Download Allergic and Pseudoallergic Drug Reactions

Allergic and Pseudoallergic
Drug Reactions
e|CHAPTER
Lynne M. Sylvia
KEY CONCEPTS
1
Hypersensitivity reactions are responsible for 6% to 10%
of adverse reactions to medications. Although some
reactions are relatively well defined, the majority are due to
mechanisms that are either unknown or poorly understood.
2
The following criteria suggest that a drug reaction may be
immunologically mediated: (a) the reaction occurs in a small
percentage of patients receiving the drug, (b) the observed
reaction does not resemble the drug’s pharmacologic
effect, (c) the type of manifestation is similar to that seen
with other allergic reactions (anaphylaxis, urticaria, serum
sickness), (d) there is a lag time between first exposure of
the drug and reaction, (e) the reaction is reproduced even
by minute doses of the drug, (f) the reaction is reproduced
by agents with similar chemical structures, (g) eosinophilia
is present, or (h) the reaction resolves after the drug has
been discontinued. Exceptions to each of these criteria are
observed commonly.
3
4
Anaphylaxis is an acute, life-threatening allergic reaction
involving multiple organ systems that generally begins
within 30 minutes but almost always within 2 hours after
exposure to the inciting allergen. Anaphylaxis requires
prompt treatment to restore respiratory and cardiovascular
function. Epinephrine is the drug of choice to counteract
bronchoconstriction and peripheral vasodilation. IV fluids
should be administered aggressively to restore intravascular
volume.
Factors that influence the likelihood of allergic drug
reactions are the chemical composition of the drug, whether
the drug contains proteins of nonhuman origin, the route of
drug administration, and the sensitivity of the individual as
determined by genetics or environmental factors. For some
drugs, genetic predisposition to specific human leukocyte
antigen alleles has been identified as a risk factor for allergicmediated skin reactions.
5
Patients with a history of an immediate reaction to penicillin
are advised not to receive cephalosporins if they can be
avoided. Patients who have negative penicillin skin test
results or experienced only mild cutaneous reactions, such
as maculopapular rashes, have a low risk of serious reactions
to cephalosporins. Similarities in the R1 side chain of the
agents should be considered when assessing the risk of
cross-reactivity.
6
Fewer than 1% of patients receiving nonionic radiocontrast
agents experience some type of adverse reaction. Of
the variety of reactions reported, about 90% are allergiclike, mostly urticarial, with severe reactions occurring as
infrequently as 0.02%.
22
7
Aspirin and other nonsteroidal antiinflammatory drugs
(NSAIDs) can produce two general types of reactions,
urticaria/angioedema and rhinosinusitis/asthma, in
susceptible patients. About 20% of individuals with
asthma are sensitive to aspirin and other NSAIDs.
8
Cross-reactivity between sulfonamide antibiotics and
nonantibiotics is low. The low cross-reactive rate may be
explained by differences in the chemical structures and
reactive metabolites of the sulfonamide antibiotics and
nonantibiotics.
9
The basic principles of management of allergic reactions to
drugs or biologic agents include (a) discontinuation of the
medication or agent when possible; (b) treatment of the
adverse clinical signs and symptoms; and (c) substitution,
if necessary, of another agent.
10
One of the most helpful tests to evaluate risk of penicillin
allergy is the skin test. Skin testing can demonstrate the
presence of penicillin-specific immunoglobulin E and predict
a relatively high risk of immediate hypersensitivity reactions.
Skin testing does not predict the risk of delayed reactions or
most dermatologic reactions.
11
When an allergenic drug is considered medically necessary,
no adequate therapeutic alternative exists, and there is no
reliable skin testing method, two options are available to the
clinician: induction of drug tolerance (previously known as
desensitization) and graded challenge.
INTRODUCTION
1 Allergic drug reactions, also known as hypersensitivity reactions, result from an overresponse of the immune system to the standard dose of a drug. The hyperresponse of the immune system to the
antigenic drug leads to host tissue damage manifesting as an organspecific or generalized systemic reaction. Adverse drug effects not
proven to be immune mediated but resembling allergic reactions in
their clinical presentation are referred to as allergic-like or pseudoallergic reactions. Immunologically mediated adverse drug reactions account for 6% to 10% of all adverse drug reactions and even
up to 15% by some estimates.1,2 Examples of allergic drug reactions are anaphylaxis from β-lactam antibiotics, halothane hepatitis,
Stevens–Johnson’s syndrome (SJS) from sulfonamides, allopurinol
hypersensitivity syndrome, and serum sickness from phenytoin.3
Examples of pseudoallergic reactions are isolated urticaria after
radiocontrast media, aspirin-induced asthma, opiate-related urticaria, and flushing after vancomycin infusion.3
Copyright © 2014 McGraw-Hill Education. All rights reserved.
329
330
The true frequency of allergic drug reactions is difficult to
determine because many reactions may not be reported, and others
may be difficult to distinguish from nonallergic adverse events. Dermatologic reactions represent the most frequently recognized and
reported form of allergic drug reaction.4
SECTION
2
MECHANISMS OF ALLERGIC
DRUG REACTIONS
Organ-Specific Function Tests and Drug-Induced Diseases
Drugs can cause hypersensitivity reactions by a variety of immunologic mechanisms. Although some reactions are relatively well
defined, most are due to mechanisms that are either unknown or
poorly understood.2,3
2 The following criteria suggest that a drug reaction may
be immunologically mediated: (a) the observed reaction does not
resemble the drug’s pharmacologic effect; (b) there is a lag time
between first exposure of the drug and reaction unless the recipient
has been sensitized by prior exposure to the drug, which can lead
to immediate reactions; (c) the reaction may occur even by minute
doses of the drug; (d) the symptoms are characteristic of an allergic
reaction (e.g., anaphylaxis, urticaria, serum sickness); (e) the reaction resolves after the drug has been discontinued; and (f) the reaction may be reproduced by agents with similar chemical structures.2
Exceptions to each of these criteria are observed commonly. Many
allergic reactions can be classified into one of four immunopathologic categories: type I, II, III, or IV (eTable 22-1 and eFig. 22-1).2,3,5
EFFECTORS OF ALLERGIC
DRUG REACTIONS
Allergic drug reactions can involve most of the major components
of the innate and adaptive immune systems, including the cellular
elements, immunoglobulins, complement, and cytokines. Most
immunoglobulin isotypes have been implicated in immunologically mediated drug reactions. Immunoglobulin E (IgE) bound to
basophils or mast cells mediates immediate (anaphylactic-type)
reactions. IgG or IgM antibodies also may be involved in allergic
reactions, resulting in destruction of cells and tissues. T lymphocytes
have a major role in hypersensitivity reactions and are involved in all
four types (I–IV) of the drug hypersensitivity reactions described by
Coombs and Gell.2,5–7
Cellular Elements
A variety of cells are involved in drug hypersensitivity. Antigenpresenting cells (APCs) include macrophages, dendritic cells,
and cutaneous Langerhans cells. APCs process the antigenic drug
for subsequent recognition by T and B lymphocytes. Basophils
and mast cells are instrumental in the development of immediate
hypersensitivity reactions, whereas eosinophils are recruited in
both immediate and nonimmediate reactions. Platelets and vascular
endothelial cells are important because they also can release a number of inflammatory mediators.8 Most cells of the body, including
nerve cells, can become involved directly or indirectly in allergic
drug reactions.
Mediators of Allergic Reactions
The release of a number of preformed, pharmacologically active
chemical mediators (e.g., histamine, heparin, proteases such as
tryptase and chymase, and a variety of other enzymes) is triggered when antigens cross-link IgE molecules on the surface of
circulating basophils and tissue mast cells. Newly formed mediators include platelet-activating factor (PAF) and arachidonic acid
metabolites (e.g., prostaglandins [PGs], thromboxanes, and leukotrienes [LTs]).
Histamine is a low-molecular-weight amine compound
formed by decarboxylation of histidine and is stored in basophil
and mast cell granules.9 Release of histamine from these cells is
triggered by antigen cross-linking IgE bound to specific receptors
on the surface membranes of mast cells and basophils. The tissue
effects of histamine are evident within 1 to 2 minutes, but it is
rapidly metabolized within 10 to 15 minutes. The major effects
of histamine on target tissues include increased capillary permeability, contraction of bronchial and vascular smooth muscle, and
hypersecretion of mucous glands. Four classes of histamine receptors (H1–H4) are present in varying degrees in organs and tissues.
H1 receptors are most prominent in blood vessels and bronchial
and intestinal smooth muscle.
Platelet-activating factor is a glyceride-derived substance that
is released by mast cells, alveolar macrophages, neutrophils, platelets, and other cells but not by basophils. It has potent bronchoconstrictor effects and causes platelet aggregation and lysis. It attracts
neutrophils and causes their activation. PAF enhances vascular permeability and can cause pain, pruritus, and erythema.
eTable 22-1 Classification of Allergic Drug Reactions
Type
Descriptor
Characteristics
Typical Onset
Drug Causes
I
Anaphylactic
(IgE mediated)
Allergen binds to IgE on basophils or mast cells,
resulting in release of inflammatory mediators.
Within 30 min to <2 hours
Penicillin immediate reaction
Blood products
Polypeptide hormones
Vaccines
Dextran
II
Cytotoxic
Cell destruction occurs because of cell-associated
antigen that initiates cytolysis by antigen-specific
antibody (IgG or IgM). Most often involves blood
elements.
Typically >72 h to weeks
Penicillin, quinidine, heparin,
phenylbutazone, thiouracils,
sulfonamides, methyldopa
III
Immune
complex
Antigen–antibody complexes form and deposit
on blood vessel walls and activate complement.
Result is a serum sickness-like syndrome.
>72 h to weeks
May be caused by penicillins,
sulfonamides, minocycline, hydantoins
IV
Cell-mediated
(delayed)
Antigens cause activation of T lymphocytes, which
release cytokines and recruit effector cells (e.g.,
macrophages, eosinophils).
>72 h
Tuberculin reaction
Maculopapular rashes to a variety
of drugs;
Contact dermatitis
Bullous exanthems
Pustular exanthems
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331
Antibody (I-III) and T-cell-orchestrated
hypersensitivity reactions (IVa-d)
Antigen
Effector
Type II
Type III
Type IVa
Type IVb
IgE
IgG
IgG
IFNγ, TNFα
TH1 cells)
IL-5,IL-4/IL-13
(TH2 cells)
Soluble antigen
Cell-or matrixassociated
antigen
Soluble antigen
Mast cell
activation
FcR+ cells
(phagocytes,
NK cells)
FcR+ cells
complement
Antigen
Antigen
presented by
presented by
cells or direct
cells or direct
T-cell stimulation T-cell stimulation
Macrophage
activation
Eosinophils
Ag
Platelets
T H1
Chemokines,
cytokines,
cytotoxins
Hemolytic
Allergic rhinitis,
anemia,
Serum sickness,
asthma, systemic
thrombocytopenia Arthus reaction
anaphylaxis
(e.g., penicillin)
CXCL-8, IL-17
GM-CSF
(T-cells)
Cell-associated
antigen or direct
T-cell stimulation
Soluble antigen
presented by
cells or direct
T-cell stimulation
T-cells
Neutrophils
TH2
IFN-γ
IL-4
IL-5
Eotaxin
Eosinophil
Example of
hypersensitivity
reaction
Perforin/
granzyme B
(CTL)
Type IVd
Tuberculin
reaction,
contact
dermatitis
(with IVc)
Cytokines,
inflammatory
mediators
Chronic asthma,
chronic allergic
rhinitis
Maculopapular
exanthema with
eosinophilia
CTL
CXCL-8
GM-CSF
PMN
Cytokines,
inflammatory
mediators
Contact
dermatitis
Maculopapular
and bullous
exanthema
hepatitis
AGEP
Behcet’s disease
eFIGURE 22-1 Types of hypersensitivity reactions. (AGEP, acute generalized exanthematous pustulosis; CTL, cytotoxic T lymphocyte;
CXCL-8, interleukin 8; GM-CSF, granulocyte-macrophage colony-stimulating factor; Ig, immunoglobulin; IL, interleukin; NK, natural
killer; PMN, polymorphonuclear leukocyte)
The LTs are metabolites of arachidonic acid produced through
the 5-lipoxygenase pathway that have potent effects on bronchial
and vascular smooth muscle. Three important LTs, LTC4, LTD4,
and LTE4, are produced by basophils or mast cells. These three
substances are also referred to as cysteinyl LTs and were previously referred to as slow-reacting substances of anaphylaxis. The
LTs have more potent and longer-lasting bronchoconstrictor effects
than histamine and can increase vascular permeability and cause
arteriolar vasoconstriction followed by vasodilation. Their effects
are slower in onset but longer lasting than those of histamine.
Another product, LTB4, is a potent chemoattractant, particularly
for neutrophils. It is also produced by neutrophils, macrophages,
and monocytes.
Prostaglandins and thromboxanes are metabolites of arachidonic acid produced through the cyclooxygenase (COX) pathway.
Some PGs have vasoconstrictive or bronchodilatory properties,
whereas others are vasodilatory or bronchoconstrictive. PGD2 is the
major PG product of mast cells. It is a potent inhibitor of platelet
aggregation and is a bronchoconstrictor. Thromboxanes cause platelet aggregation and are important regulators of coagulation.
The complement system consists of about 30 plasma proteins
and is involved in hypersensitivity through a variety of immunologic
responses, including enhancement of phagocytosis (opsonization of
target cells), cell lysis, and generation of anaphylatoxins C3a, C4a,
and C5a, which can cause non–IgE-mediated activation of mast
cells and release of inflammatory mediators.
CLASSIFICATION OF
IMMUNOPATHOLOGIC
DRUG REACTIONS
Immunologic mechanisms have been identified for some drug reactions, and many can be classified into one of four immunopathologic
reactions, first described by Coombs and Gell. Small-molecularweight molecules (<10 kDa) do not have the ability to serve as antigens on their own. With the exception of polypeptide compounds,
most drugs are smaller than 1,000 Da. To become immunogenic,
these small compounds must first covalently bind to carrier proteins in plasma or tissue. The combination of the drug bound to a
carrier protein can be recognized as foreign by APCs and T lymphocytes, culminating in an immune response. The more likely that
large amounts of the drug become chemically bound to a protein,
the greater the risk of producing an allergic reaction. Penicillin G
(356 Da) is an example of a drug that binds covalently to serum
proteins through amide or disulfide linkages. For drugs such as the
sulfonamides, the parent compound must be converted to a metabolite before it can combine with the macromolecule. The species that
combines with the carrier macromolecule is referred to as a hapten or an incomplete antigen. Some macromolecular drugs such as
insulin are referred to as complete antigens because they are large
enough to initiate an immune response without binding to another
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
Immune complex
Blood
vessel
Type IVc
e|CHAPTER Immune
reactant
Type I
332
protein. Some small-molecular-weight drugs may cause an immune
response through a nonhapten pathway.6 Known as the p-i concept,
this pathway involves a pharmacologic interaction between the drug
and the T-cell receptor that does not require the initial binding of the
drug to a carrier protein or processing by APCs.7
Type I
SECTION
2
Organ-Specific Function Tests and Drug-Induced Diseases
Type I reactions require the presence of IgE specific for the drug or
the portion of the drug that becomes a hapten. IgE specific for the
drug allergen is produced on initial exposure to the drug. It then
binds to basophils and mast cells through high-affinity receptors.
On repeat exposure to the drug, two or more IgE molecules on the
basophil or mast cell surface may bind to one multivalent antigen
molecule (referred to as cross-linking; see eFig. 22-1), initiating cellular activation. Activation causes the extracellular release of granules with preformed inflammatory mediators, including histamine,
heparin, and proteases (tryptase in the mast cell), as well as generation of newly formed mediators, as previously discussed, such as
LTs, PGs, thromboxanes, and PAF, among others.
Generation of a type I reaction can be evident as an immediate hypersensitivity reaction, or anaphylaxis. Immediate reactions may be limited to single organs, typically in the nasal mucosa
(rhinitis), respiratory tract (acute asthma), skin, or gastrointestinal
tract, or they can involve multiple organs simultaneously, termed
anaphylaxis.
Type II
Type II immunopathologic reactions involve destruction of host
cells (usually blood cells) through cytotoxic antibodies by one
of two mechanisms (see eFig. 22-1). First, the drug binds to the
cell as a hapten (e.g., the platelet or red blood cell). Antibodies
(IgG or IgM) specific for the bound drug or to a component of
the cell surface that has been altered by the drug then bind, initiating a cytolytic reaction. Cell destruction may be mediated by
complement or by phagocytic cells that have antibody Fc receptors on their surfaces. Activation of complement near the cell surface can result in loss of cell membrane integrity and cell death.
Alternatively, neutrophils, monocytes, or macrophages may bind
to an antibody-coated cell through IgG Fc receptors on their cell
surfaces, resulting in phagocytosis of the target cell. The process
of enhancement of phagocytosis by antibody binding to cell surfaces or other particles is referred to as opsonization. In addition,
cell-bound IgG may direct the nonphagocytic action of T cells or
natural killer cells, which results in cell destruction by a process
called antibody-dependent cellular cytotoxicity. This process can
proceed in a nonspecific fashion as T cells bind to the target cell
through IgG Fc receptors on the T-cell surface. Contact between
the target and effector cells is necessary.
Cells commonly affected by these types of reactions include
erythrocytes, leukocytes, and platelets, resulting in hemolytic anemia, agranulocytosis, and thrombocytopenia, respectively. This process may be initiated by drugs such as penicillin, quinidine, quinine,
phenacetin, cephalosporins, and sulfonamides.
Another type of reaction that may affect the formed elements
in blood is the “innocent bystander” reaction. With this type of reaction, antigen–antibody complexes formed in blood adhere nonspecifically to cells. Complement is then activated, resulting in cell
lysis.
Type III
Type III immunologic reactions are caused by antigen–antibody
complexes that are formed in blood. The complexes form with
drug allergen and antibody in varying ratios and may deposit
in tissues, resulting in local or disseminated inflammatory reactions. Antigen–antibody complex formation can result in platelet
aggregation, complement activation, or macrophage activation.
Chemotactic substances such as C4a also are produced. These
substances cause the influx of neutrophils and result in the release
of a number of toxic substances from the neutrophil (e.g., proteinases, collagenases, kinin-generating enzymes, and reactive
oxygen and nitrogen substances), which can cause local tissue
destruction.
Platelet aggregation may occur as a result of immune-­complex
formation, resulting in the formation of microthrombi and the
release of vasoactive mediators. Also, insoluble complexes may be
phagocytized by macrophages and activate these cells.
The formation of antigen–antibody complexes can lead to clinical syndromes such as the Arthus reaction. In this model, a high
level of preformed specific IgG antibody combines with antigen to
produce a localized edematous, erythematous reaction within 5 to
8 hours. The reaction involves local formation of insoluble antigen–
antibody complexes, complement activation with release of C3a and
C5a collectively referred to as anaphylatoxins, mast cell degranulation, and influx of polymorphonuclear cells.
Type IV
Type IV reactions are delayed hypersensitivity reactions that typically are demonstrated as dermatologic events mediated by T cells
(CD4+ or CD8+).5–7 The Coombs and Gell classification of allergic
drug reactions was developed before our understanding of the varied
roles of T cells in the immune response. Four subclasses of type IV
reactions (IVa–IVd) have been described based on the responding T
cell (e.g., T helper type 1 cell, T helper type 2 cell, cytotoxic T cell),
effector mechanism (e.g., recruitment of macrophages, eosinophils,
or neutrophils), and clinical manifestations (e.g., contact dermatitis,
bullous exanthems, maculopapular eruptions, pustular exanthems)
(eFig. 22-1).5–7 Type IV reactions require memory T cells specific
for the antigen in question. On exposure to the antigen, the immune
response is mediated by a specific subtype of T cell that orchestrates an inflammatory response through the secretion of cytokines
and the recruitment of effector cells. These reactions are associated with a wide variety of adverse effects (e.g., contact dermatitis,
maculopapular exanthemas, bullous exanthemas, eczema, or pustular exanthemas), and they also may be useful for diagnostic purposes. Examples of the latter include the purified protein derivative
(PPD) antigen from Mycobacterium tuberculosis used in the tuberculin skin test and other recall skin test antigens, such as mumps.
After intradermal injection, these antigens produce a local reaction
(erythema and induration) within 48 to 72 hours. Delayed contact
hypersensitivity also can be caused by a wide variety of chemicals
and drugs.
Other Allergic Reactions
The precise mechanism of many drug reactions is not known,
although the reactions are believed to be immune mediated. Perhaps
most common are the delayed dermatologic reactions that occur
with a variety of drugs (especially penicillins and sulfonamides).
These reactions may be evident as fixed drug eruptions; macropapular, morbilliform, or erythematous rashes; exfoliative dermatitis;
photosensitivity reactions; or eczema. These reactions also may be
manifest as late onset pruritus, urticaria, and angioedema.
A number of serious cutaneous adverse reactions, known
as SCARs, may be the result of immunologic reactions. SCARs
include drug rash with eosinophilia and systemic symptoms
(DRESS) and the mucocutaneous disorders, SJS and toxic epidermal necrolysis (TEN). Drug-induced fever also may involve
immunologic mechanisms. Other general types of reactions
Copyright © 2014 McGraw-Hill Education. All rights reserved.
333
believed to be immune mediated in some cases include hepatic
drug reactions (cholestatic or hepatocellular) and pulmonary reactions (e.g., interstitial pneumonitis, which has been associated
with nitrofurantoin).
CLINICAL MANIFESTATIONS OF
ALLERGIC AND ALLERGIC-LIKE
REACTIONS
Anaphylaxis
3 Anaphylaxis is an acute, life-threatening reaction, usually mediated by an immune mechanism, that involves multiple organ systems and occurs in 10 to 20 per 100,000 population per year.11 About
1,500 deaths from anaphylaxis occur annually in the United States.12
From 1.2% to 15% of the United States population may be at risk
for anaphylactic reactions.13 Recently reported data suggest that
the prevalence is rising, most notably in the younger age group.14
Although many drugs may cause anaphylaxis (or anaphylactoid)
reactions, the most commonly reported are penicillins, aspirin and
other NSAIDs, and insulins.10,14 In most patients, the initial signs
and symptoms occur in the skin (flushing, pruritus, urticaria, angioedema). The second most common symptoms are respiratory (tightness of the throat and chest, dysphagia, dysphonia and hoarseness,
cough, stridor, shortness of breath, dyspnea, congestion, rhinorrhea,
sneezing) followed by dizziness and gastrointestinal tract symptoms
1. Acute onset of a reaction (minutes to several hours) with
involvement of the skin, mucosal tissue, or both (e.g., generalized hives; pruritus or flushing; swollen lips, tongue,
uvula) and at least one of the following:
• Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
• Reduced blood pressure or associated symptoms of endorgan dysfunction (e.g., hypotonia, syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen (minutes to several hours):
• Involvement of skin or mucosal tissue (as above)
• Respiratory compromise (as above)
• Reduced blood pressure or associated symptoms
• Persistent gastrointestinal symptoms (e.g., crampy
abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen
(minutes to several hours)
The panel indicated that other presentations may indicate anaphylaxis, such as acute chest pain or arrhythmia without dermatologic manifestations, and that the potential exists for false-positive
results.
Anaphylaxis generally begins within 30 minutes but almost
always within 2 hours of exposure to the inciting allergen. The risk
of fatal anaphylaxis is greatest within the first few hours. Late phase
or “biphasic reactions” can occur 1 hour to 72 hours after the initial
presentation with most occurring within 10 hours. Because of the
possibility of a biphasic reaction, patients should be observed for at
least 12 hours after an anaphylactic reaction. Fatal anaphylaxis most
often results from asphyxia caused by airway obstruction either at
the larynx or within the lungs. Cardiovascular collapse may occur
as a result of asphyxia in some cases; in other cases, cardiovascular collapse may be the dominant manifestation from the release of
mediators within the heart muscles and coronary blood vessels.
Newer clinical markers may aid in the diagnosis of anaphylaxis. Serum levels of tryptase or mature tryptase (also known as
β-tryptase) peak in the serum within 0.5 to 2 hours after the onset
of anaphylaxis.14 Tryptase levels are most helpful in making the
diagnosis if they are drawn no more than 6 hours after the onset of
symptoms. Plasma histamine levels remain elevated for only 30 to
60 minutes; thus, they are not clinically useful in patients who present 1 hour or later after the onset of anaphylaxis.14
Serum Sickness and Serum
Sickness–Like Disease
Serum sickness is a clinical syndrome resulting from the effects
of soluble circulating immune complexes that form under conditions of antigen excess. The reaction commonly results from the
use of antisera containing foreign (donor) antigens such as equine
serum in the form of antitoxins or antivenoms. The onset of serum
sickness is usually 7 to 14 days after antigen administration.
The onset may be more rapid with reexposure to the same agent
in an individual with prior serum sickness. Fever, malaise, and
lymphadenopathy are the most common clinical manifestations.
Arthralgias, urticaria, and morbilliform skin eruption also may
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
Various drugs can produce reactions that are similar to anaphylaxis in clinical signs and symptoms but are not mediated by
immune mechanisms. The drugs causing these reactions can cause
release of mast cell– and basophil-derived mediators by a pharmacologic or physical effect rather than through cell-bound IgE.
These reactions are described as anaphylactoid (anaphylaxis-like)
reactions or non–immune-mediated anaphylaxis, the most severe
form of pseudoallergy.10 Pseudoallergy refers to a wide array of
reactions ranging from localized hives to life-­threatening angioedema, hypotension, and anaphylaxis, all of which are explained
by the nonimmunologic release or activation of inflammatory mediators. Drugs that can produce anaphylactoid reactions
include vancomycin, opiates, iodinated radiocontrast agents,
angiotensin-converting enzyme (ACE) inhibitors, amphotericin
B, and D-tubocurarine. The “red man syndrome” is a common
example of a pseudoallergic reaction from vancomycin. If vancomycin is infused too rapidly, it can cause the direct release of
histamine and other mediators from cutaneous mast cells, producing a typical clinical picture of itching, flushing, and hives, first
around the neck and face and then progressing to the chest and
other parts of the body usually beginning shortly after the infusion
has begun. In some cases, the cutaneous manifestations of “red
man syndrome” may be accompanied by hypotension, thereby
constituting an anaphylactoid event. Most patients who have
had “red man syndrome” will tolerate vancomycin if the rate of
infusion is slowed. In rare cases, the severity of the reaction may
preclude continued therapy with vancomycin. A number of other
agents (including aspirin) may produce anaphylactoid reactions
by altering the metabolism of inflammatory mediators such as PGs
or kinins. Angioedema from ACE inhibitors is a classic example
of an anaphylactoid reaction. Although the mechanism by which
this anaphylactic-like event occurs is not fully understood, inhibition of the breakdown of bradykinin and substance P by the ACE
inhibitor may explain the inflammation, increased vascular permeability, and vasodilation.
e|CHAPTER Anaphylactoid Reactions
(nausea, crampy abdominal pain, vomiting, diarrhea).14 About 10%
to 30% of patients develop hypotension. Additional cardiovascular effects include syncope, altered mental status, chest pain, and
dysrhythmia.11
In 2010, a consensus panel reconvened to update the definition and management of anaphylaxis.14 Anaphylaxis is highly likely
when one of the following three scenarios is present:
334
SECTION
2
be present. A milder and more transient form of serum sickness is
serum ­sickness–like disease (SSLD). The predominant feature of
SSLD is a cutaneous eruption, either urticarial or maculopapular,
that occurs within 5 to 21 days of drug administration.15 As with
serum sickness, the rash is usually preceded by a prodromal phase
consisting of fever, malaise, lymphadenopathy, and arthralgias.
SSLD has been associated with the administration of ciprofloxacin,
bupropion, hydantoins, minocycline, sulfonamides, penicillins, and
cephalosporins (especially cefaclor). SSLD is usually self-limiting
after discontinuation of the causative agent, but it can sometimes
progress to include vasculitis.
with a median reported time of 7 to 10 days after drug initiation.
Antimicrobials and antineoplastic drugs have been associated
with the shortest time to onset (median, 6 and 0.5 days, respectively), whereas CNS agents and cardiovascular drugs have longer
times to onset (median, 10 and 16 days, respectively).19 Laboratory findings such as leukocytosis, eosinophilia, elevated lactic
dehydrogenase, and elevated erythrocyte sedimentation rate may
aid in the diagnosis. Generally, withdrawal of the causative agent
results in prompt defervescence as soon as the drug is eliminated
completely. Fever usually recurs on readministration of the causative agent.
Drug Rash with Eosinophilia
and Systemic Symptoms
Drug-Induced Autoimmunity
Organ-Specific Function Tests and Drug-Induced Diseases
Previously known by the term drug hypersensitivity syndrome, the
triad of rash, eosinophilia, and internal organ involvement is currently referred to as drug rash with eosinophilia and systemic symptoms (DRESS). Bocquet and colleagues16 described the following
criteria for a diagnosis of DRESS: (a) cutaneous drug eruption
(usually a diffuse maculopapular rash accompanied by facial and
neck edema); (b) hematologic abnormalities including eosinophilia
greater than 1,500 cells/mm3 (1.5 x 109/L) or the presence of atypical lymphocytes; and (c) systemic involvement including adenopathies greater than 2 cm in diameter, hepatitis, interstitial nephritis,
interstitial pneumonia, or carditis.16 Both the allopurinol hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome are
examples of DRESS.17 Other drugs associated with DRESS include
minocycline, dapsone, lamotrigine, and the sulfonamides. The onset
of DRESS is typically delayed ranging from 3 to 8 weeks after drug
initiation, and there is a high degree of interpatient variability in
the targeted organs and the severity of organ involvement.16,17 The
mortality rate associated with DRESS is 10%, and it is largely attributed to systemic involvement of the liver, kidneys, or lungs.17 After
discontinuation of the causative drug, the skin rash resolves and
laboratory abnormalities normalize over a period of 4 to 8 weeks.
Systemic corticosteroids (0.5–1 mg/kg/day prednisone or steroid
equivalent) have been used in the treatment of DRESS based on the
severity of organ involvement.
Drug Fever
Fever may occur in response to an inflammatory process or develop
as a manifestation of a drug reaction. Drug fever has been estimated to occur in as many as 10% of hospital inpatients.18 Many
drugs have been reported to cause fever with the most frequently
implicated classes being the antimicrobials (e.g., acyclovir,
amphotericin B, β-lactams, minocycline, rifampin, sulfonamides,
tetracycline), anticonvulsants (e.g., carbamazepine, phenytoin),
antiarrhythmics (e.g., procainamide, quinidine), and other cardiac
medications (e.g., clofibrate, diltiazem, dobutamine, furosemide,
heparin, methyldopa, procainamide).19 These drugs may affect
the central nervous system (CNS) directly to alter temperature
regulation or stimulate the release of endogenous pyrogens (e.g.,
interleukin-1 and tumor necrosis factor), PGs, or nervous system
monamines that alter the thermoregulatory set point.19 Drugs also
may cause fever as a result of their pharmacologic effects on tissues (e.g., fever resulting from massive tumor cell destruction
caused by chemotherapy).
The temperature pattern of drug-induced fever is quite variable and therefore of little help in the diagnosis. Four patterns of
drug fever have been described: continuous, remittent, intermittent, and hectic. A combination of intermittent and remittent, hectic fever is the most common pattern with temperatures of 102°
to 104° F interrupting normal temperatures throughout the day.19
Drug fever may occur at any time during the course of therapy
Autoimmune diseases have been associated with drugs and may
involve a variety of tissues and organs. A commonly recognized
drug-related autoimmune disorder is systemic lupus erythematosus (SLE) induced by infliximab, etanercept, procainamide,
hydralazine, quinidine, or isoniazid.20 Exposure of susceptible
persons to these agents appears to alter normal body proteins,
RNA, or DNA in such a way as to make these components antigenic, leading to the formation of autoreactive antibodies and
cells. Most patients treated with infliximab develop antinuclear
antibodies, but only 2% of patients present with SLE symptoms.
The most common clinical manifestations include arthralgias,
myalgias, and polyarthritis. Facial rash, ulcers, and alopecia
occur less frequently. Renal or pulmonary involvement also may
occur. These reactions typically develop several months after
beginning the drug and generally resolve soon after the drug is
discontinued.21
Other syndromes believed to involve autoimmune mechanisms include drug-induced hemolytic anemia attributed to
methyldopa, interstitial nephritis produced by methicillin, and
hepatitis caused by phenytoin and halothane. Interstitial nephritis
is characterized by fever, rash, and eosinophilia associated with
proteinuria and hematuria. Hepatic damage due to drugs generally is manifested as either hepatocellular necrosis or cholestatic
hepatitis. Drug-induced hepatitis has been associated with phenothiazines, sulfonamides, halothane, phenytoin, and isoniazid (see
­eChap. 17). Hepatocellular destruction is evidenced by elevations
in serum transaminases. Hepatomegaly and jaundice sometimes
may be evident. Cholestasis may be manifested by jaundice and
elevations in serum alkaline phosphatase and sometimes by rash,
fever, and eosinophilia.
Vasculitis
Vasculitis is a clinicopathologic process characterized by inflammation and necrosis of blood vessel walls. The vasculitic process may
be limited to the skin, or it may involve multiple organs, including the liver or kidney, joints, or CNS. Characteristically, cutaneous
vasculitis is manifested by purpuric lesions that vary in size and
number. Vasculitis also may be manifested as papules, nodules,
ulcerations, or vesiculobullous lesions, generally occurring on
the lower extremities but sometimes involving the upper extremities, including the hands. Drugs associated with vasculitis include
­allopurinol, β-lactam antibiotics, sulfonamides, thiazide diuretics,
phenytoin, and vancomycin.
Dermatologic Reactions
A wide variety of dermatologic drug reactions have been reported
to have an immunologic basis.2,22 Cutaneous reactions are the
most common manifestations of allergic drug reactions. Although
most dermatologic reactions are mild and resolve promptly after
discontinuing the drug, some such as SJS and TEN are serious
Copyright © 2014 McGraw-Hill Education. All rights reserved.
335
Top 10 Drugs and Agents Reported
to Cause Skin Reactions
Reactions per 1,000 Recipients
Amoxicillin
Trimethoprim–sulfamethoxazole
Ampicillin
Iopodate
Blood
Cephalosporins
Erythromycin
Dihydralazine hydrochloride
Penicillin G
Cyanocobalamin
51.4
33.8
33.2
27.8
21.6
21.1
20.4
19.1
18.5
17.9
Data from Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs.
N Engl J Med 1994;331:1272–1285.
Drugs may produce upper or lower respiratory tract reactions,
including rhinitis and asthma. Respiratory tract manifestations may
result from direct injury to the airways or may occur as a component
of a systemic reaction (e.g., anaphylaxis). Asthma may be induced
by aspirin and other NSAIDs or by sulfites used as preservatives in
foods and medications. Other pulmonary drug reactions believed to
be immunologic include acute infiltrative and chronic fibrotic pulmonary reactions. The latter is often caused by antineoplastic agents
such as bleomycin. For a more detailed discussion of drug-induced
pulmonary disease, see eChapter 15.
Hematologic Reactions
Most formed elements and soluble components of the hematopoietic system may be affected by immunologic drug reactions.
Eosinophilia is a common manifestation of drug hypersensitivity and may be the only presenting sign. Hemolytic anemia may
result from hypersensitivity to drugs. Other hematologic reactions
include thrombocytopenia, granulocytopenia, and agranulocytosis. For a detailed discussion of hematologic drug reactions, see
eChapter 24.
FACTORS RELATED TO THE
OCCURRENCE OR SEVERITY OF
ALLERGIC DRUG REACTIONS
4 Among the factors that influence the likelihood of allergic
drug reactions are the degree to which the drug and its metabolites
bind covalently to human proteins, how the drug is metabolized,
whether the drug contains proteins of nonhuman origin (e.g., chimeric monoclonal antibodies, streptokinase) or antigenic excipients (e.g., peanut oil, FD&C dyes, sulfites, soybean emulsion), the
route of exposure, and the sensitivity of the individual as determined by genetics and environmental factors. Hypersensitivity can
occur with any dose of a drug, but sensitization is more likely to
occur with continuous dosing rather than single dosing. After a
patient has become sensitized, the severity of a reaction is often
determined by the dose and the duration of exposure. The route
of administration may also influence drug sensitivity. The topical
route of drug administration appears to be the most likely to sensitize and predispose to drug reactions. The oral route is the safest,
and the parenteral route is the most hazardous for administration
of drugs in sensitive individuals. Relatively few cases of immediate hypersensitivity-associated deaths with oral β-lactam antimicrobials have been reported.
The presence of genetically determined human leukocyte
antigen (HLA) alleles increases susceptibility to a number of drug
hypersensitivity syndromes. In patients infected with the human
immunodeficiency virus (HIV), hypersensitivity to abacavir has
been associated with the presence of HLA-B*5701.30 Severe
immune-mediated cutaneous reactions to allopurinol, including SJS
and TEN, have been associated with the presence of HLA-B*5801
in Han Chinese.31 In this same patient population, the presence of
HLA-B*1502 increases the risk of SJS and TEN with carbamazepine, phenytoin, and fosphenytion.32 Associations between HLA
alleles and drug reactivity have been described for aminopenicillins, aspirin, iodinated contrast media, gold, lamotrigine, and trimethoprim–sulfamethoxazole.33 Genetic factors can also influence
the metabolic deactivation of drugs via phase 1 and 2 metabolism.
For example, slow acetylators of procainamide and hydralazine are
at increased risk for SLE. Genes also encode for the type of T-cell
receptor and the specific cytokines involved in the signaling of allergic drug reactions.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
eTable 22-2
Respiratory Reactions
e|CHAPTER or even life-threatening reactions. Both SJS and TEN are classified as progressive bullous or “blistering” disorders that constitute
dermatologic emergencies.23 They are considered severe variants
of erythema multiforme. Similar to erythema multiforme, SJS and
TEN are associated with the widespread development of a variety
of skin lesions, including macules, purpuric lesions, and the target
iris lesion. The target lesion is discrete and round and identified by
an area of central clearing surrounded by two concentric rings of
edema and erythema. Unlike erythema multiforme, SJS and TEN
are most commonly drug induced rather than associated with recurrent herpes simplex viral infection, and they progress to include
mucous membrane erosion and epidermal detachment.23 Mucosal
membranes in the mouth, lips, nasal cavity, and conjunctivae are
usually involved. As these syndromes progress, the erythematous
lesions become more widespread on the face, trunk, and extremities, and many evolve into blisters. Within days after the onset of
the lesions, full-thickness epidermal detachment occurs. SJS and
TEN are often considered as a continuous spectrum of a disease,
with TEN being the most severe form. The extent of epidermal
detachment is used to distinguish between SJS and TEN (i.e.,
<10% detachment of body surface area with SJS; greater than 30%
detachment of body surface area with TEN). The term SJS-TEN
overlap is used to describe cases in which epidermal detachment
occurs on 10% to 30% of the body surface area.23,24 Both SJS and
TEN are associated with a number of long-term sequelae, including
permanent visual impairment, temporary nail loss, cutaneous scarring, and irregular pigmentation. Being the more severe form, TEN
is also more likely to be complicated by systemic organ involvement, including acute kidney failure, neutropenia, and respiratory
failure. A severity-of-illness scoring system known as SCORTEN
has been developed to predict prognosis in patients with TEN.25
SCORTEN uses seven independent risk factors based on an assessment within 24 hours of clinical presentation.
Cutaneous adverse reactions were reported to occur in 2.7%
of hospitalized patients.26 TEN is estimated to occur in 0.4 to 1.3
cases per 1 million people per year, and SJS has been reported in
1 to 6 cases per 1 million people per year.27,28 The mortality rates
associated with SJS and TEN range from 1% to 5% and 10% to
70%, respectively.28 eTable 22-2 lists drugs and agents associated
most commonly with cutaneous reactions.22 In general, antimicrobials are implicated most frequently as the cause of cutaneous
events with reaction rates ranging from 1% to 8%. The most likely
offenders of SJS and TEN, determined in case–control studies, are
the sulfonamides, particularly trimethoprim–sulfamethoxazole.29
Other major offenders of SJS and TEN identified in these studies are allopurinol, the aminopenicillins, carbamazepine, chlormezanone, cephalosporins, the imidazole antifungals, lamotrigine,
nevirapine, the oxicam NSAIDs, phenytoin, quinolones, and the
tetracyclines.29
336
SECTION
2
Drug allergies appear to develop with equal frequency in atopic
and nonatopic individuals. In addition, patients with a history of drug
allergy appear to be at increased risk for adverse reactions to other
pharmacologic agents.3 Age seems to be related to the risk of allergic reactions because they occur less frequently in children. This
may be related to immaturity of the immune system or decreased
exposure. The presence of some concurrent diseases, particularly
viral infections, predisposes to drug reactions. Examples include the
higher rate of morbilliform rash when ampicillin is administered to
patients with infectious mononucleosis, the higher rate of reactions
to trimethoprim–sulfamethoxazole in HIV-infected patients, and the
relationship between infection with human herpes virus 6 (HHV-6)
and the development of DRESS.
Organ-Specific Function Tests and Drug-Induced Diseases
eosinophilia, SJS, and exfoliative dermatitis. Cutaneous reactions
can occur in up to 4.4% of treatment courses of penicillin37 and in
up to 8% of those of aminopenicillins.38 The incidence of ampicillin
rash is close to 100% in patients with viral infections such as infectious mononucleosis.39
Some aspects of the mechanism of penicillin immunogenicity
have been determined. Because benzylpenicillin is a relatively small
molecule (356 Da), it must combine with macromolecules (presumably proteins) to elicit an immune response. Penicillin is rapidly
hydrolyzed to a number of reactive metabolites that have the ability
to covalently link to proteins. Of these metabolites, 95% is in the
form of benzylpenicilloyl that binds covalently to the lysine residues
of proteins such as albumin through an amide linkage involving the
β-lactam ring (eFig. 22-2). This penicilloyl–protein conjugate is
referred to as the major antigenic determinant. The other penicillin
metabolites such as penilloate and penicilloate bind in lesser quantities to proteins. These are referred to as minor antigenic determinants. The terms major and minor refer to the relative proportions
of these conjugates that are formed and not to the clinical severity
of the reactions generated. Immediate hypersensitivity reactions
may be mediated by IgE for both minor and major determinants. In
fact, the minor antigenic determinants are more likely to cause lifethreatening anaphylactic reactions.
In addition to the major and minor determinants, unique sidechain determinants may mediate allergy to some penicillins. Both
the aminopenicillins and piperacillin may cause hypersensitivity
reactions via unique side-chains on their structures.40,41 Therefore,
a patient may exhibit hypersensitivity to amoxicillin or piperacillin via a side chain determinant while exhibiting no reactivity to
other penicillins. Reports of selective allergy to amoxicillin have
become relatively common. The R-group side chain of amoxicillin is believed to be the primary epitope, but selective reactivity to
clavulanic acid has been postulated and explored in those experiencing a reaction to amoxicillin clavulanate.42–44 Careful history
taking is needed to identify patients with high likelihood of sidechain–specific reactions. Skin testing with dilute concentrations of
amoxicillin, ampicillin, and piperacillin has been used to aid in the
determination of side-chain–specific reactions.45–47
DRUGS COMMONLY CAUSING
ALLERGIC OR ALLERGIC-LIKE
DRUG REACTIONS
β-Lactam Antimicrobials
Allergy to β-lactam antibiotics is commonly reported by patients
in healthcare settings. Allergic reactions to penicillin occur in 0.7%
to 8% of treatment courses but was as high as 15% in one retrospective report of hospitalized patients treated with penicillin.34,35
Although most patients reporting penicillin allergy do not have
allergy, a reported history is associated with a higher likelihood of
positive skin test reactivity. Only 10% to 20% of patients reporting
penicillin allergy are found to be allergic by skin testing.10,36 Patients
with a history of immediate penicillin allergy who have a negative
penicillin skin test result are unlikely to react on subsequent courses
of penicillins.10,36
The most common reactions to penicillin include urticaria,
pruritus, and angioedema. All four of the major types of hypersensitivity reactions have been reported with penicillin, as well as
some reactions that do not fit into these categories. A wide variety of idiopathic reactions occur, such as maculopapular eruptions,
Benzylpenicillin
Benzylpenicillenic acid
95%
5%
NH2+
+
Benzylpenilloic acid
Benzylpenamaldic acid
Tissue protein
H
S
H
CH2
H
H
H
CO
NH
O
CH
C
CH
NH
CH3
CH3
C
CH
+
Tissue
protein
COOH
S
NH
S
Tissue
protein
Major determinant
Tissue
protein
S
H
S
H
CH2
H
H
CO
NH
CH
H
Minor determinant
eFIGURE 22-2 Formation of a benzylpenicilloyl hapten–protein complex.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
CH3
CH3
CH
C
N
CHCOO
337
Radiocontrast Media
6 Radiocontrast agents frequently cause reactions categorized as
immediate (in ≤1 hour) or nonimmediate (in 1–10 days) via both IgEmediated and non-IgE–mediated mechanisms.56 The frequency and
severity of these reactions are influenced by the type of radiocontrast
agent (ionic vs. nonionic), and patient-specific factors such as history of atopy, asthma, or prior reaction to a radiocontrast agent. Current reported estimates of the frequency of anaphylactoid reactions
with ionic and nonionic agents are 1% to 3% and less than 0.5%,
respectively.10,14 Delayed skin reactions, usually presenting as maculopapular exanthems, occur in 1% to 3% of patients over 5 to 7 days.56
Severe, immediate anaphylactic reactions occur in 0.01% to 0.04% of
patients.38 In addition, radiocontrast agents may cause dose-­dependent
toxic reactions that can produce renal impairment, cardiovascular
effects, and arrhythmias.57 The mechanism of reactions to radiocontrast agents is not clearly understood. Histamine release and mast cell
triggering have been documented in severe immediate reactions, suggesting an IgE-mediated mechanism.58 The older, high-osmolar radiocontrast agents can activate mast cells, basophils, and the complement
system directly (IgE-independent mechanism), resulting in the release
of inflammatory mediators. The delayed-onset maculopapular rash
appears to be T-cell mediated. The low-osmolar nonionic contrast
agents appear to cause fewer anaphylactoid reactions.
The risk of anaphylactoid reactions to radiocontrast media is
greater in women and in patients with a history of atopy or asthma.55
Other recognized risk factors include a history of previous reaction, severe drug allergies, cardiac disease, and treatment with
β-blockers.10,14 Despite a common misconception, seafood allergy or
iodine allergy does not predispose to radiocontrast media reactions.
Neither skin tests nor oral tests are useful for predicting reactions to
these agents.10,14 Although some regimens have been recommended
to prevent the recurrence of immediate events in patients who have
experienced reactions previously, the value of these preventive regimens has not been proven, and their use remains controversial.56,59
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
The actual risk of a cross-reaction between the penicillins and
the carbapenems appears to be much lower than originally described.
The initial estimate of the cross-reactive risk was 47.4%, but current
estimates range from 0.9% to 11%.49 The initial estimate was based
on the results of skin testing with penicillin and nonstandardized
carbapenem reagents. A number of retrospective studies reporting
variable rates of cross-reactivity relied on self-reported histories as
confirmation of penicillin allergy. Three recently published prospective studies used both skin testing methods and carbapenem challenge dosing to assess cross-reactive risk. In one of these studies,
only one of 112 patients with skin test–confirmed penicillin allergy
demonstrated a positive skin test result for imipenem.53 Challenge
dosing with imipenem to a final dose of 500 mg was subsequently
performed in 110 patients with negative imipenem skin test results;
none of the 110 patients had a reaction. Results of two additional
prospective studies, one of which was performed in children ages 3
to 14 years, suggest a low risk of cross-reactivity between penicillin
and meropenem.54,55 In both studies, only one patient with skin-test
positivity to penicillin had a positive skin test result for meropenem.
Graded challenge dosing with meropenem was tolerated in 100%
of the skin test–negative patients in both studies. It is important to
note that none of the skin test–negative patients were subsequently
treated with full therapeutic regimens of the carbapenem. However,
the high level of tolerability to challenge dosing suggests a low rate
of cross-reactivity in skin test–negative patients. Based on these
results, the routine practice of avoiding carbapenem use in patients
with history of penicillin allergy should be reconsidered.49
Of the monobactams, aztreonam only weakly cross-reacts with
penicillin and can be administered safely to most patients who are
penicillin allergic.10,49
e|CHAPTER Patients who are allergic to penicillins also may be sensitive to
other β-lactams.48,49 The exact incidence of cross-reactivity between
cephalosporins and penicillins is not known but is believed to be
low.10,47,48 The risk was originally reported as 10% to 15% in the
1970s when cephalosporins were contaminated with trace amounts of
penicillin. Current estimates of the cross-reactive risk between penicillin and the first- and second-generation cephalosporins are 5% to
7.5% and as low as 1% between penicillin and the third- and fourthgeneration cephalosporins.10 One percent to 8% of patients with
penicillin-specific IgE may develop an immediate-type hypersensitivity reaction to cephalosporins.50 In contrast, patients with reported
penicillin allergy and negative skin test results are at no greater risk.10
5 Ideally, cephalosporins should be avoided in patients
with history of an immediate hypersensitivity reaction to penicillin, although most studies suggest there is little risk of an allergic
response to a cephalosporin even in a person with a positive skin
test result to penicillin. Based on the results of one meta-­analysis,
patients with penicillin allergy have the highest risk of cross-­
reactivity with the first-generation cephalosporins (odds ratio
[OR], 4.79; 95% confidence interval [CI], 3.71–6.17).51 The odds
of reacting to a second- and third-generation cephalosporin were
1.13 (95% CI, 0.61–2.12) and 0.45 (95% CI, 0.18–1.13), respectively.51 The higher rate of cross-reactivity between penicillin and
the first-­generation cephalosporins has been attributed to similarities in the R1 side chains of these agents.10,47,48 The R1 side chain
is connected to the opened β-lactam ring, thereby influencing the
antigenicity of these agents. When assessing the potential for crossreactivity between penicillins and cephalosporins, clinicians should
evaluate the similarities in the R1 side chains of the agents.47,48,51,52
Beta-lactams having an R1 substitution chemically similar to that of
penicillin G are cephaloridine, cephalothin, and cefoxitin. In the R1
position, amoxicillin is chemically similar to ampicillin, cefaclor,
cephalexin, and cephradine. Cefotaxime, ceftizoxime, ceftriaxone,
cefpodoxime, and cefepime have chemically similar substitutions
in the R1 position that may influence the risk of cross-reactivity.52
Cephalosporins may induce immune responses mediated by
the core β-lactam structure; however, they are more likely to do so
via unique R-group side-chain determinants.48,51 In a patient with a
cephalosporin allergy, skin testing with the major and minor determinants of penicillin can be used to identify the likelihood of reactivity to the core β-lactam ring. The risk of cross-reactivity between
cephalosporins is considered to be higher than that between the
penicillins and cephalosporins. Cross-reactions may occur through
identical R1 side chains. Of note, ceftazidime shares a common side
chain with aztreonam.
338
SECTION
2
Organ-Specific Function Tests and Drug-Induced Diseases
A commonly recommended regimen in high-risk patients is oral
prednisone (50 mg) 13, 7, and 1 hours before exposure with 50 mg
of diphenhydramine given orally or intramuscularly 1 hour before
exposure to prevent immediate reactions.14 Ephedrine 25 mg orally
has also been recommended 1 hour before the radiocontrast study
as a component of the pretreatment regimen; however, ephedrine
should not be used if the patient has history of unstable angina,
hypertension, or arrhythmia.10,14 Other studies have examined
the use of H1- and H2-antihistamines, clemastine, or cimetidine,
respectively.10,14
Anaphylactoid reactions to gadolinium, a noniodinated contrast agent, have been reported at frequencies of 0.07% in adults and
0.04% in children.60 Most reactions have been mild, requiring either
no medical management or treatment with antihistamines. Moderate and severe reactions, although rare, have also been reported.
Pretreatment regimens similar to those used with iodinated contrast
studies are usually effective but have been associated with breakthrough reactions, particularly in patients with a history of reactions
to gadolinium or iodinated contrast agents.61
Insulin
Insulin is capable of producing allergic reactions through a variety
of immunologic mechanisms. A protein molecule, insulin is a complete antigen. Allergic reactions have been reported with beef, pork,
and recombinant human insulin, although the frequency of reactions
with human insulin appears low. Reactions to insulin may involve
the insulin molecule itself or other substances that have been added
to insulin (e.g., protamine). Most patients have anti-insulin IgG antibodies after a few months of therapy.
Insulin reactions may be limited to the site of injection, or they
may produce systemic reactions. Local reactions present most often
as a wheal and flare at the injection site and may occur immediately
after injection or up to 8 to 12 hours later. These reactions are generally mild, do not require treatment, and resolve with continued insulin administration. If a patient does not tolerate the local reaction
well, antihistamines may be given, or a different insulin source (or
product of higher purity) may be substituted. Rarely, systemic reactions to insulin (e.g., urticaria or anaphylaxis) occur. IgE-mediated
reactions to insulin allergy appear to be declining with greater use
of human insulins.62 Skin testing with various products can aid in
selecting the type of insulin least likely to cause a systemic reaction. Human insulin appears to be least allergenic but occasionally
may cause reactions. In some patients, insulin desensitization may
be indicated.
Aspirin and Nonsteroidal
Antiinflammatory Drugs
7 Aspirin and other NSAIDs can produce eight general types of
reactions, four of which are related to COX inhibition.63,64 These reactions can involve asthma and rhinitis, urticaria/angioedema, anaphylaxis and anaphylactoid reactions, aseptic meningitis, or pneumonitis.
The two most prevalent aspirin sensitivity reactions are respiratory
(asthma, rhinorrhea) and urticaria/angioedema. About 9% to 20% of
people with asthma are sensitive to aspirin and other NSAIDs.63,65
The rhinosinusitis/asthma syndrome typically develops in
middle-aged patients who are nonatopic and have no history of
aspirin intolerance. Women are 2.5 times more likely to develop
aspirin-induced asthma than men.66 It usually progresses from rhinitis to sinusitis with nasal polyps and steroid-dependent asthma.
It is uncommon in children and young adults. However, children
with asthma may be aspirin sensitive. Aspirin-sensitive asthma
appears to be an inherited disorder characterized by overexpression of LTC4 synthase in airways.67 In aspirin-sensitive people with
asthma, administration of aspirin and NSAIDs may provoke severe
and sometimes fatal asthmatic attacks. The mechanism of aspirin
sensitivity is not completely understood.
One suspected mechanism of aspirin and NSAID sensitivity is
COX-1 blockade, which may facilitate depletion of prostaglandin
E2 (PGE2) and production of alternative arachidonic acid metabolites (e.g., LTs).63 Whereas PGE2 prevents mast cell degranulation,
LTs cause bronchoconstriction and increased mucus production.
Increased LT production may also explain the development of
angioedema and urticaria. This proposed mechanism is supported
by the observed correlation between the degree of COX-1 blockade and the risk of a sensitivity reaction. Therefore, agents such as
acetaminophen, which minimally block COX-1, rarely cause reactions. Additional support is found in the clinical observation that LTmodifying drugs can reduce the severity of aspirin-induced asthma
and urticaria.63 It is also possible that aspirin and NSAIDs stimulate mast cells directly to release inflammatory mediators. Subjects
with aspirin-induced asthma also have a marked increase in airway
responsiveness to LTs. Aspirin and the COX-2–selective inhibitors
celecoxib and rofecoxib do not appear to be cross-reactive.68–70
In patients with aspirin sensitivity (asthma or urticaria), an oral
challenge or provocation test can be performed to diagnose the condition. A number of different protocols to detect aspirin or NSAID
sensitivity have been recommended, but the risk for anaphylaxis
cannot be reliably predicted.63,66 The challenge should be performed
with great caution in a hospital setting with resuscitation equipment at hand. For patients with aspirin-induced asthma, induction
of drug tolerance (desensitization) is recommended. A number of
aspirin desensitization protocols have been described, ranging from
2- to 4-day protocols for patients with history of asthma to rapid
(2- to 5-hour) protocols.10 Rapid desensitization protocols have been
limitedly studied, primarily in patients with history of cutaneous
reactions (urticaria or angioedema) who require aspirin for acute
coronary syndromes or before stent placement.71 Aspirin desensitization has been shown to improve asthma symptom scores and lead
to reductions in maintenance steroid doses. If desensitization is not
performed, patients with aspirin sensitivity must avoid aspirin and
the nonselective NSAIDs as the major preventive measure.
Aspirin and individual NSAIDs (e.g., ibuprofen, sulindac) can
also cause IgE-mediated hypersensitivity. These reactions occur on
reexposure to the drug and may present as urticaria, bronchospasm,
or anaphylaxis with or without hypotension. A careful and complete
allergy history may suggest true hypersensitivity to aspirin or an isolated NSAID. Such patients should be advised to avoid the specific
NSAID and any structurally similar NSAIDs (e.g., all propionic
acid derivatives, all indole acetic acid derivatives) because of the
risk of cross-reactivity.
NSAIDs have been associated with pulmonary infiltrates and
eosinophilia syndrome. Pulmonary infiltrates and eosinophilia
syndrome are associated with fever, cough, dyspnea, infiltrates on
chest radiography, and a peripheral eosinophilia that develops 2 to
6 weeks after initiating treatment. Pulmonary infiltrates and eosinophilia syndrome occurs more frequently for naproxen compared
with other NSAIDs and is noted to resolve rapidly after discontinuation of the offending agent.72
Sulfonamides
Sulfonamide drugs containing the sulfa (SO2NH2) moiety include
antibiotics, thiazide and loop diuretics, oral hypoglycemics, and carbonic anhydrase inhibitors. Allergic reactions have been reported
in 4.8% of 20,226 patients who received a sulfonamide antibiotic
and in 2% of patients who received a nonantibiotic sulfonamide.73
Although immediate IgE-mediated reactions such as anaphylaxis
can occur, sulfonamides typically cause delayed cutaneous reactions, often beginning with fever and then followed by a rash (e.g.,
maculopapular or morbilliform eruptions). Infrequently, a seemingly
Copyright © 2014 McGraw-Hill Education. All rights reserved.
339
Pharmaceutical products contain a number of “inert” additives (e.g.,
dyes, fillers, buffers, and stabilizers) in addition to the therapeutic
ingredients. These additives are not always inert and may cause
adverse effects, including allergic reactions.
The azo dye tartrazine (FD&C Yellow No. 5) is associated with
anaphylactoid reactions, acute bronchospasm, urticaria, rhinitis, and
contact dermatitis.80,81 Although the immunologic mechanisms are
unclear, about 10% of aspirin-sensitive people with asthma are also
intolerant to tartrazine,82 suggesting a role for tartrazine as a COX
inhibitor. As little as 0.85 mcg or as much as 25 mg tartrazine has
provoked positive responses.82
Sulfites (including sulfur dioxide, sodium sulfite, sodium and
potassium bisulfite, and sodium and potassium metabisulfite) are
Cancer Chemotherapy Agents
Chemotherapy agents are implicated in hypersensitivity reactions in
5% to 15% of patients who receive them.86 Up to 65% of patients
receiving l-asparaginase experience immediate hypersensitivity
reactions such as urticaria and anaphylaxis.87
The combination regimen of paclitaxel (or docetaxel) and
carboplatin is frequently responsible for producing hypersensitivity reactions. Each agent precipitates a distinct reaction, allowing for differentiation between causative factors. Hypersensitivity
or allergy-like reactions have been observed with paclitaxel and
docetaxel in as many as 34% of patients.1,88,89 The reaction typically
occurs within minutes after initiation of the first or second dose,
suggesting a non–IgE-mediated mechanism. Both the vehicles of
the taxanes (polyoxyethylated castor oil for paclitaxel; polysorbate
80 for docetaxel) and the taxanes themselves have been implicated
as the cause of the reactions. A cross-reactive risk of 90% (nine of
10 patients) between paclitaxel and docetaxel provides further evidence that the reaction is most likely attributed to the taxane moiety.90 Severe reactions are characterized by dyspnea, bronchospasm,
urticaria, and hypo- or hypertension. Minor reactions include flushing and rashes. In patients receiving a 3-hour infusion, the incidence
of severe reactions is reduced to 1.3%, and the incidence of minor
reactions is 42%.91 To reduce the risk of hypersensitivity reaction,
patients are routinely premedicated with corticosteroids and H1- and
H2-receptor antagonists. A protein-bound formulation of paclitaxel
(Abraxane®) devoid of the castor oil vehicle is available, avoiding
some but not all reactions.
Hypersensitivity to platinum-containing agents is delayed,
developing after six or more courses of carboplatin, cisplatin, or
oxaliplatin.92–95 The reaction rates differ depending on the platinum
agent with reported frequencies of 5% to 20% with cisplatin, 9% to
27% with carboplatin, and 10% to 19% with oxaliplatin.96 Reactions
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
Pharmaceutical Excipients
and Additives
used commonly as antioxidants in pharmaceutical products and
some foods. Many cases of adverse reactions associated with ingestion of sulfites (usually in foods) have been reported to the U.S.
Food and Drug Administration (FDA),83 including wheezing, dyspnea, chest tightness, urticaria, angioedema, flushing, weakness,
nausea, anaphylaxis, and death.
IgE-mediated and nonimmunologic sulfite hypersensitivity
has been demonstrated in children with a history of chronic asthma.
Adverse reactions to sulfite-preserved injectables, such as gentamicin, metoclopramide, lidocaine, and doxycycline, have been
reported. In contrast to reactions caused by foods, these reactions do
not occur more frequently in steroid-dependent people with asthma
and do not always coincide with a positive oral sulfite challenge.84
Blunted bronchodilation may be observed in individuals with
asthma after inhalation of sulfite-containing nebulizer solutions.
Although many nebulizer solutions contain sulfites, metered-dose
inhalers do not. Many aqueous epinephrine products also contain
sulfites. The FDA labeling states that in emergency situations when
sulfite-free preparations are not available, sulfite-containing epinephrine should not be withheld from a sulfite-intolerant individual
because small subcutaneous doses of sulfites usually are well tolerated. However, an increased risk of anaphylaxis exists after subcutaneous injection in rare patients with a positive oral challenge to
5 to 10 mg of sulfite.
Parabens (including methyl-, ethyl-, propyl-, and butylparaben) are used widely in pharmaceutical products as a biocidal agent.
Most allergic reactions to parabens are observed after topical exposure.85 Delayed hypersensitivity contact dermatitis occurs more
often in individuals with preexisting dermatitis.82 Immediate hypersensitivity after parenteral administration is rare. Although these
agents are chemically related to benzoic acid and p-aminobenzoic
acid, the evidence for cross-sensitivity is lacking.82
e|CHAPTER benign maculopapular rash may progress to a mucocutaneous syndrome (e.g., SJS or TEN).1 Other reactions to sulfonamides may
include hepatic, renal, or hematologic complications, which may
be fatal. Immune-mediated sulfonamide reactions depend on the
production of reactive metabolites in the liver.74 Trimethoprim–sulfamethoxazole, considered the most highly reactive sulfonamide,
contains an arylamine in the N4 position of its chemical structure,
allowing for the drug’s metabolism to two highly reactive metabolites, a hydroxylamine and a nitroso-sulfonamide.74,75 Structural differences between the sulfonamides antibiotics and nonantibiotics
may influence the metabolic conversion and resultant reactivity of
these compounds. Slow acetylator phenotype may also increase the
risk for these reactions.4
8 Cross-reactivity between sulfonamide antibiotics and nonantibiotics appears to be minimal, with cross-reactivity characterized as “highly unlikely.”76 In one study, about 10% of patients
with a history of allergy to an antibiotic sulfonamide subsequently
reacted to a nonantibiotic sulfonamide (e.g., acetazolamide, loop
diuretic, sulfonylurea, thiazide).73 This low rate of cross-reactivity
has been attributed in part to differences in the chemical structures
of the antibiotic and nonantibiotic sulfonamides. The occurrence
of allergic reactions after receipt of nonantibiotic sulfonamides
has also been attributed to a predisposition to allergic reactions in
the affected individuals rather than cross-reactivity with sulfonamide antibiotics.73 In fact, in one study, cross-reactivity between
sulfonamide antibiotics and penicillin was higher than that between
the antibiotic and nonantibiotic sulfonamides.73
Trimethoprim–sulfamethoxazole is used frequently for preventive or active treatment of Pneumocystis jiroveci pneumonia in patients
with AIDS. Adverse reactions to trimethoprim–sulfamethoxazole
occur much more frequently in HIV-positive patients.77,78 Adverse
effects to trimethoprim–sulfamethoxazole occur in 50% to 80% of
AIDS patients compared with 10% of other immunocompromised
patients.78 Trimethoprim–sulfamethoxazole was associated with
an adverse event rate of 26.3 per 100 person-years and hypersensitivity events at 22 per 100 person-years. Although reactions may
include angioedema, SJS, and thrombocytopenia, most reactions to
­trimethoprim–sulfamethoxazole in HIV-infected patients are delayed
and present as diffuse maculopapular rash with or without fever. The
mechanism by which these allergic or allergic-like reactions occur in
HIV-infected patients is unclear. It is unlikely that these reactions are
IgG or IgE mediated.75,79 Proposed mechanisms include alterations
in drug metabolism caused by glutathione deficiency, a direct toxic
or immunologic effect of the sulfonamide metabolites on body tissues, and increased expression of major histocompatibility complex
proteins with increased recognition of the drug antigen by CD4 and
CD8 cells.75,79 The adverse event rate has been related to higher CD4+
T-cell count greater than 20 cells/mm3 (>20 × 106/L), CD4-to-CD8
ratio less than 0.10, and treatment for fewer than 14 days.78
340
SECTION
2
typically develop shortly after completing the infusion or up to
3 days after therapy.92 Symptoms of severe reaction include tachycardia, dyspnea, facial swelling, rigors, and hypotension. Mild reactions include itching, erythema, and facial flushing. An association
between reactivity and the duration of the platinum-free interval has
been described for carboplatin.97 The risk of a severe reaction was
47% if the platinum-free interval was greater than 24 months versus only 6.5% within intervals less than 12 months.97 Management
strategies include decreasing the rate of infusion and administration
of corticosteroids and H1 and H2 receptor antagonists.95 Skin testing
with carboplatin has been described.93,96 Desensitization to carboplatin93,94 and oxaliplatin98,99 has been shown to be well tolerated.
Anticonvulsants
Organ-Specific Function Tests and Drug-Induced Diseases
Many anticonvulsant drugs produce a variety of hypersensitivity
reactions and pseudoallergic reactions. Drugs such as phenytoin,
phenobarbital, carbamazepine, and lamotrigine can cause an “anticonvulsant hypersensitivity syndrome” characterized by fever, rash,
lymphadenopathy, and internal organ involvement. Eosinophilia
is frequently present and many reactions meet the definition of
DRESS. The onset usually occurs several weeks into therapy.100 In
some cases, morbilliform rash develops into exfoliative dermatitis.
The risk of cross-reactivity between the aromatic anticonvulsants
(e.g., carbamazepine, phenobarbital, and phenytoin) ranges from
40% to 80%.100 Oxcarbazepine, the 10-keto derivative of carbamazepine, has exhibited both in vitro and in vivo cross-reactivity with
carbamazepine. A genetic marker for severe reactions to carbamazepine, phenytoin, and fosphenytoin is the presence of the HLAB*1502 allele.32 This allele is found in 10% to 15% of patients from
China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan. Concomitant use of valproate with lamotrigine significantly
increases the risk of hypersensitivity as a result of reduced lamotrigine metabolism, leading to a prolonged elimination half-life.101
Biologics
Biologic agents (e.g., monoclonal antibodies, fusion proteins,
recombinant proteins) are derived from living sources such as
yeast, bacteria, animal cells, or mammalian cells.102 Unlike nonbiologic agents, these large proteins can serve as complete antigens.
Examples include recombinant insulin, erythropoietin, interferon-β,
human growth hormone, infliximab, cetuximab, rituximab, and
omalizumab. Immunologic reactions to these agents range from
minor infusion or injection-site reactions to anaphylaxis. Depending
on the agent, reactions can occur on first or subsequent exposure,
and the timing may be within 4 hours of drug administration or up
to 14 days after an infusion.102
Factors influencing the antigenicity of biologic agents are
patient specific (e.g., atopy, congenital protein deficiency), production related (e.g., presence of contaminants or stabilizing agents,
degree of protein glycosylation, presence of nonhuman protein
sequences, storage temperature), and administration related (e.g.,
route of administration, frequency of use, concurrent inmmunosuppressant use).102 Of the monoclonal antibodies, reactions are most
frequently observed with the murine-derived agents (0% human) and
chimeric agents (75% human) as opposed to the humanized (>90%
human) and human (100% human) agents. Some immune reactions
to biologic agents result from the development of neutralizing antibodies that can prevent the protein from exerting its intended effect.
Neutralizing antibodies have been shown to mediate reactions to
interferon-β1b and β1a, infliximab, natalizumab, recombinant factor VIII, and recombinant factor IX.102 Anti-infliximab antibodies,
which occur in up to 60% of treated patients, are associated with
higher frequency of infusion reactions and decreased therapeutic
effect.103 Concomitant administration of immunosuppressive agents
such as prednisone or low-dose methotrexate has been shown to
decrease the incidence of antibody formation to infliximab.102,103
Delayed onset anaphylaxis, ranging from minutes to days
postinjection, has been reported with omalizumab, a humanized
monoclonal antibody targeted against IgE.104,105 Omalizumabtreated patients require observation for 2 hours after the first 3 injections and for 30 minutes after subsequent injections.105 Patients are
advised to carry an epinephrine autoinjector during and for 24 hours
after drug administration.104,105 Risk factors for this adverse event
have not been identified. Inclusion of polysorbate 80 as a stabilizing agent in the formulation, and an alteration in the protein
sequence via glycosylation, may influence the immunogenicity of
omalizumab.105
Management of allergic or allergic-like reactions to biologic
agents varies based on the culprit agent and the severity and nature
of the reaction. Immediate management with epinephrine and
permanent discontinuation of the drug may be warranted (e.g.,
omalizumab-induced anaphylaxis). Depending on the biologic
­
agent, reactions may be managed by decreasing the infusion rate
or lessened by pretreating with antihistamines or corticosteroids
or administering concomitant steroid therapy. Desensitization protocols for infliximab,96,106 cetuximab,107 rituximab,96,106 and transtuzumab96,106 have also been described.
TREATMENT
9 The basic principles for management of allergic reactions to drugs
or biologic agents include (a) discontinuation of the medication or
agent when possible; (b) treatment of the adverse clinical signs and
symptoms; and (c) substitution, if necessary, of another agent.104
Anaphylaxis
Anaphylaxis requires prompt treatment to minimize the risk of
serious morbidity or death. On presentation, attention should
be given first to stopping the likely offending agent, if possible,
and restoring respiratory and cardiovascular function. A protocol developed by the Joint Task Force on Practice Parameters for
Allergy and Immunology for treatment of anaphylaxis is presented
in eTable 22-3.14 Epinephrine is the drug of first choice, although
it is underused and often dosed suboptimally for this indication.108
It should be administered as primary treatment to counteract
bronchoconstriction and peripheral vasodilation leading to hypotension.14,108 At recommended doses, epinephrine also enhances
coronary blood flow. The recommended administration technique
is intramuscularly in the lateral aspect of the thigh.14,109 If blood
pressure is not restored by epinephrine, crystalloid IV fluids should
be administered to restore intravascular volume. Typically, 1 L of
0.9% sodium chloride is administered over 5 to 10 minutes. This
can be repeated if the patient is still believed to be volume depleted.
A maintenance IV fluid then is initiated. IV fluids should be given
early in the course of treatment in an attempt to prevent shock. An
immediate priority is to establish and maintain an airway by the
use of endotracheal intubation if necessary. When a patient with
anaphylaxis is hypotensive, vasopressors may be needed in addition to crystalloids. Norepinephrine is the vasoconstrictor agent
of choice for treatment of anaphylactic shock, although dopamine
also may be useful. Patients in shock should remain supine with
raised legs.14
Other agents may be required for treatment of anaphylactic
reactions. Corticosteroids (hydrocortisone sodium succinate IV)
should never be given in place of or before epinephrine.14 Their
onset of action is delayed, and their role is to reduce the risk of
late-phase “biphasic” reactions. In patients treated chronically with
Copyright © 2014 McGraw-Hill Education. All rights reserved.
341
eTable 22-3
Treatment of Anaphylaxis
Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management
of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:
480.e1–e42.
β-blockers, glucagon should be considered because its inotropic
and chronotropic effects do not rely on β-receptor responsiveness.14
Histamine (H1) receptor blockers (e.g., diphenhydramine) can be
administered to reduce some of the symptoms associated with anaphylaxis, but these agents are not effective as primary therapy. The
combination of diphenhydramine and an H2 receptor blocker (e.g.,
ranitidine) has been shown to be superior to diphenhydramine alone
in the treatment of anaphylaxis.14 Intraosseous access should be
considered for adult and pediatric patients in whom attempts at IV
access are unsuccessful.14
Skin Testing and Drug
Provocation Testing
10 Identification of patients at high risk for allergic drug reactions requires careful history taking with attention to the specific
agent to which the patient reacted, a complete description of the
reaction, and the time since last exposure to the culprit drug. The
importance of accurate and complete history taking cannot be
overstated. Although skin and oral provocation testing are used to
assess reactive risk to some drugs, many of the testing procedures
have not been validated. A drug provocation test (DPT) involves
the controlled administration of a drug for the purpose of diagnosing an immune response. DPTs can be used to evaluate sensitivity to aspirin.110 When available, skin testing should be performed
before a DPT because of the lesser risks incurred to the patient. For
some drugs, skin testing can reliably demonstrate the presence of
drug-specific IgE and predict a relatively high risk of immediate
Induction of Drug Tolerance
and Desensitization
11 For some patients with history of an immediate reaction to a
drug, no reasonable alternatives exist, and the inciting drug or a
related compound may be necessary for treatment of an underlying condition (e.g., infection). In this situation, the temporary
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
IM, intramuscular.
e|CHAPTER   1. Place patient in recumbent position and elevate lower extremities.
  2. Monitor vital signs frequently (every 2–5 minutes) and stay with
the patient.
  3. Administer epinephrine 1:1,000 into nonoccluded site (adults:
0.01 [mg] mL/kg up to a maximum of 0.2–0.5 [mg] mL every
5 to 10 minutes as needed, children: 0.01 [mg] mL/kg up to a
maximum dose of 0.3 [mg] mL) IM in the lateral aspect of the thigh
or subcutaneously. If deemed necessary, the 5-minute interval
between injections can be liberalized.
  4. Administer oxygen, usually 8–10 L/min; however, lower concentrations
may be appropriate for patients with chronic obstructive pulmonary
disease. Maintain airway with oropharyngeal airway device.
  5. Consider the antihistamine diphenhydramine (adults 25–50 mg;
children 1 mg/kg, up to 50 mg) IM or by slow IV infusion.
  6. Consider ranitidine 50 mg in adults and 12.5 to 50 mg (1 mg/kg) in
children. The dose may be diluted in 5% dextrose in water to a volume
of 20 mL and injected over 5 minutes.
  7. Treat hypotension with IV fluids or colloid replacement and consider
use of a vasopressor such as dopamine. In adults, 1–2 L of 0.9%
saline solution given at a rate of 5–10 mL/kg may be needed in
the first 5–10 minutes. Children should receive up to 30 mL/kg
in the first hour.
  8. Consider inhaled β-agonists (albuterol) metered-dose inhaler
two to six puffs or nebulized 2.5–5 mg in 3 mL saline; repeat as
necessary for bronchospasm resistant to epinephrine.
  9. Consider hydrocortisone, 5 mg/kg, or approximately 250 mg IV
(prednisone 20 mg orally can be given in mild cases) to reduce the risk
of recurring or protracted anaphylaxis. These doses can be repeated
every 6 hours as required.
10. In cases of refractory bronchospasm or hypotension not responding
to epinephrine because a β-adrenergic blocker is complicating
management, glucagon 1–5 mg IV (20–30 mcg/kg; maximum, 1 mg in
children) given IV over 5 minutes may be useful. A continuous infusion
of glucagon, 5–15 mcg/min may be given if required.
11. Consider intraosseous access for either adults or children if attempts
at IV access are unsuccessful.
hypersensitivity reactions. Reliable skin test reagents are not available for most culprit drugs. Moreover, skin testing should not be
performed in patients with history of severe mucocutaneous reactions (e.g., SJS, TEN) or other nonimmediate reactions (e.g., serum
sickness, vasculitis, hepatitis).
10 Skin testing can reduce the uncertainty of penicillin sensitivity and should be performed in all patients who have a history of an immediate allergy and require treatment with a β-lactam
antibiotic. Penicillin skin testing in advance of need for penicillin
treatment in patients with a history of penicillin allergy does not
appear to induce sensitization.111 Testing for the major penicillin
determinant is accomplished with penicilloyl-polylysine (PPL;
Pre-Pen), a product recently reintroduced in the United States.
Ideally, skin testing should be performed with both the major and
minor determinants. Of the minor determinants, only penicillin G
is commercially available in the United States, and it should be
used at a concentration of 10,000 units/mL with PPL in skin testing.10 If left in solution to “age,” penicillin G will not spontaneously
degrade to form the other minor determinants, penilloate and penicilloate.10 Similar reaction rates to oral penicillin challenges have
been shown in patients with skin test negativity to PPL plus penicillin G compared with those with skin test negativity to the full set
of major and minor determinants.10,36 Skin testing with the major
and minor determinants has been shown to facilitate the safe use
of penicillin in up to 90% of patients with a history of immediate
penicillin allergy.112 Fewer than 1% of patients with a negative history and up to 72% of patients with a convincing positive history
of penicillin allergy have skin test positive reactivity.113 In patients
who report a history of penicillin allergy but are skin test negative, the risk of resensitization (i.e., conversion to a positive skin
test result) after a course of penicillin ranges from 1% to 28%.48
The procedure for performing penicillin skin testing is given in
eTable 22-4. In Europe, skin testing can be accomplished with a kit
containing both the major and minor determinant mixture (Diater
Labs, Madrid, Spain).96
A negative penicillin skin test result indicates that the risk of
life-threatening immediate reactions is extremely low with administration of penicillin or other β-lactams. Such patients are candidates for treatment with full therapeutic doses of a penicillin or a
related β-lactam. Certain types of patients (e.g., those with dermatographism, taking antihistamines) may be unsuitable for skin
testing because a false-positive or false-negative test may result.
To prevent interference with skin testing, antihistamines should be
discontinued at least 1 week before skin testing. Penicillin is the
only drug for which the predictive value of skin testing has been
well established. Although the negative predictive value is high,
penicillin skin testing with the major and minor determinants does
not identify patients who are at risk for unique side chain–mediated
reactions to β-lactams (e.g., third-generation cephalosporins, piperacillin). Dilute concentrations of amoxicillin and piperacillin have
been used to skin test for side chain–mediated reactions.45–47 The
value of skin testing to predict the risk of allergic reactions to other
antibiotics (e.g., sulfonamides, tetracyclines, fluoroquinolones) is
largely unknown.
Skin testing is used to identify patients at risk for hypersensitivity reactions to carboplatin. The negative predictive value of intradermal skin testing with carboplatin has been shown to be 98% to
99% in patients who have received a number of treatment courses.93
342
eTable 22-4
Procedure for Performing Penicillin
Skin Testing
A. Percutaneous (Prick) Skin Testing (Using a 22- to 28-Gauge Needle)
SECTION
Materials
Volume
Pre-Pen 6 × 106 M
Penicillin G 10,000 units/mL
β-Lactam drug (amoxicillin) 2 mg/mL
Saline control
Histamine control (1 mg/mL)
1 drop
1 drop
1 drop
1 drop
1 drop
1. Place a drop of each test material on the volar surface of the forearm.
2. Prick the skin with the needle to make a single shallow puncture of the
epidermis through the drop.
3. Interpret skin responses during the next 15 minutes. Observe for
a wheal or erythema and the occurrence of itching.
4. A wheal in diameter of 5 mm or greater surrounding the puncture site
is considered a positive test result.
5. Wipe off the solution near the puncture site.
6. If the prick test result is negative or equivocal (wheal <5 mm in
diameter with no itching or erythema), proceed to the intradermal test.
7. If the histamine control is nonreactive, the test is considered
uninterpretable. Ensure no interference by antihistamines.
2
Organ-Specific Function Tests and Drug-Induced Diseases
B. Intradermal Skin Testinga
Materials
Volume
Pre-Pen 6 × 106 M
Penicillin G 10,000 units/mL
β-Lactam drug (amoxicillin) 2 mg/mL
Saline control
Histamine control (0.1 mg/mL)
0.02 mL
0.02 mL
0.02 mL
0.02 mL
0.02 mL
1. Inject 0.02–0.03 mL of Pre-Pen intradermally (amount sufficient to
produce a small bleb of approximately 3 mm in diameter) in duplicate
at least 2 cm apart.
2. Inject 0.02–0.03 mL of the other materials at least 5 cm from the
Pre-Pen sites.
3. Interpret skin responses after 20 minutes.
4. Itching or a significant increase in the size of the original bleb to at least
5 cm is considered a positive result. An ambiguous response is a wheal
only slightly larger than the original bleb or discordance between the
duplicates. The control site should show no increase in the original bleb.
5. If the histamine control is nonreactive, the test is considered
uninterpretable. Antihistamines may blunt the response and cause
false-negative results.
Using a 0.5- to 1-cc syringe with a 3/8- to 5/8-inch long, 26- to 30-gauge shortbevel needle
a
Pre-Pen (benzylpenicilloyl polylysine injection, solution) Product Information, AllerQuest
LLC and ALK-Abello, Inc., Round Rock TX, 2009.
induction of drug tolerance is indicated. In the past, the term
“desensitization” was used to describe the procedure of temporarily acquiring drug tolerance, whether the underlying mechanism of intolerance was immunologically mediated or not.
Experts in drug allergy currently recommend that the phrase
eTable 22-5
“induction of drug tolerance” be used in place of “desensitization” to globally describe procedures used to modify a patient’s
response to a drug and temporarily allow safe drug therapy.10
Induction of drug tolerance can involve a variety of drug mechanisms, including IgE-mediated immune mechanisms, non-IgE
mechanisms, pharmacologic mechanisms, and undefined mechanisms (eTable 22-5).10 Regardless of the underlying mechanism,
all procedures used to induce drug tolerance involve a stepwise
process of incremental dosing of the inciting drug or a related
compound. Desensitization, a form of inducing drug tolerance
specifically refers to the process in which the mast cells are rendered less responsive to degranulation. This term should be used
when the underlying mechanism of drug intolerance is believed
to be IgE mediated (i.e., anaphylaxis to penicillin).10 Immediate
reactions most amenable to desensitization include dermatologic
(e.g., flushing, pruritus, urticaria, angioedema), upper and lower
respiratory tract (e.g., sneezing, dyspnea, wheezing), gastrointestinal (e.g., abdominal pain, nausea and vomiting), and cardiovascular (e.g., hypotension).96 Procedures to induce drug tolerance
should not be used in patients with history of severe non-IgE reactions to a drug such as DRESS, SJS, TEN, exfoliative dermatitis,
hemolytic anemia, or hepatitis.
All procedures to induce drug tolerance should be performed
by a physician experienced in the risks and management of severe
allergic reactions in a hospital setting with resuscitation equipment
available. The potential risks and benefits should be discussed
with the patient. The procedures differ in starting dose, number
of steps in the dosing process, and frequency of drug dosing. The
specific procedure should be chosen based on an analysis of the
patient’s history of the reaction and with consideration to the specific inciting drug and the suspected underlying mechanism of
drug intolerance (i.e., IgE mechanism versus non-IgE mechanism
vs. pharmacologic mechanism). The starting dose for a desensitization procedure is typically one in 10,000 of the final therapeutic
dose and the procedure can be completed within 4 to 12 hours.10,36
A rapid 12-step desensitization protocol has been described and
tested in patients with both IgE- and non–IgE-mediated reactions
to antibiotics, platinum-containing chemotherapeutic agents, taxane chemotherapy agents, and monoclonal antibodies.94,96 The
12-step method starts with a 1:1,000 dilution of the final dose
of the inciting drug. Incrementally increased doses are administered every 15 minutes using three-10-fold diluted solutions.
This method has been tested in nearly 800 patients, including
patients with cystic fibrosis and allergy to antibiotics.96 In highrisk patients, desensitization is achieved with either a 16- or a
20-step protocol.94,96
In the case of penicillin or β-lactam allergy, desensitization
should be performed with the specific β-lactam antibiotic that will
Characteristics of Drug Intolerance Protocols
Underlying
Mechanism
Initial Dose
Duration
of Protocol
Duration of
Induced Tolerance
Immunologic IgE
(desensitization)
Micrograms
Hours
Example
Desensitization; render mast cells
less responsive to degranulation
Temporary
β-Lactam antibiotics; taxanes
Immunologic non-IgE
Milligrams
Hours to days (e.g.,
6 hours to 10 days)
Not known
Temporary
Delayed cutaneous
reactions to trimethoprim–
sulfamethoxazole in HIVinfected individuals
Pharmacologic
Milligrams
Hours to days (e.g.,
2 hours to 5 days)
Cautious induction of a
reaction followed by a shift in a
metabolic process
Temporary
Aspirin
Undefined
Micrograms to
milligrams
Prolonged; days
to weeks
Not known
Temporary
Isolated cutaneous reactions
to allopurinol
Potential Outcome of Process
Adapted from Solensky R, Khan DA. Drug allergy: an updated practice parameter. Annals Allergy Asthma Immunol 2010;105:273.e-273.e78.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
343
eTable 22-6
Protocol for Oral Desensitization
eTable 22-7
Phenoxymethyl Penicillin
Stepa
Concentration
(units/mL)
15
16
17
18
500,000
500,000
500,000
500,000
0.1
100
0.2
200
0.4
400
0.8
800
1.6
1,600
3.2
3,200
6.4
6,400
1.2
12,000
2.4
24,000
4.8
48,000
1.0
80,000
2.0
160,000
4.0
320,000
8.0
640,000
Observe for 30 min
0.25
125,000
0.5
250,000
1.0
500,000
2.25
1,125,000
Preparation of Solutions
Cumulative
Dose (units)
100
300
700
1,500
3,100
6,300
12,700
24,700
48,700
96,700
176,700
336,700
656,700
1,296,700
Solution 1
Solution 2
Solution 3
Total to
be Injected
in Each Bottle
Final
Concentration
(mg/mL)
250 mL
250 mL
250 mL
10 mg
100 mg
1000 mg
0.04
0.4
4
Induction of Drug Tolerance Protocol
Step
1
2
3
4
5
6
7
8
9
10
11
12
The interval between steps is 15 min.
a
Reprinted from Immunol Allerg Clin North, Vol. 18, Weiss ME, Adkinson NF, Diagnostic
Testing for Drug Hypersensitivity, Immunol Allerg Clin North, 731–734, Copyright ©
1998, with permission from Elsevier.
Volume of
Diluents (e.g.,
0.9% NSS)
Solution
Rate
(mL/h)
Time
(min)
Administered
Dose (mg)
Cumulative
Dose (mg)
1
1
1
1
2
2
2
2
3
3
3
3
2
5
10
20
5
10
20
40
10
20
40
75
15
15
15
15
15
15
15
15
15
15
15
184.4
0.02
0.05
0.1
0.2
0.5
1
2
4
10
20
40
922.13
0.02
0.07
0.17
0.37
0.87
1.87
3.87
7.87
17.87
37.87
77.87
1000
NSS, normal saline solution.
Full dose equals 1,000 mg. Total time was 349.4 minutes.
a
Reprinted from Solensky R, Khan DA. Drug allergy: an updated practice parameter.
Annals Allergy Asthma Immunol 2010;105:273.e-273.e78
be administered for treatment of the patient’s infection. Before
initiating the protocol, the patient should be stabilized and fluid,
pulmonary, and cardiovascular function optimized. Premedications (antihistamines or corticosteroids) have not been routinely
advised because these agents may mask the early signs of acute
reactions and do not reliably reduce the severity of acute reactions. However, some recently described desensitization regimens
include premedication with single doses of diphenhydramine
and famotidine. About one third of patients who have undergone
desensitization to a penicillin will experience mild, transient allergic reactions either during the desensitization procedure or during
penicillin therapy.34 Patients who can take oral medication should
undergo desensitization with oral drug. After the desensitization
protocol is begun, it should not be interrupted except for severe
reactions. Antihistamines or epinephrine can be administered to
treat reactions. In addition, if the patient completes the desensitization regimen and then undergoes full-dose treatment, a lapse
between doses of as few as 24 hours can allow for reemergence
of sensitivity. Protocols for oral penicillin and IV cephalosporin
desensitization are listed in eTables 22-6 and 22-7, respectively.
Protocols for desensitization with other β-lactam antibiotics are
also available.114,115
Most reactions to trimethoprim–sulfamethoxazole in HIVinfected patients are considered to be non–IgE-mediated, and
a number of protocols to induce tolerance to trimethoprim–­
sulfamethoxazole have been described. These regimens have
not been compared in controlled clinical trials; thus, there is no
preferred regimen. Tolerance to trimethoprim–sulfamethoxazole
can be achieved within 2 days in most HIV-infected patients.1,116
This can be accomplished by using the following schedule of oral
doses (milligrams of sulfamethoxazole–trimethoprim): day 1:
9 am, 4 and 0.8 mg; 11 am, 8 and 1.6 mg; 1 pm, 20 and 4 mg; 5 pm,
40 and 8 mg; day 2: 9 am, 80 and 16 mg; 3 pm, 160 and 32 mg; 9 pm,
200 and 40 mg; day 3: 9 am, 400 and 80 mg, and 400 and 80 mg
daily thereafter. With this regimen, the failure rate was associated
with higher relative and absolute CD4 cell counts. Other investigators have described a 6-hour oral regimen in HIV-infected
patients117 and a more gradual 9-day oral regimen.118 Induction of
drug tolerance should not be attempted in any patient with history
of an exfoliative reaction to trimethoprim–sulfamethoxazole.
Both rapid (over less than 4 hours) and traditional desensitization protocols are available for aspirin and clopidogrel.71,119 Aspirin
desensitization is more effective in patients with history of aspirininduced asthma as compared with those with angioedema/urticarial
presentation.66
Graded Challenge
Also known as test dosing, a graded drug challenge involves the
cautious introduction of a drug when the risk of a reaction is deemed
to be low. A graded drug challenge is an alternative to the induction
of drug tolerance, and it does not modify the immune or nonimmune response to the drug.10,114 Instead, graded challenge is used
when the risk of a severe reaction to a drug on reexposure is low,
no alternative drug is equally effective, and a reliable skin testing
method is not available. A classic example is the slow introduction
of a cephalosporin in a patient with a history of reacting to another
cephalosporin with a dissimilar R1 side chain.114 Graded challenge
protocols have been described for the slow introduction of furosemide in a patient with heart failure and history of sulfonamide
allergy.120,121 Challenge dosing is not recommended when there is
history of a severe drug allergy (e.g., anaphylaxis, SJS, TEN). Premedications should not be used because they may mask signs of
an early breakthrough allergic reaction. Compared with drug tolerance procedures, graded challenges involve higher starting doses
and fewer steps in the dosing process. The starting dose is typically
1/10th to 1/100th of the final treatment dose, and the oral route of
drug administration is preferred to limit the risk of a severe reaction.114 If no reaction occurs to the initial dose, the dose may be
increased in two- to fivefold increments and administered every
30 to 60 minutes until the full therapeutic dose is achieved.47,114
There is no standard protocol for graded challenge dosing; a
therapeutic dose may be achieved over a matter of hours or days.
Because of the risk of breakthrough allergic reactions, graded challenges should be performed in monitored settings.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
22
Allergic and Pseudoallergic Drug Reactions
1,000
1,000
1,000
1,000
1,000
1,000
1,000
10,000
10,000
10,000
80,000
80,000
80,000
80,000
Dose
(units)
e|CHAPTER 1
2
3
4
5
6
7
8
9
10
11
12
13
14
Volume (mL)
Induction of Drug Tolerance Protocol for
IV Cephalosporina
344
ABBREVIATIONS
SECTION
2
APC
antigen-presenting cell
DRESS drug rash with eosinophilia and systemic symptoms
HLA
human leukocyte antigen
IgE
immunoglobulin E
LTleukotriene
NSAID nonsteroidal antiinflammatory drug
PAF
platelet-activating factor
PGprostaglandin
PPD
purified protein derivative
SJS
Stevens Johnson syndrome
SLE
systemic lupus erythematosus
TEN
toxic epidermal necrolysis
Organ-Specific Function Tests and Drug-Induced Diseases
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