• 中国科技论文统计源期刊
  • 中国科技核心期刊
  • 中国高校优秀期刊
  • 安徽省优秀科技期刊
Volume 44 Issue 9
Sep.  2019
Article Contents
Turn off MathJax

Citation:

Change and effect of norepinephrine and interleukin-6 in HFMD children infected by EV71

  • Received Date: 2018-10-18
    Accepted Date: 2019-04-18
  • ObjectiveTo observe the levels of norepinephrine(NE) and interleukin-6(IL-6) during the stage Ⅱ, Ⅲ and Ⅳ hand foot mouth disease(HFMD) children infected by enterovirus 71(EV71), and investigate the correlation of levels of NE and IL-6 with EV71 infection.MethodsThe differences of the clinical presentation and laboratory examination among stage Ⅱ, Ⅲ and Ⅳ HFMD children infected by EV71 and healthy children were compared.The levels of NE and IL-6 in different period were detected, and the correlation of levels of NE and IL-6 with disease progression were analyzed.ResultsWith the progression of HFMD, the proportions of EV71 infection children with duration 72 h of high fever, poor spirit, vomiting, irritability, dysphasia, rapid heart rate, capillary refill time >2 s, white blood cell >15×109/L and glucose >8.3 mmol/L gradually increased(P < 0.05 to P < 0.01).The levels of NE and IL-6 in EV71 infection stage Ⅱ, Ⅲ and Ⅳ children were significantly higher than those in healthy children, and which gradually increased with the increasing of EV71 infection staging(P < 0.01).The results of Pearson correlation analysis showed that the level of IL-6 was positively correlated with NE level in EV71 infection children(P < 0.01).ConclusionsThe levels of NE and IL-6 in HFMD increasing with the progression of EV71 infection staging may be an important factor for the disease progression after EV71 infection, which hints that clinicians can evaluate the children's condition by analyzing the levels of NE and IL-6.
  • 加载中
  • [1] ZHU Z, ZHU S, GUO X, et al.Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008[J].Virol J, 2010, 7(1):300. doi: 10.1186/1743-422X-7-300
    [2] 中华人民共和国卫生部.手足口病诊疗指南(2010年版)[J].中国社区医师, 2010, 30(21):5. doi: 10.3969/j.issn.1007-614x.2010.21.003
    [3] SHIEH WJ, JUNG SM, HSUEH C, et al.Pathologic studies of fatal cases in outbreak of hand, foot, and mouth disease, Taiwan[J].Emerg Infect Dis, 2001, 7(1):146. doi: 10.3201/eid0701.700146
    [4] JANG S, SUH SI, HA SM, et al.Enterovirus 71-related encephalomyelitis:usual and unusual magnetic resonance imaging findings[J].Neuroradiology, 2012, 54(3):239. doi: 10.1007/s00234-011-0921-8
    [5] 王斌, 冯慧芳, 黄平, 等.随机森林模型在重症手足口病预测中的应用价值[J].郑州大学学报(医学版), 2008, 53(6):747.
    [6] STEWART CL, CHU EY, INTROCASO CE, et al.Coxsackievirus A6-induced hand-foot-mouth disease[J].JAMA Dermatol, 2013, 149(12):1419. doi: 10.1001/jamadermatol.2013.6777
    [7] TIAN H, YANG QZ, LIANG J, et al.Clinical features and management outcomes of severe hand, foot and mouth disease[J].Med Princ Pract, 2012, 21(4):355. doi: 10.1159/000334619
    [8] YASUI H, ARIMA H, HOZUMI H, et al.Neurogenic pulmonary edema without norepinephrine elevation[J].Intern Med, 2018, 57(14):2097. doi: 10.2169/internalmedicine.9825-17
    [9] WU JM, WANG JN, TSAI YC, et al.Cardiopulmonary manifestations of fulminant enterovirus 71 infection[J].Pediatrics, 2002, 109(2):E26. doi: 10.1542/peds.109.2.e26
    [10] SAKUMA S, KATO Y, NISHIGAKI F, et al.Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro[J].Int Immunopharmacol, 2001, 1(4):749. doi: 10.1016/S1567-5769(01)00008-X
    [11] BAHLOUL M, CHAARI AN, KALLEL H, et al.Neurogenic pulmonary edema due to traumatic brain injury:evidence of cardiac dysfunction[J].Am J Crit Care, 2006, 15(5):462.
    [12] SEDÝJ, ZICHA J, NEDVÁDKOVÍ J, et al.The role of sympathetic nervous system in the development of neurogenic pulmonary edema in spinal cord-injured rats[J].J Appl Physiol, 2012, 112(1):1.
    [13] LANE S, MAENDER K, AWENDER N, et al.Adrenal epinephrine increases alveolar liquid clearance in a canine model of neurogenic pulmonary edema[J].Am J Respir Crit Care Med, 1998, 158(3):760. doi: 10.1164/ajrccm.158.3.9802031
    [14] SUN JF, LI HL, SUN BX.Correlation analysis on serum inflammatory cytokine level and neurogenic pulmonary edema for children with severe hand-foot-mouth disease[J].Eur J Med Res, 2018, 23(1):33. doi: 10.1186/s40001-018-0327-8
    [15] ROBINSON CR, DOANE FW, RHODES AJ.Report of an outbreak of febrile illness with pharyngeal lesions and exanthem:Toronto, summer 1957;isolation of group A Coxsackie virus[J].Can Med Assoc J, 1958, 79(8):615.
    [16] CHEN Z, LI R, XIE Z, et al.IL-6, IL-10 and IL-13 are associated with pathogenesis in children with Enterovirus 71 infection[J].Int J Clin Exp Med, 2014, 7(9):2718.
    [17] HUANG SW, LEE YP, HUNG YT, et al.Exogenous interleukin-6, interleukin-13, and interferon-γ provoke pulmonary abnormality with mild edema in enterovirus 71-infected mice[J].Respir Res, 2011, 12(1):147. doi: 10.1186/1465-9921-12-147
    [18] KHONG WX, FOO DG, TRASTI S, et al.Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model[J].J Virol, 2011, 85(7):3067. doi: 10.1128/JVI.01779-10
  • 加载中
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Tables(2)

Article views(3623) PDF downloads(6) Cited by()

Related
Proportional views

Change and effect of norepinephrine and interleukin-6 in HFMD children infected by EV71

  • Pediatric Intensive Care Unit, Hebei Children's Hospital, Shijiazhuang Hebei 050031, China

Abstract: ObjectiveTo observe the levels of norepinephrine(NE) and interleukin-6(IL-6) during the stage Ⅱ, Ⅲ and Ⅳ hand foot mouth disease(HFMD) children infected by enterovirus 71(EV71), and investigate the correlation of levels of NE and IL-6 with EV71 infection.MethodsThe differences of the clinical presentation and laboratory examination among stage Ⅱ, Ⅲ and Ⅳ HFMD children infected by EV71 and healthy children were compared.The levels of NE and IL-6 in different period were detected, and the correlation of levels of NE and IL-6 with disease progression were analyzed.ResultsWith the progression of HFMD, the proportions of EV71 infection children with duration 72 h of high fever, poor spirit, vomiting, irritability, dysphasia, rapid heart rate, capillary refill time >2 s, white blood cell >15×109/L and glucose >8.3 mmol/L gradually increased(P < 0.05 to P < 0.01).The levels of NE and IL-6 in EV71 infection stage Ⅱ, Ⅲ and Ⅳ children were significantly higher than those in healthy children, and which gradually increased with the increasing of EV71 infection staging(P < 0.01).The results of Pearson correlation analysis showed that the level of IL-6 was positively correlated with NE level in EV71 infection children(P < 0.01).ConclusionsThe levels of NE and IL-6 in HFMD increasing with the progression of EV71 infection staging may be an important factor for the disease progression after EV71 infection, which hints that clinicians can evaluate the children's condition by analyzing the levels of NE and IL-6.

  • 手足口病(hand, foot and mouth disease,HFMD)多发生于5岁以下儿童,其传播具有季节性和较大范围的流行性,交叉传染率高,病情进展迅速可致死。目前柯萨奇病毒A16(CVA16)和肠道病毒71(EV71)是HFMD主要的病原[1]。EV71感染导致的HFMD相比CVA16更易出现严重并发症,包括脑膜炎、脑炎、脑脊髓炎、神经源性肺水肿、循环障碍、新生儿脓毒症等[2-3],死亡率较高,自2008年以来全国统计的死亡病例为1 490例。HFMD已成为发展中国家重大的公共卫生关切[4]。然而至今没有特效的抗病毒药物,因此,识别HFMD高危患儿并尽力避免神经源性肺水肿(neurogenic pulmonary edema,NPE)等危重情况出现是当下儿科面临的困境。

    HFMD典型的临床表现包括发热,咽痛,口腔黏膜、手足部或臀部皮肤红色丘疹样皮疹。NPE和循环衰竭是重症HFMD患儿病情快速进展并恶化的重要临床征象。EV71感染后侵犯脑干引起交感神经兴奋从而导致大量儿茶酚胺释放,主要包括去甲肾上腺素(norepinephrine,NE)、肾上腺素和多巴胺。儿茶酚胺的增多可引起白细胞介素6(interleukin-6)、IL-1、干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)等促炎或抗炎细胞因子的激活和释放[2-3]。其中,IL-6是肺部损伤难以逆转可能的关键因素。本研究观察EV71感染HFMD患儿不同临床分期NE、IL-6的浓度变化并分析其与病情进展的相关性,结合临床表现探讨对病情演变的影响。

1.   资料与方法
  • 选择2014-2017年河北省儿童医院感染科及PICU收治的110例EV71阳性的HFMD患儿。入选患儿均符合卫生部颁发的《HFMD诊疗指南(2010年版)》的诊断标准[2]。EV71感染Ⅱ期30例,EV71感染Ⅲ期30例,EV71感染Ⅳ期20例,另选同期体检正常的30名健康小儿作为对照组。

  • 根据指南确认HFMD患儿临床分期后次日早晨8:00采集静脉血3 mL,置于真空无菌采血管中,4 000 r/min离心5 min,分离血清,置于-20 ℃冰柜中保存。同时记录患儿生命体征(包括体温、呼吸、心率、呕吐、激惹、肢体抖动情况等),行血常规、血糖检查。

  • 采用双抗体夹心ELISA测定血清NE、IL-6水平,试剂盒由美国R & D公司生产。操作方法参考说明书。

  • 监测终止的标准是病情好转,包括:体温持续低于38 ℃大于24 h,嗜睡、肢体抖动等神经系统症状明显减轻,血常规白细胞及血糖显著降低。治愈的标准包括:体温、血常规白细胞、呼吸心率、血糖均恢复正常,无神经系统表现。

  • 收集患儿临床资料,比较性别、年龄,并分析高热是否持续72 h、精神差、呕吐、易激惹、肢体抖动、呼吸困难、心率增快、毛细血管再充盈时间(capillary refill time,CRT)>2 s、白细胞计数(white blood cell,WBC)>15×109/L、葡萄糖(glucose,Glu)>8.3 mmol/L的占比。检测并分析受试者NE、IL-6水平。

  • 采用方差分析、q检验、χ2检验和Pearson相关分析。

2.   结果
  • 各组研究对象性别、年龄、肢体抖动情况差异无统计学意义(P>0.05)。随着HFMD进展,EV71感染患儿的临床症状包括高热持续72 h、精神差、呕吐、易激惹、呼吸困难、心率增快、CRT>2 s、WBC>15×109/L、Glu>8.3 mmol/L出现的比例逐渐增加(P < 0.05~P < 0.01)(见表 1)。

    项目 对照组(n=30) EV71感染Ⅱ期(n=30) EV71感染Ⅲ期(n=30) EV71感染Ⅳ期(n=20) χ2 P
    性别(男/女) 19/11 19/11 21/9 12/8 0.61 >0.05
    年龄/月 30.22±10.54 29.33±11.12 27.62±11.31 23.18±10.22 1.89* >0.05
    高热持续72 h 0(0.00) 19(63.33) 20(66.67) 19(95.00) 8.11 < 0.05
    精神差 0(0.00) 7(23.33) 14(46.67) 16(80.00) 32.76 < 0.01
    呕吐 0(0.00) 3(10.00) 9(30.00) 16(80.00) 65.00 < 0.01
    易激惹 0(0.00) 6(20.00) 21(70.00) 16(80.00) 41.19 < 0.01
    肢体抖动 0(0.00) 21(70.00) 27(90.00) 20(100.00) 5.38 >0.05
    呼吸困难 0(0.00) 3(10.00) 4(13.33) 10(50.00) 40.80 < 0.01
    心率增快 0(0.00) 9(30.00) 14(46.67) 18(90.00) 34.36 < 0.01
    CRT>2 s 0(0.00) 1(3.33) 16(53.33) 13(65.00) 53.62 < 0.01
    WBC>15×109/L 0(0.00) 12(40.00) 13(43.33) 17(85.00) 22.61 < 0.01
    Glu>8.3 mmol/L 0(0.00) 15(50.00) 17(56.67) 15(75.00) 7.90 < 0.05
    *示F
  • NE和IL-6在EV71感染HFMD患儿Ⅱ、Ⅲ、Ⅳ期的血浓度水平均明显高于对照组(P < 0.01),且随着HFMD进展逐渐升高(P < 0.01)(见表 2)。

    分组 n NE IL-6
    对照组 30 0.47±0.39 47.84±26.53
    EV71感染Ⅱ期 30 5.69±3.46** 90.83±33.91**
    EV71感染Ⅲ期 30 10.84±4.61**△△ 148.94±78.24**△△
    EV71感染Ⅳ期 20 18.94±4.81**△△## 202.69±57.14**△△##
    F 112.87 41.10
    P < 0.01 < 0.01
    MS组内 13.28 2 767.13
    q检验:与对照组比较**P < 0.01;与EV71感染Ⅱ期比较△△P < 0.01;与EV71感染Ⅲ期比较##P < 0.01
  • Pearson相关分析显示,EV71感染HFMD患儿IL-6与NE的血浓度变化水平呈正相关关系(r=0.413,P<0.05)。

3.   讨论
  • EV71是引起重型HFMD最主要的病原体,病理学和影像学研究均证实EV71可以引起广泛的中枢神经系统病变,尤以脑干和脊髓损害最为明显,其感染所致的脑干脑炎及NPE是重症患儿致死的主要原因[5]

    NPE缺乏特异性的临床表现,早期诊断困难,同时进展迅速,通常在1~3 d内即可出现心动过速和呼吸困难,约90%患儿在12 h内死亡,其他幸存的患儿也会终身受到神经系统后遗症的困扰[5-6],因此早期预测NPE的发生意义重大。最新的指南指出,四肢抖动是最终发展为NPE的高风险因素。NPE患儿相比对照组血压高、心率快、神经系统损伤后的患儿会出现急性呼吸困难和低氧血症。有研究[7]认为下丘脑、脑干、脊髓的颈段部分是NPE的触发区。在颅内相应部位受损后,大脑会释放一些包括儿茶酚胺在内的活性物质,这些物质可以兴奋交感神经,引起全身血管收缩,导致心动过速、高血压、高血糖、呼吸困难以及炎症因子瀑布式释放、血管内皮细胞的通透性增高,并最终导致NPE发生。在脊髓损伤的动物模型试验发现,只有在肾上腺素和NE都升高的情况下才出现NPE[8]。而使用了α或β阻断剂能一定程度上缓解高儿茶酚胺浓度带来的副作用。通过预先使用抗儿茶酚胺如肾上腺素阻断剂干预或从第7颈椎水平离断脊髓可以防止NPE的发生。因此,儿茶酚胺在NPE的发生过程中扮演了重要角色。

    此外,促炎和抗炎因子在EV71感染后机体的病理变化中发挥了不容忽视的作用,其中IL-6具有代表性。在正常非感染的健康人群,IL-6在体内的表达水平很低,一旦感染其表达水平随之升高。多个临床研究报道,IL-6在EV71感染的HFMD病人和健康人群表达差别很大,并表示,IL-6可能与病人病情有一定的关联性[9];但也有研究表示,重症和轻症EV71感染的病人IL-6的升高水平和病程后期免疫球蛋白M没有相关性[10]。IL-6在EV71感染的各个阶段都有不同程度的升高,并且在第Ⅳ期水平最高[11]。EV71感染的小鼠血中IL-6出现一过性升高[12],而给予抗IL-6干预后出现病毒载量、B淋巴细胞激活程度及相关的组织损害程度减轻的现象[13]。甚至有研究认为,NPE发生的独立预测因素包括APACHEⅡ评分及较高的IL-6水平[14]

    本研究发现EV71感染HFMD患儿体内NE与IL-6几乎是并行升高的,因而猜测二者或许存在上下游的作用关系。有研究[15]发现,在应激条件下交感神经释放的NE能够直接提高肝细胞的IL-6 mRNA表达,也能够通过IL-1β的间接提高非肝脏实质细胞表面IL-6的表达。NE能够调节皮肤DC细胞包括IL-6在内的促炎因子的释放[16]。体外实验发现,NE和ATP能够协同诱导人皮肤毛细血管内皮细胞株释放IL-6,NE对IL-6的作用通过β2肾上腺素受体介导。NE能够提高血管内皮细胞分泌IL-6,在应激条件下,皮肤血管周围的交感神经分泌NE同时监测到IL-6的升高。人外周血单核细胞感染EV71 24 h后,再用NE处理24 h,收集细胞上清液检测包括IL-6、IL-10在内的若干细胞因子浓度,发现IL-6明显升高[17-18]

    综上,NE、IL-6在不同阶段EV71感染HFMD患儿中水平差异明显,且NE与IL-6水平呈正相关关系,提示临床医生可能通过分析NE、IL-6辅助制定临床干预计划。但NE、IL-6是否为NPE发生的启动因素,是否临床给予一定的拮抗治疗能够延缓甚至阻断NPE的发生尚需要进一步的研究。

Reference (18)

Catalog

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return