Influenza - Wikipedia

Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, ... Influenza FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Infectiousdisease,"theflu" Forotheruses,seeInfluenza(disambiguation),Flu(disambiguation),andGrippe(disambiguation). "Flus"redirectshere.Forthediagnosticclassofthyroidnodules,seeFLUS. NottobeconfusedwithFlue. MedicalconditionInfluenzaOthernamesFlu,theflu,GrippeInfluenzavirus,magnifiedapproximately100,000timesSpecialtyInfectiousdiseaseSymptomsFever,runnynose,sorethroat,musclepain,headache,coughing,fatigueUsualonset1–4daysafterexposureDuration2–8daysCausesInfluenzavirusesPreventionHandwashing,fluvaccinesMedicationAntiviraldrugssuchasoseltamivirFrequency3–5millionseverecasesperyear[1][2]Deaths>290,000–650,000deathsperyear[3][4] Influenza,commonlyknownas"theflu",isaninfectiousdiseasecausedbyinfluenzaviruses.Symptomsrangefrommildtosevereandoftenincludefever,runnynose,sorethroat,musclepain,headache,coughing,andfatigue.Thesesymptomsbeginfromonetofourdaysafterexposuretothevirus(typicallytwodays)andlastforabout2–8days.Diarrheaandvomitingcanoccur,particularlyinchildren.Influenzamayprogresstopneumonia,whichcanbecausedbythevirusorbyasubsequentbacterialinfection.Othercomplicationsofinfectionincludeacuterespiratorydistresssyndrome,meningitis,encephalitis,andworseningofpre-existinghealthproblemssuchasasthmaandcardiovasculardisease. Therearefourtypesofinfluenzavirus,termedinfluenzavirusesA,B,C,andD.AquaticbirdsaretheprimarysourceofInfluenzaAvirus(IAV),whichisalsowidespreadinvariousmammals,includinghumansandpigs.InfluenzaBvirus(IBV)andInfluenzaCvirus(ICV)primarilyinfecthumans,andInfluenzaDvirus(IDV)isfoundincattleandpigs.IAVandIBVcirculateinhumansandcauseseasonalepidemics,andICVcausesamildinfection,primarilyinchildren.IDVcaninfecthumansbutisnotknowntocauseillness.Inhumans,influenzavirusesareprimarilytransmittedthroughrespiratorydropletsproducedfromcoughingandsneezing.Transmissionthroughaerosolsandintermediateobjectsandsurfacescontaminatedbythevirusalsooccur. Frequenthandwashingandcoveringone'smouthandnosewhencoughingandsneezingreducetransmission.Annualvaccinationcanhelptoprovideprotectionagainstinfluenza.Influenzaviruses,particularlyIAV,evolvequickly,sofluvaccinesareupdatedregularlytomatchwhichinfluenzastrainsareincirculation.VaccinescurrentlyinuseprovideprotectionagainstIAVsubtypesH1N1andH3N2andoneortwoIBVsubtypes.Influenzainfectionisdiagnosedwithlaboratorymethodssuchasantibodyorantigentestsandapolymerasechainreaction(PCR)toidentifyviralnucleicacid.Thediseasecanbetreatedwithsupportivemeasuresand,inseverecases,withantiviraldrugssuchasoseltamivir.Inhealthyindividuals,influenzaistypicallyself-limitingandrarelyfatal,butitcanbedeadlyinhigh-riskgroups. Inatypicalyear,5–15%ofthepopulationcontractsinfluenza.Thereare3–5millionseverecasesannually,withupto650,000respiratory-relateddeathsgloballyeachyear.Deathsmostcommonlyoccurinhigh-riskgroups,includingyoungchildren,theelderly,andpeoplewithchronichealthconditions.Intemperateregionsoftheworld,thenumberofinfluenzacasespeaksduringwinter,whereasinthetropicsinfluenzacanoccuryear-round.Sincethelate1800s,largeoutbreaksofnovelinfluenzastrainsthatspreadglobally,calledpandemics,haveoccurredevery10–50years.Fiveflupandemicshaveoccurredsince1900:theSpanishfluin1918–1920,whichwasthemostsevereflupandemic,theAsianfluin1957,theHongKongfluin1968,theRussianfluin1977,andtheswineflupandemicin2009. Contents 1Signsandsymptoms 2Virology 2.1Typesofvirus 2.2Genomeandstructure 2.3Lifecycle 2.4Antigenicdriftandshift 3Mechanism 3.1Transmission 3.2Pathophysiology 3.3Immunology 4Prevention 4.1Vaccination 4.2Antiviralchemoprophylaxis 4.3Infectioncontrol 5Diagnosis 6Treatment 6.1Antivirals 7Prognosis 8Epidemiology 9History 9.1Etymology 10Research 11Inanimals 11.1Birds 11.2Pigs 11.3Otheranimals 12References Signsandsymptoms Symptomsofinfluenza,[5][6]withfeverandcoughthemostcommonsymptoms[7] Thetimebetweenexposuretothevirusanddevelopmentofsymptoms,calledtheincubationperiod,is1–4days,mostcommonly1–2days.Manyinfections,however,areasymptomatic.[8]Theonsetofsymptomsissudden,andinitialsymptomsarepredominatelynon-specific,includingfever,chills,headaches,musclepainoraching,afeelingofdiscomfort,lossofappetite,lackofenergy/fatigue,andconfusion.Thesesymptomsareusuallyaccompaniedbyrespiratorysymptomssuchasadrycough,soreordrythroat,hoarsevoice,andastuffyorrunnynose.Coughingisthemostcommonsymptom.[1]Gastrointestinalsymptomsmayalsooccur,includingnausea,vomiting,diarrhea,[9]andgastroenteritis,[10]especiallyinchildren.Thestandardinfluenzasymptomstypicallylastfor2–8days.[11]A2021studysuggestsinfluenzacancauselonglastingsymptomsinasimilarwaytolongCOVID.[12] Symptomaticinfectionsareusuallymildandlimitedtotheupperrespiratorytract,butprogressiontopneumoniaisrelativelycommon.Pneumoniamaybecausedbytheprimaryviralinfectionorbyasecondarybacterialinfection.Primarypneumoniaischaracterizedbyrapidprogressionoffever,cough,laboredbreathing,andlowoxygenlevelsthatcausebluishskin.Itisespeciallycommonamongthosewhohaveanunderlyingcardiovasculardiseasesuchasrheumaticheartdisease.Secondarypneumoniatypicallyhasaperiodofimprovementinsymptomsfor1–3weeks[13]followedbyrecurrentfever,sputumproduction,andfluidbuildupinthelungs,[1]butcanalsooccurjustafewdaysafterinfluenzasymptomsappear.[13]Aboutathirdofprimarypneumoniacasesarefollowedbysecondarypneumonia,whichismostfrequentlycausedbythebacteriaStreptococcuspneumoniaeandStaphylococcusaureus.[8][1] Virology Typesofvirus Influenzavirusnomenclature(foraFujianfluvirus) Influenzavirusescomprisefourspecies.Eachofthefourspeciesisthesolememberofitsowngenus,andthefourinfluenzageneracomprisefourofthesevengenerainthefamilyOrthomyxoviridae.Theyare:[1][14] InfluenzaAvirus(IAV),genusAlphainfluenzavirus InfluenzaBvirus(IBV),genusBetainfluenzavirus InfluenzaCvirus(ICV),genusGammainfluenzavirus InfluenzaDvirus(IDV),genusDeltainfluenzavirus IAVisresponsibleformostcasesofsevereillnessaswellasseasonalepidemicsandoccasionalpandemics.Itinfectspeopleofallagesbuttendstodisproportionatelycausesevereillnessintheelderly,theveryyoung,andthosewhohavechronichealthissues.BirdsaretheprimaryreservoirofIAV,especiallyaquaticbirdssuchasducks,geese,shorebirds,andgulls,[15][16]butthevirusalsocirculatesamongmammals,includingpigs,horses,andmarinemammals.IAVisclassifiedintosubtypesbasedontheviralproteinshaemagglutinin(H)andneuraminidase(N).[17]Asof2019,18Hsubtypesand11Nsubtypeshavebeenidentified.Mostpotentialcombinationshavebeenreportedinbirds,butH17-18andN10-11haveonlybeenfoundinbats.OnlyHsubtypesH1-3andNsubtypesN1-2areknowntohavecirculatedinhumans,[17]thecurrentIAVsubtypesincirculationbeingH1N1andH3N2.[2]IAVscanbeclassifiedmorespecificallytoalsoincludenaturalhostspecies,geographicalorigin,yearofisolation,andstrainnumber,suchasH1N1/A/duck/Alberta/35/76.[1][9] IBVmainlyinfectshumansbuthasbeenidentifiedinseals,horses,dogs,andpigs.[17]IBVdoesnothavesubtypeslikeIAVbuthastwoantigenicallydistinctlineages,termedtheB/Victoria/2/1987-likeandB/Yamagata/16/1988-likelineages,[1]orsimply(B/)Victoria(-like)and(B/)Yamagata(-like).[17][2]Bothlineagesareincirculationinhumans,[1]disproportionatelyaffectingchildren.[9]IBVscontributetoseasonalepidemicsalongsideIAVsbuthaveneverbeenassociatedwithapandemic.[17] ICV,likeIBV,isprimarilyfoundinhumans,thoughitalsohasbeendetectedinpigs,feraldogs,dromedarycamels,cattle,anddogs.[10][17]ICVinfectionprimarilyaffectschildrenandisusuallyasymptomatic[1][9]orhasmildcold-likesymptoms,thoughmoreseveresymptomssuchasgastroenteritisandpneumoniacanoccur.[10]UnlikeIAVandIBV,ICVhasnotbeenamajorfocusofresearchpertainingtoantiviraldrugs,vaccines,andothermeasuresagainstinfluenza.[17]ICVissubclassifiedintosixgenetic/antigeniclineages.[10][18] IDVhasbeenisolatedfrompigsandcattle,thelatterbeingthenaturalreservoir.Infectionhasalsobeenobservedinhumans,horses,dromedarycamels,andsmallruminantssuchasgoatsandsheep.[17][18]IDVisdistantlyrelatedtoICV.WhilecattleworkershaveoccasionallytestedpositivetopriorIDVinfection,itisnotknowntocausediseaseinhumans.[1][9][10]ICVandIDVexperienceaslowerrateofantigenicevolutionthanIAVandIBV.Becauseofthisantigenicstability,relativelyfewnovellineagesemerge.[18] Genomeandstructure Structureoftheinfluenzavirion.Thehemagglutinin(HA)andneuraminidase(NA)proteinsareshownonthesurfaceoftheparticle.TheviralRNAsthatmakeupthegenomeareshownasredcoilsinsidetheparticleandboundtoribonucleoproteins(RNP). Influenzaviruseshaveanegative-sense,single-strandedRNAgenomethatissegmented.ThenegativesenseofthegenomemeansitcanbeusedasatemplatetosynthesizemessengerRNA(mRNA).[8]IAVandIBVhaveeightgenomesegmentsthatencode10majorproteins.ICVandIDVhavesevengenomesegmentsthatencodeninemajorproteins.[10]ThreesegmentsencodethreesubunitsofanRNA-dependentRNApolymerase(RdRp)complex:PB1,atranscriptase,PB2,whichrecognizes5'caps,andPA(P3forICVandIDV),anendonuclease.[19]Thematrixprotein(M1)andmembraneprotein(M2)shareasegment,asdothenon-structuralprotein(NS1)andthenuclearexportprotein(NEP).[1]ForIAVandIBV,hemagglutinin(HA)andneuraminidase(NA)areencodedononesegmenteach,whereasICVandIDVencodeahemagglutinin-esterasefusion(HEF)proteinononesegmentthatmergesthefunctionsofHAandNA.Thefinalgenomesegmentencodestheviralnucleoprotein(NP).[19]Influenzavirusesalsoencodevariousaccessoryproteins,suchasPB1-F2andPA-X,thatareexpressedthroughalternativeopenreadingframes[1][20]andwhichareimportantinhostdefensesuppression,virulence,andpathogenicity.[21] Thevirusparticle,calledavirion,ispleomorphicandvariesbetweenbeingfilamentous,bacilliform,orsphericalinshape.Clinicalisolatestendtobepleomorphic,whereasstrainsadaptedtolaboratorygrowthtypicallyproducesphericalvirions.Filamentousvirionsareabout250nanometers(nm)by80nm,bacilliform120–250by95nm,andspherical120nmindiameter.[22]Thevirionconsistsofeachsegmentofthegenomeboundtonucleoproteinsinseparateribonucleoprotein(RNP)complexesforeachsegment,allofwhicharesurroundedbyalipidbilayermembranecalledtheviralenvelope.ThereisacopyoftheRdRp,allsubunitsincluded,boundtoeachRNP.TheenvelopeisreinforcedstructurallybymatrixproteinsontheinteriorthatenclosetheRNPs,[3]andtheenvelopecontainsHAandNA(orHEF[18])proteinsextendingoutwardfromtheexteriorsurfaceoftheenvelope.HAandHEF[18]proteinshaveadistinct"head"and"stalk"structure.M2proteinsformprotonionchannelsthroughtheviralenvelopethatarerequiredforviralentryandexit.IBVscontainasurfaceproteinnamedNBthatisanchoredintheenvelope,butitsfunctionisunknown.[1] Lifecycle Hostcellinvasionandreplicationbytheinfluenzavirus Thevirallifecyclebeginsbybindingtoatargetcell.BindingismediatedbytheviralHAproteinsonthesurfaceoftheevelope,whichbindtocellsthatcontainsialicacidreceptorsonthesurfaceofthecellmembrane.[1][15][3]ForN1subtypeswiththe"G147R"mutationandN2subtypes,theNAproteincaninitiateentry.Priortobinding,NAproteinspromoteaccesstotargetcellsbydegradingmucous,whichhelpstoremoveextracellulardecoyreceptorsthatwouldimpedeaccesstotargetcells.[3]Afterbinding,thevirusisinternalizedintothecellbyanendosomethatcontainsthevirioninsideit.TheendosomeisacidifiedbycellularvATPase[20]tohavelowerpH,whichtriggersaconformationalchangeinHAthatallowsfusionoftheviralenvelopewiththeendosomalmembrane.[21]Atthesametime,hydrogenionsdiffuseintothevirionthroughM2ionchannels,disruptinginternalprotein-proteininteractionstoreleaseRNPsintothehostcell'scytosol.TheM1proteinshellsurroundingRNPsisdegraded,fullyuncoatingRNPsinthecytosol.[20][3] RNPsarethenimportedintothenucleuswiththehelpofvirallocalizationsignals.There,theviralRNApolymerasetranscribesmRNAusingthegenomicnegative-sensestrandasatemplate.Thepolymerasesnatches5'capsforviralmRNAfromcellularRNAtoprimemRNAsynthesisandthe3'-endofmRNAispolyadenylatedattheendoftranscription.[19]OnceviralmRNAistranscribed,itisexportedoutofthenucleusandtranslatedbyhostribosomesinacap-dependentmannertosynthesizeviralproteins.[20]RdRpalsosynthesizescomplementarypositive-sensestrandsoftheviralgenomeinacomplementaryRNPcomplexwhicharethenusedastemplatesbyviralpolymerasestosynthesizecopiesofthenegative-sensegenome.[1][3]Duringtheseprocesses,RdRpsofavianinfluenzaviruses(AIVs)functionoptimallyatahighertemperaturethanmammalianinfluenzaviruses.[11] NewlysynthesizedviralpolymerasesubunitsandNPproteinsareimportedtothenucleustofurtherincreasetherateofviralreplicationandformRNPs.[19]HA,NA,andM2proteinsaretraffickedwiththeaidofM1andNEPproteins[21]tothecellmembranethroughtheGolgiapparatus[19]andinsertedintothecell'smembrane.Viralnon-structuralproteinsincludingNS1,PB1-F2,andPA-Xregulatehostcellularprocessestodisableantiviralresponses.[1][21][3]PB1-F2asointeractswithPB1tokeeppolymerasesinthenucleuslonger.[16]M1andNEPproteinslocalizetothenucleusduringthelaterstagesofinfection,bindtoviralRNPsandmediatetheirexporttothecytoplasmwheretheymigratetothecellmembranewiththeaidofrecycledendosomesandarebundledintothesegmentsofthegenome.[1][3] Progenicvirusesleavethecellbybuddingfromthecellmembrane,whichisinitiatedbytheaccumulationofM1proteinsatthecytoplasmicsideofthemembrane.TheviralgenomeisincorporatedinsideaviralenvelopederivedfromportionsofthecellmembranethathaveHA,NA,andM2proteins.Attheendofbudding,HAproteinsremainattachedtocellularsialicaciduntiltheyarecleavedbythesialidaseactivityofNAproteins.Thevirionisthenreleasedfromthecell.ThesialidaseactivityofNAalsocleavesanysialicacidresiduesfromtheviralsurface,whichhelpspreventnewlyassembledvirusesfromaggregatingnearthecellsurfaceandimprovinginfectivity.[1][3]Similartootheraspectsofinfluenzareplication,optimalNAactivityistemperature-andpH-dependent.[11]Ultimately,presenceoflargequantitiesofviralRNAinthecelltriggersapoptosis,i.e.programmedcelldeath,whichisinitiatedbycellularfactorstorestrictviralreplication.[20] Antigenicdriftandshift Antigenicshift,orreassortment,canresultinnovelandhighlypathogenicstrainsofhumaninfluenza. Twokeyprocessesthatinfluenzavirusesevolvethroughareantigenicdriftandantigenicshift.Antigenicdriftiswhenaninfluenzavirus'santigenschangeduetothegradualaccumulationofmutationsintheantigen's(HAorNA)gene.[15]Thiscanoccurinresponsetoevolutionarypressureexertedbythehostimmuneresponse.AntigenicdriftisespeciallycommonfortheHAprotein,inwhichjustafewaminoacidchangesintheheadregioncanconstituteantigenicdrift.[2][18]Theresultistheproductionofnovelstrainsthatcanevadepre-existingantibody-mediatedimmunity.[1][9]AntigenicdriftoccursinallinfluenzaspeciesbutisslowerinBthanAandslowestinCandD.[18]Antigenicdriftisamajorcauseofseasonalinfluenza,[23]andrequiresthatfluvaccinesbeupdatedannually.HAisthemaincomponentofinactivatedvaccines,sosurveillancemonitorsantigenicdriftofthisantigenamongcirculatingstrains.Antigenicevolutionofinfluenzavirusesofhumansappearstobefasterthaninfluenzavirusesinswineandequines.Inwildbirds,within-subtypeantigenicvariationappearstobelimitedbuthasbeenobservedinpoultry.[1][9] Antigenicshiftisasudden,drasticchangeinaninfluenzavirus'santigen,usuallyHA.Duringantigenicshift,antigenicallydifferentstrainsthatinfectthesamecellcanreassortgenomesegmentswitheachother,producinghybridprogeny.Sinceallinfluenzaviruseshavesegmentedgenomes,allarecapableofreassortment.[10][18]Antigenicshift,however,onlyoccursamonginfluenzavirusesofthesamegenus[19]andmostcommonlyoccursamongIAVs.Inparticular,reassortmentisverycommoninAIVs,creatingalargediversityofinfluenzavirusesinbirds,butisuncommoninhuman,equine,andcaninelineages.[24]Pigs,bats,andquailshavereceptorsforbothmammalianandavianIAVs,sotheyarepotential"mixingvessels"forreassortment.[17]Ifananimalstrainreassortswithahumanstrain,[2]thenanovelstraincanemergethatiscapableofhuman-to-humantransmission.Thishascausedpandemics,butonlyalimitednumberhaveoccurred,soitisdifficulttopredictwhenthenextwillhappen.[1][9] Mechanism Transmission Peoplewhoareinfectedcantransmitinfluenzavirusesthroughbreathing,talking,coughing,andsneezing,whichspreadrespiratorydropletsandaerosolsthatcontainvirusparticlesintotheair.Apersonsusceptibletoinfectioncanthencontractinfluenzabycomingintocontactwiththeseparticles.[13][25]Respiratorydropletsarerelativelylargeandtravellessthantwometersbeforefallingontonearbysurfaces.Aerosolsaresmallerandremainsuspendedintheairlonger,sotheytakelongertosettleandcantravelfurtherthanrespiratorydroplets.[25][4]Inhalationofaerosolscanleadtoinfection,[26]butmosttransmissionisintheareaabouttwometersaroundaninfectedpersonviarespiratorydroplets[8]thatcomeintocontactwithmucosaoftheupperrespiratorytract.[26]Transmissionthroughcontactwithaperson,bodilyfluids,orintermediateobjects(fomites)canalsooccur,suchasthroughcontaminatedhandsandsurfaces[8][25]sinceinfluenzavirusescansurviveforhoursonnon-poroussurfaces.[4]Ifone'shandsarecontaminated,thentouchingone'sfacecancauseinfection.[27] Influenzaisusuallytransmissiblefromonedaybeforetheonsetofsymptomsto5–7daysafter.[9]Inhealthyadults,thevirusisshedforupto3–5days.Inchildrenandtheimmunocompromised,thevirusmaybetransmissibleforseveralweeks.[8]Childrenages2–17areconsideredtobetheprimaryandmostefficientspreadersofinfluenza.[1][9]Childrenwhohavenothadmultiplepriorexposurestoinfluenzavirusesshedthevirusatgreaterquantitiesandforalongerdurationthanotherchildren.[1]Peoplewhoareatriskofexposuretoinfluenzaincludehealthcareworkers,socialcareworkers,andthosewholivewithorcareforpeoplevulnerabletoinfluenza.Inlong-termcarefacilities,theflucanspreadrapidlyafteritisintroduced.[9]Avarietyoffactorslikelyencourageinfluenzatransmission,includinglowertemperature,lowerabsoluteandrelativehumidity,lessultravioletradiationfromtheSun,[26][28]andcrowding.[25]InfluenzavirusesthatinfecttheupperrespiratorytractlikeH1N1tendtobemoremildbutmoretransmissible,whereasthosethatinfectthelowerrespiratorytractlikeH5N1tendtocausemoresevereillnessbutarelesscontagious.[8] Pathophysiology Howthedifferentsitesofinfection(showninred)ofH1N1andH5N1influencestheirtransmissionandlethality Inhumans,influenzavirusesfirstcauseinfectionbyinfectingepithelialcellsintherespiratorytract.Illnessduringinfectionisprimarilytheresultoflunginflammationandcompromisecausedbyepithelialcellinfectionanddeath,combinedwithinflammationcausedbytheimmunesystem'sresponsetoinfection.Non-respiratoryorganscanbecomeinvolved,butthemechanismsbywhichinfluenzaisinvolvedinthesecasesareunknown.Severerespiratoryillnesscanbecausedbymultiple,non-exclusivemechanisms,includingobstructionoftheairways,lossofalveolarstructure,lossoflungepithelialintegrityduetoepithelialcellinfectionanddeath,anddegradationoftheextracellularmatrixthatmaintainslungstructure.Inparticular,alveolarcellinfectionappearstodriveseveresymptomssincethisresultsinimpairedgasexchangeandenablesvirusestoinfectendothelialcells,whichproducelargequantitiesofpro-inflammatorycytokines.[13] Pneumoniacausedbyinfluenzavirusesischaracterizedbyhighlevelsofviralreplicationinthelowerrespiratorytract,accompaniedbyastrongpro-inflammatoryresponsecalledacytokinestorm.[1]InfectionwithH5N1orH7N9especiallyproduceshighlevelsofpro-inflammatorycytokines.[15]Inbacterialinfections,earlydepletionofmacrophagesduringinfluenzacreatesafavorableenvironmentinthelungsforbacterialgrowthsincethesewhitebloodcellsareimportantinrespondingtobacterialinfection.Hostmechanismstoencouragetissuerepairmayinadvertentlyallowbacterialinfection.Infectionalsoinducesproductionofsystemicglucocorticoidsthatcanreduceinflammationtopreservetissueintegritybutallowincreasedbacterialgrowth.[13] Thepathophysiologyofinfluenzaissignificantlyinfluencedbywhichreceptorsinfluenzavirusesbindtoduringentryintocells.Mammalianinfluenzavirusespreferentiallybindtosialicacidsconnectedtotherestoftheoligosaccharidebyanα-2,6link,mostcommonlyfoundinvariousrespiratorycells,[1][15][3]suchasrespiratoryandretinalepithelialcells.[20]AIVsprefersialicacidswithanα-2,3linkage,whicharemostcommoninbirdsingastrointestinalepithelialcells[1][15][3]andinhumansinthelowerrespiratorytract.[29]Furthermore,cleavageoftheHAproteinintoHA1,thebindingsubunit,andHA2,thefusionsubunit,isperformedbydifferentproteases,affectingwhichcellscanbeinfected.FormammalianinfluenzavirusesandlowpathogenicAIVs,cleavageisextracellular,whichlimitsinfectiontocellsthathavetheappropriateproteases,whereasforhighlypathogenicAIVs,cleavageisintracellularandperformedbyubiquitousproteases,whichallowsforinfectionofagreatervarietyofcells,therebycontributingtomoreseveredisease.[1][24][30] Immunology CellspossesssensorstodetectviralRNA,whichcantheninduceinterferonproduction.Interferonsmediateexpressionofantiviralproteinsandproteinsthatrecruitimmunecellstotheinfectionsite,andtheyalsonotifynearbyuninfectedcellsofinfection.Someinfectedcellsreleasepro-inflammatorycytokinesthatrecruitimmunecellstothesiteofinfection.Immunecellscontrolviralinfectionbykillinginfectedcellsandphagocytizingviralparticlesandapoptoticcells.Anexacerbatedimmuneresponse,however,canharmthehostorganismthroughacytokinestorm.[1][11][20]Tocountertheimmuneresponse,influenzavirusesencodevariousnon-structuralproteins,includingNS1,NEP,PB1-F2,andPA-X,thatareinvolvedincurtailingthehostimmuneresponsebysuppressinginterferonproductionandhostgeneexpression.[1][21] Bcells,atypeofwhitebloodcell,produceantibodiesthatbindtoinfluenzaantigensHAandNA(orHEF[18])andotherproteinstoalesserdegree.Onceboundtotheseproteins,antibodiesblockvirionsfrombindingtocellularreceptors,neutralizingthevirus.Inhumans,asizeableantibodyresponseoccurs~1weekafterviralexposure.[31]Thisantibodyresponseistypicallyrobustandlong-lasting,especiallyforICVandIDV.[1][18]Inotherwords,peopleexposedtoacertainstraininchildhoodstillpossessantibodiestothatstrainatareasonablelevellaterinlife,whichcanprovidesomeprotectiontorelatedstrains.[1]Thereis,however,an"originalantigenicsin",inwhichthefirstHAsubtypeapersonisexposedtoinfluencestheantibody-basedimmuneresponsetofutureinfectionsandvaccines.[2] Prevention Furtherinformation:Influenzaprevention Vaccination Mainarticle:Influenzavaccine Givinganinfluenzavaccination Annualvaccinationistheprimaryandmosteffectivewaytopreventinfluenzaandinfluenza-associatedcomplications,especiallyforhigh-riskgroups.[8][1][32]Vaccinesagainstthefluaretrivalentorquadrivalent,providingprotectionagainstanH1N1strain,anH3N2strain,andoneortwoIBVstrainscorrespondingtothetwoIBVlineages.[8][2]Twotypesofvaccinesareinuse:inactivatedvaccinesthatcontain"killed"(i.e.inactivated)virusesandliveattenuatedinfluenzavaccines(LAIVs)thatcontainweakenedviruses.[1]Therearethreetypesofinactivatedvaccines:wholevirus,splitvirus,inwhichthevirusisdisruptedbyadetergent,andsubunit,whichonlycontainstheviralantigensHAandNA.[33]Mostfluvaccinesareinactivatedandadministeredviaintramuscularinjection.LAIVsaresprayedintothenasalcavity.[1] Vaccinationrecommendationsvarybycountry.Somerecommendvaccinationforallpeopleaboveacertainage,suchas6months,[32]whereasothercountriesrecommendationislimitedforhighatriskgroups,suchaspregnantwomen,youngchildren(excludingnewborns),theelderly,peoplewithchronicmedicalconditions,healthcareworkers,[1]peoplewhocomeintocontactwithhigh-riskpeople,andpeoplewhotransmittheviruseasily.[9]Younginfantscannotreceivefluvaccinesforsafetyreasons,buttheycaninheritpassiveimmunityfromtheirmotherifinactivatedvaccinesareadministeredtothemotherduringpregnancy.[34]Influenzavaccinationalsohelpstoreducetheprobabilityofreassortment.[11] Ingeneral,influenzavaccinesareonlyeffectiveifthereisanantigenicmatchbetweenvaccinestrainsandcirculatingstrains.[8][2]Additionally,mostcommerciallyavailablefluvaccinesaremanufacturedbypropagationofinfluenzavirusesinembryonatedchickeneggs,taking6–8months.[2]Fluseasonsaredifferentinthenorthernandsouthernhemisphere,sotheWHOmeetstwiceayear,oneforeachhemisphere,todiscusswhichstrainsshouldbeincludedinfluvaccinesbasedonobservationfromHAinhibitionassays.[8][3]OthermanufacturingmethodsincludeanMDCKcellculture-basedinactivatedvaccineandarecombinantsubunitvaccinemanufacturedfrombaculovirusoverexpressionininsectcells.[2][35] Antiviralchemoprophylaxis Influenzacanbepreventedorreducedinseveritybypost-exposureprophylaxiswiththeantiviraldrugsoseltamivir,whichcanbetakenorallybythoseatleastthreemonthsold,andzanamivir,whichcanbeinhaledbythoseabovesevenyearsofage.Chemoprophylaxisismostusefulforindividualsathigh-riskofdevelopingcomplicationsandthosewhocannotreceivethefluvaccineduetocontraindicationsorlackofeffectiveness.[8]Post-exposurechemoprophylaxisisonlyrecommendedifoseltamiviristakenwithin48hoursofcontactwithaconfirmedorsuspectedinfluenzacaseandzanamivirwithin36hours.[8][9]Itisrecommendedthatitbeofferedtopeoplewhohaveyettoreceiveavaccineforthecurrentfluseason,whohavebeenvaccinatedlessthantwoweeksincecontact,ifthereisasignificantmismatchbetweenvaccineandcirculatingstrains,orduringanoutbreakinaclosedsettingregardlessofvaccinationhistory.[9] Infectioncontrol Handhygieneisimportantinreducingthespreadofinfluenza.Thisincludesfrequenthandwashingwithsoapandwater,usingalcohol-basedhandsanitizers,andnottouchingone'seyes,nose,andmouthwithone'shands.Coveringone'snoseandmouthwhencoughingorsneezingisimportant.[36]Othermethodstolimitinfluenzatransmissionincludestayinghomewhensick,[1]avoidingcontactwithothersuntilonedayaftersymptomsend,[9]anddisinfectingsurfaceslikelytobecontaminatedbythevirus,suchasdoorknobs.[1]Healtheducationthroughmediaandpostersisoftenusedtoremindpeopleoftheaforementionedetiquetteandhygiene.[8] Thereisuncertaintyabouttheuseofmaskssinceresearchthusfarhasnotshownasignificantreductioninseasonalinfluenzawithmaskusage.Likewise,theeffectivenessofscreeningatpointsofentryintocountriesisnotwellresearched.[36]Socialdistancingmeasuressuchasschoolclosures,avoidingcontactwithinfectedpeopleviaisolationorquarantine,andlimitingmassgatheringsmayreducetransmission,[1][36]butthesemeasuresareoftenexpensive,unpopular,anddifficulttoimplement.Consequently,thecommonlyrecommendedmethodsofinfectioncontrolarerespiratoryetiquette,handhygiene,andmaskwearing,whichareinexpensiveandeasytoperform.Pharmaceuticalmeasuresareeffectivebutmaynotbeavailableintheearlystagesofanoutbreak.[37] Inhealthcaresettings,infectedindividualsmaybecohortedorassignedtoindividualrooms.Protectiveclothingsuchasmasks,gloves,andgownsisrecommendedwhencomingintocontactwithinfectedindividualsifthereisariskofexposuretoinfectedbodilyfluids.Keepingpatientsinnegativepressureroomsandavoidingaerosol-producingactivitiesmayhelp,[8]butspecialairhandlingandventilationsystemsarenotconsiderednecessarytopreventthespreadofinfluenzaintheair.[4]Inresidentialhomes,newadmissionsmayneedtobecloseduntilthespreadofinfluenzaiscontrolled.Whendischargingpatientstocarehomes,itisimportanttotakecareifthereisaknowninfluenzaoutbreak.[9] Sinceinfluenzavirusescirculateinanimalssuchasbirdsandpigs,preventionoftransmissionfromtheseanimalsisimportant.Watertreatment,indoorraisingofanimals,quarantiningsickanimals,vaccination,andbiosecurityaretheprimarymeasuresused.Placingpoultryhousesandpiggeriesonhighgroundawayfromhigh-densityfarms,backyardfarms,livepoultrymarkets,andbodiesofwaterhelpstominimizecontactwithwildbirds.[1]Closureoflivepoultrymarketsappearstothemosteffectivemeasure[15]andhasshowntobeeffectiveatcontrollingthespreadofH5N1,H7N9,andH9N2.[16]Otherbiosecuritymeasuresincludecleaninganddisinfectingfacilitiesandvehicles,banningvisitstopoultryfarms,notbringingbirdsintendedforslaughterbacktofarms,[38]changingclothes,disinfectingfootbaths,andtreatingfoodandwater.[1] Iflivepoultrymarketsarenotclosed,then"cleandays"whenunsoldpoultryisremovedandfacilitiesaredisinfectedand"nocarry-over"policiestoeliminateinfectiousmaterialbeforenewpoultryarrivecanbeusedtoreducethespreadofinfluenzaviruses.Ifanovelinfluenzaviruseshasbreachedtheaforementionedbiosecuritymeasures,thenrapiddetectiontostampitoutviaquarantining,decontamination,andcullingmaybenecessarytopreventthevirusfrombecomingendemic.[1]VaccinesexistforavianH5,H7,andH9subtypesthatareusedinsomecountries.[15]InChina,forexample,vaccinationofdomesticbirdsagainstH7N9successfullylimiteditsspread,indicatingthatvaccinationmaybeaneffectivestrategy[24]ifusedincombinationwithothermeasurestolimittransmission.[1]Inpigsandhorses,managementofinfluenzaisdependentonvaccinationwithbiosecurity.[1] Diagnosis X-rayof29-year-oldpersonwithH1N1 Diagnosisbasedonsymptomsisfairlyaccurateinotherwisehealthypeopleduringseasonalepidemicsandshouldbesuspectedincasesofpneumonia,acuterespiratorydistresssyndrome(ARDS),sepsis,orifencephalitis,myocarditis,orbreakingdownofmuscletissueoccur.[13]Becauseinfluenzaissimilartootherviralrespiratorytractillnesses,laboratorydiagnosisisnecessaryforconfirmation.Commonwaysofcollectingsamplesfortestingincludenasalandthroatswabs.[1]Samplesmaybetakenfromthelowerrespiratorytractifinfectionhasclearedtheupperbutnotlowerrespiratorytract.Influenzatestingisrecommendedforanyonehospitalizedwithsymptomsresemblinginfluenzaduringfluseasonorwhoisconnectedtoaninfluenzacase.Forseverecases,earlierdiagnosisimprovespatientoutcome.[32]Diagnosticmethodsthatcanidentifyinfluenzaincludeviralcultures,antibody-andantigen-detectingtests,andnucleicacid-basedtests.[39] Virusescanbegrowninacultureofmammaliancellsorembryonatedeggsfor3–10daystomonitorcytopathiceffect.Finalconfirmationcanthenbedoneviaantibodystaining,hemadsorptionusingredbloodcells,orimmunofluorescencemicroscopy.Shellvialcultures,whichcanidentifyinfectionviaimmunostainingbeforeacytopathiceffectappears,aremoresensitivethantraditionalcultureswithresultsin1–3days.[1][32][39]Culturescanbeusedtocharacterizenovelviruses,observesensitivitytoantiviraldrugs,andmonitorantigenicdrift,buttheyarerelativelyslowandrequirespecializedskillsandequipment.[1] Serologicalassayscanbeusedtodetectanantibodyresponsetoinfluenzaafternaturalinfectionorvaccination.CommonserologicalassaysincludehemagglutinationinhibitionassaysthatdetectHA-specificantibodies,virusneutralizationassaysthatcheckwhetherantibodieshaveneutralizedthevirus,andenzyme-linkedimmunoabsorbantassays.Thesemethodstendtoberelativelyinexpensiveandfastbutarelessreliablethannucleic-acidbasedtests.[1][39] Directfluorescentorimmunofluorescentantibody(DFA/IFA)testsinvolvestainingrespiratoryepithelialcellsinsampleswithfluorescently-labeledinfluenza-specificantibodies,followedbyexaminationunderafluorescentmicroscope.TheycandifferentiatebetweenIAVandIBVbutcan'tsubtypeIAV.[39]Rapidinfluenzadiagnostictests(RIDTs)areasimplewayofobtainingassayresults,arelowcost,andproduceresultsquickly,atlessthan30minutes,sotheyarecommonlyused,buttheycan'tdistinguishbetweenIAVandIBVorbetweenIAVsubtypesandarenotassensitiveasnucleic-acidbasedtests.[1][39] Nucleicacid-basedtests(NATs)amplifyanddetectviralnucleicacid.Mostoftheseteststakeafewhours,[39]butrapidmolecularassaysareasfastasRIDTs.[32]AmongNATs,reversetranscriptionpolymerasechainreaction(RT-PCR)isthemosttraditionalandconsideredthegoldstandardfordiagnosinginfluenza[39]becauseitisfastandcansubtypeIAV,butitisrelativelyexpensiveandmorepronetofalse-positivesthancultures.[1]OtherNATsthathavebeenusedincludeloop-mediatedisothermalamplification-basedassays,simpleamplification-basedassays,andnucleicacidsequence-basedamplification.Nucleicacidsequencingmethodscanidentifyinfectionbyobtainingthenucleicacidsequenceofviralsamplestoidentifythevirusandantiviraldrugresistance.ThetraditionalmethodisSangersequencing,butithasbeenlargelyreplacedbynext-generationmethodsthathavegreatersequencingspeedandthroughput.[39] Treatment Mainarticle:Influenzatreatment Treatmentofinfluenzaincasesofmildormoderateillnessissupportiveandincludesanti-fevermedicationssuchasacetaminophenandibuprofen,[40]adequatefluidintaketoavoiddehydration,andrestingathome.[9]Coughdropsandthroatspraysmaybebeneficialforsorethroat.Itisrecommendedtoavoidalcoholandtobaccousewhilesickwiththeflu.[40]AspirinisnotrecommendedtotreatinfluenzainchildrenduetoanelevatedriskofdevelopingReyesyndrome.[41]Corticosteroidslikewisearenotrecommendedexceptwhentreatingsepticshockoranunderlyingmedicalcondition,suchaschronicobstructivepulmonarydiseaseorasthmaexacerbation,sincetheyareassociatedwithincreasedmortality.[32]Ifasecondarybacterialinfectionoccurs,thentreatmentwithantibioticsmaybenecessary.[9] Antivirals Antiviraldrugs[11] Drug Routeofadministration Approvedageofuse Oseltamivir Oral Atleasttwoweeksold Zanamivir Inhalation Atleastfiveyearsold Peramivir Intravenousinjection Atleast18yearsold Laninamivir Inhalation[1] 40milligrams(mg)doseforpeopleatleast10yearsold,20 mgforthoseunder10[42] Baloxavirmarboxil Oral[4] Atleast12yearsold[32] Antiviraldrugsareprimarilyusedtotreatseverelyillpatients,especiallythosewithcompromisedimmunesystems.Antiviralsaremosteffectivewhenstartedinthefirst48hoursaftersymptomsappear.Lateradministrationmaystillbebeneficialforthosewhohaveunderlyingimmunedefects,thosewithmoreseveresymptoms,orthosewhohaveahigherriskofdevelopingcomplicationsiftheseindividualsarestillsheddingthevirus.Antiviraltreatmentisalsorecommendedifapersonishospitalizedwithsuspectedinfluenzainsteadofwaitingfortestresultstoreturnandifsymptomsareworsening.[1][32]Mostantiviraldrugsagainstinfluenzafallintotwocategories:neuraminidase(NA)inhibitorsandM2inhibitors.[11]Baloxavirmarboxilisanotableexception,whichtargetstheendonucleaseactivityoftheviralRNApolymeraseandcanbeusedasanalternativetoNAandM2inhibitorsforIAVandIBV.[8][15][4] NAinhibitorstargettheenzymaticactivityofNAreceptors,mimickingthebindingofsialicacidintheactivesiteofNAonIAVandIBVvirions[1]sothatviralreleasefrominfectedcellsandtherateofviralreplicationareimpaired.[9]NAinhibitorsincludeoseltamivir,whichisconsumedorallyinaprodrugformandconvertedtoitsactiveformintheliver,andzanamivir,whichisapowderthatisinhalednasally.Oseltamivirandzanamivirareeffectiveforprophylaxisandpost-exposureprophylaxis,andresearchoverallindicatesthatNAinhibitorsareeffectiveatreducingratesofcomplications,hospitalization,andmortality[1]andthedurationofillness.[11][32][4]Additionally,theearlierNAinhibitorsareprovided,thebettertheoutcome,[4]thoughlateadministrationcanstillbebeneficialinseverecases.[1][32]OtherNAinhibitorsincludelaninamivir[1]andperamivir,thelatterofwhichcanbeusedasanalternativetooseltamivirforpeoplewhocannottolerateorabsorbit.[32] Theadamantanesamantadineandrimantadineareorallyadministereddrugsthatblocktheinfluenzavirus'sM2ionchannel,[1]preventingviraluncoating.[4]ThesedrugsareonlyfunctionalagainstIAV[32]butarenolongerrecommendedforusebecauseofwidespreadresistancetothemamongIAVs.[4]AdamantaneresistancefirstemergedinH3N2in2003,becomingworldwideby2008.Oseltamivirresistanceisnolongerwidespreadbecausethe2009pandemicH1N1strain(H1N1pdm09),whichisresistanttoadamantanes,seeminglyreplacedresistantstrainsincirculation.Sincethe2009pandemic,oseltamivirresistancehasmainlybeenobservedinpatientsundergoingtherapy,[1]especiallytheimmunocompromisedandyoungchildren.[4]OseltamivirresistanceisusuallyreportedinH1N1,buthasbeenreportedinH3N2andIBVslesscommonly.[1]Becauseofthis,oseltamivirisrecommendedasthefirstdrugofchoiceforimmunocompetentpeople,whereasfortheimmunocompromised,oseltamivirisrecommendedagainstH3N2andIBVandzanamiviragainstH1N1pdm09.Zanamivirresistanceisobservedlessfrequently,andresistancetoperamivirandbaloxavirmarboxilispossible.[4] Prognosis Inhealthyindividuals,influenzainfectionisusuallyself-limitingandrarelyfatal.[8][9]Symptomsusuallylastfor2–8days.[11]Influenzacancausepeopletomissworkorschool,anditisassociatedwithdecreasedjobperformanceand,inolderadults,reducedindependence.Fatigueandmalaisemaylastforseveralweeksafterrecovery,andhealthyadultsmayexperiencepulmonaryabnormalitiesthatcantakeseveralweekstoresolve.Complicationsandmortalityprimarilyoccurinhigh-riskpopulationsandthosewhoarehospitalized.Severediseaseandmortalityareusuallyattributabletopneumoniafromtheprimaryviralinfectionorasecondarybacterialinfection,[1][9]whichcanprogresstoARDS.[11] Otherrespiratorycomplicationsthatmayoccurincludesinusitis,bronchitis,bronchiolitis,excessfluidbuildupinthelungs,andexacerbationofchronicbronchitisandasthma.Middleearinfectionandcroupmayoccur,mostcommonlyinchildren.[8][1]SecondaryS.aureusinfectionhasbeenobserved,primarilyinchildren,tocausetoxicshocksyndromeafterinfluenza,withhypotension,fever,andreddeningandpeelingoftheskin.[1]Complicationsaffectingthecardiovascularsystemarerareandincludepericarditis,fulminantmyocarditiswithafast,slow,orirregularheartbeat,andexacerbationofpre-existingcardiovasculardisease.[8][9]Inflammationorswellingofmusclesaccompaniedbymuscletissuebreakingdownoccursrarely,usuallyinchildren,whichpresentsasextremetendernessandmusclepaininthelegsandareluctancetowalkfor2–3days.[1][9][13] Influenzacanaffectpregnancy,includingcausingsmallerneonatalsize,increasedriskofprematurebirth,andanincreasedriskofchilddeathshortlybeforeorafterbirth.[9]Neurologicalcomplicationshavebeenassociatedwithinfluenzaonrareoccasions,includingasepticmeningitis,encephalitis,disseminatedencephalomyelitis,transversemyelitis,andGuillain–Barrésyndrome.[13]Additionally,febrileseizuresandReyesyndromecanoccur,mostcommonlyinchildren.[1][9]Influenza-associatedencephalopathycanoccurdirectlyfromcentralnervoussysteminfectionfromthepresenceofthevirusinbloodandpresentsassuddentonsetoffeverwithconvulsions,followedbyrapidprogressiontocoma.[8]Anatypicalformofencephalitiscalledencephalitislethargica,characterizedbyheadache,drowsiness,andcoma,mayrarelyoccursometimeafterinfection.[1]Insurvivorsofinfluenza-associatedencephalopathy,neurologicaldefectsmayoccur.[8]Primarilyinchildren,inseverecasestheimmunesystemmayrarelydramaticallyoverproducewhitebloodcellsthatreleasecytokines,causingsevereinflammation.[8] Peoplewhoareatleast65yearsofage,[9]duetoaweakenedimmunesystemfromagingorachronicillness,areahigh-riskgroupfordevelopingcomplications,asarechildrenlessthanoneyearofageandchildrenwhohavenotbeenpreviouslyexposedtoinfluenzavirusesmultipletimes.Pregnantwomenareatanelevatedrisk,whichincreasesbytrimester[1]andlastsuptotwoweeksafterchildbirth.[9][32]Obesity,inparticularabodymassindexgreaterthan35–40,isassociatedwithgreateramountsofviralreplication,increasedseverityofsecondarybacterialinfection,andreducedvaccinationefficacy.Peoplewhohaveunderlyinghealthconditionsarealsoconsideredat-risk,includingthosewhohavecongenitalorchronicheartproblemsorlung(e.g.asthma),kidney,liver,blood,neurological,ormetabolic(e.g.diabetes)disorders,[8][1][9]asarepeoplewhoareimmunocompromisedfromchemotherapy,asplenia,prolongedsteroidtreatment,splenicdysfunction,orHIVinfection.[9]Currentorpasttobaccousealsoplacesapersonatrisk.[32]Theroleofgeneticsininfluenzaisnotwellresearched,[1]butitmaybeafactorininfluenzamortality.[11] Epidemiology Furtherinformation:FluseasonandFlupandemics InfluenzamortalityinsymptomaticcasesintheUSforthe2018/2019season.[43] Influenzaistypicallycharacterizedbyseasonalepidemicsandsporadicpandemics.MostoftheburdenofinfluenzaisaresultoffluseasonscausedbyIAVandIBV.AmongIAVsubtypes,H1N1andH3N2currentlycirculateinhumansandareresponsibleforseasonalinfluenza.Casesdisproportionatelyoccurinchildren,butmostseverecausesareamongtheelderly,theveryyoung,[1]andtheimmunocompromised.[4]Inatypicalyear,influenzavirusesinfect5–15%oftheglobalpopulation,[3][39]causing3–5millioncasesofsevereillnessannually[1][2]andaccountingfor290,000–650,000deathseachyearduetorespiratoryillness.[3][4][44]5–10%ofadultsand20–30%ofchildrencontractinfluenzaeachyear.[17]Thereportednumberofinfluenzacasesisusuallymuchlowerthantheactualnumberofcases.[1][34] Duringseasonalepidemics,itisestimatedthatabout80%ofotherwisehealthypeoplewhohaveacoughorsorethroathavetheflu.[1]Approximately30–40%ofpeoplehospitalizedforinfluenzadeveloppneumonia,andabout5%ofallseverepneumoniacasesinhospitalsareduetoinfluenza,whichisalsothemostcommoncauseofARDSinadults.Inchildren,influenzaisoneofthetwomostcommoncausesofARDS,theotherbeingtherespiratorysyncytialvirus.[13]About3–5%ofchildreneachyeardevelopotitismediaduetoinfluenza.[8]AdultswhodeveloporganfailurefrominfluenzaandchildrenwhohavePIMscoresandacuterenalfailurehavehigherratesofmortality.[13]Duringseasonalinfluenza,mortalityisconcentratedintheveryyoungandtheelderly,whereasduringflupandemics,youngadultsareoftenaffectedatahighrate.[11] Seasonalriskareasforinfluenza:November–April(blue),April–November(red),andyear-round(yellow) Intemperateregions,thenumberofinfluenzacasesvariesfromseasontoseason.LowervitaminDlevels,presumablyduetolesssunlight,[28]lowerhumidity,lowertemperature,andminorchangesinvirusproteinscausedbyantigenicdriftcontributetoannualepidemicsthatpeakduringthewinterseason.Inthenorthernhemisphere,thisisfromOctobertoMay(morenarrowlyDecembertoApril[11]),andinthesouthernhemisphere,thisisfromMaytoOctober(morenarrowlyJunetoSeptember[11]).Therearethereforetwodistinctinfluenzaseasonseveryyearintemperateregions,oneinthenorthernhemisphereandoneinthesouthernhemisphere.[1][9][2]Intropicalandsubtropicalregions,seasonalityismorecomplexandappearstobeaffectedbyvariousclimaticfactorssuchasminimumtemperature,hoursofsunshine,maximumrainfall,andhighhumidity.[1][45]Influenzamaythereforeoccuryear-roundintheseregions.[11]Influenzaepidemicsinmoderntimeshavethetendencytostartintheeasternorsouthernhemisphere,[45]withAsiabeingakeyreservoirofinfluenzaviruses.[11] IAVandIBVco-circulate,sothetwohavethesamepatternsoftransmission.[1]TheseasonalityofICV,however,ispoorlyunderstood.ICVinfectionismostcommoninchildrenundertheageof2,andbyadulthoodmostpeoplehavebeenexposedtoit.ICV-associatedhospitalizationmostcommonlyoccursinchildrenundertheageof3andisfrequentlyaccompaniedbyco-infectionwithanothervirusorabacterium,whichmayincreasetheseverityofdisease.Whenconsideringallhospitalizationsforrespiratoryillnessamongyoungchildren,ICVappearstoaccountforonlyasmallpercentageofsuchcases.LargeoutbreaksofICVinfectioncanoccur,soincidencevariessignificantly.[10] Outbreaksofinfluenzacausedbynovelinfluenzavirusesarecommon.[19]Dependingonthelevelofpre-existingimmunityinthepopulation,novelinfluenzavirusescanspreadrapidlyandcausepandemicswithmillionsofdeaths.Thesepandemics,incontrasttoseasonalinfluenza,arecausedbyantigenicshiftsinvolvinganimalinfluenzaviruses.Todate,allknownflupandemicshavebeencausedbyIAVs,andtheyfollowthesamepatternofspreadingfromanoriginpointtotherestoftheworldoverthecourseofmultiplewavesinayear.[1][9][32]Pandemicstrainstendtobeassociatedwithhigherratesofpneumoniainotherwisehealthyindividuals.[13]Generallyaftereachinfluenzapandemic,thepandemicstraincontinuestocirculateasthecauseofseasonalinfluenza,replacingpriorstrains.[1]From1700to1889,influenzapandemicsoccurredaboutonceevery50–60years.Sincethen,pandemicshaveoccurredaboutonceevery10–50years,sotheymaybegettingmorefrequentovertime.[45] History Themaintypesofinfluenzavirusesinhumans.Solidsquaresshowtheappearanceofanewstrain,causingrecurringinfluenzapandemics.Brokenlinesindicateuncertainstrainidentifications.[46] Itisimpossibletoknowwhenaninfluenzavirusfirstinfectedhumansorwhenthefirstinfluenzapandemicoccurred.[47]Possiblythefirstinfluenzaepidemicoccurredaround6,000BCinChina,[48]andpossibledescriptionsofinfluenzaexistinGreekwritingsfromthe5thcenturyBC.[45][49]Inboth1173–1174ADand1387AD,epidemicsoccurredacrossEuropethatwerenamed"influenza".Whethertheseepidemicsandotherswerecausedbyinfluenzaisunclearsincetherewasnoconsistentnamingpatternforepidemicrespiratorydiseasesatthattime,and"influenza"didn'tbecomecompletelyattachedtorespiratorydiseaseuntilcenturieslater.[50]InfluenzamayhavebeenbroughttotheAmericasasearlyas1493,whenanepidemicdiseaseresemblinginfluenzakilledmostofthepopulationoftheAntilles.[51][52] Thefirstconvincingrecordofaninfluenzapandemicwaschronicledin1510;itbeganinEastAsiabeforespreadingtoNorthAfricaandthenEurope.[47]Followingthepandemic,seasonalinfluenzaoccurred,withsubsequentpandemicsin1557and1580.[50]Theflupandemicin1557waspotentiallythefirsttimeinfluenzawasconnectedtomiscarriageanddeathofpregnantwomen.[53]The1580flupandemicoriginatedinAsiaduringsummer,spreadtoAfrica,thenEurope,andfinallyAmerica.[45]Bytheendofthe16thcentury,influenzawaslikelybeginningtobecomeunderstoodasaspecific,recognizablediseasewithepidemicandendemicforms.[50]In1648,itwasdiscoveredthathorsesalsoexperienceinfluenza.[47] Influenzadataafter1700ismoreinformative,soitiseasiertoidentifyflupandemicsafterthispoint,eachofwhichincrementallyincreasedunderstandingofinfluenza.[54]Thefirstflupandemicofthe18thcenturystartedin1729inRussiainspring,spreadingworldwideoverthecourseofthreeyearswithdistinctwaves,thelateronesbeingmorelethal.Thesecondflupandemicofthe18thcenturywasin1781–1782,startinginChinainautumn.[45]Fromthispandemic,influenzabecameassociatedwithsuddenoutbreaksoffebrileillness.[54]Thenextflupandemicwasfrom1830to1833,beginninginChinainwinter.Thispandemichadahighattackrate,butthemortalityratewaslow.[23][45] Aminorinfluenzapandemicoccurredfrom1847to1851atthesametimeasthethirdcholerapandemicandwasthefirstflupandemictooccurwithvitalstatisticsbeingrecorded,soinfluenzamortalitywasclearlyrecordedforthefirsttime.[54]Highlypathogenicavianinfluenzawasrecognizedin1878[54]andwassoonlinkedtotransmissiontohumans.[47]Bythetimeofthe1889pandemic,whichmayhavebeencausedbyanH2N2strain,[55]thefluhadbecomeaneasilyrecognizabledisease.[47] Initially,themicrobialagentresponsibleforinfluenzawasincorrentlyidentifiedin1892byR.F.J.PfeifferasthebacteriaspeciesHaemophilusinfluenzae,whichretains"influenza"initsname.[47][54]Inthefollowingyears,thefieldofvirologybegantoformasviruseswereidentifiedasthecauseofmanydiseases.From1901to1903,ItalianandAustrianresearcherswereabletoshowthatavianinfluenza,thencalled"fowlplague",[24]wascausedbyamicroscopicagentsmallerthanbacteriabyusingfilterswithporestoosmallforbacteriatopassthrough.Thefundamentaldifferencesbetweenvirusesandbacteria,however,werenotyetfullyunderstood.[54] Thedifferencebetweentheinfluenzamortalityagedistributionsofthe1918epidemicandnormalepidemics.Deathsper100,000personsineachagegroup,UnitedStates,fortheinterpandemicyears1911–1917(dashedline)andthepandemicyear1918(solidline).[56] From1918to1920,theSpanishflupandemicbecamethemostdevastatinginfluenzapandemicandoneofthedeadliestpandemicsinhistory.Thepandemic,probablycausedbyH1N1,likelybeganintheUSAbeforespreadingworldwidebysoldiersduringandaftertheFirstWorldWar.Theinitialwaveinthefirsthalfof1918wasrelativelyminorandresembledpastflupandemics,butthesecondwavelaterthatyearhadamuchhighermortalityrate,[45]accountingformostdeaths.Athirdwavewithlowermortalityoccurredinmanyplacesafewmonthsafterthesecond.[23]Bytheendof1920,itisestimatedthataboutathird[11]tohalfofallpeopleintheworldhadbeeninfected,withtensofmillionsofdeaths,disproportionatelyyoungadults.[45]Duringthe1918pandemic,therespiratoryrouteoftransmissionwasclearlyidentified[23]andinfluenzawasshowntobecausedbya"filterpasser",notabacterium,butthereremainedalackofagreementaboutinfluenza'scauseforanotherdecadeandresearchoninfluenzadeclined.[54]Afterthepandemic,H1N1circulatedinhumansinseasonalform[1]upuntilthenextpandemic.[54] In1931,RichardShopepublishedthreepapersidentifyingavirusasthecauseofswineinfluenza,athennewlyrecognizeddiseaseamongpigsthatwasfirstcharacterizedduringthesecondwaveofthe1918pandemic.[53][54]Shope'sresearchreinvigoratedresearchonhumaninfluenza,andmanyadvancesinvirology,serology,immunology,experimentalanimalmodels,vaccinology,andimmunotherapyhavesincearisenfrominfluenzaresearch.[54]Justtwoyearsafterinfluenzaviruseswerediscovered,in1933,IAVwasidentifiedastheagentresponsibleforhumaninfluenza.[53][57]SubtypesofIAVwerediscoveredthroughoutthe1930s,[54]andIBVwasdiscoveredin1940.[17] DuringtheSecondWorldWar,theUSgovernmentworkedondevelopinginactivatedvaccinesforinfluenza,resultinginthefirstinfluenzavaccinebeinglicensedin1945intheUnitedStates.[1]ICVwasdiscoveredtwoyearslaterin1947.[17]In1955,avianinfluenzawasconfirmedtobecausedbyIAV.[24]FourinfluenzapandemicshaveoccurredsinceWWII,eachlessseverethanthe1918pandemic.ThefirstofthesewastheAsianflufrom1957to1958,causedbyanH2N2strain[1][37]andbeginninginChina'sYunnanprovince.Thenumberofdeathsprobablyexceededonemillion,mostlyamongtheveryyoungandveryold.[45]Notably,the1957pandemicwasthefirstflupandemictooccurinthepresenceofaglobalsurveillancesystemandlaboratoriesabletostudythenovelinfluenzavirus.[23]Afterthepandemic,H2N2wastheIAVsubtyperesponsibleforseasonalinfluenza.[1]Thefirstantiviraldrugagainstinfluenza,amantadine,wasapprovedforusein1966,withadditionalantiviraldrugsbeingusedsincethe1990s.[4] In1968,H3N2wasintroducedintohumansasaresultofareassortmentbetweenanavianH3N2strainandanH2N2strainthatwascirculatinginhumans.ThenovelH3N2strainfirstemergedinHongKongandspreadworldwide,causingtheHongKongflupandemic,whichresultedin500,000–2,000,000deaths.Thiswasthefirstpandemictospreadsignificantlybyairtravel.[3][23]H2N2andH3N2co-circulatedafterthepandemicuntil1971whenH2N2wanedinprevalenceandwascompletelyreplacedbyH3N2.[3]In1977,H1N1reemergedinhumans,possiblyafteritwasreleasedfromafreezerinalaboratoryaccident,andcausedapseudo-pandemic.[23][54]Whetherthe1977"pandemic"deservestobeincludedinthenaturalhistoryofflupandemicsisdebatable.[45]ThisH1N1strainwasantigenicallysimilartotheH1N1strainsthatcirculatedpriorto1957.Since1977,bothH1N1andH3N2havecirculatedinhumansaspartofseasonalinfluenza.[1]In1980,thecurrentclassificationsystemusedtosubtypeinfluenzaviruseswasintroduced.[58] Thermalimagingcameraandscreen,photographedinanairportterminalinGreeceduringthe2009flupandemic.Thermalimagingcandetectelevatedbodytemperature,oneofthesignsofswineflu. Atsomepoint,IBVdivergedintotwolineages,namedtheB/Victoria-likeandB/Yamagata-likelineages,bothofwhichhavebeencirculatinginhumanssince1983.[17]In1996,HPAIH5N1wasdetectedinGuangdong,China[24]andayearlateremergedinpoultryinHongKong,graduallyspreadingworldwidefromthere.AsmallH5N1outbreakinhumansinHongKongoccurredthen,[30]andsporadichumancaseshaveoccurredsince1997,carryingahighcasefatalityrate.[15][39]Themostrecentflupandemicwasthe2009swineflupandemic,whichoriginatedinMexicoandresultedinhundredsofthousandsofdeaths.[23]ItwascausedbyanovelH1N1strainthatwasareassortmentofhuman,swine,andavianinfluenzaviruses.[16][4]The2009pandemichadtheeffectofreplacingpriorH1N1strainsincirculationwiththenovelstrainbutnotanyotherinfluenzaviruses.Consequently,H1N1,H3N2,andbothIBVlineageshavebeenincirculationinseasonalformsincethe2009pandemic.[1][23][24] In2011,IDVwasdiscoveredinpigsinOklahoma,USA,andcattlewerelateridentifiedastheprimaryreservoirofIDV.[10][17]Inthesameyear,[39]avianH7N9wasdetectedinChinaandbegantocausehumaninfectionsin2013,startinginShanghaiandAnhuiandremainingmostlyinChina.HPAIH7N9emergedsometimein2016andhasoccasionallyinfectedhumansincidentally.OtherAIVshavelesscommonlyinfectedhumanssincethe1990s,includingH5N6,H6N1,H7N2-4,H7N7,andH10N7-8,[15]andHPAIHsubtypessuchasH5N1-3,H5N5-6,andH5N8havebeguntospreadthroughoutmuchoftheworldsincethe2010s.Futureflupandemics,whichmaybecausedbyaninfluenzavirusofavianorigin,[24]areviewedasalmostinevitable,andincreasedglobalizationhasmadeiteasierfornovelvirusestospread,[23]sotherearecontinualeffortstoprepareforfuturepandemics[53]andimprovethepreventionandtreatmentofinfluenza.[1] Etymology ThewordinfluenzacomesfromtheItalianwordinfluenza,frommedievalLatininfluentia,originallymeaning"visitation"or"influence".Termssuchasinfluenzadifreddo,meaning"influenceofthecold",andinfluenzadistelle,meaning"influenceofthestars"areattestedfromthe14thcentury.Thelatterreferredtothedisease'scause,whichatthetimewasascribedbysometounfavorableastrologicalconditions.Asearlyas1504,influenzabegantomeana"visitation"or"outbreak"ofanydiseaseaffectingmanypeopleinasingleplaceatonce.Duringanoutbreakofinfluenzain1743thatstartedinItalyandspreadthroughoutEurope,thewordreachedtheEnglishlanguageandwasanglicizedinpronunciation.Sincethemid-1800s,influenzahasalsobeenusedtorefertoseverecolds.[59][60][61]Theshortenedformoftheword,"(the)flu",isfirstattestedin1839asfluewiththespellingflufirstattestedin1893.[62]Othernamesthathavebeenusedforinfluenzaincludeepidemiccatarrh,lagrippefromFrench,sweatingsickness,and,especiallywhenreferringtothe1918pandemicstrain,Spanishfever.[63] Research Professionalexaminingalaboratory-grownreconstructionofthe1918Spanishfluvirusinabiosafetylevel3environment Influenzaresearchiswide-rangingandincludeseffortstounderstandhowinfluenzavirusesenterhosts,therelationshipbetweeninfluenzavirusesandbacteria,howinfluenzasymptomsprogress,andwhatmakesomeinfluenzavirusesdeadlierthanothers.[64]Non-structuralproteinsencodedbyinfluenzavirusesareperiodicallydiscoveredandtheirfunctionsarecontinuallyunderresearch.[21]Pastpandemics,andespeciallythe1918pandemic,arethesubjectofmuchresearchtounderstandflupandemics.[45]Aspartofpandemicpreparedness,theGlobalInfluenzaSurveillanceandResponseSystemisaglobalnetworkoflaboratoriesthatmonitorsinfluenzatransmissionandepidemiology.[65]Additionalareasofresearchincludewaystoimprovethediagnosis,treatment,andpreventionofinfluenza. Existingdiagnosticmethodshaveavarietyoflimitationscoupledwiththeiradvantages.Forexample,NATshavehighsensitivityandspecificitybutareimpracticalinunder-resourcedregionsduetotheirhighcost,complexity,maintenance,andtrainingrequired.Low-cost,portableRIDTscanrapidlydiagnoseinfluenzabuthavehighlyvariablesensitivityandareunabletosubtypeIAV.Asaresultoftheselimitationsandothers,researchintonewdiagnosticmethodsrevolvesaroundproducingnewmethodsthatarecost-effective,lesslabor-intensive,andlesscomplexthanexistingmethodswhilealsobeingabletodifferentiateinfluenzaspeciesandIAVsubtypes.Oneapproachindevelopmentarelab-on-a-chips,whicharediagnosticdevicesthatmakeuseofavarietyofdiagnostictests,suchasRT-PCRandserologicalassays,inmicrochipform.Thesechipshavemanypotentialadvantages,includinghighreactionefficiency,lowenergyconsumption,andlowwastegeneration.[39] Newantiviraldrugsarealsoindevelopmentduetotheeliminationofadamantinesasviabledrugsandconcernsoveroseltamivirresistance.Theseinclude:NAinhibitorsthatcanbeinjectedintravenously,suchasintravenousformulationsofzanamivir;favipiravir,whichisapolymeraseinhibitorusedagainstseveralRNAviruses;pimodivir,whichpreventscap-bindingrequiredduringviraltranscription;andnitazoxanide,whichinhibitsHAmaturation.[1][11]Reducingexcessinflammationintherespiratorytractisalsosubjecttomuchresearchsincethisisoneoftheprimarymechanismsofinfluenzapathology.[11][13]Otherformsoftherapyindevelopmentincludemonoclonalandpolyclonalantibodiesthattargetviralproteins,convalescentplasma,differentapproachestomodifythehostantiviralresponse,[32][66]andstemcell-basedtherapiestorepairlungdamage.[11] MuchresearchonLAIVsfocusesonidentifyinggenomesequencesthatcanbedeletedtocreateharmlessinfluenzavirusesinvaccinesthatstillconferimmunity.[21]Thehighvariabilityandrapidevolutionofinfluenzavirusantigens,however,isamajorobstacleindevelopingeffectivevaccines.Furthermore,itishardtopredictwhichstrainswillbeincirculationduringthenextfluseason,manufacturingasufficientquantityoffluvaccinesforthenextseasonisdifficult,[2]LAIVshavelimitedefficacy,andrepeatedannualvaccinationpotentiallyhasdiminishedefficacy.[1]Forthesereasons,"broadly-reactive"or"universal"fluvaccinesarebeingresearchedthatcanprovideprotectionagainstmanyorallinfluenzaviruses.ApproachestodevelopsuchavaccineincludeHAstalk-basedmethodssuchaschimerasthathavethesamestalkbutdifferentheads,HAhead-basedmethodssuchascomputationallyoptimizedbroadlyneutralizingantigens,anti-idiotypicantibodies,andvaccinestoelicitimmuneresponsestohighlyconservedviralproteins.[2][66]mRNAvaccinestoprovideprotectionagainstinfluenzaarealsounderresearch.[67] Inanimals Birds Aquaticbirdssuchasducks,geese,shorebirds,andgullsaretheprimaryreservoirofIAVs.[15][16]Inbirds,AIVsmaybeeitherlowpathogenicavianinfluenza(LPAI)virusesthatproducelittletonosymptomsorhighlypathogenicavianinfluenza(HPAI)virusesthatcausesevereillness.SymptomsofHPAIinfectionincludelackofenergyandappetite,decreasedeggproduction,soft-shelledormisshapeneggs,swellingofthehead,comb,wattles,andhocks,purplediscolorationofwattles,combs,andlegs,nasaldischarge,coughing,sneezing,incoordination,anddiarrhea.BirdsinfectedwithanHPAIvirusmayalsodiesuddenlywithoutanysignsofinfection.[38] ThedistinctionbetweenLPAIandHPAIcangenerallybemadebasedonhowlethalanAIVistochickens.Atthegeneticlevel,anAIVcanbeusuallybeidentifiedasanHPAIvirusifithasamultibasiccleavagesiteintheHAprotein,whichcontainsadditionalresiduesintheHAgene.[16][24]MostAIVsareLPAI.NotableHPAIvirusesincludeHPAIH5N1andHPAIH7N9.HPAIviruseshavebeenamajordiseaseburdeninthe21stcentury,resultinginthedeathoflargenumbersofbirds.InH7N9'scase,somecirculatingstrainswereoriginallyLPAIbutbecameHPAIbyacquiringtheHAmultibasiccleavagesite.AvianH9N2isalsoofconcernbecausealthoughitisLPAI,itisacommondonorofgenestoH5N1andH7N9duringreassortment.[1] Migratorybirdscanspreadinfluenzaacrosslongdistances.AnexampleofthiswaswhenanH5N1strainin2005infectedbirdsatQinghaiLake,China,whichisastopoverandbreedingsiteformanymigratorybirds,subsequentlyspreadingthevirustomorethan20countriesacrossAsia,Europe,andtheMiddleEast.[15][24]AIVscanbetransmittedfromwildbirdstodomesticfree-rangeducksandinturntopoultrythroughcontaminatedwater,aerosols,andfomites.[1]Ducksthereforeactaskeyintermediatesbetweenwildanddomesticbirds.[24]Transmissiontopoultrytypicallyoccursinbackyardfarmingandliveanimalmarketswheremultiplespeciesinteractwitheachother.Fromthere,AIVscanspreadtopoultryfarmsintheabsenceofadequatebiosecurity.Amongpoultry,HPAItransmissionoccursthroughaerosolsandcontaminatedfeces,[1]cages,feed,anddeadanimals.[15]Back-transmissionofHPAIvirusesfrompoultrytowildbirdshasoccurredandisimplicatedinmassdie-offsandintercontinentalspread.[16] AIVshaveoccasionallyinfectedhumansthroughaerosols,fomites,andcontaminatedwater.[1]Directiontransmissionfromwildbirdsisrare.[24]Instead,mosttransmissioninvolvesdomesticpoultry,mainlychickens,ducks,andgeesebutalsoavarietyofotherbirdssuchasguineafowl,partridge,pheasants,andquails.[16]TheprimaryriskfactorforinfectionwithAIVsisexposuretobirdsinfarmsandlivepoultrymarkets.[15]Typically,infectionwithanAIVhasanincubationperiodof3–5daysbutcanbeupto9days.H5N1andH7N9causeseverelowerrespiratorytractillness,whereasotherAIVssuchasH9N2causeamoremildupperrespiratorytractillness,commonlywithconjunctivitis.[1]LimitedtransmissionofavianH2,H5-7,H9,andH10subtypesfromonepersontoanotherthroughrespiratorydroplets,aerosols,andfomiteshasoccurred,[1][2]butsustainedhuman-to-humantransmissionofAIVshasnotoccurred.Before2013,H5N1wasthemostcommonAIVtoinfecthumans.Sincethen,H7N9hasbeenresponsibleformosthumancases.[15] Pigs Chineseinspectorscheckingairlinepassengersforfevers,acommonsymptomofswineflu Influenzainpigsisarespiratorydiseasesimilartoinfluenzainhumansandisfoundworldwide.Asymptomaticinfectionsarecommon.Symptomstypicallyappear1–3daysafterinfectionandincludefever,lethargy,anorexia,weightloss,laboredbreathing,coughing,sneezing,andnasaldischarge.Insows,pregnancymaybeaborted.Complicationsincludesecondaryinfectionsandpotentiallyfatalbronchopneumonia.Pigsbecomecontagiouswithinadayofinfectionandtypicallyspreadthevirusfor7–10days,whichcanspreadrapidlywithinaherd.Pigsusuallyrecoverfrominfectionwithin3–7daysaftersymptomsappear.Preventionandcontrolmeasuresincludeinactivatedvaccinesandcullinginfectedherds.TheinfluenzavirusesusuallyresponsibleforswinefluareIAVsubtypesH1N1,H1N2,andH3N2.[68] SomeIAVscanbetransmittedviaaerosolsfrompigstohumansandviceversa.[1]Furthermore,pigs,alongwithbatsandquails,[17]arerecognizedasamixingvesselofinfluenzavirusesbecausetheyhavebothα-2,3andα-2,6sialicacidreceptorsintheirrespiratorytract.Becauseofthat,bothavianandmammalianinfluenzavirusescaninfectpigs.Ifco-infectionoccurs,thenreassortmentispossible.[16]Anotableexampleofthiswasthereassortmentofaswine,avian,andhumaninfluenzavirusin2009,resultinginanovelH1N1strainthatcausedthe2009flupandemic.[16][4]Spillovereventsfromhumanstopigs,however,appeartobemorecommonthanfrompigstohumans.[16] Otheranimals Influenzaviruseshavebeenfoundinmanyotheranimals,includingcattle,horses,dogs,cats,andmarinemammals.NearlyallIAVsareapparentlydescendedfromancestralvirusesinbirds.Theexceptionarebatinfluenza-likeviruses,whichhaveanuncertainorigin.ThesebatviruseshaveHAandNAsubtypesH17,H18,N10,andN11.H17N10andH18N11areunabletoreassortwithotherIAVs,buttheyarestillabletoreplicateinothermammals.[1]AIVssometimescrossoverintomammals.Forexample,inlate2016toearly2017,anavianH7N2strainwasfoundtobeinfectingcatsinNewYork.[1] EquineIAVsincludeH7N7andtwolineages[1]ofH3N8.H7N7,however,hasnotbeendetectedinhorsessincethelate1970s,[19]soitmayhavebecomeextinctinhorses.[16]H3N8inequinesspreadsviaaerosolsandcausesrespiratoryillness.[1]EquineH3N8perferentiallybindstoα-2,3sialicacids,sohorsesareusuallyconsidereddead-endhosts,buttransmissiontodogsandcamelshasoccurred,raisingconcernsthathorsesmaybemixingvesselsforreassortment.Incanines,theonlyIAVsincirculationareequine-derivedH3N8andavian-derivedH3N2.CanineH3N8hasnotbeenobservedtoreassortwithothersubtypes.H3N2hasamuchbroaderhostrangeandcanreassortwithH1N1andH5N1.AnisolatedcaseofH6N1likelyfromachickenwasfoundinfectingadog,sootherAIVsmayemergeincanines.[16] OthermammalstobeinfectedbyIAVsincludeH7N7andH4N5inseals,H1N3inwhales,andH10N4andH3N2inminks.[19]VariousmutationshavebeenidentifiedthatareassociatedwithAIVsadaptingtomammals.SinceHAproteinsvaryinwhichsialicacidstheybindto,mutationsintheHAreceptorbindingsitecanallowAIVstoinfectmammals.OthermutationsincludemutationsaffectingwhichsialicacidsNAproteinscleaveandamutationinthePB2polymerasesubunitthatimprovestoleranceoflowertemperaturesinmammalianrespiratorytractsandenhancesRNPassemblybystabilizingNPandPB2binding.[16] IBVismainlyfoundinhumansbuthasalsobeendetectedinpigs,dogs,horses,andseals.[17]Likewise,ICVprimarilyinfectshumansbuthasbeenobservedinpigs,dogs,cattle,anddromedarycamels.[10][17]IDVcausesaninfluenza-likeillnessinpigsbutitsimpactinitsnaturalreservoir,cattle,isrelativelyunknown.Itmaycauserespiratorydiseaseresemblinghumaninfluenzaonitsown,oritmaybepartofabovinerespiratorydisease(BRD)complexwithotherpathogensduringco-infection.BRDisaconcernforthecattleindustry,soIDV'spossibleinvolvementinBRDhasledtoresearchonvaccinesforcattlethatcanprovideprotectionagainstIDV.[17][18]Twoantigeniclineagesareincirculation:D/swine/Oklahoma/1334/2011(D/OK)andD/bovine/Oklahoma/660/2013(D/660).[17] References ^abcdefghijklmnopqrstuvwxyzaaabacadaeafagahaiajakalamanaoapaqarasatauavawaxayazbabbbcbdbebfbgbhbibjbkblbmbnbobpbqbrbsbtbubvbwbxbybzcacbcccdcecfcgchcicjckclcmcncocpcqcrKrammerF,SmithGJ,FouchierRA,PeirisM,KedzierskaK,DohertyPC,PaleseP,ShawML,TreanorJ,WebsterRG,García-SastreA(28June2018)."Influenza".NatureReviewsDiseasePrimers.4(1):3.doi:10.1038/s41572-018-0002-y.PMC 7097467.PMID 29955068. ^abcdefghijklmnoSauttoGA,KirchenbaumGA,RossTM(19January2018)."Towardsauniversalinfluenzavaccine:differentapproachesforonegoal".VirologyJournal.15(1):17.doi:10.1186/s12985-017-0918-y.PMC 5785881.PMID 29370862. ^abcdefghijklmnopAllenJD,RossTM(2018)."H3N2influenzavirusesinhumans:Viralmechanisms,evolution,andevaluation".HumanVaccines&Immunotherapeutics.14(8):1840–1847.doi:10.1080/21645515.2018.1462639.PMC 6149781.PMID 29641358. ^abcdefghijklmnopqLampejoT(July2020)."Influenzaandantiviralresistance:anoverview".EuropeanJournalofClinicalMicrobiology&InfectiousDiseases.39(7):1201–1208.doi:10.1007/s10096-020-03840-9.PMC 7223162.PMID 32056049. ^"FluSymptoms&Diagnosis".CentersforDiseaseControlandPrevention(CDC).10July2019.Retrieved24January2020. ^"FluSymptoms&Complications".CentersforDiseaseControlandPrevention(CDC).26February2019.Retrieved6July2019. ^CallSA,VollenweiderMA,HornungCA,SimelDL,McKinneyWP(February2005)."Doesthispatienthaveinfluenza?".JAMA.293(8):987–97.doi:10.1001/jama.293.8.987.PMID 15728170. ^abcdefghijklmnopqrstuvwxDharmapalanD(October2020)."Influenza".IndianJournalofPediatrics.87(10):828–832.doi:10.1007/s12098-020-03214-1.PMC 7091034.PMID 32048225. ^abcdefghijklmnopqrstuvwxyzaaabacadaeGhebrehewetS,MacPhersonP,HoA(7December2016)."Influenza".TheBMJ.355:i6258.doi:10.1136/bmj.i6258.PMC 5141587.PMID 27927672. ^abcdefghijSederdahlBK,WilliamsJV(13January2020)."EpidemiologyandClinicalCharacteristicsofInfluenzaCVirus".Viruses.12(1):89.doi:10.3390/v12010089.PMC 7019359.PMID 31941041. ^abcdefghijklmnopqrstPeteranderlC,HeroldS,SchmoldtC(August2016)."HumanInfluenzaVirusInfections".SeminarsinRespiratoryandCriticalCareMedicine.37(4):487–500.doi:10.1055/s-0036-1584801.PMC 7174870.PMID 27486731. ^Peoplealsosuffer'longflu',studyshowsBBC ^abcdefghijklKalilAC,ThomasPG(19July2019)."Influenzavirus-relatedcriticalillness:pathophysiologyandepidemiology".CriticalCare.23(1):258.doi:10.1186/s13054-019-2539-x.PMC 6642581.PMID 31324202. ^"VirusTaxonomy:2019Release".InternationalCommitteeonTaxonomyofViruses.Retrieved9March2021. ^abcdefghijklmnopLiYT,LinsterM,MendenhallIH,SuYC,SmithGJ(11December2019)."Avianinfluenzavirusesinhumans:lessonsfrompastoutbreaks".BritishMedicalBulletin.132(1):81–95.doi:10.1093/bmb/ldz036.PMC 6992886.PMID 31848585. ^abcdefghijklmnJosephU,SuYC,VijaykrishnaD,SmithGJ(January2017)."TheecologyandadaptiveevolutionofinfluenzaAinterspeciestransmission".InfluenzaandOtherRespiratoryViruses.11(1):74–84.doi:10.1111/irv.12412.PMC 5155642.PMID 27426214. ^abcdefghijklmnopqrsAshaK,KumarB(5February2019)."EmergingInfluenzaDVirusThreat:WhatWeKnowsoFar!".JournalofClinicalMedicine.8(2):192.doi:10.3390/jcm8020192.PMC 6406440.PMID 30764577. ^abcdefghijkSuS,FuX,LiG,KerlinF,VeitM(17November2017)."NovelInfluenzaDvirus:Epidemiology,pathology,evolutionandbiologicalcharacteristics".Virulence.8(8):1580–1591.doi:10.1080/21505594.2017.1365216.PMC 5810478.PMID 28812422. ^abcdefghiMcCauleyJW,HongoS,KaverinNV,KochsG,LambRA,MatrosovichMN,PerezDR,PaleseP,PrestiPM,RimstadE,SmithGJ(2011)."Orthomyxoviridae".InternationalCommitteeonTaxonomyofViruses.Retrieved9March2021. ^abcdefgShimJM,KimJ,TensonT,MinJ,KainovDE(12August2017)."InfluenzaVirusInfection,InterferonResponse,ViralCounter-Response,andApoptosis".Viruses.9(8):223.doi:10.3390/v9080223.PMC 5580480.PMID 28805681. ^abcdefgHaoW,WangL,LiS(3October2020)."RolesoftheNon-StructuralProteinsofInfluenzaAVirus".Pathogens.9(10):812.doi:10.3390/pathogens9100812.PMC 7600879.PMID 33023047. ^DadonaiteB,VijayakrishnanS,FodorE,BhellaD,HutchinsonEC(August2016)."Filamentousinfluenzaviruses".JGenVirol.97(8):1755–1764.doi:10.1099/jgv.0.000535.PMC 5935222.PMID 27365089. ^abcdefghijSaunders-HastingsPR,KrewskiD(6December2016)."ReviewingtheHistoryofPandemicInfluenza:UnderstandingPatternsofEmergenceandTransmission".Pathogens.5(4):66.doi:10.3390/pathogens5040066.PMC 5198166.PMID 27929449. ^abcdefghijklLycettSJ,DuchatelF,DigardP(24June2019)."Abriefhistoryofbirdflu".PhilosophicalTransactionsoftheRoyalSocietyofLondon,SeriesB.374(1775):20180257.doi:10.1098/rstb.2018.0257.PMC 6553608.PMID 31056053. ^abcdKutterJS,SpronkenMI,FraaijPL,FouchierRA,HerfstS(February2018)."Transmissionroutesofrespiratoryvirusesamonghumans".CurrentOpinioninVirology.28:142–151.doi:10.1016/j.coviro.2018.01.001.PMC 7102683.PMID 29452994. ^abcKillingleyB,Nguyen-Van-TamJ(September2013)."Routesofinfluenzatransmission".InfluenzaandOtherRespiratoryViruses.7Suppl2(Suppl2):42–51.doi:10.1111/irv.12080.PMC 5909391.PMID 24034483. ^WeberTP,StilianakisNI(November2008)."InactivationofinfluenzaAvirusesintheenvironmentandmodesoftransmission:acriticalreview".JInfect.57(5):361–373.doi:10.1016/j.jinf.2008.08.013.PMC 7112701.PMID 18848358. ^abMoriyamaM,HugentoblerWJ,IwasakiA(29September2020)."SeasonalityofRespiratoryViralInfections".AnnualReviewofVirology.7(1):83–101.doi:10.1146/annurev-virology-012420-022445.PMID 32196426. ^ShaoW,LiX,GorayaMU,WangS,ChenJL(7August2017)."EvolutionofInfluenzaAVirusbyMutationandRe-Assortment".InternationalJournalofMolecularSciences.18(8):1650.doi:10.3390/ijms18081650.PMC 5578040.PMID 28783091. ^abSteinhauerDA(25May1999)."Roleofhemagglutinincleavageforthepathogenicityofinfluenzavirus".Virology.258(1):1–20.doi:10.1006/viro.1999.9716.PMID 10329563. ^EinavT,GentlesLE,BloomJD(23July2020)."SnapShot:InfluenzabytheNumbers"(PDF).Cell.182(2):532–532.e1.doi:10.1016/j.cell.2020.05.004.PMID 32707094.S2CID 220715148. ^abcdefghijklmnopChowEJ,DoyleJD,UyekiTM(12June2019)."Influenzavirus-relatedcriticalillness:prevention,diagnosis,treatment".CriticalCare.23(1):214.doi:10.1186/s13054-019-2491-9.PMC 6563376.PMID 31189475. ^TregoningJS,RussellRF,KinnearE(4March2018)."Adjuvantedinfluenzavaccines".HumanVaccines&Immunotherapeutics.14(3):550–564.doi:10.1080/21645515.2017.1415684.PMC 5861793.PMID 29232151. ^abPrincipiN,EspositoS(4March2018)."Protectionofchildrenagainstinfluenza:Emergingproblems".HumanVaccines&Immunotherapeutics.14(3):750–757.doi:10.1080/21645515.2017.1279772.PMC 5861800.PMID 28129049. ^BarrIG,DonisRO,KatzJM,McCauleyJW,OdagiriT,TrusheimH,TsaiTF,WentworthDE(9October2018)."Cellculture-derivedinfluenzavaccinesinthesevere2017–2018epidemicseason:asteptowardsimprovedinfluenzavaccineeffectiveness".NPJVaccines.3:44.doi:10.1038/s41541-018-0079-z.PMC 6177469.PMID 30323955. ^abcJeffersonT,DelMarCB,DooleyL,FerroniE,Al-AnsaryLA,BawazeerGA,vanDrielML,JonesMA,ThorningS,BellerEM,ClarkJ,HoffmannTC,GlasziouPP,ConlyJM(20November2020)."Physicalinterventionstointerruptorreducethespreadofrespiratoryviruses".CochraneDatabaseofSystematicReviews.2020(11):CD006207.doi:10.1002/14651858.CD006207.pub5.hdl:10072/399941.PMC 8094623.PMID 33215698. ^abSaunders-HastingsP,CrispoJA,SikoraL,KrewskiD(September2017)."Effectivenessofpersonalprotectivemeasuresinreducingpandemicinfluenzatransmission:Asystematicreviewandmeta-analysis".Epidemics.20:1–20.doi:10.1016/j.epidem.2017.04.003.PMID 28487207. ^ab"AvianInfluenza(AI)".U.S.DepartmentofAgriculture,AnimalandPlantHealthInspectionService.Retrieved9March2021. ^abcdefghijklVemulaSV,ZhaoJ,LiuJ,WangX,BiswasS,HewlettI(12April2016)."CurrentApproachesforDiagnosisofInfluenzaVirusInfectionsinHumans".Viruses.8(4):96.doi:10.3390/v8040096.PMC 4848591.PMID 27077877. ^ab"Flu:MedlinePlusMedicalEncyclopedia".U.S.NationalLibraryofMedicine.Archivedfromtheoriginalon14February2010.Retrieved7February2010. ^BandayAZ,ArulA,VigneshP,SinghMP,GoyalK,SinghS(2January2021)."Kawasakidiseaseandinfluenza-newlessonsfromoldassociations".ClinicalRheumatology.40(7):2991–2999.doi:10.1007/s10067-020-05534-1.PMC 7778392.PMID 33387094. ^"Laninamivir".NationalCenterforAdvancingTranslationalSciences.Retrieved9March2021. ^"EstimatedInfluenzaIllnesses,Medicalvisits,Hospitalizations,andDeathsintheUnitedStates–2018–2019influenzaseason".CentersforDiseaseControlandPrevention(CDC).9January2020.Retrieved5March2020. ^"Upto650000peopledieofrespiratorydiseaseslinkedtoseasonalflueachyear".Geneva:WorldHealthOrganization.13December2017.Retrieved16June2021. ^abcdefghijklPotterCW(October2001)."Ahistoryofinfluenza".JournalofAppliedMicrobiology.91(4):572–579.doi:10.1046/j.1365-2672.2001.01492.x.PMID 11576290. ^PaleseP(December2004)."Influenza:oldandnewthreats".NatureMedicine.10(12Suppl):S82–87.doi:10.1038/nm1141.PMID 15577936.S2CID 1668689. ^abcdefMorensDM,TaubenbergerJK,FolkersGK,FauciAS(15December2010)."Pandemicinfluenza's500thanniversary".ClinicalInfectiousDiseases.51(12):1442–1444.doi:10.1086/657429.PMC 3106245.PMID 21067353. ^MordiniE,GreenM,eds.(2013).Internet-BasedIntelligenceinPublicHealthEmergencies:EarlyDetectionandResponseinDiseaseOutbreakCrises.IOSPress.p. 67.ISBN 978-1614991755. ^MartinPM,Martin-GranelE(June2006)."2,500-yearevolutionofthetermepidemic".EmergingInfectiousDiseases.12(6):976–980.doi:10.3201/eid1206.051263.PMC 3373038.PMID 16707055. ^abcMorensDM,NorthM,TaubenbergerJK(4December2010)."Eyewitnessaccountsofthe1510influenzapandemicinEurope".Lancet.376(9756):1894–1895.doi:10.1016/S0140-6736(10)62204-0.PMC 3180818.PMID 21155080. ^GuerraF(1988)."TheearliestAmericanepidemic.Theinfluenzaof1493".SocSciHist.12(3):305–325.doi:10.2307/1171451.JSTOR 1171451.PMID 11618144. ^GuerraF(1993)."TheEuropean-Americanexchange".HistPhilosLifeSci.15(3):313–327.PMID 7529930. ^abcdInstituteofMedicine(US)ForumonMicrobialThreats(2005)."1:TheStoryofInfluenza".InKnoblerS,MackA,MahmoudA,LemonS(eds.).TheThreatofPandemicInfluenza:AreWeReady?WorkshopSummary(2005).Washington,DC:TheNationalAcademiesPress.pp. 60–61.doi:10.17226/11150.ISBN 978-0-309-09504-4.PMID 20669448. ^abcdefghijklTaubenbergerJK,HultinJV,MorensDM(2007)."Discoveryandcharacterizationofthe1918pandemicinfluenzavirusinhistoricalcontext".AntiviralTherapy.12(4PtB):581–591.PMC 2391305.PMID 17944266. ^VijgenL,KeyaertsE,MoësE,ThoelenI,WollantsE,LemeyP,VandammeA,VanRanstM(February2005)."CompletegenomicsequenceofhumancoronavirusOC43:molecularclockanalysissuggestsarelativelyrecentzoonoticcoronavirustransmissionevent".JournalofVirology.79(3):1595–1604.doi:10.1128/JVI.79.3.1595-1604.2005.PMC 544107.PMID 15650185. ^TaubenbergerJK,MorensDM(January2006)."1918Influenza:themotherofallpandemics".EmergingInfectiousDiseases.12(1):15–22.doi:10.3201/eid1201.050979.PMC 3291398.PMID 16494711. ^SmithW,AndrewesCH,LaidlawPP(1933)."Avirusobtainedfrominfluenzapatients".Lancet.2(5732):66–68.doi:10.1016/S0140-6736(00)78541-2. ^HeinenPP(15September2003)."Swineinfluenza:azoonosis".VeterinarySciencesTomorrow.ISSN 1569-0830.Archivedfromtheoriginalon11February2007.Retrieved28December2016. ^Vázquez-EspinosaE,LaganàC,VázquezF(October2020)."TheSpanishfluandthefictionliterature".RevEspQuimioter.33(5):296–312.doi:10.37201/req/049.2020.PMC 7528412.PMID 32633114. ^"influenza(n.)".OnlineEtymologyDictionary.Retrieved9March2021. ^"influenza".OxfordEnglishDictionary.Retrieved9March2021. ^"flu(n.)".OnlineEtymologyDictionary.Retrieved20July2021. ^CalisherCH(August2009)."Swineflu".CroatianMedicalJournal.50(4):412–415.doi:10.3325/cmj.2009.50.412.PMC 2728380.PMID 19673043. ^"InfluenzaBasicResearch".NationalInstituteofAllergyandInfectiousDiseases.13March2017.Retrieved24March2021. ^"GlobalInfluenzaSurveillanceandResponseSystem(GISRS)".WorldHealthOrganization.Archivedfromtheoriginalon3October2011.Retrieved24March2021. ^abNachbagauerR,KrammerF(April2017)."Universalinfluenzavirusvaccinesandtherapeuticantibodies".ClinicalMicrobiologyandInfection.23(4):222–228.doi:10.1016/j.cmi.2017.02.009.PMC 5389886.PMID 28216325. ^RosaSS,PrazeresDM,AzevedoAM,MarquesMP(15April2021)."mRNAvaccinesmanufacturing:Challengesandbottlenecks".Vaccine.39(16):2190–2200.doi:10.1016/j.vaccine.2021.03.038.PMC 7987532.PMID 33771389. ^"Swineinfluenza".WorldOrganisationforAnimalHealth.Retrieved9March2021. ClassificationDICD-10:J10,J11ICD-9-CM:487OMIM:614680MeSH:D007251DiseasesDB:6791ExternalresourcesMedlinePlus:000080eMedicine:med/1170ped/3006PatientUK:Influenza vteInfluenzaGeneraltopics Research Vaccine Treatment Genomesequencing Reassortment Superinfection Fluseason Viruses Orthomyxoviridae InfluenzaA InfluenzaB InfluenzaC InfluenzaD InfluenzaAvirussubtypes H1N1 H1N2 H2N2 H2N3 H3N1 H3N2 H3N8 H5N1 H5N2 H5N3 H5N6 H5N8 H5N9 H6N1 H7N1 H7N2 H7N3 H7N4 H7N7 H7N9 H9N2 H10N3 H10N7 H10N8 H11N2 H11N9 H1N1Pandemics 1918(Spanishflu) 1977(Russianflu) 2009(Swineflu) Science 2009A/H1N1 H5N1Outbreaks Croatia(2005) India(2006) UK(2007) WestBengal(2008) Science Geneticstructure Transmissionandinfection Globalspread Vaccine clinicaltrials Humanmortality Socialimpact Pandemicpreparation H5N8Outbreaks 2020–2022 TreatmentsAntiviraldrugs Adamantanederivatives Amantadine Rimantadine Neuraminidaseinhibitor Oseltamivir Laninamivir Peramivir Zanamivir Peramivir(experimental) Umifenovir Baloxavirmarboxil Vaccines Liveattenuatedinfluenzavaccine Brands Pandemrix Audenz PandemicsandepidemicsPandemics Influenzapandemic(1510) Influenzapandemic(1557) Russianflu(1889–1890) Spanishflu(1918) Asianflu(1957-1958) HongKongflu(1968) 1977Russianflu Swineflu(2009) Epidemics Fujianflu(H3N2) 1989–1990UKoutbreak CentralLuzonH5N6(2017) Non-humanMammals Canine Feline Equine 2007Australianoutbreak Swine Non-mammals Avian Fujian(H5N1) Complications Acutebronchitis Bronchiolitis Croup Otitismedia Pharyngitis Pneumonia Sinusitis Strepthroat Relatedtopics Influenza-likeillness 2017–2018UnitedStatesfluseason USinfluenzastatisticsbyfluseason vteDiseasesoftherespiratorysystemUpperRT(includingURTIs,commoncold)Head sinuses Sinusitis nose Rhinitis Vasomotorrhinitis Atrophicrhinitis Hayfever Nasalpolyp Rhinorrhea nasalseptum Nasalseptumdeviation Nasalseptumperforation Nasalseptalhematoma tonsil Tonsillitis Adenoidhypertrophy Peritonsillarabscess Neck pharynx Pharyngitis Strepthroat Laryngopharyngealreflux(LPR) Retropharyngealabscess larynx Croup Laryngomalacia Laryngealcyst Laryngitis Laryngopharyngealreflux(LPR) Laryngospasm vocalcords Laryngopharyngealreflux(LPR) Vocalfoldnodule Vocalfoldparesis Vocalcorddysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotrachealstenosis LowerRT/lungdisease(includingLRTIs)Bronchial/obstructive acute Acutebronchitis chronic COPD Chronicbronchitis AcuteexacerbationofCOPD) Asthma(Statusasthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cysticfibrosis unspecified Bronchitis Bronchiolitis Bronchiolitisobliterans Diffusepanbronchiolitis Interstitial/restrictive(fibrosis)Externalagents/occupationallungdisease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxitefibrosis Berylliosis Caplan'ssyndrome Chalicosis Coalworker'spneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivitypneumonitis Bagassosis Birdfancier'slung Farmer'slung Lycoperdonosis Other ARDS Combinedpulmonaryfibrosisandemphysema Pulmonaryedema Löffler'ssyndrome/Eosinophilicpneumonia Respiratoryhypersensitivity Allergicbronchopulmonaryaspergillosis Hamman-Richsyndrome Idiopathicpulmonaryfibrosis Sarcoidosis Vaping-associatedpulmonaryinjury Obstructive/RestrictivePneumonia/pneumonitisBypathogen Viral Bacterial Pneumococcal Klebsiella Atypicalbacterial Mycoplasma Legionnaires'disease Chlamydiae Fungal Pneumocystis Parasitic noninfectious Chemical/Mendelson'ssyndrome Aspiration/Lipid Byvector/route Community-acquired Healthcare-associated Hospital-acquired Bydistribution Broncho- Lobar IIP UIP DIP BOOP-COP NSIP RB Other Atelectasis circulatory Pulmonaryhypertension Pulmonaryembolism Lungabscess Pleuralcavity/mediastinumPleuraldisease Pleuritis/pleurisy Pneumothorax/Hemopneumothorax Pleuraleffusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinaldisease Mediastinitis Mediastinalemphysema Other/general Respiratoryfailure Influenza Commoncold SARS COVID-19 Idiopathicpulmonaryhaemosiderosis Pulmonaryalveolarproteinosis vteInfectiousdiseases–viralsystemicdiseasesOncovirus DNAvirus HBV Hepatocellularcarcinoma HPV Cervicalcancer Analcancer Penilecancer Vulvarcancer Vaginalcancer Oropharyngealcancer KSHV Kaposi'ssarcoma EBV Nasopharyngealcarcinoma Burkitt'slymphoma Hodgkinlymphoma Folliculardendriticcellsarcoma ExtranodalNK/T-celllymphoma,nasaltype MCPyV Merkel-cellcarcinoma RNAvirus HCV Hepatocellularcarcinoma Splenicmarginalzonelymphoma HTLV-I AdultT-cellleukemia/lymphoma Immunedisorders HIV AIDS CentralnervoussystemEncephalitis/meningitis DNAvirus Humanpolyomavirus2 Progressivemultifocalleukoencephalopathy RNAvirus MeV Subacutesclerosingpanencephalitis LCV Lymphocyticchoriomeningitis Arbovirusencephalitis Orthomyxoviridae(probable) Encephalitislethargica RV Rabies Chandipuravesiculovirus Herpesviralmeningitis RamsayHuntsyndrometype2 Myelitis Poliovirus Poliomyelitis Post-poliosyndrome HTLV-I Tropicalspasticparaparesis Eye Cytomegalovirus Cytomegalovirusretinitis HSV Herpesoftheeye Cardiovascular CBV Pericarditis Myocarditis Respiratorysystem/acuteviralnasopharyngitis/viralpneumoniaDNAvirus Epstein–Barrvirus EBVinfection/Infectiousmononucleosis Cytomegalovirus RNAvirus IV:Humancoronavirus229E/NL63/HKU1/OC43 Commoncold MERScoronavirus MiddleEastrespiratorysyndrome SARScoronavirus Severeacuterespiratorysyndrome SARScoronavirus2 COVID-19 V,Orthomyxoviridae:InfluenzavirusA/B/C/D Influenza/Avianinfluenza V,Paramyxoviridae:Humanparainfluenzaviruses Parainfluenza Humanorthopneumovirus hMPV HumandigestivesystemPharynx/Esophagus MuV Mumps Cytomegalovirus Cytomegalovirusesophagitis Gastroenteritis/diarrhea DNAvirus Adenovirus Adenovirusinfection RNAvirus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNAvirus HBV(B) RNAvirus CBV HAV(A) HCV(C) HDV(D) HEV(E) Pancreatitis CBV Urogenital BKvirus MuV Mumps Portals:MedicineViruses InfluenzaatWikipedia'ssisterprojects:DefinitionsfromWiktionaryMediafromCommonsNewsfromWikinewsQuotationsfromWikiquoteTextsfromWikisourceTextbooksfromWikibooksTravelguidesfromWikivoyageResourcesfromWikiversityDatafromWikidataTaxafromWikispecies AuthoritycontrolNationallibraries France(data) Germany Israel UnitedStates Japan CzechRepublic Croatia 2 Other HistoricalDictionaryofSwitzerland NationalArchives(US) Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Influenza&oldid=1084720686" 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