{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T21:43:08Z","timestamp":1779918188307,"version":"3.53.1"},"reference-count":43,"publisher":"BMJ","issue":"1","funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline plc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open Resp Res"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:sec>\n                  <jats:title>Rationale<\/jats:title>\n                  <jats:p>Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Relate systemic levels of those proteins to forced expiratory volume in 1\u2009s (FEV<jats:sub>1<\/jats:sub>) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV<jats:sub>1<\/jats:sub> of \u226550\u2009and \u226470% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Participants were randomised to daily inhalations of placebo, vilanterol 25 \u00b5g (VI), fluticasone furoate 100 \u00b5g (FF) or their combination (VI 25\/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV<jats:sub>1<\/jats:sub> decline (mL\/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV<jats:sub>1<\/jats:sub>, FEV<jats:sub>1<\/jats:sub> decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF\/VI, p&lt;0.01) at 3 months.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV<jats:sub>1<\/jats:sub> decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01313676\">NCT01313676<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjresp-2019-000431","type":"journal-article","created":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T09:35:43Z","timestamp":1557135343000},"page":"e000431","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial"],"prefix":"10.1136","volume":"6","clinical-trial-number":[{"clinical-trial-number":"nct01313676","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7266-8371","authenticated-orcid":false,"given":"Bartolome R","family":"Celli","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Anderson","sequence":"additional","affiliation":[{"name":"Research & Development, GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Brook","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Calverley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Clinical Sciences Centre, University of Liverpool, University Hospital Aintree, Liverpool, Liverpool, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Cowans","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK"},{"name":"Veramed Ltd, Twickenham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Crim","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Dixon","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK"},{"name":"Veramed Ltd, Twickenham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando J","family":"Martinez","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine Samuel J Wood Library, New York City, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Morris","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Newby","sequence":"additional","affiliation":[{"name":"British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Yates","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joergen","family":"Vestbo","sequence":"additional","affiliation":[{"name":"Division of Infection, Immunity and Respiratory Medicine and Allergy, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2019,5,4]]},"reference":[{"key":"2025083110424168000_6.1.e000431.1","doi-asserted-by":"publisher","DOI":"10.1111\/resp.12660"},{"key":"2025083110424168000_6.1.e000431.2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201501-0044ST"},{"key":"2025083110424168000_6.1.e000431.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201009-1414PP"},{"key":"2025083110424168000_6.1.e000431.4","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00153207"},{"key":"2025083110424168000_6.1.e000431.5","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0037483","article-title":"Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype","volume":"7","author":"Agust\u00ed","year":"2012","journal-title":"PLoS One"},{"key":"2025083110424168000_6.1.e000431.6","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200605-713OC"},{"key":"2025083110424168000_6.1.e000431.7","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1164\/rccm.201509-1722PP","article-title":"Plasma fibrinogen qualification as a drug development tool in COPD: perspective of the COPD biomarker qualification Consortium","volume":"193","author":"Miller","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"2025083110424168000_6.1.e000431.8","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201110-1792OC"},{"key":"2025083110424168000_6.1.e000431.9","doi-asserted-by":"publisher","DOI":"10.2174\/1389450111314020005"},{"key":"2025083110424168000_6.1.e000431.10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200510-1659PP"},{"key":"2025083110424168000_6.1.e000431.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105482"},{"key":"2025083110424168000_6.1.e000431.12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201305-0892OC"},{"key":"2025083110424168000_6.1.e000431.13","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00682-2015"},{"key":"2025083110424168000_6.1.e000431.14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S2213-2600(13)70006-7","article-title":"The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the eclipse study","volume":"1","author":"Coxson","year":"2013","journal-title":"Lancet Respir Med"},{"key":"2025083110424168000_6.1.e000431.15","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201302-0247OC"},{"key":"2025083110424168000_6.1.e000431.16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201206-1013OC"},{"key":"2025083110424168000_6.1.e000431.17","unstructured":"Adamson PD , Anderson JA , Cowans NJ , et al . Cardiac troponin I and risk of cardiovascular events in patients with COPD and heightened cardiovascular risk. J Am Coll Cardiol. In Press 2018."},{"key":"2025083110424168000_6.1.e000431.18","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00087312"},{"key":"2025083110424168000_6.1.e000431.19","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1016\/S0140-6736(16)30069-1","article-title":"Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (Summit): a double-blind randomised controlled trial","volume":"387","author":"Vestbo","year":"2016","journal-title":"Lancet"},{"key":"2025083110424168000_6.1.e000431.20","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.159.1.9712108"},{"key":"2025083110424168000_6.1.e000431.21","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0158843","article-title":"A systematic review of diagnostic biomarkers of COPD exacerbation","volume":"11","author":"Chen","year":"2016","journal-title":"PLoS One"},{"key":"2025083110424168000_6.1.e000431.22","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1513\/AnnalsATS.201710-770WS","article-title":"New strategies and challenges in lung proteomics and metabolomics. An official American Thoracic Society workshop report","volume":"14","author":"Bowler","year":"2017","journal-title":"Ann Am Thorac Soc"},{"key":"2025083110424168000_6.1.e000431.23","doi-asserted-by":"crossref","unstructured":"Bradford E , Jacobson S , Varasteh J , et al . The value of blood cytokines and chemokines in assessing COPD. Respir Res 2017;18.doi:10.1186\/s12931-017-0662-2","DOI":"10.1186\/s12931-017-0662-2"},{"key":"2025083110424168000_6.1.e000431.24","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2005.042200"},{"key":"2025083110424168000_6.1.e000431.25","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200604-506OC"},{"key":"2025083110424168000_6.1.e000431.26","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00109605"},{"key":"2025083110424168000_6.1.e000431.27","doi-asserted-by":"publisher","DOI":"10.1378\/chest.103.1.196"},{"key":"2025083110424168000_6.1.e000431.28","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.5732"},{"key":"2025083110424168000_6.1.e000431.29","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.164.6.2010067"},{"key":"2025083110424168000_6.1.e000431.30","doi-asserted-by":"crossref","unstructured":"Agusti A , Calverley PMA , Celli B , et al . Characterisation of COPD heterogeneity in the eclipse cohort. Respir Res 2010;11.doi:10.1186\/1465-9921-11-122","DOI":"10.1186\/1465-9921-11-122"},{"key":"2025083110424168000_6.1.e000431.31","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00156508"},{"key":"2025083110424168000_6.1.e000431.32","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2008.102574"},{"key":"2025083110424168000_6.1.e000431.33","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/180682"},{"key":"2025083110424168000_6.1.e000431.34","doi-asserted-by":"crossref","unstructured":"Miniati M , Monti S , Basta G , et al . Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study. Respir Res 2011;12.doi:10.1186\/1465-9921-12-37","DOI":"10.1186\/1465-9921-12-37"},{"key":"2025083110424168000_6.1.e000431.35","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2016.1139084"},{"key":"2025083110424168000_6.1.e000431.36","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.2.9901044"},{"key":"2025083110424168000_6.1.e000431.37","first-page":"129","article-title":"Improved risk stratification of patients with acute coronary syndromes using a combination of hsTnT, NT-proBNP and hsCRP with the grace score","volume":"7","author":"Klingenberg","year":"2018","journal-title":"Eur Heart J Acute Cardiovasc Care"},{"key":"2025083110424168000_6.1.e000431.38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107477"},{"key":"2025083110424168000_6.1.e000431.39","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1007\/s10753-013-9625-z","article-title":"C-reactive protein measurements as a marker of the severity of chronic obstructive pulmonary disease exacerbations","volume":"36","author":"Karadeniz","year":"2013","journal-title":"Inflammation"},{"key":"2025083110424168000_6.1.e000431.40","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200404-543OC"},{"key":"2025083110424168000_6.1.e000431.41","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00023907"},{"key":"2025083110424168000_6.1.e000431.42","doi-asserted-by":"crossref","unstructured":"Dickens JA , Miller BE , Edwards LD , et al . COPD association and repeatability of blood biomarkers in the eclipse cohort. Evaluation of COPD longitudinally to identify surrogate endpoints (eclipse) Study Investigators. Respir Res 2011;12.","DOI":"10.1186\/1465-9921-12-146"},{"key":"2025083110424168000_6.1.e000431.43","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1513\/pats.200603-030MS","article-title":"Use of proteomic patterns of serum biomarkers in patients with chronic obstructive pulmonary disease: correlation with clinical parameters","volume":"3","author":"Pinto-Plata","year":"2006","journal-title":"Proc Am Thorac Soc"}],"container-title":["BMJ Open Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjresp-2019-000431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,31]],"date-time":"2025-08-31T17:42:52Z","timestamp":1756662172000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopenrespres.bmj.com\/lookup\/doi\/10.1136\/bmjresp-2019-000431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,5,4]]},"published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1136\/bmjresp-2019-000431"],"URL":"https:\/\/doi.org\/10.1136\/bmjresp-2019-000431","relation":{},"ISSN":["2052-4439"],"issn-type":[{"value":"2052-4439","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5]]}}}