Correlation of Memory CD8+ T Cells With Sepsis Severity and Mortality: a Single-center, Unblinded, Prospective, Non-interventional, Observational Study

Study Overview
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Brief Summary
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Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Severe sepsis is the most common cause of death among critically ill patients in non-coronary intensive care units (ICU). Sustained excessive inflammation and immune dysfunction have been confirmed to play a key role in organ damage and early death of sepsis patients. Therefore, it is important to reduce excessive inflammatory response mediated by immune cells and pro-inflammatory cytokines in the acute phase of sepsis. Single-cell RNA sequencing performed on both septic patients and mice suggest that changes in Tcm (CD3+ CD8+ CD44+ CD127+ CD62L+) and Tem (CD3+ CD8+ CD44+ CD127+ CD62L -) in the acute phase of sepsis may play an important role in sepsis. In addition, animal researches showed that Tcm and Tem decreased decreased continuously at 24, 48 and 72h after cecal ligation and perforation (CLP) in mice, and the adoptive transfer of Tcm , sorting from spleen of mice 24h after CLP , but not Tem improved 7-day survival rate of sepsis mice. This observational study is aimed to investigate the quantity and proliferation of Tcm and Tem in the acute phase of sepsis and their correlation with severity level and mortality of septic patients in ICU.

Official Title
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Correlation of Memory CD8+ T Cells With Sepsis Severity and Mortality: a Single-center, Unblinded, Prospective, Non-interventional, Observational Study

Conditions
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Sepsis, Inflammatory Response

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-60 years old without restriction of gender, race, religion, creed or nationality; No sedative drugs with elimination half-life were used before inclusion in the study; Patients and/or their family members know and agree to participate in the trial. Exclusion Criteria: History of solid organ or bone marrow transplantation; Diseases that may affect immune-related indicators, such as autoimmune diseases such as rheumatoid arthritis and SLE, or hematological malignancies such as leukemia and lymphoma; Have received radiotherapy or chemotherapy within the past 30 days, or have received immunosuppressive drugs (tripterygium, mycophenolate, cyclophosphamide, FK506, etc); Pregnancy or lactation; Chronic nephrosis; Severe chronic liver disease (child-Pugh: Grade C); alcohol or opioid dependence, mental illness, or severe cognitive impairment; Patients and/or their family members refuse to participate in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| septic patients<br>patients with sepsis defined based on Sepsis 3.0 criteria within 24 hours after admission | |
| non-septic patients<br>patients without sepsis defined based on Sepsis 3.0 criteria within 24 hours after admission | |
| healthy control group<br>healthy adults | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute number of CD8+T subsets in the peripheral blood (0 hour) | CD3+ CD8+ CCR7+ CD127high CD62L+ CD27high CD45RA- cells，and CD3+ CD8+ CCR7- CD127- CD62L- CD27low CD45RA- cells | 0 hour after study inclusion | 
| Absolute number of CD8+T subsets in the peripheral blood (24 hours) | CD3+ CD8+ CCR7+ CD127high CD62L+ CD27high CD45RA- cells，and CD3+ CD8+ CCR7- CD127- CD62L- CD27low CD45RA- cells | 24 hours after study inclusion | 
| Absolute number of CD8+T subsets in the peripheral blood (48 hours) | CD3+ CD8+ CCR7+ CD127high CD62L+ CD27high CD45RA- cells，and CD3+ CD8+ CCR7- CD127- CD62L- CD27low CD45RA- cells | 48 hours after study inclusion | 
| Absolute number of CD8+T subsets in the peripheral blood (72 hours) | CD3+ CD8+ CCR7+ CD127high CD62L+ CD27high CD45RA- cells，and CD3+ CD8+ CCR7- CD127- CD62L- CD27low CD45RA- cells | 72 hours after study inclusion | 
| proliferation of CD8+T subsets in the peripheral blood (0 hour) | expression of Ki67 in Tcm and Tem | 0 hour after study inclusion | 
| proliferation of CD8+T subsets in the peripheral blood (24 hours) | expression of Ki67 in Tcm and Tem | 24 hours after study inclusion | 
| proliferation of CD8+T subsets in the peripheral blood (48 hours) | expression of Ki67 in Tcm and Tem | 48 hours after study inclusion | 
| proliferation of CD8+T subsets in the peripheral blood (72 hours) | expression of Ki67 in Tcm and Tem | 72 hours after study inclusion | 
| ICU length of stay | Length of stay in the ICU | up to 4 weeks | 
| PD-1 expression of CD8+T subsets in the peripheral blood (24 hours) | expression of PD-1 in Tcm and Tem | 24 hours after study inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mechanical ventilation time after inclusion | Patients requiring mechanical ventilation after study inclusion | up to 4 weeks | 
| Total hospital length of stay | Total length of hospital stay | up to 4 weeks | 
| In-hospital mortality | Mortality rates for the entire period of hospitalization | up to 4 weeks | 
| 90-day readmission rate | Percentage of readmission to hospital within 90 days of study inclusion | up to 4 weeks | 
| Infection complications | Pulmonary infection, urinary tract infection, bloodstream infections, etc | up to 4 weeks | 
| Acute physiology and chronic health evaluation (APACHE) Ⅱ score | 0-67, higher scores correspond to more severe disease and a higher risk of death | 0h after study inclusion | 
| Acute physiology and chronic health evaluation (APACHE) Ⅱ score | 0-67, higher scores correspond to more severe disease and a higher risk of death | 24 hours after study inclusion | 
| Acute physiology and chronic health evaluation (APACHE) Ⅱ score | 0-67, higher scores correspond to more severe disease and a higher risk of death | 48 hours after study inclusion | 
| Acute physiology and chronic health evaluation (APACHE) Ⅱ score | 0-67, higher scores correspond to more severe disease and a higher risk of death | 72 hours after study inclusion | 
| Sequential organ failure assessment (SOFA) score | 0-43, higher scores correspond to more severe sepsis | 0 hour after study inclusion | 
| Sequential organ failure assessment (SOFA) score | 0-43, higher scores correspond to more severe sepsis | 24 hours after study inclusion | 
| Sequential organ failure assessment (SOFA) score | 0-43, higher scores correspond to more severe sepsis | 48 hours after study inclusion | 
| Sequential organ failure assessment (SOFA) score | 0-43, higher scores correspond to more severe sepsis | 72 hours after study inclusion | 
| Plasma cytokine levels | IL-2、IL-4、IL-6、IL-10、IL-17A、IFN-γ、TNF-α | 0 hour after study inclusion | 
| Plasma cytokine levels | IL-2、IL-4、IL-6、IL-10、IL-17A、IFN-γ、TNF-α | 24 hours after study inclusion | 
| Plasma cytokine levels | IL-2、IL-4、IL-6、IL-10、IL-17A、IFN-γ、TNF-α | 48 hours after study inclusion | 
| Plasma cytokine levels | IL-2、IL-4、IL-6、IL-10、IL-17A、IFN-γ、TNF-α | 72 hours after study inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, CD8+ T cell, central memory CD8+ T cell, inflammatory response