Study identifies specific genetic factors that influence occurrence and severity of sepsis

A study published in the June issue of Anesthesiology represents an important first step in establishing new therapeutic options targeting specific genetic areas that influence the occurrence and severity of sepsis - a life-threatening, whole-body response to infection.

Researchers at the Clinic for Anesthesiology and Intensive Medicine, and Institute for Physiology, University of Duisburg-Essen, Germany, are the first to study the regulation of hypoxia-inducible-factor-1 (HIF-1) in sepsis patients.

"Clinicians frequently encounter situations where two very similar patients with sepsis have vastly different outcomes," said lead study author Simon T. Schafer, M.D. "One patient might die, while the other survives. We still have no idea how to explain these differences in the outcome. Patient outcome seems to rest heavily on the body's response to the infection, which can range from uncontrolled immune system-driven inflammation to nearly shutting down of the immune system. This work suggests that HIF-1 is critical to that immune regulation."

HIF-1, a protein that binds to certain DNA sequences, allows immune cells in the body to function when oxygen is decreased or when bacterial infections occur. This upregulation of HIF-1 protects cells from the resulting build-up of acid in the blood and other conditions related to a lack of oxygen. In essence, the body's immune cells respond to a lack of oxygen by activating HIF-1.

When Dr. Schafer and his research team studied 147 patients at their institution (99 septic patients and 48 healthy volunteers), they found that:

•In septic patients, as early as 24 hours after diagnosing sepsis, HIF-1 was decreased by 67 percent in white blood cells compared to the healthy 48 volunteers and was associated with increased severity of illness.

•When observing the immune response in the laboratory, short-term administration of lipopolysaccharides (large molecules that elicit immune response in humans) to immune cells caused HIF-1 expression to increase. But when lipopolysaccharides were administered long-term, HIF-1 expression and HIF-1 protein were suppressed.

These results could indicate that the immune state of the septic patients, despite meeting the clinical criteria for severe sepsis or septic shock, had already shifted to an immunosuppressive pattern (as opposed to an inflammatory response), resulting in decreased HIF-1 expression.

"Understanding the mechanisms that shift the immune response from the pro-inflammatory reaction to an immunosuppressive state will be important in improving patient outcomes through personalized therapies in the intensive care unit," said Dr. Schafer. "Our research helps to understand the underlying mechanisms in severe sepsis associated with HIF-1 and genetic variations of key regulators of the immune system. This can help us to predict the chances for surviving sepsis, and may give us new treatment options."