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Topic conferenceNSAIDs
hypersensitvity Anchalee Senavonge, MD
29 July 2016
Outline
Epidemiology Classification Pathophysiology Clinical manifestation Diagnosis Management
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
Classification
1. NSAID-induced rhinitis/asthma (Aspirin-Exacerbated Respiratory Disease: AERD)
2. NSAIDs-exacerbated urticaria/angioedema3. Multiple NSAIDs-induced urticaria/angioedema4. Single NSAID-induced reactions5. Delayed reactions to NSAIDs
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011; 66: 818–829.
Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011
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
Divergent
43/107 (40.2%) could not be classified by ENDA = ‘divergent'
39/107 divergent for 1 criterion4/107 for more than 1 criteria
Cousin M.Phenotypical characterization of children with hypersensitivity reactions to NSAIDs. Pediatr Allergy Immunol, May 2016:1-6
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. 91/10
72. 15/10
73. 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
Pathophysiology
Middleton textbook 8th edition
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
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.
Overlapping entities
Two major groups1. respiratory symptoms then develop some cutaneous response-
considered initially as AERD2. 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
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
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
Environment
Human rhinovirus Staphylococcus enterotoxin IgE more abundant in nasal
polyp, higher specific IgE to staphylococcal superantigen in AERD
Middleton textbook 8th edition
Clinical manifestation
1. Aspirin-Exacerbated Respiratory Disease (AERD)
Typical “ASA triad” 1. chronic rhinosinusitis with polyp 2. moderate to severe bronchial asthma3. 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
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
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
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 urticariaHypersensitivity 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
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
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
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria and angioedema. J Allergy Clin Immunol 2015
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
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.
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
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
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)
Drug provocation testComfirm 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
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)
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
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
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
Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria and angioedema. J Allergy Clin Immunol 2015
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
Management
Avoidance and alternative drugs Desensitization Treatment of chronic underlying disease
Avoidance and alternative drugsAERD, 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 2011Middleton textbook 8th edition
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
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
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 2011Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha
treatment. J Allergy Clin Immunol 2005
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 diagnosis6. Pharmacologic treatment for asthma, rhinitis, and urticaria according to symptom
severity. Aspirin desensitization can be done when indicated.