[Ipratropium bromide in COPD. Cost effectiveness of the treatment of COPD with ipratropium bromide].
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Bronchodilator Agents↗
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Elevated oxidative stress and reciprocal reduction of vascular endothelial growth factor levels with severity of COPD.
STUDY OBJECTIVES: The prevalent theory concerning the pathogenesis of COPD is that it is an imbalance between oxidants and antioxidants. However, it has been reported that a decrease in vascular endothelial growth factor (VEGF) might affect the pathogenesis of COPD. Therefore, this study was designed to examine the differences between oxidative stress and VEGF levels, and the severity of COPD. DESIGN: Controlled cross-sectional analysis. SETTING: University hospital. PARTICIPANTS: Twelve healthy control subjects and 57 COPD patients were included in this study. These COPD patients were divided into four groups based on the Global Initiative for Chronic Obstructive Lung Disease classification (mild COPD, 14 patients; moderate COPD, 15 patients; severe COPD, 16 patients; very severe COPD, 12 patients). MEASUREMENTS AND RESULTS: Inflammatory markers, degree of oxidative stress, and VEGF levels were examined in sputum samples from all subjects. Nitrogen oxide levels in induced sputum were significantly higher in COPD patients than in healthy control subjects, and they increased with increases in the severity of COPD. In contrast, peroxynitrite inhibitory activity decreased with increases in the severity of COPD. Therefore, the mean (SD) peroxynitrite stress (ie, the nitrogen oxide level/peroxynitrite inhibitory activity ratio) steeply increased with increases in the severity of COPD (mild COPD: 8.4; SD, 1.5; p = 0.02; moderate COPD: 10.8; SD, 1.4; p < 0.0001; severe COPD: 14.5; SD, 2.5; p < 0.0001; very severe COPD: 18.3; SD, 4.1; p < 0.0001) compared with that of healthy control subjects. VEGF levels in induced sputum reciprocally decreased with severity of COPD (mild COPD: 1,360 pg/mL; SD, 800 pg/mL; p = 0.97; moderate COPD: 1,180 pg/mL; SD, 760 pg/mL; p = 0.50; severe COPD: 650 pg/mL; SD, 450 pg/mL; p = 0.007; very severe COPD: 480 pg/mL, SD, 240 pg/mL; p = 0.002). In addition, peroxynitrite inhibitory activity in COPD patients exhibited an accelerated decline from the mean VEGF level in healthy control subjects. CONCLUSIONS: Elevated oxidative stress levels and a reciprocal reduction of VEGF levels in induced sputum were prominent with increases in the severity of COPD. Thus, epithelial cell injury mediated by oxidative stress may induce the decrease in lung VEGF levels, resulting in the promotion of the development of COPD.
Cell Count↗
Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD.
Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5 micrograms is equivalent to 18 micrograms of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV(1)) were observed with inhaled tiotropium 18 micrograms once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV(1) response) more effectively than ipratropium bromide (ipratropium) 40 micrograms four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50 micrograms 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients' perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18 micrograms once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5 micrograms dose of tiotropium bromide provides 18 micrograms of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M(1), M(2), and M(3) receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M(1) and M(3) receptors over the M(2) receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent ( approximate, equals 20-fold) than ipratropium bromide in displacing [(3)H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine ( approximate, equals 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5-36 micrograms once daily for 4 weeks increased mean trough and average FEV(1) and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV(1) from baseline with tiotropium 4.5-36 micrograms were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18 micrograms. Steady-state trough FEV(1) values are achieved within 48 hours of commencing tiotrochodilation (for >/=24 hours) and an attenuation of the nocturnal decline in FEV(1) that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (C(max)) were observed within 5 minutes of inhalation of a single dose of tiotropium 18 micrograms in patients with COPD. Plasma drug levels declined to minimum concentrations (C(min)) within 1 hour of treatment in healthy volunteers. Mean steady-state C(max) concentrations (16 ng/L) were achieved after 2-3 weeks of once-daily inhaled tiotropium 18 micrograms in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved.The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20-25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae(24)) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5-6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state C(max), C(min), area under the concentration-time curve, and Ae(24) values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV(1) response (the mean change in FEV(1) from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18 micrograms once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV(1) responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40 micrograms four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV(1), mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50 micrograms twice daily, greater improvements from baseline in mean trough, peak, and average FEV(1) and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV(1) response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV(1) and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of >/=1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. (ABSTRACT TRUNCATED)
Bronchodilator Agents↗
Microsatellite DNA instability in COPD.
STUDY OBJECTIVES: Cigarette smoking is the prime cause of COPD; however, only a few smokers develop the disease. In a previous study, we demonstrated that microsatellite DNA instability (MSI) is a detectable phenomenon in sputum cells of COPD patients. Therefore, we hypothesize that this genetic alteration may indicate susceptibility to COPD. DESIGN: In order to investigate this hypothesis, we compared smokers who developed COPD with smokers who did not develop COPD (referred to as non-COPD smokers). SETTING: Seven highly polymorphic microsatellite markers were targeted on the DNA of sputum cells and of WBCs. PATIENTS AND PARTICIPANTS: We studied 60 non-COPD smokers and 59 severe COPD patients with a similar smoking history (mean +/- SD) of 48+/-25 and 54+/-33 pack-years, respectively (p = 0.77). Non-COPD smokers were tested once; COPD smokers were tested twice, with an interval of 24 months between tests. RESULTS: MSI was detected in 14 COPD patients (24%) but in none of the non-COPD smokers. In 10 COPD patients, MSI was exhibited by one microsatellite marker; in the remaining 4 COPD patients, MSI was exhibited by two different alleles. The most commonly affected marker was THRA1 on chromosome 17 (43%). No significant differences were found between MSI-positive and MSI-negative COPD patients for clinical or laboratory parameters, survival, and development of lung cancer. No change in the microsatellite alleles was found between the tests performed with a 24-month interval. CONCLUSIONS: This study demonstrated that MSI was found exclusively in the sputum cells of smokers with COPD. The results support the hypothesis that MSI could be part of the complex genetic basis of COPD, and it could be a marker of the genetic alteration caused by smoking that allows COPD to develop.
Case-Control Studies↗
An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD.
In chronic obstructive pulmonary disease (COPD) which consists of emphysema and chronic bronchitis, alveolar tissue and/or bronchiolar walls are progressively destroyed. This suggests cell death by necrosis and/or apoptosis although no direct evidence of apoptosis has been reported. It was speculated that the apoptosis-related factors are associated with the progression of COPD. Fas/Apo-1 receptor (Fas), Fas ligand (Fas-L) and soluble Fas ligand (sFas-L) are inducers, while soluble Fas (sFas) is an inhibitor of apoptosis. In this study, plasma sFas and sFas-L were measured in 19 COPD patients receiving supplemental O2 (severe COPD) and 20 COPD patients not receiving supplemental O2 (mild/moderate COPD). Twenty-two age- and sex-matched healthy volunteers (healthy controls) and 20 patients receiving supplemental O2 and with level of hypoxaemia similar to severe COPD due to other pulmonary diseases (disease controls) were also examined. Plasma sFas-L was within normal limits in all groups. Plasma sFas levels were similar among healthy controls, disease controls, and mild/moderate COPD patients, but significantly increased in severe COPD (2.6 +/- 1.1, 2.6 +/- 0.2, 2.8 +/- 0.2 and 4.8 +/- 1.0 ng ml-1, respectively). Although PaO2 was lower in severe COPD than in mild/moderate COPD, and PaCO2 was higher in severe COPD than in mild/moderate COPD, they were close between severe COPD and disease controls. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in patients with COPD, but were similar in both severe and mild/moderate COPD patients. We conclude that increased plasma sFas, which is independent of hypoxaemia, and increases in PaCO2, TNF-alpha, IL-6 and inflammation, may be associated with progression of COPD.
Aged↗
Pharmacoeconomic evaluation of COPD.
STUDY OBJECTIVES: The clinical outcomes and health-care costs of a cohort of 413 patients with COPD are reported. DESIGN: This study was a retrospective pharmacoeconomic analysis. SETTING: University teaching hospital and affiliated clinics. PATIENTS: COPD patients with an FEV(1) < 65% of predicted and an FEV(1)/FVC ratio < 70% were eligible to be included in this analysis. INTERVENTIONS: Health-care resource utilization and costs were identified through chart review and were stratified according to the severity of COPD using the American Thoracic Society stages I, II, and III. The pharmacoeconomic analysis was a cost-of-illness evaluation that included the acquisition costs of initially prescribed pulmonary drugs, acquisition cost of pulmonary drugs added during the follow-up period, oxygen therapy, laboratory and diagnostic test costs, clinic visit costs, and emergency department and hospital costs. RESULTS: Total treatment cost was highly correlated with disease severity, with stage I COPD having the lowest cost ($1,681 per patient per year), stage III COPD having the highest cost ($10, 812 per patient per year), and stage II COPD having a cost intermediate to stage I and stage III ($5,037 per patient per year). With the exception of add-on drug acquisition cost, all cost variables were the highest in stage III COPD, the lowest in stage I COPD, and intermediate in stage II COPD. Hospitalization was the most important cost variable for all three stages of COPD severity. When stratified by both disease severity and initial bronchodilator drug selection, ipratropium alone in stage I COPD patients and the combination of ipratropium plus a ss-agonist (with or without steroid therapy) in stage II and stage III COPD patients had the lowest total costs. Reasons for the lower total cost of the ipratropium and ipratropium plus ss-agonist treatment groups included lower add-on drug costs, fewer diagnostic and laboratory tests, and a lower utilization rate for clinic visits, emergency department visits, and hospitalizations. CONCLUSIONS: Our study demonstrates a strong correlation between disease severity and total treatment cost in COPD. In addition, the type of bronchodilator therapy impacts total cost in COPD. In stage I COPD, ipratropium alone had the lowest total cost, while in stage II and stage III COPD, a combination of ipratropium plus a ss-agonist had the lowest total cost. These data support the concept that adherence to published treatment guidelines will result in lower health-care costs due to COPD.
Adult↗
[Epidemiologic analysis of COPD in Guangdong province].
OBJECTIVE: To survey the prevalence of chronic obstructive pulmonary disease (COPD) in urban and rural areas in Guangdong Province and relevant risk factors. METHODS: Using the same protocol including Burden of Obstructive Lung Disease (BOLD) questionnaire, a questionnaire survey was conducted among 3449 respondents, 1370 males and 1916 females, aged over 40 with an average age of 56.8, by random disproportional cluster sampling in Liwang District of Guangzhou City and Yunyan Town, Lechang City, northern Guangdong Province. Spirometry was performed in all subjects. Lung function indices were regarded as gold criteria of diagnosis of COPD. RESULTS: There were 3286 cases with full data and good quality spirometry test, 1370 males and 1916 females, aged 56.8. The total prevalence of COPD was 9.4%. The prevalence of COPD in the males was 15.9%, significantly higher than that in the females (4.8%, P < 0.01). The prevalence in the rural area was 12.0%, significantly higher than that in the urban area (7.4%, chi(2) = 20.3, P < 0.01). 67.7% of the patients with COPD presented symptoms such as cough, expectoration and/or dyspnoea. 58.7% of the COPD patients (78.9% of the male patients and 10.9% of the female patients) smoked. The odd ratio (OR) for COPD in the smokers was 2.59 (95% CI 1.87 - 3.59). Only 15.1% of the smokers (17.9% of the male smokers and 4.1% of the female smokers) developed COPD. No significant relationship was found between pack years of cigarette smoking and COPD prevalence. The risk of COPD was increased when biomass fuels were used in house cooking (OR = 1.54 95% CI 1.08 - 2.20). Furthermore, the combination of biomass fuels and cigarette smoking further increased the risk with the OR of 4.41 (95% CI 3.22 - 6.04), indicating a synergetic impact of smoking and biomass burning on the prevalence of COPD. The Prevalence of doctor-diagnosed COPD based on the clinical manifestation was significant lower than the actual prevalence (only 31.0%). CONCLUSIONS: COPD is a very common disease in Guangdong. The prevalence of COPD is higher in the rural area than in the urban area, which may be attributed to the synergic effect of smoking and biomass burning. Lung function test is of great importance in COPD diagnosis, especially in the earlier stage of COPD and those asymptomatic COPD patients.
Adult↗
Economic analysis of the Confronting COPD survey: an overview of results.
An economic analysis of data from a large-scale international survey, Confronting COPD in North America and Europe, was conducted in seven countries (Canada, France, Italy, The Netherlands, Spain, the U.K and the U.SA.), to investigate the burden of chronic obstructive pulmonary disease (COPD). The results demonstrated the high economic impact of COPD on the healthcare system and society in each country. The mean annual direct costs of the disease were particularly high in the U.S.A. (US dollar 4119 per patient) and Spain (US dollar 3196 per patient) but relatively low in The Netherlands (US dollar 606) and France (US dollar 522). Lost productivity due to COPD had a particularly high impact on the economy in France, The Netherlands and the U.K, accounting for 67%, 50% and 41% of overall costs, respectively. The total societal cost of COPD per patient ranged from over US dollar 5646 in the U.S.A. to US dollar 1023 in The Netherlands. In five out of seven countries, the majority (52-84%) of direct costs associated with COPD were due to inpatient hospitalizations. As acute exacerbations of COPD are a key driver of secondary care costs, interventions aimed at preventing and treating exacerbations effectively could significantly reduce the economic impact of this disease. In all of the participating counties, COPD was underdiagnosed and undertreated. Between 9% and 30% of patients were undiagnosed despite having symptoms consistent with COPD, and up to 65% of patients did not receive regular prescribed medication. Patients reported poor symptom control and considerable use of healthcare resources. Therefore, reducing the burden of COPD will involve better evaluation and diagnosis of patients with COPD, as well as improved management of chronic COPD symptoms by healthcare professionals. The survey also demonstrated that the societal costs of COPD were 4-17 times higher in patients with severe COPD than in patients with mild COPD. Patients with comorbid conditions (accounting for 30-57% of patients in each country) were also particularly costly to society. These results suggest that a high priority should be given to interventions aimed at delaying the progression of disease, preventing exacerbations and reducing the risk of comorbidities, in order to alleviate the clinical and economic burden of COPD in North America and Europe.
Absenteeism↗
DNA methylation as a driver of lung fibroblast senescence in COPD.
Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of CDKN1A, CDKN2A, and CDKN2B was higher, while LMNB1 expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes CDKN1A (9), CDKN2A (1), and LMNB1 (9). Among these, seven CpG sites (4 for CDKN1A and 3 for LMNB1) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes CDKN1A and LMNB1.NEW & NOTEWORTHY This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators CDKN1A and LMNB1. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.
Humans↗
Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease.
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic condition characterised by progressive airflow limitation that is at most partially reversible. Despite the lack of reversibility patients often report symptomatic improvement with short-acting beta 2 bronchodilator medications. They are used on either an "as required" or a "regular plus as required basis" and they may be used in conjunction with other bronchodilator medicines such as ipratropium and methylxanthines. These medicines are used in the management of both stable and acute exacerbations of COPD. This review examined the effect of short-acting beta 2 bronchodilators given by inhalation in stable COPD. OBJECTIVES: To determine the clinical effect and assess the adverse effects of inhaled short-acting beta 2 agonist bronchodilators compared with placebo in stable COPD. SEARCH STRATEGY: Only randomised controlled trials (RCTs) were considered. RCTs were identified using the Cochrane Airways Group database (CENTRAL). In addition, the reference lists of review articles and RCTs retrieved in full were searched for other potentially relevant citations. SELECTION CRITERIA: Only trials with adult patients with stable COPD, as defined by internationally accepted guidelines (ATS, ERS or BTS) were included in this review. All trials had a minimum duration of 7 days of regular treatment with short-acting beta 2 bronchodilators given by inhalation and compared with placebo. Data from trials where beta 2 agonists were used alone or in combination with other medicines (e.g. ipratropium bromide) were used only if there was a direct comparison between beta 2 bronchodilator alone and placebo. DATA COLLECTION AND ANALYSIS: Outcomes were analysed as continuous or dichotomous outcomes, using standard statistical techniques. For continuous outcomes, the weighted mean difference (WMD) and 95% confidence intervals were calculated and for dichotomous outcomes, the odds ratio was calculated with 95% confidence intervals by Peto's methods. Funnel plots were used to test for publication bias. MAIN RESULTS: Thirteen studies were included in this review. Most had small sample sizes and some of the sutides used very short-acting outdated compounds. All the studies used a cross-over design and were of high quality. Spirometry done at the end of study period was measured after administration of treatment (post-bronchodilator) which showed both FEV1 (0.150 L/min, 95%CI: 0. 02-0.28) and FVC (0.310 L, 95%CI: 0.00-0.62) to improve significanly but slightly when compared to placebo. A few studies measured FRC, airway resistance or conductance at the end of the study period. In all cases these measurements were done several hours after treatment, and no significant differences (p>0.05 in all cases) were found between the bronchodilator and placebo groups. Walking test Large increases in 6MW distance was observed in two studies, however one study did not show any positive improvements. There was a large increase in the 12MW distance as shown by one study. Due to the small number of studies reporting this outcome no significant differences were found in the walking distance between the bronchodilator and placebo groups. Peak Flow Rate Both morning (36. 04 L/min; 95%CI: 0.80-71.27) and evening (36.68 L/min; 95%CI: 2. 47-70.89) PEFR were significantly higher during active treatment than during placebo. Symptoms Breatlessness was measured on various scales therefore data that were presented in a suitable form were combined using standardized means for inclusion in the analysis. A significant improvement (-0.33; 95%CI: -0.58 to -0.07 with p=0.01) in the breathlessness score was observed during treatment with beta-2 agonist when compared to placebo. Cough was reported to improve significantly (data not usable) during treatment with beta2 agonist in one study but not in two others. A non-significant decrease in sputum production was reported by Wilson 1980, however four other studies reported no
Administration, Inhalation↗
Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking Report from the Obstructive Lung Disease in Northern Sweden Studies.
BACKGROUND: There is a lack of epidemiological data on COPD by disease severity. We have estimated the prevalence and underdiagnosis of COPD by disease severity defined by the British Thoracic Society (BTS) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. The impact of smoking was evaluated by the population attributable fraction of smoking in COPD. METHODS: A random sample of 1500 responders of the third postal survey performed in 1996 of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies' first cohort (6610 subjects recruited in 1985) were invited to structured interview and spirometry. One thousand two hundred and thirty-seven subjects (82%) performed spirometry. RESULTS: The prevalence of mild BTS-COPD was 5.3%, moderate 2.2%, and severe 0.6% (GOLD-COPD: mild 8.2%, moderate 5.3%, severe 0.7%, and very severe 0.1%). All subjects with severe COPD were symptomatic, corresponding figures among mild COPD were 88% and 70% (BTS and GOLD), Subjects with severe BTS-COPD reported a physician-diagnosis consistent with COPD in 50% of cases, in mild BTS-COPD 19%, while in mild GOLD-COPD only 5% of cases. The major risk factors, age and smoking, had a synergistic effect on the COPD-prevalence. The Odds Ratio (OR) for having COPD among smokers aged 76-77 years was 59 and 34 (BTS and GOLD) when non-smokers aged 46-47 was used as reference population. CONCLUSIONS: Most subjects with COPD have a mild disease. The underdiagnosis is related to disease-severity. Though being symptomatic, only a half of the subjects with severe COPD are properly labelled. Smoking and increasing age were the major risk factors and acted synergistic.
Age Distribution↗
Impact of COPD on pulmonary complications and on long-term survival of patients undergoing surgery for NSCLC.
PURPOSE: The purpose of our study was to determine the incidence of various types of postoperative pulmonary complications and to evaluate the impact of chronic obstructive pulmonary disease (COPD) on the long-term survival of patients with non-small cell lung cancer (NSCLC) undergoing pulmonary resection. METHODS: We performed a retrospective chart review of 244 patients who had undergone lung resection for NSCLC at Indiana University. COPD, defined as predicted forced expiratory volume in 1 s (FEV1)< or =70% and FEV1/FVC< or =70%, was determined based on preoperative pulmonary function testing in 78 of 244 patients (COPD group). The remaining 166 patients were classified as non-COPD. The incidence of postoperative complications, which included air leak of > or=10 days, atelectasis, pneumothorax, pneumonia, bronchopleural fistula, empyema, acute respiratory distress syndrome, mechanical ventilation of > or =7 days, and outpatient oxygen supplementation were compared between the two groups. Long-term survival and mortality due to respiratory failure were analyzed between the two groups using the Kaplan-Meier method and log rank test. RESULTS: All of the above-stated postoperative pulmonary complications occurred more frequently in the COPD than in the non-COPD patients (all P<0.01). The overall 5-year survival rate was 36.2% in the COPD and 41.2% in the non-COPD patients (P=0.1023). Five-year cancer related survival was 43.2% in the COPD and 47.7% in the non-COPD patients (P=0.357). There was no significant difference in survival among patients with different stages of lung cancer. However, the intercurrent survival, which is associated with non-cancer related death, was 60.1% in patients with COPD and 86.2% in patients without COPD at 5 years (P<0.0001). The major cause of non-cancer related death in the COPD group was respiratory failure (P=0.0008). CONCLUSION: The presence of COPD is an acceptable predictor of postoperative pulmonary complications in patients with NSCLC. COPD is also a significant risk factor for development of respiratory-related complications, which may explain the poor long-term survival in these patients.
Aged↗
Glucocorticoid receptor mRNA levels in bronchial epithelial cells of patients with COPD: influence of glucocorticoids.
Glucocorticoids (gcs) are known to be effective in the treatment of asthma. In chronic obstructive pulmonary disease (COPD), however, no beneficial effects are demonstrated in most patients. Hypothetically, this may be explained by an overexpressed beta-glucocorticoid receptor (GR) compared to the alpha-GR. The aim of this study was to investigate alpha- and beta-GR mRNA levels and ratios in patients with COPD with or without glucocorticoid treatment. GR and, as a control, metallothionein (MT) 2 mRNA levels were compared between patients with COPD receiving glucocorticoids (COPD + gcs), glucocorticoid naive COPD-patients (COPD - gcs) and non-COPD control patients not using gcs. Bronchoscopy was performed and bronchial epithelial cells were sampled with brushing. Smoking did not influence alpha- and beta-GR levels and ratios, nor the MT2 mRNA expression level. The alpha-GR mRNA expression was lower in the COPD - gcs group than in controls. Both GR forms were higher in the COPD + gcs patients than in the COPD - gcs patients, but not different from the levels measured in the controls. alpha 1/beta-GR mRNA ratios did not differ between the groups and averaged 1.7, suggesting no inhibitory effect of the beta-GR on the alpha 1 form. MT2 levels were upregulated in the COPD + gcs patients as compared to the COPD - gcs group, indicating a pharmacological glucocorticoid effect. In the present study it is demonstrated that basal GR mRNA levels are lower in patients with COPD. Although this needs to be investigated further, this might explain, in part, the non-responsiveness of patients with COPD to gcs.
Adult↗
Reversibility to a beta2-agonist in COPD: relationship to atopy and neutrophil activation.
Chronic obstructive pulmonary disease (COPD) is characterised by limited bronchial reversibility and chronic neutrophilic inflammation. However, in some cases of COPD, eosinophilic inflammation is present. We investigated the relationship between reversibility to beta2-agonist with atopy and neutrophil activation in patients with stable COPD. For this purpose, 38 outpatients with COPD (mean age: 64 years) 12 with asthma (mean age: 51 years) and 13 healthy controls (mean age: 49 years) were tested using increasing doses of inhaled salbutamol (up to 3100 microg). According to their reversibility, COPD patients were divided into two groups: reversible COPD (deltaFEV1 > or = 12% pred, n = 16) and non-reversible COPD (deltaFEV1 < 12% pred, n = 22). Atopy, assessed by skin prick, was found at similar frequencies in both COPD groups. Total serum IgE was higher in COPD patients vs. controls, but did not differ significantly between the COPD groups. The blood eosinophil count was significantly higher in the reversible COPD group than in the non-reversible COPD, and correlated with deltaFEV % pred (Rs = 0.54, P < 0.05), as well as in asthmatics. The non-reversible COPD group had a higher level of spontaneous neutrophil activation (by reduction of nitroblue tetrazolium) versus controls. We conclude that airway reversibility in COPD patients is associated with the degree of blood eosinophilia, but not with the degree of blood neutrophil activation.
Adrenergic beta-Agonists↗
Inflammatory features of nasal mucosa in smokers with and without COPD.
BACKGROUND: To investigate whether nasal and bronchial inflammation coexists in chronic obstructive pulmonary disease (COPD), nasal and bronchial biopsy specimens from seven control subjects, seven smokers without COPD, and 14 smokers with COPD were studied. METHODS: Nasal and bronchial biopsy specimens were taken from the same patients during bronchoscopy and squamous cell metaplasia and the thickness of the epithelium and basement membrane were measured. The numbers of eosinophils (EG2), neutrophils (elastase), macrophages (CD68), and CD8 T lymphocytes (CD8/144B) were assessed by immunohistochemistry. RESULTS: Smokers with and without COPD had squamous metaplasia in the nasal and bronchial epithelium. In all groups the thickness of the nasal epithelium was greater than that of the bronchial epithelium. The thickness of the basement membrane was similar in nasal and bronchial biopsy specimens from smokers with and without COPD, but was greater in the bronchi than in the nasal epithelium of controls. Eosinophil number was higher in the nasal and bronchial mucosa of smokers without COPD than in smokers with COPD or controls. Neutrophil number was higher in the nasal and bronchial mucosa of smokers with COPD than in smokers without COPD or controls. CD8 T lymphocyte numbers were similar in smokers with and without COPD and higher than in controls. There were fewer macrophages in nasal and bronchial biopsy specimens from smokers without COPD than in those with COPD. CONCLUSION: Nasal and bronchial inflammation coexists in smokers and is characterised by infiltration of CD8 T lymphocytes. In smokers without COPD this feature is associated with an increased number of eosinophils, while in those with COPD it is linked to an increased number of neutrophils in both nasal and bronchial biopsy specimens.
Adult↗
Ventricular arrhythmias in patients with COPD are associated with QT dispersion.
STUDY OBJECTIVE: QT dispersion (QTd) and late potentials derived from signal-averaged ECG (SAECG) have been proposed as noninvasive predictors of cardiac arrhythmias that occur in patients with COPD. In this study, we aimed to investigate QTd and SAECG in patients with COPD. DESIGN: Cross-sectional study. SETTING: Teaching chest disease hospital and cardiology center in a university hospital. PATIENTS: Thirty patients with COPD (28 men and 2 women; mean +/- SD age, 60 +/- 9 years) and 31 age- and sex-matched control subjects (28 men and 3 women; mean age, 57 +/- 7 years) were included. MEASUREMENTS AND RESULTS: Respiratory function tests, arterial blood gas analyses, echocardiographic examinations, rhythm Holter recordings, and heart rate variability (HRV) analyses were performed in addition to the measurements of QT intervals and SAECG. Patients with COPD had higher rate of ventricular premature beats (VPBs) as compared to control subjects (924 +/- 493 beats vs 35 +/- 23 beats, p = 0.009). Eight patients with COPD (27%) had nonsustained runs of ventricular tachycardia (VT). QTd rates were significantly increased in patients with COPD as compared to control subjects (57.7 +/- 9.9 ms vs 37.5 +/- 8.2 ms, p < 0.001). On comparing patients with COPD with and without runs of VT, patients with VT had longer QTd (67 +/- 10 ms vs 55 +/- 8 ms, p = 0.001). However no difference in any HRV and late potential parameters were found between patients with COPD with and without runs of VT. VPB rates were strongly correlated with QTd in patients with COPD (r = 0.61, p < 0.001). On SAECG analysis, patients with COPD had significantly increased total QRS duration as compared to control subjects. Nine of the 30 patients with COPD (30%) had positive late potentials. However, QTd and VPB rates were also similar between patients with COPD with and without late potentials. CONCLUSIONS: The development of ventricular arrhythmia in patients with COPD was associated with increased QTd. Increased QTd may be associated with autonomic changes seen in patients with COPD.
Arrhythmias, Cardiac↗
One-year mortality in elderly stable patients with COPD.
A retrospective study was performed to evaluate the risks of one-year mortality in very old hospitalized patients including those suffering from chronic obstructive pulmonary disease (COPD). Six hundred and fifty-eight disabled patients (M = 194, mean age 79.2 +/- 7.4 years) consecutively admitted to and discharged from a Geriatric Evaluation and Rehabilitation Unit (GERU) after a comprehensive rehabilitation program were studied and divided into two groups: COPD (n = 337, 51%) and non-COPD (n = 321, 49%). Multidimensional evaluation including information on demographics, cognitive status [Mini Mental State Examination (MMSE)], physical health [number of diseases, Greenfield's Individual Disease Severity (IDS), and number of drugs used], functional disability [Basic Activity of Daily Living (BADL), Tinetti scale, and Physical Performance Test (PPT)], and nutritional status [Prognostic Nutritional Index (PNI)] were assessed at admission. Survival rate was assessed over a 1-year period following discharge. COPD patients mainly differed from non-COPD in terms of older age, smoking habit, number of associated diseases and drugs used. Aggregating the IDS 2-3-4 COPD classes (symptoms + functional impairment), the risk of one-year mortality was double that of the IDS 1 COPD class (symptoms only) and of non-COPD subjects (IDS 0 class) after adjusting for age, sex, disability, malnutrition, and comorbility. Moreover, IDS 2-3-4 COPD patients suffering from cor pulmonale (CP) had a fourfold 1-year risk of mortality in comparison with the IDS 1 COPD group after adjusting for the same covariates. Hospitalized stable very old COPD patients presenting functional impairment have a higher 1-year risk of mortality than only symptomatic COPD or non-COPD subjects. The presence of cor pulmonale with COPD further increases this risk.
Aged↗
[Oxygen saturation at rest, on exercise and during sleep in COPD patients undergoing pulmonary rehabilitation program. Two years prospective controlled study].
The role of pulmonary rehabilitation (PR) in COPD patients is well established. However, the PR programs includes physical exercise that may deteriorate chronic hypoxemia. The objective of the study was to evaluate impact of a long term PR program on oxygen saturation at rest, on exercise and during sleep in COPD patients no receiving supplemental oxygenation. A two--year controlled study involved 27 rehabilitated (PR-COPD patients (6 females) aged 32-76 years, mean 58.1 years on average and 19 control (C-COPD patients (3 females) aged 58-83 years, mean 68. COPD patients participating in PR program patients were younger, had higher value of FVC and FEV1 and better results of METs during symptom-limited exercise test (ET, p = 0.007). They also had better results of transcutaneus oxygen saturation (SaO2) at rest (p = 0.02), a lower maximal decrease in SaO2 during ET(p = 0.003) and a higher value of medan SaO2 during (p = 0.02). Following PR program the number of METs achieved during ET increased in PR-COPD patients (p = 0.007) and did not change in C-COPD, p = NS. The SaO2 at rest did not change significantly in both groups. Maximal drop in SaO2 during ET decreased in PR-COPD patients (p = 0.02) and did not change in C-COPD(p = NS) group. Median SaO2 at sleep did not change in PR-COPD patients (p = NS) but it decreased in C-COPD patients (p = 0.02). The study indicates that long term PR does not deteriorate the resting diurnal hypoxaemia, it prevent COPD patients from time depending exacerbation of nocturnal hypoxaemia and can improve oxygen saturation on exertion. The results could be influenced by baseline differences between PR-COPD and C-COPD patients.
Adult↗