病毒继发细菌感染

PostviralComplicationsBacterialPneumoniaJasonE.Prasso,MDa,JaneC.Deng,MD,MSb,*pneumonia,accountingformorethan90%oftheestimated50milliondeathscausedbythepandemic.1–4Duringthe1957and1968influenzapandemics,secondarybacterialinfectionwasassociatedwith50%to70%ofsevereinfections,withthedecreaseattributedtotheadventofanti-biotics.5–7Coinfectionwasnotedinapproximately30%ofthoseinfectedduringtheH1N1pandemicin2009,particularlyinfatalcases.8–11Despitesubstantialadvancesinmedicineandtheavail-abilityofpotentantibacterialandantiviralagents,influenzaandpneumoniaremainamongthelead-ingcausesofdeathintheUnitedStatesandcurrentunderstandingofhowvirallyinfectedhostsaremoresusceptibletobacterialpneumoniaaswellasthemanagementofthisimportantcompli-cationofviralinfections.CommonCausalOrganismsViral-bacterialcoinfectionsareacommonlyencounteredclinicalproblem.Althoughthepre-ciseratesofsecondarybacterialinfectionsaredifficulttoquantifybecauseofalackofcompre-hensivereportingsystemsandtheimpracticalityofobtainingmicrobiologictestinginallpatientswithrespiratoryinfections,bacterialpneumoniaDisclosures:Noneoftheauthorshaveanyfinancialconflictsofinteresttodisclose.ThisworkwassupportedbyNIHR01HL108949(J.C.Deng).aDivisionofPulmonaryandCriticalCareMedicine,UniversityofCalifornia,LosAngeles,10833LeConte48105,USAorHealthcareSys-KEYWORDS�Influenza�Respiratoryviruses�Bacterialpneumonia�Innateimmunity�Interferonsofdtennbmpsyctesstiastmed.theclinics.comClinChestMed-(2016)-–-*Correspondingauthor.DivisionofPulmonaryMedicine,VeteransAdministrationAnnArbtem,2215FullerRoad,AnnArbor,MI48105.E-mailaddress:jcdeng@med.umich.eduAvenue,CHS37-131,LosAngeles,CA90095,USA;bDivisionofPulmonaryandCriticalCareMedicine,VeteransAffairsHealthcareSystem,UniversityofMichigan,2215FullerRoad,111GPulmonary,AnnArbor,MIworldduring1918to1919,theburdenofmorbidityandmortalityresultednotonlyfrominfluenzaondaryopportunisticbacterialinfectionstoariseininfectionbutalsofromsubsequentbacterialvirallyinfectedindividuals.Thisarticlereviewsthevarietyofhostandmicrobialfactorsthatallowsec-BACKGROUNDIntroductionAstheso-calledSpanishfluragedaroundtheKEYPOINTS�Pneumoniaremainsoneoftheleadingcauses�Influenzaandotherrespiratoryviralinfectionsofcoursewithgreatermorbidityandmortalitytha�Postviralbacterialpneumoniaismediatedbycopharyngealbacterialflora,andthehostimmune�Currentmanagementstrategiesarelargelydireappropriateantimicrobialagents.�Noveldiagnostictestsandtherapiesthataddrepneumoniasareneededtomitigatethispotenongoingthreatofinfluenzapandemics.http://dx.doi.org/10.1016/j.ccm.2016.11.0060272-5231/16/PublishedbyElsevierInc.worldwide.12,13Thecomplexmechanismsunder-lyingthepathogenesisofpostviralbacterialpneu-moniaareincompletelyunderstood,butinvolveaeathintheUnitedStatesandworldwide.predisposeindividualstoamoresevereclinicalacterialpneumoniaalone.lexinteractionsbetweenviruses,normalnaso-stem.dtowardinfluenzavaccinationandselectionofthecomplexpathogenesisofpostviralbacterialllyseriouscomplication,particularlygiventhecheisestimatedtocomplicatefrom0.5%to6%ofinfluenzainfections,withhigherratesamonghos-pitalizedpatientsinintensivecareunitsandfatalcases.Influenzaisoneofmanyviralpathogensthathavebeenassociatedwithbacterialcoinfec-tions.14Humanparainfluenzavirus,adenovirus,humanmetapneumovirus,measles,respiratorysyncytialvirus(RSV),humanrhinovirus,andcoro-navirusarealsocommonlyassociatedwithsec-ondarybacterialpneumonia.15–22Oftheseviruses,influenzaisarguablymostimportantgivenitscontinuouslyevolvingvirulencefactorsandthesheernumberofindividualsinfectedonanannualbasis.Givenitspublichealthimpor-tance,aswellasthefactthatinfluenzaisthemostextensivelystudied,bacterialpneumoniafollowinginfluenzainfectionsistheprimaryfocusofthisarticle.Irrespectiveoftheoffendingviralorganism,causalagentsofsecondarybacterialpneumonialargelyreflectcolonizingnasopharyngealflora.Thisfindinghasfueledthetheorythatviralinfec-tioncausesimpairedmucosalandciliaryclear-anceofthesenormallynonpathogenicbacteria,whichenablesparticularbacteriatoflourishandcausesinvasiveinfections.Epidemiologically,StreptococcuspneumoniaeandStaphylococcusaureus(bothmethicillin-sensitiveSaureusandmethicillin-resistantSaureus[MRSA])aremostcommon,withStreptococcuspyogenesandHae-mophilusinfluenzaelessfrequentlyisolated.23–27However,infectionsinhumansareoftenpolymi-crobial,involvingcombinationsofmultiplevirusesand/orbacteria.Commonviral-bacterialcoinfec-tionsaresummarizedinTable1.ClinicalPresentationTheincidenceofbacterialpneumoniamirrorstheseasonalnatureofviralinfections,withincreasesduringpeakviralseasons.19,28–31Datafromthe2009H1N1epidemicshowthatcoinfectionusuallyoccurswithinthefirst6daysofinfluenzainfec-tion,32,33althoughitcandevelopupto14daysaf-terotherviralinfections.Thisdelaylikelyrepresentsthetimeneededforviralreplicationandtheimmunomodulatoryeffectsofinfectiontooccur.34–36Patientswithsecondarypneumoniatendtohaveamoresevere,protractedcourse,withincreasedmortalitycomparedwiththosewithoutantecedentviralinfection.7,25,30,31,33,37–41Althoughpatientswithcomorbidconditionsorattheextremesofageareatincreasedriskofcomplicatedinfluenzainfections,evenpreviouslyociCoaliitidSinusitisPrasso&Deng2Table1Commonviral-bacterialcoinfectionsandtheirassVirusKnownBacterialInfluenzaSpneumoniaeSaureusSpyogenesHinfluenzaeMoraxellacatarrhNeisseriameningRespiratorysyncytialvirusSpneumoniaeAdenovirusSpneumoniaeHinfluenzaeMcatarrhalisCoronavirusHinfluenzaeHumanrhinovirusSpneumoniaeHinfluenzaeSaureusMcatarrhalisParainfluenzavirusSpneumoniaeMcatarrhalisHumanmetapneumovirusSpneumoniaeMeaslesvirusSpneumoniaeSaureusHinfluenzaeOtitismediaPneumoniaPneumoniaBronchitisOtitismediaPneumoniaatedclinicalinfectionsinhumanhostsinfectionsAssociatedSecondaryInfectionssisPneumoniaOtitismediaSinusitisMeningitisPneumoniaBronchitis/bronchiolitisPneumoniaPneumoniaPneumoniaTracheobronchitishealthypatientscandevelopsevererespiratoryfailureanddeathfrombacterialpneumoniasfollowinginfluenza,underscoringtheclinicalsig-nificanceofthisproblem.Secondarybacterialpneumoniaisoneofseveralknowninfectiouscomplicationsofrespira-toryviruses.Viralinfectionshavealsobeenasso-ciatedwithacuteotitismediaandbacterialsinusitisinchildren.42–44Inaddition,meningo-coccalmeningitishasbeenreportedasacompli-cationofinfluenzainfections.45PATHOGENESISSeveralexcellentreviewshavebeenpublishedofthecurrentmechanisticunderstandingofhowviralinfectionsincreasesusceptibilitytosecondarybacterialpneumonias.46–49Thus,thisarticlepro-videsonlyabriefoverview,withaprimaryfocusonvirallymediatedeffectsonpulmonaryhostde-fenseandsubsequentimpairmentofbacterialclearance(Table2).However,theauthorsacknowledgethatmicrobiologicandepidemio-logicfactorscancontributetothepathogenesisofviral-bacterialcoinfections.ColonizationColonizationofthenasopharynxisgenerallythefirststepinthedevelopmentofpneumoniaandotherbacterialinfectionsoftheupperrespiratorytract,includingsinusitisandotitismedia.50,51Spneumoniae,Saureus,Hinfluenzae,Spyogenes,andMoraxellacatarrhalisarenormalinhabitantsoftheupperrespiratorytractinhealthyhumanhosts,withthelowerrespiratorytractgenerallyconsideredtohavelowabundanceofbacte-ria.52,53Althoughthesebacterianormallyexistinanequilibriumgovernedbyhost,intermicrobial,andenvironmentalfactors,54–56undertheappro-priatecircumstances,theycanproliferateandbecomeinvasive.StudieshaveshownaninverserelationshipbetweennasalcarriageofSpneumo-niaeandSaureus.55,57,58OthergroupshaveTable2KnownorsuspectedstepsinthepathogenesisofsecondarybacterialpneumoniaImmuneFunctionViral-mediatedEffectNasopharyngealcolonization�Alteredhostmicrobiota,possiblyinfavorofmorepathogenicorganismsDirectmucosal/epithelialdamage�Breakdownofmucinbyviralandbacterialneuraminidase�DestructionofepitheliumandexposureofbasementmembraneairavaterreawnlaggoucruitenimmunsibreaucairreanereagotrophilsenuretireaPostviralComplications3Neutrophilresponse�Pos�Dec�Red�ImpAlteredcytokinemilieu�Incand�Incphaneu�Attsecdec�ImpEnhancedbacterialadherence�ClebacAlveolarmacrophageresponse�Dec�Docolpha�Redrec�DesAbbreviations:AMS,alveolarmacrophages;IL,interleukin;NEatedTH17cellfunctionanddecreasedIL-17on/increasedsusceptibilitytoSpneumoniae,sedproductionofantimicrobialpeptidesmentofciliaryfunctiongeofsialicacid/exposureofreceptorsforiaonmucosalsurfacesednumberofAMsafterviralinfectionregulationofMARCO(macrophagereceptorwithenousstructure)receptorresultinginimpairedcytosisofbacteriaedchemokineexpressionandimmunecellmentsitizationofToll-likereceptors/long-termedefectslereducedrecruitmenttothelungsedphagocyticfunctionedproductionofreactiveoxygenspeciesedNETsfunctionsedtypeIinterferons/reducedmacrophageutrophilrecruitmenttothelungsedtypeIIinterferons/impairedmacrophagecyticfunction,possibleviralskewingofTs,neutrophilextracellulartraps;TH,T-helper.decreasesbacterialadherencetoepithelialoftheclassAscavengerreceptorMARCOonPrasso&Deng4cells.68–70InfluenzaandparamyxovirusessuchasRSVcanalsoaugmentbacterialadhesionbyaugment-ingexpressionofreceptorsforbacteriaontheepithelialcellsurface.Oneexampleisplatelet-activatingfactorreceptor(PAFR),whichbindstothephosphorylcholinepresentinsomebacterialcellwallsandfacilitatesbacterialinvasion.71Inamousemodelofpneumococcuspneumonia,PAFRwasshowntoincreasetotallungbacterialload,bacteremia,andmortality.72However,blockingthisreceptordidnotshowanybenefitinaninfluenzacoinfectionmodel,suggestingthatthismechanismisnotasufficientfactorforenhancingsusceptibilitytosecondarybacterialpneumonias.73Otherreceptorsinvolvedinadhe-sion,suchasCEACAM1(carcinoembryonicanti-gen-relatedcelladhesionmolecule1)andrevealedantagonisticaswellassynergisticrela-tionshipsbetweenmembersofthenormalrespira-torycommunity(eg,corynebacteriaandSaureus,CorynebacteriumaccolensandSpneumoniae,HinfluenzaeandSpneumoniae).59–62Inaddition,virusescanalterbacterialcomposi-tion.Ourlaboratoryrecentlyexaminedchangesinthenasalmicrobiomefollowingintranasaladminis-trationofliveattenuatedinfluenzavaccine.Althoughindividualhostshaddisparatemicro-biomeprofilesatbaseline,aftervaccination,therelativeabundanceofstaphylococcalandBacter-oidesspecieswassignificantlyincreased.Thisfindingsuggeststhatviralstimulicanalterthehostmicrobiota,potentiallybycreatingasuitableenvironmentinwhichanotherwisenonpathogenicorganismcangrowandbecomeinvasive.63,64MucosalBarrierFunctionandBacterialAdherenceDisruptionofthemucosalbarrierisanimportantpotentiatingmechanismforsecondarybacterialinfection.Mucinpresentintherespiratorytractcanbepartiallydegradedbyviralandbacterialneuraminidase.65,66Viralneuraminidaseistropicforthesialicacidpresentonrespiratoryepithe-lialcells,cleavageofwhichmayuncoverrecep-torsforbacterialligand,therebypromotingbacterialadhesionandinfection.Furthermore,theincreasedavailabilityofsialicacidintheairwayhasbeenshowntopromotegrowthandproliferationofpneumococcus,whichusesthismoietyasanutrientsource.67Inmurinemodels,higherlevelsofviralneuraminidaseareassoci-atedwithincreasedseverityofsecondarybacte-rialinfection,whereastreatmentwithoseltamivirICAM-1(intracellularadhesionmolecule1),areAMs,whichphagocytoseunopsonizedbacteriainthelung.34AugmentingAMnumbersandfunc-tionbyexogenousgranulocyte-macrophagecol-ony-stimulatingfactorinanimalsinfectedwithinfluenzaimprovespneumococcusclearancefollowingsecondarybacterialchallenge,increasesreactiveoxygenspecies,anddecreasesincidenceofsecondarypneumonia.90–92ViralinfectionsaffecttheabilityofAMstoattractothercelltypestothelung.Neutrophilsarerobustlyrecruitedfollowingtheelaborationofche-mokinesbyAMsandepithelialcellsinthesettingofinvasivebacterialinfection.OurlaboratoryhasshownthatmacrophageexpressionofneutrophilchemoattractantsCXCL1(C-X-Cmotifchemokineligand1)(KC)andCXCL2(C-X-Cmotifchemokineligand2)(MIP2)isreducedafterinfluenzainfec-tion,withconsequentdiminishedrecruitmentofoverlyexpressedonpulmonaryepithelialcellsaf-terviralinfectionaswell.74,75EpithelialcelldeathandbreakdownoftightjunctionsresultingfromviralinfectioncancauseincreasedtranslocationofbacteriasuchasHinflu-enzae.76,77Inaddition,certainbacterialspecieshaveaknownbindingaffinityforthebasementmembraneandextracellularmatrixproteins,78–81suggestingthatbreakdownoftheepitheliummightleadtoincreasedtranslocation,althoughthishasneverbeenprovedtobeacriticalmechanismduringinfectionswithlesscytotoxicstrainsofinfluenzainvivo.Inaddition,viralrespiratoryinfec-tionsareknowntonegativelyaffectrespiratoryciliaryfunction,therebyimpairingthehost’sabilitytomechanicallyclearaspiratedpathogensfromthelung.82,83MacrophageandNeutrophilFunctionResidentalveolarmacrophages(AMs)playanin-tegralroleinhostdefenseagainstviralandbacte-rialpathogensalike.Asthemainresidentinnateimmunecellstoencounterpathogensintherestinglung,theyengageinphagocytosisandkilling,antigenpresentation,recruitmentofothercelltypes,andparacrineandendocrinesignaling.Viralrespiratoryinfectionsareknowntoimpairmacrophagephagocyticfunctionaswellasmono-cytechemotaxistothelungearlyafterinfluenzainfection,andthishasbeenproposedasapoten-tialcauseforsecondarybacterialinfection.49,84–89Inmousemodelsofsequentialinfluenza-bacterialinfection,AMsareknowntobedecreasedinnum-berwithincreasedsusceptibilityandmortalitytosecondarybacterialchallenge.Influenzainfectionhasalsobeenshowntodownregulateexpressionneutrophilstothelung.93DesensitizationofincreasedlevelsofIFN-gammainthelung,robustPostviralComplications5Toll-likereceptors(TLRs)onalveolarmacro-phagesmaypartiallyexplainthedecreaseinneutrophilrecruitmentandimpairedbacterialclearance.MiceinfectedwithinfluenzaorRSVshoweddecreasedactivationofnuclearfactorkappa-B(NF-KB)andexpressionofKCandMIP2,resultingindecreasedneutrophilrecruit-menttothelungafterstimulationwithbacterialli-gands.94Inaddition,influenzainfectionresultsinanearly,prolongeddecreaseinPMN(polymor-phonuclearcell)phagocyticfunctionanddepressedreactiveoxygenspeciesproduc-tion.92,95–98Thus,duringviralinfection,multipleaspectsofpulmonaryinnateimmunityarecompromised,leadingtoimpairedantibacterialhostdefense.ViralEffectsontheCytokineMilieuViralinfectionelicitsarobustcytokineresponseviaactivationofTLRsandretinoicacidinduciblegene(RIG-I)inimmunecellsanddownstreamupregulationofNF-KB.ThisresponseresultsinproductionoftypeIandIIinterferons(IFN)aspartofthehostantiviralresponse,andtheseinturnalterothercytokine-mediatedeffects.TypeIinterferonsPredominantlycomprisedofmultipleIFN-alphaproteinsand1IFN-betaprotein,theseantiviralmediatorscanbesecretedbymultipledifferentimmunecellsandhelptolimitviralreplication.89,99InductionoftypeIIFNsisknowntoincreasetheriskofsecondarybacterialinfection,34,93,99–102despitetypeIIFNsalsocontributingtohostanti-bacterialresponse.103MicedeficientinthetypeIIFNreceptorareprotectedagainstsubsequentbacterialchallengeafterinfluenzainfection,likelybecausetypeIIFNsinhibitKCandMIP2produc-tionandneutrophilrecruitmenttothelung.93,104Monocyteandmacrophagerecruitmenttotheup-perrespiratorytractissuppressedbytypeIIFNsviablockadeofNod2-mediatedexpressionofCCl2(C-Cmotifchemokineligand2;amacro-phagechemoattractant),withresultantincreaseincarriageofSpneumoniae.100ThesestudieshighlighttheheterogeneouseffectsofIFNsintheimmuneresponsetopathogens.TypeIIinterferon(interferon-gamma)ViralrespiratoryinfectionalsostimulatesIFN-gammaproduction,primarilybynaturalkillercellsbutalsobyCD41T-helper(TH)cellsandCD81cytotoxicTcellsandneutrophils.Inthecontextofsecondarybacterialpneumoniafollowinginfluenza,IFN-gammahasbeenshowntoimpairphagocy-tosisinalveolarmacrophages,partiallybydownre-gulationofthescavengerreceptorMARCO.34neutrophilrecruitment,andimprovedinnatepul-monarydefenseagainstSpneumoniae.Inaddition,inmousemodelsofSpneumoniaeandSaureuspneumonia,IL-12–independentIFN-gammapro-ductionbyneutrophilsinthelungwasshowntobeessentialtobacterialclearance,possiblybecauseofIFN-gamma–regulatedproductionofneutrophilextracellulartraps(NETs).107,108Theseparadoxicfindingsinnaivehostsversushostsinfectedwithinfluenzasuggestthatneutrophilsrecruitedinthesettingofviralrespiratoryinfectionareunabletomountantibacterialfunctionsthatwouldnormallybeactivatedbyinterferon-gamma,whichmayreflectdistinctneutrophilphenotypesinthesettingofviralversusbacterialinfections.Unpublisheddatafromourlaboratoryshowstrikingtranscriptionaldifferencesinneutro-philsthatarerecruitedtothelunginthesettingofinfluenzaandsequentialinfluenza–Spneumoniaeinfection,comparedwiththoserecruitedinthesettingofSpneumoniaeinfectionalone.T-helper17cellsandinterleukin-17InfluenzainfectionisknowntoattenuateTH17cell–mediatedimmunity.TypeIIFNsdecreaseproduc-tionofIL-1bandIL-23,whicharenecessaryforpolarizationofTH17cells.109Duringinfluenza–Saureuscoinfection,thereareresultantdecreasesinIL-17,IL-22,andmonocytechemoattractantprotein-1thatcorrelatewithreducedclearanceofbacteria.101TheyalsolikelyinhibitIL-17secre-tionbygamma-deltaTcells,resultinginincreasedsusceptibilitytosecondarySpneumoniaeinfec-tion.109,110Inaddition,influenzainfectioninmicewasshowntosuppressproductionofantimicro-bialpeptidesinresponsetosubsequentSaureusinfectionviaaTH17-mediatedmechanism,leavinganimalsmoresusceptibletopneumonia.Exoge-nousadministrationoftheantimicrobialpeptidelipocalin2restoredbacterialclearanceintheseanimals.111CLINICALMANAGEMENTDiagnosticTestingDifferentiatingsevereviralinfectionfromviral-bacterialcoinfectionisacommondiagnosticdilemmaatthepointofpresentation,giventhesig-nificantoverlapinsymptomsandlaboratoryInhibitionofinterleukin(IL)-10resultsinincreasedneutrophilrecruitmenttothelungandimprovedclearanceofSpneumoniae,andcansalvageani-malsfromdeathaftersequentialinfluenza-bacterialinfection.105,106However,innormalhosts,exogenousadministrationofIL-12resultsinmarkers.Microbiologiccultureresultstakedays,lessreliable.Thus,giventheabsenceofPrasso&Deng6rapidandreliablediagnostictests,cliniciansmustalwaysconsiderthepossibilityofsecondarybacte-rialinfectioninpatientspresentingwithsevereres-piratoryinfectionsduringinfluenzaseasonandmanagethemaccordingly.VaccinationInfectionscausedbyinfluenza,measles,Hinfluen-zae,Spneumoniae,andsomestrainsofadeno-virusareallconsideredvaccine-preventableillnesses.123Althoughinfluenzavaccinationisuniversallyrecommended,vaccinationagainstinvasivepneumococcalinfectionisreservedforhigh-riskgroups,includingchildren,theelderly,andpatientswithimmunosuppressiveorchroniclungconditions.124,125Althoughrobustevidencefromrandomizedplacebo-controlledtrialsislack-ing,datafromanimalmodelsofinfluenza-bacterialcoinfectionandobservationalstudiesinpatientshaveindicatedthatinfluenzavaccinecanreducethemorbidityandmortalityassociatedwithbacte-rialpneumonia.126–134Thus,onbalance,vaccina-tionagainstinfluenzacurrentlyrepresentsthemosteffectivepublichealthstrategyforreducingtheincidenceofsecondarybacterialpneumonia.However,pneumococcalvaccinationdidnothavethesameeffectinalargestudyofelderlypa-tients,potentiallybecauseofreplacementofcoveredserotypeswiththosenotincludedinthevaccine.135,136Thisfindingmirrorsdatafromani-whereaspoint-of-careinfluenzaantigentestsareinsufficientlysensitive.PCR-basedpanelsforcom-monrespiratoryviralpathogensaremoresensitiveandcanbeuseful,butareexpensiveforroutineuseandarenotabletodistinguishbetweencoloniza-tionversustrueviralinfection.Furthermore,inlow-volumelaboratories,resultsmaynotbeavail-ablefordays.Onradiologicimaging,lobarconsol-idationwithorwithoutpleuraleffusionispresumedtobebacterial;however,multifocalinfiltratescanrepresenteithermultilobarbacterialpneumoniaoracuterespiratorydistresssyndromefromsevereviralinfectionalone.RSVandadenovirushavesomehallmarkfeaturesoncomputedtomographyscanofthechest;however,imagingstudiesaregenerallyunhelpful.112IncreasedC-reactivepro-teinlevelinthebloodcorrelateswithpresenceofpneumoniabutpoorlydistinguishesviralfrombac-terialcauses.113–115Procalcitonin(PCT),anotherserumbiomarker,isbetterabletodifferentiatethetwo.18,116–121Inonestudyofcoinfection,lowPCTlevelwasassociatedwith94%negativepredictivevalueforbacterialinfection,althoughinpatientswithshock,orinmalariaendemicareas,itmaybe121,122malmodelsofdualinfection.137Incontrast