Prognostic and predictive enrichment in sepsis

Abstract

Sepsis is a heterogeneous disease state that is both common and consequential in critically ill patients. Unfortunately, the heterogeneity of sepsis at the individual patient level has hindered advances in the field beyond the current therapeutic standards, which consist of supportive care and antibiotics. This complexity has prompted attempts to develop a precision medicine approach, with research aimed towards stratifying patients into more homogeneous cohorts with shared biological features, potentially facilitating the identification of new therapies. Several investigators have successfully utilized leukocyte-derived mRNA and discovery-based approaches to subgroup patients on the basis of biological similarities defined by transcriptomic signatures. A critical next step is to develop a consensus sepsis subclassification system, which includes transcriptomic signatures as well as other biological and clinical data. This goal will require collaboration among various investigative groups, and validation in both existing data sets and prospective studies. Such studies are required to bring precision medicine to the bedside of critically ill patients with sepsis.

Abstract

In this Review, the authors examine current efforts to develop a precision medicine approach that informs the diagnosis and treatment of patients with sepsis. Prognostic and predictive enrichment strategies in sepsis might also provide insight into the mechanisms that drive sepsis-associated acute kidney injury, a common complication of sepsis.

Key points

• Sepsis is a heterogeneous clinical syndrome and its variability at the individual patient level makes it amenable to a precision medicine approach for prevention, diagnosis and treatment.

• The concept of enrichment ─ including both prognostic and predictive enrichment ─ is fundamental to enabling precision medicine.

• Several investigators have utilized leukocyte-derived mRNA and a discovery-based approach to identify sepsis subclassification systems for both prognostic and predictive enrichment.

• An ideal approach would utilize enrichment strategies for clinical trial design and bedside decision-making in real time, but considerable work is still required to reach clinical feasibility.

• Understanding the sepsis molecular signature of a patient will likely be crucial to improving the treatment of sepsis-associated acute kidney injury, which is a common complication associated with substantial morbidity and mortality.