VALUE OF DRUG PROVOCATION TEST Professor MJ Torres Carlos Haya Hospital, University of Medicine, Malaga, Spain SESSION II: DIAGNOSIS OF HYPERSENSITIVITY TO NSAIDS IN PATIENTS WITH SELECTIVE RESPONSES
Disclosure In relation to this presentation, I declare that there are no conflicts of interest. 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.
NSAIDs are the drugs more frequently prescribed worldwide
Children with a history of drug allergy N=866 (2006-2012) % of drugs involved in the reaction 70 60 50 40 30 20 10 0 P<0.001 Benzylpenicillin Amoxicillin AX-Clavulanic Cephalosporin Azithromycin Clarithromycin Ibuprofen Dipirone Aspirin Paracetamol Anesthesics Others Corzo JL. 2013
DRUG HYPERSENSITIVITY IN CHILDREN Hypersensitivity Non-hypersensitivity p (N, %) 128 (14.78) 738 (85.22) DRUGS (N, %) NSAID Betalactams Macrolides DRUGS (%) Ibuprofen Dypirone Paracetamol ASA 57 (44,53) 55 (42,97) 2 (1,56) 55 (63.2) 0 1 (14.3) 1 (50) 41 (5,56) 587 (79,54) 20 (2,71) 32 (36.8) 2 (100) 6 (85.7) 1 (50) 0,000 0.000 Zambonino MA. 2013
PATTERN OF COMSUMPTION OVER TIME 30 DDD/1,000 patient day 25 20 15 10 Arilacetic Arilpropionic Coxib 5 0 1996 1998 2000 2002 2004 2006 1996 1998 2000 2002 2004 2006
CLASSIFICATION Timing Clinical manifestation Type of reaction Underlying disease Putative mechanism Acute (immediate to several hours exposure) Rhinitis/asthma Urticaria/angioedema Crossreactive Crossreactive Astma/rhinosinusitis/ nasal polyps Chronic urticaria COX-1 Inhib COX-1 Inhib Urticaria/angioedema Múltiple None COX-1 Inhib??? Urticaria/angioedema/ anaphylaxis Single Atopy?? Food allergy?? Drug alergy?? 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 Kowalski ML, EAACI/ENDA and GA2LEN/HANNA. Allergy. 2011;66:818
CLASSIFICATION Type of reac+on Clinical manifesta+on Timing Underlying disease Cross reac+vity Puta+ve mechanism NSAIDs exacerbated respiratory disease (NERD) NSAIDs exacerbated cutaneous disease (NECD) NSAIDs induced ur+caria/ angioedema (NIUA) Single NSAIDs induced ur+/ angio/ anap (SNIUAA) Rhini%s/asthma Acute Asthma/ rhinosinusi%s Ur%caria/ angioedema Ur%caria/ angioedema Ur%caria/ angioedema/ anaphylaxis Chronic ur%caria No underlying chronic diseases No underlying chronic diseases YES Non- allergic Cox- 1 inhibi%on Cox- 1 inhibi%on Unknown, probably COX- 1 inhibi%on NO Allergic IgE- mediated Single NSAIDs- induced delayed reac+ons (SNIDR) various symptoms and organs involved Delayed No underlying chronic diseases T cell mediated ENDA NSAID TF (Kowalsky M, 2013)
Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) DEFINITION 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 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. ENDA NSAID TF (Kowalsky M, 2013)
Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) PATHOMECHANISMS 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. CLINICAL PRESENTATION 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.
NSAIDs-induced delayed hypersensitivity reactions (NIDHR) DEFINITION 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)
NSAIDs-induced delayed hypersensitivity reactions (NIDHR) 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 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. ENDA NSAID TF (Kowalsky M, 2013)
659 patients with symptoms suggestive of NSAID hypersensitivity Selective 24% Crosssensitive 76% 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 - CROSS SENSITIVE SELECTIVE
DIFFERENTIAL CHARACTERISTICS OF SELECTIVE AND CROSS- SENSITIVE NSAID HYPERSENSITIVITY Cross sensitive Selective FREQUENCY 75% 25% TENDENCY DRUG CLINICAL SYMPTOMS Stable or Increase Ibuprofen ASA Urticaria Angioedema Blended Decrease Pyrazolones Urticaria Angioedema Anaphylaxis Delayed ATOPY YES NO FOOD ALLERGY YES? NO
How can we perform an accurate diagnosis????? How can we differentiate between selective and crosssensitivity hypersensitivity???? CLINICAL HISTORY SKIN TESTING IN VITRO TESTING NOT RELIABLE DRUG PROVOCATION TEST
DRUG PROVOCATION TEST Oral, Nasal and Bronchial route Under strict survelliance, trained personnel, special setting. Single blind placebo controlled ORAL PROVOCATION TEST Gold standard Sensitivity: 89% Specificity: 100% Time consuming Resources consuming Risky contraindications
ORAL DRUG 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 crossreactivity, 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** 13 a.m. Placebo 60 mg* 100 mg** 150 mg* 325 mg** 650 mg Stevenson et al. * If the historical reaction was severe ** Iff the historical reaction was milder 1000 500 mg Cumulative dose of aspirin (mg) 900 800 700 600 500 400 300 200 100 10 mg* 27 mg 17 mg* 44 mg 117 mg 312 mg Day 1: placebo Day 2: AAS 0 1 8:30 2 am 10:00 3 am 11:30 4 am 1:00 5 am 2:006 am Time (h) Nizakowska E et al.
DOSES RECOMENDED IN OPT DRUGS CUMMULATIVE DOSES (mg) Etoricoxib 60-90 Celecoxib 100-200 Paracetamol 100-250 - 500-1000 ADULTS Meloxicam 7,5-15 Nabumetone 500-1.000 Diclofenac 25-50 Metamizol Ibuprofen ASA 1º día: 50-100 - 250 2º dia: 575 1 día º: 50-100 - 200-400 2º día: 600 1 día º: 5-50 - 100 2º día: 250-500 CHILDREN
ORAL DRUG PROVOCATION TEST 1. FEV1 decrease more than 20% from basal levels 2. Nasoocular symptoms 3. Skin symptoms POSITIVE 4. Total cummulative doses with good tolerance NEGATIVE
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)
DRUG PROVOCATION TEST Nasal and/or bronchial symptoms Ur+caria/Angioedema Anaphylac+c reac+on NERD/AERD NECD/AECD NIUA SELECTIVE SNIUAAA NPT or BPT can be done Oral provoca+on test? Unequivocal History: DPT with ASA to exclude cross- reac+vity Equivocal history: DPT with culprit to exclude hypersensi+vity Positive ASA Positive ASA Negative NPT or BPT can be done Oral provoca+on test? NECD/AECD NIUA SELECTIVE SNIUAAA Tolerance for COX- 2 INHIBITORS 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 ASA Negative NECD/AECD NIUA SELECTIVE SNIUAAA Tolerance for COX- 2 INHIBITORS Tolerance test with chemically non- realated NSAID ENDA NSAID TF (Kowalsky M)
ORAL DRUG PROVOCATION TEST GRADING Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) 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)
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ORAL DRUG PROVOCATION TEST GRADING NSAIDs-induced delayed hypersensitivity reactions (NIDHR) 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)
CONCLUSIONS 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)
THANK YOU FUNDING SOURCES Health Ministery (FIS) PI05290 PIO61503 PIO61561 PI071220 Science and Technology Ministery (MCYT) BQU2001-3624 Health Andalucia Ministery PI-0199/2007PI-0243/2007PI-0201/2007PI-0200/2007 Science, Innovation Andalucia Ministery CTS 570 FIS Tematic Network and Co-operative Research Centres RIRAAF (RD07/0064)