NSAIDs/ASA Hypersensitivity: Diagnostic test

Theerapan Songnuy

Outlines

• Definition• Epidemiology• Classification and clinical manifestation• Diagnostic tests

NSAID/ASA Hypersensitivity

• Unintended and not predictable from the known pharmacology of the drug adverse reaction to NSAIDs

Johansson SG. Allergy, 2001;56:813-824.

Epidemiology

• NSAIDs/ASA is the 2nd most common cause of drug-induced hypersensitivity reaction*

• NSAIDs are responsible for 21-25% of adverse drugs events** including immunological and non-immunological reaction

* Gomes ER, Demoly P. Epidemiology of hypersensitivity drugs reactions. Curr Opin Allergy Clin Immunol 2005; 5: 309-316.

** Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J et al. Hypersensitivity to nonsterooidal anti-inflammatory drugs ( NSAIDs) – classification, diagnosis and management: review of the EAAC/ENDA and GA2LEN/HANNA. Allergy 2011; 66: 818-829.

Mechanism

Classification of Hypersensitivity reaction to ASA & NSAIDS

• Acute ( immediate to several hours after exposure) 1. Rhinitis/ asthma : - cross-reactive - inhibition of COX-1 - underlying; asthma, rhino-sinusitis, nasal polyps 2. Anaphylaxis/ angioedema/urticaria : - single drug-induced - IgE-mediated - underlying; atopy, food or drug allergy

Classification of Hypersensitivity reaction to ASA & NSAIDS

• Acute ( immediate to several hours after exposure) 3. Urticaria /angioedema

- cross-reactive

- inhibit COX-1 - underlying; chronic urticaria 4. Urticaria/ angioedema - multiple NSAIDs-induced - presumably COX-1 inhibition - no underlying disease

Classification of Hypersensitivity reaction to ASA & NSAIDS

• Delayed ( more than 24 hours after exposure) - Various clinical manifestations ; fixed drug eruption maculopapular rash bullous lesion contact dermatitis photo contact dermatitis pneumonitis aseptic meningitis nephritis

Classification of Hypersensitivity reaction to ASA & NSAIDS

• Delayed ( more than 24 hours after exposure) - T cell-mediated, Cyto-toxic T cells,NK cells - Single drug or multiple drug-induced - No underlying disease

Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactionto drugs that inhibit cyclooxygenase enzymes. Ann Allergy Asthma Immunol 2001; 87: 177-180

Clinical Patterns of NSAIDs Reactions

• Demographic characteristics of 164 children with suspected hypersensitivity to COX inhibitors

Number and sex 164 (102 M, 62 F) Age Mean = 7.2 y ( 7 m-17.3 y) Time between last reaction Mean = 8 m ( 4-20 m) and follow up Familial history of atopy 85 (52%) Personal atopy 102 ( 62%)

Previous known exposure to 23 (14%) the suspected drug Suspected allergic reactions to other drugs 60 (37%) EDJ, vol 18, n 5, September-October 2008

Clinical characteristics of 213 suspected allergic reactions to COX inhibitors reported by 164 children

• Type and chronology Immediate (≤ 2 h) Accelerated (≤ 48 h) Delayed (> 48 h) Total: n (%) of the reactions

Isolated urticaria and/or angioedema 45 69 15 129 (61%)

Cutaneous + respiratory symptom 16 7 10 33 ( 15.6%)

Anaphylactic shock 18 6 0 24 ( 11.4%) (± skin and/or respiratory symptoms) Isolated rash 6 7 3 16 ( 7.5%)

Isolated respiratory symptoms 0 10 0 10 ( 4.3%) (rhinitis, asthma)

Isolated conjunctivitis 0 1 0 1 ( 0.5%)

Total 85 (40.1%) 100 (46.7%) 28 (13.2%) 213 (100%)

EDJ, vol 18, n 5, September-October 2008

Hypersensitivity to nonsteroidal anti inflammatory drugs (NSAIDs) – classification, diagnosis and ‐management: review of the EAACI/ENDA# and GA2LEN/HANNA*

Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J et al. Hypersensitivity to nonsterooidal anti-inflammatory drugs ( NSAIDs) – classification, diagnosis and management: review of the EAAC/ENDA and GA2LEN/HANNA . Allergy 2011; 66: 818-829.

Oral Provocation TestClinical characteristics of pt. with NSAID-Induced Cross-Reactive Reaction

Challenge R. N Underlying Atopy SBPCOC (+/-)

Noso-ocular 8(5.3) rhinitis and/or 69.2% 42/90 asthma ( 100%)Asthma w/wo 18 ( 12)Noso-ocular

Angioedema w 14 ( 9.3)Asthma and/or Naso-ocular

Isolated angioedema 51 ( 34) rhinitis and/or asthma 100% 58/81 ( 100%)Urticaria/angioedema 59 ( 39.3) chr. Urticaria ( 21.0%) 10.1% 60/135Total 150 76.6% 54% 160/306 Quiralte J, Blanco C, Delgado J, Ortega N, Ancantara M, Castillo R, et al. Challenge-Based Clinical Patterns of 223 Spanish Patients With Nonsteroidal Anti-Inflammatory-Drug-Induced- Reactions. J Investig Clin Immunol. 2007; 17(3):182-188.

ASA Provocation Tests• Oral Provocation Test as a gold standard*

• Bronchial ( inhalation) L-lysine aspirin challenge - safer, faster, but less sensitive**

• Nasal L-ASA challenge - predominantly nasal symptom - contraindicated from oral & bronchial - negative predictive value is lower - negative test should be followed by oral or bronchial challenge test ***

* Quiralte J, et al. Allergy 1996;98: 678-685.

** Melillo G, et al. Allergy 2001; 56: 899-911.*** Casadevall J, et al. Thorax 2000;55: 921-924.

EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity

General considerations 1. Oral challenges have to be carried out under the direct supervision of a physician &

technicians skilled in performing provocation tests with aspirin. 2. Emergency resuscitative equipment should be readily available. 3. The patients should be in a stable clinical condition. 4. Baseline FEV1 should be at least 70% of the predicted value for oral challenges with

aspirin.

Contraindications for oral aspirin challenges: 1. A history of very severe anaphylactic reactions precipitated by aspirin or other NSAIDs

(nasal aspirin challenge should be considered in any such case ) 2. Severe disease of the heart, digestive tract, liver, kidney. 3. Infection of respiratory tract within 4 weeks prior to the challenge. 4. Pregnancy. 5. Current treatment with β-receptor blocker.

Niżankowska-Mogilnicka E, Bochenek G, Mastalerz L, Świerczyńska M, Picado C, Scadding C, et al. Allergy. 2007;62 ( 10): 1111-1118.

Nasal Provocation Test with ASA

20 Pt. 40Control

16/20positive

Nasal Provocation TestL- ASA ( 900 mg/ml)

37/40positive

Alonso-Liamazares, et al. Allergy 2002; 57: 632-635.

Nasal Provocation Test with ASA

• Test sensitivity 80%• Test specificity 92.5%• Positive predictive value 84.2 %• Negative predictive value 89.2 %

• N o bronchial or systemic symptom• No decrease over 20% were recorded in the FEV1

Alonso-Liamazares, et al. Allergy 2002; 57: 632-635.

• Alonso-Liamazares, et al. Allergy 2002; 57: 632-635

The values of nasal provocation test (NPT) and basophil activation

test in the different patterns of ASA/NSAID hypersensitivity

Wismol P, Putivoranat P, Buranapraditkun S, Pinnobphan P, Ruxrungtham K, Klaewsongkram J

Allergol Immunopathol ( Madr). 2012; 40: 156-63. vol.40 num 03

Background

• Oral provocation test is the current gold standard*• It’s time-consuming and has some systemic risks

• Role of nasal provocation test with l-ASA to diagnose aspirin-induced cutaneous reaction is still unclear.**

• A few papers used nasal provocation test to diagnose ASA-induced urticaria.

* Genton C. et al. J Allergy Clin Immunol. 1985;76 ( july):

40-5.** Tomaz EM. Et al. Allergy Asthma Proc. 1997; 18 ( October) : 19-22.

Objective

• Evaluate the efficacy of the nasal provocation test and the basophil activation test in the diagnosis of various subtypes of ASA hypersensitivity

Materials & Methods

• Inclusion criteria: - aged 15-70 y - history of immediate hypersensitivity reaction

to ASA/NSIADs at least 2 times - and/or had a nasal provocation test positive - total 30 patients were enrolled

Materials & Methods

• Exclusion criteria :

- massive nasal polyps - nasal septal perforation - total nasal obstruction of at least one nostril - pregnancy - exacerbation of rhinitis/asthma - URI within 2 Wk prior to the test - nose surgery within 8 Wk prior to the test - severe systemic diseases

Materials & Methods

• Normal control : 15 healthy people with no history of ASA/NSAIDs hypersensitivity

• Single-blind placebo controlled nasal provocation test • Using 0.9%NaCl to exclude non-specific nasal hyper-reactivity • Using lysine- ASA ( Aspegic, Sanofi-Aventis, France) 80 ul ( total dose 16 mg)• Interpreting with EAACI/GA2LEN guidelines • Nasal symptoms were recorded with 13-point score method • Acoustic rhinometry was used to measure nasal volume• Positive NPT test: - nasal symptoms after challenge - a 25% decrease of total nasal volume at 12 cm from baseline

Materials & Methods

• Basophil ActivationTest ( BAT) - 100 ml of pt’s whole blood - incubated with l-ASA at concentrations of 0.31, 1.25, and 5 mg/ml at 37 C. for 40 min - reaction was stopped ( putting on ice) - centrifuged for 5 min at 4 C, 1000 g - add anti-CD203c-PE & anti-IgE fluorescine isothiocyanate-FITC to label basophil - incubated for 30 min at 4 C

Materials & Methods

• Erythrocyte were lysed • Using to FACScan flowcytometer analyse at 488nm by

CellQuest software.• Double-positive IgE+ and CD203c+ cell were defined as activated basophil Receiver operating characteristic ( ROC) analysis was used to

determine the accuracy of BAT to diagnose ASA/NSAIDs hypersensitivity by using different doses of lysine-ASA

Characteristics of patients with a ASA/NSAID sensitivity (n=30).

Cutaneous Respiratory predominant (n=15) predominant (n=15)

Age (years)/range 44.3 (31–66) 42.1 (16–67) Gender (M/F) 1/14 2/13 Underlying diseases - Chronic rhinosinusitis 1 (6.7%) 4 (26.7%) - Nasal polyps 0 (0%) 5 (33.3%) - Asthma 2 (13.3%) 5 (33.3%) - Chronic urticaria 6 (40%) * 1 (6.7%)

SPT +ve to aeroallergens 8 (53.3%) 13 (86.7%) Symptom onset after drug exposure (minutes) 92 (5–360) 37 (10–60) * Symptom episodes 3.4 (2–10) 5 (2–25) Multiple NSAID hypersensitivity 5 (33% ) 9 (60%)

• = P value < 0.05.

Wismol P, et al. Allergol Immunopathol ( Madr). 2012; 40: 156-63. vol.40 num 03

Wismol P, et al. Allergol Immunopathol. 2012;40:156- 63.

Wismol P, et al. Allergol Immunopathol. 2012;40:156- 63.

Wismol P, et al. Allergol Immunopathol.2012;40:156- 63

Wismol P, et al. Allergol Immunopathol.2012;40:156- 63

In conclusion

• NPT was able to detect 60% of ASA sensitivity patients both in skin & respiratory symptoms

• The combination of using NPT & BAT with l-ASA increases test’s sensitivity• A good method to diagnose ASA/NSAIDs

hypersensitivity syndrome - good sensitivity - less side effects - less time- consuming

Thank you verymuch