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1.  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
2.  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
3.  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
4.  Diagnostic role of soluble triggering receptor expressed on myeloid cell-1 in patients with sepsis 
Biomarkers may be helpful in risk stratification and prediction of mortality in septic patients. This study aimed to investigate the diagnostic role of soluble triggering receptor expressed on myeloid cell-1(sTREM-1), procalcitonin (PCT), C-reactive protein (CRP) and other inflammatory markers in patients with sepsis.
A total of 56 patients with systemic inflammation response syndrome (SIRS) who had been admitted to the ICU department of the Second Hospital of Tianjin Medical University between May 2009 and July 2010 were enrolled. They were divided into a sepsis group (n=32) and a SIRS group (n=24). Twenty-five non-SIRS patients served as controls. The sepsis group was sub-divided into a survival group and a death group according to 28-day prognosis. The values of sTREM-1, PCT, CRP, white blood cell (WBC), and neutrophil count percentage (N) were measured. Acute physiology and chronic health evaluation II (APACHE II) score were determined within 24 hours. The correlation between sTREM-1 and APACHE II score was analyzed. Quantitative data were analyzed by the F test or the Kruskal-Wallis test.
The plasma level of sTREM-1 in the sepsis group was significantly higher than that in the SIRS group and control group. The plasma level of sTREM-1 in the non-survival group was significantly higher than that in the survival group. In the sepsis group, the plasma sTREM-1 level was positively correlated with APACHE II score (r=0.426, P= 0.032). The area under the ROC curve of sTREM-1 was 0.935, larger than that of PCT and CRP.
Plasma sTREM-1 is useful in the diagnosis of sepsis at early stage. The increased level of sTREM-1 during the first 24 hours may be correlated with poor outcome of patients with sepsis.
PMCID: PMC4129709  PMID: 25215008
Sepsis; sTREM-1; Acute physiology and chronic health evaluation II score; Enzyme-linked immunosorbent assay; Procalcitonin; C-reactive protein
5.  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
6.  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
7.  Prospective Evaluation of Procalcitonin, Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases 
PLoS ONE  2016;11(4):e0153938.
Both procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases.
Fifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 35). sTREM-1, PCT and CRP concentrations at fever onset were compared between the two groups of patients.
sTREM-1 and CRP did not differ between the two groups. PCT [median (range), ng/ml] was higher in the infection group than in the disease flare group [0.53 (0.02–12.85) vs. 0.12 (0.02–19.23), p = 0.001]. The area under the receiver-operating characteristic (ROC) for diagnosis of infection was 0.75 for PCT (p = 0.001), 0.63 for CRP (p = 0.09) and 0.52 for sTREM-1 (p = 0.79). Using 0.2 ng/ml as the cutoff value for PCT, sensitivity was 0.75 and specificity was 0.77. Negative predictive values for PCT were 92%, 87% and 82% for a prevalence of infection of 20%, 30%, and 40%, respectively. Neither immunosuppressants nor biomodulators affected the level of the three biomarkers. However, in patients treated with corticosteroids, the levels of sTREM-1 and CRP were significantly decreased compared with the untreated patients.
Setting PCT at a lower cutoff value could provide useful information on excluding infection in febrile patients with autoimmune diseases. The possible effect of corticosteroids on the level of sTREM-1 as an infection marker deserves further study.
PMCID: PMC4838219  PMID: 27096761
8.  Significance of soluble triggering receptor expressed on myeloid cells-1 elevation in patients admitted to the intensive care unit with sepsis 
BMC Infectious Diseases  2016;16:559.
Among septic patients admitted to the intensive care unit (ICU), early recognition of those with the highest risk of death is of paramount importance. Since clinical judgment is sometimes uncertain biomarkers could provide additional information likely to guide critical illness management. We evaluated the prognostic value of soluble Triggering Receptor Expressed by Myeloid cells 1 (sTREM-1), procalcitonin (PCT) and leucocyte surface expression of CD64.
This was a prospective cohort study, which included 190 septic patient admitted to the ICU in two hospitals. Blood samples for biomarker measurements were obtained upon admission and thereafter. The Simplified Acute Physiology Score (SAPS) II and the Sequential Organ Failure Assessment (SOFA) score were calculated. The primary outcome was all-cause death in the ICU.
The mortality rate reached 25.8 %. The best predictive value of the three biomarkers was obtained with baseline sTREM-1, although clinical scores outperformed this. Accuracy was greater in patients without prior exposure to antibiotics and in those with proven bacterial infection. Adding sTREM-1 levels to SAPS II increased its specificity to 98 %. The soluble TREM-1 level, core temperature and SAPS II value were the only independent predictors of death after adjustment for potential confounders. A decrease in sTREM-1 with time was also more pronounced in survivors than in non-survivors.
sTREM-1 was found to be the best prognostic biomarker among those tested. Both baseline values and variations with time seemed relevant. Although SAPS II outperformed sTREM-1 regarding the prediction of ICU survival, the biomarker could provide additional information.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1893-4) contains supplementary material, which is available to authorized users.
PMCID: PMC5059941  PMID: 27729010
9.  Soluble triggering receptor on myeloid cells-1 is expressed in the course of non-infectious inflammation after traumatic lung contusion: a prospective cohort study 
Critical Care  2011;15(2):R115.
The triggering receptor expressed on myeloid cells-1 (TREM-1) is known to be expressed during bacterial infections. We investigated whether TREM-1 is also expressed in non-infectious inflammation following traumatic lung contusion.
In a study population of 45 adult patients with multiple trauma and lung contusion, we obtained bronchoalveolar lavage (BAL) (blind suctioning of 20 ml NaCl (0.9%) via jet catheter) and collected blood samples at two time points (16 hours and 40 hours) after trauma. Post hoc patients were assigned to one of four groups radiologically classified according to the severity of lung contusion based on the initial chest tomography. Concentration of soluble TREM-1 (sTREM-1) and bacterial growth were determined in the BAL. sTREM-1, IL-6, IL-10, lipopolysaccharide binding protein, procalcitonin, C-reactive protein and leukocyte count were assessed in blood samples. Pulmonary function was evaluated by the paO2/FiO2 ratio.
Three patients were excluded due to positive bacterial growth in the initial BAL. In 42 patients the severity of lung contusion correlated with the levels of sTREM-1 16 hours and 40 hours after trauma. sTREM-1 levels were significantly (P < 0.01) elevated in patients with severe contusion (2,184 pg/ml (620 to 4,000 pg/ml)) in comparison with patients with mild (339 pg/ml (135 to 731 pg/ml)) or no (217 pg/ml (97 to 701 pg/ml)) contusion 40 hours following trauma. At both time points the paO2/FiO2 ratio correlated negatively with sTREM-1 levels (Spearman correlation coefficient = -0.446, P < 0.01).
sTREM-1 levels are elevated in the BAL of patients following pulmonary contusion. Furthermore, the levels of sTREM-1 in the BAL correlate well with both the severity of radiological pulmonary tissue damage and functional impairment of gas exchange (paO2/FiO2 ratio).
PMCID: PMC3219398  PMID: 21496225
10.  A Biomarker Panel (Bioscore) Incorporating Monocytic Surface and Soluble TREM-1 Has High Discriminative Value for Ventilator-Associated Pneumonia: A Prospective Observational Study 
PLoS ONE  2014;9(10):e109686.
Ventilator-associated pneumonia (VAP) increases mortality in critical illness. However, clinical diagnostic uncertainty persists. We hypothesised that measuring cell-surface and soluble inflammatory markers, incorporating Triggering Receptor Expressed by Myeloid cells (TREM)-1, would improve diagnostic accuracy.
A single centre prospective observational study, set in a University Hospital medical-surgical intensive Care unit, recruited 91 patients into 3 groups: 27 patients with VAP, 33 ventilated controls without evidence of pulmonary sepsis (non-VAP), and 31 non-ventilated controls (NVC), without clinical infection, attending for bronchoscopy. Paired samples of Bronchiolo-alveolar lavage fluid (BALF) and blood from each subject were analysed for putative biomarkers of infection: Cellular (TREM-1, CD11b and CD62L) and soluble (IL-1β, IL-6, IL-8, sTREM-1, Procalcitonin). Expression of cellular markers on monocytes and neutrophils were measured by flow cytometry. Soluble inflammatory markers were determined by ELISA. A biomarker panel (‘Bioscore’), was constructed, tested and validated, using Fisher’s discriminant function analysis, to assess its value in distinguishing VAP from non VAP.
The expression of TREM-1 on monocytes (mTREM-1) and neutrophils (nTREM-1) and concentrations of IL-1β, IL-8, and sTREM-1 in BALF were significantly higher in VAP compared with non-VAP and NVC (p<0.001). The BALF/blood mTREM-1 was significantly higher in VAP patients compared to non-VAP and NVC (0.8 v 0.4 v 0.3 p<0.001). A seven marker Bioscore (BALF/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1β, and serum CRP and IL-6) correctly identified 88.9% of VAP cases and 100% of non-VAP cases.
A 7-marker bioscore, incorporating cellular and soluble TREM-1, accurately discriminates VAP from non-pulmonary infection.
PMCID: PMC4188746  PMID: 25289689
11.  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
12.  Association of Serum Soluble Triggering Receptor Expressed on Myeloid Cells Levels in Malignant Febrile Neutropenic Patients with Bacteremia and Fungemia 
Iranian Journal of Pediatrics  2011;21(3):301-306.
Infections are the major cause of morbidity and mortality in febrile neutropenic patients with malignancy. Rapid diagnostic tests are needed for prompt diagnosis and early treatment which is crucial for optimal management. We assessed the utility of soluble triggering receptor expressed on myeloid cells (sTREM-1) in the diagnosis of bacteremia and fungemia in febrile neutropenic patients.
Sixty-five febrile neutropenic children with malignancy hospitalized in Mofid Children's Hospital during a period of one year from January 2007 were recruited for this cross sectional study (mean age 66.2± 37 months; 35 females and 30 males). Thirty patients (46.2%) had acute lymphoblastic leukemia, 2 (3.1%) acute myeloid leukemia, one (1.5%) lymphoma and 32 (49.2%) were under treatment for solid tumors. Simultaneous blood samples were collected for measurement of serum sTREM-1 levels and for blood cultures which were grown in BACTEC media. Gold standard for the presence of infection was a positive BACTEC culture as a more sensitive method compared to current blood culture techniques.
Blood cultures with BACTEC system were positive in 13(20%) patients (12 bacterial and one fungal culture). The mean serum sTREM-1 level in BACTEC positive patients was 948.2±592.9 pg/ml but in BACTEC negative cases it was 76.3±118.8 pg/ml (P<0.001). The optimal cut-off point of sTREM-1 for detecting patients with positive result of BACTEC was 525 pg/ml with sensitivity and specificity of 84.6% and 100%, respectively.
Our study revealed a significant association between serum sTREM-1 level and bacteremia and fungemia in febrile neutropenic patients suffering malignancy with acceptable sensitivity and specificity.
PMCID: PMC3446192  PMID: 23056805
Neutropenia; Fever; sTREM-1; BACTEC; Malignancy
13.  Correlation between triggering receptor expressed on myeloid cells-1 and clinical disease activity in Chinese patients with ulcerative colitis 
The need for reliable biomarkers for monitoring disease activity in patients with ulcerative colitis (UC) is increasing. This study aimed at characterizing the correlation between serum sTREM-1 levels and diseases activity in Chinese patients with UC. Consecutive 76 patients with UC and 20 healthy subjects were prospectively enrolled. The disease activity of UC was assessed according to Mayo Score. Expression levels of TREM-1 in peripheral blood mononuclear cells (PBMCs) and serum sTREM-1 levels were evaluated at the time when the disease activity was determined. Other laboratory parameters, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also determined. Both TREM-1 expression levels in PBMCs and serum sTREM-1 levels from patients with UC were significantly increased compared to healthy subjects. In addition, the levels of TREM-1 expression and serum sTREM-1 were significantly elevated in UC patients with moderate or severe disease compared to the patients with quiescent or mild disease. More importantly, both levels of TREM-1 expression in PBMCs and serum sTREM-1 levels were significantly correlated with disease activity. The correlation between sTREM-1 and disease activity was higher than the correlations between CRP and disease activity or ESR and disease activity. Our findings suggest that serum sTREM-1 could be a potential serum biomarker for monitoring disease activity in Chinese patients with UC, and could be a promising surrogate for CRP and ESR.
PMCID: PMC4402792  PMID: 25932145
Ulcerative colitis (UC); triggering receptor expressed on myeloid cells-1 (TREM-1); sTREM-1; disease activity; Chinese patients
14.  TREM-1 as a potential therapeutic target in neonatal sepsis 
Objective: Bacterial sepsis in neonates is associated with elevated morbidity and mortality. A role for the pro-inflammatory Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is suspected in the innate immune response to bacteria, but little is known about its activities in infants. To begin exploring the feasibility of treating neonatal sepsis by blocking leukocyte TREM-1, we compared TREM-1 membrane expression and mRNA in newborns without clinical or microbiological evidence of infection, to that of healthy adults. The functionality of pro-inflammatory reactions in leukocyte TREM-1 of newborns was also evaluated. Methods: Twenty term newborns were enrolled in this study and cord blood samples were collected at birth. For comparison, peripheral blood specimens were collected from 20 healthy adults (control adult, CA). The expression of TREM-1 protein and mRNA in leukocytes was detected with flow cytometry and real-time qPCR, respectively. Whole cord blood was also stimulated by Escherichia coli or blocked by the TREM-1-specific peptide LP17 to identify changes in the secretion of pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α, as well as soluble TREM-1 (sTREM-1) using enzyme linked immunosorbent assay (ELISA). Results: Mean fluorescence intensity (MFI) of TREM-1 on leukocytes of newborns appeared comparable to healthy adults [monocytes: 37.5 ± 6.7 vs. 37.6 ± 8.7; polymorphonuclear cells (PMNs): 32.9 ± 6.6 vs. 33.6 ± 5.8]. However, the percentage of PMNs positive for TREM-1 was lower in newborns than in healthy adults (82.3 ± 7.1 vs. 98.6 ± 4.8; P < 0.01); the percentage of TREM-1-positive CD14-positive monocytes was comparable to that of healthy adults (97.1 ± 8.3 vs. 97.5 ± 7.4). Exposure of cord blood to E. coli resulted in increased secretion of IL-6, IL-8, TNF-α, and sTREM-1. In contrast, the concentrations of IL-6, IL-8, and TNF-α decreased by a minimum of 15% when TREM-1 was blocked by LP17 then exposed to E. coli, versus E. coli alone. In addition, the concentration of sTREM-1 was positively correlated with the levels of TNF-α (r = 0.519, P < 0.05), IL-6 (r = 0.507, P < 0.05), and IL-8 (r = 0.538, P < 0.05). Conclusions: Healthy newborns exhibit expression of TREM-1 on monocytes similar to that in healthy adults, and most PMNs express TREM-1 at the newborn stage. Detection of sTREM-1 in neonatal peripheral blood should be further investigated as a potential method for the diagnosis of neonatal infection. Finally, blocking the TREM-1 signal transduction pathway may reduce inflammatory responses of neonate leukocytes and thereby provide a new strategy for treatment of neonatal infection.
PMCID: PMC4132125  PMID: 25126161
Triggering receptor expressed on myeloid cells-1; infant; leukocytes; sTREM-1
15.  Identification of Predictive Early Biomarkers for Sterile-SIRS after Cardiovascular Surgery 
PLoS ONE  2015;10(8):e0135527.
Systemic inflammatory response syndrome (SIRS) is a common complication after cardiovascular surgery that in severe cases can lead to multiple organ dysfunction syndrome and even death. We therefore set out to identify reliable early biomarkers for SIRS in a prospective small patient study for timely intervention. 21 Patients scheduled for planned cardiovascular surgery were recruited in the study, monitored for signs of SIRS and blood samples were taken to investigate biomarkers at pre-assigned time points: day of admission, start of surgery, end of surgery, days 1, 2, 3, 5 and 8 post surgery. Stored plasma and cryopreserved blood samples were analyzed for cytokine expression (IL1β, IL2, IL6, IL8, IL10, TNFα, IFNγ), other pro-inflammatory markers (sCD163, sTREM-1, ESM-1) and response to endotoxin. Acute phase proteins CRP, PCT and pro-inflammatory cytokines IL6 and IL8 were significantly increased (p<0.001) at the end of surgery in all patients but could not distinguish between groups. Normalization of samples revealed significant increases in IL1β changes (p<0.05) and decreased responses to endotoxin (p<0.01) in the SIRS group at the end of surgery. Soluble TREM-1 plasma concentrations were significantly increased in patients with SIRS (p<0.01). This small scale patient study could show that common sepsis markers PCT, CRP, IL6 and TNFα had low predictive value for early diagnosis of SIRS after cardiovascular surgery. A combination of normalized IL1β plasma levels, responses to endotoxin and soluble TREM-1 plasma concentrations at the end of surgery are predictive markers of SIRS development in this small scale study and could act as an indicator for starting early therapeutic interventions.
PMCID: PMC4532358  PMID: 26263001
16.  Elevated Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM)-1 Levels in Maternal Serum during Term and Preterm Labor 
PLoS ONE  2013;8(2):e56050.
Infection and inflammation are important mechanisms leading to preterm birth. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) belongs to a family of cell surface receptors that seems to play an important role in fine-tuning the immune response. It has been demonstrated that sTREM-1 is involved in bacterial infection as well as in non-infectious inflammatory conditions. Few studies have investigated serum sTREM-1 expression during preterm labor. Therefore, the purpose of this study was to assess sTREM-1 concentrations in maternal serum during term and preterm labor.
This case control study included 176 singleton pregnancies in the following groups: patients in (1) preterm labor, delivered before 34 weeks (PTB) (n = 52); (2) GA matched controls, not in labor, matched for gestational age (GA) with the PTB group (n = 52); (3) at term in labor (n = 40) and (4) at term not in labor (n = 32). sTREM-1 concentrations were determined by enzyme-linked immunoassay.
sTREM-1 was detected in all serum samples. Median sTREM-1 concentrations were significantly higher in women with PTB vs. GA matched controls (367 pg/ml, interquartile range (IQR) 304–483 vs. 273 pg/ml, IQR 208–334; P<0.001) and in women at term in labor vs. at term not in labor (300 pg/ml, IQR 239–353 vs. 228 pg/ml, IQR 174–285; P<0.001). Women with PTB had significantly higher levels of sTREM-1 compared to women at term in labor (P = 0.004). Multiple regression analysis, with groups recoded as three key covariates (labor, preterm and rupture of the membranes), showed significantly higher sTREM-1 concentrations for labor (+30%, P<0.001) and preterm (+15%, P = 0.005) after adjusting for educational level, history of PTB and sample age.
sTREM-1 concentrations in maternal serum were elevated during spontaneous term and preterm labor and sTREM-1 levels were significantly higher in preterm labor.
PMCID: PMC3585334  PMID: 23468854
17.  Diagnostic value of triggering receptor expressed on myeloid cells-1 and C-reactive protein for patients with lung infiltrates: an observational study 
BMC Infectious Diseases  2010;10:286.
Differential diagnosis of patients with lung infiltrates remains a challenge. Triggering receptor expressed on myeloid cells (TREM)-1 is a neutrophil and monocyte receptor up-regulated during infection. The aim of this study was to evaluate the diagnostic accuracy of TREM-1 and of C-reactive protein (CRP) from patients with lung infiltrates to discern community acquired lung infections.
68 patients admitted to a medical ward with acute respiratory illness were enrolled in the study. Neutrophil and monocyte TREM-1 expression were measured by flow cytometry, sTREM-1 by an enzyme immunoassay and C-reactive protein by nephelometry. Clinical pulmonary infection score was recorded.
34 patients were diagnosed with bacterial community acquired pneumonia (group A) and 34 with non-bacterial pulmonary disease (group B). Median serum TREM-1 concentration was 102.09 pg/ml in group A and lower than 15.10 pg/ml (p < 0.0001) in group B. Mean±SE neutrophil TREM-1 expression was 4.67 ± 0.53 MFI in group A and 2.64 ± 0.25 MFI (p = 0.001) in group B. Monocyte TREM-1 expression was 4.2 ± 0.42 MFI in group A and 2.64 ± 0.35 MFI (p = 0.007) in group B and mean±SE CRP was 18.03 ± 2 mg/ml in group A and 7.1 ± 1.54 mg/ml (p < 0.001) in group B. A cut-off of 19.53 pg/ml of sTREM-1 with sensitivity 82.6% and specificity 63% to discriminate between infectious and non-infectious pulmonary infiltrates was found. sTREM-1 at admission greater than 180 pg/ml was accompanied with unfavourable outcome.
TREM-1 myeloid expression and sTREM-1 are reliable markers of bacterial infection among patients with pulmonary infiltrates; sTREM-1 is a predictor of final outcome.
PMCID: PMC2955686  PMID: 20920231
18.  Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) as a Diagnostic Marker of Ventilator-Associated Pneumonia 
Respiratory care  2012;57(12):2052-2058.
To determine the utility of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) levels in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC) samples from patients who underwent bronchoscopy for a clinical suspicion of ventilator-associated pneumonia (VAP), to categorize patients as VAP positive and VAP negative, when compared to quantitative culture results of BALF.
Observational study conducted on admitted patients in the trauma-surgical, medical-cardiac, burn, and neurosurgical ICUs of Harborview Medical Center between March 2009 and May 2010. BALF and EBC samples were obtained from 45 patients with clinically suspected VAP. Bronchoscopy was performed on the day of clinically suspected VAP. sTREM-1 levels in EBC and BAL fluid were measured using quantikine human TREM-1 immunoassay. VAP was diagnosed by quantitative cultures of BALF.
The concentrations of sTREM-1 in BALF and EBC did not correlate with VAP status. sTREM-1 levels did not discriminate VAP positive from VAP negative patients, when compared to quantitative cultures of BALF as the gold standard. Using a cutoff value of 204 pg/mL for BALF sTREM-1 levels resulted in a sensitivity of 79% and a specificity of 23%. A cutoff value of 10 pg/mL for EBC sTREM-1 levels resulted in a sensitivity of 42% and a specificity of 50%.
EBC and BALF sTREM-1 levels did not effectively categorize patients as VAP positive or VAP negative when using direct bronchoscopic quantitative culture samples as the comparison standard.
PMCID: PMC4432465  PMID: 22613763
soluble triggering receptor expressed on myeloid cells; sTREM-1 protein; ventilator-associated pneumonia; VAP; biomarkers; bronchoalveolar lavage fluid; acute respiratory distress syndrome; ARDS; human
19.  Early changes of the kinetics of monocyte trem-1 reflect final outcome in human sepsis 
BMC Immunology  2014;15:585.
TREM-1 (triggering receptor expressed on myeloid cells), a receptor expressed on neutrophils and monocytes, is upregulated in sepsis and seems to tune the inflammatory response. We explored the expression of TREM-1 at the gene level and on cell membranes of monocytes and association with clinical outcome.
Peripheral venous blood was sampled from 75 septic patients (39 patients with sepsis, 25 with severe sepsis and 11 with septic shock) on sepsis days 1, 3 and 7. TREM-1 on monocytes was measured by flow cytometry; gene expression of TREM-1 in circulating mononuclear cells was assessed by real-time PCR. sTREM-1 was measured in serum by an enzyme immunoassay.
Although surface TREM-1, sTREM-1 and TREM-1 gene expression did not differ between sepsis, severe sepsis and septic shock on day 1, survivors had greater expression of surface TREM-1 on days 3 and 7 compared to non-survivors. sTREM-1 on non-survivors decreased on day 3 compared to baseline. Patients with increase of monocyte gene expression of TREM-1 from day 1 to day 3 had prolonged survival compared to patients with decrease of gene expression of TREM-1 from day 1 to day 3 (p: 0.031).
Early decrease of gene expression of TREM-1 in monocytes is associated with poor outcome. A reciprocal decrease of the pro-inflammatory surface receptor TREM-1 linked with sepsis-induced immunosuppression may be part of the explanation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12865-014-0063-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4335537  PMID: 25532536
Sepsis; Outcome; TREM-1; sTREM-1, Monocytes
20.  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
21.  Correlation between Soluble Triggering Receptor Expressed on Myeloid Cells-1 and Endoscopic Activity in Intestinal Behçet's Disease 
Yonsei Medical Journal  2014;55(4):960-966.
The serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have recently been shown to be correlated highly with disease activity in patients with intestinal Behçet's disease (BD). However, it remains unclear whether sTREM-1 levels reflect endoscopic activity in intestinal BD. This study aimed to evaluate the correlation of sTREM-1 levels with endoscopic activity in intestinal BD.
Materials and Methods
A total of 84 patients with intestinal BD were enrolled. Endoscopic activity was compared with sTREM-1 levels as well as other laboratory findings, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
sTREM-1 levels were significantly increased in intestinal BD patients compared with controls (37.98±27.09 pg/mL vs. 16.65±7.76 pg/mL, p=0.002), however, there was no difference between endoscopically quiescent and active diseases (43.53±24.95 pg/mL vs. 42.22±32.68 pg/mL, p=0.819). Moreover, serum sTREM-1 levels did not differ in terms of number, shape, depth, size, margin, or type of ulcer in patients with intestinal BD. However, mean ESR and CRP levels in patients with active disease were significantly higher than those in patients with quiescent disease (p=0.001, p<0.001, respectively). In addition, endoscopic activity scores for intestinal BD were correlated significantly with both CRP levels (γ=0.329) and ESR (γ=0.298), but not with sTREM-1 levels (γ=0.166).
Unlike CRP levels and ESR, serum sTREM-1 levels were not correlated with endoscopic activity in patients with intestinal BD.
PMCID: PMC4075400  PMID: 24954324
C-reactive protein; endoscopic activity; erythrocyte sedimentation rate; intestinal Behçet's disease; triggering receptor expressed on myeloid cells-1
22.  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
23.  Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease 
Alzheimer’s disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF).
We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50).
We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid-β1–42 (Aβ42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aβ42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aβ42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46).
sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aβ42, T-tau or P-tau.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-016-0182-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4848774  PMID: 27121148
Aging; Alzheimer’s disease; Amyloid beta; Microgliosis; Mild cognitive impairment; Neuroinflammation; Soluble TREM2; Tau
24.  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
25.  Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation 
Brain  2008;131(11):3081-3091.
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane-bound receptor expressed by microglia and macrophages. Engagement of TREM-2 on these cells has been reported to reduce inflammatory responses and, in microglial cells, to promote phagocytosis. TREM-2 function is critical within the CNS, as its genetic deficiency in humans causes neurodegeneration with myelin and axonal loss. Blockade of TREM-2 worsened the mouse model for multiple sclerosis. In the present study, a soluble form of TREM-2 protein has been identified by immunoprecipitation and by ELISA. Soluble TREM-2 protein (sTREM-2) was detected in human CSF, and was compared among subjects with relapsing-remitting multiple sclerosis (RR-MS; n = 52), primary progressive multiple sclerosis (PP-MS; n = 21), other inflammatory neurologic diseases (OIND; n = 19), and non-inflammatory neurologic diseases (NIND; n = 41). Compared to NIND subjects, CSF sTREM-2 levels were significantly higher in RR-MS (P = 0.004 by ANOVA) and PP-MS (P < 0.001) subjects, as well as in OIND (P < 0.001) subjects. In contrast, levels of sTREM-2 in blood did not differ among the groups. Furthermore, TREM-2 was detected on a subset of CSF monocytes by flow cytometry, and was also highly expressed on myelin-laden macrophages in eight active demyelinating lesions from four autopsied multiple sclerosis subjects. The elevated levels of sTREM-2 in CSF of multiple sclerosis patients may inhibit the anti-inflammatory function of the membrane-bound receptor suggesting sTREM-2 to be a possible target for future therapies.
PMCID: PMC2577803  PMID: 18790823
multiple sclerosis; neuroinflammation; microglia; macrophages; immune regulation

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