Articles
Characterisation of serum total tau following paediatric traumatic brain injury: a case-control study

https://doi.org/10.1016/S2352-4642(19)30194-4Get rights and content

Summary

Background

Traumatic brain injury (TBI) is a major health problem in children. Blood-based biomarkers interpreted by use of normative values might improve the accuracy of diagnosis. Ultrasensitive assays can quantify serum concentrations of the neuronal microtubule-associated protein tau, which is increased in adult brains following TBI. We aimed to determine if serum total tau correlates with TBI diagnosis, severity, and radiological findings on CT scans in children younger than 18 years.

Methods

In this case-control study, we included venous blood samples from healthy control children in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) biobank. For TBI cases, we recruited children (aged 0–17 years) who presented to the emergency department within 24 h of a TBI in three tertiary-care paediatric hospitals (Toronto, Vancouver, and Melbourne). Children were eligible if they required hospital observation for a minimum of 4 h or admission to the intensive care unit, and were excluded if they had had hospital treatment for a previous TBI, had birth trauma, or their parents could not speak English or French and therefore could not readily give consent. All available control samples were used and a case-control match was therefore not done. Venous and arterial blood samples were collected from patients with TBI within 28 h of injury (day 1). We used an ultrasensitive single-molecule immunoassay to measure serum total tau in blood samples. We first generated reference intervals of serum total tau from the control group, and used these normative data to interpret injury-associated changes in serum total tau in children with TBI. Concentrations of serum tau were measured in all CALIPER participants and patients with TBI, and no participants were excluded before analysis.

Findings

We included samples from 416 control participants from the CALIPER cohort. Median total tau concentrations did not differ between sexes (p=0·12), but three significant reference intervals based on age groups were identified (1–3 years [0·88–19·2 pg/mL], 4–15 years [0·93–5·31 pg/mL], and 16–19 years [0·79–4·20 pg/mL]). Blood samples were obtained from 158 patients with TBI recruited between April 30, 2011, and June 28, 2013. Serum total tau on day 1 of TBI was negatively associated with Glasgow Coma Scale (GCS) score (rs=–0·42, 95% CI −0·55 to −0·28, p<0·0001). Median total tau was 2·86 pg/mL (IQR 1·52–4·83) in patients with GCS score 13–15 points (n=114), 7·08 pg/mL (3·75–41·1) in those with GCS score 9–12 points (n=13), and 8·48 pg/mL (2·53–70·6) in those with GCS score 3–8 points (n=31). Notably, participants who had GCS scores of 15 points had median total tau concentrations (2·57 pg/mL [1·50–4·61]) indistinguishable from those of control participants (2·46 pg/mL [1·77–3·42]), whereas those with GCS score 13–14 points had elevated total tau (6·41 pg/mL [2·97–42·5]). Serum total tau was not strongly associated with CT findings in patients with mild TBI.

Interpretation

Serum total tau might help to differentiate between patients with mild TBI (GCS 13–14 vs GCS 15), but larger studies are needed to validate these results before this biomarker can be used for diagnosis and prognosis.

Funding

Canadian Institutes of Health Research, Ontario Neurotrauma Foundation, and Victoria Neurotrauma Foundation

Introduction

Traumatic brain injury (TBI) is the leading cause of death and acquired disability in children. In high-income countries, an estimated 691 in 100 000 children are treated in emergency departments because of TBI annually, 74 in 100 000 require hospital admission, and nine in 100 000 die.1 Diagnosis and management of TBI in children can be challenging as their physiology, injury mechanism, clinical symptoms and signs, and risk of long-term sequelae and delayed recovery vary on the basis of age and developmental stage.2, 3 Although CT scans can provide rapid diagnosis of intracranial injuries, there is concern about exposure to radiation, the need for sedation in very young children, and overuse of the technique.4

Research in context

Evidence before this study

Children have a high incidence of traumatic brain injury (TBI) caused by falls, vehicle crashes, sport participation, and abuse. In preparation for this study, we searched for blood biomarker studies in paediatric TBI in National Centre for Biotechnology Information (USA) databases from Jan 1, 1990, to Sept 30, 2018, using the search terms “traumatic brain injury”, “children OR pediatric”, “blood OR serum OR plasma”, and “biomarker”. Studies were included if participants were aged between 0 and 19 years and one or more blood proteins or metabolites were measured. Studies were excluded if participants were older than 19 years, blood biomarkers were not measured, data were derived from animal models, or if they were not primary publications. Both the number of control participants (if present) and patients with TBI, and type of control group (ie, healthy or orthopaedic injury) were used to ascertain study quality. 165 publications were found, of which 64 remained after applying the exclusion criteria above. 51 studies focused solely on paediatric TBI, and 13 studies compared patients with TBI to control participants (two studies included control children with orthopaedic injury and 11 studies included healthy children as controls). 22 studies included 50 participants or fewer, 12 studies had between 51–100 participants, and 13 studies had more than 100 participants. However, only one study had more than 100 participants in each of the TBI and control groups. Therefore, there are few studies in children that compare a well powered TBI cohort with an equally well powered control group, and valid normative data for paediatric TBI blood biomarkers are not available.

Added value of this study

Our study used a rigorous approach to establish normative data for paediatric serum total tau concentrations that meet the guidelines of the US Clinical and Laboratory Standards Institute. We studied a well powered cohort of healthy children aged 1 to less than 19 years to guide interpretation of changes in serum total tau concentrations in children after TBI. Serum total tau varies by age but not by sex in children. After TBI, serum total tau concentrations were elevated in all patients with a Glasgow Coma Scale (GCS) score below 15 points, could discriminate between patients with mild TBI (GCS 13–14 vs GCS 15), and peaked on the first day of injury, except in patients with severe TBI, in whom it remained elevated for at least 7 days.

Implications of all the available evidence

Serum total tau could help to differentiate patients with various degrees of mild TBI, as its concentrations in patients with GCS scores of 15 points subjects were indistinguishable from those of control participants, whereas concentrations in patients with GCS scores of 13–14 were elevated. Serum total tau at day 1 was not useful for predicting positive radiological findings on CT scans. As serum total tau concentrations vary widely in children younger than 4 years, its diagnostic value for TBI might be weaker in infants and toddlers compared with school-aged children and adolescents.

Blood biomarkers can potentially assist in clinical prediction and decision making. Biomarkers indicative of neuronal (γ-enolase, also known as neuron-specific enolase [NSE], and ubiquitin carboxy-terminal hydrolase isozyme L1 [UCH-L1]), axonal (neurofilament light polypeptide [NF-L] and microtubule-associated protein tau), and astroglial (glial fibrillary acidic protein [GFAP] and the calcium-binding protein S100-B [S100B]) damage in TBI have been studied.5, 6 However, studies of TBI biomarkers in children lag behind studies in adults in both size and scope.7, 8 A particular challenge is the rapid development and maturation of the CNS during childhood and adolescence, which might affect baseline and post-injury biomarker concentrations.3, 9

Serum total tau is increased after TBI in adults and might be associated with post-concussion symptoms.10, 11, 12, 13, 14, 15 However, there are no large-scale studies of serum total tau after paediatric TBI, nor have paediatric normative concentrations for serum total tau been established to guide post-TBI interpretation. We therefore aimed to establish valid reference intervals for a research assay of serum total tau for children aged 1–18 years, using healthy participants from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort, to guide the interpretation of laboratory test results.9, 16 We used these reference intervals as a proxy of tau concentrations before injury to assess the diagnostic potential of serum total tau in a cohort of patients with TBI. We characterised the response of serum total tau on day 1 of injury in relation to TBI severity and describe its temporal profile in the first week after injury.

Section snippets

Study design and participants

In this case-control study, serum samples from healthy control participants were drawn from CALIPER, a Canada-wide, multicentre collaborative project coordinated by the Hospital for Sick Children (Toronto, ON, Canada),9 as well as from the Hospital for Sick Children's core laboratory. CALIPER was initiated in 2008 and recruited healthy male and female children aged 1–18 years. For our study, we excluded CALIPER participants from the neonatal or paediatric intensive care units, those undergoing

Results

Participants were recruited between April 30, 2011, and June 28, 2013. Of 10 125 healthy children in the CALIPER cohort, 8628 blood samples were examined for eligibility and 4718 were confirmed to be eligible for analysis. Of these, 339 samples that were evenly distributed across the study age range and between sexes were randomly selected and included and analysed in this study. However, because we only had serum samples from one child younger than age 3 years and 23 children aged 3–5 years,

Discussion

To our knowledge, this is the first large-scale study to report on serum total tau concentrations in both healthy children and children with TBI. We show that serum total tau decreases with age, with three significant age partitions in healthy children: from 1 to less than 4 years, 4 to less than 16 years, and from 16 to less than 19 years. Serum total tau was significantly increased following TBI in paediatric patients with a GCS score below 15 points, suggesting that the release of tau from

Data sharing

Consent forms, case report forms, and the procedures manual for the BTBI study are available on request. The BTBI database containing de-identified data is planned to be housed in the Brain-CODE bioinformatics platform (Ontario Brain Institute, Ontario, ON, Canada) after publication of primary papers from the BTBI study, where it will be available to other researchers upon receipt and approval of database sharing protocols with complete consensus by the BTBI Steering Committee.

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