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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.
Int J Environ Res Public Health. 2021 08 30; 18(17)IJ

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.

Authors+Show Affiliations

Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. International School of Medicine, Istanbul Medipol University, Istanbul 34810, Beykoz, Turkey.Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK. Rheumatology Unit, Sheba Medical Center, Ramat Gan 5265601, Israel.Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK.Department of Surgery A, Galilee Medical Center, Nahariya 2210001, Israel. Faculty of Medicine of the Galilee, Bar-Ilan University, Safed 13100, Israel. Division of General Surgery, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada.Department of Pathology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy. Department of Pathology, University of Milano-Bicocca, 20126 Milan, Italy.Medical Faculty, University of Parma, 43125 Parma, Italy.Clalit Health Service, Akko, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 13100, Israel.Department of Internal Medicine, Ziv Medical Center, Safed 13100, Israel.Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Rheumatology Unit, Sheba Medical Center, Ramat Gan 5265601, Israel.Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Medical Department, Saint Petersburg State University, 199034 Saint Petersburg, Russia. Ariel University, Kiryat HaMada 3, Ariel 40700, Israel.Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada.Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada.Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK. Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada. Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, 16132 Genoa, Italy.Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK. Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Review
Systematic Review

Language

eng

PubMed ID

34501738

Citation

Mahroum, Naim, et al. "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." International Journal of Environmental Research and Public Health, vol. 18, no. 17, 2021.
Mahroum N, Watad A, Bridgewood C, et al. 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. Int J Environ Res Public Health. 2021;18(17).
Mahroum, N., Watad, A., Bridgewood, C., Mansour, M., Nasr, A., Hussein, A., Khamisy-Farah, R., Farah, R., Gendelman, O., Lidar, M., Shoenfeld, Y., Amital, H., Kong, J. D., Wu, J., Bragazzi, N. L., & McGonagle, D. (2021). 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. International Journal of Environmental Research and Public Health, 18(17). https://doi.org/10.3390/ijerph18179149
Mahroum N, et al. 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. Int J Environ Res Public Health. 2021 08 30;18(17) PubMed PMID: 34501738.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mahroum,Naim, AU - Watad,Abdulla, AU - Bridgewood,Charlie, AU - Mansour,Muhammad, AU - Nasr,Ahmad, AU - Hussein,Amr, AU - Khamisy-Farah,Rola, AU - Farah,Raymond, AU - Gendelman,Omer, AU - Lidar,Merav, AU - Shoenfeld,Yehuda, AU - Amital,Howard, AU - Kong,Jude Dzevela, AU - Wu,Jianhong, AU - Bragazzi,Nicola Luigi, AU - McGonagle,Dennis, Y1 - 2021/08/30/ PY - 2021/07/13/received PY - 2021/08/14/revised PY - 2021/08/23/accepted PY - 2021/9/10/entrez PY - 2021/9/11/pubmed PY - 2021/9/15/medline KW - COVID-19 KW - systematic review and meta-analysis KW - tocilizumab JF - International journal of environmental research and public health JO - Int J Environ Res Public Health VL - 18 IS - 17 N2 - 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. SN - 1660-4601 UR - https://www.unboundmedicine.com/medline/citation/34501738/Systematic_Review_and_Meta_Analysis_of_Tocilizumab_Therapy_versus_Standard_of_Care_in_over_15000_COVID_19_Pneumonia_Patients_during_the_First_Eight_Months_of_the_Pandemic_ L2 - https://www.mdpi.com/resolver?pii=ijerph18179149 DB - PRIME DP - Unbound Medicine ER -