1 / 24

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.

Antony
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related