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AERD: Diagnosis and Treatment

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Presentation by Dr. Donald Stevenson …

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

Published in: Health & Medicine

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

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