Sepset is developing a blood test for hospitals to identify septic patients in the emergency room (ER) and predict those who will have high risk for organ failure.

Drs. Hancock, Pena and colleagues made a research breakthrough discovery that has substantial clinical implications (Pena, 2014). Their conclusions were informed by both a meta-analysis of 592 patients, including both pediatric and adult sepsis cohorts, and by an initial single-blinded prospective observational clinical study. Subsequently studies on more than 400 sepsis patients (NCT04118179) and 200 hospitalized COVID-19 patients have confirmed their initial observations. Using a hypothesis-driven approach, they demonstrated that sepsis patients posses a gene expression signature characteristic of a biological phenomenon known as “Cellular Reprogramming” (CR; also termed endotoxin tolerance) which is a type of immunosuppression. CR involves the reprogramming of immune cells to a state where they are unable to respond to microbial signatures in a way that triggers protective immune responses. The CR signature is present in patients suspected of sepsis at first clinical presentation (in the emergency department) and is able to identify which patients do or do not go to develop severe sepsis (that includes organ failure). Most importantly, the strong presence of the signature was associated with worse outcomes, including multiple organ dysfunction and ICU admission (Pena, 2014).

These observations are novel and fundamental, and have enormous implications in the management of sepsis, with respect to early diagnosis and prognosis, as well as supporting early application of appropriate therapies including antimicrobial and non-pharmaceutical (e.g. immunomodulatory) strategies.

The Sepset-ER test can identify early signs of cellular reprogramming and therefore the development of immunosuppression in patients within an hour or so after their first visit to the ER, allowing a more aggressive management to increase patient survival and spare the use of expensive medical treatments and valuable antibiotics in patients that are diagnosed to not have sepsis.

Advantages of the Technology

1. Earlier diagnosis for sepsis at the time patients enter the ER and are recognized as “possible sepsis”

2. More accurate predictor for severity of sepsis (i.e. development of immune suppression and organ failure)

3. Improved diagnosis of patients that do not have sepsis.

Dr. Hancock and his collaborators have performed a large prospective, observational, multi-center international clinical study (NCT04118179) that has statistically validated the gene signature.

Immune dysfunction in sepsis survivors.

Legend: Immune dysfunction in sepsis survivors. Early in sepsis, both inflammation and immunosuppression occur concurrently. If inflammation is uncontrolled, this leads to organ failure and death. Those that avoid early death will either return to immune homeostasis, or progress to prolonged immunosuppression that continues after discharge. Prolonged immunosuppression predisposes survivors to infections, rehospitalizations, and ultimately late death. This phenomenon is marked by impaired cytokine secretion, dysfunctional T-cells, and cellular reprogramming. It is still unknown why prolonged immunosuppression occurs; however, epigenetic processes may be involved to “lock in” certain immunophenotypes. Expansion of regulatory T-cells and myeloid derived suppressor cell (MDSC) populations also occur early in sepsis and persist after sepsis, suggesting their role in maintaining this immunosuppressive phenotype. TNFα: tumor necrosis factor alpha, IL-6: interleukin-6, DAMPs: damage-associated molecular patterns, Treg: regulatory T-cell, MDSC: myeloid derived suppressor cell.