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ObjectivesTo describe the characteristics and clinical outcomes of children with fever ≥5 days presenting to emergency departments (EDs).DesignProspective observational study.Setting12 European EDs.PatientsConsecutive febrile children InterventionsChildren with fever ≥5 days and their risks for serious bacterial infection (SBI) were compared with children with fever Main outcome measuresSBI and other non-infectious serious illness.Results3778/35 705 (10.6%) of febrile children had fever ≥5 days. Incidence of SBI in children with fever ≥5 days was higher than in those with fever 0.90, but were observed infrequently (range: 0.4%–17%). Absence of warning signs was not sufficiently reliable to rule out SBI (sensitivity 0.92 (95% CI 0.87–0.95), negative likelihood ratio (LR) 0.34 (0.22–0.54)). CRP ConclusionChildren with prolonged fever have a higher risk of SBI, warranting a careful clinical assessment and diagnostic workup. Warning signs of SBI occurred infrequently but, if present, increased the likelihood of SBI. Although rare, clinicians should consider important non-infectious causes of prolonged fever.

Background Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier. Methods We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier. Results The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924–1.00] vs 0.992 [95% CI: 0.978–1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections. Conclusion We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory. Impact A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.

The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between translating assays from microarray analysis (expensive lab-based discovery method) to ISFET arrays (cheap point-of-care diagnostics) providing benefits on tackling infectious disease outbreak and diagnostic testing in hard-to-reach areas of the world.

Summary Background Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia. Methods We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18–22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , NCT02387385 . Findings We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention. Interpretation Therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available. Funding National Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation. Translations For the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section.

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., 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.

The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field, and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem combine the use of host gene signatures with our Lab-on-a-Chip (LoC) technology enabling low-cost POC expression analysis to detect Infectious Disease. Transcriptomics have been extensively investigated as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand, LoC technologies using ion-sensitive field-effect transistor (ISFET), in conjunction with isothermal chemistries, are offering a promising alternative to conventional amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as Host-Transcriptomics. In order to reliably quantify transcripts on our LoC platform enabling the classification of infectious disease on-chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R

Background Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined. Methods We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays. Results Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1. Conclusions A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease., Severe meningococcal disease may result from single-gene inborn errors of immunity, affecting bacterial colonization, biofilm formation, and invasion. Our findings demonstrate the host protective role SPLUNC1 plays in maintaining mucosal immunity in the upper respiratory tract, and preventing invasive disease.

Funding Acknowledgements Type of funding sources: None. Introduction The paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and Kawasaki disease (KD) have overlapping features. This study aimed to describe the strain segmental analysis among both entities. Methods Retrospective review of strain segmental analysis within 4 weeks of presentation of symptoms among children diagnosed with PIMS-TS between April and June 2020 and a historic cohort of typical KD from the Royal Brompton Hospital, London. Results We included 33 PIMS-TS patients (23 males, 69.7%) at a mean age of 8 ± 4,9 years old and 45 KD patients (31 males, 68,9%) at a mean age of 5,8 ± 4,5 years old. PIMS-TS patients were older at presentation (p = 0.038). Left ventricle ejection fraction (LVEF) was normal in both groups (63,3% vs 63,5%; p= 0,89), 4/33 PIMS-TS children (12,1%) had coronary arteries abnormalities (CAA), whereas 100% of KD cohort had CAA. Both groups had a normal global longitudinal strain (GLS),but in PIMS-TS it was significantly reduced compared to the KD group (-20% vs -22%; p = 0,008). Basal segments were the most affected in PIMS-TS with significant difference in the basal anterior and anterolateral strain compared to KD (respectively -18,2% vs -23,4%; p < 0,001 and - 16,7% vs -22,7%; p < 0,001). PIMS-TS had a greater anterior, anterolateral and posterior segments involvement with a significant reduction in the anterolateral mid-wall longitudinal strain (-18,3% vs -22%; p = 0,002). Apical segments were less involved, with significant difference only in the septal and inferior apical strain (respectively p = 0.001 and p = 0,032). Conclusions These preliminary data showed that after 4 weeks from the onset of symptoms, all PIMS-TS patients had a normal LVEF but they had a significant reduction in GLS and different segmental involvement compared to KD cohort. We hypothesize that these findings may be related to direct myocardial damage in PIMS-TS rather than caused by coronaries perfusion abnormalities. Abstract Figure. Bull"s eye

Background Discriminating viral from bacterial lower respiratory tract infections (LRTIs) in children is challenging thus commonly resulting in antibiotic overuse. The Feverkidstool, a validated clinical decision rule including clinical symptoms and C-reactive protein, safely reduced antibiotic use in children at low/intermediate risk for bacterial LRTIs in a multicentre trial at emergency departments (EDs) in the Netherlands. Objectives Using routine data from an observational study, we simulated the impact of the Feverkidstool on antibiotic prescriptions compared with observed antibiotic prescriptions in children with suspected LRTIs at 12 EDs in eight European countries. Methods We selected febrile children aged 1 month to 5 years with respiratory symptoms and excluded upper respiratory tract infections. Using the Feverkidstool, we calculated individual risks for bacterial LRTI retrospectively. We simulated antibiotic prescription rates under different scenarios: (1) applying effect estimates on antibiotic prescription from the trial; and (2) varying both usage (50%–100%) and compliance (70%–100%) with the Feverkidstool’s advice to withhold antibiotics in children at low/intermediate risk for bacterial LRTI (≤10%). Results Of 4938 children, 4209 (85.2%) were at low/intermediate risk for bacterial LRTI. Applying effect estimates from the trial, the Feverkidstool reduced antibiotic prescription from 33.5% to 24.1% [pooled risk difference: 9.4% (95% CI: 5.7%–13.1%)]. Simulating 50%–100% usage with 90% compliance resulted in risk differences ranging from 8.3% to 15.8%. Our simulations suggest that antibiotic prescriptions would be reduced in EDs with high baseline antibiotic prescription rates or predominantly (>85%) low/intermediate-risk children. Conclusions Implementation of the Feverkidstool could reduce antibiotic prescriptions in children with suspected LRTIs in European EDs.

BackgroundProlonged 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.MethodsThe 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).FindingsOf 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.InterpretationPatient 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.FundingEuropean Union, NIHR, NHS.

Background: Paediatric antimicrobial stewardship (PAS) networks exist in the USA and Australia but not in the UK. We sought to capture a snapshot of the current PAS landscape across UK children’s hospitals. Methods: A survey of PAS activities was conducted in tertiary children’s hospitals. Results: Infectious disease or microbiology consultants responded to the survey (n=15). All hospitals had neonatal, paediatric intensive care and surgical patients.All centres provided a PAS education programme for doctors, 7 for nurses and 9 for pharmacists as well. All centres had empirical antimicrobial prescribing guidelines. All centres with a paediatric infectious diseases (PID) team (11/15) used “audit and feedback” rounds, although their frequency and coverage varied. The PAS teams mostly included a PID consultant and/or microbiology consultants and a pharmacist. Three centres also had a nurse covering also the paediatric out-patient antibiotic treatment programme. Funding for PAS were inconsistent: Great Ormond Street Hospital had secured a dedicated full-time paediatric microbiologist, antimicrobial pharmacist and PID consultant with a ratio of 1/453 in-patient beds. 9 centres did not have dedicated funding for a paediatric antimicrobial pharmacist, 7 did not have funding for a paediatric infectious disease consultant. Only 2 hospitals had microbiology consultant time for paediatric audit and feedback. Conclusion: PAS programmes in the UK are limited, funding is inconsistent and their set up is variable, even in tertiary children’s hospitals with a strong interest in infectious diseases. We propose a national PAS network to advocate for more consistency and research into the implementation of PAS programmes.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

Background Kawasaki Disease is a paediatric inflammatory disease associated with self-limiting vasculitis. It has a world-wide distribution with an ethnic bias towards East Asian populations and is the most common cause of acquired heart disease in children in developed countries. The immunopathogenesis of KD remains poorly understood. The presence of antibody-antigens (pathogen) known as immune complexes in the blood of children with KD was established in numerous studies leading to the hypothesis that immune complexes contribute to the damages of the coronary artery. Methodology Using proteomic technologies we characterised the composition of immune complexes in KD and compare the immune complexes in KD with those in children with other febrile illnesses, TB and healthy children. Immune complexes were precipitated from the blood of 80 children with KD, 80 children with other febrile conditions, 30 with TB and 30 healthy children. We used Lumos Orbitrap mass spectrometry to identify the recovered proteins. Using the bioinformatics program PEAKS, we performed database searches and compared the protein abundances between the different comparator groups. Conclusions Immune complexes isolated from children with KD are different from those recovered from other febrile illnesses in terms of the nature of proteins within the complex. The pattern of proteins in the immune complexes containing immunoglobulins, complement proteins as well as other serum proteins, provides insight into the nature of the unique inflammatory response in KD versus the other inflammatory diseases.