Use of monoclonal antibodies to IL-6 in patients with severe COVID-19

The use of monoclonal antibodies against interleukin-6 (IL-6) receptors is considered as a potential method of treatment and prevention of complications of the new coronavirus infection 2019 (COVID-19), based on reducing the intensity of the cytokine storm. The aim. To assess the relationship between the use of IL-6 blockers and the risk of tracheal intubation in patients with severe pneumonia associated with COVID-19. Methods. The retrospective cohort study included patients over 18 years of age admitted to the intensive care unit (ICU) with confirmed COVID-19 infection, lung tissue damage of at least 25% between November 4, 2020 and December 25, 2020. All patients underwent standard therapy in accordance with the current recommendations of the Ministry of Health of the Russian Federation, including IL-6 blockers in some patients. The primary endpoint was tracheal intubation and initiation of mechanical ventilation (MV). Data on the use of IL-6 inhibitors, baseline demographic, clinical and laboratory characteristics, as well as information on tracheal intubation, fatal outcomes and length of hospitalization were obtained from the unified medical information and analytical system of the city of Moscow. To analyze the relationship between the use of IL-6 blockers and endpoints adjusted for baseline characteristics, a multivariate Cox proportional hazards model was used. Results. The study included 242 patients, in 120 (49.5%) of them IL-6 blockers were used. The independent predictors of tracheal intubation were the degree of lung tissue damage, ferritin and diabetes, while the use of IL-6 blockers was not associated with a decrease in the risk of intubation: hazard ratio (HR) 0.96 (95% confidence interval [CI] 0.63 – 1.48) and death: HR 1.05 (95% CI 0.69 – 1.62). Subgroup analysis showed that, among surviving patients, the use of IL-6 blockers was associated with an average decrease in hospital stay by 3 days (95% CI 1 – 6 days). Conclusion. The use of IL-6 blockers was not associated with a decrease in the risk of tracheal intubation or death. Among surviving patients, the use of IL-6 blockers was associated with a decrease in the length of hospital stay. These findings may contribute to medical decision making during COVID-19 pandemic associated high hospital workload.

1. Salama C., Han J., Yau L. et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N. Engl. J. Med. 2021; 384 (1): 20–30. DOI: 10.1056/NEJMoa2030340.

2. Leisman D.E., Ronner L., Pinotti R. et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med. 2020; 8 (12): 1233–1244. DOI: 10.1016/S2213-2600(20)30404-5.

3. Biran N., Ip A., Ahn J. et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. Lancet Rheumatol. 2020; 2 (10): e603–612. DOI: 10.1016/S2665-9913(20)30277-0.

4. Gordon A.C., Mouncey P.R., Al-Beidh F. et al. Interleukin-6 receptor antagonists in critically Ill patients with COVID-19 – Preliminary report. medRxiv. [Posted: January 09, 2021]. DOI: 10.1101/2021.01.07.21249390.

5. Zhang C., Wu Z., Li J.W. et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents. 2020; 55 (5): 105954. DOI: 10.1016/j.ijantimicag.2020.105954.

6. Ruan Q., Yang K., Wang W. et al. 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): 846–848. DOI: 10.1007/s00134-020-05991-x.

7. Karagiannidis C., Mostert C., Hentschker C. et al. Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study. Lancet Respir. Med. 2020; 8 (9): 853–862. DOI: 10.1016/S2213-2600(20)30316-7.

8. Richardson S., Hirsch J.S., Narasimhan M. et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020; 323 (20): 2052–2059. DOI: 10.1001/jama.2020.6775.

9. Antsiferov M.B., Belevskiy A.S., Bulanov A.Yu. et al. (eds.) [Clinical protocol for the treatment of patients with the new coronavirus infection COVID-19 who are inpatient treatment in medical organizations of the state health care system of the city of Moscow]. Moscow: GBU “NIIOZMM DZM”; 2020. Available at: https://mosgorzdrav.ru (in Russian).

10. Yaroshetskiy A.I., Gritsan A.I., Avdeev S.N. et al. [Diagnostics and intensive therapy of acute respiratory distress syndrome (Clinical guidelines of the All-Russian public organization “Federation of Anesthesiologists and Resuscitators”)]. Anesteziologiya i reanimatologiya. 2020; (2): 5–39. 2020; (2): 5–39. DOI: 10.17116/anaesthesiology20200215 (in Russian).

11. Fomina D.S., Poteshkina N.G., Beloglazova I.P. et al. [Comparative analysis of tocilizumab in severe COVID-19-associated pneumonia in patients of different age groups]. Pul’monologiya. 2020; 30 (2): 164–172. DOI: 10.18093/0869-0189-2020-30-2-164-172 (in Russian).

12. Fomina D.S., Lysenko M.A., Beloglazova I.P. et al. Temporal clinical and laboratory response to interleukin-6 receptor blockade with tocilizumab in 89 hospitalized patients with COVID-19 pneumonia. Pathog. Immun. 2020; 5 (1): 327–341. DOI: 10.20411/pai.v5i1.392.

13. Furlow B. COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. Lancet Rheumatol. 2020; 2 (10): е592. DOI: 10.1016/S2665-9913(20)30313-1.

14. Stone J.H., Frigault M.J., Serling-Boyd N.J. et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N. Engl. J. Med. 2020; 383 (24): 2333–2344. DOI: 10.1056/NEJMoa2028836.

15. Veiga V.C., Prats J.A.G.G., Farias D.L.C. 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. DOI: 10.1136/bmj.n84.

16. Campochiaro C., Della-Torre E., Cavalli G. et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur. J. Internal Med. 2020; 76: 43–49. DOI: 10.1016/j.ejim.2020.05.021.

17. Moiseev S.V., Avdeev S.N., Tao M.Yu. et al. [Efficacy of tocilizumab in patients with COVID-19 admitted to ICU: a retrospective cohort study]. Klinicheskaya farmakologiya i terapiya. 2020; (4): 17–25. DOI: 10.32756/0869-5490-2020-4-17-25 (in Russian).

18. Horby P., Lim W.S., Emberson J.R. et al. Dexamethasone in hospitalized patients with COVID-19. N. Engl. J. Med. 2021; 384 (8): 693–704. DOI: 10.1056/NEJMoa2021436.

19. Toniati P., Piva S., Cattalini M. 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. DOI: 10.1016/j.autrev.2020.102568.