Comparative analysis of tocilizumab in severe COVID-19-associated pneumonia in patients of different age groups

According to accumulated clinical data, one of the causes of severe damage to lung epithelial cells associated with SARS-CoV-2 (2019-nCoV) is an acute, timely underestimated "cytokine storm" (cytokine cascade, hypercytokinaemia) with characteristic signs of an expressed hyper-inflammatory syndrome with subsequent polyorganic failure. The study presents the results of the analysis of the effectiveness of tocilizumab therapy (TCZ) in patients (n = 181) of different age groups with developed pneumonia caused by SARS-CoV-2. The aim of the study was to evaluate the effectiveness of TCZ therapy in patients of different age groups with developed pneumonia in the frame of COVID-19. Methods. Patients (n = 181) with community-acquired pneumonia caused by coronavirus SARS-CoV-2 are included in a one-center, non-randomized, prospective study to evaluate the effectiveness of TCZ therapy conducted at the State Public Health Institution "City Clinical Hospital No.52" of the Moscow City Health Department. Patients were divided into 3 age subgroups – up to 50 years, 50–70 years and over 70 years. Patients with community-acquired SARS-CoV-2-induced pneumonia receiving non-invasive oxygen support and patients who had artificial lung ventilation (ALV) were given a single dose of 400 mg of TCZ in addition to basic therapy. Results. There are no significant differences between age groups in the severity of pneumonia according to the data of the computed tomography (CT), however, a more severe condition and a higher mortality rate (p < 0.001) were reliably observed in patients over 70 age compared to the other age groups. After TCZ treatment in patients of each age group, the severity of the condition assessed on the National Early Warning Score (NEWS2) has been significantly reduced compared to the baseline. Conclusion. According to the data of the pilot study the efficacy and safety of TCZ in patients of all presented age groups with COVID-associated pulmonary tissue lesion and signs of "cytokine storm" was demonstrated. At the same time, patients up to 50 years after the therapy of TCZ managed to achieve greater clinical efficiency compared to patients in other groups. According to the severity of the state and laboratory criteria, the lowest clinical efficacy of TCZ therapy was observed in patients over 70 years of age; as a consequence, the highest mortality rate was observed in the same group. At the same time, the TCZ therapy has not had a positive impact on the change of laboratory values and the severity of the disease in case of unfavorable outcome. 

1. Guan W.J., Ni Z.Y., Hu Y. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020; 382 (18): 1708–1720. DOI: 10.1056/NEJMoa2002032.

2. Hu Y., Wu Z.H., Luo Y. et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin. Cancer Res. 2017; 23 (13): 3297–3306. DOI: 10.1158/1078-0432.CCR-16-1799.

3. Alekseeva E.A., Denisova R.V., Valieva S.I. et al. [Tocili - zumab efficacy and safety in patients with severe systemic juvenile idiopathic arthritis]. Voprosy sovremennoy pediatrii. 2011; 10 (3): 24–32 (in Russian).

4. Panasyuk E.Yu., Amirdzhanova V.N., Aleksandrova E.N. et al. [Rapid effect of tozilizumab in rheumatoid arthritis]. Nauchno-prakticheskaya revmatologiya. 2011; 49 (4): 11–16. DOI: 10.14412/1995-4484-2011-55 (in Russian).

5. Chizhevskaya I., Belyaeva L. [Treatment of juvenile idiopathic arthritis with tocilizumab]. Nauka i innovatsii. 2019; 2 (92): 76–81 (in Russian).

6. Tanaka T., Narazaki M., Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Im - munotherapy. 2016; 8 (8): 959–970. DOI: 10.2217/imt-2016-0020.

7. Murthy H.S., Iqbal M., Chavez J.C., Kharfan-Dabaja M.A. Cytokine release syndrome: Current perspectives. Immunotargets Ther. 2019; 8: 43–52. DOI: 10.2147/ITT.S202015.

8. 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: 846–848. DOI: 10.1007/s00134-020-05991-x.

9. Ramos-Casals M., Brito-Zeron P., Lopez-Guillermo A. et al. Adult haemophagocytic syndrome. Lancet. 2014; 383 (9927): 1503–1516. DOI: 10.1016/S0140-6736(13)61048-X.

10. Karakike E., Giamarellos-Bourboulis E.J. Macrophage activation-like syndrome: A distinct entity leading to early death in sepsis. Front. Immunol. 2019;10: 55. DOI: 10.3389/fimmu.2019.00055.

11. Seguin A., Galicier L., Boutboul D. et al. Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis. Chest. 2016; 149 (5): 1294–1301. DOI: 10.1016/j.chest.2015.11.004.

12. Xu X., Han M., Li T. et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl. Acad. Sci. USA. 2020; 117 (20): 10970–10975. DOI: 10.1073/pnas.2005615117.

13. Luo P., Liu Y., Qiu L. et al. Tocilizumab treatment in COVID-19: a single center experience. J. Med. Virol. 2020; 2020: 1–5. DOI: 10.1002/jmv.25801.

14. Michot J.M., Albiges L., Chaput N. et al. Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report. Ann. Oncol. 2020. DOI: 10.1016/j.annonc.2020.03.300.

15. Zhou F., Yu T., Du R. 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): 1054–1062. DOI: 10.1016/S0140-6736(20)30-566-3.

16. Yoshikawa T., Hill T., Li K. et al. Severe Acute Respiratory Syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J. Virol. 2009; 83 (7): 3039–3048. DOI: 10.1128/JVI.01792-08.