Severe sepsis and septic shock are major healthcare problems and have high mortality rates (1, 2). Immune suppression is thought to be one of the main causes of death in patients with severe sepsis and septic shock (3, 4). Negative costimulatory molecules play an important role in immune function, as they can negatively regulate cell proliferation, differentiation, and apoptosis. As a member of the B7-CD28 superfamily, programmed cell death 1 (PD-1) plays an inhibitory role (5, 6). PD-1 and programmed death ligand-1 (PD-L1) can effectively inhibit the functions of T and B cells, including cytokine production and cytotoxic activity, and play an important role in immune regulation (7–9). Several studies have reported that the expression of PD-1on lymphocytes and PD-L1 on monocytes was increased in patients with sepsis (10–12). PD-1 has been found to have two forms: a membrane-bound form and a soluble form. Soluble PD-1 (sPD-1) is encoded by PD-1Δex3, which lacks the transmembrane region and has its own biological function; like a cytokine, sPD-1 circulates in the blood stream to exert its function in immune response (13). In recent years, sPD-1 has drawn increasing attention, and it is currently believed that sPD-1 functions as an indispensable natural inhibitor that maintains the balance of the PD-1/PD-L1 signalling pathway. Previous studies have shown that sPD-1 promotes the T-cell response via the inhibition of the PD-1/PD-L1 signalling pathway and that excessive sPD-1 may lead to an immune imbalance in which auto-reactive T cells cannot be effectively inhibited or cleared; this in turn results in pathological immune damage (13). The levels of sPD-1 have been found in patients and experimental animals with autoimmune diseases (14), chronic viral infection (15), and cancer (16); however, a correlation between the sPD-1 levels and severe sepsis or septic shock has rarely been reported.
Our research group has demonstrated a correlation between the expression of membrane-bound PD-1/PD-L1 and the prognosis of patients with severe sepsis or septic shock (17, 18). Thus, we speculate that sPD-1 in the serum may also be associated with risk stratification and prognostic evaluation. In this study, we measured the correlation among the peripheral blood levels of sPD-1 and sPD-L1, the expression of PD-1 on CD4+ and CD8+ T cells, the expression of PD-L1 on monocytes, and the disease severity to evaluate the predictive value of sPD-1 levels for the severity and 28-day mortality in patients with severe sepsis or septic shock during the first week in an intensive care unit (ICU).
PATIENTS AND METHODS
This observational clinical study was conducted in an 18-bed emergency ICU of Beijing Chao-Yang Hospital, a tertiary care teaching hospital. Consecutive patients who were admitted to the ICU with severe sepsis or septic shock were enrolled between January 2015 and January 2016. In addition, healthy volunteers were recruited as healthy controls. The diagnoses of severe sepsis and septic shock were made according to the diagnostic criteria listed in the 2001 International Sepsis Definitions Conference (19). The exclusion criteria were as follows: age<18 years, surgical trauma, blood diseases, autoimmune diseases, HIV infection, liver disease (hepatitis, cirrhosis, etc.), end-stage renal disease (requiring dialysis), cancer, pregnancy, and treatment with hormone therapy. Patients included may have had one or more previous comorbidities, including chronic obstructive pulmonary disease, cardiovascular disease (coronary heart disease and/or heart failure), chronic kidney disease (excluding diseases requiring dialysis), diabetes mellitus, and cerebrovascular disease. First, all patients were divided into the severe sepsis group or the septic shock group according to their disease severity on admission. Second, all patients with severe sepsis or septic shock were followed-up for 28 days, and a survivor group and nonsurvivor group were generated according to the 28-day outcomes. Those discharged earlier than 28 days were followed-up by telephone to define their outcomes. All treatments given to the patients followed the 2012 International Guidelines for Management of Severe Sepsis and Septic Shock (20). This study was conducted in accordance with medical ethics standards, was approved by the Ethics Committee of Beijing Chao-Yang Hospital, and was performed after informed consent was obtained from the patients or their families.
Age, gender, address, telephone number, vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation, temperature), altered consciousness state, nursing home resident status, comorbidities, contact number, medical history, routine blood tests, white blood cell differential count, blood gas analysis, liver and kidney function, coagulation function, procalcitonin (PCT) level, C-reactive protein (CRP) level, chest X-ray, and bacteriologic tests of sputum, blood, or urine of all patients were recorded or assessed upon ICU admission (day 1) as well as on day 7 after ICU treatment. The expression of PD-1 was measured on circulating CD4+ T cells and CD8+ T cells and in the serum (sPD-1). The expression of PD-L1 was measured on monocytes and in the serum (sPD-L1). Four milliliters of vein blood from each subject was obtained on days 1 and 7 and was stored in ethylene diamine tetraacetic acid anticoagulant tubes for flow cytometry analysis. Additionally, peripheral blood serum was collected and stored at −80°C for the determination of the sPD-1 and sPD-L1 levels. The Acute Physiology and Chronic Health Evaluation System II (APACHE II) score and the Sequential Organ Failure Assessment (SOFA) score were determined within 24 h of admission.
Measurements of sPD-1, sPD-L1, PCT, and CRP levels
The levels of sPD-1 and sPD-L1 were measured using an enzyme-linked immunosorbent assay kit (DuoSet Human PD-1, R&D systems, Minneapolis, Minn) in an automatic microplate reader (Multiskan MK3; Thermo, West Palm Beach, Fla). PCT levels were measured using an enzyme-linked fluorescence immunoassay and a miniVIDAS immunoassay analyzer (BioMerieux, Durham, NC). The levels of CRP were measured using the QuickRead CRP kit (Orion Diagnostica Oy, Espoo, Finland) according to the rapid immune turbidity method.
The cells were stained, and erythrocytes were lysed by researchers who were blinded to the clinical data. According to the manufacturer's recommendations, the following monoclonal antibodies and their isotype controls were used per 100 μL of whole blood: BV421-labeled anti-PD-1 (5 μL, clone EH12.1; BD Bioscience, San Jose, Calif), PE-labeled anti-PD-L1 (20 μL, clone M1H1; BD Bioscience), APC-H7-labeled anti-CD3 (5 μL, clone SK7; BD Bioscience), FITC-labeled anti-CD4 (5 μL, clone OKT4; eBioscience, San Diego, Calif), FITC-labeled anti-CD8 (20 μL, clone RPA-T8; BD Bioscience), and APC-H7-labeled anti-CD14 (5 μL, clone MϕP9; BD Bioscience). The samples were measured in a Gallios Flow Cytometer (Beckman Coulter, Inc Miami, Fla) and were analyzed by Gallios Software Version 1.0 (Beckman Coulter, Inc). Lymphocytes were gated by forward scatter and side scatter, and T-cell subsets were further distinguished by CD3+ and CD4+ staining or CD3+ and CD8+ staining. Monocytes were identified by CD14+ staining. At least 3,000 cells were analysed from each sample. The results are expressed as percentages and mean fluorescence intensities (MFIs).
Data were analysed with SPSS 17.0 (SPSS Inc, Chicago, Ill). Age, scores and test results were all non-normally distributed. These variables are presented as medians with interquartile ranges [M (QL, QU)]. The Kruskal–Wallis test was applied for multigroup comparisons, and the Mann–Whitney U test was applied for comparisons between two groups. Categorical clinical variables were tested using the chi-square test. Correlations between factors were analysed by the Spearman correlation test. Cox regression analysis was performed to adjust the prognostic value. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) values were used to compare the predictive capacities of relevant variables. For comparison of the AUCs, the formula
was used, and the test value was Z0.05 = 1.96. The cutoff value of each variable was determined by the Youden index, and each variable's sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Values of P < 0.05 indicate statistically significant differences.
Characteristics of the patients
A total of 120 patients were enrolled after screening 287 patients with severe sepsis and septic shock (Fig. 1). There were eight patients were subsequently excluded from analysis, two patients were determined not to be infected following enrollment, six patients had missing data or loss of follow-up. Eventually, 112 patients and 45 healthy volunteers were enrolled in this study. There were 72 cases of severe sepsis and 40 cases of septic shock (Table 1). On day 1 of ICU admission, no significant differences were observed in age or gender between the healthy controls and the patients with severe sepsis or septic shock (P>0.05). Compared with the white blood cell (WBC) and platelet counts in the healthy controls, the counts in the patients with severe sepsis and septic shock were significantly different (P < 0.001). However, WBC counts, platelet counts, CRP levels, and the occurrence of comorbidities (see table, Supplemental Digital Content 1, http://links.lww.com/SHK/A741) were not different between the severe sepsis group and the septic shock group (P > 0.05). The PCT levels, APACHE II score, SOFA score, and 28-day mortality were significantly different between the severe sepsis group and the septic shock group (P < 0.05).
Expression of PD-1 and PD-L1 on day 1
Compared with the levels of sPD-1 and sPD-L1, the percentages and MFI values of PD-1 on CD4+ and CD8+ T cells, and the percentages and MFI values of PD-L1 on monocytes in the healthy controls, those values in the patients with severe sepsis or septic shock on day 1 of ICU admission were significantly higher (P < 0.001). However, only the levels of sPD-1 and sPD-L1, the percentages of PD-1 on CD8+ T cells, and the percentages of PD-L1 on monocytes were significantly different between the severe sepsis and septic shock groups (P < 0.05) (Table 1). As the severity of sepsis increased, the levels of sPD-1and sPD-L1 gradually increased as well (Fig. 2).
Correlation among serum sPD-1, sPD-L1, and related parameters on day 1
The levels of sPD-1and sPD-L1 were both positively correlated with the APACHE II score (r = 0.409 and 0.250, respectively, P < 0.01) and with the SOFA score (r = 0.360 and 0.193, respectively, P < 0.05) but showed no significant correlation with age, WBC counts, CRP levels, or PCT levels (P > 0.05) (see table, Supplemental Digital Content 2, http://links.lww.com/SHK/A742). The serum sPD-1 levels were positively correlated with the serum sPD-L1 levels (r = 0.498, P < 0.001), and with the percentages and MFI values of PD-1 on CD4+ T cells (r = 0.381 and 0.292, respectively, P < 0.05), the percentages and MFI values of PD-1 on CD8+ T cells (r = 0.336 and 0.236, respectively, P < 0.05), and the percentages and MFI values of PD-L1 on monocytes (r = 0.421 and 0.232, respectively, P < 0.05). However, the levels of sPD-L1 were only positively correlated with the percentages of PD-1 on CD4+ T cells and the percentages of PD-L1 on monocytes (r = 0.206 and 0.332, respectively, P < 0.05). Negative correlations were also observed, as the levels of sPD-L1 were negatively correlated with platelet counts (r = −0.234, P = 0.013).
Comparisons between the survivor and non-survivor groups
According to the 28-day outcomes, all patients were separated into the survivor group (73 cases) or the non-survivor group (39 cases) on day 1. There were 16 patients who failed to survive the first week, and thus, 23 cases were enrolled in the non-survivor group and 73 cases were enrolled in the survivor group on day 7. On day 1, the sPD-1, sPD-L1, WBC, CRP, and PCT levels, the APACHE II score, the SOFA score, the percentages and MFI values of PD-1 on CD4+and CD8+ T cells, and the percentages and MFI values of PD-L1 on monocytes were all significantly higher in the non-survivors than in the survivors (P < 0.05). Age, gender, platelet count, and site of infection were not significantly different between the survivors and non-survivors (P > 0.05) (Table 2). Similar results were also found on day 7 (see table, Supplemental Digital Content 3, http://links.lww.com/SHK/A743). Compared with the day 1 results, the day 7 APACHE II score (median: 10, IQR: 8–13) and the SOFA score (median: 6, IQR: 4–8) were decreased in the survivor group (P < 0.001). As the severity of the disease decreased, only the levels of sPD-1 on day 7 were lower than those on day 1 (median: 1.11 ng/mL, IQR: 0.69–1.86 ng/mL; vs. median: 1.68 ng/mL, IQR: 1.04–2.40 ng/mL; P < 0.001) in the survivor group. The levels of sPD-L1, the expression of PD-1 on CD4+ and CD8+ T cells, and the expression of PD-L1 on monocytes were not significantly different between day 1 and day 7 in either the survivors or the non-survivors (P > 0.05) (Fig. 3).
According to the 7-day outcomes, on day 1, the sPD-1, sPD-L1, WBC, and CRP levels, the APACHE II score, the SOFA score, the percentages and MFI of PD-1+CD4+ T cells, the Percentage of PD-1+CD8+ T cells, and the percentages and MFI of PD-L1+ on monocytes were all significantly higher in the non-survivors (16 cases) than in the survivors (96 cases) (P < 0.05) (see table, Supplemental Digital Content 4, http://links.lww.com/SHK/A744).
Prognostic value of sPD-1
A Cox regression analysis of the sPD-1, sPD-L1, WBC, CRP, and PCT levels, the APACHE II score, the SOFA score, the percentages and MFI values of PD-1 on CD4+and CD8+ T cells, and the percentages and MFI values of PD-L1 on monocytes was performed. This analysis demonstrated that only thesPD-1 level, APACHE II score, SOFA score, and the percentage of PD-L1 on monocytes were independent prognostic factors for the 28-day mortality both on day 1 and day 7 (Table 3).
The capacities of the sPD-1 level, APACHE II score, SOFA score, the percentage of PD-L1 on monocytes, and the combinations to predict the 28-day mortality on day 1 and day 7 were compared using ROC curves (Fig. 4). No significant difference was observed among the AUCs for the sPD-1 level, percentage of PD-L1 on monocytes, APACHE II score, SOFA score, APACHE II score combined with sPD-1, or SOFA score combined with sPD-1 on day 1 (0.785, 0.849, 0.804, 0.773, 0.884, and 0.856, respectively, P > 0.05). The AUCs for the sPD-1 level, APACHE II score, SOFA score, APACHE II score combined with sPD-1, and SOFA score combined with sPD-1 (0.871, 0.934, 0.915, 0.954, and 0.946, respectively) were higher than the AUC for the percentage of PD-L1 on monocytes (0.770) on day 7 (P < 0.05). Notably, the AUC for the sPD-1 levels on day 7 was higher than that for the sPD-1 levels on day 1 (P < 0.05) (Table 4).The cutoff value of the level of sPD-1 (2.71 ng/mL) on day 7 for the prediction of the 28-day mortality showed the highest specificity (97.3%). A Kaplan–Meier survival analysis indicated that, compared with patients with lower sPD-1 levels, patients with sPD-1 levels higher than the cutoff values of 2.66 ng/mL on day 1 or 2.71 ng/mL on day 7 had a lower probability of survival at 28 days (P < 0.001) (Fig. 5).
In this study, we found that the expression of PD-1 and PD-L1 was upregulated in patients with severe sepsis or septic shock. The peripheral blood levels of sPD-1 and sPD-L1, the expression of PD-1 on CD4+ T cells and CD8+ T cells, and the expression of PD-L1 on monocytes were higher in non-survivors than in survivors, and the levels of sPD-1 and sPD-L1 were positively correlated with the severity of sepsis. With a reduction in the severity of disease in the survivor group, only the levels of sPD-1 were decreased in the first week. In addition, the sPD-1 level was an independent predictive factor for 28-day mortality both on day 1 and day 7. Monitoring the levels of sPD-1 may improve the prognostic evaluation of patients during the first week of ICU treatment. Our results suggest that sPD-1 may be used as an immunological biomarker for risk stratification and for the prediction of the prognosis of patients with severe sepsis or septic shock.
Severe immunosuppression leads to the deterioration of patients with sepsis (3), and negative costimulatory molecules such as PD-1/PD-L1 may play an important role (6). It was reported that the expression levels of PD-1 on the surface of peripheral blood macrophages and monocytes were increased in a mouse model of sepsis (21) and that a PD-l antagonist significantly improved the survival of mice with sepsis (22). Many clinical studies have shown that the expression levels of PD-1/PD-L1 on the surface of cells were upregulated in patients with severe sepsis or septic shock (10–12). We also found that the expression levels of PD-1 on CD4+ or CD8+ T cells and the expression of PD-L1 on monocytes were significantly increased in patients with severe sepsis or septic shock. Additionally, this study found that sPD-1 and sPD-L1 levels were increased in patients with severe sepsis or septic shock. This indicated that, like the membrane-bound forms, sPD-1/sPD-L1are also involved in the immune regulation of sepsis.
Our results show that the levels of sPD-1 and sPD-L1 were both positively correlated with the APACHE II score and the SOFA score and that the levels of sPD-1 and sPD-L1 were increased in the non-survivors. We demonstrated that sPD-1/sPD-L1 levels were positively correlated with the severity of disease and that a marked increase in the levels of sPD-1/sPD-L1 may indicate immune dysfunction in patients with severe sepsis or septic shock. It has been found that sPD-1/sPD-L1 is a natural signal inhibitor that plays an important role in maintaining the balance between PD-1 and PD-L1 (13). sPD-1 can competitively bind PD-1 ligands (PD-L1 and PD-L2), which blocks the interactions between PD-1 and PD-Ls on the surface of the cell membrane (23). It was also found that PD-L1+ cells can release abundant sPD-L1 and that the released sPD-L1 maintains its ability to bind to the receptor PD-1. sPD-L1 can also promote T-cell responses via inhibition of the PD-1/PD-L1 pathway(24).
We found a positive correlation between the peripheral blood levels of sPD-1/sPD-L1 and the expression levels of membrane-bound PD-1/PD-L1 in patients with severe sepsis or septic shock, and sPD-1 showed a better correlation with membrane-bound PD-1/PD-L1 than sPD-L1 did. sPD-1 can promote T-cell responses by blocking the membrane-bound PD-1/PD-L1 pathway in vitro (25). The overexpression of PD-1 on CD4+ and CD8+ T cells and elevated serum levels of sPD-1 have been found in patients with rheumatoid arthritis or aplastic anaemia (26, 27).The ability of overexpressed PD-1 on T cells to restrict excessive self-reaction is counteracted by the excessive production of sPD-1 (27). The increase in membrane-bound PD-1/PD-L1 may lead to a secondary increase in sPD-1/sPD-L1 levels. This was also the case for the membrane-bound PD-1 and PD-L1 overexpressed in rheumatoid arthritis patients, and the sPD-1/sPD-L1 levels in those patients also increased to inhibit the regulatory effect of membrane-bound PD-1 and PD-L1 (26). However, when such immune regulation is uncontrolled, excessive sPD-1 may serve as an antibody to block the PD-1/PD-L1 pathway, which leads to the aberrant activation and proliferation of T cells (13, 14). Therefore, a marked increase in sPD-1 levels may represent more severe immune damage in patients with sepsis. Recent research has found that sPD-1 was elevated in cases of critical illness and might represent a potential biomarker for acute respiratory distress syndrome (ARDS). The expression of PD-1ΔEx3 (mRNA for sPD-1) was increased in the peripheral blood of patients with ARDS. In an animal model, a similar rise in the serum levels of sPD-1 was seen in mice with ARDS (28).
Notably, in this study, with the reduction in the severity of the disease in the survivors, only the levels of sPD-1 were decreased in the first week. No significant variation was observed over time in the expression of PD-1 on T cells or in the expression of PD-L1 on monocytes. Similar results were also reported in another study of 10 patients with septic shock who were admitted to the ICU; from day 1 to day 10, no change was seen in PD-1 expression on either monocytes or lymphocytes (10). We speculate that the decrease in the levels of sPD-1 in the serum may occur earlier than changes in the expression of PD-1/PD-L1 in their membrane-bound forms. This study suggested that sPD-1 was an independent prognostic factor for 28-day mortality both on day 1 and day 7. Importantly, our results showed that the AUC for sPD-1 on day 7 was higher than that for sPD-1 on day 1. The prognostic accuracy of the sPD-1 level in the prediction of the 28-day mortality was similar to that of the APACHE II score and the SOFA score and was better than that of the percentage of PD-L1 on monocytes on day 7. This result indicated that monitoring the changes in the sPD-1level might improve the ability to predict the 28-day mortality. Moreover, the detection of serum sPD-1 is more convenient than the detection of membrane-bound PD-1/PD-L1 by flow cytometry and is conducive to rapid detection in clinical applications.
The SOFA and APACHE II scores are multiple system assessment scores for critical ill patients, but lack the evaluation of immune function. As an immunological biomarker, sPD-1 may helps to improve the predictive capacity of scoring system for the prognosis of patients with sepsis. Although the difference was not statistically significant, our result indicated that combined sPD-1 with APACHE II or SOFA score had better AUC than the scoring system used alone. It may because the sample size of our research. Maybe, a larger sample size study would have found statistically significant differences.
In this study, the levels of sPD-1 and sPD-L1 were increased in patients with severe sepsis or septic shock. However, sPD-1 demonstrated a better predictive value than sPD-L1 for prognostic evaluation. We did not detect an association between sPD-L1 and 28-day mortality, which may be related to the different effects of sPD-1/sPD-L1 on membrane-bound PD-1/PD-L1. sPD-1 binds PD-L1 and PD-L2, while sPD-L1 binds PD-1. A recent study by Liu et al. (29) proposed that serum sPD-L1 may be an independent prognostic factor for sepsis and may reflect disease severity and clinical outcomes in patients. Some reasons may explain the contradictory results between our study and the study by Liu et al. (29) First, different detection reagents should be considered. Second, differences in the severity of disease in the patient sample could also have contributed to the differences. This study selected patients with severe sepsis and septic shock, while Liu et al. (29) selected patients with general sepsis. Thus, the prognostic value of sPD-1 and sPD-L1 deserves to be examined further in a larger cohort of patients with sepsis.
This study has several limitations. First, Many investigators reported that the levels of sPD-1 were increased in autoimmune diseases (14), liver disease (15), cancer (16), and blood diseases (27), to minimize the influence of the patient's basic disease on our results, we excluded all patients with these diseases. Second, we assessed the commonly used inflammatory biomarkers of PCT and CRP for this study, but these markers showed no significant correlation with sPD-1/sPD-L1. Thus, the correlation between sPD-1/sPD-L1 and inflammatory cytokines during sepsis remains to be explored. The assessment of a combination of sPD-1 levels, inflammatory biomarkers, and a scoring system may be more effective in patients with severe sepsis or septic shock. Third, this study is only observational, and the underlying molecular mechanism should be investigated in further research. Lastly, this study was performed in an ICU in a single centre, and the sample size of our research was limited, multicentre studies with a larger sample size are required to further validate these results.
This study demonstrated that the serum levels of sPD-1 and sPD-L1, the expression of PD-1 on CD4+ T cells and CD8+ T cells, and the expression of PD-L1 on monocytes were all significantly increased in patients with severe sepsis or septic shock. The serum sPD-1 level is an independent predictive factor for 28-day mortality both on day 1 and day 7, and it shows a valuable predictive capacity for risk stratification and 28-day mortality. Monitoring the levels of sPD-1 may improve the predictive ability during the first week of ICU treatment. However, the clinical application of serum sPD-1 testing in patients with sepsis requires further investigation.
The authors express their gratitude for the generosity of the patients who participated in this study. The authors also sincerely thank the colleagues of our emergency department for their excellent clinical assistance.
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Programmed death ligand-1; programmed death-1; septic shock; severe sepsis; soluble programmed death ligand-1; soluble programmed death-1
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