Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.

Summary

In a multicountry double-blind RCT, immunophenotype-guided therapy with IV anakinra for macrophage activation-like syndrome or SC interferon-γ for immunoparalysis increased the proportion achieving a ≥1.4-point SOFA reduction by day 9 versus placebo (35.1% vs 17.9%). No significant 28-day mortality difference was observed, and safety signals included more anemia with anakinra and bleeding with interferon-γ.

Key Findings

• Primary endpoint achieved more often with precision immunotherapy: 35.1% vs 17.9% (difference 17.2%, 95% CI 6.8–27.2; P=.002)
• No statistically significant difference in 28-day mortality between groups
• Safety signals: higher anemia with anakinra; higher hemorrhage with interferon-γ

Clinical Implications

Consider feasible bedside immunophenotyping (ferritin thresholds and monocyte HLA-DR) to identify candidates for anakinra or interferon-γ in sepsis to improve early organ dysfunction, while monitoring for anemia and bleeding. Mortality benefit remains unproven.

Limitations

• Primary endpoint focuses on day-9 organ dysfunction; no mortality benefit at 28 days
• Potential generalizability constraints of immunophenotyping thresholds and operational logistics

Future Directions

Larger trials powered for mortality and patient-centered outcomes; refine immunophenotyping cutoffs; evaluate combination or sequential strategies and cost-effectiveness.