ABSTRACT
Objective
To assess whether biologics (dupilumab, mepolizumab, and omalizumab) used for conditions other than chronic rhinosinusitis with nasal polyps (CRSwNP) reduce the frequency of acute bacterial rhinosinusitis (ABRS) episodes.
Methods
This retrospective cohort study utilized the All of Us Research Program database to identify patients treated with dupilumab, mepolizumab, or omalizumab, excluding those with CRSwNP. A control group matched by race, gender, and comorbidities (asthma, allergic rhinitis, atopic dermatitis, smoking status) was created using propensity score matching (1:1 ratio) and K‐nearest neighbors. The primary outcome was the frequency of ABRS episodes in biologic‐exposed versus control groups, analyzed using χ2 tests to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
Results
Out of 2094 subjects, the biologic group had a significantly lower ABRS rate (6%) compared to controls (14%) (OR 0.4349, p < 0.0001). Dupilumab use was associated with the greatest significant reduction in ABRS risk (OR 0.1526, p < 0.001044). Mepolizumab (OR 0.6027, p = 1) and omalizumab (OR 0.7671, p = 0.4133) showed a decrease in ABRS episodes though this finding was not statistically significant.
Conclusion
Dupilumab appears to significantly reduce ABRS episodes in patients without CRSwNP, suggesting a protective effect on sinonasal health even in patients without chronic sinusitis. Further studies are needed to confirm these effects and to evaluate risks associated with long‐term biologic use in non‐CRSwNP populations.
Level of Evidence
IIIb/IV.
Keywords: acute rhinosinusitis, biologic medication, chronic rhinosinusitis, nasal polyps
In the control group, 14% experienced at least one episode of ABRS. In the biologic‐exposed group, only 6% had an ABRS episode. This difference was shown to be statistically significant, reflecting a strong protective association biologics have on ABRS episodes.
1. Introduction
Certain biologic medications are FDA approved for the treatment of chronic sinusitis with nasal polyps (CRSwNP). Published literature has exhibited compelling results in their control of sinonasal inflammation for refractory CRSwNP despite surgery [1, 2, 3, 4]. Expectedly, these biologics are also commonly prescribed for other type II inflammatory conditions unrelated to CRSwNP.
In this study, we seek to identify whether patients treated with biologics for indications other than CRSwNP exhibit a decreased frequency of acute bacterial rhinosinusitis (ABRS) episodes. The purpose of this study is not to investigate the utility of biologic medications as a treatment or prevention of acute sinusitis, but rather to improve our understanding of ABRS and its triggers.
2. Materials and Methods
This study utilized data from the National Institutes of Health's All of Us Research Program (AoURP) Registered Tier Dataset v8, a national dataset of adults in the United States. The cohort was selected by identifying individuals with the Observational Medical Outcomes Partnership (OMOP) codes representing patients treated with dupilumab, mepolizumab, or omalizumab. OMOP codes ensure standardization of the structure and content of patient data collected across disparate databases using codes adopted from national or international organizations (i.e., ICD‐9‐CM, ICD‐10‐CM, SNOMED‐CT). Patients with a diagnosis of CRSwNP or history of sinus surgery were excluded. A control group was established, consisting of individuals not on a biologic and without an aforementioned diagnosis of CRSwNP. OMOP codes were then used to identify non‐CRSwNP patients in both control and experimental cohorts. Matching parameters included race/ethnicity, gender, and a diagnosis of the following comorbidities: asthma, allergic rhinitis, smoking status, or atopic dermatitis. The aforementioned comorbid diseases were chosen based on their potential to increase a patient's risk of acute bacterial rhinosinusitis (ABRS) due to type 2 inflammation [5, 6]. Matching cohorts were then completed using propensity score matching and K‐nearest neighbors, with a 1:1 ratio of controls to experimental. Comparison of ABRS episodes was performed using the χ2‐test for categorical variables. Statistical analyses were conducted to calculate the odds ratio (OR) and 95% confidence intervals (CIs) for ABRS across the experimental and control groups.
3. Results
Of the total 2904 subjects, the racial demographics of each of the 1:1 matched cohorts (control vs. experimental) included White (56.2%–56.4%), Black or African American (16.5%–16.8%), Asian (5.8%–5.9%), and Other (18.5%–18.6%). The majority identified as non‐Hispanic or Latino (84.0%–84.1%) and female (71.0%–71.3%). The majority had asthma (54.3%), while there were fewer with allergic rhinitis (44.5%–45.1%) or atopic dermatitis (29.1%–29.3%). In total, 79 subjects were prescribed mepolizumab, 518 were prescribed dupilumab, and 509 were prescribed omalizumab (Table 1). No patients had a history of sinus surgery in either cohort. The discrepancy between the cohort size and the number of subjects prescribed biologics is attributed to how subjects were trialed on one and then switched to a different biologic.
TABLE 1.
Study demographics based on patient medical record.
| Experimental (n = 1047) | Control (n = 1047) | |
|---|---|---|
| Race | ||
| White | 588 (56.2%) | 591 (56.4%) |
| Black or African American | 176 (16.8%) | 173 (16.5%) |
| Other Race | 194 (18.5%) | 195 (18.6%) |
| Asian | 62 (5.9%) | 61 (5.8%) |
| Ethnicity | ||
| Not Hispanic or Latino | 880 (84.0%) | 881 (84.1%) |
| Hispanic or Latino | 138 (13.2%) | 139 (13.3%) |
| Other Ethnicity | 29 (2.8%) | 27 (2.6%) |
| Gender | ||
| Female | 743 (71.0%) | 746 (71.3%) |
| Male | 277 (26.5%) | 277 (26.5%) |
| History of asthma | 568 (54.3%) | 569 (54.3%) |
| History of allergic rhinitis | 466 (44.5%) | 472 (45.1%) |
| History of atopic dermatitis | 307 (29.3%) | 305 (29.1%) |
| History of smoking | 375 (35.8%) | 375 (35.8%) |
| Biologic prescription | ||
| Mepolizumab | 79 (7.5%) | 0 |
| Dupilumab | 518 (49.5%) | 0 |
| Omalizumab | 509 (48.6%) | 0 |
In the control cohort without exposure to biologics, 898 (85.8%) had no episodes of ABRS, while 149 (14.2%) did have at least one episode of ABRS. In the experimental cohort with exposure to biologics 982 (93.8%) had no episodes of ABRS and 65 (6.2%) had at least one episode of ABRS as shown in Figures 1 and 2. The odds ratio (OR) of developing ABRS while on dupilumab, mepolizumab, or omalizumab was calculated to be 0.4349 (p < 0.0001, 95% CI: 0.2557–0.7851), suggesting the experimental cohort had a significantly lower chance of experiencing ABRS while on a biologic.
FIGURE 1.
Rate of acute sinusitis in each cohort based on EHR coding.
FIGURE 2.
Number of individuals diagnosed with acute sinusitis stratified by biologic therapy exposure based on EHR coding.
Within the experimental cohort, out of the three biologics, dupilumab had the only significant association with a decrease in ABRS episodes, with the calculated OR being 0.1526 (p < 0.001044, 95% CI: 0.0530–0.6735). Neither mepolizumab nor omalizumab achieved a significant effect on ABRS incidence. The calculated OR for mepolizumab was 0.6027 (95% CI: 0.1538–4.7925) and the calculated OR for omalizumab was 0.7671 (95% CI: 0.4441–1.4004).
4. Discussion
The results of this study suggest that dupilumab exposure may confer a protective effect on sinonasal health, as evidenced by a reduced frequency of ABRS episodes, even among patients without chronic rhinosinusitis with nasal polyps (CRSwNP). Patients treated with omalizumab and mepolizumab exhibited a reduction in the frequency of ABRS, but these findings did not reach statistical significance. Overall, these findings represent an unintended positive effect when these medications are utilized for indications other than sinus disease. These results also imply potential overlapping pathophysiology underlying acute exacerbations in CRSwNP as well as ABRS episodes. Additionally, exposure to biologic medications – specifically dupilumab – may offer a protective, therapeutic role for patients with refractory recurrent acute sinusitis who continue to experience frequent episodes despite prior surgical intervention.
Biologic medications used to treat CRSwNP target the type 2 inflammation pathway. The varying efficacy of biologics can be attributed to their different mechanisms of action [7]. Dupilumab works by blocking the IL‐4 receptor to inhibit IL‐4 and IL‐13 signaling and reduces the activity of Th2 (type 2 helper T) cells, which are crucial in mediating allergic inflammation. Mepolizumab binds to IL‐5 to inhibit its interaction with its receptor, reducing eosinophil levels. Omalizumab works similarly to block Anti‐IgE antibodies from binding to its receptor, reducing the release of inflammatory mediators. Considering the varying effectiveness of each biologic in treating acute sinusitis episodes, dupilumab's effectiveness could be attributed to its targeted inhibition of IL‐4 and IL‐13 signaling, reduction in eosinophil levels, and therefore a relatively broader impact on the inflammatory pathway.
This study exhibits several important limitations. Data was extracted from a national database. As such, the conclusions drawn are reliant upon the accuracy of the data inputted. Due to the inherent structure and limited granularity of the NIH All of Us Research Program database, biologic exposure information is primarily derived from electronic health record (EHR) prescription records and codes and may not fully capture precise treatment start dates, medication adherence, especially across multiple health systems. It is also important to recognize that most diagnoses of ABRS are made by non‐otolaryngologists and are subject to false diagnosis without the use of nasal endoscopy. This is an important limitation; however, one would expect it to affect both cohorts similarly and therefore expect the false positive rate to be similar as well. Caution is advised against extrapolating that these medications should be used for the treatment of ABRS or recurrent acute sinusitis recognizing the potential risks associated with long‐term immunomodulators.
5. Conclusion
Patients treated with dupilumab for inflammatory conditions other than CRSwNP, had a significant decrease in frequency of ABRS episodes when compared to the patients without exposure to biologics. This suggests that such biologics exhibit a protective role against the development of sinonasal inflammation even for patients without CRSwNP.
Conflicts of Interest
D.B.S. (consultant—Sanofi, Aerin Medical).
Funding
The authors received no specific funding for this work.
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