Natural History and Clinical Associations of Plasma Interleukin-6 Levels in Traumatic Brain Injury

Inflammation following traumatic brain injury (TBI) may contribute to long-term morbidity. We aimed to characterize plasma interleukin-6 (IL6) trajectory after TBI and assess associations with imaging, biomarkers, and outcomes. Secondary analysis of three prospective multicenter observational cohorts: BIO-AX-TBI (United Kingdom/Europe), CREACTIVE (Europe), and TRACK-TBI (United States). Adults (≥18 years) with TBI were enrolled at trauma centers, with non-TBI trauma (NTT) and non-injured controls (CON) included in BIO-AX-TBI and TRACK-TBI. Blood was obtained at acute (≤10 days), subacute (10 days-6 weeks), and chronic (6 and 12 months) timepoints. IL6 was measured on OLINK® (BIO-AX-TBI, CREACTIVE) or MSD S-PLEX (TRACK-TBI) platforms. The Glasgow Outcome Scale-Extended (GOS-E) assessed functional outcome at chronic time points, dichotomized as unfavorable (1-4) versus favorable (5-8). Additional outcomes included neuropsychiatric symptom scores, magnetic resonance imaging (MRI) measures (lesion volume, fractional anisotropy [FA]), and neuronal/astroglial injury markers. BIO-AX-TBI included n = 195 TBI, n = 24 NTT, and n = 89 CON; CREACTIVE included n = 1146 TBI, TRACK-TBI included n = 387 TBI, n = 98 NTT, and n = 67 CON. IL6 was significantly elevated acutely in both TBI and NTT compared with CON but highest in TBI. In BIO-AX-TBI, IL6 remained elevated at 6 months (TBI median = 2.47, IQR = 1.98-2.87 vs. CON median = 2.13, IQR = 1.74-2.58; t = 2.50; p = 0.014) and 12 months (TBI median = 2.53, IQR = 2.08-3.06; t = 4.11; p < 0.001). Acute IL6 correlated with intracranial injury (GFAP; t/z = 5.14-8.14; p < 0.001), extracranial injury (t/z = 3.89-9.08; p < 0.005), and other plasma markers (r_s = 0.2-0.67; false discovery rate-corrected p < 0.05). Higher peak IL-6 was associated with greater lesion volume (t = 2.82; p = 0.0057) and reduced white matter FA (t = 2.47-2.54; p < 0.05). Elevated subacute IL6 was associated with unfavorable GOS-E across all cohorts. No associations were observed with neuropsychiatric symptoms. Post-TBI IL6 elevation persists up to 12 months and is associated with greater tissue injury and worse outcomes, suggesting IL6 as a potential therapeutic target.