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Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes

Most patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have type 2 inflammation, as do patients with eosinophilic asthma [1-3]. Asthma often accompanies CRSwNP [4, 5], and CRSwNP with comorbid asthma is associated with more severe sinonasal disease [5-7]. Furthermore, asthma is more prone to exacerbations when comorbid CRSwNP is present [5, 8]. The aim of this study was to describe the prevalence of asthma and evaluate asthma control in patients with uncontrolled CRSwNP undergoing endoscopic sinus surgery (ESS) at a tertiary centre. We also aimed to identify factors associated with asthma in this population. This cross-sectional study was conducted as part of a prospective controlled multicentre trial (AirGOs Operative) investigating the benefits of complete and limited ESS in patients with uncontrolled CRSwNP. Patients suffering from uncontrolled CRSwNP, a Sinonasal Outcome Test-22 (SNOT-22) score ≥30, a nasal polyp (NP) score ≥4, a Lund–Mackay (LM) score ≥14 and at least one of the following: ≥1 previous surgery for CRSwNP, ≥1 oral corticosteroid course or ≥3 antibiotic courses during the past 2 years were included in this study. In addition to basic characteristics and comorbidities, the data in this study comprised preoperative nasoendoscopy, NP and LM scores, exhaled nitric oxide (eNO), blood eosinophil count (B-eos), serum immunoglobulin E concentration (S-IgE), serum allergen-specific IgE measurements, Sniffin' Sticks Screening 12 Test (SST-12) and Health-Related Quality of Life (HRQoL) of the upper and lower airways (SNOT-22, Asthma Control Test [ACT] and 15D). Asthma was assessed and diagnosed systematically. Previous asthma diagnosis was based on medical record information for physician-diagnosed asthma. The prevalence of previous physician-diagnosed asthma (AB), asthma diagnosed in the preoperative tests (preAB), and no asthma were calculated. All the patients underwent spirometry and a bronchodilator test and peak expiratory flow (PEF) recording preoperatively [9]. Methacholine challenge test was performed for patients with asthma symptoms (prolonged or night-time cough, wheezing or shortness of breath with or without auscultatory wheezing) but without AB and with undiagnostic results in spirometry and PEF recording. In spirometry, improvement with a bronchodilator in forced expiratory volume in the first second (FEV1) or forced vital capacity of at least 12% and 200 mL was considered diagnostic for asthma [9]. In PEF recording, diurnal variability (≥20% and 60 L/min at least three times) or bronchodilator responsiveness (≥15% and 60 L/min at least three times) was considered diagnostic for asthma. In the methacholine challenge test, moderate or severe hyperreactivity (a cumulative dose of ≤600 μg inhaled methacholine causes a 20% reduction in FEV1) was considered diagnostic for asthma. Uncontrolled asthma in AB and preAB patients was defined as one or more of the following: ACT score <20 [9] or significant reversible airflow obstruction in PEF recording or spirometry. Statistical analyses were performed with the chi-squared test, permutation test, Kruskall–Wallis test, analysis of variance, t-test, Mann–Whitney U-test and logistic regression analysis for odds ratio. Of the 87 patients with uncontrolled CRSwNP, 69 (79%) suffered from asthma preoperatively. Fifteen patients (17%) had previously undiagnosed asthma (preAB). Eighty per cent of the patients had severely decreased HRQoL, with SNOT-22 ≥ 40. There were no differences between the AB, preAB and no-asthma groups in sex, body mass index (BMI), mean age, prevalence of high scores in questions 6 and 14 evaluating cough and night awakening in SNOT-22, ASA intolerance or NP, LM or SST-12 scores. The prevalence of allergic rhinitis was more common in the AB and preAB groups (n = 28, 52%, and n = 9, 60%, respectively) than in the no-asthma group (n = 3, 17%) (p = 0.017). B-eos was elevated in all the groups (mean 0.54 E9/L, SD 0.41, range 0–2.84 in the whole study population) but did not differ between the groups (Table 1). In patients with AB, eNO was higher than in those with no asthma (p = 0.041), but the relationship between asthma (preAB or AB) and eNO was not significant after adjusting for smoking and allergic rhinitis (p = 0.11). Allergic rhinitis had a relationship with asthma (AB or preAB) in multivariate analysis (odds ratio 5.41, 95% CI 1.24–23.61) when sex, age, BMI, smoking status and ASA intolerance were included. There was a weak correlation between the SNOT-22 and ACT scores (−0.23 [95% CI −0.42 to −0.01]). ACT total score < 20, n (%) Asthma was uncontrolled preoperatively in 40 (58%) patients suffering from asthma. Sex, age, BMI, smoking status, ASA intolerance, allergic rhinitis, B-eos, NP score, LM score, anosmia and eNO did not differ between the controlled and uncontrolled asthma groups. The small sample size was a limitation of this study, and the results should be verified with studies in other populations and with larger sample sizes. These results are likely to be applicable to patients with the clinical assessment criteria used and an indication for surgery. Most patients in this study had severely decreased HRQoL, with a SNOT-22 score of at least 40. The strengths of this study were its systematic evaluation of HRQoL with the SNOT-22, ACT and 15D questionnaires and its concurrent examination of the upper airway (LM and NP scores, SST-12) and lower airway (spirometry, PEF recording and eNO). Asthma is known to exacerbate the symptoms of CRSwNP. These results show that asthma and uncontrolled asthma are commonly found in patients with uncontrolled CRSwNP undergoing sinus surgery. These patients benefit from a comprehensive evaluation of both upper and lower airway diseases preoperatively. Data collection was performed by E.G., J.S., A.L.-H., M.L., S.H.-M., L.H., A.M., S.V., S.T.-S., and P.V. The planning of the study, data analyses, and interpretation were performed by E.G., P.K., S.T.-S., and P.V. The manuscript was written by E.G., P.K., J.S., A.L.-H., M.L., S.H.-M., L.H., A.M., S.V., S.T.-S., and P.V. This work was funded by Helsinki University Hospital research funds, The Paulo Foundation, The Foundation in Memory of Dorothea Olivia, Karl Walter and Jarl Walter Perklén, Tampere Tuberculosis Foundation, Jalmari and Rauha Ahokas Foundation, Mjölbolsta Foundation of Medical Research, Allergy Research Foundation, Foundation of the Finnish Anti-Tuberculosis Association, state funding for university-level health research, and a Helsinki ENT Hospital grant from Finnish ORL-HNS Foundation. The funders were not involved in the study design, data collection, analysis and interpretation, manuscript writing, or decision-making regarding the submission of the work. We want to thank study nurses Elisa Piccinini, Deniza Salihi, and Catharina Pomoell for their contributions and assistance in the data collection. The study nurses were funded by a Helsinki ENT Hospital grant from Finnish ORL-HNS Foundation and Tampere Tuberculosis Foundation. We also want to thank Hannu Kautiainen, PhD, for providing us with a statistical consultancy. Research permission (HUS/66/2018) was granted on June 21, 2018, by the Institutional Review Board of Helsinki University Hospital and ENT Hospital and was extended on February 22, 2023 (HUS/53/2023). The Research Ethical Board of the Helsinki and Uusimaa Hospital District approved the study design (HUS/1801/2017) on September 14, 2017. Informed consent was obtained from the study participants. The study was registered in ClinicalTrials.gov, NCT03704415. E.G. reports a lecture fee from GlaxoSmithKline, a manuscript fee from the Finnish doctors' society Duodecim, and an abroad congress fee from Orion. P.K. reports lecturing fees from GlaxoSmithKline, consultancies for Swedish Orphan Biovitrum and the Finnish Patient Insurance Center, grants from Allergy Research Foundation, positions as Principal Investigator for Theravance Pan Janus kinase inhibitor TD-0903 and president of the Finnish Respiratory Society. J.S. reports a congress fee from Sanofi and consultancy for GlaxoSmithKline. A.L.-H. reports consultancies for GlaxoSmithKline, Sanofi and Galenus Health, congress fees from Karl Storz, a confidential post at European Rhinologic Society delegate and a grant from Sanofi. S.T.S. reports consultancies for ALK-Abelló, AstraZeneca, Clario, GlaxoSmithKline, Novartis, Sanofi, Orion, Roche Products and grants from GlaxoSmithKline and Sanofi. P.V. reports lecturing fees from Sanofi and GlaxoSmithKline. M.L., S.H.-M., L.H., A.M. and S.V. report no conflicts of interest. The data are available from the corresponding author upon reasonable request. They are stored in a controlled access data storage at Helsinki University Hospital.

Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois

Suppressor of cytokine signaling 3 expression is diminished in sinonasal tissues from patients with chronic rhinosinusitis with nasal polyps

The aim of this study was, firstly, to classify patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) into inflammatory endotypes and, secondly, to investigate the relationships between blood and tissue eosinophilia and clinical outcomes in CRSwNP, including disease severity, and recurrence. This cross-sectional, observational, nonrandomized study has been realized between January 2023-December 2024 enrolling a sample of 469 consecutive patients with chronic rhinosinusitis, of which 239 patients with CRSwNP and 230 patients with CRSsNP. The classification of CRSwNP and CRSsNP into inflammatory endotypes was performed by analyzing the levels of blood and tissue eosinophilia. The prevalence of asthma and allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) in the two groups was also analyzed. In the group of patients with CRSwNP, the severity of the disease and the level of quality of life impairment were evaluated, depending on the degree of tissue eosinophilia. The importance of the association between blood vs. tissue eosinophilia and the relapse of CRSwNP was also assessed. The proportion of patients with elevated blood eosinophil levels was higher in CRSwNP than CRSsNP (17.4% vs. 4.35%). Tissue eosinophilia was identified in 163 of 235 (69.4%) patients with CRSwNP compared with 29 of 230 (12.6%) patients with CRSsNP. From an inflammatory perspective, revision surgery was strongly associated with tissue eosinophilia. In contrast, elevated blood eosinophil levels were only moderately associated with revision surgery.

Background:Chronic rhinosinusitis with nasal polyps (CRSwNP) has a complex pathogenesis and is difficult to treat, which brings a huge economic burden to society. Despite all the progress in the treatment of CRSwNP, some patients with CRSwNP still experience recurrence. Therefore, there is an urgent need to develop novel drugs and treatments for CRSwNP. Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and mediates type 2 and nontype 2 inflammation through various downstream cellular immune and inflammatory pathways. Anti-TSLP treatment with tezepelumab has been proven to be effective in treating patients with uncontrolled asthma, regardless of their peripheral blood eosinophil levels being low or high. However, there is no relevant research on the usage of anti-TSLP monoclonal antibodies for the treatment of uncontrolled CRSwNP.Objective:This is the first phase Ib/IIa study for subjects with uncontrolled CRSwNP, aiming to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of multiple ascending doses (MAD) of anti-TSLP monoclonal antibody.Methods:The DUBHE is a multicenter, randomized, double-blind, placebo-controlled, phase Ib/IIa clinical study. The study will be composed of 3 periods: a screening/run-in period of 4 weeks, a treatment period of 52 weeks (16 weeks of double-blind treatment period +36 weeks of open-label treatment period), and a safety follow-up period of 12 weeks. No more than 113 subjects with uncontrolled CRSwNP will be divided into 4 groups to receive different doses of CM326 or placebo treatments (55 mg every two weeks [Q2W] group, 110 mg Q2W group, 220 mg Q2W group, and 220 mg every four weeks [Q4W] group). Enrolled patients will be stratified by tissue eosinophil count (TEC).Results:The safety of the monoclonal antibody that targets TSLP in uncontrolled CRSwNP and its preliminary efficacy at 16 weeks of treatment.Conclusion:In this study, for the first time, the safety and preliminary efficacy of MAD of CM326 will be verified. The efficacy of CM326 in patients with eosinophilic CRSwNP (TEC ≥55/high power field [HPF]), as well as noneosinophilic CRSwNP (TEC <55/HPF) will be testified.Trial registration:NCT05324137.

Regulation and characterization of IL-17A expression in patients with chronic rhinosinusitis and its relationship with eosinophilic inflammation

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses that often coexists with asthma. The role of atopy in the development and severity of CRSwNP is still a controversial issue. Objective: The aim of our study was to propose a systematic allergy workup to identify atopic patients in the context of CRSwNP and to characterize their allergen sensitization profile (sources/molecules). Methods: Patients with a diagnosis of CRSwNP (n = 97) were studied in the otorhinolaryngologist and allergy settings. Demographic and clinical data were collected for each patient. Different allergen sensitization profiles (sources/molecules) were evaluated in atopic CRSwNP patients by using component-resolved diagnosis (CRD). Results: In our cohort of patients, the CRSwNP was frequently diagnosed during adulthood with significant impact on health-related quality of life. Asthma and atopy were the most common comorbidities with a prevalence of asthma in the atopic group. In CRSwNP patients sensitized to grass pollens and/or to house dust mites, the CRD analysis revealed a prevalence of sensitization to species-specific allergens of Phleum pratense (Phl p1, Phl p2, and Phl p5) or Dermatophagoides pteronyssinus (Der p1 and Der p2) rather than to cross-reactive ones. Conclusion: To define the allergen sensitization profile in atopic CRSwNP patients by CRD, it may be useful to better characterize type 2 inflammation, thus providing a personalized endotype-driven treatment.

Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps

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.

BackgroundChronic rhinosinusitis (CRS) current therapeutic approaches still fail in some patients with severe persistent symptoms and recurrences after surgery. We aimed to evaluate the master transcription factors gene expression levels of T cell subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) that could represent new, up-stream targets for topical DNAzyme treatment.Patients and methodsTwenty-two newly diagnosed CRS patients (14 CRSwNP and 8 CRSsNP) were prospectively biopsied and examined histopathologically. Gene expression levels of T-box transcription factor (T-bet, TBX21), GATA binding protein 3 (GATA3), Retinoic acid-related orphan receptor C (RORC) and Forkhead box P3 (FOXP3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR).ResultsEosinophilic CRSwNP was characterized by higher level of GATA3 gene expression compared to noneosinophilic CRSwNP, whereas there was no difference in T-bet, RORC and FOXP3 between eosinophilic and noneosinophilic CRSwNP. In CRSsNP, we found simultaneous upregulation of T-bet, GATA3 and RORC gene expression levels in comparison to CRSwNP; meanwhile, there was no difference in FOXP3 gene expression between CRSwNP and CRSsNP.ConclusionsIn eosinophilic CRSwNP, we confirmed the type 2 inflammation by elevated GATA3 gene expression level. In CRSsNP, we unexpectedly found simultaneous upregulation of T-bet and GATA3 that is currently unexplained; however, it might originate from activated CD8+ cells, abundant in nasal mucosa of CRSsNP patients. The elevated RORC in CRSsNP could be part of homeostatic nasal immune response that might be better preserved in CRSsNP patients compared to CRSwNP patients. Further data on transcription factors expression rates in CRS phenotypes are needed.

microRNAs (miRNAs) are directly associated with inflammatory response, but their direct role in CRSwNP (chronic rhinosinusitis with nasal polyps) remains evasive. This study aimed to compare the expression of several miRNAs in tissue samples obtained from patients with CRSwNP and controls and to evaluate if miRNAs correlate to a specific inflammatory pattern (T1, T2, T17, and Treg) or intensity of symptoms in CRSwNP. nasal polyps (from patients with CRSwNP - n=36) and middle turbinate mucosa (from control patients - n=41) were collected. Microarray determined human mature miRNA expression, and the results obtained were validated by qPCR. miRNAs that were differentially expressed were then correlated to cytokine proteins (by Luminex), tissue eosinophilia, and SNOT-22. After microarray and qPCR analyses, six microRNAs were up-regulated in CRSwNP samples when compared with controls: miR-205-5p, miR-221-3p, miR-222-3p, miR-378a-3p, miR-449a and miR-449b-5p. All these miRNAs are directly implicated with cell cycle regulation and apoptosis, and to a minor extent, with inflammation. Importantly, miR-205-5p showed a significantly positive correlation with IL-5 concentration and eosinophil count at the tissue and with the worst SNOT-22 score. miRNA 205-5p was increased in CRSwNP compared to controls, and it was especially expressed in CRSwNP patients with higher T2 inflammation (measured by both IL-5 levels and local eosinophilia) and worst clinical presentation. This miRNA may be an interesting target to be explored in patients with CRSwNP.

Studies on activation and regulation of the coagulation cascade in chronic rhinosinusitis with nasal polyps

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disease with a high postoperative recurrence rate. This study is aimed at exploring the expression of B cell-activating factor (BAFF) in CRSwNP and its association with postoperative recurrence. Methods A total of 80 CRSwNP patients, including 40 primary CRSwNP patients and 40 recurrent CRSwNP patients, 40 chronic rhinosinusitis without nasal polyps (CRSsNP) patients, and 40 healthy controls (HC) were enrolled in this study, and the serum and tissue samples were collected. The circulating and tissue BAFF expressions were detected by enzyme-linked immunosorbent assay reverse transcription-polymerase chain reaction and immunohistochemistry. Their clinical values for predicting postoperative recurrence of CRSwNP were evaluated. Results We determined serum levels of BAFF were remarkably increased in the CRSwNP group than the CRSsNP and HC groups (P < 0.05), and higher concentrations of BAFF were associated with peripheral eosinophil percentage (r = 0.614, P < 0.001). The serum BAFF concentrations were significantly higher in the recurrent CRSwNP group in comparison with the primary group (P < 0.05). Multivariate analysis and receiver operating characteristic (ROC) curve presented that serum BAFF levels were associated with the postoperative recurrence in CRSwNP patients (P < 0.05). Moreover, tissue BAFF levels were significantly increased in the CRSwNP group than the HC group, especially in the recurrent CRSwNP group (P < 0.05), and enhanced BAFF RNA expressions were correlated with serum BAFF levels (r = 0.703, P < 0.001). Conclusion Our results elucidated that the BAFF expression was enhanced in CRSwNP patients and associated with postoperative recurrence. BAFF could be a serologic biomarker for predicting postoperative recurrence in CRSwNP patients.

Obstructive sleep apnea in patients with chronic rhinosinusitis with nasal polyps: a cross-sectional study