Immune status and cytokine spectrum as predictors of the risk of severe disease and performance indicators of intensive therapy in patients with coronavirus infection COVID-19

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V.F. Sadykov1, R.A. Poltavtseva1, A.V. Chaplygina2, N.V. Bobkova2


1National Medical Research Center for Obstetrics, Gynecology, and Perinatology the name of Academician V.I. Kulakov, 4 Akademika Oparina Str., Moscow, 117997, Russian Federation
2Russian Academy of Sciences, Institute of Cell Biophysics – a Separate Division of Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 3 Institutskaya Str., Pushchino, 142290, Russian Federation


The pandemic caused by a new strain of the SARS-CoV-2 coronavirus has swept the whole world but effective methods for treating this severe pathology have not yet been created. It has now been established that a risk of a severe course of COVID-19 is not so much a patient's age itself, but so-called age-related diseases; the renin-angiotensin system (RAS) is directly or indirectly involved into their development. The SARS-CoV-19 virus interacts with one of the main regulatory elements of this system, ACE2, and disrupts the balance between the two RAS branches. This ultimately manifests itself in an increase in levels of angiotensin II, which, through binding to the angiotensin type 1 receptor (AT1R), causes a number of pathological conditions, including hypertension, atherosclerosis, and cardiovascular diseases, enhances cell proliferation, apoptosis, death of vascular endothelial cells, etc. This process has been described in many reviews by Russian and foreign authors. However, cells of innate and adaptive immunity are another less well-described but no less important target of angiotensin II. The consequences of this interaction are analyzed in detail in this review. With COVID-19, dendritic cells are activated, macrophage proliferation and neutrophil infiltration increase with further involvement of CD4-lymphocytes and other cellular elements of the adaptive immunity in this process. Hyperactivation of the immune system is accompanied with the release of a large amount of pro-inflammatory cytokines, which can lead to the occurrence of a cytokine storm. The picture is aggravated by the inhibitory effect produced by the virus itself on the synthesis of signaling interferons at initial stages in its internalization into the cell. A separate section in the review ad-dresses the problem how to predict a risk of a developing serious condition and search for its predictors by analyzing the state of the RAS and ratios of key cellular elements in the immune system. This is extremely important for making decisions concerning the amount of necessary medical care and strategies for subsequent treatment.

COVID-19, SARS-CoV-2, cytokine profile, cytokine storm, immune cells, immunodysregulation, predicting factor, immune status, renin-angiotensin system (RAS)
Sadykov V.F., Poltavtseva R.A., Chaplygina A.V., Bobkova N.V. Immune status and cytokine spectrum as predictors of the risk of severe disease and performance indicators of intensive therapy in patients with coronavirus infection COVID-19. Health Risk Analysis, 2022, no. 4, pp. 148–158. DOI: 10.21668/health.risk/2022.4.14.eng
  1. Lumbers E.R., Head R., Smith G.R., Delforce S.J., Jarrott B., Martin J.H., Pringle K.G. The interacting physiology of COVID-19 and the renin-angiotensin-aldosterone system: Key agents for treatment. Pharmacol. Res. Perspect., 2022, vol. 10, no. 1, pp. e00917. DOI: 10.1002/prp2.917
  2. Fisun A.Ya., Cherkashin D.V., Tyrenko V.V., Zhdanov K.V., Kozlov K.V. Role of renin-angiotensin-aldosterone sys-tem in the interaction with coronavirus SARS-CoV-2 and in the development of strategies for prevention and treatment of new coronavirus infection (COVID-19). Arterial'naya gipertenziya, 2020, vol. 26, no. 3, pp. 248–262. DOI: 10.18705/1607-419X-2020-26-3-248-262 (in Russian).
  3. Qiu J. Covert coronavirus infections could be seeding new outbreaks. Nature, 2020. DOI: 10.1038/D41586-020-00822-X
  4. Zhou P., Yang X.-L., Wang X.-G., Hu B., Zhang L., Zhang W., Si H.-R., Zhu Y. [et al.]. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, vol. 579, no. 7798, pp. 270–273. DOI: 10.1038/S41586-020-2012-7
  5. Gheblawi M., Wang K., Viveiros A., Nguyen Q., Zhong J.-C., Turner A.J., Raizada M.K., Grant M.B., Oudit G.Y. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ. Res., 2020, vol. 126, no. 10, pp. 1456–1474. DOI: 10.1161/circresaha.120.317015
  6. Scott A.J., O'Dea K.P., O'Callaghan D., Williams L., Dokpesi J.O., Tatton L., Handy J.M., Hogg P.J., Takata M. Re-active oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes. J. Biol. Chem., 2011, vol. 286, no. 41, pp. 35466–35476. DOI: 10.1074/jbc.m111.277434
  7. Chappell M.C. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am. J. Physiol. Heart Circ. Physiol., 2016, vol. 310, no. 2, pp. H137–H152. DOI: 10.1152/ajpheart.00618.2015
  8. WHO Director-General’s remarks at the media briefing on 2019-nCoV on 11 February 2020. World Health Organization, 2022. Available at: (May 1, 2022).
  9. Santos R.A.S., Simoes e Silva A.C., Maric C., Silva D.M.R., Machado R.P., de Buhr I., Heringer-Walther S., Pinheiro S.V.B. [et al.]. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc. Natl Acad. Sci. USA, 2003, vol. 100, no. 14, pp. 8258–8263. DOI: 10.1073/PNAS.1432869100
  10. Jiang T., Gao L., Guo J., Lu J., Wang Y., Zhang Y. Suppressing inflammation by inhibiting the NF-κB pathway con-tributes to the neuroprotective effect of angiotensin-(1–7) in rats with permanent cerebral ischaemia. Br. J. Pharmacol., 2012, vol. 167, no. 7, pp. 1520–1532. DOI: 10.1111/J.1476-5381.2012.02105.X
  11. Santos R.A.S., Ferreira A.J., Simões e Silva A.C. Recent advances in the angiotensin-converting enzyme 2–an-giotensin(1–7)–Mas axis. Experimental Physiology, 2008, vol. 93, no. 5, pp. 519–527. DOI: 10.1113/expphysiol.2008.042002
  12. Verdecchia P., Cavallini C., Spanevello A., Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med., 2020, vol. 76, pp. 14–20. DOI: 10.1016/j.ejim.2020.04.037
  13. Wösten-Van Asperen R.M., Lutter R., Specht P.A., Moll G.N., van Woensel J.B., van der Loos C.M., van Goor H., Kamilic J. [et al.]. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angio-tensin-(1–7) or an angiotensin II receptor antagonist. J. Pathol., 2011, vol. 225, no. 4, pp. 618–627. DOI: 10.1002/path.2987
  14. Savergnini S.Q., Beiman M., Lautner R.Q., de Paula-Carvalho V., Allahdadi K., Caires Pessoa D., Pereira Costa-Fraga F., Fraga-Silva R.A. [et al.]. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension, 2010, vol. 56, no. 1, pp. 112–120. DOI: 10.1161/hypertensionaha.110.152942
  15. Wiemer G., Dobrucki L.W., Louka F.R., Malinski T., Heitsch H. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1–7) on the endothelium. Hypertension, 2002, vol. 40, no. 6, pp. 847–852. DOI: 10.1161/01.hyp.0000037979.53963.8f
  16. Tao L., Qiu Y., Fu X., Lin R., Lei C., Wang J., Lei B. Angiotensin-converting enzyme 2 activator diminazene aceturate prevents lipopolysaccharide-induced inflammation by inhibiting MAPK and NF-κB pathways in human retinal pigment epithelium. Journal of Neuroinflammation, 2016, vol. 13, no. 1, pp. 35. DOI: 10.1186/S12974-016-0489-7
  17. Fandiño J., Vaz A.A., Toba L., Romaní-Pérez M., González-Matías L., Mallo F., Diz-Chaves Y. Liraglutide Enhances the Activity of the ACE-2/Ang(1–7)/Mas Receptor Pathway in Lungs of Male Pups from Food-Restricted Mothers and Prevents the Reduction of SP-A. Int. J. Endocrinol., 2018, vol. 2018, pp. 6920620. DOI: 10.1155/2018/6920620
  18. Hay M., Polt R., Heien M.L., Vanderah T.W., Largent-Milnes T.M., Rodgers K., Falk T., Bartlett M.J. [et al.]. A Novel Angiotensin-(1–7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction. J. Pharmacol. Exp. Ther., 2019, vol. 369, no. 1, pp. 9–25. DOI: 10.1124/jpet.118.254854
  19. Jackson L., Eldahshan W., Fagan S.C., Ergul A. Within the Brain: The Renin Angiotensin System. Int. J. Mol. Sci., 2018, vol. 19, no. 3, pp. 876. DOI: 10.3390/ijms19030876
  20. McMillan P., Dexhiemer T., Neubig R.R., Uhal B.D. COVID-19 – A Theory of Autoimmunity Against ACE-2 Ex-plained. Front. Immunol., 2021, vol. 12, pp. 582166. DOI: 10.3389/fimmu.2021.582166
  21. Buzhdygan T.P., DeOre B.J., Baldwin-Leclair A., McGary H., Razmpour R., Galie P.A., Potula R., Andrews A.M., Ramirez S.H. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier. bioRxiv: The Preprint Server for Biology, 2020. DOI: 10.1101/2020.06.15.150912
  22. Mowry F.E., Peaden S.C., Stern J.E., Biancardi V.C. TLR4 and AT1R mediate blood-brain barrier disruption, neuroinflammation, and autonomic dysfunction in spontaneously hypertensive rats. Pharmacol. Res., 2021, vol. 74, pp. 105877. DOI: 10.1016/j.phrs.2021.105877
  23. Choy E.H., De Benedetti F., Takeuchi T., Hashizume M., John M.R., Kishimoto T. Translating IL-6 biology into ef-fective treatments. Nature Reviews. Rheumatology, 2020, vol. 16, no. 6, pp. 335–345. DOI: 10.1038/S41584-020-0419-Z
  24. Rice G.I., Thomas D.A., Grant P.J., Turner A.J., Hooper N.M. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem. J., 2004, vol. 383, pt 1, pp. 45–51. DOI: 10.1042/BJ20040634
  25. Velavan T.P., Meyer C.G. Mild versus severe COVID-19: Laboratory markers. Int. J. Infect. Dis., 2020, vol. 95, pp. 304–307. DOI: 10.1016/j.ijid.2020.04.061
  26. Izcovich A., Ragusa M.A., Tortosa F., Marzio M.A.L., Agnoletti C., Bengolea A., Ceirano A., Espinosa F. [et al.]. Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review. PLoS One, 2020, vol. 15, no. 11, pp. e0241955. DOI: 10.1371/journal.pone.0241955
  27. Assandri R., Buscarini E., Canetta C., Scartabellati A., Viganò G., Montanelli A. Laboratory Biomarkers Predicting COVID-19 Severity in the Emergency Room. Arch. Med. Res., 2020, vol. 51, no. 6, pp. 598–599. DOI: 10.1016/j.arcmed.2020.05.011
  28. Akbari H., Tabrizi R., Lankarani K.B., Aria H., Vakili S., Asadian F., Noroozi S., Keshavarz P., Faramarz S. The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Life Sci., 2020, vol. 258, pp. 118167. DOI: 10.1016/j.lfs.2020.118167
  29. Li M., Guo W., Dong Y., Wang X., Dai D., Liu X., Wu Y., Li M. [et al.]. Elevated Exhaustion Levels of NK and CD8 + T Cells as Indicators for Progression and Prognosis of COVID-19 Disease. Front. Immunol., 2020, vol. 11, pp. 580237. DOI: 10.3389/fimmu.2020.580237
  30. Liu J., Li S., Liu J., Liang B., Wang X., Wang H., Li W., Tong Q. [et al.]. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine, 2020, vol. 55, pp. 102763. DOI: 10.1016/j.ebiom.2020.102763
  31. Becker R.C. COVID-19 update: Covid-19-associated coagulopathy. J. Thromb. Thrombolysis, 2020, vol. 50, no. 1, pp. 54–67. DOI: 10.1007/S11239-020-02134-3
  32. Hu B., Guo H., Zhou P., Shi Z.-L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol., 2021, vol. 19, no. 3, pp. 141–154. DOI: 10.1038/S41579-020-00459-7
  33. Meizlish M.L., Pine A.B., Bishai J.D., Goshua G., Nadelmann E.R., Simonov M., Chang C.-H., Zhang H. [et al.]. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv., 2021, vol. 5, no. 5, pp. 1164–1177. DOI: 10.1182/bloodadvances.2020003568
  34. Knight S.R., Ho A., Pius R., Buchan I., Carson G., Drake T.M., Dunning J., Fairfield C.J. [et al.]. Risk stratification of patients admitted to hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: development and valida-tion of the 4C Mortality Score. BMJ, 2020, vol. 370, pp. m3339. DOI: 10.1136/bmj.m3339
  35. Zhao J., Yang Y., Huang H., Li D., Gu D., Lu X., Zhang Z., Liu L. [et al.]. Relationship Between the ABO Blood Group and the Coronavirus Disease 2019 (COVID-19) Susceptibility. Clin. Infect. Dis., 2021, vol. 73, no. 2, pp. 328–331. DOI: 10.1093/cid/ciaa1150
  36. Angioni R., Sánchez-Rodríguez R., Munari F., Bertoldi N., Arcidiacono D., Cavinato S., Marturano D., Zaramella A. [et al.]. Age-severity matched cytokine profiling reveals specific signatures in COVID-19 patients. Cell Death Dis., 2020, vol. 11, no. 11, pp. 957. DOI: 10.1038/S41419-020-03151-Z
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