Sepsis can kill, but a new test will help doctors plan timely interventions
After decades of little or no progress, researchers are finally making headway at detecting and treating sepsis, a life-threatening medical condition that kills at least 250,000 Americans every year.
A new test developed by scientists now accurately predicts which patients are at a low, medium, or high risk for death from sepsis, enabling doctors to detect it at the earliest and recommend timely interventions. The biomarker test allows physicians to select the right interventions for specific patients, including which drugs and dosages, say researchers from Cincinnati Children's Hospital Medical Center.
Reporting in Science Translational Medicine, the team says they have developed and successfully tested the new rapid blood assay that measures five biomarkers to predict and categorize the different risk groups accurately.
Called the Pediatric Sepsis Biomarker Risk Model or PERSEVERE, the test allows physicians to "detect and stratify sepsis at its earliest moments, just as the body is about to unleash a storm of bacterial infection," according to study's senior investigator, Dr Hector Wong, director of Critical Care Medicine at Cincinnati Children's.
By knowing which five proteins/genes make up the assay's five-biomarker blood panel, physicians should be able to start medical interventions much earlier and with greater precision, says the team.
"The PERSEVERE platform focuses on stratification and prognostication, not diagnostics. 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." says Wong.
The research project is also expected to lead to the development of new therapeutic treatments, says the team.
According to Dr Christopher Lindsell, a key collaborator on Wong's team, an important benefit of the assay platform is that it also gives researchers important clues for studying the underlying biological mechanisms of how sepsis gets started, ramps out of control and how it can be stopped with new therapeutic approaches. Lindsell, who was formerly with the University of Cincinnati School of Medicine, is now at the Vanderbilt University Medical Center.
The tool has been in development for more than a decade. The researchers have been able to progressively reduce the number of biomarkers in the assay platform to five, down from 80. This, says the team, makes it easier to "blend advanced technologies like computer-assisted biology and informatics with laboratory experimentation" to look more efficiently for new therapies.
What is sepsis?
Sepsis usually strikes fragile young children and the elderly hospitalized in intensive care units. According to the US Centers for Disease Control and Prevention (CDC), sepsis is the body's extreme response to an infection and is a life-threatening medical emergency.
"Sepsis happens when an infection you already have — in your skin, lungs, urinary tract, or somewhere else — triggers a chain reaction throughout your body. Without timely treatment, sepsis can rapidly lead to tissue damage, organ failure, and death. When germs get into a person's body, they can cause an infection. If that infection isn't stopped, it can cause sepsis," says CDC.
According to CDC estimates, over 1.5 million people get sepsis each year in the US, and at least 250,000 Americans die from sepsis annually.
While anyone can get an infection, and almost any infection can lead to sepsis, some people are at a higher risk. This includes adults, 65 or older, children younger than one, people with weakened immune systems and those who have chronic conditions such as diabetes, lung disease, cancer, and kidney disease.
Sepsis treatment is expensive. The National Institutes of Health says it often involves a prolonged stay in the intensive care unit and complex therapies with high costs. The Agency for Healthcare Research and Quality lists sepsis as the most expensive condition treated in US hospitals, costing nearly $24 billion in 2013.
The research team further says septic shock is a major cause of disease and death globally, including in the pediatric population. Despite years of research and development, there have been no major therapeutic breakthroughs for septic shock, and there is no precision medicine approach, they add.
Treatment for septic shock has remained essentially unchanged for decades, relying primarily on care bundles, protocols, antibiotics, and intensive care unit-based organ support, say experts.
"Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis has limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies," says the study.
The analysis
More than 1,000 children have been tested by the research team over the years. However, in the current study, researchers used the latest version of PERSEVERE to test the blood samples from 461 children with sepsis as well as mouse models that faithfully mimic blood poisoning.
The team got prior permission from patient families and institutional review boards of participating institutions.
They used the tool to test children between ages 1 and 18 years, who were already admitted to intensive care units and under care for sepsis at multiple pediatric hospitals, including Cincinnati Children's. Since PERSEVERE is not yet approved for clinical use, it was not used to inform or influence patient care decisions. It was only tested for accuracy and potential future use, says the team.
The analysis shows that the five biomarkers in PERSEVERE were able to accurately predict with high reliability which patients would and would not develop severe cases of sepsis.
“We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment,” says the team in the study.
When researchers next tested the tool in their mouse models of sepsis, the same five biomarkers were able to accurately predict which mice were at low or high risk. The findings also show that mice at a greater risk of severe sepsis had significantly higher bacterial loads in their blood than lower-risk animals and that higher doses of antibiotics were able to help contain the blood infections.
According to corroborating evidence provided by the team, "children with a higher risk of mortality from sepsis also have higher bacterial loads in their blood."
"In the current study, about 13% of patients did not survive, but PERSEVERE-based stratification effectively stratified the patients into three risk categories with widely different mortality rates," says the team.
Wong says the goal of the research team's work is to push those "survival curves significantly higher among the higher-risk patients."
The researchers will continue to further test and refine the platform. An adult version of the platform is currently under development. The researchers plan to concurrently test the platform as they conduct an NIH-funded clinical trial to use corticosteroids to treat sepsis.