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A new model for an old killer

After 30 years, scientists are closer to finding sepsis treatment, thanks to pigs

By Lindsay Brownell

(BOSTON) — Sepsis, or blood poisoning, occurs when the body’s response to infection damages its own tissues and organs, leading to organ failure. It kills millions globally each year, and is the most common cause of death in people who have been hospitalized. Despite its prevalence, the standard treatment is to give patients antibiotics and fluids, and no new therapies have been developed in the last 30 years due to the high failure rate of sepsis treatments in clinical trials.

A new model for an old killer
The new swine-specific sepsis assessment criteria developed by the Wyss Institute and collaborators could help researchers and clinicians better evaluate infection and more accurately track the effect of potential sepsis treatments in preclinical pig models. SEM image: E. coli (green) bacteria captured by FcMBL magnetic beads (gray spheres), for the Wyss Institute’s PAMPs assay. Credit: Wyss Institute at Harvard University

The animals typically used to test drug candidates in preclinical trials (i.e., mice and baboons) are poor proxies for human responses to sepsis, as they are frequently resistant to the pathogens that cause sepsis-inducing infections. Pigs are a much better model organism, as 80% of their immune system shares the same machinery as humans, their blood clotting is similar, and their large size allows their vitals to be monitored in real-time. However, even in pig studies, the animals’ responses to sepsis are not currently measured with the same criteria used in human clinical practice, largely because research facilities lack the personnel, equipment, and clinical facilities needed to perform the required tests on multiple animals.

To address this problem, a team of scientists from the Wyss Institute at Harvard University and Boston Children’s Hospital has created a new approach for clinical monitoring designed to measure these sepsis responses in pigs. Analyzing pigs based on multiple physiological signs as well as organ failure, rather than death, could help provide a more accurate preview of a sepsis drug’s effect on humans before it reaches clinical trials. The research is reported in Advances in Critical Care Medicine.

Human cases of sepsis are evaluated based on a 2016 protocol called Sepsis-3 that uses Sequential Organ Failure Assessment (SOFA) scoring criteria to classify the severity of sepsis by incorporating measurements of heart, kidney, liver, lung, brain, and blood clotting function, as sepsis leads to the failure of multiple organs. Typically, animal models are evaluated by whether or not the animal dies as a result of illness, with the exact cause only being determined in an autopsy. Inspired by the Sepsis-3 assessments used clinically, the researchers created a swine-specific Sepsis-3 (ss-Sepsis-3) protocol with swine-specific SOFA (ss-SOFA) scoring criteria so that they could evaluate sepsis in living infected pigs in a manner that mirrors human clinical assessment.

“Our system goes beyond simply measuring the effects of pathogen injection on inflammation and animal survival. Because it mimics the life-threatening organ failure that is also seen in sepsis patients, it also might provide a better prediction of how sepsis therapies will perform in humans,” says Mike Super, Ph.D., Lead Senior Staff Scientist at the Wyss Institute and co-author of the paper.

Anna Waterhouse, Ph.D., a former Research Scientist at the Wyss Institute who is now Group Leader of the Cardiovascular Medical Devices Group at the University of Sydney, collaborated with a surgical team led by Boston Children’s Hospital’s Senior Veterinarian Arthur Nedder, D.V.M. on the study, in which they infused E. coli bacteria into the blood of eighteen young Yorkshire pigs and evaluated the responses of their various organs in real-time using the new protocols. Six pigs were given the bacteria while conscious, six while under anesthesia, and six did not receive E. coli but underwent the same procedures (four conscious and two anesthetized). The scientists found that increases in the total ss-SOFA scores among both conscious and anesthetized pigs were largely due to kidney and blood clotting failure, with two of the conscious animals further developing acute kidney failure.

Three of the anesthetized animals were categorized as experiencing septic shock (the highest severity level in the ss-SOFA system), based on a combination of those organ failures as well as anesthesia-induced heart failure and the lack of a fever due to lowered body temperature. These results suggested that the effects of anesthesia need to be taken into account when evaluating responses to sepsis.

Real-time monitoring of animals, whether alive or anesthetized, requires a significant investment of personnel and time, but being able to more closely replicate and study human sepsis responses could have significant benefits for drug development and testing.

“Our modified pig-specific SOFA scoring approach based on the Sepsis-3 guidelines lays the foundation for future studies that can quantify the severity of sepsis when evaluated with longer time frames, different pathogen strains, and antibiotic treatments, as well as comorbidities that typically accompany sepsis in human patients,” says corresponding author and Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

Additional authors of the study are current and former Wyss Institute researchers, including Daniel Leslie, Ph.D., Staff Scientist; Dana Bolgen, Surgical Veterinary Technician; Shanda Lightbown, Research Assistant; Nikolas Dimitrakakis, Associate Biostatistician and Data Analyst; Mark Cartwright, Ph.D., Staff Scientist; Benjamin Siler, Research Scientist; Kayla Lightbown, Research Intern; Kelly Smith, Research Assistant (currently Technical Information Specialist at Charles River Laboratories); Patrick Lombardo, Research Assistant (currently Emergency Room Technician at MetroWest Medical Center); Julia Hicks-Berthet, Research Assistant (currently a graduate student at Boston University); and Boston Children’s Hospital researchers Sam Jurek, Researcher at Boston Children’s Hospital and HMS; and Kathryn Donovan, Surgical Veterinary Technician.

This research was supported by DARPA and Harvard’s Wyss Institute for Biologically Inspired Engineering.

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