Th1/Th2细胞因子谱在血液肿瘤病儿童G+/G-菌脓毒血症鉴别诊断中的意义
摘要
目的：化疗是血液系统恶性肿瘤的主要治疗方法,但也损害了机体的免疫系统,导致粒细胞缺乏。感染是血液肿瘤患儿化疗后最常见的并发症,也是导致患儿死亡的重要原因之一。因此早期诊断及抗生素的合理使用对患儿的预后至关重要。目前临床上常用的感染指标包括血常规、C反应蛋白(CRP)、前降钙素(PCT)及血培养。但是这些指标对于感染的早期诊断敏感度或特异度较差。近年来,细胞因子越来越受到关注,国内外研究表明细胞因子与感染之间存在密切联系。然而通过分析细胞因子谱区分革兰氏阴性菌及革兰氏阳性菌感染报道罕见。本研究通过分析血液肿瘤病儿童G+/G-菌脓毒血症细胞因子水平,寻找一种快速诊断方法用于临床早期鉴别诊断G+/G-菌脓毒血症。
方法：采用流式细胞仪微球阵列(CBA)技术测定2008年1月至2010年5月间在我院血液科住院被确诊为脓毒血症190例患儿发热时、69例患儿热退后细胞因子水平。并以本院血液科同期住院无感染表现的99例患儿作为对照。采用SPSS(Statistical Package for the Social Sciences)17.0软件进行统计。发热第1天(T1)病例组和对照组,病例组内革兰氏阳性菌感染与革兰氏阴性菌感染IL-2、IL-4、IL-6、IL-10、M-α及IFN-y比较采用Mann-Whitney U非参数检验,患儿发热第1天(T1)和热退24小时内(T2)IL-2、IL-4、IL-6、IL-10、TNF-α及IFN-Υ比较采用Wilcoxon符号秩检验,各细胞因子间相关性分析采用Spearman rank相关性分析。分析G+和G-菌感染细胞因子谱的变化规律,探索G+和G-菌感染相关细胞因子谱。结果均以P<0.05为有统计学意义。
结果：发热初脓毒血症组细胞因子IL-2、IL-4、IL-6、IL-10、TNF-α、IFN-γ均明显高于对照组(P<0.01)。G-菌感染组IL-6、IL-10、TNF-α中位数值分别为284.35pg/ml、98.70pg/ml、4.45pg/ml,明显高于G+菌感染组(72.15pg/ml、10.90pg/ml、2.85pg/ml, P<0.01)。以IL-6≥100pg/ml且IL-10≥25pg/ml作为G-菌感染细胞因子谱来预测G+/G-菌脓毒血症,其特异度为83.70%,灵敏度为60.20%。以IL-6<100pg/ml或IL-10<25pg/ml作为G+菌感染细胞因子谱来预测G+/G-菌脓毒血症,其特异度为60.20%,灵敏度为83.70%。脓毒血症组热退24小时内(T2)IL-6、IL-10、TNF-α、IFN-γ中位数值分别为9.30pg/ml、5.90pg/ml、2.4pg/ml、4.8pg/ml明显低于发热初(T1)(212.2pg/ml、99.6pg/ml、3.0pg/ml、6.90pg/ml, P<0.01)。
结论：血液肿瘤病儿童脓毒血症时IL-2、IL-4、IL-6、IL-10、TNF-α及IFN-Υ水平升高。血液肿瘤病儿童脓毒血症G-菌感染时IL-6、IL-10、TNF-α水平明显高于G+菌感染。IL-6、IL-10水平可用于血液肿瘤病儿童G+/G-菌脓毒血症早期鉴别诊断。脓毒血症患儿热退24小时内IL-6、IL-10、TNF-α、IFN-γ有明显下降。
Objective:Chemotherapy is one of the main treatments of malignant tumors in pediatric hematology-oncology patients, but it may also damage the immune system of the body, leading to neutropenia. Infection is one of the most common complications after chemotherapy and the most important cause of death in these children. So early diagnosis of infection and appropriate choice of antibiotics are important to improve the prognosis of the patients. Presently, the most commonly used diagnostic methods for infections include the blood test, C reactive protein(CRP). procalcitonin(PCT). the blood culture and so on. But these methods do not have high sensitivity or specificity for early diagnosis of infection in these patients. Recently, attention has been paid to the role of cytokines. Many studies have showed the close association between cytokines and infection. But the studies on the distinguishing between the gram-positive and negative bacterial infections through the cytokine profiles are very rare. The aim of this study is to investigate the Thl/Th2 cytokines in G+/G- sepsis in pediatric hematology-oncology patients and to seek for a rapid diagnostic method to determine the type of infection in G+/G-sepsis.
Methods:The concentrations of Thl/Th2 cytokines from 190 hospitalized hematology-oncology children with positive blood culture from January 2008 through May 2010 were determined by flow cytometry bead assay (CBA) at the time of fever within 24 hours. The concentrations of these cytokines from 69 patients above-mentioned were determined within 24 hours after fever subsided.99 hospitalized hematology-oncology children without any evidence of infection were enrolled as control. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 17.0. Serum concentrations of individual cytokines were compared between the febrile group and the control group, gram-positive and gram-negative bacterial infections group, using Mann-Whitney U test. Serum concentrations of individual cytokines were compared between fever(Tl) and fever subsided(T2) using Wilcoxon rank test. The correlations among IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-y were analyzed using the Spearman Correlation analysis. The study was to analyze the cytokine profiles in G+/G-sepsis in pediatric hematology-oncology patients and to explore the rule of bacterial infection related cytokine profile (BIRCP). A two-sided P-value of<0.05 was considered to be statistically significant.
Results:IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-y levels from sepsis groups were significantly higher than those from controls at the time of fever (P< 0.01).The median levels of IL-6, IL-10, TNF-a of group G-were 284.35pg/ml,98.70pg/ml,4.45pg/ml. respectively, significantly higher than those of group G+(72.15pg/ml,10.90pg/ml, 2.85pg/ml, respectively, P< 0.01)。According to the different degrees of increased IL-6 and IL-10 levels, we named the G- bacteria infection related cytokine profile G-BIRCP and the G+ BIRCP. The specificity and sensitivity of BIRCP prediction for G-and G+ bacteria cultures were 83.70% and 60.20%.60.20% and 83.70%. respectively. The median levels of IL-6, IL-10, TNF-α, IFN-γfrom sepsis groups at the time of fever(T1) were 9.30pg/ml,5.90pg/ml,2.4pg/ml,4.8pg/ml, respectively, significantly lower than those after fever subsided(T2)(212.2pg/ml,99.6pg/ml,3.0pg/ml,6.90pg/ml, respectively, P<0.01)
Conclusions:These results showed the levels of IL-2, IL-4, IL-6, IL-10, TNF-αand IFN-γrose in sepsis in pediatric hematology-oncology patients. The levels of IL-6, IL-10, TNF-αwere higher in pediatric hematology-oncology patients with G-sepsis than in those with G+ sepsis. The IL-6 and IL-10 determination with CB A technology can be used for the early and rapid diagnosis and evaluation of G+/G- sepsis in pediatric hematology-oncology patients. The levels of IL-6, IL-10, TNF-αand IFN-γin pediatric hematology-oncology patients with sepsis began to decrease within 24 hours after fever subsides.
方法：采用流式细胞仪微球阵列(CBA)技术测定2008年1月至2010年5月间在我院血液科住院被确诊为脓毒血症190例患儿发热时、69例患儿热退后细胞因子水平。并以本院血液科同期住院无感染表现的99例患儿作为对照。采用SPSS(Statistical Package for the Social Sciences)17.0软件进行统计。发热第1天(T1)病例组和对照组,病例组内革兰氏阳性菌感染与革兰氏阴性菌感染IL-2、IL-4、IL-6、IL-10、M-α及IFN-y比较采用Mann-Whitney U非参数检验,患儿发热第1天(T1)和热退24小时内(T2)IL-2、IL-4、IL-6、IL-10、TNF-α及IFN-Υ比较采用Wilcoxon符号秩检验,各细胞因子间相关性分析采用Spearman rank相关性分析。分析G+和G-菌感染细胞因子谱的变化规律,探索G+和G-菌感染相关细胞因子谱。结果均以P<0.05为有统计学意义。
结果：发热初脓毒血症组细胞因子IL-2、IL-4、IL-6、IL-10、TNF-α、IFN-γ均明显高于对照组(P<0.01)。G-菌感染组IL-6、IL-10、TNF-α中位数值分别为284.35pg/ml、98.70pg/ml、4.45pg/ml,明显高于G+菌感染组(72.15pg/ml、10.90pg/ml、2.85pg/ml, P<0.01)。以IL-6≥100pg/ml且IL-10≥25pg/ml作为G-菌感染细胞因子谱来预测G+/G-菌脓毒血症,其特异度为83.70%,灵敏度为60.20%。以IL-6<100pg/ml或IL-10<25pg/ml作为G+菌感染细胞因子谱来预测G+/G-菌脓毒血症,其特异度为60.20%,灵敏度为83.70%。脓毒血症组热退24小时内(T2)IL-6、IL-10、TNF-α、IFN-γ中位数值分别为9.30pg/ml、5.90pg/ml、2.4pg/ml、4.8pg/ml明显低于发热初(T1)(212.2pg/ml、99.6pg/ml、3.0pg/ml、6.90pg/ml, P<0.01)。
结论：血液肿瘤病儿童脓毒血症时IL-2、IL-4、IL-6、IL-10、TNF-α及IFN-Υ水平升高。血液肿瘤病儿童脓毒血症G-菌感染时IL-6、IL-10、TNF-α水平明显高于G+菌感染。IL-6、IL-10水平可用于血液肿瘤病儿童G+/G-菌脓毒血症早期鉴别诊断。脓毒血症患儿热退24小时内IL-6、IL-10、TNF-α、IFN-γ有明显下降。
Objective:Chemotherapy is one of the main treatments of malignant tumors in pediatric hematology-oncology patients, but it may also damage the immune system of the body, leading to neutropenia. Infection is one of the most common complications after chemotherapy and the most important cause of death in these children. So early diagnosis of infection and appropriate choice of antibiotics are important to improve the prognosis of the patients. Presently, the most commonly used diagnostic methods for infections include the blood test, C reactive protein(CRP). procalcitonin(PCT). the blood culture and so on. But these methods do not have high sensitivity or specificity for early diagnosis of infection in these patients. Recently, attention has been paid to the role of cytokines. Many studies have showed the close association between cytokines and infection. But the studies on the distinguishing between the gram-positive and negative bacterial infections through the cytokine profiles are very rare. The aim of this study is to investigate the Thl/Th2 cytokines in G+/G- sepsis in pediatric hematology-oncology patients and to seek for a rapid diagnostic method to determine the type of infection in G+/G-sepsis.
Methods:The concentrations of Thl/Th2 cytokines from 190 hospitalized hematology-oncology children with positive blood culture from January 2008 through May 2010 were determined by flow cytometry bead assay (CBA) at the time of fever within 24 hours. The concentrations of these cytokines from 69 patients above-mentioned were determined within 24 hours after fever subsided.99 hospitalized hematology-oncology children without any evidence of infection were enrolled as control. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 17.0. Serum concentrations of individual cytokines were compared between the febrile group and the control group, gram-positive and gram-negative bacterial infections group, using Mann-Whitney U test. Serum concentrations of individual cytokines were compared between fever(Tl) and fever subsided(T2) using Wilcoxon rank test. The correlations among IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-y were analyzed using the Spearman Correlation analysis. The study was to analyze the cytokine profiles in G+/G-sepsis in pediatric hematology-oncology patients and to explore the rule of bacterial infection related cytokine profile (BIRCP). A two-sided P-value of<0.05 was considered to be statistically significant.
Results:IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-y levels from sepsis groups were significantly higher than those from controls at the time of fever (P< 0.01).The median levels of IL-6, IL-10, TNF-a of group G-were 284.35pg/ml,98.70pg/ml,4.45pg/ml. respectively, significantly higher than those of group G+(72.15pg/ml,10.90pg/ml, 2.85pg/ml, respectively, P< 0.01)。According to the different degrees of increased IL-6 and IL-10 levels, we named the G- bacteria infection related cytokine profile G-BIRCP and the G+ BIRCP. The specificity and sensitivity of BIRCP prediction for G-and G+ bacteria cultures were 83.70% and 60.20%.60.20% and 83.70%. respectively. The median levels of IL-6, IL-10, TNF-α, IFN-γfrom sepsis groups at the time of fever(T1) were 9.30pg/ml,5.90pg/ml,2.4pg/ml,4.8pg/ml, respectively, significantly lower than those after fever subsided(T2)(212.2pg/ml,99.6pg/ml,3.0pg/ml,6.90pg/ml, respectively, P<0.01)
Conclusions:These results showed the levels of IL-2, IL-4, IL-6, IL-10, TNF-αand IFN-γrose in sepsis in pediatric hematology-oncology patients. The levels of IL-6, IL-10, TNF-αwere higher in pediatric hematology-oncology patients with G-sepsis than in those with G+ sepsis. The IL-6 and IL-10 determination with CB A technology can be used for the early and rapid diagnosis and evaluation of G+/G- sepsis in pediatric hematology-oncology patients. The levels of IL-6, IL-10, TNF-αand IFN-γin pediatric hematology-oncology patients with sepsis began to decrease within 24 hours after fever subsides.
引文
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