Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

https://www.who.int/respiratory/copd/GOLD_WR_06.pdf

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

Chronic obstructive pulmonary disease (COPD) is a common problem in the elderly. The disease is characterised by intermittent worsening of symptoms and these episodes are called acute exacerbations. The best estimate, based on several lines of evidence, is that approximately half of all exacerbations are caused by bacteria. These lines of evidence include studies of lower respiratory tract bacteriology during exacerbations, correlation of airways’ inflammation with results of sputum cultures during exacerbations, analysis of immune responses to bacterial pathogens, and the observation in randomised, prospective, placebo-controlled trials that antibacterial therapy is of benefit. The most important bacterial causes of exacerbations of COPD are nontypeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Chlamydia pneumoniae.

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Chronic obstructive pulmonary disease

Representatives from many countries serve as a network for the dissemination and implementation of programs for diagnosis, management, and prevention of COPD. The GOLD Board of Directors is grateful to the many GOLD National Leaders who participated in discussions of concepts that appear in GOLD reports.

Global initiative for chronic obstructive lung disease.

Background The widespread application pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function attributable to the programs. This review updates that reported by Lacasse et al Lancet 1996; 748:1115-1119. Objectives To determine the impact of rehabilitation on health-related quality of life (QoL) and exercise capacity in patients with COPD. Search strategy The 14 randomized controlled trials (RCTs) included in the original meta-analysis were included. Additional RCTs were identified from the Cochrane Airways Group's registry of COPD RCTs using the strategy: [exp, lung diseases, obstructive] and [exp, rehabilitation or exp, exercise therapy] and [research design or longitudinal studies or evaluation study or randomized controlled trial]. Abstracts presented at American Thoracic Society 1980-2000, American College of Chest Physicians 1980-2000 and European Respiratory Society 1987-2000 were also searched. Selection criteria RCTs of rehabilitation in patients with COPD in which quality of life (QoL) and/or functional (FEC) or maximal (MEC) exercise capacity were measured. Rehabilitation was defined as exercise training for at least 4 weeks with or without education and/or psychological support. Control groups received conventional community care without rehabilitation. Data collection and analysis Weighted mean differences (WMD) were calculated using a random-effects model. Missing data from the primary study reports were requested from the authors. Main results 23 RCTs met the inclusion criteria. Statistically significant improvements were found for all the outcomes. In three important domains of QoL (Chronic Respiratory Questionnaire scores for Dyspnea, Fatigue and Mastery), the effect was larger than the minimal clinically important difference of 0.5 units using this instrument. For example Dyspnoea score: WMD 0.98 units, 95% Confidence Interval (95% CI) 0.74 - 1.22 units; n=9 trials. For FEC and MEC, the effect was small and a little below the threshold of clinical significance for the 6- minute walking distance: WMD 49 m, 95% CI: 26 - 72 m; n=10 trials. Reviewer's conclusions Rehabilitation relieves dyspnea and fatigue and enhances patients' sense of control over their condition. These improvements are moderately large and clinically significant. The average improvement in exercise capacity was modest. Rehabilitation forms an important component of the management of COPD.

Pulmonary rehabilitation for chronic obstructive pulmonary disease

Linda Nici, Claudio Donner, Emiel Wouters, Richard Zuwallack, Nicolino Ambrosino, Jean Bourbeau, Mauro Carone, Bartolome Celli, Marielle Engelen, Bonnie Fahy, Chris Garvey, Roger Goldstein, Rik Gosselink, Suzanne Lareau, Neil MacIntyre, Francois Maltais, Mike Morgan, Denis O’Donnell, Christian Prefault, Jane Reardon, Carolyn Rochester, Annemie Schols, Sally Singh, and Thierry Troosters, on behalf of the ATS/ERS Pulmonary Rehabilitation Writing Committee

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American Thoracic Society/European Respiratory Society Statement on Pulmonary Rehabilitation

Chronic obstructive pulmonary disease (COPD) is characterised by an inappropriate/excessive inflammatory response of the lungs to respiratory pollutants, mainly tobacco smoking. Recently, besides the typical pulmonary pathology of COPD (i.e. chronic bronchitis and emphysema), several effects occurring outside the lungs have been described, the so-called systemic effects of COPD. These effects are clinically relevant because they modify and can help in the classification and management of the disease. The present review discusses the following systemic effects of chronic obstructive pulmonary disease: 1) systemic inflammation; 2) nutritional abnormalities and weight loss; 3) skeletal muscle dysfunction; and 4) other potential systemic effects. For each of these, the potential mechanisms and clinical implications are discussed and areas requiring further research are highlighted.

https://erj.ersjournals.com/content/erj/21/2/347.full.pdf

Systemic effects of chronic obstructive pulmonary disease

Background: A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)). 

Methods: BAL fluid cell numbers and levels of tumour necrosis factor (TNFα) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples. 

Results: Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-κB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD. 

Conclusion: There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.

https://thorax.bmj.com/content/thoraxjnl/60/4/293.full.pdf

Oxidative stress and airway inflammation in severe exacerbations of COPD

Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating lymphocytes. The present study investigated whether this effect was further amplified in smokers who develop chronic obstructive pulmonary disease. Telomere length was determined by fluorescence in situ hybridisation in circulating lymphocytes harvested from 26 never-smokers, 24 smokers with normal lung function and 26 smokers with moderate-to-severe airflow obstruction (forced expiratory flow in one second 48+/-4% predicted). In contrast to never-smokers, telomere length significantly decreased with age in smokers. There was also a dose-effect relationship between the cumulative long-life exposure to tobacco smoking (pack-yrs) and telomere length. The presence and/or severity of chronic airflow obstruction did not modify this relationship. The results of the current study confirm that smoking exposure enhances telomere shortening in circulating lymphocytes. It also demonstrates a dose-effect relationship between exposure to tobacco smoking and telomere length, but failed to show that this effect is amplified in smokers who develop chronic obstructive pulmonary disease.

https://erj.ersjournals.com/content/erj/27/3/525.full.pdf

Telomere shortening in smokers with and without COPD.

Background: Weight loss, mostly due to skeletal muscle atrophy, is a frequent and clinically relevant problem in patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying this phenomenon are unclear. This study sought to investigate whether activation of the nuclear transcription factor NF-κB and upregulation of the inducible form of nitric oxide synthase (iNOS) occur in the skeletal muscle of patients with COPD and low body weight as potential molecular mechanisms leading to cachexia 

Methods: NF-κB DNA binding activity was determined by electromobility shift assay and the immunoreactivity of its inhibitory subunit IκB-κ and that of iNOS by Western blot analysis in biopsy specimens of the quadriceps femoris muscle of seven COPD patients with normal body mass index (BMI, 27.5 (1) kg/m2) and seven patients with low BMI (18.5 (1) kg/m2). 

Results: Compared with patients with normal body weight, those with low BMI showed a 30% increase in NF-κB DNA binding activity, a lower expression of IκB-α (3.37 (0.47) IOD v 5.96 (0.75) IOD, p<0.05; mean difference 2.59; 95% CI –4.53 to –0.65) and higher iNOS expression (1.51 (0.29) IOD v 0.78 (0.11) IOD, p<0.05; mean difference 0.74; 95% CI 0.04 to 1.42). 

Conclusions: NF-κB activation and iNOS induction occur in skeletal muscle of COPD patients with low body weight. These changes might contribute to the molecular pathogenesis of cachexia in COPD.

https://thorax.bmj.com/content/thoraxjnl/59/6/483.full.pdf

NF-kappaB activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight.

Tobacco smoking induces an inflammatory response in the lungs of all smokers but, for reasons that are still poorly understood, only a proportion of them develop chronic obstructive pulmonary disease (COPD). Recent evidence indicates that this inflammatory response persists after smoking cessation, suggesting some type of auto-perpetuation mechanism similar to that described in autoimmune disorders. T-lymphocytes (CD4+ and CD8+) have been implicated in the pathogenesis of both COPD and several autoimmune processes. A subtype of regulatory CD4+ T-cells expressing CD25 (Tregs) plays a critical role in the maintenance of peripheral tolerance and the prevention of autoimmunity, but their potential role in COPD has not been explored. The present study sought to evaluate maturation (CD45RA/CD45R0) and activation markers (CD28) of T-lymphocytes and to explore potential Treg abnormalities in COPD. Flow cytometry was used to characterise T-lymphocytes obtained from blood and bronchoalveolar lavage fluid (BALF) in 23 patients with moderate COPD, 29 smokers with normal lung function and seven never-smokers. The main findings were that in BALF: patients with COPD showed higher CD8+CD45RA+ and lower CD8+CD45R0+ than smokers with normal lung function; and compared with never-smokers, smokers with preserved lung function showed a prominent upregulation of Tregs that was absent in patients with COPD. These observations indicate a final maturation-activation state of CD8+ T-lymphocytes in chronic obstructive pulmonary disease and, for the first time, identify a blunted regulatory T-cell response to tobacco smoking in these patients, further supporting a potential involvement of the acquired immune response in the pathogenesis of the disease.

https://erj.ersjournals.com/content/erj/31/3/555.full.pdf

J Sauleda

Papers

Systemic effects of chronic obstructive pulmonary disease

Oxidative stress and airway inflammation in severe exacerbations of COPD

Telomere shortening in smokers with and without COPD.

NF-kappaB activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight.

Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking