Sepsis, or septic shock, kills approximately 500,000 people worldwide each year. Antibiotics remain a first line of defense for those suffering from infections, such as pneumonia, which can enter the bloodstream and cause sepsis. Once past the barriers guarding the bloodstream, bacteria and viruses can directly damage the blood vessels supplying the various organs, but worse yet, these organisms can trick the patient’s own inflammatory and blood clotting defenses into overreacting and making the damage even worse.

Our group studied the pathophysiology of sepsis caused by organisms ranging from E. coli to B. anthracis using the baboon as a model of the human diseases caused by these organisms. We used monoclonal antibodies and related antagonists against the naturally occurring mediators and regulators of the inflammatory hemostatic and tissue repair networks to manipulate the host’s innate response to these organisms.

Using the baboon model of E. coli sepsis, we developed a treatment of severe sepsis in humans using activated protein C (Xigris, Eli Lilly; no longer available) that reduced the relative mortality by 20 percent. In order to improve these results, we focused on two lines of investigation. First, we studied the effect of high concentrations of activated protein C given earlier and over a much shorter time, thus reducing the total amount of enzyme required. This attenuated the initial metabolic inflammatory disturbance in the target cells, which is one of the principal effects of Xigris. Second, we studied the natural history of E. coli sepsis that consists of a sequence of partially overlapping pathophysiologic processes, any one of which can be lethal. This smorgasbord of processes may account for why Xigris worked in some cases but not in others. Analysis of both plasma and tissues using mRNA, antigen, enzyme activity and genetic analysis over the course of the response may lead to earlier and more specific diagnosis and more appropriate treatment of severe sepsis.

One cannot treat effectively unless one can diagnose, and one cannot diagnose unless one knows severe sepsis in all its guises.

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