Controlling and preventing Asthma progression and Severity in Kids (CASK)

控制和预防儿童哮喘进展和严重程度 (CASK)

基本信息

批准号：
9318449
负责人：
WANDA PHIPATANAKUL
金额：
$ 342.1万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318449
关键词：
3 year old Address Adult Affect Aftercare Age Allergens Allergic Antibodies Antibody Formation Asthma Attenuated Birth Child Childhood Childhood Asthma Chronic Cohort Studies Cost of Illness Delayed Hypersensitivity Development Diagnosis Disease Disease Progression Double-Blind Method Environmental Exposure Exposure to Funding Future IgE Immune response Impairment Inflammation Interferon-alpha Interleukin-13 Interleukin-4 Interleukin-5 Intervention Lead Life Lower Respiratory Tract Infection Mediating Morbidity - disease rate National Institute of Allergy and Infectious Disease Natural History Participant Pathway interactions Pharmaceutical Preparations Phenotype Placebo Control Placebos Predisposition Prevalence Prevention Production Protocols documentation Public Health Quality of life Randomized Reaction Regulatory T-Lymphocyte Research Personnel Rhinovirus Risk Risk Factors Role Sampling School-Age Population Seasons Severities Signal Transduction Societies Source Steroids T-Cell Proliferation T-Lymphocyte Testing United States Viral Virus Diseases Wheezing Wit aged airborne allergen allergic response anti-IgE asthma prevention cohort cost crosslink cytokine design disability early childhood environmental allergen health care service utilization high risk mast cell mortality novel strategies omalizumab prevent primary outcome response secondary outcome treatment group

项目摘要

Project Summary/Abstract Asthma remains one of the most important challenges to pediatric public health in the US, affecting millions of children, causing significant morbidity, mortality, and source of tremendous financial burden. Prevention of asthma is a pressing, unmet need of utmost priority. The vast majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization (IgE antibody production), which remains the pivotal risk factor for developing persistent, progressive asthma throughout life. It has recently been shown that aeroallergen sensitization precedes viral wheezing and is the pivotal causal pathway and essential susceptibility factor in the persistence and progression of the disease. Most aeroallergen sensitization begins around the age of 2-3 years and escalates during school age. The progression appears to be dependent on exposures to offending allergens-- the greatest increase in development and impairment from asthma is seen in those with a tendency toward Type 2 inflammation who are sensitized and exposed to high levels of offending allergens. In addition to its role in mediating allergen-induced responses, IgE signals impair innate anti-viral immune responses which could lead to increased viral infections and thus potentially further enhance the cascade of progression to asthma. Omalizumab (anti-IgE) markedly reduces asthma exacerbations during the viral season and anti- IgE treated children have demonstrated restored IFN-α response to rhinovirus. This suggests that anti-IgE prevents IgE driven responses to offending allergen exposure in those with a Type 2 phenotype AND attenuates viral infections in this Type 2 phenotype. Thus, utilizing anti-IgE in young children has the potential to prevent the development of established asthma in susceptible children by blocking all IgE allergen-antibody interactions (including responses to subclinical exposures) AND by reducing the response to viral exposure which may lead to asthma. We hypothesize that blockade of IgE in young children (age 2-3) at high risk for development of asthma will prevent progression to established asthma. We will test this hypothesis by examining the effect of anti-IgE on the development of asthma in a double-blind, randomized, placebo- controlled parallel trial of anti-IgE vs placebo in 250 children aged 2-3 years old at high risk of developing asthma, who will be followed for 2 years after 2 years of therapy is discontinued. Primary outcome will be the proportion of participants with current, active asthma as defined in the NIAID URECA birth cohort, between the two treatment groups at the end of Year 4, the final 12 months of the trial off study medication. Secondary outcomes will include occurrence of wheezing episodes, exacerbations requiring steroids, and new and persistent allergen-specific IgE sensitizations after IgE therapy. If confirmed, anti-IgE therapy would be the first intervention to change the natural history of childhood asthma. This trial will not only allow us to expand our understanding of asthma immunopathogenesis, but will also create opportunities to identify IgE mediated and other novel approaches impacting our understanding towards preventing the disease.

项目概要/摘要哮喘仍然是美国儿科公共卫生面临的最重要挑战之一，影响着数百万儿童儿童，造成显着的发病率、死亡率，并造成巨大的经济负担。哮喘是绝大多数儿童持续和慢性的迫切且未得到满足的需求。哮喘表现出空气过敏原致敏（IgE 抗体产生），这仍然是关键的危险因素最近研究表明，空气过敏原可能会导致终生持续、进行性哮喘。致敏先于病毒性喘息，是病毒性喘息的关键因果途径和重要的易感因素。大多数空气过敏原过敏开始于 2-3 岁左右。岁，并在学龄期间升级，这种进展似乎取决于接触犯罪的情况。过敏原——有哮喘倾向的人会出现最大程度的发育增加和哮喘损害 2 型炎症，即过敏并暴露于高水平的过敏原。由于其在介导过敏原诱导反应中的作用，IgE 信号会损害先天抗病毒免疫反应这可能导致病毒感染增加，从而可能进一步增强级联进展奥马珠单抗（抗 IgE）可显着减少病毒季节期间的哮喘发作，并可抗哮喘。经 IgE 治疗的儿童已表现出对鼻病毒的 IFN-α 反应恢复，这表明抗 IgE 存在。防止具有 2 型表型的人对有害过敏原暴露产生 IgE 驱动的反应并且减轻这种 2 型表型的病毒感染，因此，在幼儿中使用抗 IgE 具有潜力。通过阻断所有 IgE 过敏原抗体来预防易感儿童发生哮喘相互作用（包括对亚临床暴露的反应）以及减少对病毒暴露的反应这可能会导致哮喘。哮喘的发展将阻止发展为已形成的哮喘。我们将通过以下方式检验这一假设。在一项双盲、随机、安慰剂研究中检查抗 IgE 对哮喘发展的影响在 250 名 2-3 岁高危儿童中进行抗 IgE 与安慰剂对照平行试验哮喘患者，在停止治疗 2 年后将进行 2 年的随访，主要结果将是。患有 NIAID URECA 出生队列中定义的当前活动性哮喘的参与者比例两个治疗组在第 4 年末，也就是试验的最后 12 个月，停止了研究药物治疗。结果将包括出现喘息发作、需要类固醇的病情加重以及新的和 IgE 治疗后持续过敏原特异性 IgE 致敏如果得到证实，将首先进行抗 IgE 治疗。改变儿童哮喘自然史的干预措施不仅能让我们扩大研究范围。了解哮喘免疫发病机制，但也将创造机会识别 IgE 介导和其他影响我们对预防这种疾病的理解的新方法。