Eosinophils are the dominant type2 marker for the current indication of biological treatment in severe uncontrolled chronic rhinosinusitis with nasal polyps.

The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) defines markers for type2 inflammation in the context of indicating biological therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) as either a total serum immunoglobulin E (total-IgE) <100 kU/L, a blood eosinophil count (BEC, expressed as -109 cells / L) >=0.25, or a tissue eosinophil count >=10 per high power field (HPF) (1). Recently, an EPOS/EUFOREA expert panel advised to lower the threshold for BEC from >=0.25 (EPOS2020) to >=0.15 (EUFOREA2023) to align with thresholds used for biological indication in asthma patients (2). As far as we know, there is no literature supporting the cut-off value for total-IgE.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

Aberrant expressions of TAM receptors are associated with postoperative recurrence in chronic rhinosinusitis with nasal polyps.

OBJECTIVES: TAM receptors (TYRO3, AXL, and MER) play important roles in inflammatory responses, but their effects in chronic rhinosinusitis with nasal polyps (CRSwNP) remain elucidated. We aim to evaluate the values of TAM receptors in disease severity and postoperative recurrence of CRSwNP. METHODS: We initially enrolled 160 patients with CRSwNP who were treated with functional endoscopic sinus surgery (FESS) and postoperative recurrence was evaluated during the follow-up period. Circulating TAM receptor levels were detected by enzyme-linked immunosorbent assay (ELISA), and tissue expressions were measured by real-time polymerase chain reaction (RT-PCR) and immunohistochemical (IHC). The relationships between TAM receptor levels and postoperative recurrence were examined. RESULTS: A total of 150 patients completed the follow-up schedule, 49 patients experienced postoperative recurrence and the remaining 101 patients were non-recurrent. In recurrent CRSwNP patients, serum levels of TAM receptors were increased compared to those in non-recurrent patients and were positively correlated with disease severity scores (P < 0.05). Circulating TYRO3 and MER were identified as potential predictors of postoperative recurrence based on receiver operating characteristics (ROC) and Kaplan-Meier plots (P < 0.05). Furthermore, tissue TAM receptor levels, as determined by both RT-PCR and IHC, were enhanced in the recurrent group than in the non-recurrent group (P < 0.05) and were predictive of postoperative recurrence (P < 0.05). Interestingly, circulating TYRO3 and MER concentrations, as well as tissue TYRO3 expression, were found to be significantly increased in patients who experienced postoperative recurrence (P < 0.05). IHC images from the same patients revealed that TAM expressions were enhanced in the recurrent tissues compared to their baseline tissue levels. CONCLUSIONS: Our laboratory results demonstrated that TAM receptors were increased in recurrent CRSwNP patients and associated with postoperative recurrence. Moreover, the new laboratory findings suggested that measuring circulating levels of TAM receptors might serve as a promising new approach to assess disease progression and predict the risk of postoperative recurrence.

Predictive Values of Serum IL-33 and sST2 in Endotypes and Postoperative Recurrence of Chronic Rhinosinusitis with Nasal Polyps.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disease with high heterogeneity and postoperative recidivation. The IL-33/ST2 axis is known to be involved in Th2 immune responses. This study is aimed at exploring levels of serum IL-33 and soluble ST2 (sST2) in CRSwNP patients and their potential for predicting CRSwNP endotypes and postoperative recurrence. Methods: The present study recruited 149 CRSwNP patients, 80 of whom were noneosinophilic (neCRSwNP) and 69 eosinophilic (eCRSwNP), as well as 60 healthy controls (HCs). Serum samples were collected from all participants, and sST2 and IL-33 concentrations were measured using ELISA. Multivariate analysis, receiver operating characteristic (ROC) curves, and Kaplan-Meier curves were used to evaluate the value of serum sST2 and IL-33 levels in distinguishing CRSwNP endotypes and predicting postoperative recurrence. Results: The levels of serum sST2 and IL-33 in CRSwNP patients were significantly higher than those in HCs, especially in the eCRSwNP group. Increased sST2 and IL-33 levels were associated with eosinophil counts and percentages in both tissue and blood. Multivariate regression and ROC curve analysis showed that serum sST2 and IL-33 exhibited potential for distinguishing CRSwNP endotypes, and the combination of serum IL-33 and sST2 showed even more predictive power. Finally, 124 CRSwNP patients completed the entire 3-year follow-up. Multivariate analysis and Kaplan-Meier curves showed that serum sST2 and IL-33 levels were associated with recurrence; serum sST2 and IL-33 each exhibited potential for predicting postoperative recurrence, and combining serum sST2 and IL-33 exhibited better accuracy and practicability. Conclusion: Our results suggested that serum sST2 and IL-33 levels were upregulated in CRSwNP patients and related to the degree of mucosal eosinophil infiltration and postoperative recurrence. Serum sST2 and IL-33 might serve as objective biomarkers for distinguishing phenotypes and predicting recurrence in CRSwNP, and their combined use outperformed either marker alone.

Circulating BAFF as novel biomarker in distinguishing chronic rhinosinusitis with nasal polyps endotypes and predicting postoperative recurrence.

BACKGROUND: B cell-activating factor (BAFF) is a proinflammatory cytokine involved in inflammatory and allergic diseases, but its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. This study aims to explore the predictive value of circulating BAFF in CRSwNP endotypes and postoperative recurrence. METHODS: We recruited 120 CRSwNP patients, including 68 non-eosinophilic CRSwNP (neCRSwNP) patients, 52 eosinophilic CRSwNP (CRSwNP) patients, and 60 healthy controls (HCs). Circulating BAFF levels of all participants were measured by enzyme-linked immunosorbent assay (ELISA), and receiver-operating characteristic (ROC) and logistic regression analyses were applied to assess the predictive ability of BAFF levels in distinguishing CRSwNP endotypes. All CRSwNP patients were followed for more than 3 years, and the predictive value of circulating BAFF for postoperative recurrence was evaluated. RESULTS: Serum BAFF levels were elevated in CRSwNP patients compared with the HCs (P < 0.01) and significantly higher in eCRSwNP patients. The increased serum BAFF concentrations positively correlated with blood eosinophil counts and percentages, tissue eosinophil counts, and serum total IgE (P < 0.05). The ROC curve showed that serum BAFF exhibited strong discriminative ability for eCRSwNP. Finally, 99 CRSwNP patients completed the follow-up schedule, 65 patients were classified into non-recurrence group and the other 34 patients were categorized into recurrence group. Serum BAFF levels were significantly higher in recurrence group than non-recurrence group (P < 0.001), and the ROC curve suggested a high predictive value of serum BAFF in predicting postoperative recurrence. Moreover, logistic regression and Kaplan-Meier curves showed that serum BAFF was an independent risk factor for postoperative recurrence (P < 0.05). CONCLUSION: Our data suggested that serum BAFF levels were upregulated in CRSwNP patients and correlated with mucosal eosinophil infiltration severity. Serum BAFF seemed to be a novel biomarker for preoperatively distinguishing CRSwNP endotypes and predicting postoperative recurrence.

The role of serum macrophage migration inhibitory factor in preoperative prediction of chronic rhinosinusitis with nasal polyps endotypes.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease and can be categorized into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP). Exploring effective biomarkers to distinguish endotypes is important for personalized therapies. The present study aims to evaluate the predictive value of serum MIF in CRSwNP endotypes. METHODS: One hundred and twenty CRSwNP patients, including 51 eCRSwNP and 69 neCRSwNP, 40 chronic rhinosinusitis without nasal polyps (CRSsNP) patients and 40 healthy controls (HC) were enrolled. Serum MIF levels were determined by enzyme-linked immunosorbent assay (ELISA). The patients' clinical variables were analyzed for correlations with serum MIF. Receiver operating characteristic (ROC) curve and multivariate analysis were utilized to assess the predictive value of serum MIF in CRSwNP endotypes. RESULTS: The serum MIF levels were significantly higher in CRSwNP group than CRSsNP group and HC group (P < 0.001), and the serum MIF levels were increased in eCRSwNP compared to neCRSwNP group (P = 0.006). Elevated serum MIF levels were significantly correlated with blood eosinophil (B-EOS) count (r = 0.411, P < 0.001), B-EOS percentage (r = 0.377, P < 0.001), visual analog scale score (r = 0.204, P = 0.025), tissue eosinophil (T-EOS) count (r = 0.705, P < 0.001) and T-EOS percentage (r = 0.671, P < 0.001) in CRSwNP patients. ROC curve demonstrated that serum MIF exhibited good preoperative prediction in CRSwNP endotypes (area under the curve = 0.925, P < 0.001). Multivariate regression analysis showed that serum MIF was an independent factor associated with CRSwNP endotypes. CONCLUSIONS: This was the first study identifying serum MIF as a possible specific biomarker for preoperatively distinguishing CRSwNP endotypes. Furthermore, the serum MIF levels were found to be closely associated with the degree of mucosal eosinophil infiltration.

Dysregulated Maresin Concentrations in Plasma and Nasal Secretions From Patients With Chronic Rhinosinusitis.

The mechanisms that lead to disease onset and propagation in patients with chronic rhinosinusitis (CRS) are not fully elucidated. Maresins (MaR) are a family of essential fatty acid-derived lipid mediators that play a central role in the regulation of inflammation with several studies demonstrating that these mediators display protective activities in airway inflammation. Therefore, in the present studies we evaluated whether concentrations of these mediators were altered in both peripheral blood and nasal secretions from CRS patients. Herein, we focused on patients with CRS that also develop nasal polyps (CRSwNP), given that therapeutic options for the treatment of these patients are limited. Thereby, insights into disease mechanisms in these patients may help design more effective treatments. For this purpose, we compared maresin concentrations from CRSwNP patients with those found in healthy volunteers or patients with an upper respiratory tract infection (URTI), as a self-resolving inflammatory condition. Using liquid chromatography tandem mass spectrometry, we found that MaR concentrations were significantly decreased in plasma from patients with CRSwNP when compared to healthy volunteers. MaR concentrations were observed to be significantly upregulated in nasal secretions from patients with CRSwNP when compared with both healthy volunteers and URTI subjects. Concentration of these mediators in both plasma and nasal secretions from CRSwNP patients were positively correlated with quality-of-life scores in these patients. Assessment of the concentrations of other pro-resolving and pro-inflammatory lipid mediators (LM) demonstrated that there was a general shift in LM levels in both plasma and nasal secretions from CRSwNP when compared with healthy volunteers and URTI subjects. Of note, incubation of peripheral blood cells from CRSwNP patients with MaR1 downregulated the expression of activation markers on peripheral blood phagocytes, including CD41 and CD62P, markers of platelet-leukocyte heterotypic aggregates. Together these findings demonstrate that both local and systemic LM concentrations, in particularly those of the MaR family, become altered in patients with CRSwNP. They also suggest that therapeutics designed around MaR1 may be useful in regulating the activation of phagocytes in patients with CRSwNP thereby potentially also limiting the local inflammatory response in these patients.

Interleukin-6 reverses Adriamycin resistance in nasal NK/T-cell lymphoma via downregulation of ABCC4 and inactivation of the JAK2/STAT3/NF-κB/P65 pathway.

Chemotherapy is generally effective for extranodal natural killer (NK)/T-cell lymphoma (ENKTCL), nasal type. Nevertheless, multidrug resistance (MDR) remains a key challenge in treating nasal NK/T-cell lymphoma. Interleukin-6 (IL-6) is reportedly an important regulator of MDR in many cancers, implicating a role of IL-6 in the chemotherapy response. However, the effects and mechanism of IL-6 in nasal NK/T-cell lymphoma remain unclear. Herein, we demonstrated that the IL-6 serum level was decreased in nasal NK/T-cell lymphoma patients compared to chronic rhinitis patients. Lower serum levels of IL-6 were closely correlated with Ki67 expression and patient survival. ATP-binding cassette (ABC) drug transporter ABCC4 in patients was abnormally upregulated. IL-6 significantly inhibited resistance to Adriamycin (ADM) in ADM-resistant SNK-6 cells (SNK-6/ADM). Moreover, IL-6 resulted in cell cycle arrest and led to apoptosis in SNK-6/ADM cells. Furthermore, IL-6 decreased ABCC4, p-JAK2, p-STAT3, and phospho-NF-κB p65 expression in SNK-6/ADM cells. IL-6 in combination with ADM inhibited tumor growth and increased the survival of SNK-6/ADM xenograft mice. In conclusion, our findings suggest that IL-6 can inhibit the upregulation of ABCC4 and inactivate the JAK2/STAT3/NF-κB/P65 pathway to sensitize NK/T-cell lymphoma to ADM, indicating that combination therapy with IL-6 and other chemotherapeutic drugs may be effective in reversing acquired resistance in nasal NK/T-cell lymphoma.

Peripheral blood eosinophil levels in chronic rhinosinusitis and its predictive value in eosinophilic chronic rhinosinusitis.

BACKGROUND: The prevalence of eosinophilic CRSwNP in China has increased significantly over the last 20 years, noninvasive methods that could assist in diagnosis are urgently needed. AIMS: The aim of this study is to explore the clinical significance of peripheral blood eosinophil in diagnosing ECRS. MATERIALS AND METHODS: We conducted a prospective study of 221 patients diagnosed with CRS. Lund-Mackay score, peripheral blood eosinophil absolute count, peripheral blood eosinophil percentage were detection to compare the clinical features with ECRS and non-ECRS. ROC curve was performed to assess the efficiency of clinical index to predict ECRS. RESULTS: The ECRS group of patients had significantly higher scores compared with those of the non-ECRS group. Different extent and severity of mucosal thickening on total Lund-Mackay scores, anterior ethmoidal, posterior ethmoidal and ostiomeatal complex have confirmed different blood eosinophil levels in CRS patients. The combination of peripheral blood eosinophil percentage and posterior ethmoidal score to predict ECRS was 0.807. CONCLUSIONS AND SIGNIFICANCE: The increase in peripheral blood eosinophil percent indicates the deterioration the inflammation of chronic rhinosinusitis and the level of posterior ethmoidal score and peripheral blood eosinophil percentage have a positive predictive value regarding ECRS identification.

Type 2 Inflammatory Shift in Chronic Rhinosinusitis During 2007-2018 in Belgium.

OBJECTIVES/HYPOTHESIS: Chronic rhinosinusitis (CRS) is a heterogenic disease with different inflammatory patterns depending on the presence (CRSwNP) or absence (CRSsNP) of polyps and geographical location. A shift toward type 2 endotype has been seen in Asia. We aim to investigate whether there has been type 2 shift in Belgium and to further endotype CRS based on clinical markers. STUDY DESIGN: Prospective descriptive study. METHODS: Four hundred and thirty eight patients with CRS undergoing sinus surgery at Ghent University Hospital between 2007 and 2018 were included and stratified based on phenotype, comorbidities, inflammatory markers in tissue, and two different time points of surgery. Tissue samples from surgery were analyzed for type 2 markers. In a subgroup of CRSwNP blood eosinophils (EBC) was available. RESULTS: There was an increase in type 2 inflammatory markers in the latter group versus the earlier, in non-asthmatic, non-allergic CRS patients regardless of phenotype. The proportion of IL-5+ patients was elevated in the latter group in CRSwNP. Inflammatory markers and comorbidities differ between IL-5+ CRSsNP and CRSwNP subjects, no difference was seen in IL-5- CRS. EBC can together with information on comorbidities help identify type 2 CRSwNP in a clinical setting. CONCLUSION: There is a shift toward type 2 inflammation within the CRS population over recent 8 years also in Belgium. This shift implies that we expect to see more cases of severe and difficult to treat CRS in the future. Polyp formation is not directly linked to the presence or concentrations of type 2 inflammatory markers. Clinical parameters and EBC > 300 cells/µL can be used to identify type 2 CRSwNP. LEVEL OF EVIDENCE: 3. Laryngoscope, 131:E1408-E1414, 2021.

Systemic Immune Profile in Patients With CRSwNP.

The immune pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remains obscure. Our aim was to compare humoral immunity and white blood cell counts in patients with CRSwNP and controls. A prospective case-control study was carried out in 37 patients with CRSwNP and 34 controls without CRS. Clinical data were gathered through a systematic interview. Computed tomography scan, skin prick test, spirometry, and immunological parameters (leukocyte differential count, immunoglobulin classes, and immunoglobulin [Ig] G subclasses) in serum specimens were obtained. Statistical analysis was performed using SPSS v.23. The prevalence of chronic lower respiratory diseases was greater in the CRSwNP group (P < .001), but atopic disease had no significant difference. A significantly higher eosinophil (P < .001) and basophil relative count (P = .022) and a lower relative neutrophil count (P = .013) were found among CRSwNP group. Patients with CRSwNP had higher IgG1 (P = .022), but lower IgG2 (P = .014) and IgG3 (P = .018) serum levels compared to controls; IgG4, total IgG, IgA, IgM, and IgE serum levels did not differ between groups, as well as the prevalence of immunoglobulin classes or IgG subclasses deficiency. The variation observed in peripheral relative leukocyte count and the systemic IgG1 subclass shift are similar to what is known to happen in nasal polyp tissue. A unique systemic immune profile seems to be present in patients with CRSwNP.

Elevated Urine Leukotriene E4 Is Associated With Worse Objective Markers in Nasal Polyposis Patients.

OBJECTIVES: Urine leukotriene E4 (uLTE4) is a biomarker of leukotriene synthesis and is elevated in patients with aspirin-exacerbated respiratory disease (AERD). It can also be useful to help delineate aspirin-tolerant chronic rhinosinusitis with nasal polyposis (CRSwNP) patients from AERD patients. The purpose of this study is to determine if uLTE4 biomarker levels are associated with objective and subjective markers of disease severity in patients with CRSwNP. METHODS: A retrospective analysis of CRSwNP patients who underwent uLTE4 testing was completed to determine the association of uLTE4 levels to markers of disease severity. uLTE4 levels, as well as presenting subjective (Sinonasal Outcome Test 22 [SNOT22] scores, asthma control test [ACT] scores) and objective data (Lund-Mackay CT score, spirometry and lab values) were collected. RESULTS: Among the 157 CRSwNP patients who met inclusion criteria, uLTE4 levels were associated with history of asthma (P < .001), aspirin sensitivity (P < .001), worse Lund-Mackay CT scores (P = .002) and other objective markers of disease severity including serum IgE (P = .05), presenting blood eosinophil level (P < .001), and the highest recorded eosinophil level (P < .001). In subgroup analysis, associations of uLTE4 to disease markers had stronger correlations in the aspirin sensitive CRSwNP group (R range 0.31-0.52) than the aspirin tolerant CRSwNP group (R range -0.30-0.24). uLTE4 levels were not associated with subjective symptom scores (SNOT22 and ACT scores). CONCLUSION: Elevated uLTE4 biomarker levels are associated with worsened objective markers of disease severity in CRSwNP patients but not patient-reported symptom measures. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:961-966, 2021.

Level of sex hormones and their association with acetylsalicylic acid intolerance and nasal polyposis.

BACKGROUND: Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet. AIM: Examine the relationship between levels of sex hormones and nasal polyposis. METHODS: Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy. RESULTS: Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01). CONCLUSION: Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required. SIGNIFICANCE: Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.

A proinflammatory marker in chronic rhinosinusitis: serum calprotectin.

INTRODUCTION: Studies have shown that calprotectin has a strong pro-inflammatory effect. Elevated calprotectin levels in the serum can be used as a strong clinical marker indicating the presence of inflammation. OBJECTIVE: To investigate serum calprotectin levels in patients with chronic rhinosinusitis (CRS) and to determine the applicability of calprotectin as a potential molecular pro-inflammatory biomarker for CRS. METHODS: The study consisted of three groups: chronic rhinosinusitis with polyps (CRSwNP group), chronic rhinosinusitis without polyps (CRSwoNP), and healthy control. CRS patients with polyps were further divided into two groups depending on the presence/absence of Samter's triad. The Nose Obstruction Symptom Evaluation (NOSE) scale score and serum calprotectin value were evaluated in all participants. RESULTS: The mean serum calprotectin value was 79.5±11.8 ng/ml for the CRSwNP group, 71.3±16 ng/ml for the CRSwoNP group, and 61.9±11.6 ng/ml for the control group (p<0.001). The Samter's triad group had a significantly higher calprotectin value than the non-Samter's triad group (p=0.03). There was a significant correlation between the NOSE scores and calprotectin levels (rho=0.734, p<0.001). CONCLUSION: Serum calprotectin values were correlated with the severity of symptoms in patients with CRS; thus, it seems to be a valuable pro-inflammatory biomarker for the diagnosis of the disease and determining its severity. Further studies with larger series are needed to evaluate the preoperative and postoperative serum calprotectin values ​​in patients undergoing surgery.

Type 2 inflammation suppression by T-regulatory cells attenuates the eosinophil recruitment in mucosa of chronic sinusitis.

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-ß and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.

Prognostic Significance of Serum Complement Component 3 in Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: The aim of this study was to assess the relationship between serum complement component 3 (C3) levels and disease recurrences in patients with chronic rhinosinusitis with nasal polyps (NPs). METHODS: Ninety-seven patients with NPs and 30 controls were recruited. Clinical features were collected. Serum concentrations of C3 and C4 were measured before and after endoscopic sinus surgery. RESULTS: Compared to the controls, increased C3 levels were found in patients with NPs. Patients with polyp recurrences had higher pre- and postoperative serum C3 levels than patients without polyp recurrences. Serum C3 levels dropped after surgery. After polyp regrowth, the mean C3 level in the recurrent group elevated again to the degree similar to that before surgery. When patients were stratified by tissue eosinophilia, no significant difference was seen in pre-/postoperative, absolute change after surgery, and post-recurrent C3 levels between patients without and with eosinophilic NPs in the group with disease recurrences. CONCLUSION: Serum C3 may be involved in the pathogenesis of NPs. Higher serum C3 levels may pinpoint patients at high risk of recurrence as an independent factor. Furthermore, the change in C3 levels after surgery may have the potential to serve as a predictor for polyp progression. Adding serum C3 measurement to the routine walk-up in the clinical management of NPs is worth further investigation and may help physicians make a more rational diagnostic and/or therapeutic decision regarding this disease.

The Association of Serum Eosinophilia with Structured Histopathology in Chronic Rhinosinusitis.

BACKGROUND: Prior studies have demonstrated associations between serum eosinophilia and chronic rhinosinusitis (CRS) pathogenesis. However, the association of serum eosinophilia with histopathology profiling in CRS has not been fully delineated and may help better characterize CRS disease burden prior to surgery. METHODS: A structured histopathology report of 13 variables was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Complete blood count (CBC) with differential was drawn within 4 weeks prior to FESS. Serum eosinophilia was defined as >6.0% (>0.60 th/µL). Histopathology variables were compared among patients. RESULTS: A total of 177 CRS patients (37 with serum eosinophilia and 140 with normal serum eosinophilia) were analyzed. Compared to CRS patients with normal serum eosinophil counts, CRS patients with serum eosinophilia demonstrated increased polypoid disease (67.6% vs 35.0%, P < .001), eosinophil aggregates (45.9% vs 20.7%, P = .003), and eosinophils per high-power field (>5/HPF) (67.6% vs 40.7%, P = .003). CONCLUSION: CRS patients with serum eosinophilia demonstrated severe disease burden on histopathology with high levels of polypoid disease and tissue eosinophilia. However, a considerable number of patients without serum eosinophilia demonstrated eosinophilic disease on histopathology, indicating that preoperative serum eosinophilia alone could not be reliably used to predict eosinophilic CRS. LEVEL OF EVIDENCE: 4.

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis.

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

Chronic rhinosinusitis in eosinophilic granulomatosis with polyangiitis: clinical presentation and antineutrophil cytoplasmic antibodies.

BACKGROUND: In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution. RESULTS: Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution. CONCLUSION: CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting.