Professor MJ Torres
Carlos Haya Hospital, University of Medicine, Malaga, Spain
SESSION II: DIAGNOSIS OF HYPERSENSITIVITY TO NSAIDS IN PATIENTS WITH SELECTIVE RESPONSES
VALUE OF DRUG PROVOCATION TEST
A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.
Disclosure
In relation to this presentation, I declare that there are no conflicts of interest.
NSAIDs are the drugs more frequently prescribed worldwide
0
10
20
30
40
50
60
70
Benzylpenicillin Amoxicillin AX-Clavulanic CephalosporinAzithromycin Clarithromycin Ibuprofen Dipirone
Aspirin Paracetamol Anesthesics Others
% o
f dru
gs in
volv
ed in
the
reac
tion
P<0.001
Children with a history of drug allergy N=866 (2006-2012)
Corzo JL. 2013
DRUG HYPERSENSITIVITY IN CHILDREN
Zambonino MA. 2013
Hypersensitivity Non-hypersensitivity p (N, %) 128 (14.78) 738 (85.22) DRUGS (N, %) NSAID Betalactams Macrolides
57 (44,53) 55 (42,97)
2 (1,56)
41 (5,56)
587 (79,54) 20 (2,71)
0,000
DRUGS (%) Ibuprofen Dypirone Paracetamol ASA
55 (63.2)
0 1 (14.3) 1 (50)
32 (36.8) 2 (100) 6 (85.7)
1 (50)
0.000
PATTERN OF COMSUMPTION OVER TIME
0
5
10
15
20
25
30
1996 1998 2000 2002 2004 2006
Arilacetic
Arilpropionic
Coxib
DDD/1,000 patient day
1996 1998 2000 2002 2004 2006
Timing Clinical manifestation
Type of reaction
Underlying disease
Putative mechanism
Acute (immediate to several hours exposure)
Rhinitis/asthma Urticaria/angioedema Urticaria/angioedema Urticaria/angioedema/ anaphylaxis
Cross-reactive
Cross-
reactive
Múltiple
Single
Astma/rhinosinusitis/ nasal polyps Chronic urticaria None Atopy?? Food allergy?? Drug alergy??
COX-1 Inhib COX-1 Inhib COX-1 Inhib??? IgE-mediated
Delayed (more than 24 hours after exposure)
Fixed drug eruptions Severe bullous skin reactions MP drug eruptions Pneumonitis Aseptic meningitis Nephritis Contact and photocontact dermatitis
Single or multiple
Ninguna T cell mediated
CLASSIFICATION
Kowalski ML, EAACI/ENDA and GA2LEN/HANNA. Allergy. 2011;66:818
Type of reac+on
Clinical manifesta+on
Timing Underlying disease
Cross reac+vity
Puta+ve mechanism
NSAIDs exacerbated respiratory disease (NERD)
Rhini%s/asthma Acute Asthma/rhinosinusi%s
YES Non-‐allergic
Cox-‐1 inhibi%on
NSAIDs exacerbated cutaneous disease (NECD)
Ur%caria/angioedema
Chronic ur%caria
Cox-‐1 inhibi%on
NSAIDs –induced ur+caria/angioedema (NIUA)
Ur%caria/angioedema
No underlying chronic diseases
Unknown , probably COX-‐1 inhibi%on
Single NSAIDs –induced ur+/angio/ anap (SNIUAA)
Ur%caria/angioedema/anaphylaxis
No underlying chronic diseases
NO Allergic IgE-‐mediated
Single NSAIDs-‐induced delayed reac+ons (SNIDR)
various symptoms and organs involved
Delayed No underlying chronic diseases
T cell mediated
CLASSIFICATION
ENDA NSAID TF (Kowalsky M, 2013)
¤ Immediate hypersensitivity reactions to a single NSAID or to several NSAIDs belonging to the same chemical group, manifesting as urticaria, angioedema and /or anaphylaxis.
¤ These subjects tolerate other chemically non-related NSAIDs, and usually do not have a history of chronic urticaria or asthma
DEFINITION
ENDA NSAID TF (Kowalsky M, 2013)
Single NSAID–induced urticaria/angioedema or anaphylaxis (SNIUAA)
EPIDEMIOLOGY ¤ Up to 30% of all NSAIDs-induced skin reactions can represent a
single drug-induced hypersensitivity reaction.
¤ The most frequently described causes of this type of reaction are pyrazolones, ibuprofen, diclofenac, aspirin and paracetamol .
¤ The clinical spectrum of symptoms and timing of reactions suggest an allergic type I mechanism.
¤ Reactions to very closely chemically related compounds within the same chemical group (e.g. to different pyrazolones) can occur suggesting epitope-specific immunological mechanism of reactions .
¤ In a small proportion of patients specific IgE can be detected in the skin test or in the serum, which may further support an IgE-mediated mechanism of drug hypersensitivity .
Single NSAID–induced urticaria/angioedema or anaphylaxis (SNIUAA)
PATHOMECHANISMS
¤ From mild urticaria and localized angioedema to laryngeal edema and anaphylaxis develop usually within minutes after a single NSAID intake .
¤ Reaction to a single NSAID usually appear at shorter intervals than NIUA and may develop within seconds or minutes.
¤ Patients usually present with a history of good tolerance to other chemically unrelated NSAIDs, including aspirin.
¤ Patients do not have a history of underlying chronic urticaria.
CLINICAL PRESENTATION
DEFINITION
ENDA NSAID TF (Kowalsky M, 2013)
NSAIDs-induced delayed hypersensitivity reactions (NIDHR)
¤ Hypersensitivity reactions to a single NSAID appearing usually within 24-48 hours after drug administration and manifesting by either skin symptoms (exanthema, fixed drug eruption), other organ specific symptoms (e. g. renal, pulmonary) or severe cutaneous adverse reactions (SCAR).
EPIDEMIOLOGY
¤ The prevalence of NSAIDs induced delayed reactions is not known.
¤ The most common delayed reactions due to NSAIDs are maculopapular eruptions (MPE), fixed drug eruptions (FDE), contact dermatitis and photosensitivity reactions.
¤ Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug induced hypersensitivity syndrome (DIHS) can be also induced by NSAIDs.
ENDA NSAID TF (Kowalsky M, 2013)
PATHOMECHANISMS
¤ The pathomechanism of NIDHRs involves the stimulation of drug-specific CD4+ and CD8+ T cells through their T cell receptors (TCR) and represents a delayed type hypersensitivity.
¤ T cell dependent mechanisms have been documented in delayed urticaria, MPE induced by aceclophenac and metamizol and in SCAR induced by ibuprofen
NSAIDs-induced delayed hypersensitivity reactions (NIDHR)
CLINICAL PRESENTATION ¤ They appear more than 24-48 hours after exposure.
¤ The skin is the organ most frequently involved, usually with mild symptoms such as MPE, FDE, photosensitivity, delayed urticaria and contact dermatitis.
¤ Although less frequent, more severe reactions such as DIHS, AGEP and SCAR and organ-specific reactions may occur.
659 patients with symptoms suggestive of NSAID hypersensitivity
Cross-sensitive
76%
Selective
24%
Doña I. Clin Exp Allergy 2010
63 children (2008-2012)
43 (68.2%) OPT culprit +
25 (58,1%) OPT ASA +
18 (41,9%) OPT ASA -
SELECTIVE CROSS SENSITIVE
Cross sensitive Selective
FREQUENCY 75% 25%
TENDENCY Stable or Increase Decrease
DRUG Ibuprofen ASA Pyrazolones
CLINICAL SYMPTOMS
Urticaria Angioedema
Blended
Urticaria Angioedema Anaphylaxis
Delayed
ATOPY YES NO
FOOD ALLERGY YES? NO
DIFFERENTIAL CHARACTERISTICS OF SELECTIVE AND CROSS-SENSITIVE NSAID HYPERSENSITIVITY
How can we perform an accurate diagnosis?????
How can we differentiate between selective and cross-sensitivity hypersensitivity????
• CLINICAL HISTORY
• SKIN TESTING
• IN VITRO TESTING
• DRUG PROVOCATION TEST
NOT RELIABLE
• Oral, Nasal and Bronchial route
• Under strict survelliance, trained personnel, special setting.
• Single blind placebo controlled
• Gold standard
• Sensitivity: 89%
• Specificity: 100%
Time consuming Resources consuming
Risky contraindications
DRUG PROVOCATION TEST
ORAL PROVOCATION TEST
Oral challenge with NSAID can be performed for three reasons:
1) with a culprit drug to confirm hypersensitivity;
2) with other than causative NSAIDs (usually challenge test with aspirin) in order to confirm/exclude cross-reactivity,
3) with the most likely tolerated alternative drug.
ENDA NSAID TF (Kowalsky M, 2013)
ORAL DRUG PROVOCATION TEST
Time Day 1 Day 2 Day 3
7 a.m. Placebo 30 mg 100 mg* 150 mg**
10 a.m. Placebo 45 mg* 60 mg**
150 mg* 325 mg**
13 a.m. Placebo 60 mg* 100 mg**
650 mg
Stevenson et al.
0
100
200
300
400
500
600
700
800
900
1000
1 2 3 4 5 6
Cum
ulat
ive
dose
of a
spiri
n (m
g)
Time (h)
10 mg*
* If the historical reaction was severe ** Iff the historical reaction was milder
17 mg* 27 mg 44 mg
117 mg
312 mg
500 mg
Nizakowska E et al.
Day 1: placebo Day 2: AAS
8:30 am 10:00 am 11:30 am 1:00 am 2:00 am
ORAL DRUG PROVOCATION TEST
DOSES RECOMENDED IN OPT DRUGS CUMMULATIVE DOSES (mg)
Etoricoxib 60 - 90
Celecoxib 100 - 200
Paracetamol 100 - 250 - 500 - 1000
Meloxicam 7,5 - 15
Nabumetone 500 - 1.000
Diclofenac 25 - 50
Metamizol 1º día: 50 - 100 - 250 2º dia: 575
Ibuprofen 1 día º: 50 - 100 - 200 - 400 2º día: 600
ASA 1 día º: 5 - 50 - 100 2º día: 250 - 500
ADULTS
CHILDREN
POSITIVE
NEGATIVE
1. FEV1 decrease more than 20% from basal levels
2. Nasoocular symptoms 3. Skin symptoms
4. Total cummulative doses with good tolerance
ORAL DRUG PROVOCATION TEST
PREDICTIVE VALUE
¥ A positive oral provocation test (OPT) is confirmatory for suspected NSAIDs hypersensitivity.
¥ The test has been documented to have a very high (97,8 %) negative predictive value allowing for safe use of NSAIDs in most patients with equivocal history of hypersensitivity to NSAIDs.
¥ The positive predictive value of OPT is close to 100%.
ENDA NSAID TF (Kowalsky M, 2013)
ORAL DRUG PROVOCATION TEST
ENDA NSAID TF (Kowalsky M)
DRUG PROVOCATION TEST
Nasal and/or bronchial symptoms
NERD/AERD
NPT or BPT can be done Oral provoca+on test?
NPT or BPT can be done Oral provoca+on test?
Positive
Ur+caria/Angioedema Anaphylac+c reac+on
NECD/AECD SELECTIVE SNIUAAA NIUA
Unequivocal History: DPT with ASA to exclude cross-‐reac+vity Equivocal history: DPT with culprit to exclude hypersensi+vity
ASA Positive
NECD/AECD NIUA
Tolerance for COX-‐2 INHIBITORS
ASA Negative
SELECTIVE SNIUAAA
Tolerance test with chemically non-‐realated NSAID
ENDA NSAID TF (Kowalsky M)
DRUG PROVOCATION TEST
Ur+caria/Angioedema Anaphylac+c reac+on
SELECTIVE SNIUAAA
Unequivocal History: DPT with ASA to exclude cross-‐reac+vity Equivocal history: DPT with culprit to exclude hypersensi+vity
ASA Positive
NECD/AECD NIUA
Tolerance for COX-‐2 INHIBITORS
ASA Negative
SELECTIVE SNIUAAA
Tolerance test with chemically non-‐realated NSAID
¤ In order to exclude a cross-reactive type of hypersensitivity an oral challenge with a chemically unrelated strong COX-1 inhibitor (preferable aspirin) may be considered (grade of recommendation D).
¤ If a SNIUAA is diagnosed, a patient can safely take other chemically unrelated NSAIDs (grade of recommendation D).
¤ If the tolerance to a possible alternative NSAIDs is not known, the first approach is to verify the possible existence of cross-intolerance by challenge with alternative NSAIDs (usually aspirin) (grade of recommendation D).
ENDA NSAID TF (Kowalsky M, 2013)
Single NSAID–induced urticaria/angioedema or anaphylaxis (SNIUAA)
ORAL DRUG PROVOCATION TEST GRADING
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DRUG PROVOCATION TEST
¤ There is no standardized protocol for DPT in delayed reactions to NSAIDs .
¤ DPT with culprit NSAIDs can be considered in MPE and FDE (grade of recommendation C).
¤ DPT with culprit NSAIDs are contraindicated in bullous drug eruptions such as toxic epidermal necrolysis, Stevens-Johnson Syndrome, AGEP (grade of recommendation C).
¤ DPT with alternative NSAIDs can be performed in all other situations (grade of recommendation D).
ENDA NSAID TF (Kowalsky M, 2013)
NSAIDs-induced delayed hypersensitivity reactions (NIDHR)
ORAL DRUG PROVOCATION TEST GRADING
Ad 1. The oral challenge test with the culprit drug remains the gold standard to confirm the diagnosis of NSAIDs hypersensitivity, and all patients with equivocal history should be tested. However, oral challenge with a culprit NSAIDs is not recommended in the following situations: - Delayed type reactions (only patients with MPE, non-immediate urticaria or angiodema and FDE can be tested) - A history of severe anaphylaxis - Non–controlled underlying chronic disease (asthma, urticaria) - Low pulmonary function test in an asthma patient - Concomitant disorders which could be aggravated by challenge or treatment
ENDA NSAID TF (Kowalsky M, 2013)
CONCLUSIONS
Ad 2. If aspirin is not the suspected culprit drug the patient should be challenged with aspirin to confirm/exclude cross-sensitivity. Positive reaction would confirm a cross-reactive type of hypersensitivity and negative reaction would speak for a single drug type reaction. If the causative drug was aspirin patient can be provoked with other strong COX-1 inhibitor to confirm the cross-reactive type of hypersensitivity.
ENDA NSAID TF (Kowalsky M, 2013)
CONCLUSIONS
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