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

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          Abstract

          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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          Most cited references12

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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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            St. George's Respiratory Questionnaire: MCID.

            The SGRQ is a disease-specific measure of health status for use in COPD. A number of methods have been used for estimating its minimum clinically important difference (MCID). These include both expert and patient preference-based estimates. Anchor-based methods have also been used. The calculated MCID from those studies was consistently around 4 units, regardless of assessment method. By contrast, the MCID calculated using distribution-based methods varied across studies and permitted no consistent estimate. All measurements of clinical significance contain sample and measurement error. They also require value judgements, if not about the calculation of the MCID itself then about the anchors used to estimate it. Under these circumstances, greater weight should be placed upon the overall body of evidence for an MCID, rather than one single method. For that reason, estimates of MCID should be used as indicative values. Methods of analysing clinical trial results should reflect this, and use appropriate statistical tests for comparison with the MCID. Treatments for COPD that produced an improvement in SGRQ of the order of 4 units in clinical trials have subsequently found wide acceptance once in clinical practice, so it seems reasonable to expect any new treatment proposed for COPD to produce an advantage over placebo that is not significantly inferior to a 4-unit difference.
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              Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes.

              To test the hypothesis-given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)-that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease. This research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a -950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements. In a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047). Greater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes. © RSNA, 2011.
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                Author and article information

                Journal
                101605555
                41464
                Lancet Respir Med
                Lancet Respir Med
                The Lancet. Respiratory medicine
                2213-2600
                2213-2619
                3 July 2017
                28 June 2017
                August 2017
                01 August 2018
                : 5
                : 8
                : 619-626
                Affiliations
                [1 ]Division of Pulmonary and Critical Care, Michigan Medicine, Ann Arbor, MI
                [2 ]Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC
                [3 ]Department of Medicine, Columbia University, New York, NY
                [4 ]Center for Genomics and Personalized Medicine Research, Department of Medicine, Wake Forest University, Winston-Salem NC
                [5 ]Division of Pulmonary and Critical Care, National Jewish, Denver, CO
                [6 ]Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, CA
                [7 ]Division of Pulmonary and Critical Care, University of Iowa, Iowa City, IA
                [8 ]Section of Pulmonary & Critical Care Medicine, Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, MI
                [9 ]Department of Thoracic Medicine, Temple University, Philadelphia, PA
                [10 ]Division of Pulmonary and Critical Care, University of Alabama, Birmingham, AB
                [11 ]Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD
                [12 ]Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA
                [13 ]Department of Medicine, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, UT
                [14 ]Division of Pulmonary & Critical Care, University of Illinois, Chicago, IL
                [15 ]Department of Medicine, University of Nebraska Medical Center, Omaha, NE
                [16 ]Early Clinical Development, AstraZeneca, Cambridge, UK
                [17 ]Imperial College, London, UK
                [18 ]Cardiovascular Research Institute, Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of California, San Francisco, CA
                [19 ]Section of Pulmonary & Critical Care Medicine, Salt Lake City Department of Veterans Affairs Medical Center, Salt Lake City, UT
                [20 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill/Cornell Medical College, NY, NY
                Author notes
                Corresponding author: MeiLan K. Han, M.D., M.S. Michigan Medicine, Ann Arbor, MI 48109, mrking@ 123456med.umich.edu , Phone: 734-936-5201, Fax: 734-936-5048
                [*]

                co-senior authors

                Article
                NIHMS890110
                10.1016/S2213-2600(17)30207-2
                5558856
                28668356
                6ede8daf-dc1a-42b4-a7cc-ad08e278d6ba

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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