Lessons learned from treating sepsis may help with COVID-19 treatment, UF researchers suggest

COVID-19 research

The mortality rate of the COVID-19 pandemic has altered the standard process of drug development, amplifying the need for lifesaving treatment and marking the start of the sprint toward a cure or gold standard treatment.

In a commentary published in Lancet Respiratory Medicine and article published in JCI insight, UF researchers and their collaborators are looking to the past for answers — specifically, to sepsis.

“Many lessons can be learned from a generation of clinical and research data obtained from efforts to combat other progressive, overwhelming microbial infections, including sepsis,” said Lyle Moldawer, Ph.D., a professor and vice chair of the UF College of Medicine’s department of surgery.

Sepsis is a life-threatening illness that occurs when an infection affects the entire body. In a healthy immune system response, the body will produce danger signals localized to the infection site. A severe infection, however, can result in these signals triggering severe inflammation throughout the body. Left untreated, sustained sepsis results in large-scale organ failure, according to the UF Sepsis and Critical Illness Research Center. But efforts to suppress the immune system to quiet the inflammation can swing too far the other way, leaving patients vulnerable to other infections in the future.

The immune system’s response to infection in septic patients parallels what has been observed in some COVID-19 cases thus far. Currently, many approaches to treatment of the virus target the initial inflammation, or cytokine storm, or an immune response where the body starts to attack its own cells. This widespread inflammation causes what researchers sometimes refer to as a “whole-body bruise.”

“When the pandemic first began, a lot of the clinical trials focused on targeting the initial inflammatory response to the COVID-19 virus,’’ said Scott Brakenridge, M.D., MSCS, FACS, an assistant professor of surgery on the acute care surgery team at the UF College of Medicine. “But at the same time, there are over 30 years of research testing different immunological approaches to the treatment of sepsis, essentially all of which were unsuccessful.”

Consequently, researchers’ current focus in sepsis and immunotherapy focuses on treating what happens after patients contract polymicrobial sepsis — a profound immunosuppression, thought to be a result of chronic antigenic stimulation and T-cell exhaustion.

Currently, one of the biggest obstacles in immunotherapy in infection-related sepsis is choosing the right chemical agents for the right person. Everyone’s immune system responds a little differently, making it difficult to drill down into finding a one-size-fits-all agent without fine-tuning precision medicine in the field of immunotherapies, Brakenridge said.

“We noticed that the first randomized control trials being proposed to treat COVID-19 were reliving the ‘sepsis wars’ all over again,” Brakenridge said. “This made us consider what we’d learned from treating septic patients and whether or not that could teach us anything about the approach to the current treatment of the pandemic.”

Considering sepsis naturally overwhelms the immune system on its own, treatments like this could worsen the patient’s immunosuppression in the long run – especially when the inflammatory response to COVID-19 is yet to be entirely understood.

Another complication to treatment of the virus is the murky way it causes death.

“We know that patients get very sick from a pulmonary standpoint, but they also undergo multiorgan dysfunction, acute blood clotting disorders, secondary infections and more,” Brakenridge said. “It’s difficult to know at this point what they’re ultimately succumbing to.”

Consequently, the co-authors suggest taking a careful consideration as to whether concentrating on the immune system’s response should make up the focus of coronavirus treatment, and caution against a uniform course of treatment due to the immune system’s complexity.

“I think the most important lesson learned from the past is that there won’t be one ‘silver bullet’ treatment,” Brakenridge said. “It will be a combination of agents, potentially even the ones being investigated right now, that will rebuild the immune system and restore the patient’s health.”