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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 Tuesday in Lancet Respiratory Medicine, UF researchers and their collaborators are looking to the past for answers 鈥� specifically, to sepsis.

鈥淢any lessons can be learned from a generation of clinical and research data obtained from efforts to combat other progressive, overwhelming microbial infections, including sepsis,鈥� said Lyle Moldawer, Ph.D., a professor in the UF College of Medicine鈥檚 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鈥檚 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, an immune response where the body starts to attack its own cells. This widespread inflammation causes what researchers sometimes refer to as a 鈥渨hole-body bruise.鈥�

鈥淲hen the pandemic first began, a lot of the clinical trials focused on targeting the initial inflammatory response to the COVID-19 virus,鈥欌�� said Scott Brakenridge, M.D., MSCS, FACS, an assistant professor of surgery on the acute care surgery team at the UF College of Medicine. 鈥淏ut 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.鈥�

Consequently, researchers鈥� current focus in sepsis and immunotherapy focuses on treating what happens after patients contract polymicrobial sepsis 鈥� 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鈥檚 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.

鈥淲e noticed that the first randomized control trials being proposed to treat COVID-19 were reliving the 鈥榮epsis wars鈥� all over again,鈥� Brakenridge said. 鈥淭his made us consider what we鈥檇 learned from treating septic patients and whether or not that could teach us anything about the approach to the current treatment of the pandemic.鈥�

Considering sepsis naturally overwhelms the immune system on its own, certain treatments could worsen the patient鈥檚 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.

鈥淲e know that patients get very sick from a pulmonary standpoint, but they also undergo multiorgan dysfunction, acute blood clotting disorders, secondary infections and more,鈥� Brakenridge said. 鈥淚t鈥檚 difficult to know at this point what they鈥檙e ultimately succumbing to.鈥�

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

鈥淚 think the most important lesson learned from the past is that there won鈥檛 be one 鈥榮ilver bullet鈥� treatment,鈥� Brakenridge said. 鈥淚t will be a combination of agents, potentially even the ones being investigated right now, that will rebuild the immune system and restore the patient鈥檚 health.鈥�