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Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review

BMJ 2011; 342 doi: (Published 08 June 2011) Cite this as: BMJ 2011;342:d3082
  1. Ann Van den Bruel, academic clinical lecturer1,
  2. Matthew J Thompson, associate professor12,
  3. Tanya Haj-Hassan, medical student3,
  4. Richard Stevens, senior statistician1,
  5. Henriette Moll, professor4,
  6. Monica Lakhanpaul, senior lecturer5,
  7. David Mant, emeritus professor1
  1. 1Department of Primary Health Care, University of Oxford, UK
  2. 2Department of Family Medicine, Oregon Health and Sciences University, USA
  3. 3University of Oxford, UK
  4. 4Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands
  5. 5Health Education Research and Development Unit, Department of Medical and Social Care Education, University of Leicester, UK
  1. Correspondence to: A Van den Bruel ann.vandenbruel{at}
  • Accepted 6 April 2011


Objective To collate all available evidence on the diagnostic value of laboratory tests for the diagnosis of serious infections in febrile children in ambulatory settings.

Design Systematic review.

Data sources Electronic databases, reference tracking, and consultation with experts.

Study selection Studies were selected on six criteria: design (studies of diagnostic accuracy or deriving prediction rules), participants (otherwise healthy children and adolescents aged 1 month to 18 years), setting (first contact ambulatory care), outcome (serious infection), features assessed (in first contact care), and data reported (sufficient to construct a 2×2 table).

Data extraction Quality assessment was based on the quality assessment tool of diagnostic accuracy studies (QUADAS) criteria. Meta-analyses were done using the bivariate random effects method and hierarchical summary receiver operating characteristic curves for studies with multiple thresholds.

Data synthesis None of the 14 studies identified were of high methodological quality and all were carried out in an emergency department or paediatric assessment unit. The prevalence of serious infections ranged from 4.5% to 29.3%. Tests were carried out for C reactive protein (five studies), procalcitonin (three), erythrocyte sedimentation rate (one), interleukins (two), white blood cell count (seven), absolute neutrophil count (two), band count (three), and left shift (one). The tests providing most diagnostic value were C reactive protein and procalcitonin. Bivariate random effects meta-analysis (five studies, 1379 children) for C reactive protein yielded a pooled positive likelihood ratio of 3.15 (95% confidence interval 2.67 to 3.71) and a pooled negative likelihood ratio of 0.33 (0.22 to 0.49). To rule in serious infection, cut-off levels of 2 ng/mL for procalcitonin (two studies, positive likelihood ratio 13.7, 7.4 to 25.3 and 3.6, 1.4 to 8.9) and 80 mg/L for C reactive protein (one study, positive likelihood ratio 8.4, 5.1 to 14.1) are recommended; lower cut-off values of 0.5 ng/mL for procalcitonin or 20 mg/L for C reactive protein are necessary to rule out serious infection. White blood cell indicators are less valuable than inflammatory markers for ruling in serious infection (positive likelihood ratio 0.87-2.43), and have no value for ruling out serious infection (negative likelihood ratio 0.61-1.14). The best performing clinical decision rule (recently validated in an independent dataset) combines testing for C reactive protein, procalcitonin, and urinalysis and has a positive likelihood ratio of 4.92 (3.26 to 7.43) and a negative likelihood ratio of 0.07 (0.02 to 0.27).

Conclusion Measuring inflammatory markers in an emergency department setting can be diagnostically useful, but clinicians should apply different cut-off values depending on whether they are trying to rule in or rule out serious infection. Measuring white blood cell count is less useful for ruling in serious infection and not useful for ruling out serious infection. More rigorous studies are needed, including studies in primary care, to assess the value of laboratory tests alongside clinical diagnostic measurements, including vital signs.


  • We thank Jason Oke for advice on statistical programming and Vanja Dukic for her help with the extended bivariate meta-analysis. ERNIE is an acronym for the European Research Network on recognising serious InfEction. The principal ERNIE investigators are: Marjolein Berger, Frank Buntinx, Tanya Haj-Hassan, Monica Lakhanpaul, David Mant, Henriette Moll, Rianne Oostenbrink, Richard Stevens, Matthew Thompson, Ann Van den Bruel, and Jan Verbakel.

  • Contributors: AVDB conceived the study, carried out the literature search and analysis, and drafted the manuscript. AVDB is guarantor for the study. MJT conceived the study, carried out the literature search and analysis, and commented on the manuscript. TH-H carried out the literature search and analysis, and co-drafted the manuscript. RS carried out some specific analyses and commented on the manuscript. HM and ML assisted in the literature search and analysis and commented on the manuscript. DM conceived the study, carried out the analysis, and co-drafted the manuscript.

  • Funding: This study was funded by the Health Technology Assessment project 07/37/05 (Systematic review and validation of clinical prediction rules for identifying children with serious infections in emergency departments and urgent-access primary care) and the National Institute for Health Research’s National School for Primary Care Research.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Copyright: This work was funded by the Health Technology Assessment and is therefore subject to standard arrangements for use of Crown copyright material by other organisations.

  • Data sharing: No additional data available.

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