The Significance Of BIRCP In Determining The Pathogen Of Infection In Children With Hematological Malignancies During Myelosuppression

Objectives:Because of the intensive chemotherapy,children with hematological malignancies are often in a period of bone marrow suppression and at a higher risk of infection.At this time,children with extremely low white blood cell counts,absolute neutrophil count,usually less than 1000/μl,nosocomial infections can easily occur.But at this period,children usually fail to stop bacterial reproduction.They often die due to lack of clear and effective anti-infective medical treatment.Today,infection remains to be one of the most important leading causes of death for children with hematological malignancies.At present,clinical assessment of infection mainly depends on symptoms such as fever and the location of infection,blood test,C-reactive protein(CRP),blood culture and other laboratory examinations.Fever is frequently the only sign of infection for children with hematological malignancies during bone marrow suppression,and is not specific.Blood test and CRP lack sensitivity and specificity.Report of blood culture is available at least after three days of culture and the positive rate is very low. Furthermore,negative blood culture results can not exclude the existence of infection. Therefore,on clinical practice,we basically treat them based on experience:once the symptoms of infection appear,physicians determine the possible pathogen(s)and select the broad-spectrum antibiotics based on their experience.This is blind and vulnerable to clinicians' own clinical experience and level of diagnosis.When infection occurs, broad-spectrum anti-bacterial+anti-fungal+anti-virus therapy were usually immediately initiated.This not only causes the abuse of antibiotics administration and leads to the emergence of drug-resistant strains,but also increases in children with physical and financial burden to a larger extent.Cytokines refer to small molecule peptides which are secreted by a variety of cells.They can regulate cell growth and differentiation,regulate immune function and are involved in inflammation and wound healing.Cytokines include interleukin,tumor necrosis factor,interferon and other types. Bacteria,viruses and other microorganisms can stimulate the immune cells to produce cytokines.A cytokine activated drives other cells and cytokines involved in the body's defensive reaction through a lot of knock-on effect.At present,many studies on single cytokine as sensitive indicator for the early diagnosis and the prognosis of infection have been reported in the literature.However,the studies on using several cytokines as a panel to determine the pathogens of infection are very rare.The aims of this study were to analyze the changes of cytokine profile before and after infection in children with hematological malignancies during bone marrow suppression,to explore the rule of bacterial infection related cytokine profile(BIRCP)and its clinical significance in identifying the nature of the causative pathogens,and to provide the clinical basis to guide the proper selection of the antibiotics based on the cytokine profile established.Methods:Using cytometric bead array(CBA)technique and CBA Human Th1/Th2 Cytokine KitⅡ,serum T-helper cell type 1 and 2 cytokines including tumor necrosis factor alpha (TNF-alpha),interleukin-2(IL-2),IL-4,IL-6,IL-10 and interferon gamma(IFN-gamma) were rapidly and quantitatively measured in 230 pediatric patients with hematological malignancies at the time of marrow suppression with fever.A total of 480 infection events occurred in those patients during marrow suppression.The serum Th1/Th2 cytokine levels of the same 230 patients at the time of no infection were considered as the baseline levels of those cytokines determined.The serum levels of the same six cytokines from 250 normal children at the time of physical examination without any signs of infection were served as normal control.The cytokines,C-reactive protein (CRP)and the blood culture were performed within 24 hours after infection and thereafter since infections were controlled.Their sensitivity was compared.The clinical manifestations and treatment responses were applied to evaluate the status and types of infection as empirical judgment.Gram positive and negative bacterial infection related cytokine profiles(G~+or G~-BIRCP)were established based on the positive blood cultures of either Gram positive or Gram negative bacterium,and the particular cytokine profiles.The infection pathogens of the cases with negative blood cultures were predicted according to the G~+BIRCP and G~-BIRCP followed by the proper selection of corresponding antibiotics and clinical responses were evaluated.Results:In 480 events of infection with fever,56 events of infection were positive for blood culture,accounting for 11.67%,while 424 events were negative,accounting for 88.33%. In culture-positive cases,the G~+bacteria,G~-bacteria and fungi were 8 events(1.67%), 42 events(8.75%)and 6 events(1.25%),respectively.In the early infection,the sensitivity of cytokines was higher than those of CRP and blood culture.In recovery phase of infection cytokines were more sensitive to reflect the status of infection control than CRP.In 82.9%of G~-bacteria infection,IL-6 and IL-10 increased highly[＞10 folds of((?)+S)];and in G~+bacteria infection only IL-6 were mildly increased[＞2 folds of((?)+S)but＜10 folds of((?)+S)];in cases of fungi culture-positive only IFN-γwere slightly higher[＞2 folds of((?)+S)but＜10 folds of((?)+S)].Highly increased IL-6 and IL-10 levels did not appear at the latter two.Based on these specific profiles,the G~+ BIRCP and G~-BIRCP were established.According to G~+and G~-BIRCPs,the pathogens in 43 cases of infection with negative blood culture were predicted.The antibiotics were selected accordingly and the clinical therapeutic efficiencies were evaluated based on improvement of the clinical manifestations,CRP,blood cultures and other laboratory examinations.The effective rate of the cases treated according to the BIRCP was 86.05%,significantly higher than that of only based on the clinical experience(the effective rate was only 65.45%,n=55,P＜0.05),while it was not significantly different from that(89.26%,n=326,P＞0.05)of broad spectrum antibiotics based solely on the clinical experience,which was apparently over treated.Conclusions:1.In the early infection,the sensitivity of cytokines was higher than those of CRP and blood culture.In recovery phase of infection cytokines were more sensitive to reflect the status of infection control than CRP.2.GBIRCP was:IL-6 and IL-10 increased highly[＞10 folds of((?)+S)],IL-2, IL-4,TNF-a were normal or mildly increased[＜2 folds of((?)+S))];G~+BIRCP was: IL-6 were mildly increased[＞2 folds of((?)+S)but＜10 folds of((?)+S)],IL-2,IL-4, IL-10,TNF-α,IFN-γwere normal or mildly increased[＜2 folds((?)+S)].3.Serum BIRCP can be used to predict the pathogens of children with hematological malignancies with infection,and to serve as a guide to the proper selection of the antibiotics.