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External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children
  1. Alexander James Martin1,2,
  2. Fabian Johannes Stanislaus van der Velden1,2,
  3. Ulrich von Both3,
  4. Maria N Tsolia4,
  5. Werner Zenz5,
  6. Manfred Sagmeister5,
  7. Clementien Vermont6,
  8. Gabriella de Vries1,6,
  9. Laura Kolberg3,
  10. Emma Lim2,7,
  11. Marko Pokorn8,9,
  12. Dace Zavadska10,
  13. Federico Martinón-Torres11,
  14. Irene Rivero-Calle11,
  15. Nienke N Hagedoorn6,
  16. Effua Usuf12,
  17. Luregn Schlapbach13,
  18. Taco W Kuijpers14,
  19. Andrew J Pollard15,
  20. Shunmay Yeung16,
  21. Colin Fink17,
  22. Marie Voice17,
  23. Enitan Carrol18,
  24. Philipp K A Agyeman19,
  25. Aakash Khanijau18,20,
  26. Stephane Paulus15,
  27. Tisham De21,
  28. Jethro Adam Herberg21,
  29. Michael Levin21,
  30. Michiel van der Flier22,
  31. Ronald de Groot22,
  32. Ruud Nijman23,24,
  33. Marieke Emonts1,2,25
  34. on behalf of the PERFORM consortium
    1. 1 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
    2. 2 Paediatric Immunology, Infectious Diseases and Allergy, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
    3. 3 Department of Pediatrics, Division of Paediatric Infectious Diseases, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
    4. 4 2nd Department of Pediatrics, 'P. and A. Kyriakou' Chlidren's Hospital, National and Kapodistrian University of Athens, Athens, Greece
    5. 5 Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria
    6. 6 Department of Paediatrics, Division of Infectious Diseases and Immunology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands
    7. 7 Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
    8. 8 Department of Infectious Diseases, University Medical Centre Ljubljana, Univerzitetni, Klinični, Ljubljana, Slovenia
    9. 9 Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
    10. 10 Department of Pediatrics, Rīgas Universitāte, Children’s Clinical University Hospital, Riga, Latvia
    11. 11 Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
    12. 12 Disease Control and Elimination, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, UK
    13. 13 Neonatal and Pediatric Intensive Care Unit, Children’s Research Center, University Children’s Hospital Zürich, Zürich, Switzerland
    14. 14 Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam University Medical Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    15. 15 Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK
    16. 16 Clinical Research Department, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK
    17. 17 Micropathology Ltd, University of Warwick Science Park, Warwick, UK
    18. 18 Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
    19. 19 Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
    20. 20 Alder Hey Children's NHS Foundation Trust, Liverpool, UK
    21. 21 Section of Paediatric Infectious Disease, Wright-Fleming Institute, Imperial College London, London, UK
    22. 22 Paediatric Infectious Diseases and Immunology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
    23. 23 Department of Paediatric Emergency Medicine, St. Mary's Hospital, Imperial College NHS Healthcare Trust, London, UK
    24. 24 Faculty of Medicine, Department of Infectious Diseases, Section of Paediatric Infectious Diseases, Imperial College London, London, UK
    25. 25 NIHR Newcastle Biomedical Research Centre, based at Newcastle upon Tyne Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK
    1. Correspondence to Professor Marieke Emonts, Paediatric Immunology, Infectious Diseases & Allergy, Newcastle upon Tyne Hospitals NHS Foundation Trust, Great North Children's Hospital, Newcastle Upon Tyne, UK; marieke.emonts{at}


    Objective To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children.

    Design International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM).

    Setting Fifteen teaching hospitals in nine European countries.

    Participants Febrile immunocompromised children aged 0–18 years.

    Methods The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated.

    Results Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25).

    Conclusion Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group.

    • Paediatrics
    • Paediatric Emergency Medicine
    • Infectious Disease Medicine
    • Allergy and Immunology

    Data availability statement

    Data are available upon reasonable request. Contact corresponding author.

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    Data are available upon reasonable request. Contact corresponding author.

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    • Twitter @CarrolEnitan, @rgnijman, @mariekeemonts

    • AJM and FJSvdV contributed equally.

    • RN and ME contributed equally.

    • Collaborators For the full list of collaborators see the online supplemental file.

    • Contributors AJM wrote the original manuscript, performed the statistical analysis and contributed to preparing the database and recruitment. FJSvdV reviewed the manuscript and was responsible for the study dataset and data quality control. GdV was involved in the preparation of the database and patient recruitment. UvB, MNT, WZ, CV, LK, EL, MP, DZ, FM-T, IR-C, NNH, EU, LS, TWK, AJP, SY, CF, MV, EC, PKAA, AK, SP, JAH, ML, MvdF, RdG, RN and ME were responsible for the conduct of the PERFORM study and patient recruitment for their respective sites. TD was responsible for the digital database system and its maintenance. RN and ME supervised the project. ME acts as guarantor. All authors reviewed and approved the final manuscript.

    • Funding This project received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 668303. RN is funded by an NIHR academic clinical lectureship award (ACL-2018-21-007). UK enrolment was supported by NIHR Biomedical Research Centres at Imperial College London and Newcastle.

    • Competing interests None declared.

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

    • 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.

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