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When the [[immune system]] is fighting [[pathogen]]s, cytokines signal immune cells such as [[T-cell]]s 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.{{Fact|date=July 2008}}
When the [[immune system]] is fighting [[pathog['pikpoipoi nen]]s, cytokines signal immune cells such as [[T-cell]]s 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.{{Fact|date=July 2008}}


The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known [[inflammation|inflammatory]] mediators (cytokines, [[oxygen free radicals]], and [[coagulation factor]]s). {{Fact|date=July 2008}} 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 [[Serous fluid|serum]] of patients experiencing a cytokine storm.{{Fact|date=July 2008}}
The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known [[inflammation|inflammatory]] mediators (cytokines, [[oxygen free radicals]], and [[coagulation factor]]s). {{Fact|date=July 2008}} 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 [[Serous fluid|serum]] of patients experiencing a cytokine storm.{{Fact|date=July 2008}}

Revision as of 16:21, 23 October 2009

Cytokine storm
SpecialtyImmunology Edit this on Wikidata

A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.[1]

Symptoms

The primary symptoms of a cytokine storm are high fever, swelling and redness, extreme fatigue and nausea. In some cases the immune reaction may be fatal.

Cause

When the immune system is fighting [[pathog['pikpoipoi nen]]s, 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, 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 lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.[citation needed]

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). [citation needed] 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.[citation needed]

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).[2] Cytokine storm may also be induced by certain medications. The experimental drug TGN1412 caused extremely serious symptoms[3] likely due to a cytokine storm[4] 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.[5] 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 pandemic, which killed a disproportionate number of young adults.[1] 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.[6] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[7] 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.[8] 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,[9] 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."[9]

Treatment

OX40 IG

A 2003 report in the Journal of Experimental Medicine published by researchers at Imperial College London demonstrates[10] 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 biologic molecule called OX40, 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[10] and reported the results in New Scientist.[11] 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.[12]

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).[13]

ACE inhibitors and Angiotensin II Receptor Blockers

The Renin Angiotensin system (RAS) has been implicated in the mediation of the cytokine storm,[14] 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.[15] 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.[16] Marshall and co-workers also found that angiotensin II was associated with cytokine-mediated lung injury[17] 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.[18]

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.[19]

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.[2]

Gemfibrozil

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. [20]

Free radical scavengers

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).[2]

TNF-alpha blockers

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[21] 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.

See also

References

  1. ^ a b Osterholm, Michael T. (2005-05-05). "Preparing for the Next Pandemic". The New England Journal of Medicine. 352 (18): 1839–1842. doi:10.1056/NEJMp058068. PMID 15872196. {{cite journal}}: |access-date= requires |url= (help)
  2. ^ a b c Drazen, Jeffrey M.; Cecil, Russell L.; Goldman, Lee; Bennett, J. Claude (2000). Cecil Textbook of Medicine (21st ed.). Philadelphia: W.B. Saunders. ISBN 0-7216-7996-X.{{cite book}}: CS1 maint: multiple names: authors list (link)
  3. ^ Thelancetoncology, (2007). "Leading Edge: High stakes, high risks". Lancet Oncology. 8 (2). The Lancet: 85. doi:10.1016/S1470-2045(07)70004-9. PMID 17267317. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: extra punctuation (link)
  4. ^ Coghlan A (2006-08-14). "Mystery over drug trial debacle deepens". Health. New Scientist. Retrieved 2009-04-29. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  5. ^ Ferrara, JL. (1993). "Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1". Transplant Proc. 2 (25): 1216–1217. PMID 8442093. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  6. ^ Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY (2005). "An interferon-gamma-related cytokine storm in SARS patients". Journal of Medical Virology. 75 (2): 185–94. doi:10.1002/jmv.20255. PMID 15602737. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Haque A, Hober D, Kasper LH (2007). "Confronting potential influenza A (H5N1) pandemic with better vaccines". Emerging Infectious Diseases. 13 (10): 1512–8. PMID 18258000. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Lacey M McNeil DG Jr (2009-04-24). "Fighting Deadly Flu, Mexico Shuts Schools". NYTimes.com. Retrieved 2009-04-29. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  9. ^ a b "Interim Guidance for Clinicians on Identifying and Caring for Patients with Swine-origin Influenza A (H1N1) Virus Infection". Centers for Disease Control and Prevention (CDC). 2009-04-29. Retrieved 2009-04-29. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  10. ^ a b Humphreys, IR (2003-10-20). "A critical role for OX40 in T cell-mediated immunopathology during lung viral infection". J Exp Med. 198 (8): 1237–1242. doi:10.1084/jem.20030351. PMC 2194232. PMID 14568982. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ Bhattacharya S (2003-10-20). "New flu drug calms the 'storm'". New Scientist. Retrieved 2009-04-29. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  12. ^ OX-40 Clinical Trial details
  13. ^ Liu B. et al. Simvastatin reduces OX40 and OX40 ligand expression in human peripheral blood mononuclear cells and in patients with atherosclerotic cerebral infarction. J Int Med 2009 May-Jun;37(3):601-10.PMID: 19589242
  14. ^ Genctoy, G (2005). "TNF alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels?". Artif Organs. 29 (2): 174–178. doi:10.1111/j.1525-1594.2005.29029.x. PMID 15670287. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  15. ^ Moldobaeva, A (2003). "Angiotensin-converting enzyme activity in ovine bronchial vasculature". J Appl Physiol. 95 (6). Department of Medicine, Johns Hopkins University: 2278–2284. doi:10.1152/japplphysiol.00266.2003. PMID 15670287. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |doi_brokendate= ignored (|doi-broken-date= suggested) (help); Unknown parameter |month= ignored (help)
  16. ^ Shigehara, K (2003). "Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis". Clin Exp Immunol. 132 (1). Sapporo Medical University School of Medicine: 152–157. doi:10.1046/j.1365-2249.2003.02105.x. PMC 1808667. PMID 12653850. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  17. ^ Marshall, RP (2004). "Angiotensin II and the fibroproliferative response to acute lung injury". Am J Physiol Lung Cell Mol Physiol. 286 (1). Royal Free and University College London Medical School: 156–164. doi:10.1152/ajplung.00313.2002. PMID 12754187. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  18. ^ Wang, R (2000). "Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo". J Cell Physiol. 185 (2). The Cardiovascular Institute, Michael Reese Hospital and Medical Center: 253–259. doi:10.1002/1097-4652(200011)185:2<253::AID-JCP10>3.0.CO;2-#. PMID 11025447. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  19. ^ Das UN (2005). "Angiotensin-II behaves as an endogenous pro-inflammatory molecule". The Journal of the Association of Physicians of India. 53: 472–6. PMID 16124358. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Budd A, Alleva L, Alsharifi M, et al. Antimicrob Agents Chemother. 2007 Aug;51(8):2965-8. Epub 2007 Jun 11 PMID: 17562808
  21. ^ Gelinck LB, van der Bijl AE, Beyer WE, Visser LG, Huizinga TW, van Hogezand RA, Rimmelzwaan GF, Kroon FP (2008). "The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination". Annals of the Rheumatic Diseases. 67 (5): 713–6. doi:10.1136/ard.2007.077552. PMID 17965123. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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