Temporal Clinical and Laboratory Response to Interleukin-6 Receptor Blockade With Tocilizumab in 89 Hospitalized Patients With COVID-19 Pneumonia

Daria Fomina, Mar’yana A. Lysenko, Irina P. Beloglazova, Zinaida Yu. Mutovina, Nataliya G. Poteshkina, Inna V. Samsonova, Tat’yana S. Kruglova, Anton A. Chernov, Alexander V. Karaulov

Abstract


Background: Pandemic COVID-19 pneumonia due to SARS-2 is an important cause of morbidity and mortality. Emerging evidence links poor outcomes to an inflammatory cytokine storm.

Methods: We treated 89 hospitalized patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) with an infusion of tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor.

Results: Clinical and laboratory evidence of improvement was evident when baseline and 1-2-day post-infusion indices were compared. Among the 72 patients receiving supplemental oxygen without mechanical ventilation, severity of condition on the NEWS2 scale scores fell from 5 to 2 (P<0.001), C reactive protein levels fell from 95 to 14 mg/L (P<0.001), and lymphocyte counts rose from 900 to 1000/uL (P=0.036). Sixty-three of 72 patients were discharged from the hospital, one patient died, and eight patients remained in the hospital at the time of this writing. Among the 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (P=0.014) and early improvements in NEWS2 scores in 10 of 17 patients, 10 patients ultimately died and the other seven remain in the hospital at the time of this writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration.

Conclusions: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of tocilizumab, an anti-IL-6 receptor antibody, is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.


Keywords


Covid-19; SARS-CoV-2; pneumonia; cytokine storm; IL-6; tocilizumab

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References


1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3. Epub 2020/02/06. doi: 10.1038/s41586-020-2012-7. PubMed PMID: 32015507; PMCID: PMC7095418.

2. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-9. Epub 2020/02/26. doi: 10.1038/s41564-020-0688-y. PubMed PMID: 32094589; PMCID: PMC7095430.

3. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80 e8. Epub 2020/03/07. doi: 10.1016/j.cell.2020.02.052. PubMed PMID: 32142651; PMCID: PMC7102627.

4. Wang X, Fang X, Cai Z, Wu X, Gao X, Min J, Wang F. Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis. Research (Wash D C). 2020;2020:2402961. Epub 2020/05/08. doi: 10.34133/2020/2402961. PubMed PMID: 32377638; PMCID: PMC7187729.

5. Bonafe M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020;53:33-7. Epub 2020/05/12. doi: 10.1016/j.cytogfr.2020.04.005. PubMed PMID: 32389499; PMCID: PMC7252014.

6. Murthy H, Iqbal M, Chavez JC, Kharfan-Dabaja MA. Cytokine Release Syndrome: Current Perspectives. Immunotargets Ther. 2019;8:43-52. Epub 2019/11/23. doi: 10.2147/ITT.S202015. PubMed PMID: 31754614; PMCID: PMC6825470.

7. Temporary guidelines for the prevention, diagnosis and treatment of new coronovirus infection (COVID-19) [Internet]. Ministry of Health of the Russian Federation; 2020 [updated 2020 Apr 28; cited 2020 May 7]. Available from: https://static-1.rosminzdrav.ru/system/attachments/attaches/000/050/122/original/28042020_%D0%9CR_COVID-19_v6.pdf.

8. Martin-Rodriguez F, Lopez-Izquierdo R, Del Pozo Vegas C, Delgado Benito JF, Carbajosa Rodriguez V, Diego Rasilla MN, Martin Conty JL, Mayo Iscar A, Otero de la Torre S, Mendez Martin V, Castro Villamor MA. Accuracy of National Early Warning Score 2 (NEWS2) in Prehospital Triage on In-Hospital Early Mortality: A Multi-Center Observational Prospective Cohort Study. Prehosp Disaster Med. 2019;34(6):610-8. Epub 2019/10/28. doi: 10.1017/S1049023X19005041. PubMed PMID: 31648657.

9. Martin-Rodriguez F, Lopez-Izquierdo R, Del Pozo Vegas C, Sanchez-Soberon I, Delgado-Benito JF, Martin-Conty JL, Castro-Villamor MA. Can the prehospital National Early Warning Score 2 identify patients at risk of in-hospital early mortality? A prospective, multicenter cohort study. Heart Lung. 2020;49(5):585-91. Epub 2020/03/15. doi: 10.1016/j.hrtlng.2020.02.047. PubMed PMID: 32169257.

10. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516-23. Epub 2008/07/16. doi: 10.1136/ard.2008.092932. PubMed PMID: 18625622; PMCID: PMC3811149.

11. Bi X, Su Z, Yan H, Du J, Wang J, Chen L, Peng M, Chen S, Shen B, Li J. Prediction of severe illness due to COVID-19 based on an analysis of initial Fibrinogen to Albumin Ratio and Platelet count. Platelets. 2020;31(5):674-9. Epub 2020/05/06. doi: 10.1080/09537104.2020.1760230. PubMed PMID: 32367765; PMCID: PMC7212543.

12. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959-64. Epub 2008/09/12. doi: 10.1182/blood-2008-05-155846. PubMed PMID: 18784373.

13. 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 U S A. 2020;117(20):10970-5. Epub 2020/05/01. doi: 10.1073/pnas.2005615117. PubMed PMID: 32350134; PMCID: PMC7245089.

14. Hashem AM, Alghamdi BS, Algaissi AA, Alshehri FS, Bukhari A, Alfaleh MA, Memish ZA. Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review. Travel Med Infect Dis. 2020;35:101735. Epub 2020/05/11. doi: 10.1016/j.tmaid.2020.101735. PubMed PMID: 32387694; PMCID: PMC7202851.

15. Wen CY, Xie ZW, Li YP, Deng XL, Chen XT, Cao Y, Ou X, Lin WY, Li F, Cai WP, Li LH. [Real-world efficacy and safety of lopinavir/ritonavir and arbidol in treating with COVID-19 : an observational cohort study]. Zhonghua Nei Ke Za Zhi. 2020;59(0):E012. Epub 2020/05/11. doi: 10.3760/cma.j.cn112138-20200227-00147. PubMed PMID: 32388937.

16. 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):814-8. Epub 2020/04/08. doi: 10.1002/jmv.25801. PubMed PMID: 32253759; PMCID: PMC7262125.

17. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li CH, Li GC, Liu HG. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020;133(9):1025-31. Epub 2020/02/12. doi: 10.1097/CM9.0000000000000744. PubMed PMID: 32044814; PMCID: PMC7147277.

18. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. Epub 2020/02/08. doi: 10.1001/jama.2020.1585. PubMed PMID: 32031570; PMCID: PMC7042881.


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