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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)

9 juli 2026 bijgewerkt door: 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.

Studie Overzicht

Toestand

Nog niet aan het werven

Conditie

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Inschrijving (Geschat)

120

Contacten en locaties

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Studiecontact

Studie Contact Back-up

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Bemonsteringsmethode

Kanssteekproef

Studie Bevolking

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.

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / 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.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Incidence of New-Onset Sepsis-Associated Acute Lung Injury
Tijdsspanne: 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

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: From enrollment through Day 28
Death from any cause after enrollment.
From enrollment through Day 28
Lowest PaO₂/FiO₂ Ratio (or SpO₂/FiO₂ Ratio)
Tijdsspanne: 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
Tijdsspanne: 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

Medewerkers en onderzoekers

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Sponsor

Southeast University, China

Onderzoekers

  • Studie stoel: Jingyuan Xu, MD, Southeast University School of Medicine

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Geschat)

6 juli 2026

Primaire voltooiing (Geschat)

15 juli 2030

Studie voltooiing (Geschat)

30 juli 2030

Studieregistratiedata

Eerst ingediend

30 juni 2026

Eerst ingediend dat voldeed aan de QC-criteria

30 juni 2026

Eerst geplaatst (Werkelijk)

7 juli 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

13 juli 2026

Laatste update ingediend die voldeed aan QC-criteria

9 juli 2026

Laatst geverifieerd

1 juli 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

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

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

ONBESLIST

Beschrijving IPD-plan

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.

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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