A Novel Framework for Phenotyping Children With Suspected or Confirmed Infection for Future Biomarker Studies

The PERFORM consortium (Personalized Risk assessment in febrile children to optimize Real-life Management across the European Union)

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Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination. Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” classification; summary AUC for PCT was 0.77 (95% CI 0.72–0.82) vs. 0.70 (95% CI 0.65–0.75); for NGAL this was 0.80 (95% CI 0.69–0.91) vs. 0.70 (95% CI 0.58–0.81); for resistin this was 0.68 (95% CI 0.61–0.75) vs. 0.64 (0.58–0.69) The three biomarkers combined had summary AUC of 0.83 (0.77–0.89) for “definite bacterial” vs. “definite viral” infections and 0.71 (0.67–0.74) for “SBI” vs. “non-SBI.” Conclusion: Biomarkers of bacterial infection were strongly associated with the diagnostic categories using the PERFORM classification system in five independent cohorts. Our proposed algorithm provides a novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies.

Original languageEnglish
Article number688272
Number of pages18
JournalFrontiers in Pediatrics
Publication statusPublished - 28 Jul 2021

Bibliographical note

Funding Information:
This project has received funding from the European Union’s
Horizon 2020 research and innovation program under grant
agreement No. 668303. RN was awarded a National Institute
of Health Research Academic Clinical Lectureship (CL-2018-
21-007), enabling this work. The studies from Alder Hey were
funded by National Institute of Health Research Liverpool
Biomedical Research Centre in Microbial Diseases, the Alder
Hey Charity (PICU) and National Institute for Health Research
Research for Innovation, Speculation and Creativity Programme
grant RC-PG-0309-10053 (EC). The study from St. Mary’s
hospital was supported by the Imperial College Comprehensive
Biomedical Research Centre (DMPED P26077 to JH); the
Wellcome Trust Centre for Respiratory Infection at Imperial
College; and the Southampton NIHR Wellcome Trust Clinical
Research Facility and NIHR Wessex Local Clinical Research
Network. The studies from the Erasmus ED and Maasstad
ED cohorts were funded by ZonMW, a Dutch organization
for health research and development, and Erasmus MC
Doelmatigheid. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of
the manuscript.

Publisher Copyright:
© Copyright © 2021 Nijman, Oostenbrink, Moll, Casals-Pascual, von Both, Cunnington, De, Eleftheriou, Emonts, Fink, van der Flier, de Groot, Kaforou, Kohlmaier, Kuijpers, Lim, Maconochie, Paulus, Martinon-Torres, Pokorn, Romaine, Calle, Schlapbach, Smit, Tsolia, Usuf, Wright, Yeung, Zavadska, Zenz, Levin, Herberg, Carrol and the PERFORM consortium (Personalized Risk assessment in febrile children to optimize Real-life Management across the European Union).

Research programs

  • EMC MM-04-54-08-A


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