A consensus immune dysregulation framework for sepsis and critical illnesses.

Summary

Across >7,074 samples from 37 cohorts, the authors derive cell-type-specific signatures that quantify myeloid and lymphoid dysregulation, linked to severity and mortality in sepsis and conserved across ARDS, trauma, and burns. Post hoc analyses of RCTs show differential mortality with anakinra and corticosteroids by dysregulation state, proposing a unifying, actionable framework.

Key Findings

• Developed cell-type-specific signatures quantifying myeloid and lymphoid dysregulation using >7,074 samples across 37 cohorts.
• Dysregulation associated with severity and mortality in sepsis and conserved in ARDS, trauma, and burns.
• RCT reanalyses showed differential mortality associations with anakinra (SAVE-MORE) and corticosteroids (VICTAS, VANISH) by dysregulation state.

Clinical Implications

Quantified myeloid/lymphoid dysregulation could guide selection and timing of immunomodulators (e.g., anakinra, corticosteroids) and support risk stratification across critical illnesses.

Limitations

• Findings on treatment interactions are observational and post hoc; not causal without prospective stratification.
• Heterogeneity in sampling platforms and clinical contexts may introduce residual confounding.

Future Directions

Implement prospective biomarker-guided RCTs using dysregulation scores; develop point-of-care assays to operationalize compartment dysregulation in ICU settings.