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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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      A Sputum 6 Gene Expression Signature Predicts Inflammatory Phenotypes and Future Exacerbations of COPD

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          Abstract

          Background

          The 6 gene expression signature (6GS) predicts inflammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway inflammation are similar, suggesting the 6GS may be useful. This study determines the diagnostic and prognostic ability of 6GS in predicting inflammatory phenotypes and exacerbation risk in COPD.

          Methods

          We performed 2 studies: a cross-sectional phenotype prediction study in stable COPD (total N=132; n=34 eosinophilic (E)-COPD, n=42 neutrophilic (N)-COPD, n=39 paucigranulocytic (PG)-COPD, n=17 mixed-granulocytic (MG)-COPD) that assessed 6GS ability to discriminate phenotypes (eosinophilia≥3%; neutrophilia≥61%); and a prospective cohort study (total n=54, n=8 E-COPD; n=18 N-COPD; n=20 PG-COPD; n=8 MG-COPD, n=21 exacerbation prone (≥2/year)) that investigated phenotype and exacerbation prediction utility. 6GS was measured by qPCR and evaluated using multiple logistic regression and area under the curve (AUC). Short-term reproducibility (intra-class correlation) and phenotyping method agreement (κ statistic) were assessed.

          Results

          In the phenotype prediction study, 6GS could accurately identify and discriminate patients with E-COPD from N-COPD (AUC=96.4%; p<0.0001), PG-COPD (AUC=88.2%; p<0.0001) or MG-COPD (AUC=86.2%; p=0.0001), as well as N-COPD from PG-COPD (AUC=83.6%; p<0.0001) or MG-COPD (AUC=87.4%; p<0.0001) and was reproducible. In the prospective cohort study, 6GS had substantial agreement for neutrophilic inflammation (82%, κ=0.63, p<0.001) and moderate agreement for eosinophilic inflammation (78%, κ=0.42, p<0.001). 6GS could significantly discriminate exacerbation prone patients (AUC=77.2%; p=0.034). Higher IL1B levels were associated with poorer lung function and increased COPD severity.

          Conclusion

          6GS can significantly and reproducibly discriminate COPD inflammatory phenotypes and predict exacerbation prone patients and may become a useful molecular diagnostic tool assisting COPD management.

          Most cited references30

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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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            Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.

            Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.
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              The unmet global burden of COPD

              Chronic respiratory diseases receive little attention and funding in comparison with other major causes of global morbidity and mortality [1]. Chronic obstructive pulmonary disease (COPD) is a major public health problem. COPD is the end result of a susceptible lung being exposed to sufficient environmental stimulus. Caused principally by tobacco smoking and household air pollution (HAP), COPD is a silent killer in low- and middle-income countries (LMICs): an estimated 328 million people have COPD worldwide [2], and in 15 years, COPD is expected to become the leading cause of death [3]. The relentless decline in lung function that characterises COPD is associated with progressive symptoms and functional impairment, with susceptibility to respiratory infections called ‘exacerbations’. Exacerbations are responsible for much of the morbidity and mortality. COPD has a significant impact on quality of life for those living with the condition, and on local economies for those affected, those caring for the affected and health services. A population literally struggling for breath is, in consequence, unproductive. The majority of cases of chronic lung disease are preventable. Exposure reduction initiatives must focus on tobacco control, and cook-stove interventions: either cleaner fuel (ideally), or better ventilation (at the least). Awareness campaigns and health programmes have the potential to revolutionise the diagnosis and management of COPD and COPD exacerbations, improving quality of life and health service cost and burden. LMICs face unique challenges in managing COPD, including sub-optimal and diverse primary care systems which present challenges with diagnosis and management, especially during exacerbations. A better understanding of how to prevent, diagnose and manage COPD in both rural and urban settings would make a real difference in countries of need. Two important aspects to consider when addressing the global economic burden of COPD are that of underdiagnosis and comorbidities [4]. Firstly, COPD remains underdiagnosed in many jurisdictions [5]. Studies included in reviews focusing on the global economic burden of COPD are all based on diagnosed COPD, and a simple multiplication of these values by the number of COPD patients to calculate the overall economic burden of COPD will underestimate the contribution of undiagnosed COPD [5]. Secondly, COPD is known to be associated with a significant number of comorbid conditions, and estimating costs that are directly attributable to COPD fails to consider the burden of such comorbidities [4]. Adjusting for comorbidities by calculating excess costs with an appropriate comparison group can provide a better opportunity, but even this results in an underestimation of the costs of the comorbidities [6–8]. Global COPD statistics More than 90% of COPD-related deaths occur in LMICs [3]. According to the Global Burden of Disease (GBD), COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030 [9]. The economic impact of COPD among LMICs is expected to increase to £1.7 trillion by 2030 [10]. In 15 years, COPD is expected to become the leading cause of death worldwide [3]. Air pollution and HAP Air pollution is the biggest environmental cause of death worldwide, with HAP accounting for about 3.5–4 million deaths every year [11]. Extensive literature supports a causal association between HAP and chronic lung diseases [12], respiratory infections and respiratory tract cancers. One-third of the world's population, some three billion people use fuel derived from organic material (biomass) or solid fuel including coal, wood and charcoal as an energy source to heat and light their homes, and to cook. Respiratory morbidity relates to products of incomplete combustion such as carbon monoxide, and to particulate matter (PM). PM include both organic and inorganic particles, and represents the sum of all solid and liquid particles suspended in the air, many of which are hazardous. PM10 is the most widely used indicator of the health hazard of indoor air pollution. The EU and the US Environmental Protection Agency have set standards for annual mean PM10 levels in outdoor air at 40  and 50 µg/m3, respectively [13]. When burning solid fuels, peak levels of PM10 in biomass-using homes can be as high as 10 000 µg/m3, 200 times more than the standard in high-income countries. PM2.5 are finer particles which penetrate deep into the lung and have the greatest health-damaging potential. Pollutants are particularly damaging and of concern to children growing up in homes with HAP, the effect on the developing lung results in lung function that does not reach maximum potential. Household air pollution statistics Air pollution is the biggest environmental cause of death worldwide [14]. Three billion people worldwide are exposed to toxic amounts of HAP every day [11]. HAP accounts for up to four million deaths annually [11]. Smoking Tobacco is a legal drug which is currently responsible for the deaths of an estimated six million people across the world each year, with many of these deaths occurring prematurely [15]. Tobacco smoking is associated with morbidity and mortality from non-communicable respiratory diseases (NCDs), including about 600 000 people who are estimated to die every year from the effects of second-hand smoke [15]. The poor tend to smoke the most. Globally, 84% of smokers live in developing and transitional economy countries [16]. Tobacco smoke potentiates the detrimental effects of biomass smoke exposure. The WHO stated that in 2015, over 1.1 billion people smoked tobacco, males smoked tobacco more than females, and although it is declining worldwide and in many countries, the prevalence of tobacco smoking appears to be increasing in the Eastern Mediterranean and Africa [17]. Tobacco and smoking statistics Due to the incomplete combustion of formaldehyde and DEET, one mosquito coil burning for 8 h releases the same amount of PM2.5 as 100 cigarettes [18]. A 1 h hookah session with shisha tobacco is equivalent to smoking over 100 cigarettes [19]. Those who have never smoked tobacco can still get COPD – think ‘biomass COPD’. COPD: under-recognition and inequity There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD. TB, HIV/AIDS and malaria all compete for headlines and funds; COPD is rarely the headline. There is global under-recognition of COPD. This needs to change and we welcome recent initiatives highlighting unmet needs in NCDs. The United Nations (UN) declaration of NCDs, and the World Health Assembly in 2012, endorsed a new health goal (the ‘25 by 25 goal’), which focuses on the reduction of premature deaths from COPD and other NCDs by 25% by the year 2025 [20]. Many NCDs occur together in the context of multi-morbidity, yet despite this initiative, COPD remains a growing but neglected global epidemic. It is under-recognised, under-diagnosed and under-treated resulting in millions of people continuing to suffer from this preventable and treatable condition. The lower an individual's socio-economic position, the higher their risk of poor health: women and children living in severe poverty have the greatest exposures to HAP [21]. In the poorest countries, cooking with solid fuels can be the equivalent of smoking two packs of cigarettes a day [22]. A 1-year old would have accumulated a two pack year smoking history having never seen tobacco. Inaction to mitigate COPD therefore exacerbates health inequalities. Climbing the ‘energy ladder’ occurs gradually as most LMIC households use a combination of fuels. The poorest, at the bottom of the ladder, use crop waste or dung which is the most harmful when undergoing incomplete combustion. Those at the top of the ladder use electricity or natural gas. Increasing prosperity and development has a direct positive correlation with increasing use of cleaner and more efficient fuels for cooking [23]. The unmet global burden of COPD is a silent killer in LMICs. In conclusion, we suggest that given the high and rising global burden of COPD, a revolution in the diagnosis and management of COPD and exacerbations of COPD in LMICs must be an urgent priority. Summary An estimated 328 million people have COPD worldwide [3]. In 15 years, COPD is expected to become the leading cause of death worldwide [3]. Three billion people worldwide are exposed to toxic amounts of HAP every day and HAP accounts for 3.5–4 million deaths annually [11]. Those who have never smoked tobacco can still get COPD – think ‘biomass COPD’.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                COPD
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                02 July 2020
                2020
                : 15
                : 1577-1590
                Affiliations
                [1 ]Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle , Callaghan, NSW, Australia
                [2 ]Department of Respiratory and Sleep Medicine, John Hunter Hospital , Newcastle, NSW, Australia
                [3 ]Respiratory Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University , Chengdu, Sichuan Province, People’s Republic of China
                [4 ]School of Nursing and Midwifery, Faculty of Health and Medicine, The University of Newcastle , Callaghan, NSW, Australia
                Author notes
                Correspondence: Katherine J Baines Hunter Medical Research Institute , Level 2 West Wing, Locked Bag 1000, New Lambton, NSW2305, Australia Email katherine.baines@newcastle.edu.au
                Author information
                http://orcid.org/0000-0002-4240-6581
                http://orcid.org/0000-0002-7957-1409
                http://orcid.org/0000-0002-3626-680X
                http://orcid.org/0000-0001-5676-6126
                http://orcid.org/0000-0002-8587-1774
                http://orcid.org/0000-0001-9890-3408
                Article
                245519
                10.2147/COPD.S245519
                7337431
                32669843
                cb64feee-7f1a-4602-915a-797370b115c0
                © 2020 Baines 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 10 January 2020
                : 24 May 2020
                Page count
                Figures: 5, Tables: 5, References: 41, Pages: 14
                Categories
                Original Research

                Respiratory medicine
                copd,airway markers,inflammation,molecular biology,eosinophil
                Respiratory medicine
                copd, airway markers, inflammation, molecular biology, eosinophil

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