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.
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
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
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.
Hinweis der Redaktion
timing, the clinical pattern of symptoms, and the presence or absence of cross-reactivity to other NSAIDs
ENDA – European Network of Drug Allergy/EAACI Interest Group on DrugHypersensitivity.
*HANNA – European Network on Hypersensitivity to Aspirin and NonSteroidal Anti-Inflammatory Drugs
recorded clinical, comorbidities and identify risk factors by multivariate analysis with possible history
Atopy asdefined by the presence of at least one positive skin prick test to the common aeroallergens of Montpellier area);
Risk factors: chronic urticaria (OR 7.7), atopic status (OR 2.5), allergic rhinoconjunctivitis (OR 1.7), no correlation between food allergy and NSAID HS
The main culprit drugs were paracetamol/acetaminophen (seven patients, 31.8% of the group) and ibuprofen (seven patients, 31.8% of the group).
Cysteinyl leukotriene
increased basal levels of cysteinyl leukotrienes may be linked to increased tissue eosinophil
and mast cells
basal levels of leu-kotriene metabolites in the urine of patients with AERD
15-Lipoxygenase Pathways. Produc-tion of lipoxin A4 (LXA4), an antiinflammatory derivative of arachidonic acid generated by transcellular metabolism involv-ing cooperation of 5-LO and 15-LO, was significantly lower in peripheral blood leukocytes from asthmatic patients with AERD
cysteinyl leukotriene receptors, cysLTR
Geneที่ 2 intense eosinophil infiltration into the upper and lower airways is a key feature
Virus proposed as both primary triggers of ASA hypersensitivity and a cause of the underlying chronic inflammation
Nasal symptoms appear by middle age and then progress to a chronic rhinosinusitis, often with nasal polyposis. Asthma usually is diagnosed a few years later.
first, persistent rhinosinusitis, commonly with polyposis, followed by asthma, and then aspirin hypersensitivity
Our study confirmed that respiratory reaction are more prevalent among patients with asthma, chronic rhinosinusitis, Although respiratory symptomsusually considered to be a component of the ‘aspirin triad', in our study only 15%, likely that these patients suffered from other than NERD type of NSAID hypersensitivity, where no underlying respiratory diseases were present
both immediate (within 15 min of ingestion) and late (up to 24 h) reactions
Due to concern of Reye syndrome, aspirin is not prescribed for children in our country, unless the patient undoubtedly needs the drug (e.g., in case of acute rheumatic fever).
1 , 123 patients turkey (with 136 drug reactions) were admitted to our clinic with suspected NSAID hypersensitivity
2 evaluated children 1-14 yr with symptoms suggestive of hypersen- reactions to one or more NSAIDs. These patients were studied in the allergy unit of the paediatric department of Carlos Haya Hospital (Malaga, Spain)
cross reactive25. Selective 18
Single: Oral challenge with aspirin and other NSAIDs should be performed to exclude cross-reactive type of hypersensitivity and to confirm the safety of alternative drugs
(27, 44, 117, 312 mg) are administered every 1.5–2 h until a cumulative dose of 500 mg is reached
severe hypersensitivity reaction (pro-found dyspnea and/or anaphylactic shock), the test is com-menced with 10 mg aspirin, and the next dose of 17 mg is administered 1.5 to 2 hours later—that is, the 27-mg dose is divided into two for safety reasons. The time interval between administrations of consecutive aspirin doses can be shortened to 1.5 hours without compromising patient safety
inter-rupted if FEV1 falls to 20% of baseline or lower (a positive reaction) or if the maximum cumulative dose of aspirin (1000 mg) is reached
Forced expiratory volume
Aspirin can induce LTC4 release from peripheral blood leucocytes (PBL)
BAT Measurement of cell surface molecule CD63 expression
Aspirin can specific trigger in vitro generation of 15-hydroxyeicosatetrenoic acid (15-HETE), an arachidonic acid metabolite, from nasal polyp epithelial cells, and peripheral blood leucocytes from ASA-sensitive patients
administering increas-ing doses over 2 to 3 days until a mild reaction occurs, and then slowly increasing the dose