Circulating sTREM-1 as a predictive biomarker of pediatric multisystemic inflammatory syndrome (MIS-C).

The exacerbation of the inflammatory response caused by SARS-CoV-2 in adults promotes the production of soluble mediators that could act as diagnostic and prognostic biomarkers for COVID-19. Among the potential biomarkers, the soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) has been described as a predictor of inflammation severity. The aim was to evaluate sTREM-1 and cytokine serum concentrations in pediatric patients during the acute and convalescent phases of COVID-19. This was a prospective study that included 53 children/adolescents with acute COVID-19 (Acute-CoV group); 54 who recovered from COVID-19 (Post-CoV group) and 54 controls (Control group). Preexisting chronic conditions were present in the three groups, which were defined as follows: immunological diseases, neurological disorders, and renal and hepatic failures. The three groups were matched by age, sex, and similar preexisting chronic conditions. No differences in sTREM-1 levels were detected among the groups or when the groups were separately analyzed by preexisting chronic conditions. However, sTREM-1 analysis in the seven multisystemic inflammatory syndrome children (MIS-C) within the Acute-Cov group showed that sTREM-1 concentrations were higher in MIS-C vs non-MIS-C acute patients. Then, the receiver operating curve analysis (ROC) performed with MIS-C acute patients revealed a significant AUC of 0.870, and the sTREM-1 cutoff value of > 5781 pg/mL yielded a sensitivity of 71.4 % and a specificity of 91.3 % for disease severity, and patients with sTREM-1 levels above this cutoff presented an elevated risk for MIS-C development in 22.85-fold (OR = 22.85 [95 % CI 1.64-317.5], p = 0.02). The cytokine analyses in the acute phase revealed that IL-6, IL-8, and IL-10 concentrations were elevated regardless of whether the patient developed MIS-C, and those levels decreased in the convalescent phase, even when compared with controls. Spearman correlation analysis generated positive indexes between sTREM-1 and IL-12 and TNF-α concentrations, only within the Acute-CoV group. Our findings revealed that sTREM-1 in pediatric patients has good predictive accuracy as an early screening tool for surveillance of MIS-C cases, even in patients with chronic underlying conditions.

Soluble TREM-1, as a new ligand for the membrane receptor Robo2, promotes hepatic stellate cells activation and liver fibrosis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.

Investigation of the Diagnostic Value of Cerebrospinal Fluid and Serum sTREM-1 Levels in Neonatal Meningitis.

Background: The aim of this study is to investigate the diagnostic value of cerebrospinal fluid (CSF) and serum levels of the soluble form of triggering receptor-1 expressed on myeloid cells (sTREM-1) in neonatal meningitis. Methods: Serum sTREM-1 levels were measured in all neonatal sepsis patients at the start of antibiotic therapy and the 48th hour of treatment. At the beginning of antibiotic therapy, CSF samples were collected for sTREM-1 measurements. Control CSF samples were also collected from the patients with meningitis at the 48th hour of treatment. Results: A total of 77 preterm (50) and term (27) patients with neonatal sepsis were included in the study. There was no significant difference between the CSF sTREM-1 levels of patients with and without meningitis. The CSF sTREM-1 levels of preterm infants with meningitis decreased significantly after treatment (p = 0.038). Although the CSF/serum sTREM-1 ratios tended to increase in babies with meningitis, no significant difference was found between the groups. CSF/serum sTREM-1 ratios (mean ± SD) were 1.42 ± 0.91 and 1.14 ± 0.85 in preterm babies with and without meningitis and 1.15 ± 0.97 and 0.97 ± 0.55 in term babies with and without meningitis, respectively. Conclusions: Serum and CSF sTREM-1 levels increase in patients with neonatal sepsis. CSF s-TREM-1 levels decrease after treatment in preterm infants with meningitis.

Relationship between levels of serum gastric inhibitory polypeptide (GIP), soluble interleukin-2 receptor (sIL-2R), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and disease condition and prognosis of patients with severe acute pancreatitis.

BACKGROUND: To explore the relationship between levels of serum gastric inhibitory polypeptide (GIP), soluble interleukin-2 receptor (sIL-2R), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and the disease condition and prognosis in patients with severe acute pancreatitis (SAP). METHODS: A total of 52 patients with SAP (SAP group) and 50 patients with mild acute pancreatitis (MAP group) admitted to Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China between April 2017 and December 2019 were included in the present study. A further 50 people who had received a healthy physical examination during the same period constituted the healthy control group. The levels of serum GIP, sIL-2R, and sTREM-1 were measured. The levels of serum GIP, sIL-2R, and sTREM-1 were compared among the SAP, MAP and healthy control groups, and the severity of disease (Ranson scoring system) was compared between the SAP and MAP groups. Pearson correlation analysis was used to analyze the correlation between the levels of serum GIP, sIL-2R, and sTREM-1 with the Ranson scores in the SAP group. A receiver operating characteristic (ROC) curve was drawn to evaluate the predictive efficacy of serum GIP, sIL-2R, and sTREM-1 on prognosis. RESULTS: The levels of serum GIP, sIL-2R, and sTREM-1 in the SAP and MAP groups were higher than those in the healthy control group, and the levels in the SAP group were higher than those in the MAP group. The Pearson correlation analysis showed that the levels of serum GIP, sIL-2R, and sTREM-1 in the SAP group were positively correlated with Ranson scores. The levels of serum GIP, sIL-2R, and sTREM-1 in the survival group were lower than those in the deceased group. The ROC curve showed that the best cut-off values of serum GIP, sIL-2R, and sTREM-1 in predicting prognostic survival were 167.040 pg/mL, 70.840 pg/mL, and 128.325 ng/mL, respectively. CONCLUSIONS: The levels of serum GIP, sIL-2R, and sTREM-1 are closely related to the severity of illness in patients with SAP and can be used as reference indicators for assessing the onset of SAP and predicting prognosis.

The relationship between the expression of serum IL-18 mRNA, CC16, and sTREM-1 and the severity and prognosis of ventilator-associated pneumonia in elderly patients.

BACKGROUND: This study aimed to explore the relationship between the severity and prognosis of elderly patients with ventilator-associated pneumonia (VAP) and the expression of serum interleukin-18 mRNA (IL-18 mRNA), Clara cell secretory protein 16 (CC16) and the soluble triggering receptor expressed on myeloid cells 1 (sTREM-1). METHODS: The patients were divided into a VAP group (n=75) and a non-VAP group (n=110). According to the Acute Physiology and Chronic Health Evaluation II (APACHEII) score, the patients with VAP were divided into a low-risk group, an intermediate-risk group and a high-risk group. According to the 28-day outcome, the patients were divided into a survival group and a death group. Serum levels of IL-18, CC16 and sTREM-1 were detected, and their value in the prediction and prognosis of VAP was analyzed using a receiver operating characteristic (ROC) curve. RESULTS: Serum levels of IL-18 and sTREM-1 in the VAP group were higher than those in the non-VAP group, while CC16 levels were lower in the VAP group than those in the non-VAP group (P<0.05). Serum levels of IL-18 and sTREM-1 decreased in order from the high-risk group to the intermediate-risk group to the low-risk group, while CC16 levels increased in order (P<0.05). ROC curve analysis showed that the Youden index and AUC of combined diagnosis of VAP with serum IL-18 mRNA, CC16 and sTREM-1 were 0.710 and 0.930, which were higher than those of single diagnosis (P<0.05). Serum levels of IL-18 mRNA and sTREM-1 in the survival group were lower than those in the death group, and the CC16 level was higher than that in the death group (P<0.05). ROC curve analysis showed that the Youden index and AUC of combined diagnosis with serum IL-18 mRNA, CC16 and sTREM-1 were 0.506 and 0.731, which were higher than those of single diagnosis (P<0.05). CONCLUSIONS: The combination of these 3 factors is of high value in predicting the severity and prognosis of VAP and can provide reference for clinical treatment.

Host-Based Prognostic Biomarkers to Improve Risk Stratification and Outcome of Febrile Children in Low- and Middle-Income Countries.

Fever is one of the leading causes for pediatric medical consultation and the most common symptom at clinical presentation in low- and middle-income countries (LMICs). Most febrile episodes are due to self-limited infections, but a small proportion of children will develop life-threatening infections. The early recognition of children who have or are progressing to a critical illness among all febrile cases is challenging, and there are currently no objective and quantitative tools to do so. This results in increased morbidity and mortality among children with impending life-threatening infections, whilst contributing to the unnecessary prescription of antibiotics, overwhelming health care facilities, and harm to patients receiving avoidable antimicrobial treatment. Specific fever origin is difficult to ascertain and co-infections in LMICs are common. However, many severe infections share common pathways of host injury irrespective of etiology, including immune and endothelial activation that contribute to the pathobiology of sepsis (i.e., pathogen "agnostic" mechanisms of disease). Importantly, mediators of these pathways are independent markers of disease severity and outcome. We propose that measuring circulating levels of these factors can provide quantitative and objective evidence to: enable early recognition of severe infection; guide patient triage and management; enhance post-discharge risk stratification and follow up; and mitigate potential gender bias in clinical decisions. Here, we review the clinical and biological evidence supporting the clinical utility of host immune and endothelial activation biomarkers as components of novel rapid triage tests, and discuss the challenges and needs for developing and implementing such tools.

Expression pattern of soluble triggering receptor expressed on myeloid cells-1 in mice with Acinetobacter baumannii colonization and infection in the lung.

BACKGROUND: Acinetobacter baumannii (A. baumannii) is one of the most troublesome opportunistic pathogens associated with hospital-acquired pneumonia (HAP). It is important to be able to discriminate A. baumannii colonization from infection in its early stages so that effective antibiotics can be promptly applied. Recent studies have reported that the secretion of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is markedly upregulated in pneumonia and sepsis, but the expression pattern of sTREM-1 in A. baumannii colonization and infection in the lung has not been explored. METHODS: C57BL/6J male mice were intraperitoneally injected with 1% streptozotocin for 5 consecutive days to establish diabetic models. Subsequently, aerosol inhalation of A. baumannii suspension was performed in these mice to induce pulmonary colonization or infection with saline as vehicle control. Mice were sacrificed and lung tissue was harvested on days 0, 1, 3, 5 and 7 after exposure. Pharyngeal swab culture, lung homogenate culture, and H&E staining of lung tissue were performed to assess the severity of infectious inflammation. sTREM-1 expressions in serum and lung supernatants, serum procalcitonin (PCT) and C-reactive protein (CRP) concentrations were measured by ELISA. RESULTS: A. baumannii colonization and infection models were verified by pharyngeal swab culture, lung homogenate culture, and H&E staining. While sTREM-1 concentrations in mice with A. baumannii colonization remained unchanged in serum and lung supernatants, sTREM-1 expression levels in infected animals were significantly upregulated. In addition, serum sTREM-1 concentration was positively correlated with serum levels of PCT and CRP. CONCLUSIONS: Dynamic secretion of sTREM-1 is associated with the development of A. baumannii infection in the lung. Therefore, sTREM-1 expression level may be a promising biomarker for discriminating A. baumannii infection from colonization.