Epidemiology of hand, foot, and mouth disease and the genetic characteristics of Coxsackievirus A16 in Taiyuan, Shanxi, China from 2010 to 2021.

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by human enteroviruses (EV). This study aimed to describe the epidemiological features of HFMD and the genetic characteristics of Coxsackievirus A16 (CVA16) in Taiyuan, Shanxi, China, from 2010 to 2021. Descriptive epidemiological methods were used to analyze the time and population distribution of HFMD and the genetic characteristics of CVA16. Except being affected by the COVID-19 epidemic in 2020, HFMD epidemics were sporadic from January to March each year, and began to increase in April, with a major epidemic peak from May to August, which declined in September, followed by a secondary peak from October to December. The prevalence of EV infection was the highest in children aged one to five years (84.42%), whereas its incidence was very low in children under one year of age (5.48%). Enterovirus nucleic acid was detected by real-time reverse transcription polymerase chain reaction in 6641 clinical specimens collected from patients with HFMD from 2010 to 2021, and 4236 EV-positive specimens were detected, including 988 enterovirus A71 (EV-A71), 1488 CVA16, and 1760 other enteroviruses. CVA16 remains prevalent and has co-circulated with other EVs in Taiyuan from 2010 to 2021. A phylogenetic tree constructed based on the VP1 region showed that all CVA16 strains belonged to two different clades of the B1 genotype, B1a and B1b. They showed a nucleotide similarity of 86.5-100%, and an amino acid similarity of 96.9-100%. Overall, these findings add to the global genetic resources of CVA16, demonstrate the epidemiological characteristics of HFMD as well as the genetic features of CVA16 in Taiyuan City during 2010-2021, and provide supporting evidence for the prevention and control of HFMD.

Hand Foot Mouth Disease During the SARS-CoV-2 Pandemic: A Multicentric Study.

OBJECTIVES: This prospective observational study aimed to identify the current trend of the circulating viral strains responsible for HFMD outbreak in four tertiary care centers in Rajasthan, amidst the COVID-19 pandemic (April-October 2022). METHODS: Cases with suspected HFMD, presenting to our skin outpatient department were assessed clinically and serologically (IgM antibodies against coxsackie virus (CV) A6, A16 and enterovirus 71) for evidence of the disease. RESULTS: We identified 718 new HFMD patients (161 adults) with peaks in May and August, 2022. Male:female ratio decreased with increasing age. Most children were asymptomatic. A total of 385/409 patients assessed serologically, were found positive, most commonly against CV-A6. CONCLUSION: Though HFMD typically affects young children, an unusually higher proportion of adults were affected during the current pandemic. There were some subtle differences between pediatric and adult presentation of HFMD.

The 2022 outbreak and the pathobiology of the coxsackie virus [hand foot and mouth disease] in India.

Outbreaks of HFMD in children aged <5 years have been reported worldwide and the major causative agents are Coxsackievirus (CV) A16, enterovirus (EV)-A71 and recently CVA6. In India, HFMD is a disease that is not commonly reported. The purpose of the study was to identify the enterovirus type(s) associated with large outbreak of Hand, foot, and mouth disease during COVID-19 pandemic in 2022. Four hundred and twenty five clinical samples from 196-suspected cases were collected from different parts of the country. This finding indicated the emergence of CVA6 in HFMD along with CVA16, soon after the gradual easing of non-pharmaceutical interventions during-pandemic COVID-19 and the relevance of continued surveillance of circulating enterovirus types in the post-COVID pandemic era.

Current status of hand-foot-and-mouth disease.

Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.

Hand Foot Mouth Disease During the SARS-CoV-2 Pandemic: A Multicentric Study.

OBJECTIVES: This prospective observational study aimed to identify the current trend of the circulating viral strains responsible for HFMD outbreak in four tertiary care centers in Rajasthan, amidst the COVID-19 pandemic (April-October 2022). METHODS: Cases with suspected HFMD, presenting to our skin outpatient department were assessed clinically and serologically (IgM antibodies against coxsackie virus (CV) A6, A16 and enterovirus 71) for evidence of the disease. RESULTS: We identified 718 new HFMD patients (161 adults) with peaks in May and August, 2022. Male:female ratio decreased with increasing age. Most children were asymptomatic. A total of 385/409 patients assessed serologically, were found positive, most commonly against CV-A6. CONCLUSION: Though HFMD typically affects young children, an unusually higher proportion of adults were affected during the current pandemic. There were some subtle differences between pediatric and adult presentation of HFMD.

Drug Repositioning for Hand, Foot, and Mouth Disease.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease in children caused by a group of enteroviruses. HFMD currently presents a major threat to infants and young children because of a lack of antiviral drugs in clinical practice. Drug repositioning is an attractive drug discovery strategy aimed at identifying and developing new drugs for diseases. Notably, repositioning of well-characterized therapeutics, including either approved or investigational drugs, is becoming a potential strategy to identify new treatments for virus infections. Various types of drugs, including antibacterial, cardiovascular, and anticancer agents, have been studied in relation to their therapeutic potential to treat HFMD. In this review, we summarize the major outbreaks of HFMD and the progress in drug repositioning to treat this disease. We also discuss the structural features and mode of action of these repositioned drugs and highlight the opportunities and challenges of drug repositioning for HFMD.

Effects of different levels of non-pharmaceutical interventions on hand, foot and mouth disease in Guangzhou, China.

BACKGROUND: Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) may have suppressed the transmission of other infectious diseases. This study aimed to evaluate the impact of different degrees of NPIs during the COVID-19 pandemic on hand, foot and mouth disease (HFMD) in Guangzhou, China. METHODS: Weekly reported HFMD cases and pathogens information during 2015-2021 in Guangzhou were collected from the China National Notifiable Disease Reporting System. The observed number of HFMD cases in 2020 and 2021 was compared to the average level in the same period during 2015-2019. Then, an interrupted time-series segmented regression analysis was applied to estimate the impact of NPIs on HFMD, such as social distancing, suspension of schools, community management and mask wearing. The effects across different subgroups stratified by gender, children groups and enterovirus subtype of HFMD were also examined. RESULTS: A total of 13,224 and 36,353 HFMD cases were reported in 2020 and 2021, which decreased by 80.80% and 15.06% respectively compared with the average number of cases in the same period during 2015-2019. A significant drop in the number of HFMD cases during time when strict NPIs were applied (relative change: 69.07% [95% confidence interval (CI): 68.84%-69.30%]). The HFMD incidence rebounded to historical levels in 2021 as the lockdown eased. The slightest reduction of HFMD cases was found among children at kindergartens or childcare centres among the three children groups (children at kindergartens or childcare centres: 55.50% [95% CI: 54.96%-56.03%]; children living at home: 72.64% [95% CI: 72.38%-72.89%]; others: 74.06% [95% CI: 73.19%-74.91%]). CONCLUSIONS: The strong NPIs during the COVID-19 epidemic may have a significant beneficial effect on mitigating HFMD. However, the incidence of HFMD rebounded as the NPIs became less stringent. Authorities should consider applying these NPIs during HFMD outbreaks and strengthening personal hygiene in routine prevention.

Explanation of hand, foot, and mouth disease cases in Japan using Google Trends before and during the COVID-19: infodemiology study.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) pandemic affects common diseases, but its impact on hand, foot, and mouth disease (HFMD) is unclear. Google Trends data is beneficial for approximate real-time statistics and because of ease in access, is expected to be used for infection explanation from an information-seeking behavior perspective. We aimed to explain HFMD cases before and during COVID-19 using Google Trends. METHODS: HFMD cases were obtained from the National Institute of Infectious Diseases, and Google search data from 2009 to 2021 in Japan were downloaded from Google Trends. Pearson correlation coefficients were calculated between HFMD cases and the search topic "HFMD" from 2009 to 2021. Japanese tweets containing "HFMD" were retrieved to select search terms for further analysis. Search terms with counts larger than 1000 and belonging to ranges of infection sources, susceptible sites, susceptible populations, symptoms, treatment, preventive measures, and identified diseases were retained. Cross-correlation analyses were conducted to detect lag changes between HFMD cases and search terms before and during the COVID-19 pandemic. Multiple linear regressions with backward elimination processing were used to identify the most significant terms for HFMD explanation. RESULTS: HFMD cases and Google search volume peaked around July in most years, excluding 2020 and 2021. The search topic "HFMD" presented strong correlations with HFMD cases, except in 2020 when the COVID-19 outbreak occurred. In addition, the differences in lags for 73 (72.3%) search terms were negative, which might indicate increasing public awareness of HFMD infections during the COVID-19 pandemic. The results of multiple linear regression demonstrated that significant search terms contained the same meanings but expanded informative search content during the COVID-19 pandemic. CONCLUSIONS: The significant terms for the explanation of HFMD cases before and during COVID-19 were different. Awareness of HFMD infections in Japan may have improved during the COVID-19 pandemic. Continuous monitoring is important to promote public health and prevent resurgence. The public interest reflected in information-seeking behavior can be helpful for public health surveillance.

Trend of hand, foot, and mouth disease from 2010 to 2021 and estimation of the reduction in enterovirus 71 infection after vaccine use in Zhejiang Province, China.

BACKGROUND: Zhejiang, ranked in the top three in HFMD (hand, foot, and mouth disease) incidence, is located in the Yangtze River Delta region of southeast China. Since 2016, the EV71 vaccine has been promoted in Zhejiang Province. This study aimed to investigate the trend and seasonal variation characteristics of HFMD from 2010 to 2021 and estimate the reduction in enterovirus 71 infection after vaccine use. METHODS: The data on HFMD cases in Zhejiang Province from January 2010 to December 2021 were obtained from this network system. Individual information on cases and deaths was imported, and surveillance information, including demographic characteristics and temporal distributions, was computed by the system. The Joinpoint regression model was used to describe continuous changes in the incidence trend. The BSTS (Bayesian structural time-series models) model was used to estimate the monthly number of cases from 2017 to 2021 based on the observed monthly incidence during 2010-2016 by accounting for seasonality and long-term trends. The seasonal variation characteristics of HFMD pathogens were detected by wavelet analysis. RESULTS: From 2010 to 2021, the annual incidence rate fluctuated between 98.81 cases per 100,000 in 2020 and 435.63 cases per 100,000 in 2018, and 1711 severe HFMD cases and 106 fatal cases were reported in Zhejiang Province, China. The annual percent change (APC) in EV71 cases was -30.72% (95% CI: -45.10 to -12.50) from 2016 to 2021. The wavelet transform of total incidence and number of cases of the three pathogens all showed significant periodicity on the 1-year scale. The average 2-year scale periodicity was significant for the total incidence, EV71 cases and Cox A16 cases, but the other enterovirus cases showed significant periodicity on the 30-month scale. The 6-month scale periodicity was significant for the total incidence, EV71 case and Cox A16 case but not for the other enteroviruses case. The relative error percentage of the performance of the BSTS model was 0.3%. The estimated number of cases from 2017 to 2021 after the EV-A71 vaccines were used was 9422, and the reduction in the number of cases infected with the EV71 virus was 73.43% compared to 70.80% when the impact of the COVID-19 epidemic in 2020 was excluded. CONCLUSIONS: Since 2010, the incidence of EV71 infections has shown an obvious downward trend. All types of viruses showed significant periodicity on the 1-year scale. The periodicity of the biennial peak is mainly related to EV71 and Cox A16 before 2017 and other enteroviruses since 2018. The half-year peak cycle of HFMD was mainly caused by EV71 and Cox A6 infection. The expected incidence will be 2.76 times(include the cases of 2020) and 2.43 times(exclude the cases of 2020) higher than the actual value assuming that the measures of vaccination are not taken. EV71 vaccines are very effective and should be administered in the age window between 5 months and 5 years.

Hand, foot, and mouth disease outbreak by Coxsackievirus A6 during COVID-19 pandemic in 2021, São Paulo, Brazil.

INTRODUCTION: Hand, foot, and mouth disease (HFMD) is an acute febrile illness characterized by fever; sore throat; and vesicular eruptions on the hands, feet, and oral mucosa. Outbreaks of HFMD in children aged <5 years have been reported worldwide and the major causative agents are Coxsackievirus (CV)A16, enterovirus (EV)-A71 and recently CVA6. AIM AND METHODS: The aim of this study was to investigated a large outbreak of Hand, foot, and mouth disease during COVID-19 pandemic in 2021 from clinical samples of 315 suspected cases, in São Paulo State, Brazil. Diagnostic evaluation was performed by RT-qPCR, culture cell isolation and serological neutralization assay. EV-positive were genotyped by partial VP1 genome sequencing. RESULTS: One hundred and forty-nine cases analyzed were positive for enterovirus (47.3%; n = 149/315) by neutralizing test (n = 10 patients) and RT-qPCR (n = 139 patients), and identified as CVA6 sub-lineage D3 by analysis of VP1 partial sequences. CONCLUSIONS: This finding indicated the reemergence of CVA6 in HFMD, soon after the gradual easing of non-pharmaceutical interventions during-pandemic COVID-19 and the relevance of continued surveillance of circulating enterovirus types in the post-COVID pandemic era.

Effectiveness of case isolation and class suspension in mitigation of enterovirus transmission in children.

BACKGROUND: Appropriate mitigation strategy to minimize enterovirus (EV) transmission among children is essential to control severe EV epidemics. Scientific evidence for the effectiveness of case isolation and class suspension is lacking. METHODS: EV-infected children ≤ eight years are asked to stay at home for seven days. Classes were suspended for seven days if there are more than two classmates having an onset of herpangina or hand, foot, and mouth disease in one classroom within one week. Study subjects are divided into two groups, group A with class suspension for one week and group B without class suspension. RESULTS: Among 4153 reported EV-infected children from 1085 classes in May and June, 2015 were enrolled. Median incidence of EV infection in a class was 7% (range 3% -60%). The incidence was higher in group A (median 14%, range 3-60%) than that in group B (median 6%, range 3-80%) (P < 0.01). The median incidence is highest in day care center (20%), followed by kindergarten (8%), and primary school (4%) (P < 0.01). Most secondary cases in group A appeared within seven days after the disease onset of index case in the same class. The incidence of EV infection remained low and was similar between the two groups eight days and beyond after the disease onset of index cases. CONCLUSIONS: Targeted class suspension for seven days with case isolation for seven days is an effective measure to mitigate transmission of EV infection in children.

Relationship between meteorological factors, air pollutants and hand, foot and mouth disease from 2014 to 2020.

BACKGROUND: Meteorological factors and air pollutants have been reported to be associated with hand, foot, and mouth disease (HFMD) epidemics before the introduction of vaccine. However, there is limited evidence for studies with long-term dimensions. METHODS: We collected the daily HFMD counts, weather and air pollution data from 2014 to 2020 in Chengdu. Distributed lag non-linear models (DLNM) were used to assess the associations of meteorological factors and air pollutants on HFMD cases. RESULTS: From 2014-2020, high relative humidity and precipitation and extremely high and low levels of PM10, O3, SO2 and CO increased the risk of HFMD. In pre-vaccination period, extreme high and low temperatures, PM10 and NO2, low precipitation and high concentrations of PM2.5 and O3 significantly increase the risk of HFMD; In post-vaccination period, high relative humidity and low level of CO can significantly increase the incidence of HFMD; During the period of COVID-19, only low temperature will significantly increase the risk of HFMD; Low concentration of air pollutants has the greatest impact on the 6-14 age group, while the high concentration of air pollutants has the greatest impact on the 0-1 age group. CONCLUSIONS: Our study suggest that high relative humidity and precipitation and extremely high and low levels of PM10, O3, SO2 and CO increased the risk of HFMD from 2014 to 2020. The results of this study provide a reference for local authorities to formulate intervention measures and establish an environment-based disease early warning system.

A large-scale outbreak of hand, foot and mouth disease, France, as at 28 September 2021.

We report a large-scale outbreak of hand, foot and mouth disease (HFMD) in France. As at 28 September 2021, 3,403 cases have been reported (47% higher than in 2018-19). We prospectively analysed 210 clinical samples; 190 (90.5%) were enterovirus-positive. Most children presented with atypical HFMD. Coxsackievirus (CV)A6 (49.5%; 94/190) was predominant; no enterovirus A71 was detected. Dermatological and neurological complications of HFMD justify prospective syndromic and virological surveillance for early detection of HFMD outbreaks and identification of associated types.

Comparison of ARIMA and LSTM in Forecasting the Incidence of HFMD Combined and Uncombined with Exogenous Meteorological Variables in Ningbo, China.

BACKGROUND: This study intends to identify the best model for predicting the incidence of hand, foot and mouth disease (HFMD) in Ningbo by comparing Autoregressive Integrated Moving Average (ARIMA) and Long Short-Term Memory Neural Network (LSTM) models combined and uncombined with exogenous meteorological variables. METHODS: The data of daily HFMD incidence in Ningbo from January 2014 to November 2017 were set as the training set, and the data of December 2017 were set as the test set. ARIMA and LSTM models combined and uncombined with exogenous meteorological variables were adopted to fit the daily incidence of HFMD by using the data of the training set. The forecasting performances of the four fitted models were verified by using the data of the test set. Root mean square error (RMSE) was selected as the main measure to evaluate the performance of the models. RESULTS: The RMSE for multivariate LSTM, univariate LSTM, ARIMA and ARIMAX (Autoregressive Integrated Moving Average Model with Exogenous Input Variables) was 10.78, 11.20, 12.43 and 14.73, respectively. The LSTM model with exogenous meteorological variables has the best performance among the four models and meteorological variables can increase the prediction accuracy of LSTM model. For the ARIMA model, exogenous meteorological variables did not increase the prediction accuracy but became the interference factor of the model. CONCLUSIONS: Multivariate LSTM is the best among the four models to fit the daily incidence of HFMD in Ningbo. It can provide a scientific method to build the HFMD early warning system and the methodology can also be applied to other communicable diseases.

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.