title: Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
abstract: Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1β and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: R G
authors.initials: RG
authors.lastname: Kumar
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: M L
authors.initials: ML
authors.lastname: Diamond
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: J A
authors.initials: JA
authors.lastname: Boles
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: R P
authors.initials: RP
authors.lastname: Berger
authors.affiliation: Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, United States.
authors.forename: S A
authors.initials: SA
authors.lastname: Tisherman
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: P M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: Wagnerak@upmc.edu.
authors.forename: A K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D000328:Adult; D001930:Brain Injuries / Q000134:cerebrospinal fluid* / Q000276:immunology / Q000534:rehabilitation; D015331:Cohort Studies; D016207:Cytokines / Q000134:cerebrospinal fluid* / Q000276:immunology; D018450:Disease Progression; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D015601:Injury Severity Score; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000134:cerebrospinal fluid* / Q000276:immunology; D016015:Logistic Models; D008297:Male; D009104:Multiple Trauma / Q000134:cerebrospinal fluid* / Q000276:immunology; D011379:Prognosis; D011446:Prospective Studies
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6
keywords: Cytokines; Inflammation; Interleukin-6; Rehabilomics; TBI