Outer Membrane Vesicle and Ferroptosis-Related Signatures in Sepsis-Associated Acute Lung Injury Caused by Extra-Pulmonary Hypervirulent Klebsiella Pneumoniae (OMV-FERRO-ALI)
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.
調査の概要
状態
詳細な説明
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.
研究の種類
入学 (推定)
連絡先と場所
研究連絡先
- 名前：Jingyuan Xu, MD
- 電話番号：+8613851417209
- メール：xujingyuanmail@163.com
研究連絡先のバックアップ
- 名前：Wanting Lin, MD
- 電話番号：+86 13523253700
- メール：linwanting2022@126.com
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
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.
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
|---|
|
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. |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Incidence of New-Onset Sepsis-Associated Acute Lung Injury
時間枠：From enrollment (T0) through Day 7
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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.
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From enrollment (T0) through Day 7
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Circulating Gram-Negative Bacterial Outer Membrane Vesicle-Related Signal
時間枠：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.
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At enrollment (T0), 24 hours, and 72 hours after enrollment
|
|
Ferroptosis-Related Biomarker Profile
時間枠：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.
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At enrollment (T0), 24 hours, and 72 hours after enrollment
|
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Ventilator-Free Days
時間枠：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.
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From enrollment through Day 28
|
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All-Cause Mortality
時間枠：From enrollment through Day 28
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Death from any cause after enrollment.
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From enrollment through Day 28
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Lowest PaO₂/FiO₂ Ratio (or SpO₂/FiO₂ Ratio)
時間枠：From enrollment through Day 7
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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.
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From enrollment through Day 7
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Respiratory Sequential Organ Failure Assessment (SOFA) Score
時間枠：From enrollment through Day 7
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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
|
協力者と研究者
捜査官
- スタディチェア：Jingyuan Xu, MD、Southeast University School of Medicine
出版物と役立つリンク
一般刊行物
- 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.
- 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.
- 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.
- 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.
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- 2025ZDSYLL431-P01
- 82572527 (その他の助成金/資金番号：The National Natural Science Foundations of China)
- BK20252100 (その他の助成金/資金番号：The General Natural Science Foundation of Jiangsu Province)
- zdyyxy29 (その他の助成金/資金番号：Jiangsu Province High-Level Hospital Pairing Assistance)
- QNRC2016808 (その他の助成金/資金番号：Jiangsu Provincial Medical Youth Talent)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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