Drug Allergy: An Updated Practice Parameter

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

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                                                                Summary Statements of the Evidence-Based Commentary
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. Immune complex reactions (Gell-Coombs type III)
                                                                                      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; the American College of Allergy, Asthma and Immunology;
and the Joint Council of Allergy, Asthma and Immunology.                                2. Drug rash with eosinophilia and systemic symptoms
   The American Academy of Allergy, Asthma and Immunology (AAAAI)                       3. Pulmonary drug hypersensitivity
and the American College of Allergy, Asthma and Immunology (ACAAI)                      4. Drug-induced lupus erythematosus
have jointly accepted responsibility for establishing “Drug Allergy: An
Updated Practice Parameter.” This is a complete and comprehensive docu-
                                                                                        5. Drug-induced granulomatous disease with or
ment at the current time. The medical environment is a changing environ-                   without vasculitis
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
authorized to provide an official AAAAI or ACAAI interpretation of these
                                                                                           a. Erythema multiforme minor
practice parameters. Any request for information about or an interpretation of             b. Erythema multiforme major/Stevens-Johnson
these practice parameters by the AAAAI or ACAAI should be directed to the                     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
use by pharmaceutical companies in drug promotion.
                                                                                        8. Serum sickness–like reactions associated with
   Reprint requests: Joint Council of Allergy, Asthma & Immunology, 50                     specific cephalosporins
N. Brockway St, #3-3, Palatine, IL 60067.                                               9. Immunologic nephropathy

273.e1                                                                                        ANNALS OF ALLERGY, 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                                 The Joint Task Force has made a concerted effort to acknowl-
    C. General clinical tests                               edge all contributors to this parameter. If any contributors
    D. Specific tests                                       have been excluded inadvertently, the Task Force will ensure
    E. Tissue diagnosis                                     that appropriate recognition of such contributions is made
  VI. Management and Prevention of Drug Allergic            subsequently.
    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. Immunologic non-IgE induction of drug tolerance      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. ␤-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. Cephalosporin administration to patients with a   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–␤-lactam antibiotics                             Mariana C. Castells, MD, PhD
    C. Antimycobacterial drugs                              Director, Desensitization Program
    D. Diabetes medications                                 Associate Director, Allergy Immunology Training Program
    E. Cancer chemotherapeutic agents                       Brigham & Women’s Hospital
    F. Human immunodeficiency virus (HIV) medications       Harvard Medical School
    G. Disease-modifying antirheumatic drugs (DMARDs)       Boston, Massachusetts
    H. Immunomodulatory agents for autoimmune diseases      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. Aspirin and nonsteroidal anti-inflammatory drugs     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-␣ 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                            individuals who also contributed substantially to the creation
Davie, Florida                                          of this parameter: Erin Shae Johns, PhD, and Jessica Karle,
David M. Lang, MD                                       MS, for their immense help with formatting and restructuring
Allergy/Immunology Section, Division of Medicine        this document; Susan Grupe for providing key administrative
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
George Washington Medical Center
Washington, DC                                          The objective of “Drug Allergy: An Updated Practice Param-
                                                        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                                      has published 26 practice parameters and updated parameters
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                                   Asthma and Immunology (AAAAI), the American College of
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                                  scientific knowledge and their effect on management of drug
Department of Medicine                                  allergy. This document was written and reviewed by special-
UCLA School of Medicine                                 ists in the field of allergy and immunology and was exclu-
Los Angeles, California                                 sively funded by the 3 allergy and immunology organizations
Stephen A. Tilles, MD                                   noted above.
Department of Medicine                                      A Working Group chaired by Roland Solensky, MD, pre-
University of Washington School of Medicine             pared the initial draft, which was then reviewed by the Joint
Redmond, Washington                                     Task Force. A comprehensive search of the medical literature
Dana Wallace, MD                                        was conducted using Ovid MEDLINE and the Cochrane
                                                        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
                                                        working draft of “Drug Allergy: An Updated Practice Param-
                                                        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
Kathleen R. May, MD – Cumberland, MD                    evidence-based; broadly accepted consensus parameter.
Myngoc T. Nguyen, MD – Piedmont, CA                         This updated parameter contains several significant
                                                        changes from the original parameter on “Disease Manage-
                                                        ment of Drug Hypersensitivity: A Practice Parameter.” The
Ad Hoc Reviewers                                        title of the parameter was changed from drug hypersensitivity
Lawrence B. Schwartz, MD                                to drug allergy. In this updated parameter the term drug

273.e3                                                               ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
allergy is defined as an immunologically mediated response          • Drug allergy is an immunologically mediated response to
to a pharmaceutical and/or formulation (excipient) agent in a         a pharmaceutical and/or formulation (excipient) agent in a
sensitized person. The implication is that drug allergy does          sensitized person.
not simply include only IgE-mediated reactions. Another             • Anaphylaxis is an immediate systemic reaction that occurs
significant change is the introduction of the new term induc-         when a previously sensitized individual is reexposed to an
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.
several new sections have been added, including a new glos-         • 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-             by non–IgE-mediated release of mediators from mast cells
gic reactions to chemotherapeutic agents, corticosteroids,            and basophils.
disease-modifying antirheumatic drugs, antimycobacterial            • Drug intolerance is an undesirable pharmacologic effect
drugs, biologic modifiers, immunosuppressive agents, immu-            that may occur at low or usual doses of the drug without
nomodulatory agents, complementary medications, and drug-             underlying abnormalities of metabolism, excretion, or bio-
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, ␤-lactam allergy, cross-reactivity       tific explanation for such exaggerated responses has not
between carbapenems and penicillin, and human 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.                                                      that is unrelated to the intended pharmacologic action of a
   The Executive Summary emphasizes the key updates since             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-
Summary has been significantly expanded to include the new            ducible on readministration. It may be due to underlying
sections and highlight the major updates to this parameter. It        abnormalities of metabolism, excretion, or bioavailability
should be noted that the Executive Summary does not discuss           (eg,: quinidine-induced drug fever).
all of this parameter’s topics in depth. An annotated algo-         • Aspirin-exacerbated respiratory disease (AERD) is a clin-
rithm in this document summarizes the major decision points           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-         with underlying asthma and/or rhinitis or sinusitis. AERD
lowed by a list of summary statements that represent the key          does not fit precisely into a specific category of adverse
points to consider in the evaluation and management of drug           drug reactions.
hypersensitivity reactions. Within the evidence-based com-          • Drug tolerance is defined as a state in which a patient with
mentary, the summary statements are repeated and are fol-             a drug allergy will tolerate a drug without an adverse
lowed by the text that supports that summary statement. The           reaction. Drug tolerance does not indicate either a perma-
evidence-based commentary first discusses general issues              nent state of tolerance or that the mechanism involved was
relating to drug allergy, including definitions, classifications,     immunologic tolerance.
risk factors, and the general approach to evaluation, diagno-       • Induction of drug tolerance, which has often been referred
sis, management, and prevention (sections I through VI).              to as drug desensitization, is more appropriately described
Subsequently, specific types of drugs are discussed (section          as a temporary induction of drug tolerance. Induction of
VII).                                                                 drug tolerance can involve IgE immune mechanisms, non-
   The Joint Task Force on Practice Parameters would like to          IgE immune mechanisms, pharmacologic mechanisms,
thank the AAAAI, ACAAI, and JCAAI, who supported the                  and undefined mechanisms. All procedures to induce drug
preparation of the updated parameter, and the large number of         tolerance involve administration of incremental doses of
individuals who have so kindly dedicated their time and effort        the drug. See Table 1 for characteristics of these 4 types of
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-            full dose is reached. The intention of a graded challenge is
  lergy, and pseudoallergic reactions.                                to verify that a patient will not experience an immediate

VOLUME 105, OCTOBER, 2010                                                                                                    273.e4
Figure 1. Algorithm for disease management of drug allergy.

273.e5                                                    ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 1. Classification of Induction of Drug Tolerance (Formerly Referred to as Desensitization)a
        Type of drug
                              Time/duration              Initial dose                    Possible outcomes                    Example

    Immunologic IgE (drug     Hours               Micrograms                     Antigen-specific mediator depletion,   Penicillin
      desensitization)                                                             downregulation of receptors
    Immunologic non-IgE       Hours to days       Milligrams                     Unknown                                Trimethoprim-
    Pharmacologic             Hours to days       Milligrams                     Metabolic shift, internalization of    Aspirin
    Undefined                 Days to Weeks       Micrograms to milligrams       Unknown                                Allopurinol
  What has often been referred to as drug desensitization is more appropriately described as induction of drug tolerance. Induction of drug
tolerance can involve IgE immune mechanisms, non-IgE immune mechanisms, pharmacologic mechanisms, and mixed or unknown mechanisms.
All involved administration of incremental doses of the drug. This table indicates the characteristics of these 4 types of drug tolerance.

  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
  scribed in conjunction with anticonvulsant drug use, it has               into 4 categories involving activation and recruitment of
  since been ascribed to a variety of drugs.                                monocytes (IVa), eosinophils (IVb), CD4⫹ or CD8⫹ 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
                                                                            entirely limited to the skin. It appears that Gell-Coombs type
Adverse drug reactions (ADRs) result in major health prob-                  IV reactions are also responsible for delayed cutaneous erup-
lems in the United States in both the inpatient and outpatient
                                                                            tions, such as maculopapular exanthems due to antibiotics
settings. ADRs are broadly categorized into predictable (type
                                                                            (eg, amoxicillin and sulfonamides) and acute generalized
A) and unpredictable (type B) reactions. Predictable reactions
                                                                            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-
macologic actions of the drug, and occur in otherwise healthy
individuals. They are estimated to comprise approximately                   temic, cutaneous, hepatic), which is useful in light of the
80% of all ADRs. Unpredictable reactions are generally dose                 difficulty that sometimes occurs in determining the immuno-
independent, are unrelated to the pharmacologic actions of                  logic mechanism involved. Table 2 highlights the spectrum of
the drug, and occur only in susceptible individuals. Unpre-                 drug allergic reactions and syndromes that will be discussed
dictable reactions are subdivided into drug intolerance, drug               in greater detail in this parameter.
idiosyncrasy, drug allergy, and pseudoallergic reactions. Both                 The p-i concept (pharmacologic interaction with immune
type A and type B reactions may be influenced by genetic                    receptors) is a recently proposed addition to drug hypersen-
predisposition of the patient.                                              sitivity classification. In this scheme, a drug binds nonco-
   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) agent in a sensitized person. The classi-              receptor. In this scenario, no sensitization is required because
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, it does not account for many common clinical problems.                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
research involving penicillin allergy. Beyond this, our knowl-              the drug, and concurrent illnesses. Host risk factors include
edge of drug allergy mechanisms is limited but emerging.                    age, sex, atopy, specific genetic polymorphisms, and inherent

VOLUME 105, OCTOBER, 2010                                                                                                               273.e6
Table 2. Drug Allergic Reactions and Syndromes
                                                 Clinical manifestations                           Examples of causative agents

 IgE mediated                    Urticaria, angioedema, bronchospasm, anaphylaxis         ␤-Lactam antibiotics, platinum-based
                                                                                            chemotherapeutics, perioperative agents
 Cytotoxic                       Hemolytic anemia, thrombocytopenia,                      Penicillin, quinine, sulfonamides
 Immune complex                  Serum sickness                                           Penicillin, infliximab, thymoglobulin
 Delayed type hypersensitivity   Contact dermatitis, exanthems                            Neomycin, glucocorticoids, penicillin, sulfonamide
 Hypersensitivity vasculitis     Cutaneous or visceral vasculitis                         Hydralazine, penicillamine, propylthiouracil
 DRESS                           Cutaneous, fever, eosinophilia, hepatic dysfunction,     Anticonvulsants, sulfonamides, minocycline,
                                   lymphadenopathy                                          allopurinol
 Pulmonary drug                  Pneumonitis, fibrosis                                    Nitrofurantoin, bleomycin, methotrexate
 Systemic drug-induced lupus      Arthralgias, myalgias, fever, malaise                   Hydralazine, procainamide, isoniazid
 Cutaneous drug-induced lupus     Erythematous/scaly plaques in photodistribution         Hydrochlorothiazide, calcium channel blockers,
   erythematosus                                                                            ACE inhibitors
 Drug-induced granulomatous       Churg-Strauss syndrome, Wegener’s                       Propylthiouracil, leukotriene modifiers
   disease                          granulomatosis
 Immunologic hepatitis            Hepatitis, cholestatic jaundice                         Para-aminosalicylic acid, sulfonamides,
 Blistering disorders             Erythema multiforme, SJS, TEN                           Sulfonamides, cephalosporins, imidazole
                                                                                            anticonvulsants, NSAIDs
 Serum sickness–like reactions    Erythema multiforme, arthralgias                        Cefaclor, cefprozil
 Immunologic nephropathy          Interstitial nephritis, membranous                      Penicillin, sulfonamides, gold, penicillamine,
                                     glomerulonephritis                                     allopurinol
Abbreviations: ACE, angiotensin-converting enzyme; DRESS, drug rash with eosinophilia and systemic symptoms; NSAIDs, nonsteroidal
anti-inflammatory drugs; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

predisposition to react to multiple unrelated drugs (multiple              life-threatening cutaneous reactions such as Stevens-Johnson
drug allergy syndrome).                                                    syndrome (SJS), toxic epidermal necrolysis (TEN), exfolia-
                                                                           tive dermatitis, and drug rash with eosinophilia and systemic
History and Physical Examination                                           symptoms (DRESS).4
The history, physical examination, and objective clinical and
laboratory tests are important components in the clinical                  Diagnostic Tests
evaluation and diagnosis of drug hypersensitivity. The history             Possible clinical tests might include but are not limited to a
should focus on such items as previous and current drug use,               chest x-ray examination, a complete blood cell count with
the toxicity and allergenicity of previously and currently used            differential, sedimentation rate, nuclear and cytoplasmic au-
drugs, and the temporal sequence of events between initiation              toantibody tests, and other specific immunologic tests. A
of therapy and onset of symptoms. Physical examination                     retrospective diagnosis of anaphylaxis may be determined by
should include all systems that could possibly account for the             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                  ␤-tryptase). The most useful test for detecting IgE-mediated
drug allergic reactions may present with noncutaneous phys-                drug reactions caused by many large-molecular-weight bio-
ical findings, these findings are generally nonspecific and are            logicals and penicillin is the immediate hypersensitivity skin
not nearly as helpful in diagnosis and management decisions.               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.                                 ation assays for detection of penicillin specific IgE in vitro.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%) but lower sensitivity (29%-68%) for penicillin specific
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            recently described method of evaluating expression of CD63

273.e7                                                                                   ANNALS OF ALLERGY, 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 ␤-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          mainly depends on the likelihood that the patient is allergic at
needed before its general acceptance as a diagnostic tool.          the time of the procedure. Patients who, based on their history
   Patch testing is the most reliable technique for diagnosis of    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          relatively higher likelihood of being allergic to a drug should
patch testing. In recent years there have been reports con-         undergo an induction of drug tolerance procedure. Graded
cerning the diagnostic utility of patch tests with systemically     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, acute generalized exanthematous pustulosis, and fixed
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
   In complex cases where multiple drugs are involved with-         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-
useful in suggesting a drug-induced eruption. However, there        tem. Table 2 lists the various other immunologic drug allergic
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
more appropriately described in this parameter as a temporary       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
state in which a patient with a drug allergy will tolerate a drug   detail.
without an adverse reaction. Drug tolerance does not indicate
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 ␤-lactam antibiotics.
temporarily allow treatment with it safely. They are indicated      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.17,18 Use of broad-spectrum antibiotics
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.            may compromise optimal medical care.19 Penicillin skin test-
Through various mechanisms, these procedures induce a tem-          ing is the most reliable method for evaluating IgE-mediated
porary state of tolerance to the drug, which is maintained only     penicillin allergy. Ideally, both major and minor determinant
as long as the patient continues to take the specific drug.         reagents are used for skin testing. Penicillin challenges of
   Where there is a definite medical indication for the agent in    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,
the specific drug in question may provide a useful confirma-        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
cautiously administer a drug to a patient who is unlikely to be     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 ␤-lactam antibiotics is not standardized, as it is for

VOLUME 105, OCTOBER, 2010                                                                                                     273.e8
penicillin. There is no allergic cross-reactivity between pen-     reactions may be the result of excipients rather than the active
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–␤-lactam antibiotics may oc-         taxane family, paclitaxel and docetaxel produce anaphylactic
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–␤-         tion,54 suggesting an anaphylactoid mechanism. Pretreatment
lactam antibiotics.                                                with systemic corticosteroids and antihistamines prevents the
   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           is to switch to docetaxel because most are able to tolerate it.59
allergic cross-reactivity between sulfonamide antibiotics and      Platinum compounds (cisplatin, carboplatin, and oxaliplatin)
nonantibiotic sulfonamides.27 Vancomycin rarely causes IgE-        typically cause hypersensitivity reactions after completion of
mediated reactions, but more than 50% of patients experience       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             mines does not prevent these reactions.62 Skin testing with the
histamine release. Red man syndrome reactions can be pre-          undiluted drug has been found to identify patients at risk of
vented by slowing the rate of infusion and premedicating with      reactions, and skin testing should be repeated before each
histamine1 receptor antihistamines. Although aminoglyco-           subsequent course with the drug.61,63,64 For patients with pos-
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-        ance protocols have been reported, but they are not uniformly
ports of IgE-mediated anaphylactic reactions to quinolones         successful.61,63,64 Recently, a 12-step desensitization protocol
appear to be increasing, possibly due to increased use of these    for a variety of chemotherapeutic agents, including platinum
agents.28-31 In vitro studies suggest a large extent of allergic   compounds, has been reported to be completely successful in
cross-reactivity among quinolones,2,28 but there are no clinical   413 procedures, with 94% of procedures having only a mild
studies to confirm this. Delayed cutaneous eruptions appear        or no reaction.58
in approximately 2% of quinolone-treated patients.32,33 There         Methotrexate is a cause of noncytotoxic pulmonary reac-
is evidence to show that drug-specific T cells are responsible     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
   Allergic drug reactions to antimycobacterial drugs can induce   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-     drug is inadvertently continued, interstitial fibrosis may ensue.
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.34 These include anaphylaxis, angioedema, pulmonary       Drug reactions are common in patients infected with the HIV
infiltrates, and cutaneous reactions.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
Since the introduction of purified human recombinant insulin,      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-
man insulin are not entirely clear but may relate to structural    ance protocols have been developed and used successfully.74-85 It
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-             types of induction of drug tolerance procedures. In a random-
garis are rare immune-mediated reactions that have been            ized trial of trimethoprim-sulfamethoxazole induction of drug
described to occur during treatment with metformin and/or          tolerance vs rechallenge (single dose), the success rates were
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-
Hypersensitivity reactions have been reported for virtually all    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           Food and Drug Administration for highly active antiretroviral

273.e9                                                                           ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
therapy of HIV-infected patients.92,93 Many of these drugs          Corticosteroids
have been associated with hypersensitivity responses ranging        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, preservatives and diluents have also been implicated.
Medications for Autoimmune Diseases
A variety of allergic reactions to disease-modifying antirheu-      Heparin
matic drugs (DMARDS) may occur, including gold salts,               Hypersensitivity reactions to unfractionated heparin and low-
D-penicillamine, sulfasalazine, hydroxychloroquine, and le-         molecular-weight heparin are uncommon and include throm-
flunomide. Reactions such as vasculitis, DRESS, photoder-           bocytopenia, various cutaneous eruptions, hypereosinophilia,
matitis, and TEN have been reported with DMARDs. 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
several of these have already occurred, it is too early to assess   by immune complexes, a component of which is heparin-
the global impact of adverse events for diverse immunologic         dependent IgG specific for platelet factor 4.112 This reaction
interventions in early development. Allergic reactions to im-       usually occurs after approximately 5 days of treatment with
munosuppressant and anti-inflammatory drugs may be en-              unfractionated heparin and is associated with development of
countered in the treatment of chronic cutaneous diseases.           thrombosis and necrosis. A recent outbreak of anaphylactic
Dermatologic immunosuppressant drugs, such as macrolides            reactions to heparin in the United States and Germany was
(eg, cyclosporine, tacrolimus, pimecrolimus, and sirolimus),        attributed to a contaminant in heparin lots, an oversulfated
dapsone, and mycophenolate mofetil, have been reported to           form of chondroitin sulfate. This oversulfated chondroitin
cause drug allergic reactions in addition to their known pre-       sulfate contaminant has been shown in vitro and in vivo to
dictable adverse reactions.                                         cause activation of the kinin-kallikrein pathway with gener-
                                                                    ation of bradykinin, a potent vasoactive mediator, and C3a
                                                                    and C5a anaphylatoxins.113 Clinically, reactions to contami-
Perioperative Agents and Blood Products                             nated heparin products were associated with hypotension and
Anaphylactic and anaphylactoid reactions during general an-         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-      pain and angioedema are somewhat analogous to C1 inhibitor
phylactic reactions cannot be distinguished from anaphylac-         deficiency in which symptoms are due to local production of
toid, nonimmune occurrences, it has been recommended that           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.100,101 Diabetic patients receiving protamine-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           due to inadvertent intravenous epinephrine effects. 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).           skin testing and incremental challenge with a local anesthetic
TRALI is a complex syndrome that has multiorgan manifes-            is a reasonable approach in the evaluation of a possible
tations and has only recently been identified to be an important    reaction.
cause of transfusion-associated morbidity and mortality.104,105
                                                                    Radiocontrast Media
Opiates                                                             Anaphylactoid reactions occur in approximately 1% to 3% 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, and can be attenuated by preadministration of histamine1       Severe life-threatening reactions are less common, occurring
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-      patients receiving nonionic agents.121 Risk factors for anaphy-
mine from skin mast cells in all patients.                          lactoid reactions to RCM include female sex, asthma, and

VOLUME 105, OCTOBER, 2010                                                                                                   273.e10
a history of previous anaphylactoid reaction to RCM;              asthma and rhinitis/sinusitis. A pharmacologic induction of
␤-blocker exposure and/or the presence of cardiovascular          drug tolerance procedure (also known as aspirin desensitiza-
conditions is associated with greater risk for more serious       tion), during which tolerance to aspirin can be induced and
anaphylactoid reaction.122-126 There is no convincing evidence    maintained, is an important therapeutic option for patients
in the medical literature that individuals with “seafood al-      with AERD.
lergy” are at elevated risk for anaphylactoid reaction to RCM        A second clinical presentation of aspirin and NSAID drug
compared with the general population. Management of a             allergic reactions is an exacerbation of urticaria or angio-
patient who requires RCM and has had a prior anaphylactoid        edema in patients with chronic idiopathic urticaria. All drugs
reaction to RCM includes the following: (1) determine             that inhibit COX-1 cross-react to cause this reaction. Selec-
whether the study is essential; (2) determine that the patient    tive COX-2 inhibitors are generally well tolerated in patients
understands the risks; (3) ensure proper hydration; (4) use a     with chronic idiopathic urticaria, although there may be rare
nonionic, iso-osmolar RCM, especially in high-risk patients       exceptions.142-144 A third type of drug allergic reaction is
(asthmatic patients, patients taking ␤-blockers and those with    aspirin or single NSAID-induced urticaria or angioedema or
cardiovascular disease); and (5) use a pretreatment regimen       anaphylactic reaction, in which case other NSAIDs are tol-
that has been documented to be successful in preventing most      erated.145-148 A fourth type of drug allergic reaction to aspirin
reactions.127-130 Delayed reactions to RCM, defined as those      and NSAIDs is urticaria or angioedema due to aspirin and any
occurring between 1 hour and 1 week after administration,         NSAID that inhibits COX-1 in patients without chronic urti-
occur in approximately 2% of patients.131 These reactions         caria. These reactions may be either drug specific or cross-
most commonly manifest as mild, self-limited cutaneous            reactive to other NSAIDs.148 Rarely, some reactions to aspirin
eruptions and do not require any treatment.131 The mechanism      or NSAIDs do not fit precisely into these categories and may
of delayed skin reactions to RCM appears to be T cell             have blended respiratory and cutaneous reactions.
mediated.132                                                         Allergic rashes are common adverse effects of clopidogrel,
                                                                  a thiopyridine inhibitor of platelet activation that is often
Aspirin, NSAIDs, and Platelet Inhibitors                          recommended in aspirin-intolerant patients. Although the
Aspirin and NSAIDs can cause a spectrum of drug allergic          mechanisms of such reactions are unknown, successful oral
reactions, including exacerbation of underlying respiratory       induction of drug tolerance protocols have been reported.
disease, urticaria, angioedema, anaphylaxis, and rarely pneu-
monitis and meningitis. AERD is a clinical entity character-
                                                                  Angiotensin-Converting Enzyme Inhibitors
ized by aspirin- and NSAID-induced respiratory reactions in
patients with chronic rhinosinusitis and asthma. AERD does        Angiotensin-converting enzyme (ACE) inhibitors have 2 ma-
not fit precisely into a specific category of adverse drug        jor adverse effects— cough and angioedema. Cough occurs in
reactions. The mechanism of AERD is related to aberrant           up to 20% of patients, is typically dry and nonproductive, and
arachidonic acid metabolism. Patients with AERD also have         occurs more commonly in women, blacks, and Asians. The
increased respiratory tract expression of the cysteinyl leuko-    cough generally begins within the first few weeks of treat-
triene 1 receptor and heightened responsiveness to inhaled        ment, but occasionally the onset may occur much later. An-
leukotriene E4.133,134 Administration of aspirin leads to inhi-   giotensin receptor blockers (ARBs) are not associated with
bition of cyclooxygenase 1 (COX-1) with resultant decrease        development of cough.
in prostaglandin E2. Prostaglandin E2 normally inhibits 5-li-        The incidence of angioedema with ACE inhibitors is ap-
poxygenase, but with a loss of this modifying effect, arachi-     proximately 0.1% to 0.7%149,150 and appears to be more com-
donic acid molecules are preferentially metabolized in the        mon in blacks.151,152 The angioedema frequently involves the
5-lipoxygenase pathway, resulting in increased production of      face or upper airway and can be life-threatening or fatal.153,154
cysteinyl leukotrienes. NSAIDs that preferentially inhibit        Reports of angioedema of the intestinal tract secondary to
COX-2 but also inhibit COX-1 at higher doses may result in        ACE inhibitors have also been described.155 Patients with C1
reactions, depending on the dose given. Selective COX-2           esterase inhibitor deficiency are at increased risk of more
inhibitors almost never cause reactions in patients with          frequent and severe episodes of angioedema with the admin-
AERD and can typically be taken safely.135-139                    istration of ACE inhibitors and should not receive these
   When patients with a history suggestive of AERD (ie,           drugs. Patients typically take ACE inhibitors for months or
asthma, rhinosinusitis, and history of respiratory reaction to    even years before angioedema occurs. It is also puzzling that
aspirin or aspirin-like drug) are challenged with aspirin, ap-    recurrent episodes of angioedema occur sporadically despite
proximately 85% will have a respiratory reaction confirming       continued daily use of ACE inhibitors. Most patients with
the diagnosis.140 A recent study showed that 100% of patients     angioedema related to ACE inhibitor usually tolerate
with a history of aspirin causing a severe reaction (poor         ARBs.156
response to albuterol with need for medical intervention) had
positive oral aspirin challenges.141 Management of patients       Biologic Modifiers
with AERD involves avoidance of aspirin and NSAIDs and            In the past decade, a number of biologic agents have been
aggressive medical and/or surgical treatment of underlying        developed to neutralize proinflammatory cytokines, their cel-

273.e11                                                                         ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 3. Classification of Adverse Reactions to Biologics          imab (chimeric mouse-human IgG1 monoclonal antibody
    Type of adverse reaction                   Example             against the epidermal growth factor receptor), including IgE-
                                                                   mediated anaphylaxis, has been reported to occur at a na-
  High dose                          Cytokine release syndrome
                                                                   tional rate of 3% or less but much higher (22%) in the Middle
  Hypersensitivity                   Delayed infusion reactions
  Secondary Immunodeficiency         Tuberculosis with anti-TNF    South region of the United States.183 IgE antibodies in this
  Autoimmunity                       SLE or vasculitis             condition are specific for an oligosaccharide galactose- ␣-1,
  Atopic disorders                   Atopic dermatitis             3-galactose, which is present on the Fab portion of the cetux-
  Cross-reactivity                   Acne from anti–epidermal      imab heavy chain. In most of these patients, specific IgE
                                       growth factor receptor      cetuximab antibodies were present in patients’ sera before
  Nonimmunologic adverse             Depression from interferons   therapy.184 Severe symptoms, such as fever, rigors, chills, and
                                                                   acute respiratory distress syndrome, may occur during admin-
Abbreviations: SLE, systemic lupus erythematosus; TNF, tumor ne-   istration of the first dose of certain monoclonal antibodies due
crosis factor.                                                     to a cytokine release syndrome.185,186
                                                                      Depending on the monoclonal antibody and type of reac-
                                                                   tion, readministration strategies may include medication pre-
lular receptors, and IgE antibody.157,158 Because the clinical
experience with these drugs varies (ie, phase 4 experiences),      treatment, slowing infusion rates, or induction of drug toler-
the spectrum of reported allergic reactions may not yet be         ance.184 In patients with immediate-type reactions, successful
fully known for all of them. A separate type of classification     induction of tolerance to rituximab, infliximab, and trastu-
for adverse reactions to biological agents has been proposed       zumab has been reported using a 6-hour protocol in combi-
based on the mechanism of reactions (Table 3).159 High-dose        nation with corticosteroid and antihistamine premedication.
reactions are related to high cytokine levels administered            Rare anaphylactic reactions to anti-IgE humanized monoclo-
directly or from cytokines released (cytokine release syn-         nal antibody (omalizumab) were described during phase 3 clin-
drome). Hypersensitivity reactions may be either antibody or       ical trials and during the postmarketing surveillance period. The
cell-mediated. Immune or cytokine dysregulation may result         mechanism of these reactions is unclear. Many cases experi-
in secondary immunodeficiency, autoimmunity, or allergic or        enced either delayed-onset (2 hours) or protracted progression of
atopic disorders. Cross-reactive reactions may occur when          signs and symptoms after dose administration. The Omalizumab
the biologic agent is intended for a pathologic cell type but      Joint Task Force report recommended that patients receiving
cross-reacts with normal cells. Finally, biologics may also        omalizumab should be directly observed, in a physician’s office,
result in nonimmunologic adverse effects.                          after receiving omalizumab for 2 hours after the first 3 doses and
   Cytokines, including interferons and anti–tumor necrosis        30 minutes after subsequent doses.187
factor ␣ (TNF-␣) drugs, have been reported to cause a variety
of drug allergic reactions. Allergic drug reactions ranging
from cutaneous lesions to severe anaphylaxis may occur             Complementary Medicines
during treatment with recombinant interferons. A variety of        The term complementary medicine includes herbal products,
immune-mediated reactions have occurred during infliximab          vitamins, minerals, amino acids, and essential oils.188 There is
(Remicade) treatment for adult and juvenile rheumatoid ar-         widespread belief that these products are safe because they
thritis, Crohn’s disease and psoriasis. These reactions include    are “natural.”189 However, well-recognized adverse effects,
urticaria, flare-up of atopic dermatitis, maculopapular rashes,    including anaphylaxis, have been reported in patients using
leukocytoclastic vasculitis, serum sickness, and at least 7        bee pollen products.190 Allergic reactions, including asthma
instances of life-threatening anaphylactic reactions.160-173       and anaphylaxis, have been reported after ingestion of echi-
Fewer adverse effects have been associated with adalimumab         nacea, an herb that is derived from several species of a
(Humira), another recently available, fully humanized anti-        flowering plant.191 A variety of cutaneous reactions and 1
TNF-␣ monoclonal antibody. These effects include injection         instance of TEN have been reported after use of Chinese
site pruritic rashes and new-onset asthma.174,175 New-onset        herbal medications, which sometimes have been adulterated
asthma may also appear during treatment with both inflix-          with synthetic medications.192,193 Because the extent of this
imab and etanercept (Enbrel). Immune-mediated reactions            problem is unknown, patients should be questioned about the
have also been rarely associated with the latter agent, a          use of herbs and health supplements.
recombinant TNF-␣ extracellular protein domain fused to
human IgG1 Fc, which neutralizes soluble TNF-␣. These
reactions include urticaria, rashes, injection site reactions,     Other Agents
leukocytoclastic vasculitis, lupus erythematosus, and 1 in-        A number of other agents have been reported to cause drug
stance of lung granulomatosis injury.176-182                       allergic reactions, including N-acetylcysteine, blue dyes, vol-
   Both cutaneous and systemic allergic reactions have been        ume expanders, iron-containing dextran, and preservatives.
reported after treatment with both murine and humanized            These reactions are discussed further in the text of the
monoclonal antibodies. Hypersensitivity reactions to cetux-        parameter.

VOLUME 105, OCTOBER, 2010                                                                                                     273.e12
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