Cihan Papan1, Alberto Argentiero2, Marian Porwoll3, Ummaya Hakim3, Edoardo Farinelli2, Ilaria Testa2, Maria Bruna Pasticci2, Daniele Mezzetti2, Katia Perruccio2, Liat Etshtein4, Niv Mastboim4, Einat Moscoviz4, Tahel Ilan Ber4, Asi Cohen4, Einav Simon4, Olga Boico4, Liran Shani4, Tanya M Gottlieb4, Roy Navon4, Eran Barash4, Kfir Oved4, Eran Eden4, Arne Simon5, Johannes G Liese6, Markus Knuf7, Michal Stein8, Renata Yacobov8, Ellen Bamberger9, Sven Schneider10, Susanna Esposito11, Tobias Tenenbaum12. 1. University Children's Hospital Mannheim, Heidelberg University, Paediatric Infectious Diseases, Mannheim, Germany; Centre for Infectious Diseases, Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany. 2. Santa Maria della Misericordia Hospital, Università degli Studi di Perugia, Perugia, Italy. 3. University Children's Hospital Mannheim, Heidelberg University, Paediatric Infectious Diseases, Mannheim, Germany. 4. MeMed, Haifa, Israel. 5. Paediatric Oncology and Haematology, Saarland University Hospital, Homburg, Germany. 6. Department of Paediatrics, University of Würzburg, Würzburg, Germany. 7. Children's Hospital, Helios Dr Horst Schmidt Klinik, Wiesbaden, and Department of Paediatrics, University Medicine, Mainz, Germany. 8. Hillel Yaffe Medical Centre, Hadera, Israel. 9. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Paediatrics, Bnai-Zion Medical Centre, Haifa, Israel. 10. Institute for Clinical Chemistry, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany. 11. Pietro Barilla Children's Hospital, Department of Medicine and Surgery, University of Parma, Parma, Italy. 12. University Children's Hospital Mannheim, Heidelberg University, Paediatric Infectious Diseases, Mannheim, Germany. Electronic address: Tobias.tenenbaum@medma.uni-heidelberg.de.
Abstract
OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.
OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.
Authors: Cihan Papan; Katharina Reifenrath; Katharina Last; Andishe Attarbaschi; Norbert Graf; Andreas H Groll; Johannes Huebner; Hans-Jürgen Laws; Thomas Lehrnbecher; Johannes Liese; Luise Martin; Tobias Tenenbaum; Stefan Weichert; Simon Vieth; Ulrich von Both; Markus Hufnagel; Arne Simon Journal: JMIR Res Protoc Date: 2022-06-20