Febrile illness in high-risk children : a prospective, international observational study

Funding Information: This project received funding under the European Union’s Horizon2020 research and innovation programme, grant agreement number 668303. UK enrolment was supported by NIHR Biomedical Research Centres at Imperial College London, and Newcastle. Publisher Copyright: © 2022, 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.publishersversionPeer reviewe

Biobanking and consenting to research : a qualitative thematic analysis of young people’s perspectives in the North East of England

Funding Information: We would like to thank the Young Person’s Advisory Group North England and their connections to local secondary schools for making this project possible. DIAMONDS consortium Michael Levin7, Aubrey Cunnington7, Jethro Herberg7, Myrsini Kaforou7, Victoria Wright7, Evangelos Bellos7, Claire Broderick7, Samuel Channon-Wells7,Samantha Cooray7, Tisham De7, Giselle D’Souza7, Leire Estramiana Elorrieta7, Diego Estrada-Rivadeneyra7, Rachel Galassini7, Dominic Habgood-Coote7, Shea Hamilton7, Heather Jackson7, James Kavanagh7, Mahdi Moradi Marjaneh7, Samuel Nichols7, Ruud Nijman7, Harsita Patel7, Ivana Pennisi7, Oliver Powell7, Ruth Reid7, Priyen Shah7, Ortensia Vito7, Elizabeth Whittaker7, Clare Wilson7, Rebecca Womersley7, Amina Abdulla8, Sarah Darnell8, Sobia Mustafa8, Pantelis Georgiou9, Jesus-Rodriguez Manzano10, Nicolas Moser9, Michael Carter11, Shane Tibby11, Jonathan Cohen11, Francesca Davis11, Julia Kenny11, Paul Wellman11, Marie White11, Matthew Fish12, Aislinn Jennings13, Manu Shankar-Hari13, Katy Fidler14, Dan Agranoff15, Julia Dudley14, Vivien Richmond14, Matthew Seal15, Saul Faust16, Dan Owen16, Ruth Ensom16, Sarah McKay16, Diana Mondo17, Mariya Shaji17, Rachel Schranz17, Prita Rughnani18, Amutha Anpananthar19, Susan Liebeschuetz20, Anna Riddell18, Divya Divakaran19, Louise Han19, Nosheen Khalid18, Ivone Lancoma Malcolm19, Jessica Schofield19, Teresa Simagan19, Mark Peters21, Alasdair Bamford21, Lauran O’Neill21, Nazima Pathan22, Esther Daubney23, Debora White23, Melissa Heightman24, Sarah Eisen24, Terry Segal24, Lucy Wellings24, Simon B Drysdale25, Nicole Branch25, Lisa Hamzah25, Heather Jarman25, Maggie Nyirenda25, Lisa Capozzi26, Emma Gardiner26, Robert Moots27, Magda Nasher28, Anita Hanson28, Michelle Linforth27, Sean O’Riordan29, Donna Ellis29, Akash Deep30, Ivan Caro30, Fiona Shackley31, Arianna Bellini31, Stuart Gormley31, Samira Neshat32, Barnaby J Scholefield33, Ceri Robbins33, Helen Winmill33, Stéphane C Paulus34, Andrew J Pollard35, Mark Anthony36, Sarah Hopton36, Danielle Miller36, Zoe Oliver36, Sally Beer36, Bryony Ward36, Shrijana Shrestha37, Meeru Gurung37, Puja Amatya37, Bhishma Pokhrel37, Sanjeev Man Bijukchhe37, Madhav Chandra Gautam37, Peter O’Reilly35, Sonu Shrestha35, Federico Martinón-Torres38, Antonio Salas38, Fernando Álvez González38, Sonia Ares Gómez38, Xabier Bello38, Mirian Ben García38, Fernando Caamaño Viña38, Sandra Carnota38, María José Curras-Tuala38, Ana Dacosta Urbieta38, Carlos Durán Suárez38, Isabel Ferreiros Vidal38, Luisa García Vicente38, Alberto Gómez-Carballa38, Jose Gómez Rial38, Pilar Leboráns Iglesias38, Narmeen Mallah38, Nazareth Martinón-Torres38, José María Martinón Sánchez38, Belén Mosquera Perez38, Jacobo Pardo-Seco38, Sara Pischedda38, Sara Rey Vázquez38, Irene Rivero Calle38, Carmen Rodríguez-Tenreiro38, Lorenzo Redondo-Collazo38, Sonia Serén Fernández38, Marisol Vilas Iglesias38, Enital D Carrol39, Elizabeth Cocklin39, Abbey Bracken39, Ceri Evans40Aakash Khanijau39, Rebecca Lenihan39, Nadia Lewis-Burke39, Karen Newall41, Sam Romaine39, Jennifer Whitbread39, Maria Tsolia42, Irini Eleftheriou42, Nikos Spyridis42, Maria Tambouratzi42, Despoina Maritsi42, Antonios Marmarinos42, Marietta Xagorari42, Lourida Panagiota43, Pefanis Aggelos43, Akinosoglou Karolina44, Gogos Charalambos44, Maragos Markos44, Voulgarelis Michalis45, Stergiou Ioanna45, Marieke Emonts1,2, Emma Lim1,5,6, John Isaacs2, Kathryn Bell46, Stephen Crulley46, Daniel Fabian46, Evelyn Thomson46, Diane Walia46, Caroline Miller46, Ashley Bell46, Fabian JS van der Velden1,2, Geoff Shenton47, Ashley Price48, Owen Treloar2, Daisy Thomas1, Pablo Rojo49, Cristina Epalza49, Serena Villaverde49, Sonia Márquez49, Manuel Gijón49, Fátima Marchín49, Laura Cabello49, Irene Hernández49, Lourdes Gutiérrez49, Ángela Manzanares49, Taco W Kuijpers50, Martijn van de Kuip50, Marceline van Furth50, Merlijn van den Berg50, Giske Biesbroek50, Floris Verkuil50, Carlijn W van der Zee50, Dasja Pajkrt50, Michael Boele van Hensbroek50, Dieneke Schonenberg50, Mariken Gruppen50, Sietse Nagelkerke50, Machiel H Jansen50, Ines Goedschalckx51, Lorenza Romani52, Maia De Luca52, Sara Chiurchiù52, Constanza Tripiciano52, Stefania Mercadante52, Clementien L Vermont53, Henriëtte A Moll54, Dorine M Borensztajn54, Nienke N Hagedoorn54, Chantal Tan54, Joany Zachariasse54, Willem A Dik55, Shen Ching-Fen56, Dace Zavadska57, Sniedze Laivacuma58, Aleksandra Rudzate57, Diana Stoldere57, Arta Barzdina57, Elza Barzdina57, Monta Madelane59, Dagne Gravele59, Dace Svile59, Romain Basmaci60, Noémie Lachaume60, Pauline Bories60, Raja Ben Tkhayat60, Laura Chériaux60, Juraté Davoust60, Kim-Thanh Ong60, Marie Cotillon60, Thibault de Groc60, Sébastien Le60, Nathalie Vergnault60, Hélène Sée60, Laure Cohen60, Alice de Tugny60, Nevena Danekova60, Marine Mommert-Tripon61, Marko Pokorn62, Mojca Kolnik62, Tadej Avčin62, Tanja Avramoska62, Natalija Bahovec63, Petra Bogovič63, Lidija Kitanovski62, Mirijam Nahtigal63, Lea Papst63, Tina Plankar Srovin63, Franc Strle63, Katarina Vincek63, Michiel van der Flier64, Wim JE Tissing65, Roelie M Wösten-van Asperen66, Sebastiaan J Vastert67, Daniel C Vijlbrief68, Louis J Bont69, Tom FW Wolfs69, Coco R Beudeker69, Sanne C Hulsmann69, Philipp KA Agyeman70, Luregn Schlapbach71, Christoph Aebi70, Mariama Usman70, Stefanie Schlüchter70, Verena Wyss70, Nina Schöbi70, Elisa Zimmermann70, Marion Meier71, Kathrin Weber71, Eric Giannoni72, Martin Stocker73, Klara M Posfay-Barbe74, Ulrich Heininger75, Sara Bernhard-Stirnemann76, Anita Niederer-Loher77, Christian Kahlert78, Giancarlo Natalucci79, Christa Relly80, Thomas Riedel81, Christoph Berger81, Colin Fink82, Marie Voice82, Leo Calvo-Bado82, Michael Steele82, Jennifer Holden82, Andrew Taylor82, Ronan Calvez82, Catherine Davies82, Benjamin Evans82, Jake Stevens82, Peter Matthews82, Kyle Billing82, Werner Zenz83, Alexander Binder83, Benno Kohlmaier83, Daniel S Kohlfürst83, Nina A Schweintzger83, Christoph Zurl83, Susanne Hösele83, Manuel Leitner83, Lena Pölz83, Alexandra Rusu83, Glorija Rajic83, Bianca Stoiser83, Martina Strempfl83, Manfred G Sagmeister83, Sebastian Bauchinger83, Martin Benesch84, Astrid Ceolotto83, Ernst Eber83, Siegfried Gallistl83, Harald Haidl83, Almuthe Hauer83, Christa Hude83, Andreas Kapper85, Markus Keldorfer86, Sabine Löffler86, Tobias Niedrist87, Heidemarie Pilch86, Andreas Pfleger88, Klaus Pfurtscheller89, Siegfried Rödl89, Andrea Skrabl-Baumgartner83, Volker Strenger84, Elmar Wallner85, Maike K Tauchert90, Ulrich von Both91, Laura Kolberg91, Patricia Schmied91, Ioanna Mavridi91, Irene Alba-Alejandre92, Katharina Danhauser93, Niklaus Haas94, Florian Hoffmann95, Matthias Griese96, Tobias Feuchtinger97, Sabrina Juranek98, Matthias Kappler96, Eberhard Lurz99, Esther Maier98, Karl Reiter95, Carola Schoen95, Sebastian Schroepf100, Shunmay Yeung101, Manuel Dewez101, David Bath102, Elizabeth Fitchett101, Fiona Cresswell101, Effua Usuf103, Kalifa Bojang103, Anna Roca103, Isatou Sarr103, Momodou Ndure1038Children’s Clinical Research Unit, St Mary’s Hospital, Praed Street, London W2 1NY, UK9Imperial College London, Department of Electrical and Electronic Engineering, South Kensington Campus, London, SW7 2AZ, UK10Imperial College London, Department of Infectious Disease, Section of Adult Infectious Disease, Hammersmith Campus, London, W12 0NN, UK11Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK12Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK13Department of Intensive Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK14Royal Alexandra Children's Hospital, University Hospitals Sussex, Brighton, UK15Dept of Infectious Diseases, University Hospitals Sussex, Brighton, UK16NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust and University of Southampton, UK17Department of R&D, University Hospital Southampton NHS Foundation Trust, UK18Royal London Hospital, Whitechapel Rd, London E1 1FR, UK19Whipps Cross University Hospital, Whipps Cross Road, London, E11 1NR, UK20Newham University Hospital, Glen Rd, London E13 8SL, UK21Great Ormond Street Hospital, London, WC1N 3JH, UK22Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK23Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK24University College London Hospital, Euston Road, London NW1 2BU, UK25St George’s Hospital, Blackshaw Road, London SW17 0QT, UK26University Hospital Lewisham, London SE13 6LH, UK27Aintree University Hospital, Lower Lane, Liverpool L9 7AL, UK28Royal Liverpool Hospital, Prescot St, Liverpool L7 8XP, UK29Leeds Children’s Hospital, Leeds LS1 3EX, UK30Kings College Hospital, Denmark Hill, London SE5 9RS, UK31Sheffield Children’s Hospital, Broomhall, Sheffield S10 2TH, UK32Leicester General Hospital, Leicester LE1 5WW, UK33Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK34Department of Paediatrics, University of Oxford, UK35Oxford Vaccine Group, University of Oxford, UK36John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK37Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal38Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain39Institute of Infection, Veterinary and Ecoological Sciences, University of Liverpool, Liverpool, UK40Alder Hey Children’s Hospital, Department of Infectious Diseases, Eaton Road, Liverpool, L12 2AP, UK41Alder Hey Children’s Hospital, Clinical Research Business Unit, Eaton Road, Liverpool, L12 2AP, UK422nd Department of Pediatrics, National and Kapodistrian University of Athens (NKUA), Children’s Hospital “P, and A. Kyriakou”, Athens, Greece431st Department of Infectious Diseases, General Hospital “Sotiria”, Athens, Greece44Pathology Department, University of Patras, General Hospital “Panagia i Voithia”, Greece45Pathophysiology Department, Medical Faculty, National and Kapodistrian University of Athens (NKUA), General Hospital “Laiko”, Athens, Greece46Great North Children’s Hospital, Paediatric Research Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom47Great North Children’s Hospital, Paediatric Oncology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom48Department of Infection & Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom49Servicio Madrileño de Salud, Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain50Amsterdam UMC, Emma Children's Hospital, Dept of Pediatric Immunology, Rheumatology and Infectious Disease, University of Amsterdam, The Netherlands51Sanquin, Dept of Molecular Hematology, University Medical Center, Amsterdam, The Netherlands52Infectious Disease Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy53Erasmus MC-Sophia Children’s Hospital, Department of Paediatric Infectious Diseases & Immunology, Rotterdam, the Netherlands54Erasmus MC-Sophia Children’s Hospital, Department of General Paediatrics, Rotterdam, the Netherlands55Erasmus MC, Department of Immunology, Rotterdam, the Netherlands56Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan57Children’s Clinical University Hospital, Riga Stradins University, Riga, Latvia58Riga East Clinical Hospital, Riga Stradins University, Riga, Latvia59Children’s Clinical University Hospital, Riga, Latvia60Service de Pédiatrie-Urgences, AP-HP, Hôpital Louis-Mourier, F-92700 Colombes, France61bioMérieux—Open Innovation & Partnerships Department, Lyon, France62University Children's Hospital, University Medical Centre Ljubljana, Slovenia63Department of Infectious diseases, University Medical Centre Ljubljana, Slovenia64Pediatric Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands65Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands66Pediatric Intensive Care Unit, University Medical Center Utrecht, Utrecht, the Netherlands67Pediatric Rheumatology, University Medical Center Utrecht, Utrecht, the Netherlands68Pediatric Neonatal Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands69Pediatric Infectious Disease and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands70Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland71Department of Intensive Care and Neonatology, and Children`s Research Center, University Children`s Hospital Zurich, Zurich, Switzerland72Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Switzerland73Department of Pediatrics, Children’s Hospital Lucerne, Lucerne, Switzerland74Pediatric Infectious Diseases Unit, Children’s Hospital of Geneva, University Hospitals of Geneva, Geneva, Switzerland75Infectious Diseases and Vaccinology, University of Basel Children’s Hospital, Basel, Switzerland76Children’s Hospital Aarau, Aarau, Switzerland77Division of Infectious Diseases and Hospital Epidemiology, Children’s Hospital of Eastern Switzerland St. Gallen, St. Gallen, Switzerland78Department of Neonatology, University Hospital Zurich, Zurich, Switzerland79Division of Infectious Diseases and Hospital Epidemiology, and Children’s Research Center, University Children’s Hospital Zurich, Switzerland80Children’s Hospital Chur, Chur, Switzerland81Division of Infectious Diseases and Hospital Epidemiology, and Children’s Research Center, University Children’s Hospital Zurich, Switzerland82Micropathology Ltd, The Venture Center, University of Warwick Science Park, Sir William Lyons Road, Coventry, CV4 7EZ, UK83Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria84Department of Pediatric Hematooncology, Medical University of Graz, Graz, Austria85Department of Internal Medicine, State Hospital Graz II, Location West, Graz, Austria86University Clinic of Pediatrics and Adolescent Medicine Graz, Medical University Graz, Graz, Austria87Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria88Department of Pediatric Pulmonology, Medical University of Graz, Graz, Austria89Paediatric Intensive Care Unit, Medical University of Graz, Graz, Austria90Biobanking and BioMolecular Resources Research Infrastructure—European Research Infrastructure Consortium (BBMRI-ERIC), Neue Stiftingtalstrasse 2/B/6, 8010, Graz, Austria91Division of Pediatric Infectious Diseases, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany92Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany93Division of Pediatric Rheumatology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany94Department of Pediatric Cardiology and Pediatric Intensive Care, University Hospital, LMU Munich, Germany95Paediatric Intensive Care Unit, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany96Division of Pediatric Pulmonology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany97Division of Pediatric Haematology & Oncology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany98Division of General Pediatrics, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany99Division of Pediatric Gastroenterology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany100Neonatal Intensive Care Unit, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany101Clinical Research Department, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK102Department of Global Health and Development, Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK103Medical Research Council at LSHTM, Fajara, the Gambia Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 848196. The funding body played no role in the design of the study and collection, analysis, interpretation of data, and in writing the manuscript. Publisher Copyright: © 2023, The Author(s).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.Peer reviewe

Febrile illness in high-risk children: a prospective, international observational study.

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

Emergency medical services utilisation among febrile children attending emergency departments across Europe:an observational multicentre study

Children constitute 6–10% of all patients attending the emergency department (ED) by emergency medical services (EMS). However, discordant EMS use in children occurs in 37–61% with fever as an important risk factor. We aimed to describe EMS utilisation among febrile children attending European EDs. This study is part of an observational multicentre study assessing management and outcome in febrile children up to 18 years (MOFICHE) attending twelve EDs in eight European countries. Discordant EMS use was defined as the absence of markers of urgency including intermediate/high triage urgency, advanced diagnostics, treatment, and admission in children transferred by EMS. Multivariable logistic regression analyses were performed for the association between (1) EMS use and markers of urgency, and (2) patient characteristics and discordant EMS use after adjusting all analyses for the covariates age, gender, visiting hours, presenting symptoms, and ED setting. A total of 5464 (15%, range 0.1–42%) children attended the ED by EMS. Markers of urgency were more frequently present in the EMS group compared with the non-EMS group. Discordant EMS use occurred in 1601 children (29%, range 1–59%). Age and gender were not associated with discordant EMS use, whereas neurological symptoms were associated with less discordant EMS use (aOR 0.2, 95%CI 0.1–0.2), and attendance out of office hours was associated with more discordant EMS use (aOR 1.6, 95%CI 1.4–1.9). Settings with higher percentage of self-referrals to the ED had more discordant EMS use (p &lt; 0.05). Conclusion: There is large practice variation in EMS use in febrile children attending European EDs. Markers of urgency were more frequently present in children in the EMS group. However, discordant EMS use occurred in 29%. Further research is needed on non-medical factors influencing discordant EMS use in febrile children across Europe, so that pre-emptive strategies can be implemented. What is Known: •Children constitute around 6–10% of all patients attending the emergency department by emergency medical services. •Discordant EMS use occurs in 37–61% of all children, with fever as most common presenting symptom for discordant EMS use in children. What is New: •There is large practice variation in EMS use among febrile children across Europe with discordance EMS use occurring in 29% (range 1–59%), which was associated with attendance during out of office hours and with settings with higher percentage of self-referrals to the ED. •Future research is needed focusing on non-medical factors (socioeconomic status, parental preferences and past experience, healthcare systems, referral pathways, out of hours services provision) that influence discordant EMS use in febrile children across Europe.</p

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe:a multicentre, prospective observational study

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.</p

External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children.

ObjectiveTo 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.DesignInternational, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM).SettingFifteen teaching hospitals in nine European countries.ParticipantsFebrile immunocompromised children aged 0-18 years.MethodsThe 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.ResultsOf 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 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 30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25).ConclusionDiscrimination 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