Immunity in Critical Sepsis

Condition(s) studied

Investigational drug(s) / intervention(s)

Individualized anti-infective therapy: Antimicrobial agents (e.g., broad-spectrum or targeted antibiotics, antifungals) selected and adjusted by the attending physician based on suspected/confirmed infection source, culture and susceptibility results, and institutional antimicrobial stewardship protocols.

Individualized immunomodulatory therapy: Immunomodulatory agents (e.g., corticosteroids, intravenous immunoglobulin) administered at the discretion of the attending physician according to the patient's immune/inflammatory status and relevant clinical guidelines.

Individualized organ function support therapy: Organ support measures (e.g., mechanical ventilation, continuous renal replacement therapy, vasoactive agents) initiated and titrated by the treating team based on the patient's evolving organ function status.

Standardized ICU nursing care strategies: Nursing care measures (e.g., protocolized sedation/analgesia management, glycemic control, pressure injury prevention, early mobilization) delivered according to unit-based standardized nursing protocols.

Study summary

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, and remains the leading cause of death in critical care medicine worldwide. According to the 2024 Global Burden of Disease data, there are 48.9 million new cases and 11 million deaths annually worldwide, with 11 million deaths accounting for 19.7% of all global deaths. In China, the incidence of sepsis continues to rise due to population aging, increased invasive procedures, overuse of antimicrobials, the prevalence of multidrug-resistant organisms, and a growing number of patients with chronic diseases. Regional studies indicate that the incidence of sepsis in Chinese ICUs ranges from 15% to 30%, with mortality rates as high as 40% to 60%-far exceeding those in developed countries. Among critically ill patients admitted to the ICU-such as those with severe trauma, major surgery, acute respiratory distress syndrome, severe pancreatitis, and advanced malignancies-hospital-acquired infections leading to secondary sepsis represent the most critical trigger for clinical deterioration, multiple organ dysfunction syndrome (MODS), and death. This creates a vicious cascade of "primary disease exacerbation → nosocomial infection → sepsis → MODS → death", resulting in skyrocketing costs, prolonged hospital stays, and heavy burdens on families and society.To address this challenge, this project aims to: (1) establish the largest and internationally leading multimodal dataset for severe sepsis in China, covering 19 tertiary ICUs nationwide over a 5-year period, with 5,300 critically ill patients including 800 sepsis cases, integrating clinical data, immunological indicators, biomarkers, microbiological data, imaging, longitudinal biospecimens, and long-term follow-up information into a standardized, shareable, and sustainable national sepsis database; (2) systematically elucidate the three core pathophysiological mechanisms of severe sepsis-identifying risk factors, pathogen profiles, antimicrobial resistance patterns, and early warning indicators; revealing the dynamic dysregulation patterns of cellular immunity, humoral immunity, and innate immunity to establish immunophenotyping standards; and clarifying the risk factors, mechanisms, and subtype characteristics of multiple organ injury; (3) foster interdisciplinary collaboration between medical and engineering sciences to develop a series of precision diagnostic and therapeutic tools, including AI-assisted early infection warning systems, rapid immunotyping assays, multi-organ injury prediction models, and individualized prognostic calculators for real-time, accurate, and non-invasive bedside assessment; (4) establish a comprehensive precision management system for sepsis, forming an integrated "prevention-early warning-diagnosis-immunotyping-stratified treatment-prognostic evaluation-rehabilitation" care pathway; (5) drive clinical translation to improve patient outcomes, aiming to reduce ICU sepsis incidence, mortality, and healthcare costs, while improving long-term quality of life, cognitive function, and psychological status of survivors and reducing readmission rates; and (6) build a national-level sepsis research platform and cultivate talent by establishing a nationwide collaborative research network, and training professionals with integrated clinical-research-translational competencies.

Eligibility

Primary outcome measure(s)

• Annual incidence of sepsis in ICU — 90 days after enrollment.
  Number of new sepsis cases (diagnosed by Sepsis-3 criteria) per 1,000 ICU admissions (or per 1,000 patient-days).
• Prevalence of sepsis in ICU — 90 days after enrollment
  Percentage of ICU admissions meeting Sepsis-3 criteria for sepsis during the study period.
• Distribution of infection site (lung/abdominal/bloodstream/urinary tract) — 90 days after enrollment
  Percentage of patients with infection originating from the lung, abdomen, bloodstream, or urinary tract, respectively.
• Distribution of infection type (community-acquired/hospital-acquired/secondary) — 90 days after enrollment
  Percentage of patients with community-acquired, hospital-acquired, or secondary infection, respectively.
• Pathogen distribution (Gram-negative/Gram-positive/fungal) — 90 days after enrollment
  Percentage of microbiological isolates classified as Gram-negative bacteria, Gram-positive bacteria, or fungi.
• Antimicrobial resistance rate (CRE/CRAB/MRSA) — 90 days after enrollment
  Percentage of isolates identified as carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), or methicillin-resistant Staphylococcus aureus (MRSA).
• ICU length of stay — Through ICU discharge, up to 90 days
  Number of days from ICU admission to ICU discharge.
• Duration of mechanical ventilation — Through 90 days
  Number of days on invasive mechanical ventilation.
• Duration of vasoactive agent use — Through 90 days
  Number of days on any vasoactive agent (e.g., norepinephrine, vasopressin, dobutamine, epinephrine).
• Duration of renal replacement therapy — Through 90 days
  Number of days receiving renal replacement therapy (continuous or intermittent).
• Daily ICU cost — Through ICU discharge, up to 90 days
  Average direct cost of ICU care per patient per day, in Chinese Yuan (CNY).
• Total hospitalization cost — Through hospital discharge, up to 90 days
  Total direct cost of hospital care per patient, in Chinese Yuan (CNY), from hospital admission to discharge.
• ICU mortality — Through ICU discharge, an average of 28 days
  Percentage of patients who die prior to ICU discharge.
• In-hospital mortality — Through hospital discharge, up to 90 days
  Percentage of patients who die prior to hospital discharge.
• 28-day all-cause mortality — 28 days after enrollment
  Percentage of patients who die from any cause within 28 days of enrollment.
• 90-day all-cause mortality — 90 days after enrollment
  Percentage of patients who die from any cause within 90 days of enrollment.
• Discriminative Performance of the Infection Risk-Prediction Model — 90 days after enrollment
  Area under the receiver operating characteristic curve (AUC/C-statistic) of the multivariable model predicting infection occurrence, developed from patient, disease, and treatment-related candidate predictors using Cox regression, LASSO, and propensity score analysis.
• Sensitivity and Specificity of the Infection Risk-Prediction Score — 90 days after enrollment
  Sensitivity and specificity (%) of the infection risk-prediction score at its optimal cutoff value, determined by the Youden index.
• Hand Hygiene Compliance Rate — 90 days after enrollment
  Percentage of observed hand hygiene opportunities performed correctly, per WHO Five Moments guidance.
• Catheter Care Bundle Compliance Rate — 90 days after enrollment
  Percentage of eligible patient-days with full compliance to central line and urinary catheter care bundle elements.
• Diagnostic Accuracy of Procalcitonin (PCT) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Procalcitonin (PCT) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of C-Reactive Protein (CRP) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum C-Reactive Protein (CRP) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Presepsin — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Presepsin concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Soluble Urokinase Plasminogen Activator Receptor (suPAR) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Soluble Urokinase Plasminogen Activator Receptor (suPAR) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Interleukin-6 (IL-6) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Interleukin-6 (IL-6) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Interleukin-8 (IL-8) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Interleukin-8 (IL-8) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• Diagnostic Accuracy of Pro-Adrenomedullin (Pro-ADM) — At enrollment (baseline), and at 72 hours after enrollment
  Area under the receiver operating characteristic curve (AUC) of serum Pro-Adrenomedullin (Pro-ADM) concentration for differentiating infection from non-infection and sepsis from non-sepsis, with corresponding sensitivity, specificity, and optimal cutoff value.
• AUC of Combined Multi-Parameter Early-Warning Model — From 24 hours before to 72 hours after infection onset
  Area under the receiver operating characteristic curve of a composite model integrating vital signs (temperature, heart rate, respiratory rate, blood pressure, SpO2), laboratory values, and the biomarkers listed above for early warning of infection.
• Diagnostic Accuracy of AI-Based Automated Warning System — From 24 hours before to 72 hours after infection onset
  Accuracy (%) of a machine-learning-based (random forest, XGBoost, deep learning) automated warning system using electronic medical record data to predict infection onset.
• Lead Time of AI-Based Warning System — Up to 24 hours before clinical diagnosis
  Time interval, in hours, between the AI system alert and the subsequent clinical diagnosis of infection.
• Time to First Effective Antibiotic Administration — Within 6 hours of infection onset
  Time, in hours, from infection recognition to administration of the first in vitro active antibiotic.
• Rate of Appropriate Empirical Antibiotic Therapy — 90 days after enrollment
  Percentage of patients receiving empirical antibiotic therapy subsequently confirmed to be active against the identified pathogen(s).
• Rate of Antibiotic Coverage of Resistant Organisms — 90 days after enrollment
  Percentage of patients with identified multidrug-resistant organisms whose empirical antibiotic regimen provided adequate in vitro coverage.
• Antibiotic De-escalation Rate — 90 days after enrollment
  Percentage of patients whose antibiotic regimen was narrowed (de-escalated) based on culture and susceptibility results.
• Duration of Antibiotic Therapy — 90 days after enrollment
  Number of days of antibiotic treatment administered for the index infection.
• Time to Source Control — 90 days after enrollment
  Time, in hours, from infection recognition to definitive source-control intervention (drainage, debridement, catheter removal, or surgery).
• Compliance Rate with SSC Bundle Elements — 90 days after enrollment
  Percentage of eligible patients/bundle elements for which Surviving Sepsis Campaign bundle elements were completed within the recommended time window.
• Total hospital length of stay — Through hospital discharge, up to 90 days
  Number of days from hospital admission to hospital discharge.

Trial sites (1)

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