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

NCT07686887 | Not Yet Recruiting

• 5 other identifiers: 2025ZDSYLL431-P0182572527BK20252100QNRC2016808zdyyxy29
• Study Type: observational
• Target: 120
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Sepsis; Klebsiella Pneumoniae Infection; Hypervirulent Klebsiella Pneumoniae Infection; Acute Lung Injury(ALI)

Keywords

Hypervirulent Klebsiella pneumoniae; Extra-pulmonary infection; Sepsis-associated acute lung injury; Bacterial outer membrane vesicles; Ferroptosis; Pulmonary microvascular endothelial cells; Lipid peroxidation; Endothelial barrier dysfunction

Outcome Measures

Primary Outcomes (1)

• Incidence of New-Onset Sepsis-Associated Acute Lung Injury

  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 Outcomes (6)

• Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal

  At enrollment (T0), 24 hours, and 72 hours after enrollment

• Ferroptosis-Related Biomarker Profile

  At enrollment (T0), 24 hours, and 72 hours after enrollment

• Lowest PaO₂/FiO₂ Ratio (or SpO₂/FiO₂ Ratio)

  From enrollment through Day 7

• Respiratory Sequential Organ Failure Assessment (SOFA) Score

  From enrollment through Day 7

• Ventilator-Free Days

  From enrollment through Day 28

Study Arms (3)

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.

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Southeast University, China: lead

Related Publications (4)

• Russo TA, Olson R, Fang CT, Stoesser N, Miller M, MacDonald U, Hutson A, Barker JH, La Hoz RM, Johnson JR. Identification of Biomarkers for Differentiation of Hypervirulent Klebsiella pneumoniae from Classical K. pneumoniae. J Clin Microbiol. 2018 Aug 27;56(9):e00776-18. doi: 10.1128/JCM.00776-18. Print 2018 Sep.

  PMID: 29925642 RESULT

• Liu P, Feng Y, Li H, Chen X, Wang G, Xu S, Li Y, Zhao L. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell Mol Biol Lett. 2020 Feb 27;25:10. doi: 10.1186/s11658-020-00205-0. eCollection 2020.

  PMID: 32161620 RESULT

• Lee JC, Lee EJ, Lee JH, Jun SH, Choi CW, Kim SI, Kang SS, Hyun S. Klebsiella pneumoniae secretes outer membrane vesicles that induce the innate immune response. FEMS Microbiol Lett. 2012 Jun;331(1):17-24. doi: 10.1111/j.1574-6968.2012.02549.x. Epub 2012 Apr 13.

  PMID: 22428779 RESULT

• Zhang J, Zhao J, Li J, Xia Y, Cao J. Outer membrane vesicles derived from hypervirulent Klebsiella pneumoniae stimulate the inflammatory response. Microb Pathog. 2021 May;154:104841. doi: 10.1016/j.micpath.2021.104841. Epub 2021 Mar 7.

  PMID: 33691173 RESULT

MeSH Terms

Conditions

Sepsis; Acute Lung Injury

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Injury; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Jingyuan Xu, MD

  Southeast University School of Medicine

  STUDY CHAIR

Central Study Contacts

Jingyuan Xu, MD

CONTACT

+8613851417209; xujingyuanmail@163.com

Wanting Lin, MD

CONTACT

+86 13523253700; linwanting2022@126.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 28 Days
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor and Director, Department of Critical Care Medicine

Study Record Dates

• First Submitted: June 30, 2026
• First Posted: July 7, 2026
• Study Start: July 6, 2026
• Primary Completion (Estimated): July 15, 2030
• Study Completion (Estimated): July 30, 2030
• Last Updated: July 13, 2026

Record last verified: 2026-07