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.
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;
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;
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.
Cohort
Prospective
Bone marrow aspirate collection
Procedure/SurgeryBone 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.
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).
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.
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.
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.
Correlation Between Bone Marrow GMP-to-CLP Ratio (Percentage and Absolute) and SOFA score
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.
Correlation Between Bone Marrow GMP-to-CLP Ratio (Percentage and Absolute) and APACHE II score
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.
Association Between Bone Marrow Myeloid Lineage Bias (Percentages and Absolute Counts) and 90-Day Secondary Infection Rate
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.
Bone Marrow Myeloid Lineage Bias (Percentages and Absolute Counts) as Predictors of 90-Day All-Cause Mortality
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.
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