| Abstract |
Introduction
Traumatic Brain Injury (TBI) is currently the leading cause of mortality, fatality and disability worldwide. Proinflammatory and anti-inflammatory cytokines or chemokines are secreted by neuronal, glial cells, and systemic immune cells, and seem to have a profound role in neuroinflammation and in the short-term or long-term process of healing following trauma with concomitant TBI. Their concerted action constitutes the pathophysiology of neuroinflammation, and seems to determine the outcome of TBI patients. On the other hand, specific neurobiomarkers such as GFAP (Glial Fibrillary Acidic Protein) and UCH-L1 (Ubiquitin C - Terminal Hydrolase L1) have recently been approved by the U.S. Food and Drug Administration for mild TBI discrimination in adults, and as a decision guide concerning the necessity of early neuroimaging. However, no reliable inflammatory biomarker or neurobiomarker has currently been included into a standard model for TBI severity classification or prognostication.
Aim of the study
The present study was designed to assess the value of certain non-specific inflammatory mediators (IL-6, IL-8, IL-10) and specific neurobiomarkers (GFAP, UCH-L1) in acute trauma with concomitant TBI, in combination with clinical, imaging, laboratory indices and prognostic clinical scales. The study also attempted a more holistic evaluation of the relationship among studied serum biomarkers and TBI severity or outcome. The study had two primary objectives:
1. To assess the value of certain inflammation markers (IL-6, IL-8, IL-10) and neurobiomarkers (GFAP, UCH-L1) as complementary TBI severity classification indices upon admission, in combination with standardised clinical, laboratory, imaging variables and scoring systems.
2. To assess the possible prognostic value of interleukins and neurobiomarkers , assessed by validated functional outcome scoring scales.
Methods
In this single-centre prospective observational study, 109 adult patients, 20 healthy controls and 17 paediatric patients from a Neurosurgical Department and two Intensive Care Units (adult and paediatric) of the University Hospital of Heraklion in Crete were recruited, during the period between 2019 and 2022. Demographic, clinical and brain imaging diagnostic variables for TBI severity classification, along with authorised outcome scales and TBI prognostic models were recorded. During the laboratory part of the study, serum quantification of Interleukin-6 (IL- 6), -8 and -10 and of two neurobiomarkers (UCH-L1 and GFAP) were performed. Blood samples were obtained within 12 hours of admission and on the 7th post-traumatic day, and serum was then stored at -80℃ until quantification analysis. The sensitivities of the assays were 4pg/ml for IL-6, 8pg/ml for IL-8, and 2pg/ml for IL-10. The detection range was around 7.8-500 pg/mL for IL-6, 15.6-1000 pg/mL for IL-8, 3.9-250 pg/mL for IL-10, 15.63-1000 pg/ml for GFAP, and 78.13-5000 pg/ml for UCH-L1. Statistical analyses were performed through SPSS software for Windows (IBM Statistics, Chicago, IL, USA, version 25).
Results
The majority of adult patients had clinical presentation consistent with mild TBI (66.9%) upon admission, whereas 16.6% of patients suffered from severe TBI. In the adult patient sample 6-month mortality was 23,5%. The majority of children had clinical presentation consistent with mild TBI (66.7%) upon admission, whereas 19% of patients suffered from severe TBI. Six-month mortality was 5,6% for the paediatric patient sample.
Elevated IL-6 and IL-10, but depressed IL-8 on day 1 (within 12 hours of admission), were found in adult TBI patients compared to healthy controls. With regard to adult TBI severity classification, higher levels of IL-6 (p=0.001) and IL-10 (p=0.009) on day 1 were associated with TBI severity (Glasgow Coma Scale <9) and with increased risk for certain severe brain imaging findings (Spearman's rho<0.442, p<0.007 for all associations) in adult patients. A multivariable logistic regression analysis revealed that early measured IL-6 (Exp(B)=0.987, p=0.025) and UCH-L1 (Exp(B)=0.993, p=0.032) in adult TBI patients were significant independent predictors for an unfavourable outcome. ROC (receiver operating curve) analysis revealed that age was the best independent predictor for severe disability or mortality in adult TBI patients based on GOS-E. However, a marginally acceptable prognostic value was also revealed for IL-6 and UCH-L1 on Day 1 as well.
Conclusions
In conclusion, non-specific neuroinflammation markers, like IL-6 and IL-10, along with standardised clinical, imaging and laboratory parameters, may prove to be valuable diagnostic tools for TBI, since an adequate diagnostic model should take into consideration both localised and systemic pathophysiological responses. Moreover, IL-6 and UCH-L1, might prove to be valuable prognostic tools for TBI. Therefore, their incorporation in standardised multivariable prognostic models might enhance the precision of their predictive ability.
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