What have we learned from Aspirin Desensitization in Aspirin Exacerbated Respiratory Disease?

Katharine M Woessner MD, FAAAAI Head, Division of Allergy, Asthma and Immunology Scripps Clinic Medical Group

DISCLOSURES • Speaker, Advisory Board

Member; Honorarium Shire

• Speaker; Honorarium Teva

LEARNING OBJECTIVES Employ the currently available methods for

aspirin desensitization to improve clinical outcomes in their patients with aspirin sensitivity

Evaluate for the possibility of silent desensitization and be able to interpret clinical outcomes

Recognize patients who have AERD which have previously been missed

ARS: Dr Stevenson’s Biography includes all of the following except? A. Responsible for launching the career of many

top Allergists/Immunologists in the US and around the world.

B. He was the bridge between the European approach and US approach to AERD, without his ongoing influence, the Europeans now call the disease NERD.

C. He met his future wife Jeannie in New York because her ship left late.

What is AERD? Chronic eosinophilic (Type 2) inflammation of

sinuses +/- the lungs with sensitivity to all COX-1 inhibiting NSAIDs

Age of onset: 3rd or 4th decade

History of prior tolerance of ASA/NSAIDs

Female: Male 2.3:1 (more severe in women)

Chronic congestion, rhinitis, anosmia, nasal polyps

Asthma develops 1-5 years after onset of rhinitis

ASA/NSAIDs induce rhinitis/asthma attacks

Progressive disease despite careful avoidance of NSAIDs and ASA

Only way to diagnose AERD is with ASA / NSAID challenge

Sinus Disease Impact

Worse baseline sinus disease

Smell Score (0-4) – 0.7 average

More aggressive polyp formation Otologic and intracranial polyposis reported

10x as many FESS as non-AERD 5.2 vs 0.53 Significantly higher rates of polyp recurrence at 6 months

1. Kim J, Kountakis SE. Ear, Nose and Throat Journal 2007;86(7):396-9.

2. Majithia A et al Am J Rhino 2007:59-63

3. Shen J et al, Otol Neurotol 2012:33;774-8

Impact on Asthma One of the “endotypes” of asthma1

Persistent airflow limitation was more likely in AERD patients than in those without aspirin sensitivity2

More likely to require high dose inhaled corticosteroids, to receive bursts of systemic corticosteroid, and to have been intubated for asthma3

In a Japanese population, AERD more likely to have multiple asthma exacerbations during the previous year (34.4% vs. 5.4%) as well as near-fatal asthma4

In one US series, 22%-51% required daily prednisone at an average dose of 7.5-8 mg per day5

Diagnosis of asthma is not essential to having AERD: some may only have asthma symptoms as part of the NSAID reaction∗

1 Lotvall J et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127:355-60. 2 Lee JH et al. Risk factors associated with perstent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest 2007;132(6):1882-9. 3Mascia K, et al. Aspirin Sensitivity and severity of asthma: Evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2005;116:970-5. 4Koga T, et al. Characterization of patients with frequent exacerbation of asthma. Respir Med 2006;100:273-278. 5 Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2002;89:474-478.

Disease development Environmental factors Environmental tobacco smoke exposure1

Childhood ETS OR – 3.46 Viral infection

Susceptible polymorphism

1. Chang J et al Ann Allergy Asthma Immunol 2012;108:14-19

ARS: AERD is characterized by which of the following?

A. Underproduction of prostaglandin E 2 (PGE2)

B. Elevated levels of COX-2 enzyme in the nasal polyp tissue

C. Adherent platelets leading to increased leukotriene production

D. Decreased levels of ILC-2 cells, IL-33 and TSLP

Known baseline abnormalities in AERD

• Decrease in PGE2

• Decrease in EP2 receptor

• Increase baseline PGD2

• Increase in TXA2 production

• Elevated LTE4 in urine, BAL and nasal secretions

• Diminished capacity to generate lipoxins

• Elevated CysLT1 receptors

• Decreased COX-2 mRNA in nasal polyps

• Higher levels of eosinophils in AERD NP vs aspirin tolerant NP

• Increased IL-33 and TSLP and ILC2s

TSLP IL-33

Woessner KM Curr Allergy Asthma Rep. 2017 Jan;17(

Membrane phospholipids

Arachidonic acid

cPLA2

15 (s)-HETE 15-lipoxygenase

5-lipoxygenase FLAP

5-HPETE 5-HETE

5-lipoxygenase

LTA4

LTB4

LTB4 hydrolase LTC4 synthase

LTC4

LTD4

LTE4

CysLT1 and CysLT2 receptors

COX-1/ COX-2

Prostaglandins

Thromboxanes

PGD2 synthase

PGD2

PGF2

PGI2

PGE2 synthase

PGE2

EP1, EP2, EP3, EP4 receptors

Lipoxins

5-lipoxygenase

Increased in AERD

Decreased in AERD

Modified from Steinke et al, J Allergy 2012

Making the diagnosis of AERD Relying upon history to make the diagnosis can

be very problematic

Patient is already on 81 mg of ASA

Role of sensitivity to alcohol

How reliable is the history of NSAID reactions in patients with asthma and nasal polyposis to diagnose AERD?

History of one reaction – positive challenge 80%

History of reaction to 2 NSAIDs – positive challenge 89%

Patients not taking NSAIDS with nasal polyps and asthma – 42%

45 patients with history of severe NSAID reactions requiring hospitalization – 100%

Dursun AB, Woessner KM, Simon RA, Karassoy JD, Stevenson DD. Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps and chronic sinusitis. Ann Allergy Asthma Clin Immunol 2008;100:420-25.

Doc, I’m already on a baby aspirin

Lee-Sarwar K et al. J Allergy Clin Immunol Pract (In Press)

Alcohol Reaction Rate

83%

43% 30%

14%

0

20

40

60

80

100

AERD ATA CRS Control NP

Respiratory Reactions

43%

Diagnosis of AERD

ASA challenge: gold standard REACTIONS TO ORAL ASA CHALLENGE

1. Classic: 20% or > decline FeV1, naso-ocular

2. Pure lower: no naso-ocular reaction

3. Partial Asthma: decline in FEV1 between 15-20% with naso-ocular reaction

4. Laryngospasm

5. Negative: no reaction following 325 mg ASA

When did aspirin challenge and desensitization begin?

First reported desensitization was by Widal et al. in 1922. Widal MF et al. Presse Med 1922, 30:189-192

37 yo female pt admitted to the hospital for extensive oral challenges over several weeks. Started in her 20’s, nasal polyposis and asthma, during oral challenges with ASA and antypyrine (First NSAID) experienced severe asthma attacks, hives and rhinorrhea. Oral challenges with non-cox-1 inhibitors were tolerated

1976: Zeiss & Lockey _ 72 h refractory period after + indomethacin challenge

Bianco: induced asthma with inhaled lysine-aspirin and also found a 72 h refractory period.

1980: Stevenson: 325 mg ASA evoked major reaction. The next day, patient tolerated 325 mg and did not wlant to stop aspirin therapy. Methacholine challenge did not change. Oral CCS were discontinued in 1 pt and reduced by 50% in a second ushering in ASA desensitzation and ASA therapy for management of AERD. Stevenson DD, Mathison DA, Simon RA. J Allergy Clin Immunol.1980;66:82

DBPC Study (N25) 3 months:

75% had improvement in sinus/nasal symptoms, less so with asthma and CCS use.

Lessons learned: dose of ASA was too low and there is a need to do debulking sinus surgery prior to desensitization. Stevenson DD et al. J Allergy Clin Immunol. 1984; 73:500

Prospective approach to analyzing outcomes in ASA desensitization Large data base accumulated over time from in-

patient protocols in the GCRC at Scripps Green Hospital and subsequent transition to the out-patient clinic

Allowed for many questions to be answered regarding ASA desensitization including long term outcomes.

Changes in Clinical Markers After ASA Desensitization Treatment (n=126)

Clinical measures Median Range Median Range P values

# sinus infections/yr 5.0 0-12 2.0 0-12 <0.0001

Olfactory scores 0.0 0-5 3.0 0-5 <0.0001

Nasal symptom scores 2.0 0-4 4.0 0-4 <0.0001

Asthma symptom scores 3.0 0-4 4.0 0-4 <0.0001

Sinus operations/yr 0.22 0-3 0.0 0-2.3 <0.0001

Hospitalizations/yr 0.0 0- 5.2 0.0 0-3 <0.0001

ER visits/yr 0.15 0-15 0.0 0-5 <0.0001

Baseline 1 year or > ASA Rx

Wilcoxon signed rank statistic: Two sided p values were reported

What you can tell patients about the expected outcome from ASA desensitization

87 % will experience a significant improvement. 48%: Improved asthma and nasal symptoms and

decreased corticosteroid use 39% improved nasal and asthma symptoms but no

change in CCS

13 % will be non-responders No change in any parameters (25%) Increased use of CCS (12%) Included in this group were pts who had LTRAs

added after completion of ASA desensitization by their MD, suggesting incomplete response

Long-term outcomes of aspirin desensitization in 172 patients

27% quit in the first year

24/46 (52%) due to side effects Gastric pain (14) Gastric bleeding (2) Urticaria (6) Bleeding: nose/ear (2)

17/46 (37%) discontinuation unrelated to side

effects 3 worsening asthma: ? Related vs URI induced 12 unrelated or unknown reasons 2 died of natural causes in first 6 months of study

5/46 (11%) discontinuation unrelated to Rx

response Planned pregnancy (1) Elective surgery (4)

What role did the addition of LTRA add to use of ASA desensitization in AERD?

6 Non-responders

25 Good

response

27 excellent response

10 Non-responders

25 Good

response

27 excellent response

1995-97: NO LTRA (58)

1998-2000 LTRA (58)

No difference in outcomes with and without LTRA (Fisher exact test p = 0.5 NS

Treatment of AERD Avoidance of all COX-1 inhibiting NSAIDs

All NSAIDs which preferentially inhibit COX-1, cross-react with ASA on first exposure. No prior sensitization required.

Degree of cross-reactivity is roughly = to NSAID concentration required to inhibit COX-1 in vitro

Highly selective COX-2 inhibitors are typically tolerated in patients with AERD. At Scripps over 200 proven- AERD pts challenged with coxibs (celecoxib and rofecoxib) had no reaction. There is a risk with less selective COX-2 inhibitors such as nimesulide and meloxicam at higher doses.

Acetaminophen generally well tolerated until ~1000mg even at that dose the reactions are mild.

Vanselow NA, Smith JR. Ann Int Med,(1967)66: 568-73 Samter M, Beers, RJ (1968). Ann Intern Med 68: 975-83

Who should be a candidate for ASA desensitization?

All AERD patients except those controlled by topical steroids, long-acting beta agonists and LTMDs alone

Patients with recurrent or chronic sinusitis and nasal polyps

Individuals who require anti-platelet therapy with ASA or other COX-1 inhibiting NSAIDs

Underutilized approach in management: survey of a large group of pts with AERD, asa desensitization and therapy most effective intervention. 35% felt no medication was helpful. Only 19% had

undergone desensitization

Ta, V et al. Survey defined patient experiences with AERD JACI Pract 2015:3:711-8

Optimization of ASA Desensitization Procedure

Confirm stable asthma, FEV1 within 10% of best prior value (and >60% predicted or 1.5L)

Continue all routine medications with exception of antihistamines, start leukotriene modifiers 2-4 weeks prior if not already taking.

Oral corticosteroids if necessary

Debulking nasal polyposis 2-4 weeks before ASA desensitization

Treat concomitant conditions (allergic rhinitis, GERD etc)

History of previous severe reaction does not preclude desensitization.

Severity of prior reactions should not be a deterrent to ASA desensitization.

Why the difference?

Graded dose challenges vs full dose

Use of LTMD (5% historical vs 77% OAC)

OAC ≠ sentinel NSAID reaction

Williams et al, J Allergy Clin Immunol 2007;120:273-7

Oral Aspirin Challenge

Time Day 1 Day 2

8 AM 20-40 mg 100-160 mg

11 AM 40-60 mg 160-325 mg

2 PM 60-100 mg 325 mg

Confirm that patient’s baseline FEV1 is the same as their prior best value and they have not used their albuterol rescue inhaler in the past week. If not, consider 1 day placebo challenge to determine stability of airways.

Using a pill cutter, 81 mg ASA tablet can be cut into a half or a fourth.

(1) Measure FEV1 every hour and wait three hours between doses. (2) FEV1 should be at least 1.5 L and > 60 % of predicted.

After a reaction has been treated and resolved go step a. a. Repeat the ASA provoking dose b. If no reaction, continue to escalate dose every 3 hours as above c. At 325 mg ASA, desensitization/tolerance is complete d. Patient should be instructed to start 650mg ASA that night as their first dose and continue with

650mg BID

.

Use of Nasal Ketorolac Challenges

Time Intranasal Ketorolac and oral aspirin Day 1 8:00 Am 1 spray (1.26 mg) 8:30 AM 2 sprays (1 each nostril) 9:00 AM 4 sprays (2 each nostril) 9:30 AM 6 sprays (3 each nostril) 10:30 AM 60 mg ASA 12:00 PM 60 mg ASA 3:00 PM Discharge instructions DAY 2 8:00 AM 150 mg 11:00 AM 325 mg 2:00 PM Discharge instructions

To prepare ketorolac: 1. Ketorolac 60 mg/2 ml and Mix with 2.75 ml saline 2. We use empty nasal spray Bottle. From pharmacy 3. Prime 5 sprays, then each Spray actuates 1.26 mg soln.

Contraindications: Complete nasal obstruction Be prepared to treat:

Bronchospasm: nebulized bronchodilator Naao-ocular: oxymetazolone Antihistamines Laryngospasm: racemic epi. GI: H2 blockers Cutaneous: antihistamines

Safety of Aspirin Challenge/Desensitization

Over 1400 patients desensitized as Scripps Clinic: 3 (0.002%) have experienced systemic reactions. All responded to 1

dose IM epinephrine

Average time to reaction is 102 minutes with oral aspirin challenge*

Typical provoking dose between 45 mg- 100 mg ASA

Ketorolac protocol reduces challenge time by 1 days (40%).

Aspirin desensitization is a cost-effective therapeutic intervention in patient with moderate-to-severe AERD

Lee RU, Stevenson D.D. Allergy, Asthma Immunol Res. 2011; 3:3-10 Shaker M. et al. J Clin Immunol 2008; 121: 81-7. Hope AP, Woessner K, Simon R, Stevenson D. J Allergy Clinical Immunol 2009; 123: 406-410 Lee RU, White D et al. Ann Allergy Asthma Immunol 2010; 105: 130-5.

Abbreviated dosing intervals:

ARS: What happens at the time of acute ASA desensitization? A. Airways hyperresponsiveness improves.

B. Cross-desensitization occurs to all COX-1 inhibiting NSAIDs therefor, any COX-1 inhibiting NSAID may be used for treatment of AERD.

C. Nasal congestion improves

D. There is a refractory period of 24 hours post desensitization

E. None of the above

Features of Acute ASA Desensitization Ingestion of 325 mg ASA without

reactions Nasal congestion improves immediately Hyperirritable airways unchanged:

methacholine challenges continue to be positive

Cross-desensitization with all NSAIDs that inhibit COX-1 enzyme (ibuprofen, naproxen etc)

Refractory period: 2-5 days post exposure ASA Universal for all AERD patients Scripps experience: 1400 consecutive ASA

desensitizations

Dosages of ASA for the Treatment of AERD

81 mg q.d. OK to remain desensitized for cardiovascular disease prevention

325 mg q.d. OK to be cross-desensitized to any doses of all NSAID’s

650 mg BID initial starting dose for treatment of AERD; about 50% can decrease to 325 mg BID after 1-6 months

Although, patient will remain desensitized to COX-1 inhibiting, NSAIDs, use of competitive inhibitors of the COX-1 enzyme (i.e. naproxen or ibuprofen), AERD will not be treated.

Lee, JA, Simon RA, Stevenson DD, J Allergy Clin Immunol (2007)

Potential issues with enhanced safety of ASA desensitization Silent Desensitization:

10 patients underwent oral aspirin challenge

Placed on montelukast and repeated challenge in 8-10 days

9/10 patients had at least nasal-ocular symptoms on second challenge, 4/9 with asthma

1/10 patients had no reaction to second challenge

Stevenson DD et al. Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics. Ann Asthma Allergy Immunol 2000;85:477-82.

“Silent Desensitization”

7 patients (pansinusitis, nasal polyps, and asthma and history of NSAID-triggered reactions. Initial negative challenge, subsequent positive challenge Stopped ML, re-challenged 10-14 days later

5 patients with extremely strong history – negative challenge x 2

White AA, Bosso JV, Stevenson DD; 2013 Allergy Asthma Proceedings

What to do if ASA challenge was negative but a strong history? 38 AERD patients underwent ASA desensitization with daily ASA 650mg BID

therapy: daily nasal and asthma symptoms, olfaction scores and use of prednisone were monitored 4 weeks before and after ASA desensitization

Instructed to keep topical nasal and bronchial CCS and LTMDs the same

Instructed to decrease systemic CCS

RESULTS: Nasal and asthma symptoms, as well as olfactory scores improved significantly

(p<0.001) For the 15 patients taking prednisone: mean dose decreased from 10.7mg/day to

5.9 mg/day (p = 0.0003) Conclusions: Aspirin Desensitization is effective during the first 4 weeks following ASA

desensitization. Berges-Gimeno MP, Simon RA, Stevenson DD. Early Effects of ASA desensitization in Treatment of Asthmatic Patients with AERD.

Ann Allergy Asthma Immunol 2003. 90: 338-41.

Barriers to ASA Desensitization

Recent survey of practicing allergists and fellows-in-training in the US found that only 62.5 % of respondents performed ASA desensitization for AERD 28 % who did not do ASA desensitization also don’t refer

those pts on to someone who does do ASA desensitization.

Deterrents: Safety concerns, logistics of nursing care, and lack of exposure to the procedure during training

PATIENT PERSPECTIVE: 46% willing to undergo after recommendation from physician Those who did not want to 45% concerned about long term safety of aspirin 27% concerned about safety of desensitization 19% the physician did not recommend it 9% too expensive

Waldram J., White AA. JACI in Pract 2016: 4(601253-55 Ta V.,White AA. JACI in Pract 2015; 3(5): 711-8.

Recent outcomes data Reviewed 204 consecutive ASA desensitizations

at Scripps Clinic between 2009-2015.

167 subjects reacted to the challenge 88% reacted during the ketorolac part of the

challenge with the average provoking dose of ketorolac at 7.5mg

39% of subjects reacted to ASA with 60 mg as the provoking dose

The most commonly administered medications during the reactions were antihistamines, bronchodilators and GI medications.

Safety and outcomes of aspirin desensitization for aspirin-exacerbated respiratory disease: A single-center study. Waldram, Jeremy; Walters, Kristen; Simon, Ronald; Woessner, Katharine; Waalen, Jill; MD, MPH; White, Andrew Journal of Allergy & Clinical Immunology. 141(1):250-256, January 2018. DOI: 10.1016/j.jaci.2017.05.006

© 2018Elsevier, Inc. Published by Elsevier. 6

TABLE IV.

TABLE IV. Characteristics of those treated with intramuscular epinephrine during desensitization

Severe Reactors: required IM epinephrine and/or

Required 3 or more doses of a Beta-agonist and/or had an FEV1 decrease > 30%

Findings:

4 pts required epinephrine all in ketorolac group for laryngospasm

GI reactors: 17 pts (10 to ketorolac) 6 to oral asa, 1 to both

8 had(47%) reported GI reaction during historical reaction to NSAIDs.

Role of omalizumab several case reports have suggested efficacy

double blind placebo controlled trial of omalizumab in patients with nasal polyps and asthma found a significant decrease in the total nasal endoscopic score in the treatment arm of which 12 of the 24 patients had a history of aspirin sensitivity (AERD not confirmed with ASA challenge)

21 adults with challenge proven AERD and documented aeroallergen sensitivity treated with omalizumab. 52% of the patients had a rapid response within the first week of treatment. They were also able to show a significant reduction in both urinary LTE4 and PGD2 metabolite

In the Scripps study: all 8 pts on omalizumab at time of ASA challenge had a positive challenge

Gevaert P et al. J Allergy Clin Immunol. 2013;131(1):110-6 e1. Hayashi H et al. J Allergy Clin Immunol. 2016;137(5):1585-7 e4.

ARS: Which of the following is most accurate? A. Leukotriene modifying drugs (montelukast in

particular) are the most important pretreatment medication in making ASA desensitization safer.

B. Pancreatitis following ASA desensitization is common and should be screened for in the months following desensitization.

C. AERD patients who are severe GI reactors cannot undergo aspirin desensitization.

D. AERD patients who are desensitized need to stop their aspirin for colonoscopies if polypectomy is planned.

Illustrative Cases

Unusual Reaction during ASA Desensitization

42 yo male referred to Scripps for ASA desens. 6 y history of nasal polyposis, anosmia and asthma. Initially on SCIT without control of symptoms. Sinus surgery with polypectomy, temporary relief but with recurrence of polyps and anosmia. Began to have allergic reactions eventually linked to intake of NSAIDs (not particularly severe but 3 treated in ER). Underwent OAC. Day 1 reached 81 mg of ASA with no symptoms Day 2: after 325mg: started to react with flushing, increasing drop in FEV1 to 36%

predicted. Given multiple treatments (bronchodilators, antihistamines etc) Despite the intervention: 6 h after the onset of symptoms developed hypotension,

tachycardia: given epinephrine x 2 and taken to ER. Elevated serum tryptase. Treated and released. No further ASA

Started on zileuton and omalizumab in addition to LABA/ICS , INS, and montelukast for 6 months. Goes through two day challenge: no symptoms. Given 650 mg ASA on day 3 : no symptoms. Discharged on ASA 650 mg BID, stop omalizumab, wean off zileuton and continue LABA/ICS, montelukast.

Worsening respiratory symptoms after ASA desensitization

30 yo woman from Venezuela with 2 year history of nasal polyps and anosmia. 3 polypectomies with recurrence of anosmia.

History of naso-ocular and respiratory reactions to ibuprofen (mild)

New onset mild EIB with normal spirometry

Premedicated: LABA/ICS, montelukast, discontinue cetirizine

Successful nasal ketorolac/aspirin desensitization with naso-ocular reaction with ketorolac. Discharged on ASA 650 mg bid, discontinue LABA/ICS, continue montelukast.

2 days post desensitization: chest tightness, wheezing, ASA decreased to 325 mg BID, still needing albuterol q 4 h.

Spirometry: FEV1 68% of predicted (baseline = 104%), FeNO: 170 ppb

Added zileuton: no relief.

Stopped ASA: back to baseline, off all inhalers. Got pregnant and no further ASA.

Severe GI/Cutaneous Reaction 21 yo male: at age 16: pansinusitis, polyposis with

Potts puffy tumor. Post-surgery, relapse of anosmia. Second FESS age 21 with polypectomy. Mild persistent asthma. Ibuprofen reaction age 18 with

wheezing. High dose acetaminophen: mild symptoms Day 1: mild urticaria at baseline. Reacted to ketorolac nasal challenge: throat tightness, acute worsening urticaria. Treatment: cetirizine, racemic epinephrine, oxymetazalone -started to improve but then developed severe GI symptoms of nausea, vomiting and diarrhea. 1 episode of emesis with bright red blood. No tachycardia, no hypotension. No further episodes of hematemesis. IVF, diphenhydramine, solumedrol, odansetron for 8 h. By 5 pm was doing better. Resolved urticaria.

Severe GI/Cutaneous Reaction continued. Discharged home with prednisone, cetirizine, ranitidine,

ondansetron.

Day 2: no desensitization. Started zileuton.

Day 3: pretreated high dose cetirizine, montelukast, zileuton 30mg ASA no reaction 60 mg ASA no reaction 100mg ASA: 1 h post dosing – 28% drop in FEV1, GI symptoms,

recurrence of urticaria Treated for 3-4 h hours with clearing of symptoms

Day 4: Baseline FEV1 73% predicted. Given albuterol. 100mg ASA: no reaction 150 mg ASA: 1 h later severe GI symptoms/urticaria treated for

multiple hours Discharged for the weekend on 81 mg ASA BID with zileuton 600mg 2 bid,

montelukast 10 mg daily, mometasone 2 puffs BID, cetirizine 20 mg bid, ranitidine 150 mg bid, pantoprazole

Severe GI/Cutaneous Reaction continued

Day 5: ASA 81 mg in AM no issues, Took PM dose: increased urticaria

Day 6: ASA 81 mg severe urticaria Did not take second dose

Day 7: ASA 81 mg bid no issues

Day 8: No GI or cutaneous symptoms at baseline 150 mg ASA no symptoms 3 h later given 325 mg ASA; few urticaria, responded quickly to

therapy.

Discharged on 325 mg ASA daily. Stopped zileuton, continued BID cetirizine and montelukast. Continued ranitidine and pantoprazole

GI reactors

Cahill et al. JACI 2014

New AERD phenotype

Predominant GI and cutaneous symptoms

Higher baseline cysLT’s and no suppression of several prostanoids at threshold aspirin dose

Addition of PGE analogue misoprostol along with cetirizine 10 mg bid, zileuton, montelukast with out without oral cromolyn will allow for successful desensitization although can be very challenging.

Protocol for ASA and Surgery

Decrease aspirin dose to 325 mg each day, beginning 8 days before surgery.

Two days before surgery, take your last aspirin tablet in the morning.

On the day before the surgery and the morning of the surgery DO NOT TAKE ANY ASPIRIN

After completing the operation and when you are completely recovered from anesthesia, take one aspirin 325 mg tablet.

On the day after surgery (post-op day 1), take one 325 mg tablet of aspirin in the morning and one 325 mg aspirin at night.

On the second day after surgery (post-op day 2), take your usual dose of aspirin (i.e. whatever dose you were doing prior to the surgery).

Economics of Aspirin Desensitization Aspirin desensitization is a cost-effective

therapeutic intervention in patient with moderate-to-severe AERD

For cardiovascular protection you do have the option of clopidogrel which is a reasonable alternative to ASA desensitization.

Shaker M. et al. An Economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease. J Clin Immunol 2008; 121: 81-7.

What we still need: Ideal world: clinical test to confirm AERD

Followed by silent desensitization in a day or less

Bits of Wisdom from the frontlines of ASA Desensitization

Consider AERD even if patient is on low dose ASA

If the pt has upper airway polyps in strange places think AERD

Patient complaining about asthma flare with ETOH? Think AERD: 50% of AERD vs 20 % ATA vs 0% CRS

Historical reaction does not predict outcomes during desensitization

Leukotriene Modifying Drugs make for a safer desensitization but there is a small but real risk for silent desensitization

Refractory Period of 48h: can restart ASA if it has been discontinued.

ASA does not need to be discontinued for colonoscopy even if needing polypectomy

To date ASA desensitization and therapy most effective treatment for AERD.

references Hedman J.et al. Int J Epidemiol 1999;28:717-22.

Vally H.et al.Thorax 2002;57:569-74.

Weber RW, et. J Allergy Clin Immunol 1979;64:32-7.

Jenkins C. et al.. BMJ 2004;328: 434.

Widal

Dursun AB, Woessner KM, Simon RA, Karassoy JD, Stevenson DD. Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps and chronic sinusitis. Ann Allergy Asthma Clin Immunol 2008;100:420-25

Berges-Gimeno MP et al. J Allergy Clnic Immunol2003:111:180-6

Shaker M. et al. An Economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease. J Clin Immunol 2008; 121: 81-7.