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Pathophysiologyandtreatmentoffeverinadults
Authors: ReuvenPorat,MD,CharlesADinarello,MD
SectionEditor: PeterFWeller,MD,FACP
DeputyEditor: AnnaRThorner,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2016.|Thistopiclastupdated:Jul26,2016.
INTRODUCTIONFever,anelevationincorebodytemperatureabovethedailyrangeforanindividual,isa
characteristicfeatureofmostinfectionsbutisalsofoundinanumberofnoninfectiousdiseasessuchas
autoimmuneandautoinflammatorydiseases.Definitionsofnormalbodytemperature,thepathophysiologyof
fever,theroleofcytokines,andthetreatmentoffeverinadultswillbereviewedhere.Feverofunknownoriginin
adults,drugfever,andthetreatmentoffeverininfantsandchildrenarediscussedseparately.(See"Approachto
theadultwithfeverofunknownorigin"and"Etiologiesoffeverofunknownorigininadults"and"Drugfever"and
"Feverininfantsandchildren:Pathophysiologyandmanagement".)
NORMALBODYTEMPERATURENormalbodytemperaturevariesoverthecourseoftheday,controlledin
thethermoregulatorycenterlocatedintheanteriorhypothalamus.Thebodyisnormallyabletomaintainafairly
steadytemperaturebecausethehypothalamicthermoregulatorycenterbalancestheexcessheatproduction,
derivedfrommetabolicactivityinmuscleandtheliver,withheatdissipationfromtheskinandlungs.However,
facedwithenvironmentalextremes,humanscannotmaintainthenarrowdailyvariationofbodytemperature
withouttheaidofclothingandprotectiveenvironments[1].
Peripheralmethodsofmonitoringtemperature(tympanicmembrane,temporalartery,axillary,andoral
thermometry)arenotasaccurateascentralmethods(pulmonaryarterycatheter,urinarybladder,esophageal,
andrectalthermometry)[2],butcentralmethodsarelesspracticalthanperipheralmethods.
In1992,adetailedstudyoftherangeoforaltemperaturereadingsin148healthymenandwomenaged18to40
wasreportedusingover700measurements[3].Oraltemperaturesinthecohortrangedfrom35.6C(96.0F)to
38.2C(100.8F)withameanof36.80.4C(98.20.7F).Lowlevelsoccurredat6AMandhigherlevelsat4
to6PM.Themaximumnormaloraltemperatureat6AMis37.2C(98.9F),andthemaximumlevelat4PMis
37.7C(99.9F),bothvaluesdefiningthe99thpercentileforhealthysubjects.Fromthesestudies,amorning
reading>37.2C(98.9F)oranafternoontemperatureof>37.7C(99.9F)wouldbeconsideredafever.Rectal
temperaturesaregenerally0.6C(1.0F)higherthanoralreadings.Oralreadingsarelowerprobablybecauseof
mouthbreathing,whichisparticularlyimportantinpatientswithrespiratoryinfectionsandrapidbreathing.
Temperaturemeasurementsfromtheloweresophagusreflectcoretemperature,andtympanicmembrane
temperaturereadingsarealsoclosetocoretemperature.
Thenormaldailytemperaturevariationistypically0.5C(0.9F).However,insomeindividualsrecoveringfroma
febrileillness,thisdailyvariationcanbeashighas1.0C.Duringafebrileillness,dailylowandhightemperature
readingsaremaintainedbutathigherlevels.
Inmenstruatingwomen,themorningtemperatureisgenerallylowerduringthetwoweekspriortoovulation,rising
byabout0.6C(1.0F)withovulationandremainingatthatleveluntilmensesoccur.Seasonalvariationinbody
temperaturehasbeendescribed,butthismayreflectametabolicchangeandisnotacommonobservation.
Elevationinbodytemperatureoccursduringthepostprandialstate,butthisisnotfever.Pregnancyand
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endocrinologicdysfunctionalsoaffectbodytemperature.Thedailytemperaturevariationappearstobefixedin
earlychildhood.Ontheotherhand,itiswellestablishedthattheabilitytodevelopfeverinolderadultsisimpaired
andthatbaselinetemperatureinolderadultsislowerthaninyoungeradults[4].Thus,olderadultpatientswith
severeinfectionsmayonlydisplayamodestfever.
FEVER,HYPERTHERMIA,ANDHYPERPYREXIAFever,hyperthermia,andhyperpyrexiaarenot
synonymousterms.
FeverFeverisregulatedatthelevelofthehypothalamus.Thethermostatdevice,whichregulatesthe
temperatureinahome,iscomparabletothewaythehypothalamuscontrolscorebodytemperature.The
thermostatsettinginthehypothalamicthermoregulatorycentershiftsupwardsduringafever,forexample,from
37to39C.Inotherwords,duringfever,the"setpoint"inthehypothalamusshiftsupwardfromthe
"normothermia"settingtofebrilelevels,similartothewaythehomethermostatisresettoahigherlevelinorder
toraisetheambienttemperatureinaroom.ElevatedlevelsofprostaglandinE2(PGE2)inthehypothalamus
appeartobethetriggerforraisingthesetpoint.Oncethehypothalamicsetpointisraised,thisactivatesneurons
inthevasomotorcentertocommencevasoconstrictionandwarmsensingneuronstoslowtheirfiringrateand
increaseheatproductionintheperiphery.
Thevasoconstrictionproducesanoticeablecoldsensationinthehandsandfeet.Bloodisshuntedawayfromthe
peripherytotheinternalorgans,essentiallydecreasingheatlossfromtheskin,andthepatientfeelscold.For
mostfevers,thisissufficienttoraisecorebodytemperature1oreven2C.
Atthesametime,thermogenesisinfatcontributestoincreasingcoretemperature.Thisistermed"nonshivering
thermogenesis."Atbirth,highlythermogenicbrownfatispresentbutrapidlydecreaseswithintheneonatal
period.Itisunclearhowmuchbrownfatremainsasasourceofheatproductionintheadult.(See"Pathogenesis
ofobesity",sectionon'Brownadiposetissueandbodytemperature'.)
Thermogenesisineitherthefatormuscletakesplacebyuncouplingproteins,whichreleaseadenosine
triphosphate(ATP)andheat.Thecombinationofheatconservationandthermogenesisaccountsforthemajority
offever.Thereisalsoincreasedheatproductionfromtheliver.
Shiveringmaybeinitiatedinordertoincreaseheatproductionfromthemuscles,butshiveringisnotrequiredfor
mostfevers.Shiveringappearstotakeplacewhenthereisarapidrisetomatchthenewfebrilesetpoint.
Inhumans,behavioralinstinctsassistinraisingbodytemperaturewithreductionofexposedsurfaces.Subjects
seekwarmrooms,addextraclothing,andreduceactivity.Theprocessesofheatconservation(vasoconstriction),
heatproduction(shivering,nonshiveringthermogenesis,increasedmetabolicactivity),andbehavioralchanges
continueuntilthetemperatureofthebloodbathingthehypothalamicneuronsmatchesthenewsetting.When
thatpointisreached,thehypothalamusnowmaintainsthenewsettingatthefebrileleveltemperature,justasit
doesatthenormothermiclevel.Infact,studieshaveshownthatthemechanismsofbalancingheatlossandheat
productioninfeverarethesameasintheafebrilestate.
Whenthehypothalamicsetpointisresetdownward,theprocessesofheatlossareacceleratedthrough
vasodilationandsweating.Theresettingofthesetpointdownwardcanbeduetoeitherareductioninthe
concentrationofpyrogensortheuseofantipyretics.Behavioralchangesarealsotriggeredatthistimeand
removalofinsulatingclothingorbeddingtakesplace.Lossofheatbysweatingandvasodilationcontinueuntilthe
temperatureofthebloodsupplyingthehypothalamusmatchesthelowersetting.
Insomerarepatients,thehypothalamicsetpointiselevatedowingtolocaltrauma,hemorrhage,tumor,or
intrinsichypothalamicmalfunction.Theterm"hypothalamicfever"issometimesusedtodescribeelevated
temperaturecausedbyabnormalhypothalamicfunction.However,themajorityofpatientswithhypothalamic
damagehavehyponothyperthermia.Thesepatientsdonotrespondproperlytominorenvironmental
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temperaturechangesinthiscondition,coretemperaturefallsuponexposuretoslightdropsintemperature,
whereasnormalhypothalamicfunctioncanmaintaincoretemperatureforafewhours.Inthoseveryfewpatients
inwhomelevatedcoretemperatureissuspectedtobeduetohypothalamicdamage,thediagnosisdependsupon
thedemonstrationofotherabnormalhypothalamicfunctions,suchasproductionofhypothalamicreleasing
factors,abnormalresponsetocold,andabsenceofcircadiantemperatureandhormonalrhythms.
HyperthermiaAlthoughthevastmajorityofpatientswithelevatedbodytemperaturehavefever,therearea
fewinstancesinwhichanelevatedtemperaturerepresentshyperthermia.Theseincludeheatstrokesyndromes,
certainmetabolicdiseases,andtheeffectsofpharmacologicagentsthatinterferewiththermoregulation.In
contradistinctiontofever,thesettingofthethermoregulatorycenterduringhyperthermiaremainsunchangedat
normothermiclevels,whilebodytemperatureincreasesinanuncontrolledfashionandoverridestheabilitytolose
heat.Exogenousheatexposureandendogenousheatproductionaretwomechanismsbywhichhyperthermia
canresultindangerouslyhighinternaltemperatures.(See"Severenonexertionalhyperthermia(classicheat
stroke)inadults".)
Itisimportanttomakethedistinctionbetweenfeverandhyperthermia.Hyperthermiacanberapidlyfatal,andits
treatmentdiffersfromthatoffever.Despitephysiologicandbehavioralcontrolofbodytemperature,excessive
heatproductioncaneasilyoccur.Asanexample,overinsulatingclothingcanresultinelevatedcoretemperature.
Hyperthermiaismostoftenobservedinpersonswhoworkorexerciseinhotenvironmentsandproduceheat
fasterthantheperipheralmechanismscanloseit.Hypohydrationisamajorcauseofhyperthermia.
Certainmetabolicdiseasessuchashyperthyroidismcanresultinmildelevationsofcoretemperature.Theeffects
ofsomepharmacologicagents(atropine)thatinterferewiththermoregulationbyblockingsweatingorvasodilation
canalsoraisecoretemperature.Thesesyndromesrepresenthyperthermiabecausetheytakeplaceinthe
presenceofanormalhypothalamicsetpoint.Therecreationaldrug"ecstasy"(3,4
methylenedioxymethamphetamine)produceshyperthermia,whichisduetoalossinheatdissipation
(vasoconstriction)andheatproductionviauncouplingprotein3.
Adiagnosisofhyperthermiaisoftenmadebecauseofaprecedinghistoryofheatexposureoruseofcertain
drugsthatinterferewithnormalthermoregulation.Thereisnorapidwaytodifferentiateelevatedcore
temperatureduetofeverfromhyperthermia.Theimmediateeventspriortotheonsetofhyperthermiausually
playanimportantroleindeterminingitscause.However,physicalexaminationcanassisttheclinicianinsome
formsofhyperthermiaforexample,theskinishotbutdryinheatstrokesyndromesandinpatientstakingdrugs
thatblocksweating.Antipyreticsdonotreducetheelevatedtemperatureinhyperthermiawhereasthereisusually
somedecreaseinbodytemperatureinpatientswithfeveroreven"hyperpyrexia"afteradequatedosesofeither
aspirinoracetaminophen.
Hyperthermiacanalsooccurwhencertainanestheticsproducearapiduncouplingofoxidativephosphorylationin
susceptibleindividuals[5].Thisisknownasmalignanthyperthermiaandisoftenfatal.Anotherformof
hyperthermiaresultsinpatientstakingcertainneurolepticdrugsandiscalled"neurolepticmalignantsyndrome"
[6,7].(See"Severenonexertionalhyperthermia(classicheatstroke)inadults"and"Neurolepticmalignant
syndrome".)
Anotherpossiblecauseofhyperthermiaistheserotoninsyndrome,whichmayresultfromanycombinationof
drugsthathastheneteffectofincreasingserotonergicneurotransmission(table1).Thesyndromeisclassically
associatedwiththesimultaneousadministrationoftwoserotonergicagents,butitcanoccurafterinitiationofa
singleserotonergicdrugorincreasingthedoseofaserotonergicdruginindividualswhoareparticularlysensitive
toserotonin.(See"Serotoninsyndrome(serotonintoxicity)".)
HyperpyrexiaHyperpyrexiaisthetermforanextraordinarilyhighfever(>41.5C),whichcanbeobservedin
patientswithsevereinfectionsbutmostcommonlyoccursinpatientswithcentralnervoussystem(CNS)
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hemorrhages.Althoughantipyreticsreducethebodytemperatureinhyperpyrexicfever,coolingblanketsandcool
waterspongingarerecommendedtoaccelerateperipheralheatlosses.However,peripheralcoolingwithcooling
blanketscanbecounterproductiveintheabsenceofantipyreticssincecoldreceptorsintheskintriggerreactive
vasoconstriction,thusreducingheatlossmechanisms.
PYROGENSThetermpyrogenisusedtodescribeanysubstancethatcausesfever.Pyrogensareeither
exogenousorendogenous.Endogenouspyrogensbelongtotheclassofbiologicallyactiveproteinscalled
cytokines.Feverproducingcytokinesaremorepreciselytermedpyrogeniccytokines.
ExogenouspyrogensExogenouspyrogens,derivedfromoutsidethehost,aremainlymicrobesortheir
products,suchastoxins.Theclassicexampleofanexogenouspyrogenisthelipopolysaccharideendotoxin
producedbyallgramnegativebacteria.Endotoxinsarepotentsubstancesnotonlyaspyrogensbutalsoas
inducersofvariouspathologicchangesobservedingramnegativeinfections[8].Endotoxinsbelongtoa
classificationofmicrobialproductstermedtolllikereceptor(TLR)ligands.TLRevolvedwithinsects,andthe
mammalianhomologuesonmacrophagesbindmicrobialproductsfromseveralbacteriaandfungiandresultin
activationofthecell.Therefore,TLRrecognitionofbacteriaexplainshowinfectionscausefever.Asdiscussed
below,theactivationofmacrophagesviatheTLRonmammaliancellsresultsintheproductionoffeverproducing
cytokines[9].
Anothergroupofbacterialsubstancesthatarepotentpyrogensisproducedbygrampositiveorganisms.The
toxicshocksyndrometoxin(TSST1)isassociatedwithstrainsofStaphylococcusaureusisolatedfrompatients
withthetoxicshocksyndrome(TSS)[10,11].TSST1andotherenterotoxinsfromS.aureusandexotoxinsfrom
groupAStreptococcusactbothasdirecttoxinsbutalsoserveas"superantigens"[12,13].Superantigensappear
toplayaroleinthepathogenesisofseveregrampositiveinfectionsbyinteractingwiththemajor
histocompatibilitycomplex(MHC)IIandanumberofTcellsubsets[14,15]toreleasepyrogeniccytokines.Like
theendotoxinsfromgramnegativebacteria,thetoxinsproducedbystaphylococciandstreptococciproducefever
inexperimentalanimalswheninjectedintravenouslyinthesubmicrogram/kgrange.Ofconsiderableimportance
isthefactthatendotoxinisahighlypyrogenicmoleculeinhumanssince2to3ng/kgproducesfeverand
generalizedsymptomsofmalaiseinvolunteers[16].
PyrogeniccytokinesPyrogeniccytokinesarespecificcytokinesproduceduponactivationofTLR[3].
Cytokinesaresmallproteins(molecularweight10to20,000Daltons)thatregulateimmune,inflammatory,and
hematopoieticprocesses(see"Roleofcytokinesintheimmunesystem").Asanexample,stimulationof
lymphocyteproliferationduringanimmuneresponsetovaccinationistheresultofvariouscytokinesincluding
interleukin(IL)2,IL4,andIL6.Acytokinecalledgranulocytecolonystimulatingfactor(GCSF)stimulates
granulocytopoiesisinthebonemarrow(see"Introductiontorecombinanthematopoieticgrowthfactors").Some
cytokinescausefeverandhencearecalledpyrogeniccytokines.
Fromahistoricalpointofview,thefieldof"cytokinebiology"beganwithlaboratoryinvestigationsintothecauseof
feverbyproductsofactivatedleukocytesinthe1940s.Thesefeverproducingmoleculeswerecalled
"endogenouspyrogens"[17].Whenendogenouspyrogenswerepurifiedfromactivatedleukocytes,theywere
showntopossessabroadrangeofbiologicalactivities,affectingallorgansystems.Cytokinescanaffectorgan
functionduringdisease,butunlesschallengedbyinfectionortrauma,cytokinesdonotseemtoplayarolein
normalphysiologicfunctions,includingtemperatureregulationorendocrinefunctions.
Thereareseveralpyrogeniccytokines,namelyIL1,IL6,tumornecrosisfactor(TNF),andciliaryneurotrophic
factor[18,19].Otherslikelyexist.Interferon(IFN)alphacanalsobeconsideredapyrogeniccytokinesinceit
producesfever.Infact,IL1,IL6,andTNFhaveeachbeeninjectedintohumansandhaveproducedfever.IL1
andTNFareparticularlypyrogenic,resultinginfeveratdosesaslowas10ng/kg(eithersubcutaneouslyor
intravenously)[18].IL6isalsopyrogenicbutmicrogram/kgratherthannanogram/kgdosesofIL6areneededto
producefeverinhumans.Nevertheless,largeamountsofIL6circulateinnearlyallfebrilediseasesandIL6
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inducedbyIL1orthecombinationofIL1plusTNFlikelyaccountsfortheclinicalfevermostoftenmeasured.
MicewithoutthegeneforIL6donotdevelopfeverduringbacterialinfection.Thus,inmostinflammatoryand
infectiousdiseases,lowconcentrationsofIL1andTNFinducelargeamountsofIL6,anditistheIL6thatlikely
triggersthehypothalamiccentersforcontrolofbodytemperature.Thus,inadditiontoexogenouspyrogensfrom
microbialsources,endogenouspyrogeniccytokinescausefever.Eachcytokineiscodedbyaseparategeneand
eachpyrogeniccytokinehasbeenshowntocausefevernotonlyinlaboratoryanimalsbutalsowheninjectedinto
humans.
Awidespectrumofexogenouspyrogensinducesthesynthesisandreleaseofpyrogeniccytokinesviaactivation
oftheTLRs.Mostoftheexogenouspyrogenicsubstancescanberecognizedfromtheirbacterialorfungal
sources.Virusesinducepyrogeniccytokinesbyinfectingcells.However,intheabsenceofmicrobialinfection,
feverisoftenpresentinavarietyofdiseases.Inflammation,trauma,orantigenantibodycomplexesinducethe
productionofIL1,TNF,andIL6,andeachorallthreecytokinestriggerthehypothalamustoraisethesetpoint
tofebrilelevels[20].Thecellularsourcesofpyrogeniccytokinesareprimarilymonocytes,neutrophils,and
lymphocytes,althoughmanydifferentcellscansynthesizethesemolecules,whenstimulated.
ELEVATIONOFTHEHYPOTHALAMICSETPOINTBYCYTOKINESDuringfever,hypothalamictissueand
thirdcerebralventriclelevelsofprostaglandinE2(PGE2)areelevated[2123].Thehighestconcentrationsof
PGE2arenearthecircumventricularvascularorgans(organvasculosumlaminaterminalis,OVLT)whichare
networksoffenestratedcapillariessurroundingthehypothalamicregulatorycenters[24].Destructionofthese
organsreducestheabilityofpyrogenstoproducefever.However,moststudiesinanimalshavenotbeenableto
showthatpyrogeniccytokinespassfromthecirculationintothebrainsubstanceitself[18].Thus,itappearsthat
bothexogenousandendogenouspyrogensinteractwiththeendotheliumofthesecapillaries,whichisprobably
thefirststepininitiatingfever.
Theinteractionofpyrogenswiththehypothalamiccircumventricularvascularendotheliumisthefirststepin
raisingthesetpointtofebrilelevels.ThefollowingAlgorithmillustratesthekeyeventsintheproductionoffever
(algorithm1).Asshown,severalcellshavethepotentialtoproducepyrogeniccytokines.Pyrogeniccytokines
suchasinterleukin(IL)1,IL6,andtumornecrosisfactor(TNF)arethenreleasedfromthecellandenterthe
systemiccirculation.Althoughthesystemiceffectsofthesecirculatingcytokinesinitiatefeverbytheirabilityto
inducethesynthesisofPGE2,theyalsoinducePGE2inperipheraltissues[18].TheincreaseinPGE2inthe
peripheryaccountsforthenonspecificmyalgiasandarthralgiasthatoftenaccompanyfever.However,itisthe
inductionofPGE2inthebrainthatstartstheprocessofraisingthehypothalamicsetpointforcoretemperature.
TherearefourreceptorsforPGE2,andeachsignalsthecellindifferentways.Studiesinmicedemonstratedthat
thethirdPGE2receptor(EP3)isessentialfortheproductionoffevermicedeficientinthegeneforthisreceptor
donotdevelopfeverfollowingtheinjectionofIL1orendotoxin[25].DeletionoftheotherPGE2receptorgenes
leavesthefevermechanismintact.AlthoughPGE2isessentialforfever,PGE2isnotaneurotransmitter.
However,releaseofPGE2fromthebrainsideofthehypothalamicendotheliumtriggersthePGE2receptoron
glialcells,andthisresultsintherapidreleaseofcyclicadenosinemonophosphate(cAMP),whichisa
neurotransmitter[18].
AsshowninthefollowingAlgorithm,releaseofcAMPfromtheglialcellsactivatesneuronalendingsfromthe
thermoregulatorycenterthatextendintothearea(algorithm1).TheelevationofcAMPisthoughttoaccountfor
changesinthehypothalamicsetpointeitherdirectlyorindirectlybyinducingthereleaseofmonoamine
neurotransmitters.ReceptorsforendotoxinsharemanysimilaritiestothoseofIL1,and,hence,activationof
endotoxinreceptorsonthehypothalamicendotheliumalsoresultsinPGE2productionandfever[26].
ProductionofcytokinesinthecentralnervoussystemSeveralviraldiseasesproduceactiveinfectionin
thebrain.GlialandpossiblyneuronalcellssynthesizeIL1,TNF,andIL6[27].Ciliaryneurotrophicfactor(CNTF)
isalsosynthesizedbyneuralaswellasneuronalcells.Thesecytokinesproducedwithinthebrainitselfappearto
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playaroleintheproductionoffever.Whenacytokineisinjecteddirectlyintothebrainofexperimentalanimals,
thedoserequiredtocausefeverisseveralordersofmagnitudelowercomparedwithintravenousinjection.Thus,
itappearsthatcentralnervoussystem(CNS)productionofthesecytokinescanraisethehypothalamicsetpoint,
bypassingthecircumventricularorgansinvolvedinthefeverthatresultsfromcirculatingcytokines.Local
productionofcytokinesintheCNSmayaccountforthehyperpyrexiaofCNShemorrhagenotedabove.
Doesanticytokinetherapymaskinfectionbypreventingfever?Anincreasingnumberofpatientswith
autoimmuneorautoinflammatorydiseasesarebeingtreatedwithbiologicagents.Thesearemostlyanticytokine
therapies,suchasIL1receptorinhibitors,TNFalphainhibitors,anIL6receptorinhibitor,antiIL12antibodies,
orantiIL23antibodies.Anticytokinetherapyhasthedistinctdrawbackofloweringhostdefenseagainstinfection
[28].InthecaseofneutralizingantibodiestoTNFalphabyinfliximaboradalimumab,opportunisticinfections
suchasMycobacteriumtuberculosiswithdisseminationhavebeenreported[29,30].Thesolublereceptorfor
TNFalpha,etanercept,isalsoassociatedwithopportunisticinfections,butlesssocomparedwiththeneutralizing
antibodies[30,31].Innearlyallreportsofinfectionsassociatedwiththeuseofanticytokinetherapies,feverisone
ofthepresentingsigns.However,itislikelythatfeverinthesepatientsisbluntedinmuchthesamewayasdoes
therapywithhighdoseglucocorticoids.(See"Tumornecrosisfactoralphainhibitorsandmycobacterialinfections"
and"Tumornecrosisfactoralphainhibitors:Bacterial,viral,andfungalinfections".)
Theabilityofapatienttopresentwithfeverdespitebeingtreatedwithananticytokineagentisduetotheother
cytokinesthatcancausefever(eg,IL1,TNFalpha,IL6,interferons,andothers)thatarenotaffectedbya
specificanticytokineagent[9].Forexample,inapatientwithstaphylococcalskininfectionbeingtreatedwithanti
TNFalphaforrheumatoidarthritis,thethreepyrogeniccytokines,TNFalpha,IL1,andIL6,areproduced,but
onlyTNFalphaisblockedbytheantiTNFalphaantibody.Thus,thefevermaybeduetoIL1andIL6.Another
explanationisthatmicrobialproductsarecapableofinducingbrainPGE2directlyviatheirtolllikereceptor(TLR).
InthecaseofthepatientwithstaphylococcalskininfectionbeingtreatedwithantiTNFalphaforrheumatoid
arthritis,staphylococcalproductsmayreachtheTLRsofthehypothalamicendotheliumandtriggerCOX2
expression.
Anticytokineagentsdramaticallyreducefeverinautoimmuneandautoinflammatorydiseases.Someautoimmune
diseasesandmostautoinflammatorydiseaseshaverecurrentfeverasaprominentpresentingsign.The
autoinflammatorydiseasesarediseasesinwhichthemonocyteratherthanthelymphocyteplaysapathological
role.TheautoinflammatorydiseasesincludeadultandjuvenileStill'sdisease,familialMediterraneanfever,hyper
IgDsyndrome,familialcoldinducedautoinflammatorysyndrome,neonatalonsetmultisystemautoinflammatory
disease,Blau'ssyndrome,Schnitzler'ssyndrome,MuckleWellssyndrome,andTNFreceptorassociatedperiodic
syndrome.Theyarecharacterizedbyrecurrentfevers,neutrophilia,andserosalinflammation.Thefever
associatedwiththesediseasesisdramaticallyreducedbyblockingIL1withtheIL1receptorantagonist,
casapse1inhibitors,orantiIL1betaneutralizingantibodies[3237].Thefebrilecourseofapatientwithspiking
dailyfeversduetoadultonsetStill'sdiseaseareunaffectedbydailyprednisonebutrapidlyfallswithasingledose
oftheIL1receptorantagonist(figure1)[32].AlthoughthefeverinautoinflammatorydiseasesismediatedbyIL
1beta,patientsalsorespondtoantipyretics.
MECHANISMSOFANTIPYRETICAGENTSThesynthesisofprostaglandinE2(PGE2)dependsuponthe
constitutivelyexpressedenzymecyclooxygenase.Thesubstrateforcyclooxygenaseisarachidonicacidreleased
fromthecellmembrane,andthisreleaseistheratelimitingstepinthesynthesisofPGE2.Inhibitorsof
cyclooxygenases(eitherCOX1orCOX2)arepotentantipyretics[38].Thereisadirectcorrelationbetweenthe
antipyreticpotencyofvariousdrugsandtheirabilitytoinhibitbraincyclooxygenase[39].(See"NSAIDs:
Mechanismofaction".)
Acetaminophenisapoorcyclooxygenaseinhibitorinperipheraltissueanddoesnotdisplaynoteworthy
antiinflammatoryactivityhowever,acetaminophenisoxidizedinthebrainbythep450cytochromesystem,and
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theoxidizedforminhibitscyclooxygenaseactivity.
Thereisnodifferencebetweenoralaspirinandacetaminopheninreducingfeverinhumans.Nonsteroidal
antiinflammatoryagents(NSAIDs),suchasnaproxenoribuprofen,arealsoexcellentantipyreticsandcanbe
usedforthispurpose.(See"NSAIDs:Mechanismofaction".)
ThereappearstobenoroleforPGE2innormalthermoregulationbaseduponobservationsthatchronicuseof
aspirinorNSAIDsinarthritisdoesnotreducenormalcorebodytemperature.
Corticosteroidsarealsoeffectiveantipyretics,whichactattwolevels[40,41]:
Similartothecyclooxygenaseinhibitors,corticosteroidsreducePGE2synthesisbyinhibitingtheactivityof
phospholipaseA2,whichisneededtoreleasearachidonicacidfromthemembrane.
CorticosteroidsblockthetranscriptionofthemRNAforthepyrogeniccytokines.
Drugsthatinterferewithvasoconstriction(eg,phenothiazines)canalsoactasantipyreticsascandrugsthatblock
musclecontractions.However,thesearenottrueantipyreticssincetheycanalsoreducecoretemperature
independentlyofhypothalamiccontrol.
TREATMENTOFFEVERANDHYPERTHERMIAElevatedcoretemperature,whetherfeverorhyperthermia,
increasesthedemandforoxygenandcanaggravatepreexistingcardiacorpulmonaryinsufficiency.Forevery
increaseofonedegreeabove37C,thereisa13percentincreaseinO2consumption.Inaddition,elevated
temperaturecaninducementalchangesinpatientswithorganicbraindisease.Althougharapidreductionin
elevatedcoretemperatureduetohyperthermiaismandatory,treatmentoffeverisoftenadebatedissue.
DecisiontotreatfeverThevastmajorityoffeversareassociatedwithselflimitedinfections,mostcommonly
ofaviralorigin,wherethecauseofthefeveriseasilyidentified.Thedecisiontoreducefeverwithantipyretics
assumesthatthereisnodiagnosticbenefitofallowingthefevertopersist.However,therearerareclinical
situationsinwhichobservationofthepatternoffevercanbehelpfuldiagnostically.Asanexample,thedailyhighs
andlowsofnormaltemperatureareexaggeratedinmostfevers,butthesefluctuationsmaybereversedin
typhoidfeveranddisseminatedtuberculosis.Temperaturepulsedissociation(relativebradycardia)isseenin
typhoidfever,brucellosis,leptospirosis,somedruginducedfevers,andfactitiousfever.Inhealthysubjects,the
temperaturepulserelationshipislinearwithanincreaseinheartrateof4.4beats/minuteforeach1C(2.44
beats/minuteforeach1F)riseincoretemperature[9].Fevermaynotbepresentduringinfectioninnewborns,
olderadults,patientswithchronicrenalfailure,andinpatientstakingcorticosteroidshypothermia,infact,can
occur.Hypothermiacanalsobeobservedinpatientswithsepticshock.
Somefebrilediseaseshavecharacteristicpatterns.Amongthesearemalariaandcyclicneutropenia.However,
mostofthefebrileillnessesthatarethoughttoexhibitaspecifictimerelatedpattern(eg,Hodgkinlymphoma)are
infact,uponcloseexamination,notreliableindicatorsorareofnodiagnosticvalue.Asanexample,thereisno
periodicityoffeverinpatientswithfamilialMediterraneanfever.(See"Clinicalmanifestationsanddiagnosisof
familialMediterraneanfever".)
Therearemanyreportsonthebeneficialeffectofelevatedtemperature(febrilerange)inanimalsduring
infectiouschallenges[42].Inaddition,invitroculturesofanimalorhumancellsatelevatedtemperatureare
supportiveofaheightenedimmuneresponseaswellasincreasedbactericidalkilling.However,thereareno
studiesdemonstratingthatfeveritselffacilitatestherecoveryfrominfectionoractsasanadjuvanttotheimmune
system.Infact,peripheralprostaglandinE2(PGE2)productionisapotentimmunosuppressantand,during
influenzavaccination,treatmentwithanonsteroidalantiinflammatoryagent(NSAID)increasestheantiinfluenza
antibodylevel[43].Hence,treatingfeveranditssymptomsdoesnoharmanddoesnotslowtheresolutionof
commonviralandbacterialinfections.
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TreatingfeverReducingfeverwithantipyreticsalsoreducessystemicsymptomsofheadache,myalgias,and
arthralgias.AspirinandNSAIDsareexcellentoralagentsbutcauseunwantedsideeffectsonplateletsandthe
gastrointestinaltract.Thus,acetaminophenisgenerallythepreferredantipyretic.Thecombinationofaspirinand
acetaminophenismoreeffectivethaneitheralone.
Incasesofhyperpyrexia,theuseofcoolingblanketsfacilitatesthereductionoftemperature,butcoolingblankets
shouldnotbeusedwithoutantipyretics.Theobjectivesintreatingfeveraretofirstreducetheelevatedsetpoint
ofthehypothalamusandthentofacilitateheatloss.Ifthepatientcannottakeoralantipyretics,parenteral
preparationsofNSAIDsorrectalsuppositoriesofvariousantipyreticscanbeused.Sincehyperpyrexiamayoccur
inpatientswithCNSdiseaseortrauma,reducingcoretemperaturehelpstoreducetheilleffectofhigh
temperatureonthebrain.
TreatinghyperthermiaThetreatmentofhyperthermiaisprimarilytargetedatrapidreductionofbody
temperaturebyphysicalmeans.Itisalsocrucialtoidentifytheunderlyingcauseofthehyperthermia,since
managementvariesdependingontheetiology.Antipyreticsareofnouseinreducingbodytemperaturedueto
hyperthermia.Rapidreductioninbodytemperaturecanbeaccomplishedbycoolortepid(20C),notcold,
bathing,preferablyusingdampsponges.Submersionshouldbeavoided,sothatbodyheatlossbyevaporation
canoccur.Alcoholaddsnothingtotepidorcoolwatersponging.Coolingblanketsareofpotentialdanger
becauseofexcessvasoconstrictionpreventingheatlossfromtheskinssurface.Intravenousfluidsshouldbe
administeredfordehydration,butifcoolfluidsareused,avoidacentrallineclosetotheheart.
Themanagementofhyperthermia,dependingontheunderlyingcause,isdiscussedindetailseparately.(See
"Severenonexertionalhyperthermia(classicheatstroke)inadults"and"Malignanthyperthermia:Clinical
diagnosisandmanagementofacutecrisis"and"Neurolepticmalignantsyndrome"and"Serotoninsyndrome
(serotonintoxicity)"and"MDMA(ecstasy)intoxication".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandare
comfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopic(see"Patienteducation:Whentoworryaboutafeverinadults(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Fever,anelevationincorebodytemperatureabovethedailyrangeforanindividual,isacharacteristic
featureofmostinfectionsbutisalsofoundinanumberofnoninfectiousdiseasessuchasautoimmuneand
autoinflammatorydiseases.(See'Introduction'above.)
Normalbodytemperatureislowintheearlymorningandhighinevening,varying0.5C(0.9F)overthe
courseoftheday,controlledinthethermoregulatorycenterlocatedintheanteriorhypothalamus.However,
insomeindividualsrecoveringfromafebrileillness,thisdailyvariationcanbeashighas1.0C.Duringa
febrileillness,dailylowandhightemperaturereadingsaremaintainedbutathigherlevels.(See'Normal
bodytemperature'above.)
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Theabilitytodevelopfeverinolderadultsisimpaired,andbaselinetemperatureinolderadultsislowerthan
inyoungeradults.Thus,olderadultpatientswithsevereinfectionsmayonlydisplayamodestfever.(See
'Normalbodytemperature'above.)
Althoughthevastmajorityofpatientswithelevatedbodytemperaturehavefever,thereareafewinstances
inwhichanelevatedtemperaturerepresentshyperthermia.Theseincludeheatstrokesyndromes,certain
metabolicdiseases,andtheeffectsofpharmacologicagentsthatinterferewiththermoregulation.Itis
importanttomakethedistinctionbetweenfeverandhyperthermia.Hyperthermiacanberapidlyfatal,andits
treatmentdiffersfromthatoffever.(See'Hyperthermia'above.)
Hyperpyrexiaisthetermforanextraordinarilyhighfever(>41.5C),whichcanbeobservedinpatientswith
severeinfectionsbutmostcommonlyoccursinpatientswithcentralnervoussystemhemorrhages.(See
'Hyperpyrexia'above.)
Patientswithautoimmunediseasesbeingtreatedwithbiologicagents,suchastumornecrosisfactoralpha
inhibitors,areatincreasedriskforroutineaswellasopportunisticinfections.Inthesepatients,alowgrade
fevermayserveasanearlywarningsignofaseriousinfection.(See'Doesanticytokinetherapymask
infectionbypreventingfever?'above.)
Inhibitorsofcyclooxygenases,suchasaspirinandnonsteroidalantiinflammatoryagents(NSAIDs),are
potentantipyretics.Althoughacetaminophenisapoorcyclooxygenaseinhibitorinperipheraltissueanddoes
notdisplaynoteworthyantiinflammatoryactivity,acetaminophenisanexcellentantipyretic.Acetaminophenis
oxidizedinthebrainbythep450cytochromesystem,andtheoxidizedforminhibitscyclooxygenaseactivity.
Thereisnodifferencebetweenaspirinandacetaminopheninreducingfever.(See'Mechanismsof
antipyreticagents'above.)
ReducingfeverwithaspirinorNSAIDsalsoreducessystemicandlocalsymptomsofheadache,myalgias,
andarthralgiasbutcausesunwantedsideeffectsonplateletsandthegastrointestinaltract.Thus,
acetaminophenisgenerallythepreferredantipyretic.(See'Treatingfever'above.)
Elevatedcoretemperature,whetherfeverorhyperthermia,increasesthedemandforoxygenandcan
aggravatepreexistingcardiacorpulmonaryinsufficiency.(See'Treatmentoffeverandhyperthermia'above.)
Thevastmajorityoffeversareassociatedwithselflimitedinfections,mostcommonlyofaviralorigin,where
thecauseofthefeveriseasilyidentified.Thedecisiontoreducefeverwithantipyreticsassumesthatthereis
nodiagnosticbenefitofallowingthefevertopersist.However,therearerareclinicalsituationsinwhich
observationofthepatternoffevercanbehelpfuldiagnostically.(See'Decisiontotreatfever'above.)
Thegoaloftreatingofhyperthermiaisprimarilytorapidlyreducebodytemperaturebyphysicalmeans.Itis
alsocrucialtoidentifytheunderlyingcauseofthehyperthermia,sincemanagementvariesdependingonthe
etiology.Antipyreticsareofnouseforhyperthermia.(See'Treatinghyperthermia'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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3.MackowiakPA,WassermanSS,LevineMM.Acriticalappraisalof98.6degreesF,theupperlimitofthe
normalbodytemperature,andotherlegaciesofCarlReinholdAugustWunderlich.JAMA1992268:1578.
4.RoghmannMC,WarnerJ,MackowiakPA.Therelationshipbetweenageandfevermagnitude.AmJMed
Sci2001322:68.
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Nerve200023:4.
6.KaragianisJL,PhillipsLC,HoganKP,LeDrewKK.Clozapineassociatedneurolepticmalignantsyndrome:
twonewcasesandareviewoftheliterature.AnnPharmacother199933:623.
7.GurreraRJ.Sympathoadrenalhyperactivityandtheetiologyofneurolepticmalignantsyndrome.AmJ
Psychiatry1999156:169.
8.BoneRC.Gramnegativesepsis:adilemmaofmodernmedicine.ClinMicrobiolRev19936:57.
9.DinarelloCA.Infection,fever,andexogenousandendogenouspyrogens:someconceptshavechanged.J
EndotoxinRes200410:201.
10.SchlievertPM,ShandsKN,DanBB,etal.Identificationandcharacterizationofanexotoxinfrom
Staphylococcusaureusassociatedwithtoxicshocksyndrome.JInfectDis1981143:509.
11.ParsonnetJ,GillisZA,PierGB.Inductionofinterleukin1bystrainsofStaphylococcusaureusfrompatients
withnonmenstrualtoxicshocksyndrome.JInfectDis1986154:55.
12.DingesMM,OrwinPM,SchlievertPM.ExotoxinsofStaphylococcusaureus.ClinMicrobiolRev200013:16.
13.ProftT,MoffattSL,BerkahnCJ,FraserJD.Identificationandcharacterizationofnovelsuperantigensfrom
Streptococcuspyogenes.JExpMed1999189:89.
14.KumWW,LauplandKB,ChowAW.Defininganoveldomainofstaphylococcaltoxicshocksyndrometoxin
1criticalformajorhistocompatibilitycomplexclassIIbinding,superantigenicactivity,andlethality.CanJ
Microbiol200046:171.
15.BannanJ,VisvanathanK,ZabriskieJB.Structureandfunctionofstreptococcalandstaphylococcal
superantigensinsepticshock.InfectDisClinNorthAm199913:387.
16.WolffSM.Biologicaleffectsofbacterialendotoxinsinman.JInfectDis1973128:733.
17.ATKINSE.Pathogenesisoffever.PhysiolRev196040:580.
18.DinarelloCA.Cytokinesasendogenouspyrogens.JInfectDis1999179Suppl2:S294.
19.ShapiroL,ZhangXX,RuppRG,etal.Ciliaryneurotrophicfactorisanendogenouspyrogen.ProcNatl
AcadSciUSA199390:8614.
20.DinarelloCA.Thermoregulationandthepathogenesisoffever.InfectDisClinNorthAm199610:433.
21.CoceaniF,BishaiI,LeesJ,SirkoS.ProstaglandinE2andfever:acontinuingdebate.YaleJBiolMed
198659:169.
22.DinarelloCA,GattiS,BartfaiT.Fever:linkswithanancientreceptor.CurrBiol19999:R147.
23.CoceaniF,AkarsuES.ProstaglandinE2inthepathogenesisoffever.Anupdate.AnnNYAcadSci1998
856:76.
24.StittJT.Evidencefortheinvolvementoftheorganumvasculosumlaminaeterminalisinthefebrileresponse
ofrabbitsandrats.JPhysiol1985368:501.
25.UshikubiF,SegiE,SugimotoY,etal.ImpairedfebrileresponseinmicelackingtheprostaglandinE
receptorsubtypeEP3.Nature1998395:281.

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26.YangRB,MarkMR,GrayA,etal.Tolllikereceptor2mediateslipopolysaccharideinducedcellular
signalling.Nature1998395:284.
27.BrederCD,DinarelloCA,SaperCB.Interleukin1immunoreactiveinnervationofthehumanhypothalamus.
Science1988240:321.
28.DinarelloCA.DifferencesbetweenantitumornecrosisfactoralphamonoclonalantibodiesandsolubleTNF
receptorsinhostdefenseimpairment.JRheumatolSuppl200574:40.
29.KeaneJ,GershonS,WiseRP,etal.Tuberculosisassociatedwithinfliximab,atumornecrosisfactoralpha
neutralizingagent.NEnglJMed2001345:1098.
30.WallisRS,BroderMS,WongJY,etal.Granulomatousinfectiousdiseasesassociatedwithtumornecrosis
factorantagonists.ClinInfectDis200438:1261.
31.WallisRS,SaliuOY,SoferC,etal.DifferentialeffectsofTNFblockersonTBimmunity.AnnRheumatDis
200564:132.
32.FitzgeraldAA,LeclercqSA,YanA,etal.Rapidresponsestoanakinrainpatientswithrefractoryadultonset
Still'sdisease.ArthritisRheum200552:1794.
33.PascualV,AllantazF,ArceE,etal.Roleofinterleukin1(IL1)inthepathogenesisofsystemiconset
juvenileidiopathicarthritisandclinicalresponsetoIL1blockade.JExpMed2005201:1479.
34.HawkinsPN,LachmannHJ,AgannaE,McDermottMF.SpectrumofclinicalfeaturesinMuckleWells
syndromeandresponsetoanakinra.ArthritisRheum200450:607.
35.HoffmanHM,RosengrenS,BoyleDL,etal.Preventionofcoldassociatedacuteinflammationinfamilial
coldautoinflammatorysyndromebyinterleukin1receptorantagonist.Lancet2004364:1779.
36.SimonA,BodarEJ,vanderHilstJC,etal.Beneficialresponsetointerleukin1receptorantagonistintraps.
AmJMed2004117:208.
37.deKoningHD,BodarEJ,SimonA,etal.BeneficialresponsetoanakinraandthalidomideinSchnitzler's
syndrome.AnnRheumDis200665:542.
38.Vane,JR.Inhibitionofprostaglandinsynthesisasamechanismsofactionfortheaspirinlikedrugs.Nature
1971231:232.
39.FlowerRJ,VaneJR.Inhibitionofprostaglandinsynthetaseinbrainexplainstheantipyreticactivityof
paracetamol(4acetamidophenol).Nature1972240:410.
40.BaileyJM.Newmechanismsforeffectsofantiinflammatoryglucocorticoids.Biofactors19913:97.
41.KnudsenPJ,DinarelloCA,StromTB.Glucocorticoidsinhibittranscriptionalandposttranscriptional
expressionofinterleukin1inU937cells.JImmunol1987139:4129.
42.GreismanLA,MackowiakPA.Fever:beneficialanddetrimentaleffectsofantipyretics.CurrOpinInfectDis
200215:241.
43.HsiaJ,TangT,ParrottM,RogallaK.Augmentationoftheimmuneresponsetoinfluenzavaccineby
acetylsalicylicacid:aclinicaltrialinageriatricpopulation.MethodsFindExpClinPharmacol199416:677.
Topic2734Version18.0

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GRAPHICS
Examplesofdrugsthatcanprecipitateserotoninsyndrome
Mechanism

Drugsinvolved

Increasesserotonin
formation

Tryptophan

Increasesreleaseof
serotonin

Amphetamines(includingdextroamphetamine,methamphetamine)
Cocaine
MDMA(Ecstasy)
Amphetaminederivatives(includingfenfluramine,dexfenfluramine,phentermine)
Levodopa,Carbidopalevodopa(indirectlycausesreleaseserotonin)

Impairsreuptakefromthe
synapticcleftintothe
presynapticneuron

Cocaine
MDMA(Ecstasy)
Meperidine
Tramadol
Pentazocine
Selectiveserotoninreuptakeinhibitors(SSRIs)(includingcitalopram,escitalopram,
fluoxetine,fluvoxamine,paroxetine,andsertraline)
Serotoninnorepinephrinereuptakeinhibitors(SNRIs)(includingdesvenlafaxine,
duloxetine,milnacipran,andvenlafaxine)
Dopaminenorepinephrinereuptakeinhibitors(includingbupropion)
Serotoninmodulators(includingnefazodone,trazodone,andvilazodone)
Tricyclicantidepressants(TCAs)(includingamitriptyline,amoxapine,clomipramine,
desipramine,doxepin,imipramine,maprotiline,nortriptyline,protriptyline,trimipramine)
St.John'swort(Hypericumperforatum)
5HT3receptorantagonists(includingdolasetron,granisetron,ondansetron,
palonosetron)
Metoclopramide
Valproate
Carbamazepine
Sibutramine
Dextromethorphan
Cyclobenzaprine

Inhibitsserotonin
metabolism(ie,inhibits
monoamineoxidase

Monoamineoxidaseinhibitors(MAOIs)(includingphenelzine,tranylcypromine,
isocarboxazid,moclobemide,selegiline,rasagiline,linezolid,tedizolid,methyleneblue,
procarbazine,Syrianrue[Peganumharmala,harmine])

activity)
Directserotoninagonist

Buspirone
Triptans(includingsumatriptan,rizatriptan,others)
Ergotderivatives(includingergotamine,methylergonovine)
Fentanyl
Lysergicaciddiethylamide(LSD)

Increasessensitivityof
postsynapticreceptor

Lithium

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Datacourtesyofauthorswithadditionaldatafrom:BoyerEW,ShannonM.Theserotoninsyndrome.NEJM2005352:1112.
Graphic64604Version12.0

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Pathwaysoffeverproduction

Startingfromthetopleft,infectiousagentsand/ormicrobialproducts,aswellascytokines
andotherinflammatoryprocesses,inducemacrophages,endothelialcells,andthe
reticuloendothelialsystemtoproduceandsecretepyrogeniccytokinesintothecirculation.
ThesepyrogeniccytokinesinducethesynthesisofprostaglandinE2(PGE2)inthe
hypothalamus.Inaddition,microbialtoxins,actingasligandstothetolllikereceptorsinthe
hypothalamus,stimulatethesynthesisofPGE2bythehypothalamus.PGE2raisesthe
thermostaticsetpointinthehypothalamustofebrilelevels.Thevasomotorcentersends
signalsforheatconservation(vasoconstriction)andheatproduction(shivering).
Corticosteroidsreducetheperipheralsynthesisofpyrogeniccytokines,whereasantipyretics
reducePGE2levelsinthebrain.
TLR:tolllikereceptorIL1:interleukin1IL6:interleukin6TNF:tumornecrosisfactorIFN:
interferonPGE2:prostaglandinE2.
CourtesyofReuvenPorat,MDandCharlesADinarello,MD.
Graphic80455Version3.0

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Temperaturereadingsinapatientreceivingthe
interleukin1receptorantagonist,anakinra

Recordingsoforaltemperatureareshownforthespecifieddayintervalsshown.
Arrowindicatesthefirstinjectionofanakinra(100mg).
Reproducedwithpermissionfrom:FitzgeraldAA,LeClercqSA,YanA,etal.Rapid
responsestoanakinrainpatientswithrefractoryadultonsetStill'sdisease.Arthritis
Rheum200552:1794.Copyright2005JohnWiley&Sons.
Graphic53770Version3.0

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ContributorDisclosures
ReuvenPorat,MD Nothingtodisclose CharlesADinarello,MD Nothingtodisclose PeterFWeller,MD,
FACP Grant/Research/ClinicalTrialSupport:GSK[AntiIL5mAbforEGPA(Mepolizumab)]. AnnaRThorner,
MD Nothingtodisclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.
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