In a potential paradigm shift for sepsis diagnostics, a new test predicts sepsis shortly after infection in mice -; long before blood clotting and organ failure -; which enables early antibiotic treatment and significantly increases survival. The findings provide a platform to quickly and easily perform clinical trials for early sepsis detection and to develop clinical intervention in human patients.
The collaborative effort by a research team that includes scientists from UC Santa Barbara, UC San Diego and Sanford Burnham Prebys Medical Discovery Institute (SBPMDI) is set out in a new study published in the Lancet journal, eBiology. The team managed to detect a catastrophic shift in blood protein abundance shortly after infection that could predict sepsis long before disease symptoms and organ damage occur.
The project was led by Professor Michael Mahan of UC Santa Barbara, along with Professors Dzung Le of UC San Diego, and Jeffrey Smith and Jamey Marth of SBPMDI. Additional collaborators include UCSB scientists Douglas Heithoff and Scott Mahan, as well as SBPMDI scientists Genaro Pimienta and Won Ho Yang, and John House, a veterinarian from the University of Sydney.
Sepsis is the number one cause of death in American hospitals. In the clinic, sepsis is diagnosed by a symptom-based approach that may include kidney or liver failure, blood clotting or bleeding -; which often occurs well after permanent organ damage. Thus, molecular diagnostics that detect infection in early stages of disease to minimize host injury are urgently needed.
The key finding was the identification of proteins in the blood that arise very soon after infection -; long before overt disease symptoms. Early detection is critical for clinical intervention to increase survival in sepsis patients. “
Michael Mahan, Professor, UC Santa Barbara
To perform the test, a small amount of blood was collected and analyzed for an increase in coagulation proteins that were induced but inactive in the early stages of infection. Such detection enabled early antibiotic treatment -; good for activated coagulation proteins causes blood clotting -; leads to markedly increased survival in mice. The technology is open source and freely accessible to all.
The study also showed that antibiotics are less effective after increasing blood proteins in response to infection. Treatment failure may be due to host injury caused by excessive blood clotting, which provides insight into why delays in antibiotic treatment in human sepsis are associated with increased risk of death.
“The future plan is to identify a biopanel of early sepsis blood proteins for incorporation into existing blood tests, enabling sepsis prediction long before excessive blood clotting and permanent organ damage,” Heithoff explained.
The researchers showed that the changes in blood proteins shortly after infection observed in mice were similar to those reported for human sepsis. They are therefore optimistic that these findings are translatable for the early detection and treatment of sepsis in humans.
“Currently, one in four patients dies from sepsis, with many survivors experiencing lifelong impairment with cognitive decline,” said Scott Mahan. “We hope technologies like these offer new ways of delivering modern molecular diagnostics that predict sepsis before permanent injury occurs.”
This research was funded by grants from the National Institutes of Health’s National Heart, Lung and Blood Institute, Santa Barbara Cottage Hospital and the US Army Research Office via the Institute for Collaborative Biotechnology Collaboration Agreement and Contract.
University of California – Santa Barbara
Heithoff, DM, et al. (2022) Coagulation factor protein abundance in the pre-septic state predicts coagulopathic activities occurring during late-stage murine sepsis. eBiology. doi.org/10.1016/j.ebiom.2022.103965.