Sepsis is a rapidly propagating excessive inflammatory reaction that occurs in response to a variety of pathogenic bacteria entering the blood system, producing a large number of toxins. The laboratory indicators used for the clinical diagnosis of sepsis include CRP, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and PCT, none of which are ideal diagnostic indicators due to their deficiencies in diagnostic specificity and sensitivity [14,15,16,17]. For many years, researchers have carried out a large number of studies and clinical trials, but the pathogenesis of sepsis is still not fully elucidated, which also hampers effective treatment, resulting in high mortality [18, 19]. Therefore, it is important to find a new diagnostic indicator to improve the treatment of sepsis and reduce mortality.
Currently, PCT is considered to be the best laboratory diagnostic indicator of sepsis, but its value for diagnosis, prognosis and the differential diagnosis with SIRS is not satisfactory [20,21,22]. A meta-analysis showed that the sensitivity and specificity of PCT in early sepsis diagnosis in critically ill patients were 77% (95% CI: 72–81%) and 79% (95% CI: 74–84%). However, since PCT levels can rise due to surgery as well as inflammatory and autoimmune diseases, its specificity in sepsis diagnosis is limited [23]. Pierrakos et al. [24] analyzed 178 diagnostic indicators of sepsis in 3370 papers, concluding that PCT is deficient for diagnosis, differential diagnosis and prognosis of sepsis. In this study, the AUC, sensitivity and specificity of PCT were determined to be 0.692, 79.4 and 55.9%, respectively, which also indicated that the diagnostic specificity of PCT was low in sepsis diagnosis. Therefore, it is urgent to find new indicators for the diagnosis and prognosis of sepsis.
SuPAR is the soluble form of urokinase type plasminogen activator receptor (uPAR). Under inflammatory stimulation, uPAR is removed from the cell surface through the activity of a variety of proteases, forming suPAR [25]. Increased suPAR levels, which were believed to be a good biomarker for sepsis diagnosis, primarily occur in patients with cancer and a variety of infectious and inflammatory diseases [26]. Recent studies have shown that suPAR levels are significantly increased in sepsis and could reflect the severity of sepsis [27,28,29]. In vivo studies have found that stimulation by high dose endotoxin can increase suPAR levels, while low dose endotoxin stimulation failed to increase suPAR levels [30]. This study found that suPAR levels were significantly increased in sepsis patients. When compared with the control group, at a cut-off point of 5.535 ng/mL, the sensitivity and specificity for diagnosis of sepsis using suPAR were 94.1 and 85.0%, and the PCT was comparable, while the area under the ROC curve was smaller than the PCT, similar to the results of the study published by Zeng [31]. When distinguishing SIRS from sepsis using suPAR, the optimal cut-off point was 8.355 ng/mL. At this point, the sensitivity and specificity were 85.3 and 73.5%, respectively, which was better than PCT, indicating that suPAR had a better sensitivity in sepsis diagnosis.
DcR3 is a member of the soluble tumor necrosis factor receptor superfamily lacking transmembrane structures. Some studies have shown that DcR3 can reduce inflammatory responses by promoting the secretion of anti-inflammatory factors and down-regulating the expression of inflammatory factors [32, 33]. Our previous study established a mouse model of sepsis and applied dose-dependent DcR3 treatment. It showed that DcR3 significantly inhibited the inflammatory reaction, and reduced lymphocyte apoptosis in the thymus and spleen, improving survival rates [34]. DcR3 can modulate macrophage differentiation and the secretion of inflammatory cytokines and chemokines, functioning as part of the immune surveillance and immune regulation systems, indicating that DcR3 may play a role in the early pathological mechanisms of sepsis [35]. In this study, we found that the DcR3 level was significantly increased in sepsis patients. Furthermore, on evaluation of the ROC curve, our findings showed that when the DcR3 cut-off point was 1.690 ng/mL, the sensitivity and specificity of DcR3 were 91.2 and 82.4%, which was better than those of suPAR and PCT to distinguish SIRS from sepsis, indicating that DcR3 shows great promise for use as a diagnostic biomarker of sepsis. Gao et al. [36] found that DcR3 increased significantly in the early stage of sepsis and monitoring its outcome, especially when sepsis patients were PCT negative. However, DcR3 levels showed no difference among various pathogens associated with sepsis.
Although the above three biological indicators have certain application value in the early diagnosis of sepsis, they are limited by various conditions and cannot be used independently as an ideal indicator for diagnosis of sepsis. Therefore, in order to improve the early diagnosis of sepsis, we also evaluated the diagnostic value of combined examination of DcR3, suPAR and PCT by the ROC curve. Our results suggested that the effect of a single indicator in the diagnosis of sepsis is not ideal, and diagnosis using multiple indicators in combination may be more effective [24]. Compared with the control group, the sensitivity and specificity of DcR3 + suPAR+PCT for sepsis were 97.1 and 98.0%, which were superior to those of suPAR+PCT or DcR3 + suPAR or DcR3 + PCT. DcR3, suPAR and PCT were used to distinguish SIRS from sepsis; when the optimal cut-off point of DcR3 + suPAR+PCT was 0.342, the sensitivity and specificity were 94.1 and 91.2%, showing that this combination enhanced the accuracy and prediction efficiency, compared to a single index. Moreover, in this study a correlation analysis was carried out among DcR3, suPAR and PCT, which showed that DcR3 was correlated with suPAR and PCT, suggesting that use of the combination of the three indexes has a higher clinical diagnostic value for sepsis.
In summary, the host response to sepsis involves hundreds of mediators and single molecules, many of which have been proposed to be sepsis biomarkers. It is unlikely that is able to satisfy all the existing needs and expectations in sepsis research and management. The combined diagnostic value of the three indicators is higher than that of the single indicator. However, the number of samples in this study was small, and further large-scale clinical studies are needed to verify the results, and to provide new ideas for the pathogenesis of sepsis and early treatment.