Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source

Laurence Lacroix; Sebastien Papis; Chiara Mardegan; Fanny Luterbacher; Arnaud L'Huillier; Cyril Sahyoun; Kristina Keitel; Niv Mastboim; Liat Etshtein; Liran Shani; Einav Simon; Eran Barash; Roy Navon; Tanya M Gottlieb; Kfir Oved; Eran Eden; Christophe Combescure; Annick Galetto-Lacour; Alain Gervaix

doi:10.1371/journal.pone.0294032

Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source

PLoS One. 2023 Nov 13;18(11):e0294032. doi: 10.1371/journal.pone.0294032. eCollection 2023.

Authors

Laurence Lacroix^{1

2}, Sebastien Papis³, Chiara Mardegan³, Fanny Luterbacher³, Arnaud L'Huillier^{2

4}, Cyril Sahyoun^{1

2}, Kristina Keitel⁵, Niv Mastboim⁶, Liat Etshtein⁶, Liran Shani⁶, Einav Simon⁶, Eran Barash⁶, Roy Navon⁶, Tanya M Gottlieb⁶, Kfir Oved⁶, Eran Eden⁶, Christophe Combescure⁷, Annick Galetto-Lacour^{1

2}, Alain Gervaix^{1

2}

Affiliations

¹ Pediatric Emergency Department, Children's Hospital, University Hospitals of Geneva, Geneva, Switzerland.
² Faculty of Medicine, University of Geneva, Geneva, Switzerland.
³ Department of General Pediatrics, Children's Hospital, University Hospitals of Geneva, Geneva, Switzerland.
⁴ Department of Pediatric Infectious Diseases, Children's Hospital, University Hospitals of Geneva, Geneva, Switzerland.
⁵ Pediatric Emergency Department, Inselspital, Bern, Switzerland.
⁶ MeMed, Tirat Carmel, Israel.
⁷ Department of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland.

Abstract

Background: Improved tools are required to detect bacterial infection in children with fever without source (FWS), especially when younger than 3 years old. The aim of the present study was to investigate the diagnostic accuracy of a host signature combining for the first time two viral-induced biomarkers, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon γ-induced protein-10 (IP-10), with a bacterial-induced one, C-reactive protein (CRP), to reliably predict bacterial infection in children with fever without source (FWS) and to compare its performance to routine individual biomarkers (CRP, procalcitonin (PCT), white blood cell and absolute neutrophil counts, TRAIL, and IP-10) and to the Labscore.

Methods: This was a prospective diagnostic accuracy study conducted in a single tertiary center in children aged less than 3 years old presenting with FWS. Reference standard etiology (bacterial or viral) was assigned by a panel of three independent experts. Diagnostic accuracy (AUC, sensitivity, specificity) of host individual biomarkers and combinatorial scores was evaluated in comparison to reference standard outcomes (expert panel adjudication and microbiological diagnosis).

Results: 241 patients were included. 68 of them (28%) were diagnosed with a bacterial infection and 5 (2%) with invasive bacterial infection (IBI). Labscore, ImmunoXpert, and CRP attained the highest AUC values for the detection of bacterial infection, respectively 0.854 (0.804-0.905), 0.827 (0.764-0.890), and 0.807 (0.744-0.869). Labscore and ImmunoXpert outperformed the other single biomarkers with higher sensitivity and/or specificity and showed comparable performance to one another although slightly reduced sensitivity in children < 90 days of age.

Conclusion: Labscore and ImmunoXpert demonstrate high diagnostic accuracy for safely discriminating bacterial infection in children with FWS aged under and over 90 days, supporting their adoption in the assessment of febrile patients.

Copyright: © 2023 Lacroix et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bacterial Infections* / complications
Bacterial Infections* / diagnosis
Biomarkers
C-Reactive Protein / metabolism
Chemokine CXCL10*
Child
Child, Preschool
Fever
Humans
Infant
Prospective Studies
Tumor Necrosis Factors

Substances

Chemokine CXCL10
Biomarkers
C-Reactive Protein
Tumor Necrosis Factors

Associated data

Dryad/10.5061/dryad.gxd2547s8

Grants and funding

This was an investigator-driven study. Alain Gervaix received financial support from MeMed to support the study. The funder provided support in the form of salaries for authors NM, LE, LS, ES, EB, RN, TG, KO, EE. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders and study sponsors had no role in the design and conduct of the study, and in interpretation of clinical data. The first version of the manuscript was written by Laurence Lacroix. The funder (MeMed) participated in data collection and analysis (ImmunoXpert assays) and in reviewing the manuscript. Annick Galetto-Lacour and Arnaud L'Huillier received funding to support the study from the Gertrude von Meissner Foundation, the Ernst and Lucie Schmidheiny Foundation and the University Hospitals of Geneva's Research and Development Project Grant. There was no additional external funding received for this study.