Assessing Cellular Responses in Sepsis☆

Sepsis – defined as a dysregulated immunological response to infection associated with some degree of associated organ dysfunction (Vincent et al., 2013) – is a common problem and still complicated by unacceptably high mortality rates. Infection is treated with antibiotics, and source control when needed, but there is no effective, specific treatment for sepsis. The only drug that has ever beenmarketed for this purpose, drotrecogin alfa (activated), was probably efficacious (Vincent, 2012), but was withdrawn, essentially because we could not identify which patients would actually benefit from it. This has been a key problem inmany sepsis trials. Indeed, over the years, sepsis has been considered primarily as a pro-inflammatory response, so we have focused on controlling pro-inflammatory mediators, including cytokines, such as tumour necrosis factor (TNF) and interleukin-1 (IL-1). However, there is also an anti-inflammatory response, which occurs simultaneously (Hotchkiss et al., 2013), and the initial greater pro-inflammatory effect is rapidly followed by a state of immunosuppression (sometimes called “immunoparalysis”). Giving an anti-TNF antibody to patientswho are already predominantly immunosuppressed is clearly not desirable and may even be harmful. Similarly, giving the pro-inflammatory growth factor, granulocyte colony-stimulating factor (G-CSF), to all septic patients was not associated with improved outcomes (Stephens et al., 2008). It is clear that sepsis therapies need to be adapted to the individual patient rather than directed at a general diagnosis of ‘sepsis’. The study by Pena et al. (in press) in this issue of EBioMedicine represents an important step in this direction. These investigators studied cellular gene expression in peripheral blood mononuclear cells (PBMCs) from septic patients. Using well established gene test approaches, they documented a clear and consistent endotoxin tolerance (also called cellular reprogramming) signature in a series of almost 600 septic patients from different cohorts. The group of investigators is reputed in this field and the results are convincing. Importantly, cellular reprogramming is not limited to Gramnegative infections and blood endotoxin levels are not increased only in the presence of Gram-negative organisms (Marshall et al., 2004; Buckley et al., 2006). The authors, therefore, proposed that cellular reprogramming could be used as a diagnostic test for sepsis. This is not straightforward conceptually though, because diagnosing sepsis