In de vorige richtlijn is er een belangrijke rol weggelegd voor c-reactive proteïne (CRP) als infectieparameter bij het kind met koorts. In de vorige richtlijn (2013) wordt slechts in enkele specifieke gevallen (o.m. invasieve infecties, kortdurende koorts) een toegevoegde waarde gegeven voor het gebruik van procalcitonine (PCT).

In de klinische praktijk is het belangrijk om tijdig onderscheid te maken tussen een ernstige bacteriële infectie (SBI; o.m. urineweginfectie, gastro-intestinale infectie) en invasieve bacteriële infectie (IBI; o.m. bacteriemie/sepsis, bacteriële meningitis). Het vroegtijdig onderscheid kunnen maken tussen deze twee entiteiten van bacteriële infectie is belangrijk voor de verdere behandeling van het kind.

Er zijn aanwijzingen in de recente literatuur die aantonen dat PCT een betere diagnostische accuratesse heeft dan CRP voor het vaststellen van een invasieve bacteriële infectie. Daar waar de beschikbaarheid en 24/7 aanvraagbaarheid van PCT de laatste jaren is toegenomen, is de inbedding van PCT in de klinische praktijk (bekendheid) nog steeds beperkt.

PCT

CRP

Description of studies

Tripella (2017) performed a systematic review and meta-analysis concerning the diagnostic accuracy of procalcitonin (PCT) for serious bacterial infections (SBI) and invasive bacterial infections (IBI) in children with fever without source. The authors searched Medline for literature published between 2007 and 2017. They included studies performed in children ≤ 18 presenting with fever without source in hospital or ambulatory settings in Western countries, serum concentrations of PCT were obtained as part of the first patient

evaluation and the results reported quantitatively, and the outcomes SBI and/or IBI were defined a priori. Studies that did not report the sensitivity and specificity of PCT were excluded. SBI was defined as a broad spectrum of conditions (e.g., bacterial meningitis, sepsis, bacteremia, urinary tract infections, pneumonia, bacterial gastroenteritis, bone- or soft tissue infections). IBI was defined as a subgroup of most severe bacterial infections (e.g. bacterial meningitis, sepsis, and bacteremia). The methodological quality of included studies was assessed using the QUADAS-2 tool; one study (Freyne, 2013) was excluded because of a high risk of bias in more than 2 domains. Twelve studies (7260 children) were included in the meta-analysis. All included studies were performed in ED settings. The prevalence of SBI/IBI varied between 1.0% and 45.9% in the included studies. The most reported cut-offs for PCT were 0.5 ng/mL (9 studies) and 2 ng/mL (6 studies). In the meta-analyses the pooled estimates of sensitivity and specificity for the cutoffs 0.5 ng/mL and 2 ng/mL were calculated.

Yo (2012) performed a systematic review and meta-analysis concerning the diagnostic accuracy of PCT, C-reactive protein (CRP) and leukocytes for SBI in children presenting to the ED with fever without source. In 2011 the authors searched the Medline, Embase, and Cochrane databases for relevant literature. Studies performed in children aged between 7 days and 36 months, reporting PCT alone or compared to other laboratory markers to detect SBI, and reporting enough data to create 2 by 2 tables were included. The authors did not define SBI a priori, and SBI was defined differently in the included studies, for instance bacteremia, pyelonephritis, lobar pneumonia, and meningitis osteoartritis (Lacour, 2001), or urinary tract infection, bacteremia, cellulitis, sepsis, bacterial gastroenteritis, and pneumonia (Olaciregui, 2009). The methodological quality of included studies was assessed using the QUADAS tool. Eight studies (1883 children) were included in the meta-analysis. All studies reported PCT, six studies reported CRP, and seven studies reported leukocytes. The prevalence of SBI/IBI varied between 3.2% and 29.2% in the included studies. The most reported cut-offs were 0.5 ng/mL for PCT (5 studies), 40 mg/L for CRP (4 studies), and 15000 cells/mm for leukocytes (6 studies). The authors used a bivariate random-effects model to calculate the overall diagnostic accuracy. Subgroup analyses were performed for the most common cut-offs.

Hubert-Dibon (2018) performed a prospective cohort study concerning the diagnostic accuracy of PCT and CRP for SBI in children aged between 6 days and 5 years who presented to a French pediatric ED with fever without source in 2016. The authors defined SBI as invasive bacterial infections, urinary tract infections, bone and joint infections, bacterial gastroenteritis, omphalitis, and cellulitis. They included 1060 children, of whom 127 (11.2%) were diagnosed with an SBI and 11 (1.0%) were diagnosed with an IBI. The median age of the included children was 17 months (IQR 6,6 to 24,3 months), and 52% of the children were boys. The authors reported the cut-offs 0.3, 0.5, 1.0 ng/mL for PCT, and the cut-offs 20 and 40 mg/L for CRP.

Gunduz (2018) performed a prospective cohort study investigating the diagnostic accuracy of PCT (cut-offs 0.58 and 2.0 ng/mL) and CRP (cut-offs 5.7, 20, and 40 mg/L) for SBI in children with fever without source. SBI was defined as sepsis, occult bacteremia, bacterial meningitis, urinary tract infection, pneumonia, septic arthritis, osteomyelitis, or bacterial gastroenteritis. The authors included children aged 3 moths to 17 years who presented to pediatric outpatient clinics in Turkey. In total, 118 children were included, of whom 14 (12%) had an SBI. The mean age of the included children was 40.3 months (SD 40.4 months), and 56% were boys.

Han (2019) performed a retrospective cohort study investigating the diagnostic accuracy of PCT (cut-off 0.5 ng/mL) and CRP (cut-offs 16.74 and 20 mg/L) for SBI in with fever without source. SBI was defined as bacterial meningitis, bacteremia, or urinary tract infection (UTI) in which known pathogens were cultured. Children presenting to a pediatric ED in Korea between July 2016 and June 2018, aged between 29 and 90 days were included. In total, 199 children were included, of whom 68 (34%) were diagnosed with an SBI.

Lee (2018) performed a retrospective cohort study investigating the diagnostic accuracy of PCT (cut-off 0.5ng/mL) and CRP (cut-off 0.5 mg/dL) for SBI in with fever without source. SBI was defined as bacteremia with pathogenic causative organism grown in blood culture; bacterial meningitis with pathological causative organism grown in CSF culture; or UTI with pyuria (WBC>5/high power field) and a single pathologic agent grown to more than 100,000 colony-forming units/mL in urine collected in a urine bag. Children presenting to a pediatric ED or outpatient department in Korea between May 2015 and February 2017, aged between 1 and 3 months were included. The authors included 336 children of whom 38 (11%) had an SBI. The mean age of the included children was 59.5 days (SD 24.5), and 63% were boys.

Park (2021) performed a retrospective cohort study concerning the diagnostic value of PCT in predicting SBI compared to CRP in children aged less than 90 days old with a fever at a single institution pediatric emergency center. Children younger than 3 months of age who presented with fever at the Asan Medical Center pediatric emergency room between January 2017 to June 2018 were included. Cases being transferred to another hospital without examination, when full diagnostic testing was not performed or temporary hyperthermia patients who had exceeded 28 days of age, were in a good general condition, their fever did not exceed 38 °C, and it did not recur after spontaneous resolution without

antipyretics, were excluded. SBI was defined as the isolation of bacterial pathogens from the blood, cerebrospinal fluid, or fecal samples, or urine cultures at 100,000 CFUs/mL. Non-bacterial infection was defined as a case in which a bacterial culture test was negative but another infection such as a viral origin was suspected based on the medical history, and

the viral polymerase chain reaction (PCR) results obtained from each sample were considered. A total of 317 children were included in the analysis, from which 61 (19%) were diagnosed with an SBI. UTI was the most common diagnosis of SBI (55/61; 90%). Median age was 32.0 days (IQR 20.0-67.0) in the SBI group and 30.0 days (IQR 20.0-63.8) in the non-SBI group. In the SBI group, more children were male (75%), compared to the non-SBI group (58%; P=0.013).

Results

1. Procalcitonine

1.1 Serious bacterial infections (SBI)

1.1.1 Diagnostic accuracy: sensitivity and specificity

For PCT cut-off 0.5 ng/mL, Tripella (2017) reported a pooled sensitivity of 55% (95% CI 52 to 58) and a pooled specificity of 85% (95% CI 84 to 86) in detecting SBI from seven studies (Milcent, 2016; Markic, 2015; Nijman, 2014; Mahajan, 2014; Gomez, 2012; Olaciregui, 2009; Andreola, 2007) including 5357 children. For PCT cut-off 2.0 ng/mL, Tripella (2017) reported a pooled sensitivity of 30% (95% CI 27 to 34) and a pooled specificity of 95% (95% CI 94 to 95) for PCT (cut-off 2 ng/mL) in detecting SBI from four studies (Milcent, 2016; Nijman, 2014; Gomez, 2012; Olaciregui, 2009) including 4651 children.

Yo (2012) performed a subgroup analysis including studies with a PCT cut-off of 0.5ng/mL. They reported a pooled sensitivity of 78% (95% CI 68 to 85) and a pooled specificity of 72% (95% CI 59 to 82) for PCT (cut-off 0.5 ng/mL) in detecting SBI from five studies (Galetto-Lacour, 2003; Thayyil, 2005; Andreola, 2007; Olaciregui, 2009; Manzano, 2010) including 1310 children.

Hubert-Dibon (2018) reported a sensitivity 46% (95% CI 37 to 56) and a specificity of 75% (95% CI 71 to 78) for PCT (cut-off 0.5 ng/mL) in detecting SBI.

Lee (2018) reported a sensitivity of 44% (95% CI 28 to 60) and a specificity of 93% (95% CI 89-95) for PCT (cut-off 0.5ng/mL) in detecting SBI.

Han (2019) reported a sensitivity of 40% (95% CI 28 to 52) and a specificity of 98% (95% CI 94 to 100) for PCT (cut-off 0.5ng/mL) in detecting SBI.

In Park (2021), the sensitivity of PCT (cut-off value ≥0.3 ng/mL) in detecting SBI was 54.1 (95% CI not reported). The specificity was 87.5 (95% CI not reported).

1.2 Invasive bacterial infections (IBI)

1.2.1 Diagnostic accuracy: sensitivity and specificity

Tripella (2017) performed separate meta-analysis regarding the diagnostic accuracy of PCT in detecting IBI. They reported a pooled sensitivity of 82% (95% CI 73 to 90) and a pooled specificity of 86% (95% CI 85 to 87) in detecting IBI using PCT (cut-off 0.5 ng/mL) in five studies (Diaz, 2016; Milcent, 2016; Gomez, 2012; Luaces-Dubells, 2012; Olaciregui, 2009) including 4692 children. They reported a pooled sensitivity of 61% (95% CI 49 to 73) and a pooled specificity of 94% (95% CI 93 to 95) in detecting IBI using (cut-off 2 ng/mL) in four studies (Diaz, 2016; Milcent, 2016; Gomez, 2012; Luaces-Dubells, 2012) including 4345 children.

Hubert-Dibon (2018) reported a sensitivity of mL 82% (95% CI 48 to 97) and a specificity of 72% (95% CI 68 to 75) in detecting IBI using PCT (cut-off 0.5 ng/mL).

2. C-reactive protein (CRP)

2.1 Serious bacterial infections (SBI)

2.1.1 Diagnostic accuracy: sensitivity and specificity

Yo (2012) performed a subgroup analysis including studies with a cut-off for CPR of 40 ng/mL. The pooled sensitivity in four studies with a total of 846 children included (Lacour, 2001; Galetto-Lacour, 2003; Andreola, 2007; Guen, 2007) in detecting SBI with a CRP cut-off of 40 ng/mL was 74% (95% CI 58 to 85). The sensitivities reported in the individual studies were, respectively; 89%, 79%, 71%, and 43%. The pooled specificity was 76% (95% CI 68 to 82). The specificities reported in the individual studies were, respectively; 75%, 79%, 81%, and 65%.

Hubert-Dibon (2018) reported a sensitivity of 47% (95% CI 37 to 57) in detecting SBI in 1060 children using a CRP cut-off of 40 mg/L. The specificity was 82% (95% CI 77 to 85).

Gunduz (2018) reported a sensitivity of 36% (95% CI 13 to 65) and a specificity of 94% (95% CI 88 to 98) for CRP (cut-off 40 mg/L) in detecting SBI.

Han (2019) reported a sensitivity of 62% (95% CI 49 to 73) and a specificity of 88% (95% CI 81 to 93) for CRP (cut-off 20 mg/L) in detecting SBI.

In Park (2021), the sensitivity of CRP (cut-off value ≥20 mg/L) in detecting SBI was 49.2 (95% CI not reported). The specificity was 89.5 (95% CI not reported).

2.2 Invasive bacterial infections (IBI)

2.2.1 Diagnostic accuracy: sensitivity and specificity

Hubert-Dibon (2018) reported a sensitivity of 64% (95% CI 32 to 88) in detecting IBI in 1060 children using a CRP cut-off of 20 mg/L. The specificity was 62% (95% CI 58 to 65).

Hubert-Dibon (2018) reported a sensitivity of 64% (95% CI 32 to 88) in detecting IBI in 1060 children using a CRP cut-off of 40 mg/L. The specificity was 78% (95% CI 75 to 81).

3. Leukocytes (WBC)

3.1 Serious bacterial infections (SBI)

3.1.1 Diagnostic accuracy: sensitivity and specificity

Yo (2012) performed a subgroup analysis including studies with a cut-off for WBC of  15000/mm³. The pooled sensitivity in six studies with a total of 1241 children included (Lacour, 2001; Galetto-Lacour, 2003; Thayyil, 2005; Guen, 2007; Olaciregui, 2009; Manzano, 2010) for detecting SBI with a WBC cut-off of 15000/mm was 61% (95% CI 52 to 70). The sensitivities reported in the individual studies were, respectively; 68%, 52%, 50%, 63%, 59% and 71%. The pooled specificity was 72% (95% CI 65 to 77). The specificities reported in the individual studies were, respectively; 77%, 74%, 53%, 66%, 79% and 75% (figure 1).

In Park (2021), the sensitivity of WBC (cut-off value ≤5000 or ≥15,000/µL) in detecting SBI was 45.9 (95% CI not reported). The specificity was 69.1 (95% CI not reported).

Figure 1. Sensitivity and specificity of PCT 0.5 ng/ml, PCT 2.0 ng/ml, CRP 20 mg/L, CRP 40 mg/L and WBC 15000/mm in detecting SBI and IBI

Level of evidence of the literature

The level of evidence regarding diagnostic accuracy of diagnosis serious or invasive bacterial infection started as high (diagnostic studies).

Sensitivity

The level of evidence regarding the outcome sensitivity of SBI for PCT and WBC was downgraded by two levels to GRADE low because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test) and inconsistent results (inconsistency).

The level of evidence regarding the outcome sensitivity of IBI for PCT was downgraded by one level to GRADE Moderate because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test).

The level of evidence regarding the outcome sensitivity of IBI for CRP was downgraded by two level to GRADE low because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test) and imprecision (low number of patients and broad confidence interval).

Specificity

The level of evidence regarding the outcome specificity of SBI for PCT was downgraded by two levels to GRADE Low because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test) and inconsistent results (inconsistency).

The level of evidence regarding the outcome specificity of IBI for WBC was downgraded by one level to GRADE Moderate because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test).

The level of evidence regarding the outcome specificity of IBI for CRP was downgraded by two level to GRADE low because of study limitations (risk of bias due to reference standard; unclear if results of reference test were independently assessed from results of index test) and imprecision (low number of patients and broad confidence interval).

A systematic review of the literature was performed to answer the following question: What is the diagnostic accuracy of biomarkers (PCT, CRP, leukocytes) in diagnosing serious or invasive bacterial infection compared to anamnesis and physical examination in children (2 months to 16 years old) with fever visiting the emergency department?

P: Children (0-16 years) with fever visiting the emergency department, suspected of a serious or invasive bacterial infection

I: Procalcitonin (PCT)

C: Leucocytes, c-reactive protein (CRP)

R: Anamnesis and physical examination, blood culture

O: Diagnostic accuracy of diagnosis serious or invasive bacterial infection

Relevant outcome measures

The guideline development group considered sensitivity as a critical outcome measure for decision making; and specificity as an important outcome measure for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

A priori, the working group did not define a minimal clinically (patient) important difference for diagnostic accuracy outcomes.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until june 22, 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 654 hits. Studies were selected based on the following criteria: systematic reviews or observational studies reporting the diagnostic accuracy of PCT in detecting SBI or IBI. Forty-nine studies were initially selected based on title and abstract screening. After reading the full text, 42 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 7 studies were included.

Results

Seven studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables. Tripella (2017), Yo (2012), and Hubert-Dibon (2018) were included in the guideline Sepsis bij kinderen (Biomarkers). For the current guideline the summary of literature, results, level of evidence of the literature, and conclusions regarding Tripella (2017), Yo (2012), and Hubert-Dibon (2018) were translated into English. The conclusions and level of evidence of the literature sections were updated after inclusion of more recent literature.