The Importance of the Timing of Tocilizumab Administration in Moderate to Severely Ill COVID-19: Single Centered Experience Case series

Eric Daniel Tenda, Setiabakti Andrian, Sedjahtera Albert, Moses M Asaf, Ceva W Pitoyo, Siti Setiati, Imam Subekti

Abstract


One of the main causes of death in COVID-19 is the dysregulation of the host’s immune system which leads to cytokine storm, a potentially fatal systemic inflammatory syndrome. Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is produced in response to infections and tissue injuries and is believed to play a pivotal role in the event of a cytokine storm, as signified by its increase in the process. Considering the role of IL-6 as a pro-inflammatory cytokine in the process of cytokine storm in COVID-19, perceiving IL-6 as a therapeutic target could prove to be promising. Tocilizumab is a monoclonal antibody that competitively inhibits the binding of IL-6 to its receptor (IL-6R). The use of IL-6R blocker is recommended for severe COVID-19 patients in the latest therapeutic guideline published by the World Health Organization (WHO), but the timing of the administration has not been specified. While previous studies about the use of tocilizumab in COVID-19 patients have shown various results, these studies do not emphasize on plasma IL-6 levels when deciding the time of tocilizumab administration. In this case series, we present three patients with moderate to severe COVID-19 infections that receive tocilizumab as an adjunct to the standard of care therapy. This case series introduces the novel idea that the timely use of tocilizumab as signified by plasma IL-6 levels in moderate to severe COVID-19 patients could potentially improve overall clinical condition and increase survival rate.

Keywords


case series; COVID-19; interleukin-6; timely; tocilizumab

References


Min CK, Cheon S, Ha NY, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep. 2016;6:25359. doi: 10.1038/srep25359. PMID: 27146253; PMCID: PMC4857172.

Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm.Immunother. 2016;8(8):959-70. doi: 10.2217/imt-2016-0020. PMID: 27381687.

Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085-94. doi: 10.1007/s10067-020-05190-5. Epub 2020 May 30. PMID: 32474885; PMCID: PMC7260446.

Copaescu A, Smibert O, Gibson A, Phillips EJ, Trubiano JA. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. J Allergy Clin Immunol. 2020;146(3):518-34.e1. doi: 10.1016/j.jaci.2020.07.001. PMID: 32896310; PMCID: PMC7471766.

REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491-502. doi: 10.1056/NEJMoa2100433. Epub 2021 Feb 25. PMID: 33631065; PMCID: PMC7953461.

Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5. doi: 289 10.1073/pnas.2005615117. Epub 2020 Apr 29. PMID: 32350134; PMCID: 290 PMC7245089.

Erlina burhan, Agus Dwi Susanto, Sally Aman Nasution, et al. Pedoman tatalaksana COVID-19. 3rd ed. Jakarta: Perhimpunan Dokter Paru Indonesia (PDPI), Perhimpunan Dokter Spesialis Kardiovaskular Indonesia (PERKI), Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia (PAPDI), Perhimpunan Dokter Anestesiologi dan Terapi Intensif Indonesia (PERDATIN); 2020.

Widysanto A, Kurniawan A, Lugito NPH, et al. Experience of using tocilizumab for treatment in Indonesian patients with severe COVID-19. Cytokine. 2021;138:155393. 300 doi: 10.1016/j.cyto.2020.155393. Epub 2020 Dec 14. PMID: 33333393; PMCID: 301 PMC7833085.

World Health Organization. Therapeutics and COVID-19: living guideline, 6 July 2021. World Health Organization; 2021.

Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. doi: 10.1016/S0140-6736(20)30211-7. 308 Epub 2020 Jan 30. PMID: 32007143; PMCID: PMC7135076.

Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30; PMID: 31986264; PMCID: PMC7159299.

Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5. doi: 318 10.1073/pnas.2005615117. Epub 2020 Apr 29. PMID: 32350134; PMCID: 319 PMC7245089.

Stone JH, Frigault MJ, Serling-Boyd NJ, et al; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-29,44. doi: 10.1056/NEJMoa2028836. Epub 2020 Oct 21. PMID: 33085857; 330 PMCID: PMC7646626.

Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1):128-36.e4. doi: 10.1016/j.jaci.2020.05.008. Epub 2020 May 18. PMID: 335 32425269; PMCID: PMC7233239.

Laguna-Goya R, Utrero-Rico A, Talayero P, et al. IL-6-based mortality risk model for hospitalized patients with COVID-19. J Allergy Clin Immunol. 2020;146(4):799-807.e9. doi: 341 10.1016/j.jaci.2020.07.009. Epub 2020 Jul 22. PMID: 32710975; PMCID: 342 PMC7375283.

Chen LYC, Hoiland RL, Stukas S, Wellington CL, Sekhon MS. Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome. Eur Respir J. 2020;56(4):2003006. doi: 10.1183/13993003.03006-2020. PMID: 346 32883678; PMCID: PMC7474149.

Quartuccio L, Sonaglia A, Pecori D, Peghin M, Fabris M, Tascini C, De Vita S. Higher levels of IL-6 early after tocilizumab distinguish survivors from nonsurvivors in COVID-19 pneumonia: A possible indication for deeper targeting 350 of IL-6. J Med Virol. 2020;92(11):2852-6. doi: 10.1002/jmv.26149. Epub 351 2020 Jul 22. PMID: 32515499; PMCID: PMC7301025.

Galván-Román JM, Rodríguez-García SC, Roy-Vallejo E, et al; REINMUN-COVID Group. IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study. J Allergy Clin Immunol. 2021;147(1):72-362 80.e8. doi: 10.1016/j.jaci.2020.09.018. Epub 2020 Sep 30. PMID: 33010257; 363 PMCID: PMC7525244.

McElvaney OJ, Curley GF, Rose-John S, McElvaney NG. Interleukin-6: obstaclesto targeting a complex cytokine in critical illness. Lancet Respir Med. 2021;9(6):643-54. doi: 10.1016/S2213-2600(21)00103-X. Epub 2021 Apr 16. 367 PMID: 33872590; PMCID: PMC8051931.

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform 370 trial. Lancet. 2021;397(10285):1637-45. doi: 10.1016/S0140- 371 6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.

Zeraatkar D, Cusano E, Diaz Martinez JP, et al. Tocilizumab and sarilumab alone or in combination with corticosteroids for COVID-19: a systematic review and network meta-analysis. 2021.

The WHO Rapid Evidence Appraisal for COVID-19 Therapies [REACT] Working Groupĺ Association of administration of interleukin-6 antagonists with mortality and other outcomes among hospitalized patients with COVID-19: a prospective meta-analysis. JAMA. 2021.


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