Rapid Blood Assay Predicts Mortality Risk Levels of Sepsis

A new rapid blood assay developed by investigators at Cincinnati Children’s Hospital Medical Center, can predict patients’ mortality risk levels from sepsis and could help inform precision medicine to treat the infections.

The study, published in Science Translational Medicine, included blood samples from 461 children with septic shock along with mouse models tested with the Pediatric Sepsis Biomarker Risk Model, known as PERSEVERE, a new assay that measures 5 biomarkers for sepsis. The study provided proof of principle for the use of PERSEVERE to guide precision treatment of sepsis.

"The PERSEVERE platform focuses on stratification and prognostication, not diagnostics," senior author Hector Wong, MD, director of critical care medicine at Cincinnati Children’s Hospital Medical Center said in a news release. "Prognostic enrichment is a fundamental tool of precision medicine. It allows us to predict the disease course and progression in individuals and tailor treatment to different groups of patients and individuals."

The study involved prospective testing in an independent cohort, allowing investigators to assess the generalizability and reliability of the tool. The cohort included heterogeneity of age, comorbidities and causative pathogen. By shedding light on the underlying biological mechanisms of sepsis, the PERSEVERE tool may help investigators develop new targeted therapeutic treatments.

After more than a decade of research, investigators narrowed down the biomarkers in the assay from 80 to 5 that were able to accurately predict which patients would develop severe cases of sepsis. The 5 biomarkers are C-C chemokine ligand 3 (CCL3), interleukin 8 (IL8), heat shock protein 70 kDa 1B (HSPA1B), granzyme B (GZMB), and matrix metallopeptidase 8 (MMP8). Investigators further refined the tool and added platelet counts as a predictor variable.

The National Institutes of Health-funded study found that those determined to be at high risk of mortality from sepsis had higher bacterial loads in their blood.

“Using this model, we tested 2 clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics,” the study noted.

The investigators have secured patents for the PERSEVERE platform and research is underway to develop an adult version of the platform, which will be tested as part of a clinical trial of corticosteroids to treat sepsis.

“PERSEVERE II has the potential to extend beyond prognosis, becoming a predictive enrichment tool, for example, to identify patients with sepsis who most warrant therapeutic drug monitoring to optimize antibiotic dosing,” the study noted. “Other potential interventions such as pharmacologic modulation of CCL3 and KC, guided by mPERSEVERE-based enrichment, also require investigation.”

Early treatment is key to reducing mortality risks of severe sepsis, which is a leading cause of morbidity and mortality in US hospitals. A recent study found that patients who received an early treatment bundle and a consultation with an infectious disease specialist within 12 hours of admission had a 40% risk reduction for in-hospital mortality.

The heterogeneity of sepsis is a challenge for practitioners, and no major breakthroughs in treating the disease have been made in decades. Recent efforts have focused on better understanding the infections. A study published earlier this year, dubbed the “Sepsis Endotyping in Emergency Care” (SENECA) project, identified 4 sepsis phenotypes.