Genetic response to injury may provide path to personalized management of trauma patients

Ronald V. Maier, MD, FACS, FRCSEd(Hon), FCSHK(Hon), FCCS(Hon)
Ronald V. Maier, MD, FACS, FRCSEd(Hon), FCSHK(Hon), FCCS(Hon)

Patients who survive massive trauma often fare poorly. Many patients heal slowly, develop surgical infections, pneumonia, urinary tract infections, and multiple other problems that do not appear to be directly related to their trauma. Research suggests that the root cause is not their physical injuries, but rather their genomic response to their injuries.

Of 20,000-plus genes examined in a study of patients who survived motor vehicle collisions, more than 16,000 genes (80 percent) showed a measurable change of function following blunt trauma. About a third of the genes—most of them associated with inflammatory processes that potentially lead to kidney failure, pulmonary dysfunction, and other tissue damage—are upregulated. Two-thirds are down-regulated following trauma, primarily affecting the adaptive immune response, according to the study, which was published in the Journal of Experimental Medicine in 2011.

“The vast majority of these down-regulated genes are related to immunity against infection and support wound healing,” said 2018−2019 American College of Surgeons (ACS) President Ronald V. Maier, MD, FACS, FRCSEd(Hon), FCSHK(Hon), FCCS(Hon). “Their immune system is depressed, wound healing is impaired, and their metabolism is dysfunctional to the point that they can’t absorb or utilize nutrients. This helps to explain why people don’t heal well after massive injury.”

Dr. Maier will discuss genomic responses to trauma during Monday afternoon’s I.S. Ravdin Lecture in the Basic and Surgical Sciences, Response to Injury: The Genomic Storm and Precision Medicine. Dr. Maier is surgeon-in-chief, Harborview Medical Center, Seattle, and the Jane and Donald D. Trunkey Professor of Trauma Surgery, University of Washington School of Medicine.

One of the practical problems in treating trauma patients is the lack of reliable clinical markers to help distinguish between patients who will recover in a few days and those who suffer complications and recover more slowly, Dr. Maier said. But genetic differences are evident.

“The difference between the faster healers and the slower healers was how quickly the individual was able to restore homeostasis, to restore genomic function to normal,” Dr. Maier said. “By 24 to 48 hours after injury, the two curves had clearly started to separate. Patients whose genomic function remained abnormal developed complications and patients who quickly returned toward baseline healed within five days.”

The researchers identified 63 specific genes that differ between faster and slower healers, Dr. Maier said. Functional variations in those genes appear to predict faster, uncomplicated recovery or slower recovery and complications following trauma. Just as specific genetic markers can be used to guide and personalize treatment for breast, lung, prostate, and other cancers, genetic markers may eventually help guide and personalize trauma interventions, Dr. Maier said.

Evidence for a genomic storm following massive trauma is not entirely unexpected, he added. Other groups have found similar genomic responses to surgical trauma, though on a much smaller scale, likely because the physical and physiologic insults from major surgery is far less than the broken bones, abdominal trauma, blood loss, and other injuries resulting from major traffic accidents.

“It’s like having a major operation is 10 percent as bad as being hit by a truck, but there are similar dysfunctional changes to the immunologic status of the patient,” Dr. Maier said. “Genomic analysis and personalized treatment is virtually a bedside technique today, and is going to spread to cardiac disease, vascular disease, and eventually to trauma and to surgery. Once you find the genes known to make outcomes worse, you can develop treatments to modify the genomic response and avoid the complications of trauma and surgery.”

This annual lecture has been sponsored by the I.S. Ravdin Surgical Society since 1964 to honor Dr. Ravdin by promoting knowledge in basic sciences with application to surgery.

I.S. Ravdin Lecture in the Basic and Surgical Sciences

Response to Injury: The Genomic Storm and Precision Medicine
Ronald V. Maier, MD, FACS, FRCSEd(Hon), FCSHK(Hon), FCCS(Hon)
4:15–5:00 pm, Monday
Moscone Center West, 3014–3018