Clinical and Translational Allergy最新文献_第3页

Milk ladder versus early oral immunotherapy in infants with cow's milk protein allergy 牛奶蛋白过敏婴儿的牛奶梯与早期口服免疫疗法。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-08-08 DOI: 10.1002/clt2.12388

Yurika Matsumoto, Mayumi Fujita, Tsukahara Ayumi, Tetsuya Takamasu, Chisato Inuo

Cow's milk protein allergy (CMPA) significantly decreases the quality of life of infants and their families, necessitating effective management. Avoidance of cow's milk protein (CMP) has been the primary approach, awaiting the development of a natural tolerance.1Oral immunotherapy (OIT) for CMPA gradually increases the use of pure CMP, such as milk, to enhance tolerance. A previous study demonstrated the efficacy and safety of early OIT (E-OIT) for infants with CMPA.2 The Milk Ladder (ML) method modifies the OIT strategy and enhances CMP tolerance through stepwise exposure to milk-containing foods.1, 3-5 Despite growing adoption, ML lacks extensive validation and requires further research.4 To the best of our knowledge, there have been no comparative studies of E-OIT and ML in infants with CMPA. This study aimed to compare the efficacy and safety of ML and E-OIT in infants with CMPA.We retrospectively analyzed infants younger than 2 years who started intervention for CMPA at the Department of Allergy at Kanagawa Children's Medical Center from April 2016 to March 2022, with a treatment protocol shift in April 2018 from E-OIT to ML. Inclusion criteria included a CMPA diagnosis based on parent-reported immediate allergic reaction to CMP ingestion or a serum milk-specific IgE level greater than 5 kUA/L.3 Patients with only gastrointestinal symptoms were excluded due to different CMPA types. The ML protocol started with baked milk (BM), advancing toward less processed forms, while E-OIT began with controlled doses of milk or yogurt. For detailed protocols, see the Supplementary materials in Supporting Information S1.CMP tolerance was defined as the ability to consume 100 mL of milk or an equivalent amount of approximately 3300 mg of CMP daily without experiencing symptoms. Low dairy tolerance for processed foods was defined as the ability to consume processed foods. Products high in dairy ingredients, such as cheese, yogurt, and pizza were excluded. These were confirmed through repeated intake at home. All patients underwent treatment review and assessment through interviews approximately every 3 months to assess progress and adjust care, as necessary.This study conformed to the guidelines established by the Declaration of Helsinki and was approved by the Kanagawa Children's Medical Center Research Ethics Committee (approval no. 2105-4). Informed consent was obtained from the parents of all patients.The analyses were performed according to the intention-to-treat principle (ITT) 2 years post intervention. The Mann–Whitney U test was used to compare continuous variables, while the Chi-squared test or Fisher's exact test was used for categorical variables. To evaluate the progression of CMP tolerance over time, Kaplan–Meier analysis with a log-rank test was performed. Statistical s

考虑到两组中方案中止率都很高，因此需要进一步改进食物阶梯的方法。首先，样本量较小，缺乏随机性和盲法。我们采用 ITT 技术分析数据，以减少选择偏差。ML组的基线CM特异性IgE水平较高，而且更年轻，可能会影响结果。有必要进行前瞻性、随机、盲法研究。其次，我们没有进行双盲口服食物挑战试验，而这是诊断和耐受 CMPA 的金标准。总之，在治疗婴儿 CMPA 方面，ML 与 E-OIT 一样有效、安全。此外，ML 比 E-OIT 更有利于 CMPA 患儿摄入加工食品：写作--原稿；调查；正式分析。藤田真由美：调查；数据整理；监督。冢原步美调查；数据整理。Tetsuya Takamasu：调查。猪尾千里构思；撰写-审阅&amp；编辑；资金获取；调查；监督；项目管理；可视化。

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引用次数: 0

Clinical and biological characteristics associated with bronchial or pulmonary abnormalities on chest CT imaging in patients with systemic mastocytosis 与全身性肥大细胞增多症患者胸部 CT 成像中支气管或肺部异常相关的临床和生物学特征。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-08-06 DOI: 10.1002/clt2.12387

Raphael Vallière, Cristina Bulai Livideanu, Thomas Villeneuve, Grégoire Prévot, Laurent L. Reber, Laurent Guilleminault

To the Editor,Mastocytosis is a heterogeneous group of diseases characterized by a numerical increase and accumulation of clonal mast cells in various organ systems. In systemic mastocytosis, the severity varies from indolent to aggressive mastocytosis, the latter being associated with a worse prognosis.1 Although the lungs are known to be rich in mast cells, comorbid respiratory diseases have only been sporadically suggested as associated with SM in case reports.2-4 To our knowledge, no data are available on chest CT scans in patients with SM.The aim of our study is to determine clinical and biological characteristics associated with bronchial or pulmonary abnormalities on chest CT scans in patients with SM.A retrospective observational study was carried out at Toulouse University Hospital Center from 2003 to 2022 using our mastocytosis registry. All patients with (1) a diagnosis of SM based on bone marrow biopsy according to criteria published elsewhere1 and (2) a CT scan image available in their medical record were included. This study was conducted in accordance with French ethics requirements (RC31/17/0095) and the guidelines of the National Commission for Data Protection and Liberties (CNIL number: 2206723 v 0).Chest CT scans were evaluated by two physicians blinded to the patients' clinical and functional details. The two observers easily established a consensus about the predominant chest CT scan pattern according to the definitions of the Fleischner Society.5Continuous data were expressed as median and interquartile range and categorical data as number of patients and percentages. An increased risk of a predominant pattern on chest CT scan was assessed for aggressive versus indolent SM and serum tryptase ≥20 μg/L versus <20 μg/L. For this analysis, we used a multivariable logistic regression with a calculation of adjusted odds ratios (aORs) with a 95% confidence interval. aORs were adjusted on the following covariates: age, sex and smoking status. We were not able to determine aOR if the CT scan abnormality was absent in the control group.A total of 103 patients with SM were included in the study (Table 1). Of them, 60.2% were females and the median age was 54 [40–60]. Mastocytosis was indolent in 70 (73%) patients, cKit mutation was found in 91 (85%) patients and median serum tryptase was 15 [30–51] µg/l. A predominant chest CT scan pattern was observed in 36 (35.0%) patients. The lung lesions were as follows: nodules (n = 11), emphysema (n = 9), bronchiectasis (n = 6), bronchial wall thickening (n = 6) and interstitial lung diseases (n = 4).According to the multivariable analysis, an increased risk of emphysema was observed for aggressive mastocytosis compared to indolent mastocytosis (aOR 5.0 [95% CI: 1.1–27.6]) (Figure 1). An increased risk of bronchi

致编辑：肥大细胞增多症是一组异质性疾病，其特征是克隆肥大细胞在不同器官系统中的数量增加和积聚。在全身性肥大细胞增多症中，病情严重程度不一，有的表现为轻度肥大细胞增多症，有的表现为侵袭性肥大细胞增多症，后者预后较差。1 虽然众所周知肺部富含肥大细胞，但仅有零星病例报告认为合并呼吸系统疾病与肥大细胞增多症有关。据我们所知，目前还没有关于 SM 患者胸部 CT 扫描的数据。我们的研究旨在确定与 SM 患者胸部 CT 扫描中支气管或肺部异常相关的临床和生物学特征。2003 年至 2022 年，图卢兹大学医院中心利用我们的肥大细胞病登记册开展了一项回顾性观察研究。所有符合以下条件的患者均被纳入研究范围：(1) 根据其他地方公布的标准1 进行骨髓活检确诊为 SM；(2) 病历中有 CT 扫描图像。这项研究符合法国伦理要求（RC31/17/0095）和国家数据保护与自由委员会的指导方针（CNIL 编号：2206723 v 0）。胸部 CT 扫描图像由两名对患者临床和功能细节保密的医生进行评估。根据弗莱施纳协会（Fleischner Society）的定义，两位观察者很容易就胸部 CT 扫描的主要模式达成共识。评估了侵袭性与非侵袭性 SM 和血清胰蛋白酶≥20 μg/L 与 <20μg/L，胸部 CT 扫描出现主要模式的风险增加。在这项分析中，我们采用了多变量逻辑回归，计算出了调整后的几率比（aORs）和 95% 的置信区间。如果对照组没有 CT 扫描异常，我们则无法确定 aOR。研究共纳入 103 名 SM 患者（表 1），其中 60.2% 为女性，中位年龄为 54 岁 [40-60]。70（73%）名患者的肥大细胞增多症不明显，91（85%）名患者发现 cKit 突变，血清胰蛋白酶中位数为 15 [30-51] µg/l。在 36 例（35.0%）患者中观察到主要的胸部 CT 扫描模式。肺部病变如下：结节（11 例）、肺气肿（9 例）、支气管扩张（6 例）、支气管壁增厚（6 例）和间质性肺病（4 例）。根据多变量分析，与惰性肥大细胞增多症相比，侵袭性肥大细胞增多症患者发生肺气肿的风险增加（aOR 5.0 [95% CI：1.1-27.6]）（图 1）。血清胰蛋白酶≥20 μg/L时，支气管壁增厚的风险增加（aOR 22.6 [95% CI：2.4-555.0]）。至于所有其他病变，所有组别均未发现风险增加。我们也没有发现甲基胆碱试验阳性的风险增加（数据未显示）。在我们的研究中，我们发现35%的SM患者在胸部CT扫描中发现支气管或肺部病变，而胸部CT扫描是我们中心系统进行的检查。在 1988 年对 58 例肥大细胞增多症患者进行的一项研究中，Travis 等人发现 9 例（16%）患者胸部影像学异常6 ，其中 4 例有局灶性纤维化区域，2 例有钱币状病变，2 例有散在纤维化区域，1 例有严重的双侧间质纤维化，1 例有多发性肺结节。未进行肺活检。在文献中，我们的研究是唯一一项描述 SM 患者胸部 CT 扫描异常的研究。我们的研究发现，侵袭性肥大细胞增多症可能与肺气肿有关。在以前的病例报告中，已观察到肥大细胞肺浸润的组织学证实在 SM 患者中出现。尽管我们的研究结果似乎与吸烟状况无关，但正如在小鼠模型中观察到的那样，吸烟习惯很可能是一个额外的风险因素。我们发现，胰蛋白酶≥20 μg/L与支气管壁增厚的风险增加有关。气道中肥大细胞的浸润可以解释我们的结果。事实上，色氨酸酶水平与肥大细胞活化相关。因此，我们推测血清中色氨酸酶水平的升高可能与肥大细胞在气道中的聚集和活化有关。这种相关性的机制仍有待阐明。我们的研究有其局限性。首先，没有患者进行肺活检。然而，胸部 CT 扫描与组织学模式之间的良好相关性已被广泛观察到。其次，对照组中没有肥大细胞增多症患者。事实上，我们的研究重点是乳腺增生症患者的胸部 CT 扫描特征。因此，我们的结果完全来自于肥大细胞增多症患者。总之，我们发现 35% 的肥大细胞增多症患者的胸部 CT 扫描发现了支气管或肺部病变。血清胰蛋白酶≥20 μg/L时，侵袭性肥大细胞增多症和支气管壁增厚的肺气肿风险增加。需要进行前瞻性研究，以评估胸部 CT 扫描在 SM 中的作用：构思；调查；方法；项目管理；验证；可视化；写作--原稿；写作--审稿&amp；编辑；数据整理；资源。克里斯蒂娜-布莱伊-利维德亚努（Cristina Bulai Livideanu）：调查；方法；验证；可视化；写作--审阅和编辑；写作--原稿；项目管理。托马斯-维伦纽夫调查；写作--原稿；方法论；验证；可视化；写作--审查和amp；编辑；项目管理。Grégoire Prévot：调查；写作--原稿；方法；验证；可视化；写作--审查和amp；编辑；项目管理。Laurent L. Reber：调查；撰写--原稿；方法；验证；可视化；撰写--审查和amp; 编辑；项目管理。Laurent Guilleminault：Laurent Guilleminault曾是阿斯利康、MSD和诺华公司临床试验的研究人员，报告了阿斯利康、葛兰素史克、诺华和赛诺菲-瑞格列奈的资助或咨询费，以及拜耳、Chiesi和MSD的咨询费，但这些资助或咨询费均与提交的工作无关。托马斯-维伦纽夫（Thomas Villeneuve）申报了勃林格殷格翰公司（Boehringer Ingelheim）和Mauna Kea Technologies公司的咨询费，但与提交的工作无关。Cristina Bulai Livideanu 曾是 Abbvie、ABScience、BluePrint Medicine、Cogent、Janssen、礼来、诺华和辉瑞临床试验的研究员，并申报了 Abbvie、Blueprint Medicine、Janssen、礼来和诺华的咨询费，这些咨询费与所提交的工作无关。Laurent L. Reber 目前或最近曾是 Argenx、诺华、Ceva 和 Neovacs 的演讲人和/或顾问，和/或接受过它们的研究资助，但与所提交的工作无关。据观察，侵袭性肥大细胞增多症和血清胰蛋白酶≥20 μg/L的支气管壁增厚患者发生肺气肿的风险增加。

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引用次数: 0

Being born in autumn or winter is associated with asthma and allergic rhinitis in Finland 在芬兰，秋季或冬季出生与哮喘和过敏性鼻炎有关。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-19 DOI: 10.1002/clt2.12383

Riikka Hänninen, Aada Murtomäki, Fanni Svärd, Aarno Dietz, Paulus Torkki, Jari Haukka, Mikko Nuutinen, Sanna Toppila-Salmi

Background

Our population-based study has previously shown that being born in winter or spring was associated with adult-onset asthma. The aim was to study if season of birth (SOB) is associated with airway allergy and related diseases: NSAID exacerbated respiratory disease (N-ERD), asthma, allergic rhinitis (AR), nonallergic rhinitis (NAR), chronic rhinosinusitis with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) in Finland.

Methods

A randomly sampled retrospective registry-based follow-up data (n = 74,868) of patients visiting Hospital District of Helsinki and Uusimaa (HUS) in Finland was used. The birth date, sex, visit date and comorbidities were collected from electronic health record data during visits from 2005 to 2019.

Results

The mean (SD, range) age of the sample was 34.53 (25.47, 0–102) years, with 48.7 % being men. We divided the whole population in four groups based on the season they were born (SOB-groups). When observing these four SOB-groups, the proportion of those having asthma was 43.1%, 42.1%, 41.1%, 42.7%, in winter, spring, summer, and autumn SOB-groups, respectively. The proportion of those having AR was 12.6%, 12.0%, 10.7%, 12.1%, respectively. When having summer as a reference, being born in any other time of year was significantly associated with AR and, being born in autumn or winter was associated with asthma. No significant association was observed in CRS or N-ERD or NAR groups in adjusted models.

Conclusions

The study suggests that early life immunological events may have a role a role in pathogenesis of asthma and AR. As no association was observed between SOB and CRSsNP, CRSwNP, N-ERD or NAR, further studies on this are warranted.

研究背景我们基于人群的研究曾表明，出生在冬季或春季与成人哮喘发病有关。我们的目的是研究出生季节（SOB）是否与气道过敏及相关疾病有关：芬兰的非甾体抗炎药加重的呼吸道疾病（N-ERD）、哮喘、过敏性鼻炎（AR）、非过敏性鼻炎（NAR）、有鼻息肉的慢性鼻炎（CRSwNP）和无鼻息肉的慢性鼻炎（CRSsNP）：方法：采用随机抽样的回顾性登记随访数据（n=74,868），这些数据来自芬兰赫尔辛基和乌西马医院区（HUS）。从2005年至2019年就诊期间的电子健康记录数据中收集了患者的出生日期、性别、就诊日期和合并症：样本的平均年龄（SD，范围）为34.53（25.47，0-102）岁，其中48.7%为男性。我们根据出生季节将整个人群分为四组（SOB 组）。在观察这四个季节组时，冬季、春季、夏季和秋季季节组的哮喘患者比例分别为 43.1%、42.1%、41.1% 和 42.7%。患有急性哮喘的比例分别为 12.6%、12.0%、10.7% 和 12.1%。以夏季为参照，在一年中的任何其他时间出生都与哮喘有显著相关性，而在秋季或冬季出生则与哮喘相关。在调整模型中，CRS、N-ERD 或 NAR 组均未观察到明显的相关性：结论：这项研究表明，生命早期的免疫事件可能在哮喘和哮喘的发病机制中起一定作用。由于未观察到 SOB 与 CRSsNP、CRSwNP、N-ERD 或 NAR 之间存在关联，因此有必要对此进行进一步研究。

{"title":"Being born in autumn or winter is associated with asthma and allergic rhinitis in Finland","authors":"Riikka Hänninen, Aada Murtomäki, Fanni Svärd, Aarno Dietz, Paulus Torkki, Jari Haukka, Mikko Nuutinen, Sanna Toppila-Salmi","doi":"10.1002/clt2.12383","DOIUrl":"10.1002/clt2.12383","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 Our population-based study has previously shown that being born in winter or spring was associated with adult-onset asthma. The aim was to study if season of birth (SOB) is associated with airway allergy and related diseases: NSAID exacerbated respiratory disease (N-ERD), asthma, allergic rhinitis (AR), nonallergic rhinitis (NAR), chronic rhinosinusitis with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) in Finland.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 A randomly sampled retrospective registry-based follow-up data (n = 74,868) of patients visiting Hospital District of Helsinki and Uusimaa (HUS) in Finland was used. The birth date, sex, visit date and comorbidities were collected from electronic health record data during visits from 2005 to 2019.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 The mean (SD, range) age of the sample was 34.53 (25.47, 0–102) years, with 48.7 % being men. We divided the whole population in four groups based on the season they were born (SOB-groups). When observing these four SOB-groups, the proportion of those having asthma was 43.1%, 42.1%, 41.1%, 42.7%, in winter, spring, summer, and autumn SOB-groups, respectively. The proportion of those having AR was 12.6%, 12.0%, 10.7%, 12.1%, respectively. When having summer as a reference, being born in any other time of year was significantly associated with AR and, being born in autumn or winter was associated with asthma. No significant association was observed in CRS or N-ERD or NAR groups in adjusted models.\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 The study suggests that early life immunological events may have a role a role in pathogenesis of asthma and AR. As no association was observed between SOB and CRSsNP, CRSwNP, N-ERD or NAR, further studies on this are warranted.\u0000 </section>\u0000 </div>","PeriodicalId":10334,"journal":{"name":"Clinical and Translational Allergy","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/clt2.12383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dupilumab induces a significant decrease of food specific immunoglobulin E levels in pediatric atopic dermatitis patients 杜匹单抗能显著降低小儿特应性皮炎患者的食物特异性免疫球蛋白 E 水平。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-17 DOI: 10.1002/clt2.12381

Lisa P. van der Rijst, Michelle S. Hilbrands, Nicolaas P. A. Zuithoff, Marjolein S. de Bruin-Weller, André C. Knulst, Thuy-My Le, Marlies de Graaf

To the Editor,Atopic dermatitis (AD) and food allergy (FA) are common chronic diseases that have a major impact on quality of life and socio-economic burden.1, 2 AD is strongly associated with the development of immunoglobulin E (IgE)-mediated FA.3-5 The associated immune response involves allergen specific T helper type 2 cells inducing a pro-inflammatory cytokine release, including interleukin (IL)-4 and IL-13, thereby causing initiation of B cell immunoglobulin class switching to specific IgE (sIgE).4 Dupilumab, a human monoclonal antibody that is approved for treatment of (moderate to) severe AD in children from the age of 6 months, blocks the IL-4 and IL-13 signaling pathway.6 Spekhorst et al. showed that dupilumab induces a profound decrease in sIgE levels of several food allergens in adult AD patients with comorbid FA, highlighting the positive effect of blocking IL-4 and IL-13 signaling on sIgE levels.5 As FA often develops at a young age, and the effect of dupilumab on food sIgE levels in pediatric patients remains unclear, it is of particular interest to evaluate the effect of dupilumab in this young patient population. Therefore, the aim of this study was to investigate the effect of dupilumab on food sIgE levels of 10 common allergens in food allergic pediatric patients with moderate to severe AD.Pediatric AD patients (aged 4–17 years) treated with dupilumab with a suggestive clinical history of FA for peanut, hazelnut, cashew nut, pistachio, almond, walnut, hen's egg, cow's milk, kiwi, and/or apple with a corresponding positive sIgE (≥0.35 kU/L) at the start of treatment (baseline), were included. Patients who were never exposed to specific food allergens, due to severe IgE-mediated reactions to other food allergens (e.g., hazelnut, leading to avoidance of other nuts) or to parental anxiety (e.g., due to severe parental FA), with a corresponding positive sIgE, were also included. sIgE levels were measured at baseline and at least once during 1 year of follow-up. Data were extracted from the prospective BioDay registry between August 2019 and July 2023. A covariance pattern model was used to analyze the development of (s)IgE values over time. All analyses were performed for each food separately using a covariance pattern model (detailed explanation of methods is described in Supporting Information S1).A total of 36 pediatric patients with a mean age of 12.5 (standard deviation ±3.6) years were included (Table 1). A total of 120 FAs, with 1008 corresponding sIgE samples, were identified (Table S1). Peanut (18.3%) and hazelnut (16.7%) were the most common foods to which patients were sensitized. Results of baseline food sIgE levels stratified by severity of FA are shown in Table S2. Two (5.6%) patients discontinued dupilumab treatment at a mean treatment duration of 16.5 weeks.A significa

阻断 IL-4/IL-13 通路的杜匹鲁单抗可能在防止 IgE 类别转换方面发挥关键作用，从而降低 sIgE 水平，并可能减轻 FA 的严重程度。只有一份病例报告描述了一名成年AD患者在接受杜必鲁单抗治疗期间对罐装玉米和开心果产生了食物耐受，并通过口服食物挑战得到了证实。7 需要进行包括治疗前、治疗期间和治疗后OFCs的前瞻性研究，以明确杜必鲁单抗治疗是否会导致更高的阈值和/或更轻的FA症状，与sIgE水平可能存在的关系，以及这种效应在治疗终止后是否会持续。此外，未来的研究还需要评估年龄较小（6 个月）时使用杜匹单抗治疗的效果。4总之，这是第一项显示中度至重度 AD 儿童食物过敏患者 10 种常见食物过敏原 sIgE 水平显著下降的研究，经过 1 年的杜比鲁单抗治疗后，sIgE 水平下降了 70.5% 至 82.5%。这些发现证实了杜比鲁单抗对合并FA的儿科AD患者的多种FA具有额外的积极作用。为了阐明杜必鲁单抗在FA治疗中的作用，需要进一步了解杜必鲁单抗在儿科患者中的临床和免疫学效应：构思；数据整理；形式分析；调查；方法论；可视化；写作-原稿；写作-审稿&amp；编辑。米歇尔-希尔布兰德（Michelle S. Hilbrands）：数据整理；形式分析；调查；方法论；写作 - 原稿。Nicolaas P. A. Zuithoff：方法论；写作 - 审核与编辑；软件；验证。Marjolein S. de Bruin-Weller：构思；项目管理；资源；监督；写作 - 审阅和amp; 编辑；获取资金。André C. Knulst：写作--审阅和编辑；监督。Thuy-My Le：概念化；方法论；监督；验证；可视化；写作--审阅和编辑；写作--原稿。Marlies de Graaf：Lisa P. van der Rijst 曾担任艾伯维公司和诺华公司的发言人；Michelle S. Hilbrands 没有任何需要披露的信息；Nicolaas P. A. Zuithoff 没有任何需要披露的信息。A. Zuithoff 未披露任何信息；Marjolein S. de Bruin-Weller 曾是艾伯维、Almirall、安进、阿斯兰、礼来、Galderma、杨森、利奥制药、辉瑞、再生元制药和赛诺菲的顾问、咨询委员会成员和/或演讲人；André C.Knulst 曾担任 ALK、赛默飞世尔、Nutricia/Danone、EUROIIMUN、DBV 和诺华的顾问、咨询委员会成员和/或演讲人；Thuy-My Le 曾担任赛默飞世尔科技、诺华和艾伯维的咨询委员会成员或演讲人；Marlies de Graaf 曾担任艾伯维、Almirall、礼来、杨森、利奥制药、诺华、辉瑞、再生元制药和赛诺菲的顾问、咨询师和/或演讲人。

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引用次数: 0

House dust mite immunotherapy: A real-world, prescription data-based analysis 屋尘螨免疫疗法：基于处方数据的真实世界分析。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-11 DOI: 10.1002/clt2.12382

R. Mösges, H. Richter, A. Sager, J. Weber, T. Müller

Background

House dust mite (HDM) sensitisation can contribute to the development of allergic rhinoconjunctivitis (AR) or allergic asthma (AA). As treatment, allergen immunotherapy (AIT) is a promising approach, since it aims building immunotolerance against allergens, therewith establishing long-term efficacy. The evaluation of AIT has been investigated in many randomised controlled trials, whereas few real-world evidence studies are available.

Methods

We used data from the longitudinal prescription data base IQVIA™ LRx. Data on initial AIT prescriptions against HDM from January 2009 to December 2013 was analysed regarding treatment (subcutaneous AIT with either depigmented polymerised allergen extract [dSCIT] or other allergens [oSCIT], or sublingual immunotherapy [SLIT]) and treatment duration. Treatment groups were compared with a control group of AR patients not receiving AIT. Data on symptomatic medication was collected until February 2017 and progression of AR and AA was compared.

Results

Data of 7260 patients with AIT prescriptions and of 21,780 control patients was analysed. AIT was associated with a significant decrease of AR medication intake compared with control (dSCIT: −34.0%, p < 0.0001; oSCIT: −25.7%, p < 0.0001; SLIT: −37.7%, p = 0.0026). In asthmatics, SCIT was associated with a significant decrease of asthma medication compared with control (dSCIT: −45.2%, p < 0.0001; oSCIT: −32.9%, p < 0.0001). Further, a significantly reduced likelihood for onset of asthma medication was demonstrated in patients treated with SCIT compared with controls (dSCIT OR: 0.759, p = 0.0476; oSCIT OR: 0.815, p = 0.0339).

Conclusion

Real-world data analyses indicate that AIT, particularly given via a subcutaneous route, reduces the need of medication against AR and AA and might delay the onset of asthma medication in patients with AR.

背景：屋尘螨（HDM）致敏可导致过敏性鼻结膜炎（AR）或过敏性哮喘（AA）的发生。过敏原免疫疗法（AIT）是一种很有前景的治疗方法，因为它旨在建立对过敏原的免疫耐受，从而确立长期疗效。许多随机对照试验都对 AIT 的评估进行了调查，但实际证据研究却很少：我们使用了纵向处方数据库 IQVIA™ LRx 中的数据。我们分析了 2009 年 1 月至 2013 年 12 月期间针对人类乳头瘤病毒的首次 AIT 处方数据，包括治疗方法（皮下 AIT，使用去色素聚合过敏原提取物 [dSCIT] 或其他过敏原 [oSCIT]，或舌下免疫疗法 [SLIT]）和治疗持续时间。治疗组与未接受 AIT 的 AR 患者对照组进行比较。收集了截至2017年2月的症状用药数据，并对AR和AA的进展情况进行了比较：分析了7260名开具AIT处方的患者和21780名对照组患者的数据。与对照组相比，AIT 与 AR 药物摄入量的显著减少有关（dSCIT：-34.0%，p 结论：AIT 与 AR 药物摄入量的显著减少有关：真实世界的数据分析表明，AIT（尤其是通过皮下注射途径）可减少 AR 和 AA 的用药需求，并可推迟 AR 患者开始使用哮喘药物的时间。

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引用次数: 0

Comparison of skin prick test and prick-to-prick test with fruits and vegetables in the diagnosis of food allergy 皮肤点刺试验与水果蔬菜点刺试验在诊断食物过敏方面的比较。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-05 DOI: 10.1002/clt2.12375

Severina Terlouw, Frank E. van Boven, Monika Borsboom-van Zonneveld, Tineke de Graaf-in ’t Veld, Roy Gerth van Wijk, Paul L. A. van Daele, Maurits S. van Maaren, Jac H. S. A. M. Kuijpers, Sharon Veenbergen, Nicolette W. de Jong

Introduction

Prick-to-prick (PTP) test with fresh food is accepted as a reliable tool for measuring sensitization to fruits and vegetables. Not all fruits and vegetables are available throughout the year. The objective of this study was to investigate whether skin prick test (SPT) performed with frozen juice of fruits and vegetables (FJFV) is a good alternative to PTP tests performed with fresh fruits and vegetables (FFV).

Methods

Adult patients suspected of having a food allergy to fruits and/or vegetables were included. A questionnaire was used to score symptoms after consumption of apple, kiwi, peach, tomato, and carrot. SPTs with FJFV, and PTP tests with FFV were performed. Intra-class correlation coefficients (ICC) between the SPT and PTP test results were calculated. The sensitivity and specificity of both diagnostic tests towards food allergen specific symptoms (FASS) were calculated.

Results

Thirty-six patients were included. FASS was positive in 75% for apple, 53% for kiwi, 44% for peach, 25% for tomato, and 22% for carrot. ICC between SPT and PTP test results were moderate for apple (0.72) and kiwi (0.71), strong for peach (0.75) and tomato (0.89), and very strong for carrot (0.94). Sensitivity was equal for the SPT and PTP tests for apple (0.93), peach (0.81), and carrot (1.00), and comparable for kiwi (0.50 resp. 0.70), and tomato (0.44 resp. 0.56). Specificity was equal for apple (0.33), peach (0.15), and carrot (0.41), and comparable for kiwi (0.29 resp. 0.21) and tomato (0.80 resp. 0.72).

Conclusions

Results of SPT with FJFV and PTP test with FFV are comparable. SPT with FJFV is a good alternative in the daily practice of the allergists.

导言：使用新鲜食物进行 "点刺 "试验（PTP）是测量对水果和蔬菜过敏性的可靠工具。但并非所有水果和蔬菜都能全年供应。本研究旨在探讨使用冷冻果蔬汁（FJFV）进行皮肤点刺试验（SPT）是否是使用新鲜果蔬（FFV）进行 PTP 试验的良好替代方法：方法：纳入怀疑对水果和/或蔬菜食物过敏的成年患者。方法：纳入怀疑对水果和/或蔬菜食物过敏的成年患者，使用问卷对患者食用苹果、猕猴桃、桃、番茄和胡萝卜后出现的症状进行评分。对 FJFV 进行了 SPT 测试，对 FFV 进行了 PTP 测试。计算了 SPT 和 PTP 测试结果之间的类内相关系数 (ICC)。计算了两种诊断测试对食物过敏原特异性症状（FASS）的敏感性和特异性：结果：共纳入 36 名患者。苹果、猕猴桃、桃子、番茄和胡萝卜的 FASS 阳性率分别为 75%、53%、44%、25% 和 22%。苹果（0.72）和猕猴桃（0.71）的 SPT 和 PTP 检测结果之间的 ICC 值中等，桃子（0.75）和番茄（0.89）的 ICC 值较高，胡萝卜（0.94）的 ICC 值非常高。SPT 和 PTP 检测对苹果（0.93）、桃子（0.81）和胡萝卜（1.00）的灵敏度相同，对猕猴桃（0.50 或 0.70）和番茄（0.44 或 0.56）的灵敏度相当。苹果（0.33）、桃子（0.15）和胡萝卜（0.41）的特异性相同，猕猴桃（0.29 resp. 0.21）和番茄（0.80 resp. 0.72）的特异性相当：使用 FJFV 的 SPT 和使用 FFV 的 PTP 测试结果相当。使用 FJFV 进行 SPT 是过敏症医生日常工作中的一个很好的选择。

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引用次数: 0

Lack of detection of aluminium-reactive T-lymphocytes in patients with SCIT-induced granulomas 在 SCIT 引起的肉芽肿患者体内未检测到铝反应性 T 淋巴细胞。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-02 DOI: 10.1002/clt2.12378

Stine Skovbo Hoffmann, Jesper Elberling, Jeanne Duus Johansen, Lars Heede Blom

Aluminium contact allergy is mainly seen in children with itching vaccination granulomas following immunization with aluminium-adsorbed vaccines, but may also occur in adults following allergen-specific subcutaneous immunotherapy, SCIT, as these vaccines too are aluminium-adsorbed.1 Traditional method of determining sensitization to aluminium is patch testing, an in vivo skin test considered the gold standard for detecting contact allergy.2 Still, it has the disadvantage of only detecting the allergic response in the skin, and not systemic reactions. In adults there is a great risk of false-negative patch test results even though new recommendations on a higher aluminium concentration, rising from 2% to 10% aluminium chloride hexahydrate (AlCl3H2O6), has been implemented.3An alternative to patch testing is the blood in vitro lymphocyte proliferation test (LPT), also known as the lymphocyte transformation test (LTT), which we investigated using a well-established LPT protocol. This has previously been shown to detect and characterize metal-specific cells and was used to detect circulating aluminium-specific proliferation. The LPT test is based on a single blood sample and has mostly been used to detect drug hypersensitivity. Still, its role in detecting metal allergy is expanding,4 with recent studies suggesting using the test as a supplement to the patch test when only a few allergens are to be investigated.5 Our study aimed to determine the diagnostic performance of LPT in adults with SCIT-induced vaccination granulomas, and to evaluate the association between LPT and patch test reactions.We included six participants with SCIT-induced granulomas and 10 healthy controls. Inclusion of patients was limited by the small number of SCIT-recipients referred to our department.Characteristics of the participants with SCIT-induced granulomas are shown in Table 1. All granulomas were long-lasting, and except for one participant with 2 granulomas, all had 3 or more palpable and itching granulomas, mainly on the upper arms but also on the flanks. The control group were matched for age and sex, and did not undergo patch testing, but had no history of post-vaccination granulomas, contact dermatitis, contact allergy, or other skin diseases, had never received SCIT and not been vaccinated with an aluminium-adsorbed vaccine within the last year.Participants with granulomas were all patch tested with AlCl3H2O6 2% (before 2021) or 10% mixed in petrolatum and applied under Finn chambers, an aluminium Finn chamber and an empty plastic chamber as control (8 mm; Smartpractice, Phoenix, AZ, USA), all applied on the upper back and secured with Scanpor® tape (Norgesplaster, Vennesla, Norway). Application time was 2 days, and patch test reactions we

4 检测结果为阴性的其他可能解释是，肉芽肿中依赖 T 细胞的炎症并非由铝引起，因为肉芽肿有各种组织病理学结果，7 或者如其他研究报告所述，由于诱导/激发和检测之间的时间间隔，铝过敏已经减弱。此外，LTT 系统中缺乏特异性增殖也可能是由于铝的配制或铝-蛋白合剂复合物在体外形成滞后所致。由于口服铝可能会产生全身反应，导致接种肉芽肿患儿出现皮肤糜烂9 ，因此对淋巴细胞反应性进行研究，以确定这些患儿发生全身反应的可能性，将是非常有意义的：数据整理；调查；撰写-原稿；撰写-审稿&amp；编辑。Jesper Elberling：构思；监督；写作 - 审阅和编辑。让娜-杜斯-约翰森（Jeanne Duus Johansen）：概念化；方法论；指导；写作 - 审阅和编辑。拉尔斯-海德-布洛姆概念化；形式分析；软件；写作 - 审核与编辑。

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引用次数: 0

Airborne pollen exposure and risk of hospital admission for allergic rhinitis in Beijing: A time-stratified case-crossover study 北京空气中花粉暴露与过敏性鼻炎入院风险：一项时间分层病例交叉研究。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-02 DOI: 10.1002/clt2.12380

Yuhui Ouyang, Jun Yang, Jingxuan Zhang, Yun Yan, Shengzhi Sun, Jiajia Wang, Xiaobo Li, Rui Chen, Luo Zhang

Background

Airborne pollen is a crucial risk factor in allergic rhinitis (AR). The severity of AR symptoms can vary based on pollen type and concentration. This study aimed to estimate the association between exposure to different pollen types and AR risk.

Methods

We obtained data from patients admitted to the Beijing Tongren Hospital for AR, and data on pollen concentration, meteorological factors, and fine particulate matter (PM_2.5) from 13 districts in Beijing from 2016 to 2019. We used a time-stratified case-crossover study design and calculated odds ratios (ORs) related to the risk of AR associated with a 10 grain/1000 mm² increase in total pollen concentrations for specific pollen types. A stratified analysis was conducted to assess whether the associations were varied by age and sex.

Results

The OR of AR associated with a 10 grain/1000 mm² increase in the 7-day average pollen concentration was 1.014 (95% CI: 1.014, 1.015), 1.076 (95% CI: 1.070, 1.082), 1.024 (95% CI: 1.023, 1.025), 1.042 (95% CI: 1.039, 1.045), 1.142 (95% CI: 1.137, 1.147), 1.092 (95% CI: 1.088, 1.097), 1.046 (95% CI: 1.035, 1.058), and 1.026 (95% CI: 1.024, 1.028) for total pollen, Ulmus, Cupressaceae, Populus, Fraxinus, Pinus, Betula, and Artemisia, respectively. Both tree pollen (Ulmus, Cupressaceae, Populus, Fraxinus, Betula, and Pinus) and weed pollen (Artemisia, Chenopodium, and Humulus) were correlated with an increased risk of AR. These associations remained consistent across distinct subgroups defined by both age and sex.

Conclusion

Exposure to pollen from trees and weeds might be associated with an increased risk of AR. This research provides valuable scientific support for both clinical practitioners and patients with AR regarding the hazards of pollen exposure.

背景：空气中的花粉是过敏性鼻炎（AR）的一个重要危险因素。花粉种类和浓度不同，过敏性鼻炎症状的严重程度也不同。本研究旨在估算暴露于不同花粉类型与过敏性鼻炎风险之间的关系：我们从北京同仁医院获得了因AR入院的患者数据，以及2016年至2019年北京13个区的花粉浓度、气象因素和细颗粒物（PM2.5）数据。我们采用了时间分层病例交叉研究设计，并计算了与特定花粉类型的总花粉浓度每增加 10 粒/1000 平方毫米相关的 AR 风险的几率比 (OR)。研究还进行了分层分析，以评估这些关联是否因年龄和性别而异：与 7 天平均花粉浓度增加 10 粒/1000 平方毫米相关的 AR OR 值分别为 1.014（95% CI：1.014，1.015）、1.076（95% CI：1.070，1.082）、1.024（95% CI：1.023，1.025）、1.042（95% CI：1.039，1.045）、1.142（95% CI：1.137，1.147）、1.092（95% CI：1.088，1.097）、1.046（95% CI：1.035，1.058）和 1.026（95% CI：1.024，1.028）。树木花粉（榆树、松柏科、杨树、梣树、桦树和松树）和杂草花粉（蒿、藜和葎草）都与 AR 风险的增加相关。这些关联在按年龄和性别划分的不同亚组中保持一致：结论：接触树木和杂草的花粉可能与 AR 风险增加有关。这项研究为临床医师和 AR 患者提供了有关接触花粉危害的宝贵科学依据。

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引用次数: 0

Treatment with the SQ tree sublingual immunotherapy tablet is safe and well tolerated in real-life 在现实生活中，使用 SQ 树舌下免疫疗法片剂进行治疗是安全且耐受性良好的。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-07-02 DOI: 10.1002/clt2.12373

Oliver Pfaar, Hendrik Wolf, Rainer Reiber, André Knulst, Kirsten Sidenius, Mika J. Mäkelä, Sverre Steinsvåg, Christer Janson, Leonard van der Zwan, Elena Uss, Peter Arvidsson, Kathrin Borchert, Helena Himmelhaus, Eike Wüstenberg

Background

The SQ tree sublingual immunotherapy (SLIT)-tablet is authorised for treatment of allergic rhinoconjunctivitis with or without asthma in trees of the birch homologous group in 21 European countries. The primary objective of this study was to explore the safety in real-life.

Methods

In a prospective, non-interventional post-authorisation safety study (EUPAS31470), adverse events (AEs) and adverse drug reactions (ADRs) at first administration and follow-up visits, symptoms, medication use, and pollen food syndrome were recorded by physicians in 6 European countries during the first 4–6 months of treatment.

Results

ADRs with the SQ tree SLIT-tablet were reported in 57.7% of 1069 total patients (median age 36.0 years, 53.7% female) during the entire observation period (severity, mild-to-moderate: 70.1%, severe: 4.7%, serious: 0.7%) and in 45.9% after first administration. ADRs were not increased with pollen exposure at first administration. With coadministration of the SQ tree and grass SLIT-tablet AEs were reported in 73.8% of patients and in 52.8% with the SQ tree SLIT-tablet alone. Nasal and eye symptoms improved in 86.9% and 80.9% of patients and use of symptomatic medication in 76.0%. PFS with symptoms was reported in 43.0% of patients at baseline and in 4.3% at the individual last visit.

Conclusions

The results of this non-interventional safety study with the SQ tree SLIT-tablet confirm the safety profile from placebo-controlled clinical trials and support effectiveness in real-life according to the published efficacy data. Safety was not impaired by pollen exposure at first administration or co-administration with other SLIT-tablets.

背景：欧洲 21 个国家授权使用 SQ 树舌下免疫疗法（SLIT）片剂治疗伴有或不伴有哮喘的桦树同族过敏性鼻结膜炎。本研究的主要目的是探讨其在实际生活中的安全性：在一项前瞻性、非干预性的授权后安全性研究（EUPAS31470）中，欧洲 6 个国家的医生记录了首次用药和随访时的不良事件 (AE) 和药物不良反应 (ADR)、症状、用药情况和花粉食物综合征：在整个观察期内，1069 名患者中有 57.7%（中位年龄 36.0 岁，53.7% 为女性）报告了 SQ tree SLIT 片剂的 ADR（严重程度：轻度至中度：70.1%，严重：4.7%，严重：0.7%），首次用药后有 45.9%的患者报告了 ADR。首次用药后，ADR 并未随着花粉暴露量的增加而增加。73.8%的患者在同时服用SQ树和草SLIT片剂时出现了不良反应，52.8%的患者在单独服用SQ树SLIT片剂时出现了不良反应。86.9%和80.9%的患者鼻部和眼部症状有所改善，76.0%的患者使用了对症药物。43.0%的患者在基线时出现症状，4.3%的患者在最后一次就诊时出现症状：这项关于SQ tree SLIT片剂的非干预性安全性研究结果证实了安慰剂对照临床试验的安全性，并根据已公布的疗效数据支持其在现实生活中的有效性。首次给药时接触花粉或与其他 SLIT 片剂同时给药不会影响安全性。

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引用次数: 0

Severe asthmatic airways have distinct circadian clock gene expression pattern associated with WNT signaling 严重哮喘气道具有与 WNT 信号相关的独特昼夜节律钟基因表达模式。

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy

Pub Date : 2024-06-28 DOI: 10.1002/clt2.12379

Nguyen Quoc Vuong Tran, Minh Khang Le, Yuki Nakamura, Atsuhito Nakao

To the Editor,The circadian clock, which consists of a network of approximately 30 clock genes, enables organisms to coordinate physiological processes including airway function in synchrony with the changing 24-h environment.1 Asthma is characterized by a marked day–night variation in symptoms and laboratory parameters in the airways, suggesting that the airway circadian clock underpins the pathology of asthma.2, 3 However, the basic question, “do asthmatic airways have normal or altered circadian clock activity?” remains unanswered. This study analyzed the expression profiles of circadian clock genes and their potential significance in asthmatic airways using a public database of patients with asthma.Gene expression data from bronchial epithelial brushing samples of patients with mild/moderate and severe asthma and healthy subjects were obtained from five publicly available NCBI-GEO datasets (GSE41861, GSE43696, GSE63142, GSE67472, and GSE89809). Two bronchial epithelial brushing sample datasets of COPD patients (GSE20257 and GSE37147) and two peripheral blood sample datasets of patients with asthma (GSE69683 and GSE207751) were used as controls. Information of datasets analyzed in this study was summarized in Table S1.Differential gene expression analysis of 34 circadian clock genes showed that NR1D2, PER2, and PER3 are downregulated in bronchial epithelial samples from patients with asthma, apparently in those from severe asthma in four of the five datasets (4/5) compared with normal subjects (Figure 1A,B, Figure S1A, Table S2). Considering the lack of information on the timing of sampling, we conducted a sensitivity analysis for gene expression using relative amplitude data for NR1D2, PER2, and PER3 from CircaDB, a database of circadian gene expression profile.4 Even after accounting for diurnal variations, the differences in PER2 expression remained significant in 3/5 datasets, while for NR1D2 and PER3, significance was observed in only 2/5 datasets (Figure 1C, Figure S1B). Corroborating our findings, a previous study using time-matched bronchial brushing samples showed that the expression of NR1D2 and PER2 was reduced in asthma patients, as determined by Real-time PCR.5Importantly, in bronchial epithelial tissue, dimension reduction by principal component analysis and t-distributed stochastic neighbor embedding using the expression of NR1D2, PER2, and PER3 showed distinct clustering between healthy subjects and patients with severe asthma (Figure 1D, Figure S1C). For comparison, we performed the same exploration on two peripheral blood sample datasets of patients with asthma and two bronchial epithelial brushing sample datasets of COPD patients. The distinct cluster was not seen in blood sample analyses from asthma pat

致编辑：昼夜节律时钟由大约 30 个时钟基因组成，它使生物体能够随着 24 小时环境的变化同步协调包括气道功能在内的生理过程。1 哮喘的特点是气道中的症状和实验室参数昼夜变化明显，这表明气道昼夜节律时钟是哮喘病理学的基础。本研究利用哮喘患者公共数据库分析了昼夜节律钟基因的表达谱及其在哮喘气道中的潜在意义。研究人员从五个公开的 NCBI-GEO 数据集（GSE41861、GSE43696、GSE63142、GSE67472 和 GSE89809）中获得了轻度/中度和重度哮喘患者以及健康受试者支气管上皮刷洗样本的基因表达数据。两个 COPD 患者的支气管上皮刷毛样本数据集（GSE20257 和 GSE37147）和两个哮喘患者的外周血样本数据集（GSE69683 和 GSE207751）被用作对照。对 34 个昼夜节律时钟基因的差异基因表达分析表明，与正常人相比，哮喘患者支气管上皮样本中的 NR1D2、PER2 和 PER3 下调，与正常人相比，5 个数据集中的 4 个数据集（4/5）中的重症哮喘患者支气管上皮样本中的 NR1D2、PER2 和 PER3 下调（图 1A、B，图 S1A，表 S2）。考虑到缺乏取样时间的信息，我们使用昼夜节律基因表达谱数据库 CircaDB 中 NR1D2、PER2 和 PER3 的相对振幅数据进行了基因表达的敏感性分析。5 重要的是，在支气管上皮组织中，利用 NR1D2、PER2 和 PER3 的表达通过主成分分析和 t 分布随机邻接嵌入进行降维显示，健康受试者和严重哮喘患者之间存在明显的聚类（图 1D，图 S1C）。为了进行比较，我们对哮喘患者的两个外周血样本数据集和慢性阻塞性肺病患者的两个支气管上皮刷洗样本数据集进行了同样的探索。尽管 NR1D2、PER2 和 PER3 显著下调（GSE69683、GSE207751）（图 1E、图 S2），但在哮喘患者的血液样本分析中（GSE20257、GSE37147）或在 COPD 患者的血液样本分析中（图 1F、图 S3）并没有发现明显的集群。因此，NR1D2、PER2 和 PER3 的改变可能是严重哮喘气道所特有的。此外，利用这三个基因建立的逻辑回归模型成功地将健康受试者与重症哮喘患者区分开来，准确率很高（0.8，95% CI：0.66-0.9，AUC：0.81）（图 1G）。为了探索三个时钟基因表达的改变在重症哮喘气道中可能具有的病理生理学意义，我们发现了 41 个与 NR1D2、PER2 或 PER3 相关的基因在健康受试者和重症哮喘患者中表达不同（表 S3 和 S4）。利用 STRING 进行的网络分析发现了这些昼夜节律基因与以 Catenin Beta 1（CTNNB1）为中心的节点之间的相互作用，CTNNB1 是 WNT 信号通路的关键组成部分（图 2A）。在维度缩减分析中，轻度/中度哮喘患者夹杂在健康对照组和重度哮喘患者中（图 2C），这表明他们的昼夜节律基因表达模式可能与健康样或重度样昼夜节律类型一致。为了进一步探讨这一问题，我们使用逻辑回归模型（图 1E）将轻度/中度哮喘患者分为健康样或重度样昼夜节律类型。通路分析表明，在 3/5 个数据集（图 2D）和重症哮喘患者（图 2B）中，重症类昼夜节律型患者的 WNT 和 NOTCH 信号活性显著降低：进一步分析发现，重症哮喘患者的 WNT 信号基因发生了变化：WNT5B 和 WNT7B 下调，而 WNT11 上调。下游的典型 WNT 信号转导基因（AXIN2、CCND1、GSK3B）呈下调趋势，而非典型信号转导基因（ROR1、ROR2）则有可能上调（图 2E，图 S4）。

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引用次数: 0