Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Serum calprotectin and joint ultrasound in the definition of disease relapse in non-systemic juvenile idiopathic arthritis: a prospective longitudinal study.

OBJECTIVES: The aim of our study was to investigate the role of serum calprotectin (SC) and muscle-skeletal ultrasound (MSUS) as predictive markers of relapse in patients with juvenile idiopathic arthritis (JIA). METHODS: Sixty non-systemic (ns) JIA patients in clinical remission were recruited to evaluate the risk of disease relapse. SC levels and JIA disease activity were assessed at every visit (3, 6, 12 and 18 months). Joint synovitis, characterised by both synovial effusion (SE) and synovial hyperplasia (SH), was measured by US score (sum of SE, SH, power Doppler and bone erosions) given to each examined joint and US ratio (US score/number of joints examined) at every visit. Associations of SC, US score and US ratio with relapse prevalence was studied longitudinally by using generalised estimating equations model. RESULTS: Thirty-one (51.6%) patients relapsed within 18 months. Patients with higher baseline US scores showed higher risk of relapse at 6 months (OR (95% confidence interval (CI)): 1.96 (1.09-3.52)). Additionally, patients with higher SC values at baseline showed higher risk of relapse at 18 months (1.66 (1.13-2.44)). Patients with higher baseline SC values showed an increased overall odds of relapse up to 18 months of follow-up (1.21 (1.08-1.36)). Furthermore, patients with higher US scores showed an increased overall odds of relapse up to 18 months of follow-up (1.96 (1.56-2.46)). Similarly, patients with higher US ratio showed an increased overall odds of relapse up to 18 months of follow-up (16.62 (7.17-38.54)). CONCLUSIONS: SC was able to identify JIA patients with unstable remission and increased risk of relapse. MSUS represents an interesting additional tool to the clinical evaluation, especially in predicting early relapse.

The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study.

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

Kidney function and renal resistive index in children with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a common pediatric rheumatic disease. Renal manifestations have been rarely observed in JIA, although amyloidosis could be a renal complication in systemic JIA (sJIA). To investigate renal damage in JIA children and to establish the relationship with treatment. Blood urea nitrogen (BUN), creatinine, cystatin C (CysC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinary albumin excretion (UAE), estimated glomerular filtration rate (eGFR), and renal resistive index (RRI) were assessed in 49 JIA children (9 boys/40 girls, mean age 10.3 ± 3.8 years) and in 49 healthy controls (24 boys/25 girls, mean age 11.3 ± 3.4 years). Twenty-two JIA patients were on methotrexate (MTX) therapy (group A) and 27 on biologic drugs (group B). CysC and BUN (respectively, 0.8 ± 0.1 vs. 0.7 ± 0.1 mg/dl; 13.3 ± 2.9 vs. 11.7 ± 1.4 mg/dl) were higher (p ≤ 0.001) whereas creatinine and eGFR (respectively, 0.5 ± 0.1 vs. 0.6 ± 0.1 mg/dl; 99.2 ± 10.5 vs. 122.5 ± 19.8 ml/min/1.73 m2) were lower in JIA children as compared to controls (p < 0.001). UAE resulted higher in patients than in controls (p = 0.003). Mean RRI was higher in JIA children than controls (0.7 ± 0.04 vs. 0.6 ± 0.04; p < 0.001). Group B showed higher mean RRI than group A (0.7 ± 0.1 vs. 0.7 ± 0.04; p < 0.001). Associations were found between RRI and ESR, JADAS-27, disease state, BMI-SDS (p < 0.001), CRP (p = 0.003) and eGFR (p = 0.001). JIA children had reduced eGFR, increased UAE and higher RRI values, than controls. RRIs were higher in patients on biologic drugs than MTX group and were associated with inflammation indexes and disease state, suggesting a direct effect of the disease.

S100B in cardiac surgery brain monitoring: friend or foe?

Recent advances in perioperative management of adult and pediatric patients requiring open heart surgery (OHS) and cardiopulmonary bypass (CPB) for cardiac and/or congenital heart diseases repair allowed a significant reduction in the mortality rate. Conversely morbidity rate pattern has a flat trend. Perioperative period is crucial since OHS and CPB are widely accepted as a deliberate hypoxic-ischemic reperfusion damage representing the cost to pay at a time when standard of care monitoring procedures can be silent or unavailable. In this respect, the measurement of neuro-biomarkers (NB), able to detect at early stage perioperative brain damage could be especially useful. In the last decade, among a series of NB, S100B protein has been investigated. After the first promising results, supporting the usefulness of the protein as predictor of short/long term adverse neurological outcome, the protein has been progressively abandoned due to a series of limitations. In the present review we offer an up-dated overview of the main S100B pros and cons in the peri-operative monitoring of adult and pediatric patients.

Serum Calprotectin a Potential Biomarker in Juvenile Idiopathic Arthritis: A Meta-Analysis.

Juvenile idiopathic arthritis (JIA) is the most common inflammatory chronic disease affecting children and adolescents. Today, there are no specific biomarkers of inflammation. Therefore, it is important to identify new markers as predictors of disease activity. Recently, some researchers have directed their interest toward a protein, calprotectin (CLP), as a potential biomarker. The primary objective of our systematic review and meta-analysis was to analyze the possible role of CLP in JIA. METHOD: A literature search was conducted using PubMed, EMBASE, Scopus, Science Direct on 10 August 2021. The selection of studies was made using the PRISMA 2020 guidelines. Cohen's d with 95% CI and p-value were used as a measure of effect size. The random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics and I2. The publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger's test. RESULTS: Our results at follow-up showed a statistically significant difference between patients with active disease compared to patients with inactive disease: 0.39 (0.16; 0.62), p = 0.001; without statistical heterogeneity. Another important aspect that emerged were the differences between the systemic disease form and any form of inactive disease showing a different concentration of calprotectin: 0.74 (0.40; 1.08), p < 0.001; without statistical heterogeneity. On the other hand, meta-regression analyses performed on gender, age, duration of disease, percentage of patients with ANA+ or RF+, medium value of ESR or CRP were not statistically significant. A statistically significant difference in serum calprotectin concentration between patients with JIA and healthy controls were observed. In fact, it presented lower values in the control group. CONCLUSIONS: The use of serum CLP could represent, in the future, a useful tool in JIA in order to stratify disease activity more accurately and may aid a more tailored approach to drug of choice in children with JIA. Further studies are needed to evaluate CLP as a predictor of flare in combination with other potential biomarkers of subclinical disease activity.

S100B protein, cerebral ultrasound and magnetic resonance imaging patterns in brain injured preterm infants.

OBJECTIVES: The early detection of preterm infants (PI) at risk for intraventricular hemorrhage (IVH) and neurological sequelae still constitutes an unsolved issue. We aimed at validating the role of S100B protein in the early diagnosis and prognosis of IVH in PI by means of cerebral ultrasound (CUS) and magnetic resonance imaging (MRI) today considered standard of care procedures. METHODS: We conducted an observational case-control study in 216 PI of whom 36 with IVH and 180 controls. Standard clinical, laboratory, radiological monitoring procedures and S100B urine measurement were performed at four time-points (first void, 24, 48, 96 h) after birth. Cerebral MRI was performed at 40-42 weeks of corrected gestational age. RESULTS: Elevated (p<0.001, for all) S100B levels were observed in the IVH group at all monitoring time-point particularly at first void when standard monitoring procedures were still silent or unavailable. S100B measured at first void correlated (p<0.001) with the grade of hemorrhage by means of CUS and with the site and extension of neurological lesion (p<0.001, for all) as assessed by MRI. CONCLUSIONS: The present results showing a correlation among S100B and CUS and MRI offer additional support to the inclusion of the protein in clinical daily management of cases at risk for IVH and adverse neurological outcome. The findings open the way to further investigations in PI aimed at validating new neurobiomarkers by means of S100B.

Pediatrician's approach to diagnosis and management of group A streptococcal pharyngitis.

Group A streptococcal (GAS) pharyngitis is responsible for 20-30% of pharyngitis cases in children (Shulman et al. Clin Infect Dis 55(10):e86-e102, 2012). Recommendations for the diagnosis and treatment of GAS pharyngitis have been published by the Italian National Institute of Health guidelines in 2012 (ESCMID Sore Throat Guideline Group et al. Clin Microbiol Infect 18(Suppl 1):1-28, 2012). Adherence to such guidance is relevant for primary prevention of complications of GAS pharyngitis, above all rheumatic fever (RF). The aim of our study was to evaluate the application of Italian guidelines by the family pediatricians from the Abruzzo region. A validated questionnaire was completed by the family pediatricians and used for data collection. The 154 family pediatricians from Abruzzo (88% of the total number of family pediatricians) participated in the study. Out of the 1232 answers, 455 (37%) were wrong. Only 8% of the participants answered correctly all the questions, whereas 0.6% missed all the questions. Through the Spearman's correlation, our study found an inverse significant correlation between the questions regarding primary prophylaxis (Score B) and the work experience of pediatricians (Rho = - 0.276, p = 0.048). The majority of the family pediatricians from the Abruzzo region, in line with studies from other countries, have significant knowledge gaps about the diagnosis and treatment of GAS pharyngitis. Therefore, strategies to increase the pediatricians' awareness of the guidelines are needed, in order to reduce the RF incidence.

Glutathione Blood Concentrations: A Biomarker of Oxidative Damage Protection during Cardiopulmonary Bypass in Children.

BACKGROUND: Pediatric open-heart surgery with cardiopulmonary bypass (CPB) still remains a risky interventional procedure at high mortality/morbidity. To date, there are no clinical, laboratory, and/or monitoring parameters providing useful information on perioperative stress. We therefore investigated whether blood concentrations of glutathione (GSH), a powerful endogenous antioxidant, changed in the perioperative period. METHODS: We conducted an observational study in 35 congenital heart disease (CHD) children in whom perioperative standard laboratory and monitoring parameters and GSH blood levels were assessed at five monitoring time points. RESULTS: GSH showed a pattern characterized by a progressive increase from pre-surgery up to 24 h after surgery, reaching its highest peak at the end of CPB. GSH measured at the end of CPB correlated with CPB duration, cross-clamping, arterial oxygen partial pressure, and with body core temperature. CONCLUSIONS: The increase in GSH levels in the perioperative period suggests a compensatory mechanism to oxidative damage during surgical procedure. Caution is needed in controlling different CPB phases, especially systemic reoxygenation in a population that is per se more prone to oxidative stress/damage. The findings may point the way to detecting the optimal temperature and oxygenation target by biomarker monitoring.

Effects of Sustained Inflation or Positive Pressure Ventilation on the Release of Adrenomedullin in Preterm Infants with Respiratory Failure at Birth.

OBJECTIVE: Delivery room (DR) management may play an important role in the development and prevention of lung injury. Therefore, in a cohort of low birth weight infants (LBW), we investigated the effects of two different lung recruitment maneuvers, such as positive pressure ventilation (PPV) and sustained inflation (SI) on adrenomedullin (AM), a well-established lung-specific vasoactive agent. STUDY DESIGN: This is a prospective case-control randomized study in 44 LBW infants spontaneously breathing with respiratory failure at birth requiring respiratory support. LBW were randomized to receive PPV (n = 22) or SI (n = 22) support. AM was measured from blood in samples collected at birth from arterial artery (BLT0) and at 1-hour (BLT1) and at 24-hour (BLT2) from peripheral venous site. AM assessment in urine samples was performed at 1-hour (URT1) and at 24-hour (URT2). RESULTS: No significant differences in AM (p > 0.05) blood (T0-T2) and urine (T1, T2) levels were observed between groups. CONCLUSION: The present data, showing the absence of any differences in AM blood and urine levels, suggest that PPV and SI are both feasible and equally effective DR maneuvers. The findings open the way to further studies evaluating the effects of PPV and SI on short-/long-term respiratory outcome through biomarkers assessment.

The Ca2+-Binding S100B Protein: An Important Diagnostic and Prognostic Neurobiomarker in Pediatric Laboratory Medicine.

In recent decades a significant scientific effort has focused on projects regarding the use of neurobiomarkers in perinatal medicine with a view to understanding the mechanisms that interfere with physiological patterns of brain development and lead to ominous effects in several human diseases. Numerous potential neurobiomarkers have been proposed for use in monitoring high-risk fetuses and newborns, including markers of oxidative stress, neuroproteins, and vasoactive agents. Nonetheless, the use of these markers in clinical practice remains a matter of debate. Recently, the calcium-binding S100B protein has been proposed as being an ideal neurobiomarker, thanks to its simple availability and easy reproducibility, to the possibility of detecting it noninvasively in biological fluids with good reproducibility, and to the possibility of a longitudinal evaluation in relation to reference curves. The present chapter contains an overview of the most significant studies on the assessment of S100B in different biological fluids as a trophic factor and/or marker of brain damage in high-risk fetuses and newborns.

MBL2 and FCN2 gene polymorphisms in a cohort of Italian children with rheumatic fever: A case-control study.

BACKGROUND: Mannose-binding lectins and human ficolins are pattern-recognition proteins involved in innate immunity. A role for MBL2 and FCN2 gene polymorphisms in the pathogenesis of recurrent severe streptococcal infections and rheumatic carditis has been suggested. OBJECTIVES: The aim of this study is to evaluate the presence of MBL2 and FCN2 gene polymorphisms (SNPs) in children with a history of rheumatic fever (RF) and to investigate their possible role in RF clinical presentation and disease course. METHODS: A total of 50 Caucasian patients with RF were recruited with a control group of 52 healthy children. DNA was extracted for analysis of MBL2 gene (exon 1, codons: 52, 54, and 57) and FCN2 gene (promoter region at position -986, -602, and -4). RESULTS: The FCN2 AG genotype at the -986 position was more frequently observed in patients, as compared to healthy subjects (p = 0.006); furthermore, the A allele was identified as a possible risk factor for the development of RF (OR = 7.14, CI: 2.439-20.89). Conversely, the GG genotype at the same position was observed more frequently in the control group and can be considered a protective factor for the development of the disease (p = 0.001, OR = 8.37, 95% CI: 2.763-25.33). In addition, the FCN2 GG and AG genotypes in the -4 position were also found to be protective factors for the development of RF and for carditis respectively (OR = 3.32, CI: 1.066-10.364; OR = 0.15, 95% CI: 0.037-0.566). Finally, the AA genotype in the -602 position was associated with a late onset of RF (p = 0.006). The analysis of the MBL2 gene only resulted in a higher frequency of the AA genotype on position 57 in controls as compared to patients (p = 0.025). CONCLUSIONS: This is the first study evaluating the FCN2 gene polymorphisms in patients with RF and rheumatic carditis finding a protective effect of -986 GG and -4 GG genotypes in the development of RF and the -4 AG genotype for the development of carditis. Our data do not support a possible role for MBL2 polymorphisms in the pathogenesis and in the clinical manifestations of RF.

Autoimmune sensorineural hearing loss as presenting manifestation of paediatric Behçet disease responding to adalimumab: a case report.

BACKGROUND: Autoimmune sensorineural hearing loss, also known as autoimmune inner ear disease (AIED) is a rare clinical entity characterized by progressive and bilateral sensorineural hearing loss often accompanied by vestibular symptoms. Diagnosis is essential as a consistent number of patients show a positive response to steroids alone or in association with other immunosuppressive drugs. AIED is defined as primary when the disease is limited to the ear, whereas in up to a third of cases it is associated to other systemic autoimmune diseases such as Behçet disease (BD). BD is a rare multisystem vasculitis characterized by recurrent oral and genital aphtosis, uveitis, skin lesions, neurological and vascular manifestations. Clinical presentation is variable thus making the diagnosis difficult in many instances. The choice of therapy is also limited by the scarceness of high-quality therapy studies. CASE PRESENTATION: We present a 15-year-old-boy with six months of history of fever, dizziness, tinnitus and ataxia. He had a final diagnosis of AIED associated to BD and was successfully treated with the anti-tumor necrosis factor (TNF)-α adalimumab. CONCLUSIONS: This case report points out to the diagnostic and therapeutic challenges of BD especially when unusual symptoms are the prominent manifestations of the disease. It also suggests that adalimumab is a good therapeutic option in children with BD and audiovestibular symptoms.