A new blood test could save lives in the treatment of sepsis. It assesses five markers in the blood to predict who is at low, medium, and high risk of death. With this knowledge, doctors could start treating the serious condition much earlier and with more precision.

Researchers from several children's hospitals in the United States have been developing the test—which they call PERSEVERE—for more than 10 years. They recently evaluated it in two ways.

First, they used the test to predict the risk of death in more than 400 children severely ill with sepsis. They then used it on mice with experimental sepsis to compare treatment decisions.

A recent paper in Science Translational Medicine gives a full account of the study and its findings.

Dr. Hector Wong, a director of Critical Care Medicine at Cincinnati Children's Hospital Medical Center in Ohio, is the study's senior investigator and first author.

He says that PERSEVERE not only puts patients into groups according to the deadliness of the sepsis but that it also enables doctors to decide which treatments to give to specific patients, such as picking the right drugs and dosages.

Unpredictable and challenging to treat

Sepsis is a serious condition in which the immune system launches an overwhelming response to infection. The cause of the infection can be any type of microbe, including fungi, bacteria, and viruses, but usually, it is bacteria.

The immune response releases inflammatory proteins into the bloodstream, causing blood clots to form and vessels to leak. This impedes blood flow and leads to organ damage.

The progress of sepsis is often unpredictable and rapid. It is a significant cause of hospital deaths and readmissions.

While anyone can develop sepsis, older adults, children, and babies are among those most at risk. People with serious injuries, cancer, AIDS, diabetes, and other medical problems are also more susceptible.

According to the National Institute of General Medical Sciences, which is one of the National Institutes of Health (NIH), sepsis affects at least 1.7 million adults and is responsible for 270,000 deaths every year in the US.

Despite significant progress in modern medicine, sepsis remains a challenge for doctors and carries a high risk of death.

Five biomarkers for sepsis prognosis

Over the 10 years or more that the researchers have been developing PERSEVERE, they have evaluated it using information from more than 1,000 children.

They started with a panel of 80 biomarkers and progressively reduced it to five.

According to the team, five is a manageable number for bringing together various advanced methods for searching and then choosing treatments.

In their study paper, the authors list the five PERSEVERE biomarkers as: "C-C chemokine ligand 3 (CCL3), interleukin 8 (IL8), heat shock protein 70 kDa 1B (HSPA1B), granzyme B (GZMB), and matrix metallopeptidase 8 (MMP8)."

Each biomarker is a protein that "reflects sepsis biology," they note.

In the new study, the team evaluated the latest version of PERSEVERE using blood samples from 461 critically ill children with sepsis who were under care at several pediatric hospitals in the US. They also tested the tool in mouse models of sepsis.

As regulators have not yet approved the tool for clinical use, the researchers did not allow the results to inform decisions about patient care and treatment. All they did was check its accuracy and evaluate its potential.

High prognostic reliability

The results showed that PERSEVERE predicted with high reliability which children would develop severe sepsis and which would not.

The researchers then used the same five biomarkers in a mouse model of sepsis. The test accurately predicted which animals were at high and low risk of death.

In addition, compared with mice at low risk, those at high risk had much greater quantities of bacteria in their blood than those at low risk and needed much higher doses of antibiotics to tackle the infection.

The researchers then went back to the children's samples and confirmed that those individuals at higher risk of death from sepsis also had much greater quantities of bacteria in their blood.

PERSEVERE can also give useful clues about the biological origins of the sepsis and the mechanisms that drive its rapid progress. This information could aid in the development of new treatments.

The researchers are continuing to develop and refine PERSEVERE as a prognostic tool and to discover more about the underlying biology of sepsis. They are also working on an adult version.

Dr. Wong points out that the main focus of PERSEVERE is not diagnostic but "prognostic enrichment." Its purpose is to help doctors better predict the course of sepsis in individuals and tailor treatments accordingly.

"Prognostic enrichment is a fundamental tool of precision medicine."

—Dr. Hector Wong