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: 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
• 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

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.

项目摘要/摘要 哮喘仍然是美国儿科公共卫生最重要的挑战之一，影响了数百万 儿童引起了巨大的发病率，死亡率和巨大的金融伯恩（Burnen）的来源。预防 哮喘是最优先的压迫，未满足的需求。绝大多数具有持久和慢性的儿童 哮喘表现出气降盐敏感性（IgE抗体产生），这仍然是关键的风险因素 为了发展一生的持久性，进步的哮喘。最近已经显示出空气果蛋白 敏化之前先于病毒式旋转，是关键因果途径和基本的敏感性因子 疾病的持久性和进展。大多数Aeroalorerregen敏感性始于2-3岁的年龄 多年，在学龄期间升级。进展似乎取决于暴露于冒犯 过敏原 - 在有趋势的人中，出现哮喘的发育和损害损害最大的增长 敏感并暴露于高水平的冒犯过敏原的2型炎症。此外 为了在介导过敏原诱导的反应中的作用，IgE信号会损害先天的抗病毒免疫反应 这可能导致病毒感染增加，从而有可能进一步增强级联进展 哮喘。奥马珠单抗（抗IGE）显着降低了病毒季节的哮喘恶化和抗 IgE治疗的儿童表现出对鼻病毒的IFN-α反应的恢复。这表明反伊格 防止IgE驱动器对具有2型表型的人的冒犯过敏原暴露的反应，并且 在这种2型表型中减弱病毒感染。那是在幼儿中使用抗IgE的潜力 通过阻断所有IgE过敏原抗体，以防止易感儿童的尚未哮喘的发展 相互作用（包括对亚临床暴露的反应），并通过减少对病毒暴露的反应 这可能导致哮喘。我们假设在幼儿（2-3岁）的IgE封锁高风险 哮喘的发展将防止发展为已建立的哮喘。我们将通过 检查抗IgE对双盲，随机，安慰剂中哮喘发育的影响 250岁的2-3岁儿童的反对与安慰剂的对照平行试验具有高度的发展 哮喘，在治疗2年后将被关注2年。主要结果将是 在NIAID尿素出生队列中定义的具有当前活性哮喘的参与者的比例 第4年底，两个治疗组是研究药物的最后12个月。次要 结果将包括发生喘息的发作，需要类固醇的加重，以及新的 IgE治疗后持续的过敏原特异性IgE敏感性。如果得到确认，抗IGE疗法将是第一次 干预以改变儿童哮喘的自然史。该审判不仅可以使我们扩大我们的 了解哮喘免疫发育生成，但也将创造机会识别IgE介导的和 其他新颖的方法影响了我们对预防疾病的理解。