Comparative Study On The Diagnostic Role Of Cytokine Patterns And Procalcitonin Among Pediatric Hematology/oncology Patients With Infections

ObjectivesInfections are a common and serious problem in pediatric haematology/oncology patients.During profound immunosuppression by chemotherapy,early diagnosis of infection is difficult,and sometimes even impossible due to minimal symptoms and signs.Therefore,it is of great significance to find an accurate,rapid and quantitative laboratory tests for the early diagnosis of infection in those patients and to provide effective treatment in time.Procalcitonin(PCT)is currently widely used as an infection-related inflammation index.We have previously applied cytometric bead arrays(CBA)to determine the Th1/Th2 cytokines to successfully distinguish between gram-positive and gram-negative bacterial infection in febrile hematology/oncology patients.However,the diagnostic and predictive power for infection between proinflammatory cytokines and PCT has not been systematically compared in children with neutropenic infection.In this study,we further investigate the diagnostic role of cytokines and PCT in febrile hematology/oncology patients with infection.MethodsA total of 3023 samples derived from 992 hospitalized hematology/oncology children whose Thl/Th2 cytokine levels measured from January 2011 through January 2014,were retrospectively analyzed.Final diagnosis was made by the hematology-oncology experts in our department.Patients were assigned to five groups:1)blood culture positive sepsis,based on a presence of signs of acute systemic inflammation and positive isolation of microorganism(s)in cultures of blood;2)clinical diagnosis of sepsis were based on clinical symptom without isolation of microorganism(s)in blood cultures;3)nonsepsis infection was defined if there was a clinically evident source of infection and/or roentogenographic signs of infection;4)viral infection and 5)systemic fungal infection.Viral infection and systemic fungal infection were considered when there was evidence of Epstein-Barr virus(EBV)/cytomegalovirus(CMV)/fungal infection other than sepsis.Patients were also grouped by disease severity.Patients who suffered from septic shock,multiple organ dysfunction syndrome(MODS)or death,were considered to have severe infection.Measurement of IL-2,IL-4,IL-6,IL-10,TNF-?,IFN-? levels were performed by CBA technology.Routine tests for serum procalcitonin,blood neutrophil count,serum CRP,blood culture and sensitivity test were also performed simultaneously.All statistical analyses were performed with SPSS software,version 21.0.Between the two groups for continuous variables were analyzed using Mann-Whitney U test while Kruskal-Wallis H test was used among more than three groups.Receiver operator characteristic(ROC)curves were derived from the cytokine levels and PCT levels for prediction disease accuracy.Correlation analysis using Spearman correlation between cytokine and PCT levels.Various interactions between the categorical variables by chi-square test and Fisher's exact test analysis.Risk factors of the results of septic shock patients were analyzed using logistic regression analysis.A two-sided p-value of<0.05 was considered to be statistically significant.Results1.Characteristics of patients with infection in paediatric haematology/oncology patients:Based on microbiological and clinical evidence,2819 febrile episodes(derived from 828 hospitalized febrile hematology/oncology children)were assigned to 1 to 5 groups:(1)blood culture positive sepsis(320 cases),(2)blood culture negative sepsis(1155 cases),(3)nonsepsis infection(1324cases),(4)viral infection(16cases),and(5)systemic fungal infection(4cases).The cohort of patients were also grouped according to the disease severity,which were divided into severe infection group(165 cases)and mild infection group(2654 cases).2.Comparative study of cytokines and PCT in different types of infection diseases:In positive blood culture sepsis group,IL-6 and IL-10 increased significantly as compared to the control group and common infection group;serum PCT and CRP levels were significantly increased in the blood culture positive sepsis group.The IL-6,IL-10,TNF-a and IFN-y were statistically different according to the granulocyte count group.In clinical sepsis with clear infection sites group,only IL-6 level was significantly different from PCT,while the remaining cytokine and PCT levels were not significantly different.In Gram-negative bacterial infection group IL-6,IL-10 and PCT AUCs were 0.686,0.747 and 0.657,respectively(P<0.001).In severe infection group,IL-6,IL-10 and PCT AUCs were 0.875,0.839 and 0.726,respectively(P<0.001).3.Comparative study of cytokines and PCT in the diagnosis of children with acute lymphoblastic leukemia and acute myeloid leukemia complicated with sepsis:There was no significant difference in terms of age and incidence of neutropenia between ALL and AML combined with laboratory confirmed sepsis groups.The use of gluococorticoids in ALL was significantly higher than that in AML.The septic shock incidence of 7.7%in AML group was significantly lower than those of 11.7%in ALL group.Laboratory diagnosis of sepsis according to ALL and AML groups,the differences in terms of IL-10,TNF-a levels were statistically significant.The median IL-6 and IL-10 levels in ALL children with sepsis were significantly higher than those of children with AML.The percentage of IL-10 higher than the normal value and TNF-a higher than the normal value were statistically different in ALL and AML gram positive group.The percentages of IL-10 higher than the normal value and TNF-a higher than the normal value were statistically different in ALL and AML gram negative group.4.Comparison between the PCT and cytokine levels in septic shock:The cytokine levels of IL-6 and IL-10 were significantly higher in the vasopressor-dependent and non-vasopressor shock,survivor and non-survivor group.In the survivor and non-survivor group,PCT levels were not significantly different,while levels were increased significantly in the vasopressor-dependent group.In septic shock patients,IL-6 and PCT,IL-10 and the PCT,IL-6 and IL-10,IL-6 and TNF-a,IL-10 and TNF-a were positively correlated.When setting cutoff values of IL-6 and IL-10 at 435.9 pg/mL and 50 pg/mL,the sensitivity rates were 46.6%and 54.5%,and specificity rates were 89.7%and 89.9%,respectively for predicting septic shock.Regarding PCT,when the cutoff point was set at 1 ng/ml,the sensitivity and specificity were 42%and 89.7%.Using Logistic regression model analysis in septic shock patients showed that IL-6,IL-10 levels correlated with death significanly(IL-6:OR=1,95%confidence interval 0.999-1.000,P =0.025;IL-10:OR=0.999,95%confidence interval 0.999-1.000,P =0.015),while PCT levels were not significantly correlated with death(P = 0.665).Conclusions1.In the bacterial infection sepsis group with neutropenia of patients with paediatric haematology/oncology diseases,IL-6 and IL-10 levels were significantly increased.The specificity of IL-6 and IL-10 is higher than PCT in identification of gram-negative bacteria and the sensitivity of IL-6 and IL-10 was also better than PCT in predicating severe infectious disease.2.The IL-10 and TNF-alevels in ALL when sepsis occurs are significantly higher than those in AML.The PCT levels was not high in AML group,which indicates that glucocorticoid induced adrenal insufficiency may be responsible in part for more possible increase of inflammatory factors in ALL,so that more attention should be paid to early administration of corticosteroids to ALL patients with severe infection.3.The levels of IL-6,IL-10 and PCT are elevated in the vasopressor-dependent group with septic shock.In septic shock patients with death,IL-6 and IL-10 levels are elevated significantly,while PCT levels are not significantly changed,suggesting that IL-6 and IL-10 were index of predicting death with septic shock.