Ane Johannessen

Implications of reversibility testing on prevalence and risk factors for chronic obstructive pulmonary disease: a community study

Background: The Global Initiative for Obstructive Lung Disease (GOLD) has defined chronic obstructive pulmonary disease (COPD) as a post-bronchodilator ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of <0.7. In the first general population based study to apply post-bronchodilator values, the prevalence and predictors of GOLD defined COPD were assessed and the implications of β2 agonist reversibility testing examined. Methods: Based on a random population sample, 2235 subjects (77%) aged 26–82 years performed spirometric tests before and 15 minutes after inhaling 0.3 mg salbutamol. Results: The prevalence of GOLD defined COPD was 7.0% (95% confidence interval (CI) 5.9 to 8.0). This estimate was 27% lower than COPD defined without bronchodilatation. One percent of the population had severe or very severe COPD. Compared with women, men had 3.1 (95% CI 2.1 to 4.8) times higher odds for COPD. Subjects with a smoking history of more than 20 pack years had an odds ratio (OR) of 6.2 (95% CI 3.4 to 11.0) for COPD relative to never-smokers, while subjects older than 75 years had an OR of 18.0 (95% CI 9.2 to 35.0) relative to those below 45 years. Subjects with primary education only had an OR of 2.8 (95% CI 1.4 to 5.3) compared with those with university education. Subjects with body mass index (BMI) <20 kg/m2 were more likely than subjects with BMI 25–29.9 kg/m2 to have COPD (OR 2.4, 95% CI 1.1 to 5.3). The adjusted proportion of COPD attributable to smoking was 68%. Conclusions: These results indicate that community programmes on prevention of COPD should focus on anti-smoking, nutritional aspects, and socioeconomic conditions. The effect of β2 reversibility testing on prevalence estimates of COPD was substantial.

Gender differences in COPD: are women more susceptible to smoking effects than men?

Background The number of female smokers developing chronic obstructive pulmonary disease (COPD) is rapidly increasing, but whether or not there exists a differential susceptibility by gender remains controversial. Methods How smoking behaviour and subsequent lung function reduction differed by gender was examined in a study including 954 subjects with COPD and 955 subjects without COPD. The study focused on two subgroups: subjects with COPD <60 years of age (early-onset group, n=316) and subjects with COPD with <20 pack-years of smoking (low exposure group, n=241). Results In the low exposure group, female subjects with COPD had lower forced expiratory volume in 1 s (FEV1) % predicted (48.7% vs 55.8%, p=0.001) and more severe disease (50.4% vs 35.6%, p=0.020, in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 3 and 4) than male subjects with COPD. Females also had lower FEV1% predicted (50.6% vs 56.0%, p=0.006) and more severe COPD (41.7% vs 31.1% in GOLD stage 3 and 4, p=0.050) in the early-onset group. Using multivariate regression, female gender was associated with 5.7% lower FEV1% predicted in the low exposure group (p=0.012) and a similar trend was observed in the early-onset group (p=0.057). The number of pack-years was not significantly associated with lung function in female subjects with COPD in this study, and the dose–response relationship between smoking and lung function differed by gender at lower levels of smoking exposure. Interaction analysis suggested that the effect of smoking on lung function might be different by gender (p=0.027 in all subjects with COPD). Conclusions Female gender was associated with lung function reduction and more severe disease in subjects with COPD with early onset of disease or low smoking exposure. The findings may suggest a gender difference in susceptibility to the lung-damaging effects of cigarette smoking, but alternative explanations should be considered.

Mortality by Level of Emphysema and Airway Wall Thickness

RATIONALE There is limited knowledge of the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness (AWT) on mortality. OBJECTIVES 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. METHODS 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. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS AWT affected mortality with increasing degree of emphysema, whereas CT measure of emphysema was a strong independent mortality predictor.

Present and future costs of COPD in Iceland and Norway: Results from the BOLD study

The Burden of Obstructive Lung Disease (BOLD) initiative provides standardised estimates of the burden of chronic obstructive pulmonary disease (COPD) worldwide. We estimate the current and future economic burden of COPD in Reykjavik, Iceland and Bergen, Norway using data from the BOLD initiative. Data on utilisation of healthcare resources were gathered from the BOLD survey, existing literature and unit costs from national sources. Economic data were applied to a Markov model using transition probabilities derived from Framingham data. Sensitivity analyses were conducted varying unit costs, utilisation and prevalence of disease. The cost of COPD was \#8364;478 per patient per yr in Iceland and \#8364;284 per patient per yr in Norway. The estimated cumulative costs of COPD for the population aged ≥40 yrs, were \#8364;130 million and \#8364;1,539 million for the following 10 yrs in Iceland and Norway, respectively. Costs of COPD accounted for 1.2 and 0.7% of healthcare budgets in Iceland and Norway, respectively. Sensitivity analyses showed estimates were most sensitive to changes in exacerbation frequency. COPD has a significant economic burden in both Iceland and Norway and will grow in the future. Interventions aimed at avoiding exacerbations will have the most impact on costs of COPD over the next 20 yrs.

Comparison of 2011 and 2007 Global Initiative for Chronic Obstructive Lung Disease Guidelines for Predicting Mortality and Hospitalization

RATIONALE 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. OBJECTIVES 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. METHODS In the GenKOLS study, 912 patients with COPD (FEV1/FVC < 0.7 and FEV1 < 80% 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. MEASUREMENTS AND MAIN RESULTS 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). CONCLUSIONS The predictive ability of GOLD 2011 did not differ significantly from GOLD 2007 in terms of hospitalizations and mortality.

α1-antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts

BACKGROUND Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-antitrypsin, but whether they have an increased risk of COPD is uncertain. METHODS We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease. RESULTS PI MZ was associated with a 3.5% lower FEV₁/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV₁/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies. CONCLUSIONS Compared with PI MM individuals, PI MZ heterozygotes had lower FEV₁/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals.

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data

BACKGROUND There is no universal consensus on the best staging system for chronic obstructive pulmonary disease (COPD). Although documents (eg, the Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2007) have traditionally used forced expiratory volume in 1 s (FEV1) for staging, clinical parameters have been added to some guidelines (eg, GOLD 2011) to improve patient management. As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aimed to investigate how individual patients were categorised by GOLD 2007 and 2011, and compare the prognostic accuracy of the staging documents for mortality. METHODS We searched reports published from Jan 1, 2008, to Dec 31, 2014. Using data from cohorts that agreed to participate and had a minimum amount of information needed for GOLD 2007 and 2011, we did a patient-based pooled analysis of existing data. With use of raw data, we recalculated all participant assignments to GOLD 2007 I-IV classes, and GOLD 2011 A-D stages. We used survival analysis, C statistics, and non-parametric regression to model time-to-death data and compare GOLD 2007 and GOLD 2011 staging systems to predict mortality. FINDINGS We collected individual data for 15 632 patients from 22 COPD cohorts from seven countries, totalling 70 184 person-years. Mean age of the patients was 63·9 years (SD 10·1); 10 751 (69%) were men. Based on FEV1 alone (GOLD 2007), 2424 (16%) patients had mild (I), 7142 (46%) moderate (II), 4346 (28%) severe (III), and 1670 (11%) very severe (IV) disease. We compared staging with the GOLD 2007 document with that of the new GOLD 2011 system in 14 660 patients: 5548 (38%) were grade A, 2733 (19%) were grade B, 1835 (13%) were grade C, and 4544 (31%) were grade D. GOLD 2011 shifted the overall COPD severity distribution to more severe categories. There were nearly three times more COPD patients in stage D than in former stage IV (p<0·05). The predictive capacity for survival up to 10 years was significant for both systems (p<0·01) but area under the curves were only 0·623 (GOLD 2007) and 0·634 (GOLD 2011), and GOLD 2007 and 2011 did not differ significantly. We identified the percent predicted FEV1 thresholds of 85%, 55% and 35% as better to stage COPD severity for mortality, which are similar to the ones used previously. INTERPRETATION Neither GOLD COPD classification schemes have sufficient discriminatory power to be used clinically for risk classification at the individual level to predict total mortality for 3 years of follow-up and onwards. Increasing intensity of treatment of patients with COPD due to their GOLD 2011 reclassification is not known to improve health outcomes. Evidence-based thresholds should be searched when exploring the prognostic ability of current and new COPD multicomponent indices. FUNDING None.

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. Known predictors and risk factors can only explain 13% of dyspnoea variation http://ow.ly/tHS0H

Feasible And Simple Exclusion Criteria For Pulmonary Reference Populations

Background: International guidelines recommend that pulmonary reference populations consist of never-smokers without respiratory diseases or symptoms, but the diseases and symptoms are not clearly specified. The present study aimed to identify simple exclusion criteria for defining pulmonary reference populations. Methods: Based on a random sample from a general population (the parent population), 2358 subjects aged 26–82 years performed spirometric tests. From this sample, subjects were stepwise excluded according to self-reported obstructive lung diseases, symptoms and smoking history. Four increasingly more healthy respiratory reference populations were formed. Prediction equations for the median and lower limit of normal lung function were derived using quantile regression analysis. Results: Subjects without self-reported obstructive lung diseases or the cardinal respiratory symptoms of breathlessness, cough or wheeze (population B), never-smokers without cardinal symptoms (population C) and never-smokers without any respiratory symptoms (population D) constituted 50% (n = 1184), 23% (n = 539) and 14% (n = 331) of the parent population (population A), respectively. The largest discrepancy between prediction equations was found between the parent population and the population without cardinal respiratory symptoms (population B) (p<0.05). Minor changes in the reference equations were also seen when excluding ever-smokers (population C). There was no additional change with exclusion of other respiratory symptoms (population D). Age-related decline in lung function was steepest in the parent population. Conclusions: Obstructive lung diseases, smoking history, breathlessness, cough and wheeze are optimal exclusion criteria for a pulmonary reference population. Further validation of the exclusion criteria identified in this study is recommended with identical wording in other and larger multinational populations.

Body composition and plasma levels of inflammatory biomarkers in COPD

Previous studies suggest a relationship between systemic inflammation and body composition in chronic obstructive pulmonary disease (COPD). We examined the relationships between body composition (fat free mass index (FFMI) kg·m−2 and fat mass index (FMI) kg·m−2) and three plasma inflammatory markers C-reactive Protein (CRP), soluble tumour necrosis factor receptor 1 (sTNF-R1) and osteoprotegerin (OPG) in 409 stable COPD patients (aged 40–75 yrs, Global Initiative for Obstructive Chronic Lung Disease (GOLD) categories II-IV, 249 male) from the Bergen COPD Cohort Study in Norway. FFMI and FMI were measured by bioelectrical impedance. Plasma CRP (&mgr;g·mL−1), sTNF-R1 (pg·mL−1) and OPG (ng·mL−1) were determined by enzyme immunoassays. Correlations and Kruskal–Wallis tests were used for bivariate analyses. Linear regression models were fitted for each of the three markers, CRP, sTNF-R1 and OPG, with FFMI and FMI as explanatory variables including sex, age, smoking habits, GOLD category, hypoxaemia, Charlson Comorbidity Index and inhaled steroid use as potential confounders. CRP and sTNF-R1 levels correlated positively with both FFMI and FMI. The adjusted regression coefficients for an increase in logCRP per unit increase in FFMI was 1.23 (1.14–1.33) kg·m−2 and 24.9 (11.8–38.1) kg·m−2 for sTNF-R1. Higher FMI was associated with a lower OPG, with adjusted regression coefficient -0.14 (-0.23– -0.04), whereas FFMI was unrelated to OPG. In conclusion, COPD patients with low FFMI had lower not higher plasma levels of CRP and sTNF-R1, whereas higher fat mass was associated with higher CRP and sTNF-R1 and lower OPG.