Precision medicine in sepsis: lessons from the TIGRIS trial and the reawakening of targeted therapy.

Abstract

Sepsis remains a leading cause of mortality worldwide, in part because it represents a biologically heterogeneous syndrome rather than a single disease entity. Numerous clinical trials targeting inflammation, coagulation, or immune pathways have failed to improve outcomes, largely due to indiscriminate enrollment of biologically diverse patient populations. Precision medicine has therefore emerged as a necessary paradigm shift in sepsis research and care. Endotoxin is a key driver of sepsis pathobiology through Toll-like receptor 4-mediated inflammatory signaling, endothelial dysfunction, and thromboinflammation. The development of the endotoxin activity assay (EAA) enabled real-time functional assessment of circulating endotoxin activity, revealing marked interindividual variability and dynamic changes during illness. These insights provided a rationale for biologically guided endotoxin-targeted therapy. Polymyxin B hemoperfusion, despite its strong mechanistic plausibility and early clinical promise, yielded inconsistent results in trials that relied on syndromic enrollment criteria. The TIGRIS trial was designed to address this limitation by refining patient selection through the integration of EAA-defined endotoxemia and organ dysfunction severity, assessed by the Sequential Organ Failure Assessment score. By defining a therapeutic window in which endotoxin was both biologically relevant and potentially modifiable, TIGRIS provides preliminary evidence suggesting that polymyxin B hemoperfusion may be effective when applied in an appropriate biological context. Beyond endotoxin removal, TIGRIS may offer insights into broader implications for precision medicine in sepsis, including biomarker-guided trial design, rational combination therapy, and reinterpretation of prior "negative" studies. Embracing biological heterogeneity may offer a credible path toward effective, individualized sepsis treatment.