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Marek L. Kowalski , M.D., Ph.D . Department of Immunology , Rheumatology and Allergy ,, Medical University of

Aspirin Exacerbated Respiratory Disease. World Allergy Forum 2010 AAAAI Annual Meeting. Marek L. Kowalski , M.D., Ph.D . Department of Immunology , Rheumatology and Allergy ,, Medical University of Łódź , Poland. Asprin-induced asthma – the oldest known asthma phenotype.

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Marek L. Kowalski , M.D., Ph.D . Department of Immunology , Rheumatology and Allergy ,, Medical University of

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  1. AspirinExacerbated Respiratory Disease WorldAllergy Forum 2010 AAAAI AnnualMeeting Marek L. Kowalski , M.D., Ph.D.Department of Immunology, Rheumatology and Allergy ,, Medical University of Łódź, Poland

  2. Asprin-induced asthma – the oldest known asthma phenotype • „Patient J.M. , 40 years old • The disease began 11 years ago (in 1912) with symptoms of rhinitis related to polypoid mucosal hypertrophy and associated with frequent „colds” and coughing, but without fever . • He had several polypectomies which relieved symptoms temporarily … • Few years later he experienced an acute asthma attack at night after ingesting a tablet of aspirin … • He suffers a severe asthma with several attacks during day and night … • Diagnosis : Asthma bronchiale.Rhinitide chronica hyperplastica polyposa (asthma reflectorium). Anaphylaxia ex usu aspirini „ M. Wierzuchowski Pol. Arch. Med. Wewn. 1925 ,2,25-75

  3. 1975 - A. Szczeklik “ prostglandininhibition” theory of AIA The milestones in the history of aspirin sensitivity • 1902 – R. Hirschberg the first case of ASA- sensitivity reported Paris, France • 1922 - F. Widal“ASA-triad” Poznań, Poland Kraków, Poland • 1967- M.SamterASA-sensitivity as a clinical entity Chicago,USA

  4. AspirinExacerbated Respiratory Disease NSAIDs - induced symptoms Clinicalphenotype 80 Hyperplastic CRS withnasalpolyps Moderate to severe asthma % of patients Aspirin triad; Widal’s Syndrome, Samter’s Syndrome; Aspirin-Induced Asthma

  5. Prevalence of aspirinsensitivityamongpatientswithasthma Prevalence (%)

  6. AERD as a severeasthmaphenotype • Higher medication requirements, including dependence on oral GCS (Szczeklik A. et al. 2000) • Irreversible airway obstruction • More likely to have been intubated and to have a steroid burst in the previous three months ( Mascia K et al. 2005) • Frequent exacerbations • ( Koga T. Et al. 2006) • Association with near fatal asthma (Plaza W. et al. 2002) Riskfactors for severeasthma OR =2.6 Odds Ratio Wheezing in childhood BMI AIA ML Kowalski et al.Allergy 2010 ,in press

  7. Severity of CRS inASA-tolerant and ASA-sensitivepatients Recurrence of nasal polyps after polypectomy( follow-up period of 4 years) CT staging of chronic rhinosinusitisinASA-sensitive and ASA-tolerantpatients * 30 % of patients 20 CT score * 10 * * * * ASA-tolerant ASA-sensitive • Patients with AERD had history of 10 times as many previous FESS procedures as had the patients without Samter's triad • ASA triad mean:5.2 • ASA (- ) mean0.53; (p < 0.001) Kowalski ML et al. WAJ 2003 Jantti-Alanko S. et al. Rhinology 1989,8.59 Kim JE Ear Nose Throat J. 2007 Jul;86(7):396-9.

  8. Mast cell EOS Pathomechanisms of Aspirin Exacerbated Respiratory Disease I. Acutesymptomsprecipitated by ASA and NSAIDs I. Acutesymptomsprecipitated by ASA and NSAIDs Leukotrienes Tryptase Histamine ECP 15-HETE Bronchial Nasal Occular symptoms ASA / NSAID’s COX I I. Chronic symptoms and underlying airway inflammation Unrelated to ASA or other NSAIDs intake !!!

  9. ASA PGE2 PGE2 COX-1 COX-2 Mast cell LTC 4 LTD4 Asthma Rhinorrhea EOS LTE 4 Cell membrane phospholipids PLA Arachidonic acid 5-LOX PGG2 PGH2 EP -R LTA4 LTC4s EP -R

  10. Pathogenesis of chronicinflammationinpatientswith AERD AA abnormalities Allergy Infections

  11. Cell membrane phospholipids PLA-2 12-LO Arachidonicacid 12-HETE COX-1 COX-2 FLAP 15-LO 5-LO PGG2 PGH2 5-LO 15-HETE LTA4 LTC4s LTA4 h Lipoxins PGE2 PGI2 TXB2 PGF2 PGD2 LTC4LTD4 LTE4 LTB4 • Specific release of 15-HETE upon ASA challenge • Abnormal lipoxins generation • Decreased production of PGE2 • Downregulation of Cyclooxygenase-2Cyclooxygenase-1(?) • Increased generation of cysLTs (urine , BAL, EAC) • Overexpression of LT receptors Several polymorphisms in AA related genes have been associated with AERD

  12. AtopicsensitizationinASA-sensitiveasthmatics Earlierstudies - no referencepopulations More recentstudieswith referencepopulations % of patients % of patients

  13. Role of infectionsinthepathogenesis of AERD • Viral hypothesis (A. Szczeklik;1988) • Flu-like symptoms precede the development of aspirin-sensitivity • Chronic viral respiratory tract infection may both initiate and perpetuate chronic airway inflammation in AERD • Enterotoxin hypothesis (C. Bachert; 2005) • (Staphylococcus aureus enterotoxins (SAE)are potent superantigens and inflammatory cell activators • Specific IgE to SAE have been found in nasal polyp tissue • sIgE to SAE are associated with eosinophilic inflammation in rhinosinusitis

  14. sIgE to SAEs in ASA-sensitive and ASA-tolerant polyps Concentration of SAE-specific IgE in nasal polyps Correlation of SEA-sIgEwith ECP and IL-5 innasalpolyps kUa/l median C. Perez-Novo et al. Int. Archs All& Imm. 2004 Y.J.Suh et al. Clin Exp Allergy 2004

  15. sIgE to Staphylococcus aureus enterotoxins in serum and asthma severity - LODZ Study Severe and non-severeasthmatics ASA- tolerant and ASA-sensitive asthmatics ** 76 70 SAE concentration kUa/l SAE concentration kUa/l N= 145 N= 52 N= 29 N= 97 N= 100 M.LKowalski ,C.Bachert et al . Allergy 2010 in press

  16. Diagnosis of respiratory type of hypersensitivity to NSAIDs • History • Aspirin challenge • Oral • Inhaled • Intranasal • In vitro testing • Cellular activation tests • BAT • ASPITest (15-HETE) • Urinary LTE4 • Genetic testing Aspirin-Sensitive Patients Identification Test (ASPITest) Sensitivity 82% PPV 79% Specificity 83% NPV 86% M.L.Kowalski et al. Allergy 2005,60,1139-45

  17. Management of ASA-sensitive rhinosinusitis/asthma Avoidance of NSAIDs Recommendations for selectiveCOX-2 inhibitors Pharmacologic treatment Intranasal /inhaled glucocorticosteroids Leukotriene antagonists – as effective as in ASA-tolerant patients Sinus surgery / polypectomy Less effective in ASA-sensitive Aspirin desensitization Clinical use: risks / benefits

  18. Arachidonic acid COX-1 COX-2 Aspirin Coxibs Celecoxib PGE, PGI2, TXB2 Prostaglandins ? Cytoprotection Regulation Inflammation

  19. Cox-2 inhibitors and in AERD • Aspirin-induced asthma is a COX-1 dependent phenomenon • Preferential COX-2 inhibitors are tolerated by 80-90% of ASA-sensitive asthmatics • Selective COX-2 inhibitors are generally well tolerated • COX-2 selective NSAIDs can be used by ASA-sensitive asthmatics, but tolerance test is recommended before an alternative drug is prescribed • Single reports of COX-2 inhibitor-induced asthmatics reactions were published • Celcoxib -3 • Rofecoxib -1 • Etoricoxib -1 FEV1% R. Munoz-Cano et al. J InvestigAllergolClinImmunol 2009,19,64

  20. Clinical efficacy of leukotriene receptor inhibitorsin ASAhypersensitive and ASA-tolerantpatients Add on therapy study : 3 months treatment with montelukast 10 mg Add on therapy study : 2 months treatment with zafirlukast 20 mg * * * Change in symptoms (%) Change in symptoms (%) * * * * * Kowalski ML et al , 2008 Ragab S. et al , C E A 2001,31,1385

  21. Endoscopic Sinus Surgery and CRS outcomes in ASA-sensitive and ASA-tolerant patients Endoscopy scores before and after ESS * Patients • 19 ASA-sensitive and 104 ASA-tolerant patients with CRS were recruited to prospective study • Patients were subjected to ESS and followed for a mean of 17,7 months after surgery Results • Similar proportions of ASA sensitive and ASA-tolerant patients had improved: • Endoscopic score • Quality of Life scores • Larger proportion of ASA-sensitive patients reported increased medication use Increaseinmedicationuse ).Robinson JL et al.. The Laryngoscope 2007 ,117,830

  22. Aspirindesensitizationinpatientswith AERD • Daily oral ASA after desensitization (300-2400mg) in some patients may lead to: • Improvement in asthma symptoms • Improvement in rhinosinusitis symptoms • Decreased need for sinus surgery/polypectomy • 1923 F. Vidal reported „desensitization” to aspirin • 1976 C. R. Zeiss & R.F. Lockey described refractory period to aspirin • 1981 D.D. Stevenson reported clinical benefits of prolonged treatment with aspirin after desensitization

  23. Indications for ASA- desensitization • Aspirin sensitive asthma/rhinosinusitis • Patients with aggressive polypoid CRS • Patients do not responding to pharmacological treatment • Corticosteroid-induced side effects • ASA-sensitive patients with • Coronary heart disease • Antiphospholytic syndrome • Chronic inflammatory diseases (AR; OA)

  24. Overlapping phenotypes in AERD Severe/non severeasthma

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