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[LIST=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][*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-2-728.jpg?cb=1316098522]2. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-3-728.jpg?cb=1316098522]3. [/URL]What is Aspirin- Exacerbated Respiratory Disease?

• AERD is a clinical tetrad of:

• Nasal polyps

• Chronic rhinosinusitis (CRS)

• Asthma

• NSAID induced respiratory reactions

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-4-728.jpg?cb=1316098522]4. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-5-728.jpg?cb=1316098522]5. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-6-728.jpg?cb=1316098522]6. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-7-728.jpg?cb=1316098522]7. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-8-728.jpg?cb=1316098522]8. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-9-728.jpg?cb=1316098522]9. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-12-728.jpg?cb=1316098522]12. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-13-728.jpg?cb=1316098522]13. [/URL]Szczeklik, A et al Am J Respir Crit Care Med 1996; 154:1608 -14[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-14-728.jpg?cb=1316098522]14. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-17-728.jpg?cb=1316098522]17. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-18-728.jpg?cb=1316098522]18. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-19-728.jpg?cb=1316098522]19. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-20-728.jpg?cb=1316098522]20. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-21-728.jpg?cb=1316098522]21. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-22-728.jpg?cb=1316098522]22. [/URL]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%)[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-23-728.jpg?cb=1316098522]23. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-24-728.jpg?cb=1316098522]24. [/URL]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%)

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-25-728.jpg?cb=1316098522]25. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-26-728.jpg?cb=1316098522]26. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-27-728.jpg?cb=1316098522]27. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-28-728.jpg?cb=1316098522]28. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-29-728.jpg?cb=1316098522]29. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-31-728.jpg?cb=1316098522]31. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-32-728.jpg?cb=1316098522]32. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-33-728.jpg?cb=1316098522]33. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-36-728.jpg?cb=1316098522]36. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-37-728.jpg?cb=1316098522]37. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-38-728.jpg?cb=1316098522]38. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-39-728.jpg?cb=1316098522]39. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-40-728.jpg?cb=1316098522]40. [/URL]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%

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-41-728.jpg?cb=1316098522]41. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-42-728.jpg?cb=1316098522]42. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-43-728.jpg?cb=1316098522]43. [/URL]

• 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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-44-728.jpg?cb=1316098522]44. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-45-728.jpg?cb=1316098522]45. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-46-728.jpg?cb=1316098522]46. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-47-728.jpg?cb=1316098522]47. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-48-728.jpg?cb=1316098522]48. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-49-728.jpg?cb=1316098522]49. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-50-728.jpg?cb=1316098522]50. [/URL]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

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-51-728.jpg?cb=1316098522]51. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-52-728.jpg?cb=1316098522]52. [/URL]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[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-54-728.jpg?cb=1316098522]54. [/URL]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.

[*][URL=https://image.slidesharecdn.com/kentuckyallergysocietyfinalsept2011-110915140225-phpapp02/95/aerd-diagnosis-and-treatment-55-728.jpg?cb=1316098522]55. [/URL]

• 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 [/LIST]

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