Immune Cell Signatures Could Revolutionize Critical Care by Guiding Personalized Treatment Decisions

Immune cell gene signatures could revolutionize how critically ill patients are treated, according to new research led by Purvesh Khatri, Ph.D., professor of biomedical informatics at Stanford University. The work, detailed in two papers published in Nature Medicine, introduces a new framework that uses blood-based tests to assess a patient’s immune system state, helping doctors make faster, more accurate decisions about diagnosis and treatment. When patients arrive in the emergency department with severe infections, trauma, or sepsis, determining the cause and appropriate treatment is often challenging. Traditional methods rely on clinical symptoms and limited lab tests, which can delay care. But Khatri’s team has developed a system that analyzes patterns of gene activity—called immune signatures—in immune cells to reveal whether a patient’s immune system is functioning properly or is dysregulated. One key tool, the FDA-cleared TriVerity test, evaluates the activity of 29 genes to generate three scores: the likelihood of a bacterial infection, a viral infection, and the risk of needing intensive care within seven days. A validation study involving 1,222 patients across 22 emergency departments in the U.S. and Europe showed that TriVerity outperformed standard clinical tests in diagnosing infections and predicting illness severity. In a second study, Khatri and colleagues analyzed over 7,000 blood samples from 37 cohorts across 13 countries. They developed a new scoring system called the Human Immune Dysregulation Evaluation Framework (HI-DEF), which identifies four immune response categories: myeloid dysregulation, lymphoid dysregulation, systemwide dysregulation (both systems affected), and balanced response. High levels of “bad” gene signatures—indicating immune imbalance—were strongly linked to worse outcomes in sepsis, burns, trauma, and acute respiratory distress. This insight is crucial because current treatments for critical illness often don’t target the immune system directly. For example, antibiotics are frequently given immediately in suspected sepsis, but if the infection is viral, antibiotics are ineffective and can promote antibiotic resistance. The new framework helps avoid such missteps. Patients with myeloid dysregulation may benefit from drugs targeting that immune arm, while those with lymphoid issues need different therapies. Those with both systems dysregulated may need combination treatments. The research also revealed that patients with high lymphoid dysregulation—whether due to sepsis or burns—tended to have better outcomes when treated with steroids. In contrast, patients with balanced immune responses saw worse outcomes when given steroids, highlighting the importance of precision in treatment. Khatri envisions a future where doctors can run a single blood test, get a full immune profile within 30 minutes, and receive a clear roadmap for diagnosis and treatment. He plans to combine TriVerity with the HI-DEF scoring system to create a comprehensive clinical tool. Beyond the ICU, Khatri believes immune dysregulation markers could be used in routine health screenings. Previous studies have shown that people with conditions like diabetes exhibit more “bad” gene signatures, suggesting immune imbalance may precede serious illness. If lifestyle changes can reverse these patterns, it could open new paths for preventive medicine. “My vision is to make immune dysregulation assessment part of your annual health checkup,” Khatri said. This could mark the beginning of a new era in precision medicine—where treatments are tailored not just to the disease, but to the individual’s immune response.