Sepsis is implicated in half of all hospital deaths and kills nearly a quarter of a million Americans every year.
Practically any type of pathogen - bacteria, fungi, parasites, and
viruses - can provoke the life-threatening condition, which leads to
the body's immune system overreacting and attacking its own tissues and
organs. Sepsis is difficult to diagnose and even more difficult to
‘Measurement of methylthioadenosine or MTA was observed to be 80% accurate in predicting death in sepsis patients.’
Duke scientists have discovered a biomarker for sepsis that could improve early diagnosis,
prognosis, and treatment to save lives.
The new biomarker, a molecule called methylthioadenosine or MTA, can
predict which patients are most likely to die from the illness. The
findings, which appear in the journal Science Advances
could also help determine whether patients could benefit from therapies
that either enhance or suppress the immune system, paving the way for
"This area has been a graveyard for the pharmaceutical industry,
with more than 100 failed clinical trials of therapies that target the
body's abnormal response to infection," said Dennis C. Ko, an assistant professor of molecular genetics and microbiology at Duke
University School of Medicine.
"It may be that these failed clinical trials are not actually
failures of treatment, but rather failures of diagnosis," Ko said. "With
better biomarkers, we may be able to group sepsis patients into more
refined categories to more effectively test and possibly even resurrect
People with sepsis are typically treated with a combination of
antibiotics and supportive care, treatments that target the offending
germs but do nothing to address the runaway immune response that,
ironically, proves more deadly than the infection itself.
In the early stages of sepsis, the immune system churns out
prodigious amounts of inflammatory proteins known as cytokines, some of
which require activation through another class of proteins called
caspases. Caspases can also trigger an explosive form of cell death
aptly called pyroptosis (fire falling) that helps destroy pathogens but
can exacerbate damage to the host if left unchecked.
In a study published five years ago in the Proceedings of the National Academy of Sciences
Ko searched for genetic variants that might predispose people to higher
or lower levels of pyroptosis. His results pointed to some variation
between patients in the components of an intracellular recycling system
known as the "methionine salvage pathway."
In this study, Ko and his colleagues focused their search on a
molecule called methylthioadenosine or MTA, which feeds into the
methionine salvage pathway. They measured levels of MTA in sepsis
survivors and sepsis non-survivors from two independent groups of
patients, and found that those who died from the disease had elevated
levels of the molecule.
They found that measurement of this single molecule was
approximately 80% accurate in predicting death, which is comparable to
the APACHE II (Acute Physiology and Chronic Health Evaluation II) score,
a measurement that is now used in hospitals.
After Ko discovered that MTA could serve as a reliable biomarker of
sepsis, he wondered whether he could change the course of infection by
manipulating levels of the molecule. His lab found that mice infected
with Salmonella lived longer when MTA was administered prior to
infection, suggesting that manipulation of the methionine salvage
pathway could be used to regulate the inflammatory response that leads
But Ko cautions that much more work needs to be done before a
diagnostic or treatment based on MTA could make it into the clinic. It
will be crucial to further examine the utility, dosing,
pharmacodynamics, and mechanism of tweaking MTA levels in animal models,
and if results are promising, to validate them in patients.
"It gets very complicated very fast," said Ko. "Some people might
have too robust of an inflammatory response, some people might not have a
robust enough response, and as a result their MTA levels will differ,
both between individuals and within an individual over the course of an
illness. Biomarkers could determine where individuals fall along that
continuum, and what treatments might work."