Tocilizumab Therapy in Critically Ill Patients with Coronavirus Disease-2019 Pneumonia – A Propensity Score-Adjusted Analysis

Yasser Nassar; Ahmed  Mokhtar; Amr Elhadidy; Marwa Elsayed  Abdelfattah; Farouk Mostafa; Ashraf Rady; Akram Eladawy; Mostafa Elshazly; Mohamed Saeed; Sherif Mokhtar; Shereen Elgengeehy; Samuel  Buschbeck; Yasser Sakr

doi:10.3889/oamjms.2023.10987

Authors

Yasser Nassar Department of Critical Care, Cairo University Hospitals, Cairo, Egypt
Ahmed Mokhtar Department of Anesthesiology, Cairo University Hospitals, Cairo, Egypt https://orcid.org/0000-0002-0504-274X
Amr Elhadidy Department of Critical Care, Cairo University Hospitals, Cairo, Egypt
Marwa Elsayed Abdelfattah Department of Critical Care, Cairo University Hospitals, Cairo, Egypt https://orcid.org/0000-0002-5767-0465
Farouk Mostafa Department of Critical Care, Cairo University Hospitals, Cairo, Egypt https://orcid.org/0000-0002-8131-5711
Ashraf Rady Department of Anesthesiology, Cairo University Hospitals, Cairo, Egypt
Akram Eladawy Department of Anesthesiology, Cairo University Hospitals, Cairo, Egypt
Mostafa Elshazly Department of Chest Diseases, Cairo University Hospitals, Cairo, Egypt https://orcid.org/0000-0002-5965-7619
Mohamed Saeed Department of Chest Diseases, Cairo University Hospitals, Cairo, Egypt https://orcid.org/0000-0002-5162-9306
Sherif Mokhtar Department of Critical Care, Cairo University Hospitals, Cairo, Egypt
Shereen Elgengeehy Department of Critical Care, Cairo University Hospitals, Cairo, Egypt
Samuel Buschbeck Deptartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany https://orcid.org/0000-0002-2067-6150
Yasser Sakr Deptartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany

DOI:

https://doi.org/10.3889/oamjms.2023.10987

Keywords:

Severe acute respiratory syndrome coronavirus 2, COVID-19, Tocilizumab, Interleukin-6, Immunomodulation

Abstract

BACKGROUND: Tocilizumab, an interleukin-6 receptor monoclonal antibody, has been proposed as a therapeutic option to mitigate coronavirus disease 2019 (COVID-19)-associated cytokine storm.

AIM: We investigated whether tocilizumab therapy is associated with the risk of death and major complications in critically ill patients with COVID-19 pneumonia admitted to the intensive care unit (ICU).

METHODS: We retrospectively included 160 patients with COVID-19 admitted to two ICUs of a university hospital in Egypt. A propensity score-adjusted multivariable Cox proportional hazard analysis with in-hospital death as the dependent variable was performed, in addition to a weighed Cox proportional hazard analysis according to inversed probability treatment weights (IPTWs) of the propensity score.

RESULTS: Tocilizumab was given to 107 patients; 84 patients within 48 h (early) and 23 patients after 48 h (late) of ICU admission. ICU/hospital mortality rate was higher in patients with than those without tocilicumab therapy (30.8 vs. 11.3%, p < 0.001). After propensity score-adjustment, tocilizumab therapy was not associated with the risk of in-hospital death (relative hazard: 0.67, 95% confidence interval: 0.23–1.93, p = 0.454). However, it was associated with high risk of acute kidney injury (AKI) in the ICU (kidney disease improving global outcomes stage 2–3, relative hazard: 3.14, 95% confidence interval: 1.1–8.98, p = 0.033) in an IPTW-weighed Cox proportional hazard analysis.

CONCLUSION: Our data do not support the routine use of tocilizumab therapy in critically ill patients with COVID-19 pneumonia. As it did not influence the risk of in-hospital death but was associated with high risk of AKI in the ICU.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255-73. https://doi.org/10.1056/NEJMra2026131 PMid:33264547

Soy M, Keser G. AtagOndOz P, Tabak F, AtagOndOz L Kayhan S. Cytokine storm in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085-94. http://doi.org/10.10071/s10067-020-05190-5 PMid:32474885

Herold T. Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin lmmunol. 2020;146(1)128-36e4 https://dol.org/10.1016/j.jaci.2020.05.008 PMid 32425269

Guirao JJ, Cabrera CM, Jimenez N, Rinc6n L, Urra JM. High serum I L-6 values increase the risk of mortality and the severity of pneumonia in patients diagnosed with COVID-19. Mollmmunol. 2020;128:64-8. http://doi.org/10.1016/j.molimm.2020.10.006 PMid 33075636

Zhang ZL, Hou YL, Li DT, Li FZ. Laboratory findings of COVID-19: A systematic review and meta-analysis. Scand J Clin Lab Invest. 2020;80(6):441-7. https://doi.org/10.1080/00365513.2020.1768587 PMid 32449374

Chen X, Zhao B. Qu Y, Chen Y, Xiong J, Feng Y, et al. Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin Infect Dis. 2020;71(8):1937-42. https://doi.org/10.1093/cid/ciaa449 PMid:32301997

Ulhaq ZS, Soraya GV. lnterleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. 2020;50(4):382-3. http://doi.org/10.1016/medmal.2020.04.002 PMid 32259560

McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced Pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020;19(6):102537. https://doi.org/10.1016/autrev.2020.102537 PMid:32251717

Lucas C, Wong P, Klein J, Castro TB. Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584{7821):463-9. https://doi.org/10.1038/s41586-020-2588-y PMid 32717743

Biran N, lp A, Ahn J, Go RC, Wang S, Mathura S, et al. Tocilizumab among patients with COVID-19 in the intensive care unit: A multicentre observational study. Lancet Rheumatol. 2020;2(1O):e603-12. https://doi.org/10.1016/82665-9913(20)30277-0 PMid:32838323

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. https://doi.org/10.1001/jamainternmed.2020.6252 PMid 33080002

lp A, Berry DA, Hansen E, Goy AH, Pecora AL, Sinclaire BA et al. Hydroxychloroquine and tocilizumab therapy in COVID-19 patients-An observational study. PLoS One. 2020;15(8) e0237693. https://doi.org/10.1371/journal.pone.0237693 PMid:32790733

Jordan SC, Zakowski P, Tran HP, Smith EA, Gaultier C, Marks G, et al. Compassionate use of tocilizumab for treatment of SARS CoV-2 pneumonia. Clin Infect Dis. 2020;71(12):3168-73. https://doi.org/10.1093/cid/ciaa812 PMid 32575124

Lewis TC, Adhikari S, Tatapudi V. Holub M. Kunichofi' 0, Troxel AB, et al. A propensity-matched cohort study of tocilizumab in patients with coronavirus disease 2019. Crit Care Explor. 2020;2(11):e0283. https://doi.org/10.1097/CCE.0000000000000283 PMid 33225307

Martlnez-Sanz J, Muriel A. Ron R, Herrera S. Perez-Molina JA. MorenoS, et al. Effects oftocilizumab on mortality in hospitalized patients with COVID-19: A multicentre cohort study. Clin Microbiol Infect. 2021;27{2):238-43. https://doi.org/10.1016/cmi.2020.09.021 PMid:32979572

Somers EC, Eschenauer GA. Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2021;73(2):e445-54.

Salvarani C, Dolci G, Massari M, Merlo OF, CavutoS. Savoldi L, et al. Effect oftocilizumab 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.

Hermine 0, Mariette X, Tharaux PL. Resche-Rigon M, Porch er R. Ravaud P, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: A randomized clinical trial. JAMA Intern Med 2021:181(1):32-40. https://doi.org/10.10011/amainternmed.2020.6820 PMid:33080017

Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD. Harvey L, Foulkes AS, et al. Eficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383{24):2333-44. https://doi.org/10.1056/NEJMoa2028836 PMid:33085857

SalamaC, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;384(1):20-30.

Lauder SN. Jones E, Smart K, Bloom A, WilliamsAS, Hindley JP. et al. lnterleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur J lmmunol. 2013:43(10) 2613-25. http://doi.org/10.1002/eji.201243018 PMid:23857287

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE 11: A severity of disease classification system. Crit Care Med. 1985;13(10):818-29. PMid:3928249

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M. Ferrer R, et al. surviving Sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43(3):304-77. https://doi.org/10.1007/sOO134-017-4683-6 PMid 28101605

Acute Respiratory Distress Syndrome Network. Brower RG. Matthay MA, Morris A, Schoenfeld D, Thompson BT. et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342{18):1301-8. https://doi.org/10.1056/N EJM200005043421801 PMid:10793162

Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA. Goldstein SL, et al. Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney lnt Suppl. 2012:2(1)1-138.

Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41-55

Allan V, Ramagopalan SV, Mardekian J, JenkinsA, Li X. Pan X. et al. Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative efectiveness research of oral anticoagulants. J Comp Et Res. 2020:9(9)603-14. http//doi.org/10.2217/cer-2020-0013 PMid 32186922

Group RC, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384(8):693-704. https://doi.org/10.1056/NEJMoa2021436 PMid:32678530

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S. Diaz JV, Slutsky AS. Villar J. et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: Ameta-analysis. JAMA. 2020;324(13):1330-41. https://doi.org/10.1001/ama 2020 17023 PMid 32876694

Rosas 10. Brau N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. 2021;384(16):1503-16. https://doi.org/10.1056/NEJMoa2028700 PMid:33631066

Veiga VC, Prats JA, Farias DL, Rosa RG. Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: Randomised controlled trial. BMJ. 2021;372:n84. https://doi.org/10.1136/bmj.n84 PMid 33472855

Sanofi Provides Update on Kevzara (Sarilumab) Phase 3 Trial in Severe and Critically Ill COVID-19 Patients Outside the U.S. Press Release. Available from: https://www.sanofi.com/en/ media-room/press-releases/2020/2020-09-01-07-00-00 [Last accessed on 2020 Sep 01].

Sanofi and Regeneron Provide Update on Kevzara (Sarilumab) Phase 3 U.S. Trial in COVID-19 Patients. Press Release. Available from: https:/AWN/.sanofi.com/en/media-room/ press-releases/2020/2020-07-02-22-30-00 [Last accessed on 2020 Jul 02].

REMAP-CAP Investigators, Gordon AC, Mouncey PR, AI-Beidh F, Rowan KM, Nichol AD, et al. lnterleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-502. https//doi.org/10.1056/NEJMoa2028700

Sinha P, Calfee CS, Cherian S, Brealey D, Cutler S, King C, et al. Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: A prospective observational study. Lancet Respir Med. 2020;8(12):1209-18. https://doi.org/10.1016/S2213-2600(20)30366-0 PMid 32861275

Sinha P, Matthay MA, Calfee CS. Is a "cytokine storm" relevant to COVID-19? JAMA Intern Med. 2020;180(9):1152-4. https://doi.org/10.1001/amainternmed. 2020.3313 PMid:32602883

Kox M, Waalders NJB, Kooistra EJ. Gerretsen J, Pickkers P. Cytokine levels in critically ill patients with COVID-19 and other conditions. JAMA 2020;324(15) 1565-7. https://doi.org/10.1001/jama.2020.17052 PMid:32880615