The Clinical Significance Of Dynamic Detection Of Th1/Th2 Cytokines In Chemotherapy Induced Neutropenia In Children With Infection

ObjectivesInfection is one of the most common complications after chemotherapy in children with hematological malignancies,and is also the most important cause of death.The low immune function,the chemotherapy induced neutropenia,the mucosal injury damage and the compromised defense capability are all contributing to the increased susceptibility of serious infections in these patients.Thus,it is necessary to treat the infection early and promptly,otherwise the infection would be difficult to control or even life threatening.Presently,the most commonly used diagnostic methods for infections include the white blood cell count and differential count,the C reactive protein(CRP),the blood culture and so on.All these analyses have its limitations which can not meet the clinical needs.Many studies have showed that there is close association between cytokines and infection.But there is no report on the distinguishing between the gram-positive and negative bacterial infections through the cytokine profiles.In this study,we investigated the cytokine changes after infection and its clinical significance by determining the serum concentrations of the IL-2,IL-4,IL-6,IL-10,TNF and IFN-γ.Material and Methods30 children(14 boys and 16 girls with a median age of 6.75 years(0.83-14 years)) with hematological malignancies in our hospital from December of 2008 to the March of 2009 were enrolled into this study.The primary diseases included 15 cases of acute lymphoid leukemia(ALL),4 cases of acute myeloid leukemia(AML),2 cases of non-Hodgkin's lymphoma(NHL),8 cases of aplastic anemia(AA) and 1 patient of ALL with auto-hemotopoietic stem cell transplantation;Infections during neutropenia included the secondary septicaemia(n=10,laboratory diagnosis),septic shock(n=3), pneumonia(n=6,with 1 positive sputum culture),upper respiratory tract infection(n=6), enteritis(n=2),perianal infection(n=1),oral mucosa infection(n=1) and urinary tract infection(n=1,with positive urine culture);The pathogens found included 13 cases with gram-negative bacteria(9 were confirmed by laboratory tests and 4 were based on clinical manifestations),9 with gram-positive bacteria(3 confirmed by laboratory tests and 6 only according to clinical manifestations) and 8 cases with unknown pathogens. The median duration of neutropenia before febrile were 7.9 days with a range of 1-30days.The median febrile duration was 4 days with a range of 1-10days.16 cases were under glucocorticoid steroid therapy before febrile and the other 14 cases were not.The sera samples were obtained at the time of the admission(T1),fever within 1 hour(T2),within 1 hour after fever subside(T3) to detect IL-2,IL-4,IL-6,IL-10,TNF and IFN-γ.If the cytokines were not return to normal in T3,an extra sample(T4) was collected in the following day.The blood routine test,CRP,blood gas analysis and electrolyte analysis were monitored simultaneously.Before antibiotics,the blood culture and sensitivity test were performed.Statistical studies:Data were expressed in median using SAS 9.0 statistical kit. Wilcoxon rank test was used to compare the IL-2,IL-4,IL-6,IL-10,TNF and IFN-γchanges before and after fever(T1 and T2,T2 and T3),the IL-6,IL-10,TNF and IFN-γbetween gram-positive and negative bacterial infections,the IL-6,IL-10,TNF and IFN-γbetween the steroid group and the non-steroid group at the time point T2 and the time of cytokines and CRP return to normal.Spearman Correlation analysis were employed to analyze the correlation between IL-2,IL-4,IL-6,IL-10,TNF,IFN-γand CRP.P≤5;0.05 was defined as statistical significance.Results1.The IL-2,IL-4,IL-6,IL-10,TNF and IFN-γrose after fever,especially the IL-6,IL-10 and TNF.There was statistical significance between T2 and T1(P<0.05). The IL-2 and IL-4 after fever subside were decreased as compared to T2,but there was no statistical significance between T2 and T3(P>0.05).The IL-6,IL-10,TNF and IFN-γwere decreased significantly(P<0.05).2.There was statistical significance between gram negative and positive bacterial infection groups(P<0.05),the former had higher levels of IL-6,IL-10 and TNF.3.The group using steroids had higher levels of IL-6 and IL-10 than the group without steroid at the time point of T2(P<0.05).The TNF and IFN-γhad no significant difference between these two groups(P>0.05).4.All the cytokines decreased to normal quickly,faster than CRP.There was statistical significance between the time periods required for the fever to return to normal in cytokines and CRP(P<0.05).5.There is no significant correlation between serum level of IL-2,IL-4,IL-6, IL-10,TNF,IFN-γand CRP(P>0.05). Conclusions1.The cytokine changes are more sensitive than CRP.It can be used as an early diagnostic method in the chemotherapy-induced neutropenic patients with infection.2.The IL-6,IL-10 and TNF can be used to distinguish the G- from G+ bacteria infection.3.Normal dosing of steroids during chemotherapy can not inhibit the infection induced cytokine changes completely.Cytokine pattern still can be considered as a marker of monitoring infection.