Immune Signatures Linked to Treatment Response, Outcomes in Critical Illness

Patients with critical illnesses such as sepsis, acute respiratory distress syndrome (ARDS), and trauma who show signs of immune cell dysregulation face significantly higher risks of severe infection and death, according to research published in Nature Medicine.¹

The study analyzed more than 7000 blood samples from 37 cohorts in 13 countries and identified consistent gene-expression patterns—called immune signatures—across thousands of patients with critical illness. Both myeloid and lymphoid dysregulation were associated with worse outcomes. In an analysis of more than 2200 patients, 51% of those with systemwide dysregulation developed severe infections compared with just 6% of those with balanced immune responses.

According to the researchers, these signatures help understand which patients are more likely to deteriorate and who might benefit from a given therapy, which in turn helps advance precision medicine in the intensive care unit (ICU).

“This work, combined with the fact that we have an FDA-cleared clinical test, is an indicator that we are likely at the beginning of the era of precision medicine in critical care,” Purvesh Khatri, PhD, study author and professor of biomedical informatics at Stanford University, said in a news release.² “We finally have all the required tools to match the right people with the right treatment at the right time.”

A Framework for Stratifying Patients

The findings support a new Human Immune Dysregulation Evaluation Framework (Hi-DEF), according to researchers, which categorizes patients into 4 immune states: myeloid dysregulation, lymphoid dysregulation, systemwide dysregulation, or balanced response.¹ Each category reflects a distinct profile of protective vs detrimental immune activity.

Patients with abnormal dysregulation on either axis were found to have a sevenfold higher likelihood of requiring ICU care or dying within 30 days compared with patients showing balanced responses (OR, 7.1; 95% CI, 5.6-8.9; P < 2.2 × 10^–16). Hi-DEF generalized across multiple conditions, including sepsis, ARDS, trauma, and burns, suggesting a common mechanism underlying critical illness.

Implications for Therapy

The framework also revealed important differences in how patients respond to immune-modulating treatments. In clinical trial data, patients with lymphoid dysregulation consistently showed survival benefit from therapies such as corticosteroids and anakinra.

In the VICTAS trial of sepsis treatment, mortality dropped to 11% in patients with lymphoid dysregulation who received hydrocortisone, vitamin C, and thiamine, compared with 39% in those on placebo. Conversely, patients with balanced immune responses sometimes experienced worse outcomes when treated with steroids.

In the VANISH trial of patients with septic shock, Hi-DEF analysis revealed that hydrocortisone treatment was linked to worse outcomes in certain subgroups. Among 176 patients with RNA expression data, overall mortality was higher in those receiving hydrocortisone (38%) compared with those who did not (22%). The increase in risk was most pronounced in patients with balanced lymphoid responses, where 28-day mortality rose to 42% with steroids vs 16% without. These findings contrasted with prior trials showing benefit in patients with lymphoid dysregulation, highlighting how Hi-DEF may help identify when corticosteroids are likely to harm rather than help.

“Collectively, these results demonstrated that Hi-DEF provides flexibility for context-specific evaluation and has the potential to identify appropriate immunomodulatory treatment for patients with critical illness, reducing the heterogeneity of treatment effects,” the authors said.

The researchers proposed integrating Hi-DEF with an existing FDA-cleared diagnostic test, TriVerity, which measures the expression of 29 genes to determine the likelihood of bacterial or viral infection and predict disease severity. They also caution that further prospective trials are needed to confirm treatment-specific benefits.

“In summary, Hi-DEF provides a launching point for further prospective multi-omic investigations into critical illness immunobiology, as well as a more readily translatable, biology-based schema for developing precision medicine tools in the ICU,” the researchers said.

References

1. Moore AR, Zheng H, Ganesan A, et al. A consensus immune dysregulation framework for sepsis and critical illnesses. Nat Med. Published online September 30, 2025. doi:10.1038/s41591-025-03956-5
2. Kay C. Immune cell ‘signatures’ could help guide treatment for critically ill patients. News release. Stanford Medicine. September 30, 2025. Accessed September 30, 2025. https://med.stanford.edu/news/all-news/2025/09/immune-cell-signature.html