Aspirin-exacerbated respiratory disease for the practicing allergist - PowerPoint Presentation

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Aspirin-exacerbated respiratory disease for the practicing allergist

Kathleen M. Buchheit, MDAssistant Director, AERD CenterAllergy & ImmunologyBrigham and Women’s HospitalSeptember 13, 2019

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Conflict of Interest Disclosure

Relevant financial relationships with commercial interests in the preceding 12 months: Regeneron, Genentech

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Learning objectives

Review clinical presentation of AERD

Discuss mechanisms and pathophysiology

Provide updates in diagnosis and management

Introduce areas of ongoing study in AERD

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Classic AERD = 35 year-old “Danielle”

Childhood  healthy, no asthma or allergies23yo  “really bad cold” and persistent nasal congestion24yo  a

sthma, continued congestion, lost sense of smell and taste25yo  saw ENT surgeon, was “full of polyps”, had 1

st polyp surgery (great improvement!), but polyps returned in 6 months25yo 

Cold-flu tablet – 2 h later sneezed, chest tightness, wheezing  3

mo later ibuprofen – to ER for albuterol and IV steroids



6 months later took

naproxen

– same reaction

Polyp surgeries: 25yo, 27yo, (no surgery while had 2 kids), 33yo, 35yo

Now



Inhaled steroids, montelukast, steroid sprays, loratadine,

albuterol 3-4 days/

wk

,

no sense of smell

, antibiotics and oral corticosteroids for sinusitis 2-3 times a year, polyps are back

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AERD presents with a stereotyped pattern and common phenotype

Not IgE-mediated allergy to aspirin1Not Mendelian inheritance2Not due to (known) environmental trigger

3

How common is it?

7% of adults with asthma14% of adults with severe asthma

25% of adults with asthma+polyps

~ 1.5 million patients in U.S.

5

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Largely adult-onset disease…

Blood eosinophilia is common

42% >500

68%

21-50yo

…but there are exceptions.

Tuttle KL, et al. JACI-IP 2016

Findings from our cohort of patients at the BWH AERD Center

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Surgical histories from cohort of patients at the BWH AERD Center

History of polyp surgery:

60% have had

>

2 surgeries

10% have had

>

5 surgeries

Selig, YK.

Nasal polyps on rhinoscopy. 2015

Bhattacharyya, N.

Nasal polyps excised. 2016

Typical appearance of polyps on rhinoscopy, and can be very large

Rate of polyp regrowth post-op:

50% report regrowth

<

6 months

Only 15% report no regrowth >2 years

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AERD: Reactions to NSAIDs

Classic reaction:Bronchoconstriction = wheezing, cough, fall in FEV1Nasal/ocular symptoms = sneezing, congestion, headache/facial pressure, rhinorrhea, eye tearing, eye redness/swellingLess common:Rash, urticaria, angioedema

Abdominal pain, nausea, vomiting1Average time to reaction is ~60 minutes after aspirin exposure and doses of ≤ 162 mg of aspirin elicited reaction in >95% of patients with AERD.

2 *3 – 6% of patients react to ≤ 650 mg acetaminophen3

*34% of patients react to > 1000 mg acetaminophen4

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Reactions to NSAIDS involve more extra-pulmonary symptoms than previously thought

Any COX-1 inhibitor can cause reaction:

aspirin

, ibuprofen, naproxen, ketorolac are most common in U.S.

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Tolerance of COX-2 inhibitors AERD

Black Box Warning: “Celecoxib is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.”Nine Publications from 6 groups have proven safety of COX-2 inhibitors in AERD.1 case report of etoricoxib-induced respiratory reaction in AERD.

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Tricks to make AERD diagnosis

What if you feel like it could be AERD, but patient says “no” to the

“Do you have any problems when you take aspirin, ibuprofen, or naproxen?”

question:

Patient has not taken aspirin/NSAIDs in a long time

Patient is on 81mg aspirin daily (already desensitized)

Patient is on montelukast or zileuton

Patient is so ridiculously stuffed up with polyps at baseline that they couldn’t even tell if got worse.

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Clinical clue: Respiratory reactions to alcohol

Cardet JC. JACI In Pract. 2014

De

Schryver

E. Clin&ExperAll 2016

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AERD: Pathophysiology

Dysregulated cysteinyl leukotrienes (CysLT)Excessive basal CysLT generationIncrease CysLT generation upon COX-1 inhibitionAirway hyperresponsiveness to CysLTsBaseline levels correlate with severity of aspirin-induced asthma attack CysLT production may be driven in part by platelet-adherent leukocytes

Mast cell activationPGD2, histamine,

tryptase, leukotrienesAt baselineDuring aspirin reactionInhibitors of mast cell activation modify reactions to aspirin

Driven in-part by innate type 2 cytokines

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4 PGE

2

receptors

(EP1-4)

Leukotriene pathway

COX pathway



LTE

4



LTC

4

S

 CysLT1R

4 PGE

2

receptors

(EP1-4)

COX1

/

COX2

PGE

2

TXA

2

COX pathway vs 5-LO pathway

PGD

2

 PGE

2

 EP2 receptor

 PGD

2

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Effector cells in AERD

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Summary: Clinical/mechanistic pointsTriad: ask all adult asthmatic patients about nasal polyps, sense of smell, and COX-1 inhibitor tolerance

Can miss diagnosis in patients LTRA or zileutonRespiratory reactions with all COX-1 inhibitors, some patients also sensitive to acetaminophen, but selective COX-2 inhibitors are toleratedDisease of dysregulated leukotrienes and mast cell activation  Activation of effector cells including Th2 cells, ILC2s, eosinophils, basophils, and neutrophils/platelets

Next: diagnosis and management updates

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Aspirin/NSAID challenge is the GOLD STANDARD for diagnosis of AERD!

Who needs a challenge?Protocol: Start at 40.5 mg aspirinDouble dose every 90 – 180 minutesPFTs prior to every dose and if reactionStop at 325 mg aspirin1

Timing of challenge is important  less sensitive post-operatively2,3

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Aspirin reactions are less severe/can be missed following endoscopic sinus surgery1,2

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Eicosanoids decrease - at baseline and during aspirin challenge - before and after endoscopic sinus surgery

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Tolerance of daily aspirin 81 mg does not preclude (and may delay) AERD diagnosis

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Updates in management of AERD

Aspirin desensitizationLeukotriene modificationBiologic therapyOmalizumabAnti-IL-5/IL-5RαDupilumab Dietary intervention

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Aspirin desensitization followed by daily, high-dose oral aspirin treatment

6 mo of ASA = 67% pts improved, 1 yr

of ASA = 87% pts improved

Stevenson, et al. JACI 1996

100%

of 7 AERD pts on very low dose aspirin had polyp recurrence within 1 year, 0% of pts on high-dose aspirin had polyp recurrence

Rozsasi

, et al. Allergy 2008

20 AERD patients (8 placebo, 12 on 624mg aspirin QD) – within 6

mo

, patients on aspirin had

 SNOT-20 & ACQ scores,  PNIF, and 5/8 had return of sense of smell

.

N

izankowska-Mogilnicka

, JACI 2014

When to desensitize?

Preferably after surgery.

What daily aspirin dose to use?

650mg vs 1300mg

Lee, JACI 2007

91%

who had been on high-dose aspirin found it “effective”

(but

<50%

had ever undergone aspirin desensitization)

Ta and White, JACI IP, 2015 (190 patients)

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Aspirin desensitization and high-dose oral aspirin (to treat) - PROTOCOL

40.5mg

81mg

162.5mg

325mg

81mg

162.5mg

325mg

325mg

Challenge

Provocation

of symptoms

Daily aspirin to maintain desensitization –



benefits occur only if aspirin is taken regularly



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Leukotrienes are dysregulated in AERD

Urinary LTE

4

(log)

Mastalerz

and

Szczeklik

, Thorax 2008

High leukotrienes at baseline

Even higher after aspirin

AERD

Aspirin-tolerant asthma

What medications can we use to decrease the production or effects of leukotrienes?

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Use of leukotriene-modifying medications in AERD

Zileuton (5-LO inhibitor) and montelukast (cysLT1 receptor antagonist) improve AERD symptoms at baseline Zileuton: ↑ FEV1, improves smell, ↓ SABA useDahlen B,

Szczeklik A et al. AJRCCM 1998

Montelukast: ↑ FEV1, improves nasal symptoms scoresDahlen S, et al. AJRCCM 2002

Micheletto

C. Allergy 2004For aspirin desensitization:

Montelukast: Blunts fall in FEV

1

= Safer desensitization

Zileuton: Can increase provocative dose or block reactions completely

Useful for gastrointestinal reactions during desensitization

28% found zileuton “extremely effective”

(only 24% had ever been on zileuton)

15% found

montelukast

“extremely effective”

(almost 90% had been on one of these)

Ta and White, JACI IP, 2015 (190 patients)

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Zileuton is more effective in patients with AERD than in aspirin-tolerant asthma

“Efficacy of Zileuton in Patients with Asthma and History of Aspirin Sensitivity: A Retrospective Analysis of Data from Two Phase 3 Studies”

AAAAI 2017 Poster L30

% Change in lung function (FEV1) from baseline on Day 85

35%

30%

25%

20%

15%

10%

5%

0

-5%

AERD patients

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Omalizumab decreases urinary LTE4/PGD2 and blunts aspirin-induced reactions in AERD

Hayashi H, et al. J Allergy

Clin Immunol 2016;137:1685.

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Mepolizumab reduces polyp size, sinonasal symptoms and need for surgery

Double blind placebo controlled, 105 nasal polyp patients total. IV Qmonth for 6 months.*P ≤ 0.05, **P≤0.01, ***P≤0.001

Bachert C, et al. J Allergy Clin Immunol. 2017;140:1024-31.

Placebo Mepolizumab

Treatment (95% CI)

*

*

*

*

Percentage needing surgery

TPS

1

Study week

Percentage of patients

in need of surgery

0.5

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

LS mean change from

baseline in total endoscopic

nasal polyp score

Study week

1

Rhinorrhea

Mucous

Congestion

Smell

Study week

Adjusted mean rhinorrhea

VAS scores (cm)

1

Study week

Adjusted mean mucous

in throat VAS scores (cm)

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

1

SNOT-22 Score

Adjusted mean nasal

blockage

VAS scores (cm)

Study week

*

*

*

*

*

*

*

*

*

1

Adjusted mean loss of smell

VAS scores (cm)

Study week

1

SNOT-22

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

p

=

0.005

In AERD:

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**

Dupilumab improves upper and lower airway symptoms in AERD**

ACQ-5

FEV1 (L)

Nasal polyp score

SNOT-22 Smell/taste

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Low omega-6 fatty acid diet

can decrease leukotrienes and improve symptoms in AERD

Schneider TR, Laidlaw TM. J Allergy Clin Immunol In Pract. 2018

Good:

Wild-caught cold-water fish

(salmon, herring, tuna)

Fat-free dairy, egg white

Leafy green vegetables

Most vegetables and fruits

Many beans, some grains

Bad:

Vegetable oils (corn, soybean, safflower)

Margarine

Meats if animals ate corn/soy

Eggs/dairy if animals ate corn/soy

Treatment diet decreased

LTE

4

in the urine

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Ongoing clinical studies: AERD

Mechanism of aspirin desensitization in AERD (BWH)Ifetroban (thromboxane receptor antagonist)Patients with symptomatic AERD (multi center)Effect of aspirin challenge (BWH)Fevipiprant (CRTH2 antagonists) Dupilumab phase III, mepolizumab phase III, omalizumab phase IIIAERD Registry and Biobank (non-BWH patients eligible to participate in Registry)

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Summary: AERD diagnosis and treatment

Aspirin challenge is the gold standard for diagnosis in AERDStop baby aspirin, montelukast, and antihistamines prior to challengeAspirin desensitization followed by high-dose aspirin therapy improves upper and lower airway symptomsCan safely be carried out using one day protocol Zileuton and montelukast improve symptoms and lung functionOmalizumab, anti-IL-5/IL-5Rα, and dupilumab

No randomized, placebo-controlled trials in an AERD population