HLA-DR Expression on Monocytes and Sepsis Index Are Useful in Predicting Sepsis

Abstract

The reduction of mortality in patients with sepsis depends on the early identification and treatment of at-risk patients. The aim was to evaluate the HLA-DR expression on the surface of monocytes (_MHLA-DR ratio), the sepsis index (CD64 expression on neutrophils/_MHLA-DR ratio), and C-reactive protein (CRP) with the development of sepsis. We prospectively enrolled 77 critically ill patients, 59 with stroke and 18 with traumatic brain injuries. The biomarkers were tested at the baseline and 3, 6, 9, 12, and 15 days later. Most patients (71%) developed sepsis (4.2 ± 1.3 days after admission). On day 3, those subsequently developing sepsis had lower levels of _MHLA-DR+ (81.7 ± 16.2% vs. 88.5 ± 12.1%, p < 0.05) and higher sepsis indexes (0.19 ± 0.19 vs. 0.08 ± 0.08, p < 0.01) than those not developing sepsis. The _MHLA-DR ratio slowly recovered before day 6, while the sepsis index remained raised in septic patients up to day 9 (p < 0.05). To predict the development of sepsis, optimal cut-offs were CRP levels > 106.90 mg/mL (74.19% sensitivity, 69.49 specificity) and _MHLA-DR expression rate < 72.80% (45.31% sensitivity, 89.47% specificity). The periodic monitoring of the _MHLA-DR expression together with CRP and sepsis index may help to identify patients in the ICU at increased risk of developing sepsis.

Keywords: biomarker; sepsis; sepsis index.

Figure 1

Gating strategy analysis using flow cytometry of CD64 expression on neutrophils and HLA-DR expression on monocytes and lymphocytes.

Figure 2

Changes in measures of immune dysfunction based on subsequent sepsis status. (a) Change in CRP levels of total patients included over time (p < 0.05). (b) Changes in CRP levels among groups (p = 0.03). (c) Change in sepsis index values among groups (p = 0.01). (d) Change in expression rate of _MHLA-DR on monocytes among groups (p = 0.04). Septic group: Baseline: 55; day + 3: 55; day + 6: 48; day + 9: 45; day + 12: 39; day + 15: 24. Non-septic group: Baseline: 22; day + 3: 22; day + 6: 22; day + 9: 13; day + 12: 9; day + 15: 1. * p < 0.05.

Figure 3

Differences in the mean fluorescence of _MHLA-DR on monocytes from septic and non-septic patients before infection. Dynamic values of mean fluorescence intensity of _MHLA-DR on monocytes from septic (pink) and non-septic (blue) patients during 15 days of follow-up over time. In the septic group, day 0 was considered when sepsis was diagnosed. The continuous lines represent the mean HLA-DR fluorescence intensity values in monocytes for septic patients (pink) and for non-septic patients (blue) before and after infection.

Figure 4

(a) ROC curves of CRP levels; (b) the expression rate of HLA-DR on monocytes; and (c) MFI of _MHLA-DR for the diagnosis of patients with higher risk to develop sepsis during their stay in ICU.