To the Editors,
Pathogenesis of primary, bilateral, chronic, uncontrolled rhinosinusitis with polyps (CRSwNP) involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, impaired immune response, and excessive tissue remodeling [1]. Sinonasal epithelium consists of ciliated, brush, goblet, granular and basal cells resting on a thick basement membrane and solitary chemosensory cells [2]. Epithelial cells release cytokines that activate epithelial cells, mast cells, macrophages and attract and activate dendritic cells, eosinophils, neutrophils, T and B cells and innate lymphoid cells (ILCs) [3]. A damaged epithelial barrier function along with the activation of DCs, Th2 cells, and ILCs initiate type 2 immune and inflammatory responses related to IL‐4, IL‐5, IL‐13, affecting the production of immunoglobulin E (IgE), and the activation of eosinophils [4].
Mepolizumab and dupilumab are used in the treatment of CRSwNP. Dupilumab is a monoclonal antibody that inhibits IL‐4 signaling through the type I receptor (IL‐4Rα/γc) and both IL‐4 and IL‐13 signaling through the type II receptor (IL‐4Rα/IL‐13Rα). Mepolizumab, is directed against IL‐5, preventing it from binding to the α chain of the receptor on eosinophils, thereby inhibiting IL‐5 signal transduction and limiting the production and survival of eosinophils.
The authors asked the question whether biological treatment affects the sinonasal epithelial and inflow cells and, consequently, improves the sense of smell in CRSwNP patients. In a retrospective, single‐centre cross‐sectional study, 23 patients with CRSwNP were treated with mepolizumab (12 patients, mean age 52.5 ± 17, 100 mg every 28 days) or dupilumab (11 patients, mean age 52.5 ± 17, 300 mg every 14 days) (Data S1). Cytological smears were collected from all patients 3 times, that is, at the beginning and after 3 and 6 months of treatment. 21 patients were also assessed after 9 months.
A cytological smear from the middle part of the left inferior turbinate was evaluated with two staining methods: May‐Grünwald‐Giemsa acc. Romanowsky and hematoxylin and eosin staining. The samples were evaluated at 400× magnification and expressed as the mean of 50 high‐power microscopic fields. Ciliated cells, goblet cells, plasma cells, neutrophils, eosinophils and mast cells were counted.
A significant decrease in the number of eosinophils was found in all the patients during 9 months of treatment with biologicals (p = 0.00067) and in both subgroups of patients treated with mepolizumab or dupilumab (p = 0.0075 and 0.02, respectively). In patients treated with mepolizumab, eosinophils decreased significantly after 3 and 6 months of treatment (p = 0.012 and 0.0077, respectively). In the subgroup of patients treated with dupilumab, eosinophils decreased significantly after 6 and 9 months of treatment (p = 0.036 and 0.028, respectively) (Figure 1).
FIGURE 1.
(a) Changes in ciliated cell (mig.) numbers in nasal cytology in patients treated with mepolizumab. Mig‐0—before treatment, mig‐1—after 3 months of treatment, mig −2—after 6 months of treatment, mig‐3—after 9 months of treatment. (b) Changes in ciliated cell numbers in nasal cytology in patients treated with dupilumab. Mig‐0—before treatment, mig‐1—after 3 months of treatment, mig‐2—after 6 months of treatment, mig −3—after 9 months of treatment. (c) Changes in eosinophil numbers in nasal cytology in patients treated with mepolizumab. Eos‐0—before treatment, eos‐1—after 3 months of treatment, eos‐2—after 6 months of treatment, eos‐3—after 9 months of treatment. (d) Changes in eosinophil numbers in nasal cytology in patients treated with dupilumab. Eos‐0—before treatment, eos‐1—after 3 months of treatment, eos‐2—after 6 months of treatment, eos‐3—after 9 months of treatment.
A significant increase in the number of ciliated cells during 9 months of treatment was found in the whole group of patients (p = 0.012) and in the subgroup of patients treated with mepolizumab (p = 0.021). In both therapeutic groups, there was a significant increase in the number of ciliated cells after 9 months of treatment (p = 0.005 and 0.0125 for mepolizumab and dupilumab treatment, respectively) (Figure 1). The numbers of other cells did not significantly change during treatment.
As ciliated cells are related to smell, changes in smell impairment were also assessed using the visual analogue scale (VAS), in which 10 points indicate maximal smell impairment, and 0 point—normal smell. A significant improvement in the sense of smell was found starting from the first control point, that is, after 3 months of treatment, in both groups, and it continued throughout the whole treatment (Table 1). A significant negative correlation between the number of ciliated cells and smell impairment was also revealed after 3 months in patients treated with mepolizumab (rs = −0.655, p < 0.05). Direct comparisons of the number of ciliated cells and VAS smell scores at baseline and after 3, 6, and 9 months between the two treatment groups revealed no significant differences, except for smell impairment, which was significantly greater after 9 months in patients treated with mepolizumab (p = 0.016) (Data S2). Moreover, a linear regression model including age, sex, blood eosinophil count, presence of asthma, allergic rhinitis, and NSAID hypersensitivity was performed to assess their relationship with the number of ciliated cells in the entire patient cohort, revealing no significant impact.
TABLE 1.
Smell impairment assessed on visual analogue scale, at point 0 (before treatment), point 1—after 3 months, point 2—after 6 months, point 3—after 9 months.
| All patients (n = 23) | Mepolizumab (n = 12) | Dupilumab (n = 11) | |
|---|---|---|---|
| Smell‐0 | 10 (10–10) | 10 (10–10) | 10 (10–10) |
| Smell‐1 | 5 (1–10) | 9.5 (4–10) | 2 (0–5) |
| Smell‐2 | 3 (0–8) | 5 (2.5–10) | 1 (0–5) |
| Smell‐3 | 2 (0–8) | 5 (1–9) | 0 (0–2) |
| p before given points | |||
| Friedman ANOVA | < 0.0001 | 0.0015 | 0.00007 |
| Point 0 vs. point 1 | 0.0006 | 0.028 | 0.0077 |
| Point 0 vs. point 2 | 0.0002 | 0.012 | 0.0051 |
| Point 0 vs. point 3 | 0.0002 | 0.0077 | 0.0077 |
| Point 1 vs. point 2 | 0.0555 | ns | ns |
| Point 1 vs. point 3 | 0.045 | ns | 0.043 |
| Point 2 vs. point 3 | ns | ns | ns |
Note: Data are expressed as median and interquartile range; “ns” means non‐significant.
The authors observed that during biological treatment with mepolizumab and dupilumab, the number of ciliated cells in the nasal mucosa significantly increased, which may be a signal suggesting repair processes after reducing the severity of type 2 inflammation. The increase in the number of ciliated cells was significant for both drugs. Moreover, attention was paid to the presence of inflammatory cell influx, and it was found that the number of eosinophils decreased significantly, slightly earlier in the group treated with mepolizumab. The reduction in eosinophilia can be explained by the direct and indirect effects of the drugs on the proliferation, chemotaxis, and activation of eosinophilic cells.
Geraldi et al. [5], after 1 year of treatment of CRSwNP patients with dupilumab, observed ciliated cells without hyperchromatic supranuclear stria and increased goblet cells, a decrease in the number of eosinophils and mast cells and an increase in the number of neutrophils and bacteria. In the conducted research, apart from an increase in the number of ciliated cells, no significant changes were found in the number of goblet cells, neither in influx cells such as neutrophils. The authors observed a decrease in the number of eosinophils and a significant increase in the number of ciliated cells for both drugs.
The consequence of epithelial regeneration and decrease in eosinophils may be the improved sense of smell observed in our patients. SINUS‐24 and SINUS‐52 studies showed that dupilumab improved the sense of smell and clinical outcomes in CRSwNP patients with anosmia. At week 24, the proportion of patients with anosmia decreased from 80.9% at baseline to 28.5% [6]. In the present study, an improvement in the sense of smell was observed for both drugs.
To the authors' knowledge, this is the first real‐life study which compared the effects of biological treatment of CRSwNP with two drugs in parallel on the building and inflow sinonasal cells together with a subjective olfactory assessment. This is a pilot study, and its main limitation is the small sample size.
Concluding, mepolizumab and dupilumab used in CRSwNP may restore the normal cytological state of the nasal mucosa by increasing the number of ciliated cells and reducing the number of infiltrating cells—eosinophils, which may together contribute to improving the sense of smell.
Author Contributions
All authors reviewed the data and contributed to its interpretation, edited the manuscript, and approved the final submitted version. Specific contributions: G.S.‐M. conception of the study, contributed to methodology, resources, and writing. J.G. original draft, data curation, formal and statistical analysis, and visualization. M.H.‐A., W.Ś. contributed to conceptualization, methodology, resources, and writing. M.O. histopathologic analysis. M.K., M.N.‐U., M.M.‐K. contributed to resources, writing, and editing.
Ethics Statement
Ethical approval was waived by the Local Ethics Committee of Medical University of Silesia. Patients signed informed consent regarding publishing their data.
Conflicts of Interest
G.S.‐M. conducted lectures for GlaxoSmithKline and Sanofi. J.G delivered presentations for AstraZeneca, GlaxoSmithKline, and Chiesi and received support for attending meetings from Sanofi Poland.”
Supporting information
Data S1.
Data S2.
Acknowledgements
The authors have nothing to report. Open Access funding enabled and organized by $BLENDED_DEAL.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Huang Z. Q., Liu J., Sun L. Y., et al., “Updated Epithelial Barrier Dysfunction in Chronic Rhinosinusitis: Targeting Pathophysiology and Treatment Response of Tight Junctions,” Allergy 79, no. 5 (2024): 1146–1165, 10.1111/all.16064. [DOI] [PubMed] [Google Scholar]
- 2. Fokkens W. J., Lund V. J., Hopkins C., et al., “European Position Paper on Rhinosinusitis and Nasal Polyps 2020,” Rhinology 58, no. S29 (2020): 1–464, 10.4193/Rhin20.600. [DOI] [PubMed] [Google Scholar]
- 3. Gon Y. and Hashimoto S., “Role of Airway Epithelial Barrier Dysfunction in Pathogenesis of Asthma,” Allergology International 67, no. 1 (2018): 12–17, 10.1016/j.alit.2017.08.011. [DOI] [PubMed] [Google Scholar]
- 4. Raphael I., Nalawade S., Eagar T. N., and Forsthuber T. G., “T Cell Subsets and Their Signature Cytokines in Autoimmune and Inflammatory Diseases,” Cytokine 74, no. 1 (2015): 5–17, 10.1016/j.cyto.2014.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Gelardi M., Giancaspro R., Quaranta V. N., La Gatta E., Ruzza A., and Cassano M., “Dupilumab's Impact on Nasal Citology: Real Life Experience After 1 Year of Treatment,” American Journal of Otolaryngology 45, no. 4 (2024): 104275, 10.1016/j.amjoto.2024.104275. [DOI] [PubMed] [Google Scholar]
- 6. Lane A. P., Mullol J., Hopkins C., et al., “Dupilumab Improves Sense of Smell and Clinical Outcomes in Patients With Severe Chronic Rhinosinusitis With Nasal Polyps With Anosmia,” Current Medical Research and Opinion 41, no. 1 (2024): 2100396, 10.1080/03007995.2024.2434083. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data S2.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.