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Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n2231 (Published 23 September 2021) Cite this as: BMJ 2021;374:n2231

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  1. Reed AC Siemieniuk, methodologist, internist12*,
  2. Jessica J Bartoszko, methodologist1*,
  3. Juan Pablo Díaz Martinez, statistician1*,
  4. Elena Kum, graduate student1*,
  5. Anila Qasim, methodologist1*,
  6. Dena Zeraatkar, methodologist1*,
  7. Ariel Izcovich, methodologist, internist3,
  8. Sophia Mangala, research assisstant1,
  9. Long Ge, methodologist4,
  10. Mi Ah Han, methodologist5,
  11. Thomas Agoritsas, methodologist, internist16,
  12. Donald Arnold, professor of hematology2,
  13. Camila Ávila, methodologist7,
  14. Derek K Chu, methodologist, immunologist12,
  15. Rachel Couban, librarian8,
  16. Ellen Cusano, internist9,
  17. Andrea J Darzi, methodologist1,
  18. Tahira Devji, methodologist10,
  19. Farid Foroutan, methodologist11,
  20. Maryam Ghadimi, methodologist1,
  21. Assem Khamis, data analyst12,
  22. Francois Lamontagne, methodologist, critical care physician13,
  23. Mark Loeb, methodologist, infectious disease physician12,
  24. Anna Miroshnychenko, graduate student1,
  25. Sharhzad Motaghi, methodologist1,
  26. Srinivas Murthy, clinical associate professor, pediatric critical care, infectious diseases physician14,
  27. Reem A Mustafa, associate professor, nephrologist115,
  28. Gabriel Rada, methodologist7,
  29. Bram Rochwerg, methodologist, critical care physician12,
  30. Charlotte Switzer, graduate student1,
  31. Per O Vandvik, methodologist, internist16,
  32. Robin WM Vernooij, methodologist1718,
  33. Ying Wang, methodologist, pharmacist1,
  34. Liang Yao, methodologist1,
  35. Gordon H Guyatt, methodologist, internist12,
  36. Romina Brignardello-Petersen, methodologist1
  1. 1Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8, Canada
  2. 2Department of Medicine, McMaster University, Hamilton, ON, Canada
  3. 3Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina
  4. 4Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
  5. 5Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, Republic of Korea
  6. 6Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  7. 7Epistemonikos Foundation, Santiago, Chile
  8. 8Department of Anesthesia, McMaster University, Hamilton, ON, Canada
  9. 9Department of Medicine, University of Calgary, Calgary, AB, Canada
  10. 10Medical school, University of Toronto, Toronto, ON, Canada
  11. 11Ted Rogers Center for Heart Research, University Health Network, Toronto, ON, Canada
  12. 12Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK
  13. 13Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada
  14. 14Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver
  15. 15Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA
  16. 16Institute of Health and Society, University of Oslo, Oslo, Norway
  17. 17Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
  18. 18Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  19. *Joint first authors
  1. Correspondence to: R Siemieniuk reed.siemieniuk{at}medportal.ca
  • Accepted 10 September 2021

Abstract

Objective To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19).

Design Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data.

Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021).

Study selection Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate.

Methods After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm.

Results As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative.

Conclusion In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.

Systematic review registration This review was not registered. The protocol established a priori is included as a data supplement.

Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321).

Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).

Footnotes

  • Contributors: RACS, JJB, JDM, EK, AQ, and DZ contributed equally to the systematic review and are joint first authors. RACS, JJB, EK, JDM, AQ, SM, DZ, LG, and RB-P were the core team leading the systematic review. JJB, RC, RWMV, SM, YW, AD, TD, AI, CS, AV-G, and MG identified and selected the studies. DZ, EK, EC, RWMV, AA, AK, YW, KH, HP-H, MAH, CF, AS, and MG collected the data. AQ, AK, LG, and GHG analysed the data. RB-P, FF, HP-H, MG, AI, AM, RAM, TD, and DC assessed the certainty of the evidence. SLM, SM, FL, BR, TA, POV, GHG, ML, DA, and GR provided advice at different stages. RACS, RB-P, and GHG drafted the manuscript.

  • All authors approved the final version of the manuscript. RACS is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Canadian Institutes of Health Research for the submitted work; ML reports personal fees and non-financial support from Sanofi, grants and personal fees from Seqirus, personal fees from Pfizer, and personal fees from Medicago outside the submitted work, and is a co-investigator on ACT randomised trial of covid-19 therapy; LG reports grants from Ministry of Science and Technology of China outside the submitted work.

  • RACS affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Dissemination to participants and related patient and public communities: The infographic and MAGICapp decision aids (available at www.magicapp.org/) were created to facilitate conversations between healthcare providers and patients or their surrogates. The MAGICapp decision aids were co-created with people who have lived experience of covid-19.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

No additional data available.

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