In this study, WRS levels progressively increased in the following group order: healthy controls, inflammation group, and sepsis group, along with the levels of other biomarkers previously considered to indicate sepsis, namely, PCT, CRP, and IL-6. The AUROC for sepsis discrimination of WRS was also higher than the AUROCs for other factors such as PCT, CRP, and IL-6 levels, and the SOFA and APACHE II scores. The AUROC of WRS for predicting 28-day overall mortality was not found to be inferior to that of the SOFA score. Furthermore, based on AUROC analyses, the cut-off values of the WRS level for sepsis discrimination and 28-day mortality prediction were 53.34 ng/mL and 97.23 ng/mL, respectively.
The recently revised Sepsis-3 definition defines sepsis as a dysregulated host response to pathogenic infection, leading to life-threatening organ dysfunction. This definition is focused on organ damage from dysregulated immune responses due to invasive infection . Furthermore, in the 2018 updated Surviving Sepsis Campaign Bundle, the guidelines changed from 3-hour and 6-hour bundles to a 1-hour bundle. The guidelines further pointed to the need for urgent assessment and treatment in patients with sepsis , indicating that an initial diagnosis is essential to manage sepsis . Other previous studies have shown that CRP and IL-6 levels could be helpful for a diagnosis of sepsis; however, their strength in the diagnosis of sepsis has been controversial [19–21]. In our study, the sepsis discrimination power of the CRP and IL-6 levels was lower than that of the other variables. Furthermore, many previous studies have investigated novel clinical biomarkers, such as IL-27, presepsin, angiopoietin-1, and high mobility group box 1, as diagnostic factors for sepsis [22–24]; however, determining a standard test for sepsis remains a challenge.
PCT is released within 3–4 hours after infection or injury , and has been widely considered as a highly predictive diagnostic marker in patients with sepsis with distinguishable specificity for bacterial infection . However, PCT levels cannot distinguish between fungal or viral infections and bacterial infections [8, 27]. Furthermore, some studies have reported that PCT levels have not always been good predictors of sepsis-related prognosis , and the determination of changes in the PCT levels is needed rather than a single PCT level measurement, to predict mortality in patients with sepsis . In our study, the sepsis discrimination power of PCT was found to be higher than that of other variables, but not with respect to 28-day overall mortality.
The SOFA score has been shown to be helpful in predicting in-hospital mortality in patients with sepsis . Our study findings also showed that SOFA scores correlated with sepsis diagnosis and 28-day overall mortality. However, the use of this score to identify patients with sepsis has also been challenged . While the SOFA score reflects the extent of organ damage in relation to mortality, it might lack discriminative power in terms of whether the cause of organ damage was infection . Moreover, the SOFA score calculation requires several laboratory test results, leading to a risk of delay in diagnosis and treatment .
WRS is an essential cytosolic aminoacyl-tRNA synthetase that is involved in the translation of mRNAs. WRS is secreted from monocytes, which play a key role in innate immunity, angiogenesis, and IFN-γ signalling despite the exact pathways being unclear . Ahn et al. reported that WRS emerges to act as a primary defence molecule against infection arising from interactions with Toll-like receptor 4 and myeloid differentiation factor 2 . Furthermore, in a previous study, WRS was found to be immediately released and detected in the extracellular space within 1 hour of infection, and thus, it was concluded that WRS forms a part of the innate immune response in the early phase of viral infection . Additionally, the secretion of WRS could be induced due to a variety of infectious pathogens including bacteria, fungi, or viruses . Our study results showed better AUROC values for other clinical predictive factors of sepsis. It was not clear why the WRS level was associated with mortality due to sepsis in our study; therefore, further studies are required to determine whether the WRS level is valuable in mortality prediction and whether it could be used a novel treatment target.
This is the first study to analyse the value of WRS in a clinical patient sample with sepsis. Our results not only showed a higher sepsis discrimination power of WRS than that of other variables, but that WRS was also associated with 28-day overall mortality in ICU patients with sepsis. Therefore, the WRS level could be a new and powerful diagnostic marker for sepsis, and we consider that a high initial WRS level can be used to predict poor prognosis in critically ill patients with sepsis.
This study had several limitations. First, this study was a single-centre, retrospective study with a small sample size making generalisability of our results difficult. Therefore, a prospective multicentre study should be undertaken to confirm our findings. Second, there was a time difference between blood sampling and analysis, and protein degradation could have occurred prior to analysis. However, blood samples were aliquoted and stored in a refrigerator at -80 ºC as soon as possible to prevent protein degradation, and we thawed the blood sample only once for analysis. Third, we could not analyse the serial results of WRS because we investigated the WRS level only once at the time of ICU admission. Further in vivo clinical trials with a randomised controlled, prospective design investigating the serial changes in the WRS level as a result of infection are needed.