Performance of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) biomarkers in predicting CT scan results and neurological outcomes in children with traumatic brain injury (BRAINI-2 paediatric study): protocol of a European prospective multicentre study

Background and rationale

Mild traumatic brain injury (mTBI) in children is a frequent reason for paediatric emergency department (ED) visits1 and a rare cause of acute complications: of the children who undergo a CT scan in the ED, between 5% and 10% exhibit intracranial lesions (ICLs) on the CT scan and less than 1% require neurosurgical intervention.2 3 Although ICL remains a serious complication requiring rapid diagnosis, physicians should not routinely order a head CT scan, as this would unnecessarily expose a large number of children to ionising radiation associated with an increased risk of cancer.4 5 Moreover, in light of the high prevalence of mTBI,6 the ED would become overcrowded and CT overused. To assist physicians in their decision-making, several clinical decision rules have been proposed in recent years7–9 with the aim of identifying children at higher or lower risk of ICL in order to better target CT scan indications. However, the rate of CT scans performed has remained high, up to 35%, and has not decreased with application of the clinical decision rules.10–12 Aside from the presence of ICLs in the acute period, other complications such as headaches, dizziness, asthenia, memory, concentration and sleep disorders can occur after an mTBI. These postconcussion symptoms (PCS) are still present in approximately 30% of children more than a month after injury,13 14 with a possible impact on their quality of life.15 Although some risk factors for prolonged PCS have been identified, such as being an adolescent13 16 or a girl,16 a history of concussion13 or reporting more acute concussion symptoms,17 18 no single factor can predict the recovery or neurological outcome.19 Thus, knowing when to scan or not and when to closely monitor a child after an mTBI remains a challenge for clinicians. Despite the incorporation of anamnestic and clinical parameters into conventional clinical decision rules, their efficacy in achieving this objective is insufficient.10–12 19 Developing new strategies to reduce CT utilisation while minimising the risk of delayed ICL diagnosis, and to identify children at higher risk of poor outcomes or PCS is imperative.

One of the most promising approaches in this context is the utilisation of blood-based brain biomarkers. Several biomarkers have been identified in recent years, such as calcium channel binding protein S100 subunit beta (S100B), glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1),20 21 which have blood concentration kinetics compatible with the time required to manage paediatric mTBI patients in ED. The latter two have the advantage over S100B that they can be measured over a longer time frame after the TBI and are not influenced by skin pigmentation and multiple traumas.22 23 GFAP is a cytoskeletal protein belonging to the class of intermediate filaments mostly specific to astrocytes, and UCH-L1 is a proteolytically stable and abundant protein found almost exclusively in the cytoplasm of neurons and involved in the ubiquitinylation and deubiquitinylation of certain proteins destined to be degraded by the proteasome.24 In mTBI, both GFAP and UCH-L1 are detectable within 1 hour of injury. GFAP peaks at 20 hours after injury and slowly declines over 72 hours. UCH-L1 increases rapidly, peaks at 8 hours after injury and declines rapidly over 24 hours. In adults, previous studies have shown the values of these biomarkers as predictors of ICL, with significantly higher concentrations in patients with ICL on CT scans compared with those without.25 26 A recent study in 1959 adults with mild and moderate TBI showed that the combination of these two biomarkers in a single test had high sensitivity (97.6%) and negative predictive value (99.6%) for detection of ICL.27

To date, there is little data on these two biomarkers in the paediatric population and on their relevance to TBI management in children. Elevated serum concentrations of GFAP and UCH-L1, assessed at a median time of 4.7 hours (range: 0.5–20.6 hours) postinjury, were observed in 45 children following TBI of any severity, in comparison to measurements in 40 healthy matched controls.28 An increasing gradient in the concentration of these biomarkers was also demonstrated along the severity continuum from mild to severe TBI.28 In cohorts of children and young adults with mild to moderate TBI, Papa et al found an area under the curve for ICL detection on CT of 0.85 (95% CI 0.72 to 0.98) for GFAP (n=92, including eight children with ICL) and 0.83 (95% CI 0.73 to 0.93) for UCH-L1 (n=151, including 17 children with ICL).29 30 With a cut-off point set to maximise sensitivity at 100%, the specificity was 36% for GFAP and 47% for UCH-L1.29 30 The performance of a test combining the two biomarkers has not been evaluated to date in children.

Several studies have shown that GFAP and UCH-L1 can predict poor outcomes as assessed by the Glasgow Outcome Scale (GOS) score after TBI.28 31 32 Regarding the association between GFAP and UCH-L1 and the presence of PCS after an mTBI, the results of the studies to date differ. Rhine et al found that neither GFAP nor UCH-L1 were predictive of PCS in 25 children over the 1 month postinjury period.33 In contrast, Mannix et al found a correlation in 13 children and young adults between GFAP concentrations and the Rivermead PCS scoring at 1 month.34 However, many unknowns remain, and the scope of the results of these studies may be limited by their small numbers.

In addition, no physiological reference values have been established to date for children in regards to UCH-L1, and only one recent study has proposed a paediatric reference interval for GFAP, in a cohort of Danish children.35 As with other brain biomarkers,36 it has been shown that age can influence their concentrations and that GFAP levels after severe trauma were higher in a paediatric cohort than in adults.31

The overall aim of the BRAINI-2 paediatric study is to provide new knowledge regarding GFAP and UCH-L1 in children and adolescents in order to improve TBI management in the paediatric population.

Objectives

The primary objective is to assess the performance of GFAP and UCH-L1 used separately and in combination as markers to detect the presence or absence of ICL on CT scans in a population of children with mTBI.

The secondary objectives are (1) to evaluate the potential of GFAP and UCH-L1 for early prediction of prognosis after TBI of any severity, including early clinical deterioration within 72 hours after TBI, as well as neurological outcome, occurrence of PCS and health-related quality of life (HRQoL) at 1 month and 3 months after TBI and (2) to establish age-specific reference values for serum GFAP and UCH-L1 concentrations in a non-TBI paediatric population.

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