Pediatrics/original research
Comparison of the Test Characteristics of Procalcitonin to C-Reactive Protein and Leukocytosis for the Detection of Serious Bacterial Infections in Children Presenting With Fever Without Source: A Systematic Review and Meta-analysis

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Study objective

We determine the usefulness of the procalcitonin for early identification of young children at risk for severe bacterial infection among those presenting with fever without source.

Methods

The design was a systematic review and meta-analysis of diagnostic studies. Data sources were searches of MEDLINE and EMBASE in April 2011. Included were diagnostic studies that evaluated the diagnostic value of procalcitonin alone or compared with other laboratory markers, such as C-reactive protein or leukocyte count, to detect severe bacterial infection in children with fever without source who were aged between 7 days and 36 months.

Results

Eight studies were included (1,883 patients) for procalcitonin analysis, 6 (1,265 patients) for C-reactive protein analysis, and 7 (1,649 patients) for leukocyte analysis. The markers differed in their ability to predict serious bacterial infection: procalcitonin (odds ratio [OR] 10.6; 95% confidence interval [CI] 6.9 to 16.0), C-reactive protein (OR 9.83; 95% CI 7.05 to 13.7), and leukocytosis (OR 4.26; 95% CI 3.22 to 5.63). The random-effect model was used for procalcitonin analysis because heterogeneity across studies existed. Overall sensitivity was 0.83 (95% CI 0.70 to 0.91) for procalcitonin, 0.74 (95% CI 0.65 to 0.82) for C-reactive protein, and 0.58 (95% CI 0.49 to 0.67) for leukocyte count. Overall specificity was 0.69 (95% CI 0.59 to 0.85) for procalcitonin, 0.76 (95% CI 0.70 to 0.81) for C-reactive protein, and 0.73 (95% CI 0.67 to 0.77) for leukocyte count.

Conclusion

Procalcitonin performs better than leukocyte count and C-reactive protein for detecting serious bacterial infection among children with fever without source. Considering the poor pooled positive likelihood ratio and acceptable pooled negative likelihood ratio, procalcitonin is better for ruling out serious bacterial infection than for ruling it in. Existing studies do not define how best to combine procalcitonin with other clinical information.

Introduction

Fever is a common reason for pediatric visits to the emergency department (ED). Although the majority of patients have minor bacterial or viral infections, it is important to recognize those having serious bacterial infections to provide appropriate care with antibiotics and early hospitalization.1, 2

After history-taking and physical examination, it is estimated that 20% of febrile infants and young children receive a diagnosis of fever without an apparent source of infection.3 Of these, about 20% may have severe bacterial infection, such as lobar pneumonia, bacteremia, bacterial meningitis, pyelonephritis, or urinary tract infection.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 After the introduction of an effective Hib and PCV7 vaccine, the rate of severe bacterial infection decreased dramatically, with occult bacteremia rates now ranging from 0.02% to 0.7%.20 However, given the serious outcomes of missed diagnoses, this is still a great diagnostic challenge for clinicians. The risk is greatest among infants and children younger than 36 months, making proper diagnosis and management paramount. For decades, investigators have attempted to find clinical or laboratory markers that can accurately differentiate severe bacterial infection from localized or viral infections in young children with fever without source21, 22, 23, 24, 25, 26, 27, 28; unfortunately, no single, ideal marker has been identified.7, 10, 12, 13, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39

The WBC count is routinely recommended as an initial screening marker in children with fever without source. C-reactive protein has been thought to be a more sensitive and specific biomarker than leukocyte count40, 41; in addition, procalcitonin, the prohormone of calcitonin, has been shown to distinguish bacterial from viral infections and to correlate well with clinical severity.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 39, 42, 43 In healthy individuals, circulating levels of procalcitonin are generally very low but can increase by hundreds- to thousands-fold within 4 to 6 hours in response to systemic bacterial infection. During the last decade, numerous studies have evaluated the accuracy of procalcitonin as a marker of severe bacterial infection in children with fever without source, and most compared it with C-reactive protein or leukocyte count. The purpose of this study was to quantitatively summarize, by means of a meta-analysis, all existing evidence in the literature from such reports.

Section snippets

Materials and Methods

We adhered to the methods and procedures of the Cochrane Collaboration44 and the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines45 for reporting systematic reviews.

We performed a comprehensive search of the MEDLINE, EMBASE, and Cochrane databases for pertinent studies published since inception to April 2011. Procalcitonin has not yet been listed as a Medical Subject Headings term, so for our initial search, we used “procalcitonin” as the text word, and we did not

Results

Our search yielded 1,856 citations, 181 of which were retrieved for full-text review. Of these, 173 articles were excluded, mainly because related exposure or outcomes were not studied or reported (Figure 1). A total of 8 citations were selected for our meta-analysis, 6 citations of which included analysis of C-reactive protein levels and 7 citations for leukocyte counts. In total, we included 1,883 patients tested for procalcitonin, 1,265 patients tested for C-reactive protein, and 1,649

Limitations

Several limitations must be considered when interpreting the findings of this meta-analysis. By pooling studies dealing with a variety of sample types, clinical settings, and study populations, we may have introduced heterogeneity. Hence, the results of this meta-analysis are applicable mainly to febrile children with fever without source who present to the ED. We conducted multiple comparisons for meta-analysis or subgroup analysis, but the number of studies was too small to protect from type

Discussion

The prevalence of severe bacterial infection in children with fever without source who are younger than 3 years is approximately 20%.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Differentiating the majority of patients who will have a benign course from those who have serious infections poses a great challenge to front-line clinicians. Missed diagnoses may cause delayed administration of antibiotics, potentially having long-term effects on morbidity and mortality. Procalcitonin is a

References (52)

  • L.J. Baraff

    Management of infants and young children with fever without source

    Pediatr Ann

    (2008)
  • S. Kuzmanović et al.

    [Fever without a focus in children 0-36 months of age]

    Med Pregl

    (2006)
  • A.G. Lacour et al.

    Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs

    Eur J Pediatr

    (2001)
  • A. Galetto-Lacour et al.

    Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center

    Pediatrics

    (2003)
  • S. Thayyil et al.

    Is procalcitonin useful in early diagnosis of serious bacterial infections in children?

    Acta Paediatr

    (2005)
  • B. Andreola et al.

    Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department

    Pediatr Infect Dis J

    (2007)
  • C.G. Guen et al.

    Contribution of procalcitonin to occult bacteraemia detection in children

    Scand J Infect Dis

    (2007)
  • V. Maniaci et al.

    Procalcitonin in young febrile infants for the detection of serious bacterial infections

    Pediatrics

    (2008)
  • I. Olaciregui et al.

    Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin

    Arch Dis Child

    (2009)
  • A. Galetto-Lacour et al.

    Validation of a laboratory risk index score for the identification of severe bacterial infection in children with fever without source

    Arch Dis Child

    (2010)
  • A.G. Lacour et al.

    A score identifying serious bacterial infections in children with fever without source

    Pediatr Infect Dis J

    (2008)
  • H.A. Kadish et al.

    Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered?

    Clin Pediatr (Phila)

    (2000)
  • S.E. Bleeker et al.

    Validating and updating a prediction rule for serious bacterial infection in patients with fever without source

    Acta Paediatr

    (2007)
  • G. Garra et al.

    Reappraisal of criteria used to predict serious bacterial illness in febrile infants less than 8 weeks of age

    Acad Emerg Med

    (2005)
  • A.L. Hsiao et al.

    Incidence and predictors of serious bacterial infections among 57- to 180-day-old infants

    Pediatrics

    (2006)
  • B.W. Trautner et al.

    Prospective evaluation of the risk of serious bacterial infection in children who present to the emergency department with hyperpyrexia (temperature of 106 degrees F or higher)

    Pediatrics

    (2006)
  • Publication date: Available online August 22, 2012.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.

    Please see page 592 for the Editor's Capsule Summary of this article.

    Supervising editor: Gregory J. Moran, MD

    Author contributions: C-HY, J-YW, and C-CL were responsible for study concept and design. C-HY, P-SH, S-HL, S-SC, K-CT, and C-CL were responsible for acquisition of data. C-HY, P-SH, S-HL, J-YW, and C-CL were responsible for analysis and interpretation of data. C-HY and C-CL were responsible for drafting the article. K-CT and C-CL were responsible for critical revision of the article for important intellectual content. C-HY, P-SH, and C-CL were responsible for statistical analysis. C-CL takes responsibility for the paper as a whole.

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