Chronic rhinosinusitis with nasal polyps causes severe symptoms and impaired quality of life. Stapokibart is a novel monoclonal antibody that targets interleukin 4Rα. To assess the efficacy and safety of stapokibart as an add-on treatment to intranasal corticosteroids in patients with severe uncontrolled chronic rhinosinusitis with nasal polyps. From August 9, 2022, to April 28, 2023, this randomized, double-blind, phase 3 clinical trial, conducted at 51 hospitals in China, enrolled adult patients with chronic rhinosinusitis with nasal polyps who had a history of systemic corticosteroid use or sinonasal surgery and a bilateral nasal polyp score of 5 or greater (on a scale of 0-8) and a weekly mean nasal congestion score of 2 or greater (on a scale of 0-3). Eosinophilic chronic rhinosinusitis with nasal polyps was defined as blood eosinophils of 6.9% or greater (without asthma) or 3.7% or greater (with asthma) or an eosinophil count of 55 per high-power field or greater or 27% or greater in nasal polyp tissue. Patient follow-up was completed on June 25, 2024. Four weeks after initiation of mometasone furoate nasal spray, 100 µg in each nostril daily, patients were randomized to receive subcutaneous stapokibart, 300 mg, or placebo (1:1) every 2 weeks for 24 weeks. Both groups then received stapokibart for 28 weeks. Co–primary end points were changes from baseline in nasal polyp score (meaningful change threshold [MCT] ≥1 point) and nasal congestion score (MCT ≥0.5 points) at week 24 in all patients and in the population with eosinophilia. Among 180 patients randomized, 179 (mean age, 45 [SD, 12.9] years; 61 [34.1%] women) received at least 1 treatment dose (n = 90 for stapokibart; n = 89 for placebo). In the overall population, the least-squares (LS) mean change in nasal polyp score from baseline to week 24 in the stapokibart vs placebo groups was −2.6 vs −0.3 points, respectively, (LS mean difference, −2.3; 95% CI, −2.6 to −1.9; P < .001); in the population with eosinophilia, the change was −3.0 vs −0.4 points, respectively (LS mean difference, −2.5; 95% CI, −2.9 to −2.1; P < .001). The LS mean change in nasal congestion score from baseline to week 24 in the stapokibart vs placebo groups was −1.2 vs −0.5 points, respectively, in the overall population (LS mean difference, −0.7; 95% CI, −0.9 to −0.5; P < .001) and −1.3 vs −0.5 points, respectively, in the population with eosinophilia (LS mean difference, −0.8; 95% CI, −1.0 to −0.6; P < .001). Serious adverse events were rare (2.2% in the stapokibart group vs 1.1% in the placebo group). Higher rates of arthralgia (7.8% vs 0%) and hyperuricemia (5.6% vs 1.1%) were reported with stapokibart vs placebo, respectively. Among patients with severe chronic rhinosinusitis with nasal polyps treated with a daily intranasal corticosteroid, stapokibart reduced polyp size and severity of nasal symptoms at 24 weeks. ClinicalTrials.gov Identifier: NCT05436275

BACKGROUND:Basal cells (BCs) play a crucial role in epithelial remodeling, a hallmark of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). Single-cell sequencing has revealed an increased number of solitary chemosensory cells (SCCs) alongside BC hyperplasia in eCRSwNP, yet the underlying mechanism of BC hyperplasia in eCRSwNP remains unclear. This study aimed to investigate the role of SCC-derived acetylcholine (Ach) in determining BC fate. METHODS:Tissue samples from healthy individuals, patients with eCRSwNP, and those with non-eCRSwNP (neCRSwNP) were analyzed to investigate BC proliferation, differentiation abnormalities, and the prevalence of SCCs. The relationship between SCC-derived Ach, BC dysfunction, and disease severity was examined. Ach sources and receptor expression patterns were characterized. In vitro studies using submerged cell cultures and air-liquid interface cultures, along with in vivo murine models, were employed to elucidate the mechanisms by which Ach influences BC fate. The inhibitory effects of tiotropium bromide (TB) on Ach-driven processes were also evaluated. RESULTS:Our results indicated that SCC-derived Ach, rather than by parasympathetic nerves, contributed to abnormal BC proliferation and differentiation through muscarinic acetylcholine receptors (mAChRs) and had potential impact on the development of eCRSwNP. These effects were associated with the activation of YAP and could be partially reversed both in vitro and in vivo by blocking mAChRs with TB. CONCLUSION:These results demonstrate that SCC-derived Ach plays a critical role in eCRSwNP by regulating BC fate. This provides a potential translational framework for developing prevention and treatment strategies targeting the cholinergic pathway.

Purpose:The study aimed to identify key genes related to lipid metabolism in chronic sinusitis and understand their biological implications, considering the growing interest in the association between chronic sinusitis - a complex inflammatory condition - and lipid metabolism due to lipids' role in inflammation and immunity. Methods:Gene expression data from bulk - RNA sequence was analyzed and intersected with lipid metabolism genes and WGCNA module genes from the MSigDB database. Immune infiltration analysis was conducted. Machine learning techniques were used to develop a diagnostic model. qRT - PCR and immunofluorescence techniques were employed to confirm gene involvement. Potential targeted drugs were identified through relevant analyses. Results:41 hub genes were identified, which were involved in pathways like G protein - coupled receptor signaling, TGF - beta receptor signaling, and responses to oxidative stress and nitrogen compounds. Enrichment analyses suggested links to ubiquitin - mediated proteolysis, mTOR signaling, and MAPK signaling. A significant presence of immune cells was detected in the chronic sinusitis group. A combined RF+Stepglm model was developed, comprising six genes (KPNA3, RAB35, GLE1, RNF139, OSMR, and PDPK1), which demonstrated good diagnostic performance (AUC = 0.848). Potential targeted drugs such as Raloxifene and Hesperidin were identified. qRT - PCR and immunofluorescence confirmed that the expression levels of RAB35, GLE1, and OSMR were significantly higher in CRS samples compared to normal ones. Conclusion:This research highlights the role of lipid metabolism in chronic sinusitis and provides a basis for the development of targeted therapies.

Objective Several monoclonal antibodies (MoAbs) targeting specific type 2 immune reactions have been developed as innovative therapeutic approaches for chronic inflammatory airway diseases, such as chronic sinusitis with nasal polyps (CRSwNP) and asthma. However, the clinical safety of these MoAbs and how to choose them are not clear. Therefore, we aimed to assess the systemic drug- and dose-based safety of MoAbs in chronic airway inflammation using network meta-analysis (NMA). Methods Electronic databases were systematically searched for relevant studies published in English between January 2009 and December 2022. Eligible studies must have clearly reported adverse events (AEs) among the MoAbs’ safety data. Results 1). Regarding serious AEs, mepolizumab was significantly safer than placebo; in terms of permanent treatment discontinuation, reslizumab and dupilumab were significantly safer than benralizumab. 2). Regarding asthma worsening, dupilumab was associated with the best safety profile; was safer than dupilumab/300 mg/q2-4w. 3). In terms of injection-site reactions, dupilumab posed a higher risk than placebo; dupilumab/300 mg/qw posed a higher risk than dupilumab/300 mg/q2w and dupilumab/300 mg/q2-4w; lebrikizumab/250 mg/q4w posed a higher risk than lebrikizumab/37.5 mg/q4w; mepolizumab/100 mg/q4w posed a higher risk than mepolizumab/75 mg/q4w; benralizumab/30 mg/q4-8w posed a higher risk than benralizumab/20 mg/q4-8w. 4) In CRSwNP patients combined with asthma, the risks of experiencing AEs were not increased. Conclusion Overall, biologics are safe and well tolerated in chronic inflammatory airway disease. This drug- and dose-based NMA provides further evidence on the different safety profiles of different emerging MoAbs. This information may help guide rational drug use and provide clinical recommendations for choosing MoAbs.Trial Registration: SYSTEMATIC REVIEW REGISTRATION (PROSPERO #CRD42023387610).

Background and Objective: Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes joint deformities and even complete loss of joint function. Artesunate (ART) is an active ingredient in Chinese herbal medicines, usually used to treat malaria. This study aimed to investigate the effect of Artesunate on collagen-induced arthritis (CIA) in rats, along with its efficacy and underlying mechanism.Methods: The CIA rat model was created using bovine type II collagen and incomplete F-style adjuvants. The rats with CIA were divided into three groups: the Model group, the tripterygium hypoglaucum hutch (THH) group, and the ART group. The model group received 0.9% normal saline, the THH group was given a daily dose of 150 mgkg(-1) THH, and the ART group was given a daily dose of 10 mgkg(-1) artesunate for 30 days. The negative control (NC) group received only an equal volume of 0.9% normal saline. The body weight, arthritis index, and paw thickness of the rats were recorded throughout the treatment. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 17A (IL-17A) in the serum of rats with CIA were assessed using enzyme-linked immunosorbent assay (ELISA). Furthermore, the indices of vital immune organs, including the thymus and spleen, were calculated. The hindpaw of each group was collected and subjected to histopathological examinations using hematoxylin-eosin (H&E) staining, safranin O-fast green staining and X-ray methods.Results: The arthritis index, the thickness of the foot, and the contents of IL-17A in the CIA model group were significantly increased compared to the NC group (p < 0.05). Moreover, synovial hyperplasia and cartilage damage were significantly decreased in the ART group (p < 0.05). However, the immune organ index and serum TNF-alpha level did not reach statistical significance (p > 0.05). Additionally, the serum IL-17A level was significantly lower than the model group (p < 0.05).Conclusion: Artesunate exerts a protective effect on joint damage in rats with CIA, which may reduce inflammation and delay the development of the disease by inhibiting the secretion of IL-17A.

Background: The occurrence of nasal polyps is related to mucosal barrier damage. The role of MG53, an important epithelial repair regulator, in nasal polyps remains unclear. This study aimed to investigate the role of MG53 in nasal epithelial repair. Methods: We divided the patients into the following three groups (n=15 each): chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP) and septal deviation (control). We performed qRT-PCR and western blotting to determine the expression of MG53, TGF-β1, Smad2/3, zonula occluden-1 (ZO-1), and collagen-a1 (Col-a1) in nasal tissues and human nasal epithelial cells (HNECs). HNECs were cultured to investigate the regulatory role of MG53 and the TGF-β1/Smad pathway in the repair of nasal epithelial cells. Results: We found that the expression of MG53, TGF-β1, Smad2/3, ZO-1, and Col-a1 was upregulated in the CRSsNP group, whereas it was downregulated in the CRSwNP group. In the HNECs of nasal polyps, the expression of TGF-β1, Smad2/3, ZO-1, and Col-a1 was downregulated after overexpressed MG53, whereas this was reversed by the knockdown of MG53. Additionally, we found that TGF-β1 stimulation resulted in significantly upregulated MG53 expression, which was impeded by TGF-β1 inhibitors. MG53 expression facilitated proliferation, promoted the secretion of Col-a1, and inhibited apoptosis in HNECs. Conclusion: MG53 inhibited the TGF-β1/Smad pathway and fibrosis, enhanced the proliferation of nasal epithelial cells, and supported nasal epithelial repair. The results of this study provide a new therapeutic regimen for the treatment of nasal polyps. Keywords: epithelial repair; mitsugumin53; nasal polyps; tight junction; TGF-β1/Smad.

Extended endoscopic sinus surgery (EESS) can reduce the recurrence rate of chronic rhinosinusitis (CRS). The purpose of this study was to investigate the effect of the application of modified “protective middle turbinate-EESS” (mEESS) on patients with CRS with nasal polyps (CRSwNP) and allergic rhinitis (AR). Forty-three patients with CRSwNP and AR were classified into 2 groups, the mEESS group (n=23) and the functional endoscopic sinus surgery (FESS) group (n=20), and were followed up for 6 months and 1 year after surgery. The disease severity was assessed by the Lund-Mackay score, the Lund-Kennedy score, and the visual analog scale (VAS) score. The patency rate of the frontal sinus was evaluated by endoscopy. Patient satisfaction was also followed up. No preoperative differences or postoperative complications were found between the 2 groups. The VAS score and Lund-Kennedy score of the 2 groups were lower at 6 months and 1 year after surgery. The olfactory function of the mEESS group was significantly better than that of the FESS group at 6 months post-operative. The patency rate of the frontal sinus orifice in the mEESS group was significantly higher than that in the FESS group at 6 months and 1 year post-operative. Patient satisfaction in the mEESS group was relatively higher than that in the FESS group. mEESS improves frontal sinus drainage, olfactory sense, and patient satisfaction in the short term.

Background:T-helper 17 (Th17) cell response is engaged in the onset of allergic rhinitis (AR). Moreover, interleukin (IL)-38 is thought to be involved in inhibiting cytokine secretion in the Th17 pathway.Objective:To evaluate the regulatory function of IL-38 on abnormal Th17 responses in Chinese patients with AR.Methods:Forty-five participants, divided into an AR group (n=25) and a control group (n=20), were recruited for the study. In addition, the expression of IL-38 and Th17-related cytokines was measured as well as the Th17 cell count in participants. By implementing recombinant IL-38 (rIL-38), the intervention of human peripheral blood mononuclear cells (PBMCs) was performed. Then, flow cytometry, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) were used to detect the Th17 milieu.Results:The expression of IL-38 in the AR group notably reduced compared with that in the control, whereas Th17 cell frequency and the expression levels of its transcription factor (RORC) and cytokines (IL-17A and IL-23) increased. The differentiation and immune function of Th17 cells in PBMCs were inhibited by rIL-38.Conclusion:Th17 responses are inhibited by IL-38 in patients with AR. Therefore, the obtained findings indicate that IL-38 is a potential therapeutic target for Chinese patients with AR.

目的:针对舌下脱敏疗法治疗变应性鼻炎的机制与2型固有淋巴细胞(ILC2s)的相关性予以探究.方法:选取变应性鼻炎患者随机分为药物治疗组20例和药物联合脱敏治疗组20例,并以15例健康人作为对照组.检测治疗前后外周血及局部鼻腔灌洗液中损伤相关分子模式DAMPs(TSLP、IL-25)的表达,同时检测外周血中ILC2s及其效应因子(IL-13、IL-5、嗜酸性粒细胞阳离子蛋白)的水平.结果:变应性鼻炎患者DAMPs、ILC2s及其效应因子水平均显著高于对照组(P＜0.05);与治疗前相比,联合治疗组的所有研究指标水平在治疗3个月后均显著降低(P＜0.05),治疗1年后,联合治疗组中除DAMPs水平仍高于对照组(P＜0.05);其余指标水平与对照组相比差异均无统计学意义(P＞0.05).结论:舌下脱敏疗法能调节变应性鼻炎患者过度活跃的ILC2s免疫应答,降低炎症反应,达到缓解和治疗变应性鼻炎的效果.

目的 探讨瘦素(leptin)对2型固有淋巴细胞(ILC2)的活化是否促进肥胖变应性鼻炎(AR)小鼠模型的发病.方法 高脂饮食及卵清蛋白(ovalbumin,OVA)建立肥胖小鼠AR模型.检测模型中leptin及leptin-R、ILC2及Th2相关因子、神经介素U(neuromedin U,NMU)及NMUR1的表达水平并分析相关指标的相关性;检测leptin干预后模型中ILC2、Th2相关因子及神经肽的变化.结果 肥胖小鼠AR组leptin、NMU及其受体的表达均明显高于非肥胖AR组及对照组(P＜0.05),其脾脏ILC2细胞数量及IL-4、IL-13水平均显著升高(P＜0.05);肥胖AR小鼠中leptin及leptin-R与ILC2呈正相关(P＜0.05);肥胖AR组中ILC2、Th2相关因子及神经肽因子的表达经leptin干预后显著升高(P＜0.05).结论 leptin对ILC2的活化作用及相关的神经免疫机制可能在肥胖AR的发病中发挥作用.

BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) was potentially due to the epithelial barrier injury. YES-associated protein (YAP) is a multifunctional transcriptional factor and plays versatile roles in the regulation and maintenance of epithelial barrier in different organs and tissues. The purpose of this study is to elucidate possible effect and mechanism of YAP on the epithelial barrier of CRSwNP. METHODS:Patients were divided into CRSwNP group (n = 12) and control group (n = 9). The location of YAP, PDZ-binding transcriptional co-activator (TAZ), and Smad7 were estimated by immunohistochemistry and immunofluorescence. Meanwhile, the expression of YAP, TAZ, Zona occludens-1 (ZO-1), E-cadherin, and transforming growth factor-beta1 (TGF-β1) were detected by Western blot. After primary human nasal epithelial cells were treated with YAP inhibitor, the expression level of YAP, TAZ, ZO-1, E-cadherin, TGF-β1, and Smad7 were measured by Western blot. RESULTS:Compared with the control group, the protein levels of YAP, TAZ, and Smad7 were significantly upregulated, while TGF-β1, ZO-1, and E-cadherin were downregulated in CRSwNP. YAP and Smad7 demonstrated lower levels, while the expression of ZO-1, E-cadherin, and TGF-β1 rose slightly after YAP inhibitor treatment in primary nasal epithelial cells. CONCLUSIONS:Higher level of YAP may lead to CRSwNP epithelial barrier injury via the TGF-β1 signaling pathway, and the inhibition of YAP can partially reverse epithelial barrier function.

Allergic rhinitis (AR) is a common inflammation that affects many people globally. Quercetin has anti-allergic biological activity in AR. Here, we aimed to explore the effects of quercetin on type 1 helper T (Th1)/Th2 and regulatory T cells (Treg)/Th17 balance. We established an ovalbumin (OVA)-induced mouse model and orally administered 20, 35, and 50 mg/kg/day quercetin. The nasal symptoms of mice were observed. The immunoglobulin levels, Treg/Th17-related factors, and pro-inflammatory factors were examined by ELISA. The differentiated inflammation cells were visualized using the diff-quick staining assay. The nasal histopathology was evaluated using H&E, periodic acid Schiff (PAS), and Giemsa staining assay. The results showed that quercetin attenuated OVA-induced rubbing and sneezing. Quercetin reduced IgE, IgG1, histamine, and increased IgG2 in serum. The number of differentiated inflammation cells and goblet cells in tissues that elevated by OVA was reduced by quercetin. Moreover, OVA increased the Treg cell percentage, the levels of IL-17, TGF-beta, IL-6, TNF-alpha, and decreased Th17 cell percentage, IL-10 and FOXP3 levels, while quercetin abrogated their levels induced by OVA. Additionally, quercetin inactivated the NF-kappa B pathway. Taken together, quercetin attenuated AR symptoms by balancing the Th1/Th2, Treg/Th17 ratios, and inactivating the NF-kappa B pathway. The results suggested that quercetin may use for AR treatment.

Type 2 innate lymphoid cells (ILC2) are upregulated in childhood allergic rhinitis (AR) and are associated with AR severity. This study aimed to investigate changes in the ILC2 milieu in pediatric patients with AR after sublingual immunotherapy (SLIT). Forty- pediatric patients with AR received house dust mite (HDM) allergen extract for SLIT group and thirty pediatric patients received placebo in the study, respectively. The levels of ILC2, ILC2-related cytokines (IL-5/IL-13) and their transcription factors (GATA binding protein 3, retinoic acid-related orphan receptor α) in the circulation were assessed after 1- and 2-year SLIT. Moreover, peripheral blood mononuclear cells (PBMCs) in patients were prepared and stimulated by recombinant thymic stromal lymphopoietin, IL-25, and IL-33 after 2-year SLIT. Subsequently, the levels of ILC2, IL-5, and IL-13 were tested. The frequency of ILC2 and the levels of their transcription factors in the circulation were significantly decreased after SLIT in the SLIT group. The levels of ILC2-related cytokines in the SLIT group showed the same trend. The frequency of ILC2 was positively correlated with transcription factors and cytokines after SLIT. SLIT was observed to reduce the ability of HDM sensitization to generate the ILC2 milieu in PBMCs. Changes in the ILC2 milieu may be correlated with the curative effect and immune regulation function of SLIT. Our results suggested that the regulatory effect on ILC2 is part of the therapeutic mechanism of SLIT.

Aim: T-regulatory (Treg)/T-helper (Th) 17 imbalance contributes to the pathogenesis of allergic rhinitis (AR). Long non-coding RNAs (lncRNAs) participate in the progression of AR. Herein, the effect of lncRNA JP X on Treg/Th17 balance in AR was explored.Methods: CD4+ T cells were isolated from patients with AR and healthy control. The percentage of Treg and Th17 cells were examined by flow cytometry. The levels of JP X, miR-378g, CCL5, T GF-β, and IL-17A were tested using qRT-P CR. The protein expression of Foxp3 and RORγt was measured by western blot.Results: The data showed that an imbalance of Treg/Th17 was associated with AR. Upregulation of JP X was found in AR, and knockdown of which improved the imbalance of Treg/Th17. Furthermore, JP X functioned as a sponge of miR-378g to upregulate CCL5. Inhibition of miR-378g reversed the effects on Treg/Th17 induced by silencing of JP X. Moreover, overexpression of CCL5 reversed miR-378g-induced effects.Conclusion: In conclusion, depletion of JP X promoted Treg/Th17 balance in AR via regulating the miR-378g/CCL5 axis. The findings provided a novel therapeutic insight for AR.

This research was aimed to explore whether the recovery of subjective symptoms and objective examination in nasal septum deviation (NSD) patients after septoplasty were related to the degree of preoperative anxiety or depression, in the hope of providing new ideas for clinical treatment. A total of 150 NSD patients were included in this prospective research. Visual analogue scale (VAS) scores, Nasal Obstruction Symptom Evaluation (NOSE) scores, self-rating anxiety scale (SAS) scores, self-rating depression scale (SDS) scores, total inspiratory and expiratory nasal resistance were recorded before and 6 months after operation. The results showed preoperative anxiety or depression was not statistically different between groups in terms of age, gender and course, but positively correlated with nasal obstruction (VAS and NOSE). The recovery of nasal obstruction in patients with anxiety or depression was worse than that in normal NSD patients 6 months after surgery, and was decreased with the increase of anxiety or depression degree. And no significant difference showed in the reduction of total inspiratory and expiratory nasal resistance between groups. In conclusion, anxiety and depression affected the improvement of nasal obstruction feeling in NSD patients after septoplasty, and the improvement was negatively correlated with the degree of anxiety and depression. It is necessary to evaluate the anxiety and depression of NSD patients before septoplasty.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a common and complex inflammatory disorder in the upper airway. Type 2 inflammation affects the severity of CRSwNP and recurrence of polyps, determining the pharmacotherapy and extent of surgery, also associated with asthma comorbidity.1 Over the past decade, biologics targeting the biomarkers of type 2 immune reaction ---- IL-4, IL-5, and IgE, have been applied to CRSwNP in phase 2 or 3 clinical trials and emerged as an effective treatment option. However, until now, the safety of these biologics has not been systematically analyzed. Thus, this study aimed to observe the incidence of adverse events (AEs) following the use of biologics, to estimate the safety of biologics in CRSwNP. A systematic search of PubMed, Medline, and Web of Science from January 2005 to May 2021 using the search terms "monoclonal antibody", "dupilumab", "mepolizumab" and "omalizumab" and ''nasal polyposis'' was conducted. Double-blind, randomized, placebo-controlled (RCT) studies with biologics-treated versus placebo-treated patients with CRSwNP were included. Eligible patients were aged 18 years or older with bilateral nasal polyps and symptoms of chronic rhinosinusitis despite intranasal corticosteroid therapy before randomization. Patients were required to have a bilateral endoscopic nasal polyp score of at least 5, with a minimum score of 2 for each nostril, and exhibit at least two of the following symptoms: nasal congestion or obstruction and either loss of smell or nasal discharge. Exclusion criteria included the requirement for continuous high-dose oral corticosteroids, treatment with other biologics in the past 12 months, or asthma exacerbations requiring hospitalization within 4 weeks of screening. Heterogeneity was calculated using the I2 statistic and the chi-squared (χ2) test. A pχ2 value < 0.1 was considered as a significant heterogeneity. The I2 values of 25%, 50%, and 75% were considered to indicate low, medium, and high heterogeneity, respectively. A fixed-effects model was used to perform the meta-analysis if I2 was <0.5; random-effects were used for analyses with high heterogeneity (I2 > 50%). After screening and eligibility assessment, we identified a total of 8 clinical trials that were represented in the data set.2-7 These studies focused on three medications: dupilumab (anti-IL4), mepolizumab (anti-IL5), and omalizumab (anti-IgE). Outcome measures included headache, asthma exacerbation, nasopharyngitis, epistaxis, worsening nasal polyps, injection-site reaction, and the common cold. To explore the influence of different medicine, in subgroup analysis, we categorized the regimens by class as treatment with omalizumab (3 cohorts), dupilumab (3 cohorts), mepolizumab (2 cohorts). The overall quality assessment for the included 8 RCTs indicated a low risk of bias. Eight RCTs with 1205 patients were analyzed. Our analysis showed that the risk of asthma exacerbation and worsening nasal polyps was significantly lower in patients treated with monoclonal antibody [RR 0.33, 95% CI 0.19–0.56, P < 0.0001, Figure 1A; RR 0.28, 95% CI 0.16–0.49, p < 0.00001, Figure 1H]. In the subgroup analysis, both patients who were treated with dupilumab or omalizumab were significantly less likely to experience asthma exacerbation than those treated with placebo]RR 0.27, 95% CI 0.13–0.57; OR 0.31, 95% CI 0.12–0.78, Figure 1B]; whereas the decreased incidence in patients who received mepolizumab failed to reach statistical significance (P = 0.79) (RR 0.82, 95% CI 0.18–3.66). The odds of experiencing headache, nasopharyngitis, epistaxis, injection-site reaction, and common cold were not significantly different between patients treated with monoclonal antibody and placebo; no fatal AE has been reported (Figure 1,C,E,G,I,J). Forest plot of the RCTs comparing rates of patients with asthma exacerbation (A, B), headache (C, D), nasopharyngitis (E, F), epistaxis (G), worsening nasal polyps (H), injection (I) and common cold (J) In this study, we found that monoclonal antibodies reduced the risk of asthma exacerbation and nasal polyps in CRSwNP. This result could ascribe to the type2 inflammation in nasal polyposis, which is correlated with asthma comorbidity. Type 2 immune response leads to the local production and secretion of IgE, IL-4, IL-5, and IL-13 in the mucosa. These cytokines play a prominent role in the type 2 pathway and contribute to the local persistent inflammation, finally participating in the pathogenesis of nasal polyp formation. Omalizumab, Mepolizumab, and Dupilumab, all these biologics inhibited the functions of type 2 cytokines, then prevented the process of local type 2 inflammation, thus reducing the risk of asthma exacerbation and worsening nasal polyps. In the past, there were some reports about the AEs associated with monoclonal antibody therapy. Benralizumab, mepolizumab and reslizumab slightly increased drug AE and drug-related serious AE in severe eosinophilic asthma.8 In 362 patients with moderate persistent asthma, who were treated with mepolizumab, nine serious adverse events were reported and two patients suffered from asthma exacerbation.9 Samira Jeimy, et al reported a case who developed amyopathic dermatomyositis associated with omalizumab therapy for steroid-refractory severe asthma.10 Besides, Dupilumab-associated arthralgia and ophthalmic complications (e.g., dry eyes, conjunctivitis, blepharitis, keratitis, and ocular pruritus) were respectively reported in aspirin-exacerbated respiratory disease and allergic diseases11, 12. Our results showed that AEs (e.g., headache, asthma exacerbation, nasopharyngitis, epistaxis, worsening nasal polyps, injection-site reaction, and the common cold)occurred with a similar incidence in both mAb and placebo groups, which indicated the acceptable safety and tolerability of biologics in NPs. Meanwhile, we speculate that CRSwNP patients with other diseases are more likely to suffer from AEs, such as CRSwNP comorbid with asthma. The included research demonstrated high quality and good homogeneity. All these studies were placebo-controlled RCTs and quality assessment showed a low risk of bias. Also, there was a low heterogeneity in most outcomes across the individual studies. All these strengthen the reliability and credibility of our analysis. Interestingly, in the pooled data, we observed that there was a slightly increased rate of injection-site reaction in the monoclonal group. However, the increase failed to reach statistical significance. Will the monoclonal antibody aggravate the erythema at the injection site? It is still uncertain. Meanwhile, in two trials (5, 6), the observed incidence of the common cold was greater in patients who received monoclonal antibodies, although the increase didn't reach significance (P = 0.05). Is there any influence of biologics on the immune response to bacteria and viruses? All these questions require more observations. To conclude, biologics were well tolerated in the application of CRSwNP and decreased the risk of asthma exacerbation and worsening nasal polyps. From a safety perspective, biologics provide a promising innovative option for the treatment of CRSwNP. Further investigations are still needed to confirm our findings and evaluate the longer-term safety and efficacy of biologics in the use of CRSwNP. Yang Shen: Writing - original draft; Equal, Writing - review & editing; Equal. Xia Ke: Data curation; Equal, Methodology; Equal. Suling Hong: Data curation; Equal, Formal analysis; Equal. Yucheng Yang: Funding acquisition; Equal, Writing - review & editing; Equal. We greatly appreciate Yalan Lv and Guanglei Chang (The Chongqing Medical University) for their help in statistical analysis. This study was supported by the National Natural Science Foundation of China (81970864). The authors declare that no financial or other conflicts of interest exist regarding the content of the article. National Natural Science Foundation of China, Grant/Award Number: 81970864; Chongqing Talents Project, Grant/Award Number: cstc2021ycjh-bgzxm0080

Objective To observe the impact of leptin on the activation of group 2 innate lymphocytes (ILC2) in obese adult patients with allergic rhinitis (AR), and investigate its role and significance in the pathogenesis of AR. Methods A total of 70 patients with AR were enrolled in the study and divided into obese AR group and non-obese AR group according to body mass index (BMI), and matched with 30 cases in the healthy control group with no difference in age and gender during the same period. Flow cytometry was used to detect the ratio of ILC2 in peripheral blood mononuclear cells (PBMCs) of each group, real-time quantitative PCR to detect the expression of leptin mRNA, and ELISA to detect the serum leptin. The correlation between leptin and ILC2 was analyzed, and the changes in the ratio of ILC2 and relevant immune indexes in PBMCs of the AR group before and after the intervention of recombinant leptin were observed. Results Compared with healthy control group, the expressions of leptin and ILC2 of the AR group increased significantly, and the level of the obese AR group was significantly higher than that of the non-obese AR group. The expressions of leptin and ILC2 in the obese AR group were positively correlated in a significant manner. After the intervention of recombinant leptin, the ILC2 level of the obese AR group increased significantly. Conclusion The pathogenesis of AR in obese adults is related to its high expression of leptin, and the activation of ILC2 mediated by leptin aggravates its pathogenetic process.

Objectives: Since the leptin participates in the upregulation of type 2 innate lymphoid cells (ILC2s). We investigated the role of the leptin/ILC2 axis in AR pathogenesis in Chinese paediatric patients with obesity. Methods: Seventy AR paediatric patients with or without obesity and 30 healthy obese subjects were enrolled. The levels of leptin, its receptor and ILC2 milieu were measured, and correlations between them and clinical symptom severity and between ILC2 milieu and leptin levels were assessed. Changes of ILC2 milieu in AR patients after leptin stimulation were also detected. Results: Levels of leptin, its receptor and ILC2 milieu levels were significantly higher in the disease than in the controls, and highest in the obese-AR group. The leptin/ILC2 axis and severity of clinical symptoms in obese patients with AR were significantly correlated, similarly to what was observed between leptin/leptin receptors and ILC2 milieu. Recombinant leptin could significantly increased the levels of ILC2 milieu in the obese-AR group. Conclusions: These findings suggest the unique function of the leptin/ILC2 axis in obese paediatric AR patients. The mechanism by which obesity promotes AR in paediatric patients may be related to the leptin/ILC2 axis.

目的 本研究旨在从Th1/Th2及Th17/Treg平衡轴的角度探讨PM2.5暴露及细菌溶解产物Broncho-Vaxom(BV)治疗与健康大鼠气道炎症的关系.方法 PM2.5暴露组鼻内滴注PM2.5混悬液,口服生理盐水;BV治疗组暴露与PM2.5暴露组相同,口服BV溶液;对照组均用生理盐水代替.对大鼠鼻黏膜进行组织病理学检查;用流式细胞仪和酶联免疫吸附试验(ELISA)检测Th1/Th2/Th17/Treg细胞的表达和功能.结果 PM2.5暴露组大鼠鼻黏膜出现炎症细胞浸润;Th2细胞和Th17细胞显著上调,Treg细胞显著下调;血清中相关细胞因子IL-4、IL-5、IL-13及IL-17显著升高,IFN-γ和IL-10显著下降.BV干预后鼻黏膜炎性细胞浸润减少、Th细胞相关免疫失衡减轻.结论 PM2.5可诱导健康大鼠产生气道炎症,PM2.5暴露所诱导的气道炎症可能与Th1/Th2和Th17/Treg细胞免疫失衡有关,BV可减轻PM2.5诱导的气道炎症及Th细胞相关免疫失衡.

目的:基于AhR信号通路激活导致Th免疫失衡,探讨PM2.5暴露及细菌溶解产物(BV)治疗对小鼠气道炎症的作用及机制.方法:30只BALB/c雌性小鼠随机分为PM2.5暴露组、BV干预组和对照组,每组10只.PM2.5暴露组和BV干预组小鼠气管滴注PM2.5混悬液,连续15 d,第16～90天,PM2.5组口服给予生理盐水,BV干预组口服给予BV溶液,对照组给予等量生理盐水.组织病理学检查评价气道炎症程度;ELISA检测血清相关炎症因子水平;Western blot和RT-qPCR检测AhR表达.结果:PM2.5暴露后,小鼠气管黏膜出现大量炎症细胞浸润,血清IL-4、IL-5、IL-13、IL-17、IL-33水平显著升高,肺组织中AhR蛋白和mRNA表达增加.BV治疗后,小鼠血清炎症因子失衡减轻,气道黏膜炎症细胞浸润缓解.结论:PM2.5暴露可导致健康小鼠气道炎症,可能与AhR通路激活有关,BV可通过调节免疫反应减轻PM2.5诱导的气道炎症.