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1.  Developing COPD: a 25 year follow up study of the general population 
Thorax  2006;61(11):935-939.
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.
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.
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.
The absolute risk of developing COPD among continuous smokers is at least 25%, which is larger than was previously estimated.
PMCID: PMC2121175  PMID: 17071833
chronic obstructive pulmonary disease; ventilatory function; smoking; prognosis
2.  Significant linkage to chromosome 12q24.32–q24.33 and identification of SFRS8 as a possible asthma susceptibility gene 
Thorax  2006;61(10):874-879.
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.
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 ⩾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.
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⩽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.
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.
PMCID: PMC2104763  PMID: 16738036
asthma; genetics; linkage; splicing factor arginine/serine‐rich 8 (SFRS8); atopy
3.  Highly significant linkage to chromosome 3q13.31 for rhinitis and related allergic diseases 
Journal of Medical Genetics  2006;43(3):e10.
Allergic diseases such as asthma and rhinitis have closely related phenotypes and often occur with atopy. They show strong familial and intra‐individual clustering, suggesting overlapping disease aetiology. Various loci and candidate genes have been suggested to underlie allergy. Many or all are still inconclusive. Following genome‐wide scans on multiple phenotypes, we previously suggested that chromosome 3q13.12–q21.2 harbours an allergy locus.
To identify candidate loci in the Danish population, two additional independent sets of sib‐pair families were fine‐scale mapped in candidate regions showing maximum likelihood scores (MLS) ⩾1.5 in the genome‐wide scans.
Twenty eight microsatellite markers in a denser map on chromosome 3q were analysed in 236 allergy sib‐pair families including 125 sib pairs with rhinitis. We report significant evidence for linkage to chromosome 3q13.31 for rhinitis (MLS 5.55, identity by descent (IBD) 63.9%) and atopy (increased specific immunoglobulin E) (MLS 3.71, IBD 61.7%). We obtained an MLS of 5.1 (IBD 67.3%) at 3q13.31 when sib pairs with both rhinitis and atopy were analysed.
This study reports the first statistically significant evidence for a genetic susceptibility locus for rhinitis and to our knowledge shows the most significant evidence to date of linkage for any allergy phenotype.
PMCID: PMC2563244  PMID: 16525028
atopy; complex trait; genetics; linkage; rhinitis
4.  Inhaled corticosteroids and decline of lung function in community residents with asthma 
Thorax  2006;61(2):100-104.
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.
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.
The decline in FEV1 in the 44 patients receiving ICS was 25 ml/year compared with 51 ml/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 ml/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.
Treatment with ICS is associated with a significantly reduced decline in ventilatory function.
PMCID: PMC2104582  PMID: 16443705
asthma; ventilatory function; inhaled corticosteroids; prognosis
5.  Convergence of the epidemiology and pathology of COPD 
Thorax  2006;61(1):86-88.
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.
PMCID: PMC2080699  PMID: 16227325
chronic obstructive pulmonary disease; pathology; epidemiology; smoking; pathogenesis
6.  Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease 
Thorax  2005;60(12):992-997.
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.
PMCID: PMC1747271  PMID: 16227327
7.  Effect of treatments on the progression of COPD: report of a workshop held in Leuven, 11–12 March 2004 
Thorax  2005;60(4):343-349.
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 FEV1 is smoking cessation. Active psychological intervention in combination with pharmacotherapy is required. Other treatments may have an effect on the rate of decline in FEV1 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.
PMCID: PMC1747377  PMID: 15790992
8.  Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease 
Thorax  2005;60(4):301-304.
Background: Combined treatment with inhaled corticosteroids and long acting ß2 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 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF 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.
PMCID: PMC1747357  PMID: 15790985
9.  COPD in the ECRHS 
Thorax  2004;59(2):89-90.
PMCID: PMC1746938  PMID: 14760140
10.  Smoking verification and the risk of myocardial infarction 
PMCID: PMC1732661  PMID: 14729900
11.  Smoking reduction, smoking cessation, and incidence of fatal and non-fatal myocardial infarction in Denmark 1976–1998: a pooled cohort study 
Design: Prospective cohort study with record linkage to mortality and hospital registers. The association of individual change in smoking with myocardial infarction was examined in Cox proportional hazard analyses with continuous heavy smokers (⩾5 cigarettes/day) as reference.
Setting: Pooled data from three population studies conducted in Copenhagen, Denmark.
Participants: 10 956 men and 8467 women with complete information on smoking habits at two examinations five to ten years apart were followed up from the second examination for a first hospital admission or death from myocardial infarction. Mean duration of follow up was 13.8 years.
Main results: A total of 643 participants who were heavy smokers at baseline reduced their daily tobacco consumption by at least 50% without quitting between first and second examination, and 1379 participants stopped smoking. During follow up 1658 men and 521 women experienced a fatal or non-fatal myocardial infarction. After adjustment for cardiovascular risk factors, people who stopped smoking had a decreased risk of myocardial infarction, hazard ratio 0.71 (95% confidence intervals 0.59 to 0.85). Smoking reduction was not associated with reduced risk of myocardial infarction, hazard ratio 1.15 (95% confidence intervals 0.94 to 1.40). These associations remained unchanged after controlling for baseline illness in different ways.
Conclusions: Smoking cessation in healthy people reduces the risk of a subsequent myocardial infarction, whereas this study provides no evidence of benefit from reduction in the amount smoked.
PMCID: PMC1732492  PMID: 12775785
12.  Risk of hospital admission for COPD following smoking cessation and reduction: a Danish population study 
Thorax  2002;57(11):967-972.
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 1260 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 to1.18)). 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.
PMCID: PMC1746230  PMID: 12403880
13.  Airway hyperresponsiveness and COPD mortality 
Thorax  2001;56(Suppl 2):ii11-ii14.
PMCID: PMC1765990  PMID: 11514701
14.  Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population 
Thorax  2001;56(8):613-616.
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.

PMCID: PMC1746111  PMID: 11462063
15.  Increase in prevalence and severity of asthma in young adults in Copenhagen 
Thorax  2000;55(10):833-836.
BACKGROUND—It is the general impression that the prevalence of asthma has increased during recent decades. A study was undertaken to investigate asthma prevalence, respiratory symptoms, and lung function in young adults in the City of Copenhagen 15 years apart.
METHODS—Men and women aged 20-35 years were sampled from the general population living in a defined area of central Copenhagen. The first examination took place in 1976-8 and comprised 1034 subjects (response rate 67.2%). A new sample comprising 1104 subjects (response rate 62.6%) from exactly the same area was examined 15 years later in 1991-4. All participants answered a questionnaire on respiratory symptoms and diseases and performed spirometric tests with measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).
RESULTS—The prevalence of self-reported asthma increased from 1.5% in the first survey to 4.8% in the second survey (p<0.001). Asthmatic subjects had, on average, poorer lung function than non-asthmatic subjects in terms of FEV1 and this difference was more pronounced in the second survey than in the first (10.0% of predicted versus 2.4% of predicted). Smoking decreased significantly from 62% in 1976-8 to 45% in 1991-4 (p<0.001).
CONCLUSIONS—The prevalence of self-reported asthma has increased significantly among young adults in Copenhagen over a 15 year period. The severity of asthma, as judged by the level of FEV1, has also increased. These findings cannot be explained by changes in smoking habits.

PMCID: PMC1745615  PMID: 10992534
16.  Socioeconomic status and chronic obstructive pulmonary disease 
Thorax  1999;54(8):737-741.
PMCID: PMC1745556  PMID: 10413728
17.  Familial predisposition and susceptibility to the effect of other risk factors for myocardial infarction 
STUDY OBJECTIVES: To assess if familial predisposition to myocardial infarction (MI) is an indicator of increased susceptibility to the effect of other established risk factors. The study assessed whether a family history of MI modifies the effect of arterial blood pressure, plasma cholesterol, high and low density lipoprotein cholesterol, % triglycerides, diabetes mellitus, body mass index, height, smoking habits, alcohol intake, physical activity level, and educational level on the incidence of MI. DESIGN: Prospective population based cohort study of cardiovascular risk and risk factors with follow up of MI by record linkage with the Cause of Death Register and The National Hospital Discharge Register until 1994. SETTING: The Copenhagen Centre for Prospective Population Studies, where data from three Danish studies are integrated. PARTICIPANTS: Subjects were 24,664 people aged 20-93, examined between 1976 and 1987. MAIN RESULTS: A total of 1763 new cases of MI occurred during 293,559 person years of observation. All risk factors, including family history of MI reported by 4012 subjects, were, as expected, associated with incidence of MI. With a few inconsistent exceptions we found no significant interactions between family history of MI and cardiovascular risk factors in their effect on MI. CONCLUSIONS: The familial predisposition to MI does not consistently modify the effect of other risk factors on the risk of MI. However, subjects with a family history of MI may still be regarded as an appropriate target group for screening for cardiovascular risk and intervention against other risk factors.
PMCID: PMC1756871  PMID: 10396532
18.  Update on the "Dutch hypothesis" for chronic respiratory disease 
Thorax  1998;53(Suppl 2):S15-S19.
PMCID: PMC1765904  PMID: 10193342
19.  Malignant neoplasms in pulmonary sarcoidosis 
Thorax  1998;53(7):624.
PMCID: PMC1745257  PMID: 9797771
21.  Risk of malignant neoplasms in patients with pulmonary sarcoidosis 
Thorax  1997;52(10):892-894.
BACKGROUND: For over 20 years the association between sarcoidosis and malignancy, particularly lymphoma and lung cancer, has been disputed with misclassification being the major concern. The aim of the present study was to analyse the incidence of malignancies in a cohort of patients with sarcoidosis by linkage to a nationwide population based cancer register. METHODS: The cohort comprised 254 patients followed for a median of 25 years until death, emigration, or 31 December 1992, whichever came first. The expected number of cancer cases was calculated using the annual age and sex specific cancer rates from the Danish Cancer Registry. RESULTS: Thirty six cancers were registered, three of which were misclassified as sarcoidosis, leaving 33 cancers compared with 23 expected (standardised incidence ratio (SIR) = 1.4; 95% CI 0.99 to 2.0). Five lung cancers were observed compared with 2.5 expected, yielding an SIR of 2.0 (95% CI 0.7 to 4.7). There was no incidence of lymphoma and only one case of leukaemia. There was a significant excess number of pharyngeal cancers based on two cases (SIR = 15.4; 95% CI 1.7 to 56). CONCLUSIONS: This study does not support the theory of an association between sarcoidosis and malignancy, and the main reason other studies have shown such an association is most likely to have been due to selection bias and misclassification. 

PMCID: PMC1758430  PMID: 9404377
22.  Effect of gender on hospital admissions for asthma and prevalence of self-reported asthma: a prospective study based on a sample of the general population. Copenhagen City Heart Study Group 
Thorax  1997;52(3):287-289.
BACKGROUND: Women are more often admitted to hospital for asthma than men. A study was undertaken to determine whether this is caused by gender differences in the prevalence or severity of the disease. METHODS: Admissions to hospital for asthma in 13,540 subjects were followed from 1977 to 1993. RESULTS: At baseline 315 subjects (2.3%) reported asthma, 2.2% of women and 2.5% of men. During follow up 160 subjects were admitted to hospital for asthma. After controlling for self-reported asthma and smoking, women had a higher risk of being admitted to hospital than men (relative risk 1.7, 95% confidence interval 1.2 to 2.4). This increased risk was not due to misclassification of chronic obstructive pulmonary disease (COPD) as asthma. CONCLUSIONS: These findings indicate gender-related differences in either the severity, perception, or management of asthma. 

PMCID: PMC1758523  PMID: 9093349
23.  Cardiovascular risk factor profile in subjects with familial predisposition to myocardial infarction in Denmark. 
STUDY OBJECTIVES: To identify possible modifiable mediators of familial predisposition to myocardial infarction (MI) by assessing the risk factor profile in individuals without MI in relation to parental occurrence of MI. DESIGN AND METHODS: Cross sectional survey of the general population. The odds of an adverse cardiovascular risk factor profile in subjects reporting parental occurrence of MI versus subjects not reporting parental occurrence were estimated by logistic regression models. SETTING: The Copenhagen Centre for Prospective Population Studies, where subjects investigated in three Danish prospective population studies are integrated. PARTICIPANTS: Subjects were 9306 females and 11,091 males aged 20-75 years with no history of MI. A total of 1370 subjects reported maternal MI and 2583 reported paternal MI. MAIN RESULTS: Increased systolic and diastolic blood pressure, increased cholesterol level, low ratio between high density lipoprotein (HDL) and total cholesterol (TC), and heavy smoking, were more frequent in subjects with parental occurrence of MI than in controls irrespective of sex and age of the subjects. Maternal MI was more predictive for increased cholesterol and decreased HDL/ TC ratio than paternal MI, and the risk of an increased cholesterol level was higher in subjects aged 20-39 years than in older subjects. No differences in body mass index, triglycerides, and physical inactivity were observed. CONCLUSIONS: Subjects free of previous MI who reported a parental occurrence of MI had an adverse cardiovascular risk factor profile regarding systolic and diastolic blood pressure, total cholesterol, the ratio between HDL and total cholesterol, and smoking. Thus, these modifiable risk factors may be mediators of the familial predisposition to MI.
PMCID: PMC1060471  PMID: 9229055
24.  Baseline characteristics are not sufficient indicators of non-response bias follow up studies. 
STUDY OBJECTIVE--The aim was to examine whether baseline characteristics from a cross sectional survey provided sufficient information regarding non-response bias in a follow up study when compared with information on hospital admissions in the intervening years. DESIGN--This was an 11 year follow up study of a cohort selected in 1974 with register information on hospital admissions during follow up. SETTING--The study was based on a sample of cement workers from a particular Portland cement factory with suitable controls from other occupations. PARTICIPANTS--A total of 1404 men participated in the first survey in 1974, including a questionnaire and lung function tests. In 1985 1070 men were alive and of these, 928 men (87%) responded to a postal questionnaire. MAIN RESULTS--Non-responders in 1985 did not differ markedly from responders when smoking habits, respiratory symptoms, and lung function were examined in 1974. During follow up, non-responders had twice as high rates of hospital admission due to respiratory diseases as responders. These differences remained present after adjusting for minor differences in age and smoking habits. CONCLUSIONS--Equal distributions of baseline characteristics among responders and non-responders in a follow up study do not preclude non-response bias.
PMCID: PMC1059680  PMID: 1494079

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