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1.  Dynamic changes of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflect sepsis severity and can predict prognosis: a prospective study 
We 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).
Fifty-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.
Serum 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.
Serum 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 Registration
Current controlled trials ChiCTR-OCH-09000745
PMCID: PMC3056794  PMID: 21356122
2.  Diagnostic Value of Dynamics Serum sCD163, sTREM-1, PCT, and CRP in Differentiating Sepsis, Severity Assessment, and Prognostic Prediction 
Mediators of Inflammation  2013;2013:969875.
Objective. To describe the dynamics changes of sCD163, soluble serum triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) during the course of sepsis, as well as their outcome prediction. Patients and Methods. An SIRS group (30 cases) and a sepsis group (100 cases) were involved in this study. Based on a 28-day survival, the sepsis was further divided into the survivors' and nonsurvivors' groups. Serum sTREM-1, sCD163, PCT, CRP, and WBC counts were tested on days 1, 3, 5, 7, 10, and 14. Results. On the ICU admission, the sepsis group displayed higher levels of sTREM-1, sCD163, PCT, and CRP than the SIRS group (P < 0.05). Although PCT and sTREM-1 are good markers to identify severity, sTREM-1 is more reliable, which proved to be a risk factor related to sepsis. During a 14-day observation, sCD163, sTREM-1, PCT, and SOFA scores continued to climb among nonsurvivors, while their WBC and CRP went down. Both sCD163 and SOFA scores are risk factors impacting the survival time. Conclusion. With regard to sepsis diagnosis and severity, sTREM-1 is more ideal and constitutes a risk factor. sCD163 is of a positive value in dynamic prognostic assessment and may be taken as a survival-impacting risk factor.
PMCID: PMC3713373  PMID: 23935252
3.  Serum Soluble Triggering Receptor Expressed on Myeloid Cells-1 and Procalcitonin Can Reflect Sepsis Severity and Predict Prognosis: A Prospective Cohort Study 
Mediators of Inflammation  2014;2014:641039.
Objective. To investigate the prognostic significance of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), N-terminal probrain natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), cytokines, and clinical severity scores in patients with sepsis. Methods. A total of 102 patients with sepsis were divided into survival group (n = 60) and nonsurvival group (n = 42) based on 28-day mortality. Serum levels of biomarkers and cytokines were measured on days 1, 3, and 5 after admission to an ICU, meanwhile the acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores were calculated. Results. Serum sTREM-1, PCT, and IL-6 levels of patients in the nonsurvival group were significantly higher than those in the survival group on day 1 (P < 0.01). The area under a ROC curve for the prediction of 28 day mortality was 0.792 for PCT, 0.856 for sTREM-1, 0.953 for SOFA score, and 0.923 for APACHE II score. Multivariate logistic analysis showed that serum baseline sTREM-1 PCT levels and SOFA score were the independent predictors of 28-day mortality. Serum PCT, sTREM-1, and IL-6 levels showed a decrease trend over time in the survival group (P < 0.05). Serum NT-pro-BNP levels showed the predictive utility from days 3 and 5 (P < 0.05). Conclusion. In summary, elevated serum sTREM-1 and PCT levels provide superior prognostic accuracy to other biomarkers. Combination of serum sTREM-1 and PCT levels and SOFA score can offer the best powerful prognostic utility for sepsis mortality.
PMCID: PMC3941582  PMID: 24672147
4.  Diagnostic value of urine sTREM-1 for sepsis and relevant acute kidney injuries: a prospective study 
Critical Care  2011;15(5):R250.
We 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).
We 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.
On 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.
Besides 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 Registration identifier NCT01333657
PMCID: PMC3334801  PMID: 22023777
urine; soluble triggering receptor expressed on myeloid cells-1(sTREM-1); sepsis; severity; prognosis; acute kidney injury (AKI); sensitivity; specificity
5.  In Critically Ill Patients, Serum Procalcitonin Is More Useful in Differentiating between Sepsis and SIRS than CRP, Il-6, or LBP 
We studied the usefulness of serum procalcitonin (PCT), interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) levels and C-reactive protein (CRP) levels, in differentiating between systemic inflammatory response syndrome (SIRS) and sepsis in critically ill patients. Methods. In this single centre prospective observational study we included all consecutive patients admitted with SIRS or sepsis to the ICU. Blood samples for measuring CRP, PCT, IL-6 and LBP were taken every day until ICU discharge. Results. A total of 76 patients were included, 32 with sepsis and 44 with SIRS. Patients with sepsis were sicker on admission and had a higher mortality. CRP, PCT, IL-6 and LBP levels were significantly higher in patients with sepsis as compared to SIRS. With PCT levels in the first 24 hours after ICU admission <2 ng/mL, sepsis was virtually excluded (negative predictive value 97%). With PCT >10 ng/mL, sepsis with bacterial infection was very likely (positive predictive value 88%). PCT was best at discriminating between SIRS and sepsis with the highest area under the ROC curve (0.95, 95% CI 0.90–0.99). Discussion. This study showed that PCT is more useful than LBP, CRP and IL-6 in differentiating sepsis from SIRS.
PMCID: PMC3113363  PMID: 21687569
6.  Diagnostic Value of sTREM-1 in Bronchoalveolar Lavage Fluid in ICU Patients With Bacterial Lung Infections: A Bivariate Meta-Analysis 
PLoS ONE  2013;8(5):e65436.
The serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker in differentiating bacterial infections from others. However, the diagnostic value of sTREM-1 in bronchoalveolar lavage fluid (BALF) in lung infections has not been well established. We performed a meta-analysis to assess the accuracy of sTREM-1 in BALF for diagnosis of bacterial lung infections in intensive care unit (ICU) patients.
We searched PUBMED, EMBASE and Web of Knowledge (from January 1966 to October 2012) databases for relevant studies that reported diagnostic accuracy data of BALF sTREM-1 in the diagnosis of bacterial lung infections in ICU patients. Pooled sensitivity, specificity, and positive and negative likelihood ratios were calculated by a bivariate regression analysis. Measures of accuracy and Q point value (Q*) were calculated using summary receiver operating characteristic (SROC) curve. The potential between-studies heterogeneity was explored by subgroup analysis.
Nine studies were included in the present meta-analysis. Overall, the prevalence was 50.6%; the sensitivity was 0.87 (95% confidence interval (CI), 0.72–0.95); the specificity was 0.79 (95% CI, 0.56–0.92); the positive likelihood ratio (PLR) was 4.18 (95% CI, 1.78–9.86); the negative likelihood ratio (NLR) was 0.16 (95% CI, 0.07–0.36), and the diagnostic odds ratio (DOR) was 25.60 (95% CI, 7.28–89.93). The area under the SROC curve was 0.91 (95% CI, 0.88–0.93), with a Q* of 0.83. Subgroup analysis showed that the assay method and cutoff value influenced the diagnostic accuracy of sTREM-1.
BALF sTREM-1 is a useful biomarker of bacterial lung infections in ICU patients. Further studies are needed to confirm the optimized cutoff value.
PMCID: PMC3667178  PMID: 23734253
7.  Soluble Triggering Receptor Expressed on Myeloid Cells-1 Is an Early Marker of Infection in the Surgical Intensive Care Unit 
Surgical Infections  2009;10(5):435-439.
To determine the value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in early differentiation of systemic inflammatory response syndrome (SIRS) from infection in patients in a surgical intensive care unit (ICU).
Patients were enrolled if there was clinical suspicion of infection and they fulfilled at least two criteria of SIRS at the time of admission to the ICU. The patients were classified as having SIRS (no infection; n = 37) or infection (n = 56) on the basis of the decision of the treating physician and bacteriological evidence of infection. The plasma concentrations of sTREM-1 in the two groups were compared.
Patients with infection had significantly higher sTREM-1 concentrations than patients with SIRS: Median 398 pg/mL (interquartile range [IQR] 302, 552) vs. 78 pg/mL (IQR 28, 150), respectively (p < 0.0001). At a cut-off of 230 pg/mL, sTREM-1 correctly identified patients suffering from infection with 96% sensitivity and 91% specificity.
In the present study, sTREM-1 was an accurate tool for differentiating SIRS from infection in patients in the surgical ICU.
PMCID: PMC2956524  PMID: 19792836
8.  Association of Serum Myeloid Cells of Soluble Triggering Receptor-1 Level with Myocardial Dysfunction in Patients with Severe Sepsis 
Mediators of Inflammation  2013;2013:819246.
Objective. To investigate the association of serum sTREM-1 with myocardial dysfunction in patients with severe sepsis. Methods. A total of 85 patients with severe sepsis were divided into severe sepsis group (n = 40) and septic shock group (n = 45). Serum levels of sTREM-1, NT-proBNP, APACHE II score, SOFA score, cardiac index, cardiac function index, global ejection fraction, and left ventricular contractility index were measured on days 1, 3, and 7 after admission to ICU. Results. Serum sTREM-1 levels of patients with septic shock were significantly higher than those with severe sepsis on days 1, 3, and 7. Serum sTREM-1 was positively correlated with APACHE II scores, SOFA scores, and NT-proBNP. However, The sTREM-1 level was markedly negatively correlated with CI, CFI, GEF, and dP/dt max, respectively. Multiple logistic regression analysis showed that sTREM-1 was independent risk factor to NT-proBNP increasing. The optimal cut-off point of sTREM-1 for detecting patients with myocardial dysfunction was 468.05 ng/mL with sensitivity (80.6%) and specificity (75.7%). There is no difference in TREM-1-mRNA expression between the two groups. Conclusions. Serum sTREM-1 is significantly associated with myocardial dysfunction and may be a valuable tool for determining the presence of myocardial dysfunction in patients with severe sepsis.
PMCID: PMC3703897  PMID: 23861562
9.  Procalcitonin Levels Predict Acute Kidney Injury and Prognosis in Acute Pancreatitis: A Prospective Study 
PLoS ONE  2013;8(12):e82250.
Acute kidney injury (AKI) has been proposed as a leading cause of mortality for acute pancreatitis (AP) patients admitted to the intensive care unit (ICU). This study investigated the predictive value of procalcitonin (PCT) for AKI development and relevant prognosis in patients with AP, and compared PCT’s predictive power with that of other inflammation-related variables.
Between January 2011 and March 2013, we enrolled 305 cases with acute pancreatitis admitted to ICU. Serum levels of PCT, serum amyloid A (SAA), interleukin-6 (IL-6), and C reactive protein (CRP) were determined on admission. Serum PCT was tested in patients who developed AKI on the day of AKI occurrence and on either day 28 after occurrence (for survivors) or on the day of death (for those who died within 28 days).
Serum PCT levels were 100-fold higher in the AKI group than in the non-AKI group on the day of ICU admission (p<0.05). The area under the receiver-operating characteristic (ROC) curve of PCT for predicting AKI was 0.986, which was superior to SAA, CRP, and IL-6 (p<0.05). ROC analysis revealed all variables tested had lower predictive performance for AKI prognosis. The average serum PCT level on day 28 (2.67 (0.89, 7.99) ng/ml) was significantly (p<0.0001) lower than on the day of AKI occurrence (43.71 (19.24,65.69) ng/ml) in survivors, but the serum PCT level on death (63.73 (34.22,94.30) ng/ml) was higher than on the day of AKI occurrence (37.55 (18.70,74.12) ng/ml) in non-survivors, although there was no significant difference between the two days in the latter group (p = 0.1365).
Serum PCT is superior to CRP, IL-6, and SAA for predicting the development of AKI in patients with AP, and also can be used for dynamic evaluation of AKI prognosis.
PMCID: PMC3862675  PMID: 24349237
10.  The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia 
Supportive Care in Cancer  2010;19(10):1593-1600.
In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis.
Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24–48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26).
At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24–48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels.
IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8.
PMCID: PMC3166608  PMID: 20803037
Febrile neutropenia; Bacterial infection; Biomarkers; Children; Mucositis
11.  Diagnostic implications of soluble triggering receptor expressed on myeloid cells-1 in patients with acute respiratory distress syndrome and abdominal diseases: a preliminary observational study 
Critical Care  2011;15(1):R50.
Patients admitted to the intensive care unit (ICU) because of acute or decompensated chronic abdominal disease and acute respiratory failure need to have the potential infection diagnosed as well as its site (pulmonary or abdominal). For this purpose, we measured soluble triggering receptor expression on myeloid cells-1 (sTREM-1) in alveolar and peritoneal fluid.
Consecutive patients (n = 21) with acute or decompensated chronic abdominal disease and acute respiratory failure were included. sTREM was measured in alveolar (A-sTREM) and peritoneal (P-sTREM) fluids.
An infection was diagnosed in all patients. Nine patients had a lung infection (without abdominal infection), 5 had an abdominal infection (without lung infection) and seven had both infections. A-sTREM was higher in the patients with pneumonia compared to those without pneumonia (1963 ng/ml (1010-3129) vs. 862 ng/ml (333-1011); P 0.019). Patients with abdominal infection had an increase in the P-sTREM compared to patients without abdominal infection (1941 ng/ml (1088-3370) vs. 305 ng/ml (288-459); P < 0.001). A cut-off point of 900 pg/ml of A-sTREM-1 had a sensitivity of 81% and a specificity of 80% (NPV 57%; PPV 93%, AUC 0.775) for the diagnosis of pneumonia. In abdominal infections, a cut-off point for P-sTREM of 900 pg/ml had the best results (sensitivity 92%; specificity 100%; NPV 90%, PPV 100%, AUC = 0.903).
sTREM-1 measured in alveolar and peritoneal fluids is useful in assessing pulmonary and peritoneal infection in critical-state patients-A-sTREM having the capacity to discriminate between a pulmonary and an extra-pulmonary infection in the context of acute respiratory failure.
PMCID: PMC3221980  PMID: 21294874
12.  The Value of Procalcitonin and the SAPS II and APACHE III Scores in the Differentiation of Infectious and Non-infectious Fever in the ICU: A Prospective, Cohort Study 
Journal of Korean Medical Science  2010;25(11):1633-1637.
Early and accurate differentiation between infectious and non-infectious fever is vitally important in the intensive care unit (ICU). In the present study, patients admitted to the medical ICU were screened daily from August 2008 to February 2009. Within 24 hr after the development of fever (>38.3℃), serum was collected for the measurement of the procalcitonin (PCT) and high mobility group B 1 levels. Simplified Acute Physiology Score (SAPS) II and Acute Physiology And Chronic Health Evaluation (APACHE) III scores were also analyzed. Sixty-three patients developed fever among 448 consecutive patients (14.1%). Fever was caused by either infectious (84.1%) or non-infectious processes (15.9%). Patients with fever due to infectious causes showed higher values of serum PCT (7.8±10.2 vs 0.5±0.2 ng/mL, P=0.026), SAPS II (12.0±3.8 vs 7.6±2.7, P=0.006), and APACHE III (48±20 vs 28.7±13.3, P=0.039) than those with non-infectious fever. In receiver operating characteristic curve analysis, the area under the curve was 0.726 (95% CI; 0.587-0.865) for PCT, 0.759 (95% CI; 0.597-0.922) for SAPS II, and 0.715 (95% CI; 0.550-0.880) for APACHE III. Serum PCT, SAPS II, and APACHE III are useful in the differentiation between infectious and non-infectious fever in the ICU.
PMCID: PMC2967001  PMID: 21060753
Fever; Intensive Care Units; Procalcitonin; SAPS II; APACHE III
13.  The Diagnostic and Prognostic Accuracy of Five Markers of Serious Bacterial Infection in Malawian Children with Signs of Severe Infection 
PLoS ONE  2009;4(8):e6621.
Early recognition and prompt and appropriate antibiotic treatment can significantly reduce mortality from serious bacterial infections (SBI). The aim of this study was to evaluate the utility of five markers of infection: C-reactive protein (CRP), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), CD163 and high mobility group box-1 (HMGB1), as markers of SBI in severely ill Malawian children.
Methodology and Principal Findings
Children presenting with a signs of meningitis (n = 282) or pneumonia (n = 95), were prospectively recruited. Plasma samples were taken on admission for CRP, PCT, sTREM-1 CD163 and HMGB1 and the performance characteristics of each test to diagnose SBI and to predict mortality were determined. Of 377 children, 279 (74%) had SBI and 83 (22%) died. Plasma CRP, PCT, CD163 and HMGB1 and were higher in HIV-infected children than in HIV-uninfected children (p<0.01). In HIV-infected children, CRP and PCT were higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and PCT and CD163 were higher in non-survivors (p = 0.001, p = 0.05 respectively). In HIV-uninfected children, CRP and PCT were also higher in children with SBI compared to those with no detectable bacterial infection (p<0.0005), and CD163 was higher in non-survivors (p = 0.05). The best predictors of SBI were CRP and PCT, and areas under the curve (AUCs) were 0.81 (95% CI 0.73–0.89) and 0.86 (95% CI 0.79–0.92) respectively. The best marker for predicting death was PCT, AUC 0.61 (95% CI 0.50–0.71).
Admission PCT and CRP are useful markers of invasive bacterial infection in severely ill African children. The study of these markers using rapid tests in a less selected cohort would be important in this setting.
PMCID: PMC2721152  PMID: 19675669
14.  Soluble Triggering Receptor Expressed on Myeloid cells-1 in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia 
Intensive Care Medicine  2009;35(7):1265-1270.
Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) has proven to be a good biomarker for sepsis. For the diagnosis ventilator-associated pneumonia (VAP), however, there have only been a few, relatively small, studies on the role of this receptor. The aim of the study was to evaluate the usefulness of sTREM-1 in bronchoalveolar lavage fluid (BALF) from Intensive Care Unit patients as rapid diagnostic test for VAP.
The concentration of sTREM-1 in 240 BALF samples was measured using a quantitative sandwich enzyme immunoassay. Two researchers who were blind to the assay results determined whether a VAP was present or not. Clinical suspicion of a VAP was confirmed by the presence of ≥2% cells containing intracellular organisms and/or a quantitative culture result of ≥104 colony forming units per millilitre BALF.
The mean concentration of sTREM-1 was significantly higher in the BALF of patients with confirmed VAP than in that of patients without confirmed VAP. However, the area under the receiver-operating characteristic curve was 0.58 (95% confidence interval 0.50–0.65, P = 0.04).
The results imply that the sTREM-1 assay in BALF may not be discriminative for VAP.
PMCID: PMC2698974  PMID: 19343323
Artificial respiration; Biological marker; Early diagnosis; Enzyme-linked immunosorbent assay; Intensive care; Respiratory tract infections
15.  Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management 
Critical Care  2012;16(4):R114.
Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections.
PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined.
We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg.
Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.
PMCID: PMC3580689  PMID: 22748193
16.  Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study 
Critical Care  2007;11(2):R38.
Accurate and timely diagnosis of community-acquired bacterial infections in patients with systemic inflammation remains challenging both for clinician and laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis and thereby survival. We therefore compared the diagnostic characteristics of novel and routinely used biomarkers of sepsis alone and in combination.
This prospective cohort study included patients with systemic inflammatory response syndrome who were suspected of having community-acquired infections. It was conducted in a medical emergency department and department of infectious diseases at a university hospital. A multiplex immunoassay measuring soluble urokinase-type plasminogen activator (suPAR) and soluble triggering receptor expressed on myeloid cells (sTREM)-1 and macrophage migration inhibitory factor (MIF) was used in parallel with standard measurements of C-reactive protein (CRP), procalcitonin (PCT), and neutrophils. Two composite markers were constructed – one including a linear combination of the three best performing markers and another including all six – and the area under the receiver operating characteristic curve (AUC) was used to compare their performance and those of the individual markers.
A total of 151 patients were eligible for analysis. Of these, 96 had bacterial infections. The AUCs for detection of a bacterial cause of inflammation were 0.50 (95% confidence interval [CI] 0.40 to 0.60) for suPAR, 0.61 (95% CI 0.52 to 0.71) for sTREM-1, 0.63 (95% CI 0.53 to 0.72) for MIF, 0.72 (95% CI 0.63 to 0.79) for PCT, 0.74 (95% CI 0.66 to 0.81) for neutrophil count, 0.81 (95% CI 0.73 to 0.86) for CRP, 0.84 (95% CI 0.71 to 0.91) for the composite three-marker test, and 0.88 (95% CI 0.81 to 0.92) for the composite six-marker test. The AUC of the six-marker test was significantly greater than that of the single markers.
Combining information from several markers improves diagnostic accuracy in detecting bacterial versus nonbacterial causes of inflammation. Measurements of suPAR, sTREM-1 and MIF had limited value as single markers, whereas PCT and CRP exhibited acceptable diagnostic characteristics.
Trial registration
NCT 00389337
PMCID: PMC2206456  PMID: 17362525
17.  A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis 
The Journal of Experimental Medicine  2004;200(11):1419-1426.
The triggering receptor expressed on myeloid cells (TREM)-1 is a recently discovered receptor expressed on the surface of neutrophils and a subset of monocytes. Engagement of TREM-1 has been reported to trigger the synthesis of proinflammatory cytokines in the presence of microbial products. Previously, we have identified a soluble form of TREM-1 (sTREM-1) and observed significant levels in serum samples from septic shock patients but not controls. Here, we investigated its putative role in the modulation of inflammation during sepsis. We observed that sTREM-1 was secreted by monocytes activated in vitro by LPS and in the serum of animals involved in an experimental model of septic shock. Both in vitro and in vivo, a synthetic peptide mimicking a short highly conserved domain of sTREM-1 appeared to attenuate cytokine production by human monocytes and protect septic animals from hyper-responsiveness and death. This peptide seemed to be efficient not only in preventing but also in down-modulating the deleterious effects of proinflammatory cytokines. These data suggest that in vivo modulation of TREM-1 by sTREM peptide might be a suitable therapeutic tool for the treatment of sepsis.
PMCID: PMC2211948  PMID: 15557347
triggering receptor expressed on myeloid cells-1; inflammation; sepsis; proinflammatory cytokines; mouse model
18.  A composite score combining procalcitonin, C-reactive protein and temperature has a high positive predictive value for the diagnosis of intensive care-acquired infections 
BMC Infectious Diseases  2013;13:159.
Nosocomial infection diagnosis in the intensive care unit (ICU) remains a challenge. We compared routine measurements of procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and temperature in the detection of ICU-acquired infections.
Prospective observational cohort study in a University hospital Medicosurgical ICU. All patients admitted to the ICU ≥ 5 days (n = 141) were included into two groups, either infected (documented infection, n = 25) or non-infected (discharged from the ICU without diagnosis of infection, n = 88).
PCT, CRP, WBC and temperature progression from day −4 (D-4) to day 0 (D0) (day of infection diagnosis or ICU discharge) was analysed. Differences (Δ) were calculated as D0 levels minus the lowest preceding value. D0 PCT and CRP were significantly increased in infected compared to non-infected patients (median, 1st and 3rd quartiles): 3.6 ng/mL (0.92-25) for PCT, 173 mg/L (126–188) for CRP versus 0.02 ng/mL (0.1-0.9) and 57 mg/mL (31–105) respectively (p < 0.0001). In multivariate analysis, D0 temperature > 38.6°C, PCT > 1.86 ng/mL, and CRP > 88 mg/L, performed well (AUCs of 0.88, 0.84, and 0.88 respectively). The sensitivity/specificity profiles of each marker (76%/94% for temperature, 68%/91% for PCT, and 92%/70% for CRP) led to a composite score (0.068 × D0 PCT + 0.005 × D0 CRP + 0.7 × temperature) more highly specific than each component (AUC of 0.90 and sensitivity/specificity of 80%/97%).
Combining CRP, PCT and temperature is an approach which may increase of nosocomial infection detection in the ICU.
PMCID: PMC3655912  PMID: 23547830
Nosocomial infection; Procalcitonin; C-reactive protein; Intensive care unit
19.  Value of Serum Procalcitonin in Evaluating the Prognosis of Sepsis in Elderly Patients with Colorectal Cancer Undergoing Emergency Colorectal Surgery 
The Indian Journal of Surgery  2012;75(2):86-93.
Serum procalcitonin (PCT) levels may have predictive value in the prognosis of postoperative sepsis in elderly patients who have undergone colorectal surgery for colorectal cancer in intensive care units (ICUs). A prospective study involving 90 critically ill patients who underwent colorectal surgery for colorectal cancer in ICUs was performed. Twenty-eight patients were diagnosed with sepsis, in accordance with the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria, and these patients were included in the sepsis group. Sixty-two patients, who were without evidence of sepsis, were enrolled in the control group. We measured the serum PCT concentrations preoperatively (immediately before induction of anesthesia), upon arrival in the ICU (ICU day 0), on the morning of the first postoperative day (postoperative day 1), and on the morning of the third postoperative day (postoperative day 3). The C-reactive protein (CRP) index, acute physiology and chronic health evaluation II (APACHE II) score, mechanical duration of ventilation, mortality rate, incidence of multiple organ failure, and usage of continuous renal replacement therapy were evaluated. The area under the curve for the receiver operating characteristic curve (AUC-ROCC) was measured to explore the association between the serum PCT and the prognosis. In the sepsis group, 12/28 patients died (mortality rate 43 %). In the control group, 6/62 patients died (mortality rate 9.7 %). On the first postoperative day, the serum PCT level was dramatically higher in the sepsis group than in the control group (2.71 ± 1.13 vs. 1.37 ± 0.57, P ≤ 0.05). The PCT level on the first postoperative day was distinctly higher than that measured upon arrival in the ICU (2.71 ± 1.13 vs. 1.31 ± 0.58, P ≤ 0.05). In the two groups, the CRP concentrations were both markedly higher on the first postoperative day than upon arrival in the ICU (138.89 ± 45.12 vs. 70.43 ± 23.54 in the sepsis group, and 133.13 ± 44.91 vs. 69.65 ± 24.98 in the control group, P ≤ 0.05). Linear regression analysis was performed. The results suggest that the PCT and APACHE-II scores were not significantly associated. On the first and third postoperative days, the PCT levels were associated with increased odds of sepsis (AUC-ROCC, 95 % confidence interval 0.817–0.973, P = 0.000, and 0.755–0.944, P = 0.000, respectively). The outcomes of patients in the sepsis group were worse than those in the control group. PCT levels appear to be early markers of postoperative sepsis in elderly patients undergoing colorectal surgery for colorectal cancer during the ICU course. These findings could allow for early identification of postoperative septic complications and be used for prognostic evaluation of these patients.
PMCID: PMC3644167  PMID: 24426400
Elderly patients; Sepsis; Emergency colorectal surgery; Procalcitonin; Prognosis
20.  Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction 
Critical Care  2004;8(4):R234-R242.
Both C-reactive protein (CRP) and procalcitonin (PCT) are accepted sepsis markers. However, there is still some debate concerning the correlation between their serum concentrations and sepsis severity. We hypothesised that PCT and CRP concentrations are different in patients with infection or with no infection at a similar severity of organ dysfunction or of systemic inflammatory response.
Patients and methods
One hundred and fifty adult intensive care unit patients were observed consecutively over a period of 10 days. PCT, CRP and infection parameters were compared among the following groups: no systemic inflammatory response syndrome (SIRS) (n = 15), SIRS (n = 15), sepsis/SS (n = 71) (including sepsis, severe sepsis and septic shock [n = 34, n = 22 and n = 15]), and trauma patients (n = 49, no infection).
PCT and CRP concentrations were higher in patients in whom infection was diagnosed at comparable levels of organ dysfunction (infected patients, regression of median [ng/ml] PCT = -0.848 + 1.526 sequential organ failure assessment [SOFA] score, median [mg/l] CRP = 105.58 + 0.72 SOFA score; non-infected patients, PCT = 0.27 + 0.02 SOFA score, P < 0.0001; CRP = 84.53 - 0.19 SOFA score, P < 0.005), although correlation with the SOFA score was weak (R = 0.254, P < 0.001 for PCT, and R = 0.292, P < 0.001 for CRP). CRP levels were near their maximum already during lower SOFA scores, whereas maximum PCT concentrations were found at higher score levels (SOFA score > 12).
PCT and CRP concentrations were 1.58 ng/ml and 150 mg/l in patients with sepsis, 0.38 ng/ml and 51 mg/l in the SIRS patients (P < 0.05, Mann–Whitney U-test), and 0.14 ng/ml and 72 mg/l in the patients with no SIRS (P < 0.05). The kinetics of both parameters were also different, and PCT concentrations reacted more quickly than CRP.
PCT and CRP levels are related to the severity of organ dysfunction, but concentrations are still higher during infection. Different sensitivities and kinetics indicate a different clinical use for both parameters.
PMCID: PMC522844  PMID: 15312223
calcitonin; C-reactive protein; infection; procalcitonin; sepsis; sequential organ failure assessment score; systemic inflammatory response syndrome
21.  Procalcitonin and quantitative C-reactive protein role in the early diagnosis of sepsis in patients with febrile neutropenia 
South Asian Journal of Cancer  2013;2(4):216-219.
Neutropenia with fever is a common syndrome in patients with hematologic malignancies who have a high risk of infectious diseases. As early diagnosis of infection in such patients is really important, the aim of this study was to investigate the sensitivity and specificity of procalcitonin (PCT) and C-reactive protein (CRP) in the diagnosis of sepsis in febrile neutropenic patients in a referral malignant care center of Isfahan in 2010-2011.
Materials and Methods:
In this analytical cross-sectional study, all the febrile neutropenic patients who were admitted in the referral malignant care center in 2010-2011 were evaluated. The data from every individual, including sex, age, admission time, and duration of fever before taking antibiotics were collected. Sixty-four subjects were involved in the study. Blood samples of the subjects were obtained and the levels of PCT, CRP, Absolute neutrophil count (ANC), and white blood cell count were measured, and blood cultures were obtained. According to the test results, the 64 subjects were divided into two groups including patients with sepsis and without sepsis.
Mean value of PCT in the sepsis group was 28.65 ± 2.68 and in the non-sepsis group was 2.48 ± 0.66, with a P value of 0.000. In case of CRP, the sepsis group had a mean of 159.48 ± 9.73 and the non-sepsis group had a mean of 126.17 ± 10.63 (P = 0.015). Sensitivity and specificity were analyzed by using receiver operating characteristic (ROC) curve and were found to be 92.5% and 97.3%, respectively, for PCT and 70.5% and 42.1%, respectively, for CRP.
PCT can be considered as a predictive factor and a diagnostic marker for the diagnosis of sepsis in febrile neutropenic patients.
PMCID: PMC3889039  PMID: 24455636
C-reactive protein; fever; neutropenia; procalcitonin
22.  Combining intermediate levels of the Endotoxin Activity Assay (EAA) with other biomarkers in the assessment of patients with sepsis: results of an observational study 
Critical Care  2012;16(3):R88.
The Endotoxin Activity Assay (EAA) is a useful test to risk stratify patients with severe sepsis and assess for Gram negative infection. However, the significance of intermediate levels of EAA (0.4-0.59) at the bedside has not been well elucidated. The purpose of this study was to interpret intermediate EAA levels in clinical practice.
This retrospective observational study included all adult patients with suspected sepsis admitted to our medico-surgical intensive care unit (ICU) in whom EAA was measured from July 2008 to September 2011. Data collected included EAA, white blood cell (WBC) count and differential, C-reactive protein (CRP), procalcitonin (PCT) and bacterial cultures. Data were analyzed by comparative statistics.
Two hundred and ten patients were studied. Ninety two (43%) patients had culture documented gram negative infection. Patients with Gram-negative organisms in cultures had significantly higher EAA levels (0.47, IQR 0.27) than those without any Gram-negative organisms in cultures (0.34, IQR 0.22) (p < 0.0001). For patients with intermediate EAA levels (0.40 to 0.59), PCT levels and presence of left shift of WBC significantly differed between patients with Gram negative organisms in their blood or other cultures and those who had no organisms in any of the cultures (4.9 versus 1.7 ng/mL, p < 0.05; 57.9 versus 18.9%, p < 0.0004, respectively).
We confirm that high levels of EAA in our cohort of patients with suspected sepsis are strongly associated with gram negative infection. In those patients with intermediate elevation in EAA levels, use of PCT and WBC differential can provide additional diagnostic value to clinicians at the bedside.
PMCID: PMC3580633  PMID: 22607642
23.  Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis - a prospective, observational study 
BMC Immunology  2013;14:8.
Sepsis is a serious disease condition and a major cause of intensive care unit (ICU) admission. Its diagnosis in critically ill patients is complicated. To diagnose an infection rapidly, and to accurately differentiate systemic inflammatory response syndrome (SIRS) from sepsis, is challenging yet early diagnosis is vital for early induction of an appropriate therapy. The aim of this study was to evaluate whether the immature granulocyte (IG) count is a useful early diagnostic marker of sepsis compared to other markers. Therefore, a total of 70 consecutive surgical intensive care patients were assessed. IGs were measured from whole blood samples using an automated analyzer. C-reactive protein (CRP), lipopolysaccharide binding protein (LBP) and interleukin-6 (IL-6) concentrations were also determined. The observation period was a maximum of 21 days and ended with the patients’ discharge from ICU or death. Receiver operating characteristic (ROC) analyses were conducted and area under the curve (AUC) was calculated to determine sensitivities and specificities for the parameters.
We found that the IG count significantly discriminates between infected and non-infected patients (P < 0.0001) with a sensitivity of 89.2% and a specificity of 76.4%, particularly within the first 48 hours after SIRS onset. Regarding the discriminative power for infection, the IG count was more indicative than other clinical parameters such as CRP, LBP and IL-6, which had a sensitivity of less than 68%. Additionally, the highest diagnostic odds ratio (DOR) with 26.7 was calculated for the IG count within the first 48 hours. During the course of the disease ROC curve analyses showed a superior positive predictive value of the IG count compared to the other measured parameters during the first five days following the fulfillment of SIRS criteria. However, the number of IGs was not correlated with ICU mortality.
The total number of IG in peripheral blood from ICU patients is a good marker to discriminate infected and non-infected patients very early during SIRS. However, the IG count is not suitable as a prognostic marker for mortality. Routine and serial measurement of IGs may provide new possibilities for rapid screening of SIRS patients on ICU with suspected infections.
PMCID: PMC3575223  PMID: 23398965
24.  Procalcitonin as a marker of sepsis and outcome in patients with neurotrauma: an observation study 
BMC Anesthesiology  2013;13:48.
Procalcitonin (PCT) is a reliable biomarker of sepsis and infection. The level of PCT associated with sepsis and infection in patients with traumatic brain injury is currently unknown. The purpose of this study was to investigate the value of PCT and C-reactive protein (CRP) as diagnostic markers of sepsis and to evaluate the prognostic value of these markers related to the severity of injury, sepsis and mortality.
105 adult patients with neurotrauma were enrolled in this study from June 2011 to February 2013. PCT and CRP were measured at admission and 2, 3, 5 and 7 days after admission. The sepsis criteria established by American College of Chest Physicians /Society of Critical Care Medicine Consensus Conference were used to identify patients. Injury Severity Score (ISS) and Glasgow Coma Score (GCS) were used to assess the severity of the injury. All these patients were monitored for 28 days.
At admission, the median level of PCT was consistent with the severity of brain injury as follows: mild 0.08 ng/ml (0.05 - 0.13), moderate 0.25 ng/ml (0.11 - 0.55) and severe 0.31 ng/ml (0.17 - 0.79), but the range of CRP levels varied greatly within the given severity of brain injury. Seventy-one (67.6%) patients developed sepsis. The initial levels of PCT at admission were statistically higher in patients with sepsis, compared with patients with systemic inflammatory response syndrome (SIRS), but there were no differences in the initial concentration of CRP between sepsis and SIRS. After adjusting for these parameters, multivariate logistic regression analysis revealed that PCT was an independent risk factor for septic complications (p < 0.05). The areas under the ROCs at admission for the prediction of mortality were 0.76 (p < 0.05) and 0.733 for PCT and CRP, respectively.
Increased levels of PCT during the course of the ICU stay could be an important indicator for the early diagnosis of sepsis after neurotrauma. In addition, high serum levels of PCT in patients with neurotrauma at admission indicate an increased risk of septic complications, and the daily measurement of PCT assists in guiding antibiotic therapy in neurotrauma patients.
PMCID: PMC3932500  PMID: 24330775
Procalcitonin; Systemic inflammatory response syndrome (SIRS); Sepsis; Mortality; Traumatic brain injury
25.  Early changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-negative sepsis 
Critical Care  2006;10(6):R166.
Our aim was to define early changes of lymphocytes and of NK cells in severe sepsis and to correlate them with serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1).
Blood was sampled from 49 patients with proven highly suspected infection by Gram-negative pathogens, within 12 hours of the advent of severe sepsis, and was also sampled from six healthy volunteers. White blood cells were targeted with monoclonal antibodies and were analyzed by flow cytometry. The concentrations of sTREM-1 were estimated by ELISA.
The presence of CD3/CD4 cells was significantly lower (P < 0.0001) and that of NK cells significantly higher among patients with sepsis compared with controls (P = 0.011). The proportions (median ± standard error) of ANNEXIN-V/CD4/CD3-positive cells, of ANNEXIN-V/CD8/CD3-positive cells and of ANNEXIN-V/CD14-positive cells of the patient population were 7.41 ± 2.26%, 7.69 ± 3.42% and 1.96 ± 4.22%, respectively. Patients with NK cells >20% survived longer compared with those patients with NK cells ≤20% (P = 0.041), and patients with sTREM-1 concentrations >180 pg/ml survived longer compared with those patients with sTREM-1 concentrations ≤180 pg/ml (P = 0.042). A negative correlation was found between the percentages of ANNEXIN-V/CD4/CD3-positive cells and of CD3/CD4 cells (rs = -0.305, P = 0.049), and a positive correlation was found between the serum sTREM-1 concentration and the percentage of NK cells (rs = +0.395, P = 0.014). NK cells isolated from two healthy volunteers released sTREM-1 upon triggering with endotoxins.
Early severe sepsis is characterized by CD4-lymphopenia and increased NK cells, providing a survival benefit for the septic patient at percentages >20%. The survival benefit resulting from elevated NK cells might be connected to elevated serum levels of sTREM-1.
PMCID: PMC1794479  PMID: 17129388

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