Summary: The levels of two protein biomarkers, GFAP and UCH-L1 found in blood samples taken 24 hours after a traumatic brain injury can help to predict which patients will die and which will obtain a severe disability.
Blood tests taken within 24 hours of a traumatic brain injury (TBI) flag which patients are likely to die and which patients are likely to survive with severe disability, according to a study headed by UC San Francisco, the University of Pennsylvania and the University of Michigan.
Their results — available within minutes — may confirm the need for prompt surgical interventions or may help guide conversations with families in cases of devastating injury.
The tests, which detect two protein biomarkers, were cleared by the Food and Drug Administration in 2018 for use in determining which patients with mild TBI should undergo CT scans. High values of these biomarkers, GFAP and UCH-L1, correlate with death and severe injury, the authors state in their study publishing in The Lancet Neurology on Aug. 10, 2022.
Co-senior author of the study, Geoffrey Manley, MD, PhD, professor and vice chair of neurosurgery at UCSF, said these blood tests are “both diagnostic and prognostic,” as well as easy to administer, swift and inexpensive.
In the study, researchers from TRACK-TBI, a UCSF-led brain injury research initiative, examined the day-of-injury blood tests of 1,696 patients with TBI, using the Abbott i-STAT Alinity, a portable blood analyzer, and the ARCHITECT assays.
The results of these blood tests were compared at patients’ six-month assessments, using the Glasgow Outcome Scale Extended, which grades outcomes and quantifies levels of disability following TBI. These outcomes range from death (level 1) to complete recovery with resumption of normal life but minor deficits in some cases (level 8).
1 in 5 Patients Died or Had Severe Disabilities
Approximately two-thirds of the patients were male, and their average age was 39. They had been evaluated at 18 Level 1 trauma centers for injuries caused primarily by traffic accidents or falls. At six months following injury, 7% of the patients had died, 14% had an “unfavorable outcome,” with level 2 to 4 injuries ranging from vegetative state to severe disability requiring daily support.
The remaining 67% had “incomplete recovery” ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.
The researchers found that the day-of-injury blood tests had a high probability of predicting death at six months, 87% for GFAP and 89% for UCH-L1; and a high probability of predicting severe disability at the same timepoint, 86% for both GFAP and UCH-L1. But they were significantly less accurate in predicting incomplete recovery versus complete recovery: 62% and 61%, respectively.
“We believe this tool may encourage clinicians to be more aggressive in their decisions to begin or continue life-saving treatment,” said Manley, who is the principal investigator of TRACK-TBI and a member of the UCSF Weill Institute for Neurosciences. “Modern trauma care can result in good outcomes in what we had once believed were non-survivable injuries.”
Their results — available within minutes — may confirm the need for prompt surgical interventions or may help guide conversations with families in cases of devastating injury. Image is in the public domain
The blood tests may also guide discussions with families in the cases of catastrophic injuries, he said, and assist in “mass casualty situations where they may play a critical role in triage and resource allocation.”
This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at six months after injury,” said first author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan.
“Although there have been previous prognostic studies, they have used a limited number of patients, which can result in imprecise estimates.”
Prognostic Models Add to Accuracy of Blood Tests
The researchers wanted to see if accuracy in predicting outcome would be boosted if the two blood tests were done together and combined with prognostic models that looked at variables like age, motor score, pupil reactivity and CT characteristics.
They found that in patients with severe and moderate TBI, the accuracy of predicting death and severe disability increased to 94% and 89%, respectively. But in patients with mild TBI, the probability of predicting complete recovery versus incomplete recovery increased only to 69%.
Structural brain injury detected by CT and MRI has been reported as an independent predictor of risk of moderate and mild disability in mild TBI, noted co-senior author Ramon Diaz-Arrastia, MD, PhD, professor of neurology at the University of Pennsylvania’s Perelman School of Medicine and director of the Traumatic Brain Injury Clinical Research Center at Penn Presbyterian Medical Center.
“Therefore, although structural brain injury, as measured by GFAP and UCH-L1, as well as CT scanning, may play a predominant role in determining poor outcome in moderate and severe TBI, mechanisms of injury relating to poor outcome after mild TBI are not yet fully understood,” said Diaz-Arrastia, noting that further study would be required to reproduce these findings.
TBI is a heterogenous condition that requires a “rich and diverse dataset like that of the TRACK-TBI study,” said Nsini Umoh, PhD, Division of Neuroscience program director at the National Institute of Neurologic Disorders and Stroke, which funded the study. “One aim of TRACK-TBI is to develop better prognostic tools for TBI patients, which could help predict recovery trajectory and inform therapeutic options.”
Co-Authors: For a full list of authors, please refer to the study.
Disclosures: Frederick Korley, MD, PhD, has consulted for and received research funding from Abbott Laboratories.
Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study
The prognostic value of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) as day-of-injury predictors of functional outcome after traumatic brain injury is not well understood. GFAP is a protein found in glial cells and UCH-L1 is found in neurons, and these biomarkers have been cleared to aid in decision making regarding whether brain CT should be performed after traumatic brain injury. We aimed to quantify their prognostic accuracy and investigate whether these biomarkers contribute novel prognostic information to existing clinical models.
We enrolled patients from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) observational cohort study. TRACK-TBI includes patients 17 years and older who are evaluated for TBI at 18 US level 1 trauma centres.
All patients receive head CT at evaluation, have adequate visual acuity and hearing preinjury, and are fluent in either English or Spanish. In our analysis, we included participants aged 17–90 years who had day-of-injury plasma samples for measurement of GFAP and UCH-L1 and completed 6-month assessments for outcome due to traumatic brain injury with the Glasgow Outcome Scale–Extended (GOSE-TBI). Biomarkers were analysed as continuous variables and in quintiles.
This study is registered with ClinicalTrials.gov, NCT02119182.
We enrolled 2552 patients from Feb 26, 2014, to Aug 8, 2018. Of the 1696 participants with brain injury and data available at baseline and at 6 months who were included in the analysis, 120 (7·1%) died (GOSE-TBI=1), 235 (13·9%) had an unfavourable outcome (ie, GOSE-TBI ≤4), 1135 (66·9%) had incomplete recovery (ie, GOSE-TBI <8), and 561 (33·1%) recovered fully (ie, GOSE-TBI=8).
The area under the curve (AUC) of GFAP for predicting death at 6 months in all patients was 0·87 (95% CI 0·83–0·91), for unfavourable outcome was 0·86 (0·83–0·89), and for incomplete recovery was 0·62 (0·59–0·64). The corresponding AUCs for UCH-L1 were 0·89 (95% CI 0·86–0·92) for predicting death, 0·86 (0·84–0·89) for unfavourable outcome, and 0·61 (0·59–0·64) for incomplete recovery at 6 months. AUCs were higher for participants with traumatic brain injury and Glasgow Coma Scale (GCS) score of 3–12 than for those with GCS score of 13–15.
Among participants with GCS score of 3–12 (n=353), adding GFAP and UCH-L1 (alone or combined) to each of the three International Mission for Prognosis and Analysis of Clinical Trials in traumatic brain injury models significantly increased their AUCs for predicting death (AUC range 0·90–0·94) and unfavourable outcome (AUC range 0·83–0·89). However, among participants with GCS score of 13–15 (n=1297), adding GFAP and UCH-L1 to the UPFRONT study model modestly increased the AUC for predicting incomplete recovery (AUC range 0·69–0·69, p=0·025).
In addition to their known diagnostic value, day-of-injury GFAP and UCH-L1 plasma concentrations have good to excellent prognostic value for predicting death and unfavourable outcome, but not for predicting incomplete recovery at 6 months. These biomarkers contribute the most prognostic information for participants presenting with a GCS score of 3–12.
US National Institutes of Health, National Institute of Neurologic Disorders and Stroke, US Department of Defense, One Mind, US Army Medical Research and Development Command.