Greece: Researchers have found in a new study that among patients with sepsis, targeted precision immunotherapy aimed at macrophage activation, such as syndrome and sepsis-induced immunoparalysis, led to greater improvement in organ dysfunction by day 9 compared with a placebo.Sepsis is a complex and heterogeneous condition characterized by varied immune responses, making the selection of effective immunotherapy challenging. A new multicenter randomized clinical trial evaluated whether tailoring immunotherapy according to a patient’s immune dysfunction could improve clinical outcomes. The findings were published in JAMA by Evangelos J. Giamarellos-Bourboulis from the National and Kapodistrian University of Athens, Greece, and colleagues.The ImmunoSep trial was conducted across multiple centers in six countries and enrolled adults diagnosed with sepsis based on Sepsis-3 criteria. Participants had infections, including community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, or bacteremia. Patients were screened to identify two specific immune dysregulation patterns: macrophage activation–like syndrome and sepsis-induced immunoparalysis. Macrophage activation–like syndrome was defined by blood ferritin levels above 4420 ng/mL. Sepsis-induced immunoparalysis was identified in patients with ferritin levels of 4420 ng/mL or lower and fewer than 5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes. These biomarkers guided the selection of immunotherapy.Of the 672 patients screened, 281 were randomized and 276 were included in the primary analysis. The mean age was 70 years, and about one-third were women. The median baseline Sequential Organ Failure Assessment (SOFA) score was 9, indicating significant organ dysfunction at enrollment.Patients were randomly assigned to receive standard care with precision immunotherapy or standard care with placebo. In the immunotherapy group, treatment was guided by immune profile: patients with macrophage activation–like syndrome received intravenous Anakinra, while those with sepsis-induced immunoparalysis received subcutaneous Recombinant Human Interferon Gamma. The placebo group received matching intravenous and subcutaneous placebo for up to 15 days.The primary outcome was improvement in organ dysfunction, defined as a reduction of at least 1.4 points in the SOFA score by day 9. The SOFA score evaluates six organ systems and ranges from 0 (no dysfunction) to 24 (severe multiorgan failure).The study led to the following findings:A reduction of at least 1.4 points in the Sequential Organ Failure Assessment (SOFA) score by day 9 was achieved in 35.1% of patients receiving precision immunotherapy compared with 17.9% of those receiving placebo, indicating a significant improvement in organ dysfunction with the tailored treatment approach.No statistically significant difference in 28-day mortality was observed between the precision immunotherapy and placebo groups.Safety analysis reported multiple treatment-emergent adverse events during the study.A higher incidence of anemia was observed among patients treated with anakinra.Hemorrhagic events were reported more frequently in patients receiving recombinant human interferon gamma.The investigators concluded that a precision immunotherapy approach targeting specific immune abnormalities in sepsis can significantly improve short-term organ dysfunction, supporting the potential role of immune-guided treatment strategies in managing this life-threatening condition.Reference: Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, et al. Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial. JAMA. 2026;335(9):775–786. doi:10.1001/jama.2025.24175