1. NSAID hypersensitivity is common, affecting up to 1.9% of the general population. It is classified into 5 types based on clinical manifestations and pathophysiology. 2. AERD is characterized by respiratory symptoms like asthma and chronic sinusitis. NSAID-exacerbated cutaneous disease presents with urticaria and angioedema. 3. Diagnosis involves a medical history, skin or oral drug challenge tests, and occasionally immunological tests. Provocation tests with aspirin or other NSAIDs can identify safe alternative medications.

1. Topic conference
NSAIDs hypersensitvity
Anchalee Senavonge, MD
29 July 2016

2. Outline
 Epidemiology
 Classification
 Pathophysiology
 Clinical manifestation
 Diagnosis
 Management

3. Epidemiology
 Second most common cause of drug-induced hypersensitivity reactions
 0.5% to 1.9% of the general population
 among adult asthmatic 4.3% to 11%
 Cutaneous manifestation 0.3% of general population
 The heteroaryl acetic acid group of NSAIDs (naproxen, diclofenac, ibuprofen) carry a higher risk of
anaphylactic reactions
 Pyrazolones are the most likely NSAIDs to induce immediate reactions
Middletont textbook 8th edition

4. Classification
1. NSAID-induced rhinitis/asthma (Aspirin-Exacerbated Respiratory Disease: AERD)
2. NSAIDs-exacerbated urticaria/angioedema
3. Multiple NSAIDs-induced urticaria/angioedema
4. Single NSAID-induced reactions
5. Delayed reactions to NSAIDs
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy 2011; 66: 818–829.

5. Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the EAACI/ENDA and
GA2LEN/HANNA, Allergy 2011

6. New possible pediatric classification
 Historical prospective study, September 1996 to July 2015
 635 Children with clinical history of possible NSAID HS who underwent an oral DPT
 Allergy unit, University Hospital of Montpellier (France)
 NSAID hypersensitivity 107/635 (16.9%)
Cousin M.Phenotypical characterization of children with hypersensitivity reactions to
NSAIDs. Pediatr Allergy Immunol, May 2016:1-6

7. Divergent
43/107 (40.2%) could not be classified by ENDA = ‘divergent'
39/107 divergent for 1 criterion
4/107 for more than 1 criteria
Cousin M.Phenotypical characterization of children with hypersensitivity reactions to
NSAIDs. Pediatr Allergy Immunol, May 2016:1-6

8.  Include presence of risk factors, neglected the underlying chronic diseases.
 Risk factors: chronic urticaria (OR 7.7), atopic status (OR 2.5), ARC (OR 1.7), no
correlation of food allergy
Group
1. 91/107
2. 15/107
3. 1/107
Cousin M.Phenotypical characterization of children with hypersensitivity reactions to
NSAIDs. Pediatr Allergy Immunol, May 2016:1-6
helpful tool to understand the mechanisms leading to reaction-guide allergists in their work-up

9. Pathophysiology

10. Middleton textbook 8th edition

11. Blanca-Lo ´pez et al. Hypersensitivity reactions to NSAIDs: from phenotyping to
genotyping. Curr Opin Allergy Clin Immunol 2014
Cyclooxygenase Hypothesis
Lipoxygenases pathways
15-Lipoxygenase Pathways
Prostaglandin E2
Deficiency
Overproduction of
Leukotrienes
Decrease
lipoxin A4

12. Pathophysiology
Single NSAID- induced reaction
 Immunologically Mediated-IgE
Delay reaction
 type IV reactions with dominant role of effector drug-specific, cytotoxic T cells
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy 2011; 66: 818–829.

13. Overlapping entities
 Two major groups
1. respiratory symptoms then develop some cutaneous response- considered initially as
AERD
2. skin manifestations, cardiovascular, lower airways involvement –belong to the Single
NSAIDs- induced group
Blanca-Lo ´pez et al. Hypersensitivity reactions to NSAIDs: from phenotyping to
genotyping. Curr Opin Allergy Clin Immunol 2014

14. Atopy association
 Atopy is a predisposing factor for both multiple NSAID–induced urticaria and AECD
 AERD
 house dust mite, pollens, mould and animal dander
 34% -64% in a European cohort, in adult-less common
 food allergy and NSAIDs has been reported-fish allergen
Blanca-Lo ´pez et al. Hypersensitivity reactions to NSAIDs: from phenotyping to
genotyping. Curr Opin Allergy Clin Immunol 2014
Middleton textbook 8th edition

15. Genetic
AERD
 HLA-DPB1*0301
 leukotriene- and prostanoid-related genes [lipoxygenase (LOX) pathway, CysLTR1 and
CysLTR2]
 Eosinophil-related genes, including CRTH2 and CCR3
NSAIDs induced urticaria
 HLA-DRB1*1302- DQB1*0609-DPB1*0201
 Neutrophil-related genes -potential targets for multiple NSAID–induced urticaria
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy 2011; 66: 818–829.
Middleton textbook 8th edition

16. Environment
 Human rhinovirus
 Staphylococcus enterotoxin IgE more abundant in nasal polyp, higher specific
IgE to staphylococcal superantigen in AERD
Middleton textbook 8th edition

17. Clinical manifestation

18. 1. Aspirin-Exacerbated Respiratory Disease (AERD)
 Typical “ASA triad”
1. chronic rhinosinusitis with polyp
2. moderate to severe bronchial asthma
3. hypersensitivity reactions
 Distinctive pattern- sequence of symptoms
 "classic" adverse reaction – bronchospasm, rhinitis symptoms and ocular injection
 NSAID- risk factor for development of severe chronic asthma, also strongly associated with
near-fatal asthma
Middleton textbook 8th edition

19. The GA2LEN survey of AERD
Makowska JS, Burney P, Jarvis D. Respiratory hypersensitivity reactions to NSAIDs in
Europe: the global allergy and asthma network (GA2LEN) survey. Allergy, May 2016
• 22 centers in 15 European countries
• 62,737 participants
• Questionnaires
• Prevalence 1.9% (vary between centers)
• Highest –Krakow and Katowice – most polluted cities in
Europe
• highest prevalence cities also had highest level of sensitization
to Staphylococcus aureus endotoxins

20. Risk factors
• asthma (OR = 5.5)
• chronic rhinosinusitis (OR =
4.28)
• older age (OR = 1.53)
• ever smoking (OR 1.62)
• female gender (OR 1.68)
Aspirin triad only 15%
Makowska JS, Burney P, Jarvis D. Respiratory hypersensitivity reactions to NSAIDs in Europe: the
global allergy and asthma network (GA2LEN) survey. Allergy, May 2016

21. 2. NSAIDs-exacerbated urticaria/angioedema
 Usually after 1 to 4 hours of drug ingestion
 local or generalized urticaria, combined with angioedema -more severe
 subside within few hours, may persist for several days –may temporary fluctuation
 Underlying chronic urticaria -12% to 30% with chronic spontaneous urticaria
 Some patients precede the development of chronic urticaria
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy 2011.
 Now classified as NSAID–exacerbated cutaneous disease (NECD)
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015

22. 3. Multiple NSAIDs-induced urticaria/angioedema
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015
 Now classified as NSAIDs-induced urticaria/angioedema (NIUA)
 Urticaria and facial angioedema within minutes or up to 24 h
 angioedema without urticaria (ibuprofen and diclofenac)
 no history of underlying chronic skin and/or respiratory disorders
 60% have atopic diseases (rhinitis and asthma), and positive skin test to inhalant allergens
(D. farinae and pteronyssinus) --> role of underlying atopy and IgE-related mechanisms

23. 4. Single NSAID-induced reactions
 Single NSAID–induced urticaria/angioedema, anaphylaxis, or both (SNIUAA)
 Wheals, angioedema, and/or anaphylaxis-anaphylactic shock observed in 18-30%
 by a single NSAID or by 2 or more NSAIDs with similar chemical structures
 almost all NSAIDs are capable, pyrazolones seem to be most common
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015

24. Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015

25. Mixed reaction
 10% of NSAIDs exacerbated cutaneous disease have respiratory symptoms
(bronchoconstriction)
 Concomitant symptoms reported 18.2% NIUA and 4.6% single-drug reactions
 39/149 (26.2%) with positive provocation NSAIDs hypersensitivity-15/39 (38%) overlap
between respiratory and cutaneous
Hypersensitivity to NSAIDs: classification of a Danish patient cohort according to EAACI/ENDA guidelines. Clinical and
Translational Allergy 2015
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015

26. 5. Delayed reactions to NSAIDs
 after more than 24 h following exposure, reintroduction may develop earlier
 usually occur several days (or even weeks)
 Cutaneous –most frequently
 Fixed drug eruption
 MP exanthema
 Contact dermatitis
 AGEP, SJS/TEN
 Aseptic meningitis, pneumonitis, nephritis
Middleton textbook 8th edition
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy 2011; 66: 818–829.

27. Clinical manifestation in children
 Prevalence among normal children 0.3%, in asthmatic children 5%
 isolated periorbital angioedema is frequent among school children, teenagers and
young adults
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011

28. Data in children
 115 children (2011-2014), mean
age= 83.10 +_56.05 months
 DPT confirmed 20/115 (17.4%)-
 15 SNIUAA ,3 NIUA, 1 AERD, 1 delayed
 ibuprofen most frequent (50%)
 13.8% had atopic sensitizations
Zambonino et al. Drug provocation tests in the diagnosis of
hypersensitivity reactions to NSAIDs in children.
Pediatric Allergy and Immunology 2013
Hakan Guvenir, M.D. NSAIDs hypersensitivity among children.
Allergy Asthma Proc 2015
 63 children (2008-2012), mean age= 9 (6.1-
11.3) years
 DPT confirmed 43/63 (68.2%)
 Angioedema 79%, angioedema +urticaria 4.6%,
uticaria 4.6%, angioedema+ asthma 4.6%,
exanthema 7%
 Ibuprofen (53.4%), ASA(37%), paracetamol
(14%)
 Atopy (D. pteronyssinus, D. farinae, olea
pollen and alternaria) associated with cross-
intolerant reactions

29. Investigation
 AERD, NECD, NICA – provocation test(confirm), in vitro (still debated)
 Single NSAID- induced reaction-SPT/IDT, specific IgE, oral challenge, BAT
 Delay reaction-patch test, in vitro -lymphocyte transformation test (LTT)

30. Drug provocation test
Comfirm diagnosis, safe alternative drugs
 Oral-gold standard, protocol valid
 Bronchial –safer, faster (soluble synthetic aspirin analog)
 Nasal, IV- safer, less sensitive (16 mg of acetylsalicylic acid, 2.26 mg of ketorolac spray)
 Contraindication - unstable asthma or an FEV1 < 70% of predicted value or less than 1.5 L
Middleton textbook 8th edition
EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity.
2007

31. Oral, single-blind, placebo-controlled diagnostic challenge test
 Challenge protocol – day 1 (placebo), day 2 (aspirin)
 FVC in 1 s is measured before each consecutive dose every 30 min
EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin
hypersensitivity. 2007
positive -FEV1 falls to 20% of baseline, appearance of
unequivocal extrabronchial symptoms (severe nasal
congestion, pronounced rhinorrhea)

32. In vitro tests in AERD
 Sulfidoleucotrienes release assay
 Basophil activation test (BAT)
 15-HETE generation assay (ASPITest)
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011

33. SPT/IDT
 For single NSAID -induced reaction (IgE mediated)
 In NECD, NIUA
 For differential diagnosis if single-drug reaction cannot be excluded
 For identify atopy status to inhalant allergens
 different dilutions of noraminophenazone, propyphenazone or aminophenazone were used in
suspected pyrazolone hypersensitivity
Middleton textbook 8th edition
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011

34. Specific IgE/BAT
 Serum-specific IgE antibodies specific demonstrated for pyrazolones
 Study in 51 patients, 2002–2006, with immediate selective reactions to pyrazolones
 BAT positive in 28 (54.9%), skin-test positive 21(41.17%), 10 (19.6%) skin-test negative but
BAT positive
 Useful in severe reaction
Immunogloblin E-mediated immediate allergic reactions to dipyrone: value of
basophil activation test in the identification of patients. 2009
IgE-mediated immediate type hypersensitivity to the pyrazolone drug propyphenazone. J
Allergy Clin Immunol 2003

35. Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria
and angioedema. J Allergy Clin Immunol 2015

36. Delay reaction
 Patch test
 lymphocyte transformation test (LTT)
 Photoallergy - photopatch tests
 oral drug provocation test - gold standard, contraindicated in severe
generalized reactions
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011

37. Management
 Avoidance and alternative drugs
 Desensitization
 Treatment of chronic underlying disease

38. Avoidance and alternative drugs
AERD, NECD, NIUA (cross- reactive group)
 weaker inhibitory potency towards prostaglandin synthase (e.g. acetaminophen) and
selective COX-2 inhibitors
SNIUAA
 Strict avoidance of the culprit and potentially cross-reactive drugs
 Alternative NSAIDs should be preceded by oral challenge to confirm tolerance
Delay
 prompt withdrawal, early -decreased risk of fatalities
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011
Middleton textbook 8th edition

39. Hypersensitivity to NSAIDs–review of the
EAACI/ENDA and GA2LEN/HANNA, Allergy
2011; 66: 818–829.
Paracetamol
• Low doses (< 500 mg) -
relatively safe
• 1000 mg –increased
bronchial reaction 30%
Meloxicam and Nimesulide -
well tolerated 86–96 % in AERD

40. Desensitization
 Recommend in AERD
 for
1 corticosteroid-dependent asthma
2 those requiring daily ASA/NSAID therapy for other medical conditions (coronary
artery disease or chronic arthritis)
Middleton textbook 8th edition
Hypersensitivity to NSAIDs–review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011

41. Treatment of underlying diseases
 Asthma
 Inhaled corticosteroid and LABA
 Many require long-term oral glucocorticosteroids
 Leukotriene receptor antagonists and synthesis inhibitors may be clinical benefit
 Urticaria
 Antihistamine +Leukotriene receptor antagonists may be benefit
 Delay reaction
 Symptomatic treatment: systemic corticosteroids, antihistamines
 SJS/TEN: ICU, corticosterids, plasmapheresis, IVIg or immunosuppressive drugs –controversial
 anti-TNF-a therapy with infliximab reported in TEN
Hypersensitivity to NSAIDs- review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011
Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment. J
Allergy Clin Immunol 2005

42. Take home messages
1. NSAID hypersensitivity is common. There are 5 classification and 3 major pathophysiology. However, there
are overlapping (divergent) cases with unclear reaction.
2. In children, urticaria/angioedema are the most common presentation. Ibuprofen is the most frequent drug.
3. Diagnosis should vary depending on mechanism.
4. Challenge with a culprit drug to confirm diagnosis and for safe alternative drugs. Skin tests (SPT/IDT) and in
vitro testing should be restricted to IgE-mediated reactions
5. Avoidance measure should always follow diagnosis
6. Pharmacologic treatment for asthma, rhinitis, and urticaria according to symptom severity. Aspirin
desensitization can be done when indicated.