NSAIDs/ASA hypersensitivity diagnostic tests Presented by Theerapan Songnuy, MD.

1. NSAIDs/ASA Hypersensitivity:
Diagnostic test
Theerapan Songnuy

2. Outlines
• Definition
• Epidemiology
• Classification and clinical manifestation
• Diagnostic tests

3. 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.

4. 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.

5. Mechanism

6. 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

7. 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

8. 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

9. 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 reaction
to drugs that inhibit cyclooxygenase enzymes. Ann Allergy Asthma Immunol 2001; 87: 177-180

10. 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

11. 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

12. 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.

13. Oral Provocation Test
Clinical 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% 60/135
Total 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.

14. 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.

15. 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, Świerczyoska M, Picado C,
Scadding C, et al. Allergy. 2007;62 ( 10): 1111-1118.

16. Nasal Provocation Test with ASA
40
20 Pt.
Control
Nasal Provocation Test
L- ASA ( 900 mg/ml)
16/20 37/40
positive positive
Alonso-Liamazares, et al. Allergy 2002; 57: 632-635.

17. 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.

18. 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

19. 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.

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

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

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

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

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

31. 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

32. Thank you verymuch