Original Investigation 

Caring for the Critically Ill Patient

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

Evangelos J. Giamarellos-Bourboulis, Antigone Kotsaki, Ioanna Kotsamidi, et al

JAMA Published Online: December 8, 2025

doi: 10.1001/jama.2025.24175

Key Points

Question  Does immunotherapy tailored to the type of immune dysregulation improve outcomes among patients with sepsis?

Findings  In this multicenter randomized clinical trial of 276 patients, precision immunotherapy, which included the administration of anakinra for patients with macrophage activation–like syndrome and recombinant human interferon gamma for patients with sepsis-induced immunoparalysis, decreased the Sequential Organ Failure Assessment score by at least 1.4 points by day 9 in 35.1% of patients in the immunotherapy group vs 17.9% in the placebo group.

Meaning  A precision strategy of immunotherapy improved organ dysfunction at day 9 among patients with sepsis.

Abstract

Importance  Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.

Objective  To investigate whether precision immunotherapy guided by the presence of macrophage activation–like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9.

Design, Setting, and Participants  A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation–like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin ≤4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024.

Interventions  Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation–like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days.

Main Outcomes and Measures  The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality.

Results  Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group.

Conclusions and Relevance  Among patients with sepsis, precision immunotherapy targeting macrophage activation–like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo.

Trial Registration  ClinicalTrials.gov Identifier: NCT04990232