Molecular Epidemiological Analysis of Echovirus 19 Isolated From an Outbreak Associated With Hand, Foot, and Mouth Disease (HFMD) in Shandong Province of China

To elucidate the genetic characterization and molecular epidemiological features of Echovirus 19 （El9） isolates collected from an outbreak associated with hand, foot and mouth disease （HFMD） in Tai＇an city of Shandong Province of China from July to September, 2003. Methods Thirty seven Echovirus 19 isolates were isolated from stool specimens and throat swabs collected during the outbreak, then major capsid （VP1） genomic sequence was determined, and phylogenetic tree was done based on the VP1 sequences among these 37 and other El9 viruses deposited in the Genbank. Also a representative strain named CHN-SD03-TN12 was selected for sequencing of 5′-untranslated regions （5′-UTR）. Results The identity rate was about 98.9%-100% among all these 37 El9 viruses. The genetic relationships between these 37 El9 isolates and other strains reported were also depicted. The identity rate was about 78.4%-78.9% compared with El9 reference strain Burke. The substitutions in the sequence of 5′-UTR resulted in changes in the conjectural properties of 5′-UTR of El9 viruses. Condusion The genetic features of El9 viruses isolated during the outbreak in Shandong Province in 2003 may be associated with a genetic and antigenic drift that changes the virulence of the Shandong isolates, but the molecular changes in Shandong El9 viruses contributing to their phenotype remain to be further illuminated. However, the sequences described in this paper substantiate the changes taken place in capsid VPI and 5′UTR regions. These substitutions may contribute to their tropism and virulence, and play a significant role in pathogenesis and clinical manifestations of the disease.

Expression and clinical significance of pattern recognition receptor-associated genes in hand, foot and mouth disease

Objective:To explore which pattern recognition receptors(PRRs)play a key role in the development of hand,foot,and mouth disease(HFMD)by analyzing PRR-associated genes.Methods:We conducted a comparative analysis of PRR-associated gene expression in human peripheral blood mononuclear cells(PBMCs)infected with enterovirus 71(EV-A71)which were derived from patients with HFMD of different severities and at different stages.A total of 30 PRR-associated genes were identified as significantly upregulated both over time and across different EV-A71 isolates.Subsequently,ELISA was employed to quantify the expression of the six most prominent genes among these 30 identified genes,specifically,BST2,IRF7,IFI16,TRIM21,MX1,and DDX58.Results:Compared with those at the recovery stage,the expression levels of BST2(P=0.027),IFI16(P=0.016),MX1(P=0.046)and DDX58(P=0.008)in the acute stage of infection were significantly upregulated,while no significant difference in the expression levels of IRF7(P=0.495)and TRIM21(P=0.071)was found between different stages of the disease.The expression levels of BST2,IRF7,IFI16 and MX1 were significantly higher in children infected with single pathogen than those infected with mixed pathogens,and BST2,IRF7,IFI16 and MX1 expression levels were significantly lower in coxsackie B virus(COXB)positive patients than the negative patients.Expression levels of one or more of BST2,IRF7,IFI16,TRIM21,MX1 and DDX58 genes were correlated with PCT levels,various white blood cell counts,and serum antibody levels that reflect disease course of HFMD.Aspartate aminotransferase was correlated with BST2,MX1 and DDX58 expression levels.Conclusions:PRR-associated genes likely initiate the immune response in patients at the acute stage of HFMD.

Effects of lonicera granules + symptomatic treatment on serum indexes and immune function in children with hand-foot-and-mouth disease

Objective:To investigate the effects of lonicera granules + symptomatic treatment on serum indexes and immune function in children with hand-foot-and-mouth disease.Methods: A total of 120 children with HFMD who were treated between April 2016 and September 2017 were divided into the control group (n=60) and lonicera granules group (n=60) by random number table method. Control group received clinical symptomatic treatment for hand-foot-mouth disease, lonicera granules group received symptomatic treatment combined with lonicera granules therapy, and the treatment lasted for 7 d. The differences in serum levels of inflammatory factors, myocardial enzyme spectrum indexes and immunoglobulin were compared between the two groups before treatment and after 7 d of treatment.Results: Before treatment, there was no statistically significant difference in serum levels of inflammatory factors, myocardial enzyme spectrum indexes and immunoglobulin between the two groups. After 7 d of treatment, serum inflammatory cytokines IL-6, IL-10, IL-12 and TNF-α levels of lonicera granules group were lower than those of control group;serum myocardial enzyme spectrum indexesα-HBDH, LDH, AST and cTnⅠ levels were lower than those of control group;serum immunoglobulin IgA, IgG and IgM levels were higher than those of control group.Conclusion: Symptomatic treatment combined with lonicera granules therapy can further inhibit the systemic inflammatory response, protect the myocardial cells and enhance the immunity of children with HFMD.

Molecular Epidemiology of Enteroviruses Associated with Hand, Foot, and Mouth Disease in the Mainland of China

Hand, foot, and mouth disease （HFMD） is a common contagious illness which occurs worldwide both sporadically and in epidemics. The disease mainly affects, children and the typical symptoms, which may resolve spontaneously, include mucocutaneous papulovesicular lesions on the hands, feet, mouth, and buttocks. In rare cases, however, the patients may also develop neurological complications such as neurogenic pulmonary edema,

A Novel Early Warning Model for Hand, Foot and Mouth Disease Prediction Based on a Graph Convolutional Network

Objectives Hand,foot and mouth disease(HFMD)is a widespread infectious disease that causes a significant disease burden on society.To achieve early intervention and to prevent outbreaks of disease,we propose a novel warning model that can accurately predict the incidence of HFMD.Methods We propose a spatial-temporal graph convolutional network(STGCN)that combines spatial factors for surrounding cities with historical incidence over a certain time period to predict the future occurrence of HFMD in Guangdong and Shandong between 2011 and 2019.The 2011-2018 data served as the training and verification set,while data from 2019 served as the prediction set.Six important parameters were selected and verified in this model and the deviation was displayed by the root mean square error and the mean absolute error.Results As the first application using a STGCN for disease forecasting,we succeeded in accurately predicting the incidence of HFMD over a 12-week period at the prefecture level,especially for cities of significant concern.Conclusions This model provides a novel approach for infectious disease prediction and may help health administrative departments implement effective control measures up to 3 months in advance,which may significantly reduce the morbidity associated with HFMD in the future.

The Comparative Study on Two Models of Syndrome Differentiation of the Hand, Foot and Mouth Disease: An Investigation Analysis of the Signs and Symptoms on 2325 Cases

Objective To realize the characteristics of "zheng" differentiation-treatment for hand, foot and mouth disease(HFMD), a new methodology of syndrome differentiation for different stages of HFMD has been explored. Methods Total of 2 325 cases with HFMD were recorded by distributing them into exterior syndrome stage, interior syndrome stage, severe syndrome stage and recovered syndrome stage, respectively, and the main symptoms and subsidiary symptoms of different stages of HFMD have been observed. The major and minor pathogenesis of HFMD in different stages were obtained, and compared with the "2010 Guideline for the Diagnosis and Treatment of HFMD". Results It was found that the major pathogenesis of exterior stage was defined as "the invation of the wenevil to the defender of the body with the collaterals got involved ", and the minor as "qi deficiency"; in interior stage, "the fury of Gan-Yang" was the main pathogenesis, and "qi in chaos and qi deficiency" was the minor; in severe syndrome stage, "the damage of heart, liver and lung" was the main pathogenesis, and "qi in chaos" was the minor; and the pathogenesis of recovered stage was "qi-yin deficiency". Compared with the "2010 Guideline for the Diagnosis and Treatment of HFMD", it showed that "the obstruction of the fei-pi qi by the mixture of shi-re evil" and "the mixture of shi-re" in vivo was quite difficult to be explained in completely different context in the general situation; in the severe stage, the TCM clinical characteristics of syndrome differentiation might lose; in the early acute severe cases, the phenomenon that xin-yang and fei-qi almost ran out was difficult to be observed, then, the line between the severe and the acute severe became vague.Conclusions The theory of syndrome differentiation by stages of HFMD was reasonable in the actual situation of clinical description on HFMD which was expected to be further tested and widely applied in the "zheng" differentiation-treatment of HFMD in the future.

Regional characteristics and spatiotemporal differentiation of the prevalence of hand, foot, and mouth disease in Xinjiang, China

In recent years,the number of hand,foot,and mouth disease(HFMD)cases in China has continued to grow,and the disease has become a serious public health issue.Xinjiang Uygur Autonomous Region is located in the arid areas of Northwest China,where the epidemiological trend of HFMD is gradually increasing and characterized by geographical heterogeneity.In this study,based on the HFMD case data in all counties and cities in Xinjiang,we employed statistical and GIS spatial analyses,and geographic probe models to characterize the spatiotemporal differentiation of HFMD epidemics in Xinjiang during the period of 2009–2018,and quantitatively analyzed the factors influencing the spatial differentiation of HFMD epidemics.The results showed that HFMD incidence rate in Xinjiang had non-stationary temporal characteristics on the interannual and monthly scales,and the monthly variation characteristics of HFMD epidemic were quite different in southern and northern Xinjiang.The spatial distribution characteristics of HFMD epidemics showed a north–south spatial differentiation pattern with the Tianshan Mountains as the boundary;cold spot and hot spot of HFMD epidemics in Xinjiang have shifted from scattered to concentrated,and the spatial differentiation pattern had gradually stabilized.Moreover,the dominant factors influencing the spatial differentiation of HFMD epidemics in Xinjiang were socioeconomic factors,such as per capita GDP and urbanization rate,while the basic factors affecting its spatial differentiation were natural environmental factors.The spatial differentiation and evolution patterns of HFMD epidemics differed between northern and southern Xinjiang.Specifically,the leading role of socioeconomic factors is more obvious in southern Xinjiang than in northern Xinjiang,while natural environmental factors(e.g.,dryness and relative humidity)contribute to the prevalence of HFMD epidemics in northern Xinjiang,and the perturbing effect of these factors was more prominent than other factors.The results of this study can provide a scientific basis for the prevention of HFMD epidemics and early warning of HFMD epidemics in Xinjiang.

The Application Research of WBC Morphology Combined with NAP in the HFMD Co-Infection of Children

In this manuscript the authors have studied the application value of White blood cell morphology combined with neutrophils alkaline phosphatase staining integral value in treatment of pediatric HFMD combined with infection. They showed that comparing the NAP positive rate of HFMD co-infection with the NAP positive rate of other three groups respectively—reference group, HFMD group and anti-infection HFMD group—the t value is 25.7964, 28.2326, 28.3696 and the values of P are 0.0000;Comparing the NAP integral value of HFMD co-infection with the NAP integral value of other three groups respectively, which are reference group, HFMD group and anti-infection HFMD, the t value is 35.8687, 36.2664, 36.1374 and the values of P are 0.0000. They concluded that it is useful to apply WBC morphological examination combined with the positive rate and integral value of NAP staining to diagnose and treatment HFMD.

Effects of recombinant human interferon α 2b atomization on serum cytokines and peripheral blood immune cells in children with HFMD

Objective:To study the effects of recombinant human interferon 2b atomization on serum cytokines and peripheral blood immune cells in children with HFMD.Methods: Children who were diagnosed with hand-foot-and-mouth disease in Tongji Hospital? Tongji Medical College Huazhong University of Science & Technology between June 2014 and August 2017 were selected as the research subjects and randomly divided into the interferonα2b group who accepted human recombinant interferonα2b atomization combined with conventional symptomatic treatment and the control group who accepted conventional symptomatic treatment. The contents of cytokines in serum and the contents of immune cells in peripheral blood were determined before treatment as well as 3 days and 5 days after treatment. Results: 3 days and 5 days after treatment, IL-6, IL-13, TNF-α, CRP, MCP-1, VCAM-1 and ICAM-1 contents in serum as well as CD19+CD24highCD27+B cell contents in peripheral blood of both groups of children were greatly lower than those before treatment whereas CD3+CD4+T cell, CD3+CD8+T cell and CD16+CD56+NK cell contents in peripheral blood were higher than those before treatment, and IL-6, IL-13, TNF-α, CRP, MCP-1, VCAM-1 and ICAM-1 contents in serum as well as CD19+CD24highCD27+B cell contents in peripheral blood of interferonα2b group were significantly lower than those of control group whereas CD3+CD4+T cell, CD3+CD8+T cell and CD16+CD56+NK cell contents in peripheral blood were higher than those of control group.Conclusion: Recombinant human interferonα2b atomization treatment of HFMD can reduce the inflammatory response and improve the immune response.

天津市手足口病防控知识科普宣讲活动及效果评价

2023年6—10月,对天津市16个区进行分层抽样,抽取4个宣传地区及其24所托幼机构,对849位幼儿家长、705名校(园)医、129名社区医生开展手足口病防控知识科普宣讲活动,宣传形式包括家长课堂宣讲,校医、社区医生现场活动和答疑解惑,以科普文章制作转发、视频播放等形式传播,并针对现场宣讲活动人群开展问卷调查。科普宣讲活动后,手足口病日常预防知识知晓率及防控行为率明显升高。提出对于需要多次强化或不易记忆的日常防护知识,可采用科普宣讲和短视频循环播放相结合的方式。

深圳市宝安区手足口病经济负担及影响因素

目的:了解深圳市宝安区2021年手足口病经济负担并分析其影响因素。方法:收集某三级甲等医院2021年9月1日—12月1日就诊的1 225例手足口病病人,设计调查问卷,采用电话询问及医院信息系统查询收集资料,评估手足口病造成的经济负担并分析其影响因素。结果:1 225例病人中,门诊病人1 195例(97.55%),住院病人30例(2.45%),无重症病例。1 195例手足口病门诊病人的总体经济负担为422.57(336.70,604.54)元/例,30例手足口病住院病人的总体经济负担为(4 386.88±1 624.61)元/例。年龄、报销类型以及诊疗次数是手足口病门诊病人总体经济负担的影响因素(P<0.05)。结论:手足口病住院病人经济负担高于门诊病人,年龄、报销类型以及诊疗次数是手足口病门诊病人经济负担的影响因素。早发现、早诊断、早治疗能有效降低疾病经济负担。

The non-stationary and spatially varying associations between hand,foot and mouth disease and multiple environmental factors:A Bayesian spatiotemporal mapping model study

The transmission and prevalence of Hand,Foot and Mouth Disease(HFMD)are affected by a variety of natural and socio-economic environmental factors.This study aims to quantitatively investigate the non-stationary and spatially varying associations between various environmental factors and HFMD risk.We collected HFMD surveillance cases and a series of relevant environmental data from 2013 to 2021 in Xi'an,Northwest China.By controlling the spatial and temporal mixture effects of HFMD,we constructed a Bayesian spatiotemporal mapping model and characterized the impacts of different driving factors into global linear,non-stationary and spatially varying effects.The results showed that the impact of meteorological conditions on HFMD risk varies in both type and magnitude above certain thresholds(temperature:30°C,precipitation:70 mm,solar radiation:13000 kJ/m^(2),pressure:945 hPa,humidity:69%).Air pollutants(PM_(2.5),PM_(10),NO_(2))showed an inverted U-shaped relationship with the risk of HFMD,while other air pollutants(O_(3),SO_(2))showed nonlinear fluctuations.Moreover,the driving effect of increasing temperature on HFMD was significant in the 3-year period,while the inhibitory effect of increasing precipitation appeared evident in the 5-year period.In addition,the proportion of urban/suburban/rural area had a strong influence on HFMD,indicating that the incidence of HFMD firstly increased and then decreased during the rapid urbanization process.The influence of population density on HFMD was not only limited by spatial location,but also varied between high and low intervals.Higher road density inhibited the risk of HFMD,but higher night light index promoted the occurrence of HFMD.Our findings further demonstrated that both ecological and socioeconomic environmental factors can pose multiple driving effects on increasing the spatiotemporal risk of HFMD,which is of great significance for effectively responding to the changes in HFMD epidemic outbreaks.

Intestinal detoxification time of hand-foot-and-mouth disease in children with EV71 infection and the related factors

Background:Hand-foot-and-mouth disease(HFMD)is a common pediatric infectious disease caused by a variety of intestinal viruses.Enterovirus 71(EV71)is the primary pathogen that might cause severe symptoms and even death in children with HFMD.This study aimed to investigate the intestinal detoxification time of HFMD children with EV71 infection and its related factors.Methods:Sixty-five HFMD children with EV71 infection were followed up.Their stool samples were collected once every 4 to 7 days.Viral nucleic acids were detected byfl uorescent polymerase chain reaction until the results became negative.The positive rates of viral nucleic acids were analyzed by the Kaplan-Meier method.The Log-rank test and Cox-Mantel test were used to analyze factors affecting the HFMD children with EV71 infection.Results:On the 2nd,4th,6th and 10th week,the positive rates of viral nucleic acids in stool samples of the 65 children were 94.6%,48.1%,17.2%and 0,respectively.Univariate analysis showed that the intestinal detoxification time of the children were related to gender,pre-admission disease course,severity of disease,and use of steroids or gamma globulin(P<0.05).Multivariate analysis showed that the severity of disease was an independent factor affecting the intestinal detoxification time(P<0.05),with a relative risk of 2.418.Conclusions:The longest intestinal detoxification time of HFMD children with EV71 infection was 10 weeks.The severity of disease was an important factor affecting the intestinal detoxification time of HFMD children with EV71 infection.Severe HFMD children with EV71 infection had a longer intestinal detoxification time.

From Monovalent to Multivalent Vaccines, the Exploration for Potential Preventive Strategies Against Hand, Foot, and Mouth Disease(HFMD)

Hand,foot,and mouth disease(HFMD)recently emerged as a global public threat.The licensure of inactivated enterovirus A71(EV-A71)vaccine was the first step in using a vaccine to control HFMD.New challenges arise from changes in the pathogen spectrum while vaccines directed against other common serotypes are in the preclinical stage.The mission of a broad-spectrum prevention strategy clearly favors multivalent vaccines.The development of multivalent vaccines was attempted via the simple combination of potent monovalent vaccines or the construction of chimeric vaccines comprised of epitopes derived from different virus serotypes.The present review summarizes recent advances in HFMD vaccine development and discusses the next steps toward a safe and effective HFMD vaccine that is capable of establishing a crossprotective antibody response.

上海市长宁区儿童家长肠道病毒71型灭活疫苗接种意愿及影响因素分析

目的 了解上海市长宁区托幼机构儿童家长为孩子接种肠道病毒71型灭活疫苗(EV71疫苗)的意愿并分析影响因素,为推广EV71疫苗接种提出建议。方法 采用随机抽样的方式抽取长宁区托幼机构就读的儿童,向儿童家长发放问卷进行调查。结果 有75.40%的家长愿意为孩子接种EV71疫苗。Logistic回归分析,不认为EV71会产生强烈副作用、疫苗犹豫量表得分越高、主动获取知识得分越低的家长更愿意为孩子接种EV71疫苗。结论 家长为儿童接种EV71疫苗的意愿受到对EV71疫苗副作用的认知、疫苗犹豫和主动获取知识情况的影响,应对家长开展相关健康教育,以提升接种率。

2016至2022年杭州地区14259例儿童肠道病毒流行特征分析

目的了解杭州地区手足口病(hand-foot-mouth disease,HFMD)病原体肠道病毒(entero virus,EV)的阳性检出情况及流行特征,为今后制定杭州地区HFMD防控策略提供科学依据。方法收集整理2016年1月至2022年12月期间杭州市儿童医院检出的EV通用型核酸阳性的14259例的病例信息,对年龄、性别、检出时间等因素进行回顾性分析。结果EV历年平均阳性检出率为45.48%(14259/31354),其中男童阳性检出率为27.20%,女童为18.28%,差异有统计学意义(P<0.01)。不同年龄段患儿EV阳性检出率随年龄增大呈下降趋势,5岁以下儿童的EV阳性检出率占所有阳性检出患儿的90.38%。在季节方面,EV夏季高发,历年夏季5月至7月的总阳性检出数占总检出数的49.16%,自2016年以来EV阳性检出率呈逐年下降趋势。结论杭州地区EV感染具有性别差异,男童易感染,尤其需要重视5岁以下儿童的EV防护。另外HFMD存在一定的季节性,夏季高发,历年检出率自2016年后逐年下降,可能与疫苗推广和健康意识提高存在一定关系。

无创与有创正压通气防治重症手足口病神经源性肺水肿的疗效分析

目的：探讨无创与有创正压通气对防治重症手足口病神经源性肺水肿（ NPE）的疗效分析。方法选择2011－05-2014－04入住我院的重症手足口病患者（2、3期）228例，分为对照组（2期）70例，按照常规治疗；经鼻持续正压气道通气（ CPAP）组108例，常规治疗基础上加简易经鼻持续气道正压通气；呼吸机组50例，常规治疗的基础上加有创机械通气。结果2期CPAP组与对照组及呼吸机组（2期）的治愈好转率比较差异无统计学意义（P＝0．26，0．156）；3期呼吸机组的病程较CPAP组短（P＝0．000），但呼吸机组的血糖水平高于CPAP组，两组比较差异有统计学意义（ P＝0．05）；3期呼吸机组进展到4期的有8例均合并NPE明显高于3期CPAP组（ P＝0.004），5例死于肺出血，病死率62.5％，3期呼吸机组的最终病死率高于CPAP组（ P＜0.01）。结论目前没有临床依据推荐在2期重症手足口病常规使用机械通气；经鼻持续气道正压通气对3期危重症手足口病的症状改善、阻止病情进展、防治神经源性肺水肿及在减少有创机械通气使用方面具有肯定的疗效与优势。

肠道病毒71型疫苗质量控制研究进展

手足口病(Hand foot and mouth disease,HFMD)已成为西太平洋区严重的公共卫生问题之一,肠道病毒71型(Enterovirus 71,EV71)是引起HFMD的主要病原体,研发疫苗是控制HFMD流行的有效手段。目前世界范围已有5个EV71全病毒灭活疫苗进入临床试验,其中中国研制的3种EV71疫苗已分别完成III期临床试验,结果表明3种疫苗都具有良好的安全性和保护效果。在EV71疫苗研发中,抗原质控的方法和标准是研发的瓶颈,其中抗原活性测定是工序工艺优化、免疫原性评价和剂量确定的关键指标。综述了EV71疫苗抗原质控的研究进展。

2014—2018年沈阳地区手足口病病原分布及流行特征

目的探讨沈阳地区手足口病病原体分布及流行特征,为手足口病的防控和临床诊治提供参考依据。方法采用描述性流行病学方法,对2014—2018年中国医科大学附属盛京医院就诊的手足口病患儿病例信息及病原学监测数据进行分析。结果共接诊临床诊断手足口病患儿25571例,17263例(67.51%)肠道病毒检测阳性,其中男患儿阳性检出率为69.72%(10305/14780),女患儿阳性检出率为64.48%(6958/10791),男女患儿阳性检出率比较,差异有统计学意义(χ2=78.167,P<0.001)。手足口病肠道病毒检测阳性患儿中,<6岁者占92.59%,其中3~岁年龄组占比最高(24.53%)。手足口病全年均有发病,但季节分布明显,呈单峰状分布,每年7、8月份最高,占比为29.94%~52.30%。手足口病分离病原体EV-71占12.71%,CV-A16占24.38%,其他肠道病毒占62.91%。结论除EV-71和CV-A16外沈阳地区手足口病患儿感染其他肠道病毒所占比例较高,每年7、8月份为手足口病高发期,以<6岁的儿童发病为主,男孩发病居多。

贵州省415例重症手足口病临床分析

目的分析贵州省重症手足口病(HFMD)的临床特征,探讨其主要致病病原体、高危因素及有效的治疗方法。方法总结分析2013年1月-2014年5月贵州省415例重症手足口病患儿的临床症状、体征、实验室检查、治疗与转归等。结果在415例重症手足口病病例中,EV71为主要致病病原体。3岁以下患儿最多见,男性患儿多于女性患儿,男女比例为1.77∶1。患儿年龄最大为7岁,最小为46 d。一年四季均有发病,4~7月为发病高峰。重型病例发展为危重型病例在2 h^6 d范围内。临床特点:皮疹,持续发热,精神差,惊跳,呼吸频率、心率增快,末梢循环差,外周血白细胞增高,高血糖。有效治疗方法应予积极降颅压,免疫球蛋白冲击治疗,糖皮质激素抑制炎症反应,机械通气等对症治疗。结论贵州省重症HFMD主要致病病原体为EV71,患儿病情进展非常迅速,需注意神经源性肺水肿以及心脏损害。密切监测患儿病情变化,早期进行机械通气、积极改善循环功能状态可改善预后,降低重症HFMD患儿死亡率。