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Objective: To assess the financial non-medical out-of-pocket costs of hospital admissions for children with a febrile illness., Design: Single-centre survey-based study conducted between March and November 2022., Setting: Tertiary level children's hospital in the North East of England., Participants: Families of patients with febrile illness attending the paediatric emergency department MAIN OUTCOME MEASURES: Non-medical out-of-pocket costs for the admission were estimated by participants including: transport, food and drinks, child care, miscellaneous costs and loss of earnings., Results: 83 families completed the survey. 79 families (95.2%) reported non-medical out-of-pocket costs and 19 (22.9%) reported financial hardship following their child's admission.Total costs per day of admission were median £56.25 (IQR £32.10-157.25). The majority of families reported incurring transport (N=75) and food and drinks (N=71) costs., Conclusions: A child's hospital admission for fever can incur significant financial costs for their family. One in five participating families reported financial hardship following their child's admission. Self-employed and single parents were disadvantaged by unplanned hospital admissions and at an increased risk of financial hardship. Local hospital policies should be improved to support families in the current financial climate., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

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: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people's (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures., Methods: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person's Advisory Group North England (YPAGne) and participating CYP's secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer., Results: One hundred two CYP completed the survey. Most were between 16-18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: 'altruism', 'potential benefits outweigh individual risk', 'frugality', and '(in)convenience'. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: 'altruism', 'body integrity' and 'sample frugality'. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80)., Conclusion: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible., (© 2023. The Author(s).)

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).)

We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3-1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2-3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1-2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1-2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8-7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7-2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2-6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5-24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1-6.9) or PICU admission (aOR 9.7, 6.1-15.5)., Conclusions: Our data show how children with comorbidities are a population at risk, as they more often are diagnosed with bacterial infections and more often require PICU admission and life-saving interventions., What Is Known: • While children with comorbidity constitute a large part of ED frequent flyers, they are often excluded from studies., What Is New: • Children with comorbidities in general are more ill upon presentation than children without comorbidities. • Children with comorbidities form a heterogeneous group; specific subgroups have an increased risk for invasive bacterial infections, while others have an increased risk of invasive interventions such as PICU admission, regardless of the cause of the fever., (© 2022. The Author(s).)

Objective: This study aims to assess the performance of biomarkers used for the prediction of bacterial, viral, and fungal infection in immunocompromised children upon presentation with fever., Methods: We performed a literature search using PubMed and MEDLINE and In-Process & Other Non-indexed Citations databases. Cohort and case-control studies assessing biomarkers for the prediction of bacterial, viral, or fungal infection in immunocompromised children vs. conventional microbiological investigations were eligible. Studies including adult patients were eligible if pediatric data were separately assessable. Data on definitions used for infections, fever, and neutropenia and predictive values were collected. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool., Results: Fifty-two studies involving 13,939 febrile episodes in 7,059 children were included. In total, 92.2% were in cancer patients ( n = 48), and 15.7% also included hematopoietic stem cell transplantation patients ( n = 8). Forty-three biomarkers were investigated, of which 6 (CRP, PCT, IL-8, IL-6, IL-10, and TNFα) were significantly associated with bacterial infection at admission, studied in multiple studies, and provided predictive data. Literature on the prediction of viral and fungal infection was too limited. Eight studies compared C-reactive protein (CRP) and procalcitonin (PCT), with PCT demonstrating superiority in 5. IL-6, IL-8, and IL-10 were compared with CRP in six, four, and one study, respectively, with mixed results on diagnostic superiority. No clear superior biomarker comparing PCT vs. IL-6, IL-8, or IL-10 was identified., Discussion: There is great heterogeneity in the biomarkers studied and cutoff values and definitions used, thus complicating the analysis. Literature for immunocompromised children with non-malignant disease and for non-bacterial infection is sparse. Literature on novel diagnostics was not available. We illustrated the challenges of diagnosing fever adequately in this study population and the need for improved biomarkers and clinical decision-making tools., Competing Interests: The 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., (Copyright © 2022 van der Velden, Gennery and Emonts.)

Pulmonary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally described as mild, and SARS-CoV-2 infection in immunocompromised children are observed as generally mild as well. A small proportion of pediatric patients will become critically ill due to (cardio)respiratory failure and require intensive care treatment. We report the case of a teenager with Hodgkin's lymphoma who acquired SARS-CoV-2 (detected by PCR) on the day of her autologous stem cell transplant and developed acute respiratory distress syndrome, successfully treated with a combination of antivirals, immunomodulation with steroids and biologicals, and ECMO., Competing Interests: The 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., (Copyright © 2022 van der Velden, van Delft, Owens, Llevadias, McKean, Pulford, Taha, Williamson, Campbell-Hewson, Hambleton, Payne, Duncan, Johnston, Spegarova and Emonts.)

Background: Paediatric focal intracranial suppurative infections are uncommon but cause significant mortality and morbidity. There are no uniform guidelines regarding antibiotic treatment. This study reviewed management in a tertiary healthcare centre in the United Kingdom and considers suggestions for empirical treatment., Methods: A retrospective, single-centre cohort review of 95 children (< 18 years of age) with focal intracranial suppurative infection admitted between January 2001 and June 2016 in Newcastle upon Tyne, United Kingdom. Microbiological profiles and empirical antibiotic regimens were analysed for coverage, administration and duration of use. Mortality and neurological morbidity were reviewed. Data was analysed using t-tests, Mann-Whitney U tests, independent-samples median tests, and χ 2 -tests where appropriate. P-values < 0.05 were considered statistically significant., Results: Estimated annual incidence was 8.79 per million. Age was bimodally distributed. Predisposing factors were identified in 90.5%, most commonly sinusitis (42.1%) and meningitis (23.2%). Sinusitis was associated with older children (p < 0.001) and meningitis with younger children (p < 0.001). The classic triad was present in 14.0%. 43.8% of 114 isolates were Streptococcus spp., most commonly Streptococcus milleri group organisms. Twelve patients cultured anaerobes. Thirty one empirical antibiotic regimens were used, most often a third-generation cephalosporin plus metronidazole and amoxicillin (32.2%). 90.5% would have sufficient cover with a third generation cephalosporin plus metronidazole. 66.3% converted to oral antibiotics. Median total antibiotic treatment duration was 90 days (interquartile range, 60-115.50 days). Mortality was 3.2, 38.5% had short-term and 24.2% long-term neurological sequelae., Conclusions: Paediatric focal intracranial suppurative infection has a higher regional incidence than predicted from national estimates and still causes significant mortality and morbidity. We recommend a third-generation cephalosporin plus metronidazole as first-choice empirical treatment. In infants with negative anaerobic cultures metronidazole may be discontinued.