Patients with AERD often develop progressive upper and lower airway disease despite treatment with maximum medical and surgical management, such as CysLT receptor antagonists, 5-LO inhibitors, topical or systemic corticosteroids, and repeat FESS. Aspirin desensitization and subsequent high-dose aspirin therapy are known to alter the trajectory of nasal polyp regrowth, to improve upper and lower respiratory symptoms, and to improve QoL (Table 19.1). Aspirin desensitization improves nasal congestion, increases the interval of time between surgeries, decreases the frequency of sinus infections, and lessens the need for topical or oral corticosteroids in patients with AERD [7, 24–27]. In the month following aspirin desensitization, many patients can experience near-immediate improvement in sense of smell, decreased need for prednisone, and improvement in nasal congestion [25]. In the long-term, patients continue to experience increased sense of smell, fewer purulent sinus infections, and a reduction in steroid treatment [24].

Patients with rapid regrowth of nasal polyps benefit from aspirin desensitization as it slows the regrowth of nasal polyps and decreases the need for repeated surgeries. One retrospective analysis assessed AERD patients with nasal polyps over a 2-year period. None of the aspirin desensitization patients required repeat surgery, whereas 80 % of the non-desensitized patient underwent repeat procedures [7]. Another study demonstrated that even AERD patients on low maintenance doses of aspirin (100 mg) required fewer nasal polypectomies than patients who were not taking aspirin at all [26]. In long-term follow-up of aspirin-desensitized patients, the need for sinus surgery decreased from once every 3 years to once every 10 years [27].

Although symptom improvement is typically more profound in the upper airway than the lower airway, asthma control often improves following aspirin desensitization as well. During a mean follow-up of 3.1 years, an uncontrolled study of 65 patients showed a significant decrease in asthma-related hospitalizations following aspirin desensitization [27]. A decrease in inhaled corticosteroid (ICS) dose following aspirin desensitization has been reported, although the number of patients requiring an ICS did not change [24].

A side benefit of aspirin desensitization is cross-desensitization to all other COX-1 inhibitors. This allows the desensitized patients to use NSAIDs for pain and antiinflammatory treatment. Cross tolerance only lasts as long as the desensitized state is maintained. Therefore, if a patient were to stop taking aspirin, they would also lose tolerance to all other COX-1 inhibitors.

Desensitization also serves as a diagnostic procedure to confirm the diagnosis of AERD. In this setting, the procedure is referred to as an aspirin challenge, and the protocol remains the same as described below. Aspirin challenges are often necessary to confirm the diagnosis of AERD in the setting of an appropriate clinical history and to rule out the diagnosis when a patient has no prior history of NSAID exposure. Clinical history of respiratory reaction to NSAIDs is not sufficient alone to make a diagnosis of AERD. In 15 % of subjects with a clinical history consistent with AERD, aspirin challenge is negative [25]. Additionally, patients with nasal polyposis and asthma who are on daily low-dose aspirin therapy may deny history of clinical reaction to NSAIDs but when formally challenged after having stopped their daily aspirin exhibit a reaction. Confirming the diagnosis of AERD with aspirin challenge is important for patient safety and optimization of treatment.

Aspirin desensitization is a cost-effective intervention for patients with moderate-to-severe AERD. In an economic analysis that accounted for the up-front cost of aspirin desensitization in a hospital or ambulatory setting, patients who underwent successful aspirin desensitization required fewer costly subsequent medical interventions and surgeries [22]. The same analysis also revealed it is more cost-effective to desensitize patients who require aspirin for secondary cardiovascular prophylaxis than to prescribe them other antiplatelet agents.

Despite the ability to successfully desensitize nearly all patients with AERD to aspirin, there remains a subset of patients with AERD who do not experience improvement in symptoms on high-dose aspirin therapy. A retrospective study of 172 AERD patients showed that 78 % of patients improved following aspirin desensitization [24]. The other 22 % of patients either did not improve on aspirin or discontinued it due to side effects. Currently, there are no available biomarkers or clinical parameters to help preselect for aspirin responders. Patients must first undergo aspirin desensitization and initiate aspirin therapy to determine if they will benefit from the treatment. Prior to aspirin desensitization, physicians should inform patients of the possibility that high-dose aspirin may not alleviate symptoms of AERD.

Aspirin desensitization is not without risk but generally can be performed in the ambulatory setting. In this controlled environment of aspirin desensitization, where the provocative dose of aspirin averages around 100 mg and patients are on montelukast, prior history of reaction severity to NSAID ingestion does not predict the severity of the clinical reaction [28]. In a study of 210 patients with AERD undergoing aspirin challenges, the majority of reactions involved naso-ocular symptoms or mild decreases in FEV₁. Only 9 % of patients in the study had a greater than 30 % decrease in FEV₁ [28]. History of emergency department visits for asthma independent of aspirin use, baseline FEV₁ of 60–80 %, and lack of leukotriene receptor antagonist use at time of challenge are predictors of a fall in FEV₁ of 21 % or greater during aspirin challenge [29]. In one retrospective series of over 670 aspirin desensitizations, no emergency room visits or hospitalizations and only one administration of intramuscular epinephrine were required during aspirin desensitization [30]. In our experience, a small subset of patients report persistent asthma symptoms that do not improve despite having been desensitized to 650 mg of aspirin. Additionally, the occurrence of rash, urticaria, or angioedema on high-dose aspirin therapy occasionally necessitates discontinuing aspirin therapy. High-dose aspirin therapy for AERD provides the same amount of antiplatelet effect as 81 mg of aspirin and therefore the same bleeding risk with doses of 650 mg twice daily showing the same or less gastrointestinal side effects, such as dyspepsia, than 325 mg twice daily [31].

Aspirin desensitization can be carried out safely in the outpatient clinic by physicians trained in the treatment of asthma and allergic diseases with experience performing aspirin desensitization and the capability to treat anaphylaxis. Typically this procedure is performed over 1–2 days. Protocols outlined in the literature involve either oral aspirin or a combination of intranasal ketorolac [32] and oral aspirin starting at doses between 20 and 40 mg of aspirin (1.26 mg of ketorolac) and doubling the dose every 90–180 min until a dose of 325 mg oral aspirin has been reached [29]. These starting doses and rate of dose escalation are in stark contrast to aspirin desensitization protocols employed in the setting of aspirin-induced urticaria or anaphylaxis which are beyond the scope of this review and are discussed elsewhere [33]. It is to be expected that patients with AERD undergoing aspirin desensitization will experience a clinical reaction, most often involving upper and lower respiratory symptoms, such that a baseline FEV₁ <50 % predicted or <1 L is the primary contraindication to performing an aspirin desensitization [34]. Premedication with montelukast and zileuton is associated with increased patient safety, decreasing airway bronchospasm and the severity of naso-ocular symptoms [30]. Use of montelukast is associated with the small (10 %) risk of completely blocking all reaction symptoms in patients with AERD [35], and a clinician may elect to withhold this premedication during a challenge procedure in order to ensure the correct diagnosis is made. Patient history of abdominal symptoms during aspirin exposure may be overcome in our experience by premedication with oral cromolyn sodium, H₂-receptor antagonists, or proton pump inhibitors (PPIs). Once a patient reaches the dose of aspirin that induces a clinical reaction (provocative dose), the reaction is treated symptomatically, and the patient is observed for the resolution of symptoms. Once aspirin-induced symptoms have resolved, repeat administration of the provocative aspirin dose and then subsequent doses of aspirin are typically well tolerated without further respiratory reaction. Patients are discharged home on 650 mg aspirin twice daily with a potential to decrease the dose to 325 mg twice daily in a subset of patients and still maintain the therapeutic benefit [31]. The best available data support the use of aspirin 650 mg twice daily as the dose that offers the most benefit in preventing nasal polyp regrowth and improving asthma control [31]. In some patients, high-dose aspirin therapy is associated with gastrointestinal side effects such as gastritis, acid reflux, and ulcer formation, and the use of PPIs (and often additional therapies such as sucralfate) to treat such side effects is warranted.

The mechanism of how aspirin ameliorates the severity of AERD remains an enigma. The process of aspirin desensitization allows patients to clinically tolerate the surge in CysLTs [36] and mast cell mediators, such as histamine, tryptase, and prostaglandin D₂ [36–38], seen following the ingestion of the provocative dose during the desensitization procedure. However, what allows the patient to go on to tolerate subsequently higher doses of aspirin without further clinical reaction is unknown. What is known is that the continued administration of aspirin after desensitization mitigates many of the features characteristic of the AERD phenotype. Desensitized subjects no longer have the characteristic surge in LT production after taking each dose of aspirin yet continue to produce CysLTs at levels unchanged from baseline levels on high-dose aspirin therapy [8]. They display diminished responsiveness to the CysLTs, reflecting, in part, decreased expression of CysLT1R in their airways following aspirin desensitization [39]. What happens to the other mediators involved in the clinical reaction to aspirin following long-term high-dose aspirin therapy has not been systematically studied.

There are several plausible mechanisms that could underlie the benefits of high-dose aspirin therapy. The baseline and reaction-induced overproduction of CysLTs reflects, in part, the striking adherence of platelets to neutrophils and eosinophils in these patients and subsequent transcellular arachidonate metabolism [40]. A clinical trial is underway exploring whether the antiplatelet effects of aspirin diminish the adherence of platelets to granulocytes (http://​clinicaltrials.​gov/​ct2/​show/​NCT01597375). In addition to supporting CysLT production, platelet-derived TxA₂ is likely pathogenic in this disorder by its direct ability to induce bronchospasm, effects that are diminished with continuous aspirin administration. Other “on-target” (cyclooxygenase-targeting) effects of aspirin include inhibited synthesis of proinflammatory and bronchospastic prostaglandins such as PGF₂α and PGD₂. Diminished PGD₂

Stay updated, free articles. Join our Telegram channel

Join