Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis

Sepsis is an on-going clinical problem, and a leading cause of death in adults and children. It has been defined as a systemic inflammatory response syndrome (SIRS) caused by bloodstream infections [1, 2] or, more recently, as life-threatening organ dysfunction caused by a deregulated host response to infection [3].

Several inflammatory mediators are involved in the pathogenesis of sepsis: coagulation, innate and adaptive immune response, intermediary metabolism products, all together interacting and leading to this abnormal response [4].

SIRS may not only be determined by infections but also non-infectious causes, such as autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery procedures. SIRS in paediatrics is defined by at least two of the following parameters, one of which must be abnormal temperature or leukocyte count: hyperthermia or hypothermia (>38.5 °C or <36 °C), tachycardia (defined as a mean heart rate more than two standard deviations above normal for age) or bradycardia for children less than 1 year old (defined as a mean heart rate < 10th percentile for age), tachypnea (mean respiratory rate more than two standard deviations above normal for age), leukocyte count elevated or depressed for age, or >10% immature neutrophils [5].

Sepsis has been categorized in the neonatal period as early onset sepsis (EOS) and late onset sepsis (LOS) if occurring in the first 72 h after birth or later. The main risk factors and the pathogens associated are different, being in EOS chorioamnionitis, bacterial colonization of the birth canal, Group B streptococci (GBS) and Escherichia coli; in LOS healthcare acquired infections, preterm delivery and Coagulase negative streptococci [6].

The diagnosis of sepsis is made in children with SIRS in presence of a proven infection by a positive blood culture, or probable infection by a complete and often a posteriori review of clinical, laboratory and radiological data [2, 4, 5]. Blood culture is currently the reference standard for the confirmation of the diagnosis of sepsis. However, even if it represents a fundamental tool for the etiologic diagnosis and for the establishment of a targeted therapy, it has important and significant limitations, such as the time delay in obtaining results and a high percentage of false negatives [7, 8]. Delay in antibiotic treatment of infected children is associated with a significant risk in terms of mortality and morbidity [6].

Biomarkers can play an important role in providing a timely diagnosis of sepsis, helping the differential diagnosis with non-infectious SIRS and the decision-making in the initial management. In paediatrics, the most frequently employed biomarker to differentiate sepsis from non-infectious SIRS is the C-reactive protein (CRP), which, however, is highly non-specific and has an unfavourable kinetics [9]. Among the different molecules investigated as biomarkers of sepsis, procalcitonin (PCT) seems to be one of the most promising [10‐12]. PCT is a 116-aminoacids pro-hormone, physiologically produced by thyroid C-cells as precursor of calcitonin, an acute phase protein secreted by several tissues in response to various endogenous and exogenous stimuli such as cytokines and lipopolysaccharide, acting as a chemo-attractant factor on blood monocytes [13]. In healthy neonates, plasma PCT values increase gradually after birth, reach peak values after 24 h of age (mean 1.5-2.5 ng/ml, range 0.1-20 ng/ml) and then decrease to normal values below 0.5 ng/ml by 48-72 h of age. A number of studies in children and neonates after 72 h of age, demonstrated that PCT values less than 0.5 ng/ml seem to be normal; increases to 0.5-2 ng/ml seem to be related to non-infectious inflammation, viral or focal bacterial infections; increases above a PCT value of 2-2.5 ng/ml, seem to be related to bacterial or fungal systemic infections [14‐16]. PCT as a diagnostic biomarker for sepsis in individuals with SIRS has been well evaluated in adults [11, 17‐25]. Various meta-analyses in paediatric age groups have been done so far [16, 26, 27], but no one has evaluated the role of PCT in sepsis for children and neonates with SIRS or suspected sepsis, the most useful setting for clinicians. Therefore, our objective was to assess the diagnostic accuracy of PCT to differentiate between sepsis and systematic inflammatory response syndromes of non-infectious origin in children and neonates with suspected sepsis.

The protocol for this review was accepted and registered on PROSPERO international prospective register of systematic reviews under the number CRD42016033809.

This is the first systematic review assessing PCT accuracy for sepsis in neonates and children with suspected sepsis or SIRS excluding healthy subjects, and therefore providing more useful information for clinicians. According to our meta-analysis, PCT at the cut-off of 2-2.5 ng/ml shows the best sensitivity and moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis. The sensitivity is high, but associated with a low specificity. Even if suboptimal, this could be considered acceptable, because of the high mortality rate of the condition, and the need to maintain a low false negative ratio.

In neonates, the PCT cut-off of <2 ng/ml shows a high sensitivity with a low specificity, similar to those of cut-off of 2-2.5 ng/mL; the PCT cut-off of >2.5 ng/ml shows lower, unacceptable values for sensitivity, and higher specificity. It is noteworthy to consider that studies on EOS with a PCT cut-off <2 ng/ml were all grouped together with LOS, and the two studies focusing on LOS only [42, 47] found that the PCT at this cut-off had a better accuracy, higher specificity and similar sensitivity, if compared with studies grouping EOS and LOS. This suggests that the use of two different cut-offs could improve accuracy in these two populations: PCT cut-off could be higher for neonates with EOS than for neonates with LOS. This is consistent with existing studies on healthy neonates [14, 29]. It is important that in future studies on EOS the diagnostic value of age-adjusted PCT cut-offs will be assessed in association with other serum biomarkers [46, 53].

Unfortunately, at present, there are not enough studies to perform a meta-analysis on the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml in older children with suspected sepsis or SIRS. In this population, the results on the PCT cut off of <2.0 ng/ml show an overall moderate accuracy, but the limited sample size and quality of the studies included indicate that further studies are needed and no clinical recommendation is possible at this stage. Additional analyses that considered the few studies only on EOS, and grouped together LOS and paediatric patients cannot overcome this limitation.

The study showed limitations linked to the current methodology of primary sepsis research, such as the non-uniform definition of sepsis: some studies considered sepsis only if confirmed by positive blood culture, microscopy or polymerase chain reaction (microbiologically confirmed) while others considered also “probable sepsis”, after a complete review of the patient chart with assessment of clinical, radiological and laboratory data. We included studied that considered both microbiologically confirmed and probable sepsis, but they did not provide detailed information about how the infection was confirmed. In addition, blood samples were drawn without a precise timing (i.e. “at time of admission” or “before antibiotic therapy”, which do not necessarily coincide). Furthermore, the scarcity of studies differentiating EOS and LOS in neonates hampered a more specific and informative analysis.

In 2016, a new definition of sepsis attributing a primary role to organ dysfunction was proposed in adults, aiming to offer greater consistency for epidemiological studies and clinical trials [3]. In order to improve diagnosis and decrease the mortality of sepsis in neonatal and paediatric population, we need soon additional studies of high methodological quality, accounting the specificity of pathophysiology and age dependent variables.

In conclusion, in this study we show that PCT has an overall moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml.

In order to deepen our scientific knowledge on the role of PCT in the diagnosis of neonatal and paediatric sepsis, larger, high quality studies are necessary. More specifically, we need studies responding to the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines, with a previously published and registered protocol, and an adequate sample size. It would also be of paramount importance to include suspected sepsis and exclude healthy subjects, in order to provide more useful information for the clinicians, and be clearly able to differentiate neonates with EOS and LOS. An updated definition of sepsis for paediatric population, similarly to that one proposed for adults, which considers the different pathophysiology and age dependent variables and overrule the current heterogeneity is warranted.

1. PCT shows a moderate diagnostic accuracy at the cut-off of 2-2.5 ng/ml for the diagnosis of sepsis in neonates with SIRS or suspected sepsis.

2. In neonates, the PCT values should be critically evaluated differentiating EOS and LOS.

3. Further studies with better methodological quality in older children with suspected sepsis evaluating the PCT cut-off of 2-2.5 ng/ml are warranted.