不同剂量重组人干扰素α-1b雾化吸入与常规抗病毒治疗对重症手足口病患儿脑保护作用的对比研究
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摘要
背景手足口病(HFMD)是由肠道病毒感染引起,以手、足、臀部及口腔黏膜疱疹为主要临床特征,少部分患儿进展为重症病例,出现惊厥、抽搐等神经系统症状,部分患儿会遗留神经系统后遗症。目前临床对该病的治疗多以常规抗病毒及对症治疗。目的比较雾化吸入不同剂量重组人干扰素α-1b(INF-α-1b)和静脉滴注利巴韦林对重症HFMD合并脑炎患儿脑组织的保护作用、疗效及不良反应。方法选取2014年3月—2015年12月河南省儿童医院收治的HFMD患儿120例,采用随机数字表法分为对照组、低剂量组、高剂量组,每组各40例。治疗方法:对照组接受利巴韦林治疗,将剂量为10 g/kg的利巴韦林加入5%的葡萄糖溶液中,分2次进行静脉滴注;低剂量组给予重组人INF-α-1b注射液2μg/kg,雾化吸入,2次/d,连续治疗5 d;高剂量组给予重组人INF-α-1b注射液4μg/kg,雾化吸入,2次/d,连续治疗5 d。治疗后第1、3、5天通过酶联免疫吸附试验(ELISA)检测血清C反应蛋白(CRP)、神经特异性烯醇化酶(NSE)、S-100B蛋白水平;观察患儿临床特征改善情况(皮疹消退时间、热程),检测治疗前后中性粒细胞计数、血小板计数。结果治疗方法和时间在CRP水平上不存在交互作用(P>0.05),治疗方法、时间在CRP水平上主效应不显著(P>0.05)。治疗方法和时间在NSE水平上存在交互作用(P<0.05),治疗方法、时间在NSE水平上主效应显著(P<0.05)。其中,治疗后第1、3、5天NSE水平比较,对照组高于低剂量组、高剂量组,低剂量组高于高剂量组(P<0.05)。治疗方法和时间在S-100B蛋白水平上存在交互作用(P<0.05),治疗方法、时间在S-100B蛋白水平上主效应显著(P<0.05)。其中,治疗后第1、3天S-100B蛋白水平比较,对照组高于低剂量组、高剂量组,低剂量组高于高剂量组(P<0.05);治疗后第5天,对照组S-100B蛋白水高于低剂量组、高剂量组(P<0.05)。低剂量组、高剂量组皮疹消退时间和热程均短于对照组,高剂量组皮疹消退时间和热程短于低剂量组(P<0.05)。3组治疗后中性粒细胞计数比较,低剂量组、高剂量组低于对照组,高剂量组低于低剂量组(P<0.05)。结论在重症HFMD治疗中,雾化吸入重组人INF-α-1b在脑保护、临床疗效方面优于静脉滴注利巴韦林,并且雾化吸入高剂量重组人INF-α-1b在脑保护作用方面优于低剂量重组人INF-α-1b,所以应根据个体病情及耐受性选择合适剂量。
Background Hand-foot-mouth disease(HFMD)is caused by enterovirus infection. It is characterized by herpes of hands,feet,buttocks and oral mucosa. Few children develop into severe cases with neurological symptoms,such as convulsions. Some children will have neurological sequelae. The current clinical treatment of this disease is routine antiviral therapy and symptomatic treatment.Objective To compare the cerebroprotective effects,therapeutic efficacy and adverse effects of inhalation of recombinant human interferon alpha-1b(INF-α-1b) at different doses versus intravenous ribavirin infusion in children with severe HFMD complicated by encephalitis.Methods A total of 120 children with severe HFMD admitted to Henan Provincial Children's Hospital from March 2014 to December 2015 were enrolled and randomized into the control group,the lowdose group and the high-dose group using a random number table,of 40 cases in each group.The subjects in the control group received intravenous infusion of 10 g/kg ribavirin in 5% glucose solution,given in two divided doses,and the cases in the lowdose group were given inhalation of recombinant human INF-α-1b injection at a dose of 2 μg/kg,twice daily for successive 5 days,while the cases in the high-dose group were given inhalation of recombinant human INF-α-1b injection at a dose of 4 μg/kg,twice daily for successive 5 days.The serum levels of C-reactive protein(CRP),neurospecific enolase(NSE) and S-100 B protein were measured using enzyme-linked immunosorbent assay(ELISA) 1,3 and 5 days post-treatment.The improvements of clinical features(time of rash disappearance and duration of fever) were observed,and platelet counts and neutrophil counts before and after treatment were recorded.Results There was no interaction between the treatment method and time in terms of the CRP concentration(P>0.05),and there was no significant main effect between the treatment method and time in terms of the CRP concentration(P>0.05).While an interaction was examined between the treatment method and time in terms of the NSE concentration(P<0.05),and there was a significant main effect between the treatment method and time in terms of the NSE concentration(P<0.05).Significantly higher NSE levels were detected in the control group than in the lowand high-dose groups,and significantly higher NSE levels were measured in the low-dose group than in the high-dose group 1,3 and 5 days post-treatment(P<0.05).In addition,there was an interaction between the treatment method and time in terms of the S-100 B level(P<0.05),and there was a significant main effect between the treatment method and time in terms of the S-100 B concentration(P<0.05).Significantly higher S-100 B levels were detected in the control group than in the low-and high-dose groups(P<0.05),and a significantly higher S-100 B level was seen in the low-dose group than in the high-dose group 1,3 days post-treatment(P<0.05),while significantly higher S-100 B concentrations were found in the control group than in the low-and high-dose groups 5 days post-treatment(P<0.05).Moreover,the time of rash disappearance and duration of fever were both shorter in the low-and high-dose groups than in the control group(P<0.05),and the time of rash disappearance and duration of fever were shorter in the high-dose group than in the low-dose group(P<0.05).Significantly lower neutrophil counts were measured in the low-and high-dose groups than in the control group(P<0.05),and the neutrophil count was significantly lower in the high-dose group than in the low-dose group post-treatment(P<0.05).Conclusion In the treatment of children with severe HFMD,inhalation of recombinant human INF-α-1b exhibits a greater cerebroprotective effect and clinical efficacy,than intravenous ribavirin infusion for the treatment of HFMD in children.In addition,inhalation of recombinant human INF-α-1b at a high dose exhibits a greater cerebroprotective effect for the treatment of HFMD in children.Therefore,recombinant human INF-α-1b should be given at an appropriate dose according to individual disease conditions and tolerance.
Background Hand-foot-mouth disease(HFMD)is caused by enterovirus infection. It is characterized by herpes of hands,feet,buttocks and oral mucosa. Few children develop into severe cases with neurological symptoms,such as convulsions. Some children will have neurological sequelae. The current clinical treatment of this disease is routine antiviral therapy and symptomatic treatment.Objective To compare the cerebroprotective effects,therapeutic efficacy and adverse effects of inhalation of recombinant human interferon alpha-1b(INF-α-1b) at different doses versus intravenous ribavirin infusion in children with severe HFMD complicated by encephalitis.Methods A total of 120 children with severe HFMD admitted to Henan Provincial Children's Hospital from March 2014 to December 2015 were enrolled and randomized into the control group,the lowdose group and the high-dose group using a random number table,of 40 cases in each group.The subjects in the control group received intravenous infusion of 10 g/kg ribavirin in 5% glucose solution,given in two divided doses,and the cases in the lowdose group were given inhalation of recombinant human INF-α-1b injection at a dose of 2 μg/kg,twice daily for successive 5 days,while the cases in the high-dose group were given inhalation of recombinant human INF-α-1b injection at a dose of 4 μg/kg,twice daily for successive 5 days.The serum levels of C-reactive protein(CRP),neurospecific enolase(NSE) and S-100 B protein were measured using enzyme-linked immunosorbent assay(ELISA) 1,3 and 5 days post-treatment.The improvements of clinical features(time of rash disappearance and duration of fever) were observed,and platelet counts and neutrophil counts before and after treatment were recorded.Results There was no interaction between the treatment method and time in terms of the CRP concentration(P>0.05),and there was no significant main effect between the treatment method and time in terms of the CRP concentration(P>0.05).While an interaction was examined between the treatment method and time in terms of the NSE concentration(P<0.05),and there was a significant main effect between the treatment method and time in terms of the NSE concentration(P<0.05).Significantly higher NSE levels were detected in the control group than in the lowand high-dose groups,and significantly higher NSE levels were measured in the low-dose group than in the high-dose group 1,3 and 5 days post-treatment(P<0.05).In addition,there was an interaction between the treatment method and time in terms of the S-100 B level(P<0.05),and there was a significant main effect between the treatment method and time in terms of the S-100 B concentration(P<0.05).Significantly higher S-100 B levels were detected in the control group than in the low-and high-dose groups(P<0.05),and a significantly higher S-100 B level was seen in the low-dose group than in the high-dose group 1,3 days post-treatment(P<0.05),while significantly higher S-100 B concentrations were found in the control group than in the low-and high-dose groups 5 days post-treatment(P<0.05).Moreover,the time of rash disappearance and duration of fever were both shorter in the low-and high-dose groups than in the control group(P<0.05),and the time of rash disappearance and duration of fever were shorter in the high-dose group than in the low-dose group(P<0.05).Significantly lower neutrophil counts were measured in the low-and high-dose groups than in the control group(P<0.05),and the neutrophil count was significantly lower in the high-dose group than in the low-dose group post-treatment(P<0.05).Conclusion In the treatment of children with severe HFMD,inhalation of recombinant human INF-α-1b exhibits a greater cerebroprotective effect and clinical efficacy,than intravenous ribavirin infusion for the treatment of HFMD in children.In addition,inhalation of recombinant human INF-α-1b at a high dose exhibits a greater cerebroprotective effect for the treatment of HFMD in children.Therefore,recombinant human INF-α-1b should be given at an appropriate dose according to individual disease conditions and tolerance.
引文
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[9]陈爱民,陈红敏.手足口病持续热患儿免疫球蛋白冲击治疗的护理[J].护理学杂志,2011,26(23):33-34.DOI:10.3870/hlxzz.2011.23.033.
[10]刘鉴峰,刘金剑,褚丽萍,等.雾化吸入干扰素α1b在兔体内的分布及代谢途径[J].医药导报,2013,32(1):1-5.DOI:10.3870/yydb.2013.01.001.LIU J F,LIU J J,ZHU L P,et al.Distribution and metabolic pathway of interferon alpha 1b in rabbits after inhalation[J].Medical Bulletin,2013,32(1):1-5.DOI:10.3870/yydb.2013.01.001.
[11]LIU M L,LEE Y P,WANG Y F,et al.TypeⅠinterferons protect mice against enterovirus 71 infection[J].J Gen Virol,2005,86(Pt12):3263-3269.DOI:10.1099/vir.0.81195-0.
[12]ASADA-KUBOTA M,UEDA T.Localization of 2'5'-oligoadenylate synthetase and the enhancement of its activity with recombinant interferon-alpha A/D in the mouse brain[J].Anat Embryol(Berl),1997,195(3):251-257.
[13]徐艳利,田庆玲,姜太一,等.雾化吸入重组人干扰素α1b对重症手足口病早期的治疗作用[J].中华实用儿科临床杂志,2015,30(8):627-630.DOI:10.3760/cma.j.issn.2095-428X.2015.08.017.XU Y L,TIAN Q L,JIANG T Y,et al.Atomization inhalation of recombinant human interferon alpha 1b in the early treatment of severe hand foot and mouth disease[J].Chinese Practical Journal of Pediatrics,2015,30(8):627-630.DOI:10.3760/cma.j.issn.2095-428X.2015.08.017.
[14]王成秀,陈静,王斌,等.干扰素α1b治疗儿童手足口病临床疗效分析[J].中外医疗,2012,31(2):122.DOI:10.3969/j.issn.1674-0742.2012.02.094.WANG C X,CHEN J,WANG B,et al.Clinical efficacy of interferon alpha 1b in treatment of children with hand foot and mouth disease[J].Foreign Medical Analysis,2012,31(2):122.DOI:10.3969/j.issn.1674-0742.2012.02.094.
[15]ZHU J,QUYYUMI A A,NORMAN J E,et al.Cytomegalovirus in the pathogenesis of atherosclerosis:the role of inflammation as reflected by elevated C-reactive protein levels[J].J Am Coll Cardiol,1999,34(6):1738.DOI:10.1016/S0735-1097(99)00410-6.
[16]BENEDICT C,CEDERNAES J,GIEDRAITIS V,et al.Acute sleep deprivation increases serum levels of neuron-specific enolase(NSE)and S-100B calcium binding protein B(S-100B)in healthy young men[J].Sleep,2014,37(1):195-198.DOI:10.5665/sleep.3336.
[2]DENG H L,ZHANG Y F,LI Y P,et al.N-terminal pro-brain natriuretic peptide levels associated with severe hand,foot and mouth disease[J].BMC Infect Dis,2016,16(1):585.DOI:10.1186/s12879-016-1929-9.
[3]LMERSG J,VOS P,VERBEEK M M,et al.Protein S-100B,neuron-specific enolase(NSE),myelin basic protein(MBP)and glial fibrillary acidic protein(GFAP)in cerebrospinal fluid(CSF)and blood of neurological patients[J].Brain Res Bull,2003,61(3):261-264.DOI:10.1016/S0361-9230(03)00089-3.
[4]张华,张茁,张微微.急性脑卒中患者血清S-100B蛋白和神经元特异性烯醇化酶的动态变化[J].北京医学,2004,26(1):28-29.DOI:10.3969/j.issn.0253-9713.2004.01.007.
[5]ABZUG M J,NONPOLIO E,KLIEGMAN R M,et al.Nelson textbook of pediatrics[M].20th ed.Philadelphia:Elsevier,2016:1561-1568.
[6]BOPEGAMAGA S.Enterovirus infections:pivoting role of the adaptive immune response[J].Virulence,2016,7(5):495-497.DOI:10.1080/21505594.2016.1175701.
[7]ZHANG D,FU J,FU J.Enterovirus 71 vaccine:close but still far[J].Int J Infect Dis,2010,14(9):739-743.DOI:10.1016/j.ijid.2009.12.002.
[8]林思恩,章青,谢华萍,等.我国广东、福建地区2000~2001年手足口病肠道病毒71型分离株的种系进化分析[J].中华实验和临床病毒学杂志,2004,18(3):227-229.DOI:10.3760/cma.j.issn.1003-9279.2004.03.008.
[9]陈爱民,陈红敏.手足口病持续热患儿免疫球蛋白冲击治疗的护理[J].护理学杂志,2011,26(23):33-34.DOI:10.3870/hlxzz.2011.23.033.
[10]刘鉴峰,刘金剑,褚丽萍,等.雾化吸入干扰素α1b在兔体内的分布及代谢途径[J].医药导报,2013,32(1):1-5.DOI:10.3870/yydb.2013.01.001.LIU J F,LIU J J,ZHU L P,et al.Distribution and metabolic pathway of interferon alpha 1b in rabbits after inhalation[J].Medical Bulletin,2013,32(1):1-5.DOI:10.3870/yydb.2013.01.001.
[11]LIU M L,LEE Y P,WANG Y F,et al.TypeⅠinterferons protect mice against enterovirus 71 infection[J].J Gen Virol,2005,86(Pt12):3263-3269.DOI:10.1099/vir.0.81195-0.
[12]ASADA-KUBOTA M,UEDA T.Localization of 2'5'-oligoadenylate synthetase and the enhancement of its activity with recombinant interferon-alpha A/D in the mouse brain[J].Anat Embryol(Berl),1997,195(3):251-257.
[13]徐艳利,田庆玲,姜太一,等.雾化吸入重组人干扰素α1b对重症手足口病早期的治疗作用[J].中华实用儿科临床杂志,2015,30(8):627-630.DOI:10.3760/cma.j.issn.2095-428X.2015.08.017.XU Y L,TIAN Q L,JIANG T Y,et al.Atomization inhalation of recombinant human interferon alpha 1b in the early treatment of severe hand foot and mouth disease[J].Chinese Practical Journal of Pediatrics,2015,30(8):627-630.DOI:10.3760/cma.j.issn.2095-428X.2015.08.017.
[14]王成秀,陈静,王斌,等.干扰素α1b治疗儿童手足口病临床疗效分析[J].中外医疗,2012,31(2):122.DOI:10.3969/j.issn.1674-0742.2012.02.094.WANG C X,CHEN J,WANG B,et al.Clinical efficacy of interferon alpha 1b in treatment of children with hand foot and mouth disease[J].Foreign Medical Analysis,2012,31(2):122.DOI:10.3969/j.issn.1674-0742.2012.02.094.
[15]ZHU J,QUYYUMI A A,NORMAN J E,et al.Cytomegalovirus in the pathogenesis of atherosclerosis:the role of inflammation as reflected by elevated C-reactive protein levels[J].J Am Coll Cardiol,1999,34(6):1738.DOI:10.1016/S0735-1097(99)00410-6.
[16]BENEDICT C,CEDERNAES J,GIEDRAITIS V,et al.Acute sleep deprivation increases serum levels of neuron-specific enolase(NSE)and S-100B calcium binding protein B(S-100B)in healthy young men[J].Sleep,2014,37(1):195-198.DOI:10.5665/sleep.3336.