The Signicance of Routine Biochemical Markers in Patients With Sepsis

Background: Sepsis is a highly complex and fatal syndrome. It is the main cause of death in the intensive care unit. Early diagnosis is benecial to reduce the mortality of sepsis and improve the prognosis of patients. Therefore, we look forward to nding cheap and fast diagnostic criteria to quickly assess the patient's condition. Methods: This is a retrospective study. The study enrolled 499 patients in the First Aliated Hospital of Xinjiang Medical University from January 1, 2018 to June 22, 2020, and 96 healthy cases in the same period. Using the diagnostic criteria of bacterial infection, SIRS criteria and Sepsis-2 consensus criteria, 499 patients and 96 healthy cases were divided into 4 groups: sepsis group (n=300), SIRS group (n=151), infection group (n= 48), the control group (n=96). We collected the results of routine laboratory tests, inammation indicators and blood culture results of these patients. Results: The sepsis group compared with the control group, MCV, NE, WBC, PLT, HB, D-Dimer, PT, CRP, PCT, IL-6, ALB, TBIL, Cr, LAC, CysC and BNP were statistically signicant. D-dimer, CRP and PCT have higher diagnostic eciency. Compared with the difference between the infection group and the SIRS group, PLT and IL-6 are statistically signicant, and have a certain diagnostic value. Sepsis group VS infection group, WBC, IL-6, NE and TBIL showed statistical differences in the comparison. The AUC of NE was 67.6, which was the largest among the three. The specicity (95.8%) was the highest, but the sensitivity (49%) was low. Conclusions: This retrospective study shows that NE, WBC, and D-dimer can help in the early diagnosis of sepsis. D-dimer performs best. WBC and NE may have a differential diagnosis signicance between the sepsis group and the infection group. This result can provide a timely and convenient assessment tool for early diagnosis of sepsis. coagulation biomarkers in early laboratory test results. We analyze the diagnostic value of NE, WBC, D-dimer and other indicators. This study aims to clarify the applicability of early inammation and coagulation routine laboratory test results as an early diagnosis of sepsis. Contribute to early diagnosis and early treatment and reduce patient mortality. = 48), and control group(n = 96) using diagnostic criteria for bacterial infection, systemic inammatory response syndrome and Sepsis2.0 diagnostic criteria. Kruskal-Wallis test was used to compare NE, WBC, D-Dimer, PT, CRP, PCT and IL-6, and ROC curve was drawn to evaluate the diagnostic ecacy of parameters. The accuracy total leukocyte parameters can provide valuable information for the diagnosis and follow-up of sepsis in patients with liver damage in ICU. statistical signicance in the comparison between is related to our use of the Sepsis2.0 diagnostic criteria. prospective cohort study of early biomarkers of sepsis in burn patients: NE can be used as a biomarker for predicting/early diagnosing sepsis. The use of therapeutic interventions for neutrophil dysfunction may reduce the incidence of nosocomial infection and sepsis after burns. The study suggests that the total number of white blood cells (p < 0.05) in patients with sepsis is higher than that in the control group, which is consistent with our analysis. There is no statistical difference in platelets between the control group and sepsis patients, which may be related to the impact of their choice of lung disease as the control group on the results (28,29). In our data analysis, although PLT is statistically different in the comparison between the sepsis group and the healthy control group (P < 0.05), it has no diagnostic value. In the comparison between the sepsis group and the SIRS group reect a certain signicance of differential diagnosis and can be used as an auxiliary indicator. A study of ICU patients with liver disease showed that it was related to signicant differences in WBC and CRP. The diagnostic accuracy of white blood cell parameters may provide valuable information for the diagnosis and follow-up of sepsis in ICU patients (especially patients with liver dysfunction) (27). There are also many studies suggesting that the combination of white blood cell count or neutrophil count with other indicators may increase the detection rate of sepsis, which can guide us in the next step of research (14). all conducive to the early detection of sepsis. In one study of mice(28), a sepsis model was created by intraperitoneal injection of liposolysaccharide (LPS). 24 hours later, there was an exudative platelet aggregation in the liver, and the levels of AST, ALT, and DBIL were signicantly elevated. This study suggests that Neutrophil Extracellular Traps (NETs) formation and platelet aggregation are the rst steps in the development of liver dysfunction in sepsis. Inammation and coagulation play a key role in the pathogenesis of septicemia, leading to multi-organ failure, echoing Sepsis3.0 diagnostic criteria.


Introduction
Sepsis is a life-threatening organ dysfunction caused by the host's dysregulated response to infection (1,2). In 2017, 48.9 million cases of sepsis and 11 million deaths from sepsis occurred. The high mortality rate has caused extensive clinical concern for sepsis (3,4).
Sepsis occurs on the basis of infection, involves systemic in ammatory response to infection, and manifests as microvascular dysfunction, coagulation disorders, and ultimately lead to multiple organ dysfunction (5,6). The clinical manifestations of sepsis are easily interfered by many factors in the early stage, and lack of speci city, making its clinical manifestations often misleading and di cult to diagnose. Cultivation of pathogenic bacteria from blood or body uids is regarded as the "gold standard" for diagnosing infection (7). However, it takes a long time to detect (mostly 3 to 5 days) and is susceptible to many factors, which can cause delays in diagnosis and treatment. Studies have suggested that the delay in the rst use of antibiotics is related to the increase in hospital mortality, and early use of antibiotics requires early identi cation of sepsis and nding effective early diagnosis indicators, which is conducive to early diagnosis and early treatment of sepsis patients and reduces patient deaths rate (8,9).
Although sepsis3.0 diagnostic criteria have been proposed, there are still controversies regarding it. Sepsis3.0 diagnostic criteria have higher speci city, while Sepsis2.0 diagnostic criteria have better sensitivity (10). Sepsis3.0 focuses on organ dysfunction. Most of the patients who died of sepsis in the clinic are patients with early sepsis who have not yet shown organ dysfunction. The application of sepsis3.0 diagnostic criteria is not conducive to early identi cation of sepsis. Studies have suggested that the Sepsis2.0 diagnostic criteria can predict the adverse consequences of sepsis in emergency patients, and speculate that those patients with sepsis who can bene t most from early treatment. In addition, the sepsis3.0 diagnostic criteria uses the SOFA score, which is not widely used in clinical practice. This study is a retrospective study and it is impossible to collect relevant data retrospectively. Therefore, the use of the Sepsis2.0 diagnostic criteria is more practical and bene cial to early diagnosis and treatment (11,12).
This article is a retrospective study that evaluated the diagnostic value of infection and coagulation biomarkers in early laboratory test results.
We analyze the diagnostic value of NE, WBC, D-dimer and other indicators. This study aims to clarify the applicability of early in ammation and coagulation routine laboratory test results as an early diagnosis of sepsis. Contribute to early diagnosis and early treatment and reduce patient mortality. 32 mmHg)and leukocytosis (≥ 12,000/cu mm) or leukopenia(≤ 4,000/cu mm) (13) . Infection diagnostic criteria: when the same strain is detected more than twice in the blood culture results, the patient is considered to have infection. According to the bacterial infection standard, SIRS diagnostic standard and sepsis diagnostic standard, 499 patients were divided into 3 groups, namely, sepsis group (infection plus SIRS), SIRS group (two or more SIRS criteria), infection group (positive blood culture with zero or one SIRS criterion). In addition to the healthy controls, there are four groups (14,15).

Materials And Methods
Exclusion Criteria

Results
Clinical data of patients A total of 596 patients are enrolled into the study,There are 300 cases (50.4%) in the sepsis group, 151 cases (25.4%) in the SIRS group, 48 cases (8.1%) in the infection group, and 96 cases (16.1%) in the control group. The clinical data of patients were shown in Table 1 and bacteriological ndings were shown in Table 2. Kruskal-Wallis test was used for the difference analysis: Neutrophil count (NE), white blood cell count (WBC), interleukin-6 (IL-6) and total bilirubin (TBIL) were signi cantly different between the sepsis group and the SIRS group (P < 0.05).

Blood Culture Data
After analyzing the biomarkers of infection and blood coagulation in the patients' early laboratory test results, we checked their microbial blood culture results. The results of microbial blood culture in the sepsis group are shown in Table 2. Among them, 283 patients had mixed infections. Table 3 shows the microbial blood culture results of the infection group, and 16 patients had mixed infections.  Sepsis group vs Control group The diagnostic value of patient laboratory examination results in patients with sepsis Table 4 lists Cutoff values, sensitivity, speci city, 95% con dence interval, and AUC for laboratory examination results. The Cutoff value is taken from the ROC curve (Fig. 2).  Sepsis group vs SIRS group The differential diagnostic value of PLT and IL-6 in patients with sepsis and SIRS K-w difference analysis indicated that PLT and IL-6 had statistical signi cance in patients with sepsis and SIRS (P < 0.05). Table 5 lists the cutoff values of PLT, IL-6, sensitivity, speci city, 95% con dence interval, and AUC. Sensitivity and speci city of the studied parameter, and the Cutoff value is calculated at the speci ed Cutoff value, which is taken from the ROC curve (Fig. 3). Although, IL-6(AUC = 55.7%,95%CI: 0.501-0.614, P < 0.05)and PLT(AUC = 57.3%,95%CI: 0.518-0.629) has differential diagnostic signi cance in patients with sepsis and SIRS, its diagnostic e cacy is general. Sepsis group vs Infection group The differential diagnostic value of NE, WBC, IL-6 and TBIL in patients with sepsis and infection Table 6 lists cutoff values of NE, WBC, IL-6, TBIL, sensitivity, speci city, 95% con dence interval, and AUC. The sensitivity and speci city of the studied parameter are calculated by the speci ed Cutoff value, which is taken from the ROC curve (Fig. 4). When the cutoff point of NE greater than 10.5 was selected, the sensitivity and speci city were 49% and 95.8%, respectively. The sensitivity and speci city of the diagnosis of sepsis were 51% and 89.6%, respectively, when the cutoff point of WBC greater than 12 was selected. When the cutoff point of IL-6 > 84.7 was selected, the sensitivity and speci city of sepsis diagnosis were 70% and 47.9%, respectively. When the cutoff point with TBIL greater than 20.2 was selected, the sensitivity and speci city for the diagnosis of sepsis were 55.3% and 64.6%, respectively. Area under the NE curve (AUC) was greater than WBC, IL-6 and TBIL (AUC = 67.6%, 95%CI: 0.613-0.738, P < 0.05), and its speci city (95.8%) was better than WBC, IL-6 and TBIL.

Discussion
Sepsis refers to the disorder of the body's response to infection and causes organ dysfunction that can threaten the body(16),Sepsis affects almost every organ system. The management of sepsis depends on early recognition and empirical antimicrobial treatment, uid resuscitation and vasopressin treatment (17,18). At present, there is no gold standard for diagnosis of sepsis, which is extremely challenging for its diagnosis and is one of the most important causes of death in the world. More than 30 million people are diagnosed with sepsis each year, and 5 million of them die. Even if the condition is relieved, many patients have long-term sequelae, which requires long-term care and brings a great burden to society and families. The World Health Assembly and WHO in 2017 make sepsis a global health priority (19). Although the global trend of sepsis reduction has been shown, it is important that there are still huge differences in the total number of sepsis between regions. Early diagnosis and early treatment are meaningful for improving patient prognosis and reducing mortality. Therefore, we hope to nd simple and cheap diagnostic criteria (15,19). PCT, IL-6, and CRP have always played an important role in the early diagnosis, disease evaluation and prognosis judgment of sepsis (20,21). However, CRP and PCT are both inconsistent in their diagnostic capabilities (22). CRP has been widely studied for sepsis. Its diagnostic accuracy is called into question because the results are inconsistent and variable depending on the severity of the disease and infection (15).
One study suggested that CRP was less sensitive (AUC81, 96% sensitivity, 79% speci city) and less diagnostic value than PCT in sepsis (23). This is consistent with the results of our study, in which PCT was superior to CRP in the diagnosis of sepsis (AUC99.9, sensitivity 97.4%, speci city 100%) compared with healthy controls, which was bene cial to the diagnosis of sepsis. However, there was no statistical signi cance in the identi cation of sepsis in the SIRS group and the infection group (P > 0.05). Studies of its diagnostic value have yielded mixed results, a meta-analysis found that the AUC of PCT was 0.85, the sensitivity and speci city of predicting sepsis in critically ill patients were 77% and 79% (24). A retrospective study found that the diagnostic utility of PCT in predicting sepsis was relatively low (15). PCT is clinically used to distinguish infectious sepsis from non-infectious diseases, which is consistent with our study. PCT levels were signi cantly higher in the sepsis group and other groups than in the healthy controls. However, PCT did not differentiate sepsis from infection or SIRS, which may be related to the diagnostic criteria of sepsis. The prognosis of infection varies, including death, remission, sepsis, etc. It may become a link in the progression to sepsis. SIRS standard and infection were used as the diagnostic criteria for sepsis, so there was no statistical signi cance in the difference analysis of PCT between the sepsis group and the infection group. For IL-6, a prospective, controlled, multicenter study found that IL-6 can be used as a diagnostic and prognostic biomarker for sepsis and septic shock (21), IL-6 is a better diagnostic indicator of sepsis than PCT and CRP (21). It was also suggested that the diagnostic value of IL-6 in patients with sepsis was almost equal to that of PCT. A meta-analysis suggested that IL-6 should be used as an adjunctive diagnosis in patients with non-infectious in ammation rather than as a diagnostic indicator (22). There are also studies suggesting that the diagnostic value of PCT is better than IL-6 (AUC59.6, sensitivity 43.6%, speci city 100%). In this study, the sepsis group and the healthy control group have the same results (AUC98. 1, P < 0.05). Considering that there are 283 mixed infection patients in the sepsis group, it may be related to the patient's severe illness and impaired immune function.
However, when sepsis is compared with the other two groups, it shows a certain differential diagnosis signi cance, which can be used as a tool to identify sepsis, which is conducive to early targeted sepsis bundle therapy to improve prognosis.
In addition, we also found that TBIL was signi cantly different in sepsis compared with infection or healthy controls, and showed certain diagnostic value. Given that hyperbilirubinemia is a common complication of sepsis, it is used as an indicator of liver function in APA CHEII and sequential organ failure scores (8), which is associated with poor prognosis of sepsis -associated liver injury (25). Some studies also believe that although TBIL is higher in the sepsis group, its correlation is not clinically signi cant because it is a parameter of the SOPA standard (26). Our study did not adopt the SOPA standard, TBIL still showed differences between groups, and comparing the sepsis group and the infection group, the AUC of TBIL was 60.0, the sensitivity was 55.3%, and the speci city was 64.6%, which is meaningful for differential diagnosis. Therefore, it is believed that it may be bene cial to early diagnosis.
Unlike other sepsis biomarkers such as PCT or CRP, WBC, NE, and D-dimer are the rst laboratory test results that clinicians can use. Therefore, we analyzed the diagnostic value of NE, WBC and D-dimer and evaluated their applicability as early diagnosis of sepsis patients. In our study, WBC, IL-6, NE, TBIL showed statistical differences in the comparison between the sepsis group and the infection group. The AUC of NE was 67.6, the largest of the four, with the highest speci city (95.8%) but the lowest sensitivity (49%). The sensitivity and speci city of WBC (AUC66.7) were 51% and 89.6%, and both NE and WBC had certain value of differential diagnosis, although their performance was general. The study suggested that the leucocyte, NE value increased gradually according to the severity of the infection (27). The diagnostic accuracy of total leukocyte parameters can provide valuable information for the diagnosis and follow-up of sepsis in patients with liver damage in ICU. Neutrophil dysfunction may actively participate in the development of sepsis (27). In our study, both NE and WBC in the sepsis group and the healthy control group showed diagnostic signi cance, and the diagnostic e ciency was fair (NE: AUC86.5, sensitivity 79.5%, speci city 100%; WBC: AUC77.9, sensitivity 66.7%, speci city 100%). The lack of statistical signi cance in the comparison between the sepsis group and the SIRS group is related to our use of the Sepsis2.0 diagnostic criteria. prospective cohort study of early biomarkers of sepsis in burn patients: NE can be used as a biomarker for predicting/early diagnosing sepsis. The use of therapeutic interventions for neutrophil dysfunction may reduce the incidence of nosocomial infection and sepsis after burns. The study suggests that the total number of white blood cells (p < 0.05) in patients with sepsis is higher than that in the control group, which is consistent with our analysis. There is no statistical difference in platelets between the control group and sepsis patients, which may be related to the impact of their choice of lung disease as the control group on the results (28,29). In our data analysis, although PLT is statistically different in the comparison between the sepsis group and the healthy control group (P < 0.05), it has no diagnostic value. In the comparison between the sepsis group and the SIRS group re ect a certain signi cance of differential diagnosis and can be used as an auxiliary indicator. A study of ICU patients with liver disease showed that it was related to signi cant differences in WBC and CRP. The diagnostic accuracy of white blood cell parameters may provide valuable information for the diagnosis and follow-up of sepsis in ICU patients (especially patients with liver dysfunction) (27). There are also many studies suggesting that the combination of white blood cell count or neutrophil count with other indicators may increase the detection rate of sepsis, which can guide us in the next step of research (14).
D-dimer is a brin degradation product, and the increase of D-dimer level indicates the presence of hypercoagulable state and secondary brinolysis in the body. Many factors can increase it, such as infection, DIC, heart or kidney damage, thrombolytic therapy, etc. Sepsis is a clinical syndrome that complicates severe infections. It is characterized by the main manifestations of in ammation (vasodilation, white blood cell accumulation, increased vascular permeability, etc.) appearing in tissues far away from the infection site (30). In ammation and clotting affect each other, Studies have shown that clotting can be activated by in ammation, which leads to endothelial damage and the formation of exudative platelet aggregation (28). In our study, D-dimer showed excellent diagnostic value in the sepsis group, and we believed that D-dimer, PCT and CRP were all conducive to the early detection of sepsis. In one study of mice(28), a sepsis model was created by intraperitoneal injection of liposolysaccharide (LPS). 24 hours later, there was an exudative platelet aggregation in the liver, and the levels of AST, ALT, and DBIL were signi cantly elevated. This study suggests that Neutrophil Extracellular Traps (NETs) formation and platelet aggregation are the rst steps in the development of liver dysfunction in sepsis. In ammation and coagulation play a key role in the pathogenesis of septicemia, leading to multi-organ failure, echoing Sepsis3.0 diagnostic criteria.

Conclusion
Infection is a link in the progression to sepsis, but the treatment regimen for infection and sepsis is different. Early identi cation of sepsis and early implementation of targeted treatment are bene cial for patients with sepsis. In this stud, traditional in ammatory markers CRP,IL-6 and PCT show diagnostic value, among which PCT shows the best performance when compared with control group, but only IL-6 shows certain differential diagnostic signi cance. In early biochemical markers, NE, WBC, and D-dimers have been found to aid in the early diagnosis of sepsis, and D-dimers perform best in this group. This has certain clinical practice value for early diagnosis of sepsis and is conducive to timely medical intervention for patients with sepsis, WBC and NE may have differential diagnostic signi cance in the sepsis and infection groups, and PLT may have differential diagnostic signi cance in the sepsis and SIRS groups. Next, we can include more patients for prospective study to further determine their diagnostic signi cance. Ethical Approval #A: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. #B: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.

Consent to Participate
Informed consent was obtained from all individual participants included in the study.

Consent to Publish
The participant has consented to the submission of the case report to the journal.