Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS).

Stefano Caserta,Martin J Llewelyn,Florian Kern,Jonathan Cohen,Sarah F Newbury,Stephen Drage

doi:10.1038/srep28006

Abstract

Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these ‘circulating inflammation-related microRNAs’ (CIR-miRNAs) were 2.64 (IQR: 2.10–3.29) and 1.52 (IQR: 1.15–1.92) fold higher for non-infective SIRS and sepsis respectively (p < 0.0001), hence CIR-miRNAs appeared less abundant in sepsis than in SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742–0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets.

Highlights

Sepsis is defined as a systemic inflammatory response syndrome (SIRS) driven by infection[1]
We studied a cohort of patients robustly characterized at the time of admission to critical care[29] and selected tightly defined groups of patients with sepsis, non-infective SIRS, and critical illness without SIRS
Two samples with free hemoglobin (Hb) > 0.6 g/L were excluded as hemolytic from further analysis (Supplementary Fig. 1A), leaving 89 samples divided into five groups (Supplementary Fig. 1B): severe sepsis (n = 21); non-severe sepsis (n = 8); severe non-infective SIRS (n = 23); non-severe non-infective SIRS (n = 21); and patients without SIRS

Summary

Introduction

Sepsis is defined as a systemic inflammatory response syndrome (SIRS) driven by infection[1]. Ill patients may develop SIRS driven by non-infective processes such as tissue ischemia. There is growing recognition of the importance of anti-inflammatory, regulatory processes which accompany SIRS and sepsis[4]. These are physiological in that they terminate inflammation during recovery, and may be pathological causing sepsis-related immunosuppression. We set out to establish definitive proof-of-principle that circulating microRNAs are differentially affected during systemic inflammation in critically ill patients depending on etiology. We used next-generation sequencing (NGS30) to identify normalizer miRNAs (present at consistent levels between patient groups) and to establish a long-list of candidate miRNAs differentially present in the blood of patients with sepsis, non-infective SIRS and without SIRS. We used miRNA qRT-PCR to validate the most differentiating miRNAs and explore their performance in distinguishing sepsis from non-infective SIRS used singly and in combination

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