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AERD: Diagnosis and Treatment
 

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

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    AERD: Diagnosis and Treatment AERD: Diagnosis and Treatment Presentation Transcript

    • 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]
    • 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
    • What is Aspirin- Exacerbated Respiratory Disease?
      • AERD is a clinical tetrad of:
        • Nasal polyps
        • Chronic rhinosinusitis (CRS)
        • Asthma
        • NSAID induced respiratory reactions
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    •  
    •  
    • 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
    • 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
      • 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
    •  
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    • 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
    • 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
    • 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
    • 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
    • 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
    • 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%)
    • 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
    • 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%)
    • 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
    • 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
    • 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
    • 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
    • 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
    •  
    • 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
    • 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
    • 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
    •  
    •  
    • 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
    • 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
    • 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
    • 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
    • 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%
    • 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
    • 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
      • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    •  
    • 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.
      • 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
    •