Drug allergy DavidA.Khan,MD,aandRolandSolensky,MDb Dallas,Tex,Corvallis,Ore Drugallergyisonetypeofadversereactiontodrugsand encompassesaspectrumofhypersensitivityreactionswith Abbreviationsused heterogeneousmechanismsandclinicalpresentations.A ACE-I: Angiotensin-convertingenzymeinhibitor thoroughhistoryisessentialtothemanagementofdrugallergy. ADR: Adversedrugreaction AERD: Aspirin-exacerbatedrespiratorydisease Laboratorytestinghasaverylimitedroleinthemanagementof ASA: Acetylsalicylicacid drugallergy.Gradeddosechallengesandprocedurestoinduce DILE: Drug-inducedlupuserythematosus drugtolerancemightberequiredinpatientswithdrugallergy DRESS: Drugrashwitheosinophiliaandsystemicsymptoms whenthereisadefiniteneedforaparticularagent.Management NSAID: Nonsteroidalanti-inflammatorydrug ofreactionstospecificagents,includingb-lactamantibiotics, NSF: Nephrogenicsystemicfibrosis sulfonamides,localanesthetics,radiocontrastmedia, PPL: Penicilloyl-polylysine angiotensin-convertingenzymeinhibitors,nonsteroidalanti- RCM: Radiocontrastmedia inflammatorydrugs,andbiologicmodifiers,willbediscussedin SJS: Stevens-Johnsonsyndrome furtherdetail.(JAllergyClinImmunol2010;125:S126-37.) TEN: Toxicepidermalnecrolysis TMP-SMX: Trimethoprim-sulfamethoxazole Keywords: Drugallergy,adversedrugreactions,drughypersensi- tivity,gradedchallenge,desensitization,tolerance,penicillin,cepha- losporin, carbapenem, sulfonamide, local anesthetic, radiocontrast media,angiotensin-convertingenzymeinhibitors,nonsteroidalanti- excretion, or bioavailability of the drug), drug idiosyncrasy inflammatorydrug,biologicmodifiers (abnormal and unexpected effect, usually caused by underlying abnormalitiesofmetabolism,excretion,orbioavailability),drug allergy(immunologicallymediatedADRs[includingIgE-medi- EPIDEMIOLOGY AND CLASSIFICATION OF ated drug allergy]), and pseudoallergic reactions (also called ADVERSE DRUG REACTIONS anaphylactoid reactions, which are due to direct release of Adverse drug reactions (ADRs) are defined by the World mediators from mast cells and basophils rather than IgE Health Organization as anynoxious, unintended, and undesired antibodies). effectofadrugthatoccursatdosesusedforprevention,diagnosis, The Gell and Coombs system of hypersensitivity is the most ortreatment.ADRsarecommonlyencounteredinbothinpatient common method of classifying immunologically mediated and outpatient settings. In a meta-analysis of inpatient ADR ADRs.Itiscomprisedofimmediate-typereactionsmediatedby prospective studies, 15.1% of patients sustained ADRs during drug-specific IgE antibodies (type I), cytotoxic reactions medi- their hospitalizations, and 6.7% of patients experienced serious ated by drug-specific IgG or IgM antibodies (type II), immune ADRs.1Ina4-weekprospectivecohortstudyofoutpatientsfol- complex reactions (type III), and delayed-type hypersensitivity lowed in primary care clinics, 25% of patients reported ADRs, reactions mediated by cellular immune mechanisms (type IV). 13%ofwhichwereserious.2 TypeIVreactionscanbesubdividedinto4categoriesinvolving ADRsarecategorizedintopredictable(typeA)andunpredict- activationandrecruitmentofmonocytes(typeIVa),eosinophils able (type B) reactions. Predictable reactions are usually dose (type IVb), CD41 or CD81 T cells (type IVc), and neutrophils dependent, related to the known pharmacologic actions of the (typeIVd).3 drug,andoccurinotherwisehealthysubjects.Predictable reac- Thepharmacologicinteractionwithimmunereceptorsconcept tionsaccountforabout80%ofallADRsandaresubdividedinto isarecentlyproposedadditiontodrughypersensitivityclassifi- overdose, side effects, secondary effects, and drug interactions. cation. In this scheme a drug binds noncovalently to a T-cell Unpredictable reactions are generally dose independent, are receptor, which can lead to an immune response through inter- unrelated to the pharmacologic actions of the drug, and occur actionwithanMHCreceptor.Inthisscenarionosensitizationis only in susceptible subjects. Unpredictable reactions are sub- required because there is direct stimulation of memory and divided into drug intolerance (an undesirable pharmacologic effector Tcellsanalogous tothe conceptof superantigens.4Al- effectthatoccursatlowandsometimessubtherapeuticdosesof thoughthesemechanisticclassificationsofdrug-inducedallergic the drug without underlying abnormalities of metabolism, reactions are useful, not all drug-induced allergic reactions can be categorized based on these limited mechanisms of FromatheUniversityofTexasSouthwesternMedicalCenterandbTheCorvallisClinic. hypersensitivity. Disclosureofpotentialconflictofinterest:D.A.KhanisaspeakerforAstraZenecaand Merck.R.SolenskyisspeakerforSepracor,AstraZeneca,andGlaxoSmithKlineand hasservedasanexpertwitnessonthetopicofdrugallergies. ReceivedforpublicationJune5,2009;revisedOctober12,2009;acceptedforpublica- CLINICAL MANIFESTATIONS OF tionOctober15,2009. Reprintrequests:DavidA.Khan,MD,UniversityofTexasSouthwesternMedicalCen- IMMUNOLOGICALLY MEDIATED ADRS ter, 5323 Harry Hines Blvd, Dallas, TX 75390-8859. E-mail: dave.khan@ Drug-induced allergic reactions can affect numerous organ utsouthwestern.edu. systemsandmanifestinavarietyofreactions,includingvarious 0091-6749/$36.00 drug-inducedallergicsyndromes,andmanydrug-inducedaller- !2010AmericanAcademyofAllergy,Asthma&Immunology doi:10.1016/j.jaci.2009.10.028 gicreactionscanhavemorethan1mechanisticpathway(TableI). S126 JALLERGYCLINIMMUNOL KHANANDSOLENSKY S127 VOLUME125,NUMBER2 TABLEI.Heterogeneityofdrug-inducedallergicreactions Organ-specificreactions Clinicalfeatures Examplesofcausativeagents Cutaneous Exanthems Diffusefinemaculesandpapules Allopurinol,aminopenicillins,cephalosporins,antiepileptic Evolveoverdaysafterdruginitiation agents,andantibacterialsulfonamides Delayed-typehypersensitivity Urticaria,angioedema Onsetwithinminutesofdruginitiation IgEmediated:b-lactamantibiotics Potentialforanaphylaxis Bradykininmediated:ACE-I OftenIgEmediated Fixeddrugeruption Hyperpigmentedplaques Tetracycline,NSAIDs,andcarbamazepine Recuratsameskinormucosalsite Pustules Acneiform Acneiform:corticosteroids,sirolimus Acutegeneralizedeczematouspustulosis(AGEP) AGEP:antibiotics,calcium-channelblockers Bullous Tenseblisters Furosemide,vancomycin Flaccidblisters Captopril,penicillamine SJS Fever,erosivestomatitis,ocularinvolvement,purpuric Antibacterialsulfonamides,anticonvulsants,oxicam maculesonfaceandtrunkwith<10%epidermal NSAIDs,andallopurinol detachment TEN SimilarfeaturesasSJSbut>30%epidermaldetachment SameasSJS Mortalityashighas50% Cutaneouslupus Erythematous/scalyplaquesinphotodistribution Hydrochlorothiazide,calcium-channelblockers,ACE-Is Hematologic Hemolyticanemia,thrombocytopenia,granulocytopenia Penicillin,quinine,sulfonamides Hepatic Hepatitis,cholestaticjaundice Para-aminosalacylicacid,sulfonamides,phenothiazines Pulmonary Pneumonitis,fibrosis Nitrofurantoin,bleomycin,methotrexate Renal Interstitialnephritis,membranousglomerulonephritis Penicillin,sulfonamides,gold,penicillamine,allopurinol Multiorganreactions Anaphylaxis Urticaria/angioedema,bronchospasm,gastrointestinal b-Lactamantibiotics,mAbs symptoms,hypotension IgE-andnon–IgE-dependentreactions DRESS Cutaneouseruption,fever,eosinophilia,hepaticdysfunction, Anticonvulsants,sulfonamides,minocycline,allopurinol lymphadenopathy Serumsickness Urticaria,arthralgias,fever Heterologousantibodies,infliximab Systemiclupuserythematosus Arthralgias,myalgias,fever,malaise Hydralazine,procainamide,isoniazid Vasculitis Cutaneousorvisceralvasculitis Hydralazine,penicillamine,propylthiouracil Cutaneous manifestationsare the most common physical mani- anticonvulsants, it has since been ascribed to a variety of other festationofdrug-inducedallergicreactions;however,manyother drugs. DRESS is atypical from other drug-induced allergic organsystemscanbeinvolved,includinghematologicabnormal- reactionsinthatthereactiondevelopslater,usually2to8weeks ities,hepatitis,pneumonitis,lymphadenopathy,orarthralgias.Al- after therapy is started; symptoms can worsen after the drug is though drug-induced allergic reactions might present with discontinued; and symptoms can persist for weeks or even noncutaneousphysicalfindings,thesefindingsaregenerallynon- months after the drug has been discontinued.6 specificand are not nearly as helpful in diagnosis and manage- ment decisions. Numerous cutaneous eruptions have been EVALUATION: HISTORY TAKING attributed to drug-induced allergic reactions and have been re- viewedelsewhere.5 Athoroughhistoryisanessentialcomponentintheevaluation ofpatientswithsuspecteddrugallergies.Thehistoryhelpsguide Because certain drug eruptions are associated with specific immunologic reactions, it is important to characterize the type theclinicianinthechoiceofdiagnostictestsandwhetheritmight be safe to reintroduce the medication. If possible, the original of eruption inregardtodetermining the cause, further diagnos- medical record that describes the drug reaction should be tic tests, and management decisions. The most common cuta- neous manifestation of drug-induced allergic reactions is a reviewed. The most important components of a drug allergy historyareasfollows. generalizedexanthem(alsoknowasamaculopapulareruption). Urticaria, angioedema, or both is another common cutaneous d Whatisthenameofthemedication?Althoughobvious,not drug reaction that can be due to IgE-mediated reactions, serum uncommonly,patientsareunabletoprovidethisbasicpiece sickness, pseudoallergic reactions, or other mechanisms (eg, of information. Reasons for this include passage of time bradykinin mediated). The most severe form of cutaneous drug andthefactthatnamesofmanymedicationssoundsimilar, reactions are Stevens-Johnson syndrome (SJS) and toxic epi- and patients who reacted to multiple drugs might confuse dermal necrolysis (TEN). The drug rash with eosinophilia and which drug caused which reaction. systemic symptoms (DRESS) syndrome is another cutaneous, d Howlong ago did the reaction occur? The time elapsed is drug-induced, multiorgan inflammatory response that can be important because some allergies, such as to penicillin, life-threatening. First described in conjunction with wane over time. S128 KHANANDSOLENSKY JALLERGYCLINIMMUNOL FEBRUARY2010 d Whichsystems(eg,cutaneous,respiratory,andgastrointes- LABORATORIES IN DRUG ALLERGY tinal) were involved in the reaction, and what were the Routinelaboratoryevaluationappropriatetotheclinicalsetting characteristics? If a cutaneous eruption occurred, what mightbe usefulfor theevaluationof apatient witha suspected kindwasit(eg,urticarial,morbilliform,bullous,orexfoli- drugreaction,dependingonthehistoryandphysicalexamination ative)? Showing the patient pictures of different types of findings. Although eosinophilia is often suggestive of a drug- rashes might be helpful. inducedallergicreaction,mostpatientswithdrug-inducedaller- d When during the course did the reaction occur? Alterna- gicreactionsdonothaveeosinophilia,andthereforetheabsence tively, was the onset of symptoms after the course was ofeosinophiliaclearlydoesnotexcludeadrug-inducedallergic completed? cause.Autoantibodiesmightbehelpfulintheevaluationofdrug- d Why was the medication prescribed? The indication is im- induced vasculitis (eg, antinuclear cytoplasmic antibody) and portantbecausesymptomsoftheunderlyingdiseasemight drug-induced lupus erythematosus (DILE). In the case of sys- bemisattributedtothemedication(eg,atruncalrashduring temicDILE,antihistoneantibodylevelsarefrequentlypositive, penicillin therapy for streptococcal pharyngitis). whereasinpatientswithcutaneousDILE,anti-Ro/SSA,anti-La/ d Wasthepatienttakingconcurrentmedicationsatthetimeof SSB,orbothlevelsarefrequentlypositive.7 the reaction? Antibiotics are usually blamed for reactions, In cases of suspect anaphylaxis, a diagnosis of anaphylaxis but drugs such as opiates and nonsteroidal anti-inflamma- might be made by detecting an increase in serum total tryptase tory drugs (NSAIDs) are frequently coadministered and levels above baseline values or in serum mature tryptase (also might be responsible instead. knownasb-tryptase)levels,whichpeak0.5to2hoursafterdrug d What was the therapeutic management required secondary administration and then decrease with a half-life of about 2 tothereaction?Self-discontinuation of a medicationsug- hours.8Additionalmethodsfordetectingsystemicmastcellme- gestsamilderreactionthanifapatientrequiredhospital- diatorreleaseincludeobtaining24-hoururinecollectionsforma- ization.Somepatientsrecalltreatmenttheyreceivedmore jorurinarymetabolitesofhistamineorprostaglandinD . 2 readily than the characteristics of the reaction itself. For immediate hypersensitivity reactions mediated by IgE d Hadthepatienttakenthesameoracross-reactingmedica- antibodies,demonstrationofthepresenceofdrug-specificIgEis tion before the reaction? Most allergic reactions require a usuallytakenassufficientevidencethatthepatientsisatsignificant period of sensitization, typically during a previous course riskofhavingatypeIreactionifthedrugisadministered.Thisis that was tolerated. helpfulinthecaseofhigh-molecular-weightagents.Inthecaseof d Has the patient been exposed to the same or similar medi- small-molecular-weight drugs, validated and reliable skin test cationsincethereaction?Forinstance,somepatientswith reagents are only available for penicillin. Haptenation of the ahistoryofpenicillinallergyreportthatlatertheytolerated b-lactamringofpenicillintoaprotein(eg,penicilloyl-polylysine a course of amoxicillin clavulanate (Augmentin; Glaxo- [PPL])enhancestheimmunogenicity,withresultantimprovement SmithKline, London, United Kingdom), not realizing the inthedetectionofspecificIgE.Thenegativepredictivevalueof latter is a penicillin-class compound. penicillin skin testing (with PPL, penicillin G, and penicilloate d Has the patient experienced symptoms similar to the reac- and/orpenilloate)forseriousimmediate-typereactionsapproaches tion in the absence of drug treatment? The most common 100%. However, insufficient knowledge about drug degradation situation is chronic recurrent idiopathic urticaria, which products,metabolites,orbothandhowtheyareconjugatedwith can be confused for drug allergy. bodyproteinshasbeenanimpedimenttodevelopingeitherskinor d Does the patient have an underlying condition that favors invitroassaysforassessingimmuneresponsestomostothersmall- reactions tocertainmedications?Examplesofsuchcondi- molecular-weightdrugchemicals.SpecificIgEinvitroassays(eg, tions include mononucleosis for ampicillin reactions and RASTs,ImmunoCAP,andImmulite)areavailable,althoughmost HIV infection for trimethoprim-sulfamethoxazole (TMP- arenotadequatelyvalidatedwithunclearspecificityandsensitivity SMX) reactions. andlackinternalpositivecontrols.Inaddition,invitroassaysfor IgEtodrugsarehamperedbecauseofdifficultieswithbindingof drugallergenstosolid-phasematrices. DIFFERENTIAL DIAGNOSIS IN DRUG ALLERGY Thebasophilactivationtestisarecentlydescribedmethodof evaluating expression of CD63 or CD203C on basophils after Drug-inducedallergicreactionscanpresentinnumerousways, stimulationwithanallergen.Thereareverylimiteddatausingthis affecting single organs or with multiorgan involvement. How- method to evaluate patients with possible drug allergies to ever,eachclinicalpresentationisnotuniqueorspecifictodrug- b-lactamantibiotics,NSAIDs,andmusclerelaxants,9andfurther induced allergicreactions,andthereforeotherconditionsmight confirmatory studies, especially with commercially available needtobeconsideredbasedonthepresentation.Forexample,a tests, are needed before its general acceptance as a diagnostic morbilliformeruptionoccurringinachildreceivingamoxicillin tool.Drugpatchtestingmightbeusefulforcertaintypesofcuta- foranupperrespiratorytractinfectionmightindeedbeduetoa neousdrugreactions,includingmaculopapularexanthems,acute viral exanthem and not a drug-induced allergic reaction. In generalizedexanthematouspustulosis,andfixeddrugeruptions, addition, patients with multiple drug allergies might actually have an underlying chronic disease and are inappropriately but generally is not helpful for SJS or urticarial eruptions.10 In complex cases in which multiple drugs are involved without a labeled with multiple drug allergies. This frequently occurs in patients with underlying chronic urticaria or anxiety disorders clear-cut temporal relationship, a skin biopsy might be useful. butcan also occur with other conditions, such as asthma, vocal However,therearenoabsolutehistologiccriteriaforthediagno- sisofdrug-inducederuptions,andaskinbiopsymightnotdefin- cord dysfunction, idiopathic anaphylaxis, or rarely even mastocytosis. itivelyexcludealternativecauses. JALLERGYCLINIMMUNOL KHANANDSOLENSKY S129 VOLUME125,NUMBER2 TABLEII.Inductionofdrugtoleranceprocedures Typeofdrugtolerance Duration Initialdose Mechanisms Example ImmunologicIgE(drugdesensitization) Hours mg Antigen-specificmediatordepletion, Penicillin downregulationofreceptors Carboplatin,cisplatin,oxaliplatin Immunologicnon-IgE Hourstodays mg Unknown TMP-SMX Pharmacologic Hourstodays mg Metabolicshift,internalizationofreceptors Aspirin Nonimmunologicmastcellactivation Hours mg Unknown Paclitaxel Undefined Weeks mg-mg Unknown Allopurinol INDUCTION OF DRUG TOLERANCE AND GRADED for starting with a lower dose is based on the concept that a CHALLENGE PROCEDURES smallerdoseofallergenwillresultinalesssevereandmoreeasily In situations in which there is a definite medical need for a treatedreaction.Unlikeinductionofdrugtoleranceprocedures,a particularagent,nosuitablealternativeagentexists,andtesting graded challenge does not modify a patient’s immunologic or with high negative predictive value does not exist, there are nonimmunologic response to a given drug. Although it is not primarily2optionsforthepatientwithadrugallergy.Ontheone possibletobeabsolutelycertainthatapatientisnotallergictoa hand, a procedure to induce temporary drug tolerance can be drug because valid diagnostic tests are not available for most performedtoallowthepatienttotakethedrugsafely.Incontrast, drugs,gradedchallengesareintendedforpatientswho,afterafull atestdoseorgradedchallengecanbeadministeredtodetermine evaluation,areunlikelytobeallergictothegivendrug.Further- whetherthepatientiscurrentlyallergictotheparticulardrug. more,thebenefitoftreatmentwiththedrugshouldoutweighthe Thetermdrugdesensitizationhasbeenwidelyusedandisde- risk of performing the graded challenge. The starting dose for finedasaprocedurethatmodifiesapatient’simmuneresponseto graded challenge is generally higher than for induction of drug adrug,allowinghimorhertotakethedrugtemporarilyinasafe tolerance procedures, and the number of steps in the procedure manner.IncasessuchasIgE-mediateddrugallergy(eg,topeni- might be 2 or several. The time intervals between doses are cillin),thetermdrugdesensitizationisaccurateinthatpatientsare dependent on the type of previous reaction, and the entire indeedsensitizedtopenicillinbeforetheprocedureandafterward procedurecantakehoursordaystocomplete.Afterasuccessful typicallyhavediminishedorabsentskintestreactionsandhence graded challenge and therapeutic course of the drug, future arelesssensitiveordesensitized.11However,thetermdrugdesen- coursesofthedrugcanbestartedwithoutanotherchallenge. sitizationhasalsobeenusedtodescribeanumberofdifferentpro- AtypicallysafestartingdoseforanIgEimmuneinductionof tocolsforpatientswithnon–IgE-mediateddrugallergieswhoin drugtolerance(desensitization)procedureisabouttwicethedose many cases are not truly sensitized initially but might react to usedinthepunctureorintradermalskintestusedtodocumentthe thedrugthroughvariousnon–IgE-mediatedorevennonimmune IgE-mediated allergy. A typical starting dose for a graded chal- mechanisms.Recently,theterminductionofdrugtolerancehas lengeis1/100thofthefinaltreatmentdose.Thisisincontrasttothe been proposed as a more appropriate term to encompass not starting dose for an IgE immune induction of drug tolerance, in only IgE-mediated desensitization procedures but other non– whichcasethestartingdoseisoften1/10,000thofthefinaldose. IgE-mediateddesensitizationsaswell.12Thetermdrugtolerance Cautionshouldbeexercisedwhenagradedchallengeconsistingof isdefinedasastateinwhichapatientwithadrugallergywilltol- morethan4or5stepsisperformedbecauseitmightinadvertently erateadrugwithoutanadversereaction.Drugtolerancedoesnot inducemodificationsofimmuneeffectorcellsandthereforeinduce indicateeitherapermanentstateoftoleranceorthatthemecha- drug tolerance in the patient. In these circumstances future nisminvolvedwasimmunologictolerance.Drugdesensitizations administrationsofthedrugshouldbemadecautiously. forIgE-mediateddrugallergyareindeedaformofimmunologic Thechoiceofwhethertointroduceaclinicallyindicateddrug drugtolerance.Inductionofdrugtoleranceproceduresmodifya throughagradedchallengeorthroughinductionofdrugtolerance patient’sresponsetoadrug(throughimmunologicorothernon- mainlydependsonthelikelihoodthatthepatientisallergicatthe immunologicmechanisms)totemporarilyallowtreatmentwithit time of the procedure. Patients who, based on their history, safely. Induction of drug tolerance can involve IgE immune diagnostictestresults,orboth,areunlikelytobeallergictoadrug mechanisms, non-IgE immune mechanisms, pharmacologic can undergo graded challenge. For example, if penicillin skin mechanisms,andundefinedmechanisms(TableII). testingisunavailableandapatientwithahistoryofamildpruritic Allprocedurestoinducedrugtoleranceinvolveadministration rashduringpenicillintreatment20yearsagorequirespenicillin ofincrementaldosesofthedrugbutvaryconsiderablyoverthe therapy,itwouldbereasonabletoadministerpenicillinthrougha starting dose and duration of the procedure. Through various graded oral challenge. Patients who have a relatively higher mechanisms, these procedures induce a temporary state of likelihoodofbeingallergictoadrugshouldundergoaninduction tolerance to the drug, which is maintained only as long as the of drug tolerance procedure. For example, if penicillin skin patientcontinuestotakethespecificdrug.Thereforethisproce- testing is unavailable and a patient with a recent history of durewouldneedtoberepeatedinthefutureifapatientrequires penicillin-induced anaphylaxis requires penicillin, it should be thedrugagainafterfinishingapriortherapeuticcourse. administered through induction of drug tolerance. Graded chal- Gradedchallenge,ortestdosing,isdefinedasaprocedureto lenge (or induction of drug tolerance) should almost never be determine whether a patient will have an adverse reaction to a performedifthereactionhistoryisconsistentwithaseverenon– particular drug by administering lower than therapeutic doses IgE-mediatedreaction, suchasSJS,TEN,DRESS,hepatitis,or overaperiodoftimewithobservationforreactions.Therationale hemolyticanemia. S130 KHANANDSOLENSKY JALLERGYCLINIMMUNOL FEBRUARY2010 FIG2. Chemicalstructuresofb-lactamantibiotics. FIG1. Chemicalstructuresofmajorandminorpenicillinallergenicdeter- minants.TheR-groupdistinguishesdifferentpenicillincompounds. asPrePenfrom1974until2004andisexpectedtoreturntothe MANAGEMENT OF COMMON ALLERGIC marketin2009.Oftheminordeterminants,onlypenicillinGis REACTIONS TO SPECIFIC AGENTS commercially available. Some medical centers synthesize peni- b-Lactam antibiotics: Penicillins cilloate and penilloate for local use. Amoxicillin or ampicillin Penicillinisthemostprevalentmedicationallergy,withabout shouldbeincludedintheskin-testingpanelwhenpatientsreport 10%ofpatientsreportingbeingallergic.Whenevaluated,how- reactionstotheseantibiotics. ever,approximately90%ofpatientswithahistoryofpenicillin Thenegativepredictivevalueofpenicillinskintestingisvery allergy are able to tolerate penicillins.13,14 This observation is high. In large-scale studies 1% to 3% of patients with negative partly due to the fact that penicillin-specific IgE antibodies skintestresponses(withbothmajorandminordeterminants)had waneovertimeandmany(butnotall)patientsoutgrowtheirpen- mild and self-limiting reactions on being challenged with the icillin allergy. In addition, many patients were probably misla- drug.13,14Somestudiesreportthatabout10%to20%ofpatients beled as being allergic at the time of their reaction because withpenicillinallergyhaveskintestreactivityonlytopenicilloate symptoms and signs of an underlying illness can be confused orpenilloate.13,14,18Theclinicalsignificanceofthesefindingsis for a penicillin-induced reaction. Patients labeled as allergic to uncertain.Penicillinchallengesofsubjectswithnegativeskintest penicillinaremorelikelytobetreatedwithmoreexpensiveand responses to PPL and penicillin G19 have similar reaction rates broad-spectrum antibiotics (eg, quinolones and vancomycin),15 comparedwiththoseinsubjectswithnegativeskintestresponses which contributes to the development and spread of multiple tothefullsetofmajorandminorpenicillindeterminants.13,14 drug-resistantbacteriaandleadstohigherhealthcarecosts. Reactionhistoryisapoorpredictorofwhowilldemonstratea The immunochemistry of penicillin was elucidated in the positivepenicillinskintestresponse.Overall,aboutonethirdof 1960s.16Underphysiologicconditions,penicillinspontaneously patientswithpositivepenicillinskintestresponsesreportvague degradestoanumberofreactiveintermediatesthatactashaptens reactionhistories.20Thereforeanypatientwithahistoryofapos- andcovalentlybindtoself-proteins,whichthencanelicitanim- sible IgE-mediated reaction to penicillin is a candidate for skin muneresponse.Approximately95%ofpenicillindegradestothe testing.Electiveskintesting(whenpatientsarewellandnotinim- penicilloylmoiety,whichisreferredtoasthemajorantigenicde- mediate need of antibiotic therapy) should be considered. The terminant(Fig1).Theremainingportionofpenicillindegradesto medicalcareofpatientslabeledashavingpenicillinallergycan several derivatives, and of these, penicilloate and penilloate are becompromisedbecauseofuseofinappropriateantibiotics.15Pa- the most important to induce allergic responses. These 2 com- tientswhohavepositiveresponsesshouldreceivepenicillinsonly pounds, along with penicillin itself, are collectively known as through an induction of drug tolerance procedure. For patients theminorantigenicdeterminants,andtheycoverallclinicallyrel- with negative skin test responses, clinicians should consider a evantallergenicdeterminantsnotcoveredbypenicilloyl. challenge with penicillin because without it, many patients are Less commonly, the R-group side chain, which distinguishes subsequentlynottreatedwithb-lactamsbecauseoffearoneither different penicillin compounds, can also serve as an allergenic thepartofthepatientortreatingphysician. determinant(Fig2).Thistypeofallergyresultsinpatientswho Resensitization after oral treatment with penicillin is rare in selectivelyreacttoamoxicillin,forexample,butareabletotoler- both pediatric and adult patients, including after repeated ate other penicillins.17 In contrast, patients allergic to the core courses.21,22Henceroutinerepeatpenicillinskintestingisnotin- b-lactam portion of penicillin cross-react tovarious penicillins. dicatedinpatientswithahistoryofpenicillinallergywhohave Selective allergy to amoxicillin or ampicillin is relatively com- tolerated1ormorecoursesoforalpenicillin.Considerationcan mon in parts of Southern Europe and quite infrequent in the begiventoretestingindividualswithrecentorparticularlysevere UnitedStates;thereasonforthesedifferencesinunknown. previous reactions. Resensitization after high-dose parenteral Insightintotheimmunochemistryofpenicillinhasallowedfor treatmentwithpenicillinmightbemorelikely,butdataarelim- thedevelopmentofvalidatedskintestreagentstodetectpenicil- ited.Nevertheless,repeatpenicillinskintestinginthissituation lin-specificIgEantibodies.13,14PPLwascommerciallyavailable mightbewarranted.23 JALLERGYCLINIMMUNOL KHANANDSOLENSKY S131 VOLUME125,NUMBER2 TABLEIII.Summaryofstudiesofcephalosporinchallengesinpatientswithahistoryofpenicillinallergywithoutprecedingpenicillin allergytesting Reference Historyofpenicillinallergy Nohistoryofpenicillinallergy Cephalosporinsadministered Dash,1975E1 25/324(7.7%) 140/17,216(0.8%) Cephalexinandcephaloridine Petz,1978E2 57/701(8.1%) 285/15,007(1.9%) Cephalexin,cephaloridine,cephalothin,cefazolin,and cefamandole Goodmanetal,2001E3 1/300(0.3%) 1/2,431(0.04%) Cefazolin(inallbut1patient) Daulatetal,2004E4 1/606(0.17%) 15/22,664(0.07%) Firstgeneration(42%),secondgeneration(21%),third/fourth generations(37%) Fonacieretal,2005E5 7/83(8.4%) Notreported Firstgeneration(59%),secondgeneration(8.4%),third generation(25%),fourthgeneration(7%) PleaseseetheOnlineRepositoryatwww.jacionline.orgforcompletereferencecitations. Withoutpenicillinskintesting,theapproachtopatientswitha dependingonthereactionhistoryandthelikelihoodthepatient historyofpenicillinallergyisbasedonthereactionhistoryand has penicillin allergy. The reaction risk is very low, but rarely, likelihoodofneedingtreatmentwithpenicillins.Patientswitha anaphylacticreactionshavebeendescribed. low likelihood of being allergic (eg, those with distant [ > 10 Allergiccross-reactivitybetweenamoxicillinandcephalospo- years] or vague reaction histories) might receive penicillins rins that share identical R-group side chains is higher than for through cautious graded challenge. On the other hand, patients patients with positive penicillin skin test responses. Twelve withseverereactionhistories(eg,anaphylaxis)orrecentreactions percent to 38% of patients proved to be selectively allergic to should receive penicillins only through an induction of drug amoxicillin (ie, able to tolerate penicillin) reacted to cefa- toleranceprocedure. droxil.26,27 Therefore patients with amoxicillin allergy should avoid cephalosporins with identical R-group side chains (cefa- b-Lactam antibiotics: Penicillin/cephalosporin droxil,cefprozil,andcefatrizine)orreceivethemthroughinduc- cross-reactivity tion of drug tolerance procedures. Similarly, patients with Retrospective studies of administration of cephalosporins to ampicillinallergyshouldavoidcephalexin,cefaclor,cephradine, patients with a history of penicillin allergy, without prior peni- cephaloglycin,andloracarbeforreceivethemthroughinduction cillinskintesting,showedmuchhigherreactionratesinthe1970s ofdrugtoleranceprocedures. compared to recently (Table III). Before 1980, cephalosporins werecontaminatedwithtraceamountsofpenicillin,whichwould overestimatethecross-reactivity.Studiesthatrelyonpatienthis- b-Lactam antibiotics: Penicillin/carbapenem cross- torytodiagnosepenicillinallergyareproblematicbecauseabout reactivity 90%ofthesepatientsdonothavepenicillinallergyatthetimeof Dataonallergiccross-reactivitybetweenpenicillinandcarba- treatmentwithcephalosporins.Furthermore,somepatientswith penemsaresimilartothoseforpenicillin/cephalosporins.TableV severepenicillinreactionhistoriesmighthavebeendeniedtreat- summarizes retrospective studies of carbapenem administration mentwithcephalosporins. topatientswithahistoryofpenicillinallergy(nopenicillinskin Table IV summarizes studies in which patients with positive testing performed). The carbapenem reaction rate is somewhat penicillin skin test responses were challengedwith cephalospo- higher in patients with a history of penicillin allergy. Table V rins. Although these studies are of higher quality by virtue of alsosummarizesstudiesinwhichpatientswithpositivepenicillin provingtypeIpenicillinsensitizationbeforecephalosporinchal- skintestresponseswerechallengedwithcarbapenems,andnopa- lenge,theystillhavelimitations,includinglackofcontrolgroups tientsexperiencedreactions(3patientswerenotchallengedbe- (eg, patients challenged with placebo or challenged with non– causeofpositivecarbapenemskintestresponses). b-lactam antibiotics) and the fact that the challenges were not Theapproachtocarbapenemadministrationinpatientswitha blinded. Patients might have an underlying propensity to react historyofpenicillinallergyisanalogoustothatforcephalospo- to unrelated drugs,24 which can account for some reactions to rins. Patients with negative penicillin skin test responses can cephalosporins in patients with penicillin allergy. In patients receivecarbapenemssafely.Patientswithpositivepenicillinskin withdocumentedallergic-likereactionstopenicillins,therelative testresponsesshouldreceivecarbapenemsthroughgradedchal- riskforallergic-likereactionswasincreasedforbothcephalospo- lenge,giventhatthechanceofreactingislessthan1%.Without rinsandsulfonamides.25 penicillinskintesting,carbapenemscanbeadministeredthrough Ideally, management of cephalosporin administration to pa- gradedchallenge.Skintestingwithcarbapenemscanbeconsid- tientswithahistoryofpenicillinallergyincludespenicillinskin ered in patients with positive penicillin skin test responses or testing (when available). About 90% of patients have negative whenpenicillinskintestingisnotperformed. penicillinskintestresponsesandcansafelyreceivecephalospo- rins(aswellasotherb-lactams).Patientswithpositivepenicillin skin test responses have a slightly increased risk of reacting to Sulfonamides cephalosporins, and therefore they should be administered Sulfonamides are defined as drugs with an SO -NH moiety. 2 2 throughgradedchallengeoraninductionoftoleranceprocedure. Sulfonamide antibiotics also contain an aromatic amine at the When penicillin skin testing is not available, cephalosporins N positionandasubstitutedringattheN position,whereasnon- 4 1 might be given through a full-dose or graded challenge, antibiotic sulfonamides do not. Beside penicillins, sulfonamide S132 KHANANDSOLENSKY JALLERGYCLINIMMUNOL FEBRUARY2010 TABLEIV.Summaryofpatientswithpositivepenicillinskintestresponseschallengedwithcephalosporins,notincludingpatientswith positiveskintestresponsestoonlyamoxicillinorampicillin(andnottomajor,minor,orbothpenicillindeterminants) Cephalosporin Reference No.ofpatients No.ofreactions Skintesting Comment Girard,1968E6 23 2(8.7%) No Bothreactionstocephaloridine AssemandVickers,1974E7 3 3(100%) No Allreactionstocephaloridine Warringtonetal,1978E8 3 0 Yes Solleyetal,1982E9 27 0 No Saxonetal,1987E10 62 1(1.6%) No Cephalosporinnotnoted Blancaetal,1989)E11 16 2(12.5%) No Bothreactionstocefamandole ShepherdandBurton,1993E12 9 0 No Audicanaetal,1994E13 12 0 Yes PichicheroandPichichero,1998E14 39 2(5.1%) No Reactiontocefaclorand? Novalbosetal,2001E15 23 0 Yes MacyandBurchette,2002E16 42 1(2.4%) No Reactiontocefixime Romanoetal,2004E17 75 0 Yes GreenbergerandKlemens,2005E18 6 0 No Parketal,2006E19 37 2(5.4%) No Cephalosporinsnotnoted PleaseseetheOnlineRepositoryatwww.jacionline.orgforcompletereferencecitations. TABLEV.Summaryofcarbapenemchallengesinpatientswithahistoryofpenicillinallergywithoutprecedingpenicillinallergytesting andinpatientswithpositivepenicillinskintestresponses Carbapenemreactionrate Historyofpenicillin Nohistoryof Historyofpenicillin Reference allergy(nopenicillinST) penicillinallergy allergy(1penicillinST) Pvalue McConnelletal,2000E20 4/63(6.3%) NA NA NA Prescottetal,2004E21 11/100(11%) 3/111(2.7%) NA .024 Sodhietal,2004E22 15/163(9.2%) 4/103(3.9) NA .164 Cunhaetal,2008E23 0/110(0%) NA NA NA Romanoetal,2006E24 NA NA 0/110* NA Romanoetal,2007E25 NA NA 0/103* NA Atanaskovicetal, NA NA 0/107* NA 2008E26 PleaseseetheOnlineRepositoryatwww.jacionline.orgforcompletereferencecitations. ST,Skintestresponse. antibioticsarethemostcommoncauseofdrug-inducedallergic doses,thetimeintervalbetweendoses,andthetotaldurationof reactions.28Theymostcommonlycausedelayedcutaneousmac- the desensitization; however, the success rates are comparable. ulopapular/morbilliform eruptions, and IgE-mediated reactions Twostudiescomparedtheeffectivenessofinductionoftolerance arerelativelyinfrequent.Sulfonamidesarebyfarthemostcom- versus rechallenge (single dose) in HIV-positive patients with moncauseofSJSandTEN.29 documented reactions to TMP-SMX, and there were no differ- Patients infected with HIV have a greatly increased risk of encesinthesuccessrates.31,32Theseresultsplaceintoquestion cutaneous reactions from sulfonamide antibiotics, which is thevalidityofpreviouslyreportedinductionoftoleranceproce- probably related to immunologic factors and frequent exposure duresthatdidnotincludeacontrolgroupofpatientswhoreceived to these antibiotics. The typical reaction to TMP-SMX in HIV- full-doseTMP-SMX. positivepatientsconsistsofageneralizedmaculopapulareruption TheN aromatic amineiscritical forthedevelopment ofde- 4 that occurs during the second week of treatment and is usually layedreactionstosulfonamideantibiotics(throughoxidationto accompaniedbypruritusandfever.Theincidenceofskinrashes hydroxyaminesandnitrosocompounds),andbasedonmorelimited toTMP-SMXinhealthysubjectsis3%to5%,whereasreaction data,theN substitutedringappearstobeimportantforIgE-medi- 1 ratesof40%to80%havebeenreportedinpatientswithHIV.28 ated reactions.28 Because nonantibiotic sulfonamides lack these BecauseTMP-SMXisthedrugofchoiceforanumberofHIV- structural components, they would not be expected to cross-react associated infections (most notably prophylaxis and treatment withsulfonamideantibiotics.Severalclinicalstudiesdemonstrated ofPneumocystiscarinii–inducedpneumonia),itisnotuncommon noincreasedriskofreactionstononantibioticsulfonamidesinpa- for HIV-positive patients with a history of reacting to sulfona- tientswithahistoryofallergytosulfonamideantibiotics.33 midestorequiretreatmentwiththeantibiotic.Consequently,var- iousinductionofdrugtoleranceprocedureshavebeendevisedto Local anesthetics safelyadministerTMP-SMXtoHIV-positivepatientswithhisto- IgE-mediated reactions to local anesthetics are extremely riesofreactingtotheantibiotic.30Theprotocolsvarygreatlyin rare,34yetmanypatientsarelabeledallergictoall‘‘caines’’andde- terms of the starting dose, the incremental increase between nied access to these drugs. Most adverse reactions to local JALLERGYCLINIMMUNOL KHANANDSOLENSKY S133 VOLUME125,NUMBER2 anesthetics are due to nonallergic factors, such as vasovagal re- reactions.43Pretreatmentisdefinedastheadministrationofmed- sponses;toxicoridiosyncraticreactionscausedbyinadvertentin- icationsbeforeadministrationofadrugtolessenthelikelihood travenousepinephrine;oranxiety.35Localanestheticsaregrouped and severity of a drug-induced allergic reaction. Medications intobenzoate estersand amides. Basedonpatch testing,thereis usedforpretreatmentarethoughttobeeffectivebecauseofblock- cross-reactivityamongthebenzoateesters(whichdonotcross-re- adeofreceptorsformastcellmediatorsorthroughreductionin actwithamides)butnotamongtheamides.Itisnotknownwhat,if mastcellmediatorrelease(mastcellstabilization).Atypicalpre- any,relevancethishasonimmediate-typereactionstolocalanes- treatment regimen consists of 50 mg of prednisone 13, 7, and thetics.IfthereactionhistoryisconsistentwithapossibletypeIre- 1hourbeforetheprocedure;50mgofdiphenhydramine1hour action, skin testing followed by graded challenge tests can be beforetheprocedure;andeither25mgofephedrineor4mgof performed with the same (epinephrine-free) local anesthetic that albuterol1hourbeforetheprocedure.However,thelatteragents isintendedtobeused.Althoughtherearedifferencesinreported mightnotbefavorablefromarisk/benefitstandpointinpatients graded challenge procedures, a rapid and convenient protocol is withcardiovasculardisease.TheuseofH antagonistsinthepre- 2 asfollows.36Skinpricktestingisfirstperformedwiththeundiluted treatment regimen is controversial because it can increase the anesthetic.Iftheresponseisnegativeafter20minutes,anintrader- RCMreactionrate.43 maltestisperformedwith0.04mLof1:100dilutionoflocalanes- DelayedreactionstoRCM,definedasthoseoccurringbetween thetic. If the response is negative after 20 minutes, a 1.0-mL 1hourand1weekafteradministration,occurinapproximately subcutaneous injection of saline as a placebo is administered. If 2% of patients.44 These reactions most commonly manifest as there is no reaction after 20 minutes, 1.0 mL of local anesthetic mild, self-limited cutaneous eruptions and do not require any isadministered,andthepatientisobservedfor20minutes. treatment.44 The mechanism of delayed skin reactions to RCM False-positive intracutaneous test results can occur in some appears to be T-cell mediated.45 Rarely, more serious and life- patients.37Also,veryrarepatientscanhavepositiveskintestre- threatening delayed reactions to RCM have been described, sponsestomethylparabensinlocalanesthetics,andsomeofthese suchasSJSandTEN.45 can be false-positive.36 In these situations preservative-free local Anaphylactoid reactions to gadolinium occur less frequently anestheticshouldbeusedforskintesting/gradedchallenge. than to contrast materials used for computed tomographic scans.46 Premedication regimens consisting of corticosteroids and antihistamines have been successfully used.47 Nephrogenic Radiocontrast media systemic fibrosis (NSF), also called gadolinium-associated sys- Anaphylactoid (non–IgE-mediated anaphylaxis) reactions temicfibrosis,isarecentlydescribeddevastatingprogressivesys- occur in about 1% to 3% of patients who receive ionic temic fibrosing disorder that afflicts patients with renal radiocontrast media (RCM) and less than 0.5% of patients dysfunctionwhorecentlyreceivedgadolinium.48Themechanism whoreceivenonionicagents.38Severelife-threateningreactions ofNSFhasnotbeenelucidated,butitishypothesizedthatdeche- are less common: 0.22% of patients receiving ionic RCM and lationofgadoliniumchelatesattractsCD341,CD451,procolla- 0.04% of patients receiving nonionic agents.39 The fatality gen-positive circulating fibrocytes.48 Gadolinium has been rate from RCM is about 1 to 2 per 100,000 procedures, and it foundinbiopsyspecimensofskinlesions.Pre-existingrenalfail- is similar for both ionic and nonionic agents.40 Risk factors uremightfacilitatethereactionbydelayingtheexcretionofgad- foranaphylactoidreactionstoRCMincludefemalesex,asthma, olinium chelates. There is no effective treatment for NSF, and and a history of a previous anaphylactoid reaction to RCM; affectedpatientshaveincreasedmortality.48 b-blocker exposure, the presence of cardiovascular conditions, orbothareassociatedwithgreaterriskformoreseriousanaphy- lactoid reactions.41 Angiotensin-converting enzyme inhibitor: Cough The pathogenesis of anaphylactoid reactions is unrelated to and angioedema ‘‘seafood allergy’’ (attributed to high iodine content); patients Angiotensin-converting enzyme inhibitors (ACE-Is) have 2 with food allergy require no special precautions before receiv- majoradverseeffects:coughandangioedema.Theincidenceof ingRCM.RCMreactionsaregenerallynotmediatedbyspecific cough from ACE-Is ranges from 5% to 35%.49 Cough occurs IgEantibodies.RCMlikelyhasdirecteffectsonmastcellsand more commonly in women, nonsmokers, and Chinese patients. basophils, leading to degranulation and systemic mediator ThecauseforACE-I–inducedcoughisunclearbutmightbere- release, which accounts for the clinical manifestations of lated to bradykinin, substance P, or other mechanisms. ACE-I– anaphylactoid reactions. Complement activation might account induced cough is typically dry and might be associated with a for some reactions. A recent European trial suggests that some ticklingsensationinthethroat.Thecoughcanoccurwithinhours RCM reactions might be IgE mediated because approximately ofthefirstdoseorwithinweeksormonthsofinitiationoftherapy. half of patients with immediate-type reactions to RCM had WithdiscontinuationoftheACE-I,thecoughusuallyresolvesin positive skin test responses, which were highly specific.42 1to4weeksandrarelylingersupto3months.49Inpatientsfor Management of patients who require RCM and experienced whomcessationofACE-Itherapyisnotdesirable,severalphar- prior anaphylactoid reactions includes the following: (1) deter- macologicagents havebeenreported in small case series to re- minewhetherthestudyisessential;(2)determinethatthepatient duce coughing, including cromolyn, theophylline, NSAIDs, understands the risks; (3) ensure proper hydration; (4) use a amlodipine, nifedipine, and ferrous sulfate.49 ACE-I–induced nonionic, iso-osmolar RCM, especially in high-risk patients cough is not dose related, and angiotensin II receptor blockers (asthmatic patients, patients taking b-blockers, and those with arenotassociatedwithanincreasedincidenceofcough.50 cardiovasculardisease);and(5)useapretreatmentregimenthat TheincidenceofangioedematoACE-Isisestimatedtooccur has been documented to be successful in preventing most in 1 to 7/1,000 patients, and this risk is higher in African- reactionsbutislesssuccessfulinpreventingrecurrenceofsevere Americanscomparedwiththatseeninwhites.51ACE-I–induced S134 KHANANDSOLENSKY JALLERGYCLINIMMUNOL FEBRUARY2010 TABLEVI.HypersensitivityreactionstoaspirinandNSAIDsand inflammatorycellsexpressingcysteinylleukotriene1receptors, cross-reactivity and greater airway responsiveness to cysteinyl leukotrienes. In addition, a number of genetic polymorphisms involving the Cross-reactivitywith Typeofreaction Underlyingdisease COX-1inhibitors leukotriene pathway have been reported to be associated with AERD,includingtheleukotrieneC promoter,thecysteinylleu- Respiratory(AERD) Rhinitis,nasalpolyps, Yes 4 kotriene1receptorpromoter,andprostanoidandthromboxanere- sinusitis,asthma ceptor–relatedgenes.57AdministrationofASAleadstoinhibition Urticaria/AE Chronicurticaria Yes of COX-1, with a resultant decrease in prostaglandin E levels. Urticaria/AE None Yesorno 2 Anaphylaxis None No Prostaglandin E2 normally inhibits 5-lipoxygenase, but with a lossofthismodifyingeffect,arachidonicacidmoleculesarepref- Thecross-reactivitypatternsdepictedinthistablearegenerallytrue,butexceptions erentially metabolized in the 5-lipoxygenase pathway, resulting canoccur. AE,angioedema. inincreasedproductionofcysteinylleukotrienes. Within minutes of ingestion of therapeutic doses of ASA or NSAIDs, patients with AERD typically have both rhinocon- angioedemaisoftenunrecognizedbecauseitsmanifestationcan junctivitisandbronchospasm.Thebronchospasminducedcanbe occuranywherebetweenafewhoursto10yearsafteranACE-I severeandresultinrespiratoryfailurewithaneedforintubation is first taken. A recent retrospective study found a mean of 1.8 andmechanicalventilation.Gastrointestinalsymptomsandurti- yearsfrominitiationofanACE-Iuntiltheonsetofangioedema.52 cariaarerareextrapulmonarymanifestationsofAERD.Patients ACE-I–induced angioedema accounts for approximately one withAERDwillreacttoASAandNSAIDsthatinhibitCOX-1. thirdofallpatientspresentingtotheemergencydepartmentfor Selective COX-2 inhibitors almost never cause reactions in angioedema.53 Characteristically, ACE-I–induced angioedema patientswithAERDandcantypicallybetakensafely. involves the head and neck primarily, especially the lips and ThereisnodiagnosticinvitroorskintestforAERD.Thediag- tongue;concomitanturticariaandpruritusarerare.Insomecases nosisisusuallyestablishedbasedonhistory,butwhenadefinitive laryngeal edema can cause fatalities. Reports of angioedema of diagnosisisrequired,acontrolledoralprovocationchallengewith the intestinal tract caused by ACE-Is have also been described. ASAcanbeperformed.Arecentstudyshowedthat100%ofpa- Bradykinin is a prominent mediator in both hereditary angioe- tientswithahistoryofaseverereactiontoaspirin(poorresponse demaandACE-I–inducedangioedema.54ACE-Isarecontraindi- toalbuterolwithneedformedicalintervention)hadpositiveoral cated in patients with hereditary angioedema. In patients with aspirin challenge esults.58 Management of patients with AERD ACE-I–induced angioedema, angiotensin II receptor blockers involvesavoidanceofaspirinandNSAIDsandaggressivemedi- are often used as alternative medications. Limited data suggest cal,surgical,orbothtypesoftreatmentofunderlyingasthmaand that in patients with angioedema, when taking an ACE-I, the rhinitis/sinusitis. A pharmacologic induction of drug tolerance riskofpersistentangioedemawhensubsequentlyswitchedtoan procedure(alsoknownasaspirindesensitization),duringwhich angiotensinIIreceptorblockersislessthan10%.55Treatmentin- tolerancetoaspirincanbeinducedoverafewdaysandthenmain- cludesdiscontinuingthemedicationandcarefulmanagementof tainedchronically,isanimportanttherapeuticoptionforpatients theairway,andinsomecasesfreshfrozenplasmahasbeenuseful. withAERDandimprovesclinicaloutcomesforbothupperand lowerrespiratorytractdisease.59,60 Acetylsalicylic acid/NSAID reactions Several other drug-induced allergic reactions to ASA or Acetylsalicylicacid(ASA)andNSAIDscancauseaspectrum NSAIDs can occur. Patients with chronic urticaria/angioedema of drug-induced allergic reactions, including exacerbation of might have exacerbation of their urticaria/angioedema with underlying respiratory disease, urticaria, angioedema, anaphy- ingestion of NSAIDs that inhibit COX-1 but typically tolerate laxis,andrarelypneumonitisandmeningitis.Someofthesedrug- COX-2 inhibitors. Patients without a history of underlying induced allergic reactions exhibit cross-reactivity to other chronic urticaria/angioedema can have acute urticaria/angioe- NSAIDs and aspirin, whereas some reactions might be drug demawithingestionofaspirinorNSAIDs.Someofthesepatients specific(TableVI). demonstratecross-reactivitytootherCOX-1inhibitors,whereas Aspirin-exacerbated respiratory disease (AERD) is a clinical others have selective reactions to a particular NSAID. Anaphy- entity characterized by ASA/NSAID-induced respiratory reac- lacticreactionstoNSAIDsaretypicallydrugspecific,andthese tions in patients with underlying chronic respiratory diseases, patientstypicallytolerateotherNSAIDs.61Finally,somepatients suchasasthma,rhinitis,sinusitis,and/ornasalpolyposis.AERD arenoteasilycategorizedwhohaveblendedreactionswithover- has been previously referred to by a number of different terms, lap of various clinical features from the above well-described includingaspirinsensitivity,aspirinintolerance,aspirinidiosyn- ASA/NSAIDreactionsyndromes. crasy, aspirin-induced asthma, and aspirin or Samter’s triad. AERD does not fit precisely into a specific category of ADRs, althoughithasoftenbeenreferredtoasatypeofpseudoallergic HIV medications reaction.AERDaffectsupto20%ofadultasthmaticpatients,is Patients infected with HIV have an increased frequency of morecommoninwomen,hasanaverageageofonsetaroundthe drug-induced allergic reactions, and the reasons behind this are age of 30 years, and usually starts with rhinitis, progressing to likely multifactorial.62 Drug exanthems from TMP-SMX are hyperplastic sinusitis and nasal polyposis.56 Asthma might be amongthemostcommondrug-inducedallergicreactionsinpa- presentsincechildhoodormightdevelopdenovo,onaverage2 tientswithHIV,aspreviouslydiscussed.Antiretroviralmedica- yearsaftertheonsetofnasalcongestionandpolyposis. tions have also been associated with numerous drug-induced Fundamental to the pathophysiology of AERD is excessive allergicreactions,rangingfrommildexanthemstolife-threaten- production of cysteinyl leukotrienes, increased numbers of ingreactions,suchasSJSorTEN. JALLERGYCLINIMMUNOL KHANANDSOLENSKY S135 VOLUME125,NUMBER2 Although many antiretroviral medications can cause drug- tobesuccessfulandsafeinplatinum-containingcompounds,tax- induced allergic reactions, abacavir deserves special mention anes,andotherchemotherapeutics.73 becauseofthesuccessfulimplementationofapharmacogenetics approach to management. Abacavir is a nucleoside reverse transcriptase inhibitor that is associated with a hypersensitivity Biologic modifiers reaction in approximately 4% of treated patients, with an Inthepastdecade,anumberofbiologicimmunemodulatory estimatedmortalityrateof0.03%.63Thismultiorganreactionin- agents have been developed to treat various inflammatory cludessymptomssuchasfever,rash,malaise/fatigue,gastrointes- diseases and tumors. They are comprised of proteins such as tinal symptoms, and respiratory symptoms. In 90% of cases, cytokines, mAbs, and fusion proteins of solubilized receptors. hypersensitivityreactionsoccurredwithinthefirst6weeksafter Theseagents differ from other drugsinthat theyare not small- initiationofabacavir.Rechallengewithabacavirresultedinrecur- molecular-weightcompoundsbutlargepotentiallyimmunogenic renceofsymptomswithinhoursofre-exposure,includinghypo- proteins. Their metabolism is different, many are naturally tension in 25% of those rechallenge reactions. Because of the occurring proteins, and all have inherent immunologic effects. severityofreactionsonrechallenge,hypersensitivitytoabacavir Becauseofallofthesedifferences,aseparatetypeofclassifica- isacontraindicationtosubsequenttreatment withanyformula- tion for adverse reactions to biologic agents has been proposed tionthatincludesit. basedonthemechanismofreactions.74High-dosereactionsare Investigations into genetic risk factors associated with these relatedtohighcytokinelevelsadministereddirectlyorfromcyto- reactions discovered that several HLA alleles, most notably kinesreleased(eg,capillaryleaksyndrome).Hypersensitivityre- HLA-B*5701, were strongly associated with risk of abacavir actions can be either antibody or cell mediated. Immune or hypersensitivity reactions.64,65 The prevalence of HLA-B*5701 cytokine dysregulation can result in secondary immunodefi- varies considerably by ethnicity and geography, with estimated ciency,autoimmunity,orallergic/atopicdisorders.Cross-reactive US prevalences of 8% for whites, 1% for Asians, and 2.5% for reactionscanoccurwhenthebiologicagentisintendedforapath- African Americans.66 A double-blind, prospective, randomized ologiccell type butcross-reacts withnormalcells. Finally, bio- study of 1,956 predominantly white patients with HIV from 19 logic agents can also result in nonimmunologic side effects. countrieswasperformedtoevaluatetheutilityofgeneticscreen- Interferonsareanexampleofbiologicagentscapableofcausing ing before initiation of abacavir therapy.67 Subjects were ran- mostofthe abovereactions,includinghigh-doseflu-likesymp- domly assigned to undergo prospectiveHLA-B*5701 screening toms, hypersensitivity reactions of urticaria, autoimmune reac- withexclusionforabacavirtreatmentifscreenedpositive.Screen- tions (including thyroid disease and psoriasis), and ingforHLA-B*5701reducedtheriskofhypersensitivityreaction nonimmunologiceffects,suchasdepression. toabacavir,withreactionratesof3.4%inthescreenedgroupver- Capillary (vascular) leak syndrome is a rare but potentially sus 7.8% in the control group. A North American study with a fatal condition that has been attributed to a number of biologic moreraciallydiversepopulationdemonstratedthatgeneticscreen- agents, including IL-2, GM-CSF, and granulocyte colony-stimu- ingdecreasedtherateofabacavirhypersensitivitytolessthan1%, latingfactor.75Clinicalandbiochemicalfindingscanincludefever, which is lower than historical rates.68 The ability to identify ge- edema(peripheral,pulmonary,ascites,andpleural/pericardialeffu- neticpredispositionstodrug-inducedallergicreactionsandimple- sions),weightgain,hypotension,hypoalbuminemia,andmultior- ment genetic screening tests, as in the case of abacavir gan failure. The mechanism of the endothelial damage with hypersensitivity,mightholdpromiseforpreventingotherdrug-in- subsequent fluidand proteinextravasation isunclearbutappears ducedallergicreactionsinsusceptiblepersons.69 toberelatedtotheinherentbiologiceffectsofthesecytokines. TNF-aantagonistsincludehumanizedandfullyhumanmAbs toTNF-a(infliximabandadalimumab)andTNF-receptorfusion proteins (etanercept). Acute infusion reactions are a relatively Cancer chemotherapeutic agents commonadversereactiontoinfliximab,oftenafterthefirstdose, Hypersensitivityreactionshavebeenreportedformostcancer usuallyoccurringwithin4hoursof theinfusion,andcharacter- chemotherapeutic agents.70 The severity of reactions can range ized by symptoms including hypotension/hypertension, chest from mild cutaneous reactions to fatal anaphylactic reactions. pain,dyspnea,fever,andurticaria/angioedema.76Thepathophys- Taxanes,suchaspaclitaxelanddocetaxel,cancauseanaphylac- iologyofthesereactionsisnotknownbutisusuallynotIgEme- toid reactions (non–IgE-mediated anaphylaxis), frequently with diated,althoughseveralcasesofanaphylaxishavebeenreported. thefirstadministration.Pretreatmentwithantihistaminesandcor- Themajorityofpatientscancontinuetheinfusionwithreduction ticosteroidswillpreventreactionsingreaterthan90%ofcases.71 in rate or with premedication.77 Delayed serum sickness–like Platinumcompounds,suchascisplatin,carboplatin,andoxalipla- reactionswithsymptomsoffever,urticaria/angioedema,andmy- tin,typicallycausehypersensitivityreactionsafterseveraltreat- algias have also been reported but are much less common. The ment courses. Results of skin testing have been found to be presence of antibodies to infliximab has correlated with both positive in the majority of patients with immediate reactions to acute and delayed infusion reactions to infliximab. Etanercept platinum-containing compounds, suggesting an IgE-mediated and, less commonly, adalimumab are associated with delayed mechanism.CetuximabisanmAbusedtotreatcolorectalcancer injectionsitereactionsthattypicallypeakat2days,usuallyoccur andsquamouscellcarcinomaoftheheadandneckandhasbeen inthefirst2monthsoftherapy,andrarelycausediscontinuation associatedwithanaphylacticreactions.IgEantibodiestocetuxi- oftreatment.Recallinjectionsitereactionsatthesitesofprevious mab have been found in the majority of anaphylactic reactions injectionscanalsooccurandcanbeT-cellmediateddelayed-type andarespecificforanoligosaccharide,galactose-a-1,3galactose, hypersensitivityreactions.78Inadditiontotheabove-mentioned which is present on the Fab portion of the cetuximab heavy infusion-orinjection-relatedreactions,anumberofotherimmu- chain.72Procedurestoinducedrugtolerancehavebeenreported nologic adverse reactions have been reported with TNF-a