Cytokine storm

A cytokine storm, also called cytokine storm syndrome (CSS) or 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 and SARS-CoV.[2][3] Other causative agents include the Epstein-Barr virus, cytomegalovirus, and group A streptococcus, as well as non-infectious conditions like graft-versus-host disease.[4]

Not to be confused with Cytokine release syndrome.

Cytokine storms versus cytokine release syndrome

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.[5]

History

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.[6][7] 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.[6]

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 50 to 100 million people. In this case, a healthy immune system may have been a liability rather than an asset.[8] Preliminary research results from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in 2003.[9] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[10] Cytokine storm has also been implicated in hantavirus pulmonary syndrome.[11]

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.[12] 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.[13]

During the COVID-19 pandemic, several deaths were attributable to cytokine storms.[14][15]

References
  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. doi:10.1007/s11739-020-02355-7. 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 : MMBR. 76 (1): 16–32. doi:10.1128/MMBR.05015-11. ISSN 1092-2172. PMC 3294426. PMID 22390970.
  5. 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.
  6. 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.
  7. 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.
  8. Osterholm MT (May 2005). "Preparing for the next pandemic". The New England Journal of Medicine. 352 (18): 1839–42. CiteSeerX 10.1.1.608.6200. doi:10.1056/NEJMp058068. PMID 15872196.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Coghlan A (2006-08-14). "Mystery over drug trial debacle deepens". Health. New Scientist. Retrieved 2009-04-29.
  14. 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. PMID 32192578.
  15. 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.
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