{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T11:30:39Z","timestamp":1791718239015,"version":"4.3.4"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T00:00:00Z","timestamp":1643932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["DRTB-HDT 847465"],"award-info":[{"award-number":["DRTB-HDT 847465"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1127276-2015"],"award-info":[{"award-number":["OPP1127276-2015"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["ACT4TB\/HIV"],"award-info":[{"award-number":["ACT4TB\/HIV"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent\n                      <jats:sup>18<\/jats:sup>\n                      F-fluorodeoxyglucose positron emission tomography\/computed tomography (PET\/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in\n                      <jats:italic>ex vivo<\/jats:italic>\n                      whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All PET\/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in\n                      <jats:italic>ex-vivo<\/jats:italic>\n                      culture was enhanced by auranofin compared to controls, but not by other HDTs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0252097","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T13:26:00Z","timestamp":1643981160000},"page":"e0252097","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6152-5183","authenticated-orcid":true,"given":"Robert S.","family":"Wallis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibuse","family":"Ginindza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Beattie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishanee","family":"Arjun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morongwe","family":"Likoti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4330-5499","authenticated-orcid":true,"given":"Modulakgotla","family":"Sebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-4760","authenticated-orcid":true,"given":"Vinodh A.","family":"Edward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Rassool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khatija","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Fielding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bintou A.","family":"Ahidjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mboyo D. T.","family":"Vangu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Churchyard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"pone.0252097.ref001","unstructured":"Global tuberculosis report. Geneva: 2019 WHO\/CDS\/TB\/2019.15."},{"issue":"3","key":"pone.0252097.ref002","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0954-6111(89)80031-9","article-title":"Chronic obstructive airways disease following treated pulmonary tuberculosis","volume":"83","author":"PA Willcox","year":"1989","journal-title":"Respir Med"},{"issue":"5","key":"pone.0252097.ref003","doi-asserted-by":"crossref","first-page":"e613","DOI":"10.1016\/S2214-109X(19)30070-1","article-title":"Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): an international, community-based cohort study","volume":"7","author":"M Duong","year":"2019","journal-title":"Lancet Glob Health"},{"issue":"10","key":"pone.0252097.ref004","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/S1473-3099(19)30309-3","article-title":"Long-term all-cause mortality in people treated for tuberculosis: a systematic review and meta-analysis","volume":"19","author":"K Romanowski","year":"2019","journal-title":"Lancet Infect Dis"},{"issue":"1","key":"pone.0252097.ref005","doi-asserted-by":"crossref","first-page":"43","DOI":"10.5588\/ijtld.14.0427","article-title":"Mortality after anti-tuberculosis treatment completion: results of long-term follow-up","volume":"20","author":"J Shuldiner","year":"2016","journal-title":"Int J Tuberc Lung Dis"},{"issue":"4","key":"pone.0252097.ref006","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nri3813","article-title":"Advancing host-directed therapy for tuberculosis","volume":"15","author":"RS Wallis","year":"2015","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"pone.0252097.ref007","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S1473-3099(13)70034-3","article-title":"Tuberculosis biomarkers discovery: developments, needs, and challenges","volume":"13","author":"RS Wallis","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"pone.0252097.ref008","article-title":"Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial","author":"RS Wallis","year":"2021","journal-title":"Lancet Respir Med"},{"issue":"5","key":"pone.0252097.ref009","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1097\/01.rlu.0000259570.69163.04","article-title":"Low-dose oral propranolol could reduce brown adipose tissue F-18 FDG uptake in patients undergoing PET scans","volume":"32","author":"O Parysow","year":"2007","journal-title":"Clin Nucl Med"},{"issue":"5","key":"pone.0252097.ref010","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1086\/655471","article-title":"Pharmacokinetics and whole blood bactericidal activity against Mycobacterium tuberculosis of single ascending doses of PNU-100480 in healthy volunteers","volume":"202","author":"RS Wallis","year":"2010","journal-title":"J Infect Dis"},{"issue":"Suppl 1","key":"pone.0252097.ref011","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1093\/clinids\/22.Supplement_1.S15","article-title":"The clinical pharmacokinetics of rifabutin","volume":"22","author":"TF Blaschke","year":"1996","journal-title":"Clin Infect Dis"},{"key":"pone.0252097.ref012","article-title":"Adjunctive host-directed therapies for pulmonary tuberculosis: A randomized, open-label phase 2 trial","author":"RS Wallis","year":"2021","journal-title":"Lancet Respir Med"},{"issue":"579","key":"pone.0252097.ref013","doi-asserted-by":"crossref","first-page":"eabd7618","DOI":"10.1126\/scitranslmed.abd7618","article-title":"Fourteen-day PET\/CT imaging to monitor drug combination activity in treated individuals with tuberculosis","volume":"13","author":"YL Xie","year":"2021","journal-title":"Science Translational Medicine"},{"issue":"265","key":"pone.0252097.ref014","first-page":"265ra166","article-title":"PET\/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis","volume":"6","author":"RY Chen","year":"2014","journal-title":"Sci Transl Med"},{"issue":"10","key":"pone.0252097.ref015","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/nm.4177","article-title":"Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure","volume":"22","author":"ST Malherbe","year":"2016","journal-title":"Nat Med"},{"issue":"2","key":"pone.0252097.ref016","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.molcel.2010.09.026","article-title":"Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress","volume":"40","author":"S Sengupta","year":"2010","journal-title":"Mol Cell"},{"issue":"17","key":"pone.0252097.ref017","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1093\/eurheartj\/ehi237","article-title":"C-reactive protein in the prediction of cardiovascular and overall mortality in middle-aged men: a population-based cohort study","volume":"26","author":"DE Laaksonen","year":"2005","journal-title":"Eur Heart J"},{"issue":"1","key":"pone.0252097.ref018","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1161\/CIRCULATIONAHA.104.504159","article-title":"C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study","volume":"112","author":"M Cushman","year":"2005","journal-title":"Circulation"},{"issue":"14","key":"pone.0252097.ref019","doi-asserted-by":"crossref","first-page":"4453","DOI":"10.1073\/pnas.1504022112","article-title":"Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis","volume":"112","author":"MB Harbut","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0252097.ref020","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.virol.2020.05.002","article-title":"The FDA-approved gold drug auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells","volume":"547","author":"HA Rothan","year":"2020","journal-title":"Virology"},{"issue":"12","key":"pone.0252097.ref021","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1136\/thx.35.12.884","article-title":"The gold rush 1925\u201335","volume":"35","author":"RY Keers","year":"1980","journal-title":"Thorax"},{"key":"pone.0252097.ref022","first-page":"401","article-title":"A clinical trial of sanocrysin in pulmonary tuberculosis","volume":"24","author":"JB Amberson","year":"1931","journal-title":"Am Rev Tuberc"},{"issue":"5","key":"pone.0252097.ref023","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/j.1875-9114.1983.tb03277.x","article-title":"Mechanism of action, pharmacology, clinical efficacy and side effects of auranofin. An orally administered organic gold compound for the treatment of rheumatoid arthritis","volume":"3","author":"DE Furst","year":"1983","journal-title":"Pharmacotherapy"},{"issue":"8","key":"pone.0252097.ref024","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1086\/319679","article-title":"A whole blood bactericidal assay for tuberculosis","volume":"183","author":"RS Wallis","year":"2001","journal-title":"J Infect Dis"},{"key":"pone.0252097.ref025","first-page":"1","volume-title":"Antituberculosis Chemotherapy Progressin Respiratory Research","author":"RS Wallis","year":"2011"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0252097","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T13:26:23Z","timestamp":1643981183000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0252097"}},"subtitle":[],"editor":[{"given":"Christophe","family":"Leroyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,4]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0252097","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,4]]}}}