High-sensitivity C-Reactive Protein is a Prognostic Biomarker of 6-month Disability After Traumatic Brain Injury: Results from the TRACK-TBI Study.

BACKGROUND Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. METHODS The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver Operating Characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). RESULTS We included 1206 TBI subjects, 122 orthopedic trauma controls (OTC), and 209 healthy controls (HC). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1-5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HC (p<0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC=0.892). Combining hsCRP and GFAP at 2 weeks produced AUC=0.939 for prediction of disability. CONCLUSIONS Serum high-sensitivity CRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.

[1]  Adam R Ferguson,et al.  Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study , 2019, The Lancet Neurology.

[2]  Adam R Ferguson,et al.  Recovery After Mild Traumatic Brain Injury in Patients Presenting to US Level I Trauma Centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. , 2019, JAMA neurology.

[3]  J. Nguyen,et al.  High-Sensitivity C-Reactive Protein: Retrospective Study of Potential Blood Biomarker of Inflammation in Acute Mild Traumatic Brain Injury , 2019, The Journal of head trauma rehabilitation.

[4]  J. Barea-Mendoza,et al.  YKL-40, SAA1, CRP and PCT are promising biomarkers for intracranial severity assessment of traumatic brain injury: Relationship with Glasgow Coma Scale and CT volumetry. , 2020, World neurosurgery.

[5]  R. Diaz-Arrastia,et al.  Biomarkers in traumatic brain injury (TBI): a review , 2018, Neuropsychiatric disease and treatment.

[6]  O. Hashim,et al.  Panel of serum protein biomarkers to grade the severity of traumatic brain injury , 2018, Electrophoresis.

[7]  K. Okuchi,et al.  Outcomes after Traumatic Brain Injury with Concomitant Severe Extracranial Injuries , 2018, Neurologia medico-chirurgica.

[8]  P. Libby,et al.  Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease , 2017, The New England journal of medicine.

[9]  S. Acheson,et al.  A blood-based biomarker panel to risk-stratify mild traumatic brain injury , 2017, PloS one.

[10]  S. Shultz,et al.  The effect of concomitant peripheral injury on traumatic brain injury pathobiology and outcome , 2016, Journal of Neuroinflammation.

[11]  C. Dinarello,et al.  Reduction in C‐reactive protein indicates successful targeting of the IL‐1/IL‐6 axis resulting in improved survival in early stage multiple myeloma , 2016, American journal of hematology.

[12]  D. Sandsmark,et al.  Clinical Outcomes after Traumatic Brain Injury , 2016, Current Neurology and Neuroscience Reports.

[13]  I. Marzi,et al.  The effect of brain injury on the inflammatory response following severe trauma. , 2016, Immunobiology.

[14]  C. Nolte,et al.  Follow-up C-reactive protein level is more strongly associated with outcome in stroke patients than admission levels , 2015, Neurological Sciences.

[15]  M. Genovese,et al.  Results of a proof of concept, double-blind, randomized trial of a second generation antisense oligonucleotide targeting high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis , 2015, Arthritis Research & Therapy.

[16]  P. Kochanek,et al.  Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome , 2015, Brain, Behavior, and Immunity.

[17]  W. Xu,et al.  Elevated C-reactive protein levels may be a predictor of persistent unfavourable symptoms in patients with mild traumatic brain injury: A preliminary study , 2014, Brain, Behavior, and Immunity.

[18]  P. Kochanek,et al.  Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward: Report of the Department of Defense Neurotrauma Pharmacology Workgroup , 2014 .

[19]  A. Parry-Jones,et al.  C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage , 2014, Stroke.

[20]  P. Rutgeerts,et al.  Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial , 2013, Gut.

[21]  B. Leong,et al.  Concomitant injuries and its influence on functional outcome after traumatic brain injury , 2013, Disability and rehabilitation.

[22]  M. Majdan,et al.  Impact of concomitant injuries on outcomes after traumatic brain injury , 2013, Archives of Orthopaedic and Trauma Surgery.

[23]  M. Morganti-Kossmann,et al.  The Role of Markers of Inflammation in Traumatic Brain Injury , 2013, Front. Neurol..

[24]  Hester F. Lingsma,et al.  Prognosis in moderate and severe traumatic brain injury: External validation of the IMPACT models and the role of extracranial injuries , 2013, The journal of trauma and acute care surgery.

[25]  D. Loane,et al.  Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention , 2012, Brain, Behavior, and Immunity.

[26]  Hester F. Lingsma,et al.  Prognostic Value of Major Extracranial Injury in Traumatic Brain Injury: An Individual Patient Data Meta-analysis in 39 274 Patients , 2012, Neurosurgery.

[27]  C. Probst,et al.  Systemic Inflammatory Effects of Traumatic Brain Injury, Femur Fracture, and Shock: An Experimental Murine Polytrauma Model , 2012, Mediators of inflammation.

[28]  M. Huber-Lang,et al.  A New Experimental Polytrauma Model in Rats: Molecular Characterization of the Early Inflammatory Response , 2012, Mediators of inflammation.

[29]  G. Manley,et al.  Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group. , 2010, Archives of physical medicine and rehabilitation.

[30]  O. Sogut,et al.  Trauma Scores and Neuron-Specific Enolase, Cytokine and C-Reactive Protein Levels as Predictors of Mortality in Patients with Blunt Head Trauma , 2010, The Journal of international medical research.

[31]  R. Hurley,et al.  Common data elements in radiologic imaging of traumatic brain injury , 2010, Journal of magnetic resonance imaging : JMRI.

[32]  W. Sandborn,et al.  Relationship of C-Reactive Protein With Clinical Response After Therapy With Ustekinumab in Crohn's Disease , 2009, The American Journal of Gastroenterology.

[33]  B. Strober,et al.  Effects of etanercept on C‐reactive protein levels in psoriasis and psoriatic arthritis , 2008, The British journal of dermatology.

[34]  H. Bramlett,et al.  Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats , 2008, Experimental Neurology.

[35]  J. Ghajar,et al.  Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. , 2008, Annals of emergency medicine.

[36]  M. Landthaler,et al.  Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial , 2007, Melanoma research.

[37]  R. Diaz-Arrastia,et al.  Usefulness of the abbreviated injury score and the injury severity score in comparison to the Glasgow Coma Scale in predicting outcome after traumatic brain injury. , 2007, The Journal of trauma.

[38]  A. V. van Vugt,et al.  Impact of additional extracranial injuries on outcome after mild traumatic brain injury. , 2006, Journal of neurotrauma.

[39]  K. Prasad.  C-reactive protein (CRP)-lowering agents. , 2006, Cardiovascular drug reviews.

[40]  N. Rothwell,et al.  The role of inflammation in CNS injury and disease , 2006, British journal of pharmacology.

[41]  E. Lilius,et al.  High sensitivity measurement of CRP and disease progression in multiple sclerosis , 2005, Neurology.

[42]  P. Toutouzas,et al.  Comparison of the effects of ramipril versus telmisartan in reducing serum levels of high-sensitivity C-reactive protein and oxidized low-density lipoprotein cholesterol in patients with type 2 diabetes mellitus. , 2005, The American journal of cardiology.

[43]  Paul Schoenhagen,et al.  Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. , 2005, The New England journal of medicine.

[44]  J. Rossi,et al.  Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[45]  N. Rothwell,et al.  An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis , 2003, Journal of Neuroimmunology.

[46]  B. Conrad,et al.  Prognostic Relevance of Early Serial C-Reactive Protein Measurements After First Ischemic Stroke , 2002, Stroke.

[47]  S. Sauerland,et al.  Association between injury pattern of patients with multiple injuries and circulating levels of soluble tumor necrosis factor receptors, interleukin-6 and interleukin-10, and polymorphonuclear neutrophil elastase. , 2002, The Journal of trauma.

[48]  N Rifai,et al.  Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. , 2001, JAMA.

[49]  A. Unterberg,et al.  Secondary insults in severe head injury—Do multiply injured patients do worse? , 2001, Critical care medicine.

[50]  M. Di Napoli,et al.  C-Reactive Protein in Ischemic Stroke: An Independent Prognostic Factor , 2001, Stroke.

[51]  P. Mcgeer,et al.  Generation of C-reactive protein and complement components in atherosclerotic plaques. , 2001, The American journal of pathology.

[52]  P. Mcgeer,et al.  Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease , 2000, Brain Research.

[53]  P. Nihoyannopoulos,et al.  Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. , 1999, Circulation.

[54]  S. Wood,et al.  The physiological structure of human C-reactive protein and its complex with phosphocholine. , 1999, Structure.

[55]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[56]  A. Pasternack,et al.  Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment. , 1996, European heart journal.

[57]  I. T. Ten Berge,et al.  CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes. , 1996, Journal of immunology.

[58]  C. Mold,et al.  Serum amyloid P component binds to histones and activates the classical complement pathway. , 1992, Journal of immunology.

[59]  E. Mackenzie,et al.  Effect of associated injuries and blood volume replacement on death, rehabilitation needs, and disability in blunt traumatic brain injury , 1991, Critical care medicine.

[60]  M. Cohen,et al.  Polytrauma associated with traumatic brain injury: incidence, nature and impact on rehabilitation outcome. , 1990, Brain injury.