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Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study

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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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Acknowledgments

This work was supported in part by funding from the National Institutes of Health (K23 GM083215—Yende; 1K23GM104022-01-Seymour). The GenIMS study was funded by National Institute of General Medical Sciences and National Institutes of Health grant R01 GM61992 (Angus, Kellum) with additional support from GlaxoSmithKline for enrollment and clinical data collection and Diagnostic Products Corporation for the cytokine assays. These funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. Bell and Mohney are employees of Metabolon, Inc. and, as such, have affiliations with or financial involvement with Metabolon, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Department of Critical Care Medicine and Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA, 15261, USA

    Christopher W. Seymour

  2. Department of Critical Care, Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh, Pittsburgh, PA, USA

    Christopher W. Seymour, Sachin Yende, Melanie J. Scott, John A. Kellum & Derek C. Angus

  3. Department of Critical Care, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Sachin Yende, John A. Kellum & Derek C. Angus

  4. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Melanie J. Scott, John Pribis & Brian S. Zuckerbraun

  5. Metabolon, Inc., Durham, NC, USA

    Robert P. Mohney & Lauren N. Bell

  6. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Yi-Fan Chen & Lisa Weissfeld

  7. Magee Women’s Research Institute, University of Pittsburgh, Pittsburgh, PA, USA

    William L. Bigbee

  8. Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Donald M. Yealy

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  1. Christopher W. Seymour
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  2. Sachin Yende
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  13. Derek C. Angus
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Correspondence to Christopher W. Seymour.

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On behalf of the Genetic and Inflammatory Markers of Sepsis (GenIMS) investigators

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Seymour, C.W., Yende, S., Scott, M.J. et al. Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study. Intensive Care Med 39, 1423–1434 (2013). https://doi.org/10.1007/s00134-013-2935-7

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