Effect of stimulating waveform and of data processing on respiratory impedance measurement.

OBJECTIVE: Several commercial and custom-made forced oscillation technique (FOT) devices are used to assess respiratory system impedance. The impulse oscillometry system (IOS) is a widespread device, which yields similar but not identical results to those provided by other FOT systems. Differences may be related to the forcing waveform, the device hardware, or the data processing algorithms. We evaluated the agreement between resistance (R rs) and reactance (X rs) measurements while alternating between different forcing waveforms and data processing algorithms. APPROACH: We performed pre- and post-bronchodilator measurements in 20 patients with respiratory complaints. We generated pulse waveforms using an IOS, and sinusoidal oscillations by replacing the IOS loudspeaker with customized loudspeaker providing a 5 Hz sinusoidal pressure signal. Pressure and flow were measured using the IOS sensors and breathing circuit. We developed a data processing algorithm compatible to both forcing signals. We also applied commercial IOS software during pulse waveform and a least mean square (lms) algorithm during sinusoidal waveform. MAIN RESULTS: The median (5th, 95th percentile) differences between R rs and X rs were (1) -0.35 (-2.49, 1.23) and 0.16 (-1.63, 3.07 cmH2O*s l-1, when the same algorithm was used during pulse vs sinusoidal stimulus; (2) 0.34 (-2.33, 5.98) and 0.57 (-2.64, 6.09) cmH2O*s l-1, when our algorithm and the IOS software were used during pulse waveform; and (3) 0.33 (-1.20, 6.05) and 0.25 (-4.94, 4.28) cmH2O*s l-1 when the IOS software was used during pulse and the lms algorithm during sinusoidal waveforms. SIGNIFICANCE: Both forcing signal and data processing contribute to differences in impedance values measured by different FOT devices.

Lung hyperinflation and functional exercise capacity in patients with COPD - a three-year longitudinal study.

BACKGROUND: Lung hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of lung hyperinflation and is associated with exercise intolerance. However, knowledge of its effect on longitudinal change in the 6-min walk distance (6MWD) in patients with COPD is scarce. We aimed to study whether the IC/TLC ratio predicts longitudinal change in 6MWD in patients with COPD. METHODS: This prospective cohort study included 389 patients aged 40-75 years with clinically stable COPD in Global Initiative for Chronic Obstructive Lung Disease stages II-IV. The 6MWD was measured at baseline, and after one and 3 years. We performed generalized estimating equation regression analyses to examine predictors for longitudinal change in 6MWD. Predictors at baseline were: IC/TLC ratio, age, gender, pack years, fat mass index (FMI), fat-free mass index (FFMI), number of exacerbations within 12 months prior to inclusion, Charlson index for comorbidities, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and light and hard self-reported physical activity. RESULTS: Reduced IC/TLC ratio (p < 0.001) was a statistically significant predictor for decline in 6MWD. With a 0.1-unit decrease in baseline IC/TLC ratio, the annual decline in 6MWD was 12.7 m (p < 0.001). Study participants with an IC/TLC ratio in the upper quartiles maintained their 6MWD from baseline to year 3, while it was significantly reduced for the patients with an IC/TLC ratio in the lower quartiles. Absence of light and hard physical activity, increased age and FMI, decreased FEV1 and FVC, more frequent exacerbations and higher Charlson comorbidity index were also predictors for lower 6MWD at any given time, but did not predict higher rate of decline over the timespan of the study. CONCLUSION: Our findings demonstrated that patients with less lung hyperinflation at baseline maintained their functional exercise capacity during the follow-up period, and that it was significantly reduced for patients with increased lung hyperinflation.

Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients.

RATIONALE: Clinical phenotyping, therapeutic investigations as well as genomic, airway secretion metabolomic and metagenomic investigations can benefit from robust, nonlinear modeling of FEV1 in individual subjects. We demonstrate the utility of measuring FEV1 dynamics in representative cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) populations. METHODS: Individual FEV1 data from CF and COPD subjects were modeled by estimating median regression splines and their predicted first and second derivatives. Classes were created from variables that capture the dynamics of these curves in both cohorts. RESULTS: Nine FEV1 dynamic variables were identified from the splines and their predicted derivatives in individuals with CF (n = 177) and COPD (n = 374). Three FEV1 dynamic classes (i.e. stable, intermediate and hypervariable) were generated and described using these variables from both cohorts. In the CF cohort, the FEV1 hypervariable class (HV) was associated with a clinically unstable, female-dominated phenotypes while stable FEV1 class (S) individuals were highly associated with the male-dominated milder clinical phenotype. In the COPD cohort, associations were found between the FEV1 dynamic classes, the COPD GOLD grades, with exacerbation frequency and symptoms. CONCLUSION: Nonlinear modeling of FEV1 with splines provides new insights and is useful in characterizing CF and COPD clinical phenotypes.

The association of tidal EFL with exercise performance, exacerbations, and death in COPD.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is frequently found in patients with COPD and can be detected by forced oscillations when within-breath reactance of a single-breath is ≥0.28 kPa·s·L-1. The present study explored the association of within-breath reactance measured over multiple breaths and EFLT with 6-minute walk distance (6MWD), exacerbations, and mortality. METHODS: In 425 patients, spirometry and forced oscillation technique measurements were obtained on eight occasions over 3 years. 6MWD was assessed at baseline and at the 3-year visit. Respiratory symptoms, exacerbations, and hospitalizations were recorded. A total of 5-year mortality statistics were retrieved retrospectively. We grouped patients according to the mean within-breath reactance [Formula: see text], measured over several breaths at baseline, calculated as mean inspiratory-mean expiratory reactance over the sampling period. In addition to the established threshold of EFLT, an upper limit of normal (ULN) was defined using the 97.5th percentile of [Formula: see text], of the healthy controls in the study; 6MWDs were compared according to [Formula: see text], as normal, ≥ ULN < EFLT, or ≥ EFLT. Annual exacerbation rates were analyzed using a negative binomial model in the three groups, supplemented by time to first exacerbation analysis, and dichotomizing patients at the ULN. RESULTS: In patients with COPD and baseline [Formula: see text] below the ULN (0.09 kPa·s·L-1), 6MWD was stable. 6MWD declined significantly in patients with [Formula: see text]. Worse lung function and more exacerbations were found in patients with COPD with [Formula: see text], and patients with [Formula: see text] had shorter time to first exacerbation and hospitalization. A significantly higher mortality was found in patients with [Formula: see text] and FEV1 >50%. CONCLUSION: Patients with baseline [Formula: see text] had a deterioration in exercise performance, more exacerbations, and greater hospitalizations, and, among those with moderate airway obstruction, a higher mortality. [Formula: see text] is a novel independent marker of outcome in COPD.

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.

Antimicrobial peptide levels are linked to airway inflammation, bacterial colonisation and exacerbations in chronic obstructive pulmonary disease.

Antimicrobial peptides (AMPs) are effectors of host defence against infection, inflammation and wound repair. We aimed to study AMP levels in stable chronic obstructive pulmonary disease (COPD) and during acute exacerbations of COPD (AECOPD), and to examine their relation to clinical parameters and inflammatory markers.The 3-year Bergen COPD Cohort Study included 433 COPD patients and 325 controls. Induced sputum was obtained and analysed for levels of the AMPs human cathelicidin (hCAP18/LL-37) and secretory leukocyte protease inhibitor (SLPI), and for the inflammatory markers interleukin (IL)-8, IL-6 and tumour necrosis factor-α (TNF-α) using immunoassays. Systemic hCAP18/LL-37 and vitamin D levels were also studied. Treating AMPs as response variables, non-parametric tests were applied for univariate comparison, and linear regression to obtain adjusted estimates. The risk of AECOPD was assessed by Cox proportional-hazard regression.Sputum AMP levels were higher in patients with stable COPD (n=215) compared to controls (n=45), and further changed during AECOPD (n=56), with increased hCAP18/LL-37 and decreased SLPI levels. Plasma hCAP18/LL-37 levels showed a similar pattern. In stable COPD, high sputum hCAP18/LL-37 levels were associated with increased risk of AECOPD, non-typeable Haemophilus influenzae colonisation, higher age, ex-smoking and higher levels of inflammatory markers.Altered levels of selected AMPs are linked to airway inflammation, infection and AECOPD, suggesting a role for these peptides in airway defence mechanisms in COPD.

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.

Peak oxygen uptake and breathing pattern in COPD patients--a four-year longitudinal study.

BACKGROUND: Activities of daily living in patients with chronic obstructive pulmonary disease (COPD) are limited by exertional dyspnea and reduced exercise capacity. The aims of the study were to examine longitudinal changes in peak oxygen uptake (V̇O2peak), peak minute ventilation (V̇Epeak) and breathing pattern over four years in a group of COPD patients, and to examine potential explanatory variables of change. METHODS: This longitudinal study included 63 COPD patients, aged 44-75 years, with a mean forced expiratory volume in one second (FEV1) at baseline of 51 % of predicted (SD = 14). The patients performed two cardiopulmonary exercise tests (CPETs) on treadmill 4.5 years apart. The relationship between changes in V̇O2peak and V̇Epeak and possible explanatory variables, including dynamic lung volumes and inspiratory capacity (IC), were analysed by multivariate linear regression analysis. The breathing pattern in terms of the relationship between minute ventilation (V̇E) and tidal volume (VT) was described by a quadratic equation, VT = a + b∙V̇E + c∙V̇E (2), for each test. The VTmax was calculated from the individual quadratic relationships, and was the point where the first derivative of the quadratic equation was zero. The mean changes in the curve parameters (CPET2 minus CPET1) and VTmax were analysed by bivariate and multivariate linear regression analyses with age, sex, height, changes in weight, lung function, IC and inspiratory reserve volume as possible explanatory variables. RESULTS: Significant reductions in V̇O2peak (p < 0.001) and V̇Epeak (p < 0.001) were related to a decrease in resting IC and in FEV1. Persistent smoking contributed to the reduction in V̇O2peak. The breathing pattern changed towards a lower VT at a given V̇E and was related to the reduction in FEV1. CONCLUSION: Increasing static hyperinflation and increasing airway obstruction were related to a reduction in exercise capacity. The breathing pattern changed towards more shallow breathing, and was related to increasing airway obstruction.

Vitamin D, vitamin D binding protein, and longitudinal outcomes in COPD.

BACKGROUND: Associations between Vitamin D3 [25(OH)D], vitamin D binding protein (VDBP) and chronic obstructive pulmonary disease (COPD) are previously reported. We aimed to further investigate these associations on longitudinal outcomes. METHODS: 426 COPD patients from western Norway, GOLD stage II-IV, aged 40-76, were followed every six-month from 2006 through 2009 with spirometry, bioelectrical impedance measurements and registration of exacerbation frequency. Serum 25(OH)D and VDBP levels were determined at study-entry by high-performance liquid chromatography coupled with mass spectrometry and enzyme immunoassays respectively. Yearly change in lung function and body composition was assessed by generalized estimating equations (GEE), yearly exacerbation rate by negative binomial regression models, and 5 years all-cause mortality by Cox proportional-hazard regression. RESULTS: 1/3 of the patients had vitamin D deficiency (<20ng/mL) and a greater decline in both FEV1 and FVC, compared to patients with normal levels; for FEV1 this difference only reached statistical significance in the 28 patients with the lowest levels (<10ng/mL, p = 0.01). Neither 25(OH)D nor VDBP levels predicted exacerbation rate, change in fat free mass index or risk of death. CONCLUSION: Severe vitamin D deficiency may affect decline in lung function parameters in COPD. Neither 25(OH)D nor VDBP levels did otherwise predict markers of disease progression.

Serial Measurements of Arterial Oxygen Tension are Associated with Mortality in COPD.

BACKGROUND: Knowledge on factors associated with mortality can help identify patients with COPD that might benefit from close monitoring and intervention. Arterial blood gases (ABGs) are related to mortality, but both arterial tension of oxygen (PaO2) and arterial tension of carbon dioxide (PaCO2) vary over time. The aim of our study was to investigate the association between repeatedly measured ABGs and mortality in men and women with COPD. METHODS: A cohort of 419 Norwegian subjects with COPD, GOLD stage II-IV, aged 40-75, was followed up with up to seven ABGs, measured during stable phase for three years. Cox proportional hazard models were used to quantify the relationship between both single and repeatedly measured ABGs and all-cause mortality after five years, adjusting for age, sex, and the updated BODE index. RESULTS: A total of 64 subjects died during follow-up. Mean initial arterial oxygen tension (standard deviation) was significantly higher in survivors compared to deceased, with PaO2 (in kPa) 9.4 (1.1) versus 8.8 (1.2), p<0.001. Corresponding numbers for PaCO2 were 5.3 (0.5) and 5.5 (0.7), p < 0.001. In analyses adjusting for age, sex, and the updated BODE index hazard ratios - HR(95% confidence intervals) - for all-cause mortality were 0.73 (0.55, 0.97) and 1.58 (0.90, 2.76) for repeated measures of PaO2 and PaCO2, respectively. CONCLUSION: Both arterial oxygen and carbon dioxide tension were related to mortality in this study, and arterial oxygen tension added prognostic information to the updated BODE index in COPD.

Variability of within-breath reactance in COPD patients and its association with dyspnoea.

The forced oscillation technique can identify expiratory flow limitation (EFL) when a large difference in inspiratory and expiratory reactance (ΔXrs) occurs. However, flow limitation can vary from breath to breath, and so we compared a multiple-breath ΔXrs approach to the traditional breath-by-breath assessment of EFL. We investigated the within- and between-day reproducibility and the factors that affect the size of ΔXrs when used as a continuous measurement over multiple breaths. In addition, we examined how multiple-breath ΔXrs relates to the sensation of breathlessness. 425 moderate to very severe chronic obstructive pulmonary disease (COPD) patients and 229 controls were included. Spirometry and impedance measurements were performed on a MasterScope CT Impulse Oscillation System. Median ΔXrs approached zero in healthy controls with little variation between measurements. COPD patients generally had higher ΔXrs and higher variability. The COPD patients with ΔXrs >0.1 kPa · L(-1) · s(-1) were prone to be more breathless and had a higher modified Medical Research Council dyspnoea scale score. In controls, the 95th percentile of ΔXrs was as low as 0.07 kPa · L(-1) · s(-1). We describe a new method to assess EFL at a patient level and propose a cut-off, mean ΔXrs >0.1 kPa · L(-1) · s(-1), as a way to identify COPD patients who are more likely to report dyspnoea.

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.

Airway obstruction, dynamic hyperinflation, and breathing pattern during incremental exercise in COPD patients.

Ventilatory capacity is reduced in chronic obstructive pulmonary disease (COPD) patients. Tidal volume (V T) is lower and breathing frequency higher at a given ventilation (V E) compared to healthy subjects. We examined whether airflow limitation and dynamic hyperinflation in COPD patients were related to breathing pattern. An incremental treadmill exercise test was performed in 63 COPD patients (35 men), aged 65 years (48-79 years) with a mean forced expiratory volume in 1 sec (FEV1) of 48% of predicted (SD = 15%). Data were averaged over 20-sec intervals. The relationship between V E and V T was described by the quadratic equation V T = a + bV E + cV E (2) for each subject. The relationships between the curve parameters b and c, and spirometric variables and dynamic hyperinflation measured as the difference in inspiratory capacity from start to end of exercise, were analyzed by multivariate linear regression. The relationship between V E and V T could be described by a quadratic model in 59 patients with median R (2) of 0.90 (0.40-0.98). The linear coefficient (b) was negatively (P = 0.001) and the quadratic coefficient (c) positively (P < 0.001) related to FEV1. Forced vital capacity, gender, height, weight, age, inspiratory reserve volume, and dynamic hyperinflation were not associated with the curve parameters after adjusting for FEV1. We concluded that a quadratic model could satisfactorily describe the relationship between V E and V T in most COPD patients. The curve parameters were related to FEV1. With a lower FEV1, maximal V T was lower and achieved at a lower V E. Dynamic hyperinflation was not related to breathing pattern when adjusting for FEV1.

Physical activity and longitudinal change in 6-min walk distance in COPD patients.

BACKGROUND: The 6-min walk distance (6MWD) is widely used to evaluate functional capacity in patients with chronic obstructive pulmonary disease (COPD). AIM: To examine predictors for longitudinal change in 6MWD including self-reported physical activity, smoking habits, body composition, exacerbations, comorbidity and lung function. METHODS: The cohort included 389 patients aged 44-75 years, with clinically stable COPD in GOLD stages II-IV. The follow-up time was 3 years. Measurements included 6MWD, spirometry, fat and fat free mass index (FMI and FFMI), and assessment of physical activity, smoking habits, comorbidities and exacerbations by questionnaires. Generalized estimating equations (GEE) regression analyses were used to analyze predictors for the change in 6MWD. RESULTS: There was a reduction in 6MWD from baseline to 3 years for patients in GOLD stages III and IV (B = -36 m, 95% CI = -51 to -7, p = 0.009 and B = -79 m, CI = -125 to -20, p = 0.007). The unadjusted GEE analysis demonstrated that baseline self-reported physical activity level, forced expiratory volume in one second (FEV1), forced vital capacity, FFMI, GOLD stages and age predicted change in 6MWD, but in the adjusted GEE analysis only self-reported physical activity level (p = 0.001) and FEV1 (p = 0.019) predicted change over time. CONCLUSION: Patients in GOLD stage II maintained their functional capacity assessed by 6MWD over 3 years, while it was significantly reduced for patients in GOLD stages III and IV. Level of physical activity and FEV1 were predictors for longitudinal change in functional capacity.

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.

TNF-α is associated with loss of lean body mass only in already cachectic COPD patients.

BACKGROUND: Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years. METHODS: The patients, aged 40-76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models. RESULTS: At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry. CONCLUSION: This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.

Different COPD disease characteristics are related to different outcomes in the 6-minute walk test.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) can lead to severe disability as the disease advances. The 6-minute walk test (6MWT) is commonly used to measure functional capacity in COPD patients and has three potential outcomes; walking distance, oxygen desaturation, and self-perceived dyspnea assessed by the Borg scale, all reflecting different aspects of COPD. The aim of this study was to identify predictors of all 3 outcomes of 6MWT in patients with COPD. METHODS: 370 COPD patients, aged 40-75 yrs, were included from the first phase of the Bergen COPD cohort study. They were examined with spirometry, bioelectrical impedance measurements, 6MWT, Center for Epidemiologic Studies of Depression (CES-D) Scale, Medical Research Council (MRC) dyspnea scale, Charlson index for co-morbidities, self-reported physical activity questionnaire, plasma levels of C-reactive protein (CRP) and arterial blood gases. RESULTS: Significant predictors in the multivariate analyses were sex, age, FEV(1) in % predicted, symptoms of dyspnea (MRC), co-morbidities (Charlson Index) and self-reported physical activity for walking distance, FEV(1) in % predicted and PaO(2) for oxygen desaturation, and body composition, smoking and co-morbidities for self-perceived dyspnea assessed by the Borg scale. CONCLUSION: Several COPD characteristics have predictive value for the 6MWT, and some COPD characteristics are more strongly related to specific 6MWT outcomes than others.

Association of exposure to environmental tobacco smoke in childhood with chronic obstructive pulmonary disease and respiratory symptoms in adults.

BACKGROUND AND OBJECTIVE: Exposure to environmental tobacco smoke (ETS) is associated with impaired lung function in childhood, which in turn, is associated with chronic obstructive pulmonary disease (COPD) in adulthood. However, little is known regarding the direct association between childhood exposure to ETS and the development of COPD. The main objective of the present study was to examine the associations between childhood ETS exposure and adult COPD and respiratory symptoms. METHODS: Patients with COPD (n = 433) and control subjects (n = 325) participated in the Bergen COPD Cohort Study during 2006-2009. Participants performed spirometry and answered extensive questionnaires. The risk factors for COPD, morning cough, cough with phlegm, chronic cough and dyspnoea were examined using logistic regression analysis. Analyses were stratified by gender. RESULTS: The prevalence of childhood exposure to ETS was 61%. After adjustment, women who were exposed to ETS during childhood had a higher risk of COPD than those who were not exposed: odds ratio 1.9, 95% confidence interval 1.0, 3.7. Other important predictors for COPD and respiratory symptoms among women were occupational dust exposure (COPD), family history of COPD (COPD, all symptoms), current exposure to ETS in the home (morning cough) and education (COPD, dyspnoea). ETS exposure during childhood was associated with respiratory symptoms among males (odds ratios 1.5-1.7). Risk factors for COPD among men were occupational dust exposure, family history of COPD and level of education. Occupational dust exposure and family history of COPD also predicted dyspnoea among males. CONCLUSIONS: Exposure to ETS during childhood was associated with COPD and respiratory symptoms in adulthood. Although active smoking is still the most important risk factor for COPD, reduction of childhood ETS exposure could contribute to the prevention of COPD and respiratory symptoms.

The prevalence of undiagnosed renal failure in a cohort of COPD patients in western Norway.

Patients with COPD are at risk for other comorbid diseases, like heart failure, coronary heart disease, and depression. However, little is known about COPD phenotypes and prevalence of sub-clinical renal failure. 433 COPD patients and 233 subjects without COPD, from Western Norway, age 40-75, GOLD stage II-IV, were examined in 2006/07 upon entry to the Bergen COPD Cohort Study. Plasma creatinine was measured in 422 of the COPD patients. The Glomerular Flow Rate (GFR) was determined with the Cockcroft Gault formula, and having a GFR < 60 was defined as renal failure. Examined explanatory factors were sex, age, smoking habits, GOLD stage, hypoxemia, exacerbation history, cachexia, use of daily inhaled steroids, Charlson comorbidity score, use of ACE inhibitors and/or ARBs, and the inflammatory plasma markers C-reactive protein (CRP), soluble tumor necrosis factor receptor 1 (sTNF-R1) and neutrophil gelatinase associated lipocalin (NGAL). Associations between explanatory variables and renal failure were examined by a logistic regression analysis. The prevalence of having GFR < 60 was 9.6% in female COPD patients and 5.1% in male COPD patients (p = 0.08). In multivariable analysis, female sex, higher age, cachexia, and the inflammatory markers sTNF-R1 and NGAL were all independently associated with a higher risk for renal failure, whereas use of inhaled steroids, Charlson score, GOLD stage, respiratory failure, and exacerbation frequency were not. Undiagnosed renal failure is a concern particularly in elderly COPD patients and COPD patients with cachexia.

High prevalence of respiratory symptoms during air travel in patients with COPD.

OBJECTIVE: The reduced pressure in aircraft cabins may cause severe hypoxemia and respiratory distress in patients with chronic obstructive pulmonary disease (COPD). The primary objective of this study was to determine the prevalence of in-flight symptoms in COPD patients and non-COPD subjects, and evaluate associations between these symptoms and pre-flight variables. METHODS: In a cross-sectional study of 391 COPD patients and 184 non-COPD subjects, we recorded lung function, blood gas values, exercise capacity, air travel habits and in-flight symptoms. RESULTS: Fifty-four percent of the COPD patients had travelled by air the last two years. Hypoxia-related symptoms during air travel were experienced in 25% of the COPD patients and 9% of the non-COPD subjects (p < 0.001). After adjusting for smoking status, age and gender, the odds ratio for COPD patients to experience dyspnea or air hunger was 6.6 (95% CI 2.5-17.3, p < 0.001) compared to non-COPD subjects. In the COPD patients, in-flight dyspnea or air hunger was strongly associated with pre-flight score on the Medical Research Council (MRC) Dyspnea scale (p < 0.001). CONCLUSION: COPD patients had significantly increased risk of in-flight dyspnea or air hunger compared to non-COPD subjects. In COPD patients these symptoms were strongly associated with pre-flight MRC Dyspnea score.