IL-6 high phenotype in childhood asthma

项目摘要 哮喘，现在是儿童最常见的慢性疾病，给少数民族儿童造成了不成比例的负担， 低收入家庭的孩子。肥胖也是儿童中的一种普遍疾病，它会增加患哮喘的风险 在成年人中。与肥胖相关的全身性炎症，通过介体如白细胞介素-6（IL-6）的产生， 脂肪细胞和巨噬细胞，可能加重气道炎症。成人哮喘患者的最新研究 提示存在一种新的“IL-6高表型”，其特征在于高浓度的血浆IL-6。 这种表型的成年人有较高的体重指数（BMI），较高的糖尿病和高血压患病率， 肺功能更差，哮喘发作次数更多。我们最近进行了一项研究， 证实在患有哮喘的黑人和白色人中存在IL-6高表型的成年人; 我们的研究表明，这种表型几乎只发生在“T2-低表型”中，并且与 体重指数。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， 成人哮喘患者抗IL-6治疗试验的阶段。然而，是否相似的IL-6高表型表达， 儿童哮喘的发病率，特别是这是否与肥胖有关，尚不清楚。我们的主要目标- 目的是确定哮喘儿童中是否存在IL-6高表型，如果存在， 与肥胖有关。在进行重大的多中心临床试验之前， 表型是必需的。我们提出了一个单中心，观察性研究，重点是6至17岁的儿童 哮喘患者在城市，学术医疗中心和周围社区。我们将使用这样的注册表 儿童，仔细描述哮喘严重程度、特应性状态、BMI、合并症和关键临床参数， 诸如肺量测定、血清IgE和血嗜酸性粒细胞等参数，结合社区参与， 芝加哥南部招募100名体重正常和肥胖的儿童，并将招募50名体重正常的 和无已知疾病的肥胖儿童作为对照。临床数据、BMI、肺功能测定和生物标志物 如血清IgE、血嗜酸性粒细胞计数和呼出的一氧化氮将与血浆IL-6浓度进行比较。 选择。将在非哮喘儿童中确定血浆IL-6的种族调整阈值。我们将 确定这种表型是否存在于儿童哮喘中，如果存在，高IL-6的儿童是否 与T2高的儿童分开，以及肥胖，定义为BMI >年龄和身高的第85百分位数，是否 与较高的IL-6浓度相关。哮喘儿童IL-6高表型的证实 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。这样的研究将奠定基础的工作，为治疗- 以IL-6为靶点的药物干预，以减轻气道炎症，并更好地控制不良的 哮喘的脆弱人群，从而提供了巨大的好处，卫生保健。

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.