Serum GFAP and UCH-L1 for the identification of clinically important traumatic brain injury in children in France: a diagnostic accuracy substudy

Background: Many children with mild traumatic brain injury (mTBI), defined by a Glasgow Coma Scale (GCS) score between 13 and 15, undergo hospitalisation or cranial CT (CCT) scans despite the absence of clinically important traumatic brain injury (ciTBI; ie, hospitalisation >2 days associated with intracranial lesions on CCT, neurosurgical intervention, intensive care admission, or death). Clinical algorithms have reduced CCT scans and hospitalisations by 10%. We aimed to established age-appropriate reference values for GFAP and UCH-L1 and evaluate their diagnostic test performance in identifying ciTBI in children.

Methods: This study was a diagnostic test accuracy substudy within the PROS100B stepped wedge cluster randomised trial that included children aged 16 years or younger, clinically managed within 3 h of mTBI, with a GCS score of 15 requiring hospitalisation or CCT scan according to French Pediatric Society guidelines (equivalent to the intermediate risk group of the PECARN algorithm). Enrolment for PROS100B occurred from Nov 1, 2016, to Oct 31, 2021, at 11 hospital emergency departments in France. Stored blood samples collected from March 1, 2015, to Oct 31, 2015, from children aged 16 years or younger who were outpatients for allergic conditions unrelated to mTBI and free of neurological disease were used as a control group to calculate reference values of GFAP and UCH-L1 across four age groups (<6 months, 6 months to <2 years, 2 years to <4 years, and 4 years to <16 years). The diagnostic test performance of GFAP and UCH-L1, both above the reference range to identify ciTBI, was evaluated in the children with mTBI. GFAP and UCH-L1 were measured with the Alinity analyser (Abbott, Chicago, IL, USA).

Findings: Reference values were calculated from GFAP and UCH-L1 measured in samples from 718 control children (378 [53%] boys and 340 [47%] girls). 531 children (334 [63%] boys and 197 [37%] girls) aged 0-16 years with mTBI were included. By applying our reference values for GFAP and UCH-L1 across four age groups the biomarker combination (both biomarkers above reference ranges) had a sensitivity of 100% (95% CI 69-100), a negative predictive value of 100% (99-100), a specificity of 67% (63-71), a positive likelihood ratio of 3·01 (2·67-3·40), a negative likelihood ratio of 0, and an area under the curve of 0·83 (0·81-0·85) in identifying ciTBI.

Interpretation: Serum GFAP and UCH-L1 identify ciTBI in children with 100% sensitivity and 67% specificity, which could potentially reduce unnecessary CCT scans and hospitalisations in children with mTBI if implemented.

Funding: French Ministry of Health.