Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Manu Shankar-Hari; Claire L Vale; Peter J Godolphin; David Fisher; Julian P T Higgins; Francesca Spiga; Jelena Savović; Jayne Tierney; Gabriel Baron; Julie S Benbenishty; Lindsay R Berry; Niklas Broman; Alexandre Biasi Cavalcanti; Roos Colman; Stefanie L De Buyser; Lennie P G Derde; Pere Domingo; Sharifah Faridah Omar; Ana Fernandez-Cruz; Thijs Feuth; Felipe Garcia; Rosario Garcia-Vicuna; Isidoro Gonzalez-Alvaro; Anthony C Gordon; Richard Haynes; Olivier Hermine; Peter W Horby; Nora K Horick; Kuldeep Kumar; Bart N Lambrecht; Martin J Landray; Lorna Leal; David J Lederer; Elizabeth Lorenzi; Xavier Mariette; Nicolas Merchante; Nor Arisah Misnan; Shalini V Mohan; Michael C Nivens; Jarmo Oksi; Jose A Perez-Molina; Reuven Pizov; Raphael Porcher; Simone Postma; Reena Rajasuriar; Athimalaipet V Ramanan; Philippe Ravaud; Pankti D Reid; Abraham Rutgers; Aranzazu Sancho-Lopez; Todd B Seto; Sumathi Sivapalasingam; Arvinder Singh Soin; Natalie Staplin; John H Stone; Garth W Strohbehn; Jonas Sunden-Cullberg; Julian Torre-Cisneros; Larry W Tsai; Hubert van Hoogstraten; Tom van Meerten; Viviane Cordeiro Veiga; Peter E Westerweel; Srinivas Murthy; Janet V Diaz; John C Marshall; Jonathan A C Sterne

doi:10.1001/jama.2021.11330

. 2021 Jul 6;326(6):1–20. doi: 10.1001/jama.2021.11330

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

A Meta-analysis

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Manu Shankar-Hari ^1,^2,^✉, Claire L Vale ³, Peter J Godolphin ³, David Fisher ³, Julian P T Higgins ^4,^5,⁶, Francesca Spiga ⁷, Jelena Savović ^4,⁶, Jayne Tierney ³, Gabriel Baron ^8,⁹, Julie S Benbenishty ¹⁰, Lindsay R Berry ¹¹, Niklas Broman ¹², Alexandre Biasi Cavalcanti ¹³, Roos Colman ¹⁴, Stefanie L De Buyser ¹⁴, Lennie P G Derde ¹⁵, Pere Domingo ¹⁶, Sharifah Faridah Omar ¹⁷, Ana Fernandez-Cruz ¹⁸, Thijs Feuth ¹⁹, Felipe Garcia ²⁰, Rosario Garcia-Vicuna ²¹, Isidoro Gonzalez-Alvaro ²¹, Anthony C Gordon ²², Richard Haynes ^23,²⁴, Olivier Hermine ^25,²⁶, Peter W Horby ^27,^28,²⁹, Nora K Horick ³⁰, Kuldeep Kumar ^31,³², Bart N Lambrecht ^33,³⁴, Martin J Landray ^23,²⁴, Lorna Leal ²⁰, David J Lederer ³⁵, Elizabeth Lorenzi ¹¹, Xavier Mariette ^36,³⁷, Nicolas Merchante ³⁸, Nor Arisah Misnan ³⁹, Shalini V Mohan ⁴⁰, Michael C Nivens ³⁵, Jarmo Oksi ¹², Jose A Perez-Molina ⁴¹, Reuven Pizov ⁴², Raphael Porcher ^8,^9,⁴³, Simone Postma ⁴⁴, Reena Rajasuriar ^17,⁴⁵, Athimalaipet V Ramanan ⁴⁶, Philippe Ravaud ^8,^9,⁴³, Pankti D Reid ⁴⁷, Abraham Rutgers ⁴⁴, Aranzazu Sancho-Lopez ⁴⁸, Todd B Seto ⁴⁹, Sumathi Sivapalasingam ³⁵, Arvinder Singh Soin ³¹, Natalie Staplin ^23,²⁴, John H Stone ^50,⁵¹, Garth W Strohbehn ⁵², Jonas Sunden-Cullberg ⁵³, Julian Torre-Cisneros ⁵⁴, Larry W Tsai ⁴⁰, Hubert van Hoogstraten ⁵⁵, Tom van Meerten ⁵⁶, Viviane Cordeiro Veiga ¹³, Peter E Westerweel ⁵⁷, Srinivas Murthy ⁵⁸, Janet V Diaz ⁵⁹, John C Marshall ⁶⁰, Jonathan A C Sterne ^4,^5,⁶¹

¹Guy’s and St Thomas’ NHS Foundation Trust, ICU Support Offices, St Thomas’ Hospital, London, England

²School of Immunology and Microbial Sciences, Kings College London, London, England

³University College London, MRC Clinical Trials Unit at UCL, London, England

⁴Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England

⁵NIHR Bristol Biomedical Research Centre, Bristol, England

⁶National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England

⁷University of Bristol, Bristol, England

⁸Assistance Publique–Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France

⁹INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France

¹⁰Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel

¹¹Berry Consultants, Austin, Texas

¹²Turku University Hospital, Department of Infectious Diseases, Turku, Finland

¹³BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil

¹⁴Department of Public Health and Primary Care, Ghent University, Ghent, Belgium

¹⁵Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands

¹⁶Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

¹⁷Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia

¹⁸Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain

¹⁹Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland

²⁰Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain

²¹Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain

²²Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England

²³Nuffield Department of Population Health, University of Oxford, Oxford, England

²⁴MRC Population Health Research Unit, University of Oxford, Oxford, England

²⁵Department of Hematology, Necker Hospital, Paris, France

²⁶Imagine Institute, University of Paris, INSERM U1153, Paris, France

²⁷Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England

²⁸International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England

²⁹Pandemic Sciences Centre, University of Oxford, Oxford, England

³⁰Department of Medicine, Massachusetts General Hospital, Boston

³¹Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India

³²Research Department, Medanta Institute of Education and Research, Gurugram, India

³³VIB Center for Inflammation Research, Ghent University, Ghent, Belgium

³⁴Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium

³⁵Regeneron Pharmaceuticals Inc, Tarrytown, New York

³⁶Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France

³⁷Department of Rheumatology, Assistance Publique–Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France

³⁸Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain

³⁹Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia

⁴⁰Genentech, South San Francisco, California

⁴¹Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain

⁴²Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel

⁴³University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France

⁴⁴Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands

⁴⁵Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia

⁴⁶Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England

⁴⁷Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois

⁴⁸Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

⁴⁹Center for Outcomes Research and Evaluation, Queen’s Medical Center, Honolulu, Hawaii

⁵⁰Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston

⁵¹Department of Medicine (Rheumatology), Massachusetts General Hospital, Boston

⁵²VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan

⁵³Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden

⁵⁴Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain

⁵⁵Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey

⁵⁶Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands

⁵⁷Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands

⁵⁸Department of Pediatrics, University of British Columbia, Vancouver, Canada

⁵⁹Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland

⁶⁰Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

⁶¹Health Data Research UK South-West, Bristol, England

^✉

Corresponding Author: Manu Shankar-Hari, MSc, PhD, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust London, East Wing, London SE17EH, England (manu.shankar-hari@kcl.ac.uk).

Group Information: The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group authors and collaborators are listed at the end of this article.

Accepted for Publication: June 24, 2021.

Published Online: July 6, 2021. doi:10.1001/jama.2021.11330

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group authors and collaborators: Manu Shankar-Hari, PhD, MSc; Claire L. Vale, PhD; Peter J. Godolphin, PhD; David Fisher, MSc; Julian P. T. Higgins, PhD; Francesca Spiga, PhD; Jelena Savović, PhD; Jayne Tierney, PhD; Gabriel Baron, PhD; Julie S. Benbenishty, PhD; Lindsay R. Berry, PhD; Niklas Broman, MD; Alexandre Biasi Cavalcanti, MD; Roos Colman, MSc; Stefanie L. De Buyser, PhD; Lennie P. G. Derde, MD, PhD; Pere Domingo, PhD; Sharifah Faridah Omar, MD; Ana Fernandez-Cruz, MD, PhD; Thijs Feuth, MD, PhD; Felipe Garcia, MD, PhD; Rosario Garcia-Vicuna, PhD; Isidoro Gonzalez-Alvaro, PhD; Anthony C. Gordon, MBBS, MD; Richard Haynes, DM; Olivier Hermine, MD, PhD; Peter W. Horby, MBBS; Nora K. Horick, MS; Kuldeep Kumar, MSc; Bart N. Lambrecht, MD, PhD; Martin J. Landray, PhD; Lorna Leal, MD, PhD; David J. Lederer, MD; Elizabeth Lorenzi, PhD; Xavier Mariette, MD, PhD; Nicolas Merchante, MD, PhD; Nor Arisah Misnan, MMed; Shalini V. Mohan, MD; Michael C. Nivens, PhD; Jarmo Oksi, MD, PhD; Jose A. Perez-Molina, PhD; Reuven Pizov, MD; Raphael Porcher, PhD; Simone Postma, MD; Reena Rajasuriar, PhD; Athimalaipet V. Ramanan, MD; Philippe Ravaud, MD, PhD; Pankti D. Reid, MD, MPH; Abraham Rutgers, MD, PhD; Aranzazu Sancho-Lopez, MD, PhD; Todd B. Seto, MD; Sumathi Sivapalasingam, MD; Arvinder Singh Soin, MS; Natalie Staplin, PhD; John H. Stone, MD, MPH; Garth W. Strohbehn, MD; Jonas Sunden-Cullberg, MD, PhD; Julian Torre-Cisneros, PhD; Larry W. Tsai, MD; Hubert van Hoogstraten, MD, PhD; Tom van Meerten, MD, PhD; Viviane Cordeiro Veiga, PhD; Peter E. Westerweel, MD, PhD; Srinivas Murthy, MD, CM, MHSc; Janet V. Diaz, MD; John C. Marshall, MD; Jonathan A. C. Sterne, PhD.

Affiliations of The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group authors and collaborators: Guy’s and St Thomas’ NHS Foundation Trust, ICU Support Offices, St Thomas’ Hospital, London, England (Shankar-Hari); School of Immunology and Microbial Sciences, Kings College London, London, England (Shankar-Hari); University College London, MRC Clinical Trials Unit at UCL, London, England (Vale, Godolphin, Fisher, Tierney); Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England (Higgins, Savović, Sterne); NIHR Bristol Biomedical Research Centre, Bristol, England (Higgins, Sterne); National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England (Higgins, Savović); University of Bristol, Bristol, England (Spiga); Assistance Publique–Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France (Baron, Porcher, Ravaud); INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France (Baron, Porcher, Ravaud); Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel (Benbenishty); Berry Consultants, Austin, Texas (Berry, Lorenzi); Turku University Hospital, Department of Infectious Diseases, Turku, Finland (Broman, Oksi); BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil (Cavalcanti, Veiga); Department of Public Health and Primary Care, Ghent University, Ghent, Belgium (Colman, De Buyser); Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands (Derde); Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Domingo); Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia (Omar, Rajasuriar); Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain (Fernandez-Cruz); Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland (Feuth); Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain (Garcia, Leal); Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain (Garcia-Vicuna, Gonzalez-Alvaro); Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England (Gordon); Nuffield Department of Population Health, University of Oxford, Oxford, England (Haynes, Landray, Staplin); MRC Population Health Research Unit, University of Oxford, Oxford, England (Haynes, Landray, Staplin); Department of Hematology, Necker Hospital, Paris, France (Hermine); Imagine Institute, University of Paris, INSERM U1153, Paris, France (Hermine); Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England (Horby); International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England (Horby); Pandemic Sciences Centre, University of Oxford, Oxford, England (Horby); Department of Medicine, Massachusetts General Hospital, Boston (Horick); Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India (Kumar, Soin); Research Department, Medanta Institute of Education and Research, Gurugram, India (Kumar); VIB Center for Inflammation Research, Ghent University, Ghent, Belgium (Lambrecht); Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium (Lambrecht); Regeneron Pharmaceuticals Inc, Tarrytown, New York (Lederer, Nivens, Sivapalasingam); Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France (Mariette); Department of Rheumatology, Assistance Publique–Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France (Mariette); Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain (Merchante); Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia (Misnan); Genentech, South San Francisco, California (Mohan, Tsai); Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain (Perez-Molina); Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel (Pizov); University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France (Porcher, Ravaud); Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands (Postma, Rutgers); Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia (Rajasuriar); Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England (Ramanan); Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois (Reid); Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain (Sancho-Lopez); Center for Outcomes Research and Evaluation, Queen’s Medical Center, Honolulu, Hawaii (Seto); Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston (Stone); Department of Medicine (Rheumatology), Massachusetts General Hospital, Boston (Stone); VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan (Strohbehn); Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden (Sunden-Cullberg); Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain (Torre-Cisneros); Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey (van Hoogstraten); Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands (van Meerten); Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands (Westerweel); Department of Pediatrics, University of British Columbia, Vancouver, Canada (Murthy); Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland (Diaz); Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (Marshall); Health Data Research UK South-West, Bristol, England (Sterne).

Author Contributions: Dr Vale had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Shankar-Hari and Vale contributed equally.

Concept and design: Shankar-Hari, Vale, Godolphin, Tierney, Misnan, Benbenishty, Omar, Garcia, Garcia-Vicuna, Gordon, Hermine, Perez-Molina, Pizov, Rajasuriar, Reid, Sancho-Lopez, Stone, Tsai, Veiga, Murthy, Diaz, Marshall, Sterne.

Acquisition, analysis, or interpretation of data: Shankar-Hari, Vale, Godolphin, Fisher, Higgins, Spiga, Savovic, Misnan, Baron, Benbenishty, Berry, Broman, Biasi Cavalcanti, Colman, De Buyser, Domingo, Derde, Omar, Fernández-Cruz, Feuth, Garcia, Garcia-Vicuna, Gonzalez-Alvaro, Gordon, Haynes, Hermine, Horby, Horick, Kumar, Lambrecht, Landray, Leal, Lederer, Lorenzi, Mariette, Merchante, Mohan, Nivens, Oksi, Perez-Molina, Pizov, Porcher, Postma, Rajasuriar, Ramanan, Ravaud, Reid, Rutgers, Seto, Sancho-Lopez, Sivapalasingam, Soin, Staplin, Strohbehn, Sunden-Cullberg, Torre-Cisneros, Tsai, van Hoogstraten, van Meerten, Veiga, Westerweel, Murthy, Marshall, Sterne.

Drafting of the manuscript: Shankar-Hari, Vale, Higgins, Baron, Benbenishty, Omar, Kumar, Pizov, Postma, Rajasuriar, Reid, Murthy, Sterne.

Critical revision of the manuscript for important intellectual content: Shankar-Hari, Vale, Godolphin, Fisher, Higgins, Spiga, Savovic, Tierney, Misnan, Baron, Berry, Broman, Biasi Cavalcanti, Colman, De Buyser, Domingo, Derde, Fernández-Cruz, Feuth, Garcia, Garcia-Vicuna, Gonzalez-Alvaro, Gordon, Haynes, Hermine, Horby, Horick, Lambrecht, Landray, Leal, Lederer, Lorenzi, Mariette, Merchante, Mohan, Nivens, Oksi, Perez-Molina, Porcher, Ramanan, Ravaud, Reid, Rutgers, Seto, Sancho-Lopez, Sivapalasingam, Soin, Staplin, Strohbehn, Stone, Sunden-Cullberg, Torre-Cisneros, Tsai, van Hoogstraten, van Meerten, Veiga, Westerweel, Murthy, Diaz, Marshall, Sterne.

Statistical analysis: Shankar-Hari, Vale, Godolphin, Fisher, Spiga, De Buyser, Feuth, Gonzalez-Alvaro, Horick, Kumar, Lorenzi, Merchante, Nivens, Oksi, Postma, Sancho-Lopez, Strohbehn, Murthy, Sterne.

Obtained funding: Derde, Gordon, Hermine, Lambrecht, Lederer, Ravaud, Stone.

Administrative, technical, or material support: Shankar-Hari, Vale, Misnan, Benbenishty, Derde, Gordon, Horby, Leal, Lederer, Mariette, Mohan, Nivens, Rajasuriar, Ramanan, Ravaud, Sancho-Lopez, Tsai, Veiga, Westerweel, Murthy, Diaz.

Supervision: Shankar-Hari, Higgins, Benbenishty, Derde, Garcia, Gordon, Hermine, Lambrecht, Nivens, Oksi, Pizov, Sancho-Lopez, Stone, Torre-Cisneros, Westerweel, Murthy, Diaz, Marshall, Sterne.

Conflict of Interest Disclosures: Dr Shankar-Hari reported being supported by clinician scientist award NIHR-CS-2016-16-011 from the UK National Institute for Health Research. Dr Vale, Mr Fisher, and Dr Tierney reported being supported by grant MC_UU_12023/24 from the UK Medical Research Council. Dr Godolphin reported being fully supported and Mr Fisher was partially supported by grant RIA 16-ST2-020 from Prostate Cancer UK. Dr Higgins reported being supported by senior investigator award NF-SI-0617-10145 from the UK National Institute for Health Research. Drs Higgins and Savović were supported by grants from the UK National Institute for Health Research Applied Research Collaboration West. Drs Higgins and Sterne reported being supported by grants from the UK National Institute for Health Research Bristol Biomedical Research Centre, Weston NHS Foundation Trust, and the University of Bristol. Dr Berry reported receiving grants from Berry Consultants. Dr Derde reported being a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. Drs De Buyser and Lambrecht reported being supported by grants from Belgian Health Care Knowledge Centre. Dr Domingo reported receiving support from the General Subdirectorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; being co-financed by the European Regional Development Fund; receiving grant support from the Instituto de Salud Carlos III for the TOCOVID clinical trial; and receiving honoraria from Merck Sharp & Dohme, Gilead Sciences, ViiV Healthcare, Janssen, Cilag, Theratechnologies, and Roche. Dr Omar reported being supported by grants from the University of Malaya. Dr Garcia-Vicuna reported receiving grants and personal fees from Sanofi and Lilly. Dr Gonzalez-Alvaro reported receiving grants from Sanofi, Biohope, and Gebro; serving on advisory boards for Lilly and Sanofi; receiving personal fees from Lilly, Sanofi, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Abbvie, Pfizer, and Novartis; and owning stock in PharmaMar. Dr Gordon reported being supported by grants from the UK National Institute for Health Research and the European Union and receiving personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. Dr Haynes reported receiving study drugs from Roche and receiving grants from Novartis and Boehringer Ingelheim. Dr Hermine reported receiving grants from Celgene, Bristol Myers Squibb, Alexion, Inatherys, and AB Science. Dr Horby reported receiving study drugs from Roche. Dr Horby reported being supported by grants from UK Research and Innovation–National Institute for Health Research. Dr Lambrecht reported receiving consultancy fees from GlaxoSmithKline, Sanofi, Argenx, Oncoarendi, and Novartis. Dr Landray reported receiving nonfinancial support from Roche and Regeneron and receiving grants from Boehringer Ingelheim, Novartis, and Janssen. Drs Lederer, Nivens, and Sivapalasingam reported being employees of and owning stock in Regeneron. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Mariette reported receiving personal fees from Bristol Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, and Sanofi and receiving grants from Biogen, Ose Pharmaceutical, and Pfizer. Dr Merchante reported receiving grants from Merck Sharp & Dome and personal fees from Gilead, Merck Sharp & Dome, and Shionogi for providing expert testimony. Drs Mohan and Tsai reported being employees of Genetech. Dr Nivens also reported receiving grants from the Biomedical Advanced Research and Development Authority. Dr Perez-Molina reported receiving grants from Roche Spain. Dr Ramanan reported receiving personal fees from Roche, Abbvie, Eli Lilly, Novartis, UCB, and the Swedish Orphan Biovitrum AB. Dr Ravaud reported being the primary investigator of the Corimmuno platform funded by the Ministry of Health in France. Drs Reid and Strohbehn reported being co-inventors of a filed patent (held by the University of Chicago) covering the use of low-dose tocilizumab for treatment of viral infections. Dr Staplin reported receiving study drugs from Roche and Regeneron and receiving grants from Boehringer Ingelheim. Dr Stone reported receiving grants from Roche/Genentech. Dr Strohbehn also reported being an employee of the US government. Dr Sunden-Cullberg reported receiving grants from the Swedish Research Council and the Center for Innovative Medicine. Dr Torre-Cisneros reported being supported by General Sub-Directorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; and being co-financed by the European Regional Development Fund. Dr Tsai also reported being involved with 2 patents pending that were filed and are owned by Genentech/Roche (one for a method to treating pneumonia, including COVID-19 pneumonia with an IL-6 antagonist, and another for tocilizumab and remdesivir combination therapy for COVID-19 pneumonia). Dr van Hoogstraten reported being an employee of and owning stock in Sanofi Genzyme. Dr Veiga reported receiving personal fees from Aspen Pharmacare, Cristália, and Pfizer for speaking and serving on advisory boards. Dr Murthy reported receiving grants from the Canadian Institutes of Health Research, Innovative Medicines Canada, and the Canadian Health Research Foundation. Dr Marshall reported receiving personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). Dr Sterne also reported being supported by grants from Health Data Research UK. No other disclosures were reported.

Funding/Support: Funding for administrative and communications support was provided by the World Health Organization.

Role of the Funder/Sponsor: The World Health Organization (WHO) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The WHO contributed to the design and conduct of the study by convening the WHO COVID-19 Clinical Management and Characterization Working Group. This group assembled information on ongoing trials and invited trial investigators to participate in this prospective meta-analysis. The WHO chief scientist invited trial investigators to participate and provided a secure portal for submission of data. Other than the contributions of Dr Diaz as a co-author, the WHO had no role in the preparation, review, or approval of the manuscript. The WHO had no role in the decision to submit the manuscript for publication.

Group Information: The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group nonauthor collaborators are listed in Supplement 14.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the opinions of the UK National Health Service, the UK National Institute for Health Research, UK Medical Research Council, the UK Department of Health and Social Care, or the US government.

^✉

Corresponding author.

PMCID: PMC8261689 PMID: 34228774

Key Points

Question

Is administration of IL-6 antagonists associated with 28-day all-cause mortality in patients hospitalized for COVID-19?

Findings

This prospective meta-analysis of 27 randomized trials included 10 930 patients, of whom 2565 died by 28 days. The 28-day all-cause mortality was lower among patients who received IL-6 antagonists compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary odds ratios for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids vs 1.09 without administration of corticosteroids.

Meaning

Administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in patients hospitalized for COVID-19.

Abstract

Importance

Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective

To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data Sources

Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study Selection

Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data Extraction and Synthesis

In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I² statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main Outcomes and Measures

The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results

A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions and Relevance

In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Trial Registration

PROSPERO Identifier: CRD42021230155

This prospective meta-analysis estimates the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Introduction

Excessive systemic inflammation and raised IL-6 levels resulting from dysregulated host immune responses^1,2,3 are associated with adverse clinical outcomes in patients hospitalized with COVID-19.⁴ This led to the design of several randomized clinical trials assessing the efficacy of IL-6 antagonists in patients with COVID-19. The IL-6 antagonists commonly investigated were monoclonal antibodies that bind either to membrane-bound and soluble IL-6 receptors (eg, tocilizumab and sarilumab) or directly to IL-6 (eg, siltuximab).⁵

To address the need for reliable efficacy data to guide clinical management, the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group developed a prospective meta-analysis protocol to perform a prospective meta-analysis of IL-6 antagonists in patients hospitalized for COVID-19. This approach was recently used⁶ to evaluate the use of corticosteroids in patients with COVID-19.⁷ During this initiative, trials variously reported potential clinical benefit,^8,9,10 no benefit,^11,12,13 and potential harm¹⁴ with IL-6 antagonists in patients hospitalized for COVID-19.

The primary objective of this prospective meta-analysis of randomized trials⁶ was to estimate the association between administration of IL-6 antagonists, compared with usual care or placebo, and mortality at 28 days after randomization in patients hospitalized for COVID-19. The secondary objectives were to estimate associations within subgroups relating to disease severity (eg, level of respiratory support), treatments at randomization (eg, receipt of corticosteroids), patient characteristics (eg, age), and risk of bias¹⁵ overall and separately for tocilizumab and sarilumab.

Methods

Identification and Eligibility of Trials

Trials were identified through systematic searches of ClinicalTrials.gov, the EU Clinical Trials Register, and the WHO International Clinical Trials Registry Platform from October 7, 2020, to January 11, 2021. The search terms used were random* AND COVID in the title or abstract, along with terms for common IL-6 antagonists individually (tocilizumab, sarilumab, clazakizumab, siltuximab, olokizumab) and the term interleukin 6. Individual searches were then combined. Searches were not restricted by trial status (ongoing or completed), publication status, or language. Additional trials were identified through contact with experts from the REACT Working Group. Queries regarding eligibility for inclusion were resolved by consensus. Eligible trials randomly assigned patients hospitalized for COVID-19 to IL-6 antagonists vs usual care or placebo. Trials in which anti–IL-6 therapies were combined with other immunomodulatory agents or with active comparators other than systemic corticosteroids were excluded.

Development of Prospective Meta-analysis Protocol

The WHO chief scientist invited investigators of eligible trials to participate in this prospective meta-analysis. Representative investigators and sponsors of potentially eligible trials were asked to participate in weekly development calls for the prospective meta-analysis protocol starting on November 23, 2020. The prospective meta-analysis protocol was registered on the PROSPERO database on January 14, 2021, and regularly updated. The PICO (patient problem or population, intervention, comparison or control, and outcome) framework, definitions of outcomes, and subgroups of interest were agreed upon prior to collection of outcome data.⁶ The final version of the prospective meta-analysis protocol was registered before analyses started on March 29, 2021.

Trial-level aggregate data sharing agreements were established. All trials had secured institutional review board approval, but approval was not required for secondary analyses. Informed consent for participation in each trial was obtained, consistent with local institutional review board requirements. Trial investigators were asked to complete baseline and outcome data collection forms that were subsequently verified by trial teams. Finalized data sets from contributing trials were received by May 11, 2021.

Outcomes and Comparisons

The primary outcome measure was all-cause mortality at 28 days after randomization. Two comparisons were specified a priori. The primary comparison investigated the class effect of IL-6 antagonists vs usual care or placebo and tocilizumab and sarilumab were examined separately. The second comparison was of IL-6 antagonists vs corticosteroids.

The secondary outcomes included: (1) invasive mechanical ventilation (IMV), extracorporeal membrane oxygenation (ECMO), or death by 28 days in patients not receiving IMV at randomization (this is the most important secondary outcome for which data on all subgroups were collected); (2) cardiovascular system support (defined as receipt of vasopressors) or death by 28 days in patients not receiving cardiovascular system support at randomization; (3) secondary infections by 28 days (this is the most important safety outcome); (4) in-hospital mortality; (5) kidney replacement therapy (KRT) or death by 28 days in patients not receiving KRT at randomization (excluding patients with underlying dialysis dependence or ≥stage III chronic kidney disease); (6) discharged alive from the hospital by 28 days; (7) mortality by 90 days; (8) duration of IMV up to 28 days (in those receiving IMV at randomization, with duration coded as 28 days for patients who died); and (9) secondary infections by 90 days. Data on serious adverse events or serious adverse reactions (as defined in each trial) were collected; however, no meta-analysis was planned because diverse definitions were used by different trials.

Subgroup Analyses

Trial investigators supplied summary data for all outcomes according to intervention group, overall, and in subgroups based on: (1) degree of respiratory support at randomization (patient not receiving supplemental oxygen therapy, patient receiving supplemental oxygen therapy [defined as oxygen flow rate ≤15 L/min by face mask or nasal cannula], patient receiving noninvasive ventilation [defined as oxygen flow rate >15 L/min, high-flow nasal cannula, continuous positive airway pressure], or patient receiving IMV or ECMO) and (2) receipt of systemic corticosteroids at randomization. In addition, the following subgroups were used for the outcomes of 28-day all-cause mortality and progression to IMV or death: (1) patients receiving acute organ support therapy at randomization (vasopressors or KRT) among those receiving noninvasive ventilation, IMV, or ECMO; (2) age (<70 years or ≥70 years); (3) sex (female or male); (4) race/ethnicity (collected by investigators in each individual trial); and (5) C-reactive protein level at baseline (categorized as <75, 75-<150, ≥150 μg/mL). The assigned dose of IL-6 antagonists was classified as low (4 mg/kg of tocilizumab; 200 mg of sarilumab) or high (>4 mg/kg of tocilizumab or multiple doses; >400 mg of sarilumab or multiple doses).

Risk of Bias Assessment

For each trial, the risk of bias (low risk, some concerns, or high risk) was assessed using version 2 of the Cochrane Risk of Bias Assessment Tool.¹⁵ Risk of bias assessments were based on the trial protocols and flowcharts following the Consolidated Standards of Reporting Trials together with information supplied by the investigators for each trial in a standard format. Risk of bias assessments were done independently by 3 of the investigators (J.P.T.H., F.S., J.S.) with disagreements resolved through discussion. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence.

Data Analyses

The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs). For the duration of IMV therapy, investigators supplied the mean difference and associated 95% CIs in days comparing the treatment and control groups. For the 90-day outcomes, the trial investigators were asked to estimate hazard ratios and 95% CIs (or log hazard ratios and associated standard errors) using Cox regression. Inconsistency in associations among the trials was quantified using the I² statistic. P values for heterogeneity were derived using the Cochran Q statistic. Precise P values were reported; however, the prospective meta-analysis protocol specified that a threshold for statistical significance would not be used. As a sensitivity analysis for the primary outcome of 28-day all-cause mortality, overall associations also were estimated using random-effects meta-analyses with a restricted maximum likelihood estimate of heterogeneity¹⁶ and Hartung-Knapp adjustment^17,18 to account for uncertainty in the estimation of between-study variance. To obtain illustrative absolute risk estimates for patients not receiving treatment with IL-6 antagonists, a mortality risk of 25% and a progression risk of 33% to IMV or death were assumed (the approximate risks among all eligible patients allocated to usual care or placebo). Meta-analytic ORs were then applied to obtain the corresponding risk with IL-6 antagonists. Because outcome data were generally complete or nearly complete across trials, we restricted the analyses to trial participants with outcomes recorded.

Differences in associations between the subgroups were quantified by calculating ratios of ORs (or analogous statistics for other outcome types) to compare the effects in the subgroups along with corresponding P values for interaction. If the ratio of ORs was equal to 1, the estimated associations in the 2 subgroups were the same. The further the ratio of ORs was from 1, the greater was the difference between the estimated associations in the 2 subgroups. Comparisons between subgroups defined by trial characteristics were made using random-effects meta-regression and appropriately accounted for common controls¹⁹ in trials with 3 treatment groups. Comparisons between subgroups defined by patient characteristics were done by estimating trial-specific ratios of ORs comparing associations between subgroups and then combining these in meta-analyses.²⁰ The ORs in patients not receiving corticosteroids were compared with patients receiving corticosteroids at randomization within the respiratory support subgroups. Subgroup-specific estimates adjusted to correspond with the ratios of ORs that were derived from the within-trial approach were also estimated.

In the sensitivity analyses, associations were estimated that (1) excluded the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial; (2) restricted the analyses to trial results at low risk of bias; (3) restricted the analyses to trials published in peer-reviewed journals; (4) restricted the analyses to placebo-controlled trials; and (5) restricted the analyses to open-label trials. The first and third of these were post hoc sensitivity analyses. All analyses were conducted using Stata version 16 (StataCorp) and new Stata commands to conduct and graph the results of the meta-analyses.^21,22

Results

A total of 72 potentially eligible trials were identified. After screening these trials, 38 ineligible trials, 3 duplicated records, and 2 trials directly comparing IL-6 antagonists with corticosteroids (NCT04329650 [n = 158 patients] and NCT04345445 [n = 59 patients]) were excluded. Of 29 eligible trials that randomized patients to receive IL-6 antagonists vs usual care or placebo, 1 trial (n = 50 patients) was unable to supply data in a timely manner and 1 trial (n = 295 patients) was still following up patients for the primary outcome.

Among the 27 trials included in the meta-analyses, 9 were published^{8,9,10,11,12,13,14,23,24} and the remaining 18 were unpublished or were reported as preprints (NCT04412772, NCT04331808 [there were 2 separate trials conducted under a common protocol], NCT04330638, NCT04479358, NCT04577534, NCT04435717, NCT04377750, NCT04409262, EU-CTR 2020-001748-24, EU-CTR 2020-001375-32, EU-CTR 2020-001442-19, NCT04324073 [there were 2 separate trials conducted under a common protocol], NCT04315298, NCT04357808, EU-CTR 2020-001531-27, and EU-CTR 2020-002037-15; Table 1 and eTables 1-3 in Supplement 1). Outcome data were supplied for 10 930 patients, representing 95.4% of all patients randomized in eligible trials (eFigure 1 in Supplement 1). Patients were recruited from 28 countries from February 26, 2020.

Table 1. Selected Characteristics of Included Trials.

Trial^a	Trial registration No.	Treatment group^b	No. of patients	Age, median (IQR), y	Concomitant therapy at randomization, No. (%)
Trial^a	Trial registration No.	Treatment group^b	No. of patients	Age, median (IQR), y	Oxygen flow rate ≤15 L/min^c	Noninvasive ventilation	Invasive mechanical ventilation	Vasoactive medication^d	KRT	Remdesivir	Corticosteroids^e	Convalescent plasma	Anticoagulant drugs^f
Sarilumab
CORIMUNO-SARI (1)	NCT04324073	Anti–IL-6	68	61.7 (53.0-71.1)	68 (100)	0	0	0	0	0	3 (4)	0	41 (60)
CORIMUNO-SARI (1)	NCT04324073	Usual care	76	62.8 (56.0-71.7)	76 (100)	0	0	0	0	0	4 (5)	0	38 (50)
CORIMUNO-SARI (ICU)	NCT04324073	Anti–IL-6	48	61.9 (53.8-66.2)	0	16 (33)	32 (67)	0	0	0	0	0	26 (54)
CORIMUNO-SARI (ICU)	NCT04324073	Usual care	33	61.2 (55.3-68.5)	0	9 (27)	24 (73)	0	0	0	2 (2)	0	17 (52)
Regeneron P2	NCT04315298	Anti–IL-6 (400 mg)	180	56.5 (45.0-68.0)	42 (23)	45 (25)	93 (52)	53 (29)	14 (8)	0	28 (16)	0	0
		Anti–IL-6 (200 mg)	187	60 (47.0-67.0)	40 (21)	41 (22)	104 (56)	58 (31)	11 (6)	0	34 (18)	0	0
		Placebo + usual care	90	60 (52.0-69.0)	28 (31)	23 (26)	39 (43)	28 (31)	3 (3)	0	14 (16)	0	0
Regeneron P3	NCT04315298	Anti–IL-6 (400 mg)	567	63.0 (53.0-72.0)	138 (24)	206 (36)	220 (39)	99 (17)	25 (4)	0	194 (34)	0	0
		Anti–IL-6 (200 mg)	477	60.0 (50.0-69.0)	137 (29)	144 (30)	193 (40)	94 (20)	28 (6)	0	151 (32)	0	0
		Placebo + usual care	286	61.0 (50.0-71.0)	78 (27)	103 (36)	104 (36)	47 (16)	8 (3)	0	99 (35)	0	0
REMAP-CAP	NCT02735707	Anti–IL-6	48	64.5 (53-72.5)	0	40 (83)	8 (17)	4 (8)	0	15 (31)	44 (92)	0	0
REMAP-CAP	NCT02735707	Usual care^g	65	65 (53-71)	0	57 (88)	8 (12)	1 (2)	0	29 (46)	52 (83)	0	0
Sanofi	NCT04327388	Anti–IL-6 (400 mg)	173	58.0 (48.0-67.0)	137 (79)	11 (6)	23 (13)	6 (4)	0	0	42 (24)	0	0
		Anti–IL-6 (200 mg)	159	58.0 (51.0-67.0)	123 (77)	14 (11)	16 (10)	5 (3)	2 (1)	0	25 (16)	0	0
		Placebo + usual care	84	60 (53.0-69.5)	70 (83)	5 (6)	9 (11)	1 (1)	0	0	16 (19)	0	0
SARCOVID	NCT04357808	Anti–IL-6	20	61.5 (50.5-72)	12 (60)	4 (20)	0	0	0	0	17 (85)	0	19 (95)
SARCOVID	NCT04357808	Control	10	62 (58-71)	10 (100)	0	0	0	0	0	8 (80)	0	10 (100)
SARICOR	NCT04357860	Anti–IL-6 (400 mg)	39	57 (49-67)	39 (100)	0	0	0	0	7 (18)	36 (92)	0	39 (100)
		Anti–IL-6 (200 mg)	37	66 (54-73)	37 (100)	0	0	0	0	3 (8)	32 (86)	0	37 (100)
		Usual care	39	57 (51-71)	39 (100)	0	0	0	0	4 (10)	39 (100)	0	39 (100)
SARTRE	EU-CTR 2020-002037-15	Anti–IL-6	70	58.8 (52-65)	70 (100)	0	0	0	0	1 (1)	70 (100)	0	0
SARTRE	EU-CTR 2020-002037-15	Usual care	70	58.0 (52-64)	70 (100)	0	0	0	0	1 (1)	70 (100)	0	0
Total			2826	57-66^h	1214 (43)	718 (25)	873 (31)	396 (14.0)	91 (3)	60 (2)	980 (35)	0	266 (9)
Siltuximab
COV-AID (B)	NCT04330638	Anti–IL-6	77	65.3 (54.3-71.4)	41 (53)	29 (38)	5 (7)	2 (3)	0	2 (3)	46 (60)	0	68 (88)
COV-AID (B)	NCT04330638	Usual careⁱ	72	63.3 (56.1-72.8)	39 (54)	23 (32)	9 (13)	4 (6)	0	3 (4)	42 (58)	0	60 (83)
Total			149	64	80 (54)	52 (35)	14 (9)	6 (4)	0	5 (3)	88 (59)	0	128 (86)
Tocilizumab
ARCHITECTS	NCT04412772	Anti–IL-6	10	61.0 (46-67)	0	0	10 (100)	5 (50)	2 (20)	8 (80)	9 (90)	10 (100)	7 (70)
ARCHITECTS	NCT04412772	Placebo + usual care	11	62.0 (54-71)	1 (9)	0	10 (91)	7 (64)	1 (9)	11 (100)	11 (100)	11 (100)	3 (37)
BACC Bay	NCT04356937	Anti–IL-6	161	61.6 (46.4-69.7)	133 (83)	5 (3)	0	2 (1)	0	34 (21)	3 (2)	0	0
BACC Bay	NCT04356937	Placebo + usual care	82	56.5 (44.7-67.8)	61 (74)	5 (6)	1 (1)	1 (1)	0	15 (18)	1 (1)	0	0
CORIMUNO-TOCI (1)	NCT04331808	Anti–IL-6	63	64.0 (57.1-74.3)	63 (100)	0	0	0	0	0	10 (16)	0	35 (56)
CORIMUNO-TOCI (1)	NCT04331808	Usual care	67	63.3 (57.1-72.3)	67 (100)	0	0	0	0	0	12 (18)	0	33 (49)
CORIMUNO-TOCI (ICU)	NCT04331808	Anti–IL-6	49	63.2 (59.4-70.9)	0	13 (27)	36 (73)	0	0	0	8 (16)	0	17 (35)
CORIMUNO-TOCI (ICU)	NCT04331808	Usual care	43	65.4 (57.6-70.5)	0	12 (28)	31 (72)	0	0	0	4 (9)	0	14 (33)
COVACTA	NCT04320615	Anti–IL-6	294	63.0 (52.0-71.0)	78 (27)	94 (32)	113 (38)	77 (26)	0	19 (6)	36 (12)	3 (1)	0
COVACTA	NCT04320615	Placebo + usual care	144	61.5 (53.8-70.0)	44 (31)	39 (27)	55 (38)	38 (26)	0	4 (3)	33 (23)	1 (1)	0
COV-AID (A)	NCT04330638	Anti–IL-6	81	62.4 (53.3-74.8)	39 (48)	32 (40)	8 (10)	5 (6)	1 (1)	6 (7)	48 (59)	0	73 (90)
COV-AID (A)	NCT04330638	Usual careⁱ	72	63.3 (56.1-72.8)	39 (54)	23 (32)	9 (13)	4 (6)	0	3 (4)	42 (58)	0	60 (83)
COVIDOSE-2 (substudy A)	NCT04479358	Anti–IL-6 (120 mg)	10	65.0 (53-69)	6 (60)	0	0	0	1 (10)	8 (80)	3 (30)	0	1 (10)
		Anti–IL-6 (40 mg)	10	65.0 (54-68)	5 (50)	1 (10)	0	0	0	7 (70)	3 (30)	0	4 (40)
		Usual care	8	65.0 (55-68)	4 (50)	1 (13)	0	0	0	5 (63)	2 (25)	0	2 (25)
COVIDSTORM	NCT04577534	Anti–IL-6	26	64.5 (15)	15 (58)	6 (23)	0	0	0	0	17 (65)	0	5 (19)
COVIDSTORM	NCT04577534	Usual care	13	68.0 (17)	7 (54)	4 (31)	0	1 (8)	0	0	13 (100)	0	2 (15)
COVINTOC	EU-CTR 2020/05/025369	Anti–IL-6	91	56.0 (47-63)	48 (53)	28 (31)	5 (6)	12 (13)	0	14 (15)	24 (26)	0	87 (96)
COVINTOC	EU-CTR 2020/05/025369	Usual care	89	54.0 (43-63)	56 (63)	20 (23)	4 (5)	12 (13)	0	13 (15)	8 (9)	0	86 (97)
COVITOZ-01	NCT04435717	Anti–IL-6 (2 doses)	7	56.0 (42-67)	5 (57)	0	0	0	0	2 (29)	4 (57)	0	5 (71)
		Anti–IL-6 (1 dose)	10	58.0 (53-64)	6 (60)	0	0	0	0	3 (30)	6 (60)	0	9 (90)
		Usual care	9	58.0 (47-62)	6 (67)	0	0	0	0	4 (44)	7 (78)	0	7 (78)
EMPACTA	NCT04372186	Anti–IL-6	249	57.0 (46-66)	161 (64)	64 (26)	0	2 (1)	3 (1)	114 (46)	174 (70)	5 (2)	228 (91)
EMPACTA	NCT04372186	Placebo + usual care	128	56.0 (45-65)	81 (64)	36 (28)	0	4 (3)	3 (2)	62 (49)	87 (69)	1 (1)	120 (95)
HMO-0224-20	NCT04377750	Anti–IL-6	37	61.8	0	16 (43)	21 (57)	27 (73)	4 (11)	9 (24)	31 (84)	0	37 (100)
HMO-0224-20	NCT04377750	Placebo + usual care	17	65.8	0	5 (29)	12 (71)	12 (71)	5 (29)	3 (18)	15 (88)	0	17 (100)
IMMCOVA	EU-CTR 2020-001748-24	Anti–IL-6	22	64.0 (56-70)	10 (46)	12 (55)	0	1 (5)	0	3 (14)	21 (96)	0	22 (100)
IMMCOVA	EU-CTR 2020-001748-24	Usual care	27	62.0 (53-68)	9 (33)	18 (67)	0	5 (19)	0	4 (15)	26 (96)	0	27 (100)
PRETOVID	EU-CTR 020-001375-32	Anti–IL-6	174	67 (60-74)	125 (72)	38 (22)	2 (1)	8 (5)	0	36 (21)	151 (87)	0	0
PRETOVID	EU-CTR 020-001375-32	Usual care	180	66 (56-75)	128 (71)	43 (24)	1 (<1)	11 (6)	0	29 (16)	162 (90)	0	0
RECOVERY	NCT04381936	Anti–IL-6	2022	63.5 (54.2-73.6)	931 (46)	819 (41)	268 (13)	0	28 (1)	544 (27)	1664 (82)	425 (21)	1178 (58)
RECOVERY	NCT04381936	Usual care	2094	64.3 (55.0-73.9)	928 (44)	867 (41)	294 (14)	0	29 (1)	573 (27)	1721 (82)	485 (23)	1244 (59)
REMAP-CAP	NCT02735707	Anti–IL-6	353	61.0 (54-71)	1 (<1)	248 (70)	104 (30)	63 (18)	0	72 (20)	214 (61)	0	0
REMAP-CAP	NCT02735707	Usual care^g	358	61.0 (53-70)	2 (1)	237 (66)	119 (33)	79 (22)	2 (1)	72 (21)	217 (63)	0	0
REMDACTA	NCT04409262	Anti–IL-6	430	61.0	29 (7)	336 (78)	65 (15)	0	0	83 (24)	367 (85)	0	0
REMDACTA	NCT04409262	Placebo + usual care	210	59.0	13 (6)	175 (83)	22 (11)	0	0	40 (19)	184 (88)	0	0
TOCIBRAS	NCT04403685	Anti–IL-6	65	54.6 (44.2-70.2)	39 (60)	15 (23)	11 (17)	9 (14)	0	0	45 (69)	0	53 (82)
TOCIBRAS	NCT04403685	Usual care	64	57.9 (46.9-69.4)	28 (44)	26 (41)	10 (16)	7 (11)	0	0	47 (73)	0	54 (84)
TOCOVID	NCT04332094	Anti–IL-6	136	52.0 (44.0-60.5)	74 (54)	0	0	0	0	0	46 (34)	0	123 (90)
TOCOVID	NCT04332094	Usual care	134	54.0 (42.0-60.0)	81 (60)	0	0	0	0	1 (1)	45 (34)	0	127 (95)
Total			8050 ^j	52-68^h	3223 (40)	3238 (40)	1211 (15)	382 (5)	79 (1)	1693 (21)	5317 (66)	941 (12)	3860 (46)
Anti–IL-6 vs corticosteroids ^k
STORM	NCT04345445	Tocilizumab	29	53.3 (14.84)	65 (81)	0	0	0	0	25 (31)	5 (6)	8 (10)	0
STORM	NCT04345445	Corticosteroids	30	53.1 (20.97)	62 (79)	0	0	0	0	26 (33)	4 (5)	11 (14)	0
SILCOR	NCT04329650	Siltuximab	80	61.33 (23.52)	17 (59)	1 (3)	0	0	0	0	0	0	0
SILCOR	NCT04329650	Corticosteroids	78	62.70 (21.2)	24 (80)	4 (13)	0	0	1 (3)	0	1 (3)	0	0

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Abbreviations: IQR, interquartile range; KRT, kidney replacement therapy.

^{^a}

Additional trial characteristics appear in eTable 1 and eTable 2 in Supplement 1.

^{^b}

Control indicates use of placebo in blinded trials and usual care alone in open-label trials.

^{^c}

By face mask or nasal cannula.

^{^d}

Norepinephrine or epinephrine.

^{^e}

Dexamethasone, methylprednisolone, prednisolone, or hydrocortisone.

^{^f}

Heparin or low-molecular-weight heparin.

^{^g}

There were 21 patients in the usual care group for both treatment comparisons.

^{^h}

Expressed as range of medians.

^ⁱ

Common control group across the COV-AID trial.

^{^j}

Baseline data but not outcome data supplied for 1 patient in the COVIDOSE substudy A and for 1 patient in the COVINTOC trial.

^{^k}

These trials were not included in the meta-analysis.

The IL-6 antagonists assessed were tocilizumab (19 trials allocating 4299 patients to tocilizumab and 3749 patients to usual care or placebo), sarilumab (9 trials allocating 2073 patients to sarilumab and 753 patients to usual care or placebo), and siltuximab (1 trial allocating 77 patients to siltuximab and 72 patients to usual care or placebo). The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia⁸ (REMAP-CAP) and COV-AID (NCT04330638) trials randomized patients to more than 1 IL-6 antagonist. Due to limited data (including outcome events), associations for siltuximab within predefined subgroups were not estimated. Similarly, due to limited data, associations were not estimated in the predefined low-dose strata (2 trials for tocilizumab [27 patients] and in 2 trials for sarilumab [307 patients]), in the no oxygen respiratory support subgroup (27 patients and 4 deaths in 3 trials), and for trials reporting secondary infections at 90 days. Because of the diversity of classification of race/ethnicity among different trials, the subgroup analyses according to race/ethnicity are not reported. Because not all trials estimated hazard ratios for 90-day mortality, the event numbers were also analyzed to estimate the ORs.

The median age across the trials was 61 years (range of medians, 52-68 years) and 3560 patients (33%) were women. Concurrent treatments at randomization varied substantially among the trials. Most patients received respiratory support at randomization. A greater proportion of patients in the sarilumab trials received IMV (31% [873/3136 patients]) compared with patients in the tocilizumab trials (15% [1211/8134 patients]) and a smaller proportion received corticosteroids (35% [890/3136 patients] vs 66% [5317/8134 patients], respectively; Table 1). The primary outcome was missing for 183 patients (1.6%). Three trials recorded no deaths by 28 days (COVID-19: Salvage Tocilizumab as a Rescue Measure [COVIDSTORM {NCT04577534}; n = 39]; Efficacy of Tocilizumab in Modifying the Inflammatory Parameters of Patients With COVID-19 [COVITOZ-01 {NCT04435717}; n = 26]; and Clinical Trial of the Use of Tocilizumab for Treatment of SARS-CoV-2 Infection [COVID-19; TOCOVID] {NCT04332094} [n = 270]).

Risk of bias was assessed to be low in 22 of the trials contributing to the meta-analysis of 28-day all-cause mortality, comprising 78% of the weight in the analysis. Six trials were judged to have some concerns, mainly due to small numbers of patients being excluded from the data set because they did not receive their assigned intervention. In 1 trial judged as high risk, comprising 0.65% of the weight, the usual procedures were not in place to ensure that the allocation sequence was concealed; however, there was no reason to suspect that the concealed allocation was not implemented as intended. Risk of bias assessments were similar for progression to IMV or death. For secondary infections, results from open-label trials were judged to have some concerns over bias in determining whether such infections had occurred due to the subjective nature of the decision (eFigure 2 and eTable 4 in Supplement 1).

Association Between IL-6 Antagonists and 28-Day All-Cause Mortality

By 28 days after randomization, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo. Using a fixed-effects meta-analysis, the summary OR was 0.86 (95% CI, 0.79-0.95; P = .003). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The summary OR was 0.89 (95% CI, 0.76-1.05; P = .16) in a sensitivity analysis using random-effects meta-analysis (eFigure 3 in Supplement 1). The certainty in this result was assessed to be high in the GRADE assessment.

In 19 trials that randomized 4299 patients to tocilizumab (960 deaths) and 3749 patients to usual care or placebo (1023 deaths), the summary OR was 0.83 (95% CI, 0.74-0.92; P < .001). This corresponds to an absolute mortality risk of 22% for tocilizumab compared with an assumed mortality risk of 25% for usual care or placebo. In 9 trials that randomized 2073 patients to sarilumab (473 deaths) and 753 patients to usual care or placebo (139 deaths), the summary OR was 1.08 (95% CI, 0.86-1.36; P = .52). This corresponds to an absolute mortality risk of 26% for sarilumab compared with an assumed mortality risk of 25% for usual care or placebo. There was little inconsistency between the trial results (I² = 18% overall, I² = 3% for tocilizumab, and I² = 0% for sarilumab). The inverse association with 28-day all-cause mortality appeared more marked for tocilizumab than for sarilumab (ratio of ORs, 0.76 [95% CI, 0.59-0.98], P = .04 for interaction; Figure 1 and Table 2).

Figure 1. — The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis.

^aCommon control group across both treatment comparisons of the COV-AID trial.

^bNA indicates not available; there were insufficient data to estimate odds ratio.

^cThe data for the PreToVid trial are based on events up until 30 days after randomization.

^dThere were 21 patients in the control group for both treatment comparisons. The analyses have been adjusted to correct for this.

Table 2. Subgroup Analysis of 3 Outcomes by Treatment Group and Respiratory Support, Organ Support, Age, Sex, and C-Reactive Protein Level.

Subgroup	All anti–IL-6 agents				Tocilizumab				Sarilumab
	No. of events/total patients		I², %	OR (95% CI)	No. of events/total patients		I², %	OR (95% CI)	No. of events/total patients		I², %	OR (95% CI)
	Anti–IL-6	Control	I², %	OR (95% CI)	Anti–IL-6	Control	I², %	OR (95% CI)	Anti–IL-6	Control	I², %	OR (95% CI)
28-d mortality
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	277/2246	283/1708	0	0.81 (0.67-0.98)	232/1622	256/1407	0	0.82 (0.67-1.00)	41/583	27/301	0	0.74 (0.42-1.30)
Noninvasive ventilation	588/2209	544/1655	8	0.83 (0.72-0.96)	463/1684	505/1479	0	0.80 (0.68-0.93)	119/496	40/191	0	1.20 (0.78-1.84)
IMV or ECMO	496/1289	305/728	0	0.95 (0.78-1.16)	250/634	244/559	6	0.92 (0.72-1.17)	246/650	64/174	20	1.05 (0.74-1.50)
Acute organ support at randomization
No cardiovascular system support	123/616	135/501	14	0.68 (0.51-0.91)	106/536	120/457	10	0.70 (0.51-0.94)	11/48	18/64	0	0.66 (0.26-1.64)
Cardiovascular system support	70/196	59/153	17	0.89 (0.56-1.42)	69/190	59/153	14	0.93 (0.58-1.47)	1/4	1/1	0	0.14 (0.00-5.95)
Age group, y
<70	674/4209	522/2931	0	0.89 (0.78-1.02)	446/2864	456/2457	0	0.86 (0.74-0.99)	225/1291	67/490	9	1.10 (0.80-1.52)
≥70	703/1727	629/1310	17	0.82 (0.70-0.95)	514/1254	567/1136	8	0.76 (0.64-0.89)	182/450	65/179	0	1.17 (0.80-1.71)
Sex
Female	413/1933	311/1335	0	0.96(0.80-1.15)	294/1365	270/1134	0	0.96 (0.79-1.17)	117/553	43/209	0	0.95 (0.62-1.46)
Male	964/4003	840/2906	1	0.83 (0.74-0.93)	666/2753	753/2459	0	0.78 (0.69-0.88)	290/1188	89/460	0	1.17 (0.88-1.55)
C-reactive protein level, μg/mL^a
<75	83/710	57/429	0	0.84 (0.56-1.26)	36/344	36/260	0	0.80 (0.46-1.39)	46/354	21/171	0	0.89 (0.49-1.62)
75-<150	451/1957	467/1635	3	0.79 (0.67-0.92)	357/1484	435/1456	9	0.76 (0.65-0.90)	90/438	33/184	0	1.01 (0.62-1.64)
≥150	678/2366	490/1625	0	0.96 (0.83-1.11)	427/1507	429/1365	0	0.91 (0.77-1.07)	246/831	64/271	4	1.16 (0.83-1.62)
Progression to IMV, EMCO, or death by 28 d
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	362/2266	396/1778	0	0.75 (0.64-0.89)	299/1724	359/1505	0	0.72 (0.60-0.86)	55/501	37/273	0	0.96 (0.60-1.53)
Noninvasive ventilation	856/2129	805/1636	14	0.77 (0.68-0.89)	694/1690	750/1483	0	0.74 (0.64-0.85)	145/410	60/168	0	1.06 (0.71-1.57)
Acute organ support at randomization
No cardiovascular system support	207/524	202/424	26	0.72 (0.55-0.95)	173/451	183/382	2	0.70 (0.53-0.93)	NA^b	NA^b	NA^b	NA^b
Cardiovascular system support	12/16	8/15	0	1.58 (0.30-8.30)	12/16	8/15	0	1.58 (0.30-8.30)	NA^b	NA^b	NA^b	NA^b
Age group, y
<70	649/3160	622/2387	0	0.78 (0.68-0.89)	523/2457	566/2079	0	0.76 (0.66-0.87)	110/654	60/320	0	0.87 (0.60-1.27)
≥70	577/1402	586/1137	0	0.75 (0.64-0.89)	477/1112	548/1017	0	0.70 (0.59-0.84)	91/267	39/123	0	1.20 (0.74-1.97)
Sex
Female	362/1526	334/1149	14	0.81 (0.68-0.98)	300/1223	306/1014	14	0.80 (0.66-0.97)	57/289	31/141	2	0.83 (0.48-1.44)
Male	864/3036	874/2375	7	0.75 (0.67-0.85)	700/2346	808/2082	0	0.71 (0.63-0.81)	144/632	68/302	0	1.08 (0.76-1.55)
C-reactive protein level, μg/mL^a
<75	87/687	77/443	0	0.74 (0.51-1.09)	52/426	55/307	0	0.69 (0.43-1.12)	33/250	23/138	0	0.83 (0.43-1.59)
75-<150	453/1632	504/1450	0	0.76 (0.65-0.89)	389/1335	481/1325	0	0.73 (0.62-0.87)	54/265	23/129	0	1.14 (0.63-2.07)
≥150	519/1595	492/1248	0	0.78 (0.67-0.92)	407/1235	453/1109	0	0.74 (0.62-0.88)	100/333	43/147	34	1.03 (0.65-1.63)
Secondary infections to 28 d ^c
Respiratory support at baseline
Oxygen flow rate ≤15 L/min	100/1244	60/789	1	1.06 (0.75-1.52)	63/620	45/488	35	1.04 (0.68-1.60)	34/583	15/301	0	1.06 (0.56-2.02)
Noninvasive ventilation	260/1052	122/487	0	0.96 (0.74-1.24)	155/567	94/352	0	0.92 (0.67-1.26)	99/456	28/135	0	1.01 (0.63-1.63)
IMV or ECMO	380/913	139/318	22	0.86 (0.65-1.15)	134/266	76/151	23	0.76 (0.49-1.20)	244/642	63/167	53	0.94 (0.65-1.34)

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Abbreviations: ECMO, extracorporeal membrane oxygenation; IMV, invasive mechanical ventilation; OR, odds ratio.

^{^a}

Normal level is less than 5 μg/mL.

^{^b}

Insufficient data to investigate the comparison of subgroups within trials.

^{^c}

Full results within extended subgroups were not collected for outcomes other than all-cause mortality and progression to IMV, ECMO, or death at 28 days.

Data on receipt of corticosteroids at randomization were available in 22 trials (9953 patients and 2495 deaths). The summary ORs for 28-day all-cause mortality comparing IL-6 antagonists with usual care or placebo were 1.09 (95% CI, 0.91-1.30) for 3637 patients (830 deaths) not receiving corticosteroids and 0.78 (95% CI, 0.69-0.88) for 6316 patients (1665 deaths) receiving corticosteroids (Figure 2). The corresponding absolute mortality risk in patients receiving corticosteroids was 21% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. Based on within-trial estimates combined across 17 trials that included patients receiving and not receiving corticosteroids, the inverse association between IL-6 antagonists and mortality was more marked in patients receiving corticosteroids (ratio of ORs, 0.72 [95% CI, 0.56-0.92]; P = .008 for interaction). The summary OR for the association with mortality for tocilizumab (15 trials, 7490 patients, and 1951 deaths) was 1.06 (95% CI, 0.85-1.33) in patients not receiving corticosteroids at randomization and was 0.77 (95% CI, 0.68-0.87) in patients receiving corticosteroids at randomization. The summary ratio of ORs (based on within-trial comparisons) was 0.69 (95% CI, 0.52-0.91; P = .008 for interaction). The corresponding summary ORs for sarilumab (8 trials, 2406 patients, and 538 deaths) were 1.18 (95% CI, 0.88-1.58) and 0.92 (95% CI, 0.61-1.38), respectively. The summary ratio of ORs (based on within-trial comparisons) was 0.77 (95% CI, 0.44-1.33; P = .34 for interaction). The corresponding absolute mortality risks in patients receiving corticosteroids were 20% for tocilizumab and 23% for sarilumab compared with an assumed mortality risk of 25% for usual care or placebo. In additional analyses, associations were compared in patients not receiving and receiving corticosteroids at randomization within the respiratory support subgroups. The tendency for more marked inverse associations among patients receiving corticosteroids appeared broadly consistent across respiratory support subgroups; however, the associations were not estimated precisely.

Figure 2. — For the outcome of progression to invasive mechanical ventilation (IMV), extracorporeal membrane oxygenation (ECMO), or death at 28 days, only patients not receiving IMV or ECMO at randomization were included in the analyses. All trials supplied data until 28 days after randomization, except for the PreToVid trial for which data are based on events up until 30 days after randomization. The ratios of odds ratios (ROR) compare the associations of anti–IL-6 agents with outcomes between patients receiving and not receiving corticosteroids within each trial. The displayed summary ROR for each comparison is based on a meta-analysis of trial-specific RORs. Only the trials that recruited patients receiving and not receiving corticosteroids at randomization contribute to these meta-analyses. The estimated RORs are not necessarily consistent with the ratios of the subgroup ORs (left panel), which were calculated from meta-analyses within subgroups defined by receipt or no receipt of corticosteroids at randomization.

^aThe odds ratios are based on raw percentages while the ratios of odds ratios account for pooling trials of different sizes.

Detailed results, forest plots, and comparisons between subgroups for 28-day all-cause mortality appear in Supplements 1 and 2. Data on respiratory support at randomization were available in 21 trials (9835 patients and 2493 deaths). The summary ORs for 28-day all-cause mortality comparing IL-6 antagonists with usual care or placebo were 0.81 (95% CI, 0.67-0.98) in 3954 patients (560 deaths) receiving supplemental oxygen at randomization, 0.83 (95% CI, 0.72-0.96) in 3864 patients (1132 deaths) receiving noninvasive ventilation or high-flow nasal cannula at randomization, and 0.95 (95% CI, 0.78-1.16) in 2017 patients (801 deaths) receiving IMV or ECMO at randomization (P = .71 for the differences between associations across these subgroups; Table 2). The corresponding summary ORs for tocilizumab were 0.82 (95% CI, 0.67-1.00), 0.80 (95% CI, 0.68-0.93), and 0.92 (95% CI, 0.72-1.17), respectively (P = .43 for differences between subgroups) and the corresponding summary ORs for sarilumab were 0.74 (95% CI, 0.42-1.30), 1.20 (95% CI, 0.78-1.84), and 1.05 (95% CI, 0.74-1.50), respectively (P = .65 for differences between subgroups).

The associations between IL-6 antagonists and 28-day all-cause mortality within other subgroups defined by patient characteristics at randomization appeared consistent across all these subgroups (all P values for comparisons between subgroups were greater than .11; Table 2 and Supplement 2).

Association Between IL-6 Antagonists and Progression to IMV or Death

Among patients not requiring IMV at randomization (24 trials), 1236 of 4650 randomized to IL-6 antagonists and 1220 of 3609 randomized to usual care or placebo progressed to requiring IMV or ECMO or died within 28 days. Most of the data (87%) were from trials assessing tocilizumab. The summary ORs compared with usual care or placebo were 0.77 (95% CI, 0.70-0.85; P < .001) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.35) for sarilumab (Figure 3). The corresponding absolute risks of progression to IMV or death were 28% for all IL-6 antagonists, 27% for tocilizumab, and 33% for sarilumab compared with an assumed risk of 33% for usual care or placebo. There was little inconsistency between the trial results (I² = 0% for each meta-analysis). The certainty in the overall result was assessed to be high in the GRADE assessment. The ratio of ORs comparing the associations for tocilizumab and sarilumab was 0.74 (95% CI, 0.54-1.01; P = .06 for interaction).

Figure 3. — The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis. Progression to requiring invasive mechanical ventilation or extracorporeal membrane oxygenation or death among patients not receiving invasive mechanical ventilation at randomization.

^aNA indicates not available; there were insufficient data to estimate odds ratio or the trial did not supply data for this outcome.

^bCommon control group across both treatment comparisons of the COV-AID trial.

^cThe data for the PreToVid trial are based on events up until 30 days after randomization.

^dThere were 21 patients in the control group for both treatment comparisons. The analyses have been adjusted to correct for this.

The summary ORs for progression to IMV or death were 0.96 (95% CI, 0.79-1.17) in 2545 patients (707 progressed) not receiving corticosteroids and 0.71 (95% CI, 0.63-0.80) in 5482 patients (1715 progressed) receiving corticosteroids (Figure 2). The corresponding absolute risk for progression to IMV or death in patients receiving corticosteroids was 26% for IL-6 antagonists compared with an assumed risk of 33% for usual care or placebo. The ratio of ORs comparing the associations in those receiving and not receiving corticosteroids was 0.78 (95% CI, 0.59-1.02; P = .07 for interaction based on within-trial estimates combined across trials). The corresponding summary ORs for tocilizumab (17 trials, 6608 patients, and 2104 progressed) were 0.95 (95% CI, 0.76-1.20) and 0.69 (95% CI, 0.61-0.78), respectively, and the corresponding ratio of ORs was 0.70 (95% CI, 0.52-0.94; P = .02 for interaction). The corresponding summary ORs for sarilumab (7 trials, 1362 patients, and 298 progressed) were 0.98 (95% CI, 0.67-1.44) and 1.08 (95% CI, 0.67-1.75), respectively, and the corresponding ratio of ORs was 1.41 (95% CI, 0.65-3.07; P = .38 for interaction). The corresponding absolute risks for progression to IMV or death in patients receiving corticosteroids were 25% for tocilizumab and 35% for sarilumab compared with an assumed risk of 33% for progression to IMV or death for usual care or placebo.

The summary ORs for progression to IMV or death comparing IL-6 antagonists with usual care or placebo were 0.75 (95% CI, 0.64-0.89) in 4044 patients (758 progressed) receiving supplemental oxygen at randomization and 0.77 (95% CI, 0.68-0.89) in 3765 patients (1661 progressed) receiving noninvasive ventilation or high-flow nasal cannula (P = .67 for differences between these associations; Table 2). The corresponding summary ORs for tocilizumab were 0.72 (95% CI, 0.60-0.86) and 0.74 (95% CI, 0.64-0.85), respectively (P = .92 for differences between subgroups) and the corresponding summary ORs for sarilumab were 0.96 (95% CI, 0.60-1.53) and 1.06 (95% CI, 0.71-1.57), respectively (P = .31 for differences between subgroups). The corresponding absolute risks for progression to IMV or death were 27% for all IL-6 antagonists, 27% for tocilizumab, and 33% for sarilumab compared with an assumed risk for progression to IMV or death of 33% for usual care or placebo.

The associations between IL-6 antagonists and progression to IMV or death within other subgroups defined by patient characteristics at randomization appeared consistent across all other subgroups (all P values for comparisons between subgroups were greater than .28; Table 2 and Supplement 3).

Association Between IL-6 Antagonists and Infections by 28 Days

Among the 22 trials that reported 28-day infection outcomes, 750 events occurred among 3428 patients randomized to IL-6 antagonists and 330 events occurred among 1787 patients randomized to usual care or placebo. The fixed-effect summary OR was 0.99 (95% CI, 0.85-1.16) and there was little inconsistency between the trial results (I² = 0%, P = .49 for heterogeneity; Figure 3). The certainty in this result was assessed to be moderate in the GRADE assessment due to minor concerns over risk of bias (because of subjectivity in the outcome assessment) and minor concerns over imprecision (because of the result being compatible with a slightly lower or higher risk among those receiving IL-6 antagonists). The ORs were 0.95 (95% CI, 0.77-1.16) for tocilizumab and 1.03 (95% CI, 0.80-1.32) for sarilumab (Figure 4 and Table 2). The summary ORs within subgroups were close to 1. Data on 28-day secondary infections appear in Supplement 4.

Figure 4. — The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis.

^aCommon control group across both treatment comparisons of the COV-AID trial.

^bNA indicates not available; the trial did not supply data for this outcome.

^cThe data for the PreToVid trial are based on events up until 30 days after randomization.

Association Between IL-6 Antagonists and Other Secondary Outcomes

Data on in-hospital mortality were available from 19 trials. The summary ORs for in-hospital mortality comparing IL-6 antagonists with usual care or placebo were 0.80 (95% CI, 0.71-0.89) in 7261 patients (1848 deaths), with little inconsistency between trials (I² = 0%) (Table 3). Most of the data (90.7%) were from 14 trials (6587 patients and 1741 deaths) assessing tocilizumab and the summary OR was 0.80 (95% CI, 0.71-0.90).

Table 3. Additional Outcomes With Analysis by Respiratory Support and Corticosteroid Use .

Outcome and patient group	All anti–IL-6 agents				Tocilizumab				Sarilumab
	No. of events/total patients		I², %	OR (95% CI)	No. of events/total patients		I², %	OR (95% CI)	No. of events/total patients		I², %	OR (95% CI)
	Anti–IL-6	Control	I², %	OR (95% CI)	Anti–IL-6	Control	I², %	OR (95% CI)	Anti–IL-6	Control	I², %	OR (95% CI)
In-hospital mortality
All patients	858/3727	990/3534	0	0.80 (0.71 to 0.89)	800/3323	941/3264	0	0.80 (0.71 to 0.90)	44/327	53/291	0	0.70 (0.44 to 1.12)
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	218/1636	262/1471	0	0.75 (0.62 to 0.92)	196/1369	241/1276	0	0.75 (0.61 to 0.93)	18/226	21/195	0	0.72 (0.36 to 1.44)
Noninvasive ventilation	409/1283	463/1280	2	0.83 (0.71 to 0.99)	387/1196	449/1232	0	0.83 (0.70 to 0.99)	14/58	15/63	0	0.98 (0.40 to 2.40)
IMV or ECMO	214/500	245/508	0	0.81 (0.63 to 1.04)	200/456	232/482	0	0.84 (0.65 to 1.10)	12/39	16/31	0	0.42 (0.16 to 1.15)
Corticosteroid use at randomization
No	229/1005	226/870	20	0.94 (0.75 to 1.18)	199/844	193/751	22	1.02 (0.80 to 1.29)	28/130	34/121	0	0.67 (0.37 to 1.22)
Yes	613/2464	743/2414	0	0.75 (0.66 to 0.85)	585/2221	728/2264	0	0.74 (0.65 to 0.85)	16/197	18/168	0	0.81 (0.38 to 1.71)
Progression to cardiovascular system support or death ^a
All patients	344/1587	343/1199	0	0.71 (0.59 to 0.86)	314/1447	316/1106	0	0.70 (0.57 to 0.85)	30/140	39/113	0	0.80 (0.42 to 1.52)
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	72/738	64/499	0	0.74 (0.51 to 1.07)	64/650	60/450	0	0.71 (0.48 to 1.05)	8/88	4/49	0	1.03 (0.31 to 3.44)
Noninvasive ventilation	192/519	209/438	8	0.65 (0.49 to 0.84)	173/475	189/397	9	0.63 (0.48 to 0.84)	19/44	30/56	0	0.64 (0.28 to 1.45)
IMV or ECMO	64/100	53/82	0	1.13 (0.57 to 2.26)	61/96	51/80	0	1.18 (0.59 to 2.39)	3/4	4/6	0	1.50 (0.09 to 25.39)
Corticosteroid use at randomization
No	143/652	123/423	0	0.80 (0.57 to 1.11)	138/636	118/407	0	0.76 (0.54 to 1.07)	5/16	6/18	0	1.81 (0.31 to 10.44)
Yes	185/841	205/687	0	0.67 (0.52 to 0.86)	160/717	184/611	0	0.66 (0.50 to 0.86)	24/124	32/93	0	0.71 (0.35 to 1.43)
Progression to kidney replacement therapy or death ^b
All patients	935/3653	1069/3351	14	0.79 (0.71 to 0.88)	920/3586	1051/3298	14	0.79 (0.71 to 0.88)	15/67	22/74	0	0.80 (0.36 to 1.76)
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	234/1489	263/1288	25	0.79 (0.65 to 0.97)	234/1477	263/1278	25	0.79 (0.65 to 0.97)	NA^c	NA^c	NA^c	NA^c
Noninvasive ventilation	439/1329	523/1298	29	0.76 (0.64 to 0.89)	428/1286	507/1258	23	0.77 (0.65 to 0.91)	NA^c	NA^c	NA^c	NA^c
IMV or ECMO	247/492	263/470	0	0.88 (0.68 to 1.15)	243/484	262/468	0	0.88 (0.68 to 1.15)	NA^c	NA^c	NA^c	NA^c
Corticosteroid use at randomization
No	261/959	239/732	0	0.98 (0.78 to 1.22)	258/952	235/721	0	0.97 (0.78 to 1.22)	3/7	5/13	0	1.55 (0.22 to 10.83)
Yes	661/2425	890/2363	2	0.74 (0.66 to 0.84)	649/2365	796/2322	8	0.75 (0.66 to 0.85)	12/60	16/59	0	0.79 (0.33 to 1.89)
Proportion discharged alive from the hospital at 28 d
All patients	4017/6432	2592/4472	16	1.22 (1.12 to 1.33)	2736/4282	2127/3740	0	1.30 (1.18 to 1.43)	1227/2073	478/753	0	0.95 (0.78 to 1.15)
Respiratory support at randomization
Oxygen flow rate ≤15 L/min	1923/2337	1371/1800	0	1.32 (1.12 to 1.55)	1390/1713	1113/1499	0	1.40 (1.18 to 1.66)	498/583	258/301	0	0.93 (0.60 to 1.43)
Noninvasive ventilation	1257/2215	820/1659	27	1.27 (1.11 to 1.45)	964/1690	726/1483	26	1.30 (1.13 to 1.51)	278/496	104/191	0	1.10 (0.77 to 1.56)
IMV or ECMO	351/1289	168/728	0	1.18 (0.94 to 1.48)	172/634	125/559	0	1.24 (0.94 to 1.63)	117/650	45/174	0	1.06 (0.72 to 1.57)
Corticosteroid use at randomization
No	1438/2458	780/1368	21	1.10 (0.95 to 1.27)	832/1293	576/986	10	1.17 (0.97 to 1.42)	580/1134	205/384	31	0.96 (0.75 to 1.22)
Yes	2240/3534	1665/2911	0	1.31 (1.18 to 1.46)	1828/2881	1474/2646	0	1.36 (1.21 to 1.52)	384/607	202/283	0	0.97 (0.68 to 1.38)
90-d mortality (binary outcome)
All patients	721/3039	383/1612	4	0.89 (0.76 to 1.04)	265/1367	231/1073	10	0.85 (0.69 to 1.05)	442/1595	156/560	0	0.92 (0.74 to 1.16)
Respiratory support
Oxygen flow rate ≤15 L/min	88/874	43/461	0	1.17 (0.78 to 1.74)	38/388	23/277	0	1.20 (0.67 to 2.12)	45/445	20/184	35	1.05 (0.59 to 1.87)
Noninvasive ventilation	252/1003	154/553	22	0.81 (0.63 to 1.04)	110/478	102/377	32	0.77 (0.56 to 1.06)	135/496	53/191	0	0.90 (0.61 to 1.33)
IMV or ECMO	382/954	175/410	0	0.88 (0.69 to 1.13)	114/299	103/241	0	0.85 (0.59 to 1.22)	266/650	75/174	27	0.91 (0.65 to 1.29)
Corticosteroid use at randomization
No	430/1744	188/783	0	0.97 (0.78 to 1.19)	118/582	93/413	2	0.86 (0.62 to 1.20)	310/1131	96/372	0	1.07 (0.81 to 1.41)
Yes	294/1138	185/665	0	0.84 (0.66 to 1.06)	144/620	135/505	0	0.84 (0.63 to 1.13)	138/472	53/178	0	0.81 (0.55 to 1.21)
Duration of IMV ^d
All patients	610	561	0	−0.84 (−1.82 to 0.13)^e	565	535	0	−0.76 (−1.76 to 0.24)^e	40	32	0	−2.07 (−10.24 to 11.57)^e
Corticosteroid use at randomization
No	304	218	0	−1.12 (−2.61 to 0.38)^e	266	195	0	−0.95 (−2.54 to 0.64)^e	NA^c	NA^c	NA^c	NA^c
Yes	298	332	0	−0.26 (−1.57 to 1.04)^e	291	330	0	−0.23 (−1.55 to 1.08)^e	NA^c	NA^c	NA^c	NA^c

Open in a new tab

Abbreviations: ECMO, extracorporeal membrane oxygenation; IMV, invasive mechanical ventilation; NA, not available; OR, odds ratio.

^{^a}

Among patients who were not receiving cardiovascular system support at randomization.

^{^b}

Among patients who were not receiving kidney replacement therapy at randomization.

^{^c}

Insufficient data to investigate the comparison of subgroups within trials.

^{^d}

Among patients who required IMV at randomization.

^{^e}

Data are expressed as weighted mean difference (95% CI).

Among patients not requiring cardiovascular system support at randomization (15 trials), 344 of 1587 patients randomized to IL-6 antagonists and 343 of 1199 patients randomized to usual care or placebo progressed to requiring cardiovascular system support or death within 28 days. Most of the data (2553/2786 patients; 91.1%) were from 13 trials assessing tocilizumab. The summary ORs were 0.71 (95% CI, 0.59-0.86) for IL-6 antagonists and 0.70 (95% CI, 0.57-0.85) for tocilizumab. Among patients not requiring KRT at randomization (13 trials), 935 of 3653 patients randomized to IL-6 antagonists and 1069 of 3351 patients randomized to usual care progressed to requiring KRT or died within 28 days. The summary OR was 0.79 (95% CI, 0.71-0.88); most of the data (6884/7004 patients; 98.2%) were from 12 trials assessing tocilizumab.

Among 10 904 patients recruited to participate in 26 trials, 6609 were discharged alive by 28 days. The summary OR comparing IL-6 antagonists with usual care or placebo was 1.22 (95% CI, 1.12-1.33), favoring IL-6 antagonists. The corresponding ORs were 1.30 (95% CI, 1.18-1.43) for tocilizumab and 0.95 (95% CI, 0.79-1.15) for sarilumab.

Data were available for all-cause mortality at 90 days in 13 trials and at 60 days in 4 trials (1104 deaths among 4651 patients). Two trials reported no events. The summary OR comparing IL-6 antagonists with usual care or placebo was 0.89 (95% CI, 0.76-1.04). The corresponding ORs were 0.85 (95% CI, 0.69-1.05) for tocilizumab and 0.92 (95% CI, 0.74-1.16) for sarilumab. Additional survival analyses for all-cause mortality at 90 days are reported in eTable 5 in Supplement 1.

Among 1171 patients who were receiving IMV at randomization and were recruited to 9 trials, the weighted mean difference comparing IL-6 antagonists with usual care or placebo in the duration of IMV was −0.84 (95% CI, −1.82 to 0.13), favoring IL-6 antagonists. Most of the data were from 8 trials assessing tocilizumab (1101/1171 patients; 94.0%).

Table 3 and Supplements 5-10 provide detailed analyses comparing IL-6 antagonists with usual care or placebo overall and in predefined subgroups for all of the secondary outcomes. Although the associations appeared broadly consistent across subgroups, many were not estimated precisely.

Serious Adverse Events or Reactions

Data describing serious adverse events were supplied by 23 trials. Risks of serious adverse events were broadly similar for patients randomized to IL-6 antagonists and to usual care or placebo across all trials. Data on secondary infections at 90 days after randomization were limited (11 trials and 310 events) (eTable 6 in Supplement 1), but the risk of secondary infections by 28 days was similar in patients treated with IL-6 antagonists (750/3428; 21.9%) and in those treated with usual care or placebo (330/1787; 17.6%) (OR accounting for trial sample sizes, 0.99 [95% CI, 0.85-1.16]).

Additional Analyses

The results of the prespecified and post hoc sensitivity analyses for the outcomes of 28-day all-cause mortality; progression to IMV, ECMO, or death by 28 days; and secondary infections by 28 days appear in eTable 7 in Supplement 1. After excluding the large RECOVERY trial, the ORs comparing tocilizumab with usual care or placebo were 0.82 (95% CI, 0.68-0.98) for 28-day all-cause mortality and 0.71 (95% CI, 0.59-0.84) for progression to IMV or death within 28 days (consistent with the primary analyses). The ORs for the trials at low risk of bias were similar to the overall ORs. The ORs restricted to trials published in peer-reviewed journals were consistent with the overall ORs for tocilizumab but were imprecisely estimated for sarilumab because of exclusion of the largest trial. The ORs were similar for open-label and placebo-controlled trials; however, the association of sarilumab compared with usual care for secondary infections appeared more marked in open-label trials (1.97 [95% CI, 0.89-4.34]) than in placebo-controlled trials (0.96 [95% CI, 0.74-1.24]). Supplement 1 includes summary details for all of the sensitivity analyses. Supplements 2-10 include details of prespecified sensitivity analyses by risk of bias and blinding status. Further additional analyses for all outcomes within patients receiving and not receiving corticosteroids at randomization appear in Supplement 11. The baseline and outcome data collection forms appear in Supplement 12. The prospective meta-analysis protocol appears in Supplement 13.

Discussion

In this prospective meta-analysis based on 10 930 patients hospitalized for COVID-19 from 27 randomized clinical trials, administration of IL-6 antagonists was associated with lower all-cause mortality 28 days after randomization. Administration of IL-6 antagonists also was associated with lower progression to IMV or death, cardiovascular support or death, and KRT or death in patients not receiving support for the corresponding organ at randomization and with a greater probability of being discharged alive by 28 days. Administration of IL-6 antagonists was not associated with an increased risk of 28-day infection compared with usual care or placebo. There was no clear association between administration of IL-6 antagonists and all-cause mortality at 90 days or in the duration of IMV among patients who required IMV at randomization; however, the data were limited.

Among the a priori–defined subgroups, the association of IL-6 antagonists with improved outcomes appeared more marked among patients who were receiving corticosteroids at randomization compared with those who were not. The association of IL-6 antagonists with lower 28-day all-cause mortality was more marked among patients who did not require IMV at randomization, consistent with the inverse association of progression to IMV or death among these patients. However, these differences between subgroups may have arisen due to sampling variation. Associations appeared broadly consistent across patient subgroups according to levels of cardiovascular support, C-reactive protein level, age, and sex.

In general, associations with improved outcomes were more marked for tocilizumab than for sarilumab, although comparisons between tocilizumab and sarilumab were indirect (made between trials). However, the trials of sarilumab were generally done earlier in the pandemic than those of tocilizumab and before corticosteroids became the standard of care.⁷ The majority of patients in trials of sarilumab were not receiving corticosteroids at randomization, whereas the majority of patients in trials of tocilizumab were receiving corticosteroids at randomization. When comparisons were made within groups defined by receipt of corticosteroids at randomization, the differences between associations for these 2 IL-6 antagonists were less marked. Nearly 3 times as many patients were randomized to trials comparing tocilizumab with usual care or placebo compared with trials comparing sarilumab with usual care or placebo. For this reason, associations were estimated more precisely for tocilizumab than for sarilumab. Both drugs were IL-6 receptor antagonists, but there may be differences between tocilizumab and sarilumab in receptor binding or lung concentrations.²⁵ Concurrent administration of IL-6 antagonists⁵ and corticosteroids,²⁶ which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.^8,9

This prospective meta-analysis included an estimated 97% of patients randomized to IL-6 receptor antagonists vs usual care worldwide. Because data were shared based on standardized definitions of outcomes and subgroups agreed upon in advance, these aggregate data meta-analyses had many of the advantages of individual-patient data meta-analyses while avoiding the need to establish formal data sharing agreements. The methods used in this meta-analysis limit bias in the selection and appraisal of trials with prespecified subgroup analyses based on clinically relevant questions. For tocilizumab, the results from other trials were similar to those from the large RECOVERY trial, supporting generalizability of the findings across settings.

Limitations

This study has several limitations. First, some of the included trials are ongoing and have not been published in peer-reviewed journals. It is possible that lack of participation or participation by some of the ongoing trials may be based on knowledge of their interim results. This limitation was addressed in the sensitivity analyses and the results were consistent with the primary analyses.

Second, there were limited data for some comparisons and questions of interest such as IL-6 antagonists vs corticosteroids and the effect of siltuximab. Third, potential differences in treatment effect by differences in the baseline risk of death (eg, that arose either from trial-specific eligibility criteria, geographic differences, or improving trends in the outcomes of patients with COVID-19 during the pandemic) could not be accounted for.

Fourth, the definitions and reporting of serious adverse events were not consistent across the trials and therefore a meta-analysis for this secondary end point was not conducted. Fifth, larger trials were mainly conducted in high-income settings; 65.9% of the tocilizumab data were provided by participants in the RECOVERY trial⁹ and 71.0% of the sarilumab data were provided by participants in the Regeneron trial (NCT04315298).

Conclusions

Supplement 1.

eFigure 1. Flow diagram showing the identification of eligible trials and participating trials

eFigure 2. Risk of bias assessments

eFigure 3. Association of anti-IL-6 agents with 28-day mortality: random effects meta-analysis (sensitivity analysis)

eTable 1. Description of included trials

eTable 2. Additional characteristics of included trials

eTable 3. Distribution of race/ethnicity as described in individual trials

eTable 4. Risk of bias assessments (all outcomes)

eTable 5. Associations of anti-IL-6 agents with 90-day mortality, analysed using hazard ratios, and duration of invasive mechanical ventilation (IMV)

eTable 6. Serious adverse events and secondary infections

eTable 7. Associations of anti-IL-6 agents with 28-day mortality, progression to IMV or death and secondary infections:Sensitivity analyses

Click here for additional data file.^{(1.9MB, pdf)}

Supplement 2.

28-day mortality (All results)

Click here for additional data file.^{(11.4MB, pdf)}

Supplement 3.

Progression to IMV or death (All results)

Click here for additional data file.^{(7.3MB, pdf)}

Supplement 4.

28-day secondary infections (All results)

Click here for additional data file.^{(7.9MB, pdf)}

Supplement 5.

In-hospital mortality (All results)

Click here for additional data file.^{(2.8MB, pdf)}

Supplement 6.

Progression to cardiovascular system (CVS) support or death by 28 days (All results)

Click here for additional data file.^{(2.5MB, pdf)}

Supplement 7.

Progression to renal replacement therapy (RRT) or death by 28 days (all results)

Click here for additional data file.^{(2MB, pdf)}

Supplement 8.

Proportion discharged at 28-days (All results)

Click here for additional data file.^{(6MB, pdf)}

Supplement 9.

90-day mortality (all results)

Click here for additional data file.^{(11.1MB, pdf)}

Supplement 10.

Duration of IMV (all results)

Click here for additional data file.^{(1.1MB, pdf)}

Supplement 11.

Anti-IL-6 PMA: Results from additional analyses

Click here for additional data file.^{(8.2MB, pdf)}

Supplement 12.

Data collection form 1: Baseline data

Click here for additional data file.^{(1.9MB, pdf)}

Supplement 13.

Trial protocol

Click here for additional data file.^{(1.6MB, pdf)}

Supplement 14.

Nonauthor Collaborators. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group nonauthor collaborators

Click here for additional data file.^{(169.9KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eFigure 1. Flow diagram showing the identification of eligible trials and participating trials

eFigure 2. Risk of bias assessments

eFigure 3. Association of anti-IL-6 agents with 28-day mortality: random effects meta-analysis (sensitivity analysis)

eTable 1. Description of included trials

eTable 2. Additional characteristics of included trials

eTable 3. Distribution of race/ethnicity as described in individual trials

eTable 4. Risk of bias assessments (all outcomes)

eTable 5. Associations of anti-IL-6 agents with 90-day mortality, analysed using hazard ratios, and duration of invasive mechanical ventilation (IMV)

eTable 6. Serious adverse events and secondary infections

eTable 7. Associations of anti-IL-6 agents with 28-day mortality, progression to IMV or death and secondary infections:Sensitivity analyses

Click here for additional data file.^{(1.9MB, pdf)}

Supplement 2.

28-day mortality (All results)

Click here for additional data file.^{(11.4MB, pdf)}

Supplement 3.

Progression to IMV or death (All results)

Click here for additional data file.^{(7.3MB, pdf)}

Supplement 4.

28-day secondary infections (All results)

Click here for additional data file.^{(7.9MB, pdf)}

Supplement 5.

In-hospital mortality (All results)

Click here for additional data file.^{(2.8MB, pdf)}

Supplement 6.

Progression to cardiovascular system (CVS) support or death by 28 days (All results)

Click here for additional data file.^{(2.5MB, pdf)}

Supplement 7.

Progression to renal replacement therapy (RRT) or death by 28 days (all results)

Click here for additional data file.^{(2MB, pdf)}

Supplement 8.

Proportion discharged at 28-days (All results)

Click here for additional data file.^{(6MB, pdf)}

Supplement 9.

90-day mortality (all results)

Click here for additional data file.^{(11.1MB, pdf)}

Supplement 10.

Duration of IMV (all results)

Click here for additional data file.^{(1.1MB, pdf)}

Supplement 11.

Anti-IL-6 PMA: Results from additional analyses

Click here for additional data file.^{(8.2MB, pdf)}

Supplement 12.

Data collection form 1: Baseline data

Click here for additional data file.^{(1.9MB, pdf)}

Supplement 13.

Trial protocol

Click here for additional data file.^{(1.6MB, pdf)}

Supplement 14.

Nonauthor Collaborators. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group nonauthor collaborators

Click here for additional data file.^{(169.9KB, pdf)}

[joi210079r1] 1.Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020;8(12):1233-1244. doi: 10.1016/S2213-2600(20)30404-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r2] 2.Laing AG, Lorenc A, Del Molino Del Barrio I, et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med. 2020;26(10):1623-1635. doi: 10.1038/s41591-020-1038-6 [DOI] [PubMed] [Google Scholar]

[joi210079r3] 3.Mathew D, Giles JR, Baxter AE, et al. ; UPenn COVID Processing Unit . Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science. 2020;369(6508):eabc8511. doi: 10.1126/science.abc8511 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r4] 4.Marshall JC, Murthy S, Diaz J, et al. ; WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection . A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20(8):e192-e197. doi: 10.1016/S1473-3099(20)30483-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r5] 5.McElvaney OJ, Curley GF, Rose-John S, McElvaney NG. Interleukin-6: obstacles to targeting a complex cytokine in critical illness. Lancet Respir Med. 2021;9(6):643-654. doi: 10.1016/S2213-2600(21)00103-X [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r6] 6.Tierney JF, Fisher DJ, Vale CL, et al. A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials. PLoS Med. 2021;18(5):e1003629. doi: 10.1371/journal.pmed.1003629 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r7] 7.Sterne JAC, Murthy S, Diaz JV, et al. ; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group . Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. doi: 10.1001/jama.2020.17023 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi210079r8] 8.Gordon AC, Mouncey PR, Al-Beidh F, et al. ; REMAP-CAP Investigators . Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-1502. doi: 10.1056/NEJMoa2100433 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

Manu Shankar-Hari, PhD, MSc

Claire L Vale, PhD

Peter J Godolphin, PhD

David Fisher, MSc

Julian P T Higgins, PhD

Francesca Spiga, PhD

Jelena Savović, PhD

Jayne Tierney, PhD

Gabriel Baron, PhD

Julie S Benbenishty, PhD

Lindsay R Berry, PhD

Niklas Broman, MD

Alexandre Biasi Cavalcanti, MD

Roos Colman, MSc

Stefanie L De Buyser, PhD

Lennie P G Derde, MD, PhD

Pere Domingo, PhD

Sharifah Faridah Omar, MD

Ana Fernandez-Cruz, MD, PhD

Thijs Feuth, MD, PhD

Felipe Garcia, MD, PhD

Rosario Garcia-Vicuna, PhD

Isidoro Gonzalez-Alvaro, PhD

Anthony C Gordon, MBBS, MD

Richard Haynes, DM

Olivier Hermine, MD, PhD

Peter W Horby, MBBS

Nora K Horick, MS

Kuldeep Kumar, MSc

Bart N Lambrecht, MD, PhD

Martin J Landray, PhD

Lorna Leal, MD, PhD

David J Lederer, MD

Elizabeth Lorenzi, PhD

Xavier Mariette, MD, PhD

Nicolas Merchante, MD, PhD

Nor Arisah Misnan, MMed

Shalini V Mohan, MD

Michael C Nivens, PhD

Jarmo Oksi, MD, PhD

Jose A Perez-Molina, PhD

Reuven Pizov, MD

Raphael Porcher, PhD

Simone Postma, MD

Reena Rajasuriar, PhD

Athimalaipet V Ramanan, MD

Philippe Ravaud, MD, PhD

Pankti D Reid, MD, MPH

Abraham Rutgers, MD, PhD

Aranzazu Sancho-Lopez, MD, PhD

Todd B Seto, MD

Sumathi Sivapalasingam, MD

Arvinder Singh Soin, MS

Natalie Staplin, PhD

John H Stone, MD, MPH

Garth W Strohbehn, MD

Jonas Sunden-Cullberg, MD, PhD

Julian Torre-Cisneros, PhD

Larry W Tsai, MD

Hubert van Hoogstraten, MD, PhD

Tom van Meerten, MD, PhD

Viviane Cordeiro Veiga, PhD

Peter E Westerweel, MD, PhD

Srinivas Murthy, MD, CM, MHSc

Janet V Diaz, MD

John C Marshall, MD

Jonathan A C Sterne, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures