Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study

Abstract

Background: Septic shock is a major healthcare problem with a high mortality rate that might be caused by immunosuppression. Programmed cell death receptor-1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1), which are co-inhibitory receptor molecules, participate in sepsis-induced immunosuppression. In this study, we investigated which PD-1-related molecules can be used to evaluate the risk stratification and prognosis of septic patients. Furthermore, we explored the prognostic significance of a combination of ideal predictors and conventional clinical risk parameters in septic shock patients.

Methods: In total, 29 healthy controls, 59 septic patients, and 76 septic shock patients were enrolled in this study. Considering that the focus of the research was on the second phase of sepsis, blood samples were obtained at days 3-4 after the onset of systemic inflammatory response syndrome (SIRS). PD-1 and PD-L1 expression were measured on circulating CD4(+) T cells, CD8(+) T cells, and monocytes (PD-L1 only) by flow cytometry.

Results: Our results showed that only monocyte PD-L1 expression gradually increased, based on the increasing severity of disease (P < 0.001). Similarly, multivariate logistic regression analysis showed that only monocyte PD-L1 expression was an independent predictor of 28-day mortality in septic shock patients. Area under the receiver operating characteristic curve analysis of the combination of monocyte PD-L1 expression and conventional clinical risk parameters indicated a more significant prognostic ability than analysis of each parameter alone.

Conclusion: Our study demonstrated that, among PD-1-related molecules, only monocyte PD-L1 expression after 3-4 days of sepsis was associated with risk stratification and mortality in septic patients. Furthermore, measurement of monocyte PD-L1 expression was a promising independent prognostic marker for septic shock patients.

Keywords: Immunosuppression; Mortality; PD-L1; Septic shock.

Fig. 1

Representative flow dot plots of monocyte gating strategy and the percentage of programmed cell death receptor ligand-1 (PD-L1) on monocytes in different groups. The monocytes (gate B) were gated in the dot plots of side-scatter characteristics (SS) vs CD14. The multiple dot plots of CD14 vs PD-L1 are representative of the percentage of monocytes in healthy control, survivor, and nonsurvivor groups

Fig. 2

Box-plot representation of programmed cell death receptor-1 (PD-1)-related molecules. Data are shown as box plot with medians (lines inside boxes), 25th and 75th quartiles (limits of boxes); whiskers indicate the range. Programmed cell death receptor ligand-1 (PD-L1) expression on monocytes and PD-1 expression on T cells (CD4⁺ and CD8⁺ T cells) were significantly increased in nonsurvivors (n = 27) in comparison with survivors (n = 49) (a–f). MFI mean of fluorescence intensities

Fig. 3

Receive operating characteristic (ROC) curve for predicting 28-day mortality in septic shock patients. AUCs: the percentage of PD-L1 on monocytes (dark blue line), 0.729; MFI of PD-L1 on monocytes (green line), 0.681; SAPS II (pink line), 0.768; SOFA score (brown line), 0.736; the percentage of PD-L1 on monocytes in combination with SAPS II (C1, red line), 0.891; MFI of PD-L1 on monocytes in combination with SAPS II (C2, yellow line), 0.881; the percentage of PD-L1 on monocytes in combination with SOFA score (C3, pale blue line), 0.829; and MFI of PD-L1 on monocytes in combination with SOFA score (C4, gray line), 0.799. MFI mean of fluorescence intensities, PD-L1 programmed cell death receptor ligand-1, SAPS II simplified acute physiology score II, SOFA sepsis-related organ failure assessment

Fig. 4

Survival curves of patients with septic shock according to the percentage of monocytes expressing PD-L1 (a) and MFI of PD-L1 on monocytes (b). MFI mean of fluorescence intensities, PD-L1 programmed cell death receptor ligand-1