Reassessing sepsis research: new clues for old players and new players for an old symptom to improve patient outcomes.

Sepsis remains a global health problem that causes millions of deaths each year. A rapid and accurate diagnosis is highly desired to allow a rapid use of appropriate antibiotics. A better understanding of the associated pathophysiology has been achieved these recent years. The initial appropriate immune response to infection evolves towards an overwhelmed inflammatory response involving both pro- and anti-inflammatory players that act concomitantly. It also includes cell deaths and cellular dysfunctions of leukocytes, endothelial cells and epithelial cells, associated with mitochondrial dysfunction. These dysregulations are responsible for organ impairment and alteration of immune status of circulating leukocytes. In contrast, within the tissues, an over-activation exists as illustrated by transcriptomic analyses of organs of patients deceased of sepsis, and revealed by the presence of a macrophage activation syndrome within the bone marrow. Despite progresses in understanding the mechanisms underlying sepsis and despite successful therapies in animal models, no real new therapies have emerged these recent decades. This failure may reflect the yin yang aspect of the same players of the host response such as fever, release of cytokines, or coagulation which can display both a beneficial or a detrimental role. Great hopes are now expected from precision medicine, based on patients' endotypes which should help to decipher the patient's sub-groups who could benefit from the different treatments, or to define some appropriate time windows for a given treatment. See also the graphical abstract(Fig. 1).