The current knowledge about PCT as a biomarker for sepsis in children has been described in previous studies (12-13). Elevation of PCT levels usually occurs earlier during the course of infection, even before the elevation of other biomarkers, peaking at 24-36 hours (12). Pontrelli et al (13) showed a moderate accuracy for the diagnosis of sepsis in neonates with a PCT cut-off of 2.0-2.5 ng/mL (14). A 2015 meta-analysis showed that PCT is highly accurate in differentiating bacterial and viral meningitis in children with 96% sensitivity (12). Studies about PCT levels in blood culture positivity by different microorganism groups in children are scarce, especially in immunocompromised hosts.
Our results show a statistically significant difference between mean PCT values for each microorganism group. Mean PCT levels in children with GNB infections were significantly higher than those with GPC and fungal infections. These findings are consistent with previous studies performed in adults (14-16). Yan et al (1) reported a 72.4% sensitivity and 51% specificity of PCT as a predictor of blood culture positivity in adults, using a 0.495 mcg/L PCT cut-off value. Watanabe et al (17), reported a 74.5% sensitivity and 59.1% specificity of PCT for predicting blood culture-proven bacteremia. In our study we found a 75% sensitivity and 53% specificity of PCT as a predictor of GNB infection, using a PCT cut-off value of 0.5 mcg/L.
Thomas-Rüddel et al (18) reported a median PCT significantly higher in GNB compared to GPC (26 ng/ml vs 7.1 ng/ml, p<0.001). The AUC in the ROC analysis was 0.69 (0.67-0.72) for differentiating GNB from GPC or candidemia, and 0.73 ( 0.71-0.74) for the prediction of GNB compared to all other blood culture results. Bassetti M et al (19), reported similar findings with a median PCT concentration of 25.1 ng/ml in GNB bacteremia compared to 8.9 ng/ml in GPC. The AUC was 0.7 (0.62-0.77) among GNB and 0.46 (0.39-0.53) among GPB. In a previous study, Shuhua et al (20) found a median PCT level of 7.47 ng/ml in GNB compared to 0.48 ng/ml in GPC. An optimal cut-off value of 3.11 ng/mL for PCT in discriminating GNB sepsis from fungal sepsis, led to a sensitivity of 63.9% and specificity of 93.3%.
The role of PCT as a predictor of GPC in blood cultures, mainly in infections caused by Staphylococci was evaluated by Shomali et al, reporting higher mean PCT levels in infections by S. aureus compared to coagulase-negative Staphylococci (0.85 mcg/L versus 0.26 mcg/L, respectively) (21). In contrast, when comparing PCT levels of patients with bacteremia by S. aureus and by coagulase-negative Staphylococci, we found higher mean PCT levels in the latter (17.3 vs 0.8 ng/mL). This difference may be attributed to a higher isolation rate of coagulase-negative Staphylococci in our hospital.
Studies that analyze PCT as a biomarker for invasive fungal infection by Candida spp are scarce and show conflicting data (22-25). In our study, mean PCT levels in Candida spp infections were 1.9 mcg/L, with a 75% sensitivity and 25% specificity. Previous studies by Cortegiani et al (25) report higher sensitivity and specificity of PCT for predicting fungal infection by Candida spp, with 86.8% and 87.4% respectively. Identification of Candida species was not performed in our study; however, previous authors have not found any difference regarding PCT levels in infections by different Candida species. Thomas-Rüddel et al (18) reported a median PCT level of 4.7 ng/ml, compared to 2.1 ng/ml by Bassetti et al (19). Median PCT levels of 0.6 ng/ml, 0.5 ng/ml, 1 ng/ml and 0.5 ng/ml were reported by Shuhua et al (20), Miglietta et al (26), Oussalah et al (27) and Leli et al (29), respectively. Consistent with previous studies, we report lower PCT levels in fungal infections compared to bacterial events (26). It has been suggested that fungal infections could trigger an alternate inflammatory response route that does not involve PCT, explaining its modest rise.
Studies on PCT in immunocompromised patients are scarce (30-34). A recent systematic review and meta-analysis in children with chemotherapy-induced neutropenic fever showed that PCT levels >0.5ng/mL have a 67% sensitivity (CI 0.53-0.79), and 73% specificity (CI 0.66-0.77) for predicting microbiologically defined infections (34). In our study according to mean PCT levels, we found a statistically significant difference between immunocompromised (26.68 mcg/L) and immunocompetent (8.78 mcg/L) children with sepsis (p <0.05). We also report an 87.5% sensitivity of PCT for predicting blood culture-proven GNB infection, making PCT a useful resource in clinical practice. PCT levels were also increased in different types of immunosuppression.
Our study has several limitations. A prospective design would aid in having better control of the variables and include a larger sample, to avoid heterogeneity of the cases. Likewise, PCT measurements were not serial, which would have allowed us to analyze PCT behavior in relation to variables such as time, isolated microorganism, treatment, and outcome.