To the editor
Aspirin-exacerbated respiratory disease (AERD) is the triad of chronic rhinosinusitis with nasal polyposis, asthma, and adverse reactions to aspirin and other cyclooxygenase-1 (COX1) inhibitors. The pathophysiology of AERD involves dysregulated arachidonic acid metabolism and overproduction of cysteinyl leukotrienes, which further increase upon exposure to COX1 inhibitors1. Paradoxically, aspirin desensitization improves upper and lower airway symptoms in 67–78% of AERD patients2. However, there are AERD patients who are in need of additional treatment options because they cannot tolerate aspirin desensitization3 or aspirin therapy2, or do not derive benefit from aspirin therapy.
The upper and lower respiratory tracts in AERD are characterized by eosinophilic infiltration. Nasal polyps (NPs) from subjects with AERD exhibit three times more eosinophils compared to NPs from aspirin-tolerant subjects4. They also contain higher levels of interleukin-5 (IL-5)5, an eosinophilic maturation and differentiation factor, and soluble IL-5 receptor alpha6. Bronchial mucosa biopsies demonstrate three times more eosinophilic cationic protein compared to aspirin-tolerant asthmatics, suggesting eosinophilic infiltration of the lower respiratory tract in patients with AERD.7 Additionally, peripheral eosinophilia greater than 300 cells/µL3 is common in AERD. These biologic characteristics suggest patients with AERD could benefit from anti-IL-5 therapy.
Two randomized, double-blinded trials explored the utility of mepolizumab in recurrent NPs. Two doses of mepolizumab 750mg IV reduced NP size8 and six monthly doses of mepolizumab 750mg IV reduced the need for NP surgery and improved sino-nasal outcome test (SNOT)-22 scores9. However, these results were not stratified based on aspirin intolerance.
No data exist on the benefit of mepolizumab for asthma or NPs in AERD. We sought to determine the clinical efficacy of mepolizumab on the upper and lower airway symptoms and lung function in subjects with AERD.
Subjects at the Brigham and Women’s Hospital AERD Center with AERD who received 3 or more mepolizumab 100mg doses through May 2017 for the treatment of severe asthma were included. The AERD diagnosis was physician-confirmed by aspirin challenge. This retrospective study was approved by the Partners Healthcare Institutional Review Board.
Data were extracted from the Partners Healthcare electronic medical record (Epic Systems, Verona, Wisconsin). Clinical demographics, medications, absolute eosinophil count (AEC), SNOT-22, asthma control test (ACT), and forced expiratory volume in 1 second (FEV1) were extracted from the medical record at the visit before initiation and after 3 or more doses of mepolizumab. The SNOT-22 is a validated questionnaire quantifying upper respiratory symptoms and scores ranging from 0–110, with higher scores indicating greater symptoms. A change of ≥8.9 points represents a minimally important difference10. The ACT is an asthma questionnaire with possible scores of 0–25, with higher scores indicating better asthma control and a change of ≥3 points representing a minimally important difference11.
All analyses were performed using GraphPad Prism (GraphPad, La Jolla, California). Data reported are means ± standard error of mean (SE) unless otherwise noted. Paired t-test and Wilcoxon signed rank test were used when appropriate for parametric or non-parametric data, respectively. All p-values are 2-sided with a P<0.05 considered statistically significant.
Of the 22 subjects with AERD treated through May 2017, 14 subjects received at least three doses of mepolizumab (Table 1). At baseline, subjects reported a mean number of 2.5 lifetime polypectomies, median time to polyp recurrence of 3 months, current (64%) or previous (100%) high-dose aspirin therapy, and mean AEC of 842/μL. Fifty percent (7) of the subjects were taking a daily oral glucocorticoid at the time mepolizumab was prescribed.
Table 1.
Characteristics of patients with AERD started on mepolizumab for severe eosinophilic asthma (at least three mepolizumab injections)
| Female, N (%) | 7 (50%) |
| Age, years, median (IQR) | 54 (14.8) |
| Weight, kg, mean ± SD | 82.3 ± 16.9 |
| Previous lifetime exposure to tobacco products, greater than 1 pack-year, N (%) | 5 (36%) |
| Age of polyp onset, years, mean (IQR) | 38.5 (15) |
| Age of asthma diagnosis, years, mean (IQR) | 35 (14) |
| Number of lifetime polypectomies, mean, (IQR) | 2.5 (1.8) |
| Time to polyp regrowth, months, median (IQR) | 3 (16) |
| Subjects on daily oral glucocorticoids for greater than 6 months per year, N, (%) | 7 (50%) |
| Subjects taking high-dose aspirin*, N (%) | 9 (64%) |
| Absolute eosinophil count, prior to starting mepolizumab, eosinophils/uL, mean ± SD | 842 ± 485 |
| FEV1, prior to starting mepolizumab, % predicted, mean ± SD | 63.5 ± 24.2 |
| Duration on mepolizumab at time of data collection, months, median (IQR) | 5.5 (6) |
high dose aspirin: either 650mg daily or 1300mg daily
After three or more mepolizumab doses (range 3–11 doses), AEC decreased significantly (N=8, P<0.01, Figure 1A). SNOT-22 scores decreased by 17.7 points (±4.9, N=11, P<0.01, Figure 1B), indicating significant improvement in sino-nasal symptoms. Anosmia (SNOT-22 question 21, Figure 1C) and nasal congestion (SNOT-22 question 22, Figure 1D) significantly decreased (both P<0.05) after treatment with mepolizumab. Treatment with mepolizumab significantly increased overall ACT scores by 5.1 (±1.3, N=14, P=0.002 Figure 1E). There was a trend toward improvement in mean FEV1% predicted (baseline 62.9±6.3%, post-mepolizumab 68.3±5.5%, N=14, P=0.16, Figure 1F).
Figure 1.
Treatment with three or more doses of mepolizumab decreased absolute eosinophil count (AEC) and sino-nasal outcome test (SNOT-22) scores, while asthma control test (ACT) scores increased. A, AEC, B, total SNOT-22 scores, including C, symptoms of anosmia (Question 21) and D, nasal congestion (Question 22) declined and E, total ACT scores increased on mepolizumab. F, no statistically significant change in FEV1% of predicted. Analysis performed using a paired t-test (A, B, E) or a Wilcoxon signed-rank test (C, D, F). Gray horizontal lines represent group means.
No subjects required sinus surgery and there were no increases in or initiation of oral glucocorticoids during the study period. Five of the 7 subjects on oral glucocorticoids for greater than 6 months per year prior to mepolizumab initiation decreased their daily oral glucocorticoid dose; 2 of those 5 subjects on oral glucocorticoids were also able to reduce their daily inhaled corticosteroid-long acting beta agonist dose (data not shown).
Physicians have a small therapeutic arsenal to treat the severe nasal polyposis, sino-nasal congestion, and anosmia characteristic of AERD. To our knowledge, this is the first study to specifically examine the role of IL-5 inhibition in a cohort of subjects with AERD. Treatment with mepolizumab, 100mg SC every 4 weeks for 3 or more doses, decreased AEC and significantly improved both upper and lower airway symptoms. Specifically, mepolizumab improved subject-reported outcomes of nasal congestion and sense of smell, important quality of life measures. The overall SNOT-22 score improved by 17 points, whereas Bachert and colleagues reported a 13.2-point increase in their study of mepolizumab in severe NPs9, indicating AERD subjects may respond better to mepolizumab than aspirin-tolerant subjects with chronic rhinosinusitis with NP.
This retrospective, pragmatic analysis of mepolizumab in AERD has limitations. It is not randomized, blinded, or placebo-controlled and involves subject-reported data. Not all patients with AERD meet criteria for severe asthma, which limits the generalizability of our results to all patients with AERD.
Subjects with AERD treated with mepolizumab for more than three months exhibited improvement in nasal congestion, anosmia, and asthma control, providing evidence that AERD represents an endotype of eosinophilic asthma and nasal polyposis responsive to IL-5 inhibition. Double-blinded, controlled studies that screen and report on aspirin intolerance in patients with asthma and recurrent nasal polyposis are necessary to confirm these data, and to properly identify the responder endotype.
Clinical Implications Box.
This study provides clinical evidence that IL-5 inhibition with mepolizumab improves upper airway symptoms, including anosmia and nasal congestion, and asthma control in subjects with AERD and severe asthma.
Acknowledgments
Funding Source:
This work was supported by the National Institutes of Health (Grants K23HL111113, K23AI118804, R01HL128241, and T32AI007306-32), and by generous contributions from the Kaye and Vinik families.
Footnotes
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Conflicts of Interest:
K Tuttle and K Buchheit report no conflicts of interest. T Laidlaw has served on scientific advisory boards for GlaxoSmithKline and Allakos and has received consultancy fees from Knopp Biosciences and Sanofi-Genzyme. K Cahill is on the boards of Teva and Optinose.
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