Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis

doi:10.1016/j.jaci.2015.10.010

Journal of Allergy and Clinical Immunology

Volume 136, Issue 6, December 2015, Pages 1431-1440

https://doi.org/10.1016/j.jaci.2015.10.010 Get rights and content

Chronic rhinosinusitis (CRS) affects more than 10% of the population in the United States and Europe. Recent findings point to a considerable variation of inflammatory subtypes in patients with CRS with nasal polyps and patients with CRS without nasal polyps. According to current guidelines, glucocorticosteroids and antibiotics are the principle pharmacotherapeutic approaches; however, they fail in a group of patients who share common clinical and laboratory markers. Several clinical phenotypes often leading to uncontrolled disease, including adult nasal polyposis, aspirin-exacerbated respiratory disease, and allergic fungal rhinosinusitis, are characterized by a common endotype: a T_H2 bias is associated with a higher likelihood of comorbid asthma and recurrence after surgical treatment. As a consequence, several innovative approaches targeting the T_H2 bias with humanized mAbs have been subjected to proof-of-concept studies in patients with CRS with nasal polyps with or without comorbid asthma: omalizumab, reslizumab, mepolizumab, and recently dupilumab. Future concepts using upstream targets, such as GATA-3, also focus on this endotype. This current development might result in advantages in the treatment of patients with the most severe CRS.

Section snippets

Epidemiology and burden of disease

Recent epidemiologic studies have revealed wide variations in the prevalence of CRS among regions globally (Fig 1). The National Health Interview Survey of 34,525 US citizens showed that 12% of the adult population have been told by health professionals that they have sinusitis.¹ In Europe a postal questionnaire survey of 57,128 subjects from 12 countries reported the overall prevalence of CRS to be 11%, with marked geographic variations from 7% to 27%² by using the European Guidelines on

From phenotypes to endotypes

Current consensus in Europe and the United States discerns 2 major phenotypes defined as subgroups of patients with homogeneous clinically observable characteristics3, 12 based on nasal endoscopic and computed tomographic (CT) findings: CRSwNP and CRSsNP. Furthermore, there are additional subtypes based on underlying conditions, such as AFRS, CRS associated with aspirin-exacerbated respiratory disease (AERD), CRS in patients with cystic fibrosis, primary ciliary dyskinesia, systemic diseases,

Asthma comorbidity, aspirin hypersensitivity, and disease recurrence after surgery

The link between CRS and asthma has long been documented and correlated to sinus CT scores and eosinophils in peripheral blood and induced sputum.3, 12 Especially patients with CRSwNP are prone to severe asthma. Studies involving large series of patients with CRSwNP show an incidence of asthma between 20% and 70%.23, 24 About 7% of asthmatic patients have CRSwNP, with a higher incidence in patients with nonatopic asthma (13%).²³ Evidence is accumulating that the lower airways have the same

Current treatment recommendations and unmet needs

The primary goal of the treatment is to achieve and maintain clinical control. Control is defined by the European Guidelines on Sinusitis and Nasal Polyposis 2012 as a disease state in which patients do not have bothersome symptoms combined with a healthy or almost healthy mucosa and the need for local medication only.³

Anti-IgE hmAbs

Omalizumab is an hmAb binding to free IgE with high affinity, which is approved in the European Union and United States for the treatment of severe allergic asthma. Given the high mucosal IgE concentrations in nasal polyp tissue and their relevance for disease severity and comorbidity, strategies to antagonize IgE might be relevant in patients with CRSwNP. In a randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with CRSwNP and comorbid asthma (n = 24),

Anti–IL-5 hmAbs

About 80% to 85% of patients with nasal polyps in the United States and Europe demonstrate a T_H2-biased inflammatory pattern with prominent eosinophilia and tissue expression of IL-5 protein and chemokines, as well as activation markers for eosinophilic granulocytes. Because IL-5 plays a key role in chemotaxis, differentiation, activation, and survival of eosinophils and because those cells represent such a prominent characteristic in the polyps, antagonism of IL-5 was considered a therapeutic

Anti–IL-4/IL-13 hmAbs

In addition to IL-5, IL-4 and IL-13 could prove to be targets for hmAbs. These cytokines signal through 2 different receptors that partly overlap in their functions, and they both contain the α subunit of the IL-4 receptor (Fig 4). The type 1 receptor that can only be activated by IL-4 is mainly expressed on lymphocytes and regulates differentiation of those cells. The type 2 receptor that is activated by IL-4 and IL-13 is expressed by a multitude of cells and has different functions, among

Approaches to come

When reviewing the hmAbs in studies of asthma, other candidates are likely to be tested in proof-of-concept studies in patients with nasal polyposis, including anti–IL-4, anti–IL-13, and anti–thymic stromal lymphopoietin hmAbs. Although the development of biologics is very promising and without a doubt serves as proof of concept for future treatments, there are still problems to solve, such as the necessity of regular systemic applications with the risk of notable side effects and the probably

GATA-3 DNAzyme

The T_H2 endotype is characterized by the predominance of activated T_H2 cells that synthesize and release the cytokines IL-4, IL-5, and IL-13. The expression and production of those cytokines is controlled by the transcription factor GATA-3, which is relevant for the differentiation and activation of T_H2 lymphocytes and also expressed in the newly discovered type 2 innate lymphoid cells; GATA-3 might be considered the “master switch” of T_H2-associated diseases (Fig 5). GATA-3 is overexpressed in

Genetically modified Lactococcus lactis

Instead of complex antibodies that have to be produced and humanized in expensive processes to be applicable systemically, it is also possible to choose approaches in which proteins or their derivatives, such as nanoproteins, are produced directly on the mucosa by nonpathogen bacteria. This approach led to the development and production of genetically modified L lactis, which has demonstrated preclinical and clinical applicability for a series of diseases.⁵⁵ Advantages are local application and

Summary

It has become obvious that the therapeutic approaches pursued up to now, as they are summarized in current European and US guidelines, do not lead to long-term control of the symptoms or risks of recurrence and comorbid asthma in a subgroup with severe persistent disease. This subgroup has recently been identified as a type 2 immune response, with increased expression of the transcription factor GATA-3; increased production of IL-4, IL-5, and IL-13; and increased local production of IgE

List of key concepts and therapeutic implications related to the topic

•
Pharmacotherapy and surgery show limitations in controlling severe CRSwNP (frequent recurrence and asthma comorbidity).
•
Severe CRSwNP is mostly characterized by a T_H2 bias, and up to 50% of subjects have IgE antibodies to S aureus enterotoxins.
•
The T_H2 cytokines IL-4, IL-5, and IL-13 and IgE served as targets for innovative interventions, mostly hmAbs (biologicals).
•
Proof-of-concept studies have been performed with omalizumab (anti-IgE), reslizumab and mepolizumab (anti–IL-5), and dupilumab

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Cited by (250)

Efficacy of the posterior nasal nerve resection combined with hormone transnasal nebulization on difficult-to-treat rhinosinusitis: a retrospective analysis
2024, Brazilian Journal of Otorhinolaryngology
A retrospective analysis was performed to explore the clinical effect of the Posterior Nasal Nerve (PNN) resection combined with hormone transnasal nebulization on Difficult-to-Treat Rhinosinusitis (DTRS).
A total of 120 DTRS patients were selected and divided into a control group (n = 60) and a study group (n = 60) according to different treatments. The control group patients were treated via PNN resection, followed by normal saline transnasal nebulization; the study group patients were given PNN resection and then treated with budesonide suspension transnasal nebulization. Subsequently, the comparison was performed between the two groups in terms of (1) Clinical baseline characteristics; (2) Sino-nasal Outcome Test (SNOT)-22 scores before treatment and after 3-months, 6-months and 12-months of treatment; (3) Lund-MacKay scores before treatment and after 10, 30, 90, and 180 days of treatment; (4) Incidence of adverse reactions during treatment.
There was no significant difference in SNOT-22 or Lund-Kennedy scores between the two groups before treatment (p > 0.05). After treatment, the SNOT-22 and Lund-Kennedy scores of the control and the study groups were decreased, and compared with the control group, the SNOT-22 and Lund-Kennedy scores in the study group improved more significantly (p < 0.05). In addition, the study group and the control group presented with 1 and 4 cases of nasal adhesion, 2 and 3 cases of epistaxis, 1 and 4 cases of sinus orifice obstruction, 1 and 3 cases of lacrimal duct injuries, respectively. The incidence of adverse reactions in the study group was significantly lower than that in the control group (8.3% vs. 23.3%) (p < 0.05).
PNN resection combined with hormone transnasal nebulization treatment can improve the symptoms and quality of life of DTRS patients, with good clinical efficacy but few adverse reactions. Therefore, such combination treatment deserves a promotion and application clinically.
Level 3.
Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update
2024, Brazilian Journal of Otorhinolaryngology
Biologics targeting type 2 inflammation have revolutionized the way we treat patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). Particularly in severe and difficult-to-control cases, these drugs have provided a new reality for these patients, allowing for the effective and safe treatment of extensive diseases that were not completely managed with the typical strategy of surgery and topical medications.
The experience achieved with the approval of these medications by ANVISA for use in CRSwNP and the knowledge obtained regarding outcomes, adverse effects, and the ideal patient profile prompted the update of the previously published guideline, with a detailed review of the most recent scientific literature, the personal experiences of experts, and the adaptation to the reality of the Brazilian healthcare system, both public and private.
We proposed a new eligibility criterion for biologics in patients with CRSwNP based on four pillars of indication: the impact of the disease on the patient’s life, whether in the presence of specific symptoms or in overall quality of life; the extent of sinonasal disease; the presence of type 2 comorbidities, considering other associated diseases that may also benefit from anti-T2 biologics, and the presence of biomarkers to define type 2 inflammation, especially those associated with worse disease prognoses.
This innovative and pioneering method has two major advantages. First, it ensures a comprehensive evaluation of patients; second, it is flexible, as advancements in our understanding of the disease and changes in cost-effectiveness can be addressed by simply adjusting the required score for indication, without the need to modify the entire evaluation scheme.
Management of CRSwNP in Latin America: A multidisciplinary consensus from an expert working group
2024, World Allergy Organization Journal
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition of the nasal and paranasal tissues, characterized by the presence of bilateral nasal polyps. While etiology and pathogenetic mechanisms are heterogeneous and complex, in most patients, disease is mediated predominantly through type 2 inflammatory processes. Clinical management is challenging, and a multidisciplinary approach is preferred. Principal treatment approaches are the use of local/systemic corticosteroids and sinonasal surgery, although outcomes can be unsatisfactory. Recent availability of biological therapies targeting underlying inflammatory processes can offer effective treatment options in uncontrolled disease. Specialist guidelines greatly assist clinical decision-making, although as these are chiefly written from a global/international perspective, they may not wholly accommodate disease patterns and clinical practice at a regional level. An expert panel of specialists from Latin America was convened to develop regional guidance on the management of CRSwNP through a consensus approach. The present article presents the chief observations and recommendations which can provide guidance for clinicians in the Latin American region.
Exposure of nonylphenol promoted NLRP3 inflammasome and GSDMD-mediated pyroptosis in allergic rhinitis mice
2024, Food and Chemical Toxicology
Studies have confirmed that the intake of nonylphenol (NP) can increase nasal symptoms, eosinophils, and Th2 responses in allergic rhinitis (AR) mice. However, the molecular mechanism of NP exacerbating AR inflammatory response remains unclear. Recent data suggest that NOD-like receptor 3 (NLRP3) inflammasome-mediated pyroptosis contributes to AR development. To investigate the effects of NP on NLRP3 inflammasomes and pyroptosis, an AR mouse model induced by ovalbumin (OVA) was established and treated with 0.5 mg/kg/d NP every other day. Nasal symptoms were evaluated after the final OVA instillation. Mast cells and Eosinophils in the nasal mucosa were observed using toluidine blue and Sirius red staining, respectively. The levels of NLRP3, Caspase-1, ASC, phospho–nuclear factor kappa B (NF-κB) p65, interleukin (IL)-6, TNF-α, IL-18, GSDMD and IL-1β, were assessed by using immunohistochemical staining, ELISA, quantitative real-time PCR, or Western blot. Exposure to NP aggravates AR symptoms and promotes eosinophils, mast cells, and inflammatory factors release, along with significantly increased of NF–κB, NLRP3, Caspase-1, ASC, and GSDMD. It was concluded that NP exposure promotes NLRP3 inflammasome and GSDMD-mediated pyroptosis of the nasal mucosa. Targeted of NLRP3 and GSDMD-mediated pyroptosis may be a novel therapeutic strategy for AR exposed to NP.
The inflammatory microenvironment of nasal polyps in patients with chronic rhinosinusitis and the relationship of this microenvironment with the nasal microbiome
2024, Asian Journal of Surgery
We investigated the characteristics of the microbial community of the nasal sinuses in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and identified the correlations of the nasal microbiome with the inflammatory microenvironment of the nasal cavity.
We collected matched nasal secretion and polyp tissue samples from 77 CRSwNP patients. Then, we extracted microbial DNA from cotton swabs, used high-throughput sequencing technology based on 16S ribosomal RNA (rRNA) to detect the bacterial community composition, and detected cytokines such as interleukin (IL)-5, IL-8, IL-17a, IL-17e, IL-18, IL-27 and interferon (INF)-gamma in the polyp tissue samples using Luminex. Eosinophils and neutrophils in the peripheral blood and polyp tissue were counted, and the relationships between inflammatory factors or inflammatory cell counts and nasal microbial diversity were analyzed.
Among the inflammatory factors evaluated, IL-5 had a positive rate of 32.47%, IFN-γ had a positive rate of 84.42%, IL-17A and IL-17E had positive rates of 75.32%, IL-18 had a positive rate of 94.81%, IL-27 had a positive rate of 68.83%, and IL-8 had a positive rate of 100%. IL-17a and IL-27 were negatively correlated with both Enterobacter and Anaerococcus, IL-8 was negatively correlated with both Enterobacter and Staphylococcus, IL-18 was positively correlated with Candidatus Arthromitus and negatively correlated with Haemophilus, and IL-27 was positively correlated with Faecalibaculum. Lactobacillus and Enterococcus were positively correlated with the degree of neutrophil infiltration in nasal polyp tissue.
In Southwest China, inflammation of the nasal polyps exhibits a variety of patterns. Enterobacteria and anaerobic bacteria may be correlated with the inflammatory pattern of nasal polyps. The neutrophil-mediated inflammatory response plays an important role in patients with CRSwNP in Southwest China.
Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype
2023, Heliyon
Chronic rhinosinusitis is a heterogenous and multifactorial disease, characterized by persistent inflammation of the nose and paranasal sinuses, which causes nasal obstruction, nasal discharge, facial pain, and smell disturbance. Chronic rhinosinusitis is divided into two phenotypes: chronic rhinosinusitis with nasal polyp and chronic rhinosinusitis without nasal polyp. Nasal polyps can be associated with many inflammatory cells including eosinophil cells, neutrophil cells, plasma cells, and lymphocytes. T2 endotype is characterized by the type-2 immune response and nasal polyps are associated with eosinophilic dominant infiltration. In contrast, in the T1 and T3 endotypes, chronic rhinosinusitis can be associated with neutrophilic dominant infiltration. In addition, there are mixed types of inflammation with different proportions of eosinophils-neutrophils in chronic rhinosinusitis. In the T2 endotype, there is an increase in the production of Th2 cytokines, including interleukin-4, interleukin-5, and interleukin-13, high levels of immunoglobulin-E in polyp tissue, and eosinophilia. Stimulation of Th2 cells, type-2 innate lymphoid cells, epithelial cell damage, Staphylococcus aureus enterotoxins, and autoimmune antibodies have important roles in the enhancement of Th2 cytokines and pathogenesis of chronic rhinosinusitis with nasal polyp. Monoclonal antibodies target type-2 inflammation, decrease nasal polyp size, and improve the clinical symptoms of CRSwNP patients. The present review will focus on factors involved in the pathogenesis of chronic rhinosinusitis and its treatment.

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: Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

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Reviews and feature articleCurrent and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis

Section snippets

Epidemiology and burden of disease

From phenotypes to endotypes

Asthma comorbidity, aspirin hypersensitivity, and disease recurrence after surgery

Current treatment recommendations and unmet needs

Anti-IgE hmAbs

Anti–IL-5 hmAbs

Anti–IL-4/IL-13 hmAbs

Approaches to come

GATA-3 DNAzyme

Genetically modified Lactococcus lactis

Summary

List of key concepts and therapeutic implications related to the topic

Otolaryngol Head Neck Surg

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol Pract

J Allergy Clin Immunol

J Allergy Clin Immunol

Curr Opin Microbiol

Summary health statistics for US adults: national health interview survey, 2011

Vital Health Stat 10

Chronic rhinosinusitis in Europe—an underestimated disease. A GALEN study

Allergy

European position paper on rhinosinusitis and nasal polyps 2012

Rhinol Suppl

Reliability of symptom criteria and nasal endoscopy in the assessment of chronic rhinosinusitis based on EPOS-guidelines—a GALEN study

Allergy

Prevalence and risk factors of chronic rhinosinusitis in Korea

Am J Rhinol Allergy

Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities

Allergy

Prevalence of chronic rhinosinusitis in Sao Paulo

Rhinology

The national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis

Clin Otolaryngol

Incremental health care utilization and expenditures for chronic rhinosinusitis in the United States

Ann Otol Rhinol Laryngol

The burden of revision sinonasal surgery in the UK-data from the Chronic Rhinosinusitis Epidemiology Study (CRES): a cross-sectional study

BMJ Open

Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy

J Allergy Clin Immunol

Reviews and feature article
Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis