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Clinical Research Needs for the Management of Chronic Rhinosinusitis with Nasal Polyps in the New Era of Biologics: A National Institute of Allergy and Infectious Diseases Workshop.

ABSTRACT: The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come.

SUBMITTER: Naclerio R

PROVIDER: S-EPMC8177483 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Management of Chronic Rhinosinusitis with Nasal Polyposis in the Era of Biologics.

Project description:Purpose of reviewChronic rhinosinusitis with nasal polyposis (CRSwNP) is a phenotypic designation of the broader condition of chronic rhinosinusitis. The advent of targeted biologics has shown promise in targeting different aspects of the inflammatory pathway, yet there remains a lack of consensus on the correct timing and use of these medications. This review seeks to provide a concise update of the available literature on the pathophysiology of CRSwNP, the evolution and cost utility of biologics as it pertains to management of patients with CRSwNP, and evidence for each available biologic and its use in CRSwNP.Recent findingsThere are two biologics with FDA approval for use in CRSwNP: dupilumab and omalizumab. Recent clinical trials of other biologic therapies targeting type 2 inflammatory pathways have also demonstrated efficacy both in symptom scores and nasal polyp reduction. However, studies have questioned the cost utility of these medications compared to other interventions. Furthermore, timing of use with respect to other interventions including surgery remains challenging.

| S-EPMC8285230 | biostudies-literature

Chronic Rhinosinusitis without Nasal Polyps.

Project description:Chronic rhinosinusitis without nasal polyps (CRSsNP) is more prevalent than chronic rhinosinusitis with nasal polyps (CRSwNP). Certain diseases predispose to whereas others are associated with CRSsNP. Predisposing diseases include allergic and nonallergic upper and lower airway diseases, epithelial cell disorders, immunodeficiencies, autoimmune diseases, and some infectious diseases. In addition, environmental and host factors, examples of which include smoking, a higher incidence of abnormal biofilms, and innate immune defects, play a role in the pathogenesis of this disease. CRSsNP is characterized by histologic abnormalities, including basement membrane thickening (fibrosis) and goblet cell hyperplasia. Neutrophils and several chemokines, TGF-β and C-X-C motif chemokine ligand (CXCL)-8, play a role in CRSsNP remodeling. However, there are conflicting data about CRSsNP endotypes, for example, whether it is characterized by neutrophilia or eosinophilia or both. In spite of advancements and the understanding of the pathogenesis of this disease, additional study is necessary to better comprehend its underlying mechanisms, endotypes, and evidence-based treatment strategies.

| S-EPMC4939221 | biostudies-literature

Biologics in chronic rhinosinusitis with nasal polyposis.

Project description:ObjectiveChronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory condition, for which the drivers of the underlying inflammation are not yet fully understood. The use of biologic therapies to target specifically relevant effector cells or cytokines in CRSwNP is a growing field of interest. The objectives of this review are to provide an update on the existing studies of biologics in CRSwNP and to identify potential future areas for further research.Data sourcesAn initial literature review of biologic therapies in CRS was performed through publications gathered from a PubMed search for title/abstract containing "biologic" and "chronic rhinosinusitis." Further manuscripts describing scientific premise for each biologic were then reviewed.Study selectionsA detailed review of all studies describing biologic therapies targeting inflammation in CRSwNP was performed.ResultsBiologic therapies targeting interleukin (IL)-4Rα, IL-5, IL-5Rα, IL-33, immunoglobulin (Ig)E, and thymic stromal lymphopoietin (TSLP) have all been developed and have been investigated for treatment in CRSwNP, or current research suggests that they may have utility in this area. Only dupilumab, which inhibits IL-4Rα, has gained Food and Drug Administration approval for the treatment of adults with inadequately controlled CRSwNP.ConclusionRecent advances in our understanding of the fundamental drivers of the chronic respiratory inflammation in CRSwNP has led to the identification of several potential therapeutic targets for this disease. Future clinical success will rely on the availability of biomarker-based endotyping and responder analyses so that clinicians can precisely match each patient to the appropriate biologic, thereby optimizing the proper treatment strategy.

| S-EPMC7113089 | biostudies-literature

Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota.

Project description:Chronic rhinosinusitis with nasal polyp (CRSwNP) patients are often characterized by asthma comorbidity and a type-2 inflammation of the sinonasal mucosa. The mucosal microbiota has been suggested to be implicated in the persistence of inflammation, but associations have not been well defined. To compare the bacterial communities of healthy subjects with CRSwNP patients, we collected nasal swabs from 17 healthy subjects, 21 CRSwNP patients without asthma (CRSwNP-A), and 20 CRSwNP patients with co-morbid asthma (CRSwNP+A). We analysed the microbiota using high-throughput sequencing of the bacterial 16S rRNA. Bacterial communities were different between the three groups. Haemophilus influenzae was significantly enriched in CRSwNP patients, Propionibacterium acnes in the healthy group; Staphylococcus aureus was abundant in the CRSwNP-A group, even though present in 57% of patients. Escherichia coli was found in high amounts in CRSwNP+A patients. Nasal tissues of CRSwNP+A patients expressed significantly higher concentrations of IgE, SE-IgE, and IL-5 compared to those of CRSwNP-A patients. Co-cultivation demonstrated that P. acnes growth was inhibited by H. influenzae, E. coli and S. aureus. The nasal microbiota of healthy subjects are different from those of CRSwNP-A and CRSwNP+A patients. However, the most abundant species in healthy status could not inhibit those in CRSwNP disease.

| S-EPMC5962583 | biostudies-literature

Characterizing the Neutrophilic Inflammation in Chronic Rhinosinusitis With Nasal Polyps.

Project description:The mechanisms underlying neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly investigated. This study aimed to examine the factors that contribute to tissue neutrophilia in CRSwNP. The numbers of neutrophils and active caspase-3-positive apoptotic neutrophils in sinonasal tissues were assessed via immunofluorescence staining. The 95th percentile of tissue neutrophil numbers in control subjects was selected as a cut-off to define neutrophil-high (Neu-high) or neutrophil-low (Neu-low) nasal polyps (NPs). The levels of 34 inflammatory mediators in sinonasal tissues were analyzed using Bio-Plex assay. Purified human peripheral blood neutrophils were incubated with nasal tissue homogenates, and the apoptotic neutrophils were assessed via flow cytometry. The cut-off for Neu-high NPs was >10 myeloperoxidase positive cells/high-power field. Compared with Neu-low NPs, Neu-high NPs had higher tissue levels of IL-1β, IL-1Ra, IL-6, IL-8, G-CSF, MCP-1, and MIP-1α, but lower levels of IL-5, IL-13, IgE, and eosinophils. Principal component and multiple correspondence analyses revealed mixed type 1, type 2, and type 3 endotypes for Neu-low NPs, and predominant type 1 and type 3 endotypes for Neu-high NPs. Neu-high NPs had lower percentages of apoptotic neutrophils than Neu-low NPs. The numbers of neutrophils and the percentages of apoptotic neutrophils correlated with G-CSF and IL-6 levels in the NPs. Tissue homogenates from Neu-high NPs, but not those from Neu-low NPs, suppressed neutrophil apoptosis in vitro, which was reversed by anti-G-CSF treatment. Tissue neutrophil numbers were associated with difficult-to-treat disease in patients with CRSwNP after surgery. We propose that G-CSF promotes neutrophilic inflammation by inhibiting neutrophil apoptosis in CRSwNP.

| S-EPMC8718617 | biostudies-literature

Visual and bibliometric analysis of chronic rhinosinusitis and nasal polyps.

Project description:BackgroundChronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. Nasal polyps (NPs) are one of the main manifestations that cause diverse clinical symptoms of CRS.ObjectiveWe sought to conduct a bibliometric and visual analysis of articles on CRS and NPs published between 2003 and 2022 to provide researchers with the current state of research and potential directions.MethodsWe searched relevant articles from 2003 to 2022 in the Web of Science database. VOSviewer and the Bibliometrix R package were used to perform the bibliometric analysis.ResultsA total of 3907 publications were retrieved. The United States made the highest contributions to global research, followed by China. Northwestern University had the most publications. The most published author was C. Bachert, followed by R. P. Schleimer and R. J. Schlosser. The authors with the most co-citations were C. Bachert, W. J. Fokkens, and P. Gevaert. Moreover, the journal with the most publications was the International Forum of Allergy & Rhinology, and the Journal of Allergy and Clinical Immunology was the most cited. "Covid-19," "biologics," and "type 2 inflammation" were the top current research hotspots.ConclusionsThe United States and Northwestern University were the leading country and institution in researching CRS and NPs. C. Bachert was the most influential expert. The International Forum of Allergy & Rhinology and the Journal of Allergy and Clinical Immunology were leading journals. "Covid-19," "biologics," and "type 2 inflammation" were the trending topics.

| S-EPMC10899047 | biostudies-literature

Elevation of activated neutrophils in chronic rhinosinusitis with nasal polyps.

Project description:BackgroundChronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is well characterized by type 2 (T2) inflammation characterized by eosinophilia in Western countries. However, the presence and roles of neutrophils in T2 CRSwNP are poorly understood.ObjectiveWe sought to clarify accumulation and inflammatory roles of neutrophils in CRSwNP in a Western population.MethodsSinonasal tissues and nasal lavage fluids were obtained from control patients and patients with CRS, and neutrophil markers were determined by ELISA. The presence of neutrophils in tissue was determined by flow cytometry. The gene expression profiles in neutrophils were determined by RNA sequencing.ResultsA neutrophil marker elastase was selectively elevated in nasal polyp (NP) tissue, whereas eosinophilic cationic protein (an eosinophil marker) was elevated in both uncinate and NP tissues of CRSwNP patients. Nasal lavage fluid myeloperoxidase (another neutrophil marker) was also significantly elevated in CRSwNP compared to control patients. Neutrophil markers were more greatly elevated in CRSwNP patients with recurrent disease. Flow cytometric analysis confirmed that neutrophil numbers were significantly elevated in NPs compared to control tissues. RNA sequencing analysis found that 344 genes were >3-fold and significantly elevated in NP neutrophils compared to peripheral blood neutrophils. Gene Ontology analysis suggested that the elevated genes in NP neutrophils were significantly associated with activation. Results suggest that neutrophils are accumulated in T2 NP tissues and that accumulated neutrophils are highly activated and contribute to inflammation in NPs.ConclusionsNeutrophils may play a heretofore unrecognized meaningful role in the pathogenesis of CRSwNP in Western countries and may be a potentially important therapeutic target in T2 CRSwNP.

| S-EPMC9081139 | biostudies-literature

Exon Array Analysis of Asthmatic Chronic Rhinosinusitis with Nasal Polyps

Project description:Asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP) is a common disruptive eosinophilic disease. Therefore, we sought to identify gene expression changes in nasosinus inflamed mucosa and adjacent polyp tissue from subjects with aCRSwNP.

2010-08-12 | GSE23552 | GEO

In-depth proteomic analysis of nasal secretions from chronic rhinosinusitis and nasal polyps

Project description:Considering the complex and multifarious features of Chronic rhinosinusitis (CRS) including immunologic patterns, novel modalities are needed to reflect clinical and pathophysiological endotypes beyond nasal polyps.We aimed to investigate the proteome of nasal secretions on filter paper from CRS patients to characterize endotypes.

2019-07-29 | PXD013330 | Pride

Association between methylation in nasal epithelial TSLP gene and chronic rhinosinusitis with nasal polyps.

Project description:Background:This study was performed to determine whether there was any association between abnormal DNA methylation of a thymic stromal lymphopoietin (TSLP) locus and pathogenesis of chronic rhinosinusitis (CRS). Methods:A total of 48 CRS patients with nasal polyps (CRSwNP), 28 CRS patients without nasal polyps (CRSsNP) and 21 control subjects were enrolled into the study; and evaluated for serum total IgE level, olfactory score and nasal resistance. Samples were obtained from nasal polyps of CRSwNP patients, ethmoid mucosae of CRSsNP patients and inferior turbinate (IT) mucosa of control subjects during surgery, and used to isolate purified primary human nasal epithelial cells (HNECs). Genomic DNA was extracted from purified primary HNECs of each subject and DNA methylation ratios for a selected region of the TSLP gene were screened the using MassARRAY EpiTYPER. Results:A total of 17 CpG units were analyzed; of which two CpG units (CpG3 and 22:23:24) had increased methylation ratios in the CRSwNP patients compared to the CRSsNP and control subjects after correction for false discovery rate (FDR) (Q?<?0.1). The methylation ratios at both CpG3 and CpG22:23:24 units were positively correlated with olfactory score (r?=?0.41, P?=?0.0001; r?=?0.25, P?=?0.021) and unilateral nasal resistance at 75 Pa (r?=?0.24, P?=?0.04; r?=?0.24, P?=?0.036) and 150 Pa (r?=?0.34, P?=?0.004; r?=?0.25, P?=?0.031). Total nasal resistance at 75 Pa/150 Pa or serum total IgE levels were not correlated with the methylation ratios at either CpG unit. Conclusions:Increased DNA methylation at the TSLP locus is likely to be associated with CRSwNP pathogenesis; however these findings need to be confirmed in larger multicentre group studies.

| S-EPMC6873565 | biostudies-literature

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