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

June 30, 2026 updated by: 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.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of New-Onset Sepsis-Associated Acute Lung Injury
Time Frame: 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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal
Time Frame: 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
Time Frame: 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
Severity of Respiratory Dysfunction
Time Frame: From enrollment through Day 7
Respiratory dysfunction assessed by the lowest PaO2/FiO2 ratio or, when arterial blood gas analysis is unavailable, the lowest SpO2/FiO2 ratio; respiratory Sequential Organ Failure Assessment score; and requirement for invasive mechanical ventilation.
From enrollment through Day 7
Ventilator-Free Days
Time Frame: 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
Time Frame: From enrollment through Day 28
Death from any cause after enrollment.
From enrollment through Day 28

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Southeast University, China

Investigators

  • Study Chair: Jingyuan Xu, MD, Southeast University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 6, 2026

Primary Completion (Estimated)

July 15, 2030

Study Completion (Estimated)

July 30, 2030

Study Registration Dates

First Submitted

June 30, 2026

First Submitted That Met QC Criteria

June 30, 2026

First Posted (Actual)

July 7, 2026

Study Record Updates

Last Update Posted (Actual)

July 7, 2026

Last Update Submitted That Met QC Criteria

June 30, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025ZDSYLL431-P01
  • 82572527 (Other Grant/Funding Number: The National Natural Science Foundations of China)
  • BK20252100 (Other Grant/Funding Number: The General Natural Science Foundation of Jiangsu Province)
  • zdyyxy29 (Other Grant/Funding Number: Jiangsu Province High-Level Hospital Pairing Assistance)
  • QNRC2016808 (Other Grant/Funding Number: Jiangsu Provincial Medical Youth Talent)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

The decision regarding sharing of de-identified individual participant data has not yet been finalized. The research team will evaluate data-sharing feasibility after study completion, taking into account participant privacy, informed consent, institutional ethics requirements, data protection regulations, and the sensitivity of clinical and microbiological data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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