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Abstract Background Almost all patients with Neurofibromatosis type 1 (NF1) develop cutaneous neurofibroma (cNF), benign dermal tumours that have a large impact on the patient’s Quality of Life (QoL). The French cNF-Skindex is the first questionnaire to specifically assess cNF-related QoL in patients with NF1. We aimed to adapt and validate a Dutch version of the cNF-Skindex. Methods The questionnaire was translated using forward and backwards translation, and subsequently administered to a sample of 59 patients on two separate occasions. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating internal consistency and test-retest reliability, by calculating Cronbach’s alpha and Spearman’s rank correlation coefficients. The EQ-5D-5L and SF-36 were used to evaluate convergent validity, using Spearman’s rank correlation coefficients. An exploratory factor analysis was performed to study the data’s internal structure. Multivariable linear regression was used to model the relationship between patient characteristics and the cNF-Skindex. Results The Dutch cNF-Skindex demonstrated excellent feasibility and reliability (Cronbach’s alpha 0.96, test-retest correlation coefficient 0.88). Convergent validity was confirmed for the EQ-5D-5L and relevant SF-36 scales. All items and subdomains from the original questionnaire were confirmed following exploratory factor analysis. The patient characteristics included in the multivariable linear regression were not significantly associated with the cNF-Skindex score. Conclusions The Dutch cNF-Skindex displayed excellent psychometric properties, enabling use in the Netherlands.

Abstract Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.

Abstract Background Half of the patients with Neurofibromatosis type 1 (NF1) develop one or more tumours called plexiform neurofibromas, which can have a significant impact on Quality of Life (QoL). The PlexiQoL questionnaire is a disease-specific QoL measure for adults with NF1-associated plexiform neurofibromas. The aim of this study was to adapt and validate a Dutch version of the PlexiQoL for the Netherlands. Methods The PlexiQoL was translated using the dual-panel methodology, followed by cognitive debriefing interviews to assess face and content validity. The psychometric properties were evaluated by administering the questionnaire on two separate occasions to a sample of adults with NF1 and plexiform neurofibromas. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating Cronbach’s alpha coefficient and test-retest reliability, using Spearman’s rank correlation coefficients. Mann-Whitney U tests were used to check for known group validity. The Nottingham Health Profile (NHP) questionnaire was used as comparator questionnaire to evaluate convergent validity. Results The translation and cognitive debriefing interviews resulted in a Dutch version of the PlexiQoL that reflected the original concept and underlying semantic meanings of the UK English version. Forty participants completed the validation survey. The Dutch PlexiQoL demonstrated excellent internal consistency (Cronbach’s α 0.825) and test-retest reliability (Spearman correlation coefficient 0.928). The questionnaire detected differences in PlexiQoL scores between participants based on self-reported general health and disease severity. Convergent validity was confirmed for relevant NHP subsections. Conclusions The Dutch PlexiQoL demonstrated excellent psychometric properties and can be reliably used to measure plexiform neurofibroma-related QoL in adults with NF1 in the Netherlands.

Abstract Advice from multiple stakeholders is required to design the optimal pediatric clinical trial. We present recommendations for acquiring advice from trial experts and patients/caregivers, derived from advice meetings that were performed through a collaboration of the Collaborative Network for European Clinical Trials for Children (c4c) and the European Patient‐CEntric ClinicAl TRial PLatforms (EU‐PEARL). Three advice meetings were performed: (1) an advice meeting for clinical and methodology experts, (2) an advice meeting for patients/caregivers, and (3) a combined meeting with both experts and patients/caregivers. Trial experts were recruited from c4c database. Patients/caregivers were recruited through a patient organization. Participants were asked to provide input on a trial protocol, including endpoints, outcomes, and the assessment schedule. Ten experts, 10 patients, and 13 caregivers participated. The advice meetings resulted in modification of eligibility criteria and outcome measures. We have provided recommendations for the most effective meeting type per protocol topic. Topics with limited options for patient input were most efficiently discussed in expert advice meetings. Other topics benefit from patient/caregiver input, either through a combined meeting with experts or a patients/caregivers‐only advice meeting. Some topics, such as endpoints and outcome measures, are suitable for all meeting types. Combined sessions profit from synergy between experts and patients/caregivers, balancing input on protocol scientific feasibility and acceptability. Both experts and patients/caregivers provided critical input on the presented protocol. The combined meeting was the most effective methodology for most protocol topics. The presented methodology can be used effectively to acquire expert and patient feedback.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Background Diagnostic errors, reframed as missed opportunities for improving diagnosis (MOIDs), are poorly understood in the paediatric emergency department (ED) setting. We investigated the clinical experience, harm and contributing factors related to MOIDs reported by physicians working in paediatric EDs.Methods We developed a web-based survey in which physicians participating in the international Paediatric Emergency Research Network representing five out of six WHO regions, described examples of MOIDs involving their own or a colleague’s patients. Respondents provided case summaries and answered questions regarding harm and factors contributing to the event.Results Of 1594 physicians surveyed, 412 (25.8%) responded (mean age=43 years (SD=9.2), 42.0% female, mean years in practice=12 (SD=9.0)). Patient presentations involving MOIDs had common undifferentiated symptoms at initial presentation, including abdominal pain (21.1%), fever (17.2%) and vomiting (16.5%). Patients were discharged from the ED with commonly reported diagnoses, including acute gastroenteritis (16.7%), viral syndrome (10.2%) and constipation (7.0%). Most reported MOIDs (65%) were detected on ED return visits (46% within 24 hours and 76% within 72 hours). The most common reported MOID was appendicitis (11.4%), followed by brain tumour (4.4%), meningitis (4.4%) and non-accidental trauma (4.1%). More than half (59.1%) of the reported MOIDs involved the patient/parent–provider encounter (eg, misinterpreted/ignored history or an incomplete/inadequate physical examination). Types of MOIDs and contributing factors did not differ significantly between countries. More than half of patients had either moderate (48.7%) or major (10%) harm due to the MOID.Conclusions An international cohort of paediatric ED physicians reported several MOIDs, often in children who presented to the ED with common undifferentiated symptoms. Many of these were related to patient/parent–provider interaction factors such as suboptimal history and physical examination. Physicians’ personal experiences offer an underexplored source for investigating and mitigating diagnostic errors in the paediatric ED.

Summary: Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals. Methods: By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence. Findings: We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. Interpretation: The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries. Funding: This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).

BackgroundDuring 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 findingsRoutine 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 ConclusionsReductions 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 registrationISRCTN91495258 https://www.isrctn.com/ISRCTN91495258.

ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation.MethodsWe assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates.ResultsOverall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain.ConclusionThe syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

This joint statement by the European Society for Emergency Paediatrics and European Academy of Paediatrics aims to highlight recommendations for dealing with refugee children and young people fleeing the Ukrainian war when presenting to emergency departments (EDs) across Europe. Children and young people might present, sometimes unaccompanied, with either ongoing complex health needs or illnesses, mental health issues, and injuries related to the war itself and the flight from it. Obstacles to providing urgent and emergency care include lack of clinical guidelines, language barriers, and lack of insight in previous medical history. Children with complex health needs are at high risk for complications and their continued access to specialist healthcare should be prioritized in resettlements programs. Ukraine has one of the lowest vaccination coverages in the Europe, and outbreaks of cholera, measles, diphtheria, poliomyelitis, and COVID-19 should be anticipated. In Ukraine, rates of multidrug resistant tuberculosis are high, making screening for this important. Urgent and emergency care facilities should also prepare for dealing with children with war-related injuries and mental health issues. Ukrainian refugee children and young people should be included in local educational systems and social activities at the earliest opportunity.

Background The early-onset sepsis (EOS) calculator was developed and validated in a setting with routine-based group B Streptococcus (GBS) screening. Purpose The study aimed to evaluate the extent of influence exerted by risk-based GBS screening on management recommendations by the EOS calculator. Methods All newborns with a gestational age greater than 35 weeks were screened for EOS risk factors in a Dutch regional teaching hospital using a risk-based GBS screening strategy. We calculated the EOS risk at birth and stratified the infants into the following 3 risk levels with corresponding management recommendations: low, 1.54 per 1000 live newborns. Thereafter, we recalculated the EOS risk and recommendation for the newborn infants without available maternal GBS screening results at birth. Results In one year, 1,877 eligible births occurred; of them, 206 infants were included. Maternal GBS status was available for 28 of 206 infants (14%) at birth, while a definitive GBS status was later available for 162 of 206 infants (79%). Median EOS risk was slightly lower after definitive GBS status was determined (0.41 vs. 0.46 per 1,000 live births, P=0.004). In 199 of 206 newborn infants (97%), the EOS calculator recommendation remained unchanged after the GBS results unavailable at birth were updated to definitive GBS status. Use of GBS status at birth versus definitive GBS status did not result in the withholding of antibiotic treatment of the newborn infants included in this study. Conclusion Risk-based GBS screening is compatible with EOS calculator recommendations. Larger studies are needed to develop the best strategy for combining GBS screening and EOS calculator recommendations.

BackgroundPoint-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 findingsA 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.ConclusionThere 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.

BackgroundAmong pediatric emergency department (ED) visits, a subgroup of children repeatedly visits the ED, making them frequent visitors (FVs). The aim of this study is to get insight into the group of pediatric ED FVs and to determine risk factors associated with a revisit.Methods and findingsData of all children aged 0-18 years visiting the ED of a university hospital in the Netherlands between 2017 and 2020 were included in this observational study based on routine data extraction. Children with 4 or more ED visits within 365 days were classified as FVs. Descriptive analysis of the study cohort at patient- and visit-level were performed. Risk factors for a recurrent ED visit were determined using a Prentice Williams and Peterson gap time cox-based model. Our study population of 10,209 children with 16,397 ED visits contained 500 FVs (4.9%) accounting for 3,481 visits (21.2%). At patient-level, FVs were younger and more often suffered from chronic diseases (CDs). At visit-level, frequent visits were more often initiated by self-referral and were more often related to medical problems (compared to trauma's). Overall, FVs presented at the ED more often because of an infection (41.3%) compared to non-FVs (27.4%), either associated or not with the body system affected by the CD. We identified the presence of a comorbidity (non-complex CD HR 1.66; 1.52-1.81 and complex CD HR 2.00; 1.84-2.16) as determinants with the highest hazard for a return visit.ConclusionPediatric ED FVs are a small group of children but account for a large amount of the total ED visits. FVs are younger patients, suffering from (complex) comorbidities and present more often with infectious conditions compared to non-FVs. Healthcare pathways, including safety-netting strategies for acute manifestations from their comorbidity, or for infectious conditions in general may contribute to support parents and redirect some patients from the ED.

Objective Understanding how paediatric emergency departments (PEDs) across Europe adapted their healthcare pathways in response to COVID-19 will help guide responses to ongoing waves of COVID-19 and potential future pandemics. This study aimed to evaluate service reconfiguration across European PEDs during the initial COVID-19 wave.Design This cross-sectional survey included 39 PEDs in 17 countries. The online questionnaire captured (1) study site characteristics, (2) departmental changes and (3) pathways for children with acute illness pre and during the first wave of COVID-19 pandemic (January–May 2020). Number of changes to health services, as a percentage of total possible changes encompassed by the survey, was compared with peak national SARS-CoV-2 incidence rates, and for both mixed and standalone paediatric centres.Results Overall, 97% (n=38) of centres remained open as usual during the pandemic. The capacity of 18 out of 28 (68%) short-stay units decreased; in contrast, 2 units (7%) increased their capacity. In 12 (31%) PEDs, they reported acting as receiving centres for diverted children during the pandemic.There was minimal change to the availability of paediatric consultant telephone advice services, consultant supervision of juniors or presence of responsible specialists within the PEDs.There was no relationship between percentage of possible change at each site and the peak national SARS-CoV-2 incidence rate. Mixed paediatric and adult hospitals made 8% of possible changes and standalone paediatric centres made 6% of possible changes (p=0.086).Conclusion Overall, there was limited change to the organisation or delivery of services across surveyed PEDs during the first wave of the COVID-19 pandemic.

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.

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–

Objective To explore how parents judge disease severity of their febrile child and to identify symptoms they associate with serious illness, minor illness or health.Design Semistructured interviews were conducted. Interviews were audio taped, transcribed verbatim and analysed thematically.Participants Parents of children aged 0–5 years with a febrile illness.Setting Participants were recruited at the paediatric ward and the emergency department.Results Twenty-six interviews were conducted, in which 37 parents participated. Parents described disease severity of their child mainly in terms of changes in their child’s normal characteristics (behaviour and physical features). They found it harder to describe specific disease symptoms such as dyspnoea or dehydration. Their child being active, eating and drinking well, and smiling were perceived as reassuring, whereas high fever, moving very little and uncertainty about the type of infections were mentioned as alarming symptoms. Previous experience with febrile illnesses in their children was of great influence on the number and accuracy of symptoms they reported.Conclusion Parents used the normal behaviour and physical features of their child as a reference frame for judging disease severity. With a larger deviation from the child’s normal characteristics, parents considered the illness more serious. They were less able to describe specific symptoms of disease such as dyspnoea or dehydration. This knowledge is important for clinicians in their communication with parents of children with febrile illness.

BACKGROUND:Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS:In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. CONCLUSIONS:In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. TRIAL REGISTRATION:Netherlands Trial Register NTR5326.

Lower respiratory tract infections (LRTIs) in children are common and, although often mild, a major cause of mortality and hospitalization. Recently, the respiratory microbiome has been associated with both susceptibility and severity of LRTI. In this current study, we combined respiratory microbiome, viral, and clinical data to find associations with the severity of LRTI. Nasopharyngeal aspirates of children aged one month to five years included in the STRAP study (Study to Reduce Antibiotic prescription in childhood Pneumonia), who presented at the emergency department (ED) with fever and cough or dyspnea, were sequenced with nanopore 16S-rRNA gene sequencing and subsequently analyzed with hierarchical clustering to identify respiratory microbiome profiles. Samples were also tested using a panel of 15 respiratory viruses and Mycoplasma pneumoniae, which were analyzed in two groups, according to their reported virulence. The primary outcome was hospitalization, as measure of disease severity. Nasopharyngeal samples were isolated from a total of 167 children. After quality filtering, microbiome results were available for 54 children and virology panels for 158 children. Six distinct genus-dominant microbiome profiles were identified, with Haemophilus-, Moraxella-, and Streptococcus-dominant profiles being the most prevalent. However, these profiles were not found to be significantly associated with hospitalization. At least one virus was detected in 139 (88%) children, of whom 32.4% had co-infections with multiple viruses. Viral co-infections were common for adenovirus, bocavirus, and enterovirus, and uncommon for human metapneumovirus (hMPV) and influenza A virus. The detection of enteroviruses was negatively associated with hospitalization. Virulence groups were not significantly associated with hospitalization. Our data underlines high detection rates and co-infection of viruses in children with respiratory symptoms and confirms the predominant presence of Haemophilus-, Streptococcus-, and Moraxella-dominant profiles in a symptomatic pediatric population at the ED. However, we could not assess significant associations between microbiome profiles and disease severity measures.

Abstract Background Children with the neurogenetic disorder neurofibromatosis type 1 (NF1) often have problems with learning and behaviour. In both parent reports and neuropsychological assessment, motor problems are reported in approximately one third to one half of the children with NF1. Studies using broad motor performance test batteries with relatively large groups of children with NF1 are limited. The aim of this cross-sectional observational study was to describe the severity of motor problems in children with NF1 and to explore the predictive value of demographics, intelligence, and behavioural problems. Methods From 2002 to 2014, 69 children with NF1, aged 4 to 16 years (age = 9.5 ± 2.8 years; 29 girls) had a motor, psychological, and neurological evaluation in an NF1 expertise centre. Data were collected about (1) motor performance (M-ABC: Movement Assessment Battery for Children), (2) intelligence, and (3) emotional and behavioural problems as rated by parents. Results Sixty-one percent of these children scored within the clinical range of the M-ABC. In ordinal logistic regression analyses, motor problems were associated with symptoms of attention-deficit/hyperactivity disorder (ADHD), symptoms of autism spectrum disorder (ASD), and externalising behavioural problems. Motor outcome was not predicted by age, intelligence, scoliosis, hypotonia, nor hypermobility. Conclusions Motor problems are among the most common comorbid developmental problems in children with NF1, and these problems do not diminish with age. Because of their impact on daily functioning, motor problems need to be specifically addressed in diagnosis, follow-up, and treatment of NF1.

ObjectivesPneumonia is the most common bacterial infection in children at the emergency department (ED). Clinical prediction models for childhood pneumonia have been developed (using chest x-ray as their reference standard), but without implementation in clinical practice. Given current insights in the diagnostic limitations of chest x-ray, this study aims to validate these prediction models for a clinical diagnosis of pneumonia, and to explore their potential to guide decisions on antibiotic treatment at the ED.MethodsWe systematically identified clinical prediction models for childhood pneumonia and assessed their quality. We evaluated the validity of these models in two populations, using a clinical reference standard (1. definite/probable bacterial, 2. bacterial syndrome, 3. unknown bacterial/viral, 4. viral syndrome, 5. definite/probable viral), measuring performance by the ordinal c-statistic (ORC). Validation populations included prospectively collected data of children aged 1 month to 5 years attending the ED of Rotterdam (2012-2013) or Coventry (2005-2006) with fever and cough or dyspnoea.ResultsWe identified eight prediction models and could evaluate the validity of seven, with original good performance. In the Dutch population 22/248 (9%) had a bacterial infection, in Coventry 53/301 (17%), antibiotic prescription was 21% and 35% respectively. Three models predicted a higher risk in children with bacterial infections than in those with viral disease (ORC ≥0.55) and could identify children at low risk of bacterial infection.ConclusionsThree clinical prediction models for childhood pneumonia could discriminate fairly well between a clinical reference standard of bacterial versus viral infection. However, they all require the measurement of biomarkers, raising questions on the exact target population when implementing these models in clinical practice. Moreover, choosing optimal thresholds to guide antibiotic prescription is challenging and requires careful consideration of potential harms and benefits.

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.

OBJECTIVES:To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED). METHODS:Randomized controlled trial with 439 febrile children, aged 1 month-16 years, attending the pediatric ED of a Dutch university hospital during 2010-2012. Febrile children were randomly assigned to the intervention (clinical decision model; n = 219) or the control group (usual care; n = 220). The clinical decision model included clinical symptoms, vital signs, and C-reactive protein and provided high/low-risks for "pneumonia" and "other SBI". Nurses were guided by the intervention to initiate additional tests for high-risk children. The clinical decision model was evaluated by 1) area-under-the-receiver-operating-characteristic-curve (AUC) to indicate discriminative ability and 2) feasibility, to measure nurses' compliance to model recommendations. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs. RESULTS:The decision model had good discriminative ability for both pneumonia (n = 33; AUC 0.83 (95% CI 0.75-0.90)) and other SBI (n = 22; AUC 0.81 (95% CI 0.72-0.90)). Compliance to model recommendations was high (86%). No differences in correct SBI determination were observed. Application of the clinical decision model resulted in less full-blood-counts (14% vs. 22%, p-value < 0.05) and more urine-dipstick testing (71% vs. 61%, p-value < 0.05). CONCLUSIONS:In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved, however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing. TRIAL REGISTRATION:Nederlands Trial Register NTR2381.

OBJECTIVE: Early recognition and treatment of febrile children with serious infections (SI) improves prognosis, however, early detection can be difficult. We aimed to validate the predictive rule-in value of the National Institute for Health and Clinical Excellence (NICE) most severe alarming signs or symptoms to identify SI in children. DESIGN, SETTING AND PARTICIPANTS: The 16 most severe ("red") features of the NICE traffic light system were validated in seven different primary care and emergency department settings, including 6,260 children presenting with acute illness. MAIN OUTCOME MEASURES: We focussed on the individual predictive value of single red features for SI and their combinations. Results were presented as positive likelihood ratios, sensitivities and specificities. We categorised "general" and "disease-specific" red features. Changes in pre-test probability versus post-test probability for SI were visualised in Fagan nomograms. RESULTS: Almost all red features had rule-in value for SI, but only four individual red features substantially raised the probability of SI in more than one dataset: "does not wake/stay awake", "reduced skin turgor", "non-blanching rash", and "focal neurological signs". The presence of ≥ 3 red features improved prediction of SI but still lacked strong rule-in value as likelihood ratios were below 5. CONCLUSIONS: The rule-in value of the most severe alarming signs or symptoms of the NICE traffic light system for identifying children with SI was limited, even when multiple red features were present. Our study highlights the importance of assessing the predictive value of alarming signs in clinical guidelines prior to widespread implementation in routine practice.

CONTEXT: Febrile children in primary care have a low risk for serious infection. Although several alarming signs and symptoms are proposed to have predictive value for serious infections, most are based on research in secondary care. The frequency of alarming signs/symptoms has not been established in primary care; however, in this setting differences in occurrence may influence their predictive value for serious infections. OBJECTIVE: To determine the frequency of alarming signs/symptoms in febrile children in primary care. DESIGN: Observational cohort study. Clinical information was registered in a semi-structured way and manually recoded. SETTING: General practitioners' out-of-hours service. SUBJECTS: Face-to-face patient contacts concerning children (aged ≤16 years) with fever were eligible for inclusion. MAIN OUTCOME MEASURES: Frequency of 18 alarming signs and symptoms as reported in the literature. RESULTS: A total of 10,476 patient contacts were included. The frequency of alarming signs/symptoms ranged from n = 1 (ABC instability; 40°C as reported by the parents; 12.9%) to 8,647 contacts (parental concern; 82.5%). CONCLUSION: Although the prevalence of specific alarming signs/symptoms is low in primary care, ≥50% of children have one or more alarming signs/symptoms. There is a need to determine the predictive value of alarming signs/symptoms not only for serious infections in primary care, but as well for increased risk of a complicated course of the illness.