Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: retrospective cohort study


Background: The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit.
Methods: The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching.
Results: Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in nontreated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission.
Conclusions: Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation.


*Modena Covid-19 Working Group (MoCo19): 
Intensive Care Unit: Massimo Girardis, Alberto Andreotti, Emanuela Biagioni, Filippo Bondi, Stefano Busani, Giovanni Chierego, Marzia Scotti, Lucia Serio, Annamaria Ghirardini, Marco Sita, Stefano De Julis, Lara Donno, Lorenzo Dall’Ara, Fabrizio Di Salvo, Carlotta Farinelli, Laura Rinaldi, Ilaria Cavazzuti, Andrea Ghidoni, Antonio Buono, Elena Ferrari, Daniela Iseppi, Anna Maria Ardito, Irene Coloretti, Sophie Venturelli, Elena Munari, Martina Tosi, Erika Roat, Ilenia Gatto, Marco Sarti.
Immuno-Lab: Andrea Cossarizza, Caterina Bellinazzi, Rebecca Borella, Sara De Biasi, Anna De Gaetano, Lucia Fidanza, Lara Gibellini, Anna Iannone, Domenico Lo Tartaro, Marco Mattioli, Milena Nasi, Annamaria Paolini, Marcello Pinti. 
Infectious Disease Unit: Cristina Mussini, Giovanni Guaraldi, Marianna Meschiari, Alessandro Cozzi-Lepri, Jovana Milic, Marianna Menozzi, Erica Franceschini, Gianluca Cuomo, Gabriella Orlando, Vanni Borghi, Antonella Santoro, Margherita Di Gaetano, Cinzia Puzzolante, Federica Carli, Andrea Bedini, Luca Corradi. Respiratory Diseases Unit: Enrico Clini, Roberto Tonelli, Riccardo Fantini, Ivana Castaniere, Luca Tabbì, Giulia Bruzzi, Chiara Nani, Fabiana Trentacosti, Pierluigi Donatelli, Maria Rosaria Pellegrino, Linda Manicardi, Antonio Moretti, Morgana Vermi, Caterina Cerbone.
Virology and Molecular Microbiology Unit: Monica Pecorari, William Gennari, Antonella Grottola, Giulia Fregni Serpini.



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Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA 2020;323:1574-81. DOI: https://doi.org/10.1001/jama.2020.5394

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43. DOI: https://doi.org/10.1001/jamainternmed.2020.0994

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;395:1054- 62. DOI: https://doi.org/10.1016/S0140-6736(20)30566-3

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;382:2012-2. DOI: https://doi.org/10.1056/NEJMoa2004500

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. Lance. 2020;395:497–506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5

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;8:475–81. DOI: https://doi.org/10.1016/S2213-2600(20)30079-5

Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA 2020;323:1612-4. DOI: https://doi.org/10.1001/jama.2020.4326

Pascarella G, Strumia A, Piliego C, Bruno F, Del Buono R, Costa F, et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med 2020;288:192-206. DOI: https://doi.org/10.1111/joim.13091

Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569–78. DOI: https://doi.org/10.1016/S0140-6736(20)31022-9

RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 - Preliminary report. N Engl J Med 2020;384:693-704. DOI: https://doi.org/10.1056/NEJMoa2021436

Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020;8:e46-7. DOI: https://doi.org/10.1016/S2213-2600(20)30216-2

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect 2020;80:607-13. DOI: https://doi.org/10.1016/j.jinf.2020.03.037

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;92:814-8. DOI: https://doi.org/10.1002/jmv.25801

ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526–33. DOI: https://doi.org/10.1001/jama.2012.5669

World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. Available from: https://apps.who.int/iris/handle/10665/331446 DOI: https://doi.org/10.15557/PiMR.2020.0003

National Society of Infectious Diseases’ (SIMIT) Guidelines for the management of COVID-19 infection. Accessed on: April 5th 2020. Available from: http://www.simit.org/medias/1569-covid19-vademecum-13-03-202.pdf

Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671–84. DOI: https://doi.org/10.1056/NEJMoa051693

Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 2018;23:943–7. DOI: https://doi.org/10.1634/theoncologist.2018-0028

Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol 2020;2:E358-67. DOI: https://doi.org/10.1016/S2665-9913(20)30096-5

Futami M, Suzuki K, Kato S, Ohmae S, Tahara Y, Nojima M, et al. The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells. PLoS One 2020;15:e0231896. DOI: https://doi.org/10.1371/journal.pone.0231896

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;46:846–8. DOI: https://doi.org/10.1007/s00134-020-05991-x

Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020;27:992-1000.e3. DOI: https://doi.org/10.1016/j.chom.2020.04.009

Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med 2020;58:1131-4. DOI: https://doi.org/10.1515/cclm-2020-0198

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–4. DOI: https://doi.org/10.1016/S0140-6736(20)30628-0

Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A Review of recent advances using tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther 2018;5:21–42. DOI: https://doi.org/10.1007/s40744-018-0102-x

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:e474–84. DOI: https://doi.org/10.1016/S2665-9913(20)30173-9

Alattar R, Ibrahim TBH, Shaar SH, Abdalla S, Shukri K, Daghfal JN, et al. Tocilizumab for the treatment of severe coronavirus disease 2019. J Med Virol 2020;92:2042-9. DOI: https://doi.org/10.1002/jmv.25964

Knorr JP, Colomy V, Mauriello CM, Ha S. Tocilizumab in patients with severe COVID-19: A single-center observational analysis. J Med Virol 2020;92:2813-20. DOI: https://doi.org/10.1002/jmv.26191

Eimer J, Vesterbacka J, Svensson A-K, Stojanovic B, Wagrell C, Sönnerborg A, et al. Tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe COVID19: a retrospective cohort study. J Intern Med 2021;289:434-6. DOI: https://doi.org/10.1111/joim.13162

Biran N, Ip A, Ahn J, Go RC, Wang S, Mathura S, et al. Tocilizumab among patients with COVID19 in the intensive care unit: a multicentre observational study. Lancet Rheumatol 2020;2:e603-12. DOI: https://doi.org/10.1016/S2665-9913(20)30277-0

Dinarello CA, van der Meer JWM. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013;25:469–84. DOI: https://doi.org/10.1016/j.smim.2013.10.008

Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2:E325-31. DOI: https://doi.org/10.1016/S2665-9913(20)30127-2

Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med 2020;180:1345-55. DOI: https://doi.org/10.1001/jamainternmed.2020.3539

Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-9. DOI: https://doi.org/10.1001/jama.2020.6775

ICNARC report on COVID-19 in critical care. 01 May 2020. Available from: https://www.icnarc.org/DataServices/Attachments/Download/f48efee2-d38b-ea11-9125-00505601089b

Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, singlearm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020;38:529-32.

Original Research Articles
COVID-19, acute respiratory distress syndrome, tocilizumab, anakinra, intensive care unit, mechanical ventilation
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How to Cite
Coloretti, I., Busani, S., Biagioni, E., Venturelli, S., Munari, E., Sita, M., Dall’Ara, L., Tosi, M., Clini, E., Tonelli, R., Fantini, R., Mussini, C., Meschiari, M., Guaraldi, G., Cossarizza, A., Alfano, G., Girardis, M., & (MoCo19)M. C.-1. W. G. (2021). Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: retrospective cohort study . Multidisciplinary Respiratory Medicine, 16. https://doi.org/10.4081/mrm.2021.737