A Histamine Pharmacodynamic Biomarker to Guide Treatment in Pediatric Asthma

摘要 迫切需要有效的客观生物标记物来预测哮喘的治疗反应。 儿童的治疗方法。需要每日使用控制性药物治疗哮喘的儿童，如 吸入类固醇被定义为持续性哮喘。在美国，大约60%的哮喘儿童 各州有顽固不化的疾病。标准指南支持的药物治疗反应的变异性 (例如，吸入类固醇、白三烯修饰剂、单抗)在持续性儿童中存在 哮喘。临床指标如IgE水平、呼出一氧化氮水平、嗜酸性粒细胞和中性粒细胞计数均未见变化 已被证实可预测儿童哮喘药物的治疗反应。这是不可能优化的 现有的哮喘治疗方法在实现治疗效果和限制不良暴露方面的作用 没有强大的非侵入性生物标志物可以推动治疗的非有效药物的影响 做决定。长期目标是推进和改进对儿科患者的治疗干预。 患有哮喘。在这一特殊应用中的目的是建立组胺离子导入的效用 激光多普勒监测(HILD)作为准确预测低成本和低成本治疗反应的生物标志物 儿童过敏性哮喘的低副作用抗组胺治疗。中心假设是“希尔德是 预测哮喘儿童对抗组胺药物的治疗反应“。这一假设一直是 由申请者雄厚的初步数据和支持文献制定。建议的理由是 研究表明，希尔德能够识别不同的组胺药效反应类型，从而预测 哮喘患者对抗组胺药物的治疗反应。在强劲的初步数据的指导下，这一假设 将通过两个特定的目的进行测试：1)确定HILD对抗组胺药物的治疗反应的预测 在过敏性哮喘儿童中；2)开发一个强大的预测模型，以预测治疗反应 过敏性哮喘儿童中的抗组胺药物。第一个目标是比较哮喘控制测试的变化 (ACT®)在左西替利嗪(LTZ)的6周2x2交叉附加试验中按组胺反应类型进行评分 在患有无法控制的过敏性哮喘的儿童中。第二个目标是确定最好的预测模型 (结合HILD和临床变量)LTZ治疗后儿童ACT®评分的变化 过敏性哮喘。这项拟议的研究意义重大，因为它有可能改变目前的治疗方法。 用于哮喘儿童的范例，其中治疗反应是先验预测的；在测试方面是创新的 以及验证准确预测儿童哮喘治疗反应的第一生物标志物。这个 所获得的知识将使第一个有效的生物标志物可用于预测儿童哮喘的治疗反应 并将改善这些儿童的治疗效果和结果。

Abstract There is a critical need for validated objective biomarkers that predict therapeutic response for asthma therapies in children. Children who require daily asthma treatment with a controller medication such as an inhaled steroid are defined to have persistent asthma. Approximately 60% of children with asthma in the United States have persistent disease. Variability in treatment response to standard guideline supported medications (e.g. inhaled steroids, leukotriene modifiers, mono-clonal antibodies) exist among children with persistent asthma. Clinical markers such as IgE level, exhaled nitric oxide level, eosinophil and neutrophil counts have not been validated to predict treatment response to asthma medications in children. It is not possible to optimize currently available treatments for asthma in achieving therapeutic efficacy and limiting exposure to adverse effects from non-efficacious medications without robust non-invasive biomarkers that can drive therapeutic decision making. The long-term goal is to advances and improve therapeutic intervention for pediatric patients with asthma. The objective in this particular application is to establish the utility of Histamine Iontophoresis with Laser Doppler monitoring (HILD) as biomarker for accurate prediction of therapeutic response to low cost and low side-effect antihistamine treatment in children with allergic asthma. The central hypothesis is that “HILD is predictive of treatment response to an antihistamine in children with asthma”. This hypothesis has been formulated by the applicant's strong preliminary data and supporting literature. The rationale for the proposed research is that HILD is able to identify distinct histamine pharmacodynamic response types that predict treatment response to antihistamine medications in asthma. Guided by strong preliminary data, this hypothesis will be tested by two specific aims: 1) to determine HILD prediction of therapeutic response to an antihistamine among children with allergic asthma; 2) to develop a robust predictive model of therapeutic response to an antihistamine among children with allergic asthma. The first aim will compare change in Asthma Control Test (ACT®) scores by histamine response type in a six week, 2x2 cross-over, add-on trial of Levocetirizine (LTZ) among children with uncontrolled allergic asthma. The second aim will determine the best predictive model (incorporating HILD and clinical variables) for change in ACT® scores after LTZ treatment among children with allergic asthma. The proposed research is significant because it has the potential to alter the current treatment paradigms for children with asthma where response to treatment is predicted a priori; and is innovative in testing and validating a first biomarker accurately predicting response to an asthma treatment in children. The knowledge gained will make available the first validated biomarker to predict treatment response in children with asthma and will improve therapeutic efficacy and outcomes in these children.