Abstract: 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 low-dose 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 low-dose 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-100B 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 low- and 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-100B level（P<0.05），and there was a significant main effect between the treatment method and time in terms of the S-100B concentration（P<0.05）．Significantly higher S-100B levels were detected in the control group than in the low- and high-dose groups（P<0.05），and a significantly higher S-100B 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-100B 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.

Key words: Hand, foot and mouth disease；Interferons；Ribavirin；Neuro-enolase；S-100B protein

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2 μg/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4 μg/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。

关键词: 手足口病, 干扰素类, 利巴韦林, 神经特异性烯醇化酶, S-100B蛋白