Background
Sepsis is a common complication that involves severe trauma, shock, infection, and surgery; it can lead to septic shock and multiple organ dysfunction syndrome (MODS). Sepsis is also a major cause of death in critical patients. It remains a remarkable challenge in clinical medicine because of its high mortality and morbidity rates. In developed countries, the incidence of sepsis reaches 100/100,000 [
1], and approximately 2% of hospitalized patients are diagnosed during admission [
2,
3]. With advancements in critical medicine, evidence-based medicine is widely used in clinical practices to address sepsis and its related conditions. However, approximately 1/5–1/2 of the patient population with sepsis dies of MODS [
4,
5].
MicroRNAs (miRNAs) are endogenous noncoding small RNAs of approximately 21–25 nucleotides in length. In 1993, Lee [
6] discovered the first miRNA (lin-4) miRNAs in new
Caenorhabditis species. Since then, thousands of miRNAs have been found. miRNAs can inhibit post-transcriptional gene expression or promote targeted mRNA degradation but cannot encode a protein. miRNAs can be detected in different fluids, such as blood, sweat, and urine. Whole panels of deregulated miRNAs have been described in the blood of patients with inflammatory/infectious diseases, thereby suggesting that circulating miRNAs might be suitable biomarkers in sepsis [
7] but not in patients with respiratory infection. This study aimed to identify the differences in microRNA expression in patients affected with pneumonia and with sepsis secondary to pneumonia.
Discussion
miRNAs have been used as biomarkers for various cancer types since the discovery of circulating miRNAs in the human peripheral sera. Several circulating miRNAs have been identified as potential biomarkers for sepsis, but their roles in infectious diseases were rarely investigated [
11‐
17]. The association of miRNAs with the diagnosis of sepsis has been studied but remains controversial. Sepsis has various causes, such as severe wound, burn, shock, infection, and surgical operation; such causes present similarities and differences. No research has investigated the role of miRNAs in sepsis secondary to pneumonia and their relation to the diagnosis of sepsis.
In this study, the expression levels of miR-7110-5p and miR-223-3p differed among healthy controls, patients with pneumonia, and patients with sepsis secondary to pneumonia. The expression levels of these miRNAs were upregulated in the plasma of patients with sepsis secondary to pneumonia. The AUCs of the ROC of miR-7110-5p and miR-223-3p for the prediction of sepsis secondary to pneumonia were 0.883 and 0.964, respectively. This finding indicated the potential use of these miRNAs as biomarkers for sepsis.
In 2009, Vasilescu [
11] first reported that miR-150 in the plasma can be used as a serum biomarker to diagnose patients with sepsis. The expression profiles of miR-150, miR-182, miR-342-5p, and miR-486 were used to distinguish patients with sepsis from healthy controls through genome-wide miRNA profiling by using microarray analysis of the peripheral blood leukocytes of eight healthy individuals and eight patients with sepsis. This result was confirmed through qRT-PCR analysis. Xie [
13] screened sepsis biomarkers in the entire genome and evaluated the relationship of miRNAs to the prognosis of sepsis. The expression levels of miR-223, miR-15a, miR-122, miR-193, and miR483-5p significantly differed between the surviving and deceased group of patients with sepsis. The combination of six miRNAs with acute physiology and chronic health score (Acute Physiology Chronic Health Evaluation II) predicts sepsis and provides a sensitivity of 96.9% [
16].
In this study, gene chip analysis revealed that six miRNAs, namely, miR-4800-5p, miR-6510-5p, miR-6740-5p, miR-7110-5p, miR-765, and miR-940, satisfied the screening criteria of p < 0.01, fold change ≥2 or < 0.5, and copy number > 50. Limited data have been presented regarding the relationship of these six miRNAs to sepsis because of the following factors: 1) sepsis displays various causes, and sepsis secondary to pneumonia has yet to be investigated in terms of the association of miRNAs with the diagnosis of sepsis; 2) unlike in previous studies, we employed Sepsis 3.0 to establish the diagnosis of sepsis; 3) the number of samples in the gene chip analysis was limited. Four miRNAs associated with sepsis in previous reports were verified through qRT-PCR analysis to compensate for the limitations of our study.
In this study, miR-223-3p was highly expressed in the circulating blood of patients with sepsis secondary to pneumonia. Wang et al. [
12] compared the levels of miR-223 among 50 patients with sepsis, patients with systemic inflammatory response syndrome (SIRS), and healthy controls. The miR-223 expression level increased in the blood of patients with sepsis and SIRS caused by infection but not in the blood of patients with non-infectious SIRS. Hence, miR-223 can be used as a biomarker to distinguish infectious SIRS from non-infectious SIRS. A cohort study involving children with sepsis and healthy ones revealed that the expression levels of miR-223 and miR-146a substantially increased; the increase in miR-223 level was positively associated with a high level of tumor necrosis factor-α, disease severity, and poor prognosis [
18]. However, these conclusions are inconsistent with other published reports. Clinical studies on non-infectious critically ill patients and patients with sepsis indicated that miR-223 levels with no significantly difference [
19] . Our previous studies on the efficacy of miR-223-3p in predicting sepsis secondary to pneumonia revealed that the AUC of the ROC curve was 0.964, thereby suggesting that the miR-223-3p expression level can be an accurate predictor for the diagnosis of sepsis. In the present study, the expression of miR-7110-5p, which has been rarely examined, was upregulated in the circulating blood of patients with sepsis secondary to pneumonia. However, the signal of miR-7110-5p was altered not only because of the presence of pneumonia or sepsis but also possibly because of the conditions induced by pneumonia or sepsis. Fourteen miRNAs differed in terms of their expression levels in cancer stem cells, CD133(+) A549 cells, and CD133(−) cells. Among these miRNAs, five were upregulated (hsa-miR-23b-3p, −23a-3p, −15b-5p, − 24-3p, and − 4734), whereas nine were downregulated (hsa-miR-1246, −30b-5p, − 5096, − 6510-5p, has-miR-7110-5p, − 7641, − 3197, − 7108-5p, and − 6791-5p). Although miR-7110-5p was downregulated [
20], its relationship to sepsis has not been studied.
This research presented several limitations. In the RT-PCR validation of miRNAs, we enrolled 52 patients with pneumonia, 44 patients with pneumonia who satisfied the Sepsis 3.0 diagnostic criteria, and 21 healthy controls. The total number of cases enrolled in the study was limited. Hence, the value of miR-7110-5p and miR-223-3p in predicting early sepsis secondary to pneumonia should be further evaluated using large samples.