AERD: Diagnosis and Treatment

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 ,[object Object],[object Object],[object Object],[object Object],[object Object]

What is Aspirin- Exacerbated Respiratory Disease? ,[object Object],[object Object],[object Object],[object Object],[object Object]

AERD vs. Samter’s triad ,[object Object],[object Object],[object Object],[object Object]

AERD Population ,[object Object],[object Object],[object Object],[object Object],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? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

IL-4, IL-5, GM-CSF ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Deficiency of PGE 2 in AERD ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Bronchial ASA-lysine challenges induce LTC 4 synthesis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Daffern, P et al JACI 104:559-64, 1999

The problem of diagnosing AERD ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

243 patients presenting for OAC ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Relationship between historical ASA/NSAIDs -induced asthma attacks and the degree of bronchospasm during oral aspirin challenges ,[object Object],[object Object],[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Pros and Cons of ICU Challenges and Desensitization in AERD patients ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Treatment of AERD ,[object Object],[object Object],[object Object]

Medical Treatment of AERD ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Treatment of AERD ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Plasma Histamine in asthmatics: 1975 -1979 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

1979-80: ASA desensitization Rx ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Stevenson DD, Simon RA, Mathison DA, JACI 1980;66:82

Features of ASA desensitization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Scripps ASA desensitization and daily ASA: studies demonstrating therapeutic efficacy ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Polyp sinus surgery before and after ASA desensitization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Study of ASA desensitization treatment 1995-2000: 1-5 year follow-up ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Berges-Gimeno MP, Simon RA, Stevenson DD JACI 2003;111:180-6

Treatment of AERD continued ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Ketorolac (cont # 2) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Lee, RU et al Ann Allergy Asthma Immunol 2010;105:130-35

Ketorolac (cont #3) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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

[object Object],* 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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Sousa et al (#3) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

In vitro cellular changes: IL-4 and IL-13 induced signal transduction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Perez, GM et al J Immunol 168:1428, 2002

Does IL-4 cause AERD ? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Selective inhibition of IL-4 gene expression in human T-cells by Salicylates but not NSAIDs ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Cianferoni, A Casolaro, V et al Blood 2001;97:1742-49

Suppression of IL-4 during aspirin desensitization treatment ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Katial RK et al JACI 2010; 126:738-44

Katial et al (cont.) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Katial RK et al JACI 2010;126:738-44

AERD: Diagnosis and Treatment

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AERD: Diagnosis and Treatment