Monocyte distribution width (MDW) performance as an early sepsis indicator in the emergency department: comparison with CRP and procalcitonin in a multicenter international European prospective study

A significant proportion of patients developing sepsis enter the health system through an emergency department (ED) [1‐4]. Because the surviving sepsis campaign promotes targeting short-term specific, goal-directed therapy bundles, early sepsis diagnosis has therefore emerged as one of the main challenges for emergency physicians [5]. Although the systemic inflammatory response syndrome (SIRS) or quick Sequential Organ Failure Assessment (qSOFA) score are helpful clinical tools for sepsis suspicion during early triage, sepsis diagnosis may still be delayed or misdiagnosed [4, 6]. So, measurement of sepsis biomarkers is largely used in current practice to improve the diagnosis accuracy [7].

MDW, a hematologic parameter measured as part of the complete blood count with differential (CBC-DIFF) and describing the size distribution of circulating monocytes, was shown in two recent North American studies [8‐10] to be a valuable new sepsis biomarker for the early detection of patients in the emergency department. However, little is known about the performance of MDW and how it compares to those of the most frequently used sepsis biomarkers: C-reactive protein (CRP) and procalcitonin (PCT) [11].

The primary objective of this study was to confirm the clinical validity and performance of MDW to identify patients who developed sepsis in a European ED population. Secondary objectives were to compare the performance of MDW with CRP and PCT and to verify MDW cutoff for tripotassium ethylenediaminetetraacetic acid (K₃EDTA) tubes.

This was an international, blinded, prospective cohort study enrolling patients presenting to two adult large EDs at the Pitié-Salpêtrière APHP-Sorbonne Université hospital in Paris (LPS), France, and the Hospital Universitari Germans Trias i Pujol in Badalona, Spain (UHG). The study assessed MDW’s ability to detect the development of sepsis in consecutive adult patients (18–89 years) presenting to the ED and who had a CBC-DIFF ordered. The study was registered in ClinicalTrials.gov (NCT03588325) and approved by the ethical committees of the respective participating countries.

As shown in the flow diagram of the study (Fig. 1), from August 2, 2018, through June 27, 2019, 1,689 patients were screened and enrolled, and 172 were excluded due to patient not meeting inclusion criteria, inadequate sample collection or screening errors. The final analysis included 1,517 patients (LPS 837, UHG 680). Demographic features are shown in Table 1. There were 837 men and 680 women, median age 64 (IQ 47–76 years). Using Sepsis-2 criteria, 819 patients (54%) were categorized as non-SIRS/non-sepsis (case controls) while 260 (17.1%) had sepsis, including 38 with severe sepsis. According to Sepsis-3 criteria, 1,016 patients (67%) were adjudicated as case controls and 144 patients (9.5%) had sepsis. Eighty-five percent of Sepsis-2 patients had at least one microbiological test performed, of which 58% were positive. Bacterial cultures grew with Gram-positive species in 16 patients, Gram-negative in 62 patients and mixed gram stain in 10. These cultures were 41 from urine, 24 from blood, 14 from sputum and 9 from other sources (Additional file 2: Sup. Table 5). Five hundred and fifty-three patients (36.5%) fell in the subgroup of the low pretest probability of sepsis (no CRP or PCT ordered by the emergency physicians).

In this multicenter clinical trial conducted in two large European EDs, we confirmed the performance of MDW as an early sepsis biomarker with an AUC of 0.81 [0.78–0.84] and 0.86 [0.84–0.88] when combined with WBC for Sepsis-2 criteria. These results are in accordance with those of two recent North American studies which reported very similar performance of MDW (AUC 0.79 [0.73–0.84] and 0.79 [0.76–0.82], respectively) [8, 9] which argues for the robustness and reproducibility of this new biomarker in different populations. At an optimal cutoff of 21.5 in K₃EDTA tubes, a sensitivity of 75% [69–80, 95% CI] and specificity of 73% [70–75, 95% CI] were observed which again agrees well with previous studies in North America and demonstrates that the anticoagulant does not affect the diagnostic accuracy of the biomarker. Moreover, we reported that MDW combined with WBC was particularly useful to detect sepsis in a low pretest probability subgroup of patients (AUC: 0.90 [0.84–0.95]), that is patients for whom no sepsis biomarker was ordered by the emergency physicians upon presentation. MDW may be displayed routinely as part of CBC with differential for most of the patients who have blood drawn in the ED and thus provides an added value to the early clinical evaluation. Indeed, early sepsis detection is warranted to initiate specific goal-directed therapy bundles [5]; hence, the systematic SIRS criteria and qSOFA score calculation are highly recommended. However, both SIRS and qSOFA lack sensitivity and specificity and may falsely lead to over or under suspicion of sepsis [4, 6, 21, 22]. In the present study, we confirmed that MDW provided an added diagnostic power to SIRS and qSOFA variables, with an overall odd of 5.5 and 7.6 for Sepsis-2 and Sepsis-3, respectively, when MDW > 21.5 (Table 2 and Fig. 5). As recently published by Crouser, et al., because MDW value can be displayed with CBC results early in the ED’s course of the patient, it may be considered as a fifth SIRS or fourth qSOFA criteria [10].

MDW combined with WBC had a similar AUC compared to CRP (0.85 [0.82–0.87]) and performed better than PCT (0.78 [0.75–0.81]) (Table 3). To our knowledge, this was the first report of the comparison between MDW, PCT and CRP in the emergency department, in contrast to the study by Polilli, et al., who reported nearly overlapping AUC for MDW and PCT (0.87 vs. 0.88, respectively) in a cohort of hospitalized patients for suspected infection or sepsis [11]. The performances of PCT and CRP we observed were much higher than what had been reported to date in the literature, with AUCs ranging from 0.64 to 0.79 and 0.57 to 0.79, respectively [23‐27]. The first explanation of the discrepancy is that our main inclusion criterion (ED patients for whom initial evaluation included a CBC-DIFF) resulted in a less selected patient population than the criteria of previous studies (patients with a suspicion of infection or sepsis). The sepsis prevalence observed in current study (Table 1) was higher than the mean prevalence in ED population [28], but much lower than what is reported in more selected populations [23, 24]. For example, Lungström, et al., reported a Sepsis-2 prevalence of 42% in a cohort of 1,572 EDs patients with a suspicion of infection, along with PCT and CRP AUCs of O.64 [0.61–0.67] and 0.57 [0.54–0.60], respectively, whereas Uusitalo-Seppälä, et al., reported a Sepsis-2 prevalence of 57% and AUCs of 0.77 [0.71–0.84] and 0.60 [0.51–0.69], respectively, for severe sepsis detection [23, 24]. The second hypothesis was that although the adjudicators were blinded to PCT and CRP results performed by protocol, they had access to PCT and CRP values obtained as standard of care, which may have contributed to an overestimation of the performance of these two sepsis biomarkers in our study.

On first analysis, our data did not support the addition of PCT and CRP testing to WBC plus MDW in the ED. However, as illustrated in Fig. 5, a sequential approach with WBC plus MDW as a systematic screening test, followed by PCT or CRP measurement in cases of discordant results (WBC abnormal–MDW normal, or WBC normal–MDW abnormal) may represent a pragmatic perspective.

We acknowledge several limitations of the study. First, as there is no gold standard for the diagnosis of sepsis, we cannot exclude the possibility of some misclassification of patients that limits or biases the accuracy of the biomarkers. However, we tried to limit this risk by adjudicating all cases using two independent adjudicators and arbitration by a third physician in case of disagreement. Second, as discussed above, the adjudicators were not blinded to PCT and CRP values ordered as standard of care, which may have contributed to an overestimation of both the prevalence of sepsis and the performance of these biomarkers. Similarly, sepsis biomarker ordering as a standard of care was different by sites (PCT and CRP in LPS, CRP only in UHG). We think that this current practice discrepancy rather enhances the validity of the combined sites results than biases it. Finally, the overall sepsis prevalence we reported was higher than the usual prevalence in EDs, arguing for a part of screening selection bias toward sepsis patients at inclusion.

MDW in combination with WBC has the diagnostic accuracy to detect sepsis, particularly when assessed in patients with lower pretest sepsis probability. We suggest the use of MDW as a systematic screening test, used together with SIRS criteria and qSOFA score to improve the accuracy of sepsis diagnosis [29, 30] in the emergency department. The place of CRP or PCT thereafter remains to be determined.