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

Summary

In 276 randomized patients, phenotype-guided precision immunotherapy increased the proportion achieving a ≥1.4-point mean SOFA decrease by day 9 versus placebo (35.1% vs 17.9%; difference 17.2%; P=.002). Twenty-eight-day mortality did not differ significantly. Anemia increased with anakinra and hemorrhage with interferon-γ.

Key Findings

• Primary endpoint met: ≥1.4-point mean SOFA decrease by day 9 in 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 precision immunotherapy and placebo.
• Serious TEAEs were common (88.8%); anemia increased with anakinra and hemorrhage with recombinant interferon-γ.

Clinical Implications

Supports immune-phenotype screening (ferritin, monocyte HLA-DR) to select patients for targeted immunotherapy; motivates protocols for early endotyping and careful safety monitoring given adverse events and lack of mortality benefit.

Limitations

• No mortality benefit at 28 days despite improved organ dysfunction
• Moderate sample size and potential heterogeneity across sites and phenotypes; safety signals (anemia, hemorrhage)

Future Directions

Larger trials powered for mortality, refinement of endotyping thresholds and timing, combination strategies, and head-to-head comparisons of targeted agents.