哮喘免疫表型

Asthma:

ImmunePhenotypesAsthmaAsthmaisclinicallydefinedasasyndromewithepisodicwheezing,shortnessofbreath,coughandsputumproductionTheconstantfeaturesareairwayirritability(hyperresponsiveness)andinflammationAsthma:EpidemiologyBetween150-300millionpatientsworldwide15-25millionintheU.S.MostcommonchronicdiseaseofchildhoodOver500,000E.R.visitsperyear25,000ICUadmissions5-6,000deathsinU.S.OntheincreaseAllergicAsthma:PathwaysIgEIL-13EosinophilsIL-5IL-13Th2Th1MastCellB-cellIL-4TCRMHCIITLymphocyte

APCCD80CD86CD28GenerationofAllergicAdaptiveImmuneResponsesSevereAsthma

DefinitionPhenotypes-Pathologic/ClinicalTherapeuticOptionsInflammationandRemodelinginAsthmaCourtesyofMarllynGlassberg,MDApproachtoManagement/ContributingFactors/Co-MorbidConditionsExamineforconcomitantmedicaldisorders,i.e.sinusitis,OSA,VCDGERD-acidandnon-acidrefluxEnvironmentalcontrolAlternativediagnosesIncorporateobjectivemeasuresintomanagementWrittenactionplanReviewmedicationtechniqueSevereAsthmaClustersMooreetal.AJRCCM2010;181:315-323AsthmaClustersCluster1:earlyonset,atopic,nllungfxn<2controllers,minimalhealthcareutilizationCluster2:earlyonset,atopic,>2controllers,nllungfxn,significanthealthcareutilizationCluster3:adultonset,obesewomanwithlowlungfxn,highmedicationrequirementandhealthcareutilizationCluster4:earlyonset,atopic,severeobstructionwithsomereversibility(FEV1:57%to76%pred),highhealthcareutilizationCluster5:earlyonset,severeobstruction,66%atopic;lessreversibility(FEV1:43%to58%),highhealthcareutilizationMooreetal.AJRCCM2010;181:315-323AsthmaPhenotypes:

HeterogeneousDiseaseClinical:

Pathologic:Fixedobstruction EosinophilicObese Non-eosinophilicAdultonset Pauci-granulocyticExacerbationprone Treatmentresistant Triggers:OccupationalAspirinExerciseMensesPathologicalPhenotypesEosinophilic/TH2(IL-4,IL-5andIL-13)Non-eosinophilic(sputumeos<2%,orperipheralbloodeos<200/µl)ClinicalFeaturesofAsthmaticswith“High”and“Low”IL-13GeneSignaturesWoodruff,etal.AJRCCM2009;180:388-395WoodruffetalAmJRespirCritCareMed180:3888-95,2009Th2“high”vs.“low”signatureresultsindifferentclinicalcharacteristicsandresponsetoICSInterleukin-13andNon-Interleukin-13InflammatoryPathwaysinAsthmaKraftM.NEnglJMed2011;365:1141BiomarkerstoidentifytheTh2phenotypeSputumeosinophilsExhalednitricoxideCirculatingeosinophilsPeriostinIgEAllergenskintestingSevereAsthma:PeriostincorrelateswithsputumandtissueeosinophilsJiaetal.JACI2012;130:647EosinophilicPhenotype:

SomeTreatment

OptionsEosinophilicPhenotype:RationaleforZileuton(LeukotrieneInhibitor)Anti-eosinophilandanti-mastcelleffectsDecreasedBALeosinnocturnalasthma

(WenzelARRD1995)DecreasedmastcelltryptasefollowingASAchallenge(Israel,ARRD1993)BroadereffectthanmontelukastInhibitsactivationofmultiplecysLTreceptorsBlocksLTB4Blocksother5LOmetabolitesEosinophilsPhenotype:Omalizumab(anti-IgE)reduces

submucosalEosinophilsEosinophils

(cells/mm2)BaselinePosttreatment020608080602004040BaselinePosttreatment8.01.56.36.4Placebo(n=14)Omalizumab(n=14)P<0.001P=0.81P=0.033Djukanovicetal.AJRCCM2004LungFunction:Inhibitionof

IL-13Correnetal.NEJM2011;365:1088Non-eosinophilicAsthmaEosinophilicandnon-eosinophilicasthma:pathologiccomparisonBerryetal.Thorax2007;62:1043InhaledCorticosteroids:

AirwaysHyperresponsivenessBerryetal.Thorax2007;62:1043InhaledCorticosteroids:

QualityofLifeBerryetal.Thorax2007;62:1043Non-eosinophilic

asthma:

othermediators?Wang,CurrOpinImmun2008;20:697-702IncreasedMembraneBoundTNF-αinRefractoryAsthmaBerry,etal.NEJM2006;354:697-708BALTNF-αLevelsareIncreasedinTheLungsofObeseAsthmatics**p<0.001,*p<0.01,#p<0.05Lugogoetal.AJRCCM2012;864:404Non-eosinophilicphenotype:treatmentoptions?AsthmaPhenotypesandMacrolidesBrusselleetal.recruited109subjectswithasthma,oncombinationtherapy(Thorax2013;177:148)Subjectswere“exacerbationprone”astheywererequiredtohavehadtwoexacerbationsrequiringoralcorticos