Immune Dysregulation Framework for Sepsis and Critical Illnesses

• In Sepsis
• Thu, 2 Oct 2025

When a critically ill patient arrives in the emergency department, physicians must make rapid, high-stakes decisions related to infection and whether that infection is bacterial or viral. There are decisions related to whether the patient needs immediate treatment, and whether they can recover safely at home or must be admitted. 

Even once an infection is identified, treatment isn’t always straightforward. Some patients with sepsis, for example, improve with steroid therapy, while others deteriorate. Researchers believe the key lies in the patient’s immune response, and new blood tests could help doctors quickly determine the right course of action.

A research team at Stanford has published two new studies outlining such tools. The team has developed and validated blood tests that analyse gene activity in immune cells, generating signatures that reveal both the presence of infection and the state of a patient’s immune system. These signatures can help clinicians decide whether treatment is necessary, and, crucially, which treatment will be most effective.

Earlier work from the group showed that immune gene signatures can diagnose infections and predict severity. That research led to TriVerity, a 29-gene test that recently received FDA clearance. TriVerity uses AI to deliver three scores: risk of bacterial infection, viral infection, and severe illness (defined as ICU-level care within a week). In a validation study of 1,222 patients across 22 emergency departments, the test outperformed standard diagnostic methods, improving accuracy in detecting infections and gauging severity while providing clearer guidance on antibiotic use.

Building on this foundation, the research team created a new framework, the Human Immune Dysregulation Evaluation Framework (HI-DEF). By analysing over 7,000 blood samples from 37 cohorts in 13 countries, the team identified good immune signatures linked to healthy responses and bad signatures tied to dangerous dysregulation. The scoring system sorts patients into four categories: myeloid dysregulation, lymphoid dysregulation, systemwide dysregulation, or balanced response, each associated with different outcomes and treatment implications.

This approach revealed striking patterns. Patients with high lymphoid dysregulation, whether suffering from sepsis or burns, often benefitted from steroid therapy; those with balanced immune responses did not, and steroids worsened mortality rates. Such insights could prevent harmful treatments and help physicians tailor therapies from the start rather than by trial and error.

The team envisions combining HI-DEF scores with the TriVerity test into a single platform that can deliver results in as little as 30 minutes, enabling clinicians to determine infection type, illness severity, and optimal treatment in one step. Looking ahead, the tool could extend beyond critical care, serving as a preventive measure to detect immune dysregulation early, perhaps even as part of a routine annual check-up.

Source: Stanford Medicine
Image Credit: skylarvision from Pixabay

References:

Moore AR, Zheng H, Ganesan A et al. (2025) A consensus immune dysregulation framework for sepsis and critical illnesses. Nat Med.