AssociationbetweenadverseclinicaloutcomeinhumandiseasecausedbynovelinfluenzaAH7N9virusandsustainedviralsheddingandemergenceofantiviralresistance.

Abstract

BACKGROUND:

OnMarch30,anovelinfluenzaAsubtypeH7N9virus(A/H7N9)wasdetectedinpatientswithsevererespiratorydiseaseineasternChina.Virologicalfactorsassociatedwithapoorclinicaloutcomeforthisvirusremainunclear.WequantifiedtheviralloadandanalysedantiviralresistancemutationsinspecimensfrompatientswithA/H7N9.

METHODS:

Westudied14patientswithA/H7N9diseaseadmittedtotheShanghaiPublicHealthClinicalCentre(SPHCC),China,betweenApril4,andApril20,2013,whoweregivenantiviraltreatment(oseltamivirorperamivir)forlessthan2daysbeforeadmission.Weinvestigatedtheviralloadinthroat,stool,serum,andurinespecimensobtainedsequentiallyfromthesepatients.WealsosequencedviralRNAfromthesespecimenstostudythemutationsassociatedwithresistancetoneuraminidaseinhibitorsandtheirassociationwithdiseaseoutcome.

FINDINGS:

Allpatientsdevelopedpneumonia,sevenofthemrequiredmechanicalventilation,andthreeofthemfurtherdeterioratedtobecomedependentonextracorporealmembraneoxygenation(ECMO),twoofwhomdied.Antiviraltreatmentwasassociatedwithareductionofviralloadinthroatswabspecimensin11survivingpatients.ThreepatientswithpersistentlyhighviralloadinthethroatinspiteofantiviraltherapybecameECMOdependent.AnArg292Lysmutationinthevirusneuraminidase(NA)geneknowntoconferresistancetobothzanamivirandoseltamivirwasidentifiedintwoofthesepatients,bothalsoreceivedcorticosteroidtreatment.Inoneofthem,wild-typesequenceArg292wasnoted2daysafterstartofantiviraltreatment,andtheresistantmutantLys292dominated9daysafterstartoftreatment.

INTERPRETATION:

Reductionofviralloadfollowingantiviraltreatmentcorrelatedwithimprovedoutcome.EmergenceofNAArg292Lysmutationintwopatientswhoalsoreceivedcorticosteroidtreatmentledtotreatmentfailureandapoorclinicaloutcome.TheemergenceofantiviralresistanceinA/H7N9viruses,especiallyinpatientsreceivingcorticosteroidtherapy,isconcerning,needstobecloselymonitored,andconsideredinpandemicpreparednessplanning.