Leading-edge research continues at UF Sepsis and Critical Illness Research Center
By Karin Lillis
The University of Florida Sepsis and Critical Illness Research Center continues to spearhead research to develop clinical solutions for sepsis, as well as illnesses that stem from it and their enduring effects.
The center, one of the first of its kind in the nation, studies long-term outcomes in patients treated for sepsis in the surgical and trauma intensive care units at UF Health Shands Hospital.
Sepsis is a severe combination of infection and organ injury that can shut down organs, depress or over-activate the immune system and cause death. While in-hospital mortality from sepsis is decreasing, incidences of sepsis are on the rise. Severe sepsis leaves lasting effects, which scientists are only beginning to understand.
Below are a few examples of recent research projects.
Developing adjuvants or immune stimulants to prevent sepsis
Shawn Larson, M.D., and James Wynn, M.D., are working toward a vaccine adjuvant to prevent sepsis in premature infants. Sepsis can affect up to six of every 10 babies born prematurely and results in death or major life-long disability in four of 10 who become infected.
Larson is an assistant professor in the division of pediatric surgery in UF’s Department of Surgery; Wynn serves as an associate professor of pediatrics in the division of neonatal-perinatal medicine in UF’s Department of Pediatrics.
Wynn and Larson’s research team believes that stimulating the baby’s innate immune system can help fight — and even prevent — sepsis.
According to their research with neonatal mice, introducing sterile components of bacteria into the bloodstream can prompt the neutrophils — a type of white blood cell — to seek and destroy invading organisms.
“Once these cells find and attack the invaders, for example viruses or bacteria, they signal other immune cells to join the fight,” Larson explained. “We believe an early and effective immune system response can prevent sepsis from occurring in response to infections.”
They hope to replicate the results in humans. With a drop of blood, they have already developed a method to gauge a premature infant’s immune system response to sepsis.
“We have to figure out what’s normal and abnormal, so we can set a baseline,” Wynn said.
“Premature infants have the highest incidence of sepsis and the worst mortality,” said Lyle Moldawer, Ph.D., a professor and vice chairman of research in the UF College of Medicine’s Department of Surgery. “Preventing sepsis in premature infants is challenging, and currently, supportive therapies like antibiotics and IV fluids are the best we have,” he noted.
Blocking a protein in blood may prevent sepsis in neonates
Another study led by Wynn has found that blocking a certain protein in the blood with medication could help protect premature infants from sepsis, according to a new study that combines findings from a mouse model and from premature infants.
“Infants born prematurely commonly experience life-threatening sepsis and die more frequently from infection than people in all other age groups — children, adolescents, adults and the elderly,” said Wynn. The findings were published in the Proceedings of the National Academy of Sciences.
In a mouse model, the team is specifically targeting a protein — interleukin 18, or IL-18 — that can severely damage the intestines in premature infants who have sepsis. Interleukins are small proteins the immune system produces as a means of communication.
The researchers found that high IL-18 concentrations during sepsis increased levels of another interleukin — IL-17A — that severely and sometimes fatally injured the intestine.
In new-born mouse models exposed to IL-18, levels of IL-17A were more than 140 times higher than those not exposed to the protein.
“Using a drug to block IL-17A in the mouse model, we significantly reduced death from sepsis caused by high IL-18 production,” Wynn said. “This discovery brings new hope for novel treatments that may reduce intestinal damage and death from sepsis in premature infants.”
Data from neonatal mouse models in the study suggest the same can happen in human infants.
The team also measured blood samples from premature infants. They found that those who were not infected with sepsis already had high levels of IL-18 circulating in their blood. The younger the patient, Wynn said, the higher the levels of the protein.
“Those levels increased even more if the baby became septic,” Wynn said.
Next, Wynn and his team hope to understand how blocking IL-17A affects other organs in premature infants who have sepsis.
“In the longer term, we hope our findings can impact other inflammatory diseases in adults and children,” Wynn said. Currently, clinical trials are underway to block IL-17 and IL-18 in other diseases, Moldawer added.
Certain type of immune cells found in cancer and sepsis patients
A study led by the UF Sepsis and Critical Illness Research Center suggests that certain types of immune cells found in cancer — myeloid-derived suppressor cells, or MDSCs — are also present in certain patients diagnosed with severe sepsis and septic shock. MDSCs are a group of immunosuppressive cells that increase when a person has cancer, inflammation and infection.
Specifically, the team believes that MDSCs may play a major role in inducing the persistent inflammation, immunosuppression and catabolism syndrome, an underlying condition linked to poor, long-term outcomes following the onset of sepsis.
“Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long-term consequences. In cancer, increased MDSCs induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis,” wrote Brittany Matthias, M.D., a research resident with the UF Department of Surgery. She is the lead author on a paper appearing online in the Annals of Surgery.
The researchers obtained blood samples from 74 patients within 12 hours of the onset of severe sepsis or septic shock, and at set intervals through 28 days. They also took blood samples from 18 healthy control patients. Among patients diagnosed with severe sepsis or septic shock, the levels of MDSCs in the bloodstream are highly elevated, linked to immunosuppression and associated with adverse outcomes.
“We found that these cells are present and in greater numbers in patients who die early — less than 14 days in the hospital or after the onset of sepsis,” Matthias said. “Patients who do survive and remain in the ICU for 14 days or longer are significantly more likely to be transferred to a long-term rehabilitation facility — rather than home — if their levels of MDSC remain persistently high.“
They are also more likely to have a repeat hospital infection, which is known to be associated with worse chronic morbidity and mortality in these patients.”
Matthias said that the current research will lead to further studies.
“As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after severe sepsis or septic shock to improve currently observed dismal long-term outcomes,” the researchers wrote.
Created in 2014, the center and its research are funded by a $12 million, five-year grant from the National Institutes of Health. Driven by the UF Department of Surgery, the center also collaborates with the College of Medicine’s Department of Aging and Geriatric Research and the College of Public Health and Health Professions.