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      International Journal of COPD (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on pathophysiological processes underlying Chronic Obstructive Pulmonary Disease (COPD) interventions, patient focused education, and self-management protocols. Sign up for email alerts here.

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      The usefulness of soluble receptor for advanced glycation end-products in the identification of COPD frequent exacerbator phenotype

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          Abstract

          Introduction

          Exacerbations of COPD (ECOPDs) are important events in the course of COPD, accelerating the rate of decline in lung function and increasing the mortality risk. A growing body of evidence suggests the significance of the “frequent exacerbator” phenotype. This phenotype seems to be associated with a more severe airflow limitation, symptoms, health-related quality of life impairment, and higher mortality. However, there is no described biomarker that would help to identify this group of patients.

          Patients and methods

          Patients with COPD in “D” GOLD category were monitored for 3 years according to events of ECOPD. Serum samples were collected from the patients. Circulating level of plasma soluble receptor for advanced glycation end-products (sRAGE) was measured using commercially available high sensitivity kits. The receiver operating characteristic (ROC) curve analysis was used to assess the usefulness of sRAGE to identify frequent exacerbator phenotype. Log-rank test was used in the analysis of time to the subsequent exacerbation. Pearson ( R) or Spearman’s rank ( R S) correlation coefficients were used for correlation analysis.

          Results

          Nineteen patients were enrolled. The area under the ROC curve (AUROC) for sRAGE for the identification of frequent exacerbator phenotype was 0.81. Analysis identified the cutoff point as 850.407 pg/mL, characterized by a sensitivity of 0.80 (95% CI: 0.28–1.0) and specificity of 0.93 (95% CI: 0.66–1.0). Additionally, in the group with sRAGE ≤850.407 pg/mL, we observed significantly shorter time to the subsequent exacerbation: median of 32 vs 105.5 days ( P=0.03). Correlation analysis revealed significant negative correlation between sRAGE and the number of exacerbations requiring hospitalization during the whole time of follow-up ( R S=−0.53; P=0.02) and significant positive correlation with FEV 1 expressed as the percentage of reference value ( R=0.6; P=0.006).

          Conclusion

          sRAGE seems to be useful in the identification of frequent exacerbator phenotype. This parameter may also be used in the prediction of time to ECOPD. Our findings should be confirmed in a sufficiently powered larger sample.

          Most cited references20

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          Frequency of Exacerbations in COPD: An Analysis of the SPIROMICS Cohort

          Background Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year. To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort. Methods We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105). We classified participants according to yearly exacerbation frequency. Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none. Results During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none. Only 2·1% had ≥2 AECOPD in each year. An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%). In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8). Conclusions Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year. Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year. In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8.
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            Case fatality of COPD exacerbations: a meta-analysis and statistical modelling approach.

            The aim of our study was to estimate the case fatality of a severe exacerbation from long-term survival data presented in the literature. A literature search identified studies reporting ≥1.5 yr survival after a severe chronic obstructive pulmonary disease (COPD) exacerbation resulting in hospitalisation. The survival curve of each study was divided into a critical and a stable period. Mortality during the stable period was then estimated by extrapolating the survival curve during the stable period back to the time of exacerbation onset. Case fatality was defined as the excess mortality that results from an exacerbation and was calculated as 1 minus the (backwardly) extrapolated survival during the stable period at the time of exacerbation onset. The 95% confidence intervals (CI) of the estimated case fatalities were obtained by bootstrapping. A random effect model was used to combine all estimates into a weighted average with 95% CI. The meta-analysis based on six studies that fulfilled the inclusion criteria resulted in a weighted average case-fatality rate of 15.6% (95% CI 10.9-20.3), ranging from 11.4% to 19.0% for the individual studies. A severe COPD exacerbation requiring hospitalisation not only results in higher mortality risks during hospitalisation, but also in the time-period after discharge and contributes substantially to total COPD mortality.
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              Slopes of a receiver operating characteristic curve and likelihood ratios for a diagnostic test.

              Y. Choi (1998)
              This paper clarifies two important concepts in clinical epidemiology: the slope of a receiver operating characteristic (ROC) curve and the likelihood ratio. It points out that there are three types of slopes in an ROC curve--the tangent at a point on the curve, the slope between the origin and a point on the curve, and the slope between two points on the curve. It also points out that there are three types of likelihood ratios that can be defined for a diagnostic test that produces results on a continuous scale--the likelihood ratio for a particular single test value, the likelihood ratio for a positive test result, and the likelihood ratio for a test result in a particular level or category. It further illustrates mathematically and empirically the following three relations between these various definitions of slopes and likelihood ratios: 1) the tangent at a point on the ROC curve corresponds to the likelihood ratio for a single test value represented by that point; 2) the slope between the origin and a point on the curve corresponds to the positive likelihood ratio using the point as a criterion for positivity; and 3) the slope between two points on the curve corresponds to the likelihood ratio for a test result in a defined level bounded by the two points. The likelihood ratio for a single test value is considered an important parameter for evaluating diagnostic tests, but it is not easily estimable directly from laboratory data because of limited sample size. However, by using ROC analysis, the likelihood ratio for a single test value can be easily measured from the tangent. It is suggested that existing ROC analysis software be revised to provide estimates for tangents at various points on the ROC curve.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2018
                29 November 2018
                : 13
                : 3879-3884
                Affiliations
                [1 ]Department of Pneumology and Allergy, Medical University of Łódź, Łódź, Poland, joanna.milkowska-dymanowska@ 123456umed.lodz.pl
                [2 ]Healthy Ageing Research Centre, Medical University of Łódź, Łódź, Poland, joanna.milkowska-dymanowska@ 123456umed.lodz.pl
                Author notes
                Correspondence: Joanna Miłkowska-Dymanowska, Department of Pneumology and Allergy, Medical University of Łódź, Kopcińskiego Street 22, Łódź 90-153, Poland, Email joanna.milkowska-dymanowska@ 123456umed.lodz.pl
                [*]

                These authors contributed equally to this work

                Article
                copd-13-3879
                10.2147/COPD.S186170
                6276626
                30568439
                0079c3f0-7234-4652-8d29-ad9efb402312
                © 2018 Miłkowska-Dymanowska et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Short Report

                Respiratory medicine
                srage,frequent exacerbator phenotype of copd,exacerbations of copd,copd,prediction of aecopd

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