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Outer Membrane Vesicle and Ferroptosis-Related Signatures in Sepsis-Associated Acute Lung Injury Caused by Extra-Pulmonary Hypervirulent Klebsiella Pneumoniae (OMV-FERRO-ALI)

2026年7月9日更新者：Jingyuan,Xu、Southeast University, China

Circulating Bacterial Outer Membrane Vesicle Signatures and Ferroptosis-Related Biomarkers in Sepsis-Associated Acute Lung Injury Among Patients With Extra-Pulmonary Hypervirulent Klebsiella Pneumoniae Infection: A Prospective Observational Translational Cohort Study

This prospective observational translational cohort study will investigate whether extra-pulmonary infection caused by hypervirulent Klebsiella pneumoniae (hvKP) is associated with an increased risk of sepsis-associated acute lung injury (SALI), compared with infection caused by classical Klebsiella pneumoniae (cKP). The study will further examine whether circulating bacterial outer membrane vesicle (OMV) signals and ferroptosis-related biomarker profiles are associated with subsequent SALI development.

Adults with Sepsis-3 and microbiologically confirmed extra-pulmonary K. pneumoniae infection will be enrolled within 6 hours of sepsis recognition. Patients with acute lung injury at enrollment will be excluded from the primary cohort. Blood samples will be collected at enrollment, 24 hours, and 72 hours. Clinical isolates will undergo molecular characterization to classify infections as hvKP or cKP. The primary outcome will be new-onset SALI within 7 days after enrollment. A nested translational substudy will evaluate the effects of patient-isolate-derived OMVs on human pulmonary microvascular endothelial cells.

The study will not alter antimicrobial therapy, source control, respiratory support, fluid management, or any other aspect of routine clinical care.

研究概览

地位

尚未招聘

条件

详细说明

Sepsis-associated acute lung injury is a major complication of severe extra-pulmonary Gram-negative bacterial infection. Hypervirulent Klebsiella pneumoniae (hvKP) is increasingly recognized as a cause of invasive infection with a high inflammatory burden and a propensity for metastatic spread. Bacterial outer membrane vesicles (OMVs) are biologically active nanoparticles that may transport lipopolysaccharide, virulence-associated molecules, and other inflammatory cargo to distant organs. Experimental evidence suggests that OMV-mediated oxidative stress and ferroptosis-related injury may contribute to pulmonary endothelial dysfunction and acute lung injury; however, the clinical relevance of these mechanisms in patients with extra-pulmonary hvKP sepsis remains unclear.

This prospective multicenter observational translational cohort study will investigate the relationship among molecularly characterized hvKP infection, circulating bacterial OMV-related signals, ferroptosis-related biomarker profiles, and the subsequent development of sepsis-associated acute lung injury. Adults with microbiologically confirmed extra-pulmonary Klebsiella pneumoniae sepsis will be enrolled early after sepsis recognition and followed during the acute phase of illness. Clinical isolates will undergo molecular characterization for prespecified hypervirulence-associated genes and additional strain-level features. Blood specimens collected during routine early follow-up will be processed using standardized procedures for plasma, serum, and peripheral blood mononuclear cell analyses.

The laboratory component will quantify circulating Gram-negative bacterial OMV-related signals in platelet-depleted plasma and evaluate systemic ferroptosis-related biomarker profiles, including lipid peroxidation products, glutathione redox status, iron-related indices, and ferroptosis-associated gene expression. Patient-derived Klebsiella pneumoniae isolates will also be cultured under standardized conditions for OMV isolation and characterization.

A nested translational substudy will compare OMVs derived from representative hvKP and classical Klebsiella pneumoniae isolates. Equal-particle-number OMV preparations will be applied to human pulmonary microvascular endothelial cells to assess lipid peroxidation, ferroptosis-related molecular changes, endothelial barrier integrity, and the in vitro rescue effect of Ferrostatin-1. No investigational intervention will be administered to study participants, and all clinical management will remain at the discretion of the treating physicians.

研究类型

观察性的

注册 (估计的)

120

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

姓名：Jingyuan Xu, MD
电话号码：+8613851417209
邮箱：xujingyuanmail@163.com

研究联系人备份

姓名：Wanting Lin, MD
电话号码：+86 13523253700
邮箱：linwanting2022@126.com

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

成人
年长者

接受健康志愿者

不

取样方法

概率样本

研究人群

Consecutively enrolled adults with clinically suspected sepsis caused by a presumed extra-pulmonary infection will be recruited from emergency departments, hospital wards, and intensive care units. Baseline blood samples will be collected during early sepsis evaluation, before culture results or bacterial molecular typing are available.

The primary analytic cohort will include participants who subsequently meet Sepsis-3 criteria, have microbiologically confirmed extra-pulmonary Klebsiella pneumoniae infection, have no acute lung injury at enrollment, and have an available clinical isolate for molecular characterization. Isolates will be classified as hypervirulent Klebsiella pneumoniae, classical Klebsiella pneumoniae, or indeterminate phenotype according to prespecified virulence-gene criteria. Patients with primary pulmonary infection, non-Klebsiella pneumoniae infection, mixed infection, culture-negative sepsis, or non-infectious diagnoses will not enter the primary analysis.

描述

Inclusion Criteria:

Age 18-85 years .
Clinical suspicion of infection with acute organ dysfunction consistent with suspected sepsis at the time of enrollment, as determined by the treating clinical team.
Presumed extra-pulmonary source of infection at enrollment, including but not limited to hepatobiliary, urinary, intra-abdominal, skin and soft-tissue, vascular catheter-related, or primary bloodstream infection.
Blood cultures and/or clinically indicated source cultures obtained or ordered as part of routine clinical care.
Enrollment and first research blood collection completed within 6 hours after initiation of the clinical sepsis evaluation.
No evidence of acute lung injury at the index time point, according to the protocol-defined criteria.
Written informed consent obtained from the participant or legally authorized representative, unless an ethics-approved deferred-consent procedure is used.

Exclusion Criteria:

Suspected or confirmed primary pulmonary infection at enrollment, including community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, or aspiration pneumonia.

Acute lung injury or acute respiratory distress syndrome present at the index time point.

Acute cardiogenic pulmonary edema, acute decompensated heart failure, or another condition that would preclude reliable adjudication of subsequent non-cardiogenic acute lung injury.
Recent inhalation injury, near-drowning, major thoracic trauma, or transfusion-related acute lung injury.
Previous enrollment in this study.
Inability to obtain informed consent from the participant or legally authorized representative when deferred-consent procedures are not permitted by the local ethics committee.

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

团体/队列数

队列和干预

团体/队列
Cohort 1 Title: Hypervirulent Klebsiella pneumoniae Infection Cohort 1 Description: Participants with subsequently confirmed extra-pulmonary Klebsiella pneumoniae infection whose clinical isolate carries iucA, iroB, peg-344, rmpA, and rmpA2.
Cohort 2 Title: Classical Klebsiella pneumoniae Infection Cohort 2 Description: Participants with subsequently confirmed extra-pulmonary Klebsiella pneumoniae infection whose clinical isolate lacks all five prespecified hypervirulence-associated genes: iucA, iroB, peg-344, rmpA, and rmpA2.
Cohort 3 Title: Indeterminate Klebsiella pneumoniae Molecular Phenotype Cohort 3 Description: Participants with subsequently confirmed extra-pulmonary Klebsiella pneumoniae infection whose clinical isolate carries one to four of the five prespecified hypervirulence-associated genes. This cohort will be included in exploratory analyses only.

研究衡量的是什么？

主要结果指标

结果测量	措施说明	大体时间
Incidence of New-Onset Sepsis-Associated Acute Lung Injury 大体时间：From enrollment (T0) through Day 7	New-onset sepsis-associated acute lung injury occurring after enrollment and within 7 days, defined by acute respiratory deterioration, new bilateral pulmonary opacities, hypoxemia, and respiratory failure not fully explained by cardiac failure or fluid overload. Acute lung injury will be adjudicated independently by two physicians blinded to bacterial molecular classification and biomarker results.	From enrollment (T0) through Day 7

次要结果测量

结果测量	措施说明	大体时间
Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal 大体时间：At enrollment (T0), 24 hours, and 72 hours after enrollment	Standardized level of lipopolysaccharide-positive extracellular nanoparticles in platelet-depleted plasma, measured using nano-flow cytometry or an equivalent validated assay. The result will be interpreted as a Gram-negative bacterial outer membrane vesicle-related signal.	At enrollment (T0), 24 hours, and 72 hours after enrollment
Ferroptosis-Related Biomarker Profile 大体时间：At enrollment (T0), 24 hours, and 72 hours after enrollment	Systemic ferroptosis-related biomarker profile assessed by plasma 4-hydroxynonenal protein adducts, malondialdehyde, glutathione, glutathione disulfide, glutathione/glutathione disulfide ratio, iron-related indices, and peripheral blood mononuclear cell expression of GPX4, SLC7A11, ACSL4, FTH1, and NCOA4.	At enrollment (T0), 24 hours, and 72 hours after enrollment
Ventilator-Free Days 大体时间：From enrollment through Day 28	Number of days alive and free from invasive mechanical ventilation during the first 28 days after enrollment. Participants who die before Day 28 will be assigned zero ventilator-free days.	From enrollment through Day 28
All-Cause Mortality 大体时间：From enrollment through Day 28	Death from any cause after enrollment.	From enrollment through Day 28
Lowest PaO₂/FiO₂ Ratio (or SpO₂/FiO₂ Ratio) 大体时间：From enrollment through Day 7	Respiratory dysfunction assessed by the lowest PaO₂/FiO₂ ratio during the observation period. If arterial blood gas analysis is unavailable, the lowest SpO₂/FiO₂ ratio will be used.	From enrollment through Day 7
Respiratory Sequential Organ Failure Assessment (SOFA) Score 大体时间：From enrollment through Day 7	Respiratory dysfunction assessed by the respiratory component of the SOFA score. The Respiratory SOFA sub-score ranges from 0 to 4, on an integer scale, with higher scores indicating worse respiratory function . The score is derived daily from the lowest PaO₂/FiO₂ ratio (or SpO₂/FiO₂ imputation) and the requirement for mechanical ventilation.	From enrollment through Day 7

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Southeast University, China

调查人员

学习椅：Jingyuan Xu, MD、Southeast University School of Medicine

出版物和有用的链接

负责输入研究信息的人员自愿提供这些出版物。这些可能与研究有关。

一般刊物

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (估计的)

2026年7月6日

初级完成 (估计的)

2030年7月15日

研究完成 (估计的)

2030年7月30日

研究注册日期

首次提交

2026年6月30日

首先提交符合 QC 标准的

2026年6月30日

首次发布 (实际的)

2026年7月7日

研究记录更新

最后更新发布 (实际的)

2026年7月13日

上次提交的符合 QC 标准的更新

2026年7月9日

最后验证

2026年7月1日