09/03/2017 Yellowfever

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Yellowfever

Author SectionEditor DeputyEditor

ThomasPMonath,MD,FACP, MartinSHirsch,MD ElinorLBaron,MD,DTMH
FASTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2017.|Thistopiclastupdated:Jan30,2017.

INTRODUCTIONYellowfeverisamosquitoborneviralhemorrhagicfeverwithahighcasefatalityrate.Clinical
manifestationsincludehepaticdysfunction,renalfailure,coagulopathy,andshock.TravelerstotropicalregionsofSouth
AmericaandsubSaharanAfricawherethediseaseisendemicareatriskforacquisitionofinfectionandrequire
immunization.

Issuesrelatedtovirology,pathogenesis,epidemiology,clinicalmanifestations,diagnosis,treatment,andpreventionof
yellowfeverwillbereviewedhere.

VIROLOGY,PATHOGENESIS,ANDHISTOPATHOLOGYYellowfeveristheprototypememberofthefamily
Flaviviridae,agroupofsmall(40to60nm),enveloped,positivesense,singlestrandedRNAvirusesthatreplicateinthe
cytoplasmofinfectedcells.Yellowfevervirusisasingleserotypeandisantigenicallyconserved,sothevaccine
protectsagainstallstrainsofthevirus.Atthenucleotidesequencelevel,itispossibletodistinguishsevenmajor
genotypesrepresentingWestAfrica(twogenotypes),CentralEastAfricaandAngola(threegenotypes),andSouth
America(twogenotypes)[1,2].Humansarehighlysusceptibletoinfectionanddisease.Mostnonhumanprimate
speciesaresusceptibletoinfection,andsomespeciesofnonhumanprimatesdevelopclinicalmanifestations.

Aninfectedfemalemosquitoinoculatesapproximately1000to100,000virusparticlesintradermallyduringblood
feeding.Virusreplicationbeginsatthesiteofinoculation,probablyindendriticcellsintheepidermis,andspreads
throughlymphaticchannelstoregionallymphnodes.Lymphoidcells,particularlymonocytemacrophagesandlarge
histiocytes,appeartobethepreferredcelltypesforprimaryreplication.Thevirusreachesotherorgansviathelymph
andthenthebloodstream,seedingothertissues.Largeamountsofvirusareproducedintheliver,lymphnodes,and
spleenandarereleasedintotheblood.Duringtheviremicphase(daysthreetosix),infectionmaybetransmittedto
bloodfeedingmosquitoes.

Yellowfeverischaracterizedbyhepaticdysfunction,renalfailure,coagulopathy,andshock[36].Themidzoneofthe
liverlobuleisprincipallyaffected,withsparingofcellsborderingthecentralveinandportaltracts[7].Viralantigen
localizestothemidzone,indicatingthatitisthesiteofdirectviralinjury.Veryhighvirusloadshavebeenfoundinthe
liverandspleenoffatalcases[8].

Injurytohepatocytesischaracterizedbyeosinophilicdegenerationwithcondensednuclearchromatin(Councilman
bodies)ratherthanbytheballooningandrarefactionnecrosisseeninviralhepatitis.Livercelldeathisduetoapoptosis.
HepatocytesinthemidzoneoftheliverlobuleexpressFasligand,andlymphocytesinfiltratingthelivermediate
apoptosis.Inflammatorycells,mainlyCD4+cells,arepresentinlownumberssmallernumbersofNKandCD8+cells
arepresent[9,10].Thereisnodisruptionofthereticulararchitectureoftheliver.Innonfatalcases,healingiscomplete
withoutpostnecroticfibrosis.Infatalcases,approximately80percentofhepatocytesundergocoagulativenecrosis.

Renaldamageischaracterizedbyeosinophilicdegenerationandfattychangeofrenaltubularepitheliumwithout
inflammation.Thesefindingsarebelievedtobearesultofbothdirectviralinjuryandnonspecificchangesdueto
hypotensionandthehepatorenalsyndrome[5].

Focalinjurytothemyocardium,characterizedbycelldegenerationandfattychange,istheresultofviralreplication.

ThehemorrhagicdiathesisinyellowfeverisduetodecreasedsynthesisofvitaminKdependentcoagulationfactorsby
theliver,disseminatedintravascularcoagulation,andplateletdysfunction.

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Thelatephaseofthediseaseischaracterizedbycirculatoryshock.Theunderlyingmechanismmaybecytokine
dysregulation,asinthesepsissyndrome.Inaseriesofpatientswithfatalyellowfever,levelsofproinflammatory
cytokines(interleukin[IL]6,IL1receptorantagonist,tumornecrosisfactor[TNF]alpha,andinterferoninducibleprotein
10)wereelevatedcomparedwithpatientswithnonfatalyellowfever[11].Patientsdyingofyellowfeverhavecerebral
edemaatautopsy,probablytheresultofmicrovasculardysfunction.Largeamountsofcomplementfixingantigen
(presumablyNS1)havebeenfoundinbloodofseverelyillyellowfeverpatients[12].

Somenonhumanprimatespeciesdevelopfatalinfectionwithfeaturessimilartothediseaseinhumans[5].Amodelof
yellowfeverinfectioninhamstershasbeendescribed[13,14].Clinical,immunologic,andpathologicfeaturesresemble
humaninfection,suggestingthatthismodelmightservetoincreasetheunderstandingofthepathogenesisofinfection
andtoexplorepossibletreatments.Interferonalpha/betareceptordeficientmicearealsosusceptibletoviscerotropic
infection[15].

EPIDEMIOLOGYYellowfeveroccursintropicalregionsofsubSaharanAfricaandSouthAmericaitisanepidemic
diseaseproblemofconsiderablemagnitude[16,17].Theincidenceofendemicdiseaseisnotwellestablished,but
approximately1percentofindividualswithseverehepatitisinendemicareasofAfricamaybecausedbyyellowfever
[18].Anestimatefromserologicandepidemiologicdataconcludedthattherewere130,000caseswithviscerotropic
diseaseand78,000deathsinAfricain2013[19].

TheincidenceofyellowfeverinAfricavarieswidely,andthediseaseoccursinepidemics[16].AlargeAedesaegypti
borneepidemicoccurredinAngolaandneighboringDemocraticRepublicoftheCongoinsouth/centralAfricabetween
December2015andJuly2016withover2930confirmedorsuspectedcasesand253deathsandresultinginthe
emergencydistributionof30milliondosesofvaccine[20,21].MosquitoborneepidemicsinAfricaoccurwherelarge
humanpopulationsresideinhighdensityandimmunizationcoverageislow.Thehighestnumberofoutbreakshas
occurredinWestAfrica,butthissituationischangingduetoaconcertedefforttoundertakemassimmunization
campaignsinthatregion.Humantohumantransmissionintheabsenceofthemosquitohasnotbeenreported.

FewercasesoccurinSouthAmericathaninAfricabecausetransmissionoccursfromenzooticsources(principally
frommonkeytohumanviamosquitovectors),thevectordensityisrelativelylow,andvaccinationcoverageisrelatively
high(80to90percentinendemicareasofSouthAmerica).Intypicalyears,thereareseveralhundredcasesofficially
notified,butinepidemicyearsupto5000casesarereported.AnoutbreakintheBrazilianstateofMinasGeraisbegan
inJanuary2017inanareawithrelativelylowvaccinationcoverage[22].

InAfricaandSouthAmerica,onlyasmallproportionofcasesisofficiallyrecordedbecausethediseaseoftenoccursin
remoteareas,recognitionofoutbreaksisdelayed,anddiagnosticfacilitiesarelimited.InAfrica,reportsofoutbreaksin
the1980snotedtheincidenceofyellowfeverinfectiontobe20to40percent,theincidenceofseverediseasetobe3to
5percent,andthecasefatalityratetobe20to30percent.Incontrast,casefatalityratesinSouthAmericaare
consistently50to60percent.Itisuncertainwhetherthesedisparitiesreflectreportingartifact,arealdifferenceinvirus
strainvirulence,and/ordifferinggeneticsusceptibilityofthehumanpopulations.Aracialdifferenceinsusceptibilityis
likely,supportedbyananalysisofepidemiologicdatafroman1878epidemicinTennessee,inwhichyellowfeverattack
ratesweresimilarintheCaucasianandnonCaucasianpopulationsofthecity,butthecasefatalityratewas6.8fold
higherinCaucasians[23].

YellowfeverepidemicshaveneverbeenreportedinAsia,andintroductiontothatregioncouldhavedevastatingeffects
sincethereisnobackgroundofspecificimmunity,andtheurbanvector(Aedesaegypti)isprevalent.Inthecontextof
the2016yellowfeveroutbreakinAngola,atleast11Chineseworkershavedevelopedyellowfeverupontravelhometo
China,illustratingthedangerofintroductionandpotentialsecondaryspread[24].

PriortothereportsamongtravelersfromAngola,yellowfeverinexpatriatesandtravelerstoandfromAfricaandSouth
AmericahasbeenraresincetheintroductionofvaccinationafterWorldWarII.Sincethattime,10caseshadbeen
recordeduptothetimeofthe2016Angolanoutbreak[8,2529].ThesituationinAngolaappearstobelinkedtoalarge
numberofChineseconstructionworkersandotherexpatriateswhoenteredthecountrywithoutvaccination.Changesin
humandemography,particularlyexpansionofurbanpopulationsthroughoutthetropics,expansionofairtravel,and
rapidspreadofotherviruses(dengue,Zika,chikungunya)transmittedbetweenhumansbyurbanAe.aegyptithroughout
thesouthernhemisphereillustratetheglobaldangersassociatedwithexportationandspreadofyellowfever.

TransmissioncyclesTheprimarytransmissioncycleinvolvesmonkeysanddaytimebitingmosquitoes(Aedes
speciesinAfrica,HaemagogusspeciesinSouthAmerica).

InAfrica,awidearrayofAedesvectorsisresponsiblefortransmission.Duringtherainyseason,theviruscirculatesvia
mosquitoesinthesavannavegetationalzoneinproximitytohumansettlements.Bothhumansandnonhumanprimates
canbehostsinthetransmissioncycle,andtherateofvirustransmissionmayacceleratetoreachepidemiclevels.
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Aedesaegypti,acommondomesticmosquitothatcanbreedincontainersusedtostorepotablewaterinheavily
settledareas,iscapableofservingasanepidemicvectorwithhumansastheintermediateviremichosts(socalled
"urbanyellowfever").

InSouthAmerica,thelarvaldevelopmentofmosquitoesoccursinareassuchastreeholescontainingrainwater.
Personsenteringforestedareasareatriskofinfection(socalled"jungleyellowfever")thisaccountsforthe
predominanceofcasesamongyoungmalesengagedinforestclearingandagriculture.Inthe1970s,theAedesaegypti
mosquitoreinvadedareasofSouthAmericawhereitpreviouslyhadbeeneradicated,increasingtheriskthaturban
yellowfevermayreemerge.Thefirstwelldocumentedinstanceofanurbancycleepidemicsince1942occurredin
Paraguayin2008[30].

CLINICALMANIFESTATIONSTheclinicalspectrumofyellowfeverincludes[31]:

Subclinicalinfection
Abortive,nonspecificfebrileillnesswithoutjaundice
Lifethreateningdiseasewithfever,jaundice,renalfailure,andhemorrhage

Yellowfeveraffectsallages,butdiseaseseverityandlethalityishighestinolderadults.Theonsetofillnessappears
abruptlythreetosixdays(median4.3days)afterthebiteofaninfectedmosquito[32].Theclassicalillnessis
characterizedbythreestages:

Periodofinfection
Periodofremission
Periodofintoxication

PeriodofinfectionTheperiodofinfectionconsistsofviremia,whichlastsforthreetofourdays.Thepatientis
febrileandcomplainsofgeneralizedmalaise,headache,photophobia,lumbosacralpain,paininthelowerextremities,
myalgia,anorexia,nausea,vomiting,restlessness,irritability,anddizziness[33].Symptomsandsignsarerelatively
nonspecificatthisphase,itisvirtuallyimpossibletodistinguishyellowfeverfromotheracuteinfections.

Onphysicalexamination,thepatientappearsacutelyillwithflushedskin,reddeningoftheconjunctivaeandgums,and
epigastrictenderness.Enlargementoftheliverwithtendernessmaybepresent.Thetongueischaracteristicallyredat
thetipandsideswithawhitecoatinginthecenter.Thepulserateisslowrelativetotheheightofthefever(Faget's
sign).Thetemperatureistypically39Cbutmayriseashighas41C.

Laboratoryabnormalitiesincludeleukopenia(1500to2500permicroL)withrelativeneutropenialeukopeniaoccurs
rapidlyaftertheonsetofillness.Serumtransaminaselevelsstarttorise48and72hoursafteronsetofillness,priorto
theappearanceofjaundice.Thedegreeofliverenzymeabnormalitiesatthisstagemaypredicttheseverityofhepatic
dysfunctionlaterintheillness[34].

PeriodofremissionAperiodofremissionlastingupto48hoursmayfollowtheperiodofinfection,characterized
bytheabatementoffeverandsymptoms.Patientswithabortiveinfectionsrecoveratthisstage.Approximately15
percentofindividualsinfectedwithyellowfevervirusenterthethirdstageofthedisease.

PeriodofintoxicationTheperiodofintoxicationbeginsonthethirdtosixthdayaftertheonsetofinfectionwith
returnoffever,prostration,nausea,vomiting,epigastricpain,jaundice,oliguria,andhemorrhagicdiathesis.Theviremia
terminatesatthisstageandantibodiesappearintheblood.Thisphaseischaracterizedbyvariabledysfunctionof
multipleorgansincludingtheliver,kidneys,andcardiovascularsystem.Multiorganfailureinyellowfeverisassociated
withhighlevelsofproinflammatorycytokinessimilartothatseeninbacterialsepsisandsystemicimmuneresponse
syndrome(SIRS)[27].

HepaticdysfunctionHepaticdysfunctionduetoyellowfeverdiffersfromotherviralhepatitidesinthatserum
aspartateaminotransferase(AST)levelsexceedthoseofalanineaminotransferase(ALT).Thismaybedueto
concomitantviralinjurytothemyocardiumandskeletalmuscle.Thelevelsareproportionaltodiseaseseverity.Inone
study,themeanASTandALTlevelsinfatalcaseswere2766and660U,respectively,whileinsurvivingpatientswith
jaundice,themeanlevelswere929and351U[35].Alkalinephosphataselevelsarenormaloronlyslightlyelevated.
Directbilirubinlevelsaretypicallybetween5and10mg/dL,withhigherlevelsinfatalthaninnonfatalcases[36].

RenaldysfunctionRenaldamageischaracterizedbyoliguria,azotemia,andveryhighlevelsofproteininthe
urine.Serumcreatininelevelsarethreetoeighttimesnormal.Insomepatientswhosurvivethehepatiticphase,renal
failurepredominates.Deathisprecededbyvirtuallycompleteanuria.

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HemorrhageHemorrhageisaprominentcomponentofthethirdphaseofillness,includingcoffeegrounds
hematemesis,melena,hematuria,metrorrhagia,petechiae,ecchymoses,epistaxis,oozingofbloodfromthegums,and
bleedingfromneedlepuncturesites.Gastrointestinalhemorrhagemaycontributetocirculatorycollapse.Laboratory
abnormalitiesincludethrombocytopenia,prolongedprothrombintime,andglobalreductionsinclottingfactors
synthesizedbytheliver(factorsII,V,VII,IX,andX).Somepatientshavefindingssuggestingdisseminatedintravascular
coagulation,includingdiminishedfibrinogenandfactorVIIIandthepresenceoffibrinsplitproducts.

MyocardialinjuryTheclinicalsignificanceofmyocardialinjuryispoorlyunderstoodandprobablyhasbeen
underestimatedinclinicalstudies.Insomecases,acutecardiacenlargementhasbeendocumentedduringthecourse
ofinfection[37].Theelectrocardiogrammayshowsinusbradycardiawithoutconductiondefects,STTabnormalities,
particularlyelevatedTwaves,andextrasystoles.Bradycardiaandmyocarditismaycontributetohypotension,reduced
perfusion,andmetabolicacidosisinseverecases.Arrhythmiahasbeensuggestedtoexplaintherarereportsoflate
deathduringconvalescence.

CentralnervoussystemdysfunctionPatientsexhibitvariablesignsofcentralnervoussystem(CNS)
dysfunctionincludingdelirium,agitation,convulsions,stupor,andcoma.Inseverecases,thecerebrospinalfluidis
underincreasedpressureandmaycontainelevatedproteinbutnocells.Pathologicchangesincludemicroscopic
perivascularhemorrhagesandedema.Giventheabsenceofinflammatorychangessuggestingviralneuroinvasionand
encephalitis,CNSalterationsareprobablyduetometabolicencephalopathy.Trueyellowfeverviralencephalitisis
exceedinglyrare.

OutcomeTheoutcomeisdeterminedduringthesecondweekafteronset,atwhichpointthepatienteitherdiesor
rapidlyrecovers.Approximately20to50percentofpatientswhoentertheperiodofintoxicationsuccumbtothe
disease.Poorprognosticsignsincludeanuria,shock,hypothermia,agitation,delirium,intractablehiccups,seizures,
hypoglycemia,hyperkalemia,metabolicacidosis,CheyneStokesrespirations,stupor,andcoma.

Convalescencemaybeassociatedwithfatiguelastingforseveralweeks.Insomecases,jaundiceandserum
transaminaseelevationsmaypersistformonths,althoughsuchpatientsmayhaveyellowfeversuperimposedonother
hematologicorhepaticdiseases.Theoutcomeofyellowfeverappearstobecomparableinpatientswithorwithout
hepatitisBsurfaceantigenemia.

Complicationsofyellowfeverincludebacterialsuperinfections,suchaspneumonia,parotitis,andsepsis.Latedeaths
duringconvalescenceoccurrarelyandhavebeenattributedtomyocarditis,arrhythmia,orheartfailure.

DIAGNOSISDiagnosisismadebyserology,detectionofviralgenomebypolymerasechainreaction(PCR),byviral
isolationorhistopathology,andimmunohistochemistryonpostmortemtissues.

SerologySerologicdiagnosisisbestaccomplishedusinganenzymelinkedimmunosorbentassay(ELISA)forIgM.
ThepresenceofIgMantibodiesinasinglesampleprovidesapresumptivediagnosisconfirmationismadebyarisein
titerbetweenpairedacuteandconvalescentsamplesorafallbetweenearlyandlateconvalescentsamples.

PersistenceofantibodiesfromearlierreceiptoftheliveattenuatedvaccinecancomplicateinterpretationofIgMresults
[38].Inaddition,crossreactionswithotherflavivirusescomplicatethediagnosisofyellowfeverbyserologicmethods,
particularlyinAfricawheremultipleflavivirusescirculate.Theneutralizationtestismorespecificbutrequiresa
specializedlaboratory.

RapiddiagnostictestsRapiddiagnostictestsincludePCRtodetectviralgenomeinthebloodortissueandELISA
fordeterminationofIgMantibody[8].NextgenerationsequencingofRNAdirectlyamplifiedfrombloodhasbeenusedto
confirmthediagnosisandcomparethepatientsstraintoknowngeographiccladesofthevirus.Thesetoolsare
increasinglyavailableinnationalandregionallaboratoriesintheendemicareas.Areversetranscriptionloopmediated
isothermalamplification(RTLAMP)yellowfeverdiagnostictest,whichdoesnotrequirethermocyclingequipmentand
canbereadvisually,hasshownpromiseasasensitiveandrapidtestforuseinfieldconditions[39].

VirusisolationVirusisolationisaccomplishedbyinoculationofmosquitoormammaliancellcultures,intracerebral
inoculationofsucklingmice,orintrathoracicinoculationofmosquitoes.Thevirusmayalsoberecoveredfrom
postmortemlivertissue.DuringayellowfeveroutbreakinIvoryCoastin1982including90confirmedcases,30percent
werediagnosedbyvirusisolationfromthebloodthemajorityofpatientshaddetectableviruspriortoonsetofjaundice
[40].

PathologyLiverbiopsyduringillnessduetoyellowfevershouldneverbeperformed,sincefatalhemorrhagemay
ensue.Postmortemhistopathologicexaminationoftheliveroftendemonstratesthetypicalfeaturesofyellowfever
includingmidzonalnecrosis.Adefinitivepostmortemdiagnosismaybemadebyimmunocytochemicalstainingfor

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yellowfeverantigenintheliver,heart,spleen,orkidney[4143].(See'Virology,pathogenesis,andhistopathology'
above.)

DIFFERENTIALDIAGNOSISThedifferentialdiagnosisofyellowfeverincludes:

Viralhepatitis(hepatitisA,B,C,D,andE)Theseentitiesarecharacterizedbyelevatedtransaminases
hepatitisAandEareacuteinfectionstransmittedmostfrequentlybythefecaloralroute,whereashepatitisB,C,
andDcanpresentacutelyorchronicallyandaretransmittedbybodyfluids.InAfrica,severeandfatalhepatitisE
inpregnancyhasfrequentlybeenmisdiagnosedasyellowfever.(Seerelatedtopics.)

InfluenzaInfluenzaisassociatedwithfever,headache,malaise,andmyalgias.Itisnotgenerallyassociatedwith
severehepaticinvolvementorjaundice.Thediagnosisisestablishedbyviraldetection(table1).(See"Clinical
manifestationsofseasonalinfluenzainadults".)

DengueDengueandyellowfeveraresimilarinthatbothareassociatedwithfever,headacheandbodyaches,
andhemorrhagicmanifestations.Hepaticinvolvementcanoccurinthesettingofseveredengueinfection.The
diagnosisofdengueisestablishedbyserology.(See"Denguevirusinfection:Clinicalmanifestationsand
diagnosis".)

MalariaMalariaischaracterizedbyfeverandanemiaclinicalmanifestationsincludejaundiceduetohemolysis.
Thediagnosisofmalariaisestablishedbyvisualizationofparasitesonperipheralsmear.(See"Clinical
manifestationsofmalariainnonpregnantadultsandchildren".)

TyphoidManifestationsoftyphoidfeverincludefeverandgastrointestinalsymptoms.Abnormalliverfunction
testsareobservedbutjaundiceisnotatypicalclinicalfeature.Thediagnosisisestablishedbyculture.(See
"Epidemiology,microbiology,clinicalmanifestations,anddiagnosisoftyphoidfever".)

LeptospirosisLeptospirosisisabacterialinfectioncharacterizedbyfever,myalgia,headache,andconjunctival
suffusion.Modestelevationofhepatictransaminasesmaybeobserved.Thediagnosisisestablishedbyserology.
(See"Epidemiology,microbiology,clinicalmanifestations,anddiagnosisofleptospirosis".)

QfeverQfeveroccursasaresultofinfectionwithCoxiellaburnetiihepaticinvolvementincludeselevated
transaminases,hepatomegalywithoutjaundice,andgranulomasonliverbiopsy.Thediagnosisisestablishedby
serology.(See"ClinicalmanifestationsanddiagnosisofQfever".)

HemorrhagicfeverYellowfevermaybedistinguishedfromotherviralhemorrhagicfevers(Lassafever,Marburg
virus,Ebolavirus,BolivianandArgentinehemorrhagicfevers)inthattheseotherviralhemorrhagicfeversarenot
usuallyassociatedwithjaundice.However,CongoCrimeanhemorrhagicfevermaybeassociatedwithsevereliver
damageRiftValleyfeveranddenguehemorrhagicfevermaypresentwiththiscomplicationaswell.(Seerelated
topics.)

TREATMENTThetreatmentofyellowfeverconsistsofsupportivecarethereisnospecificantiviraltherapyavailable
[44].Managementofpatientsmaybeimprovedbymodernintensivecare,butthisisgenerallynotavailableinremote
areaswhereyellowfeveroftenoccurs.TravelershospitalizedafterreturntotheUnitedStatesorEuropehavehadfatal
outcomesinspiteofintensivecare,demonstratingtheinexorablecourseofsevereyellowfever.

Supportivecareshouldincludemaintenanceofnutrition,preventionofhypoglycemia,nasogastricsuctiontoprevent
gastricdistentionandaspiration,treatmentofhypotensionbyfluidreplacementandvasoactivedrugsifnecessary,
administrationofoxygen,managementofmetabolicacidosis,treatmentofbleedingwithfreshfrozenplasma,dialysisif
indicatedbyrenalfailure,andtreatmentofsecondaryinfections[31].

Allantiviraltherapiesareataveryearlystageofdevelopmentforuseinyellowfever[31,44,45].Ribavirinisactive
againstyellowfevervirusbutonlyatveryhighconcentrationsthatmaynotbeachievableclinically[46].

Thebenefitofhyperimmuneglobulinormonoclonalantibodyaftertheonsetofclinicalillnessisuncertainfurtherstudy
isrequired[44,47,48].

PREVENTIONVaccinationistheprimarytoolforpreventionofyellowfever.

VaccinationAliveattenuatedvaccineagainstyellowfeverwasdevelopedin1936(yellowfever17Dvaccine).Inthe
UnitedStates,thevaccine(YFVAX)ismanufacturedbySanofiPasteur(Swiftwater,PA).Anothervaccineformulation
derivedfromadifferentpassageseriesofthesamevaccinevirusstrain,17DD,ismanufacturedinBrazil[49].Thereare
sixmanufacturersofyellowfevervaccineworldwide,whichproduceabout70to90milliondosesannuallyfourare

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approvedbytheWorldHealthOrganization(WHO)andsupplythevastmajorityofdoses.Ingeneralsupplydoesnot
meetdemandexpansionofvaccineproductionisexpected.

TheWHOmaintainsanemergencystockpileofsixmilliondosesthiswasdepletedandreplenishedthreetimesinthe
2016Angolanoutbreak.Becausevaccinewasinshortsupplyinthe2016outbreaks,andtherewasapprehensionabout
spreadofyellowfevertoothercountries,especiallyAsia,WHOconsideredandapprovedtheuseoffractional(1/5th)
doses(0.1mLgivenbysubcutaneousroute)inemergencyconditions.(See'Fractionaldosinginoutbreaks'below.)

In2016,theWHOannouncedanewprogram,EliminateYellowFeverEpidemics(EYE),whichwillincorporatethree
pillars:preventionofyellowfeverinatriskpopulations,preventionofinternationalspread,andcontainmentofoutbreaks
rapidly[50].Theprogramwillensuremoreinclusive17DvaccinationsintheExpandedProgrammeofImmunization,
massvaccinationcampaigns,andreadinessforemergencycontrolofoutbreaks,includingimprovedsurveillanceand
laboratorydiagnosis.

ClinicalapproachTheestimatedrisksofillnessanddeathduetoyellowfeverinanunvaccinatedtravelertoan
endemicareaarerelativelyhigh(1in1000and1in5000permonth,respectively)[51].IntheUnitedStates,therisksof
YELANDandYELAVDintravelersareestimatedat0.8and0.4per100,000respectively,althoughtheriskishigherin
olderadults.(See'Adverseeffects'below.)

WhomtovaccinateInaccordancewiththeUnitedStatesCentersforDiseaseControlandPrevention
(CDC),theUnitedStatesAdvisoryCommitteeonImmunizationPractices(ACIP),andtheWorldHealthOrganization,
werecommendvaccinationfortravelerstoyellowfeverendemicareasofAfricaandSouthAmericaandforresidentsof
thoseareas(figure1andfigure2)[5154].

InJune2015,theACIPissuedrecommendationsstatingthatasingleprimarydoseofyellowfevervaccineisadequate
formosttravelers[55].InJuly2016,theWorldHealthAssemblyremovedthe10yearboosterdoserequirementfrom
theInternationalHealthRegulations.

Nevertheless,theACIPdoesrecommendadditionaldosesofyellowfevervaccineforthefollowingpatients[55]:

Womenwhowerepregnantatthetimeofinitialyellowfevervaccinationshouldreceiveoneadditionaldoseof
yellowfevervaccinepriortosubsequenttraveltoanareawithriskforyellowfevervirusinfection.

Individualswhoreceivedahematopoieticstemcelltransplantafterreceivingyellowfevervaccinationandwhoare
sufficientlyimmunocompetenttobesafelyvaccinatedshouldreceiveanadditionaldoseofyellowfevervaccine
priortosubsequenttraveltoanareawithriskforyellowfevervirusinfection.

IndividualswhowereinfectedwithHIVatthetimeofprioryellowfevervaccination,withcontinuedriskforyellow
fevervirusinfection,shouldreceiveaboosterdoseofyellowfevervaccineevery10years.

Individualswhoselastdoseofyellowfevervaccinewasatleast10yearspreviouslyandplantospendaprolonged
periodinendemicareas,plantotraveltohighlyendemicareas(suchasruralWestAfrica)duringpeak
transmissionseason,orplantotraveltoanareawithanongoingoutbreakshouldreceiveanadditionaldoseof
yellowfevervaccine.

Laboratoryworkerswhoroutinelyhandleyellowfevervirusshouldhaveantibodytitersmeasuredatleastevery10
yearstodetermineifadditionalvaccinationiswarranted.

Abiweekly"BlueSheet"SummaryofHealthInformationforInternationalTravelpublishedbytheCDCprovidesupdated
informationoncountriesofficiallyreportingyellowfever[56].Inaddition,thereisafreecourseavailableonlinethat
providesinformationandtrainingaboutyellowfevertohealthcareprofessionalswhoadvisetravelers[57].TheWHOis
revisingthegeographicriskareastocreateanevidencebasedanalysisoftheprobabilityofexposuretoyellowfever
[54].

Duetotheriskofseriousadverseevents(particularlyinpersons>60yearsofage),thebenefitofimmunizationshould
beestablishedbasedoncarefulreviewofthetraveler'sitinerarywithrespecttopotentialforexposuretoyellowfever
virus[18].Individualstravelinginruralareasofcountrieswithinyellowfeverendemiczonesshouldbeimmunizedevenin
theabsenceofofficialyellowfeverreports,sinceactivetransmissionmaybeunderrecognized.

Forindividualswithallergytoeggproteinswhoclearlyrequireimmunizationduetopossibleexposuretoyellowfever
virus,epidermalscratchandintradermalskintestingmaybeperformedtohelpascertainwhetherthevaccinecanbe
givensafely.Otherwise,desensitizationmaybeused[58].Skintestinganddesensitizationarebestperformedbyan
experiencedallergist.(See"Allergicreactionstovaccines".)

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VaccinationagainstyellowfeverinendemicareasisperformedaspartoftheExpandedProgramofImmunizationat
ninemonthsofage.InsomeAfricancountries,catchupmassvaccinationcampaignsareundertakenbasedon
assessmentsofgeographicrisk,aspartofahighlysuccessfulinitiativespearheadedbytheWHOtoincreasevaccine
coverage[59,60].MasscampaignsarealsoconductedinresponsetooutbreaksinAfricaandSouthAmerica.

CertificatesIntheUnitedStates,yellowfevervaccineisdistributedonlythroughapprovedvaccinating
centers,includingtravelclinicsandsomehealthdepartments.Thesedesignatedcentersarelistedinaregistryatthe
CDCtravelwebsite[56].

SomecountriesinyellowfeverendemiczonesrequireaWorldHealthOrganizationinternationalcertificateof
vaccinationasevidenceofyellowfeverimmunizationpriortoentrythesearelistedinthepublicationsandwebsitesof
theCDCandWHO[52,56,61].Inaddition,somecountriesoutsideofyellowfeverzonesalsorequireevidenceof
immunizationspriortoentryforindividualswithrecenttravelinendemiccountries[62].

TheWHOinternationalcertificateofimmunizationforinternationaltravelisvalidforlife.

Individualswithcontraindicationsorprecautionsdeemedtoplacethetravelerathighriskofadverseeventsmayreceive
awaiverletterfromaphysicianfortraveltoareaswherevaccinationisaninternationaltravelrequirement.

The2016Angolaoutbreakrevealedthatmultipleexpatriatesworkinginthecountryhadenteredthecountrywithout
vaccinationsasaresult,therehavebeenreportsofyellowfevercasesinpersonstravellingfromAngolatothe
DemocraticRepublicoftheCongo,Kenya,andChina.Thissituationillustratesthepotentialforglobalspreadofthe
virus.

FractionaldosinginoutbreaksFractionaldosingisastrategyforextendingyellowfevervaccinesupplyin
outbreaksituations[63,64].Individualsvaccinatedwith1/10thestandardyellowfevervaccinedosehavesimilarinnate
andadaptiveimmuneresponsestoindividualsvaccinatedwiththefullstandarddose(approximately20,000infectious
unitsin0.5mL)[65,66].

InJune2016,theWHOStrategicAdvisoryGroupofExperts(SAGE)onImmunizationstatedthatvaccinationwithone
fifththestandarddoseissufficienttoprovideprotectionagainstyellowfeverforatleast12months,andtheyadvocated
shorttermuseofthisapproachamongindividuals>2yearsinemergencyconditionswhenvaccinesuppliesarelimited
[67,68].ThisstrategywasemployedintheDemocraticRepublicoftheCongoin2016.Thetiterofvaccineshouldbe
reviewedtoensurethatthedelivereddoseexceedstheminimuminternationalstandard(1000infectiousunits).
Fractionaldosingofyellowfevervaccinationnotqualityforinternationalcertificateofvaccination.(See'Certificates'
above.)

Fulldosevaccineshouldbegiventochildrenunder2yearssincetherearesomeconcernsaboutlowerefficacyofthe
vaccineinyoungchildren[69].Moreover,nostudiesoffractionaldosehavebeendoneinAfricanpopulations(which
appeartorespondlesswelltoyellowfever17D)[70],children,HIVpositiveindividuals,orpregnantwomen,andthe
durabilityoffractionaldosevaccinationbeyondoneyearisunknown.

PregnancyandbreastfeedingPregnancyisaprecautionforyellowfevervaccineadministrationin
contrast,mostotherlivevaccinesarecontraindicatedinpregnancy.Iftravelisunavoidableandtherisksforyellowfever
virusexposurearefelttooutweighthevaccinationrisks,apregnantwomanshouldbevaccinated.Iftherisksfor
vaccinationarefelttooutweightherisksforyellowfevervirusexposure,pregnantwomenshouldbeissuedamedical
waivertofulfillhealthregulations[71].

Thesafetyofyellowfevervaccinationduringpregnancyhasnotbeenclearlyestablished.Congenitalinfectionappears
tooccuratalowrate(probably1to2percent)andhasneverbeenassociatedwithfetalabnormalities[72,73].Pregnant
womanwhoinadvertentlyreceivevaccinationshouldbereassuredthereisnorationaletointerruptthepregnancy.

Administrationofyellowfevervaccinetobreastfeedingwomenshouldbeavoidedexceptinsituationswhereexposureto
yellowfevervirusescannotbeavoidedorpostponed.Yellowfevervaccineviruscanbetransmittedviabreastfeedingin
onereport,twoinfantsacquiredyellowfevervaccinevirusviabreastmilkfrommotherswhohadundergoneyellowfever
vaccinationtheinfantdevelopedYELANDrequiringhospitalization[74,75].

ImmunocompromisedindividualsYellowfever17Dvaccineshouldnotbeadministeredto
immunocompromisedindividualsbecauseoftheoreticalconcernsaboutliveattenuatedvirusvaccines[71].

Contraindicationsincludeinheritedimmunedeficiency,lymphoma,leukemia,HIV/AIDSwithlowCD4counts,
immunosuppressivechemotherapyorradiotherapy,thymusdisorders,DiGeorge'ssyndrome,andahistoryof
thymectomy.AutoimmunediseasemaybeariskfactorforYELAVDbutisnotalistedprecautioninthevaccinelabel.

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Immunogenicityseemssatisfactoryamongpatientsreceivingsystemiccorticosteroidtherapy(medianprednisone7
mg/dayfor10months),althoughlocalreactionsmayoccurmorefrequentlyinthesepatientsfurtherstudyisneeded
[76].

TravelerswithasymptomaticHIVinfectionmaybeimmunizedifpotentialexposurewarrantssuchpatientsshouldbe
advisedofthepossiblerisksofvaccination[71].InstudiesofHIVinfectedpatientswithCD4+countsabove200/microL,
allrespondedserologicallyandnonehadadverseevents[77,78].Nevertheless,itisprudenttoconfirmdevelopmentof
neutralizingantibodies,sincesuchindividualsmayhaveanimpairedabilitytorespondtoyellowfevervaccine.Antibody
testingcanbearrangedthroughstatehealthdepartmentlaboratoriesoracommerciallaboratory.Waiverletterscan
alsobeobtainedforthesepatients[71].

VaccineefficacyThe17Dvaccineproduceshighlevelsofprotection[79].Protectiveimmunityoccursin90
percentofindividualswithin10daysafterreceivingthe0.5mLsubcutaneousdoseandinnearly100percentof
individualswithinthreetofourweeksaftervaccination.Ametaanalysisofstudiesofvaccineefficacyshowedthat97.5
percentofvaccinatedindividualsmountedaprotectiveserologicresponse(95%CI82.9to99.7percent)[80].The17DD
vaccineproducessimilarlevelsofprotection[49].

Infants,toddlers,pregnantwomen,andpersonswithHIVorothercausesofimmunesuppressionmaynotrespondas
vigorouslytothe17Dvaccine[81].Inonelargestudy,theprimaryvaccinefailurerateinyoungchildrenwas
approximately9percent[69].

Immunityafterasingledoseislonglastingandmayprovidelifetimeprotection[81].TheWHOStrategicAdvisoryGroup
ofExpertsinImmunizationconcludedin2013thatasingleprimarydoseofyellowfevervaccineissufficienttoconfer
sustainedimmunityandlifelongprotectionagainstyellowfeverdisease,andaboosterdoseofthevaccineisnot
needed[82,83].InMay2014,theWorldHealthAssemblyadoptedtherecommendationtoremovethe10yearbooster
doserequirementfromtheInternationalHealthRegulationsbyJune2016.In2015,theUnitedStatesAdvisory
CommitteeonImmunizationPracticesissuedrecommendationsstatingthatasingleprimarydoseofyellowfever
vaccineisadequateformosttravelers[84].(See'Whomtovaccinate'above.)

TheWHOinternationalcertificateofimmunizationforinternationaltravelisvalidfor10yearsabooster0.5mLdoseis
requiredevery10yearsforthecertificatetobereissued.InMay2014,theWorldHealthAssemblyadoptedthe
recommendationtoremovethe10yearboosterdoserequirementfromtheInternationalHealthRegulationsandthis
wasformallyimplementedinJuly2016.Revaccinationisnolongerrequiredandacertificateofvaccinationisnowvalid
forlife.

Theliveattenuatedvaccinevirusactivatesmyeloidandplasmacytoiddendriticcellstoproduceavarietyof
proinflammatorycytokinesandturnongenesthatactivatesignalingpathways[8591].Overall,amarkedupregulationof
theinnateimmunesystempersistsforabouttwoweeksaftervaccinationanddrivestheadaptiveimmuneresponse.

AdverseeffectsMorethan600milliondosesofvaccineshavebeenadministeredsincethe17Dvaccinestrain
wasdeveloped.Seriousadversereactionstothe17Dvaccineareveryrareeventstheyincludetwosyndromes,known
asyellowfevervaccineassociatedneurotropicdisease(YELAND)andyellowfevervaccineassociatedviscerotropic
disease(YELAVD).IntheUnitedStates,therisksofYELANDandYELAVDinciviliantravelersareestimatedat0.8
and0.4per100,000respectively,althoughtheriskishigherinolderindividuals.

Mildfever,headache,myalgiaandmalaise,andsorenessatthesiteofinoculationcanoccurintheabsenceofliver
functionabnormalities[69,92].

Thevaccineiscontraindicatedforpersonswithknowneggallergyallergicreactionstoresidualeggproteinsorgelatin
stabilizerinyellowfever17Dvaccineoccur,albeitatverylowrates.

Theyellowfevervaccinevirusmaybetransmittedbytransfusionofbloodproducts.Vaccinerecipientsshoulddefer
bloodproductdonationforatleasttwoweeks[93].Inaddition,thevaccinevirusmaybetransmittedfromlactating
motherstobreastfedinfants[75].

NeurotropicdiseaseYELANDreferstoanencephalitisusuallycausedbyinfectionofthecentralnervous
systemwith17Dvirus[94].Onsetoccurstwotoeightdaysaftervaccinationtheeventisnearlyalwaysselflimitedbut
rarelyisassociatedwithneurologicalsequelae.Definitivediagnosisisbasedonvirusisolation,detectionofviral
genomebypolymerasechainreaction(PCR),ordetectionofIgMantibodyincerebrospinalfluid.Casesofneuromyelitis
optica,GuillainBarr,andacutedisseminatedencephalomyelitis(ADEM)havealsobeendescribedandpresumably
haveanautoimmuneetiology.

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YELANDhasbeenobservedininfantsandadults[62,95,96].Between2000and2006,therateofYELANDinthe
UnitedStateswas0.8per100,000[97].TheincidenceofYELANDishigherinolderadultspersons70yearshavea
rateof2.3per100,000[98,99].Amongfourcasesdescribedinadultsin2001to2002,allhadfeverandtwohad
aphasiacerebrospinalfluidwasallpositiveforyellowfeverspecificIgMinallpatientsculturesandPCRwerenegative
[62].Casesininfantshavediminishedsincerestrictionofvaccineadministrationtochildrenmorethanninemonthsof
age[62].

ViscerotropicdiseaseYELAVDreferstoasyndromeresemblingwildtypeyellowfeverinfectionthatoccurs
inthesettingofyellowfever17Dvaccination[94,100102].Casedefinitionshavebeenpublished[103].Onsetofillness
generallyoccursthreetofivedaysaftervaccinationwithfever,malaise,jaundice,oliguria,cardiovascularinstability,and
hemorrhage.ThecasefatalityrateofYELAVDis63percent,andthereisnospecifictreatment[94,104,105].

TheestimatedincidenceofYELAVDintheUnitedStatesis0.4per100,000butmaybesixfoldhigheramong
individuals60yearsofage[98].Basedontherelativelysmallseriesofcases,thereappearstobeahigherincidence
inyoungadultfemales.InPeru,anunexplained,highincidenceofYELAVDwasreportedduringamassimmunization
campaign(7.9per100,000)[106].Inalargeexperienceof38millionvaccinationsgiveninWestAfricabetween2007
and2010,duringwhichpharmacovigilancewasundertaken,fewseriousadverseeventsandonlyfivesuspectedYEL
AVDcaseswerefound[60],emphasizingthehighsafetyrecordofthevaccine.

Nevertheless,therehavebeenmorereportsofdeathsduetoYELAVDthanduetowildtypediseaseinunvaccinated
travelers.Thisemphasizestheimportanceofcarefulassessmentforvaccinationneedbasedonfullunderstandingof
diseaseepidemiologyandtravelitinerary,toavoidunnecessaryriskofvaccineadverseeffectsbuttoensurethat
patientswithriskforexposureareprotected[18].

IdentifyingriskfactorsforYELAVDisdifficultbecauseoftherelativelylowincidence.YELAVDdoesnotappeartobe
causedbymutationalchangesinthevirus[79,94,106].Rather,YELAVDisprobablyrelatedtodefectsinhostinnate
immunityinaffectedindividuals,theearlyantiviralresponseappearstobeimpaired,allowinguncheckedviral
replicationbeforeactivationoftheadaptiveimmuneresponse[107].

AcquiredhostfactorsappeartoincreasetheriskofdevelopingYELAVDaftervaccination:advancedageandthymus
diseaseandpossiblyfemalegenderinyoungerpersons[94,98,99,104,108,109].Astudyinolderadultsshowedthat
viremiacausedbyyellowfever17Dvaccinewasprolongedandtheantibodyresponsedelayed,foreshadowingtherole
ofimmunesenescenceincaseswithYELAVD[110].Thymusdisease(eg,thymoma,myastheniagravis)waspresent
in4ofthe23reportedcasesallunderwentthymectomy2to20yearsbeforevaccination[111].Inaddition,thymic
involutionincreaseswithageandtheassociatedimmunesuppressionmightcontributetotheincreaseinriskofYEL
AVDinolderadults.Afatalcaseinapatientwithathymomadetectedonlyatautopsyillustratesthedifficultyin
assessingunderlyingacquiredriskfactors[109].Thereissomeevidencethatimmunedysregulationassociatedwith
autoimmunediseases,suchassystemiclupuserythematosusandAddison'sdisease,mayalsobeariskfactorfor
YELAVD[18,106].

Newer,potentiallysafervaccinesSeriousadverseevents(exceptacutehypersensitivityreactions)arecaused
byreplicatingvirus.Therefore,effortsareunderwaytodevelopsafer,inactivatedvaccines.Awholevirioninactivated
vaccineadsorbedtoaluminumhydroxideadjuvantwasprotectiveinanimalmodelsandwasshowntobewelltolerated
andimmunogenicinaphaseIclinicaltrial[112].

ImmuneglobulinThereisnospecificyellowfeverimmuneglobulinproductavailable.Immuneglobulinproducedin
theUnitedStates(wheremanymilitarypersonnelhavebeenvaccinated)maycontainyellowfeverneutralizing
antibodies.Passiveimmunizationhasbeenusedofflabeltoprotectpersonstravelingtohighriskareaswhohave
contraindicationstovaccination[94].Ifexposuretoyellowfevervirusoccurredatadefinedtime(eg,inthecaseof
accidentalexposureinthelaboratoryortobloodfromanacutelyillpatient),postexposuretreatmentwithimmune
globulin(fromUnitedStatesdonors)orinterferonalpha(preferablynotlongeractingpegylatedinterferon)wouldbe
warranted.Treatmentwouldbeexpectedtobeeffectiveonlywithinthefirst24hoursafterexposure[44].

SUMMARYANDRECOMMENDATIONS

Yellowfeverisamosquitoborneviralhemorrhagicfeverwithahighcasefatalityrate.Travelerstotropicalregions
ofSouthAmericaandsubSaharanAfricaareatriskforacquisitionofinfectionandrequireimmunization.(See
'Introduction'above.)

MosquitoborneepidemicsinAfricaoccurwherehumanpopulationsresideinhighdensityandimmunization
coverageislow(socalled"urbanyellowfever").FewercasesoccurinSouthAmericathaninAfricabecause

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transmissionoccursprincipallyfrommonkeytohumanviamosquitovectors,thevectordensityisrelativelylow,
andvaccinationcoverageisrelativelyhigh(socalled"jungleyellowfever").(See'Epidemiology'above.)

Yellowfeverischaracterizedbythreestages:periodsofinfection,remission,andintoxication.Theperiodof
infectionconsistsofviremiawithnonspecificsymptomsandsignsincludingfever,malaise,headache,jointpain,
nausea,andvomiting.Thisisfollowedbyaperiodofremissionwithabatementoffeverandsymptomslastingup
to48hours.Thesubsequentperiodofintoxicationischaracterizedbyhepaticdysfunction,renalfailure,
coagulopathy,andshock.(See'Clinicalmanifestations'above.)

Diagnosismaybemadebyserology,bydetectionofviralgenomebypolymerasechainreaction(PCR)inserum,
byvirusisolation,orbyhistopathologyandimmunocytochemistry(postmortemsamplesonly).Serologic
diagnosisisbestaccomplishedusinganenzymelinkedimmunosorbentassay(ELISA)forIgM.Thepresenceof
IgMantibodiesinasinglesampleprovidesapresumptivediagnosisconfirmationismadebyariseintiter
betweenpairedacuteandconvalescentsamplesorafallbetweenearlyandlateconvalescentsamples.More
specificneutralizationtestsmaybeperformedbutrequireaspecializedlaboratory.(See'Diagnosis'above.)

Thetreatmentofyellowfeverconsistsofsupportivecarethereisnospecificantiviraltherapyavailable.(See
'Treatment'above.)

InaccordancewiththeUnitedStatesCentersforDiseaseControlandPrevention(CDC),theUnitedStates
AdvisoryCommitteeonImmunizationPractices(ACIP),andtheWorldHealthOrganization(WHO),we
recommendyellowfevervaccinefortravelerstoyellowfeverendemicareasofAfricaandSouthAmericaandfor
residentsofthoseareas(Grade1A).Thevaccinemaybeadministeredtoindividualsovertheageofninemonths.
(See'Prevention'aboveand'Whomtovaccinate'above.)

Seriousadversereactionstothe17Dvaccineareveryraretheyincludetwosyndromes,yellowfevervaccine
associatedneurotropicdisease(YELAND)andyellowfevervaccineassociatedviscerotropicdisease(YELAVD).
IntheUnitedStates,therisksofYELANDandYELAVDinciviliantravelersareestimatedat0.8and0.4per
100,000,respectively,althoughtheriskishigherinolderadults,personswithimmunedysregulation,andpossibly
youngfemales.Seriousadverseeventshavebeensignificantlylessfrequentlyobservedduringimmunization
campaignsinendemiccountries.InanongoingepidemicinAngola,multiplecasesofyellowfeverhavebeen
exportedtovariouscountries,includingChina.Thisillustratesthedangeroftraveltoendemicregionswithout
vaccinationandtheriskofglobalspreadofthevirus.(See'Adverseeffects'above.)

Somecountriesinyellowfeverendemiczonesrequireaninternationalcertificateofvaccinationasevidenceof
yellowfeverimmunizationpriortoentry.Inaddition,somecountriesoutsideofyellowfeverzonesalsorequire
evidenceofimmunizationspriortoentryforindividualswithrecenttravelinendemiccountries.Theinternational
certificateofimmunizationisvalidfor10yearsabooster0.5mLdoseisrequiredevery10yearsforthecertificate
tobereissued.(See'Certificates'above.)

Immunityafterasingledoseislonglasting.InMay2014,theWorldHealthAssemblyadoptedthe
recommendationtoremovethe10yearboosterdoserequirementfromtheInternationalHealthRegulationsby
June2016.Untilthistime,travelerstocountrieswithayellowfevervaccinationentryrequirementmusthave
receivedadoseofyellowfevervaccinewithinthepast10years.InJune2015,theUnitedStatesAdvisory
CommitteeonImmunizationPractices(ACIP)issuedrecommendationsstatingthatasingleprimarydoseof
yellowfevervaccineisadequateformosttravelerstheACIPdoesrecommendadditionaldosesofyellowfever
vaccineatrisklaboratorypersonnelandcertaintravelers.(See'Whomtovaccinate'above.)

Fractionaldosingisastrategyforextendingyellowfevervaccinesupplyinoutbreaksituations.In2016,theWorld
HealthOrganizationStrategicAdvisoryGroupofExpertsonImmunizationstatedthatvaccinationwithonefifththe
standarddoseissufficienttoprovideprotectionagainstyellowfeverforatleast12months,andtheyadvocated
shorttermuseofthisapproachamongindividuals>2yearsinemergencyconditionswhenvaccinesuppliesare
limited.(See'Fractionaldosinginoutbreaks'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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