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: 10615866
• 负责人: Georgios Kitsios
• 金额: $ 7.95万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615866
• 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; Circulation; Clinical; Clinical Trials; Critical Illness; Culture-independent methods; Data; Development; Emergency Situation; Endothelium; Epithelium; Etiology; Failure; Functional disorder; Gases; Genetic; 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; Phenotype; Plasma; Pulmonary Edema; Regimen; Reproducibility; Research; Role; Severities; Stratification; Survivors; Therapeutic Uses; Work; biological heterogeneity; body system; 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; pathogen; personalized management; pharmacologic; pre-pandemic; radiological imaging; systemic inflammatory response; targeted treatment; treatment response; 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; Circulation; Clinical; Clinical Trials; Critical Illness; Culture-independent methods; Data; Development; Emergency Situation; Endothelium; Epithelium; Etiology; Failure; Functional disorder; Gases; Genetic; 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; Phenotype; Plasma; Pulmonary Edema; Regimen; Reproducibility; Research; Role; Severities; Stratification; Survivors; Therapeutic Uses; Work; biological heterogeneity; body system; 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; pathogen; personalized management; pharmacologic; pre-pandemic; 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形式 肺泡/毛细血管膜导致肺水肿和低氧水平。尽管进步了 了解肺损伤机制，针对靶向药物治疗的临床试验显示有限 功效和护理仍然得到支持。值得注意的是，大多数ARD患者不会死于低氧血症，而是 从多系统器官衰竭中，但是肺外器官损伤的机制的定义很差。这 ARDS的临床意义在流行前时代证明了ARDS，占ICU入院的10％，其中有10％ 高达40％的死亡率和长期后遗症，但它已成为全球紧急事件 2019冠状病毒病大流行。最近的研究发现了两种可再现的ARDS亚表征（Hyper-VS。 低炎症），具有独特的全身性炎症生物标志物和不同临床结果的特征。 尽管有针对靶向治疗的分层框架的承诺，但ARDS子表型不是 目前用于热指导及其生物基础尚不清楚。来自新兴的工作 我们的小组强调肺微生物组是由ARDS注入和 临床结果。除了肺部，我们还发现了循环， 血浆微生物片段（即核酸和细胞壁构建体），并带有宿主注射和结果。 这种微生物碎片可能会通过破坏的牙槽/毛细管在全身循环中泄漏 膜并充当病原体相关的分子模式，刺激先天免疫细胞。然而， 微生物易位在ARDS中的程度和影响尚未彻底研究。在提议中 急性呼吸窘迫综合征严重程度（MIDAS）研究的微生物决定因素，我们将利用 在两个身体室（肺部和血液）中的宿主 - 微生物群相互作用的培养无关方法 具有和没有ARDS的患者的表现良好，以实现以下特定目的：1） 定义肺微生物群的临床和分子确定剂转运至血液，2） ARDS中宿主 - 微生物群相互作用的肺和血室亚型。 MIDAS研究将 促进我们对肺微生物组在ARDS中的作用的理解，并澄清是否微生物 ARDS受伤肺的易位是无害的表现或严重的致病性 贡献者。通过宿主 - 微生物群相互作用对ARDS患者进行快速和信息的亚表型，我们 方法有潜力将滥用的免疫调节疗法的实践转变为及时， 针对个别患者的病原体和炎症状况量身定制的个性化方案。