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Contains fulltext : 294537.pdf (Publisher’s version ) (Open Access) BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Additional file 1.

Supplementary Material 1

Contains fulltext : 291888.pdf (Publisher’s version ) (Open Access) AIM: This study investigated febrile children with petechial rashes who presented to European emergency departments (EDs) and investigated the role that mechanical causes played in diagnoses. METHODS: Consecutive patients with fever presenting to EDs in 11 European emergency departments in 2017-2018 were enrolled. The cause and focus of infection were identified and a detailed analysis was performed on children with petechial rashes. The results are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We found that 453/34010 (1.3%) febrile children had petechial rashes. The focus of the infection included sepsis (10/453, 2.2%) and meningitis (14/453, 3.1%). Children with a petechial rash were more likely than other febrile children to have sepsis or meningitis (OR 8.5, 95% CI 5.3-13.1) and bacterial infections (OR 1.4, 95% CI 1.0-1.8) as well as need for immediate life-saving interventions (OR 6.6, 95% CI 4.4-9.5) and intensive care unit admissions (OR 6.5, 95% CI 3.0-12.5). CONCLUSION: The combination of fever and petechial rash is still an important warning sign for childhood sepsis and meningitis. Ruling out coughing and/or vomiting was insufficient to safely identify low-risk patients.

Objective We surveyed the dissemination and use of point-of-care ultrasound (POCUS), physician training levels, and barriers and limitations to use of POCUS among pediatricians and pediatric emergency medicine (PEM) physicians across Europe and Israel. Methods A questionnaire was distributed through the PEM section of the European Society for Emergency Medicine and the Research in European Pediatric Emergency Medicine Network. Results A total of 581 physicians from 22 countries fully completed the questionnaire. Participants were primarily pediatric attending physicians (34.9% [203 of 581]) and PEM attending physicians (28.6% [166 of 581]). Most of the respondents, 58.5% (340 of 581), reported using POCUS in their practice, and 61.9% (359/581) had undergone POCUS training. Point-of-care ultrasound courses represented the most common method of becoming proficient in POCUS. Overall, the Focused Assessment with Sonography in Trauma scan was the mostly taught application, with 76.3% (274 of 359). Resuscitative, diagnostic, and procedural POCUS were rated as very useful or useful by the most of respondents. The lack of qualified personnel to train (76.9% [447 of 581]), and the insufficient time for physicians to learn, POCUS (63.7% [370 of 581]) were identified as the main limitations to POCUS implementation. Conclusions The dissemination of pediatric POCUS in the European and Israeli centers we surveyed is limited, and its applications are largely restricted to the Focused Assessment with Sonography in Trauma examination. This is likely related to lack of training programs. In contrast, the potential value of use of POCUS in PEM practice is recognized by the majority of respondents.

ObjectiveMost studies on febrile children have focused on infants and young children with serious bacterial infection (SBI). Although population studies have described an increased risk of sepsis in adolescents, little is known about febrile adolescents attending the emergency department (ED). We aimed to describe patient characteristics and management of febrile adolescents attending the ED.Design and settingThe MOFICHE/PERFORM study (Management and Outcome of Febrile Children in Europe/Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union), a prospective multicentre study, took place at 12 European EDs. Descriptive and multivariable regression analyses were performed, comparing febrile adolescents (12–18 years) with younger children in terms of patient characteristics, markers of disease severity (vital signs, clinical alarming signs), management (diagnostic tests, therapy, admission) and diagnosis (focus, viral/bacterial infection).Results37 420 encounters were included, of which 2577 (6.9%) were adolescents. Adolescents were more often triaged as highly urgent (38.9% vs 34.5%) and described as ill appearing (23.1% vs 15.6%) than younger children. Increased work of breathing and a non-blanching rash were present less often in adolescents, while neurological signs were present more often (1% vs 0%). C reactive protein tests were performed more frequently in adolescents and were more often abnormal (adjusted OR (aOR) 1.7, 95% CI 1.5 to 1.9). Adolescents were more often diagnosed with SBI (OR 1.8, 95% CI 1.6 to 2.0) and sepsis/meningitis (OR 2.3, 95% CI 1.1 to 5.0) and were more frequently admitted (aOR 1.3, 95% CI 1.2 to 1.4) and treated with intravenous antibiotics (aOR 1.7, 95% CI 1.5 to 2.0).ConclusionsAlthough younger children presented to the ED more frequently, adolescents were more often diagnosed with SBI and sepsis/meningitis. Our data emphasise the importance of awareness of severe infections in adolescents.

OBJECTIVE: Most studies on febrile children have focused on infants and young children with serious bacterial infection (SBI). Although population studies have described an increased risk of sepsis in adolescents, little is known about febrile adolescents attending the emergency department (ED). We aimed to describe patient characteristics and management of febrile adolescents attending the ED. DESIGN AND SETTING: The MOFICHE/PERFORM study (Management and Outcome of Febrile Children in Europe/Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union), a prospective multicentre study, took place at 12 European EDs. Descriptive and multivariable regression analyses were performed, comparing febrile adolescents (12-18 years) with younger children in terms of patient characteristics, markers of disease severity (vital signs, clinical alarming signs), management (diagnostic tests, therapy, admission) and diagnosis (focus, viral/bacterial infection). RESULTS: 37 420 encounters were included, of which 2577 (6.9%) were adolescents. Adolescents were more often triaged as highly urgent (38.9% vs 34.5%) and described as ill appearing (23.1% vs 15.6%) than younger children. Increased work of breathing and a non-blanching rash were present less often in adolescents, while neurological signs were present more often (1% vs 0%). C reactive protein tests were performed more frequently in adolescents and were more often abnormal (adjusted OR (aOR) 1.7, 95% CI 1.5 to 1.9). Adolescents were more often diagnosed with SBI (OR 1.8, 95% CI 1.6 to 2.0) and sepsis/meningitis (OR 2.3, 95% CI 1.1 to 5.0) and were more frequently admitted (aOR 1.3, 95% CI 1.2 to 1.4) and treated with intravenous antibiotics (aOR 1.7, 95% CI 1.5 to 2.0). CONCLUSIONS: Although younger children presented to the ED more frequently, adolescents were more often diagnosed with SBI and sepsis/meningitis. Our data emphasise the importance of awareness of severe infections in adolescents.

EU multicentre ED study of presenting vital signs in >5000 febrile children with an association between “shock index” and serious illness, but low sensitivity limits utility in screening. Objective (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children. Design/setting Observational study in 11 European EDs (2017-2018). Patients Febrile children with measured blood pressure. Main outcome measures Serious bacterial infection (SBI), invasive bacterial infection (IBI), immediate life-saving interventions (ILSIs) and intensive care unit (ICU) admission. The association between high Shock Index (>95th centile) and each outcome was determined by logistic regression adjusted for age, sex, referral, comorbidity and temperature. Additionally, we calculated sensitivity, specificity and negative/positive likelihood ratios (LRs). Results Of 5622 children, 461 (8.2%) had SBI, 46 (0.8%) had IBI, 203 (3.6%) were treated with ILSI and 69 (1.2%) were ICU admitted. High Shock Index was associated with SBI (adjusted OR (aOR) 1.6 (95% CI 1.3 to 1.9)), ILSI (aOR 2.5 (95% CI 2.0 to 2.9)), ICU admission (aOR 2.2 (95% CI 1.4 to 2.9)) but not with IBI (aOR: 1.5 (95% CI 0.6 to 2.4)). For the different outcomes, sensitivity for high Shock Index ranged from 0.10 to 0.15, specificity ranged from 0.95 to 0.95, negative LRs ranged from 0.90 to 0.95 and positive LRs ranged from 1.8 to 2.8. Conclusions High Shock Index is associated with serious illness in febrile children. However, its rule-out value is insufficient which suggests that the Shock Index is not valuable as a screening tool for all febrile children at the ED.

Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0

Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0–

Background: Prolonged Emergency Department (ED) stay causes crowding and negatively impacts quality of care. We developed and validated a prediction model for early identification of febrile children with a high risk of hospitalisation in order to improve ED flow. Methods: The MOFICHE study prospectively collected data on febrile children (0-18 years) presenting to 12 European EDs. A prediction models was constructed using multivariable logistic regression and included patient characteristics available at triage. We determined the discriminative values of the model by calculat-ing the area under the receiver operating curve (AUC). Findings: Of 38,424 paediatric encounters, 9,735 children were admitted to the ward and 157 to the PICU. The prediction model, combining patient characteristics and NICE alarming, yielded an AUC of 0.84 (95%CI 0.83-0.84). The model performed well for a rule-in threshold of 75% (specificity 99.0% (95%CI 98.9-99.1%, positive likeli-hood ratio 15.1 (95%CI 13.4-17.1), positive predictive value 0.84 (95%CI 0.82-0.86)) and a rule-out threshold of 7.5% (sensitivity 95.4% (95%CI 95.0-95.8), negative likelihood ratio 0.15 (95%CI 0.14-0.16), negative predic-tive value 0..95 (95%CI 0.95-9.96)). Validation in a separate dataset showed an excellent AUC of 0.91 (95%CI 0.90-0.93). The model performed well for identifying children needing PICU admission (AUC 0.95, 95%CI 0.93-0.97). A digital calculator was developed to facilitate clinical use. Interpretation: Patient characteristics and NICE alarming signs available at triage can be used to identify febrile children at high risk for hospitalisation and can be used to improve ED flow. Funding: European Union, NIHR, NHS. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0

Objectives To develop and cross-validate a multivariable clinical prediction model to identify invasive bacterial infections (IBI) and to identify patient groups who might benefit from new biomarkers. Design Prospective observational study. Setting 12 emergency departments (EDs) in 8 European countries. Patients Febrile children aged 0-18 years. Main outcome measures IBI, defined as bacteraemia, meningitis and bone/joint infection. We derived and cross-validated a model for IBI using variables from the Feverkidstool (clinical symptoms, C reactive protein), neurological signs, non-blanching rash and comorbidity. We assessed discrimination (area under the receiver operating curve) and diagnostic performance at different risk thresholds for IBI: sensitivity, specificity, negative and positive likelihood ratios (LRs). Results Of 16 268 patients, 135 (0.8%) had an IBI. The discriminative ability of the model was 0.84 (95% CI 0.81 to 0.88) and 0.78 (95% CI 0.74 to 0.82) in pooled cross-validations. The model performed well for the rule-out threshold of 0.1% (sensitivity 0.97 (95% CI 0.93 to 0.99), negative LR 0.1 (95% CI 0.0 to 0.2) and for the rule-in threshold of 2.0% (specificity 0.94 (95% CI 0.94 to 0.95), positive LR 8.4 (95% CI 6.9 to 10.0)). The intermediate thresholds of 0.1%-2.0% performed poorly (ranges: sensitivity 0.59-0.93, negative LR 0.14-0.57, specificity 0.52-0.88, positive LR 1.9-4.8) and comprised 9784 patients (60%). Conclusions The rule-out threshold of this model has potential to reduce antibiotic treatment while the rule-in threshold could be used to target treatment in febrile children at the ED. In more than half of patients at intermediate risk, sensitive biomarkers could improve identification of IBI and potentially reduce unnecessary antibiotic prescriptions.

Background: Paediatric illness, injury and medical procedures are potentially traumatic experiences with a range of possible negative psychosocial consequences. To prevent psychosocial impairment and improve medical adherence, evidence-based psychotherapy should be offered if indicated. Eye movement desensitization and reprocessing (EMDR) has been found to reduce symptoms of posttraumatic stress disorder (PTSD) in adults. The evidence for the use with children is promising. Furthermore, recent studies indicate its effectiveness for the treatment of other psychological symptomatology. However, the effectiveness of EMDR in children with subthreshold PTSD after medically related trauma has not yet been investigated. Objective: Investigating the short-term effectiveness of EMDR on posttraumatic stress, anxiety, depression and sleep problems in children with subthreshold PTSD after hospitalization through a randomized controlled trial (RCT). Method: Following baseline screening of 420 children from various Dutch hospitals, 74 children (4–15 years old) with medically related subthreshold PTSD were randomized to EMDR (n = 37) or care-as-usual (CAU; n = 37). Follow-up assessment took place after M = 9.7 weeks. Generalized Estimating Equation (GEE) analyses were performed to examine the effectiveness of EMDR compared to CAU. Results: Children in both groups improved significantly over time on all outcomes. However, the EMDR group improved significantly more as to child-reported symptoms of blood-injection-injury (BII) phobia and depression, and child-, and parent-reported sleep problems of the child. There was no superior effect of EMDR compared to CAU on subthreshold PTSD symptom reduction. Conclusions: EMDR did not perform better than CAU in reducing PTSD symptoms in a paediatric sample of children with subthreshold PTSD after hospitalization. However, the study results indicate that EMDR might be superior in reducing symptoms of blood-injection-injury phobia, depression and sleep problems.

Mintegi, Santiago/0000-0002-2342-8881; Gomez, Borja/0000-0001-6542-4494; Nijman, Ruud Gerard/0000-0001-9671-8161; Parri, Niccolo/0000-0002-8098-2504; Maconochie, Ian/0000-0001-6319-8550, WOS: 000495095400013, PubMed: 31023707, Objective Research in European Paediatric Emergency Medicine (REPEM) network is a collaborative group of 69 paediatric emergency medicine (PEM) physicians from 20 countries in Europe, initiated in 2006. To further improve paediatric emergency care in Europe, the aim of this study was to define research priorities for PEM in Europe to guide the development of future research projects. Design and Setting We carried out an online survey in a modified three-stage Delphi study. Eligible participants were members of the REPEM network. in stage 1, the REPEM steering committee prepared a list of research topics. in stage 2, REPEM members rated on a 6-point scale research topics and they could add research topics and comment on the list for further refinement. Stage 3 included further prioritisation using the Hanlon Process of Prioritisation (HPP) to give more emphasis to the feasibility of a research topic. Results Based on 52 respondents (response rates per stage varying from 41% to 57%), we identified the conditions 'fever', 'sepsis' and 'respiratory infections', and the processes/interventions 'biomarkers', 'risk stratification' and 'practice variation' as common themes of research interest. the HPP identified highest priority for 4 of the 5 highest prioritised items by the Delphi process, incorporating prevalence and severity of each condition and feasibility of undertaking such research. Conclusions While the high diversity in emergency department (ED) populations, cultures, healthcare systems and healthcare delivery in European PEM prompts to focus on practice variation of ED conditions, our defined research priority list will help guide further collaborative research efforts within the REPEM network to improve PEM care in Europe.

Additional file 3. 5th centile of systolic blood pressure and median (IQR) for boys.

Additional file 4. 5th centile of systolic blood pressure and median (IQR) for girls.

Additional file 5. Clinical cut-offs for hypotension.

Additional file 2. Clinical definitions for hypotension and range of 5th centile of systolic blood pressure for girls according to age.

Introduction: While fever is the main complaint among pediatric emergency services and high antibiotic prescription are observed, only a few studies have been published addressing this subject. Therefore this systematic review aims to summarize antibiotic prescriptions in febrile children at the ED and assess its determinants. Methods: We extracted studies published from 2000 to 2017 on antibiotic use in febrile children at the ED from different databases. Author, year, and country of publishing, study design, inclusion criteria, primary outcome, age, and number of children included in the study was extracted. To compare the risk-of-bias all articles were assessed using the MINORS criteria. For the final quality assessment we additionally used the sample size and the primary outcome. Results: We included 26 studies reporting on antibiotic prescription and 28 intervention studies on the effect on antibiotic prescription. In all 54 studies antibiotic prescriptions in the ED varied from 15 to 90.5%, pending on study populations and diagnosis. Respiratory tract infections were mostly studied. Pediatric emergency physicians prescribed significantly less antibiotics then general emergency physicians. Most frequent reported interventions to reduce antibiotics are delayed antibiotic prescription in acute otitis media, viral testing and guidelines. Conclusion: Evidence on antibiotic prescriptions in children with fever presenting to the ED remains inconclusive. Delayed antibiotic prescription in acute otitis media and guidelines for fever and respiratory infections can effectively reduce antibiotic prescription in the ED. The large heterogeneity of type of studies and included populations limits strict conclusions, such a gap in knowledge on the determining factors that influence antibiotic prescription in febrile children presenting to the ED remains.

EgeUn###, Background and Objective: Identifying international differences in the epidemiology of acute poisonings in children may help in improving prevention. We sought to evaluate the international epidemiological differences in acute poisonings in children presenting to emergency departments (EDs) from 8 different global regions. Methods: This was an international multicenter cross-sectional prospective study including children younger than 18 years with acute poisonings presenting to 105 EDs in 20 countries was conducted. Data collection started at each ED between January and September 2013, and continued for 1 year. Results: During the study period, we registered 363,245 pediatric ED presentations, of which 1727 were for poisoning (0.47%; 95% confidence interval, 0.45%-0.50%), with a significant variation in incidence between the regions. Full data were obtained for 1688 presentations. Most poisonings (1361 [80.6%]) occurred at home with either ingestion (1504 [89.0%]) or inhalation of the toxin (126 [7.6%]). Nonintentional exposures accounted for 1157 poisonings (68.5%; mainly in South America and Eastern Mediterranean region), with therapeutic drugs (494 [42.7%]), household products (310 [26.8%]), and pesticides (59 [5.1%]) being the most common toxins. Suicide attempts accounted for 233 exposures (13.8%; mainly in the Western Pacific region and North America), with therapeutic drugs (214 [91.8%], mainly psychotropics and acetaminophen) being the most common toxins. Significant differences between regions were found in both types of poisonings. Recreational poisonings were more common in Europe and Western Pacific region. No patient died. Conclusions: There are substantial epidemiological differences in acute poisonings among children in different countries and regions of the globe. International best practices need to be identified for prevention of acute poisonings in childhood.

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.

The influence of childhood nutrition on the development of constipation beyond the period of weaning and breastfeeding is relatively understudied. In addition, eating patterns in childhood can be highly correlated with overweight and sedentary behaviour, which may also have an influence on constipation. The aim of this study was to assess whether common dietary patterns, sedentary behaviour and childhood overweight are associated with constipation in childhood. The study was embedded in a population-based prospective birth cohort. Information on dietary intake was obtained by a food frequency questionnaire at the child's age of 14 months (n = 2420). The adherence scores on a 'Health conscious' and 'Western-like' diet were extracted from principal component analysis. At the age of 24, 36 and 48 months, information on constipation and sedentary behaviour, and weight and height was obtained by parental-derived questionnaires and from the child health centres, respectively. Adherence to a 'Western-like' dietary pattern was associated with a higher prevalence of constipation up to 48 months [adjusted odds ratio (aOR); 95% confidence interval (CI): 1.39; 1.02-1.87], which was not mediated by overweight or sedentary behaviour. Adherence to a 'Health Conscious' dietary pattern was only associated at short term, with a lower prevalence of constipation at 24 months (aOR; 95%CI: 0.65; 0.44-0.96). No association was found between overweight, sedentary behaviour and constipation. Our results suggest that specific dietary patterns in early childhood could be associated with higher or lower risks for constipation, but these effects are time-dependent. Overweight and sedentary behaviour seem to not have a major role on constipation in childhood.

Background: Previous studies have suggested that fetal smoke exposure is associated with increased risks of wheezing during childhood. The underlying pathways are unknown. We examined the associations of parental smoking during pregnancy with wheezing in preschool children and whether these associations are explained by postnatal smoke exposure or small for gestational age at birth. Methods: This study was embedded in a population-based prospective cohort study. Parental smoking was prospectively assessed by questionnaires. Wheezing was reported at 1 to 4 years. Small for gestational age at birth was available from registries. The analyses were based on 4,574 subjects. Results: Maternal smoking during the first trimester only was not associated with wheezing. Continued maternal smoking in pregnancy was associated with the risk of wheezing at 1 to 4 years (P for trends