Phenotypes and Endotypes of Preschool Wheeze

项目摘要/摘要 在过去的三十年里，学龄前儿童的喘息率急剧上升， 导致公共卫生危机。近50%的学龄前儿童至少经历过一次 在6岁之前，多达20%的学龄前儿童有反复的喘息发作。 早期生活与显著的发病率相关。与年龄较大的儿童相比，学龄前儿童的 急诊科就诊率，住院率的五倍，以及更高的费用。虽然 反复喘息的学龄前儿童是一个不同的群体，有着不同的疾病结果。 在这一年龄段以及与病情恶化相关的生物学和相关结局方面的研究很少 这些孩子是不被理解的。以反复喘息为目的的学龄前儿童的分割 因此，基础研究是当今儿科呼吸道研究的主要研究挑战之一，因为 目前，学龄前儿童反复喘息的临床过程仍然是一个谜，这是不可能的。 去预测。鉴于我们的广泛目标是为所有患有呼吸系统疾病的儿童推进个性化药物治疗， 我们提出了一项为期50周的表型分层队列研究(N=145)来确定表型(即， 临床)和相关的内型(即生物学)特征预测喘息加重和相关结果 12-59个月大、有反复喘息史的学龄前儿童。我们将追求三个目标：1) 确定喘息表型是否预示病情恶化(主要结果)，2)确定 喘息表型是否可以预测无发作天数(EFD)和全身治疗的反应 皮质类固醇激素(次要结果)，以及3)完善喘息加重的预测模型 内型法(细胞因子、代谢组学和免疫细胞研究)。我们假设一个更高的 患有II型(即嗜酸性粒细胞)炎症特征的儿童比例将恶化 不管病毒状态如何，这些孩子的EFD会更少，病毒比例更高- 相关的恶化，对全身皮质类固醇治疗的更大反应，以及区分 细胞因子谱，血浆代谢组生物标志物和中性粒细胞和嗜酸性粒细胞活化的标志物 功能。这个项目涉及一个具有合作历史的多学科团队，并解决了一个关键领域 在NINR战略计划中：探索疾病症状的潜在机制并发展个性化 通过症状科学研究解决这些机制的治疗方法。研究人群， 学龄前儿童反复喘息，对其认识不足，知识差距较大。这个项目 预计最终将为以下工作奠定基础：1)完善喘息加重和相关的知识 机制，2)改善对病情恶化和相关结果的临床预测，以及3)确定 未来可针对性地采用个体化的治疗方法，以降低高发病率。

PROJECT SUMMARY/ABSTRACT The prevalence of wheezing in preschool children has increased dramatically over the past three decades, resulting in a public health crisis. Nearly 50% of all preschool children experience at least one episode of wheezing before 6 years of age and up to 20% of all preschool children have recurrent wheezing episodes in early life associated with significant morbidity. Compared to older children, preschool children have twice the rate of emergency department visits, five times the rate of hospitalizations, and higher costs. Although preschool children with recurrent wheezing are a heterogeneous group with differing disease outcomes, there is a paucity of research in this age group and the associated biology of exacerbation and related outcomes in these children is not understood. Segmentation of preschool children with recurrent wheezing for the purpose of basic research is therefore one of the main research challenges in pediatric airway research today, since at present, the clinical course of preschool children with recurrent wheezing remains an enigma that is impossible to predict. Given our broad goal to advance personalized medicine for all children with respiratory disorders, we propose a 50-week phenotype-stratified cohort study (N=145) to determine whether phenotypic (i.e., clinical) and associated endotypic (i.e., biological) features predict wheeze exacerbation and related outcomes in preschool children age 12-59 months with a history of recurrent wheezing. We will pursue three aims: 1) determine whether wheezing phenotype predicts exacerbation occurrence (primary outcome), 2) determine whether wheezing phenotype predicts episode-free days (EFDs) and response to treatment with systemic corticosteroids (secondary outcomes), and 3) refine the prediction model for wheeze exacerbation with endotyping approaches (cytokines, metabolomics and immune cell studies). We hypothesize that a higher proportion of children with Type-2 (i.e., eosinophilic) inflammatory features will experience an exacerbation irrespective of viral status, and that these same children will have fewer EFDs, a higher proportion of virus- associated exacerbations, a greater response to treatment with systemic corticosteroids, and distinguishing cytokine profiles, plasma metabolomic biomarkers and markers of neutrophil and eosinophil activation and function. This project involves a multidisciplinary team with a history of collaboration and addresses a key area in the NINR Strategic Plan: to explore mechanisms underlying symptoms of illness and develop personalized treatments that address these mechanisms through symptom science research. The study population, preschool children with recurrent wheezing, is understudied and the knowledge gap is quite large. This project is ultimately expected to lay groundwork to: 1) refine knowledge of wheeze exacerbation and associated mechanisms, 2) improve clinical prediction of exacerbation and related outcomes, and 3) identify biomarkers of exacerbation that can be targeted in the future with personalized approaches, to reduce the high morbidity.