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

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，造成重大的发病率，死亡率和巨大的经济负担的来源。预防 哮喘是一个迫切的、未得到满足的最优先需要。绝大多数患有持续性和慢性 哮喘表现为吸入性过敏原致敏（IgE抗体产生），这仍然是关键的危险因素 在一生中发展为持续性、进行性哮喘。最近的研究表明， 致敏先于病毒性喘鸣，是哮喘的关键致病途径和重要易感因素。 疾病的持续和发展。大多数空气过敏原致敏开始于2-3岁左右 年，并在学龄期间升级。这种进展似乎取决于对犯罪的暴露程度 过敏原--哮喘的发展和损害的最大增加见于那些有 对2型炎症的敏感性和暴露于高水平的攻击性过敏原。此外 IgE信号在介导过敏原诱导的应答中的作用， 这可能导致病毒感染增加，从而可能进一步增强疾病的级联反应， 哮喘。奥马珠单抗（抗IgE）在病毒季节显著降低哮喘急性发作， IgE治疗的儿童表现出对鼻病毒的IFN-α应答恢复。这表明抗IgE 在具有2型表型的人中防止IgE驱动的对冒犯性变应原暴露的反应， 减弱这种2型表型的病毒感染。因此，在幼儿中使用抗IgE抗体具有潜力， 通过阻断所有IgE过敏原抗体，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）和降低对病毒暴露的反应 可能导致哮喘我们假设，在高风险的幼儿（2-3岁）中阻断IgE， 哮喘的发展将防止进展为已建立的哮喘。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， 抗IgE抗体与安慰剂在250名2-3岁高危儿童中的平行对照试验 哮喘患者，将在治疗停止2年后随访2年。主要结果将是 在NIAID URECA出生队列中定义的当前活动性哮喘受试者比例， 两个治疗组在第4年结束时，试验的最后12个月停止研究药物。二次 结果将包括喘息发作的发生，需要类固醇的加重，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治疗将是第一个 干预以改变儿童哮喘的自然史。这次审判不仅能让我们扩大 了解哮喘免疫发病机制，但也将创造机会，以确定IgE介导的， 其他新的方法影响我们对预防疾病的理解。

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.