Study offers insight into why different trauma patients respond differently to similar injuries

As any trauma surgeon will tell you, two people can suffer similar injuries from a car crash or bullet wound, yet one will live while the other dies. There's no good way to tell who will make it.

Princeton University scientists say they now are starting to get some answers.

The key, they reported in a new study, is to track activity levels in certain of the patient's genetic pathways - in particular, two that regulate inflammation and help the body recognize harmful microbes.

In theory, measuring the "flux" for these genes could help physicians to predict who is headed downhill, allowing them to provide better, more targeted care. It also opens the door to developing targeted drugs for these patients on the brink, an area of trauma research that has previously shown promise in animals, only to fizzle out in humans.

The researchers, who published their findings in PLoS Medicine, evaluated 168 people who had suffered traumatic injury in a car crash. They measured the expression of thousands of genes - essentially, the degree to which the genes were turned on or off - over 28 days. Patients also were grouped into five categories based on how well they fared on a range of measures, including whether they suffered multiple organ failure, infections, and death.

The results: Each of the five categories had its own fingerprint, as measured by the trajectories in the activity of certain broad gene sets over 28 days. The clearest patterns were evident in pathways named p38MAPK and MHC-II, which play a role in inflammation and fighting pathogens, respectively.

For example, patients in the most severe of the five outcome categories, all of whom died, displayed a marked increase in p38MAPK activity coupled with a decline in MHC-II.

This finding gave the researchers confidence in their results, said senior author John Storey, an associate professor of molecular biology at Princeton University. That's because it corresponded generally with what trauma surgeons already knew - that in patients who end up dying, inflammation spirals out of control while the body loses its ability to fight off invaders.

"We didn't use any prior knowledge," Storey said of the genetic analysis. "What very clearly emerged was a pretty interesting separation of patients that makes a lot of biological sense."

Storey and his Princeton colleagues collaborated with others at Johns Hopkins University, the University of Washington, and Harvard Medical School. The research is part of a larger 10-year, $100 million effort to understand the body's response to trauma and inflammation - a project that is federally funded and based at Massachusetts General Hospital.

David B. Hoyt, a longtime trauma surgeon and researcher who is now executive director of the American College of Surgeons, said the study was promising.

"It says to a certain extent that your response is hardwired by your genetic code," Hoyt said. "As we learn about this and can profile a patient more quickly, then we can design therapy or anticipate somebody who's going to have a complication much more precisely."

Hoyt, who was not involved with the new study, said the results would prove useful in tailoring drug trials. Previously, some drugs have shown promise in animals with traumatic injuries but not in humans, possibly because some of the human patients would have recovered anyway, he said. Statistically speaking, in other words, any positive effects of the drugs may have been obscured.

Storey agreed.

"What ends up happening is, the drugs get administered in a randomized way to lots of individuals who don't need it," Storey said.

The activity in these genetic pathways can be readily measured by any hospital lab through existing blood tests. The tab might be up to a few thousand dollars per patient, Storey said, but that cost would likely come down through widespread use.

Even before these findings are applied in future drug discovery, they could allow clinicians to give their patients better care.

Often a trauma patient will stabilize and survive the initial injury, but a week or two later will develop a systemic inflammation and soon die.

With the information from the new study, physicians could pay extra attention to those who showed a dangerous trend in the key genetic pathways.

Those whose prognosis looked good, on the other hand, could be spared unnecessary treatments.

"You end up wasting tons of resources on patients who are going to be just fine," Storey said of current practice. "This would allow you to separate these patients and really focus your resources on those patients who appear to be going in this bad direction."