practice parameter third update - The American Academy of Allergy

55 Pages·2010·0.91 MB·English

Task force report
Allergen immunotherapy: A practice parameter third update
ChiefEditors:LindaCox,MD,HaroldNelson,MD,andRichardLockey,MD
WorkgroupContributors:ChristopherCalabria,MD,ThomasChacko,MD,IraFinegold,MD,MichaelNelson,MD,PhD,
andRichardWeber,MD
TaskForceReviewers:DavidI.Bernstein,MD,JoannBlessing-Moore,MD,DavidA.Khan,MD,DavidM.Lang,MD,
RichardA.Nicklas,MD,JohnOppenheimer,MD,JayM.Portnoy,MD,ChristopherRandolph,MD,DianeE.Schuller,MD,
SheldonL.Spector,MD,StephenTilles,MD,andDanaWallace,MD
Keywords: Allergyimmunotherapy,subcutaneousimmunotherapy, TheseparametersweredevelopedbytheJointTaskForceon
sublingualimmunotherapy,allergicrhinitis,asthma,Hymenoptera, Practice Parameters, representing the American Academy of
atopic dermatitis, anaphylaxis, epinephrine, b-blockers, angioten- Allergy, Asthma & Immunology (AAAAI); the American Col-
sin-converting enzyme inhibitor, epicutaneous immunotherapy, in- legeofAllergy,Asthma&Immunology(ACAAI);andtheJoint
tralymphaticimmunotherapy,nasalimmunotherapy Council of Allergy, Asthma & Immunology. The American
AcademyofAllergy,Asthma&ImmunologyandtheAmerican
CollegeofAllergy,Asthma&Immunologyhavejointlyaccepted
responsibility for establishing ‘‘Allergen immunotherapy: A
practice parameter third update.’’ This is a complete and com-
Disclosureofpotentialconflictofinterest:L.CoxisaconsultantforGenentech/Novartis,
prehensive document at the current time. The medical environ-
Hollister-Stier, and Stallergenes; is a speaker for Novartis; has received research
supportfromStallergenes;isontheBoardofDirectorsfortheAmericanBoardof ment is a changing environment, and not all recommendations
AllergyandImmunology;andisontheUSFoodandDrugAdministration(FDA)’s will be appropriate for all patients. Because this document
AllergenicProductAdvisoryCommittee.H.NelsonisaconsultantforMerckand incorporatedtheeffortsofmanyparticipants,nosingleindivid-
PlanetBiopharmaceuticals,isaDataandSafetyMonitoringBoardmemberofDBV
ual, including those who served on the Joint Task Force, is
Technologies,andhasreceivedresearchsupportfromALK-Abell(cid:1)o.M.Nelsonhasre-
authorizedtoprovideanofficialAAAAIorACAAIinterpretation
ceivedresearchsupportfromtheDepartmentofDefense,isaspeakerfortheAmerican
CollegeofAllergy,Asthma&Immunology(ACAAI),andisamemberoftheFDA’s ofthesepracticeparameters.Anyrequestforinformationaboutor
AdvisoryCommitteeonAllergicProducts.R.Weberisonthespeakers’bureauforAs- aninterpretationofthesepracticeparametersbytheAAAAIor
traZenecaandGenentech,hasreceivedresearchsupportfromNovartisandGlaxo- the ACAAI should be directed to the Executive Offices of the
SmithKline,andisCommitteeChairoftheACAAI.D.I.Bernsteinisaconsultant
AAAAI,theACAAI,andtheJointCouncilofAllergy,Asthma&
andontheadvisoryboardforALKAmerica,isontheadvisoryboardforMerck,
andhasreceivedresearch supportfromMerckandSchering-Plough.J.Blessing- Immunology. These parameters are not designed for use by
MooreisaspeakerforMerck-Schering/AstraZeneca, Novartis,TEVA,andMeda pharmaceutical companies in drug promotion. A current list of
AlconandhasreceivedresearchsupportfromMeda.D.A.KhanisaspeakerforAs- publishedpracticeparametersoftheJointTaskForceonPractice
traZenecaandMerck,hasreceivedresearchsupportfromtheVanbergFamilyFoun-
ParametersforAllergyandImmunologycanbefoundinTableE1
dationandtheSellarsFamilyFoundation,isConjointBoardReviewChairforthe
inthisarticle’sOnlineRepositoryatwww.jacionline.org.
ACAAI,andisapastpresidentoftheTexasAllergy,AsthmaandImmunologySociety.
D.M.LangisaspeakerandconsultantforGlaxoSmithKline;isaspeakerforAstra-
Zeneca,Merck,TEVA,Sanofi-Aventis,andGenentech/Novartis;andhasreceivedre-
searchsupportfromGenentech/Novartis.R.A.NicklasisafellowfortheACAAI.J. CONTRIBUTORS
OppenheimerisaconsultantandhasprovidedlecturesforAstraZeneca,Merck,and TheJointTaskForcehasmadeaconcertedefforttoacknowl-
GlaxoSmithKline;andhasreceivedresearchsupportfromAstraZeneca,Merck,Glax-
edge all contributors to this parameter. If any contributors have
oSmithKline,andGenentech.J.M.PortnoyisaspeakerforPhadia,Merck,andCSL
Behring;hasreceivedresearchsupportfromtheUSDepartmentofHousingandUrban been excluded inadvertently, the Task Force will ensure that
Development;andisaboardmemberoftheACAAIboardofregents.S.L.Spectorhas appropriate recognition of such contributions is made subse-
received research support from Genentech, GlaxoSmithKline, Schering-Plough, quently. The Joint Task Force gratefully acknowledges the
Aventis,Novartis,Pharmaxis,BoehringerIngelheim,AstraZeneca,Johnson&John-
AAAAI Board of Directors and the ACAAI Board of Regents
son,Xyzal,Alcon,Centocor,Sepracor,UCB,Amgen,Capnia,andIVAX.S.Tilles
fortheirreviewandsupportofthisdocument.
isaspeakerforAlcon;isontheadvisoryboardforALK,Ista,Merck,andStallergenes;
hasreceivedresearchsupportfromAlcon,Amgen,Amphastar,Astellas,Boehringer TheauthorsandeditorsgratefullyacknowledgeSusanGrupe
Ingelheim,Ception,Genentech,Icagen,MAPPharma,MEDA,Merck,Novartis,Rox- andJessicaKarlefortheiradministrativeassistance.
ane,andSepracor;isAssociateEditorofAllergyWatchandAnnalsofAllergy;andisa
taskforcememberfortheJointTaskForceforPracticeParameters.D.Wallaceisa
speakerandadvisorforAlcon,isaspeakerforMerckandSanofi-Aventis,andis
CHIEF EDITORS
President-ElectoftheACAAI.Therestoftheauthorshavedeclaredthattheyhave
noconflictofinterest. LindaCox,MD
ReceivedforpublicationSeptember18,2010;acceptedforpublicationSeptember23, Department of Medicine Nova Southeastern University
2010. CollegeofOsteopathicMedicine
AvailableonlineDecember3,2010.
Davie,Florida
Reprintrequests: JointCouncilofAllergy,Asthma&Immunology,50NBrockwaySt,
#3-3,Palatine,IL60067.E-mail:[email protected].
RichardLockey,MD
0091-6749/$36.00
(cid:1)2010AmericanAcademyofAllergy,Asthma&Immunology DivisionofAllergyandImmunology
doi:10.1016/j.jaci.2010.09.034 DepartmentofInternalMedicine
S1
S2 COXETAL JALLERGYCLINIMMUNOL
JANUARY2011
UniversityofSouthFloridaCollegeofMedicineandJamesA. UniversityofMissouri–KansasCitySchoolofMedicine
HaleyVeterans’Hospital KansasCity,Missouri
Tampa,Florida
ChristopherRandolph,MD
HaroldNelson,MD YaleUniversity
DepartmentofMedicine NewHaven,Connecticut
NationalJewishHealth
DianeE.Schuller,MD
Denver,Colorado
DepartmentofPediatrics
PennsylvaniaStateUniversity
MiltonS.HersheyMedicalCollege
WORK GROUP MEMBERS
Hershey,Pennsylvania
ChristopherCalabria,MD
GlenBurnie,Maryland SheldonL.Spector,MD
DepartmentofMedicine
ThomasChacko,MD
UCLASchoolofMedicine
Roswell,Georgia
LosAngeles,California
IraFinegold,MD
StephenA.Tilles,MD
NewYork,NewYork
DepartmentofMedicine
MichaelNelson,MD,PhD UniversityofWashingtonSchoolofMedicine
Washington,DC Redmond,Washington
RichardWeber,MD DanaV.Wallace,MD
Denver,Colorado DepartmentofMedicine
NovaSoutheasternUniversity
Davie,Florida
JOINT TASK FORCE REVIEWERS
DavidBernstein,MD
DepartmentofMedicineandEnvironmentalHealth INVITED REVIEWERS
UniversityofCincinnatiCollegeofMedicine DonAaronson,MD,JD,MPH
Cincinnati,Ohio Chicago,Illinois
DavidA.Khan,MD DesireeLarenas-Linnemann,MD
DepartmentofInternalMedicine Mexicocity,Mexico
UniversityofTexasSouthwesternMedicalCenter
BryanLeatherman,MD
Dallas,Texas
Gulfport,Mississippi
JoannBlessing-Moore,MD
SandraY.Lin,MD
DepartmentsofMedicineandPediatrics
JohnsHopkinsDepartmentofOtolaryngology–Head&Neck
StanfordUniversityMedicalCenter
Surgery
DepartmentofImmunology
Baltimore,Maryland
PaloAlto,California
Oralandsublingualimmunotherapyforfoodhypersensitivity
DavidM.Lang,MD
WesleyBurkes,MD
Allergy/ImmunologySection
DukeUniversity
Division of Medicine Allergy and Immunology Fellowship
Raleigh,NorthCarolina
TrainingProgram
Venomhypersensitivity
ClevelandClinicFoundation
Cleveland,Ohio DavidGolden,MD
Baltimore,Maryland
RichardA.Nicklas,MD
DepartmentofMedicine TheodoreM.Freeman,MD
GeorgeWashingtonMedicalCenter Helotes,Texas
Washington,DC Allergenextractsection
JohnOppenheimer,MD DerekConstable,PhD
DepartmentofInternalMedicine Spokane,Washington
NewJerseyMedicalSchool
RobertEsch,PhD
PulmonaryandAllergyAssociates
Lenoir,NorthCarolina
Morristown,NewJersey
LarryGarner,CPT,BA
JayM.Portnoy,MD
Spokane,Washington
SectionofAllergy,Asthma&Immunology
TheChildren’sMercyHospital RichardLankow,PhD
DepartmentofPediatrics RoundRock,Texas
JALLERGYCLINIMMUNOL COXETAL S3
VOLUME127,NUMBER1
GregPlunkett,PhD Extract Manufacturers were invited through their organization,
RoundRock,Texas the Allergenic Products Manufacturing Association, to review
and comment on the allergen extract section. All of these in-
RonaldRabin,MD
vited reviewers who contributed to the document are acknowl-
Rockville,Maryland
edged for their efforts within the particular section that they
reviewed.
In addition, the draft was posted on the ACAAI and AAAAI
ASSIGNED REVIEWERS
Websiteswithaninvitationformemberstoreviewandcomment.
PaulGreenberger,MD
The authors carefully considered all of these comments in
NorthwesternUniversityFeinbergSchoolofMedicine
preparingthefinalversion.
Chicago,Illinois
Anannotatedalgorithminthisdocumentsummarizesthekey
BryanMartin,DO decisionpointsfortheappropriateuseofallergenimmunotherapy
OhioStateUniversity (Fig1).Thesectiononefficacysummarizestheevidencedemon-
Columbus,Ohio stratingthatallergenimmunotherapyiseffectiveinthemanage-
ment of properly selected patients with aeroallergen and
stinginginsecthypersensitivity.Thisdocumentalsocontainsrec-
PREFACE ommendationsforoptimizingtheefficacyandsafetyofallergen
This document was developed by the Joint Task Force on immunotherapy,includingspecificrecommendationsonpreven-
PracticeParameters,whichrepresentstheAmericanAcademyof tionandmanagementofadversereactionsandauniformclassifi-
Allergy, Asthma & Immunology (AAAAI); the American Col- cationsystemforgradingsystemicreactions.
legeofAllergy,Asthma&Immunology(ACAAI);andtheJoint Specific recommendations guide the physician in selecting
CouncilofAllergy,Asthma&Immunology(JCAAI). those patients for whom allergen immunotherapy is appropri-
Theobjectiveof‘‘Allergenimmunotherapy:apracticeparam- ate. Aeroallergen immunotherapy should be considered for
eter thirdupdate’’ isto optimizethe practiceof allergenimmu- patients who have symptoms of allergic rhinitis/conjunctivitis
notherapy for patients with allergic diseases. This parameter is or asthma with natural exposure to allergens and who demon-
intendedtoestablishguidelinesforthesafeandeffectiveuseof strate specific IgE antibodies to the relevant allergen or
allergenimmunotherapywhilereducingunnecessaryvariationin allergens.Thereisalsosomeevidencethatpatientswithatopic
immunotherapy practice. These guidelines have undergone an dermatitis with aeroallergen sensitivity might benefit from
extensivepeer-reviewprocessconsistentwithrecommendations immunotherapy.
of the American College of Medical Quality ‘‘Policy on devel- Candidates forimmunotherapy are patientswhose symptoms
opment and use of practice parameters for medical quality are not controlled adequately by medications and avoidance
decision-making.’’1 measures or those experiencing unacceptable adverse effects of
This document builds on the previous Joint Task Force medications or who wish to reduce the long-term use of medi-
document ‘‘Allergen immunotherapy: a practice parameter cations. Immunotherapy is recommended for patients with a
secondupdate’’publishedintheJournalofAllergyandClinical history of a systemic reaction to Hymenoptera stings who
Immunology in 2007.2 The updated practice parameter draft demonstrate Hymenoptera-specific IgE antibodies. There is ev-
was prepared by a work group that included 3 of the editors idence that venom immunotherapy (VIT) might be effective in
fromthesecondupdate,LindaCox,MD;HalNelson,MD;and reducinglargelocalreactions(LLRs)thatmightcausesignificant
RichardLockey,MD,andotherworkgroupmembersasfollows: morbidityandimpairqualityoflife.
Christopher Calabria, MD; Thomas Chacko, MD; Ira Finegold, The focus of this parameter is on allergen immunotherapy
MD;MichaelNelson,MD,PhD;andRichardWeber,MD. practice in the United States. Although several studies have
Inpreparationforthethirdupdate,theworkgroupperformeda demonstratedtheefficacyofsublingualimmunotherapy(SLIT),
comprehensive search of the medical literature, which was there is no FDA-approved formulation for SLIT, and this treat-
conducted with various search engines, including PubMed; mentrouteisconsideredinvestigationalintheUnitedStates.Oral
immunotherapy,allergicrhinitis,asthma,stinginginsectallergy, immunotherapy and SLIT for food hypersensitivity are also
andrelatedsearchtermswereused.Inadditiontothepublished consideredinvestigational.
literature from the comprehensive search, information from Thisdocumentwasapprovedbythesponsoringorganizations
articlesknowntotheauthorswasconsidered.Publishedclinical and represents an evidence-based, broadly accepted consensus
studieswereratedbycategoryofevidenceandusedtoestablish opinion.Theseclinicalguidelinesaredesignedtoassistclinicians
thestrengthofaclinicalrecommendation(TableI).3Laboratory- by providing a framework for the evaluation and treatment of
basedstudieswerenotrated. patientsandarenotintendedtoreplaceaclinician’sjudgmentor
The working draft of ‘‘Allergen immunotherapy: a practice establishaprotocolforallpatients.Notallrecommendationswill
parameter third update’’ was reviewed by a large number of be appropriate for all patients. Because this document incorpo-
individuals. Reviewers include persons appointed by the rates the efforts of many participants, no individual, including
AAAAI, ACAAI, and invited experts. Invited reviewers in- anyonewhoservedontheJointTaskForce,isauthorizedtopro-
cluded those with known expertise in specific areas (eg, oral videanofficialAAAAIorACAAIinterpretationoftheseguide-
immunotherapy or immunotherapy mechanisms), the US Food lines. Recognizing the dynamic nature of clinical practice and
and Drug Administration’s (FDA) Center for Biologics Evalu- practice parameters, the recommendations in this document
ationandResearch,andtheAmericanAcademyofOtolaryngic shouldbeconsideredapplicableforupto5yearsafterpublica-
Allergy,whoformallyendorsedthepreviouspracticeparameter tion.Requestsforinformationaboutoraninterpretationofthese
update.4 The scientific representatives of the US Allergen practiceparametersshouldbedirectedtotheExecutiveOfficesof
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TABLEI.Classificationofevidenceandrecommendations
Categoryofevidence
Ia Evidencefrommeta-analysisofrandomizedcontrolledtrials
Ib Evidencefromatleast1randomizedcontrolledtrial
IIa Evidencefromatleast1controlledstudywithoutrandomization
IIb Evidencefromatleast1othertypeofquasiexperimentalstudy
III Evidencefromnonexperimentaldescriptivestudies,suchascomparativestudies,
correlationstudies,andcase-controlstudies
IV Evidencefromexpertcommitteereportsoropinions,clinicalexperienceofrespectedauthorities,orboth
LB Evidencefromlaboratory-basedstudies
NR Notrated
Strengthofrecommendation
A DirectlybasedoncategoryIevidence
B DirectlybasedoncategoryIIevidenceorextrapolatedfromcategoryIevidence
C DirectlybasedoncategoryIIIevidenceorextrapolatedfromcategoryIorIIevidence
D DirectlybasedoncategoryIVevidenceorextrapolatedfromcategoryI,II,orIIIevidence
NR Notrated
AdaptedwithpermissionfromShekellePG,WoolfSH,EcclesM,GrimshawJ.Clinicalguidelines:developingguidelines.BMJ1999;318:593-6.
the AAAAI, ACAAI and JCAAI. These parameters are d Special considerations
not designed for use by pharmaceutical companies in drug B Pregnancy: The summary statement that states ‘‘aller-
promotion. gen immunotherapy can be continued but usually is
not initiated in the pregnant patient’’ is unchanged
from the previous update. However, the text accompa-
KEY HIGHLIGHTS OF THE UPDATE: NEW
nying the summary statement includes a review of
DEVELOPMENTS OR MODIFICATIONS
literatureonthesafetyofimmunotherapyinpregnancy.
The update also suggests that discontinuation of
d New indications for allergen immunotherapy: immunotherapy should be considered if the pregnancy
B Atopic dermatitis in subjects with aeroallergen sensiti- occurs during the build-up phase and the patient is
zation (Summary Statement 8). receiving a dose unlikely to be therapeutic (Summary
B VIT: patients who experience recurrent bothersome Statement 20).
LLRs (Summary Statement 11). B Patients with HIV infection: The summary statement
d Measurementofbaselinetryptaseisrecommendedinpa- stating that the ‘‘immunotherapy can be considered in
tients with moderate or severe anaphylactic reactions to patientswithimmunodeficiencyandautoimmunedisor-
stings. Increased serum tryptase levels are associated with ders’’isunchangedfromthepreviousupdate.However,
more frequent and severe systemic reactions to VITinjec- thetextaccompanyingthesummarystatementincludes
tions, greater failure rates during VIT, and greater relapse discussion of the published literature and case reports
rates (including fatal reactions) if VIT is discontinued on patients with HIV and allergen immunotherapy
(Summary Statement 10b). (Summary Statement 21).
d Patient age and initiation of allergen immunotherapy: d Localreactions:Thecurrentupdateincludesseveralsum-
The update states there is no specific upper or lower age mary statements on local reactions, including discussions
limit for initiating allergen immunotherapy. The update regarding:
stresses the importance of appropriate indications, the ab- B relationshipwithsystemicreactions(predictivevalueof
sence of significant comorbid conditions, and the patients’ a single local reaction or incidence of systemic reac-
ability to comply/cooperatewith allergen immunotherapy. tions in patients with frequent large local reactions);
B Pediatrics:Thereisnospecificlowerlimitforimmuno- B influenceofglycerinandallergencontentonlocalreac-
therapy if indications are present (Summary State- tions; and
ments 17 and 18). B possiblepreventionwithantihistaminesandleukotriene
B Elderly: There is no specific summary statement on receptor antagonists (Summary Statements 27-30).
immunotherapy in the elderly patient in the current d Systemic reactions, wait period after immunotherapy,
update. The previous update recommended that the anddelayedsystemicreactions:Theupdateincludesnew
risk/benefit assessment be carefully evaluated in the summarystatementsondelayedsystemicreactions,defined
elderly population because they might have comorbid asoccurring30minutesaftertheinjection,andbiphasicre-
medical conditions that could increase immunotherapy actions.Delayed-onsetsystemicreactionsmightaccountfor
risk. The current update recognizes that some of these upto50%ofreactions.Delayedsystemicreactionscanoccur
conditionscan occur more frequentlyinolder subjects, withoutanyprecedingsymptomsorcanbepartofabiphasic
but they can also be present in younger subjects. The reaction. Several large studies demonstrate that life-
current update states that the risk/benefit assessment threatening anaphylactic reactions after 30 minutes are
must be evaluated in every situation, but there is no rare. The recommendation that a patient should remain in
absolute upper age limit for initiation of immunother- the physician’s office/medical clinic for 30 minutes after
apy (Summary Statement 19). the injection is unchanged from the previous update. It is
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FIG1. Algorithmforimmunotherapy.(Continued.)
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FIG1. (Continued).
recommendedthatattheonsetofimmunotherapy,patients inhibitors were associated with more severe reactions
shouldbecounseledonthepossibilityofimmediateandde- fromVIT.ThisupdaterecommendsthatACEinhibitordis-
layedsystemicreactionsduringriskcommunication;anac- continuation be considered for patients receiving VIT.
tionplanforsuchaneventshouldbediscussed.Thedecision However,concurrentadministrationofVITandanACEin-
to prescribeepinephrine autoinjectors topatients receiving hibitor is warranted in selected cases in which there is no
immunotherapy should be at the physician’s discretion equally efficacious alternative and the risk/benefit assess-
(SummaryStatements33-36). ment is favorable. (Summary Statements 40-41).
d b-Blockermedications:Thecurrentupdateincludesadis- d Premedicationandimmunotherapy:Theupdateincludes
cussion of cardioselective b-blockers, noting that it is not 3summarystatementsonpremedicationduringaccelerated
knownwhetherthereislessriskassociatedwithimmunother- (rushandcluster)andconventionalbuild-upschedules.The
apybutthattherehavebeensomeseverecasesofanaphylaxis specificmedicationsusedinimmunotherapypremedication
fromothercausesreportedinpatientsreceivingcardioselec- regimens are discussed and include antihistamines, leuko-
tiveb-blockers(SummaryStatements37-39and41). triene receptor antagonists, omalizumab, and combination
d Angiotensin-converting enzyme (ACE) inhibitor medi- pretreatment. (Summary Statements 56-58).
cations: The update includes a new summary statement d Rush VIT and premedication: Because the risk of a
on ACE inhibitors, noting that there is some conflicting systemic reaction from flying Hymenoptera rush VIT is
information in the published literature regarding immuno- relativelylow,therecommendationthatroutinepremedica-
therapy risk in patients taking ACE inhibitors who tionisusuallynotnecessaryisunchangedfromtheprevious
receive immunotherapy. Two retrospective studies found update.Thepreviousupdatesuggestedthatimportedfireant
no increased frequency of systemic reactions in patients rush immunotherapy had a similarly low risk. However,
taking ACE inhibitors receiving VITor inhalant immuno- there are currently some conflicting data about the risk of
therapy. However, a few case reports and a prospective importedfirerushimmunotherapy,andpremedicationmight
study of 962 patients who received VIT found that ACE beconsidered(SummaryStatements55and57).
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d Aspirationbeforetheimmunotherapyinjection:Theup- efficacy of allergen immunotherapy has accumulated rapidly
dateincludesadiscussionofthedebateregardingtheneed during the past 30 years. Numerous well-designed controlled
for aspiration before the immunotherapy injection (Sum- studies demonstrate that allergen immunotherapy is efficacious
mary Statement 61). inthetreatmentofallergicrhinitis,allergicconjunctivitis,aller-
d Cockroach immunotherapy: The update includes a new gic asthma, and stinging insect hypersensitivity. Randomized
summary statement noting that there are limited data on controlledstudiesshowedthatallergenimmunotherapyprevents
the efficacy of cockroach immunotherapy (Summary the development of asthma in subjects with allergic rhinitis.8-11
Statement 71). There is some evidence of immunotherapy’s efficacy in the
d Multiallergen immunotherapy: A new summary state- treatment of patients with atopic dermatitis with aeroallergen
mentstating that there havebeenfew studies that have in- sensitization.12-16
vestigated the efficacy of multiallergen subcutaneous Allergen immunotherapy is effectivewhen appropriate doses
immunotherapy (SCIT) and that these studies have pro- of allergens are administered. Effective subcutaneous allergen
duced conflicting results has been included in this update immunotherapy appears to correlate with administration of an
(Summary Statement 72). optimal maintenance dose in the range of 5 to 20 mg of major
d Allergenextractpreparation:Theupdateincludesdiscus- allergen for inhalant allergens.17-22 It should be differentiated
sionoftheUnitedStatesPharmacopeia(USP)797allergen from unproved methods, such as neutralization-provocation
extractpreparationguidelines,aswellastheallergenextract therapy23 and low-dose subcutaneous regimens based on the
preparation guidelines developed by the AAAAI/ACAAI/ Rinkel technique,24,25 which have been found to be ineffective
JCAAI, which was included in the previous update. The in double-blind, placebo-controlled trials. The selection of al-
USP797guidelineswerefinalizedafterthepreviousparam- lergens for immunotherapy is based on clinical history, the
eterwaspublished,andtherearesomedifferencesbetween presence of specific IgE antibodies, and allergen exposure.
the2guidelines,oneofwhichisthattheUSP797guidelines This parameter offers suggestions and recommendations de-
recommendthatthepreparershouldwearaprotectivecap, rived from known patterns of allergen cross-reactivity. Recog-
facemask,andgownduringtheextractpreparationprocess nizing that the immunotherapy terminology used to describe
(SummaryStatement77). extract dilutions is sometimes ambiguous, the 2003 ‘‘Allergen
d Probable effective dosing for US-licensed standardized immunotherapy:apracticeparameter’’establishedstandardized
andnonstandardizedextractstable:Theupdateincludes terminology for describing allergen immunotherapy extract di-
a column presenting the range of major allergen content lutions, which is included in this and the 2007 update. These
inUS-licensedextracts,aswellchangesintherecommen- parameters also provided specific recommendations for immu-
deddosing for nonstandardizedextracts (SummaryState- notherapy maintenance doses for some standardized allergens
ment 81). and a suggested dosing range for nonstandardized allergen
d Noninjection routes of immunotherapy: Compared with extracts.
thepreviousupdate,thissectionincludesanexpandeddis- The therapeutic preparations for allergen immunotherapy are
cussionofSLIT,asummarystatementonoralimmunother- extracted from source materials, such as pollen, mold cultures,
apy for food hypersensitivity, and summary statements on andpelt,hencethetraditionaltermallergenextract.Thetermsal-
epicutaneous and intralymphatic immunotherapy (Sum- lergenextractorextractrefertosolutionsofproteinsorglycopro-
mary Statements 92-99). teinsextracted from source material not yet incorporated into a
d Novelformulations:Thissectionincludessummarystate- therapeuticallergenimmunotherapyextract.Thetermmanufac-
ments on allergoids andadjuvants, the immunostimulatory turer’s extract refers to the allergen extract purchased from the
oligonucleotide sequence of DNA containing a CpG motif manufacturer. The terms stock, full strength, and concentrate
(CpG), and 3-deacylated monophospholipid A (MPL; are ambiguous and should not be used. The term maintenance
Summary Statements 100-101). concentrateshouldbeusedtoidentifytheallergenimmunother-
apyextractthatcontainsatherapeuticeffectivedoseforeachofits
individualconstituents.Alldilutionsshouldbereferencedtothe
maintenance concentrate and should be noted as a volume-
INTRODUCTION to-volume dilution (eg,1:100 vol/voldilution of a maintenance
Immunity has been defined as protection against certain concentrate).
diseases. The initial immunotherapeutic interventions, which Thisparameterreinforcesthe2previousallergenimmunother-
includedtheuseofpreventivevaccinesandxenogeneicantisera apypracticeparameters’recommendationsthatvialsofallergen
by Jenner, Pasteur, Koch, and von Behring, were effective for immunotherapy extracts should be prepared individually for
disease prevention. These initial efforts in immune modulation eachpatientanddocumentedwithstandardizedallergenimmuno-
served as a model for later developments in allergen immuno- therapyprescriptionandadministrationforms.Individualizedpa-
therapy. From its empiric emergence in the early 1900s, when tient vials will allow for customized treatment specific to the
grass pollen inoculation was proposed as therapy for hay fever, patient’sidentifiedallergensensitivitiesandreducetheriskofal-
allergen immunotherapy has progressed in both theory and lergencross-contaminationandpatientidentificationerrorsinad-
practice from the passive immunologic approach to the active ministration.26,27 Standardized prescription and administration
immunologic procedures pioneered by Noon5 and Freeman.6,7 forms will improve the safety, uniformity, and standardization
Advancesinallergenimmunotherapyhavedependedontheim- of allergen immunotherapy practice. The suggested forms are
proved understanding of IgE-mediated immunologic mecha- found in this article’s Online Repository at www.jacionline.org
nisms, the characterization of specific antigens and allergens, andontheAAAAI,ACAAI,andJCAAIWebsites(www.aaaai.
and the standardization of allergen extracts. Proof of the org,www.acaai.org,andwww.jcaai.org).Theroutineuseofthese
S8 COXETAL JALLERGYCLINIMMUNOL
JANUARY2011
standardizedformsshouldimprovethequalityofimmunotherapy patient’s preference, allergen immunotherapy might or might
practice. notberecommended.Patientswithallergicrhinitis/conjunctivitis
or allergic asthma whose symptoms are not well controlled by
medications or avoidance measures or require high medication
ALGORITHM AND ANNOTATIONS FOR doses,multiplemedications,orbothtomaintaincontroloftheir
IMMUNOTHERAPY allergicdiseasemightbegoodcandidatesforimmunotherapy.Pa-
Fig1providesanalgorithmfortheappropriateuseofallergen tientswhoexperienceadverseeffectsofmedicationsorwhowish
immunotherapy. Given below are annotations for use with the toavoidorreducethelong-termuseofmedicationsareappropri-
algorithm. atecandidatesforimmunotherapy.However,asthmamustbecon-
trolledatthetimetheimmunotherapyinjectionisadministered.
Patientswithaeroallergen-inducedatopicdermatitismightbene-
Box 1 fitfromimmunotherapy.Ingeneral,patientswithflyinginsector
Immunotherapy is effective in the management of allergic importedfireanthypersensitivitywhoareatriskforanaphylaxis
asthma,allergicrhinitis/conjunctivitis,andstinginginsecthyper- shouldreceiveVITorwhole-bodyextract,respectively.VIThas
sensitivity. There is some evidence it might be effective in the alsobeenshowntodecreaseLLRstostinginginsects.
treatmentofatopicdermatitisinpatientswithaeroallergensensi-
tivity.Allergenimmunotherapymightpreventthedevelopmentof
asthmain subjects with allergic rhinitis. Evaluation of a patient Box 6
with suspected allergic rhinitis, allergic conjunctivitis, allergic After careful consideration of appropriate management op-
asthma, or stinging insect allergyincludesa detailed history, an tions,thephysicianandpatientmightdecidenottoproceedwith
appropriate physical examination, and selected laboratory tests. immunotherapy.
A definitive diagnosis depends on the results of allergy testing
(immediatehypersensitivityskintestsorinvitrotestsforserum
specificIgE). Box 7
Before immunotherapy is started, patients should understand
itsbenefits,risks,andcosts.Counselingshouldalsoincludethe
Box 2
expectedonsetofefficacyanddurationoftreatment,aswellasthe
Immediate hypersensitivity skin testing is generally the pre-
riskofanaphylaxisandimportanceofadheringtotheimmuno-
ferred method of testing for specific IgE antibodies, although
therapyschedule.
testing for serumspecificIgE antibodiesisuseful undercertain
circumstances.Immunotherapyshouldbeconsideredwhenpos-
itive test results for specific IgE antibodies correlate with
Box 8
suspectedtriggersandpatientexposure.
The physician prescribing immunotherapy should be trained
and experienced in prescribing and administering immunother-
Box 3 apy.Theprescribingphysicianmustselecttheappropriatealler-
genextractsbasedonthatparticularpatient’sclinicalhistoryand
Immunotherapyshouldnotbegiventopatientswithnegative
allergenexposurehistoryandtheresultsoftestsforspecificIgE
testresultsforspecificIgEantibodiesorthosewithpositivetest
antibodies.Thequalityoftheallergenextractsavailableisanim-
results for specific IgE antibodies that do not correlate with
portant consideration. When preparing mixtures of allergen ex-
suspected triggers, clinical symptoms, or exposure. This means
tracts, the prescribing physician must take into account the
that the presence of specific IgE antibodies alone does not
cross-reactivityofallergenextractsandthepotentialforallergen
necessarily indicate clinical sensitivity. There is no evidence
degradationcausedbyproteolyticenzymes.Theprescribingphy-
fromwell-designedstudiesthatimmunotherapyforanyallergen
sician must specify the startingimmunotherapydose,the target
iseffectiveintheabsenceofspecificIgEantibodies.
maintenancedose,andtheimmunotherapyschedule.Ingeneral,
the starting immunotherapy dose is 1,000- to 10,000-fold less
Box 4 thanthemaintenancedose.Forhighlysensitivepatients,thestart-
Themanagementofallergicasthma,allergicrhinitis/conjunc- ingdosemightbelower.Themaintenancedoseisgenerally500to
tivitis, and stinging insect hypersensitivity should include the 2000allergyunits(AU;eg,fordustmite)or1000to4000bioequi-
evaluation of different treatment options. Each of the 3 major valentallergyunits(BAU;eg,forgrassorcat)forstandardizedal-
management approaches (allergen immunotherapy, allergen ex- lergen extracts. For nonstandardized extracts, a suggested
posurereduction,andpharmacotherapy)hasbenefits,risks,and maintenancedoseis3000to5000proteinnitrogenunits(PNU)
costs.Furthermore,themanagementplanmustbeindividualized, or0.5mLofa1:100or1:200wt/voldilutionofmanufacturer’s
withcarefulconsiderationgiventothepatient’spreference.Dis- extract.Ifthemajorallergenconcentrationoftheextractisknown,
easeseverityandresponse(orlackofresponse)toprevioustreat- arangebetween5and20mgofmajorallergenistherecommen-
mentareimportantfactors. dedmaintenancedoseforinhalantallergensand100mgforHy-
menoptera venom. Immunotherapy treatment can be divided
into 2 periods, which are commonly referred to as the build-up
Box 5 andmaintenancephases.
Thephysicianandpatientshoulddiscussthebenefits,risks,and Theimmunotherapybuild-upschedule(alsocalledupdosing,
costs of the appropriate management options and agree on a induction, or the dose-increase phase) entails administration of
management plan. Based on clinical considerations and the graduallyincreasingdosesduringaperiodofapproximately8to
JALLERGYCLINIMMUNOL COXETAL S9
VOLUME127,NUMBER1
28weeks.Inconventionalschedulesasingledoseincreaseisgiven Box 12
oneachvisit,andthevisitfrequencycanvaryfrom1to3timesa Patients receiving maintenance immunotherapy should have
week. Accelerated schedules, such as rush or cluster immuno- follow-up visits at least every 6 to 12 months. Periodic visits
therapy, entail administration of several injections at increasing shouldincludeareassessmentofsymptomsandmedicationuse,
dosesonasinglevisit.Acceleratedschedulesoffertheadvantage themedicalhistorysincethepreviousvisit,andanevaluationof
ofachievingthetherapeuticdoseearlierbutmightbeassociated the clinical response to immunotherapy. The immunotherapy
withincreasedriskofasystemicreactioninsomepatients. schedule and dose, reaction history, and patient compliance
should also be evaluated. The physician can at this time make
adjustmentstotheimmunotherapyscheduleordose,asclinically
Box 9 indicated.
Immunotherapy should be administered in a setting that Therearenospecificmarkersthatwillpredictwhowillremain
permits the prompt recognition and management of adverse inclinicalremissionafterdiscontinuingeffectiveallergenimmu-
reactions. The preferred location for such administration is the notherapy.Somepatientsmightsustainlastingremissionoftheir
prescribingphysician’soffice.However,patientscanreceiveim- allergic symptoms after discontinuing allergen immunotherapy,
munotherapyinjectionsatanotherhealthcarefacilityifthephy- butothersmightexperiencearecurrenceoftheirsymptoms.As
sician and staff at that location are trained and equipped to withthedecisiontoinitiateallergenimmunotherapy,thedecision
recognizeandmanageimmunotherapyreactions,particularlyan- to discontinue treatment should be individualized, taking into
aphylaxis.Patientsshouldwaitatthephysician’soffice/medical accountfactorssuchastheseverityofthepatient’sillnessbefore
clinicforatleast30minutes aftertheimmunotherapyinjection treatment,thetreatmentbenefitsustained,theinconvenienceim-
or injections so that reactions can be recognized and treated munotherapyrepresentstoaspecificpatient,andthepotentialef-
promptlyiftheyoccur. fectaclinicalrelapsemighthaveonthepatient.Ultimately,the
Immunotherapy injections should be withheld if the patient duration of immunotherapy should be individualized based on
presents with an acute asthma exacerbation. For patients with the patient’s clinical response, disease severity, immunotherapy
asthma,considermeasuringthepeakexpiratoryflowratebefore reactionhistory,andpreference.
administering an immunotherapy injection and withholding an
immunotherapy injection if the peak expiratory flow rate is
IMMUNOTHERAPY GLOSSARY
consideredlowforthatpatient.
For more information on immunotherapy definitions, see the
articlebyKao.29
Theallergenimmunotherapyextractisdefinedasthemixture
Box 10
of the manufacturer’s allergen extract or extracts that is used
Injectionsof allergenimmunotherapyextractcancause local
for allergen immunotherapy. Allergen extracts used to prepare
or systemic reactions. Most serious systemic reactions develop
the allergen immunotherapy extract can be complex mixtures
within30minutesaftertheimmunotherapyinjection.However,
containingmultipleallergenicandnonallergenicmacromolecules
immunotherapy-induced systemic reactions can occur after 30
(proteins, glycoproteins, and polysaccharides) and low-
minutes. Patients should be counseled on the possibility of
molecular-weight compounds. Other terms used to describe the
immediateanddelayedsystemicreactionsduringriskcommuni- allergen immunotherapy extract include allergen product,30 al-
cation;anactionplanforsuchaneventshouldbediscussed.Inthe lergyserum,allergenvaccine,31andallergensolution.
event of a delayed systemic reaction, the patient should be
Allergenimmunotherapyisdefinedastherepeatedadministra-
counseledonappropriatetreatmentbasedonhisorhersymptoms.
tionofspecificallergenstopatientswithIgE-mediatedconditions
forthepurposeofprovidingprotectionagainsttheallergicsymp-
toms and inflammatory reactions associated with natural expo-
Box 11 sure to these allergens.2 Other terms that have been used for
Localreactionscanbemanagedwithlocaltreatment(eg,cool allergen immunotherapy include hyposensitization, allergen-
compresses or topical corticosteroids) or antihistamines. Sys- specificdesensitization,andthelaytermsallergyshotsorallergy
temic reactions can be mild or severe. Epinephrine is the injections.29
treatmentofchoiceinpatientswithanaphylaxis. Anaphylaxisisanimmediatesystemicreactionoftenoccurring
Antihistamines and systemic corticosteroids are secondary withinminutesandoccasionallyaslongasanhourorlongerafter
medications that might help to modify systemic reactions but exposuretoanallergen.ItcanbeIgEmediated,ascanoccurwith
shouldneverreplaceepinephrineinthetreatmentofanaphylaxis. allergen immunotherapy, or non–IgE mediated, as occurs with
Intravenoussalineorsupplementaloxygenmightberequiredin radiocontrastmedia.Itiscausedbytherapidreleaseofvasoac-
severecases.Foradditionaldetailsonanaphylaxismanagement tive mediators from tissue mast cells and peripheral blood
see, ‘‘The diagnosis and management of anaphylaxis practice basophils.
parameter:2010update.’’28 Thebuild-upphaseinvolvesreceivinginjectionswithincreas-
Theimmunotherapydoseandschedule,aswellasthebenefits ing amounts of the allergen. The frequency of injections during
andrisksofcontinuingimmunotherapy,shouldbeevaluatedafter this phase generally ranges from 1 to 3 times a week, although
any immunotherapy-induced systemic reaction. For some pa- morerapidbuild-upschedulesaresometimesused.Theduration
tients, the immunotherapy maintenance dose might need to be ofthisphasedependsonthefrequencyoftheinjectionsbutgener-
reduced. After systemic reactions to immunotherapy, the pre- allyrangesfrom3to6months(atafrequencyof2timesand1time
scribing physician can re-evaluate the risk/benefit ratio of perweek,respectively).Othertermsusedtodescribethebuild-up
continuedimmunotherapy. phaseincludeupdosing,inductionorthedose-increasephase.
S10 COXETAL JALLERGYCLINIMMUNOL
JANUARY2011
TABLEII.Calculationsformakingextractdilutions* Hyposensitization is a term formerly used interchangeably
withallergenimmunotherapy.Itwasintroducedtodistinguishal-
Alldilutionscanbecalculatedbyusingthefollowingformula:
V13C15V23C2, lergenimmunotherapyfromclassicaldesensitization.Hyposensi-
where tization denotes a state of incomplete desensitization because
V15Finalvolumeyouwanttoprepare complete desensitization is rarely accomplished with allergen
C15Concentration(wt/volorPNU)ofextractyouwanttoprepare immunotherapy.
V25Volumeofextractyouwillneedfordilution Immunomodulationisatermthatdenotesawidevarietyofdrug
C25Concentrationofextractyouwilluse. orimmunologicinterventionsthatalternormalorabnormalim-
Example:SolveforV2;(V13C1)/C25V2.
muneresponsesbymeansofdeletionofspecificTcells,Bcells,
Todeterminetheconcentrationofaniteminamixture:
orboth;immunedeviation;inductionofperipheral/centraltoler-
1.determinewhichformulayouneedtouse;
ance;ormodificationofvariousinflammatorypathways(eg,che-
2.choosethenumbers/fractionsthatwillbeinserted
motaxis,adhesions,orintracytoplasmicsignaling).
intotheformulaforV1,C1,V2,andC2;
3.changeallwt/volfractionstoadecimalnumber Immunotherapyisatreatmentmodalitythatappearedsoonaf-
andinsertintotheformula(seebelow);and teradaptiveimmuneresponseswerediscoveredandhasgradually
4.multiplyfirstandthendividetogettheanswer. evolved to encompass any intervention that might benefit
Toexpressconcentrationasapercentage: immune-inducedaberrantconditionsthroughavarietyofimmu-
1:10wt/vol1/1050.13100510%solution nologic transformations. Early definitions of the term immuno-
1:20wt/vol1/2050.05310055%solution therapy included activeand passiveimmunization to improve a
1:40wt/vol1/4050.025310052.5%solution
host’s defenses against microorganisms. Allergen immunother-
Example:
apywasoriginallyconceivedasaformofactiveimmunization,
V155mL Finalvolumeyouwanttoprepare
C151:200 Concentrationyouwanttoprepare thepurposeofwhichwastoalterthehost’sabnormalimmunere-
V25Unknown Volumeofextractyouwillneedfordilution sponsesandnotaugmentthehost’sdefensesagainstmicroorgan-
C251:10 Concentrationofextractyouwilluse isms.Themodernrubricofimmunotherapyincludesallmethods
Addvaluesintoformula: usedtoovercomeabnormalimmuneresponseswithinductionof
V13C15V23C2 53(1/200)5V23(1/10) clonaldeletion,anergy,immunetolerance,orimmunedeviation.
53(0.005)5V23(0.1) Local reactions to SCIT injections can manifest as redness,
V25(V13C1)/C2 V250.025/0.150.25 pruritus,andswellingattheinjectionsite.
Todetermineamountofdiluentneeded:
Themaintenanceconcentrateisapreparationthatcontainsin-
V12V2 520.2554.75mL
dividualextractsormixturesofmanufacturer’sallergenextracts
AdaptedfromtheGreerAllergyCompendium.Lenoir(NC):GreerLaboratories; intendedforallergenimmunotherapytreatment.Amaintenance
2005.p.71.PermissionprovidedbyRobertEsch,PhD. concentratecanbecomposedofaconcentrateddoseofasingle
allergen or a combination of concentrated allergens to prepare
an individual patient’s customized allergen immunotherapy ex-
Cluster immunotherapy is an accelerated build-up schedule tract mixture. Subsequent dilutions can be prepared from the
that entails administering several injections at increasing doses maintenanceconcentrateforthebuild-upphaseorifthepatient
(generally2-3pervisit)sequentiallyinasingledayoftreatment cannottoleratethemaintenanceconcentrate.
on nonconsecutive days. The maintenance dose is generally The maintenance dose (or effective therapeutic dose) is the
achievedmorerapidlythanwithaconventional(singleinjection dosethatprovidestherapeuticefficacywithoutsignificantadverse
pervisit)build-upschedule(generallywithin4-8weeks). localorsystemicreactions.Theeffectivetherapeuticdosemight
Desensitization is the rapid administration of incremental notbetheinitiallycalculatedprojectedeffectivedose.
dosesofallergensormedicationsbywhicheffectorcellsareren- Themaintenancegoal(orprojectedeffectivedose)isthealler-
deredlessreactiveornonreactivetoanIgE-mediatedimmunere- gendoseprojectedtoprovidetherapeuticefficacy.Notallpatients
sponse. Desensitization can involve IgE-mediated or other willtoleratetheprojectedeffectivedose,andsomepatientsexpe-
immunemechanisms.Thepositiveskintestresponsetothealler- riencetherapeuticefficacyatlowerdoses.
gensmightdiminishoractuallyconverttoanegativeresponsein Themaintenancephasebeginswhentheeffectivetherapeutic
somecasesafterthisprocedure.Tolerancetomedicationscanbe doseisreached.Oncethemaintenancedoseisreached,theinter-
achievedthroughdesensitization. valsbetweenallergyinjectionsareincreased.Thedosegenerally
Thedoseistheactualamountofallergenadministeredinthe is the same with each injection, although modifications can be
injection. Thevolume and concentration canvary such that the made based on several variables (ie, new vials or a persistent
same delivered dose can be given by changing the volume and LLRcausingdiscomfort).Theintervalsbetweenmaintenanceim-
concentration(ie,0.05mLofa1:1vol/volallergenwouldequal munotherapy injections generally range from 4 to 8 weeks for
0.5mLofa1:10vol/volallergen).Thedosecanbecalculatedby venomandevery2to4weeksforinhalantallergensbutcanbe
usingthefollowingformula:Concentrationofallergen3volume advancedastoleratedifclinicalefficacyismaintained.
of administered dose. See Table II for calculation formula for AmajorallergenisanantigenthatbindstotheIgEserafrom
makingextractdilutions. 50%ormoreofaclinicallyallergicgroupofpatients.Suchaller-
Theeffectivetherapeuticdoseormaintenancedoseisthedose gens are defined either with immunoblotting or crossed
thatprovidestherapeuticefficacywithoutsignificantadverselo- allergoimmunoelectrophoresis.
cal or systemic reactions. The effective therapeutic dose might Foradefinitionofprojectedeffectivedose,seethedefinitionof
not be the initially calculated projected effective dose (eg, 500 maintenancegoal.
BAU[highest tolerated dose]vs2000 BAU[projected effective Rushimmunotherapyisanacceleratedimmunotherapybuild-
dose]forcat). up schedule that entails administering incremental doses of