A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.

Summary

Across 68 cohorts (12,026 blood samples), a conserved 42-gene Severe-or-Mild (SoM) immune signature linked baseline risk factors to infection severity and was modifiable by drugs and lifestyle. The SoM score predicted sepsis patients likely to be harmed by hydrocortisone and was associated with all-cause mortality, suggesting utility for precision immunotherapy and trial stratification.

Key Findings

• Integrated 12,026 blood samples across 68 cohorts to analyze immune dysregulation.
• A 42-gene SoM signature associated with age, sex, obesity, smoking, and comorbidities before infection.
• The SoM signature is modifiable by immunomodulatory drugs and lifestyle changes.
• The SoM score predicted sepsis patients harmed by hydrocortisone and was associated with all-cause mortality.

Clinical Implications

The SoM score could guide corticosteroid use in sepsis (identifying patients at risk of harm), inform selection of immunomodulatory therapies, and enable baseline immune state profiling for risk stratification.

Limitations

• Observational and integrative design limits causal inference.
• Heterogeneity across cohorts; prospective interventional validation is needed for clinical deployment.

Future Directions

Prospective trials to test SoM-guided corticosteroid and immunomodulator use; embed SoM scoring into EHR pipelines; explore temporal dynamics and responsiveness monitoring.