Use of Serum Procalcitonin in Evaluation of Febrile Infants: A Meta-analysis of 2317 Patients

doi:10.1016/j.jemermed.2014.07.034

The Journal of Emergency Medicine

Volume 47, Issue 6, December 2014, Pages 682-688

https://doi.org/10.1016/j.jemermed.2014.07.034 Get rights and content

Abstract

Background

Serum procalcitonin (PCT) concentrations have been studied as a diagnostic test for serious bacterial infections (SBIs) in children. However, the utility of a single measurement in the evaluation of SBIs in febrile infants younger than 91 days is not clear.

Objective

Use a systematic review and meta-analysis to determine: 1) the ability of serum PCT concentrations to identify febrile infants < 91 days of age at high and low risk for SBIs, and 2) to compare its utility with available clinical prediction rules.

Methods

The literature search identified studies of febrile infants segregated into risk groups using serum PCT concentrations. Some authors were contacted to provide subgroups < 91 days of age or to provide data with 0.3 ng/mL PCT cutoff values. Data were combined and validated using standard methodologies.

Results

Seven studies encompassing 2317 patients were identified; five of seven studies used a PCT discriminating concentration of 0.3 ng/mL. No heterogeneity or publication bias was identified. The overall relative risk (RR) was 3.97 (95% confidence interval [CI] 3.41–4.62) and was consistent by sensitivity analysis. The RR from a systematic review of clinical prediction rules was 30.6 (95% CI 7.0–68.13) and 8.75 (95% CI 2.29–15.2) for infants untreated and treated with antibiotics, respectively.

Conclusions

Alone, measurement of serum PCT concentrations, though able to identify a group of young infants at risk for SBIs, is inferior to the available clinical prediction rules for identifying young, febrile infants at risk for SBIs. Serum concentrations ≤ 0.3 ng/mL may be helpful as an add-on test to current rules for identifying low-risk, febrile infants.

Introduction

Procalcitonin (PCT), a precursor of the vitamin D regulatory hormone calcitonin, is produced mainly by the liver, but is also produced by the kidney as well as most other tissues during sepsis and infection 1, 2, 3, 4, 5. Induction of PCT synthesis is complex and seems to be dependent on bacterial products, such as lipopolysaccharide, as well as soluble host mediators such as tumor necrosis factor-α, interleukin (IL)-2, and IL-6 2, 6. The observations that PCT mediates release of proinflammatory cytokines from circulating blood cells and that antibody blockade of this prohormone reduces mortality in a septic hamster model suggest a role for PCT in the initial host response to infection 7, 8.

PCT appears in the serum prior to other acute inflammatory markers such as peripheral leukocytes and C-reactive protein (CRP) in children with serious bacterial infections (SBIs) 9, 10. As a result, serum PCT concentrations have been studied as a diagnostic test for neonatal sepsis, severe infection in febrile, neutropenic children, sepsis in adults, and bone and joint infections 11, 12, 13, 14. These studies reported a variety of results. Yu et al., in a meta-analysis of studies focused on neonates, found PCT to have moderate accuracy, with greater specificity than sensitivity (11). Lin et al. used a meta-analysis to evaluate the use of PCT in febrile, neutropenic, pediatric oncology patients and found PCT to be comparable to CRP, with overall higher specificity but lower sensitivity (12). Simon et al., in a meta-analysis comparing PCT and CRP in all age groups with bacterial infections, found PCT to be more accurate than CRP (13). Finally, Shen et al., in a meta-analysis of bone and joint infections from all age groups, found PCT to be more specific than sensitive (14).

The assessment and management of febrile infants < 91 days of age is a vexing problem in pediatrics. These infants, particularly those without focal findings, are at significant risk for SBIs 15, 16. Many of these patients are admitted to the hospital, evaluated for serious infections including meningitis, and treated with parenteral antimicrobial therapy (17). In 1985, Dagan and his colleagues in Rochester developed a clinical prediction rule that successfully separated the population of febrile infants < 91 days of age into high-risk and low-risk for SBI groups; this rule was subsequently validated in a large, prospective study 18, 19. Based on these and other data, a modified version of this clinical prediction rule was recommended to the pediatric community at large as a guideline for the management of this patient population (20). This systematic review and meta-analysis were undertaken to determine: 1) if serum concentrations of PCT in healthy, febrile infants < 91 days of age could discriminate between those infants with SBIs and those without; and 2) if the measurement of serum concentrations of PCT was a superior discriminator to the currently used clinical prediction rules.

Section snippets

Study Identification and Abstraction

The PRISMA protocol was used (21). In September 2012 and again in March 2013, the Medline database dating back to 1966 was searched using PubMed as the primary search engine. Search terms included “procalcitonin,” “infant or neonatal or pediatric,” “infection,” “cohort,” and “observational.” Filters included “infant,” “newborn,” and “neonate.” The bibliographies of the selected studies and review articles were searched for relevant studies.

Study Selection

Included studies met the following criteria:

1.
Studied a

Results

The results of the literature search and culling process are shown in Figure 1. The initial search of Medline and selected bibliographies yielded 158 titles. Seventeen studies met inclusion criteria after abstracts and titles were scanned. Four of these articles were excluded because SBIs were not a reported study outcome 25, 26, 27, 28. Two studies included only subjects at increased risk for infection; two studies failed to report quantitative PCT data; one study did not separate infants < 91

Discussion

The evaluation and management of the febrile infant < 91 days of age is one of the most common yet complex issues in pediatrics. Roberts and Borzy described 61 febrile infants 8 weeks of age or less; 9 of these infants were bacteremic and 23 had an identified focus of infection (15). In a systematic review, Baraff et al. found that 10.5% of 306 febrile infants < 3 months of age had a serious bacterial infection (16). Given this high rate of infection and the inability to clinically

Conclusion

The data from this review suggest that serum PCT concentrations ≤ 0.3 ng/mL identify a population of febrile infants < 91 days of age at low risk for SBIs. Febrile infants with a serum concentration in excess of 0.3 ng/mL have, on average, a 3.97-fold increased risk of SBIs. Recent data suggest that infants who fail to meet standardized, low-risk, clinical criteria for SBI have, at best, an average increased risk of 8.75-fold. These differences are largely the result of the broad range of

References (44)

M. Assicot et al.
High serum procalcitonin concentrations in patients with sepsis and infection
Lancet
(1993)
R. Dagan et al.
Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis
J Pediatr
(1985)
S. Manzano et al.
Impact of procalcitonin on the mangement of children aged 1 to 36 months presenting with fever without source: a randomized controlled trial
Am J Emerg Med
(2010)
S. Bracq et al.
Calcitonin gene expression in normal human liver
FEBS Lett
(1993)
H. Redl et al.
Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin
Crit Care Med
(2000)
M. Mesiner
Pathobiochemistry and clinical use of procalcitoin
Clin Chem Acta
(2002)
N. Morganthaler et al.
Production of procalcitonin (PCT) in non-thyroidal tissue after LPS injection
Horm Metab Res
(2003)
M. Nijsten et al.
Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro
Crit Care Med
(2000)
E. Nylen et al.
Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis
Crit Care Med
(1998)
A. Liappis et al.
Exogenous procalcitonin evokes a pro-inflammatory cytokine response
Inflamm Res
(2011)

A. Galleto-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)

M. Hatherill et al.

Diagnostic markers of infection: comparison of procalcitonin with C-reactive protein and leukocyte count

Arch Dis Child

(1999)

Z. Yu et al.

The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis

Scand J Infect Dis

(2010)

S. Lin et al.

Role of procalcitonin in the diagnosis of severe infection in pediatric patients with fever and neutropenia

Pediatr Infect Dis J

(2012)

L. Simon et al.

Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis

Clin Infect Dis

(2005)

C. Shen et al.

The use of procalcitonin in the diagnosis of bone and joint infection: a systematic review and meta-analysis

Eur J Clin Microbiol Infect Dis

(2013)

K. Roberts et al.

Fever in the first eight weeks of life

Johns Hopkins Med J

(1977)

L. Baraff et al.

Probability of bacterial infections in febrile infants less than three months of age: a meta-analysis

Pediatr Infect Dis J

(1992)

K. Roberts

Management of young, febrile infants. Primum non nocere revisited

Am J Dis Child

(1983)

J. Jaskiewicz et al.

Febrile infants at low risk for serious bacterial infection-an appraisal of the Rochester criteria and implications for management. Febrile infant collaborative study group

Pediatrics

(1994)

L. Baraff et al.

Practice guideline for the managment of infants and children 0 to 36 months of age with fever without source

Pediatrics

(1993)

PRISMA: Transparent reporting of systematic reviews and meta-analyses

The PRISMA Checklist

(2009)

Cited by (31)

Diagnostic test accuracy of procalcitonin and C-reactive protein for predicting invasive and serious bacterial infections in young febrile infants: a systematic review and meta-analysis
2024, The Lancet Child and Adolescent Health
Febrile infants presenting in the first 90 days of life are at higher risk of invasive and serious bacterial infections than older children. Modern clinical practice guidelines, mostly using procalcitonin as a diagnostic biomarker, can identify infants who are at low risk and therefore suitable for tailored management. C-reactive protein, by comparison, is widely available, but whether C-reactive protein and procalcitonin have similar diagnostic accuracy is unclear. We aimed to compare the test accuracy of procalcitonin and C-reactive protein in the prediction of invasive or serious bacterial infections in febrile infants.
For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Web of Science, and The Cochrane Library for diagnostic test accuracy studies up to June 19, 2023, using MeSH terms “procalcitonin”, and “bacterial infection” or “fever” and keywords “invasive bacterial infection*” and “serious bacterial infection*”, without language or date restrictions. Studies were selected by independent authors against eligibility criteria. Eligible studies included participants aged 90 days or younger presenting to hospital with a fever (≥38°C) or history of fever within the preceding 48 h. The primary index test was procalcitonin, and the secondary index test was C-reactive protein. Test kits had to be commercially available, and test samples had to be collected upon presentation to hospital. Invasive bacterial infection was defined as the presence of a bacterial pathogen in blood or cerebrospinal fluid, as detected by culture or quantitative PCR; authors' definitions of serious bacterial infection were used. Data were extracted from selected studies, and the detection of invasive or serious bacterial infections was analysed with two models for each biomarker. Diagnostic accuracy was determined against internationally recognised cutoff values (0·5 ng/mL for procalcitonin, 20 mg/L for C-reactive protein) and pooled to calculate partial area under the curve (pAUC) values for each biomarker. Optimum cutoff values were identified for each biomarker. This study is registered with PROSPERO, CRD42022293284.
Of 734 studies derived from the literature search, 14 studies (n=7755) were included in the meta-analysis. For the detection of invasive bacterial infections, pAUC values were greater for procalcitonin (0·72, 95% CI 0·56–0·79) than C-reactive protein (0·28, 0·17–0·61; p=0·016). Optimal cutoffs for detecting invasive bacterial infections were 0·49 ng/mL for procalcitonin and 13·12 mg/L for C-reactive protein. For the detection of serious bacterial infections, procalcitonin and C-reactive protein had similar pAUC values (0·55, 0·44–0·69 vs 0·54, 0·40–0·61; p=0·92). For serious bacterial infections, the optimal cutoffs for procalcitonin and C-reactive protein were 0·17 ng/mL and 16·18 mg/L, respectively. Heterogeneity was low for studies investigating the test accuracy of procalcitonin in detecting invasive bacterial infection (I²=23·5%), high for studies investigating procalcitonin for serious bacterial infection (I²=75·5%), and moderate for studies investigating C-reactive protein for invasive bacterial infection (I²=49·5%) and serious bacterial infection (I²=28·3%). The absence of a single definition of serious bacterial infection across studies was the greatest source of interstudy variability and potential bias.
Within a large cohort of febrile infants, a procalcitonin cutoff of 0·5 ng/mL had a superior pAUC value to a C-reactive protein cutoff of 20 mg/L for identifying invasive bacterial infections. In settings without access to procalcitonin, C-reactive protein should therefore be used cautiously for the identification of invasive bacterial infections, and a cutoff value below 20 mg/L should be considered. C-reactive protein and procalcitonin showed similar test accuracy for the identification of serious bacterial infection with internationally recognised cutoff values. This might reflect the challenges involved in confirming serious bacterial infection and the absence of a universally accepted definition of serious bacterial infection.
None.
How to predict serious bacterial infections in young febrile infants in the emergency department?
2019, Pediatrics and Neonatology
Associations of Neighborhood-Level Social Determinants of Health with Bacterial Infections in Young, Febrile Infants
2018, Journal of Pediatrics
Citation Excerpt :
A deeper understanding of these relationships might not only facilitate improved predictive strategies for bacterial infection, but may also contribute to the development of preventive interventions. Many studies have sought to identify unique biomarkers to aid in more accurate recognition and prediction of bacterial infections among young febrile infants including white blood cell count, proportion of bands, absolute neutrophil count, procalcitonin, and C-reactive protein.13,17,22,25,27-30,67,80-82 This important work has enhanced the care of young, febrile infants.
To examine the sociodemographic characteristics of one population of young, febrile infants and identify associations between neighborhood-level social determinants of health (SDHs) with bacterial infections.
This was a retrospective cross sectional study of all infants ≤90 days old with a temperature of ≥38°C who presented in 2014 to the emergency department of an urban children's hospital in a large east coast city. The primary outcome was the presence of a bacterial infection, defined as a positive urine, blood, or cerebrospinal fluid culture that was treated clinically as a pathogen. The home address of each infant was geocoded and linked to neighborhood data based on census tract. Neighborhood-level SDHs included deprivation index, median household income, poverty, childhood poverty, social capital, and crowded housing. Associations were estimated using generalized estimating equations and negative binomial regression analysis. Models were adjusted for age, prematurity, and race/ethnicity.
Of 232 febrile infants, the median age was 54 days, 58% were male, 49% were Hispanic, and 88% had public health insurance; 31 infants (13.4%) had a bacterial infection. In the adjusted analyses, the risk of bacterial infection among infants from neighborhoods with high rates of childhood poverty was >3 times higher (relative risk, 3.16; 95% CI, 1.04-9.6) compared with infants from neighborhoods with low rates of childhood poverty.
Our findings suggest that SDHs may be associated with bacterial infections in young, febrile infants. If confirmed in subsequent studies, the inclusion of SDHs in predictive tools may improve accuracy in detecting bacterial infections among young, febrile infants.
Advances in the Diagnosis and Management of Febrile Infants: Challenging Tradition
2018, Advances in Pediatrics
Citation Excerpt :
There has been reluctance by academic institutions to abandon support for longstanding models of care that recommend extensive diagnostic testing and hospitalizations. The iatrogenic consequences of this approach were documented in a classic article by DeAngelis and colleagues [1] 35 years ago, followed by an extensive body of work seeking a less intensive approach for low-risk infants [2–20]. There is growing evidence that physicians in office practices and emergency departments (EDs) are not adhering to the older models [11,21–23].
Laboratory Manifestations of Infectious Diseases
2018, Principles and Practice of Pediatric Infectious Diseases
Reduction in procalcitonin level and outcome in critically ill children with severe sepsis/septic shock—A pilot study
2016, Journal of Critical Care
Citation Excerpt :
We prospectively evaluated the change in PCT level as a prognostic indicator in children with severe sepsis and septic shock and found that a significant reduction in PCT is associated with a favorable outcome. Several studies in children have evaluated the role of PCT to differentiate bacterial infections from other causes of fever [1-5]. Procalcitonin has consistently performed better than C-reactive protein in this scenario, but has its limitations.
To investigate if reduction in procalcitonin (PCT) provides useful information about 28-day mortality in children with severe sepsis or septic shock.
Design: Prospective observational study. Setting: Mixed adult-pediatric intensive care unit in a teaching hospital. Subjects: Children up to 18 years of age admitted with severe sepsis or septic shock between March 2011 and June 2013. Procalcitonin measured using electrochemiluminescence immunoassay on the day of admission with sepsis (D0) and 72-96 hours later (D4). Reduction in PCT from D0 to D4 correlated with the primary outcome, that is, 28-day mortality.
Twenty-five children of median age of 14 years (range, 6-18 years) were included, but 5 died before D4 after admission. Six of the remaining 20 children died between D4 and D28, and 14 survived to D28. At admission, the median of the Pediatric Risk of Mortality III score was 10 (interquartile range [IQR], 5-16) and that of the Sequential Organ Failure Assessment score was 11 (IQR, 7-15). The median PCT level was 9.7 ng/mL on D0 (n = 25) and 3.3 ng/mL on D4 (n = 20). On D0, the median PCT level was 25.0 ng/mL in the 14 survivors and 8.4 ng/mL in the 11 nonsurvivors (P = .075). On D4, the median PCT level was 3.1 ng/mL in the 14 survivors and 4.5 ng/mL in the 6 nonsurvivors who lived to D4 (P = .71); the reduction in PCT (D0 minus D4) was 17.3 ng/mL (IQR, 3.5-38.0 ng/mL) in the survivors and −1.1 ng/mL (IQR, −24.9 to 8.6 ng/mL) in the 6 nonsurvivors (P = .017). Percent reduction in PCT (100 * [D0 − D4]/D0) was 75.5% (IQR, 54.8%-80.7%) in the survivors and −200.3% (IQR, −937.8% to 42.4%) in the 6 nonsurvivors (P = .006).
This small pilot study suggests that further studies are indicated to determine whether children with severe sepsis or septic shock are less likely to die if they have a reduction in PCT more than 50% in the first 4 days in intensive care.

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Clinical Laboratory in Emergency MedicineUse of Serum Procalcitonin in Evaluation of Febrile Infants: A Meta-analysis of 2317 Patients

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study Identification and Abstraction

Study Selection

Results

Discussion

Conclusion

Lancet

J Pediatr

Am J Emerg Med

Calcitonin gene expression in normal human liver

FEBS Lett

Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin

Crit Care Med

Pathobiochemistry and clinical use of procalcitoin

Clin Chem Acta

Production of procalcitonin (PCT) in non-thyroidal tissue after LPS injection

Horm Metab Res

Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro

Crit Care Med

Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis

Crit Care Med

Exogenous procalcitonin evokes a pro-inflammatory cytokine response

Inflamm Res

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

Pediatrics

Diagnostic markers of infection: comparison of procalcitonin with C-reactive protein and leukocyte count

Arch Dis Child

The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis

Scand J Infect Dis

Role of procalcitonin in the diagnosis of severe infection in pediatric patients with fever and neutropenia

Pediatr Infect Dis J

Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis

Clin Infect Dis

The use of procalcitonin in the diagnosis of bone and joint infection: a systematic review and meta-analysis

Eur J Clin Microbiol Infect Dis

Fever in the first eight weeks of life

Johns Hopkins Med J

Probability of bacterial infections in febrile infants less than three months of age: a meta-analysis

Pediatr Infect Dis J

Management of young, febrile infants. Primum non nocere revisited

Am J Dis Child

Febrile infants at low risk for serious bacterial infection-an appraisal of the Rochester criteria and implications for management. Febrile infant collaborative study group

Pediatrics

Practice guideline for the managment of infants and children 0 to 36 months of age with fever without source

Pediatrics

PRISMA: Transparent reporting of systematic reviews and meta-analyses

The PRISMA Checklist

Clinical Laboratory in Emergency Medicine
Use of Serum Procalcitonin in Evaluation of Febrile Infants: A Meta-analysis of 2317 Patients