Professional Documents
Culture Documents
h5n1 Oxford Journal
h5n1 Oxford Journal
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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;
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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
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.
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
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
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,
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).
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
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
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
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.
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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ofinfluenzavaccinemanufacturers.
formeremployeeandapaidconsultanttoF.HoffmannLaRocheandhasbeenreimbursedbyanumber
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ndex.html.Accessed27Sep2011.
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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
Bangladesh
2/4
17
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
pt
Pakistan
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Table2.TimeCourseofIllnessfromOnsetofSymptomstoAntiviral(AV)
Age
CaseFatality
Presentationfor
Rate
MedicalCare
Years
MedianDaysfromSymptomOnsetto:
N*
Median
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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)
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Mediansaresignificantlydifferentbetweenagegroups.
*TotalNdiffersaccordingtocompletenessoftimingdata.
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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)
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31
(57.5%)
25/91(27.5%)
Ages
N*
(minmax)
05
225/391
AVTreatment
(N=242treated)
(minmax)
All
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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
<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
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
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
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
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
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
Oseltamivirtreatment(yes/no)
1217
UnadjustedOR
nu
sc
ri
pt
Table6:RhinorrheaandOddsRatiosforDeathamongChildren:TwoModels