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© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/., Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Supported by Wellcome Trust grant 085790/Z/08/Z for the BOLD (Burden of Obstructive Lung Disease) Study. The initial BOLD programprogramme was funded in part by unrestricted educational grants to the Operations CenterCentre in Portland, Oregon from Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfizer, Schering-Plough, Sepracor, and the University of Kentucky (Lexington, KY). A full list of local funders can be found at https://www.boldstudy.org.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Background There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012. Methods A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC Results Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication. Conclusions False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.

Rationale The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 is based on an ABCD assessment tool of symptoms and exacerbation history and grade 1-4 of airflow limitation severity, facilitating classification either into 4 groups (ABCD) or 16 groups (1A-4D). We aimed to compare the GOLD 2011, GOLD 2017 ABCD, and GOLD 2017 1A-4D classifications in terms of their distribution and prediction of mortality and hospitalizations. Methods In the GenKOLS study, 912 COPD patients with FEV1 less than 80% of the predicted answered questionnaires and performed lung function testing in 2003-2005. The patients were recruited from a hospital patient registry (n=662) and from the general population (n=250), followed up until 2011 with respect to all-cause and respiratory mortality, and all-cause and respiratory hospitalizations. We performed logistic regression and receiver operating curve (ROC) analyses for the different classifications with estimations of area under the curve (AUC) for comparisons. Results Mean age at baseline was 60 years (SD 11), 55% were male. Mean duration of follow-up was 91 months. By GOLD 2011, 21% were classified as group A, 29% group B, 6% group C, and 43% as group D, corresponding percentages for GOLD 2017 were: 25%, 52%, 3%, and 20%. The GOLD 2011 classification had higher AUC values than the GOLD 2017 group ABCD classification for respiratory mortality and hospitalization, but after inclusion of airflow limitation severity in GOLD 2017 groups 2A-4D, AUC values were significantly higher with GOLD 2017. Conclusion In a clinically relevant sample of COPD patients, the GOLD 2017 classification doubles the prevalence of group B and halves the prevalence of groups C and D as compared to the GOLD 2011 classification. The prediction of respiratory mortality and respiratory hospitalization was better for GOLD 2017 2A-4D taking airflow limitation severity into account, as compared to GOLD 2017 ABCD and GOLD 2011.

This study determined the association between respiratory symptoms and death from respiratory causes over a period of 45 years. In four cohorts of random samples of Norwegian populations with 103,881 participants, 43,731 persons had died per 31 December 2016. In total, 5,949 (14%) had died from respiratory diseases; 2,442 (41%) from lung cancer, 1,717 (29%) chronic obstructive pulmonary disease (COPD), 1,348 (23%) pneumonia, 119 (2%) asthma, 147 (2%) interstitial lung disease and 176 (3%) other pulmonary diseases. Compared with persons without respiratory symptoms the multivariable adjusted hazard ratio (HR) for lung cancer deaths increased with score of breathlessness on effort and cough and phlegm, being 2.6 (95% CI 2.1–3.2) for breathlessness score 3 and 2.1 (95% CI 1.7–2.5) for cough and phlegm score 5. The HR of COPD death was 6.4 (95% CI 5.4–7.7) for breathlessness score 3 and 3.0 (2.4–3.6) for cough and phlegm score 5. Attacks of breathlessness and wheeze score 2 had a HR of 1.6 (1.4–1.9) for COPD death. The risk of pneumonia deaths increased also with higher breathlessness on effort score, but not with higher cough and phlegm score, except for score 2 with HR 1.5 (1.2–1.8). In this study with >2.4 million person-years at risk, a positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. Respiratory symptoms are thus important risk factors, which should be followed thoroughly by health care practitioners for the benefit of public health.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objective: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

Objectives To estimate treatment- and productivity-related costs associated with COPD in two different samples, and to analyse the association between the costs and moderate and severe exacerbations. Methods We performed a baseline visit and four telephone-interviews during a one-year follow-up of 81 COPD cases and 132 controls recruited from a population-based sample, and of 205 hospital-recruited COPD patients. COPD was defined by post-bronchodilator spirometry. Total costs consisted of treatment related costs and costs of productivity losses. Exacerbation-related costs were estimated by multivariate median regression. Results The average annual disease-related costs for a COPD patient from the hospital sample was nearly twice as high as for a COPD case from the population sample (€26,518 vs €15,021), and nearly four times as high as for a control subject (€6740). For both sampling sources, the average annual costs of productivity losses were substantially higher than the treatment related costs (€17,014 vs €9,504, €11,192 vs €3,829, and €4494 vs €2,246, for the hospital COPD patients, the population-based COPD cases, and the controls, respectively). Severe exacerbations were an important cost driver for the treatment related costs in both COPD groups. Moderate exacerbations explained all the costs of productivity losses in the population-based COPD cases, but did not affect the costs of productivity losses in the hospital-recruited COPD patients. Conclusion We found that there were significant incremental costs associated with COPD, and the treatment related costs were significantly affected by exacerbations. The costs of productivity losses substantially exceeded the treatment related costs in both sampling sources.

Rationale There is limited knowledge on the effect of acute exacerbations in chronic obstructive pulmonary disease (AECOPD) on lung cancer risk in COPD patients with and without a history of asthma. This study aims to examine whether AECOPD is associated with risk of lung cancer, and whether the effect depends on a history of asthma. Methods In the GenKOLS study of 2003–2005, 852 subjects with COPD performed spirometry, and filled out questionnaires on smoking habits, symptoms and disease history. These data were linked to lung cancer data from the Cancer Registry of Norway through 2013. AECOPD, measured at baseline was the main predictor. To quantify differences in lung cancer risk, we performed Cox-proportional hazards regression. We adjusted for sex, age, smoking variables, body mass index, and lung function. Measurements and results During follow-up, 8.8% of the subjects with, and 5.9% of the subjects without exacerbations were diagnosed with lung cancer. Cox regression showed a significant increased risk of lung cancer with one or more exacerbations in COPD patients without a history of asthma, HRR = 2.77 (95% CI 1.39–5.52). We found a significant interaction between a history of asthma and AECOPD on lung cancer. Conclusions AECOPD is associated with an increased risk of lung cancer in COPD patients without a history of asthma. publishedVersion

Objective This study assessed the association between respiratory symptoms and mortality in four cohorts of the general population in Norway aged 15–75 years and in selected subgroups in the pooled sample. Methods The study comprised 158,702 persons, who were drawn randomly from the Norwegian population register. All subjects received a standardized, self-administered questionnaire on 11 respiratory symptoms between 1972 and 1998, with follow-up of death until December 31, 2017. Analyses were performed on 114,380 respondents. Results The hazard of death was closely associated with sex, age, and education. The hazard ratios (HR) for death and the 95% confidence intervals (CI) by risk factors were similar in the four cohorts. After adjustment for demographic and environmental, modifiable factors, the HR for death was 1.90 (95% CI 1.80–2.00) for breathlessness score 3, 1.28 (1.21–1.37) for cough/phlegm score 5 and 1.09 (1.05–1.14) for attack of breathlessness/wheeze score 2 compared to the referent (no symptom), respectively. The cough/phlegm score was associated with death in current smokers but not in never smokers or ex-smokers. Breathlessness score was associated with death in men and women. Conclusion Among persons aged 45–75 years, respiratory symptoms were significant predictors of all cause mortality. Education and smoking habits influenced only the associations between coughing and mortality. The associations were independent of study sites.

Source at https://doi.org/10.1186/s11556-018-0202-1. Background: Physical activity (PA) is generally beneficial for bone health, but the effect of high levels of PA over many years, in older women, is unknown. Methods: T-score from Dual-energy X-ray absorptiometry (DXA), and self-reported baseline characteristics were recorded for 24 female, cross-country-skiing-competitors, aged 68–76 years, from the Birkebeiner Ageing Study. Data from 647 women in the same age range from the Tromso-6 population study, with recorded DXA findings, were used for comparison. Results: The athletes reported a median(range) of 9(1–34) participations in the 54 km, yearly ski-race, indicating long-term PA. They also reported more moderate and high levels of PA than women in the general population (52% vs. 12 and 30% vs. 0%, respectively). The athletes had lower body mass index (BMI) than the controls (mean BMI 21.7 vs 26.9 kg/m2, p Conclusions: This pilot study suggests that long-term, high levels of PA are associated with low bone mineral density in older women, and the finding might be due to differences in BMI. Despite the lower bone mineral density the athletes did not report more fractures.

INTRODUCTION: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. METHODS: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case–control status. RESULTS: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10(−15)), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10(−6); CYP2A7, p = 7.50 × 10(−5); CYP2B6, p = 4.04 × 10(−4)). When we stratified by COPD case–control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (β = 0.11, p = 5.58 × 10(−4)) and controls (β = 0.12, p = 3.86 × 10(−5)) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10(−4)). CONCLUSIONS: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

Rationale: Evidence supporting the association of chronic obstructive pulmonary disease or airflow obstruction with use of solid fuels is conflicting and inconsistent. Objectives: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. Methods: We analyzed 18,554 adults from the BOLD (Burden of Obstructive Lung Disease) study, who had provided acceptable post-bronchodilator spirometry measurements, and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analyzed. We performed similar analyses for spirometric restriction, chronic cough, and chronic phlegm. Measurements and Main Results: We found no association between airflow obstruction and use of solid fuels for cooking or heating (odds ratio [OR] for men, 1.20 [95% confidence interval (CI), 0.94–1.53]; OR for women, 0.88 [95% CI, 0.67–1.15]). This was true for low-/middle- and high-income sites. Among never-smokers, there was also no evidence of an association of airflow obstruction with use of solid fuels (OR for men, 1.00 [95% CI, 0.57–1.76]; OR for women, 1.00 [95% CI, 0.76–1.32]). Overall, we found no association of spirometric restriction, chronic cough, or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never-smokers and those who had been exposed for 20 years or longer. Conclusions: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Dl(CO) is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of Dl(CO) could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of Dl(CO) using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for Dl(CO) in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and Dl(CO). We estimated the SNP-based heritability of Dl(CO) in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with Dl(CO): variants near TGFB2, CHRNA3, and PDE11A loci (P

Purpose: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. Method: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. Conclusion: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NOR-FIB is an investigator driven academic study. Of the 500 devices, 400 are supported by Medtronic. The study is supported by the research infrastructure of the European Cerebrovascular Research Infrastructure (ECRI).

Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma., Despite increased ICS use, only 34% of subjects with persistent asthma take ICSs on a regular basis

The predictors of autopsy and the accuracy of European short list (E) codes of respiratory diseases lack recent knowledge.A 10% random sample (n=6811) of inhabitants of Bergen, Norway, aged 20–70 years, was invited to participate in a survey in 1965–1971 (participation rate 83%).By December 31, 2005, 4387 (64%) participants had died and 1163 (27% of the deceased) had been given an autopsy. Causes of death were tuberculosis (E02, 0.2%), lung malignancy (E15, 3.5%), influenza (E38, 0.2%), pneumonia (E39, 6.5%) and chronic lower respiratory diseases (E40, 3.2%). Male sex, early deaths in the surveillance period and E15 were positive predictors of an autopsy examination, whereas old age and E39 were strong negative predictors. Among those referred for apost mortemexamination, the cause of death was verified as tuberculosis in 0.3%, lung cancer in 8.1%, acute pneumonia in 2.0% and chronic obstructive lung diseases in 4.9%. Cohen’s kappa coefficients (E codesversusautopsy) were 0.91 (95% CI 0.86–0.96) for E15, 0.37 (95% CI 0.20–0.54) for E39 and 0.65 (95% CI 0.54–0.76) for E40.These findings matter when deaths from respiratory diseases are used as end-points in epidemiological association studies and clinical trials.

Rationale : Data on the change in diffusion capacity of the lung for carbon monoxide (DL CO ) over time are limited. We aimed to examine change in DL CO (ΔDL CO ) over a 9-year period and its predictors. Methods : A Norwegian community sample comprising 1,152 subjects aged 18–73 years was examined in 1987 and 1988. Of the 1,109 subjects still alive, 830 (75%) were re-examined in 1996/97. DL CO was measured with the single breath-holding technique. Covariables recorded at baseline included sex, age, height, weight, smoking status, pack years, occupational exposure, educational level, and spirometry. Generalized estimating equations analyses were performed to examine relations between ΔDL CO and the covariables. Results : At baseline, mean [standard deviation (SD)] DL CO was 10.8 (2.4) and 7.8 (1.6) mmol·min −1 ·kPa −1 in men and women, respectively. Mean (SD) ΔDL CO was −0.24 (1.31) mmol·min −1 ·kPa −1 . ΔDL CO was negatively related to baseline age, DL CO , current smoking, and pack years, and positively related to forced expiratory volume in 1 second (FEV 1 ) and weight. Sex, occupational exposure, and educational level were not related to ΔDL CO . Conclusions : In a community sample, more rapid decline in DL CO during 9 years of observation time was related to higher age, baseline current smoking, more pack years, larger weight, and lower FEV 1 . Keywords: diffusion capacity for carbon monoxide; longitudinal change; occupational exposure; socioeconomic status; smoking (Published: 2 September 2016) Citation: European Clinical Respiratory Journal 2016, 3: 31265 - http://dx.doi.org/10.3402/ecrj.v3.31265

There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years.All patients with motor neuron disease (MND) living in Nordland County in the period 2000-2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015.We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000-2004, 2.3 in 2005-2009, and 2.0 in 2010-2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD).The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients.

Background: Studies on costs of COPD exacerbations from general populations are scarce. Objectives: To compare direct costs (treatment-related) and indirect costs (productivity-related) associated with COPD in population based and hospital-recruited samples, and to estimate the components related to moderate and severe exacerbations. Methods: We performed 4 telephone interviews with 81 COPD cases and 132 controls from a population-based survey and 205 hospital-recruited COPD-patients. A moderate exacerbation was defined by use of antibiotics or corticosteroids due to respiratory disease, and severe exacerbations by hospitalisation due to respiratory disease. The sum of direct and indirect costs gave the total costs. Initial analyses compared costs across the three groups, and multivariate quantile regression estimated the costs attributed to exacerbations. Results: The crude, annual mean total disease-related costs were €26518, €15021, and €6740 per person for the patients, cases, and controls (p Conclusion: The annual total health-related costs for a hospital-recruited COPD-patient were nearly twice that of a general population-based COPD-case. The most important cost driver was severe exacerbations.

SummaryChronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

INTRODUCTION Based on the National Lung Cancer Screening Trial (NLST), guidelines on screening programs for lung cancer have recommended low-dose computed tomography (LDCT). De Torres et al made a score for COPD patients (COPD-LUCSS) to improve their selection criteria. OBJECTIVE To examine and compare the discriminating value of both scores in a community-based cohort of COPD patients. METHODS Four hundred and twenty-two ever-smokers with COPD from the GenKOLS study in Bergen were merged with the Cancer Registry of Norway. We divided the patients into groups of high and low risk according to the COPD-LUCSS and the NLST criteria. Cox regression and logistic regression were used to analyse the associations between the scores and lung cancer. We used Harrell's C and area under the curve (AUC) to estimate discriminating values and to compare the models. RESULTS Hazard ratio for the high risk vs the low risk in the COPD-LUCSS was 3.0 (1.4-6.5 95% CI), P

Background Evidence from several studies show poor guideline adherence to COPD treatment, but no such study has been undertaken in Norway. The objectives of this study, was to estimate and compare the guideline adherence to COPD treatment in general population-based and hospital-recruited COPD patients, and find possible predictors of guideline adherence. Methods From the prospective, observational EconCOPD-study, we analysed guideline adherence for 90 population-based COPD cases compared to 245 hospital-recruited COPD patients. Overall guideline adherence was defined as correct pharmacological treatment, and influenza vaccination the preceding year, and having received smoking cessation advice. Multivariate logistic regression analysis was performed with the dichotomous outcome overall guideline adherence adjusting for relevant variables. Results The overall guideline adherence for population-based COPD cases was 6.7%, significantly lower than the 29.8% overall guideline-adherence amongst hospital-recruited COPD patients. Adherence to pharmacological treatment guidelines was 10.0 and 35.5%, for the two recruitment sources, respectively. GOLD-stage 3 to 4 was associated with significantly better guideline adherence compared to GOLD-stage 2 (OR (95% CI) 18.9 (8.37,42.7)). The unadjusted difference between the two recruitment sources was completely explained by degree of airflow obstruction. Conclusion Overall guideline adherence was very low for both recruitment sources. We call for increased attention from authorities and healthcare personnel to improve the quality of care given to this patient group. Electronic supplementary material The online version of this article (10.1186/s12890-018-0756-8) contains supplementary material, which is available to authorized users.

Introduction There are few data available on the optimal number of lung cancer patients needed to generate and compare estimates of quality between units managing lung cancer. The number of lung cancer patients per management unit varies considerably in Norway, where there are 42 hospitals that treated between 1 and 454 lung cancer patients in 2011. Aims To estimate the differences in quality indicators that are of sufficient importance to change a pulmonary physician's lung cancer management program, and to estimate the size of the patient samples necessary to detect such differences. Method Twenty-six physicians were asked about the relative differences from a national average of quality indicators that would change their own lung cancer management program. Sample sizes were calculated to give valid estimates of quality of a management unit based on prevalence of quality indicators and minimally important differences (MID). Results The average MID in quality indicators that would cause a change in management varied from 18% to 24% among 26 chest physicians, depending on the indicator. Conclusions To generate precise estimates for quality control of lung cancer care in Norway, the number of management units must be reduced. Given the present willingness of chest physicians to change their procedures for management of lung cancer according to the results of quality control indicators, we recommend a maximum of 10 units with a minimum of 200 incident lung cancer patients per year for each management center.

Background Increasing access to essential respiratory medicines and influenza vaccination has been a priority for over three decades. Their use remains low in low- and middle-income countries (LMICs), where little is known about factors influencing use, or about the use of influenza vaccination for preventing respiratory exacerbations. Methods We estimated rates of regular use of bronchodilators, inhaled corticosteroids and influenza vaccine, and predictors for use among 19 000 adults in 23 high-income countries (HICs) and LMIC sites. Results Bronchodilators, inhaled corticosteroids and influenza vaccine were used significantly more in HICs than in LMICs, after adjusting for similar clinical needs. Although they are used more commonly by people with symptomatic or severe respiratory disease, the gap between HICs and LMICs is not explained by the prevalence of chronic obstructive pulmonary disease or doctor-diagnosed asthma. Site-specific factors are likely to influence use differently. The gross national income per capita for the country is a strong predictor for use of these treatments, suggesting that economics influence under-treatment. Conclusion We still need a better understanding of determinants for the low use of essential respiratory medicines and influenza vaccine in low-income settings. Identifying and addressing these more systematically could improve the access and use of effective treatments.

Mortality statistics represent important endpoints in epidemiological studies. The diagnostic validity of cerebral stroke and ischemic heart disease recorded as the underlying cause of death in Norwegian mortality statistics was assessed by using mortality data of participants in the Bergen Clinical Blood Pressure Study in Norway and autopsy records from the Gade Institute in Bergen. In the 41 years of the study (1965-2005) 4,387 subjects had died and 1,140 (26%) had undergone a post mortem examination; 548 (12%) died from cerebral stroke and 1,120 (24%) from ischemic heart disease according to the mortality statistics, compared to 113 (10%) strokes and 323 (28%) coronary events registered in the autopsy records. The sensitivity and positive predictive value of fatal cerebral strokes in the mortality statistics were 0.75, 95% confidence interval (CI) [0.66, 0.83] and 0.86 [0.77, 0.92], respectively, whereas those of coronary deaths were 0.87 [0.84, 0.91] and 0.85 [0.81, 0.89] respectively. Cohen's Kappa coefficients were 0.78 [0.72, 0.84] for stroke and 0.80 [0.76, 0.84] for coronary deaths. In addition to female gender and increasing age at death, cerebral stroke was a negative predictor of an autopsy being carried out (odds ratio (OR) 0.69, 95% CI [0.54, 0.87]), whereas death from coronary heart disease was not (OR 1.14, 95% CI [0.97, 1,33]), both adjusted for gender and age at death. There was substantial agreement between mortality statistics and autopsy findings for both fatal strokes and coronary deaths. Selection for post mortem examinations was associated with age, gender and cause of death.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

International audience; Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.

Atrial fibrillation (AF) is the most common arrhythmia in older adults, and those with AF have an increased risk of developing stroke. Although the use of anticoagulants for stroke prevention is strongly recommended, many older people are not appropriately treated. Vitamin K antagonists (VKA) have been the only available oral anticoagulants for such patients, but recently, new oral anticoagulants have been approved for stroke prevention in AF as an alternative to VKA. Some characteristics make them an attractive treatment option; however, many gaps in evidence remain, especially in the population of older patients. This paper explores the use of anti-thrombotic treatment for the prevention of stroke in AF in old subjects in four different European countries. VKA seems to be the standard therapy in older patients, although anti-platelet drugs are still used widely in some countries. In many European countries, warfarin is replaced by coumadin derivatives. The use of new oral anticoagulants seems to be quite limited in older subjects and some degree of discrimination exists in access to these new drugs. European Society of Cardiology (ESC) 2010 and 2012 guidelines seem to be triggering a wide change in attitudes and practices. Many countries are incorporating such guidelines into official recommendations, and specific country recommendations on the use of new anticoagulants have been published, partly due to the high economic impact of these drugs. Geriatricians still have a marginal role in the prescription of anticoagulants, which in most countries usually lies on cardiologists. General practitioners are key for follow-up, as the role of anticoagulation clinics remains relevant only in The Netherlands. Most old patients have limited knowledge of anticoagulant treatment options, thus, their involvement in decision-making is low.

Introduction Coexistent respiratory failure and metabolic alkalosis is a common finding. Acidotic diuretics cause a fall in pH that may stimulate respiration. Objective The purpose of the study was to evaluate the effectiveness of short-term treatment with acetazolamide for combined respiratory failure and metabolic alkalosis. Methods A randomised, placebo-controlled and double-blind parallel group trial where oral acetazolamide 250 mg three times a day for 5 days were administered to patients hospitalised for respiratory failure because of a pulmonary disease (Pa O2 ≤ 8 kPa and/or Pa CO2 ≥ 7 kPa) who had concurrent metabolic alkalosis [base excess (BE) ≥ 8 mmol/L]. Pa O2 after 5 days was the primary effect variable. Secondary effect variables were Pa CO2 , BE and pH on day 5, and the total number of days in hospital. Results Of 70 patients enrolled (35 in each group), data from 54 were analysed per protocol, while last observation carried forward was used for the remaining 16. During the 5-day treatment, Pa O2 increased on average 0.81 kPa in the placebo group and 1.41 kPa in the acetazolamide group. After adjustment for baseline skewness, the difference was statistically significant (adjusted mean difference 0.55 kPa, 95% confidence interval 0.03-1.06). Pa CO2 decreased in both groups, but the difference was not statistically significant. As expected, pH and BE decreased markedly in the acetazolamide group. Conclusion Acetazolamide may constitute a useful adjuvant treatment mainly to be considered in selected patients with respiratory failure combined with prominent metabolic alkalosis or where non-invasive ventilation is insufficient or infeasible.

The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2011 update on chronic obstructive pulmonary disease (COPD) bases disease classification on level of dyspnea, exacerbation history, and FEV1, whereas the previous GOLD categorized disease severity according to FEV1 only. Information on how the new classification predicts long-term hospitalizations and mortality is limited.To examine how GOLD 2011 predicts hospitalizations and mortality over an 8-year period and to assess differences in predictive ability between GOLD 2011 and GOLD 2007.In the GenKOLS study, 912 patients with COPD (FEV1/FVC0.7 and FEV180% predicted) aged 40 to 91 years were clinically examined. Patients answered questionnaires and performed lung function testing in 2003-2005. The population was followed for 8 years regarding hospitalizations (all-cause, respiratory) and mortality (all-cause, respiratory, cardiovascular). We performed logistic regression and receiver operating curve analyses for GOLD 2007 and GOLD 2011 with estimations of area under the curve (AUC) to compare the different classifications.Twenty percent of patients were classified as GOLD 2011 group A (mild), 30% as group B, 6% group as C, and 44% as group D (very severe). Patients in GOLD 2011 group D had odds ratios of 4.1 (95% confidence interval [CI], 2.5-6.7), 9.6 (95% CI, 3.4-27.0), and 3.0 (95% CI, 0.7-13.2) relative to group A for all-cause, respiratory, and cardiovascular mortality, respectively, and 3.8 (95% CI, 2.4-5.9) and 13.0 (95% CI, 6.6-25.6) for all-cause and respiratory hospitalizations, respectively. Associations were similar also for GOLD 2007. The adjusted AUC values for GOLD 2011 and GOLD 2007 were 0.82/0.82 for respiratory mortality (P = 0.87) and 0.77/0.76 for respiratory hospitalizations (P = 0.51).The predictive ability of GOLD 2011 did not differ significantly from GOLD 2007 in terms of hospitalizations and mortality.

There is limited knowledge of the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness (AWT) on mortality.To examine 8-year mortality in relation to CT-measured emphysema and AWT, and assess if potential impact of these predictors remained after adjustment for lung function.In the Norwegian GenKOLS study of 2003-2005, 947 ever-smokers (49% with COPD) aged 40-85 years performed spirometry and CT examination. Mortality data from 2003-2011 were gathered from the Norwegian Cause of Death Registry. CT emphysema % low-attenuation areas (%LAA) and standardized measure for AWT (AWT-Pi10) were main predictors. We performed Laplace regression for survival data, estimating survival time for specified population percentiles within each emphysema category. Models were adjusted for sex, FEV1, COPD status, age, body mass index, smoking, and inflation level.During 8-year follow-up all-cause mortality rate was 15%. Although 4% of the subjects with %LAA less than 3 died, 18% with %LAA 3-10 and 44% with %LAA greater than or equal to 10 died. After adjustment, the comparable percentile subjects with medium and high emphysema had 19 months shorter survival than subjects who died in the lowest emphysema category. Subjects with %LAA greater than or equal to 10 had 33 and 37 months shorter survival than the lowest emphysema category with regard to respiratory and cardiovascular mortality, respectively. No significant associations were found between %LAA and cancer and lung cancer mortality. AWT did not predict mortality independently, but a positive interaction with emphysema was observed.AWT affected mortality with increasing degree of emphysema, whereas CT measure of emphysema was a strong independent mortality predictor.

Objectives: To estimate the impact of study sample and outcome definition on the incidence of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) as well as explore possible predictors of AECOPD. Methods: During a one year follow-up we performed 4 telephone interviews with 81 COPD patients and 132 controls from a population-based survey and 205 hospital-recruited COPD patients. Both a resource- and a symptom-based definition of AECOPD was applied. For the multivariate analyses we chose a negative binomial regression model. Results: COPD patients from the population- and hospital-based samples experienced 0.4 resource-defined and 2.9 symptom-defined versus 1.0 and 5.9 annual exacerbations, respectively. Increasing severity of COPD as well as receiving maintenance therapy increased the risk of AECOPD with both exacerbation definitions. In the hospital sample the risk of AECOPD was 59 - 78% higher than in the population sample. Conclusion: Any study with AECOPD as a primary outcome should recruit from population-based samples and take into account the effect of different AECOPD definitions. These choices will impact both incidence and predictors of AECOPD and likely also the size of therapeutic effects.

We welcome the important paper by Grønseth et al. [1], which used data from the Burden of Obstructive Lung Disease (BOLD) project to highlight the prevalence of breathlessness across the world. As well as being significant because it is a source of suffering that should be ameliorated, we believe that attention to breathlessness, particularly in midlife, has important implications for sustainable healthcare because it allows timely diagnosis, would drive the promotion of physical activity, forms part of a strategy to reduce the burden of comorbidities and would have beneficial environmental effects., Targeting breathlessness is important for delivering sustainable future healthcare http://ow.ly/AgKoA

There is limited knowledge about the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness in cancer.The aim of this study was to investigate if using CT to quantitatively assess the amount of emphysema and airway wall thickness independently predicts the subsequent incidence of non-pulmonary cancer and lung cancer.In the GenKOLS study of 2003–2005, 947 ever-smokers performed spirometry and underwent CT examination. The main predictors were the amount of emphysema measured by the percentage of low attenuation areas (%LAA) on CT and standardised measures of airway wall thickness (AWT-PI10). Cancer data from 2003–2013 were obtained from the Norwegian Cancer Register. The hazard ratio associated with emphysema and airway wall thickness was assessed using Cox proportional hazards regression for cancer diagnoses.During 10 years of follow-up, non-pulmonary cancer was diagnosed in 11% of the subjects with LAA This study offers a strong argument that emphysema is an independent risk factor for both non-pulmonary cancer and lung cancer.

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Prediction bias in spirometry reference equations can arise from combining equations for different age groups, rounding age or height to integers or using self-reported height. To assess the bias arising from these sources, the fit of 13 prediction equations was tested against the Global Lungs Initiative (GLI) dataset using spirometric data from 55,136 healthy Caucasians (54% female). The effects on predicted values of using whole-year age versus decimal age, and of a 1% bias in height, were quantified. In children, the prediction bias relative to GLI ranged from -22% to +17%. Switching equations at 18 yrs of age led to biases of between -846 (-14%) and +1,309 (+38%) mL. Using age in whole years rather than decimal age introduced biases from -8% to +7%, whereas a 1% overestimation of height introduced bias that ranged from +1% to +40%. Bias was greatest in children and adolescents, and in short elderly subjects. Using a single spirometry equation applicable across all ages and populations reduces prediction bias. Measuring and recording age and height accurately are also essential if bias is to be minimised.

Background: Differences in body composition are extensively investigated in subjects with COPD as low muscle mass was independently associated with increased morbidity and mortality. Also cardio-vascular co-morbidity is often reported in COPD and the contribution of fat mass in COPD related co-morbidity is gaining interest. We hypothesized that the prevalence of low muscle mass and high fat mass is higher in subjects with COPD compared to a group of current and former smokers without COPD, which result in higher reported cardiovascular co-morbidity in the COPD group. Methods: In 954 subjects with COPD and 955 subjects without COPD, body composition was assessed by bio-electrical impedance analysis and information on self-reported co-morbidity was collected. Participants were stratified for low fat free mass index and high fat mass index (resp. fat free mass index 50th percentile of the subjects without COPD). Results: Subjects with COPD were more likely to have low fat free mass index than current and former smokers without COPD. The prevalence of high fat mass index was comparable between the groups. The percentage of self-reported co-morbidity was higher in subjects with COPD, but only reports of myocardial infarction were disease specific. Conclusion: Low fat free mass index was more common in COPD, but the prevalence of high fat mass index was comparable between subjects with and without COPD. Nevertheless, subjects with COPD reported more myocardial infarction, implying that other factors than the amount of fat mass are involved in the increased co-morbidity in COPD.

Am J Respir Crit Care Med. 2012 Dec 15;186(12):1238-1247. Epub 2012 Nov 9 Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10(-8)), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552). PMID:23144326[PubMed - as supplied by publisher] Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P

BACKGROUND Physical activity (PA) is inversely associated with mortality in the general population. We wanted to quantify the association of self-reported PA with mortality from all causes, ischaemic heart disease (IHD) and stroke, and compare it with other known risk factors in different age segments. METHODS The Bergen Clinical Blood Pressure Survey examined a sample of 6811 Norwegian men and women in 1965-71 with follow-up until 2005-07. Cox proportional hazard regression ratio (HR) and population attributable fraction (PAF) were calculated for the old (>65), middle-aged (45-64) and young adults (22-44), respectively. We minimized confounding and bias by progressive comprehensive adjustments and subgroup-analyses (excluding early follow-up deaths, participants with self-reported disease and participants with changes in their PA-level prior baseline due to disease). RESULTS The HR [95% confidence interval (CI)] associated with a high PA-level was 0.63(0.56-0.71), 0.66(0.52-0.83) and 0.66(0.47-0.93) for mortality from all causes, IHD and stroke, respectively (reference: no participation in any of the listed activities, adjusted for age and gender). PAF (95% CI) of no/low activity (reference: any activity) was consistent across all age groups, varying from 7.3% (3.4-11.4) in the young adults to 9.1% (3.6-15.3) in the old. PAF of smoking and high s-cholesterol declined with increasing age [smoking from 19.9% (15.3-24.7) to 1.5% (-1.3 to 6.2) and s-cholesterol from 11.5% (5.6-17.5) to -9.5% (-18.1 to -0.7)], whereas PAF of hypertension increased from 5.3% (2.1-9.1) to 18.9% (8.3-28.4). CONCLUSION The relative importance of traditional risk factors varies between the age groups, but physical activity is a major health promoting factor across all age segments and should be encouraged particularly in an ageing population.

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2x10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p

SummaryThere is limited knowledge on the relationship between diffusing capacity of the lung for carbon monoxide (DLCO) and quantitative computed tomography (CT) measures of emphysema and airway wall thickness.Study questionWhat is the relationship between DLCO and the quantitative CT measures of emphysema and airway wall thickness in subjects with and without COPD?MethodsWe included 288 COPD subjects (70% men) and 425 non-COPD subjects (54% men). All subjects were current or ex-smokers older than 40 years and all subjects underwent spirometry, diffusing capacity tests and CT examination. Quantitative CT measures included % low attenuation areas

Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein-D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran-Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein-D (SP-D) in the ECLIPSE Study. In the NETT-NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV(1) (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.

Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity-associated (FTO) gene, and BMI (P = 4.97 × 10(-7)) and FFMI (P = 1.19 × 10(-7)). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10(-3)). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.

Introduction: Few population-based studies are available on more than 5 years survival of lung cancer patients. Objectives: The aims of this report were to study the survival and the predictors of survival in all lung cancer patients in a defined population and to determine whether and how the length of time from symptom onset to confirmed diagnosis (delay time) influenced survival. Methods: In a retrospective study, all incident cases from the Norwegian Cancer Registry and the hospital records in the Haugalandet area from 1990 to 1996 were followed until 31 December 2008. The dates of symptom onset, diagnosis, and death and information about demographics, initial stage, performance status, histology and initial symptoms were recorded. Results: Of a total of 271 patients, 57 (21%) were women, and the mean age at diagnosis was 67.4 years. One-year survival was 29.2%, and five- and 10-year survival was 8.5% and 5.5%, respectively. The median (inter quartile range, IQR) survival time was 5.7 (1.9, 14.1) months and the median (IQR) delay time was 2.2 (1.1, 3.7) months. Twenty-five patients (10% of those who died) had a non-lung cancer cause of death. No weight loss at the time of diagnosis was a significant predictor for long survival in addition to younger age, limited stage, good functional performance and surgical treatment, but delay time for diagnosis had no effect on survival time for lung cancer. Conclusion: In the whole population of lung cancer patients, long-term survival remains poor and is not influenced by the diagnostic delay time. Please cite this paper as: Skaug K, Eide GE and Gulsvik A. Predictors of long-term survival of lung cancer patients in a Norwegian community. Clin Respir J 2011; 5: 50–58.

The aim of our study was to examine sex-specific associations between different aspects of socioeconomic status (SES) (educational level, occupational status, income) and lung function in a general adult population. In the Hordaland County Cohort Study, 1,644 subjects aged 26-82 yrs at baseline answered questionnaires and performed post-bronchodilator spirometry both in 1996-1997 and in 2003-2006. We performed adjusted linear regression analysis on the effect of SES on decline in forced experimental volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC. Mean annual decline in FEV(1) from baseline to follow-up was 57 mL (se 1.3) and 48 mL (se 1.0) for males and females, respectively. Males had a larger decline in FVC than females, while females had a larger decline in FEV(1)/FVC. Lower education and low occupational status were associated with larger male lung function decline. SES did not affect female lung function decline. However, marital status was a significant predictor; unmarried females had less decline than both married and widowed females in both FEV(1) (adjusted mean annual difference 8 mL and 16 mL) and FVC (adjusted mean annual difference 8 mL and 18 mL). Low SES was associated with increased lung function decline in males. For females, marital status was more important.