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Chronic Rhinosinusitis: Aetiology, Immunology and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 35643

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Dr. Seung-Heon Shin

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Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
Interests: mucosal immunity; airway inflammation; epithelial cell biology; eosinophils; fungal infection
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Dear Colleagues,

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. However, the pathophysiology of CRS is not fully understood, and it has limited treatment options with heterogeneous disease groups.

CRS had been considered an infectious disease, with the focus being placed on identifying the pathogenic microbial organisms. However, recent studies have suggested that CRS may be related to immune-mediated diseases, the involvement of which may cause the exacerbation of local inflammatory responses. CRS is classified as eosinophilic or non-eosinophilic CRS based on the dominant inflammatory cell types. CRS can also be divided into Th1-, Th2-, and Th17-dominant CRS based on the presence of lymphocyte effector cells in sinonasal mucosa. Many researchers have tried to determine the pathogenesis of CRS by identifying key chemical mediators or transcription factors and using various animal models. In this regard, many efforts are being made to elucidate the immunopathologic mechanism of CRS. Because the CRS is a sinonasal mucosal inflammatory disease, surgical treatment has limitations. Biologics are attracting attention as a new therapeutic strategy for CRS.

This Special Issue will focus on the advances in the field of mucosal immunity and their impact on our understanding of the development of CRS and immunologic effects of biologics for the treatment of CRS. IJMS is a journal of molecular science, so the pure clinical studies are not suitbable and biomolcular experimental studies are welcome.

Dr. Seung-Heon Shin
Guest Editor

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Keywords

innate immunity
adaptive immunity
protease
cytokine
inflammation
epithelial cells
fibroblasts
eosinophils
lymphocytes
biologics

Related Special Issue

Chronic Rhinosinusitis: Aetiology, Immunology and Treatment 3.0 in International Journal of Molecular Sciences

Published Papers (13 papers)

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Research

Jump to: Review

16 pages, 2745 KiB

Open AccessArticle

Transcriptomic Differentiation of Phenotypes in Chronic Rhinosinusitis and Its Implications for Understanding the Underlying Mechanisms

by Jure Urbančič, Tanja Košak Soklič, Ajda Demšar Luzar, Irena Hočevar Boltežar, Peter Korošec and Matija Rijavec

Int. J. Mol. Sci. 2023, 24(6), 5541; https://doi.org/10.3390/ijms24065541 - 14 Mar 2023

Cited by 2 | Viewed by 1911

Abstract

Chronic rhinosinusitis (CRS) is a multifaceted disease with variable clinical courses and outcomes. We aimed to determine CRS-associated nasal-tissue transcriptome in clinically well-characterized and phenotyped individuals, to gain a novel insight into the biological pathways of the disease. RNA-sequencing of tissue samples of patients with CRS with polyps (CRSwNP), without polyps (CRSsNP), and controls were performed. Characterization of differently expressed genes (DEGs) and functional and pathway analysis was undertaken. We identified 782 common CRS-associated nasal-tissue DEGs, while 375 and 328 DEGs were CRSwNP- and CRSsNP-specific, respectively. Common key DEGs were found to be involved in dendritic cell maturation, the neuroinflammation pathway, and the inhibition of the matrix metalloproteinases. Distinct CRSwNP-specific DEGs were involved in NF-kβ canonical pathways, Toll-like receptor signaling, HIF1α regulation, and the Th2 pathway. CRSsNP involved the NFAT pathway and changes in the calcium pathway. Our findings offer new insights into the common and distinct molecular mechanisms underlying CRSwNP and CRSsNP, providing further understanding of the complex pathophysiology of the CRS, with future research directions for novel treatment strategies. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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12 pages, 2758 KiB

Open AccessArticle

Efficacy of Low-Level Laser Therapy in a Rabbit Model of Rhinosinusitis

by Seok-Rae Park, Younghwan Han, Su Jeong Lee and Ki-Il Lee

Int. J. Mol. Sci. 2023, 24(1), 760; https://doi.org/10.3390/ijms24010760 - 1 Jan 2023

Cited by 2 | Viewed by 1932

Abstract

Little is known about alternative treatment options for rhinosinusitis (RS). We aimed to evaluate the efficacy of low-level laser therapy (LLLT) for RS in experimentally induced rabbit models of RS. A total of 18 rabbits were divided into four groups: a negative control group (n = 3), an RS group without treatment (n = 5, positive control group), an RS group with natural recovery (n = 5, natural recovery group), and an RS group with laser irradiation (n = 5, laser-treated group). Computed tomography and histopathological staining were performed for each group. mRNA and protein expression levels of local cytokines (IFN-γ, IL-17, and IL-5) were also measured. Tissue inflammation revealed a significant improvement in the laser-treated group compared with the RS and natural recovery groups (p < 0.01). In addition, sinus opacification in the CT scans and cytokine expression was reduced in the laser-treated group, though without statistical significance. LLLT could be an effective option for the management of RS concerning radiological, histological, and molecular parameters. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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12 pages, 3849 KiB

Open AccessArticle

CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation

by Hanh Hong Chu, Yoshiki Kobayashi, Dan Van Bui, Yasutaka Yun, Linh Manh Nguyen, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako, Akira Kanda and Hiroshi Iwai

Int. J. Mol. Sci. 2022, 23(24), 16149; https://doi.org/10.3390/ijms232416149 - 18 Dec 2022

Cited by 6 | Viewed by 2197

Abstract

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β—a specific ligand for CCR5 receptors—was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression—a marker of activated eosinophils—as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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12 pages, 1747 KiB

Open AccessArticle

Deep Association between Transglutaminase 1 and Tissue Eosinophil Infiltration Leading to Nasal Polyp Formation and/or Maintenance with Fibrin Polymerization in Chronic Rhinosinusitis with Nasal Polyps

by Toru Sonoyama, Takashi Ishino, Kota Takemoto, Kensuke Yamato, Takashi Oda, Manabu Nishida, Yuichiro Horibe, Nobuyuki Chikuie, Takashi Kono, Takayuki Taruya, Takao Hamamoto, Tsutomu Ueda and Sachio Takeno

Int. J. Mol. Sci. 2022, 23(21), 12955; https://doi.org/10.3390/ijms232112955 - 26 Oct 2022

Cited by 1 | Viewed by 1185

Abstract

Transglutaminase (TGM) isoform catalyze the cross-linking reaction of identical or different substrate proteins. Eosinophil has been recognized in chronic rhinosinusitis with nasal polyps (CRSwNP) forming tissue eosinophil in nasal polyp (NP), and TGM isoforms are suggested to be associated with a critical role in asthma and other allergic conditions. The aim of this study was to reveal the association of specific TGM isoform with both the tissue eosinophil infiltration deeply concerning with the intractable severity of CRSwNP and the fibrin polymerization ability of TGM isoform associated with the tissue eosinophil infiltration, which lead to NP formation and/or maintenance in CRSwNP. NP tissues (CRSwNP group) and uncinate process (UP) (control group) were collected from patients with CRSwNP and control subjects. We examined: (1) the expression level of TGM isoforms by using a real-time polymerase chain reaction (PCR) and the comparison to the issue eosinophil count in the CRSwNP group, (2) the location of specific TGM isoform in the mucosal tissue using immunohistochemistry, (3) the inflammatory cell showing the colocalization of specific TGM isoform in Laser Scanning Confocal Microscopy (LSCM) imaging, and (4) the fibrin polymerase activity of specific TGM isoform using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A certain level of TGM 1, 2, 3, 5 expression was present in both the CRSwNP group and the control group. Only TGM 1 expression showed a positive significant correlation with the tissue eosinophil count in the CRSwNP group. The localization of TGM 1 in NP (CRSwNP) laid mainly in a submucosal layer as inflammatory cells and was at the cytoplasm in the tissue eosinophil. Fibrin polymerase activity of TGM 1 showed the same polymerase ability of factor XIIIA. TGM 1 might influence the NP formation and/or maintenance in CRSwNP related to the tissue eosinophil infiltration, which formed fibrin mesh composing NP stroma. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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22 pages, 2633 KiB

Open AccessArticle

Distinct Gene Set Enrichment Profiles in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Bulk RNA Barcoding and Sequencing

by Takashi Ishino, Sachio Takeno, Kota Takemoto, Kensuke Yamato, Takashi Oda, Manabu Nishida, Yuichiro Horibe, Nobuyuki Chikuie, Takashi Kono, Takayuki Taruya, Takao Hamamoto and Tsutomu Ueda

Int. J. Mol. Sci. 2022, 23(10), 5653; https://doi.org/10.3390/ijms23105653 - 18 May 2022

Cited by 6 | Viewed by 2203

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high symptom burden, including nasal congestion and smell disorders. This study performed a detailed transcriptomic analysis in CRSwNP classified as eosinophilic CRS (ECRS), nonECRS according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, and a group of ECRS with comorbid aspirin intolerant asthma (Asp). Gene expression profiles of nasal polyps and the uncinate process in CRSwNP patients and normal subjects (controls) were generated by bulk RNA barcoding and sequencing (BRB-seq). A differentially expressed genes (DEGs) analysis was performed using DESeq2 software in iDEP to clarify any relationship between gene expression and disease backgrounds. A total of 3004 genes were identified by DEGs analysis to be associated with ECRS vs control, nonECRS vs control, and Asp vs control. A pathway analysis showed distinct profiles between the groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed distinct phenotype-specific pathways of expressed genes. In the specific pathway of “cytokine–cytokine receptor interaction”, the differentially expressed genes were widely distributed. This study indicates that transcriptome analysis using BRB-seq may be a valuable tool to explore the pathogenesis of type 2 inflammation in CRSwNP. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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10 pages, 1446 KiB

Open AccessArticle

Asian Sand Dust Particles Enhance the Development of Aspergillus fumigatus Biofilm on Nasal Epithelial Cells

by Seung-Heon Shin, Mi-Kyung Ye, Dong-Won Lee and Mi-Hyun Chae

Int. J. Mol. Sci. 2022, 23(6), 3030; https://doi.org/10.3390/ijms23063030 - 11 Mar 2022

Cited by 4 | Viewed by 1796

Abstract

Background: Asian sand dust (ASD) and Aspergillus fumigatus are known risk factors for airway mucosal inflammatory diseases. Bacterial and fungal biofilms commonly coexist in chronic rhinosinusitis and fungus balls. We evaluated the effects of ASD on the development of A. fumigatus biofilm formation on nasal epithelial cells. Methods: Primary nasal epithelial cells were cultured with A. fumigatus conidia with or without ASD for 72 h. The production of interleukin (IL)-6, IL-8, and transforming growth factor (TGF)-β1 from nasal epithelial cells was determined by the enzyme-linked immunosorbent assay. The effects of ASD on A. fumigatus biofilm formation were determined using crystal violet, concanavalin A, safranin staining, and confocal scanning laser microscopy. Results: ASD and A. fumigatus significantly enhanced the production of IL-6 and IL-8 from nasal epithelial cells. By coculturing A. fumigatus with ASD, the dry weight and safranin staining of the fungal biofilms significantly increased in a time-dependent manner. However, the increased level of crystal violet and concanavalin A stain decreased after 72 h of incubation. Conclusions: ASD and A. fumigatus induced the production of inflammatory chemical mediators from nasal epithelial cells. The exposure of A. fumigatus to ASD enhanced the formation of biofilms. The coexistence of ASD and A. fumigatus may increase the development of fungal biofilms and fungal inflammatory diseases in the sinonasal mucosa. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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Review

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14 pages, 1763 KiB

Open AccessReview

The Mechanism of Action and Clinical Efficacy of Low-Dose Long-Term Macrolide Therapy in Chronic Rhinosinusitis

by Gwanghui Ryu, Eunkyu Lee, Song I Park, Minhae Park, Sang Duk Hong, Yong Gi Jung and Hyo Yeol Kim

Int. J. Mol. Sci. 2023, 24(11), 9489; https://doi.org/10.3390/ijms24119489 - 30 May 2023

Cited by 1 | Viewed by 3128

Abstract

Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for chronic rhinosinusitis (CRS) due to their immunomodulatory and anti-inflammatory actions. Currently, various immunomodulatory mechanisms of the LDLT macrolide treatment have been reported, as well as their antimicrobial properties. Several mechanisms have already been identified in CRS, including reduced cytokines such as interleukin (IL)-8, IL-6, IL-1β, tumor necrosis factor-α, transforming growth factor-β, inhibition of neutrophil recruitment, decreased mucus secretion, and increased mucociliary transport. Although some evidence of effectiveness for CRS has been published, the efficacy of this therapy has been inconsistent across clinical studies. LDLT macrolides are generally believed to act on the non-type 2 inflammatory endotype of CRS. However, the effectiveness of LDLT macrolide treatment in CRS is still controversial. Here, we reviewed the immunological mechanisms related to CRS in LDLT macrolide therapy and the treatment effects according to the clinical situation of CRS. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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20 pages, 1439 KiB

Open AccessReview

Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications

by Ara Jo and Dae Woo Kim

Int. J. Mol. Sci. 2023, 24(5), 5034; https://doi.org/10.3390/ijms24055034 - 6 Mar 2023

Cited by 14 | Viewed by 5073

Abstract

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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14 pages, 314 KiB

Open AccessReview

Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence

by Sung-Dong Kim and Kyu-Sup Cho

Int. J. Mol. Sci. 2023, 24(5), 5015; https://doi.org/10.3390/ijms24055015 - 6 Mar 2023

Cited by 3 | Viewed by 2709

Abstract

Chronic rhinosinusitis (CRS) is recognized as a heterogeneous disease with a wide range of clinical features, resulting in significant morbidity and cost to the healthcare system. While the phenotypic classification is determined by the presence or absence of nasal polyps and comorbidities, the endotype classification has been established based on molecular biomarkers or specific mechanisms. Research on CRS has now developed based on information based on three major endotypes: types 1, 2, and 3. Recently, biological therapies targeting type 2 inflammation have been clinically expanded and may be applied to other inflammatory endotypes in the future. The purpose of this review is to discuss the treatment options according to the type of CRS and summarize recent studies on new therapeutic approaches for patients with uncontrolled CRS with nasal polyps. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

13 pages, 528 KiB

Open AccessReview

Immunopathologic Role of Fungi in Chronic Rhinosinusitis

by Seung-Heon Shin, Mi-Kyung Ye, Dong-Won Lee and Sang-Yen Geum

Int. J. Mol. Sci. 2023, 24(3), 2366; https://doi.org/10.3390/ijms24032366 - 25 Jan 2023

Cited by 6 | Viewed by 1989

Abstract

Airborne fungi are ubiquitous in the environment and are commonly associated with airway inflammatory diseases. The innate immune defense system eliminates most inhaled fungi. However, some influence the development of chronic rhinosinusitis. Fungal CRS is thought of as not a common disease, and its incidence increases over time. Fungi are present in CRS patients and in healthy sinonasal mucosa. Although the immunological mechanisms have not been entirely explained, CRS patients may exhibit different immune responses than healthy people against airborne fungi. Fungi can induce Th1 and Th2 immune responses. In CRS, Th2-related immune responses against fungi are associated with pattern recognition receptors in nasal epithelial cells, the production of inflammatory cytokines and chemokines from nasal epithelial cells, and interaction with innate type 2 cells, lymphocytes, and inflammatory cells. Fungi also interact with neutrophils and eosinophils and induce neutrophil extracellular traps (NETs) and eosinophil extracellular traps (EETs). NETs and EETs are associated with antifungal properties and aggravation of chronic inflammation in CRS by releasing intracellular granule proteins. Fungal and bacterial biofilms are commonly found in CRS and may support chronic and recalcitrant CRS infection. The fungal–bacterial interaction in the sinonasal mucosa could affect the survival and virulence of fungi and bacteria and host immune responses. The interaction between the mycobiome and microbiome may also influence the host immune response, impacting local inflammation and chronicity. Although the exact immunopathologic role of fungi in the pathogenesis of CRS is not completely understood, they contribute to the development of sinonasal inflammatory responses in CRS. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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13 pages, 2692 KiB

Open AccessReview

Immunopathologic Role of Eosinophils in Eosinophilic Chronic Rhinosinusitis

by Seung-Heon Shin, Mi-Kyung Ye, Jinwoo Park and Sang-Yen Geum

Int. J. Mol. Sci. 2022, 23(21), 13313; https://doi.org/10.3390/ijms232113313 - 1 Nov 2022

Cited by 6 | Viewed by 2848

Abstract

Chronic rhinosinusitis (CRS) is a diverse chronic inflammatory disease of the sinonasal mucosa. CRS manifests itself in a variety of clinical and immunologic patterns. The histological hallmark of eosinophilic CRS (ECRS) is eosinophil infiltration. ECRS is associated with severe disease severity, increased comorbidity, and a higher recurrence rate, as well as thick mucus production. Eosinophils play an important role in these ECRS clinical characteristics. Eosinophils are multipotential effector cells that contribute to host defense against nonphagocytable pathogens, as well as allergic and nonallergic inflammatory diseases. Eosinophils interact with Staphylococcus aureus, Staphylococcal enterotoxin B, and fungi, all of which were found in the tissue of CRS patients. These interactions activate Th2 immune responses in the sinonasal mucosa and exacerbate local inflammation. Activated eosinophils were discovered not only in the tissue but also in the sinonasal cavity secretion. Eosinophil extracellular traps (EETs) are extracellular microbes trapping and killing structures found in the secretions of CRS patients with intact granule protein and filamentous chromatic structures. At the same time, EET has a negative effect by causing an epithelial barrier defect. Eosinophils also influence the local tissue microenvironment by exchanging signals with other immune cells and structural cells. As a result, eosinophils are multifaceted leukocytes that contribute to various physiologic and pathologic processes of the upper respiratory mucosal immune system. The goal of this review is to summarize recent research on the immunopathologic properties and immunologic role of eosinophils in CRS. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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12 pages, 967 KiB

Open AccessReview

Therapeutic Strategies of Biologics in Chronic Rhinosinusitis: Current Options and Future Targets

by Junhu Tai, Munsoo Han and Tae Hoon Kim

Int. J. Mol. Sci. 2022, 23(10), 5523; https://doi.org/10.3390/ijms23105523 - 15 May 2022

Cited by 12 | Viewed by 3895

Abstract

Chronic rhinosinusitis is a chronic inflammatory disease of the upper airways, for which treatment options include medical or surgical therapy. However, there are limitations to conservative treatment strategies, such as the relapse of nasal polyps. In this review, we discuss the rising role of biomolecular mechanisms associated with various biologics that have been approved or are undergoing clinical trials to treat chronic rhinosinusitis. We also highlight the potential molecular therapeutic targets for managing and treating chronic rhinosinusitis. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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16 pages, 727 KiB

Open AccessReview

Cytokine Signature and Involvement in Chronic Rhinosinusitis with Nasal Polyps

by Florent Carsuzaa, Émilie Béquignon, Xavier Dufour, Guillaume de Bonnecaze, Jean-Claude Lecron and Laure Favot

Int. J. Mol. Sci. 2022, 23(1), 417; https://doi.org/10.3390/ijms23010417 - 30 Dec 2021

Cited by 22 | Viewed by 3576

Abstract

Cytokines are well known to play a central role in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly in maintenance of the inflammatory response and the recruitment of eosinophils. The pathophysiological concepts concerning the involvement of inflammatory cytokines in CRSwNP have gradually evolved. Although the Th2 cytokines environment associated with an eosinophilic infiltration has retained a central role in the genesis of polyps, the role of other cytokine subpopulations has also and more recently been detailed, leading to a specific and complex signature in CRSwNP. The purpose of this review is to summarize the current state of knowledge about the cytokine signature in CRSwNP, the role of cytokines in the pathogenesis of this disease and in the intercellular dialog between epithelial cells, fibroblasts and inflammatory cells. Knowledge of this precise cytokine signature in CRSwNP is fundamental in the perspective of potential targeting biotherapies. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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