Acytokine storm, also calledhypercytokinemia, is a pathological reaction in humans and other animals in which theinnate immune system causes an uncontrolled and excessive release ofpro-inflammatory signaling molecules calledcytokines. Cytokines are a normal part of the body's immune response to infection, but their sudden release in large quantities may causemultisystem organ failure and death.[1]
The term "cytokine storm" is often loosely used interchangeably withcytokine release syndrome (CRS) but is more precisely a differentiablesyndrome that may represent a severe episode of cytokine release syndrome or a component of another disease entity, such asmacrophage 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]
Nicotinamide (a form ofvitamin 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]
The first reference to the termcytokine storm in the publishedmedical literature appears to be by James Ferrara in 1993 during a discussion ofgraft 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 ofpancreatitis in 2002. 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 the1918 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 fromTaiwan also indicated this as the probable reason for many deaths during theSARS epidemic in 2003.[18] Human deaths from the bird fluH5N1 usually involve cytokine storms as well.[19] Cytokine storm has also been implicated inhantavirus pulmonary syndrome.[20]
In 2006, a study atNorthwick Park Hospital in England resulted in all 6 of the volunteers given the drugtheralizumab becoming critically ill, with multiple organ failure, high fever, and a systemicinflammatory 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]
Cytokine release via activation ofJAK/STAT signalling pathway followingSARS-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 theCOVID-19 pandemic, some doctors have attributed many deaths to cytokine storms.[24][25] A cytokine storm can cause the severe symptoms ofacute 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, includingIL-6, which can increasevascular 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 anautopsy study fromKarolinska Hospital, 29pleural 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, includingADA,BTC,CA12,CAPG,CD40,CDCP1,CXCL9,ENTPD2,Flt3L,IL-6,IL-8,LRP1,OSM,PD-L1,PTN,STX8, andVEGFA; furthermore,DPP6 andEDIL3 indicated damage toarterial andcardiovascular 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 includelymphopenia,thrombocytopenia and high levels offerritin,D-dimer,aspartate aminotransferase,lactate dehydrogenase,C-reactive protein,neutrophils,procalcitonin andcreatinine as well asinterleukin-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 ofsystemic 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. Ananimal 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 pathogenicmonocytes. Highviremia is also associated with exacerbated Type I interferons response and worseprognosis.[37]Diabetes,hypertension, andcardiovascular disease are allrisk factors of cytokine storms in COVID-19 patients.[38]
^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.
^Gupta, Shruti; Wang, Wei; Hayek, Salim S.; Chan, Lili; Mathews, Kusum S.; Melamed, Michal L.; Brenner, Samantha K.; Leonberg-Yoo, Amanda; Schenck, Edward J.; Radbel, Jared; Reiser, Jochen; Bansal, Anip; Srivastava, Anand; Zhou, Yan; Finkel, Diana; Green, Adam; Mallappallil, Mary; Faugno, Anthony J.; Zhang, Jingjing; Velez, Juan Carlos Q.; Shaefi, Shahzad; Parikh, Chirag R.; Charytan, David M.; Athavale, Ambarish M.; Friedman, Allon N.; Redfern, Roberta E.; Short, Samuel A. P.; Correa, Simon; Pokharel, Kapil K.; Admon, Andrew J.; Donnelly, John P.; Gershengorn, Hayley B.; Douin, David J.; Semler, Matthew W.; Hernán, Miguel A.; Leaf, David E.; STOP-COVID Investigators (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.PMC757720.PMID33080002.
