD GOLD 2-4 in individuals susceptible to COPD compared to 8% and 1% in those without any susceptibility to COPD. Correspondingly, after 25years, 22% versus 13% developed COPD and 20% versus 8% developed COPD GOLD 2-4. More than half of incident COPD cases developed from a susceptible state. Compared to 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 2-4 after 10years, and 1.54(1.23-1.93) and 2.12(1.64-2.73) after 25years. The ability of a COPD risk score consisting of the susceptibility state 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 pre-disease 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.

COPD and Smoking Status - It Does Matter: Characteristics and Prognosis of COPD According to Smoking Status.

Background: Chronic obstructive pulmonary disease is a chronic, often progressive disease, which in most patients is caused by tobacco smoking. Our study focuses on differences in COPD-related outcomes between never smokers, former smokers, and current smokers. Methods: A nationwide, population-based cohort study utilizing Danish health registries. Clinical and socioeconomic variables including smoking status, comorbidities, and dyspnea were obtained. Poisson and Cox Regression were used to calculate the impact of these clinical parameters on the risk of moderate and severe exacerbations and mortality during 12 months of follow-up. Results: A total of 49,826 patients ≥40 years of age, with a hospital diagnosis of COPD in 2008-2017, were identified (mean age 69.2 years, 52% females). A total of 2127 (4%) were never smokers, 29,854 (60%) were former smokers and 17,845 (36%) current smokers. Compared to former and current smokers, never smokers reported a lower modified Medical Research Council score and had a milder COPD stage according to the Global Initiative for Chronic Obstructive Lung Disease classification. During follow-up, never smokers had a significantly lower risk of severe exacerbations (hazard ratio 0.87, 95% confidence interval [CI] 0.78-0.97) and a lower rate of death (mortality ratio 0.75, 95% CI 0.70-0.81) compared to patients with a smoking history. Discussion: Our nationwide study showed that COPD in never smokers is characterized by a lower level of dyspnea, milder lung function impairment, and a lower risk of exacerbations and death. At the same time, we found active smokers to have the highest risk. These findings highlight the need for campaigns to prevent smoking and may help general practitioners as well as other health care professionals to motivate patients with COPD to stop smoking.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population.

Background: Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality. Methods: The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up. Findings: Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality. Interpretation: The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment. Funding: Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.

Internal Transcribed Spacer and 16S Amplicon Sequencing Identifies Microbial Species Associated with Asbestos in New Zealand.

Inhalation of asbestos fibres can cause lung inflammation and the later development of asbestosis, lung cancer, and mesothelioma, and the use of asbestos is banned in many countries. In most countries, large amounts of asbestos exists within building stock, buried in landfills, and in contaminated soil. Mechanical, thermal, and chemical treatment options do exist, but these are expensive, and they are not effective for contaminated soil, where only small numbers of asbestos fibres may be present in a large volume of soil. Research has been underway for the last 20 years into the potential use of microbial action to remove iron and other metal cations from the surface of asbestos fibres to reduce their toxicity. To access sufficient iron for metabolism, many bacteria and fungi produce organic acids, or iron-chelating siderophores, and in a growing number of experiments these have been found to degrade asbestos fibres in vitro. This paper uses the internal transcribed spacer (ITS) and 16S amplicon sequencing to investigate the fungal and bacterial diversity found on naturally-occurring asbestos minerals, asbestos-containing building materials, and asbestos-contaminated soils with a view to later selectively culturing promising species, screening them for siderophore production, and testing them with asbestos fibres in vitro. After filtering, 895 ITS and 1265 16S amplicon sequencing variants (ASVs) were detected across the 38 samples, corresponding to a range of fungal, bacteria, cyanobacterial, and lichenized fungal species. Samples from Auckland (North Island, New Zealand) asbestos cement, Auckland asbestos-contaminated soils, and raw asbestos rocks from Kahurangi National Park (South Island, New Zealand) were comprised of very different microbial communities. Five of the fungal species detected in this study are known to produce siderophores.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

'A Missed Therapeutic Opportunity? SGLT-2 Inhibitor Use in General Medicine Patients With Heart Failure: A Retrospective Audit of Admissions to a Tertiary Health Service'.

Objective: Sodium-glucose co-transporter-2 inhibitors (SGLT2-I's) are novel oral hypoglycaemic agents, with proven decreased MACE and re-hospitalisation risk in type 2 diabetic patients with concomitant heart failure. This study aimed to assess the current practice in the use of SGLT2-I's in general medical units at a large metropolitan health service. Methods/Results: A retrospective audit was conducted of patients admitted to general medicine over a 12 month period (between April 2018 and 2019). Inclusion criteria included decompensated heart failure of any aetiology and ejection fraction, and type 2 diabetes mellitus with an HbA1c ⩾ 7 within 6 months of the admission period. A total of 150 admissions fulfilled criteria. Baseline demographics and comorbidities identified an older, more comorbid population than reference trials. These included age (75% over 75 years), smoking history (46%), hypertension (83%), chronic kidney disease grade IV or V (26%), previous myocardial infarction (57%), stroke (18%), atrial fibrillation (55%) and known left ventricular ejection fraction < 50% (38%). Co-prescribed medications included ACE-I/ARB (53%), beta-blocker (67%), loop diuretic (87%), thiazide (7%), MRA (31%), insulin (57%), metformin (47%), sulphonylurea (31%), DPP-4 Inhibitor (21%), GLP-1 analogue (6%) and 15% of patients had an HbA1c > 10. There was a significant difference between patients in our study eligible for and prescribed metformin (66/111) compared to SGLT-2 inhibitors (4/25) (P = .013). A total of 26 patients had readmissions within 28 days, of which one had been discharged on an SGLT2-I. Conclusion: The results of this study identified significant under prescribing of SGLT2-I's in eligible type 2 diabetic patients with heart failure admitted under general medicine.

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.

Potential clinical implications of targeted spirometry for detection of COPD: A contemporary population-based cohort study.

BACKGROUND: Early diagnosis of chronic obstructive pulmonary disease (COPD) through targeted spirometry may provide better treatment opportunities and in the long run reduce its high burden. We therefore investigated potential beneficial clinical implications of targeted spirometry for detection of COPD and focus on both pulmonary and extrapulmonary conditions in a contemporary general population cohort. METHODS: We recruited 29 678 randomly selected adults from the Copenhagen General Population Study from 2014 to 2017. Individuals unlikely to have undiagnosed COPD with a treatment potential were excluded (age <40 or >80, no smoking or respiratory symptoms, previous COPD/asthma diagnosis). COPD was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70 and FEV1 <80% of predicted. RESULTS: 5520 (19%) were at high risk of undiagnosed COPD, of whom 589 (11%) fulfilled our COPD criteria. Of these, 45% were smokers, 23% reported modified Medical Research Council dyspnoea scale (mMRC) ≥2, 49% reported COPD assessment test (CAT) ≥10, and 12% reported low physical activity. In addition, 8% were underweight, 28% were obese, 28% had undiagnosed hypertension, 49% had undiagnosed hypercholesterolemia, and 1% had undiagnosed diabetes. When all treatable conditions were considered, only 6.5% of individuals with undiagnosed COPD had no potentially treatable condition, while 73% had at least two treatable conditions. CONCLUSIONS: In a general population setting, one undiagnosed COPD case will be detected for every tenth spirometry in smokers with respiratory symptoms. Up to half of individuals with undiagnosed COPD could potentially benefit from smoking cessation, treatment of respiratory symptoms, increased physical activity, and treatment of other undiagnosed comorbidities. LIMITATION: Post-bronchodilator spirometry was not used to diagnose COPD.

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.

Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease: a cross-sectional analysis of ten population-based studies.

BACKGROUND: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. METHODS: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. FINDINGS: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001). INTERPRETATION: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity. FUNDING: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme.

CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting. METHODS: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively. RESULTS: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher. DISCUSSION: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.

U-Shaped Association Between Duration of Sports Activities and Mortality: Copenhagen City Heart Study.

OBJECTIVE: To investigate the association between the duration of weekly leisure-time sports activity and all-cause mortality. METHODS: As part of the prospective Copenhagen City Heart Study, 8697 healthy adults completed a comprehensive questionnaire about leisure-time sports activities. Duration (minutes per week) of leisure-time sports activities was recorded for tennis, badminton, soccer, handball, cycling, swimming, jogging, calisthenics, health club activities, weightlifting, and other sports. The primary end point was all-cause mortality, and the median follow-up was 25.6 years. The association between duration of leisure-time sports activities and all-cause mortality was studied using multivariable Cox proportional hazards regression analysis. RESULTS: Compared with the reference group of 2.6 to 4.5 hours of weekly leisure-time sports activities, we found an increased risk for all-cause mortality for those with 0 hours (hazard ratio [HR], 1.51; 95% CI, 1.29 to 1.76), for those with 0.1 to 2.5 hours (HR, 1.24; 95% CI, 1.05 to 1.46), and for those with more than 10 hours (HR, 1.18; 95% CI, 1.00 to 1.39) of weekly leisure-time sports activities. These relationships were generally consistent with additional adjustments for potential confounders among subgroups of age, sex, education, smoking, alcohol intake, and body mass index, when the first 5 years of follow-up were excluded, and for cardiovascular disease mortality. CONCLUSION: We observed a U-shaped association between weekly duration of leisure sports activities and cardiovascular and all-cause mortality, with lowest risk for those participating in 2.6 to 4.5 weekly hours, being consistent across subgroups. Participation in sport activities should be promoted, but the potential risk of very high weekly hours of sport participation should be considered for inclusion in guidelines and recommendations.

Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE. METHODS: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched. RESULTS: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected. DISCUSSION: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.

Supernormal lung function and risk of COPD: A contemporary population-based cohort study.

BACKGROUND: Investigation of the natural history of chronic obstructive pulmonary disease (COPD) has led to the recognition that individuals with higher than normal lung function may have lower risk of developing COPD. We tested the hypothesis that individuals with supernormal lung function have lower risk of COPD. METHODS: We followed 108,246 adults from the Copenhagen General Population Study recruited between 2003 and 2015 for clinical COPD outcomes until 2018. A subset of 16,892 attended another examination approximately 10 years later, allowing to investigate lung function decline and COPD development (forced expiratory volume in 1 se (FEV1)/forced vital capacity (FVC)<0·70 and FEV1<80% predicted with chronic respiratory symptom). Supernormal lung function was defined as FEV1>upper limit of normal (ULN). FINDINGS: At baseline, 3944(4%) had supernormal lung function, 91,938(85%) normal lung function, and 12,364(11%) had below normal lung function. Individuals with baseline supernormal versus normal lung function had higher FEV1 decline but did not differ in FEV1/FVC decline. None had COPD at 10 years in those with supernormal lung function, while 3% had in those with normal lung function. Early-life risk factors associated with COPD development and smoking exposure in different stages of life were less common in individuals with supernormal lung function. Compared to individuals with normal lung function, multivariable adjusted hazard ratios in those with supernormal lung function were 0·19(95% confidence interval:0·08-0·46) for acute obstructive lung disease hospitalisations, 0·56(0·45-0·69) for pneumonia hospitalisations, and 0·81(0·72-0·91) for all-cause mortality. INTERPRETATION: Supernormal lung function is associated with lower risk of developing COPD. FUNDING: Herlev and Gentofte Hospital and Lundbeck Foundation.