IL-17, IL-18, VEGF are diagnostic markers of severity and outcome of COVID-19.

Author: Matushkina Valeria Alexandrovna

Co-authors: Gorodin Vladimir Nikolaevich, Atazakhova Margarita Galimovna, Chudilova Galina Anatolyevna, Nesterova Irina Vadimovna

Federal State Budgetary Educational of Higher Professional Education “Kuban State Medical University” of the Ministry of Health of the Russian Federation

Russia, Krasnodar

Recruitment of a large number of neutrophilic granulocytes (NG) to inflammatory foci, netosis, and subsequent immunothrombosis are typical signs of severe COVID-19 [1, 2]. An increase in thrombus formation and death of endothelial cells in patients with COVID-19 indicate the leading role of cytokines in the involvement of NG in immune thrombosis [2, 3]. Known cytokines IL-17A, IL-18, vascular endothelial growth factor (VEGF-A) interacting with NG and mediating tissue damage. IL-17 is synthesized by Th17, CD8⁺, NK, and other cells of innate immunity and is involved in platelet activation, mobilization, and activation of NG [1]. IL-18 is synthesized in an inactive form in epithelial and endothelial cells, macrophages, and dendritic cells, while the precursor of IL-18 is released by protease-3 NG during cell death and netosis [4]. VEGF-A is a permeability factor involved in angiogenesis, exhibiting a pro/anti-angiogenic property and ensuring the migration of monocytes and NG to the site of inflammation [5]. NG interacting with various cell populations is capable of synthesizing VEGF. In this connection, it is of interest to identify the relationship between the increase in the levels of IL-17A, IL-18, VEGF-A with the severity of the disease, to determine the progression marker of the process and/or targets for the development of therapeutic strategies. 

Blood serum samples of patients with COVID-19 with leukocytosis and neutrophilia (n=86), moderate (group 1, n=45) and severe (group 2, n=41) forms of the disease, taken on days 7-9 of the disease, were studied. treatment; 22 samples of conditionally healthy individuals (comparison group). The concentration of cytokines was determined by ELISA (ASCENT, Finland).

It was found that in patients of group 1, there was an increase in the serum concentration of IL-18 to 672,5 (451,7; 740,1) pg/ml versus 322,5 (185,5; 388,7) pg/ml in the group comparisons (p<0,05); IL17A – 31,2 (16,7; 58,3) pg/ml versus 13,6 (7,7; 21,8) pg/ml in the comparison group (p<0,05).; VEGF-A – 1365,0 (1222,3; 1575,3) pg/ml versus 734,1 (700,0; 739,3) pg/ml in the control group (p<0,05). In group 2, there was an even more significant increase in the level of IL-18 (by 1,3 times) to 859,7 (788,9; 1059,0) pg/ml and IL17A (by 3,6 times) to 113,8 (69,2 ; 239,2) pg/ml in relation to the indicators in group 1 (p_1.2<0,05) and 2,7 times and 8,3 times, respectively, to the values ​​in the comparison group (p_1,2<0, 05).

The level of VEGF-A was 1,6 times higher than in the comparison group and amounted to 1174 (1099,0; 1446,0) pg/ml (p<0,05), but it did not differ significantly from the values ​​in group 1 (p>0,05). Thus, it has been established that the cytokines IL-18, IL-17 and VEGF certainly contribute to hyperinflammation leading to complications of the course of COVID-19, and IL-18, IL-17 can be markers of the severity and outcome of COVID-19.

Bibliography.

1. Montazersaheb S., Hosseiniyan Khatibi S.M., Hejazi M.S., Tarhriz V., Farjami A., Ghasemian Sorbeni F., Farahzadi R., Ghasemnejad T. COVID-19 infection: an overview on cytokine storm and related interventions. Virology Journal.2022, 19: 92. doi:10.1186/s12985-022-01814-1

2.Iliadi V, Konstantinidou I, Aftzoglou K, Iliadis S, Konstantinidis TG, Tsigalou C. The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19. International Journal of Molecular Sciences. 2021, 22(10):5368. doi: 10.3390/ijms22105368.

3. Ackermann M., Verleden S. E., Kuehnel M., Haverich A., Welte T., Laenger F., Vanstapel A., Werlein Ch., Stark H., Tzankov A, Li W. W., Li V. W. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. New England Journal of Medicine, 2020, 383:120-128.doi: 10.1056/NEJMoa2015432

4. Yasuda K., Nakanishi K., Tsutsui H. Interleukin-18 in Health and Disease. International Journal of Molecular Sciences. – 2019.- Vol.20(3). – P.649.  DOI: 10.3390/ijms20030649

5. Sahebnasagh A, Nabavi SM, Kashani HRK, Abdollahian S, Habtemariam S, Rezabakhsh A. Anti-VEGF agents: As appealing targets in the setting of COVID-19 treatment in critically ill patients. International Immunopharmacology. 2021, 101:108257. doi: 10.1016/j.intimp.2021.108257.