Jon A. Hardie

Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined stage 1 chronic obstructive pulmonary disease (COPD) as forced expiratory volume in one second/forced vital capacity (FEV1/FVC)% <70% and a FEV1% predicted of >80%. Stage 2 has been defined as FEV1/FVC <70% and a FEV1% pred of <80%. The authors examined the extent of COPD misdiagnosis using this definition in healthy, never-smoker, asymptomatic adults aged >70 yrs in Bergen, Norway. A respiratory questionnaire was mailed to a random sample of 2,871 persons aged>70 yrs. In a random, well-defined subgroup of 208 never-smoker respondents with no current respiratory disease and significant dyspnoea or heart disease/hypertension complicated with dyspnoea, 71 were able to perform an acceptable spirometry. Approximately 35% of these healthy, elderly never-smokers had an FEV1/FVC% of <70% and would be classified as having at least a stage 1 COPD. This percentage increased with age and in those aged >80 yrs ∼50% would be classified as having COPD and approximately one-third would have an FEV1 of <80% pred (stage 2 COPD). The estimated 5th percentile of FEV1 was consistently <80% pred. The Global Initiative for Chronic Obstructive Lung Disease criteria will probably lead to a significant degree of over-diagnosis of chronic obstructive pulmonary disease in those aged >70 yrs. The criteria used to define the various stages of chronic obstructive pulmonary disease need to be age-specific.

Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study

Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls. 409 COPD patients and 231 healthy subjects, aged 40–75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of >10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA. After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p<0.05), and higher levels of CRP (p<0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p<0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p<0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p<0.05). The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.

Chronic Obstructive Pulmonary Disease Is Associated with Low Levels of Vitamin D

Introduction COPD patients may be at increased risk for vitamin D (25(OH)D) deficiency, but risk factors for deficiency among COPD patients have not been extensively reported. Methods Serum 25(OH)D levels were measured by liquid chromatography double mass spectrometry in subjects aged 40–76 years from Western Norway, including 433 COPD patients (GOLD stage II-IV) and 325 controls. Levels <20 ng/mL defined deficiency. Season, sex, age, body mass index (BMI), smoking, GOLD stage, exacerbation frequency, arterial oxygen tension (PaO2), respiratory symptoms, depression (CES-D score≥16), comorbidities (Charlson score), treatment for osteoporosis, use of inhaled steroids, and total white blood count were examined for associations with 25(OH)D in both linear and logistic regression models. Results COPD patients had an increased risk for vitamin D deficiency compared to controls after adjustment for seasonality, age, smoking and BMI. Variables associated with lower 25(OH)D levels in COPD patients were obesity ( = −6.63), current smoking ( = −4.02), GOLD stage III- IV ( = −4.71, = −5.64), and depression ( = −3.29). Summertime decreased the risk of vitamin D deficiency (OR = 0.22). Conclusion COPD was associated with an increased risk of vitamin D deficiency, and important disease characteristics were significantly related to 25(OH)D levels.

Neutrophil gelatinase-associated lipocalin: a biomarker in COPD.

BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) is an antimicrobial peptide that could be involved in the pathogenesis of COPD. This study aimed to measure the plasma levels of NGAL in a large cohort of patients with COPD and control subjects and examine the levels of NGAL by COPD characteristics. METHODS The study included 402 patients with COPD and 229 control subjects aged 40 to 76 years from the Bergen COPD Cohort Study. All patients with COPD had an FEV(1)/FVC ratio of < 0.7, an FEV(1) < 80% predicted, and a smoking history of ≥ 10 pack-years. Plasma levels of NGAL were determined by enzyme immunoassay. Linear regression models were fitted with NGAL as the outcome variable. Confounders examined were sex, age, smoking, Charlson comorbidity score, use of inhaled steroids, neutrophil cell count, plasma creatinine and ferritin, and C-reactive protein. RESULTS Mean ± SD plasma concentrations of NGAL were 75.1 ± 31.8 ng/mL in patients with COPD and 56.5 ± 22.0 ng/mL in control subjects (P < .01). NGAL levels were bivariately associated with age, smoking, body composition, Charlson comorbidity score, neutrophil blood count, creatinine, and C-reactive protein but were significantly elevated in patients with COPD, even after adjustment for confounders. Frequent exacerbations and hypoxemia was associated with higher levels of NGAL, whereas increasing Global Initiative for Chronic Obstructive Lung Disease stage was associated with lower levels of NGAL among patients with COPD. CONCLUSIONS Plasma levels of NGAL were significantly higher in patients with COPD compared with control subjects. NGAL was related to important COPD characteristics.

Predictors of diagnostic yield in bronchoscopy: a retrospective cohort study comparing different combinations of sampling techniques.

BackgroundThe reported diagnostic yield from bronchoscopies in patients with lung cancer varies greatly. The optimal combination of sampling techniques has not been finally established.The objectives of this study were to find the predictors of diagnostic yield in bronchoscopy and to evaluate different combinations of sampling techniques.MethodsAll bronchoscopies performed on suspicion of lung malignancy in 2003 and 2004 were reviewed, and 363 patients with proven malignant lung disease were included in the study. Sampling techniques performed were biopsy, transbronchial needle aspiration (TBNA), brushing, small volume lavage (SVL), and aspiration of fluid from the entire procedure. Logistic regression analyses were adjusted for sex, age, endobronchial visibility, localization (lobe), distance from carina, and tumor size.ResultsThe adjusted odds ratios (OR) with 95% confidence intervals (CI) for a positive diagnostic yield through all procedures were 17.0 (8.5–34.0) for endobronchial lesions, and 2.6 (1.3–5.2) for constriction/compression, compared to non-visible lesions; 3.8 (1.3–10.7) for lesions > 4 cm, 6.7 (2.1–21.8) for lesions 3–4 cm, and 2.5 (0.8–7.9) for lesions 2–3 cm compared with lesions <= 2 cm. The combined diagnostic yield of biopsy and TBNA was 83.7% for endobronchial lesions and 54.2% for the combined group without visible lesions. This was superior to either technique alone, whereas additional brushing, SVL, and aspiration did not significantly increase the diagnostic yield.ConclusionIn patients with malignant lung disease, visible lesions and larger tumor size were significant predictors of higher diagnostic yield, after adjustment for sex, age, distance from carina, side and lobe. The combined diagnostic yield of biopsy and TBNA was significant higher than with either technique alone.

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

Effect of Body Position on Arterial Oxygen Tension in the Elderly

Background: It is well known that body position can have an effect on gas exchange though the magnitude of this effect has not been studied thoroughly in the elderly. Objectives: This study analyzes the effect body position change has on arterial oxygen tension (PaO2) and arterial carbon dioxide tension (PaCO2) in healthy elderly. Methods: We tested 46 ‘lung-healthy’ elderly, including 30 women and 16 men, 67–88 years of age. Blood was drawn from the radial artery first in the sitting position and subsequently in the supine position. Spirometry was performed. Results: Mean (SD) sitting PaO2 was 10.53 kPa (1.22), whereas mean supine PaO2 was 9.85 kPa (1.33). The difference between sitting and supine PaO2 was 0.68 kPa (0.86) and was statistically significant. Sitting PaCO2 was 5.06 kPa (0.47) and supine PaCO2 was 5.05 kPa (0.54). The difference between sitting and supine PaO2 correlated positively with FEV1/FVC %, negatively with the corresponding difference between sitting and supine PaCO2,and negatively with BMI. Conclusions: We conclude that the significant difference in PaO2 in sitting and supine positions clearly shows that the position needs to be considered both when attempting to establish reference values and when evaluating gas exchange in elderly persons. The positional changes in oxygenation are related to the corresponding change in PaCO2, and to FEV1/FVC % and BMI.

Non-response bias in a postal questionnaire survey on respiratory health in the old and very old

Aims: The authors wished to describe non-responders and reasons for non-response and determine the magnitude and direction of non-response bias in connection with a postal questionnaire study of respiratory symptoms and disease among the elderly. Methods: An eight-page respiratory health questionnaire was mailed to subjects in a sex-age stratified random sample of the general population of Bergen, Norway, 70 years or older (n=2,871). A reminder with repeat questionnaire was sent out to initial non-responders after three weeks. A random sample of non-responders was interviewed by telephone. Results: There were a total of 1,649 respondents (57.4%); 1,356 to the initial mailing and 293 to the reminder mailing. The response rates were highest for the age group 70 - 74 years (76.6%) and fell dramatically with age (27.1% in age group 95+years). Men responded (63.7%) better than women (52.0%) and this was consistent at every age level. Late and non-responders had slightly lower frequencies of respiratory symptoms but higher frequencies of current-smoker status. Conclusions: All found, differences between responders and non-responders were small and would have only minimal effects on the final prevalence estimates for respiratory symptoms and disease. In comparing the results based on initial responders to results based on all responders, associations between predictor variables and outcome variables were essentially the same, showing that a reminder had little effect on the results of the study.

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.

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.