nsaid hypersensitivity

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


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


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


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


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



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



Environment

Human rhinovirus Staphylococcus enterotoxin IgE more abundant in nasal

polyp, higher specific IgE to staphylococcal superantigen in AERD


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


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


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


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


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


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


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)


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

Delay reaction

Patch test lymphocyte transformation test (LTT) Photoallergy - photopatch tests oral drug provocation test - gold standard,

contraindicated in severe generalized reactions


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.

nsaid hypersensitivity

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