What’sNewinAllergyandImmunology

SamuelGubernick,DO,FAAAAI,FACAAI,FAAP

Interpretation of Laboratory Tests

• Positive skin prick test or food-specific IgE• Indicates presence of IgE antibody and not clinical

allergy• ~90% sensitivity; ~50% specificity• ~50% asymptomatic sensitization• Larger skin tests or higher sIgE levels correlate with

increased likelihood of allergy but not the severity• Negative skin prick test or food-specific IgE

• Essentially excludes IgE antibody (>95% specific)

SampsonHA,etal.JACI2014;134(5):1016-25.SampsonandHo.JACI1997;100:444-51.SampsonHA,JACI2001;891-96..

Predictive value of food-specific IgE testing in positive and negative OFC

Food >95% Positive ~50% Negative

sIgE, kIU/L SPT, mm sIgE, kIU/L SPT, mm

Peanut >14 >8 <2, + prior rxn<5, no prior rnx

<3

Milk (<2 yr) >5 >8 <2

Milk >15 >8

Egg (<2 yr) >2 >7 <2 <3

Egg >7 >8

Fish >20 ? ? ?

SampsonHA,etal.JACI2014;134(5):1016-25.e43

Molecular Diagnosis of Food Allergy• Major allergens identified in many foods• For example birch cross-reactive allergens:

• Ara h 8 in peanut and Cor a 1 in hazelnut are associated with mild oral symptoms or no symptoms at all upon ingestion.

• Storage seed proteins: • Ara h 1, 2, 3 in peanut and Cor a 9 and 14 in

hazelnut are associated with systemic reactions.

Sicherer SH,WoodRA.JACIinPractice2013;1:1-13.SampsonHA,etal.JACI2014;134(5):1016-25.e43

Egg

Ovomucoid Gald1 Heat-stableandhighlyallergenicRiskforreactiontoallformsofeggHighlevelsindicatepersistentallergy

Ovalbumin Gald2 Heat-labileMostabundanteggwhiteproteinRiskforclinicalreactiontoraworslightlyheatedegg

Conalbumin Gald3 Heat-labileRiskforclinicalreactiontoraworslightlyheatedegg

Lysozyme Gald4 RiskforclinicalreactiontoraworslightlyheatedeggLysozymeisusedasanadditiveincertainpharmaceuticalproductsandfoods

Peanut

Storageproteins: Arah1Arah2Arah3

AssociatedwithseverereactionsStabletoheatanddigestion

PR-10protein: Arah8 Associatedwithlocalreactions(e.g.OAS)LabiletoheatanddigestionAssociatedwithallergytobirchandbirchrelatedtreepollens

LTP: Arah9 AssociatedwithbothsevereandlocalreactionsStabletoheatanddigestionAssociatedwithallergytopeachandpeachrelatedfruits

Milk

Alpha-lactoglobulin Bosd4 HeatlabileRiskforreactiontofreshmilkIgElevelsfallastolerancedevelops

Beta-lactoglobulin Bosd5 HeatlabileRiskforreactiontofreshmilkIgElevelsfallastolerancedevelops

Bovineserumalbumin

Bosd6 HeatlabileRiskforreactiontofreshmilkThemainallergeninbeef

Casein Bosd8 StabletoheatRiskforreactiontoallformsofmilkHighlevelsareconnectedwithpersistentmilkallergyIgElevelsfallastolerancedevelops

Bosdlactoferrin Bos dlactoferrin HeatlabileRiskforreactionstoallfreshmilk

RandomizedTrialofPeanutConsumptioninInfantsatRiskfor

PeanutAllergyGeorgeDuToit,M.B.,B.Ch.,GrahamRoberts,D.M.,PeterH.Sayre,M.D.,Ph.D.,HenryT.Bahnson,M.P.H.,Suzana Radulovic,M.D.,AlexandraF.Santos,M.D.,HelenA.Brough,M.B.,B.S.,DeborahPhippard,Ph.D.,MonicaBasting,M.A.,MaryFeeney,M.Sc.,R.D.,VictorTurcanu,M.D.,Ph.D.,MichelleL.Sever,M.S.P.H.,Ph.D.,MargaritaGomezLorenzo,M.D.,MarshallPlaut,M.D.,andGideonLack,M.B.,B.Ch.,for theLEAPStudyTeam*

NEJM 2015; 372:803-813 February 26, 2015

LearningEarlyAboutPeanutAllergy(LEAP)• Prevalenceofpeanutallergyhasdoubledinlast10yearsfrom1.4to3%.

• InIsrael,peanutcontainingfoodsaregiventoinfantsstartingabout7monthsofage.

• IntheUnitedKingdomchildrenarenotgivenpeanutcontainingfoodsduringtheirfirstyearoflife.

• Observationthattheprevalenceofpeanutallergywas10timeshigheramongJewishchildrenintheUKcomparedtoIsraelichildrenofsimilarancestry.

• PurposeofLEAPtrialwastodetermineifearlyintroductionofdietarypeanutcouldserveasaneffectiveprimaryandsecondarystrategyforthepreventionofpeanutallergy.

LEAPtrial

• 640infants4to11monthsoldwithsevereeczema,eggallergyorboth• Skinpricktesttopeanut• Excludedinfantswithlargepositiveskinpricktests• Participantswerestratifiedinto2cohortsbasedonSPT:

• Group1:Nomeasurablewhealaftertesting• Group2:Whealmeasuring1to4mmindiameter

• Groupswerethenrandomizedtoeitherconsumingoravoidingpeanuts• Peanutconsumptiongrouphadanopen-labelpeanutchallenge• Thosewhodidnotreactonoralchallengereceivedatleast6gofpeanutproteinperweek,distributedin3ormoremealsperweek,untiltheyreached60monthsofage.

• Evaluatedforpeanutallergyat60monthsofage

LEAPtrialdefinitions

• Severeeczemadefinedaspersistentorfrequentlyrecurringeczemacovering≥10%BSAwithtypicalmorphologyanddistributionasassessedbyahealthcareproviderandrequiringfrequentneedforprescription-strengthtopicalcorticosteroids,calcineurininhibitorsorotheranti-inflammatoryagentsdespiteappropriateuseofemollients.

• Eggallergyisdefinedasaskinpricktestwhealdiameterof3mmorgreaterwitheggwhiteextractinaninfantwithahistoryofanallergicreactiontoeggorwhohasfailedaneggoralfoodchallenge.

• FYI- 2000mgofpeanutproteinisabout9peanuts

LEAPtrialprimaryoutcome

• 530of542childreninthenegativeSPTgroupwereabletobeevaluated.Prevalenceofpeanutallergyatage5was13.7%intheavoidancegroupand1.9%intheconsumptiongroup.p<0.001,86.1%relativeriskreduction.

• All98childreninthegroupwith1-4mmwhealsontheinitialSPTwereevaluated.Prevalenceofpeanutallergyatage5was35.3%intheavoidancegroupand10.6%intheconsumptiongroup.p<0.004,70%relativeriskreduction.

LEAPConclusion

• Primarypreventiontargetspersonswhoarenotsensitizedtopeanutsandsecondarypreventiontargetsthosewhoaresensitized.

• Inthisstudy,theinterventionwaseffectiveinreducingtheprevalenceofpeanutallergyintermsofbothprimaryprevention(prevalenceof6.0%intheavoidancegroupvs.1.0%intheconsumptiongroup,P=0.008)andsecondaryprevention(33.1%vs.6.8%,P<0.001.

EffectofAvoidanceonPeanutAllergyafterEarlyPeanutConsumption

GeorgeDuToit,M.B.,B.Ch.,PeterH.Sayre,M.D.,Ph.D.,GrahamRoberts,D.M.,MichelleL.Sever,M.S.P.H.,Ph.D.,Kaitie Lawson,M.S.,HenryT.Bahnson,M.P.H.,HelenA.Brough,M.B.,B.S.,Ph.D.,AlexandraF.Santos,M.D.,Ph.D.,KristinaM.Harris,Ph.D.,Suzana Radulovic,M.D.,MonicaBasting,M.A.,VictorTurcanu,M.D.,Ph.D.,MarshallPlaut,M.D.,andGideonLack,M.B.,B.Ch.,for theImmuneToleranceNetworkLEAP-OnStudyTeam*

NEngl JMed2016;374:1435-1443April12,2016DOI:10.1056/NEJMoa1514209

LEAP-ON

• LEAP-ONevaluatedwhetherparticipantswhohadconsumedpeanutformorethanfouryearswereprotectedlong-termagainstpeanutallergywhentheystoppedeatingpeanut.

• Followed556oftheoriginal640childreninLEAP(bothconsumersandavoiders)foraone-yearperiodofpeanutavoidance.

• Thiscohortincluded274previouspeanutconsumersand282previouspeanutavoiders.

LEAP-ON

• After12monthsofpeanutavoidance,4.8%oftheoriginalpeanutconsumerswerefoundtobeallergic,comparedto18.6%oftheoriginalpeanutavoiders.

• LEAP-ONdemonstratesthatpeanutallergypreventionachievedfromearlypeanutconsumptioninat-riskinfantspersistsafteraone-yearperiodofavoidingpeanut.

AddendumGuideline11

AddendumGuideline2

• TheEPsuggeststhatinfantswithmildtomoderateeczemashouldhaveintroductionofage-appropriatepeanut-containingfoodasearlyas4-6monthsofage,inaccordancewithfamilypreferencesandculturalpractices,toreducetheriskofpeanutallergy.

• Peanutshouldnotbetheinitialsolidfoodintroducedintoaninfant’sdiet.Othersolidfoodshouldbetriedfirsttoshowtheinfantis developmentallyready.

• TheEPrecommendsthatinfantsinthiscategorymayhavedietarypeanutintroducedathomewithoutanin-officeevaluation.However,theEPrecognizesthatsomecaregiversandhealthcareprovidersmaydesireanin-officeevaluation,inwhichcasethedecisionpointsshowninFigure1shouldapply.

AddendumGuideline3:

• TheEPrecommendsthatinfantswithouteczemaoranyfoodallergyhaveage-appropriatepeanut-containingfoodsfreelyintroducedinthediet,togetherwithothersolidfoods,andinaccordancewithfamilypreferencesandculturalpractices.

•

TheGlobalBurdenofAsthma

• 334millionpeoplehaveasthma• Annualworldwidedeathsduetoasthmahavebeenestimatedat250,000

• 14%ofworld’schildrenexperienceasthmasymptoms• 8.6%ofyoungadults(18to45yearsofage)experienceasthmasymptoms

• 4.5%ofyoungadultshavebeendiagnosedwithasthmaand/oraretakingtreatmentforasthma

• Theburdenofasthmaisgreatestforchildren10to14yearsofageandtheelderly75to79yearsofage

• Asthmaisthe14th mostimportantdisorderintheworldintermsoftheextentanddurationofdisability

GINA

AsthmaDefinitionGINA2016

• “Asthmaisaheterogeneousdisease,usuallycharacterizedbychronicairwayinflammation.Itisdefinedbythehistoryofrespiratorysymptomssuchaswheeze,shortnessofbreath,chesttightnessandcoughthatvaryovertimeandinintensity,togetherwithvariableexpiratoryairflowlimitation.”

• Clinicaldefinitionthatdoesnottakeintoaccounttheclinicalpresentationortheindividualresponsetotreatment

Thenewparadigm

• Asthmaisaheterogeneousdiseasewithmultiplephenotypesthathavevariableriskfactorsandresponsestotreatment.

• Whilemild-to-moderateasthmausuallyrespondstotraditionalmedications,severeasthmaisoftenrefractorytoICSs,LABAs,andLRAs.

• Phenotypingofasthmapatientsnowpartofthediagnosticworkupofallpatientsnotrespondingtostandardtherapy.

• Biomarkershelpdefinethespecificpathophysiologyofdifferentasthmaphenotypesandidentifypotentialtherapeutictargets.

• Anunderstandingofpatientphenotypesandendotypes andthebiologicalsusedtotargetspecificclassesofasthmaallowsforpersonalizedcaretoasthmaticpatients.

Phenotype

• Phenotype isanorganism'sexpressedphysicaltraits.• Phenotype isdeterminedbyanindividual'sgenotypeandexpressedgenes,randomgeneticvariation,andenvironmentalinfluences.

• Examplesofanindividual's phenotype includetraitssuchascolor,height,size,shape,andbehavior.

• Phenotypesalsoincludeobservablecharacteristicsthatcanbemeasuredinthelaboratory,suchaslevelsofenzymes,hormones,bloodcells,andinflammatorymediators.

Endotypes

• Newapproachtoasthmaclassificationbasedonendotypesthatrepresentspecificcellularpatternsalongwithclinicalcharacteristicswithineachpatientsubgroup.

• Analysisofinducedsputumsamplesallowsfordeterminationofinflammatoryendotypesaccordingtogranulocyticcomposition- eosinophilic,neutrophilic,mixedgranulocytic,orpaucigranulocytic.

• Patientswithsevereadult-onsetasthmacanbedividedintoaneutrophilicinflammatoryphenotypeorhaveeosinophilicinflammationthatisunresponsivetohigh-dosesteroids.

T-helpertype2-driveninflammationdefinesmajorsubphenotypes ofasthma.

WoodruffPG,Modrek B,ChoyDF,AbbasAR,Koth LL,ArronJR,Fahy JV

AmJRespir Crit Care Med.2009Sep 1;180(5):388-95

• T2asthmamediatedbyIL-4,IL-5andIL-13.• HalfofpatientswithpersistentasthmahaveT2inflammation.• MicroarrayandPCFRanalysesofairwayepithelialbrushingsfrom42patientswithmild-to-moderateasthmaand28healthycontrols.

• ClassifiedsubjectswithasthmabasedonhighorlowexpressionofIL-13-induciblegenes.

• Analyzedcytokineexpressioninbronchialbiopsies,markersofinflammationandremodeling,andresponsivenesstoICSs.

• FEV1measuredatbaseline,after4and8 weeksofdailyfluticasone(500 mgtwicedaily),and1 weekafterthestoppingfluticasone.

• FEV1responsetoICSisgreaterinType2asthmaandlittle/noneoccursinType1asthma

BiomarkersinAsthma

• FeNO values,peripheralbloodeosinophilcounts,andperiostin levelsreflectaT2inflammatoryresponse.

• Obviousoverlapbetweentheseindividualbiomarkers.• Instudiestoevaluatemepolizumab andlebrikizumab,forexample,therewereincreasesinFeNO,eosinophilcountsandperiostin levels.

• ThesemarkershaveageneralabsenceofspecificityforcomponentsofT2inflammationandarenotpreciseindefiningwhichtreatmentchoicewillbemosteffective.

FeNO

• NitricoxideisgeneratedbyairwayepitheliumandisamarkerofT2inflammation.

• Fractionalexhalednitricoxide(FeNO)measuredduringexhalationcanaidthediagnosisandmonitoringofT2asthma,differentialdiagnosisofeosinophilicasthma,predictionofresponsivenesstoICStherapy,anddifferentiatingnonadherencefrompoorresponders.

• Approximately50%ofasthmaattributedtoeosinophilicinflammation.• ThistypeofasthmaissensitivetotreatmentwithcorticosteroidsandismoststronglyassociatedwithelevatedlevelsofNO.

• Incontrast,inflammationassociatedwithneutrophilsisrelativelyresistanttocorticosteroidsandisnotassociatedwithelevatedlevelsofNO.

FeNO

• FeNO hasmanyconfoundingfactors.• TobaccosmokedecreasesFeNO values.• FeNO generallyhigherininatopicdiseasewithorwithoutasthma.• ObesehavelowerFeNO,andweightlosscanincreaseFeNO.• DemographicvariationsinFeNO.• ChildrenhavelowerFeNO valuesthanadults.• Maleshave25%higherFeNO thanfemales.• TheuseofFeNO asabiomarkerinasthmaisstillbeingevaluated.

Periostin

• Periostin involvedinmanyaspectsofallergicinflammation,suchaseosinophilrecruitment,airwayremodeling,developmentofT2phenotype,andincreasedexpressionofinflammatorymediators.

• PeriostinisinducedbyIL-13,aT2cytokine.• Serumperiostin levelssignificantlyhigherinasthmaticpatientswithevidenceofeosinophilicairwayinflammationcomparedtothosewithminimaleosinophilicairwayinflammation.

• SubsetsofasthmaticpatientshaveincreasedIL-13levelsintheirairwaysandperiostin canbeusedtoanddefineT2phenotypes.

• Lebrikizumab,amAb againstIL-13demonstratedsignificantimprovementinFEV1inpatientswithincreasedperiostin levelsandminimalimprovementinthosewithlowperiostin levels.

AllergicAsthma

• Mostcommonphenotype• 45-88%ofasthmaticpatientsinrecentstudies• Youngerpatientsandonsetatearlieragethannon-allergic• Higherprevalenceinchildren,but60-75%prevalenceinelderlyintworecentstudies

• Definedbasedonsensitizationandclinicalcorrelation• Morecommoninmales• Familyhistoryofallergiescommon• Seasonalvariationmorecommonthannon-allergicasthma• Exercise-symptomsmorefrequent/severethannon-allergic

PersistentSevereAsthma> 6y/o

Asthmarequiringtreatmentwithhighdoseinhaledcorticosteroidsplusasecondcontrollerand/orsystemiccorticosteroidsforatleast50%ofthepreviousyeartopreventitfrombecominguncontrollableorasthmathatremainsuncontrollabledespitethistherapy.

Eur Resp J2014;43-343-73

EosinophilicAsthma

• Pathologicstudiesledtothedescriptionofsubgroupsofsevereasthmaticsbasedonthepresenceorabsenceofeosinophils.

• Majorityofsevereasthmaticshadelevatedairwayeosinophilsdespitechronicuseofhigh-doseoralsteroids.

• Farfewerpatientswhodevelopedasthmaearlyinlifedemonstratedtissueeosinophilia,ascomparedwiththosewithlate-onsetasthma(36%versus63%)

• Inducedsputumeosinophilsarehigherinpatientswithmoresevereairflowobstructionandmethacholinereactivity.

SevereEosinophilicasthma

• Associatedwithincreasedseverity,lowerlungfunction,poorasthmacontrol,late-onsetdisease,exacerbationsinICSandsteroidrefractoriness.

• Oftenassociatedwithsinusitis,nasalpolypsandsometimesAERD,• Oftenlackofclinicalallergydespitepositiveskintestsin~75%.• “Fixed”airflowobstruction,reducedFVCandincreasedRV.• Inducedsputumcellcount(1%to3%invariousstudies)isthegoldstandardforidentifyingeosinophilicinflammation.

• Severalnoninvasivebiomarkers,includingperipheralbloodeosinophils,FeNO,andperiostin,arepotentialsurrogates.

• Normalizationofinducedsputumeosinophilcountsisaneffectivestrategyforpreventingsevereasthmaexacerbationsandhospitalizations.

Diagnosticevaluationofeosinophilicasthma–Peripheralbloodeosinophils

• Peripheralbloodeosinophilcountsareeasilyobtainedandwidelyavailable,butlackbothspecificityandsensitivity.

• Inasthmaticswithperipheraleosinophilia,thereisasuggestedcorrelationwithseverityofasthmasymptomsandaninversecorrelationinpulmonaryfunctionasmeasuredbyFEV1.

• HastieevaluatedmultiplevariablesincludingFeNO,FEV1,lIgE,andbloodeosinophilcountsinpredictingasthmaphenotype.• Peripheralbloodeosinophils>300/μL hadapoorpositivepredictivevalueinidentifyinganeosinophilicasthmaphenotypebasedonsputumeosinophilsof>2%.

• Peripheralbloodeosinophiliamaybeamarkerofdiseaseseverityinasthma,butdoesnotcorrelateconsistentlywithsputumeosinophilia.

HastieATetal.JACI,2013Jul;132(1):72-80

Diagnosticevaluationofeosinophilicasthma-IgE

• EosinophilicasthmacanbeassociatedwithT2-mediatedallergicdiseaseandallergensensitization,especiallyinearlieronsetdisease.

• LackofcorrelationbetweentotalIgE levelsandthepresenceofeosinophilsinBALfluidorbiopsyspecimens.

• TotalIgE haslittleutilityinevaluationofmostpatientswithasthma.

Diagnosticevaluationofeosinophilicasthma• Usingalogisticregressionmodelincludingage,sex,bodymassindex,IgE levels,bloodeosinophils,FeNO levels,andserumperiostin levelsin59patientswithsevereasthma,Jiaetalfoundserumperiostin wasthebestpredictorofairwayeosinophilia.

• Aserumperiostin level>25ng/mLhadapositivepredictivevalueof93%andanegativepredictivevalueof37%forsputumeosinophils(>3%)ortissueeosinophilia.

Jia Getal.JACI, 2012Sep;130(3):647-654.

Omalizumab

• RecombinantChinesehamsterovarycell-derivedhumanizedIgG1kmonoclonalantibody.

• BindscirculatingIgEregardlessofIgE specificity.

• PreventsbindingofIgEtoFceRI,thehighaffinityIgEreceptoronmastcellsandbasophils.

• Doesnotbindcell-boundIgEandthereforeshouldnotactivatemastcellsorbasophils.

• GivenSQ,dosebyweight,every2or4weeks

Omalizumab

• Efficacyinmoderate-severeasthma• Reductioninsymptomscores• Reductioninrescuealbuterol• Reductioninoralcorticosteroidbursts• Reductionin#exacerbations• ImprovedAMPEFR

AppropriateCandidatesforAnti-IgE Therapy

• Adultsandadolescents6yearsandabove• Moderatetosevereasthma• PositiveskintestorsIgE toaperennialaeroallergen• IgEbetween30-700IU/mL• Symptomsareinadequatelycontrolledwithinhaledcorticosteroids

Pre-treatmentSerumIgE

BodyWeight

30−60kg >60−70kg >70−90kg >90−150kg ≥30−100IU/mL 150mg 150mg 150mg 300mg

>100−200IU/mL 300mg 300mg 300mg

>200−300IU/mL 300mg

>300−400IU/mL SEETABLE2

>400−500IU/mL

>500−600IU/mL

Table 1. Subcutaneous Omalizumab Dosing Every 4 Weeks for Patients 12 Years of Age and Older with Asthma

Pre-treatmentSerumIgE

BodyWeight

30−60kg >60−70kg >70−90kg >90−150kg

≥30−100IU/mL SEETABLE1

>100−200IU/mL 225mg

>200−300IU/mL 225mg 225mg 300mg

>300−400IU/mL 225mg 225mg 300mg

>400−500IU/mL 300mg 300mg 375mg

>500−600IU/mL 300mg 375mg

>600−700IU/mL 375mg DONOTDOSE

Table 2. Subcutaneous Omalizumab Dosing Every 2 Weeks for Patients 12 Years of Age and Older with Asthma

Warnings

• Anaphylaxisestimatedtobe0.1%andatleast0.2%.• AnaphylaxisoccurredwiththefirstdoseofXOLAIRin2patientsandwiththefourthdosein1patient.

• Thetimetoonsetofanaphylaxiswas90minutesafteradministrationin2patientsand2hoursafteradministrationin1patient.

• Malignantneoplasmswereobservedin20of4127(0.5%)XOLAIR-treatedpatientscomparedwith5of2236(0.2%)controlpatientsininitialstudies.

• Asubsequent5-yearobservationalstudyof5007XOLAIR-treatedand2829non- XOLAIR-treatedadolescentandadultpatientsfoundthattheincidenceratesofprimarymalignancies(per1000patientyears)weresimilarinbothgroups(12.3vs13.0).

XolairAdversereactions

• Inpatients≥12yearsofage,themostcommonlyobservedadversereactionswere:arthralgia(8%),pain(general)(7%),legpain(4%),fatigue(3%),dizziness(3%),fracture(2%),armpain(2%),pruritus(2%),dermatitis(2%),andearache(2%).

• Inpediatricpatients6to<12yearsofage,themostcommonlyobservedadversereactionswere:nasopharyngitis,headache,fever,upperabdominalpain,streptococcalpharyngitis,otitismedia,viralgastroenteritis,arthropodbite,andepistaxis.

IL-5

• Recruitment,granulematuration,andsurvivalofeosinophilsintheairwaysarepromotedbyIL-3,GM-CSF,andespeciallyIL-5.

• IL-5isproducedbyCD4+Th2cells,mastcells,eosinophils,andbasophils.

• MainbiologicalroleofIL-5istocontrolproliferation,differentiation,andactivationofeosinophils.

• ItalsostimulatesthefinaldifferentiationofactivatedBcellsintoantibody-formingcells.

• RepresentafunctionallinkbetweenT-cellactivationandinflammatoryresponsesmediatedbyeosinophils.

EosinophilFunctions

• Antiparasitic - especiallyagainsthelminthsinthelarvalstage• Antiviral• Antibacterial- actsasAPC,generationofcytokinesandchemokinesandphagocytosisofintracellularbacteriasuchasmycobacterium

• Eosinophilscanbeefficientinhostdefenseagainstgram-negativebacteriaandoxygen-dependentkilling,i.e.,superoxideactinginconjunctionwithEPO,maybethemostimportantbactericidaleffectorfunctionofthesecells.Importantatmucosalinterfacesandinthemucosaof,forexample,thelargeintestine,wheretheconditionsareaerobic.

• Staphaureus,E.coli,Pseudomonas

Mepolizumab

• Mepolizumabwasthefirstanti-IL-5moleculedesignedandtestedinforeosinophilicasthma.

• Nucala (mepolizumab)isahumanizedIgG1kappamonoclonalantibodywhichbindstosolubleinterleukin-5(IL-5),preventingitsbindingtothealphachainoftheIL-5receptorcomplexexpressedontheeosinophilcellsurface.

Mepolizumab

• Indication:• Asadd-onmaintenancetreatmentofadultpatientswithsevereeosinophilicasthmawhoareinadequatelycontrolledwithhigh-doseinhaledcorticosteroidsandanadditionalasthmacontroller,andhaveabloodeosinophilcountof≥150cells/μL atinitiationoftreatmentwithmepolizumab OR≥300cells/μL inthepast12months.

• Dosage:• Afixeddoseof100mgmepolizumab (Nucala™)bysubcutaneousinjectionevery4weeks.

MepolizumabTreatmentinPatientswithSevereEosinophilicAsthma

HectorG.Ortega,M.D.,Sc.D.,MarkC.Liu,M.D.,IanD.Pavord,D.M.,GuyG.Brusselle,M.D.,J.MarkFitzGerald,M.D.,AlfredoChetta,M.D.,MarcHumbert,M.D.,Ph.D.,LynnE.Katz,Pharm.D.,OliverN.Keene,M.Sc.,StevenW.Yancey,M.Sc.,andPascalChanez,M.D.,Ph.D.,for theMENSAInvestigators*

NEngl JMed2014;371:1198-1207

ClinicalTrials:ExacerbationStudy(MENSA)

• A32-week,multicenter,randomized,DBPCparallel-groupstudyevaluatingtheefficacyandsafetyofmepolizumab100 mgSCandmepolizumab 75mgIVvsplacebointheadd-ontreatmentofsevereeosinophilicasthma(N=576).

• Primaryendpoint:• Annualizedfrequencyofclinicallysignificantexacerbations.

• Secondary endpoints:• AnnualizedfrequencyofexacerbationsrequiringhospitalizationorERvisit

• Changefrombaselineinlungfunctionatweek32.• Changefrombaselineinhealth-relatedQOLatweek32.

MENSA

• Inclusioncriteria:• Historyof≥2asthmaexacerbationsinthepastyear• Peripheralbloodeosinophils≥150cells/µLwithin6weeksoffirstdose,or≥300 cells/µLwithinpastyear

• Regularuseofhigh-doseICSplusanadditionalcontrollerwithorwithoutOCS

• Backgroundtherapy:• Allpatientsreceivedmaintenancetherapypriortoandduringthestudy,whichconsistedofhigh-doseICSplusadditionalcontroller(s),withorwithoutOCS

Results

• Efficacyresults: Exacerbations• Mepolizumab100mgSCsignificantlyreducedthefrequencyofclinicallysignificantexacerbationsvs.placebo.

• Mepolizumab100mgSCalsosignificantlyreducedthefrequencyofclinicallysignificantexacerbationsrequiringhospitalizationsand/orERvisitsby61% vs.placebo.

• Themeanchangefrombaselineinpre-bronchodilatorFEV1was183mLwithmepolizumab vs.86mLwithplaceboatweek32.

• Resultsfromclusteranalysis• Largermepolizumab treatmentresponseinclusterswithbloodeosinophillevelsof150cells/μl orgreater,withthelargesttreatmentresponseseeninobesepatientswithmorecomorbiditiesandairwayreversibility.

ClusterAnalysisandCharacterizationofResponsetoMepolizumab.AStepClosertoPersonalizedMedicineforPatientswithSevereAsthma

HectorOrtega,Hao Li,RobertSuruki,FrankAlbers,DavidGordonandStevenYancey

AnnAmThorac Soc Vol 11,No7,pp 1011–1017,Sep 2014

• ExamineddatasetfromtheDoseRangingEfficacyAndsafetywithMepolizumab(DREAM)studywiththespecificobjectiveofidentifyingclustersofdataassociatedwithexacerbationratesasobtainedbymepolizumab treatment.

• Baselinecovariatesconsideredforinclusionwereregion,sex,age,weight,numberofexacerbationsintheyearbeforethestudy,useofmaintenanceoralcorticosteroids,percentpredictedFEV1,airwayreversibility,bloodeosinophilcount,andIgE levels.

• Higherlevelsofbloodeosinophilsandgreaternumberofpreviousexacerbationsatbaselineledtogreaterreductioninexacerbationswithmepolizumab.

• Forthemajorityofpatientswithelevatedeosinophils,bloodeosinophilcountisthebiomarkerofchoiceforpredictingtreatmentoutcomewithmepolizumab insevereasthma.

• Therewasalargermepolizumab treatmentresponseinclusterswithbloodeosinophillevelsof150cells/μl orgreater,withthelargesttreatmentresponseseeninobesepatientswithmorecomorbiditiesandairwayreversibility.

Oralglucocorticoid-sparingeffectofmepolizumab ineosinophilicasthma

BelEH,WenzelSE,ThompsonPJ,Prazma CM,KeeneON,YanceySW,OrtegaHG,Pavord ID;SIRIUSInvestigators.

NEngl JMed.2014Sep 25;371(13):1189-97

ClinicalTrials:OralCorticosteroidReductionStudy(SIRIUS)

• A24-week,multicenter,randomized,DBPCparallel-groupstudythatevaluatedtheefficacyandsafetyofmepolizumab vs.placeboonreducingtherequirementformaintenanceoralcorticosteroids,whilemaintainingasthmacontrol,inpatientswithsevereeosinophilicasthma(N=135).

• PrimaryEndpoint• PercentreductionofOCSdoseoverWeeks20-24comparedwiththedoseofOCSestablishedduringtherun-in/optimizationphase.

SIRIUS

• Selectinclusioncriteria:• Peripheralbloodeosinophil≥150cells/uL inthe6weekspriortofirstdose,or≥300cells/uL intheprevious12months

• Regularuseofhigh-doseICSplusadditionalcontroller(s)• RegularmaintenancetreatmentwithOCS

• Backgroundtherapy:• Priortothestudy,patientswereonhigh-doseICSplusanadditionalcontroller(s)withOCS(5-35mg/dayprednisoneorequivalent)

• Duringa3- to8-weekrun-inphase,theOCSdosewasadjustedweeklytoestablishthelowestpossibleOCSdoserequiredtomaintainasthmacontrol.

• Afterrandomization,theOCSdosewasreducedevery4 weeksbetweenWeeks4-20untilzero,orthelowestdoserequiredtomaintainasthmacontrol.NofurtherOCSdoseadjustmentsweremadeafterWeek20.

AtWeek20-24(secondaryendpoints):

• 54%(37/69)ofmepolizumab patientsachieveda ≥50%reductioninthedailyOCSdose vs.33%(22/66)onplacebo.

• 54%(37/69)ofmepolizumab patientsachieveda reductioninthedailyOCSdoseto≤5mg vs.32%(21/66)onplacebo.

• 14% (10/69)ofpatientsonmepolizumab 100 mgSCachieveda total(100%)reduction indailyOCSdoseto0mgvs.8%(5/66)onplacebo.

Mepolizumab AdverseReactions

• Headache,pharyngitis,lowerrespiratorytractinfection,urinarytractinfection,nasalcongestion,upperabdominalpain,eczema,backpain,pyrexiaandinjectionsitereactions

• Acuteanddelayedsystemicreactions,includinghypersensitivityreactions

• Parasiticinfections• HerpesZoster- considervaricellavaccination

Reslizumab

• Reslizumab (Cinqair)isaninterleukin-5antagonistmonoclonalantibody(IgG4kappa)indicatedforadd-onmaintenancetreatmentofpatientswithsevereasthmaaged18yearsandolder,andwithaneosinophilicphenotype.

• Reslizumab bindstoIL-5inhibitingthebioactivityofIL-5byblockingitsbindingtothealphachainoftheIL-5receptorcomplexexpressedontheeosinophilsurface.

ReslizumabDosing

• Reslizumab (CINQAIR)isforintravenousinfusiononly.

• Reslizumab (CINQAIR)shouldbeadministeredinahealthcaresettingbyahealthcareprofessionalpreparedtomanageanaphylaxis

• Recommendeddosageregimenis3mg/kgevery4weeksbyIVinfusionover20-50minutes

ReslizumabforInadequatelyControlledAsthmaWithElevatedBloodEosinophilLevels :A

RandomizedPhase3Study

LeifBjermer,CatherineLemiere,JorgeMaspero,SivanWeiss,JamesZangrilli,MatthewGerminaro

ChestVolume150,Issue4,October2016,Pages789–798

Rezlizumab

• Patientsaged12to75yearswithasthmainadequatelycontrolledbyatleastamedium-doseICSandwithabloodeosinophilcount> 400.

• Of1,025screenedpatients,315wererandomlyassignedtotreatmentand265completedthestudy.

• Randomizedtoreceivereslizumab 0.3mg/kgor3.0mg/kgorplaceboadministeredonceevery4weeksfor16weeks.

• Primaryendpointwaschangefrombaselineinpre-bronchodilatorFEV1over16weeks.

• SecondaryendpointsincludedFVC,FEF25%-75%,patient-reportedcontrolofasthmasymptoms,SABAuse,bloodeosinophillevels,andsafety.

• ReslizumabsignificantlyimprovedFEV1inthetreatmentgroups.115mlinthe0.3mg/kggroupand160mlinthe3.0mg/kggroup.

• IncreasesinFVC(130mL)andFEF25%-75%(233mL/s)wereobservedwithreslizumab 3.0mg/kg.

• ReslizumabimprovedscoresontheAsthmaControlQuestionnaire(ACQ)andAsthmaQualityofLifeQuestionnaire(AQLQ)vsplacebo.

• SABAusedecreasedwithreslizumab.• 3.0-mg/kgdoseofreslizumab providedgreaterimprovementsinasthmaoutcomesvsthe0.3-mg/kgdose,withcomparablesafety.

• Mostcommonadverseeventswereworseningofasthma,headache,andnasopharyngitis.

Reslizumabforinadequatelycontrolledasthmawithelevatedbloodeosinophilcounts: resultsfromtwomulticentre,parallel,double-blind,randomised,

placebo-controlled,phase3trials.

MarioCastro,JamesZangrill,MichaelWechsler,EricDBateman,GuyGBrusselle,PhilipBarden,KevinMurphy,JorgeFMaspero,ChristopherO’Brien,StephanieKorn

LancetRespir Med, 2015May;3(5):355-66

Reslizumab

• Of2597patientsscreened,953wererandomlyassignedtoreceiveeitherreslizumab (n=477orplacebo(n=476).

• Inbothstudies,patientsreceivingreslizumab hadasignificantreductioninthefrequencyofasthmaexacerbations.

• Study1:rateratio[RR]0·50[95%CI0·37-0·67]• Study2:0·41[0·28-0·59]• Bothp<0·0001)comparedtoplacebogroup.

• Commonadverseeventsonreslizumab weresimilartoplacebo.• Themostcommonadverseeventswereworseningasthmasymptoms,URIs,andnasopharyngitis.

• Twopatientsinthereslizumab grouphadanaphylacticreactions.Bothrespondedtostandardtreatment.

Reslizumab (Cinqair)

• Anaphylaxishasbeenobservedin0.3%ofpatientsinplacebo-controlledclinicalstudies.

• Anaphylaxiswasreportedasearlyastheseconddose.• Inplacebo-controlledclinicalstudies,6/1028(0.6%)patientsreceiving3mg/kgCINQAIRhadatleast1malignantneoplasmreportedcomparedto2/730(0.3%)patientsintheplacebogroup.

• Eosinophilsmaybeinvolvedintheimmunologicalresponsetosomeparasitic(helminth)infections.Treatpatientswithpre-existinghelminthinfectionsbeforeinitiatingCINQAIR.IfpatientsbecomeinfectedwhilereceivingtreatmentwithCINQAIRanddonotrespondtoanti-helminthtreatment,discontinuetreatmentwithCINQAIRuntilinfectionresolves.

CPKelevationsandmuscle-relatedadversereactions• ElevatedbaselineCPKwasmorefrequentinpatientsrandomizedtoCINQAIR(14%)versusplacebo(9%).

• TransientCPKelevationsinpatientswithnormalbaselineCPKvalueswereobservedmorefrequentlywithCINQAIR(20%)versusplacebo(18%).

• CPKelevations>10xULNwere0.8%intheCINQAIRgroupcomparedto0.4%intheplacebogroup.

• CPKelevations>10xULNwereasymptomaticanddidnotleadtotreatmentdiscontinuation.

• Myalgiawasreportedin1%(10/1028)ofpatientsintheCINQAIR3mg/kggroupcomparedto0.5%(4/730)ofpatientsintheplacebogroup.

• Onthedayofinfusion,musculoskeletaladversereactionswerereportedin2.2%and1.5%ofpatientstreatedwithCINQAIR3mg/kgandplacebo,respectively.

• Thesereactionsincluded(butwerenotlimitedto)musculoskeletalchestpain,neckpain,musclespasms,extremitypain,musclefatigue,andmusculoskeletalpain.

•