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ZikaVirusInfection:Epidemiology,Clinical
ManifestationsandDiagnosis
GuilhermeAmaralCalvetFlaviaBarretodosSantosPatriciaCarvalhoSequeira
CurrOpinInfectDis.201629(5):459466.

AbstractandIntroduction
Abstract

PurposeofreviewZikavirus(ZIKV)isanarboviruspreviouslybelievedtocauseonlyamildandselflimitingillness.
Recently,ithasemergedasanewpublichealththreatthatcausedalargeoutbreakinFrenchPolynesiain20132014and
since2015anexplosiveoutbreakinBrazil,withanincreaseinseverecongenitalmalformations(microcephaly)and
neurologicalcomplications,mainlyGuillainBarrsyndrome(GBS).Sincethen,ithasspreadthroughtheAmericas.On1
February2016,theWHOdeclaredtheZIKVepidemicinBrazilaPublicHealthEmergencyofInternationalConcern.We
reviewedtheepidemiologyofZIKVinfection,clinicalpresentationsanddiagnosis.Wehighlightedtheclinicalfeaturesand
nonvectorbornetransmissionofthevirus.

RecentfindingsAssociationbetweenZIKVinfectionandseverefoetaloutcomes,includingmicrocephalyandotherbirth
defectsincreasedrateofGBSandotherneurologicalcomplicationsduetotheongoingZIKVoutbreakincreasedevidence
todateofZIKVbeingtheonlyarboviruslinkedtosexualtransmissionthechallengeofZIKVdiagnosisandtheneedfora
specificpointofcaretestinepidemicscenarios.

SummaryThefindingsillustratetheemergenceofaviraldiseasewiththeidentificationofnewassociateddisorders,new
modesoftransmission,includingmaternalfoetalandsexualtransmission.

Introduction

FewstudiesrelatedtoZikavirus(ZIKV)havebeenpublishedupuntil2014. [1]Aliteratureproductionincreasewas
observedfollowingtheFrenchPolynesiaoutbreakin20132014.ButitwasonlyaftertheexplosiveZIKVoutbreakinBrazil
in2015whereanincreaseinreportedcasesofmicrocephalyandneurologicaldisordersoccurredthatseveralcasereports,
editorials,letters,researchreports,perspectivesandreviewswerepublished,impactingtheglobalscientificproductionin
thefield.ThisreviewdescribesthecurrentepidemiologyofZIKVinfections,clinicalpresentationsanddiagnosis.We
highlightedtheclinicalfeaturesandnonvectorbornetransmissionofthevirus.

EpidemiologyofZikaVirus
ZIKV,amosquitotransmittedvirusinthefamilyFlaviviridaeandgenusFlavivirus,wasdiscoveredin1947withlittleimpact
inpublichealthsystemsworldwideforthefollowingsevendecades.Only14humancasesofthediseasewerereportedin
countriesinSoutheastAsiaandAfrica. [2]In2007,ZIKVwasfirstdetectedoutsideofAsiaandAfrica,causingthefirst
largeoutbreakeverreported. [3]YapState,locatedattheFederatedStatesofMicronesiaintheWesternPacific,estimated
thatover72%oftheirresidentsover3yearsofagewereinfectedwithZIKV. [4]TheoriginoftheZIKVthatcausedthis
epidemicremainstobeclarified,butithasbeenhypothesizedthataviremicpersontravellingfromthePhilippinescould
haveintroducedit. [5]

InOctober2013,ZIKVreachedtheFrenchPolynesiaintheSouthPacificregionanduntilApril2014anestimateof30000
peoplewereinfected,causingthelargestZIKVoutbreakeverdescribedatthattime. [4,6]Severeneurological
manifestationsandanincreaseinGuillanBarrsyndrome(GBS)werereported,suggestingapossibleassociation
betweenZIKVandGBS. [6]Duringandafterthisoutbreak,ZIKVrapidlyspreadtootherPacificislands. [4]NewCaledonia
healthauthoritiesdeclaredaZIKVoutbreakinFebruary2014,andbytheendofAugust,1400caseshadbeenreported. [7]
AsmalloutbreakofZIKVwasconfirmedintheCookIslandsinMarch2014,withonly905casesreported. [8]Localhealth
authoritiesreportedthefirstautochtonouscaseofZIKVinfectioninChileon28January2014aftertheconfirmationofa
suspectedcaseonEasterIsland(NationalTravelHealthNetworkandCentre,http://nathnac.net/).FiftycasesofZikain
Chilewereconfirmedbytheendoftheoutbreak. [9]

InMarch2015,researchersattheFederalUniversityofBahia,Brazil,confirmedtheintroductionofZIKVinBrazil. [10]
Serumsamplesfrom24exhantematicpatientsfromCamaari,Bahia,Brazil,weretestedandsevenofthempresented
positivediagnosisforZIKVbyrealtimePCR(RTPCR).AutochthonoustransmissioninBrazilwaslaterconfirmed[11]and,

byDecember2015,statesfromallregionsofthecountryhadalreadyreportedautochthonousvirustransmission. [12]Ithas
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byDecember2015,statesfromallregionsofthecountryhadalreadyreportedautochthonousvirustransmission. [12]Ithas
beenestimatedthatthenumberofsuspectedcasesofZIKVinfectionrangedfrom440000to1300000bytheendof
2015. [13]TwohypothesesregardingtheZIKVintroductioninBrazilhadbeeninitiallyraised,withthefirstsuggestingthat
theviruswasintroducedduringthesoccerWorldCupeventheldinBrazilin2014. [14]Anotherhypothesiswasthevirus
introductionduringtheWorldSpringCanoechampionshipheldinRiodeJaneiroin2014,fromaviremicathletefromone
oftheparticipatingPacificcountries. [15]Fariaetal. [16]haverecentlyraisedathirdhypothesisforZIKVintroductioninthe
Americas,suggestingtheviralintroductionduringthe2013ConfederationsCupsoccertournament,whichoccurredfrom15
to30June2013.Inallpotentialcases,ZIKVintroductionwasprobablyinitiallyunnoticedbecauseZIKVclinical
manifestationscanbeconfusedwiththosecausedbydengue(DENV)andchikungunya(CHIKV)viruses,bothalready
endemicinBrazil.Thecountryhasnotified120161probablecasesand39993confirmationsuntilthe16thepidemiological
weekof2016. [17]TheexplosiveZikaoutbreakinBrazilhasprovideddataontheassociationbetweenmicrocephalyand/or
neurologicaldisordersandZIKVinfection.Asaresult,on1February2016,theWHOdeclaredtheZIKVepidemicinBrazil
aPublicHealthEmergencyofInternationalConcern.

AccordingtothePanAmericanHealthOrganization(PAHO)epidemiologicalupdatefrom2June2016,atotalof39
countriesandterritoriesintheRegionoftheAmericashaveconfirmedlocal,vectorbornetransmissionofZIKVsince2015.
[18]

AnumberofimportedcasesofZIKVinfectionhavebeenreportedfromtravellersfromEurope,theAmericas,Asiaandthe
PacificreturningfromendemicareaswhereZIKVepidemicswereongoing. [1921]Theimportationofcasestoareaswhere
competentmosquitoesarepresentposesariskofmassdisseminationofZIKVglobally.

ZikaClinicalFeatures
Itisestimatedthat80%ofZIKVinfectionsareasymptomatic. [3]ThemajorityofclinicalmanifestationsofZIKVinfections
areusuallymildandselflimiting[20,2224]afteranotwellestablishedincubationperiod,butprobablysimilartootherrelated
flavivirus(3days2weeks). [25]Figures14showsomeclinicalmanifestationsofZIKVinfection.

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Figure1.

Nonpurulentconjunctivitisandfacialexanthema.

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Figure2.

Maculopapularexanthemaonthetrunk.

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Figure3.

Maculopapularexanthemaontheposteriortrunk.

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Figure4.

Oedemainthelowerlimbs.

InareportduringtheZikaoutbreakthatoccurredinthestateofRiodeJaneiro,Brazil,basedonalargenumberof
suspectedandlaboratoryconfirmedcases,themostcommonsignsorsymptomsweremacularormaculopapularrash
(97%),followedbypruritus(79%),prostration(73%),headache(66%),arthralgias(63%),myalgias(61%),nonpurulent
conjunctivitis(56%)andlowerbackpain(51%).Fever,whenpresent,waslowgradeandshortterm.Theauthorssuggest
thatpruritus,thesecondmostcommonclinicalsignpresentedbytheconfirmedcases,shouldbeaddedtothePAHOcase
definition. [26]Inanotherstudy,JimenezCoronaetal. [27]analysed93autochthonouscasesofZikainMexico.Themain
clinicalfeatureswerefever(96.6%),rash(93.3%),nonpurulentconjunctivitis(88.8%),headache(85.4%)andmyalgia
(84.3%). [27]

Usually,ZIKVinfectionrelatedfeverislowgrade, [26]butsomecasesreportedhighfever(upto40C). [11,28,29]

Lymphadenopathy, [11,20,26,29,30]severeabdominalpain, [31]thrombocytopenia,enantemaandhaematomashavebeen
describedinpatientswithZIKVinfectioninsomereports. [20,26,3236]Severethrombocytopeniaisuncommon,butthe
numberofreportsisgrowing[32,35]withsomecasesprogressingtodeath. [37,38]Haematospermiahasalsobeenreported.
[39,40]

ClinicalcharacteristicsandoutcomedataonZIKVinfectioninyoungchildrenarescarce,butbasedonlimitedinformation,
ZIKVinfectioninchildrenismildandsimilartothatinadults. [34,41]

ThearboviralburdenofdiseasescausedbycocirculationofDENV,CHIKVandZIKVintheAmericas[42,43]canleadto
coinfectionsandhasbeenreportedpreviously. [44,45]Theclinicalspectrumofmanifestationsandtheoverallepidemiological
relevanceofthosecoinfectionsarestillunknownandshouldbeaccessed.

FatalitiesattributedtoZIKVarerare,excludingfoetallossesamongwomeninfectedduringpregnancyandnewbornswith
severecongenitalZIKVdisease.However,becausethecurrentepidemicisrapidlyevolving,somedeathsrelatedtoZIKV
havebeenreported. [17,37,38,46]InOctober2015,a15yearoldgirlpreviouslydiagnosedwithsicklecelldiseasediedwith
vasoocclusion,triggeredbyinflammationandseveresplenicsequestration. [46]Anotherfourdeathswerereportedin
Colombia. [38]UntilMay2016,threepeoplediedfromcomplicationslinkedtotheZIKV,accordingtoBrazilianhealth
officials. [17]InPuertoRico,a70yearoldmandiedofcomplicationsrelatedtoseverethrombocytopeniaattheendof
February2016. [37]

NeurologicalandCongenitalZikaSyndrome

ThespectrumoftheZikaclinicalmanifestationsisincreasingastheepidemicisspreading. [18]Clinicalmanifestationshave
apparentlychangedsincethelargeFrenchPolynesianoutbreakin20132014, [5]whensevereneurologicalcomplications
werereported, [47]followedbyanincreaseinseverecongenitalmalformationsintheemergenceinBrazilin2015. [48]

Oehleretal. [48]describedthefirstGBScaseoccurringimmediatelyafteraZIKVinfection,duringtheFrenchPolynesia
outbreak.CaoLormeauetal. [47]providedfurtherevidenceforZIKVinfectioncausingGBSduringtheFrenchPolynesia
outbreak.Asof12May2016,13countriesandterritoriesworldwidehavereportedanincreasedincidenceofGBScases
followingarecentZIKVinfection. [28,4853]

Carteauxetal. [54]describedacaseofZIKVassociatedmeningoencephalitisinan81yearoldman.Mecharlesetal. [55]

reportedacaseofacutemyelitisina15yearoldgirl.ThepresenceofZIKVinthecerebrospinalfluid(CSF)ofthose
patientssuggeststhatthevirusmightbeneurotropic.Rozeetal. [56]describedtwocasesofencephalopathyinadult
patientswithZIKVinfection.

Themicrocephalyprevalenceinfoetusesandnewbornsincreasedremarkablyduring20152016inBrazil.Thelargest
increaseoccurredintheNortheastregion,whereZIKVwasfirstreported. [57]OliveiraMeloetal. [58]showedtheevidenceof
twocasesoffoetalmicrocephalyinwomenreportingZIKVlikesymptomsduringpregnancybyultrasoundimaging,with
furtherZIKVdetectionbyRTPCRintheiramnioticfluid.ThewholeZIKVgenomewascharacterizedandpublished. [59]A
caseofconfirmedZIKVinfectioninafoetaldemisewithhydropsfetalisandmicrocephalywasreportedbySarnoetal.. [60]
SeveralotherZIKVrelatedcasesofmicrocephalyhavealsobeenreported. [6164]Noronhaetal. [65]providedadditional
evidenceofthetransplacentaltransmissionandneurotropismofZIKV.

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PolynesiaestimatedthattheriskofmicrocephalyduetoZIKVinfectioninthefirsttrimesterofpregnancywas0.95%based
oneightmicrocephalycasesidentifiedretrospectivelyinapopulationofapproximately270000peoplewithanestimated
ZIKVinfectionrateof66%. [66]

SomepregnantcohortswerealreadyestablishedtostudyinfantoutcomesexposedtoZIKV. [30,67]Brasiletal. [30]published

preliminaryresultsof88pregnantwomen.Amongthe72womenwithconfirmedZIKVinfection,42underwentprenatal
ultrasonography,andfoetalabnormalitieswereobservedin12(29%)noneofthe16womenwithnegativetestshadfoetal
abnormalities.Theabnormalitiesobservedonultrasonographyvariedwidely. [30]

Since2015,severalreportswerepublisheddescribingawiderangeofcongenitalabnormalitiesprobablyassociatedwith
ZIKVinfectioninutero.TheWHO[68]hasstartedaprocessfordefiningthespectrumofthissyndrometomapandanalyse
theclinicalmanifestationsincludingvisualabnormalities[6971]andneuroimagingfindings. [7275]

NonvectorborneModesofTransmission

Apartfromperinataltransmission,thereisincreasedevidenceofnonvectorborneformsofZIKVtransmission,including
sexualtransmission. [76]Foyetal. [39]describedclinicalandserologicevidenceindicatingthatonescientisttransmitted
ZIKVtohiswifeprobablybysexualcontactafterhisreturnhome.Venturietal. [77]retrospectivelydiagnosedacaseof
ZIKVinfectionleadingtoasecondaryautochthonouscase,probablybysexualtransmission.D'Ortenzioetal. [78]presented
acasewithmoreevidencesupportingthehypothesisforZIKVsexualtransmission(eitheroralorvaginal).Deckardetal. [79]
describedthefirstreportofZIKVtransmissionfromaninfectedmantoasexpartnerthroughanalsex.

Mussoetal. [40]detectedahighZIKVreplicativeRNAloadinsemensamples.Furthermore,highviralloadinthesemen
(100000timesmore)comparedwithurineandbloodwasdescribedina32yearoldmaninfectedbyZIKV. [80]Atkinsonet
al. [81]describedthedetectionofZIKVRNAinsemen62daysaftertheonsetofillness,butinfectiousviruswasnot
cultured.TheprolongedpresenceofvirusinsemencouldindicateaprolongedpotentialforZIKVsexualtransmission. [81]
TheCDCandWHOhaveissuedinterimguidanceforthepreventionofZIKVsexualtransmission. [82,83]

ZIKVispotentiallytransmissibleviabloodproductsandorganortissuetransplantation. [84,85]Sofar,thereisnoscientific
evidencesupportingthatZIKVcouldbetransmittedthroughhumansaliva,breastmilkandurine,althoughsomestudies
havereportedinfectivityviralparticlesconfirmedbythepresenceofacytopathiceffectontoVerocells. [8688]

LaboratorialDiagnosisofZikaInfections
ThediagnosisofZikainfectionscanbeperformedonclinicalepidemiologicalandlaboratorialbases.Currently,ZIKVcan
bedetectedindistinctclinicalspecimenssuchasblood(plasma,serum),CSF,urine,saliva,breastmilk,semen,vaginal
secretion,amnioticfluidandtissues. [28,39,59,78,8996]

Overall,thelaboratorialdiagnosisofZIKVinfectionreliesonthesameusualstrategiesusedforotherarboviruses,withviral
genomedetectionbyRTPCRtestsonacutephasesamplesandserology(ELISAandimmunofluorescence)fordetection
ofspecificantibodyagainstthevirus.Thevirusisolationmayalsobeusedinacutesamples,butitisamorelaboriousand
timeconsumingapproach,alsorequiringamorerobustinfrastructure,notavailableinmostlaboratories.However,asmany
otherflaviviruses,resultsbasedonmoreroutinelyusedserologicaltestsmaybecompromisedbyacrossreactivityin
convalescentsamplesduetopreviousflavivirusesinfections.Foramorereliableresult,flavivirusesdiagnosisshouldtest
pairedacuteandconvalescentsamples,collected23weeksaftertheonsetofsymptoms.Usually,thechoiceofthe
laboratorialapproachusedwilldependonthegoaloftheanalysis,laboratoryinfrastructure,technicalexpertiseand
samplingavailability.

Duringtheacutephaseofthedisease,virusorviralnucleicaciddetectioncanbeperformed.Thevirusisolation,despite
notbeingperformedonaroutinebasis,canbeaccomplishedusingmosquitoescells(suchasAP61,Aedes
pseudoscutellarisC6/36,Aedesalbopictus)ormammaliancelllines(suchasBHK,VERO),directlyfrominfected
mosquitoesorbyinnoculationintonewbornmice. [97100]Eventhoughtheviruscharacterizationisimportant,theisolation
maybedifficultduetothelowviremiaduringtheacutephaseofZIKVinfection. [94]

ThemostcommonlyandwidelyuseddiagnostictechniqueforZIKVdiagnosisisbasedonthevirusmoleculardetectionby
conventionalorrealtimeRTPCR,andsomeprotocolshavebeendescribedfordetectingZIKVwithinthegroup[101104]or
specifictothevirus. [94,105107]Theviralgenomedetectionbymoleculartechniquesprovidesadefinitivediagnosticresult,
butasviremiaistransient,thisapproachismostreliableifperformedwithinthefirstweekofthedisease. [94]Byusing
quantitiveRTPCR,theRNAviralloadinblood(7.28106to9.3108copiesRNA/ml),urine(2.5103to8106copies

RNA/ml),semen(1.1107to2.9107copiesRNA/ml)andbreastmilk(2.9104to2106copiesRNA/ml)couldbe
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RNA/ml),semen(1.1107to2.9107copiesRNA/ml)andbreastmilk(2.9104to2106copiesRNA/ml)couldbe
determined. [5,20,89,90,94,108]AlthoughtheZIKVgenomehasbeendetectedonamnioticfluid,cordblood,CSFand
placentabyRTPCR,themethod'ssensitivityonthosespecimensisunknown. [109]

AntiZIKVIgMandIgGantibodiescanbedetectedbyserologicalassays.However,theresultsshouldbecarefullyanalysed
duetofalsepositiveresultsfrompossiblecrossreactivitywithotherflaviviruses.ThevirusspecificIgMmaybedetectable
morethan5daysafteronsetofsymptoms.Insomecase,thesebiomarkers,indicativeofanactiveinfection,mayriseas
earlyasday3ofillnessandlastover2months. [91,94,110]Seroconversionrepresentedbyatleastafourfoldincreasein
pairedsera,acuteandconvalescentsera,isdesirableforamorereliableresult.Inaflavivirusnaivepatient,aminimal
crossreactivityisobtained,butasignificantcrossreactivityinpatientsexposedtoapreviousflavivirusinfectionisobserved,
evenonyellowfevervaccinatedpatients.

Despitethegoldstandardforthespecificdetectionofantiflavivirusanitbodies,theplaquereductiontest(PRNT), [111]useful
forcrossreactiveresultsonZIKVinfectionwhereotherflaviviruscirculate,theassayisarduousandtimeconsuming,and
specializedinfrastructureandlabpersonnelareneededduetothelivevirusmanipulation.

ForthediagnosisofZikacongenitalinfection,CDCrecommendstheperformanceofbothmolecularandserologicaltests,
asitisnotknownwhichonewouldbemorereliablefortheconditioninvestigation. [112]Withtissueavailability,
immunohistochemistryassaysmayalsobeperformedforviralantigendetection. [62]Furthermore,aimingtodiagnose
congenitalZIKVinfections,CSF,placenta,bloodcordand/orumbilicalcordtissuesfromneonatesorunbornfoetusesshall
beanalysed.

Conclusion
OurcurrentunderstandingofthepathophysiologyofZIKVinfectionneedstobestrengthenedandepidemiologicalstudies
andanimalmodelsofthediseaseneedtobedeveloped.Publicpoliciesneedtobeimplemented,effectivepreventive
measuressuchasvaccinescreatedandimprovingeffortstoreducetransmissionthroughvectorsandmorestudieson
sexualtransmissionarenecessary.Accurate,portableandinexpensivepointofcaretestsareinneedtobetteridentify
cases,especiallywhereotherarbovirusescocirculate.Duetothedifficultiesinpropagatingthevirus,antigenavailabilityin
manylaboratoriesposesaburdenforthediagnosis,andthedevelopmentanduseofrecombinantantigensaredesirable.

Sidebar
KeyPoints

EmergenceofZIKVinfectioninBrazilin2015andrapidspreadofZIKVtotheAmericas.

SeverecongenitalabnormalitiesandneurologicalcomplicationssuchasGuillainBarrsyndromearelinkedtoZIKV
infection.

IncreasingevidenceofZIKVbeingtheonlyarboviruslinkedtosexualtransmissiontodate.

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