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|Classification and external resources|
A cytokine storm, also known as cytokine cascade and hypercytokinemia, is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and white blood cells, with highly elevated levels of various cytokines. The term arose in the field of pathophysiology in discussions of immune disorders in 1993, was extended to discussions of infectious disease and sepsis, and has been used to describe severe manifestations of cytokine release syndrome, an adverse effect of some drugs.
When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, the body keeps this feedback loop in check. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs. If a cytokine storm occurs in the lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.
The cytokine storm is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors). Both pro-inflammatory cytokines (such as tumor necrosis factor-alpha, Interleukin-1, and Interleukin-6) and anti-inflammatory cytokines (such as interleukin 10 and interleukin 1 receptor antagonist) are elevated in the serum of patients experiencing a cytokine storm.
Cytokine storms can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS). Cytokine storm may also be induced by certain medications, such as the CD20 antibody rituximab and the CD19 antibody tisagenlecleucel. The experimental drug TGN1412 caused extremely serious symptoms when given to six participants in a Phase I trial.
The first reference to the term cytokine storm in the published medical literature appears to be by Ferrara et al. in 1993 in 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 50 to 100 million people. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Hong Kong 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 medical study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug TGN1412 becoming critically ill, suffering from multiple organ failure, pyrexia, and a systemic inflammatory response. Parexel, a company conducting trials for pharmaceutical companies, in one of its own documents, wrote about the trial and said TGN1412 could cause a cytokine storm—the dangerous reaction the men experienced.
A 2003 report in the Journal of Experimental Medicine published by researchers at Imperial College London demonstrates the possibility of preventing a cytokine storm by inhibiting or disabling T cell response. A few days after T cells are activated, they produce a molecule called OX40 (also known as CD134), a "survival signal" that keeps activated T cells working at the site of inflammation during infection with influenza or other pathogens. The ligand of OX40, called OX40 ligand (OX40L, TNFSF4, gp34), which is expressed by antigen presenting cells, binds to OX40 on T cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40-immunoglobulin (OX40-Ig), a human-made fusion protein, prevents OX40 ligand from reaching OX40 on T cells, thus reducing the T cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with an immune overreaction while allowing the immune system to fight off the virus successfully. By blocking the OX40 receptor on T cells, researchers were able to prevent the development of the most serious flu symptoms in these experimental mice. These results were the subject of an article in the science magazine New Scientist. The drug, to be made by a company called Xenova Research (Xenova Research was purchased by Celtic Pharma, a private equity firm, in September 2005), was supposed to be in phase I clinical trial in 2004, but its status is currently unknown.
In addition, preliminary data has shown that simvastatin induced down-regulation of OX40 and OX40L mRNA and protein in a concentration-dependent manner, and antagonized the interferon-gamma-induced increase in OX40 and OX40L mRNA and protein levels. Further, serum levels of soluble OX40L and matrix metalloproteinase 9 levels were significantly reduced in patients with atherosclerotic cerebral infarction who were treated for 6 months with routine therapy plus simvastatin (n = 46) compared with patients receiving routine therapy alone (n = 30).
The renin angiotensin system (RAS) has been implicated in the mediation of the cytokine storm, suggesting a potential benefit for angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), and ACE has been implicated in inflammatory lung pathologies. Shigehara et al. published research confirming that serum angiotensin-converting enzyme (ACE) is a useful marker for disease activity in cytokine-mediated inflammatory lung disease. Marshall and co-workers also found that angiotensin II was associated with cytokine-mediated lung injury and suggested a role for ACE inhibitors.
Wang and co-workers published data that cytokine-mediated pulmonary damage (apoptosis of lung epithelial cells) in response to the pro-inflammatory cytokine TNF-alpha (implicated in the cytokine storm) requires the presence of angiotensin II, suggesting that ARBs might have clinical utility in this setting.
Das published a review of ACE inhibitor and angiotensin-II receptor blocker use in a number of cytokine-mediated inflammatory pathologies and suggested that ACE inhibitors and Angiotensin receptor blockers have theoretical benefit in downregulation of the cytokine storm.
Although frequently employed to treat patients experiencing the cytokine storm associated with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.
Preliminary data has shown that gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.
Preliminary data from clinical trials involving patients with sepsis-induced ARDS have shown a reduction in organ damage and a trend toward improvement in survival (survival in ARDS is approximately 60%) after administering or upregulating a variety of free radical scavengers (antioxidants).
Some types of arthritis medications are designed to reduce inflammation by inhibiting the tumor necrosis factor-alpha pathway to immune cell activation; these drugs are known as TNF-alpha blockers. One study found that three different TNF-alpha blockers afforded a slight reduction in antibody presentation after vaccination against influenza in a group of immunocompromised patients, however it did not significantly affect patients' protective factor gained from inoculation. More research is necessary before any conclusions may be made regarding the efficacy of TNF-alpha blockers at reducing the effects of a cytokine storm in hospitalized flu patients.