Introduction
Sepsis is a major health problem which afflicts approximately 750,000 patients in the USA each year, associated with mortality rates of 20–50% [
1]. In the past decade it has become clear that patients with severe sepsis—after an initial hyperinflammatory phase—become immunosuppressed. Indeed, patients with sepsis display features consistent with immunosuppression, including loss of delayed hypersensitivity, inability to clear infection, and predisposition to nosocomial infections. Clear evidence of immunosuppression in sepsis comes from studies showing hyporesponsiveness of immunocompetent cells to bacterial agents [
2‐
5]. Toll-like receptors (TLRs) are essential for early detection of pathogens [
6,
7], but can cause excessive inflammation when their signaling activity remains uncontrolled. To avoid detrimental inflammatory responses TLR signaling is regulated by—among other mechanisms—TLR inhibitors, such as MyD88 short, interleukin-1 receptor-associated kinase-M, and ST2, which have been suggested to play an important role during the immunosuppressive state in severe sepsis [
8‐
10].
The
st2 gene produces a soluble secreted form (sST2) and a transmembrane form (ST2L) and is expressed in several cells, including Th2 cells [
11], mast cells [
12], and macrophages [
13]. ST2L serves an important negative regulatory function for TLR signaling, as illustrated by the fact that mice lacking ST2L are unable to develop endotoxin tolerance [
10]. Recently it has become clear that interleukin (IL)-33 can bind to ST2L, thereby triggering Th2-associated responses [
14]. Soluble ST2, which is mainly secreted by fibroblasts [
15], has been suggested to act as a decoy receptor by binding IL-33, thereby inhibiting signaling by ST2L [
16,
17]. Previously it has been shown that soluble ST2 concentrations are elevated in sera of patients with various immune disorders and patients suffering from myocardial infarction [
18‐
23]. The functional role of soluble ST2 in vivo has not been fully elucidated. Mouse studies have revealed that administration of a recombinant soluble ST2-Fc fusion protein or a soluble ST2 vector reduces inflammation and lethality in hepatic and intestinal ischemia/reperfusion injury [
24,
25] and attenuates inflammatory responses in allergic lung inflammation [
26,
27].
Considering that ST2 possibly contributes to the regulation of the immune response during severe inflammation, we hypothesized that soluble ST2 levels would be elevated in patients with sepsis and possibly correlate with disease outcome. Therefore, we here performed an explorative study to determine the extent of soluble ST2 release over time in patients with severe sepsis and its correlation with disease severity and mortality.
Discussion
In light of the possible contribution of negative regulators of TLRs to the immunosuppressed state in septic patients, we were interested in investigating the extent of soluble ST2 release over time in patients with severe sepsis. Our findings demonstrate that sepsis results in sustained and stable elevation of soluble ST2, irrespective of the source of infection. Moreover, soluble ST2 levels correlate with disease severity and mortality.
Previously, others have demonstrated elevated soluble ST2 levels in serum of patients with various immune disorders such as asthma, pulmonary fibrosis, various autoimmune diseases, and dengue virus infection [
18‐
20,
32]. In addition, soluble ST2 levels have been described to be elevated in patients with sepsis [
21]. However, this study, showing soluble ST2 serum levels at only one time point (<48 h from time of diagnosis), was performed in a limited number of patients (
n = 15), which may explain the failure to demonstrate correlations between soluble ST2 and disease severity or mortality. The current study extends these findings, not only by showing elevation of soluble ST2 in a much larger population of septic patients stratified according to infection source, but also by providing information on soluble ST2 levels during the course of sepsis and correlations with concurrently measured cytokine concentrations. Of note, the first blood sample was obtained on the day of ICU admission, which was also the day the diagnosis of “severe sepsis” was made. This does not exclude, however, that severe sepsis was already present prior to admission, although given the severity of this syndrome, it seems unlikely that this would have occurred in many patients and/or for prolonged time periods. A second limitation of this study could be that patients were recruited from two ICUs, although both centers followed the
surviving sepsis guidelines [
29].
Our finding that soluble ST2 serum levels were most upregulated at day 1 from onset of disease is in line with previous studies describing soluble ST2 levels during the course of disease. Recently, patients infected with dengue virus were found to have mildly elevated levels of soluble ST2 with a peak on day 0 (day of onset) and day 1 [
32]; however, soluble ST2 levels returned to normal within 2 weeks. Moreover, studies describing soluble ST2 levels in patients suffering from myocardial infarction revealed that soluble ST2 was upregulated at day 1, but returned to normal levels after 3 days [
22,
23,
33]. In contrast, our results indicate that, relative to controls, soluble ST2 remained upregulated until 14 days after onset of sepsis. In this respect it is interesting to note that release of soluble ST2 in the circulation after myocardial infarction is thought to result from mechanical stress on cardiomyocytes [
22]. Considering that soluble ST2 is produced by fibroblasts underneath the vascular endothelium, it is tempting to speculate that soluble ST2 is only released into the circulation upon disruption of the endothelial layer, in which case soluble ST2 would be indicative of the extent of tissue injury. This would also provide an explanation for the difference in duration of elevated soluble ST2 levels in various inflammatory processes. Additional research is warranted to further investigate the exact source of soluble ST2 during sepsis and other inflammatory diseases. In addition, considering the association between ST2 and dampening of the immune response [
8], it would be of considerable interest to examine a possible relationship between soluble ST2 levels and the occurrence of secondary nosocomial infections.
Various studies have demonstrated associations between risk of death and cytokine levels during sepsis [
34‐
39]. However, cytokines have a short circulating half-life and their release primarily occurs early after exposure to an infectious challenge. Moreover, the range of cytokine levels from survivors and nonsurvivors often overlap, making them of poor prognostic value [
1]. Considering the abundant literature on the possible value of circulating cytokines as prognostic indicators in sepsis we wanted to compare our soluble ST2 data with concurrently measured cytokine concentrations. Although there were significant differences in cytokine levels (IL-6, IL-8, and IL-10) between survivors and nonsurvivors in the current investigation, cytokine levels were especially widely spread in nonsurvivors and tended to decrease sharply after 5 days. In contrast, soluble ST2 levels of nonsurvivors remained stably elevated until day 14 compared with survivors. This difference in course during sepsis is further corroborated by the fact that correlations between soluble ST2 levels and cytokine levels became less strong during the course of disease when compared with their correlations on the day of onset. Notably, serum TNF-α and IL-1β levels were low or undetectable in the current cohort of sepsis patients. Previous studies have reported highly variable circulating levels of these two proinflammatory cytokines, at least in part depending on the assays used and the severity of sepsis [
39]. Our present data fit into this extensive literature in that many earlier studies have reported low TNF-α and IL-1β concentrations in the circulation of sepsis patients, which is in accordance with the short circulating half-life of these mediators [
39].