The utility of biomarkers for the early diagnosis of SBI in children is still debated. The host response to infection is determined by several mediators and different molecules. Many of them have been proposed as possible biomarkers in preclinical or clinical studies, but no gold standard has been identified in pediatric patients, and studies are still relatively scarce (8, 20–24). It seems unlikely that one single molecule could be used as an optimal biomarker for the diagnosis and management of SBI (20, 25, 26). To date, no new candidate biomarker (including cytokine/chemokine, cell surface receptors, coagulation and complement molecules, markers of vasodilation or organ disfunction) has established to be more efficient than those already used in the clinical practice (CRP, PCT and WBC, ANC/WBC and the ratio of immature to total number of neutrophils), although some evidence is emerging about some new biomarkers (27–30).
Presently, determination of old biomarkers is less expensive and widely available. In addition to the economic aspect, a possible pitfall, when considering candidate biomarkers, is the timing of their increase and decrease, which can display wide variations. As an example, in infants IL-6, IL-8 and IL-10 are peaking soon as the suspect of sepsis is made, while PCT and CRP are reacting later, with peak concentrations at 8–16 and 16–24 hours, respectively (31). Nevertheless, the exact timing of measure is often challenging to be determined in real-life conditions. Most of the studies on biomarkers in febrile children have been performed to recognize patients with sepsis. Nevertheless, SBI are far more frequent than sepsis. Therefore, identifying a valuable biomarker for this purpose could be extremely useful to direct patient care, avoid unnecessary diagnostic tests and health care resources expenditure, as well as unnecessary antibiotic therapy, and, on the other hand, avoid missing children with possibly severe diagnosis.
In our study, only CRP showed optimal diagnostic accuracy for the diagnosis of SBI, while PCT was only marginally useful. Previous studies have shown some usefulness of PCT as an infection marker and for antibiotic stewardship in adults (32, 33). Recently, a meta-analysis evaluating the diagnostic accuracy of PCT as a biomarker of SBI in feverish children concluded that PCT did not have sufficient sensitivity and specificity to definitively rule in or rule out SBI in children, but it had better accuracy than CRP and WBC count in identifying SBI in children, and it could perform better in identifying most severe infections, such bacterial meningitis and sepsis (34). In our study, PCT had only moderate accuracy in diagnosing SBI in children and eventually appeared to perform worse than CRP. CRP is probably the most widely used in the initial workup of SBI. Nevertheless, the use of CRP could be limited by its relatively late rise, which can occur only after 18–24 hours from symptoms onset. WBC and absolute neutrophil counts may rise more rapidly, and are widely used in the routine diagnostic workup of SBI, but they have less diagnostic capacity than CRP or PCT, in particular for ruling out SBI. One study reported that WBC count did not add any additional information over CRP and PCT in a multivariate logistic regression analysis (35). Notably, in our study, ANC/WBC ratio, when evaluated in non-leukopenic patients, had a limited diagnostic performance, as demonstrated by its ROC curve AUC. However, when used in a mathematical combination with CRP, it resulted in greater accuracy than each marker taken alone.
Regarding candidate biomarkers (IL-6, IL-8, IL-10, C5b-9, PV-1, PLA2), our study shows that the effectiveness of these molecules in detecting SBI in children was quite low. The best biomarker among these was ICAM-1. ICAM-1 is expressed during the inflammatory response. It is well established that during the induction and progression of the systemic response, there is an endothelial cell activation, and it is believed that endothelium plays a key role in sepsis. This activation may lead to changes in leukocyte trafficking, vascular permeability, inflammation and microcirculatory flow that may contribute to organ damage (36, 37). ICAM-1 is part of the cell surface immunoglobulin superfamily of adhesion receptors that play a role in lymphocyte-mediated adhesion, cytotoxic T-cell activity, antigen presentation and it is also a ligand for macrophage-associated complex (MAC-1) (38). Previous studies found it could have a role in the early diagnosis of sepsis in newborns and infants and may be associated with its severity degree (38, 39), while a study on adult patients admitted to the emergency department with sepsis showed an association between levels of biomarkers of endothelial activation and sepsis severity, organ dysfunction and mortality (36). In our study we also evaluated PV-1, an endothelial protein which has a crucial role in endothelial permeability and leukocyte migration both in normal and pathologic conditions (40–42) but no association with SBIs was found.
Our study had some strengths, including the prospective design and the evaluation of some biomarkers which had never been tested before in pediatric patients with SIRS. Furthermore, there are only few studies that evaluate biomarkers for the diagnosis of SBIs, while the majority are focused only on the occurrence or the severity of sepsis. Nevertheless, some limitations need to be pointed out. The study was carried out in a diverse real-life setting including emergency department and oncology ward. We therefore had to perform a separate analysis on non-immunocompromised patients (i.e. most patients presenting to emergency department) to avoid possible biases due to immune suppression that could have artificially reduced the performance of some biomarkers. A major limitation of the study was that it was not possible to test all biomarkers in all patients because of scarcity of sampled serum, mostly due to difficult blood sampling in children in the emergency setting; this resulted in loss of statistical ability to evaluate the performance of some biomarkers and prevented the possibility of performing multivariate analysis.