Cytokine storm

Short description: Frequently fatal immune reaction

Cytokine storm

Other names| hypercytokinemia
Specialty| Immunology

A cytokine storm, also called hypercytokinemia, is a pathological 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. Cytokines are a normal part of the body's immune response to infection, but their sudden release in large quantities may cause multisystem organ failure and death.[1]

Cytokine storms may be caused by infectious or non-infectious etiologies, especially viral respiratory infections such as H1N1 influenza, H5N1 influenza, SARS-CoV-1,[2][3] SARS-CoV-2, Influenza B, and parainfluenza virus. Other causative agents include the Epstein-Barr virus, cytomegalovirus, group A streptococcus, and non-infectious conditions such as graft-versus-host disease.[4] The viruses can invade lung epithelial cells and alveolar macrophages to produce viral nucleic acid, which stimulates the infected cells to release cytokines and chemokines, activating macrophages, dendritic cells, and others.[5]

Cytokine storm syndrome is a diverse set of conditions that can result in a cytokine storm. Cytokine storm syndromes include familial 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.[6]

## Contents

* 1 Cytokine storms versus cytokine release syndrome
* 2 Research
* 3 History
* 3.1 Relationship to COVID-19
* 4 References

## 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.[7]

## Research

Nicotinamide (a form of vitamin B3) is a potent inhibitor of proinflammatory cytokines.[8][9] Low blood plasma levels of trigonelline (one of the metabolites of vitamin B3) have been suggested for the prognosis of SARS-CoV-2 death (which is thought to be due to the inflammatory phase and cytokine storm).[10][11]

Magnesium decreases inflammatory cytokine production by modulation of the immune system.[12][13]

## History

The first reference to the term cytokine storm in the published medical literature appears to be by James Ferrara in 1993 during 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.[14][15][16] 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.[14]

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed an estimated 50 million people worldwide. In this case, a healthy immune system may have been a liability rather than an asset.[17] Preliminary research results from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in 2003.[18] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[19] Cytokine storm has also been implicated in hantavirus pulmonary syndrome.[20]

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.[21] Parexel, a company conducting trials for pharmaceutical companies claimed that theralizumab could cause a cytokine storm—the dangerous reaction the men experienced.[22]

### Relationship to COVID-19

Cytokine release via activation of JAK/STAT signalling pathway following SARS-Cov-2 infection resulting in ARDS related to COVID-19. Abbreviations: ACE2: Angiotensin-converting enzyme 2, CXCL9: Chemokine (C–X–C motif) ligand 9, IL: interleukin, JAK: Janus kinase, and STAT: signal transducer and activator of transcription.[23]

During the COVID-19 pandemic, some doctors have attributed many deaths to cytokine storms.[24][25] A cytokine storm can cause the severe symptoms of acute respiratory distress syndrome (ARDS), which has a high mortality rate in COVID-19 patients.[26] SARS-CoV-2 activates the immune system resulting in a release of a large number of cytokines, including IL-6, which can increase vascular permeability and cause a migration of fluid and blood cells into the alveoli leading to such consequent symptoms as dyspnea and respiratory failure.[27] In an autopsy study from Karolinska Hospital, 29 pleural effusions of deceased COVID-19 patients were analyzed. Out of 184 protein markers, 20 markers were raised significantly in COVID-19 deceased patients. A group of markers showed over-stimulation of the immune system, including ADA, BTC, CA12, CAPG, CD40, CDCP1, CXCL9, ENTPD2, Flt3L, IL-6, IL-8, LRP1, OSM, PD-L1, PTN, STX8, and VEGFA; furthermore, DPP6 and EDIL3 indicated damage to arterial and cardiovascular organs.[23] The higher mortality has been linked to the effects of ARDS aggravation and the tissue damage that can result in organ-failure and/or death.[28]

ARDS was shown to be the cause of mortality in 70% of COVID-19 deaths.[29] A cytokine plasma level analysis showed that in cases of severe SARS-CoV-2 infection, the levels of many interleukins and cytokines are highly elevated, indicating evidence of a cytokine storm.[28] Additionally, postmortem examination of patients with COVID-19 has shown a large accumulation of inflammatory cells in lung tissues including macrophages and T-helper cells.[30]

Early recognition of a cytokine storm in COVID-19 patients is crucial to ensure the best outcome for recovery, allowing treatment with a variety of biological agents that target the cytokines to reduce their levels. Meta-analysis suggests clear patterns distinguishing patients with or without severe disease. Possible predictors of severe and fatal cases may include "lymphopenia, thrombocytopenia and high levels of ferritin, D-dimer, aspartate aminotransferase, lactate dehydrogenase, C-reactive protein, neutrophils, procalcitonin and creatinine" as well as interleukin-6 (IL-6). Ferritin and IL-6 are considered to be possible immunological biomarkers for severe and fatal cases of COVID-19. Ferritin and C-reactive protein may be possible screening tools for early diagnosis of systemic inflammatory response syndrome in cases of COVID-19.[31]

Due to the increased levels of cytokines and interferons in patients with severe COVID-19, both have been investigated as potential targets for SARS-CoV-2 therapy. An animal study found that mice producing an early strong interferon response to SARS-CoV-2 were likely to live, but in other cases the disease progressed to a highly morbid overactive immune system.[32][33] The high mortality rate of COVID-19 in older populations has been attributed to the impact of age on interferon responses.

Short-term use of dexamethasone, a synthetic corticosteroid, has been demonstrated to reduce the severity of inflammation and lung damage induced by a cytokine storm by inhibiting the severe cytokine storm or the hyperinflammatory phase in patients with COVID-19.[34]

Clinical trials continue to identify causes of cytokine storms in COVID-19 cases.[35][36] One such cause is the delayed Type I interferon response that leads to accumulation of pathogenic monocytes. High viremia is also associated with exacerbated Type I interferons response and worse prognosis.[37] Diabetes, hypertension, and cardiovascular disease are all risk factors of cytokine storms in COVID-19 patients.[38]

## 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 15 (5): 845–852. 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. 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. 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. PMID 22390970.
5. ↑ Song, Peipei; Li, Wei; Xie, Jianqin; Hou, Yanlong; You, Chongge (October 2020). "Cytokine storm induced by SARS-CoV-2". Clinica Chimica Acta; International Journal of Clinical Chemistry 509: 280–287. doi:10.1016/j.cca.2020.06.017. ISSN 0009-8981. PMID 32531256.
6. ↑ Behrens, Edward M.; Koretzky, Gary A. (2017). "Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era" (in en). Arthritis & Rheumatology 69 (6): 1135–1143. doi:10.1002/art.40071. ISSN 2326-5205. PMID 28217930.
7. ↑ "Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel". Journal of Hematology & Oncology 11 (1): 35. March 2018. doi:10.1186/s13045-018-0571-y. PMID 29499750.
8. ↑ 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. PMID 12519385.
9. ↑ 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. PMID 31308445. Bibcode: 2019NatSR...910219Y.
10. ↑ Caterino, Marianna, Michele Costanzo, Roberta Fedele, Armando Cevenini, Monica Gelzo, Alessandro Di Minno, Immacolata Andolfo et al. "The serum metabolome of moderate and severe COVID-19 patients reflects possible liver alterations involving carbon and nitrogen metabolism." International journal of molecular sciences 22, no. 17 (2021): 9548.
11. ↑ Besharati, Mohammad Reza; Izadi, Mohammad; Alireza Talebpour (2021). Blood Plasma Trigonelline Concentration and the Early Prognosis of Death in SARS-Cov-2 Patients. doi:10.5281/zenodo.5856445. https://zenodo.org/record/5856445.
12. ↑ Sugimoto J, Romani AM, Valentin-Torres AM, Luciano AA, Ramirez Kitchen CM, Funderburg N (2012). "Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism.". J Immunol 188 (12): 6338–46. doi:10.4049/jimmunol.1101765. PMID 22611240.
13. ↑ Nielsen FH (2018). "Magnesium deficiency and increased inflammation: current perspectives.". J Inflamm Res 11: 25–34. doi:10.2147/JIR.S136742. PMID 29403302.
14. ↑ 14.0 14.1 Clark, Ian A (June 2007). "The advent of the cytokine storm". Immunology & Cell Biology 85 (4): 271–273. doi:10.1038/sj.icb.7100062. PMID 17551531.
15. ↑ "Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1". Transplantation Proceedings 25 (1 Pt 2): 1216–7. February 1993. PMID 8442093.
16. ↑ Abhyankar, Sunil; Gilliland, D. Gary; Ferrara, James L.M. (1993). "Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens1". Transplantation 56 (6): 1518–1522. doi:10.1097/00007890-199312000-00045. ISSN 0041-1337. PMID 8279027.
17. ↑ "Preparing for the next pandemic". The New England Journal of Medicine 352 (18): 1839–42. May 2005. doi:10.1056/NEJMp058068. PMID 15872196.
18. ↑ "An interferon-gamma-related cytokine storm in SARS patients". Journal of Medical Virology 75 (2): 185–94. February 2005. doi:10.1002/jmv.20255. PMID 15602737.
19. ↑ "Confronting potential influenza A (H5N1) pandemic with better vaccines". Emerging Infectious Diseases 13 (10): 1512–8. October 2007. doi:10.3201/eid1310.061262. PMID 18258000.
20. ↑ "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. February 1999. doi:10.1086/314597. PMID 9878011.
21. ↑ 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.
22. ↑ Coghlan A (2006-08-14). "Mystery over drug trial debacle deepens". Health. New Scientist. https://www.newscientist.com/article/dn9734-mystery-over-drug-trial-debacle-deepens-.html.
23. ↑ 23.0 23.1 Razaghi, Ali; Szakos, Attila; Alouda, Marwa; Bozóky, Béla; Björnstedt, Mikael; Szekely, Laszlo (2022-11-14). "Proteomic Analysis of Pleural Effusions from COVID-19 Deceased Patients: Enhanced Inflammatory Markers" (in en). Diagnostics 12 (11): 2789. doi:10.3390/diagnostics12112789. ISSN 2075-4418. PMID 36428847.
24. ↑ "COVID-19: consider cytokine storm syndromes and immunosuppression". Lancet 395 (10229): 1033–1034. March 2020. doi:10.1016/S0140-6736(20)30628-0. PMID 32192578.
25. ↑ "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. March 2020. doi:10.1007/s00134-020-05991-x. PMID 32125452.
26. ↑ "How covid-19 induces cytokine storm with high mortality". Inflammation and Regeneration 40 (37): 37. October 2020. doi:10.1186/s41232-020-00146-3. PMID 33014208.
27. ↑ Farsalinos, Konstantinos; Barbouni, Anastasia; Niaura, Raymond (2020-05-09). "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. ISSN 1828-0447. PMID 32385628.
28. ↑ 28.0 28.1 Ragad, Dina (16 June 2020). "The COVID-19 Cytokine Storm; What we know so far". Front. Immunol. 11: 1446. doi:10.3389/fimmu.2020.01446. PMID 32612617.
29. ↑ Hojyo, Shintaro; Uchida, Mona; Tanaka, Kumiko; Hasebe, Rie; Tanaka, Yuki; Murakami, Masaaki; Hirano, Toshio (2020-10-01). "How COVID-19 induces cytokine storm with high mortality". Inflammation and Regeneration 40: 37. doi:10.1186/s41232-020-00146-3. ISSN 1880-9693. PMID 33014208.
30. ↑ Tang, Yujun; Liu, Jiajia; Zhang, Dingyi; Xu, Zhenghao; Ji, Jinjun; Wen, Chengping (2020-07-10). "Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies". Frontiers in Immunology 11: 1708. doi:10.3389/fimmu.2020.01708. ISSN 1664-3224. PMID 32754163.
31. ↑ Melo, Ana Karla G.; Milby, Keilla M.; Caparroz, Ana Luiza M. A.; Pinto, Ana Carolina P. N.; Santos, Rodolfo R. P.; Rocha, Aline P.; Ferreira, Gilda A.; Souza, Viviane A. et al. (29 June 2021). "Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis". PLOS ONE 16 (6): e0253894. doi:10.1371/journal.pone.0253894. PMID 34185801. Bibcode: 2021PLoSO..1653894M.
32. ↑ Channappanavar, Rudragouda; Perlman, Stanley (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology". Seminars in Immunopathology 39 (5): 529–539. doi:10.1007/s00281-017-0629-x. ISSN 1863-2297. PMID 28466096.
33. ↑ Velasquez-Manoff, Moises (2020-08-11). "How Covid Sends Some Bodies to War With Themselves" (in en-US). The New York Times. ISSN 0362-4331. https://www.nytimes.com/2020/08/11/magazine/covid-cytokine-storms.html.
34. ↑ Sharun, Khan; Tiwari, Ruchi; Dhama, Jaideep; Dhama, Kuldeep (October 2020). "Dexamethasone to combat cytokine storm in COVID-19: Clinical trials and preliminary evidence". International Journal of Surgery 82: 179–181. doi:10.1016/j.ijsu.2020.08.038. PMID 32896649.
35. ↑ Hermine, Olivier; Mariette, Xavier; Tharaux, Pierre-Louis; Resche-Rigon, Matthieu; Porcher, Raphaël; Ravaud, Philippe; CORIMUNO-19 Collaborative Group (20 October 2020). "Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial". JAMA Internal Medicine 181 (1): 32–40. doi:10.1001/jamainternmed.2020.6820. ISSN 2168-6106. PMID 33080017.
36. ↑ Gupta, Shruti; Wang, Wei; Hayek, Salim S.; Chan, Lili; Mathews, Kusum S.; Melamed, Michal L.; Brenner, Samantha K.; Leonberg-Yoo, Amanda et al. (20 October 2020). "Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19". JAMA Internal Medicine 181 (1): 41–51. doi:10.1001/jamainternmed.2020.6252. PMID 33080002.
37. ↑ Sa Ribero, Margarida; Jouvenet, Nolwenn; Dreux, Marlène; Nisole, Sébastien (2020-07-29). "Interplay between SARS-CoV-2 and the type I interferon response". PLOS Pathogens 16 (7): e1008737. doi:10.1371/journal.ppat.1008737. ISSN 1553-7366. PMID 32726355.
38. ↑ Mangalmurti, Nilam; Hunter, Christopher A. (14 July 2020). "Cytokine Storms: Understanding COVID-19". Immunity 53 (1): 19–25. doi:10.1016/j.immuni.2020.06.017. PMID 32610079.

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