sepsis is the main cause of mortality in pediatric intensive care units ( picus ) .
it is caused by numerous infectious agents , inducing multiple organ dysfunction syndrome ( mods ) , multiple organ failure ( mof ) , and even death .
several studies have demonstrated that the severity of sepsis , as well as early diagnosis and prognosis were directly related to mortality .
early diagnosis and prognosis are essential to effectively control sepsis , prevent the incidence of mods or mof , and reduce mortality in children with sepsis .
currently , the second - generation pediatric index of mortality ( pim-2 ) or pediatric risk of mortality score ( prism ) are used to assess the severity and prognosis of children with sepsis internationally , while pediatric critical illness score ( pcis ) is more commonly used in china .
pcis is based on patients heart rate , blood pressure , pao2 , ph , na , k , cr , and hb .
a lower pcis score indicates higher disease severity . in addition , a few non - specific inflammatory markers , such as cd15s , nt - probnp , soluble urokinase plasminogen activator receptor ( supar ) , procalcitonin ( pct ) , high - sensitivity c - reactive protein ( hs - crp ) , and pancreatic stone protein ( psp ) are established markers for prognostic evaluation of patients with sepsis [ 1012 ] .
baseline procalcitonin levels are linked to severity of pediatric sepsis , while the persistent elevation in procalcitonin despite therapy are associated with increased mortality risk scores .
crp , which is one of the most widely available , most studied , and most used laboratory tests for bacterial infection , has the best diagnostic accuracy when combined with another infection marker during the early phases of sepsis .
recent studies suggest that psp is a possible biomarker of multiorgan failure and mortality in sepsis .
however , its prognostic value in children with sepsis is not entirely clear . in this study
, we conducted a prospective analysis of 214 children with sepsis , to investigate the prognostic value of pct , hs - crp , and psp .
we enrolled 214 children with sepsis admitted to intensive care units ( icu ) of our hospital between march 2014 and october 2015 .
every patient was diagnosed with sepsis according to clinical criteria defined in international sepsis definitions conference in 2001 .
severe sepsis was diagnosed when organ dysfunction , hypoperfusion , or hypotension including lactic acidosis , oliguria , or acute altered mental status occurred in septic patients .
patients enrolled included 99 males and 115 females , with an average age of 4.61.5 years .
all the patients in this study signed informed consent , which was approved by the ethics committee of the first people s hospital of yichang .
age , sex , body height , weight , body mass index ( bmi ) , blood pressure , and surgical history were recorded by specialists in the icu .
pcis was evaluated by two specialists . if the two scores differed by more than 5 points , another icu physician was invited to perform the final assessment .
supernatants were obtained after centrifugation ( 4c , 3,000 rev / minutes , 10 minutes ) and stored at 80c until further analysis .
the serum levels of pct and hs - crp were tested by microparticle enzyme immunoassay ( meia ) .
continuous variables were expressed as mean  standard deviation ( sd ) , and categorical variables were displayed as counts or percentages .
student s t - test was used for the analysis of continuous variables and -test for categorical variables ; p<0.05 was considered significant .
spearman correlation was used to analyze the relationship between pct , hs - crp , psp , and pcis .
multivariate logistic regression was used to analyze the risk factors for 28-day mortality in patients with sepsis .
receiver operating characteristic ( roc ) analysis was used to compare the prognostic value of pct , hs - crp , and psp in children with sepsis .
furthermore , standard indices of validity , such as youden index , sensitivity , and specificity were calculated based on the roc results .
we enrolled 214 children with sepsis admitted to intensive care units ( icu ) of our hospital between march 2014 and october 2015 .
every patient was diagnosed with sepsis according to clinical criteria defined in international sepsis definitions conference in 2001 .
severe sepsis was diagnosed when organ dysfunction , hypoperfusion , or hypotension including lactic acidosis , oliguria , or acute altered mental status occurred in septic patients .
patients enrolled included 99 males and 115 females , with an average age of 4.61.5 years .
all the patients in this study signed informed consent , which was approved by the ethics committee of the first people s hospital of yichang .
age , sex , body height , weight , body mass index ( bmi ) , blood pressure , and surgical history were recorded by specialists in the icu .
pcis was evaluated by two specialists . if the two scores differed by more than 5 points , another icu physician was invited to perform the final assessment .
supernatants were obtained after centrifugation ( 4c , 3,000 rev / minutes , 10 minutes ) and stored at 80c until further analysis .
the serum levels of pct and hs - crp were tested by microparticle enzyme immunoassay ( meia ) .
continuous variables were expressed as mean  standard deviation ( sd ) , and categorical variables were displayed as counts or percentages .
student s t - test was used for the analysis of continuous variables and -test for categorical variables ; p<0.05 was considered significant .
spearman correlation was used to analyze the relationship between pct , hs - crp , psp , and pcis .
multivariate logistic regression was used to analyze the risk factors for 28-day mortality in patients with sepsis .
receiver operating characteristic ( roc ) analysis was used to compare the prognostic value of pct , hs - crp , and psp in children with sepsis .
furthermore , standard indices of validity , such as youden index , sensitivity , and specificity were calculated based on the roc results .
a total of 214 patients were enrolled in this study , with an average age of 4.61.5 years , and including 99 males and 115 females . after a follow - up of 28 days ,
no significant differences in patients age , sex , or weight were found between the dying and surviving groups of patients .
pcis scores in the dying patients were lower than in the surviving group ( p<0.001 ) .
further , the serum pct , hs - crp , and psp levels were higher in the dying group than in the surviving group of patients ( p<0.001 ; table 1 ) .
as shown in figure 1 , pct was negatively correlated with pcis , r=0.4474 ( p<0.001 ; figure 1a ) ; hs - crp was negatively correlated with pcis , significantly ( r=0.3479 , p<0.001 ; figure 1b ) ; and psp showed a distinctly negative correlation with pcis ( figure 1c ) .
the results indicated that the levels of pct , hs - crp , and psp were correlated with disease severity .
as shown in table 2 , multivariate logistic regression analysis revealed pcis as a protective factor in the 28-day mortality of children with sepsis ( or=0.79 ; 95% ci=0.670.89 ) .
furthermore , psp ( or=2.38 , 95% ci=1.465.76 ) was more sensitive than pct ( or=1.34 , 95% ci=1.022.25 ) , p=0.0031 .
the serum concentrations of pct , hs - crp , and psp were higher in the dying group of patients ( p<0.01 ; figures 24 ) . to further determine the prognostic value of the three markers in children with sepsis , receiver operating characteristic ( roc ) curves were used to evaluate the predictive power .
the results indicated that area under the curve ( auc ) values of pct , hs - crp , and psp were 0.83 ( 95% ci , 0.770.88 ) , 0.76 ( 95% ci , 0.700.82 ) and 0.73 ( 95% ci , 0.670.79 ) , respectively .
as illustrated in table 3 , the sensitivity and specificity of cutoff values were calculated according to roc curve analysis .
subsequently , the roc curve comparison revealed a higher prognostic value of pct compared with hs - crp and psp ( p<0.001 ) as shown in figure 5 .
multivariate logistic regression was conducted to calculate the coefficients of these biomarkers when used in predicting mortality in patients with sepsis ( pct & hs - crp & psp ) = 12.3125 + 0.068404*pct + 0.058065*hs - crp + 0.012057*psp .
the results of roc analysis of ( pct & hs - crp & psp ) are shown in table 3 .
the prognostic value of the combined pct , hs - crp , and psp levels in children with sepsis was higher than the individual levels ( p<0.001 ; figure 5 ) .
a total of 214 patients were enrolled in this study , with an average age of 4.61.5 years , and including 99 males and 115 females . after a follow - up of 28 days ,
no significant differences in patients age , sex , or weight were found between the dying and surviving groups of patients .
pcis scores in the dying patients were lower than in the surviving group ( p<0.001 ) .
further , the serum pct , hs - crp , and psp levels were higher in the dying group than in the surviving group of patients ( p<0.001 ; table 1 ) .
as shown in figure 1 , pct was negatively correlated with pcis , r=0.4474 ( p<0.001 ; figure 1a ) ; hs - crp was negatively correlated with pcis , significantly ( r=0.3479 , p<0.001 ; figure 1b ) ; and psp showed a distinctly negative correlation with pcis ( figure 1c ) .
the results indicated that the levels of pct , hs - crp , and psp were correlated with disease severity .
as shown in table 2 , multivariate logistic regression analysis revealed pcis as a protective factor in the 28-day mortality of children with sepsis ( or=0.79 ; 95% ci=0.670.89 ) .
furthermore , psp ( or=2.38 , 95% ci=1.465.76 ) was more sensitive than pct ( or=1.34 , 95% ci=1.022.25 ) , p=0.0031 .
the serum concentrations of pct , hs - crp , and psp were higher in the dying group of patients ( p<0.01 ; figures 24 ) . to further determine the prognostic value of the three markers in children with sepsis , receiver operating characteristic ( roc ) curves were used to evaluate the predictive power .
the results indicated that area under the curve ( auc ) values of pct , hs - crp , and psp were 0.83 ( 95% ci , 0.770.88 ) , 0.76 ( 95% ci , 0.700.82 ) and 0.73 ( 95% ci , 0.670.79 ) , respectively .
as illustrated in table 3 , the sensitivity and specificity of cutoff values were calculated according to roc curve analysis .
subsequently , the roc curve comparison revealed a higher prognostic value of pct compared with hs - crp and psp ( p<0.001 ) as shown in figure 5 .
multivariate logistic regression was conducted to calculate the coefficients of these biomarkers when used in predicting mortality in patients with sepsis ( pct & hs - crp & psp ) = 12.3125 + 0.068404*pct + 0.058065*hs - crp + 0.012057*psp .
the results of roc analysis of ( pct & hs - crp & psp ) are shown in table 3 .
the prognostic value of the combined pct , hs - crp , and psp levels in children with sepsis was higher than the individual levels ( p<0.001 ; figure 5 ) .
it develops into severe sepsis or septic shock , resulting in mods , mof , or even death .
interestingly , recent studies suggest that nonspecific inflammation and abnormal expression of inflammatory cytokines rather than microbial infection leads to organ damage .
early diagnosis and intervention has been shown to reduce the risk of sepsis - related mortality . in our study , the overall mortality was relatively high , which might be due to the high percentage ( 40.5% ) of post - surgery patients .
its diagnostic and predictive value in patients with sepsis has been confirmed in several studies .
found that serum pct was an early systemic marker of sepsis , which was correlated closely with mortality and inversely with serum calcium in bacterial peritonitis of hamster .
found that serum pct increased sharply during early sepsis , and that the persistent levels decreased only after effective antibiotic treatment .
in addition , nakamura et al . found that pct level was a good indicator of the severity of infection , with prognostic value in 393 adult patients with sepsis .
similarly , zurek et al . reported that serum levels of pct were positively correlated with prognosis of pediatric sepsis .
our results showed that pct levels were significantly higher in the dying patients than in the surviving group , and were negatively correlated with pcis , reminding us that pct was related to the severity of sepsis .
furthermore , the results of roc curve analysis indicated that an auc value of 0.83 ( 95% ci , 0.770.88 , supported the prognostic value of pct in children with sepsis . high - sensitivity c - reactive protein ( hs - crp ) is a key inflammatory cytokine , which is present in small amounts under normal conditions .
plasma hs - crp is an early marker of sepsis severity and poor prognosis , and is one of the risk factors for cardiovascular disease .
pancreatic stone protein ( psp ) belongs to the family of lectin - binding proteins , and is constitutively secreted by pancreatic acinar cells into pancreatic juice along with zymogens .
palmiere et al . reported that psp and pct were positively correlated with mortality in patients with or without sepsis , and that the psp levels were distinctly higher than in sepsis .
peng et al . observed a significant positive correlation between psp and wbc , as well as serum pct levels .
dynamic monitoring of psp was used to evaluate a patient s condition and assess their risk of death .
our study showed that serum hs - crp and psp levels increased in dying patients and were negatively correlated with pcis .
these results indicated that serum hs - crp and psp levels were correlated with the severity of sepsis .
furthermore , multivariate logistic regression analysis revealed that both hs - crp and psp were independent risk factors for pediatric sepsis , with hrs of 1.79 ( 95% ci , 1.312.42 ) and 2.38 ( 95% ci , 1.465.76 ) .
in addition , roc analysis showed that both hs - crp and psp levels were appropriate for clinical application .
it is unlikely that any single biomarker is a predictor of outcomes in the pediatric population .
the complexity of interactions driving host immune response and genetic variation suggests that multiple biomarkers are involved in predicting outcomes .
stratification of pediatric patients based on their genome expression is a reasonable approach to identify high- and low - risk groups . in our study , we used multivariate logistic regression to calculate each index before using the three markers : ( pct & hs - crp & psp ) = 12.3125 + 0.068404*pct + 0.058065*hs - crp + 0.012057*psp .
the roc curve analysis yielded an auc value ( pct & hs - crp & psp ) up to 0.92 , which was clearly superior to pct , hs - crp , or psp alone .
technological advances facilitate testing of multiple inflammatory cytokines rapidly and sensitively using small amounts of serum sample .
therefore , the joint detection of pct , hs - crp , and psp clearly improves the sensitivity and specificity of prognosis in children with sepsis , and represents a useful serum biomarker .
our study found that serum pct , hs - crp , and psp levels were promising biomarkers of risk and useful clinical tools for risk stratification of pediatric sepsis .
furthermore , the combination of serum pct , hs - crp , and psp is potentially a very useful biomarker with high sensitivity and specificity , and remarkable prognostic value in pediatric sepsis .
 backgroundto investigate the prognostic value of procalcitonin ( pct ) , high - sensitivity c - reactive protein ( hs - crp ) , and pancreatic stone protein ( psp ) in children with sepsis.material/methodsa total of 214 patients with sepsis during hospitalization were enrolled . 
 serum levels of pct , hs - crp , and psp were measured on day 1 of hospitalization and the survival rates of children were recorded after a follow - up of 28 days . 
 pearson s correlation analysis was conducted to test the association of pct , hs - crp , and psp with pediatric critical illness score ( pcis ) . 
 logistic regression models were used to analyze the risk factors contributing to patients death . 
 the auc was used to determine the value of pct , hs - crp , and psp in the prognosis of patients with sepsis.resultsthe expression of pct , hs - crp , and psp in the dying patients was higher than in the surviving patients ( p<0.001 ) . 
 pearson s correlation analysis showed that serum pct , hs - crp , and psp levels were negatively correlated with pcis ( p<0.001 ) . 
 multivariate logistic regression revealed that pct , hs - crp , and psp were independent risk factors for the prognosis of patients with sepsis ( p<0.001 ) . 
 roc analysis showed the auc values of pct , hs - crp , and psp were 0.83 ( 95% ci , 0.770.88 ) , 0.76 ( 95% ci , 0.700.82 ) , and 0.73 ( 95% ci , 0.670.79 ) , respectively . 
 the combined auc value of pct , hs - crp , and psp , was 0.92 ( 95% ci , 0.870.95 ) , which was significantly increased compared with pct , hs - crp , or psp ( p<0.001).conclusionsthe combination of serum pct , hs - crp , and psp represents a promising biomarker of risk , and is a useful clinical tool for risk stratification of children with sepsis . 
Background
Material and Methods
Patients
Data collection
Serum collection and testing
Statistical analysis
Results
Baseline patient demographics
Correlation of PCT, hs-CRP, and PSP with PCIS
Analysis of risk factors for 28-day mortality
Prognostic value of PCT, hs-CRP and PSP: ROC curves
Discussion
Conclusions