AT LAST treatments are being developed that directly tackle septic shock, a
condition that kills at least 1400 people worldwide every day.
Septic shock occurs when the immune system runs out of control. The resulting
inflammation, low blood pressure and abnormal blood clotting are often fatal.
The condition can be triggered by a variety of viruses, fungi, protozoans and
bacteria, including the bug that causes bacterial meningitis. 鈥淭his is a
condition which has a standard mortality of 35 to 40 per cent, even in the best
hands,鈥� says Jonathan Cohen of Imperial College, London.
At the moment, there is little that doctors can do besides give people
antibiotics and put them on life support. Experimental treatments that target
just one part of the problem, such as mopping up bacterial toxins, have had only
limited success. So researchers are instead focusing on subduing the panicked
immune response. The first fruit of this effort is a drug called Xigris, which
is on the verge of approval by the FDA.
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The drug is a synthetic form of a blood protein called activated protein C
that dampens down both inflammation and blood clotting. 鈥淴igris tackles both
sides of the problem, which is probably why it has been successful,鈥� says
Jonathan Janes of Eli Lilly, the company that developed the drug.
In reactions to trials, Xigris cut the death rate from severe infections, or
sepsis, by nearly 20 per cent鈥攁 significant step but not a complete
answer. 鈥淭here probably won鈥檛 be a single magic bullet to cure sepsis,鈥� says
Cohen. Different combinations of drugs may be needed in specific cases.
But researchers are on the brink of developing other drugs, he says. Marco
Colonna鈥檚 group at the Institute for Immunology in Basle, Switzerland, have
found a receptor called TREM-1 on the surfaces of immune cells that helps alert
the immune system to the presence of bacteria. Blocking TREM-1 in mice protected
the animals from septic shock.
What鈥檚 more, injecting a soluble form of TREM-1 also protected the animals,
probably by acting as a decoy that mops up the bacterial protein that activates
immune cells. The discovery has been patented. Colonna, now at the University of
Washington at St Louis, says the advantage of targeting TREM-1 is that it would
prevent an excessive immune response without blocking it completely. 鈥淭his could
be a good way of blocking the amplification of the response while maintaining
some inflammatory responses,鈥� he says. Cohen agrees that balance is the key. 鈥淚f
we knock the immune system too much, we will compromise the patient,鈥� he
says.
More treatments could come from strains of mice that are naturally resistant
to septic shock brought on by 鈥淕ram-negative鈥� bacteria, a group that includes
the meningitis bacterium. These bugs contain a molecule called
lipopolysaccharide, or LPS, that acts as a red rag to the immune system. Yet
mice with a faulty receptor called TLR4 are resistant to LPS-induced shock.
The need for effective treatments has never been more urgent. The incidence
of sepsis in the US has increased by more than a quarter since 1988, possibly
because of a rise in invasive surgery.