Diagnosing and Treating Asthma Patients with Aspirin Sensitivity

Vol. 11 •Issue 3 • Page 18
Drug Data

Diagnosing and Treating Asthma Patients with Aspirin Sensitivity

Aspirin has been one of the most widely used medications for 100 years because of its analgesic, antipyretic and anti-inflammatory properties. Available in a variety of forms — from pills and solutions, to effervescent tablets, chewing gum and topical creams — aspirin’s ability to inhibit platelet aggregation also has increased its use as prophylaxis against ischemic heart disease and strokes. In addition, nonsteroidal anti-inflammatory drugs (NSAIDs), which have similar properties to aspirin, have been developed for the treatment of arthritis, headaches and menstrual cramps.

As aspirin’s use has become more widespread, however, concerns about the possibility of adverse reactions, including rhinorrhea, urticaria, laryngospasm and bronchospasm, have increased for a subset of patients with asthma. While aspirin sensitivity has been reported in less than 0.2 percent of the general population, it can affect as many as 5 percent to 10 percent of adults with asthma. That percentage can soar to as high as 35 percent in patients who have both nasal polyposis and asthma.

Aspirin sensitivity was first described as being part of a triad with asthma and rhinitis with nasal polyps in 1965.1 Hypereosinophilia (>200/cu mm) also is usually found, unless the patient is receiving corticosteroids or is infected. Aspirin-induced asthma is defined as the onset of asthma within 30 minutes to three hours after the ingestion of aspirin or an NSAID.2 This response, which is uncommon in children, typically presents in people 30 to 50 years of age, with women being affected 2.5 times more than men.3 Rarely is there a past history of aspirin sensitivity or familial occurrence.2


It was once thought that aspirin-induced asthma was due to an IgE or allergic-mediated response, though this doesn’t appear to occur very often. IgE antibodies to aspirin or NSAIDs haven’t been identified in aspirin-sensitive asthmatic patients, and reactions to aspirin or NSAIDs have occurred on a first exposure, eliminating the possibility of prior immune sensitization.4 Structurally dissimilar NSAIDs also have produced similar results in this patient population.2 These observations have led to the theory that the inhibition of the cyclooxygenase pathway is responsible for the rhinorrhea, laryngospasm, bronchospasm and urticaria associated with aspirin-induced asthma.

Cyclooxygenase is involved in the metabolism of arachidonic acid (See Figure), which is cleaved from the membrane phospholipids by phospholipase A2. Cyclooxygenase then converts the arachidonic acid into prostaglandins and thromboxanes.

Aspirin and NSAIDs, however, inhibit the metabolism of arachidonic acid by two cyclooxygenase isoenzymes, COX-1 and COX-2.5 COX-1 is continually synthesized, whereas COX-2 is synthesized only during times of inflammation. Evidence suggests that this inhibition of COX-1 is responsible for aspirin-precipitated asthma. A correlation between bronchoconstriction and in vitro potency of cyclooxygenase inhibition also has been demonstrated.2 The inhibition of COX-1 and the subsequent adverse reactions have been shown to be dose dependent.6

In addition, a second metabolic pathway for arachidonic acid exists.7,8 This pathway produces leukotrienes from the metabolism of arachidonic acid by 5-lipoxygenase. Among their effects, leukotrienes cause bronchoconstriction of airway smooth muscle; attract eosinophils; increase mucous secretions; slow mucociliary clearance; and increase vascular permeability.9 With the inhibition of COX-1 by aspirin and NSAIDs, the metabolism of arachidonic acid is shifted to the 5-lipoxygenase pathway, thus increasing the production of leukotrienes (LTA4, LTB4, LTC4, LTD4 and LTE4) and also decreasing the protective bronchodilator prostaglandin PGE2 that inhibits 5-lipoxygenase.

Because of this result, pretreatment with inhaled PGE2 has been shown to inhibit previously established aspirin sensitivity.10 Likewise, pretreatment with a 5-lipoxygenase inhibitor such as zileuton or a leukotriene receptor inhibitor will block or reduce the reaction. That’s important, because aspirin-sensitive patients with asthma have a greater baseline production of 5-lipoxygenase even before aspirin or NSAIDs are taken,11-13 not to mention the fact that these patients have airways that are hyperresponsive to LTE4.14 It’s this combination of both increased levels of and greater responsiveness to leukotrienes that leads to the adverse reactions to aspirin or NSAID usage.


Because there isn’t a reliable in vitro test, the diagnosis of aspirin-induced asthma is largely based on clinical history. Sensitivity may be suggested by a previous aspirin-induced or NSAID-induced asthma attack in a patient with chronic nasal congestion, nasal polyps and rhinorrhea. Definitive diagnosis, however, only can be made by an aspirin challenge via oral, inhaled or nasal administration. Of these, oral challenges are the gold standard and require three consecutive days to complete.

To perform a challenge, the patient’s asthma must be well controlled with a baseline FEV1 of 70 percent of predicted at the time of testing. To maintain the control of asthma, patients can remain on theophylline and bronchodilators but should discontinue antihistamines because of their ability to prevent nasal and ocular symptoms. Oral steroids may be used prior to testing to establish optimal .pulmonary function.2

Skilled personnel with experience treating acute asthma should conduct the three-day challenge. Day one consists of the administration of three doses of placebo.5 Day two begins with the administration of 30 milligrams of aspirin followed by doubling the dose every 3 hours up to 120 milligrams.5 Day three involves aspirin doses of 150, 325 and 650 milligrams.2 Each day, patients are monitored every 30 to 60 minutes with spirometry and observation for bronchial, nasal and ocular symptoms.15 A positive result is defined as a decrease in FEV1 by 20 percent along with naso-ocular symptoms. If a dose of 650 milligrams doesn’t produce any of the above, the challenge is considered negative.2


For treatment, aspirin desensitization is an effective option. Followed by daily aspirin therapy in sensitive individuals with asthma and rhinosinusitis, aspirin desensitization has reduced the need for topical and systemic corticosteroids. It’s also caused a reduction in emergency department visits, hospitalizations, upper respiratory tract infections, sinus infections and the need for nasal polypectomies.16-18

Aspirin desensitization should be considered for a number of cases, including: patients with uncontrolled upper respiratory tract inflammation despite optimal medical treatment; patients who require large doses of corticosteroids; patients requiring multiple sinus surgeries; and in patients who need daily aspirin therapy for arthritis, thromboembolic disease, neurological syndromes or ischemic heart disease prophylaxis.

Because aspirin sensitive patients are more responsive to therapy with drugs that inhibit leukotrienes, it’s worthwhile to start patients on zileuton prior to initiating aspirin desensitization. Once begun, desensitization is achieved by continuing the oral aspirin challenge. Patients are given the same dose of aspirin that precipitated a reaction and once a reaction occurs it’s reversed. This same dose is given the next day and is given each day thereafter until no reaction occurs. This process is continued until the patient is able to tolerate 650 milligrams. Once desensitized to aspirin, the patient is also cross-desensitized to other NSAIDs. The desensitization can then be maintained with as little as .81 milligrams of aspirin daily.2


Two new NSAIDs, celecoxib and rofecoxib, were released in 1999. These drugs selectively inhibit the COX-2 isoenzyme.19 The original package insert stated that aspirin-induced asthma was an absolute contraindication to their use. However, the inability of celecoxib and rofecoxib to inhibit COX-1, and thus its inability to deplete PGE2, didn’t support this contraindication. In a study on the safety of rofecoxib, therapeutic doses of both 12.5 and 25 milligrams were safely used in patients with documented aspirin-induced asthma, demonstrating that rofecoxib wasn’t a cross-reactive NSAID.20

This finding differed from studies looking at acetaminophen and salsalate. While poorly inhibiting COX-1, they both showed cross-reactivity at high doses with aspirin and NSAIDs in a minority of patients with aspirin-induced asthma.21,22 Meloxicam and nimusulide also dem.onstrated a dose response.23,24

The first dose of a COX-2 inhibitor should be administered with leuko-triene antagonist protection and several hours of observation. Occasionally, a true allergic response can occur to aspirin or to NSAIDs, including the COX-2 inhibitors.25 This occurs rapidly after ingestion and is probably mediated by an IgE mechanism.

Dr. Honsinger is a practicing allergist in Los Alamos and Santa Fe, N.M., and a clinical professor at the University of New Mexico School of Medicine. Treat is a third year medical student at the Arizona College of Osteopathic Medicine in Phoenix.

For a list of references, please call John Crawford at (610) 278-1400, ext. 1499, or visit www.Respiratory-care-sleep-medicine.advanceweb.com/mrreflist.html.


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