Inhomogeneity of ventilation in smokers and mild COPD assessed by the ratio of alveolar volume to total lung capacity.

BACKGROUND: Previous studies have shown that the ratio between alveolar volume (VA) and total lung capacity (TLC) reflects ventilation heterogeneity in subjects with chronic obstructive pulmonary disease (COPD). However, the ratio and its correlation to respiratory symptoms had to our knowledge not previously been investigated in subjects with mild chronic airflow obstruction or without airflow obstruction (normal ratio FEV1/VC). The purpose of this study was to investigate potential connection between VA/TLC and respiratory symptoms, smoking habits and lung function parameters in subjects with normal spirometry and with mild chronic airflow obstruction. METHODS: We examined 450 subjects (82 non-smokers with normal spirometry, 298 subjects who smoked or had smoked earlier but had a normal spirometry and 70 subjects with chronical airflow obstruction) with routine lung function tests and a questionnaire regarding respiratory symptoms. RESULTS: This study showed 31 out of 54 subjects with a low VA/TLC had a normal ratio FEV1/VC. Of these subjects, 58.1 % had respiratory symptoms, compared to the group with normal ratio for both VA/TLC and FEV1/VC where 35.8 % had respiratory symptoms (p-value 0.02). CONCLUSION: This study has shown that within the group of subjects with a normal ratio FEV1/VC, those with a decreased ratio VA/TLC had a higher prevalence of respiratory symptoms compared to subjects with a normal VA/TLC ratio. These findings indicate that including the ratio VA/TLC in the evaluation of a pulmonary function test assessment might increase the possibility to identify subjects with early or at risk of lung disease.

Association of coronary calcium score with endothelial dysfunction and arterial stiffness.

BACKGROUND AND AIMS: The aim of the study was to determine potential associations between endothelial dysfunction and arterial stiffness, measured by peripheral arterial tonometry, and coronary artery calcium score (CACS) assessed by computed tomography (CT). METHODS AND RESULTS: The BIG3 study is a prospective longitudinal, non-interventional, pulmonary-cardiovascular cohort study exploring the three major smoking-induced diseases: cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, in a 45-75 aged cohort (mean 62 years), enriched in smokers. Computed tomography of the chest with assessment of CACS was performed in a selected subset of the participants (n = 2080). Peripheral arterial tonometry (EndoPAT) was used to assess endothelial function and arterial stiffness measured as reactive hyperaemia index (RHI) and augmentation index (AI), respectively. We observed significant associations of CACS, endothelial dysfunction, and arterial stiffness with several risk factors for coronary heart disease including age, sex, BMI, diabetes mellitus, and blood pressure. There was significant association of CACS, classified into three levels of severity, with RHI and AI (p = 0.0005 and p = 0.0009, respectively). For groups of increasing CACS (0, 1-400 and > 400 Agatston score), RHI decreased from median 1.89 (1.58-2.39), and 1.93 (1.62-2.41) to 1.77 (1.51-2.10). AI increased from median 14.3 (5.7-25.2), and 16.4 (8.1-27.6) to 18.0 (9.1-29.2). RHI, but not AI, remained significantly associated with CACS after risk factors adjustment. CONCLUSIONS: In this large study of coronary artery calcium and vascular function, we found an association between CACS and both endothelial dysfunction and arterial stiffness, indicating that they may reflect similar mechanisms for development of cardiovascular disease.

Fixed ratio or lower limit of normal for the FEV1 /VC ratio: relation to symptoms and extended lung function tests.

There is no general agreement on the spirometric definition of chronic obstructive pulmonary disease (COPD). The global initiative for obstructive lung disease recommends a fixed ratio between forced expiratory volume in one-second (FEV1 ) and forced vital capacity (FVC) of <0·7 (FR) for the diagnosis of COPD. European Respiratory Society and American Thoracic Society favour the use of the fifth percentile of the age-related FEV1 /FVC ratio (the lower limit of normal, LLN). The purpose of this study was to analyse extensive lung function tests in groups of subjects fulfilling none, either or both of the spirometric criteria for COPD. From a previous population-based study, 450 subjects were examined with spirometry, body pletysmography diffusing capacity for CO (DL,CO ), Impulse Oscillometry System (IOS) and answered a questionnaire on respiratory symptoms and diseases. Seventy subjects fulfilled both spirometric COPD criteria (FR+LLN+), 62 subjects the fixed ratio criterion (FR+) only. Of the remaining 318 subjects, 236 were ever smokers (N-ES). Significant differences between all groups were seen for FEV1 and DL,CO . Significant differences between groups were also seen for residual volume (RV) and RV/total lung capacity. For IOS, variables and symptoms increasingly abnormal values were seen from never smokers to FR+LLN+. This study shows that subjects meeting both spirometric COPD criteria frequently have symptoms and findings at extended lung function tests compatible with the diagnosis. Also subjects meeting the fixed ratio criterion only tend to have more symptoms and lung function findings compatible with COPD than ever-smoking subjects with FEV1 /VC > 0·7.

Echocardiographic consequences of smoking status in middle-aged subjects.

BACKGROUND: Smoking is known to have many short- and long-term cardiovascular effects. Cardiac index (CI), which is cardiac output indexed to body surface area, is considered to be a valid measure of cardiac performance. We investigated whether there were any differences in CI or other echocardiographic variables between never smokers, ex-smokers, and current smokers in a cardiopulmonary healthy population. METHODS: Subjects (n=355) from a previous population-based respiratory questionnaire survey (never smokers, ex-smokers, and current smokers without significant chronic obstructive lung disease) were examined with echocardiography, and CI (L/min/m2 ) was calculated. RESULTS: Current smokers had a higher CI than never smokers 2.61±0.52 L/min/m2 vs. 2.42±0.49 L/min/m2 (P<.01). Ex-smokers had a nonsignificant, numerically higher value for CI than never smokers 2.54±0.54 L/min/m2 vs. 2.42±0.49 L/min/m2 (P>.05). Smoking status had no significant effect on other echocardiographic variables. CONCLUSION: We conclude that currents smokers without known cardiac disease or significant chronic obstructive lung disease show signs of slightly altered hemodynamics.

Study on risk factors and phenotypes of acute exacerbations of chronic obstructive pulmonary disease in Guangzhou, China-design and baseline characteristics.

BACKGROUND: To describe a study design that focuses on risk factors and patterns of chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: A 2-year, single centre, observational study was conducted in Guangzhou in China. The study enrolled 318 subjects with COPD aged 40-79 years, stratified into different but equally sized groups according to global initiative for chronic obstructive lung disease (GOLD) stage (including Stage 0) and 86 lung healthy controls. An assessment each year was scheduled including questionnaires, lung function testing, Chest X-ray and blood collection. A sub-group, called sub-group X, consisting of 203 subjects with COPD and 51 lung healthy controls, was selected to answer a symptom questionnaire daily (EXACT-PRO) via a BlackBerry Personal Digital Assistant (PDA) device. Upon an alert that indicated a change in daily symptom pattern, the patients were contacted by the clinic to decide whether they had experienced an exacerbation and should have an extra visit within 24-48 hours. At an extra visit, nasal and throat swabs, induced sputum and blood were collected. Air pollution, temperature and humidity were also monitored daily. A subset of sub-group X, called sub-group M that consisted of 52 COPD patients and 15 healthy controls was dedicated to measure muscle strength and a dexa scan. RESULTS: More than 78% of the enrolled patients completed the study successfully. There appeared a difference between the patient groups and the controls in gender, age, body mass index (BMI), forced expiratory volume in 1 second (FEV1), FEV1/FVC and smoking at baseline. In sub-group X 90 out of 203 (44.4%) selected COPD patients developed one or more exacerbations in the 2-year observation period. They were more severe COPD patients according to GOLD stage at study start. On average most exacerbations occurred in the month March and the least number of exacerbations occurred in October. CONCLUSIONS: This study with the obtained patient dataset will allow a better insight in many aspects of exacerbations in COPD (e.g., the identification, the risk factors, phenotypes and the biomarkers).

Blood biomarkers and measures of pulmonary function--a study from the Swedish twin registry.

OBJECTIVE: There is great need of biomarkers for research and clinical purposes in COPD. This study explored the relationships between ten putative plasma biomarkers of COPD and physiological measures of reduced lung function. METHODS: FEV(1), FVC, residual volume/total lung capacity (RV/TLC) and CO diffusion capacity (D(L)CO) were assessed in 357 subjects from the Swedish Twin Registry. The lung function measures were studied in relation to plasma levels of desmosines, C-reactive protein (CRP), plasminogen inhibitor activator (PAI-1) concentration and activity, tissue inhibitor of metalloproteinase (TIMP-1), clara cell protein 16 (CC16), surfactant protein D (SPD), matrix metalloproteinase 9 (MMP-9), hepatocyte growth factor (HGF) and interleukin (IL)-8. RESULTS: After adjustments for age, sex, height, BMI and smoking, FEV(1) was significantly associated with PAI-1 activity and desmosines. RV/TLC was significantly associated with CC16, PAI-1 concentration and PAI-1 activity, and D(L)CO was significantly associated with desmosines, TIMP-1 and CRP. When the multivariate analysis was restricted to subjects with COPD (i.e., FEV(1)/FVC < 0.70), CRP and desmosines were inversely associated with lung function. CONCLUSION: Several biomarkers were associated with lung function in this cross-sectional study. Especially CRP and desmosines could be useful markers to assess disease severity in subjects with COPD.

Atherosclerotic plaques in the internal carotid artery and associations with lung function assessed by different methods.

BACKGROUND: Previous studies on associations between reduced lung function and cardiovascular disease (CVD) have mainly been based on forced expiratory volume in 1-s (FEV(1) ) and vital capacity (VC). This study examined potential associations between five different lung function variables and plaques in the internal carotid artery (ICA). METHODS: Subjects (n = 450) from a previous population-based respiratory questionnaire survey [current smokers without lower respiratory symptoms, subjects with a self-reported diagnosis of chronic obstructive pulmonary disease (COPD) and never-smokers without lower respiratory symptoms] were examined using spirometry, body plethysmography and measurements of diffusing capacity for CO (D(L,CO) ). Plaques in the ICA were assessed by ultrasonography. RESULTS: Two hundred and twenty subjects were current smokers, 139 ex-smokers and 89 never-smokers. COPD was diagnosed in 130 subjects (GOLD criteria). Plaques in the ICA were present in 231 subjects (52%). General linear analysis with adjustment for established risk factors for atherosclerosis, including C-reactive protein, showed that D(L,CO) was lower [77.4% versus 83.7% of predicted normal (PN), P = 0.014] and residual volume (RV) was higher (110.3% versus 104.8% of PN, P = 0.020) in subjects with than without plaques in the ICA. This analysis did not show any statistically significant association between plaques and FEV(1) or VC. CONCLUSION: The occurrence of plaques in the ICA was associated with low D(L,CO) and high RV, but not significantly with FEV(1) or COPD status. The results suggest that the relationships between reduced lung function, COPD and CVD are complex and not only linked to bronchial obstruction and low-grade systemic inflammation.

Genetic and environmental influence on lung function impairment in Swedish twins.

BACKGROUND: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. METHODS: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. RESULTS: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were 10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. CONCLUSION: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.

Twins studies as a model for studies on the interaction between smoking and genetic factors in the development of chronic bronchitis.

Smoking is the main risk factor for COPD (chronic obstructive pulmonary disease) but genetic factors are of importance, since only a subset of smokers develops the disease. Sex differences have been suggested both in disease prevalence and response to environmental exposures. Furthermore, it has been shown that acquisition of 'addiction' to smoking is partly genetically mediated. Disease cases and smoking habits were identified in 44919 twins aged >40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. The results showed that chronic bronchitis seems to be more prevalent among females, and that the heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared by smoking. In addition, 392 twins have been invited to a clinical investigation to evaluate: (i) to what extent genetic factors contribute to individual differences (variation) in FEV(1) (forced expiratory volume in 1 s), vital capacity and DL(CO) (diffusion capacity), taking sex into consideration, and (ii) whether smoking behaviour and respiratory symptoms influence these estimates.

Specific nasal symptoms and symptom-provoking factors may predict increased risk of developing COPD.

In a 1992 questionnaire study, we found that certain nasal symptoms and symptom-provoking factors were associated with prevalence of self-reported chronic bronchitis/emphysema (CBE). In this follow-up study, we examined whether any nasal features could predict an increased incidence of self-reported physician's diagnosis of CBE/chronic obstructive pulmonary disease (COPD). In 2000, a survey was performed similar to the one in 1992. Of a paired follow-up group of 4933 participants aged 28-67 years, 4280 (86.8%) returned the questionnaire. Odds ratios (ORs) for cumulative incidence (between 1992 and 2000) of self-reported physician-diagnosed CBE/COPD and asthma, respectively, were calculated by logistic regression with adjustment for age, gender and smoking habits. Reports of thick, yellow nasal discharge and nasal blockage in 1992 predicted incidence of CBE/COPD: OR 2.3 (1.2-4.2) and 1.8 (1.1-2.8) respectively. Moreover, nasal symptoms provoked by exposure to damp/cold air and tobacco smoke predicted CBE/COPD: OR 3.4 (1.9-6.0) and 2.5 (1.4-4.2). Nasal itching and nasal symptoms provoked by exposure to grass pollen and furred animals predicted incidence of asthma. These results suggest that certain nasal symptoms and nasal symptom-provoking exposures, different from those commonly associated with asthma, may predict increased risk of developing CBE/COPD. This supports the possibility of nasal co-morbidity in COPD.

Interaction between smoking and genetic factors in the development of chronic bronchitis.

RATIONALE: Smoking is a primary risk factor for chronic bronchitis, emphysema, and chronic obstructive pulmonary disease, but since not all smokers develop disease, it has been suggested that some individuals may be more susceptible to exogenous factors, such as smoking, and that this susceptibility could be genetically determined. OBJECTIVES: The aim of the present study was to assess, in a population-based sample of twins, the following: (1) to what extent genetic factors contribute to the development of chronic bronchitis, including emphysema, taking sex into consideration, and (2) whether the genetic influences on chronic bronchitis, including emphysema, are separate from those for smoking behavior. METHODS: Disease cases and smoking habits were identified in 44,919 twins older than 40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. Individuals who had smoked 10 pack-years or more were defined as smokers. Univariate and bivariate structural equation models were used to estimate the heritability specific for chronic bronchitis and that in common with smoking. MEASUREMENTS AND MAIN RESULTS: The heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared with smoking. CONCLUSIONS: Genetic factors independent of those related to smoking habits play a role in the development of chronic bronchitis.

Prevalence of hand eczema in an adult Swedish population and the relationship to risk occupation and smoking.

Using a postal questionnaire the prevalence of hand eczema was determined in a general population of 11,798 individuals aged 20-77 years who were randomly drawn from the population records. The response rate was 78.1%. One-year prevalence of hand eczema among women varied between 1.9% and 10.8%, with the highest figure among those aged 30-39 years. The corresponding figures for men were 2.3% and 5.6%, with the highest figure among those aged 20-29 years. Lifetime prevalence varied between 5.7% and 16.7% among women and between 5.2% and 9.5% among men. Using multiple logistic regression analysis female sex (OR=1.91, 95% CI 1.47-2.47) and smoking (OR=1.35, 95% CI 1.04-1.75) were independent risk factors for reporting 1-year prevalence of hand eczema, whereas age (OR=0.99, 95% CI 0.97-0.99) was inversely related to the 1-year prevalence of hand eczema. Aggregated risk occupation or categorized occupation such as medical and nursing work, production or service were not significantly associated with 1-year prevalence of hand eczema.

Influence of family history and smoking habits on the incidence of self-reported physician's diagnosis of COPD.

BACKGROUND: The incidence of chronic obstructive pulmonary disease (COPD) is little investigated. This study assessed the incidence of a self-reported physician's diagnosis of chronic bronchitis and/or emphysema (CBE) and/or COPD (CBE/COPD), and investigated the effects of a family history of CBE in 1992 and change in smoking habits (assessed in 1992 and 2000) on this incidence. METHODS: A follow-up study in 2000 of 4933 subjects who responded to a respiratory questionnaire study in 1992 was performed. Response rate was 86.8%. Odds ratios (ORs) for incident cases of CBE/COPD were calculated by multiple Logistic regression. RESULTS: The cumulative incidence of a physician's diagnosis of CBE/COPD was 2.9%. A family history of CBE predicted incident cases of CBE/COPD, OR 2.7 (95% CI 1.5-5.1). Also continuous smoking, relapse into smoking, or having stopped smoking between 1992 and 2000 had elevated ORs for incident cases of CBE/COPD, 2.6 (1.4-4.7), 7.2 (2.7-18.7), and 2.6 (1.3-5.3), while the OR for ex-smoking in 1992 as well as 2000 was 0.9 (0.4-1.8). CONCLUSIONS: A family history of CBE increases the risk for development of CBE/COPD. Sustained smoking cessation over many years may be required to significantly reduce the risk of developing CBE/COPD.

Prevalence of self-reported eczema in relation to living environment, socio-economic status and respiratory symptoms assessed in a questionnaire study.

BACKGROUND: Potential links between eczema and obstructive pulmonary diseases have been postulated. Previously we have reported the prevalence of upper and lower respiratory diseases and the relation to environmental and socio-economic factors in a randomly selected adult population in southern Sweden using a postal questionnaire. In the present study we wanted to analyse the prevalence of eczema and its relation to socio-economic status, heredity factors and environmental factors in an adult population. METHODS: Self-reported eczema, upper and lower respiratory symptoms, asthma and Chronic Bronchitis Emphysema (CBE) were examined in 12,071 adults, aged 20-59 years, living in southern Sweden by using a postal questionnaire. There were comparable numbers of males and females in all age groups. Multiple logistic regression analysis (forward conditional) was applied to estimate the association between the proposed risk factors (heredity, self-reported asthma and CBE, nasal symptoms, socio-economic group, environmental factors, age, gender and smoking habits) and self-reported eczema. RESULTS: The response rate was 70.1%. In all, 1240 subjects (14.6%) stated that they had eczema. In all age cohorts self-reported eczema was more frequently reported by women than by men (p < 0.05). The prevalence of self-reported eczema among the economically active population varied from 17.1% to 8.2% with the highest rates among assistant non-manual employees. However, when controlling for age, gender and risk occupation there was no association between low social position and eczema. Living close to heavy traffic (OR = 1.45, 95% CI 1.25-1.67) and living seaside (OR = 1.17, 95% CI 1.01-1.35) but not urban/suburban living was associated with eczema. Heredity of eczema (OR = 5.77, 95% CI 5.02-6.64), self reported allergic rhinitis (OR = 2.31, 95% CI 2.00-2.68), self reported asthma (OR = 1.98, 95% CI 1.56-2.51) and self reported CBE (OR = 1.42, 95% CI 1.08-1.87) were all associated with eczema. CONCLUSIONS: In this epidemiological study we see that self-reported eczema is a common disease in an adult population especially among women. Eczema seems to be linked to environment factors, obstructive pulmonary diseases and rhinitis.

Nasal neutrophil activity and mucinous secretory responsiveness in COPD.

Patients with chronic obstructive pulmonary disease (COPD) frequently report nasal symptoms. In the present study, we have examined whether or not COPD is associated with any nasal inflammation. Plasma exudation evoked by histamine challenges has been employed to improve the recovery of inflammatory indices in nasal lavage fluids. In 23 COPD-patients and 26 healthy subjects, all without history or signs of allergic rhinitis, nasal polyposis, or chronic rhinosinusitis, nasal saline-lavages were performed with and without histamine. alpha2-Macroglobulin, fucose, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were determined as indices of plasma exudation, mucinous secretion, eosinophil activity and neutrophil activity, respectively. The difference in MPO-levels between the histamine and the saline lavage was greater in COPD patients compared with healthy subjects (P<0.05). Also, COPD patients reporting nasal symptoms presented an increase in MPO at histamine challenge (P<0.05, cf. saline) and greater differences in MPO and fucose, respectively, between the histamine and the saline lavage (P<0.05, cf. patients without symptoms). We conclude that COPD is not associated with any marked nasal inflammation. However, our observation on increased MPO-levels at histamine challenge suggests some degree of increased neutrophil activity in this condition. Furthermore, when associated with nasal symptoms, COPD may be associated with an increased nasal secretory responsiveness.