Tracheobronchitis in the Critically Ill

危重病人的气管支气管炎

基本信息

批准号：
10410921
负责人：
Anna Christine Zemke
金额：
$ 35.31万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10410921
关键词：
Acute American Antibiotic Resistance Antibiotics Aspirate substance Bacteria Bacterial Infections Biology Blood Carbon Chronic Clinical Cluster Analysis Critical Illness Data Data Set Development Diagnosis Diagnostic Elements Environment Event Excision Financial cost Functional disorder Future Goals Growth Healthcare Systems Hospitals Host Defense Individual Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Intervention Intervention Studies Kinetics Knowledge Longitudinal cohort Measurement Measures Metagenomics Metals Micronutrients Modeling Mucosal Immunity Mucous Membrane Mutation Natural History Nested Case-Control Study Nutrient Nutritional Organism Outcome Participant Pathogenicity Patients Persons Phase Phenotype Pneumonia Population Public Health Quality of life Recovery Registries Research Infrastructure Respiratory Tract Infections Risk Shotgun Sequencing Source Sputum Symptoms Testing Time Tracheostomy procedure Ventilator Ventilator Weaning Virus Diseases acute care airway inflammation clinical predictors cohort cytokine emerging pathogen experience health care service utilization improved microbiome mortality pathogen pathogenic bacteria personalized medicine primary outcome radiological imaging respiratory respiratory virus secondary outcome systemic inflammatory response

项目摘要

Nearly 30% of people recovering from critical illness requiring tracheostomy placement experience respiratory infections - termed tracheostomy associated tracheobronchitis (TATB) for this proposal. Our understanding of TATB comes from those with acute critical illness, and does not extend to the recovery phase of critical illness. Poor understanding of TATB may contribute to antibiotic overuse and limits testing of interventions. Our objective is to define the natural history and outcomes of TATB, as well as to identify changes in the airway bacterial populations and host innate immune response that predispose to TATB. To accomplish this goal, we will assemble a longitudinal cohort of participants with tracheostomies within a Long-Term Acute Care Hospital (LTACH). In Aim 1 we will assemble a longitudinal registry cohort of people admitted with a tracheostomy to test the hypothesis that tracheobronchitis episodes in the LTACH have clinical impact on long term outcomes. Within the cohort, we will determine the event rate of TATB, measure the effect of diagnosis of TATB on outcomes, including respiratory recovery rate, mortality and healthcare utilization, and determine clinical predictors of being diagnosed with TATB. Although TATB is treated with antibiotics, we do not know how often episodes are caused by active bacterial infections. Alternative causes include viral infections and other reasons for increased respiratory secretions in a population that is colonized with at least one pathogenic organism. In Aim 2 we hypothesize that infectious TATB episodes are caused by a bloom of an existing pathogen with an acute inflammatory response. We will use shallow metagenomics (shotgun sequencing) to determine the bacterial kinetics of infection down to the strain level during episodes. Shallow metagenomics will allow us to distinguish episodes of new pathogen invasion vs a bloom or genetic change in the existing pathogens within the microbiome. We will determine which episodes of TATB are associated with either a local airway inflammatory response or a systemic inflammatory response. Alternatively, viral infections may trigger TATB or trigger pathogenic bacterial growth. We will conduct a nested case-control study to determine if infection with respiratory viruses is associated with TATB. Together, these data will determine clinical endotypes. In Aim 3, we will examine how inflammation promotes the growth of pathogenic bacteria through the release of micronutrients needed for bacteria growth. We will test the hypotheses that breaches in local mucosal immunity or local inflammatory response increase the odds of TATB diagnosis. The nutritional environment in the sputum will be assessed through measurement of bacterial nutrients such as metals and carbon sources, the nutritional environment will be correlated with odds of TATB diagnosis, and the local inflammatory state prior to diagnosis of TATB will be assessed through cytokine profiling. The results from these studies will allow us to target specific phenotypes of TATB in future intervention or scientific studies.

近 30% 从需要气管切开术的危重疾病中康复的人会出现呼吸困难感染 - 本提案称为气管造口相关气管支气管炎 (TATB)。我们的理解 TATB来自于急性危重症患者，不延伸至危重症恢复期。对 TATB 的了解不足可能会导致抗生素的过度使用并限制干预措施的测试。我们的目标是为了定义 TATB 的自然史和结果，以及识别气道细菌的变化易患 TATB 的人群和宿主先天免疫反应。为了实现这一目标，我们将在长期急症护理医院内组建一组进行气管切开术的纵向参与者（LTACH）。在目标 1 中，我们将收集接受气管切开术入院患者的纵向登记队列进行测试 LTACH 气管支气管炎发作对长期临床影响的假设结果。在队列内，我们将确定 TATB 的事件发生率，衡量 TATB 诊断的效果评估结果，包括呼吸恢复率、死亡率和医疗保健利用率，并确定临床被诊断为 TATB 的预测因素。尽管 TATB 用抗生素治疗，但我们不知道多久一次发作是由活跃的细菌感染引起的。其他原因包括病毒感染和其他原因用于增加至少一种病原微生物定殖的人群的呼吸道分泌物。在目标 2 我们假设传染性 TATB 事件是由现有病原体的繁殖引起的急性炎症反应。我们将使用浅层宏基因组学（鸟枪测序）来确定感染期间的细菌动力学低至菌株水平。浅层宏基因组学将使我们能够区分新病原体入侵的事件与现有病原体的爆发或基因变化微生物组。我们将确定哪些 TATB 发作与局部气道相关炎症反应或全身炎症反应。另外，病毒感染可能会引发 TATB 或引发致病细菌生长。我们将进行一项巢式病例对照研究，以确定是否感染呼吸道病毒与 TATB 有关。这些数据将共同确定临床内型。在目标 3 中，我们将研究炎症如何通过微量营养素的释放促进病原菌的生长细菌生长所需。我们将测试局部粘膜免疫或局部免疫破坏的假设炎症反应增加了 TATB 诊断的几率。痰中的营养环境会通过测量细菌营养物（例如金属和碳源）来评估，营养环境与 TATB 诊断的几率以及诊断前的局部炎症状态相关 TATB 的影响将通过细胞因子分析进行评估。这些研究的结果将使我们能够针对特定的目标未来干预或科学研究中 TATB 的表型。