Monocyte expression and soluble levels of the haemoglobin receptor (CD163/sCD163) and the mannose receptor (MR/sMR) in septic and critically ill non-septic ICU patients

Abstract

Background: The diagnosis of sepsis is challenging and there is an unmet need for sensitive and specific diagnostic and prognostic biomarkers. Following activation of macrophages and monocytes, the haptoglobin-haemoglobin receptor (CD163) and the mannose receptor (MR) are shed into the circulation (sCD163 and sMR).

Objective: We investigated monocyte expression of CD163 and MR, and levels of sCD163 and sMR in septic and non-septic patients, and in healthy controls. We hypothesised that these receptors are elevated during sepsis and can be used diagnostic and prognostic.

Methods: Twenty-one patients with severe sepsis or septic shock and 15 critically ill non-septic patients were included in this prospective observational study at three ICUs at Aarhus University Hospital and Randers Regional Hospital, Denmark. Fifteen age- and gender-matched healthy volunteers served as controls. Levels of sCD163 and sMR were measured using a sandwich ELISA and monocyte expression of CD163 and MR was evaluated by flow cytometry during the first four days of ICU stay. The diagnostic and prognostic values of the receptors were assessed using AUROC curves.

Results: At ICU admission and during the observation period, monocyte expression of CD163 and levels of sCD163 and sMR were significantly higher in septic patients compared with non-septic patients and healthy controls (p<0.01 for all comparisons). Monocytes did not express MR. The diagnostic values estimated by AUROC were 1.00 for sMR, 0.95 for sCD163, 0.87 for CRP, and 0.75 for monocyte-bound CD163. Among the septic patients, monocyte expression of CD163 was higher in non-survivors compared with survivors at ICU admission (p = 0.02) and during the observation period (p = 0.006). The prognostic value of monocyte-bound CD163 estimated by AUROC at ICU admission was 0.82.

Conclusion: The macrophage-specific markers CD163, sCD163, and sMR are increased in septic patients. Particularly sMR is a promising new biomarker of sepsis.

Conflict of interest statement

Competing Interests: University of Aarhus holds patent applications for the use of sCD163 and sMR as biomarkers (EP 2488863 A2: Method of prognosis and PCT/DK2014/050014: Novel Disease-Marker). HJM has received royalties from IQ-Products, NL. This does not alter the authors’ adherence to the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Levels of sCD163, sMR and the expression of monocyte-bound CD163 during the four-day observation period.

A-C: At ICU admission and during the four-day observation period, expression of monocyte-bound CD163 (Panel A), sCD163 (Panel B), and sMR (Panel C) was significantly higher in septic patients compared with non-septic patients and healthy controls. The x-axis represents time and the y-axis represents the expression or level of each potential biomarker. Dots represent the median, bars represent the interquartile range.

Figure 2. Receiver operating characteristic curve analysis and the ability to discriminate between septic patients and non-septic patients at ICU admission.

Area under the receiver operating characteristic curve (AUROC) is shown for monocyte-bound CD163, sCD163, sMR, and plasma CRP. Numbers in parentheses are 95% confidence intervals.

Figure 3. Levels of sCD163, sMR and the expression of monocyte-bound CD163 in in-hospital survivors and non-survivors within the septic group during the four-day observation period.

A: Monocyte expression of CD163 was higher in non-survivors compared with survivors, both at ICU admission and during the four-day observation period. B + C: There were no difference in the levels of sCD163 (Panel B) or sMR (Panel C) between survivors and non-survivors, neither at ICU admission nor during the observation period. The x-axis represents time and the y-axis represents the expression or level of each potential biomarker. Dots represent the median, bars represent the interquartile range.

Figure 4. Receiver operating characteristic curve analysis and the ability to discriminate between survivors and non-survivors among the septic patients at ICU admission.

Area under the receiver operating characteristic curve (AUROC) is shown for monocyte-bound CD163, sCD163, sMR, and plasma CRP. Numbers in parentheses are 95% confidence intervals.