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ICAR: Allergic Rhinitis 1 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis 1 2 3 Authors: 4 AUTHOR SPECIALTY AFFILIATION COUNTRY 1 Sarah K. Wise, MD, MSCR Otolaryngology Emory University USA 2 Sandra Y. Lin, MD Otolaryngology Johns Hopkins University USA 3 Elina Toskala, MD, PhD, MBA Otolaryngology Temple University USA 4 Richard R. Orlandi, MD Otolaryngology University of Utah USA 5 Cezmi A. Akdis, MD Allergy/Asthma Swiss Institute of Allergy and Asthma Research Switzerland 6 Jeremiah A. Alt, MD, PhD Otolaryngology University of Utah USA 7 Antoine Azar, MD Allergy/Immunology Johns Hopkins University USA 8 Fuad M. Baroody, MD Otolaryngology University of Chicago USA 9 Claus Bachert, MD, PhD Otolaryngology University of Ghent Belgium 10 G. Walter Canonica, MD Respiratory Diseases Humanitas University Italy 11 Thomas Chacko, MD Allergy/Immunology Private Practice USA 12 Cemal Cingi, MD Otolaryngology Eskisehir Osmangazi University Turkey 13 Giorgio Ciprandi, MD Allergy/Immunology Ospedale Policlinico San Martino Italy 14 Jacquelynne Corey, MD Otolaryngology University of Chicago USA 15 Linda S. Cox, MD Allergy/Immunology Private Practice USA 16 Peter Socrates Creticos, MD Allergy/Immunology Johns Hopkins University USA 17 Adnan Custovic, MSc, DM, MD, PhD Pediatric Allergy Imperial College London UK 18 Cecelia Damask, DO Otolaryngology Private Practice USA 19 Adam DeConde, MD Otolaryngology University of California San Diego USA 20 John M. DelGaudio, MD Otolaryngology Emory University USA 21 Charles S. Ebert, Jr. MD, MPH Otolaryngology University of North Carolina USA 22 Jean Anderson Eloy, MD Otolaryngology Rutgers New Jersey Medical School USA 23 Carrie E. Flanagan, MD Otolaryngology Emory University USA 24 Wytske J. Fokkens, MD, PhD Otolaryngology University of Amsterdam Netherlands 25 Christine Franzese, MD Otolaryngology University of Missouri USA 26 Jan Gosepath, MD, PhD Otorhinolaryngology Helios Kliniken Wiesbaden Germany 27 Ashleigh Halderman, MD Otolaryngology University of Texas Southwestern USA 28 Robert G. Hamilton, PhD Allergy/Immunology Johns Hopkins University USA 29 Hans Jürgen Hoffman, PhD Respiratory Diseases University of Aarhus Denmark 30 Jens M. Hohlfeld, MD Respiratory Medicine Hannover Medical School, Airway Research Fraunhofer Institute for Toxicology and Experimental Medicine, German Center for Lung Research Germany 31 Steven M. Houser, MD Otolaryngology Case Western Reserve University USA 32 Peter H. Hwang, MD Otolaryngology Stanford University USA 33 Cristoforo Incorvaia, MD Allergy/Immunology ASST Pini/CTO Milan Italy 34 Prof. Deborah Jarvis Public Health Imperial College London UK 35 Ayesha N. Khalid, MD, MBA Otolaryngology Harvard Medical School USA 36 Maritta Kilpeläinen, MD, PhD Pulmonary/Allergy Turku University Hospital Finland 37 Todd. T. Kingdom, MD Otolaryngology University of Colorado USA 38 Helene Krouse, PhD, ANP-BC Nursing University of Texas Rio Grande Valley USA 39 Desiree Larenas-Linnemann, MD Pediatric Allergy Hospital Medica Sur Mexico 40 Adrienne M. Laury, MD Otolaryngology San Antonio Military Medical Center USA 41 Stella E. Lee, MD Otolaryngology University of Pittsburgh USA 42 Joshua M. Levy, MD, MPH Otolaryngology Emory University USA 43 Amber U. Luong, MD, PhD Otolaryngology McGovern Medical School at the University of Texas Health Science Center Houston USA

ICAR: Allergic Rhinitis 1...2017/11/28  · 31 Steven M. Houser, MD Otolaryngology Case Western Reserve University USA 32 Peter H. Hwang, MD Otolaryngology Stanford University USA

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Page 1: ICAR: Allergic Rhinitis 1...2017/11/28  · 31 Steven M. Houser, MD Otolaryngology Case Western Reserve University USA 32 Peter H. Hwang, MD Otolaryngology Stanford University USA

ICAR:AllergicRhinitis 1

InternationalConsensusStatementonAllergyandRhinology:AllergicRhinitis123

Authors:4 AUTHOR SPECIALTY AFFILIATION COUNTRY1 SarahK.Wise,MD,MSCR Otolaryngology EmoryUniversity USA2 SandraY.Lin,MD Otolaryngology JohnsHopkinsUniversity USA3 ElinaToskala,MD,PhD,MBA Otolaryngology TempleUniversity USA4 RichardR.Orlandi,MD Otolaryngology UniversityofUtah USA5 CezmiA.Akdis,MD Allergy/Asthma SwissInstituteofAllergyandAsthma

ResearchSwitzerland

6 JeremiahA.Alt,MD,PhD Otolaryngology UniversityofUtah USA7 AntoineAzar,MD Allergy/Immunology JohnsHopkinsUniversity USA8 FuadM.Baroody,MD Otolaryngology UniversityofChicago USA9 ClausBachert,MD,PhD Otolaryngology UniversityofGhent Belgium10 G.WalterCanonica,MD RespiratoryDiseases HumanitasUniversity Italy11 ThomasChacko,MD Allergy/Immunology PrivatePractice USA12 CemalCingi,MD Otolaryngology EskisehirOsmangaziUniversity Turkey13 GiorgioCiprandi,MD Allergy/Immunology OspedalePoliclinicoSanMartino Italy14 JacquelynneCorey,MD Otolaryngology UniversityofChicago USA15 LindaS.Cox,MD Allergy/Immunology PrivatePractice USA16 PeterSocratesCreticos,MD Allergy/Immunology JohnsHopkinsUniversity USA17 AdnanCustovic,MSc,DM,MD,PhD PediatricAllergy ImperialCollegeLondon UK18 CeceliaDamask,DO Otolaryngology PrivatePractice USA19 AdamDeConde,MD Otolaryngology UniversityofCaliforniaSanDiego USA20 JohnM.DelGaudio,MD Otolaryngology EmoryUniversity USA21 CharlesS.Ebert,Jr.MD,MPH Otolaryngology UniversityofNorthCarolina USA22 JeanAndersonEloy,MD Otolaryngology RutgersNewJerseyMedicalSchool USA23 CarrieE.Flanagan,MD Otolaryngology EmoryUniversity USA24 WytskeJ.Fokkens,MD,PhD Otolaryngology UniversityofAmsterdam Netherlands25 ChristineFranzese,MD Otolaryngology UniversityofMissouri USA26 JanGosepath,MD,PhD Otorhinolaryngology HeliosKlinikenWiesbaden Germany27 AshleighHalderman,MD Otolaryngology UniversityofTexasSouthwestern USA28 RobertG.Hamilton,PhD Allergy/Immunology JohnsHopkinsUniversity USA29 HansJürgenHoffman,PhD RespiratoryDiseases UniversityofAarhus Denmark30 JensM.Hohlfeld,MD Respiratory

MedicineHannoverMedicalSchool,AirwayResearchFraunhoferInstituteforToxicologyandExperimentalMedicine,GermanCenterforLungResearch

Germany

31 StevenM.Houser,MD Otolaryngology CaseWesternReserveUniversity USA32 PeterH.Hwang,MD Otolaryngology StanfordUniversity USA33 CristoforoIncorvaia,MD Allergy/Immunology ASSTPini/CTOMilan Italy34 Prof.DeborahJarvis PublicHealth ImperialCollegeLondon UK35 AyeshaN.Khalid,MD,MBA Otolaryngology HarvardMedicalSchool USA36 MarittaKilpeläinen,MD,PhD Pulmonary/Allergy TurkuUniversityHospital Finland37 Todd.T.Kingdom,MD Otolaryngology UniversityofColorado USA38 HeleneKrouse,PhD,ANP-BC Nursing UniversityofTexasRioGrandeValley USA39 DesireeLarenas-Linnemann,MD PediatricAllergy HospitalMedicaSur Mexico40 AdrienneM.Laury,MD Otolaryngology SanAntonioMilitaryMedicalCenter USA41 StellaE.Lee,MD Otolaryngology UniversityofPittsburgh USA42 JoshuaM.Levy,MD,MPH Otolaryngology EmoryUniversity USA43 AmberU.Luong,MD,PhD Otolaryngology McGovernMedicalSchoolatthe

UniversityofTexasHealthScienceCenterHouston

USA

Page 2: ICAR: Allergic Rhinitis 1...2017/11/28  · 31 Steven M. Houser, MD Otolaryngology Case Western Reserve University USA 32 Peter H. Hwang, MD Otolaryngology Stanford University USA

ICAR:AllergicRhinitis 2

44 BradleyF.Marple,MD Otolaryngology UniversityofTexasSouthwestern USA

45 EdwardD.McCoul,MD,MPH Otolaryngology OchsnerClinicFoundation USA46 K.ChristopherMcMains,MD Otolaryngology UniformedServicesUniversityofHealth

SciencesUSA

47 ErikMelén,MD,PhD PediatricAllergy KarolinskaInstitutet Sweden48 JamesW.Mims,MD Otolaryngology WakeForestUniversity USA49 GiannaMoscato,MD Allergy/Immunology UniversityofPavia Italy50 JoaquimMullol,MD,PhD Otolaryngology UniversitatdeBarcelona;HospitalClinic,

IDIBAPSSpain

51 HaroldS.Nelson,MD Allergy/Immunology NationalJewishHealth USA52 MonicaPatadia,MD Otolaryngology LoyolaUniversity USA53 RubyPawankar,MD,PhD Pediatrics NipponMedicalSchool Japan54 OliverPfaar,MD Rhinology/Allergy MedicalFacultyMannheim,Heidelberg

University,CenterforRhinologyandAllergologyWeisbaden

Germany

55 MichaelP.Platt,MD,MSc Otolaryngology BostonUniversity USA56 WilliamReisacher,MD Otolaryngology WeillCornellMedicalCollege USA57 CarmenRondón,MD,PhD Allergy RegionalUniversityHospitalofMálaga Spain58 LukeRudmik,MD,MSc Otolaryngology UniversityofCalgary Canada59 MatthewRyan,MD Otolaryngology UniversityofTexasSouthwestern USA60 JoaquinSastre,MD,PhD Allergology HospitalUniversitarioFundacionJiminez

DiazSpain

61 RodneyJ.Schlosser,MD Otolaryngology MedicalUniversityofSouthCarolina USA62 RussellA.Settipane,MD Allergy/Immunology AlpertMedicalSchoolofBrownUniversity USA63 HemantP.Sharma,MD,MHS Allergy/Immunology Children’sNationalHealthSystem,

GeorgeWashingtonUniversitySchoolofMedicine

USA

64 AzizSheikh,OBE,BSc,MSc,MD Allergy/Asthma UniversityofEdinburgh UK65 TimothyL.Smith,MD,MPH Otolaryngology OregonHealthandScienceUniversity USA66 PongsakornTantilipikorn,MD,PhD Rhinology/Allergy MahidolUniversity Thailand67 JodyR.Tversky,MD Allergy/Immunology JohnsHopkinsUniversity USA68 MariaC.Veling,MD Otolaryngology UniversityofTexasSouthwestern USA69 DeYunWang,MD,PhD Otolaryngology NationalUniversityofSingapore Singapore70 MaritWestman,MD,PhD Otolaryngology KarolinskaInstitutet Sweden71 MagnusWickman,MD,PhD Environmental

MedicineKarolinskaInstitutet Sweden

72 MarkZacharek,MD Otolaryngology UniversityofMichigan USA

12ContributingAuthors:3 AUTHOR SPECIALTY AFFILIATION COUNTRY1 AnandAndiappan,PhD Immunology AgencyforScience,Technologyand

ResearchSingapore

2 PhilippBadorrek,MD RespiratoryMedicine FraunhoferInstituteforToxicologyandExperimentalMedicine

Germany

3 ChristopherD.Brook,MD Otolaryngology BostonUniversity USA4 PalomaCampo,MD,PhD Allergy RegionalUniversityHospitalofMálaga Spain5 MohamadR.Chaaban,MD,MSCR,

MBAOtolaryngology UniversityofTexasMedicalBranch USA

6 AnnaCharles-Jones,MD Medicine UniversityofOtago NewZealand7 EstherCheng,MD Otolaryngology LoyolaUniversity USA8 NipunChhabra,MD Otolaryngology CaseWesternReserveUniversity USA9 DanielCox,MD Otolaryngology UniversityofUtah USA10 PedramDaraei,MD Otolaryngology EmoryUniversity USA

Deleted: ,PhD4

Page 3: ICAR: Allergic Rhinitis 1...2017/11/28  · 31 Steven M. Houser, MD Otolaryngology Case Western Reserve University USA 32 Peter H. Hwang, MD Otolaryngology Stanford University USA

ICAR:AllergicRhinitis 3

11 AaronM.Drucker,MD,ScM Dermatology AlpertMedicalSchoolofBrownUniversity,Women’sCollegeResearchInstitute

USA,Canada

12 KaiFruth,MD,PhD Otorhinolaryngology HeliosKlinikenWiesbaden Germany13 CantingGuo,MD Medicine AlpertMedicalSchoolofBrown

UniversityUSA

14 Prof.MatthiasKopp PediatricAllergy/Pulmonology

UniversityofLubeck Germany

15 PatriciaA.Loftus,MD Otolaryngology UniversityofCaliforniaSanFrancisco USA16 MauricioLópez-Chacón,MD Otolaryngology UniversitatdeBarcelona;HospitalClinic,

IDIBAPSSpain

17 MichaelJ.Marino,MD Otolaryngology McGovernMedicalSchoolattheUniversityofTexasHealthScienceCenterHouston

USA

18 JoseMattos,MD Otolaryngology MedicalUniversityofSouthCarolina USA19 NurayBayarMuluk,MD Otolaryngology KirikkaleUniversity Turkey20 ChewLipNg,MD Otolaryngology NgTengFongGeneralHospital Singapore21 BrightI.Nwaru,PhD Allergy/Asthma UniversityofEdinburgh UK22 GianniPala,MD Allergy/Immunology UniversityofPavia Italy23 JonoPaulin,MBChB Medicine UniversityofOtago NewZealand24 MichaelPfisterer,MD Otolaryngology RutgersNewJerseyMedicalSchool USA25 AndrewJ.Rosko,MD Otolaryngology UniversityofMichigan USA26 ChloeLanRusso,MD Allergy/Immunology EmoryUniversity USA27 TheodoreAsherSchuman,MD Otolaryngology UniversityofNorthCarolina USA28 ChristineSegboer,MD Otolaryngology UniversityofAmsterdam Netherlands29 MichelaSilvestri,PhD Pediatric

Pneumology/AllergyIstitutoGianninaGaslini Italy

30 KristineA.Smith,MD Otolaryngology UniversityofCalgary Canada31 MichaelB.Soyka,MD Otorhinolaryngology UniversityHospitalZurich Switzerland32 JeanieSozanskyLujan,MD Otolaryngology CaseWesternReserveUniversity USA33 AndrewJ.Thomas,MD Otolaryngology UniversityofUtah USA34 ArjaViinanen,MD,PhD Pulmonary/Allergy TurkuUniversityHospital Finland35 ThomasJ.Willson,MD Otolaryngology BrookArmyMedicalCenter USA12Correspondenceto:3SarahK.Wise,MD,MSCR4EmoryUniversity5DepartmentofOtolaryngology-HeadandNeckSurgery6550PeachtreeStreet,MOT11thFloor7Atlanta,GA303088Email:[email protected](longlist):allergenextract,allergy,allergicrhinitis,antihistamine,asthma,atopicdermatitis,11avoidance,biologic,cockroach,conjunctivitis,consensus,corticosteroid,cough,cromolyn,12decongestant,eosinophilicesophagitis,environment,epicutaneousimmunotherapy,epidemiology,13evidence-basedmedicine,foodallergy,housedustmite,IgE,immunoglobulinE,immunotherapy,14inhalantallergy,leukotriene,microbiome,occupationalrhinitis,omalizumab,perennial,petdander,15pollen,probiotic,rhinosinusitis,saline,seasonal,sensitization,sinusitis,socioeconomic,specificIgE,16subcutaneousimmunotherapy,sublingualimmunotherapy,systematicreview,rhinitis,totalIgE,17transcutaneousimmunotherapy,validatedsurvey1819

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ICAR:AllergicRhinitis 4

Keywords(shortlist):allergyimmunotherapy,allergicrhinitis,evidence-basedmedicine,1immunotherapy,rhinitis23AuthorConflictofInterestDisclosure:Seetableattheendofthisdocument.45Funding:AdministrativesupportforthisdocumentwasfundedbytheAmericanAcademyofOtolaryngic6Allergy.78

9 10

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ICAR:AllergicRhinitis 5

ListofAbbreviationsUsed12AAAAI AmericanAcademyofAllergyAsthma&Immunology3AAO-HNS AmericanAcademyofOtolaryngology-HeadandNeckSurgery4AC allergicconjunctivitis5ACC allergenchallengechamber6ACE-I angiotensinconvertingenzymeinhibitor7ACTH adrenalcorticotropichormone8AD atopicdermatitis9AERD aspirinexacerbatedrespiratorydisease10AH adenoidhypertrophy11AHI apnea-hypopneaindex12AIT allergenimmunotherapy13ANA anti-nuclearantibody14ANCA anti-nuclearcytoplasmicantibody15APC antigenpresentingcell16AR allergicrhinitis17ARIA AllergicRhinitisanditsImpactonAsthma18ARS acuterhinosinusitis19BAFF B-cellactivatingfactor20BAT basophilactivationtest21BDNF brain-derivedneurotrophicfactor22BKC benzalkoniumchloride23CARAT10 ControlofAllergicRhinitisandAsthmaTest24CCAAPS CincinnatiChildhoodAllergenandAirPollutionStudy25CCAD centralcompartmentatopicdisease26cGMP cyclicguanosinemonophosphate27CI confidenceinterval28CNS centralnervoussystem29CO carbonmonoxide30COX cyclooxygenase31CPAP continuouspositiveairwaypressure32CPG clinicalpracticeguideline33CPT conjunctivalprovocationtest34CRD componentresolveddiagnosis35CRS chronicrhinosinusitis36CRSsNP chronicrhinosinusitiswithoutnasalpolyposis37CRSwNP chronicrhinosinusitiswithnasalpolyposis38CS CombinedScore39CSF cerebrospinalfluid40CT computedtomography41DCS DailyCombinedScore42DEP dieselexhaustparticles43DBP diastolicbloodpressure44DSCG disodiumcromoglycate45EAACI EuropeanAcademyofAllergy&ClinicalImmunology46EAN EuropeanAeroallergenNetwork47EBR evidence-basedreview(withoutrecommendations)48EBRR evidence-basedreviewwithrecommendations49EC environmentalcontrol50ECP eosinophilcationicprotein51ECRHS EuropeanCommunityRespiratoryHealthSurvey52

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ICAR:AllergicRhinitis 6

EEC environmentalexposurechamber1EGPA eosinophilicgranulomatosiswithpolyangiitis2ENS emptynosesyndrome3EoE eosinophilicesophagitis4EPOS EuropeanPositionPaperonRhinosinusitisandNasalPolyps5ESS EpworthSleepinessScale6EU EuropeanUnion7FDA FoodandDrugAdministration(US)8FEV1 forcedexpiratoryvolumein1second9FoxP3 forkheadboxP310GA2LEN GlobalAllergyandAsthmaNetworkofExcellence11GM-CSF granulocyte-macrophagecolonystimulatingfactor12GPA granulomatosiswithpolyangiitis13GWAS genome-wideassociationstudy14HD-42 SleepDisordersQuestionnaire15HDM housedustmite16HEPA highefficiencyparticulateair17HFA hydrofluoroalkane18HMW highmolecularweight19HR heartrate20IAR intermittentallergicrhinitis21ICAR InternationalConsensusStatementonAllergyandRhinology22ICAR:AR InternationalConsensusStatementonAllergyandRhinology:AllergicRhinitis23ICAR:RS InternationalConsensusStatementonAllergyandRhinology:Rhinosinusitis24IDT intradermaldilutionaltesting25IFN interferon26IgE immunoglobulinE27IL interleukin28ILC innatelymphoidcell29ILIT intralymphaticimmunotherapy30IND intranasaldecongestant31INCS intranasalcorticosteroid32INV intranasalvolume33IPB ipratropiumbromide34ISAAC InternationalStudyofAsthmaandAllergiesinChildhood35JSQ TheJenkinsQuestionnaire36LAR localallergicrhinitis37LMW lowmolecularweight38LOE levelofevidence39LPR laryngopharyngealreflux40LRRC32 leucine-richrepeat-containingprotein3241LT leukotriene42LTRA leukotrienereceptorantagonist43mAb monoclonalantibody44MAS MulticentreAllergyStudy45MCC mucociliaryclearance46MCP macrophage/monocytechemoattractantprotein47MD moleculardiagnosis48MDC macrophage-derivedchemokine49MIF macrophagemigrationinhibitoryfactor50MIP macrophageinflammatoryprotein51MQT ModifiedQuantitativeTesting52NAR non-allergicrhinitis53

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ICAR:AllergicRhinitis 7

NARES non-allergicrhinitiswitheosinophiliasyndrome1NARESMA non-allergicrhinitiswitheosinophilsandmastcells2NARMA non-allergicrhinitiswithmastcells3NARNE non-allergicrhinitiswithneutrophils4NC nasalcytology5NGF nervegrowthfactor6NHANES NationalHealthandNutritionExaminationSurvey7NO nitricoxide8NO2 nitrogendioxide9NPT nasalprovocationtest10NSAID non-steroidalanti-inflammatorydrug11O3 ozone12OAS oralallergysyndrome13OME otitismediawitheffusion14OMIT oralmucosalimmunotherapy15OR oddsratio16OSA obstructivesleepapnea17OTC overthecounter18PAR perennialallergicrhinitis19PARIS PollutionandAsthmaRisk:AnInfantStudy20PER persistentallergicrhinitis21PDE phosphodiesterase22PFAS pollenfoodallergysyndrome23PM10 particulatematter<10microns24PM2.5 particulatematter<2.5microns25PNU proteinnitrogenunit26PRISMA PreferredReportingItemsforSystematicReviewsandMeta-analyses27ppm partspermillion28PROM patientreportedoutcomemeasure29PSG polysomnogram30QOL qualityoflife31RANTES regulatedonactivation,normalT-cellexpressedandsecreted32RAP RespiratoryAllergyPredictiontest33RARS recurrentacuterhinosinusitis34RAST radioallergosorbenttest35RC-ACS Rhinoconjunctivitis-AllergyControlScore36RCT randomizedcontrolledtrial37RFA radiofrequencyablation38RM rhinitismedicamentosa39RMS RescueMedicationScore40RQLQ RhinoconjunctivitisQualityofLifeQuestionnaire41rTNSS ReflectiveTotalNasalSymptomScore42RTSS RhinitisTotalSymptomScore43RUDS reactiveupperairwaydysfunctionsyndrome44SAPALDIA SwissStudyofAirPollutionandLungDiseaseinAdults45SAR seasonalallergicrhinitis46SBP systolicbloodpressure47SCIT subcutaneousimmunotherapy48SDB sleepdisorderedbreathing49SES socioeconomicstatus50sIgE antigen-specificimmunoglobulinE51SLE systemiclupuserythematosus52SLIT sublingualimmunotherapy53

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ICAR:AllergicRhinitis 8

SMD standardizedmeandifference1SNP singlenucleotidepolymorphism2SO2 sulfurdioxide3SPT skinpricktest4SQ-U standardizedqualityunits5SSRI selectiveserotoninreuptakeinhibitor6SSS StanfordSleepinessScore7TARC thymusandactivationregulatedchemokine8TCRS TotalCombinedRhinitisScore9TDI threshold,discrimination,identification10TGF-b transforminggrowthfactorbeta11Th T-helpercell12Th0 naïveT-helpercell13tIgE totalimmunoglobulinE14TLR toll-likereceptor15TNF tumornecrosisfactor16TNSS TotalNasalSymptomScore17TOSS TotalOcularSymptomScore18TOTALL TOTalCostsofALLergicRhinitisinSweden19Treg T-regulatorycell20TSLP thymicstromallymphoprotein21US UnitedStates22VAS VisualAnalogScale23VHI VoiceHandicapIndex24WHO WorldHealthOrganization25 26

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ICAR:AllergicRhinitis 9

DetailedTableofContents12

I. Introduction page3II. Methods page4III. Definitions,classifications,anddifferentialdiagnosis page5

A. Allergicrhinitisdefinition page6B. Allergicrhinitisclassification page7C. Differentialdiagnosis page8

1.Drug-inducedrhinitis page92.Rhinitismedicamentosa page103.Occupationalrhinitis page114.Chemicalrhinitis page125.Smoke-inducedrhinitis page136.Infectiousrhinitis page147.Rhinitisofpregnancyandhormonally-inducedrhinitis page158.Foodandalcohol-inducedrhinitis page169.Non-allergicrhinitiswitheosinophiliasyndrome(NARES) page1710.Vasomotorrhinitis(non-allergicrhinopathy) page1811.Age-relatedrhinitis(i.e.elderly) page1912.Emptynosesyndromeandatrophicrhinitis page2013.Autoimmune,gramulomatous,andvasculiticrhinitis page2114.Rhinosinusitis page22

IV. Pathophysiologyandmechanisms page23A. IgE-mediatedallergicrhinitis page24

1.Systemicmechanismsandmanifestations page252.IgE-IgEreceptorcascade page263.LocalIgEproductionandlocalallergicrhinitis page27

B. Non-IgEmediatedinflammationinallergicrhinitis page28C. Unifiedairwayconcept page29D. Cellularinflammatoryinfiltrates page30E. Cytokinenetworkandsolublemediators page31F. Histologicandepithelialchanges page32G. Microbiome page33

V. Epidemiologyofallergicrhinitis page34A. Prevalenceofallergicrhinitisinadults page35B. Incidenceandprevalenceofallergicrhinitisinchildren page36C. Geographicvariationofallergicrhinitis page37

VI. Riskfactorsforallergicrhinitis page38A. Genetics page39B. Inhalantallergens(inuteroandearlychildhoodexposure) page40C. Foodallergens(inuteroandearlychildhoodexposure) page41D. Pollution page42E. Tobaccosmoke page43F. Socioeconomicfactors page44G. Protectivefactorsagainstallergicrhinitis page45

1.Breastfeeding page462.Childhoodexposuretopets page473.Hygiene(a.k.a.BiodiversityorMicroflora)hypothesis page48

VII. Diseaseburden page49A. Individualburden page50

1.Effectonqualityoflife page512.Effectonsleep page52

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ICAR:AllergicRhinitis 10

B. Societalburden page1VIII. Evaluationanddiagnosis page2

A. Clinicalexamination page3B. Nasalendoscopy page4C. Radiology page5D. Useofvalidatedsurveyinstruments page6E. Skintesting page7

1.Skinpricktesting page82.Skinintradermaltesting page93.Blendedskintestingtechniques page104.Issuesthatmayaffecttheperformanceorinterpretationofskintests 11

a.Medications page12b.Skinconditions page13

F. Invitrotesting page141.SerumtotalIgE page152.SerumspecificIgE page163.Correlationbetweenskinandinvitrotesting page174.NasalspecificIgE page185.Basophilactivationtest page196.Componentresolveddiagnosis page20

G. Sensitizationversusclinicalallergy page21H. Allergenchallengetesting page22

1.Allergenchallengechambers page232.Localallergenchallengetests page24

I. Nasalcytologyandhistology page25IX. Management page26

A. Allergenavoidance page271.Housedustmite page282.Cockroach page293.Pets page304.Other(pollen,occupational) page31

B. Pharmacotherapy page321.Antihistamines page33

a.OralH1antihistamines page34b.OralH2antihistamines page35c.Intranasalantihistamines page36

2.Corticosteroids page37a.Oralcorticosteroids page38b.Injectablecorticosteroids page39c.Intranasalcorticosteroids page40

3.Decongestants page41a.Oraldecongestants page42b.Intranasaldecongestants page43

4.Leukotrienereceptorantagonists page445.Cromolyn page456.Intranasalanticholinergics page467.Biologics page478.Nasalsaline page489.Probiotics page4910.Combinationtherapy page50

a.Oralantihistamineandoraldecongestant page51b.Oralantihistamineandintranasalcorticosteroid page52c.Oralantihistamineandleukotrienereceptorantagonist page53

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ICAR:AllergicRhinitis 11

d.Intranasalcorticosteroidandintranasalantihistamine page111.Non-traditionalandalternativetherapies page2

a.Acupuncture page3b.Honey page4c.Herbaltherapies page5

C. Surgicaltreatment page6D. Immunotherapy page7

1.Allergenextractunits,potency,andstandardization page82.Modifiedallergenextracts page93.Subcutaneousimmunotherapy page104.Sublingualimmunotherapy page115.Transcutaneousimmunotherapy page126.Intralymphaticimmunotherapy page137.Alternativeformsofimmunotherapy page148.Combinationomalizumabandsubcutaneousimmunotherapy page15

X. Associatedconditions page16A. Asthma page17

1.Definition page182.Asthmaassociationwithallergicandnon-allergicrhinitis page193.Allergicrhinitisasariskfactorforasthma page204.Treatmentofallergicrhinitisanditseffectonasthma page21

B. Rhinosinusitis page22C. Conjunctivitis page23D. Atopicdermatitis page24E. Foodallergyandpollen-foodallergysyndrome page25F. Adenoidhypertrophy page26G. Otologicconditions page27H. Cough page28I. Laryngealdisease page29J. Eosinophilicesophagitis page30K. Sleepdisturbanceandobstructivesleepapnea page31

XI. Knowledgegapsandresearchopportunities page32XII. References page33

34 35

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ICAR:AllergicRhinitis 12

1Abstract23Background.Criticalexaminationofthequalityandvalidityofavailableallergicrhinitis(AR)literatureis4necessarytoimproveunderstandingandtoappropriatelytranslatethisknowledgetoclinicalcareofthe5ARpatient.ToevaluatetheexistingARliterature,internationalmultidisciplinaryexpertswithaninterest6inARhaveproducedtheInternationalConsensusstatementonAllergyandRhinology:AllergicRhinitis7(ICAR:AR).89Methods.Usingpreviouslydescribedmethodology,specifictopicsweredevelopedrelatingtoAR.Each10topicwasassignedaliteraturereview,evidence-basedreview(EBR),orevidence-basedreviewwith11recommendations(EBRR)formatasdictatedbyavailableevidenceandpurposewithintheICAR:AR12document.Followingiterativereviewsofeachtopic,theICAR:ARdocumentwassynthesizedand13reviewedbyallauthorsforconsensus.1415Results.TheICAR:ARdocumentaddressesover100individualtopicsrelatedtoAR,includingdiagnosis,16pathophysiology,epidemiology,diseaseburden,riskfactorsforthedevelopmentofAR,allergytesting17modalities,treatment,andotherconditions/comorbiditiesassociatedwithAR.1819Conclusion.ThiscriticalreviewoftheARliteraturehasidentifiedseveralstrengths,whereproviderscan20beconfidentthattreatmentdecisionsaresupportedbyrigorousstudies.However,therearealso21substantialgapsintheARliterature.Theseknowledgegapsshouldbeviewedasopportunitiesfor22improvement,asoftenthethingsthatweteachandthemedicinethatwepracticeisnotbasedonthe23bestqualityevidence.ThisdocumentaimstohighlightthestrengthsandweaknessesoftheAR24literaturetoidentifyareasforfutureARresearchandimprovedunderstanding.2526 27

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I.Introduction1

Theavailableliteratureonallergicrhinitis(AR)growsmorequicklywitheachpassingdecade.A2searchof“allergicrhinitis”inthePubMeddatabaseyielded4,135articlespublishedbetween1945and31979.Thenext20years(1980-2000)saw7,064ARarticlespublished.Eachsubsequentdecadehas4surpassedthisnumberwith8,143ARarticlespublishedbetween2000and2010,and8,212published5from2010tothepresentday.Likemanyotherareasofmedicine,acloselookattheavailableliterature6demonstratesawidevariationinthetypeandqualityofARpublications,rangingfromcasereportsto7meta-analyses,reviewarticlestorandomizedcontrolledtrials(RCT),andlargeprospectivestudiesto8smallretrospectivecaseseries.Asamedicalprofessionalreadstheliteratureorhearsliteraturequoted9byothers,itisimportantthathe/sheunderstandthequalityoftheevidenceinordertoappropriately10translatethefindingsandrecommendationsintodailyclinicalcareoftheARpatient.WithsuchvastAR11literatureavailable,developinganappropriateunderstandingoftherelevantevidencecanbedaunting.12 ThisInternationalConsensusStatementonAllergyandRhinology:AllergicRhinitis(ICAR:AR)was13developedtosummarizethebestexternalevidencerelatingtoAR,withthegoalofgatheringand14criticallyreviewingtheavailableliteratureonARepidemiology,riskfactors,diagnosis,management,and15associatedconditions/comorbidities.Morethan100internationalauthorsfromvariousspecialties16utilizedastructuredreviewprocesstoevaluatetheevidencerelatedtoAR.Initialtopicdevelopment17andwritingbyaprimaryauthororteamofauthors,followedbyastepwiseanonymousiterativereview18processforover100ARtopicsheldthisprocesstoextremelyhighstandards.Theresultingdocument19providesastrongreviewoftheexistingARliterature.TherecommendationsforARdiagnostic20modalitiesandtreatmentcontainedhereinrelydirectlyonthisevidence,withacleardelineationofthe21benefit,harm,andcostconsiderationsthatsupportedeachrecommendationlevel.22 Likethe2016InternationalConsensusstatementonAllergyandRhinology:Rhinosinusitis23(ICAR:RS)byOrlandietal,1thisICAR:ARdocumentplaceshighvalueonthestrengthoftheevidencein24makingrecommendations.Therefore,forexample,expertopinionreceiveslowervalue.[TableII.A-1.]25Therearelimitations,however.LikeICAR:RS,thisdocumentisnotaclinicalpracticeguideline(CPG)ora26meta-analysis.Thisdocumentsummarizesthefindingsofmeta-analysesandothersystematicreviews27whenthoseareidentifiedintheliteratureforaspecificARtopicarea.However,ameta-analysiswasnot28performedonthedataincludedinthisdocument.Inaddition,muchoftheavailableARliteratureisnot29appropriateformeta-analysisduetoitsheterogeneousnatureandinconsistentmethodologies.ICAR:AR30isalsonotaCPG,asthetypicalstepsofaCPG(i.e.medicalspecialtysocietyandpatientadvocate31review)werenotemployedhere.32 Throughoutthisdocument,certaintopicareashaveverystrongevidencewhereasothertopics33demonstraterelativelyweakevidence.Manyofourcommonpracticesinthediagnosisandcareofthe34ARpatientarebaseduponweakexternalevidence.Aspractitioners,academicians,andscientists,we35mustexaminethisevidenceandstrivetoincreasethestrengthoftheevidenceinareaswheregaps36exist.37 WithintheICAR:ARdocument,recommendationsaregivenbasedontheevidenceinaspecific38topicarea.However,thisdocumentisacompilationofthebestARevidence,notamanualforthecare39oftheARpatient.Evidence-basedmedicinerequiresthattheclinicianhasthebestevidenceavailable,40butalsouseshis/herexpertiseandtakesthepatient’svaluesandexpectationsintoaccount.2Therefore,41

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withabackgroundofevidence-basedknowledge,thepractitionermustapproacheachpatientasan1individualtodeterminethemostappropriatediagnosticandtreatmentmodalitiesforthatparticular2patient.GiventhenumerouspotentialconditionsintheARdifferentialdiagnosis,variousdiagnosticand3treatmentoptionsavailable,anddiversecomorbiditiesandassociatedconditionsthatmayaccompany4AR,treatmentoftheARpatientwithanevidence-basedapproachrequirescarefulconsideration.5 AspreviouslystatedbyOrlandietal,1therecommendationsprovidedinanICARdocumentmust6beinterpretedbasedonthestrengthoftheevidencethatformstheirfoundation.The7recommendationsinthisdocumentareevidence-based.Theydonotdefinethestandardofcareor8medicalnecessity.Recommendationswritteninthisdocument,oranysimilardocument,donotdictate9thespecificcareofanindividualpatient.Therearenumerousotherfactorsthatenterintothe10treatmentdecisionsforeachindividualpatient.Finally,itisexpectedthattheserecommendationswill11changewithtimeandwithnewevidence.Weencouragenewresearch,especiallyrigorousstudiesthat12aimtofilltheidentifiedknowledgegaps.Withnewevidence,recommendationswillundergonecessary13revisionsandbetterpatientoutcomesshouldresult.14 15

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II.Methods1II.A.Topicdevelopment23 Inasimilarfashiontothe2016ICAR:RSdocumentbyOrlandietal,1thisICAR:ARdocumentis4formulatedwiththeutmostrelianceonpublishedevidence.Withthe2011RudmikandSmith35evidence-basedreviewwithrecommendations(EBRR)methodasitsfoundation,ICAR:ARstrivesto6analyzetheexistingliteratureoneachARtopic,gradingtheevidenceandprovidingliterature-based7recommendationswhereappropriate.8

ThesubjectofARwasinitiallydividedinto103topicsorcontentareas.Aseniorauthorwhoisa9recognizedexpertinallergy,rhinology,ortheassignedtopicwasappointedtoeachtopic.Authorswere10initiallyselectedviaonlineliteraturesearchesforeachICAR:ARtopic.Authorsofhigh-quality11publicationsineachtopicareawereinvitedasICAR:ARcontributors.Otherinvitedauthorsincluded12expertsintheEBRRprocess,expertsinteaching/lecturingonspecificARtopicareas,andthosewith13knowledgeofthesystematicreviewprocess.14

Someofthetopics,suchasthoseprovidingbackgroundordefinitions,wereassignedas15literaturereviewswithoutevidencegrades.Certaintopicsthatwerenotappropriateforclinical16recommendationswereassignedasevidence-basedreviewswithoutrecommendations(EBRs).Topics17thathadevidencetoinformclinicalrecommendationswereassignedasEBRRs.18

Eachtopicauthorreceivedspecificinstructionstoperformasystematicreviewforthetopic19literatureusingthePRISMA(PreferredReportingItemsforSystematicReviewsandMeta-analyses)20standardizedguidelines.4OvidMEDLINEÒ(1947-September2016),EMBASE(1974-September2016)and21CochraneReviewdatabaseswereincluded.Thesearchbeganbyidentifyinganypreviouslypublished22systematicreviewsorguidelinespertainingtotheassignedtopic.Sinceclinicalrecommendationsare23bestsupportedbyhighqualityevidence,thesearchfocusedonidentifyingRCTsandmeta-analysesof24RCTstoprovidethehighestlevelofevidence(LOE).Referencelistsofallidentifiedstudieswere25examinedtoensureallrelevantstudieswerecaptured.Iftheauthorsfeltasthoughanon-Englishstudy26shouldbeincludedinthereview,itwasinstructedthatthepaperbeappropriatelytranslatedto27minimizetheriskofmissingimportantdataduringthedevelopmentofrecommendations.428 Tooptimizetransparencyoftheevidence,allincludedstudiesinEBRandEBRRtopicsections29arepresentedinastandardizedtableformatandthequalityofeachstudywasevaluatedtoreceivea30levelbasedontheOxfordLOE(level1ato5).5Atthecompletionofthesystematicreviewandresearch31qualityevaluationforeachclinicaltopic,anaggregategradeofevidencewasproducedforthetopic32basedontheguidelinesfromtheAmericanAcademyofPediatricsSteeringCommitteeonQuality33ImprovementandManagement(AAPSCQIM).6[TableII.A-1.]34 AfterprovidinganaggregategradeofevidenceforeachEBRRtopic(AtoD),arecommendation35usingtheAAPSCQIMguidelineswasproduced.[TableII.A-2.]Itisimportanttonotethateach36evidence-basedrecommendationtookintoaccounttheaggregategradeofevidencealongwiththe37balanceofbenefit,harm,andcosts.AsummaryoftheEBRRdevelopmentprocessisprovidedinFigure38II.A-1.3940II.B.Iterativereview4142

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Followingthedevelopmentoftheinitialtopictextandanyassociatedevidencetables,evidence1grades,andrecommendations,eachsectionunderwentatwo-stageonlineiterativereviewprocess2usingtwoindependentreviewers.[FigureII.A-2.]Thepurposeofthetopiciterativereviewprocesswas3toevaluatethecompletenessoftheidentifiedliteratureandensureanyEBRRrecommendationswere4appropriate.Thecontentofthefirstdraftfromeachtopicsectionwasreviewedbyafirstreviewer,and5allchangeswereagreeduponbytheinitialauthorandthisfirstreviewer.Therevisedtopicsectionwas6thensubsequentlyreviewedbyasecondreviewer.Initialauthorsofthetopicandbothassigned7reviewersagreeduponallchangesbeforeeachsectionwasconsideredappropriatetoproceedintothe8finalICARstatementstage.910II.C.ICARstatementdevelopment1112 Afterthecontentofeachoftopicwasreviewedandconsensusreachedamongsttheinitial13authorandtwoiterativereviewers,theprincipaleditor(SKW)compiledalltopicsintooneICAR:AR14statement.ThefirstdraftofeachlargeICAR:ARportion(i.e.EvaluationandDiagnosis,15Pharmacotherapy,Immunotherapy,etc.)thenunderwentadditionalreviewsforconsistencyand16understandingusingagroupof6-8authors.Finally,thedraftICAR:ARwascirculatedtoallauthors.The17finalICAR:ARmanuscriptwasproducedwhenallauthorsagreedupontheliteratureandfinal18recommendations.Externalpeerreview,with20reviewers,wasalsoundertakenforthefinalICAR:AR19document.[FigureII.A-3.]2021II.D.Limitationsofmethodsanddatapresentation2223 Itshouldbenotedthatsinceeachtopicauthorindividuallyperformedtheliteraturesearchfor24his/herassignedtopic,searchresultsmaydemonstratesomeinherentvariabilitydespitespecificand25detailedsearchinstructions.Furthermore,whileaimingtobeascomprehensiveaspossible,this26documentmaynotpresenteverystudypublishedoneverytopic.Forcertaintopics,theliteratureis27extensiveandonlyhighqualitystudiesorsystematicreviewsarelisted.Iftheaggregateevidenceona28topicreachedahighevidencegradewithonlyhighlevelstudies,anexhaustivelistoflowerlevelstudies29(orallstudieseverperformed)isnotprovided.303132 33

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TableII.A-1.Aggregategradeofevidence61Grade ResearchqualityA Well-designedRCTs

B RCTswithminorlimitationsOverwhelmingconsistentevidencefromobservationalstudies

C Observationalstudies(casecontrolandcohortdesign)

DExpertopinionCasereportsReasoningfromfirstprinciples

RCT:randomizedcontrolledtrial234TableII.A-2.AmericanAcademyofPediatricsdefinedstrategyforrecommendationdevelopment65

Evidencequality Preponderanceofbenefitoverharm

Balanceofbenefitandharm

Preponderanceofharmoverbenefit

A.Well-designedRCT’s

Strong

recommendation

Option

Strong

recommendation

againstB.RCT’swithminorlimitations;Overwhelminglyconsistentevidencefromobservationalstudies

C.Observationalstudies(case-controlandcohortdesign) Recommendation

Recommendation

againstD.Expertopinion;Casereports;Reasoningfromfirstprinciples Option Norecommendation

RCT:randomizedcontrolledtrial6 7

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FigureII.A-1.Topicdevelopment1EBRR:evidence-basedreviewwithrecommendation;PE:principaleditor;10:primary;PRISMA:PreferredReporting2ItemsforSystematicReviewsandMeta-Analyses;AAP:AmericanAcademyofPediatrics34

5 6

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FigureII.A-2.TopicEBRRIterativeReview1PE:principaleditor;10:primary;20:secondary;30:tertiary23

45 6

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FigureII.A-3.ICAR:AllergicRhinitisstatementiterativereview1PE:principaleditor;ICAR:AR:InternationalConsensusStatementonAllergyandRhinology:AllergicRhinitis23

45

6

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III.Definitionanddifferentialdiagnosis1

ARisanimmunoglobulinE(IgE)-mediatedinflammatorynasalconditionresultingfromallergen2introductioninasensitizedindividual.7ARwasdefinedin1929asaprocesswhichincludedthree3cardinalsymptoms:sneezing,nasalobstruction,andmucusdischarge.8Symptomsoccurwithallergen4exposureintheallergicpatient.ARisawidelyprevalentconditionthatcanresultinsignificantphysical5sequelaeandrecurrentorpersistentmorbidities.76

TheprevalenceofARisapproximately10-40%,dependingongeographiclocation,9withthe7highestincidenceoccurringinchildren.10However,ARisnearlyabsentininfants,typicallynot8manifestinguntilthesecondyearoflifeattheearliest.WhenARpresentsinchildren,thisislikely9secondarytotherapidlyevolvingimmunesystem.ARoftenresultsfromanoveractiveresponseofT10helper(Th)2lymphocyteswhichcaninitiateasystemic,IgE-drivenreactionwhichmaydominatechild’s11immunesystemuntilitiscompletelymature.Duringthistime,askinpricktest(SPT)orinvitroantigen-12specificIgE(sIgE)testcanbeusedtoconfirmthediagnosisofAR.13

Intheatopicindividual,exposuretoindoorandoutdoorallergensmaypromptantigen-specific14IgEproduction.Re-introductionoftheallergentriggersearlyandlate-stagereactions,leadingtothe15clinicalmanifestationsofAR.Theearly-stagereactionoccurswithinminutesafterre-introductionofthe16sensitizedallergen,producingnasalitching,nasalcongestion,andrhinorrhea.11Thelate-stagereaction17occursduringthe4-8hourperiodafterallergenintroductionandresultsinnasalblockage,hyposmia,18increasedmucussecretion,andnasalhyper-responsivenesstothesameordifferentallergens.19Additionally,evenintheabsenceofovertsymptoms,IgEhasanincreasedpresenceinthelymphoid20tissueoftheatopicpatient,whichcanresultinpersistentmucosalinflammation.12212223III.B.Allergicrhinitisclassification24Seasonalvs.perennialAR.TheAllergicRhinitisanditsImpactonAsthma(ARIA)proposalshave25categorizedARbypresumedcauseandseasonalversusperennialpresentation.Classically,thishas26includedseasonalAR(SAR;hayfever)andperennialallergicrhinitis(PAR).7SARistriggeredbyawide27assortmentofoutdoorallergens,especiallypollens.7PARiscommonlybroughtaboutbyindoor28allergensthatarepresentthroughouttheyear,suchasdustmites,molds,insects(cockroaches),and29animaldander.73031Intermittentvs.persistentAR.Theclassificationof“seasonal”and“perennial”ARcanoftenbein32conflict,asmanifestationsofperennialallergymaynotoccurthroughouttheentireyear.Thisis33particularlythecaseforpatientsallergictohousedustmites(HDM),whomaydemonstratemildor34moderate/severeintermittentallergicrhinitis(IAR).9,13-15Inaddition,becauseoftheprimingeffecton35thenasalmucosainitiatedbylowlevelsofpollenallergens16-21andminimalpersistentnasal36inflammationinpatientswith“symptom-freerhinitis”,14,22,23symptomsmaynotoccurentirelyin37conjunctionwiththeallergenseason,thereforeresultinginnon-specificexacerbations.Airpollution38mayalsocontributetoalterationsinallergensensitivity,resultinginvaryingdegreesofsymptoms39dependingonlocationandairquality.24Furthermore,individualssensitizedtomultiplepollensmayhave40symptomsacrossseveralseasonswhileindividualswithPARmayencountersymptomsforshortperiods41

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oftimewithfrequent,repetitiverelapses.1Becauseoftheissuesoutlinedabove,ARIAproposedanewmethodofclassificationbasedon2

thelengthandrecurrenceofthesymptommanifestations.25IARischaracterizedbysymptomsforless3than4daysperweekorlessthan4consecutiveweeks.PersistentAR(PER)ischaracterizedby4symptomsoccurringmorethan4daysperweekforatleast4consecutiveweeks;therefore,PER5patientsaresymptomaticmostofthetime.26Ithasbeenrecommendedthatthepreviouscategoriesof6seasonalandperennialARnotbeusedalongwiththenewclassificationofIARandPER,astheydon't7representthesamestratificationofthediseasestate.Assuch,IARandPERarenotsynonymouswith8seasonalandperennial.25,27-30IndescribingAR,oneshoulddeterminewhichclassificationschemebest9conveysthemessagethathe/shewishestorelay:seasonal/perennialorintermittent/persistent.1011Severityofallergicrhinitis.ARcanresultinsignificantdisturbancesinqualityoflife(QOL),sleep,12exercisetolerance,productivity,andsocialfunctioning.TheARIAguidelineshavelikewiseproposedthe13stratificationofseverity(mildandmoderate-severe)inviewofthesedisabilities.13(SeeSectionVII.14DiseaseBurdenforadditionalinformationonthistopic.)1516Sensitizationvs.clinicalallergy.Monosensitizationissensitization(asindicatedbypositivereactionson17standardizedSPTsorserumsIgElevels)toonlyoneallergen,suchasgrasspollen,treepollen,HDMor18catdander(eventhoughextractsoftheseconcentratescontainnumerousdiversepolypeptides).3119Monoallergyisdefinedasasinglesensitizingallergencausingclinicalallergysymptoms.20Polysensitizationissensitizationtotwoormoreallergens.Polyallergyisaffirmedclinicalsymptomsto21twoormoresensitizingallergens.Findingsofallergytesting,eitherskintestingorsIgEmustbe22correlatedwithclinicalsymptomstoidentifytheallergen(s)likelyresponsibleforthesymptoms.3223Allergenchallenges(i.e.nasalprovocationtesting,conjunctivalchallenge,orallergentestchambers)can24reproduciblyconfirmtheclinicalsignificanceofasensitizedallergen,butthesetestsmaybedifficultto25perform,subjective,andlimitedbyirritanteffects.33AllergyskintestingandsIgEtitermustbecarefully26interpretedatthepatientlevel,andcanalsobevaluableatthepopulationlevelwhenevaluating27sensitizationforepidemiologicalstudies.34Withincreasingavailabilityofcomponent-resolveddiagnosis28(CRD),physicianswillhaveamoreobjectivemeansofidentifyingclinicallyrelevantallergensand29distinguishingtrueco-sensitizationfrompolysensitizationduetocross-reactivity.(SeeSectionVIII.F.6.30ComponentResolvedDiagnosisforadditionalinformationonthistopic.)313233III.C.Allergicrhinitisdifferentialdiagnosis34

ThesymptomsofARmaybesimilartosymptomsofothertypesofsinonasaldisease,andat35timesmultipletypesofrhinitismaycoexist.Itisimportanttocorrectlydeterminetheetiologyofrhinitis36toappropriatelytreatthepatientandhavethebestchanceofresolvinghisorhersymptoms.Inthe37followingsections,adiscussionofthedifferentialdiagnosisofARispresented,alongwithadescription38ofhoweachrhinitisentitydiffersfromAR.Ofnote,thissectiononARdifferentialdiagnosisisspecificto39variousetiologiesofrhinitis.OtherentitiesthatmayenterintothedifferentialdiagnosisofAR,suchas40

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structuralsinonasalconditions(i.e.deviatedseptum),tumors,andcerebrospinalfluidleakarenot1discussedhere.[TableIII.C.]2 3

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TableIII.C.Differentialdiagnosisofallergicrhinitis*1Typesofrhinitis#

• Drug-inducedrhinitis • Rhinitismedicamentosa • Occupationalrhinitis • Chemicalrhinitis • Smoke-inducedrhinitis • Infectiousrhinitis • Rhinitisofpregnancyandhormonally-inducedrhinitis• Foodandalcohol-inducedrhinitis• Non-allergicrhinitiswitheosinophiliasyndrome(NARES)• Vasomotorrhinitis(non-allergicrhinopathy) • Age-relatedrhinitis(i.e.elderly)• Emptynosesyndrome• Atrophicrhinitis • Autoimmune,gramulomatous,andvasculiticrhinitis• Rhinosinusitis

*Foreachoftheseconditions,thesimilaritiesanddifferencetoallergicrhinitisarediscussedwithineach2contentsection.3#Thistableisspecifictovariousetiologiesofrhinitis.Structuralsinonasalconditions(i.e.deviated4septum),tumors,andcerebrospinalfluidleakarenotlistedhere.567III.C.1.Drug-inducedrhinitis8

Rhinitissecondarytosystemicmedicationscanbeclassifiedintolocalinflammatory,neurogenic,9andidiopathictypes.35,36[TableIII.C.1.]Thelocalinflammatorytypeoccurswhenconsumptionofadrug10causesadirectchangeininflammatorymediatorswithinthenasalmucosa.Theneurogenictypeoccurs11afteruseofadrugthatsystemicallymodulatesneuralstimulation,leadingtodownstreamchangesin12thenasalmucosa.Idiopathicdrug-inducedrhinitisisusedtoclassifydrugswithoutawell-defined13mechanismcontributingtosymptoms.Topicalnasaldecongestantscancausedrug-inducedrhinitis,14knownasrhinitismedicamentosa(RM).(SeeSectionIII.C.2.RhinitisMedicamentosaforadditional15informationonthistopic.)1617Localinflammatorytype.Systemicingestionofnonsteroidalanti-inflammatorydrugs(NSAIDs)in18patientswithadisorderofeiconsanoidsynthesiscanresultinrhinitisandnasalcongestion,whichmay19alsobeassociatedwithchronicrhinosinusitis(CRS)andasthma.37Inbrief,NSAIDsinhibitcyclooxygenase20(COX)-1andCOX-2enzymes,shiftingarachidonicacidmetabolismtowardthelipoxygenasepathway,21withdecreasedproductionofprostaglandinsandthromboxaneinexchangeforinflammatory22leukotrienes(LT).ReductioninnasalmucosalprostaglandinE2,aswellasincreasedLTC4,LTD4,and23LTE4causesmucusproductionandnasalmucosaledema,hallmarksofrhinitis.35,382425Neurogenicandneuromusculartype.Neurogenictypenon-allergicrhinitis(NAR)iscausedbydrug-26inducedmodulationoftheautonomicnervoussystem.Antihypertensivesandvasodilatorsareamong27

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themanyclassesofdrugsthatcausedrug-inducedNAR.Othernonspecificdrugs,suchaspsychotropics1andimmunosuppressants,haveunknownmechanismsandarecategorizedasidiopathic,butcancause2neuromodulatoryeffectsaswell.Modulationoftheautonomicnervoussystemleadstodownstream3changesinnasalmucosa,bloodvessels,andsecretoryglands.39Forexample,aandβ-adrenergic4antagonists,andpresynapticα-agonists,causedecreasedsympathetictoneandunopposed5parasympatheticstimulationproducingmucosalengorgement,nasalcongestion,andrhinorrhea.40-426Phosphodiesterase(PDE)-5specificinhibitorspromotepenilevasodilationanderection.PDE-3and7nonselectivePDEinhibitorsresultinvasodilationandincreasedextremitybloodflow,relieving8symptomsofperipheralarterydisease.Nitricoxide(NO)/cyclicnucleotidemediatedvasodilationoccurs9inthenasalmucosaaswell,causingnasalmucosalengorgementandedema.43-46Finally,angiotensin10convertingenzymeinhibitors(ACE-I)inhibittheconversionofangiotensinItoangiotensinIIinthelungs11resultinginadecreaseinsympatheticactivity.Bradykininisalsoformed.BradykininB1andB2receptors12havebeendemonstratedinnasalmucosa;47bradykininapplicationtothenasalmucosahasbeenshown13toincreasesneezing,44,48suggestingaroleofACE-IsinNAR.1415Illicitdruguse.Thenoseprovidesauniqueportalforillicitdruguse,asnasalmucosaiswellvascularized16andeasilyaccessible.Theillicitdrugusercanavoidinvasiveintravascularorintramuscular17administrationofadesiredproductbyapplyingacrushedsolid,liquid,oraerosolizedformofthe18productdirectlytothenasalcavity.Forsomedrugs,nasaladministrationincreasesbioavailabilityand19shortenstimetoonsetwhencomparedtooralingestion.49,50Cocaineismostcommonlyassociatedwith20nasalillicitdruguseandexertsitseffectbymodulatingdopaminetransporterstoinhibitreuptakeatthe21synapse,increasingdopamineavailableforpost-synapticstimulation.51Cocaine-inducedrhinitisisa22resultofvasoconstrictiveevents,whichcanbefollowedbyreboundnasalmucosaledemaandmucous23production,similartothoseseeninRM.52-55Intherepeatuser,vasoconstriction,directtrauma24compoundedbyanestheticeffects,and/orinjurysecondarytocontaminantsmayresultinnasalseptal25perforation.56-59Similarly,prescriptionnarcotics,59antidepressants,47anticholinergics,and26psychostimulantscanbeabusedbyintranasaladministration.47,60Intranasalhydrocodonehasbeen27showntoinducenasaltissuenecrosisandlossinasimilarmannertococaine.59Antidepressantssuchas28bupropionhavebeenusedtoachieveaeuphoriasimilartothatofcocaineandmayinduceseizures.472930

Insummary,systemicmedicationsandintranasalillicitdrugsaffectthenasalmucosa.Increased31mucosaledema,vasodilationandinflammatorymediatorsareaconsequenceofsystemicmedications.32Vasoconstrictionanddirectmucosalinjuryoftenaccompaniesillicitdruguse.Thephysiologicresponse33indrug-inducedrhinitisdiffersfromARasitisnotallergen-inducednordependentonIgEmechanisms,34althoughsymptomatologymaybesimilar.3536TableIII.C.1.Medicationscausativeorcontributorytodrug-inducedrhinitis40,44,483738Typeofdrug-inducedrhinitis

Generaldrugcategory Specificdrugcategory

Examples

Localinflammatory

-NSAIDs(ibuprofen,indomethacin,diclofenac,sulindac,ketoprofen,

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naproxen,flurbiprofen,fenoprofen,piroxicam,meclofenamate,etodolac)-Aspirin-Ketolorac(ifadministeredvianasolacrimalduct)

Neurogenicandneuromuscular

a andβ-adrenergicreceptormodulators

aantagonists -α-1:doxazosin,silodosin,prazosin,tamsulosin,alfuzosin,indoramin-α-1,α-2:phentolamine

Presynapticα-2agonists

clonidine,methyldopa,guanfacine,piribedil

Beta-antagonists -β-1:metoprolol,atenolol,bisoprolol-β-1,β-2:pindolol-β-1,β-2,α-1:carvedilol,labetalol

Presynapticdepletionofnorepinephrinestores

guanethidine

Phosphodiesteraseinhibitors

Phosphodiesterase-3specific

cilostazol

Phosphodiesterase-5specific

sildenafil,tadalafil,vardenafil

Non-selectivephosphodiesterase

pentoxifylline

Angiotensinconvertingenzymeinhibitor

ramipril,captopril,lisinopril,benazepril,quinapril,enalapril

Idiopathic Psychotropics Chlorpromazine,thioridazine,amitriptyline,alprazolam,reserpine,risperadone,mianserin

Immunomodulators cyclosporine Hormones estrogen,oralcontraceptives Antihypertensives Amiloride,chlorothiazide,hydralazine,

hydrochlorothiazide Other gabapentin,gingkobiloba

12III.C.2.Rhinitismedicamentosa(RM)3

RM,orreboundrhinitis,isaconditioninducedbyprolongeduseoftopicalintranasal4decongestant(IND).26,61[TableIII.C.2.]Althoughnoconsensusdiagnosticcriteriaexist,RMisclassically5associatedwiththetriadofprolongedINDuse,constantnasalobstruction,andpoorshrinkageofthe6nasalmucosa61inthesettingofnasalcongestion,rhinorrhea,anddecreasedefficacyoffurther7INDs.55,62,63Physicalexamfindingsconsistofmucosaledema,erythema,andhyperemia.8 TheexactphysiologicmechanismcausingRMisunclear.ContinuousINDusemaydecrease9endogenousnorepinephrineproductionandcauseupregulationoftheparasympatheticsystem,leading10toreboundcongestiononcethedecongestantisdiscontinued.54,55Thismaybefurtherexacerbatedby11recurrentnasaltissuehypoxiaandnegativeneuralfeedbackwithchronicdecreaseda-2receptor12responsiveness.64Mucosalchangesincludeciliarydamageandloss,epithelialmetaplasiaand13hyperplasia,dilatedintercellularspaces,gobletcellhyperplasia,andedema.65-67Benzalkoniumchloride14(BKC),anantimicrobialpreservativeusedinmanynasaldecongestants,hasbeenimplicatedinthe15

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mechanismofRM.StudieshavesuggestedthatBKCistoxictonasalepitheliumandmaypropagateRM,1althoughthedataareinconclusive.68-712 Neitherduration,norcumulativedoseofINDneededtoinitiateRMisknown.Rebound3congestionhasdevelopedafter3-10daysofmedicationuse,55,66butmaynotoccuruntilafter304days.72,73Otherstudieshavedemonstratedalackofreboundafter8weeksofcontinuoususe.72-755Furthermore,doublingthedoseofintranasalimidazolinedidnotincreasetheextentofrebound6edema.72Althoughinconclusive,studiessuggestthatINDuseshouldbediscontinuedafterthreedaysto7avoidreboundcongestion.62,76,778 TreatmentofRMinvolvesdiscontinuationofINDs.Variousmedicationshavebeenusedto9improvenasaldecongestionincludingnasalcromolyn,sedatives,nasalsalinespray,oralantihistamines,10oraldecongestants,andintranasalcorticosteroids(INCS;sometimesusedinconjunctionwithbrief11coursesofsystemiccorticosteroids).50,62,78-82OnlytheuseofINCShasbeendemonstratedtomitigate12reboundcongestionafterdiscontinuationoftopicalINDs.67,81-83Oftenthereisanunderlyingrhinitis13and/oranatomicissuethatinitiatedthedecongestantuse.Thisunderlyingissueshouldbeaddressedto14diminishthedrivetocontinuetouseINDs.15 Importantly,RMistypicallyassociatedwithrepeatedexposuretoINDs,withincreasing16symptomsattimeswhenthemedicationiswithheld.Incontrast,ARisclassicallyassociatedwithan17allergictriggerwithsimilarsymptomsincreasinguponallergenexposure,andisdependentuponIgE-18mediatedinflammation.1920TableIII.C.2.Intranasaldecongestantsassociatedwithrhinitismedicamentosa26,6121Sympathomimeticamines phenylephrine,pseudoephedrine,ephedrine,

amphetamine,benzedrine,caffeine,mescalineImidazolinederivatives oxymetazoline,xylometazoline,naphazoline,clonidine

2223III.C.3.Occupationalrhinitis24

Occupationalrhinitisisaninflammatoryconditionofthenasalmucosa,characterizedby25intermittentorpersistentnasalcongestion,sneezing,rhinorrhea,itchingand/orhypersecretiondueto26causesandconditionsattributabletoaparticularworkenvironment,andnottostimuliencountered27outsidetheworkplace.84Occupationalrhinitisisconsideredaformof“work-relatedrhinitis”,whichalso28encompasseswork-exacerbatedrhinitis,whichispre-existingorconcurrentrhinitisthatisworsenedby29workplaceexposures.84,85[FigureIII.C.3.]30

Occupationalrhinitismaybeallergic,consequenttoexposuretoasensitisinghigh-molecular31(HMW)orlow-molecularweight(LMW)compoundactingthroughanimmunologicalmechanism,and32characterizedbythepresenceofalatencyperiodbetweenbeginningofexposureandsymptomonset.33Alternatively,occupationalrhinitismaybenon-allergic,mediatedbyandirritantornon-immunological34mechanism.Symptomsoccuraftersingleormultipleexposurestoirritantcompounds,andusually35presentwithoutalatencyperiod.Non-allergicoccupationalrhinitisresultingfromasingleexposuretoa36veryhighconcentrationofirritantsisalsoreferredasreactiveupperairwaysdysfunctionsyndrome37(RUDS).Themostsevereformofirritant-inducedoccupationalrhinitisiscorrosiverhinitis,whichis38

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characterizedbypermanentinflammationofthenasalmucosasometimesassociatedwithulcerations1andperforationofthenasalseptum.84,852

Theresultsofcrosssectionalstudiesinworkinggroupsshowawiderangeofprevalenceof3occupationalrhinitis(3-87%),86lowerprevalenceforLMW-agentexposureandhigherprevalencefor4HMW-agentexposure.ExamplesofoccupationsatincreasedriskarereportedinTableIII.C.3.87-985OccupationalrhinitisduetoHMW-agentstendtobethreetimesmoreprevalentthanoccupational6asthma,86withwhichitisoftenassociated(upto92%ofcases).997

Occupationalrhinitisandoccupationalasthmashareetiologicagentsandpathogenic8mechanisms,100andcanbeconsideredinthebroadercontextoftheUnifiedAirwayDisease9model.85,93,101,102[TableIII.C.3.]Theseverityofoccupationalrhinitismayalsoaffecttheseverityof10occupationalasthma.103Inahighproportion(20-78%)ofworkersexposedtosensitizers,work-related11nasalsymptomstendtodevelop5-6monthsbeforetheonsetofbronchialsymptoms.84,86Consequently,12occupationalrhinitismaybeconsideredamarkerofthelikelihoodofdevelopingoccupationalasthma.13

Theclinicalpresentationofoccupationalrhinitisisnonspecific.Nasalsymptomsdonotdiffer14fromthoseofnon-occupationalrhinitis.Anoccupationaloriginshouldbesoughtforallrhinitisofnew15onsetinadults,especiallyinsubjectsemployedinhigh-riskoccupations.[TableIII.C.3.]Thediagnostic16assessmentfirstincludesathoroughclinicalandoccupationalhistory,aimedtoinvestigatetypeof17symptomsandwork-relatedness,andtocollectinformationonoccupationalexposure.Typicalnasal18symptomsareoftenaccompaniedbycrustformation,sporadicepistaxis,olfactionimpairment,19conjunctivitis,orassociatewithpharyngeal,laryngealorbronchialsymptoms(whichshouldalwaysbe20evaluated).Thepresenceofalatencyperiodbetweenanoccupationalexposureandsymptomonset21suggestsanallergicmechanism.Documentationofnoxiouscompounds(sensitizersandirritants)inthe22workplacetowhichtheworkerismoredirectlyexposedaretypicallypostedbytheemployer(i.e.23MaterialSafetyDataSheets).84,8524

Nasalexaminationsbyanteriorrhinoscopyandnasalendoscopy,assessingnasalpatency85,10425andinflammationinnasalsecretions105areoftenperformedaspartoftheclinicalevaluation.26SensitizationtoasuspectedHMW-agentcanbeevaluatedthroughSPTand/orinvitrosIgEassessment,27whenstandardizedandvalidatedextractsareavailable.Asuggestivehistoryassociatedwithapositive28immunologicaltestforanoccupationalagentcouldbeconsideredasprobableallergicoccupational29rhinitis.Adefinitivediagnosisisobtainedbyobjectivedemonstrationofthecausalrelationshipbetween30rhinitisandtheworkenvironmentthroughanasalprovocationtest(NPT)withthesuspectedagent(s)in31thelaboratory,whichisconsideredthegoldstandardfordiagnosis.84,85IfNPTisnegative,further32evaluationofwork-relatedchangesinnasalparametersattheworkplaceisrecommended,especiallyin33thepresenceofahighlysuggestiveclinicalhistory.InsubjectsexposedtoHMW-agentswitha34suggestivehistoryandnegativeimmunologicaltests,thetypeofinflammatoryresponsetoNPTmight35demonstratethepresenceofanoccupationallocalallergicrhinitis(LAR).106,107Duetotherelationship36betweentheupperandlowerairways,spirometry,measurementofnon-specificairwayresponsiveness,37andmeasurementofbronchialinflammationbymeansofexhaledNOmayalsobeperformed.84,8538

Primarytreatmentofallergicoccupationalrhinitisisavoidanceorreductionofculprit39exposures.108Pharmacologictreatmentdoesnotdifferfromthatofnon-occupationalrhinitis.101In40allergicoccupationalrhinitisduetoHMW-sensitizers,specificimmunotherapymaybeproposedwhen41validatedextractsareavailable.109Thepreventionandearlyidentificationofoccupationalrhinitisduring42

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medicalsurveillanceofexposedworkersandofyoungapprenticesmayprovideanexcellentopportunity1topreventthedevelopmentofoccupationalasthma.110,1112

3TableIII.C.3.Examplesofhigh-riskoccupationsforoccupationalrhinitisandcausalagents4

Occupation AgentHighmolecularweightagentsBakers,foodindustry Cerealflours87Laboratoryworkers Laboratoryanimals(rat,mouse)88Healthcareworkers Latex89Farmers Animal-derivedallergens,plantallergens,molds90Seafoodworkers Shellfish,bonyfish91Pharmaceutical&detergentindustries Biologicalenzymes92LowmolecularweightagentsHairdressers Persulphates93Carpentry,furnituremaking Wooddust94,95Pharmaceutics,healthcareworkers Drugs96Chemicalfactories Mixtureofirritants96Cleaners Mixtureofirritants97,9856FigureIII.C.3.Classificationofwork-relatedrhinitis847AdaptedfromMoscatoG,etal.Allergy2008;63:969-980.89

10

11

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III.C.4.Chemicalrhinitis1

Chemicalrhinitislargelyfallsunderthecategoryofoccupationalrhinitis,howeverthereare2chemicalexposuresthatarenotnecessarilyoccupational(andviceversa).Somechemicalsmaycause3sensoryirritationwhichcanincludecongestion,rhinorrhea,nasaldiscomfort,post-nasaldrainage,4headache,andevenepistaxis.112Exposures,orexposurerisk,areimportantelementstoelicitinthe5history.Therearemanychemicalswithwhichspecificoccupationsarecloselyassociated,though6householdchemicalsandsport/leisureexposures(i.e.chlorine-inducedrhinitisinswimmers113)mayplay7aroleaswell.Largerchemicalparticlesaretypicallytheculpritinthisformofrhinitisassmallerparticles8usuallypassthroughtothelowerairways.Watersolubleagentssuchasammonia,formaldehyde,or9sulfurdioxidemayreadilydissolveintothemucousmembranelayer.114Theseresponsesarenon-IgE10mediatedbyareflexresponsewhichisoftentermedneurogenicinflammation.115Asubsetofthese11individualsinvolvedinhigh-levelsingleexposureincidentsmaydeveloppersistentsymptoms.This12phenomenonhasbeendescribedasRUDSwhenonlyrhinitissymptomsarepresent,andReactive13AirwaysDysfunctionSyndromewhenasthma-likesymptomsarepresent.116,11714

Althoughchemicalsarenotalwaysthoughtofassensitizers,someofthesecompoundscan15induceimmunologicdisease.Chemicalsknowntocausesensitizationoftherespiratorytractinclude16diisocyanates,acidanhydrides,someplatinumsalts,reactivedyes,glutaraldehyde,plicaticacid,and17chroamine.118-120Thereisstillmuchdebateastotheexactmechanismbehindsensitizationtothese18chemicals.However,smallerchemicalcompoundsmustassociatewithlargerproteinmoleculesto19induceanimmuneresponse.WhilespecificIgEproductiontowardchemicalscausingrespiratoryallergy20isseen,evidencetoshowsymptomsrelatedtochemicalexposurewithoutconcomitantriseinIgEhas21alsobeenpreviouslydocumented.121Itispossiblethatthesefindingsmaybeduetotheinabilityto22synthesizeappropriateinvitroconjugatesfordiagnosticassaystodetectserumIgEthatbindsthese23chemicals.122,12324

Typically,thedifferentialshouldincludecausesofbothARandNAR,aswellasmixedrhinitis,25recurrentacuterhinosinusitis(RARS),andpotentiallyCRS.Somesymptomsofchemicalrhinitismaybe26similartoARwithnasaldischarge,congestion,sneezing,anditchingallbeingreported.Nasaldischarge27maybeanteriororposteriorwithchemicalrhinitisorARbutistypicallynotunilateralwitheitherof28thesediagnoses.Chemical-inducedrhinitismaybeassociatedwitholfactorydysfunction,both29temporaryandlong-lasting.Thesedisturbancesincludehyposmia,oranosmiaaswellasdysosmiaor30agnosmia(inabilitytoidentifysmells).112Nasaldiscomfort,discharge,congestion,headaches,and31sometimesepistaxismayalsobepresent.112323334III.C.5.Smoke-inducedrhinitis35

Environmentaltobaccosmokeexposureisassociatedwithchronicrhinitisandinsomecases,36AR.124,125Inseveralstudies,self-reportedsymptomstendtobeelicitedbyexposuretosmokeandcan37correlatewithserumcotininelevels.126-128SymptomscommontobothARandsmoke-inducedrhinitis38includerhinorrheaandcongestion,butsmoke-inducedrhinitisdoesnotappeartobedrivenbyIgE-39mediatedhypersensitivity(whichtendstoexhibitaconstellationofcongestion,rhinorrhea,and40

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sneezingonexposuretoaspecificallergen).AsARsymptomsareimmunologicallymediated,theremust1beasensitizationperiodpriortotheexposurethatelicitssymptoms.Incontrast,smokeinduced-rhinitis2typicallydoesnotrequiresensitization,althoughtherehasbeenreportofpotentialallergenic3compoundsinsmoke.129Interestingly,althoughactivesmokersarelikelytohaveanelevatedserumIgE,4theyexhibitalowerskintestreactivitytoallergensthanallergicnon-smokers.1305

IncontrasttoAR,smoke-inducedrhinitisislikelymultifactorial,andothermechanismssuchas6neurogenicorirritantetiologiesplayamorepredominantrole.131,132Neurogenicnasalinflammationis7mediatedbyneuropeptidessuchassubstanceP,neurokininA,andcalcitoningene-relatedpeptide.8Thesemediatorsarereleasedbysensorynervefibersinthenoseandresultinvasodilation,edema,and9inflammation.133Patientswhoarereactivetotobaccoexposureareidentifiedbybothsubjective10(congestion,rhinorrhea,sneezing)andobjectiveresponse(increasednasalresistance)tocontrolled11challengewithtobaccosmoke.Inaprospectivestudy,patientsweredefinedasdemonstratingreactivity12ifnasalresistanceonacousticrhinometryincreasedbyover35%inresponsetotobaccosmoke.Patients13withlessthan5%increaseinnasalresistanceweredefinedasnonreactive.131Inaddition,altered14mucociliaryclearance(MCC)resultingfromtobaccosmokeexposurehasbeendemonstrated.15Congestiveresponseshavebeendemonstratedonchallengewithbothbriefandprolongedexposureto16tobaccosmoke.Inindividualswhoreportahistoryofsmoke-inducedrhinitis,briefsmokeexposure(4517partspermillion[ppm]for15minutes)ledtoincreasednasalresistanceasmeasuredbyposterior18rhinometry.Inindividualswithandwithoutahistoryofsmoke-inducedrhinitis,prolongedexposureto19moderatelevelsofsmoke(15ppmfor2hours)alsoinducedacongestiveresponselastingforanhouror20longer.134Eventhoughtheobjectiveresponsewasshortlived,patientsreportedsymptomslastinghours21todaysfollowingexposure.Significantsymptomoverlapmayexist,butathoroughhistoryandallergy22testingcanhelpfurtherdifferentiatesmoke-inducedrhinitisfromAR.(SeesectionVI.E.RiskFactorsfor23AllergicRhinitis–TobaccoSmokeforadditionalinformationonthistopic)242526III.C.6.Infectiousrhinitis27

Infectiousrhinitismaybeclassifiedintoacuteandchronicforms,withbothbacterialandviral28etiologies.Physicalfindingsandchronicityofsymptomsplayanimportantroleindifferentiating29betweendifferentformsofrhinitis,includinginfectious,allergic,andtheinflammationassociatedwith30CRS.Symptomssuggestiveofanon-infectiousetiologyincludenasalitchingandsneezing,whilefindings31ofmucosalinflammationandrhinorrheamaybepresentineitherinfectiousornon-infectiousrhinitis.2632Takeninisolation,darkorpurulentrhinorrheaisnotpathognomonicforbacterialrhinitis/rhinosinusitis.33Additionalfindingssuggestiveofinfectiousetiologiesincludeassociatedpharyngealinflammationor34cervicallymphadenopathy.13535 Viralrhinitistypicallymanifestsinanacuteform,andaccountsforupto98%ofinfectious36rhinitisintheyoungchild.Theincidenceofviralrhinitisinyoungchildrenissixepisodesperpatient-37year.136Inadultviralrhinitis,theincidenceis2-3episodesperyear.Symptomsassociatedwithviral38rhinitisincludeclearrhinorrhea,nasalobstruction,andoften,fever.Theresponsibleorganismsofviral39rhinitiscanberhinovirus,adenovirus,influenzavirus,andparainfluenzavirus.81Mostviralrhinitisisself-40limitingwithin4-5days,withprolongedsymptomslastinglongerthantwoweekssuggestiveofanon-41

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infectiousetiologyorconversiontobacterialinfection.Thereareinstanceswhencontinuedrhinitis1beyond10daysisfelttobeduetoworseninginfection(i.e.possiblesuperimposedbacterial2rhinosinusitis)andthesepatientsshouldbetreatedmoreaggressively.137Approximately2%ofviral3rhinitisepisodesaresecondarilyinfectedbybacterialorganismssuchasStreptococcuspneumoniae,4HaemophilusinfluenzaeandMoraxellacatharralis,withsubsequentpresentationofacutebacterial5infection.138678III.C.7.Rhinitisofpregnancyandhormonally-inducedrhinitis9

Thedevelopmentofatypeofrhinitisuniquetothepregnantpatienthasbeenreferredtoas10rhinitisofpregnancyorpregnancyrhinitis.Itoccursinabout22%ofpregnancies139and,although11symptomsmayoccuratanytime,ittypicallystartsafterthesecondmonthofpregnancyandismost12severeinthesecondtrimester.26,140Rhinitisofpregnancyhasbeendefinedasnasalcongestioninthe13last6ormoreweeksofpregnancy,withoutothersignsofrespiratorytractinfectionorallergiccause,14followedbycomplete,spontaneousresolutionofsymptomswithin2weeksafterdelivery.14115

Thesymptomsofrhinitisofpregnancy,likethoseofAR,includerhinorrheaandnasal16congestion,whichcanbeprominentandprolonged.Clinicalhistoryfrequentlyelicitsapriorhistoryof17chronicrhinitis,obscuringtheextenttowhichpregnancyisacausaloraggravatingfactor.139Inaddition,18pre-existingARcanworseninapproximatelyone-thirdofpregnantwomen.14219

Thereareseveraletiologicfactorspotentiallyassociatedwiththenasalsymptomsinrhinitisof20pregnancy.Hormonalchanges,suchasincreasedprogesterone,estrogen,prolactin,vasoactiveintestinal21peptideand/orplacentalgrowthhormonehavebeenimplicated,143,144butthereislittleevidenceto22supportthistheory.145Otherphysiologicphenomenaoccurringduringpregnancythatmaycontributeto23increasednasalcongestionorobstructionincludevasodilation,progesterone-inducedsmoothmuscle24relaxation,andamassiveexpansionofthecirculatingbloodvolume,whichmaycontributetoincreased25nasalvascularpooling.14626

Rhinitisofpregnancydoesnotusuallyrequiretherapy,nordoesitrespondwelltostandard27allergymedications.Itsmanagementismademoredifficultbythelackofhigh-qualitystudiesonthe28efficacyoftreatmentandfetaloutcomes.Inthosewhoseektreatment,conservativenon-29pharmacologicmeasuresaresuggested.Thesecanincludeelevationoftheheadofthebed,147nasal30dilatorstrips,148andexercise.149,150Salinelavageusinghypertonicsalinehasbeendemonstratedtobe31effectivewithoutobviousdeleteriouseffectsonthefetus.151Severalmedications,includingINCS,have32beenstudiedinrhinitisofpregnancybuthavefailedtodemonstrateclearefficacy.152Morerecently,a33systematicreviewbyKumaretal153identifiedonlyoneRCTthatfailedtodemonstrateanyadditional34benefitoffluticasonecomparedtoplaceboforsymptomcontrolinthispatientpopulation.Althoughan35extensivediscussionofrhinitisofpregnancymanagementisbeyondthescopeofthisdocument,theuse36ofvariousothermedications(i.e.topicalandoraldecongestants)iscontroversialandshouldbe37addressedattheindividualpatientlevel,withcloseinvolvementoftheobstetrician.38

Directstimulationofthenasalmucosabyestrogenmayinducemucosalglandhyperactivity39resultinginincreasednasalsecretions/rhinorrhea.154Assuch,nasalsymptomscanbeassociatedwith40conditionsotherthanpregnancythataffecthormonebalance,suchashypothyroidismand41

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acromegaly.155Rhinitismayalsoariseasaresultofchangingbloodhormoneconcentrationsduring1puberty,menstruationandtheperimenopausalyears.145Althoughoralcontraceptiveshavealsobeen2implicatedascausesofnasalsymptoms,astudybyWolstenholmeetal156foundnonasalphysiologic3effectsinpatientsreceivingoralcontraceptivetreatment.4

Insummary,therearenumerousmetabolicconditionswithsymptomslikethoseofAR.Accurate5diagnosiscanbemadeonhistoryandpresentation,butadditionaltestingmayberequiredfor6symptomsthatarepersistentorsevere.789III.C.8.Food-andalcohol-inducedrhinitis10

Food-inducedrhinitis.Certainfoodingestionsmayresultinrhinitisbasedonanon-immunologic11reaction,andthereforearenotcharacterizedasanallergy.Forinstance,insubjectswithgustatory12rhinitis,shortlyafteringestionofhotorspicyfoods,unilateralorbilateralwateryrhinorrheadevelopsin13theabsenceofnasalcongestion,pruritus,orfacialpain.Thisisconsideredareflexresponseduetoan14adrenergicandcholinergicneuralreactionofthenose.15715

Theprevalenceof“food-inducedrhinitis”seemstobeunder1%.157Whilerhinitismay16frequentlybeobservedaspartofsystemicIgE-mediatedfoodallergyreaction,itisrarelytheonly17presentingsymptom.Inadouble-blind,placebo-controlledfoodchallengestudyof480children,18518children(39%)experiencedocularandupperrespiratorysymptoms,butonly5%hadsymptoms19confinedtotheupperrespiratorytractalone.15820

Patientswithpollen-foodallergysyndrome(PFAS),alsoreferredtoasoralallergysyndrome21(OAS),oftenexperienceoropharyngealitching,tingling,and/ormildswellingofthelips,tongue,palate,22andthroat,andlesscommonlyARsymptoms,afteringestionofcertainrawfruitsandvegetables.The23assessedprevalenceofthisdisorderrangesfrom5%to17%,anditaffectsuptohalfofpollen-allergic24patients.159-161Itoccursinindividualswhoaresensitizedtopollenaeroallergensthroughtherespiratory25tract,whichthenpredisposesthemtoclinicalsymptomsofPFASafteringestionofcross-reactive,heat-26labilefoodproteinsofplantorigin.Becausetheantigensareheat-labile,patientsareusuallyableto27toleratecookedformsofthecausativefruitsandvegetables.162(SeeSectionX.E.AssociatedConditions–28FoodAllergyandPollen-FoodAllergySyndromeforadditionalinformationonthistopic.)29

30Alcohol-inducedrhinitis.Nasalsymptomscanalsooccurafteralcoholconsumption.163,164However,very31littleisknownabouttheprevalenceandpresentationofalcohol-inducednasalsymptoms.Additionally,32thereisapaucityofinformationabouttherelationshipbetweenalcohol-inducednasalsymptomsand33otherdiseases,suchasAR,nasalpolyposis,asthma,andotherchroniclowerairwaydiseases.16534

Airwaysymptomsarepredominantlyinitiatedbyinhaledcomponentsthatcontacttheairway35mucosalmembrane.However,severalformsofrhinitisandasthmamaynotoperatethroughthis36mechanism.Onesuchexampleisknownasalcohol-inducedasthma.Inthesepatients,alcoholic37beverages,particularlyredandwhitewines,havebeenshowntotriggerbronchialsymptoms.163,166,16738

Alcohol-inducednasalsymptomsareabouttwiceascommoninfemalesasinmales,165butthe39basisforthispredilectionisnotwellunderstood.168-170Nasalcongestionisthepredominantsymptom,40andredwineisthemostcommonalcoholicbeveragetoelicitsymptoms.Additionally,wine,particularly41

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red,isalsothemostwidelyrecognizedtriggerofalcohol-inducedbronchialsymptoms.163Finally,direct1alcoholutilizationhasalsobeenassociatedwithatrendtowardsdevelopingSPTpositivity,171andwith2increasedserumtotalIgE(tIgE)levels.172345III.C.9.Non-allergicrhinitiswitheosinophiliasyndrome(NARES)6

Non-allergicrhinitiswitheosinophiliasyndrome(NARES)isaclinicaldisordercomprising7symptomsconsistentwithPARinwhichanabsenceofatopyhasbeendemonstrated,andeosinophiliais8foundonnasalcytology.173ThepathophysiologyofNARESisnotwellunderstood,butakeycomponent9involveschronicaneosinophilic,self-perpetuatinginflammation,withnon-specifichistaminerelease.It10isthemostcommontypeofinflammatoryNAR,andwasfirstdescribedin1981byJacobsetal.17411

NARESpatientsreportsymptomsthataretypical,althoughoftenmorepronounced,thanthose12ofPAR.Theseinclude,nasalcongestion,profuseaqueousrhinorrhea,sneezing,andnasalandocular13pruritis.AprominentfeaturenotsharedwithARisanosmia,afrequentfindinginNARESpatients.17514NARESisdiagnosedbycarefulhistory,findingsonphysicalexam(pale,boggyturbinates,likethose15foundinPARpatients),andnegativeskinorinvitroallergytesting.CytologicexaminationinNARES16revealsthepresenceofprominenteosinophilia,usually10-20%173onnasalsmear,withadiagnostic17criterion(describedbysome)ofmorethan25%eosinophilia.176Inaddition,nasalbiopsiesfromthese18patientscommonlyshowincreasednumbersofmastcellsandprominentmastcelldegranulation.177,17819

ResearchhassupportedtheroleofchronicinflammationinthedevelopmentofNARES.Though20thereisstillalackofunderstandingastotheexactpathophysiology,studieshaveshownanincreased21transendothelialmigrationofeosinophils,attractedandactivatedbychemokinesandcytokines.179,18022Specifically,NARESischaracterizedbyelevatednasalfluidlevelsoftryptase(alsoseeninPARpatients)23andeosinophiliccationicprotein(ECP)(markedlyincreasedsolelyinNARES).181Inaddition,increased24Th2cytokines(interleukin[IL]-6andIL-17)appeartobeafactorintheremodelingprocessseenin25NARES.182Otherpro-inflammatorychemokinesthathavebeenimplicatedfortheirroleineosinophil26chemotaxisandinfiltrationincludemacrophage/monocytechemoattractantprotein(MCP)-1and27regulatedonactivation,normalT-cellexpressedandsecreted(RANTES).ElevatedRANTES28concentrationshavebeenfoundinthenasalfluidofpatientswithPARandNARES.183Recently,Pericet29al184demonstratedacorrelationbetweentheconcentrationofRANTESwithnasalsymptomsand30eosinophilcountsinPARpatients.However,levelsofMCP-1andRANTESweresignificantlyhigherinthe31nasalfluidofNAREScomparedtoPARsubjects,whichagain,correlatedwithnasalsymptomscoresand32densityofeosinophiliainthesepatients.Nasalneuraldysfunctionhasalsobeendescribedasa33contributingfactortothesymptomatologyinNARES.18534

NARESusuallyoccursinisolationbutmaybeassociatedwithaspirin-exacerbatedrespiratory35disease(AERD),characterizedbyasthma,nasalpolyps,andNSAIDintolerance.173NAREShasalsobeen36identifiedasariskfactorfortheinductionoraugmentationofobstructivesleepapnea(OSA).18637

ThetreatmentofNARcentersonitsunderlyingcause.Giventheinflammatorychanges38demonstratedonnasalcytologyandphysicalexam,NARESisprimarilytreatedwithINCSsprays.154This39methodoftreatmentisknowntodecreaseneutrophilandeosinophilchemotaxis,reducemastcelland40basophilmediatorrelease,andresultindecreasedmucosaledemaandlocalinflammation.187The41

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intranasalantihistamineazelastineisUnitedStates(US)FoodandDrugAdministration(FDA)-approved1forbothARandNAR.Inclinicaltrials,azelastinehasbeenshowntoreducesymptomsofrhinitis,2includingpostnasaldrainage,sneezing,rhinorrhea,andcongestion.188However,thesemulti-centered,3placebo-controlledtrialsstudiedazelastineforthetreatmentofvasomotorrhinitis(non-allergic4rhinopathy)ratherthanNARESspecifically.567III.C.10.Non-allergicrhinopathy(vasomotorrhinitis)8

VasomotorrhinitisisthemostcommoncauseofNAR,andisfoundin71%ofcases.189-191The9absenceofanIgE-mediatedimmuneresponsedifferentiatesvasomotorfromallergicformsofrhinitis.10110Therefore,theterm“non-allergicrhinopathy”isrecommendedtoreplacevasomotorrhinitis,as11inflammationisnotregardedasacrucialpartinthepathogenesisofnon-allergicrhinopathy.InEurope,12“Idiopathicrhinitis”hasalsobeenusedtodescribethiscondition.13

Non-allergicrhinopathyisadiagnosisofexclusion,andotheretiologicfactorsforrhinopathy14mustbeevaluated.TheseincludeCRS,NARES,AERD,infectiousrhinitis,anatomicalabnormalities,RM,15drugsideeffects,cerebrospinalfluid(CSF)rhinorrhea,andrhinitisofpregnancy.Clinicalcharacteristics16ofnon-allergicrhinopathyhavebeensummarizedinaconsensuspaperbyKalineretal.40Non-allergic17rhinopathyrepresentsachronicdiseasewithprimarysymptomsofrhinorrhea.Associatedsymptomsof18nasalcongestion,postnasaldripintheabsenceofacidreflux,throatclearing,cough,Eustachiantube19dysfunction,sneezing,hyposmiaandfacialpressure/headachemayalsobepresentwithnon-allergic20rhinopathy.Thesesymptomsmaybeperennial,persistent,orseasonal,andaretypicallyelicitedby21definedtriggers,suchascoldair,climatechanges(i.e.temperature,humidity,barometricpressure),22strongsmells,tobaccosmoke,changesinsexualhormonelevels,environmentalpollutants,physical23exercise,andalcohol.Whileoftenassociatedwithnon-allergicrhinopathy,thelackofadefinedtrigger24doesnotprecludethisdiagnosis.Inaddition,nasalhyper-reactivitytonon-specificstimulimayoccurin25bothallergicandnon-allergicrhinitis.19226

Non-allergicrhinopathyisprimarilyfoundinadults,withafemale-to-maleratioof2:1to3:1.On27physicalexam,thenasalmucosausuallyappearsnormal,butmayshowsignsoferythemaandclear28rhinorrhea.Whilesystemicallergytesting(skinorinvitrotesting)istypicallysufficienttodifferentiate29betweenARandnon-allergicrhinopathy,adiagnosisofLARmaybeconsideredinthesettingofnegative30systemictesting.IndividualswithLARsufferfromtypicalallergicsymptomsuponallergenexposure,but31displayalackofsystemicIgEsensitization.Localprovocationisnecessarytodefinitivelyexcludethis32diagnosis.193,19433

Whiletheexactpathophysiologyofnon-allergicrhinopathyremainsincompletelydescribed,34neurosensoryabnormalitiesarethoughttoplayacrucialrole.40Inapriorstudyofcentralresponsesto35olfactorystimuli,subjectswithnon-allergicrhinopathyunderwentfunctionalmagneticresonance36imagingfollowingexposuretodifferentodors(vanillaandhickorysmoke).Findingsincludedincreased37bloodflowtotheolfactorycortex,leadingtothehypothesisofanalteredneurologicresponseinnon-38allergicrhinopathy.195,196Patientswithnon-allergicrhinopathywithapredominantsymptomof39rhinorrheawilloftenrespondtotreatmentwithintranasalanticholinergicssuchasipratropiumbromide40(IPB).41

Deleted: occasionallyexistbutarenottheprimary42complaint43

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12III.C.11.Age-relatedrhinitis3

Age-relatedchangesoccurineveryorgansystem,includingtherespiratorysystem.Specificto4thenasalcavity,thephysiologicalprocessofagingresultsinneural,hormonal,mucosal,olfactory,and5histologicalterationsthatcausemorphologicalandfunctionalchangesintheagingnose.197,198This6makestheelderlypopulationmorevulnerabletosymptomssuchasrhinorrhea,nasalcongestion,7postnasaldrip,drynose,intranasalcrusting,anddecreasedolfaction.199,200Arecentpublicationby8DelGaudioandPanellareviewedtheliteraturepertainingtointranasalfindingsoftheagingnose,which9theyhavetermed“presbynasalis”.2011011Age-relatedrhinorrhea.Rhinitisoftheolderadult(i.e.“drippynose”or“senilerhinorrhea”)isawell-12recognizedentity.Rodriguezetal202usedaquestionnairetodemonstratethatclearrhinorrhea13increaseswithage.Resultsshowedthatonly33%oftheyoungeragegrouprespondents(n=76,mean14age19years)regularlyreportedclearanteriordrainageascomparedto74%oftheolderagegroup15respondents(n=82,meanage86years).16

Thephysiologicreasonforincreasedrhinorrheawithageisnotentirelyknown.However,itis17knownthata andb receptorsbecomelesssensitiveandautonomicfunctiondeclineswithage,which18leadstoanimbalanceofsympatheticandparasympathetictone.202-204Itispossiblethatdecreased19sympathetictonewithunopposedparasympatheticstimulationresultsinariseinglandularactivityin20thenasalcavity,leadingtoincreasednasaldrainage.202,205Thismechanismissimilartovasomotor21rhinitis/non-allergicrhinopathy,wheretheautonomicresponsetocertainstimulantscausesthenasal22mucosalbloodvesselstovasodilateandthemucusglandstobecomeoveractive,resultingin23hypersecretionanddrainage.206Vasomotorrhinitis/non-allergicrhinopathyisthemostcommontypeof24NAR,205andthehighestprevalenceofNARisseenintheelderly.144,189,200,207Thiswouldsuggestan25autonomicdysregulationasthereasonforincreasedrhinorrheaintheagingpopulation.2627Age-relatednasalobstructionandcongestion.Factorsthatcontributetoanincreaseinnasal28obstruction/congestionintheagingnoseincludethickermucussecondarytoadecreaseinbodywater29content,208-210nasalairflowobstructionsecondarytostructuralchangescausedbythelossofnasal30cartilageelasticityandtipsupport,198,200,210andmucusstasissecondarytolesseffectiveMCC.200,209Hoet31al211demonstratedadeclineinMCCeffectivenesswithagein90healthysubjectsaged11-90.Subjects32over40yearsofagehadaslowerciliarybeatfrequency,increasedmicrotubuledisarrangement,and33longerMCCtimesonsaccharintesting.ThickenedmucusandalesseffectiveMCCsystemmayalsolead34topostnasaldrip,whichisacommonnasalcomplaintintheelderlypopulation.20035

Anotherfactorcontributingtonasalobstruction/congestionintheelderlyisage-relatedcentral36nervoussystemchangesthataffectthephysiologicnasalcycle.208,212Mirzaetal212measuredtherelative37airflowofthetwonasalchambersat15-minuteintervalsfor6hoursacross4differentagegroups38(n=60)usingliquidcrystalthermography.Theyfoundthattheproportionofsubjectsexhibitingthe39classicnasalcycledecreasedwithage,beinglowestinthe70-85year-oldgroup.4041

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Age-relatednasaldrynessandintranasalcrusting.Nasaldrynessandintranasalcrustingaremore1commonintheelderlypopulation.Thisislikelyduetoage-relatedchangesofthenasalmucosa,199such2asadecreaseinmucosalbloodflowandanincreaseinepithelialatrophy.213Schrodteratel214evaluated3nasalmucosasamplesfromthemiddleturbinateof40healthysubjectsbetweentheagesof5and754years,andfoundanage-relatedincreaseinatrophicepitheliumandthickenedbasementmembranesin5patientsover40.6

Nasaldrynessintheelderlypopulationmayalsobecausedbyadecreaseinintranasal7temperatureandhumidity.200Lindemannetal199measuredthesevaluesin80healthypatientsand8foundthemtobesignificantlylowerinolderpatients(age61-84years)thaninyoungerpatients(age920-40years).Theauthorsattributedthedifferencetoanincreaseinintranasalvolume(INV)fromage-10relatedatrophyofthenasalmucosa,withINVmeasuredbyminimalcross-sectionalareasandvolumes11ofeachnasalcavity.AnincreaseinINVwithagehasalsobeendemonstratedbyLoftusetal215using3D-12volumetricanalysisofcomputedtomographyscansfromsubjectswithoutsinonasalpathology.Mean13INVwas15.73mLinthe20-30year-oldagegroup(n=22),17.30mLinthe40-50yearagegroup(n=20),14and18.38mLintheover70yearagegroup(n=20).1516Allergicrhinitisintheelderly.Althoughthereisoverlapbetweenage-relatedrhinitisandARinthe17elderlyintermsofsymptomsandrecommendedtreatmentwithINCS,210,216theunderlyingphysiologic18processofeachisquitedifferent.ARisatypeIIgE-mediatedhypersensitivityreaction,217,218whereas19allergyandallergensdonotplayaroleinthesymptomsandphysiologicchangesofage-relatedrhinitis.20However,ithasbeenshownthatagingdoesnotreducetheprevalenceofARandthatARintheelderly21islikelyunderdiagnosed,soARshouldbeconsideredwhendiagnosingnew-onsetnasalsymptomsinthe22elderlypopulation.210232425III.C.12.Emptynosesyndromeandatrophicrhinitis26

Thedescriptiveterm“emptynosesyndrome”(ENS)wasoriginallycoinedin1994byKernand27Stenkvisttodescribeemptyspaceintheregionoftheinferiorandmiddleturbinatesoncoronal28computedtomography(CT)imagesofpatientswhohadpartialortotalinferiorandmiddle29turbinectomies.219Today,ENSisdefinedasanupperairwaydisordercharacterizedbyimpairednasal30airflowsensationandofteninvolvestissuelossfromnasalsurgery.ENSisdividedintoatleastthree31subtypes:ENS-inferiorturbinate,ENS-middleturbinate,andENS-both,whichareclassifiedbasedonthe32siteoftissueloss.219ENS-inferiorturbinateisthemostcommontype.220AfourthsubtypetoofferisENS-33typewhereinapatienthassufficientappearingturbinatetissuebutsuffersENSsymptomsaftersurgery34affectingthemucosalsurfaceoftheturbinates.35

ENStypicallyoccursfollowingsurgeryintheturbinates.Mostturbinatesurgeryhassuccessful36outcomes,withENSoccuringafteraverysmallpercentageofsinonasalprocedures.221,222ENSoccurs37mostfrequentlyaftertotalturbinateexcision,butalsowithlesserproceduressuchassubmucosal38cauteryorresection,lasertherapy,andcryosurgery.223Patientsoftencomplainofdrynessandcrusting,39althoughthehallmarkcomplaintofENSpatientsisparadoxicalnasalcongestionthatmaybesosevere40thattheyfeelasiftheyaresuffocating.223Recentresearchhasvalidatedthattheprimaryphysiological41

Deleted: Theonsetofthisconditionmayoccurmonthsto42yearspostoperatively.21943

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mechanismthatproducesthesensationofamplenasalairflowisactivationoftrigeminalcool1thermoreceptors,specificallyTRPM8,bynasalmucosalcooling.224-228Beyondalterationsinairflowanda2reductioninsurfacearea,aberrationsinneurosensorysystemslikelyplayamajorroleintheabnormal3sensationsENSpatientsexperience.Notonlydoesturbinateresectionremovenasalmucosaand4consequentlyairflowsensingthermoreceptors,suchsurgerycausesnervedamagethatifimproperly5healed,resultsinfailuretoreturntoanormalphysiologicstate.221Differencesinnerverecoveryafter6surgerymayexplainwhyonlysomepatientsdevelopENSdespiteidenticalturbinatesurgeries.Indeed,7certainsurgeonshaveidentifiedpatientswithunilateralENSsymptomswhiletheirnormalsensingside8lookslikeamirrorimageintermsofabsentITtissue.Diagnosisismadebasedonhistory,physicalexam,9andthecottontestwhereapieceofslightlymoistcottonisplacedinthenasalcavityfor10to1030minuteswithalleviationofsymptoms,validatingthediagnosis.223Otherconditionsthatpresentwith11nasaldrynessandcrustingshouldberuledout(i.e.atrophicrhinitis,sarcoidosis,etc).TheEmptyNose12Syndrome6-ItemQuestionnairehasdocumentedvalidityinidentifyingENSpatients.229Surgeryfor13submucosalexpansionoftheinternalnasalmucosacanoftenbringreliefforpatients.223Ithasalsobeen14reportedthatdepressionandanxietyareprevalentamongstENSpatients.23015

Atrophicrhinitisisachronic,degenerativeconditioncharacterizedbyinflammationandatrophy16ofthenasalandparanasalmucosa.231Primaryatrophicrhinitisrunsaprotractedcourse.Itcanoccur17spontaneouslywithunknownetiology,butitisalsoassociatedwithabacterialinfection,almost18exclusivelyKlebsiellaozaenae.Inastudyexamining45patientsdiagnosedwithprimaryatrophicrhinitis,19allnasalcultureswerepositiveforKlebsiellaozaenae.231Mucosalinjuryishypothesizedtoresultfrom20prolongedmicrovascularorischemicinjury.231-233Secondaryatrophicrhinitisisfarmorecommonand21usuallydevelopsfollowingdirectinjuryfromtrauma,irradiation,reductivenasalorsinussurgery,orin22certainraregranulomatousdiseases.231,234Secondaryatrophicrhinitisisalsoassociatedwithabacterial23infection,butStaphylococcusaureus,Proteusmirabilis,andEscherichiacoliarethemorecommon24pathogenswithKlebsiellaozaenaerarelyisolated.23125

Atrophicrhinitispresentsasthick,adherentnasalcrusting,nasalcongestion,foulodor,and26atrophyofmucosalandturbinatesurfaces,withseverecaseshavingcompleteabsenceofrecognizable27anatomiclandmarks,septalperforations,orsaddlenosedeformity.231-233Hyposmia,epistaxis,andfacial28painorpressuremayalsooccur.Histologicalexaminationofintranasaltissuedemonstratessquamous29metaplasia,glandularatrophy,anddiffuseendarteritisobliteransinbothtypesofatrophicrhinitis.23130Diagnosisisestablishedfromclinicalexamination,nasalbiopsy,andnasalculturesforassociated31bacteria.32

BothatrophicrhinitisandENSpatientscomplainofnasalcongestion.Foratrophicrhinitis33patients,thisisoftenaresultofsignificantnasalcrusting,althoughasthediseaseprogressesand34mucosaandturbinatetissueislost,thewidenednasalcavitycanverycloselyresemblethatofanENS35patient.Thepathophysiologyoftheparadoxicalsensationofnasalcongestionatthispointisthesamein36bothdiseasestates,althoughtheoriginoftheincitingeventdiffers.37 Intheliterature,ENShasrepeatedlybeendescribederroneouslyasaformorsubsetofatrophic38rhinitis.ENSresultsfromiatrogenicremovalofturbinatetissueandisnotassociatedwithabacterial39infectionwhereasatrophicrhinitisresultsfromachronic,oftenidiopathicinflammatoryprocess40associatedwithbacterialinfectionthatprogressestoresorptionofturbinatetissue.Atrophicrhinitis41patientssufferfromheavycrustingwhereasENSpatientsexhibitonlyminorcrustingornone.42

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TodifferentiateAR[allergicrhinitis]fromatrophicrhinitis,itshouldbenotedthatARisan1immunologicalresponsetoabenignsubstance,theallergen,thatmanifestsprimarilyasnasal2inflammation.ARisIgE-dependent235andcharacterizedbysneezing,clearrhinorrhea,wateryeyes,and3nasalandocularpruritus.1ThisconditionhasacleardistinctionfromENSandatrophicrhinitisinits4clinicalpresentationandpathophysiology.567III.C.13.Autoimmune,granulomatous,andvasculiticrhinitis8

Boththeupperandlowerairwayscanbeaffectedbysystemicdisordersincludingvasculitic,9granulomatous,andautoimmunediseases.Commonly,affectedpatientsmaypresentwithnon-specific10sinonasalsymptoms(nasalobstruction,rhinorrhea,facialpain,andlossofsmell)mimickingAR.Allergy11testingwill,however,benegativeornotclinicallyrelevant.Cliniciansshouldconsiderbroadeningthe12differentialtoconsidersystemicetiologiesifeithercrustingorrecurrentepistaxisisseen.236Oral13steroidsarethemainstayoftreatmentfortheentitiesdiscussedinthissection,althoughtherecent14introductionofmonoclonalantibodiestargetingspecificbiomarkersrepresentsanimportanthallmark15forfuturetherapy.16

17Granulomatosiswithpolyangiitis(GPA).PreviouslyreferredtoasWegener’sdisease,GPAisan18idiopathicdiseasecharacterizedbynecrotizingandgranulomatousinflammationoftheupperandlower19airways(85%),glomerulonephritis(75%)andsystemicvasculitis.237-239LimitedformsofGPAinvolving20onlytheheadandneckmayalsobeseen.GPApredominantlyaffectssmalltomediumsizedarteriesand21veinwalls.240GPAaffectsbothmenandwomeninasimilarproportion,beingfrequentlydiagnosedin22thefourthtosixthdecadesoflife.240IntheUS,estimatedprevalenceis13to30casesper-millionpeople23per5-yearperiod.Nasalsymptomsincludeobstruction,rhinorrhea,recurrentepistaxis,crusting,and24painoverthenasaldorsum.237,241Nasalmucosadisruptionmayleadtoanosmiawhiletissuenecrosis25withsecondaryinfectionmayleadtocacosmia.236Nasalendoscopycanrevealanerythematous,friable26mucosawithcrustingandgranulationthatisseenintheseptumandinferiorturbinate.240Patientswith27severeformscanpresentwithnonvascularnecrosiscausingperforationorbonydestructionofthenasal28septumand/orothernasalstructures.242Diagnosisisbasedonclinicalsymptoms,physicalfindings,29radiologicalexaminations,laboratorytests(positivec-ANCA[anti-nuclearcytoplasmicantibody]in60-3090%),andbiopsyofaffectedtissueforpathologicalexamination.237,238,240Profilingthenasal31transcriptomeinGPArevealsuniquegeneexpressionsignaturesrelatedtoinnateimmunity,32inflammatorycellchemotaxis,extracellularmatrixcomposition,andepithelialbarrierintegritythatmay33eventuallybeusedclinically.243,244Treatmentincludesprednisone,cyclophosphamideor34methotrexate.237,238,245Rituximab,anti-CD20monoclonalantibody,maybeaneffective35therapyinrefractoryorrelapsingc-ANCAvasculitis,246althoughadditionalstudyisneeded.3637Eosinophilicgranulomatosiswithpolyangiitis(EGPA).PreviouslyknownasChurg-StraussSyndrome,38EGPAisararesmall-sizedvesselvasculitiswithaprevalenceof1.3casesper100,000,247typically39diagnosedinpatientsage30-50years.236Rhinitis(75%ofpatients)isoneoftheinitialmanifestationsof40EGPA,248inadditiontoCRSwithnasalpolyps,andpartial/totalsmellloss.249Diagnosisshouldbe41

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suspectedinpatientswithasthma,withincreasedperipheralbloodeosinophilcount(>10%)and1pulmonarymanifestations.238,248EGPAisoftenassociatedwiththepresenceofp-ANCA.247CRSwith2nasalpolyps(CRSwNP)ispresentinapproximately50%ofpatients.238Nasalpainwithpurulentor3bloodynasaldischarge,nasalcrustingornasalseptalperforationcanbepresentbutarelesscommon4thaninGPApatients.238,250Treatmentusuallyincludeshighdosesofcorticosteroidsand5immunosuppressants.248,251Anti-IL-5therapy(mepolizumab)isapotentialbiologicaltreatmentoffering6clinicalbenefitandstabilityandreducingcorticosteroidneeds.25278Sarcoidosis.Sarcoidosisisachronicmultisystemdisordercharacterizedbybilateralhilaradenopathy,9pulmonaryinfiltration,ocular,andskinlesions.238,253Morecommonlyseeninyoungandmiddle-aged10adults,254femalesmorefrequentlythanmales,andAfrican-Americans,255aprevalenceof50per100,00011individualshasbeenreported.236Theinvolvementoftheupperrespiratorytractepitheliumis12infrequent236andnasalsymptomsarenon-specific:obstruction,epistaxis,nasalpain,epiphora,and13anosmia.237Themostconsistentfindingsareerythematous,edematous,friable,andhypertrophied14mucosaintheseptumandinferiorturbinate.Submucosalyellownodulesrepresentativeofintramucosal15granulomasmaybeidentifiedinmucosalbiopsies,whilenasalpolyps,rhinophyma,andseptal16perforationshavealsobeenreported.238,256Aggressivenon-caseatinggranulomascancausehardorsoft17palateerosionsaswellasseptalperforationsleadingtosaddle-nosedeformity.257,258Thediagnosisof18sinonasalsarcoidosisisbasedontheclinicalfindingswitheitherpolypoidchangesorcharacteristic19yellowishsubmucosalnodularity.238Tissuefordiagnosisisusuallyobtainedbytransbronchial-lung20biopsy254ornasalbiopsy,aswellasfromskinlesions,minorsalivaryglands,andlymphnodes.238The21primarytreatmentforsarcoidosisissystemicsteroids,chloroquine,immunosuppressants,andlung-22transplantation.237,238,256,257Theemergenceofbiologicaltherapieshasincreasedthetherapeuticoptions23totreatrefractoryorgan-threateningsarcoidosis,withmonoclonalanti-TNF(tumornecrosisfactor)24agents(infliximab)beingthemostpromising.2592526Systemiclupuserythematosus(SLE).SLEisanautoimmunediseasethatcanaffectanybodysystem.SLE27predominantlyaffectswomen(10:1)withanincidenceof5.6per100,000people.260Theskinofthenose28andnasalvestibulecanalsobeinvolvedintheskinrashes.237Mucosallesionsareseenin9-18%ofcases29withoral,nasal,andpharyngealmucosabeingcommonlyaffected.260Thediagnosisrequiresadetailed30medicalhistory,aphysicalexamination,andlaboratorytests(anti-nuclearantibody[ANA]oranti-double31strandedDNA),includingacompletebloodcount,chemistrypanel,andurinalysis.236,261Therapywith32corticosteroids,immunomodulators(prasterone,vitaminD,hydroxychloroquine)or33immunosuppressants(azathioprine,cyclophosphamide,ormycophenolate)isprescribedforsymptom34control,238,262whilebelimumabisarecentbiological(anti-BAFF[B-cellactivatingfactor]monoclonal35antibody)topotentiallytreatSLE.263363738III.C.14.Rhinosinusitis39

ThesymptomsofARmayoverlapwithotherformsofnasalinflammation,including40rhinosinusitis.ItisimportanttodifferentiatebetweenARandrhinosinusitistoensurethecorrect41

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diagnosisandsubsequenttreatmentcanbepursued.ARmaybeassociatedwithcomorbid1rhinosinusitis,althoughwhetherARincreasestheriskofrhinosinusitisisdebatable.1Identifying2comorbidrhinosinusitisisessentialtoensuretheappropriatemanagementofbothconditions.Ofnote,3theseconditionsarenotmutuallyexclusiveandtheremaybeanassociationbetweenrhinosinusitisand4AR.ItispossibletohaveconcurrentARandrhinosinusitis,andthispossibilityshouldbeconsidered5whenpatientsmeetdiagnosticcriteriaforbothindependentlyandwhenpatientsymptomatologyor6responsetotreatmentdoesnotfitwithasinglediagnosis.1Ahighdegreeofclinicalsuspicionis7required;however,carefulconsiderationofthesefactorsmayhelpguideclinicianstothecorrect8diagnosisordiagnoses.9

Rhinosinusitisisabroadtermthatincludesthediagnosesofacuterhinosinusitis(ARS),RARS,10andCRS,demarcatedasCRSwNPorCRSwithoutnasalpolyposis(CRSsNP).Symptomatically,these11conditionsarecharacterizedbynasalobstruction,nasalcongestion,facialpressureorpain,anterioror12posteriornasaldischargeandanosmia/hyposmiaforvaryingdurationsoftime.1,138ARsharesseveral13overlappingsymptoms,namelyrhinorrheaandnasalcongestion,whichmaybeconfusedwiththe14subtypesofrhinosinusitis.264,265Conversely,rhinosinusitismaybemistakenforARduetothesimilar15symptomatology.1Understandingthediagnosticcriteriaforthesubtypesofrhinosinusitiswillaid16cliniciansinsolidifyingthecorrectdiagnosis,aswellasidentifyingcomorbidconditions.17

ARSisdefinedasthesuddenonsetofsinonasalsymptomswithassociatedsinonasal18inflammationthatlastslessthan4weeks.1,137,138,266,267Symptomsincludenasalcongestion,nasal19obstructionornasaldischarge,andfacialpressureorpain,oranosmia/hyposmia.Nasaldischargeis20oftenpurulentandmaybediscolored,withatendencytobeunilateralalthoughmaybebilateral.1,13821Facialpressureandpainisdescribedasmoderatetosevere.137ARSmaybeviralorbacterial.Ingeneral,22viralARSispresentforlessthan10days.AlongerdurationofillnesssuggestsbacterialARS.137,13823Progressiveworseningoverashortperiodoftime(i.e.5days)isalsosuggestiveofbacterialARS.137,138In24theEPOS(EuropeanPositionPaperonRhinosinusitisandNasalPolyps)statement,feverandelevated25serummarkersofinflammation(C-reactiveproteinorerythrocytesedimentationrate)arealsoincluded26asdiagnosticcriteria.138Feverisnotincludedinotherguidelines,duetoitslowspecificityand27sensitivity.137RARSisdefinedasatleast4episodesofARSperyear,withdiseasefreeintervalsbetween28episodes.1,137,138,266,26829

CRSisaninflammatoryconditionofthesinonasalcavitypersistingformorethan12weekswith30atleasttwosymptomsofnasalobstructionandcongestion,mucopurulentnasaldrainage(anterioror31posterior),facialpressureorpainandanosmia/hyposmia.1,137,138,266,267Inaddition,patientsmusthave32objectiveevidenceofsinonasalinflammationoneithernasalendoscopy(polyps,edema,mucopurulent33rhinorrhea)oronCTscansofthesinuses.137,138,266,267CRSisdividedintotwomainphenotypicgroups:34CRSwNPandCRSsNP.35

Comparatively,ARischaracterizedbynasalobstruction,nasalcongestion,clearwatery36rhinorrhea(anteriororposterior)andallergicsymptoms.264,265Thepresenceofthesesymptomsshould37raisesuspicionsofARaseitheraprimaryorcomorbiddiagnosis.Conversely,ARistypicallynot38associatedwithpurulentorunilateralnasaldischarge.Moderatetoseverefacialpainand/orfever39wouldalsobeatypicalforisolatedARandmayindicatethepresenceofanepisodeofARSoranacute40exacerbationofCRS,differentiatedbydurationandchronicityofsymptoms.1,137,138Thetimingof41symptomsmayalsohelpdelineatebetweenrhinosinusitisandARasARSsymptomstypicallylastdaysto42

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weeks(butnomorethan4weeks),CRSsymptomspersistdailyforgreaterthan12weeks.In1comparison,whileARsymptomsarevariableinduration,theytendtohaveseasonalorexposure-2relatedfluctuations.1,137,138ARsymptomsarepresentforatleast1houronmostsymptomaticdays;3however,patientsmayhavesymptom-freeintervals.264,265ARsymptomsarealsoexacerbatedby4exposuretoallergensinatimedependentfashion.264Theearlyreactionoccursimmediatelyafter5exposureandischaracterizedbysneezing,nasalandocularitchingandrhinorrhea,whichtypically6resolveswithin30minutes.264Thelatereactiontakesplaceupto6hoursafterexposureandis7characterizedbynasalobstructionandcongestion.264Superimposedlatereactionsmaybluntthe8manifestationofacutephasesymptomsandmakethediagnosisofARlessobvious.9

WhenattemptingtodeterminewhetherapatienthasAR,ARS,RARSorCRS,itisimportantto10elicitahistoryofspecificsymptomsfromthepatientthatincludesonsetanddurationofsymptoms.A11historyofallergicsymptomsorallergenexposure-relatedsymptomssupportapossiblediagnosisofAR,12asthesearenotassociatedwithrhinosinusitisandARmayormaynotbeseasonalinnature,whichcan13alsobeelicitedbyhistory.264,265Thedevelopmentofacute,moderatetoseveresymptomsandnasal14purulencemaybeconsistentwithARSorRARSratherthanAR.1,137,138Aprolongeddurationofsymptoms15(greaterthan12weeks)shouldraisesuspicionsforCRSandpromptfurtherinvestigation.1,137,138(See16SectionX.B.AssociatedConditions–Rhinosinusitisforadditionalinformationonthistopic.)1718

19 20

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IV.Pathophysiologyandmechanismsofallergicrhinitis1

AbackgroundunderstandingofthepathophysiologyandunderlyingmechanismsofARis2necessaryasweexaminetheclinicalpresentations,physicalmanifestations,goalsofallergytestingand3responsetotreatment.Thissectionaddressesthecellularinflammation,solublemediators,localallergic4manifestations,andsystemiceffectsassociatedwithAR.Whilethisdocumentisnotintendedtoprovide5anextensivereviewofthepathophysiologyofAR,thefollowingshortsectionprovidesafoundationfor6understandingtheclinicalexpressionofARanditstreatment.789IV.A.1.Systemicmechanismsandmanifestations10

TheimmuneresponseleadingtoIgEproductioninARisoftenasystemicphenomenon,and11patientswithARdemonstrateevidenceofsystemicatopy.269,270Onemanifestationofsystemicatopyin12ARisthecutaneousreactionelicitedduringtraditionalallergyskintesting.271Furtherevidenceforthe13systemicnatureoftheIgEresponseinARincludesthetemporalrelationshipofARtoanumberofother14allergicdiseases,includingatopicdermatitis(AD),foodallergy,andallergicasthma,aphenomenon15knownasthe“atopicmarch”.272Thispatternofatopicdiseaseprogressioniswell-knownandsupported16byprospectivestudies.27317

TheimmunologicprocessesunderlyingIgE-mediatedARaresimilartothoseofotheratopic18conditionsandinvolveactivationoftheadaptiveimmunesystem.Theadaptiveimmuneresponsecan19bebroadlyclassifiedintotwocategoriesbaseduponthepredominantThlymphocytesubtype.274The20Th1profileisresponsiblefordefenseagainstintracellularpathogens,whileTh2responsesare21implicatedinthedefenseagainstparasiticinfectionsaswellastheIgE-mediatedeosinophilic22inflammationofallergy.272WhetherARwilldevelopasaresultofinhalantallergenexposuretherefore23dependslargelyuponthebalancebetweenTh1andTh2effectorcells.27424

AnumberofstepsinthesensitizationprocessareresponsibleforelicitingtheTh2-predominant25response.Theprocessbeginswithexposureofthenasalmucosatoinhalantallergens.275Whilemucosal26epithelialcellswereoncethoughttofunctionsimplyasamechanicalbarriertoallergenpenetration,27recentresearchsuggeststhatepithelialcellsplayamuchmoresophisticatedroleinallergy28development,throughthesecretionofnumerousinflammatorymediatorsincludingcytokines,29chemokines,eicosanoids,andendopeptidases,aswellasthroughupregulationofcellularadhesion30moleculesandreleaseofmatrixmetalloproteinases.276Theyalsoprovideanimportantearlystimulus31towardaTh2-weightedimmuneresponse,throughthesecretionofthymicstromallymphopoetin32(TSLP).272,275,276TSLPcausesmaturationofdendriticcellsintoTh2-promotingsubtypes,277whichsecrete33chemokinesthatattractTh2-destinedTlymphocytes,fosterclonalamplificationofTh2cells,and34enhancesurvivalofmemoryB-cells.272TSLPalsopromotesrecruitmentofeosinophilsandenhanced35activityofbasophilsandmastcells.27236

Allergensarethenengulfedbydendriticcellswhichmigratetolymphoidorganswherethe37antigenispresentedtonaïvehelperT(Th0)cellsonMHCclassIImolecules.274Th2differentiationalso38requiresco-stimulationviatheinteractionofCD28onTcellswithCD80andCD86onantigenpresenting39cells(APCs).278Additionally,thepresenceofthecytokineIL-4isrequired.279IL-4bindsSTAT-6ontheTh040

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cell,activatingthemasterswitchGATA-3.272ThisstimulatesIL-4,IL-5,andIL-13production,274whichis1characteristicoftheTh2response.Thesecytokines,producedbythenewlydifferentiatedTh2cell,have2severaleffectsthatfurtherpromoteIgE-mediatedeosinophilicinflammationandallergy.3

IgEisproducedbyB-cellsundertheinfluenceofTh2effectorcellsandthecytokinesthey4secrete.275DevelopmentofanIgE-secretingBcellrequiresthepresenceofIL-4orIL-13,whichinduce5classswitchingviaup-regulationofe-germlinegenetranscriptionandclonalexpansion,aswellas6interactionbetweenCD40ligandontheT-cellsurfaceandCD40ontheB-cellsurface,whichpromotes7B-cellactivationandtheproductionofIgE.279Allergen-specificIgE(sIgE)isthenreleasedintothe8circulationbyplasmacells.9

IgEantibodiessubsequentlybindhigh-affinityreceptors(FcεRI)onthesurfaceofmastcellsand10basophils,renderingthemsensitized.280FutureallergenexposureresultsincrosslinkingofIgEonthe11surfaceofmastcellsandbasophilscausingdegranulation,releaseofinflammatorymediatorssuchas12histamine,andtheclassicsymptomsofAR.1314

IV.A.2.IgE-IgEreceptorcascade15

IgEplaysacentralanddefiningroleinthepathophysiologyofacuteallergicreactionsaswellas16chronicatopicdisease.281InindividualswithAR,exposuretospecificallergensresultsintheproduction17ofallergen-specificIgE,whichthenbindstoeffectorcellslikemastcellsandbasophilsviathehigh18affinityreceptorFc!RI.AlthoughIgEinplasmaisshort-lived,IgEthatisreceptor-boundremains19attachedtothesecellsforweeksormonths.Moreover,whenIgEboundtoFc!RIcrosslinkswitha20specificallergen,itinducesthereleaseofpre-formedinflammatorymediatorsfrommastcellsand21basophils,resultinginclinicalmanifestationsofallergicdiseases.22

Cytokinesincludinginterleukin(IL)-4andIL-13releasedfromTcellsandmastcellsdrivethe23differentiationofBcellsintoIgE-secretingplasmacells.Severalstudies,bothinvivoandinvitrohave24confirmedtheproductionoflocalIgEinthenasalmucosaofpatientswithAR.282-284Thelocallyproduced25IgEplaysakeyroleinongoinginflammationbyupregulatingFcεRIexpressioninmastcells.283-285The26augmentedexpressionofFcεRIallowsthemtobindgreaternumbersofIgE-antigencomplexes,whichin27turnenhancesthesensitivityofmastcellstoallergen.Thisresultsinanincreasedproductionof28immunomodulatorycytokinesandchemicalmediators,forminganimportantpositive-feedback29amplificationloopinvolvingtheIgE-IgEreceptorcascade,thusperpetuatingongoinginflammation.285,28630Interestingly,thedensityofIgEreceptorsandIgEmoleculesinmastcellswithinthenasalmucosaof31patientswithARhavebeenshowntocorrelatewithlevelsofserumIgE.285Thepresenceofelevated32levelsofIgEinnasalsecretionshasbeendemonstratedinnon-allergicrhinopathyaswell,which33potentiallyfurtherhighlightsasignificanceoftheIgE-IgEreceptorcascadeindrivingthediseaseprocess34ofrhinitis.2873536

IV.A.3.LocalIgEproductionandlocalallergicrhinitis(LAR)37

LARisaregionalinflammatoryconditiondefinedbylocalsymptomsandsIgE-mediated38inflammationwithoutevidenceofsystemichypersensitivity.107,194,284,288Itisimportanttorememberthat39

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conventionalallergytesting,suchasSPTandtheradioallergosorbenttest(RAST),onlyindicates1sensitization(atopy),butnotsymptomaticallergy.Whileitispossibleforapositiveallergyskinorin2vitrotestresulttolackclinicalrelevance,theoppositeisalsotrue,asanegativeallergyskinorinvitro3testresultdoesnotexcluderegionalIgE-mediatedsensitivity,asinthecaseofLAR.194,288-290LARmay4affectmorethan47%ofchildrenandadultspreviouslyclassifiedasNAR,290-295andpersiststhroughout5theyearswithalowrateofconversiontoclinicalAR.296-298However,LARmayevolvetothe6developmentofasthma.296,297DiagnosisofLARisbasedondemonstrationofapositiveresponsetoNPT7and/orthedetectionofnasalsIgEand/orapositivebasophilactivationtest(BAT)intheabsenceof8systemicatopy.ThepathophysiologyofLARiscomplexandnotcompletelyunderstood.Immunologic9studieshaverevealedtheexistenceofaTh2inflammatoryresponseinthenasalmucosaofLAR10patients,177,299-301withpositiveresponsetoNPT,291,300-302andlocalproductionofsIgE177,290,299-301,303-30511andinflammatorymediators.304,306,3071213NasalTh2inflammatoryresponse.Flowcytometrystudiesinnasalsecretionshaveconfirmedthat14aeroallergenexposureinducesaTh2inflammatoryresponseinthenasalmucosaofLARpatientswith15increasedeosinophils,basophils,mastcells,CD3+,andCD4+Tcells.300,301NPTstudieshave16demonstratedtheexistenceofcharacteristicimmediate/earlyandlate-phasesoftheallergicresponsein17LARpatientswithlocalproductionofsIgE,mastcellandeosinophilactivation,withmucosalsecretionof18tryptaseandECP.306,307Arecentstudyshowedthat83%ofLARsubjectssensitizedtoOleaEuropaea19pollenrespondedtoNPTwithnOlee1(themostsignificantallergenofOleaEuropea)demonstrating20thatpurifiedallergenscanalsoinduceanallergicresponsewithsecretionofECP.3082122LocalsIgEproduction.TherespiratoryairwaymucosaisasiteofIgEproductionduringallergic23inflammation,ashasbeendemonstratedinpatientswithAR309-312andLAR,299-301,303-307withbothsomatic24hypermutationandclassswitchingoccurringinthenasalmucosa.309,312-315Cellularstudieshave25confirmedtheexpressionofe-germlinegenetranscriptsandmRNAfortheeheavy-chainofIgEinnasal26mucosalB-cells.310TherateoflocalIgEproduction316issufficienttosaturateIgEreceptorsonlocalmast27cells,andpotentiallyspilloverintothecirculation.316,317InLAR,thepresenceofsIgEinnasalsecretions28hasbeenconfirmedafternaturalallergenexposure,300,301NPT,300,301,303-305andperiodsofnon-29exposure.300,301Furthermore,localsIgEinLARhasthecapabilityofactivatingbasophilsviathehigh30affinityreceptorFcεRI,leadingtothereleaseofinflammatorymediatorscharacteristicofAR.308,318313233IV.B.Non-IgEmediatedinflammationinallergicrhinitis34

ItiscommonlyacceptedthatARisprimarilyanIgE-drivenresponse.319However,inrecentyears35ourunderstandingandappreciationoftheimportantcontributionsofthenasalinnateimmune36responsetothepathogenesisofARhasgrownsubstantially.320Thepathophysiologicmechanismsof37inflammatoryairwaydiseasearerelatedtolargephysiologicnetworksthatinfluencehost-environment38interactions.Thenasalepitheliumisthefirststructuretoencounterinhaledaeroallergens.Intrinsic39proteolyticactivityofallergensmaydisruptthenasalepithelialbarrier,facilitatingallergenpenetration40andchronicinflammation.321Recentdataprovideadditionalevidencethatepithelialbarrierdysfunction41

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contributestothedevelopmentofinflammatorydiseaseslikeAR,butitremainstobeelucidatedto1whatextentprimary(genetic)versussecondary(inflammatory)mechanismsdrivethisbreakdown.3222Epithelialcellsdonotonlyactasaphysicalbarriertowardinhaledallergens,butalsoactivelycontribute3toairwayinflammationbydetectingandrespondingtoenvironmentalfactors.Thenasalepithelium4expressespatternrecognitionreceptorsintheformoftoll-likereceptors(TLR)that,afteractivationby5allergensorpathogens,leadtotheproductionofdifferentmediators.323,324Thesemediatorsaffect6recruitmentofinflammatorycellstolocaltissuesandcreateamicroenvironmentthataffectsthe7functionofimmunecells,therebypropagatinglocalinflammatoryprocesses.325Inallergicdisease,the8nasalepitheliumseemstobeinapermanentlyactivatedstate,326potentiallyasaconsequenceofthe9inabilitytoswitchofftheactivationresponse.32710

Aninterestingrecentdevelopmentwasthediscoveryofinnatelymphoidcells(ILCs)aspotential11keyplayersinthepathogenesisofTh2-typediseaseslikeAR,CRSwNP,andasthma.328-330ILCsarea12familyofeffectorcellsthatareimportantforprotectionagainstinfiltratingpathogensandrestorationof13tissueintegrity.ILCsdonotexpressantigen-specificT-cellreceptors,butcanreactpromptlyto"danger14signals"andproduceanarrayofcytokinesthatdirectensuingimmuneresponses.Threemajorsubsets15havebeendefinedbasedontheirphenotypeandfunctionalsimilaritiestoTh1(ILC1),Th2(ILC2),and16Th17(ILC3)cells.Uponexposuretoenvironmentalantigens,includingvirusesandallergens,airway17epithelialcellsrapidlyreleasethecytokinesIL-25,IL-33,andTSLPthatdirectlyactivateILC2sthatthen18producetheprototypicaltype2cytokinesIL-5andIL-13.331AllergenchallengeinARsubjectsinducesan19increasednumberofperipheralserumILC2s;332,333however,asimilarincreaseinthenasalmucosaisyet20tobedemonstrated.InadditiontotreatmentsaimedatmodulatingIgE-mediatedinflammation,novel21therapiesdirectedtowardtheinnateimmunesystemareindevelopmentfortreatmentofAR.334,335222324IV.C.Unifiedairwayconcept25

Theupperandlowerairwaysarelinkedfromanatomical,histological,andimmunological26perspectiveswithinflammationinonepartoftheairwaysinfluencingtheotherpart,thusforminga27unitedairwaysystem.336Newsystemictreatmentoptionsmakeunderstandingoftherelationship28betweenupperandlowerairwaysevenmoreimportant.33729

Themucosaoftheupperandlowerairwaysissimilar,containingpseudostratifiedepithelium30withciliatedcolumnarcellslining.Basalepithelialcellsarealsopresent,attachedtothebasement31membrane(laminareticularis),andhaveanepithelialstemcellfunction.Inthesubmucosathereare32vessels,mucusglands,fibroblastsandsomeinflammatorycells.Themaindifferenceinmucosal33componentsistheabsenceofsmoothmusclesintheupperairwaysascomparedtothelowerairways,34andthelackofextensivesub-epithelialcapillaries,arterialsystemsandvenouscavernoussinusoidsin35thelowerairwaysascomparedtotheupperairways.36

Thecharacterizationofphenotypesofrhinitisandasthmaareverysimilar,withemphasison37allergyandeosinophilia,non-allergicphenotypesinbothupperandlowerairways,andthelinkbetween38CRS,especiallywithnasalpolyps,andlateonsetasthma.319,338,339BothARandasthmamayalsobe39characterizedbyhyper-reactivitythatisnotcorrelatedtotheatopicstate.192,340Alsoinendotyping,40similaritiescanbepointedoutwithemphasisontype2versusnon-type2immuneresponses.Inallergic41

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diseases,theprominentendotypeistype2(Th2cells,type2B-cells,IL-4-producingnaturalkiller[NK]/T1cells,basophils,eosinophils,mastcells,ILC2,IL-4,IL-5,IL-13,IL-25,IL-31,IL-33).319,341Ingeneral,thetype22profileinARandasthmaisassociatedwithagoodresponsetocorticosteroidtreatment.Newtargeted3treatmentsthatfocuson(subgroup)type2elements,suchasanti-IgEantibodies,anti-IL-54(mepolizumab)andanti-IL-4/IL-13(dupilumab)arecurrentlyusedinasthma,butarenotcurrently5approvedforuseintheupperairways.342Similaritiesarenotonlyfoundintheacquiredimmune6response,butalsointheroleofinnateimmunitylikeepithelialbarrierfunction334andinnatelymphoid7cells.332Epithelialbarrierleakiness,particularlytightjunctionsthatsealtheupperandlowerrespiratory8mucosalepithelialsurface,hasbeenshowninasthma,ARandCRS.343,3449

Severalmechanismsmayexplaintheinfluenceofsinonasalinflammationonthelowerairways10i.e.alteredbreathingpattern,pulmonaryaspirationofnasalcontents,thenaso-bronchialreflexandthe11uptakeofinflammatorymediatorsinthesystemiccirculation.345Thenoseactsasafilterandair12conditioner,protectingthelowerairways.Reducedfilterandair-conditioningfunctionsofthenosemay13leadtoincreasedexposureofthelowerairwaystoallergens.Mouthbreathingisindependently14associatedwithasthmamorbidity,indicatingthatairconditioningcanbeofmajorimportance.The15efficacyofthenasalfilterdependsonthesizeoftheinhaledparticles.Smallmolecules,suchasmolds16andcatdander,aremoreassociatedwithanincreasedriskforasthma,whereaslargermolecules,such17astreeandgrasspollen,areprimarilyassociatedwithupperairwaysymptoms.Theroleofpreferential18mouthbreathinginthedevelopmentofasthmaisunclear.34619

Althoughthereisarelationshipbetweenpostnasaldripandcoughing,nodirectassociationhas20beenprovenbetweenoverproductionofnasalsecretionsandbronchialhyper-reactivity.Moreover,21afternasalapplication,depositsofradioactive-labeledallergencanbefoundinthedigestivetractbut22notintherespiratorytract.347Stimulationofpharyngolaryngealreceptorsismorelikelytobe23responsibleforapostnasaldriprelatedcough.348Interestingly,coughisnotinducedinpatientswith24rhinitisorhealthycontrolsinsimulatedmodelsofpostnasaldrip.34925

Thereisnotmuchevidencesupportingthenaso-bronchialreflexasanimportantcontributorto26theunifiedairway.Nasalallergenchallengecanbeblockedwithavasoconstrictorbutnotwith27lidocaine.Moreover,lowerairwayresponsesafterallergenchallengeareingeneralmoredelayedthan28wouldbeexpectedfollowinganasal-bronchialreflex.35029

Allergenprovocationstudiesrepresentagoodmodeltostudynasal-bronchialcrosstalkin30allergicairwaydisease.InpatientswithAR,segmentalbronchialornasalprovocationcaninduceallergic31inflammationinboththenasalandbronchialmucosa.347-349Presumably,absorptionofinflammatory32mediators(e.g.IL-5andeotaxin)fromsitesofinflammationintothesystemiccirculationresultsinthe33releaseofeosinophils,basophils,andtheirprogenitorcellsfromthebonemarrow.351Thesystemic34allergicresponseisfurthercharacterizedbyincreasedexpressionofadhesionmolecules,suchas35vascularcelladhesionmolecule1andE-selectinonnasalandbronchialendothelium,whichfacilitates36themigrationofinflammatorycellsintothetissue.35237

IncreasesinCD34+cellscapableofeosinophildifferentiation,aswellasothercirculatory38mediators(IL-5,eotaxin,andcysteinylleukotrienes),areassociatedwithimpairedlungfunction39parametersandenhancedmucosalinflammationinasthmaticpatients,353andreacttolocal40corticosteroidsinAR.354Treatmentwithanti-IL-5andotherinterleukinsrelevantintheeosinophilic41

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pathwayhasbeenshowntobeeffectiveinasthma,withsomebeneficialresultsineosinophilicupper1airwaydisease.3422

Inconclusion,thesestudiesdemonstratethatthesamemechanismsbehindARmaybe3importantinairwayinflammationthroughouttherespiratorytract,evenintheabsenceofclinical4asthma.Systemicfactors,suchasthenumberofcirculatoryeosinophilsandatopicseverityare5indicativeofmoreextensiveairwaydisease.678IV.D.Cellularinflammatoryinfiltrates9

AvarietyofcellsareinvolvedinthepathophysiologyofAR.Duetothenatureofthedisease,10withdifferentmechanismsandendotypes,itispracticallyimpossibletocomprehensivelydescribeeach11oftheseinflammatorycellsindetail.Thissuggestsaneedforanextensiveendotypingand12characterizationofthecellularinfiltrateforeachendotype.355Inaddition,manystudiesfocusingoncell13typesinallergicdiseases,includingrecentlyidentifiedcellssuchastype2ILCs,Th17andTh22cells,have14beenmostlyrestrictedtoinvestigationsofperipheralbloodcells,nottissuebiopsies.Thereisevidence15fromalimitednumberofstudiesthatdifferentcellsareinvolvedatdifferentstagesofinflammation,16suchasexacerbation,remissionandextensiveremodelling.Furthermore,differenttissuesitessuchas17sinusmucosa,polyptissueorinferiorturbinatesshowavarietyofdifferentinfiltratingimmuneand18inflammatorycells.19

Nasalepithelialcellsareattheinterfaceofthehumanbodyandtheenvironment,andoftenact20asthefirstlineofdefenseagainstexternalpathogens.Epithelialcellsinterferewithnon-selfallergens21andregulateinfiltratingcellsinARthroughtheproductionofvariousco-stimulatorymolecules,22chemokines,cytokinesandlipidmediators.Thesecytokinesstarttoorchestrateatype2immune23responsecharacteristicofAR.356However,whenallergenshaveadditionalproteaseactivityand/orthey24areaccompaniedbymicrobialcomponentssuchasendotoxinsorinorganicparticles,epithelialsecretory25responsescanleadtomixedtype2andtype17immunity,oreventype1responses.357,358Inresponseto26respiratoryviruses,epithelialcellsproduceawiderangeofmediatorssuchastypeIinterferons,27granulocytemacrophagecolony-stimulatingfactor(GM-CSF),RANTES/C-CMotifChemokine5(CCL5)28andinterferongamma-inducedprotein10/C-X-CMotifChemokine10(IP-10/CXCL10).359These29mediatorsorchestratefurtherdownstreaminnateandadaptiveantiviralcellularimmuneresponses.30

Toactivateallergen-specificCD4T-cells,adequateco-stimulationisrequired.Dendriticcellsare31professionalAPCsthataredirectlyrelatedtoAR,withincreasednumbersandconcentrationsofIgEin32atopicdisease.360TheyareinclosecontactwithepithelialcellsandILCsandcontrolT-andB-cell33activationanddifferentiation.356Also,eliminationofdendriticcellshasbeenshowntosuppressthe34developmentofAR.36035

Bothinnateandeffectormechanismsplayessentialrolesduringthedevelopmentofallergic36disease.361T-helpersubsetimbalanceandproductionoftypicalTh2cytokines362alongwithincreased37expressionofGATA-3,363isgenerallyseeninARnasalmucosa.Furthermore,CD4+memoryT-cellsand38gamma/delta-T-cellsareincreasedinPARpatients’mucosa.364EffectorTh2cellsproduceIL-4,IL-5,IL-9,39andIL-13.356,365Inaddition,TSLP,IL-25,IL-31,andIL-33,contributetothedevelopmentandintensityof40Th2responsesandinflammation.ThesecytokineshaverolesinproductionofsIgE,eosinophilia,mucus,41

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tissuemigrationofTh2cellsandeosinophils,regulationoftightjunctionsandepithelialbarrier1integrity.343,356,366,367T-regulatory(Treg)cellsubsetshavedistinctphenotypesandincludeconstitutive2andinduciblesubsetsofCD4+CD25+ForkheadboxP3(FOXP3)+Tregcells,andtype1Tregcells.368-3703AllergentoleranceandAITareoneofthemostrepresentativeareaswhereTregcellsdisplaytheirmajor4role.371-373TheproductionofIL-10andtransforminggrowthfactor(TGF)-b fromothercellsisdecisive5fortheirimmuneregulatoryfunctions.Theratiobetweeneffectorandregulatorycelltypesdetermines6whetheranallergicresponseistriggeredbyanallergenornot.7

Populationsoflymphoidcellsthatlackrearrangedantigenreceptorsandmarkersformyeloid8andlymphoidlineages,suchasT-,B-andNK-cellshavebeendefinedasILCs.Type1ILC(ILC1)mainly9produceinterferon(IFN)-g,ILC2produceIL-5andIL-13,374andILC3produceIL-17andIL-22.361Type210ILCsarefoundinAR,wheretheycloselyinteractwithepithelialandothercellscontrollingthemucosal11environment.Throughtheproductionofcytokinesandinductionofchemokines,atype2immune12responseisfavored,supportingfurtherdevelopmentofanallergictissueinflammation.37513

AlthoughitwasbelievedthatIgE-producingB-cellsresideinlymphoidfolliclesoftheWaldeyer14ring376andantibodiesarethentransferredtothemucosa,newerevidencehasidentifiedB-cellsand15plasmacellscapableofproducingIgEinnasaltissueofARpatients.377Thelocalproductionofallergen-16specificantibodiesisfurthersupportedbythedetectionofsecondarylymphoidtissueandIgEformation17toStaphyloccoccusaureusinCRSwNP.37818

Withinthenasalepitheliumofallergicindividualsincreasednumbersofmajorbasicprotein-19positiveandEG2+(activated)eosinophilscanbeencounteredduringthepollenseason.Similarly,mast20cellsarefoundwithintheepitheliumandthesubmucosallayer;however,noincreasesareobservedin21cellcountsofT-lymphocytesortheirsubsets,norneutrophilsormacrophagesduringseasonalallergen22exposure.379Basophilnumbersinthelaminapropriaofthenasalmucosaincreasewithinonehourof23allergenprovocation.380Degranulationofbothmastcells381andbasophilsoccursduringtheearlyand24latephasesofatypeIreactionafterallergenencounterandcrosslinkingofIgEmoleculesaswellas25uponstimulationbyIL-33.38226

Inthelatephaseoftheallergicreaction,theinfluxofinflammatorycellsisfacilitatedby27chemoattractantsandupregulationofadhesionmolecules.383Thisleadstofurtherinfiltrationofthe28tissuebyeosinophils,basophilsandT-cells.Lastly,thoseinflammatorycellsdrivingremodellingofthe29mucosainAR,andupregulatingfactorslikematrixmetalloproteinasesandangiogenicfactorsremainto30beidentified.384313233IV.E.Cytokinenetworkandsolublemediators34

Cytokinesareimmunomodulatoryproteinsimportantincellularsignaling.Complexinteractions35ofinnateandadaptiveimmunecells,aswellasstructuralcellsandtheircytokines,playcrucialrolesin36regulatingallergicairwayinflammation.TheinflammatoryprocessunderlyingARiscoordinatedbya37networkofcytokines.38

Type2cytokinessuchasIL-4,IL-5,IL-6andIL-13arecrucialinregulatingtheallergic39inflammatorycascadecharacterizedbyanincreasedpresenceofeosinophilsandmastcellsandan40upregulationofIgEproduction.BesidestheirroleintheinductionofIgEsynthesis,type2cytokines41

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upregulatetheproductionofothercytokinesandchemokinesfromepithelialcellsandfibroblasts,2831whichthenleadstotheinfluxofinflammatorycellsincludingeosinophilsandmastcells.385,386Scadding2etal387demonstratedtheimmunologicalaspectsofrhinitiswithnasalallergenchallenge.Afternasal3challengewithgrasspolleninsensitiveindividuals,thelevelsofIL-4,IL-5andIL-13wereelevated2-34hourspostchallengeandincreasedforupto5to6hours.387Similarly,levelsofchemokinessuchas5thymusandactivationregulatedchemokine(TARC,CCL17),macrophagederivedchemokine6(MDC,CCL22),eotaxin,RANTES,MCP-1andmacrophageinflammatoryprotein(MIP)-1αwere7elevated.388-391Increasesinthesetype2cytokinesandassociatedchemokineswerestronglycorrelated8toallergicclinicalresponses.9

Althoughtype2cytokineswereoriginallyreferredtoasTh2cytokinesaftertheirsuspected10cellularsource,severalothercellshavebeenidentifiedassignificantsourcesincludingmastcells,11epithelialcells,type2ILCs,andeosinophils.Airwaymastcellsareanimportantsourceoftype212cytokines,proinflammatorycytokines,chemokines,andtheIL-7-likecytokineTSLP.283,392-394IL-13from13mastcellsplaysacrucialroleinmastcell-inducedlocalIgEsynthesisbyBcells,286,395whichinturn14upregulateFceRIexpressiononmastcells.286Further,severalmastcellproductsheavilyinfluence15epithelialcells.TNF-a,apro-inflammatorycytokineproducedbymastcells,inconcertwithIL-4andIL-1613,enhancestheproductionofTARC,TSLPandeotaxinfromepithelialcells.385Andchemokinessuchas17tryptaseandchymasecanupregulateRANTESandGM-CSFproductionfromepithelialcells.385Thus,18thereappearstobeacrucialinterplaybetweenmastcellsandepithelialcellsinpromotingand19regulatingtheallergicinflammatorycascade.20

Inadditiontothecytokinesandchemokineslistedabove,nasalepithelialcellsareanimportant21sourceforIL-1,IL-6,IL-8,andTNF-a.Throughthesesignals,epithelialcellsplayacrucialroleinthe22migrationandactivationofeosinophils,basophilsandTh2cells.396Inaddition,epithelialcellsreleasethe23cytokinesIL-25,IL-33,andTSLPthatorchestrateboththeinnateandadaptiveType2immuneresponse.24Thesesamecytokinesarealsoreleasedbytissuedamage,pathogenrecognitionandallergenexposure.25TheycanregulateTh2cellfunctioneitherdirectlyor via innate lymphoidcells,which in turnproduce26IL-5, IL-9, IL-13,TSLP,IL-25andIL-33,whichareallincreasedinthenasalmucosaofARpatients27indicatingaroleofthesecytokinesinthepathophysiologyofAR.397-400Infact,levelsofIL-33innasal28secretionshavebeenshowntocorrelatewithtotalnasalsymptomscores.400Further,TSLPhasbeen29showntoactivatedendriticcells,promoteTh2responses,andactivatemastcells.40130

Eosinophilsareanothercelltypethatappearstoplayasignificantroleinthepathophysiologyof31AR.Theyareamajorsourceoftheinflammatorycytokinesmacrophagemigrationinhibitoryfactor32(MIF)402andnervegrowthfactor(NGF).403Eosinophilsexpress5-lipoxygenase,LTC4S,andCysLT1and33CysLT2receptors,whichplayaroleinthearachidonicacidpathway.404IL-5hasakeyrolemodulating34eosinophilmaturation,differentiation,andsurvival.405Eosinophilicchemoattractantsincludeeotaxin,35MCP4,RANTESandcysteinylleukotrienesamongothers.406-408Asdiscussedpreviously,mastcells,and36epithelialcellseitherdirectlyproduceorup-regulatethesesamechemoattractants.37

Finally,Th17cellsareauniquesubpopulationofCD4+Tcells.TheyproduceIL-17A,IL-17F,IL-22,38TNF-a,andIL-21.409TheyhavebeendemonstratedinthenasalmucosaofARpatientsandaretherefore39thoughttoplayaroleinallergicinflammation.409,410Further,IL-17Ahasbeenshowntobeupregulatedin40SARpatients5hoursafternasalallergenchallenge.411 F ina l l y , increasednumbersofIL-17A+cellsand IL-41

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17AmRNAweredemonstratedinthenasalmucosaofpatientswithdustmiteallergy,indicatinga1possibleroleinAR.4122

Insummary,ARisatype2-mediateddisease,characterizedbyimportantregulatorycytokines3likeIL-4,IL-5andIL-13.Newertype2cytokineshavebeenidentifiedinAR,includingIL-17familycytokines.4Finally,Type2ILCsandepithelialcellderivedcytokineslikeTSLP,IL-25andIL-33playacrucialroleinthe5regulationoftheallergicinflammatorycascade.678IV.F.Histologicandepithelialchanges9

Normalnasalmucosacomprisespseudostratifiedcolumnarciliatedepitheliumwithgobletcells10overabasementmembrane.Thenasalsubmucosacontainsstromalelementsincludingfibroblasts,11bloodvessels,sero-mucinousglands,sensorynerves,andleukocytes.Leukocytespresentinthenasal12mucosaincludeCD4+andCD8+Tlymphocytes,Blymphocytes,eosinophils,neutrophils,basophils,mast13cellsandmacrophages.Thecombinedfunctionsofciliatedandsecretorycellsallowfornaso-ciliary14clearance,removingpathogensandallergensasahostdefensemechanism.Inadditiontothephysical15barrier,nasalepitheliumplaysanimportantroleintheinnateandacquiredimmunologicdefense16againstpathogens359,413,414by:(1)expressingpatternrecognitionreceptorsthatrecognizepathogen-17associatedmolecularpatterns;(2)secretingavastarsenalofhostdefensemolecules,suchas18antimicrobialenzymes,opsonins,permeabilizingproteins,collectins,andbindingproteins;and(3)19producinginflammatorycytokinesinresponsetoantigenicstimuli.20

Allergymediatesepithelialchangeinthenasalmucosa.Nasalepitheliumisthickerinpatients21withARafterallergenchallenge,415,416butstudiesonepithelialthicknessinARwithoutallergen22challengeareconflicting.415-417WhileepithelialremodelingisakeyfeatureofCRS(epithelialhyperplasia,23gobletcellhyperplasia,squamousmetaplasia418-420andasthma(epithelialdesquamation,sub-epithelial24fibrosis,smoothmusclehypertrophy),remodelinginARislessmarked.Ingeneral,limitedstudieshave25foundnosignificantincreaseinbasementmembranethickness,subepithelialfibrosis,gobletcell26hyperplasiaorbloodvesselvolumeandsurfacedensity,415,421,422thoughincreasedvascularpermeability27wasnoted.423Incontrasttoepithelialremodeling,epithelialinflammatoryresponsetoallergensisakey28featureofAR.Uponallergenexposure,thereissignificantlyhigherinfiltrationofinflammatorycells,and29increasedlevelsofcytokines(suchasIL-4,IL-5,IL-13)inthenasalepitheliumofallergiccomparedto30non-allergicpatients.182Thisinflammatoryresponsetranslatesintomucosaledema,autonomicneural31stimulationandincreasedmucosalsecretions,whichmanifestasthehallmarksymptomsofnasal32obstruction,pruritus,sneezing,rhinorrhea,andsmelllossinseverecases.33

Theepithelialbarrierisnotedtohavespecificfunctionsinallergy.Penetrationofallergens34throughthisbarriermayleadtoallergensensitizationandlocaland/orsystemicinflammatoryresponse.35Inthenasalmucosa,thisbarrieriscomprisedofmucusandepithelialcells,whicharelinkedbyapical36junctionalcomplexes(tightjunctionsandadherensjunctions).367Mechanicalorinfectiveinsultstothe37epitheliumordefectiveepitheliumleadstobarrierbreachandallergenpenetration.367,424-426Lossof38functionmutationsandpolymorphismsingenescodingforepithelialbarriermarkerslikefilaggrinare39associatedwithARandeczema.427,428Someallergenscaninducejunctionaldysfunction,leadingto40penetrationoftheepithelialbarrierbyallergens.322,429Proteolyticallergensdirectlydisrupttheapical41

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junctionalcomplexviaproteolysis,leadingtobarrierdysfunction.430DetectionofallergensbyAPCs,and1theensuingTh2responsesandcytokinerelease(suchasIL4,IL-13,IFN-g)inducesfurther“leakiness”of2theapicaljunctionalcomplexviavariousmechanisms,allowingincreasedlevelsofallergen3penetration.367Evidencesuggeststhatthisbarrierimpairmentmaybereversedwithcorticosteroids.4Fluticasonepropionatehasbeenfoundtoincreaseexpressionoftightjunctionproteinszonula5occludens1andoccludinandamoreintactnasalepithelialbarrier.322Corticosteroidshavenot,6however,beenshowntocausethinningofnasalepithelium.322,4317

Allergyisnowconsideredbothasystemicandlocalepithelialcondition.337Evidencepointsto8theepitheliumbeinganactiveparticipantinthedevelopmentandprogressofallergy,ratherthanasa9passivebarrier.432BirchpollenhasbeenfoundtorapidlybindtoBetv1-bindingproteinsinsensitized10nasalepithelium,andistransportedthroughalipidraftandcaveolar-dependentprocessbeforebinding11tomastcellsinthelaminapropria.433-435Epithelialresponsetoallergensdiffersfromhealthyindividuals12inthatallergicpatientsdonotmountasrobustanepithelialdefenseresponsetoallergens,leadingto13increasedpenetrationofallergens.432141516IV.G.Microbiome17

Thehumanmicrobiomecomprisesthecomplexcommunityofmicroorganismsthatresidesin18andinteractswiththehumanbody.Anadultintestineisahaventoapproximately100trillionmicrobes19anditisthoughtthatthemicrobiomeaccountsforroughly90%ofallthecellsinthehumanbody.436,43720Themicrobiomesofindividualsvary,likelyduetothefactthatthegrowth,developmentand21compositionofthemicrobiomeareaffectedbyintricateinteractionsbetweentheenvironment,diet,22andhost-relatedfactors.43723

Withtheadventofculture-independenthighthroughputbacterialDNAsequencingtechniques,24adetaileddescriptionofthecompositionandvarietyofthemicrobiomecanbedescribedamongorgans25andindividuals.438TheHumanMicrobiomeProjectbeganin2007,andasaresult,extensivedatahave26emergedexaminingtheassociationsofthemicrobiotaoftherespiratorytract,oralcavity,gut,skinand27genitourinarytracttothedevelopmentofdiseaseprocessesincludingallergyandasthma.43728

Increasingliteratureinanimalsandhumanshasimplicatedchangesinthemicrobiomewiththe29developmentofallergicdisease.439,440Mechanistically,adisruptioningastrointestinalbacteriaisthought30toaltermucosalimmunologicaltolerance.441Severalauthorshavefoundassociationsofreducedgut31microbialdiversitywithdevelopmentofallergicdiseaseinschool-agedchildren.442,443Forexample,the32developmentofallergicsymptomsinchildrenhasbeenassociatedwithoveralllowermicrobialdiversity,33increasedprevalenceofBacteroidesandBifidobacertiumadolescentis,andlowercountsofAkkermansia34muciniphilia,Faecalibacteriumpraunitizii,andClostridium.444Inaddition,Fujimuraetal445recentlynoted35thatalowerabundanceofBifidobacertium,Akkermansia,andFaecalibacteriumwereassociatedwitha36higherriskofdevelopmentofpolysensitizationbyage2andphysician-diagnosedasthmabyage4.The37authorsconcludedthatneonatalintestinalmicrobialdysbiosismayfosterCD4+T-celldysfunction38associatedwithchildhoodallergicdisease.445,44639

Themostcomprehensivecollectionofevidenceevaluatingapotentialassociationbetweenthe40microbiomeandthedevelopmentofallergicdiseaseisfromarecentsystematicreviewbyMellietal.44441

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Studiesincludedinthissystematicreviewcomparedintestinalmicrobiotaofallergicpatientswith1healthycontrols.Atotalof21studieswerenotedtoreportanassociationbetweentheintestinal2microbiotaandallergicdiseasewhenstoolcollectionwasperformedpriortotheoutcomeassessments.3OnlyfouroftheanalyzedstudieshadspecificoutcomesrelatedtoARorsensitization.Pendersetal4474foundthatthepresenceofClostridiumdifficileatonemonthofagewasassociatedwithanincreased5riskforallergicsensitization(OR1.54;95%CI1.09-2.31)untiltheageof2years.Adlerberthetal4486notedanincreasedratioofgramnegativetogrampositivebacteriaat1yearofagetobeassociated7withIgElevelsgreaterthan100kU/Lat1.5yearsofage.Bisgaardetal449foundlowerbacterialdiversity8wasassociatedtohigherriskofallergicsensitization(p=0.003)andAR(p=0.007).Johanssonetal4509reportedlowerfrequencyofcolonizationwithLactobacilliandBifidobacertiumbifiduminallergic10children.15Ultimately,Mellietal444foundthatmostofthestudieslinkingthemicrobiometothe11developmentofatopicdiseasearevariedanddifficulttointerpretduetodifferingmethodologies,12samplessizesandculturetechniques.13

Therearesomethoughtsthatthecompositionand/ordysbiosisofthemicrobiota(viruses,fungi14and/orbacteria)ofothersitessuchasthenasopharynx,lungsandsinonasalcavitiesmayalsoplayarole15inthedevelopmentofallergicdisorders.However,thesestudiesareintheirinfancyandlittlecanbe16concludedatthistime.45117

Athoroughunderstandingoftheroleofthemicrobiomeandhowitinfluencesallergicdisease18hasnotbeenfullyelucidated.Althoughsomedatasuggestassociationsbetweenallergicdiseaseandthe19microbiota,basedonthecurrentevidenceitisdifficulttodistinguishbetweenprotective20microorganismsandthosethatincreaseriskforallergicdisease.446Futureresearchshouldprovidean21enrichedanddiverseunderstandingofthehumanmicrobiomeandthewayitimpactsAR.2223

24 25

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V.Epidemiologyofallergicrhinitis1V.A.Prevalenceofallergicrhinitisinadults23

Avarietyofpopulation-basedsurveyshavebeenusedtoestimatetheprevalenceofARwithin4theadultpopulation.Prevalenceestimateslargelyrelyonself-reportsof‘hayfever’or‘nasalallergies’,5orofnasalsymptoms‘whenyoudidnothaveacoldortheflu’.Questionsonseasonality(toseparate6seasonalfromperennialrhinitis)aresometimesasked,buttherearefewlarge-scalewell-conducted7population-basedstudiesthathaveevaluatedpersistent(lastingmorethan4days/weekformorethan84consecutiveweeks)versusintermittentsymptoms.Becausemanysurveysdifferintermsofdisease9definitions,geography,andseasonalityprevalenceestimatesdrawnfromsurveysvarywidely.10

Oneoftheearlieststudies,conductedinTecumseh,Michiganin1959-1960includedaphysician11assessmentandsuggestedthattheprevalenceofhayfever(diagnosedas‘upperrespiratorysymptoms12believedtobeallergicinoriginandoccurringpredominantlyineitherspring,summerorautumn’)was13about11%inthoseagedover20years.452About20yearslater,theNationalHealthandNutrition14ExaminationSurvey(NHANES)1976-80wasconductedamongageographicallyrepresentativesampleof15theUSpopulation.ThissurveygavebroadlysimilarestimatesforprevalenceofAR,definedas‘physician16diagnosisofhayfeverorfrequentnasaland/oreyesymptomsthatvariedbybothseasonandpollen17duringthelast12months,notcountingcoldsortheflu’.453AmorerecentreportbasedonNHANES18(2005-2006),presentedpopulationprevalencefiguresinwhichtwo-thirdswereovertheageof2019years,andshowedthelifetimeprevalenceofphysiciandiagnosedhayfeverwas11.3%,with6.6%20havingsymptomsinthelast12months.However,relianceonphysiciandiagnosisofARislikelyto21considerablyunderestimatetheactualprevalenceofAR,sincemanypatientsself-diagnoseandself-22treat.Surveysinvolvingpatientself-reportingARhaveshownthatone-thirdofthepopulationreported23‘sneezingand/ornasalsymptomsintheabsenceofcoldoraflu’,withabout24%reportingthatthiswas24seasonalinnature,andafurther10%reportingthesesymptomsoccurredyear-round(i.e.perennial).45425

Intheearly1990’s,theEuropeanCommunityRespiratoryHealthSurvey(ECRHS),amulticenter26population-basedstudyofadultsage20-44yearsin23countries(mainlyWesternEurope,butalso27AustraliaandNewZealand),usedaself-completedquestionnairetoestimatetheprevalenceof‘hay28feverornasalallergies’.Prevalencevariedbetween10%and40%acrossparticipatingcenters,455with29evenmoreparticipants(12%to65%)reportingthattheyexperiencedarunnyorstuffynoseorstarted30tosneezeonexposuretosourcesofallergen.456IfapositiveSPTwasincludedinthediseasedefinition,31theprevalenceofARfellbyavariableamount(absolutefallinprevalencebetween4%and16%across32allcenters).IntheSwissStudyofAirPollutionandLungDiseaseinAdults(SAPALDIA),conductedaround33thesametimeastheECRHS,theprevalenceofself-reported‘nasalallergiesincludinghayfever’in34adultsaged18-60yearswas17.9%,andtheprevalenceofcurrentsymptoms(‘hayfeverthisyearorlast35year’)was14.2%.457PrevalenceestimateswerelowerifapositiveSPTwasincluded(11.2%forcurrent36hayfeverwithatleastonepositiveSPTand9.1%forcurrenthayfeverwithpositiveSPTtooneofgrass,37birchorParietaria).Morerecently,theGlobalAllergyandAsthmaNetworkofExcellence(GA2LEN)study38suggestedtheprevalenceof‘nasalallergiesandhayfever’variedbetween22%and41%inadultsage1839to75yearslivinginthe12participatingEuropeannations.45840

Population-basedstudieshaveshownincreasesinARprevalenceintheadultpopulationin41recentdecades.Forexample,inRenfrewPaisley,UK,theprevalenceofhayfeverwashigherinadults42

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andchildrenin1996thanintheirmothersandfathersatanequivalentagein1972.459Hayfever1prevalencedoubledbetween1981and1990inBusselton,Australia460,increasedinItalyfrom1991to22010461andincreasedineightof11citiesinChinasurveyedin2005andagainin2011.462InUppsala,3UmeaandGoteborg,inSweden,‘hayfeverandnasalallergies’increasedfrom21%to31%between41990and2008463,althoughrecentreportsfromStockholmsuggesttheremaybealevellingoffinthe5increaseinnasalallergiesovermorerecentyears.4646

Fromthesedata,thelifetimeprevalenceofARintheUScanbeestimatedbetween11%7(physician-diagnosed)andapproximately33%(self-reported).InEurope,prevalenceofARinadults8likelyrangesbetween10-41%,dependingonthespecificcountry.91011V.B.Incidenceandprevalenceofallergicrhinitisinchildren1213

TherearerelativelyfewstudiesontheincidenceofARinchildren.ThereisevidencethatAR14maystartasearlyasduringthefirstyearoflife.IntheCincinnatiChildhoodAllergenandAirPollution15Study(CCAAPS),9%ofthe12-month-oldchildrenwithaparentalhistoryofrespiratoryallergyfulfilled16thecriteriaofAR.465InthePARISbirthcohort(PollutionandAsthmaRisk:anInfantStudy),9.1%ofthe1718month-oldchildrenhadAR-likesymptomswithastrongassociationwithatopyandsensitizationto18inhalantallergens.Ofthese,23.7%hadrhinoconjunctivitis.466Inastudyof29,662childrenfromtheUS19thatusedhealthcarerecordstofollowparticipants,theincidenceofphysiciandiagnosedARduringthe20firstyearoflifewas1%.From1to5yearsofage,theannualincidencewasbetween3.6and4.5%,with21thehighestincidencebetween2and3yearsofage.467ThisisbroadlyinlinewithestimatesofaSAR22incidenceof3-4%peryearfrom3to7yearsofagereportedinabirthcohortof1,314German23children.46824

Inlongitudinalstudies,ARoftenoccursforthefirsttimeinchildhoodandincreasesin25prevalencewithincreasingage.467-471MostchildrenwithsymptomsofARearlyinlifehavepersistent26symptomsforseveralyears.469-471TheInternationalStudyofAsthmaandAllergiesinChildhood(ISAAC)27estimatedtheprevalenceofallergicdiseasesintwodifferentagegroups,6-7yearsand13-14years,28throughamulticenterglobalsurvey.Twocross-sectionalsurveyswereperformedapproximately7years29apart(range5-10years).Overall,anincreaseinrhinoconjunctivitisprevalencewasobservedbetween30thetwosurveys.10However,thereweregeographicaldifferencesinbothbaselineprevalenceandinthe31increasesobserved;therefore,itisdifficulttodeterminewhethertheobserveddifferencesrepresented32atrueincreaseinprevalenceovertime.Theproportionofchildrenwithsymptomsofrhinoconjunctivitis33washigherintheolderagegroup.Datafromthesecondsurvey(ISAACPhaseThree1999-2004)state34thattheworldwideprevalenceofcurrentrhinoconjunctivitisinthe6-7-yearagegroupwas8.3%(range35betweencountries1.8-24.2%)andinthe13-to14-yearagegroupwas15.1%(range4.5-45.1%).472Ina36morerecentmeta-analysisofallstudiesperformedaccordingtotheISAAC-protocol(1,430,329children37aged0-18years),theoverallprevalenceofARwas12.66%.47338

Rhinoconjunctivitishasbeenreportedtobeslightlymorecommonamongboysthangirlsinthe396-7yearagegroup,withtheoppositetendencyseeninthe13-14yearoldagegroup.474However,40genderdifferenceswerenotseeninallcountriesinthesurvey.Otherstudiesdoshowagreater41prevalenceofARamongboysofallages.Forexample,intheIsleofWight(UK)birthcohortof1,45642

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children,theprevalenceofrhinitisamongboysascomparedtogirlswashigheracrossallagegroups,(41years4.7%vs.2.1%,10years14.9%vs.11.7%,18years31.0%vs.24.0%).469234V.C.Geographicvariationofallergicrhinitis56

TheprevalenceofARshowsmarkedgeographicvariation.Manyfactorslikelycontributetothis7disparityandnotallarecompletelyunderstood.ThecentraldifficultyinmeaningfullycomparingAR8prevalenceratesbetweenlocationsisthedifferenceinmethodsusedtorecruitparticipantstostudies9anddifferencesinassessingthepresenceofdisease.Forexample,Bauchauetal9diagnosedBelgian10patientsviaserologicalIgEtestingafterapositivetelephonescreenandreportedthatBelgiumhadan11ARprevalenceof28.5%(thehighestoftheEuropeancountriesevaluated).Incontrast,Bousquetetal45612skin-testedarandomsampleofBelgiansubjectsandreportedapositiverateinBelgiumof16.4%(one13ofthelowestof15countriesexamined).14

Therehavebeenmajorinternationaleffortstocomparevariationsinthenationalprevalenceof15ARusingstandardizedmethods(i.e.ECRHSandISAAC).Thesestudiesshowmarkedgeographicvariation16of‘hayfeverornasalallergies’(adults)or‘aproblemwithsneezing,orarunny,orablockednosewhen17youDIDNOThaveacoldorthefluthatwasaccompaniedbyitchy-wateryeyes?’(children).Ahigher18prevalenceoftheseresponsesisseeninpeoplelivingin‘Englishspeaking’countries(e.g.UK,Australia,19NewZealand),alowerprevalenceinEasternEuropethaninWesternEurope,andadiagnosisofARis20morefrequentlyseenincountrieswithhigherasthmaratesandsensitizationtoseasonalallergens.455,47521Becausethesestudieshaveevaluatednationalratesbasedononlyoneorafewcenterswithineach22country,substantialintra-countryvariationmayhavebeenoverlooked.23

Inunderstandingtheeffectsofgeographiclocation,differentiatingbetweenseasonaland24perennialARisanimportantconsiderationnotexaminedintheECRHSorISAACstudies.Smallerstudies25overmorelimitedgeographicregionsthatexaminedPARsuggestincreasedsensitivityratesinurban26settingsandcolderclimates.476-479Severalhypotheseshavebeenputforwardfortheseobserved27differences.Lietal477theorizedthaturbandwellersparticipateinmoreindooractivitiescomparedto28theirruralcounterparts,amplifyingtheirexposuretoHDM,andpossiblyleadingtoincreased29sensitizationtotheseperennialallergens.Additionally,somereportssuggestthatexposuretourban30pollutantsmaybeassociatedwithincreasedriskfordevelopingARinchildren.476Latitudemayalsoplay31arolewithregardtoPAR.Forexample,theprevalenceofpersistentARwasfoundtobehigherinboth32NorthernEuropeandNorthernChinacomparedtotheirsoutherncounterparts.9,47733

LatitudemayalsobeanimportantdeterminantofSAR.Allergenicplantspeciesmayhavea34propensityforgrowingincertaingeographiclocations,andpollenconcentrationsofvariousspecies35dependontheclimateconditionsofthearea.Colderclimatespresentatnorthernlatitudestendtoward36shortergrowingseasons,andmanyallergenicspeciesdonotthriveinextremenorthernclimates.For37instance,grasspollen,whichisfoundacrossEurope,causeswidevariationsinatopicsensitizations38acrossregionswithdifferentclimates.480Additionally,thisincreasedenvironmentalexposurehasbeen39showntoaffectdevelopmentofARandpatientsymptomsofatopicnasaldiseases.481,48240

Overall,improvedknowledgeoftheprevalenceandseasonalvariationsinARbasedon41geographiclocationisimportantinthatitallowspatientstoanticipateandbettermanagetheir42

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symptomsthroughavoidancetechniquesandpreemptiveuseofpharmacologictherapies.480,4821Currently,prevalencedatadonotfullyaddressthedifferentphenotypesofARandfurtherstudyis2neededtoexpandepidemiologicunderstandingofthisdisease.3 4

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VI.Riskfactorsforallergicrhinitis1VI.A.Genetics23

ARiswell-knowntoruninfamilies,andoneofthestrongestriskfactorsisthepresenceof4diseaseinfirst-degreefamilymembers.483StudiesoftwinssupportthegeneticunderpinningsofARwith5ahigherconcordanceratesforARinmonozygotictwinscomparedtodizygotictwins.484,485The6estimatedheritabilityofARhasbeensuggestedtobeashighas70-80%.Likemanycomplexdiseases,no7singlegeneorpolymorphismaccountsforthehereditaryeffectonAR.Instead,manygenesandseveral8variants,eachwithsmalleffects,arebelievedtocontributetodiseaseinitiation,persistenceand9severity.Inthissection,thecurrentliteratureonthegeneticsofARisreviewed,includingcandidate10genestudiesandrecentlarge-scalegenome-wideassociationstudies(GWASs).Inaddition,gene-11environmentinteractioneffectsandepigeneticsstudieswillbebrieflycovered.1213Singlenucleotidepolymorphisms(SNPs)associatedwithAR14Genome-wideassociationstudies.GWASswithanunbiasedapproachthatincludehundredsof15thousandsofcommongenevariants,orSNPs,havesuccessfullyidentifiedimportantvariantsfor16complexdiseasesoverthepastdecad.FiveGWASsonAR(orhayfever)havebeenpublishedasof17September2016,assummarizedinTableVI.A.SNPsinleucine-richrepeat-containingprotein3218(LRRC32)havebeenstronglyassociatedwithARinthreeoftheGWASs486-488,andwithasthma,487,48919eczema488,490andotherallergy-relatedco-morbidities.486,489,491Attheproteinlevel,LRRC32isknownto20regulateT-cellproliferation,cytokinesecretionandTGF-βactivation.492Theseassociationssuggest21sharedgeneticmechanismsforARandotherallergy-relateddiseases,evidencefurthersupportedbythe22large-scaleGWASonself-reportedcat,HDMandpollenallergies(aswellasAR)whichrevealed1623sharedsusceptibilitylociwithstrongassociation(p<5×10−8;TLR-locustophit).487Inanaccompanying24GWASonallergicsensitization,therewasstrongoverlapbetweentophitsforsensitizationandself-25reportedallergies.487,493IntheGWASbyFerreiraetal,48911variantswereassociatedwiththecombined26asthmaphenotypeandhayfeverbelowthegenome-widesignificancelevel(HLA-DQB1tophit).TLRs27playacrucialroleinimmuneregulationandSNPsindifferentTLRshavebeenassociatedwithARinboth28GWASs(TLR1,6,10)486,487andcandidategenestudies(TLR8),asdiscussedbelow.494Inadditiontoshared29geneticeffectsbetweendifferentallergy-relateddiseases,asignificantoverlapbetweensusceptibility30lociforallergyandautoimmunediseaseshasbeenobserved.4953132Candidategenestudies.Thecandidategeneapproachforselectingdisease-relevantgenesisbasedon33previousassociationsreportedfromGWASorbiologicalfeatureswhichcouldberelevantfordisease34risk.StudiesonARusingthisapproachhavefoundseveralwell-replicatedgenesassummarized35previously.496-498Notably,SNPsingenesinvolvedinantigenpresentation(forexampleHLA-DQA1),36pathogenrecognition(TLR2,7,8),ILsignalingandpro-inflammation(IL13,IL18andTSLP)areconsidered37importantsusceptibilityvariantsforAR.496-502Recently,functionalevidenceinbloodimmunecellsfor38geneticvariantsinbrain-derivedneurotrophicfactor(BDNF),asecretorypro-inflammatoryprotein39implicatedinARpathogenesis,wasreported.503However,manyofthecandidategenesreportedinthe40literaturehavenotbeenwell-replicatedacrossstudiesandpopulations.427,504Thiscouldbedueto41inadequatestatisticalpowerrelatedtosmallsamplesizes,inconsistentphenotypedefinition,orlackof42

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truediseaseassociation.Additionally,rarevariantstudiesfocusingoncandidategeneshavenotbeen1particularlysuccessful.494Thecandidategeneapproachisparticularlynecessaryforhypothesis-driven2analysesandfunctionalgeneticanalyses,forexampleinpopulationswithspecificenvironmental3exposuresorwithmixedethnicbackgrounds.45Gene-environmentinteractionsandepigeneticeffects6

Epigeneticmechanisms,definedaschangesinphenotypeorgeneexpressioncausedby7mechanisms(e.g.methylation)otherthanchangesintheunderlyingDNAsequence,havebeen8proposedtoconstitutealinkbetweengeneticandenvironmentalfactors.RecentstudiesshowthatDNA9methylationinchildrenisverystronglyinfluencedbywell-knownriskfactorsforallergicdiseasessuchas10maternalsmokingduringpregnancy505andairpollutionexposure.506Currently,however,itisnotknown11ifthesemethylationchangesarecausallyrelatedtothedevelopmentofARandasthma,orifthese12“biomarkers”aresolelymarkersofexposure.Severalstudieshaveconvincinglylinkedmethylation13profilestoAR507-509andIgE-relatedoutcomes,510,511butlarge-scalestudieshaveyettobecompleted.1415

Insummary,afamilyhistoryofARremainsariskfactorfordiseasedevelopment,andstrong16associationshavebeenidentifiedwithgenesinvolvedinT-cellactivation(e.g.LRRC32)andinnate17immunity(e.g.TLRs).SharedgeneticmechanismsforARandotherallergy-relateddiseaseshavebeen18veryclearlyidentifiedinrecentlarge-scalestudies.Thereis,however,aneedtofunctionally19characterizevariantsinthesecandidategenestounderstandmechanismsunderlyingthepathogenesis20ofAR.WithincreasingevidencefortheroleofepigeneticsinAR,futureresearchshouldalsofocuson21investigatingepigeneticmechanisms,therebyprovidingafunctionalexplanationforthelinkbetween22environmentalexposures,geneticvariantsanddiseasedevelopment.2324

• AggregateGradeofEvidence:C(Level2a:5GWASs.Candidategenestudiesnotassessed25regardinggradeofevidence.)26

27

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TableVI.A.Keyfindingsfromgenome-wideassociationstudies(GWASs)onallergicrhinitisorhayfever1Author(year)

Studydesign Samplesize Ethnicity TopSNPsforAR

p-value Nearbygene(s)

Reportedassociationwithotherallergicdiseases

Proteinfunction LOE

Bunyavanichetal512(2014)

Meta-analysisofsevencohorts

2,712ARcases2,921controls

EA,L,AA rs17133587

4.5E-09(L)

AKR1E2

No

NAD(P)H-dependentoxido-reduction

2a

rs6583203

1.4E-08(L)

DLG1

No

Scaffoldingproteininvolvedincellmetabolism

rs7780001 2.0E-08(allgroups)

FERD3L No Transcriptionfactor

Hindsetal487(2013)

Privatecompanydata(23andMe)

46,646total

>97%EA rs1438673

3.7E-19

WDR36

Asthma,487,513eczema,488atopy487

CellularprocessesandT-cellactivation

2a

rs2101521

6.0E-17

TLR1-TLR6-TLR10

Asthma,eczema,atopy487

Pathogenrecognitionandactivationofinnateimmunity

rs10189629 9.9E-15 IL1RL2-IL1RL1

Asthma,487,514eczema,487atopy487

Pro-inflammatoryeffects,T-helpercellfunction

Andiappanetal515(2011)

Nestedcase-controlwithreplication

1,132ARcases997controls

Chinese rs811930

7.3E-05

MRPL4

No

Proteinsynthesiswithinthemitochondrion

2a

rs505101 1.3E-04 BCAP(PIK3AP1)

Atopy515 Proteintyrosinekinase

Ramasamyetal488(2011)

Meta-analysisoffourcohorts

3,933ARcases8,965controls

EA rs2155219

3.8E-08

LRRC32orC11orf30SLCA25A46

Co-morbidity:asthma-atopy,489asthma-eczema,491asthma-hayfever.486Eczema,487,490

LRRC32:T-cellregulation,TGF-βactivity.C11orf30:regulationofviralimmunityandinterferonpathways

2a

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asthma,atopy487

rs17513503

7.4E-07

TMEM232or

No Transmembraneprotein

rs1044573 9.7E-07 ENTPD6 No Catabolismofextracellularnucleotides

Ferreiraetal486(2010)

Meta-analysisoffourcohorts/datasets

16,513hayfevercases17,256controls

EA,L,AA rs4833095

4E-12

TLR1

Asthma,eczema,atopy487

Pathogenrecognitionandactivationofinnateimmunity

2a

rs2155219

7E-10

LRRC32orC11orf30

Co-morbidity:asthma-atopy,489asthma-eczema,491asthma-hayfever,486Eczema,487,490asthma,atopy487

Seeabove

rs10197862 2E-09 IL1RL1 Asthma,487,514eczema,487atopy487

Pro-inflammatoryeffects,T-helpercellfunction

GWASs:genome-wideassociationstudies;AR:allergicrhinitis;LOE:levelofevidence;EA:Europeanancestry;L:Latino;AA:AfricanAmerican12 3

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1VI.Riskfactorsforallergicrhinitis2VI.B.Inhalantallergens(inuteroandearlychildhoodexposure)34

ARischaracterizedbyalossofimmunologicalandclinicaltolerancetowardaspecificallergen.5ThisinvolvesproductionofsIgEwhichinitiatesallergicinflammationfollowingallergenexposure.6Therefore,sIgEisahallmarkofallergyanditsproductiondefinessensitization.Sensitizationisacomplex7phenomenon,regulatedbygeneticandenvironmentalfactors,requiringaprimitiveexposuretoa8specificallergen.Ifasubjectisneverexposedtoanallergen,sensitizationtothatallergencannotoccur.9Ontheotherhand,itisfundamentaltodistinguishbetweensensitizationandallergy.Allergy,which10involvesthedevelopmentofsymptomsafterthesensitizingexposure,isdifferentfrommere11sensitization.Withoutsensitizationallergycannotexist,butnotviceversa.Inthissection,theinutero12andearlychildhoodexposuretoinhalantallergens,includingmites,pollens,animaldander,andfungal13allergens,willbeevaluatedasriskfactorthedevelopmentofAR.1415Mites.TherearesixstudiesonthetopicofearlymiteexposureandthedevelopmentofAR.[TableVI.B-161.]Mostofthestudiesfailedtodemonstrateanassociationbetweenearlyexposuretomitesandthe17developmentofAR.468,516-519Marinhoetal520reportedthatearlyexposuretoHDMisnotaprotective18factorforcurrentAR,andKimetal521proposedexposuretospidermitesasariskfactorforAR.19Interestingly,petsmaybearelevantsourceofmites,astheirfurisoftensettledbymites;this20associationmayconfoundARevaluationandtreatment.Ultimately,thestudiesonearlymiteexposure21andthedevelopmentofARareconflictingandadditionalresearchisneeded.2223

• AggregateGradeofEvidence:C(Level2b:5studies;Level3b:1study;TableVI.B-1.)2425

26Pollens.ThereareonlytwostudiesthataddressedtheimpactofearlypollenexposureonAR.[Table27VI.B-2.]Kihlströmetal519reportednoassociationtoallergicrhinoconjunctivitiswhereasErbasetal48128showedthatpollenexposureduringinfancyisariskfactorforhayfever.2930

• AggregateGradeofEvidence:C(Level2b:1study;Level3b:1study;TableVI.B-2.)313233Animaldander.Numerousstudieshaveevaluatedtheassociationbetweenearlyexposuretoanimal34danderandsubsequentdevelopmentofAR,withconflictingresults.[TableVI.B-3.]Studiesaredivided35accordingtothefindings:positivestudies(reportingaprotectiveeffectonARdevelopment522-535),36negativestudies,(showingthatearlyexposuretopetsrepresentsariskfactorforAR523,536-542),and37neutralstudies(reportingthatearlyexposuretoanimaldanderisnotassociatedwith38AR468,517,518,520,524,528,530,532,536,538,539,543-554).Additionalfactorsshouldbeconsidered:petage,genderand39species,numberofhouseholdpets,homecharacteristics,atopicpredispositionofthepetowners,and40others.Consideringthesecomplexvariables,debateregardingtheinfluenceofearlypetexposureon41developingallergicdiseaseremainsunresolved.Thus,evidence-basedguidelinesregardinghavingpets42

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athomecannotbeestablished.(SeeSectionVI.G.2.ProtectiveFactors–ChildhoodExposuretoPetsfor1additionalinformationonthistopic.)23

• AggregateGradeofEvidence:C(Level2b:15studies;Level3b:24studies;TableVI.B-3.)456Fungalallergens.Severalstudieshaveexploredtheroleofearlyexposuretofungalallergensasa7predisposingfactorforAR.[TableVI.B-4.]Moststudiesdemonstratedevidencethatearlyexposureto8fungalallergensrepresentsariskfactorforARdevelopment.527,538,551,553,555-560However,threestudies9demonstratedthatearlyexposuretofungalallergensisnotassociatedwithAR.465,542,557Homemoisture10level,whichiscloselyandpositivelyassociatedwiththepresenceoffungalallergensinthehome,may11beaconfoundingfactorininterpretingtheevidenceonfungalexposureandAR.Ambienthumiditymay12anintrinsicriskfactor,buthighmoistureisalsoassociatedwithincreasedlevelofmites,asmitesgrow13inpresenceofelevatedmoisture.Moisturecanbeeasilyassessedbothbydirectmeasurementwitha14hygrometerandindirectlybyobservingthepresenceofmoldspotsonthewalls.1516

• AggregateGradeofEvidence:C(Level2b:3studies;Level3b:10studies;TableVI.B-4.)171819

Insummary,theclinicalrelevanceofearlyinhalantallergenexposuretoARdevelopmentisstill20debated.Despiteseveralin-depthreviewsandagrowingbodyofliterature,561-563nodefinitiveand21consensusmaybedrawnregardingrisk-benefitofearlyinhalantallergenexposure,andfurtherresearch22iswelcomedtoaddresstheunmetneedsonthisissue.2324

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TableVI.B-1.Evidencefortheeffectsofmiteallergenexposure(inuteroandearlychildhoodexposure)onthedevelopmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Typeofexposure Conclusion

Schoosetal518

2016 2b Prospectivebirthcohort

399children(7-13yearsold)fromCOPSACstudy

Derp1industsampleat1year NoassociationwithARat7years(OR0.9,CI0.7-1.1).

Derf1industsampleat1year NoassociationwithARat7years(OR0.9,CI0.7-1.1).

Illietal517

2014 2b Prospectivebirthcohort

513children(5yearsold)fromPAULAstudy

Miteallergenexposureat3months(measuredasallergenlevelsinthelivingroomfloorandinthemother’sorchild’smattress)

NoassociationwithcurrentAR(ORnotreported).

Marinhoetal520

2007 2b Whole-populationbirthcohort

815children(5yearsold)fromMAAS

Derpexposureat0-5yearsold(measuredasallergenlevelsrecoveredfromchild’sbed,child’sbedroomfloor,parentalbedandloungefloor)

Protectivefactorforcurrentrhinoconjunctivitis(OR0.8,CI0.7-0.98).Thisfindingfailedtoreachsignificanceinmultivariateanalysis.

Corveretal516

2006 2b Prospectivebirthcohort

416children(4yearsold)fromPIAMAstudy

Derp1andDerf1exposureonthechildren’smattresses

Noassociationwithrhinitisin4thyear(OR0.9,CI0.6-1.3).

Kuligetal468

2000 2b Prospectivebirthcohort

587children(7yearsold)fromMAASstudy

Mite(Derp1+Derf1)exposureat0-18months(measuredasallergenlevelsobtainedfromcarpetdustsamples)

NoassociationwithSAR(ORnotreported).

Kimetal521

2002 3b Cross-sectional

16,624children(7-18yearsold)

Historyofspidermiteexposure Riskfactorforrhinitis(OR1.3,CI1.2-1.5).

Oddsratiosareunadjustedandreportedwith95%confidenceintervals.2LOE:levelofevidence;COPSAC:CopenhagenProspectiveStudyonAsthmainChildhood;AR:allergicrhinitis;OR:oddsratio;CI:95%confidenceinterval;3PAULA:PerinatalAsthmaandEnvironmentLong-termAllergy;MAAS:ManchesterAsthmaandAllergyStudy;PIAMA:PreventionandIncidenceofAsthma4andMiteAllergy;SAR:seasonalallergicrhinitis56

7

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TableVI.B-2.Evidencefortheeffectsofpollenallergenexposure(inuteroandearlychildhoodexposure)onthedevelopmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Typeofexposure Conclusion

Erbasetal481

2013 2b Prospectivebirthcohort

620children(6-7yearsold)fromMACSRCT(withatleastone1stdegreefamilymemberwithahistoryofeczema,asthma,hayfever,severefoodallergy)

Pollenexposure*duringinfancy(at3-6months).

Riskfactorforhayfever(OR1.1,CI1.01-1.3).

Kihlströmetal519

2002 3b Cross-sectional 583childrenwithatopicheredity(4-5yearsold)

High-doseexposuretobirchpollenat0-3months

Noassociationtoallergicrhinoconjunctivitis(OR1.0,CI0.6-1.8).

High-doseexposuretobirchpollenat1year

Noassociationtoallergicrhinoconjunctivitis(OR1.3,CI0.8-2.2)

*Definedasbirth‘inside’or‘outside’thepollenseasonandbymeasuringdaily24-houraveragepollenconcentrationsforgrassandothers(whichincludetrees,2weeds,andherbs).3Oddsratiosareadjustedandreportedwith95%confidenceintervalsinparentheses.4LOE:levelofevidence;MACS:MelbourneAtopyCohortStudy;RCT:randomizedcontrolledtrial;OR:oddsratio;CI:95%confidenceinterval56

TableVI.B-3.Evidencefortheeffectsofpetdanderexposure(inuteroandearlychildhoodexposure)onthedevelopmentofallergicrhinitis*7

Study Year LOE Studydesign Studygroups Typeofexposure Conclusion

EarlyexposuretoanimaldandersasaprotectivefactorforAR(Level2bstudieslisted.Level3bstudiesreferenced.522,523,525-528,530,533,535)

Lodgeetal534

2012 2b Prospectivebirthcohort

620children(12yearsold)withafamilyhistoryofallergicdiseases

Exposuretocatsordogsatbirth

Borderlineprotectivefactorforhayfever(OR0.7,CI0.5-1.02).Strongerprotectiveeffectsifchildrenofnon-sensitizedfathers(ORcatsalone0.3,CI0.2-0.8);(ORcatsordogs0.4,CI0.2-0.8).

Almetal531 2011 2b Prospectivebirthcohort

4,465children(4½yearsold);246childrenwithcurrentAR

Exposuretocatsat1year ProtectivefactorforAR(unadjustedOR0.5,CI0.4-0.8,notsignificantinmultivariateanalysis).

Lampietal532

2011 2b Prospectivebirthcohort

5,509adults(31yearsold)

Exposuretofarmanimals(cows,pigs,sheep,poultry,minks)

BorderlineprotectivefactorforARever(OR0.9,CI0.7-1.03).

Exposuretocatsordogsatagelessthan7yearsold

BorderlineprotectivefactorforAR(ORcat0.8,CI0.7-0.96);(ORdog0.9,CI0.8-1.01).

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Perzanowskietal529

2008 2b Birthcohort 257children(5yearsold)fromAfricanAmericanorDominicanmothers

Catownership(uptoageofhealthoutcomes)

ProtectivefactorforARat5yearsold(OR0.4,CI0.2-0.9).

Nafstadetal524

2001 2b Birthcohort 2,531children(4yearsold)

Exposuretocatsatbirth BorderlineprotectivefactorforAR(OR0.5,CI0.2-1.4).

Exposuretodogsatbirth BorderlineprotectivefactorforARtograss/pollen(OR0.8,CI0.4-1.6).

EarlyexposuretoanimaldanderasariskfactorforAR(AllstudiesLevel3b.523,530,536-542)

EarlyexposuretoanimaldanderisnotassociatedwithAR(Level2bstudieslisted.Level3bstudiesreferenced.528,530,536,538,539,543-546,548,551,553,554)Schoosetal518

2016 2b Prospectivebirthcohort

399children(7-13yearsold)fromCOPSACstudy

Prenatal(at3rdtrimesterofpregnancy)andperinatal(at1year)catexposure

NoassociationwithARat7yearsold(ORprenatal0.4,CI0.06-3.6);(ORperinatal)0.9,CI0.2-3.9).

Prenatal(at3rdtrimesterofpregnancy)andperinatal(at1year)dogexposure

NoassociationwithAR(ORprenatal,ARat13yearsold0.9,CI0.2-4.3);(ORperinatal,ARat7yearsold0.9,CI0.1-7.4).

Illietal517 2014 2b Prospectivebirthcohort

513children(5yearsold)fromPAULAstudy

Catallergenexposureat3months(measuredasallergenlevelsinthelivingroomfloorandinthemother’sorchild’smattress)

NoassociationwithcurrentAR(ORnotreportedasvalue,onlyinfigure).

Lodrup-Carlsenetal552

2012 2b Prospectivebirthcohort

22,840children(6-10yearsold)

Pet(cat,dog,bird,rodent)ownershipat0-2yearsold

NoassociationwithAR(ORcatonly1.02,CI0.8-1.3);(ORdogonly0.8,CI0.6-1.1);(ORcatanddogonly0.8,CI0.4-1.4);(ORbirdonly1.3,CI0.9-1.8);(ORrodentonly0.8,CI0.5-1.5).

Kellbergeretal550

2012 2b Prospectivepopulation-basedcohort

2,810adolescents(15-18yearsold)

Pet(cat,dog,hamster,guineapig,rabbit)ownershipat0-1yearsold

Noassociationwithincidence/persistenceofphysician-diagnosedAR.

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Sandinietal549

2011 2b Prospectivebirthcohort,RCT

1,223children(5yearsold)borntoallergicfamilies,whoparticipatedinaRCT

Dog/catathomeat0-2yearsoldor0-5yearsold

NoassociationwithAR(OR0.98,CI0.5-1.8).

Lampietal532 2011 2b Prospectivebirthcohort

5,509adults(31yearsold)

Maternalworkwithfarmanimals(cows,pigs,sheep,poultry,minks)duringpregnancy

NoassociationwithAR(OR0.9,CI0.7-1.2).

Marinhoetal520

2007 2b Whole-populationbirthcohort

815children(5yearsold)fromMAASstudy

Catanddogexposureat0-5yearsold(measuredasallergenlevelsrecoveredfromchild’sbed,child’sbedroomfloor,parentalbedandloungefloor)

Noassociationwithcurrentrhinoconjunctivitis(unadjustedORcat1.02,CI0.9-1.1);(unadjustedORdog1.03,CI0.9-1.2).

Chenetal547 2007 2b Prospectivebirthcohort

2,166children(4-6yearsold)(hayfever:66/1,599)fromLISAstudy

Catallergenexposureat3mos(measuredasFeld1levelsfromchildren’sorparents’mattress)

Noassociationwithdoctor-diagnosedhayfever(ORparents’mattress0.9,CI0.5-1.5);(ORchildren’smattress0.7,0.4-1.1).

Nafstadetal524

2001 2b Birthcohort 2,531children(4yearsold)

Catkeepingatbirth NoassociationwithAR(OR0.5,CI0.2-1.4).

Dogkeepingatbirth NoassociationwithARtograss/pollen(OR0.8,CI0.4-1.6).

Kuligetal468 2000 2b Prospectivebirthcohort

587children(7yearsold)fromMAAS

Cat(Feld1)exposureat0-18months(measuredasallergenlevelsobtainedfromcarpetdustsamples)

NoassociationwithSAR(ORnotreported).

Petsinhousehold(at18months)

NoassociationwithSAR(ORnotreported).

*Level2bstudiesarelistedinthetable.Level3bstudiesarereferenced.1Alloddsratio(OR)areadjustedunlessdifferentlyspecifiedandarereportedwith95%confidenceintervalsinparentheses2LOE:levelofevidence;AR:allergicrhinitis;OR:oddsratio;CI:confidenceinterval;COPSAC:CopenhagenProspectiveStudyonAsthmainChildhood;PAULA:3PerinatalAsthmaandEnvironmentLong-termAllergy;RCT:randomizedcontrolledtrial;MAAS;ManchesterAsthmaandAllergyStudy;LISA:Lifestyle-Immune-4System-Allergy;SAR:seasonalallergicrhinitis56

7

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TableVI.B-4.Evidencefortheeffectsoffungalallergensexposure(inuteroandearlychildhoodexposure)onthedevelopmentofallergic1rhinitis2

Study Year LOE Studydesign Studygroups Typeofexposure Conclusion

EarlyexposuretofungalallergensasariskfactorforAR

Thacheretal559

2016 2b Birthcohort 3,798adolescents(16yearsold)fromBAMSEstudy;785withAR

Visiblemoldat2months RiskfactorforAR(OR1.3,CI1.04-1.6).

Starketal555 2005 2b Birthcohort 405childrenofasthmatic/allergicparentsfrommetropolitanBoston,Massachusetts(youngerthan5yearsold)

Exposuretohighlevelsofdust-borneAspergillusat0-3months

Riskfactorfordoctor-diagnosedARat0-5years(HR:3.3,CI1.5-7.1).

Exposuretohighlevelsofdust-borneAureobasidiumat0-3months

Riskfactorfordoctor-diagnosedARat0-5years(HR:3.0,CI1.3-6.9).

Exposuretohighlevelsofdust-borneyeastsat0-3months

Riskfactorfordoctor-diagnosedARat0-5years(HR2.7,CI1.3-5.7).

Dengetal557 2016 3b Cross-sectional

2,598children(3-6yearsold)attendingkindergarten

Prenatal(wholepregnancy)orpostnatal(frombirthtothecurrent)exposuretoindoormold/dampness

Riskfactorsforrhinitis-likecurrentsymptoms:prenatal(OR1.5,CI1.2-1.9);postnatal(OR2.1,CI1.6-2.8).

Linetal558 2016 3b Cross-sectional

4,246children(3-8yearsold)from18daycares

Visibleindoormold(weekly/sometimesvs.never)at0-2years

Riskfactorfornewonsetofrhinitissymptoms(OR1.3,CI1.01-1.6).Exposurewasasignificantriskfactorfortheremissionofrhinitis(OR0.6,CI0.3-0.9).

Lametal553 2014 3b Cross-sectional

508preschoolchildren(4-6yearsold)

Exposuretomoisture/mold<1year

Riskfactorforrhinoconjunctivitis(OR2.1,CI1.2-3.8).

Kimetal551 2012 3b Cross-sectional

4,554schoolchildren(meanage9.50yearsold,SD1.73)

Moldexposureinhouseduringinfancy

RiskfactorforcurrentAR(OR1.8,CI1.4-2.4).

Lombardietal538

2010 3b Cross-sectional

20,016children(medianage7yearsold)fromSIDRIA-2Study

Moldexposureat0-1year Riskfactorforcurrentrhinoconjunctivitis(unadjustedOR1.4,CI1.2-1.6).

Ibargoyen-Rotetaetal527

2007 3b Cross-sectional

3,360schoolchildren(5-8yearsold)

Havingmoldonwallsat0-1year

Riskfactorforallergicrhinoconjunctivitis(OR2.5,CI1.5-4.0).

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Oddsratioareadjustedunlessotherwisespecified.1LOE:levelofevidence;AR:allergicrhinitis;BAMSE:Barn/ChildAllergyMilieuStockholmEpidemiology;OR:oddsratio,CI:95%confidenceinterval;HR:hazard2ratio;SD:standarddeviation;SIDRIA-2:StudiItalianisuiDisturbiRespiratoridell’InfanziaelAmbiente;SPT:skinpricktest34

Kuyucuetal556

2006 3b Cross-sectional

2,774children(9-11yearsold)

Dampness/moldat1year RiskfactorforAR(OR1.7,CI1.3-2.3).

Bornehagetal560

2005 3b Cross-sectional

10,851children(1-6yearsold)

Visiblemoldordampspotsinthechild’sorparent’sbedroomat1-6years

Riskfactorforrhinitis(OR2.7,CI1.4-5.4).

EarlyexposuretofungalallergensisnotassociatedwithAR

Biaginietal465

2006 2b Cross-sectional

585infants(1year)borntofamilieswithatleastoneparentwithpositiveSPT

Highmoldexposure(moldinoneroom(>0.2m2oracombinedareaofvisiblemoldandwaterdamageonthesamesurface>0.2m2)duringearlyinfancy(average7.5months)

NoassociationwithAR(OR1.2,CI0.6-2.5).

Lowmoldexposure(moldinoneroom(<0.2m2oracombinedareaofvisiblemoldandwaterdamageonthesamesurface<0.2m2)duringearlyinfancy(average7.5months)

NoassociationwithAR(OR3.2,CI0.7-14.8).

Dengetal557

2016 3b Cross-sectional

2,598children(3-6yearsold)attendingkindergarten

Prenatal(duringthewholepregnancy)orpostnatal(frombirthtothecurrent)exposuretoindoormoldordampness

NoassociationwithAR:prenatal(OR0.7,CI0.4-1.1),postnasal(OR1.0,CI0.6-1.7).

Yangetal542

2014 3b Cross-sectional

7,389schoolchildren(meanage13.9years,SD0.9)

Moldexposureduringinfancy NoassociationwithAR(OR0.99,CI0.8-1.3).

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VI.C.Foodallergens(inuteroandearlychildhoodexposure)12

Insomestudies,earlysensitizationtofoodallergenshasbeenlinkedtothedevelopmentofAR3

inchildhood.468,564,565

Ameta-analysesbyAlduraywishetaldemonstratedthatfoodsensitizationinthe4

first2yearsoflifewasassociatedwithanincreasedriskofARduringchildhood(OR=3.0,95%CI=2.1-5

4.2).564[TableVI.C.]Therelationshipbetweensensitizationtofoodallergensandthesubsequent6

developmentofARduringchildhoodhasbeeninvestigatedinbothpopulation-basedandhigh-risk7

cohorts.468,565-568

Whilethereisastatisticallysignificantcorrelationinthehigh-riskcohort567,thereare8

mixedresultsinthepopulation-basedstudies.566,568,569

Thesefindingspromptedprospective9

investigationoftheeffectsofallergenavoidanceinuteroandduringearlychildhood.10

InaRCTevaluatingtheeffectsofinuteroexposuretofoodantigensandthedevelopmentofAR,11

162high-riskpregnantwomen(historyofrespiratoryallergytoanimaldandersand/orpollens)were12

randomizedoneoftwodietsduringthelast3monthsofpregnancy:eitherverylowingestionofhen’s13

eggandcow’smilk,oradailyingestionofonehen’seggand1[liter]ofcow’smilk.Onehundredand14

sixty-threeinfantswerefollowedprospectivelyupto18monthsofage,atwhichtimetheincidenceof15

atopicdisease,includingAR,wasevaluatedinablindedfashion.Therewasnosignificantdifferencein16

theincidenceofARbetweenthetwogroups.570InanotherRCT,restricteddietduringpregnancy(cow's17

milk-andegg-freedietfromweek28todelivery)wasassociatedwithasmallbutstatisticallysignificant18

lowermeangestationalweightgainanddidnotprotecttheoffspringfromatopy.571Thepooledresults19

oftwotrialssuggestthatmaternalfoodantigenavoidancemaybeassociatedwithahigherriskof20

pretermbirthandapossibleadverseeffectonmeanbirthweightwithoutbeneficialeffectsonAR21

developmentinthechildren.570,571

22

Studieshavealsoevaluatedtheearlyintroductionoffoodscomparedtofoodavoidancewith23

respecttotheeffectsondevelopmentofallergicdisease.Inaprospectivebirthcohortstudy2,07324

children,delayedintroductionofsolids(past4or6monthsofage)wasnotassociatedwithdecreased25

oddsforAR,asthma,orsensitizationagainstfoodorinhalantallergensat6yearsofage.Infact,food26

sensitizationoccurredmorefrequentlyinchildrenwhowereintroducedtosolidslater.572Ina27

prospective,RCToffoodallergenavoidanceininfancy,theincidenceofsubsequentallergicdisease,28

includingAR,wasassessed.Theinterventionarmofthetrialrequiredmotherstoavoidcow'smilk,egg,29

andpeanutduringthelasttrimesterofpregnancyandsubsequentlactation,andrequiredinfantsto30

avoidcow'smilkuntilage1year(caseinhydrolysatesupplementationbeforeage1),egguntilage231

years,andpeanutandfishuntilage3years.Comparedtomaternal-infantcontrolpairswhofollowed32

standardfeedingpractices,infantsinthefood-avoidancearmshowedasignificantreductioninrates33

foodallergyandmilksensitizationbeforeage2years.However,bytheageof7,theprevalenceoffood34

allergywasnolongerdifferentbetweenthetwogroups.Furthermore,therewasnodifferenceinrates35

ofAR,AD,asthma,andotheratopicdiseaseatage7.57336

Basedonthepresentedmeta-analysis,prospectiverandomizedstudies,andalargeprospective37

birthcohortstudy,thereisnodatatosupportmaternaldietasacontributingfactorforthe38

developmentoffoodallergyandAR;however,thereissomeevidencethatthepresenceoffoodallergy39

duringchildhood(greaterthan2-years-old)isariskfactorforAR.40

41

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ICAR:AllergicRhinitis 71

• AggregateGradeofEvidence:A(Level1b:3studies;Level2a:1study;Level2b:1study;Table1

VI.C.)2

3

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TableVI.C.Evidencefortheeffectsoffoodallergenexposure(inuteroandearlychildhoodexposure)onthedevelopmentofallergicrhinitis1Study Year LOE Study

designStudygroups Clinicalendpoint Conclusion

Zeigeretal573 1995 1b RCT 1.infantswhosemothersavoidedcow'smilk,egg,andpeanutinthelasttrimesterofpregnancyandlactationandwhothemselvesavoidedcow'smilkuntilage1year(caseinhydrolysatesupplementationbeforeage1),egguntilage2years,andpeanutandfishuntilage3years2.standardfeedingpractices

Foodallergy,atopicdermatitis,AR,asthma,anyatopicdisease,lungfunction,foodoraeroallergensensitization,serumIgElevel,presenceofnasaleosinophilsorbasophiliccellsatage7.

Nosignificantdifferencebetweentreatmentgroups,thoughchildrenwithfoodallergyby4-yearshadahigher7-yearprevalenceofARandasthma.

Liljaetal570 1989 1b RCT Womenwithrespiratoryallergytoanimaldandersand/orpollensinthelast3monthsofpregnancyrandomizedto:1.verylowingestionofeggandcows'milk2.dailyingestionofeggandcows'milk.

Incidenceofatopicdiseasesat18monthsofage

Nosignificantdifferenceinthedistributionofatopicdiseaseinrelationtothematernaldietduringlatepregnancy.

Falth-Magnussonetal571

1987 1b RCT 1.strictlycow'smilk-andegg-freedietfromweek28todelivery2.normaldietincludingcow'smilkandegg

Skinprick,serumIgE,atopicmanifestations(notAR)

Maternaleliminationdietduringlatepregnancydoesnotprotectthebabyagainstatopy.Maternaleliminationdietduringlatepregnancyisassociatedwithlowweightgainandpretermbirth.

Alduraywishetal564

2016 2a Meta-analysis

Asthma,AR,eczemaorsensitizationagainstfoodallergens

Foodsensitizationinthefirst2yearsoflifecanidentifychildrenathighriskofsubsequentallergicdisease,includingAR.

Zutavernetal572

2008 2b Population-based,prospectivebirthcohortstudy

Asthma,AR,eczemaorsensitizationagainstfoodorinhalantallergens

Noevidencesupportingadelayedintroductionofsolidsbeyond4-6months.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;AR:allergicrhinitis;IgE:immunoglobulinE;2 3

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VI.D.Pollution12

TherelationshipbetweenpollutionandARhasreceivedincreasingattentionoverthepast3decade.Environmentalairpollutantscontainseveralcompounds;however,moststudieshaveprimarily4focusedonparticulatematter<10microns(PM10),particulatematter<2.5microns(PM2.5),nitrogen5dioxide(NO2),sulfurdioxide(SO2),carbonmonoxide(CO),andozone(O3).Theseparticlesmay6potentiateatopythroughmultiplemechanisms,includinginjuringthenasalepithelium,alteringthe7immuneresponse,andincreasingtheallergenicityofcertainantigens.574,575Forexample,pollutionmay8damagethenasalmucosaandimpairMCC,therebyfacilitatingtheaccessofinhaledallergenstocellsof9theimmunesystem.576Additionally,airborneparticles,includingdieselfuelexhaust,arealsoableto10carryallergens,thuspotentiallyincreasingthespreadofallergensorthedurationoftheirexposure.574In11nasalprovocationstudiesofHDM-sensitiveindividuals,acombinednasalchallengewithHDMallergens12anddieselexhaustparticlesledtoenhancedmastcelldegranulationandincreasedseverityofrhinitis13symptomscomparedtoachallengewithHDMalone.57714

NumerousstudieshaveexaminedtheeffectsofairpollutantsonthedevelopmentofARinboth15pediatricandadultpatients.[TableVI.D.]However,threeprospectivecohortstudies(thehighestlevel16ofevidenceidentifiedforthistopic)foundnosignificantcorrelation.578-580Codispotietal578specifically17lookedattherelationshipbetweenexposuretodieselexhaustparticles(DEP)at1yearofageandthe18subsequentdevelopmentofARat2,3,and4yearsofage.WhiletheyfoundthatDEPhadamarginally19positiveassociationwithaeroallergensensitizationat2and3years,andincreasedaeroallergen20sensitizationincreasedtheriskofAR,theyfailedtoidentifyasignificantdirectcorrelationbetweenDEP21andARdevelopment.Additionally,Kimetal579evaluatedexposuretoNO2,SO2,CO,andPM10inchildren22andfoundnosignificantassociationwithanewdiagnosisofARafter2years.However,theydidnotea23positiveassociationbetweenincreasedlevelsofO3andanARdiagnosisinindustrialareasonly;O3was24alsosignificantlyassociatedwiththedevelopmentofnewsensitizationstooutdoorallergens,whichmay25explainthemechanismfortherelatedincreaseinARprevalence.Finally,Gehringetal580pooled426prospectivepediatricbirthcohortstudieswith14-16yearfollow-upandfoundnoindicationthatNO2,27PM2.5,orPM10levelsinfluencedthedevelopmentofrhinoconjunctivitis.28

Severalinternationalcase-controlandcross-sectionalstudieshavealsoevaluatedthe29relationshipbetweenpollutionandARwithvariedresults.Andersonetal581performedthelargestcross-30sectionalstudyevaluatingtheeffectofPM10levelsonthedevelopmentofrhinoconjunctivitisin322,52931childrenfrom51countries.Therewasnobetween-countryassociationofrhinitiswithmodelled32pollutionlevels,andwithincountries(24countrieshadmorethanonestudycenter)therewereweakly33positiveassociationsbetweenPM10levelsandrhinoconjunctivitissymptomsin6-7yearoldsand34diagnosedhayfeverin13-14yearolds.Interestingly,theydidshowapositiveassociationbetweenhigh35PM10levelsandthedevelopmentofatopy.581Somepediatricstudieshaveidentifiedapositive36correlationbetweenincreasedexposuretovariouspollutantsandanincreaseddiagnosisofARduring37childhood.476,557,582-589Liuetal586andDengetal557evenfoundthatprenatal/gestationalexposuretohigh38concentrationsofNO2wereassociatedwithahigherprevalenceofARdiagnosisduringchildhood.39However,almostallofthesestudiesutilizenearbytrafficdensityorhomeaddressgeocodestoestimate40localpollutionexposure.Inmanycountries,peoplelivinginmorepollutedareaswithhighlevelsof41trafficmayalsobemorelikelytohaveotherconfoundingfeaturesthatinfluencetheirdevelopmentof42

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ICAR:AllergicRhinitis 74

AR(i.e.SES,exposuretodifferentaeroallergens)andnotallstudiesfullyadjustforthesepotential1confounders.Additionally,severalofthesestudieswererestrictedtospecificcitiesinAsia,inturn,2limitinggeneralizability.3

Overall,therelationshipbetweenpollutionexposureandthedevelopmentARiscurrently4unclear.Moreprospectivepediatricandadultstudiesindiversegeographiclocationsareneededto5betterunderstandthiscomplexrelationship.67

• AggregateGradeofEvidence:C(Level2b:3studies;Level3b:2studies;Level4:9studies;Table8VI.D.)910

11

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TableVI.D.Evidencefortheeffectsofpollutionexposureonthedevelopmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionCodispotietal578

2015 2b Prospectivecohort

DEPexposureat1year:1.>66thpercentile2.<66thpercentile

DevelopmentofARbyage4 HighDEPexposuredidnotcorrelatewiththedevelopmentofAR.

Gehringetal580

2015 2b Pooledprospectivecohort

1.highexposuretoNO2,PM2.5,

PM102.lowexposuretoairpollutants

Incidenceandprevalenceofrhinoconjunctivitisfromage4to14-16years

Noassociationbetweenairpollutionexposureandrhinoconjunctivitisincidenceorprevalenceatvariousages.

Kimetal579

2011 2b Prospectivecohort

Concentrationsof5airpollutants(NO2,O3,SO2,CO,PM10):1.industrialarea2.metropolitancity

DevelopmentofARinchildrenover2years

IncidenceofARisnotassociatedwithairpollutants;however,therewasapositiveassociationbetweenhigherO3levelsandARinindustrialareas.

Chiangetal587

2016 3b Case-controlstudy

ExposuretoSO2over11years:1.highexposure2.lowexposure

DiagnosisofARinchildren HighexposuretoSO2correlateswithanincreaseddiagnosisofAR.

Chungetal588

2016 3b Case-controlstudy

Exposureto5airpollutants(PM10,NOx,SO2,CO,O3):1.highexposure2.lowexposure

DiagnosisofARinpreschoolchildren

Pre-diagnosislevelsofCOandNOxweresignificantlyrelatedtoARdiagnosis.

Singhetal584

2016 4 Cross-sectional

Frequentpassageoftrucksnearhome:1.almostallday2.lessfrequent

DiagnosisofARinchildrenages6-7and13-14

FrequentpassageoftruckswascorrelatedwiththeoccurrenceofARinbothagegroups.

Wangetal585

2016 4 Cross-sectional

Exposureto6airpollutants(PM10,PM2.5,NO2,SO2,CO,O3):1.highexposure2.lowexposure

DiagnosisofARinchildren HighlevelsofPM2.5correlatewithanincreasedriskofAR.

Liuetal586

2016 4 Cross-sectional

Exposureto3airpollutants(PM10,NO2,SO2):1.highexposure2.lowexposure

DiagnosisofARinchildren HighexposurestoNO2duringgestation,thefirstyearoflife,secondyear,andthroughoutlifecorrelatedwiththedevelopmentofAR.

Dengetal557

2016 4 Cross-sectional

Exposureto3airpollutants(PM10,NO2,SO2):1.highexposure2.lowexposure

DiagnosisofARinkindergartenchildren

PrenatalexposuretohighNO2correlatedwithAR;postnatalexposuretohighPM10correlatedwithAR.

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ICAR:AllergicRhinitis 76

KimJetal476

2016 4 Cross-sectional

Exposureto5airpollutants(PM10,NO2,SO2,CO,O3):1.highexposure2.lowexposure

DiagnosisofARbytheageof6-7

HigherexposuretoCOwasassociatedwithanincreasedlifetimeprevalenceofphysician-diagnosedAR.

KimHHetal589

2016 4 Cross-sectional

Exposureto5airpollutants(PM10,NOx,SO2,BC,O3):1.highexposure2.lowexposure

ARtreatmentoverthepast12monthsinchildren

HighexposuretoBC,SO2,andNO2weresignificantlyassociatedwithincreasedtreatmentofAR.

Jungetal582

2015 4 Cross-sectional

1.livinglessthan75mfrommainroad2.livingmorethan75m

LifetimeAR,past-yearARsymptoms,diagnosedAR,andtreatedARinchildren

PositivecorrelationbetweendistancefrommainroadandARsymptoms,diagnosis,andtreatment.

Shirindeetal583

2015 4 Cross-sectional

1.truckspassingnearresidencealmostallday2.truckspassinglessfrequently

DiagnosisofARin13-14year-oldchildren

DiagnosisofARissignificantlyassociatedwiththefrequencyoftruckspassingbytheresidence.

Andersonetal581

2010 4 Cross-sectionalstudy

ExposuretoPM10:1.highexposure2.lowexposure

Diagnosisofrhinoconjunctivitisatages6-7and13-14

OnlysignificantlyincreasedassociationbetweenPM10levelsandrhinoconjunctivitisandatopyin13-14yearoldsincountrieswithmorethanonetestingcenter.

LOE:levelofevidence;DEP:dieselexhaustparticles;AR:allergicrhinitis;NO2:nitrogendioxide;PM2.5:particulatematter<2.5microns;PM10:particulate1matter<10microns;O3:ozone;SO2:sulfurdioxide;CO:carbonmonoxide;NOx:nitrogenoxides;BC:blackcarbon234 5

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VI.E.Tobaccosmoke12

ARhasfrequentlybeenassociatedwithbothactiveandpassive(secondhand)exposureto3tobaccosmoke.However,thepathophysiologybehindthisrelationshipiscomplexand,attimes,4contradictory.Studieshaveshownthattobaccosmokeexposurecanpropagatethedevelopmentof5atopicdiseasesviaseveralmechanismsincludingdirectsurfacedamagetonasalmucosa,altered6epigeneticmechanismsthroughhistoneacetylation,expressionofmicroRNA,andDNA7methylation.590,591Alternatively,ithasalsobeenshownthatnicotinemayexertanimmunosuppressive8effectonallergicdiseasebysuppressingeosinophiltraffickingandTh2cytokine/chemokine9responses.59210

Recently,twolargemeta-analyseswerepublishedwhichsoughttobetterdefinethe11relationshipbetweentobaccoandAR.[TableVI.E.]Saulyteetal593identifiedasignificantcorrelation12betweenpassivesmokeexposureandthedevelopmentofAR,butnosignificantrelationshipbetween13activesmokingormaternalprenatalpassivesmokeexposureandAR.However,theydidfinda14significantcorrelationbetweenactivesmokingandnon-allergic/chronicrhinitis.Huretal594also15systematicallyevaluatedtherelationshipbetweensecondhandsmokeandARandthatmeta-analysisof16studiesinadultsshowedanassociationbetweenpassivesmokeandAR,whileasimilaranalysisof17pediatricstudiesdidnot.Thisraisesthepossibilitythattheatopiceffectsofsecondhandsmokeinthe18nasalmucosamaytakeseveralyearstomanifest.Infact,Linetal595foundthatallergicadultsweremore19likelytohavebeenexposedtosecondhandsmoke20yearspriorwhencomparedtonon-allergicadults.20

FiveprospectivecohortstudiesexaminedtheeffectoftobaccoonthedevelopmentofAR,allof21whichfailedtofindacorrelationbetweenactiveorpassivetobaccosmokeandthedevelopmentof22AR.596-600Keiletal596foundthatwhilepassivesmokewasnotsignificantlyrelatedtoAR,itwasstrongly23associatedwithallergicsensitizationandasthmasymptomsinchildrenwithageneticpredisposition(at24least1ormoreatopicparents).Additionally,Wrightetal597foundthatwhiletherewasnosignificant25associationbetweensecondhandsmokeexposureandAR,63%ofasthmaticsborntoheavysmokers26developedrhinitisinthefirst6months,versus43%ofasthmaticswhosemothersdidnotsmoke.Finally,27Bendtsenetal598foundthatactivelysmokingmorethan15cigarettesperdayactuallydecreaseda28patient’sriskofdevelopingAR.29

Thisinversecorrelationhasbeenidentifiedinseveralotherstudies.124,601-603Erikssonetal12430foundthatwhilesmokingwasassociatedwithahighprevalenceofchronicrhinitisinbothmenand31women,itwascorrelatedwithalowprevalenceofARinmen.Additionally,theyfoundasignificantly32lowerprevalenceofsensitizationtocommonairborneallergensincurrentandex-smokerscomparedto33nonsmokers.Incontrast,thesignificantpositiveassociationbetweentobaccoandthedevelopmentof34non-allergic/chronicrhinitishasbeenrepeatedlyidentified.124,128,604Therefore,whendiscussingthe35effectsoftobaccoonrhinitis,differentiatingbetweenallergicandnon-allergic/chronicisparamount.36

Finally,tobaccodoesnotappeartoinfluencetheefficacyofARtreatment.Katotomichaelakiset37al605evaluated163patients(bothsmokersandnon-smokers)receivingsublingualimmunotherapy(SLIT)38forARandfoundthat,regardlessoftobaccostatus,totalsymptomscoresandQOLquestionnaires39equallyimproved.Overall,whilemoststudiesevaluatingARandtobaccoarecase-controlorcross-40sectionalinnature,multipleprospectivecohortstudiesandtwosystematicreviewspredominantly41foundnocorrelationbetweenactiveorpassivetobaccosmokeandAR.Additionally,somestudies42

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ICAR:AllergicRhinitis 78

suggestthattobaccomayhaveaprotectiveeffectagainstthedevelopmentofAR.Furtherinvestigation1isneededtoidentifyifspecificpatientpopulations(e.g.asthmaticsorthosewithatopicparents)or2temporalvariations(e.g.exposurefor20+years)mayalterourunderstandingofthisrelationship.34

• AggregateGradeofEvidence:C(Level2a:1study;Level2b:5studies;Level3a:1study;Table5VI.E.)67

8

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TableVI.E.Evidencefortheeffectofactiveandpassivetobaccosmokeexposureonthedevelopmentofallergicrhinitis1Study Year LOE Studydesign Activevs

PassiveSmoke

Exposure

Studygroups Clinicalendpoint

Conclusion

Saulyteetal593

2014 2a SRofcohort,cross-sectional,andcase-controlstudies

Both 1.activesmoking2.passivesmoking3.noactiveorpassivesmoking

DiagnosisofAR

Noassociationbetweenactivesmokingandmaternalpre-natalpassivesmokingandAR.SignificantassociationbetweenallotherpassivesmokingandAR.

Codispotietal599

2010 2b Prospectivecohortstudy

Passive 1.environmentaltobaccosmokeexposure2.noexposure

DiagnosisofARbyage3

EnvironmentaltobaccoexposurehasnoeffectonthedevelopmentofARbyage3.

Keiletal596 2009 2b Prospectivecohortstudy

Passive Maternalsmokingvsnosmokeexposurewith:1.2allergicparents2.1allergicparent3.non-allergicparents

DiagnosisofARoverthefirst10yearsoflife

TherewasnoassociationbetweenmaternalsmokingandthedevelopmentofARregardlessoftheallergicstatusoftheparents.

Bendtsenetal598

2008 2b Prospectivecohortstudy

Active 1.currentsmoking2.nocurrentsmoking

Self-reportedSARorPAR

Smokingmorethan15cigarettes/daywasassociatedwithadecreasedriskofSAR.

Annesi-Maesanoetal600

1997 2b Prospectivecohortstudy

Active 1.lifetimenon-smokers2.ex-smokers(>1month)3.currentsmokers

Chronicrhinitis,SAR,orperceivednasalhyper-responsiveness

NoassociationbetweensmokingandseasonalAR.Significantassociationbetweenchronicrhinitisandcurrentsmoking.

Wrightetal597

1994 2b Prospectivecohortstudy

Passive 1.maternalsmoking2.nosmokinginthefirstyear

PhysiciandiagnosedARatage6

NosignificantassociationbetweenmaternalsmokingandphysiciandiagnosedAR

Huretal594 2014 3a SRofpredominantlycase-controlstudies

Passive 1.exposuretopassivesmoking2.noexposuretopassivesmoking

DiagnosisofAR

MoststudiesdidnotshowarelationshipbetweenpassivesmokeexposureandAR.

LOE:levelofevidence;SR:systematicreview;AR:allergicrhinitis;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis23

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VI.F.Socioeconomicfactors1

In1829JohnBostockdescribed29casesintheUK,includinghimself,ofindividualswhosuffered2

fromcatarrhusaestivus,“summercold”whichhenotedoccurredinpatientsofmiddletohigh3

socioeconomicstatus(SES).606Duringthe1870s,Blackleyfoundnohayfeveramongfarmersandpeople4

livingindeprivedareasofcities.606Thepositiveassociationbetweenhayfeverandhighsocialclasswas5

laterreportedintheBritish1958and1970cohorts,607,608

aswellasaSwedishsurveyofconscriptsborn6

from1952to1977.609However,duringthestudyperiod,thisassociationseemedtoweakenwithanOR7

estimateforARamongsubjectswithlowSESchangingfrom0.79to0.92.8

In2000,apaperwaspublishedfromtheGermanMAS(MulticentreAllergyStudy)birthcohort9

including1,314childrenbornin1990.610Inthisstudy,itwasfoundthatthelifetimeprevalenceofhay10

feverwaselevatedinparentsofhighSEScomparedtolow.However,intheirchildren,theoccurrenceof11

hayfeverwasnotelevatedinfamilieswithhighSES.Alternatively,intheSwedishbirthcohortBAMSE12

(SwedishabbreviationforChildrenAllergy,Milieu,Stockholm,Epidemiology)with4,089childrenborn13

between1994-1996,itwasnotedthathighSESactuallyresultedinadecreasedriskofAR,alongwith14

decreasesinasthmaandfoodsensitizationrates.611InarecentstudyfromDenmarkof9,720children15

bornbetween1994and2006,ARwasassociatedwithloweducationalleveloftheparents.61216

Interestingly,inthefollowupoftheGermanMASbirthcohortstudy,SESwasnotassociatedwithARat17

allbytheageof20years.613Thus,amongchildrenbornintheWesternworldbefore1970highSESwas18

ariskfactor,butamongchildrenborninthesameregionsafter1990lowSES,particularlyearlyinlife,19

seemedtobeariskfactor.614[TableVI.F.]20

Morerecently,twostudiesfromKoreahavereconfirmedthepreviouslynotedassociation21

betweenhighSESandthedevelopmentofAR.Ahnetal478foundapositiveassociationbetweenhigher22

familyincomeandsymptom-basedARdiagnosis(butnotallergytestbasedARdiagnosis).Leeetal61523

alsofoundfamilyaffluence,orhighSES,tobeasignificantriskfactorforARinKoreanadolescents.24

However,additionalrecentstudiesfromSouthAmericaandEuropehaveshownvaryingresults.In2016,25

Penarandaetal616foundhighSEStobeassociatedwithARinchildren/adolescentsbutnotinadults,26

whileWronkaetal617identifiedasignificantlyhigherincidenceofARinadultfemaleuniversitystudents27

(19-25yearsold)fromfamilieswithhighSES.28

Overall,SESislikelyaproxyforvariousexposureslikenumberofsiblings,viralinfections,29

exposuretotobaccosmoke,housingconditionsandlocation,allergenexposures,dietaryfactors,and30

nutritionincludingbreastfeedingandgeneraldiet.Someofthoseexposuresareassociatedwiththe31

hygienehypothesis,introducedbyStrachaninthelate1980s.618However,Itisworthnotingthat32

exposuresrelevanttothehygienehypothesiswereimportantpredictorsforthedevelopmentofARat33

anearlyage.61434

Currently,thereisconflictingevidenceregardingtheassociationbetweenSESandAR.While35

moststudiesshowanassociationbetweenhighSESandthediagnosisofAR,thisisnotaconsistent36

outcome.Thisdisparitymaybeexplainedbytheadditionalfactorsevaluatedinseveralofthesestudies37

whichmayconfoundtheexactrelationshipbetweenSESandAR.Additionally,theremaybeatemporal38

relationshipbetweenSESandARconsideringdifferentoutcomesinchildrencomparedtoadults.39

AdditionalinvestigationisneededtodeterminethetruerelationshipbetweenARandSES.40

41

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ICAR:AllergicRhinitis 81

• AggregateGradeofEvidence:C(Level2b:4studies;Level4:6studies;TableVI.F.)1

2

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TableVI.F.Evidencefortheassociationbetweenallergicrhinitisandsocioeconomicfactors1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionGrabenhenrichet

al613

2015 2b Prospectivecohort ParentalSES:

1.rich

2.average

3.poor

DiagnosisofARbyage

20

NoassociationbetweenSESand

diagnosisofAR.

Almqvistetal611 2005 2b Prospectivecohort ParentalSES:

1.blue-collarworkers

2.low/intermediatewhitecollar

3.onehighlevelwhitecollar

4.twohighlevelwhitecollar

DiagnosisofARat4

yearsold

ParentsofhigherSEShadchildren

withalowerriskofAR,asthma,and

foodallergens.

Bergmannetal610 2000 2b Prospectivecohort

ParentalSES:

1.high

2.middle

3.low

DiagnosisofARparents

andinchildren3-6years

old

ParentalhighSEScorrelatedtohigh

ARratesinparents;however,SES

hadnocorrelationwithARin

children3-6yearsold.

Lewis&Britton608 1998 2b Prospectivecohort Levelof“socialadvantage”:

1.mostdisadvantaged

2.disadvantaged

3.average

4.advantaged

5.mostadvantaged

Diagnosisofhayfeverat

ages5,10,and16

Socialadvantagewassignificantly

relatedtothediagnosisofARwith

the“mostadvantaged”havingthe

highestprevalenceofAR.

Ahnetal478 2016 4 Cross-sectional

survey

SES:

1.greaterthanaverageincome

2.lessthanaverageincome

1.symptom-basedAR

2.allergytest-basedAR

Significantassociationbetween

higherSESandsymptom-basedAR;

butnoassociationbetweenSESand

allergytest-basedAR.

Leeetal615 2016 4 Cross-sectional

survey

FamilyAffluenceScale:

1.low

2.middle

3.high

DiagnosisofARin

adolescents

HighFamilyAffluenceScalewas

associatedwithhigherprevalenceof

AR.

Penarandaetal616 2016 4 Cross-sectional

survey

SES:

1.low

2.middle

3.high

DiagnosisofARin

childrenandadults

MiddleandhighSESwasassociated

withincreasedARsymptomsin

childrenbutnotinadults.

Wronkaetal617 2016 4 Cross-sectional

survey

SES:

1.high

2.low

DiagnosisofARin

universitystudents(ages

19-25)

HigherproportionofARinstudents

fromhighSEScomparedtolow.

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ICAR:AllergicRhinitis 83

Hammer-Helmich

etal612

2014 4 Cross-sectional

survey

ParentalSES DiagnosisofARin

children11-15and3-6

yearsold

Noassociationbetweenhousehold

incomeanddiagnosisofAR.

Brabacketal609 2005 4 Cross-sectional

study

HighvslowSES DiagnosisofARupon

enrollmentinmilitary

service

Inthe1950s,lowSESandARwere

inverselyrelated,butthisassociation

significantlydecreasedby1970.

LOE:levelofevidence;SES:socioeconomicstatus;AR:allergicrhinitis1

2

3

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VI.G.Protectivefactors1VI.G.1.Breastfeeding23

Breastfeedingisassociatedwithseveralbeneficialeffectsonmotherandchildhealthand4thereforehasbeenrecommendedforallinfants.619Onepotentialbenefitisthepreventionofallergic5disease.620Breastmilkisanimmunologicallycomplexsolution,containingmultiplecompoundsthat6supportinfantgrowthandfacilitatedevelopmentoftheinfantimmuneresponse.621,622Theassociation7betweenbreastfeedingandthepreventionofallergicdiseasehasbeenfrequentlystudiedandoften8debated.9

MimouniBlochetal623performedameta-analysisofprospectivestudiesevaluatingtheeffects10ofexclusivebreastfeedingforthefirst3monthsoflifeonthedevelopmentofAR.[TableVI.G.1.]Six11prospectivestudiesmettheinclusioncriteria.Intheirpooledanalysis,theyfoundaprotectiveeffectof12exclusivebreastfeedingforthefirst3monthsoflifethatapproachedstatisticalsignificanceinthe13generalpopulation(OR0.74;95%CI0.54-1.01).Interestingly,theprotectiveeffectwasnotseenin14childrenwithafamilyhistoryofatopicdisease(OR0.87;95%CI0.48-1.58).15

Morerecently,Lodgeetal624performedasystematicreviewandmeta-analysisin2015.Their16analysisevaluatedtheassociationbetweenbreastfeedingandARandincluded5cohort17studies550,599,607,625,626and11cross-sectionalstudies.627-637Thenumberofparticipantsvariedbetween18361and13,889forthecohorts,and1,402to206,453forthecross-sectionalstudies.Poolingof19estimatesfromthevariousstudiesfoundanon-significantprotectiveeffectofbreastfeedingonthe20developmentofAR(OR0.92;95%CI0.84-1.01).TheresultswerethenstratifiedbyincidenceofARin21differentagegroups.Afterstratificationbyage,areducedriskofARinpatientsunder5yearsofagewas22associatedwithbreastfeeding(OR0.79;95%CI0.63-0.98).However,therewasnoassociationafter523yearsofage(OR1.05;95%CI0.99-1.12).Whiletheauthorsofthismeta-analysisarguedforthebenefit24ofbreastfeedinginthepreventionofAR,theydoacknowledgethattheprotectiveeffectof25breastfeedingseeninpatientslessthan5yearsofagemayhavebeenconfoundedbyknownprotective26effectsofbreastmilkagainstviralrespiratoryinfections.Theauthorshypothesizedthat,giventhe27difficultyofdifferentiatingbetweenARandviralrhinitisinyoungchildren,areductioninviral28respiratoryinfectionshavebeenpossiblyinterpretedasareductioninrhinitissymptoms.6242930

• AggregateGradeofEvidence:C(Level3a:2studies;TableVI.G.1.)31• Benefit:PossiblebenefitfrombreastfeedingwithreductioninAR,especiallyseeninyoung32

children.33• Harm:None.Nostudieshaveshownharmwithbreastfeedingfor6months.34• Cost:Low.�35• Benefits-HarmAssessment:Possiblebenefitwithnoharm.�36• ValueJudgments:ThereisevidencethatbreastfeedingmayreducetheriskofARwithno37

perceivedharm.Giventhegeneralbenefitstothemotherandchild,breastfeedingfor4months38andpossibly6monthshadbeenadvocated.39

• PolicyLevel:OptionforbreastfeedingforthespecificpurposeofARprevention,basedupon40currentevidence.Ingeneral,breastfeedinghasbeenstronglyrecommendedduetoitsmultiple41benefits.42

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ICAR:AllergicRhinitis 85

• Intervention:Breastfeedingisgenerallyencouragedforatleast4monthsduetoitsmultiple1benefits.WhenspecificallyrelatedtothepreventionofAR,breastfeedingisanoption.23

4

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TableVI.G.1.Evidencefortheeffectsofbreastfeedingonthedevelopmentofallergicrhinitis*1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

MimouniBlochetal623

2002 3a SR Prospectivestudiesevaluatingtheeffectsofexclusivebreastfeedingforthefirst3monthsonARdevelopment

DevelopmentofAR Protectiveeffectclosetostatisticalsignificanceinthegeneralpopulationbutnotinchildrenwithafamilyhistoryofatopicdisease.

Lodgeetal624

2015 3a SR AssociationbetweenbreastfeedingandAR

DevelopmentofAR Non-significantprotectiveeffectoverall.Protectivebenefitforchildrenunder5,butnotover5.

*Thesystematicreviewspresentedaboveincludeallpublishedstudiestodate.2LOE:levelofevidence;SR:systematicreview;AR:allergicrhinitis345 6

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VI.G.2.Childhoodexposuretopets1

Amongsubjectssensitizedtopetallergens,exposuretendstoexacerbatesymptoms.However,2theassociationofpet-keepinginchildhoodwiththesubsequentdevelopmentofARismore3controversial,anddifficulttoestablish.(SeeSectionVI.B.3.RiskFactorsforAllergicRhinitis–Petsfor4additionalinformationonthistopic.)5

Prevalenceofhouseholdpetownershipisusedtoestimatepetallergenexposure.However,pet6ownersarefrequentlycontaminatedwithpetallergens,leadingtogeneralizedexposuresviasocial7contact.Therefore,anon-exposedreferencepopulationdoesnotexist,limitingourabilitytoclearly8understandtherelationshipbetweenexposuretopetallergensanddevelopmentofAR.9

Thetimingofpetallergenexposureearlyinlifemaybeanimportantfactorforthematuring10immunesystem.Therefore,self-reportedperinatalandnewbornexposuresarefrequentlyanalyzed.11Fewstudieshavemeasuredtheconcentrationofthemajorcatallergen(Feld1)orthemajordog12allergen(Canf1)inhomedust.Rather,moststudiesmerelyreportexposuretocatsand/ordogs,or13furredpets,andsometorodentsandbirds.Inasystemicreviewofepidemiologicstudiesofallergyand14asthma,only10of96includedstudiesreportedavoidanceofpets.638Additionally,studiesmayoftenfail15toaccountforconfoundingvariablessuchasafamilyhistoryofpetallergywhich,inturn,may16predisposelikelyatopicchildrentopetavoidance.17

Thereissignificantinconsistencywithregardstopetownershipinchildhoodandthe18subsequentdevelopmentofallergy.Demographicfeaturesrelatedtopet-keeping,includingrace,urban19vs.ruralenvironment,familysize,andSESmayhelpaccountforsomeoftheconflictingresults.Ameta-20analysisofthirty-twostudiesreportedalowerprevalenceofARamongsubjectswithfurredpetsin21cross-sectionalstudies,andlessasthmaamongcat-exposedsubjects.639Anextensivesystematicreview22of62studiesfounddifferentassociationsdependingonstudydesign.640Inmostofthebirthcohort23studies,dogexposureinearlychildhoodwasprotectiveforsensitizationagainstaeroallergens.640,641On24thecontrary,cross-sectionalstudiesreportedinconsistentassociationsbetweencatordogexposure25andsensitizationaswellasthesubsequentdevelopmentofatopicdiseaseslaterinlife.562,640[Table26VI.G.2.]27

TheimpactofpetavoidanceonARdevelopmentisbestevaluatedvialongitudinalbirthcohort28studies.Asystematicreviewofninestudiesconductedsolelyinurbanenvironmentsevaluatedperinatal29petexposure.642Sixstudiesfoundthatexposuretodogs,orcats/dogsprotectedagainstallergicdisease.30Twostudiesfoundincreasedriskofallergyonlyinhighlyatopicfamilies.Furthermore,inacohortof62031childrenwithfamilyhistoryofallergicdiseases,exposuretocatsordogswasprotectiveonlyinchildren32withnon-allergicfathers.53433

Inapooledanalysisof11Europeanbirthcohorts,anyfurredpetownershipduringthefirsttwo34yearswasassociatedwithlowerriskofsensitizationtoaeroallergens,butnotwithadecreased35prevalenceofARlaterinchildhood.552Inarecentstudywhichinvestigatedurbanvsruraldifferences,36theriskofARinadulthoodwas20%lowerinsubjectsexposedtopetsatbirthorduringchildhood.37However,petkeepingdidnotexplaintheprotectiveeffectoflivingonfarmwithlivestockcomparedto38urbandwelling.64339

Overall,petallergensareubiquitous.Thereisnoevidencethatpetavoidanceinchildhood40preventsthedevelopmentofARorsensitizationtoaeroallergenslaterinlife.Alternatively,earlypet41

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ICAR:AllergicRhinitis 88

exposuremayinduceimmunetoleranceandthusreducethechanceofdevelopmentofallergicdisease.1Thisprotectiveeffectseemstobestrongestinnon-allergicfamilieswithdogexposureinearly2childhood.34

• AggregateGradeofEvidence:C(Level2a:6studies;Level2b:2studies;TableVI.G.2.)56

7

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TableVI.G.2.Evidencefortheeffectofearlychildhoodpetexposureofthedevelopmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

SmallwoodandOwnby641

2012 2a SR

26articles.Exposuretodogs20weeksfromgestationtooneyear.

Associationofallergicsymptomswithexposuretodogs

Inconsistentassociation.Dogexposureatbirthmaybeprotectiveagainstallergicsymptoms.

Dharmageetal562

2012 2a SR

19studies(2011-2012):9longitudinal,8cross-sectional,2case-control

AssociationofARwithexposuretocats

Inconsistentassociation.Ifexposureduringthefirstyear,lessARorsensitization,ornoeffect.Possibleprotectiveeffectuntiladulthood.

Lodgeetal642

2012 2a SR

(2001-2008)9longitudinalstudies6498subjectsaged0-11years

Associationofphysiciandiagnosedhayfeverwithexposuretopets,orcatsanddogsduringperinatalperiodinurbanenvironment

Dogsmayreducesensitizationorallergicdiseaseinfamilieswithlowriskofallergy.Noassociationwithcats.

Lodrup-Carlsenetal552

2012 2a Pooledanalysisofindividualdatafirstyearofrecruitment

(1989-1997)11Europeanbirthcohorts,11,489participantsaged6-10years

Associationofsensitizationtoaeroallergenswithownershipofcatsonly,dogsonly,catsanddogsonly,birdsonlyorrodentsonlyduring0-2yearsofage

Dogandrodentexposureprotectiveagainstsensitizationtoaeroallergens.NoassociationwithAR.

Chenetal640

2010 2a SRofbirthandnon-birthcohortstudiesandcross-sectionalstudies

62articles(2000-2009):Subjects6-69yearsold1.17birthcohortsreportedcatexposureorFeld1indust2.13reporteddogownershiporCanf1indust3.26cross-sectionalstudiesreportedcatordogexposure

AssociationofARwithexposuretocatsordogsincross-sectionalstudies

Inconsistentassociation.Dogexposuremaybeprotective.Designofthestudyinfluencestheassociation.

Takkoucheetal639

2008 2a Meta-analysis

32studies(1985-2006);5studies(n=6818)reportedrhinitis

AssociationofARwithexposuretofurredpets

Inconsistentassociation.Possibleprotectiveeffectoffurredpetsonrhinitis.

Christensenetal643

2016 2b Populationbasedcross-sectionalstudyfollowup

RHINEcohort(2010-2012):13,376subjectsborninNorthernEurope1945-1973

AssociationofARinadulthoodwithexposuretopetsatbirth,duringchildhoodandtolivestockfarminchildhood

ExposuretopetsinchildhooddecreasestheriskofARinadulthoodindependentlyofurbanorruralupbringing.

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ICAR:AllergicRhinitis 90

Lodgeetal534

2012 2b Prospectivebirthcohort

MACScohort620infantswithfamilyhistoryofallergicdisease

Associationofhayfeverafter7yearsofagewithexposuretocatsanddogsatbirth

Inhighriskcohort,petexposureatbirthisprotectiveagainsthayfeveratage7inchildrenwithnon-sensitizedfathers

LOE:levelofevidence;SR:systematicreview;AR:allergicrhinitis;RHINE:RespiratoryHealthinNorthernEurope;MACS:MelbourneAtopyCohortStudy123 4

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VI.G.3.Hygiene(aka.BiodiversityorMicroflora)hypothesis1

Theinverseassociationofthenumberofsiblingsandtheprevalenceofhayfeverwasreported2nearlythreedecadesagoinBritishcohorts.618Strachanproposedtheterm“hygienehypothesis”and3speculatedthatexposuretofrequentinfectionsinlargefamiliescouldbetheprotectivefactor.The4hygienehypothesishasevolvedtowardsamorecontemporary“biodiversityhypothesis”thatlooks5beyondtheeffectofinfectionsandsingleprotectivemicrobestothepotentialprotectiveeffectofthe6colonizationofmucousmembranesandtheskinwithdiverseenvironmentalmicroflora.644Recently,the7term“Microbiotahypothesis”hasbeenproposed.Inaddition,theterm“microflora”shouldbe8substitutedfortheterm“microbiota”.Variousrelatedpotentialco-factorsandtheirrelationshiptothe9developmentofARarediscussedthisthissection.1011Numberofsiblings.Theassociationbetweennumberofsiblingsandpresenceofallergicdiseaseshas12beenstudiedextensively.Inameta-analysisof53studies,48studiesdemonstratedthathighernumber13ofsiblingswasassociatedwithdecreasedatopy,aneffectthatwasmoreevidentforARthanfor14sensitizationandasthma.645[TableVI.G.3.]Alargestudybasedonquestionnairedataforchildrenaged156-7yearsfrom31countriesand13-14yearsfrom52countriesconfirmedthattheinverseassociation16betweenthenumberofoldersiblingsandprevalenceofhayfeverwasstrongestinmoreaffluent17countries.6461819Farming.Sincethefirstpublicationsin1999-2000,thereisagrowinginterestinthe“farmeffect”on20allergy.Inameta-analysisofeightstudies,theriskofsensitization,measuredbysIgEorSPTinchildhood21oradulthood,was40%lower(OR0.60,95%CI0.52-0.70)amongsubjectswhohadlivedonafarm22duringthefirstyearoflife.647InarecentUScase-controlstudy,farmexposureinuteroandinearly23childhoodprotectedagainstallergensensitizationbutnotasthmainadulthood.648Theprotectivefarm24effectseemstobestrongerwhenexposedtofarmanimalsandstables.522,649-655Theprotectiveeffectis25greatestwithhighestexposureoccurringearlyinlife.6502627Bacterialendotoxin.Exposuretobacterialendotoxinhasbeenstudiedasapossibleprotectivefactor.28Inverseassociationbetweenexposuretoendotoxinininfancyandchildhoodandthedevelopmentof29allergicsensitizationhasbeenshowninruralandurbanenvironments,buttheresultshavenotbeen30uniformbetweenthestudies.656,6573132Probiotics.Ameta-analysisof29randomizedcontrolledstudiesshowednosignificantassociationof33probioticssupplementationofpregnantorbreastfeedingmothersorinfantswithsensitizationorallergic34rhinitisatage12to36months.658(SeeSectionIX.B.9.Management–Pharmacotherapy–Probioticsfor35additionalinformationonthistopic.)3637Microbialdiversity.Changesinlifestyle,urbanization,dietandtheuseofantibioticshavechangedthe38microbiotaoftheenvironment,humanskinandmucosalmembranes.Differencesinthemicrobiotamay39explainthedifferenceinatopicdiseasesbetweenruralandurbanareas,aswellasFinlandandthe40

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ICAR:AllergicRhinitis 92

RussianKarelia(apartofRussiageographicallyadjacenttoFinland).659-661Householdswithdogshave1rich,diversehousedustmicrobiotawithabundanceofFirmicutesandBacteroidesspecies.6622

IntheGABRIELstudythemattressdustoffarmchildrenandtheircontrolswasanalyzedby3quantitativeDNAanalysis.EspeciallyhighmattresslevelsofMycobacteriumsp.,Bifidobacteriacaesp.4andClostridiumsp.werefoundamongfarmchildren,andthathighlevelwasinverselyassociatedwith5atopy.6616

Lowdiversityofgutmicrobiotainearlyinfancyhasbeenrelatedtogreaterriskofasthmaand7sensitizationinsomelongitudinalstudieswithdifferentdesignsinchildhood.442,445,449,663Thedysbiosisof8themicrobiomedrivenbyhigherBacteriodesandreducedClostridiataxainadulthoodwasassociated9withgreaterprevalenceofseasonalandnutallergiesinadulthoodintheAmericanGutProject.66410

Skinmicrobiotamayalsobeassociatedwithprotectionfromatopy.Comparedwithhealthy11individuals,atopicindividualshaveshowntohavelowerenvironmentalbiodiversityathomeand12significantlylowergenericdiversityofgammaproteobacteriaontheirskin.665SkinAcinetobacter13(gammaproteobacteria)specieswereassociatedwithanti-inflammatoryimmuneresponsesonlyin14healthysubjects.6661516

Insummary,hygieneisimportanttopreventinfectionsworldwide.Urbanizationfirstinaffluent17andlaterindevelopingcountrieshasledtoreducedmicrobialdiversityintheenvironment.Large18microbialdiversityoftheskin,airwaysandgutinchildhoodisimportantforthepreventionof19sensitizationandofallergicdiseaseinpopulations.Morelongitudinalstudiesareneededtoshowthe20association.2122

• AggregateGradeofEvidence:B(Level2a:2studies;Level2b:10studies;Level3a:2studies;23Level3b:1study;TableVI.G.3.).24

• StudiesincludedintheAggregateGradeofEvidencearesystematicreviewsandmeta-analyses25forthevariousaspectsofthehygienehypothesisdiscussedabove.Alsoincludedarerecent26studies,publishedafterthenotedsystematicreviewsandmeta-analyses.Ifsystematicreviews27andmeta-analysesarenotavailable,individualstudiesarelisted.28

29

30

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TableVI.G.3.Evidenceforthehygienehypothesisinthedevelopmentofallergicrhinitis1

Study Year LOE Studydesign

Studygroups Clinicalendpoint Conclusion

Campbelletal647

2015 2a SR

29studies(1999-2014):26cross-sectional,3longitudinal.Meta-analysis:8studies.

Associationoffarmexposurewithsensitizationinchildhoodoradulthood

Protectiveeffectoffarmexposureininfancyonallergicdiseaseinchildhoodandadulthoodinmajorityofstudies.Exposureduringadulthoodhadnoconsistentrelationshipwithsensitization.

KarmausandBotezan645

2002 2a Meta-analysis

53studies(1986-2000).Hayfever:17studies,(n=253,304)Sensitization:16studies,(n=46,758)

AssociationofsensitizationandARwiththreeormoresiblingsvs.nosiblings

Highernumberofsiblingswasassociatedwithlessatopy.Effectwasnotexplainedbyhygienefactors.

Houseetal648

2016 2b Nestedcase-controlstudy

Farmersandspouses.Cases:asthma(n=1198).Controls:noasthma(n=2031).

Associationofsensitization,rhinitis,eczemaandasthmawithlivingonafarmwhenbornandwithbeingexposedtofarmenvironmentwhenmotherwasperformingfarmactivitiesduringpregnancy

Early-lifefarmexposureassociatedwithlessatopy.Noassociationwithasthma.

Fujimuraetal445

2016 2b Longitudinalbirthcohortstudy

298childrenfolloweduntilage4years

Associationofsensitizationandasthmaatage2yearswithfecalmicrobiotainneonatestargetedatage1month(n=130)or6months(n=168)

ReducedcolonizationofBifidobacteria,Lactobacillus,FaecalibacteriumandAkkermansiaandMalazzesiaduringtheneonatalperiodmayinfluencetheriskofmultisensitizationpredictiveforasthma.

Huaetal664

2016 2b Cross-sectionalstudy

1879adultsubjects

Associationofseasonalallergywithfecalmicrobialbiodiversity

Reducedfecalbiodiversityandalteredcompositionassociatedwithmoreallergy,Noassociationwithasthmaandeczema.

Valkonenetal661

2015 2b Cross-sectionalstratifiedpopulationstudy

GABRIELAstudy:224children,6-12years

Associationofsensitizationwithmattressbacterialdiversity

Exposuretomorediversebacterialfloraassociatedwithlesssensitization.

Arrietaetal663

2015 2b Longitudinalnestedcase-

319childrenfollowedfrombirthuntil5yearsofage

Associationofsensitizationandwheezingat1yearwithfecal

ReducedcolonizationofFaecalibacterium,Lachnospira,VeillonellaandRothiaduringthe

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ICAR:AllergicRhinitis 94

LOE:levelofevidence;SR:systematicreview;AR:allergicrhinitis;GABRIELA:GABRIELAdvancedSurvey;PARSIFAL:PreventionofAllergy-RiskFactorsfor1SensitizationRelatedtoFarmingandAnthroposophicLifestyle;IgE:immunoglobulinE2

controlstudy

microbiotaatage3monthsand1year

first3monthsoflifemayincreasetheriskofatopicasthma.

Strachanetal646

2015 2b Cross-sectionalstudy

Children6-7yearsofagein31countries(n=210,200);13-14yearsofagein52countries(n=337,226)

Associationofhayfeverwiththreeormoresiblingsvs.nosiblings

Protectiveeffectofolderandtotalnumberofsiblingsonself-reportedAR.Effectwassignificantlystrongerinaffluentcountries.

Tischeretal657

2011 2b Nestedcase-controlstudy

678childrenattheage6yearsfromGerman(n=346)andDutch(n=332)birthcohorts

Associationofrhinitisandasthmawithmattressdustbiologicalcomponentsofmoldandendotoxin

Inconsistentresults.MicrobialexposuresathomehaddifferenteffectsonallergyinGermanandDutchbirthcohorts.

Egeetal659 2011 2b Twocross-sectionalstudies

PARSIFALstudy:489ruralandsuburbanchildren.GABRIELAstudy:444ruralchildren.

Associationofsensitizationwithmicrobesinmattress(PARSIFAL)andinairbornedust(GABRIELA)

Farm-childrenhadlessasthmaandatopy.Indoormicrobialexposuremuchhigheranddiverseinfarmhomes.Microbialdiversityrelatedtoasthmabutnottoatopy.

Bisgaardetal449

2011 2b Longitudinalstudy

253high-asthma-riskchildrenfollowedfrombirthtoage7years

AssociationofsensitizationandARwithhighfecalmicrobialbiodiversity

ReducedbacterialdiversityassociatedwithhigherriskofsensitizationandARinchildhood.

vonHertzenetal660

2007 2b Cross-sectionalstudy

563childrenaged7-16yearsinFinnishandRussianKarelia

Associationofsensitizationwithmicrobialcontentindrinkingwatersamplesfromschoolkitchens

MicrobialcountmuchhigherandsensitizationmuchlowerinRussia.Highcountofmicrobesassociatedwithlessatopy.

Cuello-Garciaetal658

2015 3a Systematicreviewandmeta-analysis

29randomizedcontrolledtrialsininfants

AssociationofARwithprobioticsupplementationtopregnantmothers,breast-feedingwomen,orinfants

Noeffectonallergies.

SimpsonandMartinez656

2010 3a Review

6ruralstudies10urbanstudies(2000-2007)

Associationofsensitizationwithexposuretoendotoxin

Exposuretoendotoxinprotectiveinover50%ofstudies.Endotoxinmaybemarkerofotherprotectivefactors.

Abrahamssonetal442

2014 3b Longitudinalcase-controlstudy

47infants(n=20IgE-associatedeczema,n=27healthycontrols)followeduntil7yearsofage

Associationofsensitization,asthmaandARwithfecaldiversityininfancy.

Lowmicrobialdiversityassociatedwithasthmalaterinchildhood.Noassociationwithsensitizationorrhinitis.

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VII.Diseaseburden1VII.A.Individualburden2VII.A.1.Effectonqualityoflife3

TwosystematicreviewshaveevaluatedtheeffectofARonQOL,withbothconcludingthatAR4patientssufferfromsignificantlydecreasedgeneralanddisease-specificQOLduetotheimpactof5physicalandmentalhealth.Furthermore,bothstudiesdemonstratedthattreatmentofARleadsto6improvementinQOL.667,668[TableVII.A.1.]WhiletheimpactofARonQOLhasbeensuggestedinthe7literaturefordecades,onlyrecentlyhastheeffectofARonQOLbeenrigorouslystudied.Thisisinpart8duetothedevelopmentofvalidatedgeneralanddisease-specificQOLinstruments,andtheirusein9clinicalinvestigationsandtrials.ThemostcommonlyusedgeneralQOLinstrumentsintheARliterature10appeartobetheShortForm12and36(SF-12/36),669,670whichmeasuregenericphysicalandmental11health-relatedQOL.ThemostcommonlyusedARdisease-specificQOLtoolistheRhinoconjunctivitis12QualityofLifeQuestionnaire(RQLQ),oroneofitsvariations(i.e.mini-RQLQ,nocturnalRQLQ).67113However,despitetheavailabilityoftheseinstruments,manystudiesinthepublishedliteraturerely14uponnon-validatedmethodstoassessQOL,leadingtodifficultycomparingoutcomesbetweensome15studies.16

Severalhigh-qualitystudieshaveevaluatedtheimpactofARonoverallanddisease-specific17QOL.[TableVII.A.1.]Mostlevel1bevidenceincludesRCTsevaluatingtheeffectoftopicalnasal18corticosteroids671-673,antihistamines672,674-677,orAIT.678,679Thegeneralconsensusofthesestudiesisthat19ARhasasignificantnegativeimpactongeneralanddisease-specificQOL,andthatthesuccessful20treatmentofARbyanyoftheaforementionedtherapiesleadstotheimprovementofsymptomsand21QOL.OneRCTthatexaminedmonotherapyversuspolytherapyshowedthatthecombinationof22mometasonewitheitherlevocetirizineormontelukastledtogreatersymptomandQOLimprovement23thanmometasonealone,buttherewasnodifferencebetweenthelevocetirizineandmontelukast24groups.672Additionally,aRCTofacupunctureversusmedicaltherapyshowedthattheimprovementin25QOLoccurredinbothgroups,butthedegreeofimprovementwaslargerintheacupuncturegroup.68026

Whiletheremainingevidenceisoflowerquality,itincludesimportantandinterestingfindings27inadditiontotheconclusionsreachedbytheRCTsandsystematicreviews.Forexample,extra-nasal28symptoms,particularlyocularsymptoms,haveasignificantimpactonQOLandshouldnotbeignoredin29theevaluationandmanagementofAR.681-684Furthermore,theproductivity,practical/activity,30emotional,social,andmemoryfunctionofpatientsappeartobesignificantlyimpactedbyAR.685-68931

Nohigh-qualitystudieshaveexplicitlyattemptedtoestablishvariationsofQOLinARpatients32overtime,andmosthaveshortfollow-upperiodsoronlyasinglefollow-up.However,some33observationsregardingthenaturalvariationinQOLinARcanbeextractedfromtheplaceboarmsof34level1studies.TwoRCTshavestudiedtheeffectoflevocetirizineover6months.675,677TheseRCTsshow35thatovera6-monthperiod,boththeplaceboandtreatmentgroupexperienceclinicallyandstatistically36significantlyimprovementsingenericanddisease-specificQOL;however,theimprovementisgreaterin37thetreatmentarm.TheAITRCTshavelongerfollow-upperiods(12to18months)andshowsimilar38results,withplacebopatientseitherstayingattheirbaselineQOLimpairment,orimprovingtoalesser39degreethanthetreatmentarms.678,679AsexpectedinpatientswithSAR,QOLisbetteroutsideofpeak40seasonandworsensduringallergenexposure.690,69141

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1• AggregateGradeofEvidence:B(Level1b:11studies;Level2a:2studies;Level2b:16studies;2

Level2c:1study;Level3b:3studies;TableVII.A.1.)3• Benefit:SuccessfulmanagementofARleadstoimprovedoverallanddisease-specificQOL.4• Harm:ManagementstrategiesforARareassociatedwithvariablelevelsofharmandarefurther5

specifiedinSectionIX.Management.6• Cost:ManagementstrategiesforARareassociatedwithvariablelevelsofcostandarefurther7

specifiedinSectionIX.Management.8• Benefits-HarmAssessment:ThebenefitsoftreatingpatientswithARtoimproveQOLmay9

outweighrisksoftreatment.10• ValueJudgments:SuccessfulcontrolofARsymptomsleadstoimportantimprovementsin11

genericanddiseasespecificQOL.12• PolicyLevel:RecommendtreatmentofARtoimproveQOL.13• Intervention:ARpatientsmaybeofferedvariousmanagementstrategiestoimprovegeneral14

anddisease-specificQOL.1516

17

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TableVII.A.1.Effectofallergicrhinitisongeneralanddisease-specificqualityoflife1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Bousquetetal674

2013 1b RCT AR(n=716):1.desloratadine(n=360)2.placebo(n=356)

Symptomsscores,sleepquestionnaire,RQLQ,WPAIAS

Desloratadineimprovessymptoms,QOL,andfunctionalimpairment.

Tataretal672 2013 1b RCT AR(n=56):1.mometasone(n=14)2.mometasone+levocetirizine(n=21)3.mometasone+montelukast(n=21)

Mini-RQLQ QOLsignificantlyaffectedbyAR.CombinationofmometasonewithlevocetirizineormontelukastimprovesQOLmorethanmometasonealone.

Yamadaetal673

2012 1b RCT,double-blind,crossover

PAR(n=57):mometasone

TSS,QOLscore,sleepquality,nasalnitricoxide

Nasalmometasoneimprovesnasalsymptoms,QOL,andsleepqualityanddecreasesnitricoxide.

Hoibyetal678

2010 1b RCT AR(n=53):1.SCIT(n=27)2.placebo(n=26)

Symptomandmedicationscores

SCITreducessymptomandmedicationscorescomparedtoplacebo.

Holmbergetal676

2009 1b RCT,double-blind,crossover

AR(n=584):1.desloratadine(n=293)2.placebo(n=291)

RQLQ,symptomscore

DesloratadineimprovesRQLQandsymptomscoresignificantlycomparedtoplacebo.

Wittetal692 2009 1b RCT AR(n=981):1.acupuncture(n=487)2.control(n=494)

SF-36 AcupunctureimprovesQOLmorethancontrolat3months.

Brinkhausetal680

2008 1b RCT AR(n=5,237):1.randomizedtoacupuncture(n=487)2.conventionalmedicalcare(n=494)3.notrandomizedbutreceivedacupuncture(n=4,256)

RQLQ,SF-36 QOLsignificantlyaffectedbyAR.Acupuncturegroupimprovesmorethanconventionalmedicalcare.

Canonicaetal677

2006 1b RCT,double-blind

AR(n=551):1.levocetirizine(n=278)2.placebo(n=273)

RQLQ,SF-36 QOLsignificantlyaffectedbyAR.LevocetirizineimprovesQOLcomparedtoplacebo.

Colaseta679 2006 1b RCT,double-blind

AR(n=60):1.SCIT(n=41)2.control(n=19)

RQLQ,symptomsscore,medicationscore

QOLsignificantlyaffectedbyAR.SCITimprovesRQLQ,symptomandmedicationscores.

Bachertetal675

2004 1b RCT,double-blind

PAR(n=551):1.levocetirizine(n=278)2.placebo(n=273)

SF-36,RQLQ LevocetirizineimprovesQOLanddecreasesdisease-relatedcosts.

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Radcliffeetal693

2003 1b RCT,double-blind

SAR(n=183):1.enzymepotentiateddesensitization(n=90)2.placebo(n=93)

RQLQ,problem-freedays

EnzymepotentiateddesensitizationdoesnotimproveQOLcomparedtoplacebo.

GerthVanWijketal694

2000 1b RCT ARandnasalcapsaicin(n=26) VAS,RQL Capsaicindoesnotsufficientlycontrolrhinitissymptoms.

Juniperetal671

1991 1b RCT,double-blind

ARquestionnairedevelopment(n=85);validation(n=60)

RQLQ Inadditiontolocalsymptoms,patientsexperienceimpairedQOLthroughsystemic,sleep,emotionalsymptomsandpractical/activitylimitations.BeclomethasoneusecorrelatedtoRQLQ.

Linnebergetal667

2016 2a SR AR QOL PatientswithARsufferfromdecreasedQOLintermsofbothphysicalandmentalhealth.

Hahn-Pedersenetal668

2014 2a SR AR QOL ARpatientshavesignificantlyworsegeneralanddisease-specificQOLwithphysical,practicalandactivitydomainsmostaffected.SCITimprovesQOLandsymptoms.

Filanowiczetal695

2016 2b Observationalcohort

SCIT(n=200):1.allergicasthma(n=101)2.AR(n=99)

RQLQ QOLissignificantlyaffectedbyAR.SCITsignificantlyimprovedQOLinasthmaandAR.

Jaruvongvanichetal684

2016 2b Observationalcohort

AR(n=260) SF-12,TSS Extra-nasalsymptomsinARcorrelatewithphysicalandmentalhealthQOLdomains.

Bousquetetal681

2013 2b Observationalcross-sectional

AR(n=990)

VAS,RQLQ,TSS 20%midintermittent,17%mildpersistent,15%mod-severeintermittent,48%mod-severepersistent.SeverityanddurationofARimpactionQOL.OcularsymptomsimpactRQLQmorethannasalobstruction.Sneezing/rhinorrheadonotimpactRQLQ.

Demolyetal696

2013 2b Observationalcohort

AR(n=990) VAS,RQLQ,TSS 20%mildintermittent,17%mildpersistent,15%mod-severeintermittent,48%mod-severepersistent.VAScan

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detectQOLvariationswithhighsensitivity.

delaHozCaballeretal697

2012 2b Observationalcross-sectional

primarycarepatients(n=616) SF-36,genericHRQOL,WPAI

ARimpactsproductivitytoagreatermagnitudethanhypertensionandDMtypeII,butnotdepression.

Meltzeretal698

2012 2b Observationalcross-sectional

nasalallergy(n=522);nonasalallergy(n=400)

Non-validatedphoneinterviewquestions

ARpatientsrateoverallhealthlower,haveworsesleepfunction,anddecreasedproductivitythanthosenon-AR.

Ciprandietal699

2010 2b Observationalcohort

ARundergoingSLIT(n=167) RQLQ QOLissignificantlyaffectedbyAR.SLITeffectiveatimprovingQOLandsymptoms

Stulletal682 2009 2b Observationalcross-sectional

AR(n=404) Symptomscale,nocturnalRQLQ,WPAI,MOS-12Sleep,PANAS-X

Nasalcongestionismorestronglycorrelatedtooutcomes,butocularsymptomscanhavesignificantimpactofQOL.

Cadarioetal683

2008 2b RCT ARtreatedwithSLIT(n=40) Non-validatedQOLscale

QOLissignificantlyaffectedbyAR.SLITimprovesQOLandsymptoms.

Petersenetal700

2008 2b Observationalcross-sectional

AR(n=248);ARandasthma(n=121)

RQLQ;15D ARpatientshaveworsenedQOLduringallergenexposure.15DgeneratesmorecomprehensiveviewofimpactonQOLthanRQLQ.

Ciprandietal701

2007 2b Observationalcohort

AR(n=123) RQLQ QOLissignificantlyaffectedbyAR.>2sensitivities,eosinophilcount,andnasalflowrelatedtoQOL.EyesymptomscorrelatemoststronglytoQOL.

DiRienzoetal702

2006 2b RCT,double-blind

AR(n=34):1.SIT(n=19)2.placebo(n=15)

RQLQ QOLissignificantlyaffectedbyAR.SLITimprovedQOLcomparedtoplacebo.

Laforestetal703

2005 2b Observationalcohort

1.SAR(n=83)2.asthma(n=52)

Mini-RQLQ,SF-12 QOLissignificantlyaffectedbySARandasthma.Femalegender,ruralresidence,andlowereducationlevelsassociatedwithworseQOLinSAR.

Majanietal691

2001 2b Observationalcohort

SAR(n=33) SF-36,SAT-P QOLissignificantlyaffectedbyARduringpeakseason.

Leynaertetal689

2000 2b Observationalcross-sectional

1.ARandasthma(n=76)2.ARbutnotasthma(n=240)3.neitherARorasthma(n=349)

SF-36 BothasthmaandARimpactQOL.ARimpactsemotionalandmentalhealth,socialactivities,andactivitiesofdaily

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living.Co-morbidasthmacausedmorephysicallimitationsthanARalone.

Cingietal704 2013 2c Outcomesresearch

PARtreatedwithdesloratadineandmontelukast(n=40)

acousticrhinometry,RQLQ

Desloratadine+montelukastimprovesnasalobstructionandQOL

Buksteinetal688

2016 3b Observationalcohort

PARtreatedwithbeclomethasone(n=527)

RCAT,treatmentsatisfaction,WPAI,PSQI,mini-RQLQ

BeclamethasoneimprovesQOL,school-relatedactivities,satisfaction,productivity,andsleepquality.

Songetal685 2015 3b Observationalcross-sectional

Middleschoolstudents,cross-sectionalstratifiedrandomsampling(n=814)

Questionnaire ARin17.2%.ARimpactsQOL,sleep,emotions,andmemory.

Katelarisetal687

2013 3b Observationalcross-sectional

AR(n=303) Questionnaire ARimpactswork/schoolperformance,generalQOL,andsleepquality.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;AR:allergicrhinitis;RQLQ:rhino-conjunctivitisqualityoflifequestionnaire;WPAIAS:Work1ProductivityandActivityAllergySpecificquestionnaire;QOL:qualityoflife;PAR:perennialallergicrhinitis;TSS:totalsymptomscore;SCIT:2subcutaneousimmunotherapy;SF-36:shortform36;VAS:visualanaloguescale;RQL:rhinitisqualityoflife;SR;systematicreview;SF-12:shortform312;HRQOL:HealthRelatedQualityofLife;WPAI:WorkProductivityandActivityquestionnaire;DM:diabetesmellitus;SLIT:sublingual4immunotherapy;MOS-12Sleep:MedicalOutcomesStudy12-ItemSleepScale;PANAS-X:PositiveandNegativeAffectSchedule-ExpandedForm;515D:Generic15DimensionInstrumentformeasuringhealthrelatedqualityoflife;SAR:seasonalallergicrhinitis;SAT-P:satisfactionprofile;RCAT:6RhinitisControlAssessmentTest;PSQI:PittsburghSleepQualityIndex7

89 10

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VII.A.2.Effectonsleep12

Likegenericanddisease-specificQOL,validatedtoolsexistfortheassessmentofsleep-related3QOLinAR,buttheyarenotalwaysutilizedinstudiesreportedintheARliterature.Somestudies4evaluatinggenericanddisease-specificQOLsuggestthatARnegativelyimpactspatients’sleep.673,685,6875[TableVI.A.1.]SeveralstudieshavespecificallyinvestigatedtherelationshipbetweenARandsleepin6adultsandchildren.[TableVI.A.2-1.andTableVI.A.2-2.]Thegeneralconclusionfromtheaggregate7dataisthat,likeoverallandrhinitis-specificQOL,ARnegativelyimpactssleepQOLandthesuccessful8treatmentofARreducessleepdisturbance.Theoverallqualityofthedataishigherforadultsthanfor9children.Fortheadultpopulation,thereislevel1bevidencesupportingtheconclusionthatAR10negativelyimpactssleep.705-709Thesedatadealwithsubjectivereportingofdaytimesleepiness,sleep11quality,andsymptomsusuallythroughvalidatedtools,inthesettingoftestingtheeffectofnasal12corticosteroidsand/ormontelukast.ResultsdemonstratethatARpatientshaveimprovementsinsleep13qualityanddaytimesleepiness,inadditiontosinonasalsymptomsandQOLaftertreatmentwithnasal14corticosteroids705,706,709,710oracombinationofcorticosteroidsandmontelukast.709AdditionallyARhas15beenassociatedwithworsesleepfragmentation711,712andsnoring.713,714TreatmentofARhasbeenalso16suggestedtoalsoimprovecontinuouspositiveairwaypressure(CPAP)complianceinpatientswith17OSA.715ThedataontheeffectsofARonpolysomnogram(PSG)parametersinadultsismixed.Most18studiesthatincludedPSGanalysisfoundthatARissassociatedwithworsenedPSGparameters;712,714,716-19719however,twolevel3bstudiesfoundeithernodifferenceoramodestchange.720,72120

Twostudieslookedatvariationsinsleepsymptomswithchangesinnasalinflammationover21time.ItseemsthatchangesinnasalcytokinelevelsareassociatedwithchangesinPSG719andthatAR22patientshaveworsePSGparametersandsleepdisturbancewhentheirsymptomsarepresentorduring23theirpeakallergenseason.718Inchildren,level2and3studiessuggestthatARisassociatedwithsleep24disturbanceintheformofincreasedriskofsnoring,sleepdisorderedbreathing,andOSA.Furthermore,25ARhasbeensuggestedtobeariskfactorfordeteriorationofOSAQOLafteradenotonsillectomy.722(See26sectionX.K.AssociatedConditions–SleepDisturbanceforadditionalinformationonthistopic.)2728

• AggregateGradeofEvidence:B(Level1b:5studies;Level2b:10studies;Level2c:3studies;29Level3a:1study;Level3b:21studies;Level4:6studies;TablesVI.A.2-1.VI.A.2-2.)30

• Benefit:SuccessfulmanagementofARleadstodecreasedsleepdisturbance.31• Harm:ManagementstrategiesforARareassociatedwithvariablelevelsofharmandarefurther32

specifiedinSectionIX.Management.33• Cost:ManagementstrategiesforARareassociatedwithvariablelevelsofcostandarefurther34

specifiedinSectionIX.Management.35• Benefits-HarmAssessment:ThebenefitsoftreatingpatientswithARforsymptomsofsleep36

disturbancemayoutweighrisksoftreatment.37• ValueJudgments:SuccessfulcontrolofARsymptomsleadstoimprovementsinsleep.38• PolicyLevel:RecommendtreatmentofARtodecreasesleepdisturbance.39• Intervention:ARpatientsmaybeofferedvariousmanagementstrategiestoimprovesleep.40

41

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TableVI.A.2-1.Effectofallergicrhinitisonsleepinadults1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionShanqunet

al709

2009 1b RCT ARandOSA(n=89):

1.montelukast+budesonide(n=44)

2.placebo(n=45)

ESS,RQLQ,TSS,

CSAQLI,symptoms

diary

Montelukast+budesonideimprovesAR

andOSAQOL,sleepqualityanddaytime

somnolence.

Mansfield

and

Posey708

2007 1b RCT 1.fluticasone(n=16)

2.placebo(n=16)

TOVA,ESS,TSS Fluticasoneimprovesdaytimesleepiness,

cognitiveperformance,andnasal

symptoms.

Gurevichet

al705

2005 1b RCT,crossover PAR(n=26),nasalbudesonide

ESS,sleepdiary,

questionnaire

Budesonidereducesnasalcongestion,

daytimesomnolence/fatigue,andimprove

sleepqualityinPAR.

Hugheset

al706

2003 1b RCT,crossover PAR(n=22),nasalbudesonidevs

placebo

ESS,FOSQ,RQLQ,

symptomdiary

Budesonideimprovesdaytimefatigueand

sleepqualityinPAR.

Craiget

al707

1998 1b RCT,crossover AR(n=20),flunisolidevsplacebo Symptomandsleep

diary

Nasalcorticosteroidsimprovesymptoms

andsubjectivesleepcomparedtocontrols.

Parikhet

al715

2014 2b Observational

cohort

OSAandrhinitis(n=43) ESS,symptoms

scores,CPAP

compliance

Controlofrhinitis(withvaryingregimensof

steroidsprays,antihistamines,leukotrienes

inhibitors,anticholinergics,etc.)important

forOSAcontrol.Nodifference:ARvsNAR.

Acaretal716 2013 2b Observational

cohort

OSAandAR(n=80) ESS,PSG Nasalcorticosteroidsimprovesleepquality

andARsymptoms.Additionof

antihistaminedidnothaveeffect.

Lavigneet

al717

2013 2b Observational

cross-sectional

1.OSAandAR(n=34)

2.OSAwithoutrhinitis(n=21)

PSG,nasalbiopsies InAR,nasalcorticosteroidsreducenasal

inflammationandimprovePSG

parameters.

Udakaet

al723

2007 2b Observational

cross-sectional

daytimeworkers(n=3,442) Questionnaire,ESS,

SF-36

Severityofnasalobstruction(non-validated

questionnaire)correlateswithworseESS

andlowerQOL.

Mintzet

al724

2004 2b Individual

cohort

AR(n=651) NocturnalRQLQ,

PSQI

Treatmentwithtriamcinoloneimproves

nocturnalrhinitisQOLandsleepquality.

Camhiet

al713

2000 2b Case-control n=437fromTESOADwithsleep

problems/snoring

Questionnaire ARriskfactorforsnoring.

Jansonet

al725

1996 2b Observational

cross-sectional

n=2,661randompopulationofthe

ECRHS

SPT,methacholine

challenge,

questionnaire

ARindependentlyassociatedwithdifficulty

initiatingsleepanddaytimesleepiness(OR

2.0).

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ICAR:AllergicRhinitis103

Colaset

al726

2012 2c Population-

based

AR(n=2,275) TSS,RQLQ,PSQI ARdiseaseseverityhasstrongrelationship

withsleepdisturbance.

Legeret

al727

2006 2c Population-

based

AR(n=591) SDQ,ESS,symptom

score

AlldimensionsofsleepimpairedbyAR,

diseaseseveritycorrelatedwithdegreeof

sleepimpairment.

Younget

al714

1997 2c Population-

based

surveysubjects(n=4,297);objective

testingsubjects(n=911)

Questionnaire,PSG ARandnasalobstructionassociatedwith

snoring,daytimesleepiness,andSDB.

Gadietal728 2017 3b Observational

cross-sectional

sleepclinicpatients(n=157) History,laboratory

testing

62%OSA.53%ARinOSA.Nodifferencein

AR/atopybetweenOSAandnon-OSA

cohorts.

Bozkurtet

al721

2017 3b Case-control 1.PARandOSAsymptoms(n=150)

2.controls(n=95)

SPT,PSG PARdidnotaffectPSGfindingscompared

tocontrols.

Parketal729 2012 3b Observational

cross-sectional

1.OSAandAR(n=37)

2.OSAwithoutrhinitis(n=75)

ESS,stressscore,

fatiguescore,

copingscore,RQLQ

ARinOSAincreasesstressandfatigue,

worsenssleepinessandQOL.

Menget

al720

2011 3b Case-control 1.PAR(n=98)

2.controls(n=30)

PSG PSGparametersshowedmodestchangesin

PARpatients.

Rimmeret

al711

2009 3b Observational

cohort

1.PAR(n=10)

2.control(n=10)

Acitigraphy ARhasincreasedsleepfragmentationand

reducedsleepquality.

Canovaet

al730

2004 3b Case-control 1.OSA(n=72)

2.COPDcontrols(n=44)

Symptomscore,

spirometry,SPT

OSAmorelikelytobesensitizedto

perennialallergens(11%inOSAvs.2.3%

COPD).

Stucket

al731

2004 3b Observational

cohort

1.SAR(n=25)

2.controls(n=25)

ESS,SF-36,PSG SARleadstoincreaseddaytimesleepiness

comparedtocontrols.

Krouseet

al719

2002 3b Exploratory

cohort

1.AR(n=4)

2.controls(n=4)

PSG,serumand

nasalcytokines

Differingcytokinelevelsassociatedwith

variationsinPSG.

Lavieet

al712

1981 3b Observational

cohort

1.AR(n=14)

2.controls(n=7)

PSG ARpatientshad10-foldincreaseinmicro-

arousalscomparedtocontrols.

McNicholas

etal718

1982 4 Caseseries AR(n=7) Nasalresistance,

PSG

ARpatientshaveworseOSAsymptoms

whensymptomsarepresentandhavehigh

nasalresistance.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;AR:allergicrhinitis;OSA;obstructivesleepapnea;ESS:EpworthSleepinessScale;RQLQ:1

RhinoconjunctivitisQualityofLifeQuestionnaire;TSS:totalsymptomscore;CSAQLI:CalgarySleepApneaQualityofLifeIndex;QOL:qualityoflife;TOVA:Test2

ofVariablesAttention;PAR:perennialallergicrhinitis;FOSQ:FunctionalOutcomesofSleepQuestionnaire;CPAP:continuouspositiveairwaypressure;PSG:3

polysomnogram;NAR:non-allergicrhinitis;PSQI:PittsburghSleepQualityIndex;SF-36:ShortForm36;SDQ:SleepDisordersQuestionnaire;TESOAD:Tucson4

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ICAR:AllergicRhinitis104

EpidemiologyStudyofObstructiveAirwayDisease;SDB:sleepdisorderedbreathing;ECRHS:EuropeanCommunityRespiratoryHealthSurvey;SPT:skinprick1

test;OR:oddsratio;COPD:chronicobstructivepulmonarydisease;SAR:seasonalallergicrhinitis2

3

4

TableVI.A.2-2.Effectofallergicrhinitisonsleepinchildren5

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionKoinis-Mitchell

etal732

2015 2b Individual

cohort

non-whiteLatinoandAfrican

Americanurbanchildren(n=195)

Clinical

evaluationand

follow-up

PoorARandasthmacontrolrelatedtohigh

frequencyofsleepproblemsandpoorsleep

hygiene.

Kimetal722 2015 2b Individual

cohort

SDBundergoingT&A(n=70) OSA-18,SPT,

questionnaire

ARmayberiskfactorfordeteriorationof

OSAQOLafterT&A.

Baroneetal733 2009 2b Case-control 1.childrenfromsleepdisorders

clinic(n=149)2.controls(n=139)

PSG ARassociatedwithOSA,OR2.24.

Linetal734 2013 3a Systematic

review

N/A Association

betweenARand

SDB

MoststudiesshowassociationbetweenAR

andSDBinchildren,butallstudieswerelow

levelofevidence.

DiFrancesco

etal735

2016 3b Cross-

sectional

SDBundergoingT&A(n=135) PSG ARaffectedREMsleepinchildrenwithSDB

withoutOSA.ARisnotanaggravatingfactor

inAHIseverity.

Chimenzet

al736

2015 3b Case-control 1.ARandadenoidgradeI-II(n=32)

2.ARandadenoidgradeIII-IV

(n=27)

History ARmayinfluencedevelopmentofnocturnal

enuresis.

Poachanukoon

etal737

2015 3b Case-control 1.AR(n=65)

2.control(n=104)

Questionnaire HigherincidenceofsleepdisturbanceinAR.

Kwonetal738 2013 3b Population-

based

childrenwithAR(n=85,002)

Nationalsurvey

data

Associationbetweenlatesleeptimeand

shortsleepdurationwithAR.

Lietal739 2010 3b Cross-

sectional

children(n=6,349) Questionnaire HabitualsnoringassociatedwithAR(OR2.9,

CI2.0-4.2).

Vichyanondet

al740

2010 3b Case-control childrenwithrhinitis(n=302)

History Upperairwayobstructionassociatedwith

NAR.

Sogutetal741 2009 3b Cross-

sectional

Turkishchildren(n=1,030) Questionnaire ARassociatedwithhabitualsnoring(OR3.7,

CI1-13).

Liukonnenet

al742

2008 3b Population-

based

childreninHelsinki(n=2100) Questionnaire ARmorecommoninsnorers.

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ICAR:AllergicRhinitis105

Kalraetal743 2006 3b Cross-

sectional

childreninCCAAPS(n=681) Questionnaire 29%ofpatientswithHShavepositiveSPT,

significantassociation.

Ngetal744 2005 3b Cross-

sectional

schoolchildren(n=3,047) Questionnaire ARassociatedwithwitnessedapnea.

Sogutetal745 2005 3b Cross-

sectional

Turkishchildren(n=1,198) Questionnaire ARassociatedwithhabitualsnoring(OR

4.23,CI2.14-8.35).

Chngetal746 2004 3b Cross-

sectional

schoolchildren(n=11,114) Questionnaire Snoringin34%,ARassociatedwithsnoring

(OR2.9,CI2.06-4.08).

Anuntaseree

etal747

2001 3b Cross-

sectional

randomlyselectedchildren

(n=1,142)

PSG,

questionnaire

Prevalencehabitualsnoring8.5%,OSAS

0.69%.OR5.27inchildrenwithAR.

Bhattacharjee

etal748

2010 4 Prognostic

cohort

childrenundergoingATforOSA

(n=578)

PSG ARidentifiedin39%ofchildrenwithOSA

undergoingAT.

Goldbartet

al749

2005 4 Caseseries SDB(n=24) PSG,lateralneck

x-ray

Montelukasttreatmentfor16weeks

decreasedadenoidsizeandrespiratory

sleepdisturbances.

Kidonetal750 2004 4 Caseseries childrenwithARundergoingSPT

(n=202)

History 17%ofARpatientsreportedHS.

Mansfieldet

al751

2004 4 Caseseries childrenwithAR(n=14) PSG,RQLQ TreatingARdecreasesAHI.

McColleyet

al752

1997 4 Caseseries childrenwithHS(n=39) PSG PositiveskintestassociatedwithOSA.

AR:allergicrhinitis;LOE:levelofevidence;SDB:sleepdisorderedbreathing;T&A;tonsillectomyandadenoidectomy;OSA-18:18-itemquality-of-lifesurveyfor1

obstructivesleepapnea;SPT:skinpricktest;QOL:qualityoflife;PSG:polysomnogram;OR:oddsratio;REM;rapideyemovement;OSA:obstructivesleep2

apnea;AHI:apnea-hypopneaindex;CI:95%confidenceinterval;NAR:non-allergicrhinitis;CCAAPS:CincinnatiAlleryandAirPollutionStudy;HS:habitual3

snoring;OSAS:obstructivesleepapneasyndrome;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire4

5

6

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VII.B.Societalburden1

2

AsdescribedinSectionVII.A.1.,ARmayhavesignificantnegativeeffectsonQOLwith3

considerableconsequencesifleftuntreated.Formanyyears,ARhasbeentrivializeddespiteits4

prevalence,chronicity,andtheburdenitimposesonindividualsandsociety.101,681,753

Thetotalburden5

forARliesnotonlyintheimpairmentofphysicalandsocialfunctioning,butalsointhefinancialburden,6

whichisgreaterwhenitsroleincomorbidconditionssuchasasthmaandrhinosinusitisaretakeninto7

account.754-756

InEurope,thetotalsocietalcostofARanditscomorbiditiesin2002wasestimatedat8

355.06Eurosperpatientpermonth.755TheburdenofARisnowbeingrecognizedbytheEuropean9

AcademyofAllergy&ClinicalImmunology(EAACI)andalsoattheEuropeanUnion(EU)parliamentlevel10

inordertofeaturethedramaticimpactthisconditionhasontheQOLofpatientswithAR.757,758

11

Intermsoftheoveralleconomicburdenofillness,ARranksfifthamongchronicconditionsin12

theUS.759EstimatesoftheannualdirectcostofARrangefrom$2billionto$5billion,withmorethan13

halfoftheARdirectcostscomingfromprescriptionmedications.760-762

ThedirectcostsattributedtoAR14

includephysicianofficevisits,laboratorytests,medications,andAIT.763Comparedwithmatched15

controls,patientswithARhaveanalmosttwo-foldincreaseinmedicationcostsanda1.8-foldincrease16

invisitstoahealthcareprovider.756,764,765

Hiddendirectcostsincludetreatmentofcomorbidconditions17

thatoccuratanincreasedincidenceinpatientswithAR.18

Recently,theTOTALL(TOTalcostsofALLergicrhinitisinSweden)studyestimatedthetotalcost19

ofARusingasamplerepresentingtheentireSwedishworking-agepopulation.Datafromthisstudy20

suggestedthatpatientswithmildARhavelessimpactonthehealtheconomy,withcostsaveraging21

about25%ofthecostsforthosewithmoderatetoseveredisease.667,766

Patientswithmoderateto22

severeARreportedvisitingtheirprimarycareproviderfortheirARmorefrequentlythanthosewith23

mildAR(1.61vs1.19timesperyear).75324

TheindirectcostsofAR,suchasabsenteeismandpresenteeism,arealsosignificantandactually25

makeupthemajorityofthecostburdenofAR.767,768

Impairedproductivityand/ormissedworkoccurred26

asaresultofARin52%ofpatients.753Inasurveyofover8,000USemployeesat47employerlocations,27

55%reportedARsymptomsforanaverageof52.5daysperyear.Theyreportedmissing3.6daysof28

workperyearbecauseofARandreportedbeingunproductive2.3hoursperworkdaywhen29

symptomatic.Themeantotalproductivitylosses(absenteeismandpresenteeism)forARwere30

calculatedat$593peremployeeperyear.769InanotherUKstudy,patientswithmoderatetosevereAR31

reported37.7daysayearwhentheirproductivitywasaffectedbytheirARsymptoms;thisisalmost32

doublethatreportedbypatientsinthesamestudywithmildARsymptoms(21.0days).75333

HealthimpairmentsassociatedwithARareoftennotsevereenoughtocauseabsenteeism,but34

theydointerferewithcognitivefunctioning,resultinginfatigueandanimpairedabilitytolearn,35

concentrate,andmakedecisions.770InastudybyBlancetal,

771morethanone-thirdofARpatients36

reportedreducedworkplaceperformance.37

IntheUS,ARresultsin3.5millionlostworkdaysand2millionlostschooldaysannually.772On38

anygivenschooldayintheUS,approximately10,000childrenareabsentfromschoolbecauseofAR.77339

Thisabsencefromschoolmayalsoaffectparents’productivityorcausethemtobeabsentfromwork40

themselves.41

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ICAR:AllergicRhinitis107

InastudybyHellgrenetal,774theaverageproductivitylossforallSwedishworkersbecauseof1

absenteeism,presenteeism,andcaregiverabsenteeismduringayearwas5.1days,ofwhich2.3days2

wereaccountedforbyabsenteeismand2.0daysbypresenteeism.Ifonlythosewithchildrenaged0-3

7yearsintheirhouseholdwereincludedintheanalyses,theaveragenumberofdaysforcaregiver4

absenteeismwas3.6days.Thecostofcaregiverabsenteeismcomprised19%ofthemeantotalcostsper5

yearinthisstudy.Thecostrelatedtocaregiverabsenteeismwashighestforwomenaged30-44years.6

ARisthemostcommonchronicdisorderinthepediatricpopulation.ARcanaffectsleep,result7

indaytimesleepiness,andimpaircognitionandmemory,whichmaysignificantlyaffectthelearning8

processandimpactschoolperformance.Evenwhenpresentduringschoolhours,childrenwithAR9

exhibitdecreasedproductivity.ComorbiditiesassociatedwithAR,suchaslikerhinosinusitis,Eustachian10

tubedysfunctionandassociatedconductivehearinglossmayfurthercontributetolearning11

dysfunction.775,776

12

ARposesasubstantialburdentoindividualsandsociety.ItcanreduceproductivityandQOLin13

affectedpatients,andcontributetocomorbidconditions.Thisresultsinasignificantimpacttothe14

overallhealthsystem.773

15

16

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ICAR:AllergicRhinitis108

VIII.Evaluationanddiagnosis1

2

Inanindividualpatient,theclinicalsuspicionforadiagnosisofARishighlightedbytheclinical3

historyandoftensupportedbythephysicalexamination.Thediagnosisisconfirmedbyobjective4

testing,whichmaybeperformedbyvariousmeans.Thissectionreviewstheexistingevidencebehind5

variousaspectsofevaluationanddiagnosisoftheARpatient.6

7

8

VIII.A.Clinicalexamination9

History.Clinicalhistoryisanessentialpartoftheevaluationofpatientswithasuspecteddiagnosisof10

AR.7,26,218,761,777

Historytakingincludesthetypeofsymptomsexperienced,timinganddurationof11

symptoms,frequencyofsymptoms,anyenvironmentalexposureselicitingsymptomsat12

home/work/school,andmedicationsorothermeasuresthatrelieveorexacerbate13

symptoms.7,26,218,761,777,778

Inaddition,pastmedicalhistoryincludingcomorbidconditionssuchasasthma14

orobstructivesleepapnea,familyhistoryofatopicdisorders,socialhistory(i.e.pets,workexposures,15

homeenvironment),andcurrentmedicationsshouldbeobtained.7,26,218,761,777,778

Informationregarding16

patientresponsetoself-treatmentwithover-the-countermedicationsforARisalsohelpful.17

Nasalcongestionorobstruction,nasalpruritis,clearrhinorrhea,andsneezingareclassic18

symptomsofAR.7,26,218,761,777,778

Patientsmaycomplainofassociatedsymptomsofocularpruritis,19

erythema,and/ortearing,oralcavityorpharyngealpruritis,andwheezingorcough(reactiveairway20

diseaseand/orasthma).7,26,778

Additionalassociatedsymptomsmayincludehyposmiaoranosmia,21

snoringorsleep-disorderedbreathing,auralcongestionorpruritis,cough,sorethroat,and22

wheezing.778,779

Commonly,patientswithsuspectedARwillpresentwithmultiplecomplaints,with96%23

presentingwithtwoormoresymptoms.778PatientswithPARtendtoreportmorecongestivesymptoms24

(sinuspressure,nasalblockage/congestion,andsnoring)thanpatientswithSARandaremorelikelyto25

reportthepresenceofsorethroat,cough,sneezing,rhinorrhea,andpostnasaldrip.778Rhinorrhea,26

sneezing,sniffing,hyposmia/anosmia,nasalobstruction,anditchynoserankhighestfordiagnostic27

utilityamongsymptomsofAR.77928

SeveralguidelinessuggestthediagnosisofARbemadewhenpatientspresentwithahistory29

consistentwithanallergiccauseandoneormoreoftheabovelistedsymptoms,despitethelackof30

high-levelevidencetosupportsucharecommendation.7,26,218,761,777,780

[TableVIII.A.]However,thelack31

ofhigherlevelevidenceisnotsurprisingasaclinicalhistoryandphysicalexaminationisessentialtoany32

medicaldiagnosisandrandomizedstudieswouldrequireparticipantstoreceiveaninterventionwithout33

aclinicalhistory.UsingaphysicalexaminationalonetodiagnoseARhasbeenshowntohavepoor34

predictivevalue.781ThereliabilityandpredictivevalueofthepatienthistoryaloneforARexceedsthatof35

thephysicalexamalone.781Inclinicalpractice,thediagnosisofARisoftenmadebyhistoryalone.

78036

37

Physicalexamination.Physicalexaminationispartoftheevaluationofpatientswithsuspected38

AR.7,26,218,761,777

Thisincludesanassessmentofthemultipleorgansystemsoftheheadandneck,suchas39

theintegumentarysystem;externalauditorycanal,tympanicmembrane,andmiddleear;nasalcavities;40

orbitsandperiorbitaltissues;oralcavityandpharynx;larynxviaindirectlaryngoscopy;andcervical41

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ICAR:AllergicRhinitis109

tissues.26,218,761,777

Itmayincludeauscultationofthelungs,givencomorbidconditionsofasthma,or1

complaintsofwheezingorcoughingwithexposure.72

ItisnotuncommonforphysicalexaminationofpatientswithARcomplaintstobecompletely3

normal,particularlyinpatientswithintermittentexposure.779However,physicalsignssuggestiveofAR4

mayincludemouth-breathing,nasalitchingoratransversesupratipnasalcrease,throatclearing,5

periorbitaledema,or“allergicshiners”(darkdiscolorationofthelowerlidsandperiorbitalarea).26,777

6

Examinationoftheearmayrevealretractionofthetympanicmembraneortransudativefluid.26,218,777

7

Examinationofthenosemayrevealinferiorturbinatehypertrophy,congested/edematousnasal8

mucosa,purplishorbluishnasalmucosa,andclearrhinorrhea.26,218,761,777

Examinationoftheeyesmay9

revealconjunctivalerythemaand/orchemosis.26,777

10

Physicalexaminationaloneispoorlypredictiveandmorevariablewhencomparedtohistory11

takinginthediagnosisofAR,withtheaveragesensitivity,specificity,positivepredictivevalue,and12

negativepredictivevaluesofthepatienthistoryhigherthanthoseofthephysicalexamination.781Most13

guidelinesrecommendaphysicalexaminationaspartofthediagnosisofAR,despitealackofhigh-level14

evidence.Withoutaphysicalexamination,otherpotentialcausesofsymptomssuchasCRS,couldnotbe15

fullyevaluatedoreliminated.Apatienthistorycombinedwithaphysicalexaminationimproves16

diagnosticaccuracy.78117

18

19

• AggregateGradeofEvidence:D(Level3b:1study;Level4:3studies;Level5:4guidelines;Table20

VIII.A.)21

• Benefit:Improveaccuracyofdiagnosis,avoidunnecessaryreferrals,testing,ortreatment.22

PossibleimproveddiagnosisofARwithphysicalexaminationfindings,evaluation/exclusionof23

alternativediagnoses.�24

• Harm:Possiblepatientdiscomfortfromroutineexamination,notinclusiveofendoscopy.25

Potentialmisdiagnosis,inappropriatetreatment.26

• Cost:Minimal.27

• Benefits-HarmAssessment:Preponderanceofbenefitoverharm,potentialmisdiagnosisand28

inappropriatetreatmentifphysicalexamusedinisolation.�29

• ValueJudgments:MakingapresumptivediagnosisofARonhistory(ideallycombinedwith30

physicalexamination)isreasonableandwouldnotdelaytreatmentinitiation.Confirmationwith31

diagnostictestingisrequiredforprogressiontoAIT,ordesirablewithinadequateresponseto32

initialtreatment.33

• PolicyLevel:Recommendation.34

• Intervention:HistorytakingisessentialinthediagnosisofAR.Physicalexaminationis35

recommendedinthediagnosisofAR,andwhencombinedwithpatienthistory,itincreases36

diagnosticaccuracyandexcludesalternativecauses.37

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TableVIII.A.1.Evidencefortheroleofhistorytakingandphysicalexaminationinthediagnosisofallergicrhinitis1

LOE:levelofevidence;AR:allergicrhinitis;SPT:skinpricktest;sIgE:antigen-specificimmunoglobulinE 2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionRazaetal

781 2011 3b Cross-

sectional

AdultswithAR History,physical

examination,SPT

Physicalexaminationaloneyieldsunreliableand

inconsistentresultsindiagnosingAR.

Costaetal780 2011 4 Cohortstudy AdultswithAR Physicianinterviewand

structuredquestionnaire

Manypatientsdiagnosedonhistoryalonewithout

confirmatorytesting.

Shatz778 2007 4 Survey 1.adultsand

children>12years

withAR

2.physiciansof

group1

Self-completedpatient

questionnaire,physician

patientrecordform

PersistentARpatientsreportedmoresymptomsthan

intermittentARpatients.

Ngetal779 2000 4 Case-control AdultswithAR History,physical

examination,SPT,sIgE

Rhinorrhea,sneezing,sniffing,impairedsenseof

smell,blockednose,edematousnasalmucosaand

itchynoserankedhighestindiagnosticutility.

Physicalexaminationperformedtoeliminateother

potentialcausesofsymptoms.

Seidmanetal761 2015 5 Guideline Recommendationson

diagnosisandtreatmentof

AR

ClinicaldiagnosisofARmadewithahistoryand

physicalexaminationconsistentwithAR.

Wallaceetal26 2008 5 Guideline Recommendationsonthe

diagnosisandtreatmentof

rhinitis

Thoroughallergichistoryremainsthebestdiagnostic

toolavailable.Allorgansystemspotentiallyaffected

byARshouldbeexamined.Typicalallergicexam

findingsaresupportivebutnotspecific.

Smalletal777 2007 5 Guideline Recommendationson

diagnosisandtreatmentof

rhinitis

Historyofallergicsymptomsisessentialinthe

diagnosisofAR.Physicalexamaidsinsupportingthe

diagnosisofAR.

Bousquetetal7 2001 5 Guideline Recommendationsonthe

diagnosisandtreatmentof

ARinasthmaticpatients

Symptomtypeandtiming(obtainedthroughhistory)

isessentialtocorrectdiagnosis.Lungexamis

recommendedinasthmaticpatientswithsymptoms

ofAR.

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VIII.B.Nasalendoscopy1

DiagnosticnasalendoscopyisanoptionfortheevaluationofpatientswithsuspectedAR.2Severaluncontrolledobservationalstudiesevaluatedtheassociationofendoscopicfindingswith3symptomaticrhinitis,withinconsistentresults.[TableVIII.B.]Amelietal782evaluatedchildrenwith4suspectedAR,reportingthatendoscopicfindingsofinferiorormiddleturbinateseptalcontactwas5predictiveforAR,whilepaleturbinateswerenot.Conversely,Erenetal783evaluatedapopulationof6adultpatientswithrhinitis,concludingthatfindingsofnasalendoscopydonotprovideareliable7diagnosisofAR.AmongadultsandchildrenwithARthatisconfirmedbyallergytesting,nosignificant8correlationwasfoundbetweennasalendoscopyandspecificnasalsymptoms.7849 Centralcompartmentatopicdisease(CCAD)representstherecentlydescribedassociation10betweenatopicstatesandcentrally-locatedinflammationinvolvingthemiddle/superiorturbinatesor11superiornasalseptum.785-787Inarecentlypublishedparallelcaseseries(LOE=4),Brunneretal78812evaluatedpatientswithCRSwNPversusisolatedpolypoidchangeofthemiddleturbinate.Significant13findingsincludeahigherprevalenceofARinpatientswithmiddleturbinatepolypoidchange(83%vs1434%,p<.001),furthersupportingCCADasauniqueatopiccondition.15 AlthoughtheassociationofendoscopicfindingswithARhasbeenshowntobeinconsistent,16nasalendoscopymayaidintheidentificationorexclusionofotherpossiblecausesofsymptoms,suchas17nasalpolyposisorCRS.1819

• AggregateGradeofEvidence:D(Level3b:2studies;Level4:3studies;TableVIII.B.)*20• Benefit:Possibleimproveddiagnosiswithvisualizationofturbinatecontactorisolatedcentral21

compartmentedema.�22• Harm:Possiblepatientdiscomfort.23• Cost:Moderateequipmentandprocessingcosts,aswellasproceduralcharges.�24• Benefits-HarmAssessment:Equal.�25• ValueJudgments:None.26• PolicyLevel:Option.27• Intervention:Nasalendoscopymayincreasediagnosticsensitivityamongchildrenandadults28

withARandmayaidinrulingoutothercausesfornasalsymptoms.29*DuetorecentpublicationandinaccordancewithICARmethodology,DelGaudioetal787and30Brunneretal788areexcludedfromtheAggregateGradeofEvidence.31

32

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TableVIII.B.Evidencefortheroleofnasalendoscopyinthediagnosisofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Hamizanetal786

2016 3b Cross-sectional Adultswithrhinitisandnasalobstruction

Nasalendoscopy,allergytesting

MTedemaisausefulnasalendoscopicfeaturetopredictpresenceofinhalantallergy.

Whiteetal785 2014 3b Cross-sectional AdultswithisolatedMTpolypoidedema

Nasalendoscopy,allergytesting

IsolatedMTpolypoidedemaisassociatedwithpositiveallergytesting.

Erenetal783 2013 4 Caseseries Adultswithrhinitis Nasalendoscopy,ARdiagnosis

NasalendoscopicfindingsdonotprovidereliablediagnosisofAR.

Amelietal782 2011 4 Caseseries ChildrenwithsuspectedAR Nasalendoscopy,ARdiagnosis

InferiorormiddleturbinateseptalcontactwaspredictiveforAR,whereaspaleturbinateswerenot.

Jareoncharsrietal784

1999 4 Caseseries AdultsandchildrenwithPAR Nasalendoscopy,nasalsymptoms

Nosignificantcorrelationbetweenindividualsymptomsandendoscopicfindings.

LOE:levelofevidence;MT:middleturbinate;AR:allergicrhinitis;PAR:perennialallergicrhinitis2

3 4

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VIII.C.Radiology1

RoutineradiographicimagingisnotrecommendedforthediagnosisofAR,althoughmaybe2consideredtorulein/outotherconditions(i.e.rhinosinusitis).Somerecentstudieshaveestablishedthe3associationbetweencentralcompartmentmucosaldiseaseandaeroallergensensitivity.787,788However,4concernsregardingunnecessaryexposuretoionizingradiation,withtheriskforfuturecancer5development,precluderecommendationsforroutineuse.789,79067

• AggregateGradeofEvidence:Notapplicable.*8• Benefit:Noneappreciated.�9• Harm:Unnecessaryradiationexposurewithconcernfortumordevelopment.10• Cost:Highequipmentandprocessingcosts.�11• Benefits-HarmAssessment:Preponderanceofharmoverbenefit.�12• ValueJudgments:Long-termrisksofunnecessaryionizingradiationexposureoutweighpotential13

benefit.14• PolicyLevel:Recommendagainst.15• Intervention:RoutineimagingisnotrecommendedintheevaluationofsuspectedAR,butmay16

beconsideredtorulein/outothersinonasalconditions.17*DuetorecentpublicationandinaccordancewithICARmethodology,DelGaudioetal787and18Brunneretal788areexcludedfromtheAggregateGradeofEvidence.19

20

VIII.D.Useofvalidatedsurveyinstruments21

Validatedclinicaloutcomesurveysandquestionnairesmaybeusedaspreciseclinical22assessmentinstrumentstoevaluatepatientswithsuspectedAR.CliniciansoftenuseSPT,sIgEserology,23andotherlaboratoryteststoconfirmorrefutethediagnosis,butthesetestsareonlyusefulinthe24contextofaneffectiveclinicalhistory.791Validatedclinicalassessmenttoolsofferamorestructuredway25toexposeimportanthistoricalelements.Furthermore,inregionswhereresourcesarescarce,SPTand26laboratorytestingmaynotbeasreadilyavailable.Advancingtechnologiessuchasmultiplexallergen27screening,componentserology,andautomatedSPTimagingdevicesmaybeexpensiveandunattainable28bysomeclinicians.792-795Inthesesettings,validatedsurveysofferarapidandsimplepoint-of-caretoolto29formallyevaluateallergicdisease.30

Patientreportedoutcomemeasures(PROMs)canassessanumberofdifferentaspectsofhow31ARaffectspatients.796Theseincludesymptomseveritysurveys,suchastheTotalNasalSymptomScore32(TNSS)andhealth-relatedQOLquestionnaires,suchastheRQLQ.Additionalsurveysmeasureaspects33suchasmedicationusage(DailyMedicationScore),diseaseprediction(RespiratoryAllergyPrediction)34anddiseasecontrol(RhinitisControlTest).Eachofthesesurveysexaminesslightlydifferent,although35relatedaspectsofclinicaloutcomes.Severaloftheseinstrumentshavebeenusedextensivelyinmany36largeclinicaltrialstodeterminetheeffectivenessofdrugsandbiologicsfortreatingAR.797-802SPTand37nasalchallengemaybeusedtocross-validatetheseclinicalsurveytoolsbutultimately,howapatient38reportstheirownsymptomscouldverywellbethebestpredictorofdiseasecontrol.39

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ICAR:AllergicRhinitis114

ValidatedclinicalsurveysforARoftenincludequestionsaboutcongestion,rhinorrheaand/or1sneezingandmayeitherbeinstantaneousorreflectiveoveraperiodofdaysorweeks.TheTNSSis2typicallyadministeredasaninstantaneousdailysurveycomprisedofonlyfourquestionsaboutrunny3nose,nasalitching,sneezing,andcongestion.SomestudieshaveusedtheTNSSasareflectivescore4calculatedastheaverageofboththe12-hournighttimeand12-hourdaytimeaverage(rTNSS).TheTNSS5scorecanbecombinedwithquestionsaboutrescuemedicationusetoyieldtheDailyCombinedScore6(DCS)andtheTotalCombinedRhinitisScore(TCRS).Bothhavebeenusedinmanytherapeutic7interventionstudies.803TheRQLQisamorecomprehensivesurveythatasksthepatienttoreflectupon8thepastweekandincludesglobalQOLquestions.Whilethistestcansuffersomewhatfrompotential9recallbias,itcanbeadministeredonsiteandavoidsthepossibilitythatself-administereddailyscores10couldbemissedperiodicallywhenthepatientishome.TheControlofAllergicRhinitisandAsthmaTest11(CARAT10)evaluatesrhinoconjunctivitisandasthmasymptomsoverthepastfourweeksgivinga12broaderevaluationofseasonalsymptomcontrol.804TheRespiratoryAllergyPrediction(RAP)testisa13nine-questionsurveyincorporatingupperandlowerrespiratoryqueriesaswellasaquestionabout14medicationuse.Ifconjunctivitisistobeassessedsimultaneouslywithrhinitissymptoms,thenthe15RhinitisTotalSymptomScore(RTSS)canbecombinedwithRescueMedicationScore(RMS)toyieldthe16combinedscore(CS).805TableVIII.D-1.listsseveralvalidatedclinicalsurveytools.696,804,806-81317

Thechoiceofwhichvalidatedsurveytousedependsonwhichaspectofclinicaloutcomesis18beingstudied.Forexample,ifthegoalisforaprimarycarephysiciantodeterminetheneedforreferral19andfurthertesting,thentheRAPtestmaybeusedbecauseithasbeenscrutinizedinthissetting.814The20mini-RQLQandDCShavebeenusedextensivelyinclinicaltrialstoevaluatetheeffectivenessofdrugs21andimmunotherapies,797-801andthereforemaybehelpfulinselectingtherightmedicationforagiven22population.Itisimportanttonotethatsometoolsuseahigherscoretoindicateseverediseasewhereas23othertoolsuseahigherscoretoindicatebettercontrolofsymptoms.Forexample,ahighscoreonthe24RCAT,ARCTandCARAT10indicategoodcontrolofallergicsymptoms.25

Unfortunately,notallstudiesuseconsistentterminologyandinterpretationofthescoring26systems.801Inconsistentuseofquestionnairescanweakentheconclusionsdrawnincertaintherapeutic27interventionstudies.However,awell-executedandvalidatedsurveycanbeessentialinresearch28settingsandhelpcliniciansscreenpatientsforARandfurtherrenderspecificdiagnosticdecisions.29 Overall,validatedclinicalsurveyinstrumentsmaybeusedasatooltoassistwiththediagnosis30ofARanddeterminethesuccessofvarioustherapies.Thisconclusionisbasedonreviewofmorethan3130studiesofwhich9ofthesereportsrangefromlevel1ato2b(overallGradeAevidence).[Table32VIII.D-2.]Anexampleapproach,usingspecificvalidatedsurveyinstrumentsisasfollows:TheTNSSmay33beusedfordailysymptommonitoringtodeterminetheeffectivenessoftherapiesandcontrolofAR.34TheTNSSshouldbecombinedwithadailymedicationscoretoaccountfortheeffectsof35pharmaceuticalsonsymptomatology.Assessmentofbothconjunctivitisandrhinitissymptomsaswellas36medicationusecanbeperformedwiththeCombinedScore(RTSS+RMS)ortheRhinoconjunctivitis37AllergyControlScore(RC-ACS).TheRQLQormini-RQLQcanbeusedasanadditionalmeasureto38incorporatediseaseimpactonQOLandcanbeadministeredinpersonbytheclinician.Forquick39assessmentsortofollowapatient’stherapeuticsuccess,asimplevisualanaloguescale(VAS)orglobal40assessmentisacceptable.TheRAPtestcanbeusedasquickandeasytoolforprimarycarephysiciansto41

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determinetheneedtorefertoanallergistforfurthertesting.Manyvalidatedoptionsareavailablefor1ARandshouldbetailoredtothepatientandclinicalsetting.23

• AggregateGradeofEvidence:A(Level1a:2studies;Level1b:4studies;Level2b:4studies;4TableVIII.D-2.)Note:multipleadditionalstudiesreviewed,butGradeAevidencereachedwith5these10studies,soanextensivelistingofallstudiesemployingvalidatedsurveyinstrumentsis6notprovidedhere.7

• Benefit:Validatedsurveysofferasimplepoint-of-careoptionforscreeningandtracking8symptoms,QOLandcontrolofallergicdisease.9

• Harm:Minimaltonone.10• Costs:Nofinancialburdentopatients.Somefeesassociatedwithvalidatedtestsusedforclinical11

research.12• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.Lowriskofmisdiagnoses13

leadingtounnecessaryadditionaltesting.Likewise,thereisalowriskthatfalsenegative14responsesmayleadtodelayintestingandfurthermanagement.15

• ValueJudgments:Level1evidencetousevalidatedsurveysasascreeningtoolandprimaryor16secondaryoutcomemeasure.17

• PolicyLevel:Strongrecommendation.18• Intervention:ValidatedsurveysmaybeusedtoscreenforAR,followtreatmentoutcomesand19

asaprimaryoutcomemeasureforclinicaltrials.Specifictestsareoptimizedforvarious20clinicopathologicalscenariosandshouldbetailoredtothepatientandclinicalsetting.21

22

23

24

25

26

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TableIII.D-1ValidatedsurveysusedtodiagnoseARorevaluatediseaseseverityandtreatment1Survey Disease

TargetedNumberofquestions

Symptomquestions

Medicationquestions

Scoringrange

Commentsandindications

TNSSTotalNasalSymptomScore

AR 4 Yes No 0-12 Simpledailysymptomscoreto

evaluateARseverityandcontrol

usedinclinicaltrials

DMSDailyMedicationScore

AR,AC,asthma Varies No Yes 0-36* Variesdependingonmedication

scoring

DCSDailyCombinedScore

AR,AC,asthma Varies Yes Yes 0-48* Combinedsymptomand

medicationscoreforclinicaltrials

TCRSTotalCombinedRhinitisScore

AR Varies Yes Yes 0-24* Thesumofthecombined

symptomsmedicationscores

Mini-RQLQMini-RhinoconjunctivitisQualityofLife

Questionnaire

Rhinoconjunctivitis 14 Yes No 0-84 ShortenedversionofRQLQoften

usedinclinicaltrials

RQLQRhinoconjunctivitisQualityofLife

Questionnaire

Rhinoconjunctivitis 28 Yes No 0-168 Reflectiveassessmentofprevious

week’ssymptomsoftenusedin

clinicaltrials

VASVisualAnalogueScale

Rhinitis 1ormore Yes No 0-10cm Toolmaybeusedtoevaluate

multiplesymptomatologies

RCATRhinitisControlAssessmentTest

AR,NAR 6 Yes No 6-30** Self-assessmentofrhinitis

symptomcontrol

ARCTAllergicRhinitisControlTest

AR 5 Yes Yes 5-25** Self-assessmentofongoingAR

symptomscontrol

CARAT10ControlofAllergicRhinitisandAsthmaTest

AR,NAR,asthma 10 Yes Yes 0-30** Usedtocomparegroupsinclinical

trials

ACSAllergyControlScore

Rhinitis,AC,asthma 10+meds Yes Yes 0-60 Combinedtoolusedforclinical

trialsanddailyclinicalpractice

RC-ACSRhinoconjunctivitisAllergyControlScore

Rhinitis,AC 7+meds Yes Yes 0-42 SimilartoACSbutwithoutasthma

relatedquestions

RAPRespiratoryAllergyPrediction

AR,asthma 9+meds Yes Yes 0-9 Usedtodeterminetheneedfor

referralandadditionaltesting

SFARSymptomScoreForAllergicRhinitis

AR 8 Yes No 0-16 Weightedscoreusedtodetect

prevalenceofAR

RMSRescueMedicationScore

Rhinoconjunctivitis meds No Yes 0-3 Evaluatesmedicationuseonly

RTSS Rhinoconjunctivitis 6 Yes No 0-18 Evaluatessymptomsonly

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RhinoconjunctivitisTotalSymptomScore

CSCombinedScore

Rhinoconjunctivitis 6+meds Yes Yes 0-3 CombinedscoresofRTSS/6+

RMS/2

GlobalAssessmentGlobalAssessmentofSeverityofAllergy

Totalnasalandnon-

nasalsymptoms

1 Yes No 1-7 Singlequestionaboutrhinitis

severity

*Maximumscoremayvarydependingonspecificnumberofsymptomrelatedquestionsandspecificmedicationscoreincluded.1**Higherscoreequatestobettercontrolofdisease.Ascoreof0denoteszerocontrolofsymptoms.2AR:allergicrhinitis;AC:allergicconjunctivitis;NAR:non-allergicrhinitis;meds:medications345TableIII.D-2Evidencefortheroleofvalidatedsurveyinstrumentsintheevaluation,diagnosis,andfollow-upofallergicrhinitis6Study Year LOE Study

designStudygroups Clinicalend-point Conclusion

DiBonaetal815 2015 1a Systematic

review

ARC Meta-analysisofgrassSLITefficacy Combinedsymptomandmedicationscoreshowed

efficacyofgrassSLIT.

Calderonetal801 2014 1a Systematic

review

AR Comparisonofscoringsystems TNSSandcombinedmedicationscoresshouldbeused

inclinicaltrials.

Demolyetal803 2016 1b DBRPCT AR EfficacyofHDMSLITtablet TCRSconfirmedefficacyofSLIT.

Zieglmayeret

al798

2016 1b RCT AR EfficacyofB-cellvaccine TNSSscoreusedtodetermineefficacyinlargestudy.

Klimeketal805 2015 1b RCT ARC Effectivenessofrecombinantbirch

SCIT

CombinedscoreandVASrevealednodifference

betweenrecombinantandstandardbirchSCIT.

Mosbechetal799 2015 1b RCT AR EfficacyofHDMSLITforAR RQLQusedeffectivelyinthisevaluation.

Devillieretal802 2016 2b Cohort AR EvaluationofARbyVAS,RTSSand

RQLQ

Comparisonofvariousoutcomemeasuresvalidates

theirutility.

Galimbertiet

al814

2015 2b Cohort AR,AC,asthma EvaluationofRAPtest RAPtestisvalidforscreeningallergicdisease

Devillieretal813 2014 2b Cohort ARC Minimalclinicallyimportant

differenceofRTSS

RTSSvsRQLQshowedminimalclinicallyimportant

differenceof1.

Hafneretal806 2012 2b Cohort ARC EvaluationofRC-ACStestin81

subjects

RC-ACSisavalidtestforevaluatingARCwithout

asthma.

LOE:levelofevidence;ARC:allergicrhinoconjunctivitis;SLIT:sublingualimmunotherapy;AR:allergicrhinitis;TNSS:TotalNasalSymptomScore;DBRPCT:7double-blindrandomizedplacebocontrolledtrial;HDM:housedustmite;TCRS:TotalCombinedRhinitisScore;RCT:randomizedcontrolledtrial;SCIT:8subsutaneousimmunotherapy;VAS:visualanalogscale;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;RTSS:RhinoconjunctivitisTotalSymptom9Score;AC:allergicconjunctivitis;RAP:RespiratoryAllergyPrediction;RC-ACS:RhinoconjunctivitisAllergyControlScore10

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VIII.E.1.Skinpricktesting(SPT)1

SPTcanbeused,alongwiththehistoryandphysicalexamination,toconfirmthediagnosisofAR2anddifferentiatefromnon-allergictypesofrhinitis.TheconfirmationofanIgE-mediatedprocessguides3avoidancemeasuresandappropriatepharmacologictherapy.SkintestingiscrucialtodirectingAIT,and4therefore,shouldbeutilizedineligiblepatientswhenAITisbeingconsidered.AccordingtotheARIA5guidelines,patientsshouldbeconsideredforAITwhentheyhavefaileda2-to4-weektrialofmoderate-6doseINCScombinedwithantihistamines.1017

Whenanantigenisappliedtotheskinofasensitizedpatient,theantigencross-linksIgE8antibodiesonthesurfaceofcutaneousmastcellsresultingindegranulationandreleaseofmediators9(includinghistamine)whichleadstotheformationofawhealandflarereactionwithin15-2010minutes.816,817Giventhelimiteddepthofpenetration,SPTissafewithveryrarereportsofanaphylaxis11andnoreportedfatalities.818SPTcanbeperformedinanyagegroupandisofparticularvaluein12pediatricpopulationsgiventhespeedatwhichmultipleantigenscanbeappliedandthelimited13discomfortexperiencedduringtesting.14

Skintestingisnotappropriateinallpatients.ContraindicationstoSPTincludeuncontrolledor15severeasthma,severeorunstablecardiovasculardisease,concurrentbeta-blockertherapy,and16pregnancy.Certainmedicationsandskinconditionsmayinterferewithskintesting.Thesearecoveredin17detailinsectionVIII.E.4.Issuesthataffecttheperformanceorinterpretationofskintests–VIII.E.4.a.18MedicationsandVIII.E.4.b.Skinconditions,respectively.19

Asidefromanexcellentsafetyprofile,SPThasareportedsensitivityandspecificityaround2080%.818-820Itisreportedtobemoresensitivethanserumtestingwiththeaddedbenefitoflower21cost.818,821,822DespitestudiesaimedatcomparingSPT,intradermaltestingandserumtesting,conclusive22evidencemarkingoneformoftestingassuperiortotheothersislacking.76123

Thenumberandchoiceofantigensusedintestingvariesconsiderablybetweenclinical24practices.Apanelofantigensrepresentinganappropriategeographicalprofileofallergensthata25patientwouldroutinelybeexposedtoisrecommended.Positive(histamine)andnegative(glycerinor26saline)controlsshouldalwaysbeincluded.Variabilityinqualityandpotencybetweencommercially27availableallergenextractshasbeendemonstrated.823,824Therefore,wheneverpossible,standardized28allergensshouldbeused.82029

SPTisperformedwithlancets,whichcomeinavarietyofforms.Generally,lancetsaredesigned30tolimitskinpenetrationdepthto1mm.However,varyingamountsofpressureappliedtothedelivery31devicecanalterthedepthofskinpenetration,whichultimatelyinfluencestheskinreactiontoan32antigen.825Pricktestingdevicescancomeassinglelancetdevicesormultiplelancetdevices.Multiple33lancetdeviceshavetheadvantageofbeingabletorapidlyapplymultipleantigenstotheskinatone34timewithamoreconsistentamountofpressure.826,827Whealsize,sensitivity,andreproducibilityall35differfromonedevicetoanother;826-828therefore,anyhealthcareproviderperformingSPTmust36thoroughlyfamiliarizethemselveswithhis/hertestingdevice.Typically,thelancetisdippedintoawell37containinganantigenandthenappliedtotheskin.38

ThevolarsurfacesoftheforearmsandthebackarethemostcommontestingsitesforSPT.39Choiceofsiteisdirectedbytheage/sizeofthepatient.Testsshouldbeapplied2cmorgreaterapartas40placingthemclosertooneanothercancausecross-contamination.829After15-20minutes,theresults41

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arereadbymeasuringthesizeofthewhealbyitsgreatestdiameter.Awheal3mmorlargerthanthe1negativecontrolisconsideredpositive.2

ThereisalargebodyofevidencedetailingtheuseofSPTinclinicalpractice.[TableVIII.E.1.]3Baseduponseveralprospectivestudiesandsystematicreviews,SPThasbeendemonstratedtobeasafe4methodofallergytesting.Itisnotinferiortoserumorintradermaltestingandislessexpensivethan5serumtesting.Itdoescarryariskofsystemicreaction,socautionshouldalwaysbeexercised.Itisalso6associatedwithsomediscomfortduringtesting;however,thediscomfortisgenerallylessthanthat7experiencedduringintradermaltesting.Reviewingtheavailableliterature,apreponderanceofbenefit8overharmforSPTexists.Therefore,theuseofSPTisrecommendedinsituationswherethediagnosisof9ARneedstobesupportedorapatientwithpresumedARhasfailedappropriateempiricmedical10therapy.1112

• AggregateGradeofEvidence:B(Level1a:1study;Level3b:7studies;TableVIII.E.1.)13• Benefit:Supportsdiagnosisanddirectspharmacologicaltherapywhilepossiblyavoiding14

unnecessary/ineffectivetreatment,guidesavoidance,directsAIT.15• Harm:Adverseeventsfromtestingincludingdiscomfort,pruritus,erythema,worseningof16

asthmasymptoms,andanaphylaxis,inaccuratetestresults,misinterpretedtestresults.17• Cost:Low.18• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.19• ValueJudgments:Patientscanbenefitfromidentificationoftheirspecificsensitivities.SPTisa20

quickandrelativelycomfortablewaytotestseveralantigenswithaccuracysimilartoother21availablemethodsoftesting.22

• PolicyLevel:Recommendation.23• Intervention:SPTisrecommendedforevaluationofallergensensitivitiesinappropriately24

selectedpatients.RegularuseofthesameSPTdevicewillallowclinicianstofamiliarize25themselveswithitandinterpretationofresultsmaythereforebemoreconsistent.Theuseof26standardizedallergenextractscanfurtherimproveconsistencyofinterpretation.27

28

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TableVIII.E.1.Evidencefortheroleofskinpricktestinginthediagnosisofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Nevisetal830

2016 1a Systematicreviewandmeta-analysis

Notapplicable AccuracyofSPT PooledestimateforSPTsensitivityandspecificitywas85and77%,respectively.SPTisaccurateindiscriminatingsubjectswithorwithoutAR.

Krouseetal831

2004 3b Prospectivecase-control

1.AlternariaSPTpositive2.Alternariaintradermal#2dilutionpositive3.Alternarianegative

Acousticrhinometryofminimalcrosssectionalareaofnasalcavity

Analysisofnasalprovocationtestresultsamonggroupsshowedasensitivityof42%andspecificityof44%forSPTusingAlternariaantigen.

Krouseetal832

2004 3b Prospectivecase-control

1.TimothygrassSPTpositive2.Timothygrassintradermal#2dilutionpositive3.Timothygrassnegative

Acousticrhinometryofminimalcrosssectionalareaofnasalcavity

Analysisofnasalprovocationtestresultsamonggroupsshowedasensitivityof87%andspecificityof86%withmulti-testapplicationoftimothygrassantigen

Gungoretal833

2004 3b Prospectivecase-control

1.nasalprovocationtestpositive2.nasalprovocationtestnegative

SensitivityandspecificityofSPTversusSETfordiagnosingAR

SPTmoresensitive(85.3vs79.4%)andspecific(78.6vs67.9%)thanSETasascreeningprocedureformultipleantigens.SPThadagreaterPPV(82.9vs75%)andNPV(81.5vs73%)thanSET.Noneofthesedifferenceswerestatisticallysignificant.

Zareietal834

2004 3b Prospectivecase-control

1.nasalprovocationtestpositive2.nasalprovocationtestnegative

Whealsizethatbestidentifiesclinicalallergytocatbasedonnasalprovocationtesting

OnSPTwithcatantigen,awhealsizeof>3mmhadasensitivityof100%andspecificityof74.1%.Thisimprovedwithincreasingsizeofwheal.

Pumhirunetal835

2000 3b Prospectivecase-control

Perennialrhinitispatients ComparedsensitivityandspecificityofintradermaltestingtoSPTandspecificIgEassayforD.pteronyssinusandD.farinae

SPTforD.pteronyssinusandD.farinaewere90.4%and86.4%sensitiveand99.5%and93.1%,specificrespectively.Thiscomparedtosensitivityof96.3%and88.9%andspecificityof96.2%and88.9%ofspecificIgEassay.

Woodetal793

1999 3b Prospectivecase-control

Patientswithcatallergydeterminedbyhistoryandacat-exposuremodel

ComparedthepredictivevaluesofSPT,intradermaltestingandRASTsinthediagnosisofcatallergy

SPTandRASTvaluesexhibitedexcellentefficiencyindiagnosisofcatallergy.Intradermaltestingaddedlittletothediagnosticevaluation.SensitivityandspecificityofSPTwere79and91%,respectively.

Tschoopetal822

1999 3b Prospectivecase-control

Arandomlyselectedsampleof8329Swissadults

Comparedthesensitivity,specificity,

SensitivityoffluoroenzymeimmunoassaywassignificantlyhigherthanSPTandIgE.However,

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PPVandNPVofSPT,IgElevelsandfluoroenzymeimmunoassayindiagnosingAR

SPTwasmorespecificandhadabetterPPV.SPTwasthemostefficienttesttodiagnoseAR.

Seidmanetal761

2015 5 Guideline Notapplicable Notapplicable CliniciansshouldperformandinterpretorreferforspecificIgE(skinorblood)allergytestingforpatientswithaclinicaldiagnosisofARwhodonotrespondtoempirictreatmentorthediagnosisisuncertain.

Heinzerlingetal836

2013 5 Review Notapplicable Notapplicable SPTisareliablemethodtodiagnoseARwithspecificityof70-95%andsensitivityof80-90%forinhalantallergies.FurtherstandardizationofSPTisneeded.

Bernsteinetal818

2008 5 Practiceparameter

Notapplicable Notapplicable SensitivityofSPTrangesfrom85-87%whilespecificityis79-86%.ManystudieshaveverifiedthesensitivityandspecificityofSPT.

LOE:levelofevidence;SPT:skinpricktest/testing;AR:allergicrhinitis;SET:skinendpointtitration;PPV:positivepredictivevalue;NPV:negativepredictive1value;IgE:immunoglobulinE;RAST:radioallergosorbenttest23 4

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VIII.E.2.Skinintradermaltesting1

TheplacementofallergenicproteinsintheintradermalspaceisoftenusedfordiagnosingAR.2Intradermaltestinghasalsobeendescribedintheevaluationofsensitivitiestoothersubstances,3includinglocalanestheticagents,neuromuscularblockingagents,antibioticsandcontrastmedia.837-8404Whilepreviousprotocolshavedescribedtheuseofintradermaltestingforsuspectedfoodorchemical5allergies,thistypeofdiagnostictestingiscurrentlynotrecommendedinroutinepractice.841,8426Intradermaltestingmaybeusedasaprimarytestingmodality,orasasecondarytestfollowingSPT.7Intradermaltestinghasalsobeenused,primarilybyotolaryngicallergists,asamethodtohelp8determinethestartingpointforspecificAITandasavialsafetytestpriortoaninjectionfromanew9treatmentvial,thoughthelevelofevidencesupportingtheseusesislow.843,84410

Intradermaltestingmaybeperformedasasingleinjection.Ashortbevelneedleisusedtoinject11adilutedallergenicextractsolutionintothesuperficialdermis.Approximately0.02mLisused,or12enoughtoproduceawell-definedwhealwhichis4mmindiameter.845Thewhealwillexpandto5mm13byhydrostaticforces,andthereactionisobservedfor10minutes.Thepositivecontrolforintradermal14testingishistamineandthenegativecontrolsaretypicallyphenolatedsalineandaglycerinsolution15whichequalstheconcentrationofglycerininthetestsolution.Ifthediameteroftheresultingwhealis16atleast7mm,andatleast2mmwiderthantheglycerincontrol,thisisconsideredapositivetest.84617Whilethisisaveryreproducibletest,itismoretechnicallydemandingthanSPT,isdifficulttoperformin18youngchildrenandcarriesahigherriskofadversereactions.847Severeadverseeventsrelatedto19intradermaltestingarerare.Overa42-yearperiod,from1945to1987,only5fatalitieswereattributed20tointradermaltestingwithoutpriorprick/puncturetesting.84821

Intradermaltestingmayalsobeperformedusingmultipledilutionsofthesameallergentomore22preciselyquantifythelevelofsensitivitytothatallergenandsuggestastartingpointfor23immunotherapy.849Aseriesofdilutionsofconcentratedallergenicextract(typicallysuppliedasa1:2024weight/volumesolution)canbepreparedineithera1:5or1:10ratio.Intradermaldilutionaltesting(IDT,25previouslyreferredtoasskinendpointtitration,orSET)beginswiththeintradermalplacementofa26diluteallergen,alongwithappropriatecontrols,followedbytheplacementofprogressivelymore27concentrateddilutionsofthatallergen.Thedilutionproducingthefirstpositivetest,asdefinedabove,28followedbyprogressivelylargerwhealsiscalledthe“endpoint”.Toestablishprogression,a29confirmatorywheal,producedbythenexthigherconcentration,mustbeatleast2mmwiderthanthe30suspectedendpoint.IDTendpointcorrelateswithSPTwheal.844,850,851WhileIDTendpointshavebeen31showntocorrelatewithbiologicallyrelevantmeasures,suchasbasophilhistaminerelease,aclear32correlationwithothermeasures,suchasinvitrosIgElevels,hasnotyetbeenestablished.852,85333Currently,nostudieshavedemonstratedaclearbenefitofquantitativeintradermaltestingoversingle34intradermaltestingwithregardtothediagnosisofclinicalallergyortheoutcomeofspecific35immunotherapy.[TableVIII.E.2.]36

Asastand-alonediagnostictestforAR,estimatesforsensitivityforintradermaltestingrange37between60%(95%CI31-83%)and79%(63-90%),whileestimatesforspecificityrangebetween68%38(95%CI49-82%)and69%(52-86%).793,833Thisislowerthanthepooledestimatesofsensitivity(85-88%)39andspecificity(77%)forSPT,calculatedfromrecentmeta-analyses.830,854Factorsaffectingthepredictive40

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valueofintradermaltestingincludethecomparatorusedandtheconcentrationofallergenusedwith1theintradermaltest.8552

IthasbeensuggestedthatintradermaltestingcouldpotentiallyincreasethesensitivityofSPTby3injectingallergenicproteinsintodeepertissuelayersbeneaththekeratinizedepidermis.847However,4theliteraturehasnotsupportedaclearbenefitofintradermaltestingforthispurpose.Using5intradermaltestinginadditiontoSPTtopredictapositiveresponsefromnasalchallengewithtimothy6grassonlyincreasedthesensitivityfrom87-93%.832Inasimilarstudy,Krouseandcolleaguesdetermined7thataddingintradermaltestingtoSPTasamethodtopredictpositivenasalchallengetoAlternaria8increasedthesensitivityfrom42-58%.831Thesestudiessuggestmarginalincreaseinsensitivitythatmay9varybasedupontheallergenbeingtested.10

Nelsonandcolleaguesstudied28individualswithahistoryofSAR.856Onegrouphadnegative11SPTtotimothyandBermudagrass,butpositiveintradermaltestingfortimothygrass,whiletheother12grouphadnegativeSPTandnegativeintradermaltestingfortimothyandBermudagrass.Inboth13groups,11%ofindividualshadapositivenasalchallengewithtimothygrass.Likewise,when3914individualswithclinicalcatallergyandnegativeSPTunderwentacatchallenge,therewasnodifference15inthedevelopmentofupperrespiratorysymptomsbetweenthosewhohadpositiveornegative16intradermaltesting(24%vs.31%,p=0.35).793Reddy,etal857evaluatedallergytestresultsin34patients17withperennialrhinitis.Patientswithonlyintradermalpositiveskintests(SPTnegative)didnothavea18positiveRASTnorapositiveleukocytehistaminerelease.Incontrast,SPTpositivitywasassociatedwith19positiveRASTtestandleukocytehistaminereleaseassay.857Schwindt,etal858studied97subjectswith20allergicrhinoconjunctivitissymptoms.Pricktestingwasfollowedbyintradermaltestingifprickwas21negative.Ifpatientswerepricknegativeandintradermalpositive,anasalchallengewasperformed22against5differentallergens.IfSPTwiththemulti-testIIdevicewasnegative,only17%ofsubjectshada23positiveintradermaltestthatcorrespondedwithclinicalhistory.NoneofthesepositiveIDtests24correspondedwithapositivenasalchallenge.858Takentogether,thesestudiessuggestthatintradermal25testingdoesnotimprovethediagnosisofallergyinsubjectswithnegativeSPT.26

Nevisandcolleaguesconductedasystematicreviewoffourstudiestodeterminethesensitivity27andspecificityofintradermaltestingwhenusedasaconfirmatorytestfollowingnegativeSPT.83028Sensitivityrangedfrom27%(95%CI10-57%)to50%(samplesizesweretoosmalltocalculateCI),while29specificityrangedfrom69%(95%CI51-83%)to100%(95%CI83-100%).Fromaretrospectivestudyby30LarrabeeandReisacher,whentheclinicianwasguidedbyhighclinicalsuspicion,theincidenceof31positiveintradermaltestingfollowingnegativeSPTwas36.9%forindoorallergens(D.pteronyssinus,D.32farinae,cat,dogandcockroach),12.7%foroutdoorallergens(ragweed,redbirch,timothygrass,white33oakandredmaple)and9.2%formolds(Aspergillus,Candida,Penicillium,Alternariaand34Cladosporium).859However,nocorrelationbetweenpositiveintradermaltestingandnasalchallenge35testingwasperformedinthisstudy.Escuderoetal860foundthatinrhinitispatients,SPT,intradermal36andconjunctivalchallengeweremoresensitivethanserumsIgE.Alltestingmethodshadthesame37specificity.38

Insummary,currentevidencesupportstheuseofintradermaltestingforthediagnosisofAR39duetoairborneallergensasastand-alonetest,althoughthisformoftestingdemonstratesnoclear40superiorityoverSPTwhencomparingsensitivityandspecificity.Therewerenostudiesidentifiedwhich41directlycomparedsingledilutionintradermaltestingwithIDTintermsofsensitivity,specificityor42

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patientoutcomes.Thereappearstobeasmallgaininsensitivitywhenintradermaltestingisusedasa1confirmatorytestfollowingnegativeSPT;however,positiveintradermaltestresultsinthissettingcould2representfalsepositivetestresults.Itisalsomorelikelythatanintradermaltestfollowinganegative3SPTwillbepositivewhenindoorallergensarebeingtestedandleastlikelytobepositivewhentesting4formoldsensitivity.Itisunknownwhetherthetypeofallergenhasanimpactonthesensitivityand5specificity,asmoststudiesexaminedusedonlyoneallergen,butintradermaltestingseemedtobeleast6sensitiveandspecificwhenmoldwasbeingtested.Otherlimitationsofthestudiesidentifiedforthis7reviewincludelowsamplepopulationsizes(thelargestincluded120participants),variablestudydesign8andthelackofrandomized,controlledtrials.910

• AggregateGradeofEvidence:B(Level1a:1study;Level2b:11studies;Level3b:4studies;Level114:1study;TableVIII.E.2.).12

• Benefit:Generallywelltolerated,easytoperformandafavorablelevelofsensitivityand13specificitywhenusedasastand-alonediagnostictest.14

• Harm:Verylowriskofsevereadversereactions.15• Cost:Low.16• Benefits-HarmAssessment:Benefitoverharmwhenusedasastand-alonediagnostictest.17

BalanceofbenefitandharmwhenusedtoconfirmtheresultsofSPT,asaquantitative18diagnostictestorasavialsafetytest.19

• ValueJudgments:ItisimportanttodeterminethepresenceofIgE-mediatedsensitivityfor20individualswithsuspectedAR.IfSPTisnegative,thereislimitedclinicalbenefittoperforming21intradermaltestingforconfirmation.22

• PolicyLevel:Optionforusingintradermaltestingasastand-alonediagnostictestforindividuals23withsuspectedAR.Optionforusingintradermaltestingasaconfirmatorytestfollowing24negativeSPTfornon-standardizedallergens.TheevidenceforquantitativeIDTissparseand25preventsarecommendationforthisspecifictestingtechnique.26

• Intervention:Intradermaltestingmaybeusedtodeterminespecificairborneallergen27sensitizationforindividualssuspectedofhavingAR.28

29

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TableVIII.E.2.Evidencefortheroleofintradermalskintestinginthediagnosisofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionNevisetal830

2016 1a Systematicreview

ARpatientswhounderwentskintesting(n=430)

Sensitivityandspecificityofskintestingmethods

IDtestinghadhighersensitivityandspecificitywhenusedasastand-alonetestthanwhenusedtoconfirmSPT.

Larrabeeetal859

2015 2b Cohort ARpatientswhounderwentIDtestingbasedonhighsuspicionafternegativeSPT(n=87)

ResultofIDtest 21%wereIDpositive,morelikelyforindoorallergens.

Gungoretal833

2004 2b Cohort PatientswithSARandragweedsensitivity(n=62)

Nasalprovocationtesting,rhinomanometry

SensitivityandspecificityofIDtestingwascomparabletoSPT

Krouseetal832

2004 2b Cohort SAR(n=37)1.positiveSPT2.negativeSPT,positiveIDtest3.negativeSPT,negativeIDtest

Nasalprovocationwithtimothygrass,rhinomanometry

IDtestingafterSPTincreasedthesensitivityfrom87%to93%.

Krouseetal831

2004 2b Cohort AR(n=44)1.positiveSPT2.negativeSPT,positiveIDtest3.negativeSPT,negativeIDtest

NasalallergenprovocationscoreforAlternaria,visualanalogscale,rhinomanometry

IDtestingafterSPTincreasedthesensitivityfrom42%to58%.

Woodetal793

1999 2b Cohort Patientswithahistoryofsymptomswithcatexposure(n=120)

Catexposurechallenge,symptomscores,FEV1

IDscoresaddedlittlevaluebeyondSPTandRASTvalues.

Nelsonetal856

1996 2b Cohort (n=70)1.SAR,negativeSPT,positiveIDtest2.SAR,positiveSPT3.SAR,positiveSPT,positiveIDtest4.norhinitis

Nasalchallengewithtimothygrass

PositiveIDalongwithnegativeSPTdidnotindicatethepresenceofclinicallysignificantsensitivity.

Niemeijeretal846

1993 2b Cohort Allergypatients(n=41) SimultaneousSPT,IDtestingwithvaryingconcentrations

CoefficientofvariationofIDtesthistaminewhealsizeis6%withinpatientsand12%

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ofPhleumandD.pteronyssinus,aswellaspRASTonallsubjects.

betweenpatients.Optimumconcentrationoftestedallergenswas10-100BU/mL,a7.5mmIDwhealisidealcutoffvalueforpositiveresult(0.83Xthesizeofaveragehistaminewheal).

Niemeijeretal855

1993 2b Cohort Suspectedallergypatients(n=497)

SimultaneousID,pRAST,andclinicalhistorycompared.Standardizedgrasspollen,treepollen,cat,dustmitetested.

IdealcutoffforpositiveIDtestiswhealdiameter0.7timesthesizeofhistaminecontrol.IDhas83%predictivevaluevsRASTand77%predictivevaluevsclinicalhistory.

Escuderoetal860

1993 2b Cohort Rhinitispatients(n=66),31withAlternariaallergy

SPT,ID,challengetestsandinvitrosIgE.Clinicalhistoryandnasal/bronchialchallengeconsideredgoldstandard.

Forrhinitispatients,SPT,ID,andconjunctivalchallengeweremoresensitivethanserumsIgE.Alltestingmethodshadsimilarspecificity.

Pereraetal853

1975 2b Cohort Patientsreferredforallergydiagnostictesting(n=54)

PositiveclinicalhistoriescomparedtoRASTresultsandIDTresults

Highdegreesofskinreactivity(positiveIDtestsathighallergenconcentrations)correspondwithahigherrateofpositiveclinicalhistoryandpositiveRASTresults.

Reddyetal857

1978 2b Cohort Patientswithperennialrhinitis(n=34),negativeSPTfor60allergensbutwithatleastonepositiveIDtest

RAST,nasalprovocationandleukocytehistaminereleasecomparedtoIDpositivity,SPTnegativity

PatientswithonlyIDpositiveskintests(SPTnegative)didnothaveapositiveRASTnorapositiveleukocytehistaminerelease.Incontrast,SPTpositivitywasassociatedwithpositiveRASTtestandleukocytehistaminereleaseassay.WhenSPTarenegativeforperennialrhinitispatients,positiveIDtestsarenotlikelytoindicatethepresenceofIgE-mediatedallergy.

Peltier&Ryan844

2007 3b Cohort VolunteersunderwentsimultaneousSPTandIDTfor5commonallergens(n=134)

SPTwhealsizecomparedtoIDTendpoint

IDTendpointdirectlycorrelateswithSPTwhealsizeforallantigenstested,especiallyforBermuda,dustmite,andragweed.

Peltier&Ryan850

2006 3b Cohort VolunteerstestedsimultaneouslyformoldallergenswithSPTandIDT(n=86)

SPTwhealsizecomparedtoIDTendpoints

InsubjectswithclinicalsymptomsofallergytherewasadirectstatisticallysignificantcorrelationbetweenSPTwhealsizeandIDTendpoint.IDtestsidentified10%morepositiveresultscomparedtoSPTalone.

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LOE:levelofevidence;AR:allergicrhinitis;ID:intradermal;SPT:skinpricktest;SAR:seasonalallergicrhinitis;FEV1:forcedexpiratoryvolumein1second;1RAST:radioallergosorbenttest;pRAST:Phadebasradioallergosorbenttest;sIgE:antigen-specificimmunoglobulinE;IDT:intradermaldilutionaltitration;23

4

Purohitetal852

2005 3b Cohort Patientswithbirchpollenallergy(n=18)

CorrelationsamongIDTendpoint,serumsIgE,andprovocationthresholdsforbasophilhistaminerelease.

IDTendpointcorrelateddirectlywithbasophilhistaminereleaseinresponsetoallergenexposure.IDTendpointdidnotcorrelatewithrBetv1serumsIgElevel.

Schwindtetal858

2005 3b Cohort Patientswithallergy(n=97) Usingclinicalhistoryasgoldstandard,prick,IDandchallengetestresultscompared

IfSPTwithmulti-testIIdevicewasnegative,17%ofsubjectshadapositiveIDtestthatcorrespondedwithclinicalhistory.NoneofthesepositiveIDtestscorrespondedwithapositivenasalchallenge.Whenmulti-testIIresultsarenegative,positiveIDtestsareunlikelytoidentifyclinicallyrelevantaeroallergensensitivity.

Simonsetal851

2004 4 Retrospectivecohort

Allergyclinicpatients(n=34) PatientstestedforaeroallergensensitivitywithbothIDTandSPT.

AsignificantlygreaternumberofpatienttestedpositivewithIDTcomparedtoSPT.SPTwhealsizeandIDTendpointcorrelatedforseveralallergens.IDTmaybemoresensitivethanSPT.

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VIII.E.3.Blendedskintestingtechniques1

BlendedallergyskintestinginvolvesthecombineduseofSPTandintradermaltestingto2establishan‘end-point’foraspecificantigen.844,847,850Theprotocol,initiallydescribedbyKrouseand3Krouse,andreferredtoas‘modifiedquantitativetesting’(MQT),servesasanexampleofablended4technique.861MQTinvolvesanalgorithmwhereaSPTisusedinitiallytoapplyanantigen.Depending5upontheSPTresult,anintradermaltestmayormaynotbeapplied.844,847,850,861Withtheseresults,the6algorithmisusedtodetermineanendpointforeachantigentested.844,847,850,861Theendpointsignifies7theskinreactivitytotheappliedantigenonagradedscaleandisconsideredtobeasafestartingdose8fortheapplicationofAIT.861Thereisasmallamountofliteratureonblendedtechniques,butAITbased9upontheMQTresultshasbeenshowntobesuccessful,withimmunesystemalterationsinlinewith10otherskintestingtechniques.861[TableVIII.E.3.]11

Theadvantagesofblendedtechniques,suchasMQT,arethattheyprovidethepractitionerwith12bothqualitativedata(thepatientdemonstratessensitivity)andquantitativedata(endpoint;safe13startingdoseforAIT)forspecificantigensensitivitiesinlesstimethanIDT.844,847,850Disadvantages14includetheadditionalriskandtimeinvolvedinplacingintradermaltests.IncomparisontoIDTandin15vitrotestingmethods,MQThasbeenshowntobemorecost-effectivewhentheprevalenceofARina16populationis20%orhigher.862Whileblendedskintestingtechniquesmaybeconsideredinthe17evaluationofAR,especiallytodeterminethestartingpointforAIT,theevidencetosupportthis18techniqueisnotstrong.1920

• AggregateGradeofEvidence:D(Level3b:1study;Level4:4studies;TableVIII.E.3.)21• Benefit:AbilitytoestablishanendpointinlesstimethanIDT.22• Harm:Theadditionalrisks,includingsystemicoranaphylacticreactions,ofintradermaltests;23

additionaltimeanddiscomfort.24• Cost:Similartointradermaltesting.25• Benefits-HarmAssessment:Benefitoutweighsharm.�26• ValueJudgments:AITcanbeinitiatedfromSPTresultsalone;however,endpoint-basedAITmay27

decreasetimetoreachingtherapeuticdose.28• PolicyLevel:Option.29• Intervention:MQTisaskintestingtechniquethatmaybeusedtodetermineastartingpointfor30

AIT.31 32

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TableVIII.E.3.Evidencefortheroleofblendedskintestingtechniquesinthediagnosisofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Lewisetal862

2008 3b Systematicreviewwithcosteffectivenessanalysis

ComparisonofsIgE,intradermaltests,andMQTfromapayerperspective

MQTmostcost-effectivewhenpopulationprevalenceofARis20%orhigher.

Fornadley847 2014 4 Systematicreview Reviewofskintestingtechniques MQTisavalidformofskintesting.PeltierandRyan844

2007 4 Caseseries AdultswithAR(n=134)

1.Intradermaltestsfor5antigens2.SPTandsubsequentIDTfollowingMQTprotocolfor5antigens

MQTisasafealternativetoclassicIDTfordeterminingAITstartingdoses.

PeltierandRyan850

2006 4 Caseseries AdultswithAR(n=86)

1.Intradermaltestsfor6moldantigens2.MQTfor6moldantigens

MQT-basedtestingisasafemethodfordeterminingstartingAITdosesforfungalallergens.

KrouseandKrouse861

2006 4 Caseseries AdultswithAR(n=9)

1.MQT2.IgEandIgG4levelsfor3antigens3.SNOT-20,AOS,RSDI

MQT-basedAITdemonstratesimmunesystemchangesandQOLimprovement.

LOE:levelofevidence;sIgE:antigen-specificimmunoglobulinE;IDT:MQT:modifiedquantitativetesting;AR:allergicrhinitis;SPT:skinpricktesting;AIT:2allergenimmunotherapy;IgG4:immunoglobulinG4;SNOT-20:SinonasalOutcomeTest20-question;AOS:AllergyOutcomeSurvey;RSDI:Rhinosinusitis3DisabilityIndex;QOL:qualityoflife45 6

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VIII.E.4.Issuesthataffecttheperformanceorinterpretationofskintests1VIII.E.4.a.Medications2

Thewhealandflarereactionseeninallergyskintestingdependsuponthephysiologicactionsof3histaminereleasedfrommastcellsupondegranulation.Thus,anymedicationsthatinhibitmastcell4degranulationorthatfunctionashistamineH1receptorantagonistshavethepotentialtosuppress5appropriateskintestresponses.ThesuppressiveeffectsofH1antihistaminesonallergenandhistamine6inducedwhealandflareresponsesvarygreatly,863,864andthedurationofthissuppressiondependsupon7theskintissueconcentrationandhalf-lifeoftheseagents.865,866Infact,skintestsuppressioncanbeused8asabiologicalassayfortheonsetanddurationofactionofantihistamines.865Agentssuchasastemizole9(nowremovedfromthemarketduetoQTprolongation)havethepotentialtosuppressskintest10reactionsforaperiodofweeksaftercessation.867However,mostantihistaminesonlysuppressskintest11responsesforaperiodof2-7daysaftercessation.867,868Topicallyadministeredantihistamineshavethe12potentialtosuppressskinwhealandflareresponses.Onerandomizedplacebo-controlledstudyshowed13that14daysofazelastinenasalspraytreatmentreducedthehistamineinducedwhealandflare14response,andthissuppressiondisappearedby48hoursaftercessation.869[TableVIII.E.4.a-1]15

Randomized,placebo-controlledtrialshavedemonstratedthatH2receptorantagonistssuchas16ranitidinecanreduceskinwhealingresponses,870,871andonestudyshowedanadditiveeffectofH1and17H2antihistaminesonskinwhealsuppression.872Someantidepressantshavethepotentialtosuppress18skinwhealandflareresponses,inparticularthetricyclicantidepressantsthathaveantihistaminic19properties(suchasdoxepin).873However,newerclassesofantidepressantssuchasselectiveserotonin20reuptakeinhibitors(SSRI)donotappeartoaffectallergyskintestresponses.87421

Recombinanthumanizedanti-IgEmonoclonalantibody(mAb),omalizumab,interfereswithIgE22mediatedmastcelldegranulationreactionsintheallergyskintestresponse.Arandomizedplacebo-23controlledtrialdemonstratedasignificantreductioninallergen-inducedskinwhealingafter4monthsof24treatment.874Omalizumabappearstosuppressskintestreactivityintandemwithdramaticreductionsin25serumfreeIgE,andallergyskintestresponsesreturntonormalwithin8weeksofdiscontinuation.87526

Leukotrienereceptorantagonists(LTRAs)donotappeartointerferewithallergyskintest27results.HillandKrouse876aswellasSimonsetal866foundnoeffectofmontelukastonintradermalskin28testresultsinallergicsubjects.Cuhadarogluetal877foundnochangeinskinpricktestresultsinallergic29subjectsbeforeandtreatmentwithzafirlukast.30

Ingeneral,thehighestlevelevidenceshowsthatsystemicsteroidtreatmenthasnoeffecton31SPTandintradermaltestresults,878,879thoughsomelessrigorousretrospectivestudiessuggestthat32systemicsteroidtreatmentcouldaffectskinwhealingresponses.880,881Topicalsteroidtreatmenthas33beendemonstratedtosuppressthewhealandflarereactionintreatedskinareas,creatingthe34possibilityoffalsenegativetestresults.882-885Nostudieswereidentifiedthatexaminedtheeffectof35intranasalorinhaledsteroidsonskintestresults.36

Theeffectsofmanyclassesofmedicationsonallergyskintestresponsesremaininadequately37studied.Benzodiazepineshavebeenimplicatedaspossiblysuppressingskintestresponses.886,887The38calcineurininhibitortacrolimuswasshowntoinhibitskinpricktestwhealing,885whereasastudyofa39similardrug,pimecrolimus,didnotshowanyeffectonskinwhealingresponses.888Thepharmacologic40effectsofherbalpreparationsaregenerallyunstudied,anditisunclearwhichoftheseagentscould41

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interferewithallergyskintestresponses.Moreetal889performedadouble-blindplacebo-controlled,1singledosecrossoverstudyin15healthyvolunteers,examiningthehistamineinducedskintest2response.Noneofthe23herbalsupplementstestedcausedsuppressionofthehistamineinduced3whealresponse.4 Therearemanyclassesofmedicationsforwhichtheactualimpactonallergyskintestingare5unknown.Tomitigateagainsttheriskoffalsenegativeskintestresultsinducedbymedications,all6allergytestingshouldbeperformedafterapplicationofappropriatepositivecontrols(usuallyhistamine)7toensurethatthehistamineinducedskintestreactionisintactatthetimeoftesting.SeeTable8VIII.E.4.a-1.foracomprehensivereview,withAggregateGradesofEvidenceinTableVIII.E.4.a-2. 9

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1TableVIII.E.4.a-1Evidencefortheeffectofmedicationonallergyskintestreactivity2

Study Year LOE Studydesign Studygroups Clinicalendpoints ConclusionKupczyketal871

2007 1b DBPCT,crossover

Atopicsubjects(n=21).SPTwithhistamine,codeine,allergen,negativecontrolafter5daysofranitidine,loratadine,orplacebo

Wheal,flaremeasuredinmm.Pruritismeasuredwith10-pointscale

Relativetoplacebo,ranitidinereducedhistaminewheal(41%),flare(16%);allergenwheal(23%),andflare(22%).Loratadinereducedhistaminewheal(51%)andflare(33%);allergenwheal(40%)andflare(44%)respectively.Ranitidineandloratadinebothreducedpruritisscoredbyalmost30%.

Spergeletal888

2004 1b RDBT,withinsubjectcomparison

AtopicdermatitisandARorasthma(n=12adults).Vehicleorpimecrolimusoneacharm.

Allergenskinpricktestwhealandflare,beforeandaftertopical1%pimecrolimuscream

1%pimecrolimuscreamdoesnotsignificantlyimpactallergyskintestresults.

Hill&Krouse876

2003 1b RDBPCT Atopicsubjects(n=23) Intradermalwhealingresponseafterloratadine,montelukastorplacebotreatment

Loratadine,butnotmontelukast,reducedtheintradermalwhealdiameterafterallergeninjection.

Moreetal889 2003 1b RDBPCT Healthyvolunteers(n=15).Singleblindeddoseofplacebo,fexofenadine,23otherherbalpreparations.Minimum72hrwashoutperiodbetweendoses.

Histamine1mg/mLwhealatbaselineand4hoursaftersingledoseofherbalpreparation.

FexofenadinesignificantlyreducedSPTwhealsizecomparedtoplacebo.Noneofthe23herbalpreparationstestedshowedastatisticallysignificanteffectonwhealsizecomparedtoplacebo.

Nogaetal890 2003 1b RDBPCT Moderate-severeasthmatics(n=35)treatedwithplacebooromalizumab.

Skinpricktestsforallergenbeforeand16weeksaftertreatment

OmalizumabcausedsignificantreductioninSPTwhealsizecomparedtoplacebo.

Pearlmanetal869

2003 1b RPCT SARpatients(n=78) Inhibitionofhistamineinducedwhealaftersingledoseor2weeksofazelastinenasalspray

2weeksofazelastineinhibitedwhealandflareinsomepatients.Histamineskintestresponsesreturnedtobaselineat48hoursaftercessation.

Simons&Simons865

1997 1b RDBPCT,crossover

Adultmales(n=20) SPTwhealandflareresponseaftersingledaydosingofPOfexofenadineandloratadine

FexofenadineandloratadinebothinhibitedSPTwhealandflareresponsefor24hrs.

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Miller&Nelson870

1989 1b RDBT Healthysubjects(n=23) Histamineandcompound48/80inducedskinprickwhealandflareafterplaceboorraniditine150mgx7doses

Ranitidinereducedthehistamineinducedwhealandflareby22%.Nosignificantreductionincompound48/80inducedwhealandflare.

Pipkornetal891

1989 1b RDBPCT ARpatients(n=10) AllergenSPTwhealandflarebeforeandafter2to4weeksoftwicedailyclobetasolcreamappliedtoforearmskintestsites

Clobetasoltreatedskinhadsignificantlyreducedwhealandflareresponsetoallergen.Histamineinducedwhealwasreducedat4weeksbytopicalsteroid.

Andersson&Pipkorn883

1987 1b DBPCT ARpatients(n=17) Effectoftopicalclobetosol(BIDapplicationfor1week)onhistamineandallergenSPTresponse.

Topicalclobetosolsignificantlysuppressesallergeninducedwhealandflareresponse.

Slott&Zweiman879

1974 1b DBPCT,crossover

Atopicpatients(n=15) Intradermalwhealsizedifferencesforhistamine,allergen,andcompound48/80after7daysofmethylprednisolone24mgperday

Noeffectof7daysmethylprednisoloneonintradermalwhealsize.

Cooketal868 1973 1b Doubleblindrandomizedcontrolledstudy

ARpatients(n=18adults) Intradermalwhealsizesuppressionafter3daycourseofchlorpheniramine,tripelennamine,promethazine,hydroxyzineanddiphenhydramine

Allantihistaminessuppressedwhealsizetovaryingdegrees.Hydroxyzinesuppressedresponsesfor4daysaftercessationvs.2daysfordiphenhydramine.

Isiketal874 2011 2b Cohort PatientsonSSRIsfordepression(n=24)

HistamineandallergeninducedpricktestwhealresponsesbeforeandafterstartingSSRItreatment.

SSRIsfluoxetine,sertraline,andescitalopramdidnotsignificantlyaffectskinprickwhealingresponses.

Correnetal875

2008 2b Cohort PARpatients(n=40) Dustmiteallergenskintestreactivity(titratedpricktests)beforeduringandafteromalizumabtherapy.

Omalizumab(anti-IgE)therapysignificantlyreducesallergyskintestreactivity.

Gradman&Wolthers885

2008 2b Randomizedcrossovercohort

Atopiceczemapatients(n=12children)

SPTfor10allergensbeforeandafteractivetreatmentwithtopicalmometasoneortopicaltacrolimus.Skintestsiteswerepresumablytreateddailyforatotalof2weeks.

TopicalmometasoneandtacrolimussignificantlyreducedSPTwhealdiameter.Topicalmometasonealsoreducedhistamineinducedwheal,whiletacrolimusdidnot.

Narasimhaetal882

2005 2b Cohort 26subjects Effectoftopicalclobetasolapplicationonhistamineinducedwhealresponse.

Topicalclobetasolinhibitedskinprickwhealingresponsetohistamineatthesiteoftopicalsteroidapplicationinadoseanddurationdependentmanner.

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Cuhadarogluetal877

2001 2b Cohort 1.asthma/ARpatients(n=9)2.controls(n=8)

SPTtohistamineandallergensbeforeandafterzafirlukast20mgBIDforatleast5days.

Zafirlukastdidnotsuppresshistamineorallergeninducedwhealandflareresponse.

DesRochesetal878

1996 2b Cohort 1.steroiddependentasthmapatients(n=33)2.asthmaand/orAR(n=66)

CodeineanddustmiteinducedSPTresponsewithorwithoutexposuretolongtermsystemicsteroids.

SystemicsteroidtherapydoesnotalterSPTreactivitytocodeineorallergen.

Almindetal867

1988 2b Cohort Healthyindividuals(n=23) EffectonhistamineSPTwhealsizeafter2-daytreatmentwithdexchlorfeniramine,cyproheptadine,astemizole,loratidine,terfenadine.DurationofSPTwhealsuppressionaftercessation.

AllantihistaminessuppressedSPTwhealresponsetohistamine.Durationofsuppressionexceeded72hoursforallagentstested.

Raoetal873 1988 2b Cohort Healthysubjects(n=33) Histaminepricktestsfor1weekaftersingledoseofdesipramineordoxepin.

Desipramineinhibitswhealresponsefor2days;doxepininhibitswhealresponsefor4days.

Longetal863 1985 2b Cohort 18subjects.10hadpositiveSPTtograssorragweedallergens.

Effectof6differentantihistaminesonSPTwhealandflarereactiontohistamineormorphineorrelevantaeroallergen.Effectofhydroxyzyineandchlorpheniramineonskintestresponsestootherantihistamineclasses.

AntihistaminesvariedintheirabilitytosuppressSPTwhealresponse.Administrationofhydroxyzinefor3weeksleadstoreducedskintestsuppressionfortheantihistaminestested,suggestinginductiontotolerancetoantihistamineeffects.

Phillipsetal864

1983 2b Cohort Atopicsubjects(n=10) Inhibitionofallergenandhistamineinducedwhealsbylocalintradermalantihistamineandcromoglycateinjection.

Antihistaminesketotifen,clemastine,andchlorpheniraminesignificantlyinhibitskinwhealingresponses.Sodiumcromoglycatehadnoeffect.

Harvey&Schocket872

1980 2b Cohort Healthysubjects(n=10) Titratedintradermalhistaminewhealbeforeandafter.treatmentwithhydroxyzine,cimetidineorboth.

Hydroxyzineinhibitedcutaneouswhealresponsetohistamine.Cimetidinedidnot.However,the2togetherproducedsignificantlyreducedwhealingcomparedtoeitheralone.

Gengetal881 2015 3b Case-control 1.caseswithnegativehistaminecontroltestsdespiteavoidanceofantihistaminicmedications(n=52)

ORthatmultipleclinicalvariablesincludingmedicationusepredictnegativehistaminecontroltest.

ICUstay,systemicsteroiduse,H2blockersandolderageassociatedwithnegativehistaminecontroltest.

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2.controls(n=125)Shahetal886 2010 4 Retrospective

cohortHistamineSPTresponsesinpatientswithvariableexposuretoavarietyofmedications

SPTwhealareaandSPTpositivityasfunctionofmedicationexposureandtimesincelastdose.

H1antagonistsimpairedwhealingresponseswithin3daysofdiscontinuation;tricyclicantidepressants,benzodiazepines,mirtazapine,quetiapinehadwhealsuppression;otherSSRIsandSNRIsaswellasH2antagonistiswerenotindependentlyassociatedwithwhealsuppression.

Olsonetal880 1990 4 Retrospectivecohort

1.atopicpatientswithchronicsystemicsteroidtreatment(n=25)2.atopicpatientswithoutsystemicsteroiduse(n=25)

Intradermalskintestreactivitytocodeineandhistamine.

Chronicsystemicsteroidusereducescodeineinducedwhealresponsebutnothistamineinducedwhealresponse.

Duenas-Laitaetal887

2009 4 Cohort Drugabuserstakingalprazolam2mgTID(n=42)

Histamine(10mg/mL)SPT. AllsubjectstakingalprazolamhadnegativehistamineSPT.

LOE:levelofevidence;DBPCT:double-blindplacebocontrolledtrial;RDBT:randomizeddoubleblindtrial;RDBPCT:randomizeddouble-blindplacebo1controlledtrial;SPT:skinpricktest;RPCT:randomizedplacebocontrolledtrial;SAR:seasonalallergicrhinitis;PO:peros(bymouth);AR:allergicrhinitis;BID:2twiceaday;SSRI:selectiveserotoninreuptakeinhibitor;PAR:perennialallergicrhinitis;IgE:immunoglobulinE;ICU:intensivecareunit;SNRI:selective3norepinephrinereuptakeinhibitor456 7

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TableVIII.E.4.a-2Aggregategradesofevidence:medicationsthataffectallergyskintesting1H1antihistamines AggregateGradeofEvidence:A(Level1b:2studies,Level2b:3studies)

• Shouldbediscontinued2-7dayspriortotesting.H2antihistamines AggregateGradeofEvidence:B(Level1b:2studies)

• Ranitidinesuppressesskinwhealingresponse,mayresultinfalsenegatives.Topicalantihistamines(nasal,ocular) AggregateGradeofEvidence:UnabletodeterminefromoneLevel1bstudy.

• Shouldbediscontinued2dayspriortotesting.Anti-IgE(omalizumab) AggregateGradeofEvidence:A(Level1b:2studies)

• Resultsinnegativeallergyskintestresults.Leukotrienereceptorantagonists AggregateGradeofEvidence:A(Level1b:2studies,Level2b:1study)

• Maybecontinuedduringtesting.Tricyclicantidepressants AggregateGradeofEvidence:UnabletodeterminefromoneLevel2bstudy.

• Agentswithantihistaminicpropertiessuppressallergyskintestresponses.Topical(cutaneous)corticosteroids AggregateGradeofEvidence:A(Level1b:2studies,Level2b:onestudy)

• Skintestsshouldnotbeplacedatsitesofchronictopicalsteroidtreatment.Systemiccorticosteroids AggregateGradeofEvidence:C(Noeffect–Level1b:1study,Level2b:1study;Suppression–

Level3b:1study,Level4:1study)• Systemiccorticosteroidtreatmentdoesnotsignificantlyimpairskintestresponses.

Selectiveserotoninreuptakeinhibitors(SSRIs) AggregateGradeofEvidence:B(Level2b:1study,Level4:1study)• Doesnotsuppressallergyskintestresponse.

Benzodiazepines AggregateGradeofEvidence:C(Level4:1study,Level5:1casereport)• Maysuppressskintestresponses.

Topicalcalcineurininhibitors(i.e.tacrolimus,picrolimus) AggregateGradeofEvidence:D(Level1b:1study,Level2b:1study–resultsconflicting)• Conflictingresultsregardingskintestsuppression.

23 4

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VIII.E.4.b.Skinconditions1

TheusefulnessofallergyskintestingdependsupontheabilitytodetectaTypeIhypersensitivity2reactionafterallergenintroductionintotheskin.Abnormalskin(e.g.dermatitis)maynotrespond3appropriatelytohistamine,glycerin,orallergen.Additionally,thephysicaltraumaofprick/punctureor4intradermaltestingmayinducealocalinflammatoryresponse.Thewhealandflarereactionalsomaybe5difficulttodetectduetopre-existingskinchanges.Further,skincolormayinhibittheabilitytovisualize6theflarereaction,especiallyindarkerskinnedindividuals.7

Commonsensedictatesthatallergyskintestingshouldnotbeperformedatsitesofactive8dermatitis,butclinicalstudiestoinvestigatethisphenomenonarelacking.Individualswith9dermatographismmayhaveexaggeratedresponsestoallergyskintesting,requiringcloseattentionto10theresultsofnegativecontroltests.Insomecases,itmaybepreferabletoperforminvitrospecificIgE11testinginpatientwithskindiseaseordermatographism,butthisisnotbasedondataoroutcomesfrom12controlledstudies.13

Duetothelackofpublishedstudiesonthistopic,anAggregateGradeofEvidenceandevidence14basedrecommendationcannotbeprovided.151617VIII.F.Invitrotesting18VIII.F.1.SerumtotalIgE(tIgE)19

TheliteratureaddressingtheroleofserumtIgEintheevaluationanddiagnosisofallergic20diseaseoffersconflictingoutcomesanddivergentopinions.Positivestudies,demonstratingarelevant21roleofmeasuringtIgEintheevaluationanddiagnosisofAR,arelistedinTableVIII.F.1-1.Negative22studiesthatreportalimitedroleofmeasuringtIgEarelistedinTableVIII.F.1-2.Whentakentogether,23however,thisbodyofliteratureprovidessomeinformationthatcaninformdecisionsrelatedtothe24utilityoftIgEindirectingpatientcaredecisions.25

PerhapsthestrongeststatementthatcanbemadeonbehalfoftIgEisitsabilitytogenerally26identifypatientsorpopulationswithatopicorallergicdisease.Forexample,AndoandShima892reported27thattIgEishigherinchildrenwithARthaninpeerswithNAR.Marinhoetal893foundaborderline28associationbetweentIgEandcurrentrhinitis.Inaretrospectivestudy,Kalpakliogluetal894reportedthat29tIgEishigherinARthaninNAR.Jungetal895conductedaprospectivestudythatshowedatIgEcut-offof3098.7IU/mLasastrongpredictorofAR.Saloetal454performedacross-sectionalstudyreporting31significantassociationsbetweentIgElevelsandcurrenthayfeverindifferentageclasses.Demirjianet32al896demonstratedthatatIgElevelover140IU/mLissuggestiveofanatopiccauseforpatientswith33clinicalsymptomsofAR.Hatcheretal897showedthatanelevatedtIgEinthepresenceofanegative34inhalant-specificIgEscreenmaysuggestthepresenceofunidentifiedinhalantallergensensitizationor35chronicrespiratoryinflammatorydiseaseotherthanAR.Karlietal898reportedthattIgEishelpfulin36confirmingthediagnosisbutitcannotberecommendedforroutineuseduetoitshighcostandthetime37toperformthetest.Chungetal899reportedthattIgE(cut-offvalue150IU/mL)isareliablebiomarkerfor38ARdiagnosis.Jacobsetal900reportedafavorableroleofmeasuringtIgEindiagnosingAR,mainlyiflevels39arehigherthan100IU/mL.Lietal901observedthattIgEishigherinARthaninNARinaretrospective40study.Finally,ina2-yearfollow-upstudy,Parketal902showedthatinsubjectswithoutallergic41

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sensitizationattheinitialexamination,tIgEgreaterthan17.7IU/mLwasassociatedwiththeriskfor1allergicsensitization,whereasinpatientswithallergicsymptomsbutnegativeSPTresultsattheinitial2examination,tIgEgreaterthan17.4IU/mLwasassociatedwithnewlydevelopedallergicsensitization.3

Incontrast,thereare4studieswithnegativeresultsinthesettingoftIgEandAR/allergy.4Satwanietal903reportednoassociationbetweentIgElevelandARdiagnosis.Tuetal904demonstrated5aninsufficientdiagnosticaccuracyoftIgElevelstodetectallergicdiseasesregardlessofwhichcutoff6valueisbeingused;tIgEwaslinkedmoretoatopythandirectlytosymptoms.Inthesamefollow-up7studynotedabove,Parketal902reportedthatinsubjectswithoutallergicsensitizationattheinitial8examination,tIgElessthan17.7IU/mLwasnotassociatedwithnewlydevelopedallergicnasal9symptoms.Finally,Tayetal905conductedaretrospectiveanalysisinpatientswithhightIgElevels(>100010IU/mL)andconcludedthattheelevatedIgElevelinARisoflimitedclinical/diagnosticvalue.11

AnotheropportunityofferedbytIgEassessmentistheratiobetweenallergen-specificandtIgE.12IthasbeenreportedthatthisratiomightbeusefulinthepredictionofAITeffectiveness,906-908as13recentlyoutlinedbytheEAACIPositionPaper.90914

Insummary,tIgEisfrequentlyincreasedinAR,buttheclinicalutilityismodestincommon15practice.Infact,theliteratureisadivergentsetofstudiesthatfailstofindaconsistentroleorvaluefor16tIgEinthemanagementofARpatients.1718

• AggregateGradeofEvidence:C(Level2b:5studies;Level3b:10studies;TablesVIII.F.1-1.and19VIII.F.1-2.)20

• Benefit:Possibilitytosuspectallergyinawidescreening.21• Harm:Lowleveldoesnotexcludeallergy.22• Cost:Modestcostoftest.23• Benefits-HarmAssessment:Slightpreponderanceofbenefitoverharm.Inaddition,theratio24

tIgE/sIgEmaybeuseful.25• ValueJudgments:Theevidencedoesnotsupportaroutineuse.26• PolicyLevel:Option27• Intervention:TotalIgEassessmentisanoptiontoassessatopicstatus.28

29

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TableVIII.F.1-1EvidencesupportingtheuseoftotalIgEinallergicrhinitisorallergydiagnosis1

Study Year LOE Studydesign Studygroups Endpoint ConclusionParketal

902 2016 2b Prospective

cohort

313schoolchildren,2-year

follow-upstudy

Initialexamination:no

allergicsensitization,

serumtIgE>17.7IU/mL

Associatedwiththeriskforallergicsensitization

(sensitivity:46.3%;specificity:85.3%;OR:4.8).

Initialexamination:allergic

symptomsbutnegative

SPT,serumtIgE>17.4

IU/mL

Associatedwithnewlydevelopedallergic

sensitization(sensitivity:69.9%;specificity:

100.0%).

Demirjianet

al896

2012 2b Prospective

cohort

Patientsreferredtoallergy

clinic.

Totalpatients(n=358,184with

rhinitis),meanage57years.

serumtIgE(IU/mL),

continuousvariable

tIgElevels>140IU/mLissuggestiveofanatopic

etiologyforpatientswithrhinitis.

Jungetal895

2011 2b Prospective

cohort

PatientswithARsymptoms

(n=442),medianage33years.

SerumtIgE>98.7IU/mL tIgEcut-off:98.7IU/mLisastrongpredictorof

AR.

(OR6.93,CI4.19-9.62,p<0.001),(AUC:0.79

[0.74-0.83]),PPV:71.3%,NPV:73.7%.

Marinhoet

al893

2007 2b Whole-

population

birthcohort

478childrenfromMAAS SerumtIgE(kU/L),

continuousvariable

Borderlineassociationwithcurrentrhinitis

(UnAdjOR*1.2,CI1.02-1.3),notsignificantat

multivariateanalysis.Associationwithcurrent

rhinoconjunctivitis(UnAdjOR*1.3,CI1.1-1.5),

notsignificantatmultivariateanalysis.

Lietal901 2016 3b Retrospective

caseseries

Patientsfromotolaryngology

clinic.

Totalpatients(N=610adults,

349withAR),medianage27.0

years.

SerumtIgE(IU/mL),

continuousvariable

SerumtIgEwerehigherinAR(166.0[58.4-

422.5]IU/mL)thaninNARpts(68.8[24.5-

141.0])IU/mL.p<0.001

Chungetal899 2014

3b Retrospective

caseseries

Patientsfromotolaryngology

clinic.

Totalpatients(n=1073children

andadults,753withrhinitis),

meanage36.9years.

SerumtIgElevel>150

IU/mL

SerumtIgElevels(cutoffvalue:150IU/mL)has

goodPPV(89.6%),andNPV(10%)intheinvitrodiagnosisofAR(AUC:0.88).

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ICAR:AllergicRhinitis140

Jacobsetal900 2014 3b Cross-

sectional

547children(6-14years)from

randomlyselectedhouseholds;

265withskintestpositiveAR.

LogserumtIgE(kU/L) serumtIgElevelaresignificantlyassociated

withincreasedoddsofskintestpositiveARin

childrenwithasthma(OR2.3,CI1.5-3.5)but

notwiththosewithoutasthma(OR1.6,CI0.9-

2.8).ARcanbediagnosedifserumtIgE=>100

kU/Lbothinasthmatics(AUC:0.77[0.72-0.82],

PPV:85.1%,NPV:68%)andinnon-asthmatics

(AUC:0.84[0.79-0.89],PPV:77.8%,NPV:

90.9%).

Hatcheret

al897

2013 3b Retrospective

caseseries,

followedbya

prospective

study

1.30pts(>=6years)witha

negativeallergyscreenand

serumtIgE>116kU/L2.26controlptswithnegative

allergyscreenandstIgE<2.95kU/L

(Chronicsinusitisin76.9%of

studygroupand19.2%of

controlgroup[p<0.0001].)

SerumtIgE(kU/mL),

continuousvariable

ElevatedserumtIgEinthepresenceofa

negativeinhalant-specificIgEscreenmay

suggestthepresenceofunidentifiedinhalant

allergensensitizationorchronicrespiratory

inflammatorydiseaseotherthanAR.Mean

serumtIgEofthestudygroupwas363.3kU/L

vs.controlgroup2.2kU/L,p<0.0001.

Karlietal898 2013 3b Retrospective

caseseries

Patientsfromotolaryngology

clinicwithatleast2complaints

ofnasalitching,nasal

obstruction,rhinorrhea,and

sneezing,and/orpresumedAR

(n=295),meanage33.9years.

SerumtIgE(U/mL),

continuousvariable

tIgE<20U/mLin23.7%,tIgE20-100U/mLin

38.3%,tIgE>100U/mL33.8%.

tIgEisafactorinconfirmingthediagnosis,but

routineuseisnotrecommendedduetohigh

costandtestingtime.

Saloetal454 2011 3b Cross-

sectional

7,398subjects(>6years)from

NHANES2005-2006.

SerumtIgE(kU/L),

continuousvariable

AssociationwithcurrentHF(OR1.9,CI1.4-2.4).

Children(6-17years) SerumtIgE>40.8kU/L

(median).

AssociationwithcurrentHF(OR2.1,CI1.4-3.1).

SerumtIgE(kU/L),

continuousvariable

AssociationwithcurrentHF(OR2.2,CI1.1-4.4).

Adults(>18years) SerumtIgE(kU/L),

continuousvariable

AssociationwithcurrentHF(OR1.9,CI1.4-2.6).

Male SerumtIgE(kU/L),

continuousvariable

AssociationwithcurrentHF(OR2.1,1.6-2.8).

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ICAR:AllergicRhinitis141

Female SerumtIgE(kU/L),

continuousvariable

AssociationwithcurrentHF(OR1.7,1.2-2.3).

Kalpaklioglu

etal894

2009 3b Retropective

caseseries

Consecutiveandunselectedpts

fromatertiarycareclinic.

(n=323,205withAR),meanage

31.7years.

SerumtIgE(IU/mL),

continuousvariable

SerumtIgEhigherinAR(261)thaninNAR

(126),p<0.01.

Ando&

Shima892

2007 3b Cross-

sectional

Schoolchildren(n=98withAR),

9-10yearsold

SerumtIgElevels(IU/mL)

expressedasgeometric

means,continuous

variable

SerumtIgEhigherinAR(230.4,CI157.6-337.0)

thaninNAR(96.5,CI76.9-121.1),p<0.001

*TheORindicatesanincreaseintheriskofcurrentrhinitis/chronicRCperlogunitincreaseofIgElevels.1

Allreportedoddsratio(OR)areadjustedunlessdifferentlyspecifiedandarereportedwith95%confidenceintervalsinparentheses.2

IgE:ImmunoglobulinE;LOE:levelofevidence;tIgE:totalimmunoglobulinE;OR:oddsratio;CI:95%confidenceinterval;AUC:areaunderthecurve;SPT:skin3

pricktest;AR:allergicrhinitis;PPV:positivepredictivevalue;NPV:negativepredictivevalue;MAAS:ManchesterAsthmaandAllergyStudy;UnAdj:unadjusted4

oddsratio;NAR:non-allergicrhinitis;NHANES:TheNationalHealthandNutritionExaminationSurvey;HF:hayfever5

6

TableVIII.F.1-2EvidenceindicatingalimitedrolefortheuseoftotalIgEinallergicrhinitisorallergydiagnosis7

Study Year LOE Studydesign Studygroups Endpoint ConclusionParketal

902 2016 2b Prospective

cohort

313schoolchildren,2-yearfollow-

upstudy

Initialexamination:no

allergicsensitization,

serumtIgE<17.7IU/mL

Noassociationwithnewlydeveloped

allergicnasalsymptoms.

Tuetal904 2013 2b Population-based

cohort

1,321children(5-18yrs)from

PATCHstudy

SerumtIgE(kU/L) AUCofserumtIgEfordiagnosing

rhinitis:0.70.

SerumtIgE>77.7kU/L Sensitivity:74.7%,specificity:56.6%,

PPV:41.9%,NPV:84.2%

SerumtIgE>164.3kU/L Sensitivity:57.0%,specificity:71.3%,

PPV:45.5%,NPV:79.8%

SerumtIgE>100kU/L Sensitivity:68.1%,specificity:62.5%,

PPV:43.2%,NPV:82.4%

Insufficientdiagnosticaccuracyof

serumtIgElevelstodetectallergic

diseasesregardlessofcutoffvalue

used.SerumtIgEislinkedmoreto

atopythandirectlytosymptoms.

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ICAR:AllergicRhinitis142

Tayetal905

2016 3b Retrospective

caseseries

352ptswithserumtIgE>1000

IU/mLattributabletoatopic

eczema,allergicbroncho-

pulmonaryaspergillosis,helminthic

infectionandrareprimary

immunodeficiencies.(n=84with

AR).

serumtIgE(IU/mL) TheelevatedIgElevelinARisof

limiteddiagnosticutility.

Satwaniet

al903

2009 3b Cross-sectional 258pts(6months-12years)froma

PediatricMedicineUnit;(n=172

withAR).

ElevatedserumtIgE NoassociationoftIgEandAR

(UnAdjOR1.3,CI0.8-2.2).

IgE:ImmunoglobulinE;LOE:levelofevidence;tIgE:totalimmunoglobulinE;PATCH:PredictionofAllergiesinTaiwaneseChildren;AUC:areaunderthecurve;1

PPV:positivepredictivevalue;NPV:negativepredictivevalue;AR:allergicrhinitis;UnAdj:unadjustedoddsratio;CI:95%confidenceinterval2

3

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VIII.F.2.Serumantigen-specificIgE(sIgE)1

sIgEtestingbecamecommerciallyavailablein1967withanassayreliantonradioactiveanti-IgE2forlabelingIgEinserum.910,911Thisradioactivetechnique,knownasRAST,haslargelybeenreplacedwith3othertechnologiesusingenzymatically-drivenreactionstoproduceachemiluminescent,colorimetric,or4fluorimetricreactionquantifiedor“read”byanautoanalyzer.910,912Theprocessisasfollows:allergens5areboundtoasubstrate(typicallyintheformofasolidorliquidphase)towhichapatient’sserumis6added.sIgEinthepatient’sserumthenbindstotheallergenonthesubstrate.Excessserumiswashed7offandwithit,anyunboundIgE.Non-humananti-IgEantibodiestaggedbyamarkeraresubsequently8addedandbindanycorrespondingsIgEthatisimmobilized.Excessanti-IgEantibodiesarethenwashed9offandtheautoanalyzerreadstheintensityoftheradioactive,chemiluminescent,colorimetricor10fluorimetricreaction.TheintensityofthereactionisproportionaltotheamountofsIgEintheserum11andareportisgenerated.AlltestsapprovedbytheUSFDAarecalibratedagainstaWorldHealth12Organization(WHO)tIgEstandardserum.913Differentunitsarereporteddependingontheassaysystem13used,butmanyvendorsofferconversionfactors.14

SerumsIgEtestingoffersseveralbenefits.ThesafetyprofileofserumsIgEtestingisthebestof15allavailableallergytestsastheriskforanaphylaxisisnon-existent.Furthermore,theuseofskintesting16islimitedbythepresenceofcertainmedicalconditions.Inpatientswhereskintestingiscontraindicated17orpotentiallyimpactedbymedicationsorskinconditions,sIgEtestingoffersasafeandeffectiveoption18fordeterminingthepresenceofsensitizationasabiomarkerofIgE-mediatedhypersensitivitiesand19confirmingspecificallergentriggers.20

TherearesomeimportantsimilaritiesanddifferencesbetweenskintestingandsIgEtestingthat21warrantdiscussion.First,studieshaveindicatedthatwhilepatientsareacceptingofbothinvitroandin22vivoallergytesting,skintestingmaybepreferredbecauseitallowsforimmediatefeedbackandvisible23results.914Second,neitherskinorsIgEtestingcandefinitivelypredicttheseverityofapatient’s24sensitivitytoanaeroallergen.Third,cross-reactingallergensandpoly-sensitizationscanconfoundboth25skinandinvitrotesting,leadingtofalsepositiveresults.915Incontrasttoskintesting,sIgEtestsusemore26extensivelyquality-controlledallergensanddefinedhumanserumcontrols.Whereasskintesting27dependsupontheclinicianadministeringandinterpretingthetest,sIgEtestshavecoefficientsof28variationlessthan15%intheCollegeofAmericanPathologistsdiagnosticallergyproficiencysurvey,29whichisperformed3timesperyearbyallClinicalLaboratoryImprovementActof1988licensedClinical30ImmunologyLaboratories.However,severalreportshavedemonstratedpooragreementinresultsfrom31testingthesameserabydifferentcommerciallyavailableassaysystems.916,917Aswithskintesting,sIgE32resultsshouldbeinterpretedwithinthecontextofthepatient’sclinicalhistory.33

OneapplicationofsIgEtechnologyismulti-allergenscreensconsistingof10-15allergens.In34scenarioswhereaclinicianwishestoeitherruleinoroutallergyasadrivingfactorbehindsymptoms35withoutsubjectingpatientstothetimeandcostofafulltestingbattery,sIgEscreensareanoption.36Generally,eitheranegativeorpositiveresultisgiven.Screenstestingfor10-12allergens(i.e.molds,37regionalpollens,catandmite)arepositiveinupto95%ofpatientswhowouldhavetestedpositiveona38largerbattery.912,918Therefore,theyareeffectiveinidentifyingallergicpatients.Conversely,ifthetestis39negative,thereisevidencethatthisreliablysupportsanabsenceofallergy.910Asecondapplicationlies40inthefactthatlevelsofsIgEmaycorrelatewithseverityofARsymptoms.919-923Giventhatpatientswith41

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moreseveresymptomshavebeenshowntorespondbettertoAITthanthosewithmildersymptoms,1sIgEmayhelpintheselectionofcandidatesforAITandpossiblypredicttheresponse.919,924Third,in2polysensitizedpatients,itcanbedifficulttodeterminethemostrelevantallergenonSPT.Inthese3situations,sIgElevelscanhelpdiscriminatethemostrelevantallergenandguideAIT.9204

StudieshaveshownthatsIgEtestinghasasensitivitybetween67-96%andspecificityof5between80-100%.793,822,835,925,926Further,ithasbeendemonstratedthatsIgEshowsexcellent6correlationswithbothNPTandSPTinthediagnosisofAR.793,822,835,857,911Thereisgoodevidencetoshow7thatsIgEis,inmanyways,equivalenttoSPT.218,818,925ThedecisiontoperformsIgEmustbebasedupona8thoroughhistoryandphysicalexaminationtoconfirmthepresenceofallergyandguidetherapywhen9necessary.ItisimportanttonotethatwhilesIgElevelsareabiomarkerofallergicsensitization,thistest10alonecannotprovideadefinitivediagnosisofallergyduetothehighrateofclinicallyirrelevant(false11positive)testswithoutanindicativeclinicalhistory.Basedonthereviewedliterature,sIgEtestingisan12acceptablealternativetoskintestingandissafetouseinpatientswhoarenotcandidatesforskin13testing.[TableVIII.F.2]1415

• AggregateGradeofEvidence:B(Level3b:7studies;TableVIII.F.2.)16• Benefit:ConfirmssensitizationinsupportofanARdiagnosisanddirectsappropriatetherapy17

whilepossiblyavoidingunnecessary/ineffectivetreatment,guidesavoidancemeasures,directs18AIT.19

• Harm:Adverseeventsfromtestingincludingdiscomfortfromblooddraw,inaccuratetest20results,falsepositivetestresults,misinterpretedtestresults.21

• Cost:Moderatecostoftesting.22• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.23• ValueJudgments:Patientscanbenefitfromidentificationoftheirspecificsensitivities.Further,24

insomepatientswhocannotundergoskintesting,sIgEtestingisasafeandeffectivealternative.25• PolicyLevel:Recommendation.26• Intervention:SerumsIgEtestingmaybeusedintheevaluationofAR.Usingstandardized27

allergensandrigorousproficiencytestingonthepartoflaboratoriesmayimproveaccuracy.28

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TableVIII.F.2.EvidencefortheuseofserumsIgEtestinginthediagnosisofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusions

Chinoyetal927

2005 3b Prospectivecohort

PatientswithARand/orbronchialasthma(n=118)

CompareskintestreactivitywithserumsIgEantibodies

For4indoorallergens,skintestwasmoresensitivethanRAST.SkintestandRASTscoresshowedweaktomoderatecorrelation.

Pumhirunetal835

2000 3b Prospectivecohort

Perennialrhinitispatients

ComparedsensitivityandspecificityofSPTtosIgEassayforD.pteronyssinusandD.farinae

sIgEforD.pteronyssinusandD.farinaehadsensitivityof96.3%and88.9%andspecificityof96.2%and88.9%,respectively.Thiscomparedtosensitivityof90.4%and86.4%andspecificityof99.5%and93.1%forSPT.

Tschoopetal822

1998 3b Prospectivecohort

Randomlyselectedsampleof8329Swissadults

Comparedthesensitivity,specificity,PPVandNPVofSPT,tIgE,andfluoroenzymeimmunoassayindiagnosingAR

SensitivityoffluoroenzymeimmunoassaywassignificantlyhigherthanSPTandIgE.SPTwasmorespecificandhadabetterPPV.SPTwasthemostefficienttesttodiagnoseAR.

Woodetal793

1999 3b Prospectivecohort

Patientswithcatallergydeterminedbyhistoryandacat-exposuremodel

ComparedthepredictivevaluesofSPT,IDTandRASTsinthediagnosisofcatallergy

SPTandRASTvaluesexhibitedexcellentefficiencyindiagnosisofcatallergy.IDTaddedlittletothediagnosticevaluation.OverallsensitivityandspecificityofRASTwas69%and100%,respectively.

Ownby&Bailey925

1986 3b Prospectivecohort

Childrenage4-19years

DiagnosticlevelsbyMASTandRASTwerecomparedtoskintestreactionsforragweed,grass,housedustandmite

MASThadasensitivityof59%,specificityof97%,efficiencyof72%,comparedwith67%,97%,and78%,respectivelyforRAST.NeitherMASTorRASTassensitiveasskintest.

Ferguson&Murray926

1986 3b Prospectivecohort

168childrenwithclinicalsuspicionofallergytocatsand/ordogs

ComparedthepredictivevaluesofskintestsandRASTsinchildrenwithhistoryofallergytocatsand/ordogs

RASTsensitivityandspecificitywas71-74%and88-90%,respectively.SPTsensitivityandspecificity68-76%and83-86%,respectively.

Reddyetal857

1978 3b Prospectivecohort

1.34patientswithhistoryofPRbutnegativeSPT2.19patientswithhistoryPRandpositiveSPT3.Healthycontrols

Todeterminetheclinicalrelevanceofpositiveintracutaneoustestwhenepicutaneoustestisnegative

GoodagreementbetweenSPT,RASTandNPT.PooragreementbetweenpositiveIDTat1:1,000concentrationandSPT,RASTandNPtests.

Wideetal911

1967 3b Prospectivecohort

31allergicpatients AcRofminimalCSAofnasalcavity

Goodcorrelationbetweenprovocationtestsandinvitrotestsforallergy.

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Seidmanetal761

2015 5 Guideline Notapplicable Notapplicable CliniciansshouldperformandinterpretorreferforsIgE(skinorblood)allergytestingforpatientswithaclinicaldiagnosisofARwhodonotrespondtoempirictreatmentorthediagnosisisuncertain.

Bernsteinetal818

2008 5 Review-practiceparameter

Notapplicable Notapplicable SensitivityofsIgErangesfrom50-90%withanaverageof70-75%.sIgEmaybeusedalongwithhistoryandphysicalfordiagnosisofallergyandmaybepreferableincertainconditions.

LOE:levelofevidence;AR:allergicrhinitis,ST:RAST:radioallergosorbenttest,IDT:intradermaltesting,SPT:skinpricktesting,PPV:positivepredictivevalue,1NPV:negativepredictivevalue,MAST:multipleallergosorbenttest,NP:nasalprovocation,AcR:acousticrhinometry,CSA:cross-sectionalarea2345 6

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VIII.F.3.Correlationbetweenskinandinvitrotesting1

AllergenskintestinghasbeenusedtodiagnoseallergicdiseasesincefirstintroducedbyBlackley2140yearsago.791,928ThediscoveryofIgEin1969allowedforthedevelopmentofinvitroserologicaltests3whichhavebecomeincreasinglyutilized.929However,skintestingandsIgEserologyportendunique4biologicalfunctions.Therefore,thetwotestsarenotfullyinterchangeable.5

ModernSPTofaeroallergenscanbeupto25%moresensitivethansIgEserologydependingon6thepatientpopulationandthemethodologiesemployed.793,930-934IntheUnitedStates,SPTalso7generallycostsabouthalfasmuchassIgEserology($6.82versus$12.50perallergentested).935Other8factorstoconsiderincludeaccesstolaboratorytechnology,comorbiddiseaseandtheageofthe9patient.Invitrotestingavoidstheneedtowithholdmedicationsthataffectskintestingandallowsfor10testinginsubjectswithdermatographismorotherwidespreadskindisorders.SPTmeasurementsare11directlyobservablewithin20minutes,whichistypicallymuchfasterthanlaboratoryreportsare12obtained.BothsIgEserologyandSPTareconsideredverysafetechniques;however,SPTdoescarrya13verysmallriskofanaphylaxis.Nonetheless,therehaveonlybeentworecordeddeathsfromskintesting14everreportedintheliteratureandoneinvolvedover90scratchteststofoods.93615

ThesensitivityandspecificityofSPTdependsontheallergentested,qualityofreagents,the16specificmethodologiesemployed,technicianexpertise,andpatientdemographics.928,937-942Forexample,17SPTwhealsizeandsensitivitydependonthespecificdeviceselectionandthechoiceofcontrolreagents18usedfortesting.928,938Nonetheless,arecentmeta-analysisindicatesthatSPTremainsanaccuratetest,19whichwhencombinedwithadetailedclinicalhistory,helpsconfirmthediagnosisofAR.830[Table20VIII.F.3-1]21

TheperformanceandreliabilityofserumsIgEtestinglikewisedependsonseveralfactors22includingthechoiceofreagents,modernizationofequipment,andpatientdemographics.932Thecutoff23valueforapositivetestaffectsboththesensitivityandspecificity.943InaKoreanpopulation,SPTwas24foundtobesuperiortoImmunoCAPformeasuringdustmitesensitivityifthepatientwaslessthan3025yearsofage.792Forthegroupolderthanage50,ImmunoCAPwasmoresensitive.792Intradermalor26epicutaneoustestingdemonstrateshighersensitivitybutlowerspecificitythanSPTforseveral27allergens.793,856,931,932,944Basedonthis,intradermaltestsshouldbeselectedjudiciously.Thereisevidence28tosuggestthatapositiveintradermalreactiontograsspolleninthesettingofnegativepricktestingmay29notbeclinicallyrelevant.793,85630

Inrecentyears,microarrayallergytestingsystemssuchasImmunoCAPISAChavebeen31introducedinanefforttoofferacomprehensiveinvitroallergentestpanel794Theprecisionandutilityof32microarraytestingneedsmorerigorousscrutinysothatconsensusguidelinescanbemorefirmly33established.794,945ThecostofasingleImmonoCAPISACtestwhichincludes112componentsfrom5134allergensisapproximately$500-$600intheUS794,94535

VariousstudieshavecomparedsIgEserologytoallergenSPT.793,943,946,947Bothtechniquesare36sensitiveandaregenerallywellcorrelated;however,interpretationoftheresultsdependsuponthe37goldstandardreferenceusedtodefineallergicstatus.Environmentalchambers,nasalchallenge,and38validatedquestionnairesaretypicallyusedtodeterminethediagnosticaccuracyofallergentesting.39TableVIII.F.3-2summarizesseveralcomparativestudiesbetweenskintestingforaeroallergens,specific40IgEserology,andotherinvitrotests.41

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Itisimportanttounderstandthatselectionandinterpretationofallergentestingisnotbasedon1sensitivityandspecificityalone.Theintendedphysiologicalmechanismtobeinterrogatedalsoneedsto2beconsidered.SPTandintradermaltestingbothmeasureend-organpathologicalmechanisms3associatedwithsIgEboundtothesurfaceofmastcells.Incontrast,serumsIgEtestingandmicroarray4approachesmeasurecirculatingIgEthatmayormaynotrepresentdownstreamallergicinflammatory5responses.BothintradermaltestingandSPTrelyheavilyontechnicianskillforinterpretationofthe6whealandflarereaction.856,928,937Inthecaseofsubjectswithdermatographism(orotherinflammatory7skinconditionsinthetestingarea),hairyarms,ordarklypigmentedskincolor,theinterpretationofthe8SPTcanprovetobedifficult.942Specializedimagingsystemshavebeendevelopedtomeasurethewheal9reactioninanautomatedfashioninbothlightanddarkskinnedindividuals,butadditionalvalidationis10required.Untiltheseautomatedsystemsbecomemorewidespread,invitrotestingaffordsthebenefits11oftemporalandmulti-centerreproducibility.12

TheaveragepooledsensitivityofSPTis85%whichisoftenslightlyhigherthanthatofserum13sIgEtesting;830however,thisisnotuniversallytruedependingontheallergentestedandthe14characteristicsofthepatient.Basedonaccuracy,convenience,cost,andpromptnessofresults,SPTis15oftenchosenasthefirstlinediagnosticinstrumenttodetectsensitivitytoaeroallergens.Intradermal16testingcanbeusedasasecondlinetesttoexcludereactivityiftheclinicalsuspicionisveryhigh.Incases17wheredermatographismispresentand/orpatientsareunabletoweanoffmedicationsthataffectskin18testing,sIgEtestingmaybeabetterchoice.Morestudiesarerequiredtodeterminetheroleofsmall19volumebloodtestingthroughemergingmicroarraytechnologysuchastheImmunoCAPISAC.2021

• AggregateGradeofEvidence:B(Level1a:1study;Level1b:7studies;Level1c:1study;Level222a:1study;Level2b:6studies;Level3a:2studies;Level5:1study;TableVIII.F.3-1.)2324

TableVIII.F.3-1Evidenceforvariousallergytestingtechniques25Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Nevisetal830

2016 1a Systematicreview

AR SPTaccuracy VariousfactorsdetermineSPTaccuracy.

deVosetal931

2013 1b Validatingcohort

ARandasthma ConcordanceofSPTandserology

SPTandserologyarediscordant.

Sharmaetal932

2008 1b Validatingcohort

Mouseallergy RASTvs.SPTvs.intradermaltest

Sensitivityandspecificitydifferacrosstests.

Carretal939 2005 1b Prospectivecontrolledtrial

AR Evaluationof8devicesforskintesting

Consensusguidelinesonskintesting.

Woodetal793

1999 1b Validatingcohort

Catallergy RASTvs.SPTvs.intradermaltest

Sensitivityandspecificitydifferacrosstests.

Nelsonetal937

1998 1b Validatingcohort

Allsubjects Whealandflareofvariousdevices.

ResultsofSPTdependondevice,techniqueandcontrolreagentschosen.

Nelsonetal856

1996 1b Validatingcohort

ARtograss Intradermaltestvs.challenge

PositiveintradermaltestmaynotberelevantifSPTnegative.

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Adinoffetal948

1990 1b Validatingcohort

AR SPTresults SPTisaccurateforvariousaeroallergens.

Jungetal792 2010 1c Allornonecaseseries

HDMallergies ImmunoCAPversusSPT

Sensitivityandspecificitydependonpatientdemographics.

Gendo&Larson930

2014 2a Systematicreview

AR Utilityofallergytesting

Historyandpre-testprobabilitydetermineallergytestingutility.

Haxeletal947

2016 2b Retrospectivecohort

AR Nasalchallengevs.SPTvs.RAST

NasalchallengeshouldbeperformedtoconfirmeligibilityforHDMAIT.

Tantilipikornetal949

2015 2b Individualcohort

AR Intradermaltestvs.serumsIgE

IntradermaltestinghashighersensitivityandlowerspecificitythansIgEforHDM.

Tverskyetal928

2015 2b Individualcohort

Allsubjects Whealandflareofvariousdevices

ResultsofSPTdependondevice,techniqueandcontrolreagentschosen.

Choietal943 2005 2b Retrospectivecohort

HDMallergy RASTvs.SPT IgEcutoffleveldeterminesensitivityandspecificity.

McCann&Ownby942

2002 2b Individualcohort

AR SPTmeasurements SPTresultsarenotreproducibleacrosscenters.

Pastorelloetal946

1995 2b Exploratorycase-control

AR ImmunoCAPvs.SPT SpecificIgEaccuracydependoncutoffvalues.

Westwoodetal794

2016 3a SR AR Microarrayresults Utilityandcostofmicroarraytestingneedsfurthervalidation.

Muccietal791

2011 3a SR AR ReviewofAR ReviewofARdiagnosisandtreatment.

LOE:levelofevidence;AR:allergicrhinitis;SPT:skinpricktest;RAST:radioallergosorbettest;HDM:housedust1mite;AIT:allergenimmunotherapy;sIgE:allergen-specificIgE;IgE:immunoglobulinE2 34TableVIII.F.3-2Comparativestudiesofallergytestingtechniques5

Test Allergen Sensitivity Specificity GoldstandardSkinpricktest

HDM 66.3-90.5% 47.6-95.2% bronchoprovocation943,survey946,nasalchallenge943,947Grass 61.6-76% 61-85.7% survey856,946Cat 90% 90-92.7% survey948,catroom793Mouse 67% 94% nasalchallenge932

Skinintradermaltest

HDM N/A 85% nasalchallenge949Grass 78.6% 75% nasalchallenge856Cat 60% 39.5-46.2% catroom793Mouse 100% 65% nasalchallenge932

sIgE(ImmunoCap)

HDM 61.6-76.3% 47.6-72.8% bronchoprovocation943,survey946,nasalchallenge943,947,949Grass 69-75.5% 76.5% survey946Cat 48% 100% catroom793Mouse 74-92.2% 91% nasalchallenge932

HDM:housedustmite;sIgE:allergen-specificIgE678

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VIII.F.4.NasalspecificIgE1

ARisclassicallydiagnosedbyclinicalhistoryandwithobjectivetestingforconfirmation,usually2SPTorinvitrotestingwithserumsIgE.301InadditiontopositivesystemicsIgE,ARpatientshavebeen3showntohavesIgEinthenasalmucosawithevidencethatclassswitchingandantibodyproduction4occurslocally.309-312,377,950,951However,somepatientshavenegativeSPTorserumsIgEdespiteaclinical5historysuggestiveofARandmeetingARIAclinicalcriteria.101,300Thesepatientsareusuallygiventhe6diagnosesofidiopathicrhinitis,vasomotorrhinitis,orNAR.300However,ithasbeendemonstratedthat7manyofthesepatientsmayhavelocalallergicphenomenaorLAR,atypeofrhinitischaracterizedbythe8presenceofalocalizedallergicresponseinthenasaltissues,withlocalproductionofsIgEandpositive9responsetoNPTwithoutevidenceofpositiveSPTorserumsIgEelevation.107LARmayaffectmorethan1045%ofpatientsotherwisecategorizedasNAR,296,302,952andupto25%ofpatientsreferredtoallergy11clinicswithsuspectedAR.291LiketraditionalARpatients,LARcanbeclassifiedasperennialorseasonal,12andsimilarfindingsinthenasalmucosahavebeenreportedinbothofthesepopulations.300,301,953Ithas13evenbeensuggestedthatsomepatientswithoccupationalrhinitismaysufferfromLAR.107Recent14studiessuggestedalowrateofconversionofLARtosystemicAR.296,302Thefirst5yearsofalong-term15follow-upstudyperformedinacohortof194patientswithLARand130healthycontrolsfoundthat16patientswithLARofrecentonset(lessthan18monthsfromthediagnosis)hadasimilarconversionto17systemicARwhencomparedtocontrols.296Asmallretrospectivestudyperformedin19patientswitha18longclinicalhistoryofLAR(greaterthan7yearsfromthediagnosis)andnegativeSPTtoawidepanelof19allergenshadasimilarrateofdevelopmentofsystemicAR302comparedwithepidemiologicdataof20prevalenceofatopyinhealthypopulationfromthatgeographicarea.954Upcomingdatafromthe10-21yearfollow-upstudyshouldhelptoclarifytherateofalong-termconversiontosystemicARinpatients22withLAR.Infact,LARcanpresentlaterinlife,andinelderlypatientswithrhinitistheincidenceofLAR23hasbeenreportedlybeenashighas21%.30424

ThediagnosisofLARisconfirmedbypositiveresponsetoNPT,andevidenceofsIgEinthenasal25secretions.Avarietyofallergenshavebeentestedinthisfashionincludingdustmites,grasses,pollens,26andmolds.300,301,306,307,955Theproductionofnasalmastcells,eosinophils,andsIgErapidlyincreasesafter27allergen-specificstimulationinthenasalmucosa.288,294,307Differentmethodshavebeenreported28regardinghowtobestidentifynasalsIgEincludingnasallavage,cellulosedisks,mucosalbiopsy,and29brushing.[TableVIII.F.4.]Whilethereisnogoldstandard,mostofthesetechniquesappeartoyield30similarresultsinidentifyingnasalsIgEinLARpatients.Additionally,normativedatafornasalsIgElevels31andtheirclinicalcorrelationshaveyettobeestablishedandagreedupon,butworkhasbeguninthis32area.95633

Whenevaluatingarhinitispatient,inthesettingofnegativesystemictesting,thedifferentiation34ofLARfromNARcanprovideimportantinformationformanagement.Whilebothtypicallyrespondto35pharmacologictreatment,identificationofoffendingallergensinLARmaypermitallergenavoidance36andimmunotherapy.107AITisthetreatmentofchoiceforpatientswithARwhohavefailedallergen37avoidanceandmedicaltherapy.PatientswhoareclassifiedasNAR,wouldnottypicallybecandidatesfor38AIT.However,aspreviouslynoted,roughly50%ofpatientswithnegativesystemictestinghavebeen39showntohaveLAR.InthisLARpopulation,earlystudiessuggestthatAITcandecreasesymptomsand40medicationusage,andimproveQOL.288,95741

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1• AggregateGradeofEvidence:C(Level2b:13studies;Level3b:3studies;Level4:8studies;2

TableVIII.F.4.).3• Benefit:IdentifyingpatientswithLARallowsfortheopportunitytotreatasubsetofpatients4

whomayrespondtoavoidanceorAIT.IdentificationofnasalsIgEallowsfordiagnosisandAIT.5• Harm:MeasurementofnasalsIgEisminimallyinvasive,andnoadverseeffectshavebeen6

reported.7• Cost:Associatedcostsconsistofthedirectcostsoftesting,andindirectcostofincreasedtime8

andeffortforperformingnasalsIgEdiagnostictest.9• Benefits-HarmAssessment:Thebenefitsofidentifyingpatientswithanallergiccomponentto10

theirrhinitismayoutweighanyassociatedrisks.11• ValueJudgments:Inpatientswithrhiniticsymptomsandnegativesystemictesting,identifying12

nasalsIgEmayassistwithappropriatetreatment.StandardsforabnormallevelsofnasalsIgE13havenotbeenestablishednorcorrelatedwithclinicaloutcomes.14

• PolicyLevel:Option.15• Intervention:NasalsIgElevelsisanoptioninpatientswithsuspectedorknownLARtoaidin16

diagnosisorguideallergen-specifictherapy.17

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TableVIII.F.4.EvidencefornasalsIgEtesting1

Study Year LOE Studydesign

Studygroups Clinicalendpoint Conclusion

Kimetal958

2016 2b Cross-sectional

Collectiontechnique:cottonball.1.NPTpositive(n=39)2.NPTnegative(n=21)

NPT,nasalsIgE NasalsIgEdetectedinallpatients,nodifferencebetweenNPTgroups.Nocomparisonpre-andpost-NPTwasperformed.

Leeetal959 2016 2b Cross-sectional

Collectiontechnique:nasallavage.1.NAR,children(n=12)2.AR,children(n=15)3.NAR,adults(n=9)4.AR,adults(n=15)

NasalsIgE ARwithhighernasalsIgEtoHDMthanNAR,nodifferencebetweenadultsandchildren.CorrelationbetweennasalandserumIgEonlyinchildren.

Bozeketal304

2015 2b Cross-sectional

Collectiontechnique:nasallavage.Elderlypatients,(n=219)

NPT,nasalsIgE LARandARcommoninelderlypatients.21%withLAR,40.2%withAR,and38.8%withNAR.

Sakaidaetal960

2014 2b Cross-sectional

Collectiontechnique:suctionofnasalsecretions(n=46participants,33sensitizedtoallergen)

NasalsIgE 93%hadnasalsIgE,higherlevelsinsensitizedsubjects,correlationbetweennasalandserumsIgE.

Fuianoetal955

2011 2b Cross-sectional

Collectiontechnique:cellulosemembrane.1.perennialAR,children(n=20)2.perennialNAR,children(n=36)

NPT,nasalsIgE NasalsIgEtoAlternariadetectedin69%ofpositiveNPT.

Lópezetal306

2010 2b Cross-sectional

Collectiontechnique:nasallavage.1.LAR(n=40)2.control(n=50)

NasaltIgE,sIgE,tryptase,eosinophilcationicprotein,symptoms

LAR:NasalsIgEtoD.pteronyssinusdetectedin25%immediatelyandat24hours,increasemastcells/eosinophils.Controls:NegativeNPT,nasalsIgEandothermarkers.

Poweetal950

2010 2b Cross-sectional

Collectiontechnique:cottonball,immunohistochemistry.1.AR(n=90)2.NARES(n=90)3.controln=90)

NasalIgfreelightchains

FreelightchainsincreasedinARandNARnasalmucosa,suggestingroleinhypersensitivity.

Rondonetal307

2009 2b Cross-sectional

Collectiontechnique:nasallavage.1.LAR(n=30)2.control(n=30)

NasalsIgE,sIgE,tryptase,eosinophilcationicprotein

30%withnasalsIgE.LARhavelocalproductionofsIgE,mastcell/eosinophilactivation.

Rondonetal300

2008 2b Cross-sectional

Collectiontechnique:nasallavage.1.seasonalNAR(n=32)2.ARtopollen(n=35)

NPT,nasalsIgE NasalsIgEtograsspollendetectedin35%NARpatientswithpositiveNPT,andwithsimilarsIgEprofileasAR.

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3.ARtoHDM(n=30)4.control(n=50)

Rondonetal301

2007 2b Cross-sectional

Collectiontechnique:nasallavage.1.NAR(n=50)2.ARtoHDM(n=30)3.control(n=30)

NPT,nasalsIgE NasalsIgEtoHDMdetectedin22%ofNARpatientswithpositiveNPT.

Poweetal284

2003 2b Cross-sectional

Collectiontechnique:mucosalbiopsy.1.NAR(n=10)2.AR(n=11)3.control(n=12)

NasalsIgE NasalsIgEtograssdetectedin30%NAR.NonasalsIgEtoHDMwasdetected.

KleinJanetal377

2000 2b Cross-sectional

Collectiontechnique:mucosalbiopsy.1.SAR(n=12)2.PAR(n=16)3.control(n=12)

NasalBandplasmacellswithIgE

sIgEproducedinnasaltissueofARpatientsbutnothealthycontrols

KleinJanetal951

1997 2b Cross-sectional

Collectiontechnique:mucosalbiopsy.1.SAR(n=11)2.PAR(n=10)3.control(n=10)

NasalsIgEtograssandHDM

sIgEtograssandHDMfoundinSARandPARsubjects,respectively.

Takharetal312

2005 3b Cross-sectional,nonconsecutive

Collectiontechnique:mucosalbiopsy.1.AR(n=12)2.control(n=4)

NasalmRNAandgenetranscripts

AllergenstimulateslocalclassswitchingtoIgEinthenasalmucosa.

Durhametal310

1997 3b Cross-sectional,nonconsecutive

Collectiontechnique:mucosalbiopsy.1.AR(n=21)2.control(n=10)

NPT,nasalIgEheavychain

LocalIgEsynthesisandcytokineregulationoccuristhenasalmucosaofARpatients.

Huggins&Brostoff303

1975 3b Cross-sectional,nonconsecutive

Collectiontechnique:filterpaper.1.NAR(n=14)2.AR(n=6)3.control(n=5)

SPT,NPT,serumandnasalsIgEtoHDM

NasalsIgEinARandNARpatientswithpositiveNPT;butnotincontrols.

Otaetal961 2016 4 Descriptive Collectiontechnique:mucosalbiopsy.AR(n=11)

NasalandserumsIgE

DetectionofsIgEininferiorturbinatemucosaandserum.

Zicarietal292

2016 4 Descriptive Collectiontechnique:nasallavage.NAR,children(n=20)

NPT,nasalsIgE 66%hadpositiveNPT.NasalsIgEpresentin8-42%.

Beckeretal962

2015 4 Descriptive Collectiontechnique:cottonball.NARES(n=19)

NasalsIgE NodetectablenasalsIgEinanyofthepatients

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sIgE:allergen-specificimmunoglobulinE;LOE:levelofevidence;NPT:nasal[allergen]provocationtest;NAR:non-allergicrhinitis;AR:allergicrhinitis;HDM:1housedustmite;LAR:localallergicrhinitis;tIgE:totalimmunoglobulinE;NARES:non-allergicrhinitiswitheosinophiliasyndrome;Ig:immunoglobulin;SAR:2seasonalallergicrhinitis;PAR:perennialallergicrhinitis;SPT:skinpricktest;IgG:immunoglobulinG;IgA:immunoglobulinA3

Reisacher963

2013 4 Descriptive Collectiontechnique:mucosalbrush.NAR(n=20)

NasalsIgE NasalsIgEdetectedin100%ofpatients.Variedfrom0%Alternariato90%cockroach.NoassociationtoQOL.

Reisacher964

2012 4 Descriptive Collectiontechnique:mucosalbrush.AR(n=18)

NasalsIgE,SPT NasalsIgEin75%ofsubjects,associationbetweenbrushtestingandSPT.

Cokeretal309

2003 4 Descriptive Collectiontechnique:mucosalbiopsy.AR(n=6)

NasalIgEheavychain

Somatichypermutation,clonalexpansion,andclassswitchingoccurswithinthenasalmucosaofARpatients.

Sensietal965

1994 4 Descriptive Collectiontechnique:nasallavage.Childrenwithasthmaandrhinitis(n=18)

NasalandserumsIgEmeasuredafterallergenavoidance

NasalsIgEmaybemoresensitivethanserumsIgE.

Platts-Mills311

1979 4 Descriptive Collectiontechnique:nasallavage.AR(n=50)

NasalIgG,IgA,andIgE

AntibodyresponseinARpatientsislocalinthenasalmucosa.

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VIII.F.5.Basophilactivationtest(BAT)1

BATisanexvivoperipheralbloodtestthathasbeenshowntobeusefulinthediagnosisof2allergytofoodanddrugs,alongwithotherhypersensitivitysyndromes,whenfirstlinetests(SPTand3serumsIgE)arediscordantwithclinicalhistoryordonotexist,andformonitoringofAIT.966Withinthe4fieldofAR,therearesmallscaletrialsevaluatingtheutilityandreliabilityofBATintestingforthe5diagnosisofspecificallergensrelatedtoARsymptomsandmonitoringtherapy.[TableVIII.F.5.]6

BATmethodologywasfoundtobeheterogeneousbetweentrials.Mostdatapertainingtoits7accuracyusedthetetraspaninCD63(Lysosome-AssociatedMembraneGlycoprotein3;LAMP3)asan8activationmarker.967-971CD203c(ecto-nucleotidepyrophosphatase/phosphodiesterase3)isless9frequentlyused.968,972Inonetrial,itheldpotentialasasensitiveandspecificmethodoftestingforARas10comparedtoCD63.96811

ThediagnosisofARisaclinicaldecisionguidedbyskinorserologicaltests;ex-vivobasophil12testingisrarelyrequired.However,BAThasbeenshowntobecomparablewithtraditionalallergen13testingmethods.967,970,973,974BAThasbeenshowntobeusefulindefiningtheallergenresponsiblefor14LARinpatientswhohavehadfalsenegativeresultswithfirstlinetestsandahighsuspicionforclinically-15relevantallergy.308,31816

Basophilreactivity(%CD63+cellsdeterminedatoneallergenconcentration)doesnotreflect17theeffectofallergenimmunotherapy.Thereisgoodevidencetosuggestthatbasophilsensitivity(EC5018forallergenconcentration,namedCD-sensifitisinvertedandmultipliedby100)isamarkerfor19treatmenteffectofallergenimmunotherapy969-971,975-977andanti-IgEtreatment.97520

Insummary,BATmaybeausefulexvivotestwhendiagnosisofARisindoubtortheallergen21responsibleforclinicalsymptomsisunknown.Basophilsensitivityisalsousefulformeasuringresponse22toAIT.WhenthemethodologyofBATismoreclearlystandardized,itmaybecomeamoreusefulsecond23linetestinARdiagnosis,asusinganexvivotestisbeneficialintermsoftimetakentoundergotesting24andsymptomsevokedduringtesting.Moststudiesincludedsmallsamplessizeswithlessthan10025patients.Thereisanopportunityforameta-analysisofthesestudiesoralargerscaletrialtoconfirmthe26findingsoftheworksincludedinthisreview.2728

• AggregateGradeofEvidence:B(Level1b:2studies;Level2b:2studies;Level3b:8studies;29Level4:3studies;TableVIII.F.5.)30

• Benefit:Exvivotest,patientdiscomfortminimal,lesstimeconsumingthannasalprovocation31andskinpricktestingforpatient,reliablecorrelationbetweenclinicalsymptomsandbasophil32sensitivitywhenmeasuringresponsetotherapy,noriskofanaphylaxiscomparedtoprovocation33testing.34

• Harm:Noneknown.35• Cost:Requiresproximityoflaboratorytrainedinbasophiltesting.Costoftesting.36• Benefits-HarmAssessment:Balanceofbenefitoverharm.37• ValueJudgments:Basophilsensitivitymaybeausefulmarkerforfollowingresponseto38

immunotherapy.DifferencesinBATmethodologyfordiagnosisofARandrareneedfor39laboratoryteststodiagnoseARmakeitlikelytobeimplementedfordiagnosisintertiarycare40centersonly.41

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• PolicyLevel:Option.1• Intervention:BATisanoptionforARdiagnosiswhenfirst-linetestsareinconclusiveorfor2

measuringresponsetoAIT.Manysmall-scalestudieshavebeencompleted.Thereisscopefor3meta-analysisandforlargertrialstobecompleted.4

5

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TableVIII.F.5.Evidencefortheuseofbasophilactivationtestinginallergicrhinitis1Study Year LOE Study

designStudygroups Clinicalendpoint Conclusion

Schmidetal971

2014 1b OpenRCT

SARtograsspollen(n=24)1.SCIT2.opencontrol

Clinicalmeasuresofallergy,basophilsensitivity,basophilreactivity.

BasophilsensitivitychangescorrespondtoclinicalchangesinallergysymptomsinpatientsonSCIT.Basophilreactivitydidnotchange.

VanOvertveltetal978

2011 1b RCT SARtograsspollen(n=89)1.SLITtablet2.placebo

BATusingCD203cat2and4monthsoftreatment.

BATusingCD203cdidnotcorrelatewithpatientresponse.

Zidarnetal977 2015 2b Cohort1) Moderate-severeSARtograsspollen

2) 1.SCIT(n=30)3) 2.notreatment(n=20)

BATusingCD63asmarkerforbasophilresponse.Evaluatedafter1stpollenseason,after2ndpollenseason,and1-2yearsafterfinishing3-5yearsofSCIT.

BATsignificantlydecreasedwithSCIT;remainsdecreased1-2yearsafter3-5yearsofSCITtreatment.BATisanobjectivemeasureofresponsetoAITandisastablemarkerofallergenresponseoveralongperiod.

Zidarnetal976 2012 2b Cohort1) 1.positiveskintestandsIgEtotimothygrasspollen(n=26)

2) 2.positiveNPT(n=13)3) 3.negativeNPT(n=13)

4.non-sensitizedhealthycontrols(n=10)

CD-sens,CD63responsiveness.Testedbeforeandafterpollenseason.10-foldhigherinsymptomaticthanasymptomaticsubjects.Testedbeforethenafterpollinationseason.

CD-sens10-foldhigherinsymptomaticpatients.SignificantdifferencebetweenCD63responsivenessinthosewithpositiveNPTvsnegativeNPT.CD-sensagoodpredictorofallergicrhinitissymptomsinthosesensitizedtotimothygrasspollen.

Lesniaketal974

2016 3b Case-control

Allergypatients(n=30)diagnosedbyclinicalsymptoms,SPT,orserumIgE.

1) 1.Birchpositive,HDMnegative(n=15)

2) 2.Birchnegative,HDMpositive(n=15)

BAT,basophilreactivity

Sensitivityforbasophilreactivity83-100%;specificity78-89%;PPV75-87%;andNPV89-100%.BATmayreplaceNPTwhenNPTiscontraindicated.Smallnumbersofpatientsusedneedstobevalidatedinlargerstudy.

Andoetal979 2015 3b Case-control

1) 1.SARpatients(n=18)2) 2.controls(n=11)

CD203cexpressiononbasophilswhenstimulatedwithJapanesecedarpollen.

CD203cexpressionhasdiurnalvariationandshouldbeconsideredwhenusingCD203casamarker.Thiswasalsoshowninbasophilsderivedfrommarrowofmice-models.

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Campoetal308

2015 3b Case-control

1) 1.ARpatients(n=12)2) 2.LARpatients(n=12)3) 3.controls(n=12)controls4) Testedtoolivetreepollen.

NPT,serumsIgE,BAT NPTpositiveinallARand10/12LAR.SerumsIgEpositiveinAR,negativeinLAR.BATpositiveinARandin8/12LAR.NPTremainsthegoldstandard,butifunabletobedoneBATshouldbeconsidered.

Gomezetal318

2013 3b Case-control

1) 1.LARpatients(n=16)2) 2.ARpatients(n=14)3) 3.NARpatients(n=10)4) 4.controls(n=14)

TestedtoDermatophagoidespteronyssinus.

BAT,nasalsIgE,NPT

AR:BATsensitivity85%,specificity93%.LAR:BATsensitivity50%,specificity93%.BATdiagnosedatleast50%ofcasesofLARtoD.pteronyssinusandwasmoresensitivethandetectionofnasalsIgEandlesstime-consumingthanNPTs.

Ozdemiretal972

2011 3b Case-control

1) 1.SARtograsspollen(n=31)2.healthynon-atopiccontrols(n=9)

DiscriminationofpollenallergicindividualsfromcontrolsusingCD203cexpressionasmarkerofallergy;cutoffvaluesof14%.Performedduringoff-season.

BATCD203ccanbeusedtotestforgrassallergensifconventionalmeasuresnotavailable.

Noppetal969 2009 3b Case-control

1) 1.patientssensitizedtotimothygrass(n=14)

2) 2.patientssensitizedtobirch(n=19)Treatedwithconventionalorultra-rushAIT.

CD-sens CD-sensdecreasesduringearlyphasesoftreatment.Nochangeinbasophilreactivity.CD-sensgoodobjectivemeasuretousetoassessresponsetoAIT.

Ocmantetal968

2007 3b Case-control

1.catallergicpatients(n=20)2.controls(n=19)

TestedbothCD63andCD203cexpressionusingprescribedprotocol.

100%sensitivityforbothCD63andCD203cincatallergicpatients.CD203isasreliableasCD63fordiagnosisofpatientswithIgE-mediatedallergytocat.

Sanzetal967 2001 3b Case-control

1) 1.ARorasthmapatientssensitizedtoHDM(n=53)

2) 2.ARorasthmapatientssensitizedtograss(n=51)

3) 3.atopic,non-allergicpatients(n=24)

Skintests,BAT,histaminereleasetests,leukotrieneproduction

SignificantcorrelationbetweenskintestsandBAT(r=0.72,p<0.001).PositiveandsignificantcorrelationbetweenBATandhistaminereleasetests(r=0.80,p<0.001);allergen-specificLTC4,LTD4,LTE4production

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4.healthycontrols(n=38) (r=0.7,p<0.001);andtheoccurrenceofserumsIgE(r=0.71,p<0.001).BATisahighlyreliabletechniqueinthediagnosisofallergytoinhalantallergens.BATsensitivity=93.3%,specificity=98.4%,whenusingacut-offpointof15%activatedbasophilsaspositiveresult.

Lesniaketal973

2015 4 Caseseries

12patientswithARsensitizedtobirchormites.

Bloodsampletested1,4,24hoursaftersamplingcomparedtoSPT,sIgE,andNPT

NodifferencesinROCcharacteristicsbetweentests.BATcanbeausefulapproachtodeterminetheclinicallyrelevantallergeninsensitizedpatients.

Noppetal970

2013 4 Caseseries

SARtograsspollen(n=26) CD-sens,nPIF PositivenPIFandpositiveCD-sensin92%.PositivenasalsymptomscoresandpositiveCD-sensscoresin85%.Subjectstestedtwice:CD-sens100%reproduciblevs78%fornasalsymptomscoresand94%fornPIF.CD-sensresultsreproducibleandcorrelatewellwithotherallergentestingmethods.Haspotentialfordiagnosis&followupaftertreatment.

Noppetal975 2006 4 Caseseries

1) 1.SARtoTimothygrass(n=27)byclinicalhistory,positiveSPTandsIgE2.patientsreceivinganti-IgEfor4years(n=7)

CD-sens,SPT,NPT,IgEantibodyconcentration

CD-senscorrelatessignificantlywithSPT,NPT,andIgEantibodyconcentration.CD-max(reactivity)didnotcorrelatewithanysensitizationmeasures.CD-maxvariessubstantiallybetweenpatientsanddoesnotcorrelatetotreatmentorotherallergytestingmeasures.UsingCD-sensasaquantitativemeasureofresponsetotherapyortocomplementothertestingmethodsismorereliable.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;SAR:seasonalallergicrhinitis;SCIT:subcutaneousimmunotherapy;SLIT:sublingualimmunotherapy;1BAT:basophilactivationtest;AIT:allergenimmunotherapy;sIgE:specificimmunoglobulinE;NPT:nasalprovocationtest;HDM:housedustmite;PPV:positive2

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predictivevalue;NPV:negativepredictivevalue;AR:allergicrhinitis;LAR:localallergicrhinitis;LTC4,LTD4,LTE4:leukotrieneC4,D4,E4;ROC:receiver1operatingcharacteristics;nPIF:nasalpeakinspiratoryflow;IgE:immunoglobulinE23

456 7

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VIII.F.6.Componentresolveddiagnosis(CRD)1

Moleculardiagnosis(MD)orCRDisusedinallergytodefinetheallergensensitizationofa2patientattheindividualproteinlevelbymeasuringsIgEtopurifiednaturalorrecombinantallergens,3allowingidentificationofthepotentialdisease-elicitingmolecules.Overall,MDcanpotentiallyimprove4diagnosticaccuracy(specificity),distinguishcross-reactivityphenomenafromtrueco-sensitization,5resolvelow-riskmarkersfromhigh-riskmarkersofdiseaseactivity,andmayimprovetheindicationand6selectionofsuitableallergensforAITwhencomparedtodiagnosisbasedonSPTand/orsIgE7determinationwithrawcommercialextracts.980-984Indeed,changesinimmunotherapyprescription8aidedbyMDhavebeendemonstratedtobecost-effectiveinsomescenarios.985Certainpatternsof9sensitizationtograssorolivepollenallergensmayalsoidentifypatientswithhigherriskofadverse10reactionduringimmunotherapy.986,987Nevertheless,allinvitrotestresultsshouldbeevaluated11alongsidetheclinicalhistory,sinceallergensensitizationdoesnotnecessarilyimplyclinical12responsiveness.13

IgEtopurifiedorrecombinantallergensisusuallymeasuredbyusingafluorescenceenzyme14immunoassayinsingleplexplatforms.However,amultiplexplatformwith112allergensisalsoavailable15(ISAC,ThermoFisherScientific,Uppsala,Sweden).Resultsofsingleplexandmultiplexplatformsarenot16interchangeable.Whencomparingthesingle-andmultiplexassays,concordanceofresultsvary17betweenallergenstested,andthesensitivityofmultiplexplatformislowerthanthatofsingleplex,18particularlywhensIgElevelsarelow.983Otherwisesingleplexplatformsarequantitativeassaysand19multiplexaresemi-quantitative.2021Specificantigens.Inthecaseofmitesensitivity,markersofspecificsensitizationincludeDerp1andDer22p2forDermatophagoidespteronyssinusandDermatophagoidesfarinae,988Lepd2forLepidoglyphus23destructor(storagemite,withlimitedcross-reactivitywithotherHDMs)989andBlot5forBlomia24tropicalis(non-Pyroglyphidaemite).990Derp10,atropomyosinfromDermatophagoidespteronyssinus,25hasbeenshowntobeagoodmakerofclinicalsensitivitytocrustaceansbutnotamarkerof26sensitizationtomites.991,99227

Canf1,Canf2andCanf5arespecificallergencomponentsindicatingspecificsensitizationto28dog.993Interestingly,Canf5,aprostatickallikreinproducedonlybymaledogsisresponsiblefor29monosensitivityinupto25-38%ofdogallergicpatients.994,995Inthesecases,patientscantolerate30exposuretofemaledogs.Feld1isthemajorallergencomponentincatallergy,indicatingspecific31sensitization.996Othercatallergenshavesomecross-reactivitywithallergensfromothersources,e.g.,32Feld2islikelytocross-reactwithothermammalalbumins,suchasdogCanf3,horseEcuc3,pigSuss33PSAandcowBosd6997andFeld4isshowntocross-reactwithmajorallergensfromhorseEquc1,dog34orcow.998ThereforeCRDforcatallergyprovidesmoreinformationaboutcross-reactivityandspecifity35ofthediagnosis.Equc1,isthemajorallergenofhorsedanderandhassomecross-reactivitywithmouse36Musm1andcatFeld4.999Equc3isaserumalbuminshowingcross-reactivitywithothermammals’37serumalbuminsmentionedabove.Insummary,CRDinpatientswithallergytodog,cat,andhorseare38notonlypredictivemarkersofallergy,butmayalsohelpclinicianstopredictclinicalsymptomsandtheir39severity,sincesomepatternsofsensitizationarerelatedtomoresevererhinitisandasthma.994,99540

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AllergensrelatedtosensitizationtocockroachesareBlag1,Blag2,Blag4,andBlag5,1althoughincertainpopulationstropomyosins(Blag7and/orPera7)canbeimportant.1000Alta1isa2majorallergenthatisrecognizedinapproximately80-100%ofAlternaria-allergicpatients.1001Markersof3sensitizationtoseveralpollenaresummarizedinTableVIII.F.6.Sensitizationtoprofilinhasbeen4associatedwithmoresevererespiratorysymptomsingrass-allergicpatients,aswellassensitizationto5theminoroliveallergensOlee7andOlee9.987,1002IgEantibodiestoPhlp1and/orPhlp5canbeused6asspecificmarkersofsensitizationtograsspollenandPhlp4asamarkerofsensitizationtonon-7pooideaegrasses.However,Phlp6iscontainedonlyinpooideaegrasses.Allergensfromgroups1,2,58and6areonlyexpressedingrassesbutnotinotherplants,sotheydetectagenuinesensitizationto9grasses.9811011

Insummary,CRDinpatientswithARcanhelptobetterdefinethesensitizationtoinhalant12allergens,especiallyinthosewhoarepolysensitized,haveunclearsymptomsand/orsensitization13patterns,orwhodonotrespondtotreatment.Onthecontrary,monosensitizedpatientswithaclear14casehistoryandsymptomprofilemaynotbenefitfromCRDcomparedtotraditionaldiagnostictests.15Nevertheless,CRDremainsathird-levelapproach,nottobeusedasascreeningmethodincurrent16practice.OneofthemostusefulaspectsofCRDisthatitcanhelpclinicianstobetterselectpatientsand17allergensforprescribingAIT,1003andinsomecases,predicttheriskofadversereactions.Thepatternof18sensitizationtoallergensmaypredicttheseverityofthediseaseandcouldpotentiallypredictthe19efficacyofAIT,providedtheseimmunotherapyproductscontainasufficientamountofallergen.As20therearemultipleindividualallergensavailableforCRDandseveraldifferentusesforCRD,extensive21evidencegradingisnotundertakeninthisdocument.2223

TableVIII.F.6.Pollenallergens24Pollen Specificcomponents Cross-reactivitycomponents

Ragweed Amba1(peptatelyase) Mugwort Artv1(defensin)

Artv3(lipidtransferprotein)Artv3(lipidtransferprotein)

Parietaria,wallpellitory Parj2(lipidtransferprotein) Parj2(lipidtransferprotein)Russianthistleorsaltwort Salk1(pectinesterase)

Goosefoot Chea1(trypsininhibitor) Timothy Phlp1(expansin)

Phlp4(berberinebridgeenzymes)Phlp5(ribonuclease)

Phlp6(pooideaegrassonly)

Phlp4(berberine)Phlp7(polcalcin)

Phlp11(trypsininhibibitor)Phlp12(profilin)

Bermudagrass Cynd1(expansin) Cynd1andPhlp1Alder Alng1(ribonuclease) Alng1(PR10)Birch Betv1(PR-10) Betv1(PR10)

Betv2(profilin)Betv4(polcalcin)

Olive Olee1(trypsinInhibitors)Olee7(lipidtransferprotein)

Olee9(glucanase)

Japanesecedar Cryj1(pectatelyases) Cypress Cupa1(pectatelyases)

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Planetree Plaa1(invertaseinhibitor)Plaa2(polygalacturonases)

Plaa3(lipidtransferprotein)

123VIII.G.Sensitizationvs.clinicalallergy4

Sensitizationvs.allergy.AlthoughIgE-mediatedsensitizationhasbeenconsistentlyshowntobean5importantriskfactorforrhinitis,520,1004thestrengthofthisassociationisnotconsistent.1005,1006In6epidemiologyandclinicalpractice,patientsaretypicallydiagnosedasbeing“sensitized”basedona7positiveSPT(usually>3mmwhealdiameter),orapositivespecificserumIgE(usually>0.358kUA/L).1007,1008However,bothofthesetestscanbepositiveintheabsenceofanysymptoms,andneither9positiveSPTnorIgEcanconfirmtheexpressionofrhinitissymptomsuponallergenexposure.1009,101010Thus,acleardistinctionhastobemadebetween"sensitization"(whichusuallyreferstopositiveallergy11tests,irrespectiveofanysymptoms),andclinicalallergicdiseasesuchasAR,whichdenotesthepresence12ofsensitizationandrelatedclinicalsymptoms.13

14

“Positive”allergytestvs.sIgEtiterorSPTwhealsize.Quantificationofatopicsensitizationbyusingthe15levelofsIgEantibodiesorthesizeofSPTwhealsincreasesthespecificityofallergytestsinrelationto16thepresenceandseverityofrhinitis.893,1004Thishaschangedthewayweinterprettheresultsofallergy17tests,withamovefromdichotomization(labellingpatientsasbeingsensitizedbasedona“positive”test18usingarbitrarycriteria),toquantificationofbloodorskintestsusingsIgEtiterandSPTwhealsize.893,1010-19101220

21

Wholeallergenextractvs.individualallergenicmolecules.Homologousproteinspresentinthewhole22allergenextractsfromdifferentallergensourcesmaybecross-reactive(e.g.profilinsandPR-10proteins23invariousplants,ortropomyosinpresentinmites,variousinsectsandshrimp).Thus,apositivetestto24thewholeallergenextractmayreflectsensitizationtoacross-reactivecomponent.1013Measuring25sensitizationtoindividualallergenmoleculesinaCRDmaymorebeinformativethanstandardtests26usingwholeallergenextracts.470,1014-1016CurrentmultiplexCRDplatformsallowthetestingfor27component-specificIgEtomorethan100allergenicmoleculesinasingleassay,andinasmallvolumeof28serum.1013,1015Thepatternsofcomponent-specificIgEresponsestomultipleallergenicproteinshavea29reasonablediscriminationabilityforrhinoconjuinctivitis,1017anddistinctpatternsofIgEresponsesto30differentproteinfamiliesareassociatedwithdifferentclinicalsymptoms.Forexample,sensitizationto31proteinsofplantoriginstronglypredictsAR,andsensitizationtoanimallipocalinsispredictiveof32asthma.1018,1019Theriskofallergicdiseaseincreaseswiththeincreasingnumberofsensitizationsto33individualallergenicproteins,andIgEpolysensitizationtoseveralhousedustmitemoleculesstrongly34predictsrhinitis.1019,1020Itisimportanttoemphasizethattheageofonsetofsensitizationiscrucially35important,andthatdevelopmentofARmaybepredictedbytheuniquemolecularnatureofIgE36responsestoindividualallergencomponents.101937

38

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Disaggregatingatopicsensitization.Itisbecomingincreasinglyclearthat“atopicsensitization”isnota1singlephenotype,butanumbrellatermforseveraldifferentatopicvulnerabilitieswhichdifferintheir2associationwithrhinitisandasthma.1021,1022Differentsubtypesofatopyarecharacterizedbyaunique3patternoftheresponsestodifferentallergensandthetimingofonsetofallergen-specific4sensitization.1023Translationofthesefindingsintoclinicalpracticerequiresthedevelopmentof5biomarkerswhichcandifferentiatebetweendifferentsubtypesofsensitization,andcanbemeasuredat6thetimeofclinicalevaluation.7

8

BeyondIgE.Recentdatasuggestthatamongstindividualssensitizedtograsspollen,thedecreasingratio9ofgrassallergen-specificIgG/IgEantibodiesisassociatedwithincreasingriskofsymptomaticSAR,102410suggestingthattheIgG/IgEratiomayhelpdistinguishbetween“benign”sensitization(sensitizationwith11nosymptoms)and“pathologic”sensitization.1024However,themeasurementofallergen-specificIgG12cannotasyetberecommendedinaroutineclinicalpractice.1009,101013

1415VIII.H.1.Allergenchallengechambers(ACC)16

Environmentalexposurechambers(EEC)havebeenusedfordecadesforcontrolledexposureof17subjectstoawell-definedatmosphereofavarietyofsubstancessuchasallergens,particulateand18gaseousairpollutants,chemicals,orclimateconditions.Thegenerationofvalidexposureconditions19withhightemporalandspatialstabilityistechnicallydemanding,andtherearealimitedthenumberof20EECsworldwide.BesidestheopportunitytouseEECsforwell-designedmechanisticstudiesontheeffect21ofenvironmentalpollutantsonhumanhealth,allergenchallengeinthechambersettingwithinduction22ofsymptomsinpatientswithallergicdiseaseisanintriguingwayforefficacytestingofnewdrugs.23Therefore,severalchamberfacilitieswereinstalledinrecentyearswiththefocusonallergenexposure24resultingincurrently15ACCfacilitiesaroundtheglobe.102525

ACCstudieshavecontributedtoourunderstandingofthepathophysiologyofallergicdiseases.26Forexample,ithasbeendemonstratedthatcontrolledallergenexposureexacerbatesatopic27dermatitis.1026Also,theimpactofexposurewithpollenallergenfragmentsonARsymptomshasbeen28shown.1027Furthermore,theimportanceoftheintegrityoftheepithelialbarrierforinductionoflocal29andsystemicinflammatoryresponseshasbeeninvestigatedinpatientswithallergicrhinoconjunctivitis30usingtheACCsetting.102831

TheuseofACCsinclinicaltrialsforefficacytestingofinvestigationalnewdrugs,andtheir32acceptancebyregulatoryauthoritiesisperemptorilydependentonthetechnicalandclinicalvalidation33ofACCs.ManyACCshavebeenintensivelyvalidatedregardingspecificityanddose-dependencyof34symptominductionaswellastechnicalaspectssuchastemporalstabilityandspatialhomogeneityof35theallergenexposure.1029-1037Also,repeatabilityofoutcomemeasuresintheACChasbeen36systematicallyinvestigatedandfoundtohaveexcellentrepeatabilityasmeasuredbyTNSS.1038Withthe37givenleveloftechnicalandclinicalvalidation,ACCshavebeenintensivelyusedinclinicaldrug38developmenttostudypharmacologicalpropertiesofnewdrugsduringphaseIItrials,suchasdose-39finding,1039-1041onsetofaction,1042-1046anddurationofaction.1047-1049Inthisrespect,numerous40

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randomized,placebo-controlledclinicaltrialshavebeenconductedusingparallel-grouporcross-over1designsinordertotesttheefficacyofdrugswithimmediatetherapeuticactivity,suchas2antihistamines,1050-1053orwithprophylactictherapeuticpotential,suchastopicalsteroids,1054-1056novel3anti-inflammatorycompounds,1057-1060orprobiotics.1061MajoradvantagesintheACCsettingcompared4tofieldstudiesarebettersignal-to-noiseratios,asafeguardedminimumlevelofsymptomatologyinthe5ACC,andrepeatabilityofsymptomsallowingintra-individualcomparisons.6

Withavailabilityofavarietyofvalidatedallergenatmospheresinchallenge7chambers,1029,1030,1034,1035efficacytestingfordose-findingofAIThasalsobeenperformedinRCTs.1062-10668WhileregulatoryauthoritiesaccepttheuseofACCinphaseIIofdrugdevelopment,1067,1068theyhave9beenreluctanttoapprovetheminpivotalphaseIIIstudiesbecausetheclinicalvalidationisstill10imperfect.DifferencesbetweennaturalexposureinfieldstudiesandACCstudiesexistforexamplewith11regardstoexposuretime(continuousversusintermittent),exposureatmospherecomplexity(natural12mixversusartificialpurity),orselectionofstudypopulation(all-comersversusallergenchallenge13responders).Therefore,evaluationofefficacyduringnaturalexposureinphaseIIIfieldstudiesisstill14mandatory.However,recentjointactivitiesofEAACIwithexpertsfromacademia,chamberowners,and15regulatorshavedefinedthemostrelevantunmetneedsandprerequisitesforclinicalvalidationto16furtherdeveloptheuseandregulatoryacceptanceofACCinpivotalphaseIIIstudies.17

Insummary,numerouswell-designedRCTsusingtechnicallyvalidatedACCsforefficacytesting18ofinvestigationalnewdrugswithdetailedanalysisofdose-response,onsetofaction,anddurationof19actionprovideevidencefortheuseofACCsinphaseIIofclinicaldrugdevelopment.202122VIII.H.2.Localallergenchallengetests 23

Challengingthetargetorgansofrespiratoryallergy(i.e.nose,bronchi,eye)withasuspected24allergenisaimedatdemonstratingtheactualclinicalreactivitywhentheresultsoftheinitialallergy25tests(skintests,invitromeasurementofsIgE)areinconclusive.TheNPTisdesignedforAR,while26conjunctivalprovocationtest(CPT)maybeusedinpatientswithrhinoconjunctivitisorallergicrhinitis27alone.1069,10702829Nasalchallenge.Theaimofnasalchallengeistoreproducetheresponseoftheupperairwayuponnasal30exposuretoallergens.1071,1072However,currentlytheonlytechniquefulfillingthisaimistheEECas31describedintheprevioussection,whiletheallergenamountsadministeredduringaNPTusuallyexceed32naturalexposurelevels,sometimestoalargeextent.TheallergenforNPTcanbeadministeredby33variousdevices,includingsyringes,nosedroppers,micropipettes,nasalsprays,orimpregnateddisks,34noneofthembeingfreefromlimitationsorpitfalls.1071TheresultofaNPTcanbeassessedbyseveral35measures,includingsymptomscores(especiallytheTNSS),rhinomanometry,acousticrhinometry,36opticalrhinometry,peaknasalinspiratoryflow,inflammatorymarkersinnasallavagefluid,andnasalNO37concentration.1072ContraindicationstoNPTareacutebacterialorviralrhinosinusitis,exacerbationofAR,38historyofanaphylaxistoallergens,severegeneraldiseases,andpregnancy.1073Recentstudiesevaluating39thesensitivityandspecificityofthedifferenttechniquesusingspecificallergensareavailable.[Table40VIII.H.2.]ItisapparentfromthecontrastingfindingsthatastandardizedtechniqueforNPTisnotyet41

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available.Infact,inthecomingyears,theuseofNPTinthediagnosisofARislikelytodecrease,dueto1thediagnosticabilityofemergingtoolssuchasCRD1074andtheBAT1075,thatareabletoidentifythe2causativeallergeninpatientswithdubiousresultsfrominitialanalysis.3

Despiteitslimitations,apivotalroleforNPTiscurrentlyacknowledgedindiagnosisof4occupationalrhinitisandLAR.AccordingtothepositionpaperofEAACI,occupationalrhinitis“canonly5beestablishedbyobjectivedemonstrationofthecausalrelationshipbetweenrhinitisandthework6environmentthroughNPTwiththesuspectedagent(s)inthelaboratory,whichisconsideredthegold7standardfordiagnosis”.84ThebesttimetoperformaNPTisinthemorningtolimittheeffectsof8commondaily-lifestimuli.Baselineevaluationofsymptomsandnasalfunctionshouldbedoneafter9adaptationtoroomtemperature.Acontroltestmustbeperformedtoensurethatthenasalresponseis10specifictothetestedagent.1076Apositivecontroltestsuggestsrhinitisinducedbyirritantsornonspecific11hyper-responsiveness. 12

InregardtoLAR,theabsenceofsIgEinserumandintheskinrequiresthatIgEarefoundlocally13orthattheyarerevealedbyapositiveNPT.1077DespitetheintroductionoftechniquestodetectIgEin14thenoseinthe1970s,1078theabilitytomeasurelocally-presentIgEintheclinicsettingisnotcurrently15available.ThismakesNPTofcriticalimportance,thoughcontrastingobservationshavebeenreported.16NPTwithmites,pollensandAlternariawaspositivein100%of22adultswithpreviouslydiagnosed17LAR,1079butinacase-controlled,prospectivestudyon28childrenwithadiagnosisofNAR,testedwith18mitesandgrasspollen,NPTwaspositiveinonly25%ofsubjects.2931920Conjunctivalchallenge.WhileseveraldifferenttechniquesexistforNPT,CPTisgenerallyperformedby21instilling20-30µLofanallergensolutionintotheinferiorexternalquadrantoftheocularconjunctiva,22usingdiluentinthecontralateraleyeasacontrol.1069Also,thepositiveresponsetoCPTissimpleto23evaluate,becauseitconsistsofanimmediatereaction(from5to20minutesfromtheinstillation)with24ocularitching,tearing,rednessandpossiblyconjunctivaledema.In1984,astudyof20childrenwith25seasonalrhinoconjunctivitistested3timeswithCPTreportedgoodreproducibility.1080In2001,a26diagnosticsensitivityandspecificityof90%and100%,respectively,wasreportedinmiteallergic27patients.1081AveryrecentsystematicreviewwasperformedandtheresultswerepublishedintheEAACI28guidelinesfordailypracticeofCPT,withgradeBevidenceforthecapacitytoindividuatetheallergen29trigger.1082TheconclusionhighlightedthatallergistsshouldbemorefamiliarwithCPTduetoits30simplicity.However,thescalestoassessthesymptomsneedtobevalidated,thestandardizationof31allergenextractsmustbeimprovedandtheindicationtoperformCPTinpatientswithformsof32conjunctivitisotherthanallergicremainsuncertain. 33 34

• AggregateGradeofEvidenceforNasalProvocationTesting:C(Level2b:4studies).Ofnote,this35evidencegradeisbasedonthestudieslistedinTableVIII.H.2.However,duetothevariationin36NPTtechniqueandoutcomemeasures,areliableevidencegradeforNPTisdifficultto37determine.38

39

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TableVIII.H.2.Recentstudiesevaluatingthesensitivityandspecificityofnasalprovocationtesting1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Agarwaletal1083

2013 2b Opencontrolled

1.allergictomolds(n=11)2.controls(n=11)

ResultsofNPTbyopticalrhinometry

Nosignificantdifferencebetweenallergicandcontrolsubjects.

Jang&Kim1084 2015 2b Opencontrolled

Housedustmiteallergy1.stronglypositiveSPT(n=99)2.weaklypositiveSPT(n=53)3.negativeSPT(n=110)

SensitivityandspecificityofNPTbyacousticrhinometry,TNSS

TNSS≥6.5had90.6%sensitivityand77.4%specificity,acousticrhinometryhad73.4%sensitivityand58.1%specificityfordiagnosisofAR

deBlayetal1085

2015 2b Opencontrolled

1.HDMallergypatients(n=49)2.controls(n=39)

SensitivityandspecificityofarapidNPTbyclinicalsymptomsandrhinomanometry,safetyalsoevaluated

RapidNPThadasensitivityof83.7%andaspecificityof100%.Noadversereactions.

Krzych-Fałtaetal1086

2016 2b Opencontrolled

1.allergic(n=30)2.controls(n=30)

SensitivityandspecificityofNPTbyopticalrhinometry,TNSS

TNSShada93.3%sensitivityanda77.4%specificity,opticalrhinometryhada100%sensitivityandspecificityfordiagnosisofAR.

LOE:levelofevidence;NPT:nasalprovocationtest;SPT:skinpricktest;TNSS:TotalNasalSymptomScore;2

3

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VIII.I.Nasalcytologyandhistology1

Nasalcytology(NC)isasimplediagnosticprocedurethatevaluatesthehealthofthenasal2mucosabyrecognizingandcountingcelltypesandtheirmorphology.1087NCrequiresthreesteps.The3firstissamplingthesurfacecellsinthenasalmucosawithanappropriatedeviceviaanteriorrhinoscopy.4ThemostcommonlyusedcollectiondeviceistheRhino-probe(ArlingtonScientific,Springville,UT,5USA).1088ThesecondstepisstainingbytheMay-Grunwald-Giemsamethod,whichallowsfor6identificationofallinflammatorycellspresentinthenasalmucosa(i.e.neutrophils,eosinophils,7lymphocytesandmastcells)aswellasnormalmucosalcells(ciliatedandmucinous),andevenbacteria8orfungi.Thethirdstepisexaminationthroughanopticalmicroscopeabletomagnifyupto1,000X.For9theanalysis,atleast50microscopicfieldsmustbereadtobesuretodetectallthecellsinthe10sample.1087NCmaydetectviruses,fungiandbacteria(includingbiofilms)inthenose,allowingforthe11diagnosisofinfectiousrhinitis.1089SpecificcytologicalpatternsonNCcanhelpindiscriminatingamong12variousformsofrhinitis,includingAR,NAR,idiopathicrhinitis,andoverlappingforms.ARiscommonly13diagnosedbythecombinationofclinicalhistoryandresultsofinvivoand/orinvitrotestsforsIgE14antibodies.1090WhenassessedbyNC,thepredominantcelltypeistheeosinophil,followedbymastcells15andbasophils.1091-1094Inalogisticregressionmodel,elevatednasaleosinophilcountsonNChasanORof161.14(95%CI1.10-1.18)toidentifyAR.1092IthasbeendescribedthatNCinpoly-allergicpatientsshowsa17moreintenseinflammatoryinfiltratethaninmono-allergicpatients.1093NChasalsodemonstrated18seasonalchangesofinflammatorycellsinthenose,probablymirroringthevariationsinallergen19exposure,inpatientswithmite-inducedrhinitis.1095 20

NegativeallergytestinginpatientswithpersistentrhinitisusuallysuggestadiagnosisofNAR.109621ThefirstvariantofNAR,knownasNARES,wasdescribedaftertheidentificationofasubsetofpatients22withperennialrhinitis,negativeskintestsandmarkedeosinophiliainnasalsecretions.174Inmorerecent23years,othervariantshavebeendefined,includingNARwithmastcells(NARMA),withneutrophils24(NARNE),andwitheosinophilsandmastcells(NARESMA).1097Idiopathicrhinitisisalsocharacterizedby25highlevelsofeosinophilsandmastcellsinsomepatients.1098Overlappingformsmayoccur.1099 26

NCisonemethodofdiagnosingNARandhasbeenusedtodifferentiatebetweenvariantsin27experiments.1100However,fewstudiesinvestigatingthediagnosticperformanceofNCindiagnosingAR28orNARareavailable.[TableVIII.I-1]29 30

• AggregateGradeofEvidence:C(Level3b:3studies;Level4:1study;TableVIII.I-1.) 3132Nasalhistologyasassessedbybiopsiesofthenasalcavitywastheonlytechniquetostudy33

tissuesandcellsinpatientswithARformanydecades.Inthe1990s,biopsybasedinvestigationsallowed34researcherstodefinetheroleofthedifferentinflammatorycellsinAR.379Theoriginaltechniquebegins35bysprayingalocalanestheticandtopicalvasoconstrictorintothenasalpassages.Afteranesthesiahas36takeneffect,apieceoftissueisremovedfromthemiddleturbinateusingsmallpunchbiopsyforceps.37Afterimmediatelyplacingthetissueinbufferedformalin,eachspecimencanthenbestainedwith38variousreagentstodetectdifferenttissuecomponentsandcells.1101ReagentsusedincludeGiemsa,39hematoxylin/eosin,periodicacid-Schiff,Massontrichrome,azureAandchloroacetateesterase.299,415,110140

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Afterstaining,theslidesareexaminedbyanopticaldouble-headedlightmicroscope,usingagrid1reticuledividedinto100squarestoquantitatecellsandtissuepersquaremillimeter.2

TheintroductionofNCmadeitpossibletoobtainthesimilarinformationashistology,but3withouttheassociateddiscomfortandpotentialriskforbleeding.Further,NCallowsforsequential4samplingwherehistologydoesnot.Inaddition,whenLimetal415comparednasalhistologywith5cytologyinpatientswithperennialandseasonalrhinitiscomparedtocontrols,theresultssuggested6thatnasalsecretionsandthenasalmucosarepresenttwodistinctcellularcompartments.Specifically,7followingallergenchallengeaninfluxofinflammatorycellswasdetectedbycytology,whilethe8epitheliallayerassessedbyhistologywasunchangedfrombaseline.415In2005,Howarthetal1102stated9that,comparedtosimpletechniquessuchasNCornasallavage,nasalbiopsyrequiresexpertisebothin10tissuesamplingandinbiopsyprocessing,thusbeingapplicableonlyinspecialistcenters.Thisissue,as11wellasthepreviouslyreporteddrawbacks,makesnasalhistologyatechniqueofinterestintheresearch12onpathophysiologyofARbuthardlyfeasibleforroutineclinicalpractice.TableVIII.I-2.showsthe13availablestudiesonARpathophysiologyasevaluatedbynasalhistology. 1415

• AggregateGradeofEvidence:B(Level1b:8studies;Level3b:3studies;TableVIII.I-2.)16 17

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TableVIII.I-1Studiesassessingthediagnosticperformanceofnasalcytology1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Gelardietal1093

2015 3b Case-control ARpatients(n=83):1.mono-allergic(n=35)2.poly-allergic(n=48)

ComparisonofNCcellcounts Highernumberofeosinophils(p=0.005)andmastcells(p=0.001)inpoly-allergy.

DiLorenzoetal1092

2011 3b Cohort 1.AR(n=1107)2.NAR(n=404)

NCeosinophilcount Higheosinophilcounthadanoddsratioof1.14(95%CI1.10-1.18)toidentifyAR.

Gelardietal1094

2011 3b Case-control ARpatients(n=62):1.mild(n=30)2.moderate-severe(n=32)

AssociationofcellcountswithARIAstageofdisease

Inmoderate-severeARtherewasasignificantlyhighernumberofeosinophils(p=0.01),mastcells(p=0.001),neutrophils(p=0.046)andlymphocytes(p=0.001).

Gelardi1099 2014 4 Cohort PatientswithoverlappingARandNAR(n=671)

Sneezinginresponsetonasalendoscopyaccordingtotypeofrhinitisfoundoncytology

InpatientswithNARES,NARMAandNARESMAtherewasasignificantlyhigherrateofsneezing(p<0.01).

LOE:levelofevidence;AR:allergicrhinitis;NC:nasalcytology;NAR:non-allergicrhinitis;ARIA:AllergicRhinitisanditsImpactonAsthma;NARES:non-allergic2rhinitiswitheosinophiliasyndrome;NARESMA:non-allergicrhinitiswitheosinophilsandmastcells;NARMA:non-allergicrhinitiswithmastcells34

TableVIII.I-2Studiesinvestigatingallergicrhinitispathophysiologybynasalhistologyfrombiopsies5Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Sivametal1103

2010 1b DBRPCT SAR(n=17):1.mometasone(n=10)2.placebo(n=7)

Measurementofolfactoryfunctionandhistologicalanalysisoftheolfactoryregion

MometasoneuseassociatedwithreducedolfactoryeosinophilicinflammationandimprovedARsymptoms

Ulleretal1104 2010 1b DBRPCT SARtograssorbirch(n=21):1.budesonide(n=10)2.placebo(n=11)

Mucosaleosinophilia,apoptoticeosinophils,andexpressionofCCL5andCCL11(eotaxin)

InhibitionofCCL5-dependentrecruitmentofcellstodiseasedtissue,reducedcellproliferationandgeneralcellapoptosis,butnotincreasedeosinophilapoptosis,areinvolvedinearlyphasesteroid-inducedresolutionofAR.

Yangetal1105 2010 1b DBRPCT PARtodustmiteoranimalepithelia(n=100):1.ChineseherbalXin-yi-san(n=62)2.placebo(n=38)

TodeterminetheeffectivenessofXin-yi-saninthetreatmentofARandinvestigationofitsmolecularmechanismofanti-allergicactivity.

Xin-yi-sanexertsdiverseimmunomodulatoryeffects,includingsuppressionofserumIgElevelsandincreasedproductionofIL-10,sICAM-1,andIL-8comparedtoplacebogroup.

Asaietal1106 2008 1b RPCT SARtoragweed(n=19):1.AIT(n=12)

Todeterminetheinvivoeffectofshort-courseAITonCD4+CD25+

AITincreasesCD4+CD25+regulatoryT-cellinfiltrationinthenasalmucosa

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2.placebo(n=7) regulatoryT-cellsinthenasalmucosaofragweed-sensitivesubjects.

followingallergenchallengeafterseasonalragweed-pollen

Raketal1107 2005 1b DBRPCT(doubledummy)

SARtobirch(n=41):1.AIT2.budesonide

MeasurementofthenumberofCD1a+,IgE+andFceRI+cellsduringbirchpollenseason

Treatmentwithbudesonide,butnotAIT,decreasedthenumberofCD1a+,IgE+andFceRI+cells

Plewakoetal1108

2002 1b SBRPCT SARtograss(n=30):1.omalizumab(n=19)2.placebo(n=11)

Comparisonofanti-CD4,CD8,anti-eosinophilperoxidase,anti-humanneutrophillipocalin,andantibodiesagainstIgEandFceRI.

Thenumberofeosinophilperoxidase-positivestainingcellssignificantlyincreasedintheplacebo-treatedptsbutnotintheactivelytreatedpatients.

Pulleritsetal1109

2001 1b RPCT SARtograsspollen(n=21):1.beclomethasone(n=16)2.placebo(n=5)

ComparisonofIL-16expressionduringthepollenseasoninactivelyvs.placebotreatedpatients.

LocalupregulationofIL-16expressioncontributestotheinflammationobservedinseasonalAR.

Wilsonetal1110

2001 1b RPCT SARtograsspollen(n=37):1.AIT(n=20)2.placebo(n=17)

RelationshipbetweensymptomaticimprovementafterAITandeosinophilnumbersandIL-5expressioninthenasalmucosaduringthepollenseason

ImprovementinsymptomsaftergrasspollenAITmayresultfrominhibitionofIL-5-dependenttissueeosinophiliaduringthepollenseason.

Kujundzićetal1111

2013 3b Case-control AR(n=90):1.mometasone(n=30)2.control(n=30)3.untreated(n=30)

Comparebyhistochemicalstainingwithanti-CD31andVEGF-Cthevascularizationofthenasalmucosaofnon-allergic,non-treatedallergicandallergicpatientstreatedwithmometasone.

SignificantlylowervaluesofCD31andVEGF-Cexpressionwereobservedinnon-allergiccomparedwithnon-treatedallergicandpatientstreatedwithmometasone

Radulovicetal1112

2008 3b Case-control SARtograsspollen(n=22):1.AIT(n=13)2.control(n=9)

EffectofAITonthenumbersofFoxp3(+)CD4(+)andFoxp3(+)CD25(+)T-cellsinandoutofseasonandexpressionofIL-10innasalmucosa.

ThepresenceoflocalFoxp3(+)CD25(+)cellsinthenasalmucosa,theirincreaseafterAITandtheirassociationwithsuppressionofseasonalallergicinflammationsupportaroleforT-regcellsintheinductionofallergen-specifictolerance

Tilletal1113 2001 3b Case-control SARtograsspollen(n=46):1.fluticasone(n=23)2.control(n=23)

Effectofallergenexposureonnasalantigen-presentingcellandepithelialCD1a+Langerhans

RecruitmentofCD1a+LangerhanscellstothenasalmucosaduringseasonalallergenexposuremaycontributetolocalT-cellresponses

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cells,CD68+macrophagesandCD20+B-cells

LOE:levelofevidence;DBRPCT:double-blindrandomizedplacebo-controlledtrial;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;IgE:1immunoglobulinE;IL:interleukin;ICAM:intercellularadhesionmolecule;RPCT:randomizedplacebo-controlledtrial;AIT:allergenimmunotherapy;SBRPCT:2single-blindrandomizedplacebo-controlledtrial;AR:allergicrhinitis;VEGF:vascularendothelialgrowthfactor;T-reg:T-regulatorycell3 4

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IX.Management1IX.A.Allergenavoidance2

Allergenavoidanceandenvironmentalcontrols(EC)arefrequentlydiscussedaspartofthe3treatmentstrategyforAR,alongwithpharmacologicmanagementandAIT.ARpatientsarekeento4learnaboutavoidancemeasuresandEC,especiallythosewhowishtoavoidmedicationsorcannot5committoanAITregimen.Consideringthis,itisimportanttoexaminetheevidencesupportingallergen6avoidanceandECmeasuresfortheallergicpatient.78

IX.A.1.Housedustmite9

TechniquestoreduceenvironmentalHDMexposurehavebeeninvestigatedforthetreatment10ofAR.HDMsrepresentoneofthemostcommontriggersofAR,1114andECmeasureshavebeen11advocatedasamanagementstrategy,withevaluationofbothphysicalbarriersandchemical12treatments.1114-1118Variousphysicaltechniques(e.g.heating,ventilation,freezing,barriermethods,air13filtration,vacuumingandionizers)havebeenevaluatedforthetreatmentofAR,withvariablefindings.14WhileseveralstudieshavedemonstrateddecreasedconcentrationsofenvironmentalHDMantigens,1119-151124anassociatedreductioninclinicalsymptomshasnotbeenreliablydemonstrated.[TableIX.A.1.]16DespitereductionsinHDMantigenconcentration,Ghazalaetal1120andTerreehorstetal1124bothfound17noclinicalbenefitsofHDMimpermeablebeddingasanisolatedintervention.Similarfindingswere18reportedbyAntonicellietal1125followingatrialofhighefficiencyparticulateair(HEPA)filtration.19

ChemicaltechniquesincludetheuseofacaricidesinhouseholdcleanerstoreduceHDM20concentration.Geller-Bernsteinetal1119evaluatedanacaricidesprayinthebedroomsofpatientswith21HDMsensitization,demonstratingimprovedmeansymptomscoresversuscontrolpatientswithout22acaricide.SimilarfindingswerereportedbyKniestetal.1121Noseriousadverseeffectswerereported23fromanyoftheevaluatedinterventions,andnostudyevaluatedcost-effectivenessasanoutcome24measure.A2010CochranereviewexaminedtheeffectivenessofenvironmentalmeasuresforHDM25includingimpermeablecovers,HEPAfilters,acaracides,orcombinationtreatments.1126Thissystematic26reviewfoundacaricidestobethemosteffectiveasasinglemeasureorincombinationwithother27measurestodecreaseHDMlevelsandimproveARsymptoms.28

29• AggregateGradeofEvidence:B(Level1a;1study;Level1b:3studies;Level2a:1study;Level2b30

7studies;TableIX.A.1.)31• Benefit:ReducedconcentrationofenvironmentalHDMantigenswithpotentialimprovementin32

symptomscoresandQOL.33• Harm:None.34• Cost:Lowtomoderate,howevercost-effectivenesswasnotevaluated.35• Benefits-HarmAssessment:Benefitoutweighsharm.�36• ValueJudgments:Theuseofacaricidesand/orbedroom-basedcontrolprogramsinreducing37

HDMconcentrationispromising,butfurther,high-qualitystudiesareneededtoevaluateclinical38outcomes.39

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• PolicyLevel:Option.1• Intervention:ConcomitantuseofacaricidesandECmeasures,suchaspersonalizedairfiltration2

techniques,areoptionsforthetreatmentofAR.3 4

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TableIX.A.1.Evidenceoftheeffectivenessofhousedustmiteavoidanceandenvironmentalcontrolsinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionSheikhetal1126

2010 1a SR RCTsexaminingtheeffectivenessofenvironmentalmeasuresforHDM

Symptoms AcaricidesarethemosteffectiveasasinglemeasureorincombinationwithothermeasurestodecreasedHDMandimprovesymptoms.

Ghazalaetal1120

2004 1b Randomizedcross-overstudy

1.adultswithatopyanduseofimpermeableencasings2.adultswithatopywithoutuseofimpermeableencasings

Allergencontent(Derp1,Derf1,mitegroup2),subjectiveclinicalcomplaints

Impermeableencasingssignificantlyreduceallergenconcentration,withoutdifferenceinsubjectivesymptomscores.

Terreehorstetal1124

2003 1b Double-blindRCT

1.childrenwithatopyandHDMimpermeablebedding2.childrenwithatopywithoutHDMimpermeablebedding

Rhinitis-specificvisualanaloguescale,dailysymptomscore,nasalallergenprovocation,Derp1andDerf1concentration

Impermeableencasingssignificantlyreduceallergenconcentration,withoutdifferenceinsymptomsornasalprovocationtesting.

Nurmatovetal1114

2012 2a SRofRCTs 1.useofHDMimpermeablebedding(n=4)2.acaricides(n=2)3.HEPAfiltration(n=2)4.acaricidesandHDMimpermeablebeddinginisolationandcombination(n=1)

HDMload,symptomscores,medicationscores,disease-specificQOL

EnvironmentalcontrolssignificantlyreducedHDMload.Acaricidesmosteffectivesinglemethod.Combinationtherapiesmoreeffectivethansingleinterventionsandmayoffersymptomrelief.

Stillermanetal1127

2010 2b RDBPCT,crossover

1.adultswithatopyandPAF2.sameadultswithatopy,withoutPAF

Reportednasalsymptoms,QOLscoresusingthenocturnalRQLQ

PAFisassociatedwithimprovednasalsymptomandqualityoflifescores.

BrehlerandKneist1128

2006 2b RDBPCT,parallel-group

1.childrenwithatopyandHDMimpermeablebedding2.childrenwithatopywithoutHDMimpermeablebedding

Allergysymptomscores,useofanti-allergicmedication

HDMimpermeablebeddingisassociatedwithsignificantreductioninsymptomscoreswithoutchangeinanti-allergicdrugutilization.

MoonandChoi1122

1999 2b OpenRCT 1.adultsandchildrenwithatopyandmulti-modalityenvironmentalcontrol2.adultsandchildrenwithatopyandverbaladviceonallergenavoidance

ChangeinHDMload,dailyrhinitissymptomscores

Multi-modalityenvironmentalcontrolisassociatedwithreductionsinmeandustmiteconcentrationandnasalsymptomscores.

Geller-Bernsteinetal1119

1995 2b Double-blindRCT

1.childrenwithatopy,bedroomsprayedwithacaricide

Dailyrhinitisandasthmasymptomscores,medicationuse,twiceweeklyPEF

Acaricideisassociatedwithdecreasedmeansymptomscores.

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2.childrenwithatopywithoutacaricide

Kniestetal1121

1992 2b Double-blindmatchedpaircontrolledtrial

1.adultsandchildrenwithatopyandintensivehomecleaningplusacaricide2.adultsandchildrenwithatopyandintensivehomecleaningalone

Dailysymptomsandmedicationscores,physicianassessment,tIgE,sIgE,serumandnasaleosinophils,guanineexposure

Arcaricideassociatedwithimprovementinalloutcomemeasuresexceptformite-specificIgE.

Antonicellietal1125

1991 2b Randomizedcross-overstudy

1.adultsandchildrenwithatopyandHEPAfiltration2.adultsandchildrenwithatopywithoutHEPAfiltration

HDMconcentration,rhinitisandasthmasymptomscore

HEPAfiltrationhadnosignificanteffectonrhinitissymptomscores

Reismanetal1123

1990 2b Double-blindcross-overRCT

1.adultswithatopyandHEPAfiltration2.adultswithatopyandplacebofiltration

Particulatecountsinbedroomair,symptomandmedicationscores,patients’subjectiveresponsetotreatment

HEPAfiltrationisassociatedwithimprovedparticulatecountsandsymptom/medicationscores.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;HDM:housedustmite;HEPA:highefficiencyparticulateair;QOL:qualityoflife;1RDBPCT:randomizeddouble-blind-placebo-controlledtrial;PAF:personalairfiltration;RQLQ;RhinoconjunctivitisQualityofLifeQuestionnaire;PEF:peak2expiratoryflow;tIgE:totalimmunoglobulinE;sIgE:antigenspecificimmunoglobulinE;IgE:immunoglobulinE345 6

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IX.A.2.Cockroach1

Cockroachinfestationandallergenconcentrationsareoftenhighinmulti-occupantdwellingsin2denselypopulatedinnercityareas;althoughelevatedlevelsofcockroachallergenarealsofoundin3homesinwarmer,ruralregions.1129-1131Interventionsaretargetedateliminatinginfestationsandabating4cockroachallergeninhomes.AsystematicreviewbyLeCannandcolleagues,1132identifiedthreekey5strategiesforhomeenvironmentalinterventions:(1)education-basedmethodsthatincludedinstruction6onhousecleaningmeasuresandsealingcracksandcrevicesinareaswhereinfestationoccurs(i.e.7kitchens);(2)physicalmethodsusinginsecticidesorbaittraps;and(3)combinationtherapycontaining8botheducational-basedinterventionsandphysicalmethods.[TableIX.A.2.]9

Moststudiesincludedoneormoreinterventionsaimedatreducingcockroachcountsand10allergen(Blag1andBlag2)levels,1133-1140howeverafewfocusedoneliminatingmultipleallergens(e.g.11housedustmite,cockroach,rodent,cat,dog).1141,1142Themosteffectivetreatmentforeliminating12infestationandreducingallergenloadwasprofessionalpestcontrol.1135Severetal1133foundplacement13ofinsecticidebaittrapstobemoreeffectiveinreducingcockroachpopulationswithaconcomitant14reductionincockroachallergencomparedtohomesthatreceivedapplicationsofinsecticide15formulationstobaseboards,cracks,andcrevicesmonitoredovera12-monthperiod.16

Whencostwasconsidered,thepriceofbaittrapsalongwithlaborandmonitoringcostswere17foundtobelessexpensivethanmultiplecommercialapplicationsofinsecticidespraystobaseboards18andcracks.1133Astheexpenseofintegratedhomemanagementconsistingofprofessionalcleaning,19education,andpestcontrolisnoteconomicallysustainable,investigationsarefocusedonassessingthe20efficacyofsingleinterventions,suchasexterminationalone,toassesspossiblecostbenefits.1135,1143In21addition,familyadherencetohome-basedinterventionswasgenerallypoorresultinginelevated22cockroachconcentrationsovertime.113823

AlthoughthereareasubstantialnumberofRCTsthatevaluatedtheefficacyofspecific24environmentalcontrolmeasurestoeliminatethenumberofcockroachesandreducecockroachallergen25level,respiratoryhealthoutcomeswererarelymeasured.EventhoughcockroachcountandBlag1and26Blag2allergenlevelswerereducedinmanystudieswithhomeinterventions,thelevelofcockroach27allergenfollowingtreatmentremainedhigherthanacceptablemedianlevelsassociatedwithclinical28benefitsinsensitizedindividuals.1134,1137-1140Althoughcockroachcountcouldbesignificantlyreducedin29single-familyhomesusingbaittraps,re-infestationandhighallergenlevelsremainedanongoing30probleminmulti-familybuildings.1140Thusitisdifficulttodramaticallyreducecockroachallergenlevels31inthehomeunlessasignificantreductionincockroachcountsismaintainedovertime.1133Moststudies32didnotincludeclinicalendpoints,howeverthosethatdidevaluateclinicaloutcomesfocusedonasthma33symptoms,hospitalizationsoremergencyroomvisits,andmedicationusage.1141,1142Nostudiesincluded34anyassessmentofsymptomsassociatedwithARoritstreatment.3536

• AggregateGradeofEvidence:B(Level1a:1study;Level1b:8studies;Level2b:1study;Level373b:1study;TableIX.A.2.)38

• Benefit:Reductionincockroachcount,butallergenlevels(Blag1&Blag2)oftenabove39acceptablelevelsforclinicalbenefits.NostudiesincludedclinicalendpointsrelatedtoAR.40

• Harm:Nonereported.41

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• Cost:Moderate.Multipletreatmentsapplicationsrequiredaswellasamulti-interventional1approach.2

• Benefits-HarmAssessment:Balanceofbenefitandharms,givenlackofclearclinicalbenefit.3• ValueJudgments:Controlofcockroachpopulationsespeciallyindenselypopulated,multi-family4

dwellingsisimportanttocontrollingallergenlevels.5• PolicyLevel:Option.6• Intervention:Combinationofphysicalmeasures(suchasinsecticidebaittraps,housecleaning)7

andeducational-basedmethodsareoptionsinthemanagementofARrelatedtocockroach8exposure.9

10 11

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TableIX.A.2.Evidenceoftheeffectivenessofcockroachavoidanceandenvironmentalcontrolsonthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionLeCannetal1132

2016 1a SRofRCTs Homegroupinterventionsin3categories:1.education-basedmethods2.physicalmethods3.combinationofbothInterventionsincludedmultiple-allergencontrolmeasures.

Allergicandrespiratorysymptoms(e.g.cough,daytimesymptoms,wheeze,nighttimesymptoms);lungfunction;medicationuse;urgentcareuseforrespiratorysymptoms

Overallstudiessupportedeffectivenessofhomeinterventionsindecreasingrespiratorysymptomsandurgentcareuse.

Severetal1133

2007 1b 3-armRCT;followupfor12months

1.insecticidebaitsandCRmonitoring2.pestcontrolbyrandomlyassignedcommercialcompany3.control

Nodirectclinicalendpoints.CRtrapcountsandCRallergenlevels(Blag1&Blag2)

SignificantreductioninCRcountsinbothtreatmentgroupsvs.control.InsecticidebaittrapsmoreeffectiveinreducingCRinfestationthansprays.EliminationofCRpopulationsleadstoreductioninCRallergenandexposure.

Egglestonetal1141

2005 1b RCT 1.home-basededucation,CRandrodentextermination,mattressandpillowencasings,HEPAfilters2.control

Primaryoutcome:Blag1CRallergenlevel.Secondaryoutcome:asthmasymptoms.

CRallergenreducedby51%at6mos.intreatmentgroupbutnotsustainedat1year;onlymodesteffectonmorbidity.

McConnell

etal11342005 1b RCT 1.education-basedintervention

(sealingcracksandcrevices;cleaningwithbleachsolutions;insecticidebaittraps)2.comparisongroup

Nodirectclinicalendpoints;CRcountandCRallergenlevel

Achieved60%reductioninCRcountininterventiongroup.GreatestreductioninallergenlevelinhomeswithheavierCRinfestationbutlevelsstillhigherthanmedianlevelassociatedwithseveresymptoms.

Morganetal1142

2004 1b RCTwithblockedrandomization

1.education-basedintervention(environmentalremediationformultipleallergens);ProfessionalpestcontrolprovidedforCR-sensitizedchildren.2.control

Asthmasymptoms,useofhealthcareservices

Interventiongroup:ReducedlevelsofCRallergeninbedroomwerestronglycorrelatedwithdecreasedasthma-relatedmorbidity.

Arbesetal1135

2004 1b RCTwithcross-overofcontrolgroup

1.intervention:education;insecticidebaitplacement;professionalcleaning

Nodirectclinicalendpoints,Blag1&Blag2CRallergenlevel

CRallergenlevelsreducedin6monthswithprofessionalcleaningandinsecticidebaittraps;butlowerCRallergenlevelsmaintainedatmonth12withbaittrapsalone.

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2.control:nointerventionformonths0-6;insecticidebaitplacementatmonths6and9

McConnelletal1136

2003 1b RCT 1.professionalcleaning&insecticidebaittraps2.professionalcleaning&baittrapswithnoinsecticide3.nocleaningorbaittraps

Nodirectclinicalendpoints,CRcountandBlag2CRallergenlevel

DecreasedCRcountandallergenconcentrationininsecticidebaittreatmentwaslow.HomeswithhighinitialCRcountshadlargerreductionsinBlag2CRallergenconcentration.ProfessionalcleaningmayhelpinhomeswithhigherCR.

Woodetal1137

2001 1b RCT 1.professionalcleaningwithsodiumhypochloriteandinsecticidebaittraps2.controlwithoutcleaning,extermination

Nodirectclinicalendpoints,CRcountandBlag1CRallergenlevel

ProfessionalexterminationreducedCRnumbersandmedianallergenlevelsby80-90%.Cleaningsolutiondidnotaddanyimprovements.Unclearifthislevelofreductionissufficienttohaveclinicalbenefits.

Gergenetal1138

1999 1b RCT:PhaseIIofamulti-citystudy

1.education-basedinterventionforparents:asthmatriggers,environmentalcontrols;pestcontrol;housecleaning.2.control

Nodirectclinicalendpoints,Blag1CRallergenlevel

CRallergenlevelsdecreasedwithin6monthsbutreturnedorexceededbaselinelevelsby12months.Compliancewithcleaningprotocolwaspoor.

Egglestonetal1139

1999 3b Prospectivecase-control

Professionalcleaningfollowedbypestcontroltreatments

Nodirectclinicalendpoints,CRcountsandBlag1CRallergenlevel

CRnumberseliminatedinmostinner-cityhomeswithprofessionallyappliedinsecticides.CRallergenlevelsdecreasedby78-93%over8months;meanallergenconcentrationsstillabovethresholdofasthmamorbidity.

Williamsetal1140

1999 2b Single-blind,non-random,stratified,placebo-controlledstudy

1.baittrapswithinsecticide2.identicalappearingplacebobaittraps

Nodirectclinicalendpoints,CRcountsandCRallergenlevelsBlag1&Blag2

TreatedhomeshadasignificantdecreaseinnumberofCRcomparedtoplacebo,whichcontinuedfor6months.MinimalreductioninBlag1&Blag2CRallergen.Nosignificantdifference:activevsplacebo.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;CR:cockroach;HEPA:highefficiencyparticulateair1

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IX.A.3.Pets1

PetavoidanceandECrepresentoptionsforthetreatmentofAR.Petremovalisacommonly2citedstrategywithouthigh-qualityoutcomesevaluation.1118,1144,1145Sánchezetal1146evaluated3complianceratesamongsensitizedpatients(n=288),finding4%ofpatientswithdirectexposureto4homeanimalscompliedwithremovalrecommendations.[TableIX.A.3.]EChasthereforebeen5evaluatedtodecreaseantigenexposure,withmixedresults.Björnsdottiretal1147evaluatedoutcomesof6multi-modalityECamong40patientswithdiagnosedcat(Feld1)sensitization,findingsignificant7improvementsinnasalairflowandclinicalsymptoms.However,despitereductionsinenvironmental8antigens,single-modalityEChasnotbeenassociatedwithimprovedsymptoms.Woodetal1148evaluated9HEPAfiltrationinahigh-qualityrandomizedcontrolledstudyof35patientswithFeld1sensitization,10findingunchangednasalsymptomscores,sleepdisturbance,rescuemedicationusageandspirometry11followinga3-monthtrial.Severallower-qualitystudieshaveevaluatedthedurationofantigenreduction12followingpetwashing,findingthatcatanddogwashingmustbecompletedatleasttwiceweeklyto13maintainsignificantreductionsinenvironmentalantigens.1149,1150Furthermore,petremovalmayonly14resultindecreasedallergenlevelsafterseveralmonths1151andCanf1levelsinhomeswith15"hypoallergenic"animalsaregenerallysimilartohomeswithnon-hypoallergenicspecies.115216

Anadditionalstudyhasidentifiedbenefitsofpetavoidanceinthesecondarypreventionof17asthmaamongpreviouslysensitizedindividuals.1153Similarly,currentasthmatreatmentguidelines18recommendpetremovalfromasensitizedindividual’shome.115419

• AggregateGradeofEvidence:B(Level1b:1study;Level2b:2studies;TableIX.A.3.)20• Benefit:Decreasedenvironmentalantigenexposurewithpossiblereductioninnasalsymptoms21

andsecondarypreventionofasthma.22• Harm:Emotionaldistresscausedbyremovalofhouseholdpets.Financialandtimecostsof23

potentiallyineffectiveintervention.24• Cost:Lowtomoderate.25• Benefits-HarmAssessment:Equivocal.26• ValueJudgments:WhileseveralstudieshavedemonstratedanassociationbetweenECand27

reductionsinenvironmentalantigens,onlyasingle,multi-modalityRCThasdemonstrated28clinicalimprovementinnasalsymptomsamongpatientswithFeld1sensitivity.Thesecondary29preventionandtreatmentofasthmainsensitizedindividualsmustalsobeconsidered.30

• PolicyLevel:Option.31• Intervention:PetavoidanceandECstrategies,particularlymulti-modalityECamongpatients32

withdiagnosedFeld1sensitivity,areanoptionforthetreatmentofARrelatedtopets.3334

35

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TableIX.A.3.Evidenceoftheeffectivenessofpetavoidanceandenvironmentalcontrols1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Woodetal1148 1998 1b RCT Cat-sensitiveadults:1.HEPAfilter2.placebo

Catallergenlevels(airborneandsettleddust),symptomscores,medicationscores,spirometry

HEPAfiltersareassociatedwithreducedairbornebutnotsettleddust,catallergenlevelswithouteffectondiseaseactivity.

Sánchezetal1146

2015 2b CohortStudy Patientswithdiagnosedallergy

Sensitizationtohouseholdanimals,compliancewithavoidancerecommendationsandEC

Avoidancerecommendationsmaybeimpracticalwithhighratesofsensitization,indirectexposure,andlowratesofcompliance.

Björnsdottiretal1147

2003 2b* RCT Cat-allergicpatients:1.EC2.unchangedenvironment

Environmental(settleddust)Feld1levels,nasalinspiratoryflow,nasalsymptoms

Multi-modalityECisassociatedwithdecreasedallergenconcentrationandsignificantimprovementsinnasalinspiratoryflowandpatientsymptoms.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;HEPA:high-efficiencyparticulateair;EC:environmentalcontrol;2*Follow-up<80%prevents1b345 6

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IX.A.4.Other(pollen,occupational)1

Forpatientswithpollenallergy,avoidancemeasuresaimtominimizeallergenexposureduring2therespectivepollenseason.101However,pollinationisaglobalnaturalphenomenonwhichperiodically3occurs,makingitnearlyimpossibleforpatientstothoroughlyavoidexposure.Therearesomepractical4methodstominimizepatients’exposureviaECmeasures.However,thereisapaucityofclinicaltrials5evaluatingtheclinicalefficacyoftherapeuticstrategies.Mostoftherecommendedstrategiesarebased6onexpertconsensusandclinicalexperience.11557

OnepotentialECstrategyislimitingresidentialexposureduringperiodsofhighpollination(i.e.8vacationingingeographicalregionswithareducedintensityoflocalpollenconcentration).1156Patients9cangetfurtherinformationaboutthecurrentpollencountintheirrespectiveregionthroughinternet10sources(i.e.theEuropeanAeroallergenNetwork[EAN]database(https://ean.polleninfo.eu/);11FoundationGermanPollenInformationService,(www.pollenstiftung.de);AmericanAcademyofAllergy12AsthmaandImmunology[AAAAI](www.aaaai.org/global/nab-pollen-counts)).Thisinformationmaybe13used,forexample,inavoidanceofextensiveoutdoorexerciseduringpeakpollenlevelsortimingof14preventivemedication.1157,1158Althoughexpertopinionendorsesthesestrategies,thereisnoevidence15tosupporttheirclinicalefficacy.16

Inaddition,patientsmayopentheirhomewindowswhenthepollencountsareloworkeep17windowsclosedanduseairconditioningduringtimesofhighpollination.Specialdustandpollenfilters18maybeusedincarstoreducethepollenconcentrationwithinthecar.Furthermore,pollenallergic19patientsmaybeeducatedonremovalofclothingandwashingtheirhairbeforeenteringtheirbedrooms20duringpollenseasonaspollengrainssticktobothhairandclothing.Again,expertopinionendorses21thesestrategies,butthereisnoevidencetosupporttheirclinicalefficacy.1159,116022

AnotherECstrategyutilizesphysicalbarrierstominimizemucosalexposuretoairborne23allergens.Inaprospectivetrial,70patientswithSARcausedbygrasspollenwererandomizedtoreceive24wrap-aroundeyeglassesinadditiontostandardmedicalcare(firststudygroup)orjuststandardmedical25care(secondstudygroup)duringthreeconsecutivegrasspollenseasons.1161Interestingly,theauthors26foundasignificantimprovementinocularandnasalsymptomsaswellasRQLQinthegroupprovided27withwraparoundeyeglassescomparedtothecontrols.Anotherapproachisanactivenasalfilterby28meansofamembraneremovingparticlesfromtheinhaledair.1162Inaprospective,single-center,29randomizeddouble-blind,placebo-controlledcrossoverstudyperformedinanACC,24adultpatients30withgrass-polleninducedSARwererandomlyassignedtoeitheragroupthatreceivedthisnasalfiltering31membraneortoagroupthatdidnot.1162UnderrepeatedexposureintheACC,patientswiththe32membranefiltersignificantlyimprovedinsomeoftheirnasalsymptoms.However,theprimaryendpoint33measuringmaximumTNSSinthistrialwasnotsignificant;thus,meaningfulconclusionsaredifficultto34drawfromthisstudy.1162Thesmallsamplesizewasanotablelimitation.Areal-worldsingle-center35double-blindcrossovertrialof65patientsbythesameresearchers,however,didfindsignificant36reductionsindailyTNSSandmaximumTNSSwithnasalfiltersusedin-seasoncomparedtoplacebo.116337[TableIX.A.4.]38

Avoidanceofexposuretooccupationalinhalantallergensisfeasible,inprincipal,inoccupational39allergicpatients.112Severalmodalitiesofreducingworkers’exposuretoOAsuchas‘engineering40controls’and‘administrativecontrols’havebeendescribedintheliterature.1164Theformerincludes41

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substitutionofahazardouschemicalwithanonhazardousorless-hazardousalternative,isolationofthe1hazardouschemicalorefficientventilationtoreduceworkers’exposure.Thelatterincludesworkers’2educationandpersonalprotectiveequipment.Aprospectivecontrolledtrialof20patientswith3confirmeddiagnosisofoccupationalallergydemonstratedthatcessationoftheexposureofthecausal4allergenintheworkplaceledtoasignificantimprovementofpatients’nasalsymptomscoresaswellas5diseasespecificQOL.116567

• AggregateGradeofEvidence:B(Level1b:3studies;Level2b:1study;TableIX.A.4.)8• Benefit:Decreasedallergenexposurewithpossiblereductioninsymptomsandneedforallergy9

medication,alongwithimprovedQOL.10• Harm:Financialandtimecostsofpotentiallyineffectiveintervention.11• Cost:Low,butdependentontheECstrategy(i.e.foroccupationalallergyventilationmeasures12

andother‘engineeringcontrols’maybehigh)13• Benefits-HarmAssessment:Equivocal.14• ValueJudgments:AlimitednumberofstudiesshowclinicaleffectsofinvestigatedECmeasures.15

GeneralECrecommendationsaremainlybasedonexpertopinionsratherthanevidence.16• PolicyLevel:Option.17• Intervention:PollenandoccupationalallergenavoidancebyECstrategiesareanoptionforthe18

treatmentofAR;however,clinicalefficacyhasnotbeendefinitivelydemonstrated.MoreRCTs19withlargersamplesarewarrantedtoprospectivelyevaluateclinicalefficacy.20

2122 23

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TableIX.A.4.Evidenceoftheeffectivenessofpollenandoccupationalallergenavoidanceandenvironmentalcontrols1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Comertetal1161

2016 1b RCT SARtograsspollen(n=70):1.wrap-aroundeyeglassesplusstandardmedicalcare2.standardmedicalcarealone

Nasalandconjunctivalsymptomscores,rescuemedicationuse,RQLQ

Significantimprovementofocular/nasalsymptomsandRQLQinwrap-aroundeyeglassgroup

Kenneyetal1163

2015 1b Randomizeddouble-blind,placebo-controlledcrossover

AdultswithSARtograsspollen(n=65):1.nasalmembranefilter2.placebofilter

In-seasonexposure:TNSS,individualsymptoms

DailysumTNSSandmaximalTNSSweresignificant.Individualsymptoms(sneezing,wateryeyes,rhinorrhea)werealsosignificantlydecreasedcomparedtoplacebo.

Kenneyetal1162

2014 1b Randomizeddouble-blind,placebo-controlledcrossover

AdultswithSARtograsspollen(n=24):1.nasalmembranefilter2.placebofilter

FollowingACCexposure:nasalsymptomscores,conjunctivalsymptomscores,throatirritation,intranasalvolume,oralFeNO

Primaryendpoint,TNSS,wasnotsignificant.Somesecondaryendpointswerepositive.Intheabsenceofnaturalallergenexposure,theconclusionsofthistrialarelimited.

Castanoetal1165

2013 2b Cohort,prospective,opentrial

Occupationalallergy(n=20) Nasalsymptoms,disease-specificQOL,nasalpatency,nasalinflammation,olfactoryfunction

ECinoccupationalallergypatientsresultsinimprovedQOL,rhinitisassociatedsymptoms,andgeneralwell-being.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;SAR:seasonalallergicrhinitis;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;ACC:allergen2challengechamber;FeNO:fractionofexhalednitricoxide;QOL:qualityoflife3 4

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IX.Management1IX.B.Pharmacotherapy23

Whetherselectedbypatientsthemselvesorprescribedbymedicalpersonnel,medicationsare4theprimarymodalityforcontrolofallergicsymptoms.Therearenumerousoptionsfororalorsystemic5use,topicalintranasalapplication,andalternativetherapiesthatcanbeconsidered.Itis,therefore,6imperativetounderstandthedatasupportingtheefficacyandappropriateuseofthese7pharmacotherapyoptions.8

910IX.B.1.Antihistamines11IX.B.1.a.OralH1antihistamines12

HistamineisamajormediatorassociatedwiththesymptomatologyofAR.OralH113antihistaminesblocktheactionofhistaminebybindingthehistamineH1receptor,therebyinhibitingthe14pro-inflammatoryeffectsofhistamine.Antihistaminesaretypicallycategorizedbygeneration,suchas15firstorsecond-generationagents.Theolderfirst-generationagents(i.e.diphenhydramine,16chlorpheniramine,brompheniramine)werelipophilicandreadilycrossedtheblood-brainbarrier.This17causedunwantedsideeffectssuchassedation,drowsiness,fatigueandimpairedconcentrationand18memoryaswellasanti-muscariniceffects.First-generationantihistaminesarealsoinhibitorsofthe19CYP2D6hepaticenzymes.Theymay,therefore,alterthemetabolismofothermedicinesdependent20uponCYP2D6metabolism,suchastricyclicantidepressants,someantipsychotics,β-blockers,anti-21arrhythmics,andtramadol.Becauseofthesesignificantsideeffects,inpreviouslypublishedguidelines22andotherpapers,first-generationantihistamineshavenotbeenrecommendedforthetreatmentof23AR.218,1166,1167Thenewer-generationagents(i.e.loratadine,desloratadine,fexofenadine,cetirizine,24levocetirizine)weredevelopedtominimizetheadverseeffectsofearlierdrugs.Theyarehighlyselective25fortheH1receptor,lipophobicandhavelimitedpenetrationacrosstheblood-brainbarrier.26

Newer-generationantihistamines,exceptforcetirizine,levocetirizine,bilastineand27fexofenadine,aremetabolizedbythehepaticcytochromeP450CYP3A4system.Practitionersshouldbe28cognizantthattheconcurrentuseofothermedicines(e.g.macrolides,antifungalsorcalcium-channel29blockers)thatinhibitCYP3A4canresultinaccumulationofdrugconcentrationsandincreasetheriskfor30sideeffectsandtoxicity.Furthermore,adversecardiaceffects(torsadesdepointes,arrhythmiaand31prolongationoftheQTinterval)werereportedwithastemizoleandterfenadine,leadingtotheir32ultimatewithdrawalfromthemarket.1168,1169RCTshaveestablishedthelong-termsafetyandefficacyof33thenewer-generationH1antihistaminescetirizine,desloratadine,fexofenadine,levocetirizine,and34loratadine.[TableIX.B.1.a-1.]35

Becauseoralantihistamineshavebeeninusesincetheearly1940s,therehavebeenmanyRCTs36establishingoralantihistaminesasanappropriatepharmacotherapyforAR.218Assuch,thissectionwill37notlisteverypublishedstudybutsummarizethehighest-gradeevidencethathasbeenpublished.38GuidelinesonARhavebeenpublished,includingthosebytheAAO-HNS761andtheARIAgroup.1167The39AAO-HNSconcluded,baseduponRCTsandapreponderanceofbenefitoverharm,a“strong40recommendation”fortheuseofnewer-generationoralH1antihistaminesforpatientswithAR.218Similar41consensuscamefromARIAwherea“strongrecommendation”wasgivenfororalH1antihistaminesfor42

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AR.1167Furthermore,ARIAandEAACIhavepublishedasetofrecommendationsthatoutlinethe1pharmacologicalcriteriathatshouldbemetbymedicationscommonlyusedinthetreatmentofAR.11702ThemainthrustoftheARIA/EAACIcriteriawastoassesstheefficacy,safetyandpharmacologyof3newer-generationoralH1antihistaminesusinglevel1astudies.Usingthesecriteria,afavorablerisk-4benefitratiowasdeterminedforusingnewer-generationoralH1antihistaminesoverfirst-generation5oralantihistamines.1170Theevidencewasfurtherstrengthenedwithseveralmeta-analysesofthe6currentdata,whereaccurateandrobusteffectestimationscanbederivedfromalargepopulation.11717[TableIX.B.1.a-1.]8

ThechoiceofaspecificoralH1antihistamineisoftenbaseduponthedosing,onset,drug9interactionsandpotentialcost.[TableIX.B.1.a-2.]SystematicreviewsevaluatingmultipleoralH110antihistaminesnotebenefitsofcertaindrugsthatmaybeimportantindecidingwhichdrugto11recommendorprescribe.Directcostsofnewer-generationantihistaminesaresimilargiventhe12availabilityofmanyofthesedrugsasoverthecountermedications.Incontrast,thecostofprescription13onlyformulations(levocetirizineanddesloratadine)ismuchhigher.Indirectcostswouldbeexpectedto14besimilaramongstthenewer-generationoralantihistaminesgivensimilarside-effectprofiles.15

• AggregateGradeofEvidence:A(Level1a:21studies;TableIX.B.1.a-1.).Thereisa16preponderanceofhigh-gradeinvestigationsthathaveexaminedoralH1antihistamines.Only17level1astudiesaresummarizedinthetable.18

• Benefit:Reducednasalitching,sneezing,rhinorrhea,andnasalobstruction.19• Harm:Milddrowsiness,fatigue,headache,nauseaanddrymouth.20• Cost:Directcostslow(average$2perdailydose).Indirectcostsfornewergenerationagents21

lowerthanfirstgenerationagents.1172,117322• Benefits-HarmAssessment:Benefitsoutweighharmforuseofnewer-generationoralH123

antihistamines.24• ValueJudgments:Duetothecentralnervoussystemsideeffectsofthefirst-generationoralH125

antihistamines,theiruseisnotrecommendedfortypicalAR.26• PolicyLevel:Strongrecommendationforuseofnewer-generationoralantihistaminestotreat27

AR.28• Intervention:Prescribingnewer-generationoralH1antihistaminesforpatientswithARshould29

beconsideredearlyintreatment.30

31

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TableIX.B.1.a-1.EvidencefortheroleoforalH1antihistaminesinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Ridoloetal1174 2015 1a SR bilastinecetirizinedesloratadine

Subjectiveandobjectivemeasures,TNSS,RQLQ

Bilastineattherapeuticdosehassimilarefficacytoothersecond-generationoralantihistamines.DemonstratedimprovementinTNSSandRQLQwithgoodsafetyprofile.

Mulloletal1175 2015 1a SR rupatadine Allergysymptoms,ARIAcriteria,AE

Rupatadineisrecommendedforuseinadultsandchildrenforintermittent/persistentARandSAR/PAR.

Scadding1176 2015 1a Reviewofconsensusstatements:ARIA,EAACI,RoyalCollegeofPaediatricsandChildHealth

oralantihistamines

--- Second-generation,non-sedating,antihistaminesarerecommendedformildtomoderateARandincombinationforsevereAR.Sedatingantihistaminesshouldnotbeused.

CompalatiandCanonica1171

2013 1a SR rupatadine Allergysymptoms,AE Favorablerisk-benefitratioforrupatadineintreatingAR

Mösgesetal1177 2013 1a SRandmeta-analysis

desloratadineebastinefexofenadinelevocetirizine

TSSandTNSS Second-generationlevocetirizinesignificantlyimprovedsymptomscoresespeciallyinsevereARcases.

Compalatietal1178

2011 1a SRandmeta-analysis

fexofenadine TSS,individualsymptoms(sneezing,rhinorrhea,itchingcongestion),AE

Fexofenadinehasgoodefficacywithimprovementinoutcomemeasures.NosignificantAEcomparedtoplacebo.

Ferrer1179 2011 1a SR levocetirizinedesloratadinefexofenadine

TSS,PNIF,decongestiontest,QOL,pruritus,ESS,whealandflare,AE

Oralnewer-generationantihistaminesarewelltoleratedinadultsandchildren.EfficacyandimprovementinQOLandnasalobstruction.Benefitsoutweighharm.Verylowriskofsedation.NoQTprolongationfound.

Mösgesetal1180 2011 1a SRandmeta-analysis

levocetirizineloratadine

TSS,DNS,DES,inpatientswithpersistentandSAR/PAR

ImprovementinTSS,Total5SymptomsScore,daytimenasalsymptoms,andQOL

Brozeketal1167 2010 1a SRwithconsensusstatement

oralantihistamines

Evidencewasgradedandrecommendationgiven.

Strongrecommendationtousesecond-generationoralantihistaminesthatdonotcausesedationanddonotinteractwithCYP450enzyme.

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KatiyarandPrakash1181

2009 1a SR rupatadineebastinecetirizineloratadinedesloratadine

ARIAcriteriaevaluatedfor:intermittent/persistent,SAR/PAR.TSS,DTSSm,DSSm,QTchanges

Rupatadineisanon-sedative,efficacious,andsafeoralH1antihistamineforintermittent/persistent,SAR/PAR.

Bachert1182 2009 1a SR desloratadinefexofenadinelevocetirizinecetirizineloratadineterfenadine

TSS,PNIF,TSSC(withnasalobstruction),nasalcongestion&obstruction

Oralanti-histamineshavegoodefficacyforimprovingbothsubjectiveandobjectivemeasures,effectiveinrelievingnasalcongestionassociatedwithARcomparedtoplacebo.

BachertandvanCauwenberge1183

2007 1a SR desloratadine TSS,TNSS,TNNSS,PNIF,forintermittent/persistentSAR/PAR

DesloratadineiswelltoleratedandefficaciousforintermittentandpersistentARwithreductionsincongestion,TSS,TNSS,TNNSSwithimprovedQOL.

Canonicaetal1184

2007 1a SRandmeta-analysis

desloratadine TSS,TNSS,nasalairflow ReductioninTSS,TNSS,andimprovednasalairflow.

Patouetal1185 2006 1a SRandmeta-analysis

levocetirizine Nasalobstruction Improvednasalobstructionunderartificialandnaturalallergenexposure

Schenkel1186 2006 1a SR desloratadine Morningsymptoms,TSS,TNSS,TNNSS

DesloratadineimprovesTSSandimprovedQOLinpatientswithSAR/PAR.24-houractionmakesiteffectiveincontrollingmorningsymptoms.

Horeetal1187 2005 1a SRofRDBCT H1antihistaminevsplacebo

Nasalobstruction OralH1antihistaminesimprovenasalobstructionby22%overplacebo.

PassalacquaandCanonica1188

2005 1a SR levocetirizinedesloratadine

Nasalsymptoms,wheal-flareresponse,QOL,TSS

ImprovedQOLandTSSforSAR/PAR.Levocetirizinehasafasteronset.

Bousquetetal1170

2004 1a SRwithconsensusstatement

desloratadine ARIA/EAACIcriteriaefficacy,safety,pharmacology

DesloratadineisrecommendedfortreatingpatientswithAR.

Greisner1189 2004 1a SR cetirizinedesloratadinefexofenadineloratadine

Onsetofaction Inconsistentresults.Onsetofactionisdependentonhowitisdefinedandmeasured.

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LimonandKockler1190

2003 1a SR desloratadine TSS,TNSS,TNNSS,nasalcongestion,nasalairflow,TASSforSAR/PAR

DesloratadineisasafeandefficaciousforpatientswithSAR/PAR.ImprovedTSS,TNSSandTNNSS,TASS,nasalcongestion.NasalcongestionwasexcludedinthePARgroup.

Bojkowskietal1191

1989 1a SR acrivastine(40studiesreviewed)

rhinoconjunctivitissymptoms,nasalcongestion,adverseevents,drowsiness,CNSdepressionforSAR/PAR

Newer-generationoralH1antihistamineacrivastinehasexcellentefficacyforpatientswithSAR/PAR.Improvednasalcongestion.Smallincreaseindrowsinessoverterfenadine.NoCNSdepressionfound.

H1:histaminereceptorH1;LOE:levelofevidence;SR:systematicreview;AE:adverseeffects;TNSS:TotalNasalSymptomScore;RQLQ:Rhinoconjunctivitis1QualityofLifeQuestionnaire;ARIA:AllergicRhinitisanditsImpactofAsthma;AR:allergicrhinitis;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;2EAACI:EuropeanAcademyofAllergyandClinicalImmunology;TSS:TotalSymptomScore;PNIF:peaknasalinspiratoryflow;QT:measureoftimebetweenthe3onsetofventriculardepolarizationandcompletionofventricularrepolarization;ESS:EpworthSleepinessScale;QOL:qualityoflife;DNS:DaytimeNasal4Symptoms;DES:DaytimeEyeSymptoms;DTSSm:meanTotalDailySymptomScore;DSSm:meanDailySymptomScore;TSSC:TotalSymptomSeverityComplex;5TNNSS:TotalNon-NasalSymptomScore;RDBCT:randomizeddouble-blindcontrolledtrial;TASS:TotalAsthmaSymptomScore;CNS:centralnervoussystem678TableIX.B.1.a-2.Listofcommonlyusedsecond-generationantihistamines9Antihistamine Onset(h) Duration(h) Druginteractions Elimination(h) Dosage

Medication Adults Childrencetirizine 0.7h >24h Unlikely 6.5-10h 5-10mgQD 2-5y;2.5mgor5mgQD

6-12y:5-10mgQDdesloratadine 2-2.6h >24h Unlikely 27h 5mgQD 2-5y:1.25mgQD

6-11y:2.5mgQDbilastine 2h 24h Unlikely 14.5h 20mgQD 6-11y:10mgQDfexofenadine 1-3h >24h Unlikely 11-15h 60mgBIDor180mgQD 2-11y:30mgBID

levocetirizine 0.7h >24h Unlikely 7h 5mgQD 2-5y:1.25mgQD6-11y:2.5mgQD≥12y:2.5-5mgQD

Loratadine(ClaritinÒ) 2h >24h Unlikely 7.8h 10mgQDor5mgBID 2-5y;5mgQD≥6y;10mgQD

mg:milligram(mg);BID:twiceaday;QD:onceaday;h:hour;y:year;N/A:notapplicable1011

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IX.B.1.b.OralH2antihistamines1

TheroleoftheH2receptorinmediatinghistamine-relatednasalsymptomsinARis2controversial.FewsmallstudieshaveinvestigatedtheimpactofH2receptorantagonism,withvaried3results.[TableIX.B.1.b.]Further,nodataexistscomparingH2receptorantagonismefficacytocommon4modernfirstlinetherapysuchasnasaltopicalcorticosteroids.Finally,theclinicalsignificanceofthe5changesassociatedwithH2antihistamineshasnotbeenclearlydefined.Despitethesecaveats,some6studiessupporttheadditionofanH2antihistamineforpatientswithrecalcitrantnasalairway7obstructionwhileonoralH1antihistamines.Therearedrug-druginteractionsthatcanoccurwithH28antihistaminesthroughdecreasedgastricacidityandinhibitionofP450.1192However,duetothelow9costofthesemedications,clinicalsituationsmayarisethatwouldjustifytheiruse.10

AllbutoneoftheRCTsinvestigatingtheefficacyofH2antihistaminesarewithinthecontextof11pre-treatmentofasubjectpriortoanasalallergenchallenge.Wood-Bakeretal1193comparedoral12cetirizinetooralranitidine.Objectivemeasuresofnasalairwayresistanceshowedgreaterimprovement13withranitidine,yetcetirizinedecreasedobjectivemeasuresofnasalsecretionmorethanranitidine.14Taylor-Clarketal1194foundsimilarimprovementinnasalairwayresistancebetweencetirizineand15ranitidine,butasignificantimprovementwiththeuseofcombinationtherapy.Combinationtherapy16wasalsoshowntoimprovenasalairflowwhencimetidinewasaddedtocetirizine.1195Twostudiesdid17notfindimprovementinnasalairflowwiththeadditionofanH2antihistamine.1196,1197Theclinical18significanceoftheseobjectivefindingsisunclear,andthestudiesthatemployedPROMsdidnot19demonstratesubjectiveimprovementinnasalobstruction.20

FourstudiesinvestigatedtheimpactofH2antagonismonsymptoms,howeverthesestudiesdid21notutilizestandardizedoutcomemeasuresastheypre-datedthedevelopmentofsuchtools.Subjects22wereaskedtoreportsomecombinationofcongestion,blockage,itching,drainage,sneezing,eye23symptomsandasthmawithacategoricalseveritymeasure.Threeofthefourstudiesexamined24symptomsafternasalallergenchallenge,andnonedemonstratedefficacyofH2antihistamines,either25aloneorinconjunctionwithanH1antihistamineindiminishingallergicsymptoms.1195-1198Onestudyof2623subjects1198didinvestigatetheimpactofcimetidineinconjunctionwithchlorpheniramineinareal-27worldsetting.Subjectswithknownlate-summerARwererandomizedduringthisseasontoreceive28alternatingtwo-weekcoursesofeitherchlorpheniramineplusplacebo,orchlorpheniramineplus29cimetidine,andsymptomscoreswererecordedtwicedailyalongwithadjuvantmedicaltherapies30(specifically,oralcorticosteroids).PatientsreceivingbothH1andH2antihistaminesreporteddecreased31medicationusage(28corticosteroiddaysvs44corticosteroiddays,p<0.02)anddecreasedsymptoms32scoresduringoneoftheeightweekswhenweedpollencountswerehigh.Acaveatofthisstudyisits33utilizationofafirst-generationantihistaminewhichisnolongerrecommendedasafirst-linetreatment34ofAR.35

ThedataexistingontheuseofH2antihistaminesinARarelimitedinscopeandquality.The36objectivefindingsofimprovednasalairwayresistancesuggestthattheH2histaminereceptordoes37modulatenasaltissueresponsetohistamine.1193-1195However,theclinicalsignificanceofthismechanism38isnotclear,particularlyinthecontextofmoderntreatmentalgorithms.1195-1198Therelatively39manageablesideeffectprofileandcostsofH2antihistamines,doesofferpatientswithotherwise40recalcitrantARsymptomsanadditionaltreatmentoption.41

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• AggregateGradeofEvidence:B(Level1b:6studies;TableIX.B.1.b.).1• Benefit:Decreasedobjectivenasalresistance,andimprovedsymptomcontrolinonestudy2

whenusedincombinationwithH1antagonists.3• Harm:Drug-druginteraction(P450inhibition,inhibitedgastricsecretionandabsorption),4• Cost:IncreasedcostassociatedwithH2antagonist.5• Benefits-HarmAssessment:Unclearbenefitandpossibleharm.6• ValueJudgments:NostudiesevaluatingefficacyofH2antihistaminesincontextoftopicalnasal7

corticosteroids.8• PolicyLevel:Norecommendation.Thedataavailabledoesnotadequatelyaddressthequestion9

astothebenefitofH2antihistaminesinclinicalARaspartofmoderntreatmentprotocols.10• Intervention:AdditionofanoralH2antagonisttoanoralH1antagonistmayimprovesymptom11

controlinAR;however,theevidencetosupportthisisnotstrong.12

13

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TableIX.B.1.b.EvidencefortheroleoforalH2antihistaminesinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Taylor-Clarketal1194

2005 1b RCT Histaminechallengewithpremedication:1.POcetirizine2.POranitidine3.POcetirizine+ranitidine4.placebo

Nasalairwayresistance Cetirizinealoneandranitidinealoneimprovenasalresistance.Cetirizineplusranitidineimprovesnasalresistancemorethaneitheralone.

JuliussonandBende1196

1996 1b RCT Allergychallengewithpremedication:1.POterfenadine2.POcimetidine3.POterfenadine+cimetidine4.placebo

LaserDopplerflowmeter,allergicsymptoms

Nodifferenceinsymptomsorflowmetrywithcimetidine.Noadditiveeffectofcimetidinewithterfenadine.

WangDetal1195

1996 1b RCT Allergychallengewithpremedication:1.POcetirizine2.POcetirizine+cimetidine

Symptoms(itching,sneezing,rhinorrhea,congestion),sneezecount,nasalairwayresistance

Combinationofcetirizine+cimetidineshowedimprovednasalairwayresistanceandnasalairflowovercetirizinealone.

Wood-Bakeretal1193

1996 1b RCT Allergychallengewithpremedication:1.POcetirizine2.POranitidine

Nasallavagefluidproteinconcentration,nasalairwayresistance

Ranitidineimprovednasalresistancemorethancetirizine.Cetirizinedecreasedtotalproteinandalbuminmorethanranitidine.

Carpenteretal1198

1983 1b RCT Duringallergyseasonmedicatedwith:1.POchlorpheniramine2.POchlorpheniramine+cimetidine

Symptoms(rhinorrhea,sneezing,nasalcongestion,nasalpruritus,eyediscomfort),medicationusagebeyondstudytherapy

Reducedsymptomsandmedicationscoresincimetidinepluschlopheniraminegroup.

Brooksetal1197

1982 1b RCT Allergychallengewithpremedication:1.POcimetidine2.placebo

Subjectivesymptoms(congestion,itch,drainage,sneeze),nasalresistance,nasalsecretionweight

Nodifferenceinsubjectivescores.Increasedsecretionandsneezecount,nodifferenceinnasalresistance.

H2:histaminereceptorH2;LOE:levelofevidence;RCT:randomizedcontrolledtrial;PO:peros(medicationtakenorally)2

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IX.B.1.c.Intranasalantihistamines1

TheuseofintranasalantihistaminesprayforARhasbeenwellstudied.Twoagentsarecurrently2availableinNorthAmericaforintranasaluseasatopicalspray,azelastinehydrochlorideand3olopatadinehydrochloride.AsystematicreviewoftheEnglish-languageliteraturewasperformedfor4clinicaltrialsofazelastineorolopatadineforthetreatmentofAR.Atotalof44paperswereidentified5thatreportedresultsofRCTsofintranasalantihistaminemonotherapyagainsteitherplacebooractive6control.1046,1199-1241[TableIX.B.1.c.]Ofthese,11studiesincludedcomparisonofdifferentdosesof7intranasalantihistamine1204,1205,1207,1211,1212,1216,1218,1219,1231,1235,1237and29studiesutilizedinactive8placebo.1201,1202,1204,1205,1207-1209,1211-1214,1216,1218-1222,1224,1225,1227-1231,1233,1235,1237-1239Overall,therewere389studiesofazelastine1046,1199-1201,1203,1205,1207-1213,1215,1217,1220-1241and10studiesof10olopatadine1202,1204,1206,1208,1210,1211,1214,1216,1218,1219asmonotherapy.11

Outcomemeasureswerepredominantlypatient-reportedsymptomscoresorQOLassessments.12ThemostcommonoutcomemeasurewastheTNSS(23studies),whichrecordstheseverityofrunny13nose,sneezing,itchingandcongestion.OtheroutcomemeasuresincludedtheRQLQ(7studies),the14TotalOcularSymptomScore(TOSS,5studies),theCaregiverTreatmentSatisfactionQuestionnaire(215studies),thePediatricRhinoconjunctivitisQualityofLifeQuestionnaire(1study),theShortForm-36(116study),theEpworthSleepinessScale(ESS,1study),theRhinitisSeverityScore(1study)andaSubjective17GlobalAssessment(1study).Multiplestudies,particularlythosepublishedpriorto2002,usedavariety18ofnon-validatedsymptomscoringsystemsrangingfrom5to13itemseach(19studies).Objective19measuresincludednasallavage(3studies),responsetomethacholinechallenge(2studies),nasalflow20rate(2studies)andrhinomanometry(1study).21

Studydurationrangedfrom2daysto8weeks,withthemostfrequentdurationbeing14daysof22treatment.Thenumberofsubjectsineachstudyrangedfrom20to1188.Intranasalantihistaminewas23comparedtoplaceboin29studies,1201,1202,1204,1205,1207-1209,1211-1214,1216,1218-1222,1224,1225,1227-1231,1233,1235,1237-123924withprimaryoutcomesshowingsuperioritytoplaceboinallstudies.Intranasalantihistaminewastrialed25againstanactivetreatmentcomparatorofadifferentmedicationclassinin24studies.1046,1199,1203,1206,1213-261215,1217,1220,1221,1224,1226,1227,1229,1231-1236,1238-1241Althoughnotreportedinallstudies,theintranasal27antihistaminesprayconsistentlyhadamorerapidonsetofaction,occurringasearlyas15minutesafter28administration.Azelastineandolopatadineweredirectlycomparedin3studies,withnosignificant29differenceinsymptomreliefbetweenagents.1208,1210,1211In2additionalstudies,azelastinewas30comparedwithanexperimentalformulationofintranasallevocabastine,witheithercomparableor31superiorresultsforazelastine.1200,122332

IntranasalantihistaminewascomparedtoINCSin12studies,withtheprimaryoutcomefavoring33antihistaminein2studies,1213,1214corticosteroidin3studies,1224,1227,1229andshowingequivalencyin734studies.1199,1203,1206,1233,1238,1239,1241In2ofthestudiesshowingequivalency,antihistaminewassuperiorfor35ocularsymptoms.1203,1239The3studiesshowingsuperiorityofcorticosteroidswereallconductedpriorto362000andusedheterogeneousnon-validatedsymptomscoresasprimaryoutcomes.Intranasal37antihistaminewascomparedtooralantihistaminemonotherapyin8studies,withtheprimaryoutcome38favoringintranasalantihistaminein3studies1215,1217,1232andshowingequivalencyin5studies.1221,1234-391236,1240Onestudyincludedatreatmentarmwithoralchlorpheniramineasapositivecontrolwithout40intenttocompareefficacywithazelastine.1231Onestudycomparingazelastinespraywithoralloratadine41

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plusintranasalbeclomethasonefoundthatazelastinemonotherapywasatleastaseffectiveas1combinationtherapy.1226Twostudiescomparingintranasalazelastineplusoralantihistamineto2intranasalazelastinemonotherapyshowednoadditionalbenefitforcombinationtherapy.1220,12213

Theminimumageofsubjectsintheincludedstudieswasgenerally12yearsorolder.Children4aged6-12yearsoldwereincludedin3studies,whichinaggregateshowedsuperiorityofintranasal5antihistaminetoplaceboinimprovingsymptomsandQOL.1202,1204,12286

Seriousadverseeffectswerenotreportedinanystudy.Intranasalantihistaminewasgenerally7welltolerated,withthemostcommonlyreportedadverseeffectofanunpleasanttaste.Onestudythat8comparedthecommerciallyavailableformofazelastinewithareformulatedvehiclefoundnodifference9intasteaversion.1205Onestudydirectlycomparingolopatadinewithazelastinereportedbettersensory10attributesforolopatadine.1210Otherreportedadverseeffectsincludedsomnolence,headache,epistaxis11andnasaldiscomfort,alloccurringinlessthan10%ofcasesinanystudy.1213

• AggregateGradeofEvidence:A(Level1b:43studies;Level2b:1study;TableIX.B.1.c.).Dueto14thelargenumberofstudieswithhighlevelofevidence,studiesoflowerevidencelevelsarenot15consideredhere.16

• Benefit:Intranasalantihistamineshavearapidonset,aremoreeffectivefornasalcongestion17thanoralantihistamines,aremoreeffectiveforocularsymptomsthanINCS,andshow18consistentreductioninsymptomsandimprovementinQOLinRCTscomparedtoplacebo.19

• Harm:Concernsforpatienttolerance,especiallyduetotaste.Intranasalantihistaminesareless20effectiveforcongestionthanINCS.21

• Costs:Low-to-moderatefinancialburden;availableasprescriptiononly.22• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.Intranasalantihistamineas23

monotherapyisconsistentlymoreeffectivethanplacebo.Moststudiesshowintranasal24antihistaminessuperiortoINCSforsneezing,itching,rhinorrheaandocularsymptoms.Adverse25effectsareminorandinfrequent.26

• ValueJudgments:Extensivelevel1evidencecomparingintranasalantihistaminemonotherapy27toactiveandplacebocontrolsdemonstratesoveralleffectivenessandsafety.28

• PolicyLevel:Recommendation.29• Intervention:Intranasalantihistaminesmaybeusedasfirst-orsecond-linetherapyinthe30

treatmentofAR.31

32

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TableIX.B.1.c.Evidencefortheroleoftopicalintranasalantihistaminesasmonotherapyinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Carretal1199 2012 1b DBRCT(post-hocanalysis)

1.azelastine0.28mgBID2.fluticasonepropionate0.1mgsprayBID

rTNSS,rTOSS,RQLQ

Fluticasonesuperiortoazelastineforimprovingrhinorrhea;comparablesymptomandQOLimprovement.

Hanetal1200 2011 1b DBRCT

1.azelastine0.1%(dosenotgiven)2.levocabastinehydrochloride0.05%spray(dosenotgiven)

rTNSS Comparablesymptomimprovement.

Howlandetal1201

2011 1b DBRCT

1.azelastine0.82mgBID2.placebo

rTNSS,rTOSS,RQLQ

AzelastinesuperiortoplacebofornasalandeyesymptomsandQOL.

Meltzeretal1202

2011 1b DBRCT

1.olopatadine1.33mgBID2.placebo

rTNSS,rTOSS,PRQLQ,CGTSQ-AR

Olopatadinesuperiortoplaceboinreducingsymptomsinchildren,improvingQOL,andsatisfyingcaregivers.

Bergeretal1204

2009 1b DBRCT

1.olopatadine1.33mgBID2.olopatadine2.66mgBID3.placebo

TNSS,TOSS,PRQLQ,CGTSQ,SGA

Olopatadinesuperiortoplaceboinreducingsymptomsinchildren,improvingQOL,andsatisfyingcaregivers.

Bernsteinetal1205

2009 1b DBRCT

1.azelastine0.28mgBID2.reformulatedazelastine0.28mgBID3.azelastine0.56mgBID4.reformulatedazelastine0.56mgBID5.placebo2sprays

TNSS Bothazelastinesprayformulationssuperiortoplacebo;dose-responseeffectbetweendosages;nodifferenceinbittertastebetweenformulations.

Kalineretal1206

2009 1b DBRCT

1.olopatadine2.66mgBID2.fluticasone0.2mgspraydaily

rTNSS,rTOSS Bothtreatmentsimprovesymptoms;fasteronsetforolopatadine.

Shahetal1207 2009 1b DBRCT

1.azelastine0.82mgBID2.azelastine0.56mgBID3.placebo

TNSS Bothazelastinedosessuperiortoplacebo;greaterimprovementwithhigherdose.

Shahetal1208 2009 1b DBRCT

1.olopatadine2.66mgBID2.azelastine0.56mgBID3.placebo

TNSS Bothtreatmentssuperiortoplacebo;nodifferencebetweentreatments;lessbittertastewitholopatadine.

vanBaveletal1209

2009 1b DBRCT

1.azelastine0.82mgdaily2.placebo

TNSS Azelastinesuperiortoplacebo.

Meltzeretal1210

2008 1b DBRCT

1.olopatadine2.66mgBID2.azelastine0.56mgBID

Sensoryperception

Olopatadinefavoredfortaste,aftertasteandlikelihoodofuse.

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Pipkornetal1211

2008 1b DBRCT

1.olopatadine0.1%,(dosenotgiven)2.olopatadine0.2%(dosenotgiven)3.azelastine0.1%(dosenotgiven)4.placebo

4-itemsymptomscore,nasallavage

Botholopatadinedosessuperiortoplaceboforreducingsymptoms;higherconcentrationinhibitsmastcelldegranulation.

Lumryetal1212

2007 1b DBRCT

1.azelastine0.28mgdaily2.azelastine0.28mgBID3.placebo

TNSS Azelastinebothdosessuperiortoplacebo.

Pateletal1213 2007 1b DBRCT

1.azelastine0.56mgdaily2.mometasonefuroate0.2mgspayQD3.placebo

TNSS Azelastinesuperiortomometasoneandplacebo.

Pateletal1214 2007 1b DBRCT

1.olopatadine2.66mgdaily2.mometasonefuroate0.2mgsprayQD3.placebo

TNSS,patientsatisfaction

Olopatadinesuperiortoplaceboandmometasoneinreducingsymptoms;fasteronsetforolopatatine.

Bergeretal1215

2006 1b DBRCT

1.azelastine0.56mgBID2.cetirizine10mgtabletdaily

TNSS,RQLQ Azelastinesuperiorforsneezingandnasalcongestion;azelastinesuperiorforQOL.

Hampeletal1216

2006 1b DBRCT

1.olopatadine2.66mgBID2.olopatadine1.77mgBID3.placebo

TotalSymptomScore,RQLQ

Olopatadine(bothdoses)superiortoplaceboinmajorityofdomainsforQOLimprovement.

Horaketal1046

2006 1b DBRCT

1.azelastine0.4mgdaily2.desloratadine5mgtabletdaily3.placebospray

TNSS Azelastinesuperiortodesloratadineandplacebo.

Correnetal1217

2005 1b DBRCT

1.azelastine0.56mgBID2.cetirizine10mgtabletdaily

TNSS,RQLQ AzelastinesuperiorcetirizineforsymptomsandQOL.

Meltzeretal1218

2005 1b DBRCT

1.olopatadine2.66mgBID2.olopatadine1.77mgBID3.placebo

TNSS,RQLQ Olopatadine(bothdoses)superiortoplaceboforsymptomsandQOLimprovement.

Ratneretal1219

2005 1b DBRCT

1.olopatadine2.66mgBID2.olopatadine1.77mgBID3.placebo

TNSS Olopatadine(bothdoses)superiortoplacebo.

LaForceetal1220

2004 1b DBRCT

1.azelastine0.56mgBID2.azelastine0.56mgBID+fexofenadine60mgtabletBID3.placebospray+placebotablet

TNSS Azelastinesuperiortoplacebo;noadditionalbenefitofaddingoralfexofenadinetoazelastinemonotherapy.

BergerandWhite1221

2003 1b DBRCT

1.azelastine0.56mgBID2.azelastine0.56mgBID+loratadine10mgtablet

TNSS Alltreatmentssuperiortoplacebo;azelastineatleastaseffectiveasdesloratadine;noadditionalbenefitof

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ICAR:AllergicRhinitis198

3.desloratadine5mgtablet+placebospray4.placebospray+placebotablet

addingoralloradatinetoazelastinemonotherapy.

Saengpanichetal1222

2002 1b DBRCT

1.azelastine0.28mgBID2.placebo

TNSS,nasallavage,methacholinechallenge

Azelastinesuperiortoplaceboforsymptoms;noeffectonnasaleosinophilsorcytokines;azelastineinhibitsmethacholineresponse.

Falseretal1223

2001 1b DBRCT

1.azelastine0.56mgBID2.levocabastine0.2mgsprayBID

10-itemsymptomscore,globalassessment

Azelastinesuperiortolevocabastine.

Berlinetal1224

2000 1b DBRCT

1.azelastine0.56mgBID2.flunisolide0.116mgsprayBID3.placebo

9-itemsymptomscore

Flunisolidesuperiortoazeslastine;bothtreatmentssuperiortoplacebo.

Goldenetal1225

2000 1b DBRCT

1.azelastine0.56mgBID2.placebo

RSS,ESS Azelastinesuperiortoplaceboforimprovingrhinorrheaandsleepquality.

Bergeretal1226

1999 1b DBRCT

1.azelastine0.56mgBID2.loratadine10mgtabletdaily+beclomethasonedipropionate0.168mgsprayBID

5-itemsymptomscore,globalevaluation

Azelastineatleastaseffectiveascombinationtherapywithloratadineplusbeclomethasonespray.

Sternetal1227 1998 1b DBRCT

1.azelastine0.28mgBID2.budesonide0.256mgspraydaily3.placebo

3-itemsymptomscore

Budesonidesuperiortoazelastine;bothtreatmentssuperiortoplacebo.

Hermanetal1228

1997 1b DBRCT

1.azelastine0.28mgBID2.placebo

TNSS Azelastinesuperiortoplaceboforchildren.

Newson-Smithetal1229

1997 1b DBRCT

1.azelastine0.56mgBID2.beclomethasone0.2mgsprayBID3.placebo

6-itemsymptomscore

Beclomethasonesuperiortoazelastineforlong-termsymptomimprovement;bothtreatmentssuperiortoplacebo;azelastinemorerapidonset.

WeilerandMeltzer1230

1997 1b DBRCT

1.azelastine0.56mgsprayBID+azelastine0.5mgtabletBID2.placebospray+azelastine0.5mgtabletBID

13-itemsymptomscore

Azelastinesprayshowedlimitedbenefitoverplaceboinpatientsalreadytreatedwithsystemicazelastine.

LaForceetal1231

1996 1b DBRCT

1.azelastine0.56mgdaily2.azelastine0.56mgBID3.chlorpheniramine12mgtabletBID

8-itemsymptomscore

Azelastinesuperiortoplaceboatbothdoses;nocomparisonwithchlorpheniramine.

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ICAR:AllergicRhinitis199

4.placeboCharpinetal1232

1995 1b DBRCT

1.azelastine0.28mgBID2.cetirizine10mgtabletdaily

8-itemsymptomscore

Azelastinesuperiorfornasalstuffinessandrhinorrhea;nodifferenceinothersymptoms.

Pelucchietal1233

1995 1b DBRCT

1.azelastine0.28mgBID2.beclomethasonedipropionate0.1mgsprayBID3.placebo

8-itemsymptomscore,nasallavage,methacholinechallenge

Azelastinesuperiortoplaceboandcomparabletobeclomethasoneforsymptomimprovement;neithertreatmentpreventedbronchialresponsiveness;noeffectofazelastineoneosinophils.

Gastparetal1234

1994 1b DBRCT

1.azelastine0.28mgdaily2.terfenadine60mgtabletdaily

13-itemsymptomscore

Comparablesymptomimprovement.

Meltzeretal1235

1994 1b DBRCT

1.azelastine0.28mgdaily2.azelastine0.28mgBID3.chlorpheniramine12mgtabletBID4.placebo

11-itemsymptomscore

Azelastinecomparabletochlorpheniramineandsuperiortoplaceboatbothdoses.

PassaliandPiragine1236

1994 1b DBRCT

1.azelastine0.28mgBID2.cetirizine10mgtabletdaily

13-itemsymptomscore

Azelastineatleastaseffectiveascetirizine.

Ratneretal1237

1994 1b DBRCT

1.azelastine0.28mgdaily2.azelastine0.28mgBID3.placebo

8-itemsymptomscore

Azelastinetwice-dailysuperiortoplacebo.

Daviesetal1238

1993 1b DBRCT

1.azelastine0.28mgBID2.beclomethasonedipropionate0.1mgsprayBID3.placebo

TNSS,rhinomanometry

Azelastinesuperiortobeclomethasoneandplaceboforsymptoms;nochangeinairwayresistancewitheithertreatment.

Dorowetal1239

1993 1b DBRCT

1.azelastine0.28mgBID2.budesonide0.10mgsprayBID3.placebo

13-itemsymptomscore

Azelastinecomparabletobudesonidefornasalsymptomsandsuperiorforocularsymptoms;bothtreatmentssuperiortoplacebo.

Gambardella1240

1993 1b DBRCT

1.azelastine0.28mgBID2.loratadine10mgtabletdaily

12-itemsymptomscore,globalassessment

Azelastineatleastaseffectiveasloratadine.

Gastparetal1241

1993 1b DBRCT

1.azelastine0.28mgBID2.budesonide0.10mgsprayBID

10-itemsymptomscore,nasalflowrate

Azelastineatleastaseffectiveasbudesonideforsymptoms;flowrateimprovedinbothtreatmentgroups.

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ICAR:AllergicRhinitis200

KalpakliogluandKavut1203

2010 2b Single-blindRCT

1.azelastine0.56mgBID2.triamcinoloneacetonide0.22mgspraydaily

TNSS,nPIFR,ESS,SF-36,mini-RQLQ

Comparableimprovementinnasalsymptoms,nPIFR,ESSandQOL;azelastinesuperiorforocularsymptoms.

AR:allergicrhinitis;LOE:levelofevidence;DBRCT:double-blindrandomizedcontrolledtrial;RCT:randomizedcontrolledtrial;BID:twiceaday;rTNSS:1reflectiveTotalNasalSymptomScore;rTOSS:reflectiveTotalOcularSymptomScore;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;QOL:quality2oflife;CGTSQ-AR:CaregiverTreatmentSatisfactionQuestionnaireforAllergicRhinitis;TNSS:TotalNasalSymptomScore;TOSS:TotalOcularSymptom3Score;PRQLQ:PediatricRhinoconjunctivitisQualityofLifeQuestionnaire;CGTSQ:CaregiverTreatmentSatisfactionQuestionnaire;SGA:SubjectiveGlobal4Assessment;RSS:RhinitisSeverityScore;ESS:EpworthSleepinessScale;RCT:randomizedcontrolledtrial;nPIFR:nasalpeakinspiratoryflowrate;SF-36,536-ItemShortForm6

78

910 11

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IX.B.2.Corticosteroids1IX.B.2.a.Oralcorticosteroids2

Theanti-inflammatoryeffectoforalcorticosteroidsinARiswellknownandhasbeen3demonstratedexperimentallyusingthenasalchallengemodelandclinicallyinthecontextofseasonal4disease.Comparedtoplacebo,premedicationwithoralprednisonefor2dayspriortoanallergen5challengeshowedareductioninsneezes,andlevelsofhistamineandmediatorsofvascularpermeability6innasallavagesduringthelatephaseresponse.884[TableIX.B.2.a.]Further,activetreatmentresultedin7areductionintheprimingresponsetoconsecutiveallergenchallenge.884Prednisonehasalsobeen8showntoreducetheinfluxofeosinophilsandlevelsoftheeosinophilmediators(majorbasicprotein9andeosinophilderivedneurotoxin)intonasalsecretionsduringthelatephaseresponsecomparedto10placebo.1242,1243Non-placebo-controlledstudieshavedemonstratedefficacyoforalcorticosteroidsfor11SAR.Schwartzetal1244demonstratedthat15daysofcortisone25mgfourtimesdailyduringthe12ragweedseasonresultedinsignificantreliefofsymptomsin21/25patients.Similarly,100mgof13cortisonedailyfor4daycoursesduringthepollenseasonshowedrhinitissymptomreliefin42/5114patients,with20patientsrelapsingwithin7daysaftercessationoftherapy.1245Oralhydrocortisone40-1580mgdailyhasalsobeenshowntoreducesymptomsofragweedallergies.1246Brooksetal124716performedaplacebocontrolledstudycomparingtheefficacyofmethylprednisolone6,12,or24mgPO17dailyfor5daystoplaceboincontrollingnasalsymptomsduringtheragweedseason.Whereasthe6mg18and12mgdosesledtoasignificantreductioninsomeofthesymptomscomparedtoplacebo19(congestion,postnasaldrainage,andeyesymptoms),the24mgdoseresultedinasignificantreduction20ofallsymptoms(congestion,runnynose,sneezing,itching,postnasaldrainageandeyesymptoms).21

Becauseoftherecognizedsystemicadverseeventsassociatedwithoralcorticosteroids,101their22usehasbeenlargelyreplacedbytheintranasalpreparations.Inadouble-blindplacebo-controlledtrial,23theeffectofintranasalflunisolideanditsoraldosebioequivalent(anoraldosethatwouldleadto24similarsystemiclevels)werecomparedinragweedinducedSAR.1248Theintranasalpreparationwas25showntobeefficaciousinreducingrhinitissymptomswhiletheoraldosingwasnot.Thissuggestedthat26INCSachievetheirbenefitprimarilybytheirlocalactivityasopposedtosystemicbioavailability.Ina27head-to-headcomparisonoftheefficacyofintranasalvssystemicsteroids,Karakietal1249performedan28open-label,parallel,randomizedtrialduringthecedarpollenseasoninJapan.Patientsreceived29loratadine10mgdailyalone,loratadinewithintranasalmometasonefuroate(200mcgoncedaily),or30loratadinewithoralbetamethasone0.25mgtwicedailyfor1week.Thegroupsreceivingsomeformof31steroidinadditiontoloratadinehadsignificantlylowersymptomsofsneezing,rhinorrhea,andnasal32obstructioncomparedtoloratadinealone,withnosignificantdifferencebetweentheintranasaland33oralpreparations.TheoralsteroidwasmoreeffectivethantheINCSincontrollingallergiceye34symptoms.35

TheabovedatasuggestthatoralcorticosteroidsareeffectiveforthetreatmentofAR.36However,giventhesignificantsystemicadverseeffectsrelatedtousingoralcorticosteroidsfor37prolongedperiodsoftimetheseagentsarenotrecommendedfortheroutinetreatmentofAR.3839

• AggregateGradeofEvidence:B(Level1b:5studies;Level2b:1study;Level4:3studies;Table40IX.B.2.a.).41

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ICAR:AllergicRhinitis202

• Benefit:OralcorticosteroidscanattenuatesymptomsofAR.1• Harm:Oralcorticosteroidshaveknownundesirableadverseeffects.Theseincludeeffectsonthe2

hypothalamic-pituitaryaxis,growthandmusculoskeletalsystem,gastrointestinalsystem,3hypertension,glycemiccontrol,mental/emotionalstate,andothers.4

• Cost:Low.5• Benefits-HarmAssessment:Therisksofusingoralcorticosteroidsoutweighthebenefitswhen6

comparedtosimilarsymptomimprovementwiththeuseofINCS.7• ValueJudgments:InthepresenceofeffectivesymptomcontrolusingINCS,theriskofadverse8

effectsfromusingoralcorticosteroidsforARappearstooutweighthepotentialbenefits.9• PolicyLevel:RecommendationagainsttheroutineuseoforalcorticosteroidsforAR.10• Intervention:AlthoughnotrecommendedforroutineuseinAR,certainclinicalscenarios11

warranttheuseofshortcoursesofsystemiccorticosteroidsafteradiscussionoftherisksand12benefitswiththepatient.Thismayincludepatientswithsignificantnasalobstructionthatwould13precludepenetrationofintranasalagents(INCSorantihistamines).Inthesecases,ashortcourse14ofsystemicoralcorticosteroidscouldimprovecongestionandfacilitateaccessandefficacyof15thetopicalagents.16

17 18

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TableIX.B.2.a.Evidencefortheroleoforalcorticosteroidsinthemanagementofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionBrookset

al1247

1993 1b Placebo-controlled,

parallelgroupstudy

SARduringseason(n=31):

MP6,12,24mgQDx5days

Symptomscores Alldosesmoreeffectivethan

placeboinreducingsymptomswith

thehighestdosemosteffective.

Bascomet

al1243

1989 1b Placebocontrolled,

crossover,nasal

challengestudy

SARoutofseason(n=13):

prednisone60mgPOdailyfor2days

Numberofeosinophils

andlevelsofMBPand

EDNinnasallavages

Prednisonereducedthenumberof

eosinophilsandthelevelsofits

mediatorsafterallergenchallenge.

Bascomet

al1242

1988 1b Placebocontrolled,

crossover,nasal

challengestudy

SARoutofseason(n=10):

prednisone60mgPOdailyfor2days

Numberofneutrophils,

eosinophils,and

mononuclearcellsin

nasallavages

Prednisonereducedtheinfluxof

eosinophilsintonasalsecretions

afterallergenchallenge.

Pipkornet

al884

1987 1b Placebocontrolled,

crossover,nasal

challengestudy

SARoutofseason(n=13):

prednisone60mgPOdailyfor2days

Sneezes,levelsof

histamine,TAME-

esterase,kinins,PGD2,

LTC4/D4,andalbuminin

nasallavages

Prednisoneinhibitedthelatephase

responsetonasalallergen

challenge.

Kwaselowet

al1248

1985 1b Multicenter,

randomized,

double-blind,

placebo-controlled

study

SARduringseason(n=99):

1.oralflunisolide500mcgBIDx4

weeks

2.intranasalflunisolide50mcgper

nostrilBIDx4weeks

Symptomscores Intranasalpreparationonlyoneto

showefficacyinreducingrhinitis

symptoms.

Karakiet

al1249

2013 2b Openlabel,parallel,

randomizedtrial

SARduringseason(n=72):

1.loratadine10mgdaily

2.loratadinewithintranasalMF(200

mcgQD)

2.loratadinewithPO

betamethasone0.25mgBID

Symptomscores Thegroupsonsteroidshadlower

symptomscomparedtoloratadine

alone,withnosignificantdifference

betweenthem.

Schwartz1246

1954 4 Observationalcase

series

SARduringseason(n=10):

hydrocortisone40-80mgdaily

Symptomrelief 7/10patientsreportedsymptom

relief

Schillerand

Lowell1245

1953 4 Observationalcase

series

SARduringseason(n=51):

cortisone100mgdailyx4days

Symptomrelief 42/51patientsreportedsymptom

relief

Schwartzet

al1244

1952 4 Observationalcase

series

SARduringseason(n=25):

cortisone100mgdailyx15days

Symptomrelief 21/25patientsreportedsymptom

relief

LOE:levelofevidence;SAR:seasonalallergicrhinitis;MP:methylprednisolone;PO:peros(medicationtakenorally);MBP:majorbasicprotein;EDN:eosinophil2

derivedneurotoxin;TAME:N-a-p-tosyl-L-argininemethylester;PGD2:prostaglandinD2;LTC4/D4:LeukotrieneC4/D4;BID:twicedaily;MF:mometasone3

furoate4

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IX.B.2.Corticosteroids1IX.B.2.b.Injectablecorticosteroids2

Corticosteroidshavebeeninjectedintramuscularlyorintotheturbinatesformanagementof3AR.Theevidenceevaluatingdeepintramuscularinjectionswillbereviewedfirst.Overall,severalearly4studies1250-1254demonstratedclinicaleffectivenessinimprovingallergicsymptoms;however,thesafety5outcomesdemonstratedtheriskofundesiredsystemiccorticosteroidadverseeffects.Morerecent6evidence1255confirmstheincreasedriskofendogenouscortisolsuppressionalongwithother7corticosteroid-relatedadverseeffectssuchasosteoporosisandhyperglycemia.[TableIX.B.2.b.]8

Kronholm1250demonstratedthatasingleinjectionofeitherbetamethasone9dipropionate/betamethasonephosphateormethylprednisoloneacetategivenattheonsetofthehay10feverseasonledtoasignificantreductionofbothnasalandocularsymptomsduringthefiveweeksof11thestudy,withthebetamethasonecombinationbeingmoreeffective.Ohlanderetal1251compared12threelongactingcorticosteroidinjectionsgivenatthebeginningoftheseason,andshowedthatall13treatmentsledtosignificantreductionsinnasalandocularsymptomsduringtheseasonwithno14differencebetweengroups.However,allpreparationsalsosuppressedendogenouscortisol,insome15casesformorethan14daysafterinjection,andtwooutofthethreeinjectionsresultedinincreasesin16bloodsugarlevels.17

Whencomparedtootheragents,injectedcorticosteroidsdemonstratedsimilareffectiveness18outcomes.Specifically,thereweresimilarclinicaloutcomeswhencomparingpreseasonalsteroid19injectionstobothdailyoralprednisolone1252anddailyintranasalbeclomethasonedipropionate20spray.1253Anadrenalcorticotropichormone(ACTH)testperformedat3weeksshowedsignificant21suppressionofadrenalfunctionintheoralsteroidtreatmentgroupandnoevidenceofsuppressionin22thecorticosteroidinjectionortopicalintranasalcorticosteroidgroups.1252Thiswasprobablyrelatedto23theshortdurationofadrenalsuppressionexpectedafterasingleinjectionofcorticosteroidscompared24tocontinuousadministration.25

Whenevaluatingthetimingofinjectablecorticosteroidtherapy,Borumetal1254comparedthe26effectsofasingledepotinjectionofmethylprednisolonegiveneitheratthebeginningoftheallergy27seasonorlaterwhenpollencountspeaked.Comparedtoplacebo,intramuscularmethylprednisolone28wasefficaciousagainstnasalcongestionwithlesspronouncedeffectsagainstrhinorrheaandsneezing.29Theauthorsarguethatdepotinjectablesteroidsmaybeconsideredafterothersafermedicaltherapy30failsandmayprovideaneffectivealternativetreatmentevenifprovidedlateintheallergyseason.31

Injectablecorticorticosteroidpreparationsmayhavesignificantsideeffectswhichinclude32adrenalsuppressionandgrowthretardation.1256InalargeretrospectivestudyofDanishNational33Registries,therelativeriskandincidenceofbothosteoporosisanddiabeteswerehigherinallergic34individualsreceivingatleastonedepotcorticosteroidinjectionduringtheallergyseasoncomparedto35thosereceivingimmunotherapy.125536

SeveralearlyreportsdetailedsignificantimprovementinsymptomsofARinalargeproportion37ofpatientswhoreceivedintraturbinateinjectionsofcortisone,1257hydrocortisoneacetate1258or38prednisolone.1259Similar,non-controlled,studiesshowedimprovementinARsymptomsafter39intraturbinateinjections.1260,1261Amorerecentrandomized,placebo-controlledsingle-blindtrialbyYang40etal1262comparedtheefficacyofintraturbinateinjectionsofeitheronabotulinumtoxinA,41

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triamcinolone,orisotonicsalineinpatientswithPAR.BothonabotulinumtoxinAandtriamcinolone1therapyshowedbettercontrolofnasalsymptomsthanplacebowithonabotulinumtoxinAefficacy2lastinglongest.3

Orbitalcomplicationshavebeenreportedwithintraturbinatebutnotintramuscularinjections.4Basedonalargeclinicalexperience,Mabrycitesanestimatedincidenceofvisuallossafter5intraturbinateinjectionstobe0.006%.1263Othercomplicationshaveincludedtransientvisuallossand6diplopia,1264blurredvisionandtemporaryblindness,1265temporarydistortedvision,decreasedvisual7acuityandparesisofthemedialrectus.1265Martinreportedtherapidonsetofocularpain,blurred8vision,anddecreasedvisualacuityafteranintraturbinateinjectionoftriamcinoloneacetonide.12669Choroidalandretinalarterialembolizationwereconfirmedasthecauseandtheyresolvedcompletely10within24hours.Themechanismofembolizationislikelyrelatedtoretrogradeflowfromtheanteriortip11oftheinferiorturbinatetotheophthalmicartery,followedbyanterogradeflowwiththeparticles12lodgingintheendarteriesofthechoroidandretinalvessels.Largerparticlesizesteroids(e.g.13methylprednisolone)arethoughttopresenthigherriskthanlowersizedparticles(e.g.triamcinolone).1415

• AggregateGradeofEvidence:B(Level1b:3studies;Level2b:3studies,Level4:7studies;Table16IX.B.2.b.).17

• Benefit:InjectablecorticosteroidsimprovesymptomsofARinclinicalstudies.18• Harm:Injectablecorticosteroidshaveknownadverseeffectsonthehypothalamic-pituitaryaxis,19

growthsuppression,osteoporosis,hyperglycemiaandothersystemicadverseeffects.20Intraturbinatecorticosteroidshaveasmall,butpotentiallyserious,riskofocularsideeffects21includingdeclineorlossofvision.22

• Cost:Low.23• Benefits-HarmAssessment:InroutinemanagementofAR,theriskofseriousadverseeffects24

outweighsthedemonstratedclinicalbenefit.25• ValueJudgments:InjectablecorticosteroidsareeffectiveforthetreatmentofAR.However,26

giventheriskofsignificantsystemicadverseeffects,theriskofseriousocularsideeffects,and27theavailabilityofeffectivealternatives(i.e.topicalINCStherapy),injectablecorticosteroidsare28notrecommendedfortheroutinetreatmentofAR.29

• PolicyLevel:Recommendationagainst.30• Intervention:None.31

32 33

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TableIX.B.2.b.Evidencefortheroleofcorticosteroidinjectionsinthemanagementofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionYanget

al1262

2008 1b Randomized,

placebo-

controlledsingle-

blindtrial

PatientswithPARreceived

intraturbinalinjections(n=39):

1.onabotulinumtoxinA(25units

ineachturbinate)

2.triamcinolone(20mg,1ccin

eachturbinate)

3.isotonicsaline(1ccineach

turbinate)

Symptomsofrhinorrhea,

nasalobstruction,sneezing

anditchingat1,4,8,12,16

and20weeksafterinjections

Botoxcontrollednasalsymptoms

forthelongesttimeafter

injection.

Steroidinjectionwasbetterthan

placebobutthedurationofaction

wasshorterthanBotox.

Laursenet

al1253

1988 1b Doubleblind,

doubledummy,

placebo

controlled,study

SARduringseason(n=30):

1.intranasalbeclomethasone

dipropionate(400mcgdaily)for4

weeks

2.IMinjectionof2ml

betamethasone

dipropionate/betamethasone

disodiumphosphateatstartof

season

Rhinoconjunctivitissymptom

scores

IMinjectionsignificantlymore

effectivethanplaceboor

intranasalpreparation.

Borumet

al1254

1987 1b Double-blind,

placebo

controlled,

parallelstudy

during2

consecutive

pollenseasons

SARduring2consecutiveallergy

seasons(n=24):

1.IMinjectionof80mg

methylprednisolonegiveneither

atthebeginningoftheseasonor

atpeakpollencount

2.placebo

Numberofsneezesandnose

blowingduringtheday.

Symptomscoresofsneezing,

rhinorrhea,nasalblockage,

eyeitchingrecordedatthe

endoftheday.

IMinjectionwasefficacious

againstnasalcongestionwithless

pronouncedeffectsagainst

rhinorrheaandsneezinginactive

vsplacebotreatmentirrespective

oftimingofadministration.

Laursenet

al1252

1987 2b Randomized,

double-blind

comparative

SARduringseason(n=37):

1.oralprednisolone7.5mgPO

dailyx3weeks

2.singleIMinjectionof2ml

betamethasone

dipropionate/betamethasone

disodiumphosphateatstartof

season

Nasalpeakflowandsymptom

scores.

ACTHtestperformedat3

weeks.

IMandoralsteroidresultedina

significantreductionof

nasal/ocularsymptomsduring

season.Significantsuppressionof

adrenalfunctionwithoralsteroid

treatmentonly.

Ohlanderet

al1251

1980 2b Prospective,

randomized,

parallelgroup

SARduringseason(n=60).

Received1of3long-actingIM

injections:

Scoresofrhinorrhea,

congestionandocular

Alltreatmentsledtosignificant

reductionsinnoseandeye

symptomsduringseason;no

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ICAR:AllergicRhinitis207

1.betamethasonedipropionate(5

mg)

2.betamethasonedisodium

phosphate(3mg)/acetate(3mg)

3.methylprednisoloneacetate(40

mg)

symptomsat1,2,and4

weeksafterinjection.

Cortisolandglucoseblood

levelsin38subjects.

differencebetweengroups.All

preparationssuppressed

endogenouscortisol;2outof3

injectionscausedincreasesin

bloodsugarlevels.

Kronholm125

0

1979 2b Prospective,

parallel,

randomized,open

label

SARduringseason.IMinjectionat

seasononset(n=42):

1.2mlbetamethasone

dipropionate/betamethasone

phosphate(5and2mg/ml)

2.2mlmethylprednisolone

acetate(40mg/ml)

Weeklynasalandocular

symptomsfor5weeks

Bothpreparationsledtoa

significantreductionofnoseand

eyesymptoms;betamethasone

combinationwasmoreeffective.

Aasbjerget

al1255

2013 4 Retrospective

studyofDanish

National

Registries

between1995-

2011

PatientsreceivingIMsteroid

injectionsinApril-Julyor

immunotherapyagainstgrassor

birchpollen.(n=47,382)

Incidenceandrelativeriskof

osteoporosis,diabetes,

tendonruptureand

respiratorytractinfection

Relativeriskandincidenceof

osteoporosisanddiabeteswere

higherinindividualsreceivingat

leastonedepotcorticosteroid

injectionvsthosereceiving

immunotherapy.

LOE:levelofevidence;PAR:perennialallergicrhinitis;SAR:seasonalallergicrhinitis;IM:intramuscular;PO:peros(medicationtakenorally);ACTH:adrenal1

corticotropichormone2

3

4

5

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IX.B.2.c.Intranasalcorticosteroids(INCS)1

INCSareeffectiveforthetreatmentofAR.Theirpotentanti-inflammatorypropertiesdirectly2

affectthepathophysiologicmechanismsofnasalinflammationinAR.Inbothnasalallergenchallenge3

modelsandseasonaldisease,treatmentwithINCSresultsinsignificantreductioninmediatorand4

cytokinereleasealongwithasignificantinhibitionintherecruitmentofbasophils,eosinophils,5

neutrophils,andmononuclearcellstothenasalmucosaandsecretions.187,389,1267,1268INCSalsoreduce6

theantigen-inducedhyper-responsivenessofthenasalmucosatosubsequentchallengebyantigen1877

andhistamine.1269,12708

Multipleplacebo-controlledclinicaltrialsinadultsandchildrenhavedemonstratedthe9

effectivenessofINCSinthereductionofnasalsymptomsinAR,includingsneezing,itching,rhinorrhea,10

andcongestion.1271,1272Withthereductionofnasalsymptoms,INCSsignificantlyimprovetheQOL1272-127411

andsleep673,706,707,1275,1276ofthesepatients.Nosignificantdifferencesinefficacybetweenavailable12

agentshavebeendemonstratedinstudiedpopulations;1273therefore,sensoryattributesmaybean13

importantfactorinpatientpreferenceandadherencetotherapy.1277Thesesensoryattributesinclude14

aftertaste,noserunout,throatrundown,andsmell.Addressingsomeoftheseconcernsaretwo15

intranasalnon-aqueouspreparationswithhydrofluoroalkane(HFA)aerosolsrecentlyapprovedforthe16

treatmentofARintheUS.Theseincludebeclomethasonedipropionateandciclesonide,bothapproved17

andeffectiveforSARandPARinadultsandchildren12yearsandolder.688,1278-1281Onsetofactionfor18

INCSstartsattimepointsrangingfrom3-5hoursto60hoursafterfirstdosing.1282-1285Althoughthe19

recommendedcontinuousdailyuseofINCSissuperiortootherdosingstrategies,1286,1287studieshave20

demonstratedtheefficacyofas-neededuseofintranasalfluticasonepropionatecomparedto21

placebo.1288,1289[TableIX.B.2.c-1.]22

Alongwithimprovednasalsymptoms,INCShavebeneficialeffectsonallergiceyesymptoms23

includingitching,tearing,redness,andpuffiness.1290-1292Thisissecondarytoareductioninthenaso-24

ocularreflex,whichcontributestotheseeyesymptoms.1293MostINCSleadtoimprovedocular25

symptoms,buttheevidencesuggeststhattheeffectsarenotequalamongINCSpreparations.1294Some26

studieshavesuggestedthatINCSimproveasthmacontrolmeasuresinpatientssufferingfrombothAR27

andasthma.1295,1296[TableIX.B.2.c-2.]28

Incomparativestudies,INCShaveshownsuperiorefficacytoH1antihistaminesincontrolling29

nasalsymptoms,includingnasalcongestion,withnosignificantdifferenceinthereliefofocular30

symptoms.1297-1299INCSaremoreeffectivethanLTRAs.1299,1300[TableIX.B.2.c-3.]31

ThemostcommonsideeffectsofINCSarearesultoflocalirritationandincludedryness,32

burning,stinging,bloodtingedsecretions,andepistaxis.Theincidenceofepistaxiswithdifferent33

preparationsrangesfrom4%to8%overshorttreatmentperiods(2-12weeks)withnodifferences34

betweenplaceboandactivetherapy.1301,1302Instudiescarriedoveroneyear,epistaxisisashighas35

20%.1303,1304SeptalperforationsarerarecomplicationsofINCS.51Asystematicreviewofpublished36

articleslookingatbiopsystudiesinpatientswithARorCRSusingINCSidentified34studies.Ofthose,2137

studiesincludedpatientswithAR,mixedrhinitisandNAR,and13involvedpatientswithCRS38

with/withoutpolyposis.1305Noneofthestudiesthatincludedatrophyofthenasalmucosaasan39

outcomemeasurereportedanyatrophywithINCS.Ameta-analysisofasubgroupofthestudiesshowed40

nosignificantchanceofdevelopingatrophywhiletakingINCS,andnodifferencebetweenactiveand41

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ICAR:AllergicRhinitis209

controlgroupsinbasementmembranecharacteristics.Thereviewalsofoundasignificantreductionin1

theoddsratioforthedevelopmentofsquamousmetaplasiainpatientsusingINCS,suggestinga2

favorableeffect.StudiesinadultsandchildrenevaluatingeffectsofINCSonthehypothalamicpituitary3

axishaveassessedmorningcortisolconcentrations,cosyntropinstimulation,24-hrserumcortisoland4

24-hrurinaryfreecortisolexcretion.Theyshownoadverseeffects.1304,1306-1317Althoughtherehasbeena5

reportofanassociationbetweentheuseofINCSandthedevelopmentofposteriorsubcapsular6

cataracts,1318asystematicreviewofcontrolledtrialsdidnotdemonstrateaclinicallyrelevantimpactof7

INCSoneitherocularpressure,glaucoma,lensopacity,orcataractformation.1319TheeffectofINCSon8

growthinchildrenhasbeeninvestigatedincontrolledstudiesusingbothknemometryinshort-term9

studies(2-4weeks)andstadiometryinlong-term(12months)studies.Ameta-analysisof8randomized10

controlledtrialswithappropriatecontrolsshowedthat,comparedtochildrenusingplacebo,mean11

growthwassignificantlyloweramongchildrenusingINCSintrialsusingknemometry(n=4)andthat12

therewasnosignificantgrowthdifferenceinstudiesusingstadiometry(n=4).1320Thedatasuggeststhat13

INCSmighthavedeleteriouseffectsonshort-termgrowthinchildren,buttheheterogeneityinthe14

stadiometrystudiesmakestheeffectsonlong-termgrowthsuppressionunclear.[TableIX.B.2.c-4.]15

INCSarefirstlinetherapyforthetreatmentofARduetotheirsuperiorefficacyincontrolling16

nasalcongestionandothersymptomsofthisinflammatorycondition.SubjectswithknownSARshould17

startprophylactictreatmentwithINCSseveraldaysbeforethepollenseasonwithanevaluationofthe18

patient’sresponsein2weeks.Inadditiontomakingchangestothetreatmentregimenaccordingtothe19

patient’sresponse,anasalexamevaluatesforsignsoflocalirritationduetothedrugormechanical20

traumafromtheapplicatoritself.Aimingthesprayawayfromthenasalseptummayalsoredcue21

irritationinthisarea.ChildrenreceivingINCSshouldbeonthelowesteffectivedosetoavoidnegative22

growtheffects.23

24

• AggregateGradeofEvidence:A(Level1a:15studies;Level1b:33studies;Level2a:3studies;25Level2b:1study;Level5:1study;TablesIX.B.2.c.1-4).26

• Benefit:INCSareeffectiveinreducingnasalandocularsymptomsofAR.Theyhavesuperior27efficacycomparedtooralantihistaminesandLTRAs.28

• Harm:Intranasalcorticosteroidshaveknownundesirablelocaladverseeffectssuchasepistaxis29withsomeincreasedfrequencycomparedtoplaceboinprolongedadministrationstudies.There30arenoapparentnegativeeffectsonthehypothalamic-pituitaryaxis.Theremightbesome31negativeeffectsonshort-termgrowthinchildren,butitisunclearwhethertheseeffects32translateintolong-termgrowthsuppression.33

• Cost:Low.34• Benefits-HarmAssessment:ThebenefitsofusingINCSoutweightheriskswhenusedtotreat35

SARandPAR.36• ValueJudgments:None.37• PolicyLevel:StrongRecommendationfortheuseofINCStotreatAR.38• Intervention:Thewell-provenefficacyofINCS,aswellastheirsuperiorityoverotheragents,39

makethemfirstlinetherapyinthetreatmentofAR.40 41

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TableIX.B.2.c-1.Evidencefortheclinicalefficacyofintranasalcorticosteroidsinthemanagementofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionRachelefsky

and

Farrar1274

2013 1a SR

SAR(n=2290)andPAR

(n=800).

Sixteencontrolledclinical

trials>2weeksinduration.

Childrenaged2-18years.

Measuresthatassessed

impairmentand/orriskof

comorbidconditions.

Intranasalsteroidsimprovedrisk

outcomesassociatedwithasthmaand

OSA.

Rodrigoand

Neffen1272

2011 1a SRwithmeta-analysis 16trials(n=5348).

SAR:7studies;PAR:9studies.

Adultsandadolescents>12

years:13studies;children:3

studies.

FFNSvsplacebo.

Primaryoutcomes:rTOSS,

iTOSS,rTNSSandiTNSS.

Secondaryoutcomes:QOL,

andadverseeffects.

FFNSsignificantlyimprovedrTOSS,

iTOSS,rTNSS,andiTNSSscores

comparedwithplaceboinpatients

withSARandPAR.Thereweregreater

improvementsinQOLwithafavorable

safetyprofile.

Penagoset

al1271

2008 1a Meta-analysisof

RDBPCTs

16trials(n=2998).

MFNSvsplacebo.

TNSS,individualnasal

symptoms,andTNNSS.

MFNSwasassociatedwithasignificant

reductioninTNSSandTNNSS.

Significanteffectwasseenfornasal

stuffiness/congestion,rhinorrhea,

sneezingandnasalitching.

Yamadaet

al673

2012 1b Randomized,

placebo-controlled,

double-blind,

crossoverstudy

PAR(n=57).

MFNSvsplacebofor14days.

Nasalsymptomscores,QOL

andsleepquality,ESS.

MFNSsignificantlyimprovednasal

symptoms,QOL,andsleepquality.

SignificantreductionoftheESS

observedintheMFNSgroupwithhigh

sleepdisturbance.

Meltzeret

al1276

2010 1b Double-blind,parallel

group,placebo-

controlledstudy

AdultswithPAR,moderate

rhinitisanddisturbedsleep

(n=30).

MFNS200mcgvsplacebo,4-

weektrial.

Primaryendpoint:AHI.

Secondarymeasures:TNSS,

nighttimesymptomscore,

daytimePNIF,nighttime

flowlimitationindex,RQLQ,

ESS,WPAI-AS

AHIwasnotstatisticallysignificantly

differentbetweengroups.MFNS

significantlyimprovedmorningand

eveningTNSS,nasalobstruction/

blockage/congestion,dailypeaknasal

inspiratoryflow,ESS,QOLscore,and2

of5WPAI–ASdomains.

Kaiseret

al1284

2007 1b Double-blind,

parallel-group,

randomized,placebo-

controlledstudy

Adultsandadolescentswith

SAR(n=299).

FFNS110mcgvsplacebo.

Nasalandocularsymptoms

on4-pointscale.

rTNSS,iTNSS,rTOSS,iTOSS

FFNSsignificantlyimproveddaily

rTNSS,morningpre-doseiTNSS,daily

rTOSS,andpatient-ratedoverall

responsetotherapy.Onsetof

therapeuticeffectoccurredat8hours

afterinitialadministration.

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ICAR:AllergicRhinitis211

Craiget

al1275

2003 1b Double-blind,

placebo-controlled

study

PAR(n=32).

FluticasoneNSvsplacebo.

Questionnaires,QOL

instruments,dailydiary,

ESS,andpolysomnography.

Fluticasoneimprovedsubjectivesleep

vsplacebo.Therewasnodifferencein

theAHIintreatedsubjects.

Dykewiczet

al1289

2003 1b RDBPCT Adultsandadolescents>12

year(n=241),SARtofall

allergen.

FPNS200mcgPRNvsplacebo

for4weeks.

Meanchangefrombaseline

inTNSS.

PatientstreatedwithFPNSPRNhada

significantlygreaterreductionfrom

baselineinTNSS.Individualsymptoms

werealsosignificantlyimprovedby

activetherapy.

Hugheset

al706

2003 1b Double-blind,

placebo-con-

trolled,crossover

study

PAR(n=22).

Budesonide128mcg/dayor

placebofor8weeks.

ESS,FunctionalOutcomes

ofSleepQuestionnaire,

RQLQ.

Dailydiaryofnasal

symptoms,sleepproblems,

anddaytimefatigue.

Budesonidesignificantlyimproved

daytimefatigue,somnolence,and

qualityofsleepvsplacebo.

Fokkenset

al1283

2002 1b RDBPCT,parallel-

group,multicenter

PAR(n=202,age6-16years).

BANS128mcgdailyvs.

placebo.

DailynPIF,nasalsymptom

scores,andoverall

evaluationoftreatment

efficacy.Subset(n=76)QOL

byvalidatedquestionnaires.

BANSsignificantlymoreeffectivethan

placebofornPIF,combinedand

individualnasalsymptomscores,and

theoverallevaluationoftreatment

efficacy.Onsetofactionwithinthefirst

12-hourtimeintervalforcombined

nasalsymptomsandwithin48hours

fornPIF.

Dayetal1282

2000 1b RDBPCT,parallel-

group

SAR,ragweed-sensitivity

(n=217),symptomsforat

least1year.

Challengeviachamber.

BANS64mcgvsBANS256

mcgvsplacebo.

Combinednasalscore,

individualnasalsymptoms,

overallevaluationof

treatmentefficacy,nPIF.

7-12hours:BANSbetterthanplacebo

inreducingcombinednasaland

blockednosesymptoms.

nPIF:onsetofaction(3hours)was

shortestforBANS256mcg.Treatment

efficacywashigherforthosereceiving

BANScomparedwithplacebostarting

at5hours.Alltreatmentswell

tolerated,nospecificadverseevents

occurred.

Jenetal1288

2000 1b RDBPCT,parallel-

group.

Adults,SAR,ragweed

sensitivity(n=52).

FPNSPRNvsplacebofor4

weeks.

Nasalsymptomscore,QOL,

eosinophilcountand

eosinophiliccationicprotein

innasallavage.

NasalsymptomscorelowerwithFPNS

vsplacebo.QOLsignificantlyimproved

withFPNS.Eosinophilcount

significantlylowerinwithFPNS.

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ICAR:AllergicRhinitis212

Craigetal707

1998 1b Double-blind,

placebo-controlled

study

PAR(n=20).

TopicalINCSvsplacebo

Dailysymptomdiaryof

nasalsymptoms,sleep,and

daytimesleepiness.

Nasalcongestionandsubjectivesleep

improvedsignificantlyintheINCS

treatedsubjectsbutnotintheplacebo

group.

Dayand

Carrillo1285

1998 1b RDBPCT,multicenter,

parallel-group.

Adults,PAR(n=273).

BANSandFNSPnasalsprays.

Baseline:8-14days.

6weeks:Activetreatment.

Meancombinednasal

symptomsscores(nasal

blockage,runnynose,and

sneezing).

BANSsignificantlydecreasednasal

symptomsvsFPNS.Bothtreatments

significantlydecreasednasalsymptoms

vsplacebo.Timetoachievestatistically

significantimprovement:BANS36

hours,FPNS60hours.Adverseevents

weremildandtransient.

Juniperet

al1286

1990 1b Randomized,double-

blind,parallel-group

Adults,SAR,ragweed

sensitivity(n=60).

1.200mcgaqueous

beclomethasone

diproprionateNS,twicedaily,

1weekbeforeuntil1week

aftertheragweed-pollen

season(regular)

2.100mcgofthespray,taken

PRN,upto400mcgdaily

Sneezing,stuffynose,and

rhinorrhea,measuredbya

dailydiary.QOL

questionnairesandrescue

medicationuse

(terfenadine).

Nasalsymptoms,QOL,anduseof

rescuemedicationsweresignificantly

bettercontrolledintheregular-treated

groupascomparedtothePRNgroup.

Herman1273

2007 2a Reviewof

randomized,

controlled,

comparisontrials

SARandPAR.

14studiesreviewed.

BANS,MFNS,FPNS,orTANS.

Differentendpointsfor

differentstudies

AllfourINCSsadministeredoncedaily

wereeffectiveandwelltoleratedin

thetreatmentofARinadultpatients,

withsimilarefficacyandadverseevent

profiles.Basedonsensoryattributes,

patientspreferredBANSand

TANSvsMFNSandFPNS.

Juniperet

al1287

1993 2b Randomized,non-

blinded,parallel

groupcomparison

Adults,SAR,ragweed

sensitivity(n=60).

Beclomethasonedipropionate

NSregularuse(400mcgdaily)

vsPRNuse.

Dailysymptomsand

medicationuse,QOL,and

patientsatisfactionwith

symptomcontrol.

27%ofPRNpatientsreported

unsatisfactorycontrol,worseQOLand

increasedmedicationuse.Patients

whoachievedsatisfactorycontrolin

theprngrouphadsimilarsymptom

andqualityoflifescorestotheregular

group.

LOE:levelofevidence;SR:systematicreview;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;OSA:obstructivesleepapnea;FFNS:fluticasone1

furoatenasalspray;rTOSS:reflectiveTotalOcularSymptomScore;iTOSS:instantaneousTotalOcularSymptomScore;rTNSS:reflectiveTotalNasalSymptom2

Score;iTNSS:instantaneousTotalNasalSymptomScore;QOL:qualityoflife;RDBPCT:randomizeddoubleblindplacebocontrolledtrial;MFNS:mometasone3

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ICAR:AllergicRhinitis213

furoatenasalspray;TNSS:TotalNasalSymptomScore;TOSS:TotalNasalSymptomScore;ESS:EpworthSleepinessScale;AHI:apnea-hypopneaindex;nPIF:1

nasalpeakinspiratoryflow;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;WPAI-AS:WorkProductivityandActivitiesImpairment–AllergySpecific2

questionnaire;NS:nasalspray;FPNS:fluticasonepropionatenasalspray;PRN:asneeded;BANS:budesonideaqueousnasalspray;INCS:intranasal3

corticosteroid;TANS:triamcinoloneaqueousnasal4

5

6

7

TableIX.B.2.c-2.Effectofintranasalcorticosteroidsoncomorbidities:ocularsymptomsandasthma8

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionLohiaet

al1296

2013 1a SRandmeta-

analysis

AsthmaandAR.

18studies(n=2162).

EfficacyofINCSon

asthmaoutcomes.

Asthmaoutcomes:pulmonary

function,bronchialreactivity,

asthmasymptomscores,asthma-

specificQOL,andrescue

medicationuse.

UseofINCSresultedinsignificant

improvementsinFEV1,bronchial

challenge,asthmasymptomscores,

andrescuemedicationusevs

placebo.INCSimprovedmorning

andeveningPEF.AdditionofINCS

spraytoorallyinhaled

corticosteroidsdidnotresultin

additionalimprovement.

DeWesteret

al1290

2003 1a Retrospective

analysisof

multicenter,

RDBPCTs

7studies.

EfficacyofFPNS200mcg

dailyfornasalandocular

symptomsinpatients

withSAR.

Meanchangefrombaselineinthe

clinician-ratedTOSS(itching,

tearing,redness,andpuffiness)at

7and14daysoftherapy.

FPNSgrouphadsignificantly

greatermeanchangesfrom

baselineintheTOSSandinall4

individualsymptomscoresvs

placeboatdays7and14.

Taramarcaz

and

Gibson1295

2003 1a Meta-analysisof

RCTs

AsthmaandAR.

14studies(n=477).

INCSvsplacebo/routine

asthmatreatment.

Asthmaoutcomes:symptom

scores,FEV1,PEF,and

methacholineairway

responsiveness.

Nostatisticallysignificantbenefitof

INCSinasthma.

Bieloryet

al1291

2011 1a Meta-analysisof

placebo-controlled

RCTs

10studies(n=3132).

SAR:6studies.

PAR:4studies.

MFNS200mcgdaily.

Severityofreflectiveocular

symptoms(itching/burning,

redness,andtearing/watering)on

a4-pointscaleover12hours.

Overalltreatmenteffectwas

significantforallthreeindividual

ocularsymptomsinSARandPAR

studies.

Ratneret

al1292

2015 1b Randomized,

double-blind,

parallel,multicenter

study

SAR(n=614).

FPNS200mcgdailyvs

placebox14days.

Meanchangefrombaselinein

patient-ratedrTOSS

FPNSwassignificantlymore

efficaciousinreducingtheocular

symptomsofARvsplacebo.

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ICAR:AllergicRhinitis214

Baroodyet

al1293

2009 1b Double-blind,

placebo-controlled,

crossovertrial

SARoutofseason(n=20).

FFNS110mcgdailyvs

placebox1week.

Nasalantigenchallenge.

Nasalandocularsymptomsafter

allergenchallenge.

PretreatmentwithFFNS

significantlyreducedeyesymptoms

afternasalallergenchallenge.

LOE:levelofevidence;SR:systematicreview;INCS:intranasalcorticosteroid;AR:allergicrhinitis;QOL:qualityoflife;FEV1:forcedexpiratoryvolumein11

second;PEF:peakexpiratoryflow;RDBPCT:randomizeddoubleblindplacebocontrolledtrial;FPNS:fluticasonepropionatenasalspray;SAR:seasonalallergic2

rhinitis;TOSS:TotalOcularSymptomScore;RCT:randomizedcontrolledtrial;PAR:perennialallergicrhinitis;MFNS:mometasonefuroatenasalspray;rTOSS:3

reflectiveTotalOcularSymptomScore4

5

6

TableIX.B.2.c-3.Comparisonofintranasalcorticosteroidstootheragentsforthetreatmentofallergicrhinitis7

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionBenninger

etal1299

2010 1a SRofRCTsofat

least2-week

duration,and

studyingUS-

approvedINCS

indication/dose.

SAR:38studies(n=11,980

adults,946children).

PAR:12studies(n=3,800

adults,366children).

Medianpercentagechangesfrom

baselineforTNSS.

INCSproducethegreatest

improvementsinnasalsymptomsin

SAR.INCSeffectiveforPAR,but

dataqualityvariable;oral

antihistaminesmaybeequally

effectiveforsomepatients.

Wilsonet

al1300

2004 1a SRandmeta-

analysisofRCTsof

theeffectivenessof

LTRAs

SAR:11studies.

8evaluatingLTRAs(alone

orplusothertreatments)

vsplaceboorother

treatments(n=3924).

3evaluatingLTRAsplus

antihistamine(n=80).

Compositedailyrhinitissymptom

scoresandrhinitis-specificquality

oflife.

LTRAsaremodestlybetterthan

placebo,aseffectiveas

antihistamines,butlesseffective

thanINCSinimprovingsymptoms

andQOLinpatientswithSAR.

Yanezand

Rodrigo129

8

2002 1a SRofRCTs AR:9studies(n=648).

INCSvstopical

antihistamines.

Totalnasalsymptoms,sneezing,

rhinorrhea,itching,andnasal

blockage.

INCSproducedgreaterreliefof

nasalsymptomsvstopical

antihistamines.Nodifference

betweenthe2treatmentsfor

ocularsymptoms.

Weineret

al1297

1998 1a Meta-analysisof

RCTs

AR:16studies(n=2267).

INCSvsoral

antihistamines.

Nasalblockage,nasaldischarge,

sneezing,nasalitch,postnasal

drip,nasaldiscomfort,totalnasal

symptoms,nasalresistance,and

eyesymptomsandglobalratings

INCSproducedgreaterreliefof

nasalblockage,nasaldischarge,

sneezing,nasalitch,postnasaldrip,

andtotalnasalsymptomsvsoral

antihistamines.Nodifference

betweenthe2treatmentsfornasal

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ICAR:AllergicRhinitis215

discomfort,nasalresistance,oreye

symptoms.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;INCS:intranasalcorticosteroid;US:UnitedStates;SAR:seasonalallergicrhinitis;1

PAR:perennialallergicrhinitis;TNSS:TotalNasalSymptomScore;LTRA:leukotrienereceptorantagonist;QOL:qualityoflife;AR:allergicrhinitis;2

3

4

5

TableIX.B.2.c-4.Studiesevaluatingadverseeffectsofintranasalcorticosteroids6

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionAhmadiet

al1319

2015 1a SR 19studiesofINCSreporting

originalocularendpoints(10

RCTs,1case-control,8case

series)included.

IOP,lensopacity,glaucomaor

cataractincidence.

Noneofthe10RCTsreportingIOP

demonstratedchangesvscontrol.None

ofthe6RCTsreportingcataractorlens

opacitydemonstratedchangesvs

control.

Meneret

al1320

2015 1a SRwithmeta-

analysis

8RCTs(n=755)investigating

INCSforARinchildren3-12

years.

Intervalchangeingrowth.

Knemometry(n=342participants,

duration2-4weeks).

Stadiometry(n=413participants,

duration12months).

Knemometrystudies:Mean

growthloweramongchildrenusing

INCS.

Stadiometrystudies:Nosignificant

growthdifferenceinINCSvsplacebo.

Limitations:Difficultyinpredicting

longer-termorcatch-upgrowth.

Verkerket

al1305

2015 1a SR

34studies(11RCTs,5cohorts,

20caseseries)included.

INCSusewithorwithout

controlgroup.

Histopathologyofnasalmucosa.

Mucosalatrophyreportedin17

studies.

Theconceptofnasalmucosalatrophyis

poorlydefined.Nohistologicalevidence

fordeleteriouseffectsfromINCSuseon

humannasalmucosa.

Hampelet

al1317

2015 1b RDBPCT

PAR,children6-11years.

BDP800mcgdaily(n=67)vs

placebo(n=32)for6weeks.

Changein24-hourserumcortisol

frombaseline.

Serumcortisolvaluesremainedstablein

bothgroups.Concentration-time

profilessimilarfortheplaceboandBDP

groupsatbaselineandweek6.

Meltzeret

al1302

2009 1b Subanalysisof

3RDBPCTs,

focusingon

the6-11age

group

SAR:2-weekUSstudy.

PAR:12-weekglobalstudy.

HPAaxissafety:6-weekUS

study.

FF55mcgvsFF110mcgvs

placebodaily(n=948).

Differentendpointswhich

included:adverseevent

monitoring,nasalexaminations,

ophthalmicexaminations,24-

hoururinarycortisolexcretions

andserumcortisol

concentrations.

Epistaxis4%inbothactiveandplacebo

groups.Nodifferencesbetweengroups

forIOP,andnoposteriorsubcapsular

cataracts.NodifferenceinHPA

measuresbetweengroups.

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ICAR:AllergicRhinitis216

Ratneret

al1304

2009 1b Multicenter,

randomized,

controlledtrial

PAR,children6-11years

(n=255).

MFNS100mcgvsBDP168

mcgdailyfor12months.

Symptomcontrolandsafety. Therewasappropriatesymptomcontrol

inbothgroups.Adverseeventswere

mild.Incidenceofepistaxiswas12.7%

withMFNSand9.4%forBDP.

Tripathyet

al1316

2009 1b Double-blind,

randomized

parallel-group

study

PAR,children2-11years

(n=112).

FF110mcgvsplacebodaily

for6weeks.

24-hourserumandurinary

cortisol.

FFplasmameasurements.

FFwasnon-inferiortoplacebowith

respectto24-hourserumcortisol.

Urinarycortisolexcretionover24hour

atbaselineandendoftreatmentsimilar

betweentreatmentgroups.

Weinstein

etal1315

2009 1b RDBPCT,

multicenter,

parallel-group

PAR,children2-5years

(n=474).

TAA110mcgvsplacebodaily

for4weeks.

Adverseevents,morningserum

cortisollevelsandgrowthas

measuredusingoffice

stadiometry.

Adverseeventratescomparable

betweengroups.Nosignificantchange

frombaselineinserumcortisollevels

aftercosyntropininfusion.Distribution

bystature-for-agepercentileremained

stable.

Maspero

etal1301

2008 1b Double-blind,

placebo-

controlled

study.

PAR,children2-11years

(n=558).

FF110mcgvsFF55mcgvs

placebodailyfor12weeks.

Nasalsymptomscoresfor

efficacy.Nasalandophthalmic

examinations,andHPA

assessmentsforsafety.

Epistaxis6%inallgroups.Therewere

nosignificantophthalmicorHPArelated

sideeffectsinthetreatedsubjects.The

lowerdoseofFFreducednasal

symptoms.

Patelet

al1314

2008 1b RDBPCT,

parallel-group

PAR,12-65years(n=112).

FF110mcgdailyfor6weeks

vsprednisone10mgdailyfor

last7daysofstudyvs

placebo.

Changein24-hourserumcortisol

and24-hoururinaryfreecortisol,

total24-hoururinaryfree

cortisol,6-betahydroxycortisol

excretion,andplasma

concentrationofFF.

Ratiofrombaselineinserumcortisol

weightedmean:FFnoninferiorto

placebo,prednisonesignificantly

reducedtheratio.24-hoururinary

cortisolexcretionwassimilarintheFF

andplacebogroups.PlasmalevelsofFF

wereundetectableafter6weeksof

treatment.

Chervinsky

etal1313

2007 1b RDBPCT PARpatients>12years

(n=663).

Ciclesonide200mcgvs

placebodailyforupto52

weeks.

Adverseevents,examfindings,

24-hoururinaryfreecortisol,

morningplasmacortisol,IOP,

lensopacification.

Noclinicallyrelevantdifferences

observedbetweentheciclesonideand

placebogroups.

Kimet

al1312

2007 1b Twoseparate

phase3,

double-blind,

parallel-group,

PAR,children2-5years.

Safety,tolerability,and

efficacyofintranasal

Cortisollevelsweremeasuredat

thebeginningandendofeach

study.Thesystemicexposureof

ciclesonideanditsactive

Changesinplasmaorurinecortisol

levelsshowednodifferenceinactivevs

placebogroup.Serumconcentrations

werebelowthelowerlimitof

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ICAR:AllergicRhinitis217

placebo-

controlled

trials.

ciclesonide200mcgonce

daily.

Firststudy:6weeks.

Secondstudy:12weeks.

metabolitemeasuredat

treatmentendinthe6-week

study.

quantification,suggestingthatsystemic

exposuretociclesonidewaslow.

Rosenblut

etal1303

2007 1b RDBPCT,

parallel-group

PAR(n=806).

FF110mcgvsplacebodaily

for12months.

Adverseevents,24-hurinary

cortisolexcretion,nasaland

ophthalmicexaminations,

electrocardiogramsandclinical

laboratorytests

Incidenceofadverseeventssimilarto

placebo,exceptepistaxis(active20%,

placebo8%).Noclinicallymeaningful

differencesin

ophthalmicparametersorurinecortisol

excretion.

Galantet

al1311

2003 1b RDBPCT AR,children2-3years(n=65).

FP200mcgvsplacebodaily

for6weeks.

12-hoururinary-freecortisol

concentrationatbaselineand

after6weeksoftreatment.

FPgroupequivalenttoplacebogroupin

meanchangefrombaselineof12-hour

urinary-freecortisolattreatmentend.

LOE:levelofevidence;SR:systematicreview;INCS:intranasalcorticosteroid;RCT:randomizedcontrolledtrial;IOP:intraocularpressure;AR:allergicrhinitis;1

RDBPCT:randomizeddoublebloingplacebocontrolledtrial;BDP;beclomethasonedipropionate;PAR:perennialallergicrhinitis;FF:fluticasonefuroate;SAR:2

seasonalallergicrhinitis;HPA;hypothalamicpituitaryaxis;US:UnitedStates;MFNS:mometasonefuroatenasalspray;TAA:triamcinoloneacetonide;FP:3

fluticasonepropionate4

5

6

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IX.B.3.a.Oraldecongestants1

Oraldecongestants,suchaspseudoephedrine,actonadrenergicreceptorsandleadto2vasoconstriction,whichcanrelievenasalcongestioninpatientswithAR.Withextended-releaseoral3decongestantsnasaldecongestioncanlastupto24hours.Oraldecongestantsareavailablefor4usealoneorincombinationwithoralantihistamines.(SeeSectionIX.B.10.a.CombinationTherapy–Oral5AntihistamineandOralDecongestantforadditionalinformationonthistopic.)6

AvailabilityofpseudoephedrineintheUShasbeenlimitedtobehind-the-counteratpharmacies7since2006duetostrictercontroloverthedistributionandsaleofsubstancesthatcanbeusedto8manufacturemethamphetamine.InastudybyMuchaetal,1321pseudoephedrineresultedinsignificant9improvementinallsymptomsinadultswithragweed-inducedAR.[TableIX.B.3.a.]Phenylephrinehas10beenmarketedasanover-the-counter(OTC)medicationasasubstituteforpseudoephedrinefornasal11decongestion.However,aRCTbyHoraketal1322foundthatwhilepseudoephedrinewassignificantly12moreeffectiveatreducingnasalcongestionthanbothplaceboandphenylephrine,therewasno13significantdifferencebetweenphenylephrineandplacebo.Inaddition,Meltzeretal1323performeda14randomized,open-label,dose-rangetrialin539patientswithSARandfoundphenylephrinetobeno15moreeffectivethanplaceboinreducingsymptomaticnasalcongestion.16

Knownsideeffectsofthisclassofmedicationsincludeinsomnia,nervousness,anxiety,tremors,17palpitations,andincreasedbloodpressure.TwosystematicreviewsbySalernoetal1324,1325lookedatthe18effectoforaldecongestantsonbloodpressure.Thefirststudyshowedthat19phenylpropanolaminesignificantlyincreasedsystolicbloodpressure(SBP)by5.5mmHg(95%CI:3.1-8.0)20anddiastolicbloodpressure(DBP)by4.1(95%CI2.2-6.0)withnoeffectonheartrateascomparedto21placebo.1324Thesecondstudyfoundthatpseudoephedrinealsocausedasmallbutsignificantincreasein22SBPby0.99mmHg(95%CI0.08-1.9)andHRby2.83beats/min(95%CI2.0-3.6)withnoeffecton23DBP.1325Additionally,higherdosesandimmediate-releasepreparationsofpseudoephedrinewere24associatedwithgreaterBPelevations.1325Further,inastudybyKernanetal,1326phenylpropanolamine25useinwomenwasanindependentriskfactorforhemorrhagicstroke.Phenylpropanolamineisnolonger26availableonthemarket.Giventhesecardiovascularsideeffects,oraldecongestantsshouldbeusedwith27cautioninpatientswhoarealreadyatriskforhypertensionanditssequelae(e.g.coronaryartery28disease,cerebralvasculardisease,hyperthyroidism,arrhythmias).Bloodpressureshouldbeclosely29monitoredforanychangeswhenusingoraldecongestantsinthispopulation.30

Oraldecongestantsareknowntobeeffectiveinchildrenolderthan6yearsofage.However,31careshouldbetakenintheyoungerpopulation(lessthan2yearsofage)asthispopulationismore32pronetotoxicity,andsafedosingrecommendationshavenotyetbeenestablishedforthisagegroup.132733Ininfantsandyoungchildren,oraldecongestantsmayhavecentralnervoussystem(CNS)stimulatory34effectswithknowncasesofpsychosis,ataxia,andhallucinationswithingestion.1328,1329Evaluationofrisk35andbenefitsshouldbeconsideredinpatientslessthan6yearsold.3637

• AggregateGradeofEvidence:B(Level1a:2studies;Level1b:3studies;Level3b:2studies;38Level4:2studies;TableIX.B.3.a.).39

• Benefit:Reductionofnasalcongestionwithpseudoephedrine.Nobenefitwithphenylephrine.40

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ICAR:AllergicRhinitis219

• Harm:Sideeffectsincludeinsomnia,lossofappetite,irritability,palpitations,andincreased1bloodpressure.Riskoftoxicityinyoungchildren.2

• Cost:Low. 3• Benefits-HarmAssessment:Balanceofbenefitandharmforpseudoephedrine.Harmlikely4

outweighsbenefitforphenylephrine.5• ValueJudgments:Considerationofpatient’sothercomorbiditiesandageshouldbeconsidered6

beforeusage.7• PolicyLevel:Optionforpseudoephedrine.Recommendationagainstforphenylephrine.8• Intervention:Pseudoephedrineasanoraldecongestantcanbeeffectiveinreducingsymptomof9

nasalcongestioninpatientswithAR;usedforshorttermsymptomrelief.Sideeffects,10comorbidities,andageofpatientshouldbeconsideredbeforeuse.11

12 13

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TableIX.B.3.a.Evidencefortheroleoforaldecongestantsinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Salernoetal1324

2005 1a SR 1.pheynylpropanolamine2.placebo

SBP,DBP,HR PhenylpropanolaminecausedincreaseinSBP.

Salernoetal1325

2005 1a SR 1.pseudoephedrine2.placebo

SBP,DBP,HR PseudoephedrinecausedincreaseinSBPandHR.

Meltzeretal1323

2015 1b RCT 1.phenylephrine10mg(n=109)2.phenylephrine20mg(n=108)3.phenylephrine30mg(n=107)4.phenylephrine40mg(n=112)5.placebo(n=103)

Dailyreflectivenasalcongestionscore

Phenylephrineisnotbetterthanplaceboatrelievingnasalcongestion.

Horaketal1322

2009 1b RCT 1.pseudoephedrine2.phenylephrine3.placebo

Subjectiveevaluationofnasalcongestion

Pseudoephedrineresultedinimprovementinnasalcongestion.Phenylephrinedidnotimprovenasalcongestion.

Muchaetal1321

2006 1b RCT 1.pseudoephedrine2.montelukast

Nasalsymptoms,nPIF,QOL

SignificantimprovementfrombaselineinallsymptomsofAR,nPIF,andQOLwithbothpseudoephedrineandmontelukast.

Vernacchioetal1327

2008 3b Non-consecutivecohort

Pseudoephedrineuseinpediatricpopulation

Childrenlessthan2yearsofageareatthehighestriskfortoxicitywithpseudoephedrine.Safedosingrecommendationsarelackingforthisagegroup.

Kernanetal1326

2000 3b Case-control 1.historyofsubarachnoidorintracerebralhemorrhage2.control

Associationbetweentheuseofphenylpropanolamineandtheriskofahemorrhagicstroke.

Phenylpropanolamineisanindependentriskfactorforhemorrhagicstrokeinwomen.

Robergeetal1328

1999 4 Casereport 2-year-olddevelopedpsychosisandataxiaafterbeingovermedicatedwithpseudoephedrine/dextromethorphancoughpreparation.

Sauderetal1329

1998 4 Casereport 3-year-oldwithvisualhallucinationscausedbyinappropriatelyhighdosesofpseudoephedrine.

LOE:levelofevidence;SR:systematicreview;SBP:systolicbloodpressure;DBP:diastolicbloodpressure;HR:heartrate;RCT:randomizedcontrolledtrial;2nPIF:nasalpeakinspiratoryflow;QOL:qualityoflife;AR:allergicrhinitis;3

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IX.B.3.Decongestants1IX.B.3.b.Intranasaldecongestants2

Topicaldecongestants,suchasxylometazolineandoxymetazoline,arealpha-adrenergic3stimulatorsdelivereddirectlytonasalmucosaltissuethatresultinvasoconstrictionandreductionof4mucosalthickness.Inan18-daystudy,Barnesetal.foundthatnasalxylometazolinewasastronger5decongestantthannasalcorticosteroids.1330[TableIX.B.3.b.]Topicaldecongestantsrelievethesymptom6ofnasalcongestion,howevertheyhavenoeffectonothersymptomsofAR,suchassneezing,7rhinorrhea,ornasalitching.8

RM[rhinitismedicamentosa],aconditionthoughttoresultfromprolongedusageoftopical9decongestants,involvesanincreaseinsymptomaticnasalcongestion,therebyprecludinga10recommendationforchronicuseofthismedication.Studiestoidentifythedurationoftopical11decongestantusethatleadstorhinitismedicamentosahaveshownvariableresults.Somestudiesshow12prolongeduseupto8weeksdoesnotproduceanysymptomsofreboundnasalcongestion,83,1331while13othersnotedevelopmentofRMwithin3daysofuse.7214

Knownadverseeffectsoftopicaldecongestantsincludenasalburning,stinging,dryness,15epistaxis,andmucosalulceration.Whiletopicaldecongestantsareeffectiveatreducingnasal16congestion,shorttermuseofthemedication,3daysorless,isrecommendedtoavoidthepotentialfor17reboundnasalcongestionandeffectsonmucociliaryactivity.(SeesectionIII.C.2.DifferentialDiagnosis–18RhinitisMedicamentosaforadditionalinformationonthistopic.)1920

• AggregateGradeofEvidence:B(Level1b:3studies;Level2b:1study;TableIX.B.3.b.).21• Benefit:Reductionofnasalcongestionwithtopicaldecongestants.22• Harm:Sideeffectsincludenasalburning,stinging,dryness,andmucosalulceration.23

Potentialforreboundcongestionwhenusedlongterm.24• Cost:Low.25• Benefits-HarmAssessment:Harmlikelyoutweighsbenefitifusedmorethan3days.26• ValueJudgments:Topicaldecongestantscanbehelpfulforshort-termreliefofnasal27

congestion.28• PolicyLevel:Option.29• Intervention:Topicaldecongestantscanprovideeffectiveshort-termnasaldecongestionin30

patientswithAR,butrecommendagainstchronicuseduetoriskforRM.31

32

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TableIX.B.3.a.Evidencefortheroleoftopicalintranasaldecongestantsinthemanagementofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Barnesetal1330

2005 1b RCT (n=36)1.nasalxylometazoline2.nasalmometasonefuroate

nPIF,nasalforcedinspiratoryvolumein1second,nasalblockagescore

Xylometazolinewasastrongernasaldecongestantthanmometasonefuorate.

Watanabeetal1331

2003 1b RCT (n=30)1.oxymetazolineTID2.placebo

Subjectivenasalblockage,nPIF,airwayresistance,airwayvolume

Nosignificantnasalblockageorimpaireddecongestantresponsetooxymetazolinefollowing4-weektreatment.

Morrisetal72 1997 1b RCT (n=50)1.dailyoxymetazoline2.intermittentoxmetazoline3.placebo

Nasalairwayresistance,subjectivescalingofnasalpatency,clinicalexamination

Evidenceofreboundnasalcongestionwasfoundfollowing3daysofbothdailyandintermittentoxymetazolinetreatment.

Yooetal83 1997 2b Individualcohortstudy

(n=10)dailyoxymetazoline

Subjectivehistory,physicalexam,anteriorrhinomanometry

Allsubjectsremainedresponsivetooxymetazoline4weeksand8weeksafterthestudybegan.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;nPIF:nasalpeakinspiratoryflow;TID:threetimesdaily234

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IX.B.4.Leukotrienereceptorantagonists(LTRA)1

LTRAshavebeenstudiedandusedinthetreatmentofAR.MontelukastisapprovedbytheUS2

FDAforthetreatmentofSARinadultsandchildrenover2yearsofage,andforPARinadultsand3

childrenover6monthsofage.Severalsystematicreviewsandmeta-analysesofRCTshave4

demonstratedsymptomreductionandimprovedQOLinpatientstreatedwithLTRAmonotherapy5

comparedtoplacebo.1300,1332-1335

Nevertheless,inaclinicalpracticeguidelineonARfromtheAAO-HNS6

therewasarecommendationagainstLTRAmonotherapy,citingdecreasedeffectivenesscomparedto7

otherfirst-lineagents.7618

Systematicreviewidentified28studies,ofwhich19wereconsideredlevel1evidence,9

examiningtheuseofLTRAmonotherapyinAR.[TableIX.B.4.]Multiplesystematicreviews1300,1332-1335

10

andRCTs1336-1344

demonstratedthatLTRAmonotherapywassuperiortoplaceboatimprovingpatient11

symptomsandQOL.ThiseffectwasconsistentinstudiesofSAR,1340-1344

PAR,1339

andartificialallergen12

exposure.1336-1338

Furthermore,inadouble-blindRCTbyPhilipetal1341

montelukastimprovedbothAR13

andasthmadisease-specificQOLinpatientswithconcurrentSARandasthma.14

DespitemultiplestudiesdemonstratingsuperioreffectofLTRAmonotherapyoverplaceboin15

thetreatmentofAR,thereisconsistentevidencethatLTRAisinferiortoINCS.1300,1333-1335,1345,1346

Multiple16

systematicreviewsandmeta-analyseshaveshownthatINCSresultingreatersymptomreductionand17

QOLimprovementcomparedtoLTRA.1300,1333-1335

Adouble-blindedRCTbyPulleritsetal1346

showed18

decreasednumbersofactivatedtissueeosinophilsinnasalmucosabiopsiesinpatientstreatedwith19

intranasalbeclomethasonecomparedtozafirlukastandplacebo.Thereisconflictingevidenceonthe20

relativeeffectofLTRAcomparedtooralantihistamines,withtwosystematicreviewsdemonstratingthat21

oralantihistamineshavesuperiorsymptomreductionandQOLimprovement1300,1333

andathirdstudy22

indicatingequivalenteffect.1334

Moreover,adouble-blindRCTbyMuchaetal1321

indicatedthat23

montelukastandpseudoephedrineyieldedequivalentsymptomreductionandQOLimprovement.In24

thatstudy,objectivemeasurementofnasalpeakinspiratoryflowwasnotdifferentbetweenthe25

montelukastandpseudoephedrinetreatmentgroups.26

Inadditiontolessrelativeeffectivenesscomparedtootheragents,theAAO-HNSclinical27

practiceguidelineonARcitedincreasedcostsofLTRAintherecommendationagainstthisdrugclassas28

monotherapyinpatientswithARwithoutasthma.761Goodmanetal

1347examinedtherelativecost29

effectivenessofmontelukastcomparedtoseveralsecond-generationoralantihistamines.Montelukast30

wasdeterminedtohaveincreasedcostforrelativeeffectivenesscomparedtolevocetirizine,31

desloratadine,andbrandedandgenericfexofenadine.Theannualdrugandincurredmedicalcostsfor32

montelukastwereestimatedtobe$631.33

LTRAmonotherapymaybeausefulalternativeinrarepatientswithcontraindicationsforboth34

INCSandoralantihistamines,butthislimitsrecommendationsoroptionsfortheseagentsingeneral.In35

patientswithconcurrentARandasthma,LTRAcancontributetosymptommanagementofboth36

respiratorydiseases.LTRAmonotherapyisnotrecommendedasfirst-linetreatmentforpatientswith37

concurrentARandasthma,althoughthismaybeaconsiderationinpatientswithcontraindicationsto38

INCS.39

40

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ICAR:AllergicRhinitis224

• AggregateGradeofEvidence:A(Level1a:6studies;Level1b:17studies;Level2a:2studies;1

Level2b:3studies;Level4:3studies;TableIX.B.4.).2

• Benefit:ConsistentreductioninsymptomsandimprovementinQOLcomparedtoplacebo,as3

demonstratedinRCTsandsystematicreviewofRCTs.4

• Harm:ConsistentlyinferiorcomparedtoINCSatsymptomreductionandimprovementinQOLin5

RCTsandsystematicreviewsofRCTs.Equivalent-to-inferioreffectcomparedtooral6

antihistaminesinsymptomreductionandimprovementofQOL.7

• Cost:Annualincurreddrugandmedicalcostsestimatedtobe$631forgenericmontelukast.8

• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.LTRAsareeffectiveas9

monotherapycomparedtoplacebo.However,thereisaconsistentlyinferiororequivalent10

effecttoother,lessexpensiveagentsusedasmonotherapy.11

• ValueJudgments:LTRAsareequivalenttooralantihistaminealoneandmoreeffectivethan12

placeboatcontrollingbothasthmaandARsymptomsinpatientswithbothconditions.Control13

ofARsymptomswithLTRAs,however,islesseffectivethanINCS,andinferiororequivalentto14

oralantihistamines.Therefore,evidenceislackingtorecommendLTRAsasfirst-orsecond-line15

monotherapyinthemanagementofARaloneorincombinationwithasthma.16

• PolicyLevel:RecommendationagainstasfirstlinetherapyforAR.17

• Intervention:LTRAsshouldnotbeusedasmonotherapyinthetreatmentofARbutcanbe18

consideredassecond-linetherapy,suchaswhenINCSarecontraindicated.19

20

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TableIX.B.4.Evidencefortheuseofleukotrienereceptorantagonistsasmonotherapyinthetreatmentofallergicrhinitis(Level1aand1b1studiesonly)2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionDevillieretal1332

2014 1a SRofRCTs,withhomogeneity

1.LTRA2.SLIT3.placebo

Symptoms SLITsuperiorclinicaleffecttoLTRA.LTRAwithclinicaleffectcomparedtoplacebo.

Goodmanetal1347

2008 1a SRofRCTs,withhomogeneity

1.montelukast2.levocetirizine3.desloratadine4.fexofenadine

Symptoms,cost Montelukastwithhigherincrementalcost-effectivenessratiothanlevocertirizineanddesloratadine.

Grainger&Drake-Lee1333

2006 1a SRofRCTs,withhomogeneity

1.montelukast2.oralantihistamine3.INCS4.placebo

Symptoms,QOL MontelukastimprovedsymptomsandQOLcomparedtoplacebo,andwasinferiortooralantihistaminesandINCS.

Rodrigo&Yanez1334

2006 1a SRofRCTs,withhomogeneity

1.LTRA2.oralantihistamine3.INCS4.placebo

Symptoms,QOL LTRAimprovedsymptomsandQOLcomparedtoplacebo,wasequallyeffectivetooralantihistamine,andinferiortoINCS.

Wilsonetal1300 2004 1a SRofRCTs,withhomogeneity

1.montelukast2.oralantihistamine3.INCS4.placebo

Symptoms,QOL MontelukastimprovedQOLcomparedtoplacebo,andwasinferiortoantihistaminesandINCS.

Gonyeau&Partisan1335

2003 1a SRofRCTs,withhomogeneity

1.montelukast2.INCS3.placebo

Symptoms Montelukastwasmoreeffectivethanplaceboinreducingsymptoms,butwasinferiortoINCS.

Endoetal1336 2012 1b RCT 1.pranlukast2.placebo

Symptoms Pranlukastpreventedandreducedsymptomscomparedtoplaceboafterartificialintroductionofallergen.

Wakabayashietal1337

2012 1b RCT 1.pranlukast2.placebo

Symptoms Pranlukastreducedsymptomscomparedtoplaceboinchildrenwithartificialallergenexposure.

Dayetal1338 2008 1b RCT 1.montelukast2.levocetirizine3.placebo

Symptoms Bothmontelukastandlevocertirizineimprovedsymptomsfollowingartificialallergenexposures.Levocertirizinewasmoreeffectivethanmontelukast.

Jiang1348 2006 1b RCT 1.zafirlukast2.loratadine

Symptoms,acoustic

Alltreatmentgroupshadasignificantreductionofpre-treatmentsymptoms.Zafirlukastwassuperioratreductionofnasalcongestion.Therewereno

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3.loratadine+pseudoephedrine

rhinometry,rhinomanometry

differencesinacousticrhinometryandrhinomanometrybetweenthe3treatmentgroups.

Muchaetal1321 2006 1b RCT 1.montelukast2.pseuodephedrine

Symptoms,QOL,nasalpeakinspiratoryflow

Montelukastandpseudoephedrinehadequivalentimprovementofsymptoms(exceptnasalcongestionforwhichpseudoephedrinewasmoreeffective),QOL,andnasalpeakinspiratoryflow.

Pateletal1339 2005 1b RCT 1.montelukast2.placebo

Symptoms,QOL MontelukastwasmoreeffectivethanplaceboinreducingsymptomsandimprovingQOLinpatientswithperennialallergicrhinitis

Chervinskyetal1340

2004 1b RCT 1.montelukast2.placebo

Symptoms,pollencount

Montelukastwasmoreeffectivethanplaceboinreducingsymptoms.Theeffectsizewasrelatedtotheamountofpollenexposure.

Philipetal1341 2004 1b RCT 1.montelukast2.placebo

Symptoms,rhinitisQOL,asthmaQOL

Montelukastimprovedsymptoms,rhinitisQOL,andasthmaQOLcomparedtoplaceboinpatientswithconcurrentseasonalallergicrhinitisandasthma.

Ratneretal1345 2003 1b RCT 1.montelukast2.fluticasone

Symptoms,QOL FluticasonewasmoreeffectivethanmontelukastinreducingsymptomsandimprovingQOL.

vanAdelsburgetal1342

2003 1b RCT 1.montelukast2.loratadine3.placebo

Symptoms,QOL MontelukastwasmoreeffectivethanplaceboinreducingsymptomsandimprovingQOL.Montelukastnotdirectlycomparedtoloratadine.

vanAdelsburgetal1343

2003 1b RCT 1.montelukast2.loratadine3.placebo

Symptoms,QOL MontelukastwasmoreeffectivethanplaceboinreducingsymptomsandimprovingQOL.Montelukastnotdirectlycomparedtoloratadine.

Philipetal1344 2002 1b RCT 1.montelukast2.loratadine3.placebo

Symptoms,QOL,peripheraleosinophilcount

Montelukastwasmoreeffectivethanplaceboinreducingsymptomsandperipheraleosinophilcount,andimprovingQOL.Montelukastnotdirectlycomparedtoloratadine.

Pulleritsetal1346

1999 1b RCT 1.zafirlukast2.beclomethasone3.placebo

Symptoms,tissueeosinophilia

Zafirlukastwasnotdifferentfromplaceboinsymptomortissueeosinophiliareduction.Bothwereinferiortointranasalbeclomethasone.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;LTRA:Leukotrienereceptorantagonist;SLIT:sublingualimmunotherapy;INCS:1intranasalcorticosteroids;QOL:qualityoflife234 5

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IX.B.5.Cromolyn1

Disodiumcromoglycate(DSCG)[synonyms:cromolynsodium,sodiumcromoglycate,disodium24,4'-dioxo-5,5'-(2-hydroxytrimethylenedioxy)-di(4H-chromene-2-carboxylate)]wasfirstusedbyancient3Egyptiansforitsspasmolyticproperties.ItisderivedfromtheplantAmnivisnaga.DSCGisamastcell4stabilizerthatpreventshistaminerelease.Itimpedesthefunctionofchloridechannelsimportantin5regulatingcellvolumeandpreventsextracellularcalciuminfluxintothecytoplasmofthemastcell,thus6preventingthedegranulationofsensitizedcells.1349,1350DSCGisbestusedprophylacticallytopreventthe7onsetofsymptomsbyinterruptingthephysiologicalresponsetonasalallergens.8

DSCGwasdiscoveredover50yearsago,andsincethattimeothercromoglycatetypeagents9(chromones)havebeendeveloped.Thechromoneshavedemonstratedtheabilitytoinhibittheearly10phaseandlatephasereactionsofasthma.1351Initialstudiesfocusedonhistamineandcytokinerelease11frommastcells.Morerecentstudieshaveshownanti-allergyactivityunrelatedtomastcellactivation,12butratherthroughtheinhibitionofmacrophages,eosinophils,monocytes,andplatelets.1352-135413

DSCGcanbeusedinaninhaledformasaprophylacticagentinthetreatmentofmild-moderate14asthma,asanasalspraytotreatSAR,orasanophthalmicsolutiontotreatallergicorvernal15conjunctivitis.DSCGmayalsobetakenorallytocontrolallergicreactionstocertainfoods.Itcanbeused16forpatients2yearsandolderbuthasashorthalf-liferequiringdosingof3-6timesdaily.1355DSCGhasan17excellentsafetyprofile,althoughtheneedforfrequentdosingmayaffectcompliance.Minoradverse18effectsincludenasalirritationorburning,sneezing,epistaxis,andbadtaste.135519

MoststudiescomparingDSCGdirectlytoplacebohaveshownthatitiseffectiveinpatientswith20SAR.[TableIX.B.5.]StudiesontheefficacyofDSCGinPARhavebeencontroversial.1356-1360Inarecent21RCT,Lejeuneetal1356examinedtheroleofDSCGinmonosensitizedPARpatientsandfoundthatDSCG22resultedinsignificantreductioninsymptomscoresfornasalobstruction,dischargeandsneezing23comparedtoplacebo.WhencomparedtoINCS,DSCGhasbeenshowntobelesseffective.1357,1361-1369To24date,therehavebeennodirectcomparisonsbetweenDSCGandintranasalantihistamines.Ultimately,25theroleofDSCGasaprimarytreatmentforARislimitedgivenitslowerefficacywhencomparedtoINCS26andpotentialcompliancechallengessecondarytofrequentdosingregimen.2728

• AggregateGradeofEvidence:A(Level1b:13studies;Level2b:9studies;TableIX.B.5.)29• Benefit:DSCGiseffectiveinreducingsneezing,rhinorrheaandnasalcongestion.30• Harm:Rarelocalsideeffectsincludenasopharyngealirritation,sneezing,rhinorrhea,and31

headache.32• Cost:Low.33• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.Benefitisconsideredmildto34

moderate.LesseffectivethanINCS.35• ValueJudgments:Usefulforpreventativeshorttermuseinpatientswithknownexposurerisks.36• PolicyLevel:Option.37• Intervention:DSCGmaybeconsideredforthetreatmentofAR,particularlyinpatientsknown38

triggerswhocannottolerateINCS.39 40

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TableIX.B.5.Evidencefortheuseofdisodiumcromoglycateinthetreatmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Lejeuneetal1356

2015 1b DBRCT

PAR,adults:1.DSCGQID(n=14)2.placebo(n=7)

Symptomscores,nasalcytology,allergicmediators

DSCGperformedbetterthanplacebo.

Meltzer1370

2002 1b DBRCT

SAR,over12yearsold:1.DSCG4%,1sprayq4-6hours(n=580)2.placebo(n=570)

Nasalsymptoms DSCGperformedbetterthanplacebo.

Schulleretal1371

1990 1b DBRCT

SAR,12-65yearsold:1.nedocromil1%(n=80)2.DSCG4%,1sprayQID(n=7)3.placebo(n=77)

Nasalsymptoms NedocromilwasequivalenttoDSCG.Bothperformedbetterthanplacebo.

Chandraetal1372

1982 1b

DBRCT,crossover

SAR,9-41yearsold(n=47):1.DSCG4%,1sprayq3-4hours2.placebo

Nasalsymptoms,medicationuse

DSCGperformedbetterthanplacebo.

Brownetal1367

1981 1b RCT

SAR:1.DSCG2.6mg6timesperday(n=29)2.flunisolide25µgBID(n=38)

Nasalsymptoms FlunisolideperformedbetterthanDSCG.

Craigetal1373

1977 1b DBRCT SAR(n=39):1.DSCG5.2mg6timesperday(n=22)2.placebo(n=17)

Nasalsymptoms,medicationuse

NodifferencebetweenDSCGandplacebo.

Handelman

etal1374

1977 1b DBRCT SAR,6-51yearsold:1.DSCG62.4mg6timesperday(n=45)2.placebo(n=45)

Symptomscore,medicationuse

DSCGperformedbetterthanplacebo.

McDowell&Spitz1358

1977 1b DBRCT,crossover

PAR,17-71yearsold(n=13):1.DSCG2.5mg6timesperday2.placebo

Nasalsymptoms,cytology

Nosignificantdifferenceinmajorityofpatients.

Nizami&Baboo1375

1977 1b DBRCT,crossover

SAR,7-59yearsold(n=92):1.DSCG10mgQID2.placebo

Nasalsymptoms DSCGperformedbetterthanplacebo.

Posey&Nelson1376

1977 1b

DBRCT SAR,12-54yearsold:1.DSCG4%,6timesperday(n=17)2.placebo(n=17)

Symptomscore,medicationuse

Nodifference,exceptforin-seasonuseofmedicationsinDSCGgroup.

Warland&Kapstad1359

1977 1b DBRCT,crossover

PAR,15-57yearsold(n=17):1.DSCG10mgQID2.placebo

Nasalsymptoms NodifferencebetweenDSCGandplacebo.

Cohanet 1976 1b DBRCT, PAR,16-37yearsold: Symptomscore, DSCGperformedbetterthan

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al1360

crossover 1.DSCG4%,6timesperday2.placebo

medicationuse placebo.

Knightetal1377

1976 1b DBRCT

SAR:1.DSCG10mgQID(n=35)2.placebo(n=41)

Nasalsymptoms DSCGperformedbetterthanplacebo.

Langeetal1361

2005 2b RCT,noplacebo

SAR,18-65yearsold:1.MF200µgQD(n=41)2.levocabastine200µgBID(n=40)3.DSCG5.6mgQID(n=42)

Symptomscores,nPIF

MFperformedbest.

Fisher1362

1994 2b RCT,blinded,noplacebo

SAR,6-15yearsold:1.DSCG31.2mg,6timesperday(n=26)2.budesonideBID,400µg/day(n=30)

Nasalsymptoms BudesonideperformedbetterthanDSCG.

Bousquetetal1363

1993 2b DBRCT,noplacebo

SAR:1.FP200µgQD(n=110)2.DSCG5.2mgQID(n=108)

Nasal/ocularsymptoms,medicationuse

FPbetterinallexceptnasaldischarge.Nodifferenceinmedicationuse

Welshetal1364

1987 2b RCT,blinded 1.BDP2spraysBID,336µg/day2.flunisolide2spraysBID,200µg/day3.DSCG1sprayQID,41.6mg/day4.placebo

Symptomscore,medicationuse

Allmedicationswerebetterthanplacebo.DSCGwastheleasteffective.

Bjerrum&Illum1365

1985 2b DBRCT,noplacebo

SAR,15-55yearsold:1.budesonide200µgBID(n=22)2.DSCG5.2mg,5timesperday(n=21)

Nasalsymptoms BudesonidewasbetterthanDSCG.

Morrow-Brownetal1366

1984 2b RCT,noplacebo

SAR,11-71yearsold:1.BDP2spraysBID,400µg/day(n=47)2.DSCG2.6mg,6timesperday(n=39)

Symptomscore,medicationuse

BDPperformedbetterthanDSCG.Nodifferenceinrescuemedications.

Tandon&Strahan1357

1980

2b DBRCT,crossover,noplacebo

PAR,13-45yearsold(n=14):1.BDP50µgQID2.DSCG10mgQID

Nasalsymptoms BDPperformedbetterthanDSCG.

Wilson&Walker1368

1976 2b RCT,noplacebo

SAR,adults:1.DSCG10mgQID(n=10)2.BV100µgBID(n=10)

Nasalsymptoms BVperformedbetterthanDSCG.

Frankland

andWalker1369

1975 2b

DBRCT,noplacebo

SAR,adults:1.DSCG80µg,6timesperday(n=14)2.BV100µgBID(n=18)

Nasalsymptoms,nPIF

BVperformedbetterthanDSCGforsymptoms.The2medicationsperformedthesamefornPIF.

LOE:levelofevidence;DBRCT:double-blindrandomizedcontrolledtrial;PAR:perennialallergicrhinitis;DSCG:disodiumcromoglycate;QID:fourtimesdaily;1SAR:seasonalallergicrhinitis;RCT:randomizedcontrolledtrial;BID:twotimesdaily;MF:mometasonefuroate;nPIF:nasalpeakinspiratoryflow;FP:2fluticasonepropionate;BDP:beclomethasonedipropionate;BV:betamethasonevalerate3

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IX.B.6.Intranasalanticholinergics1

Ipratropiumbromide(IPB)nasalsprayactsbycontrollingwaterynasalsecretoryoutputfrom2seromucousglands.IPBisusedprimarilytoreducerhinorrheaandiseffectiveinadultsandchildren3withperennialrhinitisandcommoncold.1378,1379Ithasaquickonsetofactionandshorthalf-life4administeredupto6timesperday,withlessthan10%absorptionoverarangeof84µg/dayto3365µg/day.1380Localsideeffectsincludenasaldryness,irritation,epistaxisandburning.Systemicsideeffects6havenotbeenobservedwiththerapeuticdosing,asplasmaconcentrationsofgreaterthan1.8ng/mlare7neededtoproducesystemicanticholinergiceffects.1380However,careshouldbetakentoavoidover-8dosagethatcouldleadtohighserumconcentrationsofipratropium.9

AllstudieshaveshownthattheuseofIPBsignificantlycontrolsrhinorrheainchildrenandadults10withPAR.[TableIX.B.6.]ThecombinedusewithINCShavealsobeenshowntobemoreeffectivethan11eitheragentalone,suggestingaroleofIPBforpatientswithpersistentrhinorrhea.13811213

• AggregateGradeofEvidence:B(Level1b:9studies;Level2b:5studies;TableIX.B.6.).14• Benefit:Reductionofrhinorrheawithtopicalanticholinergics.15• Harm:Localsideeffectsincludenasopharyngealirritation,burning,headache,pharyngitis,16

epistaxis,nasaldryness,nasalcongestionanddrymouth.Careshouldbetakentoavoidover-17dosageleadingtosystemicsideeffects.18

• Cost:Lowtomoderate.19• Benefits-HarmAssessment:PreponderanceofbenefitoverharminpatientsPARpatientswith20

rhinorrhea.21• ValueJudgments:Nosignificantbenefitsincontrollingsymptomsotherthanrhinorrhea22

EvidenceforcombinedusewithINCSislimitedbutencouragingforpatientswithpersistent23rhinorrhea.24

• PolicyLevel:Option.25• Intervention:IPBnasalspraymaybeconsideredasanadjunctmedicationtoINCSinPAR26

patientswithuncontrolledrhinorrhea.27 28

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TableIX.B.6.Evidencefortheuseofipratropiumbromideinthetreatmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Dockhornetal1381

1999 1b

DBRCT PAR,8-75yearsold:1.IPB0.03%,2sprays(42µg)TID+BDP82µgBID(n=109)2.IPB0.03%,2sprays(42µg)TID(n=222)3.BDP82µgBID(n=222)4.placebo(n=55)

Rhinorrhea CombineduseofIPBwithBDPismoreeffectivethaneitheragentaloneforcontrollingrhinorrhea.

Finnetal1382

1998 1b DBRCT,crossover

PAR,18-75yearsold(n=205):1.IPB0.03%(42µg)TID+terfinadine60mgPOBID2.placebo+terfinadine

Nasalsymptoms

ControlofrhinorrheaandsneezingbetterinIPB+terbinafine.Nodifferencesinnasalcongestion.

Kaiseretal1379

1998 1b DBRCT

PAR,adults:1.IPB0.03%(42µg)TID2.IPB0.06%(84µg)TID3.placebo

Nasalsymptoms HighandlowdoseIPBresultedinsignificantreductionofnasalhypersecretionversusplacebo.

Meltzeretal1383

1997 1b DBRCT

PARandperennialNAR,6-18yearsold:1.IPB0.03%2sprays(42µg)BID(n=102)2.placebo(n=102)

Nasalsymptoms,medicationuse,QOL

InperennialNAR,IPBreducedsymptoms.InPAR,amodesteffectwasseen

Gorskietal1384

1993 1b DBRCT PAR,23-33yearsold(n=18):1.IPB80µgQID2.placebo

Sneezing,albuminandtotalproteininnasallavage

IPBresultedinadecreaseinalbumin,totalprotein,eosinophilcountandanincreaseinnasalreactivitytohistaminewithanincreaseinthenumberofsneezes.

Meltzeretal1385

1992 1b DBRCT

PAR,18-70yearsold:1.IPB21µg(n=48)or42µg(n=54),1sprayTID2.placebo(n=53)

Nasalsymptoms,nasalcytology

IPBiseffectiveincontrollingrhinorrhea.Nodifferencesinotheroutcomes.

Sanwikarja

etal13861986 1b DBRCT,

crossoverSARorPAR(n=14),non-allergicperennialrhinitis(n=10),18-49yearsold:1.IPB80µgQID2.placebo

Nasalsymptoms IPBhassuppressiveeffectsonsneezingandhypersecretion,butnoinfluenceonnasalairwayresistance.

SchultzLarsenetal1387

1983 1b RCT,crossover

PAR,23-84yearsold(n=20):1.IPB80µgQID2.placebo

Nasalsymptoms IPBiseffectiveincontrollingrhinorrhea.

Borumetal1388

1979 1b RCT,crossover

PAR,18-82yearsold(n=20):1.IPB1puff20µgQID

Nasalsymptoms IPBhadasignificanteffectonrhinorrhea.Noeffectonother

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2.placebo symptoms.Kimetal1378 2005 2b Prospective

Commoncold,SARorPAR;2-5yearsold(n=230)Allergygroup:IPB0.06%,1spray(42µg)TIDfor14days(n=187)

Nasalsymptoms IPBiseffectiveincontrollingrhinorrhea.

Milgrometal1389

1999 2b RCT,blinded,noplacebo

PAR,non-allergicperennialrhinitis,6-18yearsold:1.IPB0.03%nasalspray(42µg),2spraysBID(n=75)2.BDP(n=71)

Nasalsymptoms,QOL

Equallyeffectiveincontrollingrhinorrheaandimprovingqualityoflife.BDPmoreeffectiveincontrollingsneezing.

Kaiseretal1390

1995 2b Prospective

PAR,18-75yearsold(n=219):Firstsixmonths:0.06%IPBTID(84µg)6monthsto1year:lowestdoseIPBcontrollingrhinorrhea

Nasalsymptoms,medicationuse,QOL

IPBwaseffectiveincontrollingrhinorrhea,congestion,postnasaldripandsneezing.ReductionintheuseofmedicationsandimprovementinQOL.

LOE:levelofevidence;DBRCT:double-blindrandomizedcontrolledtrial;PAR:perennialallergicrhinitis;IPB:ipratropiumbromide;TID:threetimesdaily;BID:1twotimesdaily;BDP:beclomethasonedipropionate;NAR:non-allergicrhinitis;QOL:qualityoflife;QID:fourtimesdaily;SAR:seasonalallergicrhinitis;RCT:2randomizedcontrolledtrial345 6

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IX.B.7.Biologics1

BiologicshavebeenstudiedinthetreatmentofAR,specificallyomalizumab,eitheraloneorin2combinationwithspecificAIT.OmalizumabisahumanizedantibodythatbindstohumanIgE.No3biologiciscurrentlyapprovedbytheUSFDAforthetreatmentofAR.Onesystematicreviewandmeta-4analysisofRCTshasdemonstratedreducedsymptoms,reducedrescuemedicationuseandimproved5QOLinpatientstreatedwithomalizumab.1391However,thecostofomalizumabisveryhigh,estimated6tobeover$18,000yearintheUS.7

Systematicreviewidentifiedfivelevel1evidencestudiesexaminingtheuseofomalizumabin8AR.[TableIX.B.7.]FourRCTs1392-1395demonstratedthatomalizumabmonotherapywassuperiorto9placeboatimprovingpatientsymptomsandQOL.ThefirstRCTevaluatingdifferentdeliveryroutesand10dose-rangesdidnotshowefficacyagainstragweed-inducedAR,butreportednosignificantadverse11eventsassociatedwithomalizumab.1396Asecondstudyrandomizedbirchpollen-inducedSARpatientsto12receiveeither300mgofomalizumab(originallynamedrhumAb-E25)orplacebogiven2or3timesover13theseason,dependingonbaselineIgElevels.RhemAB-E25treatmentsignificantlyreducednasal14symptomseverityscores,theaveragenumberoftabletsofrescueantihistaminesperday,the15proportionofdayswithanySARmedicationuse,andalldomainsofQOL.1392Athirdstudyapplied16omalizumab,50mg,150mg,or300mg,versusplacebosubcutaneouslypriortoragweedseasonand17repeatedevery3to4weeksduringthepollenseasondependentonthepatient’sbaselineserumIgE.139318Atthehighestdosestudied,300mgofomalizumabsignificantlyreducednasalsymptomseverityscores19andrhinitis-specificQOLscores.AsignificantassociationwasobservedbetweenIgEreductionandnasal20symptomsandrescueantihistamineuse.Thefrequencyofadverseeventswasnotsignificantlydifferent21betweenomalizumabandplacebogroups.22

OmalizumabwasalsostudiedinthetreatmentofPAR,significantlyreducingthemeandaily23nasalseverityscoreandtherescuemedication,andimprovingQOLwhengivensubcutaneouslyevery424weeksfor16weeks.1394Omalizumabtherapywaswelltolerated.Similarly,effectivenessandsafetyof25subcutaneouslyinjectedomalizumabwasshowninthetreatmentofJapanesecedarpollen-induced26SAR.1395OmalizumabtreatmentmarkedlyreducedserumfreeIgEandtheclinicalresponsetonasal27allergenchallengeinanopenstudy,butdidnotaffectIgE-secretingBcellsandepsilonmRNAinnasal28lavagefluidsuggestingthattreatmentfor6monthsdoesnotsignificantlymodulatesynthesisofnasal29IgE.1397ThebiologicalsosuppressedtryptaseandECPlevelsinnasalsecretionsinseasonalallergy.139830Omalizumabshowedsignificantlygreaterimprovementsthansuplatasttosilate,aselectiveT-helper31type2cytokineinhibitor,inthetreatmentofSARinducedbyJapanesecedarpollens.139932

In4trials,acombinationofomalizumabwithAITwasstudiedtodeterminewhethercombined33therapycouldprovidebetterefficacyandloweradverseeventsthanAITalone.Inchildrenand34adolescentswithSARtobirchorgrasspollen,combinationtherapysignificantlyreducedsymptomload35overAITaloneindependentoftheallergen.1400Anti-IgEmonotherapyalonesignificantlydiminished36rescuemedicationuseandreducedthenumberofsymptomaticdays.ThecombinedtreatmentwithAIT37andanti-IgEshowedsuperiorefficacyonsymptomseveritycomparedwithanti-IgEalone.140138Combinationtherapymay,therefore,beusefulforthetreatmentofAR,particularlyforpolysensitized39patients.PatientsreceivingomalizumabandrushragweedAITshowedasignificantimprovementin40severityscoresduringseasoncomparedwithAITalone.1402Althoughomalizumabcarriessomeriskof41

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anaphylaxisitself,additionofomalizumabresultedinasignificantdecreaseinriskofanaphylaxiscaused1byAIT.CombinationtherapyalsosignificantlyreducedthesymptomloadinHDMallergicsubjectsbetter2thanAITmonotherapy,andimprovedasthmacontrolandQOLwithrespecttoasthmaandAR.1403These3effectswerelimitedtothecombinedtreatmentperiod.14044

Therearenootherpublishedstudiesevaluatingotherbiologics(anti-IL5,anti-IL4orIL-4R)as5monotherapyforAR.Acombinationtherapyofanti-IL4withsuboptimalAITprovidednoadditional6benefitoverSCITaloneinsuppressingtheallergen-inducedskinlate-phaseresponse.14057

Althoughthereisconsistentevidencethatomalizumabmonotherapyissuperiortoplaceboin8symptomreductionandQOLimprovementinAR,thebenefitsarerelativelysmallover9pharmacotherapy.OmalizumabissuperiorincombinationwithAITversusAITaloneandreducestherisk10ofanaphylaxisassociatedwithAIT,butthecostsofthetreatmentprecludeawidespreaduse.The11combinationtherapymightbeindicatedinselectedpatientswhoarepolysensitizedandhighlysensitive.1213

• AggregateGradeofEvidence:A(Level1a:1study;Level1b:5studies;TableIX.B.7.)14• Benefit:Consistentreductioninsymptomsandrescuemedicationaswellasimprovementin15

QOLinRCTsandsystematicreviewofRCTscomparedtoplacebo.16• Harm:Injectionsitereactions,possibilityofanaphylacticreaction.17• Costs:High.Annualincurreddrugcostsestimatedtobeabove$18,000peryearintheUS.18• Benefits-HarmAssessment:Notherapyoptionasomalizumabisnotregisteredfortreatmentof19

ARalone.ThisreviewwaslimitedtoevaluationofARonly;comorbidasthmawasnotevaluated.20• ValueJudgements:Omalizumabmonotherapyissuperiortoplacebo,buteffectsaresmallover21

pharmacotherapy.Maybeevaluatedinexceptionalcasesofhighlysensitivepolysensitized22individualsincombinationwithAIT.23

• PolicyLevel:NoindicationforthetreatmentofARalone.24• Intervention:OmalizumabshouldnotbeusedasmonotherapyinthetreatmentofARbutmay25

beconsideredincombinationwithARforhighlysensitivepoly-allergicrhinitispatientswith26increasedriskofanaphylaxis.AsomalizumabisnotcurrentlyapprovedbytheFDAforAR27treatment,intheUSthistreatmentapproachwouldlikelynotbeperformedinroutineclinical28practicepresently.29

30

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TableIX.B.7.Evidencefortheuseofomalizumabasmonotherapyinthetreatmentofallergicrhinitis(Level1aand1bstudieswithclinical1endpointsonly)2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionTsabourietal1391 2014 1a SRofRCTs,with

homogeneity1.omalizumab2.placebo

Symptomscore,rescuemedication,QOL

Omalizumabwassuperiortoplacebo.Omalizumabwasgenerallywelltolerated.

Okuboetal1395 2006 1b RCT 1.omalizumab2.placebo

Symptomscore,rescuemedication

EfficacyandtolerabilityincedarpollenAR.

Chervinskyetal1394

2003 1b RCT 1.omalizumab2.placebo

Symptomscore,rescuemedication,QOL

EfficacyandtolerabilityinPAR.

Casaleeta1393 2001 1b RCT 1.omalizumab2.placebo

Symptomscore,rescuemedication,QOL

Dose-findingtrial,300mgdoseeffectiveinimprovingsymptomsandQOLcomparedtoplacebo.

Adelrothetal1392 2000 1b RCT 1.omalizumab2.placebo

Symptomscore,rescuemedication,QOL

OmalizumabwassignificantlysuperiortoplaceboinimprovingsymptomsandQOL.Welltolerated.

Casaleetal1396 1997 1b RCT 1.omalizumab2.placebo

Symptomscore,rescuemedication,QOL

Firstdose-findingstudy,safetyconfirmed.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;QOL:qualityoflife;AR:allergicrhinitis;PAR:perennialallergicrhinitis345

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IX.B.8.Nasalsaline1

NasalsalineisfrequentlyutilizedinthetreatmentofAR.However,theterm“nasalsaline”2encompassesawidevarietyoftherapeuticregimens.Thesecanincludehypertonicsaline,3isotonic/normalsaline,seawater,bufferedornon-bufferedsolutions,andvolumesvaryingfrom300µl4to500mlperadministration.Irrigationregimensarealsousedwithvaryingfrequency.5

Thisreviewincludedonlylevel1evidencepublishedintheEnglishlanguage.Thesearch6identified5RCTsinadults151,1406-1409[TableIX.B.8-1.],6RCTsinchildren1410-1415[TableIX.B.8-2.],and17systematicreview1416encompassingallages(includedinbothTables),whichevaluatedtheefficacyof8nasalsalineinthetreatmentofAR.9

Inadults,all5studiesfoundimprovementsinclinicaloutcomeswiththeuseofvarioustypesof10nasalsaline.ThesestudiesvariedintheirevaluationofSARversusPAR,aswellasthetypeandvolume11ofsaline.StudiesbyGaravelloetal151andRogkakouetal,1407foundthattheadditionofhypertonic12salinesignificantlyimprovednasalsymptomsandQOLcomparedtonotusingsaline.Uraletal140813furthercomparedtheefficacyofhypertonictoisotonicsalineirrigations,findingimprovedmucociliary14clearancetimewiththeisotonicsolution.TheypostulatedthatinPAR,therheologicpropertiesofthe15mucusareenhancedmostbyisotonicsaline,thusimprovingmucociliaryclearance.Chusakuletal140916alsoidentifiedthatbufferedisotonicsalinewithmildalkalinityhadthegreatestimpactonreducing17nasalsymptomscoresandwaspreferredbythemostpatients.Finally,Cordrayetal1406foundthatDead18SeasalinesprayhadasignificantimprovementintheRQLQcomparedtoisotonicsaline.Cordrayand19colleaguessuggestedthatthemagnesiumintheDeadSeasalinemayhaveanti-inflammatory20properties,resultinginimprovedARoutcomes.140621

Inthepediatricpopulation,allstudiesevaluatingeitherPARorSARfoundanimprovementin22nasalsymptomsorQOLwiththeincorporationofnasalsaline.BothstudiesbyGaravelloetal1410,141123showedasignificantimprovementaftertheadditionofhypertonicsalineirrigationsTIDwhencompared24tonoirrigations.Marchisioetal1413andSatchabudhaetal1414furtheridentifiedthathypertonicsaline25irrigationsresultedinagreaterimprovementinnasalsymptomscoresinchildrenversusisotonicsaline.26Finally,Lietal1412andChenetal1415foundanadditiveeffectintheutilizationofnasalsalinesprayasan27adjuncttoanasalsteroidspraywhencomparedtoeithertherapyindependently.28

ThesystematicreviewbyHermelingmeieretal1416included10studiesofwhich7wereRCTs29evaluatingbothadultandpediatricpatients.Severalofthesestudiesarealsoincludedabove.151,1406-301408,1410-1412Thisreviewfoundthatalmostallstudiesshowedanimprovementinnasalsymptomsfrom313.1-70.5%withtheadditionofnasalsaline.Additionally,theyidentifieda24.2-100%reductionin32medicationusage,aswellasanimprovementinQOLof29.8-37.5%.Thisreviewalsosuggestedthat33isotonicsalinewasmoreeffectivethanhypertonicsaline.Perhapssurprisingly,theyfoundthatnasal34salinespraysresultedingreatersymptomimprovementthansalineirrigations.Overall,theyconcluded35thatnasalsalinewasaseffectiveasotherfrequentlyutilizedARpharmacologictreatments(i.e.nasal36antihistamines,oralantihistamines,etc.)intreatmentofbothSARandPAR.37

Overall,thereissubstantialevidencetosupporttheuseofnasalsalineasanadjuncttreatment38forSARandPAR.Itappearsthatinadults,abufferedisotonicspraymayprovidemaximumbenefit.39However,inchildren,ahypertonicsolutionmaybemoreeffective.Somestudieshavesuggestedless40intranasalirritationwhenusingisotonicsolutionsratherthanhypertonic.Hypotonicsalinehasnotbeen41

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studiedasatreatmentforAR.Addingmildalkalinity(pH7.2-7.4)tothesolutionmayfurtherimprove1tolerability.1409AlthoughnasalsalinehasbeenshowntoimprovesymptomsandQOLoutcomeswhen2usedalone,itisoftenimplementedasanadjuncttoothertherapiesincludingnasalsteroid,3antihistaminesprays,ororalantihistamines.Inbothadultsandchildren,nasalsalineappearstohavean4additiveeffectwhenusedincombinationwithotherstandardARtreatments.Further,nasalsalineisof5relativelylowcostandhasanexcellentsafetyprofile.Whileadverseeffectsarerare,theycaninclude6localirritation,earpain,nosebleeds,headache,nasalburning,nasaldrainage,andbottle7contamination.141789

• AggregateGradeofEvidence:A(Level1a:1study;Level1b:11studies;TablesIX.B.8-1.and10IX.B.8-2.).Lowerlevelstudieswerenotconsideredinthisreview.11

• Benefit:Reducednasalsymptomscores,improvedQOL,improvedmucociliaryclearance,well12toleratedwithexcellentsafetyprofile.13

• Harm:Intranasalirritation,headaches,earpain.14• Cost:Minimal.15• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.16• ValueJudgments:Nasalsalineshouldbeusedasanadjuncttootherpharmacologictreatments17

forAR.Isotonicsolutionsmaybemorebeneficialinadults,whilehypertonicmaybemore18effectiveinchildren.19

• PolicyLevel:Strongrecommendation.20• Intervention:NasalsalineisstronglyrecommendedaspartofthetreatmentstrategyforAR.21

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TableIX.B.8-1.Evidencefortheuseofnasalsalineinthetreatmentofallergicinadults1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Hermelingmeieretal1416

2012 1a SRandmeta-analysis

SARandPAR,adultsandchildren Nasalsymptomscore,medicineuse,QOL

Nasalsymptomsandmedicineusedecreasedwiththeuseofnasalsaline.Adultsbenefitmorethanchildren.

Chusakuletal1409 2013 1b DBRCT,crossover

AR:1.non-bufferedisotonicsaline2.bufferedwithmildalkalinity(pH7.2-7.4)3.bufferedwithalkalinity(pH8.2-8.4)

Nasalsymptomscore Nasalsymptomswereimprovedfrombaselineonlybybufferedsalinewithmildalkalinity.

Garavelloetal151 2010 1b RCT,noblinding

SAR,pregnantwomen:1.hypertonicsalineirrigationsTID2.noirrigations

Nasalsymptomscore,oralantihistamineuse

Hypertonicsalineirrigationsduringpollenseasonimprovesnasalsymptomsanddecreasesoralantihistamineuse.

Uraletal1408 2008 1b RCT,noblinding

PAR:1.hypertonicsalineirrigationsBID2.isotonicsalineirrigationsBID

Mucociliaryclearancetime.

Isotonicsalineimprovedmucociliaryclearancetime.

Cordrayetal1406 2005 1b SBRCT SAR:1.DeadSeasalinespray2.triamcinolonespray3.placebonasalsalinespray

RQLQ DeadSeasalinegrouphadsignificantimprovementsbutnotassignificantastriamcinolonegroup;nochangeinplacebogroup.

Rogkakouetal1407

2005 1b RCT,noblinding

PAR:1.hypertonicsalinesprayQID+cetirizine2.cetirizineonly

Nasalsymptoms,QOL(Rhinasthmaquestionnaire)

TheadditionofhypertonicsalineresultedinasignificantimprovementinsymptomsandQOL.

LOE:levelofevidence;SR:systematicreview;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;QOL:qualityoflife;DBRCT:double-blind2randomizedcontrolledtrial;AR:allergicrhinitis;RCT:randomizedcontrolledtrial;TID:threetimesdaily;BID:twotimesdaily;QID:fourtimesdaily;SBRCT:3single-blindrandomizedcontrolledtrial;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire45 6

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TableIX.B.8-2.Evidencefortheuseofnasalsalineinthetreatmentofallergicrhinitisinchildren1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Hermelingmeieretal1416

2012 1a SRandmeta-analysis

SARandPAR,adultsandchildren Nasalsymptomscore,medicineuse,QOL

Nasalsymptomsandmedicineusedecreasedwiththeuseofnasalsaline.Adultsbenefitmorethanchildren.

Chenetal1415 2014 1b RCT,noblinding

PAR:1.steroidnasalspraydaily2.seawatersprayBID3.both

Nasalsymptomscore,nasalsigns

Allgroupsimproved.Steroidsprayplusseawaterhadmoresignificantimprovementsthanotherarms.

Marchisioetal1413

2012 1b SBRCT SAR:1.hypertonicsalineirrigationsBID2.normalsalineirrigationsBID3.noirrigations

Nasalsymptomscore,turbinateandadenoidhypertrophy,oralantihistamineuse

Hypertonicsalinewassignificantlymoreeffectiveinimprovingsymptomscore,decreasingadenoidandturbinatehypertrophy,anddecreasingdurationofantihistamineuse

Satdhabudhaetal1414

2012 1b DBRCT AR:1.bufferedhypertonicsalineirrigationsBID2.normalsalineirrigationsBID

TNSS,QOL(Rcq-36),oralantihistamineuse

Greaterimprovementinsymptomswithbufferedhypertonicsaline.NosignificantdifferenceinQOLorantihistamineuseat4weeks.

Lietal1412 2009 1b RCT,noblinding

PAR:1.steroidnasalspraydaily2.isotonicnasalsalineirrigationsBID3.both

Nasalsymptoms Allgroupsimproved.Steroidsprayplussalineirrigationshadmoresignificantimprovementthanotherarms.

Garavelloetal1411

2005 1b RCT,noblinding

SAR:1.hypertonicsalineirrigationsTID2.noirrigations

Nasalsymptomscore,oralantihistamineuse

Hypertonicsalineirrigationsduringpollenseasonhadsignificantimprovementinnasalsymptomsandreductioninoralantihistamineuseafter5weeks.

Garavelloetal1410

2003 1b RCT,noblinding

SAR:1.hypertonicsalineirrigationsTID2.noirrigations

Nasalsymptomscore,oralantihistamineuse

Hypertonicsalineirrigationsduringpollenseasonimprovesnasalsymptomsanddecreasesoralantihistamineuse.

LOE:levelofevidence;SR:systematicreview;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;QOL:qualityoflife;RCT:randomizedcontrolled2trial;BID:twotimesdaily;SBRCT:single-blindrandomizedcontrolledtrial;DBRCT:double-blindrandomizedcontrolledtrial;AR:allergicrhinitis;TNSS:Total3NasalSymptomScore;TID:threetimesdaily456

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IX.B.9.Probiotics1

Therelationshipbetweenmicrobiomeanddevelopmentofatopyiscomplexandincompletely2understood.(SeeSectionIV.G.PathophysiologyandMechanisms–Microbiomeforadditional3informationonthistopic.)Preliminarydatafromobservationalstudiessuggestthatmicrobialexposure,4especiallyininfancy,shapesthegutandairwaymicrobiomeandaffectssubsequentTh2orTh15immunologicbias.Giventhelinkbetweengutfloraandatopy,manipulationofthemicrobiomevia6probioticadministrationcouldtheoreticallyleadtoclinicalimprovementofallergicdisease.Probiotics7havebeenpositedtoelicitimmunomodulatoryeffectsonatopicdiseaseviagut-associatedlymphoid8tissue.StimulationofdendriticcellsinducesTh1responsesviaIL-12andinterferon(IFN)-g,upregulation9ofTregcellsviaIL-10andTGF-b,andsuppressionofTh2pathwaysthroughdownregulationofIL-4,sIgE,10IgG1,andIgA.141811

Theoptimaltimingofprobioticadministrationforthetreatmentofatopyisunknown.Ameta-12analysisof17double-blindRCTsdemonstratedthatprobioticsinpregnancyandearlyinfancywere13associatedwithdecreasedincidenceofeczemabutnotasthmaorrhinosinusitisinearlychildhood.141914Manydouble-blindRCTsandrandomizedcrossoverstudieshaveinvestigatedtheeffectsofprobioticson15ARinolderchildrenandadults.[TableIX.B.9.]Meta-analysesofthesestudieshavebeenpublishedin1620151420and20161421withpositiveresults.Adverseeventsduetoprobioticswererareandminor,17includingdiarrhea,abdominalpain,andflatulence.18

Guvencetal1421performedasystematicreviewandmeta-analysisof22double-blindRCTs19comprising2242patientsaged2-65yearswithSARorPAR.Patientsreceiveddailyprobioticorplacebo20for4weeksto12monthsasanadjuvanttostandardallergytherapies;primaryoutcomesincludedTotal21Nasal/OcularSymptomScoresandQOL.Secondaryoutcomesincludedspecificnasalsymptomscores22andimmunologicparameters.Seventeentrialsdemonstratedclinicalbenefitofprobiotics,with23improvementinTNSS(standardizedmeandifference[SMD]-1.23,p<0.001),TOSS(SMD-1.84,p<0.001),24totalQOL(SMD-1.84,p<0.001),nasalQOL(SMD-2.30,p=0.006)andocularQOL(SMD-3.11,p=0.005).25SubgroupanalysisdemonstratedimprovementinclinicalparametersforSARandPAR.Th1:Th2ratio26wasimproved(SMD-0.78,p=0.045)intheprobioticgroup,withnodifferenceintIgE,sIgE,oreosinophil27count.28

Zajacetal1420publishedasystematicreviewandmeta-analysisof21double-blindRCTsandtwo29randomizedcrossoverstudiescomprising1919adultandpediatricpatientswithSARorPARtreated30with3weeksto12monthsofprobioticversusplacebo.Atotalof26level1bstudiesanalyzedbyGuvenc31etal1421andZajacetal1420areincludedinTableIX.B.9.Zajacetal1420limitedoutcomesmeasuresto32validatedQOLorsymptomscoresandimmunologicvariables;17studiesdemonstratedclinicalbenefit33ofprobioticsinAR.Meta-analysisdemonstratedimprovementinRQLQglobalscore(SMD-2.23,p=0.02)34andRQLQnasalsymptomscore(SMD-1.21,p<0.00001).NoeffectwasfoundforRTSS,tIgE,orsIgE.35

Thepreponderanceofdatafrommeta-analysesanddouble-blindRCTssuggestsabeneficial36effectforprobioticsinthetreatmentofSARandPARinbothadultsandchildren,butinterpretationis37limitedbytheheterogeneityofageanddiagnosis,interventions,andoutcomesincludedinthestudies.38Probioticsvariedindose,weredeliveredviamilk,yogurt,powderorcapsules,andincludedanumberof39diversestrains:19studiesemployedLactobacillusspecies,1422-14406studies40

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Bifidobacterium,1061,1433,1437,1441-1443and1studyeachTetragenococcushalophilus,1444Escherichiacoli14451andBacillusclausii.144623

• AggregateGradeofEvidence:A(Level1a:2studies;Level1b:26studies;TableIX.B.9.).4• Benefit:Improvednasal/ocularsymptomsorQOLinmoststudies.Possibleimprovementin5

immunologicparameters(Th1:Th2ratio).6• Harm:Low.7• Benefits-HarmAssessment:Balanceofbenefitandharm.8• ValueJudgments:Minimalharmassociatedwithprobiotics,butheterogeneityacrossstudies9

makesmagnitudeofbenefitdifficulttoquantify.Variationinorganismanddosingacrosstrials10preventsspecificrecommendationfortreatment.11

• PolicyLevel:Option.12• Intervention:ConsideradjuvantuseofprobioticsforpatientswithsymptomaticSARandPAR.13

14

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TableIX.B.9.Evidencefortheuseofprobioticsinthetreatmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Guvencetal1421

2016 1a SRandmeta-analysis

SARandPAR,adultsandchildren.Dailyprobioticvs.placebo.22DBRCTs(n=2242)

Symptomscores,QOL,immunologicparameters

17studiesdemonstratedclinicalbenefitofprobiotics.ImprovementinTNSS,TOSS,totalQOL,nasalQOL,andocularQOL.

Zajacetal1420 2015 1a SRandmeta-analysis

SARandPAR,adultsandchildren.Dailyprobioticvs.placebo.21DBRCTsand2crossoverstudies,(n=1919)

ValidatedQOLorsymptomscores,immunologicparameters

17studiesdemonstratedclinicalbenefitofprobiotics.ImprovementinRQLQglobalandnasalsymptomscores.

Costaetal1425 2014 1b DBRCT SARtograsspollen,adults(n=425).Lactobacillusparacasei-33x5weeks

RQLQ,RTSS ProbioticimprovedRQLQ.

Linetal1434 2014 1b DBRCT PARtoHDM,children(n=60).LactobacillusparacaseiHF.A00232x8weeks

RTSS,PRQLQ ProbioticimprovedPRQLQ,sneezing,ocularitching/swellingat12weeks.

Dolleetal1445 2013 1b DBRCT SARtograsspollen,adults(n=34).EscherichiacoliNissle1917x6months

Symptom-medicationscore

Nobenefit.

Linetal1426 2013 1b DBRCT PARtoHDM,children(n=199).Lactobacillussalivariusx12weeks

Specificsymptomscore,symptom-medicationscore,tIgE

Probioticimprovednasal,eye,medicationscores.

Singhetal1441 2013 1b DBRCT SARtograsspollen,adults(n=20).BifidobacteriumlactisNCC2818x8weeks

TNSS

ProbioticimprovedTNSS.

Lueetal1422 2012 1b Randomizedcrossover

PAR,children(n=63).LactobacillusjohnsoniiEM1

RTSS,PRQLQ ProbioticimprovedRTSS.

Janetal1438 2011 1b DBRCT PARtoHDM,children(n=240).Lactobacillusgasserix12weeks

SCORingallergicrhinitisindex.specificsymptomscore,symptom-medicationscore,tIgE,bloodeosinophilcount

Nobenefit.

Chenetal1432 2010 1b DBRCT SARandPAR,children(n=105).LactobacillusgasseriA5x8weeks

Subjectivesymptoms,tIgE Probioticdecreasednasalsymptoms.

Nagataetal1431

2010 1b DBRCT SARtoJCP,adults(n=55).Lactobacillusplantarum#14x6weeks

Symptom-medicationscore,tIgE,sIgE

Probioticimprovedsymptom-medicationscoreandocularitching.

Gotohet 2009 1b DBRCT SAR,adults(n=107). Symptom-medication Probioticimprovedsymptom-

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al1439 Lactobacillusgasserix8weeks

score,RQLQ,tIgE,sIgE,bloodeosinophilcount,Th1:Th2ratio

medicationscore.

Kawaseetal1427

2009 1b DBRCT SARtoJCP,adults(n=40).LactobacillusGGandL.gasseriTMC0356x10weeks

Meansymptomscore,meansymptom-medicationscore,tIgE,sIgE

Probioticimprovednasalblockageandmedicationscore.

Nishimuraetal1444

2009 1b DBRCT PARtoHDM,adults(n=45).TetragenococcushalophilusTh221x8weeks

Diseaseseverity,TNSS,tIgE,sIgE

ProbioticimprovedTNSSathighdose.

Ouwehandetal1433

2009 1b DBRCT SARtobirch,children(n=47).LactobacillusacidophilusNCFM&BifidobacteriumlactisB1-04x4months

Subjectivesymptoms Nobenefit.

Yonekuraetal1435

2009 1b DBRCT SARtoJCP,adults(n=116).LactobacillusparacaseiKW3110x3weeks

RQLQ,sIgE ProbioticimprovedQOLwhenpollenscatteringlow.

Ivoryetal1440 2008 1b DBRCT SARtograsspollen,adults(n=20).Lactobacilluscaseix5months

tIgE,sIgE,sIgG,cytokines ProbioticdecreasedTh2cytokines(IL-5,IL-6),sIgE,IFN-gandincreasedsIgG.

Giovanninietal1428

2007 1b DBRCT SARandPAR,children(n=187).Lactobacilluscaseix12months

Timefreeofasthma/rhinitis,numberofepisodesofrhinitis,tIgE

Probioticdecreasedannualrhinitisepisodes.

Tamuraetal1429

2007 1b DBRCT SARtoJCP,adults(n=120).LactobacilluscaseiShirotax8weeks

Symptom-medicationscore Nobenefit.

Xiaoetal1061 2007 1b Randomizedcrossover

SARtoJCP,adults(n=24).BifidobacteriumlongumBB536x4weeks

Subjectivesymptoms Probioticreducedthroatandocularsymptoms.

Xiaoetal1442 2006 1b DBRCT SARtoJCP,adults(n=40).BifidobacteriumlongumBB536x14weeks

Subjectivesymptoms Probioticdecreasedocularsymptoms.

Xiaoetal1443 2006 1b DBRCT SARtoJCP,adults(n=44).BifidobacteriumlongumBB536x13weeks

Subjectivesymptoms

Probioticimprovedrhinorrhea,congestion,compositescores.

Ciprandietal1446

2005 1b DBRCT SAR,children(n=20).Bacillusclausiix3weeks

RTSS,medicationuse Probioticreducedmedicationuse.

Ishidaetal1436

2005 1b DBRCT PARtoHDM,adults(n=49).LactobacillusacidophilusL-92x8weeks

Symptom-medicationscore,tIgE,sIgE

Probioticimprovednasalsymptom-medicationscores.

Peng&Hsu1424

2005 1b DBRCT PARtoHDM,children(n=90).Lactobacillusparacaseix30days

ModifiedPRQLQ ProbioticimprovedPRQLQ(frequency,levelofbother).

Wangetal1423

2004 1b DBRCT PARtoHDM,children(n=90).Lactobacillusparacasei-33x30days

ModifiedPRQLQ ProbioticimprovedPRQLQ(frequency,levelofbother).

Aldinucciet 2002 1b DBRCT SARandPAR,adults(n=20). Subjectivesymptoms Probioticdecreasednasal

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al1437 Lactobacillusacidophilus&Bifidobacteriumx4months

symptoms.

Helinetal1430 2002 1b DBRCT SARtobirch,adultsandchildren(n=36).Lactobacillusrhamnosusx5.5months

RTSS;nose,eye,lungsymptoms

Nobenefit.

LOE:levelofevidence;SR:systematicreview;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;DBRCT:double-blindrandomizedcontrolledtrial;1QOL:qualityoflife;TNSS:TotalNasalSymptomScore;TOSS:TotalOcularSymptomScore;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;RTSS:2RhinitisTotalSymptomScore;HDM:housedustmite;PRQLQ:PediatricRhinoconjunctivitisQualityofLifeQuestionnaire;tIgE:totalimmunoglobulinE;JCP:3Japanesecedarpollen;sIgE:antigen-specificimmunoglobulinE;sIgG:antigen-specificimmunoglobulinG;IL:interleukin:IFN:interferon4567 8

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IX.B.10.Combinationtherapy1IX.B.10.a.Oralantihistamineandoraldecongestant2

OralantihistaminesfunctionasreversiblecompetitiveantagonistsofthehistaminicH1receptor3andpreventthebindingofhistaminetoitsreceptors.Oraldecongestants,suchaspseudoephedrineand4phenylephrine,arealpha-adrenergicstimulatorydrugswhichbindtopre-andpost-capillaryblood5vesselsresultinginvasoconstrictionofnasalmucosa.1447Theunrelatedbiologictargetsofthese6medications’mechanismsofactionhasbeenshowninRCTstoresultinsynergisticimprovementinAR7symptoms.1448,14498

Thecombinationofanoralantihistaminealongwithanoraldecongestanthasbeenshowntobe9moreeffectivethanplaceboincontrollingsneezing,nasalitching,andreducingnasalcongestionin10patientswithAR.1044,1050,1052,1167,1450-1456[TableIX.B.10.a.]InvestigationsbyKaiseretal1450foundthat11bothonce-dailyortwice-dailyloratadine-pseudoephedrinewereconsistentlysuperiortoplaceboin12reducingtotalnasalandnon-nasalsymptomscoreswithsignificantlyhigherriskofinsomniaanddry13mouthinbothantihistamine-decongestantarmscomparedtoplacebo.Additionally,Nathanetal145114reportedin2006thatcetirizine-pseudoephedrinereducedARtotalsymptomseverityscores,asthma15symptomseverityscores,andimprovedasthmaQOLscoressignificantlyversusplacebo.However,they16foundnosignificantchangesinpulmonaryfunctiontestinginpatientsreceivingcetirizine-17pseudoephedrineorplaceboandtheyidentifiedsimilarratesofdiscontinuationandadverseeventsin18bothtreatmentarms.19

Oralantihistamineandoraldecongestantcombinationshavealsobeenshowntobemore20effectiveincontrollingARsymptomswhencomparedtoINCSorcomparedtotreatmentwitheitheroral21antihistaminesororaldecongestantsalone.1050,1455,1457-1460In2005,Zieglmayeretal1449foundthatthe22combinationofcetirizinewithprolongedreleasepseudoephedrinewassignificantlysuperiorto23budesonidenasalsprayforimprovingnasalcongestionafterexposuretoHDM,asmeasuredbyanterior24rhinomanometryandnasalimaging.Thecombinationofsecond-generationoralantihistaminesand25pseudoephedrinehasbeenshowntosignificantlyreducesymptomscoresinpatientswithSARmore26thaneitherdrugalone.1050,1455,1457-1462Additionally,thetypeofsecond-generationantihistamineand27medicationdosingscheduledoesnotseemtohaveasignificanteffectonefficacy.1463,146428

Oraldecongestantshavethebenefitofrelievingthesymptomsofnasalcongestionthrough29theirabilitytovasoconstrictcapillarieswithinthenasalmucosa;however,theirmechanismofactioncan30alsoresultinunfavorablesystemicadverseeffectssuchashypertensionandurinaryretention.Oral31decongestantshavealsobeenlinkedtoanincreasedincidenceofspecificbirthdefectsincludingpyloric32stenosisandendocardialcushiondefectswhenutilizedbypregnantwomen.1465Furthermore,33decongestantsarenotrecommendedforchildrenunder4yearsofagesecondarytothehighriskof34adversedrugeventsassociatedwithutilizationinthisagegroup.1466Finally,oraldecongestantshave35OTCsalesrestrictionssecondarytotheirpotentialutilizationintheproductionofmethamphetamines.36Therefore,cautionmustbeappliedintheutilizationofthesemedications,particularlyinchildrenunder374andpatientswhoarepregnantorhaveapre-existingcardiovascularcondition,hypertension,or38benignprostatichypertrophy.Oralantihistaminesarewelltolerated,withafavorablerisk-benefitratio.39However,cautionshouldstillbeexercisedasantihistamineshavecardiacsideeffects,alterthe40

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metabolismofothermedicines,andhavebeenlinkedtoahigherincidenceofadverseeventsanddrug-1druginteractionsintheelderly.2162

Itislikelybecauseofthissignificantriskofadverseeventsandpropensityforinteractionswith3othermedicationsthattheARIA2010guidelinesrecommendedagainsttheroutinetreatmentofAR4withacombinationoraldecongestantandoralantihistamine.1167The2010ARIAdocumentsuggested5thatoraldecongestantsonlybeaddedinpatientswhoarenotcontrolledbyantihistaminesaloneand6arelessaversetosideeffectsoradversereactions.Additionally,theysuggestedthatoraldecongestants7belimitedtoutilizationprimarilyasarescuemedicationduringperiodsofsignificantsymptom8exacerbations.9

Overall,despitetheavailableevidenceverifyingtheefficacyofcombinationoralantihistamines10andoraldecongestantsinimprovingARsymptoms,cautionshouldstillbeexercisedwhenprescribing11thistreatment,particularlyinpatientswithcardiovascularorurologicco-morbidities.12

13• AggregateGradeofEvidence:A(Level1b:21studies;TableIX.B.10.a.)14• Benefit:Improvedcontrolofnasalcongestionwithcombinationoforalantihistaminesand15

oraldecongestants.16• Harm:Oraldecongestantscancausesignificantadverseeffects,particularlyinpatientswith17

hypertension,cardiovasculardisease,orbenignprostatichypertrophy.Additionally,these18medicationsshouldnotbeusedinchildrenunder4yearsofageorpregnantpatients.This19shouldbeweighedagainstthepotentialbenefitspriortoprescribing.20

• Cost:Low.21• Benefits-HarmAssessment:Harmlikelyoutweighsbenefitwhenusedonaroutinebasis.22• ValueJudgments:Combinationtherapyoforalantihistaminesandoraldecongestantscan23

behelpfulforreliefofanacuteexacerbationofAR,especiallynasalsymptoms,when24exposedtotriggers.Cautionshouldbeexercisedregardinglong-termusegiventhe25possibilityofsignificantadverseeffects.26

• PolicyLevel:Option,particularlyforacuteexacerbationsofnasalcongestion.27• Intervention:Combinationtherapywithoralantihistamineandoraldecongestantcan28

provideeffectivereductionofnasalcongestionsymptomsinpatientswithAR,however29recommendagainstchronicusegiventhesignificantsideeffectprofileoforal30decongestants.31

3233

34

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TableIX.B.10.a.Evidencefororalantihistamineandoraldecongestantcombinationtherapyforthetreatmentofallergicrhinitis1Study Year LOE Study

designStudygroups Clinicalendpoint Conclusion

Badorreketal1050

2009 1b RCT (n=49)1.cetirizine-pseudoephedrine2.cetirizine3.pseudoephedrine4.placebo

Symptoms,nasalflow,nasalsecretions

Cetirizine-pseudoephedrinewasmoreeffectivethantheotherarmsinimprovingnasalobstruction,nasalflow,andnasalsecretionsaftercontrolledpollenexposures.

Grubbeetal1462

2009 1b RCT (n=598)1.desloratadine-pseudoephedrine2.desloratidine3.pseudoephedrine

TSS(withoutnasalcongestion),nasalcongestionscore

Combinationtherapywassignificantlymoreeffectivethenmonotherapyinreducingsymptoms,includingnasalcongestion.

Chenetal1464 2007 1b RCT (n=48)1.loratadine-pseudoephedrinedaily2.loratadine-pseudoephedrinetwicedaily

TSS Bothgroupsshowedsignificantimprovementwithoutsignificantdifferencebetweengroups.

Chiangetal1463

2006 1b RCT (n=51)1.cetirizine-pseudoephedrine2.loratadine-pseudoephedrine

Nasaltotalsymptomscores Bothgroupshadasignificantimprovementinsymptomswithnostatisticallysignificantdifferencebetweengroups.

Nathanetal1451

2006 1b RCT (n=274)1.cetirizine-pseudoephedrine2.placebo

Symptoms(totalandasthma),PFTs,asthmaQOL

CombinationtherapysignificantlyreducedsymptomsofSAR,asthmasymptomscores,andasthmaQOLscores.

Chervinskyetal1461

2005 1b RCT (n=650)1.desloratadine-pseudoephedrine2.desloratidine3.pseudoephedrine

TSSwithoutnasalcongestion,TSSwithnasalcongestion

Nasalcongestionsymptomsscoresweresignificantlyreducedwithdesloratadine-pseudoephedrinecomparedtomonotherapy.

Pleskowetal1460

2005 1b RCT (n=1047)1.desloratadine-pseudoephedrine2,desloratadine3.pseudoephedrine

TSS,morninginstantaneousTSS,nasalcongestionscore

CombinationtherapywasmoreeffectivethaneitherdrugaloneinreducingTSSandnasalcongestion.

Zieglmayeretal1449

2005 1b RCT (n=36)1.cetirizine+prolongedreleasepseudoephedrine2.budesonidenasalspray

Rhinomanometry,nasalcavityimages,nasalcongestion

Oralcetirizine+pseudoephedrinewassuperiortobudesonideinreducingnasalcongestionwhenexposedtoHDM.

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Moinuddinetal1467

2004 1b RCT (n=72)1.fexofenadine-pseudoephedrine2.loratadine+montelukast

RQLQ,nasalsymptoms,nPIF Fexofenadine-pseudoephedrineandloratadine-montelukastwereequallyeffectiveinimprovingRQLQ,totalsymptoms,andnPIF,exceptforthesleepdomain(loratadine-montelukastbetter).

Berkowitzetal1044

2002 1b RCT (n=298)1.fexofenadine-pseudoephedrine2.placebo

Singleexposuremajorsymptomcomplex,totalsymptomcomplex,individualsymptoms

Fexofenadine-pseudoephedrinewasmoreeffectiveinreducingallsymptomsfollowingasingleexposuretoallergen;onsetofaction:45minutes.

Stubneretal1468

2001 1b RCT (n=36)1.cetirizine-pseudoephedrine2.xylometazolinenasalspray

Nasalcongestionbyphotographsanddigitalairflow,nasalsecretions,nasalandocularsymptoms

Nasalcongestionbyphotographswassimilarbetweengroups.Cetirizine-pseudoephedrinewassignificantlybetterinimprovingallsubjectivesymptoms.

McFaddenetal1452

2000 1b RCT (n=20)1.loratadine-pseudoephedrine2.placebo

Acousticrhinometry,endoscopicinferiorturbinatephotography,QOL

Significantimprovementinnasaledemaandsecretionsandnasal/ocularsymptomsofrhinoconjunctivitisinthetreatmentgroupcomparedtoplacebo.

Sussmanetal1457

1999 1b RCT (n=651)1.fexofenadine-pseudoephedrine2.fexofenadine3.pseudoephedrine

Totalsymptoms,nasalcongestion

Combinationtherapysignificantlymoreeffectiveinimprovingtotalsymptomscoreandnasalcongestion,producedgreaterimprovementindailyactivitiesandworkproductivity.

Horaketal1052

1998 1b RCT (n=24)1.cetirizine-pseudoephedrine2.placebo

Nasalobstruction,nasalpatency/airflow

Cetirizine-pseudoephedrinewassignificantlybetterthanplaceboinimprovingnasalobstructionandairflow.

Kaiseretal1450

1998 1b RCT (n=469)1.loratadine-pseudoephedrineoncedaily2.loratadine-pseudoephedrinetwicedaily3.placebo

Totalnasalandnon-nasalsymptomscores

Loratadine-pesudoephedrine(eitherdose)wassuperiortoplaceboinreducingsymptomscores.

Serraetal1453

1998 1b RCT (n=40)1.loratadine-pseudoephedrine2.placebo

Nasalsymptomsorsigns,meanTSS

CombinationdrugwassignificantlybetterthanplaceboinimprovingsignsandTSS;bothplaceboandcombinationdrugimprovednasalsymptoms.

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Correnetal1454

1997 1b RCT (n=193)1.loratadine-pseudoephedrine2.placebo

Nasalandchestsymptoms,albuteroluse,peakexpiratoryflow

CombinationdrugsignificantlyreducedsymptomscoresandimprovedpeakflowratesandFEV1comparedtoplacebo.

Grosclaudeetal1459

1997 1b RCT (n=687)1.cetirizine-pseudoephedrine2.cetirizine3.pseudoephedrine

5dailysymptoms:congestion,sneezing,rhinorrhea,nasalandocularpruritus

Combinationwassignificantlymoreeffectingincontrollingallsymptomsandprovidingmorecomfortabledaysthaneithermedicationalone.

Bertrandetal1458

1996 1b RCT (n=210)1.cetirizine-pseudoephedrine2.cetirizine3.pseudoephedrine

Dailysymptomscores Cetirizine-pseudoephedrineresultedinsignificantlyreducedsymptomsandmoresymptomfreedaysthaneitherdrugalone.

Bronskyetal1455

1995 1b RCT (n=874)1.loratadine-pseudoephedrine2.loratadine3.pseudoephedrine4.placebo

Compositesymptomscores–total,nasalandnon-nasal

Combinationdrugwassignificantlysuperiortoeitherdrugaloneorplaceboinreducingsymptomscores.

Grossmanetal1456

1989 1b RCT (n=264)1.loratadine-pseudoephedrine2.placebo

4nasaland4non-nasalsymptoms

Treatmentgrouphadsignificantlylowernasalandnon-nasalsymptomscoresthantheplacebogroup.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;TSS:TotalSymptomScore;PFT:pulmonaryfunctiontest;QOL:qualityoflife;SAR:seasonalallergic1rhinitis;HDM:housedustmite;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;nPIF:nasalpeakinspiratoryflow;FEV1:forcedexpiratoryvolumein12second34 5

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IX.B.10.b.Oralantihistamineandintranasalcorticosteroid1

AcombinationofanoralantihistamineandINCSisoftenusedinclinicalpracticeforthe2treatmentofAR.Aspreviouslymentioned,oralantihistaminesfunctionasareversiblecompetitive3antagonistofthehistamineH1receptorandtherebypreventthebindingofhistaminethatispresentin4thecirculation.Thenewer,second-generationagents,suchasfexofenadineandcetirizine,areless5sedating,havefeweradverseeffects,andprovidegoodcontrolofsneezing,rhinorrhea,andnasal6itchingbutwithlesseffectonnasalcongestion.1448Additionally,INCS,suchasfluticasoneor7beclomethasone,haverepeatedlybeenvalidatedasaneffectivetreatmentoptionforARwhileoffering8agoodsafetyprofileandlowsystemicabsorption.14489

SeveralRCTshaveexaminedtheefficacyofcombinationtherapyutilizingbothanoral10antihistamineandINCSanddemonstratednoaddedbenefitofcombinationtherapy.[TableIX.B.10.b.]11In2000,Wilsonetal1469demonstratedthatoralcetirizineandintranasalmometasonewereeffectiveat12improvingnasalpeakinspiratoryflowratesaswellasnasalsymptomsandtotaldailysymptomsafter413weeksofuse.However,thecombinationwasnotsignificantlybetterthancetirizineandplaceboor14cetirizineandmontelukast.Inadouble-blindedcrossoverstudy,Barnesetal1470comparedthe15combinationoffluticasoneandlevocetirizineversusfluticasoneandplaceboandfound,inmost16patients,thatthebenefitsofanadditionaloralantihistaminetoaneffectivenasalsteroidregimenwere17notsignificant.Additionally,Ratneretal1471foundthatfluticasonemonotherapycomparedto18fluticasoneplusloratadinehadcomparableefficacyinnearlyallclinicianandpatientratedsymptoms.19Finally,DiLorenzoetal1472demonstratedsimilarresultsinpatientswithSARnotingthatcombination20therapydidnotappeartooffersubstantialimprovementindailynasalsymptomscoresorinreduction21ofnasallavageinflammatorymarkers.22

Incontrast,a2008studybyPinaretal1473comparedmometasonespraymonotherapyto23mometasoneplusdesloratadineandfoundthatthecombinationtherapygrouphadsignificantlybetter24nasalsymptomscoresattheendofstudyweek2andbetterQOLscoresthroughoutthestudy.Arecent25systematicreviewandmeta-analysisbyFengetal1474summarizedtheefficacyofthecombination26therapyofanoralantihistamineandINCSascomparedtoeithertherapyindependently.Theyconcluded27thatthecombinationdemonstratedsignificantimprovementinsymptomscoresinARwhencompared28toanoralantihistaminealone,butdonotprovidesignificantadditionalbenefitwhencomparedto29monotherapywithaneffectiveINCS.1474Limitationstothisdataincludethefactthatthestudiesdidnot30controlforvariationsinthespecificoralantihistaminesorINCSutilizedandthatthestudies31predominantlyevaluatedpatientswithSAR,excludingpatientswithPAR.Additionally,theconclusions32ofthismeta-analysisaresupportedbytheupdated2010ARIAguidelineswhichalsodonotrecommend33theadditionofanoralantihistaminetoaneffectiveINCS,incontrasttopriorrecommendations.1167It34shouldalsobenotedthatadverseeffectsoforalantihistamineandINCScombinationtherapiesinclude35drowsinessanddrymouth(fromoralantihistamines)aswellasepistaxisandnasalirritation(fromINCS).3637

• AggregateGradeofEvidence:B(Level1b:5studies;TableIX.B.10.b.)38• Benefit:ReductionofnasalcongestionwithcombinationoforalantihistaminesandINCS39

comparedtooralantihistaminesalone.40

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• Harm:Sideeffectsincludesedativepropertiesofantihistamines,althoughsignificantly1decreasedwiththenewersecond-generationagents.SideeffectsoftopicalINCSinclude2nasaldrynessandepistaxis,burninginthenose,andwithprolongedusage,possiblegrowth3suppressioninthepediatricpopulation.4

• Cost:Low.5• Benefits-HarmAssessment:Harmlikelyoutweighsbenefitofaddingtheoralantihistamine6

unlesstreatingsymptomsotherthannasalsymptoms.7• ValueJudgments:CombinationtherapyoforalantihistamineandINCScanbehelpfulwhen8

managingthesymptomsofnasalcongestion.9• PolicyLevel:Option.10• Intervention:CombinationtherapyofINCSandoralantihistaminedoesnotimprove11

symptomsofnasalcongestionoverINCSusealone,anddoesrisktheadverseeffectsof12systemicantihistamineuse.13

14

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TableIX.B.10.b.Evidencefortheuseofcombinationoralantihistamineandintranasalcorticosteroidsinthetreatmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Pinaretal1473

2008 1b RCT (n=95)1.mometasonefuroateINCS2.mometasonefuroateINCS+desloratadine3.mometasonefuroateINCS+montelukast4.placebo

TNSS,rhinoconjunctivitisScores,nPIF

Combinationtherapyresultedinbetternasalsymptomscoresatweek2andbetterQOLscoresthanINCSmonotherapy.

Barnesetal1470

2006 1b DBRCT,crossover

(n=27)1.fluticasone+oralcetirizine2.fluticasone+oralplacebo

TNSS,mRQLQ,nPIF,nasalnitricoxide

NasalsymptomscoresareequivalentwithcombinationtherapycomparedtoINCS.

DiLorenzoetal1472

2004 1b DBRCT,doubledummy

SAR,(n=100)1.fluticasoneINCS+cetrizine2.fluticasoneINCS3.cetirizine+montelukast4.placebo

DNSS,nasallavageeosinophilcountandECPlevel

CombinationtherapywasequivocaltomonotherapyINCSinreducingnasalsymptomsinSAR.

Wilsonetal1469

2000 1b SBRCT SAR,(n=38)1.mometasoneINCS+cetirizine2.cetirizine3.cetirizineandmontelukast

nPIF,symptomdiarycard

CombinationoforalcetirizineandmometasoneINCSwasnotsignificantlybetterthancetirizinealoneforSAR.

Ratner1471 1998 1b DBRCT,doubledummy

SAR,(n=600)1.fluticasoneINCS+lotratadine2.loratadine3.fluticasoneINCS

Symptoms

Combinationtherapy,althoughsignificantlybetterthananoralantihistaminealone,offerednosignificantadvantageoverINCSalone.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;INCS:intranasalcorticosteroid;TNSS:TotalNasalSymptomScore;nPIF:nasalpeakinspiratoryflow;2QOL:qualityoflife;DBRCT:double-blindrandomizedcontrolledtrila;mRQLQ:miniRhinoconjunctivitisQualityofLifeQuestionnaire;SAR:seasonalallergic3rhinitis;DNSS:DailyNasalSymptomScore;ECP:eosinophilcationicprotein;SBRCT:single-blindrandomizedcontrolledtrial456 7

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IX.B.10.c.Oralantihistamineandleukotrienereceptorantagonist1

CombinationtherapywithLTRAandoralantihistaminesinthetreatmentofARhasbeenstudied2inasinglesystematicreview1300andmultipleRCTs.1467,1472,1475-1483[TableIX.B.10.c.]Combinationtherapy3generallyimprovedsymptomsandQOLcomparedtoplaceboinmultipleRCTs.1472,1475,1479,1482,1483The4efficacyofcombinationtherapycomparedtomonotherapywitheitherLTRAororalantihistamineisless5clear.InthesystematicreviewbyWilsonetal,1300combinationtherapyimprovedpatientsymptoms6comparedtoeitheragentasmonotherapy,buttherewerenodifferencesinstandardizedQOL7measures.ARCTbyCingietal1477indicatedthatmontelukastandfexofenadinecombinationtherapy8wassuperioratreducingsymptomsandnasalresistancemeasuredbyrhinomanometry,comparedto9eitherfexofenadinealoneorfexofenadineadministeredconcomitantlywithplacebo.Severalother10RCTs,however,didnotdemonstrateadifferenceinsymptomreductionbetweencombinationtherapy11andoralantihistaminemonotherapy.1475,1479,148212

SeveralstudiesalsoexaminedtherelativeeffectivenessofcombinationLTRAandoral13antihistaminetherapycomparedtoINCS.CombinationtherapywasgenerallylesseffectivethanINCS14monotherapy,1472,1479,1481althoughsomestudiesdidnotdetectastatisticallysignificant15difference.1300,1484ThesystematicreviewbyWilsonetal1300didnotdiscernadifferenceinsymptom16reductionbetweenLTRAandoralantihistaminecombinationtherapyandINCS.Incontrast,threeRCTs17showedthatINCSresultedinimprovednasalsymptomscomparedtotreatmentwiththe18combination,1472,1479,1481inadditiontodecreasednasalmucosaeosinophilcounts.1472,148119

Thereisconflictingevidenceonwhethercombinationtherapyismoreeffectivethanoral20antihistaminealone,andthereappearstoberelativelyconsistentevidencethatINCSmonotherapyis21moreeffectiveatnasalsymptomreductionthanLTRAandoralantihistaminecombinationtherapy.22Therefore,combinationtherapymaybeanoptioninpatientswhosesymptomsareincompletely23controlledwithoralantihistaminemonotherapy,andinwhomINCSarenottoleratedor24contraindicated.Thismaybeparticularlyusefulinasubsetofthesepatientswithconcurrentasthma.25MontelukastmaybeeffectiveatsimultaneouslyreducingARsymptomsandimprovingasthma26control.134127

Druginteractionandsafetyareanimportantconsiderationwhenusingcombinationtherapies.28Reportedadverseeventsformontelukastandloratadineincombinationweresimilartomontelukast29andloratadinemonotherapyandplacebo.1485Themostcommonreportedadverseeventswere30headache(4.5%),fatigue(1.2%)andpharyngolaryngealpain(1.2%).Therewerenochangesofvital31signs,electrocardiogram,orphysicalexamfindingsduringthemonitoringperiod.1485CombinationLTRA32andoralantihistaminetherapycanbeadministeredwithminimaladverseevents,andwithsimilar33frequencytoeitheragentasmonotherapy.3435

• AggregateGradeofEvidence:A(Level1a:1study;Level1b:11studies;Level2b:1study;Table36IX.B.10.c.)37

• Benefit:InconsistentevidencethatcombinationLTRAandoralantihistamineweresuperiorin38symptomreductionandQOLimprovementthaneitheragentasmonotherapy.Combination39therapyisinferiorinsymptomreductioncomparedtoINCSalone.40

• Harm:Nosignificantsafetyrelatedadverseeventsfromcombinationtherapy.41

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• Costs:Genericmontelukastwasmoreexpensivethaneithergenericloratadineorcetirizineona1perdosebasis,accordingtoweeklyNADACdataprovidedbyCMS.2

• Benefits-HarmAssessment:Balanceofbenefitandharm.3• ValueJudgements:CombinationtherapyofLTRAandoralantihistaminesdoesnotresultin4

consistentlyimprovedARsymptomscomparedtoeitheragentalone.Therearefewreported5safety-relatedadverseeventsfromcombinationtherapy.TheadditionofanLTRAmayhavea6roleinmanagementofcomorbidasthma.7

• PolicyLevel:Option.8• Intervention:CombinationtherapyofLTRAandoralantihistaminesisanoptionformanagement9

ofAR,particularlyinpatientswithcomorbidasthmaorthosewhodonottolerateINCSand10symptomsarenotwell-controlledonoralantihistaminemonotherapy.11

12

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TableIX.B.10.c.Evidencefortheuseofcombinationleukotrienereceptorantagonistandoralantihistamineinthetreatmentofallergic1rhinitis2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionWilsonetal1300 2004 1a SRofRCTs,

withhomogeneity

1.LTRA+oralantihistamine2.LTRA3.oralantihistamine4.INCS

Symptoms,QOL Combinationtherapyimprovedsymptomsvseithertreatmentalone.NodifferencesinQOLmeasures.NodifferenceinsymptomsforcombinationtherapycomparedtoINCS.

Ciebiadaetal1475

2013 1b RCT 1.montelukast2.oralantihistamine3.montelukast+oralantihistamine4.placebo

Symptoms,ICAM-1levels,eosinophilia

Activetreatmentsweresuperiortoplaceboatreducingsymptoms,ICAM-1levelsandeosinophilia.Activetreatmentswerenotstatisticallydifferentfromeachother.

Yamamotoetal1476

2012 1b RCT 1.montelukast+loratadine2.montelukast+placebo

Symptoms Combinationtherapyimprovedsymptomscores,specificallysneezingandrhinorrhea.

Cingietal1477 2010 1b RCT 1.fexofenadine+montelukast2.fexofenadine+placebo3.fexofenadine

Symptoms,rhinomanometry

Combinationtherapyimprovedsymptomsanddecreasednasalresistancecomparedtofexofenadinealoneorwithplacebo.

Lietal1478 2009 1b RCT 1.fexofenadine+montelukast2.fexofenadine

Symptoms,acousticrhinometry,cytokinelevels

Combinationtherapyimprovedsymptoms,increasednasalvolumebyrhinometry.Nodifferenceincytokinelevels.

Luetal1479 2009 1b RCT 1.montelukast+loratadine2.beclomethasoneINCS3.montelukast4.loratadine5.placebo

Symptoms,QOL Combinationtherapyimprovedsymptomsmorethanplaceboormontelukastalone.Therewasnodifferencecomparedtoloratadinealone.CombinationtherapywasinferiortobeclomethasoneINCS.

Watanasomsirietal1480

2008 1b RCT 1.montelukast+loratadine2.loratadine+placebo

Symptoms,turbinatehypertrophy

Nodifferenceinsymptomswithcombinationtherapyvsantihistaminealone.Turbinateswellingsignificantlyreducedwithcombinationtherapy.

DiLorenzoetal1472

2004 1b RCT 1.montelukast+cetirizine2.fluticasoneINCS3.fluticasoneINCS+certirizine4.fluticasoneINCS+montelukast5.placebo

Symptoms,peripheraleosinophilia,nasaleosinophilcounts

Montelukast+cetirizineimprovedsymptomsanddecreasednasaleosinophilcountscomparedtoplacebo.GenerallyinferiortofluticasoneINCSaloneorincombination.

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Moinuddinetal1467

2004 1b RCT 1.montelukast+loratadine2.fexofenadine+pseudoephedrine

Symptoms,QOL,nPIF Nosignificantdifferencebetweentreatmentgroupsforsymptoms,QOL,andNPIF.Montelukast+loratadinereducedsleepdomainsymptoms.

Saengpanichetal1481

2003 1b RCT 1.montelukast+loratadine2.fluticasoneINCS

Symptoms,nasaleosinophilcount,nasalECPlevel

Nodifferenceintotalsymptomscore,butnasalsymptomsreducedinthefluticasonegroup.DecreasedeosinophilcellcountandECPlevelinthefluticasonegroup.

Nayaketal1482 2002 1b RCT 1.montelukast+loratadine2.montelukast3.loratadine4.placebo

Symptoms,QOL,peripheraleosinophilia

CombinationtherapydecreasedsymptomsandimprovedQOLcomparedtoplacebo.Effectdidnotreachstatisticalsignificancecomparedtomonotherapy.Combinationtherapydecreasedperipheraleosinophiliacomparedtoplaceboandloratadineonly.

Meltzeretal1483

2000 1b RCT 1.montelukast+loratadine2.montelukast3.loratadine4.placebo

Symptoms,QOL CombinationtherapyimprovedsymptomsandQOLcomparedtoplacebo.Combinationtherapynotdirectlycomparedtomonotherapy.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;LTRA:leukotrienereceptorantagonist;INCS:intranasalcorticosteroid;1QOL:qualityoflife;ICAM:intercellularadhesionmolecule;nPIF:nasalpeakinspiratoryflow;ECP:eosinophilcationicprotein2

3

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IX.B.10.d.Intranasalcorticosteroidandintranasalantihistamine1

TheuseofcombinationintranasalantihistamineandcorticosteroidsprayforARhasbeenwell2studied.OnetopicalformulationiscurrentlyavailableinNorthAmericaforintranasaluseasa3combinationofazelastinehydrochlorideandfluticasonepropionate(AzeFlu).Thisagentisalso4designatedintheliteratureasMP-AzeFluorMP29-02,andismarketedintheUSunderthetradename5Dymista.AsystematicreviewoftheEnglish-languageliteraturewasperformedforclinicaltrialsof6combinationINCSandintranasalantihistamineforthetreatmentofAR.Atotalof10RCTs(9double-7blind,1non-blinded)evaluatedcombinationtherapyagainsteitherplacebooractivecontrol.1486-1495An8additional2observationalstudiesintheallowablesearchdaterangeforthisdocumentreported9outcomesofAzeFluasasingletreatmentarm.1496,1497[TableIX.B.10.d.]10

Outcomemeasureswerepredominantlypatient-reportedsymptomscoresorQOLassessments.11ThemostcommonoutcomemeasurewastheTNSS(9studies),whichrecordstheseverityofrunny12nose,sneezing,itchingandcongestion.OtheroutcomemeasuresincludedtheTOSS(4studies),aVAS(313studies),theRQLQ(2studies),thePediatricRQLQ(1study)anda14threshold/discrimination/identification(TDI)score(1study).15

Theminimumageofsubjectsinmostincludedstudieswas12yearsorolder.Studydurationwas1614daysofactivetreatmentinmoststudies,except1studywitha3-monthduration1495and1studywith17a52-weekduration.1488Thenumberofsubjectsineachstudyrangedfrom47to3398.Combination18therapywithAzeFluwascomparedtoplaceboin6studies,withprimaryoutcomesshowingsuperiority19toplaceboinallstudies.1486,1487,1489-1492AzeFluwascomparedtoactivetreatmentwithfluticasone20propionatemonotherapyin6studies,allofwhichshowedsuperiorityofthecombinationtherapy.1488-211490,1492,1494,1495Similarly,intranasalAzeFluwascomparedtoactivetreatmentwithazelastine22hydrochloridemonotherapyin4studies,allofwhichshowedsuperiorityofthecombination23therapy.1489,1490,1492,1494AzeFluwasdirectlycomparedtocombinationtherapywithintranasal24olopatadineandfluticasonein1study,withnosignificantdifferenceinsymptomreliefbetween25treatmentgroups.1493Onestudyfoundsuperiorityofanexperimentalcombinationofsolubilized26azelastineandbudesonidecomparedtoeitherasuspension-typeformulationofazelastineand27budesonideorplacebo.149128

Twostudiesevaluatedchildrenagedbetween6-12yearsold.Likefindingsinadults,AzeFlu29showedsuperioritytoplaceboinimprovingsymptomsandqualityoflifeinchildren.1486,1495Several30studiesreportingtimetoonsetfoundthatAzeFluhadamorerapideffectcomparedtoINCSalone.31

Seriousadverseeffectswerenotreportedinanystudy.Intranasalantihistamineand32corticosteroidcombinationtherapywasgenerallywelltolerated,withthemostcommonlyreported33adverseeffectbeinganunpleasanttaste.Otherreportedadverseeffectsincludedsomnolence,34headache,epistaxisandnasaldiscomfort,alloccurringinlessthan5%ofcasesineachstudy.Onestudy35thatcomparedcombinationtherapyoffluticasonepropionatewitheitherazelastineorolopatadine36reportedmoretreatment-relatedeventsfortheazelastinegroup(16/68)thantheolopatadinegroup37(7/67).14933839

• AggregateGradeofEvidence:A(Level1b:9studies;Level2b:1study;Level2c:2studies;Table40IX.B.10.d.)41

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• Benefit:Rapidonset,moreeffectiveforreliefofmultiplesymptomsthaneitherINCSor1intranasalantihistaminealone.2

• Harm:Patientintolerance,especiallyduetotaste.3• Costs:Moderatefinancialburden.Averagewholesalepriceof$202USDper23grambottle(14

monthsupplywhenusedaslabeled).5• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.Combinationtherapywith6

intranasalantihistamineandINCSisconsistentlymoreeffectivethanplacebo.Lowriskofnon-7seriousadverseeffects.8

• ValueJudgments:Despitelevel1evidencedemonstratingthatcombinationspraytherapy(INCS9plusintranasalantihistamine)ismoreeffectivethanmonotherapyandplacebo,theincreased10financialcostandneedforprescriptionlimitthevalueofcombinationtherapyasaroutinefirst-11linetreatmentforAR.12

• PolicyLevel:StrongrecommendationforthetreatmentofARwhenmonotherapyfailstocontrol13symptoms.14

• Intervention:CombinationtherapywithINCSandintranasalantihistaminemaybeusedas15second-linetherapyinthetreatmentofARwheninitialmonotherapywitheitherINCSor16antihistaminedoesnotprovideadequatecontrol.17

18

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TableIX.B.10.d.Evidencefortheuseofcombinationintranasalcorticosteroidsandintranasalantihistamineinthetreatmentofallergic1rhinitis2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionBergeretal1486 2016 1b DBRCT 1.AzeFlu

2.placeborTNSS,rTOSS,PRQLQ

AzeFlusuperiortoplaceboforsymptomsandQOLimprovementinchildren;symptomsimprovedwhenchildrenself-rate.

Meltzeretal1487 2013 1b DBRCT 1.AzeFlu2.placebo

rTNSS,rTOSS AzeFlusuperiortoplaceboforallsymptoms.

Priceetal1488 2013 1b DBRCT 1.AzeFlu2.fluticasonepropionate

rTNSS,symptom-freedays

AzeFlusuperiortofluticasoneforsymptomreduction;fasteronset.

Carretal1489 2012 1b DBRCT 1.AzeFlu2.azelastine3.fluticasonepropionate4.placebo

rTNSS,rTOSS,RQLQ

AzeFlusuperiortoeithersprayaloneforsymptomandQOLimprovement;fasteronset.

Meltzeretal1490 2012 1b DBRCT 1.AzeFlu2.azelastine3.fluticasonepropionate4.placebo

rTNSS,rTOSS,RQLQ

AzeFlusuperiortoeithersprayaloneforsymptomandQOLimprovement.

Salapateketal1491

2011 1b DBRCT 1.solubilizedazelastine+budesonide(CDX-313)2.azelastine+budesonidesuspension3.placebo

TNSS Bothtreatmentssuperiortoplacebo;CDX-313superiortosuspension-typesprayforsymptomsandspeedofonset.

Hampeletal1492 2010 1b DBRCT 1.AzeFlu2.azelastine3.fluticasonepropionate4.placebo

TNSS AzeFlusuperiortoeithersprayalone;alltreatmentssuperiortoplacebo.

LaForceetal1493 2010 1b DBRCT 1.AzeFlu2.olopatadine+fluticasonepropionate

TNSS Nodifferencebetweentreatments.

Ratneretal1494 2008 1b DBRCT 1.AzeFlu2.azelastine3.fluticasonepropionate

TNSS Combinationsuperiortoeitheragentalone.

Bergeretal1495 2016 2b RCT,non-blinded

1.AzeFlu2.fluticasonepropionate

Totalsymptomscore

AzeFlusuperiortofluticasoneforchildren;fasteronset.

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Klimeketal1496 2016 2c Prospectiveobservational

AzeFlu VAS 76%ofsubjectshadsymptomcontrolafter14days;significantimprovementfrombaseline.

Klimeketal1497 2015 2c Prospectiveobservational

AzeFlu VAS Rapidsymptomreliefacrossallagegroups.

LOE:levelofevidence;DBRCT:double-blindrandomizedcontrolledtrial;AzeFlu:combinationsprayofazelastinehydrochlorideandfluticasonepropionate;1rTNSS:reflectiveTotalNasalSymptomScore;rTOSS:reflectiveTotalOcularSymptomScore;PRQLQ:PediatricRhinoconjunctivitisQualityofLifeQuestionnaire;2QOL:qualityoflife;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;TNSS:TotalNasalSymptomScore;RCT:randomizedcontrolledtrial;VAS:visual3analogscale45 6

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IX.B.11.Non-traditionalandalternativetherapies1IX.B.11.a.Acupuncture2

Incomplimentarymedicine,acupuncturehasthedistinctionofbeingoneoftheoldestformsof3healingartspracticed,withitsoriginsdatingbacktothe6th-5thcenturiesBC.1498TraditionalChinese4medicineholdstotheconceptthatthebody’svitalenergy(Qi)flowsthroughanetworkofmeridians5beneaththeskin.1499Inahealthystate,theflowoftheQiisuninterruptedwhereasdiseasestatesmark6adisruptionoftheQi.Theaimofacupunctureistostimulateacupuncturepoints(acupoints)with7needlestorecoverequilibrium.Acupointsarespecificanatomicpointslocatedalongmeridiansthatare8believedtocorrespondtotheflowofenergythroughthebody.9

TherehavebeenseveralblindedRCTsevaluatingacupunctureasatreatmentforAR.10Acupuncturehasanexcellentsafetyprofilewithonlyminorsideeffectsreported.1500,1501Somestudies11haveshownacupuncturetoinfluenceallergicandinflammatorymediatorsincludingIgEandIL-10levels12inARpatientssignificantlymorethancontrols,1501,1502suggestingapossibleimmunomodulatoryeffect.13Theclinicalsignificanceofthesechanges,however,remainstobeseen.14

Twometa-analysesaddressingacupuncturehavebeenperformed.[TableIX.B.11.a.]Thefirst,15publishedin2008reviewed7RCTsandfoundahighdegreeofheterogeneitybetweenstudieswithmost16studiesbeingoflowquality.1500NooveralleffectsofacupunctureonARsymptomscoresoruseofrelief17medicationswereidentified.1500Amorerecentmeta-analysisof13studieshadmorefavorablefindings,18demonstratingasignificantreductioninnasalsymptoms,improvementinRQLQscoresanddecreased19useofrescuemedicationsinthegroupreceivingacupuncture.1501Thismeta-analysisincluded6ofthe720studiesinthe2008reviewand7newstudies.Again,ahighlevelofheterogeneitybetweenstudiesand21variedqualityofthestudieswasnoted.Mostimportanttonoteisthatneithermeta-analysisdiscussed22thespecificconsiderationofconcomitantARmedicationuseduringthetrials,whichiscommoninmost23acupuncturetrials.TheuncontrolleduseofARmedicationscouldhavesignificantlyimpactedthe24outcomesinanyofthesestudiesandraisesconcernswheninterpretingtheresults.2526

• AggregateGradeofEvidence:B(Level1a:2studies;Level2b:13studies;TableIX.B.11.a.)Only27level1astudiesarepresentedinthetable.28

• Benefit:Unclear,asonemeta-analysisshowednooveralleffectsofacupunctureonAR29symptomsorneedforrescuemedicationsandasecondmeta-analysisshowedaneffectof30acupunctureonsymptoms,QOLandneedforrescuemedications.31

• Harm:Needlesticksassociatedwithminoradverseeventsincludingskinirritation,pruritis,32erythema,subcutaneoushemorrhage,infection,andheadache.Needformultipletreatments33andpossibleon-goingtreatmenttomaintainanybenefitgained.34

• Cost:Costofacupuncturetreatmentwithmultipletreatmentsrequired.35• Benefits-HarmAssessment:Balanceofbenefitandharm.36• ValueJudgments:Theauthorsdeterminedthattheevidencewasinconclusivebutthat37

acupuncturecouldbeappropriateforsomepatientstoconsiderasanadjuncttherapy.38• PolicyLevel:Option.39• Intervention:Inpatientswhowishtoavoidmedications,acupuncturemaybesuggestedas40

possibletherapeuticadjunct.41

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1TableIX.B.11.a.Evidencefortheuseofacupunctureinthetreatmentofallergicrhinitis2

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionFengetal1501

2015 1a SRandmeta-analysis

1.acupuncture2.shamacupuncture

Nasalsymptomscores,RQLQscores,rescuemedicationuse

Significantreductioninnasalsymptoms,improvementinRQLQscoresanduseofrescuemedicationswithacupuncture.

Robertsetal1500

2008 1a SRandmeta-analysis

1.acupuncture2.shamacupuncture

ARsymptomscores,rescuemedicationuse

NooveralleffectonARsymptomscoresorneedforrescuemedications.

LOE:levelofevidence;SR:systematicreview;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;AR:allergic3rhinitis:456IX.B.11.b.Honey7

Along-heldbeliefhasbeenthathoneyiseffectiveintreatingsymptomsofAR;however,8evidenceinsupportofthisisscarce.Itispostulatedthatenvironmentalantigenscontainedwithin9locallyproducedhoneycould,wheningestedregularly,leadtothedevelopmentoftoleranceina10mannersimilartoSLIT.ItisimportanttonotethatheavyinsectbornepollensdonotmeetThomen’s11postulates,astheyarenotairborneandhenceshouldnotbeabletoinduceallergicsensitivity.81812StudiesinanimalshavedemonstratedtheabilityofhoneytosuppressIgEantibodyresponseselicited13againstdifferentallergensandtoinhibitIgEmediatedmastcellactivation.1503-1505Asyet,thesesame14effectshavenotbeentestedforinhumans;however,studiesinhumanshavedemonstratedvarious15anti-inflammatorypropertiesofhoneywhichpointtoapotentialbenefitforitsuseinthetreatmentof16AR.1506,150717

Therehavebeentworandomized,double-blind,placebo-controlledtrialsandoneRCT18evaluatinghoneyinthetreatmentofAR.[TableIX.B.11.b.]Thestudiesdifferedingeographiclocation,19lengthofhoneytreatment,doseofhoneyandtimingregardingspecificallergyseasons.Onedouble-20blindtrialandoneRCTshowedasignificantdecreaseintotalsymptomscoresinthetreatmentgroup21comparedtocontrol.1508,1509TheRCTadditionallyreportedfewernumberofseveresymptomdaysand22decreasedneedforantihistaminesinthehoneygroup.1509Contradictingthesefindings,arandomized,23double-blind,placebo-controlledtrialbyRajanetal1510foundnobenefitofhoneyingestioncomparedto24controlsforthereliefofARsymptoms.Ofnote,ithasbeenreportedthathigherdoses(50-80gdaily25intake)ofhoneyarerequiredtoachievehealthbenefitsfromhoney1511andonlythestudybyAsha’ariet26al1508dosedpatientsatthatlevel.2728

• AggregateGradeofEvidence:B(Level1b:2studies;Level2b:1study;TableIX.B.11.b.)29• Benefit:Unclear,asstudieshaveshowndifferingresults.Honeymaybeabletomodulate30

symptomsanddecreaseneedforantihistamines.31• Harm:Somepatientsstoppedtreatmentbecausetheycouldnottoleratethelevelofsweetness.32

Somepatientscouldhaveanallergicreactiontohoneyintake,andinrareinstances,33

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anaphylaxis.Useofthistherapyinpre-diabeticsanddiabeticswouldlikelyneedtobeavoided1outofconcernforelevatedbloodglucoselevels.2

• Cost:Costofhoney;low.3• Benefits-HarmAssessment:Balanceofbenefitandharms.4• ValueJudgments:Studiesareinconclusiveandheterogeneous.5• PolicyLevel:Norecommendationduetoinconclusiveevidence.6• Intervention:None.7

89TableIX.B.11.b.Evidencefortheuseofhoneyinthetreatmentofallergicrhinitis10

Study Year LOE Studydesign

Studygroups Clinicalendpoint Conclusion

Asha’arietal1508

2013 1b RDBPCT 1.honey2.placebo

ARsymptomscores

ImprovementinoverallandindividualARsymptomswithhoney.

Rajanetal1510

2002 1b RDBPCT 1.locallycollected,unpasteurized,unfilteredhoney2.nationallycollected,pasteurized,filteredhoney3.placebo

DailyARsymptoms,rescuemedicationuse

NosignificantdifferenceinARsymptomsorneedforrescuemedication.

Saarinenetal1509

2011 2b RCT 1.birchpollenhoney2.regularhoney3.nohoney

DailyARsymptoms,numberofasymptomaticdays,rescuemedicationuse

Birchpollenhoneysignificantlyloweredtotalsymptomscoresanddecreaseduseofrescuemedications.Honeygroupshadsignificantlymoreasymptomaticdays.

LOE:levelofevidence;RDBPCT:randomizeddouble-blindplacebo-controlledtrial;AR:allergicrhinitis;RCT;11randomizedcontrolledtrial121314IX.B.11.c.Herbaltherapies15

Likeacupunctureandhoney,herbalremedieshavebeenusedforthetreatmentofvarious16physicalailments,includingAR,world-wideforthousandsofyears.Thisareaof17complementary/alternativemedicineisanattractivealternativetomainstreammedicineforpatients18whowishtoavoidtraditionalpharmacotherapyorwhohavenottoleratedvariousanti-allergic19medicationsinthepast.Thereareavastnumberofstudieslookingattheeffectivenessofnumerous20herbsandherbalsupplementsinthetreatmentofAR,however,mostaresmallandofpoorquality.21ThoseherbalremediesthathavebeensubjectedtomorerigorousstudyaresummarizedinTable22IX.B.11.c.23

Giventhelackofrobustandrepeatedlargedouble-blindrandomizedplacebo-controlledtrialson24anyoneherbalremedy,noevidencebasedrecommendationscanbemadesupportingtheroutineuse25

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ofanyoneherborcompoundandthisshouldbeconsideredanarearequiringfurtherresearchbefore1anysuchrecommendationscanbemade.23

• AggregateGradeofEvidence:Uncertain.4• Benefit:Unclear,butsomeherbsmaybeabletoprovidesymptomaticrelief.5• Harm:Someherbsareassociatedwithmildsideeffects.Also,thesafetyandqualityof6

standardizationofherbalmedicationsisunclear.7• Cost:Costofherbalsupplements;variable.8• Benefits-HarmAssessment:Unknown.9• ValueJudgments:Theauthorsdeterminedthatthereisalackofsufficientevidenceto10

recommendtheuseofherbalsupplementsinAR.11• PolicyLevel:Norecommendation.12• Intervention:None.13

14TableIX.B.11.c.Evidencefortheuseofherbaltherapiesinthetreatmentofallergicrhinitis15

Herb Mechanismofaction Evidence SideeffectsAstragalus

membranaceusUnknown RDBPCTcomparing80mgdailyx6

weeksshowedsignificantimprovementinrhinorrhea,changesinTSS,andQOL.1512

Pharyngitis,rhinosinusitis

Aller-7 Possiblythroughantioxidantandanti-inflammatorypathways1513-1515

2RDBPCTsshowedsomereliefofsymptomswithAller-7.However,thereweresomecontradictoryfindings.1516

Drymouth,gastricdiscomfort

Benifuukigreentea

InhibitstypeIandtypeIVhypersensitivityreactions1517,1518

RDBPCTshowed700mLBenifuukigreenteadailysignificantlyreducedARsymptoms,improvedQOL,andsuppressionofperipheraleosinophils.1519

Nonereported

Biminne Unknown RDBPCTfound12weeksofBiminnesignificantlyreducedsneezing.1520

Notreported

Butterbur(Petasiteshybridus)

Inhibitsleukotrieneandhistaminesynthesisandmastcelldegranulation1521

3RDBPCTsshowedButterbureffectiveinalleviatingsymptoms,attenuatingnPIFrecovery,andreducingmaximum%nPIFdecreasefrombaselineafteradenosinemonophosphatechallenge.ButterbursimilartoantihistamineforimprovingQOLandsymptomrelief.15161RDBPCTdemonstratednobenefitfornPIF,symptoms,orQOL.1516

Hepatictoxicity,headache,gastricupset

Capsaicin ThoughttodesensitizeanddepletesensoryC-fibers1522,1523

NoevidenceofatherapeuticeffectofintranasalcapsaicininAR.694,1524

Mucosalirritation,burning

Cinnamonbark,Spanishneedle,

InhibitsproductionofprostaglandinD21525

RDBPCTshowed450mgCGTIDcomparabletoloratadine10mginsymptomreduction.CGprevented

Nonereported

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acerola(ClearGuard)

increaseinprostaglandinD2releasefollowingnasalallergenchallenge.1525

GrapeSeedExtract

Containscatechinmonomerswhichmayinhibitallergen-inducedhistaminerelease1526

RDBPCTshowednobenefitof100mgGrapeseedextractBIDonnasalsymptoms,needforrescuemedicationsorQOL.1527

Nonereported

Nigellasativa(Blackseed)

Inhibitedhistaminereleasefromratmacrophages.1528ThymoquinonemayinhibitTh2cytokinesandeosinophilinfiltrationinairways.1529

2RDBPCTsshowedN.sativacapsulesand1RDBPCTshowedN.sativanasaldropsimproveARsymptoms.1530-15321RDBPCTdidnotfindsignificantdifferencesbetweentreatmentandplacebo.1530

Gastrointestinalcomplaintswithoralintake.Nasaldrynesswithtopicaldrops.

Perillafrutescens PolyphenolicphytochemicalssuchasRosmarinicacidinhibitinflammatoryprocessesandtheallergicreaction.1533-1536

RDBPCTshowed50mgor200mgPfruescensenrichedforrosmarinicaciddidnotsignificantlyimprovesymptomscores.1537

Nonereported

RCM-101 InhibitshistaminereleaseandprostaglandinE2production1538,1539

RDBPCTshowed4tabletsofRCM-101TIDfor8weekssignificantlyimprovedsymptomscoresandRQLQ.1540

Mildgastrointestinalsideeffects

Spirulina ReducesIL-4levels,1541inhibitshistaminereleasefrommastcells1542

RDBPCTshowed2000mg/daySpirulinasignificantlyimprovedsneezing,rhinorrhea,congestionandnasalitching.1543

Notreported

Ten-Cha(Rubussuavissimus)

Inhibitscyclooxygenaseactivityandhistaminereleasebymastcells1544

RDBPCTshowednosignificantimprovementinsymptomscores,RQLQ,orneedforantihistaminewith400mgdailyofTen-Chaextract.1545

NoneReported

TJ-19* InhibitshistaminesignalingandIL-4andIL-5expressioninaratmodel1546

RDBPCTshowed3gTJ-19TIDsignificantlyimprovedsneezing,stuffynoseandrunnynose.1547

Notreported

Tinofend(Tinosporacordifolia)

Possiblythroughanti-inflammatoryeffects1548

RDBPCTshowed300mgTinofendx8weekssignificantlyimprovedmultipleARsymptomsandasignificantdecreaseineosinophil,neutrophilandgobletcellcountsonnasalsmear.1548

Leukocytosis

Urticadioica(stingingnettle)

Invitro:antagonist/negativeagonistactivityagainstHistamine-1receptor,inhibitsmastcelltryptase,preventsmastcelldegranulation,inhibitsprostaglandinformation1549

1RDBPCTshowedsymptomimprovementoverplaceboat1hour.15501systematicreviewshowednosignificantintergroupdifferences.1516

Notreported

RDBPCT:randomizeddoubleblindplacebocontrolledtrial;TSS:TotalSymptomScore;QOL:qualityoflife;AR:1allergicrhinitis;nPIF:nasalpeakinspiratoryflow;CG:ClearGuard;TID:threetimesdaily;BID:twotimesdaily;2RQLQ:RhinoconjunctivitisQualityofLifeQustionnaire;IL:interleukin;*notavailableintheUSasitcontains3ephedra45

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1IX.C.Surgicaltreatment2

ARisamedicaldisease,butattimesmaybecomerefractorytomedicalmanagement.Surgery3forARisprimarilyaimedatreducingnasalobstructionand/orrhinorrhea,withthecontributing4structuresbeingthenasalseptumandturbinates.1551Vidianneurectomyishistoricallyasurgical5techniquethatalsosoughttoovercomechronicandintractablerhinitis.6

NoCochranereviewofseptoplastyorvidianneurectomyforallergicpatientscurrentlyexists.A7Cochranereviewofturbinatereductioninallergicpatientsrefractorytomedicalmanagementwas8explored,butwasunabletoidentifyanyqualifyingstudies(selectioncriteriastringentlyrequired9randomizedcontrolledtrialsofinferiorturbinatesurgeryversuscontinuedmedicaltreatmentfor10provenAR,orcomparisonsbetweenonetechniqueofinferiorturbinatesurgeryversusanother11technique,aftermaximalmedicaltreatment).1552Physiciansmust,therefore,relyuponlessscientifically12rigorousdatawhendecidinguponsurgeryforARpatients.13

TheroleofseptoplastyforthetreatmentofnasalobstructioninARispoorlyunderstood.The14nasalseptumisnotamajorcontributortoallergicdiseasebecauseitdoesnotexperiencetheextentof15dynamicchangetheturbinatetissuedoes,andtherefore,thereisapaucityofliteratureinvestigating16septoplastyalonetoimprovenasalpatencyinAR.Thenasalseptalswellbodymayservetoalternasal17airflowandhumidification,butnoliteratureexiststoimplicatearoleinAR.1553Karatzanisetal1554found18thatsubjectiveimprovementinpatientsundergoingseptoplastywashigherinthosewithoutARthan19thosewithit.Forthisreason,acautiousapproachtothemanagementofnasalseptaldeviationinARis20warranted.Ontheotherhand,KimfoundthatARpatientsundergoingseptoplastywithturbinoplasty21feltmorereliefofnasalobstructionthenthoseundergoingturbinoplastyalone.1555[TableIX.C.]22

Incontrasttotheseptum,theinferiorturbinatesareaprimetargetofallergiceffects,23characterizedbyvasodilationofcapacitancevesselsleadingtoengorgement,inturncausingnasal24obstructionandcongestion.AlthoughsurgerywillnoteliminatetheinflammatoryoriginsofAR,25additionalpatencyofthenasalcavityreducestheeffectsofedematousmucosa.Fromasurgical26standpoint,inferiorturbinatereductionisthemostbeneficialtreatmentfornasalobstructioninAR27refractorytomedicaltherapy.1552Theinferiorturbinateconsistsofthreeprimarycomponents:a28mucosalcovering,asubmucosallayer(containingthecapacitancevessels),andabonycenter.Surgeryis29typicallyaimedatthesubmucosaorbone,ortotal/partialturbinectomywhichinvolvesremovalofall30threecomponents.31

Thesubmucosaltissuecanbereducedthroughdirectremoval(e.g.,submucousbonyresection32ormicrodebridersubmucosalresection)orenergyappliedtodamagetissuewithsubsequent33remodeling(e.g.,cautery,radiofrequency,laser,CoblationTM).Thesevarioustechniqueshavesubstantial34supportintheliterature.Morietal1556reportedonlongtermoutcomesonpatientsundergoing35submucousbonyresectionovera5-yearfollow-upperiodandnotedasignificantimprovementin36symptomsandnasalallergenresponses.Additionally,QOLwasenhancedinpostoperativepatientsand37maintainedlongterm.Microdebridersubmucousreductiontargetsthecavernoustissuesurrounding38thebonyturbinate.Advantagesincludereal-timesuctionwithprecisetissueremoval.Comparedto39submucosalbonyresection,datasuggestsimprovedmucociliarytimeduetolesstissuetrauma.155740

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Laserturbinatereductionseekstoinducescarringinthesubmucosa,thoughtheoverlying1superficialmucosallayeristransgressedintheprocess.Caffieretal1558reportedontheeffectsofdiode2laserturbinoplastyin40patientswithAR.Statisticallysignificantimprovementsoccurredin3rhinomanometryandnasalobstruction,rhinorrhea,sneezing,andnasalpruritus.Theimprovementin4nasalobstructionwassustainedat2years.15585

Inradiofrequencyablation(RFA)fornasalobstruction,aprobeisinserteddirectlyintothe6inferiorturbinatetodeliveralow-frequencyenergy,causingionicagitationoftissues.1559Thethermal7effectislimitedtothesubmucosallayer,whichpreservessurfaceepitheliumandciliaryfunction.15608FollowingRFA,coagulativenecrosisoccursfirst,withscarcontractureandtissueretractionoccurring9laterinthehealingprocess.Overtime,portionsofthefibroticscarundergoresorptionandthe10submucosalscarwilladheretothebonyperiosteum,whichreducesturbinatebulkandrendersitless11susceptibletoedemaandengorgement.1560,1561Inthefirstlongtermstudyofitskind,Linetal156212publishedareporton101patientswhowerefollowedupto5yearspostoperativelyafterundergoing13RFAturbinoplastyforthetreatmentofAR.Six-monthand5-yearresponserateswere77.3%and60.5%,14respectively,andstatisticallysignificantimprovementwasachievedinnasalobstruction,rhinorrhea,15sneezing,itchynose,anditchyeyes.1562CoblationTMtechnologyreliesonelectrodissectionbymolecular16activation.Thistechnologycansimilarlytargetthesubmucosallayers.Siméonetal1563investigatedthe17efficacyofCoblationTMon9ARpatientswithameanageof12.7years.Favorabledecreasesinnasal18resistance,pruritus,sneezing,hyposmia,andrhinorrheawereobservedandsustainedat6month19follow-up.1563RFAandCoblationTMproceduresarewell-toleratedwithminimaladverseeffectsandcan20besafelyperformedintheoperatingroomortheoutpatientofficesetting.21

Bonyoutfractureseekstoshiftthebonyskeletonoftheinferiorturbinatelaterallyintothe22inferiormeatus,therebycreatingmorebreathingspace.Aksoyetal1564foundstatisticallysignificant23reductionsinthedistancebetweentheinferiorturbinateandthelateralnasalwallafteroutfracturein2440patients.Thiseffectwassustainedat6monthspostoperatively,whichsuggeststhatlateralization25persists.1564Radicalturbinateexcisionmightovercomeobstruction,but,atthecostofdrynessand26possiblyemptynosesyndrome.156527

Vidianneurectomyisanoldertechniquethatseekstodamagetheparasympatheticnerve28impulsestothenasalcavity.Tanetal1566foundsignificantimprovementinQOLmeasuresina29prospectivegroupundergoingvidianneurectomyoverseptoplasty/partialturbinectomyormedical30managementgroups.Thistechniqueisconsideredmoreeffectivefornon-allergicpatientsandseeksto31primarilyaddresssevererhinitis.1567Posteriornasalnervesectionmayalsobeconsideredfor32recalcitrantrhinorrhea;thistechniqueaimstoavoidthedryeyecomplicationsofvidianneurectomy.156833

Recentpublicationshaveidentifiedisolatedmiddleturbinatepolypoidedemaorfrankpolypsto34haveasignificantcorrelationwithinhalantallergy,especiallyinmoreseverecases.785,786Incaseswhere35thepolypoidchangesinthemiddleturbinatearesignificantenoughtocausenasalobstruction,36conservativerecontouringofthemiddleturbinate(s)canreducenasalobstructivesymptoms.37

Tosummarize,surgicaltreatmentoftheseptum,inferiorand/ormiddleturbinates,andpossibly38vidian/posteriornasalneurectomymaybeconsideredinbothallergicandnon-allergicpatients.39OutcomesofthesevarioustechniquesarevariableinpatientswithAR.4041

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• AggregateGradeofEvidence:C(Level1a:1study;Level1b:1study;Level2b:1study;Level3b:14studies;Level4:5studies;TableIX.C.)2

• Benefit:Improvedpostoperativesymptomsandnasalairway.3• Harm:Possibleseptalperforation,emptynosesyndrome,nasaldryness,mucosaldamage,4

epistaxis.5• Cost:Officeversusoperatingroomassociatedproceduralcosts.6• Benefits-HarmAssessment:Preponderanceofbenefitoverharm.7• ValueJudgments:Properlyselectedpatientscanexperienceanimprovednasalairwaywith8

judicioussurgicalintervention.9• PolicyLevel:Option.10• Intervention:TurbinatereductionwithorwithoutseptoplastymaybeconsideredinARpatients11

thathavefailedmedicalmanagement,andhaveanatomicfeatureswhichexplainsymptomsof12nasalobstruction.13

14

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TableIX.C.Evidenceforsurgeryinthetreatmentofallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Jose&Coatesworth2

2010 1a SRofRCTs TurbinatereductioninrefractoryAR

NostudiesqualifiedasRCT.

Noconclusionscouldbemade.

Chenetal1557 2008 1b RCT ARpatientsundergoingIT:1.microdebridersubmucousresection2.bonyresection

VAS,anteriorrhinomanometry,saccharintransittime

Significantimprovementinallparametersforbothtreatmentgroupsat1,2and3years.

Passalietal1236 1999 2b RCT ARpatientsundergoingIT:1.electrocautery2.cryotherapy3.laserablation4.submucosalresectionwithoutlateraldisplacement5.submucosalresectionwithlateraldisplacement6.turbinectomy

Rhinomanometry,acousticrhinometry,mucociliarytransporttime,secretoryIgAlevels,symptomscores

SubmucosalresectionwithlateraldisplacementoftheITresultsinthegreatestincreaseinnasalairflowandnasalrespiratoryfunctionwiththelowestriskoflong-termcomplications.

Tanetal1566 2012 3b Observationalcohort

ARpatientsundergoing:1.Vidianneurectomy2.turbinectomyand/orseptoplasty3.medicaltreatment

QOLoutcomes Allsubjectsimproved,butimprovementinVidianneurectomygroupexceededgroupundergoingturbinectomyand/orseptoplasty.

Kimetal1555 2011 3b Case-control ARpatientsundergoing:1.septoplastywithITturbinoplasty2.ITturbinoplastyalone

Meanrescuemedicationscore,RhinasthmaQuestionnaire

Significantimprovementinbothgroupsbutlessobstructioninseptoplastygroup.

Karatzanisetal1554

2009 3b Case-control SeptoplastyinpatientswithorwithoutAR

NOSEscores,anteriorrhinomanometry

Non-ARsubjectsshowedmoreimprovementthanARsubjects

Morietal1556 2002 3b Observationalcohort

ARpatientsundergoingITsubmucousturbinectomy

Standardsymptomscore,rhinometry,nasalchallenge

Significantimprovementseenat1and3years.

Caffieretal1558 2011 4 Caseseries ARpatientsundergoingmucosallaserreduction,95%toIT.

RhinomanometryandVAS

Objectiveandsubjectiveimprovementupto2years.

Aksoyetal1564 2010 4 Caseseries ARpatientsundergoingIToutfracture

CTsinusatpre-,and1and6monthspost-operative

Statisticallysignificantreductionswerenotedintheangleanddistancesinallsections.

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Linetal1562 2010 4 Caseseries ARpatientsundergoingITradiofrequencyturbinoplasty

SymptomsperVAS Statisticallysignificantreductionswerenotedinobstruction,rhinorrhea,sneezing,itching.

Siméonetal1563

2010 4 Caseseries ChildrenwithARundergoingITcoblationturbinoplasty

Rhinomanometry,VAS,PRQLQ

AllimprovedperPRQLQ.

Lietal1561 1998 4 Caseseries ARpatientsundergoingITradiofrequencyturbinoplasty

QuestionnairesandVAS 21of22showedimprovedsymptomsat8weeks.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;AR:allergicrhinitis:IT:inferiorturbinate;VAS:visualanalogscale;IgA:1immunoglobulinA;QOL:qualityoflife;NOSE:NasalObstructionSymptomEvaluationscore;CT:computedtomography;PRQLQ:PediatricRhinoconjunctivitis2QualityofLifeQuestionnaire3 4

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IX.Management1IX.D.Allergenimmunotherapy(AIT)2

Inadditiontoallergenavoidanceandnumerouspharmacotherapyoptions,AITisfrequently3consideredinthemanagementofAR.AITinvolvesscheduledadministrationofallergenextractsat4effectivedoseswiththegoalofinstitutingasustainedimmunologicchange.AITeffectivenessisoften5measuredthroughcontrolofallergysymptomsandreductioninallergymedicationuse.Thefollowing6sectionreviewsthespecificsofallergenextractunitsandstandardization,allergenextractadjuvantsand7modifications,subcutaneousandsublingualimmunotherapy(SCIT,SLIT),aswellaslesstraditionaltypes8ofimmunotherapy.910

IX.D.1.Allergenextractunits,potency,andstandardization11

Historically,allergytestingbeganwithpollengrainsplaceddirectlyontheconjunctiva,1569,157012butasskintestingandSCITbecamethediagnosticandimmunotherapytreatmentmethodsofchoice,13injectableallergenextractswererequired.Inhaledallergenicparticlesarecomposedofacomplex14heterogeneousmixtureofallergenicandnon-allergenicproteinsandmacromolecules.Allergenextracts15arecreatedbycollectingrawmaterialfromaparticularspeciesofplant,mold,oranimalandthenusing16asolutiontoextractproteinsfromthesource.157117

Therearemultiplesourcesofvarianceinallergenextracts.Thereisbiologicvariabilityintheraw18material,andproteinscanvaryinantigenicityandcomposition;furthermore,therelativeamountsof19allergenicproteinsmayvary.1572,1573Impuritiesinthesourcematerials,suchasmoldgrowingonpollen20granulesorbacteriaoncatpelts,mayalsobeimmunogenicevenifnon-viable.Variationoccursinthe21collectionandprocessingoftherawmaterial.1573Thereisvariabilityintheextractionprocesswith22differentmanufacturersusingdifferenttechniquesincludingfiltration,extraction,sterilization,and23preservation.1571,1572,1574,1575Onlyaverysmallfractionoftheproteinsextractedareallergenic.1571Given24thattheproteincompositionofallergenextractsisnotknown,producingandlabelingallergenextracts25thataresafeandeffectiveischallenging.2627Unitsandpotency.Allergenextractsarelabeledwithanassortmentofunitsthatprovideanindirect28indicationoftheallergencontentoftheextract.Mostallergenextractsarelabeledinunitsthatdonot29conveyinformationaboutbiologicalcompositionorpotency.Therearemultipletypesofunitsthatcan30begroupedintonon-standardized,standardized,orproprietary.Thedifferencebetweenstandardized31andnon-standardizedextractsisdiscussedlaterthissection.32

Potencyofanallergencanhavedifferentmeanings.Potencysometimesreferstothe33allergenicityofasourcematerial’sproteinsorthebiologicactivity.Forexample,grasspollensare34generallymorepotentthantreepollens.Thetypicalgrass-allergicpersonwouldhavealargerclinical35reactiontograsspollenthanatree-allergicpersontothesameamountoftreepollen.However,a36measureofpotencyofanallergenextractmayalsojustrefertothestrengthorconcentrationmeasured37inunits.3839

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Non-standardizedallergenextracts.MostallergenextractsavailableintheUSarenon-standardized.1AllergenextractsareregulatedbytheCenterofBiologicsEvaluationandResearchundertheFDAinthe2US.1576Allergenextractsarerequiredtolistthebiologicsource,apotencyunit,andanexpirationdate.34

• Weight/volume(w/v)–Weight/volumereferstotheratioofgramsofdryrawmaterialto5millilitersofextractsolvent.Commonlythisis1/20w/v,whichmeansthatforevery1gram6ofrawmaterial(pollenforexample)thereis20mLofextractsolvent.Thisdoesnotprovide7directinformationabouttheamountofallergenicproteinsintheallergenextractnorits8biologicactivity.However,itimpliesareproduciblemethodologywasemployed.15719

• ProteinNitrogenUnits(PNUs)–Thisisthesecondmostcommonnon-standardizedunit10currentlyusedintheUS.PNUreferstoanassayoftheprecipitableproteinnitrogenby11phosphotungsticacidwhichcorrelateswiththetotalprotein.Whilemostoftheproteinis12non-allergenic,thetotalproteinisanothermethodtoquantitateanallergenextract’s13content.157114

15InEurope,manymanufacturersuseproprietaryunitsandinternalqualitycontrolswhichmust16

utilizeavalidatedassay.1572ThisEuropeanmanufacturer-basedqualitycontrolisknownas“InHouse17ReferencePreparation”.1573However,theEuropeanMedicalAgencyhasbeendevelopingastandardized18frameworkbasedonproteinhomologyratherthansourcespecies.1577TheEUisalsodeveloping19additionalallergenstandardswiththeWHOstartingwithBetv1andPhlp5a.15772021Standardizedallergenextracts.IntheUS,standardizedallergenextractsaretestedbythemanufacturer22tobewithinareferencerange(70-140%)whencomparedtoastandardprovidedbytheCenterof23BiologicsandResearch(USgovernment).Thegovernment’sstandardisreferencedtothereactivityin24highlyallergicindividualscreatingastandardofbiologicactivity.25

TheCenterofBiologicsandResearchcreatesthestandardextractthroughtestinginknown26“highlyallergic”individuals.Theyuseserialintradermalthree-foldtitrationsandmeasurepotencyby27howmanydilutionsareneededtoproduceaflarereactionofacertainsize.Thesizeisdeterminedby28measuringthelargestdiameterandaddingthelengthofaline90degreestothelargestdiameterline.29Theorthogonalsumsareplottedforeachdilutionandabestfitlinedrawn.Theconcentrationthat30correspondstowheretheorthogonalsumoftheflareis50mm(ID50EAL)determinestheunitslistedin31eitherAllergyUnits(AU)orBiologicAllergyUnits(BAU).AUisusedfordustmites.AmeanID50EALof14323-folddilutionsisdefinedas100,000BAUs/mLand123-folddilutions10,000BAUs/mL.157733

TheFDAallergenstandardsarecomparedtotheproducedallergenextractsbythe34manufacturers.Theprocessisdifferentforextractswherethemajorallergenreactivitycorrelateswith35overallallergenreactivity(catandragweed)thanforextractsthatdonothaveamajorallergenthat36correlatesasstrongly.Amajorallergenisdefinedasaspecificproteinepitopethatmorethan50%of37individualsallergictothatspeciesreact.Ifthereisamajorallergenthatcorrelatesstronglywiththe38population’sclinicalreactivity,themanufacturercancomparetheirextracttothestandardextractby39gelelectrophoresiswiththegelhavingmonoclonalIgGantibodiestothemajorallergenprotein.Ifthere40isnotasingleallergenthatcorrelateswellwiththereactivityofthepopulation,themanufactured41extractandthestandardarecomparedthroughcompetitionELISAusingpooledserumIgEfromknown42

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allergicsubjects.Themanufacturer’sextractmustfallwithina70-140%rangeoftheFDA’sreference.15761Theamountofmajorallergenissometimeslistedinmcg/mL,Feld1units(cat),orAntigenEunits2(ragweed).StandardizedinhalantallergenswithintheUnitedStatesincludecat,Dermatophagoides3pteronyssinus,Dermatophagoidesfarinae,shortragweed,andmultiplegrassspecies.15774

SomeallergenextractsinEuropeusetheNordicmethodwhere10,000biologicallystandardized5units/mLiscomparabletoaskinreactionelicitedby10mg/mLofhistamine.157767

Inconclusion,aninternationalconsensushasnotbeenestablishedforallergenunitsor8standardizationofallergenextracts.Whilestandardizationandtransparentpotencyassaysincrease9manufacturingcosts,itiswidelyagreedthatgreaterstandardizationandconsistencyacross10manufacturerswouldbebeneficial.Variationsinallergenextractsbetweenmanufacturersmay11discouragemedicalprovidersfromchangingbetweenvendorsreducingtheeffectofpriceon12competition.Themultitudeofallergenextractunitsandvariabilityalsocomplicatestheinterpretation13andapplicationofpublishedstudiesbetweentheUS,theEU,andothercountries.TheWHOhas14identifiedallergenstandardizationasaproblemandtheEUfundedaprojectknownasCREATE,15“DevelopmentofCertifiedReferenceMaterialsforAllergenicProductsandValidationofMethodsfor16theQuantification.”1578Butasof2017,multipleallergenunitsarestillinuseworldwide.171819IX.D.2.Modifiedallergenextracts20

ThegoalofAITistosuppresstheunderlyinginflammatorydiathesisandinduceastateofclinical21tolerancetotherelevantallergen.Thistherebyattenuates,ifnotcompletelyarrests,theinflammation22thatmanifestsasAR.TraditionalAITwithnative,unmodifiedextractsissuccessfulbuthasseveral23limitations.Immunotherapycanleadtoadversereactionswhichrarelycanbelife-threatening.Besides24therisks,allergenextractshavesignificantproductioncostswithlimitationsofavailabilityand25consistencybetweenbatches.Variationsexistinpharmaceutical-producednativeextractsinthe26allergenamounts,potencies,andimmunogenicityofindividualallergenmoleculesthatcannotbe27controlledinthemanufacturingprocess.157928

NewadvancesinAIThavefocusedonredirectingtheuntowardallergicdiathesisthrough29upregulationofT-andB-regulatorycells,restoringthebalancebetweenTh2andTh1cellsubtypes,and30establishingT-cellimmunetolerance.Theuseofrecombinant-derivedallergens,syntheticpeptides,31allergoids,andadjuvantshasbeensoughttoprovidesafer,moreconsistent,readilyavailable,and32effectiveallergenscomparedtocommerciallyavailablenativeextracts.1580-1582[TableIX.D.2-1.]33

Thelaboratoryproductionofallergensallowsformodificationofextractsandepitopestructures34thataimtoenhanceimmunogenicitywhiledecreasingtheriskofadversereactions.Clinicalstudieshave35reportedoutcomesforAITusingrecombinant-producedmolecules,synthetically-producedpeptides,36andmodificationsofallergensviaallergoidswithadjuvantmoleculesorthroughdenaturingofproteins.3738Recombinantallergens.Recombinant-derivedallergensareproducedbycloningofnativeallergen39proteinswithuseofrecombinantDNAtechnology.Theallergyproteinisreversetranscribedtoyielda40complimentaryDNAmoleculewhichcanthenbetransferredintobacteriawhichproducecopiesofthe41

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incorporatedDNA.Thistechniqueallowsforcontrolledproductionofahigh-yieldproductwith1consistentstructure.Immunotherapytrialswithrecombinantallergenshasbeenreportedforbirch2pollenandtimothygrasspollen.[TableIX.D.2-2.]RecombinantbirchAITdemonstratedequivalent3clinicaloutcomestonativebirchextractandimprovedsymptomsoverplacebo.1583-1585Recombinant4timothygrassAITshowedimprovedoutcomescomparedtoplacebowithagoodsafetyprofile.805,15865Recently,arecombinantpeptidecarrierfusiongrassvaccinehasreportedpositiveoutcomeswithaB-6cellepitope-basedvaccineforimmunotherapyofgrasspollenallergy.79878

• AggregateGradeofEvidenceforbirch:B(Level1b:3studies;Level2b:1study).9• AggregateGradeofEvidencefortimothygrass:B(Level1b:3studies).10• Thesestudiesofrecombinantallergensforbirchandtimothygrassdemonstratesafetyand11

efficacy.1213Peptideconstructs.Syntheticpeptidesforimmunotherapyarelinearfragmentsofaminoacidsthat14correspondtoT-cellepitopes.Thesefragmentslackthesecondaryandtertiarystructurethatactivate15IgEreceptors,butcaninduceimmunologictolerancebytargetingallergen-specificT-cellstoinduce16tolerance.ThepremisewithsyntheticpeptidesisthatthelackofIgEactivationwilleliminatetheriskof17IgE-mediatedadversereactionwhilepreservingtheimmunogenicitythatleadstodesensitization.AIT18trialswithsyntheticpeptideshavebeenreportedforcat,birch,andragweedallergens.[TableIX.D.2-2.]19Overall,studieshaveshownmixedoutcomesfromsyntheticpeptideswithsomepeptidemolecules20resultinginanincreaseinlateadversereactions.Therecentlycompletedlarge-scalemulticenterfield21trial(clinicaltrials.govNCT01620762)withcatpeptidefailed;however,asofthiswriting,theHDM22peptidestudyisongoing.1587,1588Newerpeptideconstructsunderinvestigationincludeoverlapping23peptidesthatreproducetheentiresequenceofthenaturally-occurringallergeninanattempttocover24allT-cellepitopesandnaturalpeptidefragmentsthatcoverabroadpanelofepitopes.15892526

• AggregateGradeofEvidenceforcat:B(Level1b:5studies).27• AggregateGradeofEvidenceforbirch:Indeterminate,basedononly1Level1bstudy.28• AggregateGradeofEvidenceforragweed:B(Level1b:1study;Level2b:1study).29

30Allergoidsandpolymerizedallergens.Allergoidsarechemicallymodifiedallergenswhichwere31developedforimprovedimmunotherapyprotocolsviaaccelerateddosinganddecreasedsideeffects.32Initialattemptsatdevelopmentofanallergoidbypartialdenaturingoftheallergenicmoietywith33formalinresultedinreducedallergenicity;however,concurrentreductionintheimmunogenicityofthe34allergoids,asdefinedbyIgGantibodyproduction,wasseen.1590Studiesusingaglutaraldehyde-linked35polymerizationofallergensforgrassandragweedallergensdemonstratedefficacyand36tolerability.1591,1592However,standardizationcriteriaandproductionfactorsnegativelyimpacted37regulatoryapprovalintheUS.Clinicaltrialsforallergoidsemployingragweed,grass,andHDMallergens38havebeenreported.Promisingearlyresultsareseenfortheseallergoids.Inaddition,morerecentwork39hasfocusedondepigmentedallergoidconstructs,whicharecurrentlyinuseinEurope.1593,1594[Table40IX.D.2-2.]41

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1• AggregateGradeofEvidenceforragweed:B(Level1b:1study;Level2b:1study).2• AggregateGradeofEvidenceforgrass:B(Level1b:7studies).3• AggregateGradeofEvidenceforHDM:Indeterminate,basedononly1Level2bstudy.4• AllergoidorpolymerizedallergenproductshavebeenapprovedinEuropebutnonehasreceived5

USFDAapproval.67Adjuvantconstructs.Theadditionofmolecules(adjuvants)tothenativeallergenhasbeenattemptedto8improvedesensitizationprotocols.AlumwasthefirstadjuvanttogainacceptanceinAIT.Earlystudies9withalum-precipitatedextractsdemonstratedanaugmentedimmunologicresponse.However,alum10inducedaninitialIgEimmuneresponsewhichhindereditstherapeuticapplication.1595Clinicaltrialswith11adjuvantshavebeenreportsforragweed,grass,andHDMallergens.[TableIX.D.2-2.]12

Creticosreportedtheproof-of-conceptstudyforusingbacterialDNA(CpGoligonucleotide13syntheticallyderivedfrommycobacteriumbovis)toupregulateanimmunostimulatoryresponseto14allergenthroughthecorrespondingligand(TLRligand)onaspecificclassofregulatorydendriticcells.159615TheTLR-9agonistwasadministeredina2-yeardoubleblindplacebocontrolledstudyofragweed-16allergicsubjectsimmunizedwitha6-injectionregimenadministeredpriortotheinitialragweedseason.17Asimilarmagnitudeofeffectversusplacebowasobservedoverbothragweedseasonsindicatingthat18thevaccineconferredmeaningfullong-termefficacy(clinicalandimmunetolerance)over2ragweed19seasons.1596Subsequentlargescalemulticentertrialswerenotabletosatisfyregulatoryapproval20requirementsandthisspecificproductisnotgoingforwardindevelopment.1597However,thefieldof21adjuvantapproachestoimmunizationismovingforward.22

ATLR-4adjuvantisalsocurrentlyinclinicaldevelopment.Thisconstructiscomprisedof23monophosphoryllipidA,derivedfromdetoxifiedlipopolysaccharideofgramnegativebacterium24(Salmonellaminnesota,aTLR-4inducingadjuvant),andformulatedwithpollenallergoidsabsorbedonto25microcrystallinetyrosine.ThiscompoundreducesIgE-mediatedallergenicitybutpreserves26immunogenicity.Alargegrassstudyshowedsignificantimprovementinsymptomandmedication27scoresversusplacebowithsubgroupanalysisshowinggreaterbenefitinpatientswithmoresevere28symptoms.1598Anabbreviatedragweedtrialshowedclinicaleffectintheprimaryendpointversus29placebo.106630

Thesestudiesofadjuvant-modifiedextractsdemonstratepotentialforimproved31immunotherapyprotocols;however,severalchallengesremain.Eachofthemodifiedextractsrequires32robustclinicaloutcomesdatatodemonstrateshortandlong-termimprovementinbothefficacyand33safetyoverconventionalallergenicextracts.34

35• AggregateGradeofEvidenceforragweed:B(Level1b:3studies).36• AggregateGradeofEvidenceforgrass:B(Level1b:2studies).37• AggregateGradeofEvidenceforHDM:Indeterminate,basedononly1Level2bstudy.38

39Insummary,awidevarietyofimmunotherapeuticagentsarecurrentlyundergoingclinical40

developmentwiththegoalofimprovingsafetyandachievingimmunetolerancewithlong-lasting41

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therapeuticefficacy.Thisnewgenerationofvaccinesincludesrecombinantallergens,peptide1constructs,allergoids/polymerizedallergens,andadjuvantconstructs–eachofwhichmustundergo2rigorousclinicalevaluationtodemonstrateacceptablesafetyandmeaningfulclinicaloutcomesthat3meetregulatoryguidelinesforapproval.Forsomeofthestudiedpreparations,thereappearstobe4improvementoverplaceboandcomparableoutcomestonativeallergens.TheTLR-9agonisttrial5showed2yearsofefficacypostdiscontinuationofdrug.However,somepeptidemolecules6demonstratedincreasedlatereactionsaswellasmixedclinicaloutcomesdependingonthepreparation.7Allergoids,adjuvants,andpeptideshavealsoshownefficacyinmulti-yearclinicaltrials.Thereis8insufficientevidencetomakerecommendationsbasedonthelownumberofstudiesforeach9preparationandlackoflong-termoutcomes,asnostudyhasexaminedoutcomesforlongerthana2-10yearperiod.11 12 13TableIX.D.2-1.Modifiedallergenimmunotherapyconstructs* 14InjectableImmunotherapyApproachesRecombinantAllergens(SQ)PeptideConstructs(ID)Chemicalmodifications(SQ)Alumsalts(SQ)Allergoids/PolymerizedallergensAdjuvantConstructs(SQ;IM)DNAVaccinesTLR-9(CpGoligonucleotides)(SQ)-linkedtoallergen;co-combined-Nanoparticle-basedVLPs(Viral-likeparticles)TLR-4(MPL)(SQ)

SQ:subcutaneous;ID:intradermal;IM:intramuscular;TLR:toll-likereceptor;CpG:cytosinephosphorylatedto15guanine;VLP:viral-likeparticles;MPL:monophosphoryllipidA.*Modifiedandusedwithpermission;from:16CreticosPS.AllergenImmunotherapy:VaccineModification;ImmunolAllergyClinN.Am.2016(36);103-124.17 18 19

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TableIX.D.2-2.Evidencefortheuseofrecombinant,peptide,allergoid/polymerized,andadjuvantallergenimmunotherapy1

RecombinantAllergensStudy Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Zieglmayeret

al798

2016 1b RDBPCT 1.recombinantpeptidevaccinewithgrass

epitopesat3doses

2.control

Totalnasalsymptoms

scores,ocularsymptoms,

skintests

Improvementinprimary

endpointfortwohigher

dosesbutnotthelower

dose.

Nonyetal1584

2015 1b RDBPCT 1.12.5µgcGMP-graderBetv1SLIT

2.25µgcGMP-graderBetv1SLIT

3.50µgcGMP-graderBetv1SLIT

4.placebo

Symptomscores,medication

scores

SLITwithrBetv1resultedin

asignificantdecreaseof

symptomscoreand

medicationscorevsplacebo.

Meyeret

al1063

2013 1b RDBPCT 1.rBetv1-FVinmultipledoses

2.placebo

Symptomscores,changein

IgG1andIgG4

Alldosingregimenswere

moreeffectivethanplacebo.

Klimeket

al1585

2012 1b RDBPCT

recombinanttimothygrassantigens(Phlp1,

Phlp2,Phlp5a,Phlp5b,Phlp6)

1.Studygroups:20µg,40µg,80µg,120µgprotein

2.placebo

Primary:systemicallergic

reactions.

Secondary:Improvementin

symptoms,conjunctival

provocationtest

Recombinantallergenssafe

andeffectiveevenathigh

proteinlevels.

Paulietal

1583 2008 1b RDBPCT 1.recombinantbirchpollenallergen

2.licensedbirchpollenextract

3.naturalpurifiedbirchpollenallergen

4.placebo

Symptoms,immunologic

markers

Recombinantallergenswere

safeandeffectivefor2

seasons.

Juteletal1586

2005 1b RDBPCT 1.recombinanttimothygrassantigens(Phlp

1,Phlp2,Phlp5a,Phlp5b,Phlp6)

2.placebo

Symptoms,medicationuse,

RQLQ,immunologic

markers,conjunctival

provocationtest.

Recombinantallergenssafe

andeffectiveovertwograss

seasons.

Klimeketal805 2015 2b OpenRCT 1.recombinantbirchextract(rBetv1-FV)

2.nativebirchextract

Symptomscores,IgGlevels Bothweresafeandequally

efficaciousover2seasons.

PeptideConstructsStudy Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Spertiniet

al1589

2016 1b RDBPCT 1.Betv1-derivedcontiguousoverlapping

peptides50µg2.Betv1-derivedcontiguousoverlapping

peptides100µg3.placebo

Combined

rhinoconjunctivitissymptom

andmedicationscores,QOL

Improvedsymptom,

medication,andQOLscores

inbothtreatmentgroupsvs

placebo.

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Courouxet

al1599

2015 1b RDBPCT 1.Cat-PAD8doses3nmol

2.Cat-PAD4doses6nmol

3.control

Rhinoconjunctivitis

symptomscores2years

afterstartoftreatment,

symptomscoresafter

challenge

Significantreductionin

symptomswasobservedin

the6nmoldosegroupbut

nottheothergroups.

Pateletal1065

2013 1b DBPCT 1.Feld1-derivedpeptide8x3nmol2weeks

apart

2.Feld1-derivedpeptide4x6nmol4weeks

apart

3.8xplacebo

Totalrhinoconjunctivitis

scoreat20weeksand52

weeks

Durabletreatmenteffectat

1yearwithbestregimen

4x6nmolat4weeksapart.

Purohitet

al1600

2008 1b DBPCT 1.pre-seasonalBetv1primer

2.pre-seasonalBetv1fragments

3.placebocontrol

Primary:symptom

medicationscores.

Secondary:skinandnasal

sensitivities,

immunoglobulins,adverse

reactions.

Nosignificantdifferencein

symptomandmedication

scoresbetweenthegroups.

Oldfieldet

al1601

2002 1b RCT 1.Feld1peptide90µg2.placebo

Developmentoflate

respiratoryreaction

Increaseinlaterespiratory

reactionwithtreatment.

Tolerancemaydevelopwith

continuedtreatment.

Maguireet

al1602

1999 1b RCT 1.75µg/doseSCAllervaxCatpeptide2.750µg/doseSCAllervaxCatpeptide3.placebo

Improvementinpulmonary

function,adverseevents

Improvementinpulmonary

function.Increased

incidenceoflateadverse

reaction.

Normanet

al1603

1996 1b RDBPCT 1.7.5µgAllervaxCATpeptide2.75µgAllervaxCATpeptide3.750µgAllervaxCATpeptide4.placebo

Nose,lung,andsymptom

scoresduringlivecat

exposure

Doseresponsewasobserved

athighestdose,resultingin

themostsignificant

decreaseinlungandnasal

symptomsuponcat

exposure.

Litwinetal1604

1991 2b Placebo

controlled

trial

1.pre-seasonalragweed

2.pre-seasonalragweedpeptidefragments

3.histamineplacebocontrol

Symptom-medicationscores Subjectsreceivingthe

peptidefragment

preparationhadimproved

scoresvsothergroups.

Allergoids/PolymerizedAllergensStudy Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

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Klimeket

al1605

2014 1b DBPCT 1.clusterimmunotherapywithgrass/rye

polymerizedantigen

Combinedsymptomand

medicationscore,rescue

medicationuse,total

rhinoconjunctivitissymptom

score

Improvementinsymptoms

andmedicationusage

comparedtoplacebo.

Pfaaretal1594

2013 1b DBPCT 1.mixeddepigmentedpolymerizedbirch

andgrasspollenextract

2.placebo

Combinedsymptomand

medicationscore

Significantreductionin

mediancombinedscoresat

year2comparedtoplacebo.

Pfaaretal1593

2012 ib DBRCT 1.pre-seasonaldepigmentedpolymerized

grasspollenSCIT

2.placebo

Combinedsymptomand

medicationscore

Significantlyimproved

combinedscoresinpeak

seasonatyear2compared

toplacebo.

Corriganet

al1606

2005 1b DBPCT 1.pre-seasonalgrasspollenallergoid(low

dose)

2.pre-seasonalgrasspollenallergoid(high

dose)

3.placebo

Combinedsymptomand

medicationscore

Pre-seasonalgrasspollen

allergoidresultedin

significantlyimproved

symptomandmedication

scorecomparedtoplacebo.

Bousquetet

al1607

1990 1b RDBPCT 1.low-dosegrasspollenallergoid

2.high-dosegrasspollenallergoid

3.placebo

Symptomandmedication

scoresduringpollenseason

Significantreductionin

symptomandmedication

scoresforbothtreatment

groupscomparedto

placebo.

Bousquetet

al1608

1989 1b RDBPCT 1.unfractionatedgrasspollenallergoid

2.highmolecularweightgrasspollen

allergoid

3.standardizedgrasspollenextract

4.placebo

Clinicalsymptoms:rhinitis,

conjunctivitis,asthma

Highmolecularweightand

pollenextractweremost

effective,followedby

unfractionatedallergoid.All

betterthanplacebo.

Grammeret

al1592

1983 1b RDBPCT 1.pre-seasonalpolymerizedwholegrass

2.placebo

Blockingantibodies,daily

symptomscores

Significantelevationsin

blockingantibodiesand

decreaseinsymptoms

scoresintreatmentgroup.

Grammeret

al1591

1982 1b DBPCT 1.pre-seasonalpolymerizedragweed

2.placebo

3.notreatment

IgEandblockingantibodies,

dailysymptomscores

Significantelevationsin

blockingantibodiesand

decreaseinsymptoms

scoresintreatmentgroup.

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Pfaaretal1609

2016 2b RCT 1.miteallergoidSCIT6667AUeq/ml

2.miteallergoidSCIT20000AUeq/ml

3.miteallergoidSCIT50000AUeq/ml

4.miteallergoidSCIT100000AUeq/ml

5.placebo

Clinicalresponsetoa

titratednasalprovocation

test

Alldosesabove20,000

AUeq/mlshowedimproved

efficacycomparedto

placebo.

Normanet

al1590

1981 2b Opentrial 1.allergoidragweed(formaldehydetreated)

2.allergenragweed

Dailysymptomand

medicationscores

Significantimprovementof

allergoidoverallergen.

AdjuvantConstructsStudy Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Pateletal1066

2014 1b RDBPCT 1.fourweeklyinjectionsofshortragweed

pollenallergoidadsorbedtoL-tyrosine

monophosphoryllipidA

2.placebo

rhinoconjunctivitis

symptomsafterexposurein

achamber

Significantimprovementin

symptomscoresinthe

treatmentgroup.

Dubuskeet

al1598

2011 1b RCT 1.pre-seasonalgrassmodifiedallergen

tyrosineadsorbatemonophosphoryllipidA

2.placebo

Symptomandmedication

scores.

Significantimprovementin

subjectswithsevere

symptomsandlong-standing

symptomswithtreatment.

Creticoset

al1596

2006 1b RDBPCT 1.ragweedAmba1-phosphorothioate

oligodeoxyribonucleotideconjugate(TLR-9

agonist)

2.placebo

Symptoms,immune

changes,adversereactions

Efficacious,benefitslasted

for2moreseasons.

Tulicetal1610

2004 1b RCT 1.Amba1-oligodeoxyribonucleotide

conjugate

2.placebo

Primary:symptomand

medicationscores.

Secondary:tissuemarkersof

inflammation.

Nodifferenceinprimary

endpointafter1season,

chestsymptomswerebetter

inthetreatmentgroupafter

thesecondseason.

Drachenberg

etal1611

2001 1b RDBPCT 1.pre-seasonaltyrosine-adsorbed

glutaraldehyde-modifiedgrasspollenextract

containing3-deacylatedmonophosphoryl

lipid

2.placebo

Symptomscores,medication

scores,skinreactivity,IgG

andIgEantibodies

Significantimprovementin

nasal,ocular,andcombined

symptomandmedication

scoresintreatmentgroup.

Sentietal1612

2009 2b Opentrial 10weeklyinjectionsofdustmitewithA-type

CpGoligodeoxynucleotideswithvirus-like

particles

Symptoms,conjunctival

provocation,skinpricktests,

IgGandIgElevels

Significantreductionin

symptoms,improved

conjunctivaltolerance,

increaseinIgG,and

decreasedskinreactivity.

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LOE:levelofevidence;RDBPCT:randomizeddoubleblindplacebocontrolledtrial;SLIT:sublingualimmunotherapy;Ig:immunoglobulin;RQLQ:1

RhinoconjunctivitisQualityofLifeQuestionnaire;RCT:randomizedcontrolledtrial;QOL:qualityoflife;DBPCT:doubleblondplacebocontrolledtrial;SCIT:2

subcutaneousimmunotherapy;TLR:toll-likereceptor3

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IX.D.3.Subcutaneousimmunotherapy(SCIT)1

AITisatreatmentforIgE-mediatedsensitivitytoenvironmentalallergens.101,1613,1614SCIT2involvestheinjectionofincreasingdosesofanextractoftheallergeninquestion,followedbyrepeated3injectionsofthetopormaintenancedoseforperiodsof3-5years,toreducesymptomsonexposureto4thatallergen.SCIThasbeenpracticedforoveracenturyusingaqueousextractsofthenaturally5occurringallergens.1615SCIThasbeenshowntobeeffectiveforAR,allergicasthmaandsensitivityto6hymenopteravenom,alongwithdemonstratedbenefitinselectedpatientswithAD.Althoughmeta-7analysesconcludethatAITiseffective,thispositivejudgmentofefficacy(andsafety)shouldbelimited8toproductstestedintheclinicaltrials.Itisincorrecttomakeageneralassumptionthat“AITiseffective”9sincethismayleadtotheclinicaluseofproductsthathavenotbeenproperlystudied.1614,1616However,10ascurrentlypracticed,SCIThasthedrawbacksnotonlyoftheprolongedperiodoftreatmentand11multiplevisitstohealthcarefacilitiesbutalsotheever-presentriskofsystemicreactions.Therearenow12attemptstoovercometheselimitationsbymodifyingthenativeallergensorusingrecombinant13technologytoproduceextractsthatarelessreactivewithsIgEallowinghigherdosingwithgreatersafety14andshortercoursesoftreatment.1615(SeeSectionIX.D.2.ModifiedAllergenExtractsforadditional15informationonthistopic.)16 TwoUShealthcareagencieshaverecentlycommissionedsystematicreviewsofthemedical17literatureontheuseofAITinAR.1617,1618[TableIX.D.3-1.]TheNationalInstituteforHealthResearch18commissionedanupdateofthe2007CochraneReviewofAITforSAR1617andtheAgencyforHealthcare19ResearchandQualitycommissionedasystematicreviewoftheuseofSCITandSLITforthetreatmentof20ARandbronchialasthma.1618Thefirstofthesesystematicreviewsfoundhighlysignificantdifferencesin21favorofSCIToverplaceboforimprovementofsymptomsandmedicationusefortreatmentofAR,as22wellasforimprovementintherhinitisQOL,allwithap-valueof<0.00001.1617Thesecondsystematic23reviewfoundhighqualityevidenceforSCIT,comparedtoplacebo,improvingrhinitisand24rhinoconjunctivitissymptomsandQOL,withmoderatequalityofevidenceforreductioninmedication25usefortreatingAR.1618AthirdsystematicreviewusingtheEBRRmethodologyfoundthatSCITforSAR26andPARhasAggregateGradeofEvidenceAandrecommendedSCITforSARorPARpatientsnot27responsivetomedicaltherapy,whosesymptomssignificantlyaffectQOL.161928 AsearchoftheEmbase,MEDLINE,andCochraneLibrarydatabasesforsystematicreviewsand29randomizedcontrolledclinicaltrialsyieldedarecentotolaryngologyclinicalpracticeguidelineforallergic30rhinitis761andanInternationalConsensusonAllergyImmunotherapy1577,1620aswellas5double-blind,31placebo-controlledtrialsofSCITinARthatwerepublishedsincethepreviouslydiscussedsystematic32reviews.[TableIX.D.3-1.]Allfiveofthesetrialswereconductedwithaldehyde-modifiednaturalpollen33extracts(allergoids).1593,1594,1605,1621,1622ThesetrialsallsupporttheefficacyofSCITintreatingAR.34 35Patientselection.TherearethreetherapeuticoptionsforpatientswithAR:avoidance,pharmacotherapy36andimmunotherapy.TheevidencesupportingavoidanceisreviewedinSectionIX.A.ofthisdocument.37PharmacotherapyisdiscussedinSectionIX.B.TherearetwoprimaryreasonstoconsiderAIT.101,1623One38isthatadditionofAITtopharmacotherapyalonewilllikelyresultinamorepronounceddecreaseof39symptoms(evenafterashortcourseofAIT).Thesecondrelatestothefailureofpharmacotherapyto40

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altertheunderlyingimmunologicprocess.PatientsmaychooseAITlargelytoobtainalastingbenefit,1preventtheprogressionofARtobronchialasthma,orpreventnewsensitizations.1624-162623ContraindicationsforAIT.The2015EAACIPositionPapernotedcontraindicationsforinstitutingSCITfor4AR.1627Absolutecontraindicationswerepoorlycontrolledoruncontrolledasthma,activeautoimmune5disorders,andmalignantneoplasm.Relativecontraindicationswerepartiallycontrolledasthma,6autoimmunediseasesinremission,cardiovasculardiseaseanduseofbeta-adrenergicblockingagents.7TheAllergyImmunotherapy:PracticeParameters3rdUpdate,ontheotherhand,foundnosubstantive8evidencethatimmunotherapyisharmfulinpatientswithautoimmunediseases.1623ThePractice9ParametersalsolistpregnancyasacontraindicationtoinitiatingSCIT.1623Itmay,however,becontinued10ifthepatientisonmaintenancedosing.1112Extracts.IntheUSmostpollen,dander,insectandfungalextractsareavailableeitherinabuffered13salinewithphenolorin50%glycerin.Theexceptionisthoseextractsthathavebeenstandardizedbythe14USFDAwhichonlycomein50%glycerin.Thereisonelineofalum-precipitatedextracts,consisting15solelyofpollenextracts.InEurope,ontheotherhand,alum-precipitatedextractsarecommonly16employedandthereisincreasinguseofallergoidextractsconsistingofnaturalallergenspartially17denaturedbymixturewithanaldehyde.1593,1594,1605,1621,1622,1628(SeeSectionIX.D.1.AllergenExtractUnits,18Potency,andStandardizationandSectionIX.D.2.ModifiedAllergenExtractsforadditionalinformation19onthistopic.)2021Dosing.ThebeneficialresultsofSCIThavebeenrepeatedlyshowntobedependentonadministeringa22sufficientmaintenancedoseofeachextractwitheachmaintenanceinjection.1609,1629-1631Reductionof23theeffectivemaintenancedoseby90-95%causespartialorcompletelossofefficacy.1632Theresultsof24manydouble-blind,placebo-controlledstudieshavebeenutilizedtoformulatetherecommendations25fordosinginTableIX.D.3-2.,adaptedfromtheImmunotherapyPracticeParameters3rdUpdate.16232627Mono-versuspolysensitization.InmostlargestudiesofAR,80-85%ofthesubjectsaresensitizedto28morethanoneunrelatedallergen.Analysisofsomeofthesestudieshasshownthatthepolysensitized29subjectsrespondaswellto(sublingual)AITasthosewithsensitivityonlytotheadministered30allergen.1633ThereisnoimmunologicalrationalewhythisshouldbedifferentinsubcutaneousAIT,but31thisspecificquestionisanimportantunmetneedwhichshouldbeaddressedinfuturetrials.1634283233Single-versusmultiple-allergenAIT.ItisthecommonpracticeamongUSallergiststoincludeintheir34treatmentmultipleallergenextractstowhichthepatientissensitized.Arecentsurveyof670patientsin356practicesfoundameanof18allergenextractsintheirtreatment.163529Ontheotherhand,European36guidelinesrecommendtreatingwiththesinglemosttroublesomeallergenidentifiedclinically,1636orif37morethanoneextractistobegiventheyshouldbegivenatseparatesiteswithatleast30minutesin38betweenadministration.32ScientificsupportfortheUSallergists’approachofusingmultipleallergen39mixturesforSCITcanbefoundinfourdouble-blind,placebocontrolledstudies,twoinpatientswith40AR,1629,1637oneinchildrenwithasthma,1630andoneinpatientswithbothrhinitisandasthma1638allof41whichdemonstratedsignificantimprovementinpatientsreceivingmixturesofmultiple,unrelated42

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allergenextracts.However,arecentreviewconcludedthatmultiallergenimmunotherapyin1polysensitizedpatients,whetherdeliveredsublinguallyorsubcutaneously,requiresmoresupporting2evidencefromwell-designed,well-powereddoubleblind,placebocontrolledclinicaltrialstovalidateits3efficacyinpractice.163445Mixing.Ifmultiple-allergenmixturesaretobeusedforSCIT,thereareseveralconsiderations,in6additiontoensuringthateachextractinthemixtureisataconcentrationthatwillprovideaneffective7dosewhendeliveredwiththemaintenanceinjection.Theseconsiderationsare:1)avoidingmixing8extractswithstrongproteolyticactivitywithextractswhoseallergensaresusceptibletothisactivity,2)9payingattentiontoallergeniccross-reactivity,3)usingpreservativesthatareappropriateforthe10allergens.163211

Allfungalandsomeinsectbodyextracts(butnotUSHDMextracts)havestrongproteolytic12activitytowhichmanypollen,miteandanimaldanderallergensaresusceptible.1639Fungaland13cockroachextractsshouldnotbemixed,butfungalextractscanbecombined.164014

Plantpollenscontainsomeallergensthatareliketheallergensofunrelatedplants(pan-15allergens)butgenerallythemajorallergensareunique.Whentheappropriateallergensareavailablein16thetestingpanel,theuseofmoleculardiagnosisorCRDcanbeofgreatuseindifferentiatingcross-17reactivityduetopan-allergensfromthatduetomultiplerelatedmajorallergens.(SeeSectionVIII.F.6.18ComponentResolvedDiagnosisforadditionalinformationonthistopic.)Whenthepatientissensitized19tothemajorallergensofbotanicallyrelatedplantstherearetwoapproachesthatcanbeemployed.164120Oneapproachistoonlyincludethelocallymostimportantmemberofarelatedgroup(suchasragweed21ornorthernpasturegrasses);theotherapproachistouseamixturesofrelatedallergenextracts,but22treatingitasifitwereoneallergen.16412324Diluents.Diluentscontaining50%glycerinareexcellentatmaintainingextractpotencyandareusedin25theUSroutinelyforextractswithhighproteaseactivity.1639,1642Thedrawbacktousingextractswithhigh26glycerincontentisthattheycausepainwheninjected.1633Aphenol-salineextractcontaining0.3%27humanserumalbuminiswelltoleratedand,intheabsenceofhighproteolyticactivity,isanexcellent28diluentthatmaybeusedroutinelyformakingdilutionsforinitiationofSCITintheUS.16432930Regimens.Forreasonsofsafety,SCITisinitiatedatadilutionofthefinaldoseandbuiltupusuallywith31weeklyinjectionsofincreasingamountsandconcentrationsoveraperiodofweeksorevenmonths.32Oncemaintenancedosesareachieved,theintervalbetweeninjectionscanbeincreasedbutusuallynot33beyond4weekswithaqueousextractsusedintheUS,1623butupto4-6weeksfordepotextractsasused34inEurope.16143536VenueforadministeringSCIT.SCITinallergypracticesintheUSisassociatedwitharateofsevere37systemicreactionsof0.1%.1644ForthisreasontheImmunotherapyPracticeParameters3rdUpdatestate38thatinjectionsshouldbegivenonlyinamedicalfacilitywherepromptrecognitionandtreatmentof39anaphylaxisisassuredandpatientsshouldremainunderobservationforatleast30minutesfollowing40theinjection.1623ThisisinlinewiththeEuropeanperspective.32ThereisacompanyintheUSthat41promotesthepracticeofhomeadministrationofSCIT.1645Theirprotocolcallsforadministrationof42

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relativelylowdosesofSCITseveraltimesperweekresultinginacumulativedosethatapproachesthat1recommendedinthePracticeParameters.However,thereisevidencetosuggestthatitisthesizeofthe2individualdoseratherthanthecumulativeamountadministeredthatdeterminesefficacy,1646andno3blindedstudieshavebeenofferedtosupporttheefficacyofthislow-doseapproach.45AcceleratedSCITadministration.Toshortenthelengthofthebuild-up,clusterdosingissometimes6employed.Twoorthreeinjectionsaregivenoneachvisitonnon-consecutivedays,witha30-minute7waitingbetweeninjections.Ifvisitsaretwiceweekly,maintenancedosingcanbeachievedin4weeks16478orevenafterashorterperioddependingontheproductadministeredandschedulefollowed.1648A9retrospectiveanalysisofratesofsystemicreactionsinalarge,multi-physicianpractice1649andadouble-10blindrandomizedtrial1650showednoincreaseintherateofsystemicreactionsinpatients,comparing11clustertoconventionalregimens.Another(open)trialsupportsthesefindings.165112

Rushregimensadministermanyinjectionsperdayonconsecutivedays,typicallyachieving13maintenancedosinginonetothreedays.Evenwiththeuseofpremedication,thereisanincreasedrate14ofsystemicreactionscomparedtoconventionaldosing.16521516Mechanismofaction.Ingeneral,theimmunologicresponsetoSCITinvolvestwosequentialsteps.The17firstisagenerationofregulatoryT-cellssecretingIL-10andTGF-β,leadingtoaswitchfromIgEtoIgG418antibodyformation.1653,1654WithcontinuedAITtheTregresponsedeclinesandanimmunedeviation19fromTh2toTh1responsesdominates.1577,1653(SeeSectionIV.PathophysiologyandMechanismsfor20additionalinformationonthistopic.)2122Modificationofdisease.AnadvantageofSCIToverpharmacotherapyisthatitalterstheunderlying23immunologicresponsetowardsthatwhichisseeninnon-allergicindividuals.1654Theresultsofthis24alterationintheunderlyingimmuneresponsebySCITcanbeseenclinicallyinthereductioninnew25sensitizations,intheprogressionfromARtoasthma,andinthepersistingbenefitfollowinganadequate26courseoftherapy.27

Inchildren,adolescentsandyoungadults,whoaresensitizedonlytotheallergenbeing28administered,thedevelopmentofnewsensitizationsisreducednotonlyduringAITbutforseveralyears29followingcompletionofthecourseofAIT.1625,1626Asimilarprotectiveeffecthasnotbeendemonstrated30inpatientspolysensitizedattheinitiationofAIT.31

SCIThasalsobeenshowntopreventtheprogressionfromARtoasthma.Two-hundredfive32children,sensitizedtograss,birchorboth,andshowingnoevidenceofasthmaduringanobservational33year,weretreatedwithtimothyand/orbirchSCITfor3years,orstandardpharmacotherapyalone,and34observedforanadditional7yearsaftercompletionofSCITinanopentrial.1624Theriskfordeveloping35asthmawassignificantlyreducedattheendofSCITandpersistedforthesevenyearsoffollow-up.The36databaseoftheGermanNationalHealthInsurancewasusedtofollowpatientswithARwithoutasthma37whowereorwerenotplacedonAITin2006.1655Duringfive-yearfollow-up,thosepatientswhoreceived38AIT(90%onSCIT)weresignificantlylesslikelytohavedevelopedasthma.3940Durationoftreatmentandpersistenceoftreatmenteffect.Regardingpersistenceofbenefit,adouble-41blind,randomizedstudywasconductedinpatientswithARwhohadreceived3or4yearsofSCITwith42

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timothygrassextract.1656SubjectswererandomizedtocontinuemaintenanceSCITorreceiveplacebo1forthreeyears.Therewasnodifferenceinsymptom/medicationscoresoverthethreegrasspollen2seasonsbetweenthosereceivingandnotreceivingtimothyextractinjections.Inanothertrial,grassSCIT3wasdiscontinuedin108grasssensitivepatientswhohadrespondedwelltothetreatmentafter3or44yearsofSCIT.1657Thepatientswerefollowedthroughupto4grasspollenseasonslookingforrelapse.5Approximately30%relapsedbythethirdgrasspollenseason,withfewmoresubsequentlyrelapsing.6

Inthetwostudiesintheprecedingsection,1656,1657threeorfouryearsofSCITwithgrassextract7inducedremissionsthatpersistedinmostofthesubjectsforatleast3years.Thereareonlyafew8studiesthatlookatlongerorshorterperiodsoftreatment.Astudythatcompared3-or5-yearsofSCIT9withHDMextractfoundsignificantimprovementafter3yearsbutaddedclinicalimprovementinrhinitis10after5yearsofSCIT.165811

12Safety.InformationregardingtheoccurrenceoffatalreactionstoSCITwasobtainedretrospectivelyby13theImmunotherapyCommitteeoftheAAAAIbyperiodicsurveysofitsmembersfrom1985to1420011659,1660andbyanon-linewebsitesince2008.1644Theearlierretrospectivesurveyssuggestedthata15fatalreactionoccurswithevery2to2.5millioninjectionvisits.1659,1660Theon-linesurveyelicited16informationontwofatalreactionsin28.9millioninjectionvisitswhichwasthoughttorepresentan17improvementduetomorecarefulmonitoringofpatientswithasthma.1644Therateofsystemicreactions18hasremainedsteadywith1.9%ofpatientsexperiencingasystemicreaction,mostmild,butwith0.08%19experiencingagrade3and0.02%agrade4reaction.1644Theoccurrenceandsizeoflocalreactionsdo20notpredicttheoccurrenceofasystemicreactionwiththenextinjection.1661,16622122Costeffectiveness.SCITcanbeadministeredfor3-5yearswithcontinuingreliefofsymptomsforyears23afterdiscontinuation.Pharmacotherapy,ontheotherhand,mustbecontinuedindefinitely,sinceithas24nodiseasemodifyingactivity.Becauseofthisdifference,theinitialhighercostofSCITmaybeoffsetby25thecontinuingbenefitafteritisstopped.Thisfactoredintoadecision-makinganalysisthatsuggestedif26apatientwithSARrequiringnasalsteroids6monthsperyearisseenbeforeage41years,thecostwill27belessinthelongtermiftheyareplacedonSCIT.166362Ifthepatienthasperennialneedfornasal28steroids,andtheyarelessthan60yearsofage,themostcosteffectiveapproachisSCIT.Anothercost-29effectivenessanalysisfoundthatSCITforSARmaybemoreeffectiveandlessexpensivethan30pharmacotherapyfromthesocietalperspectivewhencostsofproductivitylossareconsidered.1664A31retrospectivestudycomparedUSMedicaidtreatedadultsandchildrenwhowerenewlydiagnosedwith32ARandwereorwerenotplacedonAIT.Eighteenmonthfollow-uprevealed30%and42%healthcare33costsavings,respectively,intheAITtreatedpatients.16653435

• AggregateGradeofEvidenceforSCITinthetreatmentofAR:A(Level1a:3recentstudieslisted;36Level1b:5recentstudieslisted;TableX.D.3-1.)Ofnote,duetothelargebodyofliterature37supportingSCITasatreatmentforAR,onlyrecentsystematicreviewsandselectdouble-blind,38placebo-controlledRCTsareincludedinTableX.D.3-1,astheseachieveanAggregateGradeof39EvidenceofA.40

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• Benefit:Improvementinsymptomsanddecreasedneedforrescuemedication.Decreased1likelihoodofprogressionfromARtobronchialasthma.Persistentbenefitforyearsafter2completionof3-5yearsofSCIT.3

• Harm:Inconvenienceofmultiplevisitstoamedicalfacilitytoreceiveinjections.Potentialfor4systemicreactions,includinganaphylaxis.5

• Cost:Costforpreparationofallergenextractfortreatment.Costofvisitstomedicalfacilitiesto6receiveinjections.7

• Benefits-HarmAssessment:Benefitgreaterthanharmforpatientswhocannotobtainadequate8reliefwithsymptomatictreatmentandwhosesymptomsextendmorethanafewweekseach9year.10

• ValueJudgments:Patientswhocanobtainadequatereliefofsymptomswithmedicationmust11decideiftheshort-termincreasedcostandinconvenienceofSCITiscompensatedforbythe12longtermpersistingclinicalbenefitandrelieffromneedtotakemedication.Pharmacoeconomic13studiessuggestthatinthelongterm,SCITiscosteffectiveoversymptomatictherapy.14

• PolicyLevel:StrongrecommendationforSCITinpatientsunabletoobtainadequatereliefwith15symptomatictherapy.16

• Intervention:SCITshouldberecommendedtotheARpatientwhocannotobtainadequaterelief17fromsymptomaticmedicationforsignificantperiodsoftimeeachyearandtothosewhowould18benefitfromitssecondarydisease-modifyingeffects(preventionofbronchialasthmaandnew19sensitization),particularlychildrenandadolescents.20

2122

23

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TableX.D.3-1.RecentsystematicreviewsandselectedRDBPCTsfortheuseofSCITinallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Linetal1618 2013 1a Systematicreview

Rhinoconjunctivitisand/orasthma,adultsandchildren

Efficacy,effectivenss,safety.Symptoms,medicationuse,QOL.

Rhinitisorrhinoconjunctivitis.-Symptoms(n=1734):StrengthofevidencehighforSCIT.-Medicationuse(n=564):StrengthofevidencemoderateforSCIT.-QOL(n=532):StrengthofevidencehighforSCIT.

Meadowsetal1617 2013 1a Systematicreview

SAR,adultsandchildren.

Clinicaleffectiveness,costeffectiveness.Symptoms,medicationuse,QOL.

-Symptoms(n=659active,525placebo):SMD-0.65,p<0.00001favoringSCIT.-Medicationuse(n=621active,483placebo):SMD-0.55,p<0.00001favoringSCIT.-QOL(n=955):SMD-0.53,p<0.00001,a0.74-unitreductioninRQLQcomparedwithplacebo.

Purkeyetal1619 2013 1a Systematicreview

SARandPAR,adultsandchildren,level1bevidence,single-extractAIT

Symptoms,medicationuse,QOL

SCITforSARandPARhasAggregateGradeofEvidenceA.SCITisrecommendedforSARorPARpatientsnotresponsivetomedicaltherapy,whosesymptomssignificantlyaffectQOL.

Bozeketal1622 2016 1b RDBPCT

SAR(n=55),age65-75years.Maintenancedose26.3μgPhlp5.

Combinedsymptom-medicationscore

Thirdyearcombinedsymptom-medicationscorereduced41%frombaseline(p=0.004)&37%versusplacebo.

Klimeketal1605 2014 1b RDBPCT

SAR(n=102),age18-75years.Maintenancedose24μgGp1plusGp5.

Symptoms,medicationuse Reductioninsymptoms:34%(p=0.004).Reductioninmedicationuse:40%(p=0.004).

Pfaaretal1594 2013 1b RDBPCT

SAR(n=269),age12-70years.MaintenancedoseBetv16.75μg&Phlp515.75μg.

Symptom-medicationscore Symptom-medicationscorereducedforgrass&birchpollenseasons:1styear21%(NS),2ndyear19.4%(p=0.0385).

Rajakulasingam1621 2012 1b RDBPCT

SAR(n=37),ages22-54years.Maintenancedose25.2μggroup5.

Symptomimprovementfrombaselineyear

Improvementfrombaselineyearof≥2/10insymptoms:active65%,placebo35%(p=0.024).

Pfaaretal1593 2012 1b RDBPCT

SAR(n=179),age11-69years.Maintenancedose31.5μgPhlp5.

Symptom-medicationscore Symptom-medicationscorereduced:1styear16%(p<0.01),2ndyear37%(p<0.01).

RDBPCT:randomizeddouble-blindplacebo-controlledtrial,SCIT:subcutaneousimmunotherapy;LOE:levelofevidence;QOL:qualityoflife;SAR:seasonal2allergicrhinitis;SMD:standardizedmeandifference;RQLQ:RhinconjunctivitisQualityofLifeQuestionnaire;PAR:perennialallergicrhinitis34

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12TableX.D.3-2.RecommendeddosingforSCIT*3Allergenicextract Labeledpotencyor

concentrationProbableeffectivedoserange

RangeofestimatedmajorallergencontentinUSlicensedextracts

Housedustmites:D.farinaeD.pteronyssinus

3,000,5,000,10,000,30,000AU/mL

500-2,000AU 10,000AU/mL20-160μg/mLDerp1,Derf12-180μg/mLDerp2,Derf2

Cathair 5,000,10,000BAU/mL 1,000-4,000BAU 10,000BAU/mL20-50μg/mLFeld1

Grass,standardized 100,000BAU/mL 1,000-4,000BAU 100,000BAU/mL425-1,100Phlp5

Bermuda 10,000BAU/mL 300-1,500BAU 10,000BAU/mL141-422Cynd1μg/mL

Shortragweed 1:10w/v,1:20w/v100,000AU/mL

6-12μgAmba1or1,000-4,000AU

1:10w/v300μg/mLAmba1

Acetoneprecipitated(AP)dog

1:100w/v 15μgCanf1 80-400μg/mLCanf1

Nonstandardizeddogextracts

1:10w/vto1:20w/v 15μgCanf1 0.5-10μg/mLCanf1

Nonstandardizedpollenextracts

1:10to1:40w/vor10,000to40,000PNU/mL

0.5of1:100or1:200w/v

Notavailable

Nonstandardizedfungal,cockroachextracts

1:10to1:40w/vor10,000to40,000PNU/mL

Highesttolerateddose Notavailable

SCIT:subcutaneousimmunotherapy;AU”allergyunits;BAU:bioequivalentallergyunits;w/v:weightbyvolume4*AdaptedfromCoxL,NelsonH,LockeyR,etal.Allergenimmunotherapy:apracticeparameterthirdupdate.JAllergyClinImmunol2011;127:S1-55.162356 7

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IX.D.4.Sublingualimmunotherapy(SLIT)1

SLITisanalternativeapplicationvariantofSCIT,whichwasfirstpracticedoveracenturyagoby2Noonetal.1570,1666Thefirstdouble-blindplacebo-controlledtrialwithSLITwasn’tconducteduntil19863byScaddingetal1667inLondon,UK.Afterthat,onlyseveralsmalltrialswereconducteduntilthe4beginningofthenewmillennium,whenseveral‘bigtrials’finallydemonstratedtheclinicalefficacyand5safetyofSLIT.Sincethen,manyhigh-qualitySLITtrialshavebeenreported.Asaresult,theactual6evidenceforSLITappearstobeatleastassolidasthatforSCIT.TheliteratureonSLITfor7AR/rhinoconjunctivitisisvastandseveralgoodmeta-analysesandsystematicreviewshavebeen8publishedoverthepastdecade,thedecisionwasmadetoprimarilyanalyzeresultsfromthesereviews9andtocomplementthemwithfindingsfromlargerandomizedtrialspublishedduring2016.[Table10X.D.4-1.]11

12Efficacyinadults.Mostsystematicreviewsandmeta-analysesshowalowtomoderateefficacyofSLIT13overplacebo(SMD=0.30-0.50),andthisapproacheshighefficacywithlongertreatment1668(greaterthan1412months’treatmentSMD=0.70).Itmustbeconsideredthatallpatients,boththoseintheSLITandthe15placeboarms,haveopenaccesstorescuemedication,andthatSLITresultsinanefficacyontopofthe16symptomimprovementobtainedwithrescuemedication.1718Efficacyinchildren.Overfiveyearsago,DutchcolleaguesanalyzedsystematicreviewsofSLITinchildren19andconcludedthatthemethodologicalqualityshouldbeimproved.Theyespeciallyquestionedthe20heterogeneityoftheincludedtrialsandtheriskofbias.1669Roderetal1670alsodeterminedin2008that21therewasnotenoughevidencetosupporttheusefulnessofSLITinchildren.Theseflawshavebeen22improvedinrecentstudies.Thereisstrong1671evidencethatgrasspollenSLITtabletsinchildrenreduce23symptomsofAR.TheevidenceforaqueousSLITismoderate.1672TheevidenceforHDMSLITisof24moderate-lowquality.2526EfficacyofSLIToverpharmacotherapy.ForPAR,SLITwithHDMtabletsismoreeffectivethananysingle27pharmacotherapy,includingantihistamines,antileukotrienesandINCS.1673ForSARgrassandragweed28tabletSLITisalmostaseffectiveasINCSandmoreeffectivethantheotherpharmacotherapies.1673These29datahadalreadybeenconfirmedfortheSLITgrasspollentabletsbyapreviousmeta-analysis;inthis30publicationtheseparateanalysisofthe5-grasstabletshoweditssuperiorityoverallpharmacotherapy31treatments.13323233EfficacyofSLITcomparedtoSCIT.SeveralinvestigatorshavetriedtocomparetheefficacyofSLITagainst34thatofSCIT.Mostmeta-analysesarebasedonindirectcomparisons,asthereareonlyaveryfewdirect35head-to-headrandomizedtrialscomparingbothtreatments;therefore,theevidencethatSCITismore36effectivethanSLITisweak.Alsoinchildren,SCITseemsmoreeffectivethanSLIT,butagainthequalityof37evidenceislow.16723839Safety.RaresystemicandseriousadverseeventshavebeenreportedwithSLIT,butingeneral,meta-40

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analysesfoundSLITtobesaferthanSCIT.Inthecompletedata-setofsystemicreviewstherewere71reportsoftheuseofepinephrineintheSLITgroupandonecaseofeosinophilicesophagitiswithagrass2pollenSLITtablet.TherewasnoadministrationofepinephrineintrialsoutsideoftheUS.A2012review3byCalderonetal1674estimatedtheanaphylaxisrateofSLITtobe1per100milliondoses,or1per4526,000treatmentyears.GrasspollenSLITtabletsarejustassafeinARpatientswithandwithoutmild5asthma.1675StartingSLITin-seasonappearedtobesafe.Althoughtherewere2serioustreatment-6relatedadverseeventswithco-seasonalSLITinitiation,nonerequiredepinephrineadministration.1676In7theUS,theFDArequirespatientsbeprescribedanepinephrineautoinjectorandthefirstdosebegiven8inthephysician’sofficeforthoseonSLITtablets.ContinuingAITduringpregnancydidnotaugmentthe9incidenceofadverseoutcomesduringdeliverynoraltertheriskofdevelopingatopicdiseaseinthe10offspring.NoconclusioncanbedrawnregardingthesafetyofstartingSLITinapregnantwoman,dueto11lackofcases.16771213Preventativeeffects.Therearenosystematicreviewsspecificallyaddressingthepreventativeeffectsof14SLITthatfallwithintheallowablesearchdaterangeofthisICAR:ARdocument.Thepreventativeeffect15SLITonasthmadevelopmentwasinvestigatedinanopenRCTbyMarognaetal1678involving21616childrentreatedwithSLITfor3years.Mildpersistentasthmawaslesscommoninpatienttreatedwith17SLITthanpatientsreceivingonlypharmacotherapy.Inadouble-blindRCTinvolving812childrenwith18grasspollen-inducedrhinoconjunctivitis,after3yearsoftherapywithSQ-standardizedgrasspollen19tablet,childreninthetreatmentgrouppresentedareducedriskofdevelopingasthmacomparedto20placebogroupat2-yearfollow-up(OR0.71,p<0.05).1679Althoughthesefindingsareinteresting,the21overallstrengthofevidenceforthepreventionofasthmainSLITstudiesislowatpresent,thoughthe22evidenceforasthmasymptomandmedicationreductionishigh.23

Developingnewallergensensitizationsfrequentlyoccursinthenaturalhistoryofrespiratory24allergy.PreventativeeffectsofAITontheonsetofnewsensitizationsisoftendiscussed.However,25currentlyavailableSLITdataforpreventionofnewallergensensitivitiesisalsolimited.Theabove26referencedMarognaetal1678studydidnotethattherateofnewsensitizationswaslow,corresponding27to3.1%ofSLITtreatedpatientsandto34.8%ofcontrols,withanORof16.85todevelopnew28sensitizationsincontrols.AnotherstudybyMarognaetal1680prospectivelyevaluatedthelong-term29effectofSLITgivenfor3,4,or5yearsin78SLITpatientsversus12controls.Overa15-yearfollow-up,all30thecontrolsubjectsdevelopednewallergensensitivities,whilethisoccurredinlessthan25%ofthe31patientsreceivingSLIT(21%intreatedfor3years,12%,intreatedfor4years,and11%intreatedfor532years,respectively).3334Cost-effectiveness.Themeta-analysiscomparingtheefficacyandcost-savingsofthe5-grassSLITtablet35versusthetimothygrassSLITtablethasseveralflaws,assometrialswerereportedinseveral36publicationsandthusthesepublicationsshouldbeanalyzedasone.Moreimportantly,theoutcome37variablesandtheprecisedefinitionofthepollenseasonvarybetweenthetimothygrassSLITtabletand38the5-grassSLITtablettrials,sodirectcomparisonofoutcomesshouldnotbedone,aswasreviewedin39detailpreviously.1681,1682The5-grassSLITtablet($1003Canadiandollar)wasassociatedwithcostsavings40againstyear-roundSCIT(+$2471),seasonalSCIT(+$948)andthetimothygrassSLITtablet(+$1168)41

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duringthefirstyearoftherapyandstillduringthesecondandthirdyearoftreatment.Thehighercosts1forSCITwereduetotheelevatedindirectcostsfrommissingworkinghoursandtransportationcosts2duetoin-officeSCITadministration.ThehighercostsforthetimothygrassSLITtabletwereduetothe3year-rounddosingversusthepre/co-seasonal6-monthtotaldosingof5-grassSLITtablet.4

AUKmeta-analysisofcostsshowedthatSCITandSLITmaybecost-effectivecomparedwith5standardpharmacotherapyfor6years(whenconsideringathresholdofpound20,000-30,000per6QALY).TheinvestigatorswerenotabletoestablishacleardifferencebetweenSCITandSLITincost-7effectiveness.161789

Additionaldatafromdouble-blindplacebo-controlledtrials.Someofthemostimportantrecenttrials10withdatathataddtothealreadypresentedsystematicreviewsarelistedhere:11

• HighdosetreepollenaqueousSLITwaseffectiveinreducingsymptom-medicationscoresin12childreninahigh-qualitydouble-blindplacebo-controlledtrial.168313

• Double-blindplacebo-controlledtrialswithragweedSLITreducedthecombinedsymptom-14medicationscorewhenadministeredasdrops1684,1685andastablets,particularlyatthehigh15dose.1686,168716

• Inasmalldouble-blindplacebo-controlledtrialofmoderate-highquality,AlternariaSLITforAR17(andasthma)wasshowntobeeffectiveinsignificantlyreducingtheARcombinedsymptom-18medicationscore.168819

• AsfortheSLITHDMtablets,adose-effectforareductioninARsymptoms-medicationscores20hasbeenshowninthreedouble-blindplacebo-controlledtrials.1064,1689Onetrialdemonstrateda21significantdifferenceandasymptomscorereductionof29%onlyinthosepatientswithmore22moderate-severedisease.79923

• Moderateevidenceforefficacyofdualgrasspollen-HDMSLITafter12monthsoftreatmentand241yearafterdiscontinuation.169025

• Multi-allergenSLIThasbeentestedinasingle-center,double-blind,placebo-controlledtrialwith26timothygrassmonotherapy,timothygrassplus9otherpollenallergens,orplacebo.Onlythe27timothygrassmonotherapygroupshowedstatisticallysignificantimprovementinthenasal28challengetest,titratedSPT,sIgE(reduction)andIgG4(increase).Duetoverylowpollenseason,29therewerenodifferencesinsymptom-medicationscoresbetweenanyofthegroups.169130Additionalstudyonmulti-allergenSLITisneeded.31

32Aggregategradeofevidenceandrecommendations.InTableX.D.4-2.thegradeofevidenceisshown33andhowthisleadstorecommendationsinthedecision-makingconcerningSLIT.3435

• AggregateGradeofEvidence:A(Level1a:10studies;Level1b:3studies;Level2a:11studies;36Level3a:1study;TableX.D.4-1.).37

• Benefit:SLITimprovedpatientsymptomscores,evenasadd-ontreatmentontopofrescue38medication.SLITreducedmedicationuse.TheeffectofSLITlastsforatleast2yearsaftera3-39yearcourseofhighdosetherapy.Benefitisgenerallyhigherthanwithsingle-drug40

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pharmacotherapy;however,itispossiblysomewhatlessthanwithSCIT.Althoughaveryrecent1high-qualityhead-to-headtrialdidnotshowastatisticallysignificantdifferenceinefficacy2betweenSCITandSLIT,thisevidenceisnotpresentedhere,asthepublicationdateisoutside3thereviewperiodforthismanuscript.7974

• Harm:Minimalharmwithveryfrequent,butmild,localadverseevents.Veryraresystemic5adverseevents.SLITseemstobesaferthanSCIT.6

• Cost:Intermediate,SLITbecomescost-effectivecomparedtopharmacotherapyafterseveral7yearsofadministration.DataoncostofSLITcomparedtoSCITisvariable.8

• Benefits-HarmAssessment:Benefitoftreatmentoverplaceboissmall,buttangible,andontop9ofimprovementwithmedication.Lastingeffectatleast2yearsofftreatment.Minimalharm10withSLIT,greaterriskforSCIT.11

• ValueJudgments:SLITimprovedpatientsymptomswithlowriskforadverseevents.12• PolicyLevel:13

o UseofSLIT:grasspollentablet,ragweedtablet,HDMtablet,treepollenaqueous14solution–Strongrecommendation.15

o AlternariaSLIT–Recommendation.16o EpitheliaSLIT–Option.17o DualSLITinbi-allergicpatients–Recommendation.18

• Intervention:WerecommendhighdosetabletoraqueousSLITbeadministeredinpatients19(adultsandchildren)withSARand/orPARwhowishtoreducetheirsymptomsandtheir20medicationuse.SLITcanbecontinuedsafelyinthepregnantpatient.2122

23

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TableX.D.4-1.EvidencefortheuseofSLITinthetreatmentofallergicrhinitis–systematicreviewsandmeta-analysesfromthelastdecade*1Study Year LOE Studydesign Studygroups Clinical

endpointConclusion*

DiBonaetal815

2015 1a Meta-analysisofRCTs

SLITgrasspollentabletsvsplaceboforSAR

Symptom&medicationscore

Smallimprovementinsymptomandmedicationscoresvsplacebo:(SMD-0.28;CI-0.37to-0.19;p<0.001)and(SMD-0.24;CI-0.31to-0.17;p<0.001)Adverseevents:7/2259SLITpatientsweregivenepinephrine.

Leathermanetal1692

2015 1a SystematicreviewofRCTsforSLITdoses

SLITforARversusplacebo

Dosesoftheeffectivevsdosesofnon-effectiveSLIT

Widedoserangesbetweenstudies.Forcertainantigens,effectiveandnon-effectivedoserangesoftenoverlap.Forotherallergens:insufficientdata.

Devillieretal1332

2014 1a Meta-analysisofRCTs

PollenSLITvspharmacotherapyvsplaceboforSAR

Relativeclinicalimpact**

Clinicalimpact:5-grasspollentablet>INCS>timothygrasspollentablet>montelukast>antihistamines

Makatsorietal1693

2014 1a SystematicreviewofRCTs

SLITversusplacebo Drop-outratesinSLITandplacebogroups

Notendencyforaskeweddrop-outratiobetweenSLITandplacebogroups.ConfirmstrialresultsareunbiasedandSLITappearstobesafe.

Meadowsetal1617

2013 1a Meta-analysisofRDBPCTs,costanalysis

SCITandSLITvsplaceboforSAR

Severalefficacyvariables,costs

SymptomreductionwithSCITandSLITisgreaterthanplacebo.

Linetal1694 2013 1a SystematicreviewofRCTs

AqueousSLITvsplaceboforSAR(andasthma)

Symptom&medicationscores

ModerateevidenceaqueousSLITreducessymptomsandmedicationuseinAR/ARC.

Radulovicetal1695

2011 1a Meta-analysisofRDBPCTs

SLITvsplaceboforAR

Symptom&medicationscores

SLITvsplacebo:Reductioninsymptoms(SMD-0.49)andmedicationuse(SMD-0.32).Noepinephrineuse.

DiBonaetal1696

2011 1a Meta-analysisofRDBPCTs

GrasspollenSLITvsplaceboforSAR(andasthma)

Symptom&medicationscores

SLITvsplacebo:Reductioninsymptoms(SMD-0.32)andmedicationuse(SMD-0.33).Noepinephrineuse.

Durhametal1673

2016 1b PooledanalysisfromRCTs

SAR:grassorragweedSLITtabletvs.pharmacotherapy.PAR:HDMSLITtabletvs.pharmacotherapy.

TotalNasalSymptomScore

SAR:SLITnumericallygreaterthanmontelukastandantihistamine;almostequaltomometasonefuroateINCS.PAR:SLITeffectnumericallygreaterthanallpharmacotherapy.

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Maloneyetal1675

2015 1b PooledanalysisfromRCTs

GrassSLITtabletvsplacebo.GrassSLITinARpatientswith(24%)andwithout(76%)mildasthma.

TreatmentrelatedAEfrequency

Severeasthma-relatedadverseeventsduetotreatmentin6/120SLITand2/60placebo.Nodifferencebetweenthe2groups.Bothadultsandchildrenwereincluded.

Creticosetal1676

2016 2a Systematicreview

PatientstreatedwithSLIT,startedin-season,vsout-of-seasonvsplacebo

Serioustreatment-relatedAE,systemicAEdiscontinuations

11SLITtrials(n=2668subjectstotal).Noepinephrineadministration.0-4%systemicAEwithin-vs0%out-seasoninitiation.2serioustreatment-relatedAEwithco-seasonSLITinitiation.

Oykhmanetal1677

2015 3a Systematicreviewofcohortstudies

PregnantwomenwithvswithoutSLITorSCITandtheiroff-spring.422pregnanciescontinuingAITand31startingAIT.

Pregnancyoutcome,allergyinoffspring

Nodifferenceinprematurity,proteinuria,hypertension,congenitalmalformations,perinataldeath.Nofetalcomplicationsof10/453systemicreactionstoSCIT.Noalteredriskofdevelopingatopicdiseaseinoff-spring.

SLITorSCIT:ChildrenonlyLarenas-Linnemannetal1671

2013 2a SystematicreviewofRCTs

ChildrenwithARand/orasthmatreatedwithSLITvsplacebo/opencontrols

Symptom&medicationscores

StrongevidencethatgrasspollenSLITinchildrenreducessymptomsofAR.Moderate-lowevidenceforHDMSLIT.

Roderetal1670

2008 2a SystematicreviewofRCTs

Children0-18yearswithAR:anyformofAITvsplacebo

Symptom&medicationscores

InsufficientevidencethatAITinanyformhasapositiveeffectonARinchildren.

SLITversusSCITChelladuraietal1697

2013 1a SystematicreviewofRCT

SCITvsSLIT(andvsplacebo)inAR

Symptom&medicationscores

LowgradeevidencefavorsSCIToverSLITforARsymptom&medicationreduction.Moderateevidencefornasal&eyesymptomreduction.

DiBonaetal1698

2012 1a Meta-analysisbasedcomparison

GrasspollenSCIT–placebovsgrasspollenSLIT–placeboinSAR

SMDofsymptom&medicationscores

SCITmoreeffectivethanSLIT(drops)andSLIT(tablet)forsymptomandmedicationscorereduction.

Nelsonetal1699

2015 1b Networkmeta-analysisofRCTs

GrasspollenSLITtabletsvsplacebo.

Symptom&medicationscores

SymptomandmedicationscoreswithSCIT,SLITtabletsanddropsallreducedvs.placebo,exceptforsymptomscorewithSLITdrops.

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GrasspollenSLITdropsvsplacebo.GrasspollenSCITvsplacebo.

Aasbjergetal1700

2015 2a SystematicreviewofRCTs,productinformation,registry

ARpatientsreceivingPhleumpratenseSCIT,SLITdropsorSLITtabletsvsplacebo.(Including314children.)

Safetydata Manyproductswithoutstructuredcollectionofsafetydata.Generalsafetyassessment:SLITsaferthanSCIT.

Dranitsaris&Ellis1701

2014 2a SystematicreviewofRCTs&indirectcomparison

Timothtgrasstablet,5-grasstablet,grasspollenSCITvsplaceboinSAR

Efficacy,safety,costforCanadiansetting

Symptoms:allITtreatmentsbetterthanplacebo.Costsfor5-grasstabletgreaterthancostsfortimothygrasstabletandSCIT.

Calderonetal1702

2013 2a SystematicreviewofRCTs

PatientsallergictoHDM,withARandasthma,treatedwithHDMSCITvsSLITvsplacebo

Symptomscore,ITschedule,dosing

ImprovedsymptomscorevsplacebowasobservedmorefrequentlyforSCIT.Dataisweakasthebasictreatmentparametersvarywidely.

Dretzkeetal1703

2013 2a SystematicreviewofRCT&indirectcomparison

SCITandaqueousSLITvsplacebo,SCITvsSLITinAR

Symptom&medicationscores

TrendfavoringSCIToverSLITforARsymptom&medicationscorereduction.Noconclusiveresults.

SLITvsSCIT:ChildrenonlyKimetal1672 2013 2a Systematic

reviewofRCTs&indirectcomparison

ChildrenwithSAR(asthma):AqueousSLITvsSCITvsplaceboforSAR(andasthma)

Symptom&medicationscores

Inchildren,moderateevidencethatSLITimprovesARsymptomsandmedicationuse,lowevidencethatSCITissuperiortoSLITforbothoutcomes.

Hoeksetal1704

2008 2a SystematicreviewofRCTsandOCTs

SCITvsplacebo,SLITvsplaceboinchildrenwithasthma/ARC

Symptom&medicationscores

Notenoughevidencebecauseofpoorqualityofthestudies.

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SLIT:sublingualimmunotherapy;LOE:levelofevidence;RCT:randomizedcontrolledtrial;SAR:seasonalallergicrhinitis;SMD:standardizedmeandifference;1CI:95%confidenceinterval;AR:allergicrhinitis;INCS:intranasalcorticosteroid;RDBPCT:randomizeddouble-blindplacebo-controlledtrial;SCIT:subcutaneous2immunotherapy;ARC:allergicrhinoconjunctivitis;PAR:perennialallergicrhinitis;HDM:housedustmite;AE:adverseevent;AIT:allergenimmunotherapy3*Onlyoutcomeswithstatisticallysignificancearementionedhere.4**Clinicalimpactscore=season-longnasalortotalsymptomscores:100x(scorePlacebo–scoreActive)/scorePlacebo567TableX.D.4-2.Aggregate grades of evidence for specific SLIT issues 8Issue Aggregategrade

ofevidenceDirectionofimpact

Magnitudeofimpact*

Recommendation,considering:harmandcost

SLITiseffectiveforARsymptomreductioninadults A Yes Lowimpact StrongrecommendationLOE:Lin1a;Radulovic1a;DiBona(2studies)1a;Nelson1b;Calderon2a.

SLITiseffectiveforARsymptomreductioninchildren B Yes Lowimpact RecommendationLOE:Kim2a;Larenas-Linnemann2a.Notenoughevidence:Roder2a.

SLITissafeforthetreatmentofARinadults A Yes ------- SafetyprofileisverygoodManyofthesystematicreviews(1aand2a)includedsafetyevaluation.Makatsori1a:samedrop-outratesSLITvsplacebo.

SLITissafeforthetreatmentofARinchildren B Yes ------- SafetyprofileisverygoodThesystematicreviews(Kim,Larenas-Linnemann,Roder:all2a)includedsafetyevaluation.Makatsori1a:samedrop-outratesSLITvsplacebo.

SCITismoreeffectivethanSLIT A Yes Weakevidence RecommendationLOE:Chelladurai1a;Dretzke2a;Calderon2a;Kim2a.Grasspollentablets/dropsvsSCIT:DiBona20121a;SCIT=grasspollentabletsonly,dropsslightlylesseffectiveNelson1b.

SLITissaferthanSCIT B Yes Weakevidence RecommendationLOE:Aasbjerg2a

ThetotalcostofSLITislessthanSCIT A Yes Moderateevidence RecommendationLOE:Meadows1a(UKsetting);Dranitsaris2a(Canadiansetting)

ItissafetocontinueSLITduringpregnancy B Noaddedrisk. Moderateevidence RecommendationLOE:Oykman3a

ItissafetostartSLITduringtheseason B Sightlyaddedrisk. Moderateevidence OptionLOE:Creticos2a

TabletSLITismoreeffectivethanpharmacotherapy.ExceptioninSAR:INCSareasefficaciousastabletSLIT.

A Yes Moderate:antihistiamine,montelukast

Recommendation

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Weak:INCS

LOE:Devillier1a(pollentabletSLIT);Durham1b(grasspollenorragweedtabletSLIT).

SLITiscost-effectiveinthe1styear B No Moderateevidence Option(consideringitslong-termbenefit)

LOE:Meadows1a;Dranitsaris2aSLITiscost-effectiveafterseveralyearsoftreatment B Yes Weak-moderate Recommendation

LOE:Meadows1a;Dranitsaris2aSLIThasalong-termeffectbeyond3-years’application B Yes Moderateevidence Recommendation

LOE:Durham201217052b,Didier201517062bSLITwithgrass-polleniseffectiveforSAR A Yes Lowimpact Strongrecommendation**

LOE:DiBona(2studies)1a;Nelson1b;Durham1b.SLITwithtree-polleniseffectiveforSAR A Yes Moderateeffect Strongrecommendation**

LEO:Valovirta200616831bSLITwithragweed-polleniseffectiveforSAR A Yes Moderateeffect Strongrecommendation**

LOE:Durham2016,Nolte2013,Creticos2013,1b(tabletragweed);Creticos2014(dropragweed);Skoner2010(dropragweed)1b

SLITwithHDMiseffectiveforAR A Yes Lowimpact Strongrecommendation**LOE:Nolte2015,Bergmann2014,Mosbech2015all1b;Calderon2a

SLITwithepitheliaiseffectiveforAR ------- Nodata Nodata OptionNoseparatedatainthesystematicreviews/meta-analyses;norecenttrials

SLITwithfungiiseffectiveforAR B Yes Weakevidence OptionNoseparatedatainthesystematicreviews/meta-analyses.Cortellini201016881b

SLIT:sublingualimmunotherapy;AR:allergicrhinitis;LOE:levelofevidence;SCIT:subcutaneousimmunotherapy;INCS:intranasalcorticosteroids;SAR:1seasonalallergicrhinitis2*Forthosevariableswithmeta-analysis:accordingtoCohen’sclassification:lowimpactSMD0.2-0.5,moderate0.5-0.8,highabove0.8.Forthosewithonly3systematicreview:strengthofevidence.4**consideringtheaddedlong-termpost-treatmenteffectandthepossiblepreventiveeffectsonthedevelopmentofasthmaandnewsensitizations.5678910

11

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IX.D.5.Transcutaneous/epicutaneousimmunotherapy1

Transcutaneousorepicutaneousimmunotherapyisanon-invasiveformofAITthatconsistsof2theapplicationofallergenstotheskin.TheepidermisisrichinAPCswhilebeinglessvascularized3potentiallyreducingtheriskforsystemicreaction.1707,1708Toimprovedeliveryofantigensthroughthe4stratumcorneumtotheimmunecellsoftheepidermisanddermis,differenttechniqueshavebeen5used:scarificationorscratchingoftheskin,tapestripping,microneedlearrays,andsweataccumulation6throughtheapplicationofapatch.1709Epicutaneousimmunotherapyhasrecentlybeeninvestigatedina7mousemodelusingnanoparticlescontaininganallergenencodingDNA.1710Recordsofallergen8administrationviatheskindatebackto1926,where29patientswithhayfeverreceivedintradermal9pollenextractadministrations;allbenefitedafteronly3doseswithoutsignificantsideeffects.1711The10firstRCTwasin2009.Todate,fourclinicaltrialsusingthisprocedurehavebeenpublished.[Table11IX.D.5.]12

Inasingle-center,placebo-controlled,double-blindtrial,37adultswithpositiveSPTandnasal13challengetograsspollenwererandomizedtotreatmentwithallergen(n=21)orplacebopatches14(n=16).1712Treatmentwasstartedonemonthbeforethe2006pollenseason.Theskinwastape-stripped156times;patcheswereappliedweeklyfor12weeks,andremoved48hourslater.Patientswereassessed16before,atthebeginningof,andafterthe2006pollenseason,andfollowedupbefore(n=26)andafter17(n=30)thepollenseasonof2007.Theprimaryoutcomewasnasalprovocationtestwithgrassextract;18secondaryoutcomesincludedarhinitisquestionnaire,medicationuse,andadverseevents.Ingrass19immunotherapytreatedpatients,nasalchallengetestscoressignificantlydecreasedinthefirst20(p<0.001)andsecondyear(p=0.003).Inplacebo-treatedpatients,scoresdecreasedafteryear121(p=0.03),buttheeffectdiminishedinyear2(p=0.53).However,theimprovementofnasalprovocation22testscoreswasnotsignificantlybetterinthetreatmentversusplacebogroups.Patientsinthe23treatmentarmhadimprovementinsubjectivesymptomscores,bothafterthepollenseasonsof200624(p=0.02)and2007(p=0.005).Eczemaattheapplicationsitewassignificantlyhigherinthetreatment25arm,andtherewerenoseriousadverseevents.26

Asecondsingle-centerdouble-blindRCTtreated15childrenwithgrasstranscutaneous27immunotherapyand15childrenwithplacebo.1713TheadhesivepatchwasplacedweeklyfromFebruary28toApril2008,andremovedafter24hours.Therewerenosignificantdifferencesinpricktestsbetween29groupsbeforeandaftertreatment.Bothgroupshadanincreaseinsymptoms,butthetreatmentgroup30hadlowerrhinorrhea,nasalobstruction,dyspnea,andoculartearing.Thetreatmentgrouphada31significantreductioninantihistamineuse(p=0.019).Therewerenosystemicorlocalreactions.32

Athirdsingle-center,double-blindplacebo-controlledtrial,publishedbythesameauthors33enrolled132adultswithgrasspollenallergicrhinoconjunctivitis.1714Patientsreceivedplacebo,low,34mediumandhighdosegrassextracttreatment(n=33ineacharm).Weeklyfor6weeks,startingone35monthpriortotheinitiationofthe2008pollenseason,patcheswereappliedwithsubsequentremoval36aftereighthours.SPTandconjunctivalprovocationtestsweredoneatbaseline,andafterthepollen37seasonsof2008and2009.Ninety-threeof132patientswereincludedintheefficacyanalysis.The38primaryendpointwassubjectiverhinoconjunctivitissymptomsusingaVAS.Fivemonthsafter39applicationofthefirstpatch,alltreatmentandplacebogroupsimproved.Oneyearlater,onlythehigh-40dosetreatmentgrouphadimprovedcomparedtocontrol(p=0.017);symptomswerereducedbymore41

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than30%(2008pollenseason)and24%(2009pollenseason)comparedwithplacebo.Therewereno1differencesinrescuemedicationuse,SPTsorCPTs.Localreactionsweremorefrequentwithhigher2dosesandimprovedwithsubsequentapplications.Systemicreactionsleadingtodiscontinuationof3treatmentoccurredin11patients(8.3%)within45minutesofpatchapplication;reactionsweremilder4(grade1-2)anddidnotrequiretreatmentwithepinephrine.5

Afourthsingle-center,double-blindplacebo-controlledtrial,publishedbythesameauthors6enrolled98adultswithgrassallergicrhinoconjunctivitis;48receivedgrasspatchesand50received7placebo.1715Treatmentconsistedofsixweeklypatcheskeptonfor8hours.Aftertreatmentintheyear82009,medianrhinitissymptomsimprovedby48%inthetreatmentgroupversus10%intheplacebo9group(p=0.003);ayearlater,thiswas40%comparedto18%forplacebo(p=0.43).Therewasnochange10incombinedsymptomandmedicationscores.CPTscoresimprovedafterthefirstyearinthetreatment11groupbutnottheplacebogroup.Inthefirstyear,allergen-specificIgG4increasedinthetreatment12group,whileallergen-specificIgEdecreasedintheplacebogroup;therewasnodifferenceinboth13measurescomparedtobaselineinthesecondyear.Eightsystemicreactionsledtostudyexclusion.The14authorsconcludedthatthistreatmentstrategymayhaveapotentialroleintreatingIgE-mediated15allergies,butfurtherresearchwasneededtofindanoptimalregimenthatbalancesefficacyandsafety.1617

• AggregateGradeofEvidence:B(Level1b:4studies;TableIX.D.5.)18• Benefit:Transcutaneousimmunotherapyresultedinlimitedandvariableimprovementin19

symptoms,medicationuse,andallergenprovocationtestsinpatientswithARor20conjunctivitis.21

• Harm:Transcutaneousimmunotherapyresultedinsystemicandlocalreactions.Systemic22reactionsoccurredinupto14.6%ofpatientsreceivinggrasstranscutaneous23immunotherapy.24

• Cost:Unknown.25• Benefits-HarmAssessment:Thereislimitedandinconsistentdataonbenefitofthe26

treatment,whilethereisaconcerningrateofadverseeffects.Threeoutof4studiesonthis27topicwerepublishedbythesameinvestigatorsfrom2009-2015.28

• ValueJudgments:Transcutaneousimmunotherapycouldofferapotentialalternativeto29SCITandSLIT,butfurtherresearchisneeded.30

• PolicyLevel:Recommendagainst.31• Intervention:Whiletranscutaneousimmunotherapymaypotentiallyhaveafutureclinical32

applicationinthetreatmentofAR,atthisjuncturetherearelimitedstudiesthatshow33variableandlimitedeffectiveness,andasignificantrateofadversereactions.Giventhe34aboveandtheavailabilityofalternativetreatments,transcutaneousimmunotherapyisnot35recommendedpresently.36

37

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TableIX.D.5.Evidencefortheuseoftranscutaneous/epicutaneousimmunotherapyinthetreatmentofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionSentiet

al1715

2015 1b RDBPCT Adults.

1.grasspatches(n=48)

2.placebopatches(n=50)

Subjectivesymptoms,

conjunctivalprovocation

test

Symptomscoreimprovedinthetreatment

arminyear1,butwasnotsignificantly

differentfromcontrolinyear2.Conjunctival

provocationimprovedinthetreatment

group.Systemicreactionsoccurredin7

treatment(14.6%)and1controlpatients.

Sentiet

al1714

2012 1b RDBPCT Adults.

1.placebopatches(n=33)

2.low-dosegrasspatches(n=33)

3.medium-dosegrasspatches

(n=33)

2.high-dosegrasspatches(n=33)

Subjectivesymptoms,

medicationuse,SPT,

conjunctivalprovocation

test

Symptomsimprovedonlyinthehighestdose

group.Therewasnodifferencein

medicationuse,SPT,orconjunctival

provocationtest.Localreactionswere

common.Systemicreactionsoccurredin

8.3%ofpatients.

Agostiniset

al1713

2009 1b RDBPCT Children.

1.grasspatches(n=15)

2.placebopatches(n=15)

SPTendpoint,subjective

symptoms,antihistamine

use

NodifferenceinSPTendpoint.Treatment

grouphadlessrhinoconjunctivitissymptoms

andantihistamineuse.

Sentiet

al1712

2009 1b RDBPCT Adults.

1.grasspatches(n=21)

2.placebopatches(n=17)

Nasalprovocationtest,

subjectivesymptom

score

Nosignificantdifferenceinnasal

provocationtest.Subjectivesymptomsscore

improved.Morelocalreactions(eczema)in

treatmentgroup.

LOE:levelofevidence;RDBPCT:randomizeddoubleblindplacebocontrolledtrial;SPT:skinpricktest2

3

4

5

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IX.D.6.Intralymphaticimmunotherapy1

Intralymphaticimmunotherapy(ILIT)isanovelmethodforAIT,whereallergenisinjected2directlyintolymphnodes.1716Themajoradvantagesofthisrouteofallergenapplicationarethe3markedlyreduceddurationofimmunotherapytreatment(bothtimespentandnumberofvisits)andthe4muchloweramountofallergenrequiredtoachieveresults.Thislowerdoseofallergenalsoconfersa5lowerriskofadverseallergicsideeffects.6

ClinicaltrialshaveillustratedthatareductioninARsymptomscanbeachievedwithjustthree7dosesofinjectedallergen,withadosageintervalofonemonth.1716-1720[TableIX.D.6.]Thiscontrasts8withsubcutaneousapplication,whereuptoseventydosesmaybeneededoverafive-yearperiod.ILIT9involvestheinjectionofallergendirectlyintoinguinallymphnodesunderultrasoundguidance.10

FiveoftheclinicaltrialspublishedtodatehavecomparedILITwithplacebo.In2008,Sentiet11al1716comparedILITtoSCITandnottoplacebo.Alltrialshaveusedaluminumhydroxide-adsorbed12antigenasthevaccine.Mosttrials1716,1718-1721usedcommerciallyavailablegrasspollenorbirchpollen13allergenextractastheantigen.Onetrial1717usedrecombinantmajorcatdanderallergenfusedtoa14translocationsequenceandtopartofthehumaninvariantchaingeneratingamodularantigen15transporter,or“MAT”,vaccine.16

Thegeneralprotocolforadministrationwasthreeinjectionswith1,000standardizedquality17units(SQ-U)ofaluminumhydroxide-adsorbedallergenatfourweekintervals.Variationstothisincluded18ashorterdoseintervalinonetrial1721andnotranslationofallergenquantitiesintoSQ-Uinthetrialusing19recombinantmajorcatdanderallergen.171720

Ofthesixtrialspublishedthusfar,fivehavedemonstratedclinicalefficacyandsafety.1716-1720In21total,127patientshavereceivedactivetreatmentand45patientshavereceivedplacebo.Wittenet22al1721demonstratedimmunologicalchangeswithILIT,butnoimprovementinsymptoms.Ofnote,the23doseintervalinthistrialwasshorterthaninthetrialsthatdemonstratedclinicalefficacy,withallergen24administeredattwo-weekintervalsinsteadoffour-weekintervals.25

Thegreatestvariationbetweenthetrialstodateisintheselectionofclinicalendpointsandthe26measurementofclinicaloutcomes,asillustratedinTableIX.D.6.Alltrialshaveusedsubjectivemeasures27todefineclinicalendpoints,mostcommonlyintheformofsymptomquestionnaires.28

Giventhereductionintreatmentduration,allergendose,financialburdenrelativetoSCIT,and29thelowriskofadverseeffects,ILITisapromisingnewtherapyforAR.BeforeILITisintegratedinto30clinicalpractice,awell-designedpharmaco-economicevaluationofILITvsSCITandlargerRCTsare31needed,aswellasfurtherstudiesinvestigatingtheimpactoftreatmentprotocolonoutcomes.3233

• AggregateGradeofEvidence:B(Level1b:5studies;Level2b:1study;Level4:1study;Table34IX.D.6.)35

• Benefit:Reducedtreatmentperiod,reducednumberofinjections,reduceddoseofallergen36injected,decreasedriskofadverseevents.37

• Harm:Riskofanaphylaxis.38• Cost:ILITmightbeassociatedwithreducedcostsrelativetoSCIT(reducedtime,reduced39

financialburdenforpatientsandhealthcareprovider).Applicationrequirestraining.40• Benefits-HarmAssessment:BalanceofbenefitoverharmforILITrelativetoSCIT.41

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• ValueJudgments:ILITappearstobeefficaciousinthetreatmentofAR.Preliminarydata1indicatesthat,relativetoSCIT,theburdenoftreatmentonthepatientandonthehealthcare2systemislower.3

• PolicyLevel:Option,pendingadditionalstudies.4• Intervention:Whiletheresearchispromising,furtherstudiesareneededbeforeILITcanbe5

translatedintoroutineclinicalpractice.6 7

8

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TableIX.D.6.Evidencefortheuseofintralymphaticimmunotherapyinthetreatmentofallergicrhinitis1

Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Hylanderetal1719

2016 1b RCT,blinded Birch-orgrass-pollen-inducedAR(n=36):1.aluminumhydroxideadsorbed,depotbirch-orgrass-pollenvaccine2.placebo

SeasonalallergicsymptomsbyVAS,safetyofinjections,nasalsymptomscorefollowingnasalprovocationtest,IgEandIgG4levels,inflammatorycells,rescuemedicationuse

ILITiseffectiveandsafe;resultsinamarkedreductionofseasonalallergicsymptoms.

Pattersonetal1720

2016 1b RCT,blinded Adolescents,grass-pollen-inducedAR(n=15):1.aluminumhydroxide-adsorbedgrasspollenextract2.placebo

Patientdiaryscoreofallergyandasthmasymptomsandmedicationuse,localandsystemicsymptomsscoreafterinjections

ILITiseffectiveandsafe,withnotablylowadversereactions.

Hylanderetal1718

2013 1b PilotstudyandRCT,blinded

Birch-pollen/grass-pollen-inducedAR(pilotn=6;RCTn=15):1.Threeintralymphaticinguinalinjectionsof1000SQ-Ubirchpollenorgrasspollen2.placebo

SeasonalallergicsymptomsbyVAS,SPT,validatedrhinitisQOLquestionnaire

ILITiseffectiveandsafe.

Wittenetal1721

2013 1b RCT,blinded Grasspollen-inducedAR(n=45):1.6injectionsof1000SQ-Uofdepotgrasspollenextract,minimalintervalof14days2.Threeinjectionsof1000SQ-Ufollowedby3placeboinjections3.Sixplaceboinjections

Combinedsymptomandmedicationscore,globalseasonalassessment,RQLQ

ILITproducedimmunologicalchangesbutnoimprovementinsymptoms.

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Sentietal1717

2012 1b RCT,blinded Cat-dander-inducedAR(n=20):1.MAT-Feld12.placebo(salineinalum)

Immunologicalparameters,systemicadverseeffects,nasalprovocationtest,SPT,validatedrhinitisQOLquestionnaire

ILITwithMAT–Feld1(Recombinantmajorcatdanderallergenfusedtoamodularantigentransporter)wassafeandinducedallergentoleranceafter3injections

Sentietal1716

2008 2b RCT,open

Grasspollen-inducedAR(n=165):1.Three0.1-mlinjectionswith1,000SQ-Uofaluminumhydroxide-adsorbedgrasspollenextractinjectedintolymphnodeatday0andafter4and8weeks2.54subcutaneousinjectionsover3years(cumulativedoseof4,031,540SQ-U).

SeasonalallergicsymptomsbyVAS,adverseevents,safetyofinjections,rescuemedicationuse,SPT,grass-specificIgElevels

ILITenhancedsafetyandefficacyofimmunotherapyandreducedtreatmenttimefrom3yearsto8weeks.

Schmidetal1722

2016 4 Pilotstudy,open,nocontrolgroup

Grass-pollen-allergy-inducedAR(n=7):1.Threeinjectionsof1000SQ-Uofallergen,doseinterval23-36days

Combinedsymptomandmedicationscore,RQLQ,numberofIgE+andIgE-plasmablastsspecificforgrass

ILITmayinduceallergenspecificplasmablasts.Confirmsaneffectonprovocationofmastcellsinskinandnasalmucosaduringtheensuingwinter.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;AR:allergicrhinitis;VAS:visualanalogscale;Ig:immunoglobulin;ILIT:intralymphaticimmunotherapy;1SQ-U:standardizedqualityunits;SPT:skinpricktest;QOL:qualityoflife;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;MAT:modularantigen2transporter3456 7

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IX.D.7.Alternativeformsofimmunotherapy1

Oral,nasal,andinhaled(intra-bronchial)AITrepresentalternateoptionsforthetreatmentof2AR,withprimarilyhistoricalsignificance.1623WhilealternativeformsofAIThavebeenevaluatedinan3efforttoavoidthelocaldiscomfortandresourceutilizationassociatedwithSCIT,theadoptionofSLIT4haslargelyreplacedthesemethods.16235

Non-injectable,alternativeimmunotherapiesinvolvethetopicalabsorptionofallergenextracts6viaoral/gastrointestinal,nasal,orinhalationalexposures.SLIT,intralymphatic,andepicutaneousroutes7arereviewedseparatelyinthisdocument.Double-blindplacebo-controlledstudieshaveevaluated8oral/gastrointestinalimmunotherapyforthetreatmentofbirch,1723cat,1724andragweed1725sensitivity,9withoutasignificantdeclineinnasalsymptoms,improvementsinprovocationtesting,orreductionsin10medicationutilization.Additionally,oral/gastrointestinalallergenadministrationrequiresextract11concentrationsapproaching200timesgreaterthanSCIT,andisassociatedwithadversegastrointestinal12sideeffects.1623,1724However,theefficacyoforal/gastrointestinalimmunotherapyhasbeen13demonstratedforthetreatmentoffoodhypersensitivity,wherethisapproachremains14investigational.172615

Oralmucosalimmunotherapy(OMIT)isanalternativeformofAITthatisdistinctlydifferent16fromSLITandoral/gastrointestinalstrategies.OMITutilizesaglycerin-basedtoothpastevehicleto17introduceantigentohigh-densityantigenprocessingoralLangerhanscellsintheoralvestibularand18buccalmucosa.1727Theoreticalbenefitsincludeinductionofimmunetolerancewithlowerantigen19concentrations,decreasedlocalsideeffectsandhigheradherenceversusSLIT.1728Arecentlycompleted20pilotstudyofOMITversusSLITidentifiedclinicallymeaningfulimprovementsindisease-specificQOL21measureswithasignificantriseinspecificIgG4overthefirstsixmonthsoftreatment.1729Noadverse22eventswerereported,andtherewerenosignificantdifferencesbetweenoutcomemeasuresforboth23treatmentarms.1729AdditionalstudyisneededtodefinetheroleofOMITinthetreatmentofAR.24

Localnasalimmunotherapyhasbeenestablishedasaneffectiveapproachforthetreatmentof25pollenandHDMsensitivity.1730However,highratesoflocaladversereactionslimitpatientcompliance,26withonepriorstudyfindingthat43.9%oftreatedchildrenabandonedthistreatmentoptionwithinthe27firstyearoftherapy.1731Highqualitystudiesofinhaled/intra-bronchialimmunotherapyforthe28treatmentofARhavenotyetbeencompleted,withcurrentstudieslimitedtothetreatmentofallergic29asthma.1732Inlightofthesefindings,includingpoorcomplianceandlimitedefficacy,30oral/gastrointestinal,nasal,andinhaledimmunotherapieshavelimitedutilityinthecurrenttreatment31ofAR,whileOMITrepresentsanemergingalternativetoSCITandSLIT.32

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IX.D.8.Combinationomalizumabandsubcutaneousimmunotherapy1

InconsiderationofcombinationtherapywithconcurrentbiologicalomalizumabandAIT,each2interventiontargetingdifferentmechanismsintheearlyallergiccascade.AITdesensitizesthebody’s3responsetoaspecificantigen,withalterationoftheTh1/Th2balanceandinductionofT-cellanergy.16234Omalizumabindiscriminatelytargetsthehumoraleffectorofallergicinflammation,withuseofa5humanizedmonoclonalantibodytoblockunboundIgE.1623Whilebothmodalitieshaveindependently6demonstratedefficacyastreatmentoptionsforPAR,improvedstrategiesareneeded,especiallyin7patientswithmultiplesensitizations.17338

Twobenefitsofcombinationtherapyhavebeendescribed:decreasedincidenceofAIT-9associatedsystemicallergicreactionsandimprovedcontrolofARsymptoms.1400-1402,1734-1736Anaphylaxis10isapersistentconcernwithAIT,withincidenceofreportedsystemicreactionsashighas65%following11rushprotocols.1737,1738Omalizumabpretreatmenthasthereforebeenevaluatedasastrategytoimprove12AITtolerance,withpositivefindings.Twomulti-center,randomized,placebo-controlledstudieshave13evaluatedtheincidenceofAIT-inducedsystemicallergicreactionsfollowingpretreatmentwith14omalizumab.1402,1736[TableIX.D.8.]Massanarietal1736evaluated248patientswithmoderatepersistent15asthmareceivingomalizumabpretreatmentorplacebopriortoclusterAIT,anacceleratedAITbuild-up16schedule.Asignificantlylowerincidenceofsystemicandrespiratory-relatedreactionswasreported17amongtheomalizumabgroup,withanimprovedlikelihoodofreachingmaintenancetherapycompared18tothegroupwithoutpreventivetreatmentwiththisbiological.Casaleetal1402evaluated123adult19patientswithragweedinducedARreceivingomalizumabpriortoone-dayrushAIT,findinga5-fold20decreasedriskofsystemicallergicreactionswithomalizumabpretreatment(oddsratio0.17).Further21outcomesincludedsignificantimprovementindailysymptomscoresamongpatientsreceiving22combinationtherapy(continuedomalizumab+AIT)versusAITalone.AdditionalstudyofAITforthe23treatmentoffood1739orinsectvenom1740,1741hypersensitivityhasalsodemonstratedimprovedsafety24withomalizumabpretreatment.25

TheefficacyofcombinationtherapyforthetreatmentofARhasbeenfurtherevaluatedby26severaliterativeanalysesofasingleRCT.1400,1401,1735Kuehretal1400evaluated221adolescents(6-1727years)withmoderatetosevereARandsensitizationtobirchandgrasspollen.Usingarandomized,28controlleddesign,theeffectivenessofcombinationtherapywasevaluatedduringsequentialbirchand29grasspollenseasons,withcomparisonofAIT+/-concurrentomalizumab.Significantfindingsincluded30superiorityofcombinationtherapiesversusAITalone,with48%reductioninsymptomload(sumof31meandailysymptomseverityscoreplusmeandailyrescuemedicationuse)duringanentirepollen32seasonand80%reductioninmedianrescuemedicationscore.Twoadditionalstudiesreportunique33findingsgeneratedbythistrial.1401,1735Rolinck-Werninghausetal1401completedasubgroupanalysisof34studypatientsreceivingspecificAIT+/-concurrentomalizumabduringthematchedgrassseason.35Resultsincludeddecreasedsymptomsscoresandrescuemedicationusageforpatientsreceiving36combinationversuseithertherapyalone.Koppetal1735evaluatedasubgroupof92children,with37findingsofdecreasedleukotriene(LTC4,LTD4andLTE4)releaseamongpatientsreceivingcombination38therapiesfollowinginvitroantigenstimulationofcollectedbloodcells.AnunrelatedstudybyKlunkeret39al1734providesfurtherevidencefortheefficacyofcombinationtherapy,withinvitrodemonstrationof40inhibitionofallergen-specificIgEbindingfor42weeksafterdiscontinuationofcombinationtherapy41

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(versus30weekswithomalizumabalone).1Whileapriorstudyhasestimatedthecostofomalizumab(1,253EUR/patient/month)andAIT2

therapies(425EUR/patient/year),evaluationofeconomicandproductivityoutcomeshasnotbeen3completedforpatientsundergoingcombinationtherapy.1401Finally,omalizumabhasbeenassociated4withanaphylacticreactionsin0.09to0.2%ofpatients,withcurrentrecommendationstomonitor5patientsfor30minutesfollowingadministration.1742,17436

7• AggregateGradeofEvidence:B(Level1b:4studies,plus2additionaliterativeanalysesofa8

parentstudy;TableIX.D.8.)9• Benefit:ImprovedsafetyofacceleratedclusterandrushAITprotocols,withdecreasedsymptom10

andrescuemedicationscoresamongacarefullyselectedpopulation.11• Harm:Financialcostandriskofanaphylacticreactions.12• Cost:Moderatetohigh.13• Benefits-HarmAssessment:Propensityofbenefitoverharm.14• ValueJudgments:CombinationtherapyincreasesthesafetyofAIT,withdecreasedsystemic15

reactionsfollowingclusterandrushprotocols.Associatedtreatmentcostsandlikelihoodof16systemicreactionsmustbeconsidered,withgreaterconsiderationforomalizumab17pretreatmentpriortohigher-riskAITprotocols.Whiletwohigh-qualityRCTshavedemonstrated18improvedsymptomcontrolwithcombinationtherapyoverAIToromalizumabalone,notall19patientswillrequirethisapproach.Rather,anindividualizedapproachtopatientmanagement20mustbeconsidered,withevaluationofalternativecausesforpersistentsymptoms,suchas21unidentifiedallergensensitivity.Thecurrentevidencedoesnotsupporttheutilizationof22combinationtherapyforallpatientsfailingtobenefitfromAITalone.23

• PolicyLevel:Option,basedoncurrentevidence.However,itisimportanttonotethat24omalizumabisnotcurrentlyapprovedbytheUSFDAforthetreatmentofAR.25

• Intervention:Omalizumabmaybeofferedasapremedicationpriortoinductionofclusteror26rushAITprotocols.Combinationtherapyisanoptionforacarefullyselectedpatientwith27persistentsymptomaticARfollowingAIT.Anindividualizedapproachtopatientmanagement28mustbeconsidered.Inaddition,asomalizumabisnotcurrentlyapprovedbytheFDAforAR29treatment,intheUSthistreatmentapproachwouldlikelynotbeperformedinroutineclinical30practicepresently.31

32 33

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TableIX.D.8.Evidenceforthecombinationofomalizumabandsubcutaneousimmunotherapyinthetreatmentofallergicrhinitis1Study Year LOE Study

designStudygroups Clinicalendpoint Conclusion

Massanarietal1736

2010 1b RCT Adultswithpoorlycontrolledmoderatepersistentallergicasthma:1.omalizumabpretreatment+clusterAIT2.placebo+clusterAIT

Incidenceofsystemicallergicreactions

OmalizumabpretreatmentisassociatedwithalowerincidenceofsystemicallergicreactionsandhigherlikelihoodofreachingmaintenanceAITdose.

Klunkeretal1734^

2007 1b RCT AdultswithragweedinducedAR:1.AIT-ragweed+omalizumab2.AIT-ragweedalone3.omalizumabalone4.placebo

RagweedhypersensitivityviaIgE-FABassay,allergen-specificIgG4

CombinationtherapyenhancedtheinhibitionofsIgEbindingfor42weeksafterdiscontinuation.

Casaleetal1402^ 2006 1b RCT AdultswithragweedinducedAR:1.omalizumabpretreatment+RIT2.omalizumabpretreatment+placebo[IT]3.placebo[omalizumab]+RIT4.placeboforbothinterventions

Dailysymptomseverity,incidenceofadverseevents

Pretreatmentwithomalizumabresultedina5-folddecreaseinriskofRITassociatedanaphylaxis.CombinationtherapyisassociatedwithsignificantreductioninsymptomseverityversusAITalone.

Rolinck-Werninghausetal1401#�

2004 1b RCT SubgroupanalysisofKuehretal1400study

Dailysymptomseverity,rescuemedicationuse

Combinationtherapyisassociatedwithreducedsymptomseverityandrescuemedicationscores.

Koppetal1735# 2002 1b RCT SubgroupanalysisofKuehretal1400study

Invitroleukotrienereleasefollowingantigenstimulation

Combinationtherapyisassociatedwithreducedleukotrienereleasefollowingantigenstimulation.

Kuehretal1400# 2002 1b RCT ChildrenandadolescentswithSARand:1.AIT-birch+omalizumab2.AIT-birch+placebo3.AIT-grass+omalizumab4.AIT-grass+placebo

Dailysymptomseverity,rescuemedicationuse

Combinationtherapyisclinicallysuperiortoeithercomponentmonotherapy,withreducedsymptomseverityandrescuemedicationscores.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;Ig:immunoglobulin;AIT:allergenimmunotherapy;AR:allergicrhinitis;IgE-FAB:IgE-facilitatedallergen2binding;sIgE:antigen-specificIgE;RIT:rushimmunotherapy;SAR;seasonalallergicrhinitis3^=ImmuneToleranceNetworkGroup;#=omalizumabrhinitisstudygroup4

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X.Associatedconditions1

SeveralmedicalconditionshavebeenassociatedwithAR,withvaryingprevalencedependent2uponthespecificcomorbidity.Incontrast,certainconditionsareoftenassociatedwithallergyorARby3conjecture,yettheavailableliteraturefailstoidentifyacloseassociation.Thissectionexaminesvarious4medicalconditionsthathaveapotentialassociationwithAR,specificallyexaminingtheevidencethat5supportsorrefutestheassociation6

78X.A.Asthma9X.A.1.Asthmadefinition10

Asthmaisaheterogeneousandcomplexdisease,perhapsbettercharacterizedasasyndrome11withoverlappingphenotypes.Thedefinitionofasthmahasevolvedoverthepastseveraldecades,12combiningclinicalsymptoms,examinationfindingsandfunctionalparameters.Whenanalyzingcurrent13internationalornationalasthmaguidelines,1744-1747allincluderespiratorysymptomssuchascough,14shortnessofbreath,wheezingorchesttightnessandthepresenceofavariableexpiratoryairflow15limitationthatneedstobedocumentedfrombronchodilatorreversibilitytestingorbronchialhyper-16reactivitytests(e.g.methacholinetestorothertestssuchasinhaledhistamine,mannitol,exercise,or17eucapnichyperventilation).Allguidelinesalsoincludethestatementthatsymptomsandairflow18limitationcharacteristicallyvaryovertimeandinintensityandmayresolvespontaneouslyorin19responsetomedication.Discussionofchronicairwayinflammationisincludedinallguideline20documents.Thishasbeencharacterizedbyseveralimportantcellularelementsincludingmastcells,21eosinophils,T-cells,macrophages,andneutrophils,butnoneoftheguidelinesrequiredemonstrationof22inflammationbyinvasiveornon-invasivemethods.TheGlobalInitiativeofAsthmaguidelines1744specify23thatasthmaisusuallyassociatedwithbronchialhyper-responsivenessbuthighlightthatdemonstration24ofairwayhyper-responsivenessandinflammationarenotnecessaryorsufficienttomakethediagnosis.25Asthmaisalsoclassifiedbyseverity(i.e.mild,moderate,severe)andbypersistence(i.e.intermittentvs26persistent);however,thespecificdefinitionsofthesecategoriesvarydependentuponthespecific27guideline.Sinceasthmaisdefinedasaheterogeneousdisease,orratherasasyndrome,thereappearto28existsignificantandvariableetiologiesthatmaymanifestinsimilarphenotypes.Consequently,inthe29lastdecade,thedefinitionofasthmahassoughttoincluderecognizableclustersofclinicaland/or30pathophysiologicalcharacteristicstomoreaccuratelycharacterizeendotypesthatexist.1748,1749313233X.A.2.Asthmaassociationwithallergicandnon-allergicrhinitis34

Mostpatientswithasthma(bothallergicandnon-allergic)alsohaverhinitis,whereas10%to3540%ofpatientswithARhavecomorbidasthma.101,1167Asthmaandallergymayhavesimilarunderlying36pathogenesisandimmunologicmechanisms.IgE-mediatedinflammationcaninvolveboththeupperand37lowerairways,suggestinganintegrationoftheinvolvedareasoftheairway.Thispatternofsimilarities38gaverisetotheconceptoftheunifiedairwaymodel,whichconsiderstheentirerespiratorysystemto39

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representafunctionalunitthatconsistsofthenose,paranasalsinuses,larynx,trachea,anddistal1lung.17502

Some,butnotall,studiessuggestthatasthmaismorecommoninpatientswithmoderate-to-3severepersistentrhinitisthaninthosewithmildrhinitis.25,1751-1753Otherlargestudiesfoundalink4betweentheseverityand/orcontrolofbothdiseasesinchildrenandadults.1754-1758Adultsandchildren5withasthmaanddocumentedconcomitantARexperiencemoreasthma-relatedhospitalizationsand6doctors’visitsandalsoincurhigherasthmadrugcoststhanadultswithasthmaalone.1759-1764[Table7X.A.2.]Concerningchangesinprevalenceofrhinitisandasthma,somestudieshavedemonstrateda8parallelincreasingprevalenceofasthmaandrhinitis,1765,1766whereasothershavenot.1767-1775Itappears9thatinregionsofhighestprevalence,theproportionofsubjectssufferingfromasthmaorrhinitismaybe10reachingaplateau.11

RhinitisandasthmaarecloselyassociatedandthusARshouldbeevaluatedinasthmatic12patients,andlikewise,thepossibilityofadiagnosisofasthmashouldbeevaluatedinpatientswithAR.1314

• AggregateGradeofEvidence:C(Level3b:7studies;TableX.A.2.).15

16

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TableX.A.2.Evidencefortheassociationbetweenasthma,allergicrhinitisandnon-allergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Ohtaetal1754

2011 3b Caseseries

Asthmaticpatients(n=26,680)

Rhinitisandasthmadiagnosis

Rhinitisiscommoninasthmaandimpairsasthmacontrol.

Valeroetal1756

2009 3b Caseseries

PatientswithAR(n=3225)

Rhinitiscomorbidities

AsthmawasinfluencedbyskinsensitizationandseverityofAR.

Ponteetal1755

2008 3b Caseseries Patientswithsevereasthma(n=557) Asthmaseverity Moderate/severerhinitisisastrongpredictorforgreaterseverityofasthma.

Bousquetetal25

2005 3b Case-control

PatientsconsultingENT&allergyspecialistsforAR(n=591)vs.controls(n=502)

Presenceofasthma Asthmaprevalenceincreaseswithdurationandseverityofrhinitis.

Leynaertetal1753

2004 3b Cohort

Internationalcross-sectionalstudyofrepresentativesamplesofyoungadults(n=3000)

Rhinitisandasthmadiagnosis

Associationbetweenasthmaandrhinitiswasnotfullyexplainedbyatopy.

Linnebergetal1752

2002 3b Cohort

Follow-upontwooccasionseightyearsapart(n=734)

Rhinitisandasthmainpatientssensitizedtopollen

ARandallergicasthmaaremanifestationsofthesamedisease.

Brescianietal1757

2001 3b Caseseries

Patientswithseveresteroid-dependentasthma(n=35)

Sinonasaldisease

Frequencyofrhinosinusitisinpatientswithmild-to-moderateorseveresteroid-dependentasthmaissimilar.

LOE:levelofevidence;AR:allergicrhinitis;ENT:ear,noseandthroat2

34 5

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X.A.3.Rhinitisasariskfactorforasthma1

ARandNARareriskfactorsfordevelopingasthma.Thishasbeendemonstratedinseverallarge2epidemiologicalstudies.[TableX.A.3.]TheChildren’sRespiratoryStudy597showedthatphysician-3diagnosedARduringinfancyisindependentlyassociatedwithadoublingoftheriskofdeveloping4asthmaatage11.Inchildrenandadults,ARisariskfactorforasthmaaccordingtoa23-yearfollow-up5ofcollegestudents.1776Thesestudieswereconfirmedbyotherstudies.458,1764,1777-1786Someofthese6studiesshowedthatrhinitisisasignificantriskfactorforadult-onsetasthmainbothatopicandnon-7atopicsubjects.1779,1780,1783Therefore,rhinitisisariskfactorindependentofallergyfordeveloping8asthmainbothadults1779,1780,1783andchildren.597Inadulthood,thedevelopmentofasthmainpatients9withrhinitisisoftenindependentofallergy,whereasinchildhood,itisfrequentlyassociatedwith10allergy,597,1785asalmostallasthmainchildrenisallergic.11

AsthmaandARalsosharecommonriskfactors.Sensitizationtoallergensisprobablythemost12important.Mostinhaledallergensareassociatedwithnasal1787andbronchialsymptoms,butin13epidemiologicstudies,differenceshavebeenobserved(e.g.inpollenallergy).Somegenetic14polymorphismsaredifferentinthecaseofARandasthma.Otherriskfactorsforasthmasuchasgender,15obesity,viralinfectionsininfancy,exposuretotobaccosmoke(passivesmokingoractivesmoking),diet16orstressarenotfoundascommonriskfactorsforAR.Outdoororindoorairpollutionisstillamatterof17debateasriskfactorforARorNAR.101Insummary,ARandNARareriskfactorsfordevelopingasthma.1819

• AggregateGradeofEvidence:C(Level2a:2studies;Level3b:11studies;TableX.A.3.)20 21

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TableX.A.3.Evidenceforallergicrhinitisasariskfactorforasthma1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Guerraetal1779

2006 2a Nestedcase-controlstudy

Longitudinalcohort

Asthmaonset Rhinitisisasignificantriskfactorforadult-onsetasthmainbothatopicandnon-atopicsubjects.

Wrightetal597 1994 2a Cohort Birthcohort Respiratorysymptomsatage6 Asthmainthechild(OR:4.06,CI:2.06-7.99)Ibáñezetal1764 2013 3b Cross-sectional

studyChildrenwithAR Associateddiseases Asthmawaspresentin49.5%ofpatientswith

AR.Jarvisetal458 2012 3b Cross-sectional

studyGeneralpopulation Self-reportedcurrentasthma

Asthmawasassociatedwithchronicrhinosinusitis.

Rochatetal1785

2010 3b Cohort Birthcohort Wheezingonset ARisapredictorforsubsequentwheezingonset.

Shaabanetal1783

2008 3b Cohort Population-basedstudy

Frequencyofasthma

Rhinitis,evenintheabsenceofatopy,isapowerfulpredictorofadult-onsetasthma.

Shaabanetal1784

2007 3b Cohort Generalpopulation Changesinbronchialhyper-responsivenessinnon-asthmaticsubjects

ARwasassociatedwithincreasedonsetofbronchialhyper-responsiveness.

Burgessetal1786

2007 3b Cohort Generalpopulation Incidentofasthmainpreadolescence,adolescence,oradultlife

ChildhoodARincreasedthelikelihoodofnew-onsetasthma

Bodtgeretal1777

2006 3b Cohort Population-based

Rhinitisonset Asymptomaticsensitization,butnotNAR,wasasignificantriskfactorforlaterdevelopmentofAR.

Porsbjergetal1781

2006 3b Cohort Randompopulationsample

Prevalenceofasthma Presenceofbronchialhyper-responsivenessandconcomitantatopicmanifestationsinchildhoodincreasetheriskofdevelopingasthmainadulthood.

Torenetat1780 2002 3b Case-control

Generalpopulation

Adult-onsetphysician-diagnosedasthma

Non-infectiousrhinitisandcurrentsmoking,especiallyamongnon-atopics,areassociatedwithincreasedriskforadult-onsetasthma.

Plaschkeetal1778

2000 3b Cohort Randomsample RiskfactorsandonsetorremissionofARandasthma

AR,sensitizationtopets,andsmokingwereriskfactorsforonsetofasthma.

Settipaneetal1776

2000 3b Cohort Follow-upofstudents

Asthmadevelopment Allergicasthmadependson:elevatedIgE,eosinophilia,airwayhyper-responsiveness,exposuretoallergens,andthepredominanceoftheTh2pathwayofimmunologicreactions.

LOE:levelofevidence;OR:oddsratio;CI:95%confidenceinterval;AR:allergicrhinitis;NAR:non-allergicrhinitis;IgE:immunoglobulinE2

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X.A.3.Treatmentofallergicrhinitisanditseffectonasthma1

The2015ARclinicalpracticeguidelinefromtheAAO-HNShashighlightedtheoverlapofARand2asthma,specificallyrecommendingthatcliniciansshouldassessforanddocumentassociatedmedical3comorbidconditionsincludingasthma.761Theguidelinesalsoreviewandconsidertheimpactof4comorbidasthmaontreatmentdecisionsforAR,thoughtheactionstatementsmaynotapplytoARwith5comorbidasthma.However,thereisabodyofevidencetosuggestthatARtherapies,including6INCS,1296,1788-1790oralantihistamines,1791,1792LTRAs,7,1793,1794andAIT1672,1788,1795,1796maybenefitboth7conditions.Someofthemostpromisingresultsinalteringthecourseofallergicinflammationcommon8toARandasthmahavebeenseenwithAIT.1678,1797,1798Giventhisincreasedunderstandingofthe9relationshipbetweenARandasthmaassimilarinflammatoryprocessesaffectingtheupperandlower10airways,respectively,theimportanceofunderstandingtheoverlapofARtreatmentwiththetreatment11ofasthmaisincreasinglyevident.Thestudiesreviewedinthissectionarelimitedtoprospective12randomizedtrialstominimizeinherentbiasesandweaknessesofretrospectivestudies.179413

14Allergenavoidance.Allergenavoidanceisoftenadvocatedforallergytreatment,specificallyforARand15allergicasthma.7Despitetheintuitiveacceptanceofthisandreasonablebiologicalplausibility,the16evidenceforbenefitofavoidanceandenvironmentalcontrolmeasuresinARwithassociatedasthmais17limited.ACochranereviewexaminingrandomizedtrialsofsubjectswithasthmawhounderwent18chemicalorphysicalmethodstoreduceHDMallergenfoundnobenefitwiththesemethods.1799Single19allergenavoidanceoreliminationplanssuchasremovingorwashingpets,mattresscoverings,removing20carpeting,anduseofHEPAfiltershaveshownlimitedevidence-basedclinicalbenefitforreducing21asthmaand/orARsymptoms.101,1799,1800However,thereistheoreticalbenefitofreducingallergen22exposure,apaucityofdataonmultimodalityapproachestoreduceallergenload,andminimalnegatives23toattemptingthesevarioustechniques;therefore,allergenavoidancecouldbeconsideredaspartofa24multifactorialapproachinthemanagementofasthmaassociatedwithcomorbidAR.1801,1802(SeeSection25IX.A.Management–AllergenAvoidanceforadditionalinformationonthistopic.)2627Pharmacotherapy:OralH1Antihistamines.Weidentified6RCTswhichspecificallyevaluatedoralH128antihistaminesforthetreatmentofasthmainthecontextofcoexistentAR.[TableX.A.3-1.]Thereare29manyoralH1antihistaminemedications,butcetirizineandloratadinearethetwomosthighlystudied30second-generationantihistaminesusedconcomitantlyinARandasthma.Thereisbiologicplausibilityfor31aroleofantihistaminesinthetreatmentofallergicasthma,aselevatedhistaminelevelsafterallergen32challengeareassociatedwithbronchoconstrictionresponsesinacuteasthmaepisodes.Cetirizinealso33hasbronchodilatoryeffectswhicharesignificantbothasmonotherapyaswellisincombinationwith34albuterol.1803Despiteimprovementinasthmasymptoms,objectivemeasuresusingpulmonaryfunction35testingandpeakexpiratoryflowhavefailedtodemonstratesignificantimprovements.1804-180636Alternatively,thereisgrowingevidencethatantihistaminesmayhaveapreventiveeffectonthe37developmentofasthmainatopicpatients,asshownintheEarlyTreatmentoftheAtopicChildtrial.180738Briefly,atopicinfantsweretreatedwith18monthsofcetirizineandfollowedforthedevelopmentof39asthma.Whileanalysisoftheentiregroupfoundnosignificantdifferencebetweencetirizineand40placebotreatedpatients,subgroupanalysisrevealedapproximately50%reducedriskofdeveloping41

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asthmaamongcertizine-treatedpatientswithgrasspollenandHDMsensitivities.Theauthors1hypothesizethatvariationinkeygenesrelatedtohistamineregulationmayexplainthese2differences.1807,1808(SeeSectionIX.B.1.a.Management–OralH1Antihistaminesforadditional3informationonthistopic.)45Pharmacotherapy:OralCorticosteroids.Oralcorticosteroidsareaneffectivecomponentoftheasthma6treatmentalgorithm,particularlyforcaseswhichareinadequatelycontrolledwithbronchodilatorsand7inhaledcorticosteroids.1809Theyarealsoeffectiveforsymptomsofrhinitis.1247However,oral8corticosteroidshavesignificantside-effects,especiallywithincreasingdurationofuse.7Becauseofthe9sideeffectprofileassociatedwiththesemedications,theyarenotrecommendedfortheroutine10treatmentofAR,andutilizationisonlyrecommendedforselectcasesafterthoroughdiscussionofthe11associatedrisksandbenefits.(SeeSectionIX.B.2.a.OralCorticosteroidsforadditionalinformationonthis12topic.)1314Pharmacotherapy:IntranasalCorticosteroids.Inthe1980s,topicalINCSwerereportedtoimprove15asthmasymptomsinpatientswithcoexistentARandasthma.1364,1810Sincethen,ithasbeenshownthat16verylittleintranasallyadministeredcorticosteroidreachesthelung(approximately2%),suggestingthis17effectonthelowerairwaymayberelatedtoitsintranasaleffects.1788,1811Wehaveidentifiedtwometa-18analysesand12RCTsthataddressthispotential“unifiedairway”effectofINCSonasthma.[TableX.A.3-192.]A2003CochranereviewevaluatedtheefficacyofINCSonasthmaoutcomesinpatientswith20coexistentrhinitis,findingnosignificantimprovementinasthmaoutcomeswiththeuseofINCS.129521Heterogeneityinstudydesignsmayhavelimitedthefindingsofthismeta-analysisandexplainthe22discrepancyoftheresultscomparedtohigh-qualityRCTs.Alternatively,a2013systematicreviewand23meta-analysisoftheefficacyofINCSforasthmaticswithconcomitantARdemonstratedimprovements24inasthmaoutcomeswiththeuseofINCScomparedtoplacebo,butalackoffurtherimprovementwith25INCSasanadditiontoinhaledcorticosteroids.1296Interestingly,patientswithconcomitantARand26asthmawhoreceivedtrainingontheproperuseofINCSandeducationontherelationshipofARand27asthmademonstratedsignificantreductionsinasthmasymptomsandalbuterolusecomparedto28patientsreceivingINCSwithoutadditionaleducation.1812Thisdemonstratestheimportanceofpatient29instructionforboththerapyevaluationandfuturetrialdesign.(SeeSectionIX.B.2.c.Management–30IntranasalCorticosteroidsforadditionalinformationonthistopic.)3132Pharmacotherapy:LeukotrieneReceptorAntagonists.LTRAs(montelukastandzafirlukast)have33demonstratedbenefitforthetreatmentofbothasthmaandAR,consistentwithefficacyinaddressing34inflammationinthe“unifiedairway”.1813[TableX.A.3-3.]In2008,theARIAgroupreviewedtheevidence35foreffectivenessofmontelukastintreatingpatientswithasthmaandAR,findingimprovementofboth36nasalandbronchialsymptomsaswellasreductionofb-agonistuse.101Infact,theLTRAsaretheonly37classofmedicationsspecificallydescribedinthe2008ARmanagementguideforprimarycare38physicians,andinthefullARIAreport,aseffectiveforbothasthmaandAR.101,1814The2010ARIAupdate39furthersupportstherecommendationofLTRAsforbothARandasthma,butspecifiesthatLTRAsarenot40recommendedoverotherfirst-linetherapiesfortherespectiveconditions(i.e.itisbettertotreat41asthmaandARwithbothanasalandinhaledsteroid,thantrytotreatbothwithanLTRA).Amore42

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recentreviewin2015alsoidentifiedsomeutilityofLTRAsforpatientswithconcomitantARand1asthma.1802Despitethisevidence,thelimitedadditionalbenefitandaddedcostleadstoastrong2recommendation(basedonmoderatequalityevidence)forinhaledglucocorticoidsoverLTRAsfor3single-modalitytreatmentofasthmainpatientswithcomorbidAR.1167BasedonthesummarizedRCTs,4anevidence-basedrecommendationismadeforLTRAsnottobeusedasmonotherapyforAR,butLTRAs5maybeconsideredaspartofthetreatmentofcomorbidasthmaandAR.(SeeSectionIX.B.4.6Management–LeukotrieneReceptorAntagonistsforadditionalinformationonthistopic).[TableX.A.3-73.]89PharmacotherapyrecommendationsforthetreatmentofARwithcoexistingasthma:10

• AggregateGradeofEvidence:A(Level1a:2studies;Level1b:23studies).Antihistamines(Level111b:6studies;TableX.A.3-1.).INCS(Level1a:2studies;Level1b:12studies;TableX.A.3-2.).12LTRA(Level1b:5studies;TableX.A.3-3.).13

• Benefit:Pharmacotherapyimprovessubjectiveandobjectiveseverityofasthmainpatientswith14coexistentAR.Patienteducationandtrainingonmedicationuseimprovescomplianceand15benefitsforINCS,andlikelyallpatient-administeredpharmacotherapy.16

• Harm:Pharmacotherapyotherthansystemicsteroids-minimalharmwithraremildadverse17eventssuchasdrowsiness.Noseriousadverseeventsreportedinthestudiesreviewed.18Systemiccorticosteroidshavesignificantside-effects.19

• Cost:Generallylowcostforpharmacotherapy.20• Benefits-HarmAssessment:Thereisabenefitoverplaceboforasthmatreatment,thoughno21

significantbenefitisseenoverstandardasthmapharmacotherapy.Risksofroutineuseof22systemiccorticosteroidsgenerallyoutweighsthebenefits,thoughshortcoursesforacute23indications(e.g.asthmaexacerbation)haveafavorablelikelihoodofbenefitrelativetoharm.24

• ValueJudgments:PharmacotherapyforARmayalsobenefitasthmasymptomsandobjective25parametersofpulmonaryfunctioninpatientswithcoexistingasthmaandAR,however,the26benefitforasthmashouldbeconsideredapositiveside-effectratherthananindicationforuse27asthereappearstobelimitedbenefitcomparedtostandardasthmatherapy.28

• PolicyLevel:Useofpharmacotherapyotherthansystemicsteroids:Recommendedusefor29optimalcontrolofAR,withpotentialadditionalbenefitforcoexistentasthma,thoughnot30recommendedforprimaryintentofasthmatreatment.Useofsystemiccorticosteroid:Not31recommendedforroutineuseinARwithcomorbidasthmaduetounfavorablerisk-benefit32profile,thoughcertainsituationsmayindicateashortcourse(e.g.acuteasthmaexacerbation).33

34Biologics:omalizumab.Omalizumabisananti-IgEmAbthatbindsfree-IgE,preventinginteractionswith35high-affinityIgEreceptorsandresultinginreceptordownregulationoninflammatorycells.181536OmalizumabhasdemonstratedeffectivenessseparatelyforasthmaaswellasAR.1393,1815-1818Despitea37numberofstudiesevaluatingomalizumabinARorasthma,1815,1819thereisonlyonedoubleblindRCT38whichspecificallyevaluatestheefficacyofomalizumabinpatientswithconcomitantmoderate-to-39severeasthmaandpersistentAR.1820Additionally,anotherstudyevaluatesomalizumabasanadjunctto40SCIT,1403withbothstudiesshowingareductioninsymptomsaswellasanimprovementinQOL41

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measures.[TableX.A.3-4.]The2010ARIAupdatemakesaconditionalrecommendationofusingamAb1againstIgE,suchasomalizumabfortreatmentofasthmainpatientswithbothARandasthma,where2thereisaclearIgE-dependentallergiccomponentandfailureofothermaximaltherapy.1167Additional3biologics,includinganti-IL5,anti-IL4,andIL-4receptormAbs,arecurrentlyinvaryingstagesof4development/emergencewithpositivefindingsforthetreatmentofasthmaandotheratopicdiseases.5AdditionalevaluationisneededtofurtherevaluatetheirroleforthetreatmentofcoexistentARand6asthma.(SeeSectionIX.B.7.Management–Biologicsforadditionalinformationonthistopic.)78BiologicsrecommendationsforthetreatmentofARwithcoexistingasthma:9

• AggregateGradeofEvidence:B(Level1b:2studies;TableX.A.3-4.).GradeAevidencewith10multiple1bRCTsand1areviewsexistforasthmaandARindividually,butonlyonedoubleblind11RCTspecificallyevaluatingomalizumabversusplaceboinpatientswithconcurrentconditions.12

• Benefit:Decreasedasthmaexacerbations,decreasedsymptomscores,andimprovementin13disease-specificQOLinpatientswithcoexistingasthmaandAR.14

• Harm:Thereisevidenceforacceptablesafetyforuseupto52weeks.1821Potentiallongerterm15harmunknown.Minoreventssuchasmildinjectionsitereactionsarereported.Possibilityof16anaphylaxis.17

• Cost:SubstantiallyhighercostthanconventionaltherapyforasthmaandAR.18• Benefits-HarmAssessment:Benefitsappeartooutweighpotentialharmforthetreatmentof19

moresevere/persistentcoexistentARandasthma.20• ValueJudgments:AddedbenefitofomalizumabastherapyforpatientswithARandasthma21

whichisuncontrolleddespitemaximalconventionalinterventions.However,giventhe22significantincreasedcostassociatedwithomalizumab,thevalueofthistherapyislikelygreatest23forpatientswithsevereasthmaandsymptomsthatpersistdespiteusualtherapies.24

• PolicyLevel:OmalizumabisrecommendedforthosepatientswithclearIgE-mediatedallergic25asthmawithcoexistentARwhofailconventionaltherapy.Thesignificantadditionalcostofthis26therapyshouldbeconsideredinevaluatingitsvalue.27

28

Allergenimmunotherapy.BothSCITandSLIThavebeenshowntoimprovethecontrolofcomorbidAR29conditions,suchasasthma.1618,1788,1822[TableX.A.3-5.]AITalsoappearstopreventthedevelopmentof30asthma.1678,1797,1798TheefficacyofSLITforARhasbeenconfirmedbyseveralsystematic31reviews.1694,1695,1823BothSCITandSLIThavebeenshowntobeefficaciousforAR,thoughthereisongoing32debateastowhetheroneformissuperior.1697,1703AITisalsothoughttohelphalttheprogressionof33allergicdisease,includingpreventionofnewallergicsensitivitiesandthedevelopmentof34asthma.1624,1626,1678,1797,1798,1824-1826AITalsoappearstohavelonglastingeffectsevenafterdiscontinuing35treatment,unlikepharmacotherapy.Suchpromisingresultshaveledtoa2010ARIAupdatestatement36recommendingbothSCITandSLITforthetreatmentofasthmainpatientswithARandasthma.116737RecentsystematicreviewsdemonstratethatSCITandSLITreducebothasthmaandrhinitissymptoms,38aswellasmedicationuse.1694,1822Theseevidence-basedreviewsalsodemonstratestrongevidencefor39theutilityofSCITandSLITinthetreatmentofasthmaaloneinstudiesthatdidnotspecificallyaddress40

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theconditionofcombinedasthmaandAR.1694,1822EvidenceforAIT(SCITandSLIT)forasthmaincontext1ofcomorbidasthmaandAR,isreviewedinTableX.A.3-5.(SeeSectionIX.D.Management–2Immunotherapyforadditionalinformationonthistopic.)34AllergenimmunotherapyrecommendationsforthetreatmentofARwithcoexistingasthma:5

• AggregateGradeofEvidence:A(Level1a:2studies;Level1b:4studies;Level2b:1study;Table6X.A.3-5.)7

• Benefit:AIT(bothSCITandSLIT)hasdemonstratedbenefitinconcomitantARandasthma,with8decreasedsymptoms,rescuemedicationuse,andbronchialhyper-responsiveness,aswellas9reduceddevelopmentofasthmainpatientswithARonly.10

• Harm:Localsitereactionsarecommonandthereispotentialforanaphylacticeventswithany11formofAIT.12

• Cost:IncreasedcostcomparedtostandardtherapyforARandasthma,thoughthepotentialto13treattheunderlyingdiseaseprocessandpreventprogressionofdiseasecouldreducelong-term14costs.15

• Benefits-HarmAssessment:SignificantevidencetosupporttheuseofAITforpatientswithAR16andasthma,aswellasthepotentialutilityofAITforpreventingprogressionofallergicdisease17fromARtothedevelopmentofallergicasthma.Harmsaregenerallylimitedtominorlocal18reactions,thoughthereisapotentialriskofanaphylaxis.Benefitsappeartooutweighpotential19harm,giventhatanaphylaxisisrare.20

• ValueJudgments:ThereappearstobeuniquevalueinAIT,asthistherapytreatstheunderlying21pathologyofARandasthma,withpotentialtohalttheprogressionofallergicdisease.The22uniquebenefitsofthistherapyareofvalue,despitesomeuncertaintyoftheirtruemagnitude.23

• PolicyLevel:AIT(SCITandSLIT)isrecommendedfortreatmentofARwithasthmainpatients24followinganappropriatetrialofmedicaltherapy,andmayalsobeconsideredforthebenefitof25preventingprogressionofARtoasthmainpatientswithARonly,andforwhomAITisotherwise26indicated.27

28

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TableX.A.3-1.EvidencefororalH1antihistaminesforthetreatmentofasthmainthecontextofcoexistentallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Pasqualietal1827

2006 1b DBRCT

PersistentARandasthma(n=50):1.levocetirizine5mg2.placebo

Dailyrhinitisandasthmasymptoms,QOLbyRhinasthmaquestionnaireandSF-36

Rhinitisandasthmasymptomsreducedwithlevocetirizine.RhinasthmaQOLscorereducedwithlevocetirizine.NodifferencesinSF-36.

Baena-Cagnanietal1828

2003 1b DBRCT

SARandasthma(n=924):1.desloratadine5mg2.montelukast10mg2.placebo

TASS,FEV1,b-agonistmedicationuse

Desloratadineversusplacebo:reductioninmeanTASS,improvementinFEV1,reductioninaverageb-agonistmedicationuse.Desloratadineversusmontelukast:Nodifferences.

Bergeretal1829

2002 1b DBRCT

ARandasthma(n=326):1.desloratadine5mg2.placebo

TSS,asthmasymptomscores,b-agonistmedicationuse

Desloratadinereducedrhinitissymptoms,asthmaTSS,andb-agonistmedicationuse

Aubieretal1804

2001 1b DBRCT,crossover

SARandasthma(n=12):1.cetirizine2.placebo

BHR(measuredasmethacholinePD20).NBI(measuredusingpeakexpiratoryflowmeterandcalculatedas[oralpeakflow–nasalpeakflow]dividedbyoralpeakflow).

BHR:increasewithcetirizineNBI:reducedwithcetirizinecomparedtoplaceboat6h

Aaronson1830

1996 1b DBRCT

ARandperennialasthma(n=28):1.cetirizine20mgdaily2.placebo

Dailyrhinitisandasthmasymptoms,medicationuse,PEFR,PC20,PFTs,asthmamanagement

Cetirizinereducedasthmaandrhinitissymptoms.Nodifferenceinalbuteroluse.NodifferenceinPFTs,PC20,andpatientPEFRs.Nodifferenceinasthmamanagement.*

Grantetal1831

1995 1b DBRCT

ARandasthma(n=186):1.cetirizine10mgdaily2.placebo

Rhinitisandasthmasymptoms,pulmonaryfunctionbyspirometry

Improvementinasthmasymptomswithcetirizine.Nodifferencesinobjectivemeasures.

LOE:levelofevidence;DBRCT:doubleblindrandomizedcontrolledtrial;AR:allergicrhinitis;QOL:qualityoflife;SF-36:TheShortFormHealthSurvey;SAR:2seasonalallergicrhinitis;TASS:TotalAsthmaSymptomSeverityScore;FEV1:forcedexpiratoryvolumein1second;TSS:TotalSymptomScore;BHR:bronchial3hyperresponsiveness;NBI:NasalBlockingIndex;PEFR:peakexpiratoryflowrate;PC20andPD20:provocation‘concentration’or‘dose’ofmethacholinecausing4a20%decreaseinFEV1(alsodescribedasPD20FEV1);PFT:pulmonaryfunctiontest.*Notesmallsamplesizeandnopower-analysisorsamplesizecalculation5whichlimitsinterpretationofnegativefindings.6 7

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TableX.A.3-2.Evidenceforintranasalcorticosteroidsforthetreatmentofasthmainthecontextofcoexistentallergicrhinitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Lohiaetal1296

2013 1a SRandmeta-analysis

18RCTs(n=2162):1.INCSsprayvsplacebo2.INCSsprayplusoralinhaledCSvs.oralinhaledCSalone3.nasalinhaledCSvsplacebo

Asthmasymptoms,rescuemedicationuse,FEV1,PEF,PC20,QOL

INCSimprovedFEV1,PC20,asthmasymptomscores,andrescuemedicationuse.NoasthmaoutcomechangeswithINCSplusoralinhaledCSvsoralinhaledCSalone.NasalinhaledCSimprovedPEF.

Taramarcaz&Gibson1295

2003 1a Meta-analysis 14RCTswith3interventions:1.INCSvsplacebo2.INCSvsconventionalasthmatreatment3.INCSplusconventionalvsconventionalalone

Asthmasymptomsandb-agonistuse,asthmaexacerbationevents,QOL,FEV1,PEF,PC20,andPD20,inflammatorymarkers

Non-significantsymptomimprovementINCSvsplacebo.NodifferenceinFEV1,PEF,PC20,andPD20.

Jindaletal1832

2016 1b RCT,single-blind

ARandasthma(n=120):1.FPINCS200μgtwicedaily2.montelukast10mgatnight

Symptomscoresofrhinitisandasthma,PEF

ReductioninasthmasymptomseverityscoreandincreasedinPEFwithFPINCSvsmontelukast.

Kerstenetal1789

2012 1b DBRCT

ARandmild-to-moderateexerciseexacerbatedasthma(n=32):1.fluticasonefuroateINCS2.placebo

ChangeinexerciseinduceddecreaseinFEV1,changeinAUCoftheFEV1curve,ACQscore,PAQLQscore,FeNO

ExerciseinduceddecreaseinFEV1reducedwithFP.NodifferenceinFEV1,ACQ,PAQLQ,FeNO.

Baiardinietal1833

2010 1b DBRCT

Moderate/severepersistentARwithintermittentasthma(n=47):1.MFINCS200µgperday2.placebo

QOLbyGS;symptomscores;RhinasthmascoresofRAI,LA,andUAa,rescueasthmamedicationuse

GSscorereductionwithMFINCS.LAscoredecreasedwithMFINCS.NodifferenceMFNSvsplaceboforrescuemeds

Nairetal1834 2010 1b DBRCT,double-dummy,3-waycrossover

PersistentARandasthma(n=25):1.inhaledFP100µg,inhaledplacebo,placebonasalspray,2.inhaledFP100µg,inhaledplacebo,FPINCS3.inhaledFP500µg,inhaledplacebo,placebonasalspray

MethacholinePC20,FeNO,PNIF,FEV1,asthmaandrhinitisQOL

ImprovementofPC20inallgroups.NoPC20improvementwithINCSandinhaledsteroidvsinhaledFPalone.NochangeinAsthmaQOL.FeNOandPNIFreducedonlywithINCS.

Agondietal1835

2008 1b DBRCT

ARandasthma(n=33):1.BdpINCS400µgperday2.placebonasalspray

Rhinitisandasthmasymptomscores,rescuemedicationuse,BHR(histamineprovocation)

ChangeswithBdpINCSvsplacebo:asthmasymptomsreduced,decreaseinrescuemedicationuse,BHRreduced

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Pedrolettietal1836

2008 1b DBRCT

Perennialrhinitisandallergicasthma(n=40):1.MFINCS2.placebo

FeNO,ECPinnasallavage,PEF,FEV1

NodifferenceofFeNOforMFINCSvsplacebo.NasalECPreduced.NodifferenceinPEForFEV1.

Dahletal1837 2005 1b DBRCT,doubledummy

Pollen-inducedARandasthma(n=262):1.FPINCS200µgdaily+inhaledFP250µgbid2.FPINCS+inhaledplacebo3.Intranasalplacebo+inhaledFP4.Intranasalandinhaledplacebo

AsthmaandARsymptoms,PFTs,methacholineBHR,PEF

IncreasedPEFforFPINCS+inhaledFPvsothergroups.PEFincreaseforinhaledFPvsnoinhaledFP.FEV1higherwithinhaledFP.IncreasedBHRwithFPINCS;noincreasewithinhaledFP.

Nathanetal1838

2005 1b RCT,plusopen-label

SARandpersistentasthma(n=863):1.FPINCS200µg2.montelukast10mg3.placeboAllreceivedinhaledFP-salmeterol.

DailyPEF,dailyasthmaandARsymptoms,rescuealbuteroluse

FPINCSimprovednasalsymptoms.NoasthmaoutcomeimprovementwithFPINCSadditiontoinhaledFP-salmeterol.

Stelmachetal1839

2005 1b DBRCT

PARandmild-to-moderatepersistentasthma(n=59):1.BdpINCS400µg+inhaledplacebo2.placebonasalsprayandinhaledBdp1,000µg3.BdpINCS400µgandinhaled1,000µgdaily

AsthmaandARsymptomscores,PEF,FEV1andBHR(PC20),proxyindicatorsofasthma-relatedmorbidity(workabsence,emergencydepartmentvisits,etc)

ReductionsofARandasthmasymptomsinallgroups.NochangePEForBHR.IncreasedFEV1forinhaledBdp.Asthmamorbidityreducedforall

Thioetal1840 2000 1b DBRCT

Twograsspollenseasonsoftreatment(Season1,n=21;season2,n=67):1.FPINCS200µgdaily2.placebonasalspray3.BdpINCS400µg

Asthmascores,rescueuseofsalbutamol,ethacholinePD20,FEV1

Nodifferenceinasthmascoresorrescuesalbutamolforallgroups.PD20notsignificantlydifferent.FEV1increasedwithFPandBDPinseason2.

Watsonetal1811

1993 1b DBRCT,crossover

ARandcontrolledasthma(n=21):1.BdpINCS100µgtwicedaily,thenplacebo2.Placebonasalspray,thenBdpINCS100µgtwicedaily

Asthmaandrhinitissymptoms,PC20,Bdpdeposition*

NodifferenceofallasthmasymptomswithBdp.PC20improvedwithBdp.EveningasthmasymptomsreducedwithBdp.

Correnetal1788

1992 1b DBRCT MildSARandasthma(n=18): Nasalandchestsymptoms,NBI,BHR(PC20)

PC20decreasedoverpollenseasonwithplacebo,notBdp.MorningNBI

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1.Placebonasalspray(vehicleofBdpformulation)2.BdpINCS

decreasedwithplacebo,improvedwithBdp.Nodifferenceinsymptoms.

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;INCS:intranasalcorticosteroid;CS:corticosteroid;FEV1:forcedexpiratory1volumein1second;PEF:peakexpiratoryflow;PC20andPD20:provocation‘concentration’or‘dose’ofmethacholinecausinga20%decreaseinFEV1(also2describedasPD20FEV1);QOL:qualityoflife;AR:allergicrhinitis;FP:fluticasonepropionate;DBRCT:doubleblindrandomizedcontrolledtrial;AUC:areaunder3thecurve;ACQ:AsthmaControlQuestionnaire;PAQLQ:PediatricAsthmaQualityofLifeQuestionnaire;FeNO:fractionofexhalednitricoxide;MF:4mometasonefuroate;GS:aRhinasthmaglobalsummary(GS)includesscoresfromthethreecategoriesofRAI,LA,andUA(RAI:respiratoryallergyimpact;LA:5lowerairway;UA:upperairway);PNIF:peaknasalinspiratoryflow;Bdp:beclamethasonedipropionate;ECP:eosinophilcationicprotein;PFT:pulmonary6functiontest;BHR:bronchialhyper-responsiveness;SAR:seasonalallergicrhinitis;PAR:perennialallergicrhinitis;NBI:NasalBlockingIndex.*RadiolabeledBdp7<2%depositioninlungs,20%-50%innasalcavity,and48%-78%swallowedin1993Watsonetal.study.891011TableX.A.3-3.Evidenceforleukotrienereceptorantagonistsforthetreatmentofasthmainthecontextofcoexistentallergicrhinitis12

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionKatialetal1841

2010 1b RCT SARandasthma(n=1385):1.FP-salmeterolinhaled100/50µgtwicedaily2.FP-salmeterolinhaled100/50µgtwicedaily+FPINCS200µgdaily3.FP-salmeterolinhaled100/50µgtwicedaily+montelukast10mgdaily4.montelukast10mgdaily

PEF,rescuealbuteroluse,asthmaandrhinitissymptoms

NoadditionalimprovementsinasthmawithmontelukastplusFP-salmeterol.FP-salmeterolassociatedwithimprovementinalloutcomemeasuresvsmontelukast.

Priceetal1842

2006 1b DBRCTAnalysisofCOMPACTtrialdata

Asthmasymptomsdespiteinhaledcorticosteroid.SubgroupwithcoexistentAR.(n=889)1.montelukast+budesonide2.doubledosebudesonide

ImprovementinmorningPEFcomparedtobaseline

Least-squaresmeandifferenceofmorningPEFgreaterincreasefrombaselineinmontelukast+budesonidevsdoubledosebudesonide.*

Nathanetal1838

2005 1b RCT,plusopen-label

SARandpersistentasthma(n=863):1.FPINCS200µg2.montelukast10mg3.placeboAllreceivedinhaledFP-salmeterol.

DailyPEF,dailyasthmaandARsymptoms,rescuealbuteroluse

FPINCSimprovednasalsymptoms.NoasthmaoutcomeimprovementwithFPINCSadditiontoinhaledFP-salmeterol.

Philipetal1341

2004 1b DBRCT

SARandasthma(n=831):1.monelukast10mgdaily2.placebo

Rhinitissymptoms,RQLQ,globalevaluationsof

Globalevaluationofasthmabypatientsandphysiciansimprovedwith

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asthma,b-agonistmedicationuse

montelukast.Reductioninb-agonistmedicationusemontelukast.

Baena-Cagnanietal1828

2003 1b DBRCT

SARandasthma(n=924):1.desloratadine5mg2.montelukast10mg2.placebo

TASS,FEV1,b-agonistmedicationuse

Montelukastversusplacebo:reductioninmeanTASS,improvementinFEV1,reductioninaverageb-agonistmedicationuse.Desloratadineversusmontelukast:Nodifferences.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;FP:fluticasonepropionate;INCS:intranasalcorticosteroid;PEF:peakexpiratoryflow;DBRCT:double1blindrandomizedcontrolledtrial;COMPACT:ClinicalOutcomeswithMontelukastasaPartnerAgenttoCorticosteroidTherapy;AR:allergicrhinitis;SAR:2seasonalallergicrhinitis;RQLQ:RhinoconjunctivitisQualityofLifeQuestionnaire;TASS:TotalAsthmaSymptomSeverityScore;FEV1:forcedexpiratoryvolume3in1second456TableX.A.3-4.Evidenceforomalizumabforthetreatmentofasthmainthecontextofcoexistentallergicrhinitis7

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionKoppetal1403

2009 1b DBRCT

ARandseasonalasthma.AllpatientsreceivedSCIT.(n=140)1.SCIT+omalizumab2.SCIT+placebo

ARandasthmasymptoms,rescuemedicationuse,PEF,patientandproviderGETE,asthmasymptomsbyACQ,disease-specificQOLbyAQLQandRQLQ,PFTs

OmalizumabadditiontoSCIT:reducedsymptomseverity,improvedQOLbyACQandAQLQ.Nodifferenceinrescuemedicationuse.NodifferenceinFEV1ormeanPEF.

Vignolaetal1820

2004 1b DBRCT

Moderate-to-severepersistentARandallergicasthma(n=405):1.omalizumab2.placebo

Asthmaexacerbations,disease-specificQOLbyAQLQandRQLQ,rescuemedicationuse,symptomscores,patientandinvestigatorGETE,inhaledcorticosteroiduse,FEV1,FVC,andmorningPEF

Omalizumab:reducedasthmaexacerbations;increasedAQLQandRQLQ;reducedasthmasymptoms;increasedFEV1,FVC,andPEF.Nodifferenceinb-agonistuse.

LOE:levelofevidence;DBRCT:doubleblindrandomizedcontrolledtrial;AR:allergicrhinitis;SCIT:subcutaneousimmunotherapy;PEF:peakexpiratoryflow;8GETE:GlobalEvaluationofTreatmentEffectiveness;ACQ:AsthmaControlQuestionnaire;QOL:qualityoflife;AQLQ:AsthmaQualityofLifeQuestionnaire;9RQLQ:RhinoconjunctivtisQualityofLifeQuestionnaire;PFT:pulmonaryfunctiontest;FEV1:forcedexpiratoryvolumein1second;FVC:forcedvitalcapacity10111213TableX.A.3-5.Evidenceforallergenimmunotherapyforthetreatmentofasthmainthecontextofcoexistentallergicrhinitis14

Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

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Erekosimaetal1822

2014 1a SR Systematicreviewof61RCTs(26specificallyasthmaandrhinitis):1.SCITvsplacebo2.SCITvspharmacotherapy

1.Asthmaandrhinitis/conjunctivitissymptoms2.Asthmaandrhinitis/conjunctivitismedicationuse3.SafetyofSCIT

1.SymptomsreducedwithSCITa2.MedicationusereducedwithSCITa3.Mostadversereactionsmild.

Linetal1694 2013 1a SR Systematicreviewof63RCTs(SCITandSLIT).1.SLITvsplacebo2.SLITvspharmacotherapy

1.Asthmaandrhinitis/conjunctivitissymptoms2.Combinedmedicationuseplussymptoms

1.SymptomsreducedwithSLITb2.MedicationplussymptomscoresreducedwithSLITb

Marognaetal1678

2008 1b RCT Rhintiswith/withoutintermittentasthma(n=216):1.Pharmacotherapy2.PharmacptherapyplusSLIT*

Developmentofpersistentasthma(notatbaseline),symptomandmedicationscores,dailymedicationuse,newsensitization

PersistentasthmaincidencelowerwithSLITvscontrol.Methacholine-positivepatientsafter3yearsreducedwithSLIT.LowersymptomandmedicationscoreswithSLIT.

Novembreetal1798

2004 1b RCT

Rhinoconjunctivitis,noasthma(n=97):1.SLIT,maintenance3years2.Standardsymptomatictreatment,noSLIT

Symptoms,rescuemedicationuse,developmentofasthma

RescuemedicationusereducedwithSLIT.Relativeriskofasthmaafter3yearsgreaterincontrolgroupvsSLIT.

Mölleretal1797

2002 1b RCT

Rhinoconjunctivitiswithorwithoutasthma(n=191):1.SCIT2.Control(noinjections)

Developmentofasthma(ifnoneattrialstart),BHRbyPC20,VASofsymptoms

Asthmaincidencegreaterincontrols.BHRimprovedwithSCITafter1yrpollenseason.

Grembialeetal1795

2000 1b DBRCT

HDMARandBHRtomethacholine(n=44):1.SCIT2.placebo

BHRbyPD20,serumIgElevels,rescuemedicaitonuse,additionalvisitsforsymptoms,developmentofasthma

BHRincreasedwithSCIT.NoHDMIgEdifference.Increasedmedicationuseandvisitswithplacebo.Nodifferenceofasthmaincidence.

Inaletal1825

2007 2b Open,non-randomized,prospective,parallelgroup

HDMARand/ormild-to-moderateasthma(n=147):1.SCIT2.Medicationonly

Asthmaandrhinitismedicationuse,positiveHDMskintest,developmentofasthma

DecreasedasthmamedicationusewithSCIT.ImprovedatopyscoreswithSCIT.AsthmaincidencenearlyhalfwithSCI.T

LOE:levelofevidence;SR:systematicreview;RCT:randomizedcontrolledtrial;SCIT:subcutaneousimmunotherapy;SLIT:sublingualimmunotherapy;BHR:1bronchiahyper-reactivity;PC20andPD20:provocation‘concentration’or‘dose’ofmethacholinecausinga20%decreaseinFEV1(alsodescribedasPD20FEV1);2VAS:visualanalogscale;DBRCT:doubleblindrandomizedcontrolledtrial;HDM:housedustmite;AR:allergicrhinitis;IgE:immunoglobulinE;aStrengthof3evidencemoderatetohigh,forasthma-focusedstudiesandrhinitis-focusedstudies,respectively;bThestrengthofevidenceismoderateforbothcomparisons;4*SLITadministeredassublingualdropsofstandardizedallergenforabuild-upphaseandthencontinuedformaintenancephase5

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X.B.Rhinosinusitis1

ARmaybeassociatedwithrhinosinusitisinseveralclinicalsettings.Ingeneral,ARisregardedas2adisease-modifyingfactorforrhinosinusitis.1RhinosinusitismaybebroadlydividedintoARS,RARS,3CRSwNP,orCRSsNP.TheassociationbetweeneachoftheseformsofrhinosinusitiswithARwillbe4discussedindividuallybelow.Ofnote,manyofthesestudiesusedSPTorinvitrotestingforconfirmation5ofallergicdisease.Whilepositivetestingdoesindicateevidenceofsensitization,thisdoesnot6necessarilycorrelatewithallergicnasaldisease.1843Giventhepaucityofliteratureexclusivelydiscussing7ARandrhinosinusitis(versusallergyandrhinosinusitis),thisliteraturewillbeincluded.8

ARisthoughttobeapotentialriskfactorforthedevelopmentofrhinosinusitisingeneral.9Exposuretoallergensinallergicpatientshasbeenassociatedwithincreasedeosinophiliainthe10maxillarysinus.1844,1845Inaddition,themajorityofragweedallergicpatients(60%)displayabnormal11opacificationofCTscansoftheparanasalsinusesinpeakallergicseasons.1846TheseCTfindingspersist12despitesymptomresolutionoutsidetheallergicseason.1846Thesestudiesdonotalwaysdelineate13whetherARS,RARS,orCRSistheformofrhinosinusitisassociatedwithAR.1415Allergicrhinitisandacuterhinosinusitis.Inadditiontothesemoregeneralstudies,evidenceexiststo16supporttheconceptofanincreasedriskofARSwithAR.ThereisasignificantlyhigherincidenceofARS17inbothchildrenandadultpatientswithahistoryofAR.1847,1848ChildrenwithARarealsomorelikelyto18experienceorbitalcomplicationsofARScomparedtothosewithoutAR,especiallyinpollinating19seasons.1849Amousemodelhasalsoshownthatongoingnasalallergyisassociatedwithworsened20episodesofARS.1850,1851AvailabledatasupportsanassociationbetweenARandARS.However,ARis21thoughttobeadisease-modifyingorrisk-modifyingfactorratherthanacausativeone.Thereareno22studiesexaminingtheeffectsoftreatingARontheriskofdevelopinganepisodeofARS.Forexample,it23isunclearwhethertreatingARdecreasestheincidenceofARS.Futurestudymayhelpclarifythe24interactionbetweenARandARS.[TableX.B-1.]2526

• AggregateGradeofEvidence:C(Level2a:2studies;Level2b:1study;Level3a:1study;Level273b:1study;TableX.B-1.).28

29Allergicrhinitisandrecurrentacuterhinosinusitis.ThepotentiallinkbetweenARandRARSisan30extensionofthelinkbetweenARandARS.TheincreaseinsinonasalinflammationassociatedwithARis31proposedtoincreasemucosaledema,sinusostiumobstructionandtheretentionofsinussecretions.132ThisenvironmentmaysupportsecondarybacterialovergrowthandsubsequentARSorRARS.1Two33studieshavespecificallyexaminedtheassociationbetweenRARSandAR,withafocusonpotentially34alteredinnateimmunity.Theresultsofthesetwostudiesareconflicting.Onestudysuggeststhereisa35decreaseintheantimicrobialpropertiesofsinonasalsecretionsinpatientswithRARSandARcompared36toARonlypatientsaswellascontrolpatients.1852Thesecondstudyidentifiedanup-regulationintoll-37likereceptor9expression,suggestingincreasedresistancetobacterialinfectionratherthan38susceptibility.1853FurtherstudyisrequiredtodefinetheassociationbetweenARandRARS.[TableX.B-392.]4041

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• AggregateGradeofEvidence:D(Level2b:2studies;conflictingevidence;TableX.B-2.).1 2Allergicrhinitisandchronicrhinosinusitiswithoutnasalpolyposis.CRSisaconditionofthesinonasal3cavitycharacterizedbypersistentinflammation.Thecauseoftheinflammationvariesfrompatientto4patient.AsARisacauseofsinonasalinflammation,manyhavesuspectedtheremaybeanassociation5withthepathogenesisofCRS.However,therearenocontrolledstudiesexaminingtheroleofARinthe6developmentofCRSsNP.Additionally,therearenostudiesshowingthatthetreatmentorcontrolof7allergicdiseasealterstheprogressionofCRSsNP,orviceversa.1Giventhevariedpathophysiologyof8CRSsNP,itischallengingtodeterminetheassociationbetweenallergyandCRSsNP.Wilsonetal18549performedasystematicreviewofallergyandCRS,excludingstudiesthatdidnotdifferentiatebetween10CRSsNPandCRSwNP.Theirreviewfoundfourstudiesthatsupportedanassociationbetweenallergyand11CRSsNPandfivethatdidnot.1854Becausetherelationshipremainsunclear,allergytestingislistedasan12optioninCRSsNPpatientsbasedonthetheoreticalbenefitofidentifyingandtreatingcomorbidallergic13disease.1,1854[TableX.B-3.]1415

• AggregateGradeofEvidence:D(Level1b:1study;Level3a:1study;Level3b:8studies;16conflictingevidence;TableX.B-3.).AdaptedfromWilsonetal.185417

18Allergicrhinitisandchronicrhinosinusitiswithnasalpolyposis.ThepathogenesisofCRSwNPisstrongly19associatedwithTh2-mediatedinflammation.1Additionally,nasalpolypsinCRSwNPhavehighlevelsof20tissueeosinophilia,aswellasmastcellsandbasophils.1ARfollowsasimilarinflammatorypathwayand21thissuggeststheremaybeapathophysiologicsimilaritybetweenCRSwNPandAR.Wilsonetal185422examinedtheassociationbetweenallergicdiseaseandCRSwNP.Again,theevidencewasconflicting.23Tenstudiessupportedanassociationwhilesevendidnot.Onestudyhadequivocalfindings.1854Since24thisreview,Lietal1855examinedtheassociationbetweenatopyandCRSwNPandconcludedthatthere25wasnocorrelationbetweenatopystatusanddiseaseseverity.1855Theydidnotethatatopy-positive26patientswereyoungerthanatopy-negativepatients.1855Despitesomeoverlappingpathophysiologic27featuresbetweenallergicdiseaseandCRSwNP,conflictingevidenceexistsandthereisnoclear28associationbetweenARandCRSwNP.AllergytestingisonceagainanoptioninCRSwNPpatientsbased29onthetheoreticalbenefitofidentifyingandtreatingcomorbidallergicdisease.1,1854[TableX.B-4.]3031

• AggregateGradeofEvidence:D(Level2b:1study;Level3a:1study;Level3b:15studies;Level324:4studies;conflictingevidence;TableX.B-4.).AdaptedfromWilsonetal.185433

34Insummary,ARhasamoderatelevelofevidencesupportinganassociationwithARS(LevelC).35

RegardingRARS,CRSsNPandCRSwNP,thepreponderanceofevidencedoesnotsupportanassociation,36thoughtheevidenceishighlyconflicting.Theavailableliteratureisalsolimitedasitoftenassumes37patientswhotestpositiveonallergytestinghavenasalallergicdiseaseandmaynotdifferentiate38betweensystemicallergyandnasalallergy.Furtherstudyisneededtodeterminetheassociation39betweenARandrhinosinusitis,aswellastheimpacttreatingoneprocesshasontheprogressionofthe40other.However,thediagnosisandtreatmentofcomorbidallergicdiseaseisanoptioninrhinosinusitis41

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patientsbalancingthecostandlowevidencewiththelowriskofallergicrhinosinusitistreatmentand1thetheoreticalbenefitsofreducingallergicsinonasalinflammation.12 3

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TableX.B-1.Evidenceforanassociationbetweenallergicrhinitisandacuterhinosinusitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Rantalaetal1856 2013 2a Cross-sectional Atopicandnon-atopicadultsage21-63years(n=1008)

Upperandlowerrespiratorytractinfections

IndividualswithatopicdiseasehadhigherriskofdevelopingURTI,includingRS.

Chenetal1848 2001 2a Questionnaire ChildreninTaiwan(n=8723) Rhinosinusitis ChildrenreportingallergyaremorelikelytohaveRS.

Holzmannetal1849

2001 2b Retrospectivereview

ChildrenwithorbitalcomplicationsofARS(n=102)

PrevalenceofAR Orbitalcomplicationsaremorecommoninallergyseason.

Frerichsetal1857 2014 3a SR Allergicandnon-allergicpatients

Prolongedcourse(>4weeks)ofRS

NosignificantincreaseinprolongedRSinARpatients.

Savolainen1847 1989 3b Case-control Acutemaxillarysinusitiswithandwithoutallergy(n=224)

ARS PrevalenceofAR25%and16.5%innon-ARpatients.

LOE:levelofevidence;URTI:upperrespiratorytractinfection;RS:rhinosinusitis;ARS:acuterhinosinusitis;AR:allergicrhinitis;SR:systematicreview; 2 3 45TableX.B-2.Evidenceforanassociationbetweenallergicrhinitisandrecurrentacuterhinosinusitis6

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionMelvinetal1853

2010 2b Prospectivecohort

(n=21)1.allergicpatientswithRS2.allergic-onlypatients

ExpressionofTLR9insinonasalepithelium

IncreasedexpressionofTLR9inallergicpatientswithRS

Kalfaetal1852

2004 2b Cross-sectional (n=47)1.allergicpatientswithRS2.allergic-onlypatients3.non-allergiccontrols

NasalsecretionlevelsofEDNandlysozymelevels

AllergicpatientswithRShaveelevatedlevelsofEDNanddecreasedlysozymelevels

LOE:levelofevidence;RS:rhinosinusitis;TLR9:tolllikereceptor9;EDN:eosinophil-derivedneurotoxin7 8

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TableX.B-3.Evidenceforallergicrhinitisandchronicrhinosinusitiswithoutnasalpolyposis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Baroodyetal1844

2008 1b RCT CRSsNPwithorwithoutragweedallergy(n=18)

Reactivityinragweedseasondeterminedbysymptomsandsinusinflammation

Allergicpatientshaveincreasedreactivityandsinonasalinflammationinragweedseason.

Wilsonetal1854 2014 3a SR CRSsNPwithorwithoutallergy

AssociationbetweenCRSsNPandallergy

Conflictingevidencewithnoclearassociation.

Tanetal1858 2011 3b Prospectivecase-control

CRSsNPwithorwithoutallergy(n=63)

RatesofatopyinrhinitisversusCRSsNP

Nosignificantdifferenceinratesofatopy(72%inrhinitis,79%inCRSsNP).

Pearlmanetal1859

2009 3b Prospectivecaseseries

CRSsNPwithorwithoutallergy(n=115)

CTscores NodifferenceinCTscores.

Gelinciketal1860 2008 3b Prospectivecaseseries

CRSsNPwithorwithoutallergy(n=66)

PrevalenceofCRSsNPinallergicandnon-allergicrhinitispatients

CRSsNPwasequallyprevalentinallergic(43%)andnon-allergic(50%)rhinitispatients.

Kirtsreesakul&Ruttanaphol1861

2008 3b Retrospectivecaseseries

CRSsNPwithorwithoutallergy(n=198)

Sinusx-rays,nasalendoscopy Allergicpatientshadahigherincidenceofabnormalsinusx-rays.

Robinsonetal1862

2006 3b Prospectivecaseseries

CRSsNPwithorwithoutallergy(n=193)

Lund-MackayCTscoresandsymptomsscores

AllergywasnotassociatedwithCTfindingsorsymptomsscores.

Alhoetal1863 2004 3b Prospectivecaseseries

CRSsNPwithorwithoutallergy(n=48)

CTfindingsduringviralURTI,incidenceofS.aureussensitization

AllergicpatientshadhigherCTscoresandhigherincidencesofS.aureussensitization.

VanZeleetal1864

2004 3b Prospectivecase-control

CRSsNPwithorwithoutallergy(n=31)

RatesofS.aureuscolonization Nodifferenceincolonizationrates.

Berrettinietal1865

1999 3b Prospectivecase-control

CRSsNPwithorwithoutallergy(n=77)

CTscanfindings,nasalendoscopy,nasalswabs,rhinomamometry

IncreasedCTevidenceofsinusitisinallergy(68%)versusnon-allergic(33%)patients.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;CRSsNP:chronicrhinosinusitiswithoutnasalpolyposis;SR:systematicreview;CT:computed2tomography;URTI:upperrespiratoryinfection 3

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TableX.B-4.Evidenceforallergicrhinitisandchronicrhinosinusitiswithnasalpolyposis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Houser&Keen1866

2008 2b Retrospectivecaseseries

CRSwNPwithorwithoutallergy(n=373)

Nasalpolyposis ARisassociatedwiththedevelopmentofnasalpolyposis.

Wilsonetal1854 2014 3a Systematicreview

CRSwNPwithorwithoutallergy

AssociationbetweenCRSwNPandallergy

Conflictingevidencewithnoclearassociation.

Al-Qudah1867 2016 3b Prospectivecohortstudy

CRSwNPcomparedtoCRSsNP(n=155)

Ratesoffoodsensitivity Nodifferencebetweenallergicandnon-allergicpatients.

Lietal1855 2016 3b Prospectivecohort

CRSwNPwithorwithoutallergy(n=210)

Nasalendoscopy,CTscores,seruminflammatorymarkers

Nodifferenceinallergicandnon-allergicpatients.

Gorguluetal1868 2012 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=60)

Rateofallergensensitivity Nodifferencebetweenallergicandnon-allergicpatients.

Lilletal1869 2011 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=50)

Ratesoffoodsensitivity HigherrateofmilksensitivityinCRSwNP.

Tanetal1858 2011 3b Prospectivecase-control

CRSwNPwithorwithoutallergy(n=62)

Ratesandnumberofantigensensitivity

Nodifferenceinratesofsensitivity.

MunozdelCastilloetal1870

2009 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=190)

Ratesofallergycomparedtocontrol

HigherratesofallergyinCRSwNPcomparedtocontrols.

Collinsetal1871 2006 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=40)

Ratesoffoodsensitivity HigherratesoffoodsensitivityinCRSwNP.

VanZeleetal1864

2004 3b Prospectivecase-control

CRSwNPcomparedtoCRSsNPandcontrols(n=55)

RatesofS.aureuscolonization HigherratesofcolonizationinCRSwNP.

Kirtsreesakul1872 2002 3b Prospectivecohort

CRSwNPwithorwithoutallergy(n=68)

Responsetobudesonidenasalsprays(sneezing,oralandnasalpeakflow,overallresponsetotherapy)

Improvedresponseinnon-allergicpatients.

Voegelsetal1873 2001 3b Prospectivecase-control

CRSwNPwithorwithoutallergy(n=39)

Ratesofasthmainallergicornon-allergicpatients

Higherratesofasthmainallergicpatients.

Asero&Bottazzi1874

2001 3b Prospectivecase-control

CRSwNPcomparedtonon-polypcontrols(n=68)

RatesofCandidaandhousedustsensitivity

HigherratesofsensitivityinCRSwNP.

Asero&Bottazzi1875

2000 3b Prospectivecase-control

CRSwNPcomparedtoallergiccontrols(n=20)

RatesofCandidasensitivity HigherratesofsensitivityinCRSwNP.

Pangetal1876 2000 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=80)

Ratesoffoodsensitivity HigherratesoffoodsensitivityinCRSwNP.

Pumhirunetal1877

1999 3b Prospectivecase-control

CRSwNPcomparedtocontrols(n=40)

Incidenceofhousedustandcockroachallergy

HigherratesofallergyinCRSwNPcomparedtocontrols.

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ICAR:AllergicRhinitis332

Keithetal1878 1994 3b Prospectivecase-control

CRSwNPwithorwithoutallergy(n=64)

Symptomscores,serumlevelsofinflammatorymarkers

Nodifferenceexceptinpatientswithragweedallergy.Ragweedpositivepatientshadincreasesymptomscoresandseruminflammatorymarkers.

Pearlmanetal1859

2009 4 Prospectivecaseseries

CRSwNPwithorwithoutallergy(n=40)

PrevalenceofCRSwNPinallergicornon-allergicpatients

Nodifferencebetweenallergicandnon-allergicpatients.

Bonfils&Malinvaud1879

2008 4 Prospectivecaseseries

CRSwNPwithorwithoutallergy(n=63)

Postoperativecourse,recurrence

Nodifferencebetweenallergicandnon-allergicpatients.

Erbeketal1880 2007 4 Retrospectivecaseseries

CRSwNPwithorwithoutallergy(n=83)

Polypsize,symptomscores,recurrence

Nodifferencebetweenallergicandnon-allergicpatients.

Bonfilsetal1881 2006 4 Prospectivecaseseries

CRSwNPwithorwithoutallergy(n=180)

Endoscopy,CTscores Nodifferencebetweenallergicandnon-allergicpatients.

LOE:levelofevidence;CRSwNP:chronicrhinosinusitiswithnasalpolyposis;AR:allergicrhinitis;CRSsNP:chronicrhinosinusitiswithoutnasalpolyposis;CT1computedtomography23 4

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X.C.Conjunctivitis1

Althoughtheburdenofillness(impairedQOL)associatedwithallergicconjunctivitis(AC)iswell2established,thisconditionisoftenunderrecognizedandconsequentlyundertreatedexceptwhenitis3mostsevere.1882ItsfrequentassociationwithARcontributestothesubstantialburdenassociatedwith4AR.Althoughthisassociationiswellrecognizedclinically,itsextentremainspoorlydefineddueto5methodologicdifferencesanddeficienciesofthestudieswhichhaveexaminedthisassociationinthe6literature.FurthercompoundingthisproblemisthephenotypicdiversityofbothARandAC,andthe7observationthatveryfewstudieshaveadequatelycharacterizedthephenotypesoftheirstudy8populations.Additionally,manyepidemiologicstudiesarelimitedbybeingbasedsolelyon9questionnaireresultsratherthanonobjectiveclinicalevidenceofallergicsensitization.10

ThelargestdatasourceregardingtheAR-ACassociationderivesfromtheISAACstudy,a11worldwidestudyestablishedin1991withtheaimofinvestigatingtheepidemiologyandetiologyof12asthma,rhinitisandatopicdermatitisineachcountry,usingstandardmethodologyincluding13questionnaireandSPT.ISAAChasreportedtheprevalenceofACsymptomsin257,800childrenaged614to7yearsin91centersin38countriesand463,801childrenaged13to14yearsin155centersin5615countries.AlthoughtheISAACsurveywasnotvalidatedforthediagnosisofAC,ISAACstudiessupport16thefrequentassociationofARwithitchy-wateryeyes,reportingthatocularsymptomsaffect17approximately33-50%ofchildrenwithAR.1883[TableX.C.]18

ThebestevidenceofdiseaseassociationderivesfromstudiesofARpatientsassessedforthe19prevalenceofACasacomorbidity.1884-1890TheevidencesuggeststhatARisassociatedwith35-74%20prevalenceofACandthatamongpatientswithAC,theprevalenceofARmaybeashighas97%.21

Tosummarize,thereisasubstantialbodyofevidencewhichsupportsACasafrequentlyoccurring22comorbidityofAR,particularlyinchildren.Notonlyisthisdiseaseassociationcommon,butocular23allergysymptomsalsocontributesignificantlytotheQOLimpairmentassociatedwithAR.Itisnot24surprising,therefore,thatocularsymptomsofallergicrhinoconjunctivitisareamongthemostcommon25symptomswhichcausepatientstoseekallergytreatment.1891Itisadvisable,whenassessingpatients26withAR,toalsoassessforocularsymptomsandtoconsidertreatmentspecifictoprovidingreliefofAC.2728

• AggregateGradeofEvidence:C(Level2b:2studies;Level3a:2studies;Level3b:3studies;29TableX.C.)30

31

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TableX.C.Evidenceforanassociationbetweenallergicrhinitisandallergicconjunctivitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Kimetal1884 2016 2b Cross-sectionalsurvey

Generalpopulation:14,356students,healthscreening2010-2014.“KoreanInternationalStudyofAsthmaandAllergiesinChildhood”ARdefinedassymptoms+SPTpositivity.

SPTpositivity,ARprevalence,prevalenceofcomorbidities

MostcommoncomorbidallergicdiseasesassociatedwithAR:pollenallergy(37.0%),AC(34.5%).

Hanetal1889 2015 2b Cohort

1,020childrentotal,338withAR“TheAllergicRhinitisCohortStudyforKids(ARCO-kids)”

SPT,questionnaire,endoscopicexamination.EvaluationofriskfactorsforAR.

HistoryofACidentifiedasriskfactorforAR(OR:14.25,CI:4.99-40.74)

Alexandropoulosetal1885

2012 3a Caseseries Adultnon-randompatientsreferredtoaClinicalImmunologyoutpatientclinic2001-2007(n=1,851).ARdefinedaccordingtoARIA.

SPT,questionnaire,sIgE.EvaluationofriskfactorsforAR.

ARprevalencewas38.4%.ACidentifiedasriskfactorforAR(OR:6.16,CI:4.71-8.06).

Navarroetal1890 2009 3a Cross-sectional n=4991patientsselectedbyreferralforallergyevaluation

CharacteristicsofpatientswithAR.

ARprevalencewas55%.65%hadassociatedAC.

Almaliotisetal1888

2010 3b Retrospectivecaseseries

n=448subjectsselectedbyclinicreferralanddiagnosisofACbyophthalmologist

SPT,questionnaire.Evaluationofcomorbiditiesofocularallergy.

70%ofpatientswithACalsohadAR.SymptomsofocularallergyareverycommoninpatientswithARandasthma.

Gradman&Wolthers1886

2006 3b Retrospectivesurvey

n=458children(5-15years)selectedfromasecondarypediatricoutpatientclinicwithdiagnosisofAC,asthma,AR,oreczema

PrevalenceofACinchildrenwithrhinitis,asthmaandeczema.

PrevalenceofACinchildrenwithrhinitis:42%.PrevalenceofARinchildrenwithAC:97%.

Kosrirukvongsetal1887

2001 3b Caseseries n=445patients(meanage24.5+/-16.3years)withahistoryofitching,foreignbodysensation,lacrimationandredeyes.Nocontrolgroup.

Skintest.EvaluationofclinicalfeaturesandriskfactorsofvariousACtypes.

73.8%ofpatientswithperennialAChadassociatedAR.MostcommonallergensensitizationwasHDM.

LOE:levelofevidence;AR:allergicrhinitis;SPT:skinpricktest;AC:allergicconjunctivitis;OR:oddsratio;CI:95%confidenceinterval;ARIA:AllergicRhinitisand2itsImpactonAsthma;sIgE:allergen-specificIgE;HDM:housedustmite345 6

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X.D.Atopicdermatitis(AD)1

ADisachronicand/orrelapsingskindisordercharacterizedbypruritus,scratching,and2

eczematouslesions.1892

Itsburdenofillness,impactonQOLandcomplicationsaresubstantial.1893

AD3

commonlypresentsasthefirstmanifestationofatopyininfantsandchildrenwholaterdevelopAR4

and/orasthma,apatternthathasbeenreferredtoas“theatopicmarch.”1894

5

AlthoughtheassociationbetweenARandADhaslongbeenclinicallyrecognized,theextentof6

thisassociationremainspoorlydefinedduetomethodologicdifferencesandlimitationsofthestudies7

thathaveexaminedthisassociation.537,556,636,1895-1912

[TableX.D.]Furthercompoundingthisproblemis8

thephenotypicdiversityofbothARandAD,andtheobservationthatveryfewstudieshaveadequately9

characterizedthephenotypesoftheirstudypopulations.Additionally,manyepidemiologicstudiesare10

limitedbybeingbasedpurelyonquestionnaireresultsratherthanobjectiveevidenceofallergic11

sensitization,suchasSPTorinvitrotesting.12

ThelargestdatasourceregardingAR-ADassociationcomesfromtheISAACstudy,investigating13

theepidemiologyandetiologyofasthma,rhinitisandADusingstandardmethodologyincluding14

questionnaires,SPT,andflexuraldermatitisexamination.1895

ISAACreportedtheprevalenceofAD15

symptomsin256,410childrenaged6-7yearsin90centersfrom37countries,and458,623children16

aged13-14yearsin153centersfrom56countries.ThesestudiesindicatethatADisamajorpublic17

healthproblemworldwide,affectingapproximately5-20%ofchildrenaged6-7and13-14years.1896

18

WhilelongitudinalstudiesdemonstrateimprovementorresolutionofADwithage,1897

increasing19

severityofADhasbeenshowntocorrelatewithanincreasedriskofdevelopingAR,withprevalenceof20

ARamongpeoplewithADrangingfrom15-61%.1898-1900

21

Thebestevidenceofdiseaseassociationderivesfromstudieswhichcomparetheincidenceand/or22

prevalenceofARinpopulationswithandwithoutAD.Inthisregard,thelimitedevidenceavailable23

suggeststhatADisassociatedwitha2-foldincreaseinARamongpeoplewithADcomparedwiththe24

normalpopulation.1901

Inthisstudy,amongthosechildrenwithpresentorpastAD,60.8%reportedAR25

comparedto31%insubjectswithoutAD.26

27

• AggregateGradeofEvidence:C(Level2b:4studies;Level3b:15studies;Level4:1study;Table28

X.D.).29

30

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TableX.D.Evidencefortheassociationbetweenallergicrhinitisandatopicdermatitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Mortzet

al1901

2015 2b Prospective

cohort

TheOdenseAdolescence

CohortStudy(TOACS).

-Cross-sectionalstudy

(n=15018th-graders)

-15-yearretentioncohort

(n=899)

Questionnaire,interview,

clinicalexam,serumIgE,

patchtest,SPT.

PersistenceofAD,

comorbidities

LifetimeprevalenceofADwas34.1%.

60.8%prevalenceofARinthosewithAD

vs.31%inthosewihtoutAD.Subjects

withADweretwiceaslikelytodevelop

AR.

Sybilskiet

al1902

2015 2b Cross-

sectional

-Questionnaire(n=22,703

Polishsubjects).

-Medicalevaluation

(n=4,783patients).

Questionnaire(response

rate64.4%),SPTwith15

aeroallergens.

DiagnosisofADand

comorbidities.

ADidentifiedin3.91%ofsubjects.

ComorbiditiesofADincludedARin

26.17%.AssociationofADwithrhinitis

subtypes:9.5%withperennialvs.9.3%

withseasonaland9.6%withpolyvalent

vs.9.0%monovalentsensitization

Loweet

al1907

2007 2b Prospective

birthcohortn=620infantswithfamily

historyofatopicdisease.

71.5%hadsufficientdata

foranlalysis.

SPT,interview.

RiskofARdevelopment

amongstinfantswithatopic

ADvs.thosewithnon-

atopicAD.

Childrenwithatopiceczemahada

substantiallygreaterriskofAR(OR2.91;

CI1.48-5.71).Inchildrenwitheczema

withinthefirst2yearsoflife,SPTcan

provideinformationontheriskofAR.

Kuselet

al1909

2005 2b Prospective

birthcohort

(n=263),75.3%ofthe263

followedforthefull5

years.

SPTat6months,2years,5

years.

Evaluationofriskfactorsfor

eczemainrelationtoatopic

status.

Persistenteczemasignificantly

associatedwithAR(OR2.8;CI1.5-5.3).

ARsignificantlyassociatedwithAD(OR

3.5;CI1.7-7.1).ARnotassociatedwith

nonatopicdermatitis.

Schneider

etal1900

2016 3b Cohort n=1,091infantsage3-18

monthswithADfollowed

for3years.

Developmentof

comorbiditiesinpatients

withAD.

18.5%ofpatientsdevelopedAR.Mean

ageatonsetwas2.4+1.3yearsforAR.

Comorbiditiesdevelopedmoreoftenin

infantswithgreaterbaselineADseverity.

Bozek&

Jarzab1903

2013 3b Cross-

sectional

n=7,124Polish

participants;meanage66-

67years;70%participation

Questionnaire,

examination,SPT,tIgE,sIgE

Epidemiologyofofallergic

diseaseinanelderlyPolish

population.

1.6%hadAD/eczema(CI1.1-2.0).

12.6%hadSAR(CI10.8-14.6).

17.1%hadPAR(CI15.9-19.7).

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ICAR:AllergicRhinitis337

Batlles-

Garridoet

al537

2010 3b Cross-

sectional

n=1143participants;10

and11-year-oldschool

children;49.8%response

rate.PartofISAACIIstudy.

Homologated

questionnaire,SPT.

Assessmentofprevalence,

severity,andfactorslinked

torhinitis.

Prevalenceof“rhinitis”duringthe

previousyear:8.9%.Concomitantwith

atopiceczema:3.5%.Significant

associationbetween“rhinitis”andatopic

eczema(OR1.98;CI1.36–2.88).

Batlles-

Garridoet

al1905

2010 3b Cross-

sectional

n=1143participants;10

and11-year-oldschool

children;49.8%response

rate.PartofISAACIIstudy.

Homologated

questionnaire,SPT,physical

examination.

Assessmentofprevalence,

severity,andfactorslinked

toatopiceczema.

Prevalenceofatopiceczema:11.4%.Risk

factorswassevererhinitis(OR7.7;CI

1.79-33).

Peroniet

al1906

2008 3b Cross-

sectional

n=1402preschoolchildren

aged3-5years;response

rate92%.PartofISAAC

study.

SPT.

Assessmentofprevalence

ofAD,comorbiditiesand

riskfactors.

Rhinitissymptomspresentin32.2%AD

children.Allergicsensitizationtoegg,cat,

grasspollenandmites,presenceof

symptomsofrhinitis,andfamilyhistory

ofatopywereriskfactorsforAD.

Karamanet

al1908

2006 3b Cross-

sectional

n=1217childrenin3rd,

4th,and5thgradeinIzmir,

Turkey;responserate

57.6%.

ISAACIImethodology.

Questionnaire,physical

examination,SPT.

Prevalenceandetiologic

factorsofasthma,rhinitis,

andeczema.

Prevalenceofphysician-diagnosedAR:

17%.Prevalenceofphysician-diagnosed

eczema:4.9%.Atopicsensitization

prevalence:8.8%;HDMsensitization

mostfrequent.

Kuyucuet

al556

2006 3b Cross-

sectional

n=2774Turkishschool

childrenaged9-11;

responserate:89.2%.

ISAACIIquestionnaire.

Questionnaire,SPT(subset),

lexuraldermatitis.

Prevalenceofeverrhinitis:36.3%,

currentrhinitis:30.6%,ever

hayfever:8.3%.SPTpositivity:20.4%

amongchildrenwithcurrentrhinitis.

Flexuraldermatitissignificantly

associatedwithcurrentrhinitis.

Yemaneber

hanet

al1911

2004 3b Cross-

sectional

n=12,876participants;

95%ofthoseeligibletook

partinthesurvey.

Questionnaire,SPT(subset).

PrevalenceofAD

symptoms,associationwith

rhinitissymptoms.

LifetimecumulativeprevalenceofAD

symptoms:1.2%.ADsymptomsstrongly

associatedwithrhinitissymptoms(OR

61.94;CI42.66-89.95).

Peroniet

al636

2003 3b Cross-

sectional

n=1402preschoolchildren

age3-5years;response

rate:92%.

ISAACquestionnaire.

Questionnaire,SPT.

Comparisonofdisease

associationsbetween

rhiniticandnonrhinitic

children.

Prevalenceofrhinitisinthelast12

months:16.8%.Rhiniticchildrenhad

significantlymoreAD(22.9%vs.13.9%,

P<0.001).

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ICAR:AllergicRhinitis338

Rhodeset

al1898

2002 3b Longitudinal

cohort

n=100infantsfromatopic

familiesfollowedfor22

years;63%retainedatlast

follow-up.

Examination,SPT,tIgE,

bronchialhyper-

responsivenesstoinhaled

histamine.

Developmentofallergic

rhinitisandasthma

PrevalenceofADpeakedat20%of

childrenby1yearofage,declinedto5%

atendofthestudy.ARprevalenceslowly

increasedovertimefrom3%to15%.

Minet

al1912

2001 3b Cross-

sectional

n=71,120randomly

selectedsubjectsfrom

Koreanotolaryngology

clinics

Questionnaire,

examination,SPT,serum

allergytest.

PrevalenceofPARintertiaryreferral

hospitalsinKoreais3.93%.Associated

atopicdermatitisin20.9%subjectswith

PAR.

Gustafsson

etal1899

2000 3b Longitudinal

cohort

n=94children

withADfollowedfor8

years

tIgE,sIgE,SPT.

Evaluationofdevelopment

ofARandasthma.

ADimprovedin84of92children;

45%developedAR.SeverityofADwasa

riskfactorforsubsequentdevelopment

ofAR.Consistentwithatopicmarch.

Ozdemiret

al1913

2000 3b Cross-

sectional

n=1603collegestudents

inEskisehir,Turkey;94.5%

responserate.

Questionnaire,physical

examinationandSPT

(subset)

Determineprevalenceof

asthma,AR,AD.

Eczemarate:5.4%amongfemales,6.3%

amongmales.Rhinitissymptoms:11.1%

amongfemales,8.9%amongmales.

Garcia-

Gonzalezet

al1914

1998 3b Cross-

sectional

n=365studentsfrom

Malaga,Spain.

Interview,SPT,tIgE,sIgE.

Evaluationofprevalenceof

atopicdisease.

19.9%sufferedfromrhinoconjunctivitis,

and0.8%AD.

Leung&

Ho1915

1994 3b Cross-

sectional

n=2208secondaryschool

students;responserate

over87%.

Questionnaire,SPT(subset).

Evaluationofprevalenceof

asthmaandallergicdisease.

Hayfeverprevalence:HongKong15.7%,

KotaKinabalu11.2%,SanBu2.1%.

Eczemaprevalence:HongKong20.1%,

KotaKinabalu7.6%,SanBu7.2%.

Kidonet

al1910

2005 4 Prospective

caseseries

n=175newlydiagnosedAR

patients;predominantly

Chinese;meanage7.9.

Questionnaire,SPT.

Relativeriskofsensitization

andassociatedriskfactors.

PrevalenceofAD:48%.SPTpositivefor

HDMin85%.ChildrenwithARand

concomitantADshowpreferential

sensitizationtoDermatophagoidesmites.

LOE:levelofevidence;IgE:immunoglobulinE;SPT:skinpricktest;AD:atopicdermatitis;AR:allergicrhinitis;OR:oddsratio;CI:95%confidenceinterval;tIgE;1totalimmunoglobulinE;sIgE:antigen-specificimmunoglobulinE;SAR:seasonalallergicrhinitis;par:perennialallergicrhinitis;ISAAC:InternationalStudyof2AsthmaandAllergiesinChildhood;HDM:housedustmite3

4

5

6

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X.E.Foodallergyandpollen-foodallergysyndrome(PFAS)1

Approximately5-8%ofpatientswithpollenallergywilldevelopaPFAS.1916Patientswithpollen2allergiesmayhaveallergy-relatedmanifestationsafterconsumingspecificfruits,vegetables,nutsor3spices.Theprevalenceofpollen-foodallergiesvarieswiththetypeofpollen.Asmanyas70%ofpatients4withbirchallergywillmanifestafood-relatedsensitivity.1917PFASisanIgE-mediatedreactivity,which5occursintheoralmucosa,leadingtoitching,stingingpain,angioedema,andrarelysystemicsymptoms.6Theterm,“oralallergysyndrome”(OAS),hasalsobeenfrequentlyusedandreferstoapollen-food7allergythatoccursonlyattheleveloftheoralmucosa.OASis,therefore,aspecificmanifestationofthe8broaderPFAS.ThesymptomsofOASmanifestbecauseofIgEspecificfortheoffendingpollencross-9reactingwithhighlyhomologousproteinsfoundinavarietyoffruits,vegetablesandnuts.Themost10commonexampleofthiscross-reactivityinwesternpopulationsisbirchpollenandapples.TableX.E-1.11listscommonpollenallergenswithplant-derivedfoodsthatmaydemonstratecross-reactivity.These12pollen-foodrelationshipshavebeenobservedclinicallyandarealsodemonstratedatamolecularlevel13throughidentificationofthehomologousaminoacids,cross-reactivecarbohydratedeterminantsand14lipidtransferproteins.Thebirch-applesyndromeisduetothehighhomologyofthemajorbirchallergen15Betv1andtheappleallergenMald1.191816

ThediagnosisofPFASistypicallyestablishedbyadetailedhistoryandphysicalexam.Thehistory17shouldbeguidedbyanunderstandingofthepatient’sunderlyingpollenallergyandfoodsthatshare18highlyhomologousproteins.Theclinicianshouldelicitadetailedhistoryoftheallergicresponse19includinganysystemicsymptomsandhistoryofanaphylaxis.Theestimatedrateofsystemicreaction20fromapollen-foodallergyis10%andtheestimatedrateofanaphylaxisis1.7%to10%.1742,1919,192021Systemicsymptomsarethemanifestationofanallergicresponsebyorgansystemsthathavenotcome22intodirectcontactwiththeingestedfoodandinclude:urticaria,nasalcongestion,sneezing,flushing,23wheezing,cough,diarrheaandhypotension.ThegoldstandardforestablishingadiagnosisofPFASisa24double-blindfoodchallenge.However,thisisdifficulttoperformbecauseofthebiasinherenttothe25appearance,textureandtasteoffoods.1921Oralfoodchallenge,SPTandfood-specificIgElevelshave26alsobeenusedtoestablishthediagnosis.Thediagnosticapproachshouldbeguidedbythepatient’s27historyandseverityofallergicresponse.28

ThestandardrecommendationforthetreatmentofPFAShasbeeneliminationoftheoffending29food.Patientsshouldbecounseledontheriskforsystemicandanaphylacticreactions.Patientswitha30historyofsystemicoranaphylacticreactionsshouldbeprovidedwithanepinephrineauto-injector.The31proteinsresponsibleforPFASareoftenlabileandmaybedenaturedbyheat.Thedenaturedproteins32aretypicallynotcross-reactivewiththepollenIgE.Therefore,pollen-associatedfoodsmaybecome33ediblewhenheated.Inonestudy,foodchallengeswereperformedwithcookedapple,carrot,orcelery34inpatientswithatopicdermatitisandbirchpollenallergywhohadOASanddermatologicsymptoms35uponingestionoftherawfoods.Cookedversionsoftheoffendingfoodsdidnotcauseoralallergy36symptoms.1922However,somepatientsdidmanifestalateeczematousskinreaction,whichwaslikelyT-37cell-mediated.[TableX.E-2.]38

ThereisalsooneRCTinagroupof30patientsevaluatingtheuseofanantihistaminetoreduce39PFASsymptoms,whichdemonstratedaclinicallysignificantreductioninallergysymptomscomparedto40

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ICAR:AllergicRhinitis340

placebowheningestingoffendingfoods.1923Theantihistamineusedinthisstudy,astemizole,hasbeen1removedfromthemarketduetoQTintervalprolongationonelectrocardiogram.2

Therehavebeenseveralstudiesevaluatingtheeffectoftargetedimmunotherapyforpollen3allergyatreducingPFASsymptoms.Theresultsaremixed.SeveralsmallcohortstudiesandRCTshave4shownanincreasedtolerancetotheoffendingfoodwhenpatientsaretreatedwithpollenspecific5immunotherapy.1916,1924-1926However,oneRCTfailedtodemonstrateanyimprovedtolerancetoapplein6birchallergicpatientstreatedwithbirchspecificimmunotherapycomparedtoplacebo.1921Onestudy7evaluatingthepersistenceoftoleranceforappleafterbirchimmunotherapydemonstratedthatsome8patientshadanincreasedappletoleranceforupto30monthsafterimmunotherapy.However,there9wasnostatisticallysignificantdifferencebetweentheimmunotherapyandcontrolgroups.192710ImmunotherapyisnotcurrentlyrecommendedforthesolepurposeoftreatingPFAS.Patientsreceiving11immunotherapyforthetreatmentofpollenallergiesshouldbecounseledonthepotentialbut12unsubstantiatedbenefitforimprovedfoodtolerance.13

14• AggregateGradeofEvidence:B(Level2b:8studies;Level4:1study;TableX.E-2.)15

16TableX.E-1.Pollen-foodallergycross-reactivity1928 17Pollen FoodBirch apple,pear,sweetcherry,peach,plum,apricot,almond,celery,carrot,potato,kiwifruit,

hazelnut,mangoJapanesecedar

tomato

Mugwort celery,carrot,mango,spiceGrass melon,watermelon,tomato,potato,kiwifruit,orange,peanutRagweed melon,watermelon,cantaloupe,zucchini,cucumber,bananaPlane hazelnut,apple,lettuce,corn,peanut,chickpea

18

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TableX.E-2.Evidencefortheroleofpollenallergyinpollen-foodallergysyndrome1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusions

Inuoetal1916 2015 2b Cohort ChildrenwithARtoJCPandtomatosensitization(n=23,age6-17

BasophilactivationbytomatoandJCPextract,IgEandIgG4levelsagainsttomatoandJCPantigens

Tomato-specificbasophilactivationdecreasesafterJCP-basedSCIT,suggestingefficacyintreatingPFASsymptomsinpatientswithJCPAR.

Bohleetal1922

2006 2b Case-control PatientswithbirchpollenallergyandOAS

Oralchallengeandbasophilactivationassays

T-cellcross-reactivityoccursindependentlyofIgEcross-reactivity.Theviewthatcookedpollen-relatedfoodscanbeconsumedwithoutallergologicconsequencesshouldbereconsidered.

Bolhaaretal1925

2004 2b RCT PatientswithPFAS(birch-apple,n=25)randomizedto:1.AIT2.pharmacologicintervention

Double-blindplacebo-controlledfoodchallengeandSPT

BirchpollenAITdecreasesallergytofoodscontaininghomologousallergens(apple).

SkamstrupHansenetal1921

2004 2b RCT Patientswithbirchallergy(n=74)randomizedto:1.SLIT2.SCIT3.placebo

Oralchallengewithapplebeforeandaftertreatment

AITwasnotaccompaniedbyasignificantdecreaseintheseverityofallergytoapplecomparedwithplacebo.

Asero1927 2003 2b Case-control 1.birchpollenallergicpatientswithappletoleranceaftercompletinginjectionAIT(n=30)2.birchpollenallergicpatientswithoutappleallergy(n=57)

Prevalenceofappleallergyat30monthsbysymptomsorSPT

Mostpatientshavepropensityforapplere-sensitization.NosignificantdifferencebetweeninprevalenceofPFASbetweentestgroupandcontrolsat30months.Insomepatients,pollenAITcanexertalong-lastingeffectonPFAS.

Asero1924 1998 2b Case-control PatientswithPFAS(birch-apple,n=75)assignedto:1.AIT2.nointervention

OralapplechallengeandSPTat12,24,and36monthsofAIT

AITwithbirchpollenextractseffectivelyreducesclinicalapplesensitivityandskinreactivityinmostcasesafter1yearoftreatment.

Bircheretal1929

1994 2b Case-control Serumsamplesfrom:1.patientswithpollenallergy(n=274)2.patientswithcatallergy(nopollenallergy,n=36)

PresenceofIgEfor6pollenassociatedfoods

ThereisahighprevalenceoffoodspecificIgEinpollenallergicpatients,butnotinnon-pollenallergicpatients.

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ICAR:AllergicRhinitis342

3.patientswithnoallergies(n=55)

Bindslev-Jensenetal1923

1991 2b RCT PatientswithPFAS(birch-hazelnut,n=30)randomizedto:1.antihistamine2.placebo

Symptomscore(0-5rating)withhazelnutprovocationbeforeandafter2weeksoftreatment

Treatmentwithantihistamine(astemizole)significantlyreduced(butdidnoteliminate)theseverityoflocalsymptomsafteringestionofhazelnutscomparedtoplacebo.

Mauroetal1926

2011 4 Cohort Patientswithbirchallergy(n=30)randomizedto:1.SLIT2.SCIT

Oralchallengewithapplebeforeandaftertreatment

Differentdosesofbirchextractmaybenecessarytoinduceappletoleranceamongstpatientwithbirch-applePFAS.

LOE:levelofevidence;AR:allergicrhinitis;JCP:Japanesecedarpollen;Ig:immunoglobulin;SCIT:subcutaneousimmunotherapy;PFAS:pollen-foodallergy1syndrome;OAS:oralallergysyndrome;RCT:randomizedcontrolledtrial;AIT:allergenimmunotherapy;SPT:skinpricktest;SLIT:sublingualimmunotherapy2 3 4

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X.F.Adenoidhypertrophy1

Inchildren,adenoidhypertrophy(AH)andARmayexhibitsimilarsymptomsincludingnasal2obstructionandrhinorrhea.ThepotentialrelationshipbetweenARandAHisexploredinthissection.3Adenoidenlargementmostcommonlybeginsduringinfancy;itcontinuesthroughthefirstfivetosix4yearsoflifeandinvoluteswithpuberty.1930,1931SymptomaticAHaffectsanunknownpercentageof5childrenandmaycontributetoarangeofsymptomsincludingnasalobstruction,nasaldrainage,sleep6disturbance,increasedepisodesofrhinosinusitis,increasedlowerrespiratorytractinfections,worsened7asthma,andeustachiantubedysfunction.1930,19328

CaseseriesevaluatingtherelationshipbetweenAHandallergicsensitizationfallintotwomain9categories:1)cohortsofchildrenwithallergicconditionsassessedforAHor2)childrenidentifiedwith10AHassessedforallergysensitization.Thesemaynotrepresentthesamepopulations.11

ThreestudiesassessingallergicchildrenfoundahigherrateofAHthancontrols(whenpresent).12In2015,1322children(meanage5.9+/-3.3years)treatedfor“allergicconditions”werecomparedto13100age-matchedchildrenwithnoallergicdiseaseforAH.TheyfoundAHwasmoreprevalentinthe14allergicgroup(12.4%)thancontrols(3%)(p<0.0001).AHwasstatisticallyassociatedwithARand15cigarettesmokeexposure(p=0.004).1933Similarly,Dogruetal1934foundthatamong566childrenwithAR16theprevalenceofAHwas21.2%(nocontrolgroup).Additionally,theyreportedthatchildrenwithboth17AHandARhadahigherfrequencyofpersistentrhinitis(p<0.05),moderate/severerhinitis(p=0.005),18andnasalcongestion(p=0.001)thanthosewithARalone.TheAR-onlygrouphadahigherprevalenceof19asthma(p=0.037)and“itchynose”(0.017).Inanotherstudy,adenoidsizeinseasonallyallergicchildren20wasassessedbyModrynskietal,1935concludingthatseasonaladenoidenlargementwasobservedin21birchpollenallergicchildrenmorethancontrolsnotallergicduringthetreepollenseason.Theincreased22adenoidsizeresolvedafterpollenseasoninthestudygroup,andtheseasonalincreaseinadenoidsize23wasnotobservedinbirch-allergicchildrentreatedco-seasonallywithtopicalnasalsteroidand24antihistamines.Thestudywassmall(n=67amongfourgroups)anddidnotstatewhetheritwasblinded.25[TableX.F.]26

ExposureandsensitizationtomoldandAHhasbeenspecificallyexamined.AtanSahinetal193627compared242childrenlivinginalesshumidenvironmentto142childrenlivingonthemorehumid28TurkishMediterraneancoast.Mite-sensitivechildreninthecoastalgrouphadanincreaseinAH29(p=0.01).Thoselivinginthemorehumidcoastallocationdemonstratedincreasedmoldandpollen30sensitizationbutnosignificantcorrelationwithadenoidhypertrophywasfound.Incontrast,Huanget31al1937compared315childrenwithAHandARtoage-matchedcontrolswithAR-alone.Therewasa32higherprevalenceofpositiveskinteststomoldsintheAHgroup(p0.013to<0.0001).Dogruetal193433alsoreportedanincreasedsensitizationtoAlternariainchildrenwithbothAHandARcomparedtoAR34alone(p=0.032),althoughastatisticalcorrectionformultiplevariableswasnotdescribed.35

Instudieswherechildrenwererecruitedbynasalobstruction,thedegreeofAHsometimes36showedeithernorelationshiporaninverserelationshipwiththeprevalenceofallergysensitization.37Cassanoetal1931reportedthattheprevalenceofspecificinhalantIgEsensitizationdecreasedastheAH38increased:AHfirstdegree(37%sensitized),AHseconddegree(35%sensitized),AHthirddegree(19%39sensitized).Karacaetal1938didSPTon82childrenwhopresentedwithupperairwayobstructiontoan40otolaryngologyclinicandcomparedallergysensitizationtoradiographicadenoidsizeandclinically41

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assessedtonsilsize.Theyconcludedthattherewasnotastatisticallysignificantassociationwith1adenoidsize(p=0.195)andanegativecorrelationwithtonsilsize(p=0.045).Themethodsarevagueon2howthecorrelationwasperformedwithtablesshowingpercentagesof“negative”SPTandthetext3incongruentlystating“allofthecaseswerepositiveforatleastoneofthe14allergens”.1938Ameliet4al1939assessed205children(meanage6.7years)withnasalendoscopyandSPTandfoundan5associationbetweennegativeSPTandadenoidvolume(p<0.0001).Inanexceptiontothepreviously6notedstudies,Sadeghi-Shabestarietal1940compared117childrenaged1-14yearswithadenotonsillar7hypertrophyto100controlsofsimilarageforallergenSPT,totalIgEandsmokingparents.Theyreported870.3%oftheadenotonsillarhypertrophygrouphadapositiveSPTcomparedto10%ofthecontrolgroup9(p=0.04);however,theyincludedSPTsforfoods(highestpositiveallergensubgroup)andlatex.10

Inastudythatisdifficulttocategorizebyrecruitment,155children(meanage8.7years)11referredfromPediatricAllergytoOtolaryngologywereassessedbyrigidnasalendoscopyandSPT.12Childrenonallergymedicationwereexcluded.TheyobservedanegativecorrelationbetweenAHand13allergenpositivity(r=-0.208,p=0.009).194114

Immunologicevidenceofallergyinadenoidtissueislimitedintheliterature.Nietal1942founda15higherTh17/TregratioinadenoidtissuefromchildrenwithARthancontrols.Masierietal1943reported16Th1geneexpressioninnon-allergicadenoidtissue,Th1&Th2geneexpressioninadenoidtissueinthose17withARtreatedwithantihistamines,andadownregulationinTh1andTh2geneexpressioninadenoid18tissuefromchildrentreatedwithSLIT.Bothstudiesweresmall.19

Treatmentstudiesarealsolimited.Oneretrospective,uncontrolledstudy(n=47)reported20improvementinrhinitissymptomsinsimilarpercentagesforbothAR(86%)andNAR(76%)after21adenoidectomy.1944TheeffectofINCSonreducingnasalobstructioninthesettingofAH,independentof22allergy,hasbeendemonstratedinsystematicreviews,1932,1945butwhetherthisisduetodecreasein23adenoidsizeislessclearandblindedstudiesareuncommon.194624

Inconclusion,thereisatrendamongallergicchildrenwhoareassessedforAHtohave25increasedprevalenceAHcomparedtonon-allergiccontrols.However,whenchildrenareselectedfor26upperairwayobstructionandthenassessedforinhalantallergysensitivity,aconsistentlyincreased27prevalenceofallergicsensitivityisnotfound.Onepotentialexplanationforthisdiscrepancyisthat28symptomaticAHpeaksinyoungerchildrenthanpediatricAR,withtheallergiccohortshavingahigher29averageage.ThisissupportedintheliteraturebyPagellaetal1947whoretrospectivelyreviewedrecords30ofchildrenreferredtoOtolaryngologyfornasalsymptoms(n=795).Theyfoundanassociationbetween31allergyandAHinchildrenaged8-14years(p=0.0043),butnotforchildrenaged1-7years(p=0.34).32

33• AggregateGradeofEvidence:C(Level4:11studies;TableX.F.)34

35

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TableX.F.Evidencefortheassociationbetweenallergicrhinitisandadenoidhypertrophy1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Dogruetal1934

2017 4 Retrospective,cross-sectional,non-randomized

1.AR2.ARplusAH

Symptoms,allergensensitivities,allergycomorbidities

TheARplusAHgrouphadmoreseveresymptomsthanthegroupwithARalone.

AtanSahinetal1936

2016 4 Case-control Childrenfromhumidvs.lesshumidlocations

AH,SPT,IgE,vitaminD HighhumiditygrouphadhigherprevalenceofAH,higherIgElevels,andanassociationbetweenAHandSPTfordustmite.

Erenetal1941 2015 4 Consecutivecohort 155childrenreferredtoOtolaryngologyfromPediatricAllergy

NasalendoscopyandSPT TherewasanegativecorrelationbetweenAHandSPTpositivity(r=-0.208,p=0.009).

Evicimketal1933

2015 4 Retrospective,cross-sectional,non-randomized

1.AR2.noAR

AH,cigaretteexposure,gender,age,familyhistoryofallergy,asthma,SPT

AHwasmoreprevalentintheARgroup.CigarettesmokeexposurewasassociatedwithAH.

Pagellaetal1947

2015 4 Retrospectivecaseseries

Otolaryngologyclinicfornasalsymptoms(1-7years,n=582;8-14years,n=213)

Allergytesting(n=169),endoscopicadenoidsize,clinicalsymptoms

Inthewholepopulation:AHandARnotassociatedage1-7yrs(p=0.34),AHandARassociatedwithagein8-14year-oldgroup(p=0.0043).

Amelietal1939 2013 4 Consecutivecohort 205childrenwithpersistentupperairwayobstruction

NasalendoscopyandSPT Adenoidvolumeand%withnoassociatedallergy(p<0.001)

Karacaetal1938

2012 4 Caseseries Childrenwithupperairwayobstruction(n=82)

RadiographicAH,clinicaltonsillarhypertrophy,allergysensitivity

Negativecorrelation:SPTandtonsilhypertrophy.Nocorrelation:SPTandAH.

Sadeghi-Shabestarietal1940

2011 4 Cohort 1.adenotonsillarhypertrophy(n=117)2.noadenotonsillarhypertrophy(n=100)

SPTforfood,inhalantandlatex

AdenotonsillarhypertrophyandpositiveSPT70.3%.NoadenotonsillarhypertrophyandpositiveSPT10%.(p=0.04)

Modrzynski&Zawisza1935

2007 4 Prospectiveunblindedcontrolled

1.treesensitive(n=28)2.mugwortsensitive(n=14)3.non-atopic(n=15)4.treesensitive“treated”(n=10)

Acousticrhinometry,endoscopicadenoidexam

Increasedadenoidsizeinbirchallergicchildrenduringpollenseason,decreasedafterpollenseasonandpreventedbyallergyphamacotherpy.

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Cassanoetal1931

2003 4 Cohort(recruitmentnotspecified)

Childrenwithnasalobstruction(n=98,age3-14years)

Nasalendoscopy.“AllergicrhinitiswasdiagnosedbypricktestandRASTin22patients”(20.9%)

%with“allergy”decreasedwithincreasingadenoidsize.Statisticalsignificancenotcalculated.

Huang&Giannoni1937

2001 4 Case-control 1.AR2.ARplusAH

SPT,otitismedia,sinusitis,lowerrespiratorytractinfection,secondhandsmoke,sleepdisorderedbreathing

HigherprevalenceofmoldSPTpositivityandlowerrespiratorytractinfection(insomeagegroups)inARplusAHgroup

LOE:levelofevidence;AR;Allergicrhinitis;AH:adenoidhypertrophy;SPT:skinpricktest;IgE:immunoglobulinE123 4

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X.Associatedconditions1X.G.Otologicconditions2

Eustachiantubedysfunction.EarsymptomsarecommonlyexperiencedbypatientswithAR.Earfullness3andpressure,otalgia,poppingorothersoundsduringswallowing,andtransienthearinglosscanallbe4manifestationsofEustachiantubedysfunction.TheEustachiantubeopensintothenasopharynxandis5indirectcontinuitywiththeupperrespiratorytract.Inflammationofthenasalmucosamayinvolvethe6torustubariusorEustachiantubemucosa,resultinginobstructionthatleadstonegativepressureas7middleeargasesareresorbed.Frequentsniffingorswallowingduringnasalobstructionmaytransmit8negativepressuretothemiddleearspace.ThefrequentlyobservedclinicalassociationofEustachian9tubesymptomsandARiscorroboratedbyhighlevelevidencethatdemonstratesthatinARpatients,10nasalchallengewithhistamineorrelevantaeroallergensresultsintransientEustachiantube11obstruction.1948-1950Thesestudiesusedthe9-stepinflation-deflationswallowtestofEustachiantube12functiondevelopedbyBluestoneandCantekin.1951Thedevelopmentofnegativemiddleearpressure13afterallergenchallengecorrespondswithincreasesinnasalairwayresistance.1952ARappearstoincrease14theincidenceofEustachiantubedysfunctionrelativetocontrolpopulations,1953andnaturalpollen15exposurehasbeenassociatedwithnegativemiddleearpressures1954anddefectsinEustachiantube16opening.1955ThisbodyofevidencesupportsadirectcausalroleforARinsomecasesofEustachiantube17dysfunction.[TableX.G-1.]1819

• AggregateGradeofEvidence:C(Level1b:3studies;Level2b:1study;Level3b:1study;Level4:202studies;TableX.G-1.)21

22Otitismedia.Theroleofallergyasacausativefactorinotitismediahasnotbeenclearlydemonstrated.23Historically,allergywasconsideredanimportantetiologicfactorinotitismedia.However,asclinical24definitionshavebecomemorestringentandevidenceexpectationshaveevolved,ithasbecome25apparentthataclearetiopathogenicconnectionbetweenARandotitismediaisyettobe26demonstrated.Investigationsintotheconnectionbetweenthesetwoconditionshaveexaminedthe27evidencefortype1IgE-mediatedinflammationinthemiddleearspace,epidemiologicassociations28betweenthetwoconditions,andtheeffectofallergytreatmentonotitisoutcomes.Themiddleear29mucosamaybehaveinamannersimilartonasalmucosaandbeasiteoflocalIgE-mediated30inflammatoryreactions.1956-1958However,directintranasalallergenchallengeinallergicsubjectsdoesnot31appeartocauseotitismedia.1948-1950StudiesoftheepidemiologicassociationofARoratopyandotitis32mediawitheffusion(OME)arewidelydiscordant.Somestudieshavefoundnosignificantdifferencein33allergicsensitizationorclinicalallergyinOMEpatientscomparedtocontrolgroups,1959,1960whileothers34haveshownadramaticallyincreasedprevalenceofIgEsensitizationorclinicalallergyinOME35patients,1961-1964orthatARisanindependentriskfactorforthedevelopmentofOME.1965Finally,some36studiessuggestanearlyuniversalassociationofOMEandallergicdisease.1966-1970Theseinconsistencies37intheliteraturearelikelyrelatedtohighlyselectedpatientpopulationsinspecialtypractices,variability38inallergytestmethods,andtheproblemsincumbentinidentifyingappropriatecontrolgroups.Thus,39therelationshipofallergyandOMEremainsunclear.[TableX.G-2.]40

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Ingeneral,randomizedplacebo-controlledtrialshaveshownthatINCSdonotimproveOME1outcomes.1971-1973Also,aCochranesystematicreviewfoundnobenefitofantihistaminesand/or2decongestantsinthetreatmentofOME.Thus,traditionalmedicaltreatmentsforARdonotappeartobe3aneffectiveoptionforOMEandrecentotitismediaCPGsrecommendagainsttheuseofthese4agents.1974Additionalinvestigationisneededtodiscerntheeffectofallergyontheincidenceornatural5historyofOMEandtodetermineifAIThasbeneficialeffects.67

• AggregateGradeofEvidence:C(Level2b:2studies;Level3b:3studies;Level4:11studies;8TableX.G-2.)9

10InnerEarDisease.Meniere’sdiseaseischaracterizedbyrecurringepisodesoftinnitus,hearingloss,11auralfullnessandvertigo.ThebasicpathophysiologicdefectinMeniere’sdiseaseappearstobea12dysregulationofendolymphintheinnerear(endolymphatichydrops).1975Animmunologically-mediated13disturbanceinfluidhandlingbytheendolymphaticsachasbeenpostulatedasonecauseforthe14disease.1976Thenotionthat“allergy”oftheinnerearisacauseofMeniere’sdiseasepredatesour15modernunderstandingoftype1IgE-mediatedhypersensitivity,andisstillevokedasapossiblecausative16orcontributingfactorforthediseaseinsomeindividuals.Indeed,ARhasbeenpostulatedasacauseof17innereardysfunction,1977andaconnectionbetweenallergyandinnereardisorderssuchasMeniere’s18diseaseisplausiblebasedoncompiledcircumstantialevidence.Dereberyandcolleagueshavepublished19studiessuggestingthatinhalantandfoodallergiesaremorecommoninMeniere’spatients,1978andthat20allergytreatmentincludingAITresultsinimprovedMeniere’sdiseasesymptoms.1979,1980However,these21studiesgenerallyprovidelowgradeevidence,andasidefromonesmallstudythatalsofoundahigher22prevalenceofIgE-mediatedhypersensitivityinMeniere’spatients,1981thesefindingshavenotbeen23duplicatedbyothers.Case-controlstudiesexaminingtotalserumIgElevelshaveprovidedconflicting24results.1981,1982Afewsmallstudieshaveshownchangesinobjectiveparameterssuchasthe25electrocochleographicsummatingpotential/actionpotential(SP/AP)ratioinresponsetoaeroallergenor26foodchallengeinMeniere’spatients.1983,1984Overall,theevidencesupportingaconnectionbetween27type1IgE-mediatedhypersensitivityandMeniere’diseaseisoflowgrade,withsubstantialdefectsin28studydesign.[TableX.G-3.]2930

• AggregateGradeofEvidence:C(Level3b:4studies;Level4:4studies;TableX.G-3.))31323334

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TableX.G-1.EvidencefortheroleofallergicrhinitisinEustachiantubedysfunction1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Skoneretal1950

1987 1b Doubleblindcrossoverwithprovocation(histamine)

1.AR(n=5)2.control(n=5)

Inflation-deflationswallowtestofETfunction

AllARsubjectshadETobstructionafterchallenge.

Skoneretal1949

1986 1b Cohortwithintervention(HDMnasalprovocation)

HDMsensitiveARsubjectswithnormalETfunction

Inflation-deflationswallowtestofETfunction

55%ofearsdevelopedETobstructionafterprovocation.

Friedmanetal1948

1983 1b Doubleblindcrossover,nasalprovocation(polleninsufflation)

8adultARsubjectswithragweedortimothygrassallergy

Inflation-deflationswallowtestofETfunction

AllergenintranasalchallengeinducestransientETobstruction

Osuretal1955 1989 2b Cohort ChildrenwithAR,ragweedsensitive(n=15)

9-stepETfunctiontest 60%ofchildrendevelopedETobstructionduringragweedseason.

Lazo-Saenzetal1953

2005 3b Case-control 1.AR(n=80)2.control(n=50)

Tympanometry ARptshadnegativepressure.15%ofARchildrenhadtypeBorCtympanograms.

Knightetal1954

1992 4 Cohort SARpatients Middleearpressureontympanometry,ETDsymptomsduringpollenseason

SymptomsortympanogramevidenceofETDin24%ofsubjects.Increasedto48%inpollenseason.

O’Connoretal1952

1984 4 Cohort ChildrenwithAR(n=37) Middleearpressureandnasalairwayresistanceafterpollenchallenge

69%ofchildrenhadnegativemiddleearpressureafterchallenge.

LOE:levelofevidence;AR:allergicrhinitis;ET:Eustachiantube;HDM:housedustmite;SAR:seasonalallergicrhinitis;ETD:Eustachiantubedysfunction234TableX.G-2.Evidencefortheroleofallergicrhinitisinotitismedia5

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionYeoetal1960 2007 2b Cohortwith

controlgroup1.OME(n=123children)2.controls(n=141children)

History,SPT ARwaspresentinin28%ofOMEgroupvs.24%ofcontrol.

Caffarellietal1959

1998 2b Cohortwithcontrolgroup

1.ARandOME(n=172,4-14years)2.controls(n=200)

SPTandtympanogramforallsubjects

EqualratesofsensitizationbetweenOMEgroupandcontrols.

Chantzietal1961

2006 3b Case-control 1.OME(n=88children)2.controls(n=80children)

Allergyhistoryandtests IgEsensitizationisindependentriskfactorforOME.

Coreyetal1964 1994 3b Case-control 1.OME(n=89children)2.controls(n=59children)

RAST PositiveRAST:61%inOMEgroupvs.41%incontrols

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Borge1963 1983 3b Case-control 1.serousOM(n=89)2.controls(n=67)

Allergyhistoryandtesting 41%ofserousOMpatientshadperennialrhinitisvs.11%ofcontrols.

Kreiner-Molleretal1965

2012 4 Caseseries 6year-oldchildren(n=262) AssessmentforOMEandallergy

39%ofcohorthadOME.ORof3.36forARandOME.

Hurst1966 2008 4 Cohort 1.OMEpatientstreatedwithAIT(n=89)2.OMEpatientsnottreatedwithAIT(n=21)

Resolutionofeffusionordrainageat2-8yearfollow-up

100%ofOMEhadpositiveallergytests;85%ofAITtreatedpatientscured.

Allesetal1969 2001 4 Cohort 3-8year-oldchildrenwithOME AssessmentofAR,Asthma,eczema

57%withpositiveSPT,almostallwithrhinitis.

Hurst1967 1996 4 Cohort 1.OME(n=73)2.controls(n=16)

Allergytests,effusion,ECP

Allergiesin97%ofCOME

Hurst1968 1990 4 Cohort 20OMEpatients,allallergic:17treatedwithAIT,3untreatedcontrols

AITorfoodeliminationdiet

AllptstreatedwithAITorfoodeliminationresolved.

Tomonagaetal1962

1988 4 cohort 259childrenwithOME;605nasalallergy;104controls

Allergytesting;tympanometry

50%ofOMEcaseshadnasalallergyvs.17%control.

Bernsteinetal1956

1985 4 Cohort 100patientswithOME:35allergic,65non-allergic

TotalandspecificIgEinMEEandserum

23%ofallergicOMEpatientshadevidenceoflocalIgE.

Bernsteinetal1957

1983 4 Cohort 77childrenwithrecurrentOMEandhistoryofmyringotomytubes

Allergyevaluation,serum,nasal,MEEtotalIgE

HigherlevelsofIgEinMEEofallergicchildren

Bernsteinetal1958

1981 4 cohort 41patientswithOME:20allergic,21non-allergic

TotalandspecificIgEinMEEandserum

15%ofallergicOMEcaseshadevidenceoflocalIgE.

McMahanetal1970

1981 4 Caseseries 119COMEpatients RASTtest 93%ofCOMEpositivetoinhalantallergens

LOE:levelofevidence;OME:otitismediawitheffusion;SPT:skinpricktest;AR:allergicrhinitis;RAST:radioallergosorbenttest;OM:otitismedia;AIT:allergen1immunotherapy;COME:chronicotitismediawitheffusion;IgE:immunoclobulinE;MEE:middleeareffusion234TableX.G-3.Evidencefortheroleofallergicrhinitisininnereardisease5

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionSinghetal1977 2011 3b Case-control 1.AR(n=30)

2.controls(n=20)Audiometry,OAE,ABR ARsubjectshadevidenceofinnerear

dysfunction.Kelesetal1981 2004 3b Case-control 1.Meniere’sdisease(n=46)

2.controls(n=46)Peripheralbloodlymphocytepopulations,cytokines,

Menierespatientsaremorelikelytohavepositiveallergytest.41%

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allergen-specificandtotalIgElevels

MenierespatientshadelevatedtotalIgE.

DereberyandBerliner1978

2000 3b Case-control 1.Meniere’sdisease(n=734)2.controls(n=172)

Allergysymptoms,historyquestionnaire

Meniere’sdiseasepatientshavemoreARandfoodallergy.

Hsuetal1982 1990 3b Case-control 1.Meniere’sdisease(n=42)2.controls(n=18)

SerumtotalIgE NodifferenceinserumtotalIgEbetweengroups.

Derebery1979 2000 4 Cohort 1.Meniere’sdiseasetreatedwithAITanddiet(n=113)2.controls(n=24)

Self-reportedsymptomsviaposttreatmentsurvey

Allergytreatmentreducedtinnitusandvértigo.

Gibbsetal1983 1999 4 Caseseries 7patientswithMeniere’sandinhalantallergy

ChangeinECoGafterallergenchallenge

57%ofsubjectshad>15%changeinSP/APratioafterchallenge.

DereberyandValenzuela1980

1992 4 Cohort 93Meniere’sdiseasepatientswithsuspectedallergy

intradermaltest,invitroallergytests,serumIgE,provocativefoodtesting,AITresponse

82%hadnormalserumIgE;AITimprovedvertigoin62%

ViscomiandBojrab1984

1992 4 Cohort 5patientswithMeniere’sdiseaseandAR

Allergenchallengewithintracutaneousprovocativefoodtest.>15%changeinSP/APratioonECoG,provocationofMeniere’ssymptoms

6/27intracutaneousfoodchallengeshadinductionofauralsymptomsand>15%changeinSP/APratio

AR:allergicrhinitis;LOE:levelofevidence;OAE:oto-acousticemissions;ABR:auditory-brainstemresponse;IgE:immunoglobulinE;AIT:allergen1immunotherapy;ECoG:electrocochleography234 5

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X.H.Cough1

Coughisasuddenreflexusedtoclearthebreathingpassageofanyforeignparticlesorirritants.2Thereisevidencethatvagalafferentnervesregulateaninvoluntarycough;yet,thereisalsocortical3controlofthisoverallvisceralreflex.1985CoughisoftenconsideredacomorbidityofAR.The4rhinobronchialreflexisoneofthemechanismsthatmayexplaintheabilityofstimulionthenasal5mucosa,suchasanallergen,toresultindirectbronchospasm.1986Theroleofdescendingsecretions6(post-nasaldrip)fromtheuppertolowerairwaysisanothertheory.Whilemanypractitionerslinkpost-7nasaldrainagetocough,thereisverylittleevidencetosupportthis.Whenfunctioningnormally,the8vocalfoldsprotectthelowerairwaysfromupperairwaysecretionsandforeignbodies.Thirdly,adirect9mechanismduetodiffuseinflammationandactivationofeosinophilsmayberesponsibleforthe10commonupperandlowerairwaymanifestations.TheAmericanCollegeofChestPhysiciansevidence-11basedclinicalpracticeguidelinesoncoughsuggestthetermupperairwaycoughsyndrome,ratherthan12post-nasaldripsyndrome,whendiscussingacoughoriginatingfromtheupperairwayduetothevarying13possiblecauses.198514

ARandasthmamaycoexistandmayindeedproduceacontinuumofthesameairway15disease.1167AssociationswithcoughinARpatientscanrelatetotheirunderlyingasthmaoraseasonal16asthmaduringpeakpollenseason.TheAsiaPacificBurdenofRespiratoryDiseasesstudy,a1000-person17crosssectionalobservationalstudy,revealedthatcoughwastheprimaryreasonforavisittothe18physicianforpatientswithasthmaandorCOPD.However,ARpatientsweremorelikelytopresentwith19classicwatery,sneezing,runnynose.Thestudyhoweverdidfindthat33.5%ofpatientswerediagnosed20withcombinationsofrespiratorydisease;themostfrequentwasasthmaandAR.1987,1988[TableX.F.]21

WhilepatientswithARthathaveconcomitantchestsymptomssuchascoughoftendohave22asthma,seasonalasthmaand/oranonspecificbronchialhyper-reactivity,manystudiesshow23generalizedinflammationoftheupperairwaysextendingtothelowerairways.Thereisacomplex24interplaybetweencellsandinflammatorycytokinesandhenceoneshouldconsidertheupperandlower25airwaysasasingleuniquefunctionalunit.1986Thekeypathogenicmechanismistheinflammationofthe26upperairwayswithextensiontothelowerairwaysandtheinductionofasystemicdysregulationviaa27complexinteractionbetweencellsandinflammatorycytokines.198628

ManypatientswithARandcoughdonothavethediagnosticairflowobstructionorthe29reversibilityofforcedexpiratoryvolumein1second(FEV1)followingbronchodilatoradministrationto30makeadiagnosisofasthma.1167Krzych-Faltaetal1989performedanasalchallengein30patientswithAR.31Extra-nasalsymptomswerenoted,includingacoughandbreathlessness,especiallyinthosewithPAR.In322000,Chakiretal1990performedhistochemicaltestsonbronchialbiopsiesofpatientswithARbut33withoutcurrentorhistoryofasthma.Theydemonstratedincreasednumbersoflymphocytes,eosinophil34recruitmentandIL-5expressioninthebronchialmucosaafterexposurewithnaturalpollen.1990This352000studyfollowedapriorinvestigationofdepositionoftypeIandIIIcollagensandfibronectinby36bronchialmyofibroblastsinARpatients.1991Thisissuggestiveofanactivestructuralremodelingofthe37lowerairwaysinARpatientsthatissimilartoasthmapatientsbutlesssevere.Inaddition,Budayetal199238demonstratedthatguineapigssensitizedtoHDMhadasignificantlyenhancedcoughresponse39comparedtothosethatwerenotsensitized;however,airwayresistancesdidnotchange.Thisstudyis40relevanttohumans,sincetheneurophysiologyofthevagusnerveintheguineapigisthoughttobe41

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closesttohumans.ThesestudiesdemonstratethatAR,unrelatedtoasthma,canindeedresultin1bronchialinflammation,possiblelowerairwayremodelingandultimatelyasymptomofcough.2

Alargescalecross-sectional,multinationalobservationalstudysetouttodeterminethe3symptomofcoughasitrelatestorespiratorydiseasesintheAsia-Pacificregion.Withover5,2504patientsenrolled,thestudyfoundthat47%ofpatientswithARfrequentlyreportedcoughasa5symptom;however,only11%ofthesepatientshadcoughasthemainreasonforseekingmedical6care.1993Thenumberswere61%and33%,respectively,forpatientswithasthmaandcough.Ina7prospectivestudywith2,713ARpatients,Heetal1994foundtheoccurrenceofcomorbidities,including8cough,tograduallyincreasefrommildintermittent,tomildpersistent,tomoderate-severeintermittent,9andmoderate-severepersistentAR.199410

ThereislowlevelevidencethatassociatesARwithcoughor,morecommonly,coughasa11comorbidityofAR.1990-1992TheseverityofARmayaffectitsmanifestationtowardsupperairwaycough12syndrome.1994ARisoftenacomorbiditywithasthmawhichalsohasanincreasedcorrelationwithcough.13Theexactpathwaysandmechanismsbywhichtheunifiedairwayfunctionscontinuetounfold.1415

• AggregateGradeofEvidence:C(Level2b:2studies;Level3b:2studies;Level4:4studies;Level165:1study;TableX.H.).17

18

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TableX.H.Evidencefortheassociationbetweenallergicrhinitisandcough1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Heetal1994

2016

2b Cohort,prospectivenonrandomized

ARpatients(n=2,713)

sIgE,questionnaire

D.pteronyssinuswasthemostcommonoffendingallergen.TheoccurrencecoughincreasedwithincreasingARseverity.

Passalietal1986

2011

2b Individualcohort 159patientsfrom9otolaryngologyandpulmonarycenters

Standardizationofdiagnosticapproachforrhino-bronchialsyndrome

Increasedfrequencyofrhino-bronchialsíndromewithallergicdisease(37.9%vs20.9%).Coughwasafrequentsymptom(96%).

Krzych-Faltaetal1989

2015 3b Case-control 1.AR(n=30)2.control(n=30)

Safetyevaluationofnasalallergenchallenge

Inearlyphaseofallergicreaction,extra-nasalsymptomswereobserved(cough,breathlessness),especiallyinPARpatients.

Chakiretal1991

1996 3b Case-control 1.nonasthmaticsubjectswithSAR(n=8)2.allergicasthmatics(n=6)3.controls(n=5)

Immunohistochemicalanalysisofthedistributionofcollagens,laminin,andfibronectininbronchialbiopsyspecimens

ContentoftypeIandIIIcollagenswasincreasedinrhiniticsubjectscomparedwithcontrols,suggestingactivestructuralremodelinginthelowerairwaysofARpatients.

Choetal1993

2016 4 Caseseries

Patientsages≥18yearswithasthma,AR,COPD,orrhinosinusitis(n=5250)

Patientandphysiciansurveys

Reportofcoughsymptom:COPD(73%),followedbyasthma(61%),rhinosinusitis(59%),AR(47%).Coughasthemainreasonforseekingmedicalcare:COPD(43%),asthma(33%),rhinosinusitis(13%),andAR(11%).

Ghoshaletal1988

2016 4 Caseseries

Patientsages≥18yearswithasthma,AR,COPD,orrhinosinusitis(n=1000)

Surveyregardingsymptoms,healthcareresourceutilization,workproductivity,activityimpairment.Costanalysis.

AsthmawasthemostfrequentprimarydiagnosisfollowedbyAR,COPD,andrhinosinusitis.33.5%patientswerediagnosedwithcombinationsofthefourrespiratorydiseases.

Linetal1987

2016 4 Caseseries

Patientsages≥18yearswithasthma,AR,COPD,orrhinosinusitis(n=1001)

Surveyregardingsymptoms,healthcareresourceutilization,workproductivity,activityimpairment.

ARwasthemostfrequentprimarydiagnosis(31.2%).CoughwastheprimaryreasonforthemedicalvisitforpatientswithasthmaandCOPD.NasalsymptomsweretheprimaryreasonsforARandrhinosinusitis.

Chakiretal1990

2000 4 Caseseries

AdultswithSAR,non-asthmatic(n=12)

Immunohistochemistryandcytokineexpressionofbronchialbiopsyspecimens.

Naturalpollenexposureisassociatedwithanincreaseinlymphocytenumbers,eosinophilrecruitmentandIL-5expression

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ICAR:AllergicRhinitis355

inthebronchialmucosaofnon-asthmaticsubjectswithSAR.

Budayetal1992

2016

5 Benchresearch 30guineapigsdividedintotheHDM-sensitizedgroup,OVA-sensitizedgroup,andcontrolgroup

SymptomsofARinducedbyintranasalapplicationof15μl0.5%HDMandcoughchallengeswithcitricacid.Airwayresistancemeasurements.

BothHDMandOVA-sensitizedgroupsshowedasignificantlyenhancednasalreactivityandcoughresponsecomparedwithcontrols.Theairwayresistancedatadidnotshowsignificantdifferences.

LOE:levelofevidence;AR:allergicrhinitis;sIgE:allergen-specificimmunoglobulinE;PAR:perennialallergicrhinitis;SAR:seasonalallergicrhinitis;COPD:1chronicobstructivepulmonarydisease;IL:interleukin;HDM:housedustmite;OVA:ovalbumin23

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X.I.Laryngealdisease1

ARhasbeenimplicatedasacauseoflaryngealdisease.However,furtherunderstandingofits2preciserolehasbeenlimited.Whilepreviousresearchhasprovidedanecdotalevidenceofarelationship3betweenthetwo,establishingacausalrelationshipbetweenARandlaryngealdysfunctionhadproven4difficultduetoalackofsafeandeffectivemodelsforstudyingthelarynx.1995Findingsoflaryngeal5inflammationhavelargelybeenattributedtolaryngopharyngealreflux(LPR),butvariousetiologiesmay6contributetolaryngealdysfunction.7

Vocaldysfunctioncanhaveasignificantpsychosocialimpactonpatients,includingthosewith8AR.SeveralstudieshavereportedhigherVoiceHandicapIndex(VHI)scoresinpatientswithAR9comparedtocontrolsubjects.1996-1999Dysphoniaisparticularlydisturbingforprofessionalvoiceusers.10Singerswithself-perceivedvoiceissueswere15%morelikelytohaveARthansingerswithoutvocal11complaints.2000ThelikelihoodofARincreasedasthenumberofvocalsymptomsincreased.2000When12comparingpatientswithARandNARtocontrolpatients,Turleyetal2001foundthatdysphoniawasmore13prevalentinpatientswithasthma.ApriorstudyhadsimilaroverallfindingsinpatientswithARwhile14controllingforasthma.2002StudieshavereportedtheadverseeffectsofARonvoice-relatedQOL,and15Turleyetalvalidatedthisbyshowingthatpatientswhoreportedpoorrhinitis-relatedQOLon16questionnairesalsohadpoorvoice-relatedQOLandmoreseverechroniclaryngealsymptoms.1996,1998,200117Thegreaterthedegreeofallergenload,thegreaterseverityofvocalsymptoms.1999Overall,patients18withvocaldysfunctionhaveahigherthananticipatedincidenceofARandviceversa.1999,2001,2002[Table19X.I.]20

Allergiclaryngitiscanbedifficulttodistinguishfromotherlaryngealinflammatorydisorders,21includingLPR,duetothelimitationsofcurrentdiagnosticmethods,whichoverallhavepoorspecificity22andinter-raterreliability.Inastudyofpatientspresentingwithvoicecomplaints,Randhawaetal200323notedthattwo-thirdsofpatientswerediagnosedwithallergieswhereasonlyone-thirdwerediagnosed24withLPR.However,allergytestingmaybepositiveinupto46%ofthegeneralpopulation.2004Laryngeal25findingsinARandLPRcanbeindistinguishableandincludelaryngealedema,excessivemucus,vocalfold26erythema,andarytenoiderythema.1995,2005AstudybyErenetal2005supportedthisdiagnosticchallenge27indemonstratingnosignificantdifferenceintheappearanceofthelarynxbetweenallergy-positiveand28LPR-positivesubjects;however,thickendolaryngealmucushasbeenshowntobeapredictorofallergy.29BelafskyandcolleaguesexaminedtheeffectsofDermatophagoidesonthelaryngealmucosaofguinea30pigsandfoundanincreaseineosinophiliacomparedtothoseexposedtosaline,whichprovidessome31supportforetiologiesotherthanrefluxcontributingtolaryngealdisease.2006,2007Incontrast,Krouseet32al1998wereunabletodemonstrateadifferenceinacousticandspeechaerodynamictestingor33videostroboscopicevaluationbetweenallergicpatientscomparedtocontrolsubjects.34

Despiteanecdotalevidenceimplicatingtheroleofallergiclaryngitisinlaryngealdysfunction,35therehavebeenlimitedstudiesdemonstratingadirectcausalrelationshipbetweenthetwo.Three36studieswithsimilardesignevaluatedthesymptomsandlaryngealappearanceandfunctioninpatients37withprovenallergiesexposedtodirectlaryngealstimulationbythenebulizedallergen38Dermatophagoidespteronyssinus.2008-2010Initially,Reidyetal2009wereunabletofindanysignificant39differencebetweenantigenandplacebochallengedsubjectsonanyoftheevaluatedmeasures,40includingVHI,SinusSymptomsQuestionnaire,laryngoscopicfindings,andacousticandspeech41

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aerodynamictesting.Inasubsequentstudy,Dworkinetal2010increasedtheconcentrationofallergenin1theantigenicsuspensionandnotedanincreaseinendolaryngealmucusinadditiontocoughingand2throatclearing.Thestudywasterminatedprematurelyduetoadversepulmonaryreactionsattributed3tothehigherantigenconcentration,anditispossiblethatthelowerairwayreactivitycontributedtothe4visualizedendolaryngealmucus.2010Rothetal2008thenperformedastudyusingsimilarmethodsbut5isolatedthelarynxbyutilizinganosecliptoensureoralinhalationandbyeliminatingpatientswith6reactiveairwaysbasedonmethacholinechallengetesting.Theydemonstrateanapparentcausal7relationshipbetweenallergenstimulationandimpairedvocalfunction.20088

ThereismountingevidencesuggestingarelationshipbetweenARandlaryngealdysfunction.9Therehavenotbeenconsistentlyreportedlaryngealfindingsspecifictoallergiclaryngitis,thoughthick10endolaryngealmucousshouldraisesuspicionforallergyasacause.Althoughitsexactroleinthe11pathophysiologyoflaryngitishasyettobefullyelucidated,ARshouldbeconsideredinthedifferential12diagnosisofpatientswithvocalcomplaintsasitmayhaveimplicationsontreatmentoflaryngeal13disease.1415

• AggregateGradeofEvidence:C(Level2b:8studies;Level3a:1study;Level3b:4studies;Level164:5studies;TableX.I.).17

18

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TableX.I.Evidenceforanassociationbetweenallergicrhinitisandlaryngealdisease1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

Rothetal2008

2013 2b RCT Patientsrespondingtoanadvertisement

Effectofallergenonlarynx

Relationshipbetweenallergenexposureandimpairedvocalfunctionindependentofasthmaornasalexposure.

Dworkinetal2010

2009 2b RCT AdultstestingpositiveforHDMallergy:1.D.pteronyssinuschallenge2.placebochallenge

Effectofallergenonlarynx

Laryngealabnormalitiesoccurredsecondarytolowerrespiratorystimulation.

Krouseetal1998

2008 2b Prospectivecohort

1.HDMallergy,(+)skintest2.NoHDMallergy

Effectofallergenonlarynx

SignificantchangesinVHIinpatientswithHDMallergy.FindingspresentamongsubjectswithoutsymptomaticLPR/GERD.

Millqvistetal1996

2006 2b Case-control 1.birchpollenallergy2.control

Prevalenceofvocaldysfunction

StatisticallysignificantdifferencesinVHIbetweenallergicpatientsandcontrols.

Reidyetal2009

2003 2b RCT 1.D.pteronyssinuschallenge2.placebochallenge

Effectofallergenonlarynx

Nosignificantdifferencesbetweenantigenandplaceboexposedsubjectsonanymeasure.

Roth&Ferguson1995

2010 3a Systematicreview

Relationshipofallergyandlaryngealdisease

notapplicable Furtherinvestigationsintomechanismsmediatinglaryngealresponsetoallergyarenecessary.

Brooketal2011

2015 3b Retrospectivecase-control

1.atopicpatients2.non-atopicpatients

EndoscopicfindingsinAR

Findingswithinthenasopharynx,ratherthanthelarynx,arepredictiveofpositiveatopicstatus.

Kocetal1997

2014 3b Case-control 1.ARpatients2.control

LaryngealfindingsinAR

ARpatientshadhigherincidenceofdysphoniaandmeanVHI.

TurleyRetal2001

2011 3b Case-control 1.patientswithrhinitissymptoms,(+)and(–)allergytests2.patientswithoutrhinitis

Prevalenceofdysphonia

PatientswithARorNARhadhigherprevalenceofdysphoniaversuscontrols.Patientswithworserhinitissymptomshadworsevoice-relatedQOLandmoreseverechroniclaryngealsymptoms.

Hamdanetal2000

2006 3b Retrospectivecase-control

1.singerswithoutvocalsymptoms2.singerswithvocalsymptoms

Symptomprevalence

IncidenceofARinsingersishigh.Occultallergiesmayaffectprofessionalvoice.

Brooketal2004

2016 4 Retrospectivecaseseries

Patientsundergoinginvitroallergytesting

Symptomprevalence

Yieldofinvitroallergytestingforlaryngealsymptomscomparabletoothercommonallergytestingindications.

Erenetal2005

2014 4 Caseseries PatientsreferredfromallergyclinicwithSPTtesting

LaryngealfindingsinARandLPR

Thickendolaryngealmucuswasapredictorofallergy.NoassociationbetweenallergicsensitizationandpresenceofLPR.Nosignificantdifferenceinlaryngealappearancebetweenallergy-positiveandLPR-positiveindividuals

Randhawaetal2003

2010 4 Caseseries Patientswithprimaryvoicedisorderorglobussensation

PrevalenceofARandLPR

ThreetimesasmanypatientshadallergiescomparedwithLPR,nostatisticalsignigicance.

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Randhawaetal1999

2010 4 Crosssectional

Patientspresentingtorhinologyclinic,nopriorvoice-relatedsymptoms

Allergyandvocaldysfunctionassociation

Thedegreeofallergenloadcorrelateswiththeseverityofvocalsymptoms,asperanincreaseinscoreontheVHI.

Simbergetal2002

2007 4 Crosssectional

1.allergypatientsinAITprogram2.non-allergiccontrols

Symptomprevalence

Individualswithallergieshadmoreseverevocalsymptomsthannon-allergiccontrols.PatientswhohadundergoneAIT>2yearshadfewersymptoms.

Jackson-Menaldietal2012

1997 4 Prospectivecohort

Subjectsreferredtovoicecenterwithavoiceproblem

AssociationbetweenAR,LPR,laryngealfindings

Couldnotdeterminecausativerelationshipbetweenallergyandvocalsymptoms.

Belafskyetal2006

2015 5 Benchresearch

Guineapigsexposedto:1.saline(allergencontrol)+filteredair(pollutioncontrol)2.HDM+filteredair3.saline+combustionparticulates4.HDM+combustionparticulates

Meaneosinophilicprofileintheglottic,subglottic,trachealepitheliumandsubmucosa

IronsootandHDMresultedineosinophiliainglottic,subglottic,andtrachealepitheliumandsubmucosa.

Mouadebetal2007

2009 5 Benchresearch

GuineapigsexposedtointranasalHDMfor9weeks

Histopathologicfindings

TwiceasmucheosinophiliainsupraglottisinanimalsexposedtoHDMversussaline.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;HDM:housedustmite;VHI:VoiceHandicapIndex;LPR:laryngopharyngealreflux;GERD:1gastroesophagealreflux;AR:allergicrhinitis;NAR:non-allergicrhinitis;QOL:qualityoflife;SPT:skinpricktest;AIT:allergenimmunotherapy234 5

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X.J.Eosinophilicesophagitis1

Eosinophilicesophagitisisanallergicinflammatoryconditionoftheesophaguswithinfiltrationof2eosinophils.Symptomsincludedysphagia,heartburn,andvomiting.Severalstudieshaveexaminedthe3prevalenceofclinician-diagnosedARandaeroallergensensitizationinpatientswitheosinophilic4esophagitis(EoE).[TableX.J.]AmongbothpediatricandadultpatientswithEoE,ithasconsistentlybeen5foundthat50to75percenthaveAR.2013-2020Althoughmanyofthesestudieswerecaseseries,the6consistencyofthefindingsstronglysuggeststhatmostpatientswithEoEhavecomorbidAR.7 TheevidenceforanassociationbetweenenvironmentalallergiesandEoEpathogenesisisless8clear.Afewcaseseries,amongbothchildrenandadults,haveobservedseasonalpeaksofEoEdiagnosis9inthespringandsummer.2021-2023OneofthesestudiesfoundthatEoEdiagnosiswascorrelatedwith10grasspollencounts.2021Anothershowedthatesophagealeosinophiliaonbiopsieswasleastintensein11thewinter.2023ThereisonereportedcaseofapediatricEoEpatientwhosesymptomsflaredseasonally,12inwhombiopsiesrevealedmoderatetosevereesophagealeosinophiliaduringpollenseasonswithnoor13mildinflammationinwintermonths,withnochangeindiet.2024Anothercasereportdescribed14resolutionofesophagealeosinophiliainapediatricpatientwithEoEanddustmitesensitizationaftera15courseofhigh-dosedustmiteimmunotherapy.2025Therefore,thereisverylimitedobservationaldata16suggestingapotentialassociationbetweenaeroallergensandEoEpathogenesis,butmorestudyis17needed.18

• AggregateGradeofEvidence:C(Level3a:1study;Level4:12studies;TableX.J.)19 20

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TableX.J.Evidencefortheassociationbetweenallergicrhinitisandeosinophilicesophagitis1Study Year LOE Studydesign Studygroups Clinicalendpoint Conclusion

EvidenceofARprevalenceinpatientswithEoEFurutaetal

2015 2007 3a Systematic

review

Adultandpediatric

patientswithEoE

Demographicandclinical

characteristics

50-80%hadARandsensitizationto

aeroallergens

Spergeletal2013

2009 4 Caseseries PediatricpatientswithEoE

(n=562)

Demographicandclinical

characteristics

68%wereatopicand43%hadAR

Roy-Ghantaet

al2014

2008 4 Caseseries AdultpatientswithEoE

(n=23)

Demographicandclinical

characteristics

78%hadallergicrhinitis;86%weresensitized

toaeroallergens

Assa’adetal2016

2007 4 Caseseries PediatricpatientswithEoE

(n=89)

Demographicandclinical

characteristics

79%weresensitizedtoenvironmental

allergens

Plaza-Martinet

al2017

2007 4 Caseseries PediatricpatientswithEoE

inSpain(n=14)

Demographicandclinical

characteristics

93%hadARandsensitizationtoaeroallergens

Sugnanametal2018

2007 4 Caseseries PediatricpatientswithEoE

inAustralia(n=45)

Demographicandclinical

characteristics

93%hadAR

RemediosMet

al2019

2006 4 Caseseries AdultpatientswithEoEin

Australia(n=26)

Demographicandclinical

characteristics

77%wereatopicand54%hadAR

Guajardoetal2020

2002 4 Caseseries Adultandpediatric

patientswithEoEin

worldwideregistry(n=39)

Demographicandclinical

characteristics

64%hadAR

EvidenceforroleofaeroallergensinEoEpathogenesisRamirez&

Jacobs2025

2013 4 Casereport Apediatricpatientwith

EoEanddustmiteallergy

treatedwithdustmite

immunotherapy

Eosinophilsonesophageal

biopsies

Resolutionofesophagealeosinophiliawas

observedaftercourseofdustmite

immunotherapy

Moawadetal2021

2010 4 Caseseries AdultpatientswithEoE

(n=127)

SeasonofEoEdiagnosisand

correlationwithpollen

counts

Highestpercentage(33%)diagnosedinspring

andlowest(16%)inwinter;significant

correlationwithgrasspollencounts

Almansaetal2022

2009 4 Caseseries AdultpatientswithEoE

(n=41)

SeasonofEoEdiagnosis 68%diagnosedinspringandsummerversus

32%infallandwinter

Wangetal2023

2007 4 Caseseries PediatricpatientswithEoE

(n=234)

SeasonofEoEdiagnosisand

biopsyfindingsbyseason

Significantlyfewerpatientsdiagnosedwith

EoEinWinterversusspring,summer,andfall;

leastintenseesophagealeosinophiliainwinter

Foggetal2024

2003 4 Casereport PediatricpatientwithEoE Seasonalbiopsyfindings Increasedesophagealeosinophiliaduring

pollenseasons

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LOE:levelofevidence;AR:allergicrhinitis;EoE:eosinophilicesophagitis1

2

3

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X.K.Sleepdisturbanceandobstructivesleepapnea1

Nasalcongestionisreportedbyasmanyas90%ofARpatients.2026Nocturnalnasalcongestion2cansignificantlyaffectsleepquality.NasalobstructionduetoARhasbeenwellestablishedasacauseof3sleepdisruption.707,714,2026Onepopulation-basedsurveystudyofchildrenwithARidentifiedsleep4disturbanceduetoARasasignificantfactoraffectinghealth-relatedQOL.2027Diminishedsleepquality5resultingfromARhasbeenshowntonegativelyimpactworkperformanceandproductivity.2028Another6population-basedstudyfoundthatpatientswithARweremorelikelytoreportsufferingfrominsomnia,7snoringandsleepapneathancontrolgroups.727TheseverityofARsymptomswasalsoshowntoaffect8thedurationofsleep,frequencyofdaytimesomnolenceandsleeplatency.TheinfluenceofARonsleep9ismultifactorial.Upperairwayresistance,biochemicalandhormonaleffects,andpharmacologic10interventionsallplayaroleinalteringsleep.Alargepopulation-basedsurveyofARpatients11demonstratedastrongcorrelationbetweenARdiseaseseverityandsleepdisturbance.679Thestudy12showedthatincreasingseverityofARsymptomscausedworsesleepquality.13

WhenestablishingadiagnosisofAR,theimpactofallergysymptomsonsleepshouldbe14assessedbydetailedhistory.Thereareseveraldifferentinstruments,whichhavebeenusedtoassess15theimpactofARonsleep.Theseinclude:theESS,StanfordSleepinessScore,JenkinsQuestionnaire,16PittsburghSleepQualityIndex,UniversityofPennsylvaniaFunctionalOutcomesofSleep,Sleepscale17fromtheMedicalOutcomeStudy,SleepDisordersQuestionnaire,ThePediatricSleepQuestionnaire,18andThePediatricDaytimeSleepinessScale.Thesemetricsmaybeusefulinestablishingbaseline19symptomsandmonitoringaresponsetotreatment.20

TherehavebeenseveralstudiesthathaveinvestigatedtherelationshipbetweenARandsleep-21disorderedbreathing(SDB).[TableX.K.]SDBreferstoaspectrumofconditionsincludingprimary22snoring,upperairwayresistancesyndrome,andobstructivesleepapnea.Inapopulation-basedanalysis,23Youngetal714foundthatmoderate-to-severeSDBwere1.8timesmorefrequentinparticipantswith24nasalcongestionduetoallergy.InasmallcaseseriesofpatientswithSARwhounderwentrepeatPSG,25patientswithsymptomaticARhadanaverage1.7obstructiveapneasperhourofsleepthatdecreased26to0.7perhourwhenpatientsweresymptomfree.718A2011case-controlstudyassessingdifferencesin27polysomnographybetweenpersistentARsufferersandhealthycontrolsfoundnostatisticallysignificant28differenceinapnea-hypopneaindex(AHI)betweenthetwogroups.720Thereweremodestdifferencesin29sleepefficiency,arousalindex,andsnoringtime.30

AstandardapproachtothetreatmentofARshouldhelptodecreaseoralleviatethesymptoms31thatadverselyimpactsleep.Medicationsthatacttotreatnasalcongestionaretypicallyeffectiveat32improvingsleepquality.INCShavebeenshowntoimprovenasalcongestion,daytimesomnolence,and33sleepquality.2029INCSarealsothoughttoimprovesleepqualitybyreducingpro-inflammatorycytokines,34whichhavebeenshowntonegativelyimpactsleep.2030TherehavebeenfiveRCTsassessingtheefficacy35ofICSonnasalcongestionandsleep.673,706,707,1275,1276Theresultsofallfivestudiesdemonstratedan36improvementinsleepqualityandsleep-relatedQOLmetrics.Ameta-analysisbyWeineretal1297found37thatINCSweremoreeffectivethanoralantihistaminesattreatingnasalblockage,althoughtherewas38nosignificantdifferencesbetweentreatmentsonnasalresistance.39

ThepharmacologicinterventionsusedinthetreatmentofARmayalsohaveconsequenceson40sleep.ThefirstgenerationH1antagonistsareknowntocausesedationduetothecapabilityofcrossing41

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ICAR:AllergicRhinitis364

theblood-brainbarrierandactingasadepressantonthecentralnervoussystemleadingto1drowsiness.2031Whilethismaybeadesirablesideeffectatbedtime,itisanundesirableconsequencefor2daytimesymptommanagement.Thesecond-generationH1antagonistshavelesspropensityforcrossing3theblood-brainbarrierandarethereforelesssedating.Fexofenadineandloratadinearereportedasthe4leastsedatingoralantihistaminetreatmentoptions.2032,2033Patientsshouldbecounseledregardingthe5potentialforsedationwhentakingoralH1antihistamines.TherehasbeenoneRCTstudylookingat6pseudoephedrine(takeninthemorning)andtheimpactonsleepquality,daytimesomnolence,and7fatigue.Thestudyfoundnosignificantnegativeorpositiveimpactonallmeasurescomparedto8placebo.2030Therewasastatisticallysignificantbeneficialeffectonnasalcongestion.9

TheimpactofARonsleepshouldbeassessedbyhistory,sleepandQOLquestionnairesand10carefulphysicalexamination.AstandardtreatmentalgorithmforsymptomaticmanagementofAR11shouldbeeffectiveatimprovingthesymptomswhichadverselyaffectsleep.INCSarethemosteffective12pharmacologictherapyforalleviatingnasalcongestion.Patientstreatedwithoralantihistaminesshould13bemindfulofthepotentialforsedation.1415

• AggregateGradeofEvidence:B(Level1b:5studies;Level2b:1study;Level2c:5studies;Level163b:7studies;Level4:2studies;TableX.K.)17

18

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TableX.K.Evidenceforanassociationbetweenallergicrhinitisandsleepdisturbance1

Study Year LOE Studydesign Studygroups Clinicalendpoint ConclusionYamadaetal

673 2012 1b RCT PAR,adults

(n=57)

ESSandRQLQ INCSmometasonesignificantlyimproves

nasalsymptoms,QOL,sleepquality,and

upperairwaycondition.

Meltzeretal1276

2010 1b RCT PAR,adults

(n=30)

PSG,ESS,RQLQ-SandWPAI-AS INCSmometasoneimprovesnasal

symptomsandsleepiness.

Craigetal1275

2003 1b RCT AR,adults

(n=32)

PSG,ESS,RQLQ,directsleep

questionsindailydiary

ImprovementinNCandsleepwith

treatmentwithtopicalnasalfluticasone

Hughesetal706 2003 1b RCT PAR,adults

(n=22)

ESS,SSS,FOSQ,RQLQ INCSbudesonideimproveddaytime

fatigue,somnolenceandqualityofsleep.

Craigetal707 1998 1b RCT PAR,adults

(n=20)

Directsleepquestionsindailydiary Improvementincongestionandsleep

withtreatmentwithINCSflunisolide.

Sherkatetal2030

2011 2b RCT AR,adults

(n=14)

ESS,PSQI,FOSQ,RQLQ,NRQLQ,

PennsylvaniaQualityofLife,direct

sleepquestionsindailydiary

Sleepqualityisnotsignificantlyaffected

bypseudoephedrine.

Colasetal726 2012 2c Population-based AR,adults

(n=2,275)

PSQIRQLQ,directsleepquestions

basedonEpworthscale

Moderate-severeARandNCare

associatedwithworsesleepquality.

Meltzeretal2027

2009 2c Population-based AR,children

(n=1,004)

Directsleepquestionsbytelephone

interviews

ARdisruptsthepatternandqualityof

sleep.

Bousquetet

al2028

2006 2c Population-based AR,adults

(n=3,052)

JenkinsQuestionnaire,RQLQ,WPAI-

AS

TheseverityoftheARhasmoreeffecton

QOLandsleep,thantheduration

(intermittent/persistent).

Legeretal727 2006 2c Population-based AR,adults

(n=591)

ESS,SleepDisordersQuestionnaire,

ScoreforAllergicRhinitis

Alldimensionsofsleepwereimpairedby

AR,andmoreimpairedinsevereARthan

inmildAR.

Youngetal714 1997 2c Population-based Adults(n=4,927) PSG,directsleepquestions Moderate-to-severeSDBwas1.8times

morefrequentinparticipantswithNC

duetoallergy.

Ishmanetal2034

2012 3b Case-control AR,children

(n=21)

PSQ,PDSS,ObstructiveSleepApnea-

18

ARchildrenhavehigherSDBand

sleepinessscores.

Mengetal720 2011 3b Case-control PAR,adults

(n=98)

PSG DifferencesinmostPSGparameters

includingsleepefficiency,arousalindex,

andsnoringtime,statisticallysignificant

(thoughclinicallymodest).

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ICAR:AllergicRhinitis366

Yukseletal2035

2009 3b Case-control SAR,children

(n=14)

PSQIandActigraphy Sleepdysfunctionscores,sleeplatency

andfragmentationindexaresignificantly

higherintheARgroup.

Benninger&

Benninger2036

2009 3b Case-control AR,adults

(n=701)

RSDIandsleepquestionbyRSDI ARhasasignificantnegativeimpacton

sexualfunction,sleepandfatigue.

Meltzeretal2037

2009 3b Case-control AR,adults

(n=7,024)

MOS-SleepandmRQLQ ARadverselyaffectsQOLandsleep

parameters.

Shedden2026

2005 3b Case-control AR,adultsand

children

(n=2,355)

Directsleepquestions >80%withNCaffectedinsomewayat

night,primarilycausingthemtowakeup

ormadeitdifficulttofallasleep.

Stucketal731 2004 3b Controlledtrial SAR,adults

(n=50)

ESS,SF-36,PSG SARincreasesdaytimesleepiness,and

worsensQOL.

Stulletal682 2009 4 Caseseries AR,adults

(n=404)

MOS-Sleep,NRQLQ,WPAI-AS,

PANAS-X

ThosewithmoresevereNCorocular

symptomsreportpoorerscoresonsleep

domains.

McNicholaset

al718

1982 4 Case-series SAR,adults

(n=7)

PSG InpatientswithSAR,obstructivesleep

apneasaremorefrequentduringa

periodofsymptomaticnasalobstruction.

LOE:levelofevidence;RCT:randomizedcontrolledtrial;PAR:perennialallergicrhinitis;ESS:EpworthSleepinessScale;RQLQ:RhinoconjunctivitisQualityofLife1

Questionnaire;INCS:intranasalcorticosteroid;QOL:qualityoflife;AR:allergicrhinitis;PSQI:PittsburghSleepQualityIndex;FOSQ:FunctionalOutcomesof2

Sleep;NRQLQ:NocturnalRhinoconjunctivitisQualityofLifeQuestionnaire;PSG:polysomnogram;RQLQ-S:StandardizedRhinoconjunctivitisQualityofLife3

Questionnaire;WPAI-AS:WorkProductivityandActivityImpairmentQuestionnaire-Allergy-Specific;NC:nasalcongestion;SSS:StanfordSleepinessScore;4

SDB:sleepdidorderedbreathing;PSQ:PediatricSleepQuestionnaire;PDSS:PediatricDaytimeSleepinessScale;SAR:seasonalallergicrhinitis;RSDI:5

RhinosinusitisDisabilityIndex;MOS-Sleep:SleepScalefromtheMedicalOutcomesStudy;mRQLQ:mini-RhinoconjunctivitisQualityofLifeQuestionnaire;SF-6

36:MedicalOutcomesStudy36-itemShortFormhealthsurvey;PANAS-X:PositiveandNegativeAffectSchedule-ExpandedForm7

8

9

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XI.Knowledgegapsandresearchopportunities1

TheexistingliteraturerelatedtoARisquitedeepincertainareasbutnotablylackinginothes.2[TableXI.]WecontinuetoseemoreandmorecitationsrelatedtoAReveryyear,yettheprocess3undertakentoproducethisICAR:ARdocumenthasidentifiedsomeimportantknowledgegaps.The4sectionsbelowhighlighttheneedforfutureresearchrelatedtospecificaspectsofAR.567XI.A.EpidemiologyandRiskFactors8

StudieshavepreviouslybeenundertakentodeterminetheprevalenceofARinvariouspartsof9theworld.Whilethedatafromthesestudiesisoftenquoted,itislimitedbyitsmethodologyrelating10primarilytosurveys(sometimescomplementedbyallergensensitivitytesting).Ourworldisbetter11connectedbytechnologytodaythanithadbeenpreviously.Weshouldleveragethesecapabilitiesto12betterunderstandtheepidemiologyofAR.Researchopportunitiesinclude:1314

• ImprovedunderstandingoftheincidenceandprevalenceofARanditsphenotypes(i.e.SAR,15PAR,IAR,PER)worldwide.16

• ImprovedunderstandingofARvariationbygeographicregion,patientage,andsex.17• Evaluationofclimatechangeanditseffectonthepatternanddegreeofallergenexposure.18

19OurunderstandingoftheriskfactorsforthedevelopmentofARshouldalsobeimproved.While20

certainareas(i.e.earlychildhoodexposuretopetsasariskfactorvsprotectivefactor)haveseen21numerousarticlespublished,thedataishighlyconflicting.Inotherareas,suchasearlyexposureto22pollensandmites,thedataismorelimited.Geneticstudiesprovidesomenotableevidenceforpotential23ARriskbutfunctionaldataneedstobeexpanded.Researchopportunitiesinclude:24

25• UnderstandingtheroleofcandidategenealterationsinthepathophysiologyofARviafunctional26

characterization.27• Investigationofepigeneticmechanismstoprovideafunctionalexplanationbetweengene-28

environmentinteractionsandARdiseasedevelopment.29• Improvedunderstandingofenvironmentalexposuresasarisk/protectivefactorforARdisease30

development,especiallyindiversegeographiclocations.31• FurtherstudyoftheroleofpollutantsandtobaccosmokeinthedevelopmentofARandinthe32

severityofallergicrhinitissymptoms.33• GreaterelucidationoftheenvironmentalriskfactorsandprotectivefactorsforAR,particularly34

exposuretopets,HDM,andbreastfeeding.35• LongitudinalstudyevaluatingriskfactorreductionanditseffectontheincidenceofAR.36

3738XI.B.EvaluationandDiagnosis39

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EvaluationofthepatientwithsuspectedARclassicallyreliesonathoroughhistory,often1reinforcedbyfindingsonphysicalexamination.Thediagnosisisfurthersupportedwithskinorinvitro2testingmethods.Thesetechniqueshavebeenratherdependable,providedobjectivetestingis3correlatedtothepatient’sclinicalsymptomsandnotusedinisolationtodetermineatreatmentplan,as4therearedistinctdifferencesbetweensensitizationandclinicalallergy.Asnewertestingmethodsgain5theirfooting,wehavetheopportunitytobringthemtowidespreadclinicalpracticewithsolid6supportingevidence.Researchopportunitiesinclude:78

• Improvedcharacterizationofnewertestingtechniques(i.e.nasalsIgE,BAT)inlargerpopulations9toprovidestandardizationforincorporationintomainstreamclinicalpractice.10

• NeedforcomparativestudiesforIDTandsingledilutionintradermaltesting.11• Furtherstudyoftheroleofsingleintradermaltestingafteranegativepricktest.12• DevelopmentofstandardizedtestingandinterpretationoftestingforLAR,aswellasfurther13

definingtheclinicalutilityoftesting.14• FurtherelicudationofclinicalusesforCRDinpatientmanagement.15• Needforinternationalconsensusonallergenunitsinantigenstandardization.16

1718XI.B.Management19

ThereareseveraloptionsformanagementoftheARpatient.AllergenavoidanceandEC20strategiesareoftendiscussed,yethigh-levelevidenceisfrequentlylacking,especiallyasitrelatestoAR21symptomcontrol.ManypharmacotherapyoptionshaveveryhighLOEs,whichishelpfulaswestriveto22choosethebestdrugoptionstocontrolpatientsymptoms.SCITandSLITalsohaveveryhighLOEsin23general,yetspecificissuesrelatedtoAITmanagementcouldbebolsteredwithadditionalevidence.24Researchopportunitiesinclude:2526

• ImprovedunderstandingoftheimpactofECstrategiesonARsymptomcontrolandrescue27medicationuse,especiallyforcockroach,pet,andpollenallergens.28

• ImprovedunderstandingofthepolyallergicARpatientandappropriateAITregimensinthis29population.30

• ImprovedunderstandingandcharacterizationofILITforpossibleroutineclinicalapplication.31• Furtherstudyofcomparativeefficacy/effectivenessofSLITversusSCIT.32• FurtherstudyofAITwithmultipleallergens.33• ImprovedunderstandingofcosteffectivemanagementforoptimalARcontrolandtheuseof34

multimodalitytherapy,includingcombinationsofpharmacotherapyandAIT.35• FurtherstudyofthecomparativeeffectivenessofvariousARtreatments.36

3738XI.B.Associatedconditions39

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TheevidencesupportinganassociationbetweenARandnumerousotherconditionsisweakor1conflicting.ThereisclearlyaneedtobetterdefinetherelationshipbetweenARandseveralofthe2comorbiditiesidentifiedinthisdocument(especiallyrhinosinusitis,otitismediawitheffusion,cough,3laryngealdisease,andeosinophilicesophagitis),andtofurtherdelineatetherolethatARtreatmenthas4forpotentialimprovementofassociatedconditions.567Conclusion.Insummary,theauthorsofICAR:ARhaveworkedtocollatethebestexternalevidencefor8variousaspectsofAR,providingevidencegradesandrecommendationswhereappropriate.Fromthis9evidence,knowledgegapsandresearchopportunitieshavebeenidentified.Itisoursincerehopethat10theICAR:ARdocumentwillbeareferenceforunderstandingthecurrentARevidenceandaspringboard11forfutureinvestigation.12 13

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TableXI.Aggregategradesofevidenceandrecommendationlevels1Topic #oflisted

studiesAggregategrade

ofevidenceRecommendation

levelInterpretation

RiskfactorsforARGenetics 5(GWAS) C ----- Somegeneshavebeenassociatedwith

developmentofARandotheratopicdiseases.Inuteroorearlyexposure(mites) 6 C ----- Datainconclusive.Inuteroorearlyexposure(pollen) 2 C ----- Datainconclusive.Inuteroorearlyexposure(animaldander) 39 C ----- Datainconclusive.Inuteroorearlyexposure(fungalallergens) 13 C ----- Datainconclusive.Restricteddiet(duringpregnancyandearlychildhood)

5 A ----- MaternaldietrestrictionwhilechildtheisinuterodoesnotinfluencethedevelopmentofAR.FoodallergyduringchildhoodisariskfactorforAR.

Pollution 14 C ----- Datainconclusive.Tobaccosmoke 9 A ----- Moststudiesfoundnoassociationbetweenactive

orpassivetobaccosmokeexposureandAR.Specificpatientpopulationsandtemporalvariations(i.e.lengthofexposure)shouldbefurtherevaluated.

Socioeconomicstatus 10 C ----- MoststudiesshowanassociationbetweenhighSESandAR,butthisisnotaconsistentfindingacrossallstudies.

PotentialprotectiveeffectonthedevelopmentofARBreastfeeding 2(SRs) C Option Optionforbreastfeedingforthespecificpurpose

ofARprevention.Ingeneral,breastfeedinghasbeenstronglyrecommendedduetoitsmultiplebeneficialeffects.

Petexposure 6 C ----- NoevidencethatpetavoidanceinchildhoodpreventsARlaterinlife.Earlypetexposure,especiallydogexposureinnon-allergicfamiliesearlyinchildhood,maybeprotective.

Microbialdiversity(“HygieneHypothesis”) 15 B ----- Microbialdiversityoftheskin,airwaysandgutisimportantforthepreventionofsensitizationandallergicdiseaseinpopulations.

Diseaseburden

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Qualityoflife 33 B Recommendation ARhassignificanteffectsongeneralanddisease-specificQOLTreatmentofARisrecommendedtoimproveQOL.

Effectonsleep 46 B Recommendation ARhassignificantnegativeeffectsonsleep.TreatmentofARisrecommendedtodecreasesleepdisturbance.

EvaluationanddiagnosisClinicalexamination(historyandphysical) 4 D Recommendation Despitethelackofstudiestoaddressclinical

examinationinthediagnosisofAR,historytakingisessentialandphysicalexaminationisrecommended.Multiplepriorguidelinedocumentssupportthisrecommendation.

Nasalendoscopy 5 D Option EvidencedoesnotsupporttheroutineuseofnasalendoscopyfordiagnosingAR.However,itmaybehelpfulinrulingoutothercausesofsymptoms.

Radiologicimaging 0 N/A Recommendagainst

RadiologicimagingisnotrecommendedforthediagnosisofAR.

Useofvalidatedsurveyinstruments 10 A Strongrecommendation

ValidatedsurveyinstrumentscanbeusedtoscreenforAR,followtreatmentoutcomes,andasanoutcomemeasureforclinicaltrials.

Skinpricktesting 8 B Recommendation SPTisrecommendedforevaluationofallergensensitivitiesinappropriatelyselectedpatients.ThepractitionermaydecidewhetherskinorinvitrosIgEtestingisbestinanindividualpatient.

Skinintradermaltesting 17 B Option IntradermaltestingmaybeusedtodeterminespecificairborneallergensensitizationforindividualssuspectedofhavingAR.

Blendedskintestingtechniques 5 D Option MQTisaskintestingtechniquethatmaybeusedtodetermineasafestartingdoseforAIT.

SerumtotalIgE(tIgE) 15 C Option SerumtIgEisanoptiontoassessatopicstatus.Serumantigen-specificIgE(sIgE) 7 B Recommendation SerumsIgEtestingisrecommendedforevaluation

ofallergensensitivitiesinappropriatelyselectedpatients.ThepractitionermaydecidewhetherskinorinvitrosIgEtestingisbestinanindividualpatient.

Correlationbetweenskinandinvitrotesting 19 B ----- Studiesdifferregardingtheconcordanceofvariousallergytestingmethods.

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NasalsIgE 24 C Option NasalsIgEisanoptioninpatientswithsuspectedorknownLARtoaidindiagnosisorguidetherapy.

Basophilactivationtest 12 B Option BATmaybeusedfordiagnosiswhenfirst-linetestsarediscordant,andformonitoringresponsetoAIT.

Nasalprovocationtesting 4 C ----- NPThasbeenemployedfordiagnosisofoccupationalrhinitisandLAR.

Nasalcytology 4 C ----- Nasalcytologyisaninvestigationaltool,ratherthandiagnostic.

Nasalhistology 11 B ----- NasalhistologyisusedforresearchonthepathophysiologyofARbutisnotroutinelyusedinclinicalpracticeforthediagnosisofAR.

Management–avoidancemeasuresandenvironmentalcontrolsHousedustmite 12 B Option ConcomitantuseofacaricidesandECmeasuresis

anoptionforthetreatmentofAR.Cockroach 11 B Option Combinationofphysicalmeasures(baittraps,

housecleaning)andeducationisanoptionforARmanagementrelatedtocockroachexposure.

Pets 3 B Option PetavoidancesandECstrategiesareanoptionforARrelatedtopets.

Pollenandoccupationalallergens 3 B Option PollenandoccupationalallergenavoidancebyECstrategiesareanoptionforthetreatmentofAR.

Management–pharmacotherapyOralH1antihistamines 21 A Strong

recommendationNewer-generationoralH1antihistaminesarestronglyrecommendedforthetreatmentofAR.

OralH2antihistamines 6 B Norecommendation

AvailabledatadoesnotadequatelyaddressthequestionofbenefitinthetreatmentofAR.

Intranasalantihistamines 44 A Recommendation Intranasalantihistaminesmanybeusedasfirst-orsecond-linetherapyforthetreatmentofAR.

Oralcorticosteroids 9 B Recommendagainst

Duetotherisksoforalsteroiduse,alongwiththeavailabilityofotherpharmacotherapyoptions,thistherapyisnotrecommendedforroutineARmanagement.

Injectablecorticosteroids 13 B Recommendagainst

Duetotherisksofinjectablesteroiduse,alongwiththeavailabilityofotherpharmacotherapyoptions,systemicorintraturbinateinjectionofcorticosteroidsisnotrecommendedfortheroutinetreatmentofAR.

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Intranasalcorticosteroids 53 A Strongrecommendation

INCSshouldbeusedasfirst-linetherapyinthetreatmentofAR.

Oraldecongestants 9 B Option Optionforpseudoephedrineforshort-termtreatmentofARsymptoms.

Recommendagainst

Recommendagainstphenylephrine,asithasnotbeenshowntobesuperiortoplacebo.

Topicaldecongestants 4 B Option OptionfortopicalINDuseintheshort-termfornasaldecongestion.ChronicusecarriesariskofRM.

Leukotrienereceptorantagonists 31 A Recommendagainst

LTRAsshouldnotbeusedasmonotherapyinthetreatmentofAR.

Cromolyn(DSCG) 22 A Option DSCGmaybeconsideredinthetreatmentofAR,particularlyforpatientswithknowntriggerswhocannottolerateINCS.

Intranasalanticholinergic(IPB) 14 B Option IPBnasalspraymaybeconsideredasanadjuncttoINCSinPARpatientswithuncontrolledrhinorrhea.

Omalizumab 6 A Noindication OmalizumabisnotapprovedbytheUSFDAforthetreatmentofARalone.

Nasalsaline 12 A Strongrecommendation

NasalsalineisstronglyrecommendedaspartofthetreatmentstrategyforAR.

Probiotics 28 A Option ProbioticsmaybeconsideredinthetreatmentofAR.

Combination:oralantihistamineandoraldecongestant

21 A Option Option,particularlyforacuteexacerbationswithaprimarysymptomofnasalcongestion.

Combination:oralantihistamineandINCS 5 B Option Combinationequivocalovereitherdrugalone.Combination:oralantihistamineandLTRA 13 A Option CombinationisanoptionforARmanagement,

particularlyinpatientswithcomorbidasthmawhodonottolerateINCSandarenotwell-controlledonoralantihistaminemonotherapy.

Combination:INCSandintranasalantihistamine

12 A Strongrecommendation

StrongrecommendationforcombinationtherapywhenmonotherapyfailstocontrolARsymptoms.

Acupuncture 15 B Option Inpatientswhowishtoavoidmedications,acupuncturemanybesuggestedasapossibletherapeuticadjunct.

Honey 3 B Norecommendation

Studiesareinconclusiveandheterogeneous.

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Herbaltherapies ----- ----- Norecommendation

Multipledifferentherbsstudied,withfewstudiesforeachspecifictherapy.Resultsareinconclusive.

Surgicaltreatment 12 C Option TurbinatereductionmaybeconsideredinARpatientswithnasalobstructionwhohavefailedmedicalmanagement.

Management–allergenimmnuotherapySubcutaneousimmunotherapy 8 A Strong

recommendationStrongrecommendationforSCITinpatientsunabletoobtainadequaterelieffrompharmacotherapyandthosewhowouldbenefitfromsecondarydisease-modifyingeffects.

Sublingualimmunotherapy 25 A Strongrecommendation*

StrongrecommendationforSLITinpatientsunabletoobtainadequaterelieffrompharmacotherapy.*SpecificrecommendationsforvariousSLITpreparationsandtreatmenteffectsgiveninSectionIX.D.4.

Trans/epicutaneousimmunotherapy 4 B Recommendagainst

Limitedstudiesshowvariableeffectiveness,alongwithadversereactions.Trans/epicutaneousimmunotherapyisnotrecommendedforARtreatment.

Intralymphaticimmunotherapy 7 B Option Pendingadditionalstudies,ILITmaybeaviableoptionforARtreatmentintheclinicalpopulation.

AssociatedconditionsAsthma–associationwithrhinitis 7 C ----- AsthmaisassociatedwithARandNAR.Asthma–rhinitisasariskfactor 13 C ----- ARandNARareriskfactorsfordevelopingasthma.Asthma–benefitofARtreatment ----- ------ ----- SeeSectionX.A.4.forspecificrecommendations.Acuterhinosinusitis 5 C ----- ARisthoughttobeadisease-modifyingfactorfor

ARS.Recurrentacuterhinosinusitis 2 D ----- Datainconclusive.Chronicrhinosinusitiswithoutnasalpolyps 10 D ----- Conflictingevidencefor/againstanassociation.Chronicrhinosinusitiswithnasalpolyps 21 D ----- Conflictingevidencefor/againstanassociation.Conjunctivitis 7 C ----- ACisafrequentlyoccurringcomorbidityofAR.Atopicdermatitis 20 C ----- ThereisevidenceforanassociationbetweenAR

andAD.FoodallergyandPFAS 12 B ----- Thereisevidenceforalinkbetweenpollenallergy

andPFAS.Adenoidhypertrophy 11 C ----- Datainconclusive.Otologicconditions–Eustachiantubedys. 7 C ----- ThereisacausalroleforARinsomecasesofETD.

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Otologicconditions–otitismedia 16 C ----- RelationshipbetweenARandOTEisunclear.Otologicconditions–Meniere’sdisease 8 C ----- Evidenceforanassociationisoflowgrade,with

substantialdefectsinstudydesign.Cough 9 C ----- LowlevelevidenceforanassociationbetweenAR

andcough.Laryngealdisease 18 C ----- Thereissomeevidenceforanassociationbetween

ARandlaryngealdisease.Eosinophilicesophagitis 13 C ----- Limitedobservationaldatasuggestsapotential

associationbetweenaeroallergensandEoEpathogenesis.

SleepdisturbanceandOSA 20 B ----- SleepdisturbanceisassociatedwithAR.AR:allergicrhinitis;GWAS:genome-wideassociationstudies;SES:socioeconomicstatus;SR:systematicreview;QOL:qualityoflife;SPT:skinpricktest;sIgE:1antigen-specificimmunoglobulinE;MQT:ModifiedQuantitativeTesting;AIT:allergenimmunotherapy;tIgE:totalimmunoglobulinE;LAR:localallergicrhinitis;2BAT:basophilactivationtest;NPT:nasalprovocationtesting;EC:environmentalcontrols;INCS:intranasalcorticosteroids;IND:intranasaldecongestants;RM:3rhinitismedicamentosa;LTRA:leukotrienereceptorantagonist;DSCG:disodiumchromoglycate;IPB:ipratropiumbromide;PAR:perennialallergicrhinitis;US:4UnitedStates;FDA:FoodandDrugAdministration;SCIT:subcutaneousimmunotherapy;SLIT:sublingualimmunotherapy;ILIT:intralymphaticimmunotherapy;5NAR:non-allergicrhinitis;ARS:acuterhinosinusitis;AC:allergicconjunctivitis;AD:atopicdermatitis;PFAS:pollen-foodallergysyndrome;ETD:Eustachiantube6dysfunction;OTE:otitismediawitheffusion;EoE:eosiniphilicesophagitis7 8

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2021. MoawadFJ,VeerappanGR,LakeJMetal.Correlationbetweeneosinophilicoesophagitis9andaeroallergens.AlimentPharmacolTher2010;31:509-515.10

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6 7

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ICAR:AllergicRhinitisAuthorDisclosureofConflictofInterest12Authors:34 AUTHOR NOTHING

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1 SarahK.Wise,MD,MSCR Medtronic Consultant Elron Consultant OptiNose Advisoryboard2 SandraY.Lin,MD AgencyforHealthcareResearch

andQualityResearchfunding

3 ElinaToskala,MD,PhD,MBA Medtronic Researchfunding4 RichardR.Orlandi,MD Medtronic Consultant BioInspire Consultant 480Biomedical Consultant5 CezmiA.Akdis,MD DavosDiagnostics Companyshares Allergopharma Researchfunding ActellionAG Researchfunding6 JeremiahA.Alt,MD,PhD UniversityofUtahProgramin

PersonalizedHeathandtheNationalCenterforAdvancingTranslationalSciencesoftheNIH

Researchfunding

NationalInstituteofAllergyandInfectiousDiseases

Researchfunding

NationalInstituteofDeafnessandOtherCommunicationDisorders

Researchfunding

Medtronic Consultant GlycoMiraTherapeutics Consultant Spirox Consultant AngioSonic Consultant7 AntoineAzar,MD RelezTherapeutics Researchfunding Shire Consultant8 ClausBachert,MD,PhD Sanofi Consultant GlaxoSmithKline Consultant Novartis Consultant AstraZeneca Consultant Allakos Consultant9 FuadM.Baroody,MD Allergan Consultant GlaxoSmithKline Consultant MEDA Speaker10 G.WalterCanonica,MD A.Menarini Researchorspeakeroradvisory ALK-Abello Researchorspeakeroradvisory Anallergo Researchorspeakeroradvisory AstraZeneca Researchorspeakeroradvisory BoehringerIngelheim Researchorspeakeroradvisory ChiesiFarmaceutici Researchorspeakeroradvisory Circassia Researchorspeakeroradvisory Genentech Researchorspeakeroradvisory Guidotti-Malesci Researchorspeakeroradvisory GlaxoSmithKline Researchorspeakeroradvisory HALAllergy Researchorspeakeroradvisory MEDA Researchorspeakeroradvisory Merck Researchorspeakeroradvisory

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MerckSharp&Dome Researchorspeakeroradvisory Novartis Researchorspeakeroradvisory Recordati-InnuvaPharma Researchorspeakeroradvisory Roche Researchorspeakeroradvisory Sanofi-Aventis Researchorspeakeroradvisory Stallergenees Researchorspeakeroradvisory UCBPharma Researchorspeakeroradvisory UriachPharma Researchorspeakeroradvisory Teva Researchorspeakeroradvisory ThermoFisher Researchorspeakeroradvisory Valeras Researchorspeakeroradvisory Vibor-Pharma Researchorspeakeroradvisory11 ThomasChacko,MD XXX 12 CemalCingi,MD XXX 13 GiorgioCiprandi,MD Stallergenes Consultant14 JacquelynneCorey,MD Greer-Stallergenes Consultant,speaker’sbureau CSL Advisoryboard Behring Advisoryboard IntersectENT Advisor15 LindaS.Cox,MD XXX 16 PeterSocratesCreticos,MD Stellergenes-Greer Researchfunding,consultant Circassia Researchfunding,consultant ASIT:Allergytherapeutics Consultant Merck Researchfunding NationalInstituteofAllergyand

InfectiousDiseasesResearchfunding

Patient-CenteredOutcomesResearchInstitute

Researchfunding

17 AdnanCustovic,MSc,DM,MD,PhD

Novartis Consultant

BoehringerIngelheim Consultant ALK-Abello Consultant ThermoFisher Speaker GlaxoSmithKline Speaker18 CeceliaDamask,DO AudigyMedical Consultant ALK Speaker19 AdamDeConde,MD IntersectENT Consultant StrykerEndoscopy Consultant Olympus Consultant20 JohnM.DelGaudio,MD Spirox Researchfunding IntersectENT Stockholder21 CharlesS.Ebert,Jr.MD,MPH Acclarent Consultant Medtronic Consultant22 JeanAndersonEloy,MD XXX

23 CarrieE.Flanagan,MD XXX 24 WytskeJ.Fokkens,MD MEDA Researchfunding Sanofi Researchfunding BioInspire Researchfunding GlaxoSmithKline Researchfunding25 ChristineFranzese,MD ALK Advisoryboard Greer Advisoryboard,speaker26 JanGosepath,MD,PhD XXX 27 AshleighHalderman,MD XXX 28 RobertG.Hamilton,PhD XXX 29 HansJürgenHoffman,BSc,PhD XXX

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30 JensHohlfeld,MD XXX 31 StevenM.Houser,MD XXX 32 PeterH.Hwang,MD Olympus Consultant Medtronic Consultant 480Biomedical Consultant BioInspire Consultant Arrinex Consultant33 CristoforoIncorvaia,MD Bayer Consultant Stallergenes Consultant34 Prof.DeborahJarvis XXX 35 AyeshaN.Khalid,MD,MBA CastleCreekPharma Consultant 480Biomedical Consultantandequityholder SmithandNephew Consultant Stallergenes-Greer Consultant,speaker HackingMedicalInstitute Consultant,co-founder36 MarittaKilpenäinen,MD,PhD XXX 37 Todd.T.Kingdom,MD XXX 38 HeleneKrouse,PhD,ANP-BC XXX 39 DesireeLarenas-Linnemann,MD UCB Advisoryboard,speaker GlaxoSmithKline Advisoryboard,speaker,

researchfunding MEDA Advisoryboard,speaker Astra-Zeneca Advisoryboard,speaker,

researchfunding Armstrong Advisoryboard,speaker Grunenthal Advisoryboard,speaker Novartis Advisoryboard,speaker,

researchfunding BoehringerIngelheim Advisoryboard,speaker,

researchfunding Pfizer Advisoryboard,speaker DBV Advisoryboard,speaker Teva Researchfunding Chiesi Researchfunding40 AdrienneM.Laury,MD XXX 41 StellaE.Lee,MD Sanofi-Aventis Researchfunding Allakos Researchfunding42 JoshuaM.Levy,MD,MPH XXX 43 AmberU.Luong,MD,PhD ENTvantageDiagnostics Advisoryboard,research

funding AerinMedical Consultant 480Biomedical Consultant Medtronic Consultant IntersectENT Researchfunding Allakos Researchfunding44 BradleyF.Marple,MD XXX 45 EdwardD.McCoul,MD,MPH Acclarent Consultant46 K.ChristopherMcMains,MD XXX 47 ErikMelén,MD,PhD XXX 48 JamesW.Mims,MD XXX 49 GiannaMoscato,MD XXX 50 JoaquimMullol,MD,PhD ALK-Abello Consultant,speaker Sanofi Advisoryboard,consultant Mylan Consultant,researchfunding MEDA Consultant,researchfunding UCB Speaker

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Uriakh Consultant,researchfunding51 HaroldS.Nelson,MD XXX 52 MonicaPatadia,MD XXX 53 RubyPawankar,MD,PhD XXX 54 OliverPfaar,MD,PhD ALKAbello Consultant,advisoryboard,

researchfunding Allergopharma Consultant,speaker,research

funding AllergyTherapeutics/Bencard Advisoryboard,speaker,

researchfunding Anergis Consultant,researchfunding BiotechTools Researchfunding Circassia Researchfunding HALAllergy Consultant,advisoryboard,

speaker,researchfunding LaboratoriosLETI/LETIPharma Consultant,speaker,research

funding Lofarma Consultant,speaker MobileChamberExperts Advisoryboard Stallergenes-Greer Consultant,advisoryboard,

researchfunding55 MichaelP.Platt,MD,MSc PluralPublishing Bookroyalties56 WilliamReisacher,MD Allovate Advisoryboard,stockholder Directallergy Advisoryboard CornellUniversity Patent:U.S.8.993.347B257 CarmenRondón,MD,PhD XXX 58 LukeRudmik,MD,MSc BioInspire Advisoryboard 480Biomedical Consultant59 MatthewRyan,MD XXX 60 JoaquinSastre,MD,PhD ThermoFisher Consultant Sanofi Consultant ALK Consultant LETI Consultant Stallergenes Consultant61 RodneyJ.Schlosser,MD Olympus Consultant Arrinex Consultant Entellus Researchfunding IntersectENT Researchfunding62 RussellA.Settipane,MD AstraZeneca Advisoryboard,speaker BoehringerIngelheim Speaker Genentech/Novartis Advisoryboard,research

funding,speaker Stallergenes-Greer Researchfunding,speaker Merck Researchfunding,speaker Mylan Speaker Teva Advisoryboard,speaker,

researchfunding ALK Advisoryboard Circassia Advisoryboard Sanofi/Regeneron Advisoryboard CSLBehring Advisoryboard Shire Speaker Pharming Speaker63 HemantP.Sharma,MD XXX 64 AzizSheikh,OBE,BSc,MSc,MD XXX 65 TimothyL.Smith,MD,MPH XXX

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66 PongsakornTantilipikorn,MD,PhD

XXX

67 JodyR.Tversky,MD XXX 68 MariaC.Veling,MD XXX 69 DeYunWang,MD,PhD XXX 70 MaritWestman,MD,PhD XXX 71 MagnusWickman,MD,PhD XXX 72 MarkZacharek,MD NOTALaboratories Founder,advisoryboard

12ContributingAuthors:3 AUTHOR NOTHING

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1 AnandAndiappan,PhD XXX 2 PhilippBadorrek,MD XXX 3 ChristopherD.Brook,MD XXX 4 PalomaCampo,MD,PhD XXX 5 MohamadR.Chaaban,MD,MSCR,

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6 AnnaCharles-Jones,MBChB XXX 7 EstherCheng,MD XXX 8 NipunChhabra,MD XXX 9 DanielCox,MD XXX 10 PedramDaraei,MD XXX 11 AaronM.Drucker,MD,ScM Regeneron Researchfunding Sanofi Consultant,research

funding AstellasCanada Speaker Prime,Inc. Speaker SpireLearning Speaker RTIHealthSolutions Consultant12 KaiFruth,MD,PhD XXX 13 CantingGuo,MD XXX 14 Prof.MatthiasKopp ALK-Abello Consultantorspeaker Allergopharma Consultantorspeaker Chiesi Consultantorspeaker GlaxoSmithKline Consultantorspeaker MEDA Consultantorspeaker Novartis Consultantorspeaker Infectopharm Consultantorspeaker Nutricia Consultantorspeaker Vertex Consultantorspeaker15 PatriciaA.Loftus,MD XXX 16 EdgarMauricioLópez-Chacón,MD XXX 17 MichaelJ.Marino,MD XXX 18 JoseMattos,MD XXX 19 NurayBayarMuluk,MD XXX 20 ChewLipNg,MD XXX 21 BrightI.Nwaru,PhD XXX 22 GianniPala,MD XXX 23 JonoPaulin,MBChB XXX 24 MichaelPfisterer,MD XXX 25 AndrewJ.Rosko,MD XXX 26 ChloeLanRusso,MD XXX

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