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)

• 批准号: 9189905
• 负责人: WANDA PHIPATANAKUL
• 金额: $ 284.35万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/9189905
• 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; Development; Diagnosis; Disease; Disease Progression; Double-Blind Method; Environmental Exposure; Exposure to; Funding; Future; Hypersensitivity; 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-Lymphocyte; Testing; United States; Viral; Virus Diseases; Wheezing; Wit; abstracting; 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

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。预防 哮喘是一个迫切且未得到满足的首要需求。绝大多数儿童患有持续性和慢性的 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 用于终生发展为持续性、进行性哮喘。最近的研究表明，空气过敏原 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。 疾病的持续性和进展。大多数空气过敏原敏化开始于 2-3 岁左右 年并在学龄期间升级。进展似乎取决于接触犯罪的情况 过敏原——有过敏原倾向的人，哮喘的发育和损害最大程度增加 2 型炎症，即过敏并暴露于高水平的过敏原。此外 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 哮喘。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 经过 IgE 治疗的儿童对鼻病毒的 IFN-α 反应已恢复。这表明抗 IgE 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 减弱这种 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。我们假设幼儿（2-3 岁）的 IgE 阻断具有以下风险： 哮喘的发展将防止进展为已形成的哮喘。我们将通过以下方式检验这个假设 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 岁高风险儿童中进行抗 IgE 与安慰剂对照平行试验 哮喘患者，在停止治疗 2 年后将随访 2 年。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，即试验的最后 12 个月，停止研究药物治疗。中学 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 治疗后持续的过敏原特异性 IgE 致敏。如果得到证实，抗 IgE 治疗将是首选 干预改变儿童哮喘的自然史。这次试验不仅使我们能够扩大我们的 了解哮喘免疫发病机制，同时也将创造机会识别 IgE 介导的和 其他影响我们对预防这种疾病的理解的新方法。