Recovery of Olfactory Function After Mepolizumab Treatment in Patients with Chronic Rhinosinusitis with Nasal Polyps: Influence of the Number of Surgeries

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I have no major comments, only a few minor points:

1. Could the authors clarify which statistical tests were used, particularly for Section 3.4 (influence of the number of previous surgeries) and for Table 2?
2. Has the sustained improvement in olfactory function observed at both 6 and 12 months also been reported in previous studies or clinical trials?
3. The inverse relationship between polyp size and improvement in SNOT-22 item 21 is interesting. Has a similar association also been demonstrated using other olfactory assessment tools, such as the Brief Smell Identification Test (BSIT-8)?

Author Response

.- Comments 1. Could the authors clarify which statistical tests were used, particularly for Section 3.4 (influence of the number of previous surgeries) and for Table 2?

Response 1. The statistics section has been completely rewritten. In addition to this section, the main text contains many other comments on the statistical tests used, highlighted in yellow. We do not reproduce them here, as that would amount to a repetition of the main text, most of which has been rewritten. We believe we have addressed all the issues raised by the reviewer.

 

.- Comments 2. Has the sustained improvement in olfactory function observed at both 6 and 12 months also been reported in previous studies or clinical trials? 

Response 2. Yes. Sustained improvement in olfactory function following mepolizumab treatment at both 6 and 12 months has also been reported in previous real-world studies and clinical trials. In particular, Domínguez-Sosa et al. (2026) observed progressive and sustained improvement in VAS-smell scores at 6, 12, and 24 months in patients with CRSwNP treated with mepolizumab. This information has been added to the discussion:

Line 325, reads now as follows:

“More recently, Domínguez-Sosa et al. reported sustained and progressive improvement in olfactory function at 6, 12, and 24 months in a real-world cohort of CRSwNP patients treated with mepolizumab, supporting the long-term durability of olfactory recovery observed in both clinical trials and real-life studies”

 

.- Comments 3. The inverse relationship between polyp size and improvement in SNOT-22 item 21 is interesting. Has a similar association also been demonstrated using other olfactory assessment tools, such as the Brief Smell Identification Test (BSIT-8)? 

Response 3. Although direct evidence specifically evaluating the relationship between nasal polyp size reduction and BSIT-8 improvement during mepolizumab treatment is still limited, previous studies using psychophysical olfactory tests have suggested a similar association. In the SYNAPSE-related olfactory analysis, Mullol et al. demonstrated significant improvement in smell outcomes assessed with UPSIT together with reductions in disease severity and polyp burden. Likewise, real-world studies with mepolizumab using objective olfactory tools such as Sniffin’ Sticks have also reported parallel improvements in olfactory function and nasal polyp scores. Since the BSIT-8 is a shortened version derived from UPSIT, our findings are consistent with the existing evidence suggesting that reduction in inflammatory and polyp burden may contribute to olfactory recovery.

This information has been added to the discussion section, line 349.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a review of a manuscript named "Recovery of olfactory function after mepolizumab treatment in patients with chronic rhinosinusitis with nasal polyps: influence of the number of surgeries." 

 

This prospective observational study evaluates the real-world effect of a 12-month mepolizumab treatment on olfactory recovery in 33 consecutive patients with chronic rhinosinusitis with nasal polyps. The authors utilize both subjective tools (VAS, SNOT-22) and objective psychophysical testing (BOT-8) to assess olfaction, alongside secondary measures like the Nasal Polyp Score and peripheral blood eosinophilia. The manuscript concludes that mepolizumab significantly improves olfactory function, though recovery is notably lower in patients with three or more prior sinus surgeries. 

 

While the study addresses an important clinical question regarding biologic therapies in CRSwNP, there are methodological and statistical concerns regarding the subgroup analysis that must be addressed. 

The title, abstract, and conclusions prominently highlight that patients with prior surgeries have significantly lower olfactory recovery. However, only 2 patients (6% of the cohort) fall into the "3 prior ESS" group. Comparing an experimental group of 2 against a group of 17 (1 prior surgery) to draw a major, statistically significant conclusion is statistically fragile and potentially misleading. The authors must either acknowledge that this subgroup is too small to draw definitive conclusions or re-evaluate their statistical approach. In the discussion and conclusion, the authors speculate that a subset of refractory patients fails to recover olfaction due to "central neuroinflammation" and "irreversible neuroepithelial damage". While they cite animal models and external literature to support this, the current study collected no biological, histological, or imaging data to directly measure or prove central neuroinflammation in this cohort. This conclusion should be softened to clearly indicate it is a proposed hypothesis rather than a finding derived directly from the study's data.

As the authors rightly acknowledge, the study lacks a contemporary control group, and is limited by a single-center design, which restricts the generalizability of the findings. 

Author Response

Comments 1. While the study addresses an important clinical question regarding biologic therapies in CRSwNP, there are methodological and statistical concerns regarding the subgroup analysis that must be addressed. The title, abstract, and conclusions prominently highlight that patients with prior surgeries have significantly lower olfactory recovery. However, only 2 patients (6% of the cohort) fall into the "3 prior ESS" group. Comparing an experimental group of 2 against a group of 17 (1 prior surgery) to draw a major, statistically significant conclusion is statistically fragile and potentially misleading. The authors must either acknowledge that this subgroup is too small to draw definitive conclusions or re-evaluate their statistical approach.

We thank the Reviewer for this thoughtful and constructive comment. We agree that the subgroup analysis regarding the number of previous endoscopic sinus surgeries (ESS) should be interpreted with caution due to the very limited number of patients in the subgroup with ≥3 prior surgeries (n=2). We acknowledge that this small sample size limits the statistical robustness and generalizability of the comparison and may lead to overinterpretation if presented too prominently.

Accordingly, we have revised the abstract, discussion, and conclusions to soften the interpretation of these findings. The results are now presented as exploratory observations rather than definitive evidence, and we explicitly acknowledge the limitations related to subgroup size and statistical power.

See line 437.

.-  Comments 2. In the discussion and conclusion, the authors speculate that a subset of refractory patients fails to recover olfaction due to "central neuroinflammation" and "irreversible neuroepithelial damage". While they cite animal models and external literature to support this, the current study collected no biological, histological, or imaging data to directly measure or prove central neuroinflammation in this cohort. This conclusion should be softened to clearly indicate it is a proposed hypothesis rather than a finding derived directly from the study's data.

Response 2. We also appreciate the Reviewer’s observation regarding our discussion of central neuroinflammation and irreversible neuroepithelial damage. We agree that our study did not include biological, histological, or neuroimaging assessments capable of directly demonstrating these mechanisms. Therefore, we have revised the manuscript to clearly frame these concepts as hypothetical pathophysiological explanations derived from previous experimental and translational studies, rather than conclusions directly supported by our own data.

See line 453.

.- Comments 3. As the authors rightly acknowledge, the study lacks a contemporary control group, and is limited by a single-center design, which restricts the generalizability of the findings.

Response 3. Finally, we have reinforced in the limitations section that the absence of a contemporary control group and the single-center design restrict the external validity and generalizability of our findings.

See line 436.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Although the major concerns could not be fully addressed due to study design limitations, I believe this is a valuable addition to the literature and support publication in light of the revisions made by the authors.