sepsis is the major cause of death in the intensive care unit . despite improvement of antibiotics treatment and supportive techniques , the mortality of septic shock increases to approximately 60% .
, it not only helps doctors to make an early diagnosis of sepsis , but also predicts outcomes .
there have been some biomarkers and cytokines used in both the clinical practice and laboratory including soluble triggering receptor expressed on myeloid cells-1 ( strem-1 ) , procalcitonin ( pct ) , n - terminal probrain natriuretic peptide ( nt - pro - bnp ) , c - reactive protein ( crp ) , interleukin-6 ( il-6 ) , and interleukin-10 ( il-10 ) .
trem-1 is a recently discovered member of the immunoglobulin superfamily of receptors that is specifically expressed on the surfaces of neutrophils and monocytes .
strem-1 is a soluble form of trem-1 and is upregulated when exposed to infectious diseases .
pct is a polypeptide consisting of 116 amino acids and is the precursor of calcitonin ; it was proven useful to identify nonsystemic inflammatory response syndrome and was firstly used in sepsis .
nt - pro - bnp is a biologically inactive form that is cleaved from the prohormone probrain natriuretic peptide ( pro - bnp ) by proteolytic enzymes before secretion .
crp is a widely used biomarker to discriminate the inflammatory response to sepsis . il-6 and il-10 are important proinflammatory and anti - inflammatory cytokines during sepsis course .
.   indicated that strem-1 was more accurate than pct and crp in the diagnosis of sepsis , but others showed that the prognostic utility of serum strem-1 in septic shock was inferior to that of pct .
the purpose of the study was to compare the prognostic value of biomarkers and cytokines versus clinical severity scores and improved death risk prediction .
a total of 102 patients with sepsis from single centre hospital intensive care unit were enrolled from december 2010 to august 2012 according to the 2001 international sepsis definition conference .
exclusion criteria included : age younger than 18 years , preexisting thyroid disease and lung cancer that influence procalcitonin levels , patients with acute coronary syndromes and renal dysfunction , and patients staying in icu less than 24 hours .
the study was approved by the hospital 's ethics committee and either the patients or their relatives provided informed consent .
demographic and disease data of patients included age , gender , chief complaints for admission , vital signs , length of stay in icu , infection sites , microorganisms , routine blood test results , liver and kidney functions , coagulation indicators , blood gas analysis , acute physiologic assessment and chronic health evaluation ( apache ) ii scores , and sequential organ failure assessment ( sofa ) scores .
these were recorded on 3 days ( days 1 , 3 , and 5 ) .
serum was collected at these same time points and pct , strem-1 , nt - pro - bnp , crp , il-6 , and il-10 levels were determined in the end .
pct was measured using an enzyme - linked fluorescence analysis kit ( elfa , vidas brahms pct kit , biomerieux sa , france ) .
strem-1 was determined using a double antibody sandwich elisa ( quantikine human trem-1 immunoassay elisa kit , r & d systems , minneapolis , mn , usa ) .
nt - pro - bnp was measured with an available immunoassay analyzer ( elecsys 2010 ; roche diagnostics , mannheim , germany ) .
crp was determined using scattering using a nephelometric assay ( dade - behring , sa paris , france ) . il-6 and
il-10 were determined using elisa ( immulite ; diagnostics products corporation , los angeles , ca ) .
quantitative data with normal distributions are given as means  standard deviations ( sd ) .
quantitative data that were not normally distributed were summarized as medians ( interquartile ranges ) and compared by nonparametric tests ( mann - whitney u test ) .
we made a logarithmic conversion for the nondistribution data when we did dynamic comparison in figure 2 .
proportions were used to express qualitative data and the differences in proportions between groups were compared using a chi - square test .
we compared the characteristics of survivors versus nonsurvivors using univariate analysis and used receiver operating characteristics ( roc ) curves to evaluate prognostic value of the biomarkers and cytokines predicted 28-day mortality . those variables with p values less than 0.05 on univariate analysis were then entered into a multivariate logistic regression analysis to further identify the independent predictors of 28-day mortality .
there were no significant difference in age and sex of these two groups ( p > 0.05 ) .
the apache ii and sofa scores of patients in the nonsurvival group were higher than those of patients in the survival group ( p = 0.000 , p = 0.000 , resp . ) , ( table 1 ) .
serum pct , strem-1 , il-6 levels of patients in the nonsurvival group were significantly higher than those in the survival group on day 1 ( p < 0.001 ) .
there were no differences in nt - pro - bnp and crp , il-10 levels between the two groups ( p > 0.05 ) ( table 2 ) .
the roc analysis showed that the accuracy of the pct , strem-1 , il-6 , apacheii , and sofa scores on day 1 for the prediction of 28-day mortality was moderate ( auc > 0.7 , p < 0.01 ) , whereas the accuracy of nt - pro - bnp , crp , and il-10 was low ( auc < 0.7 , p > 0.05 ) ( figure 1 ) . comparing auc of pct , strem-1 , and il-6
, we found that there was no significant difference of auc between strem-1 and pct ( p = 0.2910 ) , and the auc of the two markers were higher than that of il-6 ( p > 0.05 ) .
meanwhile , there was no significant difference of auc between apacheii and sofa scores ( p = 0.3753 ) .
the auc of apacheii and sofa scores were higher than those of strem-1 and pct ( p < 0.05 ) ( table 3 ) .
the baseline day 1 variables that were found to be significantly different between survivors and nonsurvivors on univariate analysis ( pct , strem-1 , il-6 , apacheii , and sofa scores ) were entered into a logistic regression model . among these variables ,
three variables remained independently associated with 28-day mortality : strem-1 , pct , and sofa score ( table 4 ) .
median serum biomarkers and cytokines levels were determined on days 1 , 3 , and 5 and were compared between the survival and nonsurvival groups .
serum pct , strem-1 , and il-6 levels in the nonsurvival group were higher than those in the survival group on days 1 , 3 , and 5 ( p < 0.01 ) .
there was no difference in nt - pro - bnp levels on day 1 ( p > 0.05 ) , but later the nt - pro - bnp levels in the nonsurvival group were higher than those in the survival group on days 3 and 5 ( p < 0.05 ) .
there were no differences in crp and il-10 levels on days 1 , 3 , and 5 .
serum pct , strem-1 , il-6 , and nt - pro - bnp levels showed a decrease trend in the survival group ( p < 0.05 ) , but there was no decrease tendency in the nonsurviving group for these four biomarkers ; strem-1 even had a increase trend ( p < 0.05 ) .
serum crp levels in both surviving and nonsurviving groups had decrease tendency ( p < 0.05 ) ( figure 2 ) .
recently , pct , strem-1 , crp , and nt - pro - bnp cytokines were widely used to diagnose sepsis and reflect the severity , but the results were not the same .
meanwhile , there were few studies to put so many biomarkers in one study , particularly how to combine the biomarkers , and clinical severity scores remained unclear .
the present study showed that the serum levels of strem-1 and pct in nonsurvival group were higher than those in the survival group ; meanwhile , they decreased in survival group , but stayed in high levels even increased in the nonsurvival group during sepsis time course .
many previous studies have shown that dynamic changes in strem-1 levels could predict survival and mortality of patients at the early stage of sepsis [ 10 , 11 ] .
strem-1 is widely used to diagnose sepsis [ 7 , 12 ] . in the present study ,
serum strem-1 levels of patients in the nonsurvival group were significantly higher than those in the survival group on day 1 ; it decreased in survival group , but it even increased in the nonsurvival group .
some studies failed to find the association between strem-1 and poor outcome [ 8 , 13 ] . at a cutoff of 252.05 
pg / ml , strem-1 measurements yielded a sensitivity of 85.7% , specificity of 75.7% , positive predictive value of 70.6% , negative predictive value of 88.2% , and an accuracy of 79.4% for differentiating nonsurvivors from survivors .
pct is normally produced in the c cells of the thyroid gland ; plasma pct levels in healthy humans are approximately 550  pg / ml in normal state ; its half - time is about 2233 hours in serum .
many tissues and cells except thyroid gland produce and release that pct on systemic inflammation . several previous studies reported pct could serve as a useful tool to distinguish sepsis from systemic inflammatory response syndrome [ 15 , 16 ] . on the other hand , pct could reflect the severity of sepsis and outcome .
a study by christophe clec'h and coworkers found that serum pct on day 1 was significantly higher in patients with than without septic shock .
meanwhile , among patients with sepsis , pct concentrations were significantly higher in those who died than in the survivors , at all four measurement time points .
similar results were drawn from other investigations [ 16 , 18 ] . very few studies failed to find the prognostic value . at a cutoff of 10.64  ng
/ ml , procalcitonin measurements yielded a sensitivity of 76.2% , specificity of 81.7% , positive predictive value of 53.5% , negative predictive value of 67.8% , and an accuracy of 61.8% for differentiating nonsurvivors from survivors .
nt - pro - bnp has been found to be a useful markers in the diagnosis , management , and prognosis of patients with congestive heart failure and was secreted into blood in response to atrial or ventricular wall stretch .
a recent meta - analysis suggested that an elevated nt - pro - bnp level may prove to be a powerful predictor of mortality in septic patients . in our study
, there was no difference in nt - pro - bnp level between groups on day 1 , but the nt - pro - bnp levels in the nonsurvival group were higher than those in the survival group on days 3 and 5 .
meanwhile , serum nt - pro - bnp level showed a decreased trend in the survival group , but there was no decrease tendency in the nonsurvival group .
we concluded that nt - pro - bnp may predict sepsis 28-day mortality in different stages .
one research demonstrated that elevated serum nt - pro - bnp value represented an independent predictor for poor icu outcome in the presence of clinical severity scores ; the cut - off in admission nt - pro - bnp that best predicted outcome was 941  pg / ml .
crp is an acute phase protein and a sensitive systemic marker of inflammation and tissue damage .
the secretion of crp begins within 46  h after stimulus , doubles every 8  h thereafter , and peaks at 3650  h .
the role of crp in sepsis prognostic value seemed different . in our study , there was no significant difference between survivors and nonsurvivors during the three measures , similar to previous study , indicating that crp was just an inflammatory biomarker and failed in reflecting sepsis severity .
have reported that crp levels in severe sepsis were lower than those in sepsis , suggesting that crp levels did not reflect the severity of sepsis . il-6 and il-10 are important proinflammatory and anti - inflammatory cytokines in sepsis . in our study , serum il-6 levels of patients in the nonsurvival group were significantly higher than those in the survival group on days 1 , 3 , and 5 .
the above results showed that il-6 had the prognostic utility for sepsis , whereas il-10 did not show the power .
surez - santamar and coworkers   enrolled 253 hospitalized septic patients ; they found that il-10 and il-6 were the best predictors , whereas pct showed only moderate predictive value for mortality .
another study investigated the prognostic value of il-6 , pct , and crp in critically ill patients during the first increase of fever ; only il-6 levels were significantly higher in nonsurvivors compared with survivors , in which prognostic value was superior to pct and crp . in contrast , kawczyski and polakowska   indicated that the predictive value of il-10 plasma concentration was better than that of il-6 . to sum up ,
strem-1 , pct , and il-6 serum values attribute to the prognosis of sepsis during the time course .
the dynamic changes of biomarkers and cytokines were more meaningful for predicting the sepsis procession .
schneider and coworkers   retrospectively analyzed the relationships between serum pct , il-6 , and apacheii score and prognosis of 220 patients on the first day after operation .
they found that pct was the sole independent predictor of 28-day mortality , in which prognostic ability was superior to those of il-6 and apacheii score .
zhang et al .   suggested that serum strem-1 levels reflected the severity of sepsis more accurately than those of pct and crp and were more sensitive for dynamic evaluations of sepsis prognosis .
facing the results , we wonder which was the best predictor and how to combine them together and which was more valuable compared to clinical severity scores .
apache ii and sofa scores have been widely used to validate mortality risk stratification . in our study , we used roc and logistic regression model to search for the best predictor .
based on roc analysis , strem-1 and pct showed the equal prognostic ability ( 0.792 for pct , 0.862 for strem-1 , p = 0.291 ) , whereas their prognostic utility was inferior to that of apacheii and sofa scores which had equal power to predict outcome ( 0.923 for apacheii score , 0.953 for sofa score , p = 0.375 ) .
logistic regression model showed that serum strem-1 , pct , and sofa score were the independent predictors of 28-day mortality , which was supported by other result .
as far as we know , the interrelationship between strem-1 , pct , nt - pro - bnp , cytokines , and clinical severity scores for mortality prediction in general icu patients has not been previously evaluated .
our research firstly discovered that strem-1 and pct had the equal prognostic ability for sepsis mortality and were superior to other parameters .
previous study has indicated that the iteraction of trem-1 and interact adaptor protein dap12 can stimulate neutrophil and monocyte - mediated inflammatory response via the triggering and release of pro - inflammatory cytokines and chemokines .
strem-1 increases quickly when exposued to infection , and its half - time is short . in bacterial infections ,
serum pct levels start to rise at 4  h after the onset of systemic infection and peak at between 8 and 24  h ; it decreased 50% every 24 hours along with therapy .
in contrast , crp rises slowly and peaks 36  h after an endotoxin challenge .
the mechanism of nt - pro - bnp release in sepsis is complex , and kinetics characteristic is unknown . il-6 and il-10 rise quickly and peak at 24 hours and maintain a short time .
the patients admitted to icu often delayed more than 24 hours , either crp or cytokines serum concentration was unable to reach the peak at the period of sepsis .
of course , the exact roles of biomarkers and cytokines in sepsis process are not clear , and need to be further studied .
firstly , our study chosen a part of sepsis biomarkers and did not put all biomarkers in the research .
of course , it was a costly and unnecessary task to do so . secondly , every biomarker has its own dynamic characteristics ; meanwhile the patients were not in the same sepsis stages in the study ; thus the explanation for the results would be influenced .
thirdly , we excluded patients with previous heart diseases history , but we did not perform the ucg to evaluate cardiac function .
finally , the sample size of the study was small and larger studies are needed .
in summary , elevated serum strem-1 and pct levels provide superior prognostic accuracy to other biomarkers . combination of serum strem-1 and pct levels and sofa score can offer the best powerful prognostic for sepsis mortality . in the future , in order to improve the accuracy of the prognosis of sepsis , the combination of novel biomarkers and traditional markers of sepsis , reflecting different aspects of sepsis , is an attractive advice and is worthy of further investigation .
 
 objective . to investigate the prognostic significance of serum soluble triggering receptor expressed on myeloid cells-1 ( strem-1 ) , procalcitonin ( pct ) , n - terminal probrain natriuretic peptide ( nt - pro - bnp ) , c - reactive protein ( crp ) , cytokines , and clinical severity scores in patients with sepsis . 
 methods . 
 a total of 102 patients with sepsis were divided into survival group ( n = 60 ) and nonsurvival group ( n = 42 ) based on 28-day mortality . 
 serum levels of biomarkers and cytokines were measured on days 1 , 3 , and 5 after admission to an icu , meanwhile the acute physiology and chronic health evaluation ii ( apache ii ) and sequential organ failure assessment ( sofa ) scores were calculated . results . 
 serum strem-1 , pct , and il-6 levels of patients in the nonsurvival group were significantly higher than those in the survival group on day 1 ( p < 0.01 ) . 
 the area under a roc curve for the prediction of 28 day mortality was 0.792 for pct , 0.856 for strem-1 , 0.953 for sofa score , and 0.923 for apache ii score . 
 multivariate logistic analysis showed that serum baseline strem-1 pct levels and sofa score were the independent predictors of 28-day mortality . 
 serum pct , strem-1 , and il-6 levels showed a decrease trend over time in the survival group ( p < 0.05 ) . 
 serum nt - pro - bnp levels showed the predictive utility from days 3 and 5 ( p < 0.05 ) . conclusion . in summary , elevated serum strem-1 and pct levels provide superior prognostic accuracy to other biomarkers . 
 combination of serum strem-1 and pct levels and sofa score can offer the best powerful prognostic utility for sepsis mortality . 
1. Introduction
2. Materials and Methods
3. Result
4. Discussion
5. Conclusions