Characterizing respiratory exacerbations in primary ciliary dyskinesia

原发性纤毛运动障碍呼吸加重的特征

• 批准号: 10754387
• 负责人: THOMAS W FERKOL
• 金额: $ 19.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10754387
• 关键词: Characterizing; respiratory; exacerbations; primary; ciliary

ABSTRACT Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, orphan disease characterized by pro- gressive upper and lower respiratory tract infections and inflammation. Similar to other suppurative lung dis- eases, people with primary ciliary dyskinesia experience episodic, acute respiratory exacerbations, clinically characterized by increasing productive cough, fever and fatigue, that are typically treated with antibiotics and increased airway clearance. Acute respiratory exacerbations cause significant morbidity and substantial health care utilization, school or work absenteeism, and in some suppurative airway diseases accelerate structural airway damage and airway obstruction. Given their negative impact on the lives of people with primary ciliary dyskinesia, exacerbations have been targets for interventional trials designed to establish evidence-based guide- lines for their prevention and treatment. However, the infectious precipitants that likely cause acute respiratory exacerbations are frequently undefined and could be important factors for clinical trials. This ancillary study will involve subjects with primary ciliary dyskinesia already enrolled in an NIH-funded parent longitudinal study RDCRN Protocol 5907) that is designed to define the key characteristics of respiratory exacerbations and eval- uate potential predictors and time to first exacerbations. The first Specific Aim will examine molecular approaches to detection of viruses and bacteria in patients with PCD to define the baseline microbial state and the microbial phenotype of respiratory exacerbations, using assays that can be performed on self-collected samples obtained in the home, which will test two complementary hypotheses, that the microbial phenotype of a baseline sputum sample can predict the frequency and severity of acute respiratory tract illnesses, and the microbial phenotype of a sputum sample obtained during an ARI can predict the severity of the episode. In the second Aim 2, we will use nasal gene expression profiles to characterize host response to acute respiratory tract illnesses, testing the hypothesis that assessment of the host response will distinguish between viral infections with and without clinical manifestations. This ancillary study that will enhance the parent project by further refining the characterization of respiratory tract exacerbations, and establish the feasibility of microbial phenotyping of subjects at baseline and during exacerbations on respiratory samples collected at home. We will examine the feasibility of microbial phe- notyping of subjects at baseline and during exacerbations, thus determining the role of infectious precipitants and inflammatory responses during respiratory tract exacerbations. Specifically, it will provide a highly detailed characterization of the bacteria and viruses causing acute exacerbations in the PCD population, providing pilot data that will better define respiratory tract exacerbations as a key endpoint for future clinical trials.

抽象的 原发性纤毛运动障碍 (PCD) 是一种罕见的、遗传异质性的孤儿疾病，其特征是 进行性上呼吸道和下呼吸道感染和炎症。与其他化脓性肺疾病相似 临床上，患有原发性纤毛运动障碍的人会经历阵发性急性呼吸道症状加重 其特点是咳嗽增多、发烧和疲劳，通常用抗生素和 增加气道间隙。急性呼吸系统恶化会导致严重的发病率和严重的健康问题 护理利用、学校或工作缺勤以及某些化脓性气道疾病加速结构性 气道损伤和气道阻塞。鉴于它们对原发性睫状体患者的生活产生负面影响 运动障碍、病情加重已成为干预试验的目标，旨在建立基于证据的指导 预防和治疗的路线。然而，可能引起急性呼吸道疾病的传染性沉淀物 病情加重通常是不确定的，可能是临床试验的重要因素。这项辅助研究将 涉及已参加 NIH 资助的家长纵向研究的原发性纤毛运动障碍受试者 RDCRN 协议 5907）旨在定义呼吸恶化的关键特征和评估 评估潜在的预测因素和首次恶化的时间。第一个具体目标将检查分子方法 检测 PCD 患者体内的病毒和细菌，以确定基线微生物状态和微生物水平 呼吸系统恶化的表型，使用可对自行收集的样本进行的检测 在家里，这将测试两个互补的假设，即基线痰的微生物表型 样本可以预测急性呼吸道疾病的频率和严重程度以及微生物表型 在 ARI 期间获得的痰样本可以预测发作的严重程度。在第二个目标 2 中，我们将 使用鼻基因表达谱来表征宿主对急性呼吸道疾病的反应，测试 假设对宿主反应的评估将区分有临床症状和无临床症状的病毒感染 表现形式。这项辅助研究将通过进一步细化特征来增强母项目 呼吸道恶化，并建立受试者基线和微生物表型分析的可行性 在病情加重期间在家收集的呼吸道样本。我们将研究微生物PH值的可行性 在基线和恶化期间对受试者进行分型，从而确定传染性诱发因素的作用 以及呼吸道恶化期间的炎症反应。具体来说，它将提供非常详细的 导致 PCD 人群急性加重的细菌和病毒的特征，提供试点 这些数据将更好地将呼吸道恶化定义为未来临床试验的关键终点。