An integrative model with HLA-DR, CD64, and PD-1 for the diagnostic and prognostic evaluation of sepsis

Abstract

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and progressive immunosuppression with high mortality. HLA-DR, CD64, and PD-1 were assumed to be useful biomarkers for sepsis prediction. However, the ability of a combination of these biomarkers has not been clarified.

Methods: An observational case-control study was conducted that included 30 sepsis patients, 30 critically ill patients without sepsis admitted to the intensive care unit (ICU), and 32 healthy individuals. The levels of HLA-DR, CD64, and PD-1 expression in peripheral blood immune cells and subsets was assayed on Days 1, 3, and 5, and the clinical information of patients was collected. We compared these biomarkers between groups and evaluated the predictive validity of single and combined biomarkers on sepsis mortality.

Results: The results indicate that PD-1 expression on CD4^- CD8^- T (PD-1⁺ CD4^- CD8^- T) (19.19% ± 10.78% vs. 9.88% ± 1.79%, p = .004) cells and neutrophil CD64 index (nCD64 index) (9.15 ± 5.46 vs. 5.33 ± 2.34, p = .001) of sepsis patients were significantly increased, and HLA-DR expression on monocytes (mHLA-DR⁺ ) was significantly reduced (13.26% ± 8.06% vs. 30.17% ± 21.42%, p = 2.54 × 10^-4 ) compared with nonsepsis critically ill patients on the first day. Importantly, the expression of PD-1⁺ CD4^- CD8^- T (OR = 0.622, 95% CI = 0.423-0.916, p = .016) and mHLA-DR⁺ (OR = 1.146, 95% CI = 1.014-1.295, p = .029) were significantly associated with sepsis mortality. For sepsis diagnosis, the mHLA-DR⁺ , PD-1⁺ CD4^- CD8^- T, and nCD64 index showed the moderate individual performance, and combinations of the three biomarkers achieved greater diagnostic value (AUC = 0.899, 95% CI = 0.792-0.962). When adding PCT into the combined model, the AUC increased to 0.936 (95% CI = 0.840-0.983). For sepsis mortality, combinations of PD-1⁺ CD4^- CD8^- T and mHLA-DR⁺ , have a good ability to predict the prognosis of sepsis patients, with an AUC = 0.921 (95% CI = 0.762-0.987).

Conclusion: These findings indicate that the combinations of HLA-DR, CD64, and PD-1 outperformed each of the single indicator in diagnosis and predicting prognosis of sepsis.

Keywords: CD64; HLA-DR; PD-1; predict; sepsis.

Figure 1

(A–F) Alterations in PD‐1, HLA‐DR, and CD64 expression in the peripheral blood of patients in each group. (A), (C), (E) Dot plots show the percentage of PD‐1 + CD4‐CD48‐T cells and HLA‐DR+ monocytes, the CD64 index in sepsis (S, n = 30) and nonsepsis patients (NS, n = 30) on Days 1, 3, and 5 of admission, and healthy volunteers (H, n = 32). (B), (D), (F) Dot plots show the comparison of three markers between septic survivors (SS) and nonsurvivors (SD) on Days 1, 3, and 5 of admission. D1, Day‐1; D3, Day‐3; D7, Day‐7.

Figure 2

(A), (B) ROC analyses for predicting ICU mortality. (C)‐(H) Cox regression analysis of survival curves. (A) The AUC and 95% CI of mHLA‐DR, PD‐1 + CD4‐CD8‐T, and the combined model constructed by the two indicators. (B) Cox regression analysis survival curves showed that sepsis patients with the predicted probability of the combined model ≥0.38 had higher ICU mortality (HR = 21.67, 95% CI = 4.53–103.70, p = .0001) than those with lower levels.