Accuracy of circulating microRNAs in diagnosis of sepsis: a systematic review and meta-analysis

Abstract

Objectives The aim of this study was to systematically assess the accuracy of circulating microRNAs (miRNAs) as a promising biomarker for sepsis via a meta-analysis. Methods PubMed, Cochrane Library, Embase, Web of Science, Scopus, and Ovid databases were searched up to April 3, 2020. The Quality in Prognostic Studies (QUADAS-2) tool was used to assess methodological quality. The pooled sensitivity (Sen), specificity (Spe), positive or negative likelihood ratios (PLR or NLR), diagnostic odds ratio (DOR), curve, and area under the curve (AUC) were calculated with 95% confidence interval (95% CI). The overall accuracy (OA) of miRNAs, procalcitonin (PCT), and C-reactive protein (CRP) was analyzed by the chi-square test. Results A total of 22 records were eligible for systematic review, including 2210 sepsis, 426 systemic inflammatory response syndrome (SIRS), and 1076 healthy controls (HC). The pooled Sen, Spe, and DOR of miRNAs were 0.80 (95% CI 0.75–0.83), 0.85 (95% CI 0.80–0.89), and 22 (15–32), respectively. The DOR of PCT and CRP were 17 (95% CI 4–68) and 7 (95% CI 1–48), respectively. The OA value of miRNAs (79.02%) and PCT (76.95%) were higher than CRP (61.22%) (P < 0.000). The subgroup analysis indicated that miRNAs in adults, serum type, downregulation of miRNA expression, criteria of Sepsis-3, internal reference of non-U6, and dysregulation expression of miR-223 had superior diagnostic accuracy. In addition, there was no significant publication bias among the included studies. Fagan’s nomogram showed valuable clinical utility. Conclusions Our meta-analysis indicated that the level of circulating miRNAs, particularly the miR-223, could be used as an indicator for sepsis.

Circulating miR-147b as a diagnostic marker for patients with bacterial sepsis and septic shock

“…The inflammation-related microRNAs, such as miR-146-3p, miR-147b, miR-155 and miR-223 can be used as biomarkers to support the diagnostic establishment of bacterial sepsis. [ 10 – 16 ] and is evident that miR-223 is associated with platelet derived microparticles that modulate ICAM-1 expression on endothelial cells under septic environment [ 27 ]. Our current data confirm previous findings that the expression of the three microRNAs miR-146-3p, miR-155 and miR-223 is indeed increased in patients with bacterial sepsis [ 14 , 16 , 28 , 29 ].…”

“…[ 10 – 16 ] and is evident that miR-223 is associated with platelet derived microparticles that modulate ICAM-1 expression on endothelial cells under septic environment [ 27 ]. Our current data confirm previous findings that the expression of the three microRNAs miR-146-3p, miR-155 and miR-223 is indeed increased in patients with bacterial sepsis [ 14 , 16 , 28 , 29 ]. In particular, the expression of the inverstigated microRNAs are expresed higher in patients with sepsis than in DHF patients and/or healthy controls.…”

“…Their presence in plasma and/or serum indicates the role of circulating (cell-free) miRNAs in pathogenesis and are believed to be key gene modulators of distinct inflammatory responses [ 10 ]. A number of miRNAs are differentially expressed in the peripheral blood of patients with bacterial sepsis [ 10 – 16 ]. Among those well characterized, miR-146-3p, miR-147b and miR-155 were involved in the activation of NF-κB signaling pathway, a key mediator of inflammatory responses [ 11 , 12 ] and the miR-223 involved in the regulation of monocyte-macrophage differentiation, neutrophil recruitment, and pro-inflammatory responses, and is a key regulator of innate immunity [ 17 ].…”

Novel Diagnostics and Therapeutics in Sepsis

“…The miRNA characteristics of the host-pathogen interactions of more than 50 different bacterial and viral infections have been described [ 69 ]. Although confirming the functional nature of such associations is difficult, such studies highlight the important role of miRNA in immunity and provide evidence that polymorphism in miRNA genes, at least for certain pathogens, could govern person-to-person variation in infection susceptibility [ 70 , 71 , 72 , 73 ]. To determine the accuracy of circulating miRNA as a biomarker for sepsis, one meta-analysis [ 71 ] assessed a total of 2337 patients in 14 studies of SIRS, 2 studies of local infections, and 14 studies of healthy controls.…”

“…Although confirming the functional nature of such associations is difficult, such studies highlight the important role of miRNA in immunity and provide evidence that polymorphism in miRNA genes, at least for certain pathogens, could govern person-to-person variation in infection susceptibility [ 70 , 71 , 72 , 73 ]. To determine the accuracy of circulating miRNA as a biomarker for sepsis, one meta-analysis [ 71 ] assessed a total of 2337 patients in 14 studies of SIRS, 2 studies of local infections, and 14 studies of healthy controls. Circulating miRNA proved to be an accurate method to identify sepsis, with a pooled sensitivity and specificity of 0.80 (95% CI 0.75–0.83) and 0.85 (95% CI 0.80–0.89), respectively, and the AUC was 0.89 (95% CI 0.86–0.92).…”