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

Priyen Shah; Marie Voice; Leonides Calvo-Bado; Aleksandra Rudzate; Dace Zavadska; PERFORM consortium; Arta Bārzdiņa; Dārta Deksne; Anda Balode; Dace Gardovska; Dagne Grāvele; Ilze Grope; Anija Meiere; Ieva Nokalna; Jana Pavāre; Zanda Pučuka; Katrina Selecka; Urzula Nora Urbāne

doi:10.1016/j.lanepe.2023.100682

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

Priyen Shah, Marie Voice, Leonides Calvo-Bado, Aleksandra Rudzate, Dace Zavadska, PERFORM consortium, Arta Bārzdiņa (Under clarification), Dārta Deksne (Member of the Working Group), Anda Balode (Member of the Working Group), Dace Gardovska (Member of the Working Group), Dagne Grāvele (Member of the Working Group), Ilze Grope (Member of the Working Group), Anija Meiere (Member of the Working Group), Ieva Nokalna (Member of the Working Group), Jana Pavāre (Member of the Working Group), Zanda Pučuka (Member of the Working Group), Katrina Selecka (Member of the Working Group), Urzula Nora Urbāne (Member of the Working Group)

Rīga Stradiņš University

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

5 Downloads (Pure)

Abstract

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.

Original language	English
Article number	100682
Journal	LANCET REGIONAL HEALTH-EUROPE
Volume	32
DOIs	https://doi.org/10.1016/j.lanepe.2023.100682
Publication status	Published - Sept 2023

Keywords*

Molecular diagnostics
Diagnostic
Febrile illness
Infectious disease
Bacterial
viral
Respiratory infection

Field of Science*

3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.lanepe.2023.100682Licence: CC BY

Relationship between molecularFinal published version, 2.67 MBLicence: CC BY

Cite this

Shah, P., Voice, M., Calvo-Bado, L., Rudzate, A., Zavadska, D., PERFORM consortium, Bārzdiņa, A., Deksne, D., Balode, A., Gardovska, D., Grāvele, D., Grope, I., Meiere, A., Nokalna, I., Pavāre, J., Pučuka, Z., Selecka, K., & Urbāne, U. N. (2023). Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study. LANCET REGIONAL HEALTH-EUROPE, 32, Article 100682. https://doi.org/10.1016/j.lanepe.2023.100682

@article{db27cbbc3668425b88a6a60bd7a5a8e4,

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

abstract = "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.",

keywords = "Molecular diagnostics, Diagnostic, Febrile illness, Infectious disease, Bacterial, viral, Respiratory infection",

author = "Priyen Shah and Marie Voice and Leonides Calvo-Bado and Irene Rivero-Calle and Sophie Morris and Ruud Nijman and Claire Broderick and Tisham De and Irini Eleftheriou and Rachel Galassini and Aakash Khanijau and Laura Kolberg and Mojca Kolnik and Aleksandra Rudzate and Sagmeister, {Manfred G} and Schweintzger, {Nina A} and Fatou Secka and Clare Thakker and {van der Velden}, Fabian and Clementien Vermont and Katarina Vincek and Agyeman, {Philipp K A} and Cunnington, {Aubrey J} and {De Groot}, Ronald and Marieke Emonts and Katy Fidler and Kuijpers, {Taco W} and Marine Mommert-Tripon and Karen Brengel-Pesce and Francois Mallet and Henriette Moll and St{\'e}phane Paulus and Marko Pokorn and Andrew Pollard and Schlapbach, {Luregn J} and Ching-Fen Shen and Maria Tsolia and Effua Usuf and {van der Flier}, Michiel and {von Both}, Ulrich and Shunmay Yeung and Dace Zavadska and Werner Zenz and Victoria Wright and Carrol, {Enitan D} and Myrsini Kaforou and Federico Martinon-Torres and Colin Fink and Michael Levin and Jethro Herberg and {PERFORM consortium} and Arta Bārzdiņa and Dārta Deksne and Anda Balode and Dace Gardovska and Dagne Grāvele and Ilze Grope and Anija Meiere and Ieva Nokalna and Jana Pavāre and Zanda Pu{\v c}uka and Katrina Selecka and Urbāne, {Urzula Nora}",

note = "Funding Information: EU Horizon 2020 grant 668303.We are grateful to all patients and families that contributed towards this study. This project received funding under the European Union's Horizon 2020 Research and Innovation program under grant agreement number 668303. PERFORM consortium activities included obtaining study funding, patient recruitment, clinical data collection and entry, assignment of patient phenotypes, processing and storage of research samples used in this analysis, and molecular pathogen testing. The PERFORM Consortium, The members of the PERFORM consortium are as follows: Priyen Shah, Marie Voice, Leonides Calvo-Bado, Irene Rivero Calle, Sophie Morris, Ruud Nijman, Claire Broderick, Tisham De, Irini Eleftheriou, Rachel Galassini, Aakash Khanijau, Laura Kolberg, Mojca Kolnik, Aleksandra Rudzate, Manfred Sagmeister, Nina Schweintzger, Fatou Secka, Clare Thakker, Fabian Van der Velden, Clementien Vermont, Katarina Vincek, Philipp KA Agyeman, Aubrey J Cunnington, Ronald De Groot, Marieke Emonts, Katy Fidler, Taco Kuijpers, Marine Mommert-Tripon, Karen Brengel-Pesce, Francois Mallet, Henriette Moll, St{\'e}phane Paulus, Marko Pokorn, Andrew Pollard, Luregn J Schlapbach, Ching-Fen Shen, Maria Tsolia, Effua Usuf, Michiel Van der Flier, Ulrich Von Both, Shunmay Yeung, Dace Zavadska, Werner Zenz, Victoria Wright, Enitan D Carrol, Myrsini Kaforou, Federico Martinon-Torres, Colin Fink, Michael Levin, Jethro Herberg, Lucas Baumard, Evangelos Bellos, Lachlan Coin, Giselle D'Souza, Dominic Habgood-Coote, Shea Hamilton, Cllive Hoggart, Sara Hourmat, Heather Jackson, Naomi Lin, Stephanie Menikou, Samuel Nichols, Ivonne Pena Paz, Oliver Powell, Ortensia Vito, Clare Wilson, Amina Abdulla, Ladan Ali, Sarah Darnell, Rikke Jorgensen, Ian Maconochie, Sobia Mustafa, Salina Persand, Ben Walsh, Molly Stevens, Nayoung Kim, Eunjung Kim, Benjamin Pierce, Julia Dudley, Vivien Richmond, Emma Tavliavini, Ching-Chuan Liu, Shih-Min Wang, Fernando {\'A}lves Gonz{\'a}lez, Cristina Balo Farto, Ruth Barral-Arca, Mar{\'i}a Barreiro Castro, Xabier Bello, Mirian Ben Garc{\'i}a, Sandra Carnota, Miriam Cebey-L{\'o}pez, Mar{\'i}a Jos{\'e} Curras-Tuala, Carlos Dur{\'a}n Su{\'a}rez, Luisa Garc{\'i}a Vicente, Alberto G{\'o}mez-Carballa, Jose G{\'o}mez Rial, Pilar Lebor{\'a}ns Iglesias, Nazareth Martin{\'o}n-Torres, Jos{\'e} Mar{\'i}a Martin{\'o}n S{\'a}nchez, Bel{\'e}n Mosquera P{\'e}rez, Jacobo Pardo-Seco, Lidia Pi{\~n}eiro Rodr{\'i}guez, Sara Pischedda, Sara Ray V{\'a}zquez, Carmen Rodr{\'i}guez-Tenreiro, Lorenzo Redondo-Collazo, Miguel Sadiki Ora, Antonio Sallas, Sonia Ser{\'e}n Fern{\'a}ndez, Cristina Ser{\'e}n Trasorras, Marisol Vilas Iglesias, Anda Balode, Arta B{\~a}rdzdina, D{\~a}rta Deksne, Dace Gardovska, Dagne Gr{\~a}vele, Ilze Grope, Anija Meiere, Ieve Nokalna, Jana Pav{\~a}re, Zanda Pu{\v c}uka, Katrīna Selecka, Dace Svile, Urzula Nora Urb{\~a}ne, Kalifa Bojang, Syed M A Zaman, Suzanne Anderson, Anna Roca, Isatou Sarr, Momodou Saidykhan, Saffiatou Darboe, Samba Ceesay, Umberto D'alessandro, Dorine M. Borensztajn, Nienke N. Hagedoorn, Chantal Tal, Joany Zachariasse, W Dik, Christoph Aebi, Christoph Berger, Verena Wyss, Mariama Usman, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Giancarlo Natalucci, Christa Relly, Thomas Riedel, Elizabeth Cocklin, Rebecca Jennings, Joanne Johnson, Simon Leigh, Karen Newall, Sam Romaine, Maria Tambouratzi, Antonis Marmarinos, Marietta Xagorari, Kelly Syggelou, Nikos Spyridis, Jennifer Blackmore, Rebekah Harrison, Benno Kohlmaier, Daniela S. Kohlf{\"u}rst, Christoph Zurl, Alexander Binder, Susanne H{\"o}sele, Manuel Leitner, Lena P{\"o}lz, Glorija Rajic, Sebastian Bauchinger, Hinrich Baumgart, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallisti, Gunther Gores, Harald Haidl, Almuthe Hauer, Christa Hude, Markus Keldorfer, Larissa Krenn, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Gudrun Nordberg, Tobias Niedrist, Siegfried R{\"o}dl, Andrea Skrabl-Baumgartner, Matthias Sperl, Laura Stampfer, Volker Strenger, Holger Till, Andreas Trobisch, Sabine L{\"o}ffler, Juan Emmanuel Dewez, Martin Hibberd, David Bath, Alec Miners, Elizabeth Fitchett, Catherine Wedderburn, Anne Meierford, Baptiste Leurent, Marien I. De Jonge, Koen Van Aerde, Wynand Alkema, Bryan Van den Broek, Jolein Gloerich, Alain J. Van Gool, Stefanie Henriet, Martijn Huijnen, Ria Philipsen, Esther Willems, G. P. J. M. Gerrits, M. Van Leur, J. Heidema, L. De Haan, C. J. Miedema, C. Neeleman, C. C. Obihara, G. A. Tramper-Stranders, Rama Kandasamy, Michael J. Carter, Daniel O'Connor, Sagida Bibi, Dominic F. Kelly, Meeru Gurung, Stephen Throson, Imran Ansari, David R. Murdoch, Shrijana Shrestha, Zoe Oliver, Emma Lim, Lucille Valentine, Karen Allen, Kathryn Bell, Adora Chan, Stephen Crulley, Kirsty Devine, Daniel Fabian, Sharon King, Paul McAlinden, Sam McDonald, Anne McDonell, Alisa Pickering, Evelyn Thomson, Amanda Wood, Diane Wallia, Phil Woodsford, Frances Baxter, Ashley Bell, Mathew Rhodes, Rachel Agbeko, Christine Mackerness, Bryan Baas, Lieke Kloosterhuis, Wilma Oosthoek, Tasnim Arif, Joshua Bennet, Kalvin Collings, Ilona Van der Giessen, Alex Martin, Aqeela Rashid, Emily Rowlands, Joshua Soon, Gabriella De Vries, Fabian Van der Velden, Mike Martin, Ravi Mistry, Manuela Zwerenz, Judith Buschbeck, Christoph Bidlingmaier, Vera Binder, Katharina Danhauser, Nikolaus Haas, Matthias Griese, Matthias Kappler, Eberhard Lurz, Georg Muench, Karl Reiter, Carola Schoen, Karen Brengel-Pesce, Alexandre Pachot, Marine Mommert, Katarina Vincek, Tina Plankar Srovin, Natalija Bahovec, Petra Prunk, Veronika Osterman, Tanja Avramoska, Ilse Jongerius, J. M. Van den Berg, D. Schonenberg, A. M. Barendregt, D. Pajkrt, M. Van der Kuip, A. M. Van Furth, Evelien Sprenkeler, Judith Zandstra, G. van Mierlo, J. Geissler. Funding Information: We are grateful to all patients and families that contributed towards this study. This project received funding under the European Union{\textquoteright}s Horizon 2020 Research and Innovation program under grant agreement number 668303. PERFORM consortium activities included obtaining study funding, patient recruitment, clinical data collection and entry, assignment of patient phenotypes, processing and storage of research samples used in this analysis, and molecular pathogen testing. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = sep,

doi = "10.1016/j.lanepe.2023.100682",

language = "English",

volume = "32",

journal = "LANCET REGIONAL HEALTH-EUROPE",

issn = "2666-7762",

publisher = "Elsevier Ltd.",

}

Shah, P, Voice, M, Calvo-Bado, L, Rudzate, A , Zavadska, D, PERFORM consortium, Bārzdiņa, A, Deksne, D, Balode, A, Gardovska, D , Grāvele, D , Grope, I , Meiere, A , Nokalna, I , Pavāre, J , Pučuka, Z, Selecka, K & Urbāne, UN 2023, 'Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study', LANCET REGIONAL HEALTH-EUROPE, vol. 32, 100682. https://doi.org/10.1016/j.lanepe.2023.100682

TY - JOUR

T1 - Relationship between molecular pathogen detection and clinical disease in febrile children across Europe

T2 - a multicentre, prospective observational study

AU - Shah, Priyen

AU - Voice, Marie

AU - Calvo-Bado, Leonides

AU - Rivero-Calle, Irene

AU - Morris, Sophie

AU - Nijman, Ruud

AU - Broderick, Claire

AU - De, Tisham

AU - Eleftheriou, Irini

AU - Galassini, Rachel

AU - Khanijau, Aakash

AU - Kolberg, Laura

AU - Kolnik, Mojca

AU - Rudzate, Aleksandra

AU - Sagmeister, Manfred G

AU - Schweintzger, Nina A

AU - Secka, Fatou

AU - Thakker, Clare

AU - van der Velden, Fabian

AU - Vermont, Clementien

AU - Vincek, Katarina

AU - Agyeman, Philipp K A

AU - Cunnington, Aubrey J

AU - De Groot, Ronald

AU - Emonts, Marieke

AU - Fidler, Katy

AU - Kuijpers, Taco W

AU - Mommert-Tripon, Marine

AU - Brengel-Pesce, Karen

AU - Mallet, Francois

AU - Moll, Henriette

AU - Paulus, Stéphane

AU - Pokorn, Marko

AU - Pollard, Andrew

AU - Schlapbach, Luregn J

AU - Shen, Ching-Fen

AU - Tsolia, Maria

AU - Usuf, Effua

AU - van der Flier, Michiel

AU - von Both, Ulrich

AU - Yeung, Shunmay

AU - Zavadska, Dace

AU - Zenz, Werner

AU - Wright, Victoria

AU - Carrol, Enitan D

AU - Kaforou, Myrsini

AU - Martinon-Torres, Federico

AU - Fink, Colin

AU - Levin, Michael

AU - Herberg, Jethro

AU - PERFORM consortium

A2 - Bārzdiņa, Arta

A2 - Deksne, Dārta

A2 - Balode, Anda

A2 - Gardovska, Dace

A2 - Grāvele, Dagne

A2 - Grope, Ilze

A2 - Meiere, Anija

A2 - Nokalna, Ieva

A2 - Pavāre, Jana

A2 - Pučuka, Zanda

A2 - Selecka, Katrina

A2 - Urbāne, Urzula Nora

N1 - Funding Information: EU Horizon 2020 grant 668303.We are grateful to all patients and families that contributed towards this study. This project received funding under the European Union's Horizon 2020 Research and Innovation program under grant agreement number 668303. PERFORM consortium activities included obtaining study funding, patient recruitment, clinical data collection and entry, assignment of patient phenotypes, processing and storage of research samples used in this analysis, and molecular pathogen testing. The PERFORM Consortium, The members of the PERFORM consortium are as follows: Priyen Shah, Marie Voice, Leonides Calvo-Bado, Irene Rivero Calle, Sophie Morris, Ruud Nijman, Claire Broderick, Tisham De, Irini Eleftheriou, Rachel Galassini, Aakash Khanijau, Laura Kolberg, Mojca Kolnik, Aleksandra Rudzate, Manfred Sagmeister, Nina Schweintzger, Fatou Secka, Clare Thakker, Fabian Van der Velden, Clementien Vermont, Katarina Vincek, Philipp KA Agyeman, Aubrey J Cunnington, Ronald De Groot, Marieke Emonts, Katy Fidler, Taco Kuijpers, Marine Mommert-Tripon, Karen Brengel-Pesce, Francois Mallet, Henriette Moll, Stéphane Paulus, Marko Pokorn, Andrew Pollard, Luregn J Schlapbach, Ching-Fen Shen, Maria Tsolia, Effua Usuf, Michiel Van der Flier, Ulrich Von Both, Shunmay Yeung, Dace Zavadska, Werner Zenz, Victoria Wright, Enitan D Carrol, Myrsini Kaforou, Federico Martinon-Torres, Colin Fink, Michael Levin, Jethro Herberg, Lucas Baumard, Evangelos Bellos, Lachlan Coin, Giselle D'Souza, Dominic Habgood-Coote, Shea Hamilton, Cllive Hoggart, Sara Hourmat, Heather Jackson, Naomi Lin, Stephanie Menikou, Samuel Nichols, Ivonne Pena Paz, Oliver Powell, Ortensia Vito, Clare Wilson, Amina Abdulla, Ladan Ali, Sarah Darnell, Rikke Jorgensen, Ian Maconochie, Sobia Mustafa, Salina Persand, Ben Walsh, Molly Stevens, Nayoung Kim, Eunjung Kim, Benjamin Pierce, Julia Dudley, Vivien Richmond, Emma Tavliavini, Ching-Chuan Liu, Shih-Min Wang, Fernando Álves González, Cristina Balo Farto, Ruth Barral-Arca, María Barreiro Castro, Xabier Bello, Mirian Ben García, Sandra Carnota, Miriam Cebey-López, María José Curras-Tuala, Carlos Durán Suárez, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Pilar Leboráns Iglesias, Nazareth Martinón-Torres, José María Martinón Sánchez, Belén Mosquera Pérez, Jacobo Pardo-Seco, Lidia Piñeiro Rodríguez, Sara Pischedda, Sara Ray Vázquez, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Miguel Sadiki Ora, Antonio Sallas, Sonia Serén Fernández, Cristina Serén Trasorras, Marisol Vilas Iglesias, Anda Balode, Arta Bãrdzdina, Dãrta Deksne, Dace Gardovska, Dagne Grãvele, Ilze Grope, Anija Meiere, Ieve Nokalna, Jana Pavãre, Zanda Pučuka, Katrīna Selecka, Dace Svile, Urzula Nora Urbãne, Kalifa Bojang, Syed M A Zaman, Suzanne Anderson, Anna Roca, Isatou Sarr, Momodou Saidykhan, Saffiatou Darboe, Samba Ceesay, Umberto D'alessandro, Dorine M. Borensztajn, Nienke N. Hagedoorn, Chantal Tal, Joany Zachariasse, W Dik, Christoph Aebi, Christoph Berger, Verena Wyss, Mariama Usman, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Giancarlo Natalucci, Christa Relly, Thomas Riedel, Elizabeth Cocklin, Rebecca Jennings, Joanne Johnson, Simon Leigh, Karen Newall, Sam Romaine, Maria Tambouratzi, Antonis Marmarinos, Marietta Xagorari, Kelly Syggelou, Nikos Spyridis, Jennifer Blackmore, Rebekah Harrison, Benno Kohlmaier, Daniela S. Kohlfürst, Christoph Zurl, Alexander Binder, Susanne Hösele, Manuel Leitner, Lena Pölz, Glorija Rajic, Sebastian Bauchinger, Hinrich Baumgart, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallisti, Gunther Gores, Harald Haidl, Almuthe Hauer, Christa Hude, Markus Keldorfer, Larissa Krenn, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Gudrun Nordberg, Tobias Niedrist, Siegfried Rödl, Andrea Skrabl-Baumgartner, Matthias Sperl, Laura Stampfer, Volker Strenger, Holger Till, Andreas Trobisch, Sabine Löffler, Juan Emmanuel Dewez, Martin Hibberd, David Bath, Alec Miners, Elizabeth Fitchett, Catherine Wedderburn, Anne Meierford, Baptiste Leurent, Marien I. De Jonge, Koen Van Aerde, Wynand Alkema, Bryan Van den Broek, Jolein Gloerich, Alain J. Van Gool, Stefanie Henriet, Martijn Huijnen, Ria Philipsen, Esther Willems, G. P. J. M. Gerrits, M. Van Leur, J. Heidema, L. De Haan, C. J. Miedema, C. Neeleman, C. C. Obihara, G. A. Tramper-Stranders, Rama Kandasamy, Michael J. Carter, Daniel O'Connor, Sagida Bibi, Dominic F. Kelly, Meeru Gurung, Stephen Throson, Imran Ansari, David R. Murdoch, Shrijana Shrestha, Zoe Oliver, Emma Lim, Lucille Valentine, Karen Allen, Kathryn Bell, Adora Chan, Stephen Crulley, Kirsty Devine, Daniel Fabian, Sharon King, Paul McAlinden, Sam McDonald, Anne McDonell, Alisa Pickering, Evelyn Thomson, Amanda Wood, Diane Wallia, Phil Woodsford, Frances Baxter, Ashley Bell, Mathew Rhodes, Rachel Agbeko, Christine Mackerness, Bryan Baas, Lieke Kloosterhuis, Wilma Oosthoek, Tasnim Arif, Joshua Bennet, Kalvin Collings, Ilona Van der Giessen, Alex Martin, Aqeela Rashid, Emily Rowlands, Joshua Soon, Gabriella De Vries, Fabian Van der Velden, Mike Martin, Ravi Mistry, Manuela Zwerenz, Judith Buschbeck, Christoph Bidlingmaier, Vera Binder, Katharina Danhauser, Nikolaus Haas, Matthias Griese, Matthias Kappler, Eberhard Lurz, Georg Muench, Karl Reiter, Carola Schoen, Karen Brengel-Pesce, Alexandre Pachot, Marine Mommert, Katarina Vincek, Tina Plankar Srovin, Natalija Bahovec, Petra Prunk, Veronika Osterman, Tanja Avramoska, Ilse Jongerius, J. M. Van den Berg, D. Schonenberg, A. M. Barendregt, D. Pajkrt, M. Van der Kuip, A. M. Van Furth, Evelien Sprenkeler, Judith Zandstra, G. van Mierlo, J. Geissler. Funding Information: We are grateful to all patients and families that contributed towards this study. This project received funding under the European Union’s Horizon 2020 Research and Innovation program under grant agreement number 668303. PERFORM consortium activities included obtaining study funding, patient recruitment, clinical data collection and entry, assignment of patient phenotypes, processing and storage of research samples used in this analysis, and molecular pathogen testing. Publisher Copyright: © 2023 The Authors

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

KW - Molecular diagnostics

KW - Diagnostic

KW - Febrile illness

KW - Infectious disease

KW - Bacterial

KW - viral

KW - Respiratory infection

UR - http://www.scopus.com/inward/record.url?scp=85165624641&partnerID=8YFLogxK

UR - https://ars.els-cdn.com/content/image/1-s2.0-S2666776223001011-mmc1.pdf

U2 - 10.1016/j.lanepe.2023.100682

DO - 10.1016/j.lanepe.2023.100682

M3 - Article

C2 - 37554664

SN - 2666-7762

VL - 32

JO - LANCET REGIONAL HEALTH-EUROPE

JF - LANCET REGIONAL HEALTH-EUROPE

M1 - 100682

ER -

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

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