Conference Coverage

Genomics have changed how researchers view trauma’s immunologic impact


 

EXPERT ANALYSIS FROM CCC48

– Severely injured patients often experience a massive inflammatory and immunomodulatory response that can lead to multiple organ failure, nosocomial infections, long ICU stays, and poor outcomes. But not all of them do. Some patients recover relatively rapidly, achieve earlier release, and have a faster immunologic recovery trajectory.

The longstanding theory, according to Ronald Maier, MD, a professor of surgery at the University of Washington, is that a trauma-related stimulus leads to an aggressive inflammatory response that can lead to multiple organ failure and death. In patients who recover from this early challenge, the theory goes, a counterregulatory response may overexuberantly down-regulate the inflammatory storm, which leaves the patient vulnerable to infections and poor wound healing. Then a later infection, sepsis, endotoxemia, or some other stimulus may ramp up the inflammatory system again, which leads to a crisis that can trigger mortality well after the initial trauma. Patients who recover from this challenge then return to homeostasis.

It’s a neat theory, but it’s wrong, said Dr. Maier in a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine. It has been undercut by genomic technology and high-throughput methods that have provided a new approach to investigating the underlying biology, as well as the ability to test circulating white blood cells to measure a patient’s immune response to traumatic injury.

“If you look at the underlying biology by looking at the genomic response, you can see that it’s not a sequential process. There is simultaneous up-regulation and down-regulation,” said Dr. Maier.

A study of 35 trauma patients using a gene chip found a measurable change in expression of over 17,000 genes; 5,136 genes had at least a twofold change in expression. “Eighty percent of the human genome changes measurably when you are hit by a cement truck,” said Dr. Maier.

To researchers’ surprise, more genes were found to be down-regulated in the immediate aftermath of the injury, and most of those down-regulated genes are involved in adaptive immunity. Up-regulated pathways were included in the innate and proinflammatory response. “The simultaneous down-regulation of the adaptive arm explains why the patients in the ICU with severe injuries are very susceptible to nosocomial infections, poor wound healing, and multiple complications,” said Dr. Maier.

Genomic studies also show down-regulation of genes associated with phagocytosis even out to 45 days. “Sometimes I wonder why every patient doesn’t evolve a nosocomial infection as a consequence of this impact on the immune system. In fact, I think it’s a great testimony to the countermeasures we’ve taken as far as sterility, hand washing – we’ve been able to prevent this dysfunction from being expressed as a nosocomial infection,” said Dr. Maier.

The genomic analysis can also be used to discriminate patients who regain homeostasis relatively quickly after severe trauma. There seems to be an inflection point between patients who resolve by 5 days and those who go on to experience prolonged ICU stays.

Perhaps surprisingly, the researchers found little difference between the two groups in terms of specific genes that were up- or down-regulated. Instead, the “uncomplicated” group saw their altered gene expression patterns return more quickly to baseline levels, whereas “complicated” patients lingered in the dysregulated state. “We’ve been chasing biomarkers for 35 years, and this explains why it’s very difficult. Those who do well return toward normal quickly. Those who have complications stay abnormal,” said Dr. Maier.

Instead, researchers identified a panel of 63 gene probes that can track the overall progress of the “genomic storm,” as he referred to the changes that occur in the wake of trauma. “This panel of 63 genes is the best predictor of the patient’s response to injury – better than injury severity score, better than multiple organ failure scores,” he said.

Dr. Maier is confident that such panels can alter patient management, even outside of trauma. “It may allow us to show which patients are going to have risk of early recurrence because of alterations in their adaptive immunity versus those who aren’t. We’re also going to predict those who are going to have infectious complications. Hopefully we’ll soon have a handle on which patients we need to be most aggressive with, and we can use monitoring to measure our therapeutic impact,” said Dr. Maier.

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