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Background: While stationary links between childhood hand, foot and mouth disease (HFMD) and air pollution are known, a comprehensive study on their heterogeneous relationships (nonstationarity), jointly considering numerical, temporal and spatial dimensions, has not been reported., Methods: Monthly HFMD incidence and air pollution data were collected at the county level from Sichuan-Chongqing, China (2009-2011), alongside meteorological and social environmental covariates. Key influential factors were identified using random forest (RF) under the stationary assumption. Factors' numerically, temporally, and spatially heterogeneous relationships with HFMD were assessed using generalized additive model (GAM) and geographically and temporally weighted regression (GTWR)., Results: Our findings highlighted the relatively higher stationary contributions of fine particulate matter (PM 2.5 ) and ozone (O 3 ) to HFMD incidence across Sichuan-Chongqing counties. We further uncovered heterogeneous impacts of PM 2.5 and O 3 from three nonstationary perspectives. Numerically, PM 2.5 showed an inverse 'V'-shaped relationship with HFMD incidence, while O 3 exhibited a complex pattern, with increased HFMD incidence at low PM 2.5 and moderate O 3 concentrations. Temporally, PM 2.5 's impact peaked in autumn and was weakest in spring, whereas O 3 's effect was strongest in summer. Spatially, hotspot mapping revealed high-risk clusters for PM 2.5 impact across all seasons, with notable geographical variations, and for O 3 in spring, summer, and autumn, concentrated in specific regions of Sichuan-Chongqing., Conclusions: This study underscores the nuanced and three-perspective heterogeneous influences of air pollution on HFMD in small areas, emphasizing the need for differentiated, localized, and time-sensitive prevention and control strategies to enhance the precision of dynamic early warnings and predictive models for HFMD and other infectious diseases, particularly in the fields of environmental and spatial epidemiology., (© 2024. The Author(s).)

Objective: To analyze the temporal distribution characteristics of hand, foot and mouth disease (HFMD) in Beijing and provide reference evidence in HFMD prevention and control. Methods: The monthly incidence data of HFMD in Beijing from 2008 to 2023 were collected from Notifiable Disease Management Information System of the Chinese Information System of Disease Control and Prevention, and the epidemiological characteristics of HFMD were analyzed by the methods of time series seasonal decomposition graph, concentration degree, and circular distribution.The WPS office software 2019 was used to clean the data, Python software 3.12 was used to analyze and make statistical charts. Results: The monthly incidence fluctuation of HFMD in Beijing from 2008 to 2015 was higher than that from 2016 to 2022. From 2016 to 2022, the fluctuation range of monthly incidence showed a gradually decreasing trend.From 2008 to 2015, the concentration ( M ) was 0.58, indicating a relatively strong seasonality; the mean angle ( α ) calculated by the circular distribution method was 174.95°, and the mean angle standard deviation ( s ) was 60.43°. The annual incidence peak occurred on June 27, and the incidence peak period was from April 27 to August 27. From 2016 to 2019 and 2023, the M was 0.57, indicating a relatively strong seasonality. The α was 228.05°, and s was 61.44°. The annual incidence peak occurred on August 20, and the incidence peak period was from June 18 to October 21. From 2020 to 2022, the M was 0.42, indicating a seasonality, the α was 238.27° and s was 76.35°. The annual incidence peak occurred on July 15, and the incidence peak period was from June 14 to November 14. The α of 2008-2015, 2016-2019 and 2023, and 2020-2022 were tested by the Watson-Williams method and the difference was statistically significant ( F =33 443.09, P <0.001). In 2023, the M was 0.77, indicating a strong seasonality. The incidence peak occurred on September 16, and the incidence peak period was from August 5 to October 28. Conclusions: The seasonality of HFMD in Beijing was obvious from 2008 to 2023, and the incidence peak day and peak period overall had rearward shifts. It is necessary to strengthen the comprehensive analysis of the distribution characteristics at different dimensions and the comprehensive prevention and control in key areas, places, and populations during the peak incidence period.

Hand, foot and mouth disease (HFMD) is a Class C infectious disease that carries particularly high risk for preschool children and is a leading cause of childhood death in some countries. We mimic the periodic outbreak of HFMD over a 2-year period-with differing amplitudes-and propose a dynamic HFMD model that differentiates transmission between mature and immature individuals and uses two possible optimal-control strategies to minimize case numbers, total costs and deaths. We parameterized the model by fitting it to HFMD data in mainland China from January 2011 to December 2018, and the basic reproduction number was estimated as 0.9599. Sensitivity analysis demonstrates that transmission between immature and mature individuals contributes substantially to new infections. Increasing the isolation rates of infectious individuals-particularly mature infectious individuals-could greatly reduce the outbreak risk and potentially eradicate the disease in a relatively short time period. It follows that we have a reasonable chance of controlling HFMD if we can reduce transmission in children under 7 and isolate older infectious individuals., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hand, foot, and mouth disease (HFMD) is a notable infectious disease predominantly affecting infants and children worldwide. Previous studies on HFMD have primarily focused on natural patterns, such as seasonality, but research on the influence of important social time points is lacking. Several studies have indicated correlations between birthdays and certain disease outcomes., Objective: This study aimed to explore the association between birthdays and HFMD., Methods: Surveillance data on HFMD from 2008 to 2022 in Yunnan Province, China, were collected. We defined the period from 6 days before the birthday to the exact birthday as the "birthday week." The effect of the birthday week was measured by the proportion of cases occurring during this period, termed the "birthday week proportion." We conducted subgroup analyses to present the birthday week proportions across sexes, age groups, months of birth, and reporting years. Additionally, we used a modified Poisson regression model to identify conditional subgroups more likely to contract HFMD during the birthday week., Results: Among the 973,410 cases in total, 116,976 (12.02%) occurred during the birthday week, which is 6.27 times the average weekly proportion (7/365, 1.92%). While the birthday week proportions were similar between male and female individuals (68,849/564,725, 12.19% vs 48,127/408,685, 11.78%; χ21=153.25, P<.001), significant differences were observed among different age groups (χ23=47,145, P<.001) and months of birth (χ211=16,942, P<.001). Compared to other age groups, infants aged 0-1 year had the highest birthday week proportion (30,539/90,709, 33.67%), which is 17.57 times the average weekly proportion. Compared to other months, patients born from April to July and from October to December, the peak months of the HFMD epidemic, had higher birthday week proportions. Additionally, a decreasing trend in birthday week proportions from 2008 to 2022 was observed, dropping from 33.74% (3914/11,600) to 2.77% (2254/81,372; Cochran-Armitage trend test: Z=-102.53, P<.001). The results of the modified Poisson regression model further supported the subgroup analyses findings. Compared with children aged >7 years, infants aged 0-1 year were more likely to contract HFMD during the birthday week (relative risk 1.182, 95% CI 1.177-1.185; P<.001). Those born during peak epidemic months exhibited a higher propensity for contracting HFMD during their birthday week. Compared with January, the highest relative risk was observed in May (1.087, 95% CI 1.084-1.090; P<.001)., Conclusions: This study identified a novel "birthday week effect" of HFMD, particularly notable for infants approaching their first birthday and those born during peak epidemic months. Improvements in surveillance quality may explain the declining trend of the birthday week effect over the years. Higher exposure risk during the birthday period and potential biological mechanisms might also account for this phenomenon. Raising public awareness of the heightened risk during the birthday week could benefit HFMD prevention and control., (© Pei Jiang, Xiangyu Yan, Tongjian Cai, Longxin Huang, Zhenzhong Liu, Linhui Hao, Tian Huang, Haijun Yang, Min Xu, Wenhui Shi, Tiejun Shui. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Hand, foot, and mouth disease (HFMD) is a prevalent acute infectious disease caused by enteroviruses, presenting substantial public health challenges in Shanghai, especially among children. The dynamic nature of HFMD's etiology necessitates an ongoing evaluation of its epidemiological and virological trends to inform effective control strategies. This study aims to investigate the epidemiological patterns and viral evolution of HFMD in Fengxian District, Shanghai, China, with a focus on shifts in predominant viral strains over a 14-year period. We conducted a retrospective analysis of HFMD cases reported to the National Notifiable Disease Reporting System in Fengxian District from January 1, 2009 to December 31, 2022. Epidemiological trends, strain prevalence, and demographic impacts were assessed. A total of 27,272 HFMD cases were documented during the study period, with incidence showing pronounced seasonal fluctuations-peaking in spring and summer and a lesser peak in autumn. The disease incidence demonstrated significant positive correlations with several meteorological variables: daily average temperature (r = 0.30, P < 0.05), relative humidity (r = 0.20, P < 0.05), wind speed (r = 0.17, P < 0.05), and precipitation (r = 0.17, P < 0.05). Geographically, Nanqiao Town, Fengcheng Town, and Xidu Subdistrict reported the highest incidence rates. The demographic analysis revealed a male-to-female ratio of 1.60:1, predominantly affecting children aged 1-3 years. Prior to 2017, Enterovirus 71 (EV71) and Coxsackievirus A16 (CoxA16) were the primary detected strains; post-2017, Coxsackievirus A6 (CoxA6) emerged as the dominant strain. Statistical analysis confirmed significant year-to-year variations in virus detection rates, with decreasing trends for EV71 and other enteroviruses and an increasing trend for CoxA6. The findings indicate a distinct seasonal incidence of HFMD in Fengxian District. This study underscores the need for targeted public health education, enhanced surveillance, and proactive measures in childcare facilities to mitigate disease spread during peak seasons. Moreover, the evolving viral landscape warrants accelerated efforts in vaccine development against new strains to reduce HFMD incidence., (© 2024. The Author(s).)

Hand, foot, and mouth disease (HFMD) is an acute infectious illness primarily caused by enteroviruses. The present study aimed to describe the epidemiological characteristics of hospitalized HFMD patients in a hospital in Henan Province (Zhengzhou, China), and to predict the future epidemiological parameters. In this study, we conducted a retrospective analysis of general demographic and clinical data on hospitalized children who were diagnosed with HFMD from 2014 to 2023. We used wavelet analysis to determine the periodicity of the disease. We also conducted an analysis of the impact of the COVID-19 epidemic on the detection ratio of severe illness. Additionally, we employed a Seasonal Difference Autoregressive Moving Average (SARIMA) model to forecast characteristics of future newly hospitalized HFMD children. A total of 19 487 HFMD cases were included in the dataset. Among these cases, 1515 (7.8%) were classified as severe. The peak incidence of HFMD typically fell between May and July, exhibiting pronounced seasonality. The emergence of COVID-19 pandemic changed the ratio of severe illness. In addition, the best-fitted seasonal ARIMA model was identified as (2,0,2)(1,0,1) 12. The incidence of severe cases decreased significantly following the introduction of the vaccine to the market (χ 2  = 109.9, p < 0.05). The number of hospitalized HFMD cases in Henan Province exhibited a seasonal and declining trend from 2014 to 2023. Non-pharmacological interventions implemented during the COVID-19 pandemic have led to a reduction in the incidence of severe illness., (© 2024 Wiley Periodicals LLC.)

Purpose: To investigate the clinical features of hand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 (CVA6) and this work may help early diagnose of atypical HFMD., Methods: From January 2013 to December 2019, a total of 7,208 patients with a clinical diagnosis of HFMD in Xi'an Children's Hospital, Xi'an Central Hospital, and Xi'an Jiaotong University Second Affiliated Hospital, were included in this observational study. The clinical data, specimens and follow-up results were collected. Real-time RT‒PCR was performed for the detection and typing of enterovirus nucleic acids., Results: Of the 7,208 clinically diagnosed HFMD patients, 5,622 were positive for enterovirus nucleic acids, and the positive proportions of CVA6, enterovirus 71 (EV-A71), coxsackievirus A16 (CVA16), and other enteroviruses were 31.0% (1,742/5,622), 27.0% (1,518/5,622), 35.0% (1,968/5,622), and 7.0% (394/5,622), respectively. Based on the etiology, patients were divided into CVA6 group, EV-A71group, and CVA16 group. The mean age at onset was significantly higher in the CVA6 group (4.62±2.13 years) than in the EV-A71 group and CVA16 group (3.45±2.25 years and 3.35±2.13 years, respectively; both P < 0.05). The male/female ratio was 1.45 (1,031/711) in the CVA6 group and was not significantly different from the other two groups. The incidence of fever was significantly higher in the CVA6 group [82.5% (1,437/1,742)] than in the EV-A71 group [51.3% (779/1,518)] and the CVA16 group [45.9% (903/1,968)] (P < 0.05). In the CVA6 group, the rashes were more frequently on the trunk and elbows/knees and were significantly different from the other two groups (P < 0.05). The number of patients with two or more rash morphologies was significantly higher in the CVA6 group than in the other two groups (P < 0.05). The incidence of bullous rash in the CVA6 group [20.2%; n = 352] was higher than in the EV-A71 group [0.33%; n = 5] and CVA16 group [0.66%; n = 13] (P < 0.05). The incidence of neurological complications was significantly higher in the EV-A71 group [52.1% (791/1,518)] than in the CVA16 group [5.1% (100/1,968)] and the CVA6 group [0.8% (14/1,742)] (P < 0.05). In the follow-up period, 160 patients (9.2%) with CVA6 HFMD experienced onychomadesis, but no onychomadesis was observed in the EV-A71 and CVA16 groups. The average WBC count was significantly higher in the CVA6 group than in the CVA16 group (P < 0.05). The number of patients with increased CRP was significantly larger in the CVA6 group than in the CVA16 group but was significantly smaller than that in the EV-A71 group (P < 0.05)., Conclusions: CVA6 has become one of the main pathogens of HFMD in the Xi'an area during 2013-2019. The main clinical manifestations were slightly different from those of HFMD caused by EV-A71 or CVA16, with a higher frequency of fever, diverse morphologies and diffuse distribution of rashes, fewer neurological complications and some onychomadesis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objective: In order to facilitate the tracing of infectious diseases in a small area and to effectively carry out disease control and epidemiological investigations, this research proposes a novel spatiotemporal model to estimate effective reproduction number(Re)for infectious diseases, based on the fundamental concept of contact tracing., Methods: This study utilizes the incidence of hand, foot, and mouth disease (HFMD) among children in Bishan District, Chongqing, China from 2015 to 2019. The study incorporates the epidemiological characteristics of HFMD and aims to construct a Spatiotemporal Correlation Discrimination of HFMD. Utilizing ARC ENGINE and C# programming for the creation of a spatio-temporal database dedicated to HFMD to facilitate data collection and analysis. The scientific validity of the proposed method was verified by comparing the effective reproduction number obtained by the traditional SEIR model., Results: We have ascertained the optimal search radius for the spatiotemporal search model to be 1.5 km. Upon analyzing the resulting Re values, which range from 1.14 to 4.75, we observe a skewed distribution pattern from 2015 to 2019. The median and quartile Re value recorded is 2.42 (1.98, 2.72). Except for 2018, the similarity coefficient r of the years 2015, 2016, 2017, and 2019 were all close to 1, and p <0.05 in the comparison of the two models, indicating that the Re values obtained by using the search model and the traditional SEIR model are correlated and closely related. The results exhibited similarity between the Re curves of both models and the epidemiological characteristics of HFMD. Finally, we illustrated the regional distribution of Re values obtained by the search model at various time intervals on Geographic Information System (GIS) maps which highlighted variations in the incidence of diseases across different communities, neighborhoods, and even smaller areas., Conclusion: The model comprehensively considers both temporal variation and spatial heterogeneity in disease transmission and accounts for each individual's distinct time of onset and spatial location. This proposed method differs significantly from existing mathematical models used for estimating Re in that it is founded on reasonable scientific assumptions and computer algorithms programming that take into account real-world spatiotemporal factors. It is particularly well-suited for estimating the Re of infectious diseases in relatively stable mobile populations within small geographical areas., (© 2024. The Author(s).)

Hand, foot, and mouth disease (HFMD) is a common viral infection primarily affecting children. It causes vesicles on the skin and inside the mouth. Although most cases get better on their own, severe cases can lead to complications such as brain stem encephalitis, meningoencephalitis, acute flaccid paralysis, and pulmonary edema. Hand, foot, and mouth disease is caused by various enteroviruses, with enterovirus A71 (EV-A71) and coxsackievirus A16 being the most common. However, recent studies have shown a shift in the molecular epidemiology of HFMD-causing pathogens, with coxsackievirus A6 and coxsackievirus A10 causing more infections. In addition, extensive recombination events have been identified among enterovirus strains, which may have a role in faster evolution and extinction of dominant enterovirus serotypes. Other strains of enterovirus can also cause severe complications, and there has been an increase in mortality associated with brain stem encephalitis in children under 3 years of age and teenagers. Currently, there are no effective antiviral therapies available to treat enterovirus infections. Vaccines against EV-A71 have been approved and are now used in mainland China. Studying the changing epidemiology of HFMD pathogens and the evolution patterns of its causative agents is crucial in developing effective prevention and control strategies. Increased interest in the molecular epidemiology of HFMD causative agents has led to a better understanding of the critical drivers of HFMD outbreaks, which can inform efforts to prevent and control the disease.

Background: In the past 10 years, the number of hand, foot, and mouth disease (HFMD) cases reported in Guangzhou, China, has averaged about 60,000 per year. It is necessary to conduct an in-depth analysis to understand the epidemiological pattern and related influencing factors of HFMD in this region., Objective: This study aims to describe the epidemiological characteristics and spatiotemporal distribution of HFMD cases in Guangzhou from 2013 to 2022 and explore the relationship between sociodemographic factors and HFMD incidence., Methods: The data of HFMD cases in Guangzhou come from the Infectious Disease Information Management System of the Guangzhou Center for Disease Control and Prevention. Spatial analysis and space-time scan statistics were used to visualize the spatiotemporal distribution of HFMD cases. Multifactor ordinary minimum regression model, geographically weighted regression, and geographically and temporally weighted regression were used to analyze the influencing factors, including population, economy, education, and medical care., Results: From 2013 to 2022, a total of 599,353 HFMD cases were reported in Guangzhou, with an average annual incidence rate of 403.62/100,000. Children aged 5 years and younger accounted for 93.64% (561,218/599,353) of all cases. HFMD cases showed obvious bimodal distribution characteristics, with the peak period from May to July and the secondary peak period from August to October. HFMDs in Guangzhou exhibited a spatial aggregation trend, with the central urban area showing a pattern of low-low aggregation and the peripheral urban area demonstrating high-high aggregation. High-risk areas showed a dynamic trend of shifting from the west to the east of peripheral urban areas, with coverage first increasing and then decreasing. The geographically and temporally weighted regression model results indicated that population density (β=-0.016) and average annual income of employees (β=-0.007) were protective factors for HFMD incidence, while the average number of students in each primary school (β=1.416) and kindergarten (β=0.412) was a risk factor., Conclusions: HFMD cases in Guangzhou were mainly infants and young children, and there were obvious differences in time and space. HFMD is highly prevalent in summer and autumn, and peripheral urban areas were identified as high-risk areas. Improving the economic level of peripheral urban areas and reducing the number of students in preschool education institutions are key strategies to controlling HFMD., (©Jiaojiao Liu, Hui Wang, Siyi Zhong, Xiao Zhang, Qilin Wu, Haipeng Luo, Lei Luo, Zhoubin Zhang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Background: The increasing incidence of hand, foot, and mouth disease (HFMD) associated with Coxsackievirus A6 (CVA6) has become a very significant public health problem. The aim of this study is to investigate the recombination, geographic transmission, and evolutionary characteristics of the global CVA6., Methods: From 2019 to 2022, 73 full-length CVA6 sequences were obtained from HFMD patients in China and analyzed in combination with 1032 published whole genome sequences. Based on this dataset, the phylogenetic features, recombinant diversity, Bayesian phylodynamic characteristics, and key amino acid variations in CVA6 were analyzed., Results: The four genotypes of CVA6, A, D, E, and F, are divided into 24 recombinant forms (RFs, RF-A - RF-X) based on differences in the P3 coding region. The eastern China region plays a key role in the dissemination of CVA6 in China. VP1-137 and VP1-138 are located in the DE loop on the surface of the CVA6 VP1 protein, with the former being a highly variable site and the latter having more non-synonymous substitutions., Conclusions: Based on whole genome sequences, this study contributes to the CVA6 monitoring, early warning, and the pathogenic mechanism by studying recombination diversity, geographical transmission characteristics, and the variation of important amino acid sites., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. From 2018 to 2023, a surge in severe neonatal cases and fatalities linked to a novel variant of genotype D5 was documented in China, France, and Italy. However, the prevention and control of E11 variants have been hampered by limited background data on the virus circulation and genetic variance. Therefore, the present study investigated the circulating dynamics of E11 and the genetic variation and molecular evolution of genotype D5 through the collection of strains from the national acute flaccid paralysis (AFP) and hand, foot, and mouth disease (HFMD) surveillance system in China during 2000-2022 and genetic sequences published in the GenBank database. The results of this study revealed a prevalent dynamic of E11 circulation, with D5 being the predominant genotype worldwide. Further phylogenetic analysis of genotype D5 indicated that it could be subdivided into three important geographic clusters (D5-CHN1: 2014-2019, D5-CHN2: 2016-2022, and D5-EUR: 2022-2023). Additionally, variant-specific (144) amino acid mutation sites and positive-selection pressure sites (132, 262) were identified in the VP1 region. Cluster-specific recombination patterns were also identified, with CVB5, E6, and CVB4 as the major recombinant viruses. These findings provide a preliminary landscape of E11 circulation worldwide and basic scientific data for further study of the pathogenicity of E11 variants.

Background: Hand, foot, and mouth disease (HFMD) is a global public health concern, notably within the Asia-Pacific region. Recently, the primary pathogen causing HFMD outbreaks across numerous countries, including China, is coxsackievirus (CV) A6, one of the most prevalent enteroviruses in the world. It is a new variant that has undergone genetic recombination and evolution, which might not only induce modifications in the clinical manifestations of HFMD but also heighten its pathogenicity because of nucleotide mutation accumulation., Objective: The study assessed the epidemiological characteristics of HFMD in China and characterized the molecular epidemiology of the major pathogen (CV-A6) causing HFMD. We attempted to establish the association between disease progression and viral genetic evolution through a molecular epidemiological study., Methods: Surveillance data from the Chinese Center for Disease Control and Prevention from 2021 to 2023 were used to analyze the epidemiological seasons and peaks of HFMD in Henan, China, and capture the results of HFMD pathogen typing. We analyzed the evolutionary characteristics of all full-length CV-A6 sequences in the NCBI database and the isolated sequences in Henan. To characterize the molecular evolution of CV-A6, time-scaled tree and historical population dynamics regarding CV-A6 sequences were estimated. Additionally, we analyzed the isolated strains for mutated or missing amino acid sites compared to the prototype CV-A6 strain., Results: The 2021-2023 epidemic seasons for HFMD in Henan usually lasted from June to August, with peaks around June and July. The monthly case reporting rate during the peak period ranged from 20.7% (4854/23,440) to 35% (12,135/34,706) of the total annual number of cases. Analysis of the pathogen composition of 2850 laboratory-confirmed cases identified 8 enterovirus serotypes, among which CV-A6 accounted for the highest proportion (652/2850, 22.88%). CV-A6 emerged as the major pathogen for HFMD in 2022 (203/732, 27.73%) and 2023 (262/708, 37.01%). We analyzed all CV-A6 full-length sequences in the NCBI database and the evolutionary features of viruses isolated in Henan. In China, the D3 subtype gradually appeared from 2011, and by 2019, all CV-A6 virus strains belonged to the D3 subtype. The VP1 sequences analyzed in Henan showed that its subtypes were consistent with the national subtypes. Furthermore, we analyzed the molecular evolutionary features of CV-A6 using Bayesian phylogeny and found that the most recent common ancestor of CV-A6 D3 dates back to 2006 in China, earlier than the 2011 HFMD outbreak. Moreover, the strains isolated in 2023 had mutations at several amino acid sites compared to the original strain., Conclusions: The CV-A6 virus may have been introduced and circulating covertly within China prior to the large-scale HFMD outbreak. Our laboratory testing data confirmed the fluctuation and periodic patterns of CV-A6 prevalence. Our study provides valuable insights into understanding the evolutionary dynamics of CV-A6., (© Yu Chen, Shouhang Chen, Yuanfang Shen, Zhi Li, Xiaolong Li, Yaodong Zhang, Xiaolong Zhang, Fang Wang, Yuefei Jin. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Pathogens of the enterovirus genus, including poliovirus and coxsackieviruses, typically circulate in the summer months suggesting a possible positive association between warmer weather and transmission. Here we evaluate the environmental and demographic drivers of enterovirus transmission, as well as the implications of climate change for future enterovirus circulation. We leverage pre-vaccination era data on polio in the US as well as data on two enterovirus A serotypes in China and Japan that are known to cause hand, foot, and mouth disease. Using mechanistic modeling and statistical approaches, we find that enterovirus transmission appears positively correlated with temperature although demographic factors, particularly the timing of school semesters, remain important. We use temperature projections from Coupled Model Intercomparison Project Phase 6 (CMIP6) to simulate future outbreaks under late 21st-century climate change for Chinese provinces. We find that outbreak size increases with climate change on average, though results differ across climate models depending on the degree of wintertime warming. In the worst-case scenario, we project peak outbreaks in some locations could increase by up to 40%., (© 2024. The Author(s).)

An HFMD outbreak spread over the city of Hải Phòng from summer 2011 to autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed three separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, which was possible due to a reorganization of the system in February-March 2012. An analysis at the commune level enabled us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at the district level. We developed a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of the beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave., Competing Interests: The authors declare no conflict of interest.

Introduction: Coxsackievirus A10 (CVA10) is a non-enveloped, positive-sense single-stranded RNA virus classified within the Enterovirus genus in the Picornaviridae family. It is among the pathogens that can cause hand, foot and mouth disease. This study aimed to analyze the temporal and spatial distribution of CVA10 in China to understand its epidemiological characteristics of CVA10., Methodology: We collected the VP1 sequences of CVA10 from January 1, 2004, to December 31, 2019, from the GenBank database and created the global map using MapChart. We selected 56 known CVA10 genotype sequences. Then, MEGA6.06 was used to construct a phylogenetic tree with the collected gene sequences and the known reference sequences for comparative analysis to assess the distribution of CVA10 genotypes in different countries between 2004 and 2019., Results: CVA10 has been widely detected or reported globally. In China, the prevalent genotype of CVA10 was mainly genotype B before 2008 and genotype C after 2009. In other countries, the prevalence of genotype D was dominant, followed by genotypes C and F, and the prevalence of CVA10 varied from continent to continent., Conclusions: Monitoring CVA10 genotypes or evolutionary branches should be strengthened, and the study of epidemic genotype characteristics should be enhanced. This will serve as a basis for further research and development of monovalent CVA10 or polyvalent vaccines designed for effective disease prevention., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Hua Wang, Wenhong Wang, Guoqing Chen, Chuanjie Hu, Shengjie Chen, Lingxiang Mao, Hongxing Shen.)

Background: South Korea has implemented a hand, foot, and mouth disease (HFMD) surveillance system since 2009 to monitor incidence trends and identify disease burden. This nationwide surveillance involves a network of approximately 100 pediatric clinics that report all probable and confirmed HFMD cases. Following the COVID-19 pandemic, infectious disease surveillance systems must be evaluated to ensure the effective use of limited public health resources., Objective: This study aimed to evaluate the HFMD sentinel surveillance system in South Korea from 2017 to 2022, focusing on the transition period after the COVID-19 pandemic., Methods: We retrospectively reviewed the HFMD sentinel surveillance system from the Korea Disease Control and Prevention Agency using systematic guidelines for public health surveillance system evaluation developed by the US Centers for Disease Control and Prevention. We assessed the system's overall performance in 5 main factors: timeliness, stability, completeness, sensitivity, and representativeness (ie, the age and geographic distribution of sentinels). We rated these factors as weak, moderate, or good., Results: Our study showed that the completeness, sensitivity, and age representativeness of the HFMD surveillance performance were temporarily reduced to moderate levels from 2020 to 2021 and recovered in 2022, while the timeliness and geographic representativeness were maintained at a good level throughout the study period. The stability of the surveillance was moderate from 2017 to 2021 and weak in 2022., Conclusions: This is the first study to evaluate the HFMD surveillance system after the acute phase of the COVID-19 pandemic. We identified a temporarily reduced level of performance (ie, completeness, sensitivity, and age-specific representativeness) during the acute phase of the pandemic and good performance in 2022. Surveillance system evaluation and maintenance during public health emergencies will provide robust and reliable data to support public health policy development. Regular staff training programs and reducing staff turnover will improve HFMD surveillance system stability., (© Bryan Inho Kim, Chiara Achangwa, Seonghui Cho, Jisoo Ahn, Jisu Won, Hyunkyung Do, Dayeong Lee, Bohye Yoon, Joohee Kim, Sukhyun Ryu. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

Coxsackievirus A16 (CV-A16) is a significant etiologic agent of hand, foot, and mouth disease (HFMD) and herpangina (HA), with the capacity to progress to severe complications, including encephalitis, aseptic meningitis, acute flaccid paralysis, myocarditis, and other critical conditions. Beijing's epidemiological surveillance system, established in 2008, encompasses 29 hospitals and 16 district disease control centers. From 2019 to 2021, the circulation of CV-A16 was characterized by the co-circulation of B1a and B1b clades. Multiple cases of HFMD linked to clade B1c has not been reported in Beijing until 2022. This study enrolled 400 HFMD and 493 HA cases. Employing real-time RT-PCR, 368 enterovirus-positive cases were identified, with 180 selected for sequencing. CV-A16 was detected in 18.89% (34/180) of the cases, second only to CV-A6, identified in 63.33% (114/180). Full-length VP1 gene sequences were successfully amplified and sequenced in 22 cases, revealing the presence of clades B1a, B1b, and B1c in 14, 3, and 5 cases, respectively. A cluster of five B1c clade cases occurred between June 29 and July 17, 2022, within a 7-km diameter region in Shunyi District. Phylogenetic analysis of five complete VP1 gene sequences and two full-genome sequences revealed close clustering with the 2018 Indian strain (GenBank accession: MH780757.1) within the B1c India branch, with NCBI BLAST results showing over 98% similarity. Comparative sequence analysis identified three unique amino acid variations (P3S, V25A, and I235V). The 2022 Shunyi District HFMD cases represent the first instances of spatiotemporally correlated CV-A16 B1c clade infections in Beijing, underscoring the necessity for heightened surveillance of B1c clade CV-A16 in HFMD and HA in this region., (© 2024 Wiley Periodicals LLC.)

Background: Hand, foot, and mouth disease (HFMD) is a major public health issue in China while temperature and humidity are well-documented predictors. However, evidence on the combined effect of temperature and humidity is still limited. It also remains unclear whether such an effect could be modified by the enterovirus 71 (EV71) vaccination., Methods: Based on 320,042 reported HFMD cases during the summer months between 2012 and 2019, we conducted a study utilizing Distributed Lag Non-Linear Models (DLNM) and time-varying DLNM to examine how China's HFMD EV71 vaccine strategy would affect the correlation between meteorological conditions and HFMD risk., Results: The incidence of HFMD changed with the Discomfort Index in an arm-shaped form. The 14-day cumulative risk of HFMD exhibited a statistically significant increase during the period of 2017-2019 (following the implementation of the EV71 vaccine policy) compared to 2012-2016 (prior to the vaccine implementation). For the total population, the range of relative risk (RR) values for HFMD at the 75th, 90th, and 99th percentiles increased from 1.082-1.303 in 2012-2016 to 1.836-2.022 in 2017-2019. In the stratified analyses, Han Chinese areas show stronger relative growth, with RR values at the 75th, 90th, and 99th percentiles increased by 14.3%, 39.1%, and 134.4% post-vaccination, compared to increases of 22.7%, 41.6%, and 38.8% in minority areas. Similarly, boys showed greater increases (24.4%, 47.7%, 121.5%) compared to girls (8.1%, 28.1%, 58.3%). Additionally, the central Guizhou urban agglomeration displayed a tendency for stronger relative growth compared to other counties., Conclusions: Although the EV71 vaccine policy has been implemented, it hasn't effectively controlled the overall risk of HFMD. There's been a shift in the main viral subtypes, potentially altering population susceptibility and influencing HFMD occurrences. The modulating effects of vaccine intervention may also be influenced by factors such as race, sex, and economic level., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Enteroviruses-infected hand, foot, and mouth disease (HFMD) seriously threatens human health. This study aimed to analyze the research status, hotspots, and frontiers of HFMD., Methods: Publications on HFMD between January 1, 2006, and January 31, 2023, were retrieved from the Web of Science Core database. Bibliometric tools, including CiteSpace, VOSviewer, R package "Bibiometrix," SCImago Graphica, and Charticulator, were utilized to analyze and visualize the data., Results: A total of 1860 articles from 424 journals, involving 8815 authors from 64 countries and 1797 institutions were analyzed. The number of studies on HFMD has shown an increasing trend over the past 18 years, with an annual increase observed since 2006, which is particularly prominent after 2010. Research in this field has centered on the Asian region. Notably, the research hotspots were mainly focused on vaccines, epidemiology, and pathogenesis of HFMD. Among the researchers in this field, Zhang Yong emerged as the most prolific author, while Xu Wenbo had the most significant influence. The Chinese Academy of Sciences was the most productive institution, and China was the most productive country for HFMD research., Conclusion: By bibliometric analysis, researchers in the HMFD field can efficiently identify and visually represent their research focus and limitations. In the future, it is crucial to maintain ongoing surveillance of HFMD outbreaks and their pathogenic changes. Additionally, future research should extensively explore the molecular mechanisms underlying Enteroviruses-induced HFMD with a focus on developing vaccines and therapies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hand, Foot and Mouth Disease (HFMD) is a highly contagious viral illness primarily affecting children globally. A significant epidemiological transition has been noted in mainland China, characterized by a substantial increase in HFMD cases caused by non-Enterovirus A71 (EV-A71) and non-Coxsackievirus A16 (CVA16) enteroviruses (EVs). Our study conducts a retrospective examination of 36,461 EV-positive specimens collected from Guangdong, China, from 2013 to 2021. Epidemiological trends suggest that, following 2013, Coxsackievirus A6 (CVA6) and Coxsackievirus A10 (CVA10) have emerged as the primary etiological agents for HFMD. In stark contrast, the incidence of EV-A71 has sharply declined, nearing extinction after 2018. Notably, cases of CVA10 infection were considerably younger, with a median age of 1.8 years, compared to 2.3 years for those with EV-A71 infections, possibly indicating accumulated EV-A71-specific herd immunity among young children. Through extensive genomic sequencing and analysis, we identified the N136D mutation in the 2 A protein, contributing to a predominant subcluster within genogroup C of CVA10 circulating in Guangdong since 2017. Additionally, a high frequency of recombination events was observed in genogroup F of CVA10, suggesting that the prevalence of this lineage might be underrecognized. The dynamic landscape of EV genotypes, along with their potential to cause outbreaks, underscores the need to broaden surveillance efforts to include a more diverse spectrum of EV genotypes. Moreover, given the shifting dominance of EV genotypes, it may be prudent to re-evaluate and optimize existing vaccination strategies, which are currently focused primarily target EV-A71., (© 2024. The Author(s).)

Background: The evidence on the effects of extreme meteorological conditions and high air pollution levels on incidence of hand, foot and mouth disease (HFMD) is limited. Moreover, results of the available studies are inconsistent. Further investigations are imperative to elucidate the specific issue., Methods: Data on the daily cases of HFMD, meteorological factors and air pollution were obtained from 2017 to 2022 in Jining City. We employed distributed lag nonlinear model (DLNM) incorporated with Poisson regression to explore the impacts of extreme meteorological conditions and air pollution on HFMD incidence., Results: We found that there were nonlinear relationships between temperature, wind speed, PM 2.5 , SO 2 , O 3 and HFMD. The cumulative risk of extreme high temperature was higher at the 95th percentile ( P 95 th) than at the 90th percentile( P 90 th), and the RR values for both reached their maximum at 10-day lag ( P 95 th RR = 1.880 (1.261-2.804), P 90 th RR = 1.787 (1.244-2.569)), the hazardous effect of extreme low temperatures on HFMD is faster than that of extreme high temperatures. The cumulative effect of extreme low wind speeds reached its maximum at 14-day lag ( P 95 th RR = 1.702 (1.389-2.085), P 90 th RR = 1.498(1.283-1.750)). The cumulative effect of PM 2.5 concentration at the P 90 th was largest at 14-day lag ( RR = 1.637 (1.069-2.506)), and the cumulative effect at the P 95 th was largest at 10-day lag ( RR = 1.569 (1.021-2.411)). High SO 2 concentration at the P 95 th at 14-day lag was associated with higher risk for HFMD ( RR : 1.425 (1.001-2.030))., Conclusion: Our findings suggest that high temperature, low wind speed, and high concentrations of PM2.5 and SO2 are associated with an increased risk of HFMD. This study not only adds insights to the understanding of the impact of extreme meteorological conditions and high levels of air pollutants on HFMD incidence but also holds practical significance for the development and enhancement of an early warning system for HFMD., Competing Interests: The authors declare that they have no competing interests., (© 2024 Cao et al.)

Background: Hand, foot, and mouth disease (HFMD) is a common infectious disease in children. Enterovirus A71 (EV71) and coxsackievirus A16 (CA16) have been identified as the predominant pathogens for several decades. In recent years, coxsackievirus A6 (CA6) and coxsackievirus A10 (CA10) have played increasingly important roles in a series of HFMD outbreaks. We performed a retrospective analysis of the epidemiology of HFMD and the spectrum of different viral serotypes, to elucidate the genetic and phylogenetic characteristics of the main serotypes in the Jiashan area during 2016 to 2022., Methods: Descriptive epidemiological methods were used to analyze the time and population distribution of HFMD in Jiashan during 2016 to 2022 based on surveillance data. Molecular diagnostic methods were performed to identify the viral serotypes and etiological characteristics of HFMD. Phylogenetic analyses was based on VP1 region of CA16 and CA6., Results: The average annual incidence rate of HFMD fluctuated from 2016 to 2022. Children aged 1-5 years accounted for 81.65% of cases and boys were more frequently affected than girls. Except when HFMD was affected by the COVID-19 epidemic in 2020 and 2022, epidemics usually peak in June to July, followed by a small secondary peak from October to December and a decline in February. Urban areas had a high average incidence and rural areas had the lowest. Among 560 sample collected in Jiashan, 472 (84.29%) were positive for enterovirus. The most frequently identified serotypes were CA6 (296, 52.86%), CA16 (102, 18.21%), EV71 (16, 2.86%), CA10 (14, 2.50%) and other enteroviruses (44, 7.86%). There were 71 and 142 VP1 sequences from CA16 and CA6, respectively. Substitution of N218D, A220L and V251I was detected in CA16 and may have been related to viral infectivity. Phylogenetic analysis showed that CA16 could be assigned to two genogroups, B1a and B1b, while all the CA6 sequences belonged to the D3a genogroup., Conclusion: CA6 and CA16 were the two major serotypes of enteroviruses circulating in the Jiashan area during 2016 to 2022. Continuous and comprehensive surveillance for HFMD is needed to better understand and evaluate the prevalence and evolution of the associated pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yuan, Chen, Huang, Bao, Shen, Sun and Mao.)

Background: Since December 2019, COVID-19 has spread rapidly around the world, and studies have shown that measures to prevent COVID-19 can largely reduce the spread of other infectious diseases. This study explored the impact of the COVID-19 outbreak and interventions on the incidence of HFMD., Methods: We gathered data on the prevalence of HFMD from the Children's Hospital Affiliated to Zhengzhou University. An autoregressive integrated moving average model was constructed using HFMD incidence data from 2014 to 2019, the number of cases predicted from 2020 to 2022 was predicted, and the predicted values were compared with the actual measurements., Results: From January 2014 to October 2022, the Children's Hospital of Zhengzhou University admitted 103,995 children with HFMD. The average number of cases of HFMD from 2020 to 2022 was 4,946, a significant decrease from 14,859 cases from 2014 to 2019. We confirmed the best ARIMA (2,0,0) (1,1,0) 12 model. From 2020 to 2022, the yearly number of cases decreased by 46.58%, 75.54%, and 66.16%, respectively, compared with the forecasted incidence. Trends in incidence across sexes and ages displayed patterns similar to those overall., Conclusions: The COVID-19 outbreak and interventions reduced the incidence of HFMD compared to that before the outbreak. Strengthening public health interventions remains a priority in the prevention of HFMD., (© 2024. The Author(s).)

Coxsackievirus A6 (CV-A6) has emerged as the predominant causative agent of hand, foot, and mouth disease (HFMD) in young children. Since the declaration of coronavirus disease 2019 (COVID-19) as a global pandemic, the incidence of infectious diseases, including HFMD, has decreased markedly. When social mitigation was relaxed during the COVID-19 pandemic in 2022, the re-emergence of HFMD was observed in Gwangju, South Korea, and seasonal characteristics of the disease appeared to have changed. To investigate the molecular characteristics of enterovirus (EV) associated with HFMD during 2022, 277 specimens were collected. Children aged younger than 5 years accounted for the majority of affected individuals. EV detection and genotyping were performed using real-time RT-PCR and nested RT-PCR followed by sequence analysis. The EV detection rate was found to be 82.3%, and the main genotype identified was CV-A6. Sixteen CV-A6 samples were selected for whole genome sequencing. According to phylogenetic analysis, all CV-A6 strains from this study belonged to the sub-genotype D3 clade based on VP1 sequences. Analysis of 3D polymerase phylogeny showed that only the recombinant RF-A group was identified. In conclusion, circulating EV types should be continuously monitored to understand pathogen emergence and evolution during the post-pandemic era.

A within-host and between-host hand, foot and mouth disease (HFMD) mathematical model is established and the affect of optimal control in its within-host part on HFMD transmission is studied. Through define two basic reproduction numbers, by using the fast-slow system analysis method of time scale, the global stabilities of the between-host (slow) system and within-host (fast) system are researched, respectively. An optimal control problem with drug-treatment control on coupled within-host and between-host HFMD model is formulated and analysed theoretically. Finally, the purposed optimal control measures are applied to the actual HFMD epidemic analysis in Zhejiang Province, China from April 1, 2021 to June 30, 2021. The numerical results show that the drug control strategies can reduce the virus load per capita and can effectively prevent large-scale outbreaks of HFMD., (© 2024. The Author(s).)

Competing Interests: Conflicts of interest None disclosed.

The occurrence of hand, foot, and mouth disease (HFMD) is closely related to meteorological factors. However, location-specific characteristics, such as persistent air pollution, may increase the complexity of the impact of meteorological factors on HFMD, and studies across different areas and populations are largely lacking. In this study, a two-stage multisite time-series analysis was conducted using data from 16 cities in Shandong Province from 2015 to 2019. In the first stage, we obtained the cumulative exposure-response curves of meteorological factors and the number of HFMD cases for each city. In the second stage, we merged the estimations from the first stage and included city-specific air pollution variables to identify significant effect modifiers and how they modified the short-term relationship between HFMD and meteorological factors. High concentrations of air pollutants may reduce the risk effects of high average temperature on HFMD and lead to a distinct peak in the cumulative exposure-response curve, while lower concentrations may increase the risk effects of high relative humidity. Furthermore, the effects of average wind speed on HFMD were different at different levels of air pollution. The differences in modification effects between subgroups were mainly manifested in the diversity and quantity of significant modifiers. The modification effects of long-term air pollution levels on the relationship between sunshine hours and HFMD may vary significantly depending on geographical location. The people in age＜3 and male groups were more susceptible to long-term air pollution. These findings contribute to a deepening understanding of the relationship between meteorological factors and HFMD and provide evidence for relevant public health decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hand, foot and mouth disease (HFMD) is highly prevalent in the Asia Pacific region, particularly in Vietnam. To develop effective interventions and efficient vaccination programs, we inferred the age-time-specific transmission patterns of HFMD serotypes enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), coxsackievirus A10 (CV-A10), coxsackievirus A16 (CV-A16) in Ho Chi Minh City, Vietnam from a case data collected during 2013-2018 and a serological survey data collected in 2015 and 2017. We proposed a catalytic model framework with good adaptability to incorporate maternal immunity using various mathematical functions. Our results indicate the high-level transmission of CV-A6 and CV-A10 which is not obvious in the case data, due to the variation of disease severity across serotypes. Our results provide statistical evidence supporting the strong association between severe illness and CV-A6 and EV-A71 infections. The HFMD dynamic pattern presents a cyclical pattern with large outbreaks followed by a decline in subsequent years. Additionally, we identify the age group with highest risk of infection as 1-2 years and emphasise the risk of future outbreaks as over 50% of children aged 6-7 years were estimated to be susceptible to CV-A16 and EV-A71. Our study highlights the importance of multivalent vaccines and active surveillance for different serotypes, supports early vaccination prior to 1 year old, and points out the potential utility for vaccinating children older than 5 years old in Vietnam., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hand, foot, and mouth disease (HFMD) is contagious and predominantly affects children below the age of five. HFMD-associated serotypes of Enterovirus A (EVA) family include EVA71, Coxsackievirus A type 6 (CVA6), 10 (CVA10), and 16 (CVA16). Although prevalent in numerous Asian countries, studies on HFMD-causing agents in wastewater are scarce. This study aimed to conduct wastewater surveillance in various Asian communities to detect and quantify serotypes of EVA associated with HFMD. In total, 77 wastewater samples were collected from Indonesia, the Philippines, Thailand, and Vietnam from March 2022 to February 2023. The detection ratio for CVA6 RNA in samples from Vietnam was 40 % (8/20). The detection ratio for CVA6 and EVA71 RNA each was 25 % (5/20) for the Indonesian samples, indicating the need for clinical surveillance of CVA6, as clinical reports have been limited. For the Philippines, 12 % (2/17) of the samples were positive for CVA6 and EVA71 RNA each, with only one quantifiable sample each. Samples from Thailand had a lower detection ratio (1/20) for CVA6 RNA, and the concentration was unquantifiable. Conversely, CVA10 and CVA16 RNAs were not detected in any of the samples. The minimum and maximum concentrations of CVA6 RNA were 2.7 and 3.9 log 10 copies/L and those for EVA71 RNA were 2.5 and 4.9 log 10 copies/L, respectively. This study underscores the importance of wastewater surveillance in understanding the epidemiology of HFMD-associated EVA serotypes in Asian communities. Long-term wastewater surveillance is recommended to monitor changes in dominant serotypes, understand seasonality, and develop effective prevention and control strategies for HFMD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Echovirus 25 (E25), a member of the Enterovirus B (EV-B) species, can cause aseptic meningitis (AM), viral meningitis (VM), and acute flaccid paralysis (AFP). However, systematic studies on the molecular epidemiology of E25, especially those concerning its evolution and recombination, are lacking. In this study, 18 strains of E25, isolated from seven provinces of China between 2009 and 2018, were collected based on the Chinese hand, foot, and mouth disease (HFMD) surveillance network, and 95 sequences downloaded from GenBank were also screened. Based on the phylogenetic analysis of 113 full-length VP1 sequences worldwide, globally occurring E25 strains were classified into 9 genotypes (A-I), and genotype F was the dominant genotype in the Chinese mainland. The average nucleotide substitution rate of E25 was 6.08 × 10 -3 substitutions/site/year, and six important transmission routes were identified worldwide. Seventeen recombination patterns were determined, of which genotype F can be divided into 9 recombination patterns. A positive selector site was found in the capsid protein region of genotype F. Recombination analysis and pressure selection analysis for genotype F showed multiple recombination patterns and evolution characteristics, which may be responsible for it being the dominant genotype in the Chinese mainland. This study provides a theoretical basis for the subsequent prevention and control of E25., (© 2024. The Author(s).)

We report on a 2023 outbreak of severe hand, foot, and mouth disease in southern Vietnam caused by an emerging lineage of enterovirus A71 subgenogroup B5. Affected children were significantly older than those reported during previous outbreaks. The virus should be closely monitored to assess its potential for global dispersal.

Background: Hand, foot, and mouth disease (HFMD) has remained a serious public health threat since its first outbreak in China. Analyzing the province-level spatiotemporal distribution of HFMD and mapping the relative risk in mainland China will help determine high-risk provinces and periods of infection outbreaks for use in formulating new priority areas for prevention and control of this disease. Furthermore, our study examined the effect of air pollution on HFMD nationwide, which few studies have done thus far., Methods: Data were collected on the number of provincial monthly HFMD infections, air pollution, meteorological variables, and socioeconomic variables from 2014 to 2017 in mainland China. We used spatial autocorrelation to determine the aggregate distribution of HFMD incidence. Spatiotemporal patterns of HFMD were analyzed, risk maps were developed using the Bayesian spatiotemporal model, and the impact of potential influencing factors on HFMD was assessed., Results: In our study, from 2014 to 2017, the HFMD annual incidence rate in all provinces of mainland China ranged from 138.80 to 203.15 per 100,000 people, with an average annual incidence rate of 165.86. The temporal risk of HFMD for 31 Chinese provinces exhibited cyclical and seasonal characteristics. The southern and eastern provinces had the highest spatial relative risk ( RR > 3) from 2014 to 2017. The HFMD incidence risk in provinces (Hunan, Hubei, and Chongqing) located in central China increased over time. Among the meteorological variables, except for the mean two-minute wind speed ( RR 0.6878; 95% CI 0.5841, 0.8042), all other variables were risk factors for HFMD. High GDP per capita ( RR 0.9922; 95% CI 0.9841, 0.9999) was a protective factor against HFMD. The higher the birth rate was ( RR 1.0657; 95% CI 1.0185, 1.1150), the higher the risk of HFMD. Health workers per 1,000 people ( RR 1.2010; 95% CI 1.0443, 1.3771) was positively correlated with HFMD., Conclusions: From 2014 to 2017, the central provinces (Hunan, Hubei, and Chongqing) gradually became high-risk regions for HFMD. The spatiotemporal pattern of HFMD risk may be partially attributed to meteorological and socioeconomic factors. The prevalence of HFMD in the central provinces requires attention, as prevention control efforts should be strengthened there., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Ma, Zhang, Luo, Yin and Shui.)

Background: The non-pharmaceutical interventions (NPIs) against COVID-19 may have affected the transmission of hand, foot and mouth disease (HFMD). We aimed to assess the impact of the NPIs on HFMD in the high epidemic area of HFMD, Guangdong Province., Methods: The data of HFMD cases, etiological information, and meteorological factors in Guangdong from January 1, 2012, to December 31, 2021, were collected. Using a Bayesian structural time series (BSTS) model integrated counterfactual framework, we assessed the effect of NPIs on HFMD by different intervention periods, populations (gender, age, occupation), and cities. We further explored the correlation between the reduction of HFMD and socioeconomic factors in 21 cities., Results: A total of 351,217 HFMD cases were reported and 455,327 cases were averted in Guangdong Province during 2020-2021 with a reduction of 84.94% (95%CI: 81.63-87.22%) in 2020 and 29.49% (95%CI: 15.26-39.54%) in 2021. The impact of NPIs on HFMD differed by age and gender. The effects of NPIs were more remarkable for children aged 0-2 years and scattered children. We found that the relative reductions in 21 cities were related to the composition ratio of children and COVID-19 incidence., Conclusion: The reduction of HFMD incidence was significantly associated with COVID-19 NPIs, and school closure was an effective intervention to prevent HFMD outbreaks. Our findings will contribute to the development of HFMD prevention and control measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Yang, Zhu, Zeng, Rong, Hu, Li, Zhao, Zeng, Li, Quan, Zhang, Huang, Li, Huang, Zheng, Xu, Li, Chen, Xiao and Zhang.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Hand-foot-mouth disease (HFMD) is a common childhood infectious disease. Atypical skin findings of HFMD, often associated with coxsackievirus A6 (CVA6), were first reported in 2008, with increasing reports worldwide since. Atypical lesions of HFMD often involve sites beyond the palms and soles and tend to have unusual, polymorphic morphology., Methods: A systematic review was conducted on clinical features and outcomes of pediatric HFMD with atypical cutaneous manifestations., Results: Eighty-five studies were included, representing 1359 cases with mean age 2.4 years and a male predominance of 61%. The most reported morphologies were vesicles (53%), papules (49%), and bullae (36%). Other morphologies included eczema herpeticum-like (19%), purpuric/petechial (7%), and Gianotti Crosti-like (4%). Common atypical sites included the arms and/or legs (47%), face (45%), and trunk (27%). CVA6 was identified in 63% of cases. Symptoms resolved in a mean of 10 days. Overall, 16% of cases received treatment, most commonly with acyclovir, intravenous antibiotics, or topical steroids. The most common complications were nail changes (21%) and desquamation (4%) which occurred a mean of 3 and 2 weeks after symptoms, respectively., Conclusion: Due to unusual morphologies resembling other conditions, HFMD with atypical cutaneous findings may be misdiagnosed, leading to inappropriate and unnecessary investigations, hospitalization, and treatment. Greater awareness of atypical presentations of HFMD is warranted to improve patient care and counseling on infection control precautions., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Hand-foot-and-mouth disease (HFMD), which is typically seen in the younger pediatric population, is uncommon in older adolescent and young adult populations. We report on an atypical outbreak of HFMD among college students at a mid-size university in the mid-Atlantic U.S. The outbreak included 138 qualifying cases of HFMD among students at the institution between August and November 2018. All tested samples were positive for CVA6, a less common cause of HFMD. Signs and symptoms and campus mitigation strategies are described. This case report aims to highlight an atypical outbreak of HFMD for clinicians who care for older adolescent and college-aged patients in primary care and community settings, and may see cases and/or outbreaks of HFMD in these populations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Hand, foot, and mouth disease (HFMD) is a common infectious disease that poses a serious threat to children all over the world. However, the current prediction models for HFMD still require improvement in accuracy. In this study, we proposed a hybrid model based on autoregressive integrated moving average (ARIMA), ensemble empirical mode decomposition (EEMD) and long short-term memory (LSTM) to predict the trend of HFMD., Methods: The data used in this study was sourced from the National Clinical Research Center for Child Health and Disorders, Chongqing, China. The daily reported incidence of HFMD from 1 January 2015 to 27 July 2023 was collected to develop an ARIMA-EEMD-LSTM hybrid model. ARIMA, LSTM, ARIMA-LSTM and EEMD-LSTM models were developed to compare with the proposed hybrid model. Root mean square error (RMSE), mean absolute error (MAE) and coefficient of determination (R 2 ) were adopted to evaluate the performances of the prediction models., Results: Overall, ARIMA-EEMD-LSTM model achieved the most accurate prediction for HFMD, with RMSE, MAPE and R 2 of 4.37, 2.94 and 0.996, respectively. Performing EEMD on the residual sequence yields 11 intrinsic mode functions. EEMD-LSTM model is the second best, with RMSE, MAPE and R 2 of 6.20, 3.98 and 0.996., Conclusion: Results showed the advantage of ARIMA-EEMD-LSTM model over the ARIMA model, the LSTM model, the ARIMA-LSTM model and the EEMD-LSTM model. For the prevention and control of epidemics, the proposed hybrid model may provide a more powerful help. Compared with other three models, the two integrated with EEMD method showed significant improvement in predictive capability, offering novel insights for modeling of disease time series., (© 2023. The Author(s).)

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease. The incidence of HFMD has a pronounced seasonal tendency and is closely related to meteorological factors such as temperature, rainfall, and wind speed. In this paper, we propose a combined SARIMA-XGBoost model to improve the prediction accuracy of HFMD in 15 regions of Xinjiang, China. The SARIMA model is used for seasonal trends, and the XGBoost algorithm is applied for the nonlinear effects of meteorological factors. The geographical and temporal weighted regression model is designed to analyze the influence of meteorological factors from temporal and spatial perspectives. The analysis results show that the HFMD exhibits seasonal characteristics, peaking from May to August each year, and the HFMD incidence has significant spatial heterogeneity. The meteorological factors affecting the spread of HFMD vary among regions. Temperature and daylight significantly impact the transmission of the disease in most areas. Based on the verification experiment of forecasting, the proposed SARIMA-XGBoost model is superior to other models in accuracy, especially in regions with a high incidence of HFMD.

We propose a hand, foot and mouth disease (HFMD) transmission model for children with behaviour change and imperfect quarantine. The symptomatic and quarantined states obey constant behaviour change while others follow variable behaviour change depending on the numbers of new and recent infections. The basic reproduction number R 0 of the model is defined and shown to be a threshold for disease persistence and eradication. Namely, the disease-free equilibrium is globally asymptotically stable if R 0 ≤ 1 whereas the disease persists and there is a unique endemic equilibrium otherwise. By fitting the model to weekly HFMD data of Shanghai in 2019, the reproduction number is estimated at 2.41. Sensitivity analysis for R 0 shows that avoiding contagious contacts and implementing strict quarantine are essential to lower HFMD persistence. Numerical simulations suggest that strong behaviour change not only reduces the peak size and endemic level dramatically but also impairs the role of asymptomatic transmission.

Hand, foot, and mouth disease (HFMD) is a contagious childhood disease caused by enteroviruses including enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6) and CV-A16 transmitted via direct and indirect contact. Different types of toy surfaces can affect the stability of viruses. Understanding the stability of enteroviruses on toys provides insightful data for effective disinfection in kindergartens or homes. Porous (ethylene-vinyl acetate mat foam, paper, pinewood, polyester fabric, and squishy polyurethane foam) and non-porous (acrylonitrile butadiene styrene plastic and stainless-steel coin) surfaces were inoculated with EV-A71 at 4, 24, and 35°C, and coxsackieviruses at 24°C. Infectious enteroviruses were recovered and titred in median tissue culture infectious dose assay (TCID 50 ). Atomic force microscopy (AFM) images were taken from surfaces to examine association of surface roughness with virus stability. Overall, infectious enteroviruses were persistent on all non-porous and porous surfaces. Virus persistence was longest at 4°C followed by 24°C and 35°C. EV-A71 half-lives ranged between 6.4-12.8 hours at 4°C, 2.4-6.7 hours at 24°C, and 0.13-2.7 hours at 35°C. At lower virus titres exposed to 24°C, half-lives of enteroviruses ranged from 0.1-1.4 hours. Surface roughness values from AFM suggested smooth surfaces of non-porous surfaces were associated with better virus stability. Temperature, enterovirus concentration, and type of surface affected persistence and stability of enteroviruses. Our findings suggest both porous and non-porous surfaces in kindergartens allow enterovirus persistence and should be frequently disinfected to curb HFMD outbreaks in kindergartens.

As the proportion of non-enterovirus 71 and non-coxsackievirus A16 which proportion of composition in the hand, foot, and mouth pathogenic spectrum gradually increases worldwide, the attention paid to other enteroviruses has increased. As a member of the species enterovirus A, coxsackievirus A14 (CVA14) has been epidemic around the world until now since it has been isolated. However, studies on CVA14 are poor and the effective population size, evolutionary dynamics, and recombination patterns of CVA14 are not well understood. In this study, 15 CVA14 strains were isolated from HFMD patients in mainland China from 2009 to 2019, and the complete sequences of CVA14 in GenBank as research objects were analyzed. CVA14 was divided into seven genotypes A-G based on an average nucleotide difference of the full-length VP1 coding region of more than 15%. Compared with the CVA14 prototype strain, the 15 CVA14 strains showed 84.0-84.7% nucleotide identity in the complete genome and 96.9-97.6% amino acid identity in the encoding region. Phylodynamic analysis based on 15 CVA14 strains and 22 full-length VP1 sequences in GenBank showed a mean substitution rate of 5.35 × 10 -3 substitutions/site/year (95% HPD: 4.03-6.89 × 10 -3 ) and the most recent common ancestor (tMRCA) of CVA14 dates back to 1942 (95% HPD: 1930-1950). The Bayesian skyline showed that the effective population size had experienced a decrease-increase-decrease fluctuation since 2004. The phylogeographic analysis indicated two and three possible migration paths in the world and mainland China, respectively. Four recombination patterns with others of species enterovirus A were observed in 15 CVA14 strains, among which coxsackievirus A2 (CVA2), coxsackievirus A4 (CVA4), coxsackievirus A6 (CVA6), coxsackievirus A8 (CVA8), and coxsackievirus A12 (CVA12) may act as recombinant donors in multiple regions. This study has filled the gap in the molecular epidemiological characteristics of CVA14, enriched the global CVA14 sequence database, and laid the epidemiological foundation for the future study of CVA14 worldwide.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease that primarily affects children under five years of age. It is mainly caused by serotypes of Enterovirus A (EVA): EVA71, Coxsackievirus A types 6 (CVA6), 10 (CVA10), and 16 (CVA16). Despite being highly prevalent in Japan and other countries in the Asia-Pacific region, few studies have investigated HFMD pathogens in wastewater. The present study aimed to develop a highly sensitive and broadly reactive quantitative polymerase chain reaction (qPCR) assay of dominant serotype CVA6, to revise previously developed CVA6, CVA10, and CVA16 assays, and to test these assays in wastewater samples from Yamanashi Prefecture, Japan. The new-CVA6 qPCR assay was developed with maximal nucleotide percent identity among CVA6 isolates from Japan. The new-CVA6 and revised assays were highly sensitive and had the ability to quantify respective positive controls at levels as low as 1 copy/μL. Among the 53 grab influent samples collected between March 2022 and March 2023, EVA71, CVA10, and CVA16 RNA were not detected in any samples, whereas the new-CVA6 assay could detect CVA6 RNA in 38 % (20/53) of samples. CVA6 RNA was detected at a significantly higher concentration in the summer season (3.3 ± 0.8 log 10  copies/L; 79 % (11/14)) than in autumn (2.7 ± 0.6 log 10  copies/L; 69 % (9/13)). The seasonal trend of CVA6 RNA detection in wastewater aligned with the trend of HFMD case reports in the catchment of the wastewater treatment plant. This is the first study to report the detection and seasonal trends of the EVA serotypes associated with HFMD in wastewater samples in Japan. It provides evidence that wastewater-based epidemiology is applicable even for diseases that are prevalent only in specific population groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Chongqing was seriously affected by hand, foot, and mouth disease (HFMD), but the relationships between daily mean temperature and the incidence of HFMD remain unclear. This study used distributed lag nonlinear model to evaluate the effect of daily mean temperature on the incidence of HFMD in children aged < 5 years in Chongqing. Daily HFMD data from 2012 to 2019 in Chongqing were retrieved from the notifiable infectious disease surveillance system. A total of 413,476 HFMD cases aged < 5 years were reported in Chongqing from 2012 to 2019. The exposure-response curve of daily mean temperature and daily HFMD cases was wavy-shaped. The relative risks (RRs) increased as daily mean temperature below 5.66 °C or above 9.43 °C, with two peaks at 16.10 °C and 26.68 °C. The RRs reached the highest when the daily mean temperature at 26.68 °C on the current day (RR = 1.20, 95% CI 1.09-1.32), followed by the daily mean temperature at 16.10 °C at lag 5 days (RR = 1.07, 95% CI 1.05-1.08). The RRs for girls and daycare children were much higher than those for boys and scattered children, respectively. Taken together, daily mean temperature has strong effect on HFMD in children aged < 5 years old in Chongqing, particularly for girls and daycare children., (© 2023. The Author(s).)

Background: Enterovirus 71(EV71)-associated hand, foot and mouth disease (HFMD) decreased dramatically in Beijing from 2009 to 2019. This study was to investigate the epidemiological characteristics, evolutionary dynamics, geographic diffusion pathway, and other features of EV71 in Beijing, China., Methods: We conducted a retrospective study of EV71-associated HFMD and its causative agent in Beijing, China, from 2009 to 2019. Phylogenetic and phylogeographic methods based on the EV71 genome were used to determine the evolution features, origin, and spatiotemporal dynamics. Positive selection sites in the VP1 gene were identified and exhibited in the tertiary structure. Bayesian birth-death skyline model was used to estimate the effective reproductive number (Re)., Results: EV71-associated HFMD decreased greatly in Beijing. From 2009 to 2019, EV71 strains prevalent in Beijing shared high homology in each gene segment and evolved with a rate of 4.99*10 - 3 substitutions per site per year. The genetic diversity of EV71 first increased and peaked in 2012 and then decreased with fluctuations. The time to the most recent common ancestor (TMRCA) of EV71 in Beijing was estimated around 2003 when the EV71 strains were transmitted to Beijing from east China. Beijing played a crucial role in seeding EV71 to central China as well. Two residues (E145Q/G, A293S) under positive selection were detected from both the VP1 dataset and the P1 dataset. They were embedded within the loop of the VP1 capsid and were exposed externally. Mean Re estimate of EV71 in Beijing was about 1.007., Conclusion: In recent years, EV71 was not the primary causative agent of HFMD in Beijing. The low Re estimate of EV71 in Beijing implied that strategies for preventing and controlling HFMD were performed effectively. Beijing and east China played a crucial role in disseminating EV71 to other regions in China., (© 2023. The Author(s).)

Background: Hand, foot, and mouth disease (HFMD) is an enteroviral disease that occurs as outbreaks and sporadic cases in India. In this study, we investigated and characterized the aetiology of HFMD cases that occurred in Karnataka, South India from April to October 2022., Methods: Throat swabs, vesicular swabs, urine, and blood samples from suspected cases were analysed by reverse transcription polymerase chain reaction (RT-PCR) for the detection of enteroviruses. Molecular typing of the enterovirus-positive samples was carried out by amplifying the partial virion protein 1(VP1) gene sequence, followed by sequencing and phylogenetic analysis., Results: Out of the 187 samples received from 82 cases, 93 (50%) tested positive (55/82 cases, 67%) for enteroviruses, with the majority of the HFMD cases reported in paediatric population of less than 5 years (36/55, 65.4%), while 3 cases (3/55, 5.4%) were adults. Out of the 55 enterovirus-positive cases, 31 showed partial VP1 region amplification and 19 of these cases were typed as coxsackievirus A16 (CV-A16) (13/19, 68.4%) and CV-A6 (6/19, 31.6%). The CV-A16 strains identified belonged to subclade B1c while two CV-A6 strains belonged to subclade E2. On molecular testing for other viruses causing fever-rash symptoms, 4/27 (15%) enterovirus-negative cases were detected as herpes simplex virus (1 case) and varicella zoster virus (3 cases) positive., Conclusion: The main causative agent of HFMD in Karnataka in 2022 was CV-A16, followed by CV-A6. Apart from the common paediatric HFMD cases, adult cases were also reported during this period. Further studies involving laboratory and clinical investigations are essential for monitoring and managing HFMD in the community., Competing Interests: Conflicts of interest None., (Copyright © 2023 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)