Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD.

Increased levels of growth differentiation factor-15 (GDF15) are associated with cachexia, cardiovascular disease and all-cause mortality. The role of GDF15 in chronic obstructive pulmonary disease (COPD) is unknown.The study included 413 patients with COPD from the Bergen COPD Cohort Study. All patients had a forced expiratory volume in 1 s (FEV1) <80% predicted, a FEV1 to forced vital capacity (FVC) ratio <0.7 and a history of smoking. Spirometry, fat free mass index, blood gases and plasma GDF15 were measured at baseline. Patients were followed for 3 years regarding exacerbations and changes in lung function, and 9 years for mortality. Yearly exacerbation rate, survival and yearly change in FEV1/FVC were evaluated with regression models.Median plasma GDF15 was 0.86 ng·mL-1 (interquartile range 0.64-1.12 ng·mL-1). The distribution was not normal and GDF15 was analysed as a categorical variable. High levels of GDF15 were associated with a higher exacerbation rate (incidence rate ratio 1.39, 95% CI 1.1-1.74, p=0.006, adjusted values). Furthermore, high levels of GDF15 were associated with higher mortality (hazard ratio 2.07, 95% CI 1.4-3.1, p<0.001) and an increased decline in both FEV1 (4.29% versus 3.25%) and FVC (2.63% versus 1.44%) in comparison to low levels (p<0.01 for both).In patients with COPD, high levels of GDF15 were independently associated with a higher yearly rate of exacerbations, higher mortality and increased decline in both FEV1 and FVC.

Unemployment in chronic airflow obstruction around the world: results from the BOLD study.

We aimed to examine associations between chronic airflow obstruction (CAO) and unemployment across the world.Cross-sectional data from 26 sites in the Burden of Obstructive Lung Disease (BOLD) study were used to analyse effects of CAO on unemployment. Odds ratios for unemployment in subjects aged 40-65 years were estimated using a multilevel mixed-effects generalised linear model with study site as random effect. Site-by-site heterogeneity was assessed using individual participant data meta-analyses.Out of 18 710 participants, 11.3% had CAO. The ratio of unemployed subjects with CAO divided by subjects without CAO showed large site discrepancies, although these were no longer significant after adjusting for age, sex, smoking and education. The site-adjusted odds ratio (95% CI) for unemployment was 1.79 (1.41-2.27) for CAO cases, decreasing to 1.43 (1.14-1.79) after adjusting for sociodemographic factors, comorbidities and forced vital capacity. Of other covariates that were associated with unemployment, age and education were important risk factors in high-income sites (4.02 (3.53-4.57) and 3.86 (2.80-5.30), respectively), while female sex was important in low- to middle-income sites (3.23 (2.66-3.91)).In the global BOLD study, CAO was associated with increased levels of unemployment, even after adjusting for sociodemographic factors, comorbidities and lung function.

Absolute values of lung function explain the sex difference in breathlessness in the general population.

Activity-related breathlessness is twice as common among females as males in the general population and is associated with adverse health outcomes. We tested whether this sex difference is explained by the lower absolute forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) in females.This was a cross-sectional analysis of 3250 subjects (51% female) aged 38-67 years across 13 countries in the population-based third European Community Respiratory Health Survey. Activity-related breathlessness was measured using the modified Medical Research Council (mMRC) scale. Associations with mMRC were analysed using ordered logistic regression clustering on centre, adjusting for post-bronchodilator spirometry, body mass index, pack-years smoking, cardiopulmonary diseases, depression and level of exercise.Activity-related breathlessness (mMRC ≥1) was twice as common in females (27%) as in males (14%) (odds ratio (OR) 2.21, 95% CI 1.79-2.72). The sex difference was not reduced when controlling for FEV1 % predicted (OR 2.33), but disappeared when controlling for absolute FEV1 (OR 0.89, 95% CI 0.69-1.14). Absolute FEV1 explained 98-100% of the sex difference adjusting for confounders. The effect was similar within males and females, when using FVC instead of FEV1 and in healthy never-smokers.The markedly more severe activity-related breathlessness among females in the general population is explained by their smaller spirometric lung volumes.

Comparing microbiota profiles in induced and spontaneous sputum samples in COPD patients.

BACKGROUND: Induced and spontaneous sputum are used to evaluate the airways microbiota. Whether the sputum types can be used interchangeably in microbiota research is unknown. Our aim was to compare microbiota in induced and spontaneous sputum from COPD patients sampled during the same consultation. METHODS: COPD patients from Bergen, Norway, were followed between 2006/2010, examined during the stable state and exacerbations. 30 patients delivered 36 sample pairs. DNA was extracted by enzymatic and mechanical lysis methods. The V3-V4 region of the 16S rRNA gene was PCR-amplified and prepared for paired-end sequencing. Illumina Miseq System was used for sequencing, and Quantitative Insights Into Microbial Ecology (QIIME) and Stata were used for bioinformatics and statistical analyses. RESULTS: Approximately 4 million sequences were sorted into 1004 different OTUs and further assigned to 106 different taxa. Pair-wise comparison of both taxonomic composition and beta-diversity revealed significant differences in one or both parameters in 1/3 of sample pairs. Alpha-diversity did not differ. Comparing abundances for each taxa identified, showed statistically significant differences between the mean abundances in induced versus spontaneous samples for 15 taxa when disease state was considered. This included potential pathogens like Haemophilus and Moraxella. CONCLUSION: When studying microbiota in sputum samples one should take into consideration how samples are collected and avoid the usage of both induced and spontaneous sputum in the same study.

Macrophage migration inhibitory factor, a role in COPD.

Macrophage migration inhibitor factor (MIF) is a pluripotent cytokine associated with several different inflammatory conditions, but its role within lung inflammation and chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to examine MIF in both stable COPD and during acute exacerbations (AECOPD). The study included 433 patients with COPD aged 41-76 and 325 individuals from the Bergen COPD cohort study who served as controls. All patients had an FEV1 of <80% predicted, FEV1/FVC ratio of <0.7, and a smoking history >10 pack-years. Serum levels of MIF were compared between the two groups at baseline, and for 149 patients, measurements were also carried out during AECOPD. Linear regression models were fitted with MIF as the outcome variable and adjusted for sex, age, body composition, smoking, and Charlson Comorbidity Score (CCS). Median MIF (interquartile range) in patients with COPD was 20.1 ng/ml (13.5-30.9) compared with 14.9 ng/ml (11.1-21.6) in controls (P < 0.01). MIF was bivariately associated with sex, body composition, and CCS (P < 0.05 for all). In the regression analyses, MIF was significantly higher in patients with COPD, coefficient 1.32 (P < 0.01) and 1.30 (P < 0.01) unadjusted and adjusted, respectively. In addition, in 149 patients during episodes of AECOPD, MIF was significantly elevated, with a median of 23.2 ng/ml (14.1-42.3) compared with measurements at stable disease of 19.3 ng/ml (12.4-31.3, P < 0.01). Serum levels of MIF were significantly higher in patients with COPD compared with controls. We also identified an additional increase in MIF levels during episodes of AECOPD.

Predictors of dyspnoea prevalence: results from the BOLD study.

Dyspnoea is a cardinal symptom for cardiorespiratory diseases. No study has assessed worldwide variation in dyspnoea prevalence or predictors of dyspnoea. We used cross-sectional data from population-based samples in 15 countries of the Burden of Obstructive Lung Disease (BOLD) study to estimate prevalence of dyspnoea in the full sample, as well as in an a priori defined low-risk group (few risk factors or dyspnoea-associated diseases). Dyspnoea was defined by the modified Medical Research Council questions. We used ordered logistic regression analysis to study the association of dyspnoea with site, sex, age, education, smoking habits, low/high body mass index, self-reported disease and spirometry results. Of the 9484 participants, 27% reported any dyspnoea. In the low-risk subsample (n=4329), 16% reported some dyspnoea. In multivariate analyses, all covariates were correlated to dyspnoea, but only 13% of dyspnoea variation was explained. Females reported more dyspnoea than males (odds ratio ∼2.1). When forced vital capacity fell below 60% of predicted, dyspnoea was much more likely. There was considerable geographical variation in dyspnoea, even when we adjusted for known risk factors and spirometry results. We were only able to explain 13% of dyspnoea variation.

Protected sampling is preferable in bronchoscopic studies of the airway microbiome.

The aim was to evaluate susceptibility of oropharyngeal contamination with various bronchoscopic sampling techniques. 67 patients with obstructive lung disease and 58 control subjects underwent bronchoscopy with small-volume lavage (SVL) through the working channel, protected bronchoalveolar lavage (PBAL) and bilateral protected specimen brush (PSB) sampling. Subjects also provided an oral wash (OW) sample, and negative control samples were gathered for each bronchoscopy procedure. DNA encoding bacterial 16S ribosomal RNA was sequenced and bioinformatically processed to cluster into operational taxonomic units (OTU), assign taxonomy and obtain measures of diversity. The proportion of Proteobacteria increased, whereas Firmicutes diminished in the order OW, SVL, PBAL, PSB (p<0.01). The alpha-diversity decreased in the same order (p<0.01). Also, beta-diversity varied by sampling method (p<0.01), and visualisation of principal coordinates analyses indicated that differences in diversity were smaller between OW and SVL and OW and PBAL samples than for OW and the PSB samples. The order of sampling (left versus right first) did not influence alpha- or beta-diversity for PSB samples. Studies of the airway microbiota need to address the potential for oropharyngeal contamination, and protected sampling might represent an acceptable measure to minimise this problem.

Incidence of utilization- and symptom-defined COPD exacerbations in hospital- and population-recruited patients.

OBJECTIVES: The objectives of this study were to estimate the impact of recruitment source and outcome definition on the incidence of acute exacerbations of COPD (AECOPD) and explore possible predictors of AECOPD. PATIENTS AND METHODS: During a 1-year follow-up, we performed a baseline visit and four telephone interviews of 81 COPD patients and 132 controls recruited from a population-based survey and 205 hospital-recruited COPD patients. Both a definition based on health care utilization and a symptom-based definition of AECOPD were applied. For multivariate analyses, we chose a negative binomial regression model. RESULTS: COPD patients from the population- and hospital-based samples experienced on average 0.4 utilization-defined and 2.9 symptom-defined versus 1.0 and 5.9 annual exacerbations, respectively. The incidence rate ratios for utilization-defined AECOPD were 2.45 (95% CI 1.22-4.95), 3.43 (95% CI 1.59-7.38), and 5.67 (95% CI 2.58-12.48) with Global Initiative on Obstructive Lung Disease spirometric stages II, III, and IV, respectively. The corresponding incidence rate ratios for the symptom-based definition were 3.08 (95% CI 1.96-4.84), 3.45 (95% CI 1.92-6.18), and 4.00 (95% CI 2.09-7.66). Maintenance therapy (regular long-acting muscarinic antagonists, long-acting beta-2 agonists, inhaled corticosteroids, or theophylline) also increased the risk of AECOPD with both exacerbation definitions (incidence rate ratios 1.65 and 1.73, respectively). The risk of AECOPD was 59%-78% higher in the hospital sample than in the population sample. CONCLUSION: If externally valid conclusions are to be made regarding incidence and predictors of AECOPD, studies should be based on general population samples or adjustments should be made on account of a likely higher incidence in other samples. Likewise, the effect of different AECOPD definitions should be taken into consideration.

Complications and discomfort of bronchoscopy: a systematic review.

OBJECTIVE: To identify bronchoscopy-related complications and discomfort, meaningful complication rates, and predictors. METHOD: We conducted a systematic literature search in PubMed on 8 February 2016, using a search strategy including the PICO model, on complications and discomfort related to bronchoscopy and related sampling techniques. RESULTS: The search yielded 1,707 hits, of which 45 publications were eligible for full review. Rates of mortality and severe complications were low. Other complications, for instance, hypoxaemia, bleeding, pneumothorax, and fever, were usually not related to patient characteristics or aspects of the procedure, and complication rates showed considerable ranges. Measures of patient discomfort differed considerably, and results were difficult to compare between different study populations. CONCLUSION: More research on safety aspects of bronchoscopy is needed to conclude on complication rates and patient- and procedure-related predictors of complications and discomfort.

Participation in research bronchoscopy: a literature review.

Bronchoscopy is the preferred method for collecting biological samples from the lower airways of subjects in clinical research. However, ensuring participation in clinical research can be challenging when the research includes an invasive procedure. For this report we reviewed the literature to look for information on participation in research bronchoscopy studies to better design our own study, the Bergen COPD Microbiome study (MicroCOPD). We performed a systematic literature search on participation in research bronchoscopy studies in February 2014 using the search engines of PubMed and EMBASE. The literature search resulted in seven relevant papers. Motivation was an end point in six of the seven papers, but reasons for declining participation and recruitment strategies also seemed important. Human subjects participate in research bronchoscopy studies for personal benefit and altruistic reasons. Inconvenience associated with research, in addition to fear of procedures, is considered a barrier. Radio, especially news stations, generated the most inquiries for a clinical study involving bronchoscopy. There is a lack of information on participation in research bronchoscopy studies in the literature. A bronchoscopy study has been initiated at Haukeland University Hospital, Bergen, Norway, to examine the role of the microbiome in COPD, and participation will be explored as a substudy.

Productivity losses in chronic obstructive pulmonary disease: a population-based survey.

OBJECTIVES: We aimed to estimate incremental productivity losses (sick leave and disability) of spirometry-defined chronic obstructive pulmonary disease (COPD) in a population-based sample and in hospital-recruited patients with COPD. Furthermore, we examined predictors of productivity losses by multivariate analyses. METHODS: We performed four quarterly telephone interviews of 53 and 107 population-based patients with COPD and controls, as well as 102 hospital-recruited patients with COPD below retirement age. Information was gathered regarding annual productivity loss, exacerbations of respiratory symptoms and comorbidities. Incremental productivity losses were estimated by multivariate quantile median regression according to the human capital approach, adjusting for sex, age, smoking habits, education and lung function. Main effect variables were COPD/control status, number of comorbidities and exacerbations of respiratory symptoms. RESULTS: Altogether 55%, 87% and 31% of population-based COPD cases, controls and hospital patients, respectively, had a paid job at baseline. The annual incremental productivity losses were 5.8 (95% CI 1.4 to 10.1) and 330.6 (95% CI 327.8 to 333.3) days, comparing population-recruited and hospital-recruited patients with COPD to controls, respectively. There were significantly higher productivity losses associated with female sex and less education. Additional adjustments for comorbidities, exacerbations and FEV1% predicted explained all productivity losses in the population-based sample, as well as nearly 40% of the productivity losses in hospital-recruited patients. CONCLUSIONS: Annual incremental productivity losses were more than 50 times higher in hospital-recruited patients with COPD than that of population-recruited patients with COPD. To ensure a precise estimation of societal burden, studies on patients with COPD should be population-based.

Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study.

BACKGROUND: COPD exacerbations accelerate disease progression. AIMS: To examine if COPD characteristics and systemic inflammatory markers predict the risk for acute COPD exacerbation (AECOPD) frequency and duration. METHODS: 403 COPD patients, GOLD stage II-IV, aged 44-76 years were included in the Bergen COPD Cohort Study in 2006/07, and followed for 3 years. Examined baseline predictors were sex, age, body composition, smoking, AECOPD the last year, GOLD stage, Charlson comorbidity score (CCS), hypoxemia (PaO2<8 kPa), cough, use of inhaled steroids, and the inflammatory markers leucocytes, C-reactive protein (CRP), neutrophil gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor 1 (sTNF-R1), and osteoprotegrin (OPG). Negative binomial models with random effects were fitted to estimate the annual incidence rate ratios (IRR). For analysis of AECOPD duration, a generalized estimation equation logistic regression model was fitted, also adjusting for season, time since inclusion and AECOPD severity. RESULTS: After multivariate adjustment, significant predictors of AECOPD were: female sex [IRR 1.45 (1.14-1.84)], age per 10 year increase [1.23 (1.03-1.47)], >1 AECOPD last year before baseline [1.65 (1.24-2.21)], GOLD III [1.36 (1.07-1.74)], GOLD IV [2.90 (1.98-4.25)], chronic cough [1.64 (1.30-2.06)] and use of inhaled steroids [1.57 (1.21-2.05)]. For AECOPD duration more than three weeks, significant predictors after adjustment were: hypoxemia [0.60 (0.39-0.92)], years since inclusion [1.19 (1.03-1.37)], AECOPD severity; moderate [OR 1.58 (1.14-2.18)] and severe [2.34 (1.58-3.49)], season; winter [1.51 (1.08-2.12)], spring [1.45 (1.02-2.05)] and sTNF-R1 per SD increase [1.16 (1.00-1.35)]. CONCLUSION: Several COPD characteristics were independent predictors of both AECOPD frequency and duration.

The Bergen COPD microbiome study (MicroCOPD): rationale, design, and initial experiences.

BACKGROUND: Recent methodological developments, in particular new sequencing methods for bacterial RNA/DNA, have shown that microorganisms reside in airways that do not suffer from acute infection and that respiratory microbiota might vary according to airways disease status. We aim to establish high-quality sampling methods for lower airways microbiota as well as describe the respiratory microbiome in subjects with and without chronic obstructive pulmonary disease (COPD) and to relate the microbiome to disease development, progression, and the host immune system. METHODS: The Bergen COPD microbiome study (MicroCOPD) is a longitudinal study aiming to collect data from 200 subjects with COPD as well as 150 individuals without COPD. At baseline, subjects go through a bronchoscopy in which protected specimen brushes, small-volume lavage, bronchoalveolar lavage, and bronchial biopsies provide a unique chance to analyze the microbiota and the host immune system status. These variables will be related to baseline clinical parameters (lung function, smoking status, exacerbation frequency, arterial blood gases, comorbidities, and medications) as well as follow-up parameters (lung function changes, exacerbation frequency, mortality, and more). RESULTS: Per date more than 150 bronchoscopies have been performed, equally distributed between cases and controls, with a very low complication frequency. CONCLUSIONS: MicroCOPD will provide unique data on a large material, with insight on a new field of respiratory research.