Characterizing respiratory exacerbations in primary ciliary dyskinesia

摘要 原发性纤毛运动障碍（PCD）是一种罕见的，遗传异质性，孤儿疾病的特点是前- 上、下呼吸道感染和炎症。与其他化脓性肺疾病相似- 例，原发性纤毛运动障碍患者经历发作性急性呼吸加重，临床上 其特征是咳嗽、发烧和疲劳增加，通常用抗生素治疗， 增加气道清除率。急性呼吸道疾病加重会导致严重的发病率和大量的健康问题 护理利用率，学校或工作缺勤，以及在某些化脓性气道疾病中， 气道损伤和气道阻塞。考虑到它们对原发性睫状体炎患者的生活产生的负面影响， 运动障碍、急性加重一直是旨在建立循证指南的干预性试验的目标- 预防和治疗的方法。然而，可能导致急性呼吸道疾病的传染性沉淀物 急性加重常常是不确定的，并且可能是临床试验的重要因素。本辅助研究将 涉及已入组NIH资助的母公司纵向研究的原发性睫状体运动障碍受试者 RDCRN方案5907），旨在定义呼吸恶化的关键特征，并评估 评估潜在的预测因素和至首次急性加重的时间。第一个具体目标将审查分子方法 检测PCD患者的病毒和细菌，以确定基线微生物状态和微生物 呼吸恶化的表型，使用可对获得的自我收集样本进行的测定 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期间获得的痰液样本的浓度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， 假设宿主反应的评估将区分具有和不具有临床症状的病毒感染， 表现。这一辅助研究将通过进一步完善 呼吸道急性加重，并确定基线时受试者微生物表型的可行性， 在家中采集的呼吸道样本中。我们将研究微生物phe- 在基线和急性加重期间未对受试者进行分型，从而确定感染性促发剂的作用 和呼吸道恶化期间的炎症反应。具体来说，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表征， 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。

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.