Henriette A. Moll

Background: In children, the value of routine blood pressure measurement in first assessment at the emergency department has been questioned. This has, however, not yet been evaluated in low- and middle-income countries (LMICs) where the incidence of serious illness is high. This study assessed the predictive value of low systolic blood pressure to detect serious illness in children attending acute care settings in LMICs. Methods: This observational study is based on data from children attending three acute care settings in The Gambia and Suriname. Hypotension was defined by age-adjusted reference values according to Advanced Paediatric Life Support (APLS) and Paediatric Advanced Life Support (PALS) cut-offs. The outcome measure was a composite marker of serious illness consisting of admission or referral to a higher level of care. A logistic regression analysis was used to evaluate the association between hypotension and serious illness for each setting separately. Results: 20 185 visits from Gambia rural, 398 visits from Gambia urban and 1817 visits from Suriname were included. Hypotension was present in 8.3–17.3% of visits and serious illness in 3.9–15.7%. Hypotension was not significantly associated with serious illness in Gambia urban (OR _APLS 3.2 (0.7–10.9) and OR _PALS 1.4 (0.1–7.6)) and Suriname (OR _APLS 1.3 (0.9–1.9) and OR _PALS 1.7 (0.9–3.2)), and with an inverse association in Gambia rural (OR _APLS 0.6 (0.5–0.7) and OR _PALS 0.9 (0.5–1.4)). Conclusions: Our results do not show a significant association between hypotension and serious illness in LMICs. Our results suggest that routine blood pressure measurement does not aid in the evaluation of well-appearing children attending acute care settings in LMICs.

Objective To externally validate the Paediatric Emergency Care Applied Research Network (PECARN) rule for identifying febrile infants aged Methods Secondary analysis of data from the Management and Outcomes of Fever in Children in Europe (MOFICHE) study (12 paediatric emergency departments in eight European countries, January 2017 to April 2018) and a Swedish study (four paediatric emergency departments, January 2014 to December 2020). Previously healthy febrile infants aged ≤60 days were included. We validated the original PECARN rule in a Swedish subcohort (2018–2020) and explored an adapted version using CRP in the full Swedish and MOFICHE cohorts. Results The Swedish subcohort (2018–2020) included 536 febrile infants with an SBI prevalence of 11%. The original PECARN rule showed a sensitivity of 96.6% (95% CI 88.1 to 99.6), specificity of 61.9% (95% CI 57.4 to 66.3), negative predictive value (NPV) of 99.3% (95% CI 97.4 to 99.8) and positive predictive value (PPV) of 23.5% (95% CI 21.4 to 25.8). The full Swedish cohort (2014–2020) included 2237 infants and the MOFICHE cohort of 512 infants with 12% and 10% SBI prevalence, respectively. Using CRP Conclusions The PECARN rule demonstrated high NPV (similar to the derivation cohort) and high potential in ruling out SBIs in two new European cohorts. The rule maintained good performance with CRP instead of PCT, supporting the potential use of CRP in settings where PCT is unavailable.

Importance: The upsurge in invasive disease caused by Streptococcus pyogenes among children reported in several European countries during 2022-2023 has not been fully explained. Objective: To test the hypothesis that changes in circulation of common respiratory pathogens associated with the introduction of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic altered acquisition of immunity to S. pyogenes and common respiratory viruses. Design: Cross-sectional study recruiting before (September 2016 to March 2020) and after (April 2020 to July 2023) introduction of NPIs. Setting: European hospitals in 10 countries. Participants: Children with suspected infection and afebrile controls, aged 0-4 years. Main Outcomes: Molecular detection of bacterial and viral pathogens on throat swabs and age-stratified total serum IgG reactivity to S. pyogenes cell wall extract from two strains (measured by ELISA), and respiratory syncytial virus (RSV), five influenza viruses and four common cold coronaviruses and SARS-CoV-2 measured by Mesoscale immunoassay. Results: Throat swabs from 1942 children under 5-years of age were tested for respiratory pathogens (1449 recruited before introduction of NPIs; 493 recruited after). A decrease in detection of S. pyogenes, RSV, common cold coronaviruses, and influenza viruses was observed between March 2020 to July 2021, corresponding to the maximal period of NPIs. Antibodies to S. pyogenes were measured in 252 children recruited before NPIs and 200 thereafter. Antibodies to viral antigens were measured in 230 before NPIs and 92 thereafter. Total IgG to S. pyogenes and RSV was significantly lower in children aged 3-4 years recruited after NPI introduction compared with before ( S. pyogenes emm1 : after, n=67, median 0.13 vs before, n=87, 0.35 IVIG relative-units, p=0.007. RSV: after, n=30, median 49604 vs before, n=76, 141782 mesoscale-units pS. pyogenes and RSV in children aged 3-4 years after introduction of NPIs. Equivalent to approximately a year delay in acquisition of immunity, these data provide a biological basis for the 2022-2023 upsurge in severe S. pyogenes infections in this age group.

Aim: To find proof‐of‐principle evidence for short‐term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1).Method: This was a double‐blind, parallel‐group, randomized, placebo‐controlled clinical trial (the NF1‐EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17 years 6 months. The short‐term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention‐deficit/hyperactivity problems, and executive functioning.Results: We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete‐case analysis showed no effect of lamotrigine on either performance IQ (−0.23, 95% CI −6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (−0.81, 95% CI −1.67 to 0.04).Interpretation: Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion.

Background White blood cell count (WBC) is a widely used marker for the prediction of serious bacterial infection (SBI); however, previous research has shown poor performance. This study aims to assess the value of WBC in the prediction of SBI in children at the emergency department (ED) and compare its value with C reactive protein (CRP) and absolute neutrophil count (ANC). Methods This study is an observational multicentre study including febrile children aged 0–18 years attending 1 of 12 EDs in 8 European countries. The association between WBC and SBI was assessed by multivariable logistic regression, adjusting for age, CRP and duration of fever. Additionally, diagnostic performance was assessed by sensitivity and specificity. Results were compared with CRP and ANC. Results We included 17 082 children with WBC measurements, of which 1854 (10.9%) had an SBI. WBC >15 had an adjusted OR of 1.9 (95% CI 1.7 to 2.1) for prediction of SBI, after adjusting for confounders. Sensitivity and specificity were 0.56 (95% CI 0.54 to 0.58) and 0.74 (0.73 to 0.75) for WBC >15, and 0.32 (0.30 to 0.34) and 0.91 (0.91 to 0.91) for WBC >20, respectively. In comparison, CRP >20 mg/L had a sensitivity of 0.87 (95% CI 0.85 to 0.88) and a specificity of 0.59 (0.58 to 059). For CRP >80 mg/L, the sensitivity was 0.55 (95% CI 0.52 to 057) and the specificity was 0.91 (0.90 to 0.91). Additionally, for ANC >10, the sensitivity was 0.55 (95% CI 0.53 to 0.58) and the specificity was 0.75 (0.75 to 0.76). The combination of WBC and CRP did not improve performance compared with CRP alone. Conclusion WBC does not have diagnostic benefit in identifying children with an SBI compared with CRP and should only be measured for specific indications.

Early recognition of children at risk of serious illness is essential in preventing morbidity and mortality, particularly in low- and middle-income countries (LMICs). This study aimed to validate the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in acute care settings in LMICs. This observational study is based on previously collected clinical data from consecutive children attending four diverse settings in LMICs. Inclusion criteria and study periods (2010–2021) varied. We simulated the ED-PEWS, consisting of patient age, consciousness, work of breathing, respiratory rate, oxygen saturation, heart rate, and capillary refill time, based on the first available parameters. Discrimination was assessed by the area under the curve (AUC), sensitivity and specificity (previously defined cut-offs < 6 and ≥ 15). The outcome measure was for each setting a composite marker of high urgency. 41,917 visits from Gambia rural, 501 visits from Gambia urban, 2,608 visits from Suriname, and 1,682 visits from Tanzania were included. The proportion of high urgency was variable (range 4.6% to 24.9%). Performance ranged from AUC 0.80 (95%CI 0.70–0.89) in Gambia urban to 0.62 (95%CI 0.55–0.67) in Tanzania. The low-urgency cut-off showed a high sensitivity in all settings ranging from 0.83 (95%CI 0.81–0.84) to 1.00 (95%CI 0.97–1.00). The high-urgency cut-off showed a specificity ranging from 0.71 (95%CI 0.66–0.75) to 0.97 (95%CI 0.97–0.97). The ED-PEWS has a moderate to good performance for the recognition of high urgency children in these LMIC settings. The performance appears to have potential in improving the identification of high urgency children in LMICs.

Objectives: The COVID-19 pandemic and subsequent rise of multisystem inflammatory syndrome in children have raised interest in high-sensitivity troponin (hs-TnT) and N-terminal probrain natriuretic peptide (NT-proBNP) because these have been found to be elevated in many cases of multisystem inflammatory syndrome in children. Our aim was to study hs-TnT and NT-proBNP concentrations in febrile children not affected by COVID-19. Methods: We retrospectively measured cardiac markers, hs-TnT, and NT-proBNP in leftover blood samples of febrile children (0–18 years) diagnosed and treated in a single-center emergency department (ED) (N = 67) and pediatric intensive care unit (PICU) (N = 19) that participated in a multicenter, prospective study of infection biomarkers (PERFORM). Results: Concentrations of hs-TnT, median 1.8 ng/L (interquartile range [IQR], 0.0–15.1), and NT-proBNP, 194 pg/mL (IQR, 54.9–706), were higher in febrile children than in controls (N = 25, hs-TnT 0.0 [IQR, 0–0]; NT-proBNP 56.3 [IQR, 29.7–109], both P < 0.001), whereas PICU patients had higher concentrations (hs-TnT 15.1 [IQR, 10.3–102] and NT-proBNP 828 [IQR, 657–4712], both P < 0.001) than ED patients (hs-TnT 0 [IQR, 0–7.4] and NT-proBNP 104 [IQR, 39.5–363]). No differences were found between viral and bacterial infections. Highest concentrations were found in children with either comorbidity predisposing to elevated concentrations (eg, chronic cardiac or renal disease) or children with critical illness or multiorgan failure such as those with septic shock. Conclusions: Concentrations of hs-TnT and NT-proBNP are often elevated in febrile children with different causes of fever. Concentrations were higher in children admitted to the PICU than in children attending the ED, and seem to reflect disease severity rather than the underlying cause of fever.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of −1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (−2.24 SDS) versus non-deletion (−1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (−2.60 vs −1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes.   Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.

Background: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. Methods: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final “bacterial” or “viral” phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. Results: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the “Watch” category. Conclusions: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.