Sepsis occurs when the immune system responds abnormally to an infection, often triggering life-threatening organ failure. Despite affecting around 49 million people globally each year and causing approximately 11 million deaths, treatment options remain limited. Previous attempts to use immunotherapy in sepsis showed little benefit, largely because patients were treated with a uniform approach. A new large clinical study now shows that immunotherapy can be effective when precisely matched to a patient’s immune system state.

In the study led by Radboud University Medical Center (Nijmegen, Netherlands), along with the Hellenic Institute for the Study of Sepsis (Athens, Greece), researchers focused on tailoring immunotherapy based on whether a patient’s immune response was overactive or suppressed. The approach relied on immune profiling to identify patients with either excessive inflammation or immune paralysis. Based on this stratification, patients received drugs designed either to dampen or stimulate immune activity.

The ImmunoSep consortium included 33 hospitals across six countries. Investigators assessed immune function in sepsis patients to determine how their host defense systems were responding to infection. Only patients showing clear immune dysregulation were selected for immunotherapy. Those with excessive immune activation received the immune-suppressing drug anakinra, while patients with immune paralysis were treated with the immune-stimulating agent interferon-gamma.

In total, 276 patients were enrolled and stratified based on immune status. Both immunotherapy groups showed improved outcomes compared with control patients who did not receive immune-modulating treatment. Organ dysfunction improved within the first nine days, and infections resolved more quickly within 15 days.

The findings of this multicenter clinical trial reported in JAMA demonstrate that biomarker-guided immunotherapy can meaningfully improve outcomes in sepsis when applied to the right patients. Approximately one quarter of all sepsis patients fall into the immune profiles studied, suggesting immediate clinical relevance. Researchers plan larger follow-up trials to further validate the strategy and to explore tailored immunotherapy options for the remaining sepsis populations. This precision-medicine approach could redefine how immune-based treatments are used in critical care.

“This study provides the first robust large-scale evidence that biomarker-guided, targeted selection of sepsis patients for immunotherapy leads to clinically meaningful improvement in outcomes,” said Evangelos Giamarellos-Bourboulis.

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