Aspirin Desensitizationin AERD

Adam Williams, MDAAP-AAAI Annual MeetingAugust 2019

Objectives

• Recognize the indications and contraindications for aspirin desensitization and long term aspirin treatment

• Compare and contrast the key components of the various desensitization protocols currently in clinical use

• Manage reactions that occur in the desensitization setting

Disclosures

Aspirin desensitization=

Induction of Drug Tolerance to Aspirin=

Graded oral aspirin challenge with induction of tolerance to aspirin followed by long term aspirin treatment

Outline • Patient selection and Indications• Clinical effectiveness• Mechanism of effect of aspirin in AERD• Practical aspects of procedure• Key concepts• Premedication / medication withdrawal / risk management• Oral aspirin challenge / desensitization• Intranasal ketorolac

• Managing reactions• Silent desensitization

IndicationsAspirin Challenge vs. Desensitization

• Indications for challenge in AERD• suspected AERD but no clear

history of prior NSAID reactions• as part of desensitization process

for long-term therapy

• Indications for desensitization and long-term therapy in AERD• moderate or severe asthma• intractable nasal symptoms• aggressive polyps• Prevention of relapse of polyps

following surgery• requirement for systemic steroids• indication for aspirin for CAD

prevention or NSAIDs for other conditions

Bochenek et al. Immunol Allergy Clin N Am 2013Stevenson et al. J Allergy Clin Immunol 2006

Contraindications

• Uncontrolled asthma• Respiratory tract infection / asthma exacerbation within past 4 weeks• FEV1 <70% of predicted value• History of chronic renal failure• History of GI bleeding• Pregnancy• Beta-blocker use

Aspirin Desensitization and Long-term TreatmentClinical Effectiveness

Grade A recommendation1

• Improved nasal symptom scores2,3,4,5,6

• Reduced nasal corticosteroid dose2,4,5

• Reduced sinus infections3,4,5,6

• Reduced sinus operations3,5,6

• Reduced systemic corticosteroid use3,4,5,6

• Improved asthma symptom scores3,5,6

• Reduced inhaled corticosteroid use3,5

• Reduced urgent and ER visits and hospitalizations3,4,6

Improves clinical course of 67-78% of patients with AERD7

1Sinusitis Practice Parameter, J Allergy Clin Immunol 20052Stevenson et al. J Allergy Clin Immunol 19843Sweet et al. J Allergy Clin Immunol 19904Stevenson et al. J Allergy Clin Immunol 1996

5Berges-Gimeno et al. J Allergy Clin Immunol 20036Lee et al. J Allergy Clin immunol 20077Hope et al. J Allergy Clin Immunol 2009

Mechanisms of Aspirin Desensitization

• Aspirin desensitization results in acute and chronic change in expression of arachidonic acid mediatiors and receptors• Decreased production of LTE4 and reduced airway responsiveness to LTE4• BUT this is not sufficient to explain all clinical benefits of aspirin therapy in

AERD

• IL-4 may play important role in changes that occur with long term aspirin treatment in AERD• Aspirin binds to salicylate targets on IL-4 promoter

• prevents binding to STAT6• 6 months of aspirin therapy led to 95% reduction in IL-4 levels in AERD

Burnett et al. Immunol Allergy Clin N Amer 2013

Mechanisms of Aspirin Desensitization

• ASA desensitization may work by inhibition of IL-4 (independent of COX inhibition)

• ASA inhibits IL-4 induced STAT6 activation

• Aspirin binds to salicylate targets on IL-4 promoter• prevents binding to STAT6• STAT6 unable to bind

Burnett et al. Immunol Allergy Clin N Amer 2013

process. Cianferoni and colleagues,24 in their study on aspirin inhibition of IL-4 inhuman T cells, looked at NF-kb as a possible link between the 2, but found noassociation.NFAT is another nuclear transcription factor that is involved in the regulation of

immune and inflammatory responses. Aceves and colleagues65 attempted to examinethe possible effects of salicylates on NFAT activation. Using aspirin and a trifluorome-thylated salicylate derivative (triflusal), they were able to show a dose-dependent inhi-bition of several NFAT-regulated cytokine genes, including IL-2, IL-3, IL-8, GM-CSF,TNF-a, IFN-g, and TGF-b1. Consistent with the other data we have reviewed, inhibitionoccurred only at higher therapeutic concentrations than used to inhibit COX. Themedications also inhibited NFAT-dependent transcription, although triflusal was foundto be the most potent. Mechanisms were determined to occur through possible inhi-bition of NFAT binding to DNA and NFAT transactivation. Thus, it acts differently fromcyclosporin A, which inhibits calcineurin-induced dephosphorylation of NFAT, pre-venting its translocation to the nucleus. Additional mechanisms of aspirin activityinclude inhibition of activator protein 1, activation of adenosine monophosphate-activated protein kinase, and inhibition of the mechanistic target of rapamycin, whichmay be important in the benefit of aspirin in colorectal cancer.66–68 Further research isneeded to determine if any of these mechanistic pathways play a role in either thedevelopment of AERD or the benefit seen with daily aspirin treatment afterdesensitization.

SUMMARY

AERD is a clinical syndrome characterized by severe, persistent asthma, hyperplasticeosinophilic sinusitis with nasal polyps, and an intolerance to aspirin and other NSAIDsthat preferentially inhibit COX-1. The disease is associated with increased tissue infil-tration by MC and eosinophils, overexpression of proinflammatory CysLTs, along withupregulation of CysLT1 receptors. Aspirin or COX-1 inhibiting NSAID ingestion results

Fig. 5. Mechanism of inhibition of inflammation after aspirin desensitization. Proposedcascade of events after aspirin desensitization and continued ingestion. Signal inhibitionvia an IL-4/STAT6 pathway results in downregulation of CysLT production and CysLT1Rexpression, with subsequent reduction of tissue inflammation.

Burnett et al232

Burnett et al. Immunol Allergy Clin N Amer 2013

Principles of Aspirin Desensitization

NOT an IgE-mediated reaction

• Provoking dose• Time to reaction• Predicting reaction severity

Components

• Preparation• Protocol• Managing Reactions• Long-term treatment with

aspirin

Conducting Aspirin Challenge / Desensitization

• 2 routes available in US• Oral aspirin

• “gold standard”• reported sensitivity of 89-90%

• Intranasal ketorolac / aspirin• less laryngospasm and GI reactions

• sensitivity and specificity has not been established

• Withdrawal of medications prior to challenge / desensitization• no consensus• sensitivity vs. safety

• Procedures and protocols• no consensus• several variations published

Preparation• Timing

• 3-6 weeks post-op is ideal• Role of aspirin without prior surgery is less clear

• Ensure stable asthma• Do not withdraw asthma medications• Spirometry assessment 1 week before

• allows for intervention to optimize lung function• Should be within 10% of previous best values• Should be >60% predicted or 1.5 L

• Premedication – depends on need for confirmation vs. optimizing safety• Montelukast 10 mg daily 1 week• ICS or ICS/LABA 1 week• Oral steroids ?

• Medication withdrawal

Medication WithdrawalUS Europe

SABAs Hold for 6 hours Hold for 6 hoursAntihistamines Hold for 3-7 days Hold for 3-7 daysDecongestants Hold for 3-7 days Hold for 3-7 daysAnticholinergics Hold HoldNasal corticosteroids Continue Hold for 7 daysInhaled corticosteroids Continue ContinueLeukotriene modifiers Continue Hold at least 7 daysLABAs Continue Hold at 24-48 hoursOral corticosteroids Lowest dose necessary <10 mg/d

Bochenek, et al. Immunol Allergy Clin N Amer 2013Stevenson, et al. JACI 2006

Protocol

• Various protocols have been published• no consensus

• Increasingly performed in outpatient setting• 1:1 nursing• close proximity to supervising physician and nurses station• facility capable of treating severe reactions

• Baseline spirometry

• Vitals, spirometry, and clinical assessment hourly and as indicated by symptoms

• IV access?

Key concepts• Leukotriene blockade reduces lower airway reactions / severity

• Dose dependent reaction• typical provoking dose: 60-100 mg (mean 68 mg)• reactions to <40 mg very unusual

• Allow sufficient time between doses• Mean time to reaction varies by study: 44 min 50 min 60 min 104 min

• Treat reaction symptoms early and aggressively

• Stabilize symptoms before proceeding

• Provoking dose should be repeated

• Patients typically react only ONCE• if subsequent reactions do occur, almost always much milder

• If no reaction by 325 mg, none react to 650 mgWilliams et al. J Allergy Clin Immunol 2007White et al. Immunol Clin N Am 2013

White et al. Ann Allergy Asthma Immunol 2006Hope et al. J Allergy Clin Immunol 2009

Predicting reaction severity• Previous historical reactions do not predict reaction severity in clinical setting

• stable asthma

• LTMD

• early intervention

• dose dependent severity / graded challenges

• Reactions in challenge/desensitization setting milder than index reaction(s)

• Reactions milder after sinus surgery

• Less severe reductions in lower respiratory symptoms

• Factors associated with increased risk of moderate or severe bronchial reaction

• FEV1 <80% predicted

• lack of LTMD

• previous ER visit for asthma (other than NSAID-induced)

• age 31-40*

• duration of AERD symptoms <10 yrs*

• 2 or more risk factors: 30% chance of mod-sev reaction

• all 5 risk factors: 50% chance of mod-sev reaction

• Only 1 of 26 subjects without at least one risk factor had mod reactionWilliams et al. J Allergy Clin Immunol 2007

Jerschow et al. J Allery Clin Immunol 2019

Huang et al. J Allergy Clin Immunol 2019

Hope et al. J Allergy Clin Immunol 2009

Enhancing safety• Premedicate with LTMD, at least 1 week before• Do not withdraw existing asthma treatment• Ensure stable asthma• Spirometry 1 week prior to procedure• FEV1 >60% predicted• No recent or current acute respiratory illness

• Close monitoring during the procedure• Hourly vital signs, clinical assessment, and FEV1• central location• dedicated staff person 1:1

• Early and aggressive treatment of reactionsMacy et al. Ann Allergy Asthma Clin Immunol 2007White et a. Immunol Allergy Clin N Amer 2013

Aspirin Challenge/DesensitizationProtocols• Oral Aspirin Desensitization• Scripps Clinic• Aspirin Desensitization Task Force• Univ of Texas Southwestern• BMC (unpublished)

• Intranasal Ketorolac / Aspirin

Scripps Clinic Protocol

• Doses: (30) 45 60 100 150 325 mg• FEV1 and vitals every hour and as indicated by symptoms• Monitor closely for signs or symptoms of reaction• 3 hours between doses• After reaction has been treated and stabilized, repeat

provoking dose• If no reaction, continue to escalate

Desensitization), refinement of methods, challenge locations, and protocols wereevolving. Based on the authors’ early protocols,16 most patients were admitted tothe hospital (General Clinical Research Center at Scripps Clinic) while taking their usualasthma controller medications. Antihistamines were withheld because concomitantantihistamine treatment during oral aspirin challenges (OAC) could block cutaneousand nasal reactions, leading to false-negative challenges (Table 1).17 On the firstday, patients underwent oral placebo challenges to verify stable pulmonary function.On day 2, patients began to receive initial aspirin doses of 30 mg, 45 mg, or 60 mg,followed by advancing doses of 60 mg or 100 mg, 150 mg, 325 mg, and 650 mgwith all dosing 3 hours apart. An intravenous line was routinely started before thedesensitization. Serial spirometry was performed during OAC. A fairly typical thresholddose of approximately 60 mg aspirin induced reactions in most patients. After thepatient reacted, appropriate treatment was initiated, and after recovery, the thresholdaspirin dose was repeated. Although subsequent reactions could occur at higherdoses of aspirin, these usually were less intense and easy to treat. The average patientwould require 4 to 5 days of active aspirin dosing during a positive OAC.After the appearance of leukotriene-modifying drugs (LTMDs) between 1998 and

1999, interest in using these drugs for broncho-protection was obvious. DuringOAC, the terminal leukotriene (LTE4) appears in the urine approximately 2 to 6 hoursafter the respiratory reaction.18,19 The more severe the aspirin-induced broncho-spasm, the greater the concentration of urinary LTE4.

19 This underscored the relativeimportance of initiating cysteinyl leukotriene receptor blockade during OAC.Three studies conducted at the Scripps Clinic between 2002 and 2006 shed light on

this subject. The first determined whether concomitant treatment with LTMDs wasassociated with a reduction in ASA-induced lower respiratory tract reactions, whencompared with a control group who were not taking LTMDs.20 In the LTMD-treatedgroup, 96 patients were taking leukotriene receptor antagonists and 12 were takingzileuton. In the control group, without treatment, there were 163 patients. Resultsshowed a strongly significant decrease in lower respiratory tract reactions and anincrease in nasal reactors alone in the leukotriene receptor antagonists–protectedpatients. Similar results of broncho-protection were recorded for the12 zileuton-protected patients. Thus, some of the pure nasal reactors would have been classic

Table 1Sample oral aspirin challenge/desensitization protocol for AERD

Time Day 1a Day 2

8 AM 20–40 mgb 100–160 mg

11 AM 40–60 mg 160–325 mg

2 PM 60–100 mg 325 mgc

(1) Measure FEV1 every hour andwait 3 h between doses. (2) FEV1 should be at least 1.5 L and >60%of predicted. (3) Reactions can be (a) naso-ocular alone; (b) naso-ocular and a 15% or greaterdecline in FEV1 (Classic reaction); (c) lower respiratory reaction only (FEV1 declines by >20%); (d)laryngospasm with or without a, b, or c (flat or notched inspiratory curve); (e) systemic reaction:hives, flush, gastric pain, hypotension. (4) Aspirin desensitization: (a) After a reaction has beentreated and the reaction has subsided, that provoking dose should be repeated; (b) if no reaction,continue to escalate the doses as listed above.

a A placebo challenge can be conducted the day before actual challenge begins if baselineunstable airways are suspected.

b Aspirin doses can be prepared in advance by a compounding pharmacy. A simple alternativewould to use a pill cutter; 81 mg ASA tablet can be cut into one-half or one-fourth.

c For subjects who do not react to any dose including the 325 mg dose, it is not necessary to chal-lenge with 650 mg of aspirin because this will also be negative.

White & Stevenson216

White et al. Immunol Allergy Clin N Amer 2013

Aspirin Desensitiziation Task Force(Practice Parameter)• 5 doses (aspirin mg):

20.2540.581162.5325

• Almost no one reacts at 20.25 mg• 90 minute intervals

• “may extend to 3 hours” depending on individual characteristics (?)• Repeat provoking dose• IV access• FEV1 and clinical evaluation every 90 minutes

Macy et al. Ann Allergy Asthma Clin Immunol 2007

Brigham Protocol• 4 doses (aspirin mg)

• 40.5• 81• 162.5• 325

• 90 minute intervals• Observed for 3 hours once reaction occurred, then provoking dose repeated• Patients considered desensitized once tolerated repeat of provoking dose and 1 subsequent

(incremental) dose• Not necessarily 325 mg

• Results• 44 patients

• Stable asthma, FEV1 >70% predicted• 93% completed desensitization in 1 day• Average time 9 hrs 29 min• Average time to reaction 61 minutes• No epinephrine, ER visits, hospitalizations• 29 patients completed desensitization without receiving the 325 mg dose

DeGregorio et al. J Allergy Clin Immunol Pract 2019; 1174

Provoking doses (mg)40.5 9%81 56.7%162.5 29.6%325 2.3%

University of Texas Southwestern• 6 doses (aspirin mg)

20

40

81

120

162.6

325

• 60 minute intervals

• Only for use in patients who reported onset of symptoms within 60 minutes of taking NSAID

• 15% excluded

• Repeat provoking dose

• FEV1 and clinical evaluation every 60 minutes

• Mean reaction time = 50 min (SD 21 min)

• 60% still required second day to complete desensitization

Chen et al. JACI in Practice 2015

So, which is the better interval: 60 or 90 • Comparison of 2 protocols at the same center

• Before May 2014 (90 min) and after (60 min)

• Diluted ALKA SELTZER (aspirin mg) 40 80 160 325

• Results• No differences in changes in FEV1• No differences in percent unable to complete (3 vs 5 pts, 19% vs 13%)• No differences in time to reaction (39 min vs 46 min)• No differences in mean provoking dose (80 mg)

• 60 min interval appears as safe and saves time

• Limitations: small study, retrospective

Pelletier et al. J Allergy Clin Immunol Pract 2019; 1319

Concerns

• Reducing time to completion is desirable goal

• Safety remains primary objective

• Mean time to reaction varies by study and protocol• 104 minutes – Scripps Clinic (compounded aspirin capsules)

• 61 minutes – Brigham (commercially available aspirin tablets)

• 50 minutes – UTSW (commercially available aspirin tablets)

• 39-46 minutes – Albert Einstein (Alka-Seltzer)

• Dosing intervals less than this could lead to “stacked doses” and more severe reaction

• Published data indicate these protocols are safe, so far

Bend Memorial Clinic • 4 doses:

40.581162.5325

• 2 hours between doses• Repeat provoking dose• 1 day and usually 2-4

hours on day 2

Example:8:00 40 mg 10:00 81 mg

11:45 reaction, nasal and bronchospasmTreat with albuterol by nebulization, antihistamine, prednisone1:00 symptoms stable

1:00 repeat 81 mg3:00 162.5 mg5:00 Discharge

Next day 325 mg

Williams, unpublished

Protocol 4(KPMG Denver)

• Admit to ICU

• Dose every 30 minutes

• Observe 4 hours after last dose

• BP baseline and prior to each dose (stop if >15 mmHg decrease

• Peak flow baseline and prior to each dose

<30% baseline – continue30-50% - repeat last dose>50% - STOP protocol

Step Dose1 0.1 mg

2 0.3 mg

3 1 mg

4 3 mg

5 10 mg

6 20 mg

7 40 mg

8 81 mg

9 162 mg

10 325 mg

11 650 mg

• Can aspirin desensitization be shortened? Safer?

• Lysine aspirin used in Europe but not available in US

• Intranasal ketorolac (Toradol) found to be safe and effective for challenges in AERD

• 100 consecutive pts 2007-9• historical control: 100 consecutive pts 2003-4

• Endpoints• efficacy and safety

• severity of reactions compared to control group

• time to complete desensitization

Intranasal ketorolac

There are several clinical aspects of aspirin desensitization and chronic aspirintherapy that warrant further consideration. Aspirin seems to be unique in its abilityto modify the inflammatory components of AERD. As mentioned earlier, the dose ofaspirin that is necessary for effectiveness is not the dose that would be necessaryfor antiplatelet-blocking or COX-1-blocking effects. Aspirin desensitization can bemaintained with 81 mg aspirin per day. Although there are some patients who derivetherapeutic benefit from aspirin 81 mg twice a day or 160 mg in the morning and 81mgat night, this is unusual, and most patients are taking at least 325 mg twice a day. Theauthors’ current practice is to start all patients on aspirin 650 mg twice a day for thefirst month, unless they have prior gastritis from NSAIDs or prior ulcer disease. After1 month, if nasal passages are patent, a step down of aspirin to 650 mg in the morningand 325 mg at night, followed by 325 mg twice a day, is attempted. If a reappearanceof nasal congestion occurs, aspirin dosages are increased in a stepwise fashion.Finally, and most paradoxically, is the finding that aspirin has no benefit in chronicsinus disease, with or without polyps, and asthma unless the patient has AERD.Understanding the mechanism of aspirin benefit may illuminate the answers to thepathogenesis of AERD in the first place and offer future targets for therapy.

REFERENCES

1. Widal F, Abrami P, Lermoyez J. Anaphylaxie et idiosyncrasie. La Presse Medicale1922;30:189–93.

2. Klion AD. Widal on the aspirin triad and induction of tolerance. Allergy Proc 1993;14:371–2.

3. Zeiss CR, Lockey RF. Refractory period to aspirin in a patient with aspirin-inducedasthma. J Allergy Clin Immunol 1976;57:440–8.

4. Bianco S, Robushchi M, Petrigni G. Aspirin induced tolerance in aspirin-asthmadetected by a new challenge test. IRCS J Med Sci 1977;5:129–36.

Day 1 –

Time 0 1 spray (1 in one nostril) Time 0.5 hours 2 sprays (1 in each nostril) Time 1.0 hours 4 sprays (2 in each nostril) Time 1.5 hours 6 sprays (3 in each nostril)

Time 2.5 hours Aspirin 60 mg Time 4 hours Aspirin 60 mg

Patient should be evaluated every 30 minutes throughout the daya

Instruction & Discharge

Day 2 – Time 0 Aspirin 150 mg Time 3 hours Aspirin 325 mg

Instruction & Discharge

Ketorolac nasal spray preparation

1. Take ketorolac tromethamine (60 mg/2 mL) and preservative-free normal saline (2.75 mL).

2. Mix in an emptied Nasocort AQ spray bottle.

3. Prime with 5 sprays before use, then each spray actuates 1.26 mg of solution.

4. Instruct patient and to bend head down while spraying and sniff gently (to avoid swallowing the preparation).

aAfter the patient reacts, clinical judgment should guide the timing of subsequent dosing.

Fig. 1. Sample nasal Ketorolac and modified oral aspirin challenge.

White & Stevenson220

White et al. Immunol Allergy Clin N Amer 2013.

ResultsOral Aspirin Nasal Ketorolac P

Provoking dose 54 mg 12 mg (10 sprays)

Positive challenge 92% 82%

Mean duration 2.6 d 1.9 d <0.001

No. ≤2 days 18% 68% <0.001

Naso-ocular only 35% 54% <0.001

Mean reduction in FEV1

13.5% 8.5% 0.01

% mod-severe bronchial reaction

25% 19% NS

Laryngospasm 19% 7% 0.02

GI reaction 30% 10% 0.001

82 subjects completed intranasal ketorolac / modified oral aspirin challenge90% reacted during nasal ketorolac challenge77% were completely or mainly desensitized by nasal ketorolac

ADVANTAGESIntranasal ketorolac and modified oral aspirin challenge

• Shorter time to desensitize (vs. 3-hr interval)• 1.9 vs 2.6 days on average

• Lower rate of GI and laryngeal reactions

• Less in decline in FEV1• Mean decrease 8.5% vs 13.4%• No difference in moderate or severe bronchial reactions

• 77% mainly or completely desensitized with nasal ketorolac

Caveats

• Control group (oral aspirin challenge group)

• traditional Scripps protocol• 5-steps (20 or 45 60 100 150 325)

• 3 hour interval

• fewer with asthma (88% vs. 97%, P=0.01)

• fewer on LTMD (77% vs. 93%, P=0.001)

• Disadvantages

• 1.9 days to complete

• Requires ketorolac preparation

• False negative rate may be higher, compromising diagnostic value

Aspirin challenge / desensitization protocolsSUMMARY

• Advantages and disadvantages of each protocol

• 90-120 minute dosing intervals seem ideal• 60 minute dosing interval not associated with increased risks

• Doubling doses until no longer reacting or 325 mg

• Premedicate with leukotriene blockade and ICS/LABA

• Treat reactions early

• Repeat provoking dose before proceeding to next dose

Role of Biologic Therapy in Aspirin Desensitization Setting - OMALIZUMAB• 8 of 9 patients undergoing aspirin desensitization reacted indicating

omalizumab does not block reactions (none severe)

• 2nd study, after 6 months of treatment with omalizumab (comparison with prior reaction severity)• 6 of 7 did NOT react• 1 that did react had milder reaction

• 3rd study, after 4 months of treatment with omalizumab (comparison with placebo)• 5 of 7 did not react at all• 2 had upper airway reactions only• All 4 placebo patients reacted, 2 with upper and lower airway reactions

Waldram et al. J Allergy Clin Immunol 2018Phillips-Angles et al. J Allergy Clin Immunol Pract 2017Lang et al. Ann Allergy Asthma Immunol 2018

Managing Reactions

• Expect reactions

• Treat early and aggressively

• Do not proceed until symptoms have resolved

• Repeat provoking dose before continuing with higher doses

Reaction manifestationsAERD, our study population had a mean of 5.3 sinusinfections per year (range, 0-12; SD, 4.0), 3.0 sinonasalpolypectomy operations (range, 0-13; SD, 2.3), and 4.4ED visits (range, 0-50; SD, 6.9) and 1.6 hospitalizations(range, 0-30; SD, 3.6) for asthma. Only 11 (5%) patientswere taking LTMDs at the time of their historical aspirin/NSAID reaction.

The maintenance medication regimen for patients atthe time of OAC included LTMDs in 161 (77%) patients,nasal corticosteroids in 157 (75%) patients, inhaled cor-ticosteroids in 173 (82%) patients, and scheduled systemiccorticosteroids in 42 (20%) patients.

Historical reaction severity

After a historical respiratory reaction attributed toaspirin or NSAID ingestion, 63 (30%) patients were ableto adequately control reaction symptoms without seekingacute medical care. Of the 147 patients who did seek acutemedical care for the treatment of their asthma attacks, 101(69%) were treated and released from the ED, and 46(31%) required hospitalization.

OAC reaction severity

The observed reactions to OAC by organ systeminvolvement are listed in Table I. AERD was clinicallyconfirmed on the basis of naso-ocular reactions in 188(89.5%) patients.

Of the 147 patients who reported seeking acute med-ical care for their historical aspirin- or NSAID-inducedreactions, 90 (61%) had a naso-ocular reaction to OACwithout a bronchial reaction (<15% reduction in FEV1

from baseline), 20 (14%) had a 15% to 19% decrease inFEV1 from baseline, 23 (16%) had a 20% to 29% decreasein FEV1 from baseline, and 14 (10%) had a 30% or greaterdecrease in FEV1 from baseline. In contrast, of the 63 pa-tients who reported self-treating their historical aspirin- orNSAID-induced reactions without acute medical interven-tion, 46 (73%) had naso-ocular reactions without a signif-icant reduction in FEV1, whereas 7 (11%) had a 15% to19% decrease in FEV1, 5 (8%) had a 20% to 29% decreasein FEV1, and 5 (8%) had a 30% or greater decrease inFEV1 during OAC (no significant difference betweenthe 2 groups, Table II). Of the subset of patients who re-ported requiring hospitalization after their historical aspi-rin- or NSAID-induced reactions, only 13% had a 30% orgreater decrease in FEV1 during OAC.

Of the 74 patients who had positive bronchial reactionsto OAC (defined as !15% decrease in FEV1 from base-line), the mean decrease in FEV1 from prechallenge base-line values in patients who treated their reactions at homewas 25% compared with 25% and 24% for patients whowere treated in the ED and either released or hospitalized,respectively (P 5 not significant, x2 test).

A total of 19 (9%) patients reacted to OAC withbronchial reactions that consisted of a 30% or greaterdecrease in FEV1. These patients were not significantlymore likely than those whose bronchial reactions con-sisted of a less than 30% decrease in FEV1 to have re-ported seeking acute medical care for their historical

aspirin/NSAID reactions (14/19 [73%] vs 133/191[70%]; P 5 not significant, x2 test).

Provoking doses

There were no significant differences in average pro-voking aspirin or NSAID doses among patients whotreated their reactions at home compared with those whosought acute medical care. Importantly, the mean doseof aspirin (or aspirin-equivalent dose) for historical reac-tions was almost 9 times the provoking dose during OAC:550 mg for the historical reaction and 62 mg during OAC(P 5 .0001, t test).

DISCUSSION

The beneficial effects of aspirin desensitization andcontinued treatment with aspirin on the upper and lowerrespiratory disease process in patients with AERD has beenestablished and recently reviewed.1-3,6,8 Our experiencesuggests, however, that this approach is underused. One po-tential barrier to more widespread use of aspirin challengeand desensitization involves concerns clinicians mighthave regarding the safety of performing this procedure. Inpatients with AERD, the fear of provoking severe and po-tentially life-threatening reactions might cause cliniciansand patients to consider other diagnostic or therapeutic op-tions. Furthermore, these concerns might cause clinicians tolimit such procedures to hospital or ICU settings in whichthe cost, time, or other logistic barriers then become prohib-itive. Safety concerns might further be confounded by thecommonly held assertion that asthmatic patients withAERD tend to have a more severe and persistent asthmaphenotype than asthmatic subjects without AERD.6,9

Our data suggest that OAC is relatively safe, even inpatients who report historical respiratory reactions to fulltherapeutic doses of aspirin or NSAID ingestion severeenough to warrant acute medical care, hospitalization, oradmission to the ICU. Specifically, we found that althougha majority (70%) of patients seek acute medical care fortheir historical respiratory reactions to aspirin or NSAIDs,most reactions during outpatient OAC are limited to naso-ocular reactions (65%) or mild (<20% decrease in FEV1)asthma attacks. In addition, patients requiring acute med-ical intervention in the ED or hospital for the treatmentof historical reactions to aspirin or NSAIDs were not sig-nificantly more likely to have a severe bronchospastic

TABLE I. OAC reactions

n (%)

Naso-ocular 188 (90)

Bronchial 74 (35)

15% to 19% decrease in FEV1 27 (13)

20% to 29% decrease in FEV1 28 (13)!30% decrease in FEV1 19 (9)

Gastrointestinal 49 (23)

Cutaneous 20 (10)

Laryngeal 16 (8)Negative OAC 17 (8)

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Williams et al. J Allergy Clin Immunol 2007

PNIF ≥20% decrease

Treating reaction symptoms• Naso-ocular oral, topical antihistamines

oral, topical decongestants

• Bronchial nebulized short acting beta agonistsnebulized ipratropiuminhaled cromolyn

• Laryngeal nebulized racemic epinephrineconsider IM epinephrine

• Cutaneous oral antihistamines

• GI H2-blockers, anti-emetics

• Hypotension IM epinephrineIV fluids

False negative challenge / Silent desensitization• BMC experience

• 4 patients with negative challenges• all 4 had strong history of repeated NSAID reactions and other features of AERD• all 4 had previously positive oral challenges conducted at other institutions WITHOUT surgery• all 4 had negative challenges within 3-4 weeks following sinus surgery

• Case series of 7 patients with AERD with negative challenges who subsequently reacted

• 2 recent studies: high rate of false negative challenges following sinus surgery • previous positive challenges who underwent desensitization again after surgery and did not

react• 43% (12 of 28)• 39% (6 of 16)

Williams, unpublishedWhite et al. Immunol Allergy Clin N Amer 2013White et al. Allergy Asthma Proc 2013Jerschow E et al. J Allergy Clin Immunol Pract 2019Huang et al. J Allergy Clin Immunol Pract 2019

False negative challengeSilent desensitization• Increased recognition that false negative challenges do

occur, likely related to pre-medication with LTMD and/or recent sinus surgery

• Options:• Offer diagnostic challenges BEFORE surgery to increase

diagnostic accuracy• repeat challenge / desensitization off LTMDs• assume AERD with false negative / silent desensitization

• treat with aspirin for AERD and observe for clinical response• assume not AERD, counsel patient that LTMD may have caused

false negative reaction, and to avoid taking NSAIDs if they stop LTMD

White et al. Immunol Allergy Clin N Amer 2013Jerschow E et al. J Allergy Clin Immunol Pract 2019

Silent Desensitization

Negative challenge

High pretest probability

Assume AERDTreat

Observe for response

Repeat challenge off aspirin

Low pretest probability

Assume non-AERD Consider repeat challenge

White et al. Allergy Asthma Proc 2013

Future Directions• What is the best aspirin dosing interval?• Time and resource efficiency vs. safety

• Can the repeat of the provoking dose be skipped in certain situations?

• What to do about negative challenges with high pre-test probability?• Role if biomarkers or predictive criteria?

• What is the role of biologic therapy in the desensitization setting?

Summary• Need for objective testing to confirm or rule out AERD

• Major clinical implications for management

• Aspirin desensitization and long-term treatment improves important clinical outcomes in AERD

• Aspirin challenge / desensitization is safe• History of severe reactions does not predict severe reactions in the challenge setting

• Key safety points• Patient selection• Leukotriene blockers improve safety• Repeat the provoking dose• Close monitoring and early treatment of reactions

• 60, 90, 120 minute interval protocols appear to be safe and more time efficient than original 3 hour interval protocol

• Intranasal ketorolac may be safer than oral desensitization

• Silent desensitization / false negative challenges can be problematic