Microbial Determinants of Acute Respiratory Distress Syndrome Severity (MiDAS)

急性呼吸窘迫综合征严重程度的微生物决定因素 (MiDAS)

基本信息

批准号：
10417975
负责人：
Georgios Kitsios
金额：
$ 7.92万
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：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417975
关键词：
Accounting Acute Lung Injury Acute Respiratory Distress Syndrome Admission activity Alveolar Biological Biological Assay Biological Markers Blood Blood Circulation Blood capillaries COVID-19 pandemic Caring Cell Wall Cells Clinical Clinical Trials Critical Illness Culture-independent methods Data Development Emergency Situation Endothelium Epithelial Etiology Failure Functional disorder Gases Genotype Goals Grant Heterogeneity Hypoxemia Immune Immune response Inflammation Inflammatory Inflammatory Response Intervention Lipopolysaccharides Lower respiratory tract structure Lung Mechanical ventilation Membrane Molecular Morbidity - disease rate Natural Immunity Nucleic Acids Organ Organ failure Outcome Oxygen Pathway interactions Patients Pattern Pattern recognition receptor Peripheral Permeability Pharmacology Phenotype Plasma Pulmonary Edema Regimen Reproducibility Research Role Severities Stratification Survivors Therapeutic Uses Time Work biological heterogeneity case control cell free DNA clinically significant cohort design dysbiosis host microbiome host microbiota immunomodulatory therapies improved individual patient long-term sequelae lung injury lung microbiome lung microbiota microbial microbiome microbiota microbiota profiles mortality mortality risk novel pandemic disease pathogen personalized management radiological imaging systemic inflammatory response targeted treatment treatment response

项目摘要

PROJECT SUMMARY – ABSTRACT The Acute Respiratory Distress Syndrome (ARDS) is a serious form of inflammatory lung injury that disrupts the alveolar/capillary membrane leading to pulmonary edema and low oxygen levels. Despite advancements in understanding lung injury mechanisms, clinical trials for targeted pharmacologic therapies have shown limited efficacy, and care remains mostly supportive. Notably, most patients with ARDS do not die from hypoxemia but from multisystem organ failure, but the mechanisms of extrapulmonary organ damage are poorly defined. The clinical significance of ARDS was evident in the pre-pandemic era, accounting for 10% of ICU admissions, with up to 40% mortality and long-term sequelae to survivors, yet it has become a global emergency during the COVID-19 pandemic. Recent research has uncovered two reproducible ARDS subphenotypes (hyper- vs. hypo-inflammatory), with distinct profiles of systemic inflammatory biomarkers and divergent clinical outcomes. Despite the promise of this stratification framework for targeted therapeutics, ARDS subphenotypes are not currently used for therapeutic guidance and their biological underpinnings are unknown. Emerging work from our group highlights the lung microbiome as an underappreciated determinant of ARDS inflammation and clinical outcomes. Beyond the lungs, we have also discovered provocative associations between circulating, plasma microbial fragments (i.e. nucleic acids and cell-wall constituents) with host inflammation and outcome. Such microbial fragments may leak in the systemic circulation through the disrupted alveolar/capillary membrane and act as pathogen associated molecular patterns that stimulate innate immune cells. However, the extent and impact of microbial translocation in ARDS has not been thoroughly studied. In the proposed Microbial Determinants of Acute Respiratory Distress Syndrome Severity (MiDAS) study, we will leverage culture-independent methods of host-microbiota interactions in two body compartments (lungs and blood) in a well-phenotyped cohort of patients with and without ARDS, to accomplish the following specific aims: 1) To define the clinical and molecular determinants of lung microbiota translocation to the blood, and 2) To derive lung and blood compartment subphenotypes of host-microbiota interactions in ARDS. The MiDAS study will advance our understanding of the role of the lung microbiome in ARDS and clarify whether microbial translocation from the injured lungs of ARDS is an innocuous epiphenomenon or a significant pathogenetic contributor. With rapid and informative subphenotyping of ARDS patients by host-microbiota interactions, our approach has the potential to transform the practice of indiscriminate immunomodulatory therapies to timely, personalized regimens tailored to individual patients’ pathogens and inflammatory status.

项目摘要 – 摘要急性呼吸窘迫综合征 (ARDS) 是一种严重的炎症性肺损伤，会破坏尽管在这方面取得了进展，但肺泡/毛细血管膜仍会导致肺水肿和低氧水平。了解肺损伤机制后，靶向药物治疗的临床试验显示有限值得注意的是，大多数 ARDS 患者并非死于低氧血症，而是死于低氧血症。多系统器官衰竭引起的，但肺外器官损伤的机制尚不清楚。 ARDS 的临床意义在大流行前时期就很明显，占 ICU 入院人数的 10%，其中高达 40% 的死亡率和幸存者的长期后遗症，但它已成为全球紧急情况最近的研究发现了两种可重复的 ARDS 亚型（超型与超型）。低炎症），具有不同的全身炎症生物标志物特征和不同的临床结果。尽管这种分层框架有望用于靶向治疗，但 ARDS 亚表型并非如此目前用于治疗指导的方法及其生物学基础尚不清楚。我们小组强调肺微生物组是 ARDS 炎症的一个未被充分认识的决定因素，除了肺部之外，我们还发现了循环、血浆微生物碎片（即核酸和细胞壁成分）与宿主炎症和结果。这些微生物碎片可能会通过受损的肺泡/毛细血管渗漏到体循环中。膜并充当刺激先天免疫细胞的病原体相关分子模式。微生物易位对 ARDS 的影响程度和影响尚未得到深入研究。急性呼吸窘迫综合征严重程度的微生物决定因素 (MiDAS) 研究，我们将利用在两个身体区室（肺和血液）中宿主-微生物群相互作用的独立于培养的方法患有或不患有ARDS的表型良好的患者队列，以实现以下具体目标：1）定义肺微生物群易位至血液的临床和分子决定因素，以及 2) 推导 MiDAS 研究将研究 ARDS 中宿主-微生物群相互作用的肺和血液室亚表型。增进我们对肺微生物组在 ARDS 中作用的理解，并阐明微生物组是否 ARDS 受损肺部的易位是一种无害的副现象或显着的致病性通过宿主-微生物群相互作用对 ARDS 患者进行快速且信息丰富的亚表型分析，我们的贡献者。该方法有可能将不加区别的免疫调节疗法的实践转变为及时、根据个体患者的病原体和炎症状态量身定制个性化治疗方案。