Search

Despite rapid advances in our understanding of its pathophysiology, chronic obstructive pulmonary disease (COPD) remains incurable. Although bronchodilators and theophyllines are commonly used to treat symptoms of dyspnea and cough and to acutely improve lung function, they do not modify the long-term decline in FEV(1). The principal goals of current COPD pharmacotherapy are to reduce exacerbations, improve health status, and prolong survival. There is strong evidence, including data from randomized clinical trials, that indicates inhaled corticosteroids alone, or in combination with a long-acting beta(2)-adrenoceptor agonist, improve patient symptoms, reduce morbidity, and perhaps even prolong survival in COPD. A recent individual patient-based meta-analysis of randomized, placebo-controlled trials of inhaled corticosteroids in COPD indicated that mortality over 3-4 yr was 27% lower in the group that received inhaled corticosteroids compared with the group that received placebo. Several short-term follow-up trials have also suggested a reduction in mortality with a combination of long-acting beta(2)-agonist and inhaled corticosteroids, and a large, long-term study that is currently ongoing (the Toward a Revolution in COPD Health [TORCH] study) will provide data on the effects of fluticasone propionate and salmeterol in combination on all-cause mortality. This article reviews some of the relevant epidemiologic and pathophysiologic processes that affect mortality in COPD and critically examines the effect of current COPD therapies on mortality.

Objective: To determine whether there was any change in indices of asthma control in population-based samples of patients with asthma between 1997 and 2002., Design: We examined asthma control and treatment in the community using two cross-sectional studies carried out 5 years apart in 1997 and 2002. Pharmacists handed out the questionnaires to patients with asthma; patients completed the questionnaires themselves., Setting: Community pharmacies in Alberta., Participants: Patients with physician-confirmed asthma attending pharmacies to fill prescriptions for asthma medications., Main Outcome Measure: Asthma control., Results: In 1997 and 2002, 301 and 340 completed questionnaires were received, respectively. Mean age of respondents was 42 and 39 years and the female-to-male ratio was 1.3:1 and 1.4:1, respectively. Overall asthma control was achieved by 27% (1997) and 31% (2002) of subjects, a non-significant change. Regular inhaled corticosteroid use was reported by 63% (1997) and 65% (2002) of subjects; mean daily dose of inhaled corticosteroids reported decreased from 920 mug in 1997 to 765 mug in 2002 (P < .02), which might reflect adoption of the newer guideline recommendation for lower-dose inhaled corticosteroids in combination therapy rather than a decrease in severity of asthma. Fewer respondents reported being hospitalized for asthma in 2002 (P = .02). Self-management plans were used by 7% and 5% of subjects in 1997 and 2002, respectively., Conclusion: In general, asthma control and use of inhaled corticosteroids was similar in 1997 and 2002. There was no evidence that patient education on asthma had increased. Asthma control was poor in 1997 and had not improved by 2002.

By 2020 chronic obstructive pulmonary disease (COPD) will be the third leading cause of mortality and fifth leading cause of morbidity. Research over the past two decades has shed important insights on the pathobiology of COPD, leading to the development of novel drugs. In the past, symptomatic treatment with bronchodilators was the predominant focus of COPD management. With increased awareness of the importance of airway inflammation in COPD progression, there has been a shift in emphasis to drugs that attack various targets in the inflammatory cascade. These drugs include phosphodiesterase 4 inhibitors, leukotriene modifiers and TNF antagonists, which are poised to enter the COPD market in the very near future. Tyrosine kinase antagonists, inhibitors of NF-kappaB, neutrophil elastase inhibitors, chemokine antagonists, mucolytics and novel antibiotics are being evaluated for possible effectiveness in COPD. Many of these drugs may enter the COPD market within the next decade. This paper reviews the molecular rationale for these emerging drugs and their potential efficacy in COPD.

Unlabelled: The objective of this study was to investigate the effect of docosahexaenoic acid (DHA) supplementation on blood and intestinal DHA levels and lung function in mild/moderately affected adult CF patients with the DeltaF508 genotype., Background: Cystic Fibrosis (CF) patients often present with plasma fatty acid levels indicating low levels of linoleic (18:2n-6) and docosahexaenoic (22:6n-3) acids and an increased level of arachidonic acid (20:4n-6). Improved dietary fat intake or reducing fat malabsorption with pancreatic enzymes has failed to normalize this biochemical deficiency of DHA., Methods: Five CF patients, aged 18-43, received 70 mg of DHA/kg body weight/d for six weeks. At baseline and at six weeks a physical exam, lung function, 3-day dietary intake, duodenal mucosal biopsy and blood sample were assessed. The blood was analyzed for plasma vitamin A, D and E levels, liver function tests, clinical chemistry (CBC, differential and electrolytes). Plasma and red blood cell fatty acid levels were also analyzed. At three weeks, assessment included a physical exam, lung function test and fasting blood sample (vitamin levels, liver function and clinical chemistry only)., Results: Pre- and post-measurements were compared for the four subjects who completed the study. An increase in DHA content (% w/w) was observed in all phospholipid fractions of plasma, red blood cell and mucosal samples. No significant differences in vitamin levels, liver function or lung function were observed., Conclusions: The study proves the concept that an increase in tissue DHA levels in CF patients can be achieved by supplementing for six weeks with 70 mg/kg/d DHA.

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used as maintenance therapy in patients with moderate to severe asthma or chronic obstructive pulmonary disease (COPD). The main effect of inhaled corticosteroids is thought to be mediated through suppression of airway inflammation, while long-acting beta2-adrenoceptor agonists are thought to work by inducing bronchodilation. However, there is emerging data to indicate that these two classes of drugs interact positively with each other, leading to added or perhaps synergistic benefits for patients. Corticosteroids enhance the expression of beta2-adrenoceptor, thus providing protection against desensitization and development of tolerance to beta2-adrenoceptor agonists, which may occur with prolonged use of these medications. Long-acting beta2-adrenoceptor agonists, on the other hand, may amplify the anti-inflammatory effects of corticosteroids by accelerating nuclear translocation of the glucocorticoid receptor complex, and enhancing transcription and expression of steroid-inducible genes in pro-inflammatory cells. In clinical trials, corticosteroids in combination with long-acting beta2-adrenoceptor agonists reduce exacerbation rates, and improve lung function and health status of patients with moderate to severe asthma or COPD beyond that achieved by individual component therapy. Their effects on mortality are unknown. There is a large clinical trial currently underway, which will provide mortality data by the year 2006. On balance, clinical evidence supports the use of combination therapy in moderate to severe asthma and COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the USA, and it remains one of the few diseases that continues to increase its numbers. The development and progression of COPD can vary dramatically between individuals. A low level of lung function remains the cornerstone of COPD diagnosis and is a key predictor of prognosis. Lung function, however, is not the only factor in determining morbidity and mortality related to COPD, with factors such as body mass index, exercise capability and comorbid disease being important predictors of poor outcomes. Exacerbations of COPD are additional important indicators of both quality of life and outcomes in COPD patients. Definitions of exacerbations can vary, ranging from an increase in symptoms to COPD-related hospitalisations and death. COPD exacerbations are more common in patients with lower levels of lung function and may lead to more rapid declines in lung function. Better understanding of the natural history of COPD may lead to better definitions of specific COPD phenotypes, better interventions and improved outcomes.

Rationale: Chronic inflammation has been implicated in the development of airway dysplasia and lung cancer. It is unclear whether circulating biomarkers of inflammation could be used to predict progression of airway dysplasia., Objective: We determined whether circulating levels of C-reactive protein (CRP) or other inflammatory biomarkers could predict progression of bronchial dysplasia in smokers over 6 mo., Methods: The plasma levels of CRP, interleukins 6 and 8, and monocyte chemoattractant protein 1 were measured at baseline in 65 ex- and current smokers who had at least one site of bronchial dysplasia > 1.2 mm in size. Additional bronchial biopsies were taken after 6 mo from the same sites where dysplastic lesions were discovered at baseline. Progressive dysplastic lesions were defined as worsening of the dysplastic lesion by at least two grades or development of new dysplastic lesions., Results: Half of the participants developed progressive dysplastic lesions after 6 mo. The baseline CRP levels in these participants were 64% higher than those without progressive disease (p = 0.027). Only one of eight (13%) participants with CRP < or = 0.5 mg/L developed progressive disease, whereas 31 of 57 (54%) participants with CRP > 0.5 mg/L developed progressive disease (p = 0.011). The odds of developing progressive disease were 9.6-fold higher in the latter than in the former group., Conclusion: Plasma CRP, in concert with lung function and pack-years of smoking, appears to have excellent predictive powers in identifying participants with bronchial dyplastic lesions whose lesions progress to more advanced stages of dysplasia.

Background: Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting beta2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease., Methods/design: After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting beta2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrollment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function., Discussion: If inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.

Background: Clarithromycin exhibits anti-inflammatory as well as antimicrobial activity, leading to decreased symptoms of asthma and chronic sinusitis. The mode of anti-inflammatory effects of clarithromycin on inflammatory cells is not well understood. We hypothesized that clarithromycin inhibits inflammatory cell mediator release and survival., Methods: We investigated the effects of this drug on survival and mediator release from mast cells, eosinophils and neutrophils., Results: Human eosinophil and neutrophil respiratory burst was inhibited by up to 54% after 1-2 h pretreatment with 100 microg/ml clarithromycin. Similar doses of erythromycin did not affect respiratory burst responses in these cells. Clarithromycin at doses of up to 100 microg/ml had no effect on granule-derived mediators released from mast cells and neutrophils. However, we found that clarithromycin (100 microg/ml) induced cell death in mast cells and eosinophils after 16-48 h incubation., Conclusion: Clarithromycin inhibited inflammatory cell mediator release and survival, which may enhance its ability to reduce the symptoms of chronic sinusitis and asthma., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Individuals with severely impaired lung function have an increased risk of lung cancer. Whether milder reductions in forced expiratory volume in 1 second (FEV(1)) also increase the risk of lung cancer is controversial. Moreover, there is little consensus on whether men and women have similar risks for lung cancer for similar decreases in FEV(1)., Methods: A search was conducted of PubMed and EMBASE from January 1966 to January 2005 and studies that examined the relationship between FEV1 and lung cancer were identified. The search was limited to studies that were population based, employed a prospective design, were large in size (> or = 5000 participants), and adjusted for cigarette smoking status., Results: Twenty eight abstracts were identified, six of which did not report FEV1 and eight did not adjust for smoking. Included in this report are four studies that reported FEV1 in quintiles. The risk of lung cancer increased with decreasing FEV1. Compared with the highest quintile of FEV1 (> 100% of predicted), the lowest quintile of FEV1 (< approximately 70% of predicted) was associated with a 2.23 fold (95% confidence interval (CI) 1.73 to 2.86) increase in the risk for lung cancer in men and a 3.97 fold increase in women (95% CI 1.93 to 8.25). Even relatively small decrements in FEV1 ( approximately 90% of predicted) increased the risk for lung cancer by 30% in men (95% CI 1.05 to 1.62) and 2.64 fold in women (95% CI 1.30 to 5.31)., Conclusion: Reduced FEV1 is strongly associated with lung cancer. Even a relatively modest reduction in FEV1 is a significant predictor of lung cancer, especially among women.

Study Objectives: Conditions that give rise to reduced lung function are frequently associated with low-grade systemic inflammation, which may lead to poor cardiovascular outcomes. We sought to determine the relationship between reduced FEV1 and cardiovascular mortality, independent of smoking., Design: Longitudinal population-based study and a meta-analysis of literature., Setting: Representative sample of the general population., Participants: Participants of the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study who were 40 to 60 years of age at baseline assessment (n = 1,861)., Measurements and Results: We compared the risk of cardiovascular mortality across quintiles of FEV1. Individuals in the lowest FEV1 quintile had the highest risk of cardiovascular mortality (relative risk [RR], 3.36; 95% confidence interval [CI], 1.54 to 7.34). Compared to FEV1 quintile 1, individuals in quintile 5 had a fivefold increase in the risk of death from ischemic heart disease (RR, 5.65; 95% CI, 2.26 to 14.13). We also performed a systematic review of large cohort studies (> 500 participants) that reported on the relationship between FEV1 and cardiovascular mortality (12 studies; n = 83,880 participants). Compared to participants in the highest FEV1 category, those with reduced FEV1 had a higher risk of cardiovascular mortality (pooled RR, 1.77; 95% CI, 1.56 to 1.97)., Conclusions: There is strong epidemiologic evidence to indicate that reduced FEV1 is a marker for cardiovascular mortality independent of age, gender, and smoking history.

Background: Despite significant improvements in asthma treatment and the dissemination of national and international guidelines for asthma management, there are ongoing concerns that suboptimal care is being provided for patients with asthma., Objective: To determine the current practice patterns of asthma care among primary care physicians., Design: A cross-sectional study., Setting: Province of Alberta, Canada (population: 3 million people)., Participants: Patients, 5 years of age or older, who had a physician's diagnosis of asthma, and had at least two visits for asthma between 1996 and 2001., Measurement and Results: Charts of 3072 distinct patients (from 45 unique primary care physicians) were reviewed. Previous emergency department visits or hospitalizations were experienced by 20% of the sample. A total of 25% of patients had documented evidence that they had performed spirometry. More than half of the patients had no documented evidence that they had received any form of asthma education; only 2% of the charts indicated that patients received a written action plan. Two thirds of the patients were prescribed an inhaled steroid within 6 months of the last clinic visit., Conclusions: Our study indicates a gap in the provision of asthma education, written action plans, and spirometric testing for patients diagnosed with asthma among primary care physicians.

Purpose: Respiratory failure is the leading cause of death among patients admitted with community-acquired pneumonia. We sought to determine the association between arterial carbon dioxide tension (P(a)CO(2)) and in-hospital mortality in patients admitted with pneumonia., Methods: We analyzed data from 2171 patients aged >or=17 years who had been admitted for community-acquired pneumonia to an acute care hospital in Edmonton, Alberta. We compared the risk of all-cause in-hospital mortality using a Cox proportional hazards model across categories of P(a)CO(2)., Results: Overall, in-hospital mortality was 10% (n = 218). Compared with patients with normal P(a)CO(2) values (40 to 44 mm Hg), in-hospital mortality was greater (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI]: 1.0 to 3.2) among patients with hypocapnia (P(a)CO(2) <32 mm Hg). In-hospital mortality was also greater (OR = 2.6; 95% CI: 1.5 to 4.5) in patients with hypercapnia (>or=45 mm Hg). In-hospital mortality was similar in patients with P(a)CO(2) values between 32 and 35 mm Hg (OR = 1.55; 95% CI: 0.89 to 2.79) and those with values between 36 and 39 mm Hg (OR = 1.42; 95% CI: 0.77 to 2.61)., Conclusion: Among patients admitted with community-acquired pneumonia, in-hospital mortality was greater in those with hypocapnia or hypercapnia. These data suggest that measurement of P(a)CO(2) adds prognostic information to standard prediction rules and should be used for clinical and epidemiologic purposes to risk-stratify in-hospital patients with community-acquired pneumonia.

Background: Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma., Methods: A multicentre, randomised, placebo controlled, parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of > or =3.5%., Results: Eighteen patients received low dose fluticasone (250 mug/day), 19 received montelukast (10 mg/day), and 13 were given placebo for 8 weeks. Fluticasone treatment resulted in a greater reduction in sputum eosinophils (geometric mean (SD) 11.9 (2.3)% to 1.7 (5.1)%) than montelukast (10.7 (2.3)% to 6.9 (3.8)%; p = 0.04) or placebo (15.4 (2.4)% to 7.8 (4.2)%; p = 0.002), and improvement in FEV(1) (mean (SD) 2.6 (0.9) l to 3.0 (0.9) l) than montelukast (2.8 (0.7) l to 2.8 (0.9) l; p = 0.02) or placebo (2.4 (0.8) l to 2.4 (0.9) l; p = 0.01). Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it. The effect of montelukast was maximal at 1 week and was maintained over 4 weeks. The effect of fluticasone was maintained over 8 weeks while that of montelukast was not., Conclusions: Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naive eosinophilic asthma.

Background: Low-grade systemic inflammation is commonly observed in conditions associated with reduced FEV(1). Active cigarette smoking, which is a leading risk factor for decreased FEV(1), can also independently induce systemic inflammation., Study Objectives: To determine the independent contributions of active cigarette smoking and reduced FEV(1) (as well as their potential interactions) on systemic inflammation., Design: Cross-sectional survey., Setting: The US general population., Participants: A total of 7,685 adult participants, >/= 40 years of age, in the Third National Health and Nutrition Examination Survey, who had acceptable data on spirometry and laboratory measurements such as serum C-reactive protein (CRP)., Measurements: The participants were stratified into four equal groups (quartiles) based on the percent predicted FEV(1) values. Each group was further categorized as active smokers or nonsmokers according to serum cotinine level (ie, >/= 10 or < 10 ng/mL). Serum levels of CRP, plasma fibrinogen, blood leukocytes, and platelets were compared across the predicted FEV(1) quartile groups and across smoking status using multiple logistic regression models., Results: We found that active smoking by itself increased the odds of having elevated CRP levels by 63% (adjusted odds ratio [OR], 1.63; 95% confidence interval, 1.28 to 2.09). The adjusted OR for reduced FEV(1) was 2.27 (95% confidence interval, 1.92 to 2.70). Having both risk factors increased the OR to 3.31 (95% confidence interval, 2.73 to 4.02). Similar findings were observed for blood leukocytes and plasma fibrinogen., Conclusion: These findings suggest an additive effect of active smoking and reduced FEV(1) on markers of systemic inflammation and suggest their potential interactions in the pathogenesis of systemic complications observed in patients with poor lung function.

Chronic obstructive pulmonary disease (COPD) is a serious illness that affects over 5% of the adult population. It is one of the few conditions for which the mortality and morbidity are still increasing. Experts expect COPD to become the third leading cause of death and the fifth leading cause of disability worldwide by the year 2020. Thus far, the only treatments that have been shown to make a difference to survival are smoking cessation and the use of oxygen supplements for those who are hypoxaemic at rest. The use of inhaled corticosteroids as monotherapy or in combination with a long-acting beta2-adrenoceptor agonist for COPD is controversial. Experimental data indicate that the inflammatory process in COPD may be resistant to the anti-inflammatory effects of corticosteroids. However, several large clinical studies have shown that inhaled corticosteroids in relatively high doses (e.g. budesonide 800 microg/day or fluticasone propionate 1 mg/day) reduce exacerbations by 20-30% and improve the health status of COPD patients by a similar amount compared with placebo. Withdrawal of inhaled corticosteroids may increase clinical exacerbation rates by 50% in COPD patients and by 2-fold in those with severe disease. Combined therapy with inhaled corticosteroids and long-acting beta2-adrenoceptor agonists may be superior to individual component therapy in reducing exacerbations. However, these medications must be used cautiously, as they have been associated with certain adverse effects. Inhaled corticosteroids, for instance, increase the risk for dysphonia and oral thrush by 2- to 3-fold. Skin bruising is also more common in users than in non-users of inhaled corticosteroids. On balance, for those with moderate-to-severe COPD and those who experience frequent exacerbations, judicious use of inhaled corticosteroids alone or in combination with long-acting beta2-adrenoceptor agonists appears reasonable.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Canada and elsewhere. It affects 5% of all adult Canadians and is the fourth leading cause of death. Interestingly, the leading causes of hospitalizations and mortality among COPD patients are cardiovascular events. In the Lung Health Study, over 5 800 patients with mild to moderate COPD were studied. Forty-two to 48% of all hospitalizations that occurred over the study's 5-year follow-up period were related to cardiovascular complications. Various population-based studies suggest that independent of smoking, age, and gender, COPD increases the risk of cardiovascular morbidity and mortality twofold. Alarmingly, some bronchodilators, which are commonly used to treat symptoms in COPD, may increase the risk of cardiovascular morbidity and even mortality among COPD patients. In this paper, we discuss the epidemiologic evidence linking COPD and cardiovascular events as well as the potential mechanism(s) which may be responsible for this association.

Chronic obstructive pulmonary disease and other disorders, associated with reduced lung function, are strong risk factors for cardiovascular events, independent of smoking. Overall, when the lowest quintile of lung function, as measured by FEV1 is compared with the highest quintile, the risk of cardiovascular mortality increases by approximately 75% in both men and women. Having symptoms of chronic bronchitis alone increases the risk of coronary deaths by 50%. Reduced ratio of FEV1 to FVC by itself is a modest independent risk factor for coronary events, increasing the risk by 30%. However, if patients have ventricular arrhythmias, the risk of coronary events is increased twofold, suggesting that the cardiotoxic effects of obstructive airways disease are amplified in those who have underlying cardiac rhythm disturbances. In general, for every 10% decrease in FEV1, all-cause mortality increases by 14%, cardiovascular mortality increases by 28%, and nonfatal coronary event increases by almost 20%. These data indicate that chronic obstructive pulmonary disease is a powerful, independent risk factor for cardiovascular morbidity and mortality.

Patients with chronic obstructive pulmonary disease (COPD) are predisposed to atherosclerosis and coronary artery disease, but the underlying mechanisms are unclear. Although there is wide acceptance that atherosclerosis is related to systemic inflammation, the cause(s) and mechanism(s) of pulmonary inflammation in stable COPD remain unknown. Infectious (bacterial and viral) as well as noninfectious agents can cause acute exacerbations in COPD, and they intensify local and systemic inflammation. Although it is not known how systemic inflammation develops in stable COPD, there is good evidence to suggest that it occurs and that the intensity of systemic inflammation is linked to the severity of airflow obstruction. We postulate that systemic inflammation provides the linkage between COPD and atherosclerosis. Inhaled corticosteroids have been shown to improve health outcomes in COPD, but the mechanism by which this occurs is a pivotal and challenging question that has yet to be answered. To prove the concept that inhaled corticosteroids could suppress systemic inflammation (as exemplified by serum C-reactive protein [CRP] levels), a double-blind, placebo-controlled clinical trial was conducted in a group of patients with mild to moderate COPD. We found that withdrawal of inhaled corticosteroids increased serum CRP levels, and that reintroduction of inhaled fluticasone could suppress CRP levels.

Disorders of the respiratory system, such as cystic fibrosis (CF), involve the infiltration and activation of airway inflammatory cells, including neutrophils. This leads to the secretion of peroxidases, which react further with substrates in solution to produce oxidative metabolites, such as 3-chlorotyrosine. Elevated levels of modified tyrosine residues in the airways of patients with CF may be detectable by nuclear magnetic resonance (NMR) in correlation with inflammatory cell influx. In this study, high-resolution (500 MHz) 1H NMR was used to analyze the production of modified tyrosine residues resulting from in vitro stimulation of peripheral blood eosinophils and neutrophils, as well as in sputum samples from control subjects and patients with CF. Following in vitro stimulation, purified peripheral blood neutrophils generated 3-chlorotyrosine, while eosinophils produced predominantly 3-bromotyrosine and 3,5-dibromotyrosine. Chlorinated and brominated tyrosine residues were detected in sputum samples from patients with CF (N=7), but were not detected in the control group (N=9). Neutrophil counts in CF sputum correlated strongly with the presence of 3-chlorotyrosine (r2=0.869). Our findings indicate that neutrophil and eosinophil activation in CF is detectable by NMR. NMR may be a useful tool for the detection of biological markers of inflammatory processes in patient airways.

Systemic inflammation is present in chronic obstructive pulmonary disease (COPD), which has been linked to cardiovascular morbidity and mortality. We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD. We recruited 41 patients with mild to moderate COPD. After 4 weeks during which inhaled corticosteroids were discontinued, patients were assigned to fluticasone (500 mcg twice a day), oral prednisone (30 mg/day), or placebo over 2 weeks, followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day. Withdrawal of inhaled corticosteroids increased baseline C-reactive protein (CRP) levels by 71% (95% confidence interval [CI], 16-152%). Two weeks with inhaled fluticasone reduced CRP levels by 50% (95% CI, 9-73%); prednisone reduced it by 63% (95% CI, 29-81%). No significant changes were observed with the placebo. An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline (a 29% reduction; 95% CI, 7-46%). Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD.

Purpose: Many asthmatic patients discharged from emergency departments do not have timely follow-up visits with a primary care physician. This study was conducted to determine the effectiveness of a health professional-based intervention in improving process of care and health outcomes among asthmatic patients discharged from emergency departments., Methods: We enrolled 125 asthmatic patients, aged 5 through 50 years, from the emergency department of a community-based hospital; 62 patients were assigned to usual care and 63 to enhanced care. Enhanced care consisted of usual care plus employment of a coordinator to make follow-up appointments with the patient's primary care physician with at least one reminder telephone call to the patient., Results: At 6 months of follow-up, mean (+/- SD) asthma and pediatric quality-of-life scores were higher in the enhanced care group than in the usual care group (5.7 +/- 1.2 units vs. 5.0 +/- 1.3 units, P = 0.01). The enhanced care group also had a higher rate of follow-up office visits (78% [n = 44] vs. 60% [n = 33], P = 0.003), were more likely to have written action plans (46% [n = 26] vs. 25% [n = 14], P = 0.02), and had fewer asthma symptoms (1.8 +/- 1.1 units vs. 2.2 +/- 1.3 units, P = 0.09). However, these differences disappeared by 12 months of follow-up., Conclusion: A simple intervention wherein a health professional facilitates follow-up visits can improve the process of care and health outcomes of high-risk asthmatic patients. However, the effect of this intervention is time limited and largely wears off by 12 months.

Context: Over the last 2 decades, many new pharmacological agents have been introduced to reduce the growing morbidity associated with asthma, but the long-term effects of these agents on exacerbations are unclear., Objective: To systematically review and quantitatively synthesize the long-term effects of inhaled corticosteroids, long-acting beta2 agonists, leukotriene pathway modifiers/receptor antagonists, and anti-IgE therapies on clinical outcomes and particular clinically relevant exacerbations in adult patients with chronic asthma., Data Sources: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant randomized controlled trials and systematic reviews published from January 1, 1980, to April 30, 2004. We identified additional studies by searching bibliographies of retrieved articles and contacting experts in the field., Study Selection and Data Extraction: Included trials were double-blind, had follow-up periods of at least 3 months, and contained data on exacerbations and/or forced expiratory volume in 1 second. The effects of interventions were compared with placebo, short-acting beta2 agonists, or each other., Data Synthesis: Inhaled corticosteroids were most effective, reducing exacerbations by nearly 55% compared with placebo or short-acting beta2 agonists (relative risk [RR], 0.46; 95% confidence interval [CI], 0.34-0.62; P<.001 for heterogeneity). Compared with placebo, the use of long-acting beta2 agonists was associated with 25% fewer exacerbations (RR, 0.75; 95% CI, 0.64-0.88; P =.43 for heterogeneity); when added to inhaled corticosteroids, there was a 26% reduction above that achieved by steroid monotherapy (RR, 0.74; 95% CI, 0.61-0.91; P =.07 for heterogeneity). Combination therapy was associated with fewer exacerbations than was increasing the dose of inhaled corticosteroids (RR, 0.86; 95% CI, 0.76-0.96; P =.65 for heterogeneity). Compared with placebo, leukotriene modifiers/receptor antagonists reduced exacerbations by 41% (RR, 0.59; 95% CI, 0.49-0.71; P =.44 for heterogeneity) but were less effective than inhaled corticosteroids (RR, 1.72; 95% CI, 1.28-2.31; P =.91 for heterogeneity). Use of monoclonal anti-IgE antibodies with concomitant inhaled corticosteroid therapy was associated with 45% fewer exacerbations (RR, 0.55; 95% CI, 0.45-0.66; P =.15 for heterogeneity)., Conclusions: Inhaled corticosteroids are the single most effective therapy for adult patients with asthma. However, for those unable or unwilling to take corticosteroids, the use of leukotriene modifiers/receptor agonists appears reasonable. Long-acting beta2 agonists may be added to corticosteroids for those who remain symptomatic despite low-dose steroid therapy. Anti-IgE therapy may be considered as adjunctive therapy for young adults with asthma who have clear evidence of allergies and elevated serum IgE levels.

Background: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD., Methods: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV(1)) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-alpha (TNF-alpha), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model., Results: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-alpha levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89))., Conclusions: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are increasing concerns for First Nations peoples in Canada. Although hospital utilization for asthma and COPD among First Nations peoples has been increasing, the prevalence of asthma or wheezing is comparable to national averages., Objectives: A pilot study was conducted to determine the prevalence of impaired lung function in school-aged First Nations children., Patients and Methods: A First Nations community in northern Alberta was selected to participate. Consent forms and a school health survey were completed by parents or guardians. Children with consent completed spirometry at school, and results were compared with predicted values., Results: A total of 36 children participated (response rate 70.6%). Of these, 19.4% of parents reported that their child had received a physician diagnosis of asthma at some point in their life; only 28.6% had a parental report of still having asthma. Parents smoked in 73.1% of the children's homes. The mean (+/- SD) percentage of forced expiratory volume in 1 s (FEV1) over forced vital capacity (FVC) was 82.6%+/-6.9% (94.4%+/-0.08% of predicted). Evidence of airflow obstruction was found in 25% of the children. Parental report of the child ever having asthma was associated with impaired lung function (OR 3.20; P=0.033). Children in a home with reported mold exposure were less likely to have impaired lung function (OR 0.68; P=0.030)., Conclusions: Many children in this study already have established airflow obstruction and may be at increased risk for asthma or COPD. Exposure to mold appeared to be protective. Further research is needed to evaluate the lung health concerns of this population.

Chronic obstructive pulmonary disease (COPD) affects over 5% of the adult population and is the only major cause of death in the United States where morbidity and mortality are increasing. Clinically, COPD is characterized by irreversible airflow obstruction and airway inflammation that eventually lead to dyspnea, cough and sputum production. Long-acting beta(2)-agonists (LABAs) are effective in reducing patient symptoms through their bronchodilatory action on airway smooth muscle. More importantly, when LABAs are given in conjunction with inhaled corticosteroids, they appear to provide added benefits for patients. While the mechanisms for this observation are not entirely clear, there is emerging evidence to indicate that LABAs and corticosteroids attenuate different but complementary components of the inflammatory cascade related to COPD. Moreover, LABAs and corticosteroids may beneficially interact to prevent downregulation of beta(2)-receptors in airway cells (and thereby preventing tachyphylaxis) and to facilitate translocation of glucocorticoid receptors into the nucleus of inflammatory cells (thereby, amplifying the anti-inflammatory activity of the corticosteroid). Regardless of the mechanism, several large, high-quality randomized controlled clinical trials indicate that combination therapy of LABA with inhaled corticosteroids improves patient symptoms, and reduces exacerbations by a third (compared to placebo). More importantly, combination therapy produces superior health outcomes than mono-therapy with inhaled corticosteroids or LABA, suggesting added clinical benefits of these two compounds in COPD. This article will present a comprehensive overview of the currently available clinical evidence for the use of combination therapy as well as the potential mechanisms of their actions in COPD.

Background: Because obesity promotes inflammation and imposes mechanical constraints to the airways, a high birth weight may be a risk factor for asthma in childhood. However, to our knowledge, few studies have examined this potential relationship., Objective: To determine the relationship between high birth weight and risk of emergency visits for asthma during childhood., Design: Population-based cohort study., Setting: Alberta, Canada., Participants: All neonates born at term (> or =37 weeks) between April 1, 1985, and March 31, 1988, in Alberta (N = 83,595). We divided the cohort into birth-weight categories: low (<2.5 kg), normal (2.5-4.5 kg), or high (>4.5 kg). The cohort was observed prospectively for 10 years.Main Outcome Measure Comparison of risk of emergency visits for asthma over 10 years across the birth-weight categories., Results: Neonates born with a high birth weight had a significantly increased risk of emergency visits for asthma during childhood compared with neonates born with a normal birth weight (relative risk [RR], 1.16; 95% confidence interval [CI], 1.04-1.29). The relationship between birth weight and emergency visits for asthma beyond a birth weight of 4.5 kg was linear, such that every increment of 0.10 kg in birth weight was associated with an additional 10% (95% CI, 2%-19%) increase in the risk of emergency visits for asthma. Other factors associated with an elevated risk for emergency asthma visits during childhood included male sex (RR, 1.26; 95% CI, 1.22-1.30), aboriginal status (RR, 1.20; 95% CI, 1.11-1.29), and low-income status (RR, 1.11; 95% CI, 1.06-1.16)., Conclusions: A high, but not low, birth weight is a risk factor for increased emergency visits during childhood. The risk increases linearly beyond a birth weight of 4.5 kg.

The purpose of this study was to characterize basolateral anion channels in Calu-3 and normal human bronchial epithelial cells, and their role in anion secretion. Patch clamp studies identified an outwardly rectifying Cl- channel (ORCC), which could be activated by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA). Short-circuit current measurements revealed that NECA activates a basolateral, but not an apical, anion conductance sensitive to 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid, and to 9-anthracenecarboxylic acid, but not to 4,4'-dinitrostilbene-2,2'-disulfonic acid. Apical membrane permeabilization studies confirmed the presence of basolateral anion channels, established their halide permeability sequence (Cl- >/= Br- >> I-), and demonstrated their outwardly rectifying nature. Experiments using H-89, forskolin, and Ht31 demonstrated that adenosine receptor dependent activation of basolateral ORCC was cAMP- and potentially A-kinase anchoring protein-dependent. Neither BAPTA-AM treatment nor basolateral Ca2+ removal had any effect on the activation of these channels. Anion replacement and 36Cl- flux studies show that Calu-3 cells primarily secrete HCO3- when stimulated with NECA, and that Cl- secretion can be stimulated by blocking basolateral ORCC, whereas normal human bronchial epithelial cells exclusively secrete Cl- under all conditions studied. We propose a novel model of anion secretion in which ORCC recycles Cl- across the basolateral membrane, allowing preferential HCO3- secretion.

Context: The care of patients with chronic obstructive pulmonary disease (COPD) has changed radically over the past 2 decades, and novel therapies can not only improve the health status of patients with COPD but also modify its natural course., Objective: To systematically review the impact of long-acting bronchodilators, inhaled corticosteroids, nocturnal noninvasive mechanical ventilation, pulmonary rehabilitation, domiciliary oxygen therapy, and disease management programs on clinical outcomes in patients with COPD., Data Sources: MEDLINE and Cochrane databases were searched to identify all randomized controlled trials and systematic reviews from 1980 to May 2002 evaluating interventions in patients with COPD. We also hand searched bibliographies of relevant articles and contacted experts in the field., Study Selection and Data Extraction: We included randomized controlled trials that had follow-up of at least 3 months and contained data on at least 1 of these clinical outcomes: health-related quality of life, exacerbations associated with COPD, or death. For pulmonary rehabilitation, we included studies that had a follow-up of at least 6 weeks. Using standard meta-analytic techniques, the effects of interventions were compared with placebo or with usual care. In secondary analyses, the effects of interventions were compared against each other, where possible., Data Synthesis: Long-acting beta2-agonists and anticholinergics (tiotropium) reduced exacerbation rates by approximately 20% to 25% (relative risk [RR] for long-acting beta2-agonists, 0.79; 95% CI, 0.69-0.90; RR for tiotropium, 0.74; 95% CI, 0.62-0.89) in patients with moderate to severe COPD. Inhaled corticosteroids also reduced exacerbation rates by a similar amount (RR, 0.76; 95% CI, 0.72-0.80). The beneficial effects were most pronounced in trials enrolling patients with FEV1 between 1 L and 2 L. Combining a long-acting beta2-agonist with an inhaled corticosteroid resulted in an approximate 30% (RR, 0.70; 95% CI, 0.62-0.78) reduction in exacerbations. Pulmonary rehabilitation improved the health status of patients with moderate to severe disease, but no material effect was observed on long-term survival or hospitalization rates. Domiciliary oxygen therapy improved survival by approximately 40% in patients with PaO2 lower than 60 mm Hg, but not in those without hypoxia at rest. The data on disease management programs were heterogeneous, but overall no effect was observed on survival or risk of hospitalization. Noninvasive mechanical ventilation was not associated with improved outcomes., Conclusions: A significant body of evidence supports the use of long-acting bronchodilators and inhaled corticosteroids in reducing exacerbations in patients with moderate to severe COPD. Domiciliary oxygen therapy is the only intervention that has been demonstrated to prolong survival, but only in patients with resting hypoxia.

The presentation of chronic obstructive pulmonary disease (COPD) usually is insidious, and many patients are undiagnosed until the disease is far advanced. Therefore, the early use of spirometry is recommended for anyone who is suspected to have COPD. In the early stages of the disease, the patient is only mildly symptomatic (cough and sputum production). As COPD becomes more advanced, functional impairment in the form of chronic dyspnea occurs and acute exacerbations of symptoms become more frequent, contributing to overall morbidity and mortality. The single most important known causative factor of COPD is cigarette smoking. Smoking cessation remains, therefore, the mainstay of COPD therapy. In patients with advanced disease, symptomatic treatment with the regular use of either short- or long-acting sympathomimetic and/or anticholinergic bronchodilators, singly or in combination, should be added to smoking cessation and influenza and pneumococcal vaccination therapies. An inhaled corticosteroid, either alone or more commonly in combination with a long-acting bronchodilator, can further reduce exacerbations and improve the health status of these patients. Furthermore, patients with severe COPD, particularly those who are debilitated, should be considered for pulmonary rehabilitation because these programs have been proven useful in maintaining, or in some cases improving, health status for these patients. Finally, correction of resting arterial hypoxemia with oxygen therapy for more than 15 h/d prolongs survival of COPD patients for those with a resting PaO2 lower than 55 to 60 mm Hg.

Background: Impaired lung function is a risk factor for cardiovascular morbidity. Whether circulating factors are responsible for this association is unknown. A study was undertaken to determine whether leptin, a hormone that can promote atherothrombosis, is raised in individuals with impaired lung function., Methods: Data from non-obese participants in the Third National Health, Nutrition, and Examination Survey (n=2808) were analysed to determine the relationship between circulating leptin levels and forced expiratory volume in 1 second (FEV(1)) values divided into quintiles (quintile 1, FEV(1) predicted < or =85.2%; quintile 2, 85.3-94.3%; quintile 3, 94.4-101.4%; quintile 4, 101.5-110.0%; and quintile 5, > or =110.1%)., Results: Serum leptin levels changed along the FEV(1) gradient. The highest leptin levels were found in quintile 1 (geometric mean (GM) 5.42; interquartile range (IQR) 3.00-9.60 fg/l) and the lowest in quintile 5 (GM 4.94; IQR 2.80-9.10 fg/l). Adjustments for age, body mass index, and other confounders strengthened this relationship. Compared with quintile 5, the odds of having an increased serum leptin level in quintiles 1, 2, 3, and 4 were 2.26 (95% confidence interval (CI) 1.54 to 3.31), 2.20 (95% CI 1.52 to 3.17), 1.46 (95% CI 1.01 to 2.09), and 1.28 (95% CI 0.90 to 1.83), respectively., Conclusion: Individuals with impaired lung function have raised serum leptin levels. Leptin may play a role in the pathogenesis of cardiovascular morbidity and mortality related to impaired lung function.

Study Objective: Children from poor families are much more likely to have emergency visits for asthma than those from nonpoor families, which may be related to financial access barriers to good preventive care for the poor. We sought to determine whether in a health-care system that provides free access to outpatient and hospital services, the disparities in the rates of emergency visits for asthma would be less apparent across the income gradient., Design: Longitudinal, population-based study., Setting: Alberta, Canada., Participants: All children born in Alberta, Canada between 1985 and 1988 (n = 90,845) were classified into three mutually exclusive groups based on the reported annual income of their parents from the previous year: very poor, poor, and nonpoor groups., Measurements and Results: We compared the relative risk (RR) of emergency visits for childhood asthma among children of very poor, poor, and nonpoor families using a Cox proportional hazard model during a 10-year follow-up. We found that the very poor children were 23% more likely to have had an emergency visit for asthma than those from nonpoor families (RR, 1.23; 95% confidence interval [CI], 1.14 to 1.33), adjusted for a variety of factors. The poor group, however, had a similar risk of asthma emergency visits as the nonpoor group (RR, 0.97; 95% CI, 0.91 to 1.04). The average number of office visits for asthma was similar between the very poor and nonpoor groups., Conclusions: In a setting of universal access to health care, children of poor and nonpoor families had similar rates of asthma emergency visits; the very poor children, however, continued to experience an excess risk. These findings suggest that a universal health-care system can reduce, but not fully eliminate, the disparities in emergency utilization of asthma across income categories.

The purpose of this study was to characterize the role of adenosine-dependent regulation of anion secretion in Calu-3 cells. RT-PCR studies showed that Calu-3 cells expressed mRNA for A2A and A2B but not A1 or A3 receptors, and for hENT1, hENT2 and hCNT3 but not hCNT1 or hCNT2 nucleoside transporters. Short-circuit current measurements indicated that A2B receptors were present in both apical and basolateral membranes, whereas A2A receptors were detected only in basolateral membranes. Uptake studies demonstrated that the majority of adenosine transport was mediated by hENT1, which was localized to both apical and basolateral membranes, with a smaller hENT2-mediated component in basolateral membranes. Whole-cell current measurements showed that application of extracellular nitrobenzylmercaptopurine ribonucleoside (NBMPR), a selective inhibitor of hENT1-mediated transport, had similar effects on whole-cell currents as the application of exogenous adenosine. Inhibitors of adenosine kinase and 5'-nucleotidase increased and decreased, respectively, whole-cell currents, whereas inhibition of adenosine deaminase had no effect. Single-channel studies showed that NBMPR and adenosine kinase inhibitors activated CFTR Cl- channels. These results suggested that the equilibrative nucleoside transporters (hENT1, hENT2) together with adenosine kinase and 5'-nucleotidase play a crucial role in the regulation of CFTR through an adenosine-dependent pathway in human airway epithelia.

Background: Chronic obstructive pulmonary disease (COPD) increases the risk of cardiovascular disease 2- to 3-fold. The factors responsible for this association remain largely unknown., Methods and Results: We analyzed data from participants, > or =50 years of age, of the Third National Health and Nutrition Examination Survey (n=6629) to determine whether C-reactive protein (CRP) and other systemic inflammatory markers are present in participants with chronic airflow obstruction and are associated with cardiac injury. Participants with severe airflow obstruction had circulating leukocyte, platelet, and fibrinogen levels that were 460/ microL (95% confidence interval [CI], 30 to 890/ microL), 39 510/ microL (95% CI, 21 730 to 57 290/ microL), and 41.63 mg/dL (95% CI, 19.87 to 63.39 mg/dL) higher, respectively, than in those without airflow obstruction. They were also 2.18 times (95% CI, 1.46 to 3.27) more likely to have an elevated circulating CRP level. Moderate airflow obstruction was associated with smaller but still significant increases in these levels. Moderate and severe airflow obstruction was associated with increased occurrence of ischemic changes on electrocardiograms of participants. In the presence of both highly elevated CRP and moderate or severe airflow obstruction, the Cardiac Infarction Injury Score was 2.68 and 5.88 U higher, respectively, than in those without airflow obstruction and with low CRP, which suggests an additive effect of CRP and COPD on the risk of cardiac injury., Conclusion: Low-grade systemic inflammation was present in participants with moderate to severe airflow obstruction and was associated with increased risk of cardiac injury. This may in part explain the high rates of cardiovascular complications in COPD.

Eosinophil respiratory burst is an important event in asthma and related inflammatory disorders. However, little is known concerning activation of the respiratory burst NADPH oxidase in human eosinophils. Conversely, neutrophils are known to assemble NADPH oxidase in intracellular and plasma membranes. We hypothesized that eosinophils and neutrophils translocate NADPH oxidase to distinct intracellular locations, consistent with their respective functions in O(2)(-)-mediated cytotoxicity. PMA-induced O(2)(-) release assayed by cytochrome c was 3.4-fold higher in atopic human eosinophils than in neutrophils, although membrane-permeable dihydrorhodamine-123 showed similar amounts of release. Eosinophil O(2)(-) release was dependent on Rac, in that it was 54% inhibited by Clostridium difficile toxin B (400-800 ng/ml). In eosinophils stimulated with PMA, a pronounced shift of cytosolic Rac to p22(phox)-positive plasma membrane was observed by confocal microscopy, whereas neutrophils directed Rac2 mainly to intracellular sites coexpressing p22(phox). Similarly, ex vivo sputum eosinophils from asthmatic subjects exhibited predominantly plasma membrane-associated immunoreactivity for Rac, whereas sputum neutrophils exhibited cytoplasmic Rac2 staining. Thus, activated sputum eosinophils, rather than neutrophils, may contribute significantly to the pathogenesis of asthma by extracellular release of tissue-damaging O(2)(-). Our findings suggest that the differential modes of NADPH oxidase assembly in these cells may have important implications for oxidant-mediated tissue injury.

Recent data suggest that inhaled corticosteroids reduce the number of clinical exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown whether a dose/response relationship exists. The present study was conducted to evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD mortality. Hospital discharge data were used to identify all patients aged > or = 65 yrs recently hospitalised due to COPD in Alberta, Canada (n = 6,740). The relative risk (RR) for all-cause mortality was compared across different dose categories of inhaled corticosteroids (none and low, medium and high doses) following hospital discharge. Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in risk for all-cause mortality (RR 0.75, 95% confidence interval (CI) 0.68-0.82). Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses (RR 0.77, 95% CI 0.69-0.86 for low dose; RR 0.48, 95% CI 0.37-0.63 for medium dose; and RR 0.55, 95% CI 0.44-0.69 for high dose). Use of inhaled corticosteroids following hospital discharge for chronic obstructive pulmonary disease was associated with a significant reduction in the overall mortality rate. Low- was inferior to medium- or high-dose therapy in protecting against mortality in chronic obstructive pulmonary disease.

Purpose: Because patients with obstructive airways disease may be susceptible to osteoporosis, we sought to determine the association between airflow obstruction and osteoporosis., Subjects and Methods: We analyzed data from Caucasian participants (n = 9502) in the Third National Health and Nutrition Examination Survey, conducted in the United States between 1988 and 1994. We used data from dual-energy x-ray absorptiometry measurements of the total femur to determine whether a study participant had osteoporosis (defined as total bone mineral density values < or =2.5 SD below the corresponding mean values from young, healthy participants). We calculated the odds ratio (OR) for osteoporosis in four lung function categories: none, mild, moderate, and severe airflow obstruction., Results: Overall, airflow obstruction was associated with increased odds of osteoporosis compared with without airflow obstruction (OR = 1.9; 95% confidence interval [CI]: 1.4 to 2.5). Participants with severe airflow obstruction were at especially increased risk (OR = 2.4; 95% CI: 1.3 to 4.4). Moderate but not mild airflow obstruction was also associated with osteoporosis., Conclusion: Airflow obstruction was an important risk factor for osteoporosis in the study population. These data highlight the importance of measuring bone mineral density in those with moderate-to-severe airflow obstruction for the detection and prevention of osteoporosis-related morbidity.

Chronic obstructive pulmonary disease (COPD) is a major problem in the elderly population, with approximately 10% of the population affected. Since COPD is an inflammatory disorder of the pulmonary system, corticosteroids might be expected to improve clinical outcomes of the disease. Data from large, well designed randomised clinical trials in which approximately one third of patients were > or =65 years of age indicate that inhaled corticosteroids do not modify the natural history of COPD, as measured by the rate of decline in forced expiratory volume in 1 second (FEV1). However, these same studies also suggest that corticosteroids reduce the frequency of clinical exacerbations by nearly a third (compared with placebo). This beneficial effect is particularly pronounced among those with an FEV1 less than 50% of the predicted value. Withdrawal of inhaled corticosteroids, on the other hand, leads to increased symptoms and elevates the risk of exacerbations by 50% above baseline levels. Patients' health-related quality of life is also improved by the use of inhaled corticosteroids. It is clear that inhaled corticosteroids elevate the risk of thrush, dysphonia and skin bruising by 2-fold compared with placebo. In addition, the sum of evidence suggests a modest deleterious effect for inhaled corticosteroids on bone mineral density, especially for formulations that have an increased rate of systemic absorption. However, the clinical evidence of this observation is uncertain. The effect of inhaled corticosteroids on fracture risk is controversial with some observational studies suggesting a possible association. Whether inhaled corticosteroids increase the risk of ophthalmic complications (cataracts and glaucoma) is also uncertain. In conclusion, the current evidence indicates that inhaled corticosteroid therapy produces short- and long-term clinical benefits in COPD patients with moderate-to-severe disease and should be used as adjunctive therapy for elderly patients with COPD who experience frequent exacerbations or have moderately reduced lung function.

Background: Patients who visit the emergency department (ED) because of asthma frequently have a relapse. While the use of inhaled corticosteroids has been demonstrated to improve asthma symptoms and lung function, it is not clear whether their use after discharge from the ED reduces asthma relapse rates., Objective: To determine whether inhaled corticosteroid therapy reduces ED asthma relapse rates., Methods: We analyzed ED visit and medication data on patients 5 to 60 years of age who were enrolled in a government-sponsored drug plan and who visited an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta, Canada (N = 1293). Using a Cox proportional hazards model, we determined the relative risk (RR) of relapse ED visits among users and nonusers of inhaled corticosteroids after discharge from the ED. We also compared the RR of relapse ED visits across different dose categories., Results: Users of inhaled corticosteroids after ED discharge had 45% fewer relapse ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI], 0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95% CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose therapy (RR, 0.67; 95% CI, 0.47-0.94)., Conclusions: Inhaled corticosteroid therapy after ED discharge is associated with a significant reduction in the risk of subsequent ED visits. Low-dose therapy appears to be as effective as high-dose therapy. However, further studies are needed to determine the optimal dosing regimen for inhaled corticosteroid therapy for asthma.

Background: Previous research suggests that obesity is an important risk factor for asthma. However, since obesity can cause dyspnea through mechanisms other than airflow obstruction, diagnostic misclassification of asthma could partially account for this association., Objective: To determine whether there is a relationship between obesity and airflow obstruction., Methods: A total of 16 171 participants (17 years or older) from the Third National Health and Nutrition Examination Survey (NHANES III) were divided into 5 quintiles based on their body mass index (BMI) to determine the association between BMI quintile and risk of self-reported asthma, bronchodilator use, exercise performance, and airflow obstruction. Significant airflow obstruction was defined as a ratio less than 80% the predicted value of forced expiratory volume in 1 second to forced vital capacity adjusted for age, sex, and race., Results: The highest BMI quintile (ie, the most obese participants) had the greatest risk of self-reported asthma (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.24-1.81), bronchodilator use (OR, 1.94; 95% CI, 1.38-2.72), and dyspnea with exertion (OR, 2.66; 95% CI, 2.35-3.00). Paradoxically, the highest BMI quintile had the lowest risk for significant airflow obstruction (P =.001)., Conclusions: This study demonstrates that while obesity is a risk factor for self-reported asthma, obese participants are at a lower risk for (objective) airflow obstruction. Many more obese than nonobese participants were using bronchodilators despite a lack of objective evidence for airflow obstruction. These data suggest that mechanisms other than airflow obstruction are responsible for dyspnea genesis in obesity and that asthma might be overdiagnosed in the obese population.

Background: Aboriginals in Canada bear a disproportionately higher burden of some chronic illnesses than nonaboriginals. Although there is a greater prevalence of smoking, poor housing, and overcrowding in aboriginal than nonaboriginal communities, the rates of office and emergency visits for asthma and COPD among aboriginals are not well known., Study Objective: To determine whether aboriginals require higher rates of asthma and COPD emergency and office visits than nonaboriginals., Setting: Population-based cohort of people residing in Alberta, Canada (population 2.8 million) between April 1, 1996, and March 31, 1997., Design: Retrospective cohort study., Results: We observed that aboriginals were 2.1 times (95% confidence interval [CI], 2.0 to 2.2) and 1.6 times (95% CI, 1.6 to 1.6) more likely to have an emergency and office visit for asthma or COPD, respectively, when compared to age-matched and sex-matched nonaboriginals. However, they were 55% (95% CI, 52 to 58%) less likely to see a specialist and 66% (95% CI, 63 to 70%) less likely to undergo spirometry than nonaboriginals., Conclusions: These findings indicate that aboriginals bear a disproportionately higher burden of asthma and COPD than nonaboriginals. However, lower use of spirometry and specialist services suggests that there might be access barriers to quality health care for aboriginals in Canada.

Purpose: To examine the relation between follow-up office visits after emergency discharge and the risk of emergency readmissions in patients with asthma or chronic obstructive pulmonary disease (COPD)., Subjects and Methods: We used population-based data to identify all patients in Alberta, Canada, who had at least one emergency visit for asthma or COPD between April 1, 1996, and March 31, 1997 (N = 25 256). A Cox proportional hazards model was used to estimate the adjusted relative risk (RR) of a repeat visit to an emergency department within 90 days of an initial emergency visit in patients who did or did not have an office follow-up within the first 30 days., Results: There were 7829 patients (31%) who had an office visit during the 30 days after their initial emergency encounter. Follow-up visits were associated with a significant reduction in the 90-day risk of an emergency readmission (RR = 0.79; 95% confidence interval [CI]: 0.73 to 0.86). Sensitivity analyses showed that a follow-up visit was inversely associated with a repeat emergency visit after adjusting for age, sex, area of residence, and income., Conclusion: Although these data should be interpreted with caution because of missing information on factors such as quality of care, they suggest that follow-up office visits are effective in reducing early relapses in patients who have been recently treated in emergency departments for asthma or COPD.

The regulatory actions of adenosine on ion channel function are mediated by four distinct membrane receptors. The concentration of adenosine in the vicinity of these receptors is controlled, in part, by inwardly directed nucleoside transport. The purpose of this study was to characterize the effects of adenosine on ion channels in A549 cells and the role of nucleoside transporters in this regulation. Ion replacement and pharmacological studies showed that adenosine and an inhibitor of human equilibrative nucleoside transporter (hENT)-1, nitrobenzylthioinosine, activated K(+) channels, most likely Ca(2+)-dependent intermediate-conductance K(+) (I(K)) channels. A(1) but not A(2) receptor antagonists blocked the effects of adenosine. RT-PCR studies showed that A549 cells expressed mRNA for I(K)-1 channels as well as A(1), A(2A), and A(2B) but not A(3) receptors. Similarly, mRNA for equilibrative (hENT1 and hENT2) but not concentrative (hCNT1, hCNT2, and hCNT3) nucleoside transporters was detected, a result confirmed in functional uptake studies. These studies showed that adenosine controls the function of K(+) channels in A549 cells and that hENTs play a crucial role in this process.

Area-based markers of deprivation (e.g., postal codes) are commonly used to identify groups of people with low socioeconomic status (SES); the validity of this approach, however, remains unknown. In this study, we determined the accuracy of using income quintile groups calculated on the basis of the median family income of each forward sortation area (1996 Canadian census) to identify those living in poverty (i.e., annual family income of < $12,620). The sensitivity and specificity of using the lowest income quintile to capture those in poverty were 26% and 83%, respectively (likelihood ratio (LR) of 1.49; 99% CI, 1.49 to 1.50). Among those in non-metropolitan and metropolitan areas, the LRs were 1.26 (99% CI, 1.26 to 1.27) and 2.01 (99% CI, 2.01 to 2.02), respectively. The use of postal codes as the only marker to identify people with low SES may result in substantial misclassification of personal poverty, particularly in non-metropolitan areas.