In this study, we tested the diagnostic performance of MDW for sepsis and compared it with that of conventional biomarkers (CRP, PCT, and WBC count). The diagnostic performance of MDW was presented in terms of AUC (0.71, 95%CI: 0.67–0.75), and compared with that of CRP (0.75, 0.71–0.78), PCT (0.76, 0.72–0.79), and WBC count (0.61, 0.57–0.65). The cut-off value of MDW in this study was 19.8. It is similar to 20.0 (9) and 20.5 (8), observed in previous studies. Furthermore, MDW showed 85.6% of sensitivity with its optimal cut-off value from the study cohort and it was higher than that of CRP (69.7%) and PCT (76.6).
Despite the SOFA score being good for differentiating the prognosis of sepsis, the time for gathering the information needed to assess SOFA may impede early sepsis diagnosis. In this regard, there have been many endeavors to find simple screening tool that would act as a good biomarker of sepsis(14–17), but none of them had shown superiority over others.
Among numerous biomarkers recommended for sepsis, CRP and PCT are the most widely used in clinical practice(17). CRP is an acute phase reactant produced by hepatocytes and increases within the first 6 to 8 h and peaks after 48 h. It has been suggested as a sepsis marker(11) but has also been found to increase in various medical conditions(18). PCT is a good biomarker of sepsis(19) and increases earlier than CRP(20); it also has an advantage in the management of antibiotics(21).
Since the monocytes are rapid responders of infection, Crouser ED et al. suggested MDW as a novel biomarker of sepsis under the definition of Sepsis-2(8). Additional study(9) showed that MDW was also effective under the Sepsis-3 definition. In this study, we analyzed the efficacy of MDW based on Sepsis-3 and Sepsis-2 also compared it with other biomarkers. When comparing the diagnostic performance under Sepsis-3 definition, MDW was not inferior to CRP or PCT in terms of AUC. Regarding the sensitivity with optimal cutoff from the cohort, MDW showed higher sensitivity than other markers.
In the present analysis, the AUC of all biomarkers showed weak accuracy in sepsis diagnosis; this might be because we enrolled patients regardless of immune status. We did not exclude immune-compromised patients (malignancy, cytotoxic chemotherapy, neutropenia, or other disease and drug status which affects the immune status) to reflect the real-world practice.
Additional analysis was done according to immune status. As we expected, it appeared that the diagnostic performance of MDW was affected by immune status. From the diagnostic performance for Sepsis-3, according to immune status, we observed a trend that the AUC of biomarkers was lower in immune-compromised patients than in immune-competent patients. The optimal cut-off value of MDW for sepsis was higher for immune-compromised (22.0) than for immune-competent (19.0) patients.
The AUC of ROC was not significantly different among biomarkers for patients with different immune statuses. The significant changes were, however, observed across different septic conditions regardless of the immune status except for WBC count (Additional file, Supplementary Table 2), which suggests that MDW is changed by septic condition while being affected by immune status. The number of immune-compromised patients was relatively higher (over 50% of overall population) in our cohort, compared to that in previous publications, where patients with compromised immune cell function comprised only around 17% of the study population(9). This difference might explain the lower AUC of current analysis compared to that observed in previous reports (8, 9). The additional analysis of immune-competent patients showed the AUC (0.73, 95% CI, 0.66–0.80) was comparable with that of previous data (AUC 0.73, 95% CI, 0.69–0.76) (9). The AUC of MDW was higher in immune-competent patients than in immune-compromised patients, suggesting that MDW would be more beneficial in patients not having these conditions: malignancy, chemotherapy, immune-suppressant, and organ-transplantation. Altogether, MDW may be a useful marker of sepsis but should be interpreted with caution according to patient’s immune status.
Although, in previous studies the potential benefit of combining MDW with WBC (8, 9) was reported, combined effects of MDW on WBC, CRP, and PCT were disappointing in this analysis (Additional file, Supplementary Table 3). Even the well-known combination of the sepsis markers CRP and PCT(22) did not improve the AUC (0.74, 95% CI:0.70–0.79) to beyond that achieved with the single marker (CRP[0.75, 0.71–0.78] or PCT[0.76, 0.82 − 0.79]). This suggested that with the WBC count and MDW, which can be obtained simultaneously, additional test for CRP and PCT does not have advantages in sepsis diagnosis. It is important to mention that despite the slightly higher AUC, PCT and CRP showed relatively lower sensitivity at the optimal cut-off values of 0.05 (sensitivity of 76.6% (95%CI 76.4–76.8%)) and 4.0 (sensitivity of 69.7% (95%CI 69.5–69.9)), respectively.
When combined with clinical score (qSOFA), MDW with WBC and CRP showed significant improvement in diagnostic accuracy in terms of AUC. In current guideline, the suggested algorithm for identifying sepsis uses the qSOFA for first assessment. MDW takes shorter laboratory test time than CRP or PCT and uses same blood specimen and test equipment with CBC test. Moreover, the qSOFA can be calculated in real time in clinical practice. The combination of MDW with WBC and qSOFA may provide effectiveness and convenience as an initial screening test.
We also conducted the analysis of biomarkers’ performance with Sepsis-2 criteria. Among the tested biomarkers, CRP showed the highest AUC of ROC (0.79, 95%CI: 0.75–0.82). When MDW was combined with WBC, the performance was comparable to that of CRP and PCT. The overall AUC of ROC was not significantly different from that of Sepsis-3 definition.
Previous studies, in which MDW was evaluated, the primary focus was to check the effectiveness MDW in the detection of sepsis and its validation(8, 9) and to compare with other inflammatory markers, that is, PCT and WBC(8, 9, 23). We collected not only the CBC data (WBC count and MDW) but also the conventional biomarkers such as CRP and PCT, while Polilli et al.(23) compared MDW with PCT but in limited number; CRP was not present in that study. Moreover, we compared the biomarkers with qSOFA and the combinations. We collected data from patients with various immune statuses and performed additional analysis according to the immune status to differentiate patients who would potentially benefit from determining MDW.
There are some limitations that need to be considered while interpreting the results. First, we enrolled the patients when the physicians recommended CBC-Diff; thus, there was risk of selection bias. In ED, patients who got laboratory test done were selected according to the physicians’ decision; non-infection group in this population were more likely to have an underlying disease (e.g., 34.5% of patients could have had any kind of malignancy) compared to real control (normal). Second, this was a single-center study; hence, there could be high pre-test probability of sepsis. However, the primary outcome of the study was comparison of the diagnostic performance based on AUC, which does not account for prevalence of disease. Third, because of the limited information on baseline medical conditions before the ED visit, we used the worst SOFA score in ED to diagnose sepsis; this might have resulted in incorrect SOFA score (e.g., patients with previous liver disease, renal disease or hematologic disease could have had a higher SOFA score), which could have resulted in misclassification bias. In general, there is limited information about baseline organ function for most of the patients in ED; hence, the results of our study may reflect the real-world’s practice.
Sepsis is not a single disease but a clinical syndrome. Hence, there is no perfect standard for sepsis diagnosis and there is always a risk of misdiagnosis. Considering the risk of overdiagnosis (24), the biomarker of sepsis needs to be sensitive because of poor clinical outcomes of delayed diagnosis. As earlier intervention (antibiotics and fluid resuscitation) results in better outcome in sepsis management, rapid and easily available screening tools are highly beneficial for patients with sepsis. MDW showed relatively higher sensitivity, negative predictive value, and better diagnostic performance compared to conventional inflammatory markers. Hence, when combined with WBC and qSOFA, more accurate discrimination for sepsis is possible. With CBC test, MDW may help physicians to be observant about the sepsis and proceed with further steps required for evaluating the septic condition, thus facilitating early intervention for sepsis.