Cytokine storm

A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Normally, cytokines are part of the body's immune response to infection, but their sudden release in large quantities can cause multisystem organ failure and death.[1] Cytokine storms can be caused by a number of infectious and non-infectious etiologies, especially viral respiratory infections such as H5N1 influenza, SARS-CoV-1,[2][3] and SARS-CoV-2 (COVID-19 agent). Other causative agents include the Epstein-Barr virus, cytomegalovirus, and group A streptococcus, and non-infectious conditions such as graft-versus-host disease.[4]

Cytokine storm syndrome is diverse set of conditions that can result in cytokine storm. Cytokine storm syndromes include familiar hemophagocytic lymphohistiocytosis, Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis, systemic or non-systemic juvenile idiopathic arthritis–associated macrophage activation syndrome, NLRC4 macrophage activation syndrome, cytokine release syndrome and sepsis.[5]

Cytokine storms versus cytokine release syndromeEdit

The term "cytokine storm" is often loosely used interchangeably with cytokine release syndrome (CRS) but is more precisely a differentiable syndrome that may represent a severe episode of cytokine release syndrome or a component of another disease entity, such as macrophage activation syndrome. When occurring as a result of a therapy, CRS symptoms may be delayed until days or weeks after treatment. Immediate-onset (fulminant) CRS appears to be a cytokine storm.[6]


Nicotinamide (Vitamin B3) is a potent inhibitor of proinflammatory cytokines.[7][8]

Magnesium decreases inflammatory cytokine production by modulation of the immune system.[9][10]


The first reference to the term cytokine storm in the published medical literature appears to be by Ferrara et al. in 1993 in a discussion of graft vs. host disease; a condition in which the role of excessive and self-perpetuating cytokine release had already been under discussion for many years.[11][12] The term next appeared in a discussion of pancreatitis in 2002, and in 2003 it was first used in reference to a reaction to an infection.[11]

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 17 to 50 million people. In this case, a healthy immune system may have been a liability rather than an asset.[13] Preliminary research results from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in 2003.[14] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[15] Cytokine storm has also been implicated in hantavirus pulmonary syndrome.[16]

In 2006, a study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug theralizumab becoming critically ill, with multiple organ failure, high fever, and a systemic inflammatory response.[17] Parexel, a company conducting trials for pharmaceutical companies, in one of its documents, wrote about the trial and said theralizumab could cause a cytokine storm—the dangerous reaction the men experienced.[18]

During the COVID-19 pandemic, some doctors attributed many deaths to cytokine storms.[19][20]


  1. ^ Farsalinos, Konstantinos; Barbouni, Anastasia; Niaura, Raymond (2020). "Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: Could nicotine be a therapeutic option?". Internal and Emergency Medicine. 15 (5): 845–852. doi:10.1007/s11739-020-02355-7. PMC 7210099. PMID 32385628.
  2. ^ Wong, Jonathan P.; Viswanathan, Satya; Wang, Ming; Sun, Lun-Quan; Clark, Graeme C.; D'Elia, Riccardo V. (February 2017). "Current and future developments in the treatment of virus-induced hypercytokinemia". Future Medicinal Chemistry. 9 (2): 169–178. doi:10.4155/fmc-2016-0181. ISSN 1756-8927. PMC 7079716. PMID 28128003.
  3. ^ Liu, Qiang; Zhou, Yuan-hong; Yang, Zhan-qiu (January 2016). "The cytokine storm of severe influenza and development of immunomodulatory therapy". Cellular & Molecular Immunology. 13 (1): 3–10. doi:10.1038/cmi.2015.74. ISSN 2042-0226. PMC 4711683. PMID 26189369.
  4. ^ Tisoncik, Jennifer R.; Korth, Marcus J.; Simmons, Cameron P.; Farrar, Jeremy; Martin, Thomas R.; Katze, Michael G. (2012). "Into the Eye of the Cytokine Storm". Microbiology and Molecular Biology Reviews. 76 (1): 16–32. doi:10.1128/MMBR.05015-11. ISSN 1092-2172. PMC 3294426. PMID 22390970.
  5. ^ Behrens, Edward M.; Koretzky, Gary A. (2017). "Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era". Arthritis & Rheumatology. 69 (6): 1135–1143. doi:10.1002/art.40071. ISSN 2326-5205. PMID 28217930.
  6. ^ Porter D, Frey N, Wood PA, Weng Y, Grupp SA (March 2018). "Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel". Journal of Hematology & Oncology. 11 (1): 35. doi:10.1186/s13045-018-0571-y. PMC 5833070. PMID 29499750.
  7. ^ Ungerstedt JS, Blömback M, Söderström T (2003). "Nicotinamide is a potent inhibitor of proinflammatory cytokines". Clin Exp Immunol. 131 (1): 48–52. doi:10.1046/j.1365-2249.2003.02031.x. PMC 1808598. PMID 12519385.CS1 maint: multiple names: authors list (link)
  8. ^ Yanez M, Jhanji M, Murphy K, Gower RM, Sajish M, Jabbarzadeh E (2019). "Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation". Sci Rep. 9 (1): 10219. doi:10.1038/s41598-019-46678-8. PMC 6629694. PMID 31308445.CS1 maint: multiple names: authors list (link)
  9. ^ Sugimoto J, Romani AM, Valentin-Torres AM, Luciano AA, Ramirez Kitchen CM, Funderburg N; et al. (2012). "Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism". J Immunol. 188 (12): 6338–46. doi:10.4049/jimmunol.1101765. PMC 3884513. PMID 22611240.CS1 maint: multiple names: authors list (link)
  10. ^ Nielsen FH (2018). "Magnesium deficiency and increased inflammation: current perspectives". J Inflamm Res. 11: 25–34. doi:10.2147/JIR.S136742. PMC 5783146. PMID 29403302.
  11. ^ a b Clark IA (June 2007). "The advent of the cytokine storm". Immunology and Cell Biology. 85 (4): 271–3. doi:10.1038/sj.icb.7100062. PMID 17551531. Archived from the original on 2017-05-05. Retrieved 2017-10-16.
  12. ^ Ferrara JL, Abhyankar S, Gilliland DG (February 1993). "Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1". Transplantation Proceedings. 25 (1 Pt 2): 1216–7. PMID 8442093.
  13. ^ Osterholm MT (May 2005). "Preparing for the next pandemic". The New England Journal of Medicine. 352 (18): 1839–42. CiteSeerX doi:10.1056/NEJMp058068. PMID 15872196.
  14. ^ Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY (February 2005). "An interferon-gamma-related cytokine storm in SARS patients". Journal of Medical Virology. 75 (2): 185–94. doi:10.1002/jmv.20255. PMC 7166886. PMID 15602737.
  15. ^ Haque A, Hober D, Kasper LH (October 2007). "Confronting potential influenza A (H5N1) pandemic with better vaccines". Emerging Infectious Diseases. 13 (10): 1512–8. doi:10.3201/eid1310.061262. PMC 2851514. PMID 18258000.
  16. ^ Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, et al. (February 1999). "High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome". The Journal of Infectious Diseases. 179 (2): 295–302. doi:10.1086/314597. PMID 9878011.
  17. ^ The Lancet Oncology (February 2007). "High stakes, high risks". The Lancet. Oncology. 8 (2): 85. doi:10.1016/S1470-2045(07)70004-9. PMID 17267317.
  18. ^ Coghlan A (2006-08-14). "Mystery over drug trial debacle deepens". Health. New Scientist. Retrieved 2009-04-29.
  19. ^ Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (March 2020). "COVID-19: consider cytokine storm syndromes and immunosuppression". Lancet. 395 (10229): 1033–1034. doi:10.1016/S0140-6736(20)30628-0. PMC 7270045. PMID 32192578.
  20. ^ Ruan Q, Yang K, Wang W, Jiang L, Song J (March 2020). "Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China". Intensive Care Medicine. 46 (5): 846–848. doi:10.1007/s00134-020-05991-x. PMC 7080116. PMID 32125452.