Phenotypes and Endotypes of Preschool Wheeze

学龄前喘息的表型和内型

• 批准号: 10331730
• 负责人: Anne Mentro Fitzpatrick
• 金额: $ 49.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331730
• 关键词: 6 year old; Address; Adrenal Cortex Hormones; Adult; Affect; Age; Allergic; Area; Asthma; Basic Science; Biological; Biological Markers; Biological Products; Biology; Caregivers; Cells; Characteristics; Child; Childhood; Childhood Asthma; Clinical; Clinical Trials; Cohort Studies; Collaborations; Disease; Disease Outcome; Economic Burden; Emergency department visit; Future; Goals; IgE; Immune; Immunologics; Impairment; Inflammation; Inflammatory; Interleukin-5; Intervention Studies; Knowledge; Life; Link; Molecular; Morbidity - disease rate; Nursery Schools; Outcome; Outpatients; Pathway interactions; Pharmacotherapy; Phenotype; Plasma; Preschool Child; Prevalence; Probability; Public Health; Recording of previous events; Recurrence; Research; Respiration Disorders; Schools; Strategic Planning; Symptoms; Syndrome; Testing; Time; Viral; Virus; Wheezing; Work; age group; airway obstruction; anti-IgE; base; cost; cytokine; eosinophil; experience; functional status; hospitalization rates; improved; metabolomics; multidisciplinary; neutrophil; personalized approach; personalized intervention; personalized medicine; predictive modeling; primary outcome; response; secondary outcome; study population; symptom science; treatment response

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.

项目概要/摘要 过去三十年来，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 6 岁之前出现喘息，高达 20% 的学龄前儿童有反复发作的喘息症状 早年生活与显着的发病率相关。与年龄较大的儿童相比，学龄前儿童的患病率是其两倍 急诊就诊率、住院率是其五倍，费用也更高。虽然 反复喘息的学龄前儿童是一个异质群体，其疾病结果各不相同， 该年龄组的研究很少，并且与恶化相关的生物学和相关结果 这些孩子不被理解。为此目的对反复喘息的学龄前儿童进行细分 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 目前，学龄前儿童反复喘息的临床病程仍然是一个不可能的谜 来预测。鉴于我们的宏伟目标是为所有患有呼吸系统疾病的儿童推进个性化医疗， 我们提出了一项为期 50 周的表型分层队列研究 (N=145)，以确定表型（即， 临床）和相关的内型（即生物学）特征可预测喘息加重和相关结果 12-59 个月有反复喘息病史的学龄前儿童。我们将追求三个目标：1） 确定喘息表型是否可以预测病情加重的发生（主要结果），2) 确定 喘息表型是否可以预测无发作天数 (EFD) 以及对全身治疗的反应 皮质类固醇（次要结果），以及 3) 完善喘息加重的预测模型 内型分析方法（细胞因子、代谢组学和免疫细胞研究）。我们假设更高 具有 2 型（即嗜酸性粒细胞）炎症特征的儿童比例将出现恶化 无论病毒状态如何，这些儿童的 EFD 会更少，病毒感染比例更高 相关的加重、对全身性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以及中性粒细胞和嗜酸性粒细胞活化标志物 功能。该项目涉及一个具有合作历史的多学科团队，涉及一个关键领域 NINR 战略计划中：探索疾病症状的潜在机制并制定个性化治疗方案 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的研究不足，知识差距相当大。这个项目 最终预计将为以下方面奠定基础：1）完善有关喘息加剧和相关疾病的知识 机制，2）改善恶化和相关结果的临床预测，以及 3）确定生物标志物 未来可以通过个性化方法针对病情恶化，以降低高发病率。