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Diagnosis and treatment of aspirin exacerbated respiratory disease (AERD) Donald D. Stevenson, MD Div: Allergy, Asthma and...
Case #1 <ul><li>35 yo F. Child hood 4 URIs per year without wheezing. Teen years 1-2 URIs/yr Ibuprofen 400 mg q month for ...
What is Aspirin- Exacerbated Respiratory Disease?  <ul><li>AERD is a clinical tetrad of: </li></ul><ul><ul><li>Nasal polyp...
AERD vs. Samter’s triad  <ul><li>Samter’s “triad”:  nasal polyps, asthma, aspirin induced respiratory reactions </li></ul>...
AERD Population <ul><li>0.3- 0.9% of the general population  </li></ul><ul><li>10- 20% of all asthmatics </li></ul><ul><li...
ASA/NSAID reactions ONSET  AERD: CHES + polyps Upper Airway Disease Only ASTHMA Mild intermittent Mild persistent Moderate...
Is AERD one disease or multiple  pathological defects: many diseases? <ul><li>Over stimulation of inflammation :  </li></u...
IL-4, IL-5, GM-CSF <ul><li>Stimulates : </li></ul><ul><ul><li>Th 2  lymphocytes proliferation </li></ul></ul><ul><ul><li>B...
Deficiency  of PGE 2  in AERD <ul><li>Nasal polyp epithelial cells </li></ul><ul><ul><li>Picado et al Am J Respir Crit Car...
 
 
Bronchial ASA-lysine challenges induce LTC 4  synthesis <ul><ul><li>Asthmatics: AIA  (11) compared to ATA (15) </li></ul><...
Szczeklik, A et al Am J Respir Crit Care Med 1996; 154:1608 -14
Association of urine LTE 4  with severity of ASA induced bronchospasm <ul><li>Groups of AERD patients by severity of react...
 
 
The problem of diagnosing AERD <ul><li>Underlying disease:  </li></ul><ul><ul><li>Anosmia, nasal congestion, thick nasal s...
243 patients presenting for OAC <ul><li>Number of prior historical respiratory reactions : </li></ul><ul><ul><li>One prior...
Probability that patients have + OAC  and AERD based on the severity of  their historical reaction <ul><li>Mild : 80% posi...
Problems in diagnosing AERD by relying on history of ASA associated with asthma attack <ul><li>Under Diagnosis :  </li></u...
Relationship between historical ASA/NSAIDs -induced asthma attacks and the degree of bronchospasm during oral aspirin chal...
Results of OAC challenges n = 210 GI reactions 49 (23%), Cutaneous 20 (10%), laryngeal 16 (8%) Type of respiratory reactio...
Relationship between historical ASA-induced asthma reactions and oral ASA challenges  n = 210  Williams, AN et al JACI 200...
Reasons for the differences in degree of the asthmatic reactions between:    Historical vs. OAC <ul><li>Reactions to ASA a...
Pros and Cons of ICU Challenges and Desensitization in AERD patients <ul><li>Pro: </li></ul><ul><ul><li>Critical care pers...
Treatment of AERD <ul><li>Avoiding ASA/NSAIDs does not prevent AERD from starting, continuing and progressing </li></ul><u...
Medical Treatment of AERD <ul><li>Upper airway is the primary Rx target </li></ul><ul><ul><li>Nasal obstruction:  Nocturna...
Treatment of AERD   <ul><li>Stop the cause or complications if you have the power to change them : </li></ul><ul><ul><li>A...
Plasma Histamine in asthmatics: 1975 -1979   <ul><li>Scripps  GCRC: Funded by Federal Government   </li></ul><ul><li>TSRI ...
 
1979-80: ASA desensitization Rx  <ul><li>Both patients desensitized to ASA in GCRC </li></ul><ul><li>Daily dose of ASA 325...
Features of ASA desensitization <ul><li>After reaching 325mg ASA dose: </li></ul><ul><li>Nasal decongestion  occurs immedi...
Scripps ASA desensitization and daily ASA: studies demonstrating  therapeutic efficacy <ul><li>Stevenson et al JACI 1980;6...
 
 
Polyp sinus surgery before and after ASA desensitization <ul><li>AERD patients average one sinus/ polyp operation every 3 ...
Study of ASA desensitization treatment 1995-2000: 1-5 year follow-up <ul><li>Responder but  side effects </li></ul><ul><li...
Treatment of AERD continued <ul><li>Aspirin desensitization as add on therapy : </li></ul><ul><ul><li>Prevence recurrence ...
Ends: age 82 yrs AERD Dx 1984 ASA desen in 1984 325 mg BID x 27 yr  Non-atopic Anosmia persists Asthma persists Rare infec...
Ketorolac modified OAC <ul><li>European ASA lysine for Dx and Rx </li></ul><ul><ul><ul><li>Patriarca G et al Ann Allergy A...
Ketorolac (cont # 2) <ul><li>Study populations:  Patients suspected of AERD </li></ul><ul><ul><li>Ket Nas + OAC: 100 conse...
Ketorolac (cont #3) <ul><li>OAC Challenges </li></ul><ul><li>20-40 mg </li></ul><ul><li>40-60 mg </li></ul><ul><li>60-100 ...
<ul><li>Intranasal ketorolac and ASA challenge vs. OAC </li></ul>* 2 sample t test X2 was used to test categorical variabl...
Types of bronchial and Extra-pulmonary reactions X 2  was used to test categorical variables (1 yes and o no) Reaction Ket...
Mechanisms of ASA desensitization <ul><li>Acute ASA desensitization: ASA 650 mg </li></ul><ul><ul><li>Nasal decongestion <...
Sousa et al (#3) <ul><li>Effect of ASA lysine intranasal treatment, after nasal ASA desensitization, on numbers of CD45+ c...
Sousa, A et al NEJM 2002; 347: 1493-9 % of CD45+ leukocytes cysLT 1  receptors Baseline to 2 weeks Lysine ASA p = 0.008 Pl...
Sousa et al (conclusions) <ul><li>In ASA sensitive respiratory disease : </li></ul><ul><ul><li>(1) More leukocytes express...
In vitro cellular changes: IL-4 and IL-13 induced signal transduction   <ul><li>ASA prevented activation  STAT 6 via Janus...
Does IL-4 cause AERD ? <ul><li>Th0 conversion to Th2 cells </li></ul><ul><li>Th2 synthesis  IL-5 (eosinophils) </li></ul><...
Selective inhibition of IL-4 gene expression in human T-cells by Salicylates but not NSAIDs <ul><li>CD-4+ human T cells, m...
Suppression of IL-4 during aspirin desensitization treatment <ul><li>21 patients with   history of ASA/NSAID induced asthm...
 
Katial et al (cont.) <ul><li>At 6 months: (n =14) AERD patients </li></ul><ul><ul><li>Symptom scores improved from baselin...
<ul><li>Conclusions : </li></ul><ul><ul><li>Desensitization to ASA involved airway mast cell degranulation and cohort rele...
 
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AERD: Diagnosis and Treatment

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Presentation by Dr. Donald Stevenson
Kentucky Society of Allergy, Asthma & Clinical Immunology Annual Meeting-September 2011

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Transcript of "AERD: Diagnosis and Treatment"

  1. 1. Diagnosis and treatment of aspirin exacerbated respiratory disease (AERD) Donald D. Stevenson, MD Div: Allergy, Asthma and Immunology Scripps Clinic and the Scripps Research Institute La Jolla, California 858-764-9010 Fax 858-764-9011 E-Mail: [email_address]
  2. 2. Case #1 <ul><li>35 yo F. Child hood 4 URIs per year without wheezing. Teen years 1-2 URIs/yr Ibuprofen 400 mg q month for menstrual cramps. </li></ul><ul><li>Age 30 . Another typical URI which “never went away”. Nasal congestion perennial </li></ul><ul><li>Age 30 1/2 . 2 ibuprofen (400 mg) for menstrual cramps: wheezing episode (first time asthma attack) </li></ul><ul><li>Age 31 . Nasal polyps, asthma, anosmia </li></ul><ul><li>Age 34 . First sinus/polyp surgery </li></ul>
  3. 3. What is Aspirin- Exacerbated Respiratory Disease? <ul><li>AERD is a clinical tetrad of: </li></ul><ul><ul><li>Nasal polyps </li></ul></ul><ul><ul><li>Chronic rhinosinusitis (CRS) </li></ul></ul><ul><ul><li>Asthma </li></ul></ul><ul><ul><li>NSAID induced respiratory reactions </li></ul></ul>
  4. 4. AERD vs. Samter’s triad <ul><li>Samter’s “triad”: nasal polyps, asthma, aspirin induced respiratory reactions </li></ul><ul><li>Tetrad: CRS, nasal polyps, asthma, NSAID reactions </li></ul><ul><li>Europe and Asia: aspirin induced (or intolerant) asthma (AIA) </li></ul><ul><li>Lumry’s “triad”: CRS, nasal polyps and aspirin/NSAID induced nasal ocular reactions Lumry W et al JACI 1983;71:580-7 </li></ul>
  5. 5. AERD Population <ul><li>0.3- 0.9% of the general population </li></ul><ul><li>10- 20% of all asthmatics </li></ul><ul><li>30- 43% of CRS with nasal polyps, asthma </li></ul><ul><li>More common in females/males (57/43%) </li></ul>32 yo male anosmia, nasal congestion, nasal polyps. and asthma He is atopic and receiving Immunotherapy with partial improvement
  6. 6. ASA/NSAID reactions ONSET AERD: CHES + polyps Upper Airway Disease Only ASTHMA Mild intermittent Mild persistent Moderate persistent Severe persistent 1-2 URIs per yr Allergic Rhinitis Asthma: Provoking factors Age 30 yrs
  7. 7. Is AERD one disease or multiple pathological defects: many diseases? <ul><li>Over stimulation of inflammation : </li></ul><ul><ul><li>Increased synthesis of cytokines; Over expression </li></ul></ul><ul><ul><ul><li>Mast Cell synthesis of IL-4, 5 Eosinophils IL-5 </li></ul></ul></ul><ul><ul><li>Increased LT synthesis ( increased LTC 4 S) LTC 4 ,D 4 ,E 4 </li></ul></ul><ul><ul><li>LTB 4 via BL 1 & 2 receptors Chemotactic Progenitor MC, T cells </li></ul></ul><ul><ul><li>Over expression of cysLT 1 R ( ? cysLT 2 R) </li></ul></ul><ul><ul><li>Other inflammatory systems (5-oxo-ETE) </li></ul></ul><ul><ul><li>Increased PGD 2 synthesis in Mast Cells </li></ul></ul><ul><li>Underproduction of countermeasures : Deficiency </li></ul><ul><ul><li>PGE 2 synthesis IL-10 TGF-B1, 2, 3 </li></ul></ul><ul><ul><li>EP 2 receptors Lipoxins </li></ul></ul>
  8. 8. IL-4, IL-5, GM-CSF <ul><li>Stimulates : </li></ul><ul><ul><li>Th 2 lymphocytes proliferation </li></ul></ul><ul><ul><li>Bone marrow precursor cells: MC, Eosin,T cells </li></ul></ul><ul><ul><li>Mucus gland secretion </li></ul></ul><ul><ul><li>Hyperirritability of airways </li></ul></ul><ul><ul><li>VCAM expression (IL-4): transmigration </li></ul></ul><ul><li>Chemotactic : </li></ul><ul><ul><li>for eosinophils: recruits, activates and inhibits apoptosis </li></ul></ul>
  9. 9. Deficiency of PGE 2 in AERD <ul><li>Nasal polyp epithelial cells </li></ul><ul><ul><li>Picado et al Am J Respir Crit Care Med 1999;160:291-6 </li></ul></ul><ul><ul><li>Kowalski ML et al Am J Respir Crit Care Med 2000;161:391-8 </li></ul></ul><ul><li>Deficiency of PGE 2 in lower airways: Fibroblasts </li></ul><ul><ul><li>Pierzchalska, M et al JACI 2003;111:1041 </li></ul></ul><ul><li>Deficiency of EP 2 receptors </li></ul><ul><ul><li>Ying et al JACI 2006;117:312-8 </li></ul></ul>
  10. 12. Bronchial ASA-lysine challenges induce LTC 4 synthesis <ul><ul><li>Asthmatics: AIA (11) compared to ATA (15) </li></ul></ul><ul><li>Baseline saline lavage: right middle lobe </li></ul><ul><li>Instillation of ASA-lysine 10 mg ( one dose ) </li></ul><ul><li>15 min later: BAL repeated </li></ul><ul><li>Results: AIA, when compared to ATA </li></ul><ul><ul><li>Increase in LTs, IL-5, eosinophils (stat sig.) </li></ul></ul><ul><ul><li>Histamine increased (6/11) (not stat sig.) </li></ul></ul>Szczeklik, A et al Am J Respir Crit Care Med 1996; 154:1608-14
  11. 13. Szczeklik, A et al Am J Respir Crit Care Med 1996; 154:1608 -14
  12. 14. Association of urine LTE 4 with severity of ASA induced bronchospasm <ul><li>Groups of AERD patients by severity of reactions </li></ul><ul><ul><li>React Type # age inhal steroids/day prednisone/day </li></ul></ul><ul><ul><li>Nasal 21 47 620 4.2 </li></ul></ul><ul><ul><li>20-30% 28 48 632 2.4 </li></ul></ul><ul><ul><li>>30% 25 44 528 5.7 </li></ul></ul><ul><li>Characteristics of the ASA induced reactions </li></ul><ul><ul><li>Mean drop FEV1 ASA provoking dose Naso-ocular </li></ul></ul><ul><ul><li>4.3 % 66.4 mg 21/21 </li></ul></ul><ul><ul><li>24.1% 66.6 mg 26/28 </li></ul></ul><ul><ul><li>43.8% 60.0 mg 24/25 </li></ul></ul>Daffern, P et al JACI 104:559-64, 1999
  13. 17. The problem of diagnosing AERD <ul><li>Underlying disease: </li></ul><ul><ul><li>Anosmia, nasal congestion, thick nasal secretions </li></ul></ul><ul><ul><li>IgE mediated does not exclude: co-exists </li></ul></ul><ul><ul><li>Pansinusitis </li></ul></ul><ul><li>Identifying an NSAID associated respiratory infection: </li></ul><ul><ul><li>Exposure </li></ul></ul><ul><ul><li>Recognition </li></ul></ul><ul><ul><li>Recording </li></ul></ul>
  14. 18. 243 patients presenting for OAC <ul><li>Number of prior historical respiratory reactions : </li></ul><ul><ul><li>One prior respiratory reaction to NSAID : 80% + OAC </li></ul></ul><ul><ul><li>Two or > prior respiratory reactions : 89% + OAC </li></ul></ul><ul><li>Severity of prior historical reactions : </li></ul><ul><ul><li>Mild ( responded to albuterol, reactions lasted < hr.) </li></ul></ul><ul><ul><li>Moderate (partial response to albuterol and reactions lasted >1 hour). Almost all patients to ER </li></ul></ul><ul><ul><li>Severe ( poor response to albuterol, multiple interventions up to intubation). ER or hospitalized </li></ul></ul>Dursun AB et al Predicting outcomes of OAC. Annals of Allergy, Asthma and Immunology 2008;100:420-25
  15. 19. Probability that patients have + OAC and AERD based on the severity of their historical reaction <ul><li>Mild : 80% positive OAC </li></ul><ul><li>Moderate : 84% positive OAC </li></ul><ul><li>Severe : 100% positive OAC </li></ul><ul><li>No prior exposure to ASA : 42% + OAC </li></ul><ul><li>Sense of smell </li></ul><ul><ul><li>Anosmia : 89% positive OAC </li></ul></ul><ul><ul><li>Hyposmia : 69% pos OAC </li></ul></ul><ul><li>Pansinusitis: 100% have this (not predictive) </li></ul>Dursun B et al Predicting outcomes of OAC. Annals Allergy Asthma and Immunology 2008;100:420-25
  16. 20. Problems in diagnosing AERD by relying on history of ASA associated with asthma attack <ul><li>Under Diagnosis : </li></ul><ul><ul><li>Patient never takes ASA/ NSAIDs but has syndrome </li></ul></ul><ul><ul><li>Patient takes ASA but mild or delayed reactions (3 hrs) </li></ul></ul><ul><li>Over Diagnosis : </li></ul><ul><ul><li>Patient takes ASA/NSAID, has asthma attack but the 2 events are unrelated (innocent bystander syndrome) </li></ul></ul><ul><ul><li>About 15% of suspect AERD: negative OAC </li></ul></ul><ul><li>Best histories predicting positive OAC: </li></ul><ul><ul><li>Complete anosmia: Patient cannot smell anything </li></ul></ul><ul><ul><li>Asthma attack within 1 hr after ASA/NSAID </li></ul></ul><ul><ul><li>2 different NSAIDs associated with asthma attacks </li></ul></ul><ul><ul><li>Hospital for asthma attack after ingesting an NSAID </li></ul></ul>
  17. 21. Relationship between historical ASA/NSAIDs -induced asthma attacks and the degree of bronchospasm during oral aspirin challenges <ul><li>Study of 210 consecutive patients with AERD proven during + oral ASA challenges </li></ul><ul><li>Stratified by treatment location for historical ASA (NSAID) induced asthma attacks </li></ul><ul><ul><li>Home - least severe. Albuterol Rx </li></ul></ul><ul><ul><li>ER – relatively severe. treated Nebs, “shots” </li></ul></ul><ul><ul><li>Hospital - Most to ICU. Intubation 9/46 (20%) </li></ul></ul>Williams AN, Simon RA, Stevenson DD JACI 2007; 120: 273-7
  18. 22. Results of OAC challenges n = 210 GI reactions 49 (23%), Cutaneous 20 (10%), laryngeal 16 (8%) Type of respiratory reactions n (%) Bronchial reactions: FEV1 106 (50%) 10-15% 32 (15%) 15-20 % 27 (13%) 21-30% 28 (13%) > 30% 19 (9%) All naso-ocular reactions naso-ocular ( FEV1< 10%) 188 (90%) 104 (50%)
  19. 23. Relationship between historical ASA-induced asthma reactions and oral ASA challenges n = 210 Williams, AN et al JACI 2007;120:273-7 OAC Respiratory Reactions Home N = 63 ER N = 101 Hospital N = 46 Naso-ocular and < 20 % FEV1 53 (84%) 79 (78%) 31 (67%) 21-30% FEV1 5 (8%) 14 (14%) 9 (20%) > 30% FEV1 5 (8%) 8 (8%) 6 (13%) Statistics Fishers Ex Chi Square p = NS
  20. 24. Reasons for the differences in degree of the asthmatic reactions between: Historical vs. OAC <ul><li>Reactions to ASA are dose dependent </li></ul><ul><ul><li>Historical reactions: ASA 550 mg (325- 975 mg) </li></ul></ul><ul><ul><li>OAC provoking doses: ASA 62 mg (30 -325 mg) </li></ul></ul><ul><li>Use of LTMDs </li></ul><ul><ul><li>Historical reactions: 11/210 (5%) </li></ul></ul><ul><ul><li>Oral aspirin challenges: 161/210 (77%) </li></ul></ul><ul><li>Use of Corticosteroids : </li></ul><ul><ul><li>Historical: unknown but usually some </li></ul></ul><ul><ul><li>OAC: nasal CS (75%), ICS (82%) SCS (20%) </li></ul></ul>
  21. 25. Pros and Cons of ICU Challenges and Desensitization in AERD patients <ul><li>Pro: </li></ul><ul><ul><li>Critical care personnel readily available </li></ul></ul><ul><ul><li>One RN assigned to each patient </li></ul></ul><ul><li>Con: </li></ul><ul><ul><li>Scripps OACs: never resulted in intubation </li></ul></ul><ul><ul><li>Rotating nursing: unfamiliar with OAC </li></ul></ul><ul><ul><li>Spirometry: hospital respiratory therapy </li></ul></ul><ul><ul><li>Allergist: down time out of the office </li></ul></ul><ul><ul><li>Expense increases: challenge + ICU facility </li></ul></ul><ul><ul><li>Scheduling ICU beds: usually impractical </li></ul></ul>
  22. 26. Treatment of AERD <ul><li>Avoiding ASA/NSAIDs does not prevent AERD from starting, continuing and progressing </li></ul><ul><li>Avoiding ASA/NSAIDs eliminates potential catastrophic respiratory reactions </li></ul><ul><li>Treatment of the underlying disease requires a continuous and comprehensive strategy </li></ul>
  23. 27. Medical Treatment of AERD <ul><li>Upper airway is the primary Rx target </li></ul><ul><ul><li>Nasal obstruction: Nocturnal nasal obstruction and sleep deprived fatigue </li></ul></ul><ul><ul><li>Anosmia (QOL issues. Food tastes. dangerous) </li></ul></ul><ul><ul><li>Complicating infectious sinusitis </li></ul></ul><ul><li>Lower airway asthma is usually easier to control. Exceptions: </li></ul><ul><ul><li>Viral respiratory infections, Infectious sinusitis </li></ul></ul><ul><ul><li>Other provoking factors: GERD, IgE mediated </li></ul></ul>
  24. 28. Treatment of AERD <ul><li>Stop the cause or complications if you have the power to change them : </li></ul><ul><ul><li>Allergens ETS Diesel smoke </li></ul></ul><ul><ul><li>Infectious agents: virus, bacteria, fungi </li></ul></ul><ul><li>Remove or drain hyperplastic tissues: </li></ul><ul><ul><li>Surgery: polyps and sinuses </li></ul></ul><ul><li>Controller Rx to block inflammation: </li></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><li>LTRAs and 5-LO blocker </li></ul></ul>
  25. 29. Plasma Histamine in asthmatics: 1975 -1979 <ul><li>Scripps GCRC: Funded by Federal Government </li></ul><ul><li>TSRI collaboration ( Dr. Eng Tan + Lab) </li></ul><ul><ul><li>Stevenson DD, Arroyave CM, Bhat KN, Tan EM. Oral ASA challenges in asthmatic patients: a study of plasma histamine . Clin Allergy 1976;6: 493-505 </li></ul></ul><ul><ul><li>Bhat KN, Arroyave CM, Marney SR, Stevenson DD, Tan EM. Plasma histamine changes during provoked bronchospasm in asthmatic patients . JACI 1976;647-56. </li></ul></ul><ul><ul><li>Simon RA, Stevenson DD, Arroyave CM, Tan EM. The relationship of plasma histamine to asthma activity . JACI 1977: 60: 312-16. </li></ul></ul><ul><li>Leukotrienes discovered by Prof Bengt Samuellsson Abstract Nov 1979 (published 1980 -87). Nobel Prize 1982 </li></ul>
  26. 31. 1979-80: ASA desensitization Rx <ul><li>Both patients desensitized to ASA in GCRC </li></ul><ul><li>Daily dose of ASA 325 mg/day, increasing to 325 mg BID after 6 months because of breakthrough nasal congestion: polyps decreasing over 1 yr </li></ul><ul><li>Lack of sinusitis episodes over first year </li></ul><ul><li>Both patients were taking: </li></ul><ul><ul><li>Beclomethasone: nasal and bronchial ( no change) </li></ul></ul><ul><ul><li>Systemic corticosteroids: </li></ul></ul><ul><ul><ul><li>Pt #1: Baseline methylprednisolone 8 mg q.o.d: 4 mg q.o.d </li></ul></ul></ul><ul><ul><ul><li>Pt #2: Baseline prednisone 5-10 mg q.o.d: DC at 6 months </li></ul></ul></ul>Stevenson DD, Simon RA, Mathison DA, JACI 1980;66:82
  27. 32. Features of ASA desensitization <ul><li>After reaching 325mg ASA dose: </li></ul><ul><li>Nasal decongestion occurs immediately </li></ul><ul><li>Hyperirritable airways : Methacholine challenge + </li></ul><ul><li>Cross-desensitization with all NSAIDs that inhibit COX-1: occurs in all patients </li></ul><ul><li>Refractory period : 48 hrs minimum and up to 5 days maximum, after ASA has been discontinued </li></ul><ul><li>Universal for almost all AERD patients </li></ul><ul><ul><li>One patient: failure to maintain ASA desensitization </li></ul></ul>
  28. 33. Scripps ASA desensitization and daily ASA: studies demonstrating therapeutic efficacy <ul><li>Stevenson et al JACI 1980;66:82 2 </li></ul><ul><li>Stevenson DD et al JACI 1984;73:50 25 </li></ul><ul><li>Sweet JA et al JACI 1990;86:749 107 </li></ul><ul><li>Stevenson DD et al JACI 1996;98:751 65 </li></ul><ul><li>Berges-Gimeno JACI 2003;111:180 126 </li></ul><ul><li>Total number of patients studied 325 </li></ul>
  29. 36. Polyp sinus surgery before and after ASA desensitization <ul><li>AERD patients average one sinus/ polyp operation every 3 years: “sinus revision” </li></ul><ul><li>After ASA desensitization: </li></ul><ul><ul><li>Average revision operation: one every 10 years </li></ul></ul><ul><ul><li>Majority stopped or slowed growth of polyps </li></ul></ul><ul><ul><li>With decrease in polyps, decrease infections </li></ul></ul><ul><ul><li>Decrease in need for prednisone bursts </li></ul></ul>
  30. 37. Study of ASA desensitization treatment 1995-2000: 1-5 year follow-up <ul><li>Responder but side effects </li></ul><ul><li>Treatment failures: </li></ul><ul><ul><li>Probable (stopped ASA) 15 </li></ul></ul><ul><ul><li>Known failure: 16 </li></ul></ul><ul><ul><li>Died natural causes 2 </li></ul></ul><ul><li>Treatment responders </li></ul><ul><ul><li>Probable (dc ASA for unrelated reasons) 5 </li></ul></ul><ul><ul><li>Known responders 110 </li></ul></ul><ul><li>24/172 (14%) </li></ul><ul><li>33/148 (22%) </li></ul><ul><li>115/148 (78%) </li></ul><ul><li>115/172 (67%) </li></ul>Berges-Gimeno MP, Simon RA, Stevenson DD JACI 2003;111:180-6
  31. 38. Treatment of AERD continued <ul><li>Aspirin desensitization as add on therapy : </li></ul><ul><ul><li>Prevence recurrence of polyps and need for revision sinus surgery </li></ul></ul><ul><ul><li>Decrease nasal congestion in turbinates </li></ul></ul><ul><ul><li>Decrease episodes of infectious sinusitis ( from average 6/year to 2/year) </li></ul></ul><ul><ul><li>Improves sense of smell in 50% </li></ul></ul><ul><ul><li>Improves asthma control in majority </li></ul></ul><ul><ul><li>Reduces need for systemic corticosteroids </li></ul></ul>
  32. 39. Ends: age 82 yrs AERD Dx 1984 ASA desen in 1984 325 mg BID x 27 yr Non-atopic Anosmia persists Asthma persists Rare infections Nasal congestion is Gone and no further polyps DC prednisone in 1984. Continues nasal and inhal. steroids
  33. 40. Ketorolac modified OAC <ul><li>European ASA lysine for Dx and Rx </li></ul><ul><ul><ul><li>Patriarca G et al Ann Allergy Asthma Immunol 1991;67:588-593 </li></ul></ul></ul><ul><ul><ul><li>Casadevall J Torax 2000;55:921-84 </li></ul></ul></ul><ul><li>2006 study intranasal ketorolac for Dx of AERD </li></ul><ul><ul><ul><li>White AA, Bigby T, Stevenson DD Ann Allergy Asthma Immunol 2006;97:190-95 </li></ul></ul></ul><ul><ul><li>29 patients suspected AERD: Ketorolac Nasal + OAC </li></ul></ul><ul><ul><li># pts Ketorolac nasal OAC </li></ul></ul><ul><ul><li>14 + + </li></ul></ul><ul><ul><li>7 neg neg (? Silent desensitization ) </li></ul></ul><ul><ul><li>4 + neg (? Nasal desensitization) </li></ul></ul><ul><ul><li>4 neg + ( Bronchial reaction only) </li></ul></ul><ul><ul><ul><li>Sensitivity 78% specificity 64% </li></ul></ul></ul>
  34. 41. Ketorolac (cont # 2) <ul><li>Study populations: Patients suspected of AERD </li></ul><ul><ul><li>Ket Nas + OAC: 100 consecutive suspects 2005-2009 </li></ul></ul><ul><ul><ul><li>12 not enrolled: nasal obstruction (10), decline (2) </li></ul></ul></ul><ul><ul><ul><li>8 negative: ketorolac & mod OAC challenges </li></ul></ul></ul><ul><ul><li>OAC alone: 100 consecutive suspects 2003-2004 </li></ul></ul><ul><ul><ul><li>8 negative oral aspirin challenges </li></ul></ul></ul><ul><ul><li>Study populations same except: Ket v OAC </li></ul></ul><ul><ul><ul><li>Historical infectious sinusitis/ yr. 3.7 v 5.1 (p 0.01) </li></ul></ul></ul><ul><ul><ul><li>History of asthma 97 v 88 (p 0.01) </li></ul></ul></ul><ul><ul><ul><li>LTMD use 93 v 77 (p 0.001) </li></ul></ul></ul><ul><ul><li>Comparison of positive challenges to completion of desensitization </li></ul></ul>Lee, RU et al Ann Allergy Asthma Immunol 2010;105:130-35
  35. 42. Ketorolac (cont #3) <ul><li>OAC Challenges </li></ul><ul><li>20-40 mg </li></ul><ul><li>40-60 mg </li></ul><ul><li>60-100 mg </li></ul><ul><li>100 mg </li></ul><ul><li>160 mg </li></ul><ul><li>325 mg </li></ul><ul><li>Instructions/discharge </li></ul><ul><li>Intranasal ketorolac </li></ul><ul><li>1 spray (one nostril) </li></ul><ul><li>2 prays (one in each nostril) </li></ul><ul><li>4 sprays (2 each nostril) </li></ul><ul><li>6 sprays (3 each nostril) </li></ul><ul><li>60 mg of aspirin </li></ul><ul><li>60 mg of aspirin </li></ul><ul><li>150 mg of aspirin </li></ul><ul><li>325 mg of aspirin </li></ul><ul><li>Instructions and discharge </li></ul>Day 1 8 AM 8:30 9 :00 9:30 10:30 11:00 12 Noon 1:30 2 PM 5 PM Day 2 8 AM 11:00 2 PM 5 PM
  36. 43. <ul><li>Intranasal ketorolac and ASA challenge vs. OAC </li></ul>* 2 sample t test X2 was used to test categorical variables (1 yes and o no) Positive respiratory challenges Keto + ASA n = 82 OAC n = 92 P value* PNIF mean % decrease (SD) 28.7 (20.3) NA NA FEV1 mean % decrease (SD) 8.5 (12.2) 13.4 (12.4) .01 Duration, mean (SD) days 1.9 (0.42) 2.6 (0.64) <0.001 Duration < 2 days No (%) 68 (83%) 18 (20%) <0.001 Naso-ocular reaction only Number (%) 54 (65%) 35 (38%) <0.001
  37. 44. Types of bronchial and Extra-pulmonary reactions X 2 was used to test categorical variables (1 yes and o no) Reaction Keto + ASA n =82 OAC n =92 P values* Bronchial ( FEV1 > 15%) 26 (32%) 35 (38%) 0.61 15 -19% 11 (13%) 12 (13%) 0.66 20-29% 8 (10%) 13 (14%) 0.63 > 30% 7 (9%) 10(11%) 0.45 Extra Pulmonary reactions 19 (23%) 42 (45%) 0.002 Laryngeal 6 (7%) 17 (19%) 0.02 Gastrointestinal 10 (12%) 30 (33%) .001 Cutaneous 5 (6%) 9 (10%) 0.78
  38. 45. Mechanisms of ASA desensitization <ul><li>Acute ASA desensitization: ASA 650 mg </li></ul><ul><ul><li>Nasal decongestion </li></ul></ul><ul><ul><ul><li>Blocking a vasodilator: ? Histamine, LTs, PGD 2 </li></ul></ul></ul><ul><li>Chronic ASA desensitization: > 2 weeks Rx </li></ul><ul><ul><li>Decreasing polypoid tissue in nose and sinuses </li></ul></ul><ul><ul><ul><li>Interruption of bone marrow stimulation, chemotaxis, transmigration, release mediators, stimulation of apoptosis </li></ul></ul></ul><ul><ul><ul><li>( ? Eosinophils, mast cells, others) </li></ul></ul></ul><ul><ul><li>Decrease receptors or functions for LTs (1 and 2), histamine or PGD2 </li></ul></ul><ul><ul><li>Mast cell “paralysis”: takes 3 – 7 days to reload </li></ul></ul>
  39. 46. Sousa et al (#3) <ul><li>Effect of ASA lysine intranasal treatment, after nasal ASA desensitization, on numbers of CD45+ cells expressing cysLT 1 receptors or LTB 4 receptors </li></ul><ul><li>18 of the 22 ASA sensitive patients participated: </li></ul><ul><ul><li>Double blind placebo controlled : either 2 weeks or 6 months </li></ul></ul><ul><ul><li>Intranasal corticosteroids were withheld during study </li></ul></ul><ul><ul><li>Asthma: inhaled CS were continued at the same doses </li></ul></ul><ul><ul><li>Treatment dose was ASA lysine 8 mg nasal qod vs. placebo qod </li></ul></ul>Sousa, A et al NEJM 2002; 347: 1493-9
  40. 47. Sousa, A et al NEJM 2002; 347: 1493-9 % of CD45+ leukocytes cysLT 1 receptors Baseline to 2 weeks Lysine ASA p = 0.008 Placebo p = 0.68 Baseline to 6 months Lysine ASA p = 0.02 Placebo p = 0.89 LTB 4 receptors
  41. 48. Sousa et al (conclusions) <ul><li>In ASA sensitive respiratory disease : </li></ul><ul><ul><li>(1) More leukocytes express cysLT 1 receptors </li></ul></ul><ul><ul><li>(2) Nasal ASA lysine treatment decreases cysLT 1 R </li></ul></ul><ul><ul><li>(3) LTB 4 receptors were same as ATA controlls </li></ul></ul><ul><li>Increasing expression of cysLT 1 receptors on inflammatory cells provides opportunity for additional proinflammatory stimuli in AIA pts (i.e. recruitment of eosinophils, etc.) </li></ul><ul><li>ASA desensitization Rx may inhibit intracellular transcription, decreasing receptor expression on surfaces of inflammatory cells </li></ul>
  42. 49. In vitro cellular changes: IL-4 and IL-13 induced signal transduction <ul><li>ASA prevented activation STAT 6 via Janus kinase . </li></ul><ul><li> IL-4 normally binds and signals through cytokine receptor </li></ul><ul><ul><li>Naïve Th0 cells into TH2 </li></ul></ul><ul><ul><li>VCAM expression: transmigration eosinophils tissues </li></ul></ul><ul><ul><li>Mucus hypersecretion and airway hyperirritability </li></ul></ul><ul><ul><li>Activate eosinophils and eotaxin (delay apoptosis) </li></ul></ul><ul><li>IL-13 normally binds and signals via same receptor </li></ul><ul><ul><li>Eosinophils, mast cells, smooth muscle cells, macrophages, epithelial and endothelial cells </li></ul></ul>Perez, GM et al J Immunol 168:1428, 2002
  43. 50. Does IL-4 cause AERD ? <ul><li>Th0 conversion to Th2 cells </li></ul><ul><li>Th2 synthesis IL-5 (eosinophils) </li></ul><ul><li>Mast cell growth factor (MC synthesis IL-4) </li></ul><ul><li>VCAM expression: (IL-4, IL-13) </li></ul><ul><li>Stimulates goblet cell hyperplasia: </li></ul><ul><li>Stimulates eotaxin: prolong eosinophils </li></ul><ul><li>Fibroblast: polyps, airway remodeling </li></ul>
  44. 51. Selective inhibition of IL-4 gene expression in human T-cells by Salicylates but not NSAIDs <ul><li>CD-4+ human T cells, mitogen primed </li></ul><ul><li>Stimulation with Ca++ ionophore and protein kinase C </li></ul><ul><li>Addition of ASA 10 - 5 to 10 -3 M: inhibited only secretion of IL-4 ( no effect IL-13, IL-2, IFN-g) </li></ul><ul><li>Inhibits IL-4 gene expression at transcription </li></ul><ul><li>Salicylic acid: same inhibitory effect as ASA </li></ul><ul><li>NSAIDs (indomethacin, flurbiprofen): no effect </li></ul>Cianferoni, A Casolaro, V et al Blood 2001;97:1742-49
  45. 52. Suppression of IL-4 during aspirin desensitization treatment <ul><li>21 patients with history of ASA/NSAID induced asthma </li></ul><ul><li>Underwent 2 day aspirin desensitization </li></ul><ul><li>Treated with aspirin 650 mg BID for 6 months </li></ul><ul><li>3% saline induced sputum: pre, day 2 and 6 months </li></ul><ul><li>Sputum measurement for: Tryptase, IL-4, MMP-9 </li></ul><ul><li>Matrix metalloproteinase 9 (MMP-9) recruit PMNs and eosinophils </li></ul><ul><li>6 months: clinical assessment and re-measurement of sputum mediators in 14/21 patients </li></ul>Katial RK et al JACI 2010; 126:738-44
  46. 54. Katial et al (cont.) <ul><li>At 6 months: (n =14) AERD patients </li></ul><ul><ul><li>Symptom scores improved from baseline </li></ul></ul><ul><ul><li>Decrease in sputum mediators: baseline, 1 day ….. 6 months </li></ul></ul><ul><ul><ul><li>IL-4 28.1 (SD 18-58 ), 51.1 …… 1.5 (SD 0 - 4) pg/ml (p = 0.0007) </li></ul></ul></ul><ul><ul><ul><li>Metalloproteinase 9 (MMP-9) 57.1 , 56.6 ….. 24.7 ng/ml (p = 0.05) </li></ul></ul></ul><ul><ul><li>Stable sputum mediators: Baseline, 1 day… to 6 months </li></ul></ul><ul><ul><ul><li>Tryptase 0.82, 1.44…… 1.25 ng/ml (p = NS) </li></ul></ul></ul><ul><ul><ul><li>Exhaled nitric oxide (FeNO) 33.5 ppb, 40.3 ppb…. 38 ppb (p =NS) </li></ul></ul></ul><ul><li>Controls (3): Nasal polyps, sinusitis ASA tolerant: Treated with ASA 650 mg BID for 6 months </li></ul><ul><ul><li>No comment in paper on the clinical course of the 3 controlls </li></ul></ul><ul><ul><li>Sputum samples baseline, 1 day …… 6 months </li></ul></ul><ul><ul><ul><li>Il-4 increased slightly from baseline at 6 months in 2/3 patients and no change in the 3 rd patient. </li></ul></ul></ul>
  47. 55. <ul><li>Conclusions : </li></ul><ul><ul><li>Desensitization to ASA involved airway mast cell degranulation and cohort release of MMP-9 </li></ul></ul><ul><ul><li>Tryptase and FeNO increased after acute desensitization </li></ul></ul><ul><ul><li>MMP-9 decreased over 6 months ( p 0.05) </li></ul></ul><ul><ul><li>IL-4 increased immediately after ASA desensitization </li></ul></ul><ul><ul><li>IL-4 decreased over 6 months of ASA Rx (p 0.0007) </li></ul></ul><ul><ul><li>IL-4 is a potent positive immune regulator which potentially could be responsible for stimulating much of the inflammation found in the respiratory mucosa of patients with AERD </li></ul></ul>Katial RK et al JACI 2010;126:738-44

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