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.
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.
Suspected or confirmed primary pulmonary infection at enrollment, including community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, or aspiration pneumonia.
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.
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.
Cohort
Prospective
Not listed
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.
Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal
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.
Ferroptosis-Related Biomarker Profile
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.
Lowest PaO₂/FiO₂ Ratio (or SpO₂/FiO₂ Ratio)
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.
Respiratory Sequential Organ Failure Assessment (SOFA) Score
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.
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