Article Text

Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE, a prospective observational study
  1. Nienke N Hagedoorn1,
  2. Dorine Borensztajn1,
  3. Ruud Gerard Nijman2,
  4. Daan Nieboer3,
  5. Jethro Adam Herberg2,
  6. Anda Balode4,
  7. Ulrich von Both5,6,
  8. Enitan Carrol7,8,
  9. Irini Eleftheriou9,
  10. Marieke Emonts10,11,
  11. Michiel van der Flier12,13,
  12. Ronald de Groot12,
  13. Benno Kohlmaier14,
  14. Emma Lim10,11,
  15. Ian Maconochie15,
  16. Federico Martinón-Torres16,
  17. Marko Pokorn17,
  18. Franc Strle17,
  19. Maria Tsolia9,
  20. Dace Zavadska4,
  21. Werner Zenz14,
  22. Michael Levin2,
  23. Clementien Vermont18,
  24. Henriette A Moll1
  1. 1General Paediatrics, Erasmus MC Sophia Children's Hospital, Rotterdam, Zuid-Holland, The Netherlands
  2. 2Section of Paediatric Infectious Diseases, Imperial College London, London, UK
  3. 3Public Health, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
  4. 4Paediatrics, Children clinical university hospital, Rigas Stradinas Universitate, Riga, Latvia
  5. 5Division of Paediatric Infectious Diseases, Dr von Haunersches Kinderspital Kinderklinik und Kinderpoliklinik der Ludwig Maximilian Universitat Munchen, Munchen, Bayern, Germany
  6. 6Partner site Munich, German Centre for Infection Research, Braunschweig, Niedersachsen, Germany
  7. 7Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, Merseyside, UK
  8. 8Alder Hey Children's NHS Foundation Trust, Liverpool, Merseyside, UK
  9. 9Second Department of Paediatrics, P & A Kyriakou Children's Hospital, National and Kapodistrian University of Athens, Athinon, Greece
  10. 10Paediatric Immunology, Infectious Diseases & Allergy, Great North Children's Hospital, Newcastle upon Tyne, UK
  11. 11Newcastle upon Tyne Hospital NHS Trust and Newcastle University, NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, Tyne and Wear, UK
  12. 12Paediatric Infectious Diseases and Immunology, Amalia Children's Hospital, Radboudumc, Nijmegen, Gelderland, The Netherlands
  13. 13Wilhelmina Children's Hospital, Paediatric Infectious Diseases and Immunology, UMC Utrecht, Utrecht, The Netherlands
  14. 14Department of General Paediatrics, Medical University of Graz, Graz, Steiermark, Austria
  15. 15Paediatric Emergency Medicine, Imperial College Healthcare NHS Trust, London, UK
  16. 16Genetics, Vaccines, Infections and Paediatrics Research group (GENVIP), Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Galicia, Spain
  17. 17Department of Infectious Diseases and Faculty of Medicine, Ljubljanski Univerzitetni klinicni center, Ljubljana, Slovenia
  18. 18Department of Paediatric Infectious Diseases and Immunology, Erasmus MC Sophia Children's Hospital, Rotterdam, Nederland, The Netherlands
  1. Correspondence to Professor Henriette A Moll, Paediatrics, Erasmus MC Sophia Children's Hospital, Rotterdam 3015 GJ, The Netherlands; h.a.moll{at}


Objectives To develop and cross-validate a multivariable clinical prediction model to identify invasive bacterial infections (IBI) and to identify patient groups who might benefit from new biomarkers.

Design Prospective observational study.

Setting 12 emergency departments (EDs) in 8 European countries.

Patients Febrile children aged 0–18 years.

Main outcome measures IBI, defined as bacteraemia, meningitis and bone/joint infection. We derived and cross-validated a model for IBI using variables from the Feverkidstool (clinical symptoms, C reactive protein), neurological signs, non-blanching rash and comorbidity. We assessed discrimination (area under the receiver operating curve) and diagnostic performance at different risk thresholds for IBI: sensitivity, specificity, negative and positive likelihood ratios (LRs).

Results Of 16 268 patients, 135 (0.8%) had an IBI. The discriminative ability of the model was 0.84 (95% CI 0.81 to 0.88) and 0.78 (95% CI 0.74 to 0.82) in pooled cross-validations. The model performed well for the rule-out threshold of 0.1% (sensitivity 0.97 (95% CI 0.93 to 0.99), negative LR 0.1 (95% CI 0.0 to 0.2) and for the rule-in threshold of 2.0% (specificity 0.94 (95% CI 0.94 to 0.95), positive LR 8.4 (95% CI 6.9 to 10.0)). The intermediate thresholds of 0.1%–2.0% performed poorly (ranges: sensitivity 0.59–0.93, negative LR 0.14–0.57, specificity 0.52–0.88, positive LR 1.9–4.8) and comprised 9784 patients (60%).

Conclusions The rule-out threshold of this model has potential to reduce antibiotic treatment while the rule-in threshold could be used to target treatment in febrile children at the ED. In more than half of patients at intermediate risk, sensitive biomarkers could improve identification of IBI and potentially reduce unnecessary antibiotic prescriptions.

  • epidemiology
  • therapeutics

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Twitter @rgnijman, @CarrolEnitan

  • Correction notice This paper has been amended since it was published online. The data sharing statement has been updated.

  • Contributors Conceptualisation: NNH, DB, RGN, DN, JAH, AB, UvB, EC, IE, ME, MvdF, RdG, BK, EL, IM, FM-T, MP, FS, MT, DZ, WZ, ML, CV, HAM. Data curation: NNH, DB, RGN, JAH, AB, UvB, EC, IE, ME, MvdF, RdG, JAH, BK, EL, IM, FM-T, MP, FS, MT, DZ, WZ, ML, CV, HAM. Formal analysis: NNH, DN. Methodology: NNH, DB, RGN, DN, JAH, AB, UvB, EC, IE, ME, MvdF, RdG, BK, EL, FM-T, DN, MP, MT, DZ, CV, WZ, ML, HAM. Supervision: CV, HAM. Writing—original draft: NNH. Writing—review and editing: NNH, DB, RN, DN, JAH, AB, UvB, EC, IE, ME, MvdF, RdG, BK, EL, IM, FM-T, MP, FS, MT, DZ, WZ, ML, CV, HAM.

  • Funding This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 668303. The research was supported by the National Institute for Health Research Biomedical Research Centres at Imperial College London, Newcastle Hospitals NHS Foundation Trust and Newcastle University.

  • Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests None declared.

  • Patient and public involvement statement The design of the study did not involve patients. The study results will be disseminated to members of the public, patients and experts through social media and networks.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by all the participating hospitals. No informed consent was needed for this study. Austria (Ethikkommission Medizinische Universitat Graz, ID: 28-518 ex 15/16), Germany (Ethikkommission Bei Der LMU München, ID: 699-16), Greece (Ethics committee, ID: 9683/18.07.2016), Latvia (Centrala medicinas etikas komiteja, ID: 14.07.201 6. No. Il 16-07-14), Slovenia (Republic of Slovenia National Medical Ethics Committee, ID: ID: 0120-483/2016-3), Spain (Comité Autonómico de Ética de la Investigación de Galicia, ID: 2016/331), The Netherlands (Commissie Mensgebonden onderzoek, ID: NL58103.091.16), UK (Ethics Committee, ID: 16/LO/1684, IRAS application no. 209035, confidentiality advisory group reference: 16/CAG/0136).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement An anonymized data set containing individual participant data is available in a public data repository: DOI: 10.14469/hpc/7549. For inquiries to obtain the full dataset, please contact the data manager of the PERFORM consortium ( uk).

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.