CONDITION
Nonsteroidal Anti-inflammatory Drug (NSAID)-related Urticaria and Angioedema Overview and Recommendations
Background
Nonsteroidal anti-in!ammatory drug (NSAID)-related urticaria and angioedema is a drug ●
hypersensitivity response characterized by acute urticaria, angioedema, and/or anaphy laxis after exposure to aspirin or other NSAIDs.
● NSAID-related urticaria and angioedema reactions include 3 characterizable types:
NSAID-induced urticaria or angioedema (NIUA) is the most common type. Symptoms ⚬
of NIUA usually occur within 1 hour of drug exposure, ranging up to about 6 hours af ter exposure to drug. NIUAA is a nonimmunologically mediated hypersensitivity reac tion related to cyclooxygenase-1 (COX-1) inhibition.
NSAID-exacerbated cutaneous disease (NECD) occurs in patients with underlying ⚬
chronic urticaria. Symptoms of NECD may occur within 30-60 minutes of drug expo sure. NECD is a nonimmunologically mediated hypersensitivity reaction related to COX-1 inhibition.
Single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA) is an immunologi ⚬
cally mediated (immunoglobulin E [IgE]) allergic reaction that typically occurs within minutes of exposure to aspirin or a single, speci"c NSAID or class or NSAIDs. Symp toms of anaphylaxis are more common with SNIUAA than with the other types of NSAID drug-related urticaria and angioedema.
NSAID-related urticaria and angioedema appears to be more common in adult women, ●
and likely risk factors include atopy (atopic dermatitis, rhinitis, asthma) or chronic urticaria.
Evaluation
Suspect the diagnosis in patients who develop urticaria (wheals), angioedema, or ana ●
phylaxis after recent exposure to aspirin or other NSAIDs.
The rapid appearance of symptoms (< 30 minutes) or anaphylaxis is suggestive of ⚬
SNIUAA.
Patients with a history of chronic urticaria who develop an exacerbation after aspirin ⚬
or another NSAID use can be diagnosed with NECD.
● The diagnosis is based on history and can be con"rmed by a positive oral aspirin provo-
cation challenge, if clinical history is equivocal.
While a provocation challenge con"rms the diagnosis and can establish cross-reactivi ⚬
ty, it is associated with risks of severe cutaneous reaction or anaphylaxis, therefore is not done routinely.
The decision to perform challenge testing or desensitization must be individualized, ⚬
taking into account the potential bene"ts of the NSAID or aspirin, such as for cardio protection, and the risks of the procedure.
For patients suspected of SNIUAA after exposure to a pyrazolone NSAID (such as dipy ●
rone, oxyphenbutazone, or phenylbutazone), standardized skin testing is available. Serum testing for IgE may be useful for diagnosing SNIUAA, but cannot help diagnose ●
NIUA or NECD, which are both non-IgE mediated.
Management
Management of NSAID drug-related urticaria and angioedema includes avoidance of ●
COX-1 inhibitors and guideline-based treatment of anaphylaxis, angioedema, and urticaria.
Avoid NSAIDs with COX-1 inhibitory activity, such as aspirin, ibuprofen, naproxen, ke ⚬
toprofen, indomethacin, and diclofenac.
Consider NSAIDs without COX-1 inhibitory activity or with selective COX-2 inhibitory ⚬
activity, such as acetaminophen, celecoxib, or meloxicam.
For patients with SNIUAA, consider an NSAID from a di#erent class than the culprit ⚬
NSAID.
For patients requiring aspirin for cardioprotection, consider negative challenge testing ●
with low-dose aspirin (< 100 mg) if the bene"ts of taking aspirin outweigh the risks of the challenge procedure.
Consider aspirin desensitization only if no alternative drug is available for the clinical ●
needs, and aspirin or NSAID treatment clinically is necessary, and the risks of desensiti zation (including anaphylaxis) are outweighed by the potential bene"t to the patient.
Related Topics
● Aspirin-exacerbated respiratory disease ● Chronic urticaria
General Information
Description
NSAID-related urticaria and angioedema are drug hypersensitivity reactions character ●
ized by acute urticaria, angioedema, and/or anaphylaxis triggered by exposure to as pirin (acetylsalicylic acid) or NSAIDs1,2,3
NSAID-related urticaria and angioedema reactions typically appear clinically as 3 types,
●
including1,2,3
⚬ NSAID-induced urticaria or angioedema (NIUA)
characterized by acute urticaria or angioedema to aspirin and NSAIDs in patients –
with or without history of atopy
– a nonimmunologically mediated hypersensitivity reaction ⚬ NSAID-exacerbated cutaneous disease (NECD)
characterized by acute urticaria or angioedema to aspirin and NSAIDs in patients –
with underlying chronic urticaria
– a nonimmunologically mediated hypersensitivity reaction ⚬ single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA)
characterized by immediate urticaria, angioedema, or anaphylaxis to a single, spe –
ci"c NSAID or aspirin
may re!ect an immunologically mediated (immunoglobulin E [IgE] or non-IgE) –
reaction
other NSAID-related hypersensitivity reactions include aspirin-exacerbated respiratory ●
disease (AERD) and single nonsteroidal induced delayed reaction (SNIDR)
AERD is characterized by adult-onset chronic rhinosinusitis with nasal polyposis, asth ⚬
ma respiratory reactions to aspirin and/or other cyclooxygenase-1 (COX-1) inhibiting NSAIDs
symptoms develop within 30 to 180 minutes of drug exposure, and are based on –
COX-1 inhibition
– see also Aspirin-exacerbated respiratory disease
SNIDR is characterized by immunologically mediated cutaneous responses to a sin
⚬
gle, speci"c NSAID or aspirin that occur > 24 hours after exposure2,3
examples include T-cell mediated reactions (contact dermatitis), "xed drug reac –
tions, Stevens-Johnson syndrome, or drug rash with eosinophilia and systemic symptoms (DRESS)
SNIDR not covered in this topic; see also Contact dermatitis, Drug rash with –
eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syn drome/Toxic epidermal necrolysis
Also called
● aspirin-exacerbated cutaneous disease (AECD)
Definitions
cross intolerant (CI) or cross-reactive describes hypersensitivity to multiple NSAIDs with ●
di#erent classes of chemical structures
drug provocation test (DPT) is a test where patient is challenged with drug (usually in a ●
graded-dose fashion) to determine if the drug elicits hypersensitivity response selective responders (SR) are patients with hypersensitivity response to NSAIDs within a ●
particular class of chemical structures but not those with structures outside of that class
Types
Table 1. Types of Nonsteroidal Anti-inflammatory Drug-related Urticaria and Angioedema
Abbreviations: COX, cyclooxygenase; IgE, immunoglobulin E; NECD,
NSAID-exacerbated cutaneous disease; NIUA, NSAID-induced
urticaria/angioedema; NSAID, nonsteroidal anti-in!ammatory
drug; SNIUAA, single NSAID-induced urticaria/angioedema or
anaphylaxis.
References - 1,2,3.
acute skin reactions that involve aspirin and other NSAIDs and manifest as urticaria, an
●
gioedema, or both are di#erentiated into 3 major clinical phenotypes1,2,3 ⚬ NSAID-exacerbated cutaneous disease (NECD)
occurs in patients with underlying chronic urticaria (although NECD may be initial –
manifestation of chronic spontaneous urticaria)
exposure to aspirin and other NSAIDs that inhibit cyclooxygenase-1 (COX-1) associ –
ated with
● activation of in!ammatory cells
● within minutes to 4 hours, exacerbation of urticaria occurs
exposure to alternative NSAIDs with COX-1 inhibitory activity with unrelated chemi –
cal structures similarly leads to cutaneous symptoms
– COX-2 inhibitors usually well-tolerated
discontinuation of NSAID usage prevents exacerbation of chronic urticaria, but –
does not impact underlying disease
⚬ NSAID-induced urticaria or angioedema (NIUA)
patients usually have no history of urticaria or angioedema but many have atopic –
disease
– exposure to aspirin or other NSAIDs that inhibit COX-1 associated with ● activation of in!ammatory cells
● induction of urticaria, angioedema, or both
reaction occurs usually within 1 hour, generally ranging up to 6 hours after ex ●
posure to drug
alternative NSAIDs with COX-1 inhibitory activity and unrelated chemical structures –
similarly induce cutaneous reaction
– COX-2 inhibitors usually well-tolerated
– discontinuation of aspirin and NSAID usage prevents induction
single nonsteroidal anti-in!ammatory drug-induced urticaria/angioedema/anaphylax ⚬
is (SNIUAA)
– patients usually have no history of urticaria, angioedema, or anaphylaxis – exposure to single NSAID or 2 or more chemically related NSAIDs associated with
induction of anaphylaxis and/or urticaria and angioedema may re!ect im ●
munoglobulin E (IgE)-mediated allergic reaction
● symptoms typically develop within minutes
– reaction occurs usually within 1 hour, generally ranging up to 6 hours after expo-
sure to drug
NSAIDs with unrelated chemical structures usually not associated with cutaneous –
reaction
– avoidance of NSAID reexposure prevents subsequent reactions Epidemiology
In this Section
Who is most a!ected
67%-79% of patients with NSAID-related cutaneous hypersensitivity reactions are ●
women aged 28.6 to 32.7 years (Allergol Immunopathol (Madr) 2017 Nov - Dec;45(6):573)
12%-30% of patients with chronic spontaneous urticaria will experience worsening of
●
skin symptoms following exposure to NSAID that inhibits cyclooxygenase-1 (COX-1)1,4
Incidence/Prevalence among drug-induced reactions4 ●
frequent cause of drug-induced anaphylaxis (reported as responsible for 57.8% of ⚬
cases in 1 cohort study)
second or third most common cause of cutaneous drug reactions (most common ⚬
causes include antimicrobials and contrast media)
76% of patients with NSAID-sensitivity also react to structurally unrelated NSAIDs2 ● Likely risk factors
atopy, usually manifested as atopic dermatitis, rhinitis, or asthma may increase risk for ●
NSAID-related hypersensitivity (Allergol Immunopathol (Madr) 2017 Nov - Dec;45(6):573) chronic spontaneous urticaria associated with NSAID-exacerbated cutaneous disease
●
(NECD)1,3
up to 40% of patients with chronic spontaneous urticaria may experience exacerba ⚬
tion of cutaneous symptoms (NECD) following exposure to cyclooxygenase-1 (COX-1) inhibiting NSAIDs
⚬ NECD symptoms may precede presentation of chronic spontaneous urticaria Possible risk factors
mastocytosis may be risk factor for NSAID-related anaphylaxis (Allergol Immunopathol ●
(Madr) 2017 Nov - Dec;45(6):573)
Associated conditions ● chronic spontaneous urticaria
atopic diseases seen in approximately 60% of patients with NSAID-induced urticaria or
●
angioedema (NIUA) including1
⚬ rhinitis
⚬ asthma
Etiology and Pathogenesis
Causes
exposure to aspirin and NSAIDs in susceptible individual1,2,3 ● Pathogenesis
cutaneous manifestations of hypersensitivity are characterized as either cross-intolerant
●
or single, selective reactions1,2,3
cross intolerant (CI), with theorized mechanism involving cyclooxygenase-1 (COX-1) ⚬
inhibition in either aspirin and other NSAID-exacerbated cutaneous disease (NECD) or NSAID-induced urticaria or angioedema (NIUA)
single or selective reactions, with theorized mechanisms involving immunoglobulin E ⚬
(IgE)-mediated, other immunologic, or nonimmunologic hypersensitivity in cases of single NSAID-induced urticaria and angioedema or anaphylaxis (SNIUAA)
NSAID-exacerbated cutaneous disease (NECD)1,2,3 ●
⚬ occurs in patients with chronic spontaneous urticaria ⚬ exposure to aspirin and other NSAIDs that inhibit COX-1 may lead to – inhibition of prostaglandin synthesis
– increase in histamine release
– increase in leukotriene synthesis
– activation of in!ammatory cells
– within minutes to 4 hours, exacerbation of urticaria occurs NSAID-induced urticaria or angioedema (NIUA)1,2,3 ●
patients usually have no history of urticaria or angioedema but many have atopic ⚬
disease
⚬ exposure to aspirin and other NSAIDs that inhibit COX-1 may lead to – inhibition of prostaglandin synthesis
– increase in histamine release
– activation of in!ammatory cells
– induction of urticaria, angioedema, or both
reaction occurs usually within 1 hour, generally ranging up to 6 hours after expo –
sure to drug
⚬ unclear what role may be played by atopic sensitization
single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA)1,2,3 ● ⚬ patients usually have no history of urticaria, angioedema, or anaphylaxis ⚬ some NSAID reactions may be mediated by IgE
⚬ exposure to single NSAID or 2 or more chemically related NSAIDs associated with – induction of urticaria, angioedema, and/or anaphylaxis
symptoms typically develop within 30 minutes to 1 hour, generally ranging up to 3- –
4 hours after exposure to drug
IgE speci"c to NSAID may be detectable in serum based immunoassays and skin –
testing
History and Physical History
Chief concern (CC)
rapid appearance of urticaria, or angioedema, or both following aspirin or other NSAID
●
exposure1,2,3
anaphylaxis may be presenting symptom in single NSAID-induced urticaria/angioede
●
ma/anaphylaxis (SNIUAA)1,2,3
History of present illness (HPI)
symptoms may manifest within minutes to several hours following aspirin or other
●
NSAID exposure1,2,3
symptoms < 30 minutes from exposure, or symptoms of anaphylaxis suggest im ●
munoglobulin E (IgE)-mediated reaction of single NSAID-induced urticaria/angioede ma/anaphylaxis (SNIUAA)1,2,3
ask about speci"c drug taken prior to reaction1,2,3 ●
aspirin, ibuprofen, naproxen, ketorolac, and other NSAIDs that inhibit cyclooxyge ⚬
nase-1 (COX-1) are typically implicated
⚬ ibuprofen and diclofenac may be associated with angioedema without urticaria ask about1,2,3 ●
⚬ timing of symptoms relative to exposure to NSAIDs
prior history of NSAID (including aspirin) related reactions, including respiratory ⚬
symptoms
⚬ history of similar symptoms and/or chronic urticaria
for single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA), patients may note
●
reaction to a single NSAID or to ≥ 2 NSAIDs within a similar class1
Table 2. Nonsteroidal Anti-Inflammatory Drugs by Class
Abbreviation: NSAID, nonsteroidal
anti-in!ammatory drug.
*
Pyrazolones reported as most common NSAIDs that trigger single NSAID-induced
urticaria/angioedema/anaphylaxis.
Past medical history (PMH)
ask about1,2,3 ●
⚬ previous or chronic urticaria
atopic conditions such as asthma or rhinitis (may be present in up to 60% of patients ⚬
with NSAID drug-exacerbated cutaneous disease)
Physical
General physical
if any concern of anaphylaxis, check blood pressure, heart rate, and pulse oximetry (see ●
also Anaphylaxis)
Skin
assess for characteristic wheals of urticaria, which can occur anywhere on body, with or ●
without angioedema
appearance of wheals is typically similar to the wheals of chronic spontaneous
●
urticaria1,2,3
⚬ wheals characterized by
swollen patch of clear or mildly erythematous skin with or without surrounding –
erythema
– may appear in linear, circular, or arcuate formations
size ranging from few millimeters to centimeters, and several wheals may form ad –
jacent to each other or at di#erent locations of the body
wheal will blanch with pressure, and will fade completely by 24-48 hours, without –
persistent purpura, change in pigmentation, or scarring
⚬ see also Chronic urticaria
HEENT
assess for periorbital angioedema and laryngeal angioedema1,2 ●
angioedema is characterized by transient swelling of deep layers of the skin, resulting ⚬
in nonpitting edema with poorly de"ned margins, and often asymmetric appearance voice change, hoarseness, stridor, or shortness of breath may indicate laryngeal ⚬
edema
⚬ see also Angioedema
Lungs
● assess for lower respiratory symptoms which may indicate anaphylaxis, including ⚬ dyspnea (shortness of breath, di$culty breathing)
⚬ cough
⚬ wheezing
⚬ chest tightness
⚬ intercostal retractions
⚬ accessory muscle use
References - J Allergy Clin Immunol 2014 Nov;134(5):1016, J Allergy Clin Immunol 2010 ⚬
Dec;126(6 Suppl):S1
● see also Anaphylaxis Diagnosis
Making the diagnosis
suspect the diagnosis in patients who develop urticaria, angioedema, or anaphylaxis af
●
ter recent exposure to aspirin or other NSAIDs1,2
for patients without a history of chronic urticaria, suspect NSAID-induced urticaria or an
●
gioedema (NIUA), which is characterized by the following1,2,3
⚬ symptoms arise generally > 30-60 minutes from exposure
⚬ history of atopy, such as rhinitis or asthma, common (seen in up to 60%) ⚬ possible history of similar symptoms after exposure to another NSAID in past
for patients with chronic urticaria, suspect NSAID-exacerbated cutaneous disease
●
(NECD), which is characterized by the following1,2,3
⚬ symptoms arise generally > 30-60 minutes from exposure
⚬ prior history of chronic urticaria
for patients with unknown history of prior cutaneous symptoms, also suspect single ●
NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA), which is characterized by the following1,2,3
⚬ reaction typically occurs within minutes of exposure
symptoms may be severe, and anaphylaxis may be chief clinical manifestation in ⚬
30%-58% of patients
⚬ respiratory symptoms (bronchial, nasal) may be seen in about half of patients
skin prick or intradermal testing or speci"c serum immunoglobulin E (IgE) testing may ⚬
be helpful for con"rming diagnosis but this testing has not been validated for NSAIDs
diagnosis can be con"rmed with oral graded dose challenge test, but challenge testing ●
generally considered only if clinical need, such as aspirin for cardioprotection, outweighs risks of challenge testing, which may include severe cutaneous reaction or anaphylaxis
Di!erential diagnosis
● consider other causes of urticaria, angioedema, or anaphylaxis, such as ⚬ foods, other drugs and medications, insect stings, infections
see also Causes of anaphylaxis in Anaphylaxis, Causes of angioedema in Angioedema, ⚬
Causes of acute urticaria in Acute urticaria, and Causes of chronic urticaria in Chronic urticaria
consider other dermatological conditions with similar clinical presentations as urticaria, ●
such as
⚬ viral exanthems (most common skin eruption in children)
⚬ "xed-drug skin eruptions
⚬ photosensitivity skin eruptions
⚬ serum sickness-like reactions
⚬ contact dermatitis
⚬ anaphylaxis-associated reactions
⚬ drug hypersensitivity syndrome
⚬ Stevens-Johnson syndrome/toxic epidermal necrolysis
⚬ erythema multiforme
⚬ for papular or cholinergic urticaria, bullous pemphigoid and dermatitis herpetiformis ⚬ see also Acute urticaria and Chronic urticaria
Testing overview
consider oral aspirin graded dose challenge (also known as provocation) test if bene"t ●
of a con"rmed diagnosis or negative challenge outweighs risk of testing procedure
performance of oral challenge test must be considered from an individualized ⚬
risk/bene"t standpoint; avoid challenge testing if history of anaphylaxis, severe respi-
ratory disease, or acute cardiac disease
consider to con"rm NSAID-related urticaria or angioedema or establish negative chal ⚬
lenge in patients who require aspirin or NSAIDS, such as aspirin for cardioprotection consider to con"rm single NSAID-induced urticaria/angioedema/anaphylaxis (SNI ⚬
UAA) or lack of cross-reactivity to other NSAIDs
skin testing may have utility for con"rming or ruling out a diagnosis of SNIUAA, but only ●
when immunoglobulin E (IgE)-mediated pathogenesis is suspected and there is a validat ed protocol for immediate hypersensitivity skin testing with the culprit drug
10% of patients with NSAID-exacerbated cutaneous disease (NECD) may also have ●
NSAID-exacerbated respiratory disease (NERD) symptoms (see Aspirin-exacerbated res piratory disease for additional information)
Drug provocation or challenge testing
any consideration of oral challenge should carefully weigh risks and potential
●
bene"ts1,2
consider potential risks of challenge testing including severity of prior reaction, pa ⚬
tient comorbidities, and ability to tolerate epinephrine if needed
consider need to distinguish whether suspected diagnosis is NSAID-exacerbated cuta ⚬
neous disease (NECD), NSAID-induced urticaria or angioedema (NIUA), or single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA), whether there is cross reactivity, and the implications for treatment
this may include patient's need to be treated with aspirin or other NSAIDs, such as –
with aspirin for cardioprotection
for majority of patients with NSAID-related urticaria and angioedema oral graded –
dose challenge is only done if patient has cardioprotective needs for aspirin oral aspirin graded dose challenge with low-dose aspirin (81 mg) is su$cient for –
cardioprotective needs, although will not con"rm or rule out diagnosis of NECD, NIUA, or SNIUAA (Allergy Asthma Proc 2013 Mar-Apr;34(2):138)
while challenge tests can con"rm diagnoses of NECD, NIUA, or SNIUAA, and deter –
mine whether there is cross-reactivity to other drugs, most patients with NSAID related urticaria and angioedema should be able to use alternative NSAID classes or alternative drugs (for example, acetaminophen) for clinical needs, and do not need to risk any potential adverse e#ects of drug challenge testing oral challenge may be used to determine if speci"c alternative drug is safe to use –
for patient treatment (for example, to verify that a cyclooxygenase-2 [COX-2] in hibitor does not provoke reaction in patients diagnosed with cross-intolerance to COX-1 inhibitors)
⚬ consider need for trained personnel and access to emergency resources
contraindications include history of severe drug reactions, such as Steven-Johnson ⚬
syndrome/toxic epidermal necrolysis, drug rash with eosinophilia and systemic symp toms syndrome (DRESS, or drug hypersensitivity syndrome), systemic vasculitis, blood cytopenia, or nephritis
⚬ Reference - Int J Mol Sci 2017 Jul 4;18(7):
● for more details, including protocols, see oral aspirin graded dose challenge Blood tests
serum testing for immunoglobulin E (IgE) may be useful for single NSAID-induced ur
●
ticaria/angioedema/anaphylaxis (SNIUAA)1
Other diagnostic testing Skin testing
skin prick test or intradermal (intracutaneous) test may have utility for con"rming or rul ●
ing out a diagnosis of single NSAID-induced urticaria/angioedema/ anaphylaxis (SNI UAA), if immunoglobulin E (IgE)-mediated pathogenesis is suspected and there is a vali dated protocol for immediate hypersensitivity skin testing with the culprit drug2 ⚬ more sensitive than in vitro testing for serum IgE
tests only valid when event due to IgE-mediated anaphylactic reaction and not if ⚬
event due to non-IgE-mediated anaphylactoid reaction
skin testing should be done under supervision of an experienced physician with ap ⚬
propriate rescue equipment and medication
⚬ reported useful for pyrazolone derivatives
patients should discontinue H1 antihistamines 3-7 days prior to skin testing, depend ⚬
ing on speci"c drug
duration of suppression of skin wheal and !are varies with antihistamine, typically –
3 days for cetirizine 10 mg or ebastine 10 mg (ebastine not available in United States)
– duration of suppression usually < 1 week in patients receiving regular treatment ● fexofenadine (up to 180 mg) - 2 days
● cetirizine 10 mg - 3 days
● ebastine 10 mg - 3 days
● levocetirizine 5 mg - 4 days
● dexchlorpheniramine 4 mg - 4 days
● azelastine 4 mg - 7 days
● loratadine 7 days
● cyproheptadine - 11 days
References - Ann Allergy Asthma Immunol 2015 Nov;115(5):341, commentary can be ⚬
found in Ann Allergy Asthma Immunol 2016 Mar;116(3):265, J Allergy Clin Immunol 2010 Feb;125(2 Suppl 2):S161, correction can be found in J Allergy Clin Immunol 2010 Oct;126(4):885, Allergy 2009 Sep;64(9):1256
waiting 3-4 weeks after anaphylactic episode to conduct skin tests allows times for re ⚬
covery of mast cell releasability (J Allergy Clin Immunol 2010 Feb;125(2 Suppl 2):S161), correction can be found in J Allergy Clin Immunol 2010 Oct;126(4):885
Management
Management overview
● start acute treatment for anaphylaxis if suspected
use epinephrine, airway management, IV !uids, and antihistamines, and consider ⚬
steroids or albuterol depending on the severity of the reaction
⚬ see also Anaphylaxis
for NSAID-related urticaria and angioedema, the mainstay of management is avoidance ●
of the NSAIDs that trigger the cutaneous response, and guideline-based treatment of as sociated angioedema and/or chronic urticaria, if present (see also Chronic urticaria)
for NSAID-exacerbated cutaneous disease (NECD) or NSAID-induced urticaria or an ●
gioedema (NIUA)
avoid NSAIDs that have cyclooxygenase-1 [COX-1] inhibitory activity including aspirin, ⚬
ibuprofen, naproxen, ketoprofen, indomethacin, and diclofenac (see Medications to avoid)
consider NSAIDs with selective COX-2 inhibitory activity, such as acetaminophen, cele ⚬
coxib, or meloxicam (see Analgesic medications that are tolerated)
for single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA), consider NSAIDs ●
from a di#erent class
● for patients requiring aspirin for cardioprotection
consider oral graded challenge testing with aspirin (81 mg) to determine if patient is ⚬
unreactive to low-dose aspirin
for patients with NSAID-related cutaneous hypersensitivity conditions with acute ⚬
coronary syndrome for whom challenge is not appropriate from an individualized risk/bene"t standpoint, or for whom this is favorable for other reasons, consider al ternatives to reduce platelet function
Medications to avoid
● advise patients with NSAID-exacerbated cutaneous disease (NECD) or NSAID-induced ur-
ticaria or angioedema (NIUA) to avoid preferential or nonselective cyclooxygenase-1 (COX-1) inhibitors4
⚬ NSAIDs that inhibit both COX-1 and COX-2 include
– aspirin
– diclofenac
– fenoprofen
– !urbiprofen
– ibuprofen
– indomethacin
– ketoprofen
– ketorolac
– naproxen
– piroxicam
– sulindac
⚬ NSAIDs with partial COX-1 inhibition include
– di!unisal
– etodolac
– meloxicam
– nabumetone
– nimesulide (not available in United States)
NSAID options for patients with NSAID-related cutaneous reactions
●
Table 3. Management Options for Cutaneous Nonsteroidal Anti-inflammatory Drug-related Hypersensitivity Conditions
NIUA Yes Preferential or nonselec
Selective COX-2
Feasible but generally not
tive COX-1 inhibitors
inhibitors recom mended if
avoidance is
possible
Abbreviations: COX, cyclooxygenase; IgE, immunoglobulin E; NECD,
NSAID-exacerbated cutaneous disease; NIUA,
NSAID-induced urticaria/angioedema; NSAID,
nonsteroidal anti-in!ammatory drug; SNIUAA, single
NSAID-induced
urticaria/angioedema/anaphylaxis.
*
Di$cult in presence of chronic urticaria and
concern exists that urticaria may become intractable
with repeated aspirin exposure.
**
IgE-mediated.
*** May be feasible but
risk of anaphylaxis must be balanced with clinical
need for desensitization. Not recommended especially
if patient has history of severe anaphylactic
reaction to NSAIDs.
References -
1,2,3,
Allergy 2017 Mar;72(3):498.
Analgesic medications that may be tolerated
medications less likely to cross-react with aspirin in patients with NSAID-induced ur ●
ticaria or angioedema (NIUA), NSAID-exacerbated cutaneous disease (NECD), or aspirin exacerbated respiratory disease (AERD) include
acetaminophen (generally well tolerated, but can inhibit cyclooxygenase-1 [COX-1] at ⚬
doses ≥ 1,000 mg; for this reason, 2 tablets of regular, rather than extra strength, ac etaminophen should be recommended as an analgesic/antipyretic)
⚬ azapropazone
⚬ celecoxib
sodium or choline magnesium (generally well-tolerated, but at higher doses, for ex ⚬
ample, > 2,000 mg salicylate, can inhibit COX-1)
⚬ dextropropoxyphene ⚬ lumiracoxib
meloxicam (generally well-tolerated, but at doses ≥ 15 mg, meloxicam can inhibit ⚬
COX-1)
⚬ parecoxib
⚬ salicylamide
⚬ Reference - J Allergy Clin Immunol 2014 Jan;133(1):286
STUDY SUMMARY ●
drug provocation testing reported to identify selective COX-2 inhibitors that may not induce hypersensitivity response in most patients with cross-reactive NSAID-related hypersensitivity DynaMed Level 2
COHORT STUDY: Allergol Immunopathol (Madr) 2013 May-Jun;41(3):181
Details
⚬ based on retrospective cohort
309 patients with cross-reactive NSAID-related hypersensitivity (76.3% female, mean ⚬
age 41.5 years) challenged in drug provocation tests for response to NSAIDs with se lective COX-2 inhibitory activity
NSAID-related hypersensitivity manifestations included cutaneous in 71.8% of pa ⚬
tients, respiratory in 51.5% of patients, cardiovascular in 12.9% of patients, gastroin testinal in 8.4% of patients, or involving ≥ 2 organ systems in 29.1% of patients
⚬ hypersensitivity response to COX-2 drug provocation testing seen for – meloxicam in 9.8% of 112 patients
– nimesulide in 8.1% of 74 patients
– celecoxib in 5.1% of 78 patients
– rofecoxib in 5.1% of 98 patients
– other NSAIDs in 18.6% of 26 patients
⚬ Reference - Allergol Immunopathol (Madr) 2013 May-Jun;41(3):181 Aspirin challenge
Aspirin challenge considerations
aspirin challenge should only be used if the individual patient potential for bene"t out
●
weighs the potential for harm1,2,3,4
⚬ for patients with NSAID-induced urticaria or angioedema (NIUA)
challenge recommended only if no alternative available and aspirin treatment nec –
essary, such as for cardiovascular disease
negative challenge to aspirin at top dose of 81 mg usually su$cient for clinical –
needs for cardiac patients
⚬ for patients with NSAID-exacerbated cutaneous disease (NECD)
attempts at challenge or desensitization generally fail to extinguish urticarial –
responses
desensitization using aspirin has been reported, but may also lead to intractable –
urticaria
for patients with single NSAID-induced urticaria/angioedema or anaphylaxis (SNI ⚬
UAA), desensitization would only be required if the speci"c NSAID was required for treatment, without an equally e#ective alternative that can be used
if history of anaphylaxis at antiplatelet doses (≤ 100 mg), consult an allergist along with ●
cardiologist for joint decision on how to proceed for patients with cardiac needs for aspirin
alternatives to reduce platelet function for patients with insu$cient time to complete ●
aspirin desensitization prior to percutaneous coronary interventions procedure include ⚬ antiplatelet adenosine diphosphate receptor antagonist such as clopidogrel ⚬ platelet glycoprotein IIb/IIIa inhibitor such as epti"batide, abciximab, or tiro"ban ⚬ Reference - Allergy 2017 Mar;72(3):498
● contraindications
⚬ absolute contraindications for challenge include – life-threatening or severe NSAID-related reactions
including severe mucosal ulcerations, cutaneous or systemic vasculitis, drug rash –
with eosinophilia and systemic symptoms (DRESS), or Steven-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN)
contraindications include history of severe drug reactions, such as SJS/TEN, DRESS –
(or drug hypersensitivity syndrome), systemic vasculitis, blood cytopenia, or nephritis
– Reference - Int J Mol Sci 2017 Jul 4;18(7):
relative contraindications for challenge/desensitization include patients with in ⚬
creased risk due to comorbidity such as
– hemodynamic instability
– uncontrolled asthma
– uncontrolled cardiac diseases
⚬ Reference - Allergy 2010 Nov;65(11):1357
● consider
potential risks including patient comorbidities and ability to tolerate epinephrine if ⚬
needed
⚬ need for trained personnel and access to emergency resources ⚬ Reference - Int J Mol Sci 2017 Jul 4;18(7):
● consider only after careful risk/bene"t evaluation in patients with ⚬ history of severe anaphylaxis
⚬ asthma
⚬ renal, hepatic, or other diseases
⚬ beta-blockers
⚬ Reference - Allergy 2010 Nov;65(11):1357
in patients with high suspicion of aspirin-exacerbated respiratory disease (AERD)4 ●
rapid desensitization aspirin or NSAID administration may provoke severe bron ⚬
chospasm, which may increase risk to patient during recovery from cardiac events consider desensitization protocol that is well established for patients with AERD (see ⚬
Aspirin desensitization in Aspirin-exacerbated respiratory disease)
● pretreatment considerations
for patients without serious cardiovascular disease, responses to challenge testing ⚬
may be obscured through pretreatment with antihistamines, steroids, or montelukast (see diagnostic oral aspirin challenge test)
for patients with underlying disease requiring hospitalization (such as cardiovascular ⚬
disease with unstable arterial lesions), ongoing pretreatment with antihistamines, steroids, or montelukast may be necessary to maintain patient's stability and the goal of aspirin treatment may outweigh the need to prevent masking of reaction by other treatments
⚬ Reference - Allergy 2007 Oct;62(10):1111
periprocedural aspirin challenge considerations from Aspirin Desensitization Joint Task ●
Force
⚬ preparation for oral aspirin challenge protocol
discuss risks and bene"ts of procedure with patient and document discussion in –
medical record
– advise that procedure may take several days to complete – consider need for pretreatment with leukotriene-modifying drug – for patients with NECD
consider discontinuation of antihistamine treatment for 48 hours prior to proce ●
dure to avoid antihistamine masking !are-up
as full discontinuation of antihistamines might lead to urticarial symptoms an
●
alternative for testing is to reduce dose to minimum e#ective for control4
Reference - Ann Allergy Asthma Immunol 2007 Feb;98(2):172, commentary can be ⚬
found in Ann Allergy Asthma Immunol 2007 Aug;99(2):196
● symptom relief and patient observation
if anaphylaxis suspected, use epinephrine according to guidelines; see anaphylaxis ⚬
management
cutaneous symptoms may be relieved by antihistamine and or oral or IV ⚬
corticosteroids
respiratory symptoms may be relieved by 2-4 pu#s of short-acting beta-2-agonist or ⚬
nebulization (2.5-5 mg salbutamol) until forced expiratory volume in 1 second (FEV1) within 90% of baseline
more severe symptoms may be treated with oral or IV corticosteroids (40 mg pred ⚬
nisolone or equivalent)
⚬ Reference - Allergy 2007 Oct;62(10):1111
● additional considerations in children and adolescents
⚬ consider starting challenge dose of 10%-25% of therapeutic dose by age and weight
consider lower starting doses (< 10% of therapeutic dose by age and weight) if history ⚬
of severe prior reaction
⚬ consider dosing intervals of 60 minutes
negative challenge established with total cumulative dosing: at least 15-20 ⚬
mg/kg/dose for acetaminophen, 10 mg/kg/dose for ibuprofen, and 15-20 mg/kg/dose for aspirin
⚬ observe patients for at least 1.5-2 hours after negative challenge testing ⚬ Reference - Pediatr Allergy Immunol 2018 Aug;29(5):469
● aspirin must be taken routinely following challenge to retain tolerance
tolerance can be maintained with as little as aspirin 81 mg for patients who only need ⚬
cardiovascular disease prophylaxis
some people receiving maintenance therapy with aspirin 81 mg/day will react when ⚬
given higher doses of aspirin or other NSAIDs
⚬ Reference - Immunol Allergy Clin North Am 2016 Nov;36(4):693 Aspirin graded dose challenge protocols
multiple protocols have been published, most based on expert opinion and critical re ●
view of past cases
Scripps oral aspirin graded dose challenge protocol for patients with cardiovascular dis ●
ease commonly used in the United States
⚬ if symptoms occur throughout procedure
– treat symptoms
– repeat dose that provoked symptoms before proceeding
⚬ administer 40.5 mg aspirin, observe patient for 90 minutes ⚬ administer 40.5 mg aspirin (81 mg cumulative dose)
⚬ observe patient for 90 minutes
– if patient reaction, consider another 40.5 mg dose with observation
if 81 mg is target therapeutic dose and no patient reaction, continue with mainte –
nance dose of 81 mg on following day
⚬ Reference - Allergy Asthma Proc 2013 Mar-Apr;34(2):138
protocols recommended by European Network on Drug Allergy (ENDA)/European Acad ●
emy of Allergy and Clinical Immunology (EAACI) Drug Allergy Interest Group
challenge not recommended for patients with history of severe anaphylaxis reaction ⚬
to NSAIDs
for patients with chronic ischemic heart disease (CIHD), history of NSAID-related hy ⚬
persensitivity reactions, and NO history of severe anaphylaxis reaction to NSAIDs, can consider oral aspirin graded dose challenge with dosing up to 110 mg
negative challenge indicates patient may take low-dose aspirin for cardioprotec –
tion, coronary angiography, and stenting
positive reaction at dose ≤ 100 mg indicates need for avoidance, or proceeding –
with oral aspirin graded dose challenge with very low starting dose, if felt to be in the patient's best interest prior to use for cardioprotection, coronary angiography, and stenting
Table 4. ENDA/EAACI Oral Aspirin Graded Dose Challenge Protocol
* Patient observed for 2 hours
following procedure.
** Normally procedure ends at 110 mg but
is carried to 160 mg at cardiologist's request.
– Reference - Allergy 2017 Mar;72(3):498
for patients with chronic ischemic heart disease and positive reaction to acetylsalicy ⚬
late acid (ASA) at doses < 100 mg or patients with acute coronary syndrome (ACS) re quiring rapid challenge testing
ENDA/ EAACI suggests an oral aspirin graded dose challenge/desensitization with –
cumulative dose goal of 100 mg, starting at very low dose
Table 5. Aspirin Oral Graded Dose Challenge Protocol With Very Low Starting Dose
Abbreviation: ASA,
acetylsalicylate acid; L-ASA, lysine
acetylsalicylate.
* 288 mg L-ASA,
equivalent to 160 mg of ASA, dissolved in 16 ml of
water used.
** 1-2 hours
observation after procedure.
– Reference - Allergy 2017 Mar;72(3):498
CLINICIANS' PRACTICE POINT
The dosing used in this challenge/desensitization protocol starts very low, and may not be necessary or feasible in clinical practice.
STUDY SUMMARY ⚬
ENDA/EAACI protocol for aspirin challenge at doses required for antiplatelet ther apy in patients with heart disease reported safe and e!ective for aspirin challenge in patients with NSAID/aspirin-related hypersensitivity DynaMed Level 3
CASE SERIES: Allergy 2017 Mar;72(3):498
Details
– based on case series
310 patients (45.5% male, mean age 63.9 years) with ACS (138 patients) or CIHD –
(172 patients) and history of hypersensitivity to NSAIDs or aspirin were challenged with aspirin
163 patients were challenged with 10 mg starting dose, escalating to 110 mg over –
155 minutes (110 mg protocol); 147 patients with 0.1 mg starting dose, escalating to 100.1 mg over 300 minutes (100 mg protocol)
– patients had clinical history of
hypersensitivity reaction to aspirin dose of ≤ 300 mg (38.4%) or > 300 mg ●
(61.6%)
urticaria/angioedema in 217 (70%), anaphylaxis in 50 (16.1%), bronchospasm in ●
17 (5.5%), or delayed cutaneous reactions in 26 (8.4%)
● hypersensitivity to ≥ 1 NSAIDS and aspirin in 65.8% or aspirin alone in 34.2%
– patients with severe anaphylactic reactions to aspirin were excluded
of 138 patients with ACS, 63% treated with angioplasty and or stent placement; –
16.7% were challenged with 110 mg protocol, 48.6% with 100 mg protocol of 172 patients with CIHD, 126 were challenged with 110 mg protocol, 46 with 100 –
mg protocol
– 110 mg challenge in 163 patients
doses were up to 160 mg (95 patients), up to 500 mg (48 patients), or cumulative ●
dose 110-160 mg (20 patients)
● outcomes included
reactions at ≤ 500 mg in 7 patients, and at cumulative dose of 110 mg in 3 ⚬
patients
3 reacting patients with aspirin exacerbated respiratory disease diagnosis ef ⚬
fectively desensitized
⚬ 7 reacting patients with cutaneous disease failed desensitization – 100 mg challenge in 147 patients
doses were cumulative doses of 150 mg (82 patients), 317 mg (10 patients), and ●
100 mg (55 patients)
outcomes included 10 patients with reactions but successful tolerance to 100 ●
mg dose and 2 failures
– Reference - Allergy 2017 Mar;72(3):498 Consultation and referral
consider consult with board-certi"ed allergist for patients with hypersensitivity reactions ●
that are severe, involve anaphylaxis, or require drug challenge or desensitization (Aller gy 2017 Mar;72(3):498)
Anaphylaxis management ● immediate measures
assess airway, breathing, circulation, and level of consciousness and support airway if ⚬
needed
⚬ give epinephrine
0.2-0.5 mg (0.01 mg/kg in children up to 0.3 mg) intramuscularly in anterolateral –
thigh every 5-10 minutes as needed to control symptoms and increase blood pressure
⚬ place adults and adolescents in recumbent position and pregnant women on left side
rapid !uid replacement with 1-2 L normal saline at 5-10 mL/kg within "rst 5 minutes ⚬
(30 mL/kg in "rst hour in children)
● adjunctive therapy
consider H1 antihistamine, such as diphenhydramine 25-50 mg in adults and 1 mg/kg ⚬
(maximum 50 mg) in children over 10-15 minutes
⚬ consider H2 antihistamine, such as famotidine 20 mg IV or cimetidine 4 mg/kg IV
combination of ranitidine plus diphenhydramine is more e#ective than diphenhy ⚬
dramine alone for resolution of acute urticaria DynaMed Level 1
FDA withdraws all prescription and over-the-counter ranitidine products due to ongo ⚬
ing presence of N-Nitrosodimethylamine (NDMA), a probable human carcinogen; cur rently, FDA testing has not found NDMA in certain other H2 blockers (famotidine or cimetidine) or proton pump inhibitors (FDA Press Release 2020 Apr 1 )
● additional therapies in refractory cases
IV epinephrine starting at 2 mcg/minute and increasing up to 10 mcg/minute (but risk ⚬
for potentially lethal arrhythmia)
albuterol (nebulized therapy 2.5-5 mg in 3 mL of saline or 2-6 pu#s of metered-dose ⚬
inhaler)
⚬ dopamine 2-20 mcg/kg/minute infusion for refractory hypotension
IV glucagon 1-5 mg for beta-blocker associated reaction, which may not respond to ⚬
administration of epinephrine
systemic corticosteroids often used to prevent biphasic or protracted anaphylaxis but ●
no supporting evidence
● observe patient for at least several hours, depending on treatment response ● see Anaphylaxis for details
Complications and Prognosis
Prognosis
STUDY SUMMARY ●
some patients with NSAID-induced urticaria/angioedema may lose hypersensitivity over several years of time DynaMed Level 2
COHORT STUDY: Allergy 2017 Sep;72(9):1346
Details
⚬ based on prospective cohort study
38 patients with NSAID-induced urticaria or angioedema (NIUA) (median age 38 years, ⚬
63.2% female) followed for median of 78 months, evaluated twice after NIUA diagno sis to determine stability of NSAID intolerance
⚬ patients < 14 or > 60 years old excluded
drug provocation testing involved acetylsalicylic acid (ASA) challenge, followed after ≥ ⚬
1-week interval by NSAID challenge, if ASA did not provoke response "rst follow-up hypersensitivity assessment (T1) occurred at a median of 60 months ⚬
after diagnosis
– tolerance to NSAIDs seen in 24 patients (63.2%)
– cutaneous symptoms seen in 14 patients (36.8%)
⚬ second follow-up assessment (T2) occurred at a median of 18 months after T1 – tolerance to NSAIDs seen in same 24 patients (63.2%)
– cutaneous symptoms seen in same 14 patients (36.8%)
comparing patients that developed tolerance (group T) with those that remained in ⚬
tolerant (Group I), intolerance associated with increased number of episodes – 5 episodes (group I) compared with 2.5 episodes (group T)
– odds ratio 1.9 (95% CI 1.12-3.22, p < 0.02)
⚬ Reference - Allergy 2017 Sep;72(9):1346
Prevention and Screening ● not applicable
Guidelines and Resources Guidelines
International guidelines
European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma Eu
●
ropean Network (EAACI/GA2LEN) guideline on aspirin provocation tests for diagnosis of aspirin hypersensitivity can be found in Allergy 2007 Oct;62(10):1111
European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma Eu
●
ropean Network/ European Dermatology Forum/urticaria network (EAACI/GA2 LEN/EDF/UNEV) consensus recommendations on de"nition, diagnostic testing, and man agement of chronic inducible urticarias: 2016 update and revision can be found in Aller gy 2016 Jun;71(6):780
European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma Eu
●
ropean Network/ European Dermatology Forum/World Allergy Organization (EAACI/GA2 LEN/EDF/WAO) guideline on de"nition, classi"cation, diagnosis, and management of ur ticaria: 2013 revision and update can be found in Allergy 2014 Jul;69(7):868
International Collaboration in Asthma, Allergy and Immunology (iCAALL) consensus on ●
drug allergy can be found in Allergy 2014 Apr;69(4):420
United States guidelines
American Academy of Allergy, Asthma, and Immunology/American College of Allergy, ●
Asthma, and Immunology (AAAAI/ACAAI) practice parameter on diagnosis and manage ment of acute and chronic urticaria can be found in J Allergy Clin Immunol 2014 May;133(5):1270
American College of Allergy, Asthma, and Immunology/Society for Academic Emergency ●
Medicine (ACAAI/SAEM) consensus parameter for the evaluation and management of angioedema in the emergency department can be found in Acad Emerg Med 2014 Apr;21(4):469
American Academy of Allergy, Asthma, and Immunology/American College of Allergy, ●
Asthma, and Immunology/Joint Council of Allergy, Asthma, and Immunology (AAAAI/ACAAI/JCAAI) practice parameter on drug allergy can be found in Ann Allergy Asthma Immunol 2010 Oct;105(4):259
American Academy of Allergy, Asthma, and Immunology/American College of Allergy, ●
Asthma, and Immunology (AAAAI/ACAAI)
2020 practice parameter update on anaphylaxis can be found in J Allergy Clin Im ⚬
munol 2020 Apr;145(4):1082 and at
2015 practice parameter on anaphylaxis can be found in Ann Allergy Asthma Im ⚬
munol 2015 Nov;115(5):341 and at
American Academy of Allergy, Asthma, and Immunology/American College of Allergy, ●
Asthma, and Immunology (AAAAI/ACAAI) practice parameter on emergency department diagnosis and treatment of anaphylaxis can be found in Ann Allergy Asthma Immunol 2014 Dec;113(6):599
American Academy of Allergy, Asthma, and Immunology (AAAAI) report on adverse reac ●
tions to drugs and biologics in patients with clonal mast cell disorders can be found in J Allergy Clin Immunol 2019 Mar;143(3):880
United Kingdom guidelines
National Institute for Health and Care Excellence (NICE) guideline on diagnosis and man ●
agement of drug allergy can be found at NICE 2014 Sep:CG183 PDF , summary can be found in BMJ 2014 Sep 3;349:g4852
British Society for Allergy and Clinical Immunology (BSACI) guideline on management of ●
chronic urticaria and angioedema can be found in Clin Exp Allergy 2015 Mar;45(3):547,
commentary can be found in Clin Exp Allergy 2015 Aug;45(8):1370
British Society for Allergy and Clinical Immunology (BSACI) guideline on management of ●
drug allergy can be found in Clin Exp Allergy 2009 Jan;39(1):43, commentary can be found in Clin Exp Allergy 2010 May;40(5):697
Royal College of Paediatrics and Child Health (RCPCH) care pathway for children with ur ●
ticaria, angioedema, or mastocytosis can be found in Arch Dis Child 2011 Nov;96 Suppl 2:i34
European guidelines
European Academy of Allergy and Clinical Immunology (EAACI) position paper on how to ●
classify cutaneous manifestations of drug hypersensitivity can be found in Allergy 2019 Jan;74(1):14
● European Academy of Allergy and Clinical Immunology (EAACI) position papers on
classi"cation and practical approach to diagnosis and management of hypersensitivi ⚬
ty to nonsteroidal anti-in!ammatory drugs can be found in Allergy 2013 Oct;68(10):1219, commentary can be found in Allergy 2014 Jun;69(6):815 desensitization in delayed drug hypersensitivity reactions can be found in Allergy ⚬
2013 Jul;68(7):844
pharmacovigilance of drug allergy and hypersensitivity using ENDA-DAHD database
⚬
and GA2LEN platform: the Galenda project can be found in Allergy 2009 Feb;64(2):194
EAACI task force report on recognizing the potential of the primary care physician in the ●
diagnosis and management of drug hypersensitivity can be found in Clin Transl Allergy 2018;8:16
European Network on Drug Allergy/European Academy of Allergy and Clinical Immunol ●
ogy (ENDA/EAACI)
ENDA/EAACI position paper on diagnosis and management of hypersensitivity reac ⚬
tions to non-steroidal anti-in!ammatory drugs (NSAIDs) in children and adolescents can be found in Pediatr Allergy Immunol 2018 Aug;29(5):469
ENDA/EAACI position paper on skin test concentrations for systemically administered ⚬
drugs can be found in Allergy 2013 Jun;68(6):702
ENDA/EAACI position paper on In vitro tests for drug hypersensitivity reactions can be ⚬
found in Allergy 2016 Aug;71(8):1103, editorial can be found in Allergy 2016 Aug;71(8):1079
ENDA/EAACI position paper on drug hypersensitivity in clonal mast cell disorders can ⚬
be found in Allergy 2015 Jul;70(7):755
ENDA/EAACI consensus statement on rapid desensitization for drug hypersensitivity ⚬
can be found in Allergy 2010 Nov;65(11):1357
Italian expert consensus statement on diagnosis and treatment of acute angioedema in ●
the emergency department can be found in Intern Emerg Med 2014 Feb;9(1):85
Asian guidelines
Taiwanese Dermatological Association (TDA) consensus guideline on de"nition, classi"- ●
cation, diagnosis, and management of urticaria can be found in J Formos Med Assoc 2016 Nov;115(11):968
Dermatological Society of Thailand/Allergy, Asthma, and Immunology Association of ●
Thailand/Pediatric Dermatological Society of Thailand (DST/AAIAT/PDST) clinical practice guideline on diagnosis and management of urticaria can be found in Asian Pac J Allergy Immunol 2016 Sep;34(3):190
Japanese Dermatological Association (JDA) clinical practice guideline on urticaria can be ●
found at Minds guideline listing (医療情報サービスマインズ) PDF [Japanese ⽇本語]
Japanese Dermatology Association (JDA) guideline on diagnosis and treatment of ur ●
ticaria and angioedema can be found in Allergol Int 2012 Dec;61(4):517
Central and South American guidelines
Argentina Association of Allergy and Clinical Immunology/Argentina Society of Dermatol ●
ogy (Asociacion Argentina de Alergia e Inmunologia Clinica/Sociedad Argentina de Der matologia [AAAeIC/SAD]) guideline on urticaria and angioedema can be found in Medici na (B Aires) 2014;74 Suppl 1:1 [Spanish]
Review articles
● review of NSAID hypersensitivity can be found in Neth J Med 2018 Mar;76(2):52
review of diagnosis and management of NSAID hypersensitivity in children can be found ●
in Pediatr Allergy Immunol 2018 Aug;29(5):469
review of drug provocation testing in patients with drug hypersensitivity can be found in ●
Int J Mol Sci 2017 Jul 4;18(7):E1437
review of aspirin desensitization in patients with NSAID-exacerbated respiratory disease ●
(NERD) can be found in Immunol Allergy Clin North Am 2016 Nov;36(4):705 review of NSAID-hypersensitivity can be found in Korean J Intern Med 2016 ●
May;31(3):417
review of NSAID-hypersensitivity in children and adolescents can be found in J Investig ●
Allergol Clin Immunol 2015;25(4):259
MEDLINE search
to search MEDLINE for (Nonsteroidal anti-in!ammatory drug (NSAID)-related urticaria ●
and angioedema) with targeted search (Clinical Queries), click therapy , diagnosis , or prognosis
Patient Information
● handout on angioedema from EBSCO Health Library or in Spanish
handout on allergic reactions to aspirin and other painkillers from Australasian Society ●
of Clinical Immunology and Allergy PDF
handout on medications and drug allergic reactions from American Academy of Allergy, ●
Asthma & Immunology
● handout on urticaria and angioedema from British Association of Dermatologists PDF
● handouts from Patient UK on
⚬ drug allergy PDF
⚬ hives (acute urticaria) PDF
⚬ angioedema PDF
● handout on hives (urticaria) from TeensHealth or in Spanish
References
General references used
1. Kowalski ML, Woessner K, Sanak M. Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-in!ammatory drug-related urticaria and an gioedema. J Allergy Clin Immunol. 2015 Aug;136(2):245-51
2. Sa# RR, Banerji A. Management of patients with nonaspirin-exacerbated respiratory dis ease aspirin hypersensitivity reactions. Allergy Asthma Proc. 2015 Jan-Feb;36(1):34-9
3. Blanca-Lopez N, Perez-Alzate D, Canto G, Blanca M. Practical approach to the treatment of NSAID hypersensitivity. Expert Rev Clin Immunol. 2017 Nov;13(11):1017-27
4. Modena B, White AA, Woessner KM. Aspirin and nonsteroidal antiin!ammatory drugs hypersensitivity and management. Immunol Allergy Clin North Am. 2017 Nov;37(4):727- 749
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