Manu Shankar-Hari1,2, Claire L Vale3, Peter J Godolphin3, David Fisher3, Julian P T Higgins4,5,6, Francesca Spiga7, Jelena Savovic4,6, Jayne Tierney3, Gabriel Baron8,9, Julie S Benbenishty10, Lindsay R Berry11, Niklas Broman12, Alexandre Biasi Cavalcanti13, Roos Colman14, Stefanie L De Buyser14, Lennie P G Derde15, Pere Domingo16, Sharifah Faridah Omar17, Ana Fernandez-Cruz18, Thijs Feuth19, Felipe Garcia20, Rosario Garcia-Vicuna21, Isidoro Gonzalez-Alvaro21, Anthony C Gordon22, Richard Haynes23,24, Olivier Hermine25,26, Peter W Horby27,28,29, Nora K Horick30, Kuldeep Kumar31,32, Bart N Lambrecht33,34, Martin J Landray23,24, Lorna Leal20, David J Lederer35, Elizabeth Lorenzi11, Xavier Mariette36,37, Nicolas Merchante38, Nor Arisah Misnan39, Shalini V Mohan40, Michael C Nivens35, Jarmo Oksi12, Jose A Perez-Molina41, Reuven Pizov42, Raphael Porcher8,9,43, Simone Postma44, Reena Rajasuriar17,45, Athimalaipet V Ramanan46, Philippe Ravaud8,9,43, Pankti D Reid47, Abraham Rutgers44, Aranzazu Sancho-Lopez48, Todd B Seto49, Sumathi Sivapalasingam35, Arvinder Singh Soin31, Natalie Staplin23,24, John H Stone50,51, Garth W Strohbehn52, Jonas Sunden-Cullberg53, Julian Torre-Cisneros54, Larry W Tsai40, Hubert van Hoogstraten55, Tom van Meerten56, Viviane Cordeiro Veiga13, Peter E Westerweel57, Srinivas Murthy58, Janet V Diaz59, John C Marshall60, Jonathan A C Sterne4,5,61. 1. Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, England. 2. School of Immunology and Microbial Sciences, Kings College London, London, England. 3. University College London, MRC Clinical Trials Unit at UCL, London, England. 4. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England. 5. NIHR Bristol Biomedical Research Centre, Bristol, England. 6. National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England. 7. University of Bristol, Bristol, England. 8. Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France. 9. INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France. 10. Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel. 11. Berry Consultants, Austin, Texas. 12. Turku University Hospital, Department of Infectious Diseases, Turku, Finland. 13. BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil. 14. Department of Public Health and Primary Care, Ghent University, Ghent, Belgium. 15. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. 16. Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 17. Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia. 18. Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. 19. Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland. 20. Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain. 21. Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain. 22. Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England. 23. Nuffield Department of Population Health, University of Oxford, Oxford, England. 24. MRC Population Health Research Unit, University of Oxford, Oxford, England. 25. Department of Hematology, Necker Hospital, Paris, France. 26. Imagine Institute, University of Paris, INSERM U1153, Paris, France. 27. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England. 28. International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England. 29. Pandemic Sciences Centre, University of Oxford, Oxford, England. 30. Department of Medicine, Massachusetts General Hospital, Boston. 31. Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India. 32. Research Department, Medanta Institute of Education and Research, Gurugram, India. 33. VIB Center for Inflammation Research, Ghent University, Ghent, Belgium. 34. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. 35. Regeneron Pharmaceuticals Inc, Tarrytown, New York. 36. Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France. 37. Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France. 38. Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain. 39. Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia. 40. Genentech, South San Francisco, California. 41. Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain. 42. Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel. 43. University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France. 44. Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands. 45. Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. 46. Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England. 47. Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois. 48. Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 49. Center for Outcomes Research and Evaluation, Queen's Medical Center, Honolulu, Hawaii. 50. Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston. 51. Department of Medicine (Rheumatology), Massachusetts General Hospital, Boston. 52. VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan. 53. Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. 54. Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain. 55. Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey. 56. Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands. 57. Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands. 58. Department of Pediatrics, University of British Columbia, Vancouver, Canada. 59. Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland. 60. Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 61. Health Data Research UK South-West, Bristol, England.
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.
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.
Authors: Thoyaja Koritala; Vishwanath Pattan; Raghavendra Tirupathi; Ali A Rabaan; Abbas Al Mutair; Saad Alhumaid; Ramesh Adhikari; Keerti Deepika; Nitesh Kumar Jain; Vikas Bansal; Aysun Tekin; Simon Zec; Amos Lal; Syed Anjum Khan; Juan Pablo Domecq Garces; Omar M Abu Saleh; Salim R Surani; Rahul Kashyap Journal: Infez Med Date: 2021-12-10
Authors: M Abdalbary; M Sobh; S Elnagar; M A Elhadedy; N Elshabrawy; M Abdelsalam; K Asadipooya; A Sabry; A Halawa; A El-Husseini Journal: Osteoporos Int Date: 2022-06-24 Impact factor: 5.071
Authors: Thomas Marjot; Christiane S Eberhardt; Tobias Boettler; Luca S Belli; Marina Berenguer; Maria Buti; Rajiv Jalan; Mario U Mondelli; Richard Moreau; Daniel Shouval; Thomas Berg; Markus Cornberg Journal: J Hepatol Date: 2022-07-20 Impact factor: 30.083
Authors: Graciela L Cabrera-Rivera; Ruth L Madera-Sandoval; José Israel León-Pedroza; Eduardo Ferat-Osorio; Enrique Salazar-Rios; Juan A Hernández-Aceves; Uriel Guadarrama-Aranda; Constantino López-Macías; Isabel Wong-Baeza; Lourdes A Arriaga-Pizano Journal: Clin Exp Immunol Date: 2022-08-19 Impact factor: 5.732
Authors: Wenchun Qu; Zhen Wang; Erica Engelberg-Cook; Dan Yan; Abu Bakar Siddik; Guojun Bu; Julie G Allickson; Eva Kubrova; Arnold I Caplan; Joshua M Hare; Camillo Ricordi; Carl J Pepine; Joanne Kurtzberg; Jorge M Pascual; Jorge M Mallea; Ricardo L Rodriguez; Tarek Nayfeh; Samer Saadi; Ravindra V Durvasula; Elaine M Richards; Keith March; Fred P Sanfilippo Journal: Stem Cells Transl Med Date: 2022-07-20 Impact factor: 7.655