Sepsis: Something old, something new, and a systems view

Abstract

Sepsis is a clinical syndrome characterized by a multisystem response to a microbial pathogenic insult consisting of a mosaic of interconnected biochemical, cellular, and organ-organ interaction networks. A central thread that connects these responses is inflammation that, while attempting to defend the body and prevent further harm, causes further damage through the feed-forward, proinflammatory effects of damage-associated molecular pattern molecules. In this review, we address the epidemiology and current definitions of sepsis and focus specifically on the biologic cascades that comprise the inflammatory response to sepsis. We suggest that attempts to improve clinical outcomes by targeting specific components of this network have been unsuccessful due to the lack of an integrative, predictive, and individualized systems-based approach to define the time-varying, multidimensional state of the patient. We highlight the translational impact of computational modeling and other complex systems approaches as applied to sepsis, including in silico clinical trials, patient-specific models, and complexity-based assessments of physiology.

Figure 1. Sepsis: A brief history

Our concept of sepsis has progressed from phenomenological description (antiquity) to rigid diagnostic criteria (20^th century). The future holds the potential for individualized, predictive, and multi-dimensional description of the patient’s state.

Figure 2. Sepsis: A process flow

Upon stimulation by pathogens, a multifaceted inflammatory response ensues, driven by cytokines, free radical reaction products, and damage-associated molecular patterns (DAMPs). Panel A: The inflammatory response affects, and is affected by, interactions with physiological systems (manifest as reduced physiological variability) and the coagulation and complement cascades. Panel B: The acute inflammatory response is sensed via defined receptors for both pathogen-derived products and DAMPs, and modulated via intracellular signaling pathways.

Figure 2. Sepsis: A process flow

Upon stimulation by pathogens, a multifaceted inflammatory response ensues, driven by cytokines, free radical reaction products, and damage-associated molecular patterns (DAMPs). Panel A: The inflammatory response affects, and is affected by, interactions with physiological systems (manifest as reduced physiological variability) and the coagulation and complement cascades. Panel B: The acute inflammatory response is sensed via defined receptors for both pathogen-derived products and DAMPs, and modulated via intracellular signaling pathways.

Figure 3. Towards multi-dimensional, individualized description of patient state

The future of sepsis diagnosis and therapy will depend on a growing understanding of the cellular and molecular mechanisms of inflammation by which pathogens are sensed and eliminated, along with the effects of inflammation on physiology and vice versa. These interactions will form the basis of computational models used for rational design of drugs and the clinical trials by which those drugs are tested. Multi-dimensional analysis of inflammation biomarkers and physiologic waveforms, along with mechanistic mathematical modeling, may aid in discerning individual patient states for the purposes of diagnosis and therapy.