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

Sepsis is the most important cause of morbidity and mortality in the intensive care unit; however, sepsis lacks specific clinical manifestations. Thus, it is highly desirable to find sensitive and specific indicators of infection that can be easily collected, that accurately reflect infection severity and prognosis and are clinically important. Current common clinical indicators of infection include pyrexia, white blood cell counts, C-reactive protein (CRP) and procalcitonin (PCT).

Triggering receptor expressed on myeloid cells-1 (TREM-1), discovered by Bouchon et al. in 2000 [1], is a member of the immunoglobulin superfamily of receptors that is specifically expressed on the surfaces of monocytes and neutrophils. TREM-1 expression is increased in infectious diseases and is associated with the release of soluble TREM-1 (sTREM-1). One study by Gibot et al. [2] demonstrated that the value of plasma sTREM-1 levels as an indicator of sepsis was superior to CRP and PCT, although other studies reported that the value of sTREM-1 for diagnosing sepsis was inferior to CRP and PCT [3‐5].

The purpose of this study was to track changes in serum sTREM-1, CRP and PCT levels in patients with sepsis and to compare the predictive values of these three factors for assessing sepsis and establishing prognosis.

During the course of sepsis, TREM-1 amplifies infection-induced inflammatory response signals primarily through the mediation of adapter protein DAP12 on the cell surface. sTREM-1 is the soluble form of TREM-1 that lacks the transmembrane and intracellular domains. These two domains are cleaved from TREM-1 on the membrane surface by proteolysis [8]. In 2009, a meta-analysis [9] found that the sensitivity of sTREM-1 for diagnosing bacterial infection was 0.82 (95% confidence interval [CI]: 0.68-0.90) and the specificity was 0.86 (95% CI: 0.77-0.91). These high values suggested that sTREM-1 was a reasonably reliable indicator for diagnosing bacterial infections.

Compared with previous studies, our study found that sTREM-1 was a valuable tool for diagnosing severe sepsis (severe sepsis + septic shock) with organ dysfunction. sTREM-1 levels in the severe sepsis group were significantly higher than those in the sepsis group starting at day 1 of ICU admission. Thus, sTREM-1 measurements may be useful for an early diagnosis of severe sepsis and timely intervention. There were no significant differences for either CRP or PCT levels between the sepsis and severe sepsis groups, implying that serum sTREM-1 was superior to CRP and PCT for diagnosing severe sepsis.

In our study, the sensitivity and specificity of sTREM-1 for diagnosing severe sepsis were 59.5% and 93.3%, respectively. The low sensitivity value may have been related to the small sample size, and follow-up studies should include larger samples. SOFA scores had a slightly higher sensitivity with a lower specificity. Therefore, combining both sTREM-1 levels and SOFA scores may be more valuable for diagnosing severe sepsis compared with any single indicator.

In our study, patients with more severe conditions had higher SOFA scores. Additionally, SOFA scores in the non-surviving group tended to increase over time, while they decreased gradually in the surviving group. Thus, SOFA scores can dynamically reflect an improvement in a patient's condition, or even the progression of sepsis. Consistent with the results of Dimopoulou et al. [10], we also found that serum sTREM-1 levels were positively correlated with the SOFA scores. Compared with CRP and PCT, sTREM-1 had a higher correlation with SOFA scores, suggesting that sTREM-1 was more closely related to disease conditions than both CRP and PCT.

During the 14-day observation period, sTREM-1 levels in the non-surviving group increased gradually over time, whereas sTREM-1 levels tended to gradually decrease in the surviving group. This indicates that the inflammatory indicator sTREM-1 may be associated with sepsis prognosis. That is, a progressively decreasing expression of sTREM-1 indicates that the infection-induced inflammatory responses are being controlled and that a patient's prognosis is good.

sTREM-1 is primarily produced by the hydrolysis and shedding of membrane-bound TREM-1. Thus, progressive increases of sTREM-1 levels indicate that the total expression of TREM-1 continuously increases and that more pro-inflammatory cytokines and mediators are being released in the body. TREM-1 levels are further increased via positive feedback mechanisms, suggesting the persistence or progression of excessive inflammatory responses and poor prognoses.

Different from sTREM-1 levels, CRP and PCT levels in the surviving group were lower than those in the non-surviving group, indicating that patients with higher expressions of CRP and PCT may have poorer prognoses (although CRP and PCT levels tended to decrease in both groups over time). Overall, these results suggest that dynamic changes of sTREM-1 may better reflect the body's state of inflammatory response and sepsis severity simultaneously making sTREM-1 superior to CRP and PCT. Progressive increases in serum sTREM-1 levels is an indicator of a poor prognosis.

The changing trends for sTREM-1, CRP and PCT identified in the current study were consistent with those in previous studies [11, 12]. Nonetheless, it remains debatable whether or not initial sTREM-1 levels are directly related to prognosis. Gibot et al. [11] found that initial sTREM-1 levels in a non-surviving group were lower than those in a surviving group, and suggested that prognosis would be poorer for patients with lower initial sTREM-1 levels. One possible reason for this finding is a hypothesis that sTREM-1 may compete with membrane-bound TREM-1 for ligand binding and thereby attenuate the transmission of infectious signals from membrane-bound TREM-1 into cells. Thus, the release of pro-inflammatory cytokines and mediators may be reduced and excessive inflammatory reactions and injury may be abrogated. Another possible reason is that inhibitory DAP12 receptors are present on the cell membrane that can bind with sTREM-1. DAP12 receptors negatively regulate TLR signalling pathways, thereby preventing excessive inflammatory responses. Thus, sTREM-1 may have certain anti-inflammatory and protective effects [13]. Patients with low levels of sTREM-1 are prone to excessive inflammatory responses and have poor prognoses.

Our results are consistent with those reported by Giamarellos-Bourboulis et al. [12] who reported that initial sTREM-1 levels in a non-surviving group were higher than those in a surviving group. There are several possible reasons for this observation. First, sTREM-1 is produced when membrane-bound TREM-1 is cleaved from the cell surface. High expression levels of sTREM-1 reflect the high expression of membrane-bound TREM-1. The initial disease conditions were more severe in the non-surviving group and systemic inflammatory reactions were obvious. The expression of membrane-bound TREM-1 increased and the inflammatory reaction caused injury to the body's cells and tissues resulting in the production of endogenous inflammatory pathogenic factors and an increase in the expression of TREM-1. As a result, the initial sTREM-1 levels in the non-surviving group were higher than those in the surviving group. Second, although sTREM-1 may have some anti-inflammatory effects, infections were not well controlled in the non-surviving group. As a result, inflammatory responses overwhelmed the body's compensatory anti-inflammatory capacities. This excessive inflammatory response was persistent resulting in a continuous high expression of membrane-bound TREM-1 and an increase in the total amount of sTREM-1 produced by its hydrolysis. Third, because some of our patients developed sepsis at other hospitals and were transferred to the ICU due to poor therapeutic effects, the observed initial sTREM-1 levels might not actually have been the levels at the onset of sepsis. Instead, the measured levels might actually have been at a later stage in the non-surviving group, which were higher than those measured in the surviving group. Finally, the small sample size for this study could also have influenced the results.

Although the relationship between initial sTREM-1 levels and prognosis remains controversial, multiple studies had similar findings showing that patients with progressively decreasing sTREM-1 levels had better prognoses, whereas patients with progressively increasing sTREM-1 levels had poorer prognoses.

In summary, sTREM-1 levels can reflect sepsis severity more accurately than CRP and PCT and the dynamic changes of sTREM-1 are more sensitive for predicting prognosis. However, the sample size for this study was quite small and larger studies are needed.