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

Summary

In a multinational double-blind RCT of 276 patients, biomarker-guided immunotherapy (anakinra for macrophage activation-like syndrome or interferon-γ for sepsis-induced immunoparalysis) increased the proportion achieving a ≥1.4-point SOFA decrease by day 9 versus placebo. No significant difference in 28-day mortality was observed; adverse events included more anemia with anakinra and hemorrhage with interferon-γ.

Key Findings

• Primary endpoint met: 35.1% vs 17.9% achieved ≥1.4-point SOFA decrease by day 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.
• Safety signals: increased anemia with anakinra and increased hemorrhage with interferon-γ.

Clinical Implications

For selected sepsis phenotypes, biomarker-guided anakinra or interferon-γ may improve early organ dysfunction. Implementation requires phenotype testing (ferritin, monocyte HLA-DR), vigilance for anemia/bleeding, and integration with standard sepsis care.

Limitations

• Primary endpoint focused on short-term organ dysfunction; no mortality benefit shown
• Moderate sample size; high rate of serious adverse events across groups

Future Directions

Validate phenotype definitions and algorithms, optimize dosing/duration, assess composite patient-centered outcomes and mortality, and integrate point-of-care HLA-DR/ferritin testing in pragmatic trials.