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NSAID hypersensitivity

  1. 1. Topic conference NSAIDs hypersensitvity Anchalee Senavonge, MD 29 July 2016
  2. 2. Outline  Epidemiology  Classification  Pathophysiology  Clinical manifestation  Diagnosis  Management
  3. 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. 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. 5. Hypersensitivity to NSAIDs – classification, diagnosis and management: review of the EAACI/ENDA and GA2LEN/HANNA, Allergy 2011
  6. 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. 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. 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. 9. Pathophysiology
  10. 10. Middleton textbook 8th edition
  11. 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. 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. 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. 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. 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. 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. 17. Clinical manifestation
  18. 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. 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. 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. 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. 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. 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. 24. Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria and angioedema. J Allergy Clin Immunol 2015
  25. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 35. Approaches to the diagnosis and management of patients with a history of NSAID–related urticaria and angioedema. J Allergy Clin Immunol 2015
  36. 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. 37. Management  Avoidance and alternative drugs  Desensitization  Treatment of chronic underlying disease
  38. 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. 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. 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. 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. 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

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