Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and other inflammatory mediators in malaria by Plasmodium vivax during enteroparasites coinfection.

Malaria is a major health issue with more than 200 million cases occurring annually. Moreover, in Malaria endemic area are frequently observed Malaria-enteroparasite co-infections associated with the modulation of inflammatory response. In this aspect, biomarkers play an important role in the disease prognosis. This study aimed to evaluate inflammatory mediators in malaria during coinfection with enteroparasites. A subset of serum samples already collected was analyzed and divided into four groups: Malaria (n = 34), Co-infected (n = 116), Enteroparasite (n = 120) and Control (n = 95). The serum levels of sTREM-1 and IL-6 were measured by ELISA. TNF-α, and IL-10 levels were previously carried out by flow cytometry. Higher serum levels of sTREM-1 and IL-6 were showed in malaria patients compared to healthy controls. In co-infected malarial patients sTREM-1 serum levels were similar to control group. Interestingly, co-infected malaria patients showed IL-6 serum levels decreased compared to individuals only infected with P. vivax. However, in Malaria patients and co-infected there was a positive correlation between the IL-6 and IL-10 levels (P < 0.0001). This is the first report of sTREM-1 levels in P. vivax infected. Moreover, the results revealing a divergent effect of co-infection with the increased balance between pro-and anti-inflammatory cytokines and reduced IL-6 levels but increases the anemia occurrence. The results also highlight the potential use of IL-6 as a biomarker for P. vivax and enteroparasites coinfection.

Role of triggering receptor expressed on myeloid cells-1 (TREM-1) in COVID-19 and other viral pneumonias: a systematic review and meta-analysis of clinical studies.

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) has emerged as an important inflammatory marker of immune response associated with severity and mortality outcomes in infection diseases, including viral pneumonias. AIM: (1) To evaluate the expression of TREM-1 in patients with COVID-19 and other viral pneumonias compared to healthy individuals; and (2) to analyze the levels of these biomarkers according to disease severity. MATERIALS AND METHODS: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches were performed in PubMed, Scopus, Embase, and Google Scholar. Studies were considered eligible if they were observational studies that provided data on the levels of TREM-1 in humans with viral pneumonia compared to healthy controls. The results of the meta-analysis were expressed as standardized mean difference (SMD) and an effect size of 0.8 was considered a large effect. A subgroup analysis was performed according to the disease severity. RESULTS: Seven studies were included in this systematic review. Four studies included patients with COVID-19 and three analyzed patients with different viruses. The meta-analysis was performed only with patients with COVID-19, which showed increased levels of soluble form of TREM-1 (sTREM-1) among patients with COVID-19 compared to healthy controls (SMD 1.53; 95% CI 0.53-2.52; p < 0.01). No differences were found between patients with mild-to-moderate COVID-19 and healthy controls, but higher levels of sTREM-1 were shown among patients with severe COVID-19 (SMD 1.83; 95% CI 0.77-2.88; p < 0.01). All three studies including patients with other viral pneumonias showed that TREM-1 levels were significantly elevated in infected patients compared with controls. CONCLUSION: These findings may provide evidence on the pro-inflammatory role of TREM-1 in these infections, contributing to the inflammatory profile and disease progression.

TREM-1 amplifies trophoblastic inflammation via activating NF-κB pathway during preeclampsia.

INTRODUCTION: Excessive activation of maternal systemic inflammation is one of the underlying causes of pathology during the disease course of preeclampsia (PE). The triggering receptor expressed on myeloid cells-1 (TREM-1) participates in the development and persistence of inflammation. We hypothesized that dysregulated TREM-1 may be involved in the pathogenesis of PE by promoting the secretion of trophoblastic pro-inflammatory cytokines that augment inflammation. METHODS: The localization of TREM-1 in placenta and the extravillous trophoblast cell line (TEV-1) was determined by immunohistochemical staining. The expression level of TREM-1 and pro-inflammatory cytokines in placentas were compared between normal pregnancies and PE. We used lipopolysaccharide (LPS) to simulate trophoblastic inflammation. TEV-1 cells were transfected with TREM-1 plasmid and si-TREM-1 respectively, and then were incubated with LPS. The expression levels of pro-inflammatory cytokines and key molecules featured in nuclear transcription factor-kappaB (NF-κB) pathway were detected. Transwell assays were used to detect the effects of TREM-1 on cell migration and invasion. RESULTS: TREM-1 was localized on both villous trophoblasts (VTs) and extravillous trophoblasts (EVTs). TREM-1 and pro-inflammatory cytokines were up-regulated in preeclamptic placenta. Overexpression of TREM-1 promoted the activation of NF-κB pathway and the release of pro-inflammatory factors induced by LPS, and enhanced migration and invasion of TEV-1 cells. Inhibition of TREM-1 significantly attenuated LPS-induced effects and suppressed migration and invasion. DISCUSSION: This study suggested that TREM-1 was up-regulated in PE, and may promote the production of downstream inflammatory factors by activating NF-κB pathway in trophoblastic cells, thus exerting pro-inflammatory effects in the pathogenesis of PE.

Diagnostic and prognostic predictive values of circulating sTREM-1 in sepsis: A meta-analysis.

BACKGROUND: With the increasing studies regarding the diagnostic value of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in sepsis in recent years, it is essential to make an updated meta-analysis to explore the sepsis differentiation value of circulating sTREM-1 from systemic inflammatory response syndrome (SIRS). Recently, no meta-analysis was made to explore the prognostic predictive value of circulating sTREM-1 in sepsis. Thus, the present aimed to make meta-analyses to explore the diagnostic and prognostic predictive values of circulating sTREM-1 in sepsis. METHODS: Articles published before March 2021 were searched in databases: PubMed, Web of Science, EMBASE, Medline and Google Scholar. After a summary of sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratio (DOR), the receive-operating characteristics (SROC) curve were performed to summarize true positive (TP) and false positive (FP) rates. Q test and I2 were used to explore heterogeneity between studies. RESULTS: Circulating sTREM-1 showed a high sensitivity (0.85 (95% confidence interval (CI): 0.76-0.91)) and moderate specificity (0.79 (95% CI: 0.70-0.86)) to differentiate sepsis from SIRS. The study showed a high sensitivity (0.80 (95% CI: 0.66-0.89)) and moderate specificity (0.75 (95% CI: 0.69-0.81)) to predict 28-day mortality in sepsis. CONCLUSION: In conclusion, the present study suggested that circulating sTREM-1 showed diagnostic and prognostic predictive values in sepsis.

Evaluation of the relationship between TREM-1/TREM-2 ratio and clinical course in COVID-19 pneumonia.

OBJECTIVE: The inflammatory/anti-inflammatory balance has an important role in the clinical course of SARS-CoV-2 infection (COVID-19), which has affected over 100 million people since it first appeared in China in December 2019. The aim of this study was to investigate the relationship between triggering receptor expressed on myeloid cells (TREM)-1/TREM-2 ratio and COVID-19 severity. METHODS: A total of 171 individuals were included in the study: 121 patients who were admitted to the chest diseases department and intensive care unit of our hospital and diagnosed with COVID-19 by real-time PCR of nasopharyngeal swab samples from December 2020 to March 2021 and a control group consisting of 50 asymptomatic health workers in our hospital who had negative real-time PCR results during routine COVID-19 screening. RESULTS: TREM-1 level was significantly higher in patients with severe disease compared with the moderate and control groups (P = .003, P = .001). TREM-2 levels did not differ significantly in moderate and severe patients (P = .36) but were significantly higher in both patient groups compared with the control group (P = .001 for both). TREM-1/TREM-2 ratio was significantly higher in the severe patient group than in the moderate and control groups (P = .001 for both). In receiver operating characteristic curve analysis of TREM-1/TREM-2 ratio in patients with moderate and severe COVID-19, the area under the curve was 0.723. Using a cut-off value of 0.125 for TREM-1/TREM-2 ratio in the Youden index calculation, the sensitivity was 60% and specificity was 71%. CONCLUSION: Experience with the positive effects of medical treatments to restore inflammatory balance in the course of COVID-19 is steadily increasing. TREM-1 and TREM-2 have an important role in inflammation and may serve as biomarkers and therapeutic targets in the early treatment and follow-up of COVID-19.

Role of soluble triggering receptor expressed in myeloid cells-1 in distinguishing SIRS, sepsis, and septic shock in the pediatric intensive care unit.

BACKGROUND: Research into new markers has been intensified for early diagnosis, prognosis, and differentiation of SIRS, sepsis, and septic shock in recent years. This study aimed to investigate the role of soluble triggering receptor expressed in myeloid cells-1 (sTREM-1) and interleukin (IL)-6 in distinguishing between systemic inflammatory response syndrome (SIRS), sepsis, and septic shock in pediatric intensive care unit (PICU) patients. METHODS: Between June 2014 and July 2015, 90 consecutive patients who were treated in the PICU were included in this prospective observational study. Patients were divided into four groups: control (n = 23), SIRS (n = 22), sepsis (n = 23), and septic shock (n = 22). All patients were evaluated for white blood cell (WBC), serum C-reactive protein (CRP), procalcitonin (PCT), IL-6, and sTREM-1 levels at 0, 24, and 72 h of admission. The prognostic evaluations were made using the Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction (PELOD) scores. Patients were evaluated in terms of age, gender, prognosis, pathogen growth in culture, PRISM III and PELOD score, WBC, CRP, PCT, IL-6, and sTREM-1 levels and a comparison was made between groups. RESULTS: There was no significant difference between all groups in terms of the 0-, 24-, and 72-h sTREM-1 values (p = 0.761, p = 0.360, and p = 0.822, respectively). CRP and PCT values did not differ between the septic shock, sepsis, and SIRS groups at 0, 24, and 72 h. In the septic shock group, the 0-h IL-6 value was significantly higher than that of the SIRS group (p = 0.025). The 24-h IL-6 value in the septic shock group was significantly higher than the values of the sepsis and SIRS groups (p = 0.048 and p = 0.043, respectively). No significant difference was detected between the septic shock, sepsis, and SIRS groups in terms of IL-6 values at 72 h. CONCLUSION: sTREM-1 is not useful for the diagnosis of infection and for distinguishing between sepsis, septic shock, and SIRS since it does not offer a clear diagnostic value for PICU patients, unlike other reliable markers such as WBC, CRP, and PCT. Elevated IL-6 levels may indicate septic shock in PICU patients. More research on sTREM-1 is needed in this setting.

Monocyte TREM-1 Levels Associate With Anti-TNF Responsiveness in IBD Through Autophagy and Fcγ-Receptor Signaling Pathways.

The expression of Triggering Receptor Expressed on Myeloid cells (TREM)-1 has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of TREM-1 specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment TREM-1 expression levels of CD14+ monocytes of Crohn's disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low TREM-1 expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with TREM-1 expression levels in the CD patient cohort. In conclusion, our results indicate that TREM-1 expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of TREM-1.

Surface TREM-1 as a Prognostic Biomarker in Pediatric Sepsis.

OBJECTIVES: To investigate the association between the triggering receptor expressed on myeloid cells-1 (TREM-1) levels and prognosis in septic children. METHODS: Patients admitted to pediatric intensive care units (PICU) of three tertiary centers were included in this prospective observational study. Serum samples were taken at admission from patients who were hospitalized with sepsis. RESULTS: Of the 87 patients included, 34 (39.1%) had severe sepsis and 53 (60.9%) had septic shock. The median age was 2 y (2 mo to 16 y). TREM-1 values were found to be significantly higher in septic shock patients 129 pg/ml (min 9.85- max 494.90) compared to severe sepsis 105 pg/ml (min 8.21- max 289.17) (p = 0.048). Despite higher TREM-1 levels been measured in non-survivors compared to survivors, it was not statistically significant [168.98 pg/ml (min 9.85- max 494.90) vs. 110.79 pg/ml (min 8.21- max 408.90), (p = 0.075)]. CONCLUSIONS: Admission TREM-1 levels were higher in septic shock compared to severe sepsis patients. There was no association between mortality and TREM-1 levels in sepsis. TREM-1 measurements should be used carefully in pediatric sepsis prognosis.

Salivary Biomarkers of Oral Inflammation Are Associated With Cardiovascular Events and Death Among Kidney Transplant Patients.

BACKGROUND: Triggering receptors expressed on myeloid cells (TREMs) and their ligand, peptidoglycan recognition protein 1 (PGLYRP-1), have been detected in secretions from patients with inflammatory diseases, which may lead to the formation of atherosclerotic plaques. Here, we aimed to analyze the association between salivary concentrations of soluble (s)TREM-1 and PGLYRP-1 with death and cardiovascular disease before and after kidney transplantation. MATERIALS AND METHODS: Saliva samples from 53 patients on dialysis were collected during their regular dental evaluation before treatment and after kidney transplantation. Oral inflammatory burden was assessed from panoramic radiographs and full-mouth dental examination. Demographic data, graft function, patient survival, and history of major cardiovascular events (MACEs) were retrieved from hospital records. RESULTS: Salivary sTREM-1 before transplantation increased the odds for death and MACE. In addition, PGLYRP-1 increased the odds for MACE before transplantation. After transplantation, neither salivary sTREM-1 nor PGLYRP-1 increased the odds for death or MACE, probably because of the previous eradication of oral inflammatory foci. None of the studied biomarkers correlated with kidney transplant function. CONCLUSIONS: Salivary sTREM-1 and PGLYRP-1 before transplantation were associated with MACE and death. The utility of salivary proinflammatory biomarkers for risk stratification in kidney transplant candidates requires further investigation.

Biomarkers in Pneumonia-Beyond Procalcitonin.

Pneumonia is the leading infectious cause of mortality worldwide and one of the most common lower respiratory tract infections that is contributing significantly to the burden of antibiotic consumption. Due to the complexity of its pathophysiology, it is widely accepted that clinical diagnosis and prognosis are inadequate for the accurate assessment of the severity of the disease. The most challenging task for a physician is the risk stratification of patients with community-acquired pneumonia. Herein, early diagnosis is essential in order to reduce hospitalization and mortality. Procalcitonin and C-reactive protein remain the most widely used biomarkers, while interleukin 6 has been of particular interest in the literature. However, none of them appear to be ideal, and the search for novel biomarkers that will most sufficiently predict the severity and treatment response in pneumonia has lately intensified. Although our insight has significantly increased over the last years, a translational approach with the application of genomics, metabolomics, microbiomics, and proteomics is required to better understand the disease. In this review, we discuss this rapidly evolving area and summarize the application of novel biomarkers that appear to be promising for the accurate diagnosis and risk stratification of pneumonia.

Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a potential biomarker for the diagnosis of infectious diseases.

Sensitive and useful biomarkers for the diagnosis and prognosis of infectious diseases have been widely developed. An example of these biomarkers is triggering receptor expressed on myeloid cell-1 (TREM-1), which is a cell surface receptor expressed on monocytes/macrophages and neutrophils. TREM-1 amplifies inflammation by activating the TREM-1/DAP12 pathway. This pathway is triggered by the interaction of TREM-1 with ligands or stimulation by bacterial lipopolysaccharide. Consequently, pro-inflammatory cytokines and chemokines are secreted. Soluble TREM-1 (sTREM-1) is a special form of TREM-1 that can be directly tested in human body fluids and well-known biomarker for infectious diseases. sTREM-1 level can be potentially used for the early diagnosis and prognosis prediction of some infectious diseases, including infectious pleural effusion, lung infections, sepsis, bacterial meningitis, viral infections (e.g., Crimean Congo hemorrhagic fever and dengue fever), fungal infections (e.g., Aspergillus infection), and burn-related infections. sTREM-1 is a more sensitive and specific biomarker than traditional indices, such as C-reactive protein and procalcitonin levels, for these infectious diseases. Therefore, sTREM-1 is a feasible biomarker for the targeted therapy and rapid and early diagnosis of infectious diseases.

Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis.

OBJECTIVES: Several studies have investigated the prognostic value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with infection. However, the result was controversial. Thus, the purpose of the present meta-analysis was to determine the prognostic value of the sTREM-1 level in predicting mortality at the initial stage of infection. METHODS: The literature was searched in the PubMed, EMBASE, Web of Knowledge and Cochrane databases. A 2×2 contingency table was constructed on the basis of mortality and sTREM-1 levels in patients with infection. 2 authors independently judged study eligibility and extracted data. The prognostic value of sTREM-1 in predicting mortality was determined using a bivariate meta-analysis model. Q-test and I(2) index were used to test heterogeneity. RESULTS: 9 studies were selected from 803 studies. An elevated sTREM-1 level was associated with a higher risk of death in infection, with pooled risk ratio (RR) was 2.54 (95% CI 1.77 to 3.65) using a random-effects model (I(2)=53.8%). With the bivariate random-effects regression model, the pooled sensitivity and specificity of sTREM-1 to predict mortality in infection were 0.75 (95% CI 0.61 to 0.86) and 0.66 (95% CI 0.54 to 0.75), respectively. The diagnostic OR was 6 (95% CI 3 to 10). The overall area under the summary receiver operator characteristic (SROC) curve was 0.76 (95% CI 0.72 to 0.79). When we calculated the sepsis subgroup, the pooled RR was 2.98 (95% CI 2.19 to 4.40). The pooled sensitivity and specificity were 0.74 (95% CI 0.58 to 0.85) and 0.72 (95% CI 0.62 to 0.80), respectively. The overall area under the SROC curve was 0.78 (95% CI 0.74 to 0.81). CONCLUSIONS: Elevated sTREM-1 concentrations had a moderate prognostic significance in assessing the mortality of infection in adult patients. However, sTREM-1 alone is insufficient to predict mortality as a biomarker.