Fabian J S van der Velden1,2, Gabriella de Vries1,3, Alexander Martin1,2, Emma Lim1,4, Ulrich von Both5, Laura Kolberg5, Enitan D Carrol6,7, Aakash Khanijau6,7, Jethro A Herberg8, Tisham De8, Rachel Galassini8, Taco W Kuijpers9, Federico Martinón-Torres10,11,12, Irene Rivero-Calle10, Clementien L Vermont13, Nienke N Hagedoorn3, Marko Pokorn14, Andrew J Pollard15, Luregn J Schlapbach16, Maria Tsolia17, Irini Elefhteriou17, Shunmay Yeung18, Dace Zavadska19, Colin Fink20, Marie Voice20, Werner Zenz21, Benno Kohlmaier21, Philipp K A Agyeman22, Effua Usuf23, Fatou Secka23, Ronald de Groot24, Michael Levin8, Michiel van der Flier24,25, Marieke Emonts26,27,28. 1. Paediatric Immunology, Infectious Diseases & Allergy, Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 2. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. 3. Department of General Paediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 4. Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK. 5. Division Paediatric Infectious Diseases, Dr. Von Hauner Children's Hospital, University Hospital LMU Munich, Munich, Germany. 6. Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. 7. Alder Hey Children's NHS Foundation Trust, Liverpool, UK. 8. Section of Paediatric Infectious Disease, Wright-Fleming Institute, Imperial College London, London, UK. 9. Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 10. Pediatrics Department, Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain. 11. Grupo de Genetica, Vacunas, Infecciones y Pediatria, Instituto de Investigacion Sanitaria de Santiago, Universidad de Santiago, Santiago de Compostela, Spain. 12. Consorcio Centro de Investigacion Biomedicaen Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain. 13. Department of Pediatrics, Division of Pediatric Infectious Diseases & Immunology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 14. Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. 15. Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. 16. Neonatal and Pediatric Intensive Care Unit, Children's Research Center, University Children's Hospital Zürich, University of Zürich, Zurich, Switzerland. 17. 2nd Department of Pediatrics, National and Kapodistrian University of Athens, Children's Hospital 'P, and A. Kyriakou', Athens, Greece. 18. Clinical Research Department, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK. 19. Department of Pediatrics, Rīgas Stradina Universitāte, Children's Clinical University Hospital, Riga, Latvia. 20. Micropathology Ltd, University of Warwick, Warwick, UK. 21. Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria. 22. Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 23. Medical Research Council Unit, Serrekunda, The Gambia. 24. Pediatric Infectious Diseases and Immunology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands. 25. Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht, The Netherlands. 26. Paediatric Immunology, Infectious Diseases & Allergy, Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Marieke.emonts@ncl.ac.uk. 27. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. Marieke.emonts@ncl.ac.uk. 28. NIHR Newcastle Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK. Marieke.emonts@ncl.ac.uk.
Abstract
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.
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.
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