icar: allergic rhinitis 1...2017/11/28 · 31 steven m. houser, md otolaryngology case western...
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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
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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
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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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Keywords(shortlist):allergyimmunotherapy,allergicrhinitis,evidence-basedmedicine,1immunotherapy,rhinitis23AuthorConflictofInterestDisclosure:Seetableattheendofthisdocument.45Funding:AdministrativesupportforthisdocumentwasfundedbytheAmericanAcademyofOtolaryngic6Allergy.78
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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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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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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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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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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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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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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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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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ICAR:AllergicRhinitis 22
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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ICAR:AllergicRhinitis 29
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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ICAR:AllergicRhinitis 31
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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ICAR:AllergicRhinitis 37
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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ICAR:AllergicRhinitis 38
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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ICAR:AllergicRhinitis 68
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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ICAR:AllergicRhinitis 69
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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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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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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ICAR:AllergicRhinitis 99
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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ICAR:AllergicRhinitis100
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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ICAR:AllergicRhinitis115
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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ICAR:AllergicRhinitis117
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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ICAR:AllergicRhinitis144
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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ICAR:AllergicRhinitis146
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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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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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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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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• 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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ICAR:AllergicRhinitis205
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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• 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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ICAR:AllergicRhinitis229
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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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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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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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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ICAR:AllergicRhinitis357
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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ICAR:AllergicRhinitis359
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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ICAR:AllergicRhinitis362
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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2023. WangFY,GuptaSK,FitzgeraldJF.Isthereaseasonalvariationintheincidenceor13intensityofallergiceosinophilicesophagitisinnewlydiagnosedchildren?JClin14Gastroenterol2007;41:451-453.15
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6 7
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ICAR:AllergicRhinitisAuthorDisclosureofConflictofInterest12Authors:34 AUTHOR NOTHING
TODISCLOSE
COMPANY NATUREOFRELATIONSHIP
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
TODISCLOSE
COMPANY NATUREOFRELATIONSHIP
1 AnandAndiappan,PhD XXX 2 PhilippBadorrek,MD XXX 3 ChristopherD.Brook,MD XXX 4 PalomaCampo,MD,PhD XXX 5 MohamadR.Chaaban,MD,MSCR,
MBAXXX
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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27 TheodoreAsherSchuman,MD XXX 28 ChristineSegboer,MD XXX 29 MichelaSilvestri,PhD XXX 30 KristineA.Smith,MD XXX
31 MichaelB.Soyka,MD Sanofi Consultant MEDA Advisoryboard PreclinBiosystems Researchfunding32 JeanieSozanskyLujan,MD XXX 33 AndrewJ.Thomas,MD XXX 34 ArjaViinanen,MD,PhD Novartis Speaker Chiesi Speaker BoehringerIngelheim Speaker Mundipharma Speaker Astra-Zeneca Speaker35 ThomasJ.Willson,MD XXX
1234