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TreatmentOptionsforComplicated/SevereAsthma
HenryJ.Kanarek,MDKanarekAllergyAsthmaImmunology
www.kallergy.com913-451-8555
AsthmaEpidemiology
• WorldHealthOrganization,Asthmaisoneofthemostcommonnon-communicablediseasesworldwide
• TheGlobalAsthmaNetworkin2014estimatedthatworldwide334millionindividualswereaffectedbyasthma
• Annually250,000prematuredeaths• 38%-54%ofpatientswithasthmahaveuncontrolledasthma• Themajorityofindividualsintheworldthathaveasthmaarenotdiagnosed,andthemajoritybeingtreatedforasthmaarenotreceivingtherighttreatment
Asthma
• Thesmoothmuscleofthebronchiolesconstrictcausingtheairwaytoclose,thisiscalled“bronchialconstriction”
• Thesmoothmusclewillrelaxandthisiscalled“bronchodilation”• Asthmaisadiseasewherethebronchiolesopenandclose• Themorethebronchiolesopenandclosewilldeterminehowactiveorseveretheasthmais.Orhowmuchinflammationispresent
• Theopeningandclosingofthebronchiolesisultimatelyinflammation• Inflammationleadstocollagenbuildupinthebronchioles,gobletcellsenlarge,andbronchiolehyperreactivity(moreconstriction)
• 35%ofasthmaticsmaydevelopCOPD
Asthma
• Triggersforanasthmaattack,flareuporexacerbation:• Thenumberonetriggerforasthmaisavirusorcold• Thesecondbiggesttriggerareallergies,iftheindividualhasallergies
• Approximately60%ofasthmaticshaveallergies• Anasthmaticmaybeallergictograsspollencausingitchingandsneezing,buttypicallyanallergictriggerforasthmaneedstobemorespecificlikeacat,ordog
• Thethirdbiggesttriggercanbeexercise,GERD,odors,fumes,anxiety
Asthma
• Therearevarioustoolstoassesthedegreeofasthmacontrol• GINASymptomControlTool(GlobalInitiativeforAsthma)• ACT(AsthmaControlTest)• ACQ(AsthmaControlQuestionnaire)• ATAQ(AsthmaTherapyAssessmentQuestionnaire)
• LowFEV1/ForcedVitalCapacityRatio,LowFEV1%predicted,LowFEF25-75• ElevatedNitrousOxide• Intermittentasthma:theindividualrarelyrequiresalbuterolandhasnormalspirometryandnitrousoxidereadings
• Persistentasthma:theindividualissufferingwithinflammationinthebronchiolesandpotentiallyscarringthelungsalsocalled“remodeling”---leadingtoCOPD
Asthma
• Inpersistentasthmathemostimportantmedicationistheinhaledcorticosteroid(ICS)
• Determiningiftheindividualhaspersistentasthmaiskey:• Asmallinfantcanhavepersistentasthma• Ifachildoradultrequires4albuteroltreatmentsperdayfor3-4daysinarowtotreatanasthmaexacerbation,twicein12months
• Ifthechildoradultrequires5dosesoforalsteroidsinayear• Ifthechildoradultrequires4dosesofalbuterolinaweekoutsideofsports
• Treatthisindividual,nomatterwhatage,withadailyinhaledcorticosteroidtoreducefrequentexacerbationsandavoiddevelopingCOPD
Asthma
• Thefollowingslidesshowhowasthmaisaninflammatorydisease• Themoreinflammationinvolvingthebronchiolesthemorepermanentdamagewilloccur,themoreexacerbationswilloccur
• Inflammationleadstocollagendepositinginthebronchiolesreducingairflowandlungfunction
• InflammationinthebronchiolesleadstoremodelingandChronicObstructivePulmonaryDisease(COPD),EmphysemaandChronicBronchitis
8
9
04/27/08-exp.
Asthma Control Test™ (ACT)SCORE
Asthma Control Test is a trademark of QualityMetric Incorporated.Copyright 2002, by QualityMetric Incorporated.
1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school or at home?
2. During the past 4 weeks, how often have you had shortness of breath?
3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?
4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication (such as albuterol)?
5. How would you rate your asthma control during the past 4 weeks?
TOTALACT is for patients with asthma 12 years and older. A score of ≤19 means your patient’s asthma may not be under control.
12
16
Relative Risk of Hospitalization in the United States
Donahue et al. JAMA. 1997;277:887-891.
Prescriptions per person-year
RelativeRisk
None 1-2 2-3 3-5 5-8 8+0-1
b2-agonists
TotalICS
0
12
34
5
67
8
Age 0-17Age 18-44Age 45+
TotalAge 0-17Age 18-44Age 45+
Asthma:TreatmentOptions
• InhaledCorticosteroids(ICS),sometimesdoublingortriplingthedose• InhaledICS/LABAcombinations(longactingbetaagonists)• InhaledLABA/LAMAcombinations(longactingMuscarinicantagonists)• InhaledICS/LABA/LAMAcombinations• LeukotrieneReceptorAntagonists(overusedandofquestionablebenefit)• OralSteroids• BronchialThermoplasty• Biologics
SeverePersistentAsthma
• Mostasthmaindividualscanachievegoodcontrolwiththevariousmedicationscommerciallyavailable
• Whentheindividualisnotwellcontrolledrequiringthehigherdosesofinhaledmedications,andrequiringmultipleinhaledmedications
• Whentheindividualrequiresfrequentdosesoforalsteroidsinayear,suchastwentydaysina12monthperiod
• Frequentemergencyvisits,hospitalizations,missingworkorschool• Decreasedqualityoflifeduetofrequentattacksandpoorlungfunction• Theseindividualsareconsideredtobesufferingseverepersistentasthma
SeverePersistentAsthma
• Manyfactorscancausepoorcontroloflungfunction• TreatGERDwithprotonpumpinhibitors,sometimesaprokinetic suchasMetoclopramideorDomperidone maybeneeded
• Environmentalissuessuchasallergies,smoking,obesity,homeandoccupationairquality
• Chronicsinusitiscancausepoorresponsetotherapy• Immunedeficiency• Ruleoutautoimmunediseases,sarcoidosis,interstitiallungdisease,infectiousdiseaseliketuberculosis,alphaoneantitrypsin,etc.
GERDGastroesophagealrefluxdisease
• Asweeatfoodtheloweresophagealsphincter(LES)opensallowingeverythingtoenterthestomach
• AstheacidmixeswiththefoodtheLESmaybecomeirritated,thisiscallederosionoftheLES
• ErosionoftheLESallowsair,food,watertocomeupintotheesophagus.Mostoftensilently,soitisnotfeltorcausingpain
• ThevagalnerveinnervatestheLESandthenervesendssignalstoplugtheearsandthenose,causesneezing,tighteningofthethroat,hoarsevoice,chesttightness,bronchialspasm,evendroptheheartratecausingpassingout
SeverePersistentAsthma
• Differentiatepatientsintoonecategory:• TH2phenotype(THelpercelltype2)• LowTH2phenotype
• TH2phenotypearegenerallyresponsivetoinhaledcorticosteroids,mayhaveelevatedeosinophils,maybecandidatesforbiologics
• TH2lowindividuals• GenerallywillnotrespondtoInhaledCorticosteroids• Mayrespondtoantimuscarinicsandlongactingbetaagonists• Environmentalmeasures,socialissues,obesity,GERD,ChronicSinusitis• BronchialThermoplasty• Itisimportanttoevaluateimmunestatus
EvaluationofSeverePersistentAsthma
• Spirometry• NitrousOxide
• WhenelevateduseICS,possiblybiologics• IfnotelevatedICSmaynotbebeneficial,butatrialiswarranted
• ImmunoglobulinG,A,M,E• ElevatedIgE andatopyconsiderOmalizumab• LowIgGinvestigateforimmunedeficiency
• CBC/Differential• Eosinophils150cells/ul orgreaterconsideruseofbiologics
ImmuneDeficiency
• CVID:CommonVariableImmuneDeficiency• Bronchiectasis:notresponsivetoasthmamedication• ChronicSinusitis• IrritableBowelwithseverediarrhea• Anemia,lowplatelets
• Diagnosis:CBC/Diff,ImmunoglobulinsG,A,M,E,pneumococcaltiters• LowIgG,lowIgAorIgM,lowstreptococcuspneumoniaetiters.IflowthenvaccinatewithPneumovax #23andrepeatmeasurementoftitersin4weeks
Eosinophils
• Eosinophilicphenotypeoccursinatopicandnon-atopicindividuals• EosinophilicInflammationaffects40-60%ofpatientswithsevereasthma
• Eosinophilsreleasevariousproductsthatcandamagetheairway• Cytokines• Lipidmediators• Proteins• Oxidativeactivities
• Eosinophilscauseairwayhyper-responsiveness,excessmucoussecretionandcollagendeposition
Biologics
• Thefollowingslidesintroducethebiologicsandshowthecomplicatedpathwaysthatareinvolvedinasthmaandotherinflammatorydisorders
• Thecontrolofinflammationisthekeytomanagingasthma.Inflammationistheproblem,whetheritisinthejointsleadingtoarthritis,orinthelungsleadingtochronicscarringofthebronchioles
• Biologicsareusedtostopthediseaseprocessearlyon,thisminimizesalldamage
• Biologicsappeartobemuchmoreeffectiveincontrollingthediseaseascomparedtopharmacologics,likeinhalers
BiologicsForAsthmaandAllergicDisease
• Reslizumab:(Cinqair)Anti-interleukin-5:SevereAsthma• Mepolizumab:(Nucala)Anti-interleukin-5:SevereAsthma• Benralizumab:(launchdatein2017)Anti-interleukin-5,Apoptosisofeosinophil:SevereAsthma
• Dupilumab:(Dupixent)Anti-interleukin-4andinterleukin-13:AtopicDermatitis,studiesshowsomeasthmaaffect
• Omalizumab:(Xolair)Inusesince2003,Anti-IgE:Moderate-SevereAllergicAsthma,ChronicIdiopathicUrticariasince2016
BiologicsForSeverePersistentAsthma
• Omalizumab (Xolair):• SevereAllergicIgE mediatedasthma:IgG1fraction
• Anti-IgE monoclonalantibody,approvedforuseinallergicasthmaandChronicIdiopathicUrticaria
• IgE levelsbetween30and1,300IU/mlandshowallergybyskintestorbloodtest,6yearsofageandolder
• PreventsIgE frombindingtothehigh-affinityIgE receptor• BlockingfreeIgE willdisrupttheallergicsignalingcascadeandinflammation• Mayhaveefficacyinnon-atopicindividualsbydownregulatingthehigh-affinityIgE receptoronbasophilsanddendriticcells
• ChronicIdiopathicUrticaria,noatopyrequired,noIgE levelrequired
Biologics ForSeverePersistentAsthma
• Mepolizumab (Nucala):• SeverePersistentAsthma:IgG1fraction
• Eosinophils150orhigher:AntiIL-5monoclonalantibody• Reducesthefrequencyofasthmaexacerbations• Improveslungfunction• Increasescontrolofasthmainpatientswithsevereeosinophilicasthma• Decreaseseosinophilschemotaxis,maturation,survival• Subcutaneous100mginjectionmonthly• Wasstudiedinintravenousformaswell,butapprovedforsubcutaneous
BiologicsForSeverePersistentAsthma
• Reslizumab:(Cinqair)• SeverePersistentAsthma:IgG4fraction
• Eosinophils400orhigher:AntiIL-5monoclonalantibody• Reducedfrequencyofasthmaexacerbations• Improvedlungfunction• Increasedasthmacontrol• Positiveaffectonqualityoflife• Decreaseseosinophilschemotaxis,maturation,survival• Weightbased,10mg/kgmonthly,IV20minuteinfusion
BiologicsforSeverePersistentAsthma
• Benralizumab:• SeverePersistentAsthma:IgG1fraction
• FDAapprovalpending• Eosinophils200orhigher:AntiIL-5alphareceptor• InducesapoptosisincellsexpressingtheIL-5receptor• Reducesasthmaexacerbations• Glucocorticoid-sparingeffect• DecreasesEosinophilschemotaxis,maturation,survival,inadditionapoptosis• Subcutaneous100mginjectionevery2months
Asthma
• Determineiftheasthmaisintermittentorpersistent• Persistentasthmawillleadtopermanentlungdamage• Treatintermittentwithalbuterolasneeded• Treatpersistentasthmawithaninhaledsteroid• Determinelungfunctionwithspirometryandnitrousoxideandreevaluateeverymonthto3monthsto6monthsuntilstable
• Addresstriggerswhenpossible• Allasthmaticsshouldhaveprednisoneathomeaspartoftheirasthmaactionplan
SeverePersistentAsthma
• Measurementoflungfunctionwithspirometryandnitrousoxide• Aggressiveuseofinhaledmedications,includingdoublingortriplingthenormaldoseofthesingleinhaledcorticosteroid.Inhaledsteroidsarealwayssaferthanoralsteroids.
• Measurementofeosinophilsandanimmuneworkuptodetermineifabiologicmaybeofbenefitorifimmunodeficiencymaybetheproblem
• AddresscoexistingfactorssuchasGERD(gastroesophagealrefluxdisease),allergies,lifestyle,complianceandproperuseofmedications
AsthmaActionPlan
• Ifyouhavecoughing,wheezing,chesttightness– usealbuterol• Youmayusealbuterolinhalerornebulizeragainwithin20minutes• Mayrepeatalbuterolagainin20minutes• Ifalbuterolisneeded4timesina24hourperiodthenstartoralprednisone
• Onceyoureceiveprednisoneyoumayusealbuteroleveryhalfhourtoeveryhour,keepspreadingoutalbuterolasneeded
• Youmayneedprednisonetwiceadayfor3to6days• Contactyourmedicalprovidertoalertthemofyourasthmaexacerbation