sepsis is one of the most important causes of morbidity and mortality in the intensive care unit ( icu ) .
multiple organ dysfunction syndrome ( mods ) is common among critical cases of severe sepsis and a primary cause of death .
although mortality is rather variable around the world ( the rates between 20% and 63% ) , 750,000 sepsis cases and 210,000 related deaths are reported annually in the united states during the year 2000 [ 2 , 3 ] .
a directory for sepsis diagnosis and treatment , released by the surviving sepsis campaign ( ssc ) [ 4 , 5 ] , points out that early identification and effective intervention will significantly improve prognosis and reduce death rate
. however , current common clinical indicators of infection include pyrexia , white blood cell counts , c - reactive protein ( crp ) , and procalcitonin ( pct ) are still unsatisfactory .
moreover , at present , without timely identification of etiological evidence , nearly 30% of the relevant diagnoses are not well grounded pathologically .
therefore , some of the patients with infection might have their condition worsened , develop multiple organ dysfunction or failure and die for delayed , ineffective treatment .
currently , it is imperative to identify ideal biomarkers capable of making a clear distinction between sepsis and systemic inflammatory response syndrome ( sirs ) , sepsis severity assessment , and prognostic prediction .
cd163 is the only type of hemoglobin scavenger receptor , specially expressed on the macrophage membrane .
some studies report that the release of inflammatory cytokines caused by the oxidation reduction of hemoglobin plays an important role in the development of severe sepsis .
triggering receptor expressed on myeloid cells-1 ( trem-1 ) is an immunoglobulin superfamily receptor expressed on polymorphonuclear granulocytes and mature monocytes .
bacteria or fungi infections may upregulate its expression , transmit signals downstream , induce the release of proinflammatory cytokines , and bring about relevant inflammatory responses .
pct test has been put to a wide clinical use because it is a related biomarker , indicating infection and severity , as well as prognosis in case of infectious diseases [ 13 , 14 ] .
although pct is widely used clinically , its value for sepsis diagnosis has also been challenged recently [ 12 , 15 ] .
crp is a biomarker involved in more than one inflammatory cascade amplification , now widely applied to sepsis diagnosis .
it is also faced with a very awkward situation  crp proves not to be an ideal biomarker in this field [ 17 , 18 ] .
therefore , the search for a reliable biomarker for sepsis diagnosis is to continue in the days to come .
the present study makes a comparison between four biomarkers ( strem-1 , scd163 , pct , and crp ) and one scoring system ( sofa scoring system ) , with the purpose of exploring which of these is / are more valuable in sepsis diagnosis , as well as in the prediction of its development and prognosis .
hopefully , our findings could prove to be of some help to clinicians in general .
all the subjects were selected from inpatients who were hospitalized between september 2009 and july 2011 in the respiratory icu , surgical icu , and emergency icu , chinese people 's liberation army ( cpla ) general hospital .
based on the 2001 american college of chest physicians / society of critical care medicine ( accp / sccm ) sepsis directory , patients exhibiting two or more of the following signs during their first 24  h in the icu were diagnosed as sirs : ( 1 ) temperature of > 38c or < 36c , ( 2 ) pulse rate of > 90 beats / min , ( 3 ) respiratory rate of > 20 breaths / min or hyperventilation with a partial pressure of arterial carbon dioxide ( paco2 ) of < 32  mmhg , or ( 4 ) white blood cell ( wbc ) count of > 12,000  l or < 4000  l , or > 10% immature cells .
patients exhibiting two or more of sirs signs with proven infections were to be diagnosed as sepsis .
septic shock was defined as a state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes .
based on the severity of condition , the sepsis group was further divided into subgroups for sepsis , severe sepsis , and septic shock , respectively . with 28-day survival as the demarcation line
, the sepsis patients were also divided into a survivors ' group ( 28 days survival ) and a nonsurvivors ' group ( < 28 days survival ) .
patients were excluded if they ( 1 ) were younger than 18 years of age ; ( 2 ) acquired immunodeficiency syndrome ; ( 3 ) had reduced polymorphonuclear granulocyte counts ( < 500  l ) ; ( 4 ) died within 24  h after admission into the icu , or refused to participate in the study , quit further treatment on their own will during the period of observation .
this study was approved by the ethics committee of the chinese people 's liberation army ( cpla ) general hospital ( projects no .
patients or their families were fully informed of the details and signed consent forms in this study . upon admission into the icus ,
the following items were recorded for each patient : source of patients , age , gender , chief complaints for admission , symptoms , temperature , acute physiology and chronic health evaluation ( apache ) ii scores , sofa scores , mechanical ventilation , continuous renal replacement treatment ( crrt ) , etiological factors , pathogens , and underlying diseases . within 24  h ( first day of study ) after icu admission and in the morning of days 3 , 5 , 7 , 10 , and 14 , intravenous blood samples were obtained and centrifuged at 3,000  rpm for 15  min . the supernatants were transferred to eppendorf tubes and stored at 80c .
strem-1 was determined with a double antibody sandwich enzyme - linked immunosorbent assay ( elisa ) ( quantikine human trem-1 immunoassay elisa kit , r & d systems , minneapolis , minnesota , the united states , product number dtrm10b ) ; scd163 was determined with a double antibody sandwich elisa ( soluble cd163 elisa assay for the measurement of macrophage and monocyte activation , iq products , the netherlands , product number ipq-383 ) ; crp was determined by scattering turbidimetry ( cardiophase hscrp , siemens , germany ) ; and pct , and by enzyme - linked fluorescence analysis ( elfa , vidas brahms pct kit , biomerieux sa , france ) .
elisa was performed in duplicate and all the other assays were done in strict accordance with the manufacturers ' instructions .
results for continuous variables with normal distributions , including age , temperature , wbc counts , serum crp , apache ii scores , and sofa scores , are given as means  standard deviations ( sds ) .
analysis of variance ( anova ) was made to compare means among multiple groups and interpreted based on post hoc comparisons .
results from continuous , abnormally distributed variables , including serum strem-1 , scd163 , and pct , are given as medians ( interquartile ranges ) and were compared by means of nonparametric tests .
results for qualitative variables , such as source of patients , gender , mechanical ventilation ( mv ) , crrt , etiological factors , pathogens , predisposing factors , and the mortality rate , were denoted as percentages and compared across groups by means of a chi - square test . logistic regression analysis was carried out to estimate the odds ratio ( or ) and the 95% confidence interval ( ci ) .
stepwise and forward selection procedures were introduced to select iteratively variables possibly related to sepsis . to be entered into this model , a p <
the auc ( areas under receiver operating characteristic curves ) method was employed to evaluate how well the model works in distinguishing sepsis from sirs , and severe sepsis , and in predicting prognosis . for statistical analysis ,
spss 16.0 ( spss , chicago , illinois , usa ) was used , and a two - tailed p < 0.05 was considered significant .
as this study focused on the dynamics of different biomarkers , patients who died within 24  h after being admitted into the icu , refused to participate in the study , or quit further treatment on their own within 14 days failed the requirements for continuous observation .
a total of 130 patients , selected out of 377 in accordance with relevant criteria , were formally included in this study ( see supplementary figure 1 in supplementary material available online at http://dx.doi.org/10.1155/2013/969875 ) .
30 critical patients with two or more sirs signs and negative pathologic examination results , who were from the sicu within 24  hours after aseptic surgery , were also selected as sirs control group in the study .
these patients had received a general examination to exclude infection within 24  hours before surgery . in light of the sepsis guidelines ,
the 100 sepsis patients were further divided into a sepsis subgroup ( 36 cases ) , a severe sepsis subgroup ( 35 cases ) , and a septic shock subgroup ( 29 cases ) .
apache ii and sofa scores go markedly from high to low in the following order : septic shock > severe sepsis > sepsis subgroup ( p < 0.001 ) .
more septic shock patients are in need of mechanical ventilation than sepsis patients ( p = 0.026 ) . with a 28-day survival as a criterion ,
mortality rate for the septic shock subgroup is the highest , followed by the severe sepsis subgroup , and the sepsis subgroup ranks the lowest ( p < 0.001 ) .
statistically , there are no remarkable differences in terms of age , gender , temperature , etiological factors ( excluding catheter - related bloodstream infection ) , pathogens , or accompanying underlying diseases ( excluding coronary heart disease and the immunosuppressed condition ) between groups .
additionally , it should be explained that some patients had multiple pathogens and/or infection of multiple sites . on the first day of icu enrollment ,
the sepsis group exhibited a higher level in serum strem-1 , serum scd163 , pct , and crp than the sirs group ( figure 1 ) .
the variables taken into account included serum strem-1 , scd163 , crp , pct , wbc counts , and apache ii score ( table 2 ) .
four variables , strem-1 , scd163 , crp , and apache ii score , were further selected for multivariate regression ( p < 0.001 ) . finally , only serum strem-1 entered the multivariable regression equation , with or = 1.089 ( 95% ci 1.0451.136 , p < 0.001 ) .
the receiver operating characteristic ( roc ) curves were used to calculate serum strem-1 's performance in sepsis diagnosis ( supplemental figure 2 ) .
auc turned out to be 0.978 ( 95% ci 0.9580.997 ) . with a cut - off point of 64.4  pg /
ml for strem-1 , sensitivity came out as 0.91 ; specificity , 0.896 ; ppv , 0.989 , and npv , 0.621 . 

figure 2 illustrates a pairwise comparison over serum strem-1 , wbc counts , serum crp , serum pct , and sofa score between the sepsis , severe sepsis , and septic shock groups , made on the first day of enrollment .
it turned out that the sepsis group scored the lowest in strem-1 , pct , and sofa score , which was of statistical significance , compared with any other group . as for the severe sepsis group and the septic shock group , statistically , of all the indicators , only the disparity in the sofa score between the two deserved attention .
so we combined severe sepsis and septic shock groups into a severe sepsis / shock group to express the seriousness of the sepsis condition .
higher serum strem-1 , pct level , and sofa score in severe sepsis / shock group ( p < 0.05 ) .
although severe sepsis / shock group had higher scd163 , crp , and wbc levels , a comparison of such indicators across groups is devoid of such significance .
rocs for serum strem-1 , pct , and sofa score illustrate severe sepsis / shock group , which reflect sepsis severity ; see figure 3 .  
based on the 28-day survival , sepsis patients were also divided into a survivors ' group and a nonsurvivors ' group .  
figure 4 compares these two groups in terms of dynamic changes in serum strem-1 , scd163 , wbc counts , serum crp , and serum pct levels .
the curves show that the nonsurvivors ' group had higher serum strem-1 , scd163 , wbc counts , serum pct levels , and sofa score during this period of time . for nonsurvivors ,
their serum strem-1 , scd163 , serum pct levels , and sofa score increased with the passage of time , while their wbc counts and serum crp levels tended to decline .
in contrast , all indicators of the survivors ' group revealed a tendency to decline .
the serum scd163 , strem-1 , and pct levels of nonsurvivors were higher than survivors ' at these 6 different time points ( p < 0.05 ) .
cox regression was employed to analyze the survival time of sepsis patients , as well as the factors affecting survival .
the variables taken into account included sex , age , temperature , serum strem-1 , scd163 , wbc , crp , pct , apache ii score , sofa score , use of life support technology ( e.g. , mv and crrt ) , etiological factors , pathogens , and predisposing factors . within 24  h after the icu admission , the indicators previously mentioned were derived from the patients .
finally , only scd163 and sofa entered the regression equation . for the former , the regression coefficient = 0.09 , hazard ratios = 1.09 ( 95% ci 1.0351.154 , p < 0.001 ) , whereas for the latter , the regression coefficient = 0.2 , hazard ratios = 1.23 ( 95% ci 1.1261.335 , p < 0.001 )
the roc curve denoting these two survival - affecting parameters was drawn on the icu admission day in order to predict prognosis ( figure 5 ) .
currently , the exact role of biomarkers in the assessment of septic patients remains obscure .
although 178 related sepsis biomarkers have been identified , it is still controversial which is reliable for sepsis diagnosis . in particular , pct and crp , which have been most widely used in clinical treatment ,
therefore , the exploration and discovery of sepsis biomarkers still should be paid attention to .
soluble strem-1 is identified as a marker of microbial infection by many studies [ 2427 ] .
the upregulation of cd163 at the occurrence of sepsis , caused by activating the waterfall effect from the secretion of anti - inflammatory cytokines , helps scavenge hemoglobin and reduce its oxidative impairment to the body [ 28 , 29 ] .
we found the same phenomenon that , on the admission day , the sepsis group exhibited a higher level of strem-1 , scd163 , pct , and crp than the sirs group .
multivariate logistic regression displays that serum strem-1 is the only risk indicator for sepsis diagnosis .
the roc area for serum strem-1 came out as 0.978 ( 95% ci 0.9580.997 ) and both sensitivity and specificity , around 0.9 .
the diagnostic value of strem-1 is obviously higher than scd163 , crp , and pct .
that is to say , serum strem-1 may prove a better indicator for the sepsis diagnosis .
the serum strem-1 and pct levels as well as sofa score can play a role in severity assessment of sepsis .
the value of the three indicators from the severe sepsis group , the septic shock group , and the severe sepsis / shock group all exceeded that from the sepsis group ( p < 0.01 ) . in a comparison between the severe sepsis group and the septic shock group ,
the strem-1 and pct level and the sofa score are of diagnostic value for sepsis severity .
in addition , strem-1 has the highest efficiency , with a roc area of 0.9 ; sensitivity turned out to be 0.87 , and specificity , 0.88 with 136.82 as the cut - off point for severe sepsis diagnosis .
it might be assumed that the expression of scd163 on the surface of macrophage membrane is regulated by more than one factor .
studies show that interleukin-6 ( il-6 ) and interleukin-10 ( il-10 ) stimulate , whereas lipopolysaccharide ( lps ) and interferon- ( ifn- ) contain , the expression of cd163 molecules on the surface of macrophage membrane . in the meantime , only with the involvement of metalloprotease , lps , and at least one inflammatory medium , could a drop of cd163 into scdl63 be possible , by means of activating toll - like receptors .
therefore , the state and expression of cd163 are governed by the internal environment of the human body .
it could also be assumed that the high expression of scd163 is related to the positive feedback of inflammation .
that is to say , the expressive volume of scd163 is limited right after inflammatory responses are activated .  
dynamic changes in serum strem-1 may prove helpful for prognostic assessment [ 33 , 34 ] .
more than one study reports that scd163 is more valuable for earlier prognostic assessment [ 35 , 36 ] .
we found that , seen from the dynamic tendency of the curve denoting sepsis prognosis , the differences in serum strem-1 , crp , and pct level as well as in sofa score at these six different time points were statistically significant , with the nonsurvivors ' group having higher values all the time , and showing a higher crp and wbc level even at the final stage , which was also statistically significant . for the nonsurvivors , strem-1 , scd163 , and pct level as well as
sofa score went up with the passage of time , whereas for the survivors , these indicators tended to decline .
this demonstrates that strem-1 , scd163 , and pct , as well as sofa score , have their value for clinical application in dynamic assessment of sepsis prognosis .
relevant factors affecting survival within the first 24  h of icu stay were analyzed and sorted out using cox regression .
it turned out that only the scd163 level and sofa score entered the equation and served as the independent risk factors affecting survival .
further analysis was made of scd163 level and sofa score by means of roc curve to determine the cut - off point .
therefore , these two factors are likely to function as an index for reference in terms of early prognosis assessment .
strem-1 , however , did not work well in prognostic assessment as a risk factor .
the reason may lie in the fact that it is protective to inflammation at the initial stage . at the onset
, strem-1 may combine with membrane - bound trem-1 by competitive , ligand binding , or with dap-12 , an inhibitive receptor , by specific binding , thus containing human body 's excessive responses to inflammation . with the development of the disease and the inflammatory cascade amplification ,
strem-1 accumulates and is then released into the blood in large quantities . for these reasons , strem-1 level at the initial stage may be fairly low and insensitive in early prognostic assessment and could only play a better role in later stage , dynamic prognostic assessment .  
it is very helpful to draw conclusions about decisions for individual patients and their values .
however , owing to the limitations of our sample size , prospective clinical studies are still wanted to provide further proof for the clinical diagnostic value of these biomarkers .
second , the internal environment of the human body is an important contributor to the expression of the markers identified in this study .
the internal environment can be influenced by clinical care ( drugs , timing , dose , mechanical ventilation technique , crrt , etc . ) .
clinical care environment may also have impact on the responses of their patients and therefore on their measurements .
third , the purpose of this study is to observe the dynamic changes of the various indicators . for this
, it precludes a considerable portion of candidates according to the exclusion criteria . at the same time , the sirs patients , without both prior surgery and 24  h postsurgery infections were selected as control group .
this study also does not rule out impact of the specific conditions on the enrollees . in summary , it may be concluded from the study that strem-1 is more ideal than pct and crp for early sepsis diagnosis and severity assessment and constitutes an independent risk diagnostic parameter .
scd163 and sofa scores possess positive clinical values in dynamic , prognostic assessment and function as independent , survival - affecting risk factors .
future studies with larger subject populations and with attention to the clinical care environment are expected to define the application of these parameters in clinical decision making .
 
 objective . to describe the dynamics changes of scd163 , 
 soluble serum triggering receptor expressed on myeloid cells-1 ( strem-1 ) , procalcitonin ( pct ) , and c - reactive protein ( crp ) during the course of sepsis , as well as their outcome prediction . 
 patients and methods . an sirs group ( 30 cases ) and a sepsis group ( 100 cases ) were involved in this study . based on a 28-day survival , 
 the sepsis was further divided into the survivors ' and nonsurvivors ' groups . 
 serum strem-1 , scd163 , pct , crp , and wbc counts were tested on days 1 , 3 , 5 , 7 , 10 , and 14 . 
 results . on the icu admission 
 , the sepsis group displayed higher levels of strem-1 , scd163 , pct , and crp than the sirs group ( p < 0.05 ) . 
 although pct and strem-1 are good markers to identify severity , strem-1 is more reliable , which proved to be a risk factor related to sepsis . during a 14-day observation , scd163 , strem-1 , 
 pct , and sofa scores continued to climb among nonsurvivors , while their wbc and crp went down . both scd163 and sofa scores are risk factors impacting the survival time . conclusion . 
 with regard to sepsis diagnosis and severity , strem-1 is more ideal and constitutes a risk factor . 
 scd163 is of a positive value in dynamic prognostic assessment and may be taken as a survival - impacting risk factor . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussions