Reliable Change in Inflammatory Biomarkers Following Sport-Related Concussion: A CARE Consortium Study

Anna Croghan, Medical College of Wisconsin, Milwaukee, United States
Daniel Huber, Medical College of Wisconsin, Milwaukee, United States
Bryna Goeckner, Medical College of Wisconsin, Milwaukee, United States
Jessica Gill, National Institutes of Health & Johns Hopkins School of Nursing and Medicine, Baltimore, United States
Paul Pasquina, Uniformed Services University of the Health Sciences, Bethesda, United States
Steven Broglio, University of Michigan, Ann Arbor, United States
Thomas McAllister, Indiana University School of Medicine, Indianapolis, United States
Jaroslaw Harezlak, School of Public Health-Bloomington, Indiana University, Bloomington, United States
Michael McCrea, Medical College of Wisconsin, Milwaukee, United States
Benjamin Brett, Medical College of Wisconsin, Milwaukee, United States
Timothy Meier, Medical College of Wisconsin, Milwaukee, United States


Acute elevations in blood-based inflammatory markers following sport-related concussion (SRC) have been documented on a group level, with return to baseline levels further from injury. Establishing meaningful thresholds for identifying acute elevations in inflammatory markers on the patient-specific level is critical. This study investigated the utility of reliable change indices (RCI) in assessing the acute effects of SRC on blood-based inflammatory biomarkers among collegiate athletes. The primary objectives of the study were to determine 1) if patterns of acute elevations using RCI mirror those at the group level and 2) if RCI methods can identify individual athletes exhibiting elevations in inflammatory markers at early-, mid-, and late-acute points post-injury.

Participants and Methods:

Collegiate athletes, including those with SRC (n=362) and control groups (n=345), enrolled in the Concussion Assessment, Research and Education Consortium and provided blood samples at pre-season baseline and following injury (0-12 hours post-injury[PI], 12-36 hours PI, and 36-60 hours PI). Log-transformed serum inflammatory markers included C-reactive protein (CRP), interleukin(IL)-6, IL-1RA, IL-8, IL-10, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF). RCIs for each biomarker were computed based on Jacobson and Truax’s (1991) method and derived from the baseline-to-time point differences in control group. RCIs were calculated for concussion and control groups at the three post-baseline time points. The proportion of RCI values falling above a cutoff greater than 1.65 (corresponding to the upper limit of a 90% confidence interval) were compared between control and concussion groups across the three time points for each biomarker with chi-squared tests.


A significantly greater proportion RCIs exceeding the 1.65 cutoff were observed for IL-6, χ2= 9.92, p=.002 among concussed athletes compared to controls at early-acute post-injury (0-12 hours). A similar pattern approaching statistical significant was observed for IL-1RA at the same time point, χ2=3.81, p=.051. Group differences were not observed for other markers or at the mid- to late-acute points, ps>.05. The proportion of RCIs greater than 1.65 were as follows for control and concussion groups, respectively, 1) CRP (0-12 hours=6.1% and 6.8%, 12-36 hours=8.6% and 6.7%, and 36-60 hours=7.3 and 6.1, 2) IL-1RA (0-12 hours=7.8% and 16.4%, 12-36 hours=9.3% and 7.0%, 36-60 hours=5.1% and 5.9%), 3) IL-6 (0-12 hours=3.9% and 15.9%, 12-36 hours=7.5% and 8.5%, 36-60 hours=3.2% and 1.3%), 4) IL-8 (0-12 hours=9.5% and 5.6%, 12-36 hours=6.3% and 7.4%, 36-60 hours=2.4% and 3.4%), 5) IL-10 (0-12 hours=4.0% and 2.8%, 12-36 hours=2.7% and 6.4%, 36-60 hours=7.5% and 4.6%), 6) TNF (0-12 hours=2.8% and 4.2%, 12-36 hours=7.9% and 6.7%, 36-60 hours=2.4% and 3.4%), and 7) VEGF (0-12 hours=4.5% and 4.2%, 12-36 hours=1.2% and 0.7%, 36-60 hours=2.4% and 6.3%).


The current study demonstrated that RCI methods yield comparable findings to those at the group level analysis (i.e., elevations in select inflammatory biomarkers at early-acute, but not later acute stage of recovery). The application of RCI methods to serum inflammatory biomarkers is a critical first step toward measuring athlete-specific changes acutely following SRC, as well as identifying individuals with persistent elevations during the sub-acute phase of recovery and beyond.

Category: Concussion/Mild TBI (Adult)

Keyword 1: concussion/ mild traumatic brain injury
Keyword 2: brain injury
Keyword 3: head injury (closed)