Study reveals important genetic factors that could influence survival in sepsis patients

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.”

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UNIVERSITY HOSPITAL ESSEN, THE RUHR METROPOLIS HOSPITAL
The University Hospital Essen is a maximum care hospital in the Ruhr-Metropolis. Approximately 48,679 inpatients in 1,300 beds and 163,149 outpatients were treated last year. More than 5,590 experts of different disciplines guarantee excellent and interdisciplinary diagnostic approaches and therapies based on the most recent research in 26 clinics and 20 institutes. The combination of research, teaching and patient care form the comprehensive arch of all actions at the University Hospital Essen – however, the patient always remains the center of our attention. Apart from the research areas of genetic medicine, immunology and infectiology, the University Hospital has for years been successfully concentrating on its three major focus areas: oncology, cardiovascular diseases and transplantation medicine. www.uk-essen.de