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Pathogenesisofdenguevirusinfection

OfficialreprintfromUpToDate
www.uptodate.com2014UpToDate
Pathogenesisofdenguevirusinfection
Author
AlanLRothman,MD

SectionEditor
MartinSHirsch,MD

DeputyEditor
ElinorLBaron,MD,DTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2014.|Thistopiclastupdated:Feb19,2014.
INTRODUCTIONSubstantialgapsremaininthebasicunderstandingofthepathogenesisofdengue
infection.Inlargepartthislimitationisrelatedtothelackofasuitableanimalmodel[1].Rhesusmonkeys
developviremiasimilarinpatterntohumansafterdengueviruschallengebutdonotdevelopclinicaldisease.
Carefulepidemiologicandexperimentalchallengestudiesinhumanshaveprovidedvaluableinformationon
denguevirusinfection,butdetaileddataonvirusdistributioninvivoareavailableonlyfromsmallnumbersof
patientswithmoreseveredisease,unusualmanifestations,orthelaterstagesofinfection.Littlepathogenetic
informationisavailableconcerningmilderinfections,whichconstitutethevastmajorityofcases.
THEDENGUEVIRALREPLICATIONCYCLEDenguevirusesaremembersofthefamilyFlaviviridae
genusFlavivirus.Theyaresmall,envelopedvirusescontainingasinglestrandRNAgenomeofpositive
polarity[2].Denguevirusesinfectawiderangeofhumanandnonhumancelltypesinvitro.Viralreplication
involvesthefollowingsteps:

Attachmenttothecellsurface
Entryintothecytoplasm
Translationofviralproteins
ReplicationoftheviralRNAgenome
Formationofvirions(encapsidation)
Releasefromthecell

Bindingofdenguevirionstocells,whichismediatedbythemajorviralenvelope(E)glycoprotein,iscriticalfor
infectivity[3].ThedeterminationofthethreedimensionalstructuresofthedengueEglycoproteinandtheintact
virionhasfacilitatedtheunderstandingofthisprocess[46].DenguevirusesbindviatheEglycoproteintoviral
receptorsonthecellsurface,whichmayincludeheparansulfateorthelectinDCSIGN[7,8]theycanalso
bindtocellsurfaceimmunoglobulinreceptorsinthepresenceofantibodiestotheEglycoproteinormembrane
precursor(preM)protein,asdescribedfurtherbelow[9].
Followingfusionofviralandcellmembranesinacidifiedendocyticvesicles,theviralRNAentersthe
cytoplasm.TheviralproteinsarethentranslateddirectlyfromtheviralRNAasasinglepolyprotein,whichis
cleavedtoyieldthethreestructuralandsevennonstructuralproteins[2].Cleavageofseveraloftheviral
proteinsrequiresafunctionalviralproteaseencodedinthenonstructuralproteinNS3.Thenonstructuralprotein
NS5istheviralRNAdependentRNApolymerase,whichassembleswithseveralotherviralproteinsand
severalhostproteinstoformthereplicationcomplex.ThiscomplextranscribestheviralRNAtoproduce
negativestrandviralRNA,whichservesasthetemplatefortheproductionoftheviralgenomicRNA.
Theassemblyandbuddingofprogenyvirionsisstillpoorlyunderstood.ThepreMstructuralproteiniscleaved
byacellularenzyme,furin,asoneofthefinalstepsinmaturationofprogenyvirions[10].Cleavageofthepre
Mproteinenhancestheinfectivityofthevirions100fold.
COURSEOFINFECTIONThecourseofdenguevirusinfectionischaracterizedbyearlyevents,
dissemination,andtheimmuneresponseandsubsequentviralclearance(figure1).
EarlyeventsDenguevirusisintroducedintotheskinbythebiteofaninfectedmosquito,mostcommonly
Aedesaegypti.Thespreadofvirusearlyaftersubcutaneousinjectionhasbeenstudiedinrhesusmonkeys
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[11].Duringthefirst24hours,viruscouldonlybeisolatedfromtheinjectionsite.Themajorcelltypeinfected
wasnotdefinedbothLangerhanscellsanddermalfibroblastshavebeenproposedtobetargetcellsfordengue
virusinfectionintheskin.Onestudyusinghumanskindendriticcellsdemonstratedexpressionofdenguevirus
antigensfollowinginvitroexposure,suggestingthatthesecellsarepermissivefordengueviralinfection[12].
Inrhesusmonkeys,viruswasdetectedinregionallymphnodes24hoursafterinfection[11].Inonestudy
usingamousemodeldeficientinbothtypeIandtypeIIinterferon(IFN)receptors,macrophagesanddendritic
cellsweredemonstratedtobeearlycellulartargetsforinfection[13].
DisseminationViremiabeginsinrhesusmonkeysbetweentwoandsixdaysaftersubcutaneousinjection
andlastsforthreetosixdays.Inhumansinfectedwith"natural"dengueviruses,viremiabeginsapproximately
onedaylaterthaninmonkeys,butthedurationofviremiaissimilar[14].Viremiaisdetectableinhumans6to
18hoursbeforetheonsetofsymptomsandendsasthefeverresolves[15].
Inrhesusmonkeysduringtheperiodofviremia,viruswasfrequentlydetectedinlymphnodesdistantfromthe
siteofinoculationandlesscommonlyfromspleen,thymus,lung,andbonemarrow[11].Viruswasalso
isolatedfromperipheralbloodleukocytesattheendoftheviremicperiodandsometimesforonedayafter.
Thedistributionofvirusinhumanshasbeenstudiedinblood,biopsy,andautopsyspecimensfrompatients
withnaturaldenguevirusinfection.Infectionofperipheralbloodmononuclearcellspersistsbeyondtheperiod
ofdetectableviremia[1618].Conflictingdatahavebeenpublishedregardingtheprincipalinfectedcelltypein
theperipheralblood.Anolderstudyreportedmorefrequentisolationofinfectiousvirusfromtheadherentcell
populationthanthenonadherentpopulation,suggestingthatmonocytesaretheprimarytargetcellforinfection
[16].Asimilarconclusionwasreachedinastudyusingflowcytometry,whichreportedthedetectionofdengue
viralantigeninaveryhighpercentageofcirculatingmonocytes[18].However,anearlierstudyusingflow
cytometryreportedthatthemajorityofcellassociatedviruswascontainedintheCD20+(Blymphocyte)
fraction[17].
Theyieldofdenguevirusfromtissuesobtainedatautopsyhasgenerallybeenlow.However,inonestudy
usingthemostsensitivetechniquesforvirusisolation,viruswasisolatedmostoften(4of16cases)fromliver
tissue[19].Antigenstaininghassuggestedthatthepredominantcelltypesinfectedaremacrophagesinthe
skin[20]andKupffercellsintheliver[21,22]dengueviralantigenshavealsobeendetectedinhepatocytesin
somecases[23].
ImmuneresponseandviralclearanceBothinnateandadaptiveimmuneresponsesinducedbydengue
virusinfectionarelikelytoplayaroleintheclearanceofinfection[24].Infectionoffibroblastsandmonocytes
invitroinducesproductionofinterferonbetaandalpha,respectively[25,26].Consistentwiththese
observations,elevatedserumlevelsofinterferonalphahavebeendemonstratedinchildrenwithdenguevirus
infectioninThailand[27].
Theroleofthesecytokineresponsesisuncertain.Interferoninhibitsdenguevirusinfectioninmonocytesin
vitro[26].Inaddition,denguevirusinfectedcellsaresusceptibletolysisbynaturalkillercellsinvitro[28].
However,dengueviralproteinsareabletoblocktheantiviralfunctionoftypeIinterferonsininfectedcells
[29,30].Inonestudyofhostcellgeneexpressionbymicroarrayanalysisofbloodsamplesobtainedfrom14
adultswithdengue,aclusterof24genetranscripts,manyreflectingtypeIinterferonsignaling,wasidentified
assignificantlylessabundantinthesixpatientswithdengueshocksyndrome(DSS)thanintheeightpatients
withoutDSS[31].ThesesubjectshadlowtoundetectableplasmaviralRNAandIFNalphalevelswhen
studied.Whetherattenuatedinterferonresponsesaretheresultorcauseofseveredenguediseaseis
unknown.
Theantibodyresponsetodenguevirusinfectionisprimarilydirectedatserotypespecificdeterminants,but
thereisasubstantiallevelofserotypecrossreactiveantibodies.E,preM,andNS1aretheprincipalviral
proteinsthataretargeted.Invitro,Eproteinspecificantibodiescanmediateneutralizationofinfection,direct
complementmediatedlysisorantibodydependentcellularcytotoxicityofdenguevirusinfectedcells,and
blockvirusattachmenttocellreceptors[28,32,33].PreMspecificantibodiesonlybindtovirionsthathavenot
fullymaturedandhaveremaininguncleavedpreMprotein.NS1isnotfoundinthevirionNS1specific
antibodiesarethereforeincapableofneutralizationofvirusinfectionbutcandirectcomplementmediatedlysis
ofinfectedcells[32].Inmice,passivetransferofantibodiesspecificforE,preM,orNS1wassufficientfor
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protectionagainstlethaldenguevirusinfection[32,34,35].
Thebasisofneutralizationofvirusbyantibodyisnotwellunderstood.Neutralizationclearlyrequiresa
thresholdlevelofantibodieswhentheconcentrationofantibodiesisbelowthisthreshold,theuptakeof
antibodyboundvirusbycellsthatexpressimmunoglobulinreceptorsisparadoxicallyincreased,aprocess
termedantibodydependentenhancement(ADE)ofinfection[9,36].Sincemonocytes,theputativecellular
targetsofdenguevirusinfectioninvivo,expressimmunoglobulinreceptorsandmanifestADEinvitro,this
phenomenonisthoughttobehighlyrelevantinnaturaldenguevirusinfections(seebelow).Inrhesusmonkeys,
passivetransferoflowlevelsofdengueimmunehumanseraorahumanizedchimpanzeedenguevirus
specificmonoclonalantibodyresultedina2to100foldincreaseindengue2ordengue4viremiatitersas
comparedwithcontrolanimals[37,38].Anincreaseinviraltitersinbloodandtissuesandenhanceddisease
werealsoobservedafterpassivetransferoflowlevelsofdenguevirusspecificantibodyinmicelacking
interferonreceptors[39].
Onestudycharacterized301humandenguevirusspecificmonoclonalantibodies[40].PreMspecific
antibodiesrepresentedalargerfractionofthemonoclonalantibodiesdetectedthanantibodiesdirectedatEor
NS1.PreMspecificantibodiesshowedpoorneutralizationofinfectioninvitrobutcouldmediateADE.
TheTlymphocyteresponsetodenguevirusinfectionalsoincludesbothserotypespecificandserotype
crossreactiveresponses[41].DenguevirusspecificCD4+andCD8+Tcellscanlysedenguevirusinfected
cellsinvitroandproducecytokinessuchasinterferongamma,tumornecrosisfactor(TNF)alpha,and
lymphotoxin[41,42].Invitro,interferongammacaninhibitdenguevirusinfectionofmonocytes.However,
interferongammaalsoenhancestheexpressionofimmunoglobulinreceptors,whichcanaugmenttheantibody
dependentenhancementofinfection[43].
PrimaryversussecondaryinfectionInfectionwithoneofthefourserotypesofdenguevirus(primary
infection)provideslifelongimmunitytoinfectionwithavirusofthesameserotype[14].Incontrast,immunityto
theotherdengueserotypesistransient,andindividualscansubsequentlybeinfectedwithanotherdengue
serotype(secondaryinfection).Twoprospectivecohortstudiesfoundthattheintervalbetweenprimaryand
secondarydenguevirusinfectionswassignificantlylongeramongchildrenwhoexperiencedasymptomatic
secondaryinfectionthanthosewhohadasubclinicalsecondaryinfection,suggestingthatheterotypic
protectiveimmunitywanesgraduallyoveronetotwoyears[44,45].
Inonereport,thedistributionofdenguevirusinsecondaryinfectionswasevaluatedineightrhesusmonkeys
[11].Theonsetanddurationofviremiaweresimilartoprimaryinfections.Autopsyspecimensfromsix
monkeysyieldedvirussomewhatmorefrequentlyfromvarioustissuesthanspecimensfromprimary
infections.Anotherstudyfoundhigherplasmavirustitersinsecondarythanprimarydengue2virusinfections
butnotinsecondaryinfectionswithdenguevirusesoftheotherserotypes[46].
Thereislittleinformationfromhumanstudiestoallowcomparisonsofvirusdistributionortiterinprimaryand
secondaryinfections.Severalstudieshavereportedthathigherpeakplasmavirustitersinsecondarydengue
infectionswereassociatedwithmoresevereillness[4749].Twostudiesfailedtodemonstratehigherviremia
titersinpatientswithsecondarydengueinfectionsthaninpatientswithprimarydengueinfections[50,51],buta
studyusingquantitativeRTPCRreportedhigherviralRNAlevelsinCD14+monocytesamongdenguefever
patientswithsecondaryinfectionscomparedwithdenguefeverpatientswithprimaryinfections[52].
Thekineticsofdenguevirusspecificantibodiesinsecondarydengueinfectionsdifferfromthoseofprimary
dengueinfectionsinseveralways.
Lowconcentrationsofantibodiestothevirusserotypecausingthesecondaryinfectionarepresentbefore
exposuretothevirus.Asaresult,antibodydependentenhancementofinfectioncouldoccurearlyin
secondarydenguevirusinfections.
Concentrationsofdenguevirusspecificantibodiesincreaseearlierinsecondaryinfection,reachhigher
peaktiters,andhavealowerIgM:IgGratio,suggestiveofananamnesticresponse.Thus,thelevelsof
denguevirusspecificantibodiesaremuchhigherduringthelatestageofviremiainsecondaryinfections,
withgreaterpotentialforformingimmunecomplexesofdenguevirionsandactivatingcomplement.

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ThekineticsoftheTlymphocyteresponseinsecondaryinfectionsalsodifferfromthoseofprimaryinfections.
ThefrequencyofdenguevirusspecificTlymphocytesismuchhigherpriortosecondaryinfectionthanprimary
infection.Furthermore,thesememoryTcellsrespondmuchmorerapidlyaftercontactwithantigenpresenting
cellsthannaveTcells.Asaresult,denguevirusspecificTlymphocyteproliferationandcytokineproduction
wouldbeexpectedtooccurearlierandreachhigherlevelsinsecondaryinfections.StudiesofcirculatingT
lymphocytesduringacutesecondaryinfectionshaveshownahighpercentageofcellsexpressingmarkersof
activationandhighfrequenciesofdengueantigenspecificcells,consistentwiththishypothesis[5356].
However,astudythatcomparedthefrequenciesofTcellsspecificforanimmunodominantdengueepitope
betweenprimaryandsecondarydenguevirusinfectionsfoundnosignificantdifferences,perhapsduetothe
variationinresponsesbetweensubjects[57].
TheseverityofdenguediseasehasbeencorrelatedwiththelevelandqualityofthedenguevirusspecificT
lymphocyteresponsesinsomestudiesbutnotinothers.Intwostudies,thefrequencyofdenguevirus
specificCD8+Tcellswashigherafterdenguehemorrhagicfever(DHF)thanafterdenguefever(DF)among
subjectsexperiencingsecondaryinfections[54,55].OnestudyusingHLApeptidetetramersfoundthatahigh
proportionofthedenguevirusspecificCD8+Tlymphocyteshadhigheraffinityfordengueviralserotypes
otherthantheinfectingserotypeaveryhighpercentageofthetetramerpositivecellswereapparentlyprimed
toundergoapoptosis[54].However,twosubsequentstudiesfoundnoassociationsbetweenthefrequenciesof
denguevirusspecificTcellsanddiseaseseverity[57,58]inoneofthosestudies,denguevirusspecific
CD8+Tcellswerenotdetectedbyhumanleukocyteantigen(HLA)peptidetetramerstaininguntilafterthe
developmentofplasmaleakage[58].
SomeserotypecrossreactiveTcellspresentafterprimaryinfectiondisplayqualitativelyalteredfunctional
responsestootherdengueserotypes[59].Inoneprospectivecohortstudy,specificTcellresponsespriorto
secondarydenguevirusinfectionwereassociatedwiththesubsequentoccurrenceofDHF,suchasproduction
ofTNFalphainresponsetostimulationwithdengueantigens[60].Incontrast,higherfrequenciesofCD4+T
cellsproducingIFNgammaorinterleukin(IL)2inresponsetostimulationwithdengueantigenswere
associatedwithsubclinicaldengueinfection,suggestingaprotectiveeffectaswell[61].
FACTORSINFLUENCINGDISEASESEVERITYMostdenguevirusinfectionsproducemild,nonspecific
symptomsorclassicdenguefever(DF).Themoreseveremanifestations,denguehemorrhagicfever(DHF)
anddengueshocksyndrome(DSS),occurinlessthan1percentofdenguevirusinfections.Thus,
considerableattentionhasbeenfocuseduponunderstandingtheriskfactorsforDHF(table1).
ViralfactorsDHFcanoccurduringinfectionwithanyofthefourdengueserotypesseveralprospective
studieshavesuggestedthattheriskishighestwithdengue2viruses[15,6264].Geneticanalysesofdengue
virusisolatesfromtheWesternhemispherestronglysuggestthatDHFonlyoccursduringinfectionwith
virusesthatfallintospecificgenotypeswithineachdengueserotype[65,66].These"virulent"genotypeswere
originallydetectedinSoutheastAsiabutarenowwidespread.Severalstudieshavesuggestedthat"virulent"
and"avirulent"genotypesdifferintheirabilitytoreplicateinmonocyticcells[67,68],butitisnotclearthatthis
differenceininvitroreplicationisthefactorresponsibleforvirulence.
PriordengueexposureEpidemiologicstudieshaveshownthattheriskofseveredisease(DHF/DSS)is
significantlyhigherduringasecondarydenguevirusinfectionthanduringaprimaryinfection.Thisrelationship
canbeillustratedbythefollowingobservations:
Anoutbreakofdengue2virusinfectionsinCubain1981followedanoutbreakofdengue1virus
infectionsin1977thatinvolved45percentoftheisland'spopulation98percentofcasesofDHF/DSSin
childrenandadultswereassociatedwithsecondaryinfections[69,70].
InaprospectivestudyinBangkokin1980,hospitalizationforDHFwasrequiredinnoneof47children
withprimaryinfectionscomparedwith7of56withsecondaryinfections[62].
AprospectivestudyinMyanmarfrom1984to1988foundarelativeriskofDSSinsecondaryinfections
of82to103[71].
TheincreasedriskofDHFinsecondarydenguevirusinfectionsisfelttoreflectthedifferencesinimmune
responsesbetweenprimaryandsecondarydenguevirusinfectionsdescribedabove:antibodydependent
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enhancementofinfection,enhancedimmunecomplexformation,and/oracceleratedTlymphocyteresponses.
TheincreasedriskforDHFassociatedwithsecondarydenguevirusinfectionsappearsnottoapplyto
infectionswith"avirulent"genotypes(seeabove).AprospectivestudyinIquitos,Peru,foundnocasesofDHF
orDSSduringanoutbreakofdengue2virusinfectionsthatwasestimatedtoinvolveover49,000secondary
infectionsinchildren[66].Atleast880casesofDHFwouldhavebeenexpectedbaseduponpreviousstudies
inThailand[62,63].Furthermore,therearenumerousdocumentedcasesofdenguehemorrhagicfeveroccurring
duringprimaryinfection,suggestingthatdifferencesinviralvirulence,asdiscussedabove,arealsoimportant
[1,15].
AgeTheriskforDHFappearstodeclinewithage,especiallyafterage11years.Duringthe1981epidemic
ofDHFinCuba,themodalageofDHFcasesanddeathswasfouryears,althoughthefrequencyofsecondary
dengue2infectionswassimilarinthose4to40yearsofage[72,73].
AspecificpopulationathigherriskforDHFinendemicareasisinfants,particularlythosebetween6and12
monthsofage.Thesechildrenacquiredenguevirusspecificantibodiestransplacentallyandbecome
susceptibletoprimarydenguevirusinfectionwhenantibodylevelsdeclinebelowtheneutralizationthreshold
[74,75].Thisobservationistakentosupportthehypothesisofantibodydependentenhancementofinfectionas
aprimaryfactorindeterminingtheriskforDHF.AdirectcorrelationbetweenADEactivityofpreinfection
serumandtheseverityofinfectionhasnotbeendemonstrated,however[76].
NutritionalstatusUnlikeotherinfectiousdiseases,DHF/DSSislesscommoninmalnourishedchildren
thaninwellnourishedchildren.Asanexample,malnutrition,asdeterminedbyweightforage,wasnotedin13
percentof100ThaichildrenwithDHFcomparedwith33percentof184healthyThaichildrenand71percentof
125Thaichildrenwithotherinfectiousdiseasesadmittedtothesamehospital[77].Thisnegativeassociation
mayberelatedtosuppressionofcellularimmunityinmalnutrition.
GeneticfactorsEpidemiologicstudiesinCubashowedthatDHFoccurredmoreofteninwhitesthanin
blacks[73],andasimilargeneticresistancetoDHFinblackshasbeenreportedfromHaiti[78].Racial
differenceshavebeendescribedinviralreplicationinprimarymonocytesandinthelevelofdengueserotype
crossreactiveTcellresponses[79],butitisunclearifeitheroftheseexplainsthegeneticassociation.
DHFhasbeenassociatedwithspecifichumanleukocyteantigen(HLA)genesinstudiesfromThailand[80,81],
Cuba[82],andVietnam[83].Othergeneticfactorsthatmaybeassociatedwithvaryingdegreesof
susceptibilitytoDHFincludereceptorpolymorphismsoftumornecrosisfactoralpha,vitaminD,Fcgamma
IIa,bloodgrouptype,andDCSIGNgenes[8487].
PATHOPHYSIOLOGYOFDISEASEMANIFESTATIONS
CapillaryleaksyndromePlasmaleakage,duetoanincreaseincapillarypermeability,isacardinalfeature
ofdenguehemorrhagicfever(DHF)butisabsentindenguefever(DF).Theenhancedcapillarypermeability
appearstobeduetoendothelialcelldysfunctionratherthaninjury,aselectronmicroscopydemonstrateda
wideningoftheendothelialtightjunctions[88].Denguevirusinfectshumanendothelialcellsinvitroand
causescellularactivation[89].Additionally,solubleNS1protein,whichcanbedetectedintheserumduring
acuteinfection,hasbeenreportedtobindtoendothelialcellsandmayserveasatargetforantibodybinding
andcomplementactivation[90].However,theeffectsonendothelialcellfunctionduringinfectionaremost
likelytobeindirectlycausedbydenguevirusinfectionforthefollowingreasons:
Histologicstudiesshowlittlestructuraldamagetocapillaries[91].
Infectionofendothelialcellsbydenguevirusisnotapparentintissuesobtainedatautopsy[22].
Increasedcapillarypermeabilityistransient,withrapidresolutionandnoresidualpathology.
Mostinvestigationshavefocusedonthehypothesisthatcirculatingfactorsinducethetransientincreasein
capillarypermeability.Multiplemediatorsarelikelytobeinvolvedinvivo,andinteractionsbetweenthese
differentfactorshavebeendemonstratedinexperimentalanimals.Themostimportantmediatorsarethoughtto
includetumornecrosisfactor(TNF)alpha(releasedfromvirusinfectedmonocytesandactivatedTcells),
interferon(IFN)gammaandinterleukin(IL)2(releasedfromactivatedTcells),IL8(producedbyvirusinfected
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cells),vascularendothelialgrowthfactor(VEGF,potentiallyproducedbymonocytesandendothelialcells),and
complement(activatedbyvirusantibodycomplexes)(figure2).
DenguevirusinfectedmonocyticcellsproduceTNFalphaandIL8,andtheseaffectendothelialcell
permeabilityinvitro[9294].ElevatedserumlevelsofTNFalpha[95,96],IL8[97],IFNgamma[98,99],IL2
[98],andfreeVEGF[89]havealsobeenobservedinpatientswithDHF.OtherstudiesfromThailandhave
foundreducedserumlevelsofthecomplementproteinsC3andC5inchildrenwithDHF[100],witha
correspondingincreaseintheserumconcentrationsofanaphylatoxinsC3aandC5a[101].
Itisdifficulttodetectelevatedcytokinelevelsinthecirculation,becauseoftheshorthalflifeofthese
molecules.Analysisofmorestablemarkersofimmuneactivationhasprovidedadditional,althoughindirect,
supportfortheimmunopathogenesismodelofplasmaleakage.Severalstudieshaveshownthatchildrenwith
DHFhaveelevatedcirculatinglevelsofthesolubleformsofCD8[98,99],CD4[98],IL2receptors[98,99],and
TNFreceptors[96,99,102].IncreasedplasmaconcentrationsofsolubleTNFreceptorIIwerefoundtocorrelate
withthesubsequentdevelopmentofshockinVietnamesechildrenwithDHF[96]andwiththemagnitudeof
plasmaleakageintothepleuralspace.Theintensityoftheimmuneresponsemayultimatelybedeterminedby
thelevelofviralreplication,however,asonestudyfoundthattheplasmaviremiatiterwasthestrongest
independentfactorthatcorrelatedwithplasmaleakage[27].
BloodandbonemarrowLeukopenia,thrombocytopenia,andahemorrhagicdiathesisarethetypical
hematologicfindingsindenguevirusinfections.Leukopeniaisapparentearlyinillnessandisofsimilardegree
inDHFanddenguefever[103].Itisthoughttorepresentadirecteffectofdenguevirusonthebonemarrow.
BonemarrowbiopsiesofchildreninThailandwithDHFrevealedsuppressionofhematopoiesisearlyinthe
illness,withmarrowrecoveryandhypercellularityinthelatestageandduringearlyclinicalrecovery[104].In
vitrostudieshaveshownthatdenguevirusinfectshumanbonemarrowstromalcellsandhematopoietic
progenitorcells[105,106]andinhibitsprogenitorcellgrowth[107].
SomedegreeofthrombocytopeniaiscommoninbothdenguefeverandDHF,butmarkedthrombocytopenia
(<100,000platelets/mm3)isoneofthecriteriausedtodefineDHF.Multiplefactorsarethoughttocontributeto
thefallinplateletcount,whichismostseverelateintheillness[103].Bonemarrowsuppressionmayplaya
role,butplateletdestructionisprobablymoreimportant.Inonestudy,10of11ThaichildrenwithDHFhada
shortenedplateletsurvivaltime,rangingfrom6.5to53hours[108].Adsorptionofdenguevirionsorvirus
antibodyimmunecomplexestotheplateletsurface,withsubsequentactivationofcomplement,arethoughtto
beresponsiblefortheplateletdestruction.
Manifestationsofthehemorrhagicdiathesisindenguevirusinfectionsrangefromapositivetourniquettestto
lifethreateninghemorrhage.FatalDHFmaybeassociatedwithdiffusepetechialhemorrhagesinvolvingthe
stomach,skin,heart,intestine,andlungs[91].(See"Clinicalmanifestationsanddiagnosisofdenguevirus
infection".)
Despitethenomenclature,however,theoccurrenceofhemorrhagedoesnotdefineDHFascomparedwith
denguefeversinceapositivetourniquettestmayoccurwithequalfrequencyinthetwodisorders[103].
Severaldifferentmechanisms,possiblyactingsynergistically,contributetobleedingtendencyofdenguevirus
infections.Boththevasculopathyandthrombocytopeniadescribedabovecreateapredispositiontobleeding.
Endothelialcellactivationandinjuryandactivationofcoagulationandfibrinolysishavebeenreportedin
dengue,particularlyinsevereinfections.Abnormalitiesthathavebeendescribedincludeincreasednumbersof
circulatingendothelialcells[109],elevatedlevelsofvonWillebrandfactor,tissuefactor,tissueplasminogen
activator,andplateletactivatorinhibitor[110],andanincreasedfractionalcatabolicrateoffibrinogen[111].
However,mostofthesefindingsarebasedonsmallstudiesandcomparisonwithnondenguecontrols.Frank
coagulopathyisuncommonexceptinpatientswithshock.
Afinaletiologicfactormaybemolecularmimicrybetweendengueviralproteinsandcoagulationfactors.One
studyof88Tahitianchildrenwithdenguevirusinfectionfoundthatantibodyresponsestohomologouspeptides
derivedfromthedenguevirusEproteincrossreactedwithplasminogentheseantibodiescorrelatedwiththe
occurrenceofhemorrhagicsigns(includingpetechiae)butnotwiththrombocytopeniaorshock[112].Another
studyreportedthatmonoclonalantibodiesdirectedatthedenguevirusNS1proteinboundinvitrotohuman
fibrinogen,platelets,andendothelialcellsandinducedhemorrhageinmice[113].
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LiverElevationsofserumaminotransferasesthatareusuallymildarecommonindenguevirusinfections
[103].Typicalpathologicfindingsintheliversoffatalcasesofdengueincludehepatocellularnecrosisand
Councilmanbodieswithrelativelylittleinflammatorycellinfiltration,similartothefindingsinearlyyellowfever
virusinfection[91].Thepathologicsimilaritiesbetweenthesetwodiseasesandtherelativelyfrequentisolation
ofdenguevirusfromlivertissuesoffatalcasessuggestthatliverinjuryisdirectlymediatedbydenguevirus
infectionofhepatocytesandKupffercells.Denguevirushasbeenshowntoinfectandinduceapoptosisina
humanhepatomacelllineinvitro[114].However,immunemediatedhepatocyteinjury,forexample,bystander
destructionofuninfectedhepatocytesbyactivatedCD4+Tlymphocytes,isapotentialalternativemechanism
[41].
CentralnervoussystemRarecasesofencephalopathyhavebeenattributedtodenguevirusinfections.
Trueencephalitishasbeenreported,withdetectionofdenguevirusinbraintissue[115,116],butthisisclearly
theexceptioninhumans,whereasencephalitisistheonlydiseasecausedbydenguevirusesinmice.Inone
seriesof100fatalcasesofdengue,noevidenceofcentralnervoussysteminflammationwasfound[91].
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasics
andBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoread
materials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.
Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopic(see"Patientinformation:Denguefever(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Denguevirusesaresmall,envelopedvirusesthataremembersofthefamilyFlaviviridaegenus
Flavivirus.Viralreplicationinvolvesthefollowingsteps:attachmenttothecellsurface,cellularentry,
translationofviralproteins,replicationoftheviralRNAgenome,formationofvirionsbyencapsidation,
andcellularrelease.(See'Thedengueviralreplicationcycle'above.)
Denguevirusisintroducedintotheskinbythebiteofaninfectedmosquito,mostcommonlyAedes
aegypti.(See'Earlyevents'above.)
Viremiaisdetectableinhumans6to18hoursbeforetheonsetofsymptomsandendsasthefever
resolves.(See'Dissemination'above.)
Bothinnateandadaptiveimmuneresponsesinducedbydenguevirusinfectionarelikelytoplayarolein
theclearanceofinfection.(See'Immuneresponseandviralclearance'above.)
Infectionwithoneofthefourserotypesofdenguevirus(primaryinfection)provideslifelongimmunityto
infectionwithavirusofthesameserotype[14].However,immunitytotheotherdengueserotypesis
transient,andindividualscansubsequentlybeinfectedwithanotherdengueserotype(secondary
infection).(See'Primaryversussecondaryinfection'above.)
Antibodiestoproteinsonthedenguevirussurfacecancauseincreasedinfectionofcellsbearing
immunoglobulinreceptors,aphenomenonknownasantibodydependentenhancementofinfection(ADE).
(See'Immuneresponseandviralclearance'above.)
Theseverityofdenguediseasehasbeencorrelatedwithboththelevelandqualityofthedenguevirus
specificTlymphocyteresponses.(See'Primaryversussecondaryinfection'above.)
Althoughdenguehemorrhagicfever(DHF)canoccurduringinfectionwithanyofthefourdengue
serotypes,severalprospectivestudieshavesuggestedthattheriskishighestwithdengue2viruses.
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(See'Factorsinfluencingdiseaseseverity'above.)
Epidemiologicstudieshaveshownthattheriskofseverediseaseissignificantlyhigherduringa
secondarydenguevirusinfectionthanduringaprimaryinfection.(See'Priordengueexposure'above.)
TheriskforDHFappearstodeclinewithage,especiallyafterage11years.(See'Age'above.)
Plasmaleakage,duetoanincreaseincapillarypermeability,isacardinalfeatureofDHFbutisabsentin
denguefever(DF).Theenhancedcapillarypermeabilityappearstobeduetoendothelialcelldysfunction
ratherthaninjury.(See'Pathophysiologyofdiseasemanifestations'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Acutedenguevirusinfection

Hypotheticalschemaofeventsinacutedenguevirusinfection.The
kineticsandgenerallocationofviralreplicationarediagrammedinrelation
tothepresenceofdetectableviremia,generalsymptoms(fever,myalgias,
headache,rash),andtheperiodofriskforplasmaleakage,shock,severe
thrombocytopenia,andbleedingindenguehemorrhagicfever(DHF).
Nonspecificimmuneresponsesincludetheproductionofinterferons(IFN)
andnaturalkiller(NK)cellactivity.ThekineticsofdenguevirusspecificT
lymphocyteactivationandtheproductionofdenguevirusspecific
antibodiesoccurlaterandareoflessermagnitudeinprimaryinfections
(firstexposuretodengueviruses)thaninsecondaryinfections(later
infectionwithaseconddenguevirusserotype).
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Factorsthatinfluencetheriskfordenguehemorrhagicfever
Factor

Lowrisk

Highrisk

Viralfactors
Viralserotype

Dengue2virus

Viralgenotype

"Asian"genotypes

Immunity

Priordenguevirusinfection

Age

Adult

Nutrition

Malnourished

Genetics

Black

Hostfactors

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Capillaryleakindenguevirusinfection

Proposedmodelbywhichdenguevirus(DV)producesacapillaryleaksyndrome.
Monocytes(Mo)arethoughttobetheprimarycellulartargetforDV.Serotype
crossreactiveantibodies(Ab),presentatthetimeofsecondDVinfection,bindto
virionswithoutneutralizationandthenenhancetheentryofvirusintomonocytic
cellsexpressingimmunoglobulinreceptors(FcR),asshowintheleftsideofthe
picture.SerotypecrossreactivememoryTcells,alsopresentatthetimeof
secondaryDVinfection,recognizeviralantigensinthecontextofclassIandII
majorhistocompatibilitycomplex(MHC)molecules.TheseTcellsproduce
cytokines,suchasinterferongamma(IFN)andtumornecrosisfactors(TNF)alpha
andbeta,andlyseDVinfectedmonocytes.TNFalphaisalsoproducedin
monocytesinresponsetoDVinfectionand/orinteractionswithTcells.These
cytokineshavedirecteffectsonendothelialcells(EC)toinduceplasmaleakage.
InterferongammaactivatesmonocytestoincreasetheexpressionofMHC
moleculesandimmunoglobulinreceptorsandtheproductionofTNFalpha.The
complementcascade,activatedbyvirusantibodycomplexesandbyseveral
cytokines,releasesthecomplementanaphylatoxinsC3aandC5awhichfurther
increasecapillarypermeability.Interleukin2maycontributebyfacilitatingTcell
proliferation.
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Disclosures
Disclosures:AlanLRothman,MDGrant/Research/ClinicalTrialSupport:SanofiPasteur(Dengue
vaccine[denguevaccine]).Consultant/AdvisoryBoards:SanofiPasteur(Denguevaccine[dengue
vaccine]).MartinSHirsch,MDNothingtodisclose.ElinorLBaron,MD,DTMHEmployeeof
UpToDate,Inc.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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