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 H1N1 influenza, H5N1 influenza, SARS-CoV-1, and SARS-CoV-2, Influenza B, Parainfluenza virus. Other causative agents include the Epstein-Barr virus, cytomegalovirus, 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 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. 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. 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). 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