Monday, May 31, 2010

Sepsis: A Severe Shock

At the beginning of the weekend I received a real shock: one of the other father's in TNG's Cub Scout Pack had died of sepsis after a failed endoscopic procedure. His son is a year younger than mine's, but we interacted a bunch on various outings & in my mind's eye I can still see his smiling face illuminated by a lantern at a recent campout. He was a mathematician & I have a bit of a natural draw to anyone in a technical field. Plus, it is always unsettling to have a near contemporary pass so suddenly and from such an unexpected source.

That someone relatively young and being treated in a hospital widely acclaimed as one of the world's best illustrates the grim terror of sepsis. I have never worked directly on it, though when I was an intern at Centocor the lead agent in their therapeutic pipeline was directed against gram-negative sepsis, that is sepsis resulting from an infection by gram negative bacteria. At the time I was there, Centocor and their rival Xoma were cross-suing each other over patent issues for their sepsis drugs (both monoclonal antibodies) and the Department of Defense was accepting the unapproved drug for possible use in the First Gulf War.

Both Xoma & Centocor unfortunately ended up following the path which so far has characterized sepsis: both drugs failed in the clinic, nearly pulling both organizations down with them. Numerous drugs have failed in the clinic for sepsis. A significant challenge is that in sepsis one must somehow prevent the immune system from causing collateral damage to the body while not preventing it from combating the grave infection which is triggering the reaction.

Clearly, this is a tough nut. The Centocor & Xoma drugs both tried to target a toxin (endotoxin A) which is released by dying gram negative bacteria. One thought I had at the time is that a diagnostic would be valuable which would enable distinguishing those patients with gram negative infections who could potentially benefit from those with gram positive infections who could not. In retrospect, even such a diagnostic is a tough challenge -- to be of any clinical value it would need to return results in a matter of minutes or a few hours. That's a hard problem. Other therapies which have been tried in the clinic have tried to modulate the immune system and proven no more effective.

Even running a sepsis trial is clearly an even greater challenge than your average serious disease trial. Obtaining proper informed consent from patients who are at risk of dying in a very short timespan cannot be easy. Challenges in running other trials in emergency medicine situations have befouled another biotech horror land: blood substitutes.

Quite likely a key part of the problem is that we just don't understand this area of biology well enough. Perhaps intensive proteomic and metabolomic analysis on collected samples will yield new markers which will guide better management. Perhaps better animal models can be developed and exploited to understand the complex series of events which occur in sepsis.

I wish I had some answers; on this I'll declare complete defeat. That, and a haunting image in my mind of a cheerful face which now exists only in memories and photographs.

1 comment:

Unknown said...

I don't know if any new info has been released since the original announcement (link below) but cepheid and biomerieux were working on a rapid test for sepsis using cepheids cartridge based gene expert system. This system is a real-time PCR system which can be run on single samples with very rapid results. Let's hope for success here or some other rapid test.