TOPLINE:

When added to standard care, precision immunotherapy targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo in patients with sepsis.

METHODOLOGY:

• Researchers conducted a phase 2b randomized clinical trial across six countries to assess whether immunotherapy tailored to the type of immune dysregulation — macrophage activation-like syndrome or sepsis-induced immunoparalysis — improves organ function in patients with sepsis.
• They enrolled 276 patients with sepsis (mean age, 70 years; 33.7% female) with pneumonia or primary bacteremia who had either macrophage activation-like syndrome (blood ferritin levels > 4420 ng/mL) or sepsis-induced immunoparalysis (ferritin levels ≤ 4420 ng/mL and < 5000 human leukocyte antigen-DR molecules on CD45/CD14 monocytes).
• Patients were randomly assigned to receive standard care plus precision immunotherapy (n = 131) — 200 mg of intravenous anakinra every 8 hours for macrophage activation-like syndrome or 100 μg of subcutaneous recombinant human interferon-gamma every 48 hours for sepsis-induced immunoparalysis — or standard care plus placebo (n = 145); treatments were administered for up to 15 days.
• The primary outcome was the proportion of patients achieving a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score by day 9; higher scores indicate greater organ dysfunction and mortality risk.
• Secondary endpoints included a decrease of at least 1.4 points in the mean SOFA score by day 15, reversal of sepsis-induced immune dysfunction by day 28, 28- and 90-day mortality, and infection resolution by day 15.

TAKEAWAY:

• A higher proportion of patients receiving precision immunotherapy than placebo achieved the primary outcome (35.1% vs 17.9%; P = .002), with benefits seen in both macrophage activation-like syndrome and sepsis-induced immunoparalysis.
• A higher proportion of patients in the precision immunotherapy group than in the placebo group achieved a decrease in the mean SOFA score by day 15 (P = .004) and a reversal of immune dysfunction by day 28 (P < .001).
• No significant differences were observed in 28- and 90-day mortality; by day 15, infection resolution was more frequent with precision immunotherapy.
• Serious treatment-emergent adverse events occurred in 88.8% of the patients; anemia was more frequent among those who received anakinra, and hemorrhage was more frequent among those who received recombinant human interferon-gamma.

IN PRACTICE:

“These findings are consistent with previous work targeting immune dysregulation in sepsis,” the authors of the study wrote.

“It is reassuring that the additional analyses were supportive of the primary findings. However, as noted by the authors, it would be nice to see this approach tested in a larger trial with a primary outcome that was more patient-centric,” an expert wrote in an editorial accompanying the journal article.

SOURCE:

The study was led by Evangelos J. Giamarellos-Bourboulis, MD, National and Kapodistrian University of Athens, Medical School, Athens, Greece. It was published online on December 08, 2025, in JAMA.

LIMITATIONS:

The trial used change in the SOFA score as the main outcome, which was a surrogate rather than a patient-centered outcome. Measuring ferritin and human leukocyte antigen-DR required specialized testing that may not have been feasible in all hospitals, and the complexity and turnaround time could have limited broader use. The findings were generalizable only to sepsis caused by pneumonia or bacteremia because other causes of sepsis were excluded.

DISCLOSURES:

The study was funded by the European Union’s Horizon 2020 programme. Several authors disclosed receiving personal fees or grants, serving on the executive committee and council of the International Sepsis Forum, participating on data and safety monitoring boards, or having other ties with various organizations and pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.