A.E. EVDOKIMOVA1, KH.S. KHAERTYNOV1, S.V. BOICHUK1, 2, A.R. GALEMBIKOVA1, I.S. RAGINOV1, 3

 ¹Kazan State Medical University, Kazan

²Russian Medical Academy of Continuous Professional Education, Moscow

³Kazan (Volga) Federal University, Kazan

Contact details:

Evdokimova A.E. — post-graduate student of the Department of Children’s Infections

Address:     49    Butlerov     St.,    420012    Kazan,    tel.:    +7-987-275-79-39;     e-mail: tilai.ar@yandex.ru

A hyperinflammatory response plays a key role in the development of severe forms of COVID-19. Excessive levels of proinflammatory cytokines in the blood cause the acute respiratory distress syndrome (ARDS) — the leading cause of death in COVID-19 patients.

The purpose — to assess blood levels of proinflammatory cytokines in patients with severe COVID-19.

Material and methods. The study included 15 patients with severe COVID-19, aged 34 to 84 years. The median age of the patients was 62 years. Five patients died. The control group consisted of 10 healthy people of the same age. We measured blood levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-2, interleukin-6, and granulocyte-macrophage colony- stimulating factor (GM-CSF). Blood samples were collected from patients once during the clinical and laboratory manifestations of COVID-19.

Results. We found that during the acute phase of COVID-19, all 15 patients showed elevated blood levels of TNF-alpha, IL-2, IL-6, and GM-CSF. IL-6 demonstrated the most pronounced increase, with the median level 122 times exceeding that of the control group. IL-6 levels of the deceased patients were 1.7 times higher than those of survivors, but this difference was not statistically significant (p > 0.05). Concentrations of TNF-alpha, IL-2, and GM-CSF exceeded control group values by 6.4, 4.7, and 4.8 times, respectively.

Conclusion. Analysis of the cytokine profile revealed the key role of IL-6 in the development of severe COVID-19, indicating the need for targeted therapy aimed at neutralizing IL-6.

Key words: coronavirus infection COVID-19, inflammation, proinflammatory cytokines.

 (For citation: Evdokimova A.E., Khaertynov Kh.S., Boichuk S.V., Galembikova A.R., Raginov I.S. Cytokine profile of patients with COVID-19 coronavirus infection. Practical medicine. 2025. Vol. , № , P.)

REFERENCES

1. Fajgenbaum D.C., June C.H. Cytokine Storm. N. Engl. J. Med., 2020, vol. 383 (23), pp. 2255–2273. DOI: 1. 10.1056/NEJMra2026131
2. Pelaia C., Tinello C., Vatrella A. et al. Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications. Ther. Adv. Respir. Dis, 2020, vol. 14. 1753466620933508. DOI: 2.10.1177/1753466620933508
3. Castelli V., Cimini A., Ferri C. Cytokine storm in COVID-19: When you come out of the storm, you won’t be the same person who walked in. Front. Immunol, 2020, vol. 11. 2132. DOI: 3. 10.3389/fimmu.2020.02132
4. Khayertynov Kh.S., Anokhin V.A., Zhemkova O.V. et al. Endothelial dysfunction in patients with coronavirus infection COVID-19. Prakticheskaya meditsina, 2024, vol. 22, no. 2, pp. 77–83 (in Russ.). DOI: 10.32000/2072-1757-2024-2-77-83
5. Ye Q., Wang B., Mao J. The pathogenesis and treatment of the “cytokine storm” in COVID-19. J. Infect, 2020, vol. 80 (6), pp. 607–613. DOI: 10.1016/j.jinf.2020.03.037
6. Del Valle D.M., Kim-Schulze S., Huang H.H. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med, 2020, vol. 26 (10), pp. 1636–1643. DOI: 10.1038/s41591-020-1051-9
7. Jia F., Wang G., Xu J. et al. Role of tumor necrosis factor-a in the mortality of hospitalized patients with severe and critical COVID-19 pneumonia. Aging (Albany NY), 2021, vol. 13 (21), pp. 23895–23912. DOI: 10.18632/aging.203663
8. Messing M., Sekhon M.S., Hughes M.R. et al. Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes. Front. Immunol, 2022, vol. 13. 1010216. DOI: 10.3389/fimmu.2022.1010216
9. Sun X., Wang T., Cai D. et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev, 2020, vol. 53, pp. 38–42. DOI: 10.1016/j.cytogfr.2020.04.002
10. Abbas A.K., Trotta E., Simeonov D.R. et al. Revisiting IL-2: Biology and therapeutic prospects.  Sci.  Immunol.,  2018,  vol.  3  (25).  eaat1482. DOI: 10.1126/sciimmunol.aat1482
11. Hamilton J.A., Achuthan A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol, 2013, vol. 34 (2), pp. 81–89. DOI: 10.1016/j.it.2012.08.006
12. Mazurov V.I., Belyayeva I.B., Samigullina R.R. et al. Participation of interleukin 6 in the formation of pathogenetic mechanisms of immunoinflammatory diseases. Effektivnaya farmakoterapiya, 2022, vol. 18, no. 8, pp. 22–30 (in Russ.). DOI: 10.33978/2307- 3586-2022-18-8-22-30
13. Marin V., Montero-Julian F.A., Grès S. et al. The IL-6-Soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J. Immunol, 2001, vol. 167, pp. 3435–4342. DOI: 10.4049/jimmunol.167.6.3435
14. Merad M., Blish C.A., Sallusto F., Iwasaki A. The immunology and immunopathology of COVID-19. Science, 2022, vol. 375 (6585), pp. 1122–1127. DOI: 10.1126/science.abm8108
15. Hawerkamp H.C., Dyer A.H., Patil N.D. et al. Characterisation of the pro- inflammatory cytokine signature in severe COVID-19. Front. Immunol, 2023, vol. 14, 1170012. DOI: 10.3389/fimmu.2023.1170012
16. Saguil A., Fargo M.V. Acute respiratory distress syndrome: diagnosis and management. Am. Fam. Physician, 2020, vol. 101 (12), pp. 730–738.
17. Meyer N.J., Gattinoni L., Calfee C.S. Acute respiratory distress syndrome. Lancet, 2021, vol. 398 (10300), pp. 622–637. DOI: 10.1016/S0140-6736(21)00439-6
18. Frisoni P., Neri M., D’Errico S. et al. Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1β, IL-6, IL-15 and TNF-α. Forensic Sci. Med. Pathol, 2022, vol. 18 (1), pp. 4–19. DOI: 10.1007/s12024-021-00414-9
19. Tong X., Ping H., Gong X. et al. Pyroptosis in the lung and spleen of patients died from COVID-19.  Eur.  J.  Inflam.,  2022,  vol.  20,  pp.  1–12. DOI: 10.1177/1721727X221140661
20. Zhang J., Wu H., Yao X. et al. Pyroptotic macrophages stimulate the SARS-CoV- 2-associated cytokine storm. Cell. Mol. Immunol, 2021, vol. 18, pp. 1305–1307. DOI: 10.1038/s41423-021-00665-0
21. Tang Y., Zhang P., Liu Q. et al. Pyroptotic patterns in blood leukocytes predict disease severity and outcome in COVID-19 patients. Front. Immunol, 2022, vol. 13. 888661. DOI: 10.3389/fimmu.2022.888661
22. Queiroz M.A.F., Neves P.F., Lima S.S. et al. cytokine profiles associated with acute COVID-19 and long COVID-19 syndrome. Front. Cell. Infect. Microbiol, 2022, vol. 12. 922422. DOI: 10.3389/fcimb.2022.922422
23. Broman N., Feuth T., Vuorinen T. et al. Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM-a prospective, randomized, singlecentre, open-label study. Clin. Microbiol. Infect, 2022, vol. 28 (6), pp. 844–851. DOI: 10.1016/ j.cmi.2022.02.027
24. Rosas I.O., Bräu N., Waters M. et al. Tocilizumab in hospitalized patients with severe covid-19 pneumonia. N. Engl. J. Med, 2021, vol. 384 (16), pp. 1503–1516. DOI: 10.1056/NEJMoa202870
25. Polunovsky V.A., Wendt C.H., Ingbar D.H. et al. Induction of endothelial cell apoptosis by TNF alpha: modulation by inhibitors of protein synthesis. Exp. Cell. Res, 1994, vol. 214 (2), pp. 584–594. DOI: 10.1006/excr.1994.1296
26. Huyghe J., Priem D., Bertrand M.J.M. Cell death checkpoints in the TNF pathway. Trends  Immunol.,  2023,  vol.  44  (8),  pp.  628–643. DOI: 10.1016/j.it.2023.05.007
27. Jafarzadeh A., Jafarzadeh S., Nozari P. et al. Lymphopenia an important immunological abnormality in patients with covid-19: possible mechanisms. Scand. J. Immunol, 2021, vol. 93. e12967. DOI: 10.1111/sji.12967
28. Naeini L.G., Abbasi L., Karimi F. et al. The Important Role of Interleukin-2 in COVID-19. J. Immunol. Res, 2023. 7097329. DOI: 10.1155/2023/7097329
29. Tkachenko O.YU., Pervakova M.YU., Lapin S.V. et al. Prognostic role of cytokine studies in COVID-19-associated pneumonia. Vestnik Severo- Zapadnogo gosudarstvennogo meditsinskogo universiteta im. I.I. Mechnikova, 2021, vol. 13, no. 1, pp. 59–69 (in Russ.). DOI: 10.17816/mechnikov61610
30. Maranatha D., Hasan H., Bakhtiar A. et al. Association of TNF-α, TGF-β1, amphiregulin, IL-2, and EGFR with pulmonary fibrosis in COVID-19. J. Infec. Pub. Health, 2022, vol. 15 (10), pp. 1072–1075. DOI: 10.1016/j.jiph.2022.08.007
31. Montazersaheb S., Khatibi S.M.H., Hejazi M.S. et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virology J, 2022, vol. 19, p. 92. DOI: 10.1186/s12985-022-01814-1
32. Ushach I., Zlotnik A. Biological role of granulocyte macrophage colony- stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage.  J.  Leukoc.  Biol.,  2016, vol.  100  (3),  pp.  481–489. DOI: 10.1189/jlb.3RU0316-144R
33. Lukens J.R., Barr M.J., Chaplin D.D. et al. Inflammasome-derived IL-1β regulates the production of GM-CSF by CD4(+) T cells and γδ T cells. J. Immunol, 2012, vol. 188, pp. 3107–3115. DOI: 10.4049/jimmunol.1103308
34. Zuo Y., Yalavarthi S., Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight, 2020, vol. 5 (11). e138999. DOI: 10.1172/jci.insight.138999
35. Middleton E.A., He X.-Y., Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood, 2020, vol. 136 (10), pp. 1169–1179. DOI: 10.1182/blood.2020007008