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      The role of bronchodilator treatment in the prevention of exacerbations of COPD

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          Abstract

          Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea. These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD. Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥2 per year) independently of disease severity. Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis.

          The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β 2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS). While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance. Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation. Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations.

          Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations.

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          Most cited references104

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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            The natural history of chronic airflow obstruction.

            A prospective epidemiological study of the early stages of the development of chronic obstructive pulmonary disease was performed on London working men. The findings showed that forced expiratory volume in one second (FEV1) falls gradually over a lifetime, but in most non-smokers and many smokers clinically significant airflow obstruction never develops. In susceptible people, however, smoking causes irreversible obstructive changes. If a susceptible smoker stops smoking he will not recover his lung function, but the average further rates of loss of FEV1 will revert to normal. Therefore, severe or fatal obstructive lung disease could be prevented by screening smokers' lung function in early middle age if those with reduced function could be induced to stop smoking. Infective processes and chronic mucus hypersecretion do not cause chronic airflow obstruction to progress more rapidly. There are thus two largely unrelated disease processes, chronic airflow obstruction and the hypersecretory disorder (including infective processes).
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              The nature of small-airway obstruction in chronic obstructive pulmonary disease.

              Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD. The small airways were assessed in surgically resected lung tissue from 159 patients--39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed. Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Eur Respir J
                Eur. Respir. J
                erj
                The European Respiratory Journal
                European Respiratory Society (442 Glossop Road, Sheffield, S10 2PX, UK )
                0903-1936
                1399-3003
                December 2012
                26 July 2012
                : 40
                : 6
                : 1545-1554
                Affiliations
                [* ]Centre for Respiratory Medicine, University College London , London, UK
                [# ]Respiratory Division, University Hospitals , Leuven, Belgium
                []Dept of Clinical Medical Sciences, Faculty of Medical Sciences, University of the West Indies, St Augustine Campus , St Augustine, Trinidad and Tobago
                Author notes
                J.A. Wedzicha, Centre for Respiratory Medicine, University College London, Royal Free Campus, Rowland Hill Street, Hampstead, NW3 2PF, London, UK. E-mail: w.wedzicha@ 123456ucl.ac.uk
                Article
                erj00489-2012
                10.1183/09031936.00048912
                3511775
                22835613
                0626d43e-ac6d-46c2-bf6b-0d2bfdd3fadb
                Copyright © ERS 2012

                ERJ Open articles are open access and distributed under the terms of the ( Creative Commons Attribution Licence 3.0>)

                History
                : 22 March 2012
                : 13 July 2012
                Categories
                Review
                1
                14

                Respiratory medicine
                bronchodilator,chronic obstructive pulmonary disease,dyspnoea,exacerbations,long-acting anti-muscarinic agent,long-acting β2-agonists

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