Mouse Scarb2 Modulates EV-A71 Pathogenicity in Neonatal Mice.

Enterovirus A71 (EV-A71) is a human pathogen that causes hand, foot, and mouth disease, which can progress to severe neurological disease. EV-A71 infects humans via the human scavenger receptor B2 (hSCARB2). It can also infect neonatal mice experimentally. Wild-type (WT) EV-A71 strains replicate primarily in the muscle of neonatal mice; however, susceptibility lasts only for a week after birth. Mouse-adapted (MA) strains, which can be obtained by serial passages in neonatal mice, are capable of infecting both muscle and neurons of the central nervous system. It is not clear how the host range and tropism of EV-A71 are regulated and why neonatal mice lose their susceptibility during development. We hypothesized that EV-A71 infection in neonatal mice is mediated by mouse Scarb2 (mScarb2) protein. Rhabdomyosarcoma (RD) cells expressing mScarb2 were prepared. Both WT and MA strains infected mScarb2-expressing cells, but the infection efficiency of the WT strain was much lower than that of the MA strain. Infection by WT and MA strains in vivo was abolished completely in Scarb2-/- mice. Scarb2+/- mice, in which Scarb2 expression was approximately half of that in Scarb2+/+ mice, showed a milder pathology than Scarb2+/+ mice after infection with the WT strain. The Scarb2 expression level in muscle decreased with aging, which was consistent with the reduced susceptibility of aged mice to infection. These results indicated that EV-A71 infection is mediated by mScarb2 and that the severity of the disease, the spread of virus, and the susceptibility period are modulated by mScarb2 expression. IMPORTANCE EV-A71 infects humans naturally but can also infect neonatal mice. The tissue tropism and severity of EV-A71 disease are determined by several factors, among which the virus receptor is thought to be important. We show that EV-A71 can infect neonatal mice using mScarb2. However, the infection efficiency of WT strains via mScarb2 is so low that an elevated virus-receptor interaction associated with mouse adaptation mutation and decrease in mScarb2 expression level during development modulate the severity of the disease, the spread of virus, and the susceptibility period in the artificial neonatal mice model.

Early warning of hand, foot, and mouth disease transmission: A modeling study in mainland, China.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a global infectious disease; particularly, it has a high disease burden in China. This study was aimed to explore the temporal and spatial distribution of the disease by analyzing its epidemiological characteristics, and to calculate the early warning signals of HFMD by using a logistic differential equation (LDE) model. METHODS: This study included datasets of HFMD cases reported in seven regions in Mainland China. The early warning time (week) was calculated using the LDE model with the key parameters estimated by fitting with the data. Two key time points, "epidemic acceleration week (EAW)" and "recommended warning week (RWW)", were calculated to show the early warning time. RESULTS: The mean annual incidence of HFMD cases per 100,000 per year was 218, 360, 223, 124, and 359 in Hunan Province, Shenzhen City, Xiamen City, Chuxiong Prefecture, Yunxiao County across the southern regions, respectively and 60 and 34 in Jilin Province and Longde County across the northern regions, respectively. The LDE model fitted well with the reported data (R2 > 0.65, P < 0.001). Distinct temporal patterns were found across geographical regions: two early warning signals emerged in spring and autumn every year across southern regions while one early warning signals in summer every year across northern regions. CONCLUSIONS: The disease burden of HFMD in China is still high, with more cases occurring in the southern regions. The early warning of HFMD across the seven regions is heterogeneous. In the northern regions, it has a high incidence during summer and peaks in June every year; in the southern regions, it has two waves every year with the first wave during spring spreading faster than the second wave during autumn. Our findings can help predict and prepare for active periods of HFMD.

Hand, Foot, and Mouth Disease in Thailand: A Comprehensive Modelling of Epidemic Dynamics.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease with several outbreaks in Asian-Pacific countries, including Thailand. With such epidemic characteristics and potential economic impact, HFMD is a significant public health issue in Thailand. Generally, contagious/infectious diseases' transmission dynamics vary across geolocations due to different socioeconomic situations, demography, and lifestyles. Hence, a nationwide comprehensive model of the disease's epidemic dynamics can provide information to understand better and predict a potential outbreak of this disease and efficiently and effectively manage its impact. However, there is no nationwide and comprehensive (i.e., the inclusion of reinfections in the model) model of HFDM dynamics for Thailand. This paper has endeavoured to promote nationwide comprehensive modelling of HFMD's epidemic dynamics and comprehend the reinfection cases. We have formulated the SEIRS epidemiological model with dynamic vitals, including reinfections, to explore this disease's prevalence. We also introduced periodic seasonality to reproduce the seasonal effect. The pattern of spread of this disease is uneven across the provinces in Thailand, so we used K-means clustering algorithm to cluster those provinces into three groups (i.e., highly, moderately, and least affected levels). We also analysed health records collected from district hospitals, which suggest significant reinfection cases. For example, we found that 11% (approximately) of infectious patients return for repeat treatment within the study period. We also performed sensitivity analysis which indicates that the basic reproduction number (R 0) is sensitive to the rate of transmission (ß) and the rate at which infected people recover (γ). By fitting the model with HFMD confirmed data for the provinces in each cluster, the basic reproduction number (R 0) was estimated to be 2.643, 1.91, and 3.246 which are greater than 1. Based on this high R 0, this study recommends that this disease will persist in the coming years under identical cultural and environmental conditions.

Identifying pre-outbreak signals of hand, foot and mouth disease based on landscape dynamic network marker.

BACKGROUND: The high incidence, seasonal pattern and frequent outbreaks of hand, foot and mouth disease (HFMD) represent a threat for billions of children around the world. Detecting pre-outbreak signals of HFMD facilitates the timely implementation of appropriate control measures. However, real-time prediction of HFMD outbreaks is usually challenging because of its complexity intertwining both biological systems and social systems. RESULTS: By mining the dynamical information from city networks and horizontal high-dimensional data, we developed the landscape dynamic network marker (L-DNM) method to detect pre-outbreak signals prior to the catastrophic transition into HFMD outbreaks. In addition, we set up multi-level early warnings to achieve the purpose of distinguishing the outbreak scale. Specifically, we collected the historical information of clinic visits caused by HFMD infection between years 2009 and 2018 respectively from public records of Tokyo, Hokkaido, and Osaka, Japan. When applied to the city networks we modelled, our method successfully identified pre-outbreak signals in an average 5 weeks ahead of the HFMD outbreak. Moreover, from the performance comparisons with other methods, it is seen that the L-DNM based system performs better when given only the records of clinic visits. CONCLUSIONS: The study on the dynamical changes of clinic visits in local district networks reveals the dynamic or landscapes of HFMD spread at the network level. Moreover, the results of this study can be used as quantitative references for disease control during the HFMD outbreak seasons.

Integration of a Kalman filter in the geographically weighted regression for modeling the transmission of hand, foot and mouth disease.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a common infectious disease whose mechanism of transmission continues to remain a puzzle for researchers. The measurement and prediction of the HFMD incidence can be combined to improve the estimation accuracy, and provide a novel perspective to explore the spatiotemporal patterns and determinant factors of an HFMD epidemic. METHODS: In this study, we collected weekly HFMD incidence reports for a total of 138 districts in Shandong province, China, from May 2008 to March 2009. A Kalman filter was integrated with geographically weighted regression (GWR) to estimate the HFMD incidence. Spatiotemporal variation characteristics were explored and potential risk regions were identified, along with quantitatively evaluating the influence of meteorological and socioeconomic factors on the HFMD incidence. RESULTS: The results showed that the average error covariance of the estimated HFMD incidence by district was reduced from 0.3841 to 0.1846 compared to the measured incidence, indicating an overall improvement of over 50% in error reduction. Furthermore, three specific categories of potential risk regions of HFMD epidemics in Shandong were identified by the filter processing, with manifest filtering oscillations in the initial, local and long-term periods, respectively. Amongst meteorological and socioeconomic factors, the temperature and number of hospital beds per capita, respectively, were recognized as the dominant determinants that influence HFMD incidence variation. CONCLUSIONS: The estimation accuracy of the HFMD incidence can be significantly improved by integrating a Kalman filter with GWR and the integration is effective for exploring spatiotemporal patterns and determinants of an HFMD epidemic. Our findings could help establish more accurate HFMD prevention and control strategies in Shandong. The present study demonstrates a novel approach to exploring spatiotemporal patterns and determinant factors of HFMD epidemics, and it can be easily extended to other regions and other infectious diseases similar to HFMD.

Transmission center and driving factors of hand, foot, and mouth disease in China: A combined analysis.

Hand, foot, and mouth disease (HFMD) has become a major public health issue in China. The disease incidence varies substantially over time and across space. To understand the heterogeneity of HFMD transmission, we compare the spatiotemporal dynamics of HFMD in Qinghai and Shanghai by conducting combined analysis of epidemiological, wavelet time series, and mathematical methods to county-level data from 2009 to 2016. We observe hierarchical epidemic waves in Qinghai, emanating from Huangzhong and in Shanghai from Fengxian. Besides population, we also find that the traveling waves are significantly associated with socio-economic and geographical factors. The population mobility also varies between the two regions: long-distance movement in Qinghai and between-neighbor commuting in Shanghai. Our findings provide important evidence for characterizing the heterogeneity of HFMD transmission and for the design and implementation of interventions, such as deploying optimal vaccine and changing local driving factors in the transmission center, to prevent or limit disease spread in these areas.

Interaction analysis on transmissibility of main pathogens of hand, foot, and mouth disease: A modeling study (a STROBE-compliant article).

Hand, foot, and mouth disease (HFMD) has spread widely and led to high disease burden in many countries. In this study, we aimed to analyze the interaction of the main pathogens of HFMD using a mathematical model.A dataset on reported HFMD cases was collected from April, 2009 to December, 2017 in Changsha City. A long-term etiological surveillance was conducted focusing on the pathogens of the disease including enterovirus A71 (EV71), coxsachievirus A16 (CA16), and other enteroviruses. A susceptible-infectious-recovered model was adopted to calculate the reproduction number during the ascending period of reported cases (defined as Rasc) and the descending period (defined as Rdes).About 214,178 HFMD cases (including clinically diagnosed cases and confirmed cases) were reported in Changsha City, among which 31 were death cases with a fatality of 0.01%. The number of reported HFMD cases increased yearly with a Linear model of "f(t) = 18542.68 + 1628.91t" where f(t) and t referred to number of reported cases and sequence of year, respectively. The fatality of the disease decreased yearly with a linear model of "f(t) = - 0.012 + 0.083/t". About 5319 stool or anal swab specimens were collected from the reported cases. Among them, 1201 were tested EV71 positive, 836 were CA16 positive, and 1680 were other enteroviruses positive. Rasc and Rdes of HFMD was 1.34 (95% confidence interval [CI]: 1.28-1.40) and 0.73 (95% CI: 0.69-0.76), respectively. EV71 and CA16 interacted with each other, and the interaction between EV71 and other enteroviruses and the interaction between CA16 and other enteroviruses were both directional. However, during the reported cases decreasing period, interactions only occurred between EV71 and other enteroviruses and between CA16 and other enteroviruses. These interactions all decreased Rasc but increased Rdes of affected pathogens.The interactions of the pathogens exist in Changsha City. The effective reproduction number of the affected pathogen is adjusted and verges to 1 by the interaction.

Effects of temperature fluctuations on spatial-temporal transmission of hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD), predominantly occurs among infants and children. Previous studies have shown that suitable, stable temperatures favor HFMD virus reproduction; however, temperature fluctuations also affect virus transmission, and there are, so far, no studies concerning the association between such fluctuations and the incidence of HFMD. The objective of this study was to map the spatial-temporal distribution of HFMD incidence and quantify the long-term effects of temperature fluctuations on HFMD incidence in children. HFMD cases in children under five, from January 2009 to December 2013, in Beijing, Tianjin, and Hebei provinces of China, were used in this study. The GeoDetector and Bayesian space-time hierarchy models were employed to explore the spatial-temporal association between temperature fluctuations and HFMD incidence. The results indicate that HFMD incidence had significant spatial stratified heterogeneity (GeoDetector q-statistic = 0.83, p < 0.05), and that areas with higher risk mainly appeared in metropolises and their adjacent regions. HFMD transmission was negatively associated with temperature fluctuations. A 1 °C increase in the standard deviation of maximum and minimum temperatures was associated with decreases of 8.22% and 11.87% in the risk of HFMD incidence, respectively. The study suggests that large temperature fluctuations affect virus growth or multiplication, thereby inhibiting the activity of the virus and potentially even leading to its extinction, and consequently affecting the spatial-temporal distribution of HFMD. The findings can serve as a reference for the practical control of this disease and offer help in the rational allocation of medical resources.

Estimation of the reproduction number and identification of periodicity for HFMD infections in northwest China.

Repeated outbreaks of Hand, foot and mouth disease (HFMD) infections have been observed in recent decades and dominated by various enteroviral serotypes. In particular, enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16) and coxsackievirus A6 (CV-A6) dominated the prevalence of HFMD infections alternatively in recent years with various outbreak sizes in Baoji, a city of Shaanxi Province in Northwest China. Estimating the reproduction number for various enteroviruses serotypes in northwest China (north temperate zone) and identification of cyclicity of HFMD infections are therefore an issue of great importance for future epidemics prediction and control. The basic/effective reproduction numbers for EV-A71, CV-A16 and CV-A6 were estimated based on daily new cases in 2010, 2011 and 2018, respectively, in which the corresponding pathogen dominated the epidemic. Two different methods based on serial interval were adopted and the basic reproduction number were estimated to be in the range of (1.33, 1.46) for CV-A16, (1.20, 1.29) for EV-A71, and (1.38, 1.59) for CV-A6, respectively. The estimated daily effective reproduction numbers significantly fluctuated before June or after July but varied mildly in (0.5,2) in around June to July for three serotypes. The weekly effective reproduction number for HFMD was estimated based on weekly new cases from year 2010 to 2018, and in most years it peaked in the range of (1.6,2.0) in February to March as well as in the range of (1.0,1.2) in September to October. The wavelet analysis based on the time series of HFMD cases from 2008 to 2018 showed obvious annual and semi-annual cyclicity, while the inter-annual cycles are infeasible. In this study we found that CV-A6 shows the greatest transmission ability among these three pathogens while EV-A71 exhibits the weakest ability of transmission, and moreover, the estimated values of basic reproduction number in northwest China are lower than those in Singapore, Hongkong and Guangdong, which may be due to different climatic circumstances.

Seasonality of the transmissibility of hand, foot and mouth disease: a modelling study in Xiamen City, China.

This study attempts to figure out the seasonality of the transmissibility of hand, foot and mouth disease (HFMD). A mathematical model was established to calculate the transmissibility based on the reported data for HFMD in Xiamen City, China from 2014 to 2018. The transmissibility was measured by effective reproduction number (Reff) in order to evaluate the seasonal characteristics of HFMD. A total of 43 659 HFMD cases were reported in Xiamen, for the period 2014 to 2018. The median of annual incidence was 221.87 per 100 000 persons (range: 167.98/100,000-283.34/100 000). The reported data had a great fitting effect with the model (R2 = 0.9212, P < 0.0001), it has been shown that there are two epidemic peaks of HFMD in Xiamen every year. Both incidence and effective reproduction number had seasonal characteristics. The peak of incidence, 1-2 months later than the effective reproduction number, occurred in Summer and Autumn, that is, June and October each year. Both the incidence and transmissibility of HFMD have obvious seasonal characteristics, and two annual epidemic peaks as well. The peak of incidence is 1-2 months later than Reff.

Transmission and serotype features of hand foot mouth disease in household contacts in Dong Thap, Vietnam.

BACKGROUND: Hand, foot and mouth disease (HFMD) has emerged as a major public health issue in Vietnam since 2003. We aimed to investigate the household transmission of HFMD and its causative viruses from 150 households in a high incidence province in Vietnam. METHODS: A longitudinal study was conducted in patients presenting to the provincial hospital with a HFMD-like syndrome, along with their household members between April and August 2014 in Dong Thap Province. Each participant was followed up for 2 weeks. We enrolled 150 patients aged under 15 who were clinically diagnosed with HFMD in Dong Thap Hospital, 600 household members, and 581/600 household members completed the study. All participants were interviewed using a standard questionnaire. Throat swabs and blood samples were taken for molecular detection of viruses and assessment of neutralizing antibodies, respectively. Index cases were defined using a clinical case definition, household contact cases were defined using a similar definition applied to the 2 weeks before admission and 2 weeks after discharge of the index case. Characteristics of index cases, household contacts, the attack rate, serotype features and related factors of HFMD were reported. RESULT: Among 150 index cases, 113 were laboratory confirmed: 90/150 were RT-PCR-positive, 101/142 had a ≥ 4-fold increase of neutralizing antibody against Enterovirus A71 (EV-A71), Coxsackievirus (CV) A6 or CV-A16 across the two samples collected. 80/150 (53%) were males, and 45/150 (30%) were under the age of 1. The predominant serotype was CV-A6, identified in 57/87 (65.5%) of the specimens. No deaths were reported. Among 581 household contacts, 148 were laboratory confirmed: 12/581 were RT-PCR-positive, 142/545 had a ≥ 4-fold increase of neutralizing antibodies against EV-A71, CV-A6 or CV-A16; 4 cases experienced HFMD in the past 4 weeks. Attack rate among household contacts was 148/581 (25.5%). In 7/12 (58%) instances, the index and secondary cases were infected with the same serotype. Having a relationship to index case was significantly associated with EV infection. CONCLUSION: The attack rate among household contacts was relatively high (25.5%) in this study and it seems justified to also consider the household setting as an additional target for intervention programs.

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 (Rß) 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). Rß 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.

Estimating the transmissibility of hand, foot, and mouth disease by a dynamic model.

OBJECTIVE: Hand, foot, and mouth disease (HFMD) is a serious public health issue in many countries; however, its transmissibility in county-level outbreaks remains unclear. The aim of this study is to estimate the transmissibility of HFMD epidemics on both city level and county level, for a better understanding of the transmission dynamics of HFMD epidemics. STUDY DESIGN: Simulation based on data obtained from the China Information System for Disease Control and Prevention. METHODS: The weekly number of reported HFMD cases from April 2009 to December 2017 in nine regions of Changsha City was collected. A susceptible-infectious-recovered model was used to estimate the transmissibility of HFMD. The reproduction number of reported cases during the ascending (denoted as Rasc) and descending (denoted as Rdes) period was used to describe the transmissibility of HFMD. RESULTS: The Rasc and Rdes for HFMD in Changsha was 1.44 (95% confidence interval [CI]: 1.41-1.48) and 0.71 (95% CI: 0.69-0.73), respectively. There was no statistical significance of Rasc values among nine regions (F = 1.056, P = 0.396), nor of Rdes values among nine regions (F = 1.676, P = 0.106). The average Rasc (1.53, 95% CI: 1.46-1.61) from 2009 to 2012 was higher than the one (1.37, 95% CI: 1.34-1.40) from 2013 to 2017 (t = 3.974, P < 0.001), but the average Rdes (0.67, 95% CI: 0.63-0.70) from 2009 to 2012 was lower than the one (0.74, 95% CI: 0.73-0.76) from 2013 to 2017 (t = -3.751, P < 0.001). CONCLUSIONS: The epidemic of HFMD in Changsha City is still grim, and integrated strategies should be taken for controlling and preventing HFMD.

The complex transmission seasonality of hand, foot, and mouth disease and its driving factors.

BACKGROUND: The transmission rate seasonality is an important index for transmission dynamics in many childhood infections, and has been widely studied in industrialized countries. However, it has been neglected in the study of pathogens in China. METHODS: To understand the transmission dynamics of hand, foot and mouth disease (HFMD), we examined the transmission rate seasonality of HFMD in three provinces, Henan, Anhui and Chongqing, in China, using a dynamical stochastic SIR model. We investigated potential driving factors, including school terms, the Chinese Spring Festival period, meteorological factors and population flux for their effects on the HFMD transmission seasonality using multiple regression models. RESULTS: The transmission rate of HFMD had complex seasonality with one large major peak in March and one small peak in autumn. School terms, the Chinese Spring Festival period, population flux and meteorological factors had combined effects on the HFMD transmission seasonality in mainland China. The school terms reflects the seasonal contact rate in Children, while the population flux and the Chinese Spring Festival period reflect the seasonal contact rate in population. They drove HFMD transmission rate seasonality in different time periods of the year in China. Contact rate seasonality in population dominated effects on HFMD transmission in February and March. The dramatic increase in transmission rate during February coincides with the Chinese Spring Festival period and high population flux in this month. The contact rate seasonality in children dominated effects on the transmission in the other months of the year in Chongqing. Meteorological factors can not solely explain the seasonality in HFMD transmission in mainland China; however, they may have combined effects with school terms and the highway passenger traffic on the transmission rate in Anhui during the fall semester. CONCLUSION: The transmission rate of HFMD in three provinces in China had complex seasonality. The Chinese Spring Festival period, population flux and (or) school terms explained the majority of the transmission rate seasonality of HFMD, and they drove HFMD transmission rate seasonality in different time periods of the year. The Chinese Spring Festival period dominantly caused the dramatic increase of the HFMD transmission rate during February.

A multi-group model for estimating the transmission rate of hand, foot and mouth disease in mainland China.

In order to access the influence of different age groups on the spread of hand, foot and mouth disease (HFMD), we established the multi-group model with migration following the epidemiology of HFMD. The basic reproduction number of the HFMD epidemic model was calculated by the next generation operator method. According to China's national surveillance data on HFMD, we fitted the model parameters and estimated the transmission rates among different age groups. Besides, we carried out sensitivity analysis for the basic reproduction number to find some valuable regulatory measures. Our findings showed that the children under three years of age were indeed at high risk and adult group who had more contacts with children had a crucial influence on the spread of HFMD.

Nonsexually Transmitted Genital Ulcer Secondary to Hand, Foot, and Mouth Disease.

BACKGROUND: Genital ulcers that are not the result of sexually transmitted infections (STIs) are uncommon, and case reports predominantly feature pubertal girls. CASE: A 38-year-old monogamous, nulliparous woman acutely developed painful vaginal ulcers 7 days after babysitting a child who was subsequently diagnosed with hand, foot, and mouth disease. The patient developed nonspecific systemic symptoms followed by painful and rapidly expanding genital ulcers. Laboratory test results for herpes, syphilis, human immunodeficiency virus, gonorrhea, chlamydia, and Epstein-Barr virus were all negative. The patient was treated with brief inpatient observation, oral prednisone, meticulous wound care, and debridement. The ulcers resolved over a 3-week period. CONCLUSION: Although typically associated with pubertal girls, genital ulcers that are not the result of STIs can affect adults as well. The cornerstone of management regardless of age is supportive care, debridement and wound care, and treatment with steroids.

Real-Time Forecasting of Hand-Foot-and-Mouth Disease Outbreaks using the Integrating Compartment Model and Assimilation Filtering.

Hand-foot-and-mouth disease (HFMD) is a highly contagious viral infection, and real-time predicting of HFMD outbreaks will facilitate the timely implementation of appropriate control measures. By integrating a susceptible-exposed-infectious-recovered (SEIR) model and an ensemble Kalman filter (EnKF) assimilation method, we developed an integrated compartment model and assimilation filtering forecast model for real-time forecasting of HFMD. When applied to HFMD outbreak data collected for 2008-11 in Beijing, China, our model successfully predicted the peak week of an outbreak three weeks before the actual arrival of the peak, with a predicted maximum infection rate of 85% or greater than the observed rate. Moreover, dominant virus types enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) may account for the different patterns of HFMD transmission and recovery observed. The results of this study can be used to inform agencies responsible for public health management of tailored strategies for disease control efforts during HFMD outbreak seasons.

The Effect of School Closure on Hand, Foot, and Mouth Disease Transmission in Singapore: A Modeling Approach.

Singapore implements a school closure policy for institutional hand, foot, and mouth disease (HFMD) outbreaks, but there is a lack of empirical evidence on the effect of closure on HFMD transmission. We conducted a retrospective analysis of 197,207 cases of HFMD over the period 2003-2012 at the national level and of 57,502 cases in 10,080 institutional outbreaks over the period 2011-2016 in Singapore. The effects of school closure due to 1) institutional outbreaks, 2) public holidays, and 3) school vacations were assessed using a Bayesian time series modeling approach. School closure was associated with a reduction in HFMD transmission rate. During public holidays, average numbers of secondary cases having onset the week after dropped by 53% (95% credible interval 44-62%), and during school vacations, the number of secondary cases dropped by 7% (95% credible interval 3-10%). Schools being temporarily closed in response to an institutional outbreak reduced the average number of new cases by 1,204 (95% credible interval 1,140-1,297). Despite the positive effect in reducing transmission, the effect of school closure is relatively small and may not justify the routine use of this measure.

An outbreak of Coxsackievirus A6-associated hand, foot, and mouth disease in a kindergarten in Beijing in 2015.

BACKGROUND: Coxsackievirus A6 (CVA6) is one of the major agents to cause hand, foot and mouth disease (HFMD) outbreaks globally. The objective of this study is to investigate the epidemiologic and clinical manifestations of CVA6 outbreak, and thus guide the diagnosis and treatment of the disease, as well as disease prevention. METHODS: An HFMD outbreak in a kindergarten was reported to Shijingshan District Center for Disease Control and Prevention (SCDC) on November 2, 2015 in Beijing, China. Epidemiological investigation was conducted. We performed a nine-week follow-up study to collect and analyze the clinical manifestations of HFMD cases. RESULTS: The outbreak yield 56 (15.7%) clinical diagnosed HFMD cases out of 357 registered children in the kindergarten with the mean age of 3.5 years old. This outbreak lasted for three days and ceased after initiating infectious disease controlling procedures, including periodical suspension of the kindergarten activities, environmental disinfection, and family health education. Fifty-one cases were followed for nine weeks. The positive rate of clinical manifestations of rash, fever, desquamation, pigmentation and onychomadesis were 100.0%, 84.3%, 68.6%, 17.6% and 43.1%, respectively. Children developed desquamation within the first 4 weeks after disease onset and developed onychomadesis between the 3th and 8th week after disease onset. Children with desquamation had 9.3 (95%CI: 1.836-47.437) times higher odds of developing onychomadesis compared to those without this manifestation. Ten out of 14 collected samples were CVA6 positive, and five positive samples shared a high degree of similarity in the VP1 nucleotide and amino acid sequences (99.9-100.0% and 100%). CONCLUSION: This HFMD outbreak was caused by CVA6, featured with delayed symptoms. Emerging CVA6-associated HFMD and its delayed symptoms should be paid more attention to reduce outbreaks and provide more information to doctors and parents.

Hand, foot and mouth disease as an emerging public health problem: Case report of familial child-to-adult transmission.

Hand, foot and mouth disease (HFMD) is a highly contagious viral infectious disease that commonly affects small children. Typical clinical symptoms include low-grade fever, malaise and myalgia followed by a characteristic maculovesicular eruption on hands, feet and the oral cavity. In most cases, the disease is self-limiting, but some severe complications, including pneumonia, meningitis and encephalitis, may occasionally occur. The most severe outbreaks of HFMD have been observed in Asia-Pacific region; however, epidemics in Europe and America have also occurred in the past. The disease is caused by an infection with various members of Picornaviridae family in the genus enterovirus, most commonly by Coxsackievirus A6 (CVA6), Coxsackievirus A16 (CVA16), and Enterovirus 71 (EV71). This report describes the intra-familial transmission of hand, foot and mouth disease between 2 sibling children (a 3-year-old girl and a 5-year-old boy) and their immunocompetent mother in Poland. Clinical presentation with signs, symptoms and a suggested treatment regime are discussed and illustrated.