A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts

McHugh, Leo, Seldon, Therese A., Brandon, Roslyn A., Kirk, James T., Rapisarda, Antony, Sutherland, Allison J., Presneill. Jeffrey J., Venter, Deon J., Lipman, Jeffrey, Thomas, Mervyn R., Klein Klouwenberg, Peter M.C., van Vught, Lonneke, Scicluna, Brendon, Bonten, Marc, Cremer, Olaf L., Schultz, Marcus J., van der Poll, Tom, Yager, Thomas D. and Brandon, Richard B. (2015) A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts. PLoS Medicine, 12 12: . doi:10.1371/journal.pmed.1001916


Author McHugh, Leo
Seldon, Therese A.
Brandon, Roslyn A.
Kirk, James T.
Rapisarda, Antony
Sutherland, Allison J.
Presneill. Jeffrey J.
Venter, Deon J.
Lipman, Jeffrey
Thomas, Mervyn R.
Klein Klouwenberg, Peter M.C.
van Vught, Lonneke
Scicluna, Brendon
Bonten, Marc
Cremer, Olaf L.
Schultz, Marcus J.
van der Poll, Tom
Yager, Thomas D.
Brandon, Richard B.
Title A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts
Journal name PLoS Medicine   Check publisher's open access policy
ISSN 1549-1676
Publication date 2015-12-08
Year available 2015
Sub-type Article (original research)
DOI 10.1371/journal.pmed.1001916
Open Access Status DOI
Volume 12
Issue 12
Total pages 35
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted abstract
Background

Systemic inflammation is a whole body reaction having an infection-positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs could be discovered that would (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility. The goal of this study was to identify and validate such a molecular classifier.

Methods and Findings


We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91–1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2–5; 249 patients after excluding 37 patients with an infection likelihood of “possible”) gave an AUC of 0.89 (95% CI 0.85–0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein.

Conclusions

SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Health Services Publications
Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
School of Medicine Publications
 
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