Cytokine storm
Encyclopedia
A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokine
s and immune cells, with highly elevated levels of various cytokines.
, swelling and redness, extreme fatigue and nausea
. In some cases the immune reaction may be fatal.
is fighting pathogen
s, cytokines signal immune cells such as T-cells and macrophage
s to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, this feedback loop is kept in check by the body. 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 lung
s, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.
The cytokine storm (hypercytokinemia) 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
, avian influenza, smallpox
, and systemic inflammatory response syndrome
(SIRS). Cytokine storm may also be induced by certain medications. The experimental drug TGN1412
caused extremely serious symptoms likely due to a cytokine storm 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 GVHD in February 1993.
, which killed a disproportionate number of young adults. 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. Recent reports of high mortality among healthy young adults in the 2009 swine flu outbreak has led to speculation that cytokine storms could be responsible for these deaths. However, the Centers for Disease Control and Prevention
(CDC) have indicated that symptoms reported from this strain so far are similar to those of normal seasonal flu, with the CDC stating that there is "insufficient information to date about clinical complications of this variant of swine-origin influenza A (H1N1) virus infection."
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. OX40 binds to receptors 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 from reaching the T-cell receptors, 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).
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.
, 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.
-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).
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.
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and immune cells, with highly elevated levels of various cytokines.
Symptoms
The primary symptoms of a cytokine storm are high feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, swelling and redness, extreme fatigue and nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
. In some cases the immune reaction may be fatal.
Cause
When the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
is fighting pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s, cytokines signal immune cells such as T-cells and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, this feedback loop is kept in check by the body. 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 lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.
The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
mediators (cytokines, oxygen free radicals, and coagulation factors). Both pro-inflammatory cytokines (such as Tumor necrosis factor-alpha, Interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
-1, and Interleukin-6) and anti-inflammatory cytokines (such as interleukin 10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
and interleukin 1 receptor antagonist
Interleukin 1 receptor antagonist
The interleukin-1 receptor antagonist is a protein that in humans is encoded by the IL1RN gene.IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories. IL-1RA, is an agent that binds non-productively to the cell surface interleukin-1...
) are elevated in the serum
Serous fluid
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature, that fill the inside of body cavities. Serous fluid originates from serous glands, with secretions enriched with proteins and water. Serous fluid may also...
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
Acute respiratory distress syndrome
Acute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
(ARDS), sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
, avian influenza, smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
, and systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS). Cytokine storm may also be induced by certain medications. The experimental drug TGN1412
TGN1412
TGN1412 is the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first human subjects to receive the drug....
caused extremely serious symptoms likely due to a cytokine storm when given to six participants in a Phase I trial.
The first reference to the term cytokine storm in the published medical literature
Medical literature
Medical literature refers to articles in journals and texts in books devoted to the field of medicine.Contemporary and historic views regarding diagnosis, prognosis and treatment of medical conditions have been documented for thousands of years. The Edwin Smith papyrus is the first known medical...
appears to be by Ferrara et al. in GVHD in February 1993.
Role in pandemic deaths
It is believed that cytokine storms were responsible for many of the deaths during the 1918 influenza pandemicSpanish flu
The 1918 flu pandemic was an influenza pandemic, and the first of the two pandemics involving H1N1 influenza virus . It was an unusually severe and deadly pandemic that spread across the world. Historical and epidemiological data are inadequate to identify the geographic origin...
, which killed a disproportionate number of young adults. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Hong Kong
Hong Kong
Hong Kong is one of two Special Administrative Regions of the People's Republic of China , the other being Macau. A city-state situated on China's south coast and enclosed by the Pearl River Delta and South China Sea, it is renowned for its expansive skyline and deep natural harbour...
also indicated this as the probable reason for many deaths during the SARS
Severe acute respiratory syndrome
Severe Acute Respiratory Syndrome is a respiratory disease in humans which is caused by the SARS coronavirus . Between November 2002 and July 2003 an outbreak of SARS in Hong Kong nearly became a pandemic, with 8,422 cases and 916 deaths worldwide according to the WHO...
epidemic in 2003. Human deaths from the bird flu H5N1
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
usually involve cytokine storms as well. Recent reports of high mortality among healthy young adults in the 2009 swine flu outbreak has led to speculation that cytokine storms could be responsible for these deaths. However, the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC) have indicated that symptoms reported from this strain so far are similar to those of normal seasonal flu, with the CDC stating that there is "insufficient information to date about clinical complications of this variant of swine-origin influenza A (H1N1) virus infection."
OX40 IG
A 2003 report in the Journal of Experimental Medicine published by researchers at Imperial College LondonImperial College London
Imperial College London is a public research university located in London, United Kingdom, specialising in science, engineering, business and medicine...
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
CD134
CD134, also known as OX40, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary costimulatory molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on...
), a "survival signal" that keeps activated T-cells working at the site of inflammation during infection with influenza or other pathogens. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40-immunoglobulin (OX40-Ig), a human-made fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
, prevents OX40 from reaching the T-cell receptors, 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
New Scientist
New Scientist is a weekly non-peer-reviewed English-language international science magazine, which since 1996 has also run a website, covering recent developments in science and technology for a general audience. Founded in 1956, it is published by Reed Business Information Ltd, a subsidiary of...
. 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).
ACE inhibitors and Angiotensin II Receptor Blockers
The Renin Angiotensin system (RAS) has been implicated in the mediation of the cytokine storm, suggesting a potential benefit for Angiotensin Converting Enzyme (ACE) inhibitorsACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
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
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
) 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.
Corticosteroids
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.Gemfibrozil
Preliminary data has shown that gemfibrozilGemfibrozil
Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid...
, 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.
Free radical scavengers
Preliminary data from clinical trials involving patients with sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
-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).
TNF-alpha blockers
Some types of arthritisArthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
medications are designed to reduce inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
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.