Yoğun Bakım Ünitesine Kabul Edilen COVID-19 Hastalarında Tocilizumab Kullanımının Mortalite Üzerine Etkisi

Year 2022, Volume: 24 Issue: 3, 227 - 234, 30.12.2022

Mustafa Tosun , Hasan Ölmez

https://doi.org/10.18678/dtfd.1108303

Abstract

Amaç: Koronavirüs hastalığı 2019 (coronavirus disease 2019, COVID-19) çoğunlukla hafif solunum semptomları ile seyreder, ancak bazen şiddetli pnömoni, sitokin fırtınası ve akut solunum sıkıntısı sendromu gelişebilir. Sitokin fırtınası için anti-sitokin tedaviler denenmektedir. Bu çalışmada, tocilizumabın COVID-19 ile ilişkili mortalite üzerindeki etkisinin incelenmesi amaçlandı.
Gereç ve Yöntemler: Çalışmaya, COVID-19’a bağlı orta-şiddetli akut solunum sıkıntısı sendromu olan 146 hasta dahil edildi. Hastalar sadece standart tedavi alanlar (ST grubu, n=44) ve standart tedavi ile birlikte tocilizumab tedavisi alanlar (TCZ grubu, n=102) olmak üzere iki gruba ayrıldı. Gruplar demografik, klinik ve laboratuvar verileri açısından karşılaştırıldı. Tocilizumabın mortalite üzerindeki etkisini tespit etmek için mortalite oranları da belirlendi.
Bulgular: Genel olarak, hastaların %36,3'ü (n=53) kadın, %63,7'si (n=93) erkek ve yaş ortalaması 69,5±14,2 yıl idi. Mortalite oranı TCZ grubunda %29,4 (n=30) ve ST grubunda ise %52,3 (n=23) idi (p=0,009). Hastaların yoğun bakım ünitesine (YBÜ) kabuldeki C-reaktif protein, fibrinojen ve laktat seviyeleri gruplar arasında benzer iken, TCZ grubunda ferritin seviyeleri daha yüksekti (p=0,006). YBÜ’den taburcu olduklarında TCZ grubunda C-reaktif protein'de anlamlı bir düşüş olurken (p<0,001), ferritin seviyeleri ST grubundaki seviyelere geriledi (p=0,134). Tedavi rejiminde tocilizumabın olmaması, mortalite riskinde 2,63 katlık bir artış ile ilişkili bulundu.
Sonuç: Tocilizumab YBÜ’de takip edilen COVID-19 hastalarında mortaliteyi azaltmaktadır. Bununla birlikte, tocilizumabın etkinliğini ve yan etkilerini daha iyi aydınlatmak için daha fazla çalışmaya ihtiyaç vardır.

Keywords

COVID-19;, sitokin fırtınası;, tosilizumab;, mortalite;, interlökin 6.

Effect of Tocilizumab Use on Mortality in COVID-19 Patients Admitted to Intensive Care Unit

Abstract

Aim: Coronavirus disease 2019 (COVID-19) mostly proceeds with mild respiratory symptoms, but sometimes severe pneumonia, cytokine storm, and acute respiratory distress syndrome can develop. Anti-cytokine treatments are being tried for cytokine storm. In this study, we aimed to examine the effect of tocilizumab on mortality associated with COVID-19.
Material and Methods: The study included 146 patients with moderate-to-severe acute respiratory distress syndrome diagnosed with COVID-19. The patients were divided into two groups, receiving only standard treatment (ST group, n=44), and tocilizumab treatment in addition to standard treatment (TCZ group, n=102). Groups were compared in terms of demographic, clinic, and laboratory data. Also, mortality rates were determined to detect the effect of tocilizumab on mortality.
Results: Overall, 36.3% (n=53) of the patients were female, 63.7% (n=93) were male, and the mean age was 69.5±14.2 years. The mortality rate was 29.4% (n=30) in the TCZ group and 52.3% (n=23) in the ST group (p=0.009). While C-reactive protein, fibrinogen, and lactate levels on admission to the intensive care unit (ICU) were similar across the groups, the TCZ group had higher ferritin levels (p=0.006). On discharge from ICU, the TCZ group had a significant decrease in C-reactive protein (p<0.001), while their ferritin levels decreased to levels in the ST group (p=0.134). The absence of tocilizumab in the treatment regimen was associated with a 2.63-fold increase in the mortality risk.
Conclusion: Tocilizumab reduces the mortality in COVID-19 patients in ICU. However, further studies are warranted to better elucidate the efficacy and side effects of tocilizumab.

Keywords

COVID-19;, cytokine storm;, tocilizumab;, mortality;, interleukin 6.

References

• Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.
• Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199-207.
• Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.
• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
• Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in critically ill patients in the Seattle Region - Case Series. N Engl J Med. 2020;382(21):2012-22.
• Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81.
• Gupta S, Hayek SS, Wang W, Chan L, Mathews KS, Melamed ML, et al. Factors associated with death in critically ill patients with coronavirus disease 2019 in the US. JAMA Intern Med. 2020;180(11):1436-47.
• www.who.int [Internet]. World Health Organization (WHO). WHO coronavirus (COVID-19) dashboard with vaccination data. [Updated: 2022 April 12; Cited: 2022 April 17]. Available from: https://covid19.who.int/
• Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11.
• Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9(1):558-70.
• Khiali S, Khani E, Entezari-Maleki T. A comprehensive review of tocilizumab in COVID-19 acute respiratory distress syndrome. J Clin Pharmacol. 2020;60(9):1131-46.
• Rizk JG, Kalantar-Zadeh K, Mehra MR, Lavie CJ, Rizk Y, Forthal DN. Pharmaco-immunomodulatory therapy in COVID-19. Drugs. 2020;80(13):1267-92.
• Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233-46.
• Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
• Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;19(2):181-93.
• Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, Jammal T El, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567.
• Gupta S, Wang W, Hayek SS, Chan L, Mathews KS, Melamed ML, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51.
• Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: A systematic review and meta-analysis. Rev Med Virol. 2020;30(6):1-9.
• Sciascia S, Apra F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol. 2020;38(3):529-32.
• Yakar Hİ, Pazarli AC, İnönü Köseoğlu H, Kanbay A. The effect of tocilizumab on severe COVID-19 infection: Review of current evidence. Tuberk Toraks. 2021;69(1):74-83.
• Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: The Berlin definition. JAMA. 2012;307(23):2526-33.
• www.saglik.gov.tr [Internet]. Republic of Türkiye Ministry of Health. [COVID-19 (SARS-CoV-2 infection) Adult patient treatment]. [Updated: 2022 April 12; Cited: 2022 April 22]. Available from: https://covid19.saglik.gov.tr/Eklenti/43095/0/covid-19rehberieriskinhastayonetimivetedavi-12042022pdf.pdf. Turkish.
• www.saglik.gov.tr [Internet]. Republic of Türkiye Ministry of Health. [COVID-19 (SARS-CoV-2 infection) anticytokine-anti-inflammatory treatments, coagulopathy management]. [Updated: 2020 November 7; Cited: 2022 April 16]. Available from: https://covid19.saglik.gov.tr/Eklenti/39296/0/covid-19 rehberiantisitokin-antiinflamatuartedavilerkoagulopati yonetimipdf.pdf. Turkish.
• 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.
• Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA. 2020;117(20):10970-5.
• Acat M, Çavdar Ö, Tezce A, Acat BP. Comparison of tocilizumab and anakinra in the treatment of COVID-19: A single-center experience. Duzce Med J. 2022;24(2):116-20.
• idsociety.org [Internet]. Infectious Diseases Society of America (IDSA). IDSA guidelines on the treatment and management of patients with COVID-19. [Updated: 2021 October 12; Cited: 2021 October 27]. Available from: https://www.idsociety.org/COVID19guidelines
• www.nih.gov [Internet]. National Institutes of Health (NIH). Coronavirus disease 2019 (COVID-19) treatment guidelines. [Updated: 2021 October 17; Cited: 2021 October 27]. Available from: https://www.covid19treatmentguidelines.nih.gov/
• Jain V, Yuan JM. Predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission: a systematic review and meta-analysis. Int J Public Health. 2020;65(5):533-46.
• Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
• Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020;395(10229):1014-5.
• Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846-8.
• Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19(7):102568.
• Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021-8.
• Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020;84:106504.
• Liu X, Zhang R, He G. Hematological findings in coronavirus disease 2019: indications of progression of disease. Ann Hematol. 2020;99(7):1421-8.
• Ghayda RA, Lee J, Lee JY, Kim DK, Lee KH, Hong SH, et al. Correlations of clinical and laboratory characteristics of COVID-19: A systematic review and meta-analysis. Int J Environ Res Public Health. 2020;17(14):5026.
• Kavsak PA, de Wit K, Worster A. Emerging key laboratory tests for patients with COVID-19. Clin Biochem. 2020;81:13-4.
• Lui Y, Du X, Chen J, Jin Y, Peng L, Wang HHX, et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect. 2020;81(1):e6-12.
• Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2(8):e474-84.
• Zhao J, Cui W, Tian BP. Efficacy of tocilizumab treatment in severely ill COVID-19 patients. Crit Care. 2020;24(1):524.
• Lan SH, Lai CC, Huang HT, Chang SP, Lu LC, Hsueh PR. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020;56(3):106103.
• Klopfenstein T, Zayet S, Lohse A, Balblanc JC, Badie J, Royer PY, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect. 2020;50(5):397-400.
• Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, et al. Tocilizumab treatment for cytokine release syndrome in hospitalized patients with coronavirus disease 2019: survival and clinical outcomes. Chest. 2020;158(4):1397-408.