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      Serum Metabolite Biomarkers Discriminate Healthy Smokers from COPD Smokers

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          Abstract

          COPD (chronic obstructive pulmonary disease) is defined by a fixed expiratory airflow obstruction associated with disordered airways and alveolar destruction. COPD is caused by cigarette smoking and is the third greatest cause of mortality in the US. Forced expiratory volume in 1 second (FEV1) is the only validated clinical marker of COPD, but it correlates poorly with clinical features and is not sensitive enough to predict the early onset of disease. Using LC/MS global untargeted metabolite profiling of serum samples from a well-defined cohort of healthy smokers (n = 37), COPD smokers (n = 41) and non-smokers (n = 37), we sought to discover serum metabolic markers with known and/or unknown molecular identities that are associated with early-onset COPD. A total of 1,181 distinct molecular ions were detected in 95% of sera from all study subjects and 23 were found to be differentially-expressed in COPD-smokers vs. healthy-smokers. These 23 putative biomarkers were differentially-correlated with lung function parameters and used to generate a COPD prediction model possessing 87.8% sensitivity and 86.5% specificity. In an independent validation set, this model correctly predicted COPD in 8/10 individuals. These serum biomarkers included myoinositol, glycerophopshoinositol, fumarate, cysteinesulfonic acid, a modified version of fibrinogen peptide B (mFBP), and three doubly-charged peptides with undefined sequence that significantly and positively correlate with mFBP levels. Together, elevated levels of serum mFBP and additional disease-associated biomarkers point to a role for chronic inflammation, thrombosis, and oxidative stress in remodeling of the COPD airways. Serum metabolite biomarkers offer a promising and accessible window for recognition of early-stage COPD.

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          Most cited references74

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          Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society.

          This guideline is an official statement of the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS). It represents an update of the 2007 ACP clinical practice guideline on diagnosis and management of stable chronic obstructive pulmonary disease (COPD) and is intended for clinicians who manage patients with COPD. This guideline addresses the value of history and physical examination for predicting airflow obstruction; the value of spirometry for screening or diagnosis of COPD; and COPD management strategies, specifically evaluation of various inhaled therapies (anticholinergics, long-acting β-agonists, and corticosteroids), pulmonary rehabilitation programs, and supplemental oxygen therapy. This guideline is based on a targeted literature update from March 2007 to December 2009 to evaluate the evidence and update the 2007 ACP clinical practice guideline on diagnosis and management of stable COPD. RECOMMENDATION 1: ACP, ACCP, ATS, and ERS recommend that spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 2: For stable COPD patients with respiratory symptoms and FEV(1) between 60% and 80% predicted, ACP, ACCP, ATS, and ERS suggest that treatment with inhaled bronchodilators may be used (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 3: For stable COPD patients with respiratory symptoms and FEV(1) 50% predicted. (Grade: weak recommendation, moderate-quality evidence). RECOMMENDATION 7: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (Pao(2) ≤55 mm Hg or Spo(2) ≤88%) (Grade: strong recommendation, moderate-quality evidence).
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            Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes.

            Chronic obstructive pulmonary disease (COPD) occurs in a minority of smokers and is characterized by intermittent exacerbations and clinical subphenotypes such as emphysema and chronic bronchitis. Although sphingolipids as a class are implicated in the pathogenesis of COPD, the particular sphingolipid species associated with COPD subphenotypes remain unknown.
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              Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease.

              We tested whether increased concentrations of the acute-phase reactant fibrinogen correlate with pulmonary function and rate of chronic obstructive pulmonary disease (COPD) hospitalization. We measured plasma fibrinogen and forced expiratory volume in 1 s (FEV(1)), and assessed prospectively COPD hospitalizations in 8,955 adults from the Danish general population. Smokers with plasma fibrinogen in the upper and middle tertile (> 3.3 and 2.7-3.3 g/L) had 7% (95% confidence interval [CI]: 5-8%) and 2% (0-3%) lower percentage predicted FEV(1) than smokers with fibrinogen in the lower tertile (< 2.7 g/L). The equivalent decreases in nonsmokers were 6% (4-7%) and 0% (-1-2%), respectively. Individuals with plasma fibrinogen in the upper and middle tertile had COPD hospitalization rates of 93 and 60 compared with 52 per 10,000 person-years in individuals with fibrinogen in the lower tertile (log-rank: p < 0.001 and p = 0.31). After adjusting for age, body mass index, sex, pack-years, and recent respiratory infections, relative risks for COPD hospitalization were 1.7 (95% CI: 1.1-2.6) and 1.4 (0.9-2.1) in individuals with fibrinogen in the upper and middle versus lower tertile. In conclusion, elevated plasma fibrinogen was associated with reduced FEV(1) and increased risk of COPD. This could not be explained by smoking alone.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 December 2015
                2015
                : 10
                : 12
                : e0143937
                Affiliations
                [1 ]Department of Pharmacology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, United States of America
                [2 ]Department of Genetic Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, United States of America
                Georgia Regents University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: QC RSD SSG RGC. Performed the experiments: QC RSD YM. Analyzed the data: QC YM. Contributed reagents/materials/analysis tools: RGS MS SSG. Wrote the paper: QC SSG RGC.

                Article
                PONE-D-15-19036
                10.1371/journal.pone.0143937
                4682670
                26674646
                163db573-bcd9-4e31-917d-6ec616c1302b
                © 2015 Chen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 5 May 2015
                : 11 November 2015
                Page count
                Figures: 4, Tables: 4, Pages: 20
                Funding
                These studies were supported, in part, by NIH R01HL107882, R01HL1189541, R37HL087062 and P20 HL113443. Research reported in this publication was supported in part by the Family Smoking Prevention and Tobacco Control Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration.
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                Research Article
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                All relevant data are within the paper and its Supporting Information files.

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