Clinical Features for Mild Hand,Foot and Mouth Disease in China

Background

Mild hand, foot and mouth disease (HFMD) is at a critical stage owing to its ease of communicability and a higher risk of developing severe complications and death. Clinical diagnosis of mild HFMD was made by the presenting symptoms and signs (symptoms in brief) alone. We aim to evaluate the frequencies of symptoms in a retrospective case series study.

Methods

We collected epidemiological, demographic, clinical, and laboratory data from outpatient and inpatient settings on the clinical data warehouse system. We principally described the frequencies of symptoms of mild HFMD. Correlations between symptoms with laboratory-confirmed cases were then analyzed.

Results

The clinical data warehouse system included 3649 probable cases, between 2010 and 2012, of which 956 (26.20%) were laboratory confirmed. The peak incidence was identified in children 2 years of age. A total of 370 of the 956 laboratory confirmed cases (38.70%) were associated with enterovirus 71 (EV71). Logistic regression analysis adjusted for geographical variables, age, sex, month of onset, and time from onset to diagnosis showed that the clinical features constipation (P<0.0001; adjusted OR, 95%CI (2.99, 2.28–3.91)), and blisters (P<0.0001; adjusted OR, 95%CI (2.16, 1.82–2.56)) were positively correlated with the confirmed cases.

Conclusions

This is the largest case series study, including all the guideline-mentioned symptoms of mild HFMD. Our findings suggest that blisters and constipation should be considered as potential warning signs while front-line clinicians manage surges of children diagnosed with mild HFMD during a pandemic.     

2013-2019年全国手足口病ECHO-9的分子流行病学研究

埃可病毒9型(Echovirus 9,ECHO-9)是引起无菌性脑膜炎(Aseptic meningitis,AM)和手足口病(Hand,foot,and mouth disease,HFMD)暴发流行的重要病原体,但目前全球关于ECHO-9分子流行病学研究仍比较匮乏,ECHO-9基于VP1全长的基因分型结果尚未明确。本研究依托国家HFMD监测网络,2013-2019年在中国大陆共分离到15株ECHO-9毒株,对其进行VP1区全长序列测定和分析,并与GenBank中下载的全部112条ECHO-9VP1区全长序列共同构建系统发育进化树。结果显示,全球ECHO-9分为A-G七个基因型,其中C、D和F基因型可被进一步划分为C1-C2,D1-D4和F1-F2基因亚型。各洲之间优势基因型别有显著差异,亚洲和欧洲分别以D和C基因型为绝对优势基因型。中国大陆ECHO-9优势基因型别为D基因型,但其优势基因亚型随时间推移有明显转变。2000-2005年,中国大陆ECHO-9全部为D1基因亚型,2006年开始出现D1、D2和D3基因亚型的共同流行,2010年后D1和D2基因亚型消失,D3成为中国大陆绝对优势基因型别。本研究测定的15株ECHO-9分离自2013-2019年,其中14株属于D3基因亚型,1株江西ECHO-9为C2基因亚型,推测其可能来源于境外。本研究建立了全球ECHO-9基于VP1全长的基因分型方法,揭示了ECHO-9在全国及全球范围的分子流行特征。     

Hand Foot and Mouth Disease Due to Enterovirus 71 in Malaysia

Hand foot and mouth disease is a febrile sickness complex characterized by cutaneous eruption (exanthem) on the palms and soles with simultaneous occurrence of muco-cutanous vesiculo-ulcerative lesions (enanthem) affecting the mouth. The illness is caused by a number of enteroviruses with coxsackievirus A16 and enterovirus 71 as the main causative agents. Human enterovirus 71 (EV71) belongs to the species Human enterovirus A under the genus Enterovirus within the family Picornaviridae. EV71 has been associa...     

丙种球蛋白联合注射用甲泼尼龙琥珀酸钠治疗重症手足口病患儿的临床研究

目的:探讨丙种球蛋白联合注射用甲泼尼龙琥珀酸钠治疗重症手足口病(HFMD)患儿的临床效果。方法:选择我院2013年1月至2014年1月收治的重症HFMD患儿80例,按随机数字表法平均分为两组,研究组及对照组各40例。对照组患者在常规治疗基础上给予甲泼尼龙琥珀酸钠治疗,研究组患者给予丙种球蛋白联合注射用甲泼尼龙琥珀酸钠治疗,比较两组患儿治疗疗效,发热、疱疹、神经系统受累症状消退时间及住院时间。结果:研究组患儿治疗总有效率为97.5%,明显高于对照组87.5%,比较差异具有统计学意义(x2=3.85,P0.05)。研究组患儿发热消退时间、疱疹消退时间、神经系统受累症状消退时间及住院时间均明显短于对照组,比较差异具有统计学意义(均P0.05)。结论:丙种球蛋白联合注射用甲泼尼龙琥珀酸钠治疗重症HFMD患儿疗效显著,可有效改善患儿临床症状,值得临床推广应用。     

Hand,Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

Background

Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.

Methods and Findings

Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R ₀, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.

Conclusions

The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.     

咸阳市2016-2019年手足口病病原学检测分析

本文通过对咸阳市2016-2019年手足口病(Hand,foot and mouth disease,HFMD)病原检测结果进行分析,阐明了咸阳市近四年HFMD病原谱的构成和流行特征,为HFMD防控工作提供依据.对2016-2019年收集的2711例HFMD病例标本进行荧光定量PCR检测确定肠道病毒型别,构建咸阳市HFMD病原谱并对阳性病例的流行特征进行描述性分析.2711例HFMD病例实验室确诊1444例(阳性率为53.26％),其中肠道病毒A组71型(Enterovirus 71,EV71)占病原谱构成的 12.74％、柯萨奇病毒 A组 16型(Coxsackievirus A16,CoxA16)占27.49％、柯萨奇病毒 A组 10型(Coxsackievirus A10,CoxA10)占5.19％、柯萨奇病毒 A 组6型(Coxsackievirus A6,CoxA6)占43.21％、其他肠道病毒(Enterovirus,EV)占11.36％.CoxA6和CoxA16交替居于咸阳市HFMD病原谱首位.咸阳市HFMD流行具有明显季节性和地区差异以及特定人群高发,夏季(5～7月)为发病主高峰,秋冬季(10～11月)为次高峰,主要集中在人口较多的市区,4岁以下散居儿童为易感人群,且男性发病率高于女性.今后的防控工作中应继续加强咸阳市HFMD监测,重视其他EV的监测工作,实时监测HFMD病原谱的变化.在高发季节,针对高发人群,采取积极有效干预措施,加强防控工作.     

Genotypes of the Enterovirus Causing Hand Foot and Mouth Disease in Shanghai,China, 2012-2013

Sporadic HFMD (hand foot and mouth disease, HFMD) cases and outbreaks caused by etiologic agents other than EV71 and CA16 have increased globally. We conducted this study to investigate the prevalence and genetic characteristics of enteroviruses, especially the non-EV71 and non-CA16 enteroviruses, causing HFMD in Shanghai. Clinical specimens were collected from patients with a diagnosis of HFMD. A partial length of VP1 was amplified with RT-PCR and subjected to direct sequencing. Phylogenetic analyses were performed using MEGA 5.0. The ages of the HFMD cases ranged from 3 to 96 months, and the male/female ratio was 1.41. The median hospital stay was 2.96 days. Up to 18.0% of patients had neurologic system complications such as encephalitis, meningoencephalitis or meningitis. Of the 480 samples, 417 were positive for enterovirus (86.9%) with RT-PCR. A total of 13 enterovirus genotypes were identified. The most frequent genotypes were CA6 (31.9%), EV71 (30.6%), CA16 (8.8%) and CA10 (7.5%). Infections with CA6, EV71, CA16 and CA10 were prevalent throughout the years of study, while the proportion of CA6 notably increased from Sep. 2012 to Dec. 2013. Phylogenetic analyses showed that EV71 strains belonged to the C4a subgenogroup and CA16 was identified as B1b subgenogroup. The CA6 strains were assigned to genogroup F, whereas the CA10 strains were assigned to genogroup D. Patients infected with CA6 were typically younger, had a shorter hospital stay and had a lower incidence of neurologic system complications when compared to patients infected with EV71. Our study demonstrates that the enterovirus genotypes causing HFMD were diversified, and there was an increasing prevalence of the non-EV71 and non-CA16 enteroviruses from 2012 to 2013. CA6 was the most predominant pathogen causing HFMD from Sep. 2012 to Dec. 2013, and it often caused relatively mild HFMD symptoms. Most severe HFMD cases were associated with EV71 infection.     

Time Series Analyses of Hand,Foot and Mouth Disease Integrating Weather Variables

Background

The past decade witnessed an increment in the incidence of hand foot mouth disease (HFMD) in the Pacific Asian region; specifically, in Guangzhou China. This emphasized the requirement of an early warning system designed to allow the medical community to better prepare for outbreaks and thus minimize the number of fatalities.

Methods

Samples from 1,556 inpatients (hospitalized) and 11,004 outpatients (non-admitted) diagnosed with HFMD were collected in this study from January 2009 to October 2013. Seasonal Autoregressive Integrated Moving Average (SARIMA) model was applied to establish high predictive model for inpatients and outpatient as well as three viral serotypes (EV71, Pan-EV and CA16). To integrate climate variables in the data analyses, data from eight climate variables were simultaneously obtained during this period. Significant climate variable identified by correlation analyses was executed to improve time series modeling as external repressors.

Results

Among inpatients with HFMD, 248 (15.9%) were affected by EV71, 137 (8.8%) were affected by Pan-EV+, and 436 (28.0%) were affected by CA16. Optimal Univariate SARIMA model was identified: (2,0,3)(1,0,0)₅₂ for inpatients, (0,1,0)(0,0,2)₅₂ for outpatients as well as three serotypes (EV71, (1,0,1)(0,0,1)₅₂; CA16, (1,0,1)(0,0,0)₅₂; Pan-EV, (1,0,1)(0,0,0)₅₂). Using climate as our independent variable, precipitation (PP) was first identified to be associated with inpatients (r = 0.211, P = 0.001), CA16-serotype (r = 0.171, P = 0.007) and outpatients (r = 0.214, P = 0.01) in partial correlation analyses, and was then shown a significant lag in cross-autocorrelation analyses. However, inclusion of PP [lag -3 week] as external repressor showed a moderate impact on the predictive performance of the SARIMA model described here-in.

Conclusion

Climate patterns and HFMD incidences have been shown to be strongly correlated. The SARIMA model developed here can be a helpful tool in developing an early warning system for HFMD.     

康复新液与甲泼尼龙治疗重症手足口病的临床疗效及对患儿免疫功能的影响*

目的:探讨康复新液与甲泼尼龙联合治疗重症手足口病疗效及对生化指标的影响。方法:选自2014年1月~2015年12月我院收治的重症手足口病患儿94例,随机分为观察组与对照组,每组47例。对照组采用甲泼尼龙治疗,观察组在对照组基础上结合康复新液治疗。观察并比较两组的治疗疗效、症状体征消退时间,心肌酶和免疫功能水平的变化情况,以及不良反应。结果:观察组总有效率(93.62%)高于对照组(72.34%)(P0.05);观察组体温恢复正常、口腔溃疡愈合时间、手足皮疹消退时间优于对照组(P0.05);两组肌磷酸激酶、乳酸脱氢酶水平治疗后明显降低(P0.05);观察组肌磷酸激酶、乳酸脱氢酶水平治疗后低于对照组(P0.05);两组免疫球蛋白A(Immunoglobulin A,IgA)、免疫球蛋白G(Immunoglobulin G,IgG)水平治疗后明显增加(P0.05),而免疫球蛋白M(Immunoglobulin M,IgM)水平治疗前后比较无统计学差异(P0.05);观察组IgA、IgG水平治疗后高于对照组(P0.05);两组均未见严重不良反应。结论:康复新液与甲泼尼龙联合治疗重症手足口病疗效显著,可降低患儿心肌酶指标,提高患儿免疫功能,且安全性良好。     

Serum Amyloid A and Clusterin as Potential Predictive Biomarkers for Severe Hand,Foot and Mouth Disease by 2D-DIGE Proteomics Analysis

Hand, foot, and mouth disease (HFMD) affects more than one million children, is responsible for several hundred child deaths every year in China and is the cause of widespread concerns in society. Only a small fraction of HFMD cases will develop further into severe HFMD with neurologic complications. A timely and accurate diagnosis of severe HFMD is essential for assessing the risk of progression and planning the appropriate treatment. Human serum can reflect the physiological or pathological states, which is expected to be an excellent source of disease-specific biomarkers. In the present study, a comparative serological proteome analysis between severe HFMD patients and healthy controls was performed via a two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy. Fifteen proteins were identified as differentially expressed in the sera of the severe HFMD patients compared with the controls. The identified proteins were classified into different groups according to their molecular functions, biological processes, protein classes and physiological pathways by bioinformatics analysis. The up-regulations of two identified proteins, serum amyloid A (SAA) and clusterin (CLU), were confirmed in the sera of the HFMD patients by ELISA assay. This study not only increases our background knowledge about and scientific insight into the mechanisms of HFMD, but also reveals novel potential biomarkers for the clinical diagnosis of severe HFMD.     

手足口病的流行病学特征及防治对策

手足口病是由多种肠道病毒引起的常见传染病,多发生于学龄前儿童。近年来我国许多地方不断报道有手足口病的暴发流行,且并发症发生率和病死率也有增高的趋势。2008年,我国将手足口病纳入《传染病防治法》丙类传染病管理。本文对手足口病的病原学及流行病学特征、临床症状及诊断、预防、治疗措施等进行了综述。