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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


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 .


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


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.


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.

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.


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


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


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)


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)


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).



ORAL DRUG PROVOCATION TEST GRADING

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¤ 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).



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


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.


CONCLUSIONS

THANK YOU

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)

FUNDING SOURCES

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