Metabolomics in pneumonia and sepsis: An analysis of the GenIMS cohort study
ABSTRACT PURPOSE: To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis. METHODS: Random, outcome-stratified case-control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis. RESULTS: We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors (p ≤ 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non-survivors (p ≤ 0.05). Of these, pseudouridine increased monocyte expression of TNFα and IL1β versus control (p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham (p < 0.05 for both). CONCLUSIONS: Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns.
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ABSTRACT: Sepsis is a systemic inflammatory state caused by infection. Complications of this infection with multiple organ failure lead to more lethal conditions, such as severe sepsis and septic shock. Sepsis is one of the leading causes of US deaths. Novel biomarkers with high sensitivity and specificity may be helpful for early diagnosis of sepsis and for improvement of patient outcomes through the development of new therapies. Mass spectrometry-based proteomics offers powerful tools to identify such biomarkers and furthermore to give insight to fundamental mechanisms of this clinical condition. Several studies have begun to explore the progression of septic infection, including systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock through the use of state-of-the-art proteomics technology. In this review, we summarize findings from proteomics studies of sepsis and how their applications have provided more understanding into the pathogenesis of septic infection. Across investigations in clinical populations and in rodent and mammalian animal models, biological pathways such as inflammatory and acute-phase responses, coagulation, complement, mitochondrial energy metabolism, chaperones and oxidative stress, are altered at the protein level and may provide insight for diagnosis, prognosis, and novel therapeutic targets in sepsis. This article is protected by copyright. All rights reserved.PROTEOMICS - CLINICAL APPLICATIONS 02/2014; 8(1-2). DOI:10.1002/prca.201300101 · 2.68 Impact Factor
- Intensive Care Medicine 02/2014; 40(4). DOI:10.1007/s00134-014-3235-6 · 7.21 Impact Factor
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ABSTRACT: Background:To identify metabolic biomarkers that can be used to differentiate sepsis from systemic inflammatory response syndrome (SIRS), assess severity and predict outcomes. Methods:65 patients were involved in this study including 35 patients with sepsis, 15 patients with SIRS and 15 normal patients. Small metabolites that were present in patient serum samples were measured by liquid chromatography mass spectrometry techniques and analysed using multivariate statistical methods. Results:The metabolic profiling of normal patients and patients with SIRS or sepsis was markedly different. A significant decrease in the levels of lactitol dehydrate andS-phenyl-D-cysteine and an increase in the levels of S-(3-methylbutanoyl)-dihydrolipoamide-E andN-nonanoyl glycine were observed in patients with sepsis in comparison to patients with SIRS ( p<0.05). Patients with severe sepsis and septic shock displayed lower levels of glyceryl-phosphoryl-ethanolamine, Ne,Ne dimethyllysine, phenylacetamide andD-cysteine (p<0.05) in their sera. The profiles of patients with sepsis 48 h before death illustrated an obvious state of metabolic disorder, such thatS-(3-methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z,16Z)/0:0), glycerophosphocholine andS-succinyl glutathione were significantly decreased (p<0.05). The receiver operating characteristic curve of the differential expression of these metabolites was also performed. Conclusions:The body produces significant evidence of metabolic disorder during SIRS or sepsis. Seven metabolites may potentially be used to diagnose sepsis.05/2014; 1(1). DOI:10.1136/bmjresp-2014-000056