Review Article| Volume 130, P60-68, May 2022

Biomarkers in Moderate to Severe Pediatric Traumatic Brain Injury: A Review of the Literature



      Despite decades of research, outcomes in pediatric traumatic brain injury (pTBI) remain highly variable. Brain biofluid-specific biomarkers from pTBI patients may allow us to diagnose and prognosticate earlier and with a greater degree of accuracy than conventional methods. This manuscript reviews the evidence surrounding current brain-specific biomarkers in pTBI and assesses the temporal relationship between the natural history of the traumatic brain injury (TBI) and measured biomarker levels.


      A literature search was conducted in the Ovid, PubMed, MEDLINE, and Cochrane databases seeking relevant publications. The study selection and screening process were documented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. Extraction forms included developmental stages of patients, type and biofluid source of biomarkers, brain injury type, and other relevant data.


      The search strategy identified 443 articles, of which 150 examining the biomarkers of our interest were included. The references retrieved were examined thoroughly and discussed at length with a pediatric neurocritical care intensivist specializing in pTBI and a Ph.D. scientist with a high degree of involvement in TBI biomarker research, authoring a vast amount of literature in this field.


      TBI biomarkers might serve as valuable tools in the diagnosis and prognosis of pTBI. However, while each biomarker has its advantages, they are not without limitations, and therefore, further research is critical in pTBI biomarkers.


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        • Binder S.
        • Corrigan J.D.
        • Langlois J.A.
        The public health approach to traumatic brain injury: an overview of CDC's research and programs.
        J Head Trauma Rehabil. 2005; 20: 189-195
        • Tabor E.
        Food and Drug Administration requirements for clinical studies in pediatric patients.
        Ther Innov Regul Sci. 2015; 49: 666-672
        • Langlois J.A.
        • Sattin R.W.
        Traumatic brain injury in the United States: research and programs of the Centers for Disease Control and Prevention (CDC).
        J Head Trauma Rehabil. 2005; 20: 187-188
        • Thelin E.P.
        • Tajsic T.
        • Zeiler F.A.
        • et al.
        Monitoring the neuroinflammatory response following acute brain injury.
        Front Neurol. 2017; 8: 351
        • Teasdale G.
        • Jennett B.
        Assessment of coma and impaired consciousness. A practical scale.
        Lancet. 1974; 2: 81-84
        • O'Neil M.E.
        • Carlson K.
        • Storzbach D.
        • et al.
        Complications of Mild Traumatic Brain Injury in Veterans and Military Personnel: A Systematic Review.
        Department of Veterans Affairs (US), Washington, DC2013
        • Balestreri M.
        • Czosnyka M.
        • Chatfield D.A.
        • et al.
        Predictive value of Glasgow Coma Scale after brain trauma: change in trend over the past ten years.
        J Neurol Neurosurg Psychiatry. 2004; 75: 161-162
        • Koerte I.K.
        • Hufschmidt J.
        • Muehlmann M.
        • Lin A.P.
        • Shenton M.E.
        Advanced neuroimaging of mild traumatic brain injury.
        in: Laskowitz D. Grant G. Translational Research in Traumatic Brain Injury. CRC Press/Taylor and Francis Group, Boca Raton, FL2016
        • Bigler E.D.
        • Abildskov T.J.
        • Goodrich-Hunsaker N.J.
        • et al.
        Structural neuroimaging findings in mild traumatic brain injury.
        Sports Med Arthrosc Rev. 2016; 24: e42-e52
        • Oris C.
        • Pereira B.
        • Durif J.
        • et al.
        The biomarker S100B and mild traumatic brain injury: a meta-analysis.
        Pediatrics. 2018; 141e20180037
        • Dennis E.L.
        • Caeyenberghs K.
        • Asarnow R.F.
        • et al.
        Challenges and opportunities for neuroimaging in young patients with traumatic brain injury: a coordinated effort towards advancing discovery from the ENIGMA pediatric moderate/severe TBI group.
        Brain Imaging Behav. 2021; 15: 555-575
        • Kochanek P.M.
        • Tasker R.C.
        • Carney N.
        • et al.
        Guidelines for the management of pediatric severe traumatic brain injury, third edition: update of the brain trauma foundation guidelines, executive summary.
        Neurosurgery. 2019; 84: 1169-1178
        • Sandler S.J.
        • Figaji A.A.
        • Adelson P.D.
        Clinical applications of biomarkers in pediatric traumatic brain injury.
        Childs Nerv Syst. 2010; 26: 205-213
        • Daoud H.
        • Alharfi I.
        • Alhelali I.
        • Charyk Stewart T.
        • Qasem H.
        • Fraser D.D.
        Brain injury biomarkers as outcome predictors in pediatric severe traumatic brain injury.
        Neurocrit Care. 2014; 20: 427-435
        • Sugimoto M.
        • Kuwata S.
        • Kurishima C.
        • Kim J.H.
        • Iwamoto Y.
        • Senzaki H.
        Cardiac biomarkers in children with congenital heart disease.
        World J Pediatr. 2015; 11: 309-315
        • Leeb S.
        • Buxbaum C.
        • Fischler B.
        Elevated transaminases are common in children on prophylactic treatment for tuberculosis.
        Acta Paediatr. 2015; 104: 479-484
        • Hicks S.D.
        • Johnson J.
        • Carney M.C.
        • et al.
        Overlapping MicroRNA expression in saliva and cerebrospinal fluid accurately Identifies pediatric traumatic brain injury.
        J Neurotrauma. 2018; 35: 64-72
        • Wang K.K.
        • Yang Z.
        • Zhu T.
        • et al.
        An update on diagnostic and prognostic biomarkers for traumatic brain injury.
        Expert Rev Mol Diagn. 2018; 18: 165-180
        • Park D.W.
        • Park S.H.
        • Hwang S.K.
        Serial measurement of S100B and NSE in pediatric traumatic brain injury.
        Childs Nerv Syst. 2019; 35: 343-348
        • Berger R.P.
        • Pierce M.C.
        • Wisniewski S.R.
        • et al.
        Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children.
        Pediatrics. 2002; 109: E31
        • Berger R.P.
        • Beers S.R.
        • Richichi R.
        • Wiesman D.
        • Adelson P.D.
        Serum biomarker concentrations and outcome after pediatric traumatic brain injury.
        J Neurotrauma. 2007; 24: 1793-1801
        • Pelinka L.E.
        • Hertz H.
        • Mauritz W.
        • et al.
        Nonspecific increase of systemic neuron-specific enolase after trauma: clinical and experimental findings.
        Shock. 2005; 24: 119-123
        • Verfaillie C.J.
        • Delanghe J.R.
        Hemolysis correction factor in the measurement of serum neuron-specific enolase.
        Clin Chem Lab Med. 2010; 48: 891-892
        • Ramont L.
        • Thoannes H.
        • Volondat A.
        • Chastang F.
        • Millet M.C.
        • Maquart F.X.
        Effects of hemolysis and storage condition on neuron-specific enolase (NSE) in cerebrospinal fluid and serum: implications in clinical practice.
        Clin Chem Lab Med. 2005; 43: 1215-1217
        • Thelin E.P.
        • Zeiler F.A.
        • Ercole A.
        • et al.
        Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: a systematic review.
        Front Neurol. 2017; 8: 300
        • Mondello S.
        • Linnet A.
        • Buki A.
        • et al.
        Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury.
        Neurosurgery. 2012; 70: 666-675
        • Metzger R.R.
        • Sheng X.
        • Niedzwecki C.M.
        • et al.
        Temporal response profiles of serum ubiquitin C-terminal hydrolase-L1 and the 145-kDa alpha II-spectrin breakdown product after severe traumatic brain injury in children.
        J Neurosurg Pediatr. 2018; 22: 369-374
        • Berger R.P.
        • Hayes R.L.
        • Richichi R.
        • Beers S.R.
        • Wang K.K.
        Serum concentrations of ubiquitin C-terminal hydrolase-L1 and αII-spectrin breakdown product 145 kDa correlate with outcome after pediatric TBI.
        J Neurotrauma. 2012; 29: 162-167
        • Mondello S.
        • Kobeissy F.
        • Vestri A.
        • Hayes R.L.
        • Kochanek P.M.
        • Berger R.P.
        Serum concentrations of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein after pediatric traumatic brain injury.
        Sci Rep. 2016; 6: 28203
        • Ferguson I.
        • Lewis L.
        • Papa L.
        • Wang K.
        • Mondello S.
        • Hayes R.
        Neuronal biomarkers may require age-adjusted norms.
        Ann Emerg Med. 2011; 58: 213
        • Rhine T.
        • Babcock L.
        • Zhang N.
        • Leach J.
        • Wade S.L.
        Are UCH-L1 and GFAP promising biomarkers for children with mild traumatic brain injury?.
        Brain Inj. 2016; 30: 1231-1238
        • Simon-Pimmel J.
        • Lorton F.
        • Guiziou N.
        • et al.
        Serum S100β neuroprotein reduces use of cranial computed tomography in children after minor head trauma.
        Shock. 2015; 44: 410-416
        • Babcock L.
        • Byczkowski T.
        • Mookerjee S.
        • Bazarian J.J.
        Ability of S100B to predict severity and cranial CT results in children with TBI.
        Brain Inj. 2012; 26: 1372-1380
        • Berger R.P.
        • Pierce M.C.
        • Wisniewski S.R.
        • Adelson P.D.
        • Kochanek P.M.
        Serum S100B concentrations are increased after closed head injury in children: a preliminary study.
        J Neurotrauma. 2002; 19: 1405-1409
        • Wilkinson A.A.
        • Simic N.
        • Frndova H.
        • et al.
        Serum biomarkers help predict attention problems in critically ill children with traumatic brain injury.
        Pediatr Crit Care Med. 2016; 17: 638-648
        • Park S.H.
        • Hwang S.K.
        Prognostic value of serum levels of S100 calcium-binding protein B, neuron-specific enolase, and interleukin-6 in pediatric patients with traumatic brain injury.
        World Neurosurg. 2018; 118: e534-e542
        • Anderson R.E.
        • Hansson L.O.
        • Nilsson O.
        • Dijlai-Merzoug R.
        • Settergren G.
        High serum S100B levels for trauma patients without head injuries.
        Neurosurgery. 2001; 48: 1255-1260
        • Bechtel K.
        • Frasure S.
        • Marshall C.
        • Dziura J.
        • Simpson C.
        Relationship of serum S100B levels and intracranial injury in children with closed head trauma.
        Pediatrics. 2009; 124: e697-e704
        • Portela L.V.
        • Tort A.B.
        • Schaf D.V.
        • et al.
        The serum S100B concentration is age dependent.
        Clin Chem. 2002; 48: 950-952
        • Undén J.
        • Bellner J.
        • Eneroth M.
        • Alling C.
        • Ingebrigtsen T.
        • Romner B.
        Raised serum S100B levels after acute bone fractures without cerebral injury.
        J Trauma. 2005; 58: 59-61
        • Bouvier D.
        • Castellani C.
        • Fournier M.
        • et al.
        Reference ranges for serum S100B protein during the first three years of life.
        Clin Biochem. 2011; 44: 927-929
        • Shore P.M.
        • Berger R.P.
        • Varma S.
        • et al.
        Cerebrospinal fluid biomarkers versus glasgow coma scale and glasgow outcome scale in pediatric traumatic brain injury: the role of young age and inflicted injury.
        J Neurotrauma. 2007; 24: 75-86
        • Luoto T.M.
        • Raj R.
        • Posti J.P.
        • Gardner A.J.
        • Panenka W.J.
        • Iverson G.L.
        A systematic review of the usefulness of glial fibrillary acidic protein for predicting acute intracranial lesions following head trauma.
        Front Neurol. 2017; 8: 652
        • Wang K.K.
        • Yang Z.
        • Yue J.K.
        • et al.
        Plasma anti-glial fibrillary acidic protein autoantibody levels during the acute and chronic phases of traumatic brain injury: a transforming research and clinical knowledge in traumatic brain injury Pilot study.
        J Neurotrauma. 2016; 33: 1270-1277
        • Papa L.
        • Mittal M.K.
        • Ramirez J.
        • et al.
        In children and youth with mild and moderate traumatic brain injury, glial fibrillary acidic protein out-performs S100β in detecting traumatic intracranial lesions on computed tomography.
        J Neurotrauma. 2016; 33: 58-64
        • Fraser D.D.
        • Close T.E.
        • Rose K.L.
        • et al.
        Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum.
        Pediatr Crit Care Med. 2011; 12: 319-324
        • Gill J.
        • Merchant-Borna K.
        • Jeromin A.
        • Livingston W.
        • Bazarian J.
        Acute plasma tau relates to prolonged return to play after concussion.
        Neurology. 2017; 88: 595-602
        • Zemlan F.P.
        • Jauch E.C.
        • Mulchahey J.J.
        • et al.
        C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome.
        Brain Res. 2002; 947: 131-139
        • Stukas S.
        • Higgins V.
        • Frndova H.
        • et al.
        Characterisation of serum total tau following paediatric traumatic brain injury: a case-control study.
        Lancet Child Adolesc Health. 2019; 3: 558-567
        • Korley F.K.
        • Diaz-Arrastia R.
        • Wu A.H.
        • et al.
        Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury.
        J Neurotrauma. 2016; 33: 215-225
        • Buonora J.E.
        • Yarnell A.M.
        • Lazarus R.C.
        • et al.
        Multivariate analysis of traumatic brain injury: development of an assessment score.
        Front Neurol. 2015; 6: 68
        • Di Battista A.P.
        • Buonora J.E.
        • Rhind S.G.
        • et al.
        Blood biomarkers in moderate-to-severe traumatic brain injury: potential utility of a multi-marker approach in characterizing outcome.
        Front Neurol. 2015; 6: 110
        • Chiaretti A.
        • Piastra M.
        • Polidori G.
        • et al.
        Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury.
        Intensive Care Med. 2003; 29: 1329-1338
        • Chiaretti A.
        • Antonelli A.
        • Riccardi R.
        • et al.
        Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children.
        Eur J Paediatr Neurol. 2008; 12: 195-204
        • Su E.
        • Bell M.J.
        • Kochanek P.M.
        • et al.
        Increased CSF concentrations of myelin basic protein after TBI in infants and children: absence of significant effect of therapeutic hypothermia.
        Neurocrit Care. 2012; 17: 401-407
        • Berger R.P.
        • Adelson P.D.
        • Richichi R.
        • Kochanek P.M.
        Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury.
        Dev Neurosci. 2006; 28: 327-335
        • Beers S.R.
        • Berger R.P.
        • Adelson P.D.
        Neurocognitive outcome and serum biomarkers in inflicted versus non-inflicted traumatic brain injury in young children.
        J Neurotrauma. 2007; 24: 97-105
        • Berger R.P.
        • Dulani T.
        • Adelson P.D.
        • Leventhal J.M.
        • Richichi R.
        • Kochanek P.M.
        Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: a possible screening tool.
        Pediatrics. 2006; 117: 325-332
        • Berger R.P.
        • Bazaco M.C.
        • Wagner A.K.
        • Kochanek P.M.
        • Fabio A.
        Trajectory analysis of serum biomarker concentrations facilitates outcome prediction after pediatric traumatic and hypoxemic brain injury.
        Dev Neurosci. 2010; 32: 396-405
        • Khalil M.
        • Teunissen C.E.
        • Otto M.
        • et al.
        Neurofilaments as biomarkers in neurological disorders.
        Nat Rev Neurol. 2018; 14: 577-589
        • Oliver J.M.
        • Jones M.T.
        • Kirk K.M.
        • et al.
        Serum neurofilament light in American football athletes over the course of a season.
        J Neurotrauma. 2016; 33: 1784-1789
        • Martínez-Morillo E.
        • Childs C.
        • García B.P.
        • et al.
        Neurofilament medium polypeptide (NFM) protein concentration is increased in CSF and serum samples from patients with brain injury.
        Clin Chem Lab Med. 2015; 53: 1575-1584
        • Žurek J.
        • Fedora M.
        The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury.
        Acta Neurochir (Wien). 2012; 154: 93-103
        • McKnight N.C.
        • Zhong Y.
        • Wold M.S.
        • et al.
        Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex.
        PLoS Genet. 2014; 10e1004626
        • Kumar R.G.
        • Rubin J.E.
        • Berger R.P.
        • Kochanek P.M.
        • Wagner A.K.
        Principal components derived from CSF inflammatory profiles predict outcome in survivors after severe traumatic brain injury.
        Brain Behav Immun. 2016; 53: 183-193
        • Kumar R.G.
        • Diamond M.L.
        • Boles J.A.
        • et al.
        Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
        Brain Behav Immun. 2015; 45: 253-262
        • Crichton A.
        • Ignjatovic V.
        • Babl F.E.
        • et al.
        Interleukin-8 predicts fatigue at 12 months post-injury in children with traumatic brain injury.
        J Neurotrauma. 2021; 38: 1151-1163
        • Nakae R.
        • Takayama Y.
        • Kuwamoto K.
        • Naoe Y.
        • Sato H.
        • Yokota H.
        Time course of coagulation and fibrinolytic parameters in patients with traumatic brain injury.
        J Neurotrauma. 2016; 33: 688-695
        • DeFazio M.V.
        • Rammo R.A.
        • Robles J.R.
        • Bramlett H.M.
        • Dietrich W.D.
        • Bullock M.R.
        The potential utility of blood-derived biochemical markers as indicators of early clinical trends following severe traumatic brain injury.
        World Neurosurg. 2014; 81: 151-158
        • Stein S.C.
        • Smith D.H.
        Coagulopathy in traumatic brain injury.
        Neurocrit Care. 2004; 1: 479-488
        • Swanson C.A.
        • Burns J.C.
        • Peterson B.M.
        Low plasma D-dimer concentration predicts the absence of traumatic brain injury in children.
        J Trauma. 2010; 68: 1072-1077
        • Luo H.C.
        • Fu Y.Q.
        • You C.Y.
        • Liu C.J.
        • Xu F.
        Comparison of admission serum albumin and hemoglobin as predictors of outcome in children with moderate to severe traumatic brain injury: a retrospective study.
        Medicine (Baltimore). 2019; 98e17806
        • Gao N.
        • Zhang-Brotzge X.
        • Wali B.
        • et al.
        Plasma osteopontin may predict neuroinflammation and the severity of pediatric traumatic brain injury.
        J Cereb Blood Flow Metab. 2020; 40: 35-43
        • Nam J.W.
        • Rissland O.S.
        • Koppstein D.
        • et al.
        Global analyses of the effect of different cellular contexts on microRNA targeting.
        Mol Cell. 2014; 53: 1031-1043
        • Atif H.
        • Hicks S.D.
        A review of MicroRNA biomarkers in traumatic brain injury.
        J Exp Neurosci. 2019; 131179069519832286
        • Walko 3rd, T.D.
        • Bola R.A.
        • Hong J.D.
        • et al.
        Cerebrospinal fluid mitochondrial DNA: a novel DAMP in pediatric traumatic brain injury.
        Shock. 2014; 41: 499-503

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