Cytokine Storm in Pathogenesis of COVID-19 Complications
Abstract
The aim. To explore the current literature and key findings concerning the cytokine storm contribution to pathogenesis of COVID-19 complications and mortality, and summarize clinical and pathologic features of cytokine storm in COVID-19 patients.
A cytokine storm is a hyperinflammatory state secondary to excessive production of cytokines by deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading in most severe cases even to death. Cytokine storm has recently emerged as key aspect in COVID-19 disease, as affected patients show high levels of several key pro-inflammatory cytokines, some of which also correlate with disease severity.
The current review describes the role of critical cytokines in COVID-19-mediated cytokine storm. Key findings of the studies are provided further. A cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19. Impaired acquired immune responses and uncontrolled inflammatory innate responses may be associated with the mechanism of cytokine storm in COVID-19. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. In COVID-19 patients, pyroptosis triggers the release of proinflammatory cytokines and affects macrophage and lymphocyte functions, causing peripheral lymphopenia. Cytokine storm is characterized by a clinical presentation of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multi-organ failure. The cytokine storm clinical findings are attributed to the action of pro-inflammatory cytokines like interleukin-1, interleukin-6, tumor necrosis factor alpha, vascular endothelial growth factor.
References
- Shahgolzari M, Yavari A, Arjeini Y, Miri SM, Darabi A, Mozaffari Nejad AS, et al. Immunopathology and Immunopathogenesis of COVID-19, what we know and what we should learn. Gene Rep. 2021;25:101417. https://doi.org/10.1016/j.genrep.2021.101417
- Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinicalcourse and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. https://doi.org/10.1016/S0140-6736(20)30566-3
- Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS, Tarhriz V, Farjami A, Ghasemian Sorbeni F, et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virol J. 2022;19(1):92. https://doi.org/10.1186/s12985-022-01814-1
- Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363-374. https://doi.org/10.1038/s41577-020-0311-8
- Manjili RH, Zarei M, Habibi M, Manjili MH. COVID-19 as anAcute Inflammatory Disease. J Immunol. 2020;205(1):12-19. https://doi.org/10.4049/jimmunol.2000413
- Basheer M, Saad E, Assy N. The Cytokine Storm in COVID-19: The Strongest Link to Morbidity and Mortality in the Current Epidemic. COVID. 2022;2(5):540-552. https://doi.org/10.3390/covid2050040
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
- García LF. Immune Response, Inflammation, and the Clinical Spectrum of COVID-19. Front Immunol. 2020;11:1441. https://doi.org/10.3389/fimmu.2020.01441
- Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-270. https://doi.org/10.1038/s41577-020-0308-3
- Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424-432. https://doi.org/10.1002/jmv.25685
- Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38(1):1-9. https://doi.org/10.12932/AP-200220-0772
- Tang XD, Ji TT, Dong JR, Feng H, Chen FQ, Chen X, et al. Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases. Int J Mol Sci. 2021;22(23):13009. https://doi.org/10.3390/ijms222313009
- Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin. 2023;44(4):695-709. https://doi.org/10.1038/s41401-022-00998-0
- Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529-539. https://doi.org/10.1007/s00281-017-0629-x
- Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the Eye of the Cytokine Storm. Microbiol Mol Biol Rev. 2012;76(1):16-32. https://doi.org/10.1128/MMBR.05015-11
- Trypsteen W, Van Cleemput J, Snippenberg WV, Gerlo S, Vandekerckhove L. On the whereabouts of SARS-CoV-2 in the human body: A systematic review. PLoS Pathog. 2020;16(10):e1009037. https://doi.org/10.1371/journal.ppat.1009037
- Braciale TJ, Hahn YS. Immunity to viruses. Immunol Rev. 2013;255(1):5-12. https://doi.org/10.1111/imr.12109
- Kohno K, Koya-Miyata S, Harashima A, Tsukuda T, Katakami M, Ariyasu T, et al. Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells. J Inflamm (Lond). 2021;18(1):2. https://doi.org/10.1186/s12950-020-00267-z
- Ronco C, Reis T, De Rosa S. Coronavirus Epidemic and Extracorporeal Therapies in Intensive Care: si vis pacem para bellum. Blood Purif. 2020;49(3):255-258. https://doi.org/10.1159/000507039
- Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3. https://doi.org/10.1016/j.chom.2020.04.009
- Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. Int J Mol Sci. 2019;20(23):6008. https://doi.org/10.3390/ijms20236008
- Boraschi D. What Is IL-1 for? The Functions of Interleukin-1 Across Evolution. Front Immunol. 2022;13:872155. https://doi.org/10.3389/fimmu.2022.872155
- Tanaka T, Narazaki M, Kishimoto T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. https://doi.org/10.1101/cshperspect.a016295
- Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36(2):92-101. https://doi.org/10.1016/j.it.2014.12.008
- Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888. https://doi.org/10.1016/j.bbamcr.2011.01.034
- Velazquez-Salinas L, Verdugo-Rodriguez A, Rodriguez LL, Borca MV. The Role of Interleukin 6 During Viral Infections. Front Microbiol. 2019;10:1057. https://doi.org/10.3389/fmicb.2019.01057
- Wang X, Tang G, Liu Y, Zhang L, Chen B, Han Y, et al. The role of IL-6 in coronavirus, especially in COVID-19. Front Pharmacol. 2022;13:1033674. https://doi.org/10.3389/fphar.2022.1033674
- Wang Chau C, Sugimura R. COVID-19: Locked in a pro-inflammatory state. Elife. 2022;11:e80699. https://doi.org/10.7554/eLife.80699
- Abbasifard M, Khorramdelazad H. The bio-mission of interleukin-6 in the pathogenesis of COVID-19: A brief lookat potential therapeutic tactics. Life Sci. 2020;257:118097. https://doi.org/10.1016/j.lfs.2020.118097
- Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. https://doi.org/10.1016/S0140-6736(20)30211-7
- Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, et al. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023;12(1):43. https://doi.org/10.1186/s40249-023-01086-z
- van Loo G, Bertrand MJM. Death by TNF: a road to inflammation. Nat Rev Immunol. 2023;23(5):289-303. https://doi.org/10.1038/s41577-022-00792-3
- Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12(1):49-62. https://doi.org/10.1038/nrrheum.2015.169
- Guo Y, Hu K, Li Y, Lu C, Ling K, Cai C, et al. Targeting TNF-α for COVID-19: Recent Advanced and Controversies. Front Public Health. 2022;10:833967. https://doi.org/10.3389/fpubh.2022.833967
- Ruan Q, Yang K, Wang W, Jiang L, Song J. 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. https://doi.org/10.1007/s00134-020-05991-x
- Mazzoni A, Salvati L, Maggi L, Capone M, Vanni A, Spinicci M,et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J Clin Invest. 2020;130(9):4694-4703.https://doi.org/10.1172/JCI138554
- Tzeng HE, Tsai CH, Chang ZL, Su CM, Wang SW, Hwang WL, et al. Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Biochem Pharmacol. 2013;85(4):531-540. https://doi.org/10.1016/j.bcp.2012.11.021
- 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. Int Immunopharmacol. 2021;101(Pt B):108257. https://doi.org/10.1016/j.intimp.2021
- Huertas A, Montani D, Savale L, Pichon J, Tu L, Parent F, et al.Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J. 2020;56(1):2001634. https://doi.org/10.1183/13993003.01634-2020
- Norooznezhad AH, Mansouri K. Endothelial cell dysfunction, coagulation, and angiogenesis in coronavirus disease 2019 (COVID-19). Microvasc Res. 2021;137:104188. https://doi.org/10.1016/j.mvr.2021.104188
- Josuttis D, Schwedler C, Heymann G, Gümbel D, Schmittner MD, Kruse M, et al. Vascular Endothelial Growth Factor as Potential Biomarker for COVID-19 Severity. J Intensive Care Med. 2023;38(12):1165-1173. https://doi.org/10.1177/08850666231186787
- Islam H, Chamberlain TC, Mui AL, Little JP. Elevated Interleukin-10 Levels in COVID-19: Potentiation of Pro- Inflammatory Responses or Impaired Anti-Inflammatory Action? Front Immunol. 2021;12:677008. https://doi.org/10.3389/fimmu.2021.677008
- Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123-1130. https://doi.org/10.1080/22221751.2020
- Dhar SK, K V, Damodar S, Gujar S, Das M. IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon. 2021;7(2):e06155. https://doi.org/10.1016/j.heliyon.2021.e06155
- Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473-474. https://doi.org/10.1126/science.abb8925
- Ferrara JL, Abhyankar S, Gilliland DG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc. 1993;25(1 Pt 2):1216-1217.
- Yuen KY, Wong SS. Human infection by avian influenza A H5N1. Hong Kong Med J. 2005;11(3):189-199.
- de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12(10):1203-1207. https://doi.org/10.1038/nm1477
- Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3-10. https://doi.org/10.1038/cmi.2015.74
- Teijaro JR. Cytokine storms in infectious diseases. Semin Immunopathol. 2017;39(5):501-503. https://doi.org/10.1007/s00281-017-0640-2
- Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. https://doi.org/10.1186/s40425-018-0343-9
- Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255-2273. https://doi.org/10.1056/NEJMra2026131
- Mangalmurti N, Hunter CA. Cytokine Storms: Understanding COVID-19. Immunity. 2020;53(1):19-25. https://doi.org/10.1016/j.immuni.2020.06.017
- Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62-75. https://doi.org/10.1016/j.cytogfr.2020.06.001
- Shimizu M. Clinical Features of Cytokine Storm Syndrome. In: Cron R, Behrens E, editors. Cytokine Storm Syndrome. Springer, Cham; 2019. p. 31-41. https://doi.org/10.1007/978-3-030-22094-5_3
- Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607-613. https://doi.org/10.1016/j.jinf.2020.03.037
- Lu L, Zhang H, Dauphars DJ, He YW. A Potential Roleof Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021;42(1):3-5. https://doi.org/10.1016/j.it.2020.10.012
- Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA.Pattern Recognition Receptors and the Innate ImmuneResponse to Viral Infection. Viruses. 2011;3(6):920-940. https://doi.org/10.3390/v3060920
- Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front Immunol. 2020;11:1708. https://doi.org/10.3389/fimmu.2020.01708
- Buszko M, Nita-Lazar A, Park JH, Schwartzberg PL, Verthelyi D, Young HA, et al. Lessons learned: new insights on the role of cytokines in COVID-19. Nat Immunol. 2021;22(4):404-411. https://doi.org/10.1038/s41590-021-00901-9
- Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 Autopsies, Oklahoma, USA. Am J Clin Pathol. 2020;153(6):725-733. https://doi.org/10.1093/ajcp/aqaa062
- Santa Cruz A, Mendes-Frias A, Oliveira AI, Dias L, Matos AR, Carvalho A, et al. Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia. Front Immunol. 2021;12:613422. https://doi.org/10.3389/fimmu.2021.613422
- Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-2629. https://doi.org/10.1172/JCI137244
- Chen L, Liu HG, Liu W, Liu J, Liu K, Shang J, et al. [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Feb 6;43(0):E005. Chinese. https://doi. org/10.3760/cma.j.issn.1001-0939.2020.0005. Epub ahead of print.
- 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;11:2132.https://doi.org/10.3389/fimmu.2020.02132
- Tang L, Yin Z, Hu Y, Mei H. Controlling Cytokine Storm Is Vital in COVID-19. Front Immunol. 2020;11:570993. https://doi.org/10.3389/fimmu.2020.570993