ACE: A BIOMARKER-BASED APPROACH TO IMPROVING ASTHMA CONTROL

ACE：基于生物标志物的改善哮喘控制的方法

• 批准号: 7377267
• 负责人: Gordon R. Bloomberg
• 金额: $ 14.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377267
• 关键词: ACE; BIOMARKER; BASED; APPROACH; IMPROVING

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the past two decades, the prevalence of asthma has dramatically increased in many parts of the world. There is convincing evidence that children living in the inner cities of the United States, and living under economic disadvantages, constitute a unique and special at-risk population for asthma, which is characterized by increased morbidity and morality (Akinbami et al, 2002; Cloutier et al, 2002). Given this information and the unique needs of this inner-city population, the overall objectives of the National Institutes of Allergy and Infectious Diseases Inner City Asthma Consortium (ICAC) are (1) to identify forms of immune-based therapy that are most likely to promote control and prevention of asthma, (2) to design protocols that will evaluate immune-based therapies in the treatment of asthma in low-income inner-city adolescents, and (3) to determine both the mechanisms of immune-based therapies and the potential unique mechanisms associated with the pathogenesis of asthma in low-income inner-city adolescents by the conduct of parallel mechanistic investigations with the therapeutic protocols. The recent update to the National Asthma Education and Prevention Program (NAEPP) asthma guidelines identified inhaled corticosteroid (ICS) as the preferred long-term control therapy for all forms of persistent asthma (National Asthma Education and Prevention Program Report, 2002). However, there are still a significant proportion of patients with persistent asthma who are not receiving ICS therapy or do not adhere to the treatment plan (Bauman et al, 2002). The advantages of the treatment plan profiled in the NAEPP guidelines are that it is directed to preventative therapy, is standardized, simple, and provides an algorithmic approach to management. The reluctance to embrace the concepts of anti-inflammatory therapy may be related to under-recognition of asthma severity, apprehension related to the potential adverse effects of long-term ICS, and the difficulty in applying the guidelines due to all of the reasons mentioned previously. The guidelines will continue to change with further understanding of the pathogenesis of asthma, the introduction of new medications including immunomodulators, such as anti-IgE, and the potential application of biomarkers and pharmacogenetics in the clinical management of asthma. The application of additional measures that may be specific to subpopulations of patients would theoretically create the opportunity to individualized management, especially in patients who remain refractory to the conventional approach to asthma management. One of the additional measures proposed in this study is the use of biomarkers, specifically the measurement of exhaled nitric oxide (eNO) using the Aerocrine NIOX device. It is anticipated that the application of eNO measurements in addition to using the NAEPP guidelines will enhance the level of assessment of asthma and guide medication regimens and improve overall asthma control. It is well known that exhaled nitric oxide is increased during periods of uncontrolled asthma and is decreased during treatment with inhaled corticosteroids and leukotriene modifiers (Kharitonov and Barnes, 2001; Hunt and Gaston, 2000; Silkoff et al, 2000; Kharitonov et al, 1996). Bates and Silkoff, 2003, recently reviewed the evidence citing the applicability of exhaled NO in diagnosing asthma, monitoring the response to therapy, evaluating current symptom control, and predicting exacerbations of asthma. These studies support the role of eNO in the treatment of asthma in the clinical arena, as an added approach to improve asthma control. Exhaled nitric oxide is easy to measure and can obtained in less than 15 minutes and can be performed during the same patient visit. Futhermore, the Aerocrine NIOX device was given Food and Drug Administration (FDA) approval as a medical device and this has generated increased interest in its appropriate application. It is difficult to obtain sputum eosinophils and airway hyperresponsiveness, especially in adolescents. Therefore, we propose to use exhaled nitric oxide as an additional guide to the management strategy of asthma. It could serve as a monitor of poor asthma control that could be due to poor symptom recognition, poor medication adherence, and persistent inflammation. The ICAC therefore will conduct a randomized, prospective, double blind, parallel group trial involving inner city adolescents, ages 12-20 years of age, with persistent asthma requiring or eligible for inhaled coritcosteroid therapy. The planned sample size is 500 participants randomized into one of two treatment groups: 1) NAEPP Guidelines alone (the Reference Strategy group) or 2) the NAEPP guidelines plus eNO measurements (the Biomarker Strategy group). Participants will be screened and enrolled over a 6 month period and treated for 12 months. The protocol can be viewed as consisting of two phases: run-in characterization period of 3 weeks treatment with an initial controller regimen (based on presenting asthma severity, long-term asthma history, and pulmonary function tests) and a double-blind treatment strategy period of 46 weeks. The purpose of the run-in period is to observe the participant, to standardize the baseline treatment, to assess adherence, and to train the participant in the study procedures. The study results may change the paradigm of management for persistent asthma, with the addition of a biomarker-based approach to management, that could be particularly beneficial for inner city asthma adolescents where there appear to be unique characteristics, such as allergen exposure and poor adherence to therapy that could result in persistent inflammation.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在过去二十年中，世界许多地区的哮喘患病率急剧增加。有令人信服的证据表明，生活在美国内陆城市、经济条件不利的儿童构成了一个独特的、特殊的哮喘高危人群，其特点是发病率和道德水平较高（Akinbami et al, 2002; Cloutier et al, 2002）。鉴于这些信息和市中心人口的独特需求，国家过敏和传染病研究所市中心哮喘联盟（ICAC）的总体目标是(1)确定最有可能促进哮喘控制和预防的免疫疗法形式，(2)设计方案，评估免疫疗法治疗低收入市中心青少年哮喘的效果。(3)通过与治疗方案并行的机制研究，确定免疫治疗的机制以及与低收入城市青少年哮喘发病机制相关的潜在独特机制。最近更新的国家哮喘教育和预防计划（NAEPP）哮喘指南将吸入皮质类固醇（ICS）确定为所有形式的持续性哮喘的首选长期控制治疗（2002年国家哮喘教育和预防计划报告）。然而，仍有相当比例的持续性哮喘患者没有接受ICS治疗或没有坚持治疗计划（Bauman et al, 2002）。NAEPP指南中概述的治疗计划的优点是，它针对预防性治疗，是标准化的，简单的，并提供了一种算法方法来管理。不愿意接受抗炎治疗的概念可能与对哮喘严重程度的认识不足、对长期ICS潜在不良影响的担忧以及由于上述所有原因而难以应用指南有关。随着对哮喘发病机制的进一步了解，包括抗ige等免疫调节剂在内的新药物的引入，以及生物标志物和药物遗传学在哮喘临床管理中的潜在应用，指南将继续改变。应用可能针对患者亚群的额外措施，理论上将创造个体化管理的机会，特别是对传统哮喘管理方法仍然难治的患者。本研究中提出的另一项措施是使用生物标志物，特别是使用Aerocrine NIOX装置测量呼出的一氧化氮（eNO）。预计在使用NAEPP指南的基础上，应用eNO测量将提高哮喘的评估水平，指导用药方案，并改善整体哮喘控制。众所周知，在不受控制的哮喘期间，呼出的一氧化氮增加，在吸入皮质类固醇和白三烯调节剂治疗期间减少（Kharitonov和Barnes, 2001； Hunt和Gaston, 2000； Silkoff等人，2000；Kharitonov等人，1996）。Bates和Silkoff， 2003，最近回顾了呼气NO在诊断哮喘、监测治疗反应、评估当前症状控制和预测哮喘恶化方面的适用性的证据。这些研究支持eNO在哮喘临床治疗中的作用，作为改善哮喘控制的一种附加方法。呼出的一氧化氮易于测量，可在不到15分钟内获得，并可在同一患者就诊期间进行。此外，Aerocrine NIOX设备被美国食品和药物管理局（FDA）批准为医疗设备，这增加了对其适当应用的兴趣。痰嗜酸性粒细胞和气道高反应性难以获得，特别是在青少年中。因此，我们建议使用呼出的一氧化氮作为哮喘管理策略的额外指导。它可以作为哮喘控制不良的监视器，这可能是由于症状识别不良、药物依从性差和持续炎症所致。因此，廉政公署将进行一项随机，前瞻性，双盲，平行组试验，涉及12-20岁的市中心青少年，患有需要或符合吸入皮质类固醇治疗的持续性哮喘。计划的样本大小为500名参与者随机分为两个治疗组之一：1)NAEPP指南单独（参考策略组）或2)NAEPP指南加eNO测量（生物标志物策略组）。参与者将在6个月的时间内进行筛选和登记，并接受12个月的治疗。该方案可被视为由两个阶段组成：初始对照方案（基于哮喘严重程度、长期哮喘病史和肺功能测试）治疗的3周适应期和46周双盲治疗策略期。磨合期的目的是观察参与者，规范基线治疗，评估依从性，并对参与者进行研究程序的培训。研究结果可能会改变持续性哮喘的管理模式，增加一种基于生物标志物的管理方法，这可能对市中心哮喘青少年特别有益，因为他们似乎有独特的特征，如过敏原暴露和治疗依从性差，可能导致持续性炎症。