CLINICAL RESPIRATORY
JOURNAL
æREVIEWARTICLE
Techniquesofassessingsmallairwaysdysfunction
WilliamMcNulty*andOmarS.Usmani
NationalHeartandlungInstitute,ImperialCollegeLondonandRoyalBromptonHospital,London,UK
Thesmallairwaysaredefinedasthoselessthan2mmindiameter.Theyareamajorsiteofpathologyinmanylungdiseases,notleastchronicobstructivepulmonarydisease(COPD)andasthma.Thesmallairwaysarefrequentlyinvolvedearlyinthecourseofthesediseases,withsignificantpathologydemonstrableoftenbeforetheonsetofsymptomsorchangesinspirometryandimaging.Despitetheirimportance,theyhaveprovenrelativelydifficulttostudy.Thisisinpartduetotheirrelativeinaccessibilitytobiopsyandtheirsmallsizewhichmakestheirimagingdifficult.Traditionallungfunctiontestsmayonlybecomeabnormaloncethereisasignificantburdenofdiseasewithinthem.Thishasledtotheterm‘thequietzone’ofthelung.Inrecentyears,morespecialisedtestshavebeendevelopedwhichmaydetectthesechangesearlier,perhapsofferingthepossibilityofearlierdiagnosisandintervention.Thesetestsarenowmovingfromtherealmsofclinicalresearchlaboratoriesintoroutineclinicalpracticeandareincreasinglyusefulinthediagnosisandmonitoringofrespiratorydiseases.Thisarticlegivesanoverviewofsmallairwaysphysiologyandsomeoftheroutineandmoreadvancedtestsofairwayfunction.
Keywords:chronicobstructivepulmonarydisease;asthma;lungfunction;smallairways;impulseoscillometry;multiplebreathnitrogenwashout;imaging
*Correspondenceto:WilliamMcNulty,DovehouseStreet,London,SW36NP,UK,Email:w.mcnulty13@imperial.ac.uk
Received:1September2014;Acceptedinrevisedform:11September2014;Published:17October2014
heairwaysconsistofapproximately23genera-tionsofdichotomouslybranchingtubesfromthetracheatothealveoli(1)(Fig.1).Themainfunc-tionoftheairwaysistoventilatethegasexchangingunitsofthelung.Theyalsoplayaroleintheconditioningofinhaledair,removalofparticulatematter,andimmunedefencewithinthelung.
Thefirst15generationsofairwaysarecalledtheconductingairwaysandtakenopartingasexchange.Theyconstitutetheanatomicaldeadspace,whichisapproximately100Á150mlinahumanadult(2).Beyondthisregionlietherespiratorybronchioleswhichhaveoccasionalalveolibuddingfromthem.Thesecontinuetodivideuntiltheyreachthealveolarsacswithatotalsurfaceareaof70Á80m2(3).Theseairwaystakepartingasexchangeandcomprisetheacinarairways.
Thesmallairwaysrefertothoseairwayslessthan2mmindiameter(4).Theseoccurfromapproximatelygenera-tion8andincludeaportionoftheconductingairwaysaswellasalltheacinarairways.Theyhaveimportantstruc-turalandphysiologicaldifferencesfromlargeairways.First,theylackthecartilaginoussupportseeninlargeair-waysandlackmucousglands.Theyarelinedbysurfactantwhichreducessurfacetensionandhelpspreventthemfromclosingonexpirationandatlowlungvolumes(5).
T
Throughoutsuccessiveairwaygenerations,thereisareductioninthelengthanddiameteroftheairway.Becauseoftheexponentialincreaseinairwaynumbers,thereisarapidincreaseincross-sectionalareawitheachsubsequentgeneration.Thishastwomajoreffectsonairwayphysiology.First,foranygivenflow,thevelocityofgastransitwithinthelungdecreaseswithincreasingairwaygeneration.Theresultofthisishighvelocityflowintheproximalairwayswhichisturbulentandhencedensitydependent.Inthesmallairwaysofthelung,flowislaminarandthereforeindependentofgasdensity(6).Attheinterfaceoftheconductingandacinarairways,thereisachangefrombulkconvectiveflowtodiffusiondownaconcentrationgradient.Howeverthedistancefordiffusionissmall,approximately0.2mm(7).Second,theresistancetoairflowinthesmallairwaysislowinhealth,comprisingbetween10and25%oftotalairwaysresistance(8,9).However,smallairwaysresistanceissig-nificantlyincreasedindisease(10).Smallairwaysresis-tanceislargelyindependentoflungvolumewhilstlargeairwaysresistanceisalteredsignificantlywithchangeinlungvolumes(8).Thesearrangementsinthehumanlunghelptoachieveasequitableventilationtolungunitsaspossible,whilstmaintaininglowairflowresistanceandminimalworkofbreathing.
EuropeanClinicalRespiratoryJournal2014.#2014WilliamMcNultyandOmarS.Usmani.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsCC-BY4.0License(http://creativecommons.org/licenses/by/4.0/),allowingthirdpartiestocopyandredistributethematerialinanymediumorformatandtoremix,transform,andbuilduponthematerialforanypurpose,evencommercially,providedtheoriginalworkisproperlycitedandstatesitslicense.
Citation:EuropeanClinicalRespiratoryJournal2014,1:25898-http://dx.doi.org/10.3402/ecrj.v1.25898
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Fig.1.Airwaygenerations(adaptedfromref.1).
Thesmallairwaysindisease
Bothinchronicobstructivepulmonarydisease(COPD)andasthma,thesmallairwayshavebeenshowntobethemajorsiteofairflowobstruction(9,11,12).Thesmallairwaysmaybemorepronetopathologybecauseoftheirsize.Smallinhaledparticlesandpathogensmaybedepositedhereandpathologicalchangesinairwaysdiseasemakethesmallairwayssusceptibletoocclusion.There-fore,smallairwaysmayrequireinhaledtherapeuticaero-solsofsmallersizetobeabletopenetratetheairwaystreeandreachthedistallungregion(13).Pouseille’slawstatesthattheresistancetoflowisinverselyproportionaltothefourthpoweroftheradius.Hence,airwayobstructioncanhaveprofoundeffectsonlungphysiology.Theobstructionofsmallairwayscanoccurthroughanumberofmechan-isms,includingluminalocclusionbymucus,reductioninluminaldiameterfrominflammatoryinfiltrates,smoothmusclehypertrophy,orairwaywallthickening.Inaddi-tion,lossofstructuralairwaysupportsmayenhancecollapsibilityofairways.
airways,althoughdifferencesintheextentandcomposi-tionoftheinflammatoryinfiltrateexistbetweenlargeandsmallairways.Thesmallairwaysarethemajorsiteofinflammationinasthma(15,16)withachro-nicinflammatoryinfiltrateconsistingofeosinophils,T-lymphocytes,neutrophils,andmacrophages.Inaddition,thereissmoothmusclethickeningandluminalocclusionbymucus(17Á19).Insmallairways,thedensityofthelymphocytesandeosinophilsisgreaterintheouterwallscomparedtolargeairwayswheremorecentralairwaywallinflammationpredominates(15,20).Mastcellsarefoundmorecommonlyintheperipheryofthelung(21)thanthecentralairwaysandmoremarkedneutrophilicinflammationmaybeseenintheperibronchiolarlungparenchymainfatalasthma(15).Theseverityofinflam-matorychangescorrelateswithlungfunctioninnocturnalasthma(22),severeasthma(21),andismoremarkedinpatientswithfatalasthmacomparedtonon-fatalasthma(23).
AsthmaInasthma,thesmallairwaysarethickenedwithachronicinflammatoryinfiltrateaffectingalllayersoftheairway(14).Inflammatorychangesarepresentthroughoutthe
ChronicobstructivepulmonarydiseaseCOPDischaracterisedpredominatelybyneutrophilicandlymphocyticsmallairwayinfiltrationalongwiththepresenceof(24Á26).LymphocyticinfiltrationandsmoothmusclehypertrophyaremoreprominentinCOPDthanin
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Citation:EuropeanClinicalRespiratoryJournal2014,1:25898-http://dx.doi.org/10.3402/ecrj.v1.25898
Techniquesofassessingsmallairways
asymptomaticsmokers(25).Inaddition,thereisairwayremodellingwithperibronchialfibrosis,smoothmusclehypertrophy,andluminalocclusionfrommucus(27,28).TheextentofairwayinflammationcorrelateswithdiseaseseverityinCOPD(24,29,30).However,itisairwaywallthickness,ratherthantheseverityofinflammatorychanges,thatismorestronglyassociatedwithdiseaseprogressioninCOPD(30).Thissuggeststhatregulationoftheremodellingpathwaysthroughtissuegrowthfactorsmaybealteredinsusceptiblepatients.Interestingly,smokinghasbeenshowntoincreasetissuelevelsofgrowthfactorsthatpromoteairwayremodellingpriortotheonsetofinflammatorychanges(31).Emphysematousdestructionoflungtissuemayalsoaffectthesmallairwaysbydisruptionoftheelasticfibressupportingairwaywalls.Theextentofairwayinflammationcorre-lateswiththedegreeofdisruption(32)suggestingthatperibronchiolarinflammationmaydrivetheprotease-mediateddisruptionofairwayattachments.Indeed,smallairwaysdiseasemayprecedeemphysematouschangesidentifiedbycomputedtomography(CT)(33).
Inflammatorysmallairwaysdiseasemayexacerbatesmallairwaysinjuryanddysfunctionthroughmechanicalstressesofcyclicopeningandclosingofairwaysduringtidalbreathing.
Physiologicalassessmentofthesmallairways
Smallairwaysobstructionmayleadtoareductioninairflow,increasedairwaysresistance,gastrapping,andinhomogeneityofventilation.Consequently,physiologicaltestsmeasuringthesevariablescandetectandquantifysmallairwaysdisease(34).Table1summarisesthetech-niquesavailablefortheassessmentofsmallairwaysdisease.
Lindenpostulatedthatthelatterpartofthevitalcapacitywasaffectedbyincreasedresistanceinsmallairwaysaslungvolumefell.Pathologyintheseairwayscausesexcessiveairwaynarrowingandcollapseatanearliertimeandclosertothealveolusduringexhalation.Thisresultsinareductioninthemaximumexpiratoryflowthatcanbeachieved(37).However,FEF25Á75isdependentontheFVCandthereforechangesinFVCwillaffecttheportionoftheflow-volumecurveexamined.IfFEF25Á75isnotadjustedforlungvolume,thereispoorreproducibility(38).AnotherdisadvantageisthesensitivityoftheFEF25Á75,asitisfrequentlynormaliftheFEV1/FVCratiois75%(39).Inaddition,thereispoorcorrelationwithothermarkersofsmallairwaysdiseasesuchasgastrapping(40)andhistologicalevidenceofsmallairwaysinflammation(41).TheForcedExpiratoryVolumein3sec(FEV3)toFVCratiohasbeensuggestedasanalternativemeasureofsmallairwaysdisease.Thefractionofairnotexpiredinthefirst3sec(1-FEV3/FVC)isalsocalculatedtoestimatethegrowingproportionoflongtimeconstantlungunits.AsFEV1/FVCfalls,theFEV3/FVCfallsandthe1-FEV3/FVCrises.ThesemeasureshaveabetteraccuracythanFEF25Á75,particularlyinadvancingage(42).
Gibbonsetal.(43)suggestedthatthechangeinFVCfollowingahistamineprovocationisabettermeasureofsmallairwaydysfunctioninasthmaticpatientsthanthefallinFEV1.AfallinFVCsuggestssmallairwayclosureandgastrapping.OtherspirometricmarkersthathavebeensuggesstedforassessmentofsmallairwaysdiseasehaveincludedtheratiooftheFVCtoslowvitalcapacity(SVC)(44).
Plethysmography
Plethysmographicassessmentoflungvolumesprovidesasensitivemeasureofgastrappingandlunghyperinflation.Hyperinflationmaybedefinedasanabnormalelevationoflungvolumesattheendofexpiration(45).Itisafunctionofairflowlimitation,lungelasticrecoil,andchestwallcompliance.Airwaynarrowingresultsinaprolongedtimeconstantforexpiration,andairwaysmaycloseresultingingastrapping.Theresidualvolume(RV)isanimportantmeasureofsmallairwaysdysfunctionandmayberaisedbeforetheonsetofabnormalspirometryinasthma(46,47).TheRVcorrelateswiththedegreeofinflammatorychangesinsmallairwaysinCOPD(24)andwithperipheralairwayresistanceinasthma(48).Indeed,improvementinasthmasymptomsfollowingtreatmentwithmonteleukastcorrelatedwiththereductioninRVbutnotspirometricparameters(49).
Theresidualvolume/totallungcapacity(RV/TLC)ratiomaybeamoreusefulmarkerofgastrappingastheTLCisfrequentlyraisedinobstructivelungdisease.Sorknessetal.demonstratedthattheRV/TLCratioishigherinpatientswithsevereasthmacomparedtonon-severe
Spirometry
Spirometryisthemostwidelyusedlungfunctiontestbothinthediagnosisandstratificationofseverityoflungdisease.AdiagnosisofobstructivelungdiseaseismadewhentheratiooftheForcedExpiratoryVolumein1sec(FEV1)toForcedVitalCapacity(FVC)islessthan70%(35).WhilstareductioninFEV1mayreflectairflowobstruction,itisalsodependentonlungvolumes,elasticrecoil,respiratorymusclestrength,andpatienteffort(36).Inhealth,themainsiteofairwaysresistanceoccursinthe4thÁ8thairwaygenerations.Thus,FEV1largelyreflectslargeairwaysobstruction,andasignificantamountofsmallairwaysdiseasemustaccumulatebeforeFEV1becomesabnormal.
Examinationofthemid-portionofexpiratoryflowmayoffermoreinformationonsmallairwaypathology.TheForcedExpiratoryFlowbetween25and75%oftheFVC(FEF25Á75)isoneofthemostcommonlycitedmeasuresofsmallairwayspathology.McFaddenand
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Table1.Summaryofphysiologicalandimagingtechniquesforassessingthesmallairways
Measures
LungfunctionSpirometry
FEV1,FEF25Á75,FEV1/FVC,FEV3/FVC,FEV/SVC
WidelyavailableReproducibleStandardisedcriteria
RelativelyinsensitivetoearlydiseaseandsubtlechangesEffortdependent
Notspecifictosmallairwayschanges
Plethysmography
RV,RV/TLC,airwaysresistance
WidelyavailableReproducible
RelativelyeasytoperformSensitivetoearlychange
IOS
Z,Rrs,XrsNon-invasiveandeasytoperformEffortindependentReproducibleIntra-breathanalysis
Inertgaswashout
ClosingcapacityandclosingSensitivetoearlychangevolume
PhaseIIIslope:SIII,Sacin,ScondExhalednitricoxide
FENOEasyandquicktoperform
UnclearroleinCOPD
Hand-heldanalysersavailableAffectedbysmokingstatusSensitivetochangeswithtreatmentinasthma
Imaging
Highresolutioncomputedtomography
Assessmentofairwaychanges
Assessmentofgastrapping(MLDE/I)
Widelyavailable
Quickandeasytoperform
Unabletovisualisesmallairwaysdirectly
Specialistsoftwaremayberequired
NostandardisedmeasurementsRadiationdose
Hyperpolarisedmagneticresonanceimaging
Apparentdiffusionco-efficient
Regionalventilationdefects
Nuclearmedicine(scintigraphy,SPECT,andPET)
Ventilation
Inhaleddrugorreceptordistribution
Allowsassessmentofheterogeneityindistributionofdisease
Noradiationdose
Allowsassessmentof
heterogeneityindistributionofdisease
Canbetailoredtostudyindividualdrugsorreceptors
FEV10forcedexpiratoryvolumein1sec;FEV30forcedexpiratoryvolumein3sec;FVC0forcedvitalcapacity;Rrs0respiratorysystemresistance;Xrs0respiratorysystemreactance;Z0impedance;SVC0slowvitalcapacity;RV0residualvolume;TLC0totallungcapacity;FEF25Á750forcedexpiratoryflowat25Á75%ofvitalcapacity;FENO0fractionalexpirednitricoxide;Sacin0DCDIcontributiontoSnIII;Scond0CDIcontributiontoSnIII;SIII0slopeofphaseIII;MLDE/I0expiratorytoinspirationmeanlungdensity;SPECT0singlephotonemissioncomputedtomography;PET0Positronemissiontomography.
Radiationdose
DifficulttoidentifysmallairwaysSomeisotopescanbeexpensiveavailable
ExpensiveLimitedtoresearchapplications
proximalairwaysdisease
Difficulttoperform,requiringRestrictedtoresearchsettings
Candistinguishbetweendistalandspecialistequipment
Notspecificforsmallairwaysdisease
Effortdependent
RelativelytimeconsumingEquipmentnotwidelyavailableInterferencefromswallowingandupperairwayartefact
Pros
Cons
CanhelptargetdrugstositeoflungSPECTandPETnotyetwidely
asthmaandcorrelatesinverselywithFVC(40).However,theupperlimitofnormalvaluevarieswithageandsexandthereforethepredictedvaluemayprovideabettermeasureofgastrappingthantheabsolutevalue.
Airwaysresistance(Raw)mayalsobemeasuredbyassessingpressureandflowatthemouthduringbodyplethysmography.Airwaysresistanceisincreasedinobstructivelungdiseasesandismoresensitivetochangesthanspirometryindetectingbronchodilation(50).How-ever,itisnotspecificforthesmallairwayswhichlimitsitsapplicationindiagnosingandmonitoringdistalairwaysdisease(51).
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Impulseoscillometry
Impulseoscillometry(IOS)appliesoscillatingpressurevariationsintheformofrandomnoisetotherespiratorysysteminordertodeterminethemechanicalpropertiesofthelung.Themultiplefrequenciesbetween3and20Hzareappliedovernormaltidalbreathingfromaloudspeaker.TheresultingpressureandflowchangesaremeasuredatthemouthandanalysedinaFouriertransforma-tiontodeterminetheimpedance(Z)oftherespiratorysystem.Thisiscomposedofthein-phaseor‘real’partoftheimpedance,knownasresistance(Rrs),andtheoutofphaseor‘imaginary’part,calledreactance(Xrs).Inhealth,Rrsisindependentofoscillationfrequencybutbecomesfrequencydependentinthepresenceofairwaysobstruc-tion.Reactanceisdeterminedbytheelasticandtheinertialpropertiesofthelungandisfrequencydependent.Atlowfrequencies,Xrsisnegativeandlargelyrepresentstheelasticforceswithinthelung.Athighfrequencies,Xrsispositiveandisdeterminedbyinertiancewithinthelungresultingfromaccelerationofairflow.Atapointwheretheelastanceandinertianceareequalandopposite,Xrsis0.Thisisknownastheresonantfrequency(Fres)andoccursbetween8and12Hzinhealthypatients(52).
Higherfrequencysignals(15Hz)areabsorbedbytherespiratorysystembeforereachingthesmallairwaysandhencereflectthecontributionoflargeairways.Lowfrequencies(5Hz)penetratedeepintothelungandthereforerepresentthewholelung.ThecontributionofthedistalairwaysmaybedeterminedbythedifferencebetweenR5andR20,andthereforecangiveinsightintosmallairwayspathology.However,theanatomicallocationofthetransitionbetweenthesmallandlargeairwayshasnotbeendetermined(53).Despitethis,thereisevidencethatlowfrequencyresistanceandreactancemeasurementscorrelatestronglywithtranspulmonaryresistancemeasuredbyoesophagealmanometry(54)andothertraditionalsmallairwaysmeasures(55).
Whenairwayobstructionispresent,Rrsbecomesfrequencydependentwithapredominantincreaseinlowfrequencyresistance.Thishasbeenshowntoidentifypatientswithasthma(56Á59)andCOPD(56,60,61).WhilstRrsdoesincreaseinearlystageCOPD(60),reactancemeasuresarebetteratidentifyingseverityofdisease(62)andaremorecloselyassociatedwithotherparametersincludingFEV1andmeasuresofhyperinfla-tion(61).DyspnoeascoresandhealthstatuscorrelatesignificantlywithR5Á20andX5qualityoflifeinstableCOPDandaresensitivetoimprovementsfollowingexacerbations(63).
IOSalsoallowsforthediscriminationofinspiratoryandexpiratoryresistanceandreactance.Inspiratoryminusexpiratoryreactanceat5Hz(DX5)hasbeenshowntohelpdiscriminatebetweenasthmaandCOPD(64).Inaddition,ithasalsobeenshowntobeasensitive,non-invasivemethodofdetectingexpiratoryflowlimita-
tion(EFL)inCOPD.ExpiratoryreactancefallswhenEFLispresentasthepressuresignalscannotpassthechokepointwithintheairway(65,66).Thisislikelytobeduetotheenhancedcollapsibilityofairwaysinexpirationandisamajorfactorinthedevelopmentofdynamichyperinflation.Indeed,recentstudiesusingR5Á20asanindexofdistalairwayabnormalityhaveshownthepresenceofsmallairwaysdysfunctioneveninpatientswithmild-moderateasthma(67).
StudiesexaminingtheeffectofinhaledtherapiesonlungmechanicshavedemonstratedthatIOSissensitivetobronchodilationinbothCOPD(50,68)andasthma(69,70).Ithasalsobeenusedintheassessmentoflungtransplantrecipientsforbronchiolitisobliterans(71)andfollowingenvironmentalexposuretodusts(72,73).
IOShastheadvantageofbeingsimpletouseandiseffortindependent.Itprovidescontinuousmeasurementofpulmonarymechanicsgivingahightemporalresolutionallowingintra-breathanalysis.AsIOSdoesnotrelyonforcedmanoeuvres,itmaybemoresuitableforpatientswhocannotperformtheseeasilysuchaschildrenorthosewithseverelungdiseases.Thismayalsoreducetheeffectsofprematureairwayclosureseenduringforcedspiro-metrymanoeuvres.Interferencefromupperairwaysarte-factssuchastonguemovementorswallowingcanmakeassessmentdifficult.PatientsundergoingIOSdoneedsomecoachingforaccuratemeasurestobemade.
Inertgaswashout
Gaswashouttechniqueswereintroducedinthe1950sasawayofmeasuringtheefficiencyofgasmixingwithinthelungs.Thisisdependentonthestructureofboththelargeandsmallairwaysandhenceinformationregardingthesecanbeinferredfromthetests.Themostcommonlyemployedtechniqueisthesinglebreathnitrogenwashout(SBNW)andmorerecentlythemultiplebreathnitrogenwashout(MBNW).Othergasesmaybeusedincludingheliumandsulphurhexafluoride(SF6)whosephysicalpropertiesdeterminegasflowwithinthelung.
Singlebreathnitrogenwashout
TheSBNWisperformedbyinhaling100%oxygenfromRVtoTLCfollowedbyaSVCexhalation.Theexhaledvolumeandnitrogenconcentrationismeasuredandtheresultingtracecanbebrokendownintofourdistinctphases.
InphaseI,thenitrogenconcentrationiscloseto0%asthisrepresentsanatomicaldeadspacewherethereisnogasmixing.DuringphaseII,thereisasharpriseintheexpirednitrogenconcentrationasdeadspacegasmixeswithresidentalveolargas.PhaseIIIrepresentsalveolargasandtheexpirednitrogenconcentrationbeginstoplateau,althoughthereisaslightrisefromthestarttofinishofthisphaseduetoventilationheterogeneity.
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Thisoccurswhenevertwolungunitsareventilatedtoadifferentdegreeandthebestventilatedunitwillemptypreferentiallybeforealesswell-ventilatedlungunit.Inhealth,thisoccurstoadegreebecauseofasymmetryinlungstructureandduetotheeffectsofgravityonthebaseofthelungresultinginlongertimeconstantsforemptying.Finally,inphaseIV,thereisasteepriseinexpiredN2concentrationasthemostpoorlyventilatedareas(withlittleO2mixing)empty.Thisisalsothepointatwhichthesmallairwaysstarttocloseasaresultofgravity-dependentcollapseandisknownastheclosingvolume(CV).TheCVandRVtogetherareknownastheclosingcapacity(CC).Normally,smallairwaysclosureoccursclosetoRV.However,smallairwaysdiseasemaycauseprematureairwaycollapseresultinginanincreasedCVandgastrapping.CVmaybeexpressedasaratioofVCandshouldnotexceed25%(74).TheCCmaybeexpressedasaratioofTLCandisusefulinobstructivelungdiseases.
AnalysisoftheslopeofphaseIII(SIII)providesinfor-mationontheventilationheterogeneityinthelung.Airwaysdiseasesdonotaffectthelunguniformlyandthisresultsindisparitiesintheventilationofindividualsubunits.Thismayoccurintheconductingairwayswheregasflowsbyconvection(convection-dependentventila-tioninhomogeneity,CDI)andresultsfromnarrowingofairwaysorincreasedstiffnessinthesubtendedlungunits.ItmayalsooccurintheverydistalacinarairwayswherethediffusionÁconvectionfrontarises(diffusionÁconvec-tion-dependentinhomogeneity,DCDI).Here,itoccursasaresultofstructuralasymmetrybetweenlungunits(75).Thus,whereairwaysdiseaseoccurs,thoseaffectedlungunitsmixlesswellwiththeinspiredoxygen(andthushaveahighernitrogenconcentration)andemptymoreslowly.ThiscausesanincreaseinSIII.
SBNWindiceshavebeenusedintheassessmentandresponsetotreatmentinbothasthmaandCOPD.AsthmaticpatientswithanormalFEV1haveincreasedCVandphaseIIIslopecomparedtohealthycontrols.Inaddition,thefrequencyofexacerbationscorrelateswithSIIIsuggestingitmaybeasensitivemeasureofpatientswithpoorcontrol(76).Indeed,increasedCVinpatientswithsevereasthmahasbeenshowntobeariskfactorforpredictinganexacerbation(77).Levelsofexhaledmar-kersofairwayinflammationincludingnitricoxidecorrelatewithSIIIandCC/TLCratioinasthma(78,79).Furthermore,severe,steroid-dependentasthmaticpa-tientshavemoremarkedchangesinSBNWindicesthanpatientswithmildtomoderateasthma(79).Thesemarkershavealsobeenusedtoassesschangesfollowingbothinhaledandoraltherapiesforasthma(80Á83).
Over35yearsago,theSIIIoftheSBNWwasrecognisedasbeingmorecloselyrelatedtohistologicalsmallairwaysinflammationinCOPDthanFEF25Á75(29).Furtherevidenceofitsassociationwithsmallairwaysinflamma-
tioninCOPDcamefromtheexaminationofbronchialbiopsiesandbronchoalveolarlavage(BAL)specimens(84).COPDseveritymayalsobepredictedbychangesinSBNWindicesastheSIIIcorrelateswithFEV1(85)andTLCOinalpha-1antitrypsindeficiency(86).
SBNWissensitivetoearlychangesinairwaysinsmokerswithanincreaseinCV(87),butitsuseiscontroversialinCOPD.Buistetal.demonstratedthatmanysmokerswithnormalspirometry,butabnormalsmallairwayindices,didnotgoontodevelopobstructivespirometryovera9Á11yearfollow-up.However,ofthosethatdid,theCC/TLCratiopredictedtherateofdeclineinFEV1suggestingitmaybeusefulinidentifyingatrisksmokers(88).Sta˘nescuetal.similarlyfoundthatinagroupofsmokersandex-smokerswithnormalspirome-try,overhalfhadabnormalsmallairwayindices,yetmoststillhadnormalspirometry13yearslater.Intheircohort,ahighSIIIpredictedaccelerateddeclineinFEV1(89).Despiteitssensitivity,theSBNWisnotspecifictosmallairwayspathology.Changesinanyofthegenera-tionsoftheconductingairwayswillalsoaffecttheslopeofphaseIII.Thus,whilstitispossibletoinferthatanormalSIIIindicatesnosmallairwaysdisease,thetestisunabletolocatetheanatomicalsiteofthepathology(34).
Multiplebreathnitrogenwashout
TheMBNWisamodificationofthesinglebreathtechnique.Thepatientinhales100%O2fromFRCwithafixedtidalvolumeandrespiratoryratetowashouttheresidentnitrogenfromthelungs.Thetestcontinuesuntiltheexhalednitrogenislessthan1/40thoftheoriginalconcentration(approximately2%)forthreesuccessivebreaths.Thespeedandefficiencyofgasmixingisdeter-minedbytidalvolume,breathfrequency,andventilationheterogeneity.Thus,bykeepingbreathfrequencyandtidalvolumerelativelyconstant,inferencesaboutventilationheterogeneitycanbemade(90).Figure2demonstratesthenitrogenwashoutcurvesfromaMBNWtest.
Thistechniqueallowsformeasurementoftheeffi-ciencyofgasmixinginthewholelungthroughthelungclearanceindex(LCI).Itisdefinedasthenumberoflungturnovers(FRCequivalents)requiredtowashoutthetracergasto1/40thoftheoriginalconcentration.Thisiscalculatedbymeasuringthecumulativeexpiredvolume(CEV)requiredtowashouttheresidentnitrogenanddividingitbyFRC:
LCI¼
CEVFRC
FRCmaybecalculatedduringtheMBNWfromthefollowingformula,wherebythevolumeoftracergas(i.e.N2)isdividedbytheend-tidalconcentrationofthetracer
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Fig.2.(a)MultiplebreathnitrogenwashoutcurvewithindividualbreathsdemonstratingPhaseIIIslope(SnIII)from1st(b)and10th(c)breaths.
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gasinthefirstbreathminustheend-tidalconcentrationofthetracergasinthelastbreath:
FRC¼
V½tracerCintÀCend
TheLCIhasbeenusedextensivelyasameasureofairwaysfunctionincysticfibrosisandasthma,particu-larlyinthepaediatricpopulation(91).
AsaMBNWprogresses,theSIIIofeachbreathchangesthroughoutthetest,becomingsteeperwithsuccessivebreaths.Inordertocomparebreathswithinatest,theslopesmustbenormalisedforthemeanexpirednitrogenconcentrationforeachbreath(SnIII).Innormallungs,theDCDIisthemajordeterminantoftheSnIIIandreachesitsmaximumatapproximately1.5lungturnovers.Afterthis,theincreaseinSnIIIisdiffusionindependentandhencereflectsCDI(92).ThisallowsforthequantificationofthecontributionoftheCDIcomponent,referredtoasScond,andtheDCDIcomponent,referredtoasSacin(75).Thus,theseindiceshavetheabilitytoanatomicallylocatethesiteoftheairwaypathologythatresultinventilationinhomogeneity.
Theseindiceshaveprovenverysensitive,becomingabnormalinsmokerswithmorethana10-yearpackhistory.Incontrast,spirometricabnormalitiesonlybe-comeabnormalaftera20pack-yearhistoryofsmoking.Forsmokerswitha30pack-yearhistoryandTLCOB60%predicted,therewereproportionatelylargerchangesinSacinthanScond,reflectingparenchymaldestruction(93).SmokerswithoutCOPDwhowereabletostopsmokingshowedsustainedreversibilityinScond(94).Thissupportsthehypothesisthatthemajorsiteofpathologyinsmoking-relatedlungdiseasestartsintheperipheralairways.
TheseabnormalitieshavebeenfurtherdescribedinbothasthmaandCOPD.Verbancketal.demonstratedinCOPDpatientsthatbothScondandSacinareraisedyetreflectdifferentpathologies.ScondcorrelatedwithairwaysmeasuressuchasFEV1andspecificairwaysresistancewhilstSacinwasmorecloselyassociatedwithdiffusingcapacity(95).AsthmaticpatientsalsohaveraisedScondandSacin,althoughacinarventilationheterogeneityislesspronouncedthaninCOPD,presumablyreflectingthedegreeofparenchymaldestructioninCOPD.Inaddition,asthmaticpatientsdemonstratedbronchodilatorreversi-bilityinbothSacinandScond,whilstCOPDpatientsdidnot(96).Inasthma,Sacinismorecloselyassociatedwithairwayinflammation(97)andseverityinunstablepatients(98).Ithasrecentlybeenshownthatmeasuresofventilationheterogeneityareassociatedwithlevelsofasthmacontrolandmayalsopredicttheresponsetoinhaledtherapy(99,100).Withtheirsensitivitytosmallairwaysdisease,theyhavebeenusedinavarietyofresearchsettings.Theseincludetheassessmentofinhaled
treatmentsinbothasthma(101,102)andCOPD(103),assessmentofairwayhyper-responsiveness(104,105),andmonitoringoflungtransplantrecipients(106).However,theyarenotyetusedinroutineclinicalpracticeastherearefewcommerciallyavailablemachines,andinterpretationofresultscanbedifficult.Theoretically,abnormalitiesinanyoftheconductingairwaysfromthefirstgenerationcancauseabnormalitiesinScondandthereforeitisnotspecifictosmallairways.Interpretingtheresultswithinformationfromspirometrywillhelpclarifythis.Inaddition,theoreticalmodellingforlocali-sationofairwaysdiseasewasperformedinnormalsubjects.ItispossiblethattheconvectionÁdiffusionfrontisdifferentindiseasestatesandhenceanatomicallocalisationsmaynotbeprecise.
HeliumandSulphurhexafluoridewashouttests
OtherinertgassesincludingheliumandSF6maybeusedinsmallconcentrationsastracergasses.Theserequireawash-inperiodandspecialisedanalyticalequipment.However,theyhavetheaddedbenefitthatthephysio-chemicalpropertiescanbeexploitedtogainfurtherinformationfromtheSIII.ThediffusionfrontofheliumliesmoreproximallythanSF6andthereforechangesintheheliumSIIIcomparedtoSF6SIIIsuggestmoreproximalacinarchanges.WherebothSIIIchangesothatthedifferencebetweenthemisstillthesame,thepossibilitiesareeitherachangeintheconductingairwaysorcon-comitanteffectsintheproximalanddistalpartsoftheacinus(34).TherearefewerclinicalstudiesreportingSF6asatracergasandthesehavelargelybeenperformedinchildrenwithcysticfibrosis(107Á109).
Exhalednitricoxide
Nitricoxideisproducedinboththeresidentairwaycellsandtheinflammatorycellsinthelungandhasaroleintheregulationofairwayfunction.Fractionalexhalednitricoxide(FENO)maybemeasuredinasingleexhalationduringtidalbreathing.Itreflectslevelsofinflammation,particularlyeosinophillicinflammation,withinthelung(110).Exhalednitricoxide(eNO)exhibitsflowratedependency,withaninversecorrelationbetweenflowrateandFENO(111).ThisreflectsboththetransittimeofexhaledgasanddiffusionfromthetissueaswellasthecompartmentofthelungfromwhichtheNOwasproduced.Underlowflowconditions,FENOlargelyreflectscentralairwaysandathigherflowsitrepresentsalveolarNO(112Á114).Thismayhelptolocalisethesiteofinflammationwithinthelung.Indeed,Lehtima¨kietal.demonstratedthatpatientswithalveolitishadhigherlevelsofalveolarNOthanasthmaticpatients,whointurnhavehigherbronchialNO.Inpatientswithalveolitis,alveolarNOcorrelatedwithtransferfactorandalveolarvolume,whilstbronchialNOcorrelatedwithairways’
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hyper-responsivenessinasthmaticpatients.BothgroupsofpatientsshowedanimprovementinFENOwithsteroidtreatment,suggestingitisresponsivetointervention(115).However,back-diffusionofNObetweenthealveolarandairwaycompartmentscomplicatestheinter-pretationofresults.IthasbeenrecognisedthatNOwilldiffusefromtheairwaysdownaconcentrationgradientintothealveoli,thuselevatingalveolarNOandreducingmeasuredairwayNO(116,117).Modelstocorrectthishavebeendeveloped,however,indiseasestateswhereairwaysarenarrowedoroccluded;lessNOcanback-diffuse,resultinginhigherFENOandloweralveolarconcentrations(118).ItshouldalsobenotedthatcurrentsmokingreducesFENOlevelsandthusthesmokingstatusofapatientneedstobetakenintoaccountwheninterpretingresults(110).
FENOhasbeenusedextensivelyinasthmaclinicalresearchandpractice.CentralairwaysappeartobethemajorsitesofproductionofNOinasthmabothinstablepopulationsandduringexacerbations(119).AlveolarNOconcentrationsareraisedinsevereasthmaticswheretheycorrelatewithalveolareosinophillicinflammation(120)andothermeasuresofsmallairwaysdysfunction(121).Recently,ithasalsobeenshownthatalveolarNOisalsoraisedinpatientswithmildasthma(122).FENOisimprovedbybothoral(123,124)andinhaledcorticos-teroids(ICS)(125)andaraisedFENOlevelbeforeICStreatmentpredictsanimprovementinasthmacontrol(126).ThishasmadeFENOanattractiveprospectforaddingtoasthmatreatmentalgorithms.However,theresultsofstudiesassessingimpactofmeasuringFENOhavebeenmixed.Meta-analysessuggestnooverallbenefittoasthmacontrolandqualityoflife,butthereisareductioninICSuseinadultsalthoughanincreaseinICSuseinchildren(127,128).
TheroleofFENOinCOPDislessclear.FENOmayberaisedinCOPD(129Á131),althoughitislowercomparedtoasthmaticpatients.AninversecorrelationwithFEV1,transferfactor,andoxygensaturationshasbeenreported(129).Contrarytothis,Gelbetal.foundnodifferenceinbaselinealveolarorairwayNOlevelsbetweenhealthycontrolsandaged-matchedCOPDpatients.Despitethis,theadditionofsalmeterol50mcg/fluticasone250mcgcombinationinhalersignificantlyreducedairway,butnotalveolarNO.Therewasnocorrelationbetweenemphy-semascoreandexhaledNOparameters(119).HigherFENOlevelsmayhelppredictaclinicalresponsetoICSasassessedbyFEV1reversibility(132)andthisisassociatedwithahighersputumeosinophilcount(133).
ofthesameseverity,imagingisusefulinseparatingdifferentphenotypesandlocalisingheterogeneity.How-ever,directmeasurementofsmallairwaysisdifficultastheyarelargelybeyondtheresolutionofCTandMRIscanners.Nevertheless,bothlargeairwayshavebeenassesseddirectlyandthesmallerairwaysbytheirimpactongastrappingandventilationdistribution.Thispro-videsbothanatomicalandfunctionalinformationtothephysician.
HighresolutionCT
ThesmallairwaysarebeyondtheresolutionofCTscannersanddifficulttoassessdirectly(134).Airwaysassmallas2Á2.5mmindiametercanbevisualised.McDonoughetal.foundfeweroftheseairwaysinpatientswithCOPDundergoingCTlungcancerscreen-ing.ThereductioninairwaynumberworsenedasCOPDseverityincreasedbystage,consistentwithpathologicalfindingsinlungspecimens(135).However,theaccuracyofmeasurementofsmallerairwaysmaybeproblematicduetomeasurementerrorandartefactfrombreathingorcardiogenicoscillations.Nakanoetal.demonstratedthatmeasurementofintermediate-sizedairwayscouldpredictthesmallairwaydimensionsmeasuredbyhistology(136);thus,assessmentmaystillproveusefulinestimatingtheextentofsmallairwaysdisease.QuantitativeassessmentofmoreproximalairwayluminaldiameterandairwaywallthickeningmeasuredbyCTcorrelatewithlungfunc-tioninCOPD(137Á140),withthestrengthofcorrelationincreasingformoredistalairways(139).
Smallairwaysdiseaseresultsingastrappingandmaybeseenasareasoflowattenuationdistaltothesiteofobstruction.Mosaicattenuationreflectslocalisedareasofgastrappingandsuggestsheterogeneousdistributionofairwaysdisease.Itmaybeseeninbothasthma(141)andCOPD(142).However,gastrappingisbestassessedonexpiratoryscansandmayprovideanindirectmeasureofsmallairwaysfunction(143).ComparingthemeanlungdensitybetweenexpiratoryandinspiratoryCTprovidesaquantitativemeasurecalledMLDE/I.Inasthma,MLDE/IcorrelatesstronglywithFEV1,FEV1/FVCratio,FEF25Á75,andRV/TLC,suggestingthatitreflectssmallairwaysdisease(144).Inchildren,gastrappinghasbeenshowntobeassociatedwithimprovementsinpost-bronchodilatorR5andX5measuredbyIOS(145).Gastrappingismoremarkedduringacuteexacerbationsofasthmaandshowsresponsivenesstosteroids(146).Asthmaticpatientswithgastrappingaremorelikelytohavehadasthma-relatedhospitaladmissions,intensivecaretreatment,highlevelsofairwayneutrophils,andmoresevereairflowobstructionthanthosewithout(147).ICShavebeenshowntoimprovegastrappinginasthma,althoughinthesesmallstudiesnosignificantbenefitinlungfunctionorspirometrywasseen(148,149).
Imagingofthesmallairways
Imagingalreadyplaysanextensiveroleinthemanagementofairwaysdiseaseandcanbeusedasanon-invasivemeasureofsmallairwaysfunction.Whereglobalmeasuresoflungfunctionsuchasspirometrymayclassifypatients
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TheassessmentofgastrappinginCOPDismorecomplicatedasbothsmallairwaysdiseaseandemphyse-magiverisetolowattenuationareas.Visualestimationofemphysemaprovidesbettercorrelationwithlungfunc-tionmeasuressuchasTLCO,whereasMLDE/Icorrelateswellwithlungfunctionmeasuresofgastrapping(150).InalargecohortofpatientsintheCOPDGenestudy,expiratoryscanswithathresholdof(856Hounsfieldunits(HU)forassessmentofgastrappinghadastrongercorrelationwithairflowobstructionthanemphysemascoresmeasuredbytheareaoflungwith(950HUoninspiratoryscans.Thevolumechangebetweeninspira-toryandexpiratoryscansalsoreducedasCOPDseverityincreased,reflectingmoresevereairwayobstructionandgastrapping(151).UsingMLDE/Iscorestoassessgastrappingandthe15thpercentileoflungdensitytoassessemphysema,Hartleyetal.demonstratedthatsmallair-waysdiseasecontributesmorestronglythanemphysematoseverityofCOPD(152).MLDE/Ialsocorrelateswithinflammatorychangesmeasuredbysputumneutrophils,addingfurthersupporttotheinflammatorynatureofsmallairwaysdiseaseinCOPD.MLDE/IissensitivetoearlysmallairwayschangesandcorrelateswithSIIIinSBNWinagroupofasymptomatic,non-smokers(153).However,MLDE/Icanshowconsiderablevariationbetweenscansinindividualpatientsandthereforemaybedifficulttouseasamarkerofresponsetotreatment.Recently,intheresearcharena,staticimagesobtainedwithCThavebeenmademorefunctionalbymeansofcomputationalfluiddynamics(154)andbiomarkersbasedonCTimaginghavebeendevelopedthatallowanassessmentoffunctionalsmallairwaysdisease(155).WhilstCTisauseful,non-invasivetoolforindirectlyassessingsmallairwaysfunction,ithasanumberoflimitations.Theexposuretoradiationmeansthatre-peatedassessmentformonitoringisnotfeasible.Thereisnostandardisedmeasureofgastrappingatpresentanddifferentauthorshaveuseddifferentdensitythresholdsforassessinggastrapping,makingcomparisonmoredifficult.Gastrappingisnotdiagnosticforspecificairwaysdiseasesandpatternssuchasmosaicattenuationarealsoseeninpulmonaryvasculardisease(156).
withsmokinghistory(159,160),suggestingitisasensitivemarkerofearlydamage.ItisincreasedfurtherinCOPDwhereitcorrelateswithlungfunction(161)andemphysematousdestruction(162).Indeed,ADCcorre-lateswellwithCT-derivedemphysemascoresandmorestronglywithTLCOthanCT-derivedemphysemascores(163).InCOPDpatientsobservedover26months,ADCandotherparametersderivedfrom3HeMRIhavebeenshowntodeclinewhilstFEV1remainedstable,suggestingitisalsosensitivetochangeovertime(164).Measuringdiffusionoverlongerperiodsallowstheassessmentofcollateralventilationinemphysema(165,166).
Quantificationofregionalventilationcanbeachievedbybothstaticanddynamicassessmentof3Hedistribu-tionwithinthelung.Ventilationdefectsarepresentinasthma(167,168)andCOPD(169,170),resultingfromairwaynarrowingorobstructionandunevenventilation.Inagroupofasthmaticpatients,theareasofventilationdefectswerepersistentorrecurredinthesamelocationsovertime(169).Inflammatorycellsobtainedatbronch-oalveolarlavageweremorenumerousinlobeswithhigherventilationdefectsthatthosewithout,suggestingthatthedefectsaretheresultofinflammatoryairwaynarrowing(171).Dynamicventilationisamorerecentadvancethatallowsimagingandassessmentofventilationwithahighspatialandtemporalresolutionoverthecourseofarespiratorycycle(161,172).Inasthma,areasofdiffer-entialgasclearancehavebeenobservedthatcorroboratwithevidenceofairflowobstructionandgastrappingonCT(173).
HyperpolarisedMRIhastheabilitytoassessregionallungfunctionwhichmakesitausefultoolinassessingairwaysdiseaseswhichhaveaheterogeneousdistribution.However,thetechniqueisstilllargelyrestrictedtoresearchapplicationsanditsroleintheclinicalmanage-mentofairwaysdiseaseisnotyetclear.
Nuclearmedicinetechniques
Two-dimensionalgammascintigraphyTwo-dimensional(2-D)gammascintigraphyhasbeeninuseforseveraldecades.Gamma-emittingradionucleidesdepositedwithinthelungcanbeimagedastheydecay.Thisallowsforanassessmentoftheoveralllungdepositionandtosomeextent,regionaldifferencesindeposition.Incor-poratingradionucleideintodrugcompoundsischallen-gingandhenceanisotopeboundtothedrugsuchas99mTcismorecommonlyused.Thesetechniquesmustbevalidatedtoensurethattheadditionofaradiolabeldoesnotsignificantlychangethebehaviourofthedrug(174).2-Dgammascintigraphyhasbeenusedtoassesstheeffectofparticlesizeondepositionwithinthelungs.Usmanietal.studiedthreeparticlesizesofradiolabelledsalbutamolandfoundthatwhilstsmallparticle(1.5micron)salbutamolwasassociatedwithahighertotal
Hyperpolarisedheliummagneticresonanceimaging
Hyperpolarisedheliummagneticresonanceimaging(3HeMRI)allowsfortheassessmentofdistributionofventilationandmorphometryofthedistalairwaysandlungparenchymawithoutexposuretoionisingradiation(157).Diffusionimagingvisualisesthemovementof3Heintheperipheralairspaces,boundbyalveolarandair-wayswalls.Thisiscalculatedastheapparentdiffusionco-efficient(ADC)andgivesinsightintothemicrostruc-tureofthedistalairspaces(158).ADCisincreasedinhealthysmokerswithnormallungfunctionandcorrelates
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lungdoseandmoreperipheraldeposition,itwasthelargeparticles(6micron)depositedinthemoreproximalairwaysthathadthegreatesteffectonbronchodilation(13).Inaddition,theeffectoflateinhalationofadrypowderdemonstratedthatahigherproportionreachestheperipheryofthelungwithoutachangeinthetotallungdose(175).
Whilstscintigraphydoesinvolveexposuretoionisingradiation,thedoseislowandisestimatedat0.15mSvperstudy(176).However,2-Dimagingdoesnotallowpreciselocalisationofdrugdepositionasbothcentralandsmallairwaysaswellasalveolardistributionmaycontributetogammacountsforanygivenarea.Whilstassessmentofdepositionisausefulmarkerofdrugdistribution,itdoesnotitselfprovideanassessmentofclinicalorphysiologicalresponse.Hence,thesestudiesmustbeassessedalongwithclinicalandphysiologicaldatainordertoevaluateefficacy.
acquisitiontimesunder1min.Thisallowsforassessmentofbothdepositionandclearanceoftracers(187).
PositronemissiontomographyPositronemissiontomography(PET)isanemergingtechniqueforassessmentofairwaysdisease.Itcanbeusedtoassessdrugdeposition(188),inflammation(189),andventilationperfusionrelationshipsinthelung(190).However,PETscannersandthefacilitiestoproduceradioisotopesareexpensive.Theradioisotopesusedoftenhaveashorthalf-lifeandincorporatingthemintodrugsisacomplexprocess.However,ithastheabilitytoproducehigherresolutionimagesthanSPECTandallowsfortargetingofradioisotopestospecificreceptorsandtargetswithinthelung.Therefore,itislikelytobeanareaofexcitingresearchintheassessmentofsmallairwaysdiseaseandtreatment(191).
SinglephotonemissioncomputedtomographySinglephotonemissioncomputedtomography(SPECT)isa3-Dimagingmodalityusingmultiplegammadetectorsthatrotatearoundasupinepatient.Reconstructionoftheimagescandemonstratetheradionucleidedistributioninthreedimensions,therebyofferingsuperiorassessmentofregionallungventilationorparticledistribution.SPECTmaybecombinedwithX-rayCTtorelatetheradionuclidedistributiontoanatomicalinformation(177,178).SPECTcanbeusedtoimageventilationusingeitherradiolabelledgassesorultrafineparticlessuchasTechnegas†.Thisisanultrafinecarbonparticlelabelledwith99mTcthathasbeenshowntohaveasimilarinhaleddistributioninhealthypatientstogases(179).Thisallowsmeasurementoftheextentofregionaldistributionofairflow.Inhealthypatients,airwayclosuremeasuredwithSPECTcorrelateswithCCmeasuredbySBNW.However,inasthmaticpatientsthiscorrelationislost,possiblyduetoregionalheterogeneityinairwayclosure(180).TechnegasSPECThasalsobeenshowntoidentifyregionalEFLinasthmaevenwhenflowmeasurementsornegativeexpiratorypressuretechniquesareinsensitivetoit(181).InCOPD,TechnegasSPECTcanidentifyregionaldifferencesinemphysemawhichcorrelateswithlungfunctionandemphysemascores(182,183).ThetechniquecanbecombinedwithperfusionimagingtoassessventilationÁperfusionrelationshipsinthelung(184).
SPECThasprovenausefultoolindefiningthedepositionofinhaleddrugsandcanallowfortreatmentstobemorespecificallytargetedtoareasofthelung.Ciclesonidehasbeenshowntohavegoodperipherallungdeposition,withloworopharyngealdepositioninbothhealth(185)andasthma(186).LimitationsofSPECTscanningincludehigherradiationdosestopatientsandalongeracquisitiontime.Thislimitstheassessmentofdepositionofmoleculeswithafastclearance.However,fastSPECTprotocolshavebeendevelopedwithimage
Conclusions
AnunderstandingoftheroleofsmallairwaysinCOPDandasthmaisincreasinglyimportantasitbecomesnecessarytodistinguishindividualphenotypesofthediseases.Thiswillleadtoamoretailoredapproachtoassessmentandtreatmentofpatientswiththeaimofimprovingsymptomsandfunction(192).Itmayalsoallowustoreduceunnecessaryexposuretotreatmentsthatcarrysignificantsideeffects.Giventheanatomical,functional,andphysiologicalinformationthatcanbeobtainedfromthesedifferenttests,itislikelythatacombinationofinvestigationswillberequiredtogivetheclearestpictureofanindividual’sphenotype.Atpresent,however,manyoftheseinvestigationsremainintherealmoftheresearchlaboratoryandfurtherworkisrequiredtounderstandtheirsignificanceandinterpretationinthemanagementofthesediseases.
Acknowledgements
DrOmarSUsmaniisarecipientofanNIHR(NationalInstituteofHealthResearch,UK)CareerDevelopmentFellowship.ThestudywassupportedbytheNIHRRespiratoryDiseaseBiomedicalResearchUnitattheRoyalBromptonandHarefieldNHSFounda-tionTrustandImperialCollegeLondon.
Conflictofinterestandfunding
Theauthorshavenotreceivedanyfundingorbenefitsfromindustryorelsewheretoconductthisstudy.
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