Clinical Infectious Diseases Advance Access published March 15, 2012

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H5N1AvianInfluenzainChildren

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AhmetFaikOner,1NazimDogan,2ViktorGasimov,3WikuAdisasmito,4RichardCoker,5PaulK.S.Chan,7
NelsonLee,7OwenTsang,8WannaHanshaoworakul,9MukhtiarZaman,10EbunBamgboye,11Anna
Swenson,12StephenToovey6andNancyA.Dreyer12

YuzuncuYilUniversity,Van,and2AtaturkUniversityMedicalSchool,Erzurum,Turkey;3Azerbaijan

MinistryofHealth,Baku,Azerbaijan;4UniversityofIndonesia,Depok,Indonesia;5LondonSchoolof

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HygieneandTropicalMedicine,and6RoyalFreeandUniversityCollegeMedicalSchool,Departmentof
InfectionandImmunity,AcademicCentreforTravelMedicineandVaccines,London,UnitedKingdom;
7

FacultyofMedicine,ChineseUniversityofHongKong;8PrincessMargaretHospital,HongKong,

SAR;9MinistryofPublicHealth,Nonthaburi,Thailand;10KhyberTeachingHospital,Peshawar,Pakistan;
StNicholasHospital,Lagos,Nigeria;12OutcomeSciences,Inc,Cambridge,Massachusetts

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CorrespondingAuthor:Dr.NancyA.Dreyer,OutcomeSciences,201Broadway,Cambridge,MA,02139

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(ndreyer@outcome.com)

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AlternateCorrespondingAuthor:Dr.StephenToovey,RoyalFreeandUniversityCollegeMedicalSchool,
DepartmentofInfectionandImmunity,AcademicCentreforTravelMedicineandVaccines,London,
UnitedKingdom,(malaria@sunrise.ch)

TheAuthor2012.PublishedbyOxfordUniversityPressonbehalfoftheInfectiousDiseasesSocietyofAmerica.
Allrightsreserved.ForPermissions,pleaseemail:journals.permissions@oup.com

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KeyPoints:Apatientregistry,representingthelargestglobalknowledgebaseonclinicalpresentation

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andcasefatalityforconfirmedcasesofavianinfluenza,showsthatmostpediatriccaseswhopresent
withrhinorrheasurvivethisinfection,regardlessofcountryandantiviraltreatment.

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Abstract

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Background.Avianinfluenzacontinuestoposeathreattohumansandmaintainsthepotentialfor

guideeffectivediagnosisandtreatment.

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greatertransmissibility.Understandingtheclinicalpresentationandprognosisinchildrenwillhelp

Methods.Aglobalpatientregistrywascreatedtoenablesystematiccollectionofclinical,exposure,
treatmentandoutcomesdataonconfirmedcasesofH5N1.Bivariateandmultivariatestatisticaltools
wereusedtodescribeclinicalpresentationandevaluatefactorsprognosticofsurvival.

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beeninfectedwithH5N1;35.2%ofcaseswerefromEgypt.Thecasefatalityrate(CFR)forchildrenwas
48.7%,withEgypthavingverylowpediatricCFR.Overall,childrenaged<5yearshadthelowestCFR
andwerebroughttohospitalmorequicklyandtreatedsoonerthanolderchildren.Pediatriccaseswho
presentedformedicalcarewithacomplaintofrhinorrheahada76%reductioninthelikelihoodof

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deathcomparedwiththosewhopresentedwithoutrhinorrhea,evenafterstatisticaladjustmentforage,
havingbeeninfectedinEgypt,andoseltamivirtreatment(P=0.02).Delayedinitiationoftreatmentwith
oseltamivirincreasesthelikelihoodofdeath,withanoverall75%increaseintheadjustedoddsratiofor
deathforeachdayofdelay.

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Conclusions.ThepresenceofrhinorrheaappearstoindicateabetterprognosisforchildrenwithH5N1,
withmostcasessurvivingregardlessofage,country,ortreatment.Forcasestreatedwithoseltamivir,

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earlyinitiationoftreatmentsubstantiallyenhancesthechanceofsurvival.

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Results.Datawereavailablefrom13countrieson193cases<18yearswhowereconfirmedashaving

H5N1AvianInfluenzainChildren

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Background

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Althoughmuchoftheattentiononinfluenzahasdiminished,especiallysincetherelativelymild

pandemicofH1N1swineflu,H5N1avianinfluenzacontinuestooccur,withhumancasescontinuingto
bereportedin2011[1,2].Alargeandineradicableavianreservoirforthisinfectionmeansthatitmay
reemergeasanimportantthreattohumanhealthinmanycountries[3],withanumberofcladesof
possiblydifferingvirulencecirculatingindifferentregions[4].Thispaperdescribestheclinical

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infectedwithlaboratoryconfirmedinfluenzaH5N1.
Methods

Thisinvestigationutilizedtheglobalavianinfluenzaregistry,with391casesoflaboratoryconfirmed
influenzaA(H5N1).Usingstandarddefinitionsanddatacollectionprocedures,informationwas

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gatheredfrommedicalrecords,clinicalandfieldinvestigationsincludinggovernmentsources,andfrom
publishedcasereports.Informationwassoughtaboutpresentingsymptoms,treatmentsandsurvival.
Theregistrymethodsaredescribedinfullelsewhere[5].

Caseswererecordedashavingoccurredfrom1997through2010.Theeighteenearliestcaseswere

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fromtheinitial1997outbreak,beforeWorldHealthOrganization(WHO)certifiedlaboratory
confirmationwasavailable.Oftheremaining373cases,358(96%)hadlaboratoryconfirmationfroma

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WHOaccreditedlaboratoryand15(4%)wereconfirmedbyalocallaboratory.

Nearlyhalfofthecases(193/391)wereyoungerthan18yearsatthetimeofdiagnosis.Pediatriccases
wererecordedfrom11countries:Azerbaijan(5),Bangladesh(1),Cambodia(3),China(6),Egypt(68),
HongKong(11),Indonesia(59),Laos(1),Thailand(13),Turkey(12)andVietnam(14).Pediatriccases

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presentationincludingidentificationofprognosticfactorsandtreatmenteffectivenessforchildren

arefurthercategorizedasaged05years(n=91,includingasinglecaseagedlessthanoneyear),611

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years(n=46),and1217years(n=56).

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Statisticalmethods

DifferencesincategoricalvariablesbyagegroupwereexaminedusingchisquareorFishersexacttests.
DifferencesincontinuousvariablesbyagegroupwerecomparedusingthenonparametricWilcoxon
ranksumandKruskalWallistestssincethedatawerenotnormallydistributed.APvaluelessthan0.05
wasconsideredstatisticallysignificant.ABonferronicorrectionwasusedtoaccountformultiple

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ofcomparisontogivethealphalevelconsideredstatisticallysignificantformultiplecomparisons.
Relativerisksandassociated95%confidenceintervalsarealsopresented.Amultivariatelogistic
regressionapproachwasusedtoexaminetheoddsofdeathforcaseswithandwithoutrhinorrheawhile
controllingforage,country(Egyptversusothers)andoseltamivirtreatment[6,7].Thesmallnumberof

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casesdidnotallowforadditionofpotentialconfoundersotherthanoseltamivir,ageandcountry.Two
modelswereused:oneincludedallcaseswithinformationrecordedaboutthepresenceorabsenceof
rhinorrhea(n=100),andtheotherincludedonlycaseswhohadbothinformationaboutthepresenceor
absenceofrhinorrheaandwhoweretreatedwithoseltamivir(n=44).

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Results

Table1showsthedistributionofcasesbyagegroupandcountry,andthecorrespondingcasefatality

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rates(CFR)forallagegroups.TheoverallCFRforpediatriccaseswas48.7%incontrasttotheoverall
CFRof57.5%,withsubstantialvariabilitybyageandcountry.Youngchildrenaremorelikelytosurvive
thanolderchildrenandadults,withchildrenaged5yearsshowingamarkedlylowerCFR(28%)than

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comparisonsbetweenthevariousagegroups;theoverallalphalevelof0.05wasdividedbythenumber

oldercases(p<0.01forallcomparisons).TheCFRforthoseaged611yearswasalsolowerthanthatof

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thoseaged1217years(p=0.003).

Childrenaged5yearswerebroughtformedicalattention,hospitalized,andtreatedwithantivirals

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earlierthanolderchildren,withamedianof3daysfromsymptomonsettostartoftreatmentinthe05
yearagegroupversus7daysforoldergroups(p=0.01,seeTable2).Thetimefromsymptomonsetto
antiviraltreatmentwassimilarforcasesaged611yearsandthoseaged1217years,despitethemuch
highermortalityrateinthe1217agegroup.Themedianof9daysfromsymptomonsettodeathwas

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Thereweresomedifferencesbyagegroupinsymptomsreportedatfirstpresentationformedicalcare
(Table3).Youngchildren(5years)reportedrhinorrheamorefrequently,andheadacheandmyalgia
lessfrequently,thanolderchildrenandadults.Headachewasamuchmorefrequentcomplainton
presentationforthoseaged1217yearsthanallotheragegroups(p<0.01).Bleedinggumswere

numbers.

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reportedmorefrequentlyforages6through17,thoughthesefindingsarebasedonespeciallysmall

Withrespecttowhetheranyparticularsigns,symptomsortestscarryprognosticvalueforsurvivalfrom
avianinfluenzaduringthefirst24hoursofhospitaladmission,childrenwhodiedweremorelikelyto

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havehaddecreasedleukocyte,lymphocyteandplateletcounts,andtohavehadelevatedalanine
aminotransferase(ALT),aspartateaminotransferase(AST),creatinine,andhematocritvalues;children
whosurvivedweremorelikelytohavehadlowerhemoglobinlevels(Table4).Creatinekinaseand

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lactatedehydrogenaselevelsatpresentationformedicalcaredidnotshowstatisticallysignificant

relationshipswithlikelihoodofsurvival,butsmallnumberscounselcautionininterpretation.
Examinationofthemanyclinicalsignsandsymptomsreportedatpresentationformedicalcare,shown
inTable5,demonstratedthatthepresenceofrhinorrheaisassociatedwithadecreasedriskofdeath,

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virtuallyidenticalforallages.

especiallyforchildrenaged5years(RRofdeathforcaseswithrhinorrhea=0.13;95%CI0.03,0.53).

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Also,thenonspecificsymptomcharacterizedasunexplainedrespiratoryillnesswithcough,shortness
ofbreath,ordifficultybreathingappearstocarrysomeprognosticvalue,showingadecreasedriskof

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death,particularlyinchildren5years.Similarly,fourothersymptoms(diarrhea,headache,fatigueor

malaise,andmyalgia)alsoshowedsomeweakbutconsistentevidencethattheymaybeassociatedwith
abetterprognosisinchildren.Othersymptoms,includingfever,excessivesputumproduction,sore
throat,vomiting,andtachypnea,didnotshowanyconsistentrelationtothelikelihoodofdeath.

improvedsurvivalamongcaseswhopresentedwithrhinorrheamighthavebeenduetotheirhaving

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receivedmedicalattentionsoonerorhavingbeentreatedmorequicklythanchildrenwhodidnot
presentwiththesesymptoms.Forchildrenwhopresentedwithrhinorrhea,thetimetopresentationfor
medicalcarewasnotverydifferent(medianofonevs.threedays)forcaseswhosurvivedanddied(n=9
caseswithinformationontimefromsymptomonsettopresentationformedicalcare,p=0.45).

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However,childrenwithrhinorrheawhosurvivedweretreatedmorequicklywithantivirals(medianof
2.5daysfromsymptomonsettostartofantivirals)thanthosewhodied(medianof10days,n=17cases
withinformationontimefromsymptomonsettotreatmentwithantivirals,p<0.01).Usingmultivariate
modeling,childrenwhopresentedwithrhinorrheahad76%reductionintheriskofdeath(OR0.24,95%

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CI0.08,0.77)whensimultaneouslycontrollingforoseltamivirtreatment,country,andagegroup(Table
6).Lookingonlyatchildrenprescribedoseltamivir,however,thesurvivalbenefitsassociatedwith
rhinorrheawerestillremarkable,butdidnotachievestatisticalsignificance(OR0.38,95%CI0.03,5.55).

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Lookingattimetoinitiationoftreatmentwithoseltamivir,therewasanincreasedoddsofdeathfor

eachdayofdelay(OR1.75,95%CI1.17,2.61)whencontrollingforage,rhinorrheaandcountry(Egypt).

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Althoughsmallnumbersprecludeexaminationofspecificagegroups,weinvestigatedwhetherthe

Discussion

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Theclinicalpresentationofavianinfluenzainchildrendiffersinsomemeaningfulwaysfromthatin

adults.UnlikesomeearlierreportsthatcharacterizedH5N1infectionsascarryingahighermortalityin

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children,thelowermortalityrateinchildrenaged5yearsinthislargecaseseriesisquitestriking,
especiallysincethesurvivalbenefitisevidentevenwhentypeofpresentingsymptom,antiviral

treatment,timetotreatmentinitiationandcountryaretakenintoaccount[8,9].Ofnote,usingasmall
seriesfromVietnam(N=36),Kawachietalreportedthatchildrenaged6yearswereathigherriskof

bethatthelessmaturesystemsofyoungerchildrenmountanimmuneresponselessharmfultotheir

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hosts.

Thepresenceofrhinorrheaatpresentationismorecommoninchildrenaged5years,andappearsto
beassociatedwithamarkedlydecreasedriskofdeathinthisagegroup.Thissymptomappearstohave

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prognosticvalue,evenafteraccountingforthemostobviousexplanationsfortheincreasedsurvival
seeninchildrenwiththispresentation,suchashavingbeenseensoonerorhavingreceivedtheirfirst
doseofantiviralearlyinthecourseoftheirillness,orcomingfromEgypt,whichhasalowerCFRthan
othercountries[6,7].Inthisregistry,35%(68/193)ofthecasesunder18yearsofagewerefromEgypt,
asweremorethanhalf(52%,47/91)ofthecasesaged5years.However,theprotectiveeffectof

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rhinorrheawasstillevidentinthe05yearagegroup,whentestedbothbyexcludingEgyptiancases
fromanalysisandbyusingstatisticalanalysestocontrolsimultaneouslytheeffectsofcountry(see

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ModelOneinTable6,theonlymodelwhichhadenoughcasestopermitinclusionofEgyptasan
additionalcovariate).Thus,thereremainsanintriguingdifferenceinthefrequencyofrhinorrheaasa

presentingsymptomanditsapparentprognosticvalue,whichdeclineswithincreasingage.Onemight
speculatethatthisrepresentsprimaryinoculationofthevirusintotheupperratherthanthelower

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fulminantdiseasewithacuterespiratorydistresssyndrome(ARDS)thanyoungerchildren[10].Itmight

airways,orperhapsalessinjuriouspathwaytoimmuneactivation[11].Regardlessoftheexplanation,

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thereremainedbenefitfromearlyantiviraluse.AsymptomaticandmildcasesofH5N1havebeen
previouslyreported,andonemightspeculatethatcasespresentingwithrhinorrhearepresentasubset

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ofpatientswithgenerallymilderorillness[12].

Therecordingofothersymptomsmaynotbeasreliableasrhinorrhea,whichcanbeobservedbythe
clinician.Forexample,thepaucityofmyalgiaasapresentingsymptominchildrenaged05yearsmay
simplyreflecttheinabilityofyoungchildrenortheirparentstoaccuratelyreportthissymptom,rather

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Ourfindingswithrespecttolaboratoryvaluesmightpossesssomeclinicalutility,indicatingseverityto
clinicians,andsuggestingtheneedforaggressiveantiviralandsupportivetherapy.Ourfindingsare
consistentwithothers.GroseetalreportedleukopeniaandthrombocytopeniainVietnameseandThai
childrensufferingfromH5N1infection[9].ExaminingVietnamesepediatricH5N1caseswithARDS,

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Kawachietalreportedleukopeniaandthrombocytopeniatobepredictorsoffulminantdiseasewith
ARDS[10].Furuyaetal,intheirmetaanalysisofpublishedpediatricH5N1caseseries,found
thrombocytopeniaandleukopeniatobesignificantlyassociatedwithmortality[13].Pediatricregistry
caseswhodiedconfirmedthesefindingswithrespecttoleukopenia;registrycasesthatsufferedafatal
outcomealsodemonstratedalowermedianthrombocytecountwithinthefirst24hoursofadmission,if

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notalwaysatruethrombocytopenia.Thismightsuggestafallingorrelativelylowthrombocytecount
couldbeaveryearlypointertoseverediseaseandpooroutcome.Leukopeniaandthrombocytopenia

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arenotinfrequentlyseeninotherverysevereinfections,foravarietyofreasonsincludingconsumption,
peripheralsequestration,andmyelosuppression.

FuruyaetalalsoreportedthataraisedperipheralbloodASTleveltrendedtosignificantassociationwith
mortality[13];thatassociationwasconfirmedinthislargerpatientregistrydataset.Further,ourdata

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thanatruedifferenceinsymptomoccurrencebyage.

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alsorevealedasignificantassociationbetweenaraisedALTlevelandmortalityinchildren.These

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findingsmostlikelyrepresentwidespreadcellular,andinparticularhepatocyte,insultconsequentupon
thesevereinflammatoryprocessesthataccompanyadvancedH5N1infection[14].

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Theraisedhematocritseeninfatalcasescouldbeduetoadegreeofhemoconcentrationpossibly

associatedwithdehydrationandperhapswithvascularinjuryoccasionedbythesevereinflammatory
processesknowntoaccompanyH5N1infection;thelowermeanhemoglobinlevelsseeninsurvivors
couldaccordwiththehaemoconcentrationseeninfatalcases.

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oseltamivir(91%ofallantivirals),andthesedatacontinuetoshowthebenefitsofearlytreatmentwith
oseltamivir.Wealsotestedthegeneralizabilityofthisfindingbylookingatdatafromthetwocountries
withthemostcases,EgyptandIndonesia,andcomparingantiviraleffectivenessdatabetweenthemand
therestofthecountriesintheregistry.Ascountryofinfection(andillness)isavariablethatlikely

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reflectstherelativevirulenceofthecirculatingstrainaswellthesophisticationandaccessibilityofthe
localhealthcaresystem,wecontrolledbycountryratherthanbyviralstrainorclade,eventhoughthe
lattermightwellindicaterelativevirulence[15,16].

Themediannumberofdaysfromsymptomonsettoantiviraltreatmentwasmarkedlyshorterfor

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survivingcasescomparedtofatalcasesforallpediatricagegroups,regardlessofcountry.These
findingsconfirmonceagaintheimportanceofearlyinitiationofeffectiveantiviraltherapyinhuman

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H5N1infection[5],andspecificallyinthepediatricsetting.

Overall,thedatafromthisregistryshowthatchildrenaged5yearsaremorelikelytosurviveinfection

withH5N1;theycometomedicalattentionmorequicklythanadults,andreceiveantiviraltreatment
morequicklythantheiroldercounterparts.Theresultsalsosupporttheprognosticvalueofsome

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Withrespecttoantiviraltreatment,byfarthemostfrequentlyusedantiviralinregistrycaseswas

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laboratoryfindingsonpresentationaswellthevalueofantiviraltherapy,especiallywheninitiatedearly

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inthecourseofinfection.

Manylimitationstotheanalysisandinterpretationofthesedataremain,someduetodatathatwere

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notavailableorteststhatwereeithernotperformedornotrecorded,andothers,totherelativelysmall
numbersofcasesavailableforanalyses.However,itshouldberecognizedthatthisrepresentsthe
largestcollectionofaggregatedclinicaldataonavianinfluenzainhumans,allofwhomhavelaboratory
evidenceconfirminginfectionwithH5N1.Thesedatamayprovideinsightstoclinicianstreating

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treatmentofthishighlylethaldisease.
Funding

ThisworkwassupportedbyacontracttoOutcomeSciences,Inc.,fromF.HoffmannLaRoche.The
sponsorprovidedscientificcollaborationandhadrightstononbindingreviewofmanuscriptsbutdidnot

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havetherighttodecidewhetherpapersshouldbesubmittedforpublication,tochooseauthors,orto

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approvethewordingofanymanuscripts.

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pediatriccases,andmeaningfulcluestoimmuneresponsethatcanbeharnessedformoreeffective

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Acknowledgements:None

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PotentialConflictsofInterest

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W.A.,M.Z.,A.F.O.,E.B.,andN.D.receivedmodestsupporttofacilitatedatacollectionandreview.R.C.
hasreceivedfundingfromF.HoffmannLaRoche,themanufacturerofoseltamivir.P.K.S.C.andN.L.

receivedfundingsupportfromF.HoffmannLaRocheforaninvestigatorinitiatedstudy.N.A.D.andA.S.
areemployedbyOutcomeSciences,Inc.,aprivatecompanythatspecializesinpatientregistriesand
whichreceivedfundingfromF.HoffmannLaRochetocreateandconducttheregistrystudy.S.T.isa

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ce

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ofinfluenzavaccinemanufacturers.

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formeremployeeandapaidconsultanttoF.HoffmannLaRocheandhasbeenreimbursedbyanumber

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surveillanceintheUnitedStatesusingtheAggregateHospitalizationandDeathReporting

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http://www.who.int/influenza/human_animal_interface/country/cases_table_2011_08_09/en/i

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16

Country

Pediatriccases
05years

611years

1217years

All

AllAges

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Table1.CaseFatalityRatebyCountryandAgeGroup

Pediatric

Azerbaijan

NA

0/1
(0.0%)

0/1

NA

(0.0%)
1/1
(100.0%)
China

NA

1/1

6/9

(50.0%)

(40.0%)

(66.7%)

NA

0/1

0/1

(0.0%)

(0.0%)

3/3

6/6

1/1

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Cambodia

2/5

(100.0%)

(100.0%)

(100.0%)

(100.0%)

2/6

NA

2/6

16/28

(33.3%)

(57.1%)

5/10

9/68

34/106

(33.3%)

HongKong

(18.2%)

(50.0%)

(13.2%

(32.1%)

1/8

0/1

1/2

2/11

6/18

(12.5%)

(0.0%)

(50.0%)

(18.2%)

(33.3%)

16/21

11/14

22/24

49/59

107/124

(76.2%)

(78.6%)

(91.7%)

(83.1%)

(86.3%)

NA

NA

1/1

1/1

1/1

(100.0%)

(100.0%

(100.0%)

NA

1/1

NA

(100.0%)

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Laos

Nigeria

2/11

(4.3%)

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Indonesia

2/47

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Egypt

NA

NA

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Bangladesh

2/4

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NA

NA

(25.0%)

3/3

10/13

17/25

(50.0%)

(83.3%)

(100.0%)

(76.9%)

(68.0%)

0/6

1/3

(0.0%)

(33.3%)

3/3

2/3

(100.0%)

(66.7%)

25/91

24/46

(27.5%)

(52.2%)

4/12

4/13

(100.0%)

(33.3%)

(30.8%)

7/8

12/14

26/55

(87.5%)

(85.7%)

(47.3%)

45/56

94/193

225/391

(80.4%)

(48.7%)

(57.5%)

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3/3

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5/6

Vietnam

2/4

Turkey

Total

NA

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Thailand

NA

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Pakistan

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Table2.TimeCourseofIllnessfromOnsetofSymptomstoAntiviral(AV)

Age

CaseFatality

Presentationfor

Rate

MedicalCare

Years

MedianDaysfromSymptomOnsetto:

N*

Median

nu
sc
ri

Hospitalization

N*

Median

0(020)

85

611

24/46(52.2%)

28

2(09)

44

1217 45/56(80.4%)

34

1(010)

55

5.0(013)

193

1(020)

374

5.0(025)

pte
d

Mediansaresignificantlydifferentbetweenagegroups.

*TotalNdiffersaccordingtocompletenessoftimingdata.

Ac

ce

Median

Death

(N=225fatal)

N*

(minmax)

Median

(minmax)

3(020)

33

3(011)

24

9(317)

4.5(025)

20

7(221)

22

10.5(232)

24

7(114)

44

9(331)

170

6(023)

215

9(232)

Ma

31

(57.5%)

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25/91(27.5%)

Ages

N*

(minmax)

05

225/391

AVTreatment

(N=242treated)

(minmax)

All

pt

TreatmentandDeath,ByAge(N=391)

19

AgeinYears

AtPresentation
N

05

611

1217

70/73

34/37

43/47

138/146

(95.9%)

(91.9%)

(91.5%)

(94.5%)

48/56

30/34

38/47

99/138

(85.7%)

(88.2%)

(80.9%)

(71.7%)

forMedicalCare

Fever

303

>18

Pvalue*

0.71

275

0.06

Ma

illness**

15/37

Tachypnea

182

9/28(32.1%)

9/27(33.3%)

41/90(45.6%)

0.51

6/19(31.6%) 10/55(18.2%)

0.57

(40.5%)

AbnormalBreath

Sore

6/21(28.6%)

5/18(27.8%)

pte
d

113
Sounds

13/29

14/28

19/34

169

throat/pharyngitis
Cyanosis

28/78(35.9%)

0.22

(44.8%)

(50.0%)

(55.9%)

99

2/19(10.5%)

1/15(6.7%)

1/18(5.6%)

3/47(6.4%)

0.93

132

2/20(10.0%)

3/22(13.6%)

2/27(7.4%)

15/63(23.8%)

0.19

6/24(25.0%) 5/31(16.1%)a 8/73(11.0%)a

<0.01

ce

ExcessiveSputum
Production

24/45

173

Ac

Rhinorrhea

c,d

(53.3%)

Diarrhea

180

7/30(23.3%)

5/26(19.2%)

8/33(24.2%) 20/91(22.0%)

0.97

AbdominalPain

136

5/26(19.2%)

5/19(26.3%)

8/21(38.1%) 13/70(18.6%)

0.28

Downloaded from http://cid.oxfordjournals.org/ by guest on August 11, 2015

Unexplained
respiratory

nu
sc
ri

Symptom

pt

Table3.FrequencyofFirstSymptomsReportedatMedicalCarebyAge

20

158

9/30(30.0%)

Headache

151

5/27(18.5%)c

7/22(31.8%)
4/17

18/26

(23.5%)

28/81

4/15(26.7%)

a,b,d

(69.2%)

(34.6%)

7/24(29.2%) 21/61(34.4%)

0.60

nu
sc
ri

4/21(19.1%)

0.08

<0.01

FatigueorMalaise 121

8/26(30.8%) 11/80(13.8%)

pt

Vomiting

28/68

Myalgia

135

2/23(8.7%)

6/21(28.6%)

4/23(17.4%)

0.01

(41.2%)a

Neurologic
1/21(4.8%)

2/18(11.1%)

0/16(0%)

3/51(5.9%)

0.57

91

0/19(0%)

2/14(14.3%)

1/14(7.1%)

4/44(9.1%)

0.46

133

0/23(0%)

2/23(8.7%)

3/25(12.0%)d

0/62(0.0%)c

0.02

Enlargedliver

93

0/18(0%)

1/15(6.7%)

1/16(6.3%)

1/44(2.3%)

0.62

Conjunctivitis

134

1/23(4.4%)

1/22(4.6%)

0/23(0%)

1/66(1.5%)

0.64

Psychiatric

and/ornose

Ma

Bleedinggums

pte
d

*Overallpvalue.Comparisonsbetweenagegroupsareconsideredsignificantatp<0.01,reductionin
alphalevelisduetoapplicationofaBonferronicorrectionformultiplecomparisons.
**Unexplainedrespiratoryillnessisdefinedasincludingcough,shortnessofbreathordifficulty
breathing.

Significantlydifferentfromage05,bSignificantlydifferentfrom611,cSignificantlydifferentfrom12

ce

17,dSignificantlydifferentfrom18

Ac

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106
Involvement

21

Table4.SurvivalbyMedianLaboratoryValueswithin24hoursofHospital

pt

Admission

PediatricCases(Age<18years)
FatalCases

NonFatalCases

pvalue

61

2800(40018,300)

5100(200015,900)

<0.01

21

800(2501700)

2028(10404256)

<0.01

123,000(35,000

188,000(122,500

LeukocyteCountmedian
count,permm3
LymphocyteCountmedian
count,permm3
PlateletCount
52
mediancount,permm3
CreatineKinasemedian
9
count,U/liter
Alanineaminotransferase

314,000)

528,000)

1430(523429)

297(821396)

0.54

60(88750)

22(11299)

0.03

pte
d

31

<0.01

median,U/liter

Aspartateaminotransferase

31

263(203230)

53(16107)

<0.01

11

1606(6044032)

1518(4204478)

0.93

22

0.70(0.161.04)

0.38(0.200.53)

0.02

16

21(1058)

15(722)

0.19

Hemoglobin

47

13(1037)

11(1014)

0.04

Hematocrit

35

37(451)

33(2738)

0.01

median,U/liter

Lactatedehydrogenase

ce

median,U/liter
Creatinine

Ac

median,mol/liter
Ureanitrogen

median,mg/dL

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Ma

LaboratoryParameter

nu
sc
ri

22

Table5.RelativeRiskofDeathbySymptomsonPresentationforMedicalCare

Symptom
Fever

Ageinyears
05

303

0.81(0.16,4.22)

275

0.47(0.27,0.82)

182

0.53(0.20,1.41)

113

0.83(0.34,2.05)

Unexplained
respiratoryillnesswith
cough,shortnessof
breathordifficulty

Tachypnea
AbnormalBreath

throat/pharyngitis
ExcessiveSputum
Production

1.72(0.64,4.62)

0.95(0.63,1.43)

2.80(0.50,15.53)

0.84(0.73,0.97)

0.87(0.72,1.06)

1.56(0.87,2.78)

1.29(1.03,1.62)

0.92(0.73,1.16)

1.73(0.83,3.61)

1.18(0.94,1.49)

1.16(0.80,1.68)

0.49(0.20,1.21)

1.25(0.71,2.19)

0.68(0.47,0.98)

0.89(0.66,1.20)

132

0.82(0.20,3.43)

1.06(0.44,2.52)

1.14(0.98,1.31)

0.80(0.51,1.25)

173

0.13(0.03,0.53)

0.75(0.32,1.78)

0.68(0.33,1.41)

0.49(0.20,1.20)

180

0.88(0.43,1.78)

0.60(0.20,1.83)

1.20(1.00,1.41)

1.25(1.02,1.54)

AbdominalPain

136

1.29(0.74,2.24)

1.05(0.45,2.45)

1.14(0.77,1.69)

1.22(0.99,1.52)

Vomiting

158

0.67(0.30,1.47)

1.19(0.64,2.22)

1.05(0.75,1.47)

1.09(0.80,1.48)

Headache

151

0.68(0.22,2.09)

0.72(0.25,2.05)

0.89(0.62,1.27)

1.15(0.90,1.46)

FatigueorMalaise

121

0.43(0.07,2.43)

0.46(0.08,2.72)

0.81(0.49,1.33)

0.98(0.76,1.26)

Ac

Diarrhea

>18

169

ce

Rhinorrhea

0.88(0.38,2.06)

pte
d

Sounds
Sore

1217

Ma

breathing

611

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nu
sc
ri

pt

andAgeGroup

23

Myalgia

135

NA

0.50(0.15,1.64)

0.59(0.22,1.61)

0.80(0.59,1.10)

pt

Ac

ce

pte
d

Ma

Downloaded from http://cid.oxfordjournals.org/ by guest on August 11, 2015

nu
sc
ri

24

Allcaseswithinformationonrhinorrhea

(Model1)
Rhinorrheanotedatpresentationfor

100

medicalcare(yes/no)
100

Age(years)

100

611

Egypt(vs.allothercountries)

100

pte
d

Oseltamivirtreatedcaseswith

AdjustedOR

pvalue

0.11(0.04,0.28) 100

0.24(0.08,0.77) 0.02

0.94(0.43,2.09) 100

1.41(0.50,3.96) 0.51

100

0.10(0.03,0.30)

0.15(0.04,0.52) <0.01

0.32(0.09,1.14)

0.32(0.08,1.24) 0.10

Ref

Ref

Ma

05

0.04(0.01,0.35) 100

0.16(0.02,1.78) 0.14

informationonrhinorrhea(Model2)

Rhinorrheaatpresentationformedical
care

Daysfromsymptomonsettooseltamivir

56

0.15(0.04,0.52) 44

0.38(0.03,5.55) 0.48

44

1.85(1.30,2.64) 44

1.75(1.17,2.61) 0.01

56

1.21(1.05,1.38) 44

1.38(1.02,1.85) 0.04

ce

treatment(delayinstartingtreatment)
Age(years)

Ac

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Oseltamivirtreatment(yes/no)

1217

UnadjustedOR

nu
sc
ri

pt

Table6:RhinorrheaandOddsRatiosforDeathamongChildren:TwoModels