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Pharmacotherapy:APathophysiologicApproach,9e>

eChapter22.AllergicandPseudoallergicDrug
Reactions
LynneM.Sylvia

KeyConcepts
Hypersensitivityreactionsareresponsiblefor6%to10%ofadversereactionstomedications.
Althoughsomereactionsarerelativelywelldefined,themajorityareduetomechanismsthatareeither
unknownorpoorlyunderstood.
Thefollowingcriteriasuggestthatadrugreactionmaybeimmunologicallymediated:(a)the
reactionoccursinasmallpercentageofpatientsreceivingthedrug,(b)theobservedreactiondoesnot
resemblethedrugspharmacologiceffect,(c)thetypeofmanifestationissimilartothatseenwithother
allergicreactions(anaphylaxis,urticaria,serumsickness),(d)thereisalagtimebetweenfirstexposure
ofthedrugandreaction,(e)thereactionisreproducedevenbyminutedosesofthedrug,(f)thereaction
isreproducedbyagentswithsimilarchemicalstructures,(g)eosinophiliaispresent,or(h)thereaction
resolvesafterthedrughasbeendiscontinued.Exceptionstoeachofthesecriteriaareobserved
commonly.
Anaphylaxisisanacute,lifethreateningallergicreactioninvolvingmultipleorgansystemsthat
generallybeginswithin30minutesbutalmostalwayswithin2hoursafterexposuretotheinciting
allergen.Anaphylaxisrequiresprompttreatmenttorestorerespiratoryandcardiovascularfunction.
Epinephrineisthedrugofchoicetocounteractbronchoconstrictionandperipheralvasodilation.IV
fluidsshouldbeadministeredaggressivelytorestoreintravascularvolume.
Factorsthatinfluencethelikelihoodofallergicdrugreactionsarethechemicalcompositionofthe
drug,whetherthedrugcontainsproteinsofnonhumanorigin,therouteofdrugadministration,andthe
sensitivityoftheindividualasdeterminedbygeneticsorenvironmentalfactors.Forsomedrugs,genetic
predispositiontospecifichumanleukocyteantigenalleleshasbeenidentifiedasariskfactorfor
allergicmediatedskinreactions.
Patientswithahistoryofanimmediatereactiontopenicillinareadvisednottoreceive
cephalosporinsiftheycanbeavoided.Patientswhohavenegativepenicillinskintestresultsor
experiencedonlymildcutaneousreactions,suchasmaculopapularrashes,havealowriskofserious
reactionstocephalosporins.SimilaritiesintheR1sidechainoftheagentsshouldbeconsideredwhen
assessingtheriskofcrossreactivity.
Fewerthan1%ofpatientsreceivingnonionicradiocontrastagentsexperiencesometypeofadverse
reaction.Ofthevarietyofreactionsreported,about90%areallergiclike,mostlyurticarial,withsevere
reactionsoccurringasinfrequentlyas0.02%.
Aspirinandothernonsteroidalantiinflammatorydrugs(NSAIDs)canproducetwogeneraltypesof
reactions,urticaria/angioedemaandrhinosinusitis/asthma,insusceptiblepatients.About20%of
individualswithasthmaaresensitivetoaspirinandotherNSAIDs.
Crossreactivitybetweensulfonamideantibioticsandnonantibioticsislow.Thelowcrossreactive
ratemaybeexplainedbydifferencesinthechemicalstructuresandreactivemetabolitesofthe
sulfonamideantibioticsandnonantibiotics.
Thebasicprinciplesofmanagementofallergicreactionstodrugsorbiologicagentsinclude(a)
discontinuationofthemedicationoragentwhenpossible(b)treatmentoftheadverseclinicalsignsand
symptomsand(c)substitution,ifnecessary,ofanotheragent.
Oneofthemosthelpfulteststoevaluateriskofpenicillinallergyistheskintest.Skintestingcan
demonstratethepresenceofpenicillinspecificimmunoglobulinEandpredictarelativelyhighriskof
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immediatehypersensitivityreactions.Skintestingdoesnotpredicttheriskofdelayedreactionsormost
dermatologicreactions.
Whenanallergenicdrugisconsideredmedicallynecessary,noadequatetherapeuticalternative
exists,andthereisnoreliableskintestingmethod,twooptionsareavailabletotheclinician:induction
ofdrugtolerance(previouslyknownasdesensitization)andgradedchallenge.

LearningObjectives
Oncompletionofthechapter,thereaderwillbeableto:
1.Determinethelikelihoodthatanadversedrugreactionisimmunologicallymediated.
2.Describetheroleofimmunecells,cytokines,antibodies,andothermediatorsinthemechanismof
allergicreactions.
3.Describethefourtypesofallergicreactions(typeI,II,III,andIV)andprovideanexampleofeach.
4.Describethedrugandpatientspecificfactorsthatinfluencetheriskofanallergicdrugreaction.
5.Compareandcontrastanaphylaxisandanaphylactoidreactionsonthebasisofthetimingofthereaction,
doserelationship,predisposingfactors,andclinicalfeatures.
6.Determinetheriskofallergiccrossreactivityforcephalosporinsandcarbapenemsinpatientswhoare
allergictopenicillin.
7.Determinetheriskofallergiccrossreactivitybetweenthesulfonamideantibioticsandthesulfonamide
nonantibiotics.
8.Compareandcontrastdesensitizationandgradeddrugchallengeproceduresanddeterminethe
appropriateindicationsforeachoftheseprocedures.
9.Describethepropertreatmentofanaphylacticreactions.
10.Describetheappropriateuseofskinteststodeterminetheriskofanaphylaxis.

Introduction
Allergicdrugreactions,alsoknownashypersensitivityreactions,resultfromanoverresponseofthe
immunesystemtothestandarddoseofadrug.Thehyperresponseoftheimmunesystemtotheantigenicdrug
leadstohosttissuedamagemanifestingasanorganspecificorgeneralizedsystemicreaction.Adversedrug
effectsnotproventobeimmunemediatedbutresemblingallergicreactionsintheirclinicalpresentationare
referredtoasallergiclikeorpseudoallergicreactions.Immunologicallymediatedadversedrugreactions
accountfor6%to10%ofalladversedrugreactionsandevenupto15%bysomeestimates.1,2Examplesof
allergicdrugreactionsareanaphylaxisfromlactamantibiotics,halothanehepatitis,StevensJohnsons
syndrome(SJS)fromsulfonamides,allopurinolhypersensitivitysyndrome,andserumsicknessfrom
phenytoin.3Examplesofpseudoallergicreactionsareisolatedurticariaafterradiocontrastmedia,aspirin
inducedasthma,opiaterelatedurticaria,andflushingaftervancomycininfusion.3
Thetruefrequencyofallergicdrugreactionsisdifficulttodeterminebecausemanyreactionsmaynotbe
reported,andothersmaybedifficulttodistinguishfromnonallergicadverseevents.Dermatologicreactions
representthemostfrequentlyrecognizedandreportedformofallergicdrugreaction.4

MechanismsofAllergicDrugReactions
Drugscancausehypersensitivityreactionsbyavarietyofimmunologicmechanisms.Althoughsomereactions
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arerelativelywelldefined,mostareduetomechanismsthatareeitherunknownorpoorlyunderstood.2,3
Thefollowingcriteriasuggestthatadrugreactionmaybeimmunologicallymediated:(a)theobserved
reactiondoesnotresemblethedrugspharmacologiceffect(b)thereisalagtimebetweenfirstexposureof
thedrugandreactionunlesstherecipienthasbeensensitizedbypriorexposuretothedrug,whichcanleadto
immediatereactions(c)thereactionmayoccurevenbyminutedosesofthedrug(d)thesymptomsare
characteristicofanallergicreaction(e.g.,anaphylaxis,urticaria,serumsickness)(e)thereactionresolvesafter
thedrughasbeendiscontinuedand(f)thereactionmaybereproducedbyagentswithsimilarchemical
structures.2Exceptionstoeachofthesecriteriaareobservedcommonly.Manyallergicreactionscanbe
classifiedintooneoffourimmunopathologiccategories:typeI,II,III,orIV(eTable221andeFig.221).2,3,5
eTable221ClassificationofAllergicDrugReactions
Type Descriptor

Characteristics

Anaphylactic
AllergenbindstoIgEonbasophilsormastcells,
(IgE
resultinginreleaseofinflammatorymediators.
mediated)

II

Cytotoxic

III

Immune
complex

IV

Cell
mediated
(delayed)

Typical
Onset
Within
30min
to<2
hours

DrugCauses
Penicillinimmediate
reaction
Bloodproducts
Polypeptide
hormones
Vaccines
Dextran

Celldestructionoccursbecauseofcellassociated
antigenthatinitiatescytolysisbyantigenspecific
antibody(IgGorIgM).Mostofteninvolvesblood
elements.
Antigenantibodycomplexesformanddepositon
bloodvesselwallsandactivatecomplement.Result
isaserumsicknesslikesyndrome.

Penicillin,quinidine,
Typically
heparin,phenylbutazone,
>72hto
thiouracils,sulfonamides,
weeks
methyldopa
Maybecausedby
>72hto
penicillins,sulfonamides,
weeks
minocycline,hydantoins
Tuberculinreaction
Maculopapular
rashestoavariety
AntigenscauseactivationofTlymphocytes,which
ofdrugs
releasecytokinesandrecruiteffectorcells(e.g.,
>72h
Contactdermatitis
macrophages,eosinophils).
Bullousexanthems
Pustularexanthems

eFigure221

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Typesofhypersensitivityreactions.(AGEP,acutegeneralizedexanthematouspustulosisCTL,cytotoxicT
lymphocyteCXCL8,interleukin8GMCSF,granulocytemacrophagecolonystimulatingfactorIg,
immunoglobulinIL,interleukinNK,naturalkillerPMN,polymorphonuclearleukocyte)

EffectorsofAllergicDrugReactions
Allergicdrugreactionscaninvolvemostofthemajorcomponentsoftheinnateandadaptiveimmunesystems,
includingthecellularelements,immunoglobulins,complement,andcytokines.Mostimmunoglobulinisotypes
havebeenimplicatedinimmunologicallymediateddrugreactions.ImmunoglobulinE(IgE)boundto
basophilsormastcellsmediatesimmediate(anaphylactictype)reactions.IgGorIgMantibodiesalsomaybe
involvedinallergicreactions,resultingindestructionofcellsandtissues.Tlymphocyteshaveamajorrolein
hypersensitivityreactionsandareinvolvedinallfourtypes(IIV)ofthedrughypersensitivityreactions
describedbyCoombsandGell.2,57

CellularElements
Avarietyofcellsareinvolvedindrughypersensitivity.Antigenpresentingcells(APCs)includemacrophages,
dendriticcells,andcutaneousLangerhanscells.APCsprocesstheantigenicdrugforsubsequentrecognition
byTandBlymphocytes.Basophilsandmastcellsareinstrumentalinthedevelopmentofimmediate
hypersensitivityreactions,whereaseosinophilsarerecruitedinbothimmediateandnonimmediatereactions.
Plateletsandvascularendothelialcellsareimportantbecausetheyalsocanreleaseanumberofinflammatory
mediators.8Mostcellsofthebody,includingnervecells,canbecomeinvolveddirectlyorindirectlyinallergic
drugreactions.

MediatorsofAllergicReactions
Thereleaseofanumberofpreformed,pharmacologicallyactivechemicalmediators(e.g.,histamine,heparin,
proteasessuchastryptaseandchymase,andavarietyofotherenzymes)istriggeredwhenantigenscrosslink
IgEmoleculesonthesurfaceofcirculatingbasophilsandtissuemastcells.Newlyformedmediatorsinclude
plateletactivatingfactor(PAF)andarachidonicacidmetabolites(e.g.,prostaglandins[PGs],thromboxanes,
andleukotrienes[LTs]).
Histamineisalowmolecularweightaminecompoundformedbydecarboxylationofhistidineandisstoredin
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basophilandmastcellgranules.9Releaseofhistaminefromthesecellsistriggeredbyantigencrosslinking
IgEboundtospecificreceptorsonthesurfacemembranesofmastcellsandbasophils.Thetissueeffectsof
histamineareevidentwithin1to2minutes,butitisrapidlymetabolizedwithin10to15minutes.Themajor
effectsofhistamineontargettissuesincludeincreasedcapillarypermeability,contractionofbronchialand
vascularsmoothmuscle,andhypersecretionofmucousglands.Fourclassesofhistaminereceptors(H1H4)
arepresentinvaryingdegreesinorgansandtissues.H1receptorsaremostprominentinbloodvesselsand
bronchialandintestinalsmoothmuscle.
Plateletactivatingfactorisaglyceridederivedsubstancethatisreleasedbymastcells,alveolarmacrophages,
neutrophils,platelets,andothercellsbutnotbybasophils.Ithaspotentbronchoconstrictoreffectsandcauses
plateletaggregationandlysis.Itattractsneutrophilsandcausestheiractivation.PAFenhancesvascular
permeabilityandcancausepain,pruritus,anderythema.
TheLTsaremetabolitesofarachidonicacidproducedthroughthe5lipoxygenasepathwaythathavepotent
effectsonbronchialandvascularsmoothmuscle.ThreeimportantLTs,LTC4,LTD4,andLTE4,areproduced
bybasophilsormastcells.ThesethreesubstancesarealsoreferredtoascysteinylLTsandwerepreviously
referredtoasslowreactingsubstancesofanaphylaxis.TheLTshavemorepotentandlongerlasting
bronchoconstrictoreffectsthanhistamineandcanincreasevascularpermeabilityandcausearteriolar
vasoconstrictionfollowedbyvasodilation.Theireffectsareslowerinonsetbutlongerlastingthanthoseof
histamine.Anotherproduct,LTB4,isapotentchemoattractant,particularlyforneutrophils.Itisalsoproduced
byneutrophils,macrophages,andmonocytes.
Prostaglandinsandthromboxanesaremetabolitesofarachidonicacidproducedthroughthecyclooxygenase
(COX)pathway.SomePGshavevasoconstrictiveorbronchodilatoryproperties,whereasothersare
vasodilatoryorbronchoconstrictive.PGD2isthemajorPGproductofmastcells.Itisapotentinhibitorof
plateletaggregationandisabronchoconstrictor.Thromboxanescauseplateletaggregationandareimportant
regulatorsofcoagulation.
Thecomplementsystemconsistsofabout30plasmaproteinsandisinvolvedinhypersensitivitythrougha
varietyofimmunologicresponses,includingenhancementofphagocytosis(opsonizationoftargetcells),cell
lysis,andgenerationofanaphylatoxinsC3a,C4a,andC5a,whichcancausenonIgEmediatedactivationof
mastcellsandreleaseofinflammatorymediators.

ClassificationofImmunopathologicDrugReactions
Immunologicmechanismshavebeenidentifiedforsomedrugreactions,andmanycanbeclassifiedintoone
offourimmunopathologicreactions,firstdescribedbyCoombsandGell.Smallmolecularweightmolecules
(<10kDa)donothavetheabilitytoserveasantigensontheirown.Withtheexceptionofpolypeptide
compounds,mostdrugsaresmallerthan1,000Da.Tobecomeimmunogenic,thesesmallcompoundsmust
firstcovalentlybindtocarrierproteinsinplasmaortissue.Thecombinationofthedrugboundtoacarrier
proteincanberecognizedasforeignbyAPCsandTlymphocytes,culminatinginanimmuneresponse.The
morelikelythatlargeamountsofthedrugbecomechemicallyboundtoaprotein,thegreatertheriskof
producinganallergicreaction.PenicillinG(356Da)isanexampleofadrugthatbindscovalentlytoserum
proteinsthroughamideordisulfidelinkages.Fordrugssuchasthesulfonamides,theparentcompoundmust
beconvertedtoametabolitebeforeitcancombinewiththemacromolecule.Thespeciesthatcombineswith
thecarriermacromoleculeisreferredtoasahaptenoranincompleteantigen.Somemacromoleculardrugs
suchasinsulinarereferredtoascompleteantigensbecausetheyarelargeenoughtoinitiateanimmune
responsewithoutbindingtoanotherprotein.Somesmallmolecularweightdrugsmaycauseanimmune
responsethroughanonhaptenpathway.6Knownasthepiconcept,thispathwayinvolvesapharmacologic
interactionbetweenthedrugandtheTcellreceptorthatdoesnotrequiretheinitialbindingofthedrugtoa
carrierproteinorprocessingbyAPCs.7

TypeI
TypeIreactionsrequirethepresenceofIgEspecificforthedrugortheportionofthedrugthatbecomesa
hapten.IgEspecificforthedrugallergenisproducedoninitialexposuretothedrug.Itthenbindstobasophils
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andmastcellsthroughhighaffinityreceptors.Onrepeatexposuretothedrug,twoormoreIgEmoleculeson
thebasophilormastcellsurfacemaybindtoonemultivalentantigenmolecule(referredtoascrosslinking
seeeFig.221),initiatingcellularactivation.Activationcausestheextracellularreleaseofgranuleswith
preformedinflammatorymediators,includinghistamine,heparin,andproteases(tryptaseinthemastcell),as
wellasgenerationofnewlyformedmediators,aspreviouslydiscussed,suchasLTs,PGs,thromboxanes,and
PAF,amongothers.
GenerationofatypeIreactioncanbeevidentasanimmediatehypersensitivityreaction,oranaphylaxis.
Immediatereactionsmaybelimitedtosingleorgans,typicallyinthenasalmucosa(rhinitis),respiratorytract
(acuteasthma),skin,orgastrointestinaltract,ortheycaninvolvemultipleorganssimultaneously,termed
anaphylaxis.

TypeII
TypeIIimmunopathologicreactionsinvolvedestructionofhostcells(usuallybloodcells)throughcytotoxic
antibodiesbyoneoftwomechanisms(seeeFig.221).First,thedrugbindstothecellasahapten(e.g.,the
plateletorredbloodcell).Antibodies(IgGorIgM)specificforthebounddrugortoacomponentofthecell
surfacethathasbeenalteredbythedrugthenbind,initiatingacytolyticreaction.Celldestructionmaybe
mediatedbycomplementorbyphagocyticcellsthathaveantibodyFcreceptorsontheirsurfaces.Activation
ofcomplementnearthecellsurfacecanresultinlossofcellmembraneintegrityandcelldeath.Alternatively,
neutrophils,monocytes,ormacrophagesmaybindtoanantibodycoatedcellthroughIgGFcreceptorsontheir
cellsurfaces,resultinginphagocytosisofthetargetcell.Theprocessofenhancementofphagocytosisby
antibodybindingtocellsurfacesorotherparticlesisreferredtoasopsonization.Inaddition,cellboundIgG
maydirectthenonphagocyticactionofTcellsornaturalkillercells,whichresultsincelldestructionbya
processcalledantibodydependentcellularcytotoxicity.ThisprocesscanproceedinanonspecificfashionasT
cellsbindtothetargetcellthroughIgGFcreceptorsontheTcellsurface.Contactbetweenthetargetand
effectorcellsisnecessary.
Cellscommonlyaffectedbythesetypesofreactionsincludeerythrocytes,leukocytes,andplatelets,resulting
inhemolyticanemia,agranulocytosis,andthrombocytopenia,respectively.Thisprocessmaybeinitiatedby
drugssuchaspenicillin,quinidine,quinine,phenacetin,cephalosporins,andsulfonamides.
Anothertypeofreactionthatmayaffecttheformedelementsinbloodistheinnocentbystanderreaction.
Withthistypeofreaction,antigenantibodycomplexesformedinbloodadherenonspecificallytocells.
Complementisthenactivated,resultingincelllysis.

TypeIII
TypeIIIimmunologicreactionsarecausedbyantigenantibodycomplexesthatareformedinblood.The
complexesformwithdrugallergenandantibodyinvaryingratiosandmaydepositintissues,resultinginlocal
ordisseminatedinflammatoryreactions.Antigenantibodycomplexformationcanresultinplatelet
aggregation,complementactivation,ormacrophageactivation.ChemotacticsubstancessuchasC4aalsoare
produced.Thesesubstancescausetheinfluxofneutrophilsandresultinthereleaseofanumberoftoxic
substancesfromtheneutrophil(e.g.,proteinases,collagenases,kiningeneratingenzymes,andreactiveoxygen
andnitrogensubstances),whichcancauselocaltissuedestruction.
Plateletaggregationmayoccurasaresultofimmunecomplexformation,resultingintheformationof
microthrombiandthereleaseofvasoactivemediators.Also,insolublecomplexesmaybephagocytizedby
macrophagesandactivatethesecells.
TheformationofantigenantibodycomplexescanleadtoclinicalsyndromessuchastheArthusreaction.In
thismodel,ahighlevelofpreformedspecificIgGantibodycombineswithantigentoproducealocalized
edematous,erythematousreactionwithin5to8hours.Thereactioninvolveslocalformationofinsoluble
antigenantibodycomplexes,complementactivationwithreleaseofC3aandC5acollectivelyreferredtoas
anaphylatoxins,mastcelldegranulation,andinfluxofpolymorphonuclearcells.

TypeIV
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TypeIVreactionsaredelayedhypersensitivityreactionsthattypicallyaredemonstratedasdermatologicevents
mediatedbyTcells(CD4+orCD8+).57TheCoombsandGellclassificationofallergicdrugreactionswas
developedbeforeourunderstandingofthevariedrolesofTcellsintheimmuneresponse.Foursubclassesof
typeIVreactions(IVaIVd)havebeendescribedbasedontherespondingTcell(e.g.,Thelpertype1cell,T
helpertype2cell,cytotoxicTcell),effectormechanism(e.g.,recruitmentofmacrophages,eosinophils,or
neutrophils),andclinicalmanifestations(e.g.,contactdermatitis,bullousexanthems,maculopapulareruptions,
pustularexanthems)(eFig.221).57TypeIVreactionsrequirememoryTcellsspecificfortheantigenin
question.Onexposuretotheantigen,theimmuneresponseismediatedbyaspecificsubtypeofTcellthat
orchestratesaninflammatoryresponsethroughthesecretionofcytokinesandtherecruitmentofeffectorcells.
Thesereactionsareassociatedwithawidevarietyofadverseeffects(e.g.,contactdermatitis,maculopapular
exanthemas,bullousexanthemas,eczema,orpustularexanthemas),andtheyalsomaybeusefulfordiagnostic
purposes.Examplesofthelatterincludethepurifiedproteinderivative(PPD)antigenfromMycobacterium
tuberculosisusedinthetuberculinskintestandotherrecallskintestantigens,suchasmumps.After
intradermalinjection,theseantigensproducealocalreaction(erythemaandinduration)within48to72hours.
Delayedcontacthypersensitivityalsocanbecausedbyawidevarietyofchemicalsanddrugs.

OtherAllergicReactions
Theprecisemechanismofmanydrugreactionsisnotknown,althoughthereactionsarebelievedtobe
immunemediated.Perhapsmostcommonarethedelayeddermatologicreactionsthatoccurwithavarietyof
drugs(especiallypenicillinsandsulfonamides).Thesereactionsmaybeevidentasfixeddrugeruptions
macropapular,morbilliform,orerythematousrashesexfoliativedermatitisphotosensitivityreactionsor
eczema.Thesereactionsalsomaybemanifestaslateonsetpruritus,urticaria,andangioedema.
Anumberofseriouscutaneousadversereactions,knownasSCARs,maybetheresultofimmunologic
reactions.SCARsincludedrugrashwitheosinophiliaandsystemicsymptoms(DRESS)andthe
mucocutaneousdisorders,SJSandtoxicepidermalnecrolysis(TEN).Druginducedfeveralsomayinvolve
immunologicmechanisms.Othergeneraltypesofreactionsbelievedtobeimmunemediatedinsomecases
includehepaticdrugreactions(cholestaticorhepatocellular)andpulmonaryreactions(e.g.,interstitial
pneumonitis,whichhasbeenassociatedwithnitrofurantoin).

AnaphylactoidReactions
Variousdrugscanproducereactionsthataresimilartoanaphylaxisinclinicalsignsandsymptomsbutarenot
mediatedbyimmunemechanisms.Thedrugscausingthesereactionscancausereleaseofmastcelland
basophilderivedmediatorsbyapharmacologicorphysicaleffectratherthanthroughcellboundIgE.These
reactionsaredescribedasanaphylactoid(anaphylaxislike)reactionsornonimmunemediatedanaphylaxis,
themostsevereformofpseudoallergy.10Pseudoallergyreferstoawidearrayofreactionsrangingfrom
localizedhivestolifethreateningangioedema,hypotension,andanaphylaxis,allofwhichareexplainedbythe
nonimmunologicreleaseoractivationofinflammatorymediators.Drugsthatcanproduceanaphylactoid
reactionsincludevancomycin,opiates,iodinatedradiocontrastagents,angiotensinconvertingenzyme(ACE)
inhibitors,amphotericinB,andDtubocurarine.Theredmansyndromeisacommonexampleofa
pseudoallergicreactionfromvancomycin.Ifvancomycinisinfusedtoorapidly,itcancausethedirectrelease
ofhistamineandothermediatorsfromcutaneousmastcells,producingatypicalclinicalpictureofitching,
flushing,andhives,firstaroundtheneckandfaceandthenprogressingtothechestandotherpartsofthebody
usuallybeginningshortlyaftertheinfusionhasbegun.Insomecases,thecutaneousmanifestationsofred
mansyndromemaybeaccompaniedbyhypotension,therebyconstitutingananaphylactoidevent.Most
patientswhohavehadredmansyndromewilltoleratevancomyciniftherateofinfusionisslowed.Inrare
cases,theseverityofthereactionmayprecludecontinuedtherapywithvancomycin.Anumberofotheragents
(includingaspirin)mayproduceanaphylactoidreactionsbyalteringthemetabolismofinflammatorymediators
suchasPGsorkinins.AngioedemafromACEinhibitorsisaclassicexampleofananaphylactoidreaction.
Althoughthemechanismbywhichthisanaphylacticlikeeventoccursisnotfullyunderstood,inhibitionofthe
breakdownofbradykininandsubstancePbytheACEinhibitormayexplaintheinflammation,increased
vascularpermeability,andvasodilation.

ClinicalManifestationsofAllergicandAllergicLikeReactions
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Anaphylaxis
Anaphylaxisisanacute,lifethreateningreaction,usuallymediatedbyanimmunemechanism,that
involvesmultipleorgansystemsandoccursin10to20per100,000populationperyear.11About1,500deaths
fromanaphylaxisoccurannuallyintheUnitedStates.12From1.2%to15%oftheUnitedStatespopulation
maybeatriskforanaphylacticreactions.13Recentlyreporteddatasuggestthattheprevalenceisrising,most
notablyintheyoungeragegroup.14Althoughmanydrugsmaycauseanaphylaxis(oranaphylactoid)
reactions,themostcommonlyreportedarepenicillins,aspirinandotherNSAIDs,andinsulins.10,14Inmost
patients,theinitialsignsandsymptomsoccurintheskin(flushing,pruritus,urticaria,angioedema).The
secondmostcommonsymptomsarerespiratory(tightnessofthethroatandchest,dysphagia,dysphoniaand
hoarseness,cough,stridor,shortnessofbreath,dyspnea,congestion,rhinorrhea,sneezing)followedby
dizzinessandgastrointestinaltractsymptoms(nausea,crampyabdominalpain,vomiting,diarrhea).14About
10%to30%ofpatientsdevelophypotension.Additionalcardiovasculareffectsincludesyncope,altered
mentalstatus,chestpain,anddysrhythmia.11
In2010,aconsensuspanelreconvenedtoupdatethedefinitionandmanagementofanaphylaxis.14
Anaphylaxisishighlylikelywhenoneofthefollowingthreescenariosispresent:
1.Acuteonsetofareaction(minutestoseveralhours)withinvolvementoftheskin,mucosaltissue,or
both(e.g.,generalizedhivespruritusorflushingswollenlips,tongue,uvula)andatleastoneofthe
following:
Respiratorycompromise(e.g.,dyspnea,wheeze/bronchospasm,stridor,reducedpeakexpiratory
flow,hypoxemia)
Reducedbloodpressureorassociatedsymptomsofendorgandysfunction(e.g.,hypotonia,
syncope,incontinence)
2.Twoormoreofthefollowingthatoccurrapidlyafterexposuretoalikelyallergen(minutestoseveral
hours):
Involvementofskinormucosaltissue(asabove)
Respiratorycompromise(asabove)
Reducedbloodpressureorassociatedsymptoms
Persistentgastrointestinalsymptoms(e.g.,crampyabdominalpain,vomiting)
3.Reducedbloodpressureafterexposuretoknownallergen(minutestoseveralhours)
Thepanelindicatedthatotherpresentationsmayindicateanaphylaxis,suchasacutechestpainorarrhythmia
withoutdermatologicmanifestations,andthatthepotentialexistsforfalsepositiveresults.
Anaphylaxisgenerallybeginswithin30minutesbutalmostalwayswithin2hoursofexposuretotheinciting
allergen.Theriskoffatalanaphylaxisisgreatestwithinthefirstfewhours.Latephaseorbiphasicreactions
canoccur1hourto72hoursaftertheinitialpresentationwithmostoccurringwithin10hours.Becauseofthe
possibilityofabiphasicreaction,patientsshouldbeobservedforatleast12hoursafterananaphylactic
reaction.Fatalanaphylaxismostoftenresultsfromasphyxiacausedbyairwayobstructioneitheratthelarynx
orwithinthelungs.Cardiovascularcollapsemayoccurasaresultofasphyxiainsomecasesinothercases,
cardiovascularcollapsemaybethedominantmanifestationfromthereleaseofmediatorswithintheheart
musclesandcoronarybloodvessels.
Newerclinicalmarkersmayaidinthediagnosisofanaphylaxis.Serumlevelsoftryptaseormaturetryptase
(alsoknownastryptase)peakintheserumwithin0.5to2hoursaftertheonsetofanaphylaxis.14Tryptase
levelsaremosthelpfulinmakingthediagnosisiftheyaredrawnnomorethan6hoursaftertheonsetof
symptoms.Plasmahistaminelevelsremainelevatedforonly30to60minutesthus,theyarenotclinically
usefulinpatientswhopresent1hourorlateraftertheonsetofanaphylaxis.14

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SerumSicknessandSerumSicknessLikeDisease
Serumsicknessisaclinicalsyndromeresultingfromtheeffectsofsolublecirculatingimmunecomplexesthat
formunderconditionsofantigenexcess.Thereactioncommonlyresultsfromtheuseofantiseracontaining
foreign(donor)antigenssuchasequineserumintheformofantitoxinsorantivenoms.Theonsetofserum
sicknessisusually7to14daysafterantigenadministration.Theonsetmaybemorerapidwithreexposureto
thesameagentinanindividualwithpriorserumsickness.Fever,malaise,andlymphadenopathyarethemost
commonclinicalmanifestations.Arthralgias,urticaria,andmorbilliformskineruptionalsomaybepresent.A
milderandmoretransientformofserumsicknessisserumsicknesslikedisease(SSLD).Thepredominant
featureofSSLDisacutaneouseruption,eitherurticarialormaculopapular,thatoccurswithin5to21daysof
drugadministration.15Aswithserumsickness,therashisusuallyprecededbyaprodromalphaseconsisting
offever,malaise,lymphadenopathy,andarthralgias.SSLDhasbeenassociatedwiththeadministrationof
ciprofloxacin,bupropion,hydantoins,minocycline,sulfonamides,penicillins,andcephalosporins(especially
cefaclor).SSLDisusuallyselflimitingafterdiscontinuationofthecausativeagent,butitcansometimes
progresstoincludevasculitis.

DrugRashwithEosinophiliaandSystemicSymptoms
Previouslyknownbythetermdrughypersensitivitysyndrome,thetriadofrash,eosinophilia,andinternal
organinvolvementiscurrentlyreferredtoasdrugrashwitheosinophiliaandsystemicsymptoms(DRESS).
Bocquetandcolleagues16describedthefollowingcriteriaforadiagnosisofDRESS:(a)cutaneousdrug
eruption(usuallyadiffusemaculopapularrashaccompaniedbyfacialandneckedema)(b)hematologic
abnormalitiesincludingeosinophiliagreaterthan1,500cells/mm3(1.5x109/L)orthepresenceofatypical
lymphocytesand(c)systemicinvolvementincludingadenopathiesgreaterthan2cmindiameter,hepatitis,
interstitialnephritis,interstitialpneumonia,orcarditis.16Boththeallopurinolhypersensitivitysyndromeand
anticonvulsanthypersensitivitysyndromeareexamplesofDRESS.17OtherdrugsassociatedwithDRESS
includeminocycline,dapsone,lamotrigine,andthesulfonamides.TheonsetofDRESSistypicallydelayed
rangingfrom3to8weeksafterdruginitiation,andthereisahighdegreeofinterpatientvariabilityinthe
targetedorgansandtheseverityoforganinvolvement.16,17ThemortalityrateassociatedwithDRESSis10%,
anditislargelyattributedtosystemicinvolvementoftheliver,kidneys,orlungs.17Afterdiscontinuationof
thecausativedrug,theskinrashresolvesandlaboratoryabnormalitiesnormalizeoveraperiodof4to8weeks.
Systemiccorticosteroids(0.51mg/kg/dayprednisoneorsteroidequivalent)havebeenusedinthetreatment
ofDRESSbasedontheseverityoforganinvolvement.

DrugFever
Fevermayoccurinresponsetoaninflammatoryprocessordevelopasamanifestationofadrugreaction.
Drugfeverhasbeenestimatedtooccurinasmanyas10%ofhospitalinpatients.18Manydrugshavebeen
reportedtocausefeverwiththemostfrequentlyimplicatedclassesbeingtheantimicrobials(e.g.,acyclovir,
amphotericinB,lactams,minocycline,rifampin,sulfonamides,tetracycline),anticonvulsants(e.g.,
carbamazepine,phenytoin),antiarrhythmics(e.g.,procainamide,quinidine),andothercardiacmedications
(e.g.,clofibrate,diltiazem,dobutamine,furosemide,heparin,methyldopa,procainamide).19Thesedrugsmay
affectthecentralnervoussystem(CNS)directlytoaltertemperatureregulationorstimulatethereleaseof
endogenouspyrogens(e.g.,interleukin1andtumornecrosisfactor),PGs,ornervoussystemmonaminesthat
alterthethermoregulatorysetpoint.19Drugsalsomaycausefeverasaresultoftheirpharmacologiceffectson
tissues(e.g.,feverresultingfrommassivetumorcelldestructioncausedbychemotherapy).
Thetemperaturepatternofdruginducedfeverisquitevariableandthereforeoflittlehelpinthediagnosis.
Fourpatternsofdrugfeverhavebeendescribed:continuous,remittent,intermittent,andhectic.Acombination
ofintermittentandremittent,hecticfeveristhemostcommonpatternwithtemperaturesof102to104F
interruptingnormaltemperaturesthroughouttheday.19Drugfevermayoccuratanytimeduringthecourseof
therapywithamedianreportedtimeof7to10daysafterdruginitiation.Antimicrobialsandantineoplastic
drugshavebeenassociatedwiththeshortesttimetoonset(median,6and0.5days,respectively),whereas
CNSagentsandcardiovasculardrugshavelongertimestoonset(median,10and16days,respectively).19
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Laboratoryfindingssuchasleukocytosis,eosinophilia,elevatedlacticdehydrogenase,andelevated
erythrocytesedimentationratemayaidinthediagnosis.Generally,withdrawalofthecausativeagentresultsin
promptdefervescenceassoonasthedrugiseliminatedcompletely.Feverusuallyrecursonreadministrationof
thecausativeagent.

DrugInducedAutoimmunity
Autoimmunediseaseshavebeenassociatedwithdrugsandmayinvolveavarietyoftissuesandorgans.A
commonlyrecognizeddrugrelatedautoimmunedisorderissystemiclupuserythematosus(SLE)inducedby
infliximab,etanercept,procainamide,hydralazine,quinidine,orisoniazid.20Exposureofsusceptiblepersons
totheseagentsappearstoalternormalbodyproteins,RNA,orDNAinsuchawayastomakethese
componentsantigenic,leadingtotheformationofautoreactiveantibodiesandcells.Mostpatientstreatedwith
infliximabdevelopantinuclearantibodies,butonly2%ofpatientspresentwithSLEsymptoms.Themost
commonclinicalmanifestationsincludearthralgias,myalgias,andpolyarthritis.Facialrash,ulcers,and
alopeciaoccurlessfrequently.Renalorpulmonaryinvolvementalsomayoccur.Thesereactionstypically
developseveralmonthsafterbeginningthedrugandgenerallyresolvesoonafterthedrugisdiscontinued.21
Othersyndromesbelievedtoinvolveautoimmunemechanismsincludedruginducedhemolyticanemia
attributedtomethyldopa,interstitialnephritisproducedbymethicillin,andhepatitiscausedbyphenytoinand
halothane.Interstitialnephritisischaracterizedbyfever,rash,andeosinophiliaassociatedwithproteinuriaand
hematuria.Hepaticdamageduetodrugsgenerallyismanifestedaseitherhepatocellularnecrosisorcholestatic
hepatitis.Druginducedhepatitishasbeenassociatedwithphenothiazines,sulfonamides,halothane,phenytoin,
andisoniazid(seeeChap.17).Hepatocellulardestructionisevidencedbyelevationsinserumtransaminases.
Hepatomegalyandjaundicesometimesmaybeevident.Cholestasismaybemanifestedbyjaundiceand
elevationsinserumalkalinephosphataseandsometimesbyrash,fever,andeosinophilia.

Vasculitis
Vasculitisisaclinicopathologicprocesscharacterizedbyinflammationandnecrosisofbloodvesselwalls.The
vasculiticprocessmaybelimitedtotheskin,oritmayinvolvemultipleorgans,includingtheliverorkidney,
joints,orCNS.Characteristically,cutaneousvasculitisismanifestedbypurpuriclesionsthatvaryinsizeand
number.Vasculitisalsomaybemanifestedaspapules,nodules,ulcerations,orvesiculobullouslesions,
generallyoccurringonthelowerextremitiesbutsometimesinvolvingtheupperextremities,includingthe
hands.Drugsassociatedwithvasculitisincludeallopurinol,lactamantibiotics,sulfonamides,thiazide
diuretics,phenytoin,andvancomycin.

DermatologicReactions
Awidevarietyofdermatologicdrugreactionshavebeenreportedtohaveanimmunologicbasis.2,22
Cutaneousreactionsarethemostcommonmanifestationsofallergicdrugreactions.Althoughmost
dermatologicreactionsaremildandresolvepromptlyafterdiscontinuingthedrug,somesuchasSJSandTEN
areseriousorevenlifethreateningreactions.BothSJSandTENareclassifiedasprogressivebullousor
blisteringdisordersthatconstitutedermatologicemergencies.23Theyareconsideredseverevariantsof
erythemamultiforme.Similartoerythemamultiforme,SJSandTENareassociatedwiththewidespread
developmentofavarietyofskinlesions,includingmacules,purpuriclesions,andthetargetirislesion.The
targetlesionisdiscreteandroundandidentifiedbyanareaofcentralclearingsurroundedbytwoconcentric
ringsofedemaanderythema.Unlikeerythemamultiforme,SJSandTENaremostcommonlydruginduced
ratherthanassociatedwithrecurrentherpessimplexviralinfection,andtheyprogresstoincludemucous
membraneerosionandepidermaldetachment.23Mucosalmembranesinthemouth,lips,nasalcavity,and
conjunctivaeareusuallyinvolved.Asthesesyndromesprogress,theerythematouslesionsbecomemore
widespreadontheface,trunk,andextremities,andmanyevolveintoblisters.Withindaysaftertheonsetof
thelesions,fullthicknessepidermaldetachmentoccurs.SJSandTENareoftenconsideredasacontinuous
spectrumofadisease,withTENbeingthemostsevereform.Theextentofepidermaldetachmentisusedto
distinguishbetweenSJSandTEN(i.e.,<10%detachmentofbodysurfaceareawithSJSgreaterthan30%
detachmentofbodysurfaceareawithTEN).ThetermSJSTENoverlapisusedtodescribecasesinwhich
epidermaldetachmentoccurson10%to30%ofthebodysurfacearea.23,24BothSJSandTENareassociated
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withanumberoflongtermsequelae,includingpermanentvisualimpairment,temporarynailloss,cutaneous
scarring,andirregularpigmentation.Beingthemoresevereform,TENisalsomorelikelytobecomplicated
bysystemicorganinvolvement,includingacutekidneyfailure,neutropenia,andrespiratoryfailure.A
severityofillnessscoringsystemknownasSCORTENhasbeendevelopedtopredictprognosisinpatients
withTEN.25SCORTENusessevenindependentriskfactorsbasedonanassessmentwithin24hoursof
clinicalpresentation.
Cutaneousadversereactionswerereportedtooccurin2.7%ofhospitalizedpatients.26TENisestimatedto
occurin0.4to1.3casesper1millionpeopleperyear,andSJShasbeenreportedin1to6casesper1million
peopleperyear.27,28ThemortalityratesassociatedwithSJSandTENrangefrom1%to5%and10%to70%,
respectively.28eTable222listsdrugsandagentsassociatedmostcommonlywithcutaneousreactions.22In
general,antimicrobialsareimplicatedmostfrequentlyasthecauseofcutaneouseventswithreactionrates
rangingfrom1%to8%.ThemostlikelyoffendersofSJSandTEN,determinedincasecontrolstudies,arethe
sulfonamides,particularlytrimethoprimsulfamethoxazole.29OthermajoroffendersofSJSandTEN
identifiedinthesestudiesareallopurinol,theaminopenicillins,carbamazepine,chlormezanone,
cephalosporins,theimidazoleantifungals,lamotrigine,nevirapine,theoxicamNSAIDs,phenytoin,
quinolones,andthetetracyclines.29
eTable222Top10DrugsandAgentsReportedtoCauseSkinReactions
Reactionsper1,000Recipients
Amoxicillin
51.4
Trimethoprimsulfamethoxazole 33.8
Ampicillin
33.2
Iopodate
27.8
Blood
21.6
Cephalosporins
21.1
Erythromycin
20.4
Dihydralazinehydrochloride
19.1
PenicillinG
18.5
Cyanocobalamin
17.9
DatafromRoujeauJC,SternRS.Severeadversecutaneousreactionstodrugs.NEnglJMed1994331:1272
1285.

RespiratoryReactions
Drugsmayproduceupperorlowerrespiratorytractreactions,includingrhinitisandasthma.Respiratorytract
manifestationsmayresultfromdirectinjurytotheairwaysormayoccurasacomponentofasystemicreaction
(e.g.,anaphylaxis).AsthmamaybeinducedbyaspirinandotherNSAIDsorbysulfitesusedaspreservatives
infoodsandmedications.Otherpulmonarydrugreactionsbelievedtobeimmunologicincludeacute
infiltrativeandchronicfibroticpulmonaryreactions.Thelatterisoftencausedbyantineoplasticagentssuchas
bleomycin.Foramoredetaileddiscussionofdruginducedpulmonarydisease,seeeChapter15.

HematologicReactions
Mostformedelementsandsolublecomponentsofthehematopoieticsystemmaybeaffectedbyimmunologic
drugreactions.Eosinophiliaisacommonmanifestationofdrughypersensitivityandmaybetheonly
presentingsign.Hemolyticanemiamayresultfromhypersensitivitytodrugs.Otherhematologicreactions
includethrombocytopenia,granulocytopenia,andagranulocytosis.Foradetaileddiscussionofhematologic
drugreactions,seeeChapter24.

FactorsRelatedtotheOccurrenceorSeverityofAllergicDrug
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Reactions
Amongthefactorsthatinfluencethelikelihoodofallergicdrugreactionsarethedegreetowhichthedrug
anditsmetabolitesbindcovalentlytohumanproteins,howthedrugismetabolized,whetherthedrugcontains
proteinsofnonhumanorigin(e.g.,chimericmonoclonalantibodies,streptokinase)orantigenicexcipients(e.g.,
peanutoil,FD&Cdyes,sulfites,soybeanemulsion),therouteofexposure,andthesensitivityoftheindividual
asdeterminedbygeneticsandenvironmentalfactors.Hypersensitivitycanoccurwithanydoseofadrug,but
sensitizationismorelikelytooccurwithcontinuousdosingratherthansingledosing.Afterapatienthas
becomesensitized,theseverityofareactionisoftendeterminedbythedoseandthedurationofexposure.The
routeofadministrationmayalsoinfluencedrugsensitivity.Thetopicalrouteofdrugadministrationappearsto
bethemostlikelytosensitizeandpredisposetodrugreactions.Theoralrouteisthesafest,andtheparenteral
routeisthemosthazardousforadministrationofdrugsinsensitiveindividuals.Relativelyfewcasesof
immediatehypersensitivityassociateddeathswithorallactamantimicrobialshavebeenreported.
Thepresenceofgeneticallydeterminedhumanleukocyteantigen(HLA)allelesincreasessusceptibilitytoa
numberofdrughypersensitivitysyndromes.Inpatientsinfectedwiththehumanimmunodeficiencyvirus
(HIV),hypersensitivitytoabacavirhasbeenassociatedwiththepresenceofHLAB*5701.30Severeimmune
mediatedcutaneousreactionstoallopurinol,includingSJSandTEN,havebeenassociatedwiththepresence
ofHLAB*5801inHanChinese.31Inthissamepatientpopulation,thepresenceofHLAB*1502increasesthe
riskofSJSandTENwithcarbamazepine,phenytoin,andfosphenytion.32AssociationsbetweenHLAalleles
anddrugreactivityhavebeendescribedforaminopenicillins,aspirin,iodinatedcontrastmedia,gold,
lamotrigine,andtrimethoprimsulfamethoxazole.33Geneticfactorscanalsoinfluencethemetabolic
deactivationofdrugsviaphase1and2metabolism.Forexample,slowacetylatorsofprocainamideand
hydralazineareatincreasedriskforSLE.GenesalsoencodeforthetypeofTcellreceptorandthespecific
cytokinesinvolvedinthesignalingofallergicdrugreactions.
Drugallergiesappeartodevelopwithequalfrequencyinatopicandnonatopicindividuals.Inaddition,patients
withahistoryofdrugallergyappeartobeatincreasedriskforadversereactionstootherpharmacologic
agents.3Ageseemstoberelatedtotheriskofallergicreactionsbecausetheyoccurlessfrequentlyinchildren.
Thismayberelatedtoimmaturityoftheimmunesystemordecreasedexposure.Thepresenceofsome
concurrentdiseases,particularlyviralinfections,predisposestodrugreactions.Examplesincludethehigher
rateofmorbilliformrashwhenampicillinisadministeredtopatientswithinfectiousmononucleosis,thehigher
rateofreactionstotrimethoprimsulfamethoxazoleinHIVinfectedpatients,andtherelationshipbetween
infectionwithhumanherpesvirus6(HHV6)andthedevelopmentofDRESS.

DrugsCommonlyCausingAllergicorAllergicLikeDrugReactions
LactamAntimicrobials
Allergytolactamantibioticsiscommonlyreportedbypatientsinhealthcaresettings.Allergicreactionsto
penicillinoccurin0.7%to8%oftreatmentcoursesbutwasashighas15%inoneretrospectivereportof
hospitalizedpatientstreatedwithpenicillin.34,35Althoughmostpatientsreportingpenicillinallergydonot
haveallergy,areportedhistoryisassociatedwithahigherlikelihoodofpositiveskintestreactivity.Only10%
to20%ofpatientsreportingpenicillinallergyarefoundtobeallergicbyskintesting.10,36Patientswitha
historyofimmediatepenicillinallergywhohaveanegativepenicillinskintestresultareunlikelytoreacton
subsequentcoursesofpenicillins.10,36
Themostcommonreactionstopenicillinincludeurticaria,pruritus,andangioedema.Allfourofthemajor
typesofhypersensitivityreactionshavebeenreportedwithpenicillin,aswellassomereactionsthatdonotfit
intothesecategories.Awidevarietyofidiopathicreactionsoccur,suchasmaculopapulareruptions,
eosinophilia,SJS,andexfoliativedermatitis.Cutaneousreactionscanoccurinupto4.4%oftreatmentcourses
ofpenicillin37andinupto8%ofthoseofaminopenicillins.38Theincidenceofampicillinrashiscloseto
100%inpatientswithviralinfectionssuchasinfectiousmononucleosis.39
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Someaspectsofthemechanismofpenicillinimmunogenicityhavebeendetermined.Becausebenzylpenicillin
isarelativelysmallmolecule(356Da),itmustcombinewithmacromolecules(presumablyproteins)toelicit
animmuneresponse.Penicillinisrapidlyhydrolyzedtoanumberofreactivemetabolitesthathavetheability
tocovalentlylinktoproteins.Ofthesemetabolites,95%isintheformofbenzylpenicilloylthatbinds
covalentlytothelysineresiduesofproteinssuchasalbuminthroughanamidelinkageinvolvingthelactam
ring(eFig.222).Thispenicilloylproteinconjugateisreferredtoasthemajorantigenicdeterminant.The
otherpenicillinmetabolitessuchaspenilloateandpenicilloatebindinlesserquantitiestoproteins.Theseare
referredtoasminorantigenicdeterminants.Thetermsmajorandminorrefertotherelativeproportionsof
theseconjugatesthatareformedandnottotheclinicalseverityofthereactionsgenerated.Immediate
hypersensitivityreactionsmaybemediatedbyIgEforbothminorandmajordeterminants.Infact,theminor
antigenicdeterminantsaremorelikelytocauselifethreateninganaphylacticreactions.
eFigure222

Formationofabenzylpenicilloylhaptenproteincomplex.
Inadditiontothemajorandminordeterminants,uniquesidechaindeterminantsmaymediateallergytosome
penicillins.Boththeaminopenicillinsandpiperacillinmaycausehypersensitivityreactionsviauniqueside
chainsontheirstructures.40,41Therefore,apatientmayexhibithypersensitivitytoamoxicillinorpiperacillin
viaasidechaindeterminantwhileexhibitingnoreactivitytootherpenicillins.Reportsofselectiveallergyto
amoxicillinhavebecomerelativelycommon.TheRgroupsidechainofamoxicillinisbelievedtobethe
primaryepitope,butselectivereactivitytoclavulanicacidhasbeenpostulatedandexploredinthose
experiencingareactiontoamoxicillinclavulanate.4244Carefulhistorytakingisneededtoidentifypatients
withhighlikelihoodofsidechainspecificreactions.Skintestingwithdiluteconcentrationsofamoxicillin,
ampicillin,andpiperacillinhasbeenusedtoaidinthedeterminationofsidechainspecificreactions.4547
Patientswhoareallergictopenicillinsalsomaybesensitivetootherlactams.48,49Theexactincidenceof
crossreactivitybetweencephalosporinsandpenicillinsisnotknownbutisbelievedtobelow.10,47,48The
riskwasoriginallyreportedas10%to15%inthe1970swhencephalosporinswerecontaminatedwithtrace
amountsofpenicillin.Currentestimatesofthecrossreactiveriskbetweenpenicillinandthefirstandsecond
generationcephalosporinsare5%to7.5%andaslowas1%betweenpenicillinandthethirdandfourth
generationcephalosporins.10Onepercentto8%ofpatientswithpenicillinspecificIgEmaydevelopan
immediatetypehypersensitivityreactiontocephalosporins.50Incontrast,patientswithreportedpenicillin
allergyandnegativeskintestresultsareatnogreaterrisk.10
Ideally,cephalosporinsshouldbeavoidedinpatientswithhistoryofanimmediatehypersensitivityreaction
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topenicillin,althoughmoststudiessuggestthereislittleriskofanallergicresponsetoacephalosporinevenin
apersonwithapositiveskintestresulttopenicillin.Basedontheresultsofonemetaanalysis,patientswith
penicillinallergyhavethehighestriskofcrossreactivitywiththefirstgenerationcephalosporins(oddsratio
[OR],4.7995%confidenceinterval[CI],3.716.17).51Theoddsofreactingtoasecondandthird
generationcephalosporinwere1.13(95%CI,0.612.12)and0.45(95%CI,0.181.13),respectively.51The
higherrateofcrossreactivitybetweenpenicillinandthefirstgenerationcephalosporinshasbeenattributedto
similaritiesintheR1sidechainsoftheseagents.10,47,48TheR1sidechainisconnectedtotheopened
lactamring,therebyinfluencingtheantigenicityoftheseagents.Whenassessingthepotentialforcross
reactivitybetweenpenicillinsandcephalosporins,cliniciansshouldevaluatethesimilaritiesintheR1side
chainsoftheagents.47,48,51,52BetalactamshavinganR1substitutionchemicallysimilartothatofpenicillin
Garecephaloridine,cephalothin,andcefoxitin.IntheR1position,amoxicillinischemicallysimilarto
ampicillin,cefaclor,cephalexin,andcephradine.Cefotaxime,ceftizoxime,ceftriaxone,cefpodoxime,and
cefepimehavechemicallysimilarsubstitutionsintheR1positionthatmayinfluencetheriskofcross
reactivity.52
Cephalosporinsmayinduceimmuneresponsesmediatedbythecorelactamstructurehowever,theyare
morelikelytodosoviauniqueRgroupsidechaindeterminants.48,51Inapatientwithacephalosporin
allergy,skintestingwiththemajorandminordeterminantsofpenicillincanbeusedtoidentifythelikelihood
ofreactivitytothecorelactamring.Theriskofcrossreactivitybetweencephalosporinsisconsideredtobe
higherthanthatbetweenthepenicillinsandcephalosporins.CrossreactionsmayoccurthroughidenticalR1
sidechains.Ofnote,ceftazidimesharesacommonsidechainwithaztreonam.
Theactualriskofacrossreactionbetweenthepenicillinsandthecarbapenemsappearstobemuchlowerthan
originallydescribed.Theinitialestimateofthecrossreactiveriskwas47.4%,butcurrentestimatesrangefrom
0.9%to11%.49Theinitialestimatewasbasedontheresultsofskintestingwithpenicillinand
nonstandardizedcarbapenemreagents.Anumberofretrospectivestudiesreportingvariableratesofcross
reactivityreliedonselfreportedhistoriesasconfirmationofpenicillinallergy.Threerecentlypublished
prospectivestudiesusedbothskintestingmethodsandcarbapenemchallengedosingtoassesscrossreactive
risk.Inoneofthesestudies,onlyoneof112patientswithskintestconfirmedpenicillinallergydemonstrated
apositiveskintestresultforimipenem.53Challengedosingwithimipenemtoafinaldoseof500mgwas
subsequentlyperformedin110patientswithnegativeimipenemskintestresultsnoneofthe110patientshad
areaction.Resultsoftwoadditionalprospectivestudies,oneofwhichwasperformedinchildrenages3to14
years,suggestalowriskofcrossreactivitybetweenpenicillinandmeropenem.54,55Inbothstudies,onlyone
patientwithskintestpositivitytopenicillinhadapositiveskintestresultformeropenem.Gradedchallenge
dosingwithmeropenemwastoleratedin100%oftheskintestnegativepatientsinbothstudies.Itisimportant
tonotethatnoneoftheskintestnegativepatientsweresubsequentlytreatedwithfulltherapeuticregimensof
thecarbapenem.However,thehighleveloftolerabilitytochallengedosingsuggestsalowrateofcross
reactivityinskintestnegativepatients.Basedontheseresults,theroutinepracticeofavoidingcarbapenem
useinpatientswithhistoryofpenicillinallergyshouldbereconsidered.49
Ofthemonobactams,aztreonamonlyweaklycrossreactswithpenicillinandcanbeadministeredsafelyto
mostpatientswhoarepenicillinallergic.10,49

RadiocontrastMedia
Radiocontrastagentsfrequentlycausereactionscategorizedasimmediate(in1hour)ornonimmediate(in
110days)viabothIgEmediatedandnonIgEmediatedmechanisms.56Thefrequencyandseverityofthese
reactionsareinfluencedbythetypeofradiocontrastagent(ionicvs.nonionic),andpatientspecificfactors
suchashistoryofatopy,asthma,orpriorreactiontoaradiocontrastagent.Currentreportedestimatesofthe
frequencyofanaphylactoidreactionswithionicandnonionicagentsare1%to3%andlessthan0.5%,
respectively.10,14Delayedskinreactions,usuallypresentingasmaculopapularexanthems,occurin1%to3%
ofpatientsover5to7days.56Severe,immediateanaphylacticreactionsoccurin0.01%to0.04%of
patients.38Inaddition,radiocontrastagentsmaycausedosedependenttoxicreactionsthatcanproducerenal
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impairment,cardiovasculareffects,andarrhythmias.57Themechanismofreactionstoradiocontrastagentsis
notclearlyunderstood.Histaminereleaseandmastcelltriggeringhavebeendocumentedinsevereimmediate
reactions,suggestinganIgEmediatedmechanism.58Theolder,highosmolarradiocontrastagentscanactivate
mastcells,basophils,andthecomplementsystemdirectly(IgEindependentmechanism),resultinginthe
releaseofinflammatorymediators.ThedelayedonsetmaculopapularrashappearstobeTcellmediated.The
lowosmolarnonioniccontrastagentsappeartocausefeweranaphylactoidreactions.
Theriskofanaphylactoidreactionstoradiocontrastmediaisgreaterinwomenandinpatientswithahistoryof
atopyorasthma.55Otherrecognizedriskfactorsincludeahistoryofpreviousreaction,severedrugallergies,
cardiacdisease,andtreatmentwithblockers.10,14Despiteacommonmisconception,seafoodallergyor
iodineallergydoesnotpredisposetoradiocontrastmediareactions.Neitherskintestsnororaltestsareuseful
forpredictingreactionstotheseagents.10,14Althoughsomeregimenshavebeenrecommendedtopreventthe
recurrenceofimmediateeventsinpatientswhohaveexperiencedreactionspreviously,thevalueofthese
preventiveregimenshasnotbeenproven,andtheiruseremainscontroversial.56,59Acommonly
recommendedregimeninhighriskpatientsisoralprednisone(50mg)13,7,and1hoursbeforeexposurewith
50mgofdiphenhydraminegivenorallyorintramuscularly1hourbeforeexposuretopreventimmediate
reactions.14Ephedrine25mgorallyhasalsobeenrecommended1hourbeforetheradiocontraststudyasa
componentofthepretreatmentregimenhowever,ephedrineshouldnotbeusedifthepatienthashistoryof
unstableangina,hypertension,orarrhythmia.10,14OtherstudieshaveexaminedtheuseofH1andH2
antihistamines,clemastine,orcimetidine,respectively.10,14
Anaphylactoidreactionstogadolinium,anoniodinatedcontrastagent,havebeenreportedatfrequenciesof
0.07%inadultsand0.04%inchildren.60Mostreactionshavebeenmild,requiringeithernomedical
managementortreatmentwithantihistamines.Moderateandseverereactions,althoughrare,havealsobeen
reported.Pretreatmentregimenssimilartothoseusedwithiodinatedcontraststudiesareusuallyeffectivebut
havebeenassociatedwithbreakthroughreactions,particularlyinpatientswithahistoryofreactionsto
gadoliniumoriodinatedcontrastagents.61

Insulin
Insuliniscapableofproducingallergicreactionsthroughavarietyofimmunologicmechanisms.Aprotein
molecule,insulinisacompleteantigen.Allergicreactionshavebeenreportedwithbeef,pork,and
recombinanthumaninsulin,althoughthefrequencyofreactionswithhumaninsulinappearslow.Reactionsto
insulinmayinvolvetheinsulinmoleculeitselforothersubstancesthathavebeenaddedtoinsulin(e.g.,
protamine).MostpatientshaveantiinsulinIgGantibodiesafterafewmonthsoftherapy.
Insulinreactionsmaybelimitedtothesiteofinjection,ortheymayproducesystemicreactions.Local
reactionspresentmostoftenasawhealandflareattheinjectionsiteandmayoccurimmediatelyafterinjection
orupto8to12hourslater.Thesereactionsaregenerallymild,donotrequiretreatment,andresolvewith
continuedinsulinadministration.Ifapatientdoesnottoleratethelocalreactionwell,antihistaminesmaybe
given,oradifferentinsulinsource(orproductofhigherpurity)maybesubstituted.Rarely,systemicreactions
toinsulin(e.g.,urticariaoranaphylaxis)occur.IgEmediatedreactionstoinsulinallergyappeartobedeclining
withgreateruseofhumaninsulins.62Skintestingwithvariousproductscanaidinselectingthetypeofinsulin
leastlikelytocauseasystemicreaction.Humaninsulinappearstobeleastallergenicbutoccasionallymay
causereactions.Insomepatients,insulindesensitizationmaybeindicated.

AspirinandNonsteroidalAntiinflammatoryDrugs
AspirinandotherNSAIDscanproduceeightgeneraltypesofreactions,fourofwhicharerelatedtoCOX
inhibition.63,64Thesereactionscaninvolveasthmaandrhinitis,urticaria/angioedema,anaphylaxisand
anaphylactoidreactions,asepticmeningitis,orpneumonitis.Thetwomostprevalentaspirinsensitivity
reactionsarerespiratory(asthma,rhinorrhea)andurticaria/angioedema.About9%to20%ofpeoplewith
asthmaaresensitivetoaspirinandotherNSAIDs.63,65
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Therhinosinusitis/asthmasyndrometypicallydevelopsinmiddleagedpatientswhoarenonatopicandhaveno
historyofaspirinintolerance.Womenare2.5timesmorelikelytodevelopaspirininducedasthmathan
men.66Itusuallyprogressesfromrhinitistosinusitiswithnasalpolypsandsteroiddependentasthma.Itis
uncommoninchildrenandyoungadults.However,childrenwithasthmamaybeaspirinsensitive.Aspirin
sensitiveasthmaappearstobeaninheriteddisordercharacterizedbyoverexpressionofLTC4synthasein
airways.67Inaspirinsensitivepeoplewithasthma,administrationofaspirinandNSAIDsmayprovokesevere
andsometimesfatalasthmaticattacks.Themechanismofaspirinsensitivityisnotcompletelyunderstood.
OnesuspectedmechanismofaspirinandNSAIDsensitivityisCOX1blockade,whichmayfacilitate
depletionofprostaglandinE2(PGE2)andproductionofalternativearachidonicacidmetabolites(e.g.,LTs).63
WhereasPGE2preventsmastcelldegranulation,LTscausebronchoconstrictionandincreasedmucus
production.IncreasedLTproductionmayalsoexplainthedevelopmentofangioedemaandurticaria.This
proposedmechanismissupportedbytheobservedcorrelationbetweenthedegreeofCOX1blockadeandthe
riskofasensitivityreaction.Therefore,agentssuchasacetaminophen,whichminimallyblockCOX1,rarely
causereactions.AdditionalsupportisfoundintheclinicalobservationthatLTmodifyingdrugscanreducethe
severityofaspirininducedasthmaandurticaria.63ItisalsopossiblethataspirinandNSAIDsstimulatemast
cellsdirectlytoreleaseinflammatorymediators.Subjectswithaspirininducedasthmaalsohaveamarked
increaseinairwayresponsivenesstoLTs.AspirinandtheCOX2selectiveinhibitorscelecoxibandrofecoxib
donotappeartobecrossreactive.6870
Inpatientswithaspirinsensitivity(asthmaorurticaria),anoralchallengeorprovocationtestcanbeperformed
todiagnosethecondition.AnumberofdifferentprotocolstodetectaspirinorNSAIDsensitivityhavebeen
recommended,buttheriskforanaphylaxiscannotbereliablypredicted.63,66Thechallengeshouldbe
performedwithgreatcautioninahospitalsettingwithresuscitationequipmentathand.Forpatientswith
aspirininducedasthma,inductionofdrugtolerance(desensitization)isrecommended.Anumberofaspirin
desensitizationprotocolshavebeendescribed,rangingfrom2to4dayprotocolsforpatientswithhistoryof
asthmatorapid(2to5hour)protocols.10Rapiddesensitizationprotocolshavebeenlimitedlystudied,
primarilyinpatientswithhistoryofcutaneousreactions(urticariaorangioedema)whorequireaspirinfor
acutecoronarysyndromesorbeforestentplacement.71Aspirindesensitizationhasbeenshowntoimprove
asthmasymptomscoresandleadtoreductionsinmaintenancesteroiddoses.Ifdesensitizationisnot
performed,patientswithaspirinsensitivitymustavoidaspirinandthenonselectiveNSAIDsasthemajor
preventivemeasure.
AspirinandindividualNSAIDs(e.g.,ibuprofen,sulindac)canalsocauseIgEmediatedhypersensitivity.These
reactionsoccuronreexposuretothedrugandmaypresentasurticaria,bronchospasm,oranaphylaxiswithor
withouthypotension.Acarefulandcompleteallergyhistorymaysuggesttruehypersensitivitytoaspirinoran
isolatedNSAID.SuchpatientsshouldbeadvisedtoavoidthespecificNSAIDandanystructurallysimilar
NSAIDs(e.g.,allpropionicacidderivatives,allindoleaceticacidderivatives)becauseoftheriskofcross
reactivity.
NSAIDshavebeenassociatedwithpulmonaryinfiltratesandeosinophiliasyndrome.Pulmonaryinfiltratesand
eosinophiliasyndromeareassociatedwithfever,cough,dyspnea,infiltratesonchestradiography,anda
peripheraleosinophiliathatdevelops2to6weeksafterinitiatingtreatment.Pulmonaryinfiltratesand
eosinophiliasyndromeoccursmorefrequentlyfornaproxencomparedwithotherNSAIDsandisnotedto
resolverapidlyafterdiscontinuationoftheoffendingagent.72

Sulfonamides
Sulfonamidedrugscontainingthesulfa(SO2NH2)moietyincludeantibiotics,thiazideandloopdiuretics,oral
hypoglycemics,andcarbonicanhydraseinhibitors.Allergicreactionshavebeenreportedin4.8%of20,226
patientswhoreceivedasulfonamideantibioticandin2%ofpatientswhoreceivedanonantibiotic
sulfonamide.73AlthoughimmediateIgEmediatedreactionssuchasanaphylaxiscanoccur,sulfonamides
typicallycausedelayedcutaneousreactions,oftenbeginningwithfeverandthenfollowedbyarash(e.g.,
maculopapularormorbilliformeruptions).Infrequently,aseeminglybenignmaculopapularrashmayprogress
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toamucocutaneoussyndrome(e.g.,SJSorTEN).1Otherreactionstosulfonamidesmayincludehepatic,
renal,orhematologiccomplications,whichmaybefatal.Immunemediatedsulfonamidereactionsdependon
theproductionofreactivemetabolitesintheliver.74Trimethoprimsulfamethoxazole,consideredthemost
highlyreactivesulfonamide,containsanarylamineintheN4positionofitschemicalstructure,allowingfor
thedrugsmetabolismtotwohighlyreactivemetabolites,ahydroxylamineandanitrososulfonamide.74,75
Structuraldifferencesbetweenthesulfonamidesantibioticsandnonantibioticsmayinfluencethemetabolic
conversionandresultantreactivityofthesecompounds.Slowacetylatorphenotypemayalsoincreasetherisk
forthesereactions.4
Crossreactivitybetweensulfonamideantibioticsandnonantibioticsappearstobeminimal,withcross
reactivitycharacterizedashighlyunlikely.76Inonestudy,about10%ofpatientswithahistoryofallergyto
anantibioticsulfonamidesubsequentlyreactedtoanonantibioticsulfonamide(e.g.,acetazolamide,loop
diuretic,sulfonylurea,thiazide).73Thislowrateofcrossreactivityhasbeenattributedinparttodifferencesin
thechemicalstructuresoftheantibioticandnonantibioticsulfonamides.Theoccurrenceofallergicreactions
afterreceiptofnonantibioticsulfonamideshasalsobeenattributedtoapredispositiontoallergicreactionsin
theaffectedindividualsratherthancrossreactivitywithsulfonamideantibiotics.73Infact,inonestudy,cross
reactivitybetweensulfonamideantibioticsandpenicillinwashigherthanthatbetweentheantibioticand
nonantibioticsulfonamides.73
TrimethoprimsulfamethoxazoleisusedfrequentlyforpreventiveoractivetreatmentofPneumocystisjiroveci
pneumoniainpatientswithAIDS.Adversereactionstotrimethoprimsulfamethoxazoleoccurmuchmore
frequentlyinHIVpositivepatients.77,78Adverseeffectstotrimethoprimsulfamethoxazoleoccurin50%to
80%ofAIDSpatientscomparedwith10%ofotherimmunocompromisedpatients.78Trimethoprim
sulfamethoxazolewasassociatedwithanadverseeventrateof26.3per100personyearsandhypersensitivity
eventsat22per100personyears.Althoughreactionsmayincludeangioedema,SJS,andthrombocytopenia,
mostreactionstotrimethoprimsulfamethoxazoleinHIVinfectedpatientsaredelayedandpresentasdiffuse
maculopapularrashwithorwithoutfever.Themechanismbywhichtheseallergicorallergiclikereactions
occurinHIVinfectedpatientsisunclear.ItisunlikelythatthesereactionsareIgGorIgEmediated.75,79
Proposedmechanismsincludealterationsindrugmetabolismcausedbyglutathionedeficiency,adirecttoxic
orimmunologiceffectofthesulfonamidemetabolitesonbodytissues,andincreasedexpressionofmajor
histocompatibilitycomplexproteinswithincreasedrecognitionofthedrugantigenbyCD4andCD8
cells.75,79TheadverseeventratehasbeenrelatedtohigherCD4+Tcellcountgreaterthan20cells/mm3
(>20106/L),CD4toCD8ratiolessthan0.10,andtreatmentforfewerthan14days.78

PharmaceuticalExcipientsandAdditives
Pharmaceuticalproductscontainanumberofinertadditives(e.g.,dyes,fillers,buffers,andstabilizers)in
additiontothetherapeuticingredients.Theseadditivesarenotalwaysinertandmaycauseadverseeffects,
includingallergicreactions.
Theazodyetartrazine(FD&CYellowNo.5)isassociatedwithanaphylactoidreactions,acutebronchospasm,
urticaria,rhinitis,andcontactdermatitis.80,81Althoughtheimmunologicmechanismsareunclear,about10%
ofaspirinsensitivepeoplewithasthmaarealsointoleranttotartrazine,82suggestingarolefortartrazineasa
COXinhibitor.Aslittleas0.85mcgorasmuchas25mgtartrazinehasprovokedpositiveresponses.82
Sulfites(includingsulfurdioxide,sodiumsulfite,sodiumandpotassiumbisulfite,andsodiumandpotassium
metabisulfite)areusedcommonlyasantioxidantsinpharmaceuticalproductsandsomefoods.Manycasesof
adversereactionsassociatedwithingestionofsulfites(usuallyinfoods)havebeenreportedtotheU.S.Food
andDrugAdministration(FDA),83includingwheezing,dyspnea,chesttightness,urticaria,angioedema,
flushing,weakness,nausea,anaphylaxis,anddeath.
IgEmediatedandnonimmunologicsulfitehypersensitivityhasbeendemonstratedinchildrenwithahistoryof
chronicasthma.Adversereactionstosulfitepreservedinjectables,suchasgentamicin,metoclopramide,
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lidocaine,anddoxycycline,havebeenreported.Incontrasttoreactionscausedbyfoods,thesereactionsdonot
occurmorefrequentlyinsteroiddependentpeoplewithasthmaanddonotalwayscoincidewithapositiveoral
sulfitechallenge.84Bluntedbronchodilationmaybeobservedinindividualswithasthmaafterinhalationof
sulfitecontainingnebulizersolutions.Althoughmanynebulizersolutionscontainsulfites,metereddose
inhalersdonot.Manyaqueousepinephrineproductsalsocontainsulfites.TheFDAlabelingstatesthatin
emergencysituationswhensulfitefreepreparationsarenotavailable,sulfitecontainingepinephrineshould
notbewithheldfromasulfiteintolerantindividualbecausesmallsubcutaneousdosesofsulfitesusuallyare
welltolerated.However,anincreasedriskofanaphylaxisexistsaftersubcutaneousinjectioninrarepatients
withapositiveoralchallengeto5to10mgofsulfite.
Parabens(includingmethyl,ethyl,propyl,andbutylparaben)areusedwidelyinpharmaceuticalproductsas
abiocidalagent.Mostallergicreactionstoparabensareobservedaftertopicalexposure.85Delayed
hypersensitivitycontactdermatitisoccursmoreofteninindividualswithpreexistingdermatitis.82Immediate
hypersensitivityafterparenteraladministrationisrare.Althoughtheseagentsarechemicallyrelatedtobenzoic
acidandpaminobenzoicacid,theevidenceforcrosssensitivityislacking.82

CancerChemotherapyAgents
Chemotherapyagentsareimplicatedinhypersensitivityreactionsin5%to15%ofpatientswhoreceive
them.86Upto65%ofpatientsreceivinglasparaginaseexperienceimmediatehypersensitivityreactionssuch
asurticariaandanaphylaxis.87
Thecombinationregimenofpaclitaxel(ordocetaxel)andcarboplatinisfrequentlyresponsibleforproducing
hypersensitivityreactions.Eachagentprecipitatesadistinctreaction,allowingfordifferentiationbetween
causativefactors.Hypersensitivityorallergylikereactionshavebeenobservedwithpaclitaxelanddocetaxel
inasmanyas34%ofpatients.1,88,89Thereactiontypicallyoccurswithinminutesafterinitiationofthefirst
orseconddose,suggestinganonIgEmediatedmechanism.Boththevehiclesofthetaxanes
(polyoxyethylatedcastoroilforpaclitaxelpolysorbate80fordocetaxel)andthetaxanesthemselveshavebeen
implicatedasthecauseofthereactions.Acrossreactiveriskof90%(nineof10patients)betweenpaclitaxel
anddocetaxelprovidesfurtherevidencethatthereactionismostlikelyattributedtothetaxanemoiety.90
Severereactionsarecharacterizedbydyspnea,bronchospasm,urticaria,andhypoorhypertension.Minor
reactionsincludeflushingandrashes.Inpatientsreceivinga3hourinfusion,theincidenceofseverereactions
isreducedto1.3%,andtheincidenceofminorreactionsis42%.91Toreducetheriskofhypersensitivity
reaction,patientsareroutinelypremedicatedwithcorticosteroidsandH1andH2receptorantagonists.A
proteinboundformulationofpaclitaxel(Abraxane)devoidofthecastoroilvehicleisavailable,avoiding
somebutnotallreactions.
Hypersensitivitytoplatinumcontainingagentsisdelayed,developingaftersixormorecoursesofcarboplatin,
cisplatin,oroxaliplatin.9295Thereactionratesdifferdependingontheplatinumagentwithreported
frequenciesof5%to20%withcisplatin,9%to27%withcarboplatin,and10%to19%withoxaliplatin.96
Reactionstypicallydevelopshortlyaftercompletingtheinfusionorupto3daysaftertherapy.92Symptomsof
severereactionincludetachycardia,dyspnea,facialswelling,rigors,andhypotension.Mildreactionsinclude
itching,erythema,andfacialflushing.Anassociationbetweenreactivityandthedurationoftheplatinumfree
intervalhasbeendescribedforcarboplatin.97Theriskofaseverereactionwas47%iftheplatinumfree
intervalwasgreaterthan24monthsversusonly6.5%withinintervalslessthan12months.97Management
strategiesincludedecreasingtherateofinfusionandadministrationofcorticosteroidsandH1andH2receptor
antagonists.95Skintestingwithcarboplatinhasbeendescribed.93,96Desensitizationtocarboplatin93,94and
oxaliplatin98,99hasbeenshowntobewelltolerated.

Anticonvulsants
Manyanticonvulsantdrugsproduceavarietyofhypersensitivityreactionsandpseudoallergicreactions.Drugs
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suchasphenytoin,phenobarbital,carbamazepine,andlamotriginecancauseananticonvulsant
hypersensitivitysyndromecharacterizedbyfever,rash,lymphadenopathy,andinternalorganinvolvement.
EosinophiliaisfrequentlypresentandmanyreactionsmeetthedefinitionofDRESS.Theonsetusuallyoccurs
severalweeksintotherapy.100Insomecases,morbilliformrashdevelopsintoexfoliativedermatitis.Therisk
ofcrossreactivitybetweenthearomaticanticonvulsants(e.g.,carbamazepine,phenobarbital,andphenytoin)
rangesfrom40%to80%.100Oxcarbazepine,the10ketoderivativeofcarbamazepine,hasexhibitedbothin
vitroandinvivocrossreactivitywithcarbamazepine.Ageneticmarkerforseverereactionstocarbamazepine,
phenytoin,andfosphenytoinisthepresenceoftheHLAB*1502allele.32Thisalleleisfoundin10%to15%
ofpatientsfromChina,Thailand,Malaysia,Indonesia,thePhilippines,andTaiwan.Concomitantuseof
valproatewithlamotriginesignificantlyincreasestheriskofhypersensitivityasaresultofreducedlamotrigine
metabolism,leadingtoaprolongedeliminationhalflife.101

Biologics
Biologicagents(e.g.,monoclonalantibodies,fusionproteins,recombinantproteins)arederivedfromliving
sourcessuchasyeast,bacteria,animalcells,ormammaliancells.102Unlikenonbiologicagents,theselarge
proteinscanserveascompleteantigens.Examplesincluderecombinantinsulin,erythropoietin,interferon,
humangrowthhormone,infliximab,cetuximab,rituximab,andomalizumab.Immunologicreactionstothese
agentsrangefromminorinfusionorinjectionsitereactionstoanaphylaxis.Dependingontheagent,reactions
canoccuronfirstorsubsequentexposure,andthetimingmaybewithin4hoursofdrugadministrationorup
to14daysafteraninfusion.102
Factorsinfluencingtheantigenicityofbiologicagentsarepatientspecific(e.g.,atopy,congenitalprotein
deficiency),productionrelated(e.g.,presenceofcontaminantsorstabilizingagents,degreeofprotein
glycosylation,presenceofnonhumanproteinsequences,storagetemperature),andadministrationrelated(e.g.,
routeofadministration,frequencyofuse,concurrentinmmunosuppressantuse).102Ofthemonoclonal
antibodies,reactionsaremostfrequentlyobservedwiththemurinederivedagents(0%human)andchimeric
agents(75%human)asopposedtothehumanized(>90%human)andhuman(100%human)agents.Some
immunereactionstobiologicagentsresultfromthedevelopmentofneutralizingantibodiesthatcanprevent
theproteinfromexertingitsintendedeffect.Neutralizingantibodieshavebeenshowntomediatereactionsto
interferon1band1a,infliximab,natalizumab,recombinantfactorVIII,andrecombinantfactorIX.102Anti
infliximabantibodies,whichoccurinupto60%oftreatedpatients,areassociatedwithhigherfrequencyof
infusionreactionsanddecreasedtherapeuticeffect.103Concomitantadministrationofimmunosuppressive
agentssuchasprednisoneorlowdosemethotrexatehasbeenshowntodecreasetheincidenceofantibody
formationtoinfliximab.102,103
Delayedonsetanaphylaxis,rangingfromminutestodayspostinjection,hasbeenreportedwithomalizumab,a
humanizedmonoclonalantibodytargetedagainstIgE.104,105Omalizumabtreatedpatientsrequire
observationfor2hoursafterthefirst3injectionsandfor30minutesaftersubsequentinjections.105Patients
areadvisedtocarryanepinephrineautoinjectorduringandfor24hoursafterdrugadministration.104,105
Riskfactorsforthisadverseeventhavenotbeenidentified.Inclusionofpolysorbate80asastabilizingagent
intheformulation,andanalterationintheproteinsequenceviaglycosylation,mayinfluencethe
immunogenicityofomalizumab.105
Managementofallergicorallergiclikereactionstobiologicagentsvariesbasedontheculpritagentandthe
severityandnatureofthereaction.Immediatemanagementwithepinephrineandpermanentdiscontinuationof
thedrugmaybewarranted(e.g.,omalizumabinducedanaphylaxis).Dependingonthebiologicagent,
reactionsmaybemanagedbydecreasingtheinfusionrateorlessenedbypretreatingwithantihistaminesor
corticosteroidsoradministeringconcomitantsteroidtherapy.Desensitizationprotocolsfor
infliximab,96,106cetuximab,107rituximab,96,106andtranstuzumab96,106havealsobeendescribed.

Treatment
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Thebasicprinciplesformanagementofallergicreactionstodrugsorbiologicagentsinclude(a)
discontinuationofthemedicationoragentwhenpossible(b)treatmentoftheadverseclinicalsignsand
symptomsand(c)substitution,ifnecessary,ofanotheragent.104

Anaphylaxis
Anaphylaxisrequiresprompttreatmenttominimizetheriskofseriousmorbidityordeath.Onpresentation,
attentionshouldbegivenfirsttostoppingthelikelyoffendingagent,ifpossible,andrestoringrespiratoryand
cardiovascularfunction.AprotocoldevelopedbytheJointTaskForceonPracticeParametersforAllergyand
ImmunologyfortreatmentofanaphylaxisispresentedineTable223.14Epinephrineisthedrugoffirst
choice,althoughitisunderusedandoftendosedsuboptimallyforthisindication.108Itshouldbeadministered
asprimarytreatmenttocounteractbronchoconstrictionandperipheralvasodilationleadingto
hypotension.14,108Atrecommendeddoses,epinephrinealsoenhancescoronarybloodflow.The
recommendedadministrationtechniqueisintramuscularlyinthelateralaspectofthethigh.14,109Ifblood
pressureisnotrestoredbyepinephrine,crystalloidIVfluidsshouldbeadministeredtorestoreintravascular
volume.Typically,1Lof0.9%sodiumchlorideisadministeredover5to10minutes.Thiscanberepeatedif
thepatientisstillbelievedtobevolumedepleted.AmaintenanceIVfluidthenisinitiated.IVfluidsshouldbe
givenearlyinthecourseoftreatmentinanattempttopreventshock.Animmediatepriorityistoestablishand
maintainanairwaybytheuseofendotrachealintubationifnecessary.Whenapatientwithanaphylaxisis
hypotensive,vasopressorsmaybeneededinadditiontocrystalloids.Norepinephrineisthevasoconstrictor
agentofchoicefortreatmentofanaphylacticshock,althoughdopaminealsomaybeuseful.Patientsinshock
shouldremainsupinewithraisedlegs.14
eTable223TreatmentofAnaphylaxis
1.Placepatientinrecumbentpositionandelevatelowerextremities.
2.Monitorvitalsignsfrequently(every25minutes)andstaywiththepatient.
3.Administerepinephrine1:1,000intononoccludedsite(adults:0.01[mg]mL/kguptoamaximumof
0.20.5[mg]mLevery5to10minutesasneeded,children:0.01[mg]mL/kguptoamaximumdoseof
0.3[mg]mL)IMinthelateralaspectofthethighorsubcutaneously.Ifdeemednecessary,the5minute
intervalbetweeninjectionscanbeliberalized.
4.Administeroxygen,usually810L/minhowever,lowerconcentrationsmaybeappropriateforpatients
withchronicobstructivepulmonarydisease.Maintainairwaywithoropharyngealairwaydevice.
5.Considertheantihistaminediphenhydramine(adults2550mgchildren1mg/kg,upto50mg)IMor
byslowIVinfusion.
6.Considerranitidine50mginadultsand12.5to50mg(1mg/kg)inchildren.Thedosemaybediluted
in5%dextroseinwatertoavolumeof20mLandinjectedover5minutes.
7.TreathypotensionwithIVfluidsorcolloidreplacementandconsideruseofavasopressorsuchas
dopamine.Inadults,12Lof0.9%salinesolutiongivenatarateof510mL/kgmaybeneededinthe
first510minutes.Childrenshouldreceiveupto30mL/kginthefirsthour.
8.Considerinhaledagonists(albuterol)metereddoseinhalertwotosixpuffsornebulized2.55mgin
3mLsalinerepeatasnecessaryforbronchospasmresistanttoepinephrine.
9.Considerhydrocortisone,5mg/kg,orapproximately250mgIV(prednisone20mgorallycanbegiven
inmildcases)toreducetheriskofrecurringorprotractedanaphylaxis.Thesedosescanberepeated
every6hoursasrequired.
10.Incasesofrefractorybronchospasmorhypotensionnotrespondingtoepinephrinebecausea
adrenergicblockeriscomplicatingmanagement,glucagon15mgIV(2030mcg/kgmaximum,1mg
inchildren)givenIVover5minutesmaybeuseful.Acontinuousinfusionofglucagon,515mcg/min
maybegivenifrequired.
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11.ConsiderintraosseousaccessforeitheradultsorchildrenifattemptsatIVaccessareunsuccessful.
IM,intramuscular.
LiebermanP,NicklasRA,OppenheimerJ,etal.Thediagnosisandmanagementofanaphylaxispractice
parameter:2010update.JAllergyClinImmunol2010126:480.e1e42.
Otheragentsmayberequiredfortreatmentofanaphylacticreactions.Corticosteroids(hydrocortisonesodium
succinateIV)shouldneverbegiveninplaceoforbeforeepinephrine.14Theironsetofactionisdelayed,and
theirroleistoreducetheriskoflatephasebiphasicreactions.Inpatientstreatedchronicallywith
blockers,glucagonshouldbeconsideredbecauseitsinotropicandchronotropiceffectsdonotrelyon
receptorresponsiveness.14Histamine(H1)receptorblockers(e.g.,diphenhydramine)canbeadministeredto
reducesomeofthesymptomsassociatedwithanaphylaxis,buttheseagentsarenoteffectiveasprimary
therapy.ThecombinationofdiphenhydramineandanH2receptorblocker(e.g.,ranitidine)hasbeenshownto
besuperiortodiphenhydraminealoneinthetreatmentofanaphylaxis.14Intraosseousaccessshouldbe
consideredforadultandpediatricpatientsinwhomattemptsatIVaccessareunsuccessful.14

SkinTestingandDrugProvocationTesting
Identificationofpatientsathighriskforallergicdrugreactionsrequirescarefulhistorytakingwith
attentiontothespecificagenttowhichthepatientreacted,acompletedescriptionofthereaction,andthetime
sincelastexposuretotheculpritdrug.Theimportanceofaccurateandcompletehistorytakingcannotbe
overstated.Althoughskinandoralprovocationtestingareusedtoassessreactiverisktosomedrugs,manyof
thetestingprocedureshavenotbeenvalidated.Adrugprovocationtest(DPT)involvesthecontrolled
administrationofadrugforthepurposeofdiagnosinganimmuneresponse.DPTscanbeusedtoevaluate
sensitivitytoaspirin.110Whenavailable,skintestingshouldbeperformedbeforeaDPTbecauseofthelesser
risksincurredtothepatient.Forsomedrugs,skintestingcanreliablydemonstratethepresenceofdrug
specificIgEandpredictarelativelyhighriskofimmediatehypersensitivityreactions.Reliableskintest
reagentsarenotavailableformostculpritdrugs.Moreover,skintestingshouldnotbeperformedinpatients
withhistoryofseveremucocutaneousreactions(e.g.,SJS,TEN)orothernonimmediatereactions(e.g.,serum
sickness,vasculitis,hepatitis).
Skintestingcanreducetheuncertaintyofpenicillinsensitivityandshouldbeperformedinallpatientswho
haveahistoryofanimmediateallergyandrequiretreatmentwithalactamantibiotic.Penicillinskintesting
inadvanceofneedforpenicillintreatmentinpatientswithahistoryofpenicillinallergydoesnotappearto
inducesensitization.111Testingforthemajorpenicillindeterminantisaccomplishedwithpenicilloyl
polylysine(PPLPrePen),aproductrecentlyreintroducedintheUnitedStates.Ideally,skintestingshouldbe
performedwithboththemajorandminordeterminants.Oftheminordeterminants,onlypenicillinGis
commerciallyavailableintheUnitedStates,anditshouldbeusedataconcentrationof10,000units/mLwith
PPLinskintesting.10Ifleftinsolutiontoage,penicillinGwillnotspontaneouslydegradetoformtheother
minordeterminants,penilloateandpenicilloate.10Similarreactionratestooralpenicillinchallengeshave
beenshowninpatientswithskintestnegativitytoPPLpluspenicillinGcomparedwiththosewithskintest
negativitytothefullsetofmajorandminordeterminants.10,36Skintestingwiththemajorandminor
determinantshasbeenshowntofacilitatethesafeuseofpenicillininupto90%ofpatientswithahistoryof
immediatepenicillinallergy.112Fewerthan1%ofpatientswithanegativehistoryandupto72%ofpatients
withaconvincingpositivehistoryofpenicillinallergyhaveskintestpositivereactivity.113Inpatientswho
reportahistoryofpenicillinallergybutareskintestnegative,theriskofresensitization(i.e.,conversiontoa
positiveskintestresult)afteracourseofpenicillinrangesfrom1%to28%.48Theprocedureforperforming
penicillinskintestingisgivenineTable224.InEurope,skintestingcanbeaccomplishedwithakit
containingboththemajorandminordeterminantmixture(DiaterLabs,Madrid,Spain).96
eTable224ProcedureforPerformingPenicillinSkinTesting
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A.Percutaneous(Prick)SkinTesting(Usinga22to28GaugeNeedle)
Materials
PrePen6106M
PenicillinG10,000units/mL
Lactamdrug(amoxicillin)2mg/mL
Salinecontrol
Histaminecontrol(1mg/mL)
1.Placeadropofeachtestmaterialonthevolarsurfaceoftheforearm.

Volume
1drop
1drop
1drop
1drop
1drop

2.Pricktheskinwiththeneedletomakeasingleshallowpunctureoftheepidermisthroughthedrop.
3.Interpretskinresponsesduringthenext15minutes.Observeforawhealorerythemaandthe
occurrenceofitching.
4.Awhealindiameterof5mmorgreatersurroundingthepuncturesiteisconsideredapositivetest
result.
5.Wipeoffthesolutionnearthepuncturesite.
6.Ifthepricktestresultisnegativeorequivocal(wheal<5mmindiameterwithnoitchingorerythema),
proceedtotheintradermaltest.
7.Ifthehistaminecontrolisnonreactive,thetestisconsidereduninterpretable.Ensurenointerferenceby
antihistamines.
B.IntradermalSkinTestinga
Materials
PrePen6106M

Volume
0.02mL

PenicillinG10,000units/mL
0.02mL
Lactamdrug(amoxicillin)2mg/mL
0.02mL
Salinecontrol
0.02mL
Histaminecontrol(0.1mg/mL)
0.02mL
1.Inject0.020.03mLofPrePenintradermally(amountsufficienttoproduceasmallblebof
approximately3mmindiameter)induplicateatleast2cmapart.
2.Inject0.020.03mLoftheothermaterialsatleast5cmfromthePrePensites.
3.Interpretskinresponsesafter20minutes.
4.Itchingorasignificantincreaseinthesizeoftheoriginalblebtoatleast5cmisconsideredapositive
result.Anambiguousresponseisawhealonlyslightlylargerthantheoriginalblebordiscordance
betweentheduplicates.Thecontrolsiteshouldshownoincreaseintheoriginalbleb.
5.Ifthehistaminecontrolisnonreactive,thetestisconsidereduninterpretable.Antihistaminesmayblunt
theresponseandcausefalsenegativeresults.
aUsinga0.5to1ccsyringewitha3/8to5/8inchlong,26to30gaugeshortbevelneedle
PrePen(benzylpenicilloylpolylysineinjection,solution)ProductInformation,AllerQuestLLCandALK
Abello,Inc.,RoundRockTX,2009.
Anegativepenicillinskintestresultindicatesthattheriskoflifethreateningimmediatereactionsisextremely
lowwithadministrationofpenicillinorotherlactams.Suchpatientsarecandidatesfortreatmentwithfull
therapeuticdosesofapenicillinorarelatedlactam.Certaintypesofpatients(e.g.,thosewith
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dermatographism,takingantihistamines)maybeunsuitableforskintestingbecauseafalsepositiveorfalse
negativetestmayresult.Topreventinterferencewithskintesting,antihistaminesshouldbediscontinuedat
least1weekbeforeskintesting.Penicillinistheonlydrugforwhichthepredictivevalueofskintestinghas
beenwellestablished.Althoughthenegativepredictivevalueishigh,penicillinskintestingwiththemajorand
minordeterminantsdoesnotidentifypatientswhoareatriskforuniquesidechainmediatedreactionsto
lactams(e.g.,thirdgenerationcephalosporins,piperacillin).Diluteconcentrationsofamoxicillinand
piperacillinhavebeenusedtoskintestforsidechainmediatedreactions.4547Thevalueofskintestingto
predicttheriskofallergicreactionstootherantibiotics(e.g.,sulfonamides,tetracyclines,fluoroquinolones)is
largelyunknown.
Skintestingisusedtoidentifypatientsatriskforhypersensitivityreactionstocarboplatin.Thenegative
predictivevalueofintradermalskintestingwithcarboplatinhasbeenshowntobe98%to99%inpatientswho
havereceivedanumberoftreatmentcourses.93

InductionofDrugToleranceandDesensitization
Forsomepatientswithhistoryofanimmediatereactiontoadrug,noreasonablealternativesexist,andthe
incitingdrugorarelatedcompoundmaybenecessaryfortreatmentofanunderlyingcondition(e.g.,
infection).Inthissituation,thetemporaryinductionofdrugtoleranceisindicated.Inthepast,theterm
desensitizationwasusedtodescribetheprocedureoftemporarilyacquiringdrugtolerance,whetherthe
underlyingmechanismofintolerancewasimmunologicallymediatedornot.Expertsindrugallergycurrently
recommendthatthephraseinductionofdrugtolerancebeusedinplaceofdesensitizationtoglobally
describeproceduresusedtomodifyapatientsresponsetoadrugandtemporarilyallowsafedrugtherapy.10
Inductionofdrugtolerancecaninvolveavarietyofdrugmechanisms,includingIgEmediatedimmune
mechanisms,nonIgEmechanisms,pharmacologicmechanisms,andundefinedmechanisms(eTable225).10
Regardlessoftheunderlyingmechanism,allproceduresusedtoinducedrugtoleranceinvolveastepwise
processofincrementaldosingoftheincitingdrugorarelatedcompound.Desensitization,aformofinducing
drugtolerancespecificallyreferstotheprocessinwhichthemastcellsarerenderedlessresponsiveto
degranulation.Thistermshouldbeusedwhentheunderlyingmechanismofdrugintoleranceisbelievedtobe
IgEmediated(i.e.,anaphylaxistopenicillin).10Immediatereactionsmostamenabletodesensitizationinclude
dermatologic(e.g.,flushing,pruritus,urticaria,angioedema),upperandlowerrespiratorytract(e.g.,sneezing,
dyspnea,wheezing),gastrointestinal(e.g.,abdominalpain,nauseaandvomiting),andcardiovascular(e.g.,
hypotension).96Procedurestoinducedrugtoleranceshouldnotbeusedinpatientswithhistoryofseverenon
IgEreactionstoadrugsuchasDRESS,SJS,TEN,exfoliativedermatitis,hemolyticanemia,orhepatitis.
eTable225CharacteristicsofDrugIntoleranceProtocols
Underlying
Mechanism

Durationof PotentialOutcomeof
InitialDose
Protocol
Process

Duration
of
Induced
Tolerance

Example

Desensitizationrender
mastcellsless
Temporary Lactamantibioticstaxanes
responsiveto
degranulation
Hoursto
Delayedcutaneousreactions
Immunologic
days(e.g.,6
totrimethoprim
Milligrams
Notknown
Temporary
nonIgE
hoursto10
sulfamethoxazoleinHIV
days)
infectedindividuals
Hoursto
Cautiousinductionofa
days(e.g.,2 reactionfollowedbya
Pharmacologic Milligrams
Temporary Aspirin
hoursto5 shiftinametabolic
days)
process
Micrograms Prolonged
Isolatedcutaneousreactions
Undefined
to
daysto
Notknown
Temporary
toallopurinol
milligrams weeks
Immunologic
IgE
Micrograms Hours
(desensitization)

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AdaptedfromSolenskyR,KhanDA.Drugallergy:anupdatedpracticeparameter.AnnalsAllergyAsthma
Immunol2010105:273.e273.e78.
Allprocedurestoinducedrugtoleranceshouldbeperformedbyaphysicianexperiencedintherisksand
managementofsevereallergicreactionsinahospitalsettingwithresuscitationequipmentavailable.The
potentialrisksandbenefitsshouldbediscussedwiththepatient.Theproceduresdifferinstartingdose,number
ofstepsinthedosingprocess,andfrequencyofdrugdosing.Thespecificprocedureshouldbechosenbased
onananalysisofthepatientshistoryofthereactionandwithconsiderationtothespecificincitingdrugand
thesuspectedunderlyingmechanismofdrugintolerance(i.e.,IgEmechanismversusnonIgEmechanismvs.
pharmacologicmechanism).Thestartingdoseforadesensitizationprocedureistypicallyonein10,000ofthe
finaltherapeuticdoseandtheprocedurecanbecompletedwithin4to12hours.10,36Arapid12step
desensitizationprotocolhasbeendescribedandtestedinpatientswithbothIgEandnonIgEmediated
reactionstoantibiotics,platinumcontainingchemotherapeuticagents,taxanechemotherapyagents,and
monoclonalantibodies.94,96The12stepmethodstartswitha1:1,000dilutionofthefinaldoseoftheinciting
drug.Incrementallyincreaseddosesareadministeredevery15minutesusingthree10folddilutedsolutions.
Thismethodhasbeentestedinnearly800patients,includingpatientswithcysticfibrosisandallergyto
antibiotics.96Inhighriskpatients,desensitizationisachievedwitheithera16ora20stepprotocol.94,96
Inthecaseofpenicillinorlactamallergy,desensitizationshouldbeperformedwiththespecificlactam
antibioticthatwillbeadministeredfortreatmentofthepatientsinfection.Beforeinitiatingtheprotocol,the
patientshouldbestabilizedandfluid,pulmonary,andcardiovascularfunctionoptimized.Premedications
(antihistaminesorcorticosteroids)havenotbeenroutinelyadvisedbecausetheseagentsmaymasktheearly
signsofacutereactionsanddonotreliablyreducetheseverityofacutereactions.However,somerecently
describeddesensitizationregimensincludepremedicationwithsingledosesofdiphenhydramineand
famotidine.Aboutonethirdofpatientswhohaveundergonedesensitizationtoapenicillinwillexperience
mild,transientallergicreactionseitherduringthedesensitizationprocedureorduringpenicillintherapy.34
Patientswhocantakeoralmedicationshouldundergodesensitizationwithoraldrug.Afterthedesensitization
protocolisbegun,itshouldnotbeinterruptedexceptforseverereactions.Antihistaminesorepinephrinecan
beadministeredtotreatreactions.Inaddition,ifthepatientcompletesthedesensitizationregimenandthen
undergoesfulldosetreatment,alapsebetweendosesofasfewas24hourscanallowforreemergenceof
sensitivity.ProtocolsfororalpenicillinandIVcephalosporindesensitizationarelistedineTables226and22
7,respectively.Protocolsfordesensitizationwithotherlactamantibioticsarealsoavailable.114,115
eTable226ProtocolforOralDesensitization
PhenoxymethylPenicillin
Stepa Concentration(units/mL) Volume(mL) Dose(units) CumulativeDose(units)
1
2
3
4
5
6
7
8
9
10
11
12
13
14

1,000
1,000
1,000
1,000
1,000
1,000
1,000
10,000
10,000
10,000
80,000
80,000
80,000
80,000

15
16

500,000
500,000

0.1
100
0.2
200
0.4
400
0.8
800
1.6
1,600
3.2
3,200
6.4
6,400
1.2
12,000
2.4
24,000
4.8
48,000
1.0
80,000
2.0
160,000
4.0
320,000
8.0
640,000
Observefor30min
0.25
125,000
0.5
250,000

100
300
700
1,500
3,100
6,300
12,700
24,700
48,700
96,700
176,700
336,700
656,700
1,296,700

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17
18

500,000
500,000

1.0
2.25

500,000
1,125,000

aTheintervalbetweenstepsis15min.
ReprintedfromImmunolAllergClinNorth,Vol.18,WeissME,AdkinsonNF,DiagnosticTestingforDrug
Hypersensitivity,ImmunolAllergClinNorth,731734,Copyright1998,withpermissionfromElsevier.
eTable227InductionofDrugToleranceProtocolforIVCephalosporina
PreparationofSolutions
VolumeofDiluents(e.g.,0.9% TotaltobeInjectedinEach
NSS)
Bottle
Solution1
250mL
10mg
Solution2
250mL
100mg
Solution3
250mL
1000mg
InductionofDrugToleranceProtocol
Time
AdministeredDose
Step Solution Rate(mL/h)
(min)
(mg)
1
1
2
15
0.02
2
1
5
15
0.05
3
1
10
15
0.1
4
1
20
15
0.2
5
2
5
15
0.5
6
2
10
15
1
7
2
20
15
2
8
2
40
15
4
9
3
10
15
10
10 3
20
15
20
11 3
40
15
40
12 3
75
184.4
922.13

FinalConcentration
(mg/mL)
0.04
0.4
4
CumulativeDose(mg)
0.02
0.07
0.17
0.37
0.87
1.87
3.87
7.87
17.87
37.87
77.87
1000

NSS,normalsalinesolution.
aFulldoseequals1,000mg.Totaltimewas349.4minutes.
ReprintedfromSolenskyR,KhanDA.Drugallergy:anupdatedpracticeparameter.AnnalsAllergyAsthma
Immunol2010105:273.e273.e78
MostreactionstotrimethoprimsulfamethoxazoleinHIVinfectedpatientsareconsideredtobenonIgE
mediated,andanumberofprotocolstoinducetolerancetotrimethoprimsulfamethoxazolehavebeen
described.Theseregimenshavenotbeencomparedincontrolledclinicaltrialsthus,thereisnopreferred
regimen.Tolerancetotrimethoprimsulfamethoxazolecanbeachievedwithin2daysinmostHIVinfected
patients.1,116Thiscanbeaccomplishedbyusingthefollowingscheduleoforaldoses(milligramsof
sulfamethoxazoletrimethoprim):day1:9am,4and0.8mg11am,8and1.6mg1pm,20and4mg5pm,40
and8mgday2:9am,80and16mg3pm,160and32mg9pm,200and40mgday3:9am,400and80mg,
and400and80mgdailythereafter.Withthisregimen,thefailureratewasassociatedwithhigherrelativeand
absoluteCD4cellcounts.Otherinvestigatorshavedescribeda6houroralregimeninHIVinfected
patients117andamoregradual9dayoralregimen.118Inductionofdrugtoleranceshouldnotbeattemptedin
anypatientwithhistoryofanexfoliativereactiontotrimethoprimsulfamethoxazole.
Bothrapid(overlessthan4hours)andtraditionaldesensitizationprotocolsareavailableforaspirinand
clopidogrel.71,119Aspirindesensitizationismoreeffectiveinpatientswithhistoryofaspirininducedasthma
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ascomparedwiththosewithangioedema/urticarialpresentation.66

GradedChallenge
Alsoknownastestdosing,agradeddrugchallengeinvolvesthecautiousintroductionofadrugwhentherisk
ofareactionisdeemedtobelow.Agradeddrugchallengeisanalternativetotheinductionofdrugtolerance,
anditdoesnotmodifytheimmuneornonimmuneresponsetothedrug.10,114Instead,gradedchallengeis
usedwhentheriskofaseverereactiontoadrugonreexposureislow,noalternativedrugisequallyeffective,
andareliableskintestingmethodisnotavailable.Aclassicexampleistheslowintroductionofa
cephalosporininapatientwithahistoryofreactingtoanothercephalosporinwithadissimilarR1side
chain.114Gradedchallengeprotocolshavebeendescribedfortheslowintroductionoffurosemideinapatient
withheartfailureandhistoryofsulfonamideallergy.120,121Challengedosingisnotrecommendedwhen
thereishistoryofaseveredrugallergy(e.g.,anaphylaxis,SJS,TEN).Premedicationsshouldnotbeused
becausetheymaymasksignsofanearlybreakthroughallergicreaction.Comparedwithdrugtolerance
procedures,gradedchallengesinvolvehigherstartingdosesandfewerstepsinthedosingprocess.Thestarting
doseistypically1/10thto1/100thofthefinaltreatmentdose,andtheoralrouteofdrugadministrationis
preferredtolimittheriskofaseverereaction.114Ifnoreactionoccurstotheinitialdose,thedosemaybe
increasedintwotofivefoldincrementsandadministeredevery30to60minutesuntilthefulltherapeuticdose
isachieved.47,114Thereisnostandardprotocolforgradedchallengedosingatherapeuticdosemaybe
achievedoveramatterofhoursordays.Becauseoftheriskofbreakthroughallergicreactions,graded
challengesshouldbeperformedinmonitoredsettings.

Abbreviations
APC antigenpresentingcell
DRESS drugrashwitheosinophiliaandsystemicsymptoms
HLA humanleukocyteantigen
IgE
immunoglobulinE
LT
leukotriene
NSAID nonsteroidalantiinflammatorydrug
PAF
plateletactivatingfactor
PG
prostaglandin
PPD
purifiedproteinderivative
SJS
StevensJohnsonsyndrome
SLE
systemiclupuserythematosus
TEN toxicepidermalnecrolysis

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Silverchair
Typesofhypersensitivityreactions.(AGEP,acutegeneralizedexanthematouspustulosisCTL,cytotoxicT
lymphocyteCXCL8,interleukin8GMCSF,granulocytemacrophagecolonystimulatingfactorIg,
immunoglobulinIL,interleukinNK,naturalkillerPMN,polymorphonuclearleukocyte)
Formationofabenzylpenicilloylhaptenproteincomplex.

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