Blood Biomarkers for the Management of Mild Traumatic Brain Injury in Clinical Practice.

BACKGROUND: Despite the use of validated guidelines in the management of mild traumatic brain injury (mTBI), processes to limit unnecessary brain scans are still not sufficient and need to be improved. The use of blood biomarkers represents a relevant adjunct to identify patients at risk for intracranial injury requiring computed tomography (CT) scan. CONTENT: Biomarkers currently recommended in the management of mTBI in adults and children are discussed in this review. Protein S100 beta (S100B) is the best-documented blood biomarker due to its validation in large observational and interventional studies. Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminal hydrolase L-1 (UCH-L1) have also recently demonstrated their usefulness in patients with mTBI. Preanalytical, analytical, and postanalytical performance are presented to aid in their interpretation in clinical practice. Finally, new perspectives on biomarkers and mTBI are discussed. SUMMARY: In adults, the inclusion of S100B in Scandinavian and French guidelines has reduced the need for CT scans by at least 30%. S100B has significant potential as a diagnostic biomarker, but limitations include its rapid half-life, which requires blood collection within 3 h of trauma, and its lack of neurospecificity. In 2018, the FDA approved the use of combined determination of GFAP and UCH-L1 to aid in the assessment of mTBI. Since 2022, new French guidelines also recommend the determination of GFAP and UCH-L1 in order to target a larger number of patients (sampling within 12 h post-injury) and optimize the reduction of CT scans. In the future, new cut-offs related to age and promising new biomarkers are expected for both diagnostic and prognostic applications.

Prevalence of FGF23 elevation in patients with hypophosphatemia.

BACKGROUND AND AIMS: To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. MATERIALS AND METHODS: We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. RESULTS: Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0-14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). CONCLUSION: In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.

CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes.

OBJECTIVES: The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). METHODS: A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. RESULTS: First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57-0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54-0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66-0.79) (p<0.001). The results were confirmed on a second independent cohort. CONCLUSIONS: CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

S100B vs. "GFAP and UCH-L1" assays in the management of mTBI patients.

OBJECTIVES: To compare for the first time the performance of "GFAP and UCH-L1" vs. S100B in a cohort of patients managed for mild traumatic brain injury (mTBI) according to actualized French guidelines. METHODS: A prospective study was recently carried at the Emergency Department of Clermont-Ferrand University Hospital in France. Patients with mTBI presenting a medium risk of complications were enrolled. Blood S100B and "GFAP and UCHL-1" were sampled and measured according to French guidelines. S100B was measured in patients with samples within 3 h of trauma (Cobas®, Roche Diagnostics), while GFAP and UCHL-1 were measured in all patients (samples <3 h and 3-12 h) using another automated assay (i-STAT® Alinity, Abbott). RESULTS: For sampling <3 h, serum S100B correctly identifies intracranial lesions with a specificity of 25.7 % (95 % CI; 19.5-32.6 %), a sensitivity of 100 % (95 % CI; 66.4-100 %), and a negative predictive value of 100 % (95 % CI; 92.5-100 %). For sampling <12 h, plasma "GFAP and UCH-L1" levels correctly identify intracranial lesions with a specificity of 31.7 % (95 % CI; 25.7-38.2 %), a sensitivity of 100 % (95 % CI; 73.5-100 %), and a negative predictive value of 100 % (95 % CI; 95-100 %). Comparison of specificities (25.7 vs. 31.7 %) did not reveal a statistically significant difference (p=0.16). CONCLUSIONS: We highlight the usefulness of measuring plasma "GFAP and UCH-L1" levels to target mTBI patients (sampling within 12 h post-injury) and optimize the reduction of CT scans.

Tumor-Induced Osteomalacia in Patients With Malignancy: A Meta-analysis and Systematic Review of Case Reports.

CONTEXT: Tumor-induced osteomalacia (TIO) due to fibroblast growth factor 23 (FGF23) overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature. OBJECTIVE: To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications. METHODS: Full texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. Thirty-two of 275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality. RESULTS: Prostate adenocarcinoma (n = 9) were the most tumors reported. Twenty-five of 34 patients had a metastatic disease and a poor clinical outcome was reported for 15 of 28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL, respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20 of 22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL). CONCLUSION: We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic workup, prognostication, and follow-up of patients.

S100B, Actor and Biomarker of Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) accounts for approximately 80% of all TBI cases and is a growing source of morbidity and mortality worldwide. To improve the management of children and adults with mTBI, a series of candidate biomarkers have been investigated in recent years. In this context, the measurement of blood biomarkers in the acute phase after a traumatic event helps reduce unnecessary CT scans and hospitalizations. In athletes, improved management of sports-related concussions is also sought to ensure athletes' safety. S100B protein has emerged as the most widely studied and used biomarker for clinical decision making in patients with mTBI. In addition to its use as a diagnostic biomarker, S100B plays an active role in the molecular pathogenic processes accompanying acute brain injury. This review describes S100B protein as a diagnostic tool as well as a potential therapeutic target in patients with mTBI.

Impact of storage temperature and time before analysis on electrolytes (Na+, K+, Ca2+), lactate, glucose, blood gases (pH, pO2, pCO2), tHb, O2Hb, COHb and MetHb results.

OBJECTIVES: The objective of our study is to evaluate the effect of storage temperature and time to analysis on arterial blood gas parameters in order to extend the CLSI recommendations. METHODS: Stability of 12 parameters (pH, pCO2, pO2, Na+, K+, Ca2+, glucose, lactate, hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin) measured by GEM PREMIER™ 5000 blood gas analyzer was studied at room temperature and at +4 °C (52 patients). The storage times were 30, 45, 60, 90 and 120 min. Stability was evaluated on the difference from baseline, the difference from the analyte-specific measurement uncertainty applied to the baseline value, and the impact of the variation on the clinical interpretation. RESULTS: At room temperature, all parameters except the lactate remained stable for at least 60 min. A statistically significant difference was observed for pH at T45 and T60 and for pCO2 at T60 without modification of clinical interpretation. For lactate, clinical interpretation was modified from T45 and values were outside the range of acceptability defined by the measurement uncertainty. All parameters except pO2 remained stable for at least 120 min at +4 °C. CONCLUSIONS: A one-hour transport at room temperature is compatible with the performance of all the analyses studied except lactate. If the delay exceeds 30 min, the sample should be placed at +4 °C for lactate measurement. If the samples are stored in ice, it is important to note that the pO2 cannot be interpreted.

Ionized Magnesium: Interpretation and Interest in Atrial Fibrillation.

BACKGROUND: Magnesium (Mg) is often used to manage de novo atrial fibrillation (AF) in the emergency department (ED) and intensive care unit (ICU). Point of care measurement of ionized magnesium (iMg) allows a rapid identification of patients with impaired magnesium status, however, unlike ionized calcium, the interpretation of iMg is not entirely understood. Thus, we evaluated iMg reference values, correlation between iMg and plasmatic magnesium (pMg), and the impact of pH and albumin variations on iMg levels. Secondary objectives were to assess the incidence of hypomagnesemia in de novo AF. METHODS: A total of 236 emergency department and intensive care unit patients with de novo AF, and 198 control patients were included. Reference values were determined in the control population. Correlation and concordance between iMg and pMg were studied using calcium (ionized and plasmatic) as a control in the whole study population. The impact of albumin and pH was assessed in the discordant iMg and pMg values. Lastly, we assessed the incidence of ionized hypomagnesemia (hypoMg) among de novo AF. RESULTS: The reference range values established in our study for iMg were: 0.48-0.65 mmol/L (the manufacturers were: 0.45-0.60 mmol/L). A strong correlation was observed between pMg and iMg (r = 0.85), but, unlike for calcium values, there was no significant impact of pH and albumin in iMg/pMg interpretation. The incidence of hypoMg among de novo AF patients was 8.5% (12.7% using our ranges). When using our ranges, we found a significant link (p = 0.01) between hyopMg and hypokalemia. CONCLUSION: We highlight the need for more accurate reference range values of iMg. Furthermore, our results suggest that blood Mg content is not identical to that of calcium. The incidence of ionized hypomagnesemia among de novo AF patients in our study is 8.5%.

Blood Biomarkers for Return to Play after Concussion in Professional Rugby Players.

We prospectively evaluated a panel of seven blood biomarkers (S100 calcium-binding protein B [S100B], neuron specific enolase [NSE], spectrin breakdown products [SBDP], ubiquitin C-terminal hydrolase L1 [UCHL1], glial fibrillary acidic protein [GFAP], neurofilament light chain [NFL], and tubulin-associated unit [Tau]) for sport-related concussion (SRC) in a large multi-centric cohort of 496 professional rugby players from 14 French elite teams. Players were sampled twice during the season (beginning and end) away from any sport practice. From these two baseline samples, we evaluated the intra-individual variability to establish the effect of rugby on blood biomarkers over a season. Only S100B and GFAP remained stable over the course of a season. During the period of the study, a total of 45 SRC cases was reported for 42 players. In 45 SRCs, the head injury assessment (HIA) process was performed and blood collection was realized 36 h after the concussion (HIA-3 stage). For each biomarker, raw concentrations measured 36 h after SRC were not significantly different between players with a non-resolutive SRC (n = 28) and those with a resolutive SRC (n = 17; p between 0.06 and 0.92). In a second step, blood concentrations measured 36 h after SRC were expressed according to the basal concentrations as an individual percentage change (PCH36[%]), calculated as follows: PCH36 = 100 × (([Biomarker]36h - [Biomarker]basal)/[Biomarker]basal). S100B and NFL concentrations expressed as PCH36[%] were significantly different between non-resolutive and resolutive SRCs (p = 0.006 and 0.01 respectively), with a positive delta found in non-resolutive SRCs. Among the two biomarkers, it is important to note that only the S100B protein was stable during the season. In the context of our study, during HIA-3 assessment, S100B seems to perform better than NSE, SBDP, UCHL1, GFAP, NFL, and Tau as biomarker for SRC. From a clinical standpoint, the S100B modification over baseline may be valuable, at 36 h after concussion to distinguish non-resolutive SRC from resolutive SRC.

Evaluation of serum neurofilament light in the early management of mTBI patients.

OBJECTIVES: Serum S100B allows a one-third reduction of computed tomography (CT) scans performed for mild traumatic brain injury (mTBI) patients. In this study, we evaluated the diagnostic performance of serum NF-L in the detection of intracranial lesions induced by mTBI. METHODS: One hundred seventy-nine adult mTBI patients presenting to the emergency department of Clermont-Ferrand University Hospital with a Glasgow Coma Scale (GCS) score of 14-15 were included. S100B assays were performed for clinical routine while NF-L samples were stored at -80 °C until analysis. CT scans were performed for patients with S100B levels above the decision threshold of 0.10 µg/L. Later, NF-L and S100B levels were compared to CT scan findings to evaluate the biomarkers' performances. RESULTS: The area under the ROC curve (AUC) evaluating the diagnostic ability in the prediction of intracranial lesions was 0.72 (95% CI; 0.58-0.87) for S100B and 0.58 (95% CI; 0.45-0.71) for NF-L, the specificities (at a threshold allowing a 100% sensitivity) were 35.7% for S100B, and 28% for NF-L (p=0.096). AUCs of NF-L and S100B for the identification of patients with neurological disorders were statistically different (p<0.001). The AUCs were 0.87 (95% CI; 0.82-0.93) for NF-L and 0.57 (95% CI; 0.48-0.66) for S100B. There was a poor correlation between NF-L and S100B, and NF-L levels were correlated to patients' age (Spearman coefficient of 0.79). CONCLUSIONS: NF-L showed poor performances in the early management of mTBI patients. NF-L levels are strongly correlated to neurodegeneration, whether physiological, age-related, or pathological.

Predictive Performance of Blood S100B in the Management of Patients Over 65 Years Old With Mild Traumatic Brain Injury.

BACKGROUND: We previously assessed the inclusion of S100B blood determination into clinical decision rules for mild traumatic brain injury (mTBI) management in the Emergency Department (ED) of Clermont-Ferrand Hospital. At the 0.10 µg/L threshold, S100B reduced the use of cranial computed tomography (CCT) scan in adults by at least 30% with a ~100% sensitivity. Older patients had higher serum S100B values, resulting in lower specificity (18.7%) and decreased CCT reduction. We conducted this study to confirm the age effect on S100B concentrations, and to propose new decisional thresholds for older patients. METHODS: A total of 1172 mTBI patients aged 65 and over were included. They were divided into 3 age groups: 65-79, 80-89, and ≥ 90 years old. S100B's performance to identify intracranial lesions (sensitivity [SE] and specificity [SP]) was assessed using the routine 0.10 µg/L threshold and also other more efficient thresholds established for each age group. RESULTS: S100B concentration medians were 0.18, 0.26, and 0.32 µg/L for the 65-79, 80-89, and ≥ 90 years old age groups, respectively (p < .001). The most efficient thresholds were 0.11 µg/L for the 65-79 age group and 0.15 µg/L for the other groups. At these new thresholds, SP was respectively 28.4%, 34.3%, and 20.5% for each age group versus 24.9%, 18.2%, and 10.5% at the 0.10 µg/L threshold. CONCLUSIONS: Adjustment of the S100B threshold is necessary in older patients' management. An increased threshold of 0.15 µg/L is particularly interesting for patients ≥ 80 years old, allowing a significant increase of CCT scan reduction (29.3%).

S100B Blood Level Determination for Early Management of Ski-Related Mild Traumatic Brain Injury: A Pilot Study.

Background: Mild traumatic brain injury (mTBI) management in emergency departments is a complex process involving clinical evaluation, laboratory testing, and computerized tomography (CT) scanning. Protein S100B has proven to be a useful blood biomarker for early evaluation of mTBI, as it reduces the required CT scans by one-third. However, to date, the ability of S100B to identify positive abnormal findings in the CT scans of patients suffering from mTBI caused by ski practice has not been investigated. Thus, the primary aim of this study was to investigate the diagnostic performance of S100B as an mTBI management biomarker in patients with ski-related mTBI. Materials and Methods: One hundred and thirty adult mTBI patients presenting to the emergency department of Hôpital du Valais in Sion, Switzerland, with a Glasgow Coma Scale (GCS) score of 13-15 and clinical indication for a CT scan were included in the study. Blood samples for S100B measurement were collected from each patient and frozen in 3-hour post-injury intervals. CT scans were performed for all patients. Later, serum S100B levels were compared to CT scan findings in order to evaluate the biomarker's performance. Results: Of the 130 included cases of mTBI, 87 (70%) were related to ski practice. At the internationally established threshold of 0.1 µg/L, the receiver operating characteristic curve of S100B serum levels for prediction of abnormal CT scans showed 97% sensitivity, 11% specificity, and a 92% negative predictive value. Median S100B concentrations did not differ according to sex, age, or GCS score. Additionally, there was no significant difference between skiers and non-skiers. However, a statistically significant difference was found when comparing the median S100B concentrations of patients who suffered fractures or had polytrauma and those who did not suffer fractures. Conclusion: The performance of S100B in post-mTBI brain lesion screenings seems to be affected by peripheral lesions and/or ski practice. The lack of neurospecificity of the biomarker in this context does not allow unnecessary CT scans to be reduced by one-third as expected.

Measurement of S100B protein: evaluation of a new prototype on a bioMérieux Vidas® 3 analyzer.

Background The addition of S100B protein to guidelines for the management of mild traumatic brain injury (mTBI) decreases the amount of unnecessary computed tomography (CT) scans with a significant decrease in radiation exposure and an increase in cost savings. Both DiaSorin and Roche Diagnostics have developed automated assays for S100B determination. Recently, bioMérieux developed a prototype immunoassay for serum S100B determination. For the first time, we present the evaluation of the S100B measurement using a bioMérieux Vidas® 3 analyzer. Methods We evaluated the matrix effects of serum and plasma, and their stability after storage at 2-8 °C, -20 °C and -80 °C. The new measurement prototype (bioMérieux) was compared with an established one (Roche Diagnostics), and a precision study was also conducted. Lastly, clinical diagnostics performance of the bioMérieux and Roche Diagnostics methods were compared for 80 patients referred to the Emergency Department for mTBI. Results Stability after storage at 2-8 °C, -20 °C, and -80 °C and validation of the serum matrix were demonstrated. The bioMérieux analyzer was compared to the Roche Diagnostics system, and the analytical precision was found to be efficient. Clinical diagnosis performance evaluation confirmed the predictive negative value of S100B in the management of mTBI. Conclusions The study's data are useful for interpreting serum S100B results on a bioMérieux Vidas® 3 analyzer.