Abstract
In critically ill patients with sepsis, there is a grave lack of effective treatment options to address the illness-defining inappropriate host response. Currently, treatment is limited to source control and supportive care, albeit with imminent approval of immune modulating drugs for COVID-19-associated lung failure the potential of host-directed strategies appears on the horizon. We suggest expanding the concept of sepsis by incorporating infectious stress within the general stress response of the cell to define sepsis as an illness state characterized by allostatic overload and failing adaptive responses along with biotic (pathogen) and abiotic (e.g., malnutrition) environmental stress factors. This would allow conceptualizing the failing organismic responses to pathogens in sepsis with an ancient response pattern depending on the energy state of cells and organs towards other environmental stressors in general. Hence, the present review aims to decipher the heuristic value of a biological definition of sepsis as a failing stress response. These considerations may motivate a better understanding of the processes underlying "host defense failure" on the organismic, organ, cell and molecular levels.