Predicting Experimental Sepsis Survival with a Mathematical Model of Acute Inflammation

Abstract

Sepsis is characterized by an overactive, dysregulated inflammatory response that drives organ dysfunction and often results in death. Mathematical modeling has emerged as an essential tool for understanding the underlying complex biological processes. A system of four ordinary differential equations (ODEs) was developed to simulate the dynamics of bacteria, the pro- and anti-inflammatory responses, and tissue damage (whose molecular correlate is damage-associated molecular pattern [DAMP] molecules and which integrates inputs from the other variables, feeds back to drive further inflammation, and serves as a proxy for whole-organism health status). The ODE model was calibrated to experimental data from E. coli infection in genetically identical rats and was validated with mortality data for these animals. The model demonstrated recovery, aseptic death, or septic death outcomes for a simulated infection while varying the initial inoculum, pathogen growth rate, strength of the local immune response, and activation of the pro-inflammatory response in the system. In general, more septic outcomes were encountered when the initial inoculum of bacteria was increased, the pathogen growth rate was increased, or the host immune response was decreased. The model demonstrated that small changes in parameter values, such as those governing the pathogen or the immune response, could explain the experimentally observed variability in mortality rates among septic rats. A local sensitivity analysis was conducted to understand the magnitude of such parameter effects on system dynamics. Despite successful predictions of mortality, simulated trajectories of bacteria, inflammatory responses, and damage were closely clustered during the initial stages of infection, suggesting that uncertainty in initial conditions could lead to difficulty in predicting outcomes of sepsis by using inflammation biomarker levels.