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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.

Background: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. Methods: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. Results: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p<0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for ⩾5 year mortality. Conclusions: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.

BACKGROUND There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RNgene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1β (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RNpolymorphism. METHODS We investigated whether polymorphisms in theIL1B and IL1RNgenes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. RESULTS None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RNhaplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). CONCLUSION These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.

Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation. To assess the long-term effect on mortality of a randomly applied smoking cessation program. The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years. 10 clinical centers in the United States and Canada. 5887 middle-aged volunteers with asymptomatic airway obstruction. All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease. The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler. At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. Results apply only to individuals with airway obstruction. Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.

Background: Non-specific bronchial hyperresponsiveness (NSBH) is a known predictor of accelerated rate of decline in lung function in smokers. Polymorphisms of the β2 adrenergic receptor (ADRB2) have previously been associated with NSBH and bronchodilator response (BDR) in asthmatics. Based on these associations, we hypothesised that ADRB2 polymorphisms would be associated with NSBH and BDR as well as an accelerated rate of decline in lung function among smokers. Methods: The prevalence of two ADRB2 polymorphisms, Arg16→Gly and Gln27→Glu, was examined in 587 smokers chosen from the NHLBI Lung Health Study for having the fastest (n=282) and slowest (n=305) 5 year rate of decline in forced expiratory volume in 1 second (FEV1; mean ΔFEV1 −4.14 and +1.08% predicted/year, respectively). Results: Contrary to our hypothesis, no ADRB2 allele or haplotype was associated with NSBH, BDR, or rate of decline in lung function. However, there was a significant negative association between heterozygosity at position 27 and a fast decline in lung function (adjusted odds ratio 0.56, 95% CI 0.40 to 0.78, p=0.0007). Conclusions: Heterozygosity at position 27 may be protective against an accelerated rate of decline in lung function. The polymorphism at position 16 does not contribute to the rate of decline in lung function, measures of NSBH, or BDR in smokers.

[...]most of the COPD in the latter study was \"moderate\"-that is, the participants had FEV1 values of 50-79% of the predicted normal-so it is likely that many of these were not very symptomatic.

Two primary chitinases have been identified in humans—acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host’s immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case–control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV 1 ) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV 1 and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV 1 . Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

Background: Airway inflammation may affect the decrease in lung function that occurs in response to cigarette smoke, and is an important pathological feature in chronic obstructive pulmonary disease (COPD). Group specific component (GC) can act as an inflammatory mediator and may therefore have important influences on the inflammatory reaction in the airway. Several reports have described associations between GC haplotypes and COPD but these remain controversial. In addition, most of these studies were based on a small number of subjects. Methods: We have studied the contribution of GC haplotypes to the level of lung function in a large cohort of smokers with high or low lung function (mean FEV1 % predicted 91.8 and 62.6, respectively). The frequency of the three major GC haplotypes (1S, 1F and 2) was investigated in 537 individuals with high lung function and 533 with low lung function. Results: No significant difference was found in the frequency of any GC haplotype between the high and low lung function groups. There was also no significant difference between the groups in genotype frequency of the two single nucleotide polymorphisms that underlie the haplotypes. Conclusion: The GC haplotype does not contribute to reduced lung function in this cohort of smokers.

To identify characteristics associated with respiratory symptoms due to an episode of air pollution. Mail survey. In October 1992, the population of the city of Winnipeg was exposed to elevated levels of particulate matter (total and < 10 μm size), carbon monoxide, nitrogen dioxide, and volatile organic compounds due to smoke from adjacent fields where farmers were burning agricultural residue (straw and stubble). We surveyed 428 participants in the ongoing Lung Health Study (35 to 64 years old, both sexes) with mild to moderate airways obstruction (mean FEV1 percent predicted 73±12%), and a high level of airways hyperreactivity (23% of men and 37% of women). While 37% of subjects were not bothered by smoke at all, 42% reported that symptoms (cough, wheezing, chest tightness, shortness of breath) developed or became worse due to the air pollution episode and 20% reported that they had breathing trouble. Those with symptoms were more likely to be female than male and were more likely to be ex-smokers than smokers. Subjects with asthma and chronic bronchitis were also more likely affected. The degree of airways obstruction and the level of bronchial hyperresponsiveness were not associated with increased susceptibility. Gender, smoking habit, and respiratory symptoms but not bronchial hyperresponsiveness or the degree of airways obstruction are factors influencing susceptibility to symptoms due to air pollution in adult smokers and former smokers.