Characterizing respiratory exacerbations in primary ciliary dyskinesia

摘要 原发性睫状肌运动障碍(PCD)是一种罕见的、遗传异质性的孤儿疾病，其特点是有利于 进行性上、下呼吸道感染和炎症。与其他化脓性肺病相似 临床上，患有原发性睫状肌运动障碍的人会出现阵发性急性呼吸加重 以咳嗽、发烧和疲劳增加为特征，通常使用抗生素和 增加了呼吸道通气量。急性呼吸系统恶化会导致严重的发病率和健康。 护理利用、学校或工作缺勤，以及在一些化脓性呼吸道疾病中加速结构性 呼吸道损伤和呼吸道阻塞。考虑到它们对原发纤毛患者生活的负面影响 运动障碍、病情恶化一直是旨在建立循证指南的干预试验的目标。 关于他们的预防和治疗的线路。然而，可能导致急性呼吸道感染的传染性沉淀物 病情恶化通常是不确定的，可能是临床试验的重要因素。这项辅助研究将 包括已经在NIH资助的父母纵向研究中登记的患有原发性睫状体运动障碍的受试者 RDCRN协议5907)，旨在定义呼吸加重的关键特征和评估- 评估潜在的预测因素和首次恶化的时间。第一个具体目标是研究分子方法。 对PCD患者进行病毒和细菌检测，以确定基线微生物状态和微生物 呼吸恶化的表型，使用可以对自己收集的样本进行分析的方法 在家中，这将检验两个互补的假设，即一种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期间获得的痰样本的一部分可以预测发作的严重程度。在第二个目标2中，我们将 使用鼻部基因表达谱来表征宿主对急性呼吸道疾病的反应，测试 对宿主反应的评估将区分有无临床感染的病毒感染的假设 表现形式。这项辅助研究将通过进一步细化 呼吸道恶化，并建立受试者在基线和 在病情恶化期间，在家中收集的呼吸道样本。我们将研究微生物苯丙氨酸的可行性- 在基线和病情加重期间不对受试者进行分类，从而确定传染性沉淀物的作用 以及呼吸道恶化时的炎症反应。具体地说，它将提供一个非常详细的 在PCD人群中引起急性加重的细菌和病毒的特征，提供试点 将更好地将呼吸道恶化定义为未来临床试验的关键终点的数据。

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.