Aspirin-Exacerbated Respiratory Disease (AERD)

Jenny GowanConsultant pharmacist

MediCom Medication Management ServicesTeaching Associate, Faculty of Pharmacy & Pharmaceutical Sciences, Monash University,

Clinical associate RMIT University

Topics

At the completion of the discussion session, participants will be able to:

• describe the clinical symptoms of AERD• discuss possible causes of AERD• discuss treatments for AERD

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History • Salicylic acid found in an extract from the bark of the white

willow trees – used for 1000s of years for relief of fever and pain. • 1897 Felix Hoffman chemist employed by F Bayer

acetylated it to acetylsalicylic acid – reduced the bitter taste • 1899- named “aspirin’ and patented by Bayer• Used for pain, fever, headache, arthritis• 1922 case report Widal et al described respiratory disease

exacerbated by aspirin• Also occurred with antipyrine (NSAID) synthesized in 1883

Widal et al Presse Med 1922; 30:189-93

AERD

• 1967 reported by Max Samter , USA immunologist unaware of the French report • “Samter’s triad” (nasal polyps, asthma,

sensitivity to aspirin) ▫ -non-allergic hypersensitivity reaction • Also known as ▫ aspirin intolerance ▫ aspirin idiosyncrasy▫ aspirin-induced asthma ▫ NSAID-exacerbated respiratory disease

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AERD symptoms• Symptoms usually occur 30-90 minutes after

taking aspirin or NSAIDs orally (but can be up to 3 hrs)• May include some or all of:▫ Shortness of breath▫ Severely watery nose, rhinitis or blocked nose ▫ Red eyes - puffiness around the eyes▫ Skin redness- herald patch

; Thien MJA 2006;

AIANE

0 2–5 years

Rhinitis Rhinitis

+ Polyps

Asthma

+ AIAIntolerance

Natural course of AERD

▫ More severe difficult to control asthma▫ Often steroid dependent▫ Nasal polyposis with anosmia

European Network of Aspirin Induced Asthma

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AERD – Clinical symptoms Early symptoms

▫ Perennial rhinorrhoea▫ Nasal congestion▫ Anosmia▫ Herald patch ▫ Asthma ▫ Imaging will show nasal polyps (intensely eosinophilic) and pansinusitis

• May also have reaction to alcohol – upper or lower airway hypersensitivity reactions especially red wine and beer

• Rate of polyp recurrence x3 greater in aspirin tolerant patients. Average polypectomy rate every 3 yrs.

Refs: NAC: Asthma-NSAID Intolerant asthma induced asthma ; White, Stevenson : Aspirin –Exacerbated Respiratory disease. NEJM 2018; 379:1060-70

AERD – Clinical symptoms • Mucosal swelling of the sinuses and nasal membranes,

formation of polyps, & asthma PLUS • respiratory symptoms: ultimately of the entire respiratory tract

upper airways (nasal congestion, rhinorrhea, sneezing)

lower airways (laryngospasm, cough & wheeze)1

May also get• gastrointestinal symptoms (abdominal pain & nausea)

• cutaneous symptoms (flushing & urticaria)• These are a new phenotype – may not be able to tolerate aspirin

densensitisation 2

• About 50% of cases occur after a viral respiratory infection

White, Stevenson: Aspirin –Exacerbated Respiratory disease. NEJM 2018; 379:1060-70Cahill et a.l J Allergy Clin Immunol 2015: 135:245-252

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AERD – Clinical symptoms • Acquired-appears from late childhood to adulthood • Median age at onset about age 30 years1

• Male predominance 2.3:1 BUT more severe in females.2• 66% have a history of atopy but 33% are free from

any allergies1

• AERD - Classified as a co-existing condition1

• Unique inflammatory airway disease• Linked to increased airway remodelling- increased

residual volume2

1.White, Stevenson : Aspirin –Exacerbated Respiratory disease. NEJM 2018; 379:1060-70

2.Kennedy,Stoner, Borish Am J Rhinol Allergy: 2016; 30; 407-413,

Risk factors for AERD• Risk of reaction highest in people with:▫ Severe asthma▫ Nasal polyps▫ Long-term or recurring rhinitis▫ Adult-onset asthma without known allergies as the

cause

▫ Much less common in children 2% in a challenge study

NAC: Asthma-NSAID Intolerant asthma induced asthma

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NON-AERD hypersensitivity to NSAIDS

• Hypersensitivity to NSAIDs may trigger anaphylaxis• Hives or flares of chronic urticaria after NSAIDs

have nothing to do with AERD

White, Stevenson : Aspirin –Exacerbated Respiratory disease. NEJM 2018; 379:1060-70

Tolerance

• AERD is unlikely in a person with risk factors who has used aspirin or NSAIDs without experiencing symptoms, either▫ Regularly (eg daily low-dose aspirin) or ▫ Recently (eg within past 6 months)

NAC: Asthma-NSAID Intolerant asthma induced asthma

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COX-1 & COX-2 inhibitors Highly selective COX-1 inhibitors • Acetylsalicylic acid• Diclofenac *• Flurbiprofen• Ibuprofen*• Indometacin• Ketoprofen*• Ketorolac (inc nasal,IV )• Mefenamic acid• Naproxen • Piroxicam** Including topicals

Weakly selective COX-1 inhibitors • Paracetamol (1000mg)• Diflunisal • SalsalateHighly selective COX-2 inhibitors • Celecoxib• Etoricoxib• Parecoxib (IM/IV) Preferentially selective COX-2 inhibitors (COX-1 inhibition at high doses)• Meloxicamcross reactivity up to 100%

Specific cyclooxygenase 2(COX-2) inhibitors are generally tolerated (but not always)

Prevalence• No accurate data on the general population or among

patients with asthma or nasal polyps▫ 3-11% of adults with asthma –(Ref NAC)

▫ aspirin intolerance in 20% of patients with adult onset asthma without sinus disease ( Ref: Sczeklik et al. AIANE investigators Eur Resp L 2000; 16:432-436)

• AERD: Meta-analysis of the literature ▫ 0.6 -2.5% in people with asthma▫ 14.9% people with severe asthma ▫ 9.7% patient with nasal polyps ▫ 8.7% of people with chronic sinusitis with nasal polyps

• Diagnosis rare and often missedRef: Rajan et al J Allergy Clin Immunol 2015:135(3):676-681

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Computerized search strategy

• 12.4% of patients fulfilled critical components of AERD ▫ nasal polyps ▫ asthma▫ respiratory reactions to NSAIDSDid NOT have that diagnosis in medical records and had not had oral aspirin challenges or desensitization

Cahill et al. J Allergy Clin Immunol 2017:137:139(3):819-825

Causes of AERD• Multiple• Overproduction of cysteinyl leukotrienes (cysLT) and

prostaglandin D2 (PGD2 )• Underproduction lipoxins and prostaglandin E2 (PG E2)• Genetic polymorphism of cysteinyl leukotrienes (LTC4)

synthase promoter region• Increased leukotriene (LT) receptors• Increased eosinophils

• Reaction is non-IgE mediated

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Metabolic pathway of arachidonic acid

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Aspirin challenge tests• Oral aspirin• Inhaled aspirin• Intranasal lysine/aspirin, ketorolac/aspirin

• “all patients with rhinitis, nasal polyps & pansinusitis ± asthma and avoiding NSAIDS should undergo a safe graded oral aspirin challenge in a safe medical setting … 30-44% will experience a reaction”

White, Stevenson : Aspirin –Exacerbated Respiratory disease. NEJM 2018; 379:1060-70

Aspirin desensitisation & treatmentwith aspirin • Low oral dose of aspirin 40.5mg • Gradually increase dose over 1-3 days • Drug-induced reactions become milder & shorter• When target dose of 325mg is achieved any

additional doses of aspirin or COX-1s do not induce hypersensitivity• Ongoing 325-650mg aspirin twice daily, after

debulking of nasal polyps and sinuses

• Other methods:▫ Lysine/aspirin low dose ▫ Low dose aspirin 81mg

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Oral aspirin challenge• Stop antihistamines, SABA, anticholinergics• Need to be well controlled before challenge • Doses at 3 hours▫ Day 1: (10, 17mg), 30mg, 60mg, 100mg▫ Day 2: 150mg, 250mg, 500mg• Outcome measures:

symptoms FEV1 Elevated cysteinyl leukotriene E4 (LTE4)

Other options (stop betablockers, ACEIs as well ) • Day 1: 20-40mg; 40-60mg; 60-100mg 8am, 11am, 2pm,• Day 2: 100-160mg ; 160-325mg; 325mg •

1. A Prof Janet Rimmer ( personal communication ) • 2.Kennedy,Stoner, Borish Am J Rhinol Allergy: 2016; 30; 407-413,

Other methods of desensitisation Intranasal lysine aspirin• Local therapy may be more

effective, may avoid systemic side effects▫ 500mg aspirin (40mg

retained)▫ Trial post surgery with good

irrigation access

Intranasal lysine aspirin + inhaled corticosteroids

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Benefits of aspirin desensitisation• Nasal decongestion • Improved sense of smell • Reduced rhinosinusitis episodes• Better sleep due to reduced nasal obstruction• 9 yrs prior to polyp surgeries (3 yrs prior) • Improved asthma • Decreased use of oral corticosteroids • QOL scores improved • Low cost of desensitisation• Protection from NSAID reactions

Complications of long-term aspirin desensitisation• Gastric pain or ulcer - diminished synthesis of

PG12, plus inadequate repopulation of gastric mucosal cells▫ About 10-20% - up to 50% get indigestion

• Bleeding in skin, occasionally in nose, bronchi, bladder, GI tract

• Urticaria, Tinnitus

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Medical Treatment•SABA/ICS/LABA •Leukotriene receptor antagonists (only zileuton 5-lipogenase ( 5-LO) inhibitor- montelukast is LT1 antagonist)•Antihistamines•Intranasal corticosteroids• Oral corticosteroids (subset may require ongoing)

•?Biological agents-

Aspirin desensitisation only unique treatment for AERD

Surgical treatment – severe nasal polyposisPolyps recur rapidly unless aspirin desensitisation

On the horizon – biologicalsnot specifically studied in AERD

• Omalizumab - anti-IgE but lowered LTE4, PGD2decreased nasal polyp size.

• Mepolizumab – anti-interleukin(IL) 5▫ Reduced nasal polyp size and improved symptoms

• Benralizumab - binds to IL-5 receptor - causes eosinophil destruction as well as basophils. Specific efficacy in AERD not addressed in studies

• Further studies needed

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Examples of Over-The-Counter NSAID analgesics• Oral products ▫ Aspirin 300mg ▫ Aspirin 100mg (low risk) ▫ Diclofenac 12.5, 25mg ▫ Flurbiprofen 8.75mg▫ Ibuprofen 200, 400mg ▫ Naproxen sodium 200,

275mg

• Also combination products • (High dose paracetamol)

• Topical products ▫ Diclofenac▫ Ketoprofen▫ Ibuprofen ▫ Piroxicam▫ Salicylic acid containing

products eg cholinesalicylate gels

• Some complementary medicine products

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Question – AERD symptoms

NO / Don’t know

YESAdvise AGAINST use of aspirin or NSAIDs

Have you ever had rhinitis or asthma symptoms 1–3

hours after taking aspirin or any other† pain reliever?Symptoms include runny or blocked nose, itchy throat,

wheezing or chest tightness

REFER TO PHARMACIST

Next question†Check with the pharmacist which NSAIDs are sold over the counter in your pharmacy so that you recognise them

Pharmacist question

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