Aspirin-exacerbated Respiratory Disease

Aspirin exacerbated respiratory disease is the combination of asthma, chronic rhinosinusitis with nasal polyps and respiratory reactions to aspirin and other drugs that inhibit cyclo-oxygenase-1. It affects about 7% of adults with asthma and up to 14% of those with severe asthma.

Onset is usually between 20 and 50 years, often after a viral illness, and polyps recur quickly after surgery. Women are affected more than men. It is a persistent disease that continues when the drug is avoided, and the lung and sinus disease tends to be severe.

Pathophysiology. Inhibition of cyclo-oxygenase-1 lowers prostaglandin E2, which normally restrains mast cells and eosinophils, and leads to a burst of cysteinyl leukotrienes. The baseline state already has excess leukotriene C4 synthase, platelet adherent leucocytes, interleukin-33 and thymic stromal lymphopoietin, and cysteinyl leukotriene receptor upregulation.

Persistent nasal blockage, loss of smell (often an early feature), watery rhinorrhoea, facial pressure and recurrent nasal polyps, with asthma that is often steroid dependent and difficult to control.

Reactions occur 30 minutes to 3 hours after ingestion: nasal congestion, rhinorrhoea, conjunctival injection, periorbital oedema, flushing, wheeze, cough, and sometimes abdominal pain. A severe reaction brings bronchospasm with respiratory failure.

Wheeze with stridor, hypotension, urticaria with angioedema or oxygen saturation under 92% after an anti-inflammatory dose needs emergency treatment with adrenaline 0.5 mg intramuscularly (0.3 mg in children over 6 years), repeated after 5 minutes if needed.

• A history of a respiratory reaction within 3 hours of aspirin or an NSAID in an adult with asthma and nasal polyps is strongly suggestive, and in a clear history the diagnosis is made without a challenge.
• Oral aspirin challenge in a specialist unit with resuscitation facilities when the history is uncertain: escalating doses of 40 to 100 mg, 160 mg, 325 mg and 650 mg over 1 to 3 days, with spirometry and nasal scoring, and a positive result is a fall in FEV1 of 15 to 20% or a naso ocular reaction.
• Nasal endoscopy and CT of the sinuses (opacified ethmoid and maxillary sinuses with polyps).
• Blood eosinophils, total IgE, FeNO, and urinary leukotriene E4 (raised at baseline and after reaction) where available.
• Spirometry with reversibility testing.
• Exclude cystic fibrosis in children and young adults with polyps, and allergic fungal sinusitis.

Differential diagnosis.

• Chronic rhinosinusitis with polyps and asthma that tolerates NSAIDs
• NSAID-induced urticaria and angioedema or anaphylaxis (a single drug allergy, not respiratory)
• Eosinophilic granulomatosis with polyangiitis
• Allergic bronchopulmonary aspergillosis
• Cystic fibrosis

• Avoid aspirin and all drugs that inhibit cyclo-oxygenase-1: ibuprofen, diclofenac, naproxen, indometacin, ketorolac and piroxicam. Check combination cold remedies. Paracetamol is tolerated up to 500 mg in each dose, and reactions occur in some at 1 g or more, so start with 500 mg. Selective cyclo-oxygenase-2 inhibitors (celecoxib 200 mg, etoricoxib 60 mg) are tolerated by most, and are first given under supervision.
• Asthma: inhaled corticosteroid with long acting bronchodilator, for example budesonide formoterol 160/4.5 micrograms two inhalations twice daily, with stepwise increase to high dose inhaled corticosteroid plus a long acting antimuscarinic, and montelukast 10 mg every night.
• Nasal: mometasone 200 micrograms in each nostril once daily or fluticasone furoate 55 micrograms two sprays each nostril daily, with saline irrigation. A short course of prednisolone 30 to 40 mg daily for 5 to 10 days for polyp exacerbation, and not repeated often.
• Biologics for polyps and asthma with insufficient control: dupilumab 300 mg subcutaneously every 2 weeks, omalizumab 75 to 600 mg every 2 to 4 weeks (dose by weight and IgE), mepolizumab 100 mg every 4 weeks, or benralizumab 30 mg every 4 weeks for 3 doses then every 8 weeks.
• Endoscopic sinus surgery with polypectomy for obstruction or failed medical treatment, aiming for a wide opening, and followed by aspirin therapy to delay recurrence.
• Aspirin desensitisation followed by daily aspirin, in a specialist unit: after a graded challenge at the dose that causes a reaction, continue aspirin 325 mg twice daily (a range of 325 to 650 mg twice daily is used) with a proton pump inhibitor, for years. This reduces polyp recurrence, steroid use and sinus surgery, and improves smell. A gap of 48 hours or more means desensitisation is lost, so a restart challenge is needed. Side effects: gastritis, bleeding, and in a minority bronchospasm at the start. It is also the route for patients who need aspirin for cardiovascular disease.
• Emergency plan for accidental exposure: a written action plan, with adrenaline auto injector 0.3 to 0.5 mg intramuscularly when reactions have been severe.

Monitoring. Review every 3 months at the start, then every 6 months, with spirometry, smell score, nasal endoscopy and polyp score, and annual assessment of bone health in those with repeated steroid courses.

Referral and escalation. Refer to a respiratory or allergy specialist for challenge and desensitisation, and to ENT for surgery. Refer urgently after any severe reaction.