Blood-based inflammation markers predicted recovery time in high school and college football players who had concussions, a small prospective study showed.
Circulating levels of interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) were elevated 6 hours after concussion, and IL-6 levels predicted the number of days concussion symptoms persisted, reported Timothy Meier, PhD, of the Medical College of Wisconsin in Milwaukee, and co-authors in Neurology.
“Despite the large number of concussions that occur every year during sports, we still don’t have great tools to identify athletes who may be at risk for having prolonged symptoms,” Meier told MedPage Today.
While most concussion biomarker research has focused on identifying blood markers fairly specific to brain injury, other aspects of the neurometabolic cascade hold promise, he added: “These results suggest that acute levels of general markers of inflammation may ultimately prove to be prognostic markers for sport-related concussion, though additional research is needed.”
The findings also highlight IL-6 and IL-1 pathways as possible targets for treatment development, consistent with recent research into recombinant human IL-1RA to treat severe traumatic brain injury.
“What we see in concussion is that most people completely recover, but some go on to have problems,” noted Michael Alosco, PhD, of Boston University, who was not involved with the study. “These inflammatory markers actually might be very important for identifying who does go on to have prolonged problems or delayed recovery,” he told MedPage Today.
But the markers are nonspecific; they can be elevated in other types of injuries, Alosco pointed out. “If you’re focusing on one or two biomarkers, your diagnostic accuracy goes down,” he observed. “What you really need is a panel of biomarkers that can start to tease apart different causes.”
In this study, Meier and colleagues looked at 41 high school and college football players with concussions and 43 matched control athletes. They assessed athletes before injury, at approximately 6 hours and 24 to 48 hours post-concussion, and at about 8, 15, and 45 days after injury. Team physicians or certified athletic trainers identified and diagnosed concussions, which were defined by the CDC’s HEADS UP initiative.
Athletes were male and had an average age of 18. At pre-injury (baseline) and follow-up visits, researchers collected serum levels of IL-6, IL-1β, IL-10, tumor necrosis factor, C-reactive protein, interferon-γ, and IL-1RA, and obtained Sport Concussion Assessment Tool, 3rd edition (SCAT3) symptom severity scores.
Concussed athletes had symptoms for an average of about 9 days and had SCAT3 scores that were significantly higher at the 6- and 24- to 48-hour visits.
Relative to baseline and all other visits, IL-6 and IL-1RA were significantly elevated in concussed athletes at 6 hours post-concussion. Before injury, IL-6 levels were 0.44 pg/mL in the concussion group and 0.40 pg/mL in controls; at 6 hours, they were 1.01 pg/mL in the concussion group and 0.39 pg/mL in controls. The area under receiver operating characteristic curve (AUC) for discriminating concussed athletes from controls at the 6-hour visit was 0.79 (95% CI 0.65-0.92) for IL-6 and 0.79 (95% CI 0.67-0.90) for IL-1RA.
Elevated IL-6 levels at 6 hours post-concussion were significantly associated with longer symptom recovery (HR for symptom recovery 0.61, 95% CI 0.38-0.96, P=0.031). IL-1RA levels, however, were not tied to recovery time. All injured athletes with elevated IL-6 or IL-1RA were symptom-free by the 15-day visit.
The researchers “looked out to 45 days, so this study is really acute,” Alosco said. “It will be interesting to see further follow-up: can these markers predict who’s going to develop midlife or later-life problems? In subconcussive impacts and in concussion, a very small percentage of people go on to develop symptoms that last for up to a year. Can these markers identify those people, too?”
The study has several limitations, Meier and co-authors noted. The sample size may not be large enough to determine the accuracy, precision, specificity, and sensitivity of inflammatory markers as clinical biomarkers of concussion. The study assessed only male high school and college athletes, and the findings might not apply to other groups.
Last Updated July 03, 2019
The study was supported by the Department of Defense, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Center for Advancing Translational Sciences.
The authors reported no relevant disclosures.
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