Pathogenesis of Nasal Polyposis.docx

Pathogenesis of Nasal Polyposis.docx

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PathogenesisofNasalPolyposis

PathogenesisofNasalPolyposis

KathrynE.Hulse,PhD1*,WhitneyW.Stevens,MD,PhD1,BruceK.Tan,MD2,RobertP.Schleimer,PhD1,2

1DivisionofAllergy-Immunology,DepartmentofMedicine,NorthwesternUniversityFeinbergSchoolofMedicine,Chicago,ILUSA;2DepartmentofOtolaryngology,NorthwesternUniversityFeinbergSchoolofMedicine,Chicago,IL,USA

*Correspondingauthor:

Dr.KathrynE.Hulse,DivisionofAllergy-Immunology,NorthwesternUniversityFeinbergSchoolofMedicine,240E.HuronSt.,McGawRmM-302,Chicago,IL,60611,USA.

Tel.:

312-503-2854

Fax:

312-503-0078

Email:

k-hulse@northwestern.edu

Funding:

NIHR37HL068546,R01HL078860,R01AI072570,P01106683-01,K12

HD055884,T32AI083216-04,K23DC012067andtheErnestS.BazleyTrust

Abstract

Chronicrhinosinusitiswithnasalpolyps（CRSwNP）isacomplexinflammatoryconditionthataffectsalargeproportionofthepopulationworldwideandisassociatedwithhighcostofmanagementandsignificantmorbidity.Yet,thereisalackofpopulation-basedepidemiologicstudiesusingcurrent

definitionsofCRSwNP,andthemechanismsthatdrivepathogenesisinthisdiseaseremainunclear.

Inthisreview,wesummarizethecurrentevidencefortheplethoraoffactorsthatlikelycontributetoCRSwNPpathogenesis.Defectsintheinnatefunctionoftheairwayepithelialbarrier,includingdiminishedexpressionofantimicrobialproductsandlossofbarrierintegrity,combinedwithcolonizationbyfungiandbacterialikelyplayacriticalroleinthedevelopmentofchronicinflammationinCRSwNP.Thischronicinflammationischaracterizedbyelevatedexpressionofmanykeyinflammatorycytokinesandchemokines,includingIL-5,thymicstromallymphopoietin,andCCL11,thathelptoinitiateandperpetuatethischronicinflammatoryresponse.Together,thesefactorslikelycombinetodrivetheinfluxofavarietyofimmunecells,includingeosinophils,mastcells,type2innatelymphoidcellsandlymphocytes,whichparticipateinthechronicinflammatoryresponsewithinthenasalpolyps.Importantlyhowever,futurestudiesareneededtodemonstrate

thenecessityandsufficiencyofthesepotentialdriversofdiseaseinCRSwNP.Inadditiontothe

developmentofnewtoolsandmodelstoaidmechanisticstudies,thefieldofCRSwNPresearch

alsoneedsthetypeofrobustepidemiologicdatathathasservedtheasthmacommunitysowell.Giventhehighprevalence,costs,andmorbidity,thereisagreatneedforcontinuedresearchintoCRSthatcouldfacilitatethedevelopmentofnoveltherapeuticstrategiestoimprovetreatmentforpatientsthatsufferfromthisdisease.

Introduction

Thepurposeofthisreviewistosummarizethecurrentstateofknowledgeregardingthepathogenesisofnasalpolyposis.Inthisreview,wefocusonchronicrhinosinusitiswithnasalpolyps（CRSwNP）,ratherthanotherconditionsassociatedwithnasalpolypformationsuchasantrochoanalpolyps,cysticfibrosisorallergicfungalsinusitis,duetothesignificantlyhigherprevalenceandassociatedcostsofmanagementofCRSwNP.

EpidemiologyofCRSwNP

Chronicrhinosinusitis（CRS）ischaracterizedbythepresenceoffourcardinalsymptoms:

nasalobstruction,drainage,smelllossandfacialpainorpressure,whichlastforatleastthreemonths.InsomepatientswithCRS,exuberanthyperplasticinflammatorygrowthofnasalpolypsintothenasalairwayisobserved[1-3].Thereisapaucityoflargepopulation-basedepidemiologicstudiesconductedusingcurrentdefinitionsofCRS,andfewerstudiesyetthatspecificallydelineatetheproportionofpatientswhohaveCRSwNP.Tworecentpopulation-basedstudiesconductedinEuropeandSouthKoreathatusedbothsymptomhistoriesandendoscopicexamsestimatedtheprevalenceofCRSinthegeneralpopulationat10.9%and7.0%ofadults,respectively,buttheydidnotdefinetheproportionofCRSpatientswithnasalpolyps[4,5].StudiesthathavespecificallyexaminedCRSwNPsuggestitspopulationprevalenceisaround2.7%ofadultsinasinglemunicipalityofSweden[6],anditsincidencehasbeenestimatedat0.63or0.83patientsperthousandperyearbasedonstudiesinaDanishcountyorinCentralPennsylvania,respectively[7,8].Basedonthesestudies,thereisapredominanceofmenwithCRSwNP,withamaletofemaleratiovaryingfrom1.3-2.2,andapeakincidencebetweentheagesof45and65.WhileCRSwNPisthelesscommonformofCRS,wehavenotedthattheproportionofCRSpatientswithnasalpolypsissubstantiallyhigherinsurgicalcohortsoftertiarycarepatientswhohadfailedmedicalmanagement（~50%）whencomparedwithincidentcaseswheretheproportionofCRSpatientswithnasalpolypsmaybeaslowas7%[9,10].Together,thesestudiessuggestthatcomparedtoCRSsNP,CRSwNPmaypersistforalongerduration,berelativelyrecalcitranttomedicalmanagement,morefrequentlyleadtosurgicalmanagementand/orrequiremoresurgeriestoaddress.WhiletotalCRSmanagementcostsareestimatedtobeover$8billionannuallyintheUnitedStates[11],therearenostudies,toourknowledge,thathaveprovidedestimatesofdirectcostsassociatedwithCRSwNPmanagement.Inadditiontodirectcostsofmanagement,studieshaveshownthatCRSpatientsseeninatertiarycaresettingsufferasignificantlyimpaired

qualityoflifecomparabletocongestiveheartfailureandchronicobstructivepulmonarydisease[12].AlthoughourunpublisheddatasuggeststhatpatientswithCRSwNPmayhavemarginallylessimpairmentofqualityoflifethanthosewithoutpolyps,otherstudieshaveshownthatCRSwNPpatientsaremorebotheredbyrhinorrheaandsmell/tastedisturbancesandlessbotheredbyfacialpain[13].Certainly,itiswellestablishedthatpatientswithCRSwNPdohavemorefrequentimpairmentfromco-morbidconditionssuchasasthmaandatopicmulti-sensitizationthanthegeneralpopulation[8,10].WhileepidemiologicstudyofCRSwNPisinitsinfancy,sorelyneededstudiesinprimarycarepopulationswillhopefullyyieldimportantinformationregardingtheenvironmentaloroccupationalfactorsthatdrivediseaseformationandpersistence.

Aspirin-ExacerbatedRespiratoryDisease（AERD）

ItisimportanttoemphasizethatthereisaspecificsubsetofpatientswithCRSwNPwithseverediseasethatsuffersfromaspirin-exacerbatedrespiratorydisease（AERD）,otherwiseknownasSamter’striad.Thesepatientshaveasthma,CRSwNP,anddevelopexacerbatedairwayresponsesfollowingingestionofmedicationsthatinhibitthecyclooxygenase（COX）1enzyme.AlthoughAERDpatientsoftenpresentwiththemostseveremanifestationsofbothasthmaandnasalpolyposis,thisdiseaseislesscommonthaneitherCRSwNPorasthmaandiscurrentlyunderstudied.TheprevalenceofAERDhasbeenestimatedtobeasmuchas0.6-2.5%inthegeneralpopulation,withhigherprevalenceamongasthmaticandCRSwNPpatients[14-16].However,thepublishedworkonAERDhasbeenhamperedbydifferingdefinitionsofAERDusedbydifferentgroupsofinvestigators.Forexample,whilesomerequiredocumentedairwayreactionstoCOX-1inhibitorsalongwithasthmaandCRSwNPforAERDdiagnosis,othersdonotspecifythetypeofreactiontoCOX-1inhibitorsintheirpatients,andsomestudiesdonotrequirepatientstohaveCRSwNPfortheirdefinitionofAERD.Thus,thepopulationprevalenceestimatesabovemaynottrulyreflectthepopulationofpatientswhohavethetriadof

asthma,CRSwNPandairwayresponsestoCOX-1inhibitors.Thus,itisunclearwhetherAERDrepresentsthesevereendoftheCRSwNPdiseasespectrum,orifitisadistinctclinicalentity.Although,itisclearthat,AERDpatientsuniquelyrespondtoaspirindesensitizationtherapy[17],andhavehigherbaselinelevelsofurinaryleukotrieneE4[18],suggestingthatdistinctmolecularmechanisms,suchasdysregulationofarachidonicacidmetabolism,drivethisuniquedisease[19-21].ThepathogenesisofAERDisnotdiscussedfurtherinthisreview.

AllergicFungalRhinosinusitis（AFRS）

Patientswithallergicfungalrhinosinusitis（AFRS）representanotherdistinctsubsetofCRSwNP.ThesepatientsareoftenatopicandhavehighlyelevatedserumIgElevels[22],andtheycanbedistinguishedfromotherCRSwNPpatientsbythepresenceofeosinophilicmucinwithoutfungalinvasionofthemucosa,mucuswithpositivefungalstaining,andoften,bonyerosion[23].Interestingly,theestimatedprevalenceofAFRSvarieswidelyacrossdifferentgeographicregionsoftheUnitedStates,suchthatAFRShasbeenestimatedtoaccountfor

>20%ofallpatientsundergoingendoscopicsinusproceduresinsouthernareasofthecountry,suchasMemphis,butonly0-4%ofthesesamepatientsinnorthernregionsofthecountry[24].LikeAERD,itisnotclearwhetherAFRSisdrivenbydistinctpathogenicmechanismsfromCRSwNP,orissimplypartoftheCRSwNPdiseasespectrum[23],andwewillnotdiscussthepathogenesisofAFRSfurtherinthisreview.

EasternVersusWesternPresentationsofCRSwNP

CRSwNPinWesternpopulationsisoftencharacterizedbytype2inflammation,withelevatedlevelsoftype2cytokines,suchasIL-5andIL-13,alongwitheosinophilia.However,thereisaccumulatingevidencefromAsiancountries,especiallyinChina,KoreaandJapan,thatCRSwNPintheirpopulationsmaybecharacterizedbyamixedtype1ortype3inflammation,withamoreneutrophilicinflammationthanobservedinNPinpatientsfromtheUSorEurope

[25].Themechanismsthatdrivethesedifferentphenotypesareunclearatthistime.Interestingly,recentworkfromourgroupfoundthattissuefromNPfromsecondgenerationAsianpatientsborninandlivingintheUSwereconsiderablylesseosinophilicthanNPtissuefromCaucasian,Afric