Comprehensive Olfactory Outcomes of Dupilumab in the Treatment of Chronic Rhinosinusitis With Polyposis

Olfactory improvement with biologics has primarily been evaluated using odor identification tests. Multicomponent assessment of threshold, discrimination and identification scores may provide more comprehensive insights. Approved by Clinical Trials Ontario, 15 cases of recalcitrant CRSwNP receiving dupilumab were included in the study, and the following outcomes were assessed at baseline, that is, 12 and 24 weeks: Sniffin Sticks threshold, discrimination and identification (TDI), Meltzer nasal polyp scores (NPS), SNOT-22, and quality of olfactory disorders—negative symptoms scores (QOD-NS). Age, gender, and number of previous sinus surgery (ESS) were recorded for each patient. We used the repeated measures ANOVA analysis with the Bonferroni post hoc test to compare the time points within the subjects. All subjects had undergone at least one ESS, and all except four (73%) had comorbid asthma or AERD. All our measurements of TDI scores and their subsets revealed increases of a clinically meaningful extent [1]. At baseline, all 15 patients had olfactory dysfunction with 13 (86.6%) anosmic and two (13.3%) hyposmic based on TDI assessment (11.4 ± 6.3). Significant improvement was observed at 3- and 6-month (MD = 13.6, p < 0.001, 95% CI 20.3–6.8; MD = 13.1, p < 0.001, 95% CI 19.9–6.4, respectively), with three (20%) patients becoming normosmic, nine (60%) hyposmic, and three (20%) remaining anosmic at 6 months. The 3- to 6-month difference, however, was not significant (MD = 0.4, p = 1, 95% CI −6.3 to 7.2). Similar results were also drawn from subtest analysis of threshold, discrimination and identification. Notably, improvements in discrimination and identification scores were greater than those in threshold scores. Threshold scores were 1.4 ± 1.6 at baseline and only improved to 4.7 ± 3.5 at 6 months (p = 0.005) (Table 1, Figure 1). A significant improvement was observed in SNOT-22 scores at 3 months, decreasing from 65.0 ± 21.1 to 28.2 ± 25.3 revealing improvement surpassing the MCID less than −12 (MD = 36.8, p < 0.001, 95% CI 15.6–58.1) [2], which persisted at 6 months (26.6 ± 23.2, MD = 38.46, p < 0.001, 95% CI 17.2–59.7). Subdomain analysis demonstrated similar results (Table 1). The QOD-NS scores showed comparable results, decreasing from 24.4 ± 9.6 to 14.4 ±10.8 at 3 months (MD = 10.1, p = 0.03, 95% CI 0.6–19.5), exceeding the MCID, and persisting at 6 months, reaching 11.6 ±10.5 (MD = 12.8, p = 0.005, 95% CI 3.4–22.3) [3]. Comparing QOD-NS and TDI improvements, each relative to their respective MCID, revealed a weak correlation at 3 months (Pearson correlation [r] = −0.59, p-value = 0.019) and no significant correlation at 6 months (r = −0.36, p-value = 0.188). NPS decreased significantly and consistently from a baseline of 4.7 ± 1.8 to 2.2 ± 1.8 (MD = 2.5, p = 0.001, 95% CI 0.9–4.1) at 3 months and to 1.47 ± 1.3 (MD = 3.2, p < 0.001, 95% CI 1.7–4.8) at 6 months. No significant difference was noted between 3 and 6 months (MD = 0.73, p = 0.7, 95% CI −0.8 to 2.2). Comparison between asthma/AERD and non-asthma/AERD patients showed no significant differences (p = 0.051). We did not find significant correlation between the NPS and TDI improvement at any of the time points (r = 0.050, p-value = 0.859). The lack of a significant NPS-TDI correlation in our study aligns with previous findings, reinforcing that olfactory impairment is driven more by inflammation resolution than polyp volume [4]. Full TDI testing with Sniffin’ sticks has shown that threshold improvements on dupilumab appear to be less than what is seen with supra-threshold testing (discrimination and identification) [1, 5]. The greater room for improvement in threshold suggests that threshold metrics may be a better tool for evaluating interventions aimed at achieving enhanced disease control. Future multi-center studies looking at extended follow-up of patients with full TDI testing might provide more insight into the extent of olfactory improvement attainable with dupilumab treatment. TDI assessment findings also raise the question of whether olfactory improvement is a continuous process or if it plateaus after the initial improvement. Only two patients had a single ESS, precluding subgroup analysis of surgery count and olfactory improvement. However, all four patients with no olfactory improvement on TDI testing had undergone at least three prior ESS. Threshold changes in surgery-naive patients could help assess their recovery potential with treatment. Leigh J. Sowerby served to the advisory board of GSK and Sanofi, received honorarium from GSK and Sanofi, and research support from GSK, Sanofi, Roche, AstraZeneca, Insomed, and Eli Lilly. Brian Rotenberg worked as speaker for Sanofi and consultant for Medtronic and Stryker. Andrew Thamboo served as speaker honorarium for Sanofi, GSK, AZ, and Stryker; served to the advisory board of Sanofi, GSK, and AZ; and received research funds from GSK and Sanofi. Ameen Biadsee served as speaker honorarium for Sanofi. The remaining authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.