Abstract
Tocilizumab has been reported to attenuate the “cytokine storm” in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI–7.19%–21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI–99.17% to–17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
WHO. WHO Director-General’s remarks at the media briefing on 2019-nCoV on 11 February 2020. Available at: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (accessed February 12, 2020)
Johns Hopkins University and Medicine. COVID-19 map. Johns Hopkins Coronavirus Resource Centre. https://coronavirus.jhu.edu/map.html (accessed May 20, 2020).
Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, Sun R, Tian Z, Xu X, Wei H. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev 2020; 7(6): 998–1002
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420–422
Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020; 15(5): 700–704
Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary involvement in patients with hemophagocytic lympho-histiocytosis. Chest 2016; 149(5): 1294–1301
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368(6490): 473–474
Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020; 117(20): 10970–10975
Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 2020; 18(1): 164
Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airò P, Bazzani C, Beindorf EA, Berlendis M, Bezzi M, Bossini N, Castellano M, Cattaneo S, Cavazzana I, Contessi GB, Crippa M, Delbarba A, De Peri E, Faletti A, Filippini M, Filippini M, Frassi M, Gaggiotti M, Gorla R, Lanspa M, Lorenzotti S, Marino R, Maroldi R, Metra M, Matteelli A, Modina D, Moioli G, Montani G, Muiesan ML, Odolini S, Peli E, Pesenti S, Pezzoli MC, Pirola I, Pozzi A, Proto A, Rasulo FA, Renisi G, Ricci C, Rizzoni D, Romanelli G, Rossi M, Salvetti M, Scolari F, Signorini L, Taglietti M, Tomasoni G, Tomasoni LR, Turla F, Valsecchi A, Zani D, Zuccalà F, Zunica F, Focà E, Andreoli L, Latronico N. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperin-flammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev 2020; 19(7): 102568
Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, Azar MM, Mcmanus D, Chen SC, Gleeson SE, Britto CJ, Azmy V, Kaman K, Gaston DC, Davis M, Burrello T, Harris Z, Villanueva MS, Aoun-Barakat L, Kang I, Seropian S, Chupp G, Bucala R, Kaminski N, Lee AI, LoRusso PM, Topal JE, Dela Cruz C, Malinis M. Tocilizumab treatment for cytokine release syndrome in hospitalized patients with coronavirus disease 2019: survival and clinical outcomes. Chest 2020; 158(4): 1397–1408
Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, Franceschini E, Cuomo G, Orlando G, Borghi V, Santoro A, Di Gaetano M, Puzzolante C, Carli F, Bedini A, Corradi L, Fantini R, Castaniere I, Tabbì L, Girardis M, Tedeschi S, Giannella M, Bartoletti M, Pascale R, Dolci G, Brugioni L, Pietrangelo A, Cossarizza A, Pea F, Clini E, Salvarani C, Massari M, Viale PL, Mussini C. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol 2020; 2(8): e474–e484
Arnaldez FI, O’Day SJ, Drake CG, Fox BA, Fu B, Urba WJ, Montesarchio V, Weber JS, Wei H, Wigginton JM, Ascierto PA. The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response. J Immunother Cancer 2020; 8(1): e000930
Chen H, Wang F, Zhang P, Zhang Y, Chen Y, Fan X, Cao X, Liu J, Yang Y, Wang B, Lei B, Gu L, Bai J, Wei L, Zhang R, Zhuang Q, Zhang W, Zhao W, He A. Management of cytokine release syndrome related to CAR-T cell therapy. Front Med 2019; 13(5): 610–617
Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol 2020; 92(7): 814–818
Radbel J, Narayanan N, Bhatt PJ. Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report. Chest 2020; 158(1): e15–e19
Guo C, Li B, Ma H, Wang X, Cai P, Yu Q, Zhu L, Jin L, Jiang C, Fang J, Liu Q, Zong D, Zhang W, Lu Y, Li K, Gao X, Fu B, Liu L, Ma X, Weng J, Wei H, Jin T, Lin J, Qu K. Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat Commun 2020; 11 (1): 3924
Acknowledgements
This work was supported by the Department of Science and Technology of Anhui Province and Health Commission of Anhui Province (No. 202004a07020001) and the China National Center for Biotechnology Development (No. 2020YFC0843800). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Compliance with ethics guidelines
Dongsheng Wang, Binqing Fu, Zhen Peng, Dongliang Yang, Mingfeng Han, Min Li, Yun Yang, Tianjun Yang, Liangye Sun, Wei Li, Wei Shi, Xin Yao, Yan Ma, Fei Xu, Xiaojing Wang, Jun Chen, Daqing Xia, Yubei Sun, Lin Dong, Jumei Wang, Xiaoyu Zhu, Min Zhang, Yonggang Zhou, Aijun Pan, Xiaowen Hu, Xiaodong Mei, Haiming Wei, and Xiaoling Xu declare that they have no conflict of interest. The study protocol was approved by the Medical Research Ethics Committee of Anhui Provincial Hospital, the First Affiliated Hospital of University of Science and Technology of China (approval no. 2020-XG (H)-015). We committed to protect the patient’s privacy and comply with the Helsinki Declaration.
Electronic supplementary material
11684_2020_824_MOESM2_ESM.pdf
A multi-center, open label, randomized controlled clinical study on the efficacy and safety of tocilizumab in patients with novel coronavirus pneumonia
Rights and permissions
About this article
Cite this article
Wang, D., Fu, B., Peng, Z. et al. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial. Front. Med. 15, 486–494 (2021). https://doi.org/10.1007/s11684-020-0824-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11684-020-0824-3