Hand, Foot, And Mouth Disease Surveillance Research Articles

Assessing the vaccine effectiveness for hand, foot, and mouth disease in Guangzhou, China: a time-series analysis

ABSTRACT Objective: Hand, foot, and mouth disease (HFMD) is an important public health issue in China. Although efficacy has been demonstrated by randomized controlled trials, the evidence for effectiveness of the monovalent Enterovirus 71 (EV71) vaccine against HFMD remains unknown. This study aimed to assess the vaccine effectiveness for HFMD in Guangzhou, China. Methods: Routinely collected vaccination and HFMD surveillance data were captured from the China Information System for Disease Control and Prevention. We estimated the EV71 vaccine effectiveness using spatial ecologic and time-series analysis approaches. Results: A total of 174,002 HFMD cases under 5 years of age were reported to the Guangzhou, China surveillance system from January 2016 to December 2018. A total of 408,664 children completed a two-dose EV71 vaccination series. In an ecologic analysis, a two-dose EV71 vaccination rate above the median conferred lower HFMD risk relative to a vaccination rate below the median (ratio ratio = 0.955, 95% confidence interval (CI): 0.949, 0.962; P < .001). In the time-series approach, 0.9% fewer HFMD cases were associated with a 1% increase in the two-dose EV71 vaccination rate, but without statistical significance (P = .094). However, we detected statistically significant protective associations for HFMD among children 3 years of age (0.9% fewer HFMD cases with a 1% increased vaccination rate; P = .046), and for EV71 (1.4%; P = .012) and “other viruses” (1.3%; P = .002), although not for Coxsackievirus A16 (CVA16). Conclusion: Our findings, based on real-world data, provide evidence of EV71 vaccine effectiveness for preventing EV71 and “other” viruses associated with HFMD. An expanded program of EV71 vaccination is urgently needed.

Epidemiological and aetiological characteristics of hand, foot, and mouth disease in Sichuan Province, China, 2011\u20132017

Hand, foot, and mouth disease (HFMD) remains a threat to the Asia-Pacific region. The epidemiological characteristics and pathogen spectrum of HFMD vary with space and time. These variations are crucial for HFMD interventions but poorly understood in Sichuan Province, China, particularly after the introduction of the EV-A71 vaccine. Using descriptive methods, regression analyses, spatial autocorrelation analysis, and space-time scan statistics, we analysed the epidemiological and aetiological characteristics of HFMD surveillance data in Sichuan Province between 2011 and 2017 to identify spatio-temporal variations. The dominant serotypes of HFMD have changed from enterovirus 71 and coxsackievirus A16 to other enteroviruses since 2013. The seasonal pattern of HFMD showed two peaks generally occurring from April to July and November to December; however, the seasonal pattern varied by prefecture and enterovirus serotype. From 2011 to 2017, spatio-temporal clusters were increasingly concentrated in Chengdu, with several small clusters in northeast Sichuan. The clusters observed in southern Sichuan from 2011 to 2015 disappeared in 2016–2017. These findings highlight the importance of pathogen surveillance and vaccination strategies for HFMD interventions; future prevention and control of HFMD should focus on Chengdu and its vicinity.

Isolation and molecular characterization of coxsackievirus A6 and coxsackievirus A16 from a case of recurrent Hand, Foot and Mouth Disease in Mumbai,Maharashtra, India, 2018.

Hand, Foot and Mouth Disease (HFMD) is caused by multiple Enterovirus (EV) serotypes mainly coxsackievirus A6 (CV-A6), coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71). Recurrent HFMD infections are rarely reported. An unusual rise in HFMD cases was reported in Mumbai during May-June 2018. Stool and throat swab specimens were referred from seven children from two hospitals for laboratory diagnosis. The age group of cases ranged from 9months to 5years with median age 13months. Out of seven cases, three were males and four females. One 13-month-old female case was reported twice within 21days. Stool, throat swab specimens were tested by pan enterovirus RT-PCR and also by virus isolation using human rhabdomyosarcoma cell line for detection of Enteroviruses. Out of seven HFMD cases, CV-A6 and CV-A16 viruses were isolated from five and two cases respectively. The phylogenetic analysis of CV-A6 viruses showed their similarity with CV-A6 viruses from Finland and China, whereas the two CV-A16 isolates showed similarity with those from Japan, France, China, Sarawak and Thailand. For the recurrent HFMD case, CV-A6 and CV-A16 were isolated from the stool specimens collected during the first and second episodes, respectively. There are no reports of isolation and molecular characterization of CV-A6 and CV-A16 viruses from recurrent HFMD cases. The present study reports molecular characterization of two Enterovirus serotypes CV-A6 and CV-A16 from a recurrent HFMD case, highlighting need of virological and molecular surveillance of HFMD.

Meteorological factors associated with hand, foot and mouth disease in a Central Highlands province in Viet Nam: an ecological study.

BackgroundHand, foot and mouth disease (HFMD) is a public health problem in Viet Nam, and studies have reported seasonal fluctuation in the occurrence of HFMD. This study sought to describe the occurrence of HFMD and its associated meteorological factors in Dak Lak province, Viet Nam.MethodsMonthly data on HFMD cases were collected from all commune health stations in Dak Lak province from 2012 through 2013. An HFMD case was defined as a brief febrile illness accompanied by a typical skin rash with or without mouth ulcers. Average temperature, maximum temperature, minimum temperature, humidity, rainfall, evaporation, sunshine duration and wind speed were recorded monthly at five local meteorological stations throughout Dak Lak.Data were aggregated at the district level, and the association between these meteorological factors and HFMD cases were examined by Poisson regression.ResultsIn 2012 through 2013, there were 7128 HFMD patients in Dak Lak. The number of HFMD cases increased during the rainy season. An increased risk of HFMD was associated with higher average temperature (risk ratio and 95% confidence interval: 1.06; 1.03–1.08 per 1 °C increase), higher rainfall (1.19; 1.14–1.24 per 200 mm increase) and longer sunshine duration (1.14; 1.07–1.22 per 60 hours increase). The risk of HFMD was inversely associated with wind speed (0.77; 0.73–0.81 per 1 m/s increase).ConclusionThis study suggests that there is a significant association between HFMD occurrence and climate. Temperature, rainfall, wind speed and sunshine duration could be used as meteorological predictors of HFMD occurrence in Viet Nam’s Central Highlands region. Intensified surveillance for HFMD during the rainy season is recommended.

Correlation analysis on meteorological factors regarding the incidence of hand, foot and mouth disease in Xinjiang Uygur Autonomous Region, 2011-2018

Objective: To study the correlation between meteorological factors and the incidence of hand, foot and mouth disease (HFMD) in Xinjiang Uygur Autonomous Region (Xinjiang) so as to provide scientific evidence for the early warning, prediction, prevention and control of HFMD. Methods: Data on HFMD surveillance and related population was collected from the China Information System for Disease Control and Prevention from 2011 to 2018. Meteorological data was obtained from http://www.tianqihoubao.com. Correlation analysis on meteorological factors and the incidence of HFMD in Xinjiang was conducted, using the Excel 2007, SPSS 17.0, and Spatial Distribution Map by ArcGIS 10.2 software. Results: HFMD usually occurred between April and July. Numbers of patients reached the top in May and June. Temperature was positively correlated with the incidence of HFMD (r=0.370, P<0.01) while precipitation was positively correlated with the incidence of HFMD (r=0.747, P<0.01). The temperature threshold appeared as 5 ℃-35 ℃ for the incidence of HFMD. Interval period was one month between the peak of both the incidence of HFMD and the precipitation. A power function relationship (y=0.009 4x(2.332 9), R(2)=0.898 9) was noticed between the precipitation and the incidence of HFMD. Conclusions: The incidence of HFMD was closely related to the meteorological factors including temperature and precipitation in Xinjiang during 2011-2018. Our findings have provided evidence for the development of early warning system on HFMD in Xinjiang.

Clinical and Molecular Investigations of Hand, Foot and Mouth Disease Outbreak in Navi Mumbai, India

An outbreak of Hand, Foot and Mouth Disease (HFMD) was reported in Navi Mumbai in July-October 2018. Of 15 HFMD cases, two had recurrences within a month while three had lesions extending to trunk. Coxsackie virus A6 and A16 were detected from 13 cases (CV-A6 from 10 cases and CV-A16 from 3 cases) indicating co-circulation of these viruses. The present study highlights an urgent need of HFMD surveillance.

Effectiveness of the inactivated enterovirus 71 vaccine in children aged 6–35 months: protocol for a multicentre, case-control phase IV clinical trial

Background: Inactivated enterovirus 71 (EV-A71) vaccines have already be introduced for routine childhood immunization in mainland China since 2016. However, it is not well known that the effectiveness of EV-A71 vaccine under ‘real world’ conditions. We aimed to assess the effectiveness and safety of EV-A71 vaccine against EV-A71 associated hand foot and mouth disease (HFMD) in children aged 6–35 months. Methods: This is a multicentre, phase IV, case-control study of the inactivated EV-A71 vaccine. Through the hospital-based active surveillance of HFMD, a case-control study design with two groups of controls (test-negative control and community control) will be used to estimate vaccine effectiveness of EV-A71 vaccine. We will recruit cases defined as patients aged 6–47 months admitted to presenting hospitals for laboratory-confirmed HFMD induced by EV-A71. For each case, hospital test-negative control and community control are selected. Vaccination status will be determined from electronic immunization records (EIRs) and parent-reported vaccination cards. Logistic regression analysis will be carried out to calculate vaccine effectiveness (one minus the odds ratio of vaccination) by comparing patients with HFMD cases who tested positive for EV-A71 with those who tested negative and with community controls. Discussion: This is the first evaluation of the performance of EV-A71 vaccines in the context of real-world immunization programs using case-control methodology with community controls and test-negative controls. The findings of this study will provide valid and reliable knowledge on the performance of EV-A71 vaccines in the real-world context. Trial registration: ClinicalTrial.gov Identifier: NCT03582761.

Multiple genotypes of Echovirus 11 circulated in mainland China between 1994 and 2017

Echovirus 11 (E-11) is one of the most frequently isolated enteroviruses causing meningitis and other diseases such as hand, foot, and mouth disease (HFMD) and acute flaccid paralysis (AFP). Fifty-nine newly determined E-11 VP1 sequences from the China AFP and HFMD surveillance network and 500 E-11 VP1 sequences obtained from the GenBank database, which were associated with 12 categories of diseases, were screened for phylogenetic analysis. Based on the standard method of genotype classification, E-11 strains circulated worldwide were reclassified into six genotypes as A, B, C, D, E, and F, in which genotype F is newly divided, and genotypes A and C are further divided into A1–5 and C1–4 by this research, whereas genotype D was still divided into D1–5 as in a previous study of Oberste et al. Sub-genotype A1 was the predominant sub-genotype in mainland China between 2008–2017, whereas sub-genotype D5 was the predominant sub-genotype circulated outside China from 1998–2014. However, genotype and sub-genotype spectra showed statistical significance among AFP and HFMD cases (χ2 = 60.86, P < 0.001), suggesting that different genotypes might have a tendency to cause different diseases. Strengthening the surveillance of E-11 might provide further information about pathogenic evolution or specific nucleotide mutation associated with different clinical diseases.

Cost-effectiveness of bivalent versus monovalent vaccines against hand, foot and mouth disease

ObjectivesEnterovirus 71 (EV71) and coxsackievirus A16 (CA16) were responsible for 43.3% (235 123/543 243) and 24.8% (134 607/543 243) of all laboratory-confirmed hand, foot and mouth disease (HFMD) cases during 2010–2015 in China. Three monovalent EV71 vaccines have been licensed in China while bivalent EV71/CA16 vaccines are under development. A comparative cost-effectiveness analysis of bivalent EV71/CA16 versus monovalent EV71 vaccination would be useful for informing the additional value of bivalent HFMD vaccines in China. MethodsWe used a static model parameterized with the national HFMD surveillance data during 2010–2013, virological HFMD surveillance records from all 31 provinces in mainland China during 2010–2013 and caregiver survey data of costs and health quality of life during 2012–2013. We estimated the threshold vaccine cost (TVC), defined as the maximum additional cost that could be paid for a cost-effective bivalent EV71/CA16 vaccine over a monovalent EV71 vaccine, as the outcome. The base case analysis was performed from a societal perspective. Several sensitivity analyses were conducted by varying assumptions governing HFMD risk, costs, discounting and vaccine efficacy. ResultsIn the base case, choosing the bivalent EV71/CA16 over monovalent EV71 vaccination would be cost-effective only if the additional cost of the bivalent EV71/CA16 compared with the monovalent EV71 vaccine is less than €4.7 (95% CI 4.2–5.2). Compared with the TVC in the base case, TVC increased by up to €8.9 if all the test-negative cases were CA16-HFMD; decreased by €1.1 with an annual discount rate of 6% and exclusion of the productivity loss; and increased by €0.14 and €0.3 with every 1% increase in bivalent vaccine efficacy against CA16-HFMD and differential vaccine efficacy against EV71-HFMD, respectively. ConclusionsBivalent EV71/CA16 vaccines can be cost-effective compared with monovalent EV71 vaccines, if suitably priced. Our study provides further evidence for determining the optimal use of HFMD vaccines in routine paediatric vaccination programme in China.

Spatiotemporal Distribution of Hand, Foot, and Mouth Disease in Guangdong Province, China and Potential Predictors, 2009⁻2012.

Background: Hand, foot, and mouth disease (HFMD) is a common infectious disease among children. Guangdong Province is one of the most severely affected provinces in south China. This study aims to identify the spatiotemporal distribution characteristics and potential predictors of HFMD in Guangdong Province and provide a theoretical basis for the disease control and prevention. Methods: Case-based HFMD surveillance data from 2009 to 2012 was obtained from the China Center for Disease Control and Prevention (China CDC). The Bayesian spatiotemporal model was used to evaluate the spatiotemporal variations of HFMD and identify the potential association with meteorological and socioeconomic factors. Results: Spatially, areas with higher relative risk (RR) of HFMD tended to be clustered around the Pearl River Delta region (the mid-east of the province). Temporally, we observed that the risk of HFMD peaked from April to July and October to December each year and detected an upward trend between 2009 and 2012. There was positive nonlinear enhancement between spatial and temporal effects, and the distribution of relative risk in space was not fixed, which had an irregular fluctuating trend in each month. The risk of HFMD was significantly associated with monthly average relative humidity (RR: 1.015, 95% CI: 1.006–1.024), monthly average temperature (RR: 1.045, 95% CI: 1.021–1.069), and monthly average rainfall (RR: 1.004, 95% CI: 1.001–1.008), but not significantly associated with average GDP. Conclusions: The risk of HFMD in Guangdong showed significant spatiotemporal heterogeneity. There was spatiotemporal interaction in the relative risk of HFMD. Adding a spatiotemporal interaction term could well explain the change of spatial effect with time, thus increasing the goodness of fit of the model. Meteorological factors, such as monthly average relative humidity, monthly average temperature, and monthly average rainfall, might be the driving factors of HFMD.

Surveillance, epidemiology, and pathogen spectrum of hand, foot, and mouth disease in mainland of China from 2008 to 2017

Hand, foot and mouth disease (HFMD) was reported in May 2, 2008 to be the 38th legally notifiable disease in China's National Notifiable Disease Reporting and Surveillance System. In order to solve the infection, an extensive three-level HFMD surveillance laboratory network was established. In this study, the framework of that network is assessed and the incidence of HFMD in China from 2008 to 2017 is reported using a descriptive epidemiologic method. During these 10 years, a series of techniques have been widely applied in all the network laboratories. Using information and material obtained from the network, a virus bank and database containing 18,238 viruses were established. Nationally, 18,184,834 HFMD cases, including 152,436 severe cases and 3633 fatal cases, were reported in mainland of China. The average annual incidence in the population was 133.99/100,000 people, with a maximum incidence of 205.06/100,000 people in 2014. The incidence and mortality rates of HFMD were the highest in children aged 1–2 years. The numbers of reported cases fluctuated, with a high incidence observed every 2 years. An overall increase in the number of reported cases was also observed throughout the study period. Despite this, the incidence of severe cases and the mortality rate have been decreasing. High-risk regions are located in southern, eastern, and central China. Two peaks of HFMD infection cases were observed annually except for Northeast China. Different proportions of enterovirus serotypes were observed during the studied years. The predominant enterovirus varies from year to year, but the disease severity is always closely related to the specific serotype. EV-A71 is the dominant serotype associated with severe and fatal cases, with constituent ratios of 70.03% and 92.23%, respectively. The studied highly sensitive and efficient surveillance network provides information that is critical for prevention and control of the disease. It is extremely necessary and important to continuously conduct extensive virological surveillance for HFMD.

Ongoing change of severe hand, foot, and mouth disease pathogens in Yunnan, China, 2012 to 2016.

Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enteroviruses (EVs). In this study, a total of 341 children with serious HFMD were admitted to a pediatric hospital in Yunnan, China in 2012 to 2016. EVs were detected in 283 specimens (83.0%) and were assigned to 17 EV types. Enterovirus A71 (EV-A71) was predominant, accounting for 41.6%, and was followed by coxsackievirus A16 (CV-A16; 18.8%), CV-A6 (9.1%), CV-A10 and E-9 (2.9%), CV-B5 (1.8%), CV-A9 (1.2%), E-30 (0.9%), E-18, CV-A4, C-B3, and CV-A2 (0.6%) and other EV types such as CV-A8, CV-A14, E-14, E-11, and CV-B4 (0.3%). All of the EV-A71 isolates belonged to C4a; the CV-A16 belonged to B1b or B1a, although the B1b strains were predominant; and CV-A6 belonged to D3. In 2012 to 2014, E-9 was the third most frequent serotype (8.2%, 5.0%, and 6.5%, respectively). E-9 was not detected in 2015 and 2016. CV-A6 was not detected in 2012 but was the second most frequent serotype (25.3%) in 2015. Active etiological surveillance of HFMD makes it necessary to be aware of these emerging pathogens.

Relative transmissibility of hand, foot and mouth disease from male to female individuals.

Hand, foot and mouth disease (HFMD) has spread widely and leads to high disease burden in many countries. However, relative transmissibility from male to female individuals remains unclear. HFMD surveillance database was built in Shenzhen City from 2013 to 2017. An intersex transmission susceptible-infectious-recovered model was developed to calculate the transmission relative rate among male individuals, among female individuals, from male to female and from female to male. Two indicators, ratio of transmission relative rate (Rβ) and relative transmissibility index (RTI), were developed to assess the relative transmissibility of male vs. female. During the study period, 270 347 HFMD cases were reported in the city, among which 16 were death cases with a fatality of 0.0059%. Reported incidence of total cases, male cases and female cases was 0.0057 (range: 0.0036-0.0058), 0.0052 (range: 0.0032-0.0053) and 0.0044 (range: 0.0026-0.0047), respectively. The difference was statistically significant between male and female (t = 3.046, P = 0.002). Rβ of male vs. female, female vs. female, from female to male vs. female and from male to female vs. female was 7.69, 1.00, 1.74 and 7.13, respectively. RTI of male vs. female, female vs. female, from female to male vs. female and from male to female vs. female was 3.08, 1.00, 1.88 and 1.43, respectively. Transmissibility of HFMD is different between male and female individuals. Male cases seem to be more transmissible than female.

The emerging sub-genotype C2 of CoxsackievirusA10 Associated with Hand, Foot and Mouth Disease extensively circulating in mainland of China

Coxsackievirus A10 (CV-A10) associated with Hand, foot, and mouth disease (HFMD) cases emerged increasingly in recent years. In this study, the samples from nation-wide HFMD surveillance, including 27 out of 31 provinces in China were investigated, and the continuous and extensive virological surveillance, covered 13 years, were conducted to provide a comprehensive molecular characterization analysis of CV-A10. 855 CV-A10 viruses (33 severe cases included), were isolated from HFMD children patients during 2009 to 2016 in China. 164 representative sequences from these viruses, together with 117 CV-A10 sequences downloaded from GenBank based on entire VP1 were recruited in this study. Two new genotypes (F and G) and two sub-genotypes (C1 and C2) were identified. Among 264 Chinese sequences, 9 of them were genotype B, 8 of them were C1, and the other (247) were C2, the predominant sub-genotype in China since 2012. Chinese C2 viruses showed obvious temporal characteristics and can be divided into 3 clusters (cluster 1~3). Cluster 3 viruses was circulating extensively during 2014 and 2016 with more severe cases. It is very necessary and important to continuously conduct the extensive virological surveillance for CV-A10, and further evolutionary studies will provide more evidence on its evolution and virulence.

Epidemiological Characteristics and Spatial-Temporal Distribution of Hand, Foot, and Mouth Disease in Chongqing, China, 2009-2016.

(1) Objective: Even with licensed vaccine for enterovirus 71 (EV71) put into market in 2016 in China, hand, foot, and mouth disease (HFMD) is still a threat for children’s health in Chongqing. We described the epidemiological characteristics and spatial–temporal patterns of HFMD in Chongqing from 2009 to 2016, in order to provide information and evidence for guiding public health response and intervention. (2) Methods: We retrieved the HFMD surveillance data from January 2009 to December 2016 from “National Disease Reporting Information System”, and then analyzed demographic and geographical information integrally. Descriptive analysis was conducted to evaluate the epidemic features of HFMD in Chongqing. The spatial–temporal methods were performed to explore the clusters at district/county level. (3) Results: A total of 276,207 HFMD cases were reported during the study period (total population incidence: 114.8 per 100,000 per year), including 641 severe cases (129 deaths). The annual incidence of HFMD sharply increased in even-numbered years, but remained stable or decreased in odd-numbered years. A semiannual seasonality was observed during April to July, and October to December in each year. The male-to-female ratios of the mild and severe cases were 1.4:1 and 1.5:1, with the median age of 2.3 years and 1.9 years, respectively. More than 90% of the cases were children equal to and less than 5 years old. High-incidence clustered regions included the main urban districts and northeast regions according to incidence rates comparison or space–time cluster analysis. A total of 19,482 specimen were collected from the reported cases and 13,277 (68.2%) were positive for enterovirus. EV71 was the major causative agent for severe cases, while other enteroviruses were the predominant serotype for mild cases. (4) Conclusions: The characteristics of HFMD in Chongqing exhibited a phenomenon of increasing incidence in two-year cycles and semiannual seasonality in time distribution. Children ≤5 years old, especially boys, were more affected by HFMD. EV71 was the major causative agent for severe cases. We suggest initiating mass EV71 vaccination campaigns among children aged 6 months to 5 years in Chongqing, especially in the main urban districts and northern regions, in order to reduce case fatality, and take integrated measurements for controlling and preventing HFMD attributed to other enteroviruses.

Hand-Foot-and-Mouth Disease, Aseptic Meningitis, and Encephalitis Caused by Enterovirus

Enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and CV-A6 are the major causative agents of Hand-foot-and-mouth disease (HFMD). These viruses belong to the species Enterovirus A of the genus Enterovirus of the family Picornaviridae. These viruses can also cause aseptic meningitis (AM), encephalitis and/or paralysis. EV-A71 is one of the main infectious agents related to severe encephalitis. Between 1997 and 2013, East and Southeast Asia experienced large encephalitis outbreaks caused by EV-A71 infections, which ranged from severe to lethal. In Japan, national surveillance for HFMD has been conducted since 1982 by monitoring both the notifications of HFMD patients and the causative agents. Even though EV-A71 and CV-A16 are the two major causative agents of HFMD, CV-A6 has been reported to cause atypical HFMD in Japan, since 2011. Both CV-A6 and CV-A16 also cause encephalitis: however, the reported numbers of encephalitis caused by CV-A6 and CV-A16 have been far fewer than those caused by EV-A71. Vaccines against EV-A71 have become available in some Asian countries, such as in China, but as of 2017 they remain unavailable in Japan, likely due to the sparsity of fatal cases. This article summarizes the complications of HFMD on the central nervous system, as well as its epidemiology, clinical manifestations, and treatment. Moreover, the article reviews the history of HFMD and discusses the experimental results of research aimed at the prevention, grading, sample collection, diagnosis, and treatment of severe EV-A71 infections.

Epidemiological and genetic characteristics of EV71 in hand, foot, and mouth disease in Guangxi, southern China, from 2010 to 2015.

Hand, foot, and mouth disease (HFMD) is a significant public health challenge in China. Human enterovirus 71 (EV71) is regarded as the predominant causative pathogen of HFMD. Since 2015, two inactivated EV71 vaccines have been approved in mainland China, and because their use could change the HFMD pathogen spectrum, this should now be monitored. However, the epidemiological and genetic trends of EV71 with respect to HFMD in Guangxi, southern China, are still not clear. In this study, we describe the epidemiological and genetic characterization of this virus in clinically-diagnosed HFMD reported from 2010 to 2015 in Guangxi. Data showed that a two-year epidemic cycle, with a predominance of EV71 infections, contributed to HFMD outbreaks in Guangxi. Furthermore, this virus is a major causative agent of severe and fatal HFMD. Interestingly, in Guangxi, EV71-positive rates tended to decrease over time. In particular, EV71-positive rates were found in Fangchenggang city, which reported very few severe and fatal cases over the six-year period. Phylogenetic analysis of the VP1 gene revealed that the major circulating strains belonged exclusively to genotype C, subtype 4a (C4a), and most clustered with strains circulating in southern China. The most interesting finding was that a strain isolated in 2012 clustered with Vietnamese strains isolated from 2011–2012. The data highlight the importance of pathogen surveillance for HFMD in China, especially Guangxi, which is located on the border of China and the Association of Southeast Asian Nations.

Predicting the outbreak of hand, foot, and mouth disease in Nanjing, China: a time-series model based on weather variability.

Hand, foot, and mouth disease (HFMD) is a significant public health issue in China and an accurate prediction of epidemic can improve the effectiveness of HFMD control. This study aims to develop a weather-based forecasting model for HFMD using the information on climatic variables and HFMD surveillance in Nanjing, China. Daily data on HFMD cases and meteorological variables between 2010 and 2015 were acquired from the Nanjing Center for Disease Control and Prevention, and China Meteorological Data Sharing Service System, respectively. A multivariate seasonal autoregressive integrated moving average (SARIMA) model was developed and validated by dividing HFMD infection data into two datasets: the data from 2010 to 2013 were used to construct a model and those from 2014 to 2015 were used to validate it. Moreover, we used weekly prediction for the data between 1 January 2014 and 31 December 2015 and leave-1-week-out prediction was used to validate the performance of model prediction. SARIMA (2,0,0)52 associated with the average temperature at lag of 1week appeared to be the best model (R 2=0.936, BIC=8.465), which also showed non-significant autocorrelations in the residuals of the model. In the validation of the constructed model, the predicted values matched the observed values reasonably well between 2014 and 2015. There was a high agreement rate between the predicted values and the observed values (sensitivity 80%, specificity 96.63%). This study suggests that the SARIMA model with average temperature could be used as an important tool for early detection and prediction of HFMD outbreaks in Nanjing, China.

Phylogeography of Coxsackievirus A16 Reveals Global Transmission Pathways and Recent Emergence and Spread of a Recombinant Genogroup.

Coxsackievirus A16 (CV-A16; Picornaviridae) is an enterovirus (EV) type associated with hand, foot, and mouth disease (HFMD) in children. To investigate the spatial spread of CV-A16, we used viral sequence data sampled during a prospective sentinel surveillance of HFMD in France (2010 to 2014) and phylogenetic reconstruction. A data set of 168 VP1 sequences was assembled with 416 publicly available sequences of various geographic origins. The CV-A16 sequences reported were assigned to two clades, genogroup B and a previously uncharacterized clade D. The time origins of clades B and D were assessed in 1978 (1973 to 1981) and 2004 (2001 to 2007), respectively. The shape of the global CV-A16 phylogeny indicated worldwide cocirculation of genetically distinct virus lineages over time and across geographic regions. Phylogenetic tree topologies and Bayes factor analysis indicated virus migration. Virus transportation events in clade B within Europe and Asia and between countries of the two geographic regions were assessed. The sustained transmission of clade D viruses over 4 years was analyzed at the township level in France and traced back to Peru in South America. Comparative genomics provided evidence of recombination between CV-A16 clades B and D and suggested an intertype recombinant origin for clade D. Time-resolved phylogenies and HFMD surveillance data indicated that CV-A16 persistence is sustained by continuing virus migration at different geographic scales, from community transmission to virus transportation between distant countries. The results showed a significant impact of virus movements on the epidemiological dynamics of HFMD that could have implications for disease prevention.IMPORTANCE Coxsackievirus A16 is one of the most prevalent enterovirus types in hand, foot, and mouth disease outbreaks reported in Southeast Asia. This study is based on epidemiological and viral data on HFMD caused by CV-A16 in a European country. The phylogeographic data complemented the syndromic surveillance with virus migration patterns between geographic regions in France. The results show how viral evolutionary dynamics and global virus spread interact to shape the worldwide pattern of an EV disease. CV-A16 transmission is driven by movements of infected individuals at different geographic levels: within a country (local dynamics), between neighboring countries (regional dynamics), and between distant countries (transcontinental dynamics). The results are consistent with our earlier data on EV-A71 and confirm the epidemiological interconnection of Asia and Europe with regard to EV infections.

Association between meteorological factors and reported cases of hand, foot, and mouth disease from 2000 to 2015 in Japan.

The purpose of this study was to clarify the association between hand, foot, and mouth disease (HFMD) epidemics and meteorological conditions. We used HFMD surveillance data of all 47 prefectures in Japan from January 2000 to December 2015. Spectral analysis was performed using the maximum entropy method (MEM) for temperature-, relative humidity-, and total rainfall-dependent incidence data. Using MEM-estimated periods, long-term oscillatory trends were calculated using the least squares fitting (LSF) method. The temperature and relative humidity thresholds of HFMD data were estimated from the LSF curves. The average temperature data indicated a lower threshold at 12 °C and a higher threshold at 30 °C for risk of HFMD infection. Maximum and minimum temperature data indicated a lower threshold at 6 °C and a higher threshold at 35 °C, suggesting a need for HFMD control measures at temperatures between 6 and 35 °C. Based on our findings, we recommend the use of maximum and minimum temperatures rather than the average temperature, to estimate the temperature threshold of HFMD infections. The results obtained might aid in the prediction of epidemics and preparation for the effect of climatic changes on HFMD epidemiology.