The Genes Behind Septic Shock

For most people, an infection with the bacteria Nisseria meningitidis means nothing more than a dose of antibiotics and a few days of headache and malaise. But in some patients, the infection triggers a severe reaction called septic shock, which causes organ failure and is fatal in up to 50% of cases. Now two teams of researchers report in this week's Lancet that a genetic variation may predispose some people to this deadly cascade.

N. meningitidis is a common bacterium, present in the mouth and nose of up to 20% of some populations. Occasionally, it enters the bloodstream or spinal fluid and causes disease. Most cases have few complications, but in some patients the bacterium causes the body's clotting mechanism to go haywire. Bruises form all over the body as clots form in arteries, cutting off blood to fingers, toes, and vital organs. Some patients who survive have to have limbs amputated.

Previous work had shown that several proteins involved in blood clotting were present in unusual levels in patients with septic shock. One of those proteins, called plasminogen-activator-inhibitor-1 (PAI-1) inhibits the production of another protein that breaks down blood clots; high levels of PAI-1 mean the body doesn't break down clots as efficiently. Patients who develop septic shock tend to have higher levels of this protein than those with mild infections.

Two teams of scientists tested the blood of patients with N. meningitidis infections and their families, looking for a known genetic variation that increases production of PAI-1. One group, which included Michael Levin of the Imperial College School of Medicine in London and his colleagues at Sophia Children's Hospital in Rotterdam, Netherlands, found that patients with the variation were twice as likely to die from an N. meningitidis infection. And a second group, led by physician Rudi Westendorp of Leiden University Medical Center in the Netherlands and his colleagues, found that patients who carried two copies of the variation were five times more likely to develop septic shock than those who had another genotype.

The studies are "extremely helpful in illuminating the mechanism by which people develop severe disease," says medical microbiologist Keith Cartwright of Gloucestershire Royal Hospital in the U.K. That knowledge, say the authors of the studies, will help researchers develop more effective therapies for treating septic shock and will help identify people who should be vaccinated against the bacteria.

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