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CytokinestormWikipedia,thefreeencyclopedia

Cytokinestorm
FromWikipedia,thefreeencyclopedia

Acytokinestorm,alsoknownascytokinecascadeandhypercytokinemia,isapotentially
fatalimmunereactionconsistingofapositivefeedbackloopbetweencytokinesandwhite
bloodcells,withhighlyelevatedlevelsofvariouscytokines.[1]

Contents

Cytokinestorm
Classificationandexternalresources
DiseasesDB 34296
(http://www.diseasesdatabase.com/ddb34296.htm)

1Symptoms
2Cause
3Roleinpandemicdeaths
4Treatment
4.1OX40IG
4.2ACEinhibitorsandangiotensinIIreceptorblockers
4.3Corticosteroids
4.4Gemfibrozil
4.5Freeradicalscavengers
4.6TNFalphablockers
5Seealso
6References
7Externallinks

Symptoms
Theprimarysymptomsofacytokinestormarehighfever,swellingandredness,extremefatigueandnausea.Insomecasestheimmunereactionmaybe
fatal.
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Cause
Whentheimmunesystemisfightingpathogens,cytokinessignalimmunecellssuchasTcellsandmacrophagestotraveltothesiteofinfection.In
addition,cytokinesactivatethosecells,stimulatingthemtoproducemorecytokines.[2]Normally,thisfeedbackloopiskeptincheckbythebody.
However,insomeinstances,thereactionbecomesuncontrolled,andtoomanyimmunecellsareactivatedinasingleplace.Theprecisereasonforthisis
notentirelyunderstoodbutmaybecausedbyanexaggeratedresponsewhentheimmunesystemencountersanewandhighlypathogenicinvader.
Cytokinestormshavepotentialtodosignificantdamagetobodytissuesandorgans.Ifacytokinestormoccursinthelungs,forexample,fluidsand
immunecellssuchasmacrophagesmayaccumulateandeventuallyblockofftheairways,potentiallyresultingindeath.
Thecytokinestorm(hypercytokinemia)isthesystemicexpressionofahealthyandvigorousimmunesystemresultinginthereleaseofmorethan150
knowninflammatorymediators(cytokines,oxygenfreeradicals,andcoagulationfactors).Bothproinflammatorycytokines(suchasTumornecrosis
factoralpha,Interleukin1,andInterleukin6)andantiinflammatorycytokines(suchasinterleukin10andinterleukin1receptorantagonist)areelevated
intheserumofpatientsexperiencingacytokinestorm.[3]
Cytokinestormscanoccurinanumberofinfectiousandnoninfectiousdiseasesincludinggraftversushostdisease(GVHD),acuterespiratorydistress
syndrome(ARDS),sepsis,avianinfluenza,smallpox,andsystemicinflammatoryresponsesyndrome(SIRS).[4]Cytokinestormmayalsobeinducedby
certainmedications.TheexperimentaldrugTGN1412causedextremelyserioussymptoms[5]likelyduetoacytokinestorm[6]whengiventosix
participantsinaPhaseItrial.
ThefirstreferencetothetermcytokinestorminthepublishedmedicalliteratureappearstobebyFerraraetal.[7]inGVHDinFebruary1993.

Roleinpandemicdeaths
Itisbelievedthatcytokinestormswereresponsibleformanyofthedeathsduringthe1918influenzapandemic,whichkilledadisproportionatenumber
ofyoungadults.[1]Inthiscase,ahealthyimmunesystemmayhavebeenaliabilityratherthananasset.PreliminaryresearchresultsfromHongKong
alsoindicatedthisastheprobablereasonformanydeathsduringtheSARSepidemicin2003.[8]HumandeathsfromthebirdfluH5N1usuallyinvolve
cytokinestormsaswell.[9]Recentreportsofhighmortalityamonghealthyyoungadultsinthe2009swinefluoutbreakhasledtospeculationthat
cytokinestormscouldberesponsibleforthesedeaths,sincetheSwineFluresultsfromthesameinfluenzastrainastheSpanishFluof1918.[10]
However,theCentersforDiseaseControlandPrevention(CDC)haveindicatedthatsymptomsreportedfromthisstrainsofararesimilartothoseof
normalseasonalflu,[11]withtheCDCstatingthatthereis"insufficientinformationtodateaboutclinicalcomplicationsofthisvariantofswineorigin
influenzaA(H1N1)virusinfection."[11]Cytokinestormhasalsobeenimplicatedinhantaviruspulmonarysyndrome.[12]
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Treatment
OX40IG
A2003reportintheJournalofExperimentalMedicinepublishedbyresearchersatImperialCollegeLondondemonstrates[13]thepossibilityof
preventingacytokinestormbyinhibitingordisablingTcellresponse.AfewdaysafterTcellsareactivated,theyproduceamoleculecalledOX40(also
knownasCD134),a"survivalsignal"thatkeepsactivatedTcellsworkingatthesiteofinflammationduringinfectionwithinfluenzaorotherpathogens.
OX40bindstoreceptorsonTcells,preventingthemfromdyingandsubsequentlyincreasingcytokineproduction.Acombinedprotein,OX40
immunoglobulin(OX40Ig),ahumanmadefusionprotein,preventsOX40fromreachingtheTcellreceptors,thusreducingtheTcellresponse.
ExperimentsinmicehavedemonstratedthatOX40Igcanreducethesymptomsassociatedwithanimmuneoverreactionwhileallowingtheimmune
systemtofightoffthevirussuccessfully.ByblockingtheOX40receptoronTcells,researcherswereabletopreventthedevelopmentofthemost
seriousflusymptomsintheseexperimentalmice.[13]TheseresultswerethesubjectofanarticleinthesciencemagazineNewScientist.[14]Thedrug,to
bemadebyacompanycalledXenovaResearch(XenovaResearchwaspurchasedbyCelticPharma,aprivateequityfirm,inSeptember2005),was
supposedtobeinphaseIclinicaltrialin2004,butitsstatusiscurrentlyunknown.[15]
Inaddition,preliminarydatahasshownthatsimvastatininduceddownregulationofOX40andOX40LmRNAandproteininaconcentrationdependent
manner,andantagonizedtheinterferongammainducedincreaseinOX40andOX40LmRNAandproteinlevels.Further,serumlevelsofsoluble
OX40Landmatrixmetalloproteinase9levelsweresignificantlyreducedinpatientswithatheroscleroticcerebralinfarctionwhoweretreatedfor6
monthswithroutinetherapyplussimvastatin(n=46)comparedwithpatientsreceivingroutinetherapyalone(n=30).[16]

ACEinhibitorsandangiotensinIIreceptorblockers
Thereninangiotensinsystem(RAS)hasbeenimplicatedinthemediationofthecytokinestorm,[17]suggestingapotentialbenefitforangiotensin
convertingenzyme(ACE)inhibitorsandangiotensinIIreceptorblockers(ARBs),andACEhasbeenimplicatedininflammatorylungpathologies.[18]
Shigeharaetal.publishedresearchconfirmingthatserumangiotensinconvertingenzyme(ACE)isausefulmarkerfordiseaseactivityincytokine
mediatedinflammatorylungdisease.[19]MarshallandcoworkersalsofoundthatangiotensinIIwasassociatedwithcytokinemediatedlunginjury[20]
andsuggestedaroleforACEinhibitors.
Wangandcoworkerspublisheddatathatcytokinemediatedpulmonarydamage(apoptosisoflungepithelialcells)inresponsetotheproinflammatory
cytokineTNFalpha(implicatedinthecytokinestorm)requiresthepresenceofangiotensinII,suggestingthatARBsmighthaveclinicalutilityinthis
setting.[21]

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DaspublishedareviewofACEinhibitorandangiotensinIIreceptorblockeruseinanumberofcytokinemediatedinflammatorypathologiesand
suggestedthatACEinhibitorsandAngiotensinreceptorblockershavetheoreticalbenefitindownregulationofthecytokinestorm.[22]

Corticosteroids
AlthoughfrequentlyemployedtotreatpatientsexperiencingthecytokinestormassociatedwithARDS,corticosteroidsandNSAIDshavebeenevaluated
inclinicaltrialsandhaveshownnoeffectonlungmechanics,gasexchange,orbeneficialoutcomeinearlyestablishedARDS.[4]

Gemfibrozil
Preliminarydatahasshownthatgemfibrozil,anagentthatinhibitsproductionofproinflammatorycytokinesinadditiontoitsclinicallyusefullipid
loweringactivity,increasedsurvivalinBALB/cmicethatwerealreadyillfrominfectionbyinfluenzavirusA/Japan/305/57(H2N2).Gemfibrozilwas
administeredintraperitoneallyoncedailyfromdays4to10afterintranasalexposuretothevirus.Survivalincreasedfrom26%invehicletreatedmice(n
=50)to52%inmicegivengemfibrozilat60mg/kg/day(n=46)(P=0.0026).Ifthisprincipletranslatestopatients,adrugalreadyapprovedforhuman
use,albeitbyadifferentrouteforanotherpurpose,mightbeadaptedrelativelyfastforuseagainstinfluenza,conceivablyincludinghumaninfection
withaderivativeoftheavianH5N1strain.[23]

Freeradicalscavengers
PreliminarydatafromclinicaltrialsinvolvingpatientswithsepsisinducedARDShaveshownareductioninorgandamageandatrendtoward
improvementinsurvival(survivalinARDSisapproximately60%)afteradministeringorupregulatingavarietyoffreeradicalscavengers
(antioxidants).[4]

TNFalphablockers
Sometypesofarthritismedicationsaredesignedtoreduceinflammationbyinhibitingthetumornecrosisfactoralphapathwaytoimmunecell
activationthesedrugsareknownasTNFalphablockers.Onestudy[24]foundthatthreedifferentTNFalphablockersaffordedaslightreductionin
antibodypresentationaftervaccinationagainstinfluenzainagroupofimmunocompromisedpatients,howeveritdidnotsignificantlyaffectpatients'
protectivefactorgainedfrominoculation.MoreresearchisnecessarybeforeanyconclusionsmaybemaderegardingtheefficacyofTNFalphablockers
atreducingtheeffectsofacytokinestorminhospitalizedflupatients.

Seealso
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Catastrophicantiphospholipidsyndrome
VitaminDandrespiratorytractinfections
1993FourCornershantavirusoutbreak

References
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key=Systemic%20inflammatory%20response%20syndrome).Copewithcytokines.de.Retrieved20130417.
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Proc.2(25):12161217.PMID8442093(https://www.ncbi.nlm.nih.gov/pubmed/8442093).
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CytokineProducingCellsintheLungTissuesofPatientswithFatalHantavirusPulmonarySyndrome".TheJournalofInfectiousDiseases179(2):295302.
doi:10.1086/314597(http://dx.doi.org/10.1086%2F314597).PMID9878011(https://www.ncbi.nlm.nih.gov/pubmed/9878011).
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Externallinks
ACriticalRoleforOX40inTCellmediatedImmunopathologyduringLungViralInfection(http://www.jem.org/cgi/content/full/198/8/1237)
CytokineStormandtheInfluenzaPandemic(http://www.cytokinestorm.com)
Retrievedfrom"http://en.wikipedia.org/w/index.php?title=Cytokine_storm&oldid=630078043"
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