{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:36:46Z","timestamp":1790631406928,"version":"4.1.0"},"reference-count":18,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"bundesministerium f\u00fcr bildung und forschung","doi-asserted-by":"publisher","award":["2020 62 156"],"award-info":[{"award-number":["2020 62 156"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011723","name":"canton de gen\u00e8ve","doi-asserted-by":"publisher","award":["convention 2020"],"award-info":[{"award-number":["convention 2020"]}],"id":[{"id":"10.13039\/501100011723","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosglobalpublichealth.org"],"crossmark-restriction":false},"short-container-title":["PLOS Glob Public Health"],"abstract":"<jats:p>Therapeutic efficacy in COVID-19 is dependent upon disease severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation \u2018living\u2019 guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24\/68) of trials. Of the RCTs evaluated, 69% (55\/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and\/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of \u201clack of therapeutic benefit\u201d shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data (IPD) meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. Achieving this goal will require improved coordination of the main stakeholders developing treatment guidelines and medicine regulatory agencies. Open science, including prompt data sharing, should become the standard to allow IPD meta-analyses.<\/jats:p>","DOI":"10.1371\/journal.pgph.0000561","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T13:24:04Z","timestamp":1658237044000},"page":"e0000561","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgph.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Definitions matter: Heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis"],"prefix":"10.1371","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6008-2963","authenticated-orcid":true,"given":"Philippe J.","family":"Gu\u00e9rin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3449-7142","authenticated-orcid":true,"given":"Alistair R. D.","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-9639","authenticated-orcid":true,"given":"Sumayyah","family":"Rashan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0530-9157","authenticated-orcid":true,"given":"AbdulAzeez","family":"Lawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5524-0325","authenticated-orcid":true,"given":"James A.","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Strub-Wourgaft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1897-1978","authenticated-orcid":true,"given":"Nicholas J.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"issue":"1","key":"pgph.0000561.ref001","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/S2666-5247(20)30172-5","article-title":"SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis","volume":"2","author":"M Cevik","year":"2021","journal-title":"Lancet Microbe"},{"issue":"5","key":"pgph.0000561.ref002","first-page":"493","article-title":"COVID-19: The therapeutic landscape","volume":"2","author":"CI Paules","year":"2021","journal-title":"Med (N Y)"},{"issue":"9","key":"pgph.0000561.ref003","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/psp4.12543","article-title":"Timing of Antiviral Treatment Initiation is Critical to Reduce SARS-CoV-2 Viral Load","volume":"9","author":"A Gon\u00e7alves","year":"2020","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"pgph.0000561.ref004","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3389\/fimmu.2020.01441","article-title":"Immune Response, Inflammation, and the Clinical Spectrum of COVID-19","volume":"11","author":"LF Garc\u00eda","year":"2020","journal-title":"Front Immunol"},{"issue":"8","key":"pgph.0000561.ref005","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJMoa2021436","article-title":"Dexamethasone in Hospitalized Patients with Covid-19","volume":"384","author":"The RECOVERY Collaborative Group","year":"2021","journal-title":"N Engl J Med"},{"key":"pgph.0000561.ref006","doi-asserted-by":"crossref","first-page":"m2980","DOI":"10.1136\/bmj.m2980","article-title":"Drug treatments for covid-19: living systematic review and network meta-analysis","volume":"370","author":"RA Siemieniuk","year":"2020","journal-title":"BMJ"},{"issue":"10","key":"pgph.0000561.ref007","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1056\/NEJMoa2033130","article-title":"A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19","volume":"384","author":"ACTIV-3\/TICO LY-CoV555 Study Group","year":"2021","journal-title":"N Engl J Med"},{"issue":"3","key":"pgph.0000561.ref008","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1056\/NEJMoa2029849","article-title":"SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19","volume":"384","author":"P Chen","year":"2021","journal-title":"N Engl J Med"},{"key":"pgph.0000561.ref009","first-page":"m3379","article-title":"A living WHO guideline on drugs for covid-19","volume":"370","author":"B Rochwerg","year":"2020","journal-title":"BMJ"},{"issue":"11","key":"pgph.0000561.ref010","first-page":"CD013769","article-title":"Interventions for the prevention and treatment of COVID\u201019: a living mapping of research and living network meta\u2010analysis","author":"I Boutron","year":"2020","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"pgph.0000561.ref011","unstructured":"The COVID-NMA initiative A living mapping and living systematic review of Covid-19 trials [Available from: https:\/\/covid-nma.com\/ accessed 21\/05\/2021]."},{"issue":"11","key":"pgph.0000561.ref012","doi-asserted-by":"crossref","first-page":"e4073","DOI":"10.1093\/cid\/ciaa1009","article-title":"Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial","volume":"73","author":"O Mitj\u00e0","year":"2021","journal-title":"Clin Infect Dis"},{"key":"pgph.0000561.ref013","doi-asserted-by":"crossref","unstructured":"Mitj\u00e0 O, Corbacho M, Teb\u00e9 C, Tobias A, Ballana E, Mitj\u00e0 J et al. Hydroxychloroquine alone or in combination with Cobicistat-boosted Darunavir for treatment of mild Covid-19: a cluster-randomized clinical trial. 2020. [Available at SSRN: https:\/\/ssrn.com\/abstract=3615997] https:\/\/doi.org\/10.2139\/ssrn.3615997.","DOI":"10.2139\/ssrn.3615997"},{"key":"pgph.0000561.ref014","volume-title":"Clinical management of COVID-19: interim guidance","author":"WHO","year":"2020"},{"key":"pgph.0000561.ref015","volume-title":"IMAI district clinician manual. Hospital care for adolescents and adults. 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[version 1; peer review: 1 approved]","volume":"7","author":"ARD McLean","year":"2022","journal-title":"Wellcome Open Res"}],"updated-by":[{"DOI":"10.1371\/journal.pgph.0001808","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000}}],"container-title":["PLOS Global Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgph.0000561","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T13:24:22Z","timestamp":1658237062000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgph.0000561"}},"subtitle":[],"editor":[{"given":"PLOS Manuscript","family":"Reassignment","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,7,19]]},"references-count":18,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgph.0000561","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.04.21257852","asserted-by":"object"}]},"ISSN":["2767-3375"],"issn-type":[{"value":"2767-3375","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,19]]}}}