度普利尤单抗在慢性鼻窦炎伴鼻息肉治疗中的研究进展

慢性鼻窦炎(CRS)是一种常见的鼻窦黏膜炎症性疾病,复杂的发生机制造就了CRS的高度异质性,部分患者无法从目前标准的药物治疗和手术中得到缓解。CRS具有不同的炎症内型和临床表型,慢性鼻窦炎伴鼻息肉(CRSwNP)一直是治疗难点,其症状相对较重还常合并哮喘,易对常规药物和手术的疗效不佳并伴有较高的复发风险。近年来,度普利尤单抗(dupilumab)在成人顽固性CRSwNP中疗效显著,其通过阻断Ⅱ型炎症中关键驱动因子IL-4和IL-13的信号传导,达到治疗作用。目前度普利尤单抗对国人CRSwNP治疗研究尚无报道。本文将对度普利尤单抗治疗CRSwNP的研究进展进行综述,以期为其在CRSwNP中的进一步应用研究提供参考。     

奥马珠单抗治疗慢性鼻-鼻窦炎伴鼻息肉的研究进展[综述]

慢性鼻-鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）是临床常见疾病,复发率较高。对于部分应用传统鼻内镜手术和常规药物疗效并不理想的患者,奥马珠单抗可能成为他们的治疗选择之一。奥马珠单抗是一种重组人源化单克隆抗体,近年来国外应用其治疗CRSwNP的文献多显示出良好的应用前景。本文对目前奥马珠单抗治疗CRSwNP的临床研究进展做一综述。     

血清sIgE、总IgE、EOS与慢性鼻-鼻窦炎伴鼻息肉发生的相关性分析

目的：探讨血清sIgE、总IgE浓度梯度、嗜酸粒细胞（EOS）与慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）发生的危险因素以及临床指标的筛选。方法：将152例慢性鼻-鼻窦炎患者分为慢性鼻-鼻窦炎不伴鼻息肉（CRSs—NP）组和CRSwNP组,行体外20种过敏原筛查,测定血清sIgE、总IgE、EOS百分比。结果：①CRSsNP患者血清总IgE浓度主要集中在1级,而CRSwNP患者血清总IgE浓度主要集中在2、3级（Z=0．906,P〉0．05）。分别比较两组患者血清sIgE分级．差异无统计学意义（P〉0．05）。②CRSwNP患者EOS百分比明显高于CRSsNP患者（F=4．337,P=0．039;t=3．315,P〈0．01）。且CRSwNP患者E0s百分比95％可信区间为3．90％～5．26％,5％TM值为4．3％,高于CRSsNP组及正常值。CRSwNP组患者EOS百分比,按sIgE值分梯度（分级）后,CRSwNP各组（级）之间比较差异均无统计学意义（P〉0．05）。③CRSwNP患者变应原多为混合型变应原,并且随着变应原浓度梯度的升高,混合型变应原过敏的CRSwNP组患者比例高于CRSsNP患者（χ2=8．595,P〈20．05）。结论：CRSwNP的发牛与EOS、混合变应原的存存有关。且当EOS百分比在3．90％～5．26％范围内CRSwNP更易发生。而血清总IgE、sIgE浓度不能单独作为CRswNP的发生因素。利用过敏原筛查结果结合临床症状,能更早地了解并远离过敏原,利于慢性鼻鼻窦炎围手术期治疗方案的制定。     

慢性鼻窦炎伴鼻息肉与哮喘的相关性机制及治疗策略研究进展

慢性鼻窦炎伴鼻息肉(CRSwNP)和哮喘作为上下呼吸道最具代表性的慢性炎症性疾病,二者在发病过程中常相互并存,临床诊治棘手。目前对CRSwNP和哮喘的相互作用机制尚未阐明。欧洲鼻窦炎鼻息肉诊疗指南(EPOS 2012)对治疗CRSwNP伴或不伴哮喘已给出具体的指导意见,其常规治疗包括鼻用糖皮质激素、生理盐水洗鼻等,并进一步根据CRSwNP的特点、症状严重程度等进行后续的联合治疗。据报道,鼻窦手术和药物治疗CRSwNP对合并支气管哮喘的转归有益。但CRSwNP合并哮喘患者经药物与手术治疗后的疗效判定尚缺乏足够的随机对照试验证据。     

奥马珠单抗治疗慢性鼻-鼻窦炎伴鼻息肉的研究进展

慢性鼻-鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）是临床常见疾病,复发率较高。对于部分应用传统鼻内镜手术和常规药物疗效并不理想的患者,奥马珠单抗可能成为他们的治疗选择之一。奥马珠单抗是一种重组人源化单克隆抗体,近年来国外应用其治疗CRSwNP的文献多...     

不伴有下气道疾病的慢性鼻-鼻窦炎患者肺功能及相关因素分析

目的 探讨不伴有下气道疾病的慢性鼻-鼻窦炎伴息肉患者的肺功能及其影响因素。 方法 选取161例慢性鼻-鼻窦炎伴鼻息肉患者(CRSwNP组),26例慢性鼻-鼻窦炎不伴鼻息肉患者(CRSsNP组)和34例正常人(对照组)进行肺功能检测,比较三组肺功能的各项指标,并分析CRSwNP组肺功能和临床各参数之间的关系,这些参数包括外周血嗜酸粒细胞数、血清特异性IgE、Lund-Mackay评分、呼出一氧化氮水平和视觉模拟量表评分(VAS)。 结果 CRSwNP组患者的肺功能指标FEV₁%pre低于正常组,差异有统计学意义(P=0.045);血清特异性IgE(sIgE)与VC%、FEV₁%pre、FEV₁/FVC呈负相关(P<0.05)。 结论 不伴下气道疾病的CRSwNP患者存在潜在的阻塞性肺功能改变;sIgE与CRSwNP的肺功能异常有关。     

度普利尤单抗治疗慢性鼻窦炎伴鼻息肉的疗效分析

目的 分析临床中IL-4Rα单克隆抗体(度普利尤单抗)治疗慢性鼻窦炎伴鼻息肉(CRSwNP)的疗效。方法 回顾性分析2020年8月—2021年4月使用度普利尤单抗治疗4例CRSwNP患者前后的临床疗效、实验室数据、主观及客观评分以及不良事件等情况,初步评价度普利尤单抗治疗CRSwNP的效果。结果 对4例CRSwNP患者随访4个月。在接受度普利尤单抗治疗前,4例患者慢性鼻-鼻窦炎急性加重次数平均为(3.25±1.50)次/年,在随访期间4例患者均未出现慢性鼻-鼻窦炎急性加重,其中3例患者的鼻窦炎症状得到完全控制。度普利尤单抗治疗前4例患者平均鼻腔鼻窦结局测试-22 (SNOT-22)、宾夕法尼亚大学的嗅觉测试(UPSIT)及副鼻窦CT扫描Lund-Mackay评分分别为52.00±9.42、7.25±1.26、14.50±5.45;治疗4个月后上述评分分别为8.25±5.74、29.25±6.34,7.00±6.38,治疗前后对比差异均具有统计学意义(P<0.05)。使用单抗治疗后4例患者平均口服糖皮质激素(OCS)量为(5.00±7.07)mg/d,对比治疗前(18.75±4.79) mg/d,差异具有统计学意义(P<0.05)。结论 通过特异性抑制白介素-4(IL-4)和白介素-13(IL-13)通路,度普利尤单抗可以显著改善CRSwNP患者鼻窦炎症状以及嗅觉水平,减少患者慢性鼻-鼻窦炎急性加重次数、鼻窦炎病变范围和全身糖皮质激素用量。     

上皮屏障在慢性鼻窦炎伴鼻息肉中的研究进展

慢性鼻窦炎伴鼻息肉(CRSwNP)是耳鼻咽喉科的常见病,以鼻腔和鼻窦黏膜的高度异质性慢性炎症为特征。近年来,由于其发病率不断升高且易反复发作,预后较差,严重影响患者的生活质量,增加社会医疗经济负担。鼻黏膜上皮细胞构成的上皮屏障作为“守门员”,是鼻腔抵御病原体、过敏原等入侵的第一道防线。它通过启动防御机制、激活各类理化因子和调节免疫反应等维护宿主鼻腔黏膜的健康稳态。研究表明,上皮屏障功能障碍与CRSwNP的发生密切相关,也是目前CRSwNP领域的研究热点之一。因此,深入探究调控CRSwNP上皮屏障功能障碍的潜在分子生物学机制至关重要。本文将对上皮屏障在CRSwNP形成过程中的功能、作用机制和破坏因素等方面的研究进展作一综述,以期为阐明CRSwNP的病理机制提供见解,为其诊断和治疗的研究提供新方向。     

TH2细胞因子在2型慢性鼻窦炎伴鼻息肉中的作用机制研究进展

慢性鼻窦炎(chronic rhinosinusitis with nasal polyps, CRS)根据其发病机制可分为2型和非2型炎症内型,其中2型炎症对应于嗜酸性粒细胞浸润为主的慢性鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps, CRSwNP)。典型的2型CRSwNP患者通常对目前的治疗有耐药性,表现出较高的复发率。尽管生物制剂在其治疗上取得了一定的成功,但靶向单一TH2细胞因子并不能完全消除大多数患者的2型疾病,故靶向阻断TH2细胞因子及其下游的信号转导通路可能是针对内型治疗的一种新思路。论文对各2型细胞因子(IL-4、IL-5、IL-9、IL-13、IL-25和IL-33)在2型CRSwNP中与其特异性受体相互结合后激活的细胞内信号通路进行综述,旨在为治疗2型CRSwNP提供新的靶点。     

抗IgE单克隆抗体治疗难治性鼻窦炎伴鼻息肉三例

鼻息肉是鼻腔和鼻窦黏膜最常见的慢性变态反应相关疾病之一,难治性鼻窦炎伴鼻息肉常合并哮喘,手术和药物治疗都很难控制病情。奥马珠单克隆抗体是人源性IgE单克隆抗体,国外已有应用IgE单克隆抗体治疗鼻息肉,特别是哮喘合并鼻息肉的报道。本研究对3例哮喘合并慢性鼻窦炎伴鼻息肉（CRSwNP）的患者采用奥马珠单克隆抗体治疗,随访1...     

Die Anwendung von humanisierten Anti-Immunoglobulin-E-Antikörpern

Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of allergic diseases. It has demonstrated good efficacy in patients with intermittent and persisting allergic rhinitis and in patients with moderate-to-severe allergic asthma. Omalizumab results in a marked lowering of free IgE in serum and down-regulation of IgE receptors on circulating basophils. In addition, it reduces the inflow of eosinophils into nasal and bronchial tissue and the number of IgE-positive mast cells in the bronchial mucosa. Omalizumab treatment has also been shown to be associated with down-regulation of IgE receptors on circulating dendritic cells, suggesting that blocking IgE may also inhibit chronic aspects of allergic inflammation involving T cell-activation. Patients’ clinical symptoms are attenuated and their quality of life improved by anti-IgE treatment with omalizumab; other medications effective in symptomatic treatment are therefore less necessary. Omalizumab’s broad spectrum of efficacy emphasizes the central role of IgE in the allergic-inflammatory cascade. Further areas of applications in ENT medicine could be anticipated in other IgE-related illnesses, such as allergic rhinitis, food allergies, laryingitis and chronic allergy-related rhinosinusitis.     

Application of humanized Anti-IgE antibodies (omalizumab). A new principle in the treatment of allergic diseases in ENT medicine

Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of allergic diseases. It has demonstrated good efficacy in patients with intermittent and persisting allergic rhinitis and in patients with moderate-to-severe allergic asthma. Omalizumab results in a marked lowering of free IgE in serum and down-regulation of IgE receptors on circulating basophils. In addition, it reduces the inflow of eosinophils into nasal and bronchial tissue and the number of IgE-positive mast cells in the bronchial mucosa. Omalizumab treatment has also been shown to be associated with down-regulation of IgE receptors on circulating dendritic cells, suggesting that blocking IgE may also inhibit chronic aspects of allergic inflammation involving T cell-activation. Patients' clinical symptoms are attenuated and their quality of life improved by anti-IgE treatment with omalizumab; other medications effective in symptomatic treatment are therefore less necessary. Omalizumab's broad spectrum of efficacy emphasizes the central role of IgE in the allergic-inflammatory cascade. Further areas of applications in ENT medicine could be anticipated in other IgE-related illnesses, such as allergic rhinitis, food allergies, laryngitis and chronic allergy-related rhinosinusitis.     

Adverse events of biological therapy in chronic rhinosinusitis with nasal polyps: A systematic review

The management of chronic rhinosinusitis with nasal polyps (CRSwNP) is challenging due to disease recurrence and adverse effects. Both surgical and medical treatment modalities impact the quality of patients' lives. Monoclonal antibody treatment has recently been used successfully in CRS with limited reported adverse events. We aimed to review the literature to shed more light on the safety and adverse events associated with the biological therapy of CRSwNP. A comprehensive systematic review was conducted on the safety of different biological treatments when used for managing CRSwNP. We have included 13 studies in the present systematic review, including 12 randomized controlled trials (RCTs) and one cross-sectional study. The total sample size for the included studies was 2282 patients. Six studies investigated the safety and adverse events of dupilumab; three investigated omalizumab, three investigated mepolizumab, and only one investigated reslizumab. Some studies have reported that adverse events were common with these types of drugs. However they were not specific and self-limited. Headaches, injection site reactions, and pharyngitis were the most common adverse events found among the reported adverse events. The Dupilumab trial reported pharyngitis in 225 patients (22.4 %) followed by erythema in 9.4 %, headache in 8.1 %, epistaxis in 5.1 %, and asthma in 1.7 % of patients. Trials which used omalizumab reported headaches, nasal pharyngitis, injection-site reactions to be the most common adverse events with estimated prevalence rates of 8.1 %, 5.9 %, and 5.2 %, respectively. Mepolizumab and reslizumab studies reported that 40 % of patients were complicated by nasal polyps/congestion/pharyngitis/infections, 14 had a headache (15.5 %), two developed asthma (2.2 %), and only one patient (1.1 %) had epistaxis as an adverse event. Although the literature's current investigations indicate the safety of the biologic treatment modalities, further studies are needed as some uncertainty among the trials have been reported.     

Anti-IgE therapy to Kimura's disease: A pilot study

Kimura's disease is a chronic disease that is characterized by subcutaneous granuloma of soft tissues in the head and neck region, increased eosinophil counts and high serum IgE levels. It is thought to be an IgE-mediated disease. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for IgE-mediated diseases, based on its efficacy in treating asthma and allergic rhinitis. We report a study of three patients with Kimura's disease who received anti-IgE (omalizumab) treatment. All patients were treated with a fixed schedule of eight cycles of omalizumab 300 mg, administered subcutaneously at intervals of 2 weeks. The size of tumorous regions was evaluated by MRI at base line and after 4 months of treatment. Blood samples were taken every month. In each of the patients, the size of tumorous regions and the peripheral blood eosinophil and basophil counts were all decreased after the treatment. These results suggest that omalizumab may be valuable for treatment of Kimura's disease.     

Omalizumab is effective for a patient with pollen-food allergy syndrome who experienced intractable lip edema

Pollen-food allergy syndrome (PFAS) is an immunoglobulin E (IgE)-mediated allergic reaction caused when patients with pollen allergy ingest food having cross-reactivity with pollen. To date, no effective treatment method for this has been established.Here we report the case of a patient with PFAS who experienced lip edema, causing difficulties in treatment. This report describes the case of a 12-year-old boy with perennial allergic rhinitis since the age of 8 years. After ingesting fresh fruits and raw vegetables at the age of 11 years, he started to experience lip edema repeatedly. Thus, the patient was referred to our department. Based on the results of serum antigen-specific IgE, prick-to-prick, and allergen component tests, he was diagnosed with PFAS.He has been instructed to avoid causative food. Furthermore, the treatment using an antihistamine and antileukotriene receptor antagonist was initiated for pollen allergy. Sublingual immunotherapy (SLIT) for Japanese cedar pollen was initiated because the patient experienced severe nasal allergy symptoms during the dispersal season of this pollen. These treatments alleviated the nasal symptoms; however, the lip edema persisted. Omalizumab administration improved the lip edema. The combination of SLIT and omalizumab may be an effective treatment option for patients with PFAS.     

Impact of allergy on phenotypic and endotypic profiles of nasal polyposis

ObjectivesTo assess the impact of allergy on clinical presentations (phenotypes) and inflammatory patterns (endotypes) of chronic rhinosinusitis with nasal polyps (CRSwNP).MethodsA single-center prospective study was conducted over an 18-month period. Fifty-seven patients with refractory CRSwNP were included. The diagnosis of allergy was based on concordant skin prick tests and symptoms. Phenotypes were determined on symptom severity score, polyp size classification and Lund-Mackay CT staging. Inflammatory endotypes were determined on biomarker analysis (IgE, IgA, IL-5, IL-9, ECP, EDN) in blood and nasal secretions. Eosinophil counts were obtained in blood, nasal secretions and polyps.ResultsPhenotype and endotype profiles were comparable in patients with (n = 15) or without (n = 42) allergy. Only asthma with high total IgE blood concentration showed association with allergy.ConclusionsThe present results suggest that allergy is not directly involved in the clinical expression and specific inflammatory pathways of CRSwNP. New therapies target inflammation signaling pathways, and identifying accurate blood and tissue biomarkers will be the line of research most likely to improve treatment of CRSwNP.     

Metalloproteinase function in chronic rhinosinusitis with nasal polyposis

OBJECTIVES: Chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma share characteristic inflammatory features and histopathologic findings of airway remodeling. Remodeling, which is controlled by matrix metalloproteinases (MMP), is a key event in the pathogenesis of asthma. The MMP functions have rarely been evaluated in CRSwNP. STUDY DESIGN: Prospective and in vivo. METHODS: MMP-7, MMP-8, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 concentrations were analyzed by enzyme-linked immunosorbent assay and their molecular forms by Western immunoblotting and gelatin zymography in 24 patients operated on for CRSwNP and in nasal lavages from 19 healthy controls. MMP function, protective or destructive, was evaluated by comparing MMP/TIMP-1 levels with the disease activity, estimated by tissue eosinophilia and a need for re-operations. RESULTS: Significantly increased levels of MMP-8/TIMP-1 and MMP-9/TIMP-1 were found in patients without tissue eosinophilia relative to eosinophil-positive CRSwNP patients and controls, as well as in patients who did not require re-operation in comparison with re-operated patients. In eosinophil-positive and re-operated patients, these parameters were within the same range than in controls. CONCLUSIONS: Proteolytic spectrum is different in eosinophilic and noneosinophilic CRSwNP, suggesting a new mechanism for eosinophil accumulation in the disease pathogenesis. Enhanced MMP-8 and MMP-9 expression was associated with a better prognosis/clinical outcome, and thus these results may represent a synergic, protective role of MMP-8 and MMP-9 in host response in CRSwNP. Because synthetic MMP inhibitors, capable of equilibrating the unfavorable MMP/TIMP-ratio, may be of potential therapeutic value in chronic respiratory tract diseases, the MMP functions in inflammatory conditions need to be carefully established.     

胰岛素样生长因子1在鼻息肉组织中的表达与IgE的相关性研究

目的探讨胰岛素样生长因子1(insulin-likegrowth factor 1,IGF-1)在鼻息肉组织中的表达及其与IgE的相关性。方法使用荧光定量PCR技术和免疫组织化学技术分别检测40例伴鼻息肉的慢性鼻及鼻窦炎(chronic rhinosinusitis with nasal polyps,CRSwNP)患者的鼻息肉组织(CRSwNP组)和20例鼻中隔偏曲患者的中鼻甲组织(对照组)中IGF-1 mRNA及其蛋白的表达、免疫组织化学技术检测所有标本的总IgE表达并进行统计学分析。结果 IGF-1蛋白在CRSwNP组及对照组的阳性率分别为75.3%和15.4%,IGF-1 mRNA在两组的表达分别为0.825±0.315和0.358±0.387,CRSwNP组IGF-1蛋白和IGF-1 mRNA的表达显著高于对照组(t=6.318,P<0.01;t=-5.014,P<0.05);CRSwNP组中合并变应性因素与无变应性因素亚组之间的IGF-1 mRNA表达无差异(t=0.856,P>0.05)。总IgE在两组阳性细胞数分别为14.65±3.34和3.40±1.27,CRSwNP组总IgE阳性细胞数显著高于对照组(t=-5.366,P<0.01)。IGF-1 mRNA与总IgE阳性细胞数呈正相关(r=0.319,P<0.05)。结论IGF-1参与CRSwNP的发病机制,局部变应性因素而非系统性变应性因素影响其表达,IGF-1可能通过促进细胞生长、抑制细胞凋亡以及促进IgE的生成参与局部免疫调控等途径发挥作用。     

Correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) severity and asthma control

BackgroundChronic rhinosinusitis with nasal polyposis (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high social and economic burdens. According to the “unified airway diseases theory”, CRSwNP and asthma often occur simultaneously as comorbidities, complicating their overall management.ObjectiveWe aimed to evaluate the correlation between CRSwNP severity, according to the Clinical-Cytological Grading (CCG), and asthma control.Methods151 patients suffering from both CRSwNP and asthma step Gina 4–5 were recruited. We examined patients' clinical history and administered to each patient the Asthma Control Test (ACT). Moreover, we performed nasal endoscopy and nasal cytology on all patients. According to nasal cytology findings and comorbidities each patient was assigned a CCG score. Kolmogorov-Smirnov and Shapiro-Wilk tests were performed. A ROC curve was constructed to detect the accuracy of the CCG in detecting not well controlled asthma.ResultsThe mean ACT was 18.44 ± 4.53. 57 % of patients suffered from not well controlled or poorly controlled asthma. The mean CCG score was 6.68 ± 2.01. 54.3 % of patients had a severe CCG value. Well-controlled asthmatic patients had a lower percentage of severe CCG and a higher percentage of mild CCG. 50 % of patients with non-well or poorly controlled asthma showed a mixed eosinophil-mast cell infiltrate. A CCG <6 and the absence of the simultaneous presence of eosinophils and mast cells in the nasal cytology were associated with well-controlled asthma.ConclusionsPatients with high-grade CCG, especially with mixed eosinophil-mast cell inflammatory infiltrate at nasal cytology, are more prone to uncontrolled asthma.