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The prostanoid DP receptor (PTGDR) is shown to be involved in the asthma patho-physiology and the results from the published genetic association studies are inconsistent. Four single nucleotide polymorphisms (SNPs) in PTGDR were genotyped in 342 and 294 families from UK and Denmark respectively. Asthma and asthma-related phenotypes were analyzed using family-based association analyses. In the UK families, a promoter polymorphism (−731A/G) showed significant associations with asthma (P=0.0022), atopic asthma (P=0.0044), bronchial hyperreactivity or BHR (P=0.00120) and strict asthma (P=0.0008). The P-values for asthma, BHR and strict asthma were significant even after the most stringent correction for the number of markers and the number of phenotypes analyzed (<0.0031). An intronic polymorphism (+6651C/T) also showed significant associations with asthma (P=0.0302), atopic asthma (P=0.0131), BHR (P=0.0249) and strict asthma (P=0.0261). In the Danish families, an intronic polymorphism (+6541C/T) showed significant associations with asthma (P=0.0071), atopic asthma (P=0.0348), BHR (P=0.0033) and strict asthma (P=0.0381). The results of haplotype analyses supported the ones of the single SNP analyses. Thus, we demonstrated significant evidence of association between polymorphisms in PTGDR with asthma phenotypes in the two Caucasian populations.Genes and Immunity (2007) 8, 398–403; doi:10.1038/sj.gene.6364399; published online 31 May 2007 [ABSTRACT FROM AUTHOR]

Background: Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. Methods: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. Results: PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo. In patients treated with fluticasone propionate 500 μg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 I/mm (95% confidence interval (CI) 11 to 21), 11 1/mm (95% CI 6 to 16), and 27 I/mm (95% Cl 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on REF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/ fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long term response in individual patients. Conclusions: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks. [ABSTRACT FROM AUTHOR]

Aims: Potential exists for improving the impact of quit-smoking programmes, by recruiting smokers in early motivational stages, by using active recruitment strategies, and by offering professional assistance to quit. Methods: This was a randomized population-based intervention study, in Copenhagen, Denmark. A total of 2,408 daily smokers in all motivational stages were included. All participants completed a questionnaire, and underwent a health examination and a lifestyle consultation. Smokers in the high-intensity intervention were offered assistance to quit smoking in smoking cessation groups. Results: Before the lifestyle consultation only 11% of the smokers stated that they planned to quit within one month. After the lifestyle consultation 27% accepted smoking cessation in groups and an additional 12% planned to quit without assistance. Of the smokers who accepted smoking cessation groups 23% had not been planning to quit before the lifestyle consultation. Being a woman, having high tobacco consumption, having a long smoking history, having tried to quit within the previous year, and having a higher motivation to quit predicted participation in smoking cessation groups. Conclusions: It was possible to recruit a large number of smokers in early motivational stages by using active recruitment strategies and by offering assistance to quit. Lifestyle consultations markedly increased the number of smokers willing to try to quit. Smokers preferred assistance to quit in a smoking cessation group to quitting on their own; therefore, it is important to improve recruitment strategies for smoking cessation programmes. [ABSTRACT FROM AUTHOR]

Background: Little is known about the effects of changes in smoking habits on the subsequent risk of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the relationship between smoking cessation and reduction and admission to hospital for COPD in a general population sample.Methods: A total of 19,709 participants from three prospective population studies in Copenhagen were followed with record linkage for date of first hospital admission for COPD until 1998 (mean follow up 14 years). Heavy smokers (>/=15 cigarettes/day) who reduced their tobacco consumption by at least 50% between the two initial examinations without quitting and smokers who stopped smoking during this time were compared with continuous heavy smokers using a Cox proportional hazards model.Results: During the follow up period 1,260 subjects (741 men and 519 women) were admitted to hospital for COPD. After multivariate adjustment, quitting smoking was associated with a significant reduction in the risk of hospital admission. The relative hazard (HR) was 0.57 (95% confidence interval (CI) 0.33 to 0.99). Those who reduced smoking did not show a significantly lower risk of hospitalisation than continuing heavy smokers (HR 0.93 (95% CI 0.73 to 1.18)). Exclusion of events during the first 5 study years, detailed adjustment for lung function, or restriction of analyses to participants with impaired pulmonary function did not reverse the observed trend.Conclusions: Self-reported smoking cessation is associated with a reduction in the risk of COPD morbidity of approximately 40%; the benefit of smoking reduction is questionable. [ABSTRACT FROM AUTHOR]

Background: Smoking and airway lability which is expressed by histamine airway hyperresponsiveness, are known risk factors for development of respiratory symptoms. Smoking is also associated with increased mortality risks. We studied whether airway hyperresponsiveness is associated with increased mortality and whether this risk was independent of smoking and reduced lung function. Methods: We followed up 2008 inhabitants of the communities of Vlagtwedde, Vlaardingen, and Meppel (Netherlands), who had histamine challenge test data from 1964-72 for 30 years. Follow-up was 99% successful (29 patients lost to follow-up) with 1453 participants alive and 526 deaths (246 died from cardiovascular disease, 54 from lung cancer, and 21 from chronic obstructive pulmonary disease (COPD)). Findings: Mortality from COPD increased with more severe hyper-responsiveness relative risks of 3.83 (95% Cl 0.97-15.1), 4.40 (1.16-16.7), 4.78 1.27-18.0), 6.69 (1.71-26.1), and 15.8 (3.72-67.1) were associated with histamine thresholds of 32 g/l, 16 g/l, 8 g/l, 4 g/I, and 1 g/l, respectively compared with no hyperresponsiveness. These risks were adjusted for sex, age, smoking, lung function, body mass index, positive skin tests, eosinophilia, asthma, and city of residence. Interpretation: Increased histamine airway hyper-responsiveness predicts modality from COPD. Although this trend was more pronounced in smokers, an increasing proportion of COPD deaths with increasing hyper-responsiveness was also present among individuals who had never smoked. [ABSTRACT FROM AUTHOR]

The epidemiology of chronic obstructive pulmonary disease (COPD) has been dominated by one hypothesis stating that cigarette smoking and chronic bronchitis were the key to pathogenesis and another that asthma, chronic bronchitis, and even emphysema are related to different expressions of a primary airway abnormality. The first hypothesis was rejected in the late 1960s based on a longitudinal study of working men where only a fraction of smokers developed COPD and where development of COPD was independent of the absence or presence of chronic bronchitis. Chronic bronchitis in more advanced COPD was subsequently associated with a more rapid decline in lung function and more frequent exacerbations. The second hypothesis is more difficult to test but longitudinal studies have shown that the presence of bronchial hyperresponsiveness may predict the subjects who go on to develop COPD. This brief review attempts to reconcile these findings with the pathology found in the lung. [ABSTRACT FROM AUTHOR]

A response by John R. Hurst, Jørgen Vestbo and Jadwiga A. Wedzicha to letters to the editor about their article "Susceptibility to Exacerbations in Chronic Obstructive Pulmonary Disease" in the September 16, 2010 issue is presented.

A letter to the editor is presented discussing a study which examines the effect of differences in counting and analyzing exacerbation rates on estimated treatment effects in chronic obstructive pulmonary disease.

Background: On the question of whether asthma shortens survival the published work gives no clear answer. We have prospectively analysed overall and cause-specific mortality in persons with self-reported asthma. METHODS A sample of 13 540 individuals (6104 men) 20 years of age or older, randomly selected from the general population of the city of Copenhagen, was followed for 17 years.Findings: Survival in participants with self-reported asthma was significantly poorer than in non-asthmatics, the excess mortality being limited to pulmonary mortality. After statistical adjustment for age, length of school education, and smoking, women with asthma had a 1.7 higher risk of dying than women without asthma (95% confidence interval 1.3--2.2). Although the relative risk (RR) of dying with asthma was slightly lower in men (RR = 1.5, 95% Cl 1.2-1.9) the difference between sexes was not significant. The results were similar within smoking groups and the highest risk of death associated with asthma was seen among never-smokers (RR = 2.1, 95% Cl 1.6-2.3). Inclusion of one-second forced expiratory volume, in % predicted, in the mortality analyses showed that the increased risk of death associated with asthma was mediated mainly through reduced lung function.Interpretation: We conclude that, in the general population, self-reported asthma is associated with a slight excess of mortality, mainly from respiratory diseases. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions. [ABSTRACT FROM AUTHOR]

Deals with a study which described differences in smoking characteristics between Danish men and women. Methodology; Results; Discussion.

Objectives: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. Methods: Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. Results: A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self‐reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack‐years smoked [0.65; 95% confidence interval (CI) 0.58–0.72] and wheezing (0.64; 95% CI 0.57–0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63–0.79) versus 0.65 (95% CI 0.63–0.68), respectively; P = 0.06]. Conclusions: Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH. [ABSTRACT FROM AUTHOR]

The augmentation index (AIx) is a measure of systemic arterial stiffness, and previous studies have demonstrated an association between AIx and risk factors of cardiovascular disease (CVD). However, there is limited knowledge about the age and gender differences of the observed associations. Therefore, the aim of the present study is to examine the association's consistency at different ages and to see if the associations are the same in men and women. This study is based on 3432 subjects from The Copenhagen City Heart Study, a prospective epidemiological survey of a representative population in Denmark. All subjects had AIx measured non-invasively by the SphygmoCor device (SphygmoCor, West Ryde, Australia). To analyse the association between AIx and CVD risk factors multiple linear regression analyses were used stratified by gender and age. The main determinants of AIx were age, heart rate, height and systolic blood pressure in both age groups with few gender differences. Associations between AIx and cardiovascular risk factors further differed by age: In young subjects AIx was associated with cholesterol, high-sensitive C-reactive protein, current smoking, low weight, poor education and physical inactivity, whereas in subjects above age 60 AIx was associated with weight and current smoking in men. We found a modest association between AIx and traditional CVD risk factors and the association attenuated in subjects >60 years. Further longitudinal studies are needed to determine whether AIx is primarily a marker of CVD in younger subjects. [ABSTRACT FROM AUTHOR]

Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.Methods: The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.Results: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis).Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV(1) is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study.Methods: A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 microg), FP (500 microg), or SFC (SAL 50 microg/FP 500 microg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded.Results: At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was -3.1% for placebo, -1.7% for SAL, -2.9% for FP, and -3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, -0.3%, and -0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%).Conclusions: Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo.Trial Registration: ClinicalTrials.gov Identifier: NTC00268216. [ABSTRACT FROM AUTHOR]

Background: Toll-like receptors (TLRs) are structurally and functionally related and play important roles in the innate and adaptive immune system. By genome scanning, evidence of linkage between chromosome Xp22 and asthma and related atopic disorders has previously been obtained. Xp22 harbours the TLR7 and TLR8 genes. Methods: The involvement of TLR7 and TLR8 in the aetiology of asthma and related disorders was investigated by a family based association analysis of two independently ascertained family samples comprising 540 and 424 individuals from 135 and 100 families, respectively. Ten affected individuals from families showing evidence of linkage to Xp22 were screened for sequence variations in TLR7 and 8, and nine single nucleotide polymorphisms (SNPs) identified were tested for association. Results: In both samples, significant associations were observed for single SNPs and haplotypes of both TLR7 and 8 in all four phenotypes investigated: asthma, rhinitis, atopic dermatitis and increased specific IgE. The most significant association was seen for rs2407992 (TLR8) in asthma (p = 0.00023, sample A and B combined, recessive model). In TLR7, rsl 79008 showed the strongest association. Both rsl 79008 and rs2407992 are of putative functional significance, potentially affecting TLR7 processing and TLR8 splicing, respectively. Haplotypes comprising the major alleles of these two SNPs were overtransmitted to the affected offspring (eg, p = 0.00012 in asthma, combined sample, additive model). Conclusion: The results provide strong evidence that TLR7 and 8 may confer susceptibility to asthma and related atopic disorders and highlight these receptors as interesting targets for individualised, causally directed treatment. [ABSTRACT FROM AUTHOR]

Objective. Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self-reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function. Design. Prospective substudy. Setting. Systematic screening at 11 centres. Subjects. Consecutive patients ( n = 532) admitted with HF requiring medical treatment with diuretics and an episode with symptoms corresponding to New York Heart Association class III-IV within a month prior to admission. Interventions. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured by spirometry and ventricular function by echocardiography. The diagnosis of COPD and HF were made according to established criteria. Results. The prevalence of COPD was 35%. Only 43% of the patients with COPD had self-reported COPD and one-third of patients with self-reported COPD did not have COPD based on spirometry. The prevalence of COPD in patients with preserved left ventricular ejection fraction (i.e. LVEF ≥45%) was significantly higher than in patients with impaired LVEF (41% vs. 31%, P = 0.03). FEV1 and FVC were negatively correlated with right ventricular end-diastolic diameter and tricuspid annular plane systolic excursion and FVC positively correlated with systolic gradient across the tricuspid valve. Conclusion. Chronic obstructive pulmonary disease is frequent in patients admitted with HF and self-reported COPD only identifies a minority. The prevalence of COPD was high in both patients with systolic and nonsystolic HF. [ABSTRACT FROM AUTHOR]

Increased lung CD8 cells and their expression of chemokine receptors CXCR3 and CCR5 have been previously reported in chronic obstructive pulmonary disease (COPD). Alterations of CD8-CCR3 and -CCR4 expression and their ligands in COPD patients have not been fully investigated. The objective of this study was to assess in COPD patients: (i) broncho-alveolar lavage (BAL) CD8 CCR3 and CCR4 expression in COPD patients; and (ii) airway levels of the CCR3 ligands, CCL11 and CCL5. Multi-parameter flow cytometric anlaysis was used to assess BAL CD3 and CD8-chemokine receptor expression in COPD patients, smokers and healthy non-smokers (HNS). CCL5 and CCL11 levels were measured in BAL, and from the supernatants of lung resection explant cultures. CD8-CCR3 and -CCR5 expression (means) were increased in COPD patients (22% and 46% respectively) and smokers (20% and 45%) compared with HNS (3% and 22%); P < 0·05 for all comparisons. CD3CXCR3 expression was raised in smokers and COPD while CD8CXCR3 and CD3 and CD8 CCR4 expression was similar between groups. CD8CCR5 expression correlated to smoking pack years ( r = 0·42, P = 0·01). COPD explants released more CCL5 compared with smokers ( P = 0·02), while there was low level CCL11 production. CD8CCR3 and CCR5 expression appear to be regulated by cigarette smoke exposure. We show that COPD lung tissue released more CCL5, suggesting a role for CCL5–CCR3 signalling in pulmonary CD8 recruitment in COPD. [ABSTRACT FROM AUTHOR]

Background: Asthma is a complex genetic disorder characterized by chronic inflammation in the airways. Identification of genetic risk factors for asthma has been complicated due to genetic heterogeneity and influence from environmental risk factors. Despite the fact that multiple genetic linkage studies have been carried out the results are still conflicting and call for replication experiments. A Danish genome-wide scan has prior reported evidence for candidate regions for asthma susceptibility genes on chromosomes 1p, 5q, 6p, 12q and Xp. Linkage to chromosome 12q was later confirmed in the same replication sample as used in the present study. The aim of the study was to replicate linkage to candidate regions for asthma in an independent Danish sample. Methods: We performed a replication study investigating linkage to candidate regions for asthma on chromosomes 1p36.31-p36.21, 5q15-q23.2, 6p24.3-p22.3, and Xp22.31-p11.4 using additional markers in an independent set of 136 Danish asthmatic sib pair families. Results: Nonparametric multipoint linkage analyses yielded suggestive evidence for linkage to asthma to chromosome Xp21.2 (MLS 2.92) but failed to replicate linkage to chromosomes 1p36.31-p36.21, 5q15-q23.2 and 6p24.3-p22.3. Conclusions: The replication results provide evidence for chromosome Xp21 to harbour a susceptibility gene for asthma in the Danish population. To our knowledge, the study is the first to replicate evidence for linkage to chromosome X. A susceptibility gene for asthma on chromosome X could potentially explain observed gender differences in asthma prevalence. [ABSTRACT FROM AUTHOR]

Background: Smokers are more prone to develop chronic obstructive pulmonary disease (COPD) than non-smokers, but this finding comes from studies spanning 10 years or less. The aim of this study was to determine the 25 year absolute risk of developing COPD in men and women from the general population. Methods: As part of the Copenhagen City Heart Study, 8045 men and women aged 30–60 years with normal lung function at baseline were followed for 25 years. Lung function measurements were collected and mortality from COPD during the 25 year observation period was analysed. Results: The percentage of men with normal lung function ranged from 96% of never smokers to 59% of continuous smokers; for women the proportions were 91% and 69%, respectively. The 25 year incidence of moderate and severe COPD was 20.7% and 3.6%, respectively, with no apparent difference between men and women. Smoking cessation, especially early in the follow up period, decreased the risk of developing COPD substantially compared with continuous smoking. During the follow up period there were 2912 deaths, 109 of which were from COPD. 92% of the COPD deaths occurred in subjects who were current smokers at the beginning of the follow up period. Conclusion: The absolute risk of developing COPD among continuous smokers is at least 25%, which is larger than was previously estimated. [ABSTRACT FROM AUTHOR]

Background: Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma. Methods: A two step procedure was used: (1) a genome-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of > or =1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma in a family based transmission disequilibrium test. Results: An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 (SFRS8) had an association with asthma (p < or = 0.0020-0.050) in a sample of 136 asthmatic sib pairs. SFRS8 regulates the splicing of CD45, a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region. Conclusions: Linkage and simulation studies show that the very distal part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICS) constitute the cornerstone of treatment for asthma. Many studies have reported beneficial short term effects of these drugs, but there are few data on the long term effects of ICS on the decline in forced expiratory volume in 1 second (FEV1). This study was undertaken to determine whether adults with asthma treated with ICS have a less pronounced decline in FEV1 than those not treated with ICS. Methods: Two hundred and thirty four asthmatic individuals from a longitudinal epidemiological study of the general population of Copenhagen, Denmark were divided into two groups; 44 were treated with ICS and 190 were not treated with ICS. The annual decline in FEV1 was measured over a 10 year follow up period. Results: The decline in FEV1 in the 44 patients receiving ICS was 25 mI/year compared with 51 mI/year in the 190 patients not receiving this treatment (p<0.001). The linear regression model with ICS as the variable of interest and sex, smoking, and wheezing as covariates showed that treatment with ICS was associated with a less steep decline in FEV1 of 18 mI/year (p=0.01). Adjustment for additional variables including age, socioeconomic status, body mass index, mucus hypersecretion, and use of other asthma medications did not change these results. Conclusions: Treatment with ICS is associated with a significantly reduced decline in ventilatory function. [ABSTRACT FROM AUTHOR]

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the variability and sensitivity of impulse oscillometry (R5, X5 and RF), plethysmography (Raw and sGaw) and spirometry (FEV1, FVC and MMEF) in order to determine the most powerful technique for assessing bronchodilation in COPD clinical trials.Twenty-four patients with COPD had impulse oscillometry, plethysmography and spirometry measured twice 30 mins apart, to determine variability. Then ascending doses of salbutamol (20, 50, 100, 200, 400 and 800 µg) were given and the same measurements made after each dose. Significant changes greater than variability were determined for each performed measurement (expressed as mean percentage improvement with 95% CI).Significant effects (P <0.05) were detected after 20 µg by X5 (18.5% CI 9.8–27.2) RF (11.1% CI 7.2–15.0) and sGaw (21.5% CI 10.1–32.9), and after 50 µg by R5 (16.7% CI 10.8–22.5) and Raw (19.7% CI 13.0–26.4). FEV1 was less sensitive, detecting significant bronchodilation at 100 µg (10.2% CI 7.4–12.9).We conclude that impulse oscillometry and plethysmography should be considered the preferred techniques for measuring bronchodilation in COPD clinical trials. [ABSTRACT FROM AUTHOR]

During the last decade several long term studies of interventions in patients with COPD have been published. This review analyses the potential of these interventions to alter the progression of the condition. The only treatment that has unequivocally been shown to reduce the rate of decline in FEV(1) is smoking cessation. Active psychological intervention in combination with pharmacotherapy is required. Other treatments may have an effect on the rate of decline in FEV(1) but this appears to be very small, at most. Several treatments affect the exacerbation rate and therefore might affect the progression of the disease. Further studies are warranted to examine this effect. [ABSTRACT FROM AUTHOR]

Introduction: In patients with COPD who have recently been hospitalized for their disease, we examined whether treatment with inhaled corticosteroids without or with long-acting β-adrenoceptor agonists (β-agonists) reduced rehospitalization and mortality. Study design: Retrospective cohort analysis in the UK General Practice Research Database. Methods: We compared rehospitalization for a COPD-related medical condition or death within 1 year after first hospitalization, in 3636 COPD patients receiving prescriptions for inhaled corticosteroids or long-acting β-agonists compared with 627 reference patients with COPD who were prescribed short-acting bronchodilators only. Results: Rehospitalization within a year occurred in 13.2% of the reference COPD patients, 14.0% of users of long-acting β-agonists only, 12.3% of users of inhaled corticosteroids only, and 10.4% of users of inhaled corticosteroids and long-acting β-agonists. Death within a year occurred in 24.3% of the reference COPD patients, 17.3% of users of long-acting β-agonists only, 17.1% of users of inhaled corticosteroids only, and in 10.5% of users of inhaled corticosteroids and long-acting β-agonists. In multivariate analyses the risk of rehospitalization or death was reduced by 10% in users of long-acting β-agonists only (NS), by 16% in users of inhaled corticosteroids only, and by 41% in users of combined inhaled corticosteroids and long-acting β-agonists (both p < 0.05). Conclusion: Use of inhaled corticosteroids with/without long-acting β-agonists was associated with a reduction of rehospitalization or death in COPD patients. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests a role for hormonal factors in the aetiology of asthma.Methods: Data from a large study of women selected from the general population were used to relate treatment with oral hormonal contraceptives (OCP) and postmenopausal hormone replacement therapy (HRT) to the following asthma indicators: self-reported asthma, wheezing, cough at exertion, and use of medication for asthma. The study sample comprised 1536 premenopausal and 3016 postmenopausal women who participated in the third round of the Copenhagen City Heart Study in 1991-4. A total of 377 women were taking OCP (24.5% of premenopausal women) and 458 were on HRT (15.2% of postmenopausal women).Results: In premenopausal women 4.8% reported having asthma. The prevalence of self-reported asthma, wheeze, use of asthma medication, and cough at exertion was not significantly related to use of OCP. In postmenopausal women the prevalence of self-reported asthma was 6.2%. A weak but consistent association was observed between HRT and self-reported asthma (OR 1.42 (95% CI 0.95 to 2.12)), wheeze (OR 1.29 (95% CI 1.02 to 1.64)), cough at exertion (OR 1.34 (95% CI 1.01 to 1.77)), and use of asthma medication (OR 1.45 (95% CI 0.97 to 2.18)).Conclusions: In this study of the general population no relationship was found between the use of OCP and asthma. Although an association was observed between HRT and asthma and asthma-like symptoms, this was relatively weak and it is concluded that there is no necessity to change present prescription practice. [ABSTRACT FROM AUTHOR]

Background: Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD.Methods: We used a parallel-group, randomised, double-blind, placebo-controlled design in a singlecentre study, nested in a continuing epidemiological survey (the Copenhagen City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of forced expiratory volume in 1 s (FEV1) and vital capacity of 0.7 or less; FEV1 which showed no response (<15% change) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days. 290 patients were randomly assigned budesonide, 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months, or placebo for 36 months. The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86% of predicted. The main outcome measure was rate of FEV1 decline. Analyses were by intention to treat.Findings: The crude rates of FEV1 decline were slightly smaller than expected (placebo group 41.8 mL per year, budesonide group 45.1 mL per year). The estimated rates of decline from the regression model did not differ significantly (49.1 mL vs 46.0 mL per year; difference 3.1 mL per year [95% CI -12.8 to 19.0]; p=0.7). Before the study, the minimum relevant difference was defined as 20 mL per year; this difference was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 316 exacerbations occurred during the study period, 155 in the budesonide group and 161 in the placebo group. Treatment was well tolerated.Interpretation: Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD. [ABSTRACT FROM AUTHOR]

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow-up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1s, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55–0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24–0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39–0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2–3 years. Reproduced with permission from the BMJ Publishing Group. [Copyright &y& Elsevier]