Multicenter Prospective Cohort of Sepsis and ARDS in China

Background:

Sepsis and acute respiratory distress syndrome (ARDS) are common life-threatening conditions in critically ill patients and are associated with high mortality and long-term functional impairment. Sepsis is an important cause of ARDS, and the two conditions frequently overlap. Both syndromes show substantial heterogeneity in clinical presentation, organ dysfunction, inflammatory and immune responses, and outcomes. Better characterization of this heterogeneity may improve disease classification, risk assessment, and prognostic prediction.

Study Design and Data Collection:

This is a prospective, multicenter, observational cohort study enrolling 6,000 adults with sepsis and/or ARDS at multiple hospitals in China.

Clinical data collected during hospitalization include demographic characteristics, comorbidities, disease severity, laboratory findings, organ function, treatments, organ support, complications, and clinical outcomes. Longitudinal data are collected to assess changes in disease status and organ function over time. Peripheral blood and other available biological samples are collected at predefined time points and stored for subsequent biomarker and multi-omics studies, forming a multicenter clinical cohort and biobank.

Biological and Phenotypic Analyses:

Clinical data are integrated with inflammatory and immune markers and multi-omics profiles to investigate the clinical and biological heterogeneity of sepsis and ARDS. Analyses focus on identifying relevant phenotypes and biological subgroups and exploring biomarkers associated with disease severity, organ dysfunction, treatment response, and mortality. Clinical and biological data will also be used to develop and evaluate models for risk stratification and outcome prediction.

Outcomes and Long-term Follow-up:

The primary outcome is all-cause mortality at 90 days. Secondary outcomes include 28-day mortality, in-hospital mortality, ventilator-free days alive through day 28, organ support-free days alive through day 28, and other clinically relevant outcomes during hospitalization.

Survivors of ARDS are followed at 1, 6, 12, and 24 months after hospital discharge. Follow-up assessments include survival status, rehospitalization, pulmonary function, respiratory muscle strength, six-minute walk distance, chest computed tomography, inflammatory markers, quality of life, and psychological health.

The overall objective is to establish a large, multicenter clinical cohort and biobank for sepsis and ARDS in China, characterize their clinical and biological heterogeneity, identify clinically relevant phenotypes and biomarkers, and develop models for risk stratification and outcome prediction.

• Surveys (Other): Participants will complete the EuroQol-5 Dimension-5 Level (EQ-5D-5L) quality of life assessment in person. Assessments will be conducted at 1, 6, 12, and 24 month(s) following hospitalization. For participants who do not attend in-person follow-up visits, surveys will be conducted via email, text message, or phone.
• 6-Minute Walk Test (Other): The patient sits at rest while baseline vital signs and exertion scores are taken.The patient then walks back and forth along a flat, marked corridor at their own pace for 6 minutes, followed immediately by repeating vital signs and exertion measurements at the finish. At visits 1, 6, 12 and 24 month(s) following hospitalization.
• Blood collection (Other): Venous blood is collected via direct needle stick into a vein. Arterial blood is collected by a direct needle puncture into an artery (typically the radial artery) using a heparinized syringe. At visits 1, 6, 12 and 24 month(s) following hospitalization.
• Pulmonary & Respiratory Muscle Function Testing (Diagnostic test): The patient sits upright, wears a nose clip, and breathes through a mouthpiece connected to the testing device, performing guided forced breathing and single-breath hold maneuvers. Respiratory muscle strength is measured by having the patient inhale and exhale forcefully against a temporarily blocked mouthpiece. At visits 1, 6, 12 and 24 month(s) following hospitalization.
• CT Scan (Radiation): The patient lies flat on the CT scanner bed and follows automated breathing prompts to hold their breath for a few seconds while images are acquired. Additional body regions may be scanned if clinically indicated. At visits 1, 6, 12 and 24 month(s) following hospitalization.
• Blood Collection (Other): Blood samples will be collected on Day 1, Day 3, and Day 7. Day 1 samples will be collected within 48 hours after ARDS diagnosis. Day 7 samples can be collected between Day 6 and Day 8. Plasma、 PBMCs and Serum will be collected in each corresponding tube and will be separated and stored for later testing. Citrate plasma will be collected in sodium citrate tubes and then will be centrifuged within 1 hour, and the plasma will be stored at -80°C for later testing.
• Bronchoalveolar Lavage Fluid (Other): Bronchoalveolar lavage fluid (BALF) will be collected on Day 1, Day 3, and Day 7 and stored for later testing.
• HME filter samples (Other): HME filter samples will be collected on Day 1, Day 3, and Day 7 and stored for later testing. If the patient is extubated, dies, or leaves the hospital before the planned BALF or HME sample collection, the last sample will be collected before or on the same day.

Primary outcomes

• All cause mortality [28-day mortality]
• EuroQol-5 Dimension-5 Level (EQ-5D-5L) quality of life assessment [1, 6, 12, 24 month(s)]: The EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire assesses health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, participants select one of five response levels, ranging from no problems to extreme problems or inability to perform the activity; the distribution of response levels within each dimension will be summarized as percentages. Responses across the five dimensions will also be converted to an EQ-5D-5L index score using a prespecified value set, with higher index scores indicating better health-related quality of life. Participants will additionally rate their overall health using the EQ Visual Analogue Scale (EQ VAS), ranging from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

Secondary outcomes

• 60-day all-cause mortality [60 days after ARDS diagnosis]: Death from any cause within 60 days after ARDS diagnosis
• 90-day all-cause mortality [90 days after ARDS diagnosis]: Death from any cause within 90 days after ARDS diagnosis
• ICU mortality [From ICU admission through ICU discharge, up to 90 days]: Death occurring during the ICU stay
• In-hospital mortality [From hospital admission through hospital discharge, up to 90 days]: Death occurring during the index hospitalization

Other outcomes

• Ventilator-Free Days (VFD) [28 days after ARDS diagnosis]
• Extracorporeal Membrane Oxygenation-Free Days (ECMO-free days) [28 days after ARDS diagnosis]
• Renal Replacement Therapy-Free Days [28 days after ARDS diagnosis]
• Lymphocyte Subsets （CD19+ B, CD3+ T, CD4+ Th, CD8+ Ts, CD4/CD8, CD16+CD56+ NK） [1, 6, 12, 24 month(s)]
• Inflammatory Cytokines Panel （TNF-alpha, IL-1beta, sIL-2R, IL-6, IL-8, IL-10） [1, 6, 12, 24 month(s)]
• KL-6 [1, 6, 12, 24 month(s)]: Mucin-like glycoprotein expressed by damaged regenerating type II alveolar epithelial cells
• D-Dimer [1, 6, 12, 24 month(s)]
• Renal Function Tests (BUN, Serum Creatinine, Uric Acid) [1, 6, 12, 24 month(s)]
• Lactate Dehydrogenase [1, 6, 12, 24 month(s)]
• Liver Function Tests (TBIL, DBIL, ALT, AST, Albumin) [1, 6, 12, 24 month(s)]
• C-Reactive Protein [1, 6, 12, 24 month(s)]
• Complete Blood Count Profile [1, 6, 12, 24 month(s)]: Complete blood count parameters will include white blood cell count and differential, hemoglobin concentration, and platelet count. Each parameter will be analyzed and reported separately using its corresponding unit of measurement.
• PaO2/FiO2 Ratio [1, 6, 12, 24 month(s)]: Oxygenation assessed by the ratio of arterial oxygen partial pressure to fraction of inspired oxygen
• Peripheral Oxygen Saturation (SpO2) Before and After the Six-Minute Walk Test (6MWT) [1, 6, 12, 24 month(s)]: Peripheral oxygen saturation (SpO2) will be measured at rest before and immediately after completion of the Six-Minute Walk Test (6MWT) and reported as a percentage.
• Heart Rate (HR) Before and After the Six-Minute Walk Test (6MWT) [1, 6, 12, 24 month(s)]: Heart rate (HR) will be measured at rest before and immediately after completion of the Six-Minute Walk Test (6MWT) and reported in beats per minute.
• Modified Borg Dyspnea Scale Score Before and After the Six-Minute Walk Test (6MWT) [1, 6, 12, 24 month(s)]: Perceived dyspnea will be assessed at rest before and immediately after completion of the Six-Minute Walk Test (6MWT) using the Modified Borg Dyspnea Scale. Scores range from 0 to 10, with higher scores indicating greater perceived breathlessness.
• Modified Borg Fatigue Scale Score Before and After the Six-Minute Walk Test (6MWT) [1, 6, 12, 24 month(s)]: Perceived fatigue will be assessed at rest before and immediately after completion of the Six-Minute Walk Test (6MWT) using the Modified Borg Fatigue Scale. Scores range from 0 to 10, with higher scores indicating greater perceived fatigue.
• Six-Minute Walk Distance (6MWD) [1, 6, 12, 24 month(s)]: Total distance covered on a flat surface in 6 minutes
• Maximal Expiratory Pressure (MEP) [1, 6, 12, 24 month(s)]: Measures the maximal positive pressure generated during exhalation
• Maximal Inspiratory Pressure (MIP) [1, 6, 12, 24 month(s)]: Maximum negative airway pressure generated during a forceful inspiratory effort against an occluded airway, used to assess inspiratory muscle strength.
• Diffusing Capacity of the Lung for Carbon Monoxide, Single-Breath % Predicted (DLCO-SB%) [1, 6, 12, 24 month(s)]: Evaluates gas transfer across the alveolar-capillary membrane into the blood
• Total Lung Capacity, Single-Breath % Predicted (TLC-SB%) [1, 6, 12, 24 month(s)]: Total gas volume in the lungs at maximal inspiration
• Residual Volume by Single-Breath Method, % Predicted (RV-SB%) [1, 6, 12, 24 month(s)]: Volume of air remaining in the lungs after maximal forced exhalation
• Functional Residual Capacity by Single-Breath Method, % Predicted (FRC-SB%) [1, 6, 12, 24 month(s)]: Volume of gas remaining in the lungs after a normal passive expiration, compared to predicted values
• Forced Expiratory Flow Between 25% and 75% of Forced Vital Capacity, % Predicted (FEF25%-75%) [1, 6, 12, 24 month(s)]: Mean forced expiratory flow during the mid-portion of FVC
• Forced Expiratory Flow at 75% of Forced Vital Capacity, % Predicted (FEF75%) [1, 6, 12, 24 month(s)]: Instantaneous flow rate at 75% of exhaled FVC
• FEF50% [1, 6, 12, 24 month(s)]: Instantaneous expiratory flow rate at 50% of exhaled FVC
• FEV1/FVC [1, 6, 12, 24 month(s)]: The absolute ratio of FEV1 to FVC
• FEV1/FVC% [1, 6, 12, 24 month(s)]: The measured FEV1/FVC ratio expressed as a percentage
• FEV1% [1, 6, 12, 24 month(s)]: The percentage of predicted volume exhaled during the first second of a forced exhalation
• FVC% [1, 6, 12, 24 month(s)]: The percentage of predicted total air volume exhaled forcefully after full inspiration.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥18 years.
2. Meets the diagnostic criteria for sepsis and/or acute respiratory distress syndrome (ARDS):

   Sepsis: Sepsis is defined according to the Sepsis-3 criteria as suspected or confirmed infection accompanied by acute organ dysfunction attributable to infection, operationalized as an increase in the Sequential Organ Failure Assessment (SOFA) score of ≥2 points from baseline.

   ARDS: ARDS is diagnosed according to the 2024 Global Definition of ARDS, including an acute predisposing condition or risk factor, acute onset or worsening of respiratory symptoms, bilateral pulmonary opacities on chest imaging or lung ultrasound not fully explained by pleural effusion, atelectasis, or pulmonary nodules, hypoxemia meeting the corresponding oxygenation criteria, and pulmonary edema not primarily attributable to cardiogenic causes or fluid overload.
3. Admitted to an ICU or other designated inpatient unit at a participating study center, including emergency or respiratory care units where appropriate.
4. Written informed consent is obtained from the participant or a legally authorized representative, or deferred consent is used when permitted by local ethical requirements.

Exclusion Criteria:

1. The acute clinical condition is primarily explained by an alternative diagnosis without sepsis or ARDS, such as isolated cardiogenic pulmonary edema or fluid overload without ARDS.
2. Terminal illness with an expected survival of <24 hours, or a decision for comfort measures only has been made before enrollment.
3. Informed consent cannot be obtained in accordance with applicable ethical requirements.
4. Previous enrollment in this cohort. Each participant may be enrolled only once; subsequent episodes of sepsis and/or ARDS may be recorded as clinical events but will not result in repeated enrollment.
5. Any other condition that, in the investigator's judgment, makes participation inappropriate.

Withdrawal and Loss to Follow-up:

1. Participant withdrawal: Participants or their legally authorized representatives may withdraw consent at any time. No new study-specific data will be collected after withdrawal. The use of previously collected data and stored biological samples will follow the participant's consent and applicable ethical requirements.
2. Investigator-initiated withdrawal: Participants may be withdrawn if subsequent review identifies a major protocol violation, duplicate enrollment, unreliable study data, or another condition that makes continued participation inappropriate.
3. Loss to follow-up: Participants who cannot be contacted after repeated attempts and for whom follow-up information cannot be obtained through other permitted sources will be considered lost to follow-up. Data collected before loss to follow-up may be retained and analyzed according to the statistical analysis plan.