Medicine, Faculty of
Non UBC
Population and Public Health (SPPH), School of
DSpace
UBCV
Khalili M, Chegeni M, Javadi S, Farokhnia M, Sharifi H. Karamouzian, M. (12/2020)Therapeutic interventions for COVID-19: A living overview of reviews. Therapeutic advances in respiratory disease. 14:1753466620976021.
Authors
Khalili, Malahat
Chegeni, Maryam
Javadi, Sara
Farokhnia, Mehrdad
Sharifi, Hamid
Karamouzian, Mohammad
Background: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, but safe and effective treatment options remain unavailable. Numerous systematic reviews of varying qualities have tried to summarize the evidence on the available therapeutic interventions for COVID-19. This overview of reviews aims to provide a succinct summary of the findings of systematic reviews on different pharmacological and non-pharmacological therapeutic interventions for COVID-19. Methods: We searched PubMed, Embase, Google Scholar, Cochrane Database of Systematic Reviews, and WHO database of publications on COVID-19 from 1 December 2019 through to 11 June 2020 for peer-reviewed systematic review studies that reported on potential pharmacological or non-pharmacological therapies for COVID-19. Quality assessment was completed using A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2) measure. Results: Out of 816 non-duplicate studies, 45 were included in the overview. Antiviral and antibiotic agents, corticosteroids, and anti-malarial agents were the most common drug classes used to treat COVID-19; however, there was no direct or strong evidence to support their efficacy. Oxygen therapy and ventilatory support was the most common non-pharmacological supportive care. The quality of most of the included reviews was rated as low or critically low. Conclusion: This overview of reviews demonstrates that although some therapeutic interventions may be beneficial to specific subgroups of COVID-19 patients, the available data are insufficient to strongly recommend any particular treatment option to be used at a population level. Future systematic reviews on COVID-19 treatments should adhere to the recommended systematic review methodologies and ensure that promptness and comprehensiveness are balanced.
https://doi.org/10.1177/1753466620976021 https://doi.org/10.1177/1753466620976021Therapeutic Advances in Respiratory Diseasejournals.sagepub.com/home/tar 1Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Ther Adv Respir Dis2020, Vol. 14: 1–34DOI: 10.1177/ 1753466620976021© The Author(s), 2020. Article reuse guidelines: sagepub.com/journals-permissionsIntroductionSevere acute respiratory coronavirus 2 (SARS-CoV-2) was first detected in patients linked with Wuhan’s wet markets, but soon grew out of China and the coronavirus disease 2019 (COVID-19) was declared a pandemic on 11 March 2020.1 Healthcare systems worldwide have been over-whelmed and continue to struggle with the soar-ing number of patients, limited supplies of personal protective equipment (PPE), and venti-lators. Based on the existing evidence, the risk is relatively low for the general population, although elderly populations, immunocompromised peo-ple, and those with pre-existing medical condi-tions are at an increased risk of adverse outcomes.2,3 As of 5 October 2020, 35,330,119 COVID-19 patients have been detected, 1,038,958 of whom have died and 24,564,100 have recovered;4 figures that are most likely underestimated due to the lim-ited number of SARS-CoV-2 tests completed, inadequate confidence in the sensitivity and speci-ficity of diagnostic testing, and various systems of case reporting and recovery definitions across the world.5Therapeutic interventions for COVID-19: a living overview of reviewsMalahat Khalili , Maryam Chegeni, Sara Javadi, Mehrdad Farokhnia, Hamid Sharifi and Mohammad KaramouzianAbstractBackground: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, but safe and effective treatment options remain unavailable. Numerous systematic reviews of varying qualities have tried to summarize the evidence on the available therapeutic interventions for COVID-19. This overview of reviews aims to provide a succinct summary of the findings of systematic reviews on different pharmacological and non-pharmacological therapeutic interventions for COVID-19.Methods: We searched PubMed, Embase, Google Scholar, Cochrane Database of Systematic Reviews, and WHO database of publications on COVID-19 from 1 December 2019 through to 11 June 2020 for peer-reviewed systematic review studies that reported on potential pharmacological or non-pharmacological therapies for COVID-19. Quality assessment was completed using A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2) measure.Results: Out of 816 non-duplicate studies, 45 were included in the overview. Antiviral and antibiotic agents, corticosteroids, and anti-malarial agents were the most common drug classes used to treat COVID-19; however, there was no direct or strong evidence to support their efficacy. Oxygen therapy and ventilatory support was the most common non-pharmacological supportive care. The quality of most of the included reviews was rated as low or critically low.Conclusion: This overview of reviews demonstrates that although some therapeutic interventions may be beneficial to specific subgroups of COVID-19 patients, the available data are insufficient to strongly recommend any particular treatment option to be used at a population level. Future systematic reviews on COVID-19 treatments should adhere to the recommended systematic review methodologies and ensure that promptness and comprehensiveness are balanced.The reviews of this paper are available via the supplemental material section.Keywords: COVID-19, pandemic, review, therapeuticsReceived: 17 August 2020; revised manuscript accepted: 21 October 2020.Correspondence to: Mohammad Karamouzian School of Population and Public Health, University of British Columbia, 2206 E Mall, Vancouver, BC V6T 1Z3, CanadaKaramouzian.m@alumni.ubc.caMalahat Khalili Maryam Chegeni Sara Javadi Hamid Sharifi HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, IranMehrdad Farokhnia Department of Internal Medicine, Faculty of Medicine, Afzalipour Hospital, Kerman University of Medical School, Kerman, Iran976021 TAR0010.1177/1753466620976021Therapeutic Advances in Respiratory DiseaseM Khalili, M Chegeniresearch-article20202020Systematic ReviewTherapeutic Advances in Respiratory Disease 142 journals.sagepub.com/home/tarThe current evidence suggests that most COVID-19 patients may remain asymptomatic or experi-ence mild clinical symptoms that require no specific treatments. Severe cases, however, suffer from a range of life-threatening conditions such as pneumonia, acute respiratory distress syndrome (ARDS),6 and respiratory failure.3,7 To date, highly effective treatments for COVID-19 are unavailable;8 however, numerous trials and stud-ies have been conducted and are ongoing to develop and assess various pharmacological and non-pharmacological therapeutic options for the treatment and prevention of COVID-19.9,10 As of 5 October 2020, 3507 clinical trials have been reg-istered on ClinicalTrials.gov11 and the effective-ness of several classes of drugs such as antiviral, antibiotic, antimalarial agents, and corticosteroids are being investigated.11Given the urgency of the issue and the novelty of the disease, numerous systematic reviews of vary-ing qualities and scope have tried to summarize the evidence on available therapeutic interven-tions for COVID-19; papers that have been pub-lished in several journals over a very short time. While these review papers are helpful, the over-whelming amount of information and the unprec-edented number of COVID-19-related evidence syntheses of unclear quality, create challenges for policymakers and healthcare providers to sift through relevant and reliable research findings. This living overview of reviews aims to provide a succinct summary of the findings of peer-reviewed systematic reviews on different pharmacological and non-pharmacological therapeutic options for COVID-19, and assess the methodological and reporting quality of the existing systematic reviews.MethodsThe living overview of systematic reviews was guided by the methodological guidance on the conduct of overviews of reviews published by the Cochrane collaboration12 and other recently developed guidelines.13,14 Inclusion criteria and analytical approaches were designed a priori and are documented in a protocol published in the Open Science Framework (https://osf.io/sby9u/).Databases and search strategyFollowing the peer review of electronic search strate-gies guidelines,15 we searched PubMed, Embase, Google Scholar, Cochrane Database of Systematic Reviews, and WHO database of publications on COVID-19 from 1 December 2019 through to 11 June 2020, for peer-reviewed review studies that synthesized and reported on potential pharmaco-logical or non-pharmacological therapies for COVID-19. Search terms were combined using appropriate Boolean operators, and included subject heading terms and keywords relevant to COVID-19 and different treatment approaches. We also screened the reference lists of the included articles. Preprint papers that had not gone through peer review were excluded, given their potential for mis-informing our conclusions. The live nature of our overview allows for relevant publications to be added to our body of evidence as they become visible in peer-reviewed journals. A detailed overview of the search strategy is provided in Supplemental Table 1.Inclusion criteriaSystematic reviews, scoping reviews, and rapid reviews that summarized and synthesized primary studies about the effectiveness of pharmacologi-cal and non-pharmacological treatments for peo-ple with a confirmed diagnosis of COVID-19 using real-time reverse transcription polymerase chain reaction (RT-PCR), nasal/pharyngeal swabs, or other prespecified diagnostic approaches such as clinical or radiological findings were included in this overview. Studies on children or pregnant women were not excluded. Interventions could be of any duration, delivery, frequency, and inten-sity. Reviews were eligible if they provided an explicit description of inclusion criteria and included a systematic search of at least one elec-tronic database. Letters, commentaries, expert opinion, theoretical and unstructured reviews as well as narrative reviews not meeting the above-mentioned eligibility criteria were excluded. Studies were not excluded based on language, and records published in languages other than English were assessed for eligibility using Google Translate (https://translate.google.com/).Study selectionTwo authors (MKH and MC) completed the title and abstract screening, independently. Citations that met our eligibility criteria or were unclear, were screened at full text by two independent reviewers (MKH and MC). Disagreements over the inclusion of studies were resolved through discussion or arbitration with the senior author (MK). Duplicate records were excluded.M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 3Table 1. Characteristics of the included studies in the overview of reviews.AuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesLiu et al.203 June 2020Canadian Medical Association JournalJIF = 7.7Authors should follow PRISMA guidelines.SR & MAMEDLINE, Embase, CENTRAL, Clinical-Trials.gov, PubMed, CNKI, Wanfang Data, SinoMed, Chongqing VIP Information, medRxiv, and Chinaxiv.19 April 2020835519 (12 on COVID-19)4127(Including 1931 for COVID-19)Mean: 41.059.3%7 RCTs, 11 Cohort, 1 Case controlQu et al.2129 May 2020Stem Cells Translational MedicineJIF = 5.980SRMEDLINE, Embase, CENTRAL, Clinical-Trials.gov, Cochrane Database of Systematic Reviews, and Scopus.31 March 202026919 (1 on COVID-19)200(Including 10 for COVID-19)Mean: 59.4NR1 Phase I clinical trialDas et al.2228 May 2020Clinical Drug InvestigationJIF = 2.158Authors should follow PRISMA guidelines.SRPubMed, Embase, ClinicalTrials.gov, ICTRP, Cochrane Library, medRxiv, and Research Square.10 May 2020663123543Mean: 44.058.1%4 Prospective observational studies, 4 Retrospective observational studies, 4 RCTsFajgenbaum et al.2327 May 2020Infectious Diseases and TherapyJIF = 0Authors should follow PRISMA guidelines.SRPubMed, bioRxiv, medRxiv, and ChinaXiv.27 March 202027111569152Mean: 44.454.6%84 Case reports, 72 Case seriesYe et al.2427 May 2020Canadian Medical Association JournalJIF = 7.7Authors should follow PRISMA guidelines.SR & MAMEDLINE, Embase, PubMed, CENTRAL, ClinicalTrials.gov, medRxiv, CNKI, Wanfang Data, Chongqing VIP Information, and ChinaXiv.19 April 2020512011 (6 on COVID-19)8473(Including 763 for COVID-19)NRNR10 Cohort, 1 RCTHernandez et al.2527 May 2020Annals of Internal MedicineJIF = 19.315Authors should follow PRISMA guidelines.SRPubMed, Embase, Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, Clinical Trials.gov, ICTRP, and Chinese Clinical Trials Registry.8 May 2020838235499Range of mean: 44–69Range: 42–100%4 RCTs, 10 Cohort studies, 9 Case series(Continued)Therapeutic Advances in Respiratory Disease 144 journals.sagepub.com/home/tarAuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesRodrigo et al.2626 May 2020Clinical Microbiology and InfectionJIF = 6.425Authors should follow PRISMA guidelines.SRPubMed, Embase, Scopus, Web of Science, CENTRAL, Chinese Clinical Trials Registry, and medRxiv.3 April 2020226719 (6 on COVID-19)NR.NRNR17 RCTs, 2 ProspectivestudiesJorgensen et al.2723 May 2020PharmacotherapyJIF = 3.196Authors should follow PRISMA guidelines.SRPubMed.5 May 2020NR671NRNR1 Case series, 5 Case reportAng et al.2823 May 2020Journal of Clinical MedicineJIF = 5.688Authors should follow PRISMA guidelines.SR & MAPubMed, Embase, Allied and Complementary Medicine Database, CENTRAL, Chinese National Knowledge Infrastructure Database, Chinese Science and Technique Journals Database, CBM, Wanfang Data, Korean Association of Medical Journal database, Korean Medical database, Research Information Service System, and OASIS database.12 May 202020277855Mean: 51.155.2%7 RCTsSchunemann et al.2922 May 2020Annals of Internal MedicineJIF = 19.315Authors should follow PRISMA guidelines.SR & MAMEDLINE, PubMed, Embase, CINAHL, Cochrane Library, COVID-19 Open Research Dataset, COVID-19 Research Database maintained, Epistemonikos, ClinicalTrials.gov, U.S. National Library of Medicine’s register of clinical trials, and ICTRP.1 May 202038942123(45 on COVID-19)NRNRNR57 Case series, 24 Cohort, 2 Case control, 2 Case studies, 1 Cost study, 9 Retrospective studies, 1 RCTTable 1. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 5AuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesAntwi-Amoabeng et al.3021 May 2020Journal of Medical VirologyJIF = 2.049Invited reviews only.SRPubMed, Embase, and MEDLINE.27 April3521129Mean: 6382.8%4 Case series, 7 Case reportsTahvildari et al.3115 May 2020Frontiers in MEDICINEJIF = 3.113Authors should follow PRISMA guidelines.SRPubMed, Embase, Web of Science, and Cochrane Library.24 April 202011023499Mean: 46.247.7%23 Case reports, 11 Case seriesValk et al.3214 May 2020Cochrane database of systematic reviewsJIF = 7.755Cochrane Reviews are prepared by author teams who work with Cochrane Review Group.RRWHO COVID-19 Global Research Database, MEDLINE, Embase, PubMed, Center for Disease Control and Prevention COVID-19 Research Article Database, Cochrane COVID-19 Study Register, ClinicalTrials.gov, and ICTRP.23 April 20201267832NRNR7 Case series, 1 Clinical trialZhang et al.3314 May 2020Clinical Infectious DiseasesJIF = 9.117SR & MAMEDLINE, Embase, CENTRAL, and PubMed.15 March 20201481454203Mean: 4566.5%Non-randomized, Retrospective observational studiesLiu et al.3412 May 2020Pharmacological ResearchJIF = 5.574Review articles and MAs are welcome but should be topical and not just an overview of the literature.SR & MAPubMed, Embase, Cochrane Library, CNKI, Wanfang Data, and CBM.24 March 2020121211982NR58.5%4 RCTs, 7 Case-Control StudiesSingh et al.3512 May 2020Diabetes & Metabolic SyndromeJIF = 0SRPubMed, ClinicalTrial.org, and medRxiv.5 May 2020NR111778NRNR3 Case studies, 4 Clinical trials, 4 Ongoing RCTsTable 1. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 146 journals.sagepub.com/home/tarAuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesGbinigie and Frie1012 May 2020BJGP OpenJIF = 0Invited reviews only; Authors should follow PRISMA guidelines.RRPubMed, TRIP Database, EPPI COVID Living Map, medRxiv, Google Scholar, and Google.16 April 202023033645.0NR2 in vitro; 1 RCTSingh et al.3612 May 2020Diabetes & Metabolic SyndromeJIF = 0SR & MAPubMed, Scopus, Cochrane Library, and medRxiv.30 April 2020211102042Mean: 50.1NR3 RCTs, 1 nRCT, 1 qRCT, 2 Retrospective studies, 3 Prospective studiesLi et al.376 May 2020Drug discoveries & therapeuticsJIF = 1.11RRPubMed and MEDLINE.NRNR12 (10 on COVID-19)NRNRNR7 Ongoing RCTs, 3 Experimental studies, 1 Case report, 1 Cross-sectional studyLi et al.385 May 2020LeukemiaJIF = 12.104SR & MAPubMed, Web of Science, MEDLINE, Wanfang Data, and ZhiWang Database.20 March 2020878811 (4 on COVID-19)5249(Including 1426 for COVID-19)Mean = 51.9NR1 RCT, 10 ObservationalXu et al.395 May 2020Military Medical ResearchJIF = 1.73SRPubMed and Cochrane Library.NR1325301949NRNR2 Prospective cohort studies, 5 RCTs, 4 Retrospective cohort studies, 8 Case series, 7 Cohort studies, 4 Case report, 1 MA, 1 Case control studiesAlijotas-Reig et al.403 May 2020Autoimmunity ReviewsJIF = 7.716SRMEDLINE, PubMed, and Cochrane Library.30 March 2020NRNRNRNRNRNRRawson et al.412 May 2020Clinical Infectious DiseasesJIF = 9.117RRMEDLINE and Embase.18 April 2020100718 (9 on COVID-19)7033(Including 2010 for COVID-19)NRNRNRChowdhury et al.422 May 2020Academic Emergency MedicineJIF = 2.963Authors should follow PRISMA guidelines.RRCochrane Library, MEDLINE, Embase, medRxiv, and ClinicalTrials.gov.26 April 20205936 (29 ongoing RCTs)486NRNR6 Clinical trials, 1 letterTable 1. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 7AuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesZhang et al.431 May 2020Annals of translational medicineJIF = 3.689Authors should follow PRISMA guidelines.RRCochrane library, MEDLINE, Embase, Web of Science, China Biology Medicine disc, CNKI, Wanfang Data, ICTRP, ISRCTN Registry, ClinicalTrials.gov, Google Scholar, medRxiv, bioRxiv, and SSRN.31 March 202015196 (2 on COVID-19)112 for COVID-19Mean in case series: 55Range in case report: 34–5657.1%4 Case series, 1 Case report, 1 RCTRajendran et al.441 May 2020Journal of Medical VirologyJIF = 2.049Invited reviews only.SRPubMed, Embase, and MEDLINE.NR110527Range: 28–7356%3 Case report, 2 Case seriesLu et al.451 May 2020Annals of translational medicineJIF = 3.689Authors should follow PRISMA guidelines.SR & MACochrane library, MEDLINE, Embase, Web of Science, China Biology Medicine, CNKI, Wanfang Data, ICTRP, ISRCTN Registry, ClinicalTrials, Google Scholar, medRxiv, bioRxiv, and SSRN.31 March 2020250923 (5 on COVID-19)13815(Including 926 for COVID-19)Mean: 51.2855.2%1 RCT, 22 Cohort studiesShi et al.46May 2020Annals of translational medicineJIF = 3.689Authors should follow PRISMA guidelines.RR PubMed, Embase, Web of Science, Cochrane Library, China Biology Medicine, CNKI, Wanfang Data, ICTRP, US National Institutes of Health Trials Register, International Standard Randomized Controlled Trial Number Register, Google Scholar, Official websites of WHO and Centers for Disease Control, bioRxiv, medRxiv, and SSRN.31 March 2020410123 (7 on COVID-19, 13 on SARS, 3 on MERS)6008Range: 26.7 to 67.443%6 RCTs, 17 Cohort studiesTable 1. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 148 journals.sagepub.com/home/tarAuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesWang et al.47May 2020Annals of translational medicineJIF = 3.689Authors should follow PRISMA guidelines.RRCochrane library, PubMed, Embase, Web of Science, China Biology Medicine disc, CNKI, Wanfang, Data, ICTRP, US National Institutes of Health Trials Register, ISRCTN Registry, and Google Scholar.31 March 2020218333 (including 4 on children only)3203 (including 48 children)Mean: 37.3NR10 Case reports, 20 Case series, 1 Cohort, 1 Descriptive, 1 Cross-sectional studyAlzghari and Acuña4830 April 2020Journal of Clinical VirologyJIF = 3.02SRPubMed, Embase, Scopus, and Web of Science.NR63640Mean: 62.782.7%2 Retrospective analyses, 4 case reportsZhong et al.4930 April 2020Pharmacological ResearchJIF = 5.574Authors should follow PRISMA guidelines.SR & MAEmbase, Cochrane Library, CNKI, China Science and Technology Journal Database, Wanfang Data, medRxiv, and bioRxiv.20 April 2020557018 (7 on COVID-19)5002(Including 644 for COVID-19)Mean: 50.2354.8%5 RCTs, 13 Controlled cohortPascarella et al.5029 April 2020Journal of Internal MedicineJIF = 6.051SRPubMed, Google Scholar, MEDLINE, UpToDate, Embase, and Web of Science.3 April 2020NRNRNRNRNRNRVeronese et al.5124 April 2020Frontiers in MEDICINEJIF =3.113Authors should follow PRISMA guidelines.SREmbase, PubMed, Web of Science, CNKI, MEDLINE, CINAHL, Toxline, Scopus, and Wanfang Data.15 March 2020314542Mean: 52.455%4 Retrospective cohort studiesSarma et al.5216 April 2020Journal of Medical VirologyJIF = 2.049Invited reviews only.SR & MAPubMed, CINAHL, Scopus, Wiley online library, Web of Science, CENTRAL, Embase, medRxiv, bioRxiv, TRIP Database, Nature, Epistemonikos, Science Direct, Virtual Health Library, Pan American Health Organization, CNKI, and Mediterranee-infection.com/pre-prints-ihu.8 April 202040871358NRNRNRTable 1. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 9AuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesFord et al.5315 April 2020Journal of the International AIDS SocietyJIF = 5.192Authors should follow PRISMA guidelines.SRPubMed, Embase, Cochrane Library, WHO database of publications on COVID-19, Clinicaitrials.gov, and Chictr.org.cn.30 March 202043326 (Including 17 on COVID-19)2260 (Including 662 for COVID-19)NRNR2 RCTs and 24 Observational; For COVID-19: 2 RCTs, 3 Case reports, 1 Case series, 7 Retrospective cohorts, 1 Comparative cohort.Fu et al.710 April 2020Journal of InfectionJIF = 5.099Authors should follow PRISMA guidelines.SR & MAPubMed, Embase, Web of Science, and CNKI.2 March 20202247433600Median: 4156.5% Median (29–77%)40 Retrospective case series, 1 Cross-sectional, 2 Prospective studiesYang et al.5410 April 20Journal of InfectionJIF = 5.099Authors should follow PRISMA guidelines.SR & MAPubMed, Embase, Cochrane library, and CNKI.15 March 2020168515 (Including 2 on COVID-19)5270 (Including 179 on COVID-19)NRNR15 Retrospective studiesGbinigie and Frie557 April 2020BJGP OpenJIF = 0Inviting reviews only; Authors should follow PRISMA guidelines.RRPubMed, Google Scholar, and Google.NRNR666Mean: 51 Intervention group, 42 Control groupNR3 in vitro, 1 Open-label randomized trial, 1 Open-label non-randomized trial, 1 LetterYousefifard et al.566 April 2020Archives of Academic Emergency MedicineJIF = 0Authors should follow PRISMA guidelines.SRPubMed, Embase, Scopus, CENTRAL, Web of Science, Google, and Google Scholar.15 March 20204997222856Mean: 43.947.3%1 Clinical trial, 16 Case-series, 5 Case-reportsTobaiqy et al.576 April 2020Infection Prevention in PracticeJIF = 0Inviting reviews only; Authors should follow PRISMA guidelines.SREmbase, MEDLINE, and Google Scholar.26 March 2020449418806Mean: 50.824% Male, 34% Other, 0.3% Unspecified3 Clinical trials, 7 Case reports, 10 Case series, 11 Retrospective, 10 Prospective studiesTable 1. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 1410 journals.sagepub.com/home/tarAuthorPublication dateJournal and impact factorStudy designInformation sourcesSearch dateNo. studies screenedNo. included primary studiesSample sizeAge (years)Sex (male %)Study design of included studiesInsiat Islam584 April 2020Journal of Pharmacy and Pharmaceutical SciencesJIF = 2.042SRPubMed, Google Scholar, and Science Direct databases.25 March 2020115322NRNRNR8 Case reports, 4 Laboratory tests, 1 Animal trial, 9 Recommendations other viral infection (i.e. malaria, Ebola, SARS, MERS)Guida182 April 2020Inter American Journal of Medicine and HealthJIF = 0SRPubMed, Scielo, Brazilian Registry of Clinical Trials, and ClinicalTrials.gov.30 March 20204113651.2 Intervention group, 37.3 Control groupNR1 Open-label non-randomized clinical trial, 3 Ongoing clinical trialsPacheco and Riera931 March 2020Journal of Evidence-Based HealthcareJIF = 0RRCochrane Library, Embase, Literatura Latino-Americana e do Caribeem, Ciências da Saúde, PubMed, Opengrey, ClinicalTrials.gov, ICTRP, and Chinese Clinical Trial Registry.26 March 202022330In 2 clinical trials: 66Mean:51 Intervention group, 42 Control groupNR1 Open-label randomized trial, 1 Open-label non-randomized trial, 28 Ongoing clinical studies‎Borges do Nascimento et al.1930 March 2020Journal of Clinical MedicineJIF = 5.688Authors should follow PRISMA guidelines.SR & MAMEDLINE, CENTRAL, Embase, Scopus, and LILACS.24 February 2020270160 (Only 26 were about pharmacological and/or supportive interventions)59254, (1876 about pharmacological and/or supportive interventions)Range: 3 months to 99 years54%20 Case reports, 37 Case series, 3 Epidemiological reportsSingh et al.5926 March 2020Diabetes & Metabolic SyndromeJIF = 0SRPubMed and ClinicalTrials.gov.21 March 2020NR11> 136Mean: In one study: 51.2 Intervention group, 37.3 Control groupNR9 in vitro studies, 1 Open-label non-randomized trial, 1 LetterStudies are listed on the chronological order of their publication dates.CBM, Chinese Biomedical Database; CNKI, China National Knowledge Infrastructure; CENTRAL, Cochrane Central Register of Controlled Trials; ICTRP, WHO International Clinical Trials Registry Platform; JIF, Journal Impact Factor; ISRCTN, International Standard Randomized Controlled Trial Number; MA, Meta-Aanalysis; MERS, Middle East Respiratory Syndrome; NR, Not Rreported; nRCT, non-Randomized Controlled Trial; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Anlyses; qRCT, quasi-Randomized Controlled Trial; RCTs, Randomized Controlled Trials; RR, Rapid Review; SARS: Severe Acute Respiratory Syndrome; SR, Systematic Review; SSRN, Social Science Research Network; WHO, World Health Organization.Table 1. (Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 11Data extractionA data extraction sheet was designed and piloted by two independent authors (MKH and MC). Data were extracted independently by the two authors (MKH and MC), and discrepancies were resolved through discussion or arbitration with the senior author (MK). Data were extracted on study type (e.g. systematic review, rapid review), publication date, information sources (e.g. MEDLINE, Embase), search date, number of included studies in each review, total sample size, age and sex of the participants, study design of included studies in the review, description of the pharmacological (e.g. antivi-rals, antibiotics, antimalarial) and non-pharma-cological (e.g. oxygen therapy, invasive or non-invasive mechanical ventilation) treat-ments, and main findings.Quality and overlap assessment of individual reviewsTwo reviewers (MKH and MK) independently evaluated the methodological quality of included reviews using A MeaSurement Tool to Assess sys-tematic Reviews-2 (AMSTAR-2).16 This tool contains 16 items to appraise the methodological aspects of the systematic reviews that include ran-domized or non-randomized primary studies. The methodological quality for each review was rated as critically low (i.e. more than one critical flaw with or without non-critical weaknesses), low (i.e. one critical flaw with or without non-critical weak-nesses), moderate (i.e. more than one non-critical weakness), and high (i.e. no or one non-critical weakness). Scores on the AMSTAR-2 tool range from 0 to 16 and higher scores correspond to higher quality of systematic reviews.16 We also assessed the degree of overlap within the system-atic reviews by calculating the recently developed metric of corrected covered area (CCA) based on the following recommended cut-offs (i.e. slight overlap: CCA of 0–5%; moderate overlap: 6–10%; high overlap: 11–15%; and very high overlap: >15%).17Data synthesisStudies were summarized in a narrative fashion, and an overview of their methods and main find-ings were presented. Data synthesis was based on the pharmacological and non-pharmacological nature of the treatments.Living overview of reviewsGiven the rapidly increasing number of system-atic reviews on COVID-19 treatment options, we will screen the online databases listed above on a bimonthly basis through December 2020 for new relevant evidence. If resources are available, we plan to update the overview of reviews when new peer-reviewed evidence that significantly alters the direction or strength of our original conclu-sions emerges.ResultsLiterature searchThe online database and reference search retrieved 992 studies, 176 of which were dupli-cate records and were excluded. A total of 686 records were excluded after the title and abstract screening. Of the remaining 130 articles that were assessed in the full-text screening phase, 45 were included in the overview (Figure 1). No addi-tional systematic reviews were found through ref-erence list screening.Characteristics of the included reviewsTable 1 summarizes the overall characteristics of the 45 included reviews. All reviews were published between April and June 2020 and search dates were as early as 2 March 2020.7 Reviews were published in 30 different journals, most of which had specific submission requirements for systematic reviews. The journal impact factor (JIF) of journals that published the systematic reviews ranged from 0 to 19.315 (median JIF = 3.689). All included reviews were published in English. The number of included primary studies in the reviews varied greatly from one18 to 6019 (median number of primary stud-ies = 11). The majority (n = 30; 67%) of the reviews did not include a meta-analysis in their statistical analysis. Most reviews investigated pharmacologi-cal treatments for COVID-19.A range of study designs was included across dif-ferent systematic reviews; most of which included retrospective/prospective observational studies and case series/case reports. The target popula-tion was confirmed cases of COVID-19 patients and included children in three reviews43,46,47 and adult patients in the remaining studies. None of the included reviews reported on pregnant women.Therapeutic Advances in Respiratory Disease 1412 journals.sagepub.com/home/tarQuality of included reviewsSupplemental Table 2 shows the details of AMSTAR-2 scores for each systematic review. The AMSTAR-2 score had a mean of 6.0 (range 0–13) and methodological drawbacks were fre-quent. According to AMSTAR-2, 29 systematic reviews were of critically low quality, nine were of low quality, and seven were of moderate quality. Seventeen reviews had pre-specified their clinical research question and inclusion criteria according to the components of population, intervention, comparators, and outcomes (PICO). Study selec-tion and data extraction were performed in dupli-cate in 31 and 22 reviews, respectively. Only three reviews conducted a comprehensive literature search, and 13 reviews provided a list of excluded studies. Twenty-seven reviews described the characteristics of included studies in adequate detail and, 13 reviews assessed the risk of bias. In 15 reviews, appropriate meta-analysis methods were used for the statistical combination of results. Seven reviews provided sufficient expla-nation for any heterogeneity observed in the results, and eight studies carried out an adequate investigation of publication bias. Only in two reviews, the authors assessed the potential impact of risk of bias in individual studies on the results of the meta-analysis.24,28 Only three reviews accounted for the risk of bias when discussing the results.24,26,32 The value of the CCA was approxi-mately 1.7, which corresponded to a slight overlap.Therapeutic interventions for COVID-19Details of the pharmacological and non-pharma-cological therapeutic interventions and the main findings of each systematic review are summa-rized in Table 2. Most systematic reviews were conducted on observational studies without hav-ing suitable control groups for comparison. Moreover, systematic reviews reported on a range of different outcomes (e.g. viral clearance, viral load, improvement in radiology findings, time to a clinically meaningful response, mortality, inten-sive care unit [ICU] admission or duration, need for mechanical ventilation, disease progression, time to recovery, C-reactive protein level, white Figure 1. Flowchart of screened and included studies in the overview of reviews on therapeutic interventions for COVID-19.M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 13Table 2. Overview of therapeutic interventions for COVID-19 patients included in the study.AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Liu et al.20To address the benefits and harms of antiviral treatments for COVID-19.Antivirals: Favipiravir (1600 mg, 12/h, on day 1 and 600 mg, 12/h on days 2–14) in 2 studies, Lopinavir (200–400 mg, 12/h)/Ritonavir (50–100 mg, 12/h) 1–14 days in 5 studies, Arbidol (200 mg, 8/h, 7–10 days) in 5 studies, Interferon-α by aerosol inhalation (60 μg/5 mIU, 12/h) in 3 studies.NR.Lopinavir/Ritonavir: RR = 0.99 viral clearance at day 14, RD = 5 length of stay in ICU;Reported only very low-quality evidence with little or no suggestion of benefit for most treatments.11 Antimalarial: HCQ (400–800 mg/day, 5–21 days) in 5 studies.HCQ: RR = 0.98 viral clearance at day 14; RR = 0.96 progressing from non-severe to severe; RR = 1.48 mortality.Qu et al.21To determine the potential value of mesenchymal stromal cells therapy for treating COVID-19 patients with ARDS.NR.Mesenchymal stromal cells in 1 study.All symptoms disappeared in all patients, oxygen saturations rose to ⩾95% at rest, with or without oxygen uptake at 2–4 d after transplantation; Signs of pneumonia and ground-glass opacity on CT improvement on day 9.10Das et al.22To systematically review the therapeutic role of HCQ in COVID-19.Intervention groups:Antimalarial: HCQ (600 mg, daily, 10 days) alone or with Azithromycin (500 mg on day 1, 250 mg on days 2–5) in 7 studies; (400–600 mg, daily) in 3 studies;HCQ (1200 mg, daily, 3 days, then 800 mg, daily, 2–3 weeks) in 1 study;HCQ (1200 mg, daily, 1 day, then 400 mg, 4 days), daily for 4 days; optional Azithromycin (500 mg on day 1, 250 mg on days 2–5) in 1 study.Control groups: Standard treatment in 6 studies.NR.In 5 studies: Good virological and clinical outcomes with HCQ therapy alone or in combination with azithromycin;In 5 studies: Negative or equivocal results along with the risk of adverse reactions;In 1 study: No significant effect of HCQ on intubation or death in COVID-19 patients.2Fajgenbaum et al.23To review all treatments that have been reported through any study design to be given to COVID-19 patients.Antivirals in 71.5% of patients: Lopinavir/Ritonavir in 21.9% of patients, Interferon-α/b in 19.3% of patients, Arbidol in 10.6% of patients, Oseltamivir in 10.2% of patients, Ganciclovir in 2.3% of patients, Ribavirin in 1.7% of patients, Favipiravir in 1.6% of patients.NR.Mean of time to clinically meaningful response: 19.8 days Oseltamivir (longest average), 9.9 days Interferon-a/b (shortest time), 11.7 days Lopinavir/Ritonavir (most frequently administered), 10.9 days Umifenovir.4 Antibiotics in 46.6% of patients: Moxifloxacin in 6.5% of patients, Azithromycin in 1.4% of patients.Mean of time to clinically meaningful response: 16.2 days Moxifloxacin. Corticosteroids in 26.1% of patients: 4.6% Methylprednisolone.Mean of time to clinically meaningful response: 14.2 days Methylprednisolone. Immunostimulants in 20.3% of patients;Immunoglobulins: Immunoglobulin human normal in 11.5% of patients;Herbal Medicine in 7.6% of patients;Pituitary/Hypothalamic in 1.6% of patients; Antimycotics in 1.6% of patients;Antithrombotics in 1.5% of patients: Heparin in 1.4% of patients;Antimalarial: HCQ/CQ in 1.2% of patients;Blood substitutes in 1.2% of patients; Other category in 4.2% of patients: Thymosin-a1 in 1.7% of patients.Effects of medications were not reported.(Continued)Therapeutic Advances in Respiratory Disease 1414 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Ye et al.24To examine the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses.Corticosteroids in 6 studies.NR.In patients with COVID-19 and ARDS: HR = 0.41 mortality;In patients with COVID-19 but without ARDS: HR = 2.3 mortality; increase in the composite outcome of mortality or ICU admission; prolonged viral shedding.12Hernandez et al.25To summarize the evidence about the benefits and harms of HCQ or CQ for the treatment or prophylaxis of COVID-19.Intervention groups:Antimalarial: HCQ (400–600 mg, daily) in 8 studies, HCQ + Azithromycin (400–800 mg, daily + 500 mg on day 1 and 250 mg, 2–5 days) in 12 studies; CQ (300–600 mg, daily) in 4 studies.Oxygen therapy in 3 studies.CQ: RD = 0.0%, 24% all-cause mortality, RD = 9.5% need for mechanical ventilation, RD = 0.0%, 40.9% ICU admission, MD = –0.7 symptom resolution, upper respiratory viral clearance (RD = –8.3%, 16.4%, 34%);HCQ: RD = –26.9%, 6.1%, 16.4% and RD: –0.6% to 9.8% all-cause mortality, RD = 17.4% composite of intubation or death, RD = –0.8%, 0.0%, 14.4% need for mechanical ventilation, RD = –12.9%, 6.7%, 4.4%, MD = 0.47 severe disease progression, MD = –1.1, 0.0 symptom resolution, RD = –22.6, –13.3% progression of pulmonary lesions on CT, RD = 25.8% improvement in pulmonary lesions on CT, RD = –43.1%, 57.6%, –0.4% upper respiratory virologic clearance.4 Antivirals: Lopinavir/Ritonavir and/or Interferon beta in 1 study;Antibiotics: Ceftriaxone in 1 study;IL-6 blockade: Tocilizumab in 1 study;Steroids in 1 study;Control groups: Low-dosage CQ (450 mg, 3 days + 150 mg), and placebo (1 tablet, 12/h, daily on day 0, 3) in 1 study; Standard care in 13 studies.Effect of medications were not reported.Rodrigo et al.26To summarize evidence from human clinical studies for using HCQ or CQ as antivirals for any viral infection.Intervention groups:Antimalarial: HCQ (400 mg–600 mg, daily, 5–10 days) in 3 studies; HCQ (200 mg, daily, 3 days, then 800 mg, daily, 14–21 days) in 1 study; CQ (600–1200 mg, daily 10 days) in 2 studies;Control groups: Standard/supportive treatment in 4 studies, Lopinavir/Ritonavir (400/100 mg, 12/h, 10 days) in 1 study, CQ (900 mg, day 1 and 450 mg, daily, 4 days) in 1 study.NR.In 2 studies no statistically significant difference between HCQ and Standard treatment: in the clearance of viremia by day 7 and 28, symptom resolution by day 28, fever clearance time, total duration of hospitalization;In 1 study rate of clearance of viremia by day 6 of illness: 70% HCQ versus 12.5% placeboIn 1 study faster fever recovery and cough relief in HCQ group.CQ: No statistically significant difference in viraemia clearance; Faster radiological resolution and reduced hospital stay than Lopinavir/Ritonavir; Significantly higher mortality in high dose (1200 mg versus 900 mg).6Table 2. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 15AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Jorgensen et al.27To critically review the data on Remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics and in vitro activity against coronaviruses, and clinical experience in COVID-19 clinical trials.Antivirals: Remdesivir (200 mg, on day 1, then 100 mg, on days 2–5) in 6 studies.NR.67.9% improvement in oxygen support category at median 18 days after Remdesivir initiation; 13.2% died in hospital after median 15 days; 5/6 symptoms resolved; 4/6 discharged; 2 case report extubated and stable in hospital.4Ang et al.28To evaluate the effectiveness and adverse events of herbal medicines for the treatment of COVID-19.Intervention groups:Herbal medicines: Lianhua Qingke granules (1 packet, 2–3 times daily, 7–14 days) in 2 studies, Shufeng Jiedu capsule (4 capsules, 3 times daily, 2 weeks) in 1 study, Jinhua Qinggan granules (2 packets, 3 times daily, 5 days) in 1 study, Toujie Quwen granules (1 packet per time, 2 times daily, 10–15 days) in 2 studies, Herbal decoction (2 times daily, 7 days) in 1 study.NR.Herbal medicine + Western medicine versus Western medicine:RR = 1.23 total effective rate, RR = 1.42 discharge rate, RR = 1.35,Symptom disappearance rate: RR = 1.45 cough, RR = 1.73 sputum production, RR = 1.51 fever, Mean difference = –6.32 C-reactive protein level, Mean difference = 3.83 lymphocyte percentage, Mean difference = 0.41 white blood cell counts.13 Intervention and control groups:Antivirals: Lopinavir/Ritonavir (200 mg, 12/h, 14 days) in 3 studies, 5 Arbidol (200–500 mg, 8/h) in 3 studies, Ribavirin (dosage not reported, 12/h) in 1 study, Alpha interferon (dosage not reported,12/h) in 2 studies;Secretolytics: Ambroxol (30 mg, 8/h, 3 days) in 3 studies;Antimalarial: CQ (500 mg) in 1 study;Antibiotics: Moxifloxacin in 2 studies.Effect of medications were not reported.Schunemann et al.29To review multiple streams of evidence on the benefits and harms of ventilation techniques for coronavirus infections, including COVID-19.NR.Oxygen therapy, NIV, IMV, and HFNCHR = 1.61 mortality with NIV versus IMV;Higher death rate in patients receiving helmet CPAP or other NIV compared with IMV; A large reduction in mortality with NIV compared with conventional oxygen therapy;Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality.8Antwi-Amoabeng et al.30To summarize the baseline characteristics of COVID-19 patients who received tocilizumab.IL-6 blockade: Tocilizumab in 100% of patients.NR.20.7% Death; Higher IL-6 level after the initiation of Tocilizumab (376.6 pg/mL) versus baseline of (71.1 pg/mL); C-reactive protein level was significantly lower after the initiation of Tocilizumab.4 Corticosteroids in 34.5% of patients;Antimalarial: HCQ in 24.1% of patients; Antivirals: Lopinavir/Ritonavir in 20.7% of patients, Ribavarin in 3.4% of patients, Arbidol in 3.4% of patients.Effect of medications were not reported.Table 2. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 1416 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Tahvildari et al.31To characterize the clinical, diagnostic, and treatment characteristics of patients presenting with COVID-19.Antivirals: Lopinavir in 9% of patients, Arbidol in 6% of patients, Oseltamivir in 5% of patients, Veletonavir in 1% of patients, Remdesivir in 1% of patients, Ribavirin in 1% of patients, Ritonavir in 1% of patients, Gancyclovir in 1% of patients, Interferon alpha-2b in 2% of patients; Antibiotics: Moxifloxacin in 5% of patients, Vancomycin in 1% of patients, Cefepime in 1% of patients, Meropenem in 2% of patients, Piperacillin tazobactam in 2% of patients, Cefoselis in 1% of patients, Linezolid in 1% of patients, Levofloxacin in 1% of patients; Corticosteroids: Methylprednisolone in 6% of patients;Immunoglobulin in 4% of patients; Herbal Medicine in 3% of patients.Non-invasive ventilation in 10% of patients.2% death, 32% hospitalization, 12% discharged, 2% ARDS. A wide range of therapeutic modalities was tried across studies, with antiviral treatments being the most used; There is currently not a well-established gold standard therapy for the treatment of diagnosed COVID-19.5Valk et al.32To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19.Convalescent plasma therapy or Hyper-immune immunoglobulin transfusion in 8 studies.Convalescent plasma or Hyper-immune immunoglobulin transfusion:15 participants discharged, 6 still hospitalized, 11 unclear;In all studies: Improvement of clinical symptoms;4–35 days, time to discharge from hospital after convalescent plasma therapy;In 6 studies: A decrease in ICU duration or required mechanical ventilation.In 2 critically ill patients requiring intubation and mechanical ventilation, both received a tracheotomy and one extubated by day 18;40% Decreasing respiratory support within 3 days.11 Antivirals, Antifungals or Antibiotics, Corticosteroids, Antimalarials: HCQ.Respiratory support in 87.5% of patients: Mechanical ventilation in 5 studies, HFNC in 2 studies, ECMO in 2 studies, Nasal cannula in 2 studies.Effect of medications and interventions were not reported.Zhang et al.33To investigate the predictive value of laboratory investigations for severe disease and adverse outcomes, and evaluate the efficacy of antivirals and corticosteroids for COVID-19.Corticosteroids in 57.3% of patients.NR.Corticosteroids: 7.2% mortality rate; 22.7% ARSD rate.4Table 2. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 17AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2) Antivirals: Lopinavir/Ritonavir in 15.1% of patients, Oseltamivir, Ganciclovir, Ribavirin, Arbidol.Lopinavir-Ritonavir: 6.2% mortality rate, 15.6% ARDSOther/non-specified antivirals: 5.5% mortality rate, 24.2% ARDS. Antibiotics: Moxifloxacin, Ceftriaxone, Azithromycin.Effect of medications were not reported.Liu et al.34To assess the efficacy and safety of Integrated Traditional Chinese and Western Medicine to COVID-19.Intervention groups:Traditional Chinese Medicine in 11 study: Diammonium glycyrrhizinate enteric-coated capsules (150 mg, 8/h) in 1 study, Qingfeitouxie fuzhengfang (150 ml, 12/h) in 1 study, Shufeng Jiedu Capsule (2.08 g,tid) in 2 studies, Lianhua Qingwen granules (6 g, 8/h) in 2 studies, Reyanning mixture (10–20 ml,12/h) in 1 study, Tongjiequwen granule (150 ml, 12/h) in 1 study, Jinhua Qinggan granules (10 g, 8/h) in 1 study.NR.Traditional Chinese Medicine versus Western Medicine alone:RR = 1.23 overall response rate; RR = 1.60 cure rate; RR = 0.35 severity of illness; WMD = –1.991 hospital stay; RR = 1.32 Fever disappearance rate;Better improve the symptoms disappearance rate and reduced the symptoms disappearance time;Significantly increased disappearance rate of fever, cough, expectoration, fatigue, chest tightness and anorexia in patients and reduced patients’ fever, and fatigue time.12 Intervention and control groups:Western Medicine in 11 study: Lopinavir (100–500 mg, 12/h) in 2 studies, Interferon-α (5 mU, 12/h) in 2 studies, Ribavirin (500 mg, 12/h) in 2 studies, Arbidol (200 mg, 8/h) in 3 studies.Effect of medications were not reported.Singh et al.35To understand the pharmacology and clinical effects of Remdesivir in patients with COVID-19.Intervention groups: Remdesivir (200 mg then 100 mg, OD, 2–10 days) in 7 studies;Control groups: Placebo or standard care.NR.Initial compassionate use of Remdesivir has shown a fairly good result (clinical improvement);Very first RCT conducted in Wuhan, did not find any significant benefit compared to the control;The preliminary result of another similar multi-country trial has shown a significant faster time to recovery (%31) but without any difference in mortality.2Gbinigie and Frie10To review the evidence for the effectiveness and safety of azithromycin in treating COVID-19.Antimalarial & Antibiotics: HCQ + Azithromycin in 3 studies.NR.6 patients who received Azithromycin combined with HCQ were significantly more likely to test negative for SARS-CoV- 2 on Days 3, 4, 5, and 6. On Day 6, 57.1% of the HCQ group, compared to 100% of the combined HCQ and azithromycin group, were virologically cured.In vivo: Azithromycin + HCQ inhibited viral replication.6Table 2. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 1418 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Singh et al.36To study the efficacy of HCQ compared to the control in COVID-19 subjects.Antimalarial & Antibiotics:HCQ: 2 (400 mg, daily, 5 days), 2 (600 mg, daily, 7–10 days), 1 (1200 mg, daily, 3 days, followed by 800 mg, daily, 2 weeks (mild/moderate cases) or 3 weeks (severe cases)), 1 (800 mg, daily, 1–2 days, followed by 200–400 mg, OD, 3–4 days);HCQ + Azithromycin: 3 (600 mg, daily, 10 days + 500 mg on day 1 and 250 mg, 2–5 days).NR.RR = 0.744 RT-PCR negativity, RR = 2.17 death.5Li et al.37To critically assess the potential anti-coronavirus effect of Remdesivir on COVID-19 and other coronaviruses.Antivirals: Remdesivir in 10 studies.NR.In experimental study: Remdesivir therapeutically inhibited SARS-CoV-2 replication, while no prophylactic effect was found. Remdesivir could inhibit SARS-CoV-2 infection in human liver cancer Huh-7 cells;In human studies: Recovery of a patient; Clinical improvement in 68% of the 53 recruited patients who had severe COVID-19.0Li et al.38To determine safety and efficacy of corticosteroids in SARS-CoV-2, SARS-CoV, and MERS-CoV infections.Corticosteroids in 4 studies.NR.RR = 1.07 mortalityCorticosteroid use in subjects with SARS-CoV-2, SARS-CoV, and MERS-CoV infections delayed virus clearing and did not convincingly improve survival, reduce hospitalization duration or ICU admission rate and/or use of mechanical ventilation.6Xu et al.39To summarize the clinical evidence of investigational adjunctive treatments used in COVID-19 patients.Antimalarial: CQ or HCQ in 7 studies.Limited benefit from CQ/HCQ in general.3 Antivirals: Lopinavir/Ritonavir in 5 studies, Arbidol in 2 studies, Remdesivir in 4 studies.The equivocal benefit of Lopinavir/Ritonavir on clinical improvement and viral clearance;Higher discharge and survive in Arbidol groups;Possibility of decreasing the viral load of COVID-19 and delaying the progression of lung lesions with combination of Lopinavir/Ritonavir and Arbidol; No conclusions can be drawn about efficacy or safety of Remdesivir. Corticosteroids in 2 studies.No routine use of corticosteroids in critically ill patients; No survival advantage; Associated with longer hospital stay Anticoagulants: Heparin in 2 studies.Heparin may improve 28-day mortality in severe COVID-19 patients meeting sepsis-induced coagulopathy criteria or markedly elevated Ddimer IL-6 blockade: Tocilizumab in 2 studies.Tocilizumab could improve clinical status in severe to critically ill patients(Continued)Table 2. (Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 19AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2) Convalescent plasma in 3 studies;Mesenchymal stem cell in 2 studies.Convalescent plasma could improve clinical status in critically ill patients with ARDS;Symptoms, pulmonary function biochemistry apparently may be improved after mesenchymal stem cell transplantation.Alijotas-Reig et al.40To study immunomodulatory therapy for the management of severe COVID-19.Immunoglobulins: IVIG/Hyperimmune immunoglobulin;IL-6 blockade: Tocilizumab, Sarilumab; IL-1 blockade: Anakinra; IL-2 inhibition: Cyclosporin A, Tacrolimus;Janus kinase pathway inhibition: Ruxolitinib;Anticoagulants: Heparin, Fondaparinux;Glucocorticoids; ACE agonists; Statins;Antimalarials: CQ, HCQ.Convalescent plasma therapy.In severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, data on the effectiveness of different immunomodulating drugs are scarce.3Rawson et al.41To explore the current literature surrounding bacterial/fungal co- infection in patients with coronavirus infection.Antibacterial in 72% of patients: Quinolone in 3 studies, Cephalosporins in 3 studies, Carbapenems in 2 studies, Linezolid in 2 studies, Moxifloxacin in 3 studies;Antifungals in 4 studies.NR.Despite low rates of bacterial/fungal co-infection reported in patients with COVID-19, high rates of antimicrobial prescribing are reported.4Chowdhury et al.42To review the literature regarding the clinical use of CQ and HCQ as treatment in COVID-19 patients.Intervention groups:Antimalarial: HCQ (600 mg, 1–10 days) + Azithromycin (500 mg first day, 250 mg 2–5 days) in 2 studies; HCQ (400 mg D,1–5 days) in 2 studies; HCQ (1200 mg 1–3 days, then 800 mg, 4–21 days) in 1 study;CQ (500 mg, 12/h, 1–10 days) in 1 study; CQ (500 mg, 12/h, 1–10 days) + Lopinavir/Ritonavir (400 mg/100 mg, 12/h, 1–10 days) in 1 study;Control groups: Standard care in 4 studies; Lopinavir/ritonavir (400 mg/100 mg, 1–10 days) in 1 study.NR.Optimized the time to clinical recovery and radiologic improvement versus supportive care; HR = 8.83 alleviation of clinical symptoms; Controlling inflammation and preventing disease progression (6.98 versus 2.72 in standard of care).In one study: No difference in clinical improvement, imaging findings, and duration of disease course versus supportive care.5Zhang et al.43To explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19.Immunoglobulins in 2 studies: IVIG (25 g, daily, 5 days) in 50% of patients.In 1 case series: The risk of death was not associated with the use of IVIG in the patients with ARDS;In 1 case report: A high dose IVIG administered at the appropriate point could successfully block the progression of disease cascade, and finally improve the outcome of COVID-19.8 In 2 studies: Antibiotics; Glucocorticoids; Interferons; Antivirals.Oxygen therapy in 1 study.Effects of the medications and interventions were not reported.(Continued)Table 2. (Continued)Therapeutic Advances in Respiratory Disease 1420 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Rajendran et al.44To evaluate the effectiveness of convalescent plasma transfusion therapy in COVID-19 patients.Convalescent plasma in 5 studies.55.6% discharge from hospital; may reduce mortality in critically ill patients, reducing viral load and increasing level of neutralizing antibody over time in all studies; improvements of clinical symptoms.4 Antivirals in 100% of patients: Arbidol, Lopinavir/Ritonavir, Interferon-Alpha-2b, Oseltamivir, Ribavirin, Peramivir;Antibacterial/Antifungal in 37% of patients: Imipenem, Vancomycin, Levofloxacin;Antimalarial: HCQ in 1 study.Mechanical ventilation in 51.9% of patients, ECMO in 25.9% of patients, Nasal cannula in 11.1% of patients, HFNC in 11.1% of patients.Effects of the medications and interventions were not reported.Lu et al.45To summarize the evidence on the effectiveness and safety of glucocorticoid therapy for patients with COVID-19.Corticosteroids in 5 studies: Methylprednisolone in 4 studies.NR.In patients receiving versus not receiving glucocorticoid therapy:RR = 2.0 risk of death; –3.23 duration of fever; –1.0 lung inflammation absorption time; 2.43 Length of stay.10Shi et al.46To assess the effectiveness and safety of antivirals for COVID-19 in children.Antivirals: Lopinavir/Ritonavir, Arbidol, Interferon, Ribavirin, Oseltamivir, Combination of Ribavirin/Interferon, Favipiravir.Oxygen therapy:69% of patients receiving Arbidol versus 86% of patients not receiving Arbidol; Non-invasive mechanical ventilation: 22.5% of patients receiving Favipiravir versus 18.1% of patients receiving Arbidol.For adults with COVID-19: Lopinavir/Ritonavir versus no antivirals:RR = 0.77 mortality; RR = 0.98 negative PCR result; RR = 1.02 radiographic abnormalities remission; Arbidol versus no antivirals:RR = 1.27 negative PCR result; RR = 1.23 radiographic abnormalities remission; RR = 1.02 incidence of clinical symptoms improvement; RR = 0.8 incidence of receiving oxygen therapy; Favipiravir versus Arbidol:RR = 1.18 rate of clinical recovery of day 7; RR = 1.03 respiratory failure.No direct evidence for children with COVID-19 was found and the effectiveness and safety of Antivirals for children with COVID-19 is uncertain.9 Antimalarial: HCQ.HCQ versus none:RR = 0.93 negative PCR result; RR = 1.47 radiographic abnormalities remission.Wang et al.47To evaluate the efficacy and safety of antibiotic agents in children with COVID-19.Antibiotic in 19.4–100% of patients:Meropenem in 4 studies, Linezolid in 2 studies, Quinolones in 2 study, Cefoperazone in 3 studies, Sulbactam in 2 studies, Carbapenems in 2 studies, Tigecycline in 1 study, Moxifloxacin in 14 studies, Levofloxacin in 4 studies, Ceftriaxone in 1 study, Azithromycin in 5 studies, Imipenem in 2 studies, Doxycycline in 1 study, Cefepime in 1 study, Cepalosporins in 3 study, Piperacillin sulbactam in 1 study, Cefdinir in 1 study.NR.There was no evidence to support the use of antibiotic agents for children with COVID-19 in the absence of bacterial coinfection.8Table 2. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 21AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Alzghari and Acuña48To evaluate outcomes associated with tocilizumab treatment in patients with COVID-19.IL-6 blockade: Tocilizumab (80–600 mg) in 6 studies.NR.Preliminary investigations are showing benefits with Tocilizumab for COVID-19; It is a potential supportive treatment for COVID-19.Patients remained clinically stable; 7.5% death.3 Corticosteroids: Methylprednisolone in 2 studies; Antivirals: Lopinavir in 1 study.Effects of the medications and interventions were not reported.Zhong et al.49To evaluate the efficacy and safety of current therapies forSARS, MERS, and COVID-19.Antivirals: 4 Lopinavir/Ritonavir (400 mg/100 mg, 12/h, 5–21 days) in 4 studies, Arbidol (200 mg, 8/h, 5–21 days) in 3 studies, Interferon-α spray in 1 study, Interferon- α2b spray in 1 study.NR.On COVID-19, SARS & MERS:Lopinavir/Ritonavir: RR = 0.77 mortality, RR = 0.97 virological clearance, RR = 1.52 clinical improvement, RR = 0.46 ARDS;Arbidol: RR = 1.07 virological clearance; Arbidol & Lopinavir/Ritonavir: RR = 2.34 radiological improvement.8 Antimalarial: HCQ (400–800 mg, daily, 5–21 days) in 3 studies; HCQ (600 mg, daily, 10 days) ± Azithromycin (day 1: 500 mg; day 2–5: 250 mg daily) in 1 study.HCQ: RR = 1.14 virological clearance, RR = 1.47 radiological improvement.Pascarella et al.50To summarize the currently available data on the clinical features and treatment options for COVID-19.Antivirals: Remdesivir, Lopinavir/Ritonavir.The efficacy of specific Antivirals to treat COVID-19 has been shown in vitro & animal models;Lopinavir/Ritonavir: Reducing the viral load, no clinical benefit.2 Antimalarials: CQ (500 mg, 12/h)/HCQ (200 mg, 12/h).CQ/HCQ: Efficacy in COVID-19 patients; may act synergistically with macrolides (e.g. azithromycin) for enhanced antiviral effect’Tracheal intubation should not be delayed in patients with a low oxygenation index, worsening of respiratory distress symptoms or multi-organ failure; ECMO could be a viable treatment option for patients with severe ARDS and not responding to treatment protocols. Oxygen therapy, ECMO, Intubation.Effect of other medications and interventions were not reported.Table 2. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 1422 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Veronese et al.51To investigate the effectiveness of glucocorticoid therapy in patients with COVID-19.Glucocorticoids in 31.2% of patients: Methylprednisolone in 2 studies.NR.Methylprednisolone did not show significant benefits;With a greater risk of ICU admission: 72.2% versus 35.3%;HR = 0.35 risk of death in subjects having ARDS for COVID-19;Longer duration of viral RNA detection: 15 versus 8.0 days.4Sarma et al.52To evaluate the safety and efficacy of HCQ in the treatment of COVID-19 patients.Intervention group:Antimalarials: 2 HCQ (400–600 mg, daily, 1–5 days) in 2 studies;HCQ (200–600 mg, 8/h, 10 days)/Azithromycin (First day 500 mg, 250 mg day 2–5) in 5 studies;Control group: Standard care in 3 studies.NR.HCQ:Less number of radiological progressions of lung disease (OR = 0.31), no difference in virological cure (OR = 2.37), death or clinical worsening of disease (OR = 1.37), and safety (OR = 2.19);5 studies reported either the safety or efficacy of HCQ + Azithromycin.10Ford et al.53To summarize the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses.Intervention groups:Antivirals: 14 Lopinavir (200–400 mg, 12/h, 1–21 days)/Ritonavir (100–500 mg, 12/h, 1–21 days) in 14 studies, Arbidol in 1 study, Peramivir in 1 study, Oseltamivir in 1 study, Ganciclovir in 1 study, Interferon alfa-2b in 4 studies.3.7% death in Lopinavir/Ritonavir group;It is uncertain whether in Lopinavir/Ritonavir and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID-19.4 Antibiotics in 3 studies;Immunoglobulins: Gama-globulin in 1 study;Corticosteroids in 3 studies: Methylprednisolone in 1 study;Traditional Chinese medicine in 2 studies; Control group: Supportive care alone in 1 study; Antivirals: Arbidol in 2 studies, Favipiravir in 1 study, No antivirals in 2 studies.Oxygen supplementation in 4 studies.Effects of the medications and interventions were not reported.Fu et al.7To provide a comprehensive characterization of COVID-19 to better inform control and treatment efforts.Antivirals in 90% of patients; Antibiotics in 71.5% of patients; Corticosteroids in 30.1% of patients; Immunoglobulin in 28.1% of patients;17 studies used guidelines on COVID-19 Treatment and Prevention issued by the National Health Commission.Oxygen therapy in 54.8% of patients, IMV in 22.2% of patients, Mechanical ventilation in 13.8% of patients, NIV in 8.5% of patients, CRRT in 3.3% of patients, ECMO in 1.6% of patients.Death in 3.6% of patients; severe COVID-19 in 25.6% of patients; ARDS in 15.7% of patients, shock in 4.3% of patients; renal insufficiency in 2.7% of patients, cardiac failure in 6.5% of patients.10Table 2. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 23AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Yang et al.54To evaluate the influence of corticosteroids on patients with coronavirus infection.Corticosteroids in 39.7% of patients (32 patients in ICU, 39 patients Non-ICU).Patients with severe conditions were more likely to require corticosteroids therapy (RR = 2.36).10 Antivirals in 2 studies; Antibiotics in 2 studies.ECMO in 1 study, CRRT in 1 study.Effects of other medications and interventions were not reported.Gbinigie and Frie55To establish the current evidence for the effectiveness of CQ and HCQ in treating COVID-19.Antimalarial: HCQ (400 mg/day for 5 days and 600 mg/day for 6 days) (with or without Azithromycin) in 2 studies; CQ (dosage not reported) in 1 study.NRCQ versus control group:Inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course; Dosage 600 mg/daily: A higher frequency of negative viral load on day-6; Dosage 400 mg/daily: No difference between HCQ and standard treatment group on day-7.Some in vitro data supporting the ability of CQ and HCQ to inhibit SARS-CoV-2 activity.3Yousefifard et al.56To identify potential treatment options for COVID-19.Antivirals in 65.9% of patients: Lopinavir/Ritonavir in 9 studies, Oseltamivir in 7 studies, Arbidol in 5 studies, Gancivlovire in 1 study, 1 Ribavirin in 1 study.Clinical improvement and mortality rate are similar in Lopinavir–Ritonavir treated and standard care groups; Administration of oseltamivir did not decrease ICU admission and need for ventilator or death; Antivirals have no effects on the mortality rate, outcome or the duration of hospital stay.5 All of the studies used Antibiotics, Immunoglobulins, Interferon, Corticosteroids (Methylprednisolone), Antiparasitics and Antifungals in addition to Antivirals.Invasive or Non-invasive ventilation & ECMO in 1 study.Effects of the medications and interventions were not reported.Tobaiqy et al.57To report any evidence of therapeutics used for the management of COVID-19 patients in clinical practice.Corticosteroids in 25 studies: Corticosteroid in 21 studies, Methylprednisolone in 3 studies, Dexamethasone in 1 study.Corticosteroids should not be used routinely in patients with COVID-19 for treatment of viral pneumonia, ARDS or septic shock.5 Antivirals: Lopinavir in 3 studies, 18 Lopinavir/Ritonavir in 18 studies, Oseltamivir in 16 studies, Interferon alfa in 10 studies, Arbidol in 8 studies, Ganciclovir in 4 studies.Absence of conclusive scientific evidence about Antivirals; No benefit of Lopinavir/Ritonavir treatment compared with standard care was observed. Antimalarial: HCQ (200 mg, 8/h, 10 days) + Azithromycin in 1 study.More virologically clearance in patients treated with HCQ (57.1%) than control group (12.5%).Table 2. (Continued)(Continued)Therapeutic Advances in Respiratory Disease 1424 journals.sagepub.com/home/tarAuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2) Convalescent plasma therapy in 1 study and 6 patients.Inadequate information about the efficacy of convalescent plasma. Antibiotics: Moxifloxacin in 4 studies, Tigecycline in 1 study;Traditional Chinese medicine in 2 studies;Antifungals in 8 studies; Immunoglobulin in 7 studies.Effects of other medications and interventions were not reported.Insiat Islam58To review the published literature on the effectiveness of suggested and applied treatment to control COVID-19.Clinical Studies: Glucocorticoids + IL-6 blockade + JAK inhibitors in 1 study;Antimalarials: CQ/HCQ in 1 study, Azithromycin plus HCQ in 1 study;Antivirals: Favipiravir (n = 35) versus Lopinavir or Ritonavir (n = 45), + Interferon alfa in all in 1 study; Lopinavir/Ritonavir in 3 studies; Arbidol in 1 study; Remdesivir in 1 study;Traditional Chinese Medicine in 3 studies: Qingfei paidu decoction in 1 study; Shufeng Jiedu in 1 study.NR.Clinical Studies: Glucocorticoids + IL-6 antagonist + JAK inhibitors + CQ/HCQ: Improved clinical outcome;Azithromycin plus HCQ: An improved efficacy to eradicate the virus;Favipiravir versus Lopinavir/Ritonavir: Shorter COVID-19 clearance and improved chest imaging;Lopinavir/Ritonavir: Reduced COVID-19 load, improved clinical symptoms;Lopinavir/Ritonavir + Arbidol + Shufeng Jiedu: Effective treatment;Remdesivir: Patient recovered;Traditional Chinese Medicine: Improved clinical symptoms and recovery.2 In vitro/Laboratory studies: 1 Lianhuaqingwen (Laboratory test using African green monkey kidney epithelial (VeroE6) cells and the human hepatocellular carcinoma (Huh-7) cells) in 1 study;Antimalarial: HCQ and CQ in 3 studies, Mefloquine in 1 study;JAK2 Inhibitor: Fedratinib in 1 study, Fedratinib in 1 study; JAK inhibitor: Baricitinib in 1 study; JAK 1 and 2 Inhibitor: Ruxolitinib in 1 study;Anti-inflammatory: Cepharanthine in 1 study; Anti-parasitic: Selamectin in 1 study;CRISPR/Cas13 d strategy in 1 study;Antivirals: Remdesivir in 2 studies, Ribavirin in 1 study, Penciclovir + Nitazoxanide + Nafamostat + Favipiravir in 1 study.In vitro/Laboratory test:All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trial to be suitable for clinical use. Guida18To assess the effectiveness and safety of HCQ and CQ on the treatment of COVID-19.Intervention group:Antimalarial & Antibiotic: HCQ (600 mg/daily), with or without Azithromycin in 20 patients; Control group: Standard care in 16 patients.NR.Viral load clearance in day 6: Intervention group: 70% Control group: 12.5%.5Table 2. (Continued)(Continued)M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 25AuthorObjective(s)Pharmaceutical treatmentsNon-pharmaceutical treatmentsMain findingsQuality assessment (AMSTAR-2)Pacheco and Riera9To identify, systematically assess and summarize the evidence on the efficacy and safety of the use of HCQ and CQ for COVID-19.Antimalarial and Antibiotic: HCQ (400 mg, daily, 5 days) and (600 mg, daily, 6 days) with or without Azithromycin in 2 studies.NR.Dosage 600 mg/daily: A higher frequency of negative viral load on day-6; Dosage 400 mg/daily: No difference between HCQ and standard treatment group on day-7; There is very low evidence of certainty and its routine use for this situation should not be recommended until the results of ongoing studies could provide a proper assessment of their effects.7Borges do Nascimento et al.19To review clinical, laboratory, epidemiological, and chest imaging data related to SARS-CoV-2.43.4% Antivirals: 66.8% Oseltamivir, 6.6% Arbidol, 9.3% Ganciclovir, 1.3% Ritonavir, 1% Interferon-alpha; 44.6% Antibiotics: Most did not mention exact ‎compound administered antibiotics, Different antibiotics in single patients (Vancomycin, Azithromycin, Meropenem, Cefaclor, Cefepime, ‎Tazobactam), 8.7% Linezolid, 0.4% Moxifloxacin;9.8% Corticosteroids; 12.4% Immunoglobulin; 2.5% Antifungal therapy; Fluid ‎therapy; Vitamin K1.‎38.9% Nasal cannula oxygen therapy, 7.1% NIV, 28.7% Mechanical ventilation, 0.9% ECMO, CRRT, Blood transfusions.0.3% all-cause mortality, 8.3% ICU admission; It was not possible to perform subgroup analysis to check the effectiveness of antivirals, antibiotics and other medications on the prognosis. Studies were descriptive in nature and lacked suitable control groups for comparison of clinical efficacy.9Singh et al.59To review the efficacy of CQ and HCQ in the treatment of patients with COVID-19.Antimalarials in 2 studies: CQ in 1 study (dosage not reported);Intervention group: HCQ (600 mg/daily), with or without Azithromycin in 20 patients; Control groups: Standard care in 16 patients.NR.CQ: Inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course; HCQ with or without Azithromycin: Viral load clearance in day 6: 70% Intervention group, 12.5% Control group; Two small human studies have shown significant improvement in some parameters in patients with COVID-19.2Studies are listed in the chronological order of their publication dates.ACE, Angiotensin-Converting Enzyme; ARDS, Acute Respiratory Distress Syndrome; CPAP, Continuous Positive Airway Pressure; CQ, Chloroquine; CRRT, Continuous Renal Replacement Therapy; ECMO, Extracorporeal Membrane Oxygenation; HCQ, Hydroxychloroquine; HFNC, High Flow Nasal Cannula; HR, Hazard Ratio; ICU, Intensive Care Unit; IL, Interleukin; JAK2, Janus Kinase2; IMV, Invasive Mechanical Ventilation; IVIG, Intravenous Immunoglobulin; MD; Mean Difference, MERS-CoV, Middle East Respiratory Syndrome Coronavirus; NIV, Non-Invasive Ventilation; NR, Not Reported; OR, Odds Ratio; PCR, Polymerase Chain Reaction; RCT, Randomiized Controlledd Trials;g RD, Risk Difference; RNA, Ribonucleic Acid; RR, Risk Ratio; RT-PCR, Real-time Reverse Transcription Polymerase Chain Reaction; SARS-CoV, Severe Acute Respiratory Syndrome Coronavirus; WMD, Weighted Mean Difference.Table 2. (Continued)Therapeutic Advances in Respiratory Disease 1426 journals.sagepub.com/home/tarblood cell count, ARDS, hospitalization, fever reduction, cardiac failure) that made compari-sons across the studies and drawing conclusions challenging.Antiviral agents. Most reviews reported antivirals as a common treatment for patients. The most commonly used antiviral treatment modalities included HIV protease inhibitor (e.g. lopina-vir20,23,25,28,30–34,39,42,44,46,48,53,56,58,60 and ritona-vir),19,20,23,25,28,30,31,33,39,42,44,46,49,50,53,56,58,60 Influenza treatments (e.g. arbidol hydrochlo-ride,20,23,28,30,31,33,34,44,46,49,53,56,58,60 and favipira-vir),20,23,46,53,58 neuraminidase inhibitors (e.g. oseltamivir),19,23,31,33,44,46,53,56,60 nucleoside ana-logues (e.g. ribavirin),23,28,31,33,34,44,46,56,58 nucleo-tide analogues (e.g. remdesivir27,31,35,37,39,50,58 and ganciclovir),19,23,33,53,60 and biological response modifier-cytokines (e.g. interferon alfa).28,31,32,34,43,44,46,49,53,56,58,60 Study findings on the effective-ness of antiviral drugs in the treatment of COVID-19 were equivocal and varied greatly across different reviews. For example, the sys-tematic review of case reports by Insiat Islam58 showed that antiviral agents such as lopinavir/ritonavir and arbidol reduced SARS-CoV-2 viral load, and improved clinical symptoms. That study also reported that patients receiving favipi-ravir had a shorter SARS-CoV-2 clearance and improved chest imaging as compared with the lopinavir/ritonavir group.58 However, in another review by Ford et al., lopinavir/ritonavir use was associated with a non-statistically significant shorter time to clinical improvement and lower mortality compared to the control group.53 Moreover, Liu et al.,20 Xu et al.,39 and Chowd-hury et al.42 reported no meaningful benefit for lopinavir/ritonavir. In addition, Shi et al. reported the safety and effectiveness of antiviral agents for children with COVID-19 as unclear.46 Overall, four reviews did not specify what antiviral agents were used in the treatment of COVID-19 patients7,43,48,54 and several studies did not report specific findings for antiviral agents used among the patients.Antibiotic agents. Antibiotics to treat patients with COVID-19 were reported in 13 reviews.7,19,23,25,28,31–33,43,47,54,56,60 Macrolides (e.g. azithromycin),9,10,18,19,22,23,25,33,36,42,47,49,52,55,58,59 fluoroquinolone (e.g. moxifloxacin,19,23,28,31,33,41,47,60 levofloxacin),31,44,47 glycopeptides (e.g. tigecycline,47,57 vancomycin),19,31,44 cephalosporins (e.g. cefopera-zone,47 cefoselis,31 cefdinir,47 and cefepime),19,31,47 beta-lactams (e.g. imipenem sulbactam,47 meropenem,19,31,47 piperacillin tazobactam),31 and oxazolidinones (e.g. linezolid)47 were the main classes of antibiotics used to treat COVID-19. Antibiotics were mainly used for addressing bacterial co-infections along with antivirals or antimalarial agents; however, their effectiveness was not directly investigated. Wang et al., who specifically evaluated the efficacy and safety of antibiotic agents in children with COVID-19, concluded that there was no direct evidence to support their efficacy.47 Six reviews did not spec-ify the antibiotic agents used in the treatment of infected patients.7,32,43,53,54,56Chloroquine and hydroxychloroquine. A total of 23 sys-tematic reviews evaluated the efficacy of chloroquine and hydroxychloroquine on treating COVID-19 patients,9,10,18,20,22,25,26,28,30,32,36,39,40,42,44,46,49,50,52,55,57–59 most of which concluded that these drugs were ineffi-cient and unhelpful for COVID-19 patients. However, some in vitro data supported the ability of chloroquine and hydroxychloroquine in inhibiting the activity of SARS-CoV-2 and reported them as beneficial in both prophylactic and therapeutic interventions.10,58 More-over, several systematic reviews9,18,20,22,25,26,36,42,49,52 that reported in favor of using this class of drugs, cited an open-label non-randomized controlled trial by Gautret et al.,61 and concluded that hydroxychloro-quine treatment (600 mg/daily) was associated with SARS-CoV-2 viral load reduction/disappearance, and its effects were reinforced by azithromycin. Other stud-ies also reported that using a 400 mg/daily dosage led to no clinical difference between hydroxychloroquine and the standard treatment group on day 7.9,10,20,22,42,52 Conversely, very few studies reported some clinically meaningful outcomes associated with the use of these drugs (e.g. a smaller number of cases showing radiological progression of lung disease,25,49,52 faster fever recovery and cough relief,26 and virological clearance).57Corticosteroids and glucocorticoids. Corticoste-roids including methylprednisolone and dexa-methasone were another common drug category used to treat COVID-19, mainly in addition to other classes of drugs such as antivirals and antibiotics.7,19,23,24,30–33,38–40,43,45,48,51,53,54,56–58 The evidence, however, was inconsistent about admin-istering corticosteroids for COVID-19 patients. For example, Tobaiqy et al.57 and Zhang et al.33 recommended against using corticosteroids among COVID-19 patients due to increased risks of mortality. Lu et al. also reported higher rates of M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 27death (Relative risk [RR] = 2.0) among COVID-19 patients who were receiving corticosteroids in comparison with those who did not.45 Conversely, Yang et al.54 and Alijotas-Reig et al.40 showed that patients with severe conditions were more likely to benefit from corticosteroid therapy. In addi-tion, Ye et al.24 reported that corticosteroids were only beneficial in reducing mortality (Hazard ratio [HR] = 0.41) among COVID-19 patients who also had ARDS. Some studies also reported no clinically meaningful benefits or harms for using corticosteroids among COVID-19 patients.38,39,51Other pharmacological treatments. Ten reviews repor-ted that immunoglobulin was used to treat some of the COVID-19 patients.7,19,23,31,32,40,43,53,56,57 These medications were used as co-interventions in COVID-19 treatment and their specific efficacy was not evaluated. Valk et al.32 reported that the use of immunoglobulin was associated with improve-ment in clinical symptoms and a reduction in hos-pitalization period among COVID-19 patients. Moreover, Alijotas-Reig et al.40 recommended a high intensity anti-inflammatory and immuno-modulatory therapy for severe patients as a poten-tial therapeutic option. In six studies, Interleukin-6 (IL-6) agents such as tocilizumab and sarilumab were used as supportive treatments for COVID-19.25,30,39,40,48,58 Some studies showed that tocili-zumab could improve clinical status in severe to critically ill patients.39,40,48,58 The C-reactive pro-tein level was significantly lower after the initiation of tocilizumab in patients.30 In addition, five stud-ies19,41,44,56,57 reported the usage of antifungal agents in the treatment of patients in some studies, mainly as an add-on therapy. Traditional Chinese medicine34,53,57,58 and herbal medicine23,28,31 were some of the other treatment co-interventions examined for COVID-19, yet their effectiveness was not fully assessed and few details were pro-vided for these interventions.Non-pharmacological interventions. Oxygen therapy and invasive or non-invasive mechanical ventilation were the two main supportive non-pharmacological interventions used in COVID-19 treatment approaches.7,19,25,29,31,32,43,44,46,50,53,54,56 As these interventions were mainly used as an add-on treatment in COVID-19 patients with severe or in critical conditions, reviews did not specifically assess or discuss their efficacy. As ARDS was one of the frequently reported complications among COVID-19 patients, the prin-ciples of treatment for these patients were focused on improving oxygenation and supporting the function of multiple organs.33 However, included reviews did not specify the effectiveness of oxygen therapy and ventilation in COVID-19 patients. Moreover, two studies reported on the use of mesenchymal stromal cells but provided few details about its efficacy,21,39 five reported on the use of convalescent plasma,32,39,40,44,57 and three reported on the use of con-tinuous renal replacement therapies (CRRT);7,19,54 none of which reported on the specific efficacy of these interventions.Adverse drug eventsA total of 13 systematic reviews reported adverse drug events (ADEs) for hydroxychloroquine/ chloroquine phosphate.10,20,22,25,35,39,40,46,50,52,53,57,59 Two systematic reviews and meta-analyses showed that there was no statistically significant difference in the incidence of ADEs between hydroxychloro-quine therapy and the control group (Odds ratio [OR] = 2.19, 95% confidence interval [CI] 0.59– 8.18,52 and RR = 1.65, 95% CI 0.50–5.50).46 Studies found hydroxychloroquine to be safe with mild adverse reactions such as diarrhea, nausea, vomiting, rash, headache, lethargy, blurred vision, and transient abnormal liver func-tions.22,25,34,39,50,52,55,59 Moreover, hydroxychloro-quine was not found to increase the occurrence of abnormal liver function test results, increased serum creatinine level, rash, headache, or anemia in comparison with the control group.25 Some studies reported QT prolongation associated with hydroxychloroquine treatment.22,25,52,59 Hernandez et al. reported that more patients receiving hydrox-ychloroquine plus azithromycin had a QTc inter-val of 500 ms or greater [mean difference = 1.8%, 95% CI –14.9–18.5%]. Moreover, more patients had a QTc interval increase of ⩾ 60 ms compared to baseline (mean difference = 5.1%, 95% CI –7.6% to 17.8%) versus hydroxychloroquine alone.25 Other electrocardiogram changes were first-degree atrio-ventricular block22,59 and left bundle-branch block.59 One patient died in the hydroxychloro-quine arm on day three despite a negative RT-PCR.52,59 Severe ADEs were not reported in patients treated with chloroquine,10,59 but those receiving a higher dose of chloroquine therapy experienced a slight increase in anemia and a large increase in serum creatinine level compared with those receiving a lower dose.25 Moreover, 23% (22 of 95) of patients receiving chloroquine had a QTc interval greater than 500 ms.25Therapeutic Advances in Respiratory Disease 1428 journals.sagepub.com/home/tarADEs were also reported in 60% of patients taking remdesivir,27,39 and the most common ADEs were rash, diarrhoea, hypotension, nausea, abnormal liver function, and renal impairment. Serious ADEs (e.g. acute kidney injury, septic shock, multi-organ failure, and acute respiratory failure) were noted in 18–23% of patients and 8–12% of patients discontinued remdesivir because of mild or serious ADEs.27,35,39 The review of Shi et al. reported no statistically significant difference in the incidence of ADEs (RR = 1.24, 95% CI 0.67–2.28) and serious ADEs (RR = 0.62, 95% CI 0.38–1.01) among patients receiving lopinavir/ritonavir and others groups.46 The most common reported ADEs were gastrointestinal reactions, abnormal liver function, anemia, insomnia, bradycardia, or hypoxemia.20,39,46,50,53 Moreover, 13% of patients were unable to complete the full course of treat-ment due to anorexia, nausea, abdominal discom-fort, or diarrhoea.39 In the study by Tobaiqy et al., the patients who took up lopinavir/ritonavir also complained about psychiatric symptoms, gastroin-testinal ADEs, skin eruptions, and hypokalemia. Abnormal liver function, raised serum uric acid, psychiatric symptom reactions, and gastrointesti-nal ADEs were also detected in the patients receiv-ing favipiravir and arbidol.57 Moreover, favipiravir caused diarrhoea, and two systematic reviews reported no ADEs for arbidol.20,39 Furthermore, no obvious ADEs were reported in children receiv-ing antiviral therapies.46The combined therapy of herbal medicine with western medicine had minor ADEs including, nausea and vomiting, diarrhoea, liver damage, and reduced blood cell count. There was no sta-tistically significant difference between the com-bination of herbal medicine and western medicine versus western medicine alone (risk differ-ence = 0.06, 95% CI –0.04 to 0.15).28,34 Valk et al. reported moderate fever after the transfusion of convalescent plasma32 and no other adverse reactions were reported.32,44 Moreover, ADEs were not reported for intravenous immunoglobu-lin (IVIG).43 Mild adverse reactions were reported in patients treated with mesenchymal stromal cells (e.g. grade I allergic reaction, generalized skin rash, diarrhoea, transient desaturation, dysp-nea, and hypotension).21 Finally, hyperglycemia, hypernatremia, hypokalemia, coinfections (bacte-rial or fungal), multiple organ dysfunction syn-drome, and ARDS were the most common ADEs associated with corticosteroid use and required routine monitoring.24,45,57DiscussionThis overview of reviews summarized the system-atic reviews describing therapeutic interventions for COVID-19 patients. While the antiviral and antibiotic agents, corticosteroids, and antimalar-ial agents were the most common drug classes used to treat COVID-19, the systematic reviews showed no strong evidence to support their effi-cacy. Oxygen therapy and ventilatory support were also the most common supportive care in patients with respiratory distress and low oxygen saturation levels. The outcomes reported in the included review studies were either incomplete or unclear, and most did not report on ADEs of dif-ferent treatment options which made interpreta-tions and comparisons about the efficacy and safety of treatments challenging.Given the lack of an effective antiviral treatment for COVID-19, drugs previously developed to treat other viral infections are being tested. The most widely used antiviral agents are lopinavir, ritonavir, oseltamivir, arbidol, remdesivir, and cytokines. The timing, duration, and dose of anti-viral agents varied greatly across the studies, and most patients were provided with other interven-tions that may have contributed to outcomes such as recovery and death. Overall, although there are early findings about the potential promise in the safety and efficacy of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin, the evidence supporting their efficacy and safety has been rather inconsistent and uncertain.20,39,42,46,49,53,62 The evi-dence on remdesivir has also been mixed and requires further higher quality data for better assessment of its efficacy and safety. While remde-sivir use was not associated with statistically signifi-cant clinical benefits and only led to a numerical reduction in time to clinical improvement among 237 patients enrolled in a randomized, double-blind, multicentre clinical trial in China,63 there is some evidence that supports a modest improve-ment in clinical outcomes among COVID-19 patients who have received remdesivir.27,35,37 Nonetheless, as outlined in several systematic reviews in our study, the certainty of the evidence for the efficacy and safety of antiviral agents in COVID-19 treatment remains low. On the other hand, a high proportion of patients with COVID-19 were treated with antibiotics, despite the lack of aetiological evidence. This is concerning as an emerging body of evidence suggests that secondary bacterial or fungal infections such as Acinetobacter baumannii, Klebsiella pneumonia, and Aspergillus M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 29flavus may occur in COVID-19 patients.47,64 For example, a brief report describing the characteris-tics of 3200 COVID-19-related deaths from Italy reported superinfection in 8.5% of patients.65Despite the initial excitement about the potential significant effectiveness of chloroquine and hydroxychloroquine for treating COVID-19,52,61,66 the findings of our overview are in line with more recent high-quality studies67–69 such as the Randomized Evaluation of COVid-19 thERapY (RECOVERY) trial70 that suggest little to no ben-efits in using these drugs for COVID-19 treat-ment. Moreover, in a large multinational study of over 96,000 patients with confirmed COVID-19 in 671 hospitals around the world, hydroxychloro-quine or chloroquine, used alone or with a macrolide, were indeed harmful to in-hospital outcomes for COVID-19.69,71 Findings from another well-designed recent randomized con-trolled trial also indicated that in comparison with standard of care, hydroxychloroquine was not associated with higher rates of negative conversion and led to a higher probability of experiencing ADEs among its recipients.67 Overall, the harms of using this group of drugs seem to overweigh their benefits for COVID-19 patients and the US Food and Drug Administration’s decision to cau-tion against the use of these drugs seems well sup-ported by the existing evidence.72,73Corticosteroids were also assessed as largely unhelpful in most reviews. Patients with severe conditions were more likely to require corticoster-oids and they were associated with increased mor-tality in patients with coronavirus pneumonia.54 Moreover, recent studies have recommended against using corticosteroids for the routine treat-ment of COVID-19 patients due to increased risks of steroid-induced osteonecrosis of the femoral head (ONFH).74,75 Corticosteroids may still be a viable option for patients in critical conditions or septic shock, and prescribing them with bisphos-phonates and vitamin E might help address some of the complications such as mortality and mechan-ical ventilation.76–78 Immunoglobulin, gamma globulin, traditional Chinese and herbal medicine were other treatment options for treating COVID-19; however, they were relatively uncommon at the time of writing this review and data about their efficacy are limited.79Previous studies have shown that an increased level of cytokines, IL-6 in severe patients in particular, may be attributed to cytokine release syndrome.80,81 As IL-6 plays an important role in the cytokine storm,80,81 it may serve as a possible treatment approach in severe patients. Based on six systematic reviews that assessed tocilizumab, this IL-6 blockade agent could be beneficial in the treatment of severely ill COVID-19 patients. These findings are in line with recent cohort stud-ies that have suggested that the IL-6 blockade does not impair the specific antibody response against SARS-CoV-2 and may help reduce the risk of death among severely ill COVID-19 patients;82,83 nonetheless, they warrant further investigation in sufficiently controlled trials.This overview identified oxygen therapy and ven-tilation as the two main non-pharmacological interventions used for COVID-19 patients. As the disease progresses, greater amounts of oxygen are needed. In patients with COVID-19, the deci-sion to use high-flow oxygen via a nasal cannula or the initiation of non-invasive ventilation is con-troversial and there are no data describing whether these modalities were successful at avoiding intu-bation.84 A systematic review on severe and criti-cally severe COVID-19 patients suggested that the principles of treatment for these patients should be lung-protective and focus on improving oxygenation.85 CRRT and convalescent plasma therapy were other therapeutics assessed by some reviews but their effects on COVID-19 patients were not fully evaluated. The result of a retro-spective cohort study showed the patients in the CRRT group had better survival rates than those in the non-CRRT group.86 Furthermore, case series showed that convalescent plasma therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases.8,87,88 However, the optimal dose, time point, and the clinical benefits of this intervention need further investigations in larger and well-controlled trials.Most systematic reviews scored poorly on the AMSTAR-2 tool; 29 were assessed as critically low, nine as low quality, and seven as moderate quality. Most of the included studies in the reviews were observational, which was indeed inevitable as the findings of large clinical trials are not fully available. We also noted that the findings of the studies were not likely to be biased due to overlap. Nonetheless, these limitations have sig-nificant implications for policy and clinical deci-sion-making. It is important to ensure that the Therapeutic Advances in Respiratory Disease 1430 journals.sagepub.com/home/tarurgency for summarizing information on the effective treatment options for COVID-19 is not used as a justification for low-quality evidence syntheses. Indeed, promptness and comprehen-siveness must be balanced to ensure decision-makers and clinicians are not provided with misleading information. Moreover, reporting out-comes about the safety of treatment options for COVID-19 is of utmost importance and should not be overlooked.We acknowledge four main limitations of our over-view of reviews. First, the actual effects of different treatments is still unclear, and our understanding continues to improve; however, our findings are important and informative for the decisions that need to be made based on the existing evidence. Second, evaluating the efficacy of therapeutic interventions was not a primary objective in most of the included systematic reviews; therefore, suf-ficient information and details were not provided in some studies. Third, the heterogeneity of the studied population, unclear definition of treatment and outcome variables as well as comparison groups of reviews limited our statistical analysis and we could not conduct a meta-analysis or net-work meta-analysis. We are hoping to update our live overview as more high-quality data and statis-tically comparable outcomes become available. Finally, the methodological quality of reviews was very concerning and the evidence on treatments was mostly from a few countries, China in particu-lar. It is important to revisit what we know as treat-ment data from other countries are released. Despite these limitations, this overview followed a rigorous methodological approach and contributes to the literature by providing a comprehensive summary of all available evidence about COVID-19 treatment options as well as assessing the con-fidence in the findings of the existing systematic reviews.ConclusionThe number of reviews on pharmacological and non-pharmacological therapies for COVID-19 is rapidly increasing. However, many reviews still show significant methodological flaws limiting definite conclusions about the efficacy and safety of therapeutic interventions. In particular, very little is known about the cost-effectiveness of existing treatments, particularly in low and mid-dle-income countries. More high-quality, evi-dence-based clinical trials with proper design and adequate sample size would help reach more reli-able results about the use of specific therapeutic interventions in the treatment of COVID-19 in the short and long term. Overall, this review dem-onstrates that although some therapeutic inter-ventions (e.g. corticosteroids, remdesivir) may be helpful to certain subgroups of COVID-19 patients, the available data are insufficient to strongly recommend any particular treatment to be used at a population level.Author contribution(s)Malahat Khalili: Conceptualization; Supervision; Validation; Data and narrative syn-thesis; Investigation; Methodology; Writing-original draft.Maryam Chegeni: Data curation; Data and narrative synthesis; Investigation; Methodology; Writing-original draft.Sara Javadi: Data curation; Data and narrative synthesis; Investigation; Methodology; Writing-review & editing.Mehrdad Farokhnia: Conceptualization; Methodology; Project administration; Validation; Writing-review & editing.Hamid Sharifi: Conceptualization; Project administration; Data and narrative synthesis; Methodology; Validation; Writing-review & editing.Mohammad Karamouzian: Conceptualization; Data curation; Data and narrative synthesis; Investigation; Methodology; Project administra-tion; Supervision, Validation; Visualization; Writing-review & editing.Conflict of interestThe author(s) declare that there is no conflict of interest.EthicsGiven the secondary nature of this overview and no interaction with humans, ethics approval was not required.Funding Mohammad Karamouzian is a member of Pierre Elliot Trudeau Foundation’s COVID-19 impact committee, and is supported by the Vanier Canada Graduate Scholarship as well as the Pierre Elliott Trudeau Foundation Doctoral Scholarship.M Khalili, M Chegeni et al.journals.sagepub.com/home/tar 31ORCID iDMalahat Khalili https://orcid.org/0000-0001- 6160-0913Supplemental materialThe reviews of this paper are available via the supplemental material section.References 1. 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Therapeutic interventions for COVID-19 : a living overview of reviews
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