Phenotypes and Endotypes of Preschool Wheeze

项目总结/摘要 在过去的三十年里，学龄前儿童喘息的患病率急剧增加， 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岁之前发生喘息，在所有学龄前儿童中，高达20%的儿童在6岁之前发生反复喘息。 早期生活与显著的发病率相关。与年龄较大的儿童相比，学龄前儿童有两倍的 急诊就诊率、五倍住院率和更高的费用。虽然 反复喘息的学龄前儿童是一个具有不同疾病结局的异质性群体， 缺乏对该年龄组的研究，以及急性加重的相关生物学和相关结果， 这些孩子不被理解。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气道研究的主要研究挑战之一，因为在 目前，学龄前儿童反复喘息的临床过程仍然是一个谜， 来预测。鉴于我们的广泛目标是为所有患有呼吸系统疾病的儿童提供个性化医疗， 我们提出了一项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）特征可预测喘鸣加重及相关结果 年龄在12-59个月的学龄前儿童，有反复喘息病史。我们将追求三个目标：1） 确定喘息表型是否预测急性发作的发生（主要结果），2）确定 喘鸣表型是否可预测无发作天数（EFD）和对全身化疗的反应， 皮质类固醇（次要结局），和3）完善喘息加重的预测模型， 内定型方法（细胞因子、代谢组学和免疫细胞研究）。我们假设， 2型糖尿病儿童的比例（即，嗜酸性粒细胞）炎症特征将经历恶化 无论病毒状态如何，这些儿童的EFD会更少，病毒比例会更高- 相关的急性加重，对全身性皮质类固醇治疗的反应更大， 细胞因子谱、血浆代谢组学生物标志物以及中性粒细胞和嗜酸性粒细胞活化的标志物， 功能该项目涉及一个具有合作历史的多学科团队， NINR战略计划：探索疾病症状的潜在机制， 通过症状科学研究解决这些机制的治疗。研究人群， 学龄前儿童反复喘息，研究不足，知识差距相当大。这个项目 最终有望为以下方面奠定基础：1）完善喘息加重和相关 机制，2）改善急性加重和相关结果的临床预测，和3）鉴定 在未来可以通过个性化方法针对急性加重，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.