Cytokine Storm

A cytokine storm, also called hypercytokinemia, is a physiological 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. Normally, cytokines are part of the body's immune response to infection, but their sudden release in large quantities can cause multisystem organ failure and death. Cytokine storms can be caused by a number of infectious and non-infectious etiologies, especially viral respiratory infections such as H5N1 influenza, SARS-CoV-1, and SARS-CoV-2 (COVID-19 agent). Other causative agents include the Epstein-Barr virus, cytomegalovirus, and group A streptococcus, and non-infectious conditions such as graft-versus-host disease. 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.

Cytokine storm syndrome is diverse set of conditions that can result in cytokine storm. Cytokine storm syndromes include familiar 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.

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.

Research

Nicotinamide (a form of vitamin B₃) is a potent inhibitor of proinflammatory cytokines.

Magnesium decreases inflammatory cytokine production by modulation of the immune system.

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. 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.

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

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. Parexel, a company conducting trials for pharmaceutical companies, in one of its documents, wrote about the trial and said theralizumab could cause a cytokine storm—the dangerous reaction the men experienced.

Relationship to COVID-19

During the COVID-19 pandemic, some doctors attributed many deaths to cytokine storms. Severe symptoms of acute respiratory distress syndrome (ARDS) with high mortality in COVID-19 patients are caused by a cytokine storm. SARS-CoV-2 activates the innate immune system and results 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 as well as the consequent symptoms such as dyspnea and respiratory failure. The higher mortality is being linked to the result of ARDS aggravation and the tissue damage that can result in organ-failure and/or death.

ARDS was shown to be the cause of mortality in 70% of COVID-19 deaths. In a cytokine plasma level analysis of those with severe Sars-CoV-2, the levels of many interleukins and cytokines are extremely elevated, showing evidence of a cytokine storm in those most harshly affected. Additionally, postmortem examination of patients with COVID-19 has shown large accumulation of inflammatory cells in lung tissues, including macrophages and T-helper cells.

Early recognition of this cytokine storm in COVID-19 patients is crucial to ensure the best outcome, allowing for treatment with a variety of biological agents that target the cytokines to reduce their levels.

Due to the increased levels of cytokines and interferons in those with severe Sars-CoV-2, both are being investigated as potential therapies for COVID-19. An animal study done on mice found that those producing early strong interferon responses to SARS-CoV, which also originated from bats, were more likely to live, while other cases were likely to experience a highly morbid overactive immune system. The high mortality rate of COVID-19 in older populations were linked 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 the cytokine storm; it inhibits the severe cytokine storm, or the hyperinflammatory phase in patients with COVID-19.

Trials continue to identify causes of cytokine storms in COVID-19 cases. One possible cause is the delayed type I INF response, because it leads to accumulation of pathogenic monocytes. High viremia is also associated with exacerbated type I INF response and worse prognosis. Diabetes, hypertension, and cardiovascular disease are all risk factors of cytokine storms in COVID-19 patients.