Asthma Plus Three: Aspirin-Exacerbated Respiratory Disease
Jeannette Y. Wick, RPh, MBA, FASCP
This potentially serious condition is only partially understood, and its triad of symptoms often goes unrecognized.
Aspirin-exacerbated respiratory disease (AERD) occurs in adults and is somewhat of a misnomer since aspirin sensitivity is not its only component, nor is aspirin the only aggravating analgesic. The Centers for Disease Control indicates that 8.2% of the US population has asthma, and up to 9% of adult asthmatics have this nonallergic hypersensitivity reaction. Patients experience 3 annoying and potentially life-threatening symptoms, dubbed the “Samter triad”—severe chronic rhinosinusitis, nasal polyposis (multiple polyps), and aspirin sensitivity. Onset usually occurs between the ages of 30 and 40 years, although a small number of children develop this condition, and it is more common in women.1
Patients frequently report having had a “never-ending cold,” causing researchers to think that a viral infection may start the inflammatory cascade. AERD patients react to even small doses of aspirin (ASA) and other COX-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs, which include ASA) with nasal congestion and bronchospasm within 30 minutes to 3 hours. Of note, patients can and do react to NSAIDs on the first dose, unlike the situation when an allergy is present and reaction occurs only after a sensitizing dose.2 Most patients are allergy free—and within 2 years, they develop asthma.
AERD creates a considerable burden on the health care system.3 AERD affects more than 30 million Americans and global estimates indicate that AERD costs the health system more than $6 billion.4,5
Some patients report that the attacks are random and erratic, but NSAIDs usually precipitate acute attacks. Patients may not link their use of NSAIDs to asthma exacerbations. AERD’ s exacerbations can occur often and may be severe enough to require hospitalization or tracheal intubation. Asthmatic patients with AERD have more compromised lung function and poorer quality of life (QoL) than asthmatics without AERD. Around half of patients need high doses of inhaled corticosteroids or maintenance oral corticosteroids. Corticosteroids decrease QoL may not completely relieve obstruction, and create significant adverse effects.6,7 Formation of nasal polyps is aggressive; polyps may fill the nasal cavity and protrude into the face, causing deformation and mid-facial expansion, or into the nasopharynx, pressuring bones.8,9 Patients then require nasal polypectomy, sometimes repeatedly.7 AERD patients often respond poorly to traditional treatments.
Clinicians frequently fail to recognize this syndrome, so patients are undiagnosed and inadequately treated—a concern for all patients and practitioners.7,10,11
AERD’s mechanism is only partially understood. Researchers have determined that defective eicosanoid metabolism is a known problem. Arachidonic acid breakdown products are directed toward leukotriene production, increasing pro-inflammatory cysteinyl leukotrienes, and away from prostaglandin production, reducing anti-inflammatory prostaglandin E2. NSAIDs, unless selective for COX-2, decrease prostaglandin and thromboxane production, intensifying the shift to leukotriene production. Often, AERD features devastating upper and lower airway eosinophil infiltration.10,14
The gold standard for the diagnosis of AERD is an oral provocation test under close clinical supervision. The challenge test should be performed when asthma is stable (ie, forced expiratory volume in the first second of expiration is >70% of expected value, with a variability of <10%). The supervising clinician administers increasing doses of aspirin every 1.5 to 2 hours, monitoring response carefully. This can be done in an outpatient setting, but is inadvisable unless emergency medication and equipment is available, since life-threatening reactions can occur.15
There is no cure for AERD. Treatment goals are reduction of inflammation of affected mucosa; prevention of nasal polyp formation; and control of sinusitis, other infections, and asthma.16
AERD patients must avoid NSAIDs and NSAID-containing medications. Pharmacists must educate patients to be vigilant about over-the-counter preparations, which often contain NSAIDs. For analgesia, most patients can take highly selective COX-2 inhibitors.17 Low-dose acetaminophen (<500 mg) poorly inhibits COX-1 and COX-2, but high-dose acetaminophen (>1000 mg) triggers symptoms in more than one-third of patients.18
AERD patients must control their asthma using the most current approaches for their asthma severity (Table 2).
Aspirin desensitization can help some AERD patients with upper and lower airway inflammation. Several studies have demonstrated that desensitization can decrease symptoms, hospitalizations, dependence on corticosteroids, and costs.22-25 Experts recommend desensitization for AERD patients with corticosteroid-dependent asthma, nonresponsive asthma, or those who need NSAID therapy for other conditions including coronary artery disease or chronic arthritis.26
Desensitization starts with a pretreatment with montelukast, then very low dose aspirin for 1 to 5 days, with incremental increases until the patient reacts to a dose. Then that reactive dose is repeated, and the patient generally does not react. Then dose escalation begins again and continues up to 325 mg. The patient goes home on a dose of 325 mg or 650 mg twice a day. Patients take this dose chronically, because resensitization occurs if even a few days are skipped.25,27 The exact mechanism by which desensitization occurs is unclear. Studies are under way to determine the lowest possible aspirin dose that will maintain desensitization.25
More research is needed to understand AERD. Better understanding of its pathogenic mechanism may help develop effective treatments. Disease management requires carefully planned polypharmacy with leukotriene inhibitors, antihistamines, and inhaled or systemic corticosteroids, even if aspirin desensitization is tried and successful.
Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance clinical writer.
- Sladek K, Szczeklik A. Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma. Eur Respir J. 1993;6:391-399.
- Stevenson DD. Aspirin sensitivity and desensitization for asthma and sinusitis. Curr Allergy Asthma Rep. 2009;9:155-163.
- Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma: AIANE investigators: European Network on Aspirin-Induced Asthma. Eur Respir J. 2000;16:432-436.
- Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Aller Clin Immunol. 1999;103:408-414.
- Klimek L, Pfaar O. Aspirin intolerance: does desensitization alter the course of the disease? Immunol Allergy Clin North Am. 2009;29:669-675.
- Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on nasal polyps. Rhinology. 2007;45(suppl 20):1-139.
- Kowalski ML. Rhinosinusitis and nasal polyposis in aspirin sensitive and aspirin tolerant patients: are they different? Thorax. 2000;55(2, suppl):S84-S86.
- Picado C. Aspirin intolerance and nasal polyposis. Curr Allergy Asthma Rep. 2002;2:488-493.
- Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L. TENOR Study Group. 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;116:970-975.
- Szczeklik A. Aspirin-induced asthma: a tribute to John Vane as a source of inspiration. Pharmacol Rep. 2010;62:526-529.
- Garrel R, Gardiner Q, Khudjadze M, et al. Endoscopic surgical treatment of sinonasal polyposis -- medium term outcomes (mean follow-up of 5 years). Rhinology. 2003;41:91-96.
- Stevenson DD, Szczeklik A. Clinical and pathologic perspectives on aspirin sensitivity and asthma. J Allergy Clin Immunol. 2006;118:773-786.
- Pierzchalska M, Szabó Z, Sanak M, Soja J, Szczeklik A. Deficient prostaglandin E2 production in bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J Allergy Clin Immunol. 2003;111:1041-1048.
- Ferguson BJ, Otto B, Pant H. When surgery, antibiotics and steroids fail to resolve chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009;29:719-732.
- Simon R. Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs. Curr Allergy Asthma Rep. 2004;4:17-24.
- Szczeklik A, Nizankowska E, Bochenek G, Nagraba K, Mejza F, Swierczynska M. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy. 2001;31:219-225.
- Heo Y, Saxson A, Hankinson O. Effect of diesel exhaust particles and their components on the allergen-specific IgE and IgG1 response in mice. Toxicology. 2001;159:143-158.
- Settipane RA, Stevenson DD. Cross sensitivity with acetaminophen in aspirin sensitive asthmatics. J Allergy Clin Immunol. 1989;84:26-33.
- Johnstone RAW, Plimmer J. The chemical constituents of tobacco and tobacco smoke. Chem Rev. 1959;59:885-936.
- Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA. Aspirin sensitivity: implications for patients with coronary artery disease. JAMA. 2004;292:3017-3023.
- Sweet JM, Stevenson DD, Simon RA, Mathison DA. Long term effects of aspirin desensitization treatment for aspirin-sensitive rhinosinusitis asthma. J Allergy Clin Immunol. 1990;85(1, pt 1):59-65.
- Castells M. Rapid desensitization for hypersensitivity reactions to medications. Immunol Allergy Clin North Am. 2009;29:585-606.
- Simon R. Prevention and treatment of reactions to NSAIDs. Clin Rev Allergy Immunol. 2003;24:189-197.
- Rizk H. Role of aspirin desensitization in the management of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2011;19:210-217.
- Lee RU, White AA, Ding D, et al. Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2010;105:130-135.
- Lee JY, Simon RA, Stevenson DD. Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2007;119:157-164.