Tolerance of daily low-dose aspirin does not preclude aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, eosinophilic nasal polyposis, rhinosinusitis, and respiratory reactions to COX-1 inhibitors including aspirin and other nonsteroidal anti-inflammatory drugs. Patients with AERD with symptoms refractory to guideline-based management of asthma, nasal polyposis, or rhinosinusitis benefit from aspirin desensitization and treatment with high-dose aspirin. Daily doses of at least 300 mg of aspirin, with some patients requiring up to 1300 mg, are effective in reducing the burden of disease. Studies investigating daily doses of lower than 300 mg have yielded inconsistent results, with the weight of evidence suggesting that low doses of aspirin are not effective. Clinical observation suggests that a subset of patients with AERD report taking daily low-dose (81 mg) aspirin for months to years without clinical history of an adverse reaction to aspirin. These patients come to attention because of recurrent eosinophilic nasal polyposis. When they undergo oral aspirin challenge after holding their daily aspirin for 10 days, they develop stereotypical respiratory reactions. To our knowledge, such patients with AERD have not been previously described in the literature. The goal of the present study was to identify a group of these patients and investigate their characteristics, with attention to their response to treatment with high-dose aspirin. We performed a retrospective chart review of 163 subjects with AERD who were referred to Brigham and Women’s Hospital or Massachusetts General Hospital for evaluation of possible AERD and who agreed to participate in our AERD registry between September 2013 and August 2014. We identified subjects who were taking 81 mg aspirin daily at the time of AERD evaluation and who reported no clinical history of aspirin hypersensitivity. All subjects who were taking daily low-dose aspirin at the time of AERD evaluation stopped taking aspirin for at least 10 days and then underwent aspirin challenge. The electronic medical record was reviewed for all subjects. Comprehensive clinical and questionnaire data were available for 91 subjects. There were 7 subjects (4.3% of 163) with AERD who had tolerated chronic daily aspirin (81-mg aspirin group). Six of the 7 subjects underwent positive aspirin challenge tests at our institution and developed a characteristic upper and/or lower airway reaction; the seventh reported a positive nonsteroidal anti-inflammatory drug challenge done elsewhere. Their demographic characteristics are given in Table I, and aspirin challenge results are given in Table II. The dose of aspirin that provoked a clinical reaction was 81 mg or less in 5 of the 6 patients. Subjects in the 81 mg aspirin group were significantly older at the time of aspirin challenge than other subjects with AERD (59.6 vs 48.3 years; P < .05), though there was no significant difference between groups in time between subjectreported onset of nasal polyposis and date of aspirin challenge. There was no significant difference between groups in the number of lifetime polypectomies, but fewer subjects in the 81mg aspirin group had a clinical history of asthma (5 of 7 vs 83 of 84; P < .05). Of the subjects in the 81-mg aspirin group, one started taking daily low-dose aspirin before the onset of AERD symptoms and another started taking daily low-dose aspirin before the onset of nasal polyps but had had mild intermittent asthma since childhood. Five had symptoms of AERD at the time they started taking daily low-dose aspirin. Of these, 3 were not taking montelukast and 2 could not recall their use of montelukast when they initiated daily low-dose aspirin. Four subjects in the 81-mg aspirin group were desensitized to aspirin and began high-dose aspirin therapy of at least 325 mg twice daily, and have been followed for a mean of 26 months (range, 5-37 months). Since beginning high-dose aspirin, none has required repeat polypectomy and all report improvement in nasal symptoms. Those with asthma (n 1⁄4 3) report improvement in asthma symptoms, with increases in FEV1 of 12.2%, 15.3%, and 41.4% at the first visit after the initiation of high-dose aspirin, which occurred 6, 12, and 6 weeks after aspirin desensitization, respectively. The patient whose FEV1 increased by 41.4% restarted zileuton, which he had temporarily stopped taking, around the same time that he started taking high-dose aspirin. Of the remaining 3 subjects in the 81-mg aspirin group, 2 will pursue polypectomy before aspirin desensitization and 1 has elected not to pursue highdose aspirin therapy. There are several explanations for why some patients with AERD apparently tolerate daily low-dose aspirin. First, they may initiate daily aspirin early in the clinical course of AERD before they develop aspirin hypersensitivity. However, only 1 subject in our group began taking baby aspirin before the onset of AERD symptoms. Second, the use of montelukast at the time of aspirin initiation could blunt their reaction, producing a “silent desensitization,” though most of the subjects we studied were not taking montelukast when they began taking daily low-dose aspirin. Given our findings, the most likely explanation is that they develop a reaction to their first ingestion of low-dose aspirin, but fail to connect the reaction with their aspirin use and subsequently become desensitized to aspirin through daily use. Although asthma is a prominent clinical feature of AERD, it is possible to have AERD without asthma. Subjects in our 81-mg aspirin group had significantly lower prevalence of asthma than did subjects who had not been taking aspirin daily. Patients with AERD who have more severe asthma may be less likely to tolerate daily low-dose aspirin without clinically obvious