Significance of soluble triggering receptor expressed on myeloid cells-1 elevation in patients admitted to the intensive care unit with sepsis

Sepsis remains a leading cause of death worldwide, especially in the intensive care unit (ICU) setting [1]. It is currently accepted that improving the outcome of critically ill patients with sepsis relies mainly on the adequacy and the timeliness of key interventions such as administering appropriate antibiotics and sufficient amounts of fluid, especially the sickest ones [2].

It is therefore mandatory to accurately assess the severity of the acute illness in such patients. Severity scores based on the assessment of underlying disease and organ failure have been derived from large studies [3]. However, these large cohorts included patients without sepsis. In addition, the interest of repeated clinical assessments has not been validated with such scoring systems, and one should consider only the worst values of the physiological and biological parameters within the first 24 h following ICU admission. As a result, the Simplified Acute Physiology Score (SAPS) II is not theoretically available before day 2 and finally of limited value in clinical practice. In contrast, the Sequential Organ Failure Assessment (SOFA) score, which is easier to calculate since it relies solely on daily organ dysfunction assessment, could be more suitable. In addition, it was first evaluated in septic patients [4, 5]. However, as organ failure is the end-stage complication of sepsis, it would be useful to predict it before it becomes clinically obvious, in order to prevent or at least to attenuate it whenever possible. In addition, clinical judgment may lack objectivity, thus leading to wrong evaluations and potentially inappropriate interventions. Moreover, the administration of innovative therapies is thought to provide the greatest benefit if given early to the potentially sickest septic patients.

In addition to the clinical evaluation, biomarkers provide a unique but only theoretical opportunity to predict the risk of bad outcomes reliably and promptly in patients with sepsis. Since the host inflammatory response is of paramount importance, measuring some of its most relevant mediators as well as surrogates within various body fluids including plasma has been proposed as a promising way to improve the management of such patients. Among these biomarkers, procalcitonin (PCT) and the soluble Triggering Receptor Expressed by Myeloid cells 1 (sTREM-1) have been shown to exhibit good diagnostic accuracy for bacterial sepsis [6‐8]. More recently, we showed that the CD64 leucocyte index measured upon ICU admission was even more accurate [9].

The prognostic value of these biomarkers, however, remains to be clearly established and compared with relevant clinical scores. Actually, although it is tempting to believe that the same biomarker could be both a reliable diagnosis tool for sepsis and a powerful outcome predictor, none of those mentioned above has demonstrated these abilities within the same cohort of patients.

We therefore assessed the predictive value of PCT, sTREM-1 and the PMN CD64 index, with regard to the risk of a bad outcome in a large cohort of ICU septic patients included in a prospective observational study that aimed primarily to evaluate their diagnostic accuracy.

The methodology has already been extensively described elsewhere [9].

The whole data set is available as supplementary material (Additional file 1).

Accurately evaluating the severity of acute illness in septic patients on admission to an ICU is challenging. It usually relies on a combination of various clinical and biological data, including the assessment of organ failure, as well as knowledge of underlying disease(s). Although of paramount importance, clinical judgment might be biased given the need for prompt decision-making. Indeed, having an objective overview of a patient’s risk of death remains a matter of concern. Calculating clinical scores is fastidious and could remain subjective. Measuring biomarkers could overcome these drawbacks.

The main findings of the present study were the following: (i) the PMN CD64 index had no prognostic value despite its promising accuracy regarding the diagnosis of sepsis; (ii) the predictive value of sTREM-1 regarding the risk of death was greater than that of PCT, especially when considering early mortality. In addition, among the biomarkers tested, sTREM-1 was an independent predictor of death and sTREM-1 kinetics looked different between survivors and non survivors. Nonetheless, both biomarkers were outperformed by clinical scores; (iii) the combination of sTREM-1 and SAPS II offered the best accuracy for predicting ICU survival in our cohort; (iv) none of the indicators tested were valuable tools for reliably predicting clinical worsening within the first 48 h of the ICU stay.

Several studies have aimed to evaluate biomarkers including sTREM-1 as prognostic factors in critically ill patients with sepsis. However, despite interesting findings, it remains unclear whether they are of any value or not (Table 8).

TREM-1 is a member of the immunoglobulin superfamily of receptors that is specifically expressed on the surface of neutrophils and monocytes. The primary role of all TREM is both the tuning and integration of multiple signals rather than the direct initiation of an inflammatory response. Soluble TREM-1 is the soluble form of TREM-1, which is up-regulated when the host innate immune system is exposed to infectious invaders. Any sustained increase in the sTREM-1 level indicates that the overall expression of TREM-1 is continuously rising, along with the release of larger amounts of pro-inflammatory mediators. Thereafter, any further increase in sTREM-1 suggests a protracted inflammatory response generally related to a poor clinical outcome.

To our knowledge, this study is the largest to date to evaluate the prognostic interest of measuring sTREM-1 in septic patients. Concerning the predictive value of baseline sTREM-1 levels, our findings are in accordance with those obtained by Li et al., who showed in 102 ICU patients that day-1 sTREM-1 concentrations yielded an AUROCC of 0.85 regarding the risk of death at day-28 [13]. In this study, PCT was also showed a good predictive value. The far higher mortality rate reported in the Li et al. cohort than in ours (41.2 vs. 25.8 %, respectively) may account for the greater accuracy in predicting death. Moreover, the number of patients with antibiotic exposure prior to biomarker measurement was quite high in our study, as was the number of patients with negative cultures. These characteristics probably diminished the predictive value of sTREM-1 [14]. Finally, Jeong et al. also found that the sTREM-1 concentration on admission was the best biomarker regarding the short-term prognosis in patients presenting with severe sepsis, outperforming baseline blood lactate levels [15].

Altogether, however, these results are apparently conflicting if compared with the data previously obtained by our group in 63 septic patients, among whom more than half presented with shock, that the lower the sTREM-1 baseline level, the poorer the outcome [16]. Similar findings were obtained recently in a small cohort of cancer patients. Indeed, Ravetti et al. showed that levels of sTREM-1 over time were higher in survivors than in non-survivors [17]. This may be subsequent to the dual significance of plasma levels of sTREM-1. Basically, it may reflect the overall expression of TREM-1, including the membrane anchored as well as the soluble form. Then, high levels might be deleterious for the host since they could result in an overwhelming inflammatory response. Conversely, the release of large amounts of sTREM-1 could be protective through the neutralization of yet unknown TREM-1 ligands likely to amplify the host inflammatory response [18]. An anti-inflammatory effect of sTREM-1 could then be expected as suggested by findings made in a small cohort of patients with sepsis related to ventilator-associated pneumonia [19, 20]. Moreover, as suggested by previous works, elevated sTREM-1 does not necessarily reflect TREM-1 gene expression [21]. In addition, one could speculate that depending on the immunoassay, either one or more isoforms of sTREM-1, with or without its shed form, were detected, thus accounting for such a discrepancy. Finally, TREM-1 expression on immune cell surfaces is known to be highly time-dependent, but also variable according to the pathogen involved and the source of infection [14]. Differences may exist regarding these points in the different cohorts mentioned above and account for these apparently conflicting findings. However, the present findings may be more representative since a larger number of patients were included in two distinct ICUs.

In addition, we should admit that several other studies failed to demonstrate any interest of sTREM-1 as a predictor of prognosis. For example, Phua et al. found that baseline sTREM-1 was a poor predictor of death in the ICU, as did Zhang et al. [22, 23]. Procalcitonin performed even better in the former study. One larger study published by Su et al. showed similar results, although the sTREM-1 level was probably helpful in diagnosing sepsis, and in differentiating between sepsis, severe sepsis and septic shock [24].

To overcome the above-described issues regarding the interpretation of a single sTREM-1 value, serial measurements are of potential interest. As previously reported, we showed herein that an early decrease in sTREM-1 levels was associated with a better outcome in the ICU [15, 16, 23, 25]. The high rate of previous exposure to antibiotics (around 30 %) in our cohort may account for the lack of correlation between PCT time-course and the outcome. Actually, we and others have previously shown in large cohorts of critically ill patients that a decrease in PCT levels within the first 72 h of sepsis management was closely related to the outcome [26, 27].

Finally, we compared biomarkers with clinical scores since they are still considered the “gold-standard” for predicting the outcome of critically ill patients [4, 10, 28]. It is worth noting that in our study the AUROCC achieved with both SOFA on admission and SAPS II was found to be greater than that for sTREM-1. However, adding sTREM-1 to SAPS II improved its specificity, since it reached 98 %, and showed a positive likelihood ratio of 27.3. In addition, the baseline sTREM-1 level remained an independent predictor of death in the ICU as did the SAPS II score, after adjustment for potential confounders, whereas neither lactate levels nor the SOFA score did. We could then consider that measuring sTREM-1 upon admission to the ICU, provides relevant information regarding the severity of sepsis in addition to clinical data.

There are, however, some limitations. First, our cohort was small, thus precluding the external validity of our findings. Second, sTREM-1 levels were not routinely measured since it relies on one ELISA assay that so far has not been automated. Finally, one can argue that given the large proportion of patients with negative bacterial cultures, non-septic inflammatory states were included in our study. However, this could be easily explained by the fact that prior exposure to antibiotics before ICU admission was quite frequent, thus reflecting “real life” conditions.

In this cohort of critically ill patients with sepsis, sTREM-1 was found to be the best prognostic biomarker among those tested including PCT. Although SAPS II outperformed sTREM-1 regarding the prediction of ICU survival, the biomarker could provide additional information. Accordingly, our findings emphasize the fact that reliable tools to diagnose sepsis such as PCT are not necessarily essential to predict the prognosis [29].

Nevertheless, further studies are needed to determine to what extent measuring sTREM-1 upon ICU admission in septic patients could be useful for the decision-making process and for patients selection in the setting of clinical trials. Moreover, TREM-1 could be considered a potential therapeutic target in septic patients [30].