Cytokine storm

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Cytokine storm
Other nameshypercytokinemia
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]

Contents

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]

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. Cytokine release following SARS-Cov-2 infection resulting in ARDS related to COVID-19.png
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.

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]

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Myocarditis</span> Inflammation of the heart muscle

Myocarditis, also known as inflammatory cardiomyopathy, is an acquired cardiomyopathy due to inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat. The duration of problems can vary from hours to months. Complications may include heart failure due to dilated cardiomyopathy or cardiac arrest.

In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

<span class="mw-page-title-main">Asymptomatic carrier</span> Organism which has become infected with a pathogen but displays no symptoms

An asymptomatic carrier is a person or other organism that has become infected with a pathogen, but shows no signs or symptoms.

<span class="mw-page-title-main">Hemophagocytic lymphohistiocytosis</span> Immune disorder in the blood leading to hyperinflammation

In hematology, hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis, and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited (acquired) causes of HLH.

<span class="mw-page-title-main">Interleukin 18</span> Protein-coding gene in the species Homo sapiens

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">Toll-like receptor 7</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). STAT2 sequence identity between mouse and human is only 68%.

Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders, and coronary heart disease.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

The co-epidemic of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major global health challenges in the present time. The World Health Organization (WHO) reports 9.2 million new cases of TB in 2006 of whom 7.7% were HIV-infected. Tuberculosis is the most common contagious infection in HIV-Immunocompromised patients leading to death. These diseases act in combination as HIV drives a decline in immunity while tuberculosis progresses due to defective immune status. This condition becomes more severe in case of multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Tuberculosis can occur at any stage of HIV infection. The risk and severity of tuberculosis increases soon after infection with HIV. A study on gold miners of South Africa revealed that the risk of TB was doubled during the first year after HIV seroconversion. Although tuberculosis can be a relatively early manifestation of HIV infection, it is important to note that the risk of tuberculosis progresses as the CD4 cell count decreases along with the progression of HIV infection. The risk of TB generally remains high in HIV-infected patients, remaining above the background risk of the general population even with effective immune reconstitution and high CD4 cell counts with antiretroviral therapy.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">COVID-19</span> Contagious disease caused by SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the virus SARS-CoV-2. The first known case was identified in Wuhan, China, in December 2019. The disease quickly spread worldwide, resulting in the COVID-19 pandemic.

<span class="mw-page-title-main">Multisystem inflammatory syndrome in children</span> Disease of children; pediatric comorbidity from COVID-19

Multisystem inflammatory syndrome in children (MIS-C), or paediatric inflammatory multisystem syndrome, or systemic inflammatory syndrome in COVID-19 (SISCoV), is a rare systemic illness involving persistent fever and extreme inflammation following exposure to SARS-CoV-2, the virus responsible for COVID-19. MIS-C has also been monitored as a potential, rare pediatric adverse event following COVID-19 vaccination. It can rapidly lead to medical emergencies such as insufficient blood flow around the body. Failure of one or more organs can occur. A warning sign is unexplained persistent fever with severe symptoms following exposure to COVID-19. Prompt referral to paediatric specialists is essential, and families need to seek urgent medical assistance. Most affected children will need intensive care. The official MIS-C Awareness Week is in December created by the nonprofit CircumSTANCE. Official awareness items and ribbon can be found on their social media pages or on www.abovecircumstances.org

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

<span class="mw-page-title-main">Impact of the COVID-19 pandemic on neurological, psychological and other mental health outcomes</span> Effects of the COVID-19 pandemic and associated lockdowns on mental health

There is increasing evidence suggesting that COVID-19 causes both acute and chronic neurologicalor psychological symptoms. Caregivers of COVID-19 patients also show a higher than average prevalence of mental health concerns. These symptoms result from multiple different factors.

PANoptosis is an inflammatory cell death pathway. Genetic, molecular, and biochemical studies identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers, leading to the conceptualization of PANoptosis. PANoptosis is defined as a unique innate immune inflammatory cell death pathway driven by caspases and RIPKs and regulated by multi protein PANoptosome complexes. PANoptosis is implicated in driving innate immune responses and inflammation in disease. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer.

<span class="mw-page-title-main">Alzheimer's disease and COVID-19</span>

Studies have shown that Alzheimer's disease (AD) patients are at an increased risk of morbidity and mortality from SARS-CoV-2, the virus that causes COVID-19. AD is the most common cause of dementia worldwide and is clinically defined by amyloid beta plaques, neurofibrillary tangles, and activation of the brain's immune system. While COVID-19 has been known to more severely impact elderly populations, AD patients have been shown to have a higher rate of SARS-CoV-2 infection compared to cognitively normal patients. The disproportionate risk of COVID-19 in AD patients is thought to arise from an interplay of biological and social factors between the two diseases. Many common biological pathways are shared between COVID-19 and AD, notably those involved in inflammation. Genetic factors that put individuals at risk for AD, such as the APOE4 genotype, are associated with worse outcomes during SARS-CoV-2 infection. Cognitive impairment in AD may prevent patients from following proper public health guidelines, such as masking and social distancing, increasing their risk of infection. Additionally, studies have shown cognitively normal COVID-19 patients are at an increased risk of AD diagnosis following recovery, suggesting that COVID-19 has the potential to cause AD.

References

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  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. PMC   7472975 . 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. PMC   7577198 . PMID   33080017.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  36. ↑ 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. PMC   757720 . 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. PMC   7390284 . 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. PMC   7321048 . PMID   32610079.
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