Cytokines are natural mediators that regulate immune responses and communication between cells. The way they interact with the body and each other is extremely complex. A cytokine storm occurs when an extreme amount of mediators act unchecked in the body, amplifying the immune response to critical levels and causing significant damage to the body.

Normal Cytokine Reaction

The body tightly controls the normal cytokine reaction. In a healthy person, cytokine levels are undetectable, but when that person gets sick, cytokines can increase a much as 1,000-fold. When they behave normally, elevated cytokines in the blood are biomarkers that help medical professionals understand how some diseases progress and how a person responds to treatment. A cytokine storm is an extreme and abnormal reaction.

Abnormal Response

Nearly every type of disease elicits a cytokine response indicative of inflammation somewhere in the body. In a normal reaction, understanding how cytokines react as regulators could help determine treatments. When a cytokine storm occurs, though, the immune response is excessive and causes critical damage to the body. Treatment shifts to maintaining an appropriate cardiac output, oxygenation, ventilation, and fluid and electrolyte balance.

Interferons

Multiple types of cytokines can cause a cytokine storm. Normally, interferons play a role in maintaining immunity to viruses. They bind to receptors, initiating signals that result in the activation of hundreds of genes. These genes encode proteins with properties that modulate the immune response. When this reaction gets out of control, it results in a cytokine storm.

Interleukins

Interleukins are another type of cytokine that can cause a cytokine storm. Interleukins are very diverse. They, directly and indirectly, elicit a wide range of responses in the body and can be pro- or anti-inflammatory. One of their many functions is to increase signaling in the acute phase of the disease, encouraging an immune response at the site of infection. They produce secondary cytokines, as well, that can also contribute to a cytokine storm.

Chemokines

Chemokines can also contribute to cytokine storms. These small proteins act as chemoattractants, controlling the mitigation of immune system cells. Most chemokines are pro-inflammatory. Several types of cells release them, but they are highly selective and attract specific blood cells, including neutrophils, eosinophils, and monocytes, to the site of infection.

Colony-Stimulating Factors

Another cytokine that elicits an inflammatory response is colony-stimulating factor. These stimulate hematopoietic progenitor cells, which are similar to stem cells but cannot differentiate indefinitely. Evidence suggests that colony-stimulating factors might be involved in a pro-inflammatory network of cytokines that amplifies inflammatory reactions. This makes them a possible contributor to a cytokine storm.

Tumor Necrosis Factor

Tumor necrosis factor plays an important role in cytokine storm literature. It is considered the primary cytokine in viral responses, and all cell types have receptors for it. This means it has the potential to elicit a widespread response, which is why it is key to cytokine storms. Tumor necrosis factor inhibitors have been successfully used to treat some chronic autoimmune and inflammatory diseases but have not been successful at treating sepsis or a cytokine storm.

Symptoms

Cytokine storm symptoms are life-threatening and can evolve rapidly. They include uncontrolled inflammation throughout the body that leads to high and persistent fevers, a reduced number of mature blood cells, and coagulopathies that can lead to severe internal bleeding. This can rapidly progress to multi-system organ failure and even death.

Treatment of Cytokine Storm

Treatment of cytokine storm focuses on suppressing the immune system and controlling the underlying disease. This varies depending on the trigger. For example, if a cytokine storm is the result of a systemic infection, it is treated with antibiotics or antivirals. Current treatment to stop the immune response suppresses the entire immune system, but researchers are hoping to create more targeted therapies.

Challenges

Treating a cytokine storm is extremely difficult. Common treatments for severe responses to infection — corticosteroids, monoclonal antibodies, plasma exchange, and anti-cytokine and anti-chemokine agents — have proven ineffective. In some cases, they result in a worse outcome. Despite the knowledge that a patient is experiencing a cytokine storm, it is not always possible to intervene and improve the outcome.