Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.[1,2] Septic shock, the most severe form of sepsis, is characterized by circulatory and cellular/metabolic abnormalities, and can increase mortality to >40%.[1-3] Early recognition and risk stratification of septic shock are crucial but challenging because of the heterogeneity of its presentation and progression. Although blood culture is recognized as the gold standard for detecting sepsis, it usually takes several days to obtain result, which may delay the diagnosis. Therefore, with the advantage of rapid screening of pathogens, bedside biomarker detection has been widely used for identifying high-risk patients. Procalcitonin (PCT), C-reactive protein (CRP) and presepsin are the most commonly used biomarkers for sepsis.[4] However, there has been no research comparing the predictive value of presepsin, PCT and CRP for septic shock and risk stratification. Therefore, this study aimed to compare the accuracy of presepsin, PCT and CRP in identifying septic shock and assessing organ dysfunction in a large sample of septic patients.
METHODS
Study population
A secondary analysis of our previous prospective cohort studies on sepsis databases, involving patients in emergency intensive care units, infectious disease departments, and general intensive care units of ten university-affiliated teaching hospitals in China from March 2011 to December 2019 was conducted.[5,6] The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital (approval number: 2022-P2-029-01). Given the retrospective nature and minimal risk of this study, written informed consent was waived.
Inclusion and exclusion criteria
Adult (≥18 years) diagnosed with sepsis or septic shock based on the Sepsis-3 criteria[1] within 24 h of emergency department admission were included. Patients with septic shock can be identified by a clinical diagnosis of sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg (1 mmHg=0.133 kPa) and a serum lactate level >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation.[1] Individuals who were immunosuppressed, taking chemotherapy for cancer, had rejected invasive rescue procedures, were HIV-positive, were pregnant or lactating, had poor prognoses (e.g., uncontrolled tumors or end-stage disease), or had any combination of these conditions were excluded from the study..
Data collection
We obtained data on patients with sepsis and septic shock from databases developed in our previous studies based on the Sepsis-3 criteria. Demographics, comorbidities, laboratory data, biomarkers, etiologies, and outcomes were collected. The biomarkers PCT, presepsin and CRP were measured by point-of-care testing (POCT) within 24 h of a diagnosis of sepsis or septic shock. We calculated the Acute Physiological and Chronic Health Assessment II (APACHE II), Sequential Organ Failure Assessment (SOFA), Mortality in Emergency Department Sepsis (MEDS), Simplified Acute Physiology Score II (SAPS II), and International Society on Thrombosis and Hemostasis (ISTH) scores within the first 24 h post-admission. We recorded the incidences of septic shock, acute respiratory distress syndrome (ARDS),[7] and acute kidney injury (AKI),[8] hospitalization costs, and 28-day mortality. The patients were divided into sepsis group (non-septic shock) and septic shock group or SOFA <5 and SOFA ≥5 groups based on the Sepsis-3 criteria.
Statistical analysis
Continuous variables are presented as medians and interquartile ranges, while categorical variables are expressed as counts and percentages. The differences between the sepsis and septic shock cohorts were assessed using the Kruskal-Wallis test for continuous variables and Fisher’s exact test or Pearson’s Chi-square test for categorical variables. Kaplan-Meier survival curves were analyzed via the log-rank test and outcomes were categorized based on shock presence and SOFA score. Receiver operating characteristic (ROC) curves were used to assess the efficacy of biomarkers in identifying septic shock, and linear regression was used to explore the correlation between the biomarkers and SOFA scores. After adjusting the confounding factors, multivariate logistic regression was used to investigate the relationship of biomarkers on poor outcomes (SOFA score ≥5). All the data were analyzed with R Statistical Software (v4.3), and a two-tailed P <0.05 was considered statistically significant.
RESULTS
Characteristics of patients with sepsis and septic shock
Of the 2,255 patients enrolled in the sepsis database, 1,970 (87.4%) had sepsis and 285 (12.6%) had septic shock (Table 1). Compared to those in the sepsis group, the patients in the septic shock group had higher prevalence of chronic heart disease and higher levels of PCT and presepsin. Patients with septic shock showed lower PaO2/FiO2 ratios, higher lactate levels, and higher APACHE II, SOFA, MEDS and SAPS II scores than those in sepsis patients. Patients with septic shock experienced about twice the incidence of AKI and 28-day mortality compared to those in sepsis patients.
Table 1.
Characteristics and outcomes of patients with sepsis and septic shock
Kaplan-Meier analysis of sepsis and septic shock
After excluding 401 cases with missing follow-up data, the survival outcomes of 1,657 sepsis and 197 septic shock patients were analyzed. Patients with septic shock had a lower 28-day survival rate than patients without shock (log-rank test, P<0.001, Figure 1).
Figure 1.
Kaplan–Meier survival analysis stratified by shock status.
Performance of CRP, PCT, and presepsin for predicting septic shock
The AUC of PCT for predicting septic shock was 0.719 (95%CI: 0.686–0.719; P<0.001) with a cutoff of 5.5 μg/L (sensitivity 63.5%, specificity 70.3%). The AUC of presepsin was 0.661 (95%CI: 0.621–0.661; P<0.001). The specificity for predicting septic shock was 92.2% and the sensitivity was 39.6% using a presepsin cut-off of 2,553.5 pg/mL. CRP had a low AUC of 0.541 (95%CI: 0.501–0.541; P=0.026) with a specificity of 78.3% and a sensitivity of 39.6% (Figure 2).
Figure 2.
Receiver operating characteristic curves comparing CRP, PCT, and presepsin for diagnosing septic shock. CRP: C-reactive protein; PCT: procalcitonin.
Characteristics of sepsis patients stratified by SOFA score
Among 2,255 sepsis patients, 1,028 had SOFA scores <5 and 1,227 had SOFA scores ≥5 (Supplemental Table 1). Compared to patients with SOFA scores <5, patients with SOFA scores ≥5 had higher prevalence of chronic heart disease (51.5% vs. 42.5%, P<0.01) and AKI (58.6% vs. 22.7%, P<0.001), higher levels of PCT (3.0 μg/L vs. 1.0 μg/L, P<0.001) and presepsin (1,601 pg/mL vs. 776 pg/mL, P<0.001). Additionally, they had higher lactate levels, ISTH, APACHE II, MEDS, and SAPS II scores (all P<0.001), and 28-day mortality (45.9% vs. 18.9%, P<0.001) .
Kaplan–Meier analysis of patients stratified by SOFA score
The analysis included 906 patients with SOFA<5 and 948 patients with SOFA≥5, after excluding 401 patients with missing follow-up data. Patients with SOFA scores≥5 had a lower 28-day survival rate than patients with SOFA scores<5 (log-rank test, P<0.01, Supplemental Figure 1).
Association of CRP, PCT, and presepsin levels with SOFA score in sepsis and septic shock patients
Presepsin showed a positive correlation (r=0.520; P<0.001), PCT exhibited a moderate positive correlation (r=0.206; P<0.001), while CRP showed a weak negative correlation (r=-0.067; P=0.001) with SOFA scores, respectively (Supplemental Figure 2).
Effects of CRP, PCT, and presepsin on organ dysfunction severity in patients with sepsis
According to the logistic regression model, PCT (OR=1.013; 95%CI:1.007–1.019; P<0.001) and presepsin (OR=1.001; 95%CI:1.001–1.001; P<0.001) were found to be independent predictors of SOFA score ≥5, but not of CRP (OR=0.999; 95%CI: 0.997–1.001; P=0.183).
DISCUSSION
This secondary analysis study demonstrated that the levels of presepsin and PCT in patients with septic shock or SOFA≥5 were higher than those in patients without septic shock or SOFA <5. Survival analysis confirmed worse outcomes in patients with septic shock or SOFA≥5. PCT and presepsin, but not CRP, were found to be independent predictors of septic shock and organ dysfunction severity.
Biomarkers such as PCT and CRP are increasingly used to improve sepsis diagnosis and risk-stratification.[9] Presepsin is an emerging marker of phagocyte activation that has shown promising diagnostic accuracy in preliminary studies.[10] Our findings supported those of a previous study[11] and showed that individuals with septic shock had elevated PCT and presepsin levels than those with sepsis, but not CRP. This might due to the role of PCT and presepsin as sensitive markers of systemic inflammation specifically triggered by infection,[5,12] while CRP is an acute-phase reactant induced by diverse inflammatory stimuli.[13] Furthermore, ROC analysis revealed that PCT had the highest AUC, indicating a preferable diagnostic precision with reasonable sensitivity and specificity. Presepsin also displayed a moderate accuracy. Although its diagnostic efficiency was inferior to that of PCT, presepsin demonstrates as a complementary tool for assessing septic shock risk. In contrast, CRP had poor discriminatory capacity.
Stratifying sepsis patients using SOFA scores provided insights into understanding the relationship between biomarker levels and clinical outcomes and the severity of the illness. Patients with SOFA scores ≥5, indicating substantial organ dysfunction, had a distinct phenotypic profile marked by exaggerated inflammation, greater resource utilization, and a 2-fold higher mortality than those with SOFA scores <5. Both PCT and presepsin levels were positively correlated with SOFA scores and were found to be independent predictors of SOFA scores ≥5. This supports prior studies that found a correlation between increased PCT and presepsin levels and the severity of sepsis.[14,15]
This study has several limitations. First, as this was a secondary analysis of several retrospective multicenter observational studies, the data were inconsistent and some data were missing. Therefore, we converted the data to a unified unit and removed patients whose primary indicators were missing. Second, instead of employing dynamic monitoring, we measured the biomarker levels within 24 h following a sepsis diagnosis. The goal of our research is quickly screen for pathogens, even if dynamic biomarker detection is commonly used to track the effectiveness of antibiotics or special design.
CONCLUSION
This study indicated that PCT and presepsin were identified as independent predictors of septic shock and organ dysfunction severity, and thus appeared to be promising biomarkers for the early diagnosis of septic shock and risk stratification in septic patients.
Footnotes
Funding: This work was supported by the National Natural Science Foundation of China (no. 82374069), the Beijing Municipal Administration of Hospitals’ Youth Program (no. QML20170105), and the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support “Yangfan” Project (no. ZYLX201802).
Ethical approval: The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital (approval number: 2022-P2-029-01).
Conflicts of interest: None.
Author contributions: CSL contributed to the conception and design of the study. EFR, HLX, GXW, YZZ, and HY contributed to the acquisition of data. CSL, EFR, and HLX contributed to the analysis and interpretation of the data. EFR contributed to the statistical analyses and drafted the manuscript. HLX revised it critically for important intellectual content. All authors read and approved the final manuscript. All listed authors consented to the submission and all data were used with the consent of the person generating the data.
All the supplementary files in this paper are available at http://wjem.com.cn.
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