Improved Early Detection of Sepsis in the ED With a Novel Monocyte Distribution Width Biomarker

Abstract

Background: Sepsis most often presents to the ED, and delayed detection is harmful. WBC count is often used to detect sepsis, but changes in WBC count size also correspond to sepsis. We sought to determine if volume increases of circulating immune cells add value to the WBC count for early sepsis detection in the ED.

Methods: A blinded, prospective cohort study was conducted in two different ED populations within a large academic hospital.

Results: Neutrophil and monocyte volume parameters were measured in conjunction with routine CBC testing on a UniCel DxH 800 analyzer at the time of ED admission and were evaluated for the detection of sepsis. There were 1,320 subjects in the ED consecutively enrolled and categorized as control subjects (n = 879) and those with systemic inflammatory response syndrome (SIRS) (n = 203), infection (n = 140), or sepsis (n = 98). Compared with other parameters, monocyte distribution width (MDW) best discriminated sepsis from all other conditions (area under the curve [AUC], 0.79; 95% CI, 0.73-0.84; sensitivity, 0.77; specificity, 0.73; MDW threshold, 20.50), sepsis from SIRS (AUC, 0.74; 95% CI, 0.67-0.84), and severe sepsis from noninfected patients in the ED (AUC, 0.88; 95% CI, 0.75-0.99; negative predictive value, 99%). The added value of MDW to WBC count was statistically significant (AUC, 0.89 for MDW + WBC vs 0.81 for WBC alone; P < .01); a decision curve analysis also showed improved performance compared with WBC count alone.

Conclusions: The incorporation of MDW with WBC count is shown in this prospective cohort study to improve detection of sepsis compared with WBC count alone at the time of admission in the ED.

Trial registry: ClinicalTrials.gov; No.: NCT02232750; URL: www.clinicaltrials.gov.

Keywords: ED; biomarker; blood; cell volume; monocyte; sepsis.

Figure 1

A, B, Cell population distribution analysis. Representative histograms of WBC populations derived from the Beckman Coulter DxH 800 analyzer. (A) Example of a nonseptic donor. (B) Two-dimensional histogram corresponds to an example of a patient with septic shock. (A) The rotated one-dimensional histogram represents the distribution of the monocyte population volumes. The dotted blue line on top of the distribution represents the mean monocyte volume. The dotted red line represents 1 SD from the mean of the distribution (ie, monocyte distribution width), which is shown to be increased in the patient with sepsis.

Figure 2

A-D, Neutrophil and monocyte cell population distribution performance for sepsis in the ED population. (A) MNV is noted to be lowest in the control group, highest in the sepsis group, with intermediate values in the SIRS and infection groups. (B) The NDW shows a similar pattern. *P < .001 for sepsis group vs control group or infection group or SIRS group (individual comparisons) and for sepsis group vs control + infection + SIRS groups combined. (C) MMV is noted to be lowest in the control group, highest in the sepsis group, with intermediate values in the SIRS and infection groups. (D) The MDW shows a similar pattern, and the MDW is statistically higher in the sepsis group compared with each of the other groups. *P < .001 for sepsis group vs control group or infection group or SIRS group (individual comparisons) and for sepsis group vs control + infection + SIRS groups combined. MDW = monocyte distribution width; MMV = mean monocyte volume; MNV = mean neutrophil volume; NDW = neutrophil distribution width; SIRS = systemic inflammatory response syndrome.

Figure 3

A, B, ROC for sepsis and SIRS in subjects in the ED using MDW alone and in combination with the WBC count. (A) Comparing sepsis to all other patients in the ED: the area under the curve (AUC) for MDW (cutoff value, 20.5) is comparable with WBC count (cutoff value, 12.0); however, the addition of MDW to WBC count (using 20.5 and 12.2 as the cutoff values for MDW and WBC count, respectively) increases the AUC by 8% relative to WBC count alone, which is statistically significant (see text). (B) Comparing sepsis with SIRS, and using the same cutoff values, the AUC for MDW is higher than for the WBC count and is higher yet when MDW is added to the WBC count. ROC = receiver operating characteristic. See Figure 2 legend for expansion of other abbreviations.

Figure 4

Decision probability curves for sepsis detection reflecting the added value of MDW compared with WBC count alone. The net benefit of WBC count alone (blue line) and in combination with MDW (red line) for the detection of sepsis was calculated over a range of pretest probabilities for sepsis (see Methods for details). The control (gray line) represents a model that provides no insight into the diagnosis of sepsis. MDW + WBC count show greater benefit than WBC count alone over a wide range of sepsis probabilities (2%-70%). The models converge > 70% sepsis probability, a situation that is not representative of the ED population. See Figure 2 legend for expansion of abbreviation.