Tocilizumab treatment in critically ill patients with COVID-19: A retrospective observational study
Edmund Huang, Sharon Isonaka, Haoshu Yang, Erin Salce, Elisa Rosales, Stanley C Jordan
International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.02.057
Objective: Elevated levels of pro-inflammatory cytokines are observed in severe COVID-19 infections, and cytokine storm is associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, is used to treat chimeric antigen receptor T cell-induced cytokine release syndrome and may attenuate the dysregulated immune response in COVID-19. We compared outcomes among tocilizumab-treated and non-tocilizumab-treated critically ill COVID-19 patients. Design, setting, and participants: This was a retrospective observational study conducted at a tertiary referral center investigating all patients admitted to the intensive care unit for COVID-19 who had a disposition from the hospital because of death or hospital discharge between March 1 and May 18, 2020 (n = 96). The percentages of death and secondary infections were compared between patients treated with tocilizumab (n = 55) and those who were not (n = 41). Measurements and main results: More tocilizumab-treated patients required mechanical ventilation (44/ 55, 80%) compared to non-treated patients (15/41, 37%; P < 0.001). Of 55 patients treated with tocilizumab, 32 (58%) were on mechanical ventilation at the time of administration, and 12 (22%) progressed to mechanical ventilation after treatment. Of patients treated with tocilizumab requiring mechanical ventilation, 30/44 (68%) were intubated within 1 day of administration. Fewer deaths were observed among tocilizumab-treated patients, both in the overall population (15% vs 37%; P = 0.02) and among the subgroup of patients requiring mechanical ventilation (14% vs 60%; P = 0.001). Secondary infections were not different between the 2 groups (tocilizumab: 31%, non-tocilizumab: 17%; P = 0.16) and were predominantly related to invasive devices, such as urinary and central venous catheters. Conclusions: Tocilizumab treatment was associated with fewer deaths compared to non-treatment despite predominantly being used in patients with more advanced respiratory disease.
Conflicts of interest
References
Biran, Ip, Ahn, Go, Wang et al., Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study, Lancet Rheumatol
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., Coalition Covid-19 Brazil II. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19, N Engl J Med
Copaescu, Smibert, Gibson, Phillips, Trubiano, The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection, J Allergy Clin Immunol
Guaraldi, Meschiari, Cozzi-Lepri, Milic, Tonelli et al., Tocilizumab in patients with severe COVID-19: a retrospective cohort study, Lancet Rheumatol
Gupta, Wang, Hayek, Chan, Mathews et al., Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19, JAMA Intern Med
Hermine, Tharaux, Resche-Rigon, Porcher, Ravaud, Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial, JAMA Intern Med
Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Imai, Parodo, Kajikawa, De Perrot, Fischer et al., Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome, JAMA
Jordan, Zakowski, Tran, Smith, Gaultier et al., Compassionate use of tocilizumab for treatment of SARS-CoV-2 pneumonia, Clin Infect Dis
Le, Li, Yuan, Shord, Nie et al., FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome, Oncologist
Mahallawi, Khabour, Zhang, Makhdoum, Suliman, MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile, Cytokine
Parsons, Eisner, Thompson, Matthay, Ancukiewicz et al., Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury, Crit Care Med
Price, Altice, Shyr, Koff, Pischel et al., Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes, Chest
Ranieri, Giunta, Suter, Slutsky, Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome, JAMA
Recovery Collaborative Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in hospitalized patients with Covid-19preliminary report, N Engl J Med
Roschewski, Lionakis, Sharman, Roswarski, Goy et al., Inhibition of Bruton tyrosine kinase in patients with severe COVID-19, Sci Immunol
Salvarani, Dolci, Massari, Merlo, Cavuto 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
Somers, Eschenauer, Troost, Golob, Gandhi et al., Tocilizumab for treatment of mechanically ventilated patients with COVID-19, Clin Infect Dis
Stone, Frigault, Serling-Boyd, Fernandes, Harvey et al., Efficacy of tocilizumab in patients hospitalized with Covid-19, N Engl J Med
Wong, Lam, Wu, Ip, Lee et al., Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome, Clin Exp Immunol
Yehya, Harhay, Curley, Schoenfeld, Reeder, Reappraisal of ventilator-free days in critical care research, Am J Respir Crit Care Med
Zhao, Cui, Tian, Efficacy of tocilizumab treatment in severely ill COVID-19 patients, Crit Care
Zhou, Yang, Wang, Hu, Zhang et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
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