Drug Allergy: An Updated Practice Parameter

78 Pages·2010·0.9 MB·English

Drug Allergy: An Updated Practice Parameter
These parameters were developed by the Joint Task Force on Practice Parameters, representing the
American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma
and Immunology, and the Joint Council of Allergy, Asthma and Immunology.
Chief Editors
Roland Solensky, MD, and David A. Khan, MD
Workgroup Contributors
I. Leonard Bernstein, MD; Gordon R. Bloomberg, MD; Mariana C. Castells, MD, PhD; Louis M. Mendelson, MD; and
Michael E. Weiss, MD
Task Force Reviewers
David I. Bernstein, MD; Joann Blessing-Moore, MD; Linda Cox, MD; David M. Lang, MD; Richard A. Nicklas, MD;
John Oppenheimer, MD; Jay M. Portnoy, MD; Christopher Randolph, MD; Diane E. Schuller, MD; Sheldon L. Spector, MD;
Stephen Tilles, MD; and Dana Wallace, MD
Reviewers
Paul J. Dowling, MD – Kansas City, MO
Mark Dykewicz, MD – Winston-Salem, NC
Paul A. Greenberger, MD – Chicago, IL
Eric M. Macy, MD – San Diego, CA
Kathleen R. May MD – Cumberland, MD
Myngoc T. Nguyen, MD – Piedmont, CA
Lawrence B. Schwartz, MD, PhD – Richmond, VA
TABLE OF CONTENTS SummaryStatementsoftheEvidence-BasedCommentary
Preface Evidence-Based Commentary
Glossary I. Introduction
Executive Summary II. Definitions
Algorithm for Disease Management of Drug Hyper- III. Classification of Immunologically Mediated Drug
sensitivity Reactions
Annotations for Disease Management of Drug Hyper- A. IgE-mediated reactions (Gell-Coombs type I)
sensitivity B. Cytotoxic reactions (Gell-Coombs type II)
C. Immunecomplexreactions(Gell-CoombstypeIII)
D. Cell-mediated reactions (Gell-Coombs type IV)
These parameters were developed by the Joint Task Force on Practice E. Miscellaneous syndromes
Parameters, representing the American Academy of Allergy, Asthma and 1. Hypersensitivity vasculitis
Immunology;theAmericanCollegeofAllergy,AsthmaandImmunology;
2.Drugrashwitheosinophiliaandsystemicsymptoms
andtheJointCouncilofAllergy,AsthmaandImmunology.
TheAmericanAcademyofAllergy,AsthmaandImmunology(AAAAI) 3. Pulmonary drug hypersensitivity
andtheAmericanCollegeofAllergy,AsthmaandImmunology(ACAAI) 4. Drug-induced lupus erythematosus
have jointly accepted responsibility for establishing “Drug Allergy: An 5. Drug-induced granulomatous disease with or
UpdatedPracticeParameter.”Thisisacompleteandcomprehensivedocu-
without vasculitis
mentatthecurrenttime.Themedicalenvironmentisachangingenviron-
ment, and not all recommendations will be appropriate for all patients. 6. Immunologic hepatitis
Because this document incorporated the efforts of many participants, no 7. Blistering disorders
single individual, including those who served on the Joint Task Force, is a. Erythema multiforme minor
authorizedtoprovideanofficialAAAAIorACAAIinterpretationofthese
b.Erythemamultiformemajor/Stevens-Johnson
practiceparameters.Anyrequestforinformationaboutoraninterpretationof
thesepracticeparametersbytheAAAAIorACAAIshouldbedirectedtothe syndrome
Executive Offices of the AAAAI, the ACAAI, and the Joint Council of c. Toxic epidermal necrolysis
Allergy, Asthma and Immunology. These parameters are not designed for 8. Serum sickness–like reactions associated with
usebypharmaceuticalcompaniesindrugpromotion.
specific cephalosporins
Reprintrequests:JointCouncilofAllergy,Asthma&Immunology,50
N.BrockwaySt,#3-3,Palatine,IL60067. 9. Immunologic nephropathy
273.e1 ANNALSOFALLERGY,ASTHMA&IMMUNOLOGY
F. Other classification systems for drug allergy U. Complementary medicines
IV. Risk Factors V. Other agents
V. Clinical Evaluation and Diagnosis of Drug Allergy
A. History CONTRIBUTORS
B. Physical examination TheJointTaskForcehasmadeaconcertedefforttoacknowl-
C. General clinical tests edge all contributors to this parameter. If any contributors
D. Specific tests havebeenexcludedinadvertently,theTaskForcewillensure
E. Tissue diagnosis that appropriate recognition of such contributions is made
VI. Management and Prevention of Drug Allergic subsequently.
Reactions
A. General CHIEF EDITORS
B. Induction of drug tolerance Roland Solensky, MD
C. Immunologic IgE induction of drug tolerance Division of Allergy and Immunology
(drug desensitization) The Corvallis Clinic
D.Immunologicnon-IgEinductionofdrugtolerance Corvallis, Oregon
for nonanaphylactic reactions David A. Khan, MD
E. Pharmacologic induction of drug tolerance (eg, Professor of Medicine
aspirin desensitization) Division of Allergy & Immunology
F. Undefined induction of drug tolerance University of Texas Southwestern Medical Center
G. Graded challenge Dallas, Texas
VII. Specific Drugs
A. (cid:1)-Lactam antibiotics WORKGROUP CONTRIBUTORS
1. Penicillin I. Leonard Bernstein, MD
2. Ampicillin and amoxicillin Professor of Clinical Medicine
3. Cephalosporins University of Cincinnati College of Medicine
4.Cephalosporinadministrationtopatientswitha Cincinnati, Ohio
history of penicillin allergy Gordon R. Bloomberg, MD
5. Penicillin administration to patients with a Associate Professor, Department of Pediatrics
history of cephalosporin allergy Division of Allergy & Pulmonary Medicine
6. Monobactams (aztreonam) Washington University School of Medicine
7. Carbapenems Saint Louis, Missouri
B. Non–(cid:1)-lactam antibiotics Mariana C. Castells, MD, PhD
C. Antimycobacterial drugs Director, Desensitization Program
D. Diabetes medications AssociateDirector,AllergyImmunologyTrainingProgram
E. Cancer chemotherapeutic agents Brigham & Women’s Hospital
F. Humanimmunodeficiencyvirus(HIV)medications Harvard Medical School
G.Disease-modifyingantirheumaticdrugs(DMARDs) Boston, Massachusetts
H. Immunomodulatoryagentsforautoimmunediseases Louis M. Mendelson, MD
I. Modifying drugs for dermatologic diseases Clinical Professor
J. Perioperative agents University of Connecticut
K. Blood and blood products Partner, Connecticut Asthma & Allergy Center, LLC
L. Opiates West Hartford, Connecticut
M. Corticosteroids Michael E. Weiss, MD
N. Protamine Clinical Professor of Medicine,
O. Heparin University of Washington, School of Medicine
P. Local anesthetics Seattle, Washington
Q. Radiocontrast media (RCM)
R.Aspirinandnonsteroidalanti-inflammatorydrugs TASK FORCE REVIEWERS
(NSAIDs) David I. Bernstein, MD
S. Angiotensin-converting enzyme (ACE) inhibitors Department of Clinical Medicine, Division of Immunology
T. Biologic modifiers University of Cincinnati College of Medicine
1. Cytokines Cincinnati, Ohio
2. Anti–TNF-(cid:2)drugs Joann Blessing-Moore, MD
3. Monoclonal antibodies Department of Immunology
4. Omalizumab Stanford University Medical Center
5. Anticancer monoclonal antibodies Palo Alto, California
VOLUME 105, OCTOBER, 2010 273.e2
Linda Cox, MD Acknowledgments
Department of Medicine The Joint Task Force wishes to acknowledge the following
Nova Southeastern University individualswhoalsocontributedsubstantiallytothecreation
Davie, Florida of this parameter: Erin Shae Johns, PhD, and Jessica Karle,
David M. Lang, MD MS,fortheirimmensehelpwithformattingandrestructuring
Allergy/Immunology Section, Division of Medicine thisdocument;SusanGrupeforprovidingkeyadministrative
Cleveland Clinic Foundation help to the contributors and reviewers of this parameter; and
Cleveland, Ohio Brett Buchmiller, MD, for his assistance in creating the
Richard A. Nicklas, MD algorithms in this parameter.
Department of Medicine
PREFACE
George Washington Medical Center
Theobjectiveof“DrugAllergy:AnUpdatedPracticeParam-
Washington, DC
eter” is to improve the care of patients by providing the
John Oppenheimer, MD
practicing physician with an evidence-based approach to the
Department of Internal Medicine
diagnosis and management of adverse drug reactions. This
New Jersey Medical School
document was developed by a Working Group under the
Morristown, New Jersey
aegis of the Joint Task Force on Practice Parameters, which
Jay M. Portnoy, MD
haspublished26practiceparametersandupdatedparameters
Section of Allergy, Asthma & Immunology
for the field of allergy/immunology (these can be found
The Children’s Mercy Hospital
online at www.jcaai.org). The 3 national allergy and immu-
University of Missouri-Kansas City School of Medicine
nology societies—the American Academy of Allergy,
Kansas City, Missouri AsthmaandImmunology(AAAAI),theAmericanCollegeof
Christopher Randolph, MD Allergy, Asthma and Immunology (ACAAI), and the Joint
Center for Allergy, Asthma and Immunology Council of Allergy, Asthma and Immunology (JCAAI)—
Yale Hospital have given the Joint Task Force the responsibility for both
Waterbury, Connecticut creating new parameters and updating existing parameters.
Diane E. Schuller, MD This parameter builds on “Disease Management of Drug
Department of Pediatrics Hypersensitivity: A Practice Parameter,” which was pub-
Pennsylvania State University lished in 1999 by the Joint Task Force on Practice Parame-
Milton S. Hershey Medical College ters. It follows the same general format as that document,
Hershey, Pennsylvania with some substantive changes reflecting advancements in
Sheldon L. Spector, MD scientificknowledgeandtheireffectonmanagementofdrug
Department of Medicine allergy.Thisdocumentwaswrittenandreviewedbyspecial-
UCLA School of Medicine ists in the field of allergy and immunology and was exclu-
Los Angeles, California sivelyfundedbythe3allergyandimmunologyorganizations
Stephen A. Tilles, MD noted above.
A Working Group chaired by Roland Solensky, MD, pre-
Department of Medicine
pared the initial draft, which was then reviewed by the Joint
University of Washington School of Medicine
TaskForce.Acomprehensivesearchofthemedicalliterature
Redmond, Washington
was conducted using Ovid MEDLINE and the Cochrane
Dana Wallace, MD
Database and Keywords relating to drug allergy. Published
Department of Medicine
clinical studies were rated by category of evidence and used
Nova Southeastern University
to establish the strength of clinical recommendations. The
Davie, Florida
workingdraftof“DrugAllergy:AnUpdatedPracticeParam-
eter” was reviewed by a large number of experts in allergy
Invited Reviewers and immunology. These experts included reviewers ap-
Paul J. Dowling, MD – Kansas City, MO pointed by the AAAAI and ACAAI. The authors carefully
Mark S. Dykewicz, MD – Winston Salem, NC reviewed and considered additional comments from these
Paul A. Greenberger, MD – Chicago, IL reviewers. The revised final document presented here was
Eric M. Macy, MD – San Diego, CA approved by the sponsoring organizations and represents an
evidence-based; broadly accepted consensus parameter.
Kathleen R. May, MD – Cumberland, MD
This updated parameter contains several significant
Myngoc T. Nguyen, MD – Piedmont, CA
changes from the original parameter on “Disease Manage-
ment of Drug Hypersensitivity: A Practice Parameter.” The
Ad Hoc Reviewers titleoftheparameterwaschangedfromdrughypersensitivity
Lawrence B. Schwartz, MD to drug allergy. In this updated parameter the term drug
273.e3 ANNALSOFALLERGY,ASTHMA&IMMUNOLOGY
allergy is defined as an immunologically mediated response • Drug allergy is an immunologically mediated response to
toapharmaceuticaland/orformulation(excipient)agentina apharmaceuticaland/orformulation(excipient)agentina
sensitized person. The implication is that drug allergy does sensitized person.
not simply include only IgE-mediated reactions. Another • Anaphylaxisisanimmediatesystemicreactionthatoccurs
significantchangeistheintroductionofthenewterminduc- whenapreviouslysensitizedindividualisreexposedtoan
tion of drug tolerance to encompass classic IgE-mediated allergen. It is caused by rapid IgE-mediated immune re-
drug desensitizations and other non–IgE-mediated “desensi- lease of vasoactive mediators from tissue mast cells and
tization” procedures for various medications. In addition, peripheral basophils with a potential late component.
severalnewsectionshavebeenadded,includinganewglos- • Pseudoallergic (anaphylactoid) reactions are immediate
sary with new terms, new classifications and subclassifica- systemic reactions that mimic anaphylaxis but are caused
tions for drug reactions, and new sections on drug aller- bynon–IgE-mediatedreleaseofmediatorsfrommastcells
gic reactions to chemotherapeutic agents, corticosteroids, and basophils.
disease-modifying antirheumatic drugs, antimycobacterial • Drug intolerance is an undesirable pharmacologic effect
drugs,biologicmodifiers,immunosuppressiveagents,immu- that may occur at low or usual doses of the drug without
nomodulatoryagents,complementarymedications,anddrug- underlyingabnormalitiesofmetabolism,excretion,orbio-
induced granuloma with or without vasculitis. Significant availability of the drug. Humoral or cellular immune
updates to sections on cutaneous manifestations of drug re- mechanisms are not thought to be involved, and a scien-
actions, laboratory testing, (cid:1)-lactam allergy, cross-reactivity tific explanation for such exaggerated responses has not
betweencarbapenemsandpenicillin, andhuman immunode- been established (eg, aspirin-induced tinnitus at low
ficiency virus medications have been added. Finally, a num- doses).
ber of protocols for induction of drug tolerance procedures • Drug idiosyncrasy is an abnormal and unexpected effect
have been added. thatisunrelatedtotheintendedpharmacologicactionofa
TheExecutiveSummaryemphasizesthekeyupdatessince drug and has an unknown mechanism. It is not mediated
the 1999 drug hypersensitivity parameter. This Executive by a humoral or cellular immune response but is repro-
Summaryhasbeensignificantlyexpandedtoincludethenew ducible on readministration. It may be due to underlying
sectionsandhighlightthemajorupdatestothisparameter.It abnormalities of metabolism, excretion, or bioavailability
shouldbenotedthattheExecutiveSummarydoesnotdiscuss (eg,: quinidine-induced drug fever).
all of this parameter’s topics in depth. An annotated algo- • Aspirin-exacerbatedrespiratorydisease(AERD)isaclin-
rithminthisdocumentsummarizesthemajordecisionpoints ical entity characterized by aspirin- or nonsteroidal anti-
for the evaluation and treatment of patients who have expe- inflammatory–induced respiratory reactions in patients
rienced possible adverse drug reactions (Fig 1). This is fol- withunderlyingasthmaand/orrhinitisorsinusitis.AERD
lowedbyalistofsummarystatementsthatrepresentthekey does not fit precisely into a specific category of adverse
pointstoconsiderintheevaluationandmanagementofdrug drug reactions.
hypersensitivity reactions. Within the evidence-based com- • Drugtoleranceisdefinedasastateinwhichapatientwith
mentary, the summary statements are repeated and are fol- a drug allergy will tolerate a drug without an adverse
lowedbythetextthatsupportsthatsummarystatement.The reaction. Drug tolerance does not indicate either a perma-
evidence-based commentary first discusses general issues nentstateoftoleranceorthatthemechanisminvolvedwas
relatingtodrugallergy,includingdefinitions,classifications, immunologic tolerance.
risk factors, and the general approach to evaluation, diagno- • Inductionofdrugtolerance,whichhasoftenbeenreferred
sis, management, and prevention (sections I through VI). toasdrugdesensitization,ismoreappropriatelydescribed
Subsequently, specific types of drugs are discussed (section as a temporary induction of drug tolerance. Induction of
VII). drugtolerancecaninvolveIgEimmunemechanisms,non-
TheJointTaskForceonPracticeParameterswouldliketo IgE immune mechanisms, pharmacologic mechanisms,
thank the AAAAI, ACAAI, and JCAAI, who supported the andundefinedmechanisms.Allprocedurestoinducedrug
preparationoftheupdatedparameter,andthelargenumberof tolerance involve administration of incremental doses of
individualswhohavesokindlydedicatedtheirtimeandeffort thedrug.SeeTable1forcharacteristicsofthese4typesof
to the preparation and review of this document. drug tolerance.
• Drug desensitization is one form of induction of immune
GLOSSARY drug tolerance (see above) by which effector cells are
• Adverse drug reactions include all unintended pharmaco- rendered less reactive or nonreactive to IgE-mediated im-
logic effects of a drug except therapeutic failures, inten- mune responses by rapid administration of incremental
tional overdosage, abuse of the drug, or errors in admin- doses of an allergenic substance.
istration. They can be classified as predictable or • Graded challenge or test dosing describes administration
unpredictable. Unpredictable reactions are further subdi- of progressively increasing doses of a medication until a
vided into drug intolerance, drug idiosyncrasy, drug al- fulldoseisreached.Theintentionofagradedchallengeis
lergy, and pseudoallergic reactions. to verify that a patient will not experience an immediate
VOLUME 105, OCTOBER, 2010 273.e4
Figure1.Algorithmfordiseasemanagementofdrugallergy.
273.e5 ANNALSOFALLERGY,ASTHMA&IMMUNOLOGY
Table1.ClassificationofInductionofDrugTolerance(FormerlyReferredtoasDesensitization)a
Typeofdrug
Time/duration Initialdose Possibleoutcomes Example
tolerance
ImmunologicIgE(drug Hours Micrograms Antigen-specificmediatordepletion, Penicillin
desensitization) downregulationofreceptors
Immunologicnon-IgE Hourstodays Milligrams Unknown Trimethoprim-
sulfamethoxazole
Pharmacologic Hourstodays Milligrams Metabolicshift,internalizationof Aspirin
receptors
Undefined DaystoWeeks Microgramstomilligrams Unknown Allopurinol
aWhat has often been referred to as drug desensitization is more appropriately described as induction of drug tolerance. Induction of drug
tolerancecaninvolveIgEimmunemechanisms,non-IgEimmunemechanisms,pharmacologicmechanisms,andmixedorunknownmechanisms.
Allinvolvedadministrationofincrementaldosesofthedrug.Thistableindicatesthecharacteristicsofthese4typesofdrugtolerance.
adverse reaction to a given drug. The medication is intro- There have, however, been great strides made in our under-
duced in a controlled manner to a patient who has a low standing of other drug allergies and adverse drug reactions
likelihood of reacting to it. Unlike procedures that induce such as aspirin-exacerbated respiratory disease (AERD).
drug tolerance, graded challenges usually involve fewer Drug allergy may be classified by the Gell-Coombs clas-
doses, are of shorter duration, and are not intended to sification of human hypersensitivity: IgE-mediated (type I),
induce drug tolerance. cytotoxic (type II), immune complex (type III), and cellular
• The drug rash with eosinophilia and systemic symptoms mediated (type IV). Delayed hypersensitivity type IV reac-
(DRESS) syndrome is a drug-induced, multiorgan inflam- tions are mediated by cellular immune mechanisms. A re-
matory response that may be life threatening. First de- cently proposed modification subdivides type IV reactions
scribedinconjunctionwithanticonvulsantdruguse,ithas into 4 categories involving activation and recruitment of
since been ascribed to a variety of drugs. monocytes (IVa), eosinophils (IVb), CD4(cid:1) or CD8(cid:1) T cells
(IVc), and neutrophils (IVd).1 The classic reaction in this
EXECUTIVE SUMMARY
category is contact dermatitis, a condition in which the top-
ical induction and elicitation of sensitization by a drug is
Classification of Adverse Reactions to Drugs
entirelylimitedtotheskin.ItappearsthatGell-Coombstype
Adverse drug reactions (ADRs) result in major health prob-
IVreactionsarealsoresponsiblefordelayedcutaneouserup-
lemsintheUnitedStatesinboththeinpatientandoutpatient
tions, such as maculopapular exanthems due to antibiotics
settings.ADRsarebroadlycategorizedintopredictable(type
(eg, amoxicillin and sulfonamides) and acute generalized
A)andunpredictable(typeB)reactions.Predictablereactions
exanthematous pustulosis. Drug allergy may also be classi-
are usually dose dependent, are related to the known phar-
fied by the predominant tissue or organ involved (eg, sys-
macologicactionsofthedrug,andoccurinotherwisehealthy
temic, cutaneous, hepatic), which is useful in light of the
individuals. They are estimated to comprise approximately
difficultythatsometimesoccursindeterminingtheimmuno-
80%ofallADRs.Unpredictablereactionsaregenerallydose
logicmechanisminvolved.Table2highlightsthespectrumof
independent, are unrelated to the pharmacologic actions of
drug allergic reactions and syndromes that will be discussed
the drug, and occur only in susceptible individuals. Unpre-
in greater detail in this parameter.
dictable reactions are subdivided into drug intolerance, drug
The p-i concept (pharmacologic interaction with immune
idiosyncrasy,drugallergy,andpseudoallergicreactions.Both
receptors) is a recently proposed addition to drug hypersen-
type A and type B reactions may be influenced by genetic
sitivity classification. In this scheme, a drug binds nonco-
predisposition of the patient.
In this parameter, drug allergy is defined as an immuno- valently to a T-cell receptor, which may lead to an immune
logically mediated response to a pharmaceutical and/or for- response via interaction with an major histocompatibility
mulation(excipient)agentinasensitizedperson.Theclassi- receptor.Inthisscenario,nosensitizationisrequiredbecause
fication of drug allergies is impeded by our limited there is direct stimulation of memory and effector T cells,
understanding of the underlying mechanisms. Although the analogous to the concept of superantigens.2,3
Gell-Coombs classification served a useful purpose in its The structural characteristics of certain drugs, such as
time,itdoesnotaccountformanycommonclinicalproblems. penicillin and peptides, may help predict the type of hyper-
Nevertheless, when applicable we will still refer to recent sensitivity reaction; however, this is not always the case.
modifications of that system. Our knowledge of IgE-medi- Other drug-specific risk factors include the dose, route of
ated drug allergy is derived chiefly from the vast amount of administration, duration of treatment, repetitive exposure to
researchinvolvingpenicillinallergy.Beyondthis,ourknowl- the drug, and concurrent illnesses. Host risk factors include
edge of drug allergy mechanisms is limited but emerging. age,sex,atopy,specificgeneticpolymorphisms,andinherent
VOLUME 105, OCTOBER, 2010 273.e6
Table2.DrugAllergicReactionsandSyndromes
Clinicalmanifestations Examplesofcausativeagents
IgEmediated Urticaria,angioedema,bronchospasm,anaphylaxis (cid:1)-Lactamantibiotics,platinum-based
chemotherapeutics,perioperativeagents
Cytotoxic Hemolyticanemia,thrombocytopenia, Penicillin,quinine,sulfonamides
granulocytopenia
Immunecomplex Serumsickness Penicillin,infliximab,thymoglobulin
Delayedtypehypersensitivity Contactdermatitis,exanthems Neomycin,glucocorticoids,penicillin,sulfonamide
antibiotics
Hypersensitivityvasculitis Cutaneousorvisceralvasculitis Hydralazine,penicillamine,propylthiouracil
DRESS Cutaneous,fever,eosinophilia,hepaticdysfunction, Anticonvulsants,sulfonamides,minocycline,
lymphadenopathy allopurinol
Pulmonarydrug Pneumonitis,fibrosis Nitrofurantoin,bleomycin,methotrexate
hypersensitivity
Systemicdrug-inducedlupus Arthralgias,myalgias,fever,malaise Hydralazine,procainamide,isoniazid
erythematosus
Cutaneousdrug-inducedlupus Erythematous/scalyplaquesinphotodistribution Hydrochlorothiazide,calciumchannelblockers,
erythematosus ACEinhibitors
Drug-inducedgranulomatous Churg-Strausssyndrome,Wegener’s Propylthiouracil,leukotrienemodifiers
disease granulomatosis
Immunologichepatitis Hepatitis,cholestaticjaundice Para-aminosalicylicacid,sulfonamides,
phenothiazines
Blisteringdisorders Erythemamultiforme,SJS,TEN Sulfonamides,cephalosporins,imidazole
anticonvulsants,NSAIDs
Serumsickness–likereactions Erythemamultiforme,arthralgias Cefaclor,cefprozil
Immunologicnephropathy Interstitialnephritis,membranous Penicillin,sulfonamides,gold,penicillamine,
glomerulonephritis allopurinol
Abbreviations: ACE, angiotensin-converting enzyme; DRESS, drug rash with eosinophilia and systemic symptoms; NSAIDs, nonsteroidal
anti-inflammatorydrugs;SJS,Stevens-Johnsonsyndrome;TEN,toxicepidermalnecrolysis.
predisposition to react to multiple unrelated drugs (multiple life-threateningcutaneousreactionssuchasStevens-Johnson
drug allergy syndrome). syndrome (SJS), toxic epidermal necrolysis (TEN), exfolia-
tivedermatitis,anddrugrashwitheosinophiliaandsystemic
History and Physical Examination symptoms (DRESS).4
Thehistory,physicalexamination,andobjectiveclinicaland
laboratory tests are important components in the clinical Diagnostic Tests
evaluationanddiagnosisofdrughypersensitivity.Thehistory Possible clinical tests might include but are not limited to a
shouldfocusonsuchitemsaspreviousandcurrentdruguse, chest x-ray examination, a complete blood cell count with
thetoxicityandallergenicityofpreviouslyandcurrentlyused differential, sedimentation rate, nuclear and cytoplasmic au-
drugs,andthetemporalsequenceofeventsbetweeninitiation toantibody tests, and other specific immunologic tests. A
of therapy and onset of symptoms. Physical examination retrospectivediagnosisofanaphylaxismaybedeterminedby
shouldincludeallsystemsthatcouldpossiblyaccountforthe detecting an increase in serum total tryptase levels above
clinical presentation. Cutaneous manifestations are the most baseline or in serum mature tryptase (also known as
common presentation for drug allergic reactions. Although (cid:1)-tryptase). The most useful test for detecting IgE-mediated
drugallergicreactionsmaypresentwithnoncutaneousphys- drug reactions caused by many large-molecular-weight bio-
icalfindings,thesefindingsaregenerallynonspecificandare logicals and penicillin is the immediate hypersensitivity skin
notnearlyashelpfulindiagnosisandmanagementdecisions. test. Relatively few studies with small numbers of patients
Therefore, the emphasis in this parameter on the physical have evaluated the specificity and sensitivity of third-gener-
examination focuses on cutaneous findings. ationassaysfordetectionofpenicillinspecificIgEinvitro.5,6
Characterization of cutaneous lesions is important in re- These studies demonstrate relatively high specificity (97%-
gard to determining the cause, further diagnostic tests, and 100%)butlowersensitivity(29%-68%)forpenicillinspecific
management decisions. Numerous cutaneous reaction pat- IgE. Therefore, although a positive in vitro test result for
terns have been reported in drug allergy, including exan- penicillin specific IgE is highly predictive of penicillin al-
thems, urticaria, angioedema, acne, bullous eruptions, fixed lergy, a negative in vitro test result does not adequately
drug eruptions, erythema multiforme, lupus erythematosus, exclude penicillin allergy. The basophil activation test is a
photosensitivity, psoriasis, purpura, vasculitis, pruritus, and recentlydescribedmethodofevaluatingexpressionofCD63
273.e7 ANNALSOFALLERGY,ASTHMA&IMMUNOLOGY
on basophils after stimulation with an allergen.7 There are creased risk for future reactions compared with the general
limited data using this method to evaluate patients with population.
possible allergies to (cid:1)-lactam antibiotics and nonsteroidal The choice of whether to introduce a clinically indicated
anti-inflammatory drugs (NSAIDs).8-10 Further confirmatory drug via graded challenge or via induction of drug tolerance
studies, especially with commercially available tests, are mainlydependsonthelikelihoodthatthepatientisallergicat
needed before its general acceptance as a diagnostic tool. thetimeoftheprocedure.Patientswho,basedontheirhistory
Patchtestingisthemostreliabletechniquefordiagnosisof and/or diagnostic test results, are unlikely to be allergic to a
contact dermatitis caused by topically applied drugs. The drug may undergo graded challenge. Patients who have a
diagnosis of contact dermatitis usually can be verified by relativelyhigherlikelihoodofbeingallergictoadrugshould
patch testing. In recent years there have been reports con- undergo an induction of drug tolerance procedure. Graded
cerningthediagnosticutilityofpatchtestswithsystemically challenge (or induction of drug tolerance) should almost
administered drugs in non–IgE-mediated cutaneous drug re- never be performed if the reaction history is consistent with
actions.11 Drug patch testing may be useful for certain types a severe non–IgE-mediated reaction, such as SJS, TEN, in-
of cutaneous drug reactions, including maculopapular exan- terstitial nephritis, hepatitis, or hemolytic anemia.
thems,acutegeneralizedexanthematouspustulosis,andfixed
drug eruptions,12-14 but generally is not helpful for SJS or Other Immunologic Drug Allergy Syndromes
urticarial eruptions.12-15 Specific drugs or classes of drugs may be associated with
Incomplexcaseswheremultipledrugsareinvolvedwith- characteristic syndromes, which may not conform to typical
out a clear-cut temporal relationship, a skin biopsy may be presentations defined by the Gell-Coombs classification sys-
usefulinsuggestingadrug-inducederuption.However,there tem.Table2liststhevariousotherimmunologicdrugallergic
are no absolute histologic criteria for the diagnosis of drug- syndromes discussed in the parameter.
induced eruptions, and a skin biopsy may not definitively
exclude alternative causes.16 Specific Drugs and Biologic Agents
Drug allergic reactions have been reported to most all med-
Induction of Drug Tolerance and Graded Challenges ications. However, certain drugs are more frequently associ-
What has often been referred to as drug desensitization is ated with specific types of reactions. Significant updates on
moreappropriatelydescribedinthisparameterasatemporary the following drugs and biologic agents have been made in
induction of drug tolerance. Drug tolerance is defined as a this updated parameter and are discussed elsewhere in more
stateinwhichapatientwithadrugallergywilltolerateadrug detail.
withoutanadversereaction.Drugtolerancedoesnotindicate
either a permanent state of tolerance or that the mechanism Antimicrobials
involved was immunologic tolerance. Induction of drug tol- The most important causes of immediate hypersensitivity
erance procedures modify a patient’s response to a drug to reactions are antibiotics, particularly (cid:1)-lactam antibiotics.
temporarilyallowtreatmentwithitsafely.Theyareindicated Approximately 10% of patients report a history of penicillin
only in situations where an alternate non–cross-reacting allergy. However, up to 90% of these individuals are able to
medication cannot be used. Induction of drug tolerance can tolerate penicillin and are designated as having “penicillin
involve IgE immune mechanisms, non-IgE immune mecha- allergy”unnecessarily.17,18Useofbroad-spectrumantibiotics
nisms, pharmacologic mechanisms, and undefined mecha- in patients designated as being “penicillin allergic” is asso-
nisms (Table 1). All procedures to induce drug tolerance ciated with higher costs, increased antibiotic resistance, and
involve administration of incremental doses of the drug. maycompromiseoptimalmedicalcare.19Penicillinskintest-
Throughvariousmechanisms,theseproceduresinduceatem- ing is the most reliable method for evaluating IgE-mediated
porarystateoftolerancetothedrug,whichismaintainedonly penicillinallergy.Ideally,bothmajorandminordeterminant
as long as the patient continues to take the specific drug. reagents are used for skin testing. Penicillin challenges of
Wherethereisadefinitemedicalindicationfortheagentin individuals skin test negative to penicilloylpolylysine and
question, either induction of drug tolerance or graded chal- penicillin G20,21 have similar reaction rates compared with
lenge procedures may be considered, depending on the his- individuals skin test negative to the full set of major and
tory of the previous reaction and the likelihood that the minor penicillin determinants.17,18
patient is currently allergic to that agent. If there is a low Varying degrees of allergic cross-reactivity between peni-
likelihood of drug allergy, a graded challenge or test dose to cillin and cephalosporins have been documented. Overall,
thespecificdruginquestionmayprovideausefulconfirma- most patients with a history of penicillin allergy tolerate
tion that administration of the drug will not result in an cephalosporins,22 but there are rare reports of anaphylactic
immediate reaction. The purpose of graded challenge is to reactions, including fatal reactions.23 Patients with a history
cautiouslyadministeradrugtoapatientwhoisunlikelytobe of penicillin allergy who have negative skin test results to
allergic to it and there is no intention to induce tolerance to penicillin using major and minor determinants may receive
the drug. Patients who tolerate a graded challenge are con- cephalosporins safely.24 Skin testing for cephalosporins and
sidered to not be allergic to the drug and are not at in- other (cid:1)-lactam antibiotics is not standardized, as it is for
VOLUME 105, OCTOBER, 2010 273.e8
penicillin. There is no allergic cross-reactivity between pen- reactionsmaybetheresultofexcipientsratherthantheactive
icillin and monobactams. The degree of cross-reactivity be- drug, such as Cremophor-EL, a lipid solvent vehicle used in
tween penicillin and carbapenems appears to be low.25,26 paclitaxel and other intravenous chemotherapeutics. In the
IgE-mediated reactions to non–(cid:1)-lactam antibiotics may oc- taxanefamily,paclitaxelanddocetaxelproduceanaphylactic
cur but are less common. There is no standardized skin reactions in as many as 42% of patients on first administra-
testing for evaluation of immediate-type allergy to non–(cid:1)- tion,54suggestingananaphylactoidmechanism.Pretreatment
lactam antibiotics. withsystemiccorticosteroidsandantihistaminespreventsthe
Sulfonamide antibiotics rarely cause IgE-mediated reac- reaction in more than 90% of patients.55 Patients who react
tions and more commonly result in delayed maculopapular despite pretreatment can usually be successfully desensi-
exanthems, particularly in human immunodeficiency virus tized.56-58 Another option for patients who react to paclitaxel
(HIV)–positive patients. There is no evidence to suggest istoswitchtodocetaxelbecausemostareabletotolerateit.59
allergic cross-reactivity between sulfonamide antibiotics and Platinum compounds (cisplatin, carboplatin, and oxaliplatin)
nonantibioticsulfonamides.27VancomycinrarelycausesIgE- typicallycausehypersensitivityreactionsaftercompletionof
mediatedreactions,butmorethan50%ofpatientsexperience several treatment courses,60,61 suggesting an immunologic
immediate cutaneous erythema, flushing, and pruritus (red mechanism. Pretreatment with corticosteroids and antihista-
man syndrome), which is the result of non–IgE-mediated minesdoesnotpreventthesereactions.62Skintestingwiththe
histamine release. Red man syndrome reactions can be pre- undiluted drug has been found to identify patients at risk of
ventedbyslowingtherateofinfusionandpremedicatingwith reactions, and skin testing should be repeated before each
histamine receptor antihistamines. Although aminoglyco- subsequentcoursewiththedrug.61,63,64Forpatientswithpos-
1
sides rarely cause hypersensitivity reactions, there are indi- itive skin test results, various rapid induction of drug toler-
vidual case reports of IgE-mediated systemic reactions. Re- anceprotocolshavebeenreported,buttheyarenotuniformly
ports of IgE-mediated anaphylactic reactions to quinolones successful.61,63,64 Recently, a 12-step desensitization protocol
appeartobeincreasing,possiblyduetoincreaseduseofthese for a variety of chemotherapeutic agents, including platinum
agents.28-31 In vitro studies suggest a large extent of allergic compounds,hasbeenreportedtobecompletelysuccessfulin
cross-reactivityamongquinolones,2,28buttherearenoclinical 413 procedures, with 94% of procedures having only a mild
studies to confirm this. Delayed cutaneous eruptions appear or no reaction.58
inapproximately2%ofquinolone-treatedpatients.32,33There Methotrexate is a cause of noncytotoxic pulmonary reac-
isevidencetoshowthatdrug-specificTcellsareresponsible tions.65,66 Methotrexate pneumonitis occurs most frequently
for delayed maculopapular exanthems from quinolones.2 within the first year of treatment, and the reported incidence
Allergicdrugreactionstoantimycobacterialdrugscaninduce of this reaction varies from 0.86% to 6.9%.67,68 If use of the
both minor and life-threatening reactions. Many allergic reac- drugisinadvertentlycontinued,interstitialfibrosismayensue.
tions were also encountered after use of second-generation
drugs, including isoniazid, ethambutol, pyrazinamide, and ri- Medications for Patients With HIV Infections and AIDS
fampicin.34Theseincludeanaphylaxis,angioedema,pulmonary DrugreactionsarecommoninpatientsinfectedwiththeHIV
infiltrates,andcutaneousreactions.35-39 virus, and in some cases, the incidence of reactions may be
related to the degree of immunodeficiency.69-73 Adverse re-
Insulin and Oral Antidiabetic Drugs actions to sulfonamides may complicate both treatment and
Sincetheintroductionofpurifiedhumanrecombinantinsulin, prophylaxis of Pneumocystis jiroveci pneumonia in many
allergy to insulin is rare and is now encountered in less than patients with AIDS. The most common reaction to sulfon-
1% of patients.40-43 However, life-threatening allergic reac- amides is a morbilliform, maculopapular eruption often as-
tions to human insulin and insulin analogs (Aspart, Lispro, sociated with fever that occurs after 7 to 12 days of therapy.
and Glargine) have been documented and can be confirmed For HIV-positive individuals who develop typical delayed
by appropriate intracutaneous and/or in vitro testing.44,45 The maculopapular rashes after trimethoprim and sulfamethox-
mechanisms of immunogenic reactions to recombinant hu- azole administration, many different induction of drug toler-
maninsulinarenotentirelyclearbutmayrelatetostructural anceprotocolshavebeendevelopedandusedsuccessfully.74-85It
changes of insulin, including insulin aggregation (fibrilla- is not clear how or to what extent the immune response to
tion).46 Leukocytoclastic vasculitis, generalized arteritis, trimethoprim-sulfamethoxazole is modified during these
granulomatous hepatitis, and autoimmune pemphigus vul- typesofinductionofdrugtoleranceprocedures.Inarandom-
garis are rare immune-mediated reactions that have been izedtrialoftrimethoprim-sulfamethoxazoleinductionofdrug
described to occur during treatment with metformin and/or tolerancevsrechallenge(singledose),thesuccessrateswere
sulfonylurea antidiabetic agents.47-53 79% and 72%, respectively, and the difference was not sta-
tistically significant.83 Sulfadiazine, acyclovir, zidovudine,
Cancer Chemotherapeutic Agents dapsone, and pentamidine induction of drug tolerance proto-
Hypersensitivityreactionshavebeenreportedforvirtuallyall cols have also been developed for patients with AIDS.86-91
commonly used chemotherapeutic agents. Reactions range At least 20 antiretroviral drugs are approved by the US
from mild cutaneous eruptions to fatal anaphylaxis. Some FoodandDrugAdministrationforhighlyactiveantiretroviral
273.e9 ANNALSOFALLERGY,ASTHMA&IMMUNOLOGY
therapy of HIV-infected patients.92,93 Many of these drugs Corticosteroids
havebeenassociatedwithhypersensitivityresponsesranging Allergic contact dermatitis due to topical application of cor-
from mild cutaneous rashes to life-threatening SJS and ticosteroids is the most common type of allergic reaction
TEN.94. Abacavir, a nucleoside-analogue reverse transcrip- induced by this class of drugs. Very rarely, immediate-type
tase inhibitor, causes severe hypersensitivity in 4% to 5% of allergic reactions to corticosteroids have been described.
patients.95,96 Such reactions have been identified with a ge- Most such reported reactions are due to intravenous admin-
netic risk factor, the presence of HLA B 5701.97,98 istration of methylprednisolone and hydrocortisone106-111;
however,preservativesanddiluentshavealsobeenimplicated.
Medications for Autoimmune Diseases
Heparin
Avarietyofallergicreactionstodisease-modifyingantirheu-
matic drugs (DMARDS) may occur, including gold salts, Hypersensitivityreactionstounfractionatedheparinandlow-
D-penicillamine, sulfasalazine, hydroxychloroquine, and le- molecular-weightheparinareuncommonandincludethrom-
flunomide. Reactions such as vasculitis, DRESS, photoder- bocytopenia,variouscutaneouseruptions,hypereosinophilia,
matitis,andTENhavebeenreportedwithDMARDs.Newer and anaphylaxis. Mild thrombocytopenia is due to platelet
immunomodulator agents have been introduced for several aggregation and occurs in 1% to 3% of patients treated with
autoimmune diseases. Although hypersensitivity reactions to unfractionated heparin. Severe thrombocytopenia is caused
severalofthesehavealreadyoccurred,itistooearlytoassess by immune complexes, a component of which is heparin-
theglobalimpactofadverseeventsfordiverseimmunologic dependent IgG specific for platelet factor 4.112 This reaction
usually occurs after approximately 5 days of treatment with
interventions in early development. Allergic reactions to im-
unfractionatedheparinandisassociatedwithdevelopmentof
munosuppressant and anti-inflammatory drugs may be en-
thrombosis and necrosis. A recent outbreak of anaphylactic
countered in the treatment of chronic cutaneous diseases.
reactions to heparin in the United States and Germany was
Dermatologic immunosuppressant drugs, such as macrolides
attributed to a contaminant in heparin lots, an oversulfated
(eg, cyclosporine, tacrolimus, pimecrolimus, and sirolimus),
form of chondroitin sulfate. This oversulfated chondroitin
dapsone, and mycophenolate mofetil, have been reported to
sulfate contaminant has been shown in vitro and in vivo to
cause drug allergic reactions in addition to their known pre-
cause activation of the kinin-kallikrein pathway with gener-
dictable adverse reactions.
ation of bradykinin, a potent vasoactive mediator, and C3a
and C5a anaphylatoxins.113 Clinically, reactions to contami-
Perioperative Agents and Blood Products natedheparinproductswereassociatedwithhypotensionand
Anaphylacticandanaphylactoidreactionsduringgeneralan- abdominal pain, and variably angioedema, but typically
esthesia may be due to induction agents, neuromuscular lacked urticaria and pruritus.114 The findings of abdominal
blocking agents, antibiotics, opiates, and latex. Because ana- painandangioedemaaresomewhatanalogoustoC1inhibitor
phylactic reactions cannot be distinguished from anaphylac- deficiencyinwhichsymptomsareduetolocalproductionof
toid,nonimmuneoccurrences,ithasbeenrecommendedthat bradykinin.
plasma histamine, tryptase, and specific IgEs (if available)
may be ordered at the time of reaction and skin tests be Local Anesthetics
performed later.99 Immediate generalized reactions to prota-
Most adverse reactions to local anesthetics are not due to
mine, including hypotension, shock, and death, have been
IgE-mediated mechanisms but are due to nonallergic factors
reported.100,101Diabeticpatientsreceivingprotamine-contain-
that include vasovagal responses, anxiety, toxic reactions
ing insulins appear to be at 40 to 50 times greater risk for
including dysrhythmias, and toxic or idiosyncratic reactions
developing anaphylaxis.102,103 Reactions due to blood and
duetoinadvertentintravenousepinephrineeffects.Documen-
blood products include urticaria, anaphylaxis (particularly in
tation of IgE-mediated reactions is extremely rare.115-118
patients with complete IgA deficiency), anaphylactoid reac-
When there is concern about a previously reported reaction,
tions, and transfusion-related acute lung injury (TRALI).
skintestingandincrementalchallengewithalocalanesthetic
TRALI is a complex syndrome that has multiorgan manifes-
is a reasonable approach in the evaluation of a possible
tationsandhasonlyrecentlybeenidentifiedtobeanimportant
reaction.
causeoftransfusion-associatedmorbidityandmortality.104,105
Radiocontrast Media
Opiates Anaphylactoidreactionsoccurinapproximately1%to3%of
Opiates and their analogs are a common cause of pseudoal- patients who receive ionic radiocontrast media (RCM) and
lergic reactions that are generally mild, are not life-threaten- less than 0.5% of patients who receive nonionic agents.119,120
ing,andcanbeattenuatedbypreadministrationofhistamine Severe life-threatening reactions are less common, occurring
1
receptor antihistamines. Skin test results to opiates are diffi- in 0.22% of patients receiving ionic RCM and 0.04% of
cult to interpret because these agents cause release of hista- patientsreceivingnonionicagents.121Riskfactorsforanaphy-
mine from skin mast cells in all patients. lactoid reactions to RCM include female sex, asthma, and
VOLUME 105, OCTOBER, 2010 273.e10