Risk Stratification and Precision Medicine: Is It Feasible for Severe Infections?

Abstract

The principles of precision treatment for severe infection require the development of one readily measurable biomarker that is informative of the activation of either one specific immune pathway or one specific endotype. Immunotherapy should then be administered to modulate the implicated pathway. In sepsis, endotypes are recognized from large-scale clinical studies including both discovery and validation cohorts. Among these endotypes, SRS1 and Mars1 endotypes are associated with risk for death driven through sepsis-induced immunoparalysis. Clinical studies have shown that two main strata of immune activation may be recognized in sepsis, namely macrophage activation-like syndrome using increased ferritin; and sepsis-induced immunoparalysis using a combination of low ferritin and low numbers of HLA-DR receptors on CD14-monocytes. In severe coronavirus disease (COVID)-19, the only biomarker informative of specific immune pathway activation is soluble urokinase plasminogen activator receptor (suPAR); levels of 6 ng/ml or more indicate activation of the interleukin (IL)-1 pathway and signify risk for unfavorable outcome. SAVE-MORE is the first randomized clinical trial using a precision treatment approach for severe infections. Patients with increased suPAR were allocated to randomized treatment with standard-of-care and placebo or anakinra; this approach maximized treatment efficacy by 64%.