Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction

The novel concepts within Sepsis‑3 criteria include a focus on dysregulated host responses, removal of the systemic inflammation response syndrome (SIRS) criteria from sepsis diagnosis, the use of Sepsis-related (Sequential) Organ Failure Assessment (SOFA) scores to define organ dysfunction, and the explicit recognition of the septic shock as a subset of sepsis. Protection against infection requires a surveillance system, an effector response against "perceived" pathogens, a method for regaining immune homeostasis following an immune response, and generation of immunological memory. In comparison to normally regulated responses to infection, the innate immune system shows profoundly abnormal neutrophil and macrophage function. Similarly, the adaptive immune system is typically depleted numerically of lymphocytes and functionally with T and B cell exhaustion. Although there are numerous proposed mechanisms by which these dysregulated immune responses may be associated with organ failure, it is unclear what the unifying organ failure mechanisms in sepsis are. Furthermore, in sepsis survivors, the epigenetic changes on immune cells and widespread changes to lymphocyte populations may increase the risk of adverse events such as rehospitalisation and mortality. Finally, our current gaps in understanding of the immune response trajectory and the associated modifiable mechanisms in sepsis leave us a long way from successful immunomodulation for these patients. This article is freely available.