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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

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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