Bright prognosis for brain injury biomarkers

At Dr. Diaz-Arrastia’s institution, the markers are being used for research, though discussions are underway for adopting GFAP and UCH-L1 for clinical care. There’s great interest in reducing unnecessary CTs, and the markers might help. “But that’s not an absolute given,” he concedes. Even if it’s supported by evidence, “You’d have to change the practice style of physicians, which is not always an easy thing to do,” he says with a laugh.

The comparison to troponin is apt in this regard too, Dr. Diaz-Arrastia says, given that it took well over a decade for cardiac troponin markers to become widely accepted in EDs. “Boy, I hope it doesn’t take that long for these TBI biomarkers,” he adds.

The markers might also be useful in triaging patients in mass casualty situations and in low-resource settings, to assess whether someone needs to be evacuated to a higher level of care.

Though the studies show the markers are most useful in predicting outcomes in more severely injured patients (GCS 3–12), there’s interest in exploring use for patients with GCS scores 13 to 15.

“There was a little disappointment that in the less severely injured the markers were not as useful in predicting outcomes,” Dr. Korley says. “But again, it probably just speaks to the fact that for the less severely injured, maybe it’s not about how much brain injury they had; it’s more what they brought to the injury in terms of past medical history including mental health conditions and prior brain injury.”

“We’re still learning about these markers and how they work,” he adds. But he’s hopeful they may eventually be useful even for less severely injured patients, who don’t show high elevations. He offers the example of a patient who is classified as GCS 15, has low biomarker levels, but exhibits many symptoms. “Then the question is: Is it more the anxiety or depression they had prior to the injury that is contributing to symptoms or their extracranial injuries, as opposed to damage of the brain cells? So it could help us with making sure we’re treating the patients appropriately.”

The truly important question for many clinicians, however, has less to do with CT use and more with helping the 20 to 30 percent who are likely to have disabling and perhaps permanent problems after discharge from the ED. That can help with counseling, Dr. Diaz-Arrastia says. “And it’s the only way we’re going to develop therapies. Because it’s impractical to do a clinical trial when the expected placebo response is 70 to 80 percent.”

Traumatic brain injury experts are hoping the markers can help bring about a shift in thinking as well as in patient care.

CT scanning is most useful for identifying the small fraction—one to two percent—of patients who need a neurosurgical intervention. However, it’s not useful for identifying pathologies that result in long-term disabilities after TBI. Dr. Diaz-Arrastia notes the substantial variability in the way patients respond to TBIs, which is in part due to the lack of precise tools to define and measure TBI. “We have many people who appear to have a seemingly mild injury and are told by ED physicians they’ll feel better in a few days.” While that’s often the case, 20 to 30 percent “are still having significant problems months later” after being told they had a mild concussion, such as being unable to return to work or school or to fulfill family responsibilities.

“That’s a significant number,” Dr. Diaz-Arrastia continues. “Certainly none of us would call that a mild injury by any means. And from a clinical point of view, we have no way of predicting who those people are going to be.”

Dr. Korley hesitates to use the term “mild traumatic brain injury” because, he says, it “does a disservice to the people who are going through it.” When physicians use the term, “We’re just saying it’s mild because they’re not in a coma,” though the impact on patients’ lives can be huge, ranging from debilitating headaches to job loss. “So increasingly we’re moving toward using the term GCS 15 traumatic brain injury.”

Words matter, Dr. Manley agrees. “As a specialty we’re working hard to get rid of some of these old terms that don’t help patients.” Older terminology was based on a coma score developed half a century ago, when coma was the primary marker for identifying those at risk for death. Those who didn’t need neurosurgical intervention were “sort of pushed off to the side.”

But longitudinal studies have shown that 50 percent of patients with milder forms of acute injury—those who come to level one trauma centers with a GCS 13 to 15—are not fully recovered after one year. “So there’s really nothing ‘mild’ about that at all,” Dr. Manley says. On the flip side, moreover, many patients who are labeled as having “severe” injuries do far better than initially thought.

Says Dr. Manley: “These terms are not only outdated, but they create bias. We trivialize patients who show up with higher GCS scores, and we are nihilistic about patients with lower GCS scores.”

The new biomarkers could alter such perceptions. If a blood-based biomarker is quite high, that’s concerning. “It’s the same with troponin, right?” Dr. Manley says. “If your troponin is elevated, that’s bad.” And if a blood-based biomarker is low, that’s not necessarily an all-clear for the patient, so to speak, but it does indicate a lower risk of a bad outcome.

Dr. Manley welcomes the objectivity a laboratory test brings. “To me, because we can see blood-based biomarkers in people with a GCS of 15, we’re now getting down to some biology and not a clinical scoring system.”

The markers are only now entering the clinical marketplace, but the military has already begun using them (the Department of Defense helped fund the study, along with the National Institutes of Health), and Dr. Manley says early experience suggests they’ve been helpful in avoiding unnecessary transport of wounded personnel.

He and his laboratory colleagues are considering how the markers might best be used. Right now the focus is on limiting unnecessary head CTs. “The way this is set up currently is to have a very, very high negative predictive value, which means the threshold is low. You don’t ever want to miss anybody who has a positive head CT.”

Managing resources is critical, he says. On a busy weekend at a level one trauma center, there can be plenty of people waiting for a head CT. “Sadly, some of those people needed to be at the front of the line, but you didn’t know that until they decompensated.” Thus, the plan is to start with a point-of-care device that will streamline care on the forefront; eventually they plan to bring on a core lab test, which will be useful should the markers be approved for diagnostic use. Ultimately, he says, he’d like to see the markers used for ruling in the need for an imaging test. In another study involving a TRACK-TBI cohort (Yue JK, et al. Lancet Neurol. 2019;18[10]:953–961), “we looked at GFAP and UCH-L1 levels in patients with normal CTs.” Those with elevated GFAP had MRI findings.

It’s likely that companies will develop both point-of-care and large platform assays, says Dr. Diaz-Arrastia, adding that while his own hospital system does not use POC testing in the emergency department, others might find it useful.

TRACK-TBI used Abbott’s point-of-care i-Stat TBI plasma test, as well as Abbott’s Architect core lab test, switching partway through. A previous study looked at GFAP and UCH-L1 values measured on both types of platforms, showing strong concordance between the two, Dr. Korley says. The researchers also developed equations for predicting point-of-care results based on core laboratory results.

When the TRACK-TBI study began, Dr. Korley says, the researchers used the point-of-care device because it was the most robust assay available. “However, we decided to switch to the core lab assay when it became available because it was easier to assay many samples in a single batch. When you’re doing the point-of-care assay, it’s kind of painful to assay one sample at a time.” The switch, then, “was more out of convenience, and we had previously demonstrated that the results from either assay were nearly equivalent.”

Abbott’s i-Stat TBI plasma test has received FDA 510(k) clearance. The company says it is seeking FDA clearance under breakthrough designation for the TBI test on its Alinity i and Architect core laboratory instruments.

Given the interest in and need for these biomarkers, it’s unlikely GFAP and UCH-L1 will have the final words.

Dr. Diaz-Arrastia predicts neurofilament light might soon receive FDA clearance. NfL is an axonal protein that behaves somewhat differently from GFAP and UCH-L1, he says, but might provide complementary information in evaluating TBI.

As useful as GFAP and UCH-L1, and possibly neurofilament light, appear to be, “we are likely going to need additional biomarkers to help with identifying patients likely to have long-term disability,” Dr. Diaz-Arrastia says. Or perhaps a combination of biomarkers will be useful. “At the end of the day, or even the medium of the day, we’re going to need more than two biomarkers.” Given the complexity of the brain and the heterogeneous pathologies that can lead to disability post-TBI, a panel of six to eight biomarkers might be needed.

Dr. Manley agrees: “I can easily see these markers becoming part of a standard trauma panel.”

In the meantime, laboratories should be aware that the already approved biomarkers are likely to be adopted in many of the major neurotrauma centers—at the very least, Dr. Diaz-Arrastia says. And more will be coming in the future.

“I’m convinced we’re in the early days of this story,” Dr. Diaz-Arrastia says. “There’s actually a lot more to come over the next several years.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.