7 Asthma Patho

7/31/2019 7 Asthma Patho

1/50

Asthma

Asthma

2contacthours:$18

Authors:JoAnnO'Toole,BSNLaurenRobertson,BA,MPT

CourseSummary:Clinicalcharacteristicsofasthmaandrelatedairwayinflammation,plushostandenvironmentalfactorsthatcontributetoasthmaandtheeffectsofinterventiononthenaturalhistoryofasthmainchildrenandadults.

COI/CommercialSupport:Theplannersandauthorsofthiscoursehavedeclarednoconflictofinterestandallinformationisprovidedfairlyandwithoutbias.Wereceivednocommercialsupportforthisactivityanddonotapproveorendorseanycommercialproductsdisplayed.

Off-LabelUse:Nooff-labeluseswerediscussedorrecommendedinthiscourse.

CriteriaforSuccessfulCompletion:80%orhigherontheposttest,acompletedevaluationform,andpaymentwhererequired.Nopartialcreditwillbeawarded.

Thiscoursewasderivedfromthe2007ExpertPanelReport3(EPR3)GuidelinesonAsthma.

Thiscoursewillbereviewedeverytwoyears.ItwillbeupdatedordiscontinuedonJune1,2011.

AccreditationInformation

Nursing:ATrainEducationisanapprovedproviderofcontinuingnursingeducatio

nbytheArizonaStateNursesAssociation*(AzNA),anaccreditedapproverbytheAmericanNursesCredentialingCenter'sCommissiononAccreditation(ANCC).

*AzNAandANCCCommissiononAccreditationdonotapproveorendorseanycommercialproductsdisplayed.

PhysicalTherapy:ATrainEducationisanapprovedreviewerandproviderbythePhysicalTherapyBoardofCaliforniaandanapprovedproviderbytheNewYorkStateBoardforPhysicalTherapy.

OccupationalTherapy:ATrainEducationisanapprovedproviderbytheAmericanOccupationalTherapyAssociation.Ifyouareanoccupationaltherapistoroccupationaltherapyassistantpleasenotethefollowing:

TargetAudience:OccupationalTherapists,OTAsInstructionalLevel:IntermediateContentFocus:Category1DomainofOT,Clientfactors


2/50

Otherprofessionsandaccreditations:SeetheATrainCEUAccreditationpageathttp://www.ATrainCeu.com/accreditation.php.

ATrainEducation,Inc.707459-1315


3/50

Asthma

Instructions

1.Readthecoursematerialandthencompletethefollowingforms:A.PostTestB.EvaluationLearningActivityC.RegistrationForm2.Ifyouarenotpayingbycreditcard,prepareacheckfortheamountofthecoursemadeoutto:ATrainEducation,Inc.3.Mailthecompletedformsandyourpaymentto:ATrainEducation,Inc5171RidgewoodRdWillits,CA95490

Whenwereceiveyourformsandpayment,wewillmail(oremail,atyourrequest)yourcompletioncertificate.Ifyouhaveanyquestions,[email protected].

CourseObjectives

Whenyoufinishthiscourse,youwillbeableto:

Describetheclinicalcharacteristicsandpathophysiologyofasthma.OutlinethepathophysiologicmechanismsinthedevelopmentofairwayinflammationDiscussthehostandenvironmentalfactorsthatcontributetothedevelopmentofasthma.Discussthenaturalhistoryofasthmainchildrenandadults.

Summarizetheeffectofinterventionsonnaturalhistoryofasthma.ATrainEducation,Inc.707459-1315


4/50

Asthma

Introduction

Asthmaisachronicinflammatorydiseaseoftheairways.IntheUnitedStates,asthmaaffectsmorethan22millionpersons.Itisoneofthemostcommonchronicdiseasesofchildhood,affectingmorethan6millionchildren.TherehavebeenimportantgainssincethereleaseofthefirstNationalAsthmaEducationandPreventionProgram(NAEPP)clinicalpracticeguidelinesin1991.Forexample,thenumberofdeathsduetoasthmahasdeclined,eveninthefaceofanincreasingprevalenceofthedisease;fewerpatientswhohaveasthmareportlimitationstoactivities;andanincreasingproportionofpeoplewhohaveasthmareceiveformalpatienteducation.

Hospitalizationrateshaveremainedrelativelystableoverthelastdecade,withlowerratesinsomeagegroupsbuthigherratesamongyoungchildren04yearsofage.Thereissome

indicationthatimprovedrecognitionofasthmaamongyoungchildrencontributestotheserates.However,theburdenofavoidablehospitalizationsremains.Collectively,peoplewhohaveasthmahavemorethan497,000hospitalizationsannually.Furthermore,ethnicandracialdisparitiesinasthmaburdenpersist,withsignificantimpactonAfricanAmericanandPuertoRicanpopulations.Thechallengeremainstohelpallpeoplewhohaveasthma,particularlythoseathighrisk,receivequalityasthmacare.Thiscoursepresentsadefinitionofasthma,adescriptionoftheprocessesonwhichthatdefinitionisbasedthepathophysiologyandpathogenesiso

fasthma,andthenaturalhistoryofasthma.

DefinitionofAsthma

Asthmaisacommonchronicdisorderoftheairwaysthatiscomplexandcharacterizedbyvariableandrecurringsymptoms,airflowobstruction,bronchialhyper-responsiveness,andanunderlyinginflammation(Box1).Theinteractionofthesefeaturesofasthmadeterminestheclinicalmanifestationsandseverityofasthma(Figure1)andtheresponsetotreatment.This

interactioncanbehighlyvariableamongpatientsandwithinpatientsovertime.

Box1.CharacteristicsofClinicalAsthma-Symptoms

AirwayobstructionInflammation


5/50

Hyper-responsivenessATrainEducation,Inc.707459-1315


6/50

Asthma

Figure1.TheInterplayandinteractionbetweenairwayinflammationandtheclinicalsymptomsandpathophysiologyofasthma.Adaptedfrom:http://www.nhlbi.nih.gov/guidelines/asthma/03_sec2_def.pdf

Theconceptsunderlyingasthmapathogenesishaveevolveddramaticallyinthepast25yearsandarestillundergoingevaluationasvariousphenotypesofthisdiseasearedefinedandgreaterinsightlinksclinicalfeaturesofasthmawithgeneticpatterns.Centraltothevariousphenotypicpatternsofasthmaisthepresenceofunderlyingairwayinflammation,whichisvariableandhasdistinctbutoverlappingpatternsthatreflectdifferentaspectsofthedisease,suchasintermittentversuspersistentoracuteversuschronicmanifestations.Acutesymptomsofasthmausuallyarisefrombronchospasmandrequireandrespondtobronchodilatortherapy.

Acuteandchronicinflammationcanaffectnotonlytheairwaycaliberandairflowbutalsounderlyingbronchialhyper-responsiveness,whichenhancessusceptibilitytobronchospasm.Treatmentwithanti-inflammatorydrugscan,toalargeextent,reversesomeoftheseprocesses;however,thesuccessfulresponsetotherapyoftenrequiresweekstoachieveand,insomesituations,maybeincomplete.

Forsomepatients,thedevelopmentofchronicinflammationmaybeassociatedwithpermanentalterationsintheairwaystructurereferredtoasairwayremodelingthatarenotpr

eventedbyorfullyresponsivetocurrentlyavailabletreatments.Therefore,theparadigmofasthmahasbeenexpandedoverthelast10yearsfrombronchospasmandairwayinflammationtoincludeairwayremodelinginsomepersons.

Theconceptthatasthmamaybeacontinuumoftheseprocessesthatcanleadtomoderateandseverepersistentdiseaseisofcriticalimportancetounderstandingthepathogenesis,pathophysiology,andnaturalhistoryofthisdisease.AlthoughresearchsincethefirstNAEPP

guidelinesin1991hasconfirmedtheimportantroleofinflammationinasthma,thespecificprocessesrelatedtothetransmissionofairwayinflammationtospecificpathophysiologicconsequencesofairwaydysfunctionandtheclinicalmanifestationsofasthmahaveyettobefullydefined.



7/50


8/50

Asthma

Similarly,muchhasbeenlearnedaboutthehost-environmentfactorsthatdeterminethesusceptibilityoftheairwaytotheseprocesses,buttherelativecontributionsofeither(andthepreciseinteractionsbetweenthem)thatleadstotheinitiationorpersistenceofdiseasehaveyettobefullyestablished.Nonetheless,currentscienceregardingthemechanismsofasthmaandfindingsfromclinicaltrialshasledtotherapeuticapproachesthatallowmostpeoplewhohaveasthmatoparticipatefullyinactivitiestheychoose.Aswelearnmoreaboutthepathophysiology,phenotypes,andgeneticsofasthma,treatmentswillbecomeavailabletoensureadequateasthmacontrolforallpersonsand,ideally,toreverseandevenpreventtheasthmaprocesses.

Asaguidetodescribingasthmaandidentifyingtreatmentdirections,aworkingdefinitionofasthmaputforthinthepreviousExpertPanelReportremainsvalid.Asthmaisachronic

inflammatorydisorderoftheairwaysinwhichmanycellsandcellularelementsplayarole:inparticular,mastcells,eosinophils,Tlymphocytes,macrophages,neutrophils,andepithelialcells.Insusceptibleindividuals,thisinflammationcausesrecurrentepisodesofwheezing,breathlessness,chesttightness,andcoughing,particularlyatnightorintheearlymorning.Theseepisodesareusuallyassociatedwithwidespreadbutvariableairflowobstructionthatisoftenreversibleeitherspontaneouslyorwithtreatment.Theinflammationalsocausesanassociatedincreaseintheexistingbronchialhyper-responsivenesstoavarietyofstimuli.Reversibilityo

fairflowlimitationmaybeincompleteinsomepatientswithasthma.

Thisworkingdefinitionanditsrecognitionofkeyfeaturesofasthmahavebeenderivedfromstudyinghowairwaychangesinasthmarelatetothevariousfactorsassociatedwiththedevelopmentofairwayinflammation(e.g.,allergens,respiratoryviruses,andsomeoccupationalexposures)andrecognitionofgeneticregulationoftheseprocesses.Fromthesedescriptiveapproacheshasevolvedamorecomprehensiveunderstandingofasthmapathogenesis,the

processesinvolvedinthedevelopmentofpersistentairwayinflammation,andthesignificantimplicationsthattheseimmunologicaleventshaveforthedevelopment,diagnosis,treatment,andpossiblepreventionofasthma.



9/50

Asthma

PathophysiologyandPathogenesisofAsthma

Airflowlimitationinasthmaisrecurrentandcausedbyavarietyofchangesintheairwayincludingbronchoconstriction,airwayedema,airwayhyper-responsiveness,andairwayremodeling.

Figure2.Normalversusasthmaticairway.From:http://www.nhlbi.nih.gov/health/dci/images/asthma.gif

BronchoconstrictionInasthma,thedominantphysiologicaleventleadingtoclinicalsymptomsisairwaynarrowingandasubsequentinterferencewithairflow.Inacuteexacerbationsofasthma,bronchialsmoothmusclecontraction(bronchoconstriction)occursquicklytonarrowtheairwaysinresponsetoexposuretoavarietyofstimuliincludingallergensorirritants.

Allergen-inducedacutebronchoconstrictionresultsfromanIgE-dependentreleaseofmediatorsfrommastcellsthatincludeshistamine,tryptase,leukotrienes,andprostaglandinsthatdirectlycontractairwaysmoothmuscle.Aspirinandothernonsteroidalanti-inflammatorydrugscanalsocauseacuteairflowobstructioninsomepatients,andevidenceindicatesthatthisnon-IgEdependentresponsealsoinvolvesmediatorreleasefromairwaycells.

Inaddition,otherstimuli(includingexercise,coldair,andirritants)cancauseacuteairflow

obstruction.Themechanismsregulatingtheairwayresponsetothesefactorsarelesswelldefined,buttheintensityoftheresponseappearsrelatedtounderlyingairwayinflammation.Stressmayalsoplayaroleinprecipitatingasthmaexacerbations.Themechanismsinvolvedhaveyettobeestablishedandmayincludeenhancedgenerationofpro-inflammatorycytokines.

AirwayEdema

Asthediseasebecomesmorepersistentandinflammationmoreprogressiveotherfactorslimitairflow.Theseincludeedema,inflammation,mucushypersecretionandtheformati

onofinspissatedmucousplugs,aswellasstructuralchangesincludinghypertrophyandhyperplasiaoftheairwaysmoothmuscle.Theselatterchangesmaynotrespondtousualtreatment.



10/50

Asthma

AirwayHyper-responsiveness

Airwayhyper-responsivenessanexaggeratedbronchoconstrictorresponsetoawidevarietyofstimuliisamajor,butnotnecessarilyunique,featureofasthma.Thedegreetowhichairwayhyper-responsivenesscanbedefinedbycontractileresponsestochallengeswithmethacholine(Provocholine)correlateswiththeclinicalseverityofasthma.Themechanismsinfluencingairwayhyper-responsivenessaremultipleandinclude:

InflammationDysfunctionalneuroregulationStructuralchangesInflammationappearstobeamajorfactorindeterminingthedegreeofairwayhyper-responsiveness.Treatmentdirectedtowardreducinginflammationcanreduceairwa

yhyper-responsivenessandimproveasthmacontrol.

AirwayRemodeling

Insomepersonswhohaveasthma,airflowlimitationmaybeonlypartiallyreversible.Permanentstructuralchangescanoccurintheairway,whichareassociatedwithaprogressivelossoflungfunctionthatisnotpreventedbyorfullyreversiblebycurrenttherapy.

Airwayremodelinginvolvesanactivationofmanyofthestructuralcells,withconsequent

permanentchangesintheairwaythatincreaseairflowobstructionandairwayresponsivenessandrenderthepatientlessresponsivetotherapy.Thesestructuralchangescanincludethickeningofthesub-basementmembrane,subepithelialfibrosis,airwaysmoothmusclehypertrophyandhyperplasia,bloodvesselproliferationanddilation,andmucousglandhyperplasiaandhypersecretion(Box2).Regulationoftherepairandremodelingprocessisnotwellestablished,butboththeprocessofrepairanditsregulationarelikelytobekeyeventsinexplainingthepersistentnatureofthediseaseandlimitationstoatherapeuticresponse.

Box2.FeaturesofAirwayRemodeling

InflammationMucoushypersecretionSubepithelialfibrosus


11/50

AirwaysmoothmusclehypertrophyAngiogenesis(bloodvesselproliferationanddilation)ATrainEducation,Inc.707459-1315


12/50

Asthma

PathophysiologicMechanismsintheDevelopmentofAirwayInflammation

Inflammationhasacentralroleinthepathophysiologyofasthma.Asnotedinthedefinitionofasthma,airwayinflammationinvolvesaninteractionofmanycelltypesandmultiplemediatorswiththeairwaysthateventuallyresultsinthecharacteristicpathophysiologicalfeaturesofthedisease:bronchialinflammationandairflowlimitationthatresultinrecurrentepisodesofcough,wheeze,andshortnessofbreath.

Theprocessesbywhichtheseinteractiveeventsoccurandleadtoclinicalasthmaarestillunderinvestigation.Moreover,althoughdistinctphenotypesofasthmaexist(e.g.,intermittent,persistent,exercise-associated,aspirin-sensitive,orsevereasthma),airwayinflammationremainsaconsistentpattern.Thepatternofairwayinflammationinasthma,however,doesnotnecessarilyvary

dependingupondiseaseseverity,persistence,anddurationofdisease.Thecellularprofileandtheresponseofthestructuralcellsinasthmaarequiteconsistent.

InflammatoryCells

Lymphocytes

Anincreasedunderstandingofthedevelopmentandregulationofairwayinflammationinasthmafollowedthediscoveryanddescriptionofsubpopulationsoflymphocytes,Thelper1cellsandThelper2cells(Th1andTh2),withdistinctinflammatorymediatorprofilesande

ffectsonairwayfunction.Afterthediscoveryofthesedistinctlymphocytesubpopulationsinanimalmodelsofallergicinflammation,evidenceemergedthat,inhumanasthma,ashift,orpredilection,towardtheTh2-cytokineprofileresultedintheeosinophilicinflammationcharacteristicofasthma.

Inaddition,generationofTh2cytokines(e.g.,interleukin-4(IL-4),IL-5,andIL-13)couldalsoexplaintheoverproductionofIgE,presenceofeosinophils,anddevelopmentofairwayhyper-responsiveness.Therealsomaybeareductioninasubgroupoflymphocytesregulat

oryTcellswhichnormallyinhibitTh2cells,aswellasanincreaseinnaturalkiller(NK)cellsthatreleaselargeamountsofTh1andTh2cytokines.

Tlymphocytes,alongwithotherairwayresidentcells,alsocandeterminethedevelopmentanddegreeofairwayremodeling.AlthoughitisanoversimplificationofacomplexprocesstodescribeasthmaasaTh2disease,recognizingtheimportanceofnfamiliesofcy


13/50

tokinesandchemokineshasadvancedourunderstandingofthedevelopmentofairwayinflammation.

Mastcells

Activationofmucosalmastcellsreleasesbronchoconstrictormediators(histamine,cysteinylleukotrienes,prostaglandinD2).Althoughallergenactivationoccursthroughhigh-affinityIgEreceptorsandislikelythemostrelevantreaction,sensitizedmastcellsalsomaybeactivatedbyosmoticstimulitoaccountforexercise-inducedbronchospasm(EIB).Increasednumbersofmastcellsinairwaysmoothmusclemaybelinkedtoairwayhyper-responsiveness.Mastcellsalsocanreleasealargenumberofcytokinestochangetheairwayenvironmentandpromoteinflammationeventhoughexposuretoallergensislimited.



14/50

Asthma

Eosinophils

Increasednumbersofeosinophilsexistintheairwaysofmost,butnotall,personswhohaveasthma.Thesecellscontaininflammatoryenzymes,generateleukotrienes,andexpressawidevarietyofpro-inflammatorycytokines.Increasesineosinophilsoftencorrelatewithgreaterasthmaseverity.Inaddition,numerousstudiesshowthattreatingasthmawithcorticosteroidsreducescirculatingandairwayeosinophilsinparallelwithclinicalimprovement.

However,theroleandcontributionofeosinophilstoasthmaisundergoingareevaluationbasedonstudieswithananti-IL-5treatmentthathassignificantlyreducedeosinophilsbutdidnotaffectasthmacontrol.Therefore,althoughtheeosinophilmaynotbetheonlyprimaryeffectorcellinasthma,itlikelyhasadistinctroleindifferentphasesofthedisease.

Neutrophils

Neutrophilsareincreasedintheairwaysandsputumofpersonswhohavesevereasthma,duringacuteexacerbations,andinthepresenceofsmoking.Theirpathophysiologicalroleremainsuncertain;theymaybeadeterminantofalackofresponsetocorticosteroidtreatment.Theregulationofneutrophilrecruitment,activation,andalterationinlungfunctionisstillunderstudy,butleukotrieneB4maycontributetotheseprocesses.

DendriticCells

Thesecellsfunctionaskeyantigen-presentingcellsthatinteractwithallergensfromtheairwaysurfaceandthenmigratetoregionallymphnodestointeractwithregulatorycellsandultimatelytostimulateTh2cellproductionfromnaveTcells.

Macrophages

Macrophagesarethemostnumerouscellsintheairwaysandalsocanbeactivatedbyallergensthroughlow-affinityIgEreceptorstoreleaseinflammatorymediatorsandcytokinesthatamplifytheinflammatoryresponse.

ResidentCellsoftheAirway

Airwaysmoothmuscleisnotonlyatargetoftheasthmaresponsebyundergoingcontractiontoproduceairflowobstructionbutalsocontributestoit(viatheproductionofitsownfamilyofpro-inflammatorymediators).Asaconsequenceofairwayinflammationandthegenerationofgrowthfactors,theairwaysmoothmusclecellcanundergoproliferation,activat


15/50

ion,contraction,andhypertrophyeventsthatcaninfluenceairwaydysfunctionofasthma.

EpithelialCells

Airwayepitheliumisanotherairwayliningcellcriticallyinvolvedinasthma.Thegenerationofinflammatorymediators,recruitmentandactivationofinflammatorycells,andinfectionbyrespiratoryvirusescancauseepithelialcellstoproducemoreinflammatorymediatorsortoinjuretheepitheliumitself.Therepairprocess,followinginjurytotheepithelium,maybeabnormalinasthma,thusfurtheringtheobstructivelesionsthatoccurinasthma.



16/50

Asthma

InflammatoryMediators

Chemokinesareimportantinrecruitmentofinflammatorycellsintotheairwaysandaremainlyexpressedinairwayepithelialcells.Eotaxinisrelativelyselectiveforeosinophils,whereasthymusandactivation-regulatedchemokines(TARCs)andmacrophage-derivedchemokines(MDCs)recruitTh2cells.Thereisanincreasingappreciationfortherolethisfamilyofmediatorshasinorchestratinginjury,repair,andmanyaspectsofasthma.

Cytokinesdirectandmodifytheinflammatoryresponseinasthmaandlikelydetermineitsseverity.Th2-derivedcytokinesincludeIL-5,whichisneededforeosinophildifferentiationandsurvival,andIL-4whichisimportantforTh2celldifferentiationandwithIL-13isimportantforIgEformation.KeycytokinesincludeIL-1andtumornecrosisfactor-(TNF-),whichamplifytheinflammatoryresponse,andgranulocyte-macrophagecolony-stimulatingfactor(GM-

CSF),whichprolongseosinophilsurvivalinairways.Recentstudiesoftreatmentsdirectedtowardsinglecytokines(e.g.,monoclonalantibodiesagainstIL-5orsolubleIL-4receptor)havenotshownbenefitsinimprovingasthmaoutcomes.

Cysteinyl-leukotrienesarepotentbronchoconstrictorsderivedmainlyfrommastcells.Theyaretheonlymediatorwhoseinhibitionhasbeenspecificallyassociatedwithanimprovementinlungfunctionandasthmasymptoms.RecentstudieshavealsoshownleukotrieneB4cancontributeto

theinflammatoryprocessbyrecruitmentofneutrophils.

Nitricoxide(NO)isproducedpredominantlyfromtheactionofinduciblenitricoxidesynthaseinairwayepithelialcells;itisapotentvasodilator.MeasurementsoffractionalexhaledNO(FeNO)maybeusefulformonitoringresponsetoasthmatreatmentbecauseofthepurportedassociationbetweenFeNOandthepresenceofinflammationinasthma.

ImmunoglobulinE(IgE)

IgEistheantibodyresponsibleforactivationofallergicreactionsandisimpo

rtanttothepathogenesisofallergicdiseasesandthedevelopmentandpersistenceofinflammation.IgEattachestocellsurfacesviaaspecifichigh-affinityreceptor.ThemastcellhaslargenumbersofIgEreceptors;these,whenactivatedbyinteractionwithantigen,releaseawidevarietyofmediatorstoinitiateacutebronchospasmandalsotoreleasepro-inflammatorycytokinestoperpetuateunderlyingairwayinflammation.Othercells,basophils,dendriticcel


17/50

ls,andlymphocytesalsohavehigh-affinityIgEreceptors.

ThedevelopmentofmonoclonalantibodiesagainstIgEhasshownthatthereductionofIgEiseffectiveinasthmatreatment.TheseclinicalobservationsfurthersupporttheimportanceofIgEtoasthma.



18/50

Asthma

ImplicationsofInflammationforTherapy

Recentscientificinvestigationshavefocusedontranslatingtheincreasedunderstandingoftheinflammatoryprocessesinasthmaintotherapiestargetedatinterruptingtheseprocesses.Someinvestigationshaveyieldedpromisingresults,suchasthedevelopmentleukotrienemodifiersandanti-IgEmonoclonalantibodytherapy.

Otherstudies,suchasthosedirectedatIL-4orIL-5cytokines,underscoretherelevanceofmultiplefactorsregulatinginflammationinasthmaandtheredundancyoftheseprocesses.Alloftheseclinicalstudiesalsoindicatethatphenotypesofasthmaexist,andthesephenotypesmayhaveveryspecificpatternsofinflammationthatrequiredifferenttreatmentapproaches.

Currentstudiesareinvestigatingnoveltherapiestargetedatthecytokines,chemokines,andinflammatorycellsfartherupstreamintheinflammatoryprocess.Forexample,dr

ugsdesignedtoinhibittheTh2inflammatorypathwaymaycauseabroadspectrumofeffectssuchasairwayhyper-responsivenessandmucushypersecretion.Furtherresearchintothemechanismsresponsibleforthevaryingasthmaphenotypesandappropriatelytargetedtherapymayenableimprovedcontrolforallmanifestationsofasthma,and,perhaps,preventionofdiseaseprogression.

Pathogenesis

Whatinitiatestheinflammatoryprocessinthefirstplaceandmakessomeperson

ssusceptibletoitseffectsisanareaofactiveinvestigation.Thereisnotyetadefinitiveanswertothisquestion,butnewobservationssuggestthattheoriginsofasthmaprimarilyoccurearlyinlife.

Theexpressionofasthmaisacomplex,interactiveprocessthatdependsontheinterplaybetweentwomajorfactorshostfactors(particularlygenetics)andenvironmentalexposuresthatoccuratacrucialtimeinthedevelopmentoftheimmunesystem.

Figure3.Effectsofgeneticpredispositionandenvironmentalfactorsonasthma.Adaptedfrom:http://www.niehs.nih.gov/research/atniehs/labs/lrb/enviro-cardio/images/asthma.gif.NationalInstituteofEnvironmentalHealthStudies,NIH.



19/50


20/50

Asthma

HostFactors

InnateImmunity

Thereisconsiderableinterestintheroleofinnateandadaptiveimmuneresponsesassociatedwithboththedevelopmentandregulationofinflammation.Inparticular,researchhasfocusedonanimbalancebetweenTh1andTh2cytokineprofilesandevidencethatallergicdiseases,andpossiblyasthma,arecharacterizedbyashifttowardaTh2cytokine-likedisease,eitherasoverexpressionofTh2orunder-expressionofTh1.

Airwayinflammationinasthmamayrepresentalossofnormalbalancebetweentwoopposing

populationsofThlymphocytes.TwotypesofThlymphocyteshavebeencharacterized:Th1andTh2.Th1cellsproduceIL-2andinterferon-.(IFN-.),whicharecriticalincellulardefense

mechanismsinresponsetoinfection.Th2,incontrast,generatesafamilyofcytokines(IL-4,-5,-6,9,and-13)thatcanmediateallergicinflammation.

Thecurrenthygienehypothesisofasthmaillustrateshowthiscytokineimbalancemayexplainsomeofthedramaticincreasesinasthmaprevalenceinwesternizedcountries.ThishypothesisisbasedontheassumptionthattheimmunesystemofthenewlybornisskewedtowardTh2cytokinegeneration.Followingbirth,environmentalstimulisuchasinfectionswillactivateTh1responsesandbringtheTh1/Th2relationshiptoanappropriatebalance.

Evidenceindicatesthattheincidenceofasthmaisreducedinassociationwithcertaininfections(M.tuberculosis,measles,orhepatitisA),exposuretootherchildren(e.g.,presenceofoldersiblingsandearlyenrollmentinchildcare),andlessfrequentuseofantibiotics.Furthermore,theabsenceoftheselifestyleeventsisassociatedwiththepersistenceofaTh2cytokinepattern.Undertheseconditions,thegeneticbackgroundofthechildwhohasacytokineimbalancetowardTh2willsetthestagetopromotetheproductionofIgEantibodiestokeyenvironmentalantigens,suchas

house-dustmite,cockroach,Alternaria,andpossiblycat.Therefore,agene-by-environmentinteractionoccursinwhichthesusceptiblehostisexposedtoenvironmentalfactorsthatarecapableofgeneratingIgE,andsensitizationoccurs.Preciselywhytheairwaysofsomeindividualsaresusceptibletotheseallergiceventshasnotbeenestablished.

Therealsoappearstobeareciprocalinteractionbetweenthetwosub-populationsinwhichTh1


21/50

cytokinescaninhibitTh2generationandviceversa.AllergicinflammationmaybetheresultofanexcessiveexpressionofTh2cytokines.Alternatively,recentstudieshavesuggestedthepossibilitythatthelossofnormalimmunebalancearisesfromacytokinedysregulationinwhichTh1activityinasthmaisdiminished.Thefocusonactionsofcytokinesandchemokinestoregulateandactivatetheinflammatoryprofileinasthmahasprovidedongoingandnewinsightintothepatternofairwayinjurythatmayleadtonewtherapeutictargets.

Genetics

Itiswellrecognizedthatasthmahasaninheritablecomponenttoitsexpression,butthegeneticsinvolvedintheeventualdevelopmentofasthmaremainacomplexandincompletepicture.Todate,manygeneshavebeenfoundthateitherareinvolvedinorlinkedtothepresenceofasthmaandcertainofitsfeatures.Thecomplexityoftheirinvolvementinclinicalasthmaisnotedbylinkagestocertainphenotypiccharacteristics,butnotnecessarilythepathophysiologicdisease

processorclinicalpictureitself.



22/50

Asthma

TheroleofgeneticsinIgEproduction,airwayhyper-responsiveness,anddysfunctionalregulationofthegenerationofinflammatorymediators(suchascytokines,chemokines,andgrowthfactors)hasappropriatelycapturedmuchattention.Inaddition,studiesareinvestigatinggeneticvariationsthatmaydeterminetheresponsetotherapy.Therelevanceofpolymorphismsinthebeta-adrenergicandcorticosteroidreceptorsindeterminingresponsivenesstotherapiesisofincreasinginterest,butthewidespreadapplicationofthesegeneticfactorsremainstobefullyestablished.

Sex

Inearlylife,theprevalenceofasthmaishigherinboys.Atpuberty,however,thesexratioshifts,andasthmaappearspredominantlyinwomen.Howspecificallysexandsexhormones,orrelatedhormonegeneration,arelinkedtoasthmahasnotbeenestablished,buttheymay

contributetotheonsetandpersistenceofthedisease.

EnvironmentalFactors

Twomajorenvironmentalfactorshaveemergedasthemostimportantinthedevelopment,persistence,andpossiblyseverityofasthma:

AirborneallergensViralrespiratoryinfections

Inthesusceptiblehost,andatacriticaltimeofdevelopment,bothrespiratoryinfectionsandallergenshaveamajorinfluenceonasthmadevelopmentanditslikelypersistence.Itisalsoapparentthatallergenexposure,allergicsensitization,andrespiratoryinfectionsarenotseparateentitiesbutfunctioninteractivelyintheeventualdevelopmentofasthma.

Allergens

Theroleofallergensinthedevelopmentofasthmahasyettobefullydefinedorresolved,butit

isobviouslyimportant.Sensitizationandexposuretohouse-dustmiteandAlternariaareimportantfactorsinthedevelopmentofasthmainchildren.Earlystudiesshowedthatanimaldandersparticularlydogandcatwereassociatedwiththedevelopmentofasthma.

Recentdatasuggestthat,undersomecircumstances,dogandcatexposureinearlylifemayactuallyprotectagainstthedevelopmentofasthma.Thedeterminantofthesediverseoutcomes


23/50

hasnotbeenestablished.Studiestoevaluatehouse-dustmiteandcockroachexposurehaveshownthattheprevalenceofsensitizationandsubsequentdevelopmentofasthmaarelinked.Exposuretocockroachallergen,forexample,amajorallergenininner-citydwellings,isanimportantcauseofallergensensitization,ariskfactorforthedevelopmentofasthma.Inaddition,allergenexposurecanpromotethepersistenceofairwayinflammationandlikelihoodofanexacerbation.

RespiratoryInfections

Duringinfancy,anumberofrespiratoryviruseshavebeenassociatedwiththeinceptionordevelopmentoftheasthma.Inearlylife,respiratorysyncytialvirus(RSV)andpara-influenzavirusinparticular,causebronchiolitisthatparallelsmanyfeaturesofchildhoodasthma.Anumberoflong-termprospectivestudiesofchildrenadmittedtohospitalwithdocumentedRSVhaveshownthatapproximately40%oftheseinfantswillcontinuetowheezeorhaveasthmainlater

childhood.



24/50

Asthma

Symptomaticrhinovirusinfectionsinearlylifealsoareemergingasriskfactorsforrecurrentwheezing.Ontheotherhand,evidencealsoindicatesthatcertainrespiratoryinfectionsearlyinlifeincludingmeaslesandevenRSVorrepeatedviralinfections(otherthanlowerrespiratorytractinfections)canprotectagainstthedevelopmentofasthma.Thehygienehypothesisofasthmasuggeststhatexposuretoinfectionsearlyinlifeinfluencesthedevelopmentofachildsimmunesystemalonganon-allergicpathway,leadingtoareducedriskofasthmaandotherallergicdiseases.Althoughthehygienehypothesiscontinuestobeinvestigated,thisassociationmayexplainobservedassociationsbetweenlargefamilysize,laterbirthorder,daycareattendance,andareducedriskofasthma.

Theinfluenceofviralrespiratoryinfectionsonthedevelopmentofasthmamaydependonaninteractionwithatopy.Theatopicstatecaninfluencethelowerairwayresponse

toviralinfections,andviralinfectionsmaytheninfluencethedevelopmentofallergicsensitization.Theairwayinteractionsthatmayoccurwhenindividualsareexposedsimultaneouslytobothallergensandvirusesareofinterestbutarenotdefinedatpresent.

OtherEnvironmentalExposures

Tobaccosmoke,airpollution,occupations,anddiethavealsobeenassociatedwithanincreasedriskfortheonsetofasthma,althoughtheassociationhasnotbeenasclearlyestablishedaswith

allergensandrespiratoryinfections.Inuteroexposuretoenvironmentaltobaccosmokeincreasesthelikelihoodforwheezingintheinfant,althoughthesubsequentdevelopmentofasthmahasnotbeenwelldefined.Inadultswhohaveasthma,cigarettesmokinghasbeenassociatedwithanincreaseinasthmaseverityanddecreasedresponsivenesstoinhaledcorticosteroids(ICSs).

Theroleofairpollutioninthedevelopmentofasthmaremainscontroversialandmayberelatedtoallergicsensitization.Onerecentepidemiologicstudyshowedthatheavyexercise(threeor

moreteamsports)outdoorsincommunitieswithhighconcentrationofozonewasassociatedwithahigherriskofasthmaamongschool-agechildren.Therelationshipbetweenincreasedlevelsofpollutionandincreasesinasthmaexacerbationsandemergencycarevisitshasbeenwelldocumented.

Anassociationoflowintakeofantioxidantsandomega-3fattyacidshasbeennotedin


25/50

observationalstudies,butadirectlinkasacausativefactorhasnotbeenestablished.Increasingratesofobesityhaveparalleledincreasingratesinasthmaprevalence,buttheinterrelationisuncertain.Obesitymaybeariskfactorforasthmaduetothegenerationofuniqueinflammatorymediatorsthatleadtoairwaydysfunction.

Insummary,ourunderstandingofasthmapathogenesisandunderlyingmechanismsnowincludestheconceptthatgene-by-environmentalinteractionsarecriticalfactorsinthedevelopmentofairwayinflammationandeventualalterationinthepulmonaryphysiologythatischaracteristicofclinicalasthma.



26/50

Asthma

NaturalHistoryofAsthma

Ifthepersistenceandseverityofasthmainvolvesaprogressionofairwayinflammationtoairwayremodelingandsomeeventualirreversibleairwayobstruction,thenanimportantquestioniswhetheranti-inflammatorymedicationsuchasinhaledcorticosteroids(ICS),givenearlyinthecourseofdiseasemightinterruptthisprocessandpreventpermanentdeclinesinlungfunction.Forearlyinitiationofinhaledcorticosteroidstobemorebeneficialthandelayedinitiation,twoassumptionsmustbevalid:

(1)Asagroup,peoplewhohavemildormoderatepersistentasthmaexperienceaprogressivedeclineinlungfunctionthatismeasurableandclinicallysignificant,and(2)Treatmentwithinhaledcorticosteroidspreventsorslowsthisdecline,inadditiontoprovidinglong-termcontrolofasthma.Reviewsoftheliteraturewereconductedin2002andforthiscurrentreportto

evaluatetheeffectofinterventionwithinhaledcorticosteroidsinalteringtheprogressionofdisease.

NaturalHistoryofPersistentAsthma

Children

Itiswellestablishedthatasthmaisavariabledisease.Asthmacanvaryamongindividuals,anditsprogressionandsymptomscanvarywithinanindividualsexperienceovertime.Thecourseofasthmaovertime,eitherremissionorincreasingseverity,iscommonlyreferred

toasthenaturalhistoryofthedisease.Ithasbeenpostulatedthatthepersistenceorincreaseofasthmasymptomsovertimeisaccompaniedbyaprogressivedeclineinlungfunction.Recentresearchsuggeststhatthismaynotbethecase.Rather,thecourseofasthmamayvarymarkedlybetweenyoungchildren,olderchildrenandadolescents,andadults,andthisvariationisprobablymoredependentonagethanonsymptoms.

Aprospectivecohortstudyinwhichfollowupbeganatbirthrevealedthat,inchildrenwhose

asthma-likesymptomsbeganbefore3yearsofage,deficitsinlunggrowthassociatedwiththeasthmaoccurredby6yearsofage.Continuedfollowuponlungfunctionmeasurestakenat1116yearsofagefoundthat,comparedtothegroupofchildrenwhoexperiencednoasthmasymptomsforthefirst6yearsoflife,thegroupofchildrenwhoseasthmasymptomsbeganbefore3yearsofageexperiencedsignificantdeficitsinlungfunctionat1116yearsofage;


27/50

however,nofurtherlossinforcedexpiratoryvolumein1second(FEV1)occurredcomparedtochildrenwhodidnothaveasthma.Thegroupwhoseasthmasymptomsbeganafter3yearsofagedidnotexperiencedeficitsinlungfunction.

Alongitudinalstudyofchildren810yearsofagefoundthatbronchialhyper-responsivenesswasassociatedwithdeclinesinlungfunctiongrowthinbothchildrenwhohaveactivesymptomsofasthmaandchildrenwhodidnothavesuchsymptoms.Thus,symptomsneitherpredictednordeterminedlungfunctiondeficitsinthisagegroup.

AstudybySearsandcolleaguesin2003assessedlungfunctionrepeatedlyfromages9to26inalmost1,000childrenfromabirthcohortinDunedin,NewZealand.TheyfoundthatchildrenwhohadasthmahadpersistentlylowerlevelsofFEV1/forcedvitalcapacity(FVC)ratioduringthefollowup.Regardlessoftheseverityoftheirsymptoms,however,theirlevelsoflungfunctionparalleledthoseofchildrenwhodidnothaveasthma,andnofurtherlossesoflungfunctionwere

observedafterage9.



28/50

Asthma

BaselinedatafromtheChildhoodAsthmaManagementProgram(CAMP)studysupportthefindingthattheindividualsageatthetimeofasthmaonsetinfluencesdeclinesinlungfunctiongrowth.Atthetimeofenrollmentofchildrenwhohadmildormoderatepersistentasthmaat512yearsofage,aninverseassociationbetweenlungfunctionanddurationofasthmawasnoted.Althoughtheanalysisdidnotdistinguishbetweenageofonsetanddurationofasthma,itcanbeinferredthat,becausetheaveragedurationofasthmawas5yearsandtheaverageageofthechildrenwas9years,mostchildrenwhohadthelongerdurationofasthmastartedexperiencingsymptomsbefore3yearsofage.

Thedatasuggestthatthesechildrenhadthelowestlungfunctionlevels.After46yearsoffollowup,thechildrenintheCAMPstudy,onaverage,didnotexperiencedeficitsinlunggrowth(asdefinedbypost-bronchodilatorFEV1),regardlessoftheirsymptomlevelsor

thetreatmenttheyreceived.However,afollowupanalysisoftheCAMPdatashowedthatasubgroupofthechildrenexperiencedprogressive(atleast1%ayear)reductionsinlunggrowth,regardlessoftreatmentgroup.Predictorsofthisprogressivereduction,atbaselineofthestudy,weremalesexandyoungerage.

TheCAMPstudynotedthatwhenmeasuresotherthanFEV1areusedtoassesslungfunctionmeasuresovertimeinchildhoodasthma,progressivedeclinesareobserved:theFEV1/FVCratio

beforebronchodilatorusewassmallerattheendofthetreatmentperiodthanatthestartinallthreetreatmentgroups;thedeclineintheICSgroupwaslessthanthatoftheplacebogroup(0.2%versus1.8%).

InacomparisonoflungfunctionmeasuresofCAMPstudyparticipantswithlungfunctionmeasuresofchildrenwhodidnothaveasthma,byyearfromages5through18,theFEV1/FVCratiowassignificantlylowerforthechildrenwhohadasthmacomparedtothosewhodidnothaveasthmaatage5(meandifference7.3percentforboysand7.1percentforgirls),andt

hedifferenceincreasedwithage(9.8%forboysand9.9%forgirls).

Cumulatively,thesestudiessuggestthatmostofthedeficitsinlungfunctiongrowthobservedinchildrenwhohaveasthmaoccurinchildrenwhosesymptomsbeginduringthefirst3yearsoflife,andtheonsetofsymptomsafter3yearsofageusuallyisnotassociatedwithsignificantdeficitsinlungfunctiongrowth.Thus,apromisingtargetforinterventionsdesignedto


29/50

preventdeficitsinlungfunction,andperhapsthedevelopmentofmoreseveresymptomslaterinlife,wouldbechildrenwhohavesymptomsbefore3yearsofageandseemdestinedtodeveloppersistentasthma.However,itisimportanttodistinguishthisgroupfromthemajorityofchildrenwhowheezebefore3yearsofageanddonotexperienceanymoresymptomsafter6yearsofage.

Untilrecently,novalidatedalgorithmswereavailabletopredictwhichchildrenamongthosewhohadasthma-likesymptomsearlyinlifewouldgoontohavepersistentasthma.Dataobtainedfromlong-termlongitudinalstudiesofchildrenwhowereenrolledatbirthhavegeneratedsuchapredictiveindex.Thestudiesfirstidentifiedanindexofriskfactorsfordevelopingpersistentasthmasymptomsamongchildrenyoungerthan3yearsofagewhohadmorethanthreeepisodesofwheezingduringthepreviousyear.Theindexwasthenappliedtoabirthcohortthatwasfollowedthrough13yearsofage.



30/50

Asthma

Seventy-sixpercentofthechildrenwhowerediagnosedwithasthmaafter6yearsofagehadapositiveasthmapredictiveindexbefore3yearsofage;97%ofthechildrenwhodidnothaveasthmaafter6yearsofagehadanegativeasthmapredictiveindexbefore3yearsofage.Theindexwassubsequentlyrefinedandtestedinaclinicaltrialtoexamineiftreatingchildrenwhohadapositiveasthmapredictiveindexwouldpreventdevelopmentofpersistentwheezing.

Theasthmapredictiveindexgeneratedbythesestudiesidentifiesthefollowingriskfactorsfordevelopingpersistentasthmaamongchildrenyoungerthan3yearsofagewhohadfourormoreepisodesofwheezingduringthepreviousyear:

Either(1)oneofthefollowing:oparentalhistoryofasthma,

oaphysiciandiagnosisofatopicdermatitis,oroevidenceofsensitizationtoaeroallergens.Or(2)twoofthefollowing:oevidenceofsensitizationtofoods,o=4percentperipheralbloodeosinophilia,orowheezingapartfromcolds.Adults

Acceleratedlossoflungfunctionappearstooccurinadultswhohaveasthma.Inastudyofadultswhohaveasthmaandwhoreceived2weeksofhigh-doseprednisoneifairflowobstructionpersistedafter2weeksofbronchodilatortherapy,thedegreeofpersistentairflowobstructioncorrelatedwithboththeseverityandthedurationoftheirasthma.

Twolarge,prospectiveepidemiologicalstudiesevaluatedtherateofdeclineinpulmonaryfunctioninadultswhohadasthma.Inan18-yearprospectivestudyof66nonsmokerswhohad

asthma,26smokerswhohadasthma,and186controlparticipantswhohadnoasthma,spirometrywasperformedat3-yearintervals.Seventy-threepercentofthestudygroupunderwentatleastsixspirometricevaluations.

Theslopefordeclineinlungfunction(FEV1)wasapproximately40%greaterfortheparticipantswhohadasthmathanforthosewhohadnoasthma.Thisdidnotappeartoresultfromextreme


31/50

measurementproducedbyafewparticipants,becausefewerthan25%oftheparticipantswhohadasthmaweremeasuredwithaslopelesssteepthanthemeanforthosewhodidnothaveasthma.Inanotherstudy,threespirometryevaluationswereperformedin13,689adults(778hadasthma,and12,911didnothaveasthma)overa15-yearperiod.

TheaveragedeclineinFEV1wassignificantlygreater(38mLperyear)inthosewhohadasthmathaninthosewhodidnothaveasthma(22mLperyear).Although,inthisstudy,asthmawasdefinedsimplybypatientreport,theresearchersnotedthat,becausethe6percentprevalencerateforasthmadidnotincreaseinthiscohortastheyincreasedinage,itislikelythatthesubjectswhoreportedhavingasthmadidindeedhaveasthmaratherthanchronicobstructivepulmonarydisease(COPD).Itisnotpossibletodeterminefromthesestudieswhetherthelossofpulmonaryfunctionoccurredinthosewhohadmildormoderateasthmaoronlyinthosewhohadsevereasthma.Nevertheless,thedatasupportthelikelihoodofpotentialacceleratedlossofpulmonary

functioninadultswhohaveasthma.



32/50

Asthma

NewstudieshaveaddressedthisissuesincetheExpertPanelReviewUpdate2002.JamesandcolleaguesreanalyzedthedatafromthestudyofdeclineinlungfunctionfromBusselton,Australia,afteraddinganewsurveyin19941995.Subjects(N=9,317)hadparticipatedasadults(19yearsorolder)inoneormoreofthecross-sectionalBusseltonHealthSurveysbetween1966and1981orinthefollowupstudyof19941995.

Usingthewholedatasample,Jamesandcolleaguesfoundthatsubjectswhohadasthmashowedsignificantlylowerlungfunctionduringthewholefollowupperiod,butmostofthedifferenceswereduetodeficitsinlungfunctionpresentatthebeginningoffollowup(whensubjectswereage19).Oncetheeffectofsmokingwastakenintoaccount,theexcessdeclineinFEV1attributabletoasthmawas3.78mLperyearforwomenand3.69mLperyearformen.Althoughtheseresultswerestatisticallysignificant,theirclinicalrelevanceisdebatable.

In2003,Sherrillandcoworkersre-analyzedthedatafromtheTucsonEpidemiologicStudyofAirwayObstructiveDisease.Atotalof2,926subjects,withlongitudinaldataforlungfunctionassessedinupto12surveysspanningaperiodofupto20years,wereincluded.Theyfoundthat,unlikesubjectswhohadadiagnosisofCOPD,inthosewhohaddiagnosisoflongstandingasthma,FEV1didnotdeclineatamorerapidratethannormal.ThiswasalsotrueforsubjectswhohadasthmaandCOPD.In2001,Griffithandcolleaguesstudieddeclineinlungfunctionin

5,242participantsintheCardiovascularHealthStudywhowereoverage65atenrollment.Eachparticipanthaduptothreelungfunctionmeasurementsovera7-yearinterval.

SubjectswhohadasthmahadlowerlevelsofFEV1thanthosewhoreportednoasthma.However,afteradjustmentforemphysemaandchronicbronchitis,therewerenosignificantincreasesintherateofdeclineinFEV1inparticipantswhohadasthma.

Summary

Takentogether,theselongitudinalepidemiologicalstudiesandclinicaltrialsi

ndicatethattheprogressionofasthma,asmeasuredbydeclinesinlungfunction,variesindifferentagegroups.Declinesinlungfunctiongrowthobservedinchildrenappeartooccurby6yearsofageandoccurpredominantlyinthosechildrenwhoseasthmasymptomsstartedbefore3yearsofage.

Children512yearsofagewhohavemildormoderatepersistentasthma,onaverage,donot


33/50

appeartoexperiencedeclinesinlungfunctionthrough1117yearsofage,althoughasubsetofthesechildrenexperienceprogressivereductionsinlunggrowthasmeasuredbyFEV1.

Furthermore,thereisemergingevidenceofreductionsintheFEV1/FVCratio,apparentinyoungchildrenwhohavemildormoderateasthmacomparedtochildrenwhodonothaveasthma,thatincreasewithage.Thereisalsoevidenceofprogressivelydeclininglungfunctioninadultswhohaveasthma,buttheclinicalsignificanceandtheextenttowhichthesedeclinescontributetothedevelopmentoffixedairflowobstructionareunknown.



34/50

Asthma

EffectofInterventionsonNaturalHistoryofAsthma

Dataontheeffectofinterventionsontheprogressionofasthma,asmeasuredbydeclinesinlungfunction,airwayhyper-responsiveness,ortheseverityofsymptoms,wereevaluatedforEPRUpdate2002andthecurrentupdate.TheExpertPaneldoesnotrecommendusinginhaledcorticosteroidsforthepurposeofmodifyingtheunderlyingdiseaseprocess(e.g.,preventingpersistentasthma).Evidencetodateindicatesthatdailylong-termcontrolmedicationdoesnotaltertheunderlyingseverityofthedisease.

Althoughapreliminarystudysuggeststhatappropriatecontrolofchildhoodasthmamaypreventmoreseriousasthmaorirreversibleobstructioninlateryears,theseobservationswerenotverifiedinarecentlong-termrandomizedcontroltrial(RCT)in1,041children512yearsofage.Thisstudydoesnotsupporttheassumptionthat,onaverage,children512yearsofage

whohavemildormoderatepersistentasthmahaveaprogressivedeclineinlungfunction.ChildrenintheplacebogroupdidnotexperienceadeclineinpostbronchodilatorFEV1overthe5-yeartreatmentperiod,andtheyhadpostbronchodilatorFEV1levelssimilartochildrenintheICSandnedocromiltreatmentgroupsattheendofthestudy.

ObservationalprospectivedatafromotherstudiesoflargegroupsofchildrensuggestthatthetimingoftheCAMPinterventionwastoolate,asmostlossoflungfunctioninchildhoodasthma

appearstooccurinthefirst35yearsoflife.However,inarecentrandomized,controlledprospectivestudy,children23yearsofagewhowereathighriskofdevelopingpersistentasthmaweretreatedfor2yearswithinhaledcorticosteroidsandobservedfor1additionalyearaftertreatmentwasdiscontinued.Thatstudydemonstratedthattheinterventiongrouphadlungfunctionandasthmasymptomlevelssimilartotheplacebogroupattheendofthestudy.

Tworecentstudiesaddressedthepossibilitythatinhaledcorticosteroidsmaypreventtheputative

declinesinlungfunctionbelievedtooccurshortlyafterthebeginningofthediseaseinadultswhohavelate-onsetasthma.Aretrospectivestudyreportedtheresultsofanobservationalstudyofadultswhohadmild-to-moderateasthmaandweretreatedfor5yearswithaninhaledcorticosteroid.Onegroup,treatedearlyinthedisease(lessthan2yearsafterdiagnosis),hadbetteroutcomesintermsoflungfunctionthanthosewhostartedtreatmentmorethan2years


35/50

afterdiagnosis.Thegroupinwhichtreatmentwasstartedmorethan2yearsafterdiagnosis,however,hadlowerlevelsoflungfunctionatthebeginningofthetrial.Therefore,itisnotpossibletodeterminefromthesedatawhattheresultswouldhavebeeninarandomizedtrial.

Tworecentlong-termobservationalstudiesreportanassociationbetweeninhaledcorticosteroidtherapyandreduceddeclineinFEV1inadultswhohaveasthma.However,long-termRCTswillbenecessarytoconfirmacausalrelationship.

TheSTARTstudyenrolled7,241subjects,566yearsofage,whohadmildasthmaoflessthan2yearsduration,accordingtoeachsubjectsreport.Participantswererandomizedtoalow-doseinhaledcorticosteroidorplaceboandwerefollowedprospectivelyfor3years.Thestudyfoundaslightlybetterlevelofpostbronchodilatorlungfunctioninparticipantsintheactivearmthanintheplaceboarm,butthedifferencewasmoreprominentafter1yearoftreatment(+1.48percentpredictedFEV1)thanattheendofthetreatmentperiod(+0.88percentpredicted

FEV1),suggestingnoeffectintheputativeprogressivelossinlungfunctioninthesesubjects.



36/50

Asthma

Withrespecttothepotentialroleofinhaledcorticosteroidsinchangingthenaturalcourseofasthma,therelevantclinicalquestionis:Aretheyassociatedwithlessdiseaseburdenafterdiscontinuationoftherapy?Thebestavailableevidenceinchildren512yearsofageand23yearsofagedemonstratedthat,althoughinhaledcorticosteroidsprovidesuperiorcontrolandpreventionofsymptomsandexacerbationsduringtreatment,symptomsandairwayhyper-responsivenessworsenwhentreatmentiswithdrawn.Thisevidencesuggeststhatcurrentlyavailabletherapycontrolsbutdoesnotmodifytheunderlyingdiseaseprocess.

ImplicationsofCurrentInformation

Airwayinflammationisamajorfactorinthepathogenesisandpathophysiologyofasthma.Theimportanceofinflammationtocentralfeaturesofasthmacontinuestoexpandandunderscorethischaracteristicasaprimarytargetoftreatment.Ithasalsobecomeapparent,ho

wever,thatairwayinflammationisvariableinmanyaspectsincludingintensity,cellular/mediatorpattern,andresponsetotherapy.Asknowledgeofthevariousphenotypesofinflammationbecomeapparent,itislikelythattreatmentalsowillalsohavegreaterspecificityand,presumably,effectiveness.

Itisalsoapparentthatasthma,anditspersistence,beginsearlyinlife.Althoughthefactorsthatdeterminepersistentversusintermittentasthmahaveyettobeascertained,thisinformationwill

becomeimportantindeterminingthetypeoftreatment,itsduration,anditseffectonvariousoutcomesofasthma.Earlystudieshaveindicatedthatalthoughcurrenttreatmentiseffectiveincontrollingsymptoms,reducingairflowlimitations,andpreventingexacerbations,presenttreatmentdoesnotappeartopreventtheunderlyingseverityofasthma.

Despitetheseunknowns,thecurrentunderstandingofbasicmechanismsinasthmahasgreatlyimprovedappreciationoftheroleoftreatment.TheExpertPanelsrecommendationsforasthmatreatment,whicharedirectedbyknowledgeofbasicmechanisms,shouldresultin

improvedcontrolofasthmaandagreaterunderstandingoftherapeuticeffectiveness.

Reference

NationalHeart,Lung,andBloodInstitute(2007).ExpertPanelReport3(EPR3):GuidelinesfortheDiagnosisandManagementofAsthma.Section2:Definition,Pathophysiology,andPathogenesisofAsthmaandNaturalHistoryofAsthma.Accessed8-1-08from:


37/50

http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.



38/50

Asthma

Glossary

Alternaria

Awidespreadtypeofmoldfoundbothindoorsandoutdoorsthatcantriggerallergicreactionsandasthma.

Antigen

Substancesforeigntothebodysuchasviruses,disease-causingbacteria,andotherinfectiousagents.

Atopy

Thegenetictendencytodevelopcertainallergicresponsessuchasasthma,allergicrhinitis,anddermatitis.

Chemokine

Atypeofsmallcytokine.

Cysteinyl-leukotrienes

Potentbronchoconstrictorsderivedmainlyfrommastcells.

Cytokine

Smallproteinsthatactovershortdistancesandarecriticaltothefunctioningoftheimmunesystem.Cytokinesdirectandmodifytheinflammatoryresponseinasthmaandlikelydetermineits

severity.

Eotaxin

Atypeofchemokinethatisimplicatedinthenarrowingoftheairwaysinasthma.

Hyperplasia

Anabnormalorincreasedgrowthofcellsinnormaltissuesororgans.

IgE

ImmunoglobulinE,atypeofantibodyreleasedinresponsetothepresenceofanallergen.Itisresponsibleforactivationofallergicreactionsandisimportanttothepathogenesisofallergicdiseasesandthedevelopmentandpersistenceofinflammation.

Inspissated

Driedorthickenedinconsistencyduetoevaporationoffluids.


39/50

Leukotrienes

Ahormonethatcausesvasodilation,mucosalswelling,andotherinflammatoryresponsesseeninhayfeverandasthma.

Mastcells

Cellsthatsynthesizeandstorehistamines,whicharereleasedduringanallergicreaction.Thereleaseofhistaminefrommastcellscausesanimmediatereddeningoftheskin.



40/50

Asthma

Methacholine

Adruggiveninincreaseddosestotestairwaysensitivity,whichisusedtotestforthepresenceandseverityofasthma.

Monoclonalantibodies

Proteinsproducedinthelabdesignedtoseekoutanddestroyspecificantigens.

NAEPP

NationalAsthmaEducationandPreventionProgram

Nave

AmatureTcellthatisnotyetactivatedbyanantigen.Naturalhistory:Thecourseofadiseaseovertime,eitherremissionorincreasingseverity,iscommonlyreferredtoasthenaturalhistoryofthedisease.

Nitricoxide(NO)

Apotentvasodilator.

Phenotype

Theobservabletraitsorcharacteristicsofanorganism,forexamplehaircolor,weight,orthepresenceorabsenceofadisease.Phenotypictraitsarenotnecessarilygenetic.

Pro-inflammatorycytokines

Cellsinvolvedwiththeamplificationoftheinflammatoryprocess.

Subepithelialfibrosis

Thedevelopmentofexcessiveconnectivetissueandscarringinthelungsoftenseeninsevereasthma.

(continuedonnextpage)


22


41/50

Asthma

PostTest

UsetheAnswerSheetfollowingthetesttorecordyouranswers.

1.Airwayinflammation:a.Isusuallytemporaryanddoesnotleadtobronchospasm.b.Isonlyseeninchronicasthmac.Canaffectairwaycaliberandairflow.d.Doesnotaffectbronchialhyper-responsiveness.2.Airwayremodeling:a.Candecreaseairflowobstructionandmakethepatientmoreresponsivetotherapy.b.Isamajorfactorindeterminingthedegreeofairwayhyper-responsiveness.c.Causespermanentstructuralchangesandlossoflungfunction.d.Isanexaggeratedbronchoconstrictorresponse.3.Smoothmusclecontractionoftheairwayscausedbyallergensorirritantsiscalled:a.Inflammation.b.Airwayhyper-responsiveness.c.Inspissation.d.Bronchospasm.

4.Factorsthatlimitairflowasairwaydiseaseprogressesare:a.Edemaandinflammationb.Methacholineandmucusplugs.c.Phenotypetraitsandinspissation.d.Innateimmunityandinflammatorycytokines.5.Airwayhyper-responsivenessincludesallofthefollowingexcept:a.Inflammation.b.Decreasedreleaseofhistamine.c.Dysfunctionalneuroregulation.d.Structuralchanges.6.Airwayremodelingis:a.Atemporaryalterationinairwaystructure.b.Anobservabletraitorcharacteristicofanorganism.

c.Anacutesymptomofasthma.d.Notpreventedbyorfullyresponsivetocurrenttreatments.7.Airwayremodelingcausespermanentchangesintheairwaythatincreaseobstructionandrenderthepatientlessresponsivetotherapy.a.Trueb.FalseATrainEducation,Inc.707459-1315


42/50

Asthma

8.Angiogenesisisafeatureof:a.Dysfunctionalneuroregulation.b.Airwayremodeling.c.Mucusplugs.d.Releaseofhistaminefrommastcells.9.Airwayinflammationinasthmaisonlyseeninexercise-associatedandaspirin-sensitivephenotypes.Falsea.Trueb.False10.Whenactivatedbyallergensmucosalmastcellsrelease:a.Cytokinesandchemokines.b.RegulatorT-cells.c.Lymphocytes.d.Bronchoconstrictormediators.11.Exercise-inducedbronchospasmiscausedby:a.Decreasedsensitivitytousualtreatments.b.Sensitizedmastcellsactivatedbyosmoticstimuli.c.T-lymphocytesandotherairwayresidentcells.d.Allergenactivationofmastcells.12.Airwayinflammationisseenonlyinexercise-inducedandaspirin-inducedast

hma.a.Trueb.False13.Treatmentwithcorticosteroids:a.Reducescirculatingandairwayeosinophilsthatcontaininflammatoryenzymes.b.Causesanincreaseincirculatingeosinophilsinparallelwithclinicalimprovement.c.Increasestheriskoflungremodeling.d.Cancauseincreasedmucushypersecretion.14.Allergenexposure:a.Isnotassociatedwiththedevelopmentofasthmainchildren.b.Isakeyfactorinthepersistenceofairwayinflammation.

c.Decreasesthelikelihoodofanexacerbation.d.Hasbeenproventoprotectagainstthedevelopmentofasthma.15.Infectionsassociatedwiththedevelopmentofasthmaare:a.Respiratorysyncytialvirusandparainfluenza.b.MeaslesandE-coli.c.Respiratorysyncytialvirusandmeasles.d.Yeastinfectionsandparainfluenza.ATrainEducation,Inc.707459-1315


43/50

Asthma

16.Thehygienehypothesissuggeststhat:a.Peoplewholiveindevelopedcountriesarelesslikelytodevelopasthma.b.Earlyexposuretoallergensleadstoareducedriskofasthma.c.Peoplefromlargefamiliesareatincreasedriskofasthma.d.Frequentbathingcaninfluencethedevelopmentoftheimmunesystemalonganon-allergicpathway.17.Riskfactorsfordevelopmentofpersistentasthmainclude:a.Oneepisodeofwheezingbeforeage3.b.Developmentofwheezingafterage3.c.Wheezingapartfromcoldsandfoodsensitivities.d.Useofbronchodilators.18.Inhaledcorticosteroids:a.Changetheunderlyingdiseaseprocessofasthma.b.Donotprovidecontrolandpreventionofsymptomsduringuse.c.Increaseasthmasymptomsandhyper-responsivenesswhenwithdrawn.d.Helptoslowprogressivelossoflungfunctioninpatients.(answersheetonnextpage)



44/50

Asthma

AnswerSheet

Asthma

Name(Pleaseprintyourname):_____________________________________________Date:__________________

Passingscoreis80%

1._____2._____3._____4._____5._____6._____7._____8._____9._____10._____11._____12._____

13._____14._____15._____16._____17._____18._____(continuedonnextpage)



45/50

Asthma

CourseEvaluation

Pleaseusethisscaleforyourcourseevaluation.Itemswithasterisks(*)arerequired.

5=Stronglyagree4=Agree3=Neutral2=Disagree1=Stronglydisagree*1.Uponcompletionofthecourse,Iwasableto:

a.Describetheclinicalcharacteristicsandpathophysiologyofasthma...5..4..3..2..1b.Outlinethepathophysiologicmechanismsinthedevelopmentofairwayinflammation

..5..4..3..2..1c.Discussthehostandenvironmentalfactorsthatcontributetothedevelopmentofasthma...5..4..3..2..1d.Discussthenaturalhistoryofasthmainchildrenandadults...5..4..3..2..1e.Summarizetheeffectofinterventionsonnaturalhistoryofasthma...5..4..3..2..1*2.Thecoursewaswritteninawaythatfacilitatedmylearning.

..5..4..3..2..1*3.Thiscoursewasfreefromcommercialbias.

..5..4..3..2..1(continuedonnextpage)



46/50

Asthma

*4.Thecoursemetmycontinuingeducationneeds.

..5..4..3..2..1*5.Thematerialpresentedwassupportedbyevidence...5..4..3..2..1*6.Theauthoravoidedtheuseofanecdotalinformationasthemainsourceofmaterial...5..4..3..2..1*7.Thecoursewasfreeofproductpromotion...Yes..No****Ifyouansweredno,pleaseanswer#8.8.Wasproductpromotionthesolepurposeofthepresentation?..Yes..No*9.Ittookme60minutespercontacthourtocompletethecourse,test,andevaluation...Yes..No****Ifyouranswerwasno,howlongdidittake?_____________________________

(continuedonnextpage)



47/50

Asthma

10.Myprofessionaleducationallevelis(checkone):Nursing

..NurseAide..LVN/LPN..RN(diploma)..RN(AD)

..BSN..MSN..NursePractitioner/AdvancedPracticeNurse

..PhD/DNScTherapy

..OTAide..COTA..OT..MOT..OTD

..PTAide..PTA..PT..MPT..MSPT..DPT..PhDOther(pleasespecify):_________________________________________11.IheardaboutATrainEducationfrom:..Searchengine..Advertisement..GovernmentorBoardwebsite..ReturningcustomerFriend..Publication(Magazine,etc.)

..Other__________________________12.IfoundtheATrainCEU.comwebsiteeasytouse:..Yes..No13.Commentsorsuggestions(optional):

(Registrationinformationonnextpage)



48/50

Asthma

RegistrationInformation

Pleaseanswerallofthefollowingquestions(*required).

*Name:_________________________________________________________________*Address:_________________________________________________________________*City:______________________________________________State:______Zip:_________*Phone:_____________________________________________________________________*ProfessionalDesignation:___________________________________________________*LicenseNumberandState:_________________________________________________Pleaseemailmycertificate:..Yes..NoEmail(requiredifyouwantyourcertificatesentbyemail):_____________________(IfyourequestanemailcertificatewewillnotsendacopyofthecertificatebyUSMail.)

PaymentOptions

Youmaypaybycreditcardorbycheck.

Filloutthissectiononlyifyouarepayingbycreditcard.2contacthours:$18

Creditcardinformation:

Name_______________________________________________________________________

Address(ifdifferentfromabove):____________________________________________

City:__________________________________________________State:____Zip:________

Cardtype:..Visa..MC..AmericanExpress..Discover

Cardnumber_________________________________________CVS#________________

Expirationdate______________________________________________________________

TestCompletionandMailingInstructions

1.Completeallforms:..AnswerSheet..EvaluationLearningActivity..RegistrationForm(thispage)2.Ifyouarepayingbycheck,prepareacheckfor$18madeouttoATrainEducat

ion,Inc.3.Mailthecompletedformsandyourpaymentto:ATrainEducation,Inc5171RidgewoodRdWillits,CA95490Whenwereceiveyourformsandpayment,wewillmail(oremail,ifyourequestit)yourcertificateofcompletion.Ifyouhaveanyquestionsorconcerns,pleasecallorcontactusatSharon@ATrainCEU.com.AndthanksfortakingtheATrain!


49/50



50/50

7 Asthma Patho

Documents

Transcript of 7 Asthma Patho