IL-6 high phenotype in childhood asthma

儿童哮喘中 IL-6 高表型

• 批准号: 10043029
• 负责人: Christina Elizabeth Ciaccio
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043029
• 关键词: Absenteeism; Academic Medical Centers; Address; Adipocytes; Adult; Affect; African American; Age; American; Asthma; Attenuated; Biological Markers; Body mass index; Chicago; Child; Childhood; Childhood Asthma; Chronic Disease; Clinical; Clinical Data; Communities; Diabetes Mellitus; Disease; Enzyme-Linked Immunosorbent Assay; Eosinophilia; Exhalation; Gender; Healthcare; Height; High Prevalence; Hypertension; IgE; Inflammation; Inflammatory; Interleukin-6; Intervention; Longitudinal Studies; Measures; Mediator of activation protein; Multi-Institutional Clinical Trial; Neighborhoods; Nitric Oxide; Obesity; Observational Study; Patients; Pediatric Hospitals; Phenotype; Plasma; Prevalence; Production; Publishing; Race; Recording of previous events; Registries; Research; Respiratory physiology; Risk; Role; Schools; Serum; Severities; Side; Spirometry; Tenuate; Testing; Therapeutic Intervention; Therapeutic Trials; Urban Health; Vulnerable Populations; Woman; Work; airway inflammation; asthma exacerbation; asthmatic patient; atopy; cohort; community organizations; comorbidity; eosinophil; inner city; lower income families; macrophage; men; minority children; multidisciplinary; obesity in children; programs; receptor; recruit; targeted treatment; urban children

PROJECT SUMMARY Asthma, now the most common chronic disease in childhood, disproportionately burdens minority children and children from low-income families. Obesity, also a prevalent disorder in children, increases the risk of asthma in adults. Systemic inflammation related to obesity, via production of mediators such as interleukin-6 (IL-6) by adipocytes and macrophages, may worsen airway inflammation. Recent studies in adult patients with asthma suggest the existence of a new “IL-6 high phenotype” characterized by high concentrations of plasma IL-6. Adults in this phenotype have a higher body mass index (BMI), a higher prevalence of diabetes and hyperten- sion, worse lung function, and a greater number of asthma exacerbations. We recently performed a study in adults that corroborated the existence of the IL-6 high phenotype in both black and white patients with asthma; our study shows that this phenotype occurs almost exclusively in the “T2-low phenotype” and correlates with BMI. This study and other recent work clearly suggests the clinical importance of this phenotype and sets the stage for anti-IL-6 therapeutic trials in adults with asthma. However, whether a similar IL-6 high phenotype ex- ists in children with asthma, and particularly whether this is related to obesity, is not known. Our major objec- tive is to determine whether an IL-6 high phenotype exists in children with asthma, and if so, whether this is associated with obesity. Prior to embarking on major multi-center clinical trials, a clear demonstration of this phenotype is required. We propose a single-center, observational study that focuses on children ages 6 to 17 with asthma in an urban, academic medical center and surrounding community. We will use a registry of such children, carefully characterized for asthma severity, atopy status, BMI, co-morbidities, and key clinical param- eters such as spirometry, serum IgE, and blood eosinophils, combined with community engagement in the south side of Chicago to recruit 100 normal-weighted and obese children, and will recruit 50 normal-weighted and obese children without known disease to serve as contrtols. Clinical data, BMI, spirometry, and biomarkers such as serum IgE, blood eosinophil count and exhaled nitric oxide will be compared to plasma IL-6 concentra- tions. Race-adjusted threshold values for plasma IL-6 will be established in the non-asthmatic children. We will determine whether this phenotype exists in pediatric asthma and, if so, whether the children with high IL-6 are separated from T2-high children, and whether obesity, defined as a BMI > 85th percentile for age and height, is associated with higher IL-6 concentrations. Demonstration of a IL-6 high phenotype in children with asthma in a single-center, observational trial will lead to larger studies that determine associations between IL-6, obesity, and asthma control, particularly in urban and minority children. Such studies will lay the ground-work for thera- peutic interventions that target IL-6 to attenuate airway inflammation and gain better control of poorly-controlled asthma in a vulnerable population, thereby providing a substantial benefit to health care.

项目概要 哮喘现在是儿童时期最常见的慢性疾病，给少数民族儿童和儿童造成了不成比例的负担。 低收入家庭的儿童肥胖也是一种常见的儿童疾病，会增加患哮喘的风险。 在成人中，通过产生白介素 6 (IL-6) 等介质，导致与肥胖相关的全身炎症。 脂肪细胞和巨噬细胞可能会加重成年哮喘患者的气道炎症。 表明存在一种新的“IL-6 高表型”，其特征是血浆 IL-6 浓度高。 这种表型的成年人体重指数（BMI）较高，糖尿病和高血压的患病率也较高。 我们最近进行了一项研究。 成年人证实了黑人和白人哮喘患者均存在 IL-6 高表型； 我们的研究表明，这种表型几乎只出现在“T2-低表型”中，并且与 BMI。这项研究和其他最近的工作清楚地表明了这种表型的临床重要性，并设定了 成人哮喘患者的抗 IL-6 治疗试验处于阶段性阶段，但是否存在类似的 IL-6 高表型？ 哮喘儿童的发病率，特别是这是否与肥胖有关，我们的主要目标尚不清楚。 目的是确定哮喘儿童是否存在 IL-6 高表型，如果存在，这是否是 在开展大型多中心临床试验之前，已经清楚地证明了这一点。 我们建议开展一项针对 6 至 17 岁儿童的单中心观察性研究。 在城市、学术医疗中心和周边社区患有哮喘的患者，我们将使用此类登记册。 儿童，仔细描述哮喘严重程度、特应性状态、体重指数、合并症和关键临床参数 诸如肺活量测定、血清 IgE 和血液嗜酸性粒细胞等，并结合社区参与 芝加哥南区招募100名正常体重和肥胖儿童，并将招募50名正常体重儿童 和无已知疾病的肥胖儿童作为对照，包括临床数据、BMI、肺活量测定和生物标志物。 例如血清 IgE、血液嗜酸性粒细胞计数和呼出一氧化氮将与血浆 IL-6 浓度进行比较 我们将在非哮喘儿童中建立血浆 IL-6 的种族调整阈值。 确定儿童哮喘中是否存在这种表型，如果存在，IL-6 高的儿童是否患有 与 T2 高儿童分开，肥胖（定义为 BMI > 年龄和身高的第 85 个百分位）是否是 与较高的 IL-6 浓度相关 证明了哮喘儿童的 IL-6 高表型。 单中心观察性试验将导致更大规模的研究，以确定 IL-6、肥胖、 和哮喘控制，特别是在城市和少数民族儿童中，此类研究将为治疗奠定基础。 以 IL-6 为靶点的临时干预措施可减轻气道炎症并更好地控制控制不佳的炎症 弱势群体的哮喘，从而为医疗保健提供实质性好处。