Biological treatment of chronic rhinosinusitis with polyps increases number of nasal ciliated cells -- real-life experience

Biological treatment of chronic rhinosinusitis with polyps increases number of nasal ciliated cells -- real-life experience | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 28 January 2025 V1 Latest version Share on Biological treatment of chronic rhinosinusitis with polyps increases number of nasal ciliated cells -- real-life experience Authors : Grażyna Stryjewska- Makuch , Maria Humeniuk-Arasiewicz , Magdalena Onyszczuk , Magdalena Kokoszka 0000-0001-8091-2840 [email protected] , Marcelina Niemiec-Urbańczyk , Marta Michalak-Kolarz , Wojciech Ścierski , Radoslaw Gawlik , and Joanna Gluck Authors Info & Affiliations https://doi.org/10.22541/au.173809430.05142144/v1 197 views 137 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Chronic rhinosinusitis (CRS) is a complex, multifactorial inflammatory disease of the nasal mucosa and paranasal sinuses, in which disruption of the integrity of the mucosal barrier initiates an inflammatory cascade. It results, among other things, in the formation of polyps, increased secretion and impaired sense of smell. The aim of the study was to investigate the effect of biological treatment with mepolizumab or dupilumab on the cytological examination of the nasal mucosa in CRSwNP patients. The study included 23 patients who underwent cytological examinations at least 3 times during 6 months of treatment. 21 patients were treated for 9 months. Samples were evaluated at 400x magnification and expressed as the mean of 50 high-power microscopic fields (HPF) that had been assessed. Ciliated cells, goblet cells, plasma cells, neutrophils, eosinophils and mast cells were counted. All patients had their sense of smell tested every 3 months using a visual analogue scale (VAS). During biological treatment of CRSwNP patients with mepolizumab and dupilumab, cytological examinations revealed an increase in the number of ciliated cells, a decrease in the number of eosinophils correlated with an improvement in the sense of smell on the VAS scale. \received DD MMMM YYYY \acceptedDD MMMM YYYY Title: Biological treatment of chronic rhinosinusitis with polyps increases number of nasal ciliated cells – real-life experience Short Title: Biological Treatment of CRSwNP- ciliated cells Authors: Grażyna Stryjewska- Makuch 1 , Maria Humeniuk-Arasiewicz 1 , Magdalena Onyszczuk 2,3 , Magdalena Kokoszka 4 , Marcelina Niemiec-Urbańczyk 1 , Marta Michalak-Kolarz 1 , Wojciech Ścierski 5 , Radosław Gawlik 6 , Joanna Gluck 6 ORCID: Grażyna Stryjewska-Makuch https://orcid.org/0000-0001-7967-6887 Maria Humeniuk-Arasiewicz https://orcid.org/0009-0008-9563-4589 Magdalena Onyszczuk https://orcid.org/0000-0001-7704-1124 Magdalena Kokoszka https://orcid.org/0000-0001-8091-2840 Marcelina Niemiec-Urbańczyk https://orcid.org/0000-0003-4507-5113 Marta Michalak-Kolarz https://orcid.org/0009-0002-8164-1151 Wojciech Ścierski https://orcid.org/0000-0003-3242-8047 Radosław Gawlik https://orcid.org/0000-0002-8537-9165 Joanna Gluck https://orcid.org/0000-0001-6339-9053 Affiliations: 1 Department of Laryngology and Laryngological Oncology, Leszek Giec Upper-Silesian Medical Centre of the Silesian Medical University, Katowice, Poland 2 Department and Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland 3 Department of Pathomorphology, Leszek Giec Upper-Silesian Medical Centre of the Medical University of Silesia, Katowice, Poland 4 Department of Pediatric Otolaryngology, Head and Neck Surgery, Department of Pediatric Surgery, Faculty of Medical Sciences, Medical University of Silesia, Katowice, Poland 5 Department of Otorhinolaryngology and Laryngological Oncology in Zabrze, Medical University of Silesia, Katowice, Poland 6 Clinical Department of Internal Diseases, Allergology and Clinical Immunology in Katowice, Medical University of Silesia, Katowice, Poland ACKNOWLEDGEMENTS: Not applicable. Abstract Chronic rhinosinusitis (CRS) is a complex, multifactorial inflammatory disease of the nasal mucosa and paranasal sinuses, in which disruption of the integrity of the mucosal barrier initiates an inflammatory cascade. It results, among other things, in the formation of polyps, increased secretion and impaired sense of smell. The aim of the study was to investigate the effect of biological treatment with mepolizumab or dupilumab on the cytological examination of the nasal mucosa in CRSwNP patients. The study included 23 patients who underwent cytological examinations at least 3 times during 6 months of treatment. 21 patients were treated for 9 months. Samples were evaluated at 400x magnification and expressed as the mean of 50 high-power microscopic fields (HPF) that had been assessed. Ciliated cells, goblet cells, plasma cells, neutrophils, eosinophils and mast cells were counted. All patients had their sense of smell tested every 3 months using a visual analogue scale (VAS). During biological treatment of CRSwNP patients with mepolizumab and dupilumab, cytological examinations revealed an increase in the number of ciliated cells, a decrease in the number of eosinophils correlated with an improvement in the sense of smell on the VAS scale. Keywords: biological treatment, CRSwNP, nasal cytology. 1 | Introduction Chronic rhinosinusitis (CRS) is a complex, multifactorial inflammatory disease of the nasal mucosa and paranasal sinuses, the diagnosis of which is based on the criteria set out in the European Position Paper on Rhinosinusitis 2020 (EPOS) [1]. Pathogenesis of primary, bilateral, uncontrolled rhinosinusitis with polyps (CRSwNP) involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, impaired immune response, and excessive tissue remodelling [2]. Within the nasal cavity and paranasal sinuses, there is an epithelium consisting of ciliated, brush, goblet, granular and basal cells resting on a thick basement membrane. In the olfactory part, apart from olfactory cells, there are supporting and basal cells as well as Bowman’s glands. Additionally, solitary chemosensory cells have been identified in the sinonasal epithelium, playing a role in T2 immunity [1, 3]. The neural function influenced by infection and the immune system also contributes to CRSwNP pathogenesis, including olfactory loss, with dysfunctional innervation and neuropeptides playing significant roles [4]. The impairment of the epithelial barrier function facilitates the activation of the underlying immune system and subsequently leads to chronic inflammation [5]. Epithelial cells release inflammatory cytokines, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, alarmins, and several chemokines that activate epithelial cells, mast cells, macrophages and attract and activate dendritic cells (DCs), eosinophils, neutrophils, T and B cells and innate lymphoid cells (ILCs) [6,7]. 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), the activation of macrophages via the alternative pathway and the activation of eosinophilia [8]. The possibility of precise, personalized treatment of CRSwNP allows for limiting the inflammatory process and improving the quality of life of patients. Thanks to knowing the pathomechanism of inflammation in CRSwNP, mepolizumab and dupilumab were introduced into the treatment. Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits IL-4 signalling through the type I receptor (IL-4Rα/γc) and both IL-4 and IL-13 signalling through the type II receptor (IL-4Rα/IL-13Rα). Mepolizumab, an IgG1 kappa monoclonal antibody, 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 with mepolizumab or dupilumab affects the epithelial and inflow cells of the nasal mucosa and, consequently, improves the sense of smell in CRSwNP patients. 2 | Material and methods We performed a retrospective, single-centre cross-sectional study of CRSwNP patients treated with mepolizumab or dupilumab who were recruited in accordance with the EPOS/EUFOREA 2023 guidelines from March 2023 to November 2024. The patients received mepolizumab at a dose of 100 mg every 28 days and dupilumab at a dose of 300 mg every 14 days. Cytological smears were collected from all treated patients on the day of administration of the first dose of the drug, and thereafter every 3 months. 23 patients were qualified for the study. Each patient had cytological examination performed at least 3 times, i.e., when starting the treatment, after 3 and 6 months of treatment. 21 patients were also assessed after 9 months. 12 patients were treated with mepolizumab (6 females [50%], mean age 52.5±17), and 11 patients with dupilumab (6 females [54%], mean age 46.2±8). All patients took intranasal steroids at a dose of 200 mcg daily. At least 12 weeks before the initiation of biological treatment, patients did not receive treatment with systemic steroids. A cytological smear was taken from the middle part of the left inferior turbinate. The material was collected with a cytobrush with a straight tip and a smear was made on two glass slides, one of which was fixed with Cytofix. Two staining methods were used for cytological evaluation: May-Grünwald-Giemsa acc. Romanowsky and hematoxylin and eosin staining. The samples were evaluated at 400x magnification and expressed as the mean of 50 high-power microscopic fields (HPF) that had been assessed. Ciliated cells, goblet cells, plasma cells, neutrophils, eosinophils and mast cells were counted. The results are expressed as mean ± standard deviations (if normally distributed) or median and interquartile range (if not normally distributed). Normality was checked using the Shapiro-Wilk test. Quantitative variables were compared with nonparametric Wilcoxon signed-rank or Friedman ANOVA tests because of the low number of subjects. Correlations were assessed with Spearman’s rank test. All analyses were performed with a software package (The STATISTICA 13.3, StatSoft Poland). P values less than 0.05 were considered significant. The study had a retrospective design. The patients consented to the proposed routine procedures upon hospital admission. The consent of the Bioethics Committee was not required. 3 | Results 3.1 | Nasal eosinophils A significant decrease in the number of eosinophils was found in all the patients during 9 months of treatment with biologicals (p=0.00067, Friedman ANOVA) and in both subgroups of patients treated with mepolizumab or dupilumab (p=0.0075 and 0.02, respectively, Friedman ANOVA). In the subgroup of patients treated with mepolizumab, there was a significant decrease in the number of eosinophils after three and six months of treatment (p=0.012 and 0.0077, respectively, Wilcoxon signed-rank test). In the subgroup of patients treated with dupilumab, there was a significant decrease in the number of eosinophils after six and nine months of treatment (p=0.036 and 0.028, respectively, Wilcoxon signed-rank test) (Fig 1-2, Tab. 1). 3.2 | Nasal Ciliated Cells 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, Friedman ANOVA) and in the subgroup of patients treated with mepolizumab (p=0.021, Friedman ANOVA). In both therapeutic groups, there was a significant increase in the number of ciliated cells after nine months of treatment (p =0.005 and 0.0125 for mepolizumab and dupilumab treatment, respectively, Wilcoxon signed-rank). The test results are presented for the entire study group and divided into drugs used (Fig. 3-4, Table 1). 3.3 | Stability in Other Nasal Cell Types The numbers of other cells did not significantly change during treatment. 3.4 | Assessment of Smell Impairment 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, i.e. after three months of treatment, in both groups, and it continued throughout the whole treatment (Tab. 2). A significant negative correlation between the number of ciliated cells and smell impairment was also revealed after three months in patients treated with mepolizumab (rs=-0.655, p<0.05). 4 | Discussion 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. However, it was higher in patients treated with mepolizumab. Moreover, attention was paid to the presence of inflammatory cell influx (eosinophils, neutrophils, mast cells, plasma cells) in the nasal mucosa, and it was found that the number of eosinophils in the cytological image decreased significantly during treatment, slightly earlier in the group treated with mepolizumab. The reduction in eosinophilia can be explained by the direct and indirect effects of drugs on the proliferation, chemotaxis and activation of eosinophilic cells. In healthy subjects without any diseases of the nasal cavity, cytological examinations show ciliated cells, mucinous cells, basal cells/striated cells; only sparse neutrophils can be found occasionally. The normal ciliated/mucinous cell rate is around 4:1 [9]. From a cytological viewpoint, any damage of the nasal mucosa firstly affects ciliated cells, with an architectural rearrangement that favours mucinous cells (mucinous metaplasia) [10]. Geraldi [11], after 1 year of treatment of CRSwNP patients with dupilumab, observed ciliated cells without hyperchromatic supranuclear stria (SNS) and increased goblet cells. Moreover, he noted a decrease in the number of eosinophils and mast cells in cytological smears 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. The authors of the study also observed the presence of neutrophils in cytological images. However, there was no significant increase in the number of neutrophils during treatment. It seems that the consequence of epithelial regeneration and the decrease in eosinophils is the improved sense of smell observed in the treated patients. There are reports in the literature that improved sense of smell was observed in more than half of patients with CRSwNP after just 28 days of treatment with dupilumab [12]. According to the results of the SINUS-24 and SINUS-52 studies, dupilumab improved the sense of smell and clinical outcomes in patients with severe chronic rhinosinusitis with nasal polyps with anosmia. At week 24, the proportion of patients with anosmia decreased from 80.9% at baseline to 28.5% [13]. These findings are consistent with a recent real-world study in patients with severe CRSwNP that reported an anosmia rate of 70% [14]. The causes of olfactory impairment are unclear; it has been found that the higher the levels of type 2 inflammation biomarkers, the more often anosmia occurs [15,16]. 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 patients with two drugs in parallel on the building and inflow cells of the nasal mucosa and used a subjective olfactory test. The limitation of the study is the small study group, because patients were enrolled in the treatment over an 18-month period and not all of them achieved the planned follow-up period. 5 | Conclusions Biological treatment with mepolizumab and dupilumab in CRSwNP patients may restore the normal cytological image 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. TABLE 1. Number of ciliated cells (Mig) and eosinophils (Eos) assessed at point 0 (before treatment), point 1 – after three months, point 2 – after six months, point 3 – after nine months. Data for ciliated cells are expressed as mean standard deviations, data for number of eosinophils as median and interquartile range, “ns” means non-significant. Mig-0 33.9 ± 15 34.9 ± 17.7 32.9 ± 12.2 Mig-1 35.1 ± 24.2 35.4 ± 25.5 34.8 ± 23 Mig-2 56.5 ± 40.3 58.7 ± 41.6 54.2 ± 40.8 Mig-3 58.9 ± 24.3 58.7 ± 25.9 50.6 ± 23 Friedman ANOVA 0.012 0.021 0.49 Point 0 vs point 1 ns ns ns Point 0 vs point 2 0.033 ns ns Point 0 vs point 3 0.0004 0.005 0.0125 Point 1 vs point 2 ns ns ns Point 1 vs point 3 0.003 0.007 ns Point 2 vs point 3 ns ns ns Eos-0 4 (1-7) 3.5 (1-10) 4 (1-5) Eos-1 1 (1-2) 1 (0-1.5) (1–2) Eos-2 1 (0-1) 0 (0-1) 1 (0-1) Eos-3 1 (0-1) 0 (0-1) 0 (0-1) Friedman ANOVA 0.00067 0.0075 0.02 Point 0 vs point 1 0.02 0.012 ns Point 0 vs point 2 0.0008 0.0077 0.036 Point 0 vs point 3 0.012 ns 0.028 Point 1 vs point 2 ns ns ns Point 1 vs point 3 ns ns 0.028 Point 2 vs point 3 ns ns ns TABLE 2. Smell impairment assessed on visual analogue scale, at point 0 (before treatment), point 1 – after three months, point 2 – after six months, point 3 – after nine months. Data are expressed as median and interquartile range, “ns” means non-significant. 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) 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 References 1. Fokkens WJ, Lund VJ, Hopkins C, et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. (2020)58(Suppl. S29):1-464. doi:10.4193/Rhin20.600 2. Huang ZQ, Liu J, Sun LY, et al. Updated epithelial barrier dysfunction in chronic rhinosinusitis: Targeting pathophysiology and treatment response of tight junctions. Allergy. 2024 May;79(5):1146-1165. doi: 10.1111/all.16064 3. M. A. Kohanski, A. D. Workman, N. N. Patel, et al. Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2018 Aug;142(2):460-469.e7. doi: 10.1016/j.jaci.2018.03.019 4. M. Hoggard, A. Nocera, K. Biswas, M. W. Taylor, R. G. Douglas, and B. S. Bleier. The sinonasal microbiota, neural signaling, and depression in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2018 Mar;8(3):394-405. doi: 10.1002/alr.22074 5. Toppila-Salmi S, Reitsma S, Hox V, et al. Endotyping in Chronic Rhinosinusitis-An EAACI Task Force Report. Allergy. 2025 Jan;80(1):132-147. doi: 10.1111/all.16418 6. Gon Y, Hashimoto S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma. Allergol Int. 2018 Jan;67(1):12-17. doi: 10.1016/j.alit.2017.08.011 7. Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011; 127(3): 701-721.e1-70. doi: 10.1016/j.jaci.2010.11.050 8. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015 Jul;74(1):5-17. doi: 10.1016/j.cyto.2014.09.011 9. Gelardi M, Iannuzzi L, Quaranta N, Landi M, Passalacqua G. NASAL cytology: practical aspects and clinical relevance. Clin Exp Allergy. 2016 Jun;46(6):785-92. doi: 10.1111/cea.12730 10. Gelardi M, Cassano P, Cassano M, Fiorella ML. Nasal cytology: description of a hyperchromatic supranuclear stria as a possible marker for the anatomical and functional integrity of the ciliated cell. Am J Rhinol. 2003 Sep-Oct;17(5):263-8. 11. Gelardi M, Giancaspro R, Quaranta VN, La Gatta E, Ruzza A, Cassano M. Dupilumab’s impact on nasal citology: Real life experience after 1 year of treatment. Am J Otolaryngol. 2024 Jul-Aug;45(4):104275. doi: 10.1016/j.amjoto.2024.104275 12. Otten JJ, Lans RJ, Elzinga HB et al. More than half of chronic rhinosinusitis with nasal polyps (CRSwNP) patients treated with dupilumab experience early and fast olfactory improvement within 28 days. Allergy. 2024 Nov;79(11):3166-3168. doi: 10.1111/all.16357 13. Lane AP, 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. Curr Med Res Opin. 2024 Dec 14:1-7. doi: 10.1080/03007995.2024.2434083 14. De Corso E, Settimi S, Montuori C, et al. Effectiveness of Dupilumab in the Treatment of Patients with Severe Uncontrolled CRSwNP: A ”Real-Life” Observational Study in the First Year of Treatment. J Clin Med. 2022 May 10;11(10):2684. doi: 10.3390/jcm11102684 15. Mullol J, Bachert C, Amin N, et al. Olfactory Outcomes With Dupilumab in Chronic Rhinosinusitis With Nasal Polyps. J Allergy Clin Immunol Pract. 2022 Apr;10(4):1086-1095.e5. doi: 10.1016/j.jaip.2021.09.037 16. Hox V, Bobic S, Callebaux I, Jorissen M, Hellings PW. Nasal obstruction and smell impairment in nasal polyp disease: correlation between objective and subjective parameters. Rhinology. 2010 Dec;48(4):426-32. doi: 10.4193/Rhino10.049 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. FUNDING No funding was received for conducting this study. CONFLICT OF INTEREST STATEMENT G.S-M conducted lectures for GlaxoSmithKline and Sanofi. J.G delivered presentations for AstraZeneca, GlaxoSmithKline and Chiesi. 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Keywords biologics ent (rhinitis nasal polyps...) rhinitis sinusitis Authors Affiliations Grażyna Stryjewska- Makuch Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Maria Humeniuk-Arasiewicz Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Magdalena Onyszczuk Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Magdalena Kokoszka 0000-0001-8091-2840 [email protected] Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Marcelina Niemiec-Urbańczyk Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Marta Michalak-Kolarz Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Wojciech Ścierski Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Radoslaw Gawlik Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Joanna Gluck Slaski Uniwersytet Medyczny w Katowicach View all articles by this author Metrics & Citations Metrics Article Usage 197 views 137 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Grażyna Stryjewska- Makuch, Maria Humeniuk-Arasiewicz, Magdalena Onyszczuk, et al. 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