Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

Kumar, Raj G.; Diamond, Matthew L.; Boles, Jennifer A.; Berger, Rachel P.; Tisherman, Samuel A.; Kochanek, Patrick M.; Wagner, Amy K.

doi:10.1016/j.bbi.2014.12.021

Cited by 128 publications

(103 citation statements)

References 72 publications

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“…1,2,6,8,9,[11][12][13]30,32 Similar to TNF-a, it is detectable by 1 hour postinjury and peaks in brain parenchyma at approximately 2-8 hours. 32 However, unlike TNF-a, particularly related to the DAI model, IL-6 levels do not depend on the injury model, and this is a more sensitive marker.…”

Section: Cytokinesmentioning

confidence: 99%

“…Similarly, the role of proinflammatory (interleukin [IL]-6, IL-1, tumor necrosis factor-a [TNF-a]) and antiinflammatory (IL-4, IL-10, transforming growth factor) cytokines has been validated in recent trials. 1,2,6,8,9,[11][12][13]22,26,27,30,36 More recently, posttraumatic suppression of the hypothalamic-pituitary-adrenal axis and an increase in cytokine-mediated peripheral aromatase activity, leading to an imbalance in sex steroid (estrogen [Eg], progesterone [Pg], and testosterone) serum levels, have been areas of active interest for precise understanding of the mechanisms involved. 5,15,23,25,29 Most of the recent literature deals with these biomarkers in isolation, and there is a paucity of existing literature for establishing a comprehensive model dealing with all 3 domains together.…”

mentioning

confidence: 99%

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Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

Raheja¹,

Sinha²,

Samson³

et al. 2016

JNS

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abbreviatioNs AUC = area under the curve; BBB = blood-brain barrier; DAI = diffuse axonal injury; Eg = estrogen; FIM = functional independence measure; GCS = Glasgow Coma Scale; GFAP = glial fibrillary acidic protein; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; IL = interleukin; IQR = interquartile range; NGF = nerve growth factor; NSE = neuron-specific enolase; Pg = progesterone; ROC = receiver operating characteristic; sTBI = severe traumatic brain injury; TNF-a = tumor necrosis factor-a. Pg]). This analysis was performed using the sandwich enzyme-linked immunosorbent assay technique at admission and 7 days later for 86 patients, irrespective of assigned group. The long-term predictive values of serum biomarkers for dichotomized Glasgow Outcome Scale (GOS) score, functional independence measure, and survival status at 6 and 12 months were analyzed using an adjusted binary logistic regression model and receiver operating characteristic curve. results A favorable GOS score (4-5) at 1 year was predicted by higher admission IL-6 (above 108.36 pg/ml; area under the curve [AUC] 0.69, sensitivity 52%, and specificity 78.6%) and Day 7 Pg levels (above 3.15 ng/ml; AUC 0.79, sensitivity 70%, and specificity 92.9%). An unfavorable GOS score (1-3) at 1 year was predicted by higher Day 7 GFAP levels (above 9.50 ng/ml; AUC 0.82, sensitivity 78.6%, and specificity 82.4%). Survivors at 1 year had significantly higher Day 7 Pg levels (above 3.15 ng/ml; AUC 0.78, sensitivity 66.7%, and specificity 90.9%). Nonsurvivors at 1 year had significantly higher Day 7 GFAP serum levels (above 11.14 ng/ml; AUC 0.81, sensitivity 81.8%, and specificity 88.9%) and Day 7 IL-6 serum levels (above 71.26 pg/ml; AUC 0.87, sensitivity 81.8%, and specificity 87%). In multivariate logistic regression analysis, independent predictors of outcome at 1 year were serum levels of Day 7 Pg (favorable GOS-OR 3.24, CI 1.5-7, p = 0.003; and favorable survival-OR 2, CI 1.2-3.5, p = 0.01); admission IL-6 (favorable GOS-OR 1.04, CI 1.00-1.08, p = 0.04); and Day 7 GFAP p = 0.01; p = 0.01). coNclusioNs Serial Pg, GFAP, and IL-6 monitoring could aid in prognosticating outcomes in patients with acute sTBI. A cause and effect relationship or a mere association of these biomarkers to outcome needs to be further studied for better understanding of the pathophysiology of sTBI and for choosing potential therapeutic targets.Clinical trial registration no

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Section: Cytokinesmentioning

confidence: 99%

mentioning

confidence: 99%

Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

Raheja¹,

Sinha²,

Samson³

et al. 2016

JNS

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“…Eine rezente Studie konnte anhand von seriellen CSF-IL-6 Messungen in den ersten fünf Tagen nach Auftreten des Traumas zwei unterschiedliche akut-CSF-IL-6 Profile herausarbeiten, mit dem Resultat, dass Patienten im höheren Profil nach 6 Monaten schlechtere Werte nach GOS erzielten [80]. Auffallend war hier, dass in der niedrigeren Gruppe in den Tagen 3 bis 5 ein Abfall der CSF-IL-6 Konzentrationen registriert wurde, der in der höheren Gruppe nicht präsent war.…”

Section: Schädel-hirn-traumataunclassified

“…Auffallend war hier, dass in der niedrigeren Gruppe in den Tagen 3 bis 5 ein Abfall der CSF-IL-6 Konzentrationen registriert wurde, der in der höheren Gruppe nicht präsent war. Die schlechtere Prognose von Patienten im höheren CSF-IL-6 Profil könnte somit durch eine persistierende Erhöhung von CSF-IL-6 bedingt sein [80].…”

Section: Schädel-hirn-traumataunclassified

Interleukin 6 im Liquor – diagnostische Wertigkeit

Gruber

Werner

Germann

et al. 2015

LaboratoriumsMedizin

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Zusammenfassung: Interleukin 6 (IL-6) wurde bereits 1985 als Differenzierungsfaktor für B-Zellen (B-cell stimulatory Factor 2) identifiziert, unter dessen Einfluss B-Zellen in Antikörper-bildende Zellen maturierten. In zahlreichen Studien wurde seither der pleiotrope Charakter von IL-6 belegt, das neben seinen Funktionen in der Immunabwehr, auch eine bedeutende Rolle in der Regulation von Hämatopoese, Inflammation und Onkogenese übernimmt. In Bezug auf das ZNS wurde die Beteiligung von IL-6 an der Neurogenese sowie an der Reaktion von Neuronen und Glia-Zellen auf Verletzungen beschrieben. Infektionen des ZNS, cerebrale Ischämien, schwere ZNSTraumata oder chronisch entzündliche Erkrankungen wie Neuro-Lupus oder Neuro-Sarkoidose gehen mit erhöhten IL-6 Konzentrationen im Liquor einher. Aufgrund der Prä-senz des Neuropoetins IL-6 im Rahmen dieser Erkrankungen wird ein möglicher Einsatz des Parameters IL-6 im Liquor zur Diagnostik und, in manchen Fällen, zur Verlaufsbeurteilung und Therapieüberwachung überprüft. In diesem Review geben wir einen Überblick über die derzeitige Studienlage und die diagnostische Wertigkeit von IL-6 im Liquor.Schlüsselwörter: cerebrale Ischämie; CSF-IL-6; diagnostische Wertigkeit; Enzephalitis; Meningitis; Multiple Sklerose; Schädel-Hirn-Trauma; Systemischer Lupus erythematodes. Abstract:In 1985 interleukin 6 (IL-6) was first identified as a differentiation factor for B-cells (B-cell stimulatory factor 2) which caused B-cells to mature and produce antibodies. Numerous studies now demonstrate the pleiotropic character of IL-6, which has been shown to possess important functions in the immune system, the regulation of hematopoesis, inflammation and oncogenesis. In the central nervous system (CNS), IL-6 is involved in neurogenesis and the response of neurons and glia-cells to various injuries. CNS infections, cerebral ischaemia, CNS traumata or chronic inflammatory diseases with CNS manifestations such as neuro-lupus or neuro-sarcoidosis are associated with increased IL-6 levels in the cerebrospinal fluid (CSF). Thus, the use of IL-6 as a diagnostic and prognostic tool in these diseases is being investigated. In this review we aim to provide an overview of current studies and evaluate the diagnostic significance of CSF-IL-6.

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“…It is unclear if this immune response is a result of local production of immune mediators or leakage of these proteins across a compromised BBB. Regardless, there appears to be an association between proinflammatory proteins and poor clinical outcome in mTBI (90,94,95). A pilot study of 16 pediatric mTBI patients showed that increased concentrations of both IL-6 and MMP9 had a sensitivity of 81% and specificity of 94% for mTBI diagnosis (96).…”

Section: Biomarkers Of Neuroinflammationmentioning

confidence: 99%