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      C-reactive protein and N-terminal prohormone brain natriuretic peptide as biomarkers in acute exacerbations of COPD leading to hospitalizations

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          Abstract

          There are currently no accepted and validated blood tests available for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this study, we sought to determine the discriminatory power of blood C-reactive protein (CRP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in the diagnosis of AECOPD requiring hospitalizations. The study cohort consisted of 468 patients recruited in the COPD Rapid Transition Program who were hospitalized with a primary diagnosis of AECOPD, and 110 stable COPD patients who served as controls. Logistic regression was used to build a classification model to separate AECOPD from convalescent or stable COPD patients. Performance was assessed using an independent validation set of patients who were not included in the discovery set. Serum CRP and whole blood NT-proBNP concentrations were highest at the time of hospitalization and progressively decreased over time. Of the 3 classification models, the one with both CRP and NT-proBNP had the highest AUC in discriminating AECOPD (cross-validated AUC of 0.80). These data were replicated in a validation cohort with an AUC of 0.88. A combination of CRP and NT-proBNP can reasonably discriminate AECOPD requiring hospitalization versus clinical stability and can be used to rapidly diagnose patients requiring hospitalization for AECOPD.

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          The meaning and use of the area under a receiver operating characteristic (ROC) curve.

          A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.
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            Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.

            Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV(1)) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-alpha (TNF-alpha), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-alpha levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.
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              Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.

              B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension. We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay. The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure. Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea. Copyright 2002 Massachusetts Medical Society.
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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
                22 March 2017
                2017
                : 12
                : 3
                : e0174063
                Affiliations
                [1 ]Centre for Heart Lung Innovation, James Hogg Research Centre, St. Paul’s Hospital, Vancouver, British Columbia, Canada
                [2 ]Institute for Heart Lung Health, St. Paul’s Hospital, Vancouver, British Columbia, Canada
                [3 ]PROOF Centre of Excellence, Vancouver, British Columbia, Canada
                [4 ]Department of Radiology, St. Paul’s Hospital, Vancouver, British Columbia, Canada
                [5 ]Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
                [6 ]Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
                [7 ]The Lung Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada
                [8 ]Department of Computer Sciences, University of British Columbia, Vancouver, British Columbia, Canada
                National and Kapodistrian University of Athens, GREECE
                Author notes

                Competing Interests: YRC, VC, ZH, CJH, BMM, JMF, and RTN have nothing to disclose. JAL reports personal fees from GE Healthcare, outside the submitted work. MLD reports grants from Genome Canada, Genome British Columbia, Genome Quebec, Canadian Institutes for Health Research (CIHR), Networks of Centres of Excellence Centre of Excellence for Commercialization and Research, St. Paul's Hospital Foundation, and the Canadian Respiratory Research Network, which is funded by the Institute of Circulatory and Respiratory Health Emerging Network of CIHR, the Canadian Lung Association, the Canadian Thoracic Society, and the Canadian Respiratory Health Professionals, during the conduct of the study. DS reports grants from Genome Canada, grants from Canadian Institutes of Health Research, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Novartis, grants from Merck, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                • Conceptualization: YRC VC ZH DS.

                • Data curation: YRC VC ZH DS.

                • Formal analysis: YRC VC ZH.

                • Funding acquisition: DS.

                • Investigation: YRC VC ZH JAL CJH.

                • Methodology: YRC VC ZH DS.

                • Project administration: ZH.

                • Resources: DS.

                • Software: YRC VC ZH DS.

                • Supervision: YRC ZH DS.

                • Validation: YRC VC ZH DS.

                • Visualization: YRC VC ZH.

                • Writing – original draft: YRC.

                • Writing – review & editing: VC ZH JAL CJH MLD JMF BMM RTN DS.

                Author information
                http://orcid.org/0000-0001-8626-7205
                Article
                PONE-D-16-33005
                10.1371/journal.pone.0174063
                5362097
                28328968
                5befe3a7-c28a-4996-8539-eb807f43fd11
                © 2017 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
                : 17 August 2016
                : 2 March 2017
                Page count
                Figures: 5, Tables: 4, Pages: 16
                Funding
                Funded by: Genome Canada (CA)
                Funded by: Genome British Columbia (CA)
                Funded by: Genome Quebec
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Funded by: PROOF Centre
                Funded by: St Paul's Hospital Foundation
                Funded by: Providence Health Care
                Funded by: COPD Clinical Research Network
                Funding was provided by Genome Canada, Genome British Columbia, Genome Quebec, the Canadian Institutes of Health Research, PROOF Centre of Excellence, St. Paul's Foundation, Providence Health Care Research Institute, the Canadian Respiratory Research Network, and the National Heart, Lung, and Blood Institute’s COPD Clinical Research Network (Grants U10 HL074441, U10 HL074418, U10 HL074428, U10 HL074409, U10 HL074407, U10 HL074422, U10 HL074416, U10 HL074408, U10 HL074439, U10 HL0744231, and U10 HL074424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Biology and Life Sciences
                Biochemistry
                Hormones
                Peptide Hormones
                Natriuretic Peptide
                Brain Natriuretic Peptide
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Cardiology
                Heart Failure
                Biology and Life Sciences
                Biochemistry
                Proteins
                C-Reactive Proteins
                Biology and Life Sciences
                Biochemistry
                Prohormones
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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