Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation

Jing Wang, Yizhu Sun, Shengnan Teng, Kefeng Li, Jing Wang, Yizhu Sun, Shengnan Teng, Kefeng Li

Abstract

Background: Sepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways.

Methods: We searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis.

Results: The meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76-0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78-0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78-0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9-89.4%) and 78.8% (95% CI 62.3-89.3%), respectively.

Conclusions: DRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction.

Trial registration: The meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).

Keywords: Blood; Death-related metabolic pathways; Meta-analysis; Metabolomics; Outcome; Prediction; Sepsis.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of the included studies
Fig. 2
Fig. 2
The vote count of the chemical classes for the differential metabolites between survivors and nonsurvivors (a) and the pooled fold changes (nonsurvivors/survivors), and P values for the dramatically altered metabolic pathways in sepsis nonsurvivors compared to the survivors (b). For the pie chart (a), the vote count indicated the frequency of a chemical class being identified as statistically different between sepsis nonsurvivors and survivors. For the volcano plot (b), a metabolic pathway was assigned to each differential metabolite. The pooled fold change and P value were calculated using random effects in the meta-analysis. We also added the vote-counting analysis to the volcano plot, which showed the frequency of a metabolic pathway being identified as statistically different between sepsis nonsurvivors and survivors. P < 0.05 was considered statistically significant
Fig. 3
Fig. 3
The pooled AUROC for the prediction accuracy of sepsis death using metabolite biomarkers without summarizing the pathways. LysoPG, lysophosphatidylglycerol; S-3dE, S-(3-methylbutanoyl)-dihydrolipoamide-E; Cer, ceramides; LysoPC, lysophosphatidylcholine; PC, phospholipids
Fig. 4
Fig. 4
The AUROC for the prediction accuracy of sepsis death using metabolites from a lysophospholipid metabolism, b amino acid, and c mitochondrial metabolism. Results were presented as individual and pooled AUROC and 95% CI
Fig. 5
Fig. 5
The pooled AUROCs for the prediction accuracy of sepsis death using DRMPs. The DRMPs were lysophospholipid, amino acid, and mitochondrial metabolism. Results were presented as individual and pooled AUROCs and 95% CI
Fig. 6
Fig. 6
The comparison of the pooled AUROCs for the prediction accuracy of sepsis death using different biomarkers. One-way ANOVA was performed, and columns indexed by the same letter indicated that the differences are not significant (P > 0.05)
Fig. 7
Fig. 7
ROC analysis showed the prediction accuracy of sepsis death using a SOFA scores. b APACHE II scores. c DRMPs in the validation cohort. The multi-biomarkers used for ROC analysis were isoleucine (amino acid), alanine (amino acid), acetylcarnitine (mitochondrial metabolism), lactic acid (mitochondrial metabolism), pyruvic acid (mitochondrial metabolism), LysoPG (22:0) (lysophospholipids metabolism), and LysoPC (24:0). The ROC curve was generated by Monte Carlo cross-validation of random forest models. Repeated random cross-validation (rdCV) and permutation test were used for internal validation of the classification model
Fig. 8
Fig. 8
The death-related metabolic pathways (DRMPs) in the blood of sepsis nonsurvivors. Briefly, sepsis induces acute kidney injury (AKI), followed by ischemia and hypoxia in other organs such as the liver and lung. Acute respiratory distress syndrome (ARDS) in the lung contributes to the subsequent systemic metabolic responses, including inflammatory responses, defects of organ healing capability, mitochondrial dysfunction in energy production, and systemic uncontrolled proteolysis. These produce unique metabolic signatures in the blood of sepsis nonsurvivors, which can be measured by metabolomics. For example, the sharp increase of pro-inflammatory eicosanoids, the accumulation of TCA cycle metabolites (lactate, pyruvate, and citric acid), the increase of acylcarnitines and amino acids, and the significant reduction of lysophospholipids in the plasma and serum of sepsis nonsurvivors. The aggregate of these metabolites in DRMPs leads to multi-organ failure and death. This figure was created by ourselves

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