Could Biomarkers Direct Therapy for the Septic Patient?

Abstract

Sepsis is a serious medical condition caused by a severe systemic inflammatory response to a bacterial, fungal, or viral infection that most commonly affects neonates and the elderly. Advances in understanding the pathophysiology of sepsis have resulted in guidelines for care that have helped reduce the risk of dying from sepsis for both children and older adults. Still, over the past three decades, a large number of clinical trials have been undertaken to evaluate pharmacological agents for sepsis. Unfortunately, all of these trials have failed, with the use of some agents even shown to be harmful. One key issue in these trials was the heterogeneity of the patient population that participated. What has emerged is the need to target therapeutic interventions to the specific patient's underlying pathophysiological processes, rather than looking for a universal therapy that would be effective in a "typical" septic patient, who does not exist. This review supports the concept that identification of the right biomarkers that can direct therapy and provide timely feedback on its effectiveness will enable critical care physicians to decrease mortality of patients with sepsis and improve the quality of life of survivors.

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

“…The diagnosis, risk stratification, and treatment of sepsis in both children and adults is challenging due to its inherent heterogeneity and the absence of a gold standard for diagnosis. This has traditionally led to poor clinical outcomes and has contributed to a plethora of failed pharmacotherapy clinical trials . Diagnostic and prognostic tools are sparse and largely based on clinical signs and symptoms.…”

“…This has traditionally led to poor clinical outcomes and has contributed to a plethora of failed pharmacotherapy clinical trials. 14,15 Diagnostic and prognostic tools are sparse and largely based on clinical signs and symptoms. These parameters can vary in children, depending on age (Table 1).…”

“…One of the more intriguing aspects of metabolomics is the potential to provide early clinically relevant information on an individual's eligibility and response to treatment. 15,35,36,57 With the current focus on resistant pathogens and antibiotic stewardship, pharmacometabolomics could permit customization and targeting of therapy early, thereby decreasing the prevalence of multidrug-resistant organisms. In the case of most infections, results of diagnostic tests for pathogen detection are not available for days to weeks after treatment is initiated.…”

Rolipram Improves Outcome in a Rat Model of Infant Sepsis-Induced Cardiorenal Syndrome

“…Clinical trials for sepsis therapy have often resulted in a worsening of patient outcomes because preclinical studies often do not use age-appropriate models nor evaluate therapy for multiple organ dysfunction (Fink and Warren, 2014; Cohen et al, 2015; Sims et al, 2016). Using our model of type 5 CRS in the rat pup, we present preclinical pharmacological evidence that the PDE4 inhibitor rolipram may offer a more targeted approach to treating the septic infant.…”

Innovation Management? Orienting Sepsis R&D and Technology Transfer Towards Stratified Medicine

“…Biomarkers that rapidly establish diagnosis and prognosis early in the course of sepsis are of particular interest for proactive interventions. Yet, the existing biomarker or diagnostic candidates fall quite short of the desired clinical sensitivity and specificity ( Sims et al, 2016 ). There is no “typical” sepsis patient, nor a “universal therapy”, given that sepsis is a complex syndrome driven by host-environment interactions.…”