Systematic Review and Meta-Analysis of Tocilizumab Therapy versus Standard of Care in over 15,000 COVID-19 Pneumonia Patients during the First Eight Months of the Pandemic

Naim Mahroum, Abdulla Watad, Charlie Bridgewood, Muhammad Mansour, Ahmad Nasr, Amr Hussein, Rola Khamisy-Farah, Raymond Farah, Omer Gendelman, Merav Lidar, Yehuda Shoenfeld, Howard Amital, Jude Dzevela Kong, Jianhong Wu, Nicola Luigi Bragazzi and Dennis McGonagle
Additional contact information
Naim Mahroum: Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel
Abdulla Watad: Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel
Charlie Bridgewood: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK
Muhammad Mansour: Department of Surgery A, Galilee Medical Center, Nahariya 2210001, Israel
Ahmad Nasr: Department of Pathology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy
Amr Hussein: Medical Faculty, University of Parma, 43125 Parma, Italy
Rola Khamisy-Farah: Clalit Health Service, Akko, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 13100, Israel
Raymond Farah: Department of Internal Medicine, Ziv Medical Center, Safed 13100, Israel
Omer Gendelman: Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel
Merav Lidar: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Yehuda Shoenfeld: Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel
Howard Amital: Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel
Jude Dzevela Kong: Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada
Jianhong Wu: Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada
Nicola Luigi Bragazzi: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK
Dennis McGonagle: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK

IJERPH, 2021, vol. 18, issue 17, 1-28

Abstract: Background. Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called “cytokine storm” related to SARS-CoV-2 virus infection, but its effectiveness, use in relation to concomitant corticosteroid therapy and safety were unproven despite widespread use in numerous studies, mostly open label at the start of the pandemic. Methods: We performed a systematic review and meta-analysis of case-control studies utilising tocilizumab in COVID-19 on different databases (PubMed/MEDLINE/Scopus) and preprint servers (medRxiv and SSRN) from inception until 20 July 2020 (PROSPERO CRD42020195690). Subgroup analyses and meta-regressions were performed. The impact of tocilizumab and concomitant corticosteroid therapy or tocilizumab alone versus standard of care (SOC) on the death rate, need for mechanical ventilation, ICU admission and bacterial infections were assessed. Results. Thirty-nine studies with 15,531 patients (3657 cases versus 11,874 controls) were identified. Unadjusted estimates ( n = 28) failed to demonstrate a protective effect of tocilizumab on survival (OR 0.74 ([95%CI 0.55–1.01], p = 0.057), mechanical ventilation prevention (OR 2.21 [95%CI 0.53–9.23], p = 0.277) or prevention of ICU admission (OR 3.79 [95%CI 0.38–37.34], p = 0.254). Considering studies with adjusted, estimated, tocilizumab use was associated with mortality rate reduction (HR 0.50 ([95%CI 0.38–0.64], p < 0.001) and prevention of ICU admission (OR 0.16 ([95%CI 0.06–0.43], p < 0.001). Tocilizumab with concomitant steroid use versus SOC was protective with an OR of 0.49 ([95%CI 0.36–0.65], p < 0.05) as was tocilizumab alone versus SOC with an OR of 0.59 ([95%CI 0.34–1.00], p < 0.001). Risk of infection increased (2.36 [95%CI 1.001–5.54], p = 0.050; based on unadjusted estimates). Conclusion: Despite the heterogeneity of included studies and large number of preprint articles, our findings from the first eight of the pandemic in over 15,000 COVID-19 cases suggested an incremental efficacy of tocilizumab in severe COVID-19 that were confirmed by subsequent meta-analyses of large randomized trials of tocilizumab. This suggests that analysis of case-control studies and pre-print server data in the early stages of a pandemic appeared robust for supporting incremental benefits and lack of major therapeutic toxicity of tocilizumab for severe COVID-19.

Keywords: COVID-19; tocilizumab; systematic review and meta-analysis (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2021
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