Improving survival in sepsis

How immune cells die can influence patient mortality

Sepsis is the leading cause of death among critically ill patients in the United States. About three-quarters of a million people develop sepsis every year, and more than 210,000 die. It usually attacks the sickest of the sick, patients who already are in the hospital with pneumonia or with serious abdominal injuries from car accidents or gunshot wounds.

Sepsis patients develop toxins in the bloodstream that cause their body temperature either to rise to abnormally high levels or to fall to abnormally low ones. Many go into shock. Some have a fluid buildup in the lungs that can progress to respiratory failure. Eventually, the syndrome contributes to what doctors call Multiple Organ Dysfunction Syndrome, which can involve kidney failure, liver dysfunction, blood-clotting abnormalities and other life-threatening problems.

Patients in intensive care units are kept alive with breathing machines, dialysis, tube feeding and other extraordinary measures until their bodies can begin to recover from critical illness or traumatic injury.
Patients in intensive care units are kept alive with breathing machines, dialysis, tube feeding and other extraordinary measures until their bodies can begin to recover from critical illness or traumatic injury.

For many years, scientists called sepsis blood poisoning and believed that it was the result of an uncontrolled inflammatory response, but several studies that involved anti-inflammatory drugs were not successful at improving survival.

Now, researchers at Washington University School of Medicine in St. Louis have found that how immune cells die during sepsis might be a key to whether patients survive. If the immune cells die through a process known as programmed cell death, or apoptosis, the survival rate appears to be much lower than if cells die through a different mechanism called necrosis.

They have reported on their work in several scientific journals, including the Proceedings of the National Academy of Sciences, the New England Journal of Medicine and the Journal of Immunology.

Necrosis causes cells to swell, rupture and release their contents into the body, a process accompanied by inflammation. Cells also can die through a cell suicide process called apoptosis. During apoptosis, the cell initiates a genetic program in which it causes itself to die.

When cells die through necrosis, the body gets a warning that something is wrong, and it up-regulates the immune system. But billions of cells undergo apoptosis every day, and the body doesn’t need to go on alert every time that happens, so apoptosis doesn’t rev up immunity. If anything, it tends to suppress it. That may be part of the problem for patients with sepsis.

“Our laboratory has shown that in sepsis there is a lot of apoptotic cell death,” says Richard S. Hotchkiss, M.D., professor of anesthesiology and of medicine and associate professor of surgery and of molecular biology and pharmacology at Washington University School of Medicine. “The fact that cells are dying through apoptosis may contribute to depression of the immune system at the very time it’s needed most to fight the infections and other problems associated with sepsis.”

Hotchkiss and co-investigator Irene E. Karl, Ph.D., research professor of medicine, have been studying the impact of apoptosis and necrosis on survival. In a mouse model of sepsis, they transferred immune cells that had been frozen and then thawed, causing them to die through necrosis, into septic mice. Others received a transplant of immune cells that had been irradiated, causing those cells to die through apoptosis.

“When we gave the necrotic cells, we up-regulated the immune system, and the animals had improved survival when they became septic,” Hotchkiss says. “But when we gave the apoptotic cells, there was a depression of the immune system, and the septic animals had a decrease in survival.”

Such a transfer of dying immune system cells probably wouldn’t work as a treatment for humans. For one thing, animals in the study received the transplants before they actually became septic. But Hotchkiss and Karl believe the study does demonstrate that how the cells die is important in whether the patients die. Finding a way to block apoptosis may be a key to improving survival.

“Roughly 30 to 50 percent of people with sepsis will die,” Hotchkiss says. “If we could find a way to interfere with apoptosis in immune cells, we might prevent a large number of those deaths.”

Patients with sepsis lose large numbers of immune cells called lymphocytes. Those are the T cells and B cells in the immune system that fight infections. In addition, Hotchkiss says the fact that those cells tend to die through apoptosis suppresses their immunity even more. That’s two strikes against a patient before any treatment can begin, but their mouse research has suggested there still may be a chance to interfere with the disease cascade.

When mice received transplants of cells that died through necrosis, they experienced increases in the levels of a chemical called interferon-gamma, which raises the question of whether treating septic patients with doses of interferon-gamma might improve their survival. The fact that it seems to work for mice doesn’t mean increasing levels of interferon-gamma will work in humans, but some method of up-regulating immunity might help.

Karl and Hotchkiss are focusing on ways to interfere with apoptosis. They are studying a class of drugs called caspase inhibitors that are designed to prevent the breakdown of cells during apoptosis. Another potential therapy uses methods of stimulating lymphocytes to prevent cell death.

“We’ve been looking at blood samples from patients, and we see that when they aren’t septic, they tend to have very low levels of lymphocyte apoptosis,” Hotchkiss says. “As they become septic, the rate of apoptosis gets higher. In some patients, up to 30 percent of lymphocytes might be dying through apoptosis. As they recover, the rate of apoptosis in lymphocytes starts to decline again. Our preliminary data suggest that this lymphocyte apoptosis correlates with the activity of the sepsis.”

Hotchkiss RS, Chang KC, Grayson MH, Tinsley KW, Dunne BS, Davis CG, Osborne DF, Karl IE. Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proceedings of the National Academy of Sciences, vol. 100 (11), 6724-6729, May 27, 2003.

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. The New England Journal of Medicine, vol. 348: 138-150, Jan. 9, 2003.

Funding from the National Institutes of Health and the Alan A. and Edith L. Wolff Foundation supported this research.