Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Chronic obstructive pulmonary disease (COPD) is a global health problem, and since 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents the main contents of the second 5-year revision of the GOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry is required for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation. The document highlights that the assessment of the patient with COPD should always include assessment of (1) symptoms, (2) severity of airflow limitation, (3) history of exacerbations, and (4) comorbidities. The first three points can be used to evaluate level of symptoms and risk of future exacerbations, and this is done in a way that splits patients with COPD into four categories-A, B, C, and D. Nonpharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority, and a separate section in the document addresses management of comorbidities as well as COPD in the presence of comorbidities. The revised document also contains a new section on exacerbations of COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholders and will hopefully inspire future national and local guidelines on the management of COPD.

Impaired circadian variation of platelet activity in patients with sleep apnea.

BACKGROUND: Cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSAS). There is evidence that the day-night pattern of myocardial infarction and sudden cardiac death observed in the general population is altered in patients with OSAS. This study investigates potential abnormalities in the circadian profiles of platelet activity in OSAS. METHODS: We studied 37 patients with OSAS [7 of whom were also studied after 3 months on continuous positive airway pressure (CPAP) treatment] and 11 controls. In each subject, we obtained six different blood samples during 24-h period (2200, 0200, 0600, 1000, 1400, and 1800 hours). Platelet activity was determined by flow cytometry immediately after sampling. RESULTS: We found that nocturnal platelet activity was significantly increased in patients with OSAS (p = 0.043) and that effective treatment with CPAP decreased platelet activity in these patients but differences just failed to reach statistical significance (p = 0.063). CONCLUSIONS: OSAS is associated with increased platelet activity during the night, and that this appears to be improved by chronic use of CPAP. These results may contribute to explain the high prevalence of cardiovascular events during sleep in OSAS.

The influence of obesity and obstructive sleep apnea on metabolic hormones.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by excessive daytime sleepiness and repetitive upper airway obstruction episodes during sleep. Clinically, obesity is a major risk factor for developing OSAS. However, OSAS has been associated with hormonal and metabolic alterations that could predispose patients to obesity. The aim of this study was to investigate the independent role of apneas and obesity on plasma levels of metabolic hormones (adiponectin, ghrelin, and leptin) in patients with OSAS. METHODS: We have studied patients with OSAS and controls with and without obesity. All patients were male, had an apnea-hypopnea index of 20/h or greater, and were eligible for nasal continuous positive airway pressure (nCPAP) treatment. Patients were considered obese (n = 28) when their BMI was higher than 30 kg/m(2) and non-obese (n = 21) when it was lower than 27 kg/m(2). Non-obese control subjects (n = 20) were non-snorers with a normal cardiorespiratory sleep study, while obese control subjects (n = 10) were recruited from those obese subjects who were visited in our sleep unit and for whom OSAS was excluded by full polysomnography. A single blood sample was obtained from an antecubital vein in all participants after the completion of the nocturnal sleep laboratory recording. Plasma leptin, adiponectin, and ghrelin levels were determined by radioimmunoassay. RESULTS: The adiponectin, ghrelin, and leptin plasma levels were similar in both patients and controls. There were differences in leptin and adiponectin plasma levels between the obese and non-obese in both patient and control groups. In the case of ghrelin, differences between obese and non-obese subjects were only seen in patients. There were no significant differences in hormone levels between the obese controls and obese patients or between non-obese controls and non-obese patients. After 3 months of nCPAP treatment, adiponectin levels decreased significantly both in obese and non-obese patients, and leptin levels decreased in obese patients. Finally, nCPAP did not reduce ghrelin in either obese or non-obese patients. CONCLUSIONS: The basal levels of leptin, adiponectin, and ghrelin were mostly associated with obesity. We found that sleep apnea was not a determinant factor in leptin, adiponectin, and ghrelin hormonal levels. Interestingly, nCPAP treatment diminishes leptin in obese OSA patients and adiponectin levels in obese and non-obese patients with OSAS.

Non-synonymous polymorphism in the neuropeptide S precursor gene and sleep apnea.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a complex disease with a strong genetic basis. One of the primary molecular domains affected by OSAS is sympathetic activity. Neuropeptide S (NPS) plays an important role in the regulation of the sleep-wakefulness cycle, anxiety states, and daytime sleepiness. It is important to study neuropeptides related to sympathetic activity regulation and how their function could be modified by genetic variants affecting the expression of these molecules. OBJECTIVES: We investigated the association of the non-synonymous polymorphism rs4751440 in the NPS precursor gene with OSAS and certain variables related to OSAS (daytime sleepiness, body mass index (BMI), insulin resistance, and blood pressure). This polymorphism causes an amino acid substitution in exon 3 of the human NPS precursor gene. PATIENTS AND METHODS: We included 253 OSAS patients and 70 healthy subjects. Genotyping was done by polymerase chain reaction using specific flanking primers and agarose gel electrophoresis. Daytime sleepiness, BMI, plasma levels of high-density lipoprotein, glucose, total cholesterol, insulin, triglycerides, and the homeostasis model assessment index were also determined. RESULTS: A similar genotypic and allelic distribution was found in OSAS patients and controls. The risk of OSAS was not associated with the rs4751440 polymorphism. There was no significant interaction between daytime sleepiness or metabolic variables and the rs4751440 polymorphism. CONCLUSION: Genotypic and allelic frequency distribution of the rs4751440 polymorphism was similar in OSAS patients and controls. In this population-based study, we could not show a significant association between rs4751440 polymorphism and susceptibility to OSAS or certain phenotypes related to OSAS (daytime sleepiness, BMI, systolic blood pressure, and insulin resistance) with the exception of diastolic blood pressure.

Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index.

BACKGROUND: The BODE index (including body-mass index, airflow obstruction, dyspnoea, and exercise capacity) was an important contribution to the prognostic assessment of patients with chronic obstructive pulmonary disease (COPD). However, no study has assessed whether the risk of mortality predicted by the BODE index matches the observed mortality in different populations. We assessed the calibration of the BODE index, updated it to improve its calibration, and developed and validated a simplified index for use in primary-care settings. METHODS: We included 232 patients from the Swiss Barmelweid cohort with longstanding and severe COPD and 342 patients from the Spanish Phenotype and Course of COPD cohort study who had had their first hospital admission due to moderate-to-severe COPD. In both cohorts we compared the observed 3-year risk of all-cause mortality with the risk predicted by the BODE index. We then updated the BODE index and developed a simplified ADO index (including age, dyspnoea, and airflow obstruction) from the Swiss cohort, and validated both in the Spanish cohort. FINDINGS: Calibration of the BODE index was poor, with relative underprediction of 3-year risk of mortality by 36% in the Swiss cohort (median predicted risk 21.7% [IQR 12.7-31.7] vs 34.1% observed risk; p=0.013) and relative overprediction by 39% in the Spanish cohort (16.7% [12.7-31.7] vs 12.0%; p=0.035). The 3-year risk of mortality predicted by both the updated BODE (median 10.7% [8.1-13.8]) and ADO indices (11.8% [9.1-14.3]) matched the observed mortality in the Spanish cohort well (p=0.99 and p=0.98, respectively). INTERPRETATION: Both the updated BODE and ADO indices could lend support to the prognostic assessment of patients with COPD in specialised and primary-care settings. Such assessment enhances the targeting of treatments to individual patients. FUNDING: Swiss National Science Foundation; Klinik Barmelweid; Fondo de Investigación Sanitaria Ministry of Health, Spain; Agència d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA; Red RCESP; Fondo de Investigación Sanitaria; Fondo de Investigación Sanitaria; Fundació La Marató de TV3; Novartis Farmacèutica, Spain.

Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke.

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-alpha) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-alpha secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-alpha secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.

Characteristics of patients admitted for the first time for COPD exacerbation.

BACKGROUND: This study describes the characteristics of a large sample of patients hospitalised for the first time for a chronic obstructive pulmonary disease (COPD) exacerbation. METHODS: All subjects first admitted for a COPD exacerbation to nine teaching Spanish hospitals during January 2004-March 2006, were eligible. COPD diagnosis was confirmed by spirometry under stability. At admission, sociodemographic data, lifestyle, previous treatment and diagnosis of respiratory disease, lung function and Charlson index of co-morbidity were collected. A comprehensive assessment, including dyspnea, lung function, six-minute walking test, and St. George's Respiratory Questionnaire (SGRQ), was completed 3 months after admission, during a clinically stable disease period. RESULTS: Three-hundred and forty-two patients (57% of the eligible) participated in the study: 93% males, mean (SD) age 68 (9) years, 42% current smokers, 50% two or more co-morbidities, 54% mild-to-moderate dyspnea, post-bronchodilator FEV(1) 52 (16)% of predicted (54% mild-to-moderate COPD in ATS/ERS stages), 6-min walking distance 440 m, total SGRQ score 37 (18), and 36% not report respiratory disease. The absence of a previous COPD diagnosis, positive bronchodilator test, female gender, older age, higher DLco and higher BMI were independently associated with less severe COPD. CONCLUSIONS: We show that the patients admitted after presenting with their first COPD exacerbation have a wide range of severity, with a large proportion of patients in the less advanced COPD stages.

A controlled trial of noninvasive ventilation for chronic obstructive pulmonary disease exacerbations.

PURPOSE: This prospective, multicenter, double-blind, placebo-controlled study tested the hypothesis that noninvasive positive pressure ventilation reduces the need for endotracheal intubation in patients hospitalized in a pulmonary ward because of acute exacerbation of chronic obstructive pulmonary disease. MATERIALS AND METHODS: Seventy-five consecutive patients with exacerbation (pH, 7.31 +/- 0.02; Pao(2), 45 +/- 9 mm Hg; Paco(2), 69 +/- 13 mm Hg) were randomly assigned to receive noninvasive ventilation or sham noninvasive ventilation during the first 3 days of hospitalization on top of standard medical treatment. RESULTS: The need for intubation (according to predefined criteria) was lower in the noninvasive ventilation group (13.5% vs 34%, P < .01); in 31 patients with pH not exceeding 7.30, these percentages were 22% and 77%, respectively (P < .001). Arterial pH and Paco(2) improved in both groups, but changes were enhanced by noninvasive ventilation. Length of stay was lower in the noninvasive ventilation group (10 +/- 5 vs 12 +/- 6 days, P = .06). In-hospital mortality was similar in both groups. CONCLUSIONS: These results demonstrate that noninvasive positive pressure ventilation, in a pulmonary ward, reduces the need for endotracheal intubation, particularly in the more severe patients, and leads to a faster recovery in patients with acute exacerbation of chronic obstructive pulmonary disease.

Physical activity and clinical and functional status in COPD.

BACKGROUND: The mechanisms underlying the benefits of regular physical activity in the evolution of COPD have not been established. Our objective was to assess the relationship between regular physical activity and the clinical and functional characteristics of COPD. METHODS: Three hundred forty-one patients were hospitalized for the first time because of a COPD exacerbation in nine teaching hospitals in Spain. COPD diagnosis was confirmed by spirometry under stable conditions. Physical activity before the first COPD hospitalization was measured using the Yale questionnaire. The following outcome variables were studied under stable conditions: dyspnea, nutritional status, complete lung function tests, respiratory and peripheral muscle strength, bronchial colonization, and systemic inflammation. RESULTS: The mean age was 68 years (SD, 9 years), 93% were men, 43% were current smokers, and the mean postbronchodilator FEV(1) was 52% predicted (SD, 16% predicted). Multivariate linear regression models were built separately for each outcome variable and adjusted for potential confounders (including remaining outcomes if appropriate). When patients with the lowest quartile of physical activity were compared to patients in the other quartiles, physical activity was associated with significantly higher diffusing capacity of the lung for carbon monoxide (Dlco) [change in the second, third, and fourth quartiles of physical activity, compared with first quartile (+ 6%, + 6%, and + 9% predicted, respectively; p = 0.012 [for trend])], expiratory muscle strength (maximal expiratory pressure [Pemax]) [+ 7%, + 5%, and + 9% predicted, respectively; p = 0.081], 6-min walking distance (6MWD) [+ 40, + 41, and + 45 m, respectively; p = 0.006 (for trend)], and maximal oxygen uptake (Vo(2)peak) [+ 55, + 185, and + 81 mL/min, respectively; p = 0.110 (for trend)]. Similarly, physical activity reduced the risk of having high levels of circulating tumor necrosis factor alpha (odds ratio, 0.78, 0.61, and 0.36, respectively; p = 0.011) and C-reactive protein (0.70, 0.51, and 0.52, respectively; p = 0.036) in multivariate logistic regression. CONCLUSIONS: More physically active COPD patients show better functional status in terms of Dlco, Pemax, 6MWD, Vo(2)peak, and systemic inflammation.

Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease.

Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early transcript 1 (RAET1) as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.

Prediction of risk of COPD exacerbations by the BODE index.

OBJECTIVES: This study assesses the power of the BODE index, a multidimensional grading system that predicts mortality, to predict subsequent exacerbations in patients with COPD. DESIGN: Prospective cohort study. PATIENTS AND INTERVENTIONS: A total of 275 COPD patients were followed every 6 months up to 8 years (median of 5.1 years). Baseline clinical variables were recorded and the BODE index was calculated. We investigated the prognostic value of BODE quartiles (scores 0-2, 3-4, 5-6 and 7-10) for both the number and severity of exacerbations requiring ambulatory treatment, emergency room visit, or hospitalization. RESULTS: The annual rate of COPD exacerbations was 1.95 (95% CI, 0.90-2.1). The mean time to a first exacerbation was inversely proportional to the worsening of the BODE quartiles (7.9 yrs, 5.7 yrs, 3.4 yrs and 1.3 yrs for BODE scores of 0-2, 3-4, 5-6 and 7-10, respectively). Similarly, the mean time to a first COPD emergency room visit was 6.7 yrs, 3.6 yrs, 2.0 yrs and 0.8 yrs for BODE quartiles (all p<0.05). Using ROC curves, the BODE index was a better predictor of exacerbation than the FEV(1) alone (p<0.01). CONCLUSIONS: The BODE index is a better predictor of the number and severity of exacerbations in COPD than FEV(1) alone.

Increased plasma levels of asymmetric dimethylarginine and soluble CD40 ligand in patients with sleep apnea.

BACKGROUND: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). OBJECTIVES: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). METHODS: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). RESULTS: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. CONCLUSIONS: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease.

RATIONALE: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families. OBJECTIVES: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD. METHODS: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema. MEASUREMENTS AND MAIN RESULTS: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD. CONCLUSIONS: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease.

OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. PATIENTS AND METHODS: To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 +/- 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 +/- 5% ref). RESULTS: We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. CONCLUSIONS: This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1beta, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.

Endothelial function and circulating endothelial progenitor cells in patients with sleep apnea syndrome.

BACKGROUND: Endothelial dysfunction and cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSA). Circulating endothelial progenitor cells (EPCs) contribute to repair dysfunctional endothelium and have been related to increased cardiovascular risk. OBJECTIVES: We tested the hypothesis that the number of circulating EPCs may be altered in OSA patients. METHODS: EPCs (CD34+ VEGF-R2+) were isolated and quantified from peripheral blood samples of OSA patients (n = 13) and healthy controls (n = 13) matched for age and sex. All subjects were free of any other known cardiovascular risk factors. The plasma levels of vascular endothelial growth factor (VEGF) were also determined, and the endothelium-dependent and endothelium-independent vascular function was assessed in all subjects. RESULTS: Patients with OSA had lower levels of EPCs (p < 0.05) and higher plasma levels of VEGF (p < 0.05) than controls. Endothelial function was not different between OSA and controls. CONCLUSIONS: Patients with OSA free of any other known cardiovascular risk factor show a reduced number of circulating EPCs and an increase in plasma VEGF levels. These alterations may contribute to future endothelial dysfunction in these patients.

Pulmonary and systemic hepatocyte and keratinocyte growth factors in patients with chronic obstructive pulmonary disease.

BACKGROUND: The potential role of growth factors in chronic obstructive pulmonary disease (COPD) has begun to be addressed only recently and is still poorly understood. For this study, we investigated potential abnormalities of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in patients with COPD. METHODS: To this end, we compared the levels of HGF and KGF, measured by enzyme-linked immunosorbent assay (ELISA), in bronchoalveolar lavage (BAL) fluid and in serum in 18 patients with COPD (62 +/- 9 yrs, forced expiratory volume in one second [FEV1] 57 +/- 12% ref, X +/- standard deviation of mean), 18 smokers with normal lung function (58 +/- 8 yrs, FEV1 90 +/- 6% ref) and 8 never smokers (67 +/- 9 yrs, 94 +/- 14% ref). RESULTS: We found that in BAL, HGF levels were higher in patients with COPD than in the other two groups whereas, in serum, HGF concentration was highest in smokers with normal lung function (p < 0.01). KGF levels were not significantly different between groups, neither in blood nor in BAL (most values were below the detection limit). CONCLUSIONS: These results highlight a different response of HGF in BAL and serum in smokers with and without COPD that may be relevant for tissue repair in COPD.

Angiotensin-converting-enzyme gene polymorphisms, smoking and chronic obstructive pulmonary disease.

While tobacco smoking is the main risk factor for chronic obstructive pulmonary disease (COPD) only a fraction of smokers go on to develop the disease. We investigated the relationship between the insertion (I)--deletion (D) polymorphisms in the Angiotensin converting enzyme (ACE) gene and the risk of developing COPD in smokers by determining the distribution of the ACE genotypes (DD, ID and II) in 151 life-long male smokers. 74 of the smokers had developed COPD (62 +/- 2 years; FEV1 44 +/- 6% reference) whereas the rest retained normal lung function (56 +/- 2 yrs; FEV1 95 +/- 3% reference). In addition, we genotyped 159 males recruited randomly from the general population. The prevalence of the DD genotype was highest (p = 0.01) in the smokers that developed COPD and its presence was associated with a 2-fold increase in the risk for COPD (OR 2.2; IC95% 1.1 to 5.5). Surprisingly, the 151 individuals in the smoking population did not demonstrate Hardy-Weinberg equilibrium unlike the 159 recruited from the general population. Our results suggest that ACE polymorphisms are associated with both the smoking history of an individual and their risk of developing COPD.

Effect of continuous positive airway pressure on the risk of road accidents in sleep apnea patients.

BACKGROUND: Continuous positive airway pressure (CPAP) reduces daytime somnolence in the obstructive sleep apnea syndrome (OSAS) and may contribute to a reduction in the risk of motor vehicle accidents. OBJECTIVE: To evaluate the effects of CPAP on automobile collisions in patients with OSAS. METHODS: We compared the number of motor vehicle accidents in 80 patients with OSAS and 80 healthy subjects during the 2 years before and the 2 years after study entry, at which CPAP treatment was initiated. RESULTS: Patients with OSAS had a 2.6 times higher risk of suffering an automobile collision compared to controls (rate ratio, RR=2.57; 95% confidence interval, CI=1.30-5.05). After 2 years of CPAP treatment, the rate of collisions was reduced more than half in patients with OSAS (RR=0.41; 95% CI=0.21-0.79), but this occurred also in controls (RR=0.49; 95% CI=0.17-1.40). The magnitude of this fall between groups was not different (p for interaction=0.68), even after adjusting for body mass index, alcohol intake and Epworth scale. CONCLUSIONS: Patients with OSAS have an increased risk of suffering a traffic collision. This risk was significantly reduced after their inclusion in the study. Yet, as this reduction also occurred in the control group, this effect may not be due to CPAP therapy.

Expression of Toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation which flare-up during episodes of acute exacerbation (AECOPD). Given the role of Toll-like receptors (TLRs) in the induction of inflammatory responses we investigated the involvement of TLRs in COPD pathogenesis. METHODS: The expression of TLR-2, TLR-4 and CD14 in monocytes was analyzed by flow cytometry. To study the functional responses of these receptors, monocytes were stimulated with peptidoglycan or lipopolysaccharide and the amounts of TNFalpha and IL-6 secreted were determined by ELISA. RESULTS: We found that the expression of TLR-2 was up-regulated in peripheral blood monocytes from COPD patients, either clinically stable or during AECOPD, as compared to never smokers or smokers with normal lung function. Upon stimulation with TLR-2 ligand monocytes from COPD patients secreted increased amounts of cytokines than similarly stimulated monocytes from never smokers and smokers. In contrast, the expressions of TLR-4 and CD14 were not significantly different between groups, and the response to lipopolysaccharide (a TLR-4 ligand) stimulation was not significantly different either. At discharge from hospital TLR-2 expression was down-regulated in peripheral blood monocytes from AECOPD patients. This could be due to the treatment with systemic steroids because, in vitro, steroids down-regulated TLR-2 expression in a dose-dependent manner. Finally, we demonstrated that IL-6, whose plasma levels are elevated in patients, up-regulated in vitro TLR-2 expression in monocytes from never smokers. CONCLUSION: Our results reveal abnormalities in TLRs expression in COPD patients and highlight its potential relationship with systemic inflammation in these patients.

Systemic effects of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) affects various structural and functional domains in the lungs. It also has significant extrapulmonary effects, the so-called systemic effects of COPD. Weight loss, nutritional abnormalities, and skeletal muscle dysfunction are well-recognized systemic effects of COPD. Other less well-known but potentially important systemic effects include an increased risk of cardiovascular disease and several neurologic and skeletal defects. The mechanisms underlying these systemic effects are unclear, but they are probably interrelated and multifactorial, including inactivity, systemic inflammation, tissue hypoxia and oxidative stress among others. These systemic effects add to the respiratory morbidity produced by the underlying pulmonary disease and should be considered in the clinical assessment as well as the treatment of affected patients.