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NCT Number: NCT07667153

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

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.

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Key information

Conditions

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

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Observational

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

  • Inclusion Criteria

(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;
  • Willing and able to provide written informed consent.
  • Exclusion Criteria

(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;
  • All other exclusion criteria listed for the Sepsis-Associated Critical Illness Cohort (items 1-10) apply.

(3) Healthy Volunteer Control Cohort

  • History of infection within the past 1 month;
  • Abnormalities at the puncture site: infection, rash, trauma, or anatomical deformity at the posterior superior iliac spine;
  • Pregnancy or breastfeeding.

Treatment and study plan

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.

Primary outcomes

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

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

    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).

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

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

    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.

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

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

    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.

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

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

    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.

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

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

    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.

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

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

    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.

  7. Percentage and Absolute Count of PMN-MDSCs in Bone Marrow

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

    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.

  8. Percentage and Absolute Count of M-MDSCs in Bone Marrow

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

    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.

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

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

    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.

  10. Percentage and Absolute Count of T Cells in Bone Marrow

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

    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.

  11. Percentage and Absolute Count of NK Cells in Bone Marrow

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

    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.

  12. Percentage and Absolute Count of Monocytes in Bone Marrow

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

    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.

  13. Percentage and Absolute Count of Neutrophils in Bone Marrow

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

    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.

Secondary outcomes

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

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

    Correlation between the baseline bone marrow GMP-to-CLP composite indices (both ratio based on percentages and ratio based on absolute counts) and SOFA score. SOFA score is calculated at enrollment and on days 1, 3, and 5. Correlation analyzed using Spearman correlation coefficients.

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

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

    Correlation between the baseline bone marrow GMP-to-CLP composite indices (both ratio based on percentages and ratio based on absolute counts) and APACHE II score. APACHE II score is calculated at enrollment and on days 1, 3, and 5. Correlation analyzed using Spearman correlation coefficients.

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

    Time frame: From enrollment through 90-day follow-up

    Evaluate whether the degree of baseline bone marrow myeloid lineage bias (measured by GMP-to-CLP ratio, percentage and absolute counts of PMN-MDSCs and M-MDSCs, and absolute count of PD-L1⁺ MDSCs) is independently associated with the occurrence of secondary infections within 90 days. Secondary infection is defined as a new infectious episode occurring ≥48 hours after enrollment, diagnosed by positive culture and/or clinical criteria requiring new antibiotic therapy. Logistic regression will be used, adjusting for baseline SOFA and APACHE II scores.

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

    Time frame: From enrollment through 90-day follow-up

    Evaluate the predictive value of baseline bone marrow cellular indices (GMP-to-CLP ratio, percentage and absolute counts of PMN-MDSCs and M-MDSCs, and absolute count of PD-L1⁺ MDSCs) for 90-day all-cause mortality. Survival analysis using Kaplan-Meier curves with Log-rank tests, and Cox proportional hazards regression calculating hazard ratios adjusted for age, SOFA score, and APACHE II score.

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

    Time frame: From enrollment through hospital discharge (up to 90 days)

    Evaluate the association between baseline bone marrow myeloid lineage bias indices (percentage and absolute counts of progenitor and MDSC subsets) and short-term mortality endpoints, including ICU mortality and in-hospital mortality. Logistic regression will be used to calculate odds ratios adjusted for baseline severity scores.

  6. Correlation Between Bone Marrow MDSC Absolute Counts and Peripheral Blood Lymphocyte Absolute Counts

    Time frame: Baseline (bone marrow and peripheral blood at 48-72 hours; peripheral blood also on days 1, 5, 7 for longitudinal correlation)

    Assess the correlation between bone marrow PMN-MDSC and M-MDSC frequencies and absolute counts (along with their PD-L1 expression) and peripheral blood lymphocyte subset absolute counts per μL (and percentages). Peripheral blood immunophenotyping includes: CD3⁺ total T cells, CD3⁺CD4⁺ helper T cells, CD3⁺CD8⁺ cytotoxic T cells, CD3-CD16⁺CD56⁺ NK cells, and CD19⁺ B lymphocytes. This provides mechanistic evidence linking the absolute burden of bone marrow MDSCs to the severity of systemic lymphopenia-a hallmark of sepsis-induced immunosuppression.

  7. Association Between Bone Marrow Myeloid Progenitor Absolute Counts and Peripheral Blood Cytokine Profile

    Time frame: Baseline (bone marrow and peripheral blood at 48-72 hours); CRP/PCT on days 1, 3, 5, 7

    Association between baseline bone marrow absolute counts of myeloid progenitors (GMPs, total MDSCs) and peripheral blood serum cytokine levels (measured in pg/mL). Serum cytokines are measured by multiplex assay and include: IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α. Inflammatory markers CRP and PCT are measured on days 1, 3, 5, and 7.

  8. Longitudinal Dynamics of Peripheral Blood Lymphocyte and MDSC Percentages and Absolute Counts During the First Week

    Time frame: Days 1, 3, 5, 7 post-enrollment (peripheral blood)

    Track the dynamic changes in peripheral blood percentages and absolute counts per μL of CD3⁺ T cells (and CD4⁺/CD8⁺ subsets), CD19⁺ B cells, CD3-CD16⁺CD56⁺ NK cells, PMN-MDSCs, and M-MDSCs on days 1, 3, 5, and 7 after enrollment. Day 1 is the early systemic immune baseline preceding peak bone marrow remodeling (day 3); day 3 coincides with the primary aspiration for direct cross-sectional correlation; days 5 and 7 track post-remodeling trajectories. This temporal hierarchy tests whether bone marrow absolute myeloid burden drives subsequent peripheral immunosuppression.

  9. Bone Marrow Microenvironment Cytokine and Chemokine Profile (Concentration)

    Time frame: Baseline (bone marrow supernatant at 48-72 hours)

    Cytokine and chemokine concentrations (pg/mL) in bone marrow supernatant obtained from the aspirate, measured by ELISA or Luminex multiplex assay. Analytes include: G-CSF, GM-CSF, IL-6, IL-1β, TNF-α, IL-10, CXCL1, CXCL12, and CCL2. Levels are compared across the three cohorts to identify sepsis-specific bone marrow microenvironment alterations that may drive the myeloid lineage bias and MDSC accumulation.

  10. Exploratory Single-Cell Transcriptomic Profiling of Bone Marrow Hematopoietic Cells

    Time frame: Baseline (bone marrow aspirate at 48-72 hours)

    Single-cell RNA sequencing (scRNA-seq) on bone marrow mononuclear cells from a subset of sepsis patients and healthy controls to identify differentially expressed genes and transcriptional pathways associated with myeloid lineage bias. Includes differential expression analysis and pathway enrichment (e.g., IFN signaling, STAT3, CEBPB, emergency granulopoiesis signatures).

  11. Correlation Between Gut Microbiota Alpha Diversity and Bone Marrow Myeloid Lineage Bias

    Time frame: At 48-72 hours post-enrollment (rectal swab and bone marrow synchronized)

    Assess the correlation between gut microbiota alpha diversity indices (Shannon index, Simpson index, Chao1 index) and bone marrow myeloid lineage bias indices, including: GMP-to-CLP ratio, percentage and absolute counts of PMN-MDSCs and M-MDSCs, PD-L1 expression on MDSCs, and HSC/CMP/MEP/CLP counts.

  12. Correlation Between Key Dysbiotic Gut Bacterial Taxa and Bone Marrow Myeloid Lineage Bias

    Time frame: At 48-72 hours post-enrollment (rectal swab and bone marrow synchronized)

    Identify key gut bacterial taxa that are significantly altered in sepsis and assess their correlation with bone marrow myeloid lineage bias indices, including: GMP-to-CLP ratio, percentage and absolute counts of PMN-MDSCs and M-MDSCs, PD-L1 expression on MDSCs, and HSC/CMP/MEP/CLP counts.

  13. Association Between Gut Microbiota-Derived Metabolites and Bone Marrow Myeloid Lineage Bias

    Time frame: Rectal swab and bone marrow at 48-72 hours post-enrollment (synchronized)

    Identify gut microbiota-derived metabolites associated with bone marrow myeloid lineage bias using untargeted metabolomics (LC-MS/MS) on rectal swab samples. Metabolite profiles are correlated with bone marrow myeloid lineage bias indices, including: GMP-to-CLP ratio, percentage and absolute counts of PMN-MDSCs and M-MDSCs, PD-L1 expression on MDSCs, and HSC/CMP/MEP/CLP counts.

Study contacts

Contact information is provided by the study sponsor or research team.

Zhang Jiancheng, MD, PhD

CONTACT

[email protected]

+8613554105815

Sponsors and collaborators

Lead sponsor

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

Other

Registry information

Official study title

Myeloid Bias in the Bone Marrow of Septic Patients

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Jun 24, 2026
Registry last updated
Jun 24, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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