Elevated High-Sensitivity Troponin and NT-proBNP Values in Febrile Children.

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.

European study confirms the combination of fever and petechial rash as an important warning sign for childhood sepsis and meningitis.

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.

Increase in Invasive Group a Streptococcal Infections in Children in the Netherlands, A Survey Among 7 Hospitals in 2022.

Following an increase in notifiable invasive group A streptococcal (iGAS) infections in the Netherlands, we conducted a survey among 7 hospitals. Pediatric iGAS case numbers were 2-fold higher between July 2021 and June 2022 versus pre-COVID-19. A sharp increase occurred early 2022, most pronounced in <5 years old and for diagnoses empyema and necrotizing fasciitis. This recent pediatric iGAS surge warrants investigation and vigilance.

Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians.

BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study.

BACKGROUND: During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. METHODS AND FINDINGS: Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2.26, 95% CI 1.90 to 2.70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0.86, 95% CI 0.84 to 0.89; 2 to <5 years IRR 0.80, 95% CI 0.78 to 0.82; 5 to <12 years IRR 0.68, 95% CI 0.67 to 0.70; 12 to 18 years IRR 0.72, 95% CI 0.70 to 0.74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1.30, 95% CI 1.16 to 1.45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1.10, 95% CI 1.08 to 1.12; emergent and very urgent triage IRR 1.53, 95% CI 1.49 to 1.57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. CONCLUSIONS: Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. TRIAL REGISTRATION: ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258.

Febrile children with comorbidities at the emergency department - a multicentre observational study.

We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3-1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2-3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1-2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1-2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8-7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7-2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2-6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5-24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1-6.9) or PICU admission (aOR 9.7, 6.1-15.5). CONCLUSIONS: Our data show how children with comorbidities are a population at risk, as they more often are diagnosed with bacterial infections and more often require PICU admission and life-saving interventions. WHAT IS KNOWN: • While children with comorbidity constitute a large part of ED frequent flyers, they are often excluded from studies. WHAT IS NEW: • Children with comorbidities in general are more ill upon presentation than children without comorbidities. • Children with comorbidities form a heterogeneous group; specific subgroups have an increased risk for invasive bacterial infections, while others have an increased risk of invasive interventions such as PICU admission, regardless of the cause of the fever.

Characteristics and management of adolescents attending the ED with fever: a prospective multicentre study.

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.

Improving triage for children with comorbidity using the ED-PEWS: an observational study.

OBJECTIVE: To assess the value of the Emergency Department-Pediatric Early Warning Score (ED-PEWS) for triage of children with comorbidity. DESIGN: Secondary analysis of a prospective cohort. SETTING AND PATIENTS: 53 829 consecutive ED visits of children <16 years in three European hospitals (Netherlands, UK and Austria) participating in the TrIAGE (Triage Improvements Across General Emergency departments) project in different periods (2012-2015). INTERVENTION: ED-PEWS, a score consisting of age and six physiological parameters. MAIN OUTCOME MEASURE: A three-category reference standard as proxy for true patient urgency. We assessed discrimination and calibration of the ED-PEWS for children with comorbidity (complex and non-complex) and without comorbidity. In addition, we evaluated the value of adding the ED-PEWS to the routinely used Manchester Triage System (MTS). RESULTS: 5053 (9%) children had underlying non-complex morbidity and 5537 (10%) had complex comorbidity. The c-statistic for identification of high-urgency patients was 0.86 (95% prediction interval 0.84-0.88) for children without comorbidity, 0.87 (0.82-0.92) for non-complex and 0.86 (0.84-0.88) for complex comorbidity. For high and intermediate urgency, the c-statistic was 0.63 (0.62-0.63), 0.63 (0.61-0.65) and 0.63 (0.55-0.73) respectively. Sensitivity was slightly higher for children with comorbidity (0.73-0.75 vs 0.70) at the cost of a lower specificity (0.86-0.87 vs 0.92). Calibration was largely similar. Adding the ED-PEWS to the MTS for children with comorbidity improved performance, except in the setting with few high-urgency patients. CONCLUSIONS: The ED-PEWS has a similar performance in children with and without comorbidity. Adding the ED-PEWS to the MTS for children with comorbidity improves triage, except in the setting with few high-urgency patients.

Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study.

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.

Rapid Viral Testing and Antibiotic Prescription in Febrile Children With Respiratory Symptoms Visiting Emergency Departments in Europe.

BACKGROUND: Inappropriate antibiotic prescribing often occurs in children with self-limiting respiratory tract infections, contributing to antimicrobial resistance. It has been suggested that rapid viral testing can reduce inappropriate antibiotic prescribing. We aimed to assess the association between rapid viral testing at the Emergency Department (ED) and antibiotic prescription in febrile children. METHODS: This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending 12 European EDs. In children with respiratory symptoms visiting 6 EDs equipped with rapid viral testing, we performed multivariable logistic regression analysis regarding rapid viral testing and antibiotic prescription adjusted for patient characteristics, disease severity, diagnostic tests, focus of infection, admission, and ED. RESULTS: A rapid viral test was performed in 1061 children (8%) and not performed in 11,463 children. Rapid viral test usage was not associated with antibiotic prescription (aOR 0.9, 95% CI: 0.8-1.1). A positive rapid viral test was associated with less antibiotic prescription compared with children without test performed (aOR 0.6, 95% CI: 0.5-0.8), which remained significant after adjustment for CRP and chest radiograph result. Twenty percent of the positively tested children received antibiotics. A negative rapid viral test was not associated with antibiotic prescription (aOR 1.2, 95% CI: 1.0-1.4). CONCLUSIONS: Rapid viral test usage did not reduce overall antibiotic prescription, whereas a positive rapid viral test did reduce antibiotic prescription at the ED. Implementation of rapid viral testing in routine emergency care and compliance to the rapid viral test outcome will reduce inappropriate antibiotic prescribing at the ED.

Parents' experiences with a sick or injured child during the COVID-19 lockdown: an online survey in the Netherlands.

OBJECTIVE: To assess the impact of the COVID-19 lockdown on parents' health-seeking behaviour and care for a sick or injured child in the Netherlands. DESIGN AND SETTING: An online survey on parents' experiences with a sick or injured child during the COVID-19 lockdown periods was disseminated through social media. PARTICIPANTS: Parents living in the Netherlands with a sick or injured child during the lockdown periods from March to June 2020 and from December 2020 to February 2021 were eligible to participate. OUTCOME MEASURES: Descriptive statistics and thematic analysis were used to analyse family and children's characteristics, parents' response to a sick or injured child, and the perceived impact of the lockdown on child's severity of illness and treatment reported by parents. Analyses were stratified for children with and without chronic conditions. RESULTS: Of the 105 parents who completed the survey, 83% reported they would have sought medical help before lockdown compared with 88% who did seek help during lockdown for the same specific medical problem. Parents reported that changes in health services affected their child's severity of illness (31%) and their treatment (39%), especially for children with chronic conditions. These changes included less availability of healthcare services and long waiting lists, which mostly led to worsening of the child's illness. During lockdown, there was no change in health-seeking behaviour by parents of children with a chronic condition (N=51) compared with parents of children without a chronic condition. CONCLUSION: Parents in the Netherlands who completed the survey were not deterred from seeking medical help for their sick or injured child during the COVID-19 lockdown periods. However, changes in health services affected child's severity of illness and treatment, especially for children with chronic conditions.

A NICE combination for predicting hospitalisation at the Emergency Department: a European multicentre observational study of febrile children.

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 calculating 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 likelihood 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 predictive 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.

A clinical prediction model to identify children at risk for revisits with serious illness to the emergency department: A prospective multicentre observational study.

BACKGROUND: To develop a clinical prediction model to identify children at risk for revisits with serious illness to the emergency department. METHODS AND FINDINGS: A secondary analysis of a prospective multicentre observational study in five European EDs (the TRIAGE study), including consecutive children aged <16 years who were discharged following their initial ED visit ('index' visit), in 2012-2015. Standardised data on patient characteristics, Manchester Triage System urgency classification, vital signs, clinical interventions and procedures were collected. The outcome measure was serious illness defined as hospital admission or PICU admission or death in ED after an unplanned revisit within 7 days of the index visit. Prediction models were developed using multivariable logistic regression using characteristics of the index visit to predict the likelihood of a revisit with a serious illness. The clinical model included day and time of presentation, season, age, gender, presenting problem, triage urgency, and vital signs. An extended model added laboratory investigations, imaging, and intravenous medications. Cross validation between the five sites was performed, and discrimination and calibration were assessed using random effects models. A digital calculator was constructed for clinical implementation. 7,891 children out of 98,561 children had a revisit to the ED (8.0%), of whom 1,026 children (1.0%) returned to the ED with a serious illness. Rates of revisits with serious illness varied between the hospitals (range 0.7-2.2%). The clinical model had a summary Area under the operating curve (AUC) of 0.70 (95% CI 0.65-0.74) and summary calibration slope of 0.83 (95% CI 0.67-0.99). 4,433 children (5%) had a risk of > = 3%, which was useful for ruling in a revisit with serious illness, with positive likelihood ratio 4.41 (95% CI 3.87-5.01) and specificity 0.96 (95% CI 0.95-0.96). 37,546 (39%) had a risk <0.5%, which was useful for ruling out a revisit with serious illness (negative likelihood ratio 0.30 (95% CI 0.25-0.35), sensitivity 0.88 (95% CI 0.86-0.90)). The extended model had an improved summary AUC of 0.71 (95% CI 0.68-0.75) and summary calibration slope of 0.84 (95% CI 0.71-0.97). As study limitations, variables on ethnicity and social deprivation could not be included, and only return visits to the original hospital and not to those of surrounding hospitals were recorded. CONCLUSION: We developed a prediction model and a digital calculator which can aid physicians identifying those children at highest and lowest risks for developing a serious illness after initial discharge from the ED, allowing for more targeted safety netting advice and follow-up.

Shortness of breath in children at the emergency department: Variability in management in Europe.

OBJECTIVE: Our aim was to describe variability in resource use and hospitalization in children presenting with shortness of breath to different European Emergency Departments (EDs) and to explore possible explanations for variability. DESIGN: The TrIAGE project, a prospective observational study based on electronic health record data. PATIENTS AND SETTING: Consecutive paediatric emergency department visits for shortness of breath in five European hospitals in four countries (Austria, Netherlands, Portugal, United Kingdom) during a study period of 9-36 months (2012-2014). MAIN OUTCOME MEASURES: We assessed diversity between EDs regarding resource use (diagnostic tests, therapy) and hospital admission using multivariable logistic regression analyses adjusting for potential confounding variables. RESULTS: In total, 13,552 children were included. Of those, 7,379 were categorized as immediate/very urgent, ranging from 13-80% in the participating hospitals. Laboratory tests and X-rays were performed in 8-33% of the cases and 21-61% was treated with inhalation medication. Admission rates varied between 8-47% and PICU admission rates varied between 0.1-9%. Patient characteristics and markers of disease severity (age, sex, comorbidity, urgency, vital signs) could explain part of the observed variability in resource use and hospitalization. However, after adjusting for these characteristics, we still observed substantial variability between settings. CONCLUSION: European EDs differ substantially regarding the resource use and hospitalization in children with shortness of breath, even when adjusting for patient characteristics. Possible explanations for this variability might be unmeasured patient characteristics such as underlying disease, differences in guideline use and adherence or different local practice patterns.

Variation in hospital admission in febrile children evaluated at the Emergency Department (ED) in Europe: PERFORM, a multicentre prospective observational study.

OBJECTIVES: Hospitalisation is frequently used as a marker of disease severity in observational Emergency Department (ED) studies. The comparison of ED admission rates is complex in potentially being influenced by the characteristics of the region, ED, physician and patient. We aimed to study variation in ED admission rates of febrile children, to assess whether variation could be explained by disease severity and to identify patient groups with large variation, in order to use this to reduce unnecessary health care utilization that is often due to practice variation. DESIGN: MOFICHE (Management and Outcome of Fever in children in Europe, part of the PERFORM study, www.perform2020.org), is a prospective cohort study using routinely collected data on febrile children regarding patient characteristics (age, referral, vital signs and clinical alarming signs), diagnostic tests, therapy, diagnosis and hospital admission. SETTING AND PARTICIPANTS: Data were collected on febrile children aged 0-18 years presenting to 12 European EDs (2017-2018). MAIN OUTCOME MEASURES: We compared admission rates between EDs by using standardised admission rates after adjusting for patient characteristics and initiated tests at the ED, where standardised rates >1 demonstrate higher admission rates than expected and rates <1 indicate lower rates than expected based on the ED patient population. RESULTS: We included 38,120 children. Of those, 9.695 (25.4%) were admitted to a general ward (range EDs 5.1-54.5%). Adjusted standardised admission rates ranged between 0.6 and 1.5. The largest variation was seen in short admission rates (0.1-5.0), PICU admission rates (0.2-2.2), upper respiratory tract infections (0.4-1.7) and fever without focus (0.5-2.7). Variation was small in sepsis/meningitis (0.9-1.1). CONCLUSIONS: Large variation exists in admission rates of febrile children evaluated at European EDs, however, this variation is largely reduced after correcting for patient characteristics and therefore overall admission rates seem to adequately reflect disease severity or a potential for a severe disease course. However, for certain patient groups variation remains high even after adjusting for patient characteristics.

Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE, a prospective observational study.

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.

Management of children visiting the emergency department during out-of-office hours: an observational study.

BACKGROUND: The aim was to study the characteristics and management of children visiting the emergency department (ED) during out-of-office hours. METHODS: We analysed electronic health record data from 119 204 children visiting one of five EDs in four European countries. Patient characteristics and management (diagnostic tests, treatment, hospital admission and paediatric intensive care unit admission) were compared between children visiting during office hours and evening shifts, night shifts and weekend day shifts. Analyses were corrected for age, gender, Manchester Triage System urgency, abnormal vital signs, presenting problems and hospital. RESULTS: Patients presenting at night were younger (median (IQR) age: 3.7 (1.4-8.2) years vs 4.8 (1.8-9.9)), more often classified as high urgent (16.3% vs 9.9%) and more often had ≥2 abnormal vital signs (22.8% vs 18.1%) compared with office hours. After correcting for disease severity, laboratory and radiological tests were less likely to be requested (adjusted OR (aOR): 0.82, 95% CI 0.78-0.86 and aOR: 0.64, 95% CI 0.60-0.67, respectively); treatment was more likely to be undertaken (aOR: 1.56, 95% CI 1.49-1.63) and patients were more likely to be admitted to the hospital (aOR: 1.32, 95% CI 1.24-1.41) at night. Patterns in management during out-of-office hours were comparable between the different hospitals, with variability remaining. CONCLUSIONS: Children visiting during the night are relatively more seriously ill, highlighting the need to keep improving emergency care on a 24-hour-a-day basis. Further research is needed to explain the differences in management during the night and how these differences affect patient outcomes.

Sex-specific differences in children attending the emergency department: prospective observational study.

OBJECTIVE: To assess the role of sex in the presentation and management of children attending the emergency department (ED). DESIGN: The TrIAGE project (TRiage Improvements Across General Emergency departments), a prospective observational study based on curated electronic health record data. SETTING: Five diverse European hospitals in four countries (Austria, The Netherlands, Portugal, UK). PARTICIPANTS: All consecutive paediatric ED visits of children under the age of 16 during the study period (8-36 months between 2012 and 2015). MAIN OUTCOME MEASURES: The association between sex (male of female) and diagnostic tests and disease management in general paediatric ED visits and in subgroups presenting with trauma or musculoskeletal, gastrointestinal and respiratory problems and fever. Results from the different hospitals were pooled in a random effects meta-analysis. RESULTS: 116 172 ED visits were included of which 63 042 (54%) by boys and 53 715 (46%) by girls. Boys accounted for the majority of ED visits in childhood, and girls in adolescence. After adjusting for age, triage urgency and clinical presentation, girls had more laboratory tests compared with boys (pooled OR 1.10, 95% CI 1.05 to 1.15). Additionally, girls had more laboratory tests in ED visits for respiratory problems (pooled OR 1.15, 95% CI 1.04 to 1.26) and more imaging in visits for trauma or musculoskeletal problems (pooled OR 1.10, 95% CI 1.01 to 1.20) and respiratory conditions (pooled OR 1.14, 95% CI 1.05 to 1.24). Girls with respiratory problems were less often treated with inhalation medication (pooled OR 0.76, 95% CI 0.70 to 0.83). There was no difference in hospital admission between the sexes (pooled OR 0.99, 95% CI 0.95 to 1.04). CONCLUSION: In childhood, boys represent the majority of ED visits and they receive more inhalation medication. Unexpectedly, girls receive more diagnostic tests compared with boys. Further research is needed to investigate whether this is due to pathophysiological differences and differences in disease course, whether girls present signs and symptoms differently, or whether sociocultural factors are responsible.

Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study.

BACKGROUND: The prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe. METHODS AND FINDINGS: Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0-18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35,650 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%-41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%-90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%-29.3%), and inconclusive in 22.5% (range across EDs: 0.4%-60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%-59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%-47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%-100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country. CONCLUSIONS: In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance.