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      Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

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          Abstract

          Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.

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          Most cited references117

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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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            Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.

            The purpose of this study was to calculate robust quantitative estimates of the predictive value of aortic pulse wave velocity (PWV) for future cardiovascular (CV) events and all-cause mortality by meta-analyses of longitudinal studies. Arterial stiffness is increasingly recognized as a surrogate end point for CV disease. We performed a meta-analysis of 17 longitudinal studies that evaluated aortic PWV and followed up 15,877 subjects for a mean of 7.7 years. The pooled relative risk (RR) of clinical events increased in a stepwise, linear-like fashion from the first to the third tertile of aortic PWV. The pooled RRs of total CV events, CV mortality, and all-cause mortality were 2.26 (95% confidence interval: 1.89 to 2.70, 14 studies), 2.02 (95% confidence interval: 1.68 to 2.42, 10 studies), and 1.90 (95% confidence interval: 1.61 to 2.24, 11 studies), respectively, for high versus low aortic PWV subjects. For total CV events and CV mortality, the RR was significantly higher in high baseline risk groups (coronary artery disease, renal disease, hypertension) compared with low-risk subjects (general population). An increase in aortic PWV by 1 m/s corresponded to an age-, sex-, and risk factor-adjusted risk increase of 14%, 15%, and 15% in total CV events, CV mortality, and all-cause mortality, respectively. An increase in aortic PWV by 1 SD was associated with respective increases of 47%, 47%, and 42%. Aortic stiffness expressed as aortic PWV is a strong predictor of future CV events and all-cause mortality. The predictive ability of arterial stiffness is higher in subjects with a higher baseline CV risk.
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              Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD.

              Chronic obstructive pulmonary disease (COPD) is associated with important chronic comorbid diseases, including cardiovascular disease, diabetes and hypertension. The present study analysed data from 20,296 subjects aged > or =45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). The sample was stratified based on baseline lung function data, according to modified Global Initiative for Obstructive Lung Disease (GOLD) criteria. Comorbid disease at baseline and death and hospitalisations over a 5-yr follow-up were then searched for. Lung function impairment was found to be associated with more comorbid disease. In logistic regression models adjusting for age, sex, race, smoking, body mass index and education, subjects with GOLD stage 3 or 4 COPD had a higher prevalence of diabetes (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1-1.9), hypertension (OR 1.6, 95% CI 1.3-1.9) and cardiovascular disease (OR 2.4, 95% CI 1.9-3.0). Comorbid disease was associated with a higher risk of hospitalisation and mortality that was worse in people with impaired lung function. Lung function impairment is associated with a higher risk of comorbid disease, which contributes to a higher risk of adverse outcomes of mortality and hospitalisations.
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                Author and article information

                Contributors
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central
                1741-7015
                2013
                14 August 2013
                : 11
                : 181
                Affiliations
                [1 ]Centre for Respiratory Medicine, Royal Free Campus, University College London, Rowland Hill Street, Hampstead, London NW3 2PF, UK
                Article
                1741-7015-11-181
                10.1186/1741-7015-11-181
                3750926
                23945277
                9cca3986-9055-4903-a8cf-b05115c4fed7
                Copyright ©2013 Wedzicha et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 May 2013
                : 9 July 2013
                Categories
                Review

                Medicine
                chronic obstructive pulmonary disease (copd),exacerbations,frequent exacerbator phenotype,comorbidities

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