Sepsis is an important cause of mortality, causing an estimated 60,000 deaths yearly. Sepsis is also expensive to treat, and is associated with expensive medical procedures, such as life support and intensive care. Despite advances in supportive care over the last 30 years, the mortality rates have remained stubbornly high, as much as 30-40%.

Persistently high mortality has prompted many researchers and funding organizations to seek immune modulating drugs to decrease the apparently harmful inflammatory effects of sepsis. Inflammation is tightly linked with blood clotting. In sepsis, which has been described as an out of control inflammatory response, both inflammation and blood clotting have been linked with increased mortality.

One thing that biomedical researchers noticed was that septic patients who die often had low levels of activated protein C. A recombinant form of activated protein C, called  Xigris, was developed as an anticoagulant (blood thinner) that also has anti-inflammatory properties. Since inflammation was thought to be out of control in the systemic inflammatory immune response, it stood to reason that an inhibitor of inflammation and clotting might reduce deaths in sepsis.

In 2001 the PROWESS study appeared to show just that.

10 years late, on October 25, 2011 the FDA recommended that Xigris be withdrawn from the market. Remarkably, the company selling Xigris, Eli Lilly, was able to profit from this ineffective drug for nearly the entirety of the time Xigris was under patent. The long road to arrive at this conclusion is an interesting story:

http://pulmccm.org/2012/randomized-controlled-trials/xigris-epitaph-prowess-shock-results-nejm/

Does it also hold lessons for the functioning of the immune system, and for evolution? Yes. This example and many others suggests that anti-inflammatory therapy in sepsis won’t work. These results also indicate that the immune response in sepsis is adaptive, not maladaptive. Further efforts to discover “silver bullet” immunotherapies in sepsis should be abandoned*.

(*unless the intervention has a direct anti-microbial effect. More on that later…)

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine