Immune Mechanisms and ECMO Strategies for Moderate-to-Severe ARDS

Mechanistic Investigation of Inflammatory and Immune Dysregulation in Moderate-to-Severe ARDS and Rescue Strategies With Extracorporeal Membrane Oxygenation

Acute respiratory distress syndrome (ARDS) poses a major threat to human health. Despite extracorporeal membrane oxygenation (ECMO) support, mortality among patients with ARDS remains high due to severe complications and suboptimal mechanical ventilation strategies. Elucidating the mechanisms underlying ECMO-related complications and lung injury repair, and establishing a precision intervention pathway covering the entire course of ECMO management, are urgent unmet needs for improving outcomes in ARDS patients and addressing major public health challenges.

This project focuses on five key scientific questions:

1. How can moderate-to-severe ARDS be classified into distinct clinical-immune phenotypes, and what are the optimal therapeutic targets for each phenotype?
2. What are the molecular mechanisms underlying severe complications in ARDS patients receiving ECMO support?
3. Which key immune biomarkers are associated with clinical benefit from awake ECMO?
4. How should mechanical ventilation strategies be optimized in moderate-to-severe ARDS patients supported with ECMO?
5. How can a comprehensive, full-cycle ECMO management pathway be established for patients with moderate-to-severe ARDS?

The project consists of five interrelated subprojects:

Subproject 1. Construction of Clinical-Immune Phenotypes and Identification of Therapeutic Targets in Moderate-to-Severe ARDS Clinical phenotypes and longitudinal multidimensional biospecimens collected throughout the disease course in moderate-to-severe ARDS patients, including those receiving ECMO support, will be analyzed to characterize the heterogeneity and spatiotemporal interactions of inflammatory and immune cell subsets and to identify effective therapeutic targets.

Subproject 2. Mechanisms and Interventions for Immune Dysregulation Underlying Severe ECMO-Related Complications This subproject aims to elucidate the inflammatory and immune mechanisms responsible for major complications occurring in ARDS patients receiving ECMO support. Major complications of interest include acute kidney injury, bleeding and thrombosis, and infection.

Subproject 3. Development and Validation of a Clinical-Immune Phenotype-Guided Decision System for Awake ECMO By integrating multidimensional data, a comprehensive ARDS phenotyping framework will be established to identify patients most likely to benefit from awake ECMO. A clinical decision-making system will be developed and subsequently validated through multicenter studies to assess its effectiveness.

Subproject 4. Molecular Mechanisms of Lung Repair and Optimization of Mechanical Ventilation During ECMO Support This subproject will investigate the lung-protective effects of different invasive mechanical ventilation strategies and ventilation parameters during ECMO support. Multi-omics analyses of ARDS biospecimens will be performed to elucidate the mechanisms through which lung rest promotes tissue repair and recovery.

Subproject 5. Establishment and Evaluation of a Full-Cycle ECMO Management Strategy for Moderate-to-Severe ARDS Based on evidence-based medicine and multidisciplinary collaboration, a comprehensive ECMO management pathway covering the entire disease course will be developed for patients with moderate-to-severe ARDS. Real-world studies will be conducted to evaluate its clinical effectiveness and facilitate continuous optimization.

Overall, this project aims to provide mechanistic insights into immune dysregulation, ECMO-related complications, and lung repair, while establishing a precision, full-cycle ECMO management framework to improve outcomes in patients with moderate-to-severe ARDS.**

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome (ARDS)

Detailed Description

Acute respiratory distress syndrome (ARDS) poses a major threat to public health and consumes substantial healthcare resources. Based on the National Hospital Quality Monitoring System (HQMS), our group found that more than 2.5 million patients with ARDS are admitted to intensive care units (ICUs) annually in China, resulting in total hospitalization costs of approximately RMB 29.32 billion. The in-hospital mortality rate is about 39%, which is substantially higher than the international average (12-37%). Extracorporeal membrane oxygenation (ECMO) represents the most important rescue therapy for patients with moderate-to-severe ARDS; however, mortality among ARDS patients receiving ECMO support remains as high as 60%. Therefore, reducing mortality in moderate-to-severe ARDS is essential for achieving the goals of the Healthy China 2030 Initiative.

Inflammatory and immune dysregulation occurs in 38.7-70% of patients with ARDS, frequently leading to multiple organ dysfunction. Despite ECMO support, mortality among patients with severe ARDS remains extremely high. Three major challenges contribute to poor outcomes. First, immune dysregulation under ECMO support significantly increases the incidence and mortality of severe complications, while targeted therapeutic strategies based on underlying mechanisms are lacking. Second, the marked heterogeneity of ARDS complicates the identification of optimal timing and modalities of ECMO support. Third, the effects of different invasive mechanical ventilation strategies on lung injury and repair remain poorly understood, and mechanism-guided precision ventilation approaches are still unavailable.

Building upon the largest ARDS and ECMO clinical-biological database in China established by our group, this project aims to develop a Chinese precision management strategy for ECMO-supported patients with moderate-to-severe ARDS.

1. Comprehensive characterization of immune spatiotemporal dynamics in moderate-to-severe ARDS is essential for identifying therapeutic targets Current biomarkers reflecting disease progression in ARDS are largely limited to static clinical parameters and single-dimensional measurements, making biomarker-guided precision therapy difficult. Previous studies have identified biomarkers such as soluble receptor for advanced glycation end-products (sRAGE), angiopoietin-2 (Ang-2), and surfactant protein D (SPD) as prognostic indicators, yet these markers provide limited mechanistic insights and have not translated into individualized therapeutic strategies. Our group has established the largest ARDS and ECMO biospecimen cohort in China and has preliminarily characterized the spatiotemporal immune landscape of moderate-to-severe ARDS. We identified VCAM1 and tRF-5004b as potential immune-related targets closely associated with disease progression, providing a solid foundation for the proposed study.
2. Elucidating inflammatory and immune mechanisms underlying severe ECMO-related complications is critical for targeted intervention Among ARDS patients receiving ECMO support, the incidence rates of acute kidney injury (AKI), bleeding/thrombosis, and infection are approximately 45.7%, 40.2%, and 44.7%, respectively. Systemic inflammatory and immune dysregulation is considered a major contributor to these complications, although the underlying mechanisms remain unclear. In addition to the excessive inflammatory response characteristic of ARDS, restoration of oxygen delivery after ECMO initiation may trigger bursts of reactive oxygen species, calcium overload, and endothelial injury, thereby exacerbating inflammation and causing multiple organ dysfunction. Clarifying these mechanisms is essential for developing individualized interventions against severe ECMO-related complications.
3. Establishing multidimensional ARDS subphenotypes provides the basis for precision awake ECMO therapy ARDS is highly heterogeneous with respect to etiology, clinical manifestations, pathophysiology, and molecular characteristics, resulting in variable responses to ECMO support. Conventional classification based on oxygenation or isolated physiological parameters fails to capture the complex biological and immunological evolution of the disease. Our group previously identified hyperinflammatory and hypoinflammatory ARDS phenotypes using multidimensional clinical and biological data, but differences in ECMO responsiveness between these phenotypes have not been systematically investigated. Therefore, comprehensive characterization of ARDS biological heterogeneity and development of an integrated subphenotyping model incorporating clinical, physiological, imaging, and immune molecular features are required to identify patients most likely to benefit from awake ECMO.
4. Deciphering mechanisms of lung injury and repair is crucial for individualized mechanical ventilation strategies Inappropriate mechanical ventilation can exacerbate ventilator-induced lung injury and impair lung repair. Understanding the cellular and molecular mechanisms underlying lung injury and regeneration and clarifying the relationship between ventilatory parameters and tissue stress responses are fundamental to achieving personalized lung-protective ventilation. This project will integrate multimodal imaging, respiratory mechanics, and multi-omics data to characterize the dynamic processes governing lung injury and repair in ARDS, thereby establishing precision mechanical ventilation strategies to enhance lung protection and promote tissue recovery.

Perspectives and Expected Impact Focusing on the major challenges in the management of moderate-to-severe ARDS, this project will elucidate the mechanisms responsible for severe complications during ECMO support, establish a multidimensional phenotyping framework to identify patients most likely to benefit from awake ECMO, and decode the mechanisms of lung injury and repair to develop individualized ventilation strategies. Ultimately, this work will provide a comprehensive precision management framework for ECMO-supported ARDS patients, improve the standard of care for moderate-to-severe ARDS in China, and reduce disease-related mortality.

• Study Type: Observational
• Enrollment (Estimated): 1776

Contacts and Locations

• Study Contact: Name: yingzi Huang Yingzi，Huang; Phone Number: 18271428804; Email: yz_huang@126.com

Study Locations

• China
  • Changchun, China
    • Not yet recruiting
    • The Second Hospital of Jilin University
  • Chenzhou, China
    • Recruiting
    • The First People's Hospital of Chenzhou
    • Contact: Feng Yang
  • Dalian, China
    • Not yet recruiting
    • The Second Affiliated Hospital of Dalian Medical University
  • Guangzhou, China
    • Recruiting
    • The First Affiliated Hospital of Guangzhou Medical University
    • Contact: Yan Wang; Phone Number: 18026020316
  • Hangzhou, China
    • Not yet recruiting
    • Hangzhou First People's Hospital, Westlake University School of Medicine
  • Ha’erbin, China
    • Not yet recruiting
    • The First Affiliated Hospital of Harbin Medical University
  • Ha’erbin, China
    • Recruiting
    • The Second Affiliated Hospital of Harbin Medical University
    • Contact: Yue Li; Phone Number: 0451-86605052; Email: liyuevickey@126.com
  • Huai'an, China
    • Not yet recruiting
    • Huai'an First People's Hospital
    • Contact: Peng Zhang
  • Kunshan, China
    • Not yet recruiting
    • Kunshan First People's Hospital
  • Lanzhou, China
    • Not yet recruiting
    • The First Hospital of Lanzhou University
  • Lianyungang, China
    • Not yet recruiting
    • The First People's Hospital of Lianyungang
  • Liuzhou, China
    • Recruiting
    • Liuzhou People's Hospital
    • Contact: Wenfang Jiang
  • Naning, China
    • Not yet recruiting
    • People's Hospital of Guangxi Zhuang Autonomous Region
    • Contact: Hangchun Wen
  • Nanjing, China
    • Not yet recruiting
    • Jiangsu Province Hospital
  • Nanjing, China
    • Recruiting
    • Nanjing Drum Tower Hospital
    • Contact: Danjiang Dong; Phone Number: 13605164240; Email: dongdanjiang@sina.com
  • Nanning, China
    • Not yet recruiting
    • The First Affiliated Hospital of Guangxi Medical University
  • Nanning, China
    • Not yet recruiting
    • The Second Affiliated Hospital of Guangxi Medical University
  • Nantong, China
    • Not yet recruiting
    • Affiliated Hospital of Nantong University
    • Contact: Chenliang Sun
  • Ningxiang, China
    • Not yet recruiting
    • General Hospital of Ningxia Medical University
  • Quzhou, China
    • Recruiting
    • Quzhou People's Hospital
  • Sichuan, China
    • Not yet recruiting
    • West China Tianfu Hospital, Sichuan University
  • Suining, China
    • Not yet recruiting
    • Suining Central Hospital
  • Suzhou, China
    • Not yet recruiting
    • The First Affiliated Hospital of Soochow University
  • Wuxi, China
    • Recruiting
    • Wuxi People's Hospital
    • Contact: Hongyang Xu; Phone Number: 13706180910; Email: 940216583@qq.com
  • Xi'an, China
    • Recruiting
    • The Second Affiliated Hospital of Xi'an Jiaotong University
    • Contact: Jing Geng; Phone Number: 18020766810; Email: jgeng18@xjtu.edu.cn
  • Xiamen, China
    • Not yet recruiting
    • The First Affiliated Hospital of Xiamen University
  • Xining, China
    • Not yet recruiting
    • Affiliated Hospital of Qinghai University
  • Xinyang, China
    • Not yet recruiting
    • Xinyang Central Hospital
  • Xuzhou, China
    • Not yet recruiting
    • Affiliated Hospital of Xuzhou Medical University
  • Yangzhou, China
    • Not yet recruiting
    • Subei People's Hospital
  • Zhengzhou, China
    • Recruiting
    • Henan Provincial People's Hospital
    • Contact: Huanzhang Shao; Phone Number: 18538297681
  • Zhengzhou, China
    • Not yet recruiting
    • The First Affiliated Hospital of Zhengzhou University
  • Zhongshan, China
    • Recruiting
    • Zhongshan Hospital of Traditional Chinese Medicine
    • Contact: min Nie
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Recruiting
      • Beijing Anzhen Hospital, Capital Medical University
      • Contact: Zhongtao Du; Phone Number: 18610846901; Email: zhongtaodu@126.com
  • Fujian
    • Fuzhou, Fujian, China
      • Recruiting
      • Fujian provincial hospital
      • Contact: xiuling shang; Phone Number: 13763895158; Email: zksxling@163.com
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Recruiting
      • Zhongda Hospital, Southeast University
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Qilu Hospital of Shandong University
      • Contact: Hao Wang; Phone Number: 18560081013; Email: wanghao34@126.com
  • Sichuan
    • Chengdu, Sichuan, China
      • Recruiting
      • Sichuan Provincial People's Hospital
      • Contact: Hongli He; Phone Number: 17744339836; Email: hhl0408@163.com
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • The Second Affiliated Hospital, Zhejiang University School of Medicine
      • Contact: Cuiping Xie; Phone Number: 18757156046

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of adult patients diagnosed with moderate-to-severe Acute Respiratory Distress Syndrome (ARDS) who are admitted to the Intensive Care Units (ICUs) of participating tertiary hospitals. This cohort includes patients requiring advanced respiratory support, specifically focusing on those managed with or without Extracorporeal Membrane Oxygenation (ECMO) based on clinical indications.

Description

Inclusion Criteria:

• 1.Age ≥ 18 years 2.Meet the global new definition of moderate-to-severe Acute Respiratory Distress Syndrome (ARDS).

Exclusion Criteria:

- 1.Patients with a prior tracheostomy. 2.Patients who have received a lung transplant or initiated VV-ECMO support as a bridge to lung transplantation.

3.Patients with comorbid cardiogenic shock requiring VA-ECMO or VAV-ECMO support.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
ECMO Supported Group; Moderate-to-severe ARDS patients who receive Extracorporeal Membrane Oxygenation (ECMO) support as part of their clinical management.
Non-ECMO Control Group; Moderate-to-severe ARDS patients who receive standard-of-care mechanical ventilation and medical management without Extracorporeal Membrane Oxygenation (ECMO) support.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day Mortality	The proportion of participants in each group (ECMO vs. Non-ECMO) who die from any cause within 90 days after enrollment. This will be used to evaluate the survival benefit associated with the precision ECMO salvage system compared to conventional treatment.	Up to 90 days after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU Mortality	The proportion of participants who die during the ICU stay will be compared between the pre-implementation usual care group and the post-implementation ECMO management pathway group.	From ICU admission to ICU discharge or death, assessed up to 90 days after ECMO initiation
ICU Length of Stay	ICU length of stay is defined as the number of days from ICU admission to ICU discharge or death.	From ICU admission to ICU discharge, assessed up to 90 days after ECMO initiation
Respiratory Support at ICU Discharge	Respiratory support status at ICU discharge will be recorded, including tracheostomy, invasive mechanical ventilation, noninvasive ventilation or high-flow nasal cannula, conventional oxygen therapy, or no oxygen therapy.	At ICU discharge, assessed up to 90 days after ECMO initiation
Hospital Mortality	The proportion of participants who die during hospitalization will be compared between the pre-implementation usual care group and the post-implementation ECMO management pathway group.	From hospital admission to hospital discharge or death, assessed up to 90 days after ECMO initiation
Hospital Length of Stay	Hospital length of stay is defined as the number of days from hospital admission to hospital discharge or death.	From hospital admission to hospital discharge, assessed up to 90 days after ECMO initiation
Respiratory Support at Hospital Discharge	Respiratory support status at hospital discharge will be recorded, including tracheostomy, invasive mechanical ventilation, noninvasive ventilation or high-flow nasal cannula, conventional oxygen therapy, or no oxygen therapy.	At hospital discharge, assessed up to 90 days after ECMO initiation
Successful Liberation From Mechanical Ventilation	Successful liberation from mechanical ventilation is defined as survival without reintubation or death within 7 days after extubation in patients without tracheostomy, or survival without reconnection to mechanical ventilation or death within 7 days after discontinuation of ventilatory support in patients with tracheostomy.	From initiation of invasive mechanical ventilation to 7 days after liberation from mechanical ventilation, assessed up to hospital discharge
28-Day All-Cause Mortality	The proportion of participants who die from any cause within 28 days after ECMO initiation will be compared between the pre-implementation usual care group and the post-implementation ECMO management pathway group.	From enrollment to 28 days after enrollment.
Bleeding complications during ECMO support	Bleeding complications during ECMO support will be recorded and classified as major or minor bleeding. Major bleeding is defined as life-threatening bleeding, bleeding requiring surgical intervention, or transfusion of ≥2 units of red blood cells within 24 hours due to active bleeding. Minor bleeding is defined as persistent oozing that does not meet the criteria for major bleeding.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Thrombotic complications during ECMO support	Thrombotic complications will include cerebral infarction, pulmonary embolism, venous thrombosis, ECMO circuit thrombosis, and oxygenator thrombosis. ECMO circuit thrombosis is defined as thrombosis requiring replacement of the circuit or any circuit component.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Infectious complications during ECMO support	Infectious complications will be recorded according to infection site, including bloodstream infection, respiratory tract infection, ventilator-associated pneumonia, surgical site infection, catheter-related infection, urinary tract infection, abdominal infection, skin and soft tissue infection, or other infections. The causative pathogen will be recorded when available.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Hemolysis during ECMO support	Hemolysis is defined as plasma-free hemoglobin greater than 50 mg/dL during ECMO support.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Cannulation-related complications during ECMO support	Cannulation-related complications will include vascular injury, cannulation-site bleeding requiring surgical intervention, retroperitoneal bleeding, pneumothorax, cardiac perforation, cardiac tamponade, and limb ischemia.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Acute kidney injury during ECMO support	Acute kidney injury will be defined and staged according to KDIGO criteria. The need for continuous renal replacement therapy will also be recorded.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.
Oxygenator replacement during ECMO support	Oxygenator replacement is defined as replacement of the ECMO oxygenator during ECMO support. The date and time of replacement will be recorded.	From ECMO initiation to ECMO discontinuation, ICU discharge, or day 90, whichever occurs first.

Collaborators and Investigators

• Sponsor: Southeast University, China

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): February 1, 2030

Study Registration Dates

• First Submitted: July 21, 2026
• First Submitted That Met QC Criteria: July 21, 2026
• First Posted (Actual): July 27, 2026

Study Record Updates

• Last Update Posted (Actual): July 27, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ARDS; ECMO; Acute Respiratory Distress Syndrome; Extracorporeal Membrane Oxygenation; Immune Phenotype; Lung-protective Ventilation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Respiratory Distress Syndrome
• Other Study ID Numbers: 2026ZDSYLL080-P01; 2026ZD0555500 (Other Grant/Funding Number: National Key R&D Program of China)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No