Abstract
Introduction. Novel coronavirus infection (COVID-19) is characterized by systemic hyper-inflammation with elevated inflammatory cytokines, that has been recognized as a leading cause of severity COVID-19. Many clinical evidences have indicated the importance of anti-inflammatory immunomodulation therapy in severe COVID-19, especially anti-IL6 monoclonal antibodies.
Objectives. Comparative study of the monoclonal anti-IL6 antibodies in severe COVID-19 patients.
Materials and methods. Single-center observational retrospective cohort study included three groups of hospitalized COVID-19 patients treated with one-dose tocilizumab (Group 1, 200 patients), levilimab (Group 2, 100 patients), and olokizumab (Group 3, 100 patients). Main parameters at baseline included: C-reactive protein serum concentration, and lung CT score. End-points included: sepsis and in-hospital death.
Results. No significant difference in demographic characteristics and main parameters at baseline were found. A comparative analysis of clinical outcomes in the group revealed a statistically significant increase in the risk of sepsis and death in the levilimab group compared with the tocilizumab and olokizumab groups. When comparing the “Lethal outcome” indicator depending on the drug, we were unable to identify significant differences (p = 0.259, Fisher’s exact test for multi-field tables), as in the “Sepsis” outcome (p = 0.587, Fisher’s exact test for multi-field tables) When comparing tocilizumab for s/c and i.v. administration, we were unable to identify statistically significant differences (p = 0.293, Exact test Fisher) The odds of sepsis in the subcutaneous group were 2.28 times lower than in the intravenous group; the odds differences were not statistically significant (OR = 0.44, 95% CI 0.1–1.88).
Conclusions. The use in patients with severe COVID-19 of different drugs of monoclonal antibodies against interleukin 6 did not reveal significant differences in deaths between tocilizumab, levilimab and olokizumab. The identified differences between the drugs in the incidence of sepsis and death require further randomized controlled trials.
References
- Moore J.B., June C.H. Cytokine release syndrome in severe COVID-19. Science. 2020; 368(6490): 473–474. DOI:1126/science.abb8925
- Song P., Li W., Xie J., et al. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020; 509: 280–287. DOI: 10.1016/j.cca.2020.06.017
- Zhao Z., Wei Y., Tao C. An enlightening role for cytokine storm in coronavirus infection. Clin Immunol. 2021; 222: DOI: 10.1016/j.clim.2020.108615
- Lavillegrand J.R., Garnier M., Spaeth A. et al. Elevated plasma IL-6 and CRP levels are associated with adverse clinical outcomes and death in critically ill SARS-CoV-2 patients: inflammatory response of SARS-CoV-2 patients. Ann Intensive Care. 2021; 11(1): 9. DOI: 10.1186/s13613-020-00798-x
- Potempa L.A., Rajab I.M., Hart P.C., et al. Insights into the Use of C-Reactive Protein as a Diagnostic Index of Disease Severity in COVID-19 Infections, Am J Trop Med Hyg. 2020; 103(2): 561–563. DOI: 10.4269/ajtmh.20-0473
- Yonas E., Alwi I., Pranata R., et al. Elevated interleukin levels are associated with higher severity and mortality in COVID 19. A systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr. Nov-Dec 2020; 14(6): 2219–2230. DOI: 10.1016/j.dsx.2020.11.011
- Conti P., Ronconi G., Caraffa A., et al. Induction of proinflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: antiinflammatory strategies. J Biol Regul Homeost Agents. 2020; 4(2): 327–331. DOI: 10.23812/CONTI-E
- Moradian N., Gouravani M., Salehi M.A., et al. Cytokine release syndrome: inhibition of pro-inflammatory cytokines as a solution for reducing COVID-19 mortality. Eur. Cytokine Netw. 2020; 31(3): 81–93. DOI: 10.1684/ecn.2020.0451
- Pum A., Ennemoser M., Adage T., Kungl A.J. Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm. Biomolecules. 2021; 11(1): DOI: 10.3390/biom11010091
- Chen J., Zhang L., Hou H., et al. Interleukin 6 signaling blockade treatment for cytokine release syndrome in COVID 19 (Review). Exp Ther Med. 2021; 21(1): 24. DOI: 10.3892/etm.2020.9456
- Crisafulli S., Isgrò V., La Corte L., et al. Potential Role of Anti interleukin (IL) 6 Drugs in the Treatment of COVID 19: Rationale, Clinical Evidence and Risks. BioDrugs. 2020; 34(4): 415–422. DOI: 10.1007/s40259-020-00430-1
- Hashizume M. Outlook of IL-6 signaling blockade for COVID-19 pneumonia. Inflamm Regen. 2020; 40: DOI: 10.1186/s41232-020-00134-7
- Nasonov E., Samsonov M. The role of Interleukin 6 inhibitors in therapy of severe COVID-19. Biomed Pharmacother. 2020; 131: DOI: 10.1016/j.biopha.2020.110698
- Zhou Z., Price C. Overview on the use of IL-6 agents in the treatment of patients with cytokine release syndrome (CRS) and pneumonitis related to COVID-19 disease. Expert Opin Investig Drugs. 2020; 29(12): 1407–1412.DOI: 10.1080/13543784.2020.1840549
- Salvarani C., Dolci G., Massari M., et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021; 181(1): 24–31. DOI: 10.1001/jamainternmed.2020.6615
- CORIMUNO-19 Collaborative group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021; 9(3): 295–304. DOI: 10.1016/S2213-2600(20)30556-7
- Stone J.H, Frigault M.J., Serling-Boyd N.J., et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020; 383(24): 2333–2344. DOI: 10.1056/NEJMoa2028836
- Nugroho C.W., Suryantoro S.D., Yuliasih Y., et al. Optimal use of tocilizumab for severe and critical COVID-19: a systematic review and meta-analysis [version 1; peer review: 1 approved] F1000 Research 2021, 10:73 Proc Natl Acad Sci U S A. 2020; 117(20): 10970–10975. DOI: 10.1073/pnas.2005615117
- Kow C.S., Hasan S.S. The effect of tocilizumab on mortality in hospitalized patients with COVID-19: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2021; 1–6. DOI: 10.1007/s00228-021-03087-z
- Berardicurti O., Ruscitti P., Ursini F., et al. Mortality in tocilizumab-treated patients with COVID-19: a systematic review and meta-analysis. Clin Exp Rheumatol. 2020; 38(6): 1247–1254.
- Kim M.S., An M.H., Kim W.J. et al. Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network metaanalysis. PLoS Med. 2020; 17(12): e1003501. DOI: 10.1371/journal.pmed.1003501
- The REMAP-CAP Investigators, Gordon A.C., Mouncey P.R., et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 — Preliminary report. MedRxiv. 2021. DOI: 10.1101/2021.01.07.21249390
- Knight S.R., Ho A., Pius R., et al. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score. BMJ. 2020; 370: m3339. DOI: 10.1136/bmj.m3339
- Catoire P., Tellier E., de la Rivière C., et al. Assessment of the SpO2/FiO2 ratio as a tool for hypoxemia screening in the emergency department. Am J Emerg Med. 2021; 44: 116–120. DOI: 10.1016/j.ajem.2021.01.092
- Wang X., Kattan M.W. Cohort Studies: Design, Analysis, and Reporting. Chest, 2020; 158(1S): S72– DOI: 10.1016/j.chest.2020.03.014
- Burmester G.R., Rubbert-Roth A., Cantagrel A., et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis. 2014; 73(1): 69–74. DOI: 10.1136/annrheumdis-2013-203523
- Le R.Q., Li L., Yuan W., et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018; 23(8): 943–947. DOI: 10.1634/theoncologist.2018-0028. Epub 2018 Apr 5.
- Kaminski M., Sunny S., Balabayova K., et al. Tocilizumab therapy for COVID-19: A comparison of subcutaneous and intravenous therapies. Int J Infect Dis. 2020; 101: 59–64. DOI: 10.1016/j.ijid.2020.09.1447
- Navas N., Hermosilla J., Torrente-López A., et al. Use of subcutaneous tocilizumab to prepare intravenous solutions for COVID-19 emergency shortage: Comparative analytical study of physicochemical quality attributes. J Pharm Anal. 2020; 10(6): 532–545. DOI: 10.1016/j.jpha.2020.06.003
- Potere N., Di Nisio M., Rizzo G., et al. Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation. International Journal of Infectious Diseases. Int J Infect Dis. 2020; 100: 421–424. DOI: 10.1016/j.ijid.2020.07.078
- Mazzitelli M., Arrighi E., Serapide F., et al. Use of subcutaneous tocilizumab in patients with COVID‐19 pneumonia. J Med Virol. 2021; 93(1): 32–34. DOI: 10.1002/jmv.26016
- Greco G., Ripamonti D., Binda F., et al. Potential Role of Subcutaneous Tocilizumab Injections in Patients With COVID-19 associated Pneumonia. J Med Virol. 2021; 93(2): 686–688. DOI: 10.1002/jmv.26494
- Mastroianni A., Greco S., Apuzzo G., et al. Subcutaneous tocilizumab treatment in patients with severe COVID-19 related cytokine release syndrome: An observational cohort study. EClinicalMedicine. 2020; 24: 100410. DOI: 10.1016/j.eclinm.2020.100410
- Di Nisio M., Potere N., Candeloro M., et al. Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19. Eur J Intern Med. 2021; 83: 34–38. DOI: 10.1016/j.ejim.2020.10.020
- Ганюкова Н.Г., Ликстанов М.И., Косинова М.В. идр. Эффективность таргетной терапии ингибитором ИЛ-6 (олокизумаб) в купировании гипервоспаления при среднетяжелой пневмонии, обусловленной вирусом Sars-Cov-2. Фундаментальная и клиническая медицина. 2020; 5(4): 8–13. [Ganyukova N.G., Likstanov M.I., Kosinova M.V., et al. Efficiency of il-6 inhibitor (olokizumab) in suppressing inflammation in patients with moderate COVID-19 pneumonia. Fundamental and Clinical Medicine. 2020; 5(4): 8–13. DOI: 10.23946/2500-0764-2020-5-4-8-13. (In Russ)]
- ЦветовВ.М., Матвеев А.В., Сычев Д.А. Целесообразность рутинного применения препарата олокизумаб при COVID-19. Качественная клиническая практика. 2020; S4: 68–70. [Tsvetov V.M., Matveev A.V., Sychev D.A. Rationality of routine clinical use of olokizumab in COVID-19. Kachestvennaya Klinicheskaya Praktika = Good Clinical Practice. 2020; (4S): 68–70. DOI: 10.37489/2588-0519-2020-S4-68-70. (In Russ)]
- Potere N., Di Nisio M., Cibelli D., et al. Interleukin-6 receptor blockade with subcutaneous tocilizumab in severe COVID-19 pneumonia and hyperinflammation: a case–control study. Ann Rheum Dis. 2021; 80(2): 1–2. DOI: 10.1136/annrheumdis-2020-218243
- Malekzadeh R., Abedini A., Mohsenpour B., et al. Subcutaneous tocilizumab in adults with severe and critical COVID-19: A prospective open-label uncontrolled multicenter trial. Int Immunopharmacol. 2020; 89(Pt B): 107102. DOI: 10.1016/j.intimp.2020.107102
- Guaraldi G., Meschiari M., Cozzi-Lepri A., et al. 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
- De Rossi N., Scarpazza C., Filippini C., et al. Montichiari COVID-19 Study Group. Early use of low dose tocilizumab in patients with COVID-19: A retrospective cohort study with a complete follow-up. EClinicalMedicine. 2020; 25: DOI:10.1016/j.eclinm.2020.100459
- Sciascia S., Aprà F., Baffa A., et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in severe patients with COVID-19. Clin Exp Rheumatol. 2020; 38(3): 529–532.
- Takeuchi T., Smolen J.S., Choy E.H., et al. Considering new lessons about the use of IL-6 inhibitors in arthritis. Considerations in Medicine. 2018; 2: 7–11. DOI: 10.1136/conmed-2018-000002
- Smolen J.S., Aletaha D., Choy E.H., et al. Targeting IL-6: A review of data. Considerations in Medicine. 2018; 2: 12–18. DOI: 10.1136/conmed-2018-000003
- Минздрав России. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)» версия 10 (08.02.2021) [Электронный ресурс]. Режим доступа: https://staticminzdrav.gov.ru/system/attachments/attaches/000/054/588/original/%D0%92%D1%80%D0%B5%D0%BC%D0%B5%D0%BD%D0%BD%D1%8B%D0%B5_%D0%9C%D0%A0_COVID-19_%28v.10%29-08.02.2021_%281%29.pdf. Ссылка активна на 03.03.2021. [Ministry of Health Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” version 10 (02/08/2021) [Electronic resource]. Access mode of the Ministry of Health of Russia Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” version 10 (02/08/2021) [Electronic resource]. Available from: https://static0.minzdrav.gov.ru/system/attachments/attaches/000/054/588/original/%D0%92%D1%80%D0%B5%D0%BC%D0%B5%D0%BD%D0%BD%D1%8B%D0%B5_%D0%9C%D0%A0_COVID-19_%28v.10%29-08.02.2021_%281%29.pdf (accessed 03.03.2021). (In Russ)]
- Руднов В.А., Кулабухов В.В. СЕПСИС-3: Обновленные ключевые положения, потенциальные проблемы и дальнейшие практические шаги. Вестник анестезиологии и реаниматологии. 2016; 13(4): 4–11. [Rudnov V.A., Kulabukhov V.V. SEPSIS-3: updated main definitions, potential problems and next practical steps. Messenger of anesthesiology and resuscitation. 2016; 13(4): 4–11. (In Russ.) DOI:21292/2078-5658-2016-13-4-4-11]

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