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What is a cytokine storm?

Immune, Inflammation | April 15, 2020 | Author: Naturopath

Immune, Inflammation

What is a cytokine storm?

A cytokine storm is a result of an immune system becoming too zealous in its war against disease. It is a description of the harmful consequences of excessive or uncontrolled release of proinflammatory cytokines which generate inflammatory responses. This is seen in both infective and non-infective conditions and can occur throughout the body, including the central nervous system. A cytokine storm is associated with widespread tissue damage.

With infectious disease, the damage is not caused directly by a pathogen, but by an overzealous innate immune response, by the host, towards the pathogen.  

Cytokine storms can be bought on by some illnesses

Cytokine storms can be bought on by some illnesses

  • Bacterial infection which lead to sepsis. Sepsis occurs when chemicals released in the bloodstream to fight an infection trigger inflammation throughout the body. 
     
  • Viruses - Such as the herpes virus family (Epstein-Barr virus and cytomegalovirus), Ebola and Dengue fever. There is speculations whether a cytokine storm is responsible for deaths of many formally healthy young people during The pandemic flu in 1918, Bird Flu (H5N1) (1997)
    and SARS Coronavirus (2003).
  • Rheumatic diseases such as juvenile arthritis and lupus can cause cytokine storm
  • Leukemias and lymphomas may cause a cytokine storm

But why? Scientist are still researching why a cytokine storm may occur in some people in certain conditions. What they do know is in some cases there is a genetic component. 

Genetics

  • Hemophagocytic lymphohistiocytosis, also known as haemophagocytic lymphohistiocytosis, and hemophagocytic or haemophagocytic syndrome is and uncommon hematologic disorder seen mainly in children. It is a life threatening illness of severe hyperinflammation and considered a cytokine storm syndrome.
     
  • Genetic mutations – such as defective perforin delivery or function has been under research. Perforin is a protein, released by killer cells of the immune system, which destroys targeted cells. Cytotoxic T-cells and natural killer cells of the immune system use perforin to punch holes in the walls of infected or cancerous cell and then poor in toxic enzyme (granzyme B), which induces the cells to self-destruct. If perforin is defective or the delivery system dysfunctional, this process fails to destroy the pathogen. One hypothesis is that these signals could spark the intense inflammatory response seen in cytokine storm syndrome. One study showed the immune spent five times longer to respond to a pathogen invasion and then released a flurry of cytokines, even though their lack of perforin made them incapable of destroying their target cell. 

What are cytokines

What are cytokinesCytokines are proteins secreted by cells for the use as intercellular signalling and communicators. They are the control of cell proliferation (the process of increasing the cell number);  differentiation (process of forming a variety of cell types that have specific functions); the regulation of angiogenesis (the development of new blood vessels) and immune and inflammatory response.

Specific cytokines are involved in paracrine, autocrine and/or endocrine activity and through receptor binding, can elicit a variety of responses depending on the cells they are targeting.

Cytokines are the basis of innate immunity, and have many essential physiological roles.

Major types and actions of Cytokines

Interferons – these regulate the innate immune system, activate antiviral activity and have antiproliferative effects (suppress cell growth).

Interleukins – are responsible for growth and differentiation of leukocytes (white blood cells). Many are proinflammatory.

Chemokines – these control chemotaxis (movement of a cell in a particular direction due to attraction to a chemical substance – how cells of the immune system find their target). Many are proinflammatory.

Colony-stimulating factors – Stimulation of hematopoietic progenitor cell proliferation and differentiation (cells with the ability to replenish themselves by self-renewal).

Tumor necrosis factor – activates cytotoxic T cells (cells which kill virally infected cells and tumours). Is proinflammatory.

The Cytokine Storm

A cytokine storm begins with Inflammation at a site of infection with the usual signs of infection - redness (rubor), swelling and oedema, heat, pain and loss of function, and then spreads though the body via systemic circulation (blood vessels supplying oxygenated blood to and returning deoxygenated blood from the tissues of the body). Symptoms can include an enlarged spleen, excessive bleeding, low blood cell counts, multiple organ failure and death.

Biological consequences of a cytokine storm

An immune system gone wild can lead to organ failure and death.

Biological consequences of a cytokine stormIn cases of severe infection, such as severe influenza, the proinflammatory cytokines which manifest outside of the infectious site (i.e. the lung) to other organs and tissue of the body may increase the severity of influenza.

A life-threatening complication of an infection which can damage multiple organ systems, leading them to fail. The severity of sepsis is due to activation cascade which can result in a cytokine storm.
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Cytokine storms are typical in chronic neurogenerative states; post-traumatic brain injury, post-strokes and Alzheimer’s disease where excessive or unrelenting amounts of cytokines within the brain leads to non-resolving inflammation.

How to reduce a cytokine storm

Research is still underway as to best treat or reduce a cytokine storm. This is made complicated as many cytokines are actually doing a positive job - such as clearing away viral debris, repairing damaged tissue and regulating the severity of cytokines. Reducing inflammation may also result in reducing the ability of the immune system being able to do other important roles.

Medication used to block specific cytokines or reduce the immune response, such as steroids, may not be helpful in this case as they also suppress beneficial regulatory cytokines.

How to reduce a cytokine stormUnderstanding cytokine storms in their persistence, severity and how acute they become is necessary to evaluate the pathophysiology of many diseases and how best to treat them.

Cytokine storms happen whilst a patient is in the critical care unit or intensive care unit in hospital when an infection has reached an advanced stage with multiply organ failure and sepsis.

Whether a cytokine storm at the is stage is due to a major attempt by the body to win the war against infection, treatment in the intense situation will be individual with the goal to maintain life.

In summary

The immune system is the most effective weapon against disease and recovery from pathogen attack is most often due to a small army of immune cells enabling the body to cure itself. Supporting the body by taking time to rest is often all that is needed when threatened with infection.

Unfortunately, in some cases of infection, cytokines forget to shut off after the initial call for help and the alarm continues, resulting in too many helpers. Immune cells produce toxic molecules when they fight an infection and these toxins can cause tissue damage. Inflammation, fever and aches, not due to the original pathogen, are a symptom of a cytokine storm occurring in other tissue sites of the body.  

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References

Into the Eye of the Cytokine Storm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/

https://medical-dictionary.thefreedictionary.com/chemotaxis

https://www.immunology.org/public-information/bitesized-immunology/cells/helper-and-cytotoxic-t-cells

The meteorology of cytokine storms, and the clinical usefulness of this knowledge https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495849/

Proinflammatory Cytokine Responses in Extra-Respiratory Tissues During Severe Influenza. https://www.ncbi.nlm.nih.gov/pubmed/28973159

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779301/

Cytokine storm and sepsis disease pathogenesis. https://www.ncbi.nlm.nih.gov/pubmed/28555385

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). https://www.ncbi.nlm.nih.gov/pubmed/26903338?dopt=Abstract

New fronts emerge in the influenza cytokine storm. https://www.ncbi.nlm.nih.gov/pubmed/28555383

https://www.npr.org/sections/health-shots/2020/04/07/828091467/why-some-covid-19-patients-crash-the-bodys-immune-system-might-be-to-blame

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128721/

https://www.newswise.com/articles/here-s-a-playbook-for-stopping-deadly-cytokine-storm-syndrome

Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860100/

New fronts emerge in the influenza cytokine storm. https://www.ncbi.nlm.nih.gov/pubmed/28555383

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102614/

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