Indian Journal of Medical Biochemistry

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VOLUME 24 , ISSUE 2 ( May-August, 2020 ) > List of Articles


A Review of Cytokine Storm in COVID-19

Meenakshi, Amit Samadhiya, Rajeev Goyal

Citation Information : M, Samadhiya A, Goyal R. A Review of Cytokine Storm in COVID-19. Indian J Med Biochem 2020; 24 (2):59-61.

DOI: 10.5005/jp-journals-10054-0151

License: CC BY-NC 4.0

Published Online: 01-12-2020

Copyright Statement:  Copyright © 2020; The Author(s).


Aim: To review pathogenesis of cytokine storm in COVID-19 cases. Background: Human coronaviruses (hCoV) mainly infect upper airways and cause seasonal mild to moderate cold-like respiratory symptoms or severe pneumonia leading to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Recent clinical investigation reveals that mild COVID-19 patients had high level of IL1B, IFN-γ, CXCL10/IP-10, and CCL2/MCP-1, while patients requiring ICU admission had higher level of GCSF, CXCL10/IP-10, CCL2/MCP-1, and CCL3/MIP-1A, indicating inflammatory cytokine release is critical in COVID-19 progression. IL-1 and IL-6 are responsible for elevation of acute-phase reactants, such as C-reactive protein, serum amyloid A, fibrinogen, hepcidin, and inhibition of albumin synthesis which all together causes a procoagulant environment. In a meta-analysis including nine studies (total 1426 patients), mean IL-6 levels were more than 3 times higher in patients with complicated COVID-19 compared to those with uncomplicated disease, and high IL-6 levels were associated with mortality risk. IL-6 is an important marker of inflammation and can guide the clinicians in recognizing patients with severe COVID-19 early in the disease course. Delay in the interferon release and presence of LPS by secondary bacterial infections increases the severity of cytokine storm. Thus, commencement of early broad-spectrum antibiotic course is advisable. Cytokine storm appears after first week of symptoms when viral load starts decreasing, and this indicates the immunopathogenesis of the ARDS. Conclusion: The aberrant release of multiple cytokines in COVID-19 produces immunopathogenic damage to tissues and organs, even while the immune response tries to overcome the evading mechanisms of virus. Delay in the interferon release and presence of lipopolysaccharide by secondary bacterial infections increase the severity of cytokine storm. IL-6 could be used as a potential marker for severity of the ARDS. However, anti-IL6 antibody Tocilizumab failed to prove effective in clinical trials. Corticosteroid therapy is being given for moderate and severe cases of ARDS, but it needs a very fine balance to outweigh immunosuppressive effects.

  1. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the cytokine storm in COVID-19. J Infect 2020;80(6):607–613. DOI: 10.1016/j.jinf.2020.03.037.
  2. Li H, Wang Y, Ji M, et al. Transmission route analysis of SARS-CoV-2: a systematic review and case report. Front Cell Dev Biol 2020;8:618. DOI: 10.3389/fcell.2020.00618.
  3. Farcas GA, Poutanen SM, Mazzulli T, et al. Fatal severe acute respiratory syndrome is associated with multiorgan involvement by a coronavirus. J Infect Dis 2005;191(2):193–197. DOI: 10.1086/426870.
  4. Peiris J, Chu C, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus associated SARS pneumonia: a prospective study. Lancet 2003;361(9371):767–772. DOI: 10.1016/S0140-6736(03)13412-5.
  5. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497–506. DOI: 10.1016/S0140-6736(20)30183-5.
  6. Huang KJ, Su IJ, Theron M, et al. An interferon gamma related cytokine storm in SARS patients. J Med Virol 2005;75(2):185–194. DOI: 10.1002/jmv.20255.
  7. Teijaro JR, Walsh KB, Rice S, et al. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proc Natl Acad Sci USA 2014;111(10):3799–3804. DOI: 10.1073/pnas.1400593111.
  8. Levy DE, Marie IJ, Durbin JE. Induction and function of type I and III interferon in response to viral infection. Curr Opin Virol 2011;1(6):476–486. DOI: 10.1016/j.coviro.2011.11.001.
  9. Uze G, Monneron D. IL-28 and IL-29: newcomers to the interferon family. Biochimie 2007;89(6-7):729–734. DOI: 10.1016/j.biochi.2007.01.008.
  10. Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol 2012;86(6):2900–2910. DOI: 10.1128/JVI.05738-11.
  11. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999;18(49):6853–6866. DOI: 10.1038/sj.onc.1203239.
  12. Overby AK, Popov VL, Niedrig M, et al. Tick borne encephalitis virus delays interferon induction and hides its double stranded RNA in intracellular membrane vesicles. J Virol 2010;84(17):8470–8483. DOI: 10.1128/JVI.00176-10.
  13. He R, Leeson A, Andonov A, et al. Activation of AP-1 signal transduction pathway by SARS coronavirus nucleocapsid protein. Biochem Biophys Res Commun 2003;311(4):870–876. DOI: 10.1016/j.bbrc.2003.10.075.
  14. Kopecky-Bromberg SA, Martinez-Sobrido L, Frieman M, et al. SARS coronavirus proteins Orf 3b, Orf 6, and nucleocapsid function as interferon antagonists. J Virol 2006;81(2):548–557. DOI: 10.1128/JVI.01782-06.
  15. Ye Y, Hauns K, Langland JO, et al. Mouse hepatitis coronavirus A59 nucleocapsid protein is a type I interferon antagonist. J Virol 2007;81(6):2554–2563. DOI: 10.1128/JVI.01634-06.
  16. Wathelet MG, Orr M, Frieman MB, et al. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol 2007;81(21):11620–11633. DOI: 10.1128/JVI.00702-07.
  17. Züst R, Cervantes-Barragán L, Kuri T, et al. Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines. PLoS Pathog 2007;3(8):e109. DOI: 10.1371/journal.ppat.0030109.
  18. Kamitani W, Narayanan K, Huang C, et al. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc Natl Acad Sci USA 2006;103(34):12885–12890. DOI: 10.1073/pnas.0603144103. Describes a novel mechanism of viral protein-induced inhibition of host gene expression.
  19. Tan YJ, Fielding BC, Goh PY, et al. Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. J Virol 2004;78(24):14043–14047. DOI: 10.1128/JVI.78.24.14043-14047.2004.
  20. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I interferon and inflammatory monocyte macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 2016;19(2):181–193. DOI: 10.1016/j.chom.2016.01.007.
  21. Hoffmann-La Roche's announcement about COVACTA's failure to meet study end points see
  22. Venkatesh B, Finfer S, Cohen J, et al. ADRENAL trial Investigators and the Australian–New Zealand intensive care society clinical trials group, adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378(9):797–808. DOI: 10.1056/NEJMoa1705835.
  23. Bhimraj A, Morgan L, Shumaker RL, et al., 2020. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19. (Accessed June 28, 2020).
  24. Grifoni E, Valoriani A, Cei F, et al. Interleukin-6 as prognosticator in patients with COVID-19. J Infect 2020;81(3):452–482. DOI: 10.1016/j.jinf.2020.06.008.
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