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.
Electronic Supplementary Material
Supplementary material is available in the online version of this article at 10.1007/s11684-020-0824-3 and is accessible for authorized users.
Keywords: tocilizumab, Coronavirus disease 2019 (COVID-19), cytokine storm
Electronic supplementary material
A multi-center, open label, randomized controlled clinical study on the efficacy and safety of tocilizumab in patients with novel coronavirus pneumonia
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.
Footnotes
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.
These authors contributed equally to this work.
Contributor Information
Xiaodong Mei, Email: hfmxd@sina.com.
Haiming Wei, Email: ustcwhm@ustc.edu.cn.
Xiaoling Xu, Email: xxlahh8@ustc.edu.cn.
References
- 1.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)
- 2.Johns Hopkins University and Medicine. COVID-19 map. Johns Hopkins Coronavirus Resource Centre. https://coronavirus.jhu.edu/map.html (accessed May 20, 2020).
- 3.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. doi: 10.1093/nsr/nwaa041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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. doi: 10.1016/S2213-2600(20)30076-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.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. doi: 10.1016/j.jtho.2020.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary involvement in patients with hemophagocytic lympho-histiocytosis. Chest. 2016;149(5):1294–1301. doi: 10.1016/j.chest.2015.11.004. [DOI] [PubMed] [Google Scholar]
- 7.Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473–474. doi: 10.1126/science.abb8925. [DOI] [PubMed] [Google Scholar]
- 8.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. doi: 10.1073/pnas.2005615117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18(1):164. doi: 10.1186/s12967-020-02339-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.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. doi: 10.1016/j.autrev.2020.102568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.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. doi: 10.1016/j.chest.2020.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.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. doi: 10.1016/S2665-9913(20)30173-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.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. doi: 10.1136/jitc-2020-000930. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.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. doi: 10.1007/s11684-019-0714-8. [DOI] [PubMed] [Google Scholar]
- 15.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. doi: 10.1002/jmv.25801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.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. doi: 10.1016/j.chest.2020.04.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.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. doi: 10.1038/s41467-020-17834-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
A multi-center, open label, randomized controlled clinical study on the efficacy and safety of tocilizumab in patients with novel coronavirus pneumonia