Th1／Th2细胞因子谱在儿童噬血细胞综合征诊断中的意义

Diagnostic significance of Th1/Th2 cytokine pattern in childhood hemophagocytic lymphohistiocytosis

目的探讨Th1／Th2细胞因子检测在儿童噬血细胞综合征（HLH）诊断中的意义。方法用流式细胞微球阵列术（CBA）检测50例HLH患儿血清的Th1／Th2细胞因子水平，包括1干扰素（IFN-1）、肿瘤坏死因子（TNF）、白介素（IL）-10、IL-6、IL-4、IL-2共6种。同时设健康对照（250例健康儿童）及感染对照组（235例脓毒症患儿）。结果50例患儿在HLH急性期各细胞因子水平的中位值如下：IFN-1为1138．5（49．2～5000．0）ng／L、TNF为3．4（1．0～25．1）ng／L、IL-10为740．5（26．5～5000．0）ng／L、IL-6为66．1（3．9～4472．6）ng／L、IL-4为3．9（1．0～32．8）ng／L、IL-2为4．0（1．0～51．1）ng／L，缓解后各细胞因子的水平明显下降。其中IFN-γ、IL-10和IL-6的急性期水平均明显高于缓解期和健康对照组（P均〈0．001）。而脓毒症组IFN-1、IL-10和IL-6水平分别为3．1（1．0～150．1）ng／L、46．5（3．1～5000．0）ng／L和251．3（8．4～5000．0）ng／L，其中IL-6水平明显高于HLH组（P〈0．001），但IFN-1和IL-10却显著低于HLH患儿（P均〈0．001）。根据ROC曲线设定HLH的细胞因子诊断标准如下：IFN-1〉100ng／L，IL-10〉60ng／L，且IFN-1水平高于IL-6水平。在本研究队列的HLH和脓毒症患儿中，该标准对于HLH诊断的敏感度88．0％、特异度98．7％，阳性预测值93．6％、阴性预测值97．5％。结论IFN-1和IL-10显著升高，IL-6中等升高的Th1／Th2细胞因子谱对于HLH有很高的敏感度和特异度，对于HLH的诊断具有重要的参考价值。

Objective To illustrate the diagnostic value of Th1/Th2 cytokine pattern in childhood hemophagocytic lymphohistiocytosis （HLH） and its diagnostic accuracy. Method The BDTM CBA Human Th1/Th2 Cytokine Kit Ⅱ was used to measure the serum Thl and Th2 cytokines, including Interferongamma （IFN-3,）, tumor necrosis factor （TNF） , interleukin （1L）-10, IL-6, IL-4 and IL-2 in 50 patients with de novo HLH admitted to our hospital from Oct. 2005 to Aug. 2009. The above cytokine levels were also determined in 250 healthy volunteers and 235 patients with sepsis as controls. Result The primary features of these patients were prolonged high-grade fever （50/50）, hepatomegaly （44/50） , splenomegaly （38/50）, hemocytopenia （47/50） , hyperferritinemia （49/50）, coagulopathy （44/50）, hemophagocytosis in bone marrow （42/50） , liver dysfunction （42/50） and hypertriglyceridemia （42/50）. The IFN-γ, TNF, IL-10, IL-6, IL-4 and IL-2 levels for healthy children were （4.6 ± 1.8） ng/L, （4.0 ± 1.2） ng/L, （6.5 ± 1.3） ng/L, （6.0 ± 1.5） rig/L, （2.9 ± 0.8） ng/L and （2.6 ± 0.7） mg/L, while the median levels of them in acute phase of HLH children were 1138.5 （49. 2-5000. 0） mg/L, 3.4 （ 1.0-25. 1 ） ng/L,740.5 （26.5-5000.0） ng/L, 66.1 （3.9-4472.6） ng/L, 3.9 （1.0-32.8） ng/L and 4.0 （1.0-51.1） ng/L, respectively. The eytokine levels decreased to 9. 1 （ 1.9-180. 1 ） ng/L, 2. 9 （1.0-11.0） ng/L, 11.4 （2. 9-184. 2） ng/L, 6. 5 （ 1.0-44. 8） ng/L, 2. 7 （ 1.0-6. 5 ） ng/L and 4. 1 （ 1.0-12. 0） ng/L respectively after remission. The IFN-＇y, IL-10 and IL-6 levels in acute phase were significantly higher than those after remission and those of the healthy control （ P all 〈 0. 001 ）. IL4, IL-2 and TNF slightly elevated or at normal range in acute phase of HLH. The patients with sepsis showed a different eytokine pattern, with an extremely high level of IL-6 （ median ： 251.3 ng/L, range ： 8.4- 〉 5000. 0 ng/L） and moderately elevated level of IL-10 （median： 46. 5 ng/L, range： 3.1-5000. 0 ng/L） , whereas IFN-γ was only slightly elevated （median： 9. 2 ng/L, range： 1.3-498.8 ng/L）. When the criteria for HLH set as the following： IFN-γ 〉 100 ng/L, IL-10 〉 60 ng/L and the concentration of IFN-γ higher than that of IL-6, the specificity reached as high as 98.7% and the sensitivity was 88.0% for the diagnosis of HLH among patients with HLH and sepsis. Meanwhile, the positive predictive value （PPV） and negative predictive value （NPV） could reach 93.6% and 97. 5% , respectively. Conclusion The significant increase of IFN-γ and IL-10 with slightly increased level of IL-6 is a sensitive and specific cytokine pattern for childhood HLH, which is helpful for its diagnosis and differential diagnosis.