Myeloid Bias in the Bone Marrow of Septic Patients and Its Correlation With Disease Severity and Prognosis: A Single-Center, Prospective Cohort Study

NCT07667153 | Not Yet Recruiting DMC

• 1 other identifier: ZJC202603
• Study Type: observational
• Target: 45
• Locations: 0 countries
• Sites: N/A

Brief Summary

Sepsis remains a leading cause of critical illness worldwide, yet the underlying mechanisms driving its profound and persistent immune dysfunction are incompletely understood. The bone marrow, as the birthplace of all immune cells, plays a central role in orchestrating systemic immune responses. Emerging evidence from animal models suggests that sepsis triggers emergency myeloid-biased hematopoiesis in the bone marrow, characterized by expansion of myeloid progenitors and myeloid-derived suppressor cells (MDSCs) at the expense of lymphoid and erythroid lineages. This bone marrow remodeling precedes peripheral immune alterations and may represent the initiating event of sepsis-induced immunosuppression. However, direct clinical evidence in humans is scarce. This prospective, single-center cohort study aims to systematically characterize bone marrow hematopoietic remodeling in patients with septic shock, compared to critically ill non-septic patients and healthy volunteers, and to determine whether the degree of myeloid lineage bias correlates with disease severity, immunosuppression, and adverse clinical outcomes. This study will enroll three cohorts. Bone marrow aspirates and peripheral blood samples will be collected at 48-72 hours post-enrollment for flow cytometric immunophenotyping of hematopoietic stem/progenitor cells, MDSC subsets, and PD-L1 expression, as well as cytokine profiling and exploratory single-cell transcriptomics. Rectal swabs will be collected synchronously for 16S rRNA sequencing and untargeted metabolomics to investigate the association between gut microbiota, microbial metabolites, and bone marrow myeloid skewing, testing the gut-bone marrow-immune axis hypothesis. Clinical severity (SOFA/APACHE II), secondary infections, and 90-day mortality will be assessed to evaluate prognostic value. By integrating bone marrow hematopoiesis, gut microbiome, and clinical outcomes, this study seeks to provide novel mechanistic insights into sepsis-induced immunoparalysis and identify potential biomarkers or therapeutic targets for immune restoration.

Conditions

Sepsis; Septic Shock

Keywords

Sepsis; Bone marrow; Myeloid bias; Prognosis

Outcome Measures

Primary Outcomes (13)

• Percentage and Absolute Count of Hematopoietic Stem Cells (HSCs) in Bone Marrow

  HSCs are defined as Lin- CD34⁺ CD38- CD90⁺ CD45RA- cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count per 10⁶ total bone marrow nucleated cells. Comparison is made between the sepsis-associated critical illness cohort and the two control groups (critically ill non-septic cohort and healthy cohort).

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Common Myeloid Progenitors (CMPs) in Bone Marrow

  CMPs are defined as Lin- CD34⁺ CD38⁺ CD123⁺ CD45RA- cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Granulocyte-Monocyte Progenitors (GMPs) in Bone Marrow

  GMPs are defined as Lin- CD34⁺ CD38⁺ CD123⁺ CD45RA⁺ cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. This is a core indicator of myeloid lineage expansion. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Megakaryocyte-Erythroid Progenitors (MEPs) in Bone Marrow

  MEPs are defined as Lin- CD34⁺ CD38⁺ CD123- CD45RA- cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. This indicator reflects erythroid/megakaryocytic lineage suppression. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Common Lymphoid Progenitors (CLPs) in Bone Marrow

  CLPs are defined as Lin- CD34⁺ CD38⁺ CD127⁺ cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. This indicator reflects lymphoid lineage suppression. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• GMP-to-CLP Ratio and Absolute Differential Count Index in Bone Marrow (Primary Composite Index)

  The primary composite index of myeloid lineage bias consists of two parallel metrics: (a) the GMP-to-CLP ratio, calculated as (percentage of GMPs)/(percentage of CLPs); and (b) the absolute differential index, calculated as (absolute count of GMPs)/(absolute count of CLPs). Both metrics quantify myeloid-versus-lymphoid lineage skewing. A higher value indicates greater myeloid bias. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of PMN-MDSCs in Bone Marrow

  Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are defined as CD45⁺ CD11b⁺ CD14- CD15⁺ CD33⁺ HLA-DR-/low cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of M-MDSCs in Bone Marrow

  Monocytic myeloid-derived suppressor cells (M-MDSCs) are defined as CD45⁺ CD11b⁺ CD14⁺ HLA-DR-/low CD15- cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• PD-L1 Expression Level and PD-L1⁺ Absolute Count on Bone Marrow MDSCs

  PD-L1 (programmed death-ligand 1) expression on both PMN-MDSCs and M-MDSCs is measured as three parallel metrics: (a) the percentage of PD-L1⁺ cells within each MDSC subset; (b) the median fluorescence intensity (MFI) of PD-L1 on these cells; and (c) the absolute count of PD-L1⁺ PMN-MDSCs and PD-L1⁺ M-MDSCs. These indicators reflect the immunosuppressive functional burden of MDSCs. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of T Cells in Bone Marrow

  T cells are defined as CD45⁺ CD56- CD3⁺ cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of NK Cells in Bone Marrow

  Natural killer (NK) cells are defined as CD45⁺ CD3- CD56⁺ cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Monocytes in Bone Marrow

  Monocytes are defined as CD45⁺ CD3- CD56- HLA-DR⁺ CD14⁺ CD15- cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

• Percentage and Absolute Count of Neutrophils in Bone Marrow

  Neutrophils are defined as CD45⁺ CD3- CD56- CD11b⁺ CD14- CD15⁺ cells. The outcome is measured as both (a) the percentage among total bone marrow nucleated cells, and (b) the absolute count. Comparison is made between the sepsis cohort and the two control groups.

  Between 48 and 72 hours after enrollment (preferably day 3)

Secondary Outcomes (13)

• Correlation Between Bone Marrow GMP-to-CLP Ratio (Percentage and Absolute) and SOFA score

  Baseline (bone marrow at 48-72 hours) and days 1, 3, 5, 7 (severity scores)

• Correlation Between Bone Marrow GMP-to-CLP Ratio (Percentage and Absolute) and APACHE II score

  Baseline (bone marrow at 48-72 hours) and days 1, 3, 5, 7 (severity scores)

• Association Between Bone Marrow Myeloid Lineage Bias (Percentages and Absolute Counts) and 90-Day Secondary Infection Rate

  From enrollment through 90-day follow-up

• Bone Marrow Myeloid Lineage Bias (Percentages and Absolute Counts) as Predictors of 90-Day All-Cause Mortality

  From enrollment through 90-day follow-up

• Association Between Bone Marrow Myeloid Lineage Bias (Percentages and Absolute Counts) and ICU / In-Hospital Mortality

  From enrollment through hospital discharge (up to 90 days)

Study Arms (3)

Sepsis-Associated Critical Illness Cohort

Patients admitted to the intensive care unit (ICU) with a confirmed or highly suspected infection and meeting the Sepsis-3 criteria (an acute change in Sequential Organ Failure Assessment \[SOFA\] score ≥ 2 points in the presence of infection).

Procedure: Bone marrow aspirate collection

Non-Septic Critical Illness Cohort

Critically ill patients admitted to the same ICU with an acute life-threatening condition that is not attributed to infection. Typical etiologies include severe trauma, major elective or emergency surgery (e.g., abdominal, or neurosurgical procedures), acute pancreatitis, or massive haemorrhage, all without any clinical or microbiological evidence of infection at enrolment.

Procedure: Bone marrow aspirate collection

Healthy Volunteer Control Cohort

Community-dwelling adults with no acute or chronic medical conditions that could affect haematopoiesis or immune function. They are recruited from the same geographical region and during the same calendar period to minimise seasonal and demographic biases.

Procedure: Bone marrow aspirate collection

Interventions

Bone marrow aspirate collection PROCEDURE

Bone marrow aspiration was performed at the posterior superior iliac spine under local anesthesia 24-48 hours after enrollment. Using a standard aspirate needle and strict aseptic technique, approximately 2-3 mL of bone marrow aspirate was collected.

Healthy Volunteer Control Cohort; Non-Septic Critical Illness Cohort; Sepsis-Associated Critical Illness Cohort

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This prospective single-centre study will enrol three independent cohorts: (1) adult ICU patients (18-80 years) with sepsis per Sepsis-3.0, admitted for 48-72 hours with an expected ICU stay ≥7 days; (2) adult ICU patients with non-infectious critical illnesses (e.g., severe pancreatitis, major trauma, post-major surgery, acute cerebrovascular events) who do not meet Sepsis-3.0 criteria; and (3) healthy community volunteers with no acute/chronic diseases and normal blood counts. All participants (or legally authorised representatives for incapacitated patients) must provide written informed consent, with re-consent obtained once patients regain capacity. Common exclusions include primary haematological disorders, active malignancy, immunosuppression, recent transfusion, severe chronic organ dysfunction, local contraindications to bone marrow puncture, pregnancy, and concurrent participation in other interventional trials.

You may qualify if:

• (1) Sepsis-Associated Critical Illness Cohort
• Age 18-80 years, both genders;
• Meets the Sepsis-3.0 criteria: confirmed or suspected infection with an acute increase in SOFA score of ≥2 points;
• Admitted to the intensive care unit (ICU) for 48-72 hours at the time of enrolment;
• Expected ICU length of stay ≥7 days;
• Written informed consent provided by the patient or their legally authorized representative.
• (2) Non-Septic Critical Illness Cohort
• Age 18-80 years, both genders;
• Admitted to the ICU for 48-72 hours with a diagnosis of non-infectious critical illness, including but not limited to: (a) severe acute pancreatitis; (b) major trauma (Injury Severity Score ≥16); (c) post-major surgery (e.g., cardiovascular surgery, hepatectomy); (d) acute cerebrovascular disease (ischaemic stroke, intracerebral haemorrhage); (e) other critical conditions requiring ICU support;
• Expected ICU length of stay ≥7 days;
• Written informed consent provided by the patient or their legally authorized representative.
• (3) Healthy Volunteer Control Cohort
• Age 18-80 years, both genders.
• No acute or chronic medical history; recent health check-up results are normal.
• Normal complete blood count: white blood cell count, haemoglobin, and platelet count within the normal reference ranges;

You may not qualify if:

• (1) Sepsis-Associated Critical Illness Cohort
• Haematological disorders: previous or current primary haematological diseases affecting bone marrow haematopoiesis, including leukaemia, myelodysplastic syndromes, aplastic anaemia, multiple myeloma, lymphoma, etc;
• Active malignancy or receipt of chemotherapy/radiotherapy within the past 3 years;
• Immunosuppressed state: (a) use of immunosuppressive agents within the past 3 months (including glucocorticoids ≥0.5 mg/kg/day for ≥2 weeks); (b) history of solid organ or haematopoietic stem cell transplantation; (c) HIV infection or AIDS; (d) congenital immunodeficiency;
• Blood transfusion or bone marrow transplantation within the past 3 months;
• Severe chronic organ dysfunction: (a) Child-Pugh Class C liver disease; (b) end-stage renal disease (eGFR \<30 mL/min) without regular dialysis;
• Abnormalities at the puncture site: infection, rash, trauma, or anatomical deformity at the posterior superior iliac spine;
• Pregnancy or breastfeeding;
• Moribund state with expected survival \<24 hours;
• Participation in another interventional clinical trial within 3 months before or at enrolment;
• Refusal to sign informed consent by the patient or legal representative.
• (2) Non-Septic Critical Illness Cohort
• Evidence of infection: confirmed or suspected active infection (including pneumonia, intra-abdominal infection, urinary tract infection, bloodstream infection, etc.) within 48 hours of ICU admission;
• (3) Healthy Volunteer Control Cohort
• History of infection within the past 1 month;

Sponsors & Collaborators

• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology: lead

MeSH Terms

Conditions

Sepsis; Shock, Septic

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Central Study Contacts

Zhang Jiancheng, MD, PhD

CONTACT

+8613554105815; zhjcheng1@126.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 90 Days
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: June 18, 2026
• First Posted: June 24, 2026
• Study Start: July 15, 2026
• Primary Completion (Estimated): June 15, 2027
• Study Completion (Estimated): December 30, 2027
• Last Updated: June 24, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share