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In Switzerland and other high-income countries, one out of 3000 to 5000 term and late preterm neonates develops early onset sepsis (EOS) associated with a mortality of around 3%, while incidence and mortality of EOS in very preterm infants are substantially higher. Exposure to antibiotics for suspected EOS is disproportionally high compared to the incidence of EOS with consequences for future health and antimicrobial resistance (AMR). A safe reduction of unnecessary antibiotic treatment has to be a major goal of new management strategies and guidelines. Antibiotics should be administered immediately in situations with clinical signs of septic shock. Group B streptococcus (GBS) and Escherichia coli (E. coli) are the leading pathogens of EOS. Amoxicillin combined with an aminoglycoside remains the first choice for empirical treatment. Serial physical examinations are recommended for all neonates with risk factors for EOS. Neonates without any clinical signs suggestive of EOS should not be treated with antibiotics. In Switzerland, we do not recommend the use of the EOS calculator, a risk stratification tool, due to its unclear impact in a population with an observed antibiotic exposure below 3%. Not all neonates with respiratory distress should be empirically treated with antibiotics. Isolated tachypnea or respiratory distress starting immediately after delivery by elective caesarean section or a clearly assessed alternative explanation than EOS for clinical signs may point towards a low probability of sepsis. On the other hand, unexplained prematurity with risk factors has an inherent higher risk of EOS. Before the start of antibiotic therapy, blood cultures should be drawn with a minimum volume of 1 ml in a single aerobic blood culture bottle. This standard procedure allows antibiotics to be stopped after 24 to 36 h if no pathogen is detected in blood cultures. Current data do not support the use of PCR-based pathogen detection in blood as a standard method. Lumbar puncture is recommended in blood culture-proven EOS, critical illness, or in the presence of neurological symptoms such as seizures or altered consciousness. The accuracy of a single biomarker measurement to distinguish inflammation from infection is low in neonates. Therefore, biomarker guidance is not a standard part of decision-making regarding the start or stop of antibiotic therapy but may be used as part of an algorithm and after appropriate education of health care teams. Every newborn started on antibiotics should be assessed for organ dysfunction with prompt initiation of respiratory and hemodynamic support if needed. An elevated lactate may be a sign of poor perfusion and requires a comprehensive assessment of the clinical condition. Interventions to restore perfusion include fluid boli with crystalloids and catecholamines. Neonates in critical condition should be cared for in a specialized unit. In situations with a low probability of EOS, antibiotics should be stopped as early as possible within the first 24 h after the start of therapy. In cases with microbiologically proven EOS, reassessment and streamlining of antibiotic therapy in neonates is an important step to minimize AMR., Conclusion:  This guideline, developed through a critical review of the literature, facilitates a probability-based approach to the management of neonates at risk of early onset sepsis., What Is Known: • Neonatal exposure to antibiotics is disproportionally high compared with the incidence of early onset sepsis with implications for future health and antimicrobial resistance., What Is New: • A probability-based approach may facilitate a more balanced management of neonatal sepsis and antibiotic stewardship., (© 2024. The Author(s).)

RSV hospitalization epidemiology is subject to rapid changes brought about by the COVID-19 pandemic and the prospect of vaccine prevention. The purpose of this report is to characterize recent epidemiologic and clinical fluctuations and to analyze their potential impact on an immunization program with nirsevimab. This is a 2018-2024 retrospective analysis of all hospitalizations caused by RSV in patients below 16 years of age occurring at an academic Children's Hospital that serves a defined population. We simulated the vaccine impact against RSV hospitalization by applying the expected effects of the infant immunization program with nirsevimab proposed in Switzerland to observed case counts. We analyzed 1339 hospitalizations. The consecutive occurrence of two major epidemics in 2022-2023 and 2023-2024 had never been recorded previously. The 2023-2024 season witnessed a major shift to older age. Only 61% of patients were below 12 months of age, while prepandemic long-term surveillance since 1997 found a range between 64 and 85% (median, 73%). Age below 3 months, prematurity, airway anomalies, congenital heart disease, and neuromuscular disorders were independently associated with ICU admission. Simulation of the vaccine impact using two scenarios of coverage and efficacy (scenario 1, 50% and 62%, respectively; scenario 2, 90% and 90%) and three different age distributions resulted in an infant vaccine impact of 31.0% (scenario 1) and 81.0% (scenario 2), respectively. Vaccine impact for all patients below 16 years ranged from 22.7 to 24.9% (scenario 1) and 54.2 to 68.8% (scenario 2)., Conclusion: RSV hospitalization epidemiology was characterized by substantial variability in patient age on admission. As the proposed RSV immunization program primarily targets infants, year-to-year fluctuation of cases among older children will cause a variability of vaccine impact of approximately 15%. This information may be useful for physicians and hospital administrators when they anticipate the resources needed during the winter season., What Is Known: • RSV hospitalization epidemiology was subject to massive disturbances during the COVID-19 pandemic. • Extended half-life monoclonal antibodies and active maternal immunization offer new means of passive protection of infants against severe RSV disease., What Is New: • We demonstrate substantial year-to-year fluctuation of the age distribution at the time of RSV hospitalization. • Up to 40% of annual RSV hospitalizations in a given season occur in children above 12 months of age who do not benefit from maternal RSV immunization and may not be eligible for receipt of a monoclonal antibody., (© 2024. The Author(s).)

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week., Methods: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases., Results: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths., Conclusions: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases., Impact: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs., Competing Interests: Competing interests: Alberto Berardi reported receiving personal fees from Atheneum Partners, GmbH outside the submitted work. Joseph M. Bliss reported receiving personal fees from Mead Johnson Nutrition outside the submitted work. No other disclosures were reported., (© 2024. The Author(s).)

A Europe-wide outbreak of invasive pediatric group A streptococcal infections (iGAS) began in fall 2022. Here, we report the evolution of GAS hospitalizations in children and adolescents during the second outbreak year in 2023-2024 at a tertiary center in Switzerland. Using prospective monitoring of all in-patient GAS cases below 16 years of age, including those with iGAS, we compared case frequencies and clinical characteristics in three time periods (2013-2020; 2022-2023; 2023-2024). Annual GAS hospitalizations increased from a median of 25 cases (range 11-28) in 2013-2020 to 89 and 63 cases, respectively, in 2022-2023 and 2023-2024. iGAS cases evolved similarly (2013-2020, 4 cases (3-8); 2022-2023, 32 cases; 2023-2024, 21 cases). The decline in cases from 2022-2023 to 2023-2024 included all types of GAS organ involvement, except suppurative infections in the head area, which remained largely unchanged (48 vs. 45 cases). Pleural empyema declined from 13 to 7 cases, possibly explained by a poor overlap of the GAS and influenza curves, respectively, in 2023-2024 compared to 2022-2023. These data document the prolongation of the GAS outbreak into its second winter season in 2023-2024.

Competing Interests: PMMS, JT and PKAA have participated in advisory board meetings for Nirsevimab organised by Sanofi. JT has received speaker fees from Sanofi and is member of a data safety monitoring board for mRNA-based RSV vaccines by Moderna.

Background: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing., Methods: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification., Results: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category., Conclusions: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship., Competing Interests: Potential conflicts of interest. A. J. C. reports 2 grants from UK Research and Innovation (principal investigator), outside the submitted work, a grant from the National Institute of Health and Care Research (as joint lead of the Global Health Research Group), and a role as chair of the Committee for Scientific Affairs and Awards for European Society for Paediatric Infectious Disease. F. M-T. reports financial support for educational activities from Sanofi, MSD, Moderna, GlaxoSmithKline (GSK), Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer, outside the submitted work; travel expenses and meeting fees covered by Pfizer, MSD, GSK, and Sanofi; participation on a data safety monitoring board or advisory board for Pfizer and Biofabri; ; roles as coordinator of Spanish Pediatric Critical Trials Network and coordinator of the World Health Organization (WHO) Collaborating Centre for Vaccine Safety of Santiago de Compostela; and roles as principal investigator in randomized controlled trials for Ablynx, Abbott, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK. A. J. P. reports consulting fees from Shionogi, outside the submitted work; grants or contracts paid to the institution from the Bill & Melinda Gates Foundation, the Wellcome Trust, Cepi, the Medical Research Council, and the National Institute for Health and Care Research; royalties or licenses from AstraZeneca (Oxford University has entered into a partnership with AstraZeneca for development of coronavirus disease 2019 [COVID-19] vaccines); and unpaid roles as chair of the Department of Health and Social Care's Joint Committee on Vaccination and Immunisation and as a member of the WHO Strategic Advisory Group of Experts on Immunization (SAGE) until 2022. P. K. A. A. was a member of the Sanofi advisory board for nirsevimab in 2022. M. N. T. reports consulting fees for an MSD advisory board, support for attending IDWeek 2022 from Pfizer and IDWeek 2023 from Janssen, and unpaid participation on the Scientific Advisory Group of Experts for COVID-19 (Greece) and the National Committee for immunization Practices (Greece). U. v. B. reports financial support for educational activities (lectures on antimicrobial stewardship; pediatric educational curricula) from MSD, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Seroepidemiologic studies of human tularemia have been conducted throughout the northern hemisphere. The purposes of this study were (1) to provide an overview of Francisella tularensis seroprevalence data, and (2) to generate an estimate of the proportion of study participants whose infection remained subclinical., Methods: We conducted a systematic review of F tularensis seroprevalence studies according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched PubMed, Embase, and Web of Science covering the period from 1951 to 2023., Results: The weighted pooled seroprevalence among 44 486 participants recruited in 52 studies was 3.7% (95% confidence interval [CI], 2.7-5.1). Reported seroprevalences ranged between 0.2% and 31.3%. Occupational activities associated with an increased likelihood of exposure (risk ratio, 3.51 [95% CI, 3.2-3.86]) and studies from North America versus Europe and Asia (4.53 [4.15-4.94]) were associated with significantly increased seropositive rates. Twenty-eight data sets (47%) reported clinical information on a total of 965 seropositive participants. The weighted pooled estimate for subclinical seropositivity was 84.4% (95% CI, 72.9%-991.7%). Studies from F tularensis type A areas (risk ratio, 0.37 [95% CI, .27-.51) and studies from sites where pulmonary tularemia prevailed (0.38 [.28-.51]) reported lower subclinical seropositivity rates than studies from type B areas and from areas of predominance of (ulcero)glandular or oropharyngeal tularemia, respectively., Conclusions: Throughout the northern hemisphere, only a small proportion of study participants showed serologic evidence of exposure to F tularensis. Eight of 10 seropositive participants had no historical evidence of past clinical tularemia., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children., Design: International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM)., Setting: Fifteen teaching hospitals in nine European countries., Participants: Febrile immunocompromised children aged 0-18 years., Methods: The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated., Results: Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25)., Conclusion: Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h., Methods: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores., Findings: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%., Interpretation: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics., Funding: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation., Competing Interests: Declaration of interests AJP, AJC, MP, SM, MNT, ML, WZ, RdG, and UvB disclose payments made to institution through the PERFORM consortium from EU Horizon 2020 Programme (grant number 668303). AJC discloses funding from National Institute for Health and Care Research (NIHR; grant number NIHR134694), EPSRC (grant number EP/T029005/1), and EU Horizon Europe Programme (grant number 848196) in addition to support from the European Society for Paediatric Infectious Disease and Excellence in Paediatrics Institute for attending or travelling to meetings; a patent for a new diagnostic method for infection in children unrelated to the current study; and an unpaid role as Chair of Committee for Scientific Affairs and Awards, European Society for Paediatric Infectious Disease. AJP discloses funding from The Bill & Melinda Gates Foundation, the Wellcome Trust, Cepi, Medical Research Council, and NIHR to their institution, an Institutional (Oxford University) partnership with AstraZeneca for development of COVID-19 vaccines, consulting fees from Shionogi for a COVID-19 vaccine, and acting as unpaid chair of the UK's Department of Health and Social Care's Joint Committee on Vaccination and Immunisation and an unpaid member of WHO's SAGE until 2022. MWT discloses support from Janssen and Pfizer for attending or travelling to meetings, unpaid contributions to the National Committee on Immunization Practices, Greece and the Scientific Advisory Group of Experts for COVID-19, Greece, and acting as the President of the Hellenic Society for Paediatric Infectious Diseases. FM-T discloses consulting fees from Sanofi, MSD, Moderna, GSK, Biofabri, AstraZeneca, Novovax, Jansenn, and Pfizer as honoraria for lectures and presentations; support from Pfizer, MSD, GSK, and Sanofi for travel expenses and meeting fees; participation on a data safety monitoring board or advisory board for Pfizer and Biofabri; is a member of The European Technical Advisory Group of Experts (ETAGE) with WHO Europe, Coordinator of Spanish Pediatric Critical Trials Network, and Coordinator of WHO Collaborating Centre for Vaccine Safety of Santiago de Compostela; and is principal investigator in randomised controlled trials of Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis, and GSK. PKAA discloses Sanofi Nirsevimab payment to institution. HRJ, JZ, ML, MK, TWK and MIdJ have filed a patent application for the six-protein signature described here. CF is co-founder and Medical Director of Micropathology. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood., Methods: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children., Findings: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures., Conclusions: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis., Funding: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC., Competing Interests: Declaration of interests The authors declare that a patent application on the method described in this manuscript has been filed (2304229.4/GB/PRV, 23-03-2023)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Fever in neutropenia (FN) remains a serious complication of childhood cancer therapy. Clinical decision rules (CDRs) are recommended to help distinguish between children at high and low risk of severe infection. The aim of this analysis was to develop new CDRs for three different outcomes and to externally validate published CDRs., Procedure: Children undergoing chemotherapy for cancer were observed in a prospective multicenter study. CDRs predicting low from high risk infection regarding three outcomes (bacteremia, serious medical complications (SMC), safety relevant events (SRE)) were developed from multivariable regression models. Their predictive performance was assessed by internal cross-validation. Published CDRs suitable for validation were identified by literature search. Parameters of predictive performance were compared to assess reproducibility., Results: In 158 patients recruited between April 2016 and August 2018, 360 FN episodes were recorded, including 56 (16%) with bacteremia, 30 (8%) with SMC and 72 (20%) with SRE. The CDRs for bacteremia and SRE used four characteristics (type of malignancy, severely reduced general condition, leucocyte count <0.3 G/L, bone marrow involvement), the CDR for SMC two characteristics (severely reduced general condition and platelet count <50 G/L). Eleven published CDRs were analyzed. Six CDRs showed reproducibility, but only one in both sensitivity and specificity., Conclusions: This analysis developed CDRs predicting bacteremia, SMC or SRE at presentation with FN. In addition, it identified six published CDRs that show some reproducibility. Validation of CDRs is fundamental to find the best balance between sensitivity and specificity, and will help to further improve management of FN., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Santschi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice., Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed., Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively., Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics., Funding: EU Horizon 2020 grant 668303., Competing Interests: AC received research funding from UK-NIHR and EPSRC. He has unpaid roles at ESPID, and the Excellence in Paediatrics Institute. He filed a patent for a new diagnostic method in children. AP received grant funding from Gates Foundation, Wellcome Trust, Cepi, UK-MRC and NIHR. He received consulting fees from Shionogi. He leads the UK Joint Committee on Vaccination and Immunisation, and was a memeber of WHO-SAGE until 2022. Oxford University has entered into a partnership with AZ for development of COVID19 vaccines. CB received UK-NIHR research funding. FMT received funding from Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Referencia Competitiva, and Instituto de Salud Carlos III. MT has unpaid role at the National Committee on Immunization Practices, and at the Scientific Advisory Group of Experts for COVID-19. TK has unpaid roles at the National Working Party on Immunodeficiencies, and the National Advisory Committee on SARS-CoV-2 vaccination. UVB received funding from TeleKasper—Innovationsfonds, German G-BA, and has received funds for lectures at MSD—Workshop Pädiatrie. The other authors have no conflict of interests., (© 2023 The Authors.)

Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections., Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39)., Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV., Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011-2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli , Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important., Competing Interests: UH declares consulting fees from Global Pertussis Initiative (since 2001, Sanofi-Pasteur USA); Central and Eastern Europe Pertussis Awareness Group (since 2011, Sanofi-Pasteur France) and lecture fees (product independent) from Infectopharm Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cook, Atkinson, Kronenberg, Agyeman, Schlapbach, Swiss Pediatric Sepsis Study Group, Berger and Bielicki.)

Antibiotic exposure at the beginning of life can lead to increased antimicrobial resistance and perturbations of the developing microbiome. Early-life microbiome disruption increases the risks of developing chronic diseases later in life. Fear of missing evolving neonatal sepsis is the key driver for antibiotic overtreatment early in life. Bias (a systemic deviation towards overtreatment) and noise (a random scatter) affect the decision-making process. In this perspective, we advocate for a factual approach quantifying the burden of treatment in relation to the burden of disease balancing antimicrobial stewardship and effective sepsis management., (© 2023. The Author(s).)

Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001)., Conclusion: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease., What Is Known: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited., What Is New: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the 'Biomarker Validation in HR patients' database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1-4.6)) and HIV (OR 10.4 (95% CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3-0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522).   Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known: • Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom. • Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New: • Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective. • The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers., (© 2023. The Author(s).)

Background: Infective endocarditis (IE) in pediatric patients is a severe cardiac disease and its actual epidemiology and clinical outcome in Switzerland is scarcely studied., Methods: Retrospective nationwide multicenter data analysis of pediatric IE in children (<18 years) between 2011 and 2020., Results: 69 patients were treated for definite (40/69;58%) or possible IE (29/69;42%). 61% (42/69) were male. Diagnosis was made at median 6.4 years (IQR 0.8-12.6) of age with 19 patients (28%) during the first year of life. 84% (58/69) had congenital heart defects. IE was located on pulmonary (25/69;35%), mitral (10/69;14%), tricuspid (8/69;12%) and aortic valve (6/69;9%), and rarely on ventricular septal defect (VSD;4/69;6%) and atrial septal defect (ASD;1/69;1%). In 22% (16/69) localization was unknown. 70% (48/69) had postoperative IE, with prosthetic material involved in 60% (29/48; right ventricular to pulmonary artery conduit (24), VSD (4), ASD (1)). Causative organisms were mostly Staphylococci spp. (25;36%) including Staphylococcus aureus (19;28%), and Streptococci spp. (13;19%). 51% (35/69) suffered from severe complications including congestive heart failure (16;23%), sepsis (17;25%) and embolism (19;28%). Staphylococcus aureus was found as a predictor of severe complications in univariate and multivariate analysis (p = 0.02 and p = 0.033). In 46% (32/69) cardiac surgery was performed. 7% (5/69) died., Conclusions: IE in childhood remains a severe cardiac disease with relevant mortality. The high morbidity and high rate of complications is associated with Staphylococcus aureus infections. Congenital heart defects act as a risk factor for IE, in particular the high number of cases associated with prosthetic pulmonary valve needs further evaluation and therapeutic alternatives., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: International Classification of Diseases 10th edition (ICD-10) is widely used to describe the burden of disease., Aim: To describe how well ICD-10 coding captures sepsis in children admitted to the hospital with blood culture-proven bacterial or fungal infection and systemic inflammatory response syndrome., Methods: Secondary analysis of a population-based, multicenter, prospective cohort study on children with blood culture-proven sepsis of nine tertiary pediatric hospitals in Switzerland. We compared the agreement of validated study data on sepsis criteria with ICD-10 coding abstraction obtained at the participating hospitals., Results: We analyzed 998 hospital admissions of children with blood culture-proven sepsis. The sensitivity of ICD-10 coding abstraction was 60% (95%-CI 57-63) for sepsis; 35% (95%-CI 31-39) for sepsis with organ dysfunction, using an explicit abstraction strategy; and 65% (95%-CI 61-69) using an implicit abstraction strategy. For septic shock, the sensitivity of ICD-10 coding abstraction was 43% (95%-CI 37-50). Agreement of ICD-10 coding abstraction with validated study data varied by the underlying infection type and disease severity ( p  < 0.05). The estimated national incidence of sepsis, inferred from ICD-10 coding abstraction, was 12.5 per 100,000 children (95%-CI 11.7-13.5) and 21.0 per 100,000 children (95%-CI 19.8-22.2) using validated study data., Conclusions: In this population-based study, we found a poor representation of sepsis and sepsis with organ dysfunction by ICD-10 coding abstraction in children with blood culture-proven sepsis when compared against a prospective validated research dataset. Sepsis estimates in children based on ICD-10 coding may thus severely underestimate the true prevalence of the disease., Supplementary Information: The online version contains supplementary material available at 10.1007/s44253-023-00006-1., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2023.)

Importance: Appropriate use of antibiotics is life-saving in neonatal early-onset sepsis (EOS), but overuse of antibiotics is associated with antimicrobial resistance and long-term adverse outcomes. Large international studies quantifying early-life antibiotic exposure along with EOS incidence are needed to provide a basis for future interventions aimed at safely reducing neonatal antibiotic exposure., Objective: To compare early postnatal exposure to antibiotics, incidence of EOS, and mortality among different networks in high-income countries., Design, Setting, and Participants: This is a retrospective, cross-sectional study of late-preterm and full-term neonates born between January 1, 2014, and December 31, 2018, in 13 hospital-based or population-based networks from 11 countries in Europe and North America and Australia. The study included all infants born alive at a gestational age greater than or equal to 34 weeks in the participating networks. Data were analyzed from October 2021 to March 2022., Exposures: Exposure to antibiotics started in the first postnatal week., Main Outcomes and Measures: The main outcomes were the proportion of late-preterm and full-term neonates receiving intravenous antibiotics, the duration of antibiotic treatment, the incidence of culture-proven EOS, and all-cause and EOS-associated mortality., Results: A total of 757 979 late-preterm and full-term neonates were born in the participating networks during the study period; 21 703 neonates (2.86%; 95% CI, 2.83%-2.90%), including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, received intravenous antibiotics during the first postnatal week. The proportion of neonates started on antibiotics ranged from 1.18% to 12.45% among networks. The median (IQR) duration of treatment was 9 (7-14) days for neonates with EOS and 4 (3-6) days for those without EOS. This led to an antibiotic exposure of 135 days per 1000 live births (range across networks, 54-491 days per 1000 live births). The incidence of EOS was 0.49 cases per 1000 live births (range, 0.18-1.45 cases per 1000 live births). EOS-associated mortality was 3.20% (12 of 375 neonates; range, 0.00%-12.00%). For each case of EOS, 58 neonates were started on antibiotics and 273 antibiotic days were administered., Conclusions and Relevance: The findings of this study suggest that antibiotic exposure during the first postnatal week is disproportionate compared with the burden of EOS and that there are wide (up to 9-fold) variations internationally. This study defined a set of indicators reporting on both dimensions to facilitate benchmarking and future interventions aimed at safely reducing antibiotic exposure in early life.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted., (© 2022. The Author(s).)

Background: Epidemiology of Clostridioides difficile infection (CDI) in paediatric cancer patients is uncertain. The primary objective was to describe the prevalence of CDI outcomes among paediatric patients receiving cancer treatments. Secondary objectives were to describe clinical features of CDI, propose a definition of severe CDI and to determine risk factors for CDI clinical outcomes., Methods: A multi-centre retrospective cohort study that included paediatric patients (1-18 years of age) receiving cancer treatments with CDI. Severe CDI definition was achieved by consensus. Univariable and multivariable regression was conducted to evaluate risk factors for CDI outcomes., Results: There were 627 eligible patients who experienced 721 CDI episodes. The prevalence of clinical cure was 82.9%, recurrence was 9.6%, global cure was 75.0% and repeated new CDI episode was 12.8%. The proposed definition of severe CDI was the presence of colitis, pneumatosis intestinalis, pseudomembranous colitis, ileus or surgery for CDI, occurring in 70 (9.7%) episodes. In univariable regression, initial oral metronidazole or initial oral vancomycin were not significantly associated with failure to achieve clinical cure or CDI recurrence. In multiple regression, oral metronidazole was significantly associated with higher odds (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.0-2.7) and oral vancomycin was significantly associated with lower odds (OR 0.4, 95% CI 0.2-0.8) of repeated new episodes., Conclusion: The prevalence of clinical cure was 82.9% and recurrence was 9.6% in pediatric patients receiving cancer treatments. Severe CDI, as per our proposed definition, occurred in 9.7% episodes. Initial oral vancomycin was significantly associated with a reduction in repeated new CDI episodes., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas H Groll has research support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and served at the speakers’ bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; Thomas Lehrnbecher has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas, and Roche; and serves at the speakers’ bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer, and GlaxoSmithKline. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Motivation: Sepsis is a leading cause of death and disability in children globally, accounting for ∼3 million childhood deaths per year. In pediatric sepsis patients, the multiple organ dysfunction syndrome (MODS) is considered a significant risk factor for adverse clinical outcomes characterized by high mortality and morbidity in the pediatric intensive care unit. The recent rapidly growing availability of electronic health records (EHRs) has allowed researchers to vastly develop data-driven approaches like machine learning in healthcare and achieved great successes. However, effective machine learning models which could make the accurate early prediction of the recovery in pediatric sepsis patients from MODS to a mild state and thus assist the clinicians in the decision-making process is still lacking., Results: This study develops a machine learning-based approach to predict the recovery from MODS to zero or single organ dysfunction by 1 week in advance in the Swiss Pediatric Sepsis Study cohort of children with blood-culture confirmed bacteremia. Our model achieves internal validation performance on the SPSS cohort with an area under the receiver operating characteristic (AUROC) of 79.1% and area under the precision-recall curve (AUPRC) of 73.6%, and it was also externally validated on another pediatric sepsis patients cohort collected in the USA, yielding an AUROC of 76.4% and AUPRC of 72.4%. These results indicate that our model has the potential to be included into the EHRs system and contribute to patient assessment and triage in pediatric sepsis patient care., Availability and Implementation: Code available at https://github.com/BorgwardtLab/MODS-recovery. The data underlying this article is not publicly available for the privacy of individuals that participated in the study., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The incidence of tularemia has recently increased throughout Europe. Pediatric tularemia typically presents with ulceroglandular or glandular disease and requires antimicrobial therapy not used in the empirical management of childhood acute lymphadenitis. We describe the clinical presentation and course in a case series comprising 20 patients., Methods: This is a retrospective analysis of a single-center case series of microbiologically confirmed tularemia in patients <16 years of age diagnosed between 2010 and 2021., Results: Nineteen patients (95%) presented with ulceroglandular (n = 14) or glandular disease (n = 5), respectively. A characteristic entry site lesion (eschar) was present in 14 (74%). Fever was present at illness onset in 15 patients (75%) and disappeared in all patients before targeted therapy was initiated. The diagnosis was confirmed by serology in 18 patients (90%). While immunochromatography was positive as early as on day 7, a microagglutination test titer 1:≥160 was found no earlier than on day 13. Sixteen patients (80%) were initially treated with an antimicrobial agent ineffective against F. tularensis . The median delay (range) from illness onset to initiation of targeted therapy was 12 (6-40) days. Surgical incision and drainage were ultimately performed in 12 patients (60%)., Conclusions: Pediatric tularemia in Switzerland usually presents with early, self-limiting fever and a characteristic entry site lesion with regional lymphadenopathy draining the scalp or legs. Particularly in association with a tick exposure history, this presentation may allow early first-line therapy with an agent specifically targeting F. tularensis , potentially obviating the need for surgical therapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: To determine circulating levels of ascorbic acid (VitC) and thiamine (VitB1) in neonates and children with blood culture-proven sepsis., Design: Nested single-center study of neonates and children prospectively included in the Swiss Pediatric Sepsis Study., Setting: One tertiary care academic hospital., Patients: Sixty-one neonates and children 0-16 years old., Interventions: None., Measurements and Main Results: VitC and VitB1 were quantified in serum of patients (median age, 10.5 mo; interquartile range [IQR], 0.5-62.1 mo) with blood culture-proven sepsis. Median time between sepsis onset and sampling for measurement of vitamins was 3 days (IQR, 2-4 d). Median serum levels of VitC and VitB1 were 32.4 μmol/L (18.9-53.3 μmol/L) and 22.5 nmol/L (12.6-82 nmol/L); 36% of the patients (22/61) had low VitC and 10% (6/61) had VitC deficiency; and 72% (44/61) had low VitB1 and 13% (8/61) had VitB1 deficiency. Children with low VitC were older (p = 0.007) and had higher C-reactive protein (p = 0.004) compared with children with VitC within the normal range. Children with low VitB1 levels were older (p = 0.0009) and were less frequently receiving enteral or parenteral vitamin supplementation (p = 0.0000003) compared with children with normal VitB1 levels., Conclusions: In this cohort of newborns and children with sepsis, low and deficient VitC and VitB1 levels were frequently observed. Age, systemic inflammation, and vitamin supplementation were associated with vitamin levels during sepsis., Competing Interests: Dr. Rezzi’s institution received funding from Insel Gruppe AG; he disclosed that he was an employee of Nestlé Institute of Health Sciences. Dr. Giannoni is supported by the Leenaards Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based., Procedure: Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules., Results: In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11., Conclusions: This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease., Methods: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity., Results: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity., Conclusion: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population., Competing Interests: Conflict of interest statement A.H.G. has research support from Gilead Sciences, Merck Sharp and Dohme and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer. A.A. is a consultant for Jazz Pharmaceuticals, Amgen, Novartis, Gilead Sciences and MSD/Merck and served at the speakers' bureau of Jazz Pharmaceuticals, Amgen and Novartis. T.L. has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer and GlaxoSmithKline. All the other authors do not have to declare a conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In anticipation of an interseasonal respiratory syncytial virus (RSV) epidemic, a clinician-led reporting system was rapidly established to capture RSV infections in Swiss hospitals, starting in January 2021. Here, we present details of the reporting system and first results to June 2021. An unusual epidemiology was observed with an interseasonal surge of RSV infections associated with COVID-19-related non-pharmacological interventions. These data allowed real-time adjustment of RSV prophylaxis guidelines and consequently underscore the need for and continuation of systematic nationwide RSV surveillance.

We report the unprecedented complete absence of pediatric enteroviral meningitis in 2020 in the area of Bern, Switzerland. Presumably an unintended effect of coronavirus disease 2019 public health measures, this finding highlights the potential of community-wide nonpharmaceutical interventions for controlling the circulation of a major pediatric pathogen, which is mainly transmitted by the fecal-oral route., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Discrimination of infectious and noninfectious complications in children with inflammatory signs after cardiac surgery is challenging. Given the low prevalence of infectious complications after heart surgery, there might be a risk of excessive antibiotic usage. We performed this study to determine the rate of invasive bacterial or fungal infections in children after cardiac surgery at our institution and to evaluate our postoperative management., Methods: This single-center retrospective observational cohort study included children 16 years of age or younger who underwent cardiac surgery at our institution between January 2012 and December 2015., Results: We analyzed 395 surgical procedures. Thirty-five postoperative invasive bacterial or fungal infections were detected in 29 episodes (7%, 0.42 per 100 admission days). Among bacterial infections, the most common infection sites were bacteremia and pneumonia, accounting for 37% (13/35) and 23% (8/35) of infections respectively. The rate of postoperative infections was associated with surgical complexity score and length of postoperative pediatric intensive care unit (PICU) stay. In 154 (43%) of 357 episodes without microbiologically documented infection, uninterrupted postoperative antibiotic administration was continued for more than 3 days and in 80 (22%) for more than 5 days., Conclusions: The rate of postoperative bacterial or fungal infection at our institution is comparable to current literature. High surgical complexity score and prolonged length of PICU stay were risk factors for bacterial or fungal infections in this patient population., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium . Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

Background: Fever in neutropenia (FN) is a potentially life-threatening complication of chemotherapy in pediatric cancer patients. The current standard of care at most institutions is emergency hospitalization and empirical initiation of broad-spectrum antibiotic therapy., Methods: We analyzed in retrospect FN episodes with bacteremia in pediatric cancer patients in a single center cohort from 1993 to 2012. We assessed the distribution of pathogens, the in vitro antibiotic susceptibility patterns, and their trends over time., Results: From a total of 703 FN episodes reported, we assessed 134 FN episodes with bacteremia with 195 pathogens isolated in 102 patients. Gram-positive pathogens (124, 64%) were more common than Gram-negative (71, 36%). This proportion did not change over time (p = 0.26). Coagulase-negative staphylococci (64, 32%), viridans group streptococci (42, 22%), Escherichia coli (33, 17%), Klebsiella spp. (10, 5%) and Pseudomonas aeruginosa (nine, 5%) were the most common pathogens. Comparing the in vitro antibiotic susceptibility patterns, the antimicrobial activity of ceftriaxone plus amikacin (64%; 95%CI: 56%-72%), cefepime (64%; 95%CI 56%-72%), meropenem (64%; 95%CI 56%-72), and piperacillin/tazobactam (62%; 95%CI 54%-70%), respectively, did not differ significantly. The addition of vancomycin to those regimens would have increased significantly in vitro activity to 99% for ceftriaxone plus amikacin, cefepime, meropenem, and 96% for piperacillin/tazobactam (p < 0.001)., Conclusions: Over two decades, we detected a relative stable pathogen distribution and found no relevant trend in the antibiotic susceptibility patterns. Different recommended antibiotic regimens showed comparable in vitro antimicrobial activity., Competing Interests: The authors have declared that no competing interests exist.

Background: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes., Methods: We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported., Results: There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants., Conclusions: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Mycobacterium chelonae infections usually resolve with adequate therapy. We report the case of an adolescent with a chronic and progressive M chelonae infection refractory to combined antimicrobial and surgical therapy. Whole genome sequence analysis of consecutive isolates distinguished reinfection from recurrence and contributed to the diagnosis of a factitious disorder., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety., Methods: This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231., Findings: 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98)., Interpretation: In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation., Funding: Swiss Cancer League (KLS-3645-02-2015)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In pediatric oncology, there is no evidence-based definition of the temperature limit defining fever (TLDF), which itself is essential for the definition of fever in chemotherapy-induced severe neutropenia (FN). Lowering the TLDF can increase the number of FN episodes diagnosed. This prospective, single center observational study collected data on all temperature measurements, complete blood counts (CBCs), and measures of diagnostics and therapy performed at and after FN diagnosis in pediatric oncology patients using a high standard TLDF (39 °C ear temperature). In 45 FN episodes in 20 patients, 3391 temperature measurements and 318 CBCs, plus information on antibiotics, anti-fungal therapy, antipyretics, blood cultures taken and on discharge were collected. These data can mainly be used to study the influence of virtually lowering the TLDF on diagnostic measures, treatment and length of hospitalization in pediatric FN, which in turn are directly related to costs of FN therapy, and quality of life. This approach can be expanded to include as well different definitions of neutropenia.

Background: Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study., Methods: The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS)., Results: Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7-2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4-19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1-7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (β coefficient 0.2, 95% CI .1-1.1; P = .01)., Conclusions: The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To assess the epidemiology of blood culture-proven early- (EOS) and late-onset neonatal sepsis (LOS)., Study Design: All newborn infants admitted to tertiary care neonatal intensive care units in Switzerland and presenting with blood culture-proven sepsis between September 2011 and December 2015 were included in the study. We defined EOS as infection occurring <3 days after birth, and LOS as infection ≥3 days after birth. Infants with LOS were classified as having community-acquired LOS if onset of infection was ≤48 hours after admission, and hospital-acquired LOS, if onset was >48 hours after admission. Incidence was estimated based on the number of livebirths in Switzerland and adjusted for the proportion of admissions at centers participating in the study., Results: We identified 444 episodes of blood culture-proven sepsis in 429 infants; 20% of cases were EOS, 62% hospital-acquired LOS, and 18% community-acquired LOS. The estimated national incidence of EOS, hospital-acquired LOS, and community-acquired LOS was 0.28 (95% CI 0.23-0.35), 0.86 (0.76-0.97), and 0.28 (0.23-0.34) per 1000 livebirths. Compared with EOS, hospital-acquired LOS occurred in infants of lower gestational age and was more frequently associated with comorbidities. Community-acquired LOS was more common in term infants and in male infants. Mortality was 18%, 12%, and 0% in EOS, hospital-acquired LOS, and community-acquired LOS, and was higher in preterm infants, in infants with septic shock, and in those requiring mechanical ventilation., Conclusions: We report a high burden of sepsis in neonates with considerable mortality and morbidity. EOS, hospital-acquired LOS, and community-acquired LOS affect specific patient subgroups and have distinct clinical presentation, pathogens and outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Blood cultures are essential for the diagnosis and further appropriate treatment in children with suspected sepsis. In most hospitals, children will be empirically treated or closely monitored for at least 48 h awaiting results of blood cultures. Several studies have challenged the optimal duration of empiric treatment in the era of continuously monitored blood culture systems. The aim of our study was to investigate time-to-positivity (TTP) of blood cultures in children with proven sepsis. Methods: The Swiss Pediatric Sepsis Study prospectively enrolled children 0-16 years of age with blood culture positive sepsis between September 2011 and October 2015. TTP was prospectively assessed in six participating academic pediatric hospitals by fully automated blood culture systems. Results: In 521 (93%) of 562 bacteremia episodes (493 children, median age 103 days, range 0 days-16.9 years) a valid TTP was available. Median TTP was 12 h (IQR 8-17 h, range 0-109 h). By 24, 36, and 48 h, 460 (88%), 498 (96%), and 510 (98%) blood cultures, respectively, were positive. TTP was independent of age, sex, presence of comorbidities, site of infection and severity of infection. Median TTP in all age groups combined was shortest for group B streptococcus (8.7 h) and longest for coagulase-negative staphylococci (16.2 h). Conclusion: Growth of bacteria in blood cultures is detectable within 24 h in 9 of 10 children with blood culture-proven sepsis. Therefore, a strict rule to observe or treat all children with suspected sepsis for at least 48 h is not justified.

Background: Sepsis is a leading cause of childhood mortality worldwide. We assessed population-based incidence and outcomes of blood culture-proven bacterial sepsis in children in Switzerland., Methods: We did a multicentre, prospective, cohort study at ten paediatric hospitals in Switzerland. We included neonates and children younger than 17 years with blood culture-proven bacterial sepsis. Children were eligible if they met criteria for systemic inflammatory response syndrome-according to 2005 paediatric consensus definition- at the time of blood culture sampling. Incidence was calculated by dividing the number of annual sepsis episodes in the study for the years 2012-15 by the end-of-year resident paediatric population in Switzerland. The primary outcome was in-hospital mortality in the first 30 days after sepsis onset., Findings: Between Sept 1, 2011, and Dec 31, 2015, we enrolled 1096 children to our study. Of 1181 episodes of blood culture-proven bacterial sepsis, 382 (32%) occurred in 379 previously healthy children, 402 (34%) in 391 neonates, and 397 (34%) in 341 children with comorbidities. Incidence was 25·1 cases per 100 000 (95% CI 23·8-26·4) in children and 146·0 cases per 100 000 (133·2-159·6) in neonates. Central line-associated bloodstream infections and primary bloodstream infections accounted for 569 (48%) of 1181 episodes, and organ dysfunction was present in 455 (39%) of 1181 episodes. Escherichia coli (242 of 1181 [20%]), Staphylococcus aureus (177 of 1181 [15%]), coagulase-negative staphylococci (135 of 1181 [11%]), and Streptococcus pneumoniae (118 of 1181 [10%]) were the most prevalent pathogens in our study, accounting for 57% of episodes. The overall case-fatality ratio was 7% (82 of 1181 episodes; 95% CI 5·6-8·6), and it was higher in neonates (11%, 45 of 402 episodes; 8·4-14·8; adjusted odds ratio [OR] 4·41, 95% CI 1·75-11·1) and children with comorbidities (7%, 27 of 397 episodes; 4·6-9·9; OR 4·97, 1·84-13·4) compared with previously healthy children (3%, ten of 382 episodes; 1·3-4·9). The case-fatality ratio was 1% (five of 726 episodes [95% CI 0·3-1·7]) for children without organ dysfunction, which increased to 17% (77 of 455 episodes [13·7-20·8]) when organ dysfunction was present (adjusted OR 4·84, 95% CI 1·40-16·7)., Interpretation: The burden of blood culture-proven bacterial sepsis on child health remains considerable. We recorded key differences in predominant organisms, severity, and outcome between neonates, previously healthy children, and children with comorbidities. Although for most episodes of blood culture-proven bacterial sepsis, no organ dysfunction was seen, presence of organ dysfunction was strongly associated with mortality., Funding: Swiss National Science Foundation, Swiss Society of Intensive Care, Bangerter Foundation, Vinetum and Borer Foundation, and Foundation for the Health of Children and Adolescents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)