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)

• 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
• 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

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， 肺泡/毛细血管膜导致肺水肿和低氧水平。尽管在技术上有所进步 了解肺损伤的机制，靶向药物治疗的临床试验显示有限 疗效，护理仍然主要是支持性的。值得注意的是，大多数ARDS患者不是死于低氧血症，而是 多系统器官衰竭，但肺外器官损害的机制尚不清楚。这个 ARDS的临床意义在大流行前时代很明显，占ICU入院人数的10%， 高达40%的死亡率和对幸存者的长期后遗症，但它已成为全球紧急情况 新冠肺炎大流行。最近的研究发现了两种可重复的ARDS亚型(hyper-vs. 低炎性)，具有不同的全身炎性生物标志物和不同的临床结果。 尽管这一分层框架有望用于靶向治疗，但ARDS亚型并不是 目前用于治疗指导的药物及其生物学基础尚不清楚。新出现的工作来自 我们小组强调，肺微生物群是ARDS炎症和炎症的一个被低估的决定因素 临床结果。除了肺部，我们还发现了血液循环、 血浆微生物片段(即核酸和细胞壁成分)与宿主炎症和结局有关。 这样的微生物碎片可能会通过被破坏的肺泡/毛细血管在体循环中泄漏 作为病原体相关的分子模式，刺激先天免疫细胞。然而， ARDS中微生物易位的程度和影响尚未得到彻底的研究。在建议的 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 在两个身体隔室(肺和血液)中非培养的宿主-微生物区系相互作用的方法 患有和不患有ARDS的表型良好的患者队列，以实现以下特定目标：1) 确定肺微生物区系移位到血液的临床和分子决定因素，以及2)推导出 急性呼吸窘迫综合征患者宿主-微生物区系相互作用的肺和血液亚型。迈达斯的研究将 促进我们对肺部微生物群在ARDS中的作用的理解，并澄清微生物 ARDS患者受损肺的移位是一种无害的附带现象或重要的致病因素 贡献者。通过宿主-微生物区系相互作用对ARDS患者进行快速和信息丰富的亚型分型，我们的 该方法有可能将不分青红皂白的免疫调节疗法的做法转变为及时、 针对个别患者的病原体和炎症状态量身定做的个性化方案。