Cytokine storm

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A cytokine storm, synonymous hypercytokinemia, is a particularly strong form of the cytokine release syndrome (CRS), from which it only differs in its severity. The immune system releases high concentrations of inflammation- relevant cytokines , which in turn cause leukocytes to form further cytokines ( positive feedback ).

properties

In the course of an immune reaction , cytokines are formed in order to allow other immune cells to migrate to the site of the inflammation and to activate them, whereupon these also form cytokines in order to intensify the immune reaction. In a cytokine storm, leukocytes are activated so strongly that the immune reaction does not automatically calm down, which usually happens when the antigen is no longer present. As a result of a cytokine release syndrome or a cytokine storm, various cytokines, radicals and coagulation factors are formed and immune cells accumulate at the site of the inflammation, which can impair the function of a tissue , up to and including organ failure .

The symptoms of a cytokine storm include fever , swelling , redness , tiredness, and nausea , which in severe forms can be life-threatening. During a cytokine storm, high concentrations of the cytokines IL-6 and IL-8 as well as the chemokines CCL2 , CCL5 , CXCL10 and CXCL9 are formed.

Occurrence

A cytokine release syndrome or a cytokine storm can arise especially with CAR T cell therapy , in which it represents an "on-target" effect, as the therapy aims at T cell activation. Other diseases and therapies can also lead to increased cytokine release, including the graft-versus-host reaction (GVHD), acute respiratory distress syndrome (ARDS), sepsis , and systemic inflammatory response syndrome (SIRS) and with infectious diseases such as COVID-19 , Ebola fever , H5N1 bird flu , smallpox , or rabbit plague . With COVID -19, a cytokine storm can be the cause of severe courses.

A cytokine storm can also be induced by drugs such as B. the Serious Adverse Event in the Phase I study of TGN1412 , after administration of interleukin-2 or, in rare cases, after an infusion of rituximab . A controlled and limited "cytokine storm" (which then corresponds more to a cytokine release syndrome) is triggered by active fever therapy with mixed bacterial vaccines (MBV) according to William Coley ; it is used for oncological and certain chronic diseases.

therapy

Various active substances are investigated for the treatment of cytokine release syndrome and Zytokinsturms, including corticosteroids , PPAR - agonists , sphingosine-1-phosphate receptor 1 agonists, COX-2 inhibitors , antioxidants , inhibition of tumor necrosis factor , infusion of antibodies , statins and Arbidiol .

The monoclonal antibody tocilizumab has been approved for the treatment of cytokine release syndrome (and thus also the cytokine storm) since 2017. In June 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Marketing Authorization Authority (EMA) recommended an approval extension for tocilizumab also for the countries of the EU.

history

The term was first used in 1993 to refer to a graft-versus-host reaction.

Individual evidence

  1. ^ Michael T. Osterholm: Preparing for the Next Pandemic . In: The New England Journal of Medicine . 352, No. 18, May 5, 2005, pp. 1839-1842. doi : 10.1056 / NEJMp058068 . PMID 15872196 .
  2. ↑ Murphy, K .; Travers, P .; Walport, M .: Signaling Through Immune System Receptors. . In: Janeway's Immunobiology. , 7th. Edition, Garland, London 2007, ISBN 0-8153-4123-7 .
  3. ↑ JR Tisoncik, MJ Korth, CP Simmons, J. Farrar, TR Martin, MG Katzen: Into the eye of the cytokine storm. In: Microbiology and molecular biology reviews: MMBR. Volume 76, number 1, March 2012, pp. 16-32, doi: 10.1128 / MMBR.05015-11 , PMID 22390970 , PMC 3294426 (free full text).
  4. ↑ BG Chousterman, FK Swirski, GF Weber: Cytokine storm and sepsis disease pathogenesis. In: Seminars in immunopathology. Volume 39, number 5, 07 2017, pp. 517-528, doi : 10.1007 / s00281-017-0639-8 , PMID 28555385 (review).
  5. ↑ Randy Cron and W. Winn Chatham: How doctors can potentially significantly reduce the number of deaths from Covid-19. In: Vox . March 12, 2020, accessed on March 14, 2020 .
  6. ↑ L. Falasca, C. Agrati et al. a .: Molecular mechanisms of Ebola virus pathogenesis: focus on cell death. In: Cell death and differentiation. Volume 22, number 8, August 2015, pp. 1250–1259, doi : 10.1038 / cdd.2015.67 , PMID 26024394 , PMC 4495366 (free full text) (review).
  7. ↑ JR Tisoncik, MJ Korth u. a .: Into the eye of the cytokine storm. In: Microbiology and molecular biology reviews: MMBR. Volume 76, number 1, March 2012, pp. 16-32, doi : 10.1128 / MMBR.05015-11 , PMID 22390970 , PMC 3294426 (free full text) (review).
  8. ↑ Drazen, Jeffrey M .; Cecil, Russell L .; Goldman, Lee; Bennett, J. Claude: Cecil Textbook of Medicine , 21st. Edition, WB Saunders, Philadelphia 2000, ISBN 0-7216-7996-X .
  9. ^ RV D'Elia, K. Harrison, PC Oyston, RA Lukaszewski, GC Clark: Targeting the "cytokine storm" for therapeutic benefit. In: Clinical and vaccine immunology: CVI. Volume 20, number 3, March 2013, pp. 319-327, doi: 10.1128 / CVI.00636-12 , PMID 23283640 , PMC 3592351 (free full text).
  10. ↑ Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al .: On the Alert for Cytokine Storm: Immunopathology in COVID-19. Ed .: Arthritis Rheumatol. tape 72 , no. 7 , 2020, p. 1059-63 .
  11. ↑ Thelancetoncology: Leading Edge: High stakes, high risks . In: The Lancet (Ed.): Lancet Oncology . 8, No. 2, February 2007, p. 85. doi : 10.1016 / S1470-2045 (07) 70004-9 . PMID 17267317 .
  12. ↑ MC Panelli, R. White et al. a .: Forecasting the cytokine storm following systemic interleukin (IL) -2 administration. In: Journal of translational medicine. Volume 2, number 1, June 2004, p. 17, doi : 10.1186 / 1479-5876-2-17 , PMID 15175100 , PMC 434535 (free full text).
  13. ↑ M. Williams, T. Khalid, S. Hughes, D. Bonney, R. Wynn: Rituximab-induced Cytokine Storm in the Absence of Overt Lymphoproliferative Disease. In: Journal of pediatric hematology / oncology. Volume 38, Number 1, January 2016, pp. E29 – e31, doi: 10.1097 / MPH.0000000000000485 , PMID 26583621 .
  14. ↑ E. Göhring: The perfect storm of the cytokines. Active fever therapy with MBV - Coley's Toxins. 2nd Edition. Epubli, Berlin 2016, ISBN 978-3-7375-2266-3 .
  15. ^ Q. Liu, YH Zhou, ZQ Yang: The cytokine storm of severe influenza and development of immunomodulatory therapy. In: Cellular & Molecular Immunology. Volume 13, number 1, January 2016, pp. 3–10, doi: 10.1038 / cmi.2015.74 , PMID 26189369 , PMC 4711683 (free full text).
  16. ↑ FDA approves Roche's Actemra / RoActemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome , Roche PM, August 30, 2017, accessed September 9, 2017.
  17. ↑ RoActemra tocilizumab , Summary of opinion (post authorization) of the EMA, accessed on July 17, 2018.
  18. ↑ Ferrara JL, Abhyankar S, Gilliland DG: Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1 . In: Transplant Proc. . 2, No. 25, February 1993, pp. 1216-1217. PMID 8442093 .