Rapid blood test results for five biomarkers correlated with sepsis outcomes in a study of children treated in intensive care units, which suggests potential for use as a predictive test for risk of death. The findings were published online November 13 in Science Translational Medicine.
The test -- dubbed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) -- was developed and patented by researchers at Cincinnati Children's Hospital Medical Center toward the goal of preventing life-threatening septic shock, which is particularly risky for fragile children in critical care settings.
The performance of the original model and a refined and improved version (called PERSEVERE I and II, respectively) was reported for a cohort of 461 pediatric patients with septic shock by Dr. Hector Wong, director of critical care medicine at Cincinnati Children's Hospital, and colleagues. The test was evaluated prospectively, though it was not used to direct outcomes.
In the overall patient population, the 28-day mortality rate was 12.6%. The researchers looked at test results within the first 24 hours of a diagnosis of septic shock and stratified patients by low, medium, and high risk for death based on test results.
"Whereas PERSEVERE had just modest performance, PERSEVERE II had excellent performance," Wong and colleagues reported. "This is consistent with our previous observation that PERSEVERE II appears to have greater generalizability across a broad range of children with septic shock."
PERSEVERE study results in pediatric intensive care patients | ||
Performance for mortality risk | PERSEVERE I | PERSEVERE II |
Sensitivity | 60% (CI, 47%-73%) | 86% (CI, 74%-93%) |
Specificity | 75% (CI, 71%-79%) | 69% (CI, 64%-73%) |
Positive predictive value | 26% (CI, 19%-34%) | 29% (CI, 22%-36%) |
Negative predictive value | 93% (CI, 89%-95%) | 97% (CI, 94%-99%) |
Sepsis: A tough nut to crack
Sepsis is survivable, but the mortality rate for septic shock is very high. More than 200,000 people die of sepsis as a medical complication each year in the U.S., according to a statement about the data from Cincinnati Children's Hospital, and young children and the elderly in critical care settings are particularly at risk. The risk of death sometimes leads to hasty treatment with antibiotics, and a recent study found that this reduces the sensitivity of blood culture tests.
Wong and colleagues noted the "extensive biological heterogeneity" of septic shock and that there is no single mechanism to treat. Consequently, years of research have resulted in countless failures of therapies in late-stage development, "despite seemingly robust preclinical data," they wrote.
In developing PERSEVERE as a prognostic model, the researchers identified many biomarkers associated with sepsis biology and then narrowed the list to the five they thought were most important:
- C-C motif chemokine ligand 3 (CCL3)
- Interleukin-8 (IL-8)
- Heat shock protein 70 kDa 1B (HSPA1B)
- Granzyme B (GZMB)
- Matrix metallopeptidase 8 (MMP8)
PERSEVERE II is an improved version that includes the five biomarkers plus platelet count as a predictor variable.
The study presented in Science Translational Medicine recruited patients between the ages of 1 and 18 who were admitted to various hospital intensive care units with sepsis. The researchers noted that mortality rates differed greatly depending on whether patients were deemed to be at low, medium, or high risk according to PERSEVERE. While the mortality rate overall was 12.6%, it was 45% in high-risk patients.
Compared with PERSEVERE I, PERSEVERE II had greater generalizability across a broad range of children with septic shock, the researchers found. They expressed confidence that PERSEVERE could be used as a predictive tool and not just a prognostic test in sepsis because it reflects underlying biology.
"On the basis of our findings, we suggest that PERSEVERE II might identify a subgroup of children with septic shock who will benefit most from targeted therapeutic drug monitoring to ensure optimal dosing of antibiotics," the authors wrote.
Risk appears to be associated with the degree of pathogen burden, and those with more severe cases may need higher doses of antibiotics, they suggested.
In addition to the data in children, Wong et al also reported preclinical research they said shows that the PERSEVERE biomarkers are reliably associated with mortality in mice with sepsis. The plan is to test the use of the biomarkers as a predictive model, evaluating different treatment strategies in mice based on risk level.
"This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis," they wrote.
The researchers are now looking for an industry partner, with hopes of getting the test into the clinic in the next few years.