The latter response is described as an anaphylactoid reaction because it resembles
true anaphylaxis, but it does not involve IgE-antibody formation.
potentially severe reactions needs to be considered when prescribing agents known
to be associated with anaphylactoid reactions. For example, the prophylactic use of
antibiotics such as ciprofloxacin to prevent meningococcal infections during an
outbreak was associated with a relatively high rate (1:1,000) of serious
92 This would be of potentially greater importance in the
setting of a mass prophylaxis program to combat exposure to anthrax. Unlike true
allergic reactions, which require an induction period during which a patient becomes
sensitized to an antigen, pseudoallergic reactions can occur on the first exposure to a
drug. The development of pseudoallergic reactions can be dose related, manifesting
when large doses of the drug are administered, when the dose is increased, or when
the rate of IV administration is increased.
C.C. has experienced a common pseudoallergic reaction to vancomycin, usually
referred to as the “red man syndrome” or “red neck syndrome,” which primarily
occurs when large doses of vancomycin are administered rapidly. Differentiating
between a true allergic response and a pseudoallergic response can be difficult
because the signs and symptoms can be indistinguishable. For example, each of the
symptoms experienced by C.C. (flushing, tachycardia, pruritus, and hypotension) is
caused by histamine release and can occur during an anaphylactic episode (see Case
32-2, Question 2). To conclusively determine the cause of the reaction would require
immunologic testing for antibodies to the suspect drug or agent, which is not always
possible or practical. In this case, C.C. had uneventfully received vancomycin
previously and has tolerated five doses during this hospitalization; therefore, it is
unlikely that the reaction is immunologically mediated (i.e., a true allergic reaction).
Furthermore, the reaction occurred after an increase in his vancomycin dose, which
further supports the diagnosis of a pseudoallergic reaction.
CASE 32-6, QUESTION 2: Why did vancomycin cause a pseudoallergic reaction in C.C.?
Pseudoallergic reactions from vancomycin occur because of a drug-induced
formation. Several other drugs (e.g., deferoxamine, opiates, pentamidine,
phytonadione protamine, radiocontrast media) are known to directly stimulate
Some drugs (e.g., radiocontrast media and protamine) cause pseudoallergic
reactions via both complement activation and direct-histamine release mechanisms.
Furthermore, some drugs (e.g., vancomycin, quaternary ammonium muscle relaxants,
and ciprofloxacin) can cause both true allergic reactions and pseudoallergic
Hypersensitivity Reactions to Drugs: Pseudoallergic Reactions
Frequency Highly variable, depending on the agent involved. For example, up to 30% of
patients taking aspirin exhibit a cutaneous pseudoallergic response. On the
other hand, pseudoallergic reactions to other agents, such as phytonadione and
clinicalsyndrome indistinguishable from anaphylaxis. Commonly require a
higher drug dose to elicit the response than a true IgE-mediated reaction. May
arise less quickly (>15 minutes after exposure) than true allergic reaction.
Diagnostic workup Skin tests and identification of specific antibodies are negative.
Treatment Pseudoallergic reactions are treated the same as true allergic reactions (i.e.,
according to the clinical presentations of the patient). Thus, some reactions
simply may require removal of the suspect agent, whereas some anaphylactoid
reactions may require aggressive therapy (e.g., epinephrine, antihistamines,
Prognosis As with true allergic reactions, patients who have experienced a
pseudoallergic drug reaction may have a similar reaction on reexposure. The
severity of response may lessen, however, with repeated administration.
Furthermore, for some drugs, the frequency and severity of the reaction also
may be influenced by the dose or rate of intravenous administration.
Pretreatment regimens to reduce the frequency and the severity of responses
have been developed for some drugs well known to cause pseudoallergic
reactions (e.g., radiocontrast media).
symptoms). Med Clin North Am. 2010;94:853.
CASE 32-6, QUESTION 3: How should C.C.’s pseudoallergic reaction be treated? Does treatment of
pseudoallergic reactions differ from that of true allergic reactions?
The first step in treating C.C.’s reaction is to eliminate the underlying cause. Thus,
his vancomycin infusion should be held until the reaction resolves. Because the
reaction is histamine-mediated, administration of an antihistamine such as
diphenhydramine 50 mg IV is warranted. Observation of his BP and heart rate is
mandatory. Intravenous fluids should be administered if his BP continues to fall or
fails to stabilize. Patients with allergic reactions should be treated based on their
clinical signs and symptoms, regardless of the mechanism behind the reaction. Thus,
for all intents and purposes, pseudoallergic reactions are treated in the same manner
CASE 32-6, QUESTION 4: Can C.C. continue to receive vancomycin? How can future reactions be
It is not necessary to discontinue vancomycin therapy in C.C. This reaction can be
prevented by administering smaller doses of the drug more frequently (e.g., 1,000 mg
every 8 hours rather than 1,500 mg every 12 hours) or infusing the dose for a longer
interval, typically 2 hours. Alternatively, pretreatment with an antihistamine 1 hour
before vancomycin administration is effective. In addition, tachyphylaxis to
vancomycin-induced red man syndrome is independent of pretreatment with
antihistamine and is another characteristic that differentiates a pseudoallergic
reaction from a true allergic reaction. Pretreatment regimens to prevent
pseudoallergic reactions to various other drugs (e.g., radiocontrast media) are also
well described and can be effective.
CASE 32-6, QUESTION 5: What other drugs are commonly associated with pseudoallergic reactions?
Many other agents have been associated with pseudoallergic reactions.
the agents more commonly associated with pseudoallergic reactions are described
Aspirin/Nonsteroidal Anti-Inflammatory Drugs
After penicillins, aspirin is the drug most commonly reported as causing “allergic”
reactions. Reactions to aspirin can be divided into three broad categories:
respiratory reactions, cutaneous manifestations, and anaphylaxis. None of these
reactions has been consistently associated with IgE.
The prevalence of bronchospasm with rhinoconjunctivitis is 0% to 28% in children
with aspirin sensitivity. In adult asthmatics, the prevalence of aspirin sensitivity
ranges from 5% to 20%. The prevalence of aspirin sensitivity during aspirin
challenge in adult asthmatics with a history of aspirin-induced respiratory reaction
94 Symptoms usually occur within 30 minutes to 3 hours of
ingestion. The triad seen in many sensitive patients is aspirin sensitivity, nasal
polyps, and asthma. All potent inhibitors of cyclo-oxygenase can cause respiratory
symptoms in aspirin-sensitive patients. Thus, patients who react to aspirin should be
considered sensitive to NSAIDs, and vice versa. Weak cyclo-oxygenase inhibitors,
such as acetaminophen, choline magnesium salicylate, salicylamide, salsalate, and
sodium salicylate, are generally well tolerated in patients with aspirin sensitivity.
The prevalence of cutaneous reactions to aspirin depends on the type of reaction and
the population studied. For example, urticaria-angioedema occurs in 0.5% of
children, 3.8% of the general adult population, and in 21% to 30% of patients with a
history of chronic urticaria. Disease activity at the time of aspirin challenge plays an
important role in those with a history of chronic urticaria. In one study, 70% of
patients whose urticaria was active at the time of challenge reacted to aspirin,
compared with only 6.6% of patients whose urticaria was not active at the time of
challenge. Furthermore, aspirin or NSAID may aggravate preexisting urticaria.
Other dermatologic reactions to aspirin occur with less frequency; for example,
eczema, purpura, and erythema multiforme occur in 2.4%, 1.5%, and 1% of the
The true prevalence of aspirin-induced or NSAID-induced anaphylaxis is unknown,
but it may range from 0.07% of the general population to 10% of patients with
anaphylactic symptoms. Although IgE is not consistently associated with aspirin or
that point to IgE as a cause. First, the reaction occurs after two or more exposures to
the offending agent, suggesting that preformed IgE antibodies are responsible.
Second, patients do not have underlying nasal polyposis, asthma, or urticaria. Third,
the patient who reacts to aspirin or a single NSAID can tolerate a chemically
unrelated NSAID, suggesting that a drug-specific IgE antibody has been formed.
The NSAIDs that selectively inhibit cyclo-oxygenase-2 (COX-2) while sparing
cyclo-oxygenase-1 (COX-1) include celecoxib, rofecoxib, and valdecoxib, among
others. Celecoxib is the only COX-2 inhibitor currently marketed in the United
States. Selective inhibition of COX-2 provides anti-inflammatory effects while
minimizing the renal effects, GI toxicity, and antiplatelet effects seen with inhibition
reactions have been reported with celecoxib, and it appears that the rate of
hypersensitivity is comparable to that of traditional NSAIDs.
prescribing information states that, as with any NSAID, use is contraindicated in
patients who have experienced asthma, urticaria, or allergic-type reactions after
taking aspirin or other NSAIDs. Several reports, however, describe successful
administration of celecoxib and other COX-2 selective agents to patients with
aspirin-sensitive asthma or a history of hypersensitivity reactions to traditional
NSAIDs, and evidence suggests that inhibition of COX-1 rather than COX-2 is key to
97–100 Nevertheless, COX-2 selective agents can still elicit
allergic responses by other means (e.g., IgE-mediated hypersensitivity). Thus,
appropriate precautions and monitoring should be followed when initiating therapy in
any patient with a history of allergic reactions to aspirin or other NSAIDs.
Angiotensin-Converting Enzyme Inhibitors and
Angiotensin II–Receptor Blockers
speech but is able to swallow; she has red and swollen lips and tongue, and puffy eyes. Her
Angioedema refers to a localized, transient swelling of the deep skin layers or the
upper respiratory or gastrointestinal mucosa. Angioedema commonly manifests as
localized erythematous edema, involving the tongue, lips, eyelids, and mucous
membranes of the mouth, nose, and throat. However, in rare cases it can occur in the
lower gastrointestinal tract. Angioedema can be caused by a variety of mechanisms
involving complement, histamine, substance P, and bradykinin that can be hereditary,
immunologically acquired, or pharmacologic. ACE inhibitors are the most common
pharmacologic cause and have been associated with this adverse effect in about
0.1% to 0.7% of individuals treated with this drug class and account for up to 60% of
cases of angioedema that present to emergency departments.
dose-related and occurs with all ACE inhibitors. ACE inhibition causes
accumulation of excess bradykinin leading to capillary leakage. Bradykinin receptor
B2 is a G-protein– coupled receptor found in blood vessels and encoded by the
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