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.“l(fā)ow”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”astheywererequiredtohavehadtwoexacerbationsrequiringoralcorticosteroidsorLTRIrequiringantibioticsintheprevious12monthsAzithromycinvs.placeboaddedtocombinationtherapyfor6monthsinadouble-blindfashionPrimaryoutcomewastherateofexacerbationsandLTRIrequiringantibioticsAsthmaPhenotypesandMacrolides-ResultsintheEntireCohortBrusselleetal.Thorax2013;177:148NonoesinophilicAsthma:

Only(definedasbloodeos<200/μl)Brusselleetal.Thorax2013;177:148SevereAsthma:TiotropiumKerstjensetal.NEJM2012Environmentandimmunity:impactonasthmapathogenesis?NEJM347:911,2002EpidemiologicaltrendsininfectionsandchronicdiseasesInnateandAdaptiveImmunityInnateAntigenindependentPattern-RecognitionReceptors Toll-likereceptors(TLRs)NOD-likereceptors(NLRs)Collectins (SP-A/D)AdaptiveAntigendependentTandBcellsAntigenSpecificReceptorsTCRToll-likeReceptorFamilyIgIg-likeLeucine-rich

domainLeucine

RichLRRCTLeucine-rich

repeatC-terminal

domainTIRTollInterleukin1

resistanceTIRTLR1

762aaTIRTLR2

766aaTIRTLR3

881aaTIRTLR4

816aaLeucine

RichLeucine

RichLRRCTTIRTLR7

1023aaLeucine

RichLeucine

RichTIRTLR8

1015aaLeucine

RichTIRTLR10

792aaLeucine

RichLRRCTLeucine

RichLeucine

RichLRRCTLRRCTLRRCTTIRTLR5

838aaLeucine

RichLRRCTTIRTLR9

1007aaLeucine

RichLRRCTTIRTLR6

796aaLeucine

RichLRRCTLeucine

RichLeucine

RichLRRCTLeucine

RichLeucine

RichLeucine

RichLeucine

RichLeucine

RichLeucine

RichLeucine

RichLpAPpg

TLR4APCTcellCD28costimulationCD86CD80MHCTCRtranscriptionIkBPPPPG

LPSNF-κBactivationTLR2CD14MyD88InnateandAdaptiveImmunityLancet358:1129,2001EarlylifeexposuretofarmanimalsreducesasthmaandhayfeverNYAsthmaRates:NYCChildren15% Bronx 1996, AECOM21-23% HuntsPoint, 2006,NYC Bronx HeathDept38% Homeless 2007,Children Children HealthDept

Percentageofasthma Location DataSourceTCellProliferationanddifferentiationTH1cellTH2cellIFN-TNF-

IL-15IL-18IL-12APCIL-10IL-13IL-4IL-5IL-6MHCTCRCOSTIMULATIONTh1/Th2CytokineExpressionWhatTCellSubsets

(inAdditiontoTh1,Th2)

AreInvolved

inAllergicResponses?TCellProliferationanddifferentiationTH1cellTH2cellIFN-IL-15IL-18IL-12APCIL-13IL-4IL-5COSTIMULATIONTCellSubsetsTh17TregIL-17IL-10TGF-TRegulatoryCells(Tregs)TcellsubtypeknownasTregulatory(Treg)cells.SuppressesTCells.DistinctsubsetsofCD4+Tcellsprotectfromchronicintestinalinflammation.Powrie,FetalInt.Immunol.5,1461–14711993.CD4+CD25+,GITR,L