Blood-based biomarkers of inflammation in mild traumatic brain injury: A systematic review

Visser, Koen; Koggel, Milou; Blaauw, Jurre; Horn, Harm Jan van der; Jacobs, Bram; Naalt, Joukje van der

doi:10.1016/j.neubiorev.2021.11.036

Cited by 68 publications

(43 citation statements)

References 82 publications

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“…Despite the predictive value of the GCS being described some decades ago, at present, there are no biomarkers known to predict patient outcomes in routine clinical use. Several markers have been suggested to be predictive of long-term outcomes in TBI patients, such as inflammatory mediators including IL-1β, IL-10, IL-33, TNF-α and IL-6 [ 32 , 41 , 42 , 44 – 46 ]. Preliminary studies have also suggested a prognostic role for neuron- or glial cell-specific proteins, such as S100B, neurofilament light, neuro-specific enolase, myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), phosphorylated axonal neurofilament subunit H (pNF-H), tau protein and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

et al. 2022

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Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

et al. 2022

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“…There is sufficient laboratory evidence for neuroinflammation and systemic inflammation following mTBI, characterized by level changes of inflammatory markers in the acute phase after brain injury ( Visser et al, 2021 ). However, patients with mTBI are not likely to accept invasive techniques, such as lumbar puncture, to take a cerebrospinal fluid examination.…”

Section: Discussionmentioning

confidence: 99%

“…In clinical practice, the inflammatory indicator change that is most likely to draw attention from doctors is the abnormal increase in white blood cell count in circulation, but it does not have any clinical guiding significance for the lack of specificity. Recent studies have suggested that several systemic inflammatory indicators may correlate with the development and outcome of mTBI ( Visser et al, 2021 ). Specifically, NLR has been widely investigated as an available prognostic biomarker and inflammatory indicator for TBI ( Sabouri et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Blood Inflammatory Indicator for Predicting Deterioration Risk of Mild Traumatic Brain Injury

Zhu

et al. 2022

Front. Aging Neurosci.

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Mild traumatic brain injury (mTBI) has a relatively higher incidence in aging people due to walking problems. Cranial computed tomography and magnetic resonance imaging provide the standard diagnostic tool to identify intracranial complications in patients with mTBI. However, it is still necessary to further explore blood biomarkers for evaluating the deterioration risk at the early stage of mTBI to improve medical decision-making in the emergency department. The activation of the inflammatory response is one of the main pathological mechanisms leading to unfavorable outcomes of mTBI. As complete blood count (CBC) analysis is the most extensively used laboratory test in practice, we extracted clinical data of 994 patients with mTBI from two large clinical cohorts (MIMIC-IV and eICU-CRD) and selected inflammation-related indicators from CBC analysis to investigate their relationship with the deterioration after mTBI. The combinatorial indices neutrophil-to-lymphocyte ratio (NLR), red cell distribution width-to-platelet ratio (RPR), and NLR times RPR (NLTRP) were supposed to be potential risk predictors, and the data from the above cohorts were integratively analyzed using our previously reported method named MeDICS. We found that NLR, RPR, and NLTRP levels were higher among deteriorated patients than non-deteriorated patients with mTBI. Besides, high NLTRP was associated with increased deterioration risk, with the odds ratio increasing from NLTRP of 1–2 (2.69, 1.48–4.89) to > 2 (4.44, 1.51–13.08), using NLTRP of 0–1 as the reference. NLTRP had a moderately good prognostic performance with an area under the ROC curve of 0.7554 and a higher prediction value than both NLR and RPR, indicated by the integrated discrimination improvement index. The decision curve analysis also showed greater clinical benefits of NLTRP than NLR and RPR in a large range of threshold probabilities. Subgroup analysis further suggested that NLTRP is an independent risk factor for the deterioration after mTBI. In addition, in vivo experiments confirmed the association between NLTRP and neural/systemic inflammatory response after mTBI, which emphasized the importance of controlling inflammation in clinical treatment. Consequently, NLTRP is a promising biomarker for the deterioration risk of mTBI. It can be used in resource-limited settings, thus being proposed as a routinely available tool at all levels of the medical system.

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“…Levels of GFAP (LLD 20 pg/mL, LOQ 20 pg/mL, IVC 3.4%) and neurofilament light (LLD 7.8 pg/mL, LOQ 20 pg/mL, IVC 4.6%) were determined in duplo using the Human GFAP DuoSet ELISA (R&D Systems, Oxford, UK) and Cusabio Human Neurofilament protein L ELISA kit (Bio-Connect Services, Huissen, The Netherlands), respectively, both according to manufacturer's instructions (all GFAP measurements were done on 1 day, NFL was measured on 2 days). The selection of cytokines was based on a recent systematic review on blood-based inflammatory biomarkers in mTBI that was published by our research group, showing the potential value of IL6 and IL10 ( 10 ); selection of brain-specific markers was based on studies that were published in recent years ( 11 , 12 ). The lab technician who measured biomarker levels was blinded for clinical parameters.…”

Section: Methodsmentioning

confidence: 99%

Long-Term Stability of Blood Serum Biomarkers in Traumatic Brain Injury: A Feasibility Study

et al. 2022

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Few studies on traumatic brain injury (TBI) have investigated the stability of blood serum biomarkers after long-term storage at low temperatures. In the current feasibility study we analyzed acute phase serum samples from patients with mild TBI as well as patients with moderate and severe TBI that were collected more than 10 years ago (old samples). We were particularly interested in mild TBI, because injury effects are more subtle in this category as compared to moderate-severe TBI. Therefore, the primary objective was to find out whether several biomarkers were still detectable for these patients. Additionally, we examined whether biomarker levels varied as a function of injury severity. For comparison, we also analyzed samples from an ongoing mTBI cohort (new samples) and healthy controls. Samples were treated with care and were not being subjected to freeze-thaw cycles. We measured concentrations of interleukins (IL6 and 10) and brain specific markers (total tau, UCH-L1, GFAP, and NF-L). No significant differences in biomarker concentrations were found between old and new mild TBI samples. For IL6, IL10, and UCH-L1 higher concentrations were found in moderate and severe TBI as compared to mild TBI. In conclusion, our study shows that long-term storage does not rule out the detection of meaningful biomarker concentrations in patients with TBI, although further research by other laboratories is warranted.

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Blood-based biomarkers of inflammation in mild traumatic brain injury: A systematic review

Cited by 68 publications

References 82 publications

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

A Novel Blood Inflammatory Indicator for Predicting Deterioration Risk of Mild Traumatic Brain Injury

Long-Term Stability of Blood Serum Biomarkers in Traumatic Brain Injury: A Feasibility Study

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