Relationship Between Molecular Pathogen Detection and Clinical Disease in Febrile Children Across Europe

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Shah, Priyen, Voice, Marie, Calvo-Bado, Leonides, Calle, Irene Rivero, Morris, Sophie, Nijman, Ruud, Broderick, Claire, De, Tisham, Eleftheriou, Irini, Galassini, Rachel et al (show 39 more authors) , Khanijau, Aakash, Kolberg, Laura, Kolnik, Mojca, Rudzate, Aleksandra, Sagmeister, Manfred, Schweintzger, Nina, Secka, Fatou, Thakker, Clare, van der Velden, Fabian, Vermont, Clementien, Vincek, Katarina, Agyeman, Philipp KA, Cunnington, Aubrey, De Groot, Ronald, Emonts, Marieke, Fidler, Katy, Kuijpers, Taco, Mallet, Francois, Moll, Henriette, Paulus, Stéphane, Pokorn, Marko, Pollard, Andrew J, Schlapbach, Luregn J, Shen, Ching-Fen, Tsolia, Maria, Usuf, Effua, van der Flier, Michiel, von Both, Ulrich, Yeung, Shunmay, Zavadsaka, Dace, Zenz, Werner, Wright, Victoria J, Carrol, Enitan ORCID: 0000-0001-8357-7726, Kaforou, Myrsini, Martinon-Torres, Federico, Fink, Colin, Levin, Michael, Herberg, Jethro A and Consortium, PERFORM (2022) Relationship Between Molecular Pathogen Detection and Clinical Disease in Febrile Children Across Europe [Preprint]

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Abstract

Background: Current management of febrile children aims to distinguish the minority with bacterial infection from the majority with viral illness. The Personalized Risk assessment in Febrile illness to Optimise Real-life Management (PERFORM) multi-country observational study aimed to understand the microbiological causes of febrile illness in European children through comparison of molecular pathogen detection and assignment of illness based on current clinical practice.Methods: Centralized molecular tests (CMT) for 19 respiratory and 27 blood pathogens were evaluated in all children with available samples. Each child was assigned to a standardized diagnostic category, based on retrospective review of clinical data, including 'best practice' local microbiological investigations, and blinded to results from CMT.Findings: Of 4,334 febrile children, 608(14%) were classified as having definite bacterial infection (DB), 447(10%) as having definite viral infection (DV), the remaining 3,289(76%) had uncertain etiology. Additionally 944 controls were included. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (odds ratio (OR): 3.37, 95% confidence interval (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, Influenza B and RSV were more common in DV than DB cases (OR and 95%CI for detection in DB vs DV cases 0.25 [0.11-0.46], 0.12 [0.02-0.37] and 0.16 [0.06-0.36] respectively). Two of 16 blood viruses were detected more often in DV than DB cases - enterovirus and EBV (OR and 95%CI for detection in DB vs DV cases 0.43[0.23-0.72] and 0.71[0.56-0.90] respectively). Combined local diagnostics and CMT detected blood viruses in 56% of DB cases, and respiratory viruses in 25%. Detection of a virus in blood or respiratory swabs were poor predictors for ruling-out bacterial infection, with predictive values of 0.64 and 0.68 respectively.Interpretation: Viruses are detected in a high proportion of patients with bacterial infection. The data challenge the concept that bacterial and viral infections are separate pathological events that should be managed with a corresponding dichotomous approach. The sensitivity and specificity of pathogen detection as snapshots were insufficient to determine the most appropriate clinical intervention, including the need for antibiotics and highlights the need for new approaches to managing febrile children.Funding Information: PERFORM was funded by the European Union’s Horizon 2020 program under GA No 668303. Enrolment of patients in UK was supported by NIHR Biomedical Research Centres at Imperial College London, and Newcastle.Declaration of Interests: None declared.Ethics Approval Statement: Ethical approval was obtained at the coordinating site (Imperial College London, 16/LO/1684) and separately at each participating center, using a consortium-wide clinical study protocol. All patients were recruited with informed parental consent, and assent from older children.

Item Type:	Preprint
Uncontrolled Keywords:	3207 Medical Microbiology, 32 Biomedical and Clinical Sciences, 3202 Clinical Sciences, Biodefense, Emerging Infectious Diseases, Pediatric Research Initiative, Lung, Infectious Diseases, 2.2 Factors relating to the physical environment, Infection, 3 Good Health and Well Being
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	10 Jun 2024 09:22
Last Modified:	26 Feb 2026 22:12
DOI:	10.2139/ssrn.4053491
Related Websites:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3182102
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