Yanhong Jia

Serum MicroRNA Signatures Identified by Solexa Sequencing Predict Sepsis Patients’ Mortality: A Prospective Observational Study

Background Sepsis is the leading cause of death in Intensive Care Units. Novel sepsis biomarkers and targets for treatment are needed to improve mortality from sepsis. MicroRNAs (miRNAs) have recently been used as finger prints for sepsis, and our goal in this prospective study was to investigate if serum miRNAs identified in genome-wide scans could predict sepsis mortality. Methodology/Principal Findings We enrolled 214 sepsis patients (117 survivors and 97 non-survivors based on 28-day mortality). Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays was used to test for differences in the levels of miRNAs between survivors and non-survivors. miR-223, miR-15a, miR-16, miR-122, miR-193*, and miR-483-5p were significantly differentially expressed. Receiver operating characteristic curves were generated and the areas under the curve (AUC) for these six miRNAs for predicting sepsis mortality ranged from 0.610 (95%CI: 0.523–0.697) to 0.790 (95%CI: 0.719–0.861). Logistic regression analysis showed that sepsis stage, Sequential Organ Failure Assessment scores, Acute Physiology and Chronic Health Evaluation II scores, miR-15a, miR-16, miR-193b*, and miR-483-5p were associated with death from sepsis. An analysis was done using these seven variables combined. The AUC for these combined variables’ predictive probability was 0.953 (95% CI: 0.923–0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712–0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672–0.832), and procalcitonin levels (0.689; 95% CI: 0.611–0.784). With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%. Additionally, miR-193b* had the highest odds ratio for sepsis mortality of 9.23 (95% CI: 1.20–71.16). Conclusion/Significance Six serum miRNA’s were identified as prognostic predictors for sepsis patients. Trial Registration ClinicalTrials.gov NCT01207531

Value of soluble TREM-1, procalcitonin, and C-reactive protein serum levels as biomarkers for detecting bacteremia among sepsis patients with new fever in intensive care units: a prospective cohort study.

BackgroundThe purpose of this study was to explore the diagnostic value of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for differentiating sepsis from SIRS, identifying new fever caused by bacteremia, and assessing prognosis when new fever occurred.MethodsWe enrolled 144 intensive care unit (ICU) patients: 60 with systemic inflammatory response syndrome (SIRS) and 84 with sepsis complicated by new fever at more than 48 h after ICU admission. Serum sTREM-1, PCT, and CRP levels were measured on the day of admission and at the occurrence of new fever (>38.3°C) during hospitalization. Based on the blood culture results, the patients were divided into a blood culture-positive bacteremia group (33 patients) and blood culture-negative group (51 patients). Based on 28-day survival, all patients, both blood culture-positive and -negative, were further divided into survivor and nonsurvivor groups.ResultsOn ICU day 1, the sepsis group had higher serum sTREM-1, PCT, and CRP levels compared with the SIRS group (P <0.05). The areas under the curve (AUC) for these indicators were 0.868 (95% CI, 0.798–0.938), 0.729 (95% CI, 0.637–0.821), and 0.679 (95% CI, 0.578–0.771), respectively. With 108.9 pg/ml as the cut-off point for serum sTREM-1, sensitivity was 0.83 and specificity was 0.81. There was no statistically significant difference in serum sTREM-1 or PCT levels between the blood culture-positive and -negative bacteremia groups with ICU-acquired new fever. However, the nonsurvivors in the blood culture-positive bacteremia group had higher levels of serum sTREM-1 and PCT (P <0.05), with a prognostic AUC for serum sTREM-1 of 0.868 (95% CI, 0.740–0.997).ConclusionsSerum sTREM-1, PCT, and CRP levels each have a role in the early diagnosis of sepsis. Serum sTREM-1, with the highest sensitivity and specificity of all indicators studied, is especially notable. sTREM-1, PCT, and CRP levels are of no use in determining new fever caused by bacteremia in ICU patients, but sTREM-1 levels reflect the prognosis of bacteremia.Trial registrationClinicalTrial.gov identifier NCT01410578

Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjects

Abstract Background : Serum microRNAs may be useful biomarkers for diagnosing human diseases. We investigated serum levels of miR-15a and miR-16 in patients with sepsis and systemic inflammatory response syndrome (SIRS) without infection. Methods : We enrolled 166 sepsis patients, 32 SIRS patients, and 24 normal controls. Serum miR-15a and miR-16 expression levels were determined by quantitative reverse transcriptase polymerase chain reaction assays (qRT-PCR). Results : Serum miR-15a (p<0.001) and miR-16 (p<0.05) were both significantly higher in sepsis patients compared with normal controls, and miR-15a (p<0.001) and miR-16 (p<0.01) levels in SIRS patients were also significantly higher than those in normal controls. Serum miR-15a and miR-16 levels were not correlated with white blood cell counts. Receiver operating characteristic curves showed that miR-15a had the highest area under the curve of 0.858 [95% confidence interval (CI) 0.800–0.916] for the diagnosis of sepsis compared with C reactive protein and procalcitonin with areas under the curve of 0.572 (95% CI 0.479–0.665; p=0.198) and 0.605 (95% CI 0.443–0.767; p=0.168), respectively. When its cut-off point was set at 0.21, serum miR-15a had a sensitivity of 68.3% and a specificity of 94.4%. Conclusions : Serum miR-15a and miR-16 can both distinguish sepsis/SIRS from normal controls. miR-15a may be a biomarker that distinguishes between sepsis and SIRS.

Dynamic changes of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflect sepsis severity and can predict prognosis: a prospective study

BackgroundWe examined the utility of serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for the diagnoses, severity assessments, and predicting the prognoses of patients with sepsis and compared sTREM-1 values with those of C-reactive protein (CRP) and procalcitonin (PCT).MethodsFifty-two patients with sepsis were included: 15 sepsis cases and 37 severe sepsis cases (severe sepsis + septic shock). Serum levels of sTREM-1, CRP, and PCT were determined on days 1, 3, 5, 7, 10, and 14 after admission to an ICU.ResultsSerum sTREM-1 levels of patients with severe sepsis were significantly higher than for those with sepsis on day 1 (240.6 pg/ml vs. 118.3 pg/ml; P < 0.01), but CRP and PCT levels were not significantly different between the two groups. The area under an ROC curve for sTREM-1 for severe sepsis patients was 0.823 (95% confidence interval: 0.690-0.957). Using 222.5 pg/ml of sTREM-1 as the cut-off value, the sensitivity was 59.5%, the specificity was 93.3%, the positive predictive value was 95.6%, the negative predictive value was 48.3%, the positive likelihood ratio was 8.92, and the negative likelihood ratio was 0.434. Based on 28-day survivals, sTREM-1 levels in the surviving group showed a tendency to decrease over time, while they tended to gradually increase in the non-surviving group. sTREM-1 levels in the non-surviving group were higher than those in the surviving group at all time points, whereas CRP and PCT levels showed a tendency to decrease over time in both groups. sTREM-1 levels and Sequential Organ Failure Assessment (SOFA) scores were positively correlated (r = 0.443; P < 0.001), and this correlation coefficient was greater than the correlation coefficients for both CRP and PCT.ConclusionsSerum sTREM-1 levels reflected the severity of sepsis more accurately than those of CRP and PCT and were more sensitive for dynamic evaluations of sepsis prognosis.Trial RegistrationCurrent controlled trials ChiCTR-OCH-09000745

Four serum microRNAs identified as diagnostic biomarkers of sepsis.

BACKGROUND Serum microRNAs (miRNAs) can be used as biomarkers for many kinds of diseases, and some are even better than current indicators. The aim of this study was to investigate a diagnostic role for serum miRNAs in sepsis patients. METHODS We recruited 166 patients with sepsis and 24 normal controls. Blood samples for these patients were obtained upon their admission in intensive care units of the Chinese PLA General Hospital. The expression levels of miR-223, miR-15b, miR-483-5p, miR-499-5p, miR-122, and miR-193b* were determined by quantitative reverse transcriptase polymerase chain reaction assays. RESULTS Expression levels of miR-223 were significantly higher in patients with mild sepsis (p < 0.001) and patients with severe sepsis and septic shock (p < 0.001) than in normal controls, and levels of miR-499-5p, miR-122, and miR-193b* were significantly lower than in normal controls. In addition, only miR-223 (p = 0.035) and miR-499-5p (p < 0.001) were significantly different between patients with mild sepsis and patients with severe sepsis and septic shock. miR-499-5p had the highest area under a receiver operating characteristic curve of 0.686 (95% confidence interval, 0.592–0.779). In addition, Sequential Organ Failure Assessment scores (p < 0.001), Acute Physiology and Chronic Health Evaluation II scores (p < 0.001), and procalcitonin levels (p < 0.001) also could distinguish a mild sepsis group from a severe sepsis and septic shock group. In a binary logistic regression model, only miR-499-5p and Sequential Organ Failure Assessment scores had good diagnostic values to distinguish between mild sepsis and severe sepsis and septic shock. CONCLUSION Four serum miRNAs were identified as novel biomarkers of sepsis. LEVEL OF EVIDENCE II, diagnostic study.

Serum miR-574-5p: a prognostic predictor of sepsis patients.

ABSTRACT Serum micro-RNAs (miRNAs) can be used for the diagnosis and prognosis of various diseases. Using genome-wide scans, we sought to identify serum miRNAs that could be used as prognostic predictors for sepsis patients. We used microarray screens to identify differentially expressed serum miRNAs by comparing samples from 12 surviving and 12 nonsurviving sepsis patients. These differentially expressed serum miRNAs were validated by quantitative reverse transcriptase–polymerase chain reaction assays for 118 sepsis patients. The validated miRNAs along with sepsis patients’ clinical indictors were analyzed in a multivariate logistic regression model. Microarray analysis showed that miR-297 and miR-574-5p were differentially expressed in sepsis survivors and nonsurvivors. Upon validation with 118 sepsis patients’ samples, these two miRNA expressions were significantly different, with P < 0.001. miR-297 was more closely associated with survival from sepsis, whereas miR-574-5p was associated with death from sepsis. Multivariable logistic regression analysis showed that a combination of sepsis stage, Sepsis-Related Organ Failure Assessment scores, and miR-574-5p was correlated with the death of sepsis patients. The predictive capability of these three combined variables was analyzed by a receiver operating characteristic curve; the area under the curve was 0.932 (95% confidence interval, 0.887–0.977). When the cutoff point was set at 0.288, these three combined variables provided 78.13% sensitivity and 91.84% specificity. Our results showed that serum miR-574-5p was correlated with the death of sepsis patients. The combined predictive capability of sepsis stage, Sepsis-Related Organ Failure Assessment scores, and serum miR-574-5p for the death of sepsis patients was better than any single indicator.

Diagnostic value of urine sTREM-1 for sepsis and relevant acute kidney injuries: a prospective study

IntroductionWe explored the diagnostic value of a urine soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for early sepsis identification, severity and prognosis assessment, and for secondary acute kidney injury (AKI). We compared this with white blood cell (WBC) counts, serum C-reactive protein (CRP), serum procalcitonin (PCT), urine output, creatinine clearance (CCr), serum creatinine (SCr), and blood urea nitrogen (BUN).MethodsWe enrolled 104 subjects admitted to the ICU: 16 cases with systemic inflammatory response syndrome (SIRS); 35 with sepsis and 53 with severe sepsis. Results for urine sTREM-1, WBC, serum CRP and serum PCT were recorded on days 1, 3, 5, 7, 10, and 14. For 17 sepsis cases diagnosed with secondary AKI, comparisons between their urine sTREM-1, urine output, CCr, SCr and BUN at diagnosis and 48 h before diagnosis were made.ResultsOn the day of admission to the ICU, and compared with the SIRS group, the sepsis group exhibited higher levels of urine sTREM-1 and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) scores (P < 0.05). Areas under the curve (AUC) shaped by the scores were 0.797 (95% CI 0.711 to 0.884) and 0.722 (95% CI 0.586 to 0.858), respectively. On days 1, 3, 5, 7, 10, and 14, urine sTREM-1, serum PCT and WBC levels registered higher in the severe sepsis group in contrast to the sepsis group (P < 0.05). Urine sTREM-1 and serum PCT levels continuously increased among non-survivors, while WBC and serum CRP levels in both groups declined. For 17 patients with AKI, urine sTREM-1, SCr and BUN levels at 48 h before AKI diagnosis were higher, and CCr level was lower than those for non-AKI subjects (P < 0.05). AUC for urine sTREM-1 was 0.922 (95% CI 0.850 to 0.995), the sensitivity was 0.941, and the specificity was 0.76 (based on a cut-off point of 69.04 pg/ml). Logistic regression analysis showed that urine sTREM-1 and severity were risk factors related to AKI occurrence.ConclusionsBesides being non-invasive, urine sTREM-1 testing is more sensitive than testing WBC, serum CRP, and serum PCT for the early diagnosis of sepsis, as well as for dynamic assessments of severity and prognosis. It can also provide an early warning of possible secondary AKI in sepsis patients.Trial RegistrationClinicalTrial.gov identifier NCT01333657

Characterization and Identification of novel serum microRNAs in sepsis patients with different outcomes.

Abstract Circulating microRNAs (miRNAs) are an emerging biomarker for sepsis patients. The purpose of this study was to identify novel miRNAs in the sera of sepsis patients and determine their prognostic value. Ninety-four serum samples were collected from sepsis patients within 24 h of intensive care unit admission. Solexa sequencing followed by bioinformatics analysis was used to predict novel miRNAs in survivors (n = 9) and nonsurvivors (n = 9). A total of 650 novel miRNAs were predicted by bioinformatics analysis after Solexa sequencing, and 41 novel miRNAs were validated in 10 survivors, 10 nonsurvivors, and 10 healthy controls by quantitative reverse transcriptase–polymerase chain reaction. Among these 41 miRNAs, 18 were present in both survivors and nonsurvivors, and nine were differentially expressed between the two groups. The expression levels of the nine miRNAs were determined by quantitative reverse transcriptase–polymerase chain reaction in 24 nonsurvivors and 32 survivors, and six were differentially expressed. Conjoint analysis of the six miRNAs and severity scores (Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score) showed that the area under the receiver operating characteristic curve for the predictive value of the six miRNAs was 0.969 (95% confidence interval, 0.930–1.000). When the cutoff point was set at 0.714, the six miRNAs and severity score provided a sensitivity of 100% and a specificity of 82.6%. In conclusion, 41 novel miRNAs were detectable in the sera of sepsis patients, and six of them might be related to sepsis outcome.

Clinical Significance of Soluble Hemoglobin Scavenger Receptor CD163 (sCD163) in Sepsis, a Prospective Study

Objective We investigated serum soluble CD163 (sCD163) levels for use in the diagnosis, severity assessment, and prognosis of sepsis in the critical ill patients and compared sCD163 with other infection-related variables. Methods During july 2010 and April 2011, serum was obtained from 102 sepsis patients (days 1, 3, 5, 7, and 10 after admission to an ICU) and 30 systemic inflammatory response syndrome (SIRS) patients with no sepsis diagnosed. Serum levels of sCD163, procalcitonon (PCT), and C reactive protein (CRP) were determined respectively. Sequential organ failure assessment (SOFA) scores for sepsis patients were also recorded. Then evaluated their roles in sepsis. Results The sCD163 levels were 0.88(0.78–1.00)ug/mL for SIRS patients, 1.50(0.92–2.00)ug/mL for moderate sepsis patients, and 2.95(2.18–5.57)ug/mL for severe sepsis patients on day1. The areas under the ROC curves for sCD163, CRP, and PCT for the diagnosis of sepsis were, respectively, 0.856(95%CI: 0.791–0.921), 0.696(95%CI: 0.595–0.797), and 0.629(95%CI: 0.495–0.763), At the recommended cut-off 1.49 ug/mL for sCD163, the sensitivity is 74.0% with 93.3% specificity. Based on 28-day survivals, sCD163 levels in the surviving group stay constant, while they tended to gradually increase in the non-surviving group.The area under the ROC curve for sCD163 for sepsis prognosis was 0.706(95%CI 0.558–0.804). Levels of sCD163 with cut-off point >2.84 ug/mL have sensitivity of 55.8.0%, specificity 80.4%.Common risk factors for death and sCD163 were included in multivariate logistic regression analysis; the odds ratios (OR) for sCD163 and SOFA scores for sepsis prognosis were 1.173 and 1.396, respectively (P<0.05). Spearman rank correlation analysis showed that sCD163 was weakly, but positively correlated with CRP, PCT, and SOFA scores (0.2< r <0.4, P<0.0001), but not with leukocyte counts (r <0.2, P = 0.450). Conclusion Serum sCD163 is superior to PCT and CRP for the diagnosis of sepsis and differentiate the severity of sepsis. sCD163 levels were more sensitive for dynamic evaluations of sepsis prognosis. Serum sCD163 and SOFA scores are prognostic factors for sepsis. Trial Registration www.chictr.org ChiCTR-ONC-10000812

Serum miR-122 levels are related to coagulation disorders in sepsis patients

Abstract Background: Coagulation abnormalities may have a major impact on the outcome of sepsis in patients. This study aimed to explore the relationship between miRNA levels and coagulation disorders during sepsis. Methods: Blood samples from 123 sepsis patients were collected on the day of admission and another 45 sepsis patients on days 1, 3, 5, 7, 10, and 14 following admission to the intensive care unit. miR-223, miR-15a, miR-16, miR-122, miR-193b*, and miR-483-5p levels were evaluated by quantitative reverse transcription polymerase chain reaction. Based on the International Society on Thrombosis and Haemostasis (ISTH) Disseminated Intravascular Coagulation (DIC) score, sepsis patients were divided into coagulation abnormal (CA) group and coagulation normal (CN) group. Results: Only the levels of miR-122 were significantly higher in CA patients than in CN patients (p<0.001). Serum levels of miR-122 were correlated to the serum activated partial thromboplastin time (APTT) ratios (R=0.426, p=0.008) and the fibrinogen (FIB; R=0.398, p=0.008) and antithrombin III (R=0.913, p<0.001) levels. In addition, Pearson’s correlation coefficients for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with miR-122 were 0.663 (p<0.001) and 0.445 (p=0.001), respectively. In the 45 patients, the miR-122 levels were significantly higher on day 1, 3, 7, and 10 in the CA group than in the CN group, and no difference in the ISTH-DIC scores was evident. Conclusions: Serum levels of miR-122 were correlated to the coagulation disorder in sepsis patients.