Next Article in Journal
Role of Ganetespib, an HSP90 Inhibitor, in Cancer Therapy: From Molecular Mechanisms to Clinical Practice
Next Article in Special Issue
Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications
Previous Article in Journal
Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature
Previous Article in Special Issue
Immunopathologic Role of Fungi in Chronic Rhinosinusitis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 5
10.3390/ijms24055015
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

by
Sung-Dong Kim
and
Kyu-Sup Cho
*
Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, 179 Gudeok-Ro, Seo-gu, Busan 602-739, Republic of Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(5), 5015; https://doi.org/10.3390/ijms24055015
Submission received: 31 December 2022 / Revised: 26 February 2023 / Accepted: 3 March 2023 / Published: 6 March 2023
(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)
Review Reports Versions Notes

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.

1. Introduction

Chronic rhinosinusitis (CRS) is a heterogeneous disease with a wide range of clinical features and mechanisms that results in significant morbidity and cost to the healthcare system. CRS affects approximately 3–6% [1,2] of the general population and causes poor quality of life (QOL) and personal productivity in up to 10% of the adult population. CRS leads to more than one million surgical procedures worldwide each year. CRS is diagnosed when there is objective evidence of inflammation or polypoid tissue on endoscopy and CT scans of the sinuses, along with symptoms such as nasal congestion, stuffiness, runny nose, facial pain or tightness, difficulty or loss of smell (anosmia), cough, and fatigue persisting for at least 12 weeks [3].
Although the 2017 European Position Paper on Rhinosinusitis and Nasal Polyposis (EPOS) guidelines divided CRS into two main phenotypes, CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) [3], the new 2020 EPOS guidelines categorize primary CRS into type 2 and non-type 2 [4]. Type 2 includes allergic fungal rhinosinusitis, eosinophilic CRS among CRSwNP, and central compartment allergic diseases [4]. Recently, as studies on biomarkers reflecting biological mechanisms have been conducted, more personalized medicine has become available.
The EPOS guidelines define CRS as controlled, partially controlled, or uncontrolled, on the basis of objectively determining the degree of subjective symptom reduction, mucosal condition, side effects, need for systemic medications, and need for functional endoscopic sinus surgery.
This review aimed to discuss the treatment options according to the type of CRS and, in particular, to summarize recent studies on new therapeutic approaches for patients with uncontrolled CRSwNP.

2. Phenotype and Endotype

The phenotypic classification of CRS is based on clinically observable features, usually distinguished by the presence (CRSwNP) or absence (CRSsNP) of nasal polyps, which are one of the clinically observable features along with discharge in most patients. Patients are typically classified according to the presence or absence of polyps, determine treatment methods, and determine differences in pathological and biological mechanisms. In addition, sub-classification according to comorbidity is used, and asthma and allergy, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and CRS with immunodeficiency are representative [5,6,7,8,9]. This may be related to the unique features of this subgroup of diseases with high rates of local recurrence, low responsiveness to treatment, and high rates of recurrence after surgical intervention.
CRSsNP is characterized by increased levels of pro-inflammatory cytokines (tumor necrosis factor α and interleukin [IL]-1β), type 1-associated cytokines (interferon [IFN]-γ), transforming growth factor β1, and tissue fibrosis [10,11]. Conversely, CRSwNP has histologically severe eosinophil infiltration and increased IgE and T helper 2 (Th2) cytokines, such as IL-4, IL-5, and IL-13 [10,11]. CRSwNP is a relatively common inflammatory disease in asthma patients, with an increased prevalence of 7–15%, especially in 50% of patients with severe asthma [12,13].
CRSwNP shows different histological characteristics and prevalence depending on the geographical region. European and American patients show high expression of eosinophilia and Th2 cytokines, and Asian patients show more neutrophilic tissue inflammation [14,15]. These different patterns of inflammation suggest that a complex relationship between environmental and genetic factors may contribute to determining predominant expression. In Korea and China, the proportion of eosinophilic nasal polyps has increased significantly with rapid industrialization over the past 20 years [16]. In addition to types classified according to the presence or absence of nasal polyps, in some phenotypes, the characteristics of type 1 and type 2 are combined. Depending on the presence or absence of diseases classified into subgroups, each has unique characteristics that are not included in conventional classifications.
Endotypic classification is based on histological features, such as the presence of neutrophilia, eosinophilia, fibrosis, glandular hypertrophy, and epithelial dysplasia in the early studies [17,18,19]. CRSwNP is associated with eosinophils and mast cells, whereas CRSsNP has a relatively high number of neutrophils [20,21].
Recently, a structured histopathological classification system was proposed based on a combination of effector cell invasion and tissue remodeling changes [22]. Although there is current evidence that polyposis reflects the formation of a fibrin matrix, histopathological features have not been defined in the guidelines and remain experimental [23]. In early molecular studies, IL-5 and IgE were biomarkers for eosinophilic CRS, and IL-8 was a biomarker for neutrophilic CRS [24,25]. Tomassen et al. classified 10 endotypes using cluster analysis for the presence of biomarkers for the differential association between endotypes and the existence of phenotypes of nasal polyps or asthma [2]. The 10 endotypes were subdivided into three subgroups according to low IL-5, absence of IL-5, and high IL-5, including CRSwNP-expressing IgE against Staphylococcus aureus enterotoxins [26]. This study accelerated research on biomarkers by theoretically defining treatment methods according to endotypes. The current view of endotypes can be classified into three endotypes based on their inflammatory profiles, which are composed of specific inflammatory mediators and immune cells observed in tissues [27,28]. Although early studies identified distinct features confined to CD4+ T cells, termed Th1, Th2, and Th17, which contribute to the cytokine patterns observed in type 1, type 2, and type 3 inflammatory endotypes, respectively, other types of cells, including innate lymphoid cells and macrophages, can also be classified into type 1, type 2, and/or type 3 inflammatory profiles (Table 1).
Type 1 inflammatory endotypes are characterized by the expression of T1 cytokines such as IFN-γ and IL-12 produced by Th1 cells, cytotoxic T cells, NK cells, and group 1 innate lymphoid cells (ILC1s). In contrast, type 2 inflammatory endotypes are characterized by the expression of T2 cytokines, such as IL-4, IL-5, and IL-13, produced by Th2 cells, eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). More recently, type 3 inflammatory endotypes have been characterized by the expression of regulatory cytokines such as IL-17 and IL-22 produced by Th17 cells and group 3 innate lymphoid cells (ILC3s).
CRSwNP and CRSsNP are not completely dichotomous depending on the presence or absence of polyps and show overlapping signs of inflammation [29,30,31]. There is also a report that type 2 inflammatory endotypes dominate in both types of phenotypes, and microarray analysis also shows strong similarities between different endotypes [29,30,31,32]. In some CRS patients, a mixture of two or more inflammatory endotypes may appear, and certain cytokines may not be significantly expressed [29].
Several studies have reported that the inflammatory endotype of CRS varies geographically worldwide [31,33,34,35]. In the case of CRSwNP, more than 80% of patients in Western countries show elevated levels of T2 cytokines and eosinophils, which are T2 markers, whereas similar rates of type 2 inflammatory endotype and non-type2 such as type 1 and type 3 are found in Asian patients [31,35].
Recent studies have reported that neutrophilic inflammation may play a role in the pathogenesis of nasal polyps in Asia as well as in the West. In particular, an increase in IL-36 in type 2 CRSwNP and IL-36R+ neutrophils in non-type 2 CRSwNP has been reported in China [36,37,38]. This suggests that the role of neutrophils differs depending on the type and may not be an important biomarker that determines the major inflammatory endotype in nasal polyps.
In the case of CRSsNP, type 1 inflammation associated with elevated IFN-γ is dominant, but other follow-up studies have reported heterogeneous inflammatory patterns [11,33]. Type 2 inflammation was reported in 55% of patients in the United States and 33% and 40% in Europe and Australia [31,39]. Type 1 inflammation, characterized by elevated IFNγ, IL-5, or IL-17, has been reported most frequently in China (58%), but the majority of patients have an atypical phenotype without characteristic increases in cytokines [31].
Therefore, CRSsNP, like CRSwNP, has very heterogeneous and geographically diverse endotypes [31,33,34]. Type 1, type 3, or mixed inflammatory endotypes are common in Asian CRSsNP, and there are reports of CRSsNP with type 2 inflammatory endotypes in the West [31,33,34].
Several studies have reported that genetic and environmental factors can also affect the inflammatory endotypes of CRS. Although 87% of CRSwNP patients in the United States had a type 2 inflammatory endotype, second-generation Asian patients residing in the United States had significantly lower nasal polyp eosinophil counts than non-Asians patients [39,40]. However, longitudinal studies of Asian CRS patients have reported that the prevalence of type 2 inflammatory endotypes has increased over the past 20 years, with a westernized environment being an important factor [41,42].
Furthermore, in China, there are differences according to city. In Beijing, 60% of CRSwNP patients showed type 2 inflammatory endotypes, whereas in Chengdu, it was reported in only 20% of cases, suggesting regional variability even in a single country [31].
This suggests that the CRS endotype may vary with geographical location. Further studies on the effects of genetic or environmental factors on the combination of type 1, type 2, or type 3 inflammatory endotypes are needed.

3. Phenotype and Endotype Based Treatment

Although many studies on treatment methods according to phenotype have been reported, reports on the treatment of CRS according to endotype have rarely been performed. This is because the definition of disease recurrence and treatment success is not clear at the CT scan or endoscopy level, and the time points of therapeutic intervention or evaluation are diverse. Despite these limitations, it is necessary to use appropriate pharmacotherapy, surgical approach, or biological agents according to the endotype to prevent repetitive intervention due to recurrence, reduce the risk of disease progression, and tailor treatment for single patients (Table 2).

3.1. Antibiotics

According to existing guidelines, antibiotics, such as macrolides and doxycycline, can be considered for the treatment of CRS [3,43]. However, as several studies have reported, there is no recommendation for antibiotic use for CRS, given the lack of placebo-controlled studies [4,44,45]. Bacterial infections based on the endotype are type 3, which is the rationale for antibiotic use in this setting [10]. More than 50% of CRSsNP patient tissues have a partial type 2 endotype, and CRS patients with type 3 endotypes, including those with cost, are likely to respond well to broad-spectrum antibiotics [33]. In a recent study using 625 mg amoxicillin–clavulanic acid, significant objective and subjective results were reported only in the non-type 2 endotype [46]. Although Staphylococcus aureus has been reported to play an important role in type 2 inflammation in CRS, objective studies on the efficacy of antibiotics based on this have been lacking [47,48].
Macrolides are characterized by antibiotic properties and immunomodulation by the inhibition of inflammatory cytokines [16,45,49] and are considered for long-term use as a CRS treatment based on randomized controlled trials [50,51]. Non-type 2 patients with low serum IgE responded well to treatment and showed significantly reduced IL-8 levels [50]. One study targeting eosinophilic CRSwNP patients also showed a significant therapeutic effect; however, additional research is needed to determine whether the effect is greater when used in combination with steroids and biological agents for significant effects in type 1, type 3, or mixed endotypes [52,53,54,55]. Doxycycline is characterized by its antibiotic properties through the inhibition of cytokines and chemokines. It has a significant effect on reducing the size of polyps and improving symptoms by suppressing the type 2 response caused by Staphylococcus aureus in type 2 CRSwNP patients [56,57,58]. Although additional research is needed, it has been reported that the effect of antibiotic response in CRSwNP patients can be predicted using low type 2 biomarkers [59,60].

3.2. Corticosteroids

Corticosteroids are considered a mainstream treatment for CRS with anti-inflammatory properties, and are more useful for suppressing type 2 inflammation than type 1 or type 3 inflammation, suppressing ILC2s, Th2 cells, basophils, and eosinophils. This therapy has been used in the treatment of CRSwNP patients rather than CRSsNP [61,62,63,64,65]. Neutrophils are relatively resistant to the effects of corticosteroids, and the reduced effect compared to Western CRSwNP, especially in type 3 inflammation, is supported by studies of Asian CRSwNP and CRSsNP patients [66,67,68,69,70,71,72].
Topical corticosteroid sprays are used in conjunction with oral medications to treat CRS. Although access to sinus tissue is limited, drug delivery has been improved with high-volume steroid irrigation or steroid-impregnated implants [73,74,75,76,77]. A recent study reported that the higher the nasal IL-8 level in CRS patients after surgery, the more difficult it is to control inflammation with topical steroids [78].
In CRS, barrier defects can exacerbate inflammation by increasing the antigen access. Furthermore, epithelial barrier remodeling defects or basal cell hyperplasia induced by type 2 inflammation can be partially ameliorated by corticosteroids [79,80,81,82].

3.3. Leukotriene Antagonist

AERD is classified as a type 2 sub-endotype with increased production of prostaglandin D2 (PGD2) and cysteinyl leukotrienes [83]. A recent study reported that PGD2 activates the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), which is important for the recruitment and activation of eosinophils, basophils, and lymphocytes [84].

3.4. Surgery

Surgical treatment can be considered selectively if it does not respond to appropriate pharmacological treatment, and the scope of surgery is controversial [45,85]. Standard endoscopic sinus surgery (ESS) aims to remove inflammatory tissue, ventilate and drain the sinuses, and improve the delivery of topical agents [86]. Although mucus retention due to sinus obstruction promotes microbial overgrowth and infectious inflammation in type 1 and type 3 inflammation, it is relatively less important in CRSwNP and CRSsNP related to type 2 inflammation [87,88].
The important point in standard ESS is to preserve the sinus mucosa as much as possible while extensively dilating the outflow tract of the sinuses and removing the ethmoid lamella, which can cause obstruction [89,90]. The index of successful surgical treatment is the recurrence rate, and the rate of reoperation for 5 years is reportedly 15–20%; the recurrence rate is higher in CRSwNP than in CRSsNP [91]. Although the recurrence rate can be reduced through the use of high-volume corticosteroid nasal irrigation or systemic steroids after surgery, some researchers have reported that more extensive removal of the sinus mucosa, including the floor of the frontal sinus, is required [92,93,94].
Extensive surgery is termed “re-boot” surgery and significant reductions in eosinophilic cationic protein and IL-5 in postoperative nasal secretions have been reported. However, in terms of the endotype, surgical failure is correlated with the presence and intensity of type 2 eosinophilic inflammation and blood eosinophilia [95,96,97,98]. For standard ESS failures, nasalization and Draf III (endoscopic lothrop) can be considered, including re-boot surgery [92,93,94]. The nasalization procedure aggressively removes the middle turbinate and paranasal mucosa to induce healing of normal mucosa. The Draf III procedure maximizes access to the frontal and ethmoid sinuses by removing all the bones and mucosa of the upper part of the middle turbinate and the floor of the frontal sinuses. Re-boot surgery includes both the previous surgeries to remove mucosa in the nasal and paranasal sinuses and the floor of the frontal sinuses [92,93,94]. Although the effectiveness of the aggressive surgical approach is controversial, there are reports of positive results in recurrent or high-risk type 2 type CRSwNP [95]. In addition, there is a potential benefit of improved drug delivery after surgical treatment, and some studies have reported that it is effective in type 1 or type 3 inflammatory endotypes [97].
Several studies have reported on the prediction of surgical outcomes according to endotype. In one study, cluster analysis was performed to determine the correlation between endotypes and treatment outcomes. The treatment outcome was worst when asthma was accompanied by type 2 inflammation, in which IL-5, Immunoglobulin E (IgE), and eosinophils were increased in the nasal mucosa [99]. In another study, the T2 cytokine IL-5 and the type 2 biomarkers periostin and C-C motif chemokine ligand 26 (CCL26) were higher in patients with difficult-to-treat CRSwNP but were not associated with treatment outcome. However, yet another study reported that type 2 inflammation correlated with the epithelial secreted cysteine proteinase inhibitor cystatin SN and was associated with poor outcome [100]. Some studies have reported that higher intensities of type 1 and type 3 inflammations are associated with surgical failure [99,101].

3.5. Biological Treatment

Biologics, a new treatment option for CRS, are increasingly being used mainly in CRSwNP patients and are effective in suppressing type 2 inflammation and minimizing side effects. Several monoclonal antibodies have been approved or are under development for the treatment of CRS, particularly in association with asthma, secondary or exacerbated disease, and recurrence after surgery (Table 3).
Omalizumab is a humanized recombinant DNA-derived IgG1k monoclonal antibody that specifically binds to free IgE in interstitial and blood fluid and to membrane-bound forms of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes [102]. The mechanism of reduced sensitivity to allergen stimulation is the gradual downregulation of FcεRI receptors on basophils, mast cells, and dendritic cells by free IgE binding to omalizumab. In particular, omalizumab does not bind to IgE, which is already bound to the high-affinity IgE receptor (FceRI) on the surface of antigen-presenting dendritic cells, basophils, and mast cells [103]. Nasal polyps, local eosinophilic inflammation, and asthma are associated with elevated local IgE levels. Several studies have reported that omalizumab reduces the size of polyps and significantly improves the quality of life of CRSwNP patients [104,105,106]. Although endoscopic finding and CT score showed improvement, there was no significant improvement in tissue and blood eosinophilia [107]. Based on this, Omalizumab was approved by the FDA for the treatment of nasal polyps in 2020.
Reslizumab and Mepolizumab are monoclonal antibodies that block IL-5, which contributes to the activation, maturation, and survival of eosinophils [108]. IL-5 is an important mediator of tissue eosinophilia in CRSwNP patients and is derived from T cells and ILC2s [109]. Reslizumab reported improvement in nasal polyp scores in a small study, and mepolizumab reported significant improvements in nasal polyp severity and symptom scores, along with a reduction in the need for surgery in CRSwNP patients in a multicenter randomized controlled trial study [110,111]. In particular, Mepolizumab showed a significant improvement to visual analogue score (VAS), Sino-Nasal Outcome Test (SNOT-22) score, nasal polyposis severity, and endoscopic nasal polyp score compared with placebo groups [112]. Based on this, mepolizumab has recently been reported in phase 3 trials for subjective and objective efficacy for CRSwNP, and the FDA approved its use [112].
Benralizumab is a cytotoxic monoclonal antibody that blocks the IL-5 receptors to eliminate eosinophils. Several studies have reported that it reduces annual asthma exacerbation rates and increases the lung function in uncontrolled asthma. Moreover, a phase 3 trial of CRSwNP was conducted [113,114,115,116]. However, additional studies on CRS patients are needed in the future.
Dupilumab is a monoclonal antibody that blocks IL-4 and IL-13, which are important in type 2 inflammation by binding to the α component of the shared receptor and is approved for the treatment of unregulated CRSwNPs. In two multicenter phase 3 trial randomized controlled trials, dupilumab improved quality of life in patients with severe CRSwNP, as well as reported reductions in nasal polyp size, nasal congestion, and sense of smell [117]. In addition, Ryu et al. reported that dupilumab significantly reduced the use of systemic corticosteroids compared to placebo and reduced nasal surgery by 76%. When serum and nasal secretions of CRSwNP patients were analyzed, type 2 inflammatory markers were significantly reduced in nasal secretions [118]. Table 4 summarizes the effects of FDA approved biologics for the treatment of CRS.
In a study comparing dupilumab and functional endoscopic sinus surgery (FESS) in CRSwNP patients, both methods were effective in reducing symptoms following the Sino-Nasal Outcome Test (SNOT-22). Furthermore, patients treated with FESS reported greater reductions in polyp burden than patients treated with dupilumab, whereas patients treated with dupilumab reported an improved sense of smell and greater reductions in postnasal drip, cough, and thick nasal drainage [119]. When the combination use of FESS and biologics is required, a retrospective matched cohort study on the timing of biologic use was reported [120]. The treatment effect size of dupilumab versus placebo was generally significantly greater in patients who had recent surgery, especially within 3 years. On the other hand, the number of surgeries did not show significant results.
Different biologics and ASA-D reported significant clinical improvement in patient outcomes in a meta study including 29 randomized controlled trials evaluating eight treatments (n = 3461) comparing monoclonal antibodies and aspirin desensitization (ASA-D) in CRSwNP patients [121]. In this study, dupilumab showed the best results for all indicators, including sinusitis symptoms, quality of life, and rescue of oral corticosteroids.
Although monoclonal antibodies are effective drugs for suppressing type 2 inflammation, there are no guidelines on which biological agents should be used first in patients with type 2 inflammation, because each target mechanism is different. There are reports of the various effects mentioned above, but a direct comparative evaluation for each has not been conducted. However, several recommendations for clinicians were presented at a recent expert board meeting, and dupilumab was reported to have the highest efficacy and objectivity among the currently available monoclonal antibodies [122]. However, a dosing interval has not yet been established. In a randomized, double-blind, phase 3 trial of dupilumab, there was no statistically significant difference in efficacy between a group of patients treated with dupilumab every 2 weeks for 52 weeks and another group treated with dupilumab every 2 weeks for 24 out of 52 weeks and then every 4 weeks for 28 weeks [117]. This may be positive in terms of patient burden if a certain level of therapeutic effect can be maintained by extending the dosage interval.
The probability of reoperation within 5 years is reported to be 20%, but it is also questionable whether biologics should be used first in patients who have not undergone surgery [123,124]. Although these drugs are very effective, there is no change in the quality of life compared to before treatment, and nasal polyps may not be cured [117].
The ideal treatment strategy should be determined for each patient; however, in the case of patients with multiple recurrences, the combination of biological agents after planned surgery may be the most effective and practical treatment.

4. Conclusions

CRS was previously classified based on its phenotype; however, as the knowledge of immunopathological mechanisms has significantly increased, it is necessary to establish a new pathway for the treatment of CRS patients based on the three major endotypes of type 1, type 2, and type 3.
CRS may be differentiated between other types and type 2 inflammation of immune responses associated with more severe clinical features and comorbidities, such as relapse and asthma. Type 2 inflammation can be found in both the CRSwNP and CRSsNP phenotypes, and is higher in the West than in Asia, but is also increasing in Asia due to rapid industrialization.
Although many studies have demonstrated the safety and efficacy of FDA-approved biologics are being reported, there are currently no guidelines for the selection of specific biologics for individual patients. To prevent inefficient treatment and excessive burden on patients, regular clinical monitoring of biological agents and the establishment of appropriate durations and intervals of use are also required.

Author Contributions

Conceptualization: K.-S.C., Writing—original draft preparation: S.-D.K., Literature search and data analysis: S.-D.K., Writing—review and editing: K.-S.C., Supervision: K.-S.C. All authors have read and agreed to the published version of the manuscript.

Funding

The authors have no relevant financial or non-financial interests to disclose.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Data Availability Statement

The study did not report any date.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dietz de Loos, D.; Lourijsen, E.S.; Wildeman, M.A.M.; Freling, N.J.M.; Wolvers, M.D.J.; Reitsma, S.; Fokkens, W.J. Prevalence of chronic rhinosinusitis in the general population based on sinus radiology and symptomatology. J. Allergy Clin. Immunol. 2019, 143, 1207–1214. [Google Scholar] [CrossRef] [PubMed]
  2. Tomassen, P.; Vandeplas, G.; Van Zele, T.; Cardell, L.O.; Arebro, J.; Olze, H.; Forster-Ruhrmann, U.; Kowalski, M.L.; Olszewska-ziaber, A.; Holtappels, G.; et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 2016, 137, 1449–1456. [Google Scholar] [CrossRef] [Green Version]
  3. Fokkens, W.J.; Lund, V.J.; Hopkins, C.; Hellings, P.W.; Kern, R.; Reitsma, S.; Cohen, N.; Cervin, A.; Douglas, R.; Gevaert, P.; et al. EPOS 2012, European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012, 50, 1–12. [Google Scholar] [CrossRef]
  4. Fokkens, W.J.; Lund, V.J.; Hopkins, C.; Hellings, P.W.; Kern, R.; Reitsma, S.; Cohen, N.; Cervin, A.; Douglas, R.; Gevaert, P.; et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology 2020, 58 (Suppl. S29), 1–464. [Google Scholar] [CrossRef] [PubMed]
  5. Song, W.J.; Lee, J.H.; Won, H.K.; Bachert, C. Chronic rhinosinusitis with nasal polyps in older adults, clinical presentation, pathophysiology, and comorbidity. Curr. Allergy Asthma Rep. 2019, 19, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Chang, E.H.; Stern, D.A.; Willis, A.L.; Guerra, S.; Wright, A.L.; Martinez, F.D. Early life risk factors for chronic sinusitis, a longitudinal birth cohort study. J. Allergy Clin. Immunol. 2018, 141, 1291–1297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. DelGaudio, J.M.; Loftus, P.A.; Hamizan, A.W.; Harvey, R.J.; Wise, S.K. Central compartment atopic disease. Am. J. Rhinol Allergy. 2017, 31, 228–234. [Google Scholar] [CrossRef]
  8. Abdullah, B.; Vengathajalam, S.; Md Daud, M.K.; Wan Mohammad, Z.; Hamizan, A.; Husain, S. The Clinical and Radiological Characteizations of the Allergic Phenotype of Chronic Rhinosinusitis with Nasal Polyps. J. Asthma Allergy. 2020, 13, 523–531. [Google Scholar] [CrossRef]
  9. Delgado-Dolset, M.I.; Obeso, D.; Sánchez-Solares, J.; Mera-Berriatua, L.; Fernández, P.; Barbas, C.; Fresnillo, M.; Chivato, T.; Barber, D.; Escribese, M.M.; et al. Understanding Systemic and Local Inflammation Induced by Nasal Polyposis, Role of the Allergic Phenotype. Front. Mol. Biosci. 2021, 8, 662–792. [Google Scholar] [CrossRef]
  10. Van Zele, T.; Claeys, S.; Gevaert, P.; Van Maele, G.; Holtappels, G.; Van Cauwenberge, P.; Bachert, C. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy 2006, 61, 1280–1289. [Google Scholar] [CrossRef]
  11. Van Bruaene, N.; Pe’rez-Novo, C.A.; Basinski, T.M.; Zele, T.V.; Holtappels, G.; Ruyck, N.D.; Schnidt-Weber, C.; Akdis, C.; Van Cauwenberge, P.; Bachert, C. T-cell regulation in chronic paranasal sinus disease. J. Allergy Clin. Immunol. 2008, 121, 1435–1441. [Google Scholar] [CrossRef] [PubMed]
  12. Larsen, K. The clinical relationship of nasal polyps to asthma. Allergy Asthma Proc. 1996, 17, 243–249. [Google Scholar] [CrossRef]
  13. ten Brinke, A.; Grootendorst, D.C.; Schmidt, J.T.; De Bruine, F.T.; Buchem, M.A.; Sterk, P.J.; Rabe, K.F.; Bel, E.H. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J. Allergy Clin. Immunol. 2002, 109, 621–626. [Google Scholar] [CrossRef] [Green Version]
  14. Van Crombruggen, K.; Zhang, N.; Gevaert, P.; Tomassen, P.; Bachert, C. Pathogenesis of chronic rhinosinusitis, Inflammation. J. Allergy Clin. Immunol. 2011, 128, 728–732. [Google Scholar] [CrossRef] [PubMed]
  15. Zhang, N.; Holtappels, G.; Claeys, C.; Huang, G.; Van Cauwenberge, P.; Bachert, C. Pattern of inflammation and impact of Staphylococcus aureus enterotoxins in nasal polyps from southern China. Am. J. Rhinol. 2006, 20, 445–450. [Google Scholar] [CrossRef]
  16. Zhang, Y.; Gevaert, E.; Lou, H.; Wang, X.; Zhang, L.; Bacheert, C.; Zhang, N. Chronic rhinosinusitis in Asia. J. Allergy Clin. Immunol. 2017, 140, 1230–1239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Bachert, C.; Gevaert, P.; Holtappels, G.; Johansson, S.G.O.; Van Cauwenberge, P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J. Allergy Clin. Immunol. 2001, 107, 607–614. [Google Scholar] [CrossRef] [PubMed]
  18. Kern, R.C.; Conley, D.B.; Walsh, W.; Chandra, R.; Kato, A.; Tripathi-Peters, A.; Grammer, L.C.; Scheimer, R.P. Perspectives on the etiology of chronic rhinosinusitis, an immune barrier hypothesis. Am. J. Rhinol. 2008, 22, 549–559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Abreu, N.A.; Nagalingam, N.A.; Song, Y.; Roediger, F.C.; Pletcher, S.D.; Goldberg, A.N.; Lynch, S.V. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci. Transl. Med. 2012, 4, 151ra124. [Google Scholar] [CrossRef] [Green Version]
  20. Huvenne, W.; van Bruaene, N.; Zhang, N.; Zele, T.V.; Patou, J.; Cevaert, P.; Claeys, S.; Cauwenberge, P.V.; Bachert, C. Chronic rhinosinusitis with and without nasal polyps, what is the difference? Curr. Allergy Asthma Rep. 2009, 9, 213–220. [Google Scholar] [CrossRef]
  21. Sobol, S.E.; Christodoulopoulos, P.; Manoukian, J.J.; Hauber, H.P.; Frenkiel, S.; Desrosiers, M.; Fukakusa, M.; Schloss, M.D.; Hamid, Q. Cytokine profile of chronic sinusitis in patients with cystic fibrosis. Arch. Otolaryngol. Head Neck Surg. 2002, 128, 1295–1298. [Google Scholar] [CrossRef] [Green Version]
  22. Brescia, G.; Alessandrini, L.; Marioni, G. Structured histopathology for endotyping and planning rational treatment in chronic rhinosinusitis. Am. J. Otolaryngol. 2021, 42, 102795. [Google Scholar] [CrossRef]
  23. Chen, C.L.; Yao, Y.; Pan, L.; Hu, S.T.; Ma, J.; Wang, Z.C.; Liu, Z. Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes. J. Allergy Clin. Immunol. 2020, 146, 677–681. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Bachert, C.; Wagenmann, M.; Rudack, C.; Höpken, K.; Hiltebrandt, M.; Wang, D.; Van Cauwenberge, P. The role of cytokines in infectious sinusitis and nasal polyposis. Allergy 1998, 53, 2–13. [Google Scholar] [CrossRef] [PubMed]
  25. Suzuki, H.; Takahashi, Y.; Wataya, H.; Ikeda, K.; Nakabayashi, S.; Shimomura, A.; Takasaka, T. Mechanism of neutrophil recruitment induced by IL-8 in chronic sinusitis. J. Allergy Clin. Immunol. 1996, 98, 659–670. [Google Scholar] [CrossRef] [PubMed]
  26. Bachert, C.; Akdis, C.A. Phenotypes and emerging endotypes of chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 2016, 4, 621–628. [Google Scholar] [CrossRef]
  27. Eberl, G.; Colonna, M.; Di Santo, J.P.; McKenzie, A.N. Innate lymphoid cells. Innate lymphoid cells, a new paradigm in immunology. Science 2015, 348, 6566. [Google Scholar] [CrossRef] [Green Version]
  28. Abbas, A.K.; Lichtman, A.H.; Pillai, S. Differentiation and Functions of CD4+ Effector T cells. In Cellular and Molecular Immunology, 9th ed.; Elsevier Saunders: Philadelphia, PA, USA, 2018; pp. 225–242. [Google Scholar]
  29. Tan, B.K.; Klingler, A.I.; Poposki, J.A.; Stevens, W.W.; Peters, A.T.; Suh, L.A.; Norton, F.; Carter, R.G.; Hulse, K.E.; Harris, K.E. Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois. J. Allergy Clin. Immunol. 2017, 139, 699–703. [Google Scholar] [CrossRef] [Green Version]
  30. Tyler, M.A.; Russell, C.B.; Smith, D.E.; Rottman, J.B.; Dietz, C.J.P.; Hu, X.; Citardi, M.J.; Fakhri, S.; Assassi, S.; Luong, A. Large-scale gene expression profiling reveals distinct type 2 inflammatory patterns in chronic rhinosinusitis subtypes. J. Allergy Clin. Immunol. 2017, 139, 1061–1064. [Google Scholar] [CrossRef] [Green Version]
  31. Wang, X.; Zhang, N.; Bo, M.; Holtappels, G.; Zheng, M.; Lou, H.; Wang, H.; Zhang, L.; Bachert, C. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis, A multicenter study in Europe, Asia, and Oceania. J. Allergy Clin. Immunol. 2016, 138, 1344–1353. [Google Scholar] [CrossRef] [Green Version]
  32. Klingler, A.I.; Stevens, W.W.; Tan, B.K.; Peters, A.T.; Poposki, J.A.; Grammer, L.C.; Welch, K.C.; Smoth, S.S.; Conely, D.B.; Kern, R.C.; et al. Mechanisms and biomarkers of inflammatory endotypes in chronic rhinosinusitis without nasal polyps. J. Allergy Clin. Immunol. 2021, 147, 1306–1317. [Google Scholar] [CrossRef]
  33. Heffler, E.; Malvezzi, L.; Boita, M.; Brussino, L.; Virgilio, A.D.; Ferrando, M.; Puggioni, F.; Racca, F.; Stomeo, N.; Spriano, G.; et al. Immunological mechanisma underlying chronic rhinosinusitis with nasal polyps. Expert Rev Clin Immuno. 2018, 14, 731–737. [Google Scholar] [CrossRef]
  34. Stevens, W.W.; Peters, A.T.; Tan, B.K.; Klingler, A.I.; Poposki, J.A.; Hulse, K.E.; Grammer, L.C.; Welch, K.C.; Smith, S.S.; Conley, D.B.; et al. Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 2019, 7, 2812–2820. [Google Scholar] [CrossRef] [PubMed]
  35. Wen, W.; Liu, W.; Zhang, L.; Bai, J.; Fan, Y.; Xia, W.; Luo, Q.; Zheng, J.; Wang, H.; Li, Z.; et al. Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy. J. Allergy Clin. Immunol. 2012, 129, 1522–1528. [Google Scholar] [CrossRef]
  36. Pothoven, K.L.; Norton, J.E.; Suh, L.A.; Carter, R.G.; Harris, K.E.; Biyasheva, A.; Welch, K.; Shintani-smith, S.; Conley, D.B.; Liu, M.C.; et al. Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease. J. Allergy Clin. Immunol. 2017, 139, 1966–1978. [Google Scholar] [CrossRef]
  37. Delemarre, T.; Holtappels, G.; De Ruyck, N.; Zhang, N.; Nauwynck, H.; Bachert, C.; Gevaert, E. A substantial neutrophilic inflammation as regular part of severe type 2 chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2021, 147, 179–188. [Google Scholar] [CrossRef] [PubMed]
  38. Wang, H.; Li, Z.Y.; Jiang, W.X.; Liao, B.; Zhai, G.T.; Wang, N.; Zhen, Z.; Ruan, J.W.; Long, X.B.; Wang, H.; et al. The activation and function of IL-36gamma in neutrophilic inflammation in chronic rhinosinusitis. J. Allergy Clin. Immunol. 2018, 141, 1646–1658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Kato, A.; Peters, A.T.; Stevens, W.W.; Schleimer, R.P.; Tan, B.K.; Kern, R.C. Endotypes of chronic rhinosinusitis, Relationships to disease phenotypes, pathogenesis, clinical findings, and treatment approaches. Allergy 2022, 77, 812–826. [Google Scholar] [CrossRef] [PubMed]
  40. Mahdavinia, M.; Suh, L.A.; Carter, R.G.; Stevens, W.W.; Norton, J.E.; Kato, A.; Tan, B.K.; Kern, R.C.; Conley, D.B.; Chandra, R.; et al. Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J. Allergy Clin. Immunol. 2015, 135, 576–579. [Google Scholar] [CrossRef] [Green Version]
  41. Katotomichelakis, M.; Tantilipikorn, P.; Holtappels, G.; De Ruyck, N.; Feng, L.; Van Zele, T.; Muangsomboon, S.; Jareonchasri, P.; Bunnag, C.; Danielides, V.; et al. Inflammatory patterns in upper airway disease in the same geographical area may change over time. Am. J. Rhinol. Allergy 2013, 27, 354–360. [Google Scholar] [CrossRef] [PubMed]
  42. Kim, S.J.; Lee, K.H.; Kim, S.W.; Cho, J.S.; Park, Y.K.; Shin, S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period. Otolaryngol. Head Neck Surg. 2013, 149, 431–437. [Google Scholar] [CrossRef]
  43. Rosenfeld, R.M.; Piccirillo, J.F.; Chandrasekhar, S.S.; Brook, I.; Ashok Kumar, K.; Kramper, M.; Orlandi, R.R.; Palmer, J.N.; Patel, Z.M.; Peters, A.; et al. Clinical practice guideline (update), adult sinusitis. Otolaryngol. Head Neck Surg. 2015, 152 (Suppl. S2), S1–S39. [Google Scholar] [CrossRef] [Green Version]
  44. Smith, S.S.; Evans, C.T.; Tan, B.K.; Chandra, R.K.; Smith, S.B.; Kern, R.C. National burden of antibiotic use for adult rhinosinusitis. J. Allergy Clin. Immunol. 2013, 132, 1230–1232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Orlandi, R.R.; Kingdom, T.T.; Smith, T.L.; Bleier, B.; DeConde, A.; Luong, A.U.; Poetker, D.M.; Soler, Z.; Welch, K.C.; Wise, S.K.; et al. International consensus statement on allergy and rhinology, rhinosinusitis 2021. Int. Forum Allergy Rhinol. 2021, 11, 213–739. [Google Scholar] [PubMed]
  46. Gunel, C.; Bleier, B.S.; Meteoglu, I. Antibiotics in eosinophilic chronic rhinosinusitis, Rethinking maximal antimicrobial medical therapy. Laryngoscope 2017, 127, 794–796. [Google Scholar] [CrossRef]
  47. Lan, F.; Zhang, N.; Holtappels, G.; De Ruyck, N.; Krysko, O.; Van Crombruggen, K.; Braun, H.; Johnston, S.L.; Papadopoulos, N.G.; Zhang, L.; et al. Staphylococcus aureus Induces a mucosal Type 2 immune response via epithelial cell-derived cytokines. Am. J. Respir. Crit. Care Med. 2018, 198, 452–463. [Google Scholar] [CrossRef] [PubMed]
  48. Bachert, C.; Holtappels, G.; Merabishvili, M.; Meyer, T.; Murr, A.; Zhang, N.; Crombruggen, K.V.; Gevaert, E.; Volker, U.; Broker, B.M.; et al. Staphylococcus aureus controls interleukin-5 release in upper airway inflammation. J. Proteom. 2018, 180, 53–60. [Google Scholar] [CrossRef]
  49. Healy, D.P. Macrolide immunomodulation of chronic respiratory diseases. Curr. Infect. Dis. Rep. 2007, 9, 7–13. [Google Scholar] [CrossRef]
  50. Wallwork, B.; Coman, W.; Mackay-Sim, A.; Greiff, L.; Cervin, A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope 2006, 116, 189–193. [Google Scholar] [CrossRef]
  51. Videler, W.J.; Badia, L.; Harvey, R.J.; Gane, S.; Georgalas, C.; Van Der Meulen, F.W.; Menger, D.J.; Lehtonen, M.T.; Toppila-Salmi, S.K.; Vento, S.I.; et al. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis, a randomized controlled trial. Allergy 2011, 66, 1457–1468. [Google Scholar] [CrossRef]
  52. Bezerra TF, P.; Pezato, R.; Barros PM, D.; Coutinho, L.L.; Costa, L.F.; Pinna, F.; Voegels, R. Prospective evaluation of clarithromycin in recurrent chronic rhinosinusitis with nasal polyps. Braz. J. Otorhinolaryngol. 2019, 87, 298–304. [Google Scholar] [CrossRef] [PubMed]
  53. Huang, Z.; Zhou, B. Clarithromycin for the treatment of adult chronic rhinosinusitis, a systematic review and meta-analysis. Int. Forum Allergy Rhinol. 2019, 9, 545–555. [Google Scholar] [CrossRef] [PubMed]
  54. Oakley, G.M.; Harvey, R.J.; Lund, V.J. The role of macrolides in chronic rhinosinusitis (CRSsNP and CRSwNP). Curr. Allergy Asthma Rep. 2017, 17, 30. [Google Scholar] [CrossRef]
  55. Seresirikachorn, K.; Suwanparin, N.; Srisunthornphanich, C.; Chitsuthipakorn, W.; Kanjanawasee, D.; Snidvongs, K. Factors of success of low-dose macrolides in chronic sinusitis, systematic review and meta-analysis. Laryngoscope 2019, 129, 1510–1519. [Google Scholar] [CrossRef] [Green Version]
  56. De Schryver, E.; Derycke, L.; Calus, L.; Holtappels, G.; Hellings, P.W.; Zele, T.V.; Bachert, C.; Gevaert, P. The effect of systemic treatments on periostin expression reflects their interference with the eosinophilic inflammation in chronic rhinosinusitis with nasal polyps. Rhinology 2017, 55, 152–160. [Google Scholar] [CrossRef] [PubMed]
  57. Lees, K.A.; Orlandi, R.R.; Oakley, G.; Alt, J.A. The role of macrolides and doxycycline in chronic rhinosinusitis. Immunol. Allergy Clin. North Am. 2020, 40, 303–315. [Google Scholar] [CrossRef]
  58. Henehan, M.; Montuno, M.; De Benedetto, A. Doxycycline as an anti-inflammatory agent, updates in dermatology. J. Eur. Acad. Derm. Venereol. 2017, 31, 1800–1808. [Google Scholar] [CrossRef]
  59. Cardell, L.O.; Stjarne, P.; Jonstam, K.; Bachert, C. Endotypes of chronic rhinosinusitis, impact on management. J. Allergy Clin. Immunol. 2020, 145, 752–756. [Google Scholar] [CrossRef] [Green Version]
  60. Pinto Bezerra Soter, A.C.; Bezerra, T.F.; Pezato, R.; Teles Abdo, T.R.; Pilan, R.M.; Pinna, F.R.; Gevaert, P.; Zele, T.V.; Bachert, C.; Voegels, R.L. Prospective open-label evaluation of long-term low-dose doxycycline for difficult-to-treat chronic rhinosinusitis with nasal polyps. Rhinology 2017, 55, 175–180. [Google Scholar] [CrossRef]
  61. Banuelos, J.; Lu, N.Z. A gradient of glucocorticoid sensitivity among helper T cell cytokines. Cytokine Growth Factor Rev. 2016, 31, 27–35. [Google Scholar] [CrossRef] [Green Version]
  62. Strehl, C.; Ehlers, L.; Gaber, T.; Buttgereit, F. Glucocorticoids-all- rounders tackling the versatile players of the immune system. Front. Immunol. 2019, 10, 1744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Walford, H.H.; Lund, S.J.; Baum, R.E.; White, A.A.; Bergeron, C.M.; Husseman, J.; Bethel, K.J.; Scott, D.R.; Khorrma, N.; Miller, M.; et al. Increased ILC2s in the eosinophilic nasal polyp endotype are associated with corticosteroid responsiveness. Clin. Immunol. 2014, 155, 126–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Doherty, T.A.; Broide, D.H. Pathways to limit group 2 innate lymphoid cell activation. J. Allergy Clin. Immunol. 2017, 139, 1465–1467. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Ogasawara, N.; Poposki, J.A.; Klingler, A.I.; Tan, B.K.; Weibman, A.R.; Hulse, K.E.; Stevens, W.W.; Peters, A.T.; Grammer, L.C.; Scheimer, R.P.; et al. IL-10, TGF-beta, and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells. J. Allergy Clin. Immunol. 2018, 141, 1147–1151. [Google Scholar] [CrossRef] [Green Version]
  66. Schleimer, R.P.; Freeland, H.S.; Peters, S.P.; Brown, K.E.; Derse, C.P. An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. J. Pharm. Exp. Ther. 1989, 250, 598–605. [Google Scholar]
  67. Ray, A.; Kolls, J.K. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017, 38, 942–954. [Google Scholar] [CrossRef]
  68. Chong, L.Y.; Head, K.; Hopkins, C.; Philpott, C.; Burton, M.J.; Schilder, A.G. Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database Syst. Rev. 2016, 4, CD011993. [Google Scholar] [CrossRef] [Green Version]
  69. Head, K.; Chong, L.Y.; Piromchai, P.; Hopkins, C.; Philpott, C.; Schilder, A.G.; Burton, M.J. Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database Syst. Rev. 2016, 4, CD011994. [Google Scholar] [CrossRef] [Green Version]
  70. Zhou, B.; He, G.; Liang, J.; Cheng, L.; Mehta, A.; Liu, S.; Yu, W.; Wang, Z.; Han, D. Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients, a double-blind, randomized, placebo-controlled trial. Int. Forum Allergy Rhinol. 2016, 6, 88–94. [Google Scholar] [CrossRef]
  71. Britt, R.D., Jr.; Thompson, M.A.; Sasse, S.; Pabelick, C.M.; Gerber, A.N.; Prakash, Y.S. Th1 cytokines TNF-alpha and IFN-gamma promote corticosteroid resistance in developing human airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 2019, 316, L71–L81. [Google Scholar] [CrossRef]
  72. Nabe, T. Steroid-resistant asthma and neutrophils. Biol. Pharm. Bull. 2020, 43, 31–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Harvey, R.J.; Snidvongs, K.; Kalish, L.H.; Oakley, G.M.; Sacks, R. Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. Int. Forum Allergy Rhinol. 2018, 8, 461–470. [Google Scholar] [CrossRef] [PubMed]
  74. Kern, R.C.; Stolovitzky, J.P.; Silvers, S.L.; Singh, A.; Lee, J.T.; Yen, D.M.; Iloreta, A.M.; Langford, F.P.; Karanfilov, B.; Matheny, K.E.; et al. A phase 3 trial of mometasone furoate sinus implants for chronic sinusitis with recurrent nasal polyps. Int. Forum Allergy Rhinol. 2018, 8, 471–481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Fokkens, W.; Reitsma, S. New delivery forms of nasal corticosteroids. J. Allergy Clin. Immunol. 2019, 143, 87–88. [Google Scholar] [CrossRef] [Green Version]
  76. Tait, S.; Kallogjeri, D.; Suko, J.; Kukuljan, S.; Schneider, J.; Piccirillo, J.F. Effect of budesonide added to large-volume, low-pressure saline sinus irrigation for chronic rhinosinusitis, a randomized clinical trial. JAMA Otolaryngol. Head Neck Surg. 2018, 144, 605–612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Leopold, D.A.; Elkayam, D.; Messina, J.C.; Kosik-Gonzalez, C.; Djupesland, P.G.; Mahmoud, R.A. Navigate II, randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis. J. Allergy Clin. Immunol. 2019, 143, 126–134. [Google Scholar] [CrossRef] [Green Version]
  78. Zeng, M.; Wang, H.; Liao, B.; Wang, H.; Long, X.B.; Ma, J.; Liu, J.X.; Liu, Z. Clinical and biological markers predict the efficacy of glucocorticoid-and macrolide-based postoperative therapy in patients with chronic rhinosinusitis. Am. J. Rhinol. Allergy 2021, 35, 596–606. [Google Scholar] [CrossRef]
  79. Schleimer, R.P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu. Rev. Pathol. 2017, 12, 331–357. [Google Scholar] [CrossRef] [Green Version]
  80. Ordovas-Montanes, J.; Dwyer, D.F.; Nyquist, S.K.; Buchheit, K.M.; Vukovic, M.; Deb, C.; Wadsworth, M.H.; Hughes, T.K.; Kazer, S.W.; Yoshimoto, E.; et al. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 2018, 560, 649–654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Sekiyama, A.; Gon, Y.; Terakado, M.; Takeshita, I.; Kozu, Y.; Maruoka, S.; Matsumoto, K.; Hashimoto, S. Glucocorticoids enhance airway epithelial barrier integrity. Int. Immunopharmacol. 2012, 12, 350–357. [Google Scholar] [CrossRef]
  82. Steelant, B.; Farre, R.; Wawrzyniak, P.; Belmans, J.; Dekimpe, E.; Vanheel, H.; Gerven, L.V.; Krohn, I.K.; Bullens, D.M.; Ceuppens, J.L.; et al. Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression. J. Allergy Clin. Immunol. 2016, 137, 1043–1053. [Google Scholar] [CrossRef] [Green Version]
  83. Cahill, K.N.; Bensko, J.C.; Boyce, J.A.; Laidlaw, T.M. Prostaglandin D(2), a dominant mediator of aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 2015, 135, 245–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Corren, J. New targeted therapies for uncontrolled asthma. J. Allergy Clin. Immunol. Pract. 2019, 7, 1394–1403. [Google Scholar] [CrossRef] [PubMed]
  85. Ghogomu, N.; Kern, R. Chronic rhinosinusitis, the rationale for current treatments. Expert Rev. Clin. Immunol. 2017, 13, 259–270. [Google Scholar] [CrossRef]
  86. Chandra, R.K.; Kern, R.C.; Cutler, J.L.; Welch, K.C.; Russell, P.T. REMODEL larger cohort with long-term outcomes and meta-analysis of standalone balloon dilation studies. Laryngoscope 2016, 126, 44–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Leung, R.M.; Kern, R.C.; Conley, D.B.; Tan, B.K.; Chandra, R.K. Osteomeatal complex obstruction is not associated with adjacent sinus disease in chronic rhinosinusitis with polyps. Am. J. Rhinol. Allergy 2011, 25, 401–403. [Google Scholar] [CrossRef]
  88. Snidvongs, K.; Kalish, L.; Sacks, R.; Sivasubramaniam, R.; Cope, D.; Harvey, R.J. Sinus surgery and delivery method influence the effectiveness of topical corticosteroids for chronic rhinosinusitis, systematic review and meta-analysis. Am. J. Rhinol. Allergy 2013, 27, 221–233. [Google Scholar] [CrossRef] [Green Version]
  89. DeConde, A.S.; Smith, T.L. Outcomes after frontal sinus surgery, an evidence-based review. Otolaryngol. Clin. N. Am. 2016, 49, 1019–1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Bassiouni, A.; Ou, J.; Rajiv, S.; Cantero, D.; Vreugde, S.; Wormald, P.J. Subepithelial inflammatory load and basement membrane thickening in refractory chronic rhinosinusitis with nasal polyposis, a histopathological study. Int. Forum Allergy Rhinol. 2016, 6, 248–255. [Google Scholar] [CrossRef] [PubMed]
  91. Alanin, M.C.; Hopkins, C. Effect of functional endoscopic sinus surgery on outcomes in chronic rhinosinusitis. Curr. Allergy Asthma Rep. 2020, 20, 27. [Google Scholar] [CrossRef]
  92. Barham, H.P.; Ramakrishnan, V.R.; Knisely, A.; Do, T.Q.; Chan, L.S.; Gunaratne, D.A.; Weston, J.D.; Seneviratne, S.; Marcells, G.N.; Sacks, R.; et al. Frontal sinus surgery and sinus distribution of nasal irrigation. Int. Forum Allergy Rhinol. 2016, 6, 238–242. [Google Scholar] [CrossRef] [PubMed]
  93. Alsharif, S.; Jonstam, K.; van Zele, T.; Gevaert, P.; Holtappels, G.; Bachert, C. Endoscopic sinus surgery for Type-2 CRS wNP, an endotype-based retrospective study. Laryngoscope 2019, 129, 1286–1292. [Google Scholar] [CrossRef]
  94. Morrissey, D.K.; Bassiouni, A.; Psaltis, A.J.; Naidoo, Y.; Wormald, P.J. Outcomes of modified endoscopic Lothrop in aspirin-exacerbated respiratory disease with nasal polyposis. Int. Forum Allergy Rhinol. 2016, 6, 820–825. [Google Scholar] [CrossRef] [PubMed]
  95. Jonstam, K.; Alsharif, S.; Bogaert, S.; Suchonos, N.; Holtappels, G.; Park, J.J.; Bachert, C. Extent of inflammation in severe nasal polyposis and effect of sinus surgery on inflammation. Allergy 2021, 76, 933–936. [Google Scholar] [CrossRef]
  96. Khairuddin, N.K.; Salina, H.; Gendeh, B.S.; Wan Hamizan, A.K.; Lund, V.J. Quality of life and recurrence of disease in patients with eosinophilic and non-eosinophilic 1 chronic rhinosinusitis with nasal polyposis. Med. J. Malays. 2018, 73, 1–6. [Google Scholar]
  97. Rosati, D.; Rosato, C.; Pagliuca, G.; Cerbelli, B.; Rocca, C.D.; Cristofano, C.D.; Martellucci, S.; Gallo, A. Predictive markers of long-term recurrence in chronic rhinosinusitis with nasal polyps. Am. J. Otolaryngol. 2020, 41, 102286. [Google Scholar] [CrossRef]
  98. Pan, L.; Liao, B.; Guo, C.L.; Liu, J.X.; Wanh, H.; Long, X.B.; Liu, Z. Inflammatory features and predictors for postsurgical outcomes in patients with nasal polyps stratified by local and systemic eosinophilia. Int. Forum Allergy Rhinol. 2021, 11, 846–856. [Google Scholar] [CrossRef]
  99. Liao, B.; Liu, J.X.; Li, Z.Y.; Zhen, Z.; Cao, P.P.; Long, X.B.; Long, X.B.; Wang, H.; Wang, Y.; Schleimer, R.; et al. Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes. Allergy 2018, 73, 1459–1469. [Google Scholar] [CrossRef]
  100. Wu, D.; Yan, B.; Wang, Y.; Wang, C.; Zhang, L. Prognostic and pharmacologic value of cystatin SN for chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2021, 148, 450–460. [Google Scholar] [CrossRef]
  101. Ryu, G.; Kim, D.K.; Dhong, H.J.; Eun, K.M.; Lee, K.E.; Kong, I.G.; Kim, H.Y.; Chung, S.K.; Kim, D.Y.; Rhee, C.S.; et al. Immunological characteristics in refractory chronic rhinosinusitis with nasal polyps undergoing revision surgeries. Allergy Asthma Immunol. Res. 2019, 11, 664–676. [Google Scholar] [CrossRef]
  102. Chang, T.W.; Davis, F.M.; Sun, N.C.; Sun, C.R.; MacGlashan, D.W., Jr.; Hamilton, R.G. Monoclonal antibodies specific for human IgE-producing B cells, a potential therapeutic for IgE-mediated Allergic diseases. Biotechnology 1990, 8, 122–126. [Google Scholar] [CrossRef] [PubMed]
  103. Chang, T.W.; Wu, P.C.; Hsu, C.L.; Hung, A.F. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv. Immunol. 2007, 93, 63–119. [Google Scholar]
  104. Buchheit, K.M.; Dwyer, D.F.; Ordovas-Montanes, J.; Katz, H.R.; Lewis, E.; Vukovic, M.; Kau, J.; Bankova, L.G.; Bhattacharyya, N.; Schalek, A.; et al. IL-5Ralpha marks nasal polyp IgG4-and IgE-expressing cells in aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 2020, 145, 1574–1584. [Google Scholar] [CrossRef] [PubMed]
  105. Feldman, S.; Kasjanski, R.; Poposki, J.; Hernandez, D.; Chen, J.N.; Norton, J.E.; Suh, L.; Carter, R.G.; Stevens, W.W.; Peters, A.T.; et al. Chronic airway inflammation provides a unique environment for B cell activation and antibody production. Clin. Exp. Allergy 2017, 47, 457–466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Gevaert, P.; Omachi, T.A.; Corren, J.; Mullol, J.; Han, J.; Lee, S.E.; Kaufman, D.; Ligueros-Saylan, M.; Howard, M.; Zhu, R.; et al. Efficacy and safety of omalizumab in nasal polyposis, 2 randomized phase 3 trials. J. Allergy Clin. Immunol. 2020, 146, 595–605. [Google Scholar] [CrossRef]
  107. Gevaert, P.; Calus, L.; Van Zele, T.; Blomme, K.; De Ruyck, N.; Bauters, W.; Hellings, P.; Brusselle, G.; Bacquer, D.D.; Cauwenberge, P.V.; et al. Omalizumab is effective in allergic and non-allergic patients with nasal polyposis and co-morbid asthma. J. Allergy Clin. Immunol. 2013, 131, 110–116. [Google Scholar] [CrossRef] [PubMed]
  108. Nussbaum, J.C.; Van Dyken, S.J.; von Moltke, J.; Cheng, L.E.; Mohapatra, A.; Molofsky, A.B.; Thornton, E.E.; Krummel, M.F.; Chawla, A.; Liang, H.E.; et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 2013, 502, 245–248. [Google Scholar] [CrossRef] [Green Version]
  109. Kato, A. Immunopathology of chronic rhinosinusitis. Allergol. Int. 2015, 64, 121–130. [Google Scholar] [CrossRef] [Green Version]
  110. Gevaert, P.; Lang-Loidolt, D.; Lackner, A.; Stammberger, H.; Staudinger, H.; Van Zele, T.; Holtappels, G.; Tavernier, J.; Cauwenberge, P.V.; Bachert, C. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J. Allergy Clin. Immunol. 2006, 118, 1133–1141. [Google Scholar] [CrossRef]
  111. Bachert, C.; Sousa, A.R.; Lund, V.J.; Scadding, G.K.; Gevaert, P.; Nasser, S.; Durham, S.R.; Cornet, M.E.; Kariyawasam, H.H.; Gilbert, J.; et al. Reduced need for surgery in severe nasal polyposis with mepolizumab, randomized trial. J. Allergy Clin. Immunol. 2017, 140, 1024–1031. [Google Scholar] [CrossRef] [Green Version]
  112. Han, J.K.; Bachert, C.; Fokkens, W.; Desrosiers, M.; Wagenmann, M.; Lee, S.E.; Smith, S.G.; Martin, N.; Mayer, B.; Yancey, S.W.; et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE), a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Resp. Med. 2021, 9, 1141–1153. [Google Scholar] [CrossRef] [PubMed]
  113. Bleecker, E.R.; FitzGerald, J.M.; Chanez, P.; Papi, A.; Weinstein, S.F.; Barker, P.; Sproule, S.; Gilmartin, G.; Aurivillius, M.; Werkstrom, V.; et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO), a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016, 388, 2115–2127. [Google Scholar] [CrossRef]
  114. Goldman, M.; Hirsch, I.; Zangrilli, J.G.; Newbold, P.; Xu, X. The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma, subanalyses of the Phase III SIROCCO and CALIMA studies. Curr. Med. Res. Opin. 2017, 33, 1605–1613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Park, H.S.; Lee, S.H.; Lee, S.Y.; Kim, M.K.; Lee, B.J.; Werkström, V.; Baker, P.; Zangrilli, J.G. Efficacy and Safety of Benralizumab for Korean Patients with Severe, Uncontrolled Eosinophilic Asthma. Allergy Asthma Immunol. Res. 2019, 11, 508–518. [Google Scholar] [CrossRef]
  116. Korn, S.; Bourdin, A.; Chupp, G.; Cosio, B.G.; Arbetter, D.; Shah, M.; Gil, E.G. Integrated Safety and Efficacy Among Patients Receiving Benralizumab for Up to 5 Years. J. Allergy Clin. Immunol. Pract. 2021, 9, 4381–4392. [Google Scholar] [CrossRef]
  117. Bachert, C.; Han, J.K.; Desrosiers, M.; Hellings, P.W.; Amin, N.; Lee, S.E.; Mullol, J.; Greos, L.S.; Bosso, J.V.; Laidlaw, T.M.; et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52), results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet 2019, 394, 1638–1650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Bachert, C.; Mannent, L.; Naclerio, R.M.; Mullol, J.; Ferguson, B.J.; Gevaert, P.; Hellings, P.; Jiao, L.; Wang, L.; Evans, R.R.; et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis, a randomized clinical trial. JAMA 2016, 315, 469–479. [Google Scholar] [CrossRef]
  119. Dharmarajan, H.; Falade, O.; Lee, S.E.; Wang, E.W. Outcomes of dupilumab treatment versus endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2022, 12, 986–995. [Google Scholar] [CrossRef]
  120. Hopkins, C.; Wagenmann, M.; Bachert, C.; Desrosiers, M.; Han, J.K.; Hellings, P.W.; Lee, S.E.; Msihid, J.; Radwan, A.; Rowe, P.; et al. Efficacy of duplimab in patients with a history of prior sinus surgery for chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2021, 11, 1087–1101. [Google Scholar] [CrossRef]
  121. Oykhman, P.; Paramo, F.A.; Bousquet, J.; Kennedy, D.W.; Brignardello-Petersen, R.; Chu, D.K. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis, A systematic review and network meta-analysis. J. Allergy Clin. Immunol. 2022, 149, 1286–1295. [Google Scholar] [CrossRef]
  122. Bachert, C.; Han, J.K.; Wagenmann, M.; Hosemann, W.; Lee, S.E.; Backer, V.; Mullol, J.; Gevaert, P.; Klimek, L.; Prokopakis, E.; et al. EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics, definitions and management. J. Allergy Clin. Immunol. 2021, 147, 29–36. [Google Scholar] [CrossRef] [PubMed]
  123. Smith, T.L.; Schlosser, R.J.; Mace, J.C.; Alt, J.A.; Beswick, D.M.; DeConde, A.S.; Detwiller, K.Y.; Mattos, J.L.; Soler, Z.M. Long-term outcomes of endoscopic sinus surgery in the management of adult chronic rhinosinusitis. Int. Forum Allergy Rhinol. 2019, 9, 831–841. [Google Scholar] [CrossRef] [PubMed]
  124. Smith, K.A.; Orlandi, R.R.; Oakley, G.; Meeks, H.; Curtin, K.; Alt, J.A. Long-term revision rates for endoscopic sinus surgery. Int. Forum Allergy Rhinol. 2019, 9, 402–408. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Characteristics of inflammatory endotype in CRS.
Table 1. Characteristics of inflammatory endotype in CRS.
EndotypeT1T2T3
Origin cellTh1 cell
ILC1		Th2 cell
ILC2		Th17 cell
ILC3
Inflammatory cytokinesTNF-α, IL-1β, IFN-γ, IL-12IL-4, IL-5, IL-13IL-17
Effector cellsNK cell
M1 Macrophage		Basophil
Eosinophil
M2 Macrophage		Neutrophil
Target pathogensMicrobes, protozoa, virusesParasiteBacteria, fungi
Clinical characteristicsMucopurulent discharge
Nasal polyp (limited)		Anosmia, Nasal polyposis, AsthmaMucopurulent discharge
Nasal polyp (limited)
Th, T helper cell; ILC, innate lymphoid cell; TNF-α, tumor necrosis factor; IFN-γ, interferon gamma; IL, interleukin; NK, natural killer.
Table
Table 2. Potential management of inflammatory endotype in CRS.
Table 2. Potential management of inflammatory endotype in CRS.
EndotypeT2Non-T2
PharmacotherapyTopical and oral corticosteroids
Doxycycline		Macrolide
SurgeryNasalization
Endoscopic Lothrop
Re-boot surgery		Conventional FESS
BiologicsOmalizumab
Mepolizumab
Dupliumab
Benralizumab
Reslizumab		Not defined yet
FESS, functional endoscopic sinus surgery.
Table
Table 3. Biologics for the target of CRS and approval status.
Table 3. Biologics for the target of CRS and approval status.
BiologicsTrade NameTargetApproval State
OmalizumabXolair®anti IgEFDA approved
MepolizumabNucala®anti IL-5FDA approved
DupilumabDupixent®anti IL-4RαFDA approved
BenralizumabFasenra®anti IL-5RαPhase 3 trials
(FDA approved for severe asthma)
ReslizumabCINQAIR®anti IL-5Phase 2 trials
(FDA approved for severe asthma)
Ig E, immunoglobulin E; IL, interleukin.
Table
Table 4. Effects of biologics on CRS.
Table 4. Effects of biologics on CRS.
BiologicsIncrease of Quality of Life and OlfactionEndoscopic Nasal Polyp ScoreLund-Mackay CT Scan ScoreReduction of Serum IgE LevelsReduction of Tissue Eosinophil LevelsReduction of Blood Eosinophil Levels
OmalizumabOOOO
MepolizumabOO OO
DupilumabOOOOOO
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kim, S.-D.; Cho, K.-S. Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence. Int. J. Mol. Sci. 2023, 24, 5015. https://doi.org/10.3390/ijms24055015

AMA Style

Kim S-D, Cho K-S. Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence. International Journal of Molecular Sciences. 2023; 24(5):5015. https://doi.org/10.3390/ijms24055015

Chicago/Turabian Style

Kim, Sung-Dong, and Kyu-Sup Cho. 2023. "Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence" International Journal of Molecular Sciences 24, no. 5: 5015. https://doi.org/10.3390/ijms24055015

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop