The immunology of sepsis: translating new insights into clinical practice

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Treatments that influence this dysregulated host response are sparse. The immunopathophysiology of sepsis entails overzealous inflammation causing acute organ dysfunction, as well as a profound and/or persistent anti-inflammatory response that increases susceptibility to secondary infection. The immune response in sepsis is under the influence of various endogenous and exogenous factors, including genetic makeup, age, sex, comorbidities, metabolism, prior microbial exposure and medications. The consequent heterogeneity of the syndrome hampers immunomodulatory treatment strategies that rely on a 'one-size-fits-all' approach. A precision medicine approach is therefore warranted. Balanced application of prognostic- and predictive-enrichment strategies is instrumental to achieve precision medicine. Phenotyping of patients using clinical, physiological, microbiological and/or molecular ('omics') data enables the identification of more homogeneous patient subgroups. Several studies suggest that such approaches can be used to tailor adjunctive immunomodulatory therapies in patients with sepsis. As well as repurposing existing drugs to treat sepsis, new drugs aimed at restoring immune homeostasis are under investigation. New clinical trial methodologies, including flexible platform trials, Bayesian statistics and embedding trials in health care systems are increasingly being used to keep pace with rapid developments in the field of sepsis immunobiology and ultimately to improve clinical outcomes.